Best Synthetic Methods: Acetylenes, Allenes and Cumulenes (Best Synthetic Methods)

Synthesis of Acetylenes, Allenes and Cumulenes: Methods and Techniques BEST SYNTHETIC METHODS Brandsma: Synthesis of ...

Author: Lambert Brandsma

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Synthesis of Acetylenes, Allenes and Cumulenes: Methods and Techniques

BEST SYNTHETIC METHODS Brandsma: Synthesis of Acetylenes, Allenes and Cumulenes: Methods and Techniques, 2004

Other Volumes in the Series Gronowitz and Ho¨rnfeldt: Thiophenes, 2004 Osborn: Carbohydrates, 2003 Jones: Quaternary Ammonium Salts: Their Use in Phase-Transfer Catalysed Reactions, 2001 Varvoglis: Hypervalent Iodine in Organic Synthesis, 1997 Grimmett: Imidazole and Benzimidazole Synthesis, 1997 Wakeﬁeld: Organomagnesium Methods in Organic Synthesis, 1995 Metzner: Sulfur Reagents in Organic Synthesis, 1994 Pearson: Iron Compounds in Organic Synthesis, 1994 Petragnani: Tellurium in Organic Synthesis, 1994 Motherwell: Free Radical Chain Reactions in Organic Synthesis, 1991

Related Titles of Interest Books Cordell: The Alkaloids Levy & Tang: Chemistry of C-Glycosides Pietra: Biodiversity and Natural Product Diversity Rahman: Studies in Natural Product Chemistry Sturgeon: Advances in Macromolecular Carbohydrate Research Major Reference Works Barton, Nakanishi & Meth-Cohn: Comprehensive Natural Products Chemistry Katritzky, Meth-Cohn & Rees: Comprehensive Organic Functional Group Transformations Katritzky, Rees & Scriven: Comprehensive Heterocyclic Chemistry II Sainsbury: Rodd’s Chemistry of Carbon Compounds Journals Bioorganic and Medicinal Chemistry Bioorganic and Medicinal Chemistry Letters Carbohydrate Research Heterocycles (distributed by Elsevier) Journal of Supramolecular Chemistry Phytochemistry Tetrahedron Tetrahedron: Asymmetry Tetrahedron Letters

Synthesis of Acetylenes, Allenes and Cumulenes: Methods and Techniques Lambert Brandsma Bilthoven The Netherlands

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ELSEVIER Ltd The Boulevard, Langford Lane Kidlington, Oxford OX5 1GB, UK ß 2004 Elsevier Ltd. All rights reserved. This work is protected under copyright by Elsevier and the following terms and conditions apply to its use: Photocopying Single photocopies of single chapters may be made for personal use as allowed by national copyright laws. Permission of the Publisher and payment of a fee is required for all other photocopying, including multiple or systematic copying, copying for advertising or promotional purposes, resale, and all forms of document delivery. Special rates are available for educational institutions that wish to make photocopies for non-proﬁt educational classroom use. Permissions may be sought directly from Elsevier’s Rights Department in Oxford, UK: phone: (þ44) 1865 843830, fax: (þ44) 1865 853333, e-mail: [email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting ‘Customer Support’ and then ‘Obtaining Permissions’. In the USA, users may clear permissions and make payments through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA; phone: (þ1) (978) 7508400, fax: (þ1) (978) 7504744, and in the UK through the Copyright Licensing Agency Rapid Clearance Service (CLARCS), 90 Tottenham Court Road, London W1P 0LP, UK; phone: (þ44) 207 631 5555; fax: (þ44) 207 631 5500. Other countries may have a local reprographic rights agency for payments. Derivative Works Tables of contents may be reproduced for internal circulation, but permission of Elsevier is required for external resale or distribution of such material. Permission of the Publisher is required for all other derivative works, including compilations and translations. Electronic Storage or Usage Permission of the Publisher is required to store or use electronically any material contained in this work, including any chapter or part of a chapter. Except as outlined above, no part of this work may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission of the Publisher. Address permissions requests to: Elsevier’s Rights Department, at the phone, fax and e-mail addresses noted above. Notice No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent veriﬁcation of diagnoses and drug dosages should be made.

First edition 2004 ISBN: 0-12-125751-7 ISSN: 1478-9914 The paper used in this publication meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper). Printed and bound in Great Britain.

Preface By combining and updating my previous laboratory manuals (1971, 1981 and 1988), this book documents the most important synthetic methods in the ﬁelds of acetylenes, allenes and cumulenes, as well as isolation techniques for compounds with low stability or high volatility, illustrating experimental procedures on a preparative scale that were either carried out by the author or under his close supervision. Most procedures have been updated, with some of the original procedures that seemed unsafe or time-consuming being replaced by easier alternatives. Some useful practical tips are provided in the ﬁrst chapter and in a number of procedures explanation is given about the reaction conditions applied. In most cases, however, these implicitly reﬂect the knowledge about reactivity and reaction mechanisms in the ﬁeld, acquired from the literature and during extensive bench experience. During the last 10 to 15 years the safety rules for experimentation have become much more severe. A number of reagents and solvents are no longer commercially available or have become extremely expensive. In practical courses syntheses are now carried out on a much smaller scale for reasons of safety and economy. The changed situation is taken into account in this new work by the inclusion of procedures and results for smaller scale reactions. In some procedures DMSO is used as a solvent instead of HMPT, which is considered to be a carcinogen. Some procedures present the use of organic solvents (e.g. DMSO–THF) as an alternative to performing reactions in liquid ammonia, which often has to be freed from water by a time-consuming, evaporation-condensation operation. A number of procedures from more recent research in the author’s group as well as several selected unchecked methods from the literature are included, mostly in tabular form. I am very grateful for the pleasant and fruitful cooperation of Mr Hermann D. Verkruijsse that I have enjoyed over four decades. I am also indebted to Dr Nina A. Nedolya for the painstaking correction of the manuscript and for useful suggestions. I dedicate this book to my wife Liesbeth who continuously supported me during my career in chemistry. L. Brandsma June, 2003

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Contents Chapter 1

Procedures and Equipment 1.1 1.2 1.3

Chapter 2

General ................................................................. Reactions in liquid ammonia..................................... Some practical hints ................................................

Preparation, Puriﬁcation and Storage of Some Solvents and Reagents 2.1 Solvents ................................................................ 2.2 Reagents ............................................................... 2.3 Experimental section................................................ References ........................................................................

Chapter 3

1 1 3

11 13 16 23

Generation of Metallated Acetylenes, Allenes and Cumulenes 3.1

Deprotonation of acetylenes with a terminal triple bond................................................. 3.2 Side reactions ......................................................... 3.3 In situ generation of metallated acetylenes and cumulenes by elimination reactions ............................ 3.4 1,3-Dimetallated acetylenes ....................................... 3.5 Metallation of allenes and acetylenes with a non-terminal triple bond .......................................... 3.6 Addition of organolithium compounds and lithium alanate to compounds with an enyne or diyne system ...................................................... 3.7 Formation of alkali acetylides from acetylenes with a non-terminal triple bond and from allenes by the action of strong bases ......................................... 3.8 Generation of metallated acetylenes by successive dehalogenations or by successive dehydrohalogenation and dehalogenation ................................................. 3.9 Experimental section................................................ 3.10 Replacement of the lithium by other metals and application in synthesis ............................................ 3.11 Solubilities of alkali acetylides ................................... References ........................................................................

Chapter 4

25 27 28 30 31 34 35 36 38 80 81 81

Reactions of Metallated Acetylenes and Allenes with Alkylating Agents 4.1 4.2

Alkylation with alkyl halides ..................................... Reaction with oxiranes and oxetanes ..........................

vii

85 88

viii

CONTENTS 4.3

Reaction of metallated acetylenes and allenes with -haloethers .................................................... 4.4 Reaction with orthoesters ......................................... 4.5 Experimental section................................................ References ........................................................................

Chapter 5

Reactions with Aldehydes and Ketones 5.1 Survey of laboratory methods ................................... 5.2 Experimental section................................................ References ........................................................................

Chapter 6

135 138 139 142 158

Silylation, Stannylation and Phosphorylation 7.1 Introduction........................................................... 7.2 Experimental section................................................ References ........................................................................

Chapter 8

119 121 133

Carboxylation, Acylation and Related Reactions 6.1 Introduction........................................................... 6.2 Reactions with heterocumulenes ................................ 6.3 Acylation reactions.................................................. 6.4 Experimental section................................................ References ........................................................................

Chapter 7

89 90 90 117

161 162 173

Sulphenylation and Related Reactions 8.1

Methods for the direct introduction of sulphur, selenium and tellurium ............................................. 8.2 Experimental section................................................ References ........................................................................

Chapter 9

Halogenation of Acetylenes 9.1 Methods for the direct introduction of halogen ............ 9.2 Experimental section................................................ References ........................................................................

Chapter 10

191 192 202

Acetylenes, Allenes and Cumulenes by Elimination Reactions 10.1 Survey of methods .................................................. 10.2 Experimental section................................................ References ........................................................................

Chapter 11

175 177 188

203 206 227

Cumulenes by Dehalogenation of Geminal Dihalogenocyclopropanes 11.1 Introduction........................................................... 11.2 Experimental section................................................ References ........................................................................ viii

229 230 234

CONTENTS

Chapter 12

ix

Acetylenic and Allenic Derivatives by Substitution on sp- and sp2-Carbon 12.1 Nucleophilic 1,1-substitution on sp-carbon .................. 12.2 Nucleophilic 1,3-substitution on sp- and sp2-carbon ...... 12.3 Electrophilic 1,3-substitutions .................................... 12.4 Experimental section................................................ References ........................................................................

Chapter 13

Aminoalkylation of Acetylenic Compounds 13.1 Introduction........................................................... 13.2 Experimental section................................................ References ........................................................................

Chapter 14

Introduction........................................................... Scope and limitations .............................................. Relative rates of coupling ......................................... Regiochemistry ....................................................... Synthetic applications of the cross-coupling reactions with acetylenes ....................................................... 16.6 Practical aspects of the coupling reactions ................... 16.7 Experimental section................................................ References ........................................................................

293 294 298 299 300 301 304 317

Base-Catalysed Isomerisations of Acetylenic Compounds 17.1 Introduction........................................................... 17.2 Experimental section................................................ References ........................................................................

Chapter 18

281 283 291

Transition Metals-Catalysed Couplings of Acetylenes with sp2-Halides 16.1 16.2 16.3 16.4 16.5

Chapter 17

273 276 279

Copper Halide-Catalysed Oxidative Coupling of Acetylenes 15.1 Methods, scope and limitations ................................. 15.2 Experimental section................................................ References ........................................................................

Chapter 16

267 268 272

Cross-coupling between 1-Alkynes and 1-Bromo-1-alkynes 14.1 Introduction........................................................... 14.2 Experimental section................................................ References ........................................................................

Chapter 15

235 236 237 241 264

319 320 340

Allenic Compounds by 2,3- and 3,3-Sigmatropic Rearrangements 18.1

2,3-Sigmatropic rearrangements .................................

341

x

CONTENTS 18.2 3,3-Sigmatropic rearrangements ................................. 18.3 Experimental section................................................ References ........................................................................

Chapter 19

Miscellaneous Reactions of Acetylenic and Allenic Compounds 19.1 Elimination reactions resulting in additional unsaturation 19.2 Removal of protecting groups ................................... 19.3 Partial reductions of conjugated systems of triple bonds. References ........................................................................

Chapter 20

342 343 351

353 359 362 367

Transformation of Functional Groups in Acetylenic and Allenic Compounds 20.1 20.2 20.3

Acetylenic halogen compounds .................................. Acetylenic amino and imino compounds ..................... Acetylenic and allenic nitriles, thiocyanates and isothiocyanates ....................................................... 20.4 Acetylenic aldehydes, ketones and carboxylic acids ....... 20.5 Acetylenic esters, dithioesters and carboxamides ........... 20.6 Ethers ................................................................... 20.7 Acetylenic sulphides and thiols .................................. 20.8 Acetylenic and allenicsulphoxides, sulphones, sulphinamides and sulphonamides .............................. 20.9 Dimetallated acetylenic compounds and their functionalisation ..................................................... 20.10 Copper(I) bromide-catalysed formation of 2-propargylhetarenes ............................................... References ........................................................................

369 381 390 395 397 402 412 417 420 423 424

Appendix A: 1H- and 13C-NMR Chemical Shifts of Acetylenic, Allenic and Cumulenic Compounds .......................................... 427 Appendix B: Class–Compound–Method Index .............................................. 431 Appendix C: Complementary Subject Index.................................................. 455

List of Tables Table 3.1

Generation of metallated acetylenes and cumulenes by 1,2- and 1,4-elimination reactions

29

Table 3.2

Elimination reactions from literature

30

Table 3.3

Metallation of allenes and acetylenes with a non-terminal triple bond

32

Table 3.4

Base-promoted ‘contrathermodynamic’ isomerisations

37

Table 3.5

Lithium acetylides, RCCLi, from organyl-di- or trihalogenoalkenes and alkyllithium

37

Table 3.6

Solubilities of metallated acetylenic compounds

40

Table 6.1

Reactions of metallated acetylenic and allenic compounds, RM, with heterocumulenes

136

Table 6.2

Acylation of metallated acetylenes, R CCM, and allenes, R1R2C¼C¼CHLi

140

1,3-Substitutions with acetylenic, allenic and cumulenic derivatives

238

Table 14.1

Cadiot–Chodkiewicz cross-couplings

278

Table 15.1

Copper(I) chloride-catalysed oxidative coupling of acetylenic compounds

284

Table 12.1

1

Table 16.1a Pd/Cu-Catalysed cross-couplings of ethynyl(trimethyl)silane with sp2-halides

295

Table 16.1b Pd/Cu-Catalysed cross-couplings of acetylenic alcohols with sp2-halides

296

Table 16.1c

Other Pd/Cu-catalysed cross-couplings

297

Table 17.1

Base-catalysed isomerisations of acetylenic compounds

321

xi

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Detailed Contents Chapter 1

Procedures and Equipment 1.1 General ................................................................ 1.2 Reactions in liquid ammonia.................................... 1.3 Some practical hints ............................................... Apparatuses (Figs. 1.1–1.11) ............................................... Abbreviations ...................................................................

Chapter 2

Preparation, Puriﬁcation and Storage of Some Solvents and Reagents 2.1 2.2 2.3

Solvents ............................................................... Reagents .............................................................. Experimental section............................................... 2.3.1 Alkali amides in liquid ammonia ................ 2.3.2 Lithium diisopropylamide .......................... 2.3.3 n-BuLi TMEDA in hexane ....................... 2.3.4 n-BuLi–t-BuOK in tetrahydrofuran ............. 2.3.5 n-Butyllithium in hexane ........................... 2.3.6 n-Butyllithium lithium bromide in diethyl ether ............................................ 2.3.7 n-Butylmagnesium chloride in diethyl ether ... 2.3.8 t-Butylmagnesium chloride in tetrahydrofuran 2.3.9 Allenylmagnesium bromide in diethyl ether... 2.3.10 Magnesium bromide-etherate ..................... 2.3.11 Palladium(II) chloride bis(triphenylphosphane), PdCl2(PPh3)2 ............................... 2.3.12 Tetrakis(triphenylphosphane)palladium(0), Pd(PPh3)4 ............................................... References .......................................................................

Chapter 3

1 1 3 7 10

11 13 16 16 18 18 18 19 20 20 21 21 22 23 23 23

Generation of Metallated Acetylenes, Allenes and Cumulenes 3.1 3.2 3.3 3.4 3.5 3.6

Deprotonation of acetylenes with a terminal triple bond Side reactions ........................................................ In situ generation of metallated acetylenes and cumulenes by elimination reactions .......................................... 1,3-Dimetallated acetylenes ...................................... Metallation of allenes and acetylenes with a non-terminal triple bond ................................ Addition of organolithium compounds and lithium alanate to compounds with an enyne or diyne system ........................................ xiii

25 27 28 30 31 34

xiv

DETAILED CONTENTS 3.7 3.8 3.9

Formation of alkali acetylides from acetylenes with a non-terminal triple bond and from allenes by the action of strong bases .......................... Generation of metallated acetylenes by successive dehalogenations or by successive dehydrohalogenation and dehalogenation ................... Experimental section............................................... 3.9.1 Sodium acetylide from acetylene and sodium in liquid ammonia .................................... 3.9.2 Sodium acetylide from acetylene and sodamide in liquid ammonia .................................... 3.9.3 Alkali alkynylides from 1-alkynes and alkali amides in liquid ammonia ................. 3.9.4 General procedure for the lithiation of 1-alkynes with BuLi in Et2O or THF and subsequent conversion into alkynylzinc chlorides................................. 3.9.5 Monolithium acetylide in tetrahydrofuran by reaction of acetylene with BuLi TMEDA .... 3.9.6 Lithiation of propargyl bromide and propargyl chloride .................................................. 3.9.7 Ethynylmagnesium bromide in tetrahydrofuran ..................................................... 3.9.8 Acetylene-1,2-bis(magnesium bromide) in tetrahydrofuran ....................................... 3.9.9 Alkynylmagnesium bromides in diethyl ether 3.9.10 Alkynylmagnesium bromides in tetrahydrofuran ....................................... 3.9.11 1,3-Dilithiation of acetylenes with a terminal triple bond using BuLi in tetrahydrofuran .... 3.9.12 1,3-Dilithiation of 1-alkynes with BuLi TMEDA in hexane .......................... 3.9.13 1,3-Dimetallation of methyl propargyl ether.. 3.9.14 Lithiation of propadiene (Table 3.3, entry 1) . 3.9.15 General procedure for lithiation of allenes (Table 3.3, entries 1, 2, 3, 5, 6 and 10) ......... 3.9.16 Lithiation of 2-alkynes (Table 3.3, entries 4, 7 and 19) ................................... 3.9.17 Metallation of 2-alkynyl ethers (Table 3.3, entries 12, 14, 16 and 20) ........... 3.9.18 Metallation of N,N-diethyl-1-propyn-1-amine (Table 3.3, entry 11) ................................. 3.9.19 Regioselective metallation of 2-alkynyl amines (Table 3.3, entries 17 and 18) ..................... 3.9.20 Metallation of 1-alkynyl sulphides with n-BuLi t-BuOK (Table 3.3, entry 9) ............ 3.9.21 Elimination of hydrogen bromide from 1,2-dibromo compounds with alkali amide (Table 3.1) ..................................... 3.9.22 10-Undecynoic acid starting from 10-undecenoic acid ...................................

35 36 38 38 38 39

39 42 43 43 44 44 45 46 47 47 48 48 49 49 50 50 51 51 54

DETAILED CONTENTS 3.9.23 3.9.24 3.9.25 3.9.26 3.9.27 3.9.28 3.9.29 3.9.30 3.9.31 3.9.32 3.9.33 3.9.34 3.9.35 3.9.36

3.9.37 3.9.38 3.9.39 3.9.40 3.9.41

3.9.42 3.9.43

xv Lithium ethoxyacetylide from (E/Z)-1-bromo2-ethoxyethene and lithium amide ............... 1,5-Hexadiyne starting from 1,5-hexadiene.... Ethynylcyclopentane and ethynylcyclohexane from geminal 1,1-dichlorides and sodamide .. Mono- or disodium diacetylide from 1,4-dichloro-2-butyne and sodamide ............ 4-Pentyn-1-ol from 2-(chloromethyl) tetrahydrofuran and sodamide.................... Methoxyacetylene and ethoxyacetylene from 2-chloro-1,1-dialkoxyethanes and sodamide .. 1-Ethoxy-1-buten-3-yne from 1,4-diethoxy-2-butyne and sodamide ............ 1-Ethoxy-1,2,3-butatriene from 1,4-diethoxy-2-butyne and alkyllithium ........ 1,4-Diethoxy-1,2,3-butatriene from 1,1,4-triethoxy-2-butyne and alkyllithium ..... N,N-4-Trimethyl-1,2,3-pentatrien-1-amine from 4-methoxy-N,N-4-trimethyl-2-pentyn-1amine and butyllithium ............................. N,N-Diethyl-2,4-pentadiyn-1-amine from (Z)-N,N-diethyl-5-ethylthio-4-penten-2-yn-1amine and sodamide ................................. 3-Methoxy-3-penten-1-yne from 4-ethoxy-3methoxy-1,2-pentadiene and sodamide ......... 5-Octen-7-yn-1-ol from 2-(1-propynyl)tetrahydropyran and sodamide............................. Conversion of N,N-dialkyl-3-buten-1-yn-1amine into (E þ Z)-N,N-dialkyl-1-buten-3yn-1-amine by reaction with potassium amide ...................................... Conversion of 1-(1-propynyl)cyclohexene into 1-(2-propynylidene)cyclohexane by reaction with potassium amide ............................... 3-Alkynoic acids from 2-alkynoic acids and sodamide ................................................ 1-Alkylthio-1,2-alkadienes from 1-alkynyl sulphides and sodamide (Table 3.3, entries 8 and 9) .................................................... N,N-Diethyl-4-methoxy-2,3-butadien-1-amine from N,N-diethyl-4-methoxy-2-butyn-1-amine and butyllithium ...................................... Lithiation of 1-(2,3-butadienyl)benzene with alkyllithium and rearrangement of the intermediary lithium compound to 4-lithium-1(3-butynyl)benzene ................................... Conversion of an acetylenic tertiary amine into the allenic isomer via a metallic intermediate . Preparation of 10-undecyn-1-ol by treatment of 2-undecyn-1-ol with the monopotassium derivative of 1,3-propanediamine ................

55 56 57 58 59 60 61 62 62 63 64 65 66

66 67 68 69 70

70 71 72

xvi

DETAILED CONTENTS 3.9.44

1-Ethynylpyrrole from 1-[1,2-dichloroethenyl]pyrrole and methyllithium ......................... 3.9.45 Allenic derivatives by addition of alkyllithium to enyne compounds ................................. 3.9.46 3,4-Pentadien-1-ol from 2-penten-4-yn-1-ol and lithium alanate .................................. 3.9.47 (E)-Enyne alcohols by reduction of diyne alcohols with lithium alanate...................... 3.9.48 Conversion of 1-N,N-dimethylamino-3-buten1-yne into N,N-dimethylaminobutatriene ...... 3.9.49 Conversion of 1-metallated 2-alkynyl ethers into 1-metallated allenic ethers ................... 3.9.50 4-Methyl-1-methoxy-1,2,3-pentatriene from 1,4-dimethoxy-4-methyl-2-pentyne and alkyllithium ............................................ 3.10 Replacement of the lithium by other metals and application in synthesis ..................................... 3.11 Solubilities of alkali acetylides .................................. References .......................................................................

Chapter 4

73 74 75 76 76 78 79 80 81 81

Reactions of Metallated Acetylenes and Allenes with Alkylating Agents 4.1 4.2 4.3 4.4 4.5

Alkylation with alkyl halides .................................... Reaction with oxiranes and oxetanes ......................... Reaction of metallated acetylenes and allenes with -haloethers ......................................... Reaction with orthoesters ........................................ Experimental section............................................... 4.5.1 Methylation of lithiated N,N-diethyl-2propyn-1-amine ....................................... 4.5.2 1,3-Pentadiyne by methylation of sodium diacetylide .............................................. 4.5.3 2,4-Hexadiyne by methylation of disodium diacetylide .............................................. 4.5.4 Methylation of the lithiated O-protected propargyl alcohol ..................................... 4.5.5 Methylation of a lithiated acetylene in a THF–DMSO mixture ............................... 4.5.6 1,3-Hexadiyne by reaction of sodium diacetylide with ethyl bromide .................... 4.5.7 Alkylation of lithium ethoxyacetylide .......... 4.5.8 1-Pentyne, 1-hexyne and 1-heptyne.............. 4.5.9 1,3-Diynes by reaction of sodium diacetylide with n-propyl and n-butyl bromide .............. 4.5.10 C-Alkylation of dilithiated propargyl alcohol ..................................... 4.5.11 C-Alkylation of dilithiated propargyl alcohol with a higher alkyl bromide .......................

85 88

4.5.12

99

1-Octyne, 1-nonyne and 1-decyne ................

89 90 90 91 92 93 94 95 95 96 97 97 98 98

DETAILED CONTENTS Terminal diynes from sodium acetylide and ,!-dibromoalkanes.................................. 4.5.14 Alkylation of a lithiated acetylene in a THF–DMSO mixture ............................... 4.5.15 Reaction of sodium acetylide with epichlorohydrine ...................................... 4.5.16 Reaction of lithium acetylides with oxirane in liquid ammonia ....................................... 4.5.17 Reaction of lithium acetylides with oxiranes after replacement of liquid ammonia by DMSO .............................................. 4.5.18 Reaction of phenylethynyllithium with oxirane in a THF–DMSO mixture ......................... 4.5.19 Reaction of a 1-lithiated acetylene with an -chloroether........................................... 4.5.20 Reaction of 2-chlorotetrahydropyran and 2,3-dibromotetrahydropyran with ethynylmagnesium bromide ........................ 4.5.21 Regiospeciﬁc alkylation of 1,3-dilithiated propyne with benzyl chloride ..................... 4.5.22 Regiospeciﬁc hydroxyalkylation of a 1,3-dilithiated 1-alkyne with oxirane ............ 4.5.23 Acetylenic acetals from alkynylmagnesium bromide and triethoxymethane ................... 4.5.24 Alkylation of lithiated propadiene ............... 4.5.25 Reaction of methoxyallenyllithium with alkyl bromides ................................................ 4.5.26 Alkylation of a metallated 1-alkynyl sulphide 4.5.27 Reaction of a metallated 1-alkynyl sulphide with oxirane ............................................ 4.5.28 Reaction of 1-lithiated methoxyallene with oxirane................................................... 4.5.29 Reaction of lithiomethoxyallene with -chloroethers ......................................... 4.5.30 Regioselective alkylation of a lithiated 2-alkynyl ether ........................................ 4.5.31 Preparation of 1-alken-4-ynes and 1,4-alkadiynes by reaction of 1-alkynylmagnesium bromide with allyl bromide or propargyl bromide in the presence of copper(I) chloride 4.5.32 Preparation of 1,4-diynes by copper(I) halide-catalysed reaction of propargyl tosylate with alkynyllmagnesium bromide ................ 4.5.33 Synthesis of 5-hexyn-1-ol using acetylene and tetrahydrofuran as building units ................ References .......................................................................

xvii

4.5.13

Chapter 5

100 100 101 102 103 103 104 105 106 107 107 108 109 110 111 111 112 113

113 114 116 117

Reactions with Aldehydes and Ketones 5.1 5.2

Survey of laboratory methods .................................. Experimental section...............................................

119 121

xviii

DETAILED CONTENTS 5.2.1

Reaction of alkynyllithium with paraformaldehyde .................................... 5.2.2 General procedure for the coupling of lithium alkynylides with aldehydes and ketones in THF or Et2O .......................................... 5.2.3 Coupling of butadiynyllithium with acetone .. 5.2.4 Ethynylation of acrolein and croton aldehyde in liquid ammonia .................................... 5.2.5 Reaction of ethynylmagnesium bromide with -Ionone ................................................ 5.2.6 Ethynylation of ketones with t-BuOK and acetylene in tetrahydrofuran....................... 5.2.7 Ethynylation of ketones in DMSO–KOH mixtures ................................................. 5.2.8 Reaction of lithiated propargyl chloride with polymeric formaldehyde ............................ 5.2.9 Reaction of allenylmagnesium bromide with aldehydes................................................ 5.2.10 Reaction of lithiated methoxyallene with carbonyl compounds ................................ 5.2.11 1-Ethynylcycloheptanol from lithium acetylide and cycloheptanone in liquid ammonia ........ 5.2.12 1-Ethynylcycloheptanol from acetylene and cycloheptanone (KOH method) .................. References .......................................................................

Chapter 6

121 123 125 126 127 128 130 130 131 132 132 133 133

Carboxylation, Acylation and Related Reactions 6.1 6.2 6.3 6.4

Introduction.......................................................... Reactions with heterocumulenes ............................... Acylation reactions................................................. Experimental section............................................... 6.4.1 General procedure for the carboxylation of acetylenes ............................................... 6.4.2 Acetylenic esters from lithium alkynylides and alkyl chloroformates ........................... 6.4.3 General procedure for the formylation of acetylenes with N,N-dimethylformamide....... 6.4.4 Methyl alkynyl ketones from alkynyllithium and N,N-dimethylacetamide ....................... 6.4.5 Acylation with N,N-dimethylbenzamide ....... 6.4.6 Acylation with acetic anhydride .................. 6.4.7 Acetylenic ketones by reaction of alkynylzinc chloride with acyl halides .......................... 6.4.8 Acetylenic ketones by Pd(0)-catalysed coupling of alkynylzinc chlorides with acyl halides ..... 6.4.9 N,N-Dimethyl-2-pentynamide from butynyllithium and dimethylcarbamyl chloride ........ 6.4.10 Addition of propynyllithium to phenyl isocyanate ...............................................

135 138 139 142 142 143 144 146 146 147 148 149 150 151

DETAILED CONTENTS Addition of t-butylethynyllithium to methyl isothiocyanate ............................... 6.4.12 Addition of t-butylethynyllithium to phenylsulphinylamine................................ 6.4.13 Carboxylation of lithiated propadiene .......... 6.4.14 2,3-Pentadienedioic acid from dilithiopropyne and carbon dioxide................................... 6.4.15 Formylation of 1-ethenylidenecyclohexyllithium with N,N-dimethylformamide .......... 6.4.16 Reaction of lithiated 2-butyne to methyl isothiocyanate and subsequent S-methylation .......................................... 6.4.17 Reaction of 2-butynylpotassium with CS2 and subsequent S-methylation .......................... 6.4.18 Reaction of allenylmagnesium bromide with phenylsulphinyl amine .............................. References .......................................................................

xix

6.4.11

Chapter 7

152 153 153 154 155 156 157 158 158

Silylation, Stannylation and Phosphorylation 7.1 7.2

Introduction.......................................................... Experimental section............................................... 7.2.1 Ethynyl(trimethyl)silane from ethynylmagnesium bromide and chloro(trimethyl)silane in tetrahydrofuran ....................................... 7.2.2 Procedures for the reaction of alkynyllithium and alkynylmagnesium bromides with chloro(trimethyl)silane .............................. 7.2.3 Reaction of lithiated propargyl chloride with chloro(trimethyl)silane .............................. 7.2.4 Reaction of lithiated propargyl bromide with chloro(trimethyl)silane .............................. 7.2.5 Trimethyl[(2-trimethylsilyl)ethynyl]silane from acetylene-1,2-bis(magnesium bromide) and chloro(trimethyl)silane .............................. 7.2.6 1,3-Butadiynyl(tributyl)stannane from butadiynyllithium and chloro(tributyl)stannane ... 7.2.7 Reaction of allenylmagnesium bromide with chloro(trimethyl)silane and chloro(tributyl)stannane ................................................. 7.2.8 Trimethylsilylation of lithiated N,N-diethyl-1allenamine .............................................. 7.2.9 Trimethylsilylation of a lithiated 2-alkyne ..... 7.2.10 Trimethylsilylation of a lithiated cumulenic amine .................................................... 7.2.11 Trimethylsilylation of lithiated methoxyallene 7.2.12 3-(Trimethylsilyl)-2-propyn-1-ol .................. 7.2.13 Regioselective monosilylation of 1,3-dilithiated alkynes ............................... 7.2.14 Dibutyl(ethynyl)phosphane ........................

161 162

162 163 164 165 166 166 167 168 169 169 170 170 171 171

xx

DETAILED CONTENTS 7.2.15 Diethynyl(phenyl)phospane ........................ 7.2.16 Tri(1-propynyl)phosphane ......................... References .......................................................................

Chapter 8

172 173 173

Sulphenylation and Related Reactions 8.1

Methods for the direct introduction of sulphur, selenium and tellurium ................................ 8.2 Experimental section............................................... 8.2.1 Reaction of metallated acetylenes with sulphenylating agents in liquid ammonia ...... 8.2.2 C-Thiomethylation of acetylenic alcohols in liquid ammonia ....................................... 8.2.3 Reaction of lithiated acetylenes with sulphenylating agents in diethyl ether or tetrahydrofuran ....................................... 8.2.4 4-Ethylthio-1-buten-3-yne, 4-methylseleno-1buten-3-yne and 4-methyltelluro-1-buten-3yne from in-situ generated vinylethynylsodium, sulphur, selenium or tellurium and alkyl halides ................................................... 8.2.5 1-(Ethylseleno)-1-propyne and 1-(ethyltelluro)-1-propyne from in-situ generated propynylsodium, selenium or tellurium and ethyl bromide ................................................. 8.2.6 Reaction of alkynyllithium in tetrahydrofuran with sulphur or selenium and subsequent alkylation ............................................... 8.2.7 Reaction of alkynethiolates with acetyl bromide and ethyl chloroformate ................ 8.2.8 1-Propynyl trimethylsilyl sulphide from lithium propynethiolate and chloro(trimethyl)silane ..................................................... 8.2.9 Methyl 1-propynyl sulphoxide from propynyllithium and methanesulphinyl chloride ......... 8.2.10 Di(1-alkynyl) sulphides and di(1-alkynyl) sulphoxides from alkynyllithium and sulphur dichloride or thionyl chloride ..................... 8.2.11 Di(1-alkynyl) tellurides from tellurium tetrachloride and lithium acetylides ............. 8.2.12 Bis(alkylthio)acetylenes from sodium acetylide and alkyl thiocyanates .............................. 8.2.13 Bis(alkylthio)acetylenes from lithium chloroacetylide and dialkyl disulphides .............................................. References .......................................................................

Chapter 9

175 177 177 178 179

179

181 181 182 183 184 185 186 187 187 188

Halogenation of Acetylenes 9.1 9.2

Methods for the direct introduction of halogen ........... Experimental section...............................................

191 192

DETAILED CONTENTS 1-(2-Chloroethynyl)benzene from lithium phenylacetylide and benzenesulphonyl chloride .................................................. 9.2.2 1-Bromo-1-alkynes from alkynyllithium and bromine ........................................... 9.2.3 Bromination of acetylenes with aqueous hypobromite ........................................... 9.2.4 1-Bromo-1-propyne and 1-bromo-1-butyne from the 1-alkynes and potassium hypobromite ........................................... 9.2.5 Bromination of lithiated acetylenes with cyanogen bromide .................................... 9.2.6 1-Iodo-1-alkynes from 1-alkynyllithium and iodine in organic solvents .......................... 9.2.7 1-Iodo-1-alkynes from 1-alkynyllithium and iodine in liquid ammonia........................... 9.2.8 1-(2-Chloroethynyl)benzene from phenylethynyllithium and chlorine ............................. References .......................................................................

xxi

9.2.1

Chapter 10

192 194 195 197 197 199 199 201 202

Acetylenes, Allenes and Cumulenes by Elimination Reactions 10.1

10.2

Survey of methods ................................................. 10.1.1 1,1-Elimination of hydrogen halide with simultaneous migration of an organic group ........ 10.1.2 Double 1,2-elimination of hydrogen halide from geminal or vicinal dihalogen compounds: RC(Cl2)Me; RCH2CHCl2; RCH(Br)CH2Br or Cl; RCH(Br)CH(Br)R or Cl....................... 10.1.3 Elimination of hydrogen halide from halo-oleﬁnic compounds ............................ 10.1.4 Tele-eliminations of hydrogen chloride from 1,4-dichlorobutene, 1,4-dichlorobutyne and 1,6-dichlorohexadiyne ............................... 10.1.5 Tele-elimination of alcohol or thiol from acetylenic, allenic or cumulenic derivatives.... 10.1.6 1,2- and 1,4-Dehalogenation using zinc powder................................................... Experimental section............................................... 10.2.1 3,3-Dimethyl-1-butyne starting from 3,3-dimethyl-1-butene ............................... 10.2.2 Phenylacetylene starting from styrene .......... 10.2.3 1-Butyne from 1,2-dibromobutane by the phase-transfer method............................... 10.2.4 3,3-Dimethyl-1-butyne from 1,1-dichloro-3,3dimethylbutane by the phase-transfer method 10.2.5 Ethoxyacetylene from 1-bromo-2-ethox yethene and potassium hydroxide................ 10.2.6 Vinylacetylene from (E)-1,4-dichloro-2-butene by the phase-transfer method .....................

203 203

204 204 204 205 206 206 206 207 208 209 210 211

xxii

DETAILED CONTENTS 10.2.7

Butadiyne from 1,4-dichloro-2-butyne and KOH in a water–DMSO mixture ................ 10.2.8 Hexatriyne from 1,6-dichloro-2,4-hexadiyne and t-BuOK in tetrahydrofuran .................. 10.2.9 Cyclooctyne from 1-bromo-1-cyclooctene and lithium diisopropylamide ........................... 10.2.10 t-Butylnitroacetylene from 2-iodo-3,3dimethyl-1-nitro-1-butene and potassium hydroxide ............................................... 10.2.11 N1,N1,N2,N2-Tetraalkyl-1-acetylenediamines from 2-chloro-N,N,N1,N1-tetraalkyl-1,1-ethylenediamines and potassium amide .............. 10.2.12 4-Ethoxy-1-buten-3-yne from 1,4-diethoxy1,2-butadiene and butyllithium ................... 10.2.13 N,N-Dimethyl-3-buten-1-yn-1-amine from N,N-dimethyl-4-methoxy-2-butyn-1-amine and t-BuOK ............................................ 10.2.14 4-Methylthio-1-buten-3-yne from 1,4-bis(methylthio)-2-butyne and t-BuOK ..... 10.2.15 Propadiene from 2,3-dichloro-1-propene and zinc in ethanol ......................................... 10.2.16 Butatriene from 1,4-dichloro-2-butyne and zinc in dimethylsulphoxide ......................... 10.2.17 1,2,3-Pentatriene from 1,4-dichloro-2-pentyne and zinc in dimethylsulphoxide ................... References .......................................................................

Chapter 11

213 215 216 218 222 223 224 225 226 226 227

Cumulenes by Dehalogenation of Geminal Dihalogenocyclopropanes 11.1 11.2

Introduction.......................................................... Experimental section............................................... 11.2.1 Synthesis of [1-(2,3-butadienyl)benzene]........ 11.2.2 Cyclonona-1,2-diene ................................. 11.2.3 1,2,3-Cyclodecatriene ................................ 11.2.4 Tetramethylbutatriene ............................... References .......................................................................

Chapter 12

212

229 230 230 231 232 233 234

Acetylenic and Allenic Derivatives by Substitution on sp- and sp2-Carbon 12.1 12.2 12.3 12.4

Nucleophilic 1,1-substitution on sp-carbon ................. Nucleophilic 1,3-substitution on sp- and sp2-carbon ..... Electrophilic 1,3-substitutions ................................... Experimental section............................................... 12.4.1 N,N-dialkylaminoalkynes from 1-alkynyl ethers and lithium dialkylamides ................. 12.4.2 1-(N,N-Dimethylamino)-2-phenylacetylene from 1-chloro-2-phenylacetylene and lithium dimethylamide .........................................

235 236 237 241 241 242

DETAILED CONTENTS 12.4.3 12.4.4 12.4.5 12.4.6 12.4.7 12.4.8 12.4.9 12.4.10 12.4.11

12.4.12 12.4.13 12.4.14 12.4.15

12.4.16 12.4.17 12.4.18 12.4.19 12.4.20 12.4.21

xxiii 1,2-Heptadiene from methyl propargyl ether and n-butylmagnesium chloride .................. t-Butylallene from propargyl chloride and t-butylmagnesium chloride ......................... 1-Ethoxy-1,2-heptadiene from 3,3-diethoxy-1propyne and butylmagnesium chloride ......... 1-(2-Propynyl)cyclopentane from cyclopentylmagnesium chloride and methoxyallene........ Reaction of an acetylenic sulphinate with alkylcopper ............................................. Reaction of an acetylenic tosylate with phenylcopper........................................... Copper bromide-catalysed reaction of 2-ethynyltetrahydropyran with alkylmagnesium bromide ........................... 3,4-Hexadienenitrile from 1-methyl-2propynyl-4-methylbenzenesulphonate and the copper derivative of acetonitrile ............. 2,3-Alkadienenitriles from the reaction between acetylenic bromides and alkali cyanide in the presence of catalytic amounts of copper(I) cyanide ................................. CuCl-catalysed isomerisation of 3-phenyl-3chloro-1-propyne to 1-(3-chloro-1,2-propadienyl)benzene ............................................. Copper bromide-catalysed isomerisation of propargyl bromide to bromoallene .......... Copper bromide-catalysed isomerisation of 3-bromo-1-nonyne to 1-bromo-1,2nonadiene ............................................... 1-(3-Bromo-1,2-propadienyl)benzene by CuBr-catalysed reaction of 1-phenyl-2-propyn1-ol with concentrated aqueous hydrogen bromide ................................................. 1-Bromo-3-methyl-1,2-butadiene by CuBrcatalysed reaction of 2-methyl-3-butyn-2-ol with concentrated aqueous hydrogen bromide 1-Bromo-1,2-butadiene by CuBr-catalysed reaction of 3-butyn-2-ol with concentrated aqueous hydrogen bromide ........................ 1-Iodo-1,2-butadiene by reaction of 3-butyn-2-ol with triphenylphosphitemethiodide in N,N-dimethylformamide ........ 1-Iodo-3-phenylpropadiene by CuI-catalysed reaction of 1-phenyl-2-propyn-1-ol with concentrated aqueous hydrogen iodide ......... Allenic alcohols from the reaction between lithium alanate and chlorine-containing acetylenic alcohols.................................... Allenic alcohols from the reaction between acetylenic alcohols containing an ether group and lithium alanate ..................................

243 244 245 245 246 247 248 248

249 250 251 252

253 254 254 255 256 256 257

xxiv

DETAILED CONTENTS 12.4.22

Allenes by reaction of propargylic chlorides with zinc–copper in ethanol ....................... 12.4.23 Vinylidenecyclohexane by reaction of 1-chloro-1-ethynylcyclohexane with zinc–copper in ethanol .............................. 12.4.24 1,2,4-Hexatriene by reaction of 5-bromo-3hexen-1-yne with zinc–copper in hexanol ...... 12.4.25 Copper(I) chloride-catalysed reaction of propargyl alcohol with propargyl chloride in aqueous medium. Preparation of 4,5-hexadien-2-yn-1-ol ............................... 12.4.26 Methyl propargyl ketone by zinc chloride-catalysed reaction of allenyl tributyltin with acetyl chloride .................... 12.4.27 Allenic sulphides from the copper halide-catalysed reaction between propargylic halides and lithium thiolates ...................... References .......................................................................

Chapter 13

Introduction.......................................................... Experimental section............................................... 13.2.1 Preparation of (dimethylamino)methanol and (diethylamino)methanol....................... 13.2.2 Mannich reactions with gaseous acetylenes ... 13.2.3 Mannich reactions with liquid acetylenes ...... 13.2.4 Mannich reactions with acetylenic alcohols ... References .......................................................................

261

262 263 264 264

267 268 268 269 270 271 272

Cross-Coupling between 1-Alkynes and 1-Bromo-1-Alkynes 14.1 14.2

Introduction.......................................................... Experimental section............................................... 14.2.1 General remarks and some observations....... 14.2.2 General procedure for the Cadiot–Chodkiewicz coupling .................... References .......................................................................

Chapter 15

259

Aminoalkylation of Acetylenic Compounds 13.1 13.2

Chapter 14

258

273 276 276 277 279

Copper Halide-Catalysed Oxidative Coupling of Acetylenes 15.1 15.2

Methods, scope and limitations ................................ Experimental section............................................... 15.2.1 Oxidative coupling of propargyl alcohol in aqueous medium ...................................... 15.2.2 Coupling of 3-butyn-2-ol using copper(I) chloride TMEDA in acetone ..................... 15.2.3 Oxidative coupling of 3,3-diethoxy-1-propyne using CuCl TMEDA in DMF ...................

281 283 283 285 286

DETAILED CONTENTS 15.2.4 15.2.5 15.2.6

Oxidative coupling of 5-hexyn-1-ol in pyridine Oxidative coupling of 2-ethynylpyridine ....... Oxidative coupling of 1-butyne catalysed by CuCl and 1,8-diaza[5.4.0]bicycloundec-7-ene (DBU) ................................................... 15.2.7 Oxidative coupling of 2-ethynyl-1-methylpyrrole catalysed by CuCl and DBU ................ 15.2.8 Oxidative coupling of ethynyl(trimethyl)silane 15.2.9 Oxidative coupling of the HCl–salt of 2-methyl-3-butyn-2-amine .......................... References .......................................................................

Chapter 16

xxv 287 287

288 289 289 290 291

Transition Metals-Catalysed Couplings of Acetylenes with sp2-Halides 16.1 16.2 16.3 16.4 16.5 16.6

16.7

Introduction.......................................................... Scope and limitations ............................................. Relative rates of coupling ........................................ Regiochemistry ...................................................... Synthetic applications of the cross-coupling reactions with acetylenes ...................................................... Practical aspects of the coupling reactions .................. 16.6.1 Performance of the reactions and isolation of the products ............................................ 16.6.2 Choice of the solvent and catalysts for coupling reactions .................................... Experimental section............................................... 16.7.1 Pd/Cu-catalysed cross-coupling of propargyl alcohol with vinyl bromide ........................ 16.7.2 2,6-Dimethyl-5-hepten-3-yn-2-ol from 1-bromo-2-methyl-1-propene and 2-methyl-3butyn-2-ol............................................... 16.7.3 (E )-1-chloro-1-decen-3-yne from (E )-1,2-dichloroethene and 1-octyne ............ 16.7.4 Other cross couplings, using similar conditions ..................................... 16.7.5 1,2-Bis(4-acetylphenyl)ethyne from acetylene and 4-bromoacetophenone ......................... 16.7.6 1-Nitro-4-(trimethylsilylethynyl)benzene from 1-bromo-4-nitrobenzene and ethynyl (trimethyl)silane ....................................... 16.7.7 3-(4-Nitrophenyl)prop-2-yn-1-ol from 1-bromo-3-nitrobenzene and propargyl alcohol ................................................... 16.7.8 4-(4-Methoxyphenyl)-2-methyl-3-butyn-2-ol from 1-bromo-4-methoxybenzene and 2-methyl-3-butyn-2-ol ............................... 16.7.9 3-(2-Thienyl)-2-propyn-1-ol from 2-bromothiophene and propargyl alcohol .....

293 294 298 299 300 301 301 303 304 304 305 306 306 307 308 308 309 309

xxvi

DETAILED CONTENTS 16.7.10

4-(4-Dimethylaminophenyl)-2-methyl-3butyn-2-ol from p-bromoaniline and 2-methyl3-butyn-2-ol ............................................ 16.7.11 1,3-Bis(trimethylsilylethynyl)benzene from 1,3-dibromobenzene and ethynyl(trimethyl) silane ..................................................... 16.7.12 3-(1-Cyclooctenyl)-2-propyn-1-ol from 1-bromo-1-cyclooctene and propargyl alcohol 16.7.13 1-Methoxy-4-(trimethylsilylethynyl)benzene from 1-bromo-4-methoxybenzene and ethynyl(trimethyl)silane ............................. 16.7.14 4-(3-Furyl)-2-methyl-3-butyn-2-ol from 3-bromofuran and 2-methyl-3-butyn-2-ol ...... 16.7.15 1-Ethynyl-1-cyclooctene starting from 1-bromocyclooctene and ethynyl(trimethyl) silane ..................................................... 16.7.16 2-Ethynylthiophene starting from 2-bromothiophene and 2-methyl-3-butyn-2-ol 16.7.17 Reaction of 2,3-dibromothiophene with 2-methyl-3-butyn-2-ol. Selective substitution of the bromine atom at the 2-position.......... 16.7.18 Pd(0)-catalysed reaction of an alkynylzinc chloride with iodoheteroaromates ............... 16.7.19 Pd(0)-catalysed reaction of an alkynylzinc chloride with (het)aryl bromides ................. References .......................................................................

Chapter 17

310 310 311 311 312 312 313 314 315 316 317

Base-Catalysed Isomerisations of Acetylenic Compounds 17.1 17.2

Introduction.......................................................... Experimental section............................................... 17.2.1 Isomerisation of 1-alkynes to 2-alkynes ........ 17.2.2 Isomerisation of 10-undecyn-1-ol to 9-undecyn-1-ol ......................................... 17.2.3 Isomerisation of N,N-diethyl-2-propyn-1amine to N,N-diethyl-1-propyn-1-amine ....... 17.2.4 N,N-Dimethyl-1-allenamine from N,N-dimethyl-2-propyn-1-amine ................. 17.2.5 1-(1,2-Propadienyl)morpholine from 4-(2-propynyl)morpholine ..................................... 17.2.6 Isomerisation of N,N-diethyl-4-penten-2-yn-1amine to N,N-diethyl-3-penten-1-yn-1-amine . 17.2.7 N,N-diethyl-1,3-pentadiyn-1-amine from N,N-diethyl-2,4-pentadiyn-1-amine .............. 17.2.8 Methoxyallene from 3-methoxy-1-propyne .... 17.2.9 t-Butoxyallene from 3-t-butoxy-1-propyne .... 17.2.10 1-Ethoxyethoxyallene starting from propargyl alcohol and ethoxyethene .......................... 17.2.11 Isomerisation of 1,4-bis(alkoxy)-2-butynes to the corresponding allenes ....................... 17.2.12 1,2,4-Pentatriene from 1-penten-4-yne ..........

319 320 320 322 323 324 325 326 327 328 329 330 331 332

DETAILED CONTENTS 17.2.13 17.2.14

1,2-Pentadien-4-yne from 1,4-pentadiene ...... Isomerisation of 3-ethylthio-1-propyne to 1-ethylthio-1-propyne................................ 17.2.15 Isomerisation of 1-(phenylthio)-3-propyne to 1-(phenylthio)-1-propyne ........................... 17.2.16 1,1-Diethoxy-3-heptyne from 1,1-diethoxy-2heptyne .................................................. 17.2.17 3-Vinylidene-1-cyclohexene from 1-ethynylcyclohexene................................................ 17.2.18 Sodamide-catalysed isomerisation of 2-alkynyl ethers to allenic ethers .............................. 17.2.19 4,5-Hexadien-3-one from 5-hexyn-2-one ....... 17.2.20 2,4,5-Hexatrienenitrile from 5-bromo-3penten-1-yne and potassium cyanide ............ References .......................................................................

Chapter 18

xxvii 333 334 336 336 337 338 338 339 340

Allenic Compounds by 2,3- and 3,3-Sigmatropic Rearrangements 18.1 18.2 18.3

2,3-Sigmatropic rearrangements ................................ 3,3-Sigmatropic rearrangements ................................ Experimental section............................................... 18.3.1 Methyl 1,2-propadienyl sulphoxide from propargyl alcohol and methanesulphenyl chloride .................................................. 18.3.2 Phenyl 1,2-propadienyl sulphoxide from benzenesulphenyl chloride and propargyl alcohol ................................................... 18.3.3 Methyl 3-methyl-1,2-butadienyl sulphone from 2-methyl-3-butyn-2-ol and methanesulphinyl chloride .................................................. 18.3.4 1,2-Propadienyl diphenylphosphinate from propargyl alcohol and chlorodiphenylphosphane .......................... 18.3.5 N,N-Diethyl-2-methyl-3,4-pentadienamide from the boron triﬂuoride-catalysed reaction of propargyl alcohol with N,N-diethyl-1propyn-1-amine ....................................... 18.3.6 6-Methylhepta-4,5-heptadien-2-one from the acid-catalysed reaction of 2-methyl-3-butyn-2ol with methyl isopropenyl ether ................. 18.3.7 Ethyl 3,4-pentadienoate from the acid-catalysed reaction of propargyl alcohol with ethyl orthoacetate ............................................ 18.3.8 Ethyl 3,4-pentadienedithioate from the reaction of ethyl ethanedithioate with lithium amide and propargyl bromide .......... 18.3.9 Ethyl 3,4-hexadienoate from the acid-catalysed reaction of 3-butyn-2-ol with ethyl orthoacetate ............................................

341 342 343

343 344 345 346

346 347 348 348 349

xxviii

DETAILED CONTENTS 18.3.10

Synthesis of 2,2-dimethyl-3,4-pentadienal starting from propargyl alcohol and 2-methylpropanal................................................. 18.3.11 Silver perchlorate-catalysed rearrangement of 1,1-dimethyl-2-propynyl acetate to 3-methyl1,2-butadienyl acetate ............................... References .......................................................................

Chapter 19

350 351 351

Miscellaneous Reactions of Acetylenic and Allenic Compounds 19.1

19.2

19.3

Elimination reactions resulting in additional unsaturation.......................................................... 19.1.1 2-Methyl-1-buten-3-yne from 2-methyl-3butyn-2-ol and acetic anhydride .................. 19.1.2 1-Ethynyl-1-cyclohexene from 1-ethynylcyclohexanol and phosphoryl chloride in pyridine.................................................. 19.1.3 3,1-Enynes by 1,2-elimination of p-toluenesulphonic acid from propargylic tosylates using KOH in a water–DMSO mixture ................ 19.1.4 3,5-Heptadien-1-yne from 5-hepten-1-yn-4-ol in a one-pot procedure using p-toluenesulphonic chloride and potassium hydroxide as reagents.................................................. 19.1.5 6-Ethynyl-2,3-dihydro-4H-pyran from 3-bromo-2-ethynyltetrahydro-2H-pyran and t-BuOK in tetrahydrofuran ........................ 19.1.6 2-Ethoxy-2-penten-4-yne from 5-bromo-4ethoxy-1-pentyne and sodamide .................. 19.1.7 4,1-Enynes by elimination of bromine and ethoxy groups from 5-bromo-4-ethoxy-1alkynes with zinc in dimethylsulphoxide ....... Removal of protecting groups .................................. 19.2.1 1,3-Diynes by potassium hydroxide-catalysed elimination of acetone from the corresponding diyne carbinols ........................................ 19.2.2 General procedure for the base-catalysed desilylation of silylated acetylenes ............... 19.2.3 Acid-catalysed conversion of O-protected alcohols into the free alcohols .................... 19.2.4 Acid-catalysed conversion of acetylenic acetals into the aldehydes .................................... Partial Reductions of Conjugated systems of Triple Bonds ..................................................... 19.3.1 Partial reduction of 3,5-octadiyne with activated zinc powder ............................... 19.3.2 Regiospeciﬁc and stereospeciﬁc partial reduction of 1-trimethylsilyl-1,3-heptadiyne with activated zinc powder ........................

353 353 354 354

355 356 357 358 359

359 360 361 361 362 362 364

DETAILED CONTENTS Regiospeciﬁc and stereospeciﬁc partial reduction of 2,5-octadiyn-1-ol with activated zinc powder ............................... 19.3.4 Regiospeciﬁc and stereospeciﬁc partial reduction of O-protected diyne alcohols and acetals with a conjugated diyne system using activated zinc .......................................... References .......................................................................

xxix

19.3.3

Chapter 20

365

365 367

Transformation of Functional Groups in Acetylenic and Allenic Compounds 20.1

20.2

Acetylenic halogen compounds ................................. 20.1.1 Propargyl bromide from propargyl alcohol and phosphorus tribromide ........................ 20.1.2 Homologues of 3-bromo-1-propyne from propargylic alcohols and phosphorus tribromide 20.1.3 3-Bromo-3-methyl-1-butyne from 2-methyl-3butyn-2-ol and phosphorus tribromide ......... 20.1.4 3-Bromo-1-nonyne from the corresponding tosylate and lithium bromide...................... 20.1.5 4-Bromo-1-butyne from the corresponding tosylate and lithium bromide in DMSO ....... 20.1.6 1,4-Dichloro-2-butyne from 2-butyn-1,4-diol and thionyl chloride ................................. 20.1.7 1,6-Dichloro-2,4-hexadiyne from 2,4-hexadiyne-1,6-diol and thionyl chloride ... 20.1.8 5-Chloro-3-hexen-1-yne and 5-bromo-3hexen-1-yne from 4-hexen-1-yn-3-ol and concentrated aqueous HCl or HBr .............. 20.1.9 3-Chloro-3-methyl-1-butyne from 2-methyl-3butyn-2-ol and concentrated aqueous HCl in the presence of copper(I) chloride ............... 20.1.10 1-Chloro-1-ethynylcyclohexane from 1-ethynylcyclohexanol and concentrated aqueous HCl in the presence of copper(I) chloride ..... 20.1.11 ‘Contrathermodynamic’ formation of propargyl iodide from the bromide and sodium iodide in absolute ethanol ................................... 20.1.12 Zinc chloride-catalysed conversion of 2-alkynyl ethers into the corresponding chlorides................................................. Acetylenic amino and imino compounds .................... 20.2.1 Propargylamine from propargyl bromide and liquid ammonia ....................................... 20.2.2 Propargylic tertiary amines from propargyl bromide and aliphatic or cycloaliphatic secondary amines ..................................... 20.2.3 N,N-Dimethyl-2-propyn-1-amine from propargyl bromide and dimethylamine .........

369 369 370 371 372 373 374 376 377 378 379 379 380 381 381 383 385

xxx

DETAILED CONTENTS 20.2.4

20.3

20.4

20.5

1,4-Bis(diethylamino)-2-butyne starting from 1,4-dibromo-2-butyne ............................... 20.2.5 N,N-Diethyl-5-hexyne-1-amine from the corresponding tosylate and diethylamine ........................................... 20.2.6 2-Heptyne-1-amine from 1-bromo-2-heptyne and hexamethylenetetramine ..................... 20.2.7 2-Methyl-3-butyne-2-amine from 3-chloro-3methyl-1-butyne and sodamide ................... 20.2.8 1-Ethynylcyclohexanamine from 1-chloro-1ethynylcyclohexane and sodamide ............... 20.2.9 1-Propargylpyrrole from pyrrole, potassium amide and propargyl bromide .................... 20.2.10 Acetylenic imines (general method, not checked) ................................................. Acetylenic and allenic nitriles, thiocyanates and isothiocyanates ................................................ 20.3.1 Preparation of 2-alkynenitriles from 1-bromo1-alkynes and copper(I) cyanide in the presence of lithium bromide ....................... 20.3.2 2,3-Decadienenitrile from corresponding bromo compound and copper(I) cyanide in the presence of lithium bromide .................. 20.3.3 3-Alkynenitriles from 1-bromo-2-alkynes and copper(I) cyanide ..................................... 20.3.4 4-Pentynenitrile from 3-butynyl tosylate and sodium cyanide in DMSO ......................... 20.3.5 2-Heptynenitrile from the corresponding carboxamide and phosphorus pentoxide ....... 20.3.6 2-Propynyl thiocyanate from propargyl bromide and potassium thiocyanate ............ 20.3.7 Propargyl isothiocyanate from propargylamine and thiophosgene ............... Acetylenic aldehydes, ketones and carboxylic acids ..................................................... 20.4.1 Propiolaldehyde, HCCCH¼O .................. 20.4.2 Ethynyl ketones from corresponding ethynyl carbinols and chromic acid ........................ 20.4.3 5-Hexyn-3-one from 5-hexyn-3-ol and chromic acid ........................................... 20.4.4 Propynoic acid, HCCCOOH.................... Acetylenic esters, dithioesters and carboxamides .......... 20.5.1 General procedure for the preparation of acetylenic acetates .................................... 20.5.2 2-Propynyl propanedithioate from bromomagnesium propanedithioate and propargyl bromide ................................... 20.5.3 General procedures for the preparation of acetylenic methanesulphinates and methanesulphonates.................................. 20.5.4 General procedure for the preparation of acetylenic 4-methylbenzenesulphonates .........

385 386 387 387 388 389 390 390 390 391 392 393 393 394 394 395 395 396 396 397 397 397 398 399 400

DETAILED CONTENTS 20.5.5

20.6

20.7

20.8

Conversion of ethyl 2-heptynoate into the corresponding carboxamide ....................... Ethers .................................................................. 20.6.1 3-Methoxy-1-propyne from propargyl alcohol, NaOH and dimethyl sulphate ..................... 20.6.2 1,4-Dimethoxy-2-butyne from 2-butyne-1,4diol, NaOH and dimethyl sulphate .............. 20.6.3 Di-(2-propynyl) ether from propargyl alcohol, propargyl bromide and NaOH ................... 20.6.4 O-Methylation of an acetylenic tertiary alcohol with dimethyl sulphate ................... 20.6.5 O-Methylation of an O-lithiated acetylenic tertiary alcohol with methyl iodide .............. 20.6.6 Methylation of an in situ prepared acetylenic lithium alcoholate with methyl iodide .......... 20.6.7 Protection of the OH group in alcohols with ethyl vinyl ether ....................................... 20.6.8 3-(t-Butoxy)-1-propyne by acid-catalysed addition of propargyl alcohol to isobutene ... 20.6.9 Conversion of acetylenic chlorohydrines into oxiranes ........................................... 20.6.10 O-Silylation of acetylenic tertiary alcohols .... 20.6.11 O-Methylation of alcohols with methyl iodide and potassium hydroxide ........................... Acetylenic sulphides and thiols ................................. 20.7.1 Methyl 2-propynyl sulphide from sodium methanethiolate and propargyl chloride ....... 20.7.2 1,4-Bis(methylthio)-2-butyne from sodium methanethiolate and 1,4-dichloro-2-butyne ... 20.7.3 (Z )-1-Ethylthio-1-buten-3-yne from ethanethiol and butadiyne ......................... 20.7.4 1,1-Bis(ethylthio)-2-butyne by zinc chloridecatalysed substitution of the ethoxy groups in the corresponding acetal by ethylthio groups....................................... 20.7.5 2-Propyne-1-thiol from propargyl bromide and potassium hydrosulphide ..................... 20.7.6 2-(Propargylthio)thiophene from in situ prepared lithium mercaptothiophene and propargyl bromide ................................... Acetylenic and allenic sulphoxides, sulphones, sulphinamides and sulphonamides ............................. 20.8.1 Conversion of 1-ethylthio-1-propyne into the sulphoxide .............................................. 20.8.2 Conversion of 1-ethylthio-1-propyne into the sulphone................................................. 20.8.3 Conversion of 1-methylthiopropadiene into methyl propadienyl sulphoxide ................... 20.8.4 Conversion of 1-methylthio-1,2-pentadiene into methyl 1,2-pentadienyl sulphoxide ........ 20.8.5 Conversion of methyl propadienyl sulphoxide into methyl propadienyl sulphone ...............

xxxi

402 402 402 404 405 405 406 407 408 409 410 411 412 412 412 413 414

414 415 416 417 417 417 418 419 419

xxxii

DETAILED CONTENTS 20.8.6

Oxidation of 1-alkyne-1-sulphinamides with 3-chlorobenzenecarboperoxoic acid....... 20.9 Dimetallated acetylenic compounds and their functionalisation .................................................... 20.9.1 Preparation of dilithiated 2-methyl-1-buten-3yne and its regioselective functionalisation with c-hexyl bromide and oxirane ............... 20.9.2 Dilithiation of phenylacetylene and subsequent regioselective formylation .......................... 20.10 Copper(I) bromide-catalysed formation of 2-propargylhetarenes .............................................. References .......................................................................

420 420 420 422 423 424

Appendix A: 1H- and 13C-NMR Chemical Shifts of Acetylenic, Allenic and Cumulenic Compounds .......................................... 427 Appendix B: Class–Compound–Method Index ............................................. 431 Appendix C: Complementary Subject Indexes ............................................. 455

1 Procedures and Equipment

1.1

GENERAL

For most of the procedures described in this book a round-bottomed, threenecked flask equipped with a combination of a dropping funnel and an inlet for inert gas, a mechanical stirrer and a combination of a thermometer and an outlet is recommended (Figure 1.1). If during the performance of the procedure no gases are evolved from the reaction mixture, the inlet for inert gas may be omitted and the outlet connected to a balloon or relatively big flask filled with inert gas. Depending upon the required efficiency of stirring a simple glass rod with a flattened end, a chromium-plated paddle (Figure 1.2) or other types may be used. A flask having both of the outer necks in a non-vertical position is impractical since it is difficult to place the thermometer or gas inlet tube such that contact with the stirrer is avoided. Instead of the usual mercury, alcohol or pentane thermometer an electronic thermometer may be used. If relatively small volumes of reagents have to be added over a short period, the combination of a syringe and a rubber septum may be more convenient than the dropping funnel. Magnetic stirring may be carried out if the volume of the reaction mixture is limited, not much suspended material is present and continuous control of the temperature by using a cooling bath is not very essential.

1.2

REACTIONS IN LIQUID AMMONIA

Anhydrous liquid ammonia is an excellent solvent for many reactions involving acetylenic compounds. The conversions can be carried out under atmospheric pressure at the boiling point (33 C) or if necessary, at lower temperatures. Depending upon the conditions of the procedure, the standard set-up (Figure 1.1) or a variant may be used. Liquid ammonia of good quality (water content less than 0.1%, absence of rust particles) can be drawn from cylinders with or without a dip tube (cf. A. I. Vogel’s Textbook of Practical 1

2

1.

PROCEDURES AND EQUIPMENT

Organic Chemistry, 4th edn., Longmans, p. 98) and transferred through a plastic tube into the reaction flask. Plugs of cotton wool are temporarily placed on the necks, after which the flask is equipped as desired. However, in many laboratories no ammonia of good quality is available and purification by distillation may be necessary. Small pieces of sodium are added with manual swirling to 0.6 litre of ammonia in a 1-litre round-bottomed flask. After the blue colour has persisted, an additional amount (2 g) of sodium is introduced and connection is made with the flask as shown in Figure 1.9. The flask containing the solution of sodium is occasionally placed in a bath at 35 C, while condensation of the vapour is achieved by (occasionally) cooling the flask (Figure 1.9) in liquid nitrogen. The distillation can be completed in 1 to 1.5 h. Disposal of the sodium residue by addition of ethanol should be carried out immediately after termination of the distillation. Many reactions in liquid ammonia can be carried out at its boiling point. Evaporation can be limited by insulating the flask in cotton wool. If a volatile compound is to be prepared or a volatile or ammonia-sensitive reagent (e.g. methyl iodide) is added, it is desirable to keep the reaction mixture below the boiling point of ammonia (33 C). This can be done by occasional cooling with liquid nitrogen or a mixture of dry ice and acetone in a Dewar vessel (Figure 1.6). Strong evaporation of ammonia during exothermic reactions can be avoided by cooling the reaction mixture below the boiling point of ammonia. For slow reactions, which require several hours and which can be carried out without stirring, a flask with an evacuated space between the walls (Figure 1.4) is recommended. If the flask is covered with aluminium foil, the rate of evaporation of ammonia is very low. An example is the reaction between lithium acetylide and oxirane (Chapter 4, exp. 4.5.16). If a reaction in ammonia is very fast and work-up has to be carried out immediately, it may be more convenient to use a wide-necked round-bottomed flask with the stirrer placed centrally (Figure 1.5). An example is described in Chapter 3, exp. 3.9.28. Note The complicated equipment prescribed for performing reactions in liquid ammonia,* even in some Organic Synthesis procedures (use of a reflux *Some examples: A. L. Henne and K. W. Greenlee, J. Am. Chem. Soc. 67, 484 (1945); Inorg. Synth. 2, 128 (1946); K. E. Schulte and K. P. Reiss, Chem. Ber. 86, 777 (1953); 87, 964 (1954); R. F. Parcell and C. B. Pollard, J. Am. Chem. Soc. 72, 2385 (1950); R. W. Bradshaw, A .C. Day, E. R. H. Jones, C. B. Page, V. Thaller and R. A. V. Hodge, J. Chem. Soc. [C], 1156 (1971).

1.3

SOME PRACTICAL HINTS

3

condenser, cooled with dry ice, placed on the reaction flask) may be an important reason to prefer organic solvents. It should be emphasised, however, that it is possible to carry out most reactions in ammonia without using a reflux condenser. If strong evaporation is expected, for example during dehydrohalogenations, the reaction flask may be insulated in cotton wool or be placed in a bath with a dry ice–acetone mixture or liquid nitrogen as described above.

1.3

SOME PRACTICAL HINTS

During some conversions in liquid ammonia, frothing may occur, especially in the case of very thick suspensions. This can result in the loss of part of the reaction mixture. The reaction flask therefore should never be more than half-filled. Frothing may effectively be suppressed by adding small amounts of diethyl ether (if the product to be isolated is not volatile), by lifting the stirring motor so that the paddle rotates just below the surface of the reaction mixture or by shortly cooling the flask in a bath with liquid nitrogen. If the product of a reaction in liquid ammonia is not very volatile (bp>110 C at atmospheric pressure), the ammonia may be allowed to evaporate overnight or during the weekend. After removal of the usual equipment, the flask is connected with a tube filled with cotton wool placed on the level of the bottom of the flask so that a protecting atmosphere of ammonia remains in the flask (Figure 1.7). Alternatively, the ammonia may be quickly removed by placing the flask in a bath at 34–40 C. In the case of volatile products (bp <110 C), removal of the ammonia by evaporation gives rise to considerable losses. These can be considerably minimised by adding a high-boiling solvent (e.g. a petroleum ether fraction with bp >170 C) to the reaction mixture after the reaction has finished. Subsequently the mixture is poured on to a relatively large amount of finely crushed ice in a large wide-necked round-bottomed flask (Figure 1.8) or in a large beaker. The reaction is carried out at temperatures below the boiling point of ammonia (cooling in dry ice–acetone or liquid nitrogen). In some elimination reactions in liquid ammonia an alkali acetylide is formed. In some cases, for example in the preparation of methoxyand ethoxyacetylene, it is for reasons of safety essential to hydrolyse the alkynylide before all ammonia has evaporated. This can be done by successively adding the extraction solvent and a large amount of crushed

4

1.

PROCEDURES AND EQUIPMENT

ice over a very short period (cf. Chapter 3, exp. 3.9.28). For this reason the reaction is carried out in a large one-necked round-bottomed flask (Figure 1.5). For the isolation of volatile or unstable products from the solution in a highboiling solvent the set-up of Figure 1.10 is used. After evacuation (between <1 and 25 Torr) the solution is warmed until a small amount of the extraction solvent has passed over. The volatile product is collected in a strongly cooled (bath with dry ice–acetone, 78 C) receiver. If a water aspirator is used, and entrance of moisture is undesired (for example in Chapter 3, exp. 3.9.48), a tube filled with a drying agent should be placed between the receiver and the aspirator. Distillation can be accompanied by foaming especially in the case of compounds with a long carbon chain. Foaming can be suppressed by completely immersing the distillation flask in the liquid of the heating bath or by adding a few drops of some anti-foaming liquid prior to carrying out the distillation. Although special columns can be used for preventing the foam passing over, it is, in general, advisable to use a relatively big distillation flask in such cases. Recovery by distillation of acetylenes or allenes that have been stored for a long period may involve the risk of an explosive decomposition of the residue. This danger can be minimised by adding a certain amount (20 ml for the distillation of 50 ml of product) of paraffin oil prior to the distillation. The residue will not remain as a compact mass but as an emulsion or dispersion in the oil after termination of the distillation. Concentrations of reactants in the procedures described in this book generally are between 0.5 and 1 mol/litre of solvent. A good estimate of the time necessary for 100% conversion requires much experience and knowledge. For the lithiation of a 1-alkyne with butyllithium, for example, one has to know that the deprotonation of acetylenes with such very strongly basic reagents is an extremely fast reaction. This means that the heat of this deprotonation is liberated over a very short period. Metallation of allenes, compounds which are much less strongly acidic than 1-alkynes, proceeds less fast. Nevertheless, one can make a rather good estimate of the time necessary for (almost) complete lithiation of, for example methoxyallene, H2C¼C¼CHOMe, by performing the following experiment. A solution of 0.05 mol of n-BuLi in 33 ml of hexane (the usual 1.6 mol/litre concentration of the commercially available reragent) and 40 ml of tetrahydrofuran is cooled down to 70 C, then the cooling bath is removed and the flask is insulated in cotton wool. The increase of the temperature of the slowly stirred solution is observed during a few minutes (an electronic thermometer is more convenient than the usual one). Usually, rising of the temperature will amount by a few degrees only. The temperature of the solution is adjusted

1.3

SOME PRACTICAL HINTS

5

again at 70 C by dipping the reaction flask for a few seconds in the cooling bath. Methoxyallene (0.05 mol) is then added in one portion. This will result in a rising of the temperature by several (at least 20) degrees over less than 1 min. Even if smaller amounts of the allenic ether are added in one portion, the effect is clearly visible. One may carry out a blank experiment by adding at 70 C the same volume of THF. In this case the temperature rises by a few (< 5) degrees only. Of course, for completion of the lithiation the reaction mixture has to be stirred for a (limited) additional period at a temperature higher than 70 C. Reactions between strongly basic anionic species and aldehydes or ketones usually proceed almost instantly, even at temperatures far below 0 C in solvents of low polarity. Silylations (with R3SiCl) and sulphenylations (with disulphides, RSSR or thiocyanates, RSCN) of organoalkali compounds are other examples of very fast reactions, which are easy to follow by temperature observation. Reactions in boiling liquid ammonia (bp 33 C) may be followed by keeping the end of a small slip of paper 1 cm from the outlet. When there is no or a very slow reaction (e.g. when the reaction has subsided) the flow of escaping ammonia is relatively weak and the position of the slip remains vertical. In the case of very fast reactions much ammonia may evaporate in a short time and the vigorous flow from the outlet causes the slip to move off from the outlet. Dehydrohalogenations as mentioned in Chapter 3, Section 3.3 are extremely fast and exothermic so that addition of small portions of the halogen compound causes a vigorous outward flow of ammonia. For reactions carried out at temperatures below the boiling point of ammonia the method described above for methoxyallene may be used. It should be pointed out that heating effects can also be made visible by performing the reaction on a very small (1 mmolar) scale in a reagent tube (wrapped in cotton wool) using an electronic thermometer. Some reactions, if carried out on a preparative scale and with ‘preparative’ concentrations of the reactants, can be followed by observing the temperature in the solution boiling under constant intensity of the reflux stirred at a constant rate. A good example is the Pd/Cu-catalysed cross-coupling between ethynyl(trimethyl)silane (bp 53 C) and 1-bromo-1-cyclooctene in piperidine (bp 106 C) described in Chapter 16, exp. 16.7.15. The temperature of the reaction mixture, in the beginning 90 C, reaches a maximum (110 C, somewhat higher than the boiling point of piperidine, due to the presence of dissolved HBr salt) when most of the volatile acetylene has reacted with bromocyclooctene. The isomerisation of methyl propargyl ether (bp 61 C) to methoxyallene (bp 51 C) in the presence of potassium t-butoxide in a small amount of DMSO (Chapter 17, exp. 17.2.8) can be followed by looking at the thermometer in the refluxing solution.

6

1.

PROCEDURES AND EQUIPMENT

The temperature drops as a result of the formation of a more volatile compound. In other procedures, carried out with high concentrations of starting compounds, the refractive index of the solution can be measured, for example in the isomerisation of HCCCH(Br)C6H13 to BrCH¼C¼CHC6H13 under the catalytic influence of lithium dibromocuprate, CuBr LiBr (Chapter 12, exp. 12.4.14), and in the bromination of 1,3-diynes, RCCCCH, with potassium hypobromite (Chapter 9, exp. 9.2.3). In a single case the only necessary instruments are the eyes. The conversion of propargyl bromide into the corresponding iodide, using a hot (70 C) solution of sodium iodide in absolute ethanol (Chapter 20, exp. 20.1.11) is accompanied by precipitation of sodium bromide. The reaction is finished when salt crystals are no longer being formed in the supernatant layer (stirring is not necessary). Particularly in the cases of hydroxyacetylenes, the question ‘How many extractions with diethyl ether still have to be carried out?’ may arise. The following practical tip may be useful. Take a small (0.5 ml) sample from the extract with a Pasteur pipette and allow the solution to flow along a ground-glass stopper. Further extraction is no longer necessary when after evaporation of the ether no residue is visible on the ground glass. A quick and extremely simple method to investigate whether volatile polymerisable liquids such as oxirane, ethyl vinyl ether and vinyl bromide contain polymers is to put 1 ml on a watch glass and to blow air over the liquid. If not any oil-like residue is visible on the glass, purification is not necessary. The following generally valid advice with respect to the work-up of reaction mixtures resulting from syntheses with Grignard reagents should be given. If water or aqueous ammonium chloride is added at too fast a rate to the reaction mixture, much heat will be evolved and as a result part of the reaction mixture will be lost, especially if diethyl ether is used as a solvent. Therefore, the reaction mixture always should be (cautiously) poured into water or into aqueous ammonium chloride. If the product is not acid-sensitive, dilute mineral acid can be used. Alternatively, water or the aqueous solution of ammonium chloride or acid may be added slowly to the efficiently stirred reaction mixture, preferably under cooling.

1.3

SOME PRACTICAL HINTS

Figure 1.1

Figure 1.4

Figure 1.2

7

Figure 1.3

Figure 1.5

8

1.

Figure 1.6

Figure 1.8

PROCEDURES AND EQUIPMENT

Figure 1.7

Figure 1.9

1.3

SOME PRACTICAL HINTS

Figure 1.10

Figure 1.11

9

10

1.

PROCEDURES AND EQUIPMENT

ABBREVIATIONS Et2O THF DMSO HMPT LDA DMF TMEDA rt (in experimental procedures) BuLi t-BuOK

TMS c-C6H11 Me Et n-Pr n-Bu t-Bu (CH2)5C

diethyl ether tetrahydrofuran dimethylsulphoxide hexamethylphosphoric triamide (Me3N)3P¼O lithium diisopropylamide N,N-dimethylformamide N1,N1,N2,N2-tetramethylethanediamine room temperature n-butyllithium potassium tert-butoxide (the commercially available non-complexed base) trimethylsilyl group cyclohexyl group CH3 group C2H5 group n-C3H7 group n-C4H9 group (CH3)3C group cyclohexane ring, in tables

2 Preparation, Purification and Storage of Some Solvents and Reagents

2.1

SOLVENTS

Many syntheses described in this book are carried out in tetrahydrofuran (THF). This solvent sometimes contains peroxides and small amounts of water, especially after a long period of careless storage. Peroxides are easily detected by shaking a few millilitre of the solvent with an aqueous solution of alkali iodide. The intensity of the brown colour developed gives a rough indication of the peroxide content. Peroxides and water are effectively removed by shaking the THF with machine-powdered potassium hydroxide (100 g/2 litre). If no special machine for grinding pellets is available, mechanical stirring with a relatively large amount of pellets may be considered. For most of the procedures in this book the THF, dried over KOH, can be used after rapid filtration. For use in sluggishly proceeding preparations of Grignard reagents, e.g. t-butylmagnesium chloride, distillation from lithium alanate, LiAlH4, or sodium-benzophenone is necessary. THF is best stored in a brown flask under inert gas, preferably argon. Diethyl ether (Et2O) may be purified by a similar procedure. For most purposes (except some Grignard preparations, e.g. t-butylmagnesium chloride), however, it suffices to dry the solvent over KOH followed by rapid filtration, distillation being unnecessary. The addition of HexaMethylPhosphoric Triamide (Me3N)3P¼O (HMPT, the English abbreviation is HMPA) as a co-solvent in small amounts (in molarity equal to the organometallic intermediate) can cause a considerable acceleration of some reactions, especially alkylations and reactions with oxiranes. The commercial solvent often contains water and other impurities. Purification may be carried out by distillation from commercial t-BuOK (a few grams for 200 ml) in a high vacuum followed by redistillation at 5 to 20 Torr (bp 110 C/15 Torr). HMPT is a cancer-suspect compound, moreover it has become very expensive. For these reasons, in cases of 11

12

2.

PURIFICATION OF SOLVENTS AND REAGENTS

frequent use dimethylsulphoxide should be seriously considered as an alternative. However, this solvent cannot be used in reactions with strongly basic organometallic intermediates because of an easy proton/metal exchange. The non-toxic cyclic urea derivative 1,3-dimethyl-2-oxo-hexahydropyrimidine (N,N-dimethylpropyleneurea, DMPU), has been proposed [1], but unfortunately large amounts (compared to HMPT) of it seemed to be required. Dimethylsulphoxide (DMSO) can be made water-free by a procedure similar to that applied for HMPT. Although DMSO can replace HMPT as a co-solvent for some reactions involving organometallics that are not more strongly basic than acetylides, care should be taken to keep the temperature as low as possible during the functionalisations. Upon heating solutions of acetylides RCH2CCM (M ¼ alkali metal) proton/metal exchange between the alkali acetylide and DMSO occurs. The resulting free acetylene, RCH2CCH, undergoes a subsequent isomerisation to the 2-alkyne, RCCMe, catalysed by the DMSO anion formed in small equilibrium concentrations from the alkali acetylide and DMSO [2]. In the case of metallated allenes (e.g. H2C¼C¼CHM) or 2-alkynes (e.g. MeCCCH2M), much more strongly basic than RCH2CCM, this exchange will be very easy, making DMSO unsuitable as a co-solvent for derivatisations of mesomeric acetylenic-allenic anions. It has been shown that in liquid ammonia 1-metallated allenic ethers, H2C¼C¼C(Na)OR, are rapidly converted into the 3-metallated species NaCH¼C¼CHOR and metallated propargylic ethers, NaCCCH2OR. Obviously, these isomerisations are the result of a proton donation (by ammonia) and subsequent deprotonation (by alkali amide) at the 3-position of the allenic system [11,12]. 1-Metallated allenic sulphides, R1CH¼C¼C(M)SR, have a reasonable kinetic stability in liquid ammonia [13]. Traces of water in tertiary amines such as triethylamine and pyridine can be detected by adding a few drops of chloro(trimethyl)silane to 1 ml of the amine in a dry reagent tube resulting in the formation of the suspended HCl salt of the amine. Potassium hydroxide, preferably machine-powdered, is a suitable drying agent. Perfectly dry N1,N1,N2,N2-tetramethyl-1,2-ethanediamine (TMEDA, bp 120–122 C) can be obtained by distillation of the KOH-dried amine from lithium alanate, LiAlH4, in a partial vacuum (100 Torr). The best way to obtain dry benzene, dichloromethane, chloroform, carbon tetrachloride, alkyl halides, etc. is to subject the liquid to a distillation under normal pressure until clear condense (no longer turbid) flows through the condenser. After 10% of distillate has been collected, the condenser should be cleaned and the distillation continued to ensure the absence of turbid condense. The remaining liquid in the distillation flask is perfectly dry. Another effective method of removing small amounts of water is to shake

2.2

REAGENTS

13

the liquid during half a minute with a small amount of phosphorus pentoxide. After decanting the liquid from the syrup it is shaken with a second small portion of phosphorus pentoxide. When this remains in suspension after shaking, the drying procedure can be considered to be complete and (after filtration) a distillation can be carried out. Chloroform and carbon tetrachloride, used as solvents for NMR spectroscopy, may contain traces of HCl (or DCl). These can cause E/Z interconversion in the case of systems with the structural units C¼C–X in which X represents an amino, ether or thioether group. The measured integration ratio of the signals for the two isomers therefore may be different from the actual ratio. For surety the solvents may be shaken with a very small amount of aqueous potassium carbonate, dried over the anhydrous salt and finally distilled as described above. Storage in brown bottles under inert gas may prevent the formation of acid.

2.2

REAGENTS

Acetaldehyde polymerises very easily giving the cyclic trimer ‘paraldehyde’. It is therefore absolutely necessary to use the freshly distilled (bp 21 C at normal pressure) reagent for reactions, even after opening of a sealed bottle. Since traces of acid on the glass of the distillation apparatus can cause trimerisation, the condenser and receiver should be first rinsed with a dilute solution of a volatile amine in acetone and subsequently blown dry. Monomeric acetaldehyde can also be obtained by addition (with manual swirling) of 1 ml of concentrated sulphuric or phosphoric acid to 300 ml of the (commercially available) cyclic trimer followed by distillation through a column of 30 to 40 cm. Aliphatic aldehydes also can undergo trimerisation (and oxidation) during storage, therefore it is absolutely necessary to distil the reagents before use: the lower homologues at atmospheric pressure, hexanal and higher homologues under reduced pressure. Acrolein, croton aldehyde and methyl vinyl ketone should always be distilled before use and be stored in the refrigerator. Extensive advice and instructions for handling and storage of alkali metals can be found in the laboratory manual [3] and in Houben-Weyl, Vol. E/19d, Thieme-Verlag, Stuttgart, 1994, p. 99. Alkali amides are extensively used reagents in the chemistry of acetylenes and allenes. Improved procedures for their preparation in liquid ammonia are described in this chapter. Alkynyl- and allenylzinc halides are simply prepared by addition of anhydrous zinc salts to solutions of the corresponding alkynyl- or allenyllithium

14

2.

PURIFICATION OF SOLVENTS AND REAGENTS

compounds. The analogous organomagnesium halogenides may be prepared from the lithium derivatives and magnesium bromide etherate, MgBr2 Et2O (for the preparation of this reagent see below). Benzaldehyde can be freed from benzoic acid by shaking with a 2% aqueous solution of KOH, followed by drying over magnesium sulphate and distillation under reduced pressure. The purified aldehyde should be stored under inert gas in a well-closed bottle. n-Butyllithium in hexane is commercially available in screw-capped bottles provided with a self-closing septum through which the needle of the syringe can be stuck for taking the desired volume. The solution in hexane (often 1.6 molar, in this case 63 ml of the solution contains 0.10 mol of the reagent) is stable at room temperature. For many reactions the hexane solution of butyllithium has to be mixed with a certain volume of THF. During this operation care should be taken to keep the temperature of the mixture below 0 C in order to prevent attack of THF by the reagent [4]. Et2O reacts much less fast with butyllithium. If desired, the hexane can be completely replaced by another solvent. For this, the hexane is removed under reduced pressure, the last traces in a high vacuum. The remaining viscous liquid is then dissolved in the desired solvent, e.g. a high-boiling alkane, in the case of THF with cooling below 70 C. n-Butyllithium in hexane or Et2O can be easily prepared from butyl chloride or bromide and lithium containing 1% of sodium (see experimental part). The ethereal butyllithium solution obtained from the reaction between lithium and butyl bromide contains complexed lithium bromide. For extensive information about alkyllithium reagents the reader should consult the above-mentioned laboratory manual and the Houben-Weyl volume. The n-BuLi t-BuOK reagent is prepared by combining equimolar amounts of the ingredients in THF–hexane mixtures, while keeping the temperature below 85 C. In many cases it is simpler to generate the reagent in situ, i.e. by adding BuLi under strong cooling to a mixture of the substrate and t-BuOK or the latter to a strongly cooled mixture of the substrate and BuLi. The reagent is used for deprotonations that proceed sluggishly with BuLi or BuLi TMEDA. The complex n-BuLi TMEDA in hexane can be obtained by adding TMEDA at room temperature to a solution of BuLi in hexane. Chloro(trimethyl)silane may contain hydrogen chloride and hexamethyldisiloxane, Me3SiOSiMe3, formed by entrance of moisture due to repeated use and careless closing of the bottle. Purification can best be carried out by adding a small amount (10%) of N,N-diethylaniline, followed by distillation through an efficient column (the difference between the boiling points of Me3SiCl and Me3SiOSiMe3 is about 40 C). The reagent should

2.2

REAGENTS

15

never be stored in the refrigerator since moisture can leak between the screw cap and the glass. It is, in general, not necessary to use analytically pure copper halides for the coupling and substitution reactions described in this book. The commercially available salts as a rule can be used as such. The polymer of formaldehyde (‘paraformaldehyde’) sometimes contains some moisture. This can be removed by heating the powder for 1 h at 60 C in a vacuum of 10–20 Torr. Under these conditions some depolymerisation occurs. The preparation of Grignard reagents from alkyl or aryl bromides in THF or Et2O, dried over potassium hydroxide, usually can be carried out without problems if the magnesium is first activated by addition of iodine or 1,2-dibromoethane (cf. [8]). Traces of water in the bromides can be removed by azeotropic distillation as described above for some solvents. The reaction of magnesium with alkyl chlorides, especially t-butyl chloride, is often difficult to get started. It seems essential to use carefully dried and distilled solvents. It may be even considered to heat the magnesium for a limited period in a high vacuum if the presence of moisture is suspected. t-Butyl chloride may contain small amounts of dissolved hydrogen chloride and t-butyl alcohol formed by hydrolysis. These can seriously hamper the reaction with magnesium. We found that this problem does not occur when this halide is shaken with a relatively large amount of finely powdered calcium carbonate and distilled. The only way to prepare allenylmagnesium bromide, H2C¼C¼CHMgBr, with satisfactory results is to carry out the reaction of propargyl bromide in diethyl ether at 0 C with magnesium activated with mercury chloride. For extensive practical information about other special Grignard reagents the manual [6] should be consulted. Grignard reagents react with oxygen. Their preparation therefore has to be carried out under inert gas. Grignard solutions should be stored at room temperature in flasks closed with regularly greased ground-glass stoppers. In some cases (especially in THF) part of the dissolved compound crystallises out. It is therefore necessary to warm the solution in a bath at 35 C until all solid has dissolved before using the reagent for a synthesis. Lithium dialkylamides, LiNR2, are less strongly basic than BuLi. The reagents are used for chemoselective deprotonations and for dehydrohalogenations. The reagents are prepared by adding the aliphatic secondary amine to a solution of BuLi in THF or Et2O. Lithium halides are very hygroscopic and the salts in bottles that have been frequently opened may contain some water. The best way to remove this is to put the salt in a thin layer on the bottom of a relatively big

16

2.

PURIFICATION OF SOLVENTS AND REAGENTS

round-bottomed flask and to heat this for at least 1 h in a bath at 150–180 C under a low pressure, preferably less than 1 Torr. The salts should be stored in a bottle or flask closed with a rubber stopper. Magnesium bromide–Et2O is readily obtained by adding 1,2-dibromoethane to a mixture of magnesium (slight excess) and refluxing diethyl ether. Sodium t-butoxide and potassium t-butoxide, both uncomplexed bases, are commercially available. The reagents are used in isomerisation, metallation and elimination reactions. It is not easy to remove the alcohol from the 1:1 complexes obtained by dissolving the metals in t-butyl alcohol. The uncomplexed reagents are soluble in THF and DMSO. Potassium t-pentyloxide dissolves also in pentane and hexane. A good quality of the commercially available reagent is maintained if stored in a bottle closed by a rubber stopper. Mixtures of palladium(II) chloride-bis(triphenylphoshane), PdCl2(PPh3)2, or tetrakis(triphenylphosphane)palladium(0), Pd(PPh3)4, and copper(I) bromide or iodide are efficient catalysts in cross-couplings involving acetylenic compounds. The complexes can be readily prepared. Pd(PPh3)4 should be stored under inert gas. After long periods the colour of the powder, originally yellow, can become dark brown. However, the catalytic activity is maintained. The usual procedure for making commercial anhydrous zinc chloride water-free consists of heating (with swirling) the salt (50 g) in an evacuated (< 1 Torr) round-bottomed flask until practically all solid has melted [7]. This procedure may be repeated a few times. After cooling, the salt may be dissolved in Et2O.

2.3 2.3.1

EXPERIMENTAL SECTION

Alkali amides in liquid ammonia

Scale: 0.40 molar; Apparatus: Figure 1.3, 1 litre 2.3.1.1

Procedure for LiNH2

In the flask is placed 400 ml of anhydrous liquid ammonia. Iron(III) nitrate ( 100 mg, the hydrate may be used, Note 1) is added. After formation of a uniformly brown solution 0.2 g of lithium is introduced in a few small pieces. The outlets are removed so that some air can enter (Note 2). After a few min a dark-grey suspension has formed. A stopper and a powder funnel are placed on the necks and 0.40 mol of lithium minus 0.2 g, cut in pieces of

2.3

EXPERIMENTAL SECTION

17

0.1 g above the powder funnel, is introduced in three equal portions (Note 3). After addition of the last portion the powder funnel is replaced again with the outlet. When all lithium has converted, a rather thick white suspension has formed. Notes 1.

2.

3.

If much more ferric nitrate is added, problems may arise during the aqueous work-up in further syntheses. Under the influence of oxygen the zerovalent iron is converted into a gel of Fe(OH)3 making separation of the layers difficult. In the absence of air (especially when nitrogen is introduced) the conversion into zerovalent iron, the actual catalyst, may proceed very sluggishly during this initial stage. It may be more effective to introduce air during a few seconds. Also for the preparation of sodamide some air appears to be necessary, but in the case of potassium it is not necessary to introduce air. If all lithium is cut in at once, serious frothing may occur. In the preparation of the other alkali amides, which form a less thick suspension (NaNH2) or solution (KNH2), the metals can be introduced very quickly after the initial generation of zerovalent iron.

2.3.1.2 Procedure for NaNH2 and KNH2 After the generation of the catalyst from 100 mg of iron nitrate and 1 g of alkali metal as described above (introduction of air is not necessary in the case of potassium) the cleaned metal (0.40 mol minus 1 g, Note 1) is introduced in 1-g pieces. The conversion into the alkali amides is usually ready within half an hour (Note 2). Sodium amide appears as a white, rather coarse suspension in a greyish-black solution (colloidal iron), potassium amide is completely soluble (greyish-black solution). Notes 1.

2.

The crust of oxide is first removed, in the case of potassium preferably under paraffin oil or high-boiling petroleum ether. The cleaned lumps are dipped into a volatile petroleum ether fraction in order to remove the non-volatile protecting liquid. Subsequently, the required amount of metal is weighed, cut into 1-g-pieces, which in the case of potassium are immediately introduced into a beaker containing a sufficient amount of a dry volatile liquid. In spite of thoroughly removing the oxide crusts minute particles of potassium surrounded by oxide and protecting oil remain present. These are not

18

2.

PURIFICATION OF SOLVENTS AND REAGENTS

converted into the alkali amide and may cause a fire during the aqueous work-up and extraction with Et2O of the product from a further synthesis. It is therefore necessary to remove these particles. This has to be done by cooling the solution of potassium amide to below 50 C followed by quick filtration through a small plug of glass wool kept in a funnel by means of a glass rod. This simple operation, taking only about 3 min, may result in some loss of potassium amide. This should be compensated for by using 0.5 g excess of potassium. Warning: One should never try to dissolve remnants or small particles of potassium by adding ethanol to the solvents used for cleaning and protection of potassium as this may cause fire. Paraffin oil or high-boiling petroleum should be returned into the storing bottle, volatile cleaning and protecting solvents are best poured outside (never in the waste container!). If tissues are used for removal of paraffin oil, these should never be directly thrown into the waste container since small particles of metal may adhere to the tissue. The safest way of disposal consists of burning it down outside. 2.3.2

Lithium diisopropylamide

A solution of 0.05 mol of lithium diisopropyl amide, LiN(i-Pr)2, in 40 ml of THF or Et2O and 32 ml of hexane may be obtained by adding a solution of 0.05 mol of n-BuLi in 32 ml of hexane to a mixture of 0.05 mol of diisopropyl amine and 40 ml of THF or Et2O, cooled at 40 C. External cooling is not necessary and the BuLi can be added within a few seconds. Inverse-order addition is also possible. Other secondary amines react under similar conditions. The lithiations are extremely fast. 2.3.3

n-BuLi TMEDA in hexane

A solution of n-BuLi TMEDA in hexane is obtained by adding 0.05 mol of TMEDA to a solution of 0.05 mol of BuLi in 32 ml of hexane. External cooling is not necessary. 2.3.4

n-BuLi–t-BuOK in tetrahydrofuran

A solution of the n-BuLi–t-BuOK reagent (0.05 mol) in 32 ml of hexane and 40 ml of THF may be obtained by adding 0.05 mol of BuLi–hexane solution over a few min to a solution of 0.05 mol of t-BuOK in the THF. During this mixing the temperature has to be kept between 100 and

2.3

EXPERIMENTAL SECTION

19

85 C in order to avoid attack of the THF by the strongly basic complex. As the solution of t-BuOK in THF is rather viscous at very low temperatures, the mixing is less efficient. It is therefore more convenient to add the solution of t-BuOK to the BuLi solution, likewise with strong cooling. The obtained solution of the complex should be used without delay. 2.3.5

n-Butyllithium in hexane

Scale: 0.20 molar; Apparatus: 250-ml round-bottomed two-necked flask, equipped with a thermometer and an outlet connected to a balloon filled with argon (Note 1). Instead of the balloon a relatively big flask filled with argon may be used. Stirring is carried out magnetically. 2.3.5.1 Procedure In the flask is placed 100 ml of carefully dried and distilled hexane. A rod of lithium (4 g, containing 0.5–1% of sodium) is flattened with a clean hammer on a clean surface to a thickness of 1 mm, after which the metal is immediately cut into small pieces ( 4 3 1 mm). These are at the same time introduced into the flask through a powder funnel. Carefully dried and distilled BuCl (0.25 mol, Note 2) is added, after which the air in the flask is replaced by argon (temporary vigorous flow). Stirring is started and after a few minute the solution becomes turbid while the temperature rises slowly. The reaction mixture is kept closely around 30 C by occasional cooling. After about 2 h the heating effect has become very weak and cooling is no longer necessary. After an additional 2 h the greyish-black suspension is transferred into a 250-ml bottle (filled with argon) with a graduated scale (a syringe may be used). The excess of lithium (Note 3) and some salt are rinsed twice with small portions of hexane. Using these solutions, the volume of the BuLi solution is brought to 125 ml. Usually this solution appears to contain 0.20 mol of BuLi.

Notes 1. 2. 3.

Under nitrogen the conversion into BuLi proceeds sluggishly, possibly due to covering of the metal by nitride. The ‘yield’ of BuLi is at least 80%. Using an excess of 0.05 mol of BuCl 0.20 mol of BuLi is obtained. This lithium is very active and has to be disposed immediately by adding 100 ml of methanol.

20 2.3.6

2.

PURIFICATION OF SOLVENTS AND REAGENTS

n-Butyllithium lithium bromide in diethyl ether

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml; instead of continuously introducing inert gas, the outlet may be connected with a balloon or relatively big flask filled with inert gas. 2.3.6.1

Procedure

Dry Et2O (200 ml) is placed in the flask. Lithium (4 g, excess), treated as described in the preceding experiment, is added, after which the flask is equipped as shown in Figure 1.1. After replacing the air in the flask by inert gas (temporary vigorous flow, with stirring) the inlet is closed and the outlet connected with the supply of inert gas. The slowly stirred mixture is cooled to 20 C and a few grams of the 0.20 mol of butyl bromide are added. After about 10 min the Et2O becomes turbid and heat is evolved. The remaining butyl bromide is added over 30 min while keeping the temperature of the reaction mixture between 10 and 20 C. After an additional 30 min the cooling bath is removed and stirring is continued for half an hour. The gloss on the pieces of lithium, originally present, gradually disappears. It is not necessary to remove the excess of lithium as the required amount of the reagent can be withdrawn by syringe. After placing well-greased stoppers on the flask it is stored at 20 to 30 C. The strength of the solution (determined by titration [5]) then remains unchanged during at least one week. The ‘yield’ is at least 85%. For disposal of the excess of lithium see preceding experiment. If part of the solution is needed, the flask is kept in a water bath at rt prior to opening. Ethyl- and methyllithium can be prepared in a similar way from the corresponding bromides. Methyl bromide (bp 6 C) is added portionwise as a cold (5 C) solution in Et2O (0.20 mol in 30 ml). Methyllithium lithium iodide can be prepared in a high yield from methyl iodide and lithium at 5 to 10 C.

2.3.7

n-Butylmagnesium chloride in diethyl ether

Scale: 0.40 molar; Apparatus: Figure 1.1, 500 ml; after the reaction has started, the thermometer is replaced with a reflux condenser. 2.3.7.1

Procedure

The flask is charged with 100 ml of dry Et2O and 15 g (excess) of dry magnesium turnings (see Section 2.2, Grignard reagents). After replacing the air in the

2.3

EXPERIMENTAL SECTION

21

flask by inert gas, 2 ml of 1,2-dibromoethane is added. After a few minutes a vigorous reaction starts and some cooling is applied to prevent the ether from refluxing. When the evolution of heat has stopped, 5 g of carefully purified n-butyl chloride (see Section 2.2) is added. As a rule the reaction starts slowly (continuous observation of the temperature and some patience are necessary). When it has become clear that the reaction has started (the temperature has risen to 35 C), the thermometer is replaced with a reflux condenser. After the (gentle) reflux has stopped, a mixture of 200 ml of Et2O and the remaining amount (0.40 mol minus 5 g) of n-butyl chloride is added at a rate (over 1 h) such that a gentle reflux is maintained. The conversion is brought to completion by refluxing for an additional 1 h. The resulting greyish solution is transferred (under a blanket of inert gas) into a storing flask with a graduated scale and the excess of magnesium is rinsed with two small portions of Et2O. The ‘yield’ as derived from reactions carried out with the reagent is at least 90%. t-BuMgCl, c-HexylMgCl and c-PentylMgCl in Et2O are prepared as described for n-BuMgCl. ‘Yields’ are somewhat lower. 2.3.8

t-Butylmagnesium chloride in tetrahydrofuran

Scale: 0.40 molar; Apparatus: Figure 1.1, 500 ml 2.3.8.1 Procedure Amounts of t-butyl chloride, magnesium, dibromoethane and the solvent (THF) are the same as described for n-butylmagnesium chloride. After the activation of the magnesium with 1,2-dibromoethane (the temperature may rise to 50 C or higher, while ethene is evolved), the reaction mixture is warmed to 55 C and 5 g of t-butyl chloride is added. If this addition results in a temperature increase to above 60 C, the remainder of the 0.40 mol of the chloride, dissolved in 200 ml of THF, is added at a rate such that the temperature of the reaction mixture is maintained between 55 and 60 C. After an additional period of 1 h (heating at 55 C) the conversion is considered to be complete and the greyish solution is transferred into a storing flask as described for n-butylmagnesium chloride. The maximal ‘yield’ is 70% or somewhat higher. 2.3.9

Allenylmagnesium bromide in diethyl ether

22

2.

PURIFICATION OF SOLVENTS AND REAGENTS

Scale: 0.50 molar; Apparatus: Figure 1.1, 500 ml 2.3.9.1

Procedure

Magnesium turnings (0.6 mol, excess) and dry Et2O (250 ml) are placed in the flask. After replacing the air in the flask by inert gas, 0.7 g of mercury(II) chloride (Note 1) is added and the mixture is stirred for 30 min at rt. After cooling to 0–2 C in a bath with ice and ice water, 4 ml of freshly distilled propargyl bromide (Chapter 20, exp. 20.1.1) is added. The reaction usually starts after about 15 min as evidenced by a distinct rise of the temperature by several degrees in spite of cooling in the bath. If necessary, the mixture is cooled for a few seconds to bring the temperature below 10 C. The remainder of the propargyl bromide (0.50 mol minus 4 ml) is added over 1 h. After an additional 45 min (at 5 C) the grey solution is decanted from the excess of magnesium (Note 2) under a blanket of inert gas or withdrawn by syringe. The solution contains 0.40 mol of the Grignard reagent and can be stored for several days at 20 C.

Notes 1.

Attempts to prepare the reagent under the usual conditions give rise to undesired side reactions such as the formation of 1,2,4,5-hexatetraene, H2C¼C¼CHCH¼C¼CH2, and 1,2-hexadien-5-yne, HCCCH2CH¼C¼ CH2 (cf. [9]). 2. This magnesium is strongly activated and should be disposed by addition of an aqueous solution of ammonium chloride.

2.3.10

Magnesium bromide-etherate

A mixture of 120 ml of dry Et2O and 0.25 mol of magnesium turnings is placed in a pre-weighed 500-ml, one-necked round-bottomed flask, which is provided with a magnetic stirring bar and a reflux condenser. 1,2-Dibromoethane (0.20 mol) is added portionwise over 30 min through the reflux condenser. When the intensity of the reflux has subsided, the flask is placed in a heating bath and refluxing is continued for half an hour. A two-layer system consisting of a small, almost colourless upper layer and a dark-grey, oil-like under layer has formed. Et2O is removed by evacuation until the upper layer has decreased to a few mm only. If 0.10 mol is needed, the two-layer system is homogenised by shaking and about half of the contents (weight decrease) is used. The complex should be stored at rt. The stopper on the flask should be regularly greased.

REFERENCES 2.3.11

2.3.11.1

23

Palladium(II) chloride bis(triphenylphosphane), PdCl2(PPh3)2 Procedure

A stirred mixture of 20 mmol of finely powdered PdCl2, 4 g of anhydrous LiCl and 150 ml of methanol is heated at 60 C until the brown solid has dissolved ( 15 min). Subsequently, a solution of 50 mmol (excess) of triphenylphosphane in 25 ml of THF (50 C) is added in one portion. After stirring for 1–2 h at 50 C, the brown colour has disappeared completely. The yellow suspension is cooled to rt, then the solid is filtered off on a sinteredglass funnel, rinsed twice with 30-ml portions of methanol and once with Et2O. The powder is dried in a vacuum. The yield is at least 90%.

2.3.12

2.3.12.1

Tetrakis(triphenylphosphane)palladium(0), Pd(PPh3)4 Procedure (cf. [10])

Finely powdered PdCl2 (20 mmol) and triphenylphosphane (100 mmol) are dissolved in 240 ml of DMSO with heating and stirring. When at 140 C all PdCl2 has dissolved, heating is stopped and 4.1 g of hydrazine hydrate is added over 1 min by syringe. The colour of the solution becomes darker and nitrogen is evolved. One minute after this addition the flask is cooled in a water bath until the solution becomes turbid. Stirring is continued for 20 min without cooling, after which the suspension is brought to rt. The yellow solid is filtered off on a sinteredglass funnel and successively rinsed three times with 35-ml portions of ethanol and twice with 40-ml portions of Et2O. The powder is dried in a vacuum (the last traces of solvent are removed in a high vacuum with warming in a bath at 45 C). The yield is 95%.

REFERENCES 1. D. Seebach and T. Mukhopadhyay, Helv. Chim. Acta 65, 385 (1982). 2. J. A. P. Thyman, Synth. Commun. 5, 21 (1975). 3. L. Brandsma and H. D. Verkruijsse, Preparative Polar Organometallic Chemistry. SpringerVerlag, Heidelberg, 1987, Vol. 1, p. 11–17. 4. H. E. Jung and R. B. Blum, Tetrahedron Lett., 3791 (1977). 5. A. I. Vogel, Textbook of Practical Organic Chemistry. Longmans, London, 1991, 5th edn., p. 531. 6. B. J. Wakefield, Organomagnesium Methods in Organic Synthesis. Ac. Press, London, 1995.

24 7. 8. 9. 10. 11. 12. 13.

2.

PURIFICATION OF SOLVENTS AND REAGENTS

S. Danishefsky, T. Kitahara and P. F. Schuda, Org. Synth., Coll. Vol. 7, 313 (1990). A. I. Vogel, Textbook of Practical Organic Chemistry. 4th edn., p. 326, 1978. H. Hopf, Angew. Chem. 82, 703, Int. edn., 732 (1970). D. R. Coulson, Inorg. Synthesis 13, 121 (1972). S. Hoff, L. Brandsma and J. F. Arens, Recl. Trav. Chim. Pays-Bas 87, 916 (1968). J. J. van Daalen, A. Kraak and J. F. Arens, Recl. Trav. Chim. Pays-Bas 80, 810 (1961). L. Brandsma, H. E. Wijers and J. F. Arens, Recl. Trav. Chim. Pays-Bas 82, 1040 (1963).

3 Generation of Metallated Acetylenes, Allenes and Cumulenes*

3.1

DEPROTONATION OF ACETYLENES WITH A TERMINAL TRIPLE BOND

The preparation of many acetylenic compounds proceeds via metallated acetylenes, MCCR (M ¼ Li, Na, K or MgX), generated by abstraction of the ethynyl proton with a strong base or a Grignard reagent, usually EtMgBr. The most frequently applied bases are alkali amides in liquid ammonia or alkyllithium in diethyl ether or tetrahydrofuran (THF). The use of lithium dialkylamides is relevant if in the ethynyl compound atoms or groups are present that are sensitive to alkyllithium, for example in propargyl bromide, HCCCH2Br [1]. This compound undergoes Li/Br exchange upon treatment with butyllithium. Other useful applications of lithium dialkylamides are described in Refs. 2–5.

Since the bases used for the metallations are much stronger (in a thermodynamic sense) than the acetylides, the deprotonations are essentially complete, a condition which has to be met for most functionalisation reactions. Some ethynylations are an exception. A number of acetylenic tertiary alcohols can be obtained with excellent yields by adding a ketone to a suspension of potassium *This Chapter is restricted to reactions affording metallated compounds. Procedures involving their hydrolysis or protolysis are included. Functionalisation reactions are treated in the Chapters 4–9.

25

26

3.

GENERATION OF METALLATED ACETYLENES. . .

acetylide (or even KOH) in THF while introducing acetylene. The formation of potassium acetylide is likely to be an equilibrium (see Chapter 5) [6]. The metallations with the various basic reagents are extremely fast, even at temperatures in the region of –80 C. Deprotonations with the kinetically less strongly basic Grignard reagents, however, do not proceed instantly. The complete grignardation of 1-hexyne with ethylmagnesium bromide in Et2O at reflux temperature takes at least one hour, in THF at least 15 min (at concentrations between 0.5 and 1 mol/litre). 1,3-Diynes, HCCCCR and heterosubstituted acetylenes HCCX (X¼OR, SR, SiR3) react more smoothly with Grignard reagents [7]. The monolithiation of acetylene requires special conditions. During introduction of acetylene at room temperature into a solution of butyllithium in THF or Et2O a fine suspension of dilithium acetylide, LiCCLi, is formed immediately and irreversibly. Ammonia and other amines, for example 1,2-ethanediamine [8], H2N(CH2)2NH2, or TMEDA [7], and to a lesser extent lithium bromide [9], stabilise the monolithium compound. Thus, introduction of acetylene into a strongly cooled solution of the BuLi TMEDA complex in a THF/hexane mixture gives a clear solution giving excellent results in the reaction with aldehydes (for a variant using no stabilising agent, cf. [10]). The Organic Syntheses procedures [11] for the preparation of ethynylmagnesium bromide, HCCMgBr, in THF require careful experimentation. A solution of alkylmagnesium bromide in THF is slowly added to a solution of acetylene in THF, which is kept saturated with acetylene by continuous introduction of this gas. To prevent (suspected) disproportionation of HCCMgBr into BrMgCCMgBr and acetylene, the temperature is carefully kept below 30 C. A more simple procedure consists of quick introduction of acetylene into a not too concentrated solution of ethylmagnesium bromide with cooling below 20 C. Subsequent reaction with chloro(trimethyl)silane and chloro(tributyl)stannane gives the corresponding silyl- and stannylacetylenes in excellent yields [12]. Suspensions of BrMgCCMgBr and LiCCLi are obtained by simply introducing acetylene into a solution of EtMgBr in THF above 40 C and BuLi in Et2O above 0 C, respectively. Solutions of LiCCH and NaCCH in liquid ammonia can be quickly prepared by introduction of acetylene into the suspensions of the alkali amides, preferably in the presence of a small amount of triphenylmethane. The pink colour of the triphenylmethane anion disappears after a small excess of acetylene has been introduced. The solutions of the alkali acetylides are also conveniently prepared by the so-called titration method, which involves controlled addition of pieces of metal to boiling ammonia while introducing acetylene, the blue colour of the dissolved metal serving as an indicator. It is assumed from the results of derivatisation reactions that mainly mono-alkali

3.2

SIDE REACTIONS

27

acetylide is formed. This method is also applicable in the case of homologues, but is less attractive for economical reasons as one-third of the acetylene is reduced to the alkene. Alkali acetylide has also been prepared from acetylene and a Na/K alloy at the low-melting eutectic in inert solvents at elevated temperatures [13,14]. Summarising, the following methods are available for the preparation of mono-metallated and di-metallated ethyne. 1. 2. 3. 4. 5. 6. 7. 8.

Li or Na in liquid ammonia LiNH2 or NaNH2 in liquid ammonia BuLi in THF at low temperature BuLi/TMEDA in THF at low temperature EtMgBr in THF at <20 C BuLi in THF or Et2O at room temperature, gives LiCCLi EtMgBr in THF at >40 C, gives BrMgCCMgBr Na dispersion in an inert solvent

3.2

SIDE REACTIONS

The heterosubstituted acetylenes ethynyl(trialkyl)silanes, HCCSiR3, and ethynyl(trialkyl)stannanes, HCCSnR3, cannot be metallated with alkali amides in liquid ammonia because the bonds between C and Si and between C and Sn are cleaved [7]. Ethynyl alkyl selenides, HCCSeR, and ethynyl (dialkyl)phosphanes, HCCPR2, undergo disproportionation into HCCH and bis(alkylseleno)acetylenes, RSeCCSeR, or bis(dialkylphosphino)acetylenes, R2PCCPR2, respectively, under the influence of alkali amides [15,16]. Metallation with BuLi or MeLi presumably will give satisfactory results, provided that inverse-order addition is applied. The metallation of 3,1-enynes and 1,3-diynes with butyllithium requires careful experimentation, because dilithiation, and, in the case of the enynes, formation of dimers occurs when the base is present in excess [7,17]. Therefore, inverse-order addition has to be carried out.

28

3.

GENERATION OF METALLATED ACETYLENES. . .

With the less strongly basic alkali amides in liquid ammonia, and, presumably also with lithium dialkylamides in organic solvents, these complications do not occur. Vinylacetylene, HCCCH¼CH2, undergoes a fast oligomerisation when treated with a slight excess of butyllithium [7]:

Treatment of ‘skipped’ enynes, HCCCH2CH¼CHR, with alkali amides, MNH2, presumably will lead to extensive isomerisation giving MCCCH¼ CHCH2R. Similar complications arise with propargylic sulphides, HCCCH2SR, and propargylbenzene, HCCCH2Ph [7]. If alkyllithium bases are used, dimetallation can be avoided by applying inverse-order addition technique. This reaction is likely to be even more serious in the case of the 1,4-diynes, HCCCH2CCR, since the CH2-protons have kinetic acidities comparable with that of the ethynyl proton. 3.3

IN SITU GENERATION OF METALLATED ACETYLENES AND CUMULENES BY ELIMINATION REACTIONS

Generation of a metallated acetylene or cumulene by elimination of hydrogen halide or other molecules from a suitable precursor and excess of a strongly basic reagent may be preferred to isolating first the free acetylene or cumulene and subsequently metallating it with the strong base. Table 3.1 gives a number of examples from the author’s group. Other examples of eliminations, affording metallated enynes, are the following [21,89]:

3.3

GENERATION OF METALLATED ACETYLENES

29

Table 3.1 Generation of metallated acetylenes and cumulenes by 1,2- and 1,4-elimination reactions Substrate

BrCH2CH(Br)Alkyl BrCH2CH(Br)SAlkyl BrCH2CH(Br)CH(OEt)2 BrCH2CH(Br)(CH2)8COOH [BrCH2CH(Br)CH2]2 BrCH2CH(Br)-2-thienyl BrCH2CH(Br)-2-pyridyl BrCH¼CHOEt ClCH2-2-furfuryl ClCH2CCCH2Cl ClCH2CCCH2Cl (E)-ClCH2CH¼CHCH2Cl EtOCH2CCCH2OEt EtOCH2CCCH2OEt EtOCH2CCCH(OEt)2 Me2C(OMe)CCCH2OMe Me2C(OMe)CCCH2NMe2 EtSCH¼CHCCCH2NEt2 EtSCH¼CHCCAlky1 H2C¼C¼C(OMe)CH(R)OEt EtSCH¼CHCH¼CH(Het)Ar ClCH2CH(OMe)2 or (OEt)2 Cl2CHCH2-c-Alkyl Cl2CHCH2-t-Bu Cl2CHCH2-i-Pr

Metallation conditions

3 3 3 4 4 3 3 2 3 3 4 3 3 2 2 2 2 2 2 2 2 3 3 3 3

Li- or NaNH2/liq. NH3 NaNH2/1iq. NH3 NaNH2/1iq. NH3 NaNH2/1iq. NH3 NaNH2/liq. NH3 NaNH2/liq. NH3 NaNH2/liq. NH3 Li- or NaNH2/liq. NH3 NaNH2/liq. NH3 NaNH2/liq. NH3 NaNH2/liq. NH3 NaNH2/liq. NH3 NaNH2/liq. NH3 EtLi/Et2O, low temp. EtLi/Et2O, low temp. BuLi/Et2O, low temp. BuLi/THF, low temp. NaNH2/liq. NH3 NaNH2/liq. NH3 NaNH2/liq. NH3 NaNH2/liq. NH3 NaNH2/liq. NH3 NaNH2/liq. NH3 NaNH2/1iq. NH3 NaNH2/1iq. NH3

Product Li- or NaCCAlkyl NaCCSAlkyl NaCCCH(OEt)2 NaCC(CH2)8COONa NaCC(CH2)2CCNa NaCC-2-thienyl NaCC-2-pyridyl LiCCOEt NaCC(CH2)3ONa NaCCCCH NaCCCCNa NaCCCH¼CH2 NaCCCH¼CHOEt H2C¼C¼C¼C(Li)OEt EtOCH¼C¼C¼C(Li)OEt Me2C¼C¼C¼C(Li)OMe Me2C¼C¼C¼C(Li)NMe2 NaCCCCCH2NEt2 NaCCCCAlkyl NaCCC(OMe)¼CHR NaCCCH¼CH(Het)Aryl NaCCOMe (or -OEt) NaCC-c-Alkyl NaCC-t-Bu NaCC-i-Pr

Refs., notes

21 a b

89 53 53 53 18 7 19 88 20 c d d d

a

Moderate to fair yields of the acetylenes, after hydrolysis. Both geometrical isomers are converted into lithium ethoxyacetylide [21]. c Yields of the ethynylethers obtained by hydrolysis fair to good. d Yields of acetylenes, after hydrolysis, moderate to fair [29]. b

It is proposed that cumulenic systems occur as intermediates in some of the diyne- or enyne-forming eliminations. Thus, reaction of 1,4-dichloro-2-butyne, ClCH2CCCH2Cl, with sodamide in liquid ammonia will give chlorobutatriene, ClCH¼C¼C¼CH2, as the first intermediate. The diyne system is formed therefrom by a second 1,4-elimination. Interaction in liquid ammonia between 1,4-diethoxy-2-butyne, EtOCH2CCCH2OEt, and sodamide may either give rise to a concerted 1,4-elimination, affording the intermediary ethoxybutatriene, H2C¼C¼C¼CHOEt, or proceed through the intermediate EtOCH(Na)CCCH2OEt or EtOCH¼C¼C(Na)CH2OEt, which loses ethanol

30

3.

GENERATION OF METALLATED ACETYLENES. . . Table 3.2 Elimination reactions from literature

Substrate

Metallation conditions

(Z )-RCCCH¼CHOMe (Z )-HCCCH¼CHOMe (Z )-BrCH¼CHOSiR3 (Z )-BrCH¼CHO-t-Bu ClCH¼CHCCR ClCH2CH(OEt)2 RC[OP(OEt)2]¼CH2 (ClCH¼CH)2S 2-(MeCC12)-4-Methiophene

2 3 2 2 2 3 2 4 3

LDA/THF, –50 , 2 h BuLi/THF LDA/THF, 0 LDA/THF, –60 ! rt NaNH2/liq. NH3 LiNEt2/THF, 0 LDA/THF NaNH2/liq. NH3 NaNH2/liq. NH3

Product

Refs., notes

LiCCCCR LiCCCCLi LiCCOSiR3 LiCCO-t-Bu NaCCCCR LiCCOEt LiCCR (NaCC)2S 2-(NaCC)-4-Methiophene

23, a 24 25, b 26 27 28 2 30 31

a

Starting compound prepared by functionalisation of (Z )-1-methoxy-1-buten-3-yne, HCCCH¼CHOMe [23,24]. On an industrial scale made by base-catalysed addition of methanol to 1,3-butadiyne; nowadays no longer commercially available or very expensive. b R is a bulky group.

with formation of the cumulenic ether. Strong evidence for this stepwise proceeding elimination is provided by the isolation, in good yields, of ethyl derivatives of the latter intermediates when the bis-ether is treated with sodamide in the presence of ethyl bromide. The conversion of the cumulenic ether into the enyne ether under the action of alkali amide has been demonstrated in separate experiments [22]. A number of other elimination reactions are summarised in Table 3.2. 3.4

1,3-DIMETALLATED ACETYLENES

Lithiated 1-alkynes can be metallated relatively smoothly in the 3-position, using an extra equivalent of butyllithium [32–37]. The efficiency of the dimetallation may be at least 90%, as can be concluded from the excellent results of the quenching reaction with Me3SiCl [32].

3.5

METALLATION OF ALLENES AND ACETYLENES

31

The dilithiation can be carried out with BuLi in Et2O or THF at temperatures varying from about –20 C for R ¼ R1S, Ph, vinyl, to þ30 C in the case of aliphatic hydrocarbons [7]. 1,3-Dimetallation of the latter compounds proceeds excellently also with BuLi TMEDA in refluxing hexane [37]. Further metallation of 1-lithiated propargylic ethers, LiCCCH2OR, has to be carried out with the superbase BuLi t-BuOK in THF [7]. The introduction of the second metal atom with this base proceeds at a sufficient rate at temperatures in the region of –50 C. This low temperature is necessary in view of the limited stability of MCCCH(M)OR. Abstraction of a proton remote from the ethynyl group is possible if this proton is sufficiently activated. Synthetically useful examples are the dimetallations of phenylacetylene [38–40], 1-naphthylacetylene [41], 1-ethynylpyrrole [42] and isopropenylacetylene (Chapter 20, Section 20.9) [43,44].

3.5

METALLATION OF ALLENES AND ACETYLENES WITH A NON-TERMINAL TRIPLE BOND

The protons in compounds with the systems –HC¼C¼C< and –CH–CC are much less acidic than the ethynyl proton in HCC– systems, unless strongly stabilising substituents, such as S¼O, are present [45]. The acidities of most allenic compounds or isomers CH–CC and those of aliphatic secondary amines, ammonia and DMSO are comparable. This means that, in general, for the generation of anionic species with a high kinetic stability alkyllithium reagents or variants are required. Thioether groups stabilise negative charge. Thus, the metallated sulphides RCH¼C¼C(M)SR1 (M ¼ Li, Na) can be generated in liquid ammonia and have a sufficient kinetic stability in this solvent for allowing successful functionalisations. The oxygen analogues undergo immediate protonation in this solvent [46]. Complete lithiation of 2-alkynyl amines and ethers, RCCCH2X (X ¼ NR12 or OR1), is only possible with alkyllithium reagents. The more weakly basic lithium dialkylamides can be used for the metallation of the sulphur analogues [47, 48]. N,N-Dialkylamino groups have a very weak stabilising effect, even weaker than ether groups. Treatment of the 2-alkynyl amines RCH2CCCH2NMe2 and RCH2CCCH2-piperidyl (R ¼ H or Alkyl) with butyllithium results in deprotonation adjacent to nitrogen. In the N,N-diethylamino compound MeCCCH2NEt2 the steric effect of the bulkier NEt2 group competes with the activating effect of this group and only the terminal methyl group is deprotonated [7]. Reaction conditions for the metallation of a number of allenes and acetylenes with a non-terminal triple bond are summarised in Table 3.3.

32 3.

Table 3.3

Allene or acetylenea

Reaction conditionsb,c

1. 2. 3. 4. 5. 6. 7. 8. 9.

H2C¼C¼CH2 (15) t-BuCH¼C¼CH2 (10) Me2C¼C¼CH2 (10) C6H13CCCH3 MeOCH¼C¼CH2 (10) AlkylS- or ArylSCH¼C¼CH2 MeSCCCH3 EtSCCCH3 EtSCCCH2Alkyl

10. 11. 12. 13. 14. 15. 16. 17.

Me2NCH¼C¼CH2 Et2NCCCH3 (10) MeOCH2CCCH2NMe2 Et2NCH2CCCH2NEt2 MeOCH2CC-n-Bu MeOCH2CCSMe MeOCH2CCPh Me2NCH2CC-n-Bu (or 1-piperidyl, 1-morpholyl)

BuLi/THF, –80 þ 15! –60 BuLi/THF, –50 þ 30! –15 þ 15 BuLi/THF, –50 þ 45! –15 þ 15 BuLi/THF, (10), 10 þ 2!25 þ 30 BuLi/THF, –70 þ 15! –30 BuLi/THF, –70 þ 2! –30 BuLi/THF, –10 þ 0!5 NaNH2/1iq. NH3, –33 þ 1 NaNH2/1iq. NH3, –33 þ 2 or BuLi t-BuOK/THF, –80! –60 þ 10 BuLi/THF, –70 þ 5! –30 BuLi t-BuOK/THF, –85 þ 5! –60 BuLi/THF, (10) –90!60 þ 20 BuLi t-BuOK/THF, –90 þ 5! –40 BuLi/THF, –70 ! –50 þ 30 BuLi/THT, –90 ! –30 BuLi/THF, –90! –60 þ 5 BuLi/THF, (10), –40 !20 þ 30, or BuLi t-BuOK/THF, –90 ! –70 þ 20

Notes d

e

f g

GENERATION OF METALLATED ACETYLENES. . .

Metallation of allenes and acetylenes with a non-terminal triple bond

a

BuLi/THF, (10), –70! –40 þ 10 BuLi/THF, (10), –20! 25 þ 30, or BuLi t-BuOK/THF, –90! –70 þ 20 BuLi/THF, –90! –70 þ 10 BuLi/THF, (10), –100 ! –70 þ 1 BuLi t-BuOK/THF, (30),–90 þ 5 BuLi/THF,–90! –75 þ 15 BuLi/THF, –100! –60 þ 10 (c-C6H11)2NLi/THF, –55

h i j k

Abstracted proton in bold. Excesses in mol% are given between parentheses. The numbers give a global impression of the conditions used by the author. Concentrations of the metallated compounds between 0.5 and 1.0 mol/litre. Numbers (x þ y!z or x þ y) refer to temperature of addition ( C) of the substrate þ period of stirring at this temperature (min) ! final temperature ( C). Meaning of x! y þ z: temperature of addition ( C) ! final temperature þ additional period (min) of stirring at this temperature. In all reactions with BuLi a mixture of about equal amounts of THF and hexane was used. c Yields of derivatisation reactions good to excellent. d The lithiation of other allenes RCH¼C¼CH2 (R ¼ Alkyl) is not completely regiospecific: in the case of R ¼ Me 15% MeC(Li)¼C¼CH2 is formed, for n-BuCH¼C¼CH2 5% nonterminal lithiation occurs [7]. e 20% Et2NCH¼C¼CH2 present in starting material. In Ref. 49, n-BuLi TMEDA is used. f With 2 equivalents of n-BuLi the dilithium compound is formed [50]. g Cf. Ref. 106. h Refs. 18 and 51. i Ref. 52. j At somewhat higher temperatures the lithium compound loses LiOEt to give 1,4-diethoxy-1,2,3-butatriene, EtOCH¼C¼C¼CHOEt [53]. k >90% g-Lithiation is reported [109]. b

METALLATION OF ALLENES AND ACETYLENES

20. 21. 22. 23. 24. 25.

Me2NCH2CCPh Et2NCH2CCCH3 (or n-Pr2N) MeOCH2CCC(Me)¼CH2 Me2NCH2CCC(Me)¼CH2 Me2NCCCH¼CH2 1-Pyrrolyl-CH¼C¼CH2 EtOCH2CCCH(OEt)2 t-BuOCH¼C¼CH2

3.5

18. 19.

33

34

3.

GENERATION OF METALLATED ACETYLENES. . .

2-Alkynoic acids, RCH2CCCOOH (R ¼ alkyl), react with an excess of sodamide in liquid ammonia to give suspensions of dimetallated carboxylic acids. Acid hydrolysis affords the isomeric 3-alkynoic acids, RC CCH2COOH, in excellent yields [54].

2-Butynoic acid, MeCCCOOH, is converted into H2C¼C¼C(Na)COONa under similar conditions. Addition of dilute mineral acid gives 2,3-butadienoic acid, H2C¼C¼CHCOOH [54]. Trimethyl(1-propynyl)silane, MeCCSiMe3, has been lithiated by treatment with BuLi/TMEDA in pentane at temperatures in the region of –20 C [55,56], but presumably a smooth lithiation is also possible with BuLi in THF at room temperature. The lithium derivative is a useful synthon [55,56].

3.6

ADDITION OF ORGANOLITHIUM COMPOUNDS AND LITHIUM ALANATE TO COMPOUNDS WITH AN ENYNE OR DIYNE SYSTEM

Organolithium compounds add to 1,3-enynes with formation of allenyllithium derivatives. The addition is particularly successful with the strongly basic alkyllithium reagents [57,58].

Several examples from Russian literature, including additions of lithium dialkylamides to enyne systems, are tabulated in the review by M. Murray in Houben-Weyl, Vol. V/2a (1977). The reduction with lithium alanate of alcohols with an enyne or diyne system, illustrated below, proceeds through transfer of hydride to the unsaturated system with formation of a lithiated intermediate [110,111].

3.7

FORMATION OF ALKALI ACETYLIDES

3.7

35

FORMATION OF ALKALI ACETYLIDES FROM ACETYLENES WITH A NON-TERMINAL TRIPLE BOND AND FROM ALLENES BY THE ACTION OF STRONG BASES

Acetylenes with a non-terminal triple bond usually are thermodynamically more stable than the isomeric 1-alkynyl derivatives. Thus, under equilibrium conditions (under the catalytic influence of t-BuOK) the 1-alkynes HCCCH2R are converted completely into 2-alkynes MeCCR. This isomerisation proceeds through the allenes H2C¼C¼CHR. The ‘contra-thermodynamic’ process can be achieved by treating the 2-alkyne or the allene with an equivalent amount of a strong base, e.g. BuLi in an aprotic organic solvent or an alkali amide in liquid ammonia, or (at elevated temperatures) in a (highboiling) aprotic solvent. In liquid ammonia the isomerisation may proceed by a sequence of deprotonation and proton donation (intramolecular proton transfer may be another possibility) the driving force being the higher kinetic stability of the acetylide anion. When the reaction is carried out with BuLi (in THF) or with alkali amide in an organic solvent (at elevated temperatures), a suchlike process seems unlikely because no proton donor is available. It has been suggested [37] that 1,3-hydride shifts allowed according to Woodward-Hoffmann are involved:

36

3.

GENERATION OF METALLATED ACETYLENES. . .

A similar mechanism might be involved when the reaction is carried out in solvents that are capable of donating a proton. A migration of the triple bond over several positions [59–62], for example in the conversion of 2-undecyn-1-ol, C8H17CCCH2OH, into KCC(CH2)9OK using KNH(CH2)3NH2 in 1,3-propanediamine [60a,61,62], might occur through a sequence of deprotonations and 1,3-hydride shifts. Useful variants are sodium hydride in 1,3-propanediamine [60b] or LiNHCH2CH2NH2 in 1,2-ethanediamine [60c,113]. Compounds containing a non-terminal enyne system, R–C¼CCC(CH2)nMe, have been converted into R(CH2)nC¼CCCH by treatment with NaNHCH2CH2NH2 in 1,2-ethanediamine [112]. Disubstituted conjugated diynes, RCCCC (CH2)nMe, give the terminal diynes, R(CH2)nþ1CCCCH, by an analogous procedure using LiNHCH2CH2NH2 in 1,2-ethanediamine [114]. The peculiar reversal of the enyne system H2C¼CHCCNEt2, resulting in the formation of KCCCH¼CHNEt2, takes place under the action of potasium amide in liquid ammonia [63]. Evidently, the first step is the abstraction of a vinylic proton with the formation of H2C¼C(K)CCNEt2 or H2C¼C¼C¼C(K)NR2. This anionic species may be subsequently converted into the end product by protonation of the butatrienyl amine and its deprotonation on the terminal carbon atom. Allenes, RCH¼C¼CH2, 2-alkynyl derivatives, MeCCR, and compounds with the enyne system, MeCCCH¼CHR, have been converted into the alkali acetylides, MCCCH2R and MCCCH¼CHCH2R, respectively by treatment with alkali amide, preferably potassium amide, in liquid ammonia or by BuLi in THF [7,21]. Table 3.4 summarises the results of a number of successful ‘contra-thermodynamic’ isomerisations, proceeding through metallated acetylenes under the influence of strongly basic reagents, obtained in the author’s laboratory. 3.8 GENERATION OF METALLATED ACETYLENES BY SUCCESSIVE DEHALOGENATIONS OR BY SUCCESSIVE DEHYDROHALOGENATION AND DEHALOGENATION Interaction between the easily accessible organyl-di- or trihalogenoalkenes and alkyllithium constitutes a very useful method for the generation of a lithium acetylide. An example is the preparation of N-lithioethynylpyrrole from N-(1,2-dichloroethenyl)pyrrole and methyllithium [64,65].

3.8

GENERATION OF METALLATED ACETYLENES

37

Table 3.4 Base-promoted ‘contrathermodynamic’ isomerisations Starting compound (E )-MeCCCH¼CH-c-C6H11 MeCCCH¼CHCH2NEt2 (E )-MeCCCH¼CHCH2OH MeCCCH2NEt2 MeCC-c-C6H11 MeCCCH¼CHAlkyl MeCCCH¼CHOAlkyl

Base

Product (after hydrolysis)

Refs., notes

2 KNH2/liq. NH3 KNH2/liq. NH3 2 KNH2/liq. NH3 KNH2/liq. NH3 KNH2/liq. NH3 KNH2/liq. NH3 KNH2/liq. NH3 KNH2/liq. NH3

HCCCH¼CHCH2-c-C6H11 HCCCH¼CH(CH2)2NEt2 HCCCH¼CH(CH2)2OH HCC(CH2)2NEt2 HCCCH2-c-C6H11 HCCCH¼CHCH2Alky1 HCCCH¼CHCH2OAlky1

Z/E 9 7, 21 Z/E 9, 21 21, a 21, b 7, 21 7, 21 7, 21

KNH2/liq. NH3 H2C¼CHCCNEt2 C8H17CCCH2OH RCH2CCSR1 H2C¼C¼CHCH2Ph H2C¼C¼CH-c-C6H11

KNH2/liq. NH3 2 KAPA NaNH2/1iq. NH3 EtLi/Et2O BuLi/THF

7, 21 HCCCHCHNEt2 HCC(CH2)9OH RCH¼C¼CHSR1 HCC(CH2)2Ph HCCCH2-c-C6H11

63 80, c 79, d 79 81

Yield 70%; N,N-diethyl-1,3-butadien-l-amine, H2C¼CHCH¼CHNEt2, was isolated as a side product in 20%. b No conversion when HMPT (50 ml on 300 ml liquid ammonia in a 0.10-molar scale experiment) is omitted. c KAPA ¼ KNH(CH2)3NH2 dissolved in 1,3-propanediamine. d R ¼ Alkyl or Ph; see also Table 3.3, entry 9. a

Table 3.5 Lithium acetylides, RCCLi, from organyl-di- or trihalogenoalkenes and alkyllithium Starting compound

Starting compound

Refs.

PhCH¼CHCH¼CC12 EtSC(Cl)¼CHCl ROC(Cl)¼CBr2 (R ¼ Alkyl) R1R2NC(Cl)¼CC12 (R1R2N ¼ Et2N, morpholino) R1C(Cl or F)¼CC12 (R1 ¼ R2NCC, R2NCCCC) RCH¼CBr2 (R ¼ C7H15, 4-cyclohexenyl, Ph) RCH¼CCl2 (R ¼ 2- or 4-methoxyphenyl) Th-2-Th-2-CH¼CBr2 (Th ¼ thienyl) R1R2NCCC(Cl)¼CCl2

PhCH¼CHCCLi EtSCCLi ROCCLi R1R2NCCLi

66 67 68 69, 70

RCCLi

71–74

RCCLi

75

RCCLi

76

Th-2-Th-2-CCLi

77

R1R2NCCCCLi

78

38

3.

GENERATION OF METALLATED ACETYLENES. . .

A number of related methods using either a 1,1-dihalogeno- or trihalogenoalkene are listed in Table 3.5.

3.9

EXPERIMENTAL SECTION

Notes 1. For the preparation of alkali amides in liquid ammonia and alkyllithium reagents see Chapter 2. 2. Most of the reactions in organic solvents or in liquid ammonia at temperatures below its boiling point are carried out under inert gas. 3.9.1

Sodium acetylide from acetylene and sodium in liquid ammonia

Scale: 0.50 molar; Apparatus: Figure 1.11, 1 litre 3.9.1.1

Procedure

Anhydrous liquid ammonia (500 ml) is placed in the flask. Acetylene, freed from acetone by passing it through two traps cooled at –78 C, is introduced at a rate of 500 ml/min. Pieces of sodium (1 g each, 0.50 mol) are cut and at the same time introduced through the powder funnel. The rate of addition is such that the solution does not become uniformly blue. After the addition of the last pieces the intensity of the flow of acetylene is decreased to about 200 ml/min. An excess of acetylene is not detrimental in most cases A solution of lithium acetylide is prepared in a similar way. A too fast introduction of acetylene may give rise to frothing: this may be suppressed by adding small amounts of Et2O or by occasionally cooling the reaction mixture to below the bp of ammonia, using a bath with liquid nitrogen. 3.9.2

Sodium acetylide from acetylene and sodamide in liquid ammonia

Scale: 0.40 molar; Apparatus: Figure 1.9, 1 litre

3.9

EXPERIMENTAL SECTION

39

3.9.2.1 Procedure To a suspension of 0.40 mol of sodamide in 400 ml of liquid ammonia (Chapter 2, exp. 2.3.1) is added 300 mg of finely powdered triphenylmethane dissolved in 2 ml of THF. A dark red solution is formed. Purified acetylene (see preceding exp.) is introduced at a rate between 0.5 and 1 litre/min until the red colour has vanished and the suspended sodamide has completely passed into solution. This takes less than 10 min. If loss of ammonia due to evaporation is undesired, the flask may be temporarily cooled in a bath with liquid nitrogen. Lithium acetylide may be prepared in a similar way. In order to suppress frothing the thick suspension may be cooled by temporarily placing the flask in a bath with liquid nitrogen 3.9.3

Alkali alkynylides from 1-alkynes and alkali amides in liquid ammonia

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml 3.9.3.1 Procedure (For scope and limitations, see Section 3.2) The acetylenic compound (0.20 mol), dissolved in 40 ml of Et2O or THF, is added over 10 min to a suspension of 0.20 mol of the alkali amide in 300 ml of liquid ammonia. In the case of very volatile acetylenes this solvent and the acetylene are pre-cooled to below –40 C. During this addition the flask is occasionally cooled (liquid nitrogen) at temperatures between –40 and –60 C while inert gas (100 ml/min) is introduced. In some cases very thick suspensions are formed (for solubilities of the alkali acetylides see Table 3.6). After a few minutes further conversions can be carried out. 3.9.4

General procedure for the lithiation of 1-alkynes with BuLi in Et2O or THF and subsequent conversion into alkynylzinc chlorides

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml

40

Table 3.6

Counter ion

HCC–

Li Li Li Li Na Na MgBr MgBr Li Li MgBr Li Li Li Na MgBr Li Li Na MgBr Li Li or Na

HCC– HCC– – CC– MeC¼C–

BuCC–

t-BuCC–

Chelating agent TMEDA NH3

LiBr

TMEDA

Solvent THF THF DMSO liq. NH3 liq. NH3 THF THF THF Et2O or THF Et2O Et2O THF THF liq. NH3 liq. NH3 THF liq. NH3 Et2O liq. NH3 Et2O or THF hexane liq. NH3

Solubility good good good good good insoluble moderate low insoluble low ‘oil’ moderate good good low good low good low good good low

GENERATION OF METALLATED ACETYLENES. . .

Acetylide

3.

Solubilites of metallated acetylenic compounds*

Et2O liq. NH3 liq. NH3 THF liq. NH3 liq. NH3 or THF liq. NH3 or THF liq. NH3 or THF Et2O Et2O Et2O Et2O Et2O liq. NH3 Et2O or THF liq. NH3

good low low low low good good good low ‘oil’ good good good good good good

EXPERIMENTAL SECTION

MeSCH2CC– ClCH2CC– BrCH2CC– LiOCH2CC– PhCC–

Li Li or Na Li Li Li Li Li Li Li MgBr Li Li Li Li Li Li or Na

3.9

c-C6H11CC– Et2NCH2CC– Me2NCC– (EtO)2CHCC EtOCC– EtSCC– MeOCH2CC–

*The qualifications are valid for ‘preparative concentrations’ (0.5 to 1.0 mol/litre). The following trends are observed: 1. The solubility of RCCM in liq. NH3 decreases with increasing length of the carbon chain in R. 2. The solubility of RCCMgBr or RCCLi in THF or Et2O increases with increasing length of the carbon chain. 3. Addition of chelating agents (TMEDA, LiBr) to RCCLi in THF, Et2O or hexane, causes dissolution of the suspension or an increase of the solubility. 4. Acetylides, RCCM, having a double or triple bond in conjugation with the terminal triple bond are more soluble in NH3 or organic solvents than acetylides, in which this conjugation is absent. 5. The solubility of RCCM decreases with increasing size of the counter ion. Most potassium acetylides are insoluble in liq. NH3 and in organic solvents.

41

42

3.

3.9.4.1

GENERATION OF METALLATED ACETYLENES. . .

Procedure

(For the scope, see Section 3.2, for solubilities of lithiated acetylenes, Table 3.6.) A solution of 0.10 mol of BuLi in 63 ml of hexane is added over a few minutes (Note 1) to a mixture of 0.105 mol (5% excess) of the alkyne and 70 ml of Et2O or THF with cooling below –30 C (Note 2). The alkynylzinc chloride is prepared by adding a solution of 0.10 mol of anhydrous zinc chloride (Chapter 2, Section 3.2) in 40 ml of THF to the solution or suspension of the lithiated acetylene, cooled at temperatures below rt. Depending upon the ratio of THF or Et2O and hexane a homogeneous solution or a two-layer system is formed. Notes 1. 2.

Instead of the dropping funnel a syringe may be used. In the case of 1-butyne and propyne it is more practical to add a slight excess of a strongly cooled solution of the alkynes in 30 ml of THF to a cold solution of BuLi in THF or Et2O and hexane.

The carbenoid LiCCCH2Cl, formed by lithiation of propargyl chloride, is very unstable. It is therefore desired to add the solution of BuLi in hexane with strong cooling (<–70 C) to a mixture of the halide and Et2O. 6-Bromo-1-hexyne, HCC(CH2)4Br, can be lithiated with excellent results by adding BuLi to a mixture of the halide and THF with cooling at –80 C. 3.9.5

Monolithium acetylide in tetrahydrofuran by reaction of acetylene with BuLi TMEDA

Scale: 0.10 molar; Apparatus: Figure 1.9, 500 ml 3.9.5.1

Procedure

Acetylene, freed from acetone (exp. 3.9.1), is introduced with vigorous stirring into a mixture of 0.10 mol of BuLi TMEDA in 63 ml of hexane (Chapter 2, exp. 2.3.2) and 70 ml of THF (Note 1). During the introduction, which is carried out at a rate of 0.5 litre/min, the temperature of the solution is kept between –50 and –70 C (liquid nitrogen). After a few minutes the evolution of heat is no longer observable (Note 2).

3.9

EXPERIMENTAL SECTION

43

Notes 1. 2.

During mixing the solution of BuLi TMEDA in hexane with THF the temperature should be kept below –10 C. An excess of acetylene is not detrimental in most reactions.

3.9.6

Lithiation of propargyl bromide and propargyl chloride

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 3.9.6.1 Lithiation of propargyl bromide A solution of 0.10 mol of LDA in 63 ml of hexane and 100 ml of Et2O (Chapter 2, exp. 2.3.2) is cooled to below –80 C. Freshly distilled propargyl bromide (0.10 mol) is added over a few minutes while keeping the temperature of the reaction mixture between –80 and –90 C. After an additional 5 min the clear solution is used for further reactions. 3.9.6.2 Lithiation of propargyl chloride A solution of 0.10 mol of BuLi in 63 ml of hexane is added dropwise to a mixture of 0.11 mol of freshly distilled propargyl chloride and 100 ml of Et2O (THF also may be used). The temperature of the clear solution is kept between –90 and –100 C. Occasional cooling in a bath with liquid nitrogen permits a very quick addition.

3.9.7

Ethynylmagnesium bromide in tetrahydrofuran

Scale: 0.30 molar; Apparatus: Figure 1.9, 1 litre

44 3.9.7.1

3.

GENERATION OF METALLATED ACETYLENES. . .

Procedure

A solution of 0.30 mol of ethylmagnesium bromide in 350 ml of THF, prepared from 0.35 mol of ethyl bromide and 0.50 mol of magnesium turnings, is transferred into the three-necked flask Figure 1.9 (the excess of magnesium is rinsed with small portions of THF). Acetylene freed from acetone (cf. exp. 3.9.1) is introduced with efficient stirring at a rate of 1 litre/min during 10 min, while keeping the temperature of the suspension between 5 and 10 C (this operation requires efficient cooling because the heating effect is rather strong). The introduction of acetylene is then continued for another 30 min at a rate of 200 ml/min, while maintaining the temperature at 15 C. After this period the rate of stirring is diminished and the suspension is stirred for an additional 1 h without external cooling with slow (50 ml/min) introduction of acetylene. Introduction of acetylene in the beginning at 20–25 C into a more concentrated solution of the Grignard reagent may result in the formation of a gelatinous suspension of BrMgCCMgBr.

3.9.8

Acetylene-1,2-bis(magnesium bromide) in tetrahydrofuran

Scale: 0.30 molar (EtMgBr); Apparatus: Figure 1.9, 1 litre 3.9.8.1

Procedure

A solution of 0.30 mol of ethylmagnesium bromide in 400 ml of THF (prepared from 0.35 mol of ethyl bromide and excess of magnesium) is heated to 50 C. Acetylene (freed from acetone, cf. exp. 3.9.1) is introduced at a rate of 300 ml/min (a flow meter may be used) with vigorous stirring, while keeping the temperature of the gelatinous suspension between 50 and 55 C. Introduction of acetylene is stopped when the temperature has dropped to between 40 and 45 C (without external cooling). In order to remove most of the excess acetylene the suspension is warmed for an additional 30 min at 50 C with introduction of nitrogen (200 ml/min).

3.9.9

Alkynylmagnesium bromides in diethyl ether

3.9

EXPERIMENTAL SECTION

45

Scale: 0.30 molar; Apparatus: Figure 1.1, 500 ml, the thermometer-outlet combination is replaced with a reflux condenser; the reaction is carried out under an inert gas environment. 3.9.9.1 Procedure The acetylene (0.35 mol, excess, Note) is added over 45 min to a solution of 0.30 mol of ethylmagnesium bromide in 300 ml of Et2O, kept under gentle reflux. The metallation of more strongly acidic alkynes (HCCCCR, HCCAryl, HCCSiMe3, HCCOR, HCCSR) is ready after half an hour, in the other cases, refluxing is continued for 2 h. Note Gaseous acetylenes (propyne, 1-butyne, vinylacetylene), partly swept along with the escaping ethane, have to be collected in a cold trap connected to the reflux condenser. The condensed vapour has to be reintroduced into the reaction mixture. It is more simple, however, to lithiate the acetylenes first with BuLi and subsequently add (at rt) an equivalent amount of magnesium bromide in Et2O (cf. exp. 3.9.4) prepared from 1,2-dibromoethane and magnesium in refluxing Et2O (Chapter 2, exp. 2.3.9). 3.9.10

Alkynylmagnesium bromides in tetrahydrofuran

Scale: 0.20 molar; Apparatus: Figure 1.1, 250 ml Grignardations of acetylenes in THF proceed more smoothly than in Et2O making the use of a reflux condenser unnecessary in most cases. 3.9.10.1

Procedure

Acidic acetylenes (HCCCCR, HCCOR, HCCSR, HCCSiMe3, HCC-aryl, 0.21 mol) are added over 20 min to a solution of 0.20 mol of EtMgBr in 150 ml of THF while maintaining the temperature of the reaction mixture between 0 and 10 C. After stirring the solution for an additional 15 min at rt, further conversions can be carried out. Other, non-volatile acetylenes (bp >60 C, 0.22 mol) are added over 15 min, after which the solution is heated for 1 h at 50 C. Volatile acetylenes (bp <60 C, 0.22 mol) are added over 30 min at 50 C, the outlet being connected to a cold trap in which part of the acetylene is swept along with the ethane condenses. The contents of the trap are returned to the reaction mixture, after which heating is continued for 15 min.

46

3.

GENERATION OF METALLATED ACETYLENES. . .

In the case of gaseous acetylenes the procedure of introduction of the acetylene, condensing the part swept along with ethane in a cold trap and repeating these operations, is rather laborious and requires continuous attention. The procedure of lithiation with BuLi and subsequent exchange with a solution of the magnesium bromide Et2O complex is more simple (cf. exp. 3.9.4).

3.9.11

1,3-Dilithiation of acetylenes with a terminal triple bond using BuLi in tetrahydrofuran

Scale: 0.05 molar (1-alkyne); Apparatus: Figure 1.1, 250 ml, a syringe is used instead of the dropping funnel.

3.9.11.1

Procedure

A solution of x mol (Note) of BuLi in 63, 75 or 81 ml of hexane is placed in the flask. THF (75 ml) is added with cooling below 0 C. The solution is cooled to –40 C and a mixture of 0.05 mol of propyne, 1-butyne or a higher homologue, benzylacetylene or methyl propargyl sulphide and 25 ml of THF (in the case of propyne and butyne cooled to –30 C) is added dropwise or in portions over 10 min, while keeping the temperature of the reaction mixture below –30 C. After the addition, the cooling bath is removed. In the case of methyl propargyl sulphide the still cold, brown solution can be used after 5–10 min for further reactions. The dilithiation of propargylbenzene is complete (brown solution) when the temperature has reached 10 C. The dilithiations of propyne (white suspension) and butyne (yellow suspension) are completed by heating for an additional 1 to 1.5 h at 35 C, for the higher homologues (brown solutions) the additional period of heating at 35 C is 3 h. x ¼ 0.10 for HCCCH2Ph and HCCCH2SMe x ¼ 0.12 for propyne and 1-butyne and 0.13 for the higher homologues (Note)

Note The excess of BuLi compensate for the loss due to its competitive reaction with THF. Any BuLi remaining after completion of the metallations reacts with THF with formation of ethene and H2C¼CHOLi, which will not interfere in further synthetic operations.

3.9

EXPERIMENTAL SECTION

3.9.12

47

1,3-Dilithiation of 1-alkynes with BuLi TMEDA in hexane

Scale: 0.05 molar; Apparatus: Figure 1.1, 250 ml, the addition is carried out by syringe, a reflux condenser is used instead of the thermometer outlet combination; the top of the condenser is connected to a washing bottle filled with hexane. 3.9.12.1

Procedure

The 1-alkyne (0.05 mol, R>Et) is added over a few minutes to a solution of 0.11 mol (slight excess) of BuLi TMEDA (Chapter 2, exp. 2.3.3) in 69 ml of hexane without external cooling. The yellow solution is heated under gentle reflux for 3 h. The evolution of butane has then stopped (occasional sucking back of the hexane in the washing bottle). Addition of an excess of chloro (trimethyl)silane after mixing the brown solution with 50 ml of THF gives the bis-silylated acetylene in an excellent yield. 3.9.13

1,3-Dimetallation of methyl propargyl ether

Scale: 0.05 molar (HCCCH2OMe); Apparatus: Figure 1.1, 500 ml 3.9.13.1

Procedure

(Note) A solution of 0.11 mol of BuLi in 69 ml of hexane is cooled to between –90 and –100 C. THF (35 ml) is added and subsequently, over 5 min, a solution of 0.11 mol of t-BuOK in 45 ml of THF, while keeping the temperature between –90 and –100 C by occasional cooling in liquid nitrogen. Methyl propargyl ether (0.05 mol) is added over 10 min with cooling at –80 C, then the temperature is allowed to rise to –45 C over 30 min. After stirring at a low rate for an additional 1 h, at –45 C (cooling in a bath with dry ice and acetone) the brown solution can be used for further conversions. Note Attempts to dilithiate propargylic ethers using the procedures 3.9.11 and 3.9.12 gave unsatisfactory results due to the instability of the dilithium compounds.

48

3.

GENERATION OF METALLATED ACETYLENES. . .

The isolation of 4,4-dimethyl-1-pentyn-3-ol, HCCCH(t-Bu)OH, after aqueous work-up of the reaction mixture from 3-(tert-butoxy)-1-propyne, HCCCH2O–t-Bu, and BuLi suggests the occurrence of a Wittig rearrangement. At temperatures below –20 C the dilithiation is too sluggish. Using the super basic combination of BuLi and t-BuOK dipotassiation can be readily achieved. Replacement of potassium by lithium (if desired) is possible by addition of anhydrous lithium bromide. 3.9.14

Lithiation of propadiene (Table 3.3, entry 1)

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 3.9.14.1

Procedure

A cold (<–40 C) mixture of 0.12 mol of propadiene (Chapter 10, exp. 10.2.15) and 40 ml of THF is added over a few minutes to a solution of 0.10 mol of BuLi in 63 ml of hexane and 40 ml of THF. The temperature of the reaction mixture is kept between –80 and –70 C by occasional cooling with liquid nitrogen. After stirring for an additional 30 min at –70 C, further reactions are carried out without delay (Note).

Note At somewhat higher temperature allenyllithium rearranges to propynyllithium, MeCCLi. 3.9.15

General procedure for lithiation of allenes (Table 3.3, entries 1, 2, 3, 5, 6 and 10)

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 3.9.15.1

Procedure

The allenic compound in Table 3.3 (0.11 mol) is added over 10 min to a solution of 0.10 mol of BuLi in 63 ml of hexane and 70 ml of THF (or 0.10 mol of BuLi LiBr in 90 ml Et2O in the case of methoxyallene). During the addition the reaction mixture is kept at the temperature mentioned in Table 3.3. After the period at this temperature indicated in the table the

3.9

EXPERIMENTAL SECTION

49

cooling bath is removed and the temperature is allowed to rise to the final temperature indicated.

3.9.16

Lithiation of 2-alkynes (Table 3.3, entries 4, 7 and 19)

Scale: 0.05 molar; Apparatus: Figure 1.1, 250 ml, addition by syringe instead of from a dropping funnel. 3.9.16.1

Procedure

The 2-alkyne (0.05 mol) is added over a few seconds to a solution of 0.06 mol (0.05 mol in the case R ¼ SMe) of BuLi in 32 ml of hexane and 40 ml of THF, while keeping the temperature at the levels indicated in the table. The cooling bath is removed and the temperature is allowed to rise to 25 C and kept at this level for 30 min.

3.9.17

Metallation of 2-alkynyl ethers (Table 3.3, entries 12, 14, 16 and 20)

Scale: 0.05 mol; Apparatus: Figure 1.1, 250 ml, addition by syringe 3.9.17.1

Procedure

The 2-alkynyl ether (0.05 mol) is added over a few minutes to a solution of 0.05 mol of BuLi in 32 ml of hexane and 40 ml of THF cooled at the temperature mentioned in Table 3.3. The cooling bath is removed and the temperature of the reaction mixture allowed to rise to the level mentioned in the table, at which stirring is continued for the additional period mentioned in the table. In the case of R ¼ Ph the resulting solution is very dark. Further synthetic operations should be carried out without delay.

50 3.9.18

3.

GENERATION OF METALLATED ACETYLENES. . .

Metallation of N,N-diethyl-1-propyn-1-amine (Table 3.3, entry 11)

Scale: 0.05 molar; Apparatus: Figure 1.1, 250 ml, addition may be carried out by syringe.

3.9.18.1

Procedure

The freshly distilled mixture (0.055 mol) of the acetylenic and the allenic amine (Chapter 17, exp. 17.2.3) is added to a solution of 0.05 mol of t-BuOK in 40 ml of THF with cooling below 0 C. The mixture is cooled to between –85 and –90 C and a solution of 0.05 mol of BuLi in 32 ml of hexane is added over 5 min, while keeping the temperature of the reaction mixture between –80 and –90 C. After an additional 5 min the cooling bath is removed and the temperature is allowed to rise to –60 C. N-[4-(Diethylamino)-2-butynyl]-N,N-diethylamine, Et2NCH2CCCH2NEt2 (Table 3.3, entry 13), can be metallated by a similar procedure.

3.9.19

Regioselective metallation of 2-alkynyl amines (Table 3.3, entries 17 and 18)

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml, addition by syringe

3.9.19.1

Procedure

The 2-alkynyl amine (0.10 mol, Chapter 13, exp. 13.2.3) is added over a few seconds to a solution of 0.11 mol of BuLi in 69 ml of hexane and 70 ml of THF cooled at –40 C. After the addition the cooling bath is removed and the temperature is allowed to rise to 25 C. After keeping the solution for 30 min at that level, further reactions can be carried out.

3.9

EXPERIMENTAL SECTION

3.9.20

51

Metallation of 1-alkynyl sulphides with n-BuLi t-BuOK (Table 3.3, entry 9)

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 1-Propynyl sulphides, MeCCSR, are easily and neatly metallated by BuLi in tetrahydrofuran. The methylene protons in the homologues are kinetically less acidic and higher temperatures are required for their metallation with BuLi, which involves the risk of attack on sulphur with formation of BuSR and RCCLi. The use of equal amounts of BuLi and t-BuOK permits the metallation to be successfully carried out at low temperatures. It is assumed that under these conditions the potassiated sulphides are formed. Conversion into the lithium compounds is achieved by addition of anhydrous lithium bromide. 3.9.20.1

Procedure [84]

The 1-alkynyl sulphide (0.10 mol, Chapter 8, exps. 8.2.1 and 8.2.3) is added at –70 C to a solution of 0.10 mol of t-BuOK in 70 ml of THF., then a solution of 0.10 mol of BuLi in 63 ml of hexane is added dropwise over 10 min, while keeping the temperature of the suspension between –65 and –75 C. After an additional 10 min further conversions can be carried out. The lithium compound is formed by addition of a solution of 0.10 mol of anhydrous lithium bromide (Chapter 2.2) in 35 ml of THF at low temperatures. 3.9.21

Elimination of hydrogen bromide from 1,2-dibromo compounds with alkali amide (Table 3.1)

Scale: 0.10 molar; Apparatus: Figure 1.1, 1 litre, addition may be carried out by syringe. 3.9.21.1

Procedure

The 1,2-dibromo compound (0.10 mol) is added over 15 min to a suspension of 0.32 mol (excess) of sodamide (Chapter 2, lithium amide also gives good

52

3.

GENERATION OF METALLATED ACETYLENES. . .

results) in 300 ml of liquid ammonia with cooling between the bp (–33 C) of ammonia and –45 C in a bath with dry ice and acetone or with liquid nitrogen. If no cooling bath is used, much of the ammonia will evaporate due to the very exothermic reaction. 3.9.21.2

Procedure for the 1-alkylthio-1-alkynes HCCSMe and HCCSEt (cf. [82])

After addition (at –35 to –45 C) of the crude 1,2-dibromo-1-(alkylthio)ethane, CH2CH(Br)SR (0.10 mol, prepared as described below), the cooling bath is removed, a high-boiling solvent (bp >170 C, for example decane, 100 ml) is added and most of the ammonia is removed by placing the flask in a bath at 35 C. In the last stage of this operation, when a thick slurry is left, a weak flow of nitrogen is introduced, the flask is placed in a bath with ice water, and 100 ml of ice water is added over 5 to 10 min with vigorous stirring. After dissolution of the solid material, the layers are separated and the organic layer is dried over a small portion of magnesium sulphate. The extracts are transferred into a 500-ml round-bottomed flask, which is equipped for a distillation in a vacuum of 7 to 20 Torr (Figure 1.10). The volatile ethynyl sulphides condense in the strongly cooled receiver. The distillation is stopped as soon as the solvent begins to reflux in the head of the column. Repetition of this evacuation operation (temperature of the heating bath not higher than 40 C) gives the pure ethynyl sulphides. Yields of 0.50 molar-scale experiments are between 60 and 70%. 3.9.21.3

Procedure for the 3,3-dialkoxy-1-propynes HCCCH(OMe)2 and HCCCH(OEt)2 (cf. [82])

After addition of the crude dibromo compound (0.10 mol, prepared as described below and freed from traces of solvent by evacuation) the cooling bath is removed and 100 ml of a high-boiling solvent (bp >180 C) or 150 ml of a 1:1 mixture of pentane and Et2O is cautiously added in the cases of R ¼ CH(OMe)2 and CH(OEt)2, respectively. After removal of the equipment the mixture is cautiously poured on to 600 g of finely crushed ice in a 2- or 3-litre wide-necked round bottomed flask (Figure 1.8) or spread on the bottom of a 5-litre beaker. The reaction flask is rinsed with 100 ml of ice water and the rinsing added to the main portion. After separation of the layers and melting of the remaining ice, two extractions with small portions of solvent are carried out. The organic solutions are dried over potassium carbonate. 3,3-Dimethoxy-1-propyne, HCCCH(OMe)2, is isolated as described above for HCCSMe. Redistillation at atmospheric pressure (760 Torr) gives the pure acetal, bp 100 C.

3.9

EXPERIMENTAL SECTION

53

3,3-Diethoxy-1-propyne, HCCCH(OEt)2, is obtained by distilling off the greater part of the solvents at atmospheric pressure followed by vacuum distillation of the remaining liquid: bp 38 C/10 Torr. Yields of 1 molar-scale procedures are between 70 and 80% 3.9.21.4

Procedure for 2-ethynylpyridine

After addition of the crude 2-(1,2-dibromoethyl)pyridine (for the preparation see below) to the suspension of sodamide the equipment is removed and the greater part of the ammonia is evaporated by warming the flask in a water bath at 40 C. The remaining slurry is treated with 200 ml of Et2O and 100 ml of ice water. After separation of the layers four extractions with small portions of Et2O are carried out. The combined solutions are dried (washing is not carried out) over potassium carbonate and subsequently concentrated under reduced pressure. 2-Ethynylpyridine, bp 74 C/15 Torr, is obtained in moderate to fair yields (50 in a 0.5 molar-scale procedure, based on 2-vinylpyridine). The modest yield may be explained by the fact that the addition of bromine to vinylpyridine is not a clean reaction. Possibly bromine first complexes to N with formation of ¼NþBr Br2, instead of adding across the electron-poor vinyl group. At very low temperature a red-coloured solution is formed, at somewhat higher temperature (–45 C) the solution turns yellow and at a later stage an insoluble yellow precipitate is formed. When the addition of bromine is carried out too quickly, more of the yellow solid is formed and as a result the yield of ethynylpyridine is lower. From 4-vinylpyridine and bromine a very thick yellow precipitate is formed and treatment with sodamide does not give 4-ethynylpyridine. 3.9.21.5

Procedure for the addition of bromine

Methyl vinyl sulphide and ethyl vinyl sulphide are prepared as described [84], 2-vinylpyridine and acrolein are commercially available. The freshly distilled starting compound (0.10 mol) is mixed with 50 ml of dry Et2O or CH2Cl2. Bromine (0.10 mol þ 1 g excess) is added dropwise over 15 min, while keeping the temperature of the reaction mixture between –40 and –50 C. In the case of the addition to acrolein the colour of the solution initially turns brown, but after a few minutes the colour disappears and the brown colour returns after addition of the excess of bromine. In the reactions with the vinylic sulphides and vinylpyridine a faint yellow or brown colour is present throughout the addition, so that the colour is not a reliable indicator. In any case, it is advisable to add a slight excess of bromine in all cases. The adducts are not stable and should be either used without delay or stored at –25 C.

54

3.

GENERATION OF METALLATED ACETYLENES. . .

If dichloromethane is used in the addition, it should be scrupulously removed by evacuation prior to using the adduct for the dehydrohalogenation. 3.9.21.6

Preparation of 1,2-dibromo-3,3-dialkoxypropanes BrCH2CH(Br)CH(OR)2

The solution of 2,3-dibromopropanal, BrCH2CH(Br)CH¼O in Et2O (0.10 mol, containing the slight excess of bromine) is mixed at 10 C with 0.12 mol of freshly distilled orthoformate, HC(OR)3, and 1 ml of methanol or ethanol is added in the cases of R ¼ Me or Et, respectively. The temperature gradually rises until 40 C or higher. When the reaction has subsided, 1 g of powdered anhydrous zinc chloride is added at 35 C causing a limited rising of the temperature. After an additional 30 min (at 40 C) an additional amount of 1 g ZnCl2 is added and the reaction mixture is kept for 15 min at 40 C, then it is poured into 100 ml of a saturated aqueous solution of ammonium chloride. After vigorous shaking, the aqueous layer is dried over potassium carbonate and subsequently concentrated under reduced pressure. 3.9.22

10-Undecynoic acid starting from 10-undecenoic acid

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 3.9.22.1

Procedure (cf. [85])

The light-brown solution of the bromine adduct in 100 ml of Et2O, obtained by adding a slight excess of bromine at –30 C to the solution of 10-undecenoic acid, is added over 30 min to a vigorously stirred suspension of 0.50 mol (excess) of sodamide in 500 ml of liquid ammonia. During the addition the temperature of the very thick suspension is kept just below the bp of ammonia (–33 C) by occasional cooling in a bath with liquid nitrogen (much heat is evolved). After the addition the flask is equipped as shown in Figure 1.7. When, after standing overnight the ammonia has evaporated, the flask is evacuated. When the pressure does no longer drop, inert gas is admitted and 250 ml of ice water is added. Concentrated hydrochloric acid is added portionwise with swirling until the pH of the aqueous layer has reached 3. Four

3.9

EXPERIMENTAL SECTION

55

extractions with a 1:1 mixture of Et2O and pentane or hexane are carried out. The combined organic solutions are dried over magnesium sulphate and subsequently concentrated in vacuo. Pure 10-undecynoic acid, mp 41–42 C, is obtained in > 85% yield. 3.9.23

Lithium ethoxyacetylide from (E/Z)-1-bromo-2-ethoxyethene and lithium amide

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml 3.9.23.1

Procedure

The mixture of (E )- and (Z)-1-bromo-2-ethoxyethene (0.20 mol, preparation see below) is added dropwise over 20 min to a suspension of 0.40 mol of lithium amide in 250 ml of liquid ammonia. During the addition the temperature of the reaction mixture (initially a thick, later a more coarse suspension) is kept between –35 and –45 C. Functionalisation experiments can be carried out after an additional 15 min. 3.9.23.2

Procedure for (E/Z )-1-bromo-2-ethoxyethene BrCH¼CHOEt

Bromine (0.50 mol) is added dropwise over 15 min to a mixture of 0.55 mol of freshly distilled ethyl vinyl ether and 200 ml of Et2O with cooling below –40 C. The solvent is removed under reduced pressure and the remaining liquid mixed with 1 mol (excess) of N,N-diethylaniline. The mixture is brought to 80 C and kept at that level during 30 min (occasional heating or cooling with manual swirling), then the temperature is gradually raised to 95 C and heating is continued for an additional 20 min. Heating at temperatures higher than 100 C may lead to formation of tar and a lachrimatory compound, possibly bromoacetaldehyde. After cooling to below 70 C, 250 ml of ice water is added and the solution of the diethylaniline HBr salt is cooled to 0 C. A mixture of 45 g of 36% hydrochloric acid and 100 ml of ice water is added over a few minutes with vigorous stirring (the use of more HCl involves the risk of acid hydrolysis of the bromovinyl ether). The aqueous layer is extracted seven times with small portions of a 1:1 mixture of pentane and Et2O. The combined organic solutions are dried over magnesium sulphate, after which the greater part of the solvent is distilled off at atmospheric pressure through an efficient column. Careful distillation in vacuo using a receiver cooled at 0 C gives the

56

3.

GENERATION OF METALLATED ACETYLENES. . .

mixture of both geometrical isomers of 1-bromo-2-ethoxyethene (the Z-isomer usually predominates), bp 28–47 C/12 Torr, in 65% yield. The greater part of the diethylaniline may be recovered by adding KOH to the aqueous layer. 3.9.24

1,5-Hexadiyne starting from 1,5-hexadiene

Scale: 0.20 molar; Apparatus: Figure 1.5, 3 litre 3.9.24.1

Procedure

A concentrated solution of 0.20 mol of the crude 1,2,5,6-tetrabromohexane in 40 ml of Et2O, prepared by removing the Et2O partly (see below), is added over 15 min (addition by syringe) to an efficiently stirred suspension of 1.4 mol (excess) of sodamide in 1.2 litre of liquid ammonia. The reaction is very vigorous and much of the ammonia evaporates. Ten minutes after completion of the addition the stirrer is removed, 150 ml of high-boiling petroleum ether (bp >180 C) is added and the flask is placed in a water bath at 40 C. When the flow of escaping ammonia vapour has become weak, 500 g of finely crushed ice is added over a few seconds, followed by vigorous manual swirling. After dissolution of the solid and melting of the remaining ice, the layers are separated and two extractions with 30-ml portions of petroleum ether are carried out. The combined extracts are washed with dilute hydrochloric acid, dried over a small portion of magnesium sulphate and transferred into a 1-litre round bottomed flask, which is equipped for a distillation under reduced pressure (Figure 1.10). The receiver is cooled in a bath with dry ice and acetone. The system is evacuated (P < 20 Torr) and the solution heated until the petroleum ether begins to pass over. Careful distillation of the contents of the receiver gives 1,5-hexadiyne, bp 87 C/760 Torr. The overall yield based on allyl bromide (see below) of 0.50 molar scale procedures is between 65 and 75%. 3.9.24.2

Procedure for 1,2,5,6–tetrabromohexane, [BrCH2CH(Br)]2

Dry magnesium turnings (0.20 mol) and dry Et2O (200 ml) are placed in the flask. After activation of the magnesium with iodine, the flask is warmed until

3.9

EXPERIMENTAL SECTION

57

the Et2O begins to reflux. Allyl bromide (0.40 mol) is added dropwise over 45 min causing a gentle reflux of the Et2O. After heating for an additional half an hour 250 mg of copper(I) bromide or chloride is added at 20 C in order to bring about the reaction between allylMgBr with allyl bromide to completion. After 15 min the two-layer system is cooled to below –30 C and bromine (0.40 mol) is added dropwise until the solution has become uniformly brown. Towards the end of the addition the temperature is raised to –10 C. The thick brown suspension is cautiously poured into a 2-litre wide-necked conical flask containing 250 ml of a concentrated solution of ammonium chloride (never add this solution to the reaction mixture as this causes vigorous reflux and possibly loss of part of the reaction mixture). The suspension remaining in the reaction flask is rinsed out with a small amount of ammonium chloride solution. The aqueous layer is extracted twice with Et2O, the combined ethereal solutions are dried over magnesium sulphate and subsequently concentrated in vacuo to a volume of about 40 ml.

3.9.25

Ethynylcyclopentane and ethynylcyclohexane from geminal 1,1-dichlorides and sodamide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre 3.9.25.1

Procedure

A mixture of 0.20 mol of the crude dichloride (see below) and 50 ml of Et2O is added over 1 h to a vigorously stirred suspension of 0.8 mol (excess) of sodamide in 500 ml of liquid ammonia. During the addition the flask is cooled in a bath with dry ice and acetone (occasional cooling with liquid nitrogen is also possible), so that the temperature of the reaction mixture remains just below –33 C, the bp of ammonia. After stirring for an additional 30 min, the flask is equipped as shown in Figure 1.7 and the ammonia is allowed to evaporate overnight. Pentane (100 ml) and ice water (300 ml) are successively added, after which the solid is hydrolysed by vigorous manual swirling. If necessary, two extractions with pentane are carried out. Separation of the layers may be rather difficult due to the presence of resinous material. This can be separated from the organic solution by filtration on sintered glass covered with a 1-cm layer of celiteR. After drying over

58

3.

GENERATION OF METALLATED ACETYLENES. . .

magnesium sulphate a rough distillation in vacuo is carried out (Figure 1.10) collecting the volatile material in a strongly cooled receiver. Redistillation affords ethynylcyclopentane, bp 105 C/760 Torr, and ethynylcyclohexane, bp 131 C/760 Torr, in moderate yields (35–45% in 0.50 molar scale procedures).

3.9.25.2

Procedure for 1-(2,2-dichloroethyl)cycloalkanes, RCH2CHCl2

The cycloalkyl chloride (0.20 mol, carefully freed from water and the corresponding alcohols by distillation under atmospheric pressure) is placed in the flask (250 ml, Figure 1.1) and cooled to –40 C. Powdered sublimed aluminium chloride (2 g) and 5 ml of liquefied vinyl chloride (–30 C) are successively added. After an initial period of a few minutes the temperature rises and the mixture turns orange. After the exothermic reaction has subsided, the remaining amount of vinyl chloride ( 0.3 mol, excess) is added portionwise over 45 min, while keeping the temperature of the reaction mixture between –35 and –45 C. After the addition, the temperature is allowed to rise to –15 C, then 30 ml of concentrated hydrochloric acid is added and the layers are separated (a small amount of Et2O may be added to facilitate the separation, the excess of vinyl chloride is removed by evacuation). The remaining liquid is used for the dehydrohalogenation. 3.9.26

Mono- or disodium diacetylide from 1,4-dichloro-2-butyne and sodamide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre

3.9.26.1

Procedure

A suspension of 0.60 or 0.80 mol of sodamide in 300 or 400 ml, respectively, of liquid ammonia is prepared as described in Chapter 2, exp. 2.3.1. 1,4Dichlorobutyne (0.20 mol, see Chapter 20, exp. 20.1.6) is added dropwise over 30 min, while keeping the temperature of the reaction mixture between –40 and –50 C by occasional cooling in a bath with liquid nitrogen and introducing nitrogen at a rate of 200 ml/min. After an additional 15 min the mixture is ready for further reactions. Lithium amide presumably also can be used.

3.9

EXPERIMENTAL SECTION

3.9.27

59

4-Pentyn-1-ol from 2-(chloromethyl)tetrahydrofuran and sodamide

Scale: 0.30 mol; Apparatus: Figure 1.5, 3 litre 3.9.27.1

Procedure (cf. [86])

2-(Chloromethyl)tetrahydrofuran (0.30 mol, preparation see below) is added dropwise over 20 min to an efficiently stirred suspension of 0.92 mol of sodamide in 1500 ml of liquid ammonia. After an additional 30 min 60 g of finely powdered ammonium chloride is added portionwise over 15 min, then the flask is placed in a water bath at 40 C and most of the ammonia is removed by evaporation. In the last stage of this operation the stirrer is removed and heating is continued until the flow of escaping ammonia vapour has become very weak. The solid mass is vigorously swirled (manually) with 300 ml of Et2O warmed at 30 C, after which the mixture is subjected to suction filtration on sintered glass. The salt is rinsed well with warm Et2O. Concentration of the filtrate under reduced pressure followed by distillation gives 4-pentyn-1-ol, bp 53 C/15 Torr, in >70% yield. Note This procedure of working up is much quicker than addition of water and subsequent continuous extraction. 3.9.27.2

Procedure for 2-(chloromethyl)tetrahydrofuran

Thionyl chloride (0.50 mol) is added dropwise over 30 min to a mixture of 0.50 mol of tetrahydro-2-furanylmethanol and 150 ml of pyridine. The temperature is kept between 70 and 80 C by occasional cooling. The thick suspension formed in the beginning disappears gradually and the reaction mixture turns very dark. After an additional period of 1.5 h the mixture is cooled to rt, after which 500 ml of ice water is added as quickly as possible with vigorous stirring. Fifteen extractions with Et2O are carried out. Dissolved pyridine is removed by shaking the combined extracts with cold 2 N hydrochloric acid. After drying over magnesium sulphate, the greater part of the Et2O is distilled off under atmospheric pressure. 2-(Chloromethyl)tetrahydrofuran, bp 45 C/10 Torr, is obtained in at least 70% yield.

60 3.9.28

3.

GENERATION OF METALLATED ACETYLENES. . .

Methoxyacetylene and ethoxyacetylene from 2-chloro-1,1-dialkoxyethanes and sodamide

Scale: 0.50 molar; Apparatus: Figure 1.5, 3 litre This procedure seems nerve-racking, but is, in the author’s opinion, safer than the original one [87]. It has been experienced that alkali alkoxyacetlides can explode very vigorously in a dry state. For this reason complete evaporation of the ammonia after addition of the 2-chloro-1,1-dialkoxyethane has to be avoided and hydrolysis has to be carried out very quickly by addition of crushed ice through the wide neck of the reaction flask when rather much liquid ammonia is still present. This prevents the material on the bottom of the flask from getting dry. Losses of the volatile ethynyl ethers are limited by addition of a high-boiling extraction solvent prior to carrying out the aqueous work-up. 3.9.28.1

Procedure (cf. [87])

The 2-chloro-1,1-dialkoxyethane (0.50 mol) is added in portions of about 5 g over 45 min to an efficiently stirred suspension of 1.7 mol of sodamide in 1.5 litre of liquid ammonia (addition by syringe is most convenient). After an additional 30 min the stirrer is removed and the flask is warmed (with occasional manual swirling) in a water bath at 40 C. When about 70% of the ammonia has evaporated, 250 ml of high-boiling petroleum ether (bp >170 C) is added and the evaporation procedure is continued taking care that no dry crust is formed at the bottom of the flask. When the flow of ammonia vapour has decreased considerably, a vigorous flow of inert gas is introduced for 2 min, after which 700 g of finely crushed ice is added within a few seconds through the wide neck. Dissolution of the solid is achieved by vigorous manual swirling. After melting the remaining ice (warming in a water bath), the layers are separated without delay and seven extractions with small portions of petroleum ether are carried out. The combined organic solutions are dried (washing is not carried out) over magnesium sulphate. Methoxyacetylene is isolated by heating the solution in a <20 Torr vacuum and condensation in a trap cooled in liquid nitrogen (the vapour should enter the large annular space of the trap where it solidifies). Distillation at atmospheric pressure gives the pure methoxyacetylene, bp 20–25 C/760 Torr, in 50% yield. Ethoxyacetylene is isolated by heating the solution in vacuo

3.9

EXPERIMENTAL SECTION

61

(<20 Torr) and condensing the vapour in a receiver cooled at –70 to –80 C (Figure 1.10). Distillation at atmospheric pressure gives the pure compound, bp 53 C/760 Torr, in 75% yield. In both cases the receiver is cooled in an ice water bath.

3.9.29

1-Ethoxy-1-buten-3-yne from 1,4-diethoxy-2-butyne and sodamide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre, the thermometer is omitted

3.9.29.1

Procedure

The 1,4-dialkoxy-2-butyne (0.20 mol, Chapter 20, exp. 20.6.2) is added dropwise over 30 min to a suspension of 0.50 mol (excess) of sodamide in 400 ml of liquid ammonia. After the addition the flask is placed in a water bath at 40 C. When most of the ammonia has evaporated, 75 ml of Et2O is added. The flask is placed in a bath with ice and ice water. Ice water (200 ml) is added over about 15 min, while introducing N2. During this operation the mixture is vigorously stirred. After dissolution of all solid material, the layers are separated and the aqueous layer is extracted five times with small portions of Et2O. The organic solutions are washed with saturated aqueous NH4Cl and subsequently dried over MgSO4. The greater part of the Et2O is distilled off through a 40-cm Vigreux column, keeping the bath temperature below 80 C. After cooling to rt, the product is isolated by distillation in vacuo using a single receiver, cooled at 0 C (Figure 1.10). 1-Ethoxy-1-buten-3-yne, bp 30–35 C/ 10 Torr, ((Z):(E) 15:85), is obtained in greater than 70% yields. 1-(1-Ethoxyethoxy)-1-buten-3-yne, HCCCH¼CHOCH(Me)OEt ((Z):(E) 10:90), bp 66–68 C/10 Torr, is obtained by a similar procedure in 70% yield from 4-(1-ethoxyethoxy)-2-butynyl 1-ethoxyethyl ether, ROCH2C CCH2OR, in which R represents CH(Me)OEt. In this elimination three (instead of two) equivalents of sodamide are required since the eliminated NaOCH(Me)OEt decomposes into EtONa and MeCH¼O, the aldehyde consuming an extra equivalent of alkali amide for its conversion into H2C¼CHONa.

62 3.9.30

3.

GENERATION OF METALLATED ACETYLENES. . .

1-Ethoxy-1,2,3-butatriene from 1,4-diethoxy-2-butyne and alkyllithium

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml In principle, a mixture of commercial BuLi in hexane and diethyl ether can be used, but ethyllithium in diethyl ether is better, as the rather volatile cumulenic ether and diethyl ether are more easily separated. Another possibility involves removal of the hexane in vacuo from the BuLi solution and addition of cold diethyl ether to the remaining syrup. 3.9.30.1

Procedure [53]

A solution of 0.25 mol of ethyllithium in 200 ml of Et2O (Chapter 2, exp. 2.3.6) is added over 30 min to a mixture of 0.10 mol of 1,4-diethoxy-2butyne (Chapter 20, exp. 20.6.2) and 50 ml of Et2O, while keeping the temperature between –35 and –45 C. After an additional 20 min the light-brown solution is poured into 200 ml of ice water, which has been saturated with nitrogen by repeated alternate evacuation and admission of nitrogen. After shaking (under nitrogen) and separation of the layers, two extractions with very small portions of pentane are carried out. The combined organic solutions are dried over a small amount of magnesium sulphate and subsequently transferred into a 500-ml round bottomed flask equipped for a vacuum distillation, the receiver cooled in a bath at 0 C (Figure 1.10). The Et2O is removed by evaporation in a vacuum (bath temperature not higher than 25 C). In the last stage, when practically all Et2O has been removed, the temperature of the heating bath is raised to 60 C. Water of the bath is poured along the column in order to minimise the hold-up. The volatile 1-ethoxy-1,2,3butatriene passes over between 24 and 40 C/15 Torr. After cooling to rt, inert gas is admitted. The cumulenic ether is obtained in a good yield (>70% in a 0.25 molar-scale procedure). The compound is extremely air-sensitive. 3.9.31

1,4-Diethoxy-1,2,3-butatriene from 1,1,4-triethoxy-2-butyne and alkyllithium

3.9

EXPERIMENTAL SECTION

63

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml It has been shown [7] that this elimination proceeds through the lithium compound EtOCH(Li)CCCH(OEt)2. This intermediate is formed when the starting compound 1,1,4-triethoxy-2-butyne is treated with BuLi in THF at temperatures lower than –60 C. Under these conditions it is stable, allowing successful derivatisation reactions to be carried out. At higher temperature lithium ethoxide is eliminated with formation of free 1,4-diethoxy1,2,3-butatriene, which consumes alkyllithium in a fast subsequent reaction. 3.9.31.1

Procedure [53]

A solution of 0.25 mol of ethyllithium in 250 ml of Et2O (BuLi in hexane presumably can also be used) is added over 15 min to a solution of 1,1,4-triethoxy-2-butyne in 50 ml of THF and 50 ml of Et2O cooled between –40 and –50 C. After stirring for an additional 30 min at –40 C, the solution is poured into 150 ml of saturated aqueous ammonium chloride. After shaking and separation of the layers, one extraction with pentane is carried out. The combined organic solutions are dried over magnesium sulphate and concentrated under reduced pressure. Distillation of the remaining liquid through a short column gives 1,4-diethoxy-1,2,3-butatriene, bp 50 C/ 0.2 Torr, in at least 80% yield.

Note All operations should be scrupulously carried out under inert gas, while too high bath temperatures during the distillation have to be avoided.

3.9.32

N,N-4-Trimethyl-1,2,3-pentatrien-1-amine from 4-methoxyN,N-4-trimethyl-2-pentyn-1-amine and butyllithium

Scale: 0.05 molar; Apparatus: Figure 1.1, 500 ml

64

3.

GENERATION OF METALLATED ACETYLENES. . .

Like butatrienyl ethers (e.g. 1-ethoxy-1,2,3-butatriene) the amino derivatives are thermally unstable and extremely air-sensitive. Furthermore, they readily undergo base-catalysed isomerisation. Thus, if the intermediate Me2C¼C¼C¼C(Li)NMe2 is hydrolysed by addition of water at low temperatures, a mixture of the free cumulenic amine and the enyne amine Me2C¼CHCCNMe2 is obtained. It is assumed that the initially formed cumulenic amine isomerises under catalytic influence of the (still non-hydrolysed) lithium derivative. This undesired reaction can be avoided, if the lithium compound is protonated with t-butyl alcohol at very low temperatures.

3.9.32.1

Procedure [18]

4-Methoxy-N,N-trimethyl-2-pentyn-1-amine (0.05 mol, for the preparation cf. Chapter 13) is dissolved in 100 ml of THF. A solution of 0.11 mol of BuLi in 67 ml hexane (1.6 M) is added over 10 min at –30 C. After an additional period of 1.5 h at the same temperature, the reaction mixture is cooled to –90 C, 4 ml of t-BuOH is added with vigorous stirring and cooling to below –80 C, then the reaction mixture is poured into 300 ml of water. The aqueous layer is extracted twice with Et2O. After drying the organic solution over potassium carbonate and removal of the solvents under reduced pressure, the remaining liquid is distilled to give N,N-4-trimethyl-1,2,3-pentatrien-1amine, bp 69 C/17 Torr, n20 D 1.5836, in >70% yield.

3.9.33

N,N-Diethyl-2,4-pentadiyn-1-amine from (Z)-N,N-diethyl-5ethylthio-4-penten-2-yn-1-amine and sodamide

Scale: 0.10 molar; Apparatus: Figure 1.1, 1 litre, no thermometer is used. This method for the preparation of 1,3-diynes from the readily available (Z)enyne sulphides (Chapter 20, exp. 20.7.3) resembles the synthesis starting from the commercially available (Z)-1-methoxy-1,3-butenyne using LDA for the elimination of methanol [23,24]. In our procedure [19], sodamide in liquid ammonia is used for the elimination, but we presume that LDA will work as

3.9

EXPERIMENTAL SECTION

65

well. Our method can be used for the preparation of other diynes, for example alcohols HCCCCC(R1)(R2)OH and hydrocarbons RCCCCH [19]. 3.9.33.1

Procedure

The starting compound (0.10 mol, see Chapter 13, exp. 13.2.3) is dissolved in 100 ml of Et2O and the solution is added over 20 min to a suspension of 0.30 mol (excess) of sodamide in 350 ml of liquid ammonia. The outlet and thermometer are removed and the ammonia is removed by placing the flask in a bath at 40 C. When the flow of ammonia vapour has decreased considerably, the flask is cooled in a bath with ice water and nitrogen is introduced. Ice water (200 ml) is added over 10 min with vigorous stirring. After separation of the layers, seven extractions with small portions of Et2O are carried out. The combined organic solutions are washed with saturated aqueous ammonium chloride, dried over potassium carbonate and concentrated under reduced pressure. Distillation of the remaining liquid through a short column gives N,N-diethyl-2,4-pentadiyn-1-amine, bp 50 C/0.4 Torr, in an excellent yield.

3.9.34

3-Methoxy-3-penten-1-yne from 4-ethoxy-3-methoxy1,2-pentadiene and sodamide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre, the thermometer is omitted. 3.9.34.1

Procedure [88]

4-Ethoxy-3-methoxy-1,2-pentadiene (0.20 mol, Chapter 4, exp. 4.5.29) is added over 15 min to a suspension of 0.5 mol (excess) of sodamide in 300 ml of liquid ammonia. After the addition, the outlet is removed and the flask is placed in a water bath at 40 C. Towards the end of this operation 200 ml of pentane is added and nitrogen is introduced. The flask is cooled in a bath with ice water and 150 ml of ice water is slowly added with vigorous stirring. The organic layer and one extract are washed with water and dried over magnesium sulphate. The greater part of the pentane is distilled off through an efficient column. Continuation of the distillation in a vacuum of 40 Torr gives 3methoxy-3-penten-1-yne, bp 40 C/40 Torr, in an excellent yield (E/Z ratio 63:37).

66 3.9.35

3.

GENERATION OF METALLATED ACETYLENES. . .

5-Octen-7-yn-1-ol from 2-(1-propynyl)tetrahydropyran and sodamide

Scale: 0.10 molar; Apparatus: Figure 1.1, 1 litre, the thermometer is omitted. 3.9.35.1

Procedure [89]

A mixture of 0.10 mol of 2-(1-propynyl)tetrahydropyran (cf. Chapter 4, exp. 4.5.19) and 50 ml of Et2O is added over 30 min to a suspension of 0.40 mol (excess) of sodamide in 400 ml of liquid ammonia. After an additional 20 min the outlet is removed and most of the ammonia is removed by placing the flask in a water bath at 40 C, stirring being continued. When practically all ammonia has evaporated, 100 ml of Et2O is added and the flask is cooled in a bath with ice water. Ice water (100 ml) is added with vigorous stirring. After separation of the layers, the aqueous layer is extracted twice with Et2O. The organic solutions are dried over magnesium sulphate and subsequently concentrated under reduced pressure. The remaining liquid is distilled through a short column to give an alcohol, bp 104–112 C/12 Torr, in 90% yield (E/Z ratio 1). Several other examples of 1,4-eliminations are mentioned in Ref. 89.

3.9.36

Conversion of N,N-dialkyl-3-buten-1-yn-1-amine into (E 1 Z)-N,N-dialkyl-1-buten-3-yn-1-amine by reaction with potassium amide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre, no thermometer is used. 3.9.36.1

Procedure [63]

The N,N-dialkyl-3-buten-1-yn-1-amine (0.20 mol, Chapter 10, exp. 10.2.13) is mixed with 50 ml of dry Et2O and the solution is added over 15 min to a

3.9

EXPERIMENTAL SECTION

67

solution of 0.25 mol of potassium amide in 350 ml of liquid ammonia. A fine suspension is formed. After an additional hour the outlet is replaced with a powder funnel and 15 g of powdered ammonium chloride is introduced in 0.5-g portions over about 10 min. The dropping funnel is then replaced with a gas inlet and introduction of N2 is started (500 ml/min). The ammonia is removed by placing the flask in a water bath at 35–40 C. The remaining brown solid is rinsed five to eight times with small portions of dry Et2O (which are cautiously decanted from the solid). After concentrating the solution in vacuo, the remaining liquid is distilled through a 30-cm Vigreux column to give the amines R ¼ Me, bp 58 C/15 Torr, and R ¼ Et, bp 78 C/15 Torr, in excellent yields. The (E)/(Z) ratio is 94:6 for both compounds.

3.9.37

Conversion of 1-(1-propynyl)cyclohexene into 1-(2-propynylidene)cyclohexane by reaction with potassium amide

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml, the thermometer is omitted.

3.9.37.1

Procedure

1-(1-Propynyl)-1-cyclohexene (0.10 mol) is added dropwise over 15 min to a solution of 0.15 mol of (filtered, see Chapter 2, exp. 2.3.1) potassium amide in 200 ml of liquid ammonia. A fine, white suspension is formed. After 2 h, when most of the ammonia has evaporated, 150 ml of Et2O is added, followed by dropwise addition of 100 ml of water under vigorous stirring. After dissolution of all solid material, the layers are separated and one extraction with pentane is carried out. The organic solution is dried over magnesium sulphate and then concentrated under reduced pressure. Distillation of the remaining liquid gives 1-(2-propynylidene)cyclohexane, bp 55 C/10 Torr, in an excellent yield. (E)-1-Buten-3-ynyl-cyclohexane, c-C6H11CH¼CHCCH, bp 71 C/10 Torr, is obtained in a similar way by treating 1-(2-butynylidene)cyclohexane with KNH2. Reaction of N,N-diethyl-2-butyn-1-amine, MeCCCH2NEt2, with KNH2 gives a mixture of N,N-diethyl-3-butyn-1-amine, HCCCH2CH2NEt2, and N,N-diethyl-1,3-butadien-1-amine, H2C¼CHCH¼CHNEt2, from which the

68

3.

GENERATION OF METALLATED ACETYLENES. . .

acetylenic compound can be isolated (bp 33 C/10 Torr) in 70% yield by very careful distillation through a 40-cm Vigreux column. Enyne alcohols MeCCCH¼CH(CH2)nOH can be converted with good yields into the isomers HCCCH¼CH(CH2)nþ1OH . From (E)-hexen1-yn-1-ol, MeCCCH¼CHCH2OH, (obtained by C-methylation of LiC CCH¼CHCH2OLi in liquid ammonia a 90:10 mixture of (Z) and (E)-3hexen-5-yn-1-ol, HCCCH¼CHCH2CH2OH, is obtained.

3.9.38

3-Alkynoic acids from 2-alkynoic acids and sodamide

Scale: 0.10 molar; Apparatus: Figure 1.5, 3 litre.

3.9.38.1

Procedure (cf. [54])

A mixture of 0.10 mol of the 2-alkynoic acid (Chapter 6, exp. 6.4.1) and 50 ml of THF is added over a few minutes to an efficiently stirred suspension of 0.40 mol (excess!) of sodamide in 400 ml of liquid ammonia. The addition is carried out by means of a syringe, keeping the end of the needle a few cm above the surface of the ammonia. The initially formed solution quickly changes into a rather thick white suspension. After an additional 30 min 40 g of powdered ammonium chloride is added over 5 min with vigorous stirring. The ammonia is then removed by placing the flask in a water bath at 50 C (continuous swirling by hand is necessary in order to suppress bumping). Towards the end of this operation, a rubber stopper provided with an outlet is placed on the flask. Warming is continued until the flow of ammonia from the outlet has become very faint. Et2O (200 ml) is then added and warming at 50 C is continued until the flow of ammonia has stopped completely. After cooling to rt, 200 g of finely crushed ice is added. After dissolution of the solid material, 5 N hydrochloric acid is added with swirling until the pH of the solution has become lower than 3. The solution is then saturated with ammonium chloride, after which ten extractions with small portions of Et2O are carried out. The extracts are dried over MgSO4 and subsequently concentrated in vacuo. Traces of water are removed in a vacuum of 0.5 to 1 Torr by

3.9

EXPERIMENTAL SECTION

69

warming the remaining liquid for 30 min at 30 C. The remaining brown solid (3-alkynoic acids, purity >95% according to 1H NMR, yield 90%) gives the pure acid by crystallisation from pentane as described [54]. 3.9.39

1-Alkylthio-1,2-alkadienes from 1-alkynyl sulphides and sodamide (Table 3.3, entries 8 and 9)

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml, addition by syringe, no thermometer is used. 3.9.39.1

Procedure

A suspension of 0.22 mol of sodamide in 200 ml of liquid ammonia is cooled to –45 C. The 1-alkynyl sulphide (0.20 mol, Chapter 8, exps. 8.2.1 and 8.2.3) is added over 1 min and the cooling bath is removed. The brown reaction mixture is stirred for 1 to 2 min after the ammonia has started to boil (33 C), then 200 ml of a 1:1 mixture of Et2O and pentane is added. The mixture is cautiously poured on to 300 g of finely crushed ice in a wide-necked round-bottomed flask (Figure 1.8) or spread on the bottom of a large beaker. The aqueous layer (after melting of the remaining ice) and two pentane extracts are dried over magnesium sulphate and transferred into a 1-litre round bottomed flask equipped for distillation under reduced pressure (Figure 1.10). The receiver is cooled in a bath at 0 C. The organic solution is warmed in a bath at 35 C and the apparatus evacuated. When about 30 ml of solution is left in the distillation flask, nitrogen is admitted, the contents of the flask is transferred into one of 100 ml and distillation is carried out. The allenic sulphides R ¼ H, bp 30 C/12 Torr, and R ¼ Me, bp 45 C/12 Torr, are collected in the cooled receiver. Yields are higher than 70%. Phenyl-1,2-pentadienyl sulphide, H2C¼C¼CHSPh, bp 70 C/0.01 Torr, is obtained in a high yield by adding phenyl 1-propynyl sulphide to a suspension of 10% molar excess of sodamide and pouring the reaction mixture after 3 min on to crushed ice. Note Allenic sulphides are air-sensitive. Too strong heating during the distillation may give rise to dimerisation.

70 3.9.40

3.

GENERATION OF METALLATED ACETYLENES. . .

N,N-Diethyl-4-methoxy-2,3-butadien-1-amine from N,N-diethyl-4-methoxy-2-butyn-1-amine and butyllithium

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 3.9.40.1

Procedure (cf. [90])

N,N-Diethyl-4-methoxy-2-butyn-1-amine (0.10 mol, Chapter 13, exp. 13.2.3) is added over a few minutes to a solution of 0.11 mol of BuLi in 69 ml of hexane and 70 ml of THF with cooling between –35 and –45 C. After an additional 15 min 50 ml of a saturated solution of ammonium chloride is added with vigorous stirring. The upper layer and four ethereal extracts are dried over potassium carbonate and concentrated under reduced pressure. Distillation of the remaining liquid through a short column gives a mixture of 90% of N,N-diethyl-4-methoxy-2,3-butadien-1-amine and 10% of the starting compound, bp 50 C/12 Torr, in 80% yield. Note A similar procedure with 2-alkynyl ethers, RCCCH2OR, gives considerably lower relative amounts of the allenic isomers, cf. [91]. 3.9.41

Lithiation of 1-(2,3-butadienyl)benzene with alkyllithium and rearrangement of the intermediary lithium compound to 4-lithium-1-(3-butynyl)benzene

Scale: 0.05 molar; Apparatus: 250 ml three-necked, round-bottomed flask, equipped with a gas inlet, a thermometer and an outlet; magnetic stirring. 3.9.41.1

Procedure (cf. [92])

1-(2,3-Butadienyl)benzene (0.05 mol, Chapter 11, exp. 11.2.1) is added to a solution of 0.07 mol (excess) of BuLi LiBr (Chapter 2, exp. 2.3.6) in 80 ml

3.9

EXPERIMENTAL SECTION

71

of Et2O cooled at –30 C, then the cooling bath is removed and the solution is warmed for 15 min at 30 C. The solution is poured into 200 ml of ice water. The ethereal layer is dried over magnesium sulphate and concentrated under reduced pressure. 1-(3-Butynyl)benzene, bp 72 C/15 Torr, is obtained in a high yield.

Note BuLi in THF–hexane or Et2O–hexane mixtures may also be used [81]. 3.9.42

Conversion of an acetylenic tertiary amine into the allenic isomer via a metallic intermediate

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml Like in the case of the analogous 2-alkynyl ethers [91], successive lithiation and protolysis does not give the pure allenic amines, the starting compound usually being present in appreciable amounts. If prior to the protolysis an equivalent amount of t-BuOK is added, the regioselectivity is rather good. In view of the water-sensitivity of allenic amines the protonation is carried out with t-butyl alcohol and the product is isolated by a dry work-up. It has been shown that amines of the type MeCCCH2NR2 in which R represents Et or n-Prop undergo deprotonation at the methyl group, whereas in 2-alkynyl amines with NR2 ¼ NMe2 or piperidyl are deprotonated adjacent to nitrogen. There are indications that in diethylaminoalkynes, RCH2CCCH2NEt2, with R ¼ alkyl, abstraction from both methylene groups occurs at comparable rates [7]. Since NR2 groups have weak electron-withdrawing capacities, steric influences may play an important role. 3.9.42.1

Procedure

N,N-Dimethyl-2-heptyn-1-amine (0.10 mol, Chapter 13, exp. 13.2.3) is added over a few seconds to a solution of 0.12 mol of BuLi in 75 ml of hexane and 60 ml of THF, cooled at –40 C. After stirring the solution for 20 min at –20 C, it is cooled again to –40 C and a solution of 0.12 mol of t-BuOK in 30 ml of

72

3.

GENERATION OF METALLATED ACETYLENES. . .

THF is added while allowing the temperature to rise to –20 C. After an additional 10 min the reaction mixture is cooled to –40 C and 0.12 mol of t-BuOH (dissolved in a few ml of THF) is added in one portion with vigorous stirring. Paraffin oil (70 ml) is added, after which the solvents are removed on the rotary evaporator. When most of the solvent has been removed, the flask is equipped for distillation (very short column) under very low pressure, the receiver being cooled in a bath at –70 C (Figure 1.10). After the last traces of solvent have condensed in the receiver, the minimal pressure (<0.5 Torr) can be attained. The temperature of the heating bath is gradually raised to 80 C. Redistillation of the contents of the receiver gives fairly pure (92% by NMR) N,Ndimethyl-1,2-heptadien-1-amine, bp 55 C/12 Torr, in 75% yield. 3.9.43

Preparation of 10-undecyn-1-ol by treatment of 2-undecyn-1-ol with the monopotassium derivative of 1,3-propanediamine

Scale: 0.20 molar; Apparatus: 2-litre one-necked round-bottomed flask 3.9.43.1

Procedure [61]

A filtered solution of 0.50 mol of potassium amide in 300 ml of liquid ammonia is prepared as described in Chapter 2. The solution is concentrated to a volume of 100–150 ml by placing the flask in a water bath at 35 C (only the lower part of the flask is dipped in the water). 1,3-Propanediamine (350 ml, dried over machine-powdered KOH and subsequently distilled in a vacuum) is cautiously added to the remaining very concentrated solution of potassium amide. An efficient reflux condenser equipped with a narrow outlet on the top is placed on the flask, which is subsequently placed in a water bath at 50 C. The flask is occasionally swirled by hand. When the stream of ammonia vapour has become very faint, the outlet is connected with a 20-cm long tube filled with KOH pellets, which in its turn is connected with the vacuum aspirator. The flask is evacuated and gradually warmed until 1,3-propanediamine begins to reflux (in the beginning it may be necessary to interrupt heating when frothing becomes vigorous). Heating and refluxing are continued for 1 to 1.5 h until all solid material has disappeared. Nitrogen is admitted and the greyish solution is cooled to 15 C. 2-Undecyn-1-ol (0.20 mol,

3.9

EXPERIMENTAL SECTION

73

(Chapter 4, exp. 4.5.11) is added in one portion, after which the mixture is vigorously swirled by hand in order to effect homogenisation. A thermometer is placed in the flask. The temperature of the solution rises within a few minutes to over 60 C. When the evolution of heat has stopped and the temperature begins to drop, the flask is placed in a water bath at 70 C. The brown solution becomes very viscous. After 1 h the reaction mixture is cooled to rt and 1 litre of ice water is added. After vigorous swirling, five to eight extractions with a 1:1 mixture of Et2O and pentane are carried out. The combined organic solutions are washed twice with water and subsequently dried over magnesium sulphate. The liquid remaining after concentration of the solution in vacuo is distilled through a short Vigreux column to give 10-undecyn-1-ol, bp 95 C/1 Torr, in good to excellent yields.

3.9.44

1-Ethynylpyrrole from 1-[1,2-dichloroethenyl]pyrrole and methyllithium

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml

3.9.44.1

Procedure [64]

A solution of 0.45 mol of methyllithium (cf. Chapter 2, exp. 2.3.6) in 350 ml of Et2O is added over 20 min to a mixture of 0.20 mol of 1-(1,2-dichloroethenyl)pyrrole (see below) and 50 ml of Et2O with cooling between 0 and –5 C. After an additional 2 h (at –10 C) the solution is cooled to –50 C and 50 ml of ice water is added with vigorous stirring, while keeping the temperature below 10 C. After drying the organic layer over MgSO4, the greater part of the Et2O is distilled off at atmospheric pressure through an efficient column. The temperature of the heating bath should not be higher than 85 C in the last stage of the distillation. The distillation is continued under reduced pressure and the volatile product collected in a single receiver, which is placed in a bath at –20 C (Figure 1.10) when the pressure has dropped below 50 Torr. Repetition of the distillation gives pure 1-ethynylpyrrole in 80% yield. A small part is distilled: bp 109 C/760 Torr.

74

3.

GENERATION OF METALLATED ACETYLENES. . .

Note It is possible to use commercially available BuLi, provided that first the hexane is thoroughly removed by evacuation and Et2O is added to the remaining concentrated BuLi. 3.9.44.2

Preparation of 1-(1,2-dichloroethenyl)pyrrole

A solution of 0.60 mol of t-BuOK (100 mol% excess) in 150 ml of THF is added over a few minutes to a mixture of 0.30 mol of 1H-pyrrole and 220 ml of THF cooled at –40 C. Subsequently, 0.30 mol of 1,1,2-trichloroethylene is added portionwise over 15 min, while keeping the temperature between –30 and –40 C. The temperature of the gelatinous mixture is raised to –20 C. After 30 min a second portion of 0.30 mol of 1,1,2-trichloroethylene is added at –20 C and the temperature is gradually raised over 40 min to 0 C. GLC usually shows the presence of very small amounts of the starting pyrrole. Ice water (300 ml) is added with vigorous stirring. The aqueous layer is extracted three times with small portions of pentane. After successive washing of the combined organic solutions with brine or concentrated ammonium chloride and drying over potassium carbonate, 10 g of N,N-diethylaniline is added (for stabilisation of the product) and the solvents are removed under reduced pressure. Careful fractionation of the remaining brown liquid gives, after a small first fraction of 1-(t-butoxy)1,2-dichloroethene, t-BuOC(Cl)¼ CHCl, 1-(1,2-dichloroethenyl)pyrrole, bp 67–70 C/15 Torr, in 75% yield. The compound should be stored at –20 C in the presence of a very small amount of N,N-diethylaniline.

3.9.45

Allenic derivatives by addition of alkyllithium to enyne compounds

3.9

EXPERIMENTAL SECTION

75

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml, the thermometer is omitted 3.9.45.1

Procedure (cf. [57,58])

The enyne derivative (0.10 mol; 0.05 mol if R ¼ CH2CH2OH) is dissolved in 100 ml of Et2O and the solution is cooled in a bath at –50 C. A solution of 0.12 mol of EtLi in 100 ml of Et2O (commercially available alkyllithiums in hexane also give good results) is added over 15 min, then the cooling bath is removed and the temperature is allowed to rise to >10 C (–10 C if R ¼ SMe). A concentrated solution of 20 g of ammonium chloride is added over a few minutes with vigorous stirring and cooling in a bath at –40 C. The organic layer and two ethereal extracts are dried over magnesium sulphate and concentrated under reduced pressure. Distillation of the remaining liquid through a short column gives the addition products in excellent yields. R¼CH2CH2OH, bp 87 C/15 Torr; R ¼ CH2NMe2, bp 84 C/15 Torr; R ¼ SMe, bp 60 C/15 Torr. 3.9.46

3,4-Pentadien-1-ol from 2-penten-4-yn-1-ol and lithium alanate

Scale: 0.10 molar; Apparatus: 500-ml three-necked, round-bottomed flask with a dropping funnel, a mechanical stirrer and a reflux condenser. 3.9.46.1

Procedure [110,111]

A solution of 4.0 g of lithium alanate in 90 ml of Et2O is added over 15 min to 0.10 mol of 2-penten-4-yn-l-ol (Chapter 4, exp. 4.5.14). The Et2O begins to reflux and a rubber-like greyish precipitate is formed. After heating for 1 h under reflux, the flask is placed in an ice þ ice water bath and a solution of 10 g of water in 40 ml of THF is added dropwise with vigorous stirring. After this operation the organic solution is decanted off and the aqueous jelly layer is extracted ten times with Et2O. The ethereal extracts are dried (without washing) over magnesium sulphate and subsequently concentrated under reduced pressure. Careful distillation of the residue affords 3,4-pentadien-1-ol, bp 55 C/ 15 Torr, in 70% yield. The first fraction (1.5 g) contains some water.

76 3.9.47

3.

GENERATION OF METALLATED ACETYLENES. . .

(E)-Enyne alcohols by reduction of diyne alcohols with lithium alanate

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 3.9.47.1

Procedure (cf. [110,111])

A solution of 4.0 g (slight excess) of lithium alanate in 50 ml of THF is added over 30 min to a mixture of 0.10 mol of the 2-methyl-3,5-hexadiyn-2-ol (Chapter 5, exp. 5.2.3) and 75 ml of THF, while keeping the temperature at 0 C. Fifteen minutes after completion of the addition, the cooling bath is removed. After stirring for an additional 1 h at rt 10 ml of water, dissolved in 40 ml of THF, is added dropwise with vigorous stirring and cooling in a bath at 0 C. The almost clear solution is decanted and the slurry thoroughly rinsed with Et2O. The combined organic solutions are dried over magnesium sulphate and concentrated under reduced pressure. The remaining 2-methyl-3-hexen-5yn-2-ol boils at 65 C/10 Torr and is obtained in an excellent yield. 3.9.48

Conversion of 1-N,N-dimethylamino-3-buten-1-yne into N,N-dimethylaminobutatriene

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml; addition by syringe. It has been shown that the order of the double and triple bond in the enyne amines, H2C¼CHCCNR2, can be reversed with formation of the ynene amines [63], HCCCH¼CHNR2, by the catalytic action of t-BuOK in DMSO or by reaction with alkali amide in liquid ammonia (cf. exp. 3.9.36). This isomerisation proceeds most likely through the anionic intermediate H2C¼C–CCNR2 $ H2C¼C¼C¼C–NR2. Protonation of this gives the free cumulenic amines, H2C¼C¼C¼CHNR2. In the reactions mentioned above

3.9

EXPERIMENTAL SECTION

77

these occur as transient intermediates, reacting further to afford the amines with the reversed enyne system, HCCCH¼CHNR2. Apparently, these are thermodynamically more stable than H2C¼CHCCNR2. Metallation of the latter with a suitable strongly basic reagent under absolutely aprotic conditions should give the anionic species just mentioned. Using the super-basic 1:1 molar combination of BuLi and t-BuOK this metallation can be achieved. Subsequent quenching of the obtained solution with t-butyl alcohol at very low temperatures affords the butatrienyl amines regiospecifically [51]. Primary alcohols or water appear to be unsuitable protonating agents as these cause a rapid isomerisation of the cumulenic amines to the ynene amines, HCCCH¼CHNR2. This isomerisation occurs through the addition of a proton (from the alcohol or water) [115]. 3.9.48.1

Procedure [51]

A solution of 0.14 mol (excess) of BuLi in 88 ml of hexane is added in 1 min to a mixture of 0.10 mol of the enyne amine and 60 ml of THF, while keeping the temperature between –90 and –100 C. Subsequently, a solution of 0.14 mol of t-BuOK in 40 ml of THF is added within 3 min, likewise with cooling between –90 and –100 C. After an additional 5 min a mixture of 0.30 mol (Note 1) of dry (dried by distillation from a small amount of potassium) t-BuOH and 20 ml of Et2O is added with efficient stirring, while keeping the temperature of the reaction mixture below –70 C. The temperature of the reaction mixture is then allowed to reach –20 C and 100 ml of dry paraffin oil, together with some boiling stones are added. The equipment is removed, two stoppers are placed on the outer necks, and the reaction flask is equipped for distillation (cf. Figure 1.10), using a 10-cm Vigreux column, the receiver being cooled in a bath at –70 C. A tube filled with KOH pellets is placed between the receiver and the water aspirator. The system is evacuated (10–20 Torr) and the temperature of the bath gradually raised from 10 to 30 C with decreasing amount of solvent in the flask. Evacuation is continued until the evaporation of solvent has stopped (depression in the centre of the surface of the liquid in the receiver no longer visible). Inert gas is admitted and the receiver is replaced with a small one (100-ml), cooled in a bath at –50 C (Note 2). The system is evacuated again, now by means of a mercury diffusion pump. Warming of the flask is started when the pressure has dropped to below 0.1 Torr. The temperature of the heating bath is gradually raised from rt to 70 C. After heating the flask during an additional 30 min at 70 C, inert gas is admitted. The contents of the receiver consist of (mainly) the yellow cumulenic amine and some t-BuOH and THF. These volatile components are removed by evacuating the receiver for half an hour (10–20 Torr) with warming in a bath at 30 C. The remaining liquid is mainly N,N-dimethylaminobutatriene, yield 70% (5–10% of

78

3.

GENERATION OF METALLATED ACETYLENES. . .

N,N-dimethyl-1-buten-3-yn-1-amine, HCCCH¼CHNMe2, being present). The product has an amazingly high refractive index n20 D 1.639, which is much higher than that of the starting compound (1.493). Notes This amount is required for formation of the 1:1 complex t-BuOK tBuOH. Any non-complexed t-BuOK remaining after protolysis is likely to catalyse isomerisation of the cumulenic amine to N,N-dimethyl-1-buten3-yn-1-amine, HCCCH¼CHNMe2. The complex is a much less active catalyst. 2. All parts of the distillation set-up should be scrupulously dried. The cumulenic amine is very easily converted into HCCCH¼CHNMe2 under the influence of moisture [115].

1.

3.9.49

Conversion of 1-metallated 2-alkynyl ethers into 1-metallated allenic ethers

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml Lithiation of 2-alkynyl ethers, in general, proceeds at the 1-position. Whereas the subsequent reaction with alkyl halides or chloro(trimethyl)silane affords 3-functionalised allenic ethers [50], hydrolysis gives mixtures of the starting compounds and allenic ethers [91]. The ratio of the isomers depends upon the nature of the ether group and the substituents in the acetylenic part in the starting compound. In some cases the allenic ether predominates (cf. [91] and exp. 3.9.40), but in general this metallation-hydrolysis procedure has little synthetic value. If prior to carrying out the aqueous work-up an equivalent of t-BuOK is added to the solution of the lithiated 2-alkynyl ether, almost pure allenic ethers are obtained [116]. After reaction with chloro(trimethyl)silane and alkyl halides allenic ethers functionalised at the 1-position are obtained. Apparently, the hydrogen atom in RC CCH(Li)OMe has migrated to the 3-position after addition of t-BuOK. This migration, which takes place under absolutely aprotic conditions, is

3.9

EXPERIMENTAL SECTION

79

considerably facilitated by addition of a small amount of (the aprotic) HMPT [116]. The mechanism of this migration is not clear. There are many analogue cases known (cf. exp. 3.9.41). 3.9.49.1

Procedure [116]

A solution of 0.12 mol of BuLi in 75 ml of hexane is added with cooling below –80 C to a mixture of 0.10 mol of the 2-alkynyl ether and 70 ml of THF, then the reaction mixture is cooled to –85 C and a solution of 0.12 mol of t-BuOK in 40 ml of THF is added over a few minutes, likewise with strong cooling. Ten minutes after this addition 30 ml (a smaller amount presumably suffices) of dry HMPT is introduced at –85 C. In the case of the reactions with N,Ndiethyl-4-methoxy-2-pentyn-1-amine, MeOCH2CCCH2NEt2, however, no HMPT is added. After stirring the brown solution for 20 min at –85 C, 150 ml of water is added with vigorous stirring. After separation of the layers, two extractions with pentane are carried out. The combined organic solutions are washed three times with small portions of concentrated aqueous ammonium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The allenic ethers 1-methoxy-1,2-heptadiene, nBuCH¼C¼CHOMe, bp 61 C/20 Torr, and N,N-diethyl-4-methoxy-2,3-butadien-1-amine, Et2NCH2CH¼C¼CHOMe, bp 75 C/17 Torr, are obtained in yields of 60 and 75%, respectively. 3.9.50

4-Methyl-1-methoxy-1,2,3-pentatriene from 1,4-dimethoxy-4-methyl-2-pentyne and alkyllithium

Scale: 0.15 molar; Apparatus: Figure 1.1, 500 ml 3.9.50.1

Procedure

A solution of 0.30 mol of BuLi LiBr in 250 ml of Et2O (Chapter 2, exp. 2.3.6) is added over 20 min to a mixture of 0.15 mol of 1,4-dimethoxy-4-methyl-2pentyne (prepared in analogy with the procedures in Chapter 20, exps. 20.6.5 and 20.6.6) and 100 ml of Et2O. During and for 15 min after this addition, the temperature of the reaction mixture is kept between –40 and –50 C. A solution of 15 g of ammonium chloride in 100 ml of water (saturated with nitrogen) is added with vigorous stirring to the still cold reaction mixture. The organic layer is dried over magnesium sulphate and subsequently concentrated

80

3.

GENERATION OF METALLATED ACETYLENES. . .

under reduced pressure. 4-Methyl-1-methoxy-1,2,3-pentatriene, bp 40 C/11 Torr, is obtained in a high yield. In principle, the commercially available solution of BuLi in hexane may be used, but during the removal of the solvents, which in that case has to be carried out by distillation under atmospheric pressure the cumulenic ether will partly polymerise.

Note The cumulenic ether is extremely oxygen-sensitive: A small plug of cotton wool, on which a few drops are sprayed, ignites within a minute. All operation during the work-up therefore must be scrupulously carried out under an atmosphere of inert gas.

3.10

REPLACEMENT OF THE LITHIUM BY OTHER METALS AND APPLICATION IN SYNTHESIS

Replacement of lithium by other metals in lithium acetylides is easily performed by addition of metal halides to solutions of alkynyllithium compounds. The resulting metal derivatives have found useful application in the synthesis of acetylenic ketones, R1CCCOR2, from R1CCBF3Li and esters, R2COOR, or carboxamides [93], R2CONR2, from R1CCCu and acid chlorides [94–97], R2COCl, and from the reaction of R1CCZnCl with acid chlorides [98]. The latter reaction is considerably facilitated by catalytic amounts of Pd(PPh3)4. Trialkylaluminum compounds formed from alkynyllithium and aluminum chloride react with t-alkyl halides to give t-alkylalkynes [99]. Sec- and t-alkyl-substituted acetylenes, R1CCR2 (R2 ¼ sec- or tert-alkyl), can be obtained in high yields from lithium trialkynylboronates [100], R1CCBR23 Li. Reaction of allenic-propargylic anions with an electrophile in many cases gives a mixture of the allenic and the acetylenic derivative. The ratio of the functionalisation products depends inter alia upon the nature of the counter ion. In many cases useful regioselectivities can be achieved by replacing lithium by another metal. Especially allenic-propargylic copper and -zinc derivatives are used to enable successful cross couplings with organohalides and carbonyl compounds. Lithium can be replaced by sodium or potassium by addition of sodium or potassium tert-butoxide to the lithium derivative [79,84]. Allenylcopper(I) compounds, R1R2C¼C¼CHCu, and diallenylcuprates, [R1R2C¼C¼CH]2Cu, can be prepared by addition of one or half an equivalent

REFERENCES

81

of copper(I) halide, respectively, to a solution of the allenyllithium derivative [101,102]. Allenylsilver compounds are obtained by reaction of the lithium derivatives with silver bromide solubilised by addition of anhydrous lithium bromide in tetrahydrofuran [103]. Lithium–zinc exchange can be achieved by addition of anhydrous zinc halide to the allenylic–propargylic lithium compound [104–106]. Complexes of allenylic–propargylic lithium compounds with triorganoaluminum or -boron [107] and tetraalkyl titanates [108] can be used in regioselective couplings with carbonyl compounds and allylic halides. Conversion of acetylenes RCCH into their Grignard derivatives generally proceeds less easily than lithiation with alkyllithium. In some cases it may be more convenient to prepare first the lithium alkynylide and subsequently add an equivalent amount of magnesium bromide–Et2O, which is readily obtained by reaction of 1,2-dibromoethane with magnesium in ether. Especially the Grignardation of gaseous acetylenes such as propyne with ethylmagnesium halide is a tedious procedure since the acetylene is swept along by the ethane evolved in this reaction.

3.11

SOLUBILITIES OF ALKALI ACETYLIDES

In the various procedures involving functionalisation dealt with in Chapters 4–9 the solubility of metallated acetylenes is an important aspect. It can have a strong influence on the reactivity and may determine the choice of the reaction conditions applied in a given experimental procedure. Table 3.6 (on p. 40–41) gives a qualitative picture of the solubilities of several metallated acetylenes in liquid ammonia and in organic solvents.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.

H. D. Verkruijsse and L. Brandsma, Synth. Commun. 20, 3375 (1990). E. I. Negishi, A. O. King and J. M. Tour, Org. Synth. 64, 44 (1986). A. Krebs, T. Wehlage and C.-P. Kramer, Tetrahedron Lett. 31, 3533 (1990). P. A. Rose, S. R. Abrams and A. C. Shaw, Tetrahedron Asymmetry 3, 443 (1990). J. A. Marshall and W. L. Gung, Tetrahedron Lett. 29, 1657 (1988). H. D. Verkruijsse, W. de Graaf and L. Brandsma, Synth. Commun. 18, 131 (1988). Unpublished results from the author’s laboratory. W. N. Smith and O. F. Beumel, Jr., Synthesis, 441 (1974). P. E. van Rijn, S. Mommers, R. G. Visser, H. D. Verkruijsse and L. Brandsma, Synthesis, 459 (1981). 10. M. M. Midland, J. Org. Chem. 40, 2250 (1975).

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GENERATION OF METALLATED ACETYLENES. . .

11. E. R. H. Jones, L. Skattebøl and M. C. Whiting, Org. Synth., Coll. Vol. 4, 792 (1953); A. B. Holmes and C. N. Sporikou, Org. Synth., Coll. Vol. 8, 606 (1993). 12. L. Brandsma and H. D. Verkruijsse, Synthesis, 1727 (1999). 13. E. Hengge and A. Baumegger, J. Organometal. Chem. 369, C39 (1989). 14. E. Hengge, A. Baumegger, M. Eibl, E. Hohenester and C. Kraty, Angew. Chem. 102, 722 (1990); Int. Edn. 29, 641 (1990). 15. W. Voskuil and J. F. Arens, Recl. Trav. Chim., Pays-Bas 81, 993 (1962). 16. L. Brandsma, Recl. Trav. Chim., Pays-Bas 83, 307 (1964). 17. P. A. A. Klusener, H. Hommes, J. C. Hanekamp, A. C. H. T. M. van der Kerk and L. Brandsma, J. Organometal. Chem. 409, 67 (1991). 18. P. E. van Rijn and L. Brandsma, J. Organometal. Chem. 233, C25 (1982). 19. L. Brandsma, H. D. Verkruijsse and M. Fossatelli, Recl. Trav. Chim., Pays-Bas 110, 131 (1991). 20. M. Fossatelli, A. C. T. H. M. van der Kerk, S. F. Vasilevsky and L. Brandsma, Tetrahedron Lett. 33, 4229 (1992). 21. L. Brandsma, Preparative Acetylenic Chemistry. Elsevier, Amsterdam, 1971. 22. P. E. van Rijn, R. H. Everhardus and L. Brandsma, Recl. Trav. Chim., Pays-Bas 99, 179 (1980). 23. E. C. Stracker and G. Zweifel, Tetrahedron Lett. 31, 6815 (1990); J. Anthony and F. Diederich, Tetrahedron Lett. 32, 3787 (1991). 24. G. Zweifel and S. Rajagopalan, J. Am. Chem. Soc. 107, 700 (1985). 25. D. L. Danheiser, A. Nishida, S. Savarovar and M. Trova, Tetrahedron Lett. 29, 4917 (1988). 26. E. Valenti, M. A. Pericar and F. Serratosa, J. Org. Chem. 55, 395 (1990). 27. E. Negishi, N. Okukado, S. F. Lovich and F.-T. Luo, J. Org. Chem. 49, 2629 (1984). 28. S. Raucher and B. L. Bray, J. Org. Chem. 52, 2332 (1987). 29. J. H. van Boom, P. P. Montijn, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 84, 31 (1965). 30. L. Brandsma, Recl. Trav. Chim., Pays-Bas 82, 1119 (1963). 31. A. Vaitiekunas and F. F. Nord, J. Org. Chem. 19, 902 (1954). 32. H. Hommes, H. D. Verkruijsse and L. Brandsma, Recl. Trav. Chim., Pays-Bas 99, 113 (1980). 33. S. Bhanu and F. Scheinmann, J. Chem. Soc., Chem. Comm., 817 (1975). 34. A. J. G. Sagar and F. Scheinmann, Synthesis, 321 (1976). 35. G. R. Khan, K. A. Povev and F. Scheinmann, J. Chem. Soc., Chem. Comm., 215 (1979); J. Chem. Soc., Perkin I, 1609 (1976); 2338 (1980). 36. L. Brandsma, Preparative Acetylenic Chemistry. Elsevier, Amsterdam, 1988, 2nd edn., p. 33. 37. J. Klein, in his review in The Chemistry of the C–C Triple Bond (ed. S. Patai). John Wiley, 1978, p. 373. 38. H. Hommes, H. D. Verkruijsse and L. Brandsma, J. Chem. Soc., Chem. Comm., 366 (1981). 39. H. Hommes, H. D. Verkruijsse and L. Brandsma, Tetrahedron Lett. 22, 2495 (1981). 40. H. Hommes, H. D. Verkruijsse, R. L. P. de Jong and L. Brandsma, Recl. Trav. Chim., PaysBas 104, 226 (1985). 41. J. C. Hanekamp, P. A. A. Klusener and L. Brandsma, Synth. Commun. 19, 2691 (1989). 42. A. G. Mal’kina, O. A. Tarasova, H. D. Verkruijsse, A. C. H. T. M. van der Kerk, L. Brandsma and B. A. Trofimov, Recl. Trav. Chim., Pays-Bas 114, 18 (1995). 43. W. Kulik, H. D. Verkruijsse and R. L. P. de Jong, Tetrahedron Lett. 24, 2203 (1983). 44. P. A. A. Klusener, W. Kulik and L. Brandsma, J. Org. Chem. 52, 5261 (1987). 45. J. B. Baudin, S. A. Julia and R. Lome, Synlett 7, 509 (1991). 46. S. Hoff, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 87, 916 (1968). 47. R. M. Carlson, R. W. Jones and A. S. Hatcher, Tetrahedron Lett. 16, 1741 (1975). 48. R. M. Carlson and J. L. Islor, Tetrahedron Lett. 14, 4819 (1973). 49. E. J. Corey and D. E. Cane, J. Org. Chem. 35, 3405 (1970). 50. Y. Leroux and R. Mantione, Tetrahedron Lett., 591 (1971).

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51. L. Brandsma, P. E. van Rijn, H. D. Verkruijsse, P. von and R. Schleyer, Angew. Chem. 94, 875 (1982); Int. Edn. 21, 862. 52. O. A. Tarasova, F. Taherirastgar, H. D. Verkruijsse, A. G. Mal’kina, L. Brandsma and B. A. Trofimov, Recl. Trav. Chim., Pays-Bas 115, 145 (1996). 53. R. Mantione, A. Alves, P. P. Montijn, G. A. Wildschut, H. J. T. Bos and L. Brandsma, Recl. Trav. Chim., Pays-Bas 89, 97 (1970). 54. J. C. Craig and M. Moyle, J. Chem. Soc., 4402 and 5356 (1963). 55. E. J. Corey and H. A. Kirst, Tetrahedron Lett., 5041 (1968). 56. E. J. Corey, H. A. Kirst and J. A. Katzenellebogen, J. Am. Chem. Soc. 92, 6314 (1970). 57. A. A. Petrov, I. A. Maretina and V. A. Kormer, J. Gen. Chem. (USSR) 33, 407 (1963); Zh. Obschei Khim 33, 413 (1963). 58. L. N. Cherkasov, V. A. Kormer, Kh. V. Bal’yan and A. A. Petrov, J. Org. Chem. (USSR) 2, 1533 (1966); Zh. Org. Khim 2, 1573 (1966). 59. J. H. Wotiz, W. E. Billups and D. T. Christian, J. Org. Chem. 31, 2069 (1966). 60. (a) C. A. Brown and A. Yamashita, J. Chem. Soc., Chem. Comm., 959 (1976); (b) S. R. Macaulay, J. Org. Chem. 43, 734 (1980); (c) L. A. Remizova, A. V. Kryukov, I. A. Balova and I. A. Favorskaya, Zh. Org. Khim. 21, 1001 (1985); Engl. page 909. 61. H. Hommes and L. Brandsma, Recl. Trav. Chim., Pays-Bas 96, 160 (1977). 62. J. C. Lindhoudt, G. L. van Mourik and H. J. J. Pabon, Tetrahedron Lett., 2565 (1976). 63. W. Verboom, J. W. Zwikker, R. H. Everhardus and L. Brandsma, Recl. Trav. Chim., Pays-Bas 99, 325 (1980). 64. L. Brandsma, A. G. Mal’kina and B. A. Trofimov, Synth. Commun., 2721 (1994). 65. M. S. Paley, D. O. Frazier, H. Abeledeyem, S. P. McManus and S. E. Zutaut, J. Am. Chem. Soc. 114, 3247 (1992). 66. J. Villieras, P. Perriot and J. F. Normant, Synthesis, 458 (1975). 67. J.-F. Normant, Bull. Soc. Chim. France, 1976 (1963). 68. R. H. Smithers, Synthesis, 556 (1985). 69. J. Ficini and C. Barbara, Bull. Soc. Chim. France, 871 (1964); 2787 (1965). 70. J. Ficini, J. Besseyre and A. Krief, Bull. Soc. Chim. France, 987 (1976). 71. G. Himbert, H. Umbach and M. Barz, Z. Naturforsch, Teil B 29, 661 (1984). 72. D. Faul and G. Himbert, Liebigs Ann. Chem., 1466 (1986). 73. A. Lo¨ffler and G. Himbert, Synthesis, 232 (1991). 74. A. Bartolome, U. Sta¨mpfli and M. Neuenschwander, Helv. Chim. Acta 74, 1264 (1991). 75. E. J. Corey and P. L. Fuchs, Tetrahedron Lett., 3760 (1972). 76. J. Villieras, P. Perriot and J. F. Normant, Synthesis, 458 (1975). 77. T. B. Patrick and J. L. Honegger, J. Org. Chem. 39, 3791 (1974). 78. G. Himbert and M. Feustel, Tetrahedron Lett. 24, 2165 (1983); Liebigs Ann. Chem., 586 (1984). 79. L. Brandsma and H. D. Verkruijsse, Synthesis of Acetylenes, Allenes and Cumulenes. A Laboratory Manual. Elsevier, Amsterdam, 1981, p. 103. 80. p. 245 of Ref. 36. 81. F. Taherirastgar and L. Brandsma, Synth. Commun. 27, 4035 (1997). 82. G. Pourcelot and P. Cadiot, Bull. Soc. Chim. France, 1890 (1960); 1278 (1962); 3016, 3025 (1966). 83. J. P. Ward and D. A. van Dorp, Recl. Trav. Chim., Pays-Bas 85, 117 (1966). 84. L. Brandsma and H. D. Verkruijsse, Preparative Polar Organometallic Chemistry. SpringerVerlag, Heidelberg, 1987, Vol. 1, p. 107. 85. N. A. Khan, Org. Synth., Coll. Vol. 4, 969 (1963). 86. E. R. H. Jones, G. Eglinton and M. C. Whiting, Org. Synth., Coll. Vol. 4, 755 (1963). 87. E. R. H. Jones, G. Eglinton, B. L. Shaw and M. C. Whiting, Org. Synth., Coll. Vol. 4, 404 (1963). 88. S. Hoff, B. H. Steenstra, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 88, 1284 (1969).

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89. P. P. Montijn, H. M. Schmidt, J. H. van Boom, H. J. T. Bos, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 84, 271 (1965). 90. R. Mantione and B. Kirchla¨ger, Compt. Rend., Acad. Sci. (Paris) 212, 786 (1971). 91. E. J. Corey and S. Terashima, Tetrahedron Lett., 1815 (1972). 92. L. Brandsma and E. Mugge, Recl. Trav. Chim., Pays-Bas 92, 628 (1973). 93. M. Yamagughi, K. Shibato, S. Fujiwara and L. Hirao, Synthesis, 421 (1986). 94. J.-F. Normant and M. Bourgain, Tetrahedron Lett., 2659 (1970). 95. J.-F. Normant and M. Bourgain, Bull. Soc. Chim. France 1777, 2139 (1973). 96. H. O. House and M. J. Umen, J. Org. Chem. 38, 3893 (1973). 97. J.-F. Normant, Synthesis, 63 (1972). 98. E. Negishi, V. Bagheri, S. Chatterjee, F.-T. Luo, J. A. Miller and A. T. Stol, Tetrahedron Lett. 24, 5181 (1983). 99. E. Negishi and S. Baba, J. Am. Chem. Soc. 97, 7385 (1975). 100. A. Suzuki, N. Miyaura, S. Abiko, M. Itoh, H. C. Brown, J. A. Sinclair and M. M. Midland, J. Am. Chem. Soc. 95, 3080 (1973). 101. D. Michelot and G. Linstrumelle, Tetrahedron Lett., 275 (1976). 102. K. Ruitenberg, J. Meijer, R. J. Bullee and P. Vermeer, J. Organometal. Chem. 217, 267 (1981). 103. J. Meijer, K. Ruitenberg, H. Westmijze and P. Vermeer, Synthesis, 551 (1981). 104. F. Mercier, R. Epzstein and S. Holand, Bull. Soc. Chim. France, 690 (1972). 105. F. Mercier and R. Epzstein, J. Organometal. Chem. 108, 165 (1976). 106. R. Epzstein and F. Mercier, Synthesis, 183 (1977); J. C. Craig, N. N. Ekwuribe, Tetrahedron Lett., 275 (1976). 107. N. R. Pearson, G. Hahn and G. Zweifel, J. Org. Chem. 47, 3364 (1982); G. Zweifel, S. J. Backlund and T. Leung, J. Am. Chem. Soc. 100, 5561 (1978). 108. D. Hoppe and G. Gonschorrek, Tetrahedron Lett. 28, 275 (1987). 109. J.-C. Clinet and G. Linstrumelle, Tetrahedron Lett., 1137 (1978). 110. E. B. Bates, E. R. H. Jones and M. C. Whiting, J. Chem. Soc., 1854 (1954). 111. F. Bohlmann, R. Enkelmann and W. Plettner, Chem. Ber. 97, 2118 (1964). 112. A. Jo¨gi and U. Ma¨org, ARKIVOC. 26 (2001); U. Ma¨org, L. Talu and K. Kallas, Proc. Estonian Acad. Sci. Chem. 45, 140 (1996). 113. A. Mostamandu, L. A. Remisova, L. V. Yakimovich and I. A. Favorskaya, Zh. Org. Khim. 17, 1166 (1981). 114. I. A. Balova, S. N. Morozkina, D. W. Knight and S. F. Vasilevski, Tetrahedron Lett. 44, 107 (2003); I. A. Balova, L. A. Remisova and I. A. Favorskaya, Zh. Org. Khim. 24, 2523 (1988). 115. P. E. van Rijn, W. Klop, H. D. Verkruijsse, P. von R. Schleyer and L. Brandsma, J. Chem. Soc., Chem. Comm., 79 (1983). 116. H. D. Verkruijsse, W. Verboom, P. E. van Rijn and L. Brandsma, J. Organometal. Chem. 232, C1 (1982).

4 Reactions of Metallated Acetylenes and Allenes with Alkylating Agents

4.1

ALKYLATION WITH ALKYL HALIDES

Compared to many other types of synthetic intermediates, 1-alkynylides, RCCM (M ¼ Li, Na, K), show a moderate reactivity towards alkyl halides in the usual organic solvents Et2O and THF and in liquid ammonia. In this respect acetylides resemble enolates, >C¼COM. In the absence of dipolar aprotic co-solvents (DMSO or HMPT), lithium alkynylides, RCCLi, react sluggishly in Et2O or THF with most alkyl halides. In liquid ammonia, the alkylation of alkali alkynylides with the lower (up to C-5) primary alkyl bromides or iodides proceeds at a satisfactory rate. A certain amount of DMSO added to the reaction mixture increases the solubility of halides with a longer carbon chain. A second effect of the addition of this co-solvent is that the temperature of the reaction mixture can gradually rise when most of the ammonia has evaporated. In this way, the reaction can proceed gradually over the range from –33 C (bp NH3) to room temperature. At higher temperatures isomerisation of 1-alkynes, RCH2CCH, obtained from MCCH and RCH2X (X ¼ Br or I), to 2-alkynes, RCCMe, may occur when the acetylide HCCM is present in a large excess, especially if M ¼ Na or K [1a]. DMF has been successfully used as a solvent in alkylations with higher alkyl bromides of sodium acetylide prepared in liquid ammonia [1b]. High yields are obtained also in the alkylation of the readily available LiCCH-1,2-ethanediamine complex in DMSO [1c]. This solvent [9] as well as N,N-dimethylpropyleneurea (DMPU) [1d] allows a smooth alkylation of lithium alkynylides, RCCLi, in THF under mild conditions. Selective alkylation on acetylenic carbon takes place if an equivalent amount of an alkyl halide is added to dilithiated propargyl alcohol, LiCCCH2OLi, in liquid ammonia [10]. With the di-sodium compound the alkylation is not selective. This reaction may be extended to other types of acetylenic alcohols 85

86

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REACTIONS OF METALLATED ACETYLENES. . .

such as 2-penten-4-yn-1-ol, HCCCH¼CHCH2OH, and 5-hexyn-1-ol, HCC(CH2)4OH [9].

The more strongly basic alkali metal compounds with the structure systems MC¼C¼C or CC–CM, obtained by metallation of non-terminal acetylenes or allenes, are much more reactive towards alkylating agents. 1,3-Dilithiated acetylenes, LiCCCH(Li)R, are alkylated with high regioselectivity at the most strongly basic propargylic site [2–8]. This method gives access to acetylenes with a sec-alkyl group, not obtainable by reaction of alkali acetylides with secondary alkyl halides.

Successful alkylation reactions of alkali acetylides are restricted to primary alkyl halides and alkylating agents with the general structure XCH2CH2R, in which, X ¼ Br or Cl and R ¼ Alkyl, OAlkyl, NH2 or NR12 [11]. Tertiary and secondary alkyl halides, as well as 2-substituted ethyl halides, RCH2CH2X, in which R ¼ R1S, Ph, R1CC, R1CH¼CH, COOH, etc., undergo dehydrohalogenation. 1,3-Dibromopropane gave decreased yields [9] of 1,6-heptadiyne in its reaction with alkali acetylides in liquid ammonia. 1-Bromo-2-methylpropane, Me2CHCH2Br, 1-bromo-2,2-dimethylpropane, Me3CCH2Br, and 2-bromo-1,1-diethoxyethane, BrCH2CH(OEt)2, did not react or reacted sluggishly [9]. With allylic, propargylic and benzylic halides, complicated mixtures resulting from isomerisation of the initially formed coupling products are obtained. In the case of benzyl halide formation of 1,2-diphenylethene, ArCH2CH2Ar, is also possible [12,13]. An excellent method for connecting 1-alkynes with sec- and tert-alkyl groups consists of reacting the trialkynylaluminium with the halide [14].

4.1

ALKYLATION WITH ALKYL HALIDES

87

Allylic and propargylic bromides or tosylates can be coupled with alkynylmagnesium halides in the presence of catalytic amounts of copper(I) halides [15–19].

Tosylates react somewhat more easily, which permits the couplings to be carried out at temperatures in the region of 0 C [19]. Using these conditions the following side reaction is suppressed. Moreover, the amounts of 1,3-substitution products, 1,2-alkadien-4-ynes, RCCCH¼C¼CH2, are somewhat less if tosylates are used [19].

Anionic species –CCC $ C¼C¼C–, formed by deprotonation of acetylenes with a non-terminal triple bond or of allenic compounds, show a much higher reactivity towards alkyl halides than do acetylenic anions, –CC. The former species show less limitations with regard to the nature of the alkyl halide [9]. In many cases the alkylation proceeds smoothly in THF in the absence of polar co-solvents at temperatures below 0 C. Some species, however, are only stable at very low temperatures and for a smooth alkylation the assistance of a strongly polar co-solvent is needed. Unfortunately, DMSO is useless because it undergoes an easy deprotonation by the strongly basic anionic species. It has been shown that HMPT, added in stochiometric amounts only, gives excellent results in the reaction of lithiated propadiene, LiCH¼C¼CH2, and of lithiated methoxyallene, H2C¼C¼C(Li)OMe, with alkyl bromides at very low temperatures [9]. If HMPT is not available or working with it is not allowed, one may use alkyl iodides or carry out the reaction in the presence of N,N-dimethylpropyleneurea (DMPU). Lithiated 2-alkynyl ethers, RCCCH(Li)OR1, react with alkyl halides to give exclusively allenic products [42a], RC(R2)¼C¼CHOR1, the analogous lithiated thioethers undergo this regioselective g-alkylation also if R is not a

88

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REACTIONS OF METALLATED ACETYLENES. . .

bulky group [9,42b]. Lithiated acetylenic amines, RCCCH(Li)NR12 (R ¼ Ph or Alkyl, R12 N ¼ piperidyl or morpholyl), have been reported to undergo methylation with dimethyl sulphate with formation of 1,2-dienyl-1-amines [42c], RC(Me)¼C¼CHNR12 .

4.2

REACTION WITH OXIRANES AND OXETANES

The b-hydroxyalkylation of lithium and sodium alkynylides with monosubstituted oxiranes proceeds with excellent results in liquid ammonia [24]. Completion of the reaction takes at least 12 h. In DMSO and HMPT the reactions are much faster [9].

Lewis acids effectively assist in the ring opening by acetylides. Reaction of cyclohexeneoxide (7-oxabicyclo[4.1.0]heptane) and cyclopenteneoxide (6-oxabicyclo[3.1.0]hexane) with a lithiated 1-alkyne in THF proceeds under the influence of BF3-etherate with high yields [20]. Similar results have been obtained with LiCCSPh and cycloalkeneoxides [21]. Lithium acetylides, LiCCH and LiCCPh (used in large excess), in THF have been reacted with oxetane and substituted oxetanes in the presence of BF3-etherate to give the g-hydroxyalkylation products in good yields [23]. In the absence of this Lewis acid lithium acetylides do not react with oxetanes. Lithium bromide also seems to be capable in assisting ring opening of oxiranes. Whereas a solution of lithiomethoxyallene in THF prepared by metallation of methoxyallene with commercial BuLi reacted very sluggishly with epoxyethane [9], an excellent result was obtained when BuLiLiBr prepared from butyl bromide and lithium in diethyl ether was used for the metallation [22].

The peculiar formation of (E)-pentenynol (3), in a fair yield, from the reaction between sodium acetylide and epichlorohydrine (1) in liquid ammonia [24] may be explained by assuming successive substitution of chlorine by the

4.3

REACTION OF METALLATED ACETYLENES

89

ethynyl group and eliminating ring opening of 2-(2-propynyl)oxirane (2) by sodium acetylide. The modest yield (50%) of (E)-2-penten-3-yn-1-ol (3) is explained by the easy ring closure of the (Z)-enynolate to the volatile 2-methylfuran, which is entrained by the evaporating ammonia [25].

If lithium acetylide is used, a mixture of comparable amounts of both geometrical isomers is obtained in high yield [26]. Metallated allenic sulphides, RCH¼C¼C(Na)SR1, react smoothly with oxirane in liquid ammonia to give the expected alcohols RCH¼C¼ C(SR1)CH2CH2OH in high yields [9]. From the reaction of t-butylallenyllithium with oxirane at low temperature in THF in the presence of HMPT 6,6-dimethyl-3,4-heptadien-1-ol, t-BuCH¼C¼CHCH2CH2OH, is obtained [9]. Possibly, HMPT is not necessary in this case. Like alkyl halides, oxiranes show a strong preference for reaction with the most strongly basic sites in 1,3-dimetallated acetylenes [2].

4.3

REACTION OF METALLATED ACETYLENES AND ALLENES WITH a-HALOETHERS

Reactions of a-haloethers are not very demanding with regard to the polarity of the solvent and the nature of the counter ion. Alkali acetylides as well as the Grignard derivatives react smoothly, even in diethyl ether [27]. Ammonia and strongly dipolar solvents, such as DMSO, do not seem suitable media since ammonolysis or dehydrohalogenation may predominate. In the reaction of a,b-dibromoethers, RCH(Br)CH(Br)OR1, with Grignard compounds, the a-bromine atom is specifically displaced [28]. The reaction of lithium alkynylides

90

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REACTIONS OF METALLATED ACETYLENES. . .

with 1,2-dihaloethers gives poor results (much tar) [9]. Lithiated methoxyallene and a-chloroethers also give the expected products [29]. Allenylmagnesium bromide reacts with a,b-dibromoethers to form the acetylenic compound as the main product [30].

4.4

REACTION WITH ORTHOESTERS

Alkynyl Grignard compounds and trialkoxymethanes give acetylenic acetals in good yield. The reaction is usually carried out in diethyl ether [31]. Alkali acetylides do not react. This substitution reaction requires the assistance of magnesium halide, which complexes with an ether group in the trialkoxymethane thus facilitating the attack of the acetylide.

4.5

EXPERIMENTAL SECTION

Note: In most of the procedures the reaction mixture is kept under inert gas.

4.5

EXPERIMENTAL SECTION

91

The reason for not illustrating the reaction of alkali acetylides in liquid ammonia with fewer experimental procedures is that there are several factors determining the nature and number of the various operations including the work-up. For example, the sensitivity of methyl iodide towards ammonia requires this reagent to be introduced by syringe in a way such that the end of the needle is kept just above or just under the rotating reaction mixture (e.g. exp. 4.5.2). It may be further necessary to cool a reaction mixture to below the boiling point of ammonia to prevent loss of volatile product due to entraining with the ammonia vapour. Cooling also may be applied to suppress frothing, which often occurs when the alkali metal compound has a low solubility in liquid ammonia forming a thick suspension. For obtaining an optimal yield of relatively volatile products it may be desirable to apply a special technique of working up, consisting of pouring the reaction mixture onto crushed ice followed by extraction with a high-boiling solvent. This extraction technique is also useful if the product is not very stable. The product can be isolated from the extract by evacuation and condensation in a strongly cooled receiver. Too strong heating of the extract can be avoided by this operation. In the case of a volatile extraction solvent this has to be distilled off at atmospheric pressure, which requires relatively prolonged heating of the solution. Of the various factors solubility of the metallic intermediate is an important one. It may have an influence on its reactivity as well as on the mobility of the reaction mixture. DMSO can be used as a co-solvent in reactions of alkali acetylides with higher alkyl halides in liquid ammonia, which react sluggishly due to their low solubility in this solvent. 4.5.1

Methylation of lithiated N,N-diethyl-2-propyn-1-amine

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre, addition by syringe

4.5.1.1 Procedure Methyl iodide (0.25 mol, excess) is added (Note 1) over 15 min to a vigorously stirred suspension of the lithiated propynamine (Chapter 3, exp. 3.9.4) prepared from 0.20 mol of the amine and 0.25 mol of lithium amide (Note 2) in 300 ml of liquid ammonia. During this addition the temperature of the reaction mixture is kept just below the bp of ammonia while inert gas is slowly introduced. The thick suspension, present in the beginning, disappears almost

92

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REACTIONS OF METALLATED ACETYLENES. . .

completely. After an additional 10 min the flask is equipped as shown in Figure 1.7 and the ammonia is allowed to evaporate. To the remaining salty mass 200 ml of water is added and extraction with Et2O is carried out. The organic solution is dried over potassium carbonate and concentrated under reduced pressure, after which the remaining liquid is carefully fractionated. The methylation product, N,N-diethyl-2-butyn-1-amine, bp 40 C/12 Torr, is obtained in an excellent yield. Notes 1.

In order to minimise contact of the sensitive methyl iodide with the ammonia vapour, the end of the needle of the syringe should be kept a few cm only above the reaction mixture. 2. The excess of lithium amide and methyl iodide serves to re-metallate some free acetylenic compound resulting from reaction of the lithium compound with MeNH2HI formed by competitive attack of methyl iodide by liquid ammonia.

4.5.2

1,3-Pentadiyne by methylation of sodium diacetylide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre, addition by syringe, stirrer Figure 1.2 4.5.2.1

Procedure [32–34]

Methyl iodide (0.20 mol) is added dropwise over 20 min to a vigorously stirred suspension prepared from 0.20 mol of 1,4-dichloro-2-butyne and 0.60 mol of sodamide in 250 ml of liquid ammonia (Chapter 3, exp. 3.9.26, Note 1), while keeping its temperature between 40 and 45 C and introducing nitrogen slowly. During the addition the end of the needle of the syringe is kept a few cm above the reaction mixture. The ‘viscosity’ of the reaction mixture gradually decreases. After an additional 15 min 100 ml of high-boiling petroleum ether (bp > 170 C/760 Torr) is added and the reaction mixture is poured on to 300 g of finely crushed ice in a wide-necked 2-litre round-bottomed flask (Figure 1.8) or spread on the bottom of a large beaker. The remaining slurry is rinsed out of the reaction flask with a small amount of water. After melting

4.5

EXPERIMENTAL SECTION

93

of the ice and separation of the layers six extractions with very small portions of petroleum ether (Note 2) are carried out. The combined organic solutions are washed with cold dilute hydrochloric acid (Note 3), dried over a small amount of magnesium sulphate and then transferred into a 1-litre flask, equipped for a vacuum distillation (40-cm Vigreux column, single receiver cooled in a bath at –70 C, Figure 1.10). The flask is heated until the petroleum ether begins to pass over. A small amount of crystals of 2,4-hexadiyne appears in the head of the column. Repetition of this procedure with the contents of the receiver, now keeping the temperature of the heating bath below 40 C, gives fairly pure ( 94%) 1,3-pentadiyne. Some 2,4-hexadiyne still remains present. Yields may be as high as 80%. Notes 1. 2. 3.

For obtaining optimal yields high concentrations seem to be essential. Frequent extraction has been found to be essential. It is important to follow exactly the instructions for the preparation of sodamide in Chapter 2. The use of too much ferric nitrate for the preparation of sodamide gives rise to the formation of a Fe(OH)3 gel during the work-up making separation of the layers very difficult.

4.5.3

2,4-Hexadiyne by methylation of disodium diacetylide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre, addition by syringe, stirrer Figure 1.2 4.5.3.1 Procedure A concentrated solution of disodium diacetylide is prepared (Chapter 3, exp. 3.9.26) from 0.20 mol of 1,4-dichloro-2-butyne and 0.80 mol of sodamide in 400 ml of liquid ammonia. Methyl iodide (0.45 mol) is added over 20 min in a way such that the end of the needle of the syringe is kept just above the reaction mixture, which is cooled to –45 C during the addition. After an additional 15 min 150 ml of pentane is added and the reaction mixture is treated with 500 g of crushed ice as described in the preceding experiment. After melting of the ice three extractions with small portions of pentane are carried out. After drying

94

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REACTIONS OF METALLATED ACETYLENES. . .

the organic solution over magnesium sulphate, the greater part (70%) of the pentane is distilled off at atmospheric pressure through a 30-cm Vigreux column. Strong cooling of the concentrated solution gives light-brown crystals, which are isolated by suction filtration on sintered glass. Concentration of the mother liquor and cooling gives a second crop, bringing the yield at 75%. Very pure crystals of 2,4-hexadiyne, mp 67 C, may be obtained by sublimation. The higher homologues RCCCCR (R ¼ Et, n-Prop) are prepared by adding the alkyl bromides (0.50 mol) over 1 h to the solution of NaC CCCNa with cooling just below the bp of ammonia. After stirring for an additional 2 h, the ammonia is allowed to evaporate (Figure 1.7) and the remaining salty mass is treated with water. After extraction with pentane, drying and removal of the solvent under reduced pressure, the remaining liquid is distilled in vacuo. 3,5-Octadiyne, bp 47 C/15 Torr and 4,6-decadiyne, bp 80 C/15 Torr, are obtained in 60% yields.

4.5.4

Methylation of the lithiated O-protected propargyl alcohol

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml, addition by syringe 4.5.4.1

Procedure

Methyl iodide (0.25 mol) is added dropwise over 15 min to a solution of 0.20 mol of the lithiated O-protected propargyl alcohol prepared by reaction of 0.20 mol of 3-(1-ethoxyethoxy)-1-propyne with 0.25 mol (excess, Note 1) of lithium amide in 300 ml of liquid ammonia (Chapter 3, exp. 3.9.3). During this addition the reaction mixture is kept between 40 and 45 C and inert gas is introduced. For the technique of addition see preceding experiments. Ten minutes after the addition the ammonia is allowed to evaporate (Figure 1.7). After dissolution of the salt in 150 ml of water two extractions with Et2O are carried out. The organic solutions are dried over potassium carbonate and concentrated under reduced pressure. After addition of 1 ml of diethylamine (Note 2) the remaining liquid is distilled through a 20-cm Vigreux column to give 1-(1-ethoxyethoxy)-2-butyne, bp 50 C/15 Torr, in excellent yield.

4.5

EXPERIMENTAL SECTION

95

Note 1.

2.

Competitive reaction of methyl iodide with ammonia gives MeNH2HI, which protonates the lithium acetylide. The excess of lithium amide serves to re-generate the lithium compound. The O-protected alcohol may undergo decomposition under the influence of traces of acid that might adhere to the glass. The amine effectively neutralises this acid.

4.5.5

Methylation of a lithiated acetylene in a THF–DMSO mixture

Scale: 0.10 molar; Apparatus: Figure 1.1, 250 ml, addition by syringe 4.5.5.1 Procedure Methyl iodide (0.12 mol) is added over a few min to a solution of lithiated 3-(1ethoxyethoxy)-1-propyne (Chapter 3, exp. 3.9.4) at rt. Dry DMSO (20 ml) is added and the temperature of the solution is allowed to rise to 30 C. After 1 h, 100 ml of water is added and three extractions with pentane are carried out. The organic solutions are washed twice with water and dried over potassium carbonate. 1-(1-Ethoxyethoxy)-2-butyne is isolated in an excellent yield as described in the preceding experiment. Dimethyl sulphate (0.11 mol) can also be used and in this case the work-up is carried out with dilute potassium hydroxide.

4.5.6

1,3-Hexadiyne by reaction of sodium diacetylide with ethyl bromide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre, stirrer Figure 1.2

96 4.5.6.1

4.

REACTIONS OF METALLATED ACETYLENES. . .

Procedure

To an efficiently stirred suspension in 400 ml of liquid ammonia containing 0.20 mol of sodium diacetylide (Chapter 3, exp. 3.9.26) is added 0.30 mol of ethyl bromide over 45 min with cooling between 35 and 40 C. After an additional 1 h, 100 ml of high-boiling petroleum ether (bp>170 C) is added and the mixture is poured on to 500 g of finely crushed ice in a 3-litre widenecked round-bottomed flask or spread on the bottom of a large beaker. The remaining slurry is rinsed out from the reaction flask with some water. After separation of the layers three extractions with small portions of petroleum ether are carried out. The organic solution is washed with dilute hydrochloric acid and dried over a small amount of magnesium sulphate. The rather volatile 1,3-hexadiyne is isolated as described in exp. 4.5.2 (a few millilitres of petroleum are allowed to pass over in the first distillation procedure). Distillation of the contents of the cold receiver (pressure 10 to 20 Torr) gives the pure diyne in 55% yield. 4.5.7

Alkylation of lithium ethoxyacetylide

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml 4.5.7.1

Procedure

Ethyl bromide (0.25 mol), propyl bromide (0.22 mol) or butyl bromide (0.20 mol) is added dropwise over 45 min to a solution of 0.20 mol of lithium ethoxyacetylide in 250 ml of liquid ammonia (Chapter 3, exp. 3.9.23) kept at a temperature between 35 and 40 C. In the case of butyl bromide 50 ml of DMSO is subsequently added. After an additional 1.5 h the flask is equipped as shown in Figure 1.7 and the ammonia is allowed to evaporate. The salt is dissolved by addition of 150 ml of water, after which three extractions with small portions of pentane are carried out. After washing with water (in the case of the butylation) and drying the organic solution over potassium carbonate, the greater part of the pentane is distilled off at atmospheric pressure through an efficient column. The temperature of the heating bath should be kept below 80 C (1-alkynyl ethers eliminate ethylene upon strong heating [35]). The remaining liquid is distilled in vacuo. 1-Ethoxy-1-butyne, bp 50 C/90 Torr, 1-ethoxy-1-pentyne, bp 45 C/40 Torr, and 1-ethoxy-1-hexyne, bp 45 C/12 Torr, are obtained in at least 70% yields.

4.5 4.5.8

EXPERIMENTAL SECTION

97

1-Pentyne, 1-hexyne and 1-heptyne

Scale: 0.50 molar (RBr); Apparatus: Figure 1.1, 1 litre, stirrer Figure 1.2 4.5.8.1 Procedure A solution of 0.70 mol (excess) of sodium acetylide in 400 ml of liquid ammonia is prepared as described in Chapter 3, exp. 3.9.1. After equipping the flask as shown in Figure 1.1, the alkyl bromide (0.50 mol) is added dropwise over 1 h, while keeping the temperature of the reaction mixture just below the bp of ammonia. After an additional period of 1.5 h, 120 ml of high-boiling petroleum ether (bp >170 C) is added and the reaction mixture is cautiously poured onto 500 g of finely crushed ice in a 3-litre wide-necked round-bottomed flask (Figure 1.8) or spread on the bottom of a large beaker. The aqueous layer is extracted twice with small portions of petroleum ether. After shaking the organic solution with dilute hydrochloric acid and drying over magnesium sulphate, the volatile alkynes are distilled off at 760 Torr through a 30-cm Vigreux column. Redistillation of the distillate that has passed over below 110 C gives 1-pentyne, bp 41 C/760 Torr and 1-hexyne, bp 71 C/760 Torr, in >70% yields. 1-Heptyne, bp 100 C/760 Torr, is obtained by a similar procedure. The alkylation with pentyl bromide is carried out in the presence of 100 ml of DMSO. 4.5.9

1,3-Diynes by reaction of sodium diacetylide with n-propyl and n-butyl bromide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre, stirrer Figure 1.2 4.5.9.1 Procedure To an efficiently stirred suspension in 400 ml of liquid ammonia containing 0.20 mol of sodium diacetylide (Chapter 3, exp. 3.9.26) is added 0.22 mol of the alkyl bromide over 45 min with cooling just below the bp of ammonia. After the addition 100 ml of DMSO is cautiously added, the cooling bath is removed and stirring is continued for 1.5 h, then the ammonia is allowed to evaporate

98

4.

REACTIONS OF METALLATED ACETYLENES. . .

(Figure 1.7). After treatment of the remaining salty mass with a sufficient amount of water and extraction with pentane, the organic solution is shaken with dilute hydrochloric acid and dried over magnesium sulphate. 1,3-Heptadiyne, bp 40 C/40 Torr, is isolated by distilling off most of the pentane under atmospheric pressure (bath temperature not higher than 80 C), followed by distillation in a partial vacuum. 1,3-Octadiyne, bp 40 C/ 15 Torr, is obtained by removing the pentane under reduced pressure (bath temperature <25 C) and subsequently vacuum distilling the remaining liquid in vacuum. Yields are 60%. 4.5.10

C-Alkylation of dilithiated propargyl alcohol

Scale: 0.30 molar; Apparatus: Figure 1.1, 1 litre, stirrer Figure 1.2 4.5.10.1

Procedure

Freshly distilled (bp 40 C/100 Torr) propargyl alcohol (0.30 mol) is added over a few min to a suspension of 0.60 mol of lithium amide in 600 ml of liquid ammonia. The alkyl bromide (0.30 mol) is added dropwise over 1 h with efficient stirring to the greyish solution. After an additional 2 h (with the flask insulated in cotton wool) the ammonia is allowed to evaporate (Figure 1.7). Water (100 ml, saturated with NH4Cl) is added to the remaining mass and six extractions with Et2O are carried out. The extracts are dried over magnesium sulphate, then the ether is removed under reduced pressure. The alcohols are obtained in high yields by distillation through a 30-cm Vigreux column. The bp of 2-heptyn-1-ol, n-BuCCCH2OH, is 83 C/12 Torr. 4.5.11

C-Alkylation of dilithiated propargyl alcohol with a higher alkyl bromide

4.5

EXPERIMENTAL SECTION

99

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 4.5.11.1

Procedure

A solution of 0.12 mol of dilithiated propargyl alcohol in 250 ml of liquid ammonia is prepared from 0.12 mol of propargyl alcohol and 0.24 mol of lithium amide (see exp. 4.5.10). A mixture of 0.10 mol of bromooctane and 120 ml of dry DMSO is added over a few minutes. The temperature of the reaction mixture rises gradually and salt begins to separate. The ice crust on the flask is regularly removed by spraying with acetone. Stirring at 10 to 15 C is continued for an additional 1 h, then 400 ml of ice water is added and seven extractions with Et2O are carried out. The organic solution is washed twice with water and dried over magnesium sulphate. Removal of the ether under reduced pressure followed by distillation through a short column gives 2-undecyn-1-ol, bp 90 C/0.5 Torr, in greater than 75% yield. Other alcohols with long carbon chains can be prepared in a similar way.

4.5.12

1-Octyne, 1-nonyne and 1-decyne

Scale: 0.20 molar (RBr); Apparatus: Figure 1.1, 1 litre 4.5.12.1

Procedure

The alkyl bromide (0.20 mol) and dry DMSO (150 ml) are successively added to a solution of 0.30 mol (excess) of lithium acetylide (Note) in 200 ml of liquid ammonia (Chapter 3, exp. 3.9.1). The ice crust on the flask is regularly removed by spraying with acetone. After the temperature of the reaction mixture has reached 10 C, the heating effect becomes clearly observable and the temperature rises over a short period to þ10 C or higher. After stirring for an additional 30 min at 10 to 15 C (occasional cooling), the reaction mixture is treated with 400 ml of ice water and extraction with pentane is carried out. The organic solution is washed twice with dilute hydrochloric acid and dried over magnesium sulphate. In the cases of octyne and nonyne, the pentane is distilled off under atmospheric pressure, in the case of decyne the solvent is removed by evacuation. 1-Octyne, bp 128 C/760 Torr, 1-nonyne, bp 42 C/12 Torr and 1-decyne, bp 58 C/12 Torr, are obtained in >70% yields. There are small residues of disubstituted acetylenes.

100

4.

REACTIONS OF METALLATED ACETYLENES. . .

1-Alkynes with longer carbon chains can be prepared in a similar way, using somewhat more DMSO.

Note The risk of isomerisation to the 2-alkyne under the influence of the alkali acetylide, in combination with DMSO, is less, if lithium acetylide is used [1a]. 4.5.13

Terminal diynes from sodium acetylide and a,x-dibromoalkanes

Scale: 0.20 molar (dibromide); Apparatus: Figure 1.1, 1 litre, no thermometer is used

4.5.13.1

Procedure

The dibromide (0.20 mol) is added dropwise over 45 min to a solution of 0.50 mol (excess) of sodium acetylide in 600 ml of liquid ammonia. After 4 h finely crushed ice (150 g) and ice water (200 ml) are cautiously added with vigorous stirring. 1,7-Octadiyne, bp 37 C/10 Torr, 1,8-nonadiyne, bp 52 C/ 10 Torr and 1,9-decadiyne, bp 70 C/10 Torr, are obtained in >75% yields by extraction with pentane, drying, removal of the solvent under reduced pressure (under atmospheric pressure if n ¼ 4) and distillation.

4.5.14

Alkylation of a lithiated acetylene in a THF–DMSO mixture

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml, the dropping funnel is omitted Alkylations of lithiated acetylenes with alkyl bromides in THF or Et2O proceed very sluggishly. Addition of a small amount (equal to the molar amount of the lithium compound) of HMPT causes a dramatic acceleration of the alkylation. Unfortunately HMPT has lost its popularity as a co-solvent

4.5

EXPERIMENTAL SECTION

101

because it is suspected to be carcinogenic. DMF cannot be used because it reacts with lithium acetylides in organic solvents (see Chapter 6). A good possibility would be DMPU (N,N-dimethylpropyleneurea) [1d,36], but DMSO is much cheaper. The procedure is a selected example of a generally applicable alkylation method. 4.5.14.1

Procedure

To a solution of 0.11 mol of lithiated 1-methoxy-2-propyne in a THF–hexane mixture (Chapter 3, exp. 3.9.4) is added 0.10 mol of n-pentyl bromide at rt . No reaction takes place. Dry DMSO (35 ml) is added, causing a gradual rise of the temperature (occasional cooling in a bath at rt may be necessary). After the evolution of heat has subsided, the reaction mixture is heated for 30 min in a bath at 50 C. Water (200 ml) is added, followed by three extractions with pentane. The combined organic solutions are washed three times with water, dried over magnesium sulphate and concentrated under reduced pressure. 1-Methoxy-2-octyne, bp 61 C/15 Torr, is obtained in >70% yield.

4.5.15

Reaction of sodium acetylide with epichlorohydrine

Scale: 0.50 molar; Apparatus: Figure 1.1, 1 litre 4.5.15.1

Procedure

Epichlorohydrine (0.50 mol) is added dropwise over 2 h to a solution of 1.2 mol of sodium acetylide (Chapter 3, exp. 3.9.1, a higher concentration is used) in 600 ml of liquid ammonia. During this addition the temperature of the reaction mixture is maintained at a level close to –55 C (reactions at the bp of ammonia give lower yields). After an additional 1.5 h the cooling bath is removed and stirring at the bp of ammonia is continued for 2 h, then the flask is equipped as shown in Figure 1.7 and the ammonia is allowed to evaporate. The remaining mass is treated with 250 ml of a saturated aqueous ammonium chloride solution, after which 15 extractions with small portions of Et2O are carried out. The organic solutions are dried over potassium carbonate and subsequently concentrated in vacuo. The remaining brown liquid is first subjected to a flash distillation at <1 Torr. Redistillation of the contents of the cooled receiver

102

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REACTIONS OF METALLATED ACETYLENES. . .

gives (E)-2-penten-4-yn-1-ol, bp 63–70 C/15 Torr, in 50% yield or somewhat higher. A small amount of the (Z)-isomer may be present. 4.5.16

Reaction of lithium acetylides with oxirane in liquid ammonia

Scale: 0.30 molar; Apparatus: Figure 1.4, 1 litre

4.5.16.1

Procedure

A solution of 0.32 (0.02 mol excess as compensation for losses during the transfer) mol of the alkali acetylide (M ¼ Li is preferred, Note), prepared as described in Chapter 3, exps. 3.9.1 and 3.9.3, is poured (after cooling to below the bp of ammonia) into the Dewar flask, Figure 1.4. Oxirane (0.5 mol, excess, cooled to below 20 C) is added over a few min with manual swirling, after which a rubber stopper with a narrow hole is placed on the flask. This is covered with aluminium foil. After 24 to 30 h (small amounts of ammonia may be added if too much has evaporated) the reaction mixture is poured into a 2- or 3-litre widenecked flask. The Dewar flask is rinsed with a small amount of water (less than 50 ml) and the rinsing combined with the reaction mixture. The ammonia is removed by placing the flask in a bath at 40 C. To the residue 100 ml of a saturated aqueous solution of ammonium chloride is added. Several extractions with small portions of Et2O are carried out (for R ¼ H, 15 to 20 times; continuous extraction takes much more time, in the case of R ¼ Me or larger groups less frequently, see hint extraction in Chapter 1.3). The organic solution is dried over potassium carbonate, after which the Et2O is removed under reduced pressure (if R ¼ H, distilled off at atmospheric pressure). 3-Butyn-1-ol, HCC(CH2)2OH, bp 34 C/12 Torr (single receiver cooled at 0 C, Figure 1.10), 3-pentyn-1-ol, MeCC(CH2)2OH, bp 54 C/12 Torr, and 3-hexyn-1-ol, EtCC(CH2)2OH, bp 67 C/12 Torr, are obtained in >70% yields.

Note An excess of oxirane is necessary because there is some loss due to entraining with the ammonia vapour. If M ¼ Na, further reaction between RC C(CH2)2ONa and oxirane with formation of RCC(CH2)2OCH2CH2ONa may occur.

4.5

EXPERIMENTAL SECTION

4.5.17

103

Reaction of lithium acetylides with oxiranes after replacement of liquid ammonia by DMSO

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre 4.5.17.1

Procedure

Dry DMSO (120 ml) is cautiously added to a solution of 0.20 mol of the lithium acetylide (Chapter 3, exps. 3.9.1 and 3.9.3) in 200 ml of liquid ammonia. The greater part of the ammonia is then removed by placing the flask in a bath at 40 C. It may be necessary to remove the thermometer temporarily; in the case of frothing small amounts of Et2O may be added and heating is interrupted. When the thermometer indicates a temperature of 10 C, the heating bath is removed and the oxirane (0.25 mol, pre-cooled to below 20 C; 0.22 mol of 2-ethyloxirane; 0.20 mol of 2-phenyloxirane) is added in one portion. The ensuing rather strongly exothermic reactions are kept under control by occasional cooling. After stirring for 1 h at 25 to 30 C (2 h if R1 ¼ Ph), 200 ml of a saturated solution of ammonium chloride is added and several extractions with Et2O are carried out (see hint about extraction frequency in Chapter 1.3). In the case R ¼ H, R1 ¼ Et washing with water is not carried out, in the other cases the combined extracts are washed twice with saturated aqueous ammonium chloride in order to remove DMSO. Examples of alcohols prepared: R ¼ H, R1 ¼ Et, bp 48 C/10 Torr (careful fractionation is necessary); R ¼ EtCC, R1 ¼ H, bp 90 C/1 Torr; R ¼ H, R1 ¼ Ph, bp 120 C/12 Torr. Yields are excellent, in the case R1 ¼ Ph 70%.

4.5.18

Reaction of phenylethynyllithium with oxirane in a THF–DMSO mixture

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml Reactions between lithium acetylides and oxiranes have been successfully achieved either in the presence of the Lewis acid BF3-etherate [37], in strongly

104

4.

REACTIONS OF METALLATED ACETYLENES. . .

polar liquid ammonia and in mixtures of THF and HMPT [37]. For performance on a relatively small scale liquid ammonia is a less convenient solvent because it is difficult to maintain absolutely anhydrous conditions. The procedure below illustrates the use of THF–DMSO for couplings between oxiranes and lithium alkynylides generated in THF. 4.5.18.1

Procedure

Oxirane (0.13 mol, pre-cooled to below 20 C) is added to a stirred solution of 0.10 mol of lithium phenylacetylide in 63 ml of hexane and 70 ml of THF (Chapter 3, exp. 3.9.4) cooled to 10 C. Dry DMSO (30 ml) is added and the temperature is allowed to rise to 45 C. This temperature is maintained for an additional 45 min, then a solution of 20 g of ammonium chloride in 300 ml of water is added to the two-layer system. 4-Phenyl-3-butyn-1-ol, bp 100 C/ 0.2 Torr, is isolated in an excellent yield via extraction with Et2O (5 times), washing with water, drying over magnesium sulphate. If less stable acetylides, e.g. RCCCCLi, are to be b-hydroxyalkylated, more DMSO may be used so that the reaction can proceed at lower temperatures. 4.5.19

Reaction of a 1-lithiated acetylene with an a-chloroether

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 4.5.19.1

Procedure

Undistilled 1-chloro-1-ethoxyethane (0.10 mol, see below) is added over a few minutes to a solution of 0.10 mol of 1-lithiated 3-ethoxy-1-propyne (Chapter 3, exp. 3.9.4) in 63 ml of hexane and 70 ml of THF (Et2O also can be used) cooled to 50 C. The cooling bath is removed and the temperature allowed rising to rt. After an additional 15 min, ice water (100 ml) is added and the aqueous layer is extracted with Et2O. Drying of the organic solution over magnesium sulphate, removal of the solvents under reduced pressure and vacuum distillation gives 1,4-diethoxy-2-pentyne, bp 85 C/10 Torr, in >70% yield. Reactions of lithiated acetylenes with other a-halogenoethers are carried under similar conditions. 1-Chloro-1-ethoxyethane, MeCH(Cl)OEt, is prepared by introducing 0.10 mol of dry, gaseous hydrogen chloride (weight increase) into a mixture

4.5

EXPERIMENTAL SECTION

105

of 0.20 mol (excess) of freshly distilled ethyl vinyl ether and 30 ml of dry Et2O at 10 to 0 C. The solution can be used directly in the procedure. 2-Chlorotetrahydropyran is prepared by introducing 0.10 mol of dry, gaseous hydrogen chloride (weight increase) into a mixture of 0.15 mol of freshly distilled dihydropyran and 20 ml of Et2O at 10 C. Chloromethyl alkyl ethers, ClCH2OR (R ¼ Me or higher alkyl) are obtained by introducing hydrogen chloride into a stirred mixture of 0.30 mol ROH and 9.3 g (corresponds to 0.30 mol of the monomer) paraformaldehyde, cooled between 0 and 10 C, until copious fumes escape from the reaction mixture. Stirring is stopped and the mixture is cooled in a bath at 70 C. The upper layer is cautiously decanted from the ice crust on the bottom of the flask. The excess of hydrogen chloride is removed by evacuation (bath temperature 10 C). This operation is stopped when the pressure has dropped to 50 Torr. Yields of the crude a-chloroethers with R>ethyl are greater than 80%, in the cases of R ¼ Me and R ¼ Et, there are some losses due to evaporation. Warning: a-Halogenoethers are suspected carcinogens. 4.5.20

Reaction of 2-chlorotetrahydropyran and 2,3-dibromotetrahydropyran with ethynylmagnesium bromide

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 4.5.20.1

Procedure

A solution of 0.13 mol (excess) of ethynylmagnesium bromide (Note) in 130 ml of THF is prepared by introducing acetylene at 10 to 15 C into a solution containing 0.13 mol of ethylmagnesium bromide (Chapter 3, exp. 3.9.7). Crude 2-chlorotetrahydropyran (0.10 mol, see preceding exp.) or 2,3-dibromotetrahydropyran (0.10 mol, see below) is added over a few minutes to the suspension of ethynylmagnesium bromide with cooling at 15 and at þ10 C, respectively. In the procedure with chlorotetrahydropyran the cooling bath is removed, the temperature is allowed to rise to rt and stirring is continued for another 1 h. In the case of the dibromoether the reaction mixture is stirred

106

4.

REACTIONS OF METALLATED ACETYLENES. . .

for an additional 2 h at rt and then allowed to stand overnight at rt. In both cases a cold solution of 25 g of ammonium chloride in 100 ml of water is added with vigorous stirring. After extraction with Et2O, the organic solution is dried over magnesium sulphate. 2-Ethynyltetrahydropyran, bp 35 C/10 Torr, is isolated in 70% yield by distilling off the greater part of the solvents under atmospheric pressure and subsequently distilling the remaining liquid in vacuo, the receiver being cooled in a bath at 0 C. 3-Bromo-2-ethynyltetrahydropyran, bp 50 C/0.2 Torr, is obtained in >70% yield by removal of the solvents under reduced pressure followed by distillation through a short column. 2,3-Dibromotetrahydrofuran and alkynylmagnesium bromide give the expected product [9]. Other a,b-dibromoethers, for example 1,2-dibromo-1-ethoxyethane, BrCH2CH(Br)OEt, react under similar conditions with acetylenic Grignard compounds. 4-Bromo-3-ethoxy-1-butyne, BrCH2CH(OEt)CCH, bp 64 C/ 12 Torr, is obtained in 70% yield. With the lithiated acetylenes results are poor, possibly due to HBr elimination by the lithium acetylide. 2,3-Dibromotetrahydropyran is prepared by adding bromine (0.10 mol) to a mixture of 0.12 mol of freshly distilled dihydropyran and 20 ml of dichloromethane (Et2O presumably also can be used) with cooling below 50 C. The obtained solution should be used without delay; removal of the solvent is not necessary. Note Lithium alkynylides also give good results in reactions with 2-chlorotetrahydropyran [9]. 4.5.21

Regiospecific alkylation of 1,3-dilithiated propyne with benzyl chloride

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 4.5.21.1

Procedure

Benzyl chloride (0.10 mol) is added dropwise over 30 min to a suspension of 0.22 mol of 1,3-dilithiopropyne in 140 ml of THF and 138 ml of hexane (Chapter 3, exp. 3.9.11) with cooling between 10 and 15 C. After stirring

4.5

EXPERIMENTAL SECTION

107

for an additional 1 h at 5 C, the reaction mixture is treated with ice water. 1-(3-Butynyl)benzene, bp 72 C/15 Torr, is isolated in 70% yield by extraction with Et2O, drying over magnesium sulphate, removal of the solvents under reduced pressure and distillation through a short column. 5-Chloro-1-hexyne, HCC(CH2)4Cl, bp 60 C/45 Torr, is obtained in 70% yield by adding, at –40 C, 0.09 mol (less than the equivalent amount) of 1-bromo-3-chloropropane over 5 min, after which the cooling bath is removed. Above –20 C the evolution of heat is clearly visible. After a few minutes all suspended material has passed into solution. The solution is heated for 1 h at 40 C and then treated with ice water. The upper layer and two ethereal extracts are dried over magnesium sulphate, after which the greater part of the solvents is distilled off under normal pressure. 4.5.22

Regiospecific hydroxyalkylation of a 1,3-dilithiated 1-alkyne with oxirane

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 4.5.22.1

Procedure

A solution of 1,3-dilithiated hexyne, prepared as described in Chapter 3, exp. 3.9.12, is cooled to rt and 150 ml of THF is added. After standing for 1 h at 30 C (during this period the excess of BuLi is neutralised by its reaction with THF), the solution is cooled to 40 C and a cold solution of 0.12 mol of oxirane in 20 ml of THF is added over 30 min. The colour gradually turns light yellow. After the addition, the temperature is allowed to rise to 10 C and the reaction mixture is treated with a cold solution of 25 g of ammonium chloride in 100 ml of water. The organic layer and three ethereal extracts are dried over magnesium sulphate and concentrated under reduced pressure. 3-Propyl-4pentyn-1-ol, bp 80 C/15 Torr, is obtained in 75% yield. 4.5.23

Acetylenic acetals from alkynylmagnesium bromide and triethoxymethane

108

4.

REACTIONS OF METALLATED ACETYLENES. . .

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml, reflux condenser instead of a thermometer 4.5.23.1

Procedure

Freshly distilled triethoxymethane (0.25 mol) is added in one portion to a solution of 0.20 mol of alkynylmagnesium halide in 200 ml of Et2O (Chapter 3, exp. 3.9.9). The temperature rises by a few degrees only (as observed by temporarily placing a thermometer in the liquid). The mixture is heated for at least 7 h under reflux with efficient stirring, during which period a white suspension is formed. After cooling to rt, the suspension is cautiously poured (the hydrolysing operation should never be carried out in the inverse sense, as much heat is evolved) into a cold solution of 25 g of NH4Cl in 200 ml of water. After shaking, the layers are separated and the aqueous layer is extracted three times with Et2O. The combined solutions are dried over MgSO4 and subsequently concentrated in vacuo. Careful distillation through an efficient column (for R is Me or Et) or a 40-cm Vigreux column gives the acetylenic acetals, generally in excellent yields. 4.5.23.2

Examples

1,1-Diethoxy-2-butyne, MeCCCH(OEt)2, bp 62 C/12 Torr; 1,1-diethoxy2-pentyne, EtCCCH(OEt)2, bp 72 C/10 Torr; 1,1-diethoxy-2-heptyne, n-BuCCCH(OEt)2, bp 97 C/10 Torr; 1,1-diethoxy-4-penten-2-yne, EtCH¼ CHCCCH(OEt)2, bp 96–103 C/12 Torr (E/Z 1:1); 1,1-diethoxy-2,4-pentadiyne, C3H7CCCCCH(OEt)2, bp 100 C/0.5 Torr.

Note Propynyl- and butynylmagnesium bromide may be obtained by addition of MgBr2–Et2O (prepared from Mg and 1,2-dibromoethane in Et2O, Chapter 2, exp. 2.3.10) to the suspensions of the alkynyllithium derivatives in Et2O.

4.5.24

Alkylation of lithiated propadiene

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml

4.5

EXPERIMENTAL SECTION

4.5.24.1

109

Procedure (cf. [38], Note)

Dry HMPT (20 ml) is added over a few minutes to a solution of 0.25 mol of allenyllithium (Chapter 3, exp. 3.9.15 and Table 3.3) cooled at 80 C. 1-Bromo-3-chloropropane (0.20 mol) is added dropwise over 10 min. The temperature of the solution is kept below 60 C by occasional cooling with liquid nitrogen. After an additional 10 min the temperature is allowed to rise to 30 C and 200 ml of water is added with vigorous stirring, after which five extractions with Et2O are carried out. The organic solution is dried over magnesium sulphate, after which the solvents are distilled off as completely as possible under normal pressure. 6-Chloro-1,2-hexadiene, bp 40 C/15 Torr, is obtained in an excellent yield.

Note The reaction has not been carried out in the absence of HMPT but we presume that a good result can be obtained if stirring at 70 C is continued for a sufficiently long period (>30 min) after the addition of the alkyl halide. Formation of 10% of 1-undecyne in the reaction of propadienyllithium with octyl iodide (in the absence of HMPT) has been reported [38].

4.5.25

Reaction of methoxyallenyllithium with alkyl bromides

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml

4.5.25.1

Procedure (cf. [39])

To a solution of 0.22 mol of methoxyallenyllithium in a THF–hexane mixture (Chapter 3, exp. 3.9.15 and Table 3.3) is added 0.20 mol of the alkyl bromide at 30 C. Dry HMPT (30 ml) is then added over a few minutes while keeping the temperature of the reaction mixture between 0 and 10 C. After an additional 30 min at 10 C the cooling bath is removed and the temperature is allowed to reach rt. The reaction mixture is then treated with a solution of 1 ml of diethylamine or concentrated aqueous ammonia (Note) in 150 ml of ice water. The aqueous layer is extracted three times with small portions of pentane. The combined organic solutions are washed three times with water and

110

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REACTIONS OF METALLATED ACETYLENES. . .

subsequently dried over potassium carbonate. After addition of 1 ml of diethylamine, the solvent is removed under reduced pressure. In the case of rather volatile products (R
Note Traces of acid adhering to the glass can cause isomerisation of the alkylation products, H2C¼C¼C(OMe)CH2R1, to the conjugated dienes [40], H2C¼ CHC(OMe)¼CHR1.

4.5.26

Alkylation of a metallated 1-alkynyl sulphide

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 4.5.26.1

Procedure [41]

1-Butynyl ethyl sulphide (0.10 mol, Chapter 8, exps. 8.2.1 and 8.2.3) is added in one portion to a suspension of 0.12 mol of sodamide in 170 ml of liquid ammonia. After 3 min, the brown solution is cooled to 45 C and ethyl bromide (0.12 mol) is added over a few minutes. The reaction is very fast and the ammonia may start boiling. The thermometer-outlet combination is removed and the flask is placed in a bath at 40 C, stirring being continued as long as possible. When all ammonia has evaporated, Et2O (100 ml) and water (100 ml) are successively added with vigorous stirring and introduction of nitrogen. The organic layer and two ethereal extracts are dried over potassium carbonate and subsequently concentrated under reduced pressure. After addition of a few drops of diethylamine (see Note of preceding exp.) the remaining liquid is distilled to give 4-ethylthio-2,3-hexadiene, bp 65 C/10 Torr, in >65% yield.

4.5

EXPERIMENTAL SECTION

4.5.27

111

Reaction of a metallated 1-alkynyl sulphide with oxirane

Scale: 0.10 molar; Apparatus: Figure 1.1, 1 litre 4.5.27.1

Procedure

1-Methylthio-1-pentyne (0.10 mol) is converted into the sodium compound as described in the preceding experiment. The brown solution is cooled to 60 C, after which a cold mixture of 0.13 mol of oxirane and 20 ml of Et2O is added in one portion. The cooling bath is removed. Within a few minutes the temperature of the reaction mixture has risen above 40 C. When the ammonia has started boiling, the thermometer is removed and 10 g of ammonium chloride is added in small portions. The ammonia is removed by placing the flask in a bath at 40 C, after which 3-methylthio-3,4-heptadien-1-ol, bp 100 C/0.4 Torr, is isolated (>70% yield) as described in the preceding experiment. 4.5.28

Reaction of 1-lithiated methoxyallene with oxirane

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml 4.5.28.1

Procedure [22]

Methoxyallene (0.25 mol) is added at 20 C to a solution of 0.20 mol of BuLiLiBr in 200 ml of Et2O (Chapter 2, exp. 2.3.6, Note). After stirring for 1 h at this temperature, the solution is cooled to 50 C and a cold mixture of 0.20 mol of oxirane and 20 ml of Et2O is added in one portion. After having allowed the temperature to rise to 15 C, the mixture is stirred for 2.5 h at this level, then it is poured into 200 ml of a saturated solution of ammonium chloride to which a few millilitres of aqueous ammonia (see Note of exp. 4.5.25) are added. The aqueous layer is extracted six times with small portions of Et2O. The organic solution is dried over potassium carbonate and subsequently concentrated under reduced pressure. Distillation of the remaining

112

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REACTIONS OF METALLATED ACETYLENES. . .

liquid through a short column gives 3-methoxy-3,4-pentadien-1-ol, bp 55 C/ 1 Torr, in 75% yield. Note A solution of 1-lithiomethoxyallene prepared by lithiation with a mixture of commercial BuLi in THF–hexane did not react with oxirane below þ20 C. At higher temperature a reaction started, the reaction mixture turned brown and the desired alcohol is obtained in a low yield [9]. It seems that the lithium bromide present in the solution of BuLi prepared from butyl bromide and lithium assists in the ring opening. 4.5.29

Reaction of lithiomethoxyallene with a-chloroethers

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre 4.5.29.1

Procedure [29]

The crude a-chloroether (0.20 mol, exp. 4.5.18) is added over 10 min to a solution of 0.23 mol of methoxyallenyllithium (Note) prepared by addition of 0.25 mol of methoxyallene at 70 C to a solution of 0.23 mol of BuLi in 146 ml of hexane and 120 ml of THF and subsequently allowing the temperature to rise to 30 C. After the addition of the a-chloroether, which is carried out at 40 C, the cooling bath is removed and the temperature is allowed to rise to rt. A solution of 30 g of ammonium chloride in 200 ml of water containing 5 ml of aqueous ammonia is added with vigorous stirring and three extractions with Et2O are carried out. The organic solution (washing is not carried out) is dried over potassium carbonate and 2 ml of diethylamine (see Note in exp. 4.5.25) is added, after which the greater part of the solvents is distilled off under normal pressure (bath temperature not higher than 90 C). Careful distillation of the remaining liquid gives the products, 4-ethoxy-3-methoxy-1,2butadiene, R ¼ H, bp 40 C/10 Torr, and 4-ethoxy-3-methoxy-1,2-pentadiene, R ¼ Me, bp 47 C/10 Torr, in excellent yields. Note An excess of the lithiated allenic ether is used to ensure complete reaction of the a-chloroether. Its hydrolysis during the work-up would give hydrochloric acid, which can catalyse addition of water to the allenic product [27b].

4.5

EXPERIMENTAL SECTION

4.5.30

113

Regioselective alkylation of a lithiated 2-alkynyl ether

Scale: 0.05 molar; Apparatus: Figure 1.1, 250 ml, magnetic stirring

4.5.30.1

Procedure

Methyl iodide (0.06 mol) is added at –50 C to a solution of the lithiated 2-alkynyl ether (Chapter 3, Table 3.3 and exp. 3.9.17) and the cooling bath is removed. After 10 min water is added followed by two extractions with Et2O. 1-t-Butoxy-3-methyl-1,2-pentadiene, bp 60 C/15 Torr, is isolated via drying over magnesium sulphate, removal of the solvents under reduced pressure and distillation. Reactions of lithiated 2-alkynyl ethers with higher alkyl iodides and bromides also proceed very easily in the absence of a co-solvent to afford exclusively g-alkylated derivatives [42].

4.5.31

Preparation of 1-alken-4-ynes and 1,4-alkadiynes by reaction of 1-alkynylmagnesium bromide with allyl bromide or propargyl bromide in the presence of copper(I) chloride

Scale: 0.30 molar; Apparatus: Figure 1.1, 1 litre 4.5.31.1

Procedure

A solution of 0.30 mol of 1-octynylmagnesium bromide in 300 ml of THF is prepared from 0.35 mol of ethyl bromide and 0.30 mol of 1-octyne (Chapter 3, exp. 3.9.10). Powdered copper(I) chloride (2 g, technical grade) is added at rt. Allyl bromide (0.37 mol) is added dropwise over 15 min, while keeping the temperature of the green suspension between 40 and 50 C. The conversion is completed by heating the mixture for an additional 30 min at 60 C. After cooling to 20 C, the suspension is poured into 250 ml of an aqueous solution of 5 g of KCN or NaCN and 40 g of NH4Cl. The mixture is vigorously shaken, after which the layers are separated. The aqueous layer is extracted twice with

114

4.

REACTIONS OF METALLATED ACETYLENES. . .

pentane or Et2O. The combined organic solutions are washed with aqueous NH4Cl, dried over MgSO4 and subsequently concentrated under reduced pressure. Distillation through a 40-cm Vigreux column gives 1-undecen-4-yne, bp 79 C/10 Torr, in a high yield. There is a small high-boiling residue. 1,4-Decadiyne, C5H11CCCH2CCH, bp 69 C/10 Torr, is obtained in fair yields (between 55 and 60%) by a similar procedure from C5H11CCMgBr and HCCCH2Br (20 mol% excess). The greater part of the THF and extraction solvent are distilled off at atmospheric pressure through a 40-cm Vigreux column (bath temperature maximally 80 C). During this distillation the 1,2-decadien-4-yne, C5H11CCCH¼C¼CH2, is converted into high-boiling products. The remaining liquid is first subjected to a flash distillation in vacuo (10–15 Torr) using a 20-cm Vigreux column and a single receiver, cooled at 70 C (see Figure 1.10). The considerable high-boiling residue is discarded. Careful redistillation of the contents of the receiver gives the 1,4-diyne. Warning: The aqueous layer, which contains alkali cyanide should never be poured in a waste container used for disposing of acidic solutions. 4.5.32

Preparation of 1,4-diynes by copper(I) halide-catalysed reaction of propargyl tosylate with alkynyllmagnesium bromide

Scale: 0.50 molar; Apparatus: Figure 1.1, 2 litre

4.5.32.1

Procedure

A solution of 0.65 mol of ethynylmagnesium bromide in 1 litre of THF (Chapter 3, exp. 3.9.7) is cooled to 0 C (a suspension is formed) and 2 g of powdered copper(I) bromide (or chloride) is added. After 15 min, 0.50 mol of propargyl tosylate (Chapter 20, exp 20.5.4) is added over 10 min while keeping the temperature between 0 and 5 C. After the addition, the cooling bath is removed and the temperature is allowed to rise over 1 h to 15 C (occasional cooling may be necessary). Most of the suspended material dissolves. Highboiling petroleum ether (200 ml, bp >170 C) is added to the brown solution. The mixture is then poured into 2 litre of 2 N aqueous hydrochloric acid. After

4.5

EXPERIMENTAL SECTION

115

vigorous shaking, the layers are separated and the organic layer is washed 15 times with 300-ml portions of 4 N aqueous HCl. The combined washings and first aqueous layer are extracted twice with 30-ml portions of petroleum ether. The two petroleum ether solutions are combined and washed five times with 200 ml-portions of 4 N HCl. After drying over magnesium sulphate, the combined organic solutions are subjected to a flash distillation at 10 to 20 Torr and the volatile diyne is collected in the strongly cooled receiver (Figure 1.10). The ‘distillation’ is stopped after 10 ml of petroleum ether has passed over (bp 50–60 C/15 Torr). The distillate is heated under reflux for 30 min under nitrogen, then the flash distillation is repeated, now leaving the small amount of petroleum ether in the distillation flask. Redistillation of the contents of the receiver under N2 under atmospheric pressure through a 20-cm Vigreux column gives the desired product, bp 62 C/760 Torr, in 60% yield. 5% of HCCCH¼C¼CH2 may still be present, and in some cases THF. This solvent can be removed by shaking the product with cold 4 N aqueous HCl in a small dropping funnel. 1,4-Hexadiyne, MeCCCH2CCH, bp 55 C/100 Torr, is obtained in greater than 70% yield from HCCMgBr and MeCCCH2OTs by a similar procedure. The compound can also be prepared from MeCCMgBr and HCCCH2OTs, but in that case the desired compound is contaminated with 1,2-hexadien-4-yne, MeCCCH¼C¼CH2, which has to be removed by heating the crude product. Trimethyl(1,4-pentadiynyl)silane, Me3SiCCCH2CCH, bp 35 C/10 Torr (single receiver, cooled at 0 C), (containing 5–7% of Me3SiCCCH¼ C¼CH2), is obtained in 70% yield from the reaction of trimethylsilylethynylmagnesium bromide, Me3SiCCMgBr, (0.11 mol) in THF with HCCCH2OTs (0.10 mol) at 0 to 15 C. After addition of 100 ml of pentane, the reaction mixture is hydrolysed and the greater part of the THF is removed by the washing procedure described above. Most of the solvent is distilled off at atmospheric pressure (under N2) through a 40-cm Vigreux column (bath temperature 120 C at the end). After cooling to rt, the remaining liquid is carefully distilled in a water-aspirator vacuum. 1-Ethoxyethynylmagnesium bromide, EtOCCMgBr, and MeC CCH2OTs, react in THF at 0 to 15 C to give 1-ethoxy-1,4-hexadiyne, EtOCCCH2C CMe. This compound (bp 50 C/15 Torr) is isolated in an excellent yield via the conventional procedure of working up (extraction with Et2O or pentane after hydrolysis, washing, drying, removal of the solvent in vacuo, then distillation). Allylacetylene, HCCCH2CH¼CH2, bp 42 C/760 Torr, may be obtained from HCCMgBr and H2C¼CHCH2OTs by a procedure similar to that applied for HCCCH2CCH.

116 4.5.33

4.

REACTIONS OF METALLATED ACETYLENES. . .

Synthesis of 5-hexyn-1-ol using acetylene and tetrahydrofuran as building units

Scale: 0.40 molar; Apparatus: for the ring opening 500-ml round-bottomed flask and inlet tube; for the protection Figure 1.1, 500 ml; for the reaction with lithium acetylide Figure 1.1, 1 litre; for the deprotection 500-ml roundbottomed flask. 4.5.33.1

Procedure

Dry HBr (Note 1) is introduced with manual swirling into 120 ml of THF until the weight increase is 33 g (0.40 mol). The temperature of the solution should be kept below 50 C (preferably around 40 C). The use of a bath with dry ice and acetone (70 C) permits a rapid introduction of HBr. After standing for an additional 10 min at 40 C, the almost colourless solution is cooled to 5 C, and then added to 50 g (excess) of freshly distilled ethyl vinyl ether (Note 2) in a number of portions. If there is no clearly observable heating effect after adding the first 10 to 20%, 50–100 mg of p-toluenesulphonic acid should be added at 25 C before continuing the addition. The temperature of the mixture is kept between 5 and 5 C by occasional cooling in a bath with dry ice and acetone. After an additional 20 min at 0 C, 2 ml of triethylamine is added to neutralise traces of acid. The obtained solution is added (without removing the excess of THF and vinyl ether) over 20 min to an efficiently stirred solution of 0.6 mol of lithium acetylide (Chapter 3, exp. 3.9.1) in 400 ml of liquid ammonia. Subsequently 175 ml of DMSO is cautiously added over a few minutes and the mixture is stirred for an additional 2 h. The flask is then placed in a water bath at 40 C (the dropping funnel is replaced with a rubber stopper with a wide hole). The temperature rises gradually while salt separates from the solution. After stirring the mixture for an additional 30 min at þ10 C, a solution of 20 g of ammonium chloride in 1 litre of ice water is slowly added with vigorous stirring. The solution is extracted four times with Et2O. After washing of the combined organic solutions four times with a saturated aqueous solution of NH4Cl, the solvent is removed using a rotary evaporator (drying is not necessary). Methanol (75 ml) and subsequently 1 ml

REFERENCES

117

of 36% HCl is added to the remaining liquid. The solution is heated for 15 min at 50 C, and 5 ml of a saturated aqueous solution of KOH is then added. The volatile compounds are removed on the rotary evaporator. The remaining liquid is quickly distilled at <1 Torr and collected in a single receiver (Figure 1.10). Redistillation through a 40-cm Vigreux column gives 5-hexyn1-ol, bp 75 C/15 Torr, in greater than 80% yield. 5-Heptyn-1-ol, MeCC(CH2)4OH, bp 110 C/10 Torr, is obtained in >80% yield by a similar procedure, using a 15% molar excess of MeCCLi. Notes 1.

2.

If no cylinder is available, HBr can be prepared by dropwise addition of a slight excess of water to a vigorously stirred 3:1 (v/v) mixture of PBr3 and CCl4 in a round-bottomed flask equipped with a reflux condenser. The HBr is led through a tube containing lumps of anhydrous calcium chloride and introduced directly into the THF. Many chemists seem to prefer dihydropyran as a reagent for the protection. It should be pointed out, however, that both protection and deprotection proceed more satisfactorily using ethyl vinyl ether.

REFERENCES 1. (a) J. A. P. Thyman, Synth. Commun. 5, 21 (1975); (b) E. F. Jenny and K. D. Meier, Angew. Chem. 71, 245 (1959); (c) W. N. Smith and O. F. Beumel, Jr., Synthesis, 441 (1974); (d) E. C. Stracker and G. Zweifel, Tetrahedron Lett. 31, 6815 (1990). 2. H. Hommes, H. D. Verkruijsse and L. Brandsma, Recl. Trav. Chim., Pays-Bas 99, 113 (1980). 3. S. Bhanu and F. Scheinmann, J. Chem. Soc., Chem. Comm., 817 (1975). 4. A. J. G. Sagar and F. Scheinmann, Synthesis, 321 (1976). 5. G. R. Khan, K. A. Povev and F. Scheinmann, J. Chem. Soc., Chem. Comm., 215 (1979); J. Chem. Soc., Perkin I, 1609 (1976); 2338 (1980). 6. L. Brandsma and E. Mugge, Recl. Trav. Chim., Pays-Bas 92, 628 (1972); J. Klein and S. Brenner, J. Org. Chem. 36, 1319 (1971). 7. A. L. Smith, K.-C. Hwang, G. E. Pitsinos, R. Scarlato and K. C. Nicolaou, J. Am. Chem. Chem. Soc. 114, 3134 (1992). 8. H. J. Reich, S. K. Shah, P. M. Gold and R. E. Olson, J. Am. Chem. Soc. 103, 3112 (1981). 9. Unpublished observations in the author’s laboratory. 10. M. D. D’Eugenieres, M. Mioque and J. A. Gautier, Bull. Soc. Chim. France, 2471, 2477, 2480 (1964). 11. V. Ja¨ger, in Houben-Weyl, Methoden der Organischen Chemie, Band 5/2a. Thieme Verlag, Stuttgart, 1977. 12. R. Ko¨ster, A. Bussmann and G. Schroth, Liebigs Ann. Chem., 2130 (1975). 13. T. Ando and N. Tokura, Bull. Chem. Soc. Japan 31, 2130 (1958). 14. E. Negishi and S. Baba, J. Am. Chem. Soc. 97, 7385 (1975). 15. F. Sondheimer and Y. Gaoni, J. Am. Chem. Soc. 83, 4863 (1961).

118 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

4.

REACTIONS OF METALLATED ACETYLENES. . .

H. Taniguchi, I. M. Mathai and S. I. Miller, Tetrahedron 22, 867 (1966). D. A. Ben Efraim and F. Sondheimer, Tetrahedron 25, 2823 (1969). D. van der Steen and D. A. van Dorp, Recl. Trav. Chim., Pays-Bas 82, 1015 (1963). H. D. Verkruijsse and M. Hasselaar, Synthesis, 292 (1979). M. Avignon-Tropis, M. Treilhou, J. R. Pougny, I. Frechard-Ortuno and G. Linstrumelle, Tetrahedron 47, 7279 (1991). A. Herunsalee, M. Isobe and T. Goto, Tetrahedron 47, 3727 (1991); Same authors and Y. Fukuda, Synlett, 701 (1990). S. Hoff, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 88, 609 (1969). M. Yamagughi, Y. Nobayashi and I. Hirao, Tetrahedron 40, 4261 (1984); Same authors, Tetrahedron Lett. 24, 5121 (1983). L. J. Haynes, I. Heilbron, E. R. H. Jones and F. Sondheimer, J. Chem. Soc., 1583 (1947). H. D. Verkruijsse, L. Brandsma, Synth. Commun. 21, 235 (1991). J. A. Kepler, R. C. Strickland, Org. Prep. Proced. Int. 5, (1973) 41. (a) R. Epzstein, Bull. Soc. Chim. France, 158 (1956); (b) J. H. van Boom, P. P. Montijn, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 84, 31 (1965). H. Baganz and K. Praefke, Chem. Ber. 95, 1566 (1962); L. Gouin, Ann. Chim. (Paris) 5, 529 (1960). S. Hoff, B. H. Steenstra, L. Brandsma, J. F. Arens, Recl. Trav. Chim., Pays-Bas 88, 1284 (1969). L. Brandsma, Preparative Acetylenic Chemistry. Elsevier, Amsterdam, 1971, p. 174. R. A. Raphael and F. Sondheimer, J. Chem. Soc. 2693 (1951); C. F. H. Allen and C. O. Edens, Org. Synth. 25, 92 (1945). H. D. Verkruijsse and L. Brandsma, Synth. Commun. 21, 141 (1991). E. R. H. Jones and M. C. Whiting, J. Chem. Soc., 3317 (1953). J. B. Armitage, E. R. H. Jones and M. C. Whiting, J. Chem. Soc., 44 (1951). H. Olsman, A. Graveland and J. F. Arens, Recl. Trav. Chim., Pays-Bas 83, 301 (1964). D. Seebach and T. Mukhopadhyay, Helv. Chim. Acta 65, 385 (1982). J. Backes in Houben-Weyl, Methoden der Organischen Chemie, E19d. Thieme-Verlag, Stuttgart, 1994, p. 114. G. Linstrumelle, D. Michelot, J. Chem. Soc., Chem. Comm., 561 (1975); J.-C. Clinet and G. Linstrumelle, Nouv. J. Chem. 1, 373 (1977). S. Hoff, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 87, 916 (1968). H. E. Wijers, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 85, 601 (1966). L. Brandsma, H. E. Wijers and J. F. Arens, Recl. Trav. Chim., Pays-Bas 82, 1040 (1963). (a) Y. Leroux and C. Roman, Tetrahedron Lett., 2585 (1973); (b) R. Mantione, Y. Leroux, Compt. Rend., Acad. Sci [C] 272, 2201 (1971); (c) J. C. Craig and N. N. Ekwuribe, Tetrahedron Lett., 2587 (1980).

5 Reactions with Aldehydes and Ketones

5.1

SURVEY OF LABORATORY METHODS

a-Hydroxyacetylenes, compounds with the general structure R1C CC(R2)(R3)OH, are extremely important intermediates and end products in acetylenic chemistry. They are generally prepared by coupling of the acetylene R1CCH with the carbonyl compound R2R3C¼O. Laboratory methods mostly deal with reactions of an alkali metal alkynylide or Grignard derivative with the carbonyl compound in an organic solvent or in liquid ammonia [1,2].

Industrial methods are beyond the scope of this Chapter. In the industrial manufacture of important starting compounds such as 2-propyn-1-ol, HCCCH2OH, 3-butyn-1-ol, HCCCH(Me)OH, and 2-butyne-1,4-diol, HOCH2CCCH2OH, high pressure techniques are employed using alkali hydroxides or copper acetylide as catalysts. For extensive reviews on the alkynylation processes the reader is referred to the monograph [1] and review on this subject [3]. The general scheme for preparation in the laboratory has a number of variants. The choice of a particular method is determined by the availability of the starting acetylene, R1CCH, the desired scale of the preparation (e.g. a few millimoles, 100 mmolar, 1 molar or more) and a number of other factors. The most versatile method, suitable for working on scales varying from a few mmoles to 0.50 mol, is the reaction of a lithium alkynylide with a carbonyl compound in a tetrahydrofuran-hexane mixture. If R1 is H, a complexing agent, e.g. 1,2-ethanediamine [4], H2NCH2CH2NH2, or TMEDA [5] is necessary to stabilise monolithium acetylide. In some cases, addition of lithium 119

120

5.

REACTIONS WITH ALDEHYDES AND KETONES

bromide has the favourable effect of solubilisng the lithium alkynylide resulting in improved yields [6]. The combination of RCCMgX (X is usually Br) and THF usually guarantees a good result. Diethyl ether may suffice as well, except in those cases where the metallated acetylene is sparingly soluble and a suspension or oily under-layer is produced. Reduced yields of acetylenic alcohols are often caused by deprotonation of the carbonyl compound:

The extent to which this side-reaction occurs depends upon the acidity of the carbonyl compound, the thermodynamic basicity of the acetylide (related to the pK value), its kinetic basicity (which decreases in the order K>Na>Li>MgX), and the polarity of the solvent (which also influences the kinetic basicity of RCCM). Examples of easily enolisable ketones are cyclopentanone, acetophenone, b-ionone and 4,4-dimethoxy-2-butanone, MeC(¼O)CH2CH(OMe)2. The result of their coupling with a metallated acetylene shows a strong dependency upon the reaction conditions. In the polar solvent ammonia, formation of enolates from these ketones is often a serious side reaction. The ketones are liberated during the aqueous work-up and have to be separated from the alcohols, mostly via fractional distillation. Particularly in the case of ethynyl groups, this distillative separation is difficult due to the small differences in boiling points. Successful couplings in liquid ammonia are mostly restricted to less basic acetylides, e.g. RCCCCLi, PhCCLi, RSCCLi, RSCH¼CHCCLi, ClCCLi, and to non- (or hardly) enolisable carbonyl compounds, e.g. benzenecarbaldehyde, PhCH¼O, acrylaldehyde, H2C¼CHCH¼O, 2-butenal, MeCH¼CHCH¼O. An additional competing reaction of aldehydes is the reaction of NH3 with the C¼O group or – in the case of an a,b-unsaturated aldehyde – addition of NH3 to the C¼C–C¼O system. In the Favorsky reaction [1,3], acetylene is coupled with a carbonyl compound in the presence of powdered alkali hydroxide suspended in an organic solvent in which acetylene has a good solubility. Some acetylenic alcohols, derived from ketones (including the readily enolisable cyclopentanone) can be obtained in high yields by introducing acetylene at atmospheric pressure and at room temperature into a KOH–DMSO mixture and subsequently adding the ketone [7,8]. The intermediate possibly is a metal acetylide formed in a low equilibrium concentration.

5.2

EXPERIMENTAL SECTION

121

We found that a number of alcohols can be prepared in excellent yields by adding the ketone to the suspension, prepared by introducing an excess of acetylene into a solution of t-BuOK in THF [9]. This method shows some resemblance with the Favorsky reaction. The reactive intermediate probably is potassium acetylide or a complex of it with t-BuOH or acetylene.

The hydroxyalkylation of allenic $ acetylenic anionic species is in many cases carried out with the lithium derivatives. The regiochemistry, i.e. the ratio of the acetylenic and allenic derivatives, depend upon the counter ion, the nature of the carbonyl compound, the organometallic group and upon the solvent. There is a vast amount of data on this coupling reaction [10,11]. It is in many cases possible to achieve a very selective regiochemistry by replacing Li by Zn, Al, Ti or B. Examples can be found in the Refs. [11–15].

5.2

EXPERIMENTAL SECTION

Note: In most of the procedures the reaction mixture is kept under inert gas. 5.2.1

Reaction of alkynyllithium with paraformaldehyde

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre Organolithium and Grignard derivatives can be hydroxymethylated with paraformaldehyde in diethyl ether or tetrahydrofuran [16]. This reaction proceeds smoothly at 20–35 C and is very general. Yields (particularly with lithium compounds, cf. Vogel’s Textbook [17]) are usually high. The difference in ease of the reaction with the various organometallic intermediates ranging from acetylides to very strongly basic organometallics is small. The rate-limiting step probably is the depolymerisation of the –OCH2–OCH2–O–chain, which may be assisted to some extent by interaction between oxygen and the Lewis

122

5.

REACTIONS WITH ALDEHYDES AND KETONES

acid þMgX or Liþ. The procedure for 2-heptyn-1-ol described below is representative. For lithium acetylides with a poor solubility THF is a better solvent than Et2O.

5.2.1.1

Procedure [16]

Dry (Note 1) powdered paraformaldehyde (8 g, corresponding to an excess) is added over a few seconds (using a powder funnel) to a solution of 0.20 mol of hexynyllithium (Chapter 3, exp. 3.9.4) in THF (or Et2O) and hexane, cooled to 0 C. The temperature is then allowed to rise. The heating effect becomes observable in the temperature range 15–25 C. The flask is occasionally cooled in a bath with ice and ice water. When, in the region of 25 C, the evolution of heat has ceased, the reaction mixture is warmed to 35–40 C (in the case of Et2O gentle reflux). After 1.5 h the mixture is poured into 250 ml of an aqueous solution of 25 g of ammonium chloride. After vigorous shaking, the layers are separated and the aqueous layer is extracted five times with Et2O (Note 2). The organic solutions (washing is not carried out) are dried over MgSO4 and subsequently concentrated under reduced pressure. The remaining liquid is first distilled under oil-pump pressure using a short Vigreux column and a single receiver, cooled at a sufficiently low temperature (Figure 1.10) (Note 3). Redistillation through a 30-cm Vigreux column gives 2-heptyn- 1-ol, bp 83 C/12 Torr, in 80% yield. Examples of other alcohols prepared by this procedure are: 4-methyl4-penten-2-yn-1-ol, H2C¼C(Me)CCCH2OH, bp 70 C/12 Torr; 4-penten2-yn-1-ol, H2C¼CHCCCH2OH, bp 64 C/12 Torr; 2,4-nonadiyn-1-ol, n-BuCCCCCH2OH, bp 96 C/0.2 Torr. Yields are between 75 and 85%.

Notes 1.

Azeotropic removal of water with benzene may be envisaged. During the distillation of the benzene, the suspension should be stirred mechanically or magnetically. 2. In the case of alcohols with a good solubility in water (e.g. H2C¼CHCCCH2OH) or other alcohols with a limited number of C-atoms, more extractions should be carried out. 3. If the alcohol is expected to have a limited thermal stability (e.g. MeCCCCCH2OH, RSCCCH2OH), 20–30 ml of paraffin oil should be added (see Chapter 1.3). The use of a mercury diffusion pump (P < 0.01 Torr) is advised. Redistillation of the product at a pressure higher than 1 Torr should not be attempted.

5.2 5.2.2

EXPERIMENTAL SECTION

123

General procedure for the coupling of lithium alkynylides with aldehydes and ketones in THF or Et2O

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 5.2.2.1 Procedure The aldehyde (0.12 mol, Note 1) or ketone (0.12 mol) is added over 5–10 min to a solution of 0.10 mol of the lithium alkynylide in THF or Et2O and hexane (Chapter 3, exps. 3.9.4, 3.9.5 and 3.9.6) with cooling below –50 C (Note 2). In the cases of slightly soluble R1CCLi in THF (e.g. MeCCLi, EtCCLi) a solution of anhydrous lithium bromide (0.12 mol, Note 3) in 40 ml of THF is added with some cooling, prior to introducing the carbonyl compound [6]. The reactions generally are extremely fast so that it suffices to remove the cooling bath after completion of the addition and to allow the temperature to rise to – 20 or 0 C. The work up is usually (Note 4) carried out by pouring the reaction into ice water (200 ml, which may contain 20–30 g of NH4Cl), shaking, separating the layers, extracting the aqueous phase with Et2O (Note 5), and drying the combined organic solutions over anhydrous MgSO4 or K2CO3 (Note 6). The solvent is removed under reduced pressure (rotary evaporator, Note 7) after which the remaining liquid is distilled in vacuo (Note 8). Yields are generally greater than 70% and often excellent. Examples of alcohols prepared by this procedure: 1-phenyl-2-propyn-1-ol, HCCCH(Ph)OH, bp 110 C/Torr, from LiC CHTMEDA–THF–hexane (Chapter 3, exp. 3.9.5) and PhCH¼O. Aliphatic aldehydes RCH¼O, with R>n-Pr presumably can also be ethynylated with this stabilised acetylide; 1-(1-propynyl)cyclopentanol, MeCCC(CH2)4OH, bp 78 C/10 Torr, from MeCCLi þ LiBr in THF–hexane and cyclopentanone at –30 C [6]. After an additional period of 20 min (at –30 C) the temperature is allowed to rise to 0 C and the mixture is hydrolysed; 1-(1-propynyl)cyclohexanol, MeCCC(CH2)5OH, bp 92 C/10 Torr, in an analogous way from MeCCLi þ LiBr in THF–hexane and cyclohexanone [6]; 1-[2-(dimethylamino)-1-propynyl]cyclopentanol, Me2NCH2CCC(CH2)4 (OH), bp 130 C/10 Torr, from Me2NCH2C CLi þ LiBr in THF– hexane and cyclopentanone at –40 to –20 C and an additional half an hour at –20 C [6];

124

5.

REACTIONS WITH ALDEHYDES AND KETONES

4-ethoxy-2-methyl-3-butyn-2-ol, EtOCCCMe2OH, bp 72 C/12 Torr, from EtOCCLi in THF or Et2O–hexane and acetone at < –40 C. This alcohol is acid-sensitive [18]. The NH4Cl-solution used for the work-up should contain a small amount of ammonia. All glassware should be ‘rinsed’ with gaseous ammonia. A neutral drying agent (Na2SO4) is recommended. Bath temperatures during the distillation should not exceed 100 C. Alcohols from ethoxyacetylene and aldehydes are even less stable, and distillation should be carried out at very low pressure, using a strongly cooled receiver (Figure 1.10); 5-chloro-3-pentyn-2-ol, ClCH2CCCH(Me)OH, bp 86 C/10 Torr, from ClCH2CCLi in Et2O–hexane and acetaldehyde at –70 C; 6-methoxy-1-hexen-4-yn-3-ol, MeOCH2CCCH(OH)CH¼CH2, bp 108 C/ 12 Torr, from MeOCH2CCLi in THF–hexane and (freshly distilled) acrolein at –20 to 0 C and an additional 5 min. The aqueous layer is extracted 10–15 times with Et2O, the organic solutions are not washed with water.

Notes 1.

Only freshly distilled aldehydes should be used. Monomeric acetaldehyde (bp 21 C) is prepared 1–2 h in advance by heating the trimer, paraldehyde, with a few ml of 96% sulphuric acid in a distillation apparatus and collecting the acetaldehyde in a cooled receiver. All glassware should be made neutral by successive rinsing with distilled water, and acetone containing a trace of Et3N, and blowing dry with air. The dropping funnel is treated in the same way. 2. Unstable LiCCR1 should be prepared and converted with carbonyl compounds below –70 C. This holds also for the reaction of chloroketones, RCOCH2Cl, since the alcoholates R1CCC(R)(OLi)CH2Cl may undergo cyclisation to an oxirane at higher temperatures. 3. Yields are considerably lower and much ketone is recovered, when this addition is omitted. The beneficial effect of LiBr is strongest in the case of slightly soluble (in THF) LiCCR1. A possible explanation is that LiBr causes solubilisation of the alkynylide (for the preparation of the required anhydrous LiBr from the commerical anhydrous salt see Chapter 2.2). Dissolution of this salt in THF is effected by vigorous shaking (the heating effect is rather strong). 4. If the alcohol is rather volatile (bp<70 C/15 Torr), a considerable amount of the THF and hexane can be removed under reduced pressure prior to the hydrolysis, using a rotary evaporator. The chance of the retro-reaction (to R1CCLi and R2R3C¼O) is small if the bath temperature is kept

5.2

5. 6. 7. 8.

EXPERIMENTAL SECTION

125

below 45 C. The remaining viscous solution is cooled to 0 C and a cold aqueous solution of NH4Cl is added. By reducing the amount of THF and hexane, losses of product during the removal of solvent after aqueous work-up are minimised. The procedure seems risky when R1 ¼ EtO or Me3Si. Repeated extraction is necessary in the cases of alcohols having a short carbon chain, an alkoxy- or a dialkylamino group. K2CO3 is more effective, MgSO4 should not be used if acid-sensitive groups (e.g. CC–O, O–C–O) are present in the alcohol. If the bp of the product is lower than 70 C/15 Torr, the bath temperature should not be higher than 40 C. It is generally advisable to first carry out a flash distillation at oil-pump or mercury diffusion-pump pressure and to collect the products in a strongly cooled single receiver (Figure 1.10).

5.2.3

Coupling of butadiynyllithium with acetone

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 5.2.3.1 Procedure A solution of 0.10 mol of BuLi in 63 ml of hexane is added over 10 min to a solution of 0.15 mol (Note 1) of freshly prepared butadiyne (Chapter 10, exp. 10.2.7) in 80 ml of THF, while keeping the temperature below –50 C. The mixture (partly suspension) is cooled to –80 C and acetone (0.10 mol) is added over 5 min. The cooling bath is removed and the suspended material disappears within a few minutes. After an additional 10 min a solution of 10 g of ammonium chloride in 100 ml of water is added with vigorous stirring. After separation of the layers, three extractions with Et2O are carried out. The organic solutions are dried (washing is not carried out) over magnesium sulphate and subsequently concentrated in vacuo, leaving the practically pure alcohol in >90% yield. Distillation of the light-brown liquid from a relatively big flask (500 ml), using a short Vigreux column and a single receiver cooled below –20 C (Figure 1.10), gives the pure 2-methyl-3,5-hexadiyn-2-ol, bp 40 C/1 Torr, in 85–90% yield. During distillation the bath temperature

126

5.

REACTIONS WITH ALDEHYDES AND KETONES

should be kept as low as possible. The distillate rapidly turns dark upon standing at rt (Note 2).

Notes 1.

The monolithium compound is presumed to equilibrate with butadiyne and its dilithium derivative. By using an excess of butadiyne the concentration of the monolithium compound is increased and formation of diols is suppressed. 2. Products derived from aldehydes are even less stable and distillation should not be attempted.

5.2.4

Ethynylation of acrolein and croton aldehyde in liquid ammonia

Scale: 0.30 molar; Apparatus: Figure 1.1, 1 litre, addition by syringe 5.2.4.1

Procedure (cf. [19,20])

Freshly distilled acrolein or crotonaldehyde (0.30 mol) is added dropwise over 15 min to a vigorously stirred concentrated solution of 0.40 mol of lithium acetylide in 250 ml of liquid ammonia (Chapter 3, exp. 3.9.1). During this addition the temperature of the suspension is kept between –70 and –78 C, while N2 is introduced ( 300 ml/min). After an additional 15 min (without cooling) the reaction mixture is cautiously poured into a 3-litre wide-necked round-bottomed flask. The reaction flask is rinsed twice with a small amount of liquid ammonia. Powdered ammonium chloride (30 g) is introduced in small portions with occasional manual swirling. The ammonia is then removed by placing the flask in a bath at 50–60 C. The remaining solid is dissolved in the minimal amount of water ( 50 ml) and the solution is extracted with Et2O, 15–20 times in the case R ¼ H and 10–15 times in the case R ¼ Me (Note 1). The combined ethereal solutions are dried over K2CO3, after which most of the ether is distilled off at normal pressure through a 40-cm Vigreux column. The remaining liquid is subsequently distilled in a water-aspirator vacuum, the receiver being cooled in a

5.2

EXPERIMENTAL SECTION

127

bath at –70 C (Figure 1.10). The temperature of the heating bath should not exceed 100 C in the case R ¼ H. A viscous residue remains after the distillation of the acrolein alcohol. An additional small amount of the alcohol may be obtained from this residue by lowering the pressure to <2 Torr (oil pump) (Note 2). Careful redistillation through a 40-cm Vigreux column gives the alcohols: 1-penten-4-yn-3-ol, R ¼ H, bp 40 C/15 Torr, and 4-hexen-1-yn-3-ol, R ¼ Me, bp 60 C/12 Torr, in greater than 75% yields. The products contain 2–5% water. 3-Methyl-1-penten-4-yn-3-ol, HCCC(OH)(Me)CH¼CH2, bp 30 C/12 Torr, is obtained in 60% yield by a similar procedure, with the difference that 0.15 mol only of (freshly distilled and water-free) methyl vinyl ketone is added to 0.30 mol of LiCCH. There remains a considerable amount of viscous residue after the distillation.

Notes 1.

2.

Saturation of the solution with K2CO3 may reduce the number of extractions necessary. Otherwise continuous extraction may be considered (after addition of more water). Especially the alcohol prepared from acrolein has a limited thermal stability. Bath temperatures higher than 90 C during distillation should be avoided.

5.2.5

Reaction of ethynylmagnesium bromide with b-Ionone

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml b-Ionone is very readily converted into the enolate ¼C–C(OM)¼CH2 by basic reagents, especially under polar conditions. Attempts to ethynylate this ketone with lithium or sodium acetylide in liquid ammonia gave the alcohol in moderate yields, along with much b-ionone, re-formed from the enolate produced during the reaction with the alkali acetylide [5]. Separation of b-ionone and its alkynylation product by distillation is not easy because of the slight

128

5.

REACTIONS WITH ALDEHYDES AND KETONES

difference of the boiling points. Grignard reagents are highly reactive in additions to carbonyl groups, but show little tendency to deprotonate ketones or aldehydes at the a-position of the C¼O group. Therefore, they are the reagents of choice if base-sensitive compounds such as b-ionone are to be alkynylated. 5.2.5.1

Procedure

A solution (partly suspension) of ethynylmagnesium bromide is prepared by introducing acetylene into a solution of 0.15 mol of EtMgBr in 150 ml of THF (Chapter 3, exp. 3.9.7). After cooling to 0 C, freshly distilled b-ionone (0.10 mol) is added over a few minutes. The reaction is weakly exothermic. After an additional 15 min the cooling bath is removed and stirring is continued for 1 h. The reaction mixture is then poured into 100 ml of a concentrated aqueous solution of ammonium chloride. After vigorous shaking and separation of the layers, three extractions with Et2O are carried out. The solvent is removed under reduced pressure and the remaining viscous liquid distilled through a short column to give 3-methyl-5-(2,6,6-trimethyl-1-cyclohexenyl)-4-penten-1yn-3-ol, bp 100 C/0.2 Torr, in >85% yield. There is a small high-boiling residue decomposing during attempted distillation. Benzaldehyde or hexanal and HCCMgBr (additions at –20 C, then allowing the temperature to rise to rt), give 1-phenyl-2-propyn-1-ol or 1-octyn-3-ol, respectively, in 85–90% yields. Coupling of b-ionone with BrMgCCCH¼C(Me)CH¼CHOMe in THF under conditions similar to those described above, gives the expected product in an excellent yield (distillation is not possible). This alcohol can be converted into Vitamin A aldehyde via reduction with LiAlH4 and subsequent treatment with dilute acid [21]. 5.2.6

Ethynylation of ketones with t-BuOK and acetylene in tetrahydrofuran

Scale: 0.30 molar; Apparatus: Figure 1.1, 500 ml A number of saturated aliphatic and cycloaliphatic ketones can be ethynylated with excellent results by adding the ketone to a suspension of potassium acetylide in THF, while continuously introducing acetylene. Potassium acetylide is generated by introducing acetylene into a solution of t-BuOK in THF.

5.2

EXPERIMENTAL SECTION

129

Although its formation presumably is an equilibrium, it appears to be possible to convert the ketones into the ethynyl alcohols with greater than 90% yield, using a 1:1 molar ratio of t-BuOK and ketone. In the case of cyclohexanone even a 1:2 molar ratio gave >85% yield of ethynylcyclohexanol [5]. However, the formation of acetylene diols appears to become increasingly significant when the ratio t-BuOK/ketone is diminished. The method gives unsatisfactory results in the cases of b-ionone and acetophenone, PhCOMe, (extensive formation of enol, etc.) and is totally unsuitable for the ethynylation of benzaldehyde.

5.2.6.1 Procedure [9] Potassium tert-butoxide (0.30 mol) is dissolved in 300 ml of THF. Acetylene (1–1.5 litre/min) is introduced with vigorous stirring (high turbulence) and cooling in a bath with ice water. A jelly-like suspension is formed and the temperature may rise above 30 C (stirring may become less efficient). When no further rise in temperature is observed (after 10 min), the flow of acetylene is adjusted to 300 ml/min and the temperature of the suspension brought to 15 C. The ketone (0.30 mol) is then added over 15 min with vigorous agitation. The suspension gradually disappears. The temperature of the reaction mixture is maintained between 10 and 20 C. Stirring and introduction of acetylene are continued for an additional 10 min, then the light-brown solution is cautiously (some acetylene may escape) poured into a solution of 30 g of ammonium chloride in 150 ml of water. After vigorous shaking, the layers are separated and the aqueous layer is extracted four times (at least) with Et2O. The combined organic solutions are washed twice with 100-ml portions of a saturated aqueous solution of NH4Cl and subsequently dried over a large amount (100 g) of MgSO4 (stirring for 30 min). After filtration through sintered glass and thorough rinsing of the drying agent with Et2O, the greater part of the solvent is distilled off at atmospheric pressure through a 40-cm Vigreux column. After cooling, the remaining liquid is carefully distilled in vacuo through the same column. The following alcohols are obtained in excellent yields: 3,5-Dimethyl-1-hexyn-3-ol, R1 ¼ Me, R2 ¼ i-Bu, bp 75 C/18 Torr; 3,4,4-trimethyl-1-pentyn-3-ol, R1 ¼ Me, R2 ¼ t-Bu, bp 64 C/15 Torr; 3-methyl-1nonyn-3-ol, R1 ¼ Me, R2 ¼ C6H13, bp 87 C/15 Torr; 1-ethynylcyclopentanol, R1R2C¼(CH2)4C, bp 57 C/15 Torr; 1-ethynyl-1-cyclohexanol R1R2C¼ (CH2)5C, bp 75 C/15 Torr (solid fraction); 1-ethynyl-1-cycloheptanol, R1R2C ¼(CH2)6C, bp 88 C/15 Torr. In all cases small high-boiling residues of the diol are left behind. The amount of residue is significant when the ketone is added at too fast a rate.

130 5.2.7

5.

REACTIONS WITH ALDEHYDES AND KETONES

Ethynylation of ketones in DMSO–KOH mixtures

Scale: 0.50 molar; Apparatus: Figure 1.1, 500 ml

5.2.7.1

Procedure

(Taken from Ref. 7, not checked, but slightly modified.) The flask was charged with 250 ml of dry DMSO and 0.4 mol of KOH pellets (28 g, 82%-technical quality). The stirred mixture was heated until the KOH had melted (120–130 C) and was subsequently cooled to 40 C. Introduction of acetylene was then started. Continuing the introduction at 15 to 17 C, 0.50 mol of cyclohexanone was added over 1 h. The reaction was followed by GLC. After 1 to 1.5 h all ketone had reacted. Water (300 ml) was added, after which several extractions with small portions of Et2O were carried out. The combined extracts were washed twice with water, dried over magnesium sulphate and concentrated under reduced pressure. Vacuum distillation gave 1-ethynylcyclohexanol in 98% yield. Cyclopentanone (0.10 mol) was ethynylated (84% yield) under similar conditions using 20 g of KOH and 50 ml of DMSO. 5.2.8

Reaction of lithiated propargyl chloride with polymeric formaldehyde

Scale: 0.50 molar; Apparatus: Figure 1.1, 1 litre 5.2.8.1

Procedure

Dry, powdered paraformaldehyde (17 g, corresponding to an excess) is added at –75 C to a solution of 0.50 mol of lithiated propargyl chloride (Chapter 3, exp. 3.9.6) in a mixture of 315 ml of hexane and 300 ml of Et2O. After addition the temperature of the mixture is allowed to rise to –40 C over 1 h and is kept at this level for 3 h, then the cooling bath is occasionally removed and the temperature of the reaction mixture is slowly raised (over 1 h) to rt. After an additional 1 h the reaction mixture is hydrolysed by cautious addition of 100 ml of ice water. Ten extractions with small portions of Et2O are carried out. The

5.2

EXPERIMENTAL SECTION

131

combined solutions are dried over magnesium sulphate. Concentration under reduced pressure followed by distillation gives the alcohol, bp 95 C/20 Torr in 50% yield.

5.2.9

Reaction of allenylmagnesium bromide with aldehydes

Scale: 0.30 molar; Apparatus: Figure 1.1, 1 litre There is an abundance of data on the regio- and stereochemistry of reactions between metallated (Li, MgX, Al, Zn, Ti) allenes and carbonyl compounds [22–24]. In many cases, the metallic intermediates were prepared from propargylic bromides and magnesium, aluminium or zinc. Allenic aluminium and Grignard reagents have been shown to react with carbonyl compounds to give only acetylenic products. 5.2.9.1 Procedure A solution of 0.30 mol of allenylmagnesium bromide in 300 ml of Et2O (Chapter 2, exp. 2.3.9), is cooled to –40 C. The aldehyde (0.30 mol, freshly distilled, Note 1) is then added dropwise over 20 min with vigorous stirring. After the addition, the temperature is allowed to rise from –40 to þ10 C. In most cases a coarse suspension is formed. The reaction mixture is hydrolysed by pouring it into a solution of 50 g of ammonium chloride in 300 ml of ice water (Note 2), after which the small amount of suspension remaining in the flask is treated with the NH4Cl solution. After swirling and (subsequent) vigorous shaking, the layers are separated and the aqueous phase is extracted with Et2O (Note 3). The organic solution is dried (washing is not carried out) over 15 to 25 g of MgSO4 (mechanical stirring for 20 min), after which the drying agent is filtered off on a sintered-glass funnel and rinsed with Et2O. The solvent is removed under reduced pressure (Note 4) and the remaining liquid is distilled through a 30 or 40-cm Vigreux column under water-aspirator or oilpump pressure (depending on the volatility of the product). Yields are generally good to excellent. Examples of alcohols prepared: 1-heptyn-4-ol, R ¼ n-Pr, bp 58 C/12 Torr; 1-hexen-5-yn-3-ol, R ¼ CH ¼ CH2, bp 55 C/12 Torr; (E)-5-hepten-1-yn-4-ol, R ¼ (E)-CH¼CHMe, bp 68 C/ 12 Torr.

132

5.

REACTIONS WITH ALDEHYDES AND KETONES

Notes 1. Freshly distilled aldehydes should be used, see Chapter 2, Section 2.2. 2. If the hydrolysis is carried out by inverse addition, much heat is evolved, which may result in partial loss of the ethereal solution. 3. Frequent extraction is necessary in the cases of the lower homologues. 4. In the case of alcohols from acetaldehyde and propionaldehyde, the Et2O should be distilled off at atmospheric pressure. 5.2.10

Reaction of lithiated methoxyallene with carbonyl compounds

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml

5.2.10.1

Procedure

The carbonyl compound (0.10 mol, for aldehydes see note 1 of preceding experiment) is added at –40 C or lower temperature to a solution of 0.10 mol of the lithiated allenic ether (Chapter 3, exp. 3.9.15 and Table 3.3). A few minutes later a solution of 20 g of ammonium chloride and a few millilitres of aqueous ammonia (Note) is added and extraction with Et2O is carried out. The organic solution is dried over potassium carbonate and subsequently concentrated under reduced pressure. After adding a few drops of diethylamine (Note), the remaining liquid is distilled. The desired alcohols are obtained in excellent yields. Examples: 3-methoxy-3,4-pentadien2-ol, R1 ¼ H, R2 ¼ Me, bp 58 C/12 Torr; 3-ethyl-4-ethoxy-4,5-hexadien-3-ol, R1 ¼ R2 ¼ Et, bp 68 C/12 Torr; 1-(1-methoxy-1,2-propadienol)cyclohexanol, R1R2C ¼ C(CH2)5, bp 100 C/12 Torr. Note: The products are acid-sensitive.

5.2.11

1-Ethynylcycloheptanol from lithium acetylide and cycloheptanone in liquid ammonia

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml (cf. the scheme below the Section 5.2.4, p. 126)

REFERENCES 5.2.11.1

133

Procedure

Cycloheptanone (0.20 mol) is added over 15 min to a solution of 0.22 mol of lithium acetylide in 250 ml of (boiling) liquid ammonia saturated with acetylene. Thirty minutes after this addition, 15 g of powdered ammonium chloride is added in small portions (the thermometer is replaced with a powder funnel). The ammonia is allowed to evaporate. After addition of water three extractions with Et2O are carried out. The organic solution is dried and the ether removed under reduced pressure. Careful distillation through an efficient column gives, after a large first fraction of cycloheptanone, 1-ethynylcycloheptanol, bp 84 C/ 10 Torr, in 50% yield. From cyclopentanone the alcohol is obtained in 20% yield only. 5.2.12

1-Ethynylcycloheptanol from acetylene and cycloheptanone (KOH method)

Scale: 0.20 molar; Apparatus: Figure 1.9, 500 ml, long gas inlet tube (cf. the scheme below the Section 5.2.7, p. 130)

5.2.12.1

Procedure

In the flask are placed 150 ml 1,2-dimethoxyethane and 60 g of machinepowdered KOH. The flask is cooled in a bath at 0 C and acetylene is introduced at a rate of 300 ml/min during 20 min. After this period the flow of acetylene is adjusted at 100 ml/min and 0.20 mol of cycloheptanone is added over 1.5 h (the inlet tube is combined with a dropping funnel). After an additional 30 min (with continuation of the acetylene flow) the reaction mixture is poured on to 300 g of crushed ice. Six extractions with Et2O are carried out. The organic solution is washed with concentrated aqueous ammonium chloride and dried over magnesium sulphate. The acetylenic alcohol (cf. preceding exp.) is obtained in an excellent yield.

REFERENCES 1. W. Ziegenbein, Einfu¨rung der A˜thinyl- und Alkinyl-Grupe in Organischen Verbindungen. Verlag Chemie, 1963. 2. V. Ja¨ger, in Houben-Weyl, Methoden der Organischen Chemie, Band 5/2a. Thieme-Verlag, Stuttgart, 1977. 3. W. Ziegenbein, in Chemistry of Acetylenes (ed. H. G. Viehe). Marcel Dekker, New York, 1969, p. 130. 4. R. E. A. Dear and F. L. M. Pattison, J. Am. Chem. Soc. 85, 622 (1963); W. N. Smith and O. F. Beumel, Jr., Synthesis, 441 (1974).

134

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REACTIONS WITH ALDEHYDES AND KETONES

5. Unpublished observations in the author’s laboratory. 6. P. E. van Rijn, S. Mommers, R. G. Visser, H. D. Verkruijsse and L. Brandsma, Synthesis, 459 (1981). 7. B. A. Trofimov, L. N. Sobenina, S. E. Korostova, A. I. Mikhaleva, N. I. Shishov, V. D. Fel’dman, S. G. Shevchenko and A. N. Vasil’ev, Zh. Prikl. Khim. 60, 1366 (1987); Chem. Abstr. 108, 204191 (1988). 8. L. I. Zakharkin, A. P. Pryanishnikov and S. T. Ovseenko, Zh. Org. Khim. 25, 779 (1989); Engl, P.699. 9. H. D. Verkruijsse, W. de Graaf and L. Brandsma, Synth. Commun. 18, 131 (1988). 10. R. Epzstein, review in Comprehensive Carbanion Chemistry, part B (eds. E. Buncel and T. Durst). Elsevier, Amsterdam, 1984, p. 99. 11. H. Yamamoto, in Comprehensive Organic Synthesis, Vol. 2, part 2 (ed. B. M. Trost). Pergamon Press, Oxford, 1991, p. 81. 12. F. Mercier, R. Epzstein and S. Holand, Bull. Soc. Chim. France, 690 (1972); R. Epzstein and F. Mercier, Synthesis, 183 (1977); D. A. Evans and J. V. Nelson, J. Am. Chem. Soc. 102, 774 (1980). 13. D. Hoppe and G. Gonschorrek, Tetrahedron Lett. 28, 275 (1987). 14. N. R. Pearson, G. Hahn and G. Zweifel, J. Org. Chem. 47, 3364 (1982). 15. M. Ishiguro, N. Ikeda and H. Yamamoto, J. Org. Chem. 47, 2225 (1982). 16. A. Schaap, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 84, 1200 (1965). 17. A. I. Vogel, Textbook of Practical Organic Chemistry, 4th edn. Longmans, 1978. 18. L. Brandsma, H. J. T. Bos and J. F. Arens, in Chemistry of Acetylenes (ed. H. G. Viehe). Marcel Dekker, New York, 1969, p. 751. 19. F. Bohlmann and H. G. Viehe, Chem. Ber. 87, 712 (1954). 20. J. M. Shackelford, W. A. Michalowicz and L. H. Schwartzman, J. Org. Chem. 29, 1631 (1962). 21. H. A. M. Jacobs, M. H. Berg, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 84, 1113 (1965). 22. R. Epzstein, review in Comprehensive Carbanion Chemistry, part B (eds. E. Buncel and T. Durst). Elsevier, Amsterdam, 1984, pp. 123–140. 23. W. Chodkiewicz et al., Bull. Soc. Chim. France, 1417 (1972); Tetrahedron Lett. 759 (1971) and their previous articles mentioned. 24. J. L. Moreau and M. Gaudemar, Bull. Soc. Chim. France, 2171, 2175 (1970).

6 Carboxylation, Acylation and Related Reactions

6.1

INTRODUCTION

Acetylenic derivatives in which the triple bond is conjugated with a C¼O group are versatile intermediates in organic synthesis, especially in cycloaddition reactions [1]. A number of these systems have been prepared by transformation of other functional groups. Acetylenic aldehydes, R1CCCH¼O, for example, can be obtained by acid hydrolysis of acetylenic acetals, R1CCCH(OR2)2, which, in their turn, are accessible from acetylenic Grignard reagents, R1CCMgBr, and trialkoxymethanes, HC(OR2)3. Acetylenic ketones, R1CCCOR2, are formed by oxidation of the alcohols, R1CCCH(OH)R2, with chromic acid [2]. In most cases, however, the C¼O function can be introduced in a direct manner and this chapter gives several excellent procedures. These generally use an organic solvent. Tetrahydrofuran and diethyl ether are the most favoured ones, the former often being preferred for reasons of solubility. While the use of strongly polar solvents such as DMSO and HMPT, does not offer special advantages – the acylation and carboxylation reactions proceed at a convenient rate in THF or Et2O – it could give rise to difficulties in the purification of the desired compounds. Liquid ammonia is generally unsuitable due to the ammonia-sensitivity of the functionalisation reagent or of the product. For most derivatisations of acetylides Liþ is preferred to Naþ, Kþ or XMgþ as a counter ion, mainly because of a better solubility of the acetylide. The general experience is that lithium compounds react more satisfactorily than do the Grignard derivatives. For data on carboxylations, acylations and related reactions of acetylenic $ allenic carbanionic species and on their regiochemistry the reader is referred to the reviews [3–8]. A number of reactions with heterocumulenes is summarised in Table 6.1. 135

136

Table 6.1 Reactions of metallated acetylenic and allenic compounds, RM, with heterocumulenesa RM (M ¼ Li or K)

RCOOH RC(¼O)NHPh RC(¼O)NMePh RC(¼S)NHMe RC(SMe)¼NPh RS(¼O)NHPh RCOOH RCOOH HOOCCH¼C¼CHCOOH H2C¼C-C(Me)COOH RC(OSiMe3)¼NPh RC(SMe)¼NMe RC(SMe)¼NMe RC(¼O)NH-n-Pr RC(SMe)¼NPh RC(¼O)NH-n-Bu RC(SMe)¼N-i-Pr R1S(¼O)NHPh (R1¼ HCCCMe2)

Refs., notes 9 8,9 8,9 9 8,9 34,36 9 9 9 18 10,c 11 12,d 13 14,e 13, cf. 21 15 33,f

CARBOXYLATION, ACYLATION AND . . .

t-BuCCLi MeCCLi t-BuCCLi H2C¼C¼CHLi t-BuCH¼C¼CHLi LiCH2CCLi MeCH(Li)CCLi t-BuCH¼C¼CHLi t-BuCH¼C¼CHLi H2C¼C¼C(OMe)Li H2C¼C¼C(OMe)Li H2C¼C¼C(SMe)Li Me2C¼C¼CHLi Me2C¼C¼CHLi Me2C¼C¼CHMgBr

CO2, <0; HCl, H2O PhN¼C¼O, –40 ! 10; H2O PhN¼C¼O, –40 !10; Me2SO4, DMSO, –40 ! 10 MeN¼C¼S, –10!rt; H2O PhN¼C¼S, 0!35; MeI, 0!40 PhN¼S¼O,–10!0; HCl, H2O CO2, –90; HCl, H2O CO2, –90; HCl, H2O CO2,; KOH, H2O; HCl, H2O CO2, –80; KOH, H2O, rt; HCl, H2O PhN¼C¼O, –100; Me3SiC1, –80 MeN¼C¼S, –100; MeI, –40 MeN¼C¼S, –80; MeI, –40 n-PrN¼C¼O, –90; NH4Cl, H2O PhN¼C¼S, –75; MeI, –75 n-BuN¼C¼O, –90; HCl, H2O i-PrN¼C¼S, –90; MeI, –40 PhN¼S¼O, –105; HCI, H2O, –70

Product

6.

MeCCLi MeCCLi MeCCLi

Reaction conditionsb

CS2, –80; MeI, –40

R1C(¼S)SMe (R1¼ HCCCMe2) RCSSMe R1C(SMe)¼NMe (R1 ¼ H2C¼C¼CMe) HCCC(Me)¼C(SMe)2

t-BuCH¼C¼CHLi MeCCCH2Li

CS2, –80; MeI, –10 !10 MeN¼C¼S, –100; MeI, –70

MeCCCH2K (2 equiv.) Et2NCCCH2K (2 equiv.) H2C¼C¼CHMgBr (solvent Et2O)

8,9,h

CS2, –80; MeI, –10 !10

(MeS)2C¼C(NEt2)CCH

8,9,h

PbN¼S¼O, –100! –30; HCl, H2O

R1S(¼O)NHPh (R1¼ HCCCH2)

9,16 8,9 17,g

INTRODUCTION

CS2, –60; NaOH, H2O, –60; MeI, 0

6.1

Me2C¼C¼CHLi

36

All reactions are performed in 1:1 mixtures of THF and hexane. Temperatures in C. The various operations are separated by a semicolon. c Crude product; heating at 140 C gives 4-neopentyl-2-[(trimethylsilyl)oxy]quinoline in high yield. d Crude product; treatment with Cu(I)Br gives 3-methoxy-1-methyl-2-(methylthio)pyrrole. e Crude product; heating at >100 C gives 2,3-bis(methylthio)quinoline in a good overall yield, cf. ref. 19. f With the lithiated allene, comparable amounts of the allenic and acetylenic product were obtained; the addition of 1,2-pentadienylmagnesium bromide, EtCH¼C¼CHMgBr, gave only N-phenyl-l-pentyne-3-sulphinamide, HCCCH(Et)S(¼O)NHPh. g Strong heating gives 5-methyl-6-(methylthio)-2,3-dihydropyridine in good yield. h The potassium compound is prepared by treatment of the acetylene with an equimolar mixture of n-BuLi and t-BuOK at temperatures below –80 C. a

b

137

138

6. 6.2

CARBOXYLATION, ACYLATION AND . . .

REACTIONS WITH HETEROCUMULENES

Carboxylation of acetylenes with a terminal triple bond is most conveniently carried out by introducing gaseous carbon dioxide at temperatures below 0 C into a solution of the lithium acetylide in a mixture of THF and hexane. Application of the traditional procedure, consisting of pouring the solution of the metallated compound on to dry ice covered with diethyl ether, is not relevant as in the case of lithium acetylides there is little risk of a subsequent reaction between the carboxylate and the metal compound. Yields are mostly excellent. For carboxylation of the much more strongly basic (and hence more reactive) acetylenic $ allenic anionic species inverse-addition technique must be applied. This may be realised by adding the solution of the intermediate to a strongly cooled saturated solution of carbon dioxide in THF. There are not many reports on regioselective carboxylation of the species mentioned. Reaction of the lithium compound Me2C¼C¼CHLi with CO2 gives the allenic acid as the only product [26], but in general, mixtures of allenic and acetylenic carboxylic acids are obtained from lithium as well as from Grignard derivatives. Alkali metal acetylides, MCCR, and carbon disulphide react very sluggishly and attempts to prepare dithiocarboxylic acids, HSSCCCR, have not been successful [9]. The alkali metal derivatives of the type [CCC– $–C¼C¼C]Mþ react vigorously with this heterocumulene. In most cases, the initial adducts undergo deprotonation by the metalated acetylene or allene resulting in a geminal dithiolate (Table 6.1). This can either be methylated on sulphur to give an S,S-acetal, or be forced to cyclise with formation of a thiophene ring [8]. Terminally as well as non-terminally metallated acetylenes or allenes react very easily with isocyanates, RN¼C¼O, analogous isothiocyanates [8,13], RN¼C¼S, and sulphinyl amines [33–36], RN¼S¼O. The adducts can be protonated or alkylated to afford carboxamides, thioamides and sulphinamides or imidates and thioimidates, respectively. Table 6.1 gives a number of examples of conversions affording one product. In general, however, both the acetylenic and the allenic derivative are formed from the reactions with acetylenic $ allenic anionic species. As usual in such cases, the ratio of these products depends inter alia upon the counter ion. In many reactions with isothiocyanates the additions proceed with a high regioselectivity. Further conversions with the initial adducts or their alkylation products give rise to new routes for a wide variety of cyclic and heterocyclic systems [8,13,20,35]. This chapter will deal only with the initial addition reactions.

6.3

ACYLATION REACTIONS 6.3

139

ACYLATION REACTIONS

For the introduction of CH¼O, RC¼O, COOR and R2NC¼O substituents the following methods are available; R representing in most cases an acetylenic group (Table 6.2). a.

Reaction of a lithium or Grignard derivative with a N,N-disubstituted formamide or formic ester followed, in the case of formamides, by treatment with dilute acid:

The adduct from the reaction of an acetylide with a N,N-disubstituted formamide has some stability at low temperatures. The aldehyde is liberated by treatment with dilute acid. Using Grignard derivatives [27] yields are somewhat lower than with lithium compounds. We found that the use of formylpiperidine, HC(¼O)Piperidine, has no special advantages over DMF. The disadvantage of using formic esters, compared to formamides, lies in the fact that OR1 is a better leaving group than NR12 . The adduct RCH(OR1)OM immediately eliminates R1OM with formation of the aldehyde, which may undergo further attack by RM affording a secondary alcohol, R2C(H)OH. b. Ketones may be prepared analogously by reaction between the organometallic compound and a carboxamide:

A number of acetylenic methyl and phenyl ketones can be prepared with excellent yields from a lithium alkynylide and N,N-dimethylacetamide, MeCONMe2, (DMA), or N,N-dimethylbenzenecarboxamide, PhCONMe2. Less strongly basic acetylides such as PhCCLi and RCCCCLi give unsatisfactory results (incomplete conversion) with DMA. Also the amides from other aliphatic carboxylic acids, e.g.

140

Table 6.2 Acylation of metallated acetylenes, R1CCM, and allenes, R1R2C¼C¼CHLi Reaction conditionsa (temp. in C)

R2OC(¼O)Cl R22 NCð¼ OÞCl [R2C(¼O)]2O R2C(¼O)Cl M2NC(¼O)R2

Li Li Li Zn Li

THF, hexane, <–10 THF, hexane, –30 ! rt Et2O, hexane, –70 ! 0 THF, hexane, < 0 Et2O or THF, hexane, –60 ! rt, then Hþ, H2O Et2O or THF, hexane, –70 ! rt, then Hþ, H2O BF3, THF, –78

R1CCC(¼O)OR2 R1CCC(¼O)NR22 R1CCC(¼O)R2 R1CCC(¼O)R2 R1CCC(¼O)R2

THF, hexane, <–90, then Hþ, H2O same conditions

M2NCH¼O R2C(¼O)OR3 or R2 Cð¼OÞNR32 M2NCH¼O M2NC(¼O)Me a

Li or Mg BF3Li Li Li

Product

Refs., notes 22 b

R1CCCH¼O

c

R1CCC(¼O)R2

28

R1R2C¼C¼CHCH¼O

d

RCH¼C¼CHC(¼O)Me

d

Conditions of most reactions applied in the author’s laboratory. Some acid chlorides, for example benzenecarbonyl chloride, PhC(¼O)Cl, react slowly. In the presence of catalytic amounts of Pd(PPh3)4 smooth conversions are achieved [23]. c The use of tetrahydro-1(2H)-pyridinecarbaldehyde, HC(¼O)N(CH2)5, has been recommended [24], but we obtained similar results with N,N-dimethylformamide. d Cf. Ref. 25; R1R2C ¼ (CH2)5C, R ¼ alkyl; the products have a low thermal stability. b

CARBOXYLATION, ACYLATION AND . . .

Metal, M

6.

Acylation agent

6.3

ACYLATION REACTIONS

141

N,N,2,2-tetramethylpropanamide, t-BuCONMe2, and N,N-dimethylbutanamide, PropCONMe2, react incompletely [9].

Good results are reported, however, if the lithium alkynylide is first treated with BF3Et2O (formation of R1CCBF3Li) and then carboxylic esters as well as acid amides can be employed [28]. Acid anhydrides, e.g. acetic anhydride, (MeCO)2O, give fair yields (60– 65%) in couplings with lithium alkynylides, provided that the acetylide is added to an excess of the anhydride. In our opinion, the acylation of alkynylzinc chloride with acyl halides is the most versatile method [38].

c.

d.

The organozinc intermediates can be prepared simply and quantitatively by an exchange reaction, using good quality zinc chloride. The reactions with benzoyl chloride and unsaturated acid halides, e.g. acryloyl chloride, H2C¼CHC(¼O)Cl, and 2-alkanoyl chlorides, RCCC(¼O)Cl, are slow, probably because of mesomeric stabilisation of the positive charge on the carbonyl carbon atom. In the presence of a catalytic amount of Pd(PPh3)4, however, a smooth conversion can be achieved [23]. Thus, ketones with the systems C¼CC(¼O)CC and CCC(¼O)CC, interesting substrates for the synthesis of cyclic compounds, are accessible in a direct way. Although this method seems to overshadow the acylation of copper acetylides with acyl halides [29], the latter variant could have significance as a mild method for the preparation of sensitive ketones. N,N-Disubstituted acetylenic carboxamides can be obtained in high yields by reacting metallated acetylenes with a dialkylcarbamyl chloride [30]:

Carboxylic esters, R1CCCOOR2, are prepared by reaction of metallated (preferably lithiated) acetylenes with chloroformates, ClCOOR2. Good results can be obtained if the solution of the lithiated acetylene is added to an excess of chloroformate.

142

6.

CARBOXYLATION, ACYLATION AND . . .

Although, in principle, the methods mentioned above also can be applied to functionalise metallated allenes or disubstituted acetylenes, there are very few reports on this subject. A number of allenic aldehydes and ketones have been prepared by reaction of lithiated allenes or Grignard derivatives with DMF and N,N-dimethylcarboxamides [25,31]. For the synthesis of compounds with the systems C¼C¼C–C(¼O) and C¼C¼C–C(¼O)OR a variety of other approaches, for example base-promoted isomerisation of the corresponding acetylenic derivatives, has been reported (Ref. 7, pp. 179–204).

6.4

EXPERIMENTAL SECTION

Note: In most of the procedures the reaction mixture is kept under inert gas.

6.4.1

General procedure for the carboxylation of acetylenes

Scale: 0.30 molar; Apparatus: Figure 1.9, 1 litre

6.4.1.1

Procedure

Dry carbon dioxide is introduced at a rate of 0.5–1 litre/min into a vigorously agitated solution of 0.30 mol of a lithium alkynylide in 190 ml of hexane and 150 ml of THF (Chapter 3, exp. 3.9.4). During this introduction the solution is kept between 0 and –10 C (preferably lower temperature) by cooling in a bath with dry ice and acetone. After 10 to 20 min (depending upon the rate of introduction) the exothermic reaction has ceased. The resulting solution is then cautiously poured into 200 ml of ice water. After vigorous swirling and subsequently shaking, the layers are separated. The organic layer is extracted twice with 40-ml portions of water and then discarded. The aqueous washings are combined with the first aqueous layer. Concentrated hydrochloric acid is added in small portions with cooling in an ice bath and swirling until a pH of 1 has been reached. The mixture is then extracted with Et2O, the number of extractions depending upon the solubility of the carboxylic acid (in the case of 2-butynoic acid, MeCCCOOH, and 2-pentynoic acid, EtCCCOOH, several extractions are needed, consult hint in Chapter 1.3). The extracts (washing is not carried out) are dried over a large amount (100 g) of

6.4

EXPERIMENTAL SECTION

143

MgSO4 (stirring for half an hour), after which the drying agent is filtered off on a sintered-glass funnel and rinsed well with Et2O. After concentration of the solution under reduced pressure, the residue is distilled through a short Vigreux column to give (after a small forerun) 2-butynoic acid, MeCCCOOH, bp 85 C/15 Torr; 2-pentynoic acid, EtCCCOOH, bp 103 C/12 Torr; 2-hexynoic acid, PrCCCOOH, bp 118 C/15 Torr; (E) þ (Z)-4-hexen-2-ynoic acid, MeCH¼CHCCCOOH, bp 120 C/12 Torr. The products solidify upon standing or during the distillation in the condenser (the use of an air condenser is recommended). In the cases of 3-phenyl-2-propynoic acid, PhCCCOOH, and 2,4-nonadiynoic acid, n-BuCCCCCOOH, the residue remaining after concentration of the extract in vacuo is heated for 1–2 h at 70 C in a vacuum of 1 Torr or less. The products are subsequently crystallised from Et2O or pentane, respectively (at –25 C). PhCCCOOH has mp 132–133 C, n-BuCCCCCOOH has mp 38–40 C. Yields are generally higher than 90%.

6.4.2

Acetylenic esters from lithium alkynylides and alkyl chloroformates

Scale: 0.30 molar; Apparatus: Figure 1.1, 1 litre

6.4.2.1 Procedure A solution of 0.30 mol of the lithiated acetylene (when R ¼ Me partly suspension) in 200 ml of THF and 190 ml of hexane (Chapter 3, exp. 3.9.4) is added in 10 equal portions to a mixture of 0.60 mol (large excess) of the alkyl chloroformate and 50 ml of THF. During this addition, which is carried out over 30 min, the temperature is kept between –25 and –35 C. Stirring at this temperature is continued for another 30 min, then the cooling bath is removed and the temperature allowed rising to þ10 C. The reaction mixture (fine suspension or solution) is then poured into 200 ml of a saturated aqueous solution of NH4Cl. After vigorous shaking and separation of the layers, three extractions with Et2O are carried out. The combined organic solutions are dried over MgSO4 and subsequently concentrated in vacuo. In the case of R being Me, however, the greater part of the solvent is distilled off at atmospheric pressure through a 40-cm Vigreux column. Careful distillation of the remaining

144

6.

CARBOXYLATION, ACYLATION AND . . .

liquid through a 40-cm Vigreux column under reduced pressure gives the following esters. Methyl 2-butynoate, MeCCCOOMe, bp 45 C/15 Torr; ethyl 2-hexynoate, n-PropCCCOOEt, bp 76 C/12 Torr; ethyl 2-heptynoate, n-BuCCCOOEt, bp 90 C/12 Torr; methyl 4-methyl-4-penten-2-ynoate, H2C¼C(Me)CCCOOMe, bp 65 C/15 Torr. Yields are between 70 and 85%. Methyl-4-chloro-2-butynoate, ClCH2CCCOOMe3, bp 40 C/0.5 Torr, is obtained in 65% yield (cf. [32]) by adding 0.20 mol of ClCOOMe as one portion to a solution of 0.10 mol of LiCCCH2Cl (Chapter 3, exp. 3.9.6) cooled to –95 C. The temperature is then maintained for 1.5 h at –40 C and subsequently allowed to rise to 15 C. The brown reaction mixture is hydrolysed and the work-up is carried out as described above. HCCCCLi and MeCCCCLi (in THF–hexane) unexpectedly gave very intractable black reaction mixtures [9]. When alkynylmagnesium halides are used in the reaction with ClCOOR, yields are considerably lower. 6.4.3

General procedure for the formylation of acetylenes with N,N-dimethylformamide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre Additions of polar organometallic intermediates to the C¼O group in N,Ndisubstituted formamides proceed less easily than the reactions with aldehydes. Whereas (soluble) lithium alkynylides react almost instantaneously with aldehydes, even at temperatures in the region of –70 C, the adduct formation from N,N-dimethylformamide and RCCLi at –70 to –50 C in THF or Et2O is slow. This is reflected in the low yield of aldehyde obtained from the subsequent acid hydrolysis immediately after the addition of DMF at these low temperatures. Upon mixing a solution of RCCLi in THF or Et2O with DMF at –60 C a significant heating effect is observed (in the case of poorly soluble alkynyllithium the solution becomes clear upon addition of DMF). However, practically no acetylenic aldehyde is formed when the mixture is treated with dilute acid after a few minutes. The observed heating effect is probably caused by solvation. For obtaining optimal yields of 2-alkynals, RCCCH¼O, it is necessary to allow the temperature rising to þ10–20 C prior to the hydrolysis.

6.4

EXPERIMENTAL SECTION

145

If during the hydrolysis the pH rises above 7, the amine liberated may add to the a,b-unsaturated system. It is therefore essential to add the organic solution of the adduct from RCCLi and the formamide to a slight excess of dilute acid. The pH is then brought to 6–7 by controlled addition of sodium hydrogen carbonate. 6.4.3.1 Procedure DMF (or tetrahydro-(2H)-pyridinecarbaldehyde) (0.25 mol) is added over a few minutes to a solution or suspension of 0.20 mol of alkynyllithium in Et2O (Chapter 3, exp. 3.9.4), cooled to –70 C. The cooling bath is then removed and the temperature allowed rising. Stirring at þ10 to 15 C is continued for an additional 20 min, then the (almost) clear solution is added over a few minutes to a vigorously stirred mixture of 250 ml of ice water and 45 g (slight excess) of 36% aqueous hydrochloric acid. Addition by syringe may be convenient. Subsequently, a concentrated aqueous solution of NaHCO3 is added dropwise with vigorous stirring until a pH between 6 and 7 has been reached. The layers are separated, after which the aqueous layer is extracted four times with pentane or Et2O. The combined organic solutions are dried over MgSO4 and then concentrated under reduced pressure (in the case of volatile aldehydes the greater part of the Et2O is first distilled off at normal pressure). Vacuum distillation gives the aldehydes in 70% or higher yields: 2-heptynal, n-BuCCCH¼O, bp 58 C/15 Torr; 3-(1-cyclohexenyl)-2-propynal, 1-cyclohexenyl-CCCH¼O (from 1-ethynylcyclohexene), bp 105 C/10 Torr (partial polymerisation); 3-phenyl-2-propynal, PhCCCH¼O, bp 70 C/0.5 Torr; 3-trimethylsilyl)-2-propynal, Me3SiCCCH¼O, bp 30 C/10 Torr. 2,4-Hexadiynal, MeCCCCCH¼O, is obtained in 75% yield (undistilled) from MeCCCCLi and DMF in a THF–hexane mixture and subsequent treatment with dilute aqueous acid. This aldehyde is solid at rt. Attempts to distil this compound resulted in a vigorous decomposition [9]. Reaction of LiCCCH2Cl with DMF led to the formation of an intractable suspension containing brown, amorphous and tarry material. Subsequent acid hydrolysis did not give the aldehyde [9]. It should be pointed out that the use of a (commercially available) solution of BuLi in hexane gives rise to problems during the isolation of volatile (bp <40 C/10 Torr) aldehydes. In these cases, one should use BuLiLiBr in Et2O for the metallation of the acetylene. The aldehydes 2-pentynal, MeCCCH¼O, and 2-hexynal, EtCCCH¼O, for example, can be prepared in good yields from the reaction of MeCCLi and EtCCLi in Et2O (containing LiBr) with DMF. Several extractions with pentane or Et2O have to be carried out after hydrolysis. The solvent is then slowly distilled off through an efficient column at atmospheric pressure.

146 6.4.4

6.

CARBOXYLATION, ACYLATION AND . . .

Methyl alkynyl ketones from alkynyllithium and N,N-dimethylacetamide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre 6.4.4.1

Procedure (for introduction cf. exp. 6.4.3)

N,N-Dimethylacetamide (0.25 mol) is added over a few minutes to a solution of 0.20 mol of 1-alkynyllithium in 126 ml of hexane and 140 ml of Et2O (Chapter 3, exp. 3.9.4, THF is preferred when the alkynyllithium derivative is slightly soluble in Et2O), cooled to –60 C. The temperature is allowed to rise to 15– 20 C and stirring is continued for an additional half an hour. The solution is then hydrolysed with a slight excess of dilute hydrochloric acid, as described in the preceding experiment. Working up (see also exp. 6.4.3) gives the following ketones in greater than 90% yields: 4-(1-cyclohexenyl)-3-buten-2-one, c-C6H9CCC(¼O)Me, bp 50 C/0.5 Torr; 3-octyn-2-one, n-BuCCCOMe, bp 60 C/10 Torr. With PhCCLi, a 3:2 mixture of 4-phenyl-buten-2-one, PhCCCOMe, and PhCCH is obtained. Also 1,3-diynes, RCCCCH, react very incompletely with MeCONMe2. N,N,2,2-Tetramethylpropanamide, t-BuCONMe2, does not react with a solution of EtCCLi in THF–hexane. Under similar conditions the much stronger base 2-thienyllithium and t-BuCONMe2 gave 2thienylCOt-Bu in an excellent yield (after hydrolytic work-up). The reaction of EtCCLi with n-BuCONMe2 ‘stopped’ after 50% conversion [9]. 6.4.5

Acylation with N,N-dimethylbenzamide

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml

6.4

EXPERIMENTAL SECTION

147

6.4.5.1 Procedure This preparation is carried out in a manner similar to that described in exp. 6.4.4. N,N-Dimethylbenzenecarboxamide, PhCONMe2 (0.10 mol), is added at –20 C to a suspension of 0.12 mol (excess is used to avoid separation problems) MeCCLi in 75 ml of hexane and 80 ml of THF. The suspension clears gradually. After stirring for an additional hour at þ 15 C, the reaction mixture is worked up to give 1-phenyl-2-butyn-1-one, PhCOCCMe, bp 80 C/0.5 Torr, in 80% yield. 6.4.6

Acylation with acetic anhydride

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 6.4.6.1 Procedure A solution of 0.10 mol of the alkynyllithium derivative (Chapter 3, exp. 3.9.4) in 70 ml of Et2O and 63 ml of hexane is added over 30 min to a mixture of 0.20 mol (large excess) of freshly distilled acetic anhydride and 50 ml of Et2O with cooling between –60 and –70 C. After an additional 15 min the cooling bath is removed and the temperature of the suspension allowed rising to 0 C. A solution of 30 g of NH4Cl in 200 ml of water is then added followed by dropwise addition of 15 ml of concentrated aqueous ammonia over 30 min with vigorous stirring. The layers are separated and the aqueous layer extracted four times with Et2O. The combined organic solutions are washed with concentrated aqueous NH4Cl, dried over MgSO4 and then concentrated in vacuo. The remaining liquid is distilled at <1 Torr using a very short column and the distillate collected in a single receiver, cooled below –30 C (Figure 1.10). The contents of the receiver are redistilled through a 20-cm Vigreux column (Note). The following ketones are obtained in 60–65% yields: 3-octyn-2-one, BuCCCOMe, bp 68 C/12 Torr; (Z)-5-nonen-3-yn-2-one, PrCH¼CHC CCOMe, bp 50 C/0.5 Torr; 3,5-nonadiyn-2-one, PrCCCCCOMe (purity 94%), bp 55 C/0.5 Torr. Note Bath temperatures should be kept below 90 C. Especially the ketones with systems C¼CCC and CCCC have a limited thermal stability.

148 6.4.7

6.

CARBOXYLATION, ACYLATION AND . . .

Acetylenic ketones by reaction of alkynylzinc chloride with acyl halides

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml Although it should be possible to prepare acetylenic ketones in moderate to reasonable yields by controlled addition of alkynyllithium to an excess of acyl halide, this procedure does not seem very attractive for sensitive products. It is very difficult to prevent the subsequent reaction of the ketones with alkynyllithium, which results in the formation of dialkynyl carbinols. These will accumulate in the distillation residue and may give rise to explosive decomposition. The reaction of copper alkynylides (generated in situ from alkynyllithium or alkynyl Grignard reagents and copper(I)halide) with acyl halides has been applied to synthesise acetylenic ketones [29]. Here too, problems may arise during the work-up and isolation: removal of the copper salts requires the use of alkali cyanide. The alkaline conditions during the work-up may cause further reactions of the acetylenic ketone, for example, Michael additions or base-catalysed isomerisation. Another way to ‘tame’ alkynylides consists of conversion into alkynylzinc halides by addition of an equivalent amount of zinc halide. The zinc salts are easily removed during the work-up. The alkynylzinc method appears to give very good results with saturated aliphatic acyl halides (cf. [23]). 6.4.7.1

Procedure [38]

The acyl halide (0.10 mol, freshly distilled) is added dropwise over 15 min to a solution (sometimes two-layer system) of 0.10 mol of alkynylzinc halide (Chapter 3, exp. 3.9.4) in THF and hexane, maintained between 5 and 10 C. After the addition, the cooling bath is removed and the temperature allowed rising. Stirring is continued for 45 min at rt, then the mixture is cooled to –10 C and a solution of 20 g of NH4Cl in 200 ml of water is added with vigorous stirring. After separation of the layers, three extractions with Et2O are carried out. The combined organic solutions are washed four times with a saturated aqueous solution of NH4Cl (to remove traces of zinc salts) and subsequently dried over MgSO4. The liquid remaining after concentration of the solution in vacuo is distilled under low pressure (see preceding experiment). The following ketones are prepared in 70 to 80% yields: 2-heptyn-4-one, MeCCCOPr, bp 55 C/15 Torr; 4-phenyl-3-butyn-2-one,

6.4

EXPERIMENTAL SECTION

149

PhCCCOMe, bp 80 C/0.5 Torr; 3,5-nonadiyn-2-one, PrCCCCCOMe, bp 70 C/0.3 Torr. 6.4.8

Acetylenic ketones by Pd(0)-catalysed coupling of alkynylzinc chlorides with acyl halides

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml Unsaturated acyl halides, such as pentynoyl chloride and acryloyl chloride, as well as benzoyl chloride, are much less reactive towards alkynylzinc halide than the saturated ones. Attempts to prepare the unsaturated ketones at higher temperatures gave only ‘polymeric’ products [9]. The palladium complex Pd(PPh3)4 shows a strong catalytic effect, allowing the reactions to proceed in a short time under mild conditions. Although during the aqueous work-up most of the palladium compounds precipitate, traces remain. These may cause decomposition of the product during distillation and therefore have to be removed by flash chromatography on neutral aluminium oxide. 6.4.8.1 Procedure A solution of 0.7 g of Pd(PPh3)4 (Chapter 2, exp. 2.3.12) in 15 ml of THF is added to a solution of 0.11 mol of the alkynylzinc chloride (Chapter 3, exp. 3.9.4) in THF and hexane cooled to 0 C. Pentynoyl chloride (0.11 mol, see below) or acryloyl chloride (0.12 mol freshly distilled, commercially available) is then added dropwise over 2 min, while keeping the temperature between 0 and 5 C. After an additional 5 min (at 5–10 C) 300 ml of pentane is added and the reaction mixture is poured into 250 ml of a saturated aqueous solution of NH4Cl. After vigorous shaking, the layers are separated and the aqueous layer is extracted once with 100 ml of pentane. The combined organic solutions are washed four times with 150-ml portions of a saturated aqueous solution of NH4Cl (Note 1) and are subsequently dried over MgSO4. The lightbrown liquid remaining after concentration of the organic solution under reduced pressure is diluted with 30 ml of Et2O. This solution is cautiously poured on a 4-cm layer of neutral Al2O3 (covered with a sheet of filter paper) in a sintered-glass funnel (G-3) of 3–4 cm diameter. Elution is carried out with Et2O. The eluate is concentrated under reduced pressure and the

150

6.

CARBOXYLATION, ACYLATION AND . . .

remaining liquid is distilled at very low pressure from a 100-ml flask, using a very short Vigreux column (B-29 glass is recommended). The product is collected in a single receiver, cooled at –78 C (Figure 1.10). A small brown, viscous residue remains in the distillation flask. Redistillation gives 3,6-nonadiyn-5-one, (EtCC)2C¼O, bp 70 C/0.5 Torr, and 1-decen-4-yn-3-one, C5H11C CCOCH¼CH2, bp 60 C/0.5 Torr, in yields varying between 40 and 80% (Note 2). Benzoyl chloride (0.12 mol) reacts smoothly at 10–15 C. After an additional 15 min (at 25 C) pentane is added and the reaction mixture is poured into an aqueous solution of NH4Cl containing a small amount of ammonia (to remove the excess of benzoyl chloride). 1-Phenyl-2-pentyn-1-one, PhCOCCEt, bp 90 C/0.5 Torr, is obtained in 80% yield. 2-Pentynoyl chloride is prepared as follows: Pentynoic acid (0.20 mol, see exp. 6.4.1) and dichloromethane (20 ml) are placed in a 250-ml two-necked flask, equipped with a dropping funnel and a reflux condenser. The mixture is warmed in a bath at 80 C and 0.20 mol of freshly distilled thionyl chloride is added dropwise over 15 min with casional swirling. After heating the mixture for an additional 30 min at 80 C (while introducing N2) a careful distillation is carried out, giving the acid chloride, bp 35 C/10 Torr, in 75% yield.

Notes 1. 2.

It seems essential to remove traces of zinc salts. The procedures have been carried out only a few times. More research may result in improved yields. Short reaction times seem to be essential for obtaining good yields.

6.4.9

N,N-Dimethyl-2-pentynamide from butynyllithium and dimethylcarbamyl chloride

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml N,N-Disubstituted acid amides are usually prepared by reaction of acyl halides with secondary amines. This method is attractive when the acyl halide is readily available. This is not the case with pentynoyl chloride, which has to be synthesised by a two-step procedure from butyne (see exp. 6.4.8). In analogy with the carboxyalkylation with alkyl chloroformates (exp. 6.4.2), a carboxamide group

6.4

EXPERIMENTAL SECTION

151

can be introduced in a one-step operation with a dialkylcarbamyl chloride [30] (commercially available and inexpensive). The usual procedure involves addition of the organometallic intermediate to a solution of an excess of the carbamyl halide. Applying the normal addition procedure in the case of the reaction of 1-butynyllithium with dimethylcarbamyl chloride, a mixture of 3,6-nonadiyn-5-one, (EtCC)2C¼O, and the desired product N,N-dimethyl2-pentynamide, EtCCC(¼O)NMe2, is obtained. Warning: Dimethylcarbamyl chloride is said to be carcinogen. 6.4.9.1 Procedure A solution of 0.10 mol of 1-butynyllithium in 80 ml of THF and 63 ml of hexane (Chapter 3, exp. 3.9.4) is placed in the dropping funnel. The solution is added over 30 min to a mixture of 0.20 mol of dimethylcarbamyl chloride (a lesser excess presumably will suffice) and 80 ml of THF, while keeping the temperature of the reaction mixture between –25 and –30 C. After completion of the addition, the cooling bath is removed and the temperature is allowed to rise to 10–15 C. Ice water (50 ml, saturated with ammonium chloride) is then added with vigorous stirring and cooling in an ice bath. After separation of the layers, the aqueous layer is extracted three times with small portions of THF. The combined organic solutions are dried (without preceding washing) over MgSO4 and subsequently concentrated under reduced pressure. Distillation of the remaining liquid through a 20-cm Vigreux column gives N,N-dimethyl-2pentynamide, bp 85 C/1 Torr, in 85% yield. LiCCHTMEDA in THF–hexane and Me2NCOCl gave only black tars. 6.4.10

Addition of propynyllithium to phenyl isocyanate

Scale: 0.10 molar; Apparatus: Figure 1.1, 250 ml, addition by syringe 6.4.10.1

Procedure

Freshly distilled phenyl isocyanate (0.10 mol) is added in one portion to a suspension of 0.11 mol of propynyllithium (Chapter 3, exp. 3.9.4) in 80 ml

152

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CARBOXYLATION, ACYLATION AND . . .

of THF and 69 ml of hexane at –60 C. The cooling bath is removed and the temperature allowed rising. The heating effect is weak. The suspension gradually becomes a little bit gelatinous. After stirring for an additional 15 min at þ10 C, a mixture of 12 g (0.10 mol) of 36% aqueous HCl and 100 ml of water is added with vigorous stirring. After separation of the layers, three extractions with Et2O are carried out. The combined organic solutions are dried over MgSO4 and subsequently concentrated under reduced pressure. The brown residue is dissolved in a 2:1 mixture of pentane and Et2O and the solution kept at –25 C for 12 h. The light-brown crystals are filtered off on sintered glass, rinsed with cold pentane and dried in vacuo. From the concentrated mother liquor a second crop of crystals is obtained, bringing the yield to 90%. The mp of N-phenyl-2-butynamide (after a second crystallisation from a pentane–Et2O mixture) is 111–112 C. 6.4.11

Addition of t-butylethynyllithium to methyl isothiocyanate

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml

6.4.11.1

Procedure

A solution of 0.10 mol of methyl isothiocyanate in 30 ml of THF is added over a few minutes to a solution of 0.11 mol of t-butylethynyllithium (Chapter 3, exp. 3.9.4) in 80 ml of THF and 69 ml of hexane, cooled to –10 C. The cooling bath is removed and the temperature allowed rising. The light-yellow solution gradually turns brown. After stirring for an additional 45 min at 15 C, the solution is cooled to –20 C and a mixture of 12 g (0.10 mol) of 36% aqueous HCl and 100 ml of water is added with vigorous stirring. After separation of the layers, three extractions with Et2O are carried out. The combined solutions are dried over MgSO4 and subsequently concentrated under reduced pressure. Crystallisation (at –25 C) from a 2:1 mixture of pentane and Et2O gives N,4,4trimethyl-2-pentynethioamide, mp 87–88 C, in 75% yield. MeCCLi and EtCCLi react with MeN¼C¼S under similar conditions to give viscous brown liquids, reasonably pure thioamides according to 1H NMR. HCCLiTMEDA in THF–hexane and MeN¼C¼S give an intractable, dark reaction mixture [9].

6.4

EXPERIMENTAL SECTION

153

Phenyl isothiocyanate reacts somewhat less readily with alkynyllithium than methyl isothiocyanate. The thioamide from the reaction of MeCCLi with PhN¼C¼S is not easy to obtain in a crystalline state. Attempted distillation leads to decomposition [9]. 6.4.12

Addition of t-butylethynyllithium to phenylsulphinylamine

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml; stirrer Figure 1.2 6.4.12.1

Procedure (cf. [34])

A mixture of 0.10 mol of PhN¼S¼O [37] and 100 ml of Et2O is added over 15 min to a vigorously agitated solution of 0.11 mol of t-BuCCLi (Chapter 3, exp. 3.9.4) in 80 ml of THF and 69 ml of hexane, maintained between –10 and 0 C. A thick white suspension is formed. After stirring without cooling for an additional 5 min (when the yellow colour has disappeared) the mixture is treated with dilute HCl as described in the preceding experiments. Isolation of the product, a light brown syrup, is also carried out as described in these experiments. The product is dissolved in 50 ml of refluxing Et2O, after which 100 ml of pentane is added. After cooling to below –30 C, white crystals separate from the solution. Suction filtration followed by rinsing with cold pentane and drying of the crystals in vacuo gives pure 3,3-dimethyl-Nphenyl-1-butyn-1-sulphinamide, mp 68–69 C, in an excellent yield. 6.4.13

Carboxylation of lithiated propadiene

Scale: 0.20 molar; Apparatus: Figure 1.9, 1 litre 6.4.13.1

Procedure

A vigorous flow of CO2 (1 litre/min) is introduced during 5 min into 200 ml of THF, while keeping the temperature of the solution between –80 and –90 C

154

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CARBOXYLATION, ACYLATION AND . . .

by occasional cooling in liquid nitrogen. Care is taken that the solution does not solidify on the bottom of the flask. A cold (< –60 C) solution of 0.20 mol of lithiated propadiene (Chapter 3, exp. 3.9.14) is cautiously added portionwise over 3 min through the third neck (the thermometer is temporarily removed) with vigorous stirring and continuing the introduction of CO2 at a rate of 200 ml/min. After the addition, introduction of gas is stopped and the temperature is allowed rising to –20 C. The suspension is poured into a mixture of 22 g of 36% HCl and 150 ml of water in a large beaker. After saturation with ammonium chloride, 5 extractions with small portions of THF are carried out. The combined organic solutions are dried over 100 g of magnesium sulphate (with mechanical stirring), then filtered through sintered glass (thorough rinsing of the drying agent with Et2O) and concentrated under reduced pressure, in the last stage under <0.1 Torr. The remaining liquid solidifies at rt and is practically pure butadienoic acid. The yield is at least 70%. Recrystallisation from a 1:5 mixture of dichloromethane and pentane gives pure 2,3-butadienoic acid, mp 62 C. 5,5-Dimethyl-2,3-hexadienoic acid, t-BuCH¼C¼CHCOOH, mp 43 C, is prepared in good yields by a similar procedure from the lithiated allene (Chapter 3, exp. 3.9.15 and Table 3.3). From 1,2-butadiene, MeCH¼C¼ CH2, and homologues, BuLi and CO2, impure products were obtained in 45% yields after distillation [9]. 6.4.14

2,3-Pentadienedioic acid from dilithiopropyne and carbon dioxide

Scale: 0.10 molar; Apparatus: Figure 1.9, 1 litre 6.4.14.1

Procedure

The operations before the work-up are similar to those described in the preceding experiment. A cold (–50 C) suspension of 0.10 mol of dilithiopropyne in THF–hexane (Chapter 3, exp. 3.9.11), in 126 ml of hexane and 150 ml of THF is poured over a few minutes into a saturated solution of CO2 in 125 ml of THF, which is kept below –80 C. After this addition the cooling bath is

6.4

EXPERIMENTAL SECTION

155

removed and the temperature allowed rising to 20 C. The reaction mixture is then poured into a solution of 6 g of KOH in 100 ml of ice water (Note 1). After standing during 1 h at rt, the pH of the aqueous layer is brought at 1 by dropwise addition of concentrated HCl, then ammonium chloride is added until saturation and ten extractions with small portions of THF (Note 2) are carried out. The combined brown solutions are stirred for 3 h with 50 g of magnesium sulphate. After filtration through sintered glass and rinsing of the drying agent with THF, the solvents are removed under reduced pressure. In order to remove the last traces of solvent and undesired products, the flask containing the crude acid is connected to an air condenser (no column is used) and receiver. The system is evacuated (P < 0.1 Torr) and the flask heated during 1 h at 80 C. The greater part of mono-acids (2- and 3-butynoic acid) deposits as a solid in the condenser. The residue consists of fairly pure 2,3-pentadienedioic acid according to the NMR. Yield 60%. 2-Methyl-1,3-pentadienedioic acid, HOOCC(Me)¼C¼CHCOOH, is obtained in 40% yield by a similar procedure from 1,3-dilithio-1-butyne [18], LiCCCH(Me)Li, and carbon dioxide. The initial acetylenic acid isomerises under the influence of KOH. Small amounts of the mono-acids can be removed by warming the crude product (syrup) with dichloromethane under reflux. Notes 1. 2.

The primary product probably is LiOOCCH2CCCOOLi. The treatment with KOH leads to conversion into 2,3-pentadienedioic acid. With Et2O continuous extraction has to be carried out.

6.4.15

Formylation of 1-ethenylidenecyclohexyllithium with N,N-dimethylformamide

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 6.4.15.1

Procedure [25]

A solution of lithiated 1-ethenylidenecyclohexane in 63 ml of hexane and 70 ml of THF is prepared as indicated in Chapter 3, Table 3.3, entry 3 and exp. 3.9.15.

156

6.

CARBOXYLATION, ACYLATION AND . . .

After cooling the solution to –100 C, a mixture of 0.12 mol of dry DMF and 30 ml of THF is added over a few minutes. After an additional period of 15 min (at –80 to –90 C) the solution is poured into 2.5 litre of a vigorously stirred 0.1 M solution of hydrochloric acid. The mixture is extracted several times with pentane. The combined extracts are washed with water, dried over magnesium sulphate and concentrated under reduced pressure. Distillation through a short column gives 3-cyclohexylideneacrylaldehyde, bp 94 C/12 Torr, in 50% yield. During the distillation some polymerisation occurs. 3,4-Nonadien-2-one, n-BuCH¼C¼CHC(¼O)Me, bp 80 C/10 Torr, is obtained in 50% yield by a similar procedure from 1,2-heptadiene, BuLi and MeC(¼O)NMe2. The main impurity is 3-butyl-3,4-pentadien-2-one, H2C¼ C¼C(Bu)COMe (8%), formed from 3-lithio-1,2-heptadiene, H2C¼C¼ C(Li)Bu.

6.4.16

Reaction of lithiated 2-butyne to methyl isothiocyanate and subsequent S-methylation

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 6.4.16.1

Procedure

A mixture of 0.11 mol of methyl isothiocyanate and 10 ml of THF is added over a few seconds to a vigorously stirred solution of 0.10 mol of lithiated 2-butyne in 63 ml of hexane and 70 ml of THF (Chapter 3, exp. 3.9.16 and Table 3.3, entry 4). The reaction is very exothermic so that cooling in a bath with liquid nitrogen is necessary. After the addition the cooling bath is removed. At –70 C, 0.13 mol of methyl iodide is added in one portion. When the temperature of the reaction mixture has reached 0 C, 50 ml of water is added and two extractions with pentane are carried out. After drying the organic solution over magnesium sulphate, the solvent is removed under reduced pressure (temperature of the heating bath <40 C). The remaining liquid is distilled through a very short column. Methyl N,2-dimethyl-2,3butadienimidothioate, bp 45 C/0.4 Torr, is obtained in 80% yield. The small residue consists of 6-methylthio-5-methyl-2,3-dihydropyridine. During distillation the pressure and the bath temperature should be kept as low as possible.

6.4

EXPERIMENTAL SECTION

157

Several metallated allenes or metallated disubstituted acetylenes react with high regioselectivity with alkyl isothiocyanates to give, after S-alkylation, the allenic thioimidates. Examples are: t-BuCH¼C¼CHLi, Me2C¼C¼CHLi, H2C¼C¼C(Li)OMe or –SMe, RCCCH(Li)OMe (R ¼ alkyl, (het)aryl, OMe, SMe, H2C¼C(Me)–, R12 N–CH2), RCCCH2NR12 (R ¼ alkyl, aryl, H2C¼C(Me)–, SMe, CH2NR12 ). A few addition products can be isolated, but in most cases cyclisation to a pyrrole or 2,3-dihydropyridine derivative occurs under mild conditions [8].

6.4.17

Reaction of 2-butynylpotassium with CS2 and subsequent S-methylation

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml

6.4.17.1

Procedure

A solution of 0.10 mol of t-BuOK in 40 ml of THF is added at < –40 C to a solution of 0.10 mol of 2-butynyllithium in 63 ml of hexane and 70 ml of THF (Chapter 3, exp. 3.9.16 and Table 3.3, entry 4). The mixture is cooled to –100 C, after which a mixture of 0.05 mol of carbon disulphide and 10 ml of THF is added over a few seconds with vigorous stirring and cooling so that the temperature of the reaction mixture remains below –70 C. After the exothermic reaction the cooling bath is removed. When the temperature has reached –10 C, 0.11 mol of methyl iodide is added in one portion. After an additional 30 min, 100 ml of water is added and the work-up described in the preceding experiment is carried out. The liquid remaining after removal of the solvents under reduced pressure is distilled through a short column to give 2-methyl-1,1-bis(methylthio)-1-buten-3-yne, bp 63 C/0.1 Torr, in 55% yield (calculated on 2-butynyllithium). 1,1-Bis(methylthio)-1-buten-3-ynes, RCCC(R)¼C(SMe)2 with R¼n-alkyl, SMe, OMe, NMe2, NEt2 and CH2NEt2 can be obtained in fair yields by similar procedures starting with disubstituted acetylenes or allenic compounds [8].

158 6.4.18

6.

CARBOXYLATION, ACYLATION AND . . .

Reaction of allenylmagnesium bromide with phenylsulphinyl amine

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 6.4.18.1

Procedure [36]

An ethereal solution of 0.11 mol of allenylmagnesium bromide (Chapter 2, exp. 2.3.9) is added over a few minutes to a solution of 0.10 mol of phenylsulphinyl amine in 150 ml of Et2O cooled at –100 C. After the addition the cooling bath is removed and the temperature is allowed to rise to –30 C. A mixture of 10 g of 36% HCl and 70 ml of water is then added with vigorous stirring. The aqueous layer is extracted twice with Et2O, the combined organic solutions are dried over magnesium sulphate and the solvent removed under reduced pressure. The residue crystallises in the refrigerator. N-Phenyl-2-propyne-1-sulphinamide, mp 77 C, is obtained in 80% yield. Treatment of the product with aqueous KOH at 50 C for a short period gave a 4:1 mixture of the acetylenic and the allenic isomer. It has not been investigated whether or not this ratio corresponds to the equilibrium situation [36]. The Grignard solution obtained from MeCCCH2Li and MgBr2 gave, in a high yield, a 2.5:1 mixture of N-phenyl-2-butyn-1-sulphinamide, MeCCCH2S(¼O)NHPh, and N-phenyl-2,3-butadien-2-sulphinamide, H2C¼ C¼C(Me)S(¼O)NHPh, in a similar procedure [36]. Me2C¼C¼CHLi and PhN¼S¼O gave the allenic and acetylenic derivative with a 2:1 ratio; after Li/MgBr exchange the ratio was somewhat higher. From the procedures with 1,2-pentadienylmagnesium bromide, EtCH¼C¼ CHMgBr, and 1-ethylidenecyclohexylmagnesium bromide, (CH2)5C¼C¼ CHMgBr, only the acetylenic sulphinamide was isolated. The predominant product from the synthesis with t-BuCH¼C¼CHMgBr was 4,4-dimethyl-Nphenyl-1-pentyne-3-sulphinamide, HCCCH(t-Bu)S(¼O)NHPh, seemingly violating steric influence of the t-butyl group [33].

REFERENCES 1. V. Ja¨ger and H. G. Viehe, in Houben-Weyl, Methoden der Organischen Chemie, Band 5/2a. Thieme-Verlag, Stuttgart, 1977, p. 1.

REFERENCES

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2. K. Bowden, I. M. Heilbron, E. R. H. Jones and B. C. L. Weedon, J. Chem. Soc., 39 (1946). 3. M. Murray, in Houben-Weyl, Methoden der Organischen Chemie, Band 5/2a. Thieme-Verlag, Stuttgart, 1977. 4. H. Hopf, in The Chemistry of Ketenes, Allenes and Related Compounds (ed. S. Patai). John Wiley, Chichester, New York, 1980. 5. J.-L. Moreau, in The Chemistry of Ketenes, Allenes and Related Compounds (ed. S. Patai). John Wiley, Chichester, New York, 1980, p. 117. 6. R. Epzstein, in Comprehensive Carbanion Chemistry, part B (eds. E. Buncel and T. Durst). Elsevier, Amsterdam, 1984, p. 107. 7. H. E. Schuster and G. M. Coppola, Allenes in Organic Synthesis. Wiley-Interscience, New York, 1984, p. 179. 8. L. Brandsma, microreview in Eur. J. Org. Chem., 4569 (2001) and refs. mentioned. 9. Unpublished observations and results from the author’s laboratory. 10. N. A. Nedolya, L. Brandsma and B. A. Trofimov, Mendeleev Commun., 92 (1997). 11. N. A. Nedolya, L. Brandsma, R.-J. de Lang and B. A. Trofimov, Russ. J. Org. Chem. 33, 580 (1997). 12. N. A. Nedolya, L. Brandsma, O. A. Tarasova, H. D. Verkruijsse and B. A. Trofimov, Tetrahedron Lett. 39, 2409 (1998). 13. N. A. Nedolya, N. I. Schlyakhtina, V. P. Zinov’eva, A. I. Albanov and L. Brandsma, Tetrahedron Lett. 43, 1569 (2002). 14. L. Brandsma, N. A. Nedolya, R.-J. de Lang and B. A. Trofimov, Izv. Akad. Nauk, Ser. Khim. 3024 (1996); Russ. Chem. Bull. 45, 2873 (1996). 15. N. A. Nedolya, L. Brandsma, H. D. Verkruijsse, N. L. Owen, Du Li and B. A. Trofimov, Tetrahedron Lett. 38, 6905 (1997). 16. H. Westmijze, K. Ruitenberg, J. Meijer and P. Vermeer, Synthesis, 551 (1981). 17. N. A. Nedolya, L. Brandsma and B. A. Trofimov, Dokl. Akad. Nauk 350, 68 (1996). 18. G. R. Khan, K. A. Povev and F. Scheinmann, J. Chem. Soc., Chem. Comm., 215 (1979); J. Chem. Soc., Perkin I, 1609 (1976); 2338 (1980). 19. G. Darnault, M. Saquet and A. Thuiller, Chem. Ind., 391 (1983). 20. L. Brandsma, A. L. Spek, B. A. Trofimov, O. A. Tarasova, N. A. Nedolya, A. V. Afonin and S. V. Zinchenko, Tetrahedron Lett. 42, 4687 (2001). 21. L. N. Cherkasov and K. V. Balyan, Zh. Org. Khim. 1, 1811 (1965); Eng. P. 1843. 22. F. L. M. Pattison and R. E. A. Dear, Can. J. Chem. 41, 2600 (1963). 23. E. Negishi, V. Bagheri, S. Chatterjee, F.-T. Luo, J. A. Miller and A. T. Stoll, Tetrahedron Lett. 24, 5181 (1983). 24. G.A. Olah and M. Arvanaghi, Angew. Chem. 93, 925 (1981). 25. J.-C. Clinet and G. Linstrumelle, Nouv. J. Chim. 1, 373 (1977). 26. X. Creary, J. Am. Chem. Soc. 99, 7632 (1977). 27. E. R. H. Jones, L. Skattebøl and M. C. Whiting, J. Chem. Soc., 1054 (1958). 28. M. Yamaguchi, K. Shibato, S. Fujiwara and I. Hirao, Synthesis, 421 (1986). 29. J.-F. Normant and M. Bourgain, Tetrahedron Lett., 2659 (1970); J.-F. Normant and M. Bourgain, Bull. Soc. Chim. France, 1777 and 2137 (1973); J.-F. Normant, Synthesis, 63 (1972). 30. R. Epzstein, Compt. Rend. Acad. Sci., Paris 240, 989 (1955); Chem. Abstr. 50, 5520 (1956). 31. F. Gaudemar-Bardone, Ann. Chim. (Paris) 3, 52 (1958). 32. M. Olomucki, J.-Y. Le Gall and I. Barrand, J. Chem. Soc., Chem. Comm., 1290 (1982). 33. L. Brandsma, N. A. Chernysheva, S. V. Zinchenko and B. A. Trofimov, Sulphur Lett. (2001), p. 1. 34. H. A. Selling and H. J. Mak, Synth. Commun. 6, 129 (1976). 35. K. Ruitenberg and P. Vermeer, J. Organometal. Chem. 256, 175 (1983).

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36. L. Brandsma, N. A. Chernysheva and B. A. Trofimov, Phosphorus, Sulphur and Silicon 159, 143 (2000). 37. G. Kreszke, A. Maschke, R. Ahlbrecht, K. Bederke, H. Smalla, H. P. Patzschke and A. Trede, Angew. Chem., Int. Edn. 1, 89 (1962). 38. H. D. Verkruijjse, Y. A. Heus and L. Brandsma, J. Organomet. Chem. 338, 289 (1988).

7 Silylation, Stannylation and Phosphorylation

7.1

INTRODUCTION

Silylated acetylenes are useful synthetic intermediates. Numerous examples are mentioned in the reviews [1,2]. One can subdivide the applications. In the first group, the silyl function merely serves as a protector, removed in the last step of the synthesis. An example is the silylation of a diyne [3], RCCCCH, to give RCCCCSiMe3, which by partial reduction with Pd/H2 or activated zinc in ethanol gives (Z)-RCH¼CHCCSiMe3. Treatment of this enyne with alkali hydroxide in methanol or silver nitrate and cyanide [4] finally gives (Z)RCH¼CHCCH. A second type of application concerns reactions in which the silyl group is substituted by another functionality, e.g. RC(¼O) or halogen. These transformations are often catalysed by Lewis acids [2]. In the third category, there can be placed conversions in which silyl substituents facilitate deprotonation of structure systems CHCCSi, CCCHSi, SiC¼C¼CH and SiCH¼C¼C. Stannylated and phosphorylated acetylenes have, so far, found fewer applications as synthetic intermediates. One disadvantage of many organotin compounds is their low volatility and poor propensity to crystallise making purification by column chromatography necessary. This makes them less attractive for working on a larger scale. Silylation, stannylation and phosphorylation of lithium and Grignard derivatives can be carried out under mild conditions in diethyl ether as well as in tetrahydrofuran. A survey on the silylation and stannylation of mesomeric acetylenic–allenic anions can be found on pp. 158–161 of the review [5], for applications of silylated allenes in organic synthesis pp. 252–259 of the monograph [6] may be referred. Like in the case of other functionalisations, silylation and stannylation of acetylenic-allenic anions can give either the acetylenic or allenic derivative as the only product, or afford mixtures of the isomers. The product 161

162

7.

SILYLATION, STANNYLATION AND PHOSPHORYLATION

composition is determined by the counter ion, solvent and substituents in the anionic species and in the silylation and stannylation reagents [5]. Reaction of allenylmagnesium bromide, H2C¼C¼CHMgBr, with chloro(tributyl)stannane, Bu3SnCl, for example, gives a 95:5 mixture of the allenic and acetylenic stannane, whereas with Ph3SnCl the ratio allenic:acetylenic stannane is 10:90 and with Me3SnCl 70:30 [7]. Reaction of 1,3-dilithiated acetylenes, LiCCCH(Li)R (R ¼ Alkyl, Phenyl, SMe) with one equivalent of chloro(trimethyl)silane occurs at the most strongly basic propargylic site [8].

7.2

EXPERIMENTAL SECTION

Notes a. In most of the procedures the reaction mixture is kept under inert gas. b. Pure chloro(trimethyl)silane is obtained by distillation from 10% PhNEt2. c. Chloro(trimethyl)silane is best stored at room temperature in flasks or bottles with regularly greased ground-glass stoppers. The reagent should never be stored in screw-capped bottles in the refrigerator, not even when recommended by the supplier. 7.2.1

Ethynyl(trimethyl)silane from ethynylmagnesium bromide and chloro(trimethyl)silane in tetrahydrofuran

Scale: 0.40 molar; Apparatus: Figure 1.1, 1 litre 7.2.1.1

Procedure [9] (cf. [10,11])

Chloro(trimethyl)silane (0.40 mol) is added in two portions over two minutes (Note) to a vigorously stirred suspension (partly solution) of ethynylmagnesium bromide prepared starting from 0.60 mol of ethyl bromide (corresponding to an excess, Chapter 3, exp. 3.9.7). During and for 30 min after this addition, the temperature of the reaction mixture is kept between 15 and 20 C, subsequently for 30 min at 35 C. The heating effect is not strong. High-boiling petroleum ether (150 ml, bp > 170 C) is then added and the slurry is poured into a cold (–5 C) solution of 75 g of ammonium chloride in 1 litre of water. After cautious swirling and shaking, the layers are separated. The organic layer is ‘washed’ 10 to 15 times with 250-ml portions of ice water in order to remove

7.2

EXPERIMENTAL SECTION

163

the THF. After drying over magnesium sulphate, the ethynylsilane is distilled off at normal pressure (30-cm Vigreux column). The fraction, collected between 45 and 110 C, still contains some THF. This can be removed by shaking 5 times with cold dilute hydrochloric acid in a small (100-ml) separating funnel. Redistillation after drying over a small amount of magnesium sulphate gives ethynyl(trimethyl)silane, bp 55 C/760 Torr, in 75–80% yield (on a 1 molar scale). Ethynyl(tributyl)stannane, bp 92 C/1 Torr, is prepared in 85% yield by a similar procedure using the same molar excess of ethynylmagnesium bromide. Extraction is carried out with pentane. The synthesis from the LiCCH. 1,2-ethanediamine complex and Bu3SnCl gave 31% yield only [12].

Note Slow, dropwise addition involves the chance on formation of Me3SiCCSiMe3 by proton-metal exchange between BrMgCCH and the kinetically very acidic HCCSiMe3 and subsequent silylation. 7.2.2

Procedures for the reaction of alkynyllithium and alkynylmagnesium bromides with chloro(trimethyl)silane

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml, addition by syringe

7.2.2.1 General procedure for non-volatile silylacetylenes Chloro(trimethyl)silane (0.12 mol) is added over a few minutes to a solution of the metallated acetylene cooled at –20 C, then the cooling bath is removed and the temperature is allowed rising to rt. After an additional 30 min the reaction mixture (fine or thick suspension) is poured into 100 ml of an aqueous solution containing 25 g of ammonium chloride. After extraction with Et2O or pentane and drying over magnesium sulphate, the solvents are removed under reduced pressure and the remaining liquid distilled in vacuo. Yields are generally excellent. 7.2.2.2 Rather volatile silylacetylenes (2-Ethoxyethynyl)(trimethyl)silane, EtOCCSiMe3, bp 37 C/10 Torr, is obtained in >70% yield from the lithium compound (this being used in

164

7.

SILYLATION, STANNYLATION AND PHOSPHORYLATION

10% excess, Note) and Me3SiCl in Et2O (obtained by removing the greater part of the hexane from the BuLi solution under reduced pressure subsequently adding Et2O to the remaining very concentrated solution of BuLi). The silylation product is isolated by distillation of the greater part of the Et2O at normal pressure (bath temperature < 70 C) followed by distillation of the remaining liquid in vacuo. A similar procedure is followed for the isolation of 3-buten-1ynyl-(trimethyl)silane, H2C¼CHCCSiMe3, bp 40 C/25 Torr (receiving flask cooled at –5 C, Figure 1.10). 7.2.2.3

Volatile silylacetylenes

Trimethyl(1-propynyl)silane, MeCCSiMe3, bp 96 C/760 Torr, is prepared as follows: Chloro(trimethyl)silane (0.30 mol) is added in one portion at 0 C to a suspension of 0.35 mol of propynyllithium in 300 ml of Et2O (prepared from an excess of propyne, cf. Chapter 3, exp. 3.9.4, and BuLiLiBr in Et2O (Chapter 2, exp. 2.3.6). The thermometer is replaced with a reflux condenser. The mixture is stirred at rt for 1 h and subsequently for 6 h under reflux. After cooling to below 5 C, the suspension is poured into 100 ml of ice water with occasional swirling. The aqueous layer is extracted once with a small portion of Et2O, then the organic solution is dried over magnesium sulphate. Careful fractionation through an efficient column gives the desired silylation product, bp 95 C/ 760 Torr, in > 70% yield. A similar procedure may be applied to prepare EtCCSiMe3.

Note 1-Alkynyl ethers very easily react with water in the presence of acid to give esters. The use of an excess of the lithiated acetylenic ether guarantees the absence of acid during the work-up.

7.2.3

Reaction of lithiated propargyl chloride with chloro(trimethyl)silane

Scale: 0.10 molar; Apparatus: Figure 1.1 , 500 ml, addition by syringe

7.2

EXPERIMENTAL SECTION

165

7.2.3.1 Procedure Freshly distilled chloro(trimethyl)silane (0.09 mol, less than the equivalent amount, Note 1) is added at –90 C to a solution of 0.10 mol of lithiated propargyl chloride in a mixture of THF (Note 2) and hexane (Chapter 3, exp. 3.9.6). Dry DMSO (25 ml) is added over 1–2 min at –90 C, after which the cooling bath is removed and the temperature allowed rising to rt. Water (100 ml) is added, followed by extraction with pentane. The organic solution is dried over magnesium sulphate. The greater part of the solvents is distilled off under atmospheric pressure. (3-Chloro-1-propynyl)(trimethyl)silane, bp 45 / 15 Torr, is obtained in > 70% yield. Notes 1.

2.

There should be no risk that any Me3SiCl remains unconverted. This will form hexamethyldisiloxane, Me3SiOSiMe3, during the aqueous work-up. Complete separation of this compound and the product is not possible. Et2O presumably also can be used and addition of DMSO is probably unnecessary when THF is used as the main solvent.

7.2.4

Reaction of lithiated propargyl bromide with chloro(trimethyl)silane

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml, addition by syringe 7.2.4.1 Procedure [13] Chloro(trimethyl)silane (0.30 mol, excess) is added over 5 min to a solution of 0.20 mol of lithiated propargyl bromide in 200 ml of Et2O and 126 ml of hexane (Chapter 3, exp. 3.9.6) cooled to between –80 and –90 C. Subsequently a mixture of 25 ml of dry HMPT or DMSO and 30 ml of Et2O is added dropwise over 5 min with efficient stirring while carefully keeping the temperature within this range. After this addition the cooling bath is occasionally removed and the temperature is allowed to rise gradually over 30 min to –40 C, and subsequently to 10 C. The white suspension is then poured into 500 ml of 2 N aqueous HCl and the product is isolated as described in exp. 7.2.3 (the solvent and volatile components are removed under reduced pressure). Careful distillation through a 40-cm Vigreux column gives (3-bromo1-propynyl)(trimethyl)silane, bp 58 C/15 Torr, in 80% yield. Possibly, good

166

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SILYLATION, STANNYLATION AND PHOSPHORYLATION

results can be obtained also when a smaller amount or no co-solvent is used: in this case the mixture of lithiated propargyl bromide and chloro(trimethyl)silane has to be stirred for at least 2 h at –80 C.

7.2.5

Trimethyl[(2-trimethylsilyl)ethynyl]silane from acetylene-1,2-bis(magnesium bromide) and chloro(trimethyl)silane

Scale: 0.50 molar (Me3SiCl); Apparatus: Figure 1.1, 1 litre The trimethylsilylation of the di-Grignard derivative of acetylene has to be carried out at temperatures that are considerably higher than necessary for the silylation of ethynyl mono-magnesium bromide. This decreased reactivity may be ascribed to the slight solubility of the intermediate. 7.2.5.1

Procedure

Chloro(trimethyl)silane (0.60 mol) is added dropwise over 20 min to a suspension of 0.25 mol of acetylene dimagnesium bromide in 500 ml of THF (cf. Chapter 3, exp. 3.9.8) kept between 50 and 55 C by occasional cooling or heating. The suspension disappears gradually. The mixture is heated to 50–55 C for an additional period of 2 h, then cooled to 30 C and subsequently poured into a solution of 25 g of NH4Cl in 200 ml of water. After vigorous shaking, the aqueous layer is extracted twice with 75-ml portions of pentane. The combined organic solutions are washed 10 times with 50-ml portions of an aqueous solution of NH4Cl (150 g/litre) in order to remove as much of THF as possible. The organic layer is dried over MgSO4. Distillation of the remaining liquid through a 40-cm Vigreux column gives trimethyl [2-(trimethylsilyl)ethynyl]silane, Me3SiCCSiMe3, bp 128–138 C/ 760 Torr in greater than 80% yield. The product solidifies slowly at rt.

7.2.6

1,3-Butadiynyl(tributyl)stannane from butadiynyllithium and chloro(tributyl)stannane

Scale: 0.10 molar (Bu3SnCl); Apparatus: Figure 1.1, 500 ml

7.2

EXPERIMENTAL SECTION

167

In some derivatisation reactions with mono-metallated butadiyne considerable amounts of disubstituted diacetylene are formed. Their presence can hamper the purification of the desired mono-substitution products, particularly when the boiling point is high and the thermal stability limited. The formation of disubstitution products can be effectively suppressed, however, by using a large excess of butadiyne. The preparation of butadiynyl tributyltin is an illustrative example.

7.2.6.1 Procedure A solution of 0.13 mol of BuLi in 82 ml of hexane is added dropwise over 20 min to a mixture of 0.25 mol of diacetylene (freshly prepared, or stored as a THF solution at –80 C, see Chapter 10, exp. 10.2.7) and 100 ml of THF. During this addition the temperature is kept below –40 C. Chloro(tributyl)stannane (0.10 mol) is then added at –30 C over 2 min, after which the cooling bath is removed. The mixture is stirred for an additional 2 h at 0 C, then it is poured into a solution of 25 g of NH4Cl in 200 ml of water. After separation of the layers, one extraction with pentane is carried out. The organic solutions are dried over MgSO4 and subsequently concentrated in vacuo. The last traces of volatile components are removed in a vacuum of 0.5 Torr or less. The residue is 100% pure 1,3-butadiynyl(tributyl)stannane, as indicated by 1H NMR. Distillation is not carried out.

7.2.7

Reaction of allenylmagnesium bromide with chloro(trimethyl)silane and chloro(tributyl)stannane

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml

7.2.7.1 Procedure A solution of allenylmagnesium bromide in 150 ml of Et2O, prepared from 0.15 mol of propargyl bromide (Chapter 2, exp. 2.3.9) is cooled to –10 C. Freshly distilled chloro(trimethyl)silane (0.10 mol) or chloro(tributyl)stannane (0.10 mol) is added dropwise over 20 min with efficient stirring while maintaining the temperature at the level mentioned. A thick suspension is formed in

168

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SILYLATION, STANNYLATION AND PHOSPHORYLATION

the case X ¼ Si. After an additional 15 min, as much of the suspension as possible is poured into a solution of 20 g of ammonium chloride in 100 ml of water. The suspension remaining in the flask is hydrolysed by cautious addition of aqueous NH4Cl. After vigorous shaking, the layers are separated. The combined organic layer and one extract, using only a small amount of Et2O, are dried over MgSO4, after which a very careful distillation through an efficient column is carried out. Trimethyl(2-propynyl)silane (containing 8% of trimethyl(1,2-propadienyl)silane), bp 92 C/760 Torr, is obtained in a fair yield (>75% in 0.5 molar-scale experiments). In the case of X ¼ Sn, the reaction mixture is kept at rt during the night, followed by the work-up described above. Removal of the Et2O under reduced pressure gives an 95:5 mixture of tributyl(1,2-propadienyl)stannane and tributyl(2-propynyl)stannane in quantitative yield.

7.2.8

Trimethylsilylation of lithiated N,N-diethyl-1-allenamine

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml

7.2.8.1

Procedure [14]

A solution of 0.12 mol of anhydrous lithium bromide in 40 ml of THF is added at – 50 C to a solution of 0.10 mol of the potassiated N,N-diethyl1-propyn-1-amine in THF and hexane prepared as described in Chapter 3, exp. 3.9.18. Subsequently, Me3SiCl (0.12 mol) is added over 10 min at –60 C to the resulting gel-like suspension. The cooling bath is removed and when the temperature has reached 10 C, the mixture is poured into 150 ml of an aqueous solution of 5 g of potassium carbonate. After shaking, extraction with Et2O (3 times) and drying over potassium carbonate, the solvents are removed under reduced pressure. Distillation of the crude product gives N,N-diethyl-3-(trimethylsilyl)-1-propyn-1-amine, bp 75 C/15 Torr, in greater than 80% yield. A similar procedure, carried out without preceding addition of lithium bromide, gives a 2:1 mixture of the silylated acetylenic amine and N,Ndiethyl-3-(trimethylsilyl)-1-allenamine. The lithium derivative H2C¼C¼ C(Li)NMe2 and Me3SiCl give equal amounts of the acetylenic and the allenic silane [14].

7.2

EXPERIMENTAL SECTION

7.2.9

169

Trimethylsilylation of a lithiated 2-alkyne

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml, addition by syringe 7.2.9.1 Procedure Chloro(trimethyl)silane (0.12 mol) is added in one portion to a solution of lithiated 2-nonyne (Chapter 3, exp. 3.9.16 and Table 3.3) cooled at –60 C, after which the cooling bath is removed. After 10 min water is added, followed by extraction of the aqueous layer. The organic solution is dried and concentrated under reduced pressure. Trimethyl(2-nonynyl)silane, bp 95 C/15 Torr, is obtained in an excellent yield. Lithiated 2-alkynyl ethers, RCCCH(Li)OR1, can be silylated under similar conditions to give pure allenic derivatives [15], RC(SiMe3)¼C¼CHOR1.

7.2.10

Trimethylsilylation of a lithiated cumulenic amine

Scale: 0.05 molar; Apparatus: Figure 1.1, 500 ml, addition by syringe 7.2.10.1

Procedure [18]

Chloro(trimethyl)silane (0.05 mol) is added over a few seconds to a solution of the lithiated N,N,4-trimethyl-1,2,3-pentatrien-1-amine (Chapter 3, exp. 3.9.32) in THF–hexane cooled at –80 C, after which the cooling bath is removed. When the temperature has reached –30 C, water (100 ml) is added with vigorous stirring, care being taken to keep the temperature below 5 C. The organic layer and two ethereal extracts are dried over potassium carbonate and concentrated under reduced pressure. Distillation of the crude product through a very short column gives [N,N,4-trimethyl-1-(trimethylsilyl)-1,2,3pentatrien-1-amine, bp 52 C/0.2 Torr, in 65% yield. The product is extremely oxygen-sensitive.

170

7.

7.2.11

SILYLATION, STANNYLATION AND PHOSPHORYLATION Trimethylsilylation of lithiated methoxyallene

Scale: 0.10 molar (Me3SiCl); Apparatus: Figure 1.1, 500 ml, addition by syringe 7.2.11.1

Procedure

Chloro(trimethyl)silane (0.10 mol) is added over a few minutes at –30 C to a solution of 0.12 mol of 1-lithio-1-methoxyallene (excess, Note) prepared as indicated in Chapter 3, exp. 3.9.15 and Table 3.3 from methoxyallene and BuLiLiBr in Et2O (Chapter 2, exp. 2.3.6). The cooling bath is removed and the suspension is allowed to reach rt, then 100 ml of an aqueous solution of 20 g of ammonium chloride is added with vigorous stirring. After extraction with Et2O, the organic solution is dried over magnesium sulphate and the Et2O is distilled off under normal pressure (bath temperature < 90 C) through a 40-cm Vigreux column. Distillation of the remaining liquid gives (1-methoxy1,2-propadienyl) (trimethyl)silane, bp 25 C/15 Torr, (receiver cooled in a bath at –5 C, Figure 1.10) in 70% yield. Stannylation of lithiomethoxyallene (10% excess) with Bu3SnCl (–30 C ! rt) gives tributyl(1-methoxy-1,2-propadienyl)stannane (not distilled) contaminated with 10% of tributyl(3-methoxy-2-propynyl)stannane, Bu3SnCH2C COMe, in almost 100% yield.

Note Allenic ethers react with water in the presence of acid. The use of an excess of the lithiated allenic ether ensures the absence of acid during the aqueous work-up.

7.2.12

3-(Trimethylsilyl)-2-propyn-1-ol

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml, addition by syringe

7.2

EXPERIMENTAL SECTION

7.2.12.1

171

Procedure

Freshly distilled (under 100 Torr) propargyl alcohol (0.10 mol) is added over a few minutes to a solution of 0.20 mol of BuLi LiBr (Chapter 2, exp. 2.3.6) in 200 ml of Et2O with cooling between –10 and –30 C. Subsequently, 0.22 mol of chloro(trimethyl)silane is added over 15 min at –10 C. The suspension is stirred for an additional 2 h at rt, then a mixture of 10 g of acetic acid and 70 ml of water is added with vigorous stirring. Stirring is continued for 4 h at rt. The aqueous layer is extracted four times with Et2O. The combined organic solutions are shaken with a saturated aqueous solution of NaHCO3 in order to remove the acetic acid. After drying over magnesium sulphate, the Et2O is removed under reduced pressure. 3(Trimethylsilyl)-2-propyn-1-ol, bp 71 C/15 Torr, is obtained in a high yield. If the disilyl compound appears to be present, the product should be stirred for a few minutes with 1 M hydrochloric acid. The dilithiation of propargyl alcohol can be carried out also with a mixture of commercial BuLi in hexane and THF. 7.2.13

Regioselective monosilylation of 1,3-dilithiated alkynes

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 7.2.13.1

Procedure [8]

Chloro(trimethyl)silane (0.10 mol) is added dropwise over 30 min to a solution of the 1,3-dilithiated acetylene in THF and hexane (Chapter 3, exp. 3.9.11) with cooling at –70 C, then the cooling bath is removed. After an additional 30 min ice water is added, followed by extraction. The organic solution is dried over magnesium sulphate and concentrated under reduced pressure. Trimethyl (1-phenyl-2-propynyl)silane, HCCCH(SiMe3)Ph, bp 102 C/18 Torr, trimethyl[1-methylthio-2-propynyl]silane, HCCCH(SiMe3)SMe, bp 65 C/ 18 Torr, and (1-butyl-2-propynyl)(trimethyl)silane, HCCCH(SiMe3)Bu, bp 55 C/17 Torr, are obtained in > 70% yields. 7.2.14

Dibutyl(ethynyl)phosphane

172

7.

SILYLATION, STANNYLATION AND PHOSPHORYLATION

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 7.2.14.1

Procedure [16]

(Note 1) Into a solution of 0.2 mol of ethynylmagnesium bromide in 200 ml of THF (Chapter 3, exp. 3.9.7) acetylene is introduced (100 ml/min) for 15 min with cooling at –15 C. The resulting suspension is cooled to –25 C, after which dibutylphosphinous chloride [17] (0.10 mol) is added over 15 min. After this addition, the cooling bath is removed and the temperature is allowed rising to þ10 C. A solution of 20 g of NH4Cl in 200 ml of water is then added over a few minutes with vigorous stirring. After separation of the layers and extraction of the aqueous layer with Et2O, the extracts are dried over MgSO4 (Note 2) and subsequently concentrated under reduced pressure. Distillation through a 30-cm Vigreux column gives dibutyl(ethynyl)phosphane, bp 85 C/10 Torr, in 75% yield (Note 3). Crystallisation of the solid residue from Et2O gives a small amount of Bu2PCCPBu2, mp 32–33 C. Notes 1.

In view of the oxygen-sensitivity of phosphanes all operations must be carried out in a nitrogen atmosphere. 2. The amount of MgSO4 should be as small as possible. Instead of being filtered, the organic solution is carefully decanted from the drying agent, which is rinsed a few times with Et2O. 3. After termination of the distillation nitrogen must be admitted!

7.2.15

Diethynyl(phenyl)phospane

Scale: 0.10 molar (PhPCl2); Apparatus: Figure 1.1, 500 ml 7.2.15.1

Procedure (cf. exp. 7.2.14)

(Note 1) Acetylene ( 300 ml/min) is introduced for 5 min into a suspension of 0.25 mol of ethynylmagnesium bromide in 300 ml of THF (Chapter 3, exp. 3.9.7) cooled to between –20 and –30 C. Subsequently dichlorophenylphosphane (0.10 mol, commercially available) is added dropwise over 15 min while keeping the temperature between –10 and –20 C. After an additional

REFERENCES

173

30 min the cooling bath is removed and the temperature allowed rising to 0 C. The suspension is then treated with a solution of NH4Cl in water as described in exp. 7.2.14. The work-up is also carried out in a similar way. Distillation of the remaining brown liquid through a very short and wide column (preferably B-29 glass joints) in a high vacuum (mercury-diffusion pump, pressure 0.01 Torr or lower) gives the acetylenic phosphine, bp 50–60 C/0.01 Torr, in 50% yield. The temperature of the heating bath should not exceed 80 C since the residue may decompose vigorously upon excessive heating. 7.2.16

Tri(1-propynyl)phosphane

Scale: 0.10 molar (PCl3); Apparatus: Figure 1.1, 1 litre 7.2.16.1

Procedure [16]

(Note) A solution of 0.45 mol of propynylmagnesium bromide (Chapter 3, exp. 3.9.9, note) in 350 ml of THF is added dropwise or portionwise over 30 min to a mixture of 0.10 mol of freshly distilled PCl3 and 100 ml of THF while keeping temperature between –70 and –90 C by occasional cooling in a bath with liquid N2. After the addition, the temperature of the reaction mixture is allowed to rise gradually over 3–4 h to 0 C. Stirring at 0 C is continued for another 1 h. The brown suspension is then poured into a concentrated aqueous solution of NH4Cl. After vigorous shaking and separation of the layers, the aqueous layer is extracted with Et2O. The organic solution is dried over MgSO4 and subsequently concentrated under reduced pressure, giving reasonably pure (94%) tri(1-propynyl)phosphane. Recrystallisation from Et2O gives the pure compound in 80% yield, mp 95–96 C. Note All operations, including the work-up, must be carried out under nitrogen.

REFERENCES 1. D. R. M. Walton, in Protective Groups in Organic Chemistry (ed. J. F. W. McOmie). Plenum Press, 1973, p. 2. 2. E. W. Colvin, Silicon in Organic Synthesis. Butterworths, 1981.

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3. M. H. P. J. Aerssens, R. van der Heiden, M. Heus and L. Brandsma, Synth. Commun. 20, 3421 (1990). 4. H. M. Schmidt and J. F. Arens, Recl. Trav. Chim., Pays-Bas 86, 1138 (1967). 5. R. Epzstein, review in Comprehensive Carbanion Chemistry, Part B (eds. E. Buncel and T. Durst). Elsevier, Amsterdam, 1984, p. 99. 6. H. E. Schuster and G. M. Coppola, Allenes in Organic Synthesis. Wiley-Interscience, New York, 1984, p. 252. 7. M. le Quan and P. Cadiot, Bull. Soc. Chim. France, 45 (1965); J.-C. Masson, M. le Quan and P. Cadiot, Bull. Soc. Chim. France, 777 (1967). 8. H. Hommes, H. D. Verkruijsse and L. Brandsma, Recl. Trav. Chim. Pays- Bas 99, 113 (1980). 9. L. Brandsma and H. D. Verkruijsse, Synthesis, 1727 (1999). 10. E. R. H. Jones, L. Skattebøl and M. C. Whiting, Org. Synth., Coll. Vol. 4, 792. 11. A. B. Holmes and C. N. Sporikou, Org. Synth., Coll. Vol. 8, 606 (1993). 12. A. F. Renaldo, J. F. Labadie and J. K. Stille, Org. Synth., Coll. Vol. 8, 268 (1993). 13. H. D. Verkruijsse, L. Brandsma, Synth. Commun. 20, 3375 (1990). 14. Unpublished observations and results from the author’s laboratory. 15. Y. Leroux and C. Roman, Tetrahedron Lett., 2585 (1973). 16. W. Voskuil and J. F. Arens, Recl. Trav. Chim., Pays-Bas 88, 993 (1962); 83, 1301 (1964). 17. K. Issleib and W. Seidel, Chem. Ber. 92, 2681 (1959). 18. P. E. van Rijn and L. Brandsma, J. Organometal. Chem. 233, C25 (1982).

8 Sulphenylation and Related Reactions

8.1

METHODS FOR THE DIRECT INTRODUCTION OF SULPHUR, SELENIUM AND TELLURIUM

The most practical methods for compounds containing the system CC–S (and the Se- or Te analogues) consist of reacting a metallated acetylene with elemental sulphur (Se or Te) or a sulphenyl derivative with a suitable leaving group L. Sulphoxides may be prepared by analogous coupling reactions. The various methods can be represented by the following scheme (Y ¼ S, Se, Te) [1]:

The insertion of a sulphur atom into the C–metal bond is analogous to the well-known formation of alkali thiocyanate from alkali cyanide and sulphur. The insertion reaction has been successfully applied to introduce sulphur (or Se and Te) into an aromatic or heteroaromatic ring system. The reaction of metallated acetylenes with the elements S, Se and Te constitutes a ready access to several derivatives with the CC–Y systems. Although derivatisation of the mesomeric anion RCCY $ RC¼C¼Y with an 175

176

8.

SULPHENYLATION AND RELATED REACTIONS

‘electrophilic’ reagent ‘Eþ’ in principle may give products from both structures, the only isolated type of derivative is RCC–YE. In the case of selenium and tellurium, yields of the alkylation products are significantly better than with sulphur. The reactions with sulphur and subsequent derivatisations usually give appreciable amounts of high-boiling residues, which might in part result from further reactions of the thioketenes RC(E)¼C¼S. The insertions proceed most easily in liquid ammonia. However, functionalisations in this solvent are restricted to alkylation reactions. Reactions in tetrahydrofuran or diethyl ether are generally carried out with lithium alkynylides, which react much more smoothly than sodium or potassium derivatives because of a better solubility. A wide variety of derivatives with the structure system CC–Y are accessible via the lithium chalcogenates RCC–YLi in organic solvents [1,20]. Alkali acetylides react very easily with disulphides, R1SSR1, thiocyanates, 1 R SCN, and thiosulphonates, R1SSO2R1. The reactions can be carried out in liquid ammonia as well as in organic solvents and generally give excellent yields of the acetylenic sulphides [2,3], RCCSR1. Although sulphenyl halides seem suitable reagents for the introduction of alkylthio or arylthio groups, they are seldom used for this reaction, because of their sensitivity and the chance of further reaction with the products. Di(1-alkynyl) sulphides are formed in excellent yields, if (freshly distilled) sulphur dichloride is added to a solution or suspension of a lithium alkynylide in diethyl ether [4]. In an analogous manner, di(1-alkynyl) sulphoxides are formed from thionyl chloride and alkynyllithium [4], while sulphinyl chlorides R1S(¼O)Cl may be used to prepare the sulphoxides RCCS(¼O)R1. Preliminary experiments [2] suggest that interaction between alkynyllithium and sulphonyl chlorides R1SO2Cl can give both sulphones RCCSO2R1 and chloroalkynes, RCCCl. There are few examples of analogous reactions with metallated allenes or disubstituted acetylenes. Like in the case of functionalisation with other electrophiles mixtures of acetylenic and allenic derivatives can be expected. An exception is the reaction of 1-lithio-1-methoxyallene with dimethyl disulphide, which affords 1-methoxy-1-methylthioallene, H2C¼C¼C(OMe)SMe as the only product [5]. Allenyllithiums, R2C¼C¼CHLi, have been converted into allenic sulphides [6], R2C¼C¼CHSR1 or selenides [7], R2C¼C¼CHSePh, using R1SSR1 and PhSeSePh, respectively, as reagents. Reaction of alkyl sulphinates, RS(¼O)O-alkyl with allenic Grignards gives the sulphoxides with the structures [8] RS(¼O)C(Me)¼C¼CHMe. In the case of an asymmetric sulphur atom, induction of chirality takes place stereospecifically in the allenic system.

8.2

EXPERIMENTAL SECTION 8.2

177

EXPERIMENTAL SECTION

Notes 1. 2.

For the preparation of alkali amides in liquid ammonia and alkyllithium reagents see Chapter 2. Most of the reactions in organic solvents or liquid ammonia at temperatures below its boiling point are carried out under inert gas.

8.2.1

Reaction of metallated acetylenes with sulphenylating agents in liquid ammonia

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml, the thermometer is omitted A convenient and quick method to prepare acetylenic sulphides consists of adding a disulphide, thiosulphonate or thiocyanate to a lithium or sodium alkynylide in liquid ammonia. The reaction proceeds almost instantaneously, except in the case of di-(t-butyl) disulphide (reaction with RCCLi in an organic solvent at higher temperatures, or the use of t-BuSCN may be considered). Ethynyl sulphides, HCCSR1, cannot be obtained using this method, since they are immediately deprotonated by alkali acetylide MCCH and then a second R1S group is introduced with the formation of the bis-thioethers [2,17], R1SCCSR1. Sulphides with conjugated unsaturated systems, e.g. 4-(alkylthio)-1-buten-3-ynes, H2C¼CHCCSR1, and 1-(alkylthio)-1,3-alkadiynes, RCCCCSR1, readily undergo nucleophilic addition of thiolate R1S–. Therefore, thiocyanates or thiosulphonates should be used for the sulphenylation of alkali compounds from 1,3-enynes and 1,3-diynes and also in those cases in which there is a chance of a subsequent reaction of the product with thiolate. 8.2.1.1 Procedure (cf. [3]) A solution or suspension of 0.22 mol of the lithium or sodium alkynylide in 250 ml of liquid ammonia is prepared as described in Chapter 3, exp. 3.9.3. The disulphide, thiosulphonate [9] or thiocyanate (0.20 mol, see exp. 8.2.2, diluted with 50 ml of Et2O, is added dropwise over 10 min with efficient stirring. In many cases a rather thick suspension is formed: an additional volume of 100 ml of liquid ammonia may then be introduced. The ammonia may either be removed by placing the flask in a water bath at 40 C (after

178

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SULPHENYLATION AND RELATED REACTIONS

having replaced the equipment on the outer necks with outlets), or allowed to evaporate (Figure 1.7). After addition of 200 ml of Et2O to the solid residue, 300 ml of ice water is added with vigorous stirring or swirling by hand. After separation of the layers, the aqueous phase is extracted with Et2O, and the organic solution dried over MgSO4. The solvent is removed under reduced pressure and the remaining liquid distilled in vacuo. The following examples give an impression of the scope: 1-(Methylthio)-1-pentyne, n-PrCCSMe, bp 50 C/12 Torr, yield 90%, from n-PrCCLi, and MeSCN; 1-[2-(methylthio)ethynyl]-1-cyclohexene, 1-cyclohexenylCCSMe, bp 120 C/12 Torr, in 85%, yield from 1-cyclohexenyllithium and MeSSMe; 1-(methylthio)-1,3-pentadiyne, MeCCCCSMe, bp 80 C/12 Torr, in 80%, yield from MeCCCCLi and MeSSO2Me, 1-[(4-chlorobutyl)thio]-1-propyne, MeCCS(CH2)4Cl, bp 90 C/1 Torr, yield 80%, from MeCCLi and 4-chlorobutyl thiocyanate, Cl(CH2)4SCN. 8.2.2

C-Thiomethylation of acetylenic alcohols in liquid ammonia

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml, no thermometer 8.2.2.1

Procedure

2-Propyn-1-ol (0.10 mol) or 3-butyn-1-ol, (0.10 mol) is added dropwise over 10 min to a vigorously stirred suspension of 0.25 mol of lithium amide in 500 ml of liquid ammonia (see Chapter 4, exp. 4.5.10). Most of the suspended material disappears. Methylthiocyanate (0.25 mol (see below) is then added dropwise over 10 min. The ammonia is subsequently removed by placing the flask in a water bath at 40 C, stirring being continued as long as possible (the dropping funnel and the thermometer are removed). To the remaining dark residue 200 ml of ice water is added, after which five to ten extractions with Et2O are carried out. The organic solution is dried over MgSO4 and subsequently concentrated in vacuo using a rotary evaporator. Distillation of the remaining liquid through a 30-cm Vigreux column gives 3-(methylthio)-2-propyn-1-ol, MeSCCCH2OH, bp 60 C/0.2 Torr, in 70% yield (redistillation gives bp 95 C/12 Torr) and 4-(methylthio)-3-butyn-1-ol, MeSCCCH2CH2OH, bp 108 C/15 Torr, in 80% yield. Methyl thiocyanate is prepared by adding at 60 C 1 mol of dimethyl sulphate to a mixture of 1 mol of potassium thiocyanate and a small amount (50 ml) of water. After an additional period of 45 min heating at 90 C, ice

8.2

EXPERIMENTAL SECTION

179

water, just enough for dissolution of the salt, is added. The upper layer is dried and distilled under normal pressure. The yield is excellent, provided that for the reaction a small amount of water is used. 8.2.3

Reaction of lithiated acetylenes with sulphenylating agents in diethyl ether or tetrahydrofuran

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 8.2.3.1 Procedure (for Introduction see exp. 8.2.1) The sulphenyl compound (0.10 mol) is added over a few minutes to a solution or suspension of 0.11 mol of RCCLi in Et2O or THF (see Chapter 3, exps. 3.9.4 and 3.9.6). This solution is cooled to 75 C in the cases of X ¼ CN and MeSO2, or to –40 C when X ¼ MeS. The cooling bath is removed and the temperature allowed rising to 0 C. In the case of a very thick suspension, an additional amount of Et2O or THF should be added. Ice water (100 ml) is added to the vigorously stirred reaction mixture, followed by extraction of the aqueous layer with Et2O and drying the organic solvent over MgSO4. The following compounds have been prepared in yields of at least 80%: 1-(Methylthio)-1-hexyne, n-BuCCSMe, bp 65 C/12 Torr, (MeSSMemethod); 3,3-dimethoxy-1-(methylthio)-1-propyne, (MeO)2CHCCSMe, bp 86 C/ 12 Torr, (MeSCN-method) and 3-chloro-1-(methylthio)-1-propyne, MeSC CCH2Cl, bp 65 C/15 Torr, (MeSSO2Me-method). 1-[(2-Chloroethyl)thio]-1-propyne, MeCCSCH2CH2Cl, bp 78 C/15 Torr, is obtained in an excellent yield from MeCCLi in THF–hexane (–70 C ! rt) and 2-chloroethyl thiocyanate, NCSCH2CH2Cl. 8.2.4

4-Ethylthio-1-buten-3-yne, 4-methylseleno-1-buten-3-yne and 4-methyltelluro-1-buten-3-yne from in-situ generated vinylethynylsodium, sulphur, selenium or tellurium and alkyl halides

180

8.

SULPHENYLATION AND RELATED REACTIONS

Scale: 0.10 molar (dichlorobutene); Apparatus: Figure 1.1, 500 ml; for the addition of the elements the dropping funnel is replaced with a powder funnel. AlkylSe and alkylTe groups can be introduced by reaction with diselenides and ditellurides, RYYR, but the desired products can be prepared in a more practical and economical way by successive addition of the elements and the alkyl halide. The insertion of the elements proceeds most easily in liquid ammonia, provided that grey Te powder and red Se powder is used. Black Te powder, obtained by precipitation, is not reactive, possibly because of the presence of an oxide coating, while the black modification of Se, ‘selenium nigrum’, is also less reactive. In Et2O or THF, temperatures in the range 0–20 C are necessary for a smooth reaction of the elements. 8.2.4.1

Procedure (cf. [18,19])

(E)-1,4-Dichloro-2-butene (0.10 mol, commercially available, Note 1) is added dropwise over 15 min to a suspension of 0.30 mol of sodamide in 300 ml of liquid ammonia with cooling between –35 and –40 C. After an additional 15 min the dropping funnel is replaced with a powder funnel and dry, powdered sulphur (3.0 g), red selenium (7.0 g) or grey tellurium (12 g) is introduced in small portions over 15 min, while maintaining the temperature between –35 and –40 C. Small amounts of the elements in the powder funnel and the neck are rinsed into the reaction mixture with Et2O (20–40 ml). After an additional 15–30 min, when the powder has dissolved completely (Note 2), the reaction mixture is cooled to –55 C. Methyl iodide (0.15 mol) or ethyl bromide (0.17 mol) is added over a few seconds by syringe. After an additional 10 min the cooling bath is removed and the mixture is stirred for 1 h. The ammonia is then allowed to evaporate (Figure 1.7). After addition of water to the remaining salt mass, the product is isolated by extraction with Et2O, drying of the extracts over MgSO4 and concentration of the organic solution in vacuo (Note 3). Distillation of the remaining liquid at < 0.5 Torr, using a single receiver, cooled in a bath at < –20 C (Figure 1.10), gives 4-(methylseleno)-1-buten-3yne, H2C¼CHCCSeMe, in 80% and 4-(methyltelluro)-1-buten-3-yne, H2C¼CHCCTeMe, (yellowish-brown liquid), in 70% yield. Pure 4-(ethylthio)-1-buten-3-yne H2C¼CHCCSEt, bp 47 C/10 Torr, is obtained in 55% yield by careful redistillation of the contents of the receiver. Notes 1.

The reaction of the (Z)-isomer with NaNH2 proceeds less satisfactorily, and gives a considerable amount of resinous product.

8.2 2. 3.

EXPERIMENTAL SECTION

181

A small amount of coarse Te powder may remain. The tellurium compound is air-sensitive, and the work-up should therefore be carried out under nitrogen.

8.2.5

1-(Ethylseleno)-1-propyne and 1-(ethyltelluro)-1-propyne from in-situ generated propynylsodium, selenium or tellurium and ethyl bromide

Scale: 0.10 molar (dibromopropane); Apparatus: Figure 1.1, 500 ml 8.2.5.1 Procedure (cf. exp. 8.2.4) Red selenium powder (7.0 g) or grey tellurium powder (12.0 g) is added to a suspension of 0.10 mol of propynylsodium in 200 ml of liquid ammonia (Chapter 3, Table 3.1 and exp. 3.9.21). The addition is carried out over 15 min through a powder funnel, which temporarily replaces the dropping funnel. During this addition the temperature of the reaction mixture is maintained between –35 and –40 C. Small amounts of powder in the funnel or in the neck are rinsed into the flask with a few millilitres of Et2O. After 15 to 30 min the Se or Te has disappeared (a small amount of coarse Te powder may remain unconverted). Ethyl bromide (0.15 mol) is then added over 15 min without external cooling. After an additional 1 h stirring is stopped and the ammonia is allowed to evaporate (Figure 1.7). The remaining salt is dissolved by addition of 100 ml of water, after which the mixture is extracted four times with Et2O. After drying the organic solution over MgSO4, the solvent is removed by evacuation and the remaining liquid distilled through a 30-cm Vigreux column. 1-(Ethylseleno)-1-propyne, MeCCSeEt, bp 44 C/10 Torr, and 1-(ethyltelluro)-1-propyne, MeCCTeEt, bp 66 C/10 Torr, are obtained in good yields. Sodium acetylide, NaCCH, selenium and ethyl bromide give bis (ethylseleno)acetylene, EtSeCCSeEt. This compound is formed by disproportionation [10] of the initially formed HCCSeEt under the influence of HCCSeNa. 8.2.6

Reaction of alkynyllithium in tetrahydrofuran with sulphur or selenium and subsequent alkylation

182

8.

SULPHENYLATION AND RELATED REACTIONS

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 8.2.6.1

Procedure

Dry, powdered sulphur (3.2 g) or red selenium (8.0 g) is added over a few minutes to a solution of 1-alkynyllithium, RCCLi (0.10 mol in 70 ml of THF and 63 ml of hexane, Chapter 3, exp. 3.9.4), cooled at –40 C. The cooling bath is removed and the temperature allowed rising to 15 C. After an additional period of 15–30 min (when the powder has dissolved) 0.30 mol (large excess) of bromochloromethane is added over a few seconds. In the case of the preparation of sulphides, the brown solution is allowed to stand for 12–15 h at rt, the alkyneselenolates react faster so that a period of about 4 h is sufficient. The reaction mixture is poured into 150 ml of ice water and, after vigorous shaking, the layers are separated. The organic layer and three ethereal extracts are dried over MgSO4 and subsequently concentrated under reduced pressure. The remaining liquid is first distilled at low (< 0.5 Torr) pressure through a very short column and the distillate collected in a single receiver cooled below –30 C (Figure 1.10). Redistillation gives the following products: 1-(chloromethylthio)-1-butyne, EtCCSCH2Cl, bp 65 C/12 Torr; 1-(chloromethylthio)-1-propyne, MeCCSCH2Cl, bp 58 C/12 Torr; 1-(chloromethylthio)-3,3-dimethyl-1-butyne, t-BuCCSCH2Cl, bp 70 C/12 Torr; 2-[(chloromethyl)thio]ethynyl(trimethyl)silane, Me3SiCCSCH2Cl, bp 78 C/ 12 Torr; 1-(chloromethylseleno)-1-butyne, EtCCSeCH2Cl, bp 35 C/0.01 Torr. Yields of the sulphides are between 55 and 60%, the selenium compound is obtained in > 70% yield. Thioethers and selenoethers RCCYalkyl can be prepared by a similar procedure using a lesser excess of an alkyl bromide or alkyl iodide.

8.2.7

Reaction of alkynethiolates with acetyl bromide and ethyl chloroformate

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre

8.2

EXPERIMENTAL SECTION

183

8.2.7.1 Procedure [11] (cf. [20]) A suspension or solution of 0.20 mol of alkynyllithium in 140 ml of Et2O and 127 ml of hexane (Chapter 3, exp. 3.9.4) is cooled to –40 C and 6.4 g dry, powdered sulphur is added over 1 min. The cooling bath is removed and the temperature allowed rising to rt. In all cases brown solutions are formed. Stirring at rt is continued for about 1 h until all sulphur has dissolved. The solution is then transferred into the dropping funnel and added over 30 min to a mixture of 0.22 mol of freshly distilled acetyl bromide or 0.25 mol of ethyl chloroformate, and 200 ml of Et2O. During, and for 30 min after this addition, the temperature of the mixture is maintained between –30 and –40 C. The cooling bath is then removed and the temperature allowed rising to 0 C. Ice water (100 ml) is then added with vigorous stirring and cooling at 0 C. The layers are then separated and extraction with Et2O is carried out (Note 1). After drying over MgSO4, the solvent is removed under reduced pressure. The remaining lachrymatory liquid is first distilled at < 0.5 Torr, using a very short column and the distillate collected in a single receiver cooled below –30 C (Figure 1.10). Redistillation through a 20-cm Vigreux column gives the desired products (Note 2). Examples: S-(1-hexynyl)ethanethioate, BuCCSC(¼O)Me, bp 100 C/10 Torr, yield 50%; S-(1-butynyl)O-ethyl)carbonothioate, EtCCSC(¼O)OEt, bp 88 C/10 Torr, yield 55%. Notes 1.

2.

Since the products are water sensitive [12] (BuCCSC(¼O)Me is converted into S-(2-oxohexyl) ethanethiolate, BuC(¼O)CH2SC(¼O)Me), the workup should be carried out without delay. Part of the sulphur is converted into Li2S, while a corresponding part of RCCLi remains in the reaction mixture. With acetyl chloride, MeCOCl, and ethyl chloroformate, ClCOOEt, 3-alkyn-2-ones, RCCCOMe, and ethyl 2-alkynoates, RCCCOOEt, respectively, are formed. Careful distillation is necessary to separate these more volatile by products from the desired compounds. Too strong heating during the distillation should be avoided as the compounds have limited thermal stability.

8.2.8

1-Propynyl trimethylsilyl sulphide from lithium propynethiolate and chloro(trimethyl)silane

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre

184 8.2.8.1

8.

SULPHENYLATION AND RELATED REACTIONS

Procedure [13,14]

A solution of 0.20 mol of lithium propynethiolate is prepared from 6.4 g of dry, powdered sulphur and a suspension of 0.20 mol of propynyllithium (exp. 8.2.6 and Chapter 3, exp. 3.9.4) in 126 ml of hexane and 140 ml of Et2O. The brown solution is added dropwise over 45 min to a mixture of 0.30 mol (excess) of freshly distilled chloro(trimethyl)silane and 100 ml of Et2O (Note 1) cooled between –30 and –40 C. The cooling bath is then removed and the temperature allowed rising to 10–15 C. The solvent and other volatile components are removed under reduced pressure. The bath temperature should not exceed 30 C during this operation. The remaining dark brown liquid is then subjected to vacuum distillation (P < 1 Torr), collecting the volatile product in a single receiver cooled below –50 C (Note 2). Careful redistillation of the contents of the receiver through an efficient column gives the desired product, bp 50 C/12 Torr, in 55% yield (Note 3). Notes 1.

If the addition is carried out in the normal sense, some dimer of the thioketene 2-(trimethylsilyl)-1-propene-1-thione, MeC(SiMe3)¼C¼S, a dithiole derivative, is formed. 2. Since the silyl sulphide is very water-sensitive, all glassware should be dried carefully. 3. In the cases of higher boiling compounds a small amount of paraffin oil should be added prior to the distillation. The oil serves as a heat conductor in the last stage of the distillation, when mainly salt is present in the distillation flask. 8.2.9

Methyl 1-propynyl sulphoxide from propynyllithium and methanesulphinyl chloride

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml 8.2.9.1

Procedure

Methanesulphinyl chloride [15] (0.20 mol) is added over 15 min to a suspension of 0.20 mol of propynyllithium in 150 ml of THF and 126 ml of hexane

8.2

EXPERIMENTAL SECTION

185

(Chapter 3, exp. 3.9.4) with cooling between –60 and –80 C (cooling in a bath with liquid N2 allows a quick addition). Ten minutes after this addition, the reaction mixture is poured into 100 ml of water. After vigorous shaking, the layers are separated and the aqueous layer is extracted ten times with small portions of chloroform. The combined organic solutions are dried over MgSO4, after which the solvent is removed in vacuo. The remaining liquid is distilled at oil pump pressure to give methyl-1-propynyl sulphoxide, bp 70 C/0.5 Torr, in 75% yield. Methylsulphonyl chloride, MeSO2Cl, and 4-methylbenzenesulphonoyl chloride give low to moderate yields of the sulphones RCCSO2Me and RCCSO2–C6H4–4-Me. Part of the sulphonyl chloride reacts with the lithium alkynylide to give a chloroalkyne. A more succesful method to prepare acetylenic sulphones involves oxidation of acetylenic sulphides with peracids (see Chapter 20, Section 20.9). 8.2.10

Di(1-alkynyl) sulphides and di(1-alkynyl) sulphoxides from alkynyllithium and sulphur dichloride or thionyl chloride

Scale: 0.10 molar (SCl2 or SOCl2); Apparatus: Figure 1.1, 500 ml 8.2.10.1

Procedure [4]

Freshly distilled (bp 58–62 C/760 Torr) sulphur dichloride (0.10 mol, diluted with 30 ml of Et2O, cooled to –40 C) or thionyl chloride (0.10 mol, freshly distilled, diluted with 30 ml of Et2O) is added dropwise over 10 to 15 min to a vigorously stirred suspension or solution of 0.20 mol of alkynyllithium (Chapter 3, exp. 3.9.4) in 126 ml of hexane and x ml (Note 1) of Et2O. During this addition, the temperature is kept between –85 and –95 C by occasional cooling in a bath with liquid N2, care being taken that no solid layer of solvent is formed on the bottom of the flask. Ten minutes after the addition, the suspension is poured into y ml (Note 2) of ice water. After vigorous shaking and separation of the layers, the aqueous layer is extracted three times with Et2O (in the case of the sulphide) or three times with dichloromethane (in the case of the sulphoxides).

186

8.

SULPHENYLATION AND RELATED REACTIONS

The organic solutions are dried (without preceding washing) over MgSO4, and then concentrated in vacuo. In the case of the sulphides, the remaining liquid is subjected to a high-vacuum distillation (P < 0.5 Torr) and the distillate collected in a strongly cooled single receiver (Figure 1.10, Note 3). Redistillation gives the following sulphides: di(1-propynyl) sulphide, (MeCC)2S, bp 30 C/ 0.2 Torr, yield 65%; di(1-butynyl) sulphide,(EtCC)2S, bp 45 C/0.2 Torr, yield 70%; bis(3,3-dimethyl-1-butynyl) sulphide, (t-BuCC)2S, bp 50 C/ 0.2 Torr, yield 75%; bis[2-(trimethylsilyl)ethynyl] sulphide, (Me3SiCC)2S, bp 55 C/0.2 Torr, yield 70%. Di(1-propynyl) sulphoxide, (MeCC)2S¼O, mp 69.5–70 C, di(1-butynyl) sulphoxide, (EtCC)2S¼O, (oil, not distilled), and bis(3,3-dimethyl-1-butynyl) sulphoxide, (t-BuCC)2S¼O, mp 47–47.5 C are obtained in 70% yields. The solid compounds are crystallised from a 1:1 mixture of Et2O and pentane. Attempts to prepare the corresponding sulphones from the reaction with sulphuryl chloride failed

Notes 1. x ¼ 200 in the cases of the sulphoxides and 400, 300 and 200, respectively, in the cases of the sulphides R ¼ Me, Et and t-Bu (or Me3Si). When THF is used instead of Et2O, yields of the sulphides R ¼ Me or Et are 30% only. A possible explanation is that the very base-sensitive di(1-alkynyl) sulphides (MeCC)2S and (EtCC)2S are attacked by alkynyllithium. In the more polar THF this attack is more serious than in Et2O while the solubility of RCCLi in Et2O is much less. 2. y ¼ 150 in the case of the sulphides and 50 in the case of the sulphoxides. 3.

The viscous, brown residue may undergo vigorous decomposition. This explains the necessity of a first flash distillation at very low pressure with moderate heating.

8.2.11

Di(1-alkynyl) tellurides from tellurium tetrachloride and lithium acetylides

Scale: 0.05 molar (TeCl4); Apparatus: Figure 1.1, 500 ml

8.2

EXPERIMENTAL SECTION

8.2.11.1

187

Procedure [16]

A cold (–40 C, made immediately before the addition) solution of 0.05 mol of TeCl4 in 40 ml of THF is added quickly with cooling at –25 C to a solution of 0.25 mol (excess) of alkynyllithium (Chapter 3, exp. 3.9.4) in 160 ml of hexane and 100 ml of THF. The light brown solution is heated for 40 min at 45 to 50 C (for R ¼ Me or Et) or 1 h at 60 C (if R ¼ t-Bu and Me3Si), then cooled to 0 C and treated with 200 ml of deoxygenated ice water (tellurium compounds are very air-sensitive). After extraction of the aqueous layer with pentane and drying of the organic solution over magnesium sulphate, the solvents are removed under reduced pressure. Distillation of the remaining liquids through a very short column gives the following compounds: di(1-propynyl) telluride, bp 110 C/15 Torr, mp 50–52 C after crystallisation from pentane, yield 40%; di(1-butynyl) telluride, bp 125 C/15 Torr, yield 55%; di(1-pentynyl) telluride, bp 68 C/0.07 Torr, yield 70%; di(3,3-dimethyl-1-butynyl) telluride, bp 130 C/15 Torr, mp 62–64 C, yield 60%; bis(2-trimethylsilylethynyl) telluride, bp 135 C/15 Torr, yield 60%. 8.2.12

Bis(alkylthio)acetylenes from sodium acetylide and alkyl thiocyanates

Scale: 0.30 molar; Apparatus: Figure 1.1, 1 litre 8.2.12.1

Procedure [17]

Methyl thiocyanate or ethyl thiocyanate (0.30 mol) is added dropwise over 15 min to a solution of 0.30 mol of sodamide in 350 ml of liquid ammonia (Chapter 3, exp. 3.9.1, care should be taken to stop introduction of acetylene as soon as the blue colour of dissolved sodium has vanished). The ammonia is allowed to evaporate (Figure 1.7) or is removed by placing the flask in a bath at 35–40 C. After addition of 300 ml of water extraction with Et2O or pentane is carried out. The organic solution is concentrated under reduced pressure after drying. The bis(alkylthio)acetylenes, R ¼ Me, bp 72/10 Torr, and R ¼ Et, bp 90 C/10 Torr, are obtained in excellent yields. 8.2.13

Bis(alkylthio)acetylenes from lithium chloroacetylide and dialkyl disulphides

188

8.

SULPHENYLATION AND RELATED REACTIONS

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 8.2.13.1

Procedure

A gently (Note) stirred solution of 0.20 mol of lithium amide in 250 ml of liquid ammonia is cooled to –50 C. A mixture of 0.10 mol of 1,2-dichloroethene (mixture of isomers) and 40 ml of Et2O is added dropwise over 10 min while introducing nitrogen (500 ml/min, Note). After an additional 10 min (at –40 C) 0.10 mol of dialkyl disulphide dissolved in 30 ml of Et2O is added dropwise over 15 min without further cooling. After 2 h the thermometeroutlet combination is removed and 20 g of powdered ammonium chloride is added over 10 min. The ammonia is allowed to evaporate (Figure 1.7). After addition of 150 ml of water extraction with Et2O or pentane is carried out. The extracts are dried and concentrated under reduced pressure, after which the products are isolated in high yields by distillation in vacuum (for bp see preceding exp). Note If stirring is carried out vigorously, the solution of LiCCCl may splash against the upper part of the flask and in the necks where it cannot react with the disulphide in the next step. During the aqueous work-up the highly explosive chloroacetylene may be formed from this unconverted LiCCCl. If no inert gas is introduced, moisture and air can enter and as a result small amounts of chloroacetylene will be formed.

REFERENCES 1. L. Brandsma, H. J. T. Bos and J. F. Arens, in Chemistry of Acetylenes (ed. H. G. Viehe). Marcel Dekker, New York, 1969, p. 751. 2. Unpublished observations and results from the author’s laboratory. 3. J. R. Nooi and J. F. Arens, Recl. Trav. Chim., Pays-Bas 80, 244 (1961). 4. W. Verboom, M. Schoufs, J. Meijer, H. D. Verkruijsse and L. Brandsma, Recl. Trav. Chim., Pays-Bas 97, 244 (1978). 5. S. Hoff, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 87, 1179 (1968). 6. X. Creary, J. Am. Chem. Soc. 99, 7632 (1977). 7. A. Haces, E. M. G. A. van Kruchten and W. H. Okamura, Tetrahedron Lett. 23, 2707 (1982). 8. M. Cinquini, S. Colonna and C. J. M. Stirling, J. Chem. Soc., Chem. Comm., 256 (1975). 9. H. J. Backer, Recl. Trav. Chim., Pays -Bas 67, 894 (1948). 10. L. Brandsma, Recl. Trav. Chim., Pays-Bas 83, 307 (1964). 11. H. E. Wijers, P. P. Montijn, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 84, 1284 (1965). 12. W. Drenth and G. H. E. Nieuwdorp, Recl. Trav. Chim., Pays-Bas 88, 307 (1969). 13. R. S. Sukhai, J. Meijer and L. Brandsma, Recl. Trav. Chim., Pays-Bas 96, 179 (1977).

REFERENCES

189

14. S. J. Harris and D. R. M. Walton, J. Chem. Soc., Chem. Comm., 1008 (1976). 15. I. B. Douglass and R. V. Norton, J. Org. Chem. 33, 2104 (1968). 16. R. W. Gedridge, Jr., L. Brandsma, R. A. Nissan, H. D. Verkruijsse, S. Harder, R. L. P. de Jong and C. J. O’Connor, Organometallics 11, 418 (1992). 17. H. D. Verkruijsse and L. Brandsma, Synthesis, 818 (1991). 18. A. A. Petrov, S. I. Radchenko, K. S. Mingaleva, I. G. Savich and V. B. Lebedev, Zh. Obsch. Khim. 34, 1899 (1964). 19. A. A. Petrov, I. A. Maretina and N. A. Pogorzhel’skaya, Zh. Org. Khim. 11, 1757 (1966). 20. R. Raap and R Micetich, Can. J. Chem. 46, 1057 (1968).

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9 Halogenation of Acetylenes

9.1

METHODS FOR THE DIRECT INTRODUCTION OF HALOGEN

The principal methods for the preparation of 1-halogeno-1-acetylenes from the corresponding 1-alkynes are represented in the following equations [1].

A general method for 1-chloro-1-alkynes is the reaction of a metallated acetylene with an arenesulphonyl halide in an organic solvent [1,2]. Sodium alkynylides have been most often used, but it has been shown [13] that also the lithium compounds give satisfactory results. Working with the lithium compounds is more convenient, as their solubility is better. A useful variant of the sulphonyl chloride method is chlorination with N-chlorosuccinimide in organic solvents [5]. 1-Bromo-1-acetylenes can be prepared analogously from lithium alkynylides or alkynyl Grignard reagents and N-bromosuccinimide [6]. A disadvantage of the halosuccinimide method is the very thick suspension of the metal succinimide formed in this reaction. This makes it necessary to use relatively large volumes of solvents. In this respect the bromination with cyanogen bromide is more convenient. In many cases, the free halogens dissolved in a suitable solvent such as Et2O (for Br2 or I2), THF (for I2) or strongly cooled pentane (for Cl2) can be used. Generally, the iodinations give the highest yields, as there is little competition of addition of I2 to the unsaturated system. The halogenations with Cl2, Br2 and I2 are carried out most conveniently with the lithium alkynylides [3,4]. Subsequent addition of Cl2 and Br2 to the triple bond can, in many cases, be 191

192

9.

HALOGENATION OF ACETYLENES

avoided by a sufficiently slow addition of the solution of the halogen to a strongly cooled solution or suspension of the lithiated alkyne in Et2O or THF. 1-Halogeno-1-alkynes are also formed from alkynes and aqueous solutions of hypohalites. In these reactions, alkynylide anions are transient intermediates. The conversions give good results when the acetylene has a relatively low pK (e.g. ArylCCH and RCCCCH) or good solubility in water (e.g. 2-methyl-3-butyn-2-ol, HCCC(Me)2OH). The hypohalite method has found most applications in the synthesis of bromoacetylenes [7,8]. Finally, the peculiar formation of 1-iodo-1-alkynes from iodine and acetylenes with relatively low (<25) pK values in liquid ammonia should be mentioned [9]. The most likely occuring intermediates are acetylide ‘anions’ formed in very low concentrations from the acetylene and the base ammonia. The conversions proceed very slowly and iodination of the lithiated alkynes in the same solvent is undoubtedly a superior method.

9.2

EXPERIMENTAL SECTION

Note: All reactions are carried out under inert gas.

Warnings 1. Especially haloalkynes with a conjugated unsaturated system or heterosubstituents are unstable and may undergo vigorous decomposition upon heating. Even during storage at low temperatures extensive deterioration may occur. It therefore has little sense to prepare large amounts for use over a long period. Structurally simple haloalkynes such as 1-iodo-1-propyne, MeCCI, and 1-bromo-1-butyne, EtCCBr, have been stored for several months at –20 C without deterioration. 2. In view of possible physiological effects, contact with the skin and inhalation of vapours should be avoided.

9.2.1

1-(2-Chloroethynyl)benzene from lithium phenylacetylide and benzenesulphonyl chloride

9.2

EXPERIMENTAL SECTION

193

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml, at a later stage the thermometer is replaced with a reflux condenser.

9.2.1.1 Procedure [13] (cf. [2]) Phenylacetylene (0.20 mol) is added over a few seconds to a mixture of 0.25 mol of (commercially available) lithium amide (Note 1) and 200 ml of THF, then a solution of 1.5 g of t-BuOK in 5 ml of THF (Note 2) is added and the mixture is warmed to 40 C. The mixture is stirred for 30 min at 40–50 C (occasional cooling may be necessary). The evolution of ammonia gradually sets in, while a coarse suspension of PhCCLi solvated by NH3 is formed. The conversion is completed by heating the mixture under reflux for an additional 45 min. The evolution of ammonia has then ceased and the suspension has virtually dissolved (a faint turbidity due to a small amount of PhCCK remains). Traces of dissolved ammonia are removed by distilling off 50 ml of THF from the solution (rotary evaporator). The solution is cooled to –20 C and a mixture of 0.22 mol of benzenesulphonyl chloride and 60 ml of THF is added over 30 min, while keeping the temperature of the mixture between –20 and –10 C. A yellowish-brown, thick suspension is formed. The temperature is subsequently allowed to rise to 15 C. When heat is no longer evolved, the temperature is raised to 35 C and maintained at this level for an additional 15 min. Water (300 ml) is then added with vigorous stirring. After separation of the layers, four to six extractions with pentane are carried out. The combined organic solutions are dried over MgSO4 and subsequently concentrated under reduced pressure (keeping the bath temperature below 35 C, Note 3). The remaining dark liquid is subjected to a careful distillation through a 40-cm Vigreux column. After a small first fraction of phenylacetylene, the chloroalkyne distils and a small viscous residue remains. Redistillation gives 1-(2-chloroethynyl)benzene, bp 64 C/ 15 Torr, in 65% yield. 1-(2-Chloroethynyl)cyclohexene, 1-c-C6H9–CCCl, bp 75 C/15 Torr, is obtained in 70% yield from 1-ethynylcyclohexene , LiNH2 and PhSO2Cl by a similar procedure.

Notes 1. 2. 3.

BuLi in hexane–THF also can be used for the metallation of PhCCH (Chapter 3, exp. 3.9.4). This base is added to activate the amide [10]. When the solvent is distilled off too quickly, lower yields are obtained.

194 9.2.2

9.

HALOGENATION OF ACETYLENES

1-Bromo-1-alkynes from alkynyllithium and bromine

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml A good method for preparing 1-bromo-1-alkynes, RCCBr, in which R represents an alkyl or cycloalkyl group consists of adding bromine to a strongly cooled solution of the lithiated alkyne in Et2O or THF. Yields are generally high. The method is not suitable for the preparation of the volatile 1-bromopropyne because its isolation requires a time-consuming distillation. The bromoalkyne can undergo subsequent addition of bromine. This reaction can be avoided by adding bromine at a sufficiently low rate and low temperature. 9.2.2.1

Procedure

Bromine (0.20 mol, dried by shaking with 96% H2SO4 and subsequent distillation) is added dropwise over 30 min to an efficiently stirred solution of 0.20 mol of the 1-lithiated acetylene in Et2O or Et2O–hexane (prepared from the acetylene and a solution of BuLiLiBr in Et2O or in Et2O–hexane, respectively, Chapter 3, exp. 3.9.4) with cooling below –60 C. The reaction mixture (at low temperatures a salt suspension) is then poured into 500 ml of ice water and the flask rinsed with water and Et2O. After shaking and separation of the layers, two extractions with Et2O are carried out. The combined organic solutions are dried over MgSO4, after which most of the solvent is distilled off at atmospheric pressure (Note 1) under inert gas. The remaining liquid is distilled in vacuo. 1-Bromo-1-butyne, EtCCBr, bp 50 C/200 Torr, 1-bromo-3,3dimethyl-1-butyne, t-BuCCBr, bp 70 C/150 Torr, and 1-bromo-1-hexyne, n-BuCCBr, bp 66 C/50 Torr, are obtained in greater than 70% yields (Note 2). Notes In the case of 1-bromo-1-butyne, EtCCBr, the Et2O (hexane cannot be used as co-solvent) is slowly distilled off through an efficient column. The temperature of the heating bath is raised to 110 C in the last stage of the distillation. 2. A small, high-boiling residue, presumably the addition product of Br2 and the bromoalkyne is left behind.

1.

3,1-Enynes, RCH¼CHCCH, may be brominated by a similar procedure. 1-Bromo-3-hexen-1-yne, EtCH¼CHCCBr (bp 30 C/10 Torr), is obtained

9.2

EXPERIMENTAL SECTION

195

in 65% yield from a mixture of (E)- and (Z)-3-hexen-1-yne, HC CCH¼CHEt. There is a considerable residue. In general, bromination with hypobromite is the preferred method for 1-bromo-3-alken-1-ynes, RCH¼ CHCCBr, and 1-bromo-1,3-diynes, RCCCCBr. For the bromination of enynes and diynes of the types RCH¼CHCH2CCH (4-en-1-ynes) and RCCCH2CCH (1,4-diynes), the reaction of the Grignard derivative with N-bromosuccinimide or cyanogen bromide, BrCN, seems the best method since these conditions involve the least risk of an isomerisation of the skipped system. This method is also recommended for the bromination of hydrocarbons with systems C¼C(CH2)nCCH, having n > 2. 9.2.3

Bromination of acetylenes with aqueous hypobromite

Scale: 0.30 molar; Apparatus: Figure 1.1, 500 ml The bromination with alkali hypobromite in aqueous solution gives good results with (hetero)arylacetylenes, 3,1-enynes, RCH¼CHCCH, and 1,3diynes, RCCCCH; all acetylenes that are more acidic than acetylenes in the aliphatic or cycloaliphatic series with an isolated triple bond. For the conjugated systems the hypobromite method is superior to the reaction of metallated acetylenes with bromine. Various acetylenic alcohols also are brominated smoothly, which can be explained in part by their better solubility in water. Since in the case of primary and secondary ethynyl alcohols, oxidation of the alcohol can occur, the use of an excess of hypobromite should be avoided. The best procedure is dropwise addition of less than an equivalent amount of hypobromite to a mixture of alcohol and water. If the bromoalkyne to be prepared is not too volatile, small amounts of THF or dioxane may be added to effect a better solubility of the alkyne in the aqueous phase. Addition of a co-solvent may be desired also when the starting compound is a solid (e.g. 1-ethynylcyclohexanol).

9.2.3.1 Procedure Bromine (80 g) is added to a vigorously stirred solution of 75 g (excess) of potassium hydroxide in 200 ml of water with cooling between –5 and 0 C. A pale yellow solution is formed. This solution of KOBr should be used without delay.

196

9.

HALOGENATION OF ACETYLENES

4-Bromo-2-methyl-3-butyn-2-ol, BrCCC(Me)2OH, bp 70 C/15 Torr, is obtained in greater than 90% yield by adding 2-methyl-3-butyn-2-ol, HCCC(Me)2OH (0.30 mol), over 15 min to the solution of KOBr (corresponding with a large excess), while keeping the temperature between 10 and 20 C (occasional cooling). After an additional 15 min at rt the mixture (turbid aqueous phase and lower layer) is extracted four times with Et2O. The organic solutions are dried over MgSO4, Et2O is removed under reduced pressure, and the remaining liquid distilled off through a 20-cm Vigreux column. 4-Bromo-3-butyn-2-ol, BrCCCH(Me)OH, (undistilled), is obtained in 85% yield as a viscous liquid after removal of the Et2O from the extracts. Of the KOBr solution 60% (corresponding with 0.3 mol) is added dropwise over 30 min to a mixture of 0.32 mol (slight excess) of 3-butyn-2-ol, HCCCH(Me)OH, and 40 ml of water. During this addition, the temperature of the mixture is kept between 5 and 10 C. After an additional 15 min (at 10 C) four extractions with Et2O are carried out. The organic solutions are dried (without preceding washing) over MgSO4. 1-(2-Bromoethynyl)benzene, PhCCBr, (undistilled), is obtained in almost 100% yield by vigorously agitating during 3 h under N2 a mixture of 0.25 mol of phenylacetylene and the KOBr solution (corresponding to a large excess) described above. The reaction is carried out in a 500-ml flask insulated by cotton wool. The initial temperature is 20 C. After 2.5 h, the nD of the upper layer (interruption of stirring) has become 1.605 and the temperature 31 to 33 C. After stirring for 3 h, the product is isolated by adding 200 ml of ice water and extracting four times with Et2O. The combined organic solutions are dried over MgSO4 and subsequently concentrated in vacuo. Other ArCCBr and 2-(2-bromoethynyl)thiophene, 2-Thienyl-CCBr (bp 50 C/0.06 Torr) can be prepared in a similar way. 1-Bromo-3-hepten-1-yne, n-PrCH¼CHCCBr ((E)/(Z)–mixture), is prepared in a way similar to that described for PhCCBr. After 4 to 5 h, the nD of the upper layer has reached a maximum (1.51). The mixture is then extracted with very small portions of pentane. The combined organic solutions are concentrated in vacuo (bath temperature < 25 C) after drying over MgSO4. The yield of the bromoenyne (undistilled, satisfactory purity) is at least 75%. Distillation (bp 58 C/15 Torr) gives the pure bromoenyne. In the case of bromination of 1,3-diynes, RCCCCH (R¼Me or higher alkyl), the diyne may be diluted with a small amount of pentane (50% v/v) and stirring (at 25–30 C) is continued for a few hours. The reaction can be followed by determining the nD of the mixture of diyne and pentane. Distillation of these bromodiynes seems risky.

9.2 9.2.4

EXPERIMENTAL SECTION

197

1-Bromo-1-propyne and 1-bromo-1-butyne from the 1-alkynes and potassium hypobromite

Scale: 0.30 molar; Apparatus: Figure 1.1, 500 ml 9.2.4.1 Procedure [11] Bromine (75 g) is added over 15 min to an efficiently stirred solution of 70 g of potassium hydroxide in 150 ml of water, while keeping the temperature between 0 and –5 C. High-boiling petroleum ether (30 ml, bp > 170 C) cooled to 0 C is added and the air in the flask is completely replaced by inert gas. After cooling the mixture to 0 C, a cold (–25 C) solution of 0.30 mol of propyne or 1-butyne in 90 ml of petroleum ether is added in four equal portions over 15 min with vigorous stirring. After addition of the last portion the reaction is monitored by measuring the refractive index of the upper layer, stirring being temporarily stopped. The temperature of the reaction mixture gradually rises to rt. Stirring is continued for an additional 30 min, when nD has become maximal. Water (150 ml) is added and the layers are separated. The organic solution is transferred into a 1-litre round-bottomed flask and 10 g of magnesium sulphate is added. After vigorous shaking, the flask is equipped for a vacuum distillation (10 to 20 Torr), the receiver being cooled in a bath at –70 C (Figure 1.10). The flask is evacuated and heated until the petroleum begins to pass over (50 C/10 Torr). Repetition of this operation with the contents of the receiver, now not allowing the petroleum to pass over, gives pure 1-bromo-1-propyne and 1-bromo-1-butyne in high yields. 1-Bromo-1-pentyne and 1-bromo-1-hexyne can be prepared in good yields by stirring the 1-alkynes with an excess of KOBr in water until nD has reached its maximal value. In these cases no solvent is used. The bromination of the higher homologues (exp. 9.2.2) by this procedure proceeds too slowly because of their decreased solubility in the aqueous phase.

9.2.5

Bromination of lithiated acetylenes with cyanogen bromide

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml

198

9.

HALOGENATION OF ACETYLENES

A convenient and quick way to prepare 1-bromo-1-alkynes consists of adding an ethereal solution of cyanogen bromide to a strongly cooled solution of a metallated (Li or MgX) acetylene in an organic solvent (Et2O or THF) [3]. The method seems very general and excellent yields can be obtained provided that the ethereal solution of BrCN (which is prepared from an aqueous solution) is dried well. The advantage of this method over the introduction with elemental bromine is that CC double bonds in enynes do not react. 9.2.5.1

Procedure

A solution of cyanogen bromide in 150 ml of Et2O (Note 1), prepared on a 0.25 molar scale (large excess) from bromine and potassium cyanide is added over 15 min to a solution of 0.10 mol of the lithiated acetylene (Chapter 3, exp. 3.9.4) in 63 ml of hexane and 80 ml of THF (Note 2). During this addition the temperature is maintained between –70 and –50 C. After an additional period of 10–15 min (at –30 to –40 C) water (200 ml) is added with vigorous stirring to the white suspension. After separation of the layers, three extractions with Et2O are carried out. The combined organic solutions are dried over MgSO4, after which the solvent is removed in vacuo (if the volatility of the product allows). The remaining liquid is carefully distilled through a 30-cm Vigreux column. 1-Bromo-1-octyne, bp 90 C/15 Torr, and 1-(2-bromoethynyl)cyclohexene, c-C6H9CCBr, bp 50 C/0.5 Torr, are obtained in 80% yields. Distillation of thermally unstable bromoalkynes, e.g. RCCCCBr, should not be carried out. Notes 1.

The procedure in Organic Synthesis [12], in which the KCN is added over 2 h and the BrCN is isolated by steam distillation, is modified. To a vigorously stirred mixture of 0.25 mol of bromine and 40 ml of water is added over 10 min a solution of 0.25 mol of potassium cyanide in 50 ml of water. During this addition the reaction mixture is cooled between 0 and 10 C. The white suspension of cyanogen bromide is subsequently extracted three times with small portions (total amount 120 ml) of Et2O. The colourless extract is first shaken (without washing) at 0 C with a relatively small amount of potassium carbonate, then decanted and subsequently vigorously shaken (with cooling at 0 to –10 C) with a small portion of phosphorus pentoxide. The solution is decanted from the syrupy mass and shaken with a second small portion of P2O5 (which now remains suspended; if not, the procedure is repeated).

9.2 2.

EXPERIMENTAL SECTION

199

The reaction with cyanogen bromide presumably can also be carried out successfully with RCCLi in Et2O–hexane mixtures or with alkynylmagnesium halides (at higher temperatures) in Et2O or THF.

9.2.6

1-Iodo-1-alkynes from 1-alkynyllithium and iodine in organic solvents

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre 9.2.6.1 Procedure Finely powdered iodine (0.20 mol, the dropping funnel is replaced with a powder funnel) or a saturated solution of 0.20 mol of iodine in Et2O or THF is added over 15 to 30 min to a solution or suspension of 0.20 mol of the 1-alkynyllithium (Chapter 3, exp. 3.9.4) in a mixture of Et2O and hexane or THF and hexane with cooling between –15 and –30 C. After this addition the cooling bath is removed and the temperature is allowed to rise to 0 C (suspensions of RCCLi may react more slowly). Water (200 ml) is then added with vigorous stirring, and, after separation of the layers, the aqueous layer is extracted with Et2O (small amounts of iodine can be removed with an aqueous Na2S2O3 solution). The organic solution is dried over MgSO4 and subsequently concentrated in vacuo, followed by distillation of the remaining liquid. 1-Iodo-1-heptyne, n-BuCCI, bp 60 C/10 Torr, is obtained in > 80% yield. Volatile iodoacetylenes (bp < 40 C/10 Torr) can best be prepared by using Et2O as the only solvent. The lithium alkynylide is generated from the acetylene and BuLi LiBr in Et2O (Chapter 2, exp. 2.3.6 and Chapter 3, exp. 3.9.4). For another useful procedure for volatile iodoacetylenes see below. Acetylenic Grignard derivatives in Et2O or THF also give 1-iodo-1-alkynes upon addition of iodine at –10 to –20 C. 9.2.7

1-Iodo-1-alkynes from 1-alkynyllithium and iodine in liquid ammonia

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre

200

9.

HALOGENATION OF ACETYLENES

In the presence of water, iodine reacts with ammonia to give explosive NI3 as a black precipitate. In anhydrous liquid ammonia at –33 C (or at lower temperatures) practically no conversion takes place, however. This appears most convincingly from the preparation of aryl- or heteroaryl iodoacetylenes in excellent yields by stirring a mixture of equimolar amounts of iodine and the acetylene in liquid ammonia for several hours [9]. For the less acidic alkylacetylenes, this method has no practical significance because very long reaction times are necessary. A much quicker procedure is to add iodine as a solution in Et2O or THF to an ammoniacal solution of the lithium alkynylide, cooled to below –33 C. This reaction is extremely fast and generally gives iodoacetylenes in excellent yields. The volatile 1-iodo-1-propyne, for example, can be prepared by adding an ethereal solution of iodine to a solution of propynyllithium in ammonia cooled to below –60 C

9.2.7.1

Procedure

A solution of 0.20 mol of alkynyllithium in 250 ml of liquid ammonia is prepared as described in Chapter 3, exp. 3.9.3. 1-Propynyllithium and 1-butynyllithium can best be prepared by dropwise addition (over 20 min) of the 1,2dibromoalkanes (0.20 mol, cf. Chapter 3, exp. 3.9.21) to a suspension of an excess of LiNH2 (0.65 mol) in 400 ml of liquid ammonia (Chapter 2, exp. 2.3.1). The solutions in ammonia are cooled to below –60 C (occasional cooling in a bath with liquid N2), while N2 is passed through the flask (0.2 litre/min). A solution of 0.25 mol (excess) of iodine in Et2O ( 300 ml) or THF (250 ml) is then added over 15 min with efficient stirring, while keeping the temperature between –50 and –70 C (for the volatile 1-iodo-1alkynes with bp < 50 C/15 Torr, Et2O should be used). After an additional 15 min (at –50 C), the reaction mixture is cautiously poured onto 500 g of finely crushed ice, contained in a 2 to 3-litre wide-necked conical flask. The reaction flask is rinsed with a small amount of ice water. A solution of 20 g of Na2S2O3 in 150 ml of water is then added to the mixture. After melting of the ice (some warming may be applied) and vigorous shaking, the layers are separated. The aqueous layer is extracted three to five times with small portions of pentane (this gives a better separation than Et2O). The combined organic solvents are dried over MgSO4, after which the greater part of the solvent is removed. In the cases of 1-iodo-1-propyne, MeCCI, 1-iodo-1-butyne, EtCCI and 1-iodo-1-pentyne, n-PrCCI, the Et2O is distilled off at atmospheric pressure through a 40-cm Vigreux column, keeping the bath temperature below 100 C. In the other cases the solvent can be removed using a rotary evaporator. The remaining liquid is carefully distilled through a 40-cm Vigreux column under a reduced pressure, appropriate for the volatility of

9.2

EXPERIMENTAL SECTION

201

the product: 1-Iodo-1-propyne, MeCCI, bp 50 C/100 Torr, and 1-iodo-1heptyne, C5H11CCI, bp 78 C/10 Torr, are obtained in excellent yields. 9.2.8

1-(2-Chloroethynyl)benzene from phenylethynyllithium and chlorine

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml In analogy with the reaction of lithiated acetylenes with bromine, chloroalkynes can be prepared by chlorination of metallated acetylenes at low temperatures with free chlorine. Since the solvents Et2O and THF are readily attacked by chlorine, introduction of gaseous chlorine seems a risky operation. In the procedure for 1-(2-chloroethynyl)benzene, a solution of chlorine in dichloromethane (prepared by diluting liquid chlorine with strongly cooled dichloromethane) is added at a low temperature to a solution of lithium phenylacetylide in Et2O and hexane. Presumably an aliphatic or alicyclic acetylene RCCH (R ¼ alkyl or cycloalkyl) with a sufficiently higher bp than that of hexane, can be chlorinated in a similar way. For chloroalkynes containing double bonds or other chlorine-sensitive groups, the procedure of exp. 9.2.1 seems better. Instead of lithiated acetylenes, Grignard derivatives can be employed. Since chlorine can react with MgBr2 to give free bromine, the acetylenic Grignard derivatives have to be prepared with alkylmagnesium chlorides.

9.2.8.1 Procedure (cf. [4]) A solution of 0.20 mol of lithium phenylacetylide in 126 ml of hexane and 150 ml of Et2O (Chapter 3, exp. 3.9.4) is cooled to below –60 C. A mixture of 0.20 mol of chlorine and 30 ml of dry dichloromethane (prepared just before, by adding the strongly cooled solvent to the liquid chlorine) is added by pouring from the cold trap, over 10 min to the vigorously stirred solution, which is kept below –70 C. Occasional cooling in a bath with liquid N2 allows this quick addition. After an additional 2 min, the mixture is hydrolysed, the layers separated and the organic solution dried over MgSO4. After evaporation of the solvent in vacuo, the remaining liquid is distilled through a 30-cm Vigreux column to give 1-(2-chloroethynyl)benzene in greater than 80% yield (cf. exp. 9.2.1). Since lithium alkynylides that are more strongly basic than

202

9.

HALOGENATION OF ACETYLENES

PhCCLi, react easily with CH2Cl2, it is better to add the chlorine portionwise as a solution in strongly cooled pentane or hexane (<–50 C) in these cases.

REFERENCES 1. S. Y. Delavarenne and H. G. Viehe, in Chemistry of Acetylenes (ed. H. G. Viehe). Marcel Dekker, New York, 1969, p. 651. 2. R. Truchet, Ann. Chim., Paris 16, 309 (1931). 3. F. G. Drakesmith, R. D. Richardson, O. J. Stewart and P. Tarrant, J. Org. Chem. 33, 286 (1968). 4. L. I. Zakharkin, V. V. Gavrilenko and B. A. Paley, J. Organometal. Chem. 21, 269 (1970). 5. W. Verboom, H. Westmijze, L. J. de Noten, P. Vermeer and H. J. T. Bos, Synthesis 296 (1979). 6. C. Burgess, D. Burn, P. Fether, M. Howarth and V. Petrow, Tetrahedron 22, 2829 (1966). 7. F. Strauss, L. Kolleck and W. Heyn, Chem. Ber. 63, 1833 (1930); G. R. Ziegler, C. A. Welch, C. E. Orzech, S. Kikkawa and S. I. Miller, J. Am. Chem. Soc. 85, 1648 (1963). 8. F. Stauss, L. Kolleck and H. Hauptmann, Chem. Ber. 63, 1886 (1930); S. I. Miller, G. R. Ziegler and R. Wieleseck, Org. Synth. 45, 86 (1965). 9. T. H. Vaugn and J. A. Nieuwland, J. Am. Chem. Soc. 55, 2150 (1933). 10. P. Caube`re, Accounts Chem. Res. 7, 301 (1974). 11. L. Brandsma and H. D. Verkruijse, Synthesis 984 (1990). 12. W. W. Hartmann and E. E. Dreger, Org. Synth., Coll. Vol. 2, 150 (1943). 13. Unpublished observations and results from the author’s laboratory.

10 Acetylenes, Allenes and Cumulenes by Elimination Reactions

10.1

SURVEY OF METHODS

Part of Chapter 3 deals with the synthesis of acetylenic and some cumulenic derivatives by 1,1-, 1,2-, 1,4- and 1,6-elimination of hydrogen halide, alcohol or thiol from suitable substrates under the influence of strongly basic alkali amides or alkyllithium. The product in the reaction mixture is a metallated acetylene or cumulene, from which the free acetylene or cumulene can be obtained by addition of a suitable proton donor. The methods in the present chapter, all concerned with elimination reactions, afford the free acetylene, allene or cumulene directly. The following subdivision is made. 10.1.1

1,1-Elimination of hydrogen halide with simultaneous migration of an organic group

The formation of diphenylacetylene [1] by treatment of Ph2C¼CHCl with strong bases has little significance as a preparative method for disubstituted acetylenes. The 1,1-elimination of hydrogen chloride from 2-chloroN,N,N1,N1-tetraalkyl-1,1-ethylenediamines (chloroketene aminals) under the influence of strong bases gives access to the interesting bis(N,N-dialkylamino)acetylenes. Like in the formation of diarylacetylenes, the initial carbenoid loses halide with concomitant migration of a dialkylamino group [2].

203

204 10.1.2

10.

ELIMINATION REACTIONS

Double 1,2-elimination of hydrogen halide from geminal or vicinal dihalogen compounds: RC(Cl2)Me; RCH2CHCl2; RCH(Br)CH2Br or Cl; RCH(Br)CH(Br)R or Cl

Geminal and vicinal dihalogen compounds can be converted into acetylenes by treatment with potassium hydroxide in the presence of a phase-transfer catalyst [3]. Since potassium t-butoxide in DMSO causes rapid isomerisation of 1-alkynes to 2-alkynes under the required conditions, this reagent–solvent system is unsuitable for the preparation of 1-alkynes, HCCCH2R (cf. [4]).

10.1.3

Elimination of hydrogen halide from halo-olefinic compounds

Ethoxyacetylene is readily obtained by warming the (E)/(Z)-mixture of 1-bromo-2-ethoxyethene, BrCH¼CHOEt, with powdered potassium hydroxide. Only the (Z)-isomer, which is usually formed as a major product from 1,2-dibromo-1-ethoxyethane, BrCH2CH(Br)OEt, and N,N-diethylaniline, reacts [5]. Another example is the elimination of hydrogen iodide by heating 1-alkyl-1-iodo-2-nitroethenes, RC(I)¼CHNO2, with KOH [6]. For the preparation of cyclooctyne from 1-bromo-1-cyclooctene, lithium diisopropylamide (LDA) appears to be the base of choice [7].

10.1.4

Tele-eliminations of hydrogen chloride from 1,4-dichloro butene, 1,4-dichlorobutyne and 1,6-dichlorohexadiyne

Vinylacetylene (1-buten-3-yne) is formed by heating (E)-1,2-dichloro-2-butene with aqueous KOH in the presence of a phase-transfer catalyst [8]. The formation of butadiyne [9] from 1,4-dichloro-2-butyne and KOH in a water–DMSO mixture probably proceeds through chlorobutatriene, ClCH¼C¼C¼CH2. This extremely unstable compound can be isolated by

10.1

SURVEY OF METHODS

205

heating dichlorobutyne with powdered KOH in a high vacuum and trapping in a strongly cooled receiver [10]. Hexatriyne can be prepared in a surprisingly high yield by treating 1,6-dichloro-2,4-hexadiyne with potassium t-butoxide in THF at very low temperatures [10]. This highly unstable compound has been obtained as a dilute solution in an organic solvent in moderate yields by the reaction of the dichloride with sodamide in liquid ammonia [11].

10.1.5

Tele-elimination of alcohol or thiol from acetylenic, allenic or cumulenic derivatives

Potassium t-butoxide dissolved in THF eliminates alcohol from N,N-dialkyl-4alkoxy-2-butyn-1-amines, R2NCH2CCCH2OR, with formation of N,Ndialkyl-3-buten-1-yn-1-amines [12]. Two possible pathways are presented.

4-Alkylthio-1-buten-3-ynes, RSCCCH¼CH2, are obtained in an analogous way from the reaction between 1,4-bis(alkylthio)-2-butynes, RSCH2CCCH2SR, and t-BuOK in liquid ammonia [13]. The oxygen analogues 4-alkoxy-1-buten-3-ynes, ROCCCH¼CH2, result from treatment of 1,4-dialkoxy-1,2-butadienes, ROCH¼C¼CHCH2OR, with alkyllithium [10]. Butatrienyl ethers, R2C¼C¼C¼CHOMe, are formed from 1,1-substituted 1-alkoxy-4-methoxy-2-butynes and sodamide in liquid ammonia [14].

The formation of 1-ethoxy-1,5-hexadien-3-yne, H2C¼CHCCCH¼CHOEt, from MeCH¼CHCCCH(OEt)2 and the 1:1 complex t-BuOK–t-BuOH in DMSO may be considered as a result of a 1,6-elimination of ethanol and subsequent base-catalysed isomerisation of the intermediary cumulenic ether 1-ethoxy-1,2,3,5-hexatetraene, H2C¼CHCH¼C¼C¼CHOEt [10].

206 10.1.6

10.

ELIMINATION REACTIONS

1,2- and 1,4-Dehalogenation using zinc powder

Allene, H2C¼C¼CH2, is obtained in a high yield by treatment of 2,3-dichloro1-propene, H2C¼C(Cl)CH2Cl, with zinc powder in ethanol–water mixtures [15]. Di- and trifluoroallenes have also been prepared by this dehalogenation method. Butatriene and some volatile homologues are trapped in strongly cooled receivers by heating 1,4-dichloro-2-butyne, 1,4-dichloro-2-pentyne or 4-chloro1-alkyl-2-butynyl methanesulphinates, ClCH2CCCH(R)OS(¼O)Me, with zinc powder in vacuum [16,17].

10.2

EXPERIMENTAL SECTION

Notes 1. For the preparation of alkali amides in liquid ammonia and alkyllithium reagents see Chapter 2. 2. Reactions in organic solvents or in liquid ammonia at temperatures below its boiling point are generally carried out under inert gas. 10.2.1

3,3-Dimethyl-1-butyne starting from 3,3-dimethyl-1-butene

Scale: 0.20 molar; Apparatus: 1-litre two-necked, round-bottomed flask connected to a 40-cm Vigreux column, condenser and receiver; on the other neck of the flask is placed a dropping funnel

10.2.1.1

Procedure

1,2-Dibromo-3,3-dimethylbutane (0.20 mol, obtained by addition of bromine to a mixture of 0.22 mol of 3,3-dimethyl-1-butene (commercially available) and 75 ml of Et2O at <–40 C, followed by thorough removal of Et2O under reduced pressure) is added over 5–10 min to a solution of 0.50 mol (large excess) of t-BuOK in 140 ml of DMSO. During this addition the flask is gently swirled to effect homogenisation. A vigorous reaction takes place and

10.2

EXPERIMENTAL SECTION

207

part of the t-butylacetylene is collected in the single receiver cooled below –10 C. The flask is heated for 30 min in a bath at 100 C. After cooling to 30 C, the dropping funnel is replaced with a stopper and the apparatus is evacuated (Figure 1.10). Small amounts of dissolved t-butylacetylene condense in the receiver, which is cooled at –70 C. Redistillation of the contents of the receiver gives pure t-butylacetylene, bp 38–40 C, in >70% yield.

10.2.2

Phenylacetylene starting from styrene

Scale: 0.50 molar; Apparatus: 1-litre three-necked, round-bottomed flask, equipped with a dropping funnel, a mechanical stirrer and a thermometeroutlet combination, which for the dehydrohalogenation is replaced with a reflux condenser.

10.2.2.1

Procedure

Freshly distilled styrene (0.50 mol) and dichloromethane (250 ml) are placed in the flask. Bromine ( 0.52 mol, just sufficient to give a persisting brown solution at the end) is added dropwise, while keeping the temperature below –20 C. The equipment is then removed and stoppers are placed on the two outer necks. The solvent is thoroughly removed on a rotary evaporator. The flask is then equipped as indicated above and a solution of 1.5 mol (excess) of sodium ethoxide in 550 ml of absolute ethanol (Note) is added over 15 min to the solid. The temperature rises to 60 C or higher. When the evolution of heat has ceased, the mixture is heated under reflux for an additional period of 3 h. The resulting suspension is then cooled to rt and poured into 2.5 litre of water. Six to eight extractions with small portions of pentane (if Et2O is used, relatively large amounts are needed in the first extractions) are carried out. The combined organic solutions are washed three times with cold dilute hydrochloric acid and subsequently dried over MgSO4. The greater part of the solvent is distilled off at atmospheric pressure. Distillation of the remaining liquid gives phenylacetylene, bp 40 C/15 Torr, in 70% yield. The residue consists mainly of 1-(1-bromovinyl)benzene, PhC(Br)¼CH2. Diphenylacetylene, PhCCPh, can be prepared in an excellent yield from 1-(1,2-dibromo-2-phenylethyl)benzene, PhCHBrCHBrPh, and ethanolic potassium hydroxide.

208

10.

ELIMINATION REACTIONS

Heteroarylacetylenes, e.g. 2-thienyl–CCH, can be prepared from the olefins by a procedure similar to the one described above. Note If 96% ethanol is used, the second elimination of HBr proceeds sluggishly and much PhC(Br)¼CH2 is isolated. 10.2.3

1-Butyne from 1,2-dibromobutane by the phase-transfer method

Scale: 0.50 molar; Apparatus: 2-litre round-bottomed, three-necked flask, equipped with a dropping funnel, a mechanical stirrer and a reflux condenser connected to a cold trap (–78 C); all connections are made gas-tight; a stirrer of the type displayed in Figure 1.2, is used A simple method for the preparation of simple 1-alkynes consists of heating a 1,2-dibromo compound with an excess of powdered potassium hydroxide at 80 C or higher temperatures in the presence of catalytic amounts of tetraoctylammonium halide and pinacol [3]. The alkoxide of pinacol formed with KOH is extracted by the phase-transfer catalyst (p.t.c.) into the organic phase where the double dehydrohalogenation takes place. The elimination can also be carried out with aqueous KOH and the phase-transfer catalyst, but the rate of elimination is then much lower. In the procedures with powdered KOH, an inert solvent is used, e.g. petroleum ether. This has a double function in that it serves as a conductor of heat supplied by the bath, and it ensures sufficient mixing of the halogen compound with the KOH. For less volatile acetylenes, e.g. ethynylbenzene, PhCCH (bp 140 C at atmospheric pressure), a lower-boiling petroleum ether fraction (bp <100 C) should be used, while in the case of volatile acetylenes the halogen compound is diluted with higher boiling solvents. The choice of the solvent depends also on the temperature required for a smooth dehydrohalogenation. For example, 1,1-dichloro-3,3-dimethylbutane, t-BuCH2CHCl2, and 2,2-dichloro-3,3-dimethylbutane, t-BuCCl2Me, are converted only partially at temperatures below 120 C, making a high boiling (bp > 150 C) solvent necessary. For the preparation of ethynylcyclohexane from 1-(2,2-dichloroethyl)cyclohexane, c-C6H11CH2CHCl2, the

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use of paraffin oil might be considered. The solid KOH-phase-transfer method cannot be applied to synthesise thermally less stable acetylenes, e.g. ethoxyacetylene, EtOCCH. Moreover, the starting compound 1,2-dibromo-1-ethoxyethane, EtOCHBrCH2Br, is likely to undergo other reactions. Neither can acetylenes that easily undergo base-catalysed isomerisation reactions be prepared by this method. 10.2.3.1

Procedure

Freshly and finely machine-powdered potassium hydroxide (85% technical grade, 6 mol) and high-boiling petroleum ether (bp > 170 C, 250 ml) are placed in the flask. Methyl trioctylammonium chloride (75% aqueous solution, 7 g) and anhydrous pinacol (7 g) are added with vigorous stirring. The suspension is heated to 90 C (temperature of the oil bath) and 1,2-dibromobutane (0.50 mol, obtained by addition of bromine at < –40 C to a mixture of 1-butene and Et2O followed by thorough removal of this solvent under reduced pressure) is added dropwise over 20 min. A temporary vigorous reflux (presumably a mixture of 2-bromo-1-butene, EtC(Br)¼CH2, and 1-bromo-1butene, EtCH¼CHBr, is formed) is observed. The temperature of the bath is gradually raised over 30 min to 120 C. During this period the intensity of reflux decreases while 1-butyne begins to condense in the cold trap. When the reflux has practically stopped, the temperature of the bath is raised to 140–145 C and kept at this level for an additional 1 h. The dropping funnel is then replaced with a gas inlet tube, reaching to the middle of the flask. Nitrogen (200 ml/min) is then passed through the flask for 10 min. Finally, the trap containing the 1-butyne is connected to another trap cooled at –78 C and then placed in a water bath which is gradually warmed (initial temperature 15 C) to ca. 50 C. Pure 1-butyne is obtained in >70% yield.

10.2.4

3,3-Dimethyl-1-butyne from 1,1-dichloro-3,3-dimethylbutane by the phase-transfer method

Scale: 0.50 molar; Apparatus: 1-litre round-bottomed, three-necked flask, equipped with a dropping funnel, a mechanical stirrer (Figure 1.2) and a 40-cm Vigreux column, connected to a condenser and receiver, cooled in an ice-water bath.

210 10.2.4.1

10.

ELIMINATION REACTIONS

Procedure (for Introduction see exp. 10.2.3)

Freshly machine-powdered KOH (85%, 9 mol) and high-boiling petroleum ether (200 ml, bp > 170 C/760 Torr) are placed in the flask. Stirring is started and the suspension is heated to 130 C (oil bath). Methyl trioctylammonium chloride or tetraoctylammonium chloride (70% aqueous solution, 10 g) and anhydrous pinacol (10 g) are added, followed by 0.50 mol of 1,1-dichloro3,3-dimethylbutane (cf. Chapter 3, exp. 3.9.25, the same procedure as described for other geminal dichlorides is followed). t-Butylacetylene begins to distil out after 15–30 min. The temperature of the bath is gradually raised over 1 h to 155 C and maintained at 160 C for an additional 1 h. When distillation has stopped, the suspension (part of the KOH may form a liquid layer on the bottom of the flask) is allowed to cool. The distillate is redistilled through a 40-cm Vigreux column to give 3,3-dimethyl-1-butyne, bp 38–40 C, in 60% yield. An additional 5–10% yield of the acetylene may be obtained by evacuating the apparatus (after cooling to below 40 C) and collecting the volatile product in a receiver cooled at –78 C (Figure 1.10). Isopropylacetylene (bp 28 C) can be prepared by a similar procedure. 10.2.5

Ethoxyacetylene from 1-bromo-2-ethoxyethene and potassium hydroxide

Scale: 0.50 molar; Apparatus: 1-litre round-bottomed flask connected to a distillation system consisting of a 30-cm Vigreux column, condenser and receiver, cooled at –78 C (Figure 1.10). 10.2.5.1

Procedure

Freshly machine-powdered potassium hydroxide (85% technical grade, 3.0 mol) is placed in the flask. 1-Bromo-2-ethoxyethene (0.50 mol, rich in the (Z)-isomer, Chapter 3, exp. 3.9.23) is added in one portion and the mixture is immediately shaken or swirled (by hand) to form a homogeneous slurry and subsequently connected to the column of the distillation apparatus. The flask is heated in an oil bath at 120 C. A very exothermic reaction starts after a short time and the greater part of the ethoxyacetylene passes over. Fifteen minutes after this distillation has stopped, the system is evacuated (water-aspirator pressure) without external heating. The remainder of the

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ethoxyacetylene and some (E)-1-bromo-2-ethoxyethene condense in the strongly cooled receiver. After warming the receiver to rt, sufficient magnesium sulphate is added in small portions, with shaking, to just form a coagulate with the moisture. The almost clear liquid is decanted from the drying agent and subsequently distilled at normal pressure through a 30-cm Vigreux column. Ethoxyacetylene, bp 52 C/760 Torr, is obtained in excellent yields (calculated on the amount of (Z)-isomer present in the mixture of isomers).

10.2.6

Vinylacetylene from (E)-1,4-dichloro-2-butene by the phase-transfer method

Scale: 0.50 molar (for Apparatus see exp. 10.2.3) 10.2.6.1

Procedure

Freshly machine-powdered KOH (85%, 300 g) and high-boiling petroleum ether (200 ml, bp >150 C) are placed in the flask. Stirring is started and 5 g of methyl trioctylammonium chloride (75% aqueous solution; tetraoctylammonium chloride also may be used) and 5 g of pinacol are added (with temporary removal of the dropping funnel). The mixture is heated for 30 min in an oil bath at 120 C, then 1,4-dichloro-2-butene (E-isomer, 0.50 mol) is added dropwise over 25 min. Nitrogen ( 100 ml/min) is passed through the apparatus. The vinylacetylene condenses in two traps cooled at –78 C. After the addition the temperature of the bath is gradually raised over 30 min to 135 C. Stirring and introduction of N2 ( 100 ml/min) are continued for another 1 h. The traps are successively connected to an empty one (cooled at –78 C) and then placed in a water bath at rt. The temperature of the bath is gradually raised to 50 C. A small amount of 1-chloro-1,3-butadiene may remain in one of the traps. The yield of pure (> 95%) vinylacetylene is usually greater than 70%. Vinylacetylene can also be prepared in high yields by slow addition (over 45 min) of (E)-1,4-dichloro-2-butene (0.45 mol), to a vigorously stirred mixture of 3 g MeNþOct3Cl–, 250 g of KOH and 250 ml of water, heated at 100 C (bath temperature). N2 is slowly (100 ml/min) introduced both during and for 30 min after the addition of dichlorobutene. The contents of the cold traps are then ‘redistilled’ as described above.

212 10.2.7

10.

ELIMINATION REACTIONS

Butadiyne from 1,4-dichloro-2-butyne and KOH in a water–DMSO mixture

Scale: 0.50 molar; Apparatus: 1-litre round-bottomed, three-necked flask, equipped with a combination of dropping funnel and gas inlet tube, an efficient gas-tight mechanical stirrer (Figure 1.2) and a combination of a thermometer and an efficient reflux condenser. The top of the condenser is via two tubes (20 cm long) filled with lumps of CaCl2 connected to two traps cooled at –78 C. Both traps contain 50 g of dry THF (or any other solvent, e.g. MeOH, Et2O; traps þ solvent are weighed). The inlet tube in the traps dips 0.5 cm below the surface of the THF (Note 1). All connections are made gas-tight. 1,4-Dichloro-2-butyne reacts sluggishly with concentrated aqueous KOH at 70 C, because it is slightly soluble in the aqueous phase. If a small amount of the phase-transfer catalyst MeNOct3Cl (Aliquat) is present, however, the double elimination of hydrogen chloride proceeds smoothly at that temperature. Addition of a sufficient amount of DMSO instead of Aliquat causes an increase of the solubility of dichlorobutyne and the effect is similar to that obtained with Aliquat. It seems useful to explain some other experimental conditions. The slow introduction of nitrogen into the apparatus serves to transport butadiyne to the cold traps. A second function of nitrogen is to dilute the gaseous diyne (the estimated bp at 760 Torr is between 10 and 20 C), and thus to diminish the danger of (explosive) decomposition. It seems essential to pass the nitrogen through the aqueous reaction mixture. In this manner, butadiyne is helped to escape from the aqueous phase. The first elimination product is the extremely unstable chlorobutatriene, ClCH¼C¼C¼CH2. A too quick addition of dichlorobutyne results in a too high concentration of this cumulene and consequently in the formation of polymer. If the flow of N2 is too rapid, the volatile cumulene is swept out of the solution and forms a layer of brown polymer in the upper part of the flask and in the condenser. The results obtained with the DMSO–water mixture (yields up to 95%) are markedly better than that obtained with phase-transfer catalysis. In the latter case much amorphous black or brown material is formed, while diacetylene is obtained in yields up to 65% [10]. 10.2.7.1

Procedure [9]

In the flask is dissolved 130 g of 85% KOH in 200 ml of water. DMSO (40 ml) is added. N2 is introduced at a rate of 200 ml/min. The solution is heated up

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to 72 C (internal) and 0.50 mol of 1,4-dichloro-2-butyne (Chapter 20, exp. 20.1.6) is added dropwise over 30 min, while maintaining the temperature between 70 and 75 C. Butadiyne condenses in the THF. After completion of the addition, the brown reaction mixture is brought to 95 C and held at this temperature for an additional 15 min. The total weight increase of the traps corresponds to yields up to 90% (Notes 2 and 3). Notes 1. 2. 3.

If the tube is ending above the level of the THF, some diacetylene may condense as white leaves in the upper, cooled part of the first trap. Lower yields are obtained when dichlorobutyne is added too quickly. The solution can be stored for at least 3 days without deterioration at –20 C in a well-sealed bottle.

10.2.8

Hexatriyne from 1,6-dichloro-2,4-hexadiyne and t-BuOK in tetrahydrofuran

Scale: 0.10 molar; Apparatus: Figure 1.1, 1 litre; stirrer: Figure 1.2 Hexatriyne has been obtained in a moderate yield from the reaction of 2,6dichloro-2,4-hexadiyne with alkali amide in liquid ammonia [11]. The compound is extremely unstable and the crystalline substance, isolated from the organic solution, readily explodes [10]. Generation under conditions similar to those applied for the preparation of butadiyne (exp. 10.2.7) is likely to give only decomposition products. In the procedure described below hexatriyne is obtained in surprisingly high yields. In analogy with the elimination of hydrogen chloride from 1,4-dichloro-2-butyne it may be assumed that the first elimination gives chlorohexapentaene, ClCH¼C¼C¼C¼C¼CH2. This compound probably does not accumulate but undergoes a rapid tele-elimination of HCl to give hexatriyne. Since the elimination reaction is strongly exothermic, it is easy to follow the progress of the reaction. The t-butylalcohol formed in the elimination forms the much less reactive 1:1 complex with t-BuOK, therefore a large excess of base is used. Hexatriyne is expected to be much more ‘acidic’ than acetylene and part of the compound possibly remains in solution (as a ‘complex’ with KOH) when, after addition of water to the reaction mixture, the base is not neutralised. As extraction

214

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ELIMINATION REACTIONS

solvent high-boiling petroleum ether is used. THF and t-butylalcohol are removed by repeated washing of the solution with cold dilute hydrochloric acid. Hexatriyne is subsequently isolated by evacuation while gradually raising the temperature of the petroleum ether solution. Although it is not difficult to collect the compound as a solid in the strongly cooled receiver, it seems safer to put a (weighed) amount of an inert organic solvent with a comparable volatility (e.g. heptane) in the receiver prior to carrying out the evacuation. 10.2.8.1

Procedure

A mixture of 0.10 mol of 1,6-dichloro-2,4-hexadiyne (Chapter 20, exp. 20.1.7) and 150 ml of THF is cooled to –90 C. A solution of 0.40 mol of t-BuOK in 150 ml of THF is added dropwise over 25 min with vigorous stirring and occasional cooling in a bath with liquid N2 to maintain this low temperature. Care should be taken that the THF does not solidify on the bottom of the flask. Should it do so, the addition should be interrupted until the THF has melted. After completion of the addition the mixture is stirred for an additional 30 min at –65 to –70 C. High-boiling petroleum ether (bp > 190 C, 150 ml) is then added to the dark reaction mixture, followed by 200 ml of 2 N hydrochloric acid. The layers are separated as soon as possible (Note 1) and the aqueous layer extracted twice with 30-ml portions of petroleum ether. The combined organic solutions are washed ten to fifteen times with 150-ml portions of cold (–10 C) 2 N HCl in order to remove the THF and t-BuOH thoroughly. After drying for a few minutes over MgSO4, the brown solution is transferred into a 1-litre round-bottomed flask, which is equipped for a vacuum distillation (Figure 1.10). The receiver (250-ml round-bottomed flask) is filled with 50 g of cold (<–50 C) heptane (Note 2), after which this system is evacuated by means of the water aspirator. The extract is gradually warmed until the solvent (bp 70 C/15 Torr) begins to reflux in the top of the column (40-cm Vigreux). During this operation a small amount of petroleum ether co-distils. The evacuation operation is therefore repeated with the contents of the receiver. In the beginning no heating is applied, at a later stage the flask is placed in a bath at 10–15 C. A mixture of hexatriyne and heptane is collected in the pre-weighed receiver (cooled at –78 C). This contains up to 56 g of heptane solution, corresponding to a yield of 85% of hexatriyne.

Notes 1. All operations should be carried out under N2, without delay. 2. If no heptane or other solvent is used, the triyne is collected as a white solid in the receiver, turning violet under the influence of (traces of) oxygen. In

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view of the explosive character of the triyne, we do not recommend its isolation in an undiluted state.

10.2.9

Cyclooctyne from 1-bromo-1-cyclooctene and lithium diisopropylamide

Scale: 0.25 molar (BuLi and diisopropylamine); Apparatus: Figure 1.1, 1 litre Cyclooctyne has been prepared in low yield by dehydrohalogenation of 1-bromo-1-cyclooctene with sodamide in an organic solvent [18]. We have carried out the reaction with sodamide in liquid ammonia and also obtained low yields [10]. Isomerisation to 1,2-cyclooctadiene under the influence of the base probably is a serious subsequent reaction. This allene is a very short-living compound and dimerises, giving rise to a considerable amount of high-boiling residue. Butyllithium is neither suitable as dehydrohalogenating agent, since it adds very smoothly to cyclooctyne. Moreover, interaction between 1-bromocyclooctene and butyllithium gives rise to bromine–lithium exchange. Lithium diisopropylamide generally shows little tendency to attack on bromine or to add across multiple bond systems, but is a potent proton abstractor. In our procedure for cyclooctyne [7], a solution of LDA in THF and hexane is successfully used to convert the readily available 1-bromo1-cyclooctene into cyclooctyne. The subsequent base-induced isomerisation to 1,2-cyclooctadiene can be largely suppressed by using a large excess of 1-bromo-1-cyclooctene. This can easily be separated from cyclooctyne by fractional distillation. Cyclooctyne has a reasonable thermal stability. It can be stored for at least one month at –20 C with only slight polymerisation. 10.2.9.1

Procedure

THF (100 ml) is added to a solution of 0.25 mol of butyllithium in 159 ml of hexane, cooled below –35 C. Subsequently 0.25 mol of diisopropylamine is added with cooling below 0 C. The obtained solution is cooled to –40 C and 0.50 mol of 1-bromo-1-cyclooctene (see below) is added over a few minutes. The temperature of the mixture is allowed to rise over 1.5 h to þ15 C and maintained at this level for an additional 1.5 h. The resulting brown solution is then poured into a mixture of 1 litre of ice water and 30 g of 36% hydrochloric

216

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ELIMINATION REACTIONS

acid. After vigorous shaking, the layers are separated (Note). The organic layer is subsequently washed five times with cold (0 C) 2 N HCl in order to remove most of the THF. The original aqueous layer and the washings are combined and then extracted twice with small portions of pentane. The combined organic solutions are washed with water, dried over MgSO4 and subsequently concentrated in a water-aspirator vacuum (bath temperature not higher than 25 C). Careful distillation of the remaining liquid through an efficient column gives cyclooctyne, bp 48 C/16 Torr, in at least 70% yield. Most of the excess of 1-bromo-1-cyclooctene (bp 85 C/15 Torr) is recovered. There is only a small high-boiling residue. Note Cyclooctyne has a very strong, unpleasant odour. The odour of the aqueous layers disappears upon shaking with a small amount of bromine. 10.2.9.2

Procedure for 1-bromo-1-cyclooctene

Bromine (0.81 mol, slight excess) is added dropwise to a mixture of 250 ml of dichloromethane and 0.80 mol of freshly distilled cyclooctene with cooling between –40 and –60 C. The solvent is thoroughly removed on the rotary evaporator. Et2O (350 ml) is added to the remaining liquid and the solution is cooled to –10 C. A solution of 1.6 mol (excess, Note) of t-BuOK in 160 ml of THF is added over 30 min, while maintaining a temperature of –10 C. After an additional 2.5 h at 0 to 5 C, 500 ml of ice water is added and three extractions with Et2O are carried out. The organic solution is washed twice with saturated aqueous ammonium chloride, dried over magnesium sulphate and then concentrated in a vacuum. Careful distillation of the residue through a 40-cm Vigreux column gives 1-bromo-1-cyclooctene, bp 90 C/18 Torr, in at least 70% yield. The first fraction contains some cyclooctyne. Note The t-BuOH produced in the elimination forms a 1:1 complex with t-BuOK, which is much less reactive. 10.2.10

t-Butylnitroacetylene from 2-iodo-3,3-dimethyl-1-nitro1-butene and potassium hydroxide

10.2

EXPERIMENTAL SECTION

217

Scale: 0.05 molar; Apparatus: 250-ml two-necked (vertical necks!), roundbottomed flask, equipped with an evacuable dropping funnel and a very short ( 5 cm) Vigreux column, connected to a short condenser and a single receiver cooled in a bath at –50 C or lower (cf. Figure 1.10). B24 glass joints should be used. The preparation of the unstable and extremely base-sensitive nitroacetylenes, RCCNO2, from the readily available 2-iodonitroalkenes and solid potassium hydroxide was described in 1969 [6]. 2-Iodo-3,3-dimethyl-1-nitro-1-butene, t-BuC(I)¼CHNO2, reacts smoothly with powdered KOH in Et2O at 20–30 C, but no trace of the nitroalkyne can be isolated. In the original procedure, the vapour of the iodo compound is led over KOH pellets in a tube heated at 100 C. The reaction is carried out at low pressure and the vapour of the nitroalkyne is condensed in a strongly cooled receiver. In this way, the contact time of the nitroalkyne with the base is extremely short. The best results are obtained with the t-butyl derivative, which in fact is the only representative that can be prepared in reasonable yield. The compound is stored best at –20 C or lower temperature as a dilute solution in a (volatile) organic solvent. Distillation of a sample ( 5 g) which had been allowed to stand for 24 h at rt, gave only 70% recovery [10]. Our procedure is a variant of the one published. Although our yields are somewhat lower, the procedure can be completed within 1 h. In the literature procedure, the iodo compound is added over several hours. 10.2.10.1

Procedure (cf. [6])

In the flask are placed 50 g of KOH pellets and 20 ml of dry paraffin oil (this is added for better conduction of the heat from the bath) and in the dropping funnel 0.05 mol of 2-iodo-3,3-dimethyl-1-nitro-1-butene (see below). The apparatus is evacuated by means of a mercury diffusion pump (pressure preferably 0.01 Torr) and the flask is heated in a bath at 100–120 C (at higher bath temperatures the KOH ‘melts’ during the addition of the iodo compound). After heating for 15 min at the temperature indicated, the addition of the iodo compound is started. The reaction is very fast and is accompanied by rather strong foaming. After completion of the addition (over 15 to 20 min), heating and evacuation are continued for an additional 10 min, then nitrogen is admitted. Pentane (50 ml) is added to the contents of the receiver. After warming to rt, the yellow organic solution is separated from the small amount of water and subsequently dried over a small amount of MgSO4. The clear organic solution is decanted from the MgSO4 (which is rinsed with some pentane). The liquid remaining after concentration of the combined pentane solutions in vacuo, is distilled as quickly as possible through

218

10.

ELIMINATION REACTIONS

a 20-cm Vigreux column. t-Butylnitroacetylene bp 50 C/10 Torr, is obtained in yields varying between 50 and 75%. 10.2.10.2 Procedure for 2-iodo-1-nitro-t-butylethene t-Butylacetylene (0.30 mol, exps. 10.2.1 and 10.2.4), dichloromethane (75 ml) and iodine (0.20 mol, 51 g) are placed in the flask. A solution of 0.20 mol (excess) of dinitrogen tetroxide in 50 ml of dichloromethane (Note) is added in 20 equal portions over 1.5 h at 25–30 C. The brown reaction mixture is kept for 30 h at rt, then the excess of N2O4 is removed by evacuation. The remaining brown liquid is dissolved in 100 ml of Et2O and the solution is shaken with 100 ml of an aqueous solution of 20 g of Na2S2O3 in order to remove the excess of iodine. After drying the solution and removing the Et2O under reduced pressure, the remaining yellow liquid is distilled through a short column to give the product, bp 80 C/0.5 Torr, as an (E)/(Z) mixture in 80% yield. Note N2O4 is commercially available in lecture bottles, but presumably can be made by dissolving copper in nitric acid with simultaneous introduction of air. 10.2.11

N1,N1,N2,N2-Tetraalkyl-1-acetylenediamines from 2-chloro-N,N,N1,N1-tetraalkyl-1,1-ethylenediamines and potassium amide

Scale: 0.30 molar; Apparatus: Figure 1.1, 1 litre, no thermometer is used N1,N1,N2,N2-Tetraalkyl-1-acetylenediamines, R2NCCNR2 (R ¼ Me or Et), have been prepared from chloroketene aminals, ClCH¼C(NR2)2, with sodamide in an organic solvent [2]. N1,N1,N2,N2-Tetramethyl-1,2-acetylenediamine, Me2NCCNMe2, was obtained in a one-pot procedure by treating 1,1,3trichloroethylene, Cl2C¼CHCl, with sodamide in liquefied dimethylamine [2]. In our procedure for the N1,N1,N2,N2-tetraalkyl-1-acetylenediamines [19], which is based on the published ones, the 1-chloro-2,2-ethylenediamines are dehydrochlorinated by potassium amide in liquid ammonia. Under these conditions (polar medium, good solubility of the base) the conversions into the ynediamines proceed very smoothly and the work up is simple. After

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evaporation of the ammonia the products are isolated by extraction of the remaining salt mass with dry Et2O. Contact with water must be avoided, since the ynediamines are extremely water-sensitive. 10.2.11.1

Procedure

(Note 1) A solution of 0.35 mol of potassium amide in 350 ml of liquid ammonia is prepared as described in Chapter 2 (it is not necessary to filter the solution of KNH2). The 1-chloro-2,2-ethylenediamine [20] (0.30 mol, see below) is added over 20 min with efficient stirring. The reaction with the methyl derivative is faster than that of the ethyl derivative (difference in solubility). After an additional 10 min, the ammonia is removed by placing the flask in a water bath at 30 C. In the last stage of this operation, 150 ml of a 1:1 mixture of Et2O and pentane is added to the salt slurry (Note 2). Warming is continued until the flow of ammonia vapour has become very faint. After cooling to rt, the supernatant organic solution is carefully decanted from the salt, which is rinsed four times with small portions of the Et2O–pentane mixture. The combined organic solutions are concentrated in a water-aspirator vacuum (in the case of R¼Me, the bath temperature should not exceed 20 C). The remaining liquid is distilled through a 30-cm Vigreux column. N1,N1,N2,N2-Tetramethyl-1-acetylenediamine, bp 40 C/20 Torr (collected in a single receiver, cooled in an ice- water bath, Figure 1.10), and N1,N1,N2,N2-tetraethyl-1-acetylenediamine, bp 78 C/15 Torr, are obtained in > 70% yields.

Notes 1. 2.

The ynediamines are extremely water-sensitive and anhydrous conditions must be maintained throughout the experiments. The salt may contain minute particles of potassium. Cleaning of the flask with water should only be carried out when the organic solvent has completely evaporated or removed by passing a vigorous flow of nitrogen through the flask.

10.2.11.2

a.

Procedure for 2-chloro-N,N,N1,N1-tetraalkyl1,1-ethylenediamines [20]

In a 1-litre three-necked, round-bottomed flask, equipped with a mechanical stirrer and a reflux condenser, is placed a solution of

220

10.

ELIMINATION REACTIONS

1,1,2-trichloroethene (0.20 mol) in Et2O (120 ml). The solution is cooled to 90 C and a suspension or solution of lithium dialkylamide [prepared in a separate flask by addition at –40 C of BuLi (0.20 mol) in hexane (126 ml) to a mixture of the amine (0.20 mol) and Et2O (l00 ml)] is added over 5 min. During this addition, the temperature of the reaction mixture containing dichloroacetylene is maintained below –70 C by occasional cooling in a bath with liquid nitrogen. Subsequently, the dialkylamine (0.40 mol) is added and the contents of the flask are warmed to 30 C using a water bath. After stirring the suspension for 30 min at this temperature, it is cooled to 20 C and then subjected to suction filtration (G-2 sintered-glass funnel covered with a thin layer of anhydrous potassium carbonate). The solid on the filter is rinsed well with dry Et2O. The filtrate is concentrated in vacuo, using a water bath at 25–30 C. Subsequent distillation of the remaining liquid gives the compounds ClCH¼C(Cl)NR2, R ¼ Me, bp 30 C/15 Torr, and R ¼ Et, bp 30 C/0.5 Torr, in 70–80% yields. In view of the sensitivity of these compounds towards oxygen and moisture, the appropriate techniques are applied during their isolation. The compounds should be stored in well-closed bottles at low temperatures. b. A mixture of ClCH¼C(Cl)NR2, R ¼ Et (0.20 mol) and diethylamine (0.30 mol) is placed in a 250-ml three-necked, round-bottomed flask, provided with a nitrogen inlet, a mechanical stirrer and a reflux condenser. The mixture is heated under reflux while salt separates from the solution. An additional amount of diethylamine (0.30 mol) is added in three equal portions over 1 h. After an additional 5 to 6 h the mixture is cooled to rt and Et2O (50 ml) is added. Suction filtration through a sintered-glass funnel, followed by concentration of the filtrate in vacuo and distillation gives 2-chloro-N,N,N1,N1-tetraethyl-1,1-ethylenediamine [20], ClCH¼C[NEt2]2, bp 55 C/0.3 Torr, in 80% yield.

10.2.11.3 Preparation of 2-chloro-N,N,N1,N1-tetramethyl1,1-ethylenediamine [20], ClCH¼C[NMe2]2 1. From ClCH¼C(Cl)NMe2 In a 500-ml three-necked, round-bottomed flask provided with a nitrogen inlet, a thermometer, a mechanical stirrer and a gas outlet, is placed a solution of ClCH¼C(Cl)NMe2 (0.20 mol) in dry Et2O (50 ml). The solution is cooled to –10 C and a suspension or solution of lithium dimethylamide (0.22 mol) in Et2O and hexane, prepared as described above, is added over 5 min.

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EXPERIMENTAL SECTION

221

Subsequently, liquefied dimethylamine (0.40 mol) is added, and the mixture is warmed to 30 C. This temperature is maintained for an additional 6 h. After cooling, the contents of the flask to rt, the salt mass is filtered off on a G-3 sintered-glass funnel and rinsed with dry Et2O. Concentration of the filtrate in vacuo followed by distillation affords 2-chloro-N,N,N1,N1-tetramethyl-1,1ethylenediamine, bp 50 C/10 Torr, in 70–75% yield. 2.

From trichloroethene, sodamide and dimethylamine

In a 3-litre round-bottomed flask is placed 1 litre of anhydrous liquid ammonia. After adding ferric nitrate hydrate (100 mg), the flask is swirled manually and sodium (3 g) is introduced in 0.5-g pieces. After the blue colour of the dissolved sodium has disappeared and a grey solution has formed, further sodium (43 g) is introduced (total amount 2.0 mol). The flask is swirled occasionally. After all sodium has converted into amide, the flask is placed in a water bath at 40 C in order to remove the excess of ammonia. The last traces of ammonia are removed by evacuation (water aspirator). The solid is scratched from the glass wall by means of a curved spatula, after which the flask is again evacuated. During this operation the flask is shaken vigorously in order to break down the lumps of sodamide. The powder is transferred to a 1-litre three-necked, round-bottomed flask, provided with a mechanical stirrer, a dropping funnel combined with a gas inlet and a dry-ice condenser filled with acetone and solid carbon dioxide (a so-called cold finger). Anhydrous liquefied dimethylamine (240 ml) is placed in the flask and a slow stream of nitrogen is passed through the apparatus. 1,1,2Trichloroethene (0.30 mol) is added dropwise over 10 min with stirring at a moderate rate, care being taken that the suspension is not swept into the upper part of the flask. The dropping funnel is then replaced with a combination of a thermometer and a gas inlet. The temperature indicates 6–7 C just after all trichloroethene has been added. The rate of the reflux from the condenser increases gradually, while the temperature of the mixture drops (ammonia liberated in the initial reaction escapes from the solution, condenses and returns with a temperature of ca –78 C). After 1 to 1.5 h the temperature of the mixture has reached a minimum of –11 C. Stirring is continued for another 2.5 h, then a 1:1 mixture of dry Et2O and pentane (400 ml) is added, the cold finger is removed and the flask is placed in a water bath at 45 C. A gas outlet is placed on the flask. When the volume of the mixture has decreased to 350 ml, the solid material is filtered off on a sintered-glass funnel and rinsed well with dry Et2O. Paraffin oil (50 ml) is then added to the brown solution and the solvent is removed by evacuation, using a water bath at 30–35 C (the bulk of the solvent may first be removed on the rotary evaporator). Subsequently, the product is distilled from the

222

10.

ELIMINATION REACTIONS

paraffin oil at a pressure lower than 0.5 Torr, using a 20 to 30-cm Vigreux column. The product, which is collected in a single receiver cooled at –70 C (Figure 1.10), is carefully redistilled (bp 50 C/10 Torr) through a 40-cm Vigreux column. The yield is 70%.

10.2.12

4-Ethoxy-1-buten-3-yne from 1,4-diethoxy-1,2-butadiene and butyllithium

Scale: 0.20 molar; Apparatus: 500-ml flask, Figure 1.1 10.2.12.1 Procedure [10] To a solution of 0.20 mol of 1,4-diethoxy-1,2-butadiene (see Chapter 17, exp. 17.2.11) in 50 ml of dry Et2O is added with cooling at –60 to –70 C a solution of 0.20 mol of butyllithium (Chapter 2, exp. 2.3.6, Note 1) in 250 ml of Et2O. The addition takes 30–40 min. The temperature of the reaction mixture is then allowed to rise gradually to –20 C over 30 min, after which the brown reaction mixture is poured into 200 ml of water. After shaking, the upper layer is separated and the aqueous layer is extracted four times with small portions of Et2O. The combined ethereal solutions are washed with water and dried over magnesium sulphate. The greater part of the Et2O is distilled off at normal pressure through a 40-cm Vigreux column, keeping the bath temperature below 65 C (Note 2). The distillation flask is then cooled to 20–30 C and the remaining Et2O is removed in a water-aspirator vacuum, keeping the receiver immersed in a bath at –10 C (Figure 1.10). The volatile 4ethoxy-1-buten-3-yne passes over between 20 and 35 C/12 Torr, and is obtained in 65% yield. A smal1 amount ( 5%) of ethoxybutatriene, EtOCH¼C¼C¼CH2, may be present.

Notes 1.

Butyllithium in hexane cannot be used since separation of the volatile enyne ether from the hexane would result in serious losses of product. 2. At higher temperatures some of the product might decompose into ethene and vinylketene.

10.2

EXPERIMENTAL SECTION

10.2.13

223

N,N-Dimethyl-3-buten-1-yn-1-amine from N,N-dimethyl-4methoxy-2-butyn-1-amine and t-BuOK

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml

10.2.13.1

Procedure

A solution of 0.40 mol of t-BuOK(100 mol% excess) in 75 g of dry THF is heated at 50 C. N,N-Dimethyl-4-methoxy-2-butyn-1-amine (0.20 mol, Chapter 13, exp. 13.2.3) is added in one portion. The temperature rises in a few minutes to 60 C or higher and a thick precipitate is formed. The thermometer and outlet are replaced with a reflux condenser and the mixture is heated under reflux for 30 min. It is then cooled to 30 C and 100 ml of dry, redistilled pentane is added. The solid material is filtered off on a sintered-glass funnel and, after some pressing, rinsed with pentane. The pentane and the greater part of the THF and t-BuOH are distilled off from the filtrate through a 40-cm Vigreux column (bath temperature not higher than 110 C) in a slow stream of nitrogen. When the distillation has stopped, the residue in the distillation flask is cooled to 30–40 C and the distillation is continued at 40 Torr, using an efficient column. After THF and t-BuOH have distilled, N,Ndimethyl-3-buten-1-yn-1-amine passes over between 45 and 55 C. The yield is at least 70%. N,N-Diethyl-3-buten-1-yn-1-amine, H2C¼CHCCNEt2, bp 49 C/15 Torr, is obtained in 75% yield by heating a 2:1 molar mixture of t-BuOK and N,N-diethyl-4-methoxy-2-butyn-1-amine (Chapter 13, exp. 13.2.3) in THF under reflux for 30 min and subsequently carrying out the dry work-up described above.

Note Aqueous work-up and extraction with Et2O also can be carried out but will take longer. In the proposed procedure, the distilled reaction product is collected in a cooled receiver. Without cooling the required pressure of 10–15 Torr cannot be attained because of the presence of volatile components in the reaction mixture.

224

10.

10.2.14

ELIMINATION REACTIONS

4-Methylthio-1-buten-3-yne from 1,4-bis(methylthio)-2butyne and t-BuOK

Scale: 0.20 molar (dichlorobutyne); Apparatus: Figure 1.1, 1 litre, no dropping funnel; stirrer Figure 1.2. 10.2.14.1 Procedure In the flask is placed 500 ml of liquid ammonia. Sodium (0.42 mol) is introduced in 1-g pieces. After 15 min (Note 1), 0.20 mol of dimethyl disulphide (commercially available) is introduced in 1- or 2-ml portions by means of a pipette or syringe. During the addition, which is carried out over 20 min (vigorous reaction) the mixture is stirred vigorously. The temperature of the reaction mixture is kept between –35 and –45 C. After completion of the addition the blue colour should have disappeared completely (if not, a few more drops of dimethyl disulphide are added). 1,4-Dichloro-2-butyne (0.20 mol) (Chapter 20, exp. 20.1.6) is then added over 15 min with vigorous stirring and cooling between –35 and –45 C. After 10 min, 0.30 mol of powdered t-BuOK is introduced very rapidly (within 3 min) with vigorous stirring (Note 2). Three minutes later, 75 g of finely crushed ice is added within 1 min (Note 2). The greater part of the ammonia is then removed by placing the flask for 30 min in a water bath at 50 C. To the remaining mixture are added 300 ml of ice water, then five extractions with redistilled pentane are carried out. The combined extracts are washed three times with water and dried over magnesium sulphate. The greater part of the pentane is distilled off at normal pressure through a 40-cm Vigreux column. The remaining liquid is distilled through the same column to give 4-methylthio-1-buten-3-yne, bp 34 C/Torr, in 75% yield. Notes 1.

If the sodium is not allowed to dissolve completely, the pieces of sodium may be covered with sodium methanethiolate during the addition of dimethyl disulphide and it takes at least 1 h for all of the sodium to be converted.

10.2 2.

EXPERIMENTAL SECTION

225

The potassium methanethiolate formed in the elimination readily adds to the enyne sulphide and rapid working is therefore necessary. Addition of ice prior to the work-up causes inactivation of the potassium methanethiolate by solvation.

10.2.15

Propadiene from 2,3-dichloro-1-propene and zinc in ethanol

Scale: 1.0 molar; Apparatus: 1-litre three-necked round-bottomed flask with a dropping funnel, a gas-tight mechanical stirrer and a very efficient condenser. The top of the condenser is connected to a cold trap (–80 C). 10.2.15.1

Procedure

In the flask are placed 120 g of powdered zinc (Merck), 250 ml of 96% ethanol and 40 ml of water, in the dropping funnel 1.0 mol of 2.3-dichloro-1-propene (commercially available). The mixture is stirred at a rate such that the zinc powder is suspended completely. After heating the mixture up to 80 C (gentle refluxing of the ethanol), the bath is removed and dropwise addition of the dichloride is started. The addition, which is carried out at a rate such that the ethanol gently refluxes, takes 1.5 h. The conversion is completed by heating the mixture under reflux for an additional 30 min. The trap is connected to an empty one cooled at –80 C and is subsequently placed in a water bath at 5 C. When the greater part of the allene has evaporated and the evolution of gaseous allene has subsided, the bath temperature is increased to 35 C. The remaining mixture of ethanol and dichloropropene is discarded. The yield of pure propadiene is 85%.

Note Allene has a bp of –34.5 C. Because of the high volatility, precise weighing of amounts for small-scale procedures (0.05–0.10 mol) is difficult. It is therefore better to prepare a stock solution by adding a sufficient amount (50–100 g) of the pre-cooled (–50 C) reaction solvent (mostly THF) to a fixed amount of allene (e.g. 0.50 mol). The required amount of allene can be obtained by weighing part of the solution.

226 10.2.16

10.

ELIMINATION REACTIONS

Butatriene from 1,4-dichloro-2-butyne and zinc in dimethylsulphoxide

Scale: 0.20 molar; Apparatus: 1-litre flask with a dropping funnel, a gastight mechanical stirrer and a very efficient reflux condenser; the top of the condenser is connected with a trap. A tube containing anhydrous CaCl2 is placed between the trap and the water aspirator. The connection with the trap is made in such a way that the cumulene vapour can enter the large annular space (the long inner tube being connected to the water aspirator) of the trap.

10.2.16.1 Procedure The flask is charged with 70 ml of dry DMSO, 35 g of zinc powder and 10 g of sodium iodide. In the dropping funnel is placed 0.20 mol of 1,4-dichloro-2butyne (Chapter 20, exp. 20.1.6). After the system has been evacuated to 10–20 Torr, stirring is started and the flask is heated until the DMSO begins to reflux. The trap is immersed in liquid nitrogen and the dichlorobutyne is added over 15 min from the dropping funnel. The reaction is vigorous and occasional cooling may be necessary in order to moderate refluxing. After the addition, heating under reflux (occasional heating) is continued for 20 min. Nitrogen is then admitted and the trap containing the solid butatriene is placed in a bath with dry ice and acetone. The yield of pure butatriene is generally higher than 90%. The compound should be used directly after its preparation. If diluted with an inert organic solvent it can be stored for 12–24 h at –80 C under nitrogen. If the undiluted compound is warmed to 0 C, it may explode violently.

10.2.17

1,2,3-Pentatriene from 1,4-dichloro-2-pentyne and zinc in dimethylsulphoxide

REFERENCES

227

Scale: 0.20 molar; Apparatus: 500-ml three-necked, round-bottomed flask, provided with a dropping funnel, a gas-tight mechanical stirrer and an efficient reflux condenser. A trap is placed between the condenser and the water aspirator in such a way that during the reaction the vapour of the product enters the large annular space of the trap. A drying tube is placed between the trap and the water aspirator. 10.2.17.1

Procedure

In the flask are placed 70 ml of dry DMSO, 40 g of powdered zinc and 8 g of sodium iodide, and in the dropping funnel 0.20 mol of 1,4-dichloro-2-pentyne (Chapter 20, exp. 20.1.6). The system is evacuated by means of the water aspirator and the trap is then placed in liquid nitrogen. The flask is heated until the DMSO begins to reflux in the lower part of the condenser. The heating bath is removed and the dichloride is added dropwise over 10 min (Note 1). After the addition, the mixture is heated for 45 min under gentle reflux. Pure nitrogen is then admitted and the trap is placed in a bath at –75 C. The NMR spectrum (Note 2) shows the product to be reasonably pure. Traces of DMSO (swept along with the cumulene) are sometimes present. The increase in weight of the trap corresponds to a yield of 70%. The cumulene polymerises completely within a few hours at rt, but can be stored without change at –80 C under nitrogen for 12–24 h. Notes 1.

2.

The heat developed by the reaction is just enough to cause gentle refluxing, provided that the mixture is not stirred too vigorously. If refluxing stops during the addition, external heating must be applied. Traces of oxygen will induce polymerisation of the cumulene. The NMR tube must therefore be filled with nitrogen before bringing the sample in it. Low-temperature NMR gives the most representative results.

REFERENCES 1. P. Fritsch, W. P. Buttenberg and H. Wiechell, Liebigs Ann. Chem. 279, 319, 324, 337 (1894). 2. S. Y. Delavarenne and H. G. Viehe, Chem. Ber. 103, 1209 (1970); L. Rene´, Z. Janousek and H. G. Viehe, Synthesis 645 (1982). 3. E. V. Dehmlov and R. Thieser, Tetrahedron 3569 (1986). 4. J. A. P. Thyman, Synth. Commun. 5, 21 (1975). 5. J. F. Arens, in Advances in Organic Chemistry, Methods and Results Interscience Publ., New York, 1962, Vol. 2, 117.

228 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

10.

ELIMINATION REACTIONS

V. Ja¨ger and H. G. Viehe, Angew. Chem., Int. Edn. 9, 273 (1969). L. Brandsma and H. D. Verkruijsse, Synthesis 290 (1978). H. D. Verkruijsse and L. Brandsma, Synth. Commun. 20, 3355 (1990). H. D. Verkruijsse and L. Brandsma, Synth. Commun. 21, 657 (1991). Unpublished observations and results from the author’s laboratory. F. Bohlmann, Chem. Ber. 86, 657 (1953); J. B. Armitage, C. L. Cook, E. R. H. Jones and M. C. Whiting, J. Chem. Soc. 2010 (1952). W. Verboom, R. H. Everhardus, H. J. T. Bos and L. Brandsma, Recl. Trav. Chim., Pays-Bas 98, 508 (1979). R. H. Everhardus and L. Brandsma, Synthesis 359 (1978). P. P. Montijn, J. H. van Boom, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 86, 115 (1967). H. N. Cripps and E. F. Kiefer, Org. Synth. 42, 12 (1962). P. P. Montijn, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 86, 126 (1987); M. Maurer, H. Hopf, Angew. Chem. 99, 687 (1976). H. Kleijn, H. Westmijze, A. Schaap, H. J. T. Bos and P. Vermeer, Recl. Trav. Chim., Pays-Bas 86, 129 (1987). G. Wittig and H.-L. Dorsch, Liebigs Ann. Chem. 711, 46 (1968). L. Brandsma and H. D. Verkruijsse, Synth. Commun. 21, 811 (1991). R. van der Heiden and L. Brandsma, Synthesis 76 (1987).

11 Cumulenes by Dehalogenation of Geminal Dihalogenocyclopropanes

11.1

INTRODUCTION

A wide variety of allenic and cumulenic derivatives, including cyclic ones, can be synthesised by addition of dihalocarbene to an olefinic compound and subsequent treatment of the geminal dihalocyclopropane with a reducing reagent. As such zinc, magnesium, sodium, NaEt3BH, a copper(0) isonitrile complex, Grignard reagents, chromium(II) chloride and alkyllithium reagents have been used. The latter are generally employed. For literature the reader of this book is referred to monographs [1,2] and reviews [3–9]. The generally accepted course of the reaction between geminal dihalocyclopropanes and alkyllithium involves a sequence of halogen/lithium exchange, elimination of lithium halide from the intermediary carbenoid and rupture of the cyclopropane ring in the transient carbene with formation of two cumulated double bonds.

If suitably positioned functionalities are present in the cyclopropane derivative, the carbene may undergo an insertion into a C–H bond (e.g. in the case of –CH2–O–CCH2Me) or add to a double bond (of (C)nCH¼C) resulting in the formation of exotic bi- and polycyclic structures as by or main products.

229

230

11. 11.2

11.2.1

CUMULENES BY DEHALOGENATION

EXPERIMENTAL SECTION

Synthesis of [1-(2,3-butadienyl)benzene]

Scale: 0.20 molar (last step); Apparatus: Figure 1.1, 500 ml

11.2.1.1

Procedure for allylbenzene

To a refluxing solution of phenylmagnesium bromide in 650 ml of Et2O, prepared from 1.15 mol of bromobenzene, is added 1.00 mol of allyl bromide at a rate such that refluxing is maintained (about 30 min). Thirty minutes after refluxing has stopped, a trace of copper(I) bromide is added in order to complete the conversion. The reaction mixture is cautiously poured on to 500 g of finely crushed ice, then 200 ml of 4 N hydrochloric acid is added. After the remaining ice has melted, the layers are separated and the aqueous layer is extracted three times with Et2O. The combined ethereal solutions are washed with saturated NaCl solution and dried over magnesium sulphate. The greater part of the Et2O is distilled off at normal pressure through a 40-cm Vigreux column. Distillation of the residue gives allylbenzene, bp 44 C/15 Torr, in 90% yield.

11.2.1.2

Procedure for 1-[(2,2-dibromocyclopropyl)methyl]benzene

To a solution of 250 g of NaOH in 275 ml of water is added at rt 0.5 g of triethylbenzyl ammonium chloride (TEBA), 5 ml of ethanol, 0.50 mol of allylbenzene and 1.00 mol of bromoform and the mixture is vigorously stirred. The temperature rises to about 45 C in 10–15 min and is kept at that level by occasional cooling. Stirring is continued for 10 h at rt after the exothermic reaction has subsided. After addition of 1 litre of ice water, the product is extracted with Et2O (for the first extraction a sufficient amount has to be used to obtain an upper layer). The combined ethereal solutions are washed with water and dried over magnesium sulphate. After the Et2O has been

11.2

EXPERIMENTAL SECTION

231

removed by evaporation in a water-aspirator vacuum, the residue is subjected to a high-vacuum distillation (0.5 Torr), keeping the temperature of the heating bath below 100 C. The residue remaining after the unconverted bromoform has been distilled off (bp <60 C/0.1–0.5 Torr) weighs 120 g and consists of the reasonably pure cyclopropane derivative.

11.2.1.3

Procedure for 4-phenyl-1,2-butadiene

Of the crude adduct, 65 g (corresponding to 0.20 mol plus an excess) is dissolved in 175 ml of dry Et2O. A solution of 0.20 mol of BuLi in 126 ml of hexane is added dropwise over 30 min, while maintaining the temperature at –60 C. After the addition, the temperature is allowed to rise to –25 C and stirring at that level is continued for an additional 30 min. The mixture is then poured with swirling into 1 litre of ice water. The upper layer and two extracts of the aqueous layer are combined and dried over magnesium sulphate. The solvents are removed in a water-aspirator vacuum. Distillation of the residue gives 4-phenyl-1,2-butadiene, bp 75 C/15 Torr, in >80% yield.

11.2.2

Cyclonona-1,2-diene

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml

11.2.2.1

Procedure

A mixture of 0.20 mol of 9,9-dibromobicyclo[6.1.0]nonane (procedure similar to preceding experiment) and 250 ml of dry Et2O is cooled to –65 C. A solution of 0.21 mol of BuLi LiBr in 200 ml of Et2O (Chapter 2, exp. 2.3.6) or 0.21 mol of (commercial) BuLi in 133 ml of hexane is added over 15 min with cooling between –60 and –50 C. After the addition, the cooling bath is removed, the temperature is allowed to rise to –10 C and the reaction mixture is poured into 200 ml of ice water. The aqueous layer is extracted twice with Et2O. After drying, the solvent is removed under reduced pressure and the remaining liquid is distilled through a 40-cm Vigreux column. 1,2-Cyclononadiene, bp 62 C/22 Torr, is obtained in >80% yield.

232 11.2.3

11.

CUMULENES BY DEHALOGENATION

1,2,3-Cyclodecatriene

Scale: 0.05 molar (last step); Apparatus: 250-ml three-necked flask, equipped with a gas inlet, a thermometer and an outlet; magnetic stirring; addition by syringe 11.2.3.1

Procedure for 10,10-dichlorobicyclo[7.1.0]-1-decene

To 75 ml of a 50% aqueous solution of KOH are added 0.25 mol of chloroform, 0.2 g of triethylbenzyl ammonium chloride (TEBA) and 0.10 mol of freshly distilled 1,2-cyclononadiene (see preceding exp.). The mixture is stirred vigorously for 10–12 h at rt. Water (200 ml) is then added and the product is extracted with Et2O. The extract is dried over magnesium sulphate, concentrated under reduced pressure and the residue is distilled through a short Vigreux column. The dichlorocyclopropane derivative, bp 80 C/0.15 Torr, is obtained in 75% yield. 11.2.3.2

Procedure for 1,2,3-cyclodecatriene

A solution of 0.06 mol of BuLi LiBr (Chapter 2, exp. 2.3.6) in 50 ml of Et2O is added in 15 min to a solution of 0.05 mol of 10,10-dichlorobicyclo[7.1.0]1-decene in 40 ml of Et2O. After this addition, carried out at –55 C, the temperature is allowed to rise to –25 C. The colour of the mixture changes from light yellow to green. After addition of 50 ml of a saturated ammonium chloride solution (Note) and shaking, the layers are separated and the upper layer is dried over magnesium sulphate. The aqueous layer is extracted twice with Et2O or pentane and the combined solutions are concentrated under reduced pressure. The last traces of solvent are removed in a high vacuum. During this operation the bath temperature is kept at 10 C. The residue (yield > 90%) consists of reasonably pure 1,2,3-cyclodecatriene (1H NMR). Attempted distillation results in polymerisation. Note Cumulenes are extremely air-sensitive. All operations during the work-up must be carried out under nitrogen.

11.2

EXPERIMENTAL SECTION

11.2.4

233

Tetramethylbutatriene

Apparatus: Ketene generator (500 ml distillation flask) [10] for the preparation of tetramethylallene; for the addition of dichlorocarbene a 1-litre roundbottomed, three-necked flask, provided with a mechanical stirrer, a thermometer and an outlet; for the dechlorination a 500-ml flask (Figure 1.1) 11.2.4.1

Preparation of 2,4-dimethyl-2,3-pentadiene

The ketene generator is connected to two cold traps (–80 C). Between the traps and the water aspirator is placed a tube filled with calcium chloride lumps. In the distillation flask is placed 1.0 mol of the commercially available 3,3-dimethyl-4-(1-methylethylidene)-2-oxetanone. After evacuation of the apparatus (10–20 Torr) the flask is heated in a bath at 95–105 C and the voltage is adjusted ( 50 V) so that complete decomposition of the lactone vapour occurs (no reflux). After 60–80 min, the electrical heating of the glowing spiral is terminated and the heating bath is removed. After the generator has cooled, nitrogen is admitted and the contents of the traps are distilled under normal pressure. 2,4-Dimethyl-2,3-pentadiene, bp 86 C/760 Torr, is obtained in 80% yield. The residue in the reaction flask of the ketene apparatus consists mainly of starting compound. 11.2.4.2

Addition of dichlorocarbene to 2,4-dimethyl-2,3-pentadiene

To 250 ml of a 50% aqueous solution of KOH is added 0.45 mol of tetramethylallene, 0.90 mol of chloroform and 0.10 g of triethylbenzylammonium chloride and the mixture is agitated vigorously without external cooling. After 4 h the mixture is cooled to rt and 200 ml of ice water is added. After extraction with Et2O and drying of the light yellow solution over magnesium sulphate, the solvent is removed under reduced pressure. Distillation (Note 1) gives 1,2-dichloro-2,2-dimethyl-3-(1-methylethylidene)cyclopropane, bp 59 C/Torr, in 80% yield.

234 11.2.4.3

11.

CUMULENES BY DEHALOGENATION

Preparation of 2,5-dimethyl-2,3,4-hexatriene

A solution of 0.10 mol of 1,2-dichloro-2,2-dimethyl-3-(1-methylethylidene)cyclopropane in 130 ml of dry Et2O is cooled to –35 C. A solution of 0.12 mol of BuLi in 76 ml of hexane is added dropwise over 30 min, while maintaining the temperature of the reaction mixture close to –30 C. After this addition the cooling bath is removed, the temperature is allowed to rise to –10 C and a concentrated aqueous solution (50 ml) of ammonium chloride is added with vigorous stirring. The upper layer is separated and dried (without washing) over magnesium sulphate. The volatile components are removed under reduced pressure, keeping the bath temperature below 20 C. The residue is distilled through a short column and collected in a single receiver cooled at 0 C. Tetramethylbutatriene passes over at 40 C/18 Torr. It solidifies in the receiver. The yields vary from 60 to 80% (Note 2). Notes 1. 2.

In view of strong foaming, a 500-ml distillation flask should be used. Traces of oxygen cause polymerisation of the cumulene. All operations must be carried out under nitrogen. 3. Under pure nitrogen at 80 C the compound can be kept unchanged for several days.

REFERENCES 1. 2. 3. 4. 5. 6. 7.

T. F. Rudledge, Acetylenes and Allenes. Reinhold Book Corp., New York, 1969, p. 4. H. F. Schuster and G. M. Coppola, Allenes in Organic Synthesis. John Wiley, New York, 1984. M. V. Mavrov and V. F. Kucherov, Russ. Chem. Revs. 36, 233 (1967). D. R. Taylor, Chem. Revs. 67, 317 (1967). M. Bertrand, Bull. Soc. Chim. France, 3044 (1968). R. Rossi and P. Diversi, Synthesis, 25 (1973). H. Hopf, in The Chemistry of Ketenes, Allenes and Related Compounds (ed. S. Patai). WileyInterscience, New York, 1980, p. 779. 8. J.-L. Moreau in the same volume. 9. M. Murray, in Houben-Weyl, Methoden der Organischen Chemie, Band 5/2a. Thieme-Verlag, Stuttgart, 1977. 10. L. F. Fieser and M. Fieser, in Reagents for Organic Synthesis, Vol. 1, John Wiley and Sons, New York, 1967, p. 529.

12 Acetylenic and Allenic Derivatives by Substitution on sp- and sp2-Carbon

12.1

NUCLEOPHILIC 1,1-SUBSTITUTION ON sp-CARBON

1-Alkynyl ethers, RCCOEt, react with lithium dialkylamides, LiNR12 , to afford yneamines, RCCNR12 , in good yields [1]. This substitution is probably not a direct one (as generalised by equation (1)), but the result of an addition of the dialkylamide group across the triple bond and subsequent elimination of ethoxide from the adduct as visualised in the general scheme (2). In this scheme S represents the dialkylamide group and L the OEt substituent.

Strong evidence for this mechanism is obtained by heating 1-alkynyl ethers, RCCOEt, with R1CCLi in dioxane for 12 h at 100 C. In addition to the substitution product RCCCCR1, appreciable amounts of the adduct (E)-RCH¼C(OEt)CCR1 are formed. Lengthening of the reaction time gives exclusively the diyne. Using t-butyllithium it is possible to prepare t-butyl-substituted acetylenes [2]. The above-mentioned yneamines can also be prepared from 1-chloro-1alkynes and lithium dialkylamides, but in analogy with the formation of the adducts 1-chloro-2-alkylthioalkenes, RS(R1)C¼CHCl, from 1-chloro1-alkynes, R1CCCl, and thiolate RS–, the reaction may proceed through a b-adduct, which loses chloride with simultaneous migration of the 235

236

12.

ACETYLENIC AND ALLENIC DERIVATIVES

N,N-dialkylamino group [3,4]:

As an excellent alternative to the preparation from alkynyllithium and the poisonous cyanogen chloride [5] alkynenitriles, RCCCN, are accessible by reaction of 1-bromo-1-alkynes, RCCBr, with copper(I) cyanide in THF in the presence of a small amount of anhydrous lithium bromide, which solubilises the copper cyanide. 2,3-Alkadienenitriles, RCH¼C ¼CHCN, similarly are obtainable by reaction between the corresponding allenic nitriles and copper(I) cyanide (see Chapter 20 for these substitution reactions).

12.2

NUCLEOPHILIC 1,3-SUBSTITUTION ON sp- AND sp2-CARBON

The impressive number of nucleophilic substitution reactions with acetylenic, allenic and cumulenic derivatives may be considered to proceed as indicated by the general equations (3), (4) and (5).

These equations, in general, give only the overall results of the interactions. In a number of cases there is clear evidence for an addition-elimination mechanism [6]. It has been shown that transition metal salts, e.g. iron salts, considerably facilitate the formation of allenic compounds from Grignard reagents and acetylenic halides or ethers [7–9]. The leaving group L in the

12.3

ELECTROPHILIC 1,3-SUBSTITUTIONS

237

equations may represent halide [7,10], tosylate [11], acetate [12], sulphinate [13], an ether [9] or epoxide function [14,15]. Some reactions are carried out with pre-formed organocopper reagents. The formation of allenic alcohols by reaction of lithium alanate with an acetylenic alcohol bearing a suitable leaving group on the other side of the triple bond proceeds in the absence of any catalyst:

Table 12.1 gives several examples of nucleophilic and electrophilic 1,3-substitutions. In the experimental section a number of representative procedures are given (indicated with * in this table).

12.3

ELECTROPHILIC 1,3-SUBSTITUTIONS 0

Electrophilic 1,3-substitutions (SE ) of acetylenic and allenic derivatives may be represented by the generalised equations (6) and (7), respectively.

In this scheme M mostly represents a metal (e.g. ZnHlg, SnR3, SiR3) and the electrophile Eþ can be a proton [16–18] (from an alcohol HOR), an acyl group (from ClC(¼O)R), a sulphonyl group [19] (from RSO2Cl) or halogen (e.g. from I2) [20]. Synthetically useful examples are the reduction of acetylenic halides with a zinc–copper couple in alcohols [18,21] (as a variant acetylenic acetates may be used [22]) or with lithium alanate [23–25] and the formation of alkyl propargyl ketones by reaction of the readily available allenyl tributyltin with acid chlorides [38].

238

12.

ACETYLENIC AND ALLENIC DERIVATIVES Table 12.1

1,3-Substitutions with acetylenic, allenic and cumulenic derivatives Reactants, catalyst (additive)

Conditionsa,b

HCCCH2OMe, n-BuMgCl, CuBr* HCCCH2Cl, t-BuMgCl, CuBr* HCCCH2OMe, c-C6H11MgCl, CuBr HCCCH2OMe, PhMgBr, CuBr HCCCH(Cl)Me, MeMgBr, CuBr EtCCCH2OMe, PhMgBr, CuBr t-BuCCCH2OTs, t-BuMgCl, CuBr MeCCCH2OTs, PhCu, (MgBr2)* HCCCH(Ph)OSOMe, PhCu, (MgBr2)d

Et2O, –5 ! rt

n-BuCH¼C¼CH2

THF, –15 ! rt

t-BuCH¼C¼CH2

Et2O, –5 ! rt

c-C6H11CH¼C¼CH2

Et2O, –5 ! rt

PhCH¼C¼CH2

THF, –20 ! 0

MeCH¼C¼CHMec

Et2O, reflux

Et(Ph)C¼C¼CH2

THF, 0 ! rt

(t-Bu)2C¼C¼CH2

THF, –10

Me(Ph)C¼C¼CH2

THF, –40 þ 30

PhCH¼C¼CHPh

Product

THF, –10

H2C¼C(Me)CCCH2OMe, EtMgBr, CuBr Et2NCH2CCCH2OMe, MeMgBr, CuBr HCCCH(OEt)2,n-BuMgCl, CuBr* HCCCH(OEt)2, t-BuMgCl, CuBr MeCCCH(OEt)2, EtMgBr, CuBr 2-THP–CCH, EtMgBr, CuBre,* Me3SiCCCH2OSOMe, n-BuCu, LiBrd,* H2C¼C¼CHOMe, c-C5H9MgCl, CuBr* H2C¼C¼CHOMe, PhMgBr, CuBr H2C¼C¼CHOMe, p-FC6H4MgBr, CuBr

Et2O, rt

H2C¼C(Me)C(Et)¼C¼CH2

Et2O, reflux

Et2NCH2(Me)C¼C¼CH2

Et2O, 0 þ 30

n-BuCH¼C¼CHOEt

Et2O, reflux

t-BuCH¼C¼CHOEt

Et2O, rt þ 30

Me(Et)C¼C¼CHOEt

Et2O, rt þ 30

EtCH¼C¼CH(CH2)4OH

THF, –50 ! 0

Me3Si(n-Bu)C¼C¼CH2

Et2O, 0 ! rt

c-C5H9CH2CCH

Et2O, 0 ! rt

PhCH2CCH

Et2O, 0 ! rt

p-FC6H4CH2CCH (Continued)

12.3

ELECTROPHILIC 1,3-SUBSTITUTIONS

239

Table 12.1 Continued Reactants, catalyst (additive)

Conditionsa,b

BuCH¼C¼CHOEt, n-BuMgBr, CuBr EtOCH¼C¼C¼CHOEt, MeMgBr, CuBr HCCCH(Me)OTs, CuCH2COOBut, (LiBr) HCCCH(Me)OTs, CuCH2CN, (LiBr)*

Et2O, reflux

(n-Bu)2CHCCH

Et2O, rt þ 90

EtOCH¼C(Me)CCH

THF, –30! –10

ButOOCCH2CH¼C¼CHMe

THF, –30! rt

NCCH2CH¼C¼CHMe

THF, 25

Me(Ph)C¼C¼C(Me)CH2OH

H2O, 55 H2O, EtOH, 70

NCCH¼C¼CH2f NCCH¼C¼CHMe

HCCCH2Br, KCN, CuCN HCCCH(Me)Br, KCN, CuCN* HCCCH(Me)Cl, CuCl, (LiCl) HCCCH(Ph)Cl, CuCl, (LiCl)* HCCCH2Br, CuBr, (LiBr)* HCCCH(C6H13)Br, CuBr, (LiBr)* HCCCH(Me)OH, HBr, CuBr, (NH4Br)* HCCC(Me)2OH, HBr, CuBr, (NH4Br)* HCCCH(Ph)OH, HBr, CuBr, (NH4Br)* HCCCH(Ph)OH, HI, CuI, (NH4I)* HCCCH(Me)OH, (PhO)3P þ MeI* HCCCH(Me)OH, HI, CuI, (NH4I)* HCCC(Cl)Me2, PhSLi, CuBr, (LiBr) ClCH2CCCH2OH, LiAlH4* Me2C(OR)CCCH2OH, LiAlH4h,*

Product

THF, reflux ! 87 ClCH¼C¼CHMeg THF, 40 þ 45

ClCH¼C¼CHPh

THF, reflux, 3 h

BrCH¼C¼CH2

THF, reflux, 3 h

BrCH¼C¼CHC6H13

H2O, rt þ 18 h

BrCH¼C¼CHMe

H2O, 40 þ 15

BrCH¼C¼CMe2

H2O, 0 þ 2 h

BrCH¼C¼CHPh

H2O, 0 þ 1 h

ICH¼C¼CHPh

DMF, 100 þ 30

ICH¼C¼CHMe

H2O, 0 þ 1 h

ICH¼C¼CHMe

THF, reflux, 15

PhSCH¼C¼CMe2

Et2O, reflux, 30

H2C¼C¼CHCH2OH

Et2O, reflux, 1 h

Me2C¼C¼CHCH2OH (Continued)

240

12.

ACETYLENIC AND ALLENIC DERIVATIVES Table 12.1 Continued

Reactants, catalyst (additive)

Conditionsa,b

Product

HCCCH2OH, HCCCH2Cl, CuCl* HCCCH(Me)Cl, Zn/Cu* HCCC(Me)2Cl, Zn/Cu*

H2O, MeOH

HOCH2CCCH¼C¼CH2

EtOH, heat EtOH, heat EtOH, heat

H2C¼C¼CHMe H2C¼C¼C(Me)2

hexanol, heat

H2C¼C¼CHCH¼CHMe

heat

HCCCH2C(¼O)Me

HCCCH¼CHCH(Me)Br, Zn/Cu* Bu3SnCH¼C¼CH2, MeC(¼O)Cl, ZnCl2*

Meaning of *: procedure is described in this chapter. a Experiments carried out and checked in the author’s laboratory. b For more details see Experimental Section; temperatures in C; reaction time in minutes or hours. c Ratio of MeCH¼C¼CHMe/Me2CHCCH 70:30, separation by fractional distillation. d OSO ¼ sulphinate group; introduced by reaction of the corresponding alcohol with MeS(¼O)Cl in the presence of Et3N. e 2-THP ¼ 2-tetrahydropyranyl. f Initially, a mixture of the acetylenic and allenic nitriles might have formed; the acetylenic nitrile isomerises under the influence of KCN. g 15% of the starting compound was present; separation by fractional distillation. h R ¼ OCH(Me)OEt.

12.4

EXPERIMENTAL SECTION 12.4

241

EXPERIMENTAL SECTION

Note In most of the procedures the reaction mixture is kept under inert gas.

12.4.1

N,N-dialkylaminoalkynes from 1-alkynyl ethers and lithium dialkylamides

Scale: 0.30 molar; Apparatus: Figure 1.1, 500 ml, see further below 12.4.1.1

Procedure

The dialkylamine (0.31 mol) is added to a solution of 0.30 mol of BuLi in 270 ml of Et2O (prepared from butyl bromide and lithium, Chapter 2, exp. 2.3.6) with cooling below 0 C. The 1-alkynyl ether (0.30 mol, Chapter 4, exp. 4.5.7) is subsequently added in one portion at 0 C. The mechanical stirrer is then replaced with a magnetic stirring bar and the flask is equipped for a distillation, using a 40-cm Vigreux column. The Et2O is slowly distilled off over 2 h while a slow stream of N2 is passed through the apparatus. The temperature of the heating bath is gradually raised to 100–110 C. Then most of the ether has distilled off. After heating for an additional half an hour at this temperature, the reaction mixture is allowed to cool to rt. The Vigreux column is replaced with a much shorter (10 cm) one and two stoppers are placed on the flask (Note 1). The receiver is placed in a bath at –78 C (Figure 1.10) and a tube filled with KOH pellets is placed between the receiver and the water aspirator. The system is evacuated and the temperature of the heating bath gradually raised to 200 C (Note 2). When the distillation has stopped completely, nitrogen is admitted. The contents of the receiver are carefully redistilled through an efficient column. The following compounds have been obtained in yields between 60 and 70%: N,N-diethyl-1-butyn-1-amine, EtCCNEt2, bp 42 C/10 Torr; N,Ndipropyl-1-butyn-1-amine, EtCCNn-Pr2, bp 65 C/10 Torr; 1-(1-butynyl)piperidine, EtCC-piperidine, bp 73 C/10 Torr; N,N-diethyl-1-pentyn1-amine, n-PrCCNEt2, bp 56 C/10 Torr; N,N-diethyl-1-hexyn-1-amine, n-BuCCNEt2, bp 71 C/10 Torr.

242

12.

ACETYLENIC AND ALLENIC DERIVATIVES

Notes 1. 2.

Distillation at oil-pump pressure may be more effective. In the final stage of the distillation, hot oil may be poured on the column by means of a spoon. In this way as much as possible of the product is forced to pass over.

12.4.2

1-(N,N-Dimethylamino)-2-phenylacetylene from 1-chloro-2-phenylacetylene and lithium dimethylamide

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml; at a later stage the thermometer-outlet combination is replaced with a reflux condenser

12.4.2.1

Procedure

Liquefied dimethylamine (0.12 mol) is mixed with 50 ml of dry Et2O, cooled to –40 C. The solution is added to a solution of 0.10 mol of BuLi LiBr in 120 ml of Et2O (Chapter 2, exp. 2.3.6) with cooling between –20 and –40 C. Subsequently 0.10 mol of 1-(2-chloroethynyl)benzene (Chapter 9, exp. 9.2.1) is added dropwise over 15 min with cooling between –15 and –20 C. After the addition, the cooling bath is removed and the temperature is allowed rising. At rt a weakly exothermic reaction can be observed. The dark brown mixture is then heated for 1 h under reflux. After cooling to rt, the salt is filtered off on a (dry) sintered-glass funnel and rinsed well with dry Et2O. The solution is concentrated in vacuo, 5 ml of paraffin oil is added (to conduct the heat supplied by the oil bath during the distillation) and the product is distilled in a high vacuum (mercury diffusion pump) through a 5 to 10-cm Vigreux column. The product is collected in a (single) receiver, cooled in a bath at a temperature of –20 C or lower (Figure 1.10). During the distillation the temperature of the heating bath is gradually raised to 150 C. Redistillation of the contents of the receiver gives N,N-dimethyl-2-phenyl-1-acetylenamine, bp 107 C/10 Torr, in at least 60% yield. 2-(1-Cyclohexenyl)-N,N-diethyl-1-acetylenamine, 1-cyclohexenylCCNEt2, is obtained in 40% yield from the corresponding chloroenyne and LiNEt2 by a similar procedure.

12.4

EXPERIMENTAL SECTION

12.4.3

243

1,2-Heptadiene from methyl propargyl ether and n-butylmagnesium chloride

Scale: 0.40 molar; Apparatus: Figure 1.1, 1 litre 12.4.3.1

Procedure [8]

To a mixture of 0.40 mol of freshly distilled 3-methoxy-1-propyne (Chapter 20, exp. 20.6.1 ) and 80 ml of dry Et2O is added 1 g of finely powdered copper(I) bromide. A solution of butylmagnesium chloride (Note) in 250 ml of Et2O (prepared from 0.60 mol of BuCl, Chapter 2, exp. 2.3.7) is added with vigorous stirring and efficient cooling, so that the temperature of the reaction mixture can easily be kept between 0 and –10 C. The addition takes 30 min. The cooling bath is then removed, a small additional amount ( 0.5 g) of CuBr is added, after which stirring is continued for a further 30 min. The greyish suspension is cautiously poured with manual swirling on to a mixture of 200 g of finely crushed ice, 20 g of ammonium chloride and 100 ml of 36% hydrochloric acid in a 2-litre conical flask. The remaining salt mass in the reaction flask is treated with dilute (2N) hydrochloric acid. After separation of the layers, the aqueous layer is extracted four times with small portions of Et2O and the combined ethereal solutions are dried over magnesium sulphate. Careful distillation through an efficient column gives 1,2-heptadiene, bp 105 C/760 Torr. The remaining liquid is distilled in a partial vacuum (60–100 Torr, bp 40–70 C) and the distillate is redistilled at normal pressure to gives an additional amount of 1,2-heptadiene, bringing the yield to >70%. Closely similar procedures (cf. Table 12.1) can be followed for the reactions between 3-methoxy-1-propyne, HCCCH2OMe, and c-C6H11MgCl or PhMgBr; between 1-methoxy-2-pentyne, EtCCCH2OMe, or PhMgBr; between EtMgBr and 5-methoxy-2-methyl-1-pentene-3-yne; between H2C¼C(Me)CCCH2OMe and t-BuMgCl or 1,1-dimethyl-2-pentynyl4-methylbenzenesulphonate, t-BuCCCH2Otosyl; between N,N-diethyl1-methoxy-2-butyn-1-amine, Et2NCH2CCCH2OMe and MeMgBr. If the volatility of the products allows, the extract may be concentrated under reduced pressure. Note Butylmagnesium bromide can also be used, but the yield is lower ( 65%) due to the inactivation of the CuBr in a later stage of the reaction by the MeOMgBr slurry. Moreover, this makes efficient mixing of the reagents difficult.

244

12.

12.4.4

ACETYLENIC AND ALLENIC DERIVATIVES

t-Butylallene from propargyl chloride and t-butylmagnesium chloride

Scale: 0.50 molar; Apparatus: Figure 1.1, 1 litre 12.4.4.1

Procedure

A mixture of 50 ml of dry THF, 0.50 mol of propargyl chloride and 2 g of copper(I) bromide is cooled to –40 C. A solution of 0.60 mol of t-BuMgCl (Chapter 2, exp. 2.3.8) in 300 ml of THF is added from the dropping funnel over 1 h. The temperature of the reaction mixture is initially kept between –20 and –15 C, but precipitation of large amounts of salt makes it necessary to increase the temperature gradually to 0–10 C. Stirring then becomes more efficient (Note 1). After the addition of the Grignard solution stirring is continued for an additional 30 min, then the mixture is poured into 500 ml of ice-cold 3 N hydrochloric acid. High-boiling petroleum ether (150 ml, bp >170 C at normal pressure) is added and, after vigorous shaking, the layers are separated. The organic layer is shaken at least ten times with 150-ml portions of 3 N HCl in order to remove the THF. The combined aqueous layers are extracted once with 50 ml of petroleum ether and the upper layer is freed from THF by shaking five times with 50-ml portions of 3 N HC1. The combined petroleum ether solutions are dried over a small amount of magnesium sulphate, then the solution is decanted from the magnesium sulphate and poured into a 1-litre round-bottomed flask. After adding some boiling stones, the flask is connected to a 40-cm Vigreux column, condenser a receiver cooled at –70 C and the system is evacuated (10–20 Torr) the flask being heated in a water bath (Figure 1.10). The volatile allene condenses in the receiver. The ‘distillation’ is stopped when the temperature in the top of the column has reached 55–60 C. Redistillation of the contents of the receiver through an efficient column gives 4,4-dimethyl-1,2-pentadiene, bp 79–82 C/ 760 Torr, in 80% yield (Note 2).

Notes 1. 2.

If the reaction mixture becomes too thick, more THF should be added. In order to minimise the hold-up, a partial vacuum ( 100 Torr) may be applied during the last stage of the distillation; the fraction obtained in this way can be redistilled at normal pressure in a small apparatus.

12.4

EXPERIMENTAL SECTION

12.4.5

245

1-Ethoxy-1,2-heptadiene from 3,3-diethoxy-1-propyne and butylmagnesium chloride

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 12.4.5.1

Procedure [9]

To a mixture of 0.10 mol of 3,3-diethoxy-1-propyne (Chapter 3, exp. 3.9.21) and 150 ml of dry Et2O is added 0.7 g of finely powdered copper (I) bromide. The mixture is cooled to –30 C and from the dropping funnel is added over 20 min a solution of n-BuMgCl in 100 ml of Et2O, prepared from 0.12 mol of butyl chloride (Chapter 2, exp. 2.3.7). During the first 10 min the temperature is kept at –30 C. The remainder of the Grignard solution is added at a somewhat higher temperature (–10 C to rt) since stirring becomes more difficult at –30 C. A thick suspension of ethoxymagnesium chloride is formed. After stirring for an additional 30 min at 0 C, the mixture is hydrolysed by cautious addition of and solution of 3 g of KCN and 10 g of NH4Cl in 50 ml of ice water. During this operation, carried out with vigorous stirring, the flask is cooled in a bath with ice water. After separating the layers, three extractions with Et2O are carried out. The combined ethereal solutions are washed with a saturated ammonium chloride solution and dried over potassium carbonate. The Et2O is removed under reduced pressure. Careful distillation of the remaining liquid through an efficient column gives 1-ethoxy-1,2-heptadiene, bp 63 C/15 Torr, in 80% yield. A similar procedure is applicable for the reaction between 3,3-diethyoxy1-propyne and t-BuMgCl or the reaction between 1,1-diethoxy-2-butyne, MeCCCH(OEt)2, and EtMgBr (cf. Table 12.1).

12.4.6

1-(2-Propynyl)cyclopentane from cyclopentylmagnesium chloride and methoxyallene

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml

246 12.4.6.1

12.

ACETYLENIC AND ALLENIC DERIVATIVES

Procedure [26]

A solution of 0.20 mol of cyclopentylmagnesium chloride in 130 ml of Et2O, prepared from 0.25 mol of cyclopentyl chloride (cf. Chapter 2, exp. 2.3.7) is added over 30 min to a mixture of 0.20 mol of freshly distilled methoxyallene (Chapter 17, exp. 17.2.8), 150 ml of Et2O and 0.5 g of finely powdered copper(I) bromide. During this addition the temperature of the reaction mixture is kept between –5 and þ5 C by cooling in a bath of dry ice and acetone. A white suspension is formed. After the addition, the cooling bath is removed and stirring is continued for a further 45 min, then the reaction mixture is poured cautiously into 200 ml of ice water (some cooling may be necessary). After dissolution of the solid material a small amount of 4 N HCl is added, so that the layers become clear. The aqueous layer is extracted three times with small portions of Et2O. The combined extracts are washed with concentrated ammonium chloride solution and subsequently dried over magnesium sulphate. The greater part of the Et2O is distilled off at normal pressure through a 40-cm Vigreux column. The remaining liquid is distilled and collected in a single receiver, cooled at 0 C. 1-(2-Propynyl)cyclopentane, bp 30 C/20 Torr, is obtained in a high yield. Closely similar procedures can be followed for the preparation of: 1-(3butynyl)benzene, PhCH2CCH, from PhMgBr and methoxyallene; of 1ethoxy-4,4-dimethyl-1,2-pentadiene, t-BuCH¼C¼CHOEt, from t-BuMgCl and HCCCH(OEt)2; of 3-butyl-1-heptyne, (n-Bu)2CHCCH, from 1ethoxy-1,2-heptadiene, n-BuCH¼C¼CHOEt, and n-BuMgBr; of 1-ethoxy-2methyl-1-buten-3-yne, HCCC(Me)¼CHOEt, from 1,4-diethoxybutatriene, EtOCH¼C¼C¼CHOEt, and MeMgBr (Table 12.1). 12.4.7

Reaction of an acetylenic sulphinate with alkylcopper

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 12.4.7.1

Procedure [27]

To a solution of 0.10 mol of butylmagnesium bromide in 200 ml of THF, prepared from 0.12 mol of butyl bromide, a solution of 0.12 mol of dry copper(I) bromide and 0.12 mol of anhydrous lithium bromide in 50 ml of dry THF is added with cooling between –50 and –60 C. After an additional

12.4

EXPERIMENTAL SECTION

247

30 min at –50 C a solution of 0.10 mol of O-[3-(trimethylsilyl)-2-propynyl] methanesulphinothioate, prepared from 0.10 mol of 3-trimethylsilyl2-propyn-1-ol, Me3SiCCCH2OH, (Chapter 7, exp. 7.2.12) and MeS(¼O)Cl, as described in Chapter 20, exp. 20.5.3 (Note 1), in 40 ml of dry THF is added in 15 min with cooling at –50 C. The cooling bath is removed after this addition and the temperature is allowed to rise to 0 C. The greyish solution is poured into 250 ml of an aqueous solution of 40 g of ammonium chloride and 25 g of KCN or NaCN. After vigorous shaking, the layers are separated. The aqueous layer is extracted three times with redistilled pentane and the combined solutions are dried over magnesium sulphate (Note 2). The greater part of the solvents is distilled off at normal pressure through a 40-cm Vigreux column (bath temperature not higher than 110 C). The remaining liquid is carefully distilled through the same column to afford 3-trimethylsilyl1,2-heptadiene, bp 55 C/15 Torr, in 70% yield. Notes 1.

2.

Several experimental examples are given in Ref. 26 (see also Table 12.1). In some cases methanesulphonates can be successfully applied when the use of the sulphinic esters leads to mixtures of 1,1-and 1,3-substitution products. The remaining aqueous layer should not be poured into a waste container containing acids!

12.4.8

Reaction of an acetylenic tosylate with phenylcopper

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 12.4.8.1

Procedure [11]

A solution of PhMgBr in 200 ml THF is prepared from 21 g of bromobenzene and 5 g of magnesium. This solution is transferred into the reaction flask and a solution of 17 g of copper(I) bromide and 11 g of anhydrous lithium bromide in 50 ml of THF is added over 10 min at –30 C. Fifteen minutes later a solution of 0.10 mol 2-butynyl tosylate (Chapter 20, exp. 20.5.4) in 30 ml of THF is added over 20 min at –35 C. The cooling bath is then removed and the temperature is allowed to rise to –10 C. The dark reaction mixture is poured into a

248

12.

ACETYLENIC AND ALLENIC DERIVATIVES

solution of 25 g of NaCN and 25 g of ammonium chloride in 250 ml of water. After vigorous shaking, the layers are separated and the aqueous layer is extracted three times with Et2O (cf. Note 2 of preceding exp.). The combined solutions are dried over magnesium sulphate and subsequently concentrated under reduced pressure. The remaining liquid is distilled through and 25-cm Vigreux column to give 1-(1-methyl-1,2-propadienyl)benzene, bp 75 C/15 Torr, in 80% yield. 12.4.9

Copper bromide-catalysed reaction of 2-ethynyltetrahydropyran with alkylmagnesium bromide

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml 12.4.9.1

Procedure

A solution of 0.25 mol of ethylmagnesium bromide in 200 ml of Et2O, prepared from 0.30 mol of ethyl bromide, is added dropwise to a mixture of 0.20 mol of 2-ethynyltetrahydropyran (Chapter 4, exp. 4.5.20), 100 ml of dry Et2O and 1 g of finely powdered copper(I) bromide. During this addition, which is carried out over 30 min, the temperature is kept between –5 and þ5 C. The cooling bath is then removed and stirring is continued for a further 30 min. The dark reaction mixture is poured into 200 ml of an aqueous solution of 20 g of NH4Cl and 5 g of KCN or NaCN. The black copper suspension disappears after vigorous shaking. The aqueous layer is extracted with Et2O. The ethereal solutions are dried over magnesium sulphate and then concentrated under reduced pressure. Distillation of the residue through a 40-cm Vigreux column gives 5,6-nonadien-1-ol, bp 110 C/24 Torr, in 80% yield. Ring opening reactions with acetylenic oxiranes can be carried out by a similar procedure. An example is given in Table 12.1. 12.4.10

3,4-Hexadienenitrile from 1-methyl-2-propynyl-4methylbenzenesulphonate and the copper derivative of acetonitrile

12.4

EXPERIMENTAL SECTION

249

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 12.4.10.1

Procedure [28]

To a solution of 0.12 mol of dry diisopropylamine in 200 ml of dry THF is added at rt a solution of 0.10 mol of butyllithium in 63 ml of hexane. After cooling the solution to –40 C, 0.13 mol of dry acetonitrile (dried over phosphorus pentoxide and subsequently distilled) is added over 10 min. A white suspension is formed. Ten minutes after this addition a solution of 18.0 g of CuBr and 12.0 g of anhydrous LiBr in 50 ml of dry THF is added at rt over 10 min. After an additional 15 min (at rt) the mixture is cooled to –35 C and a solution of 0.12 mol of the acetylenic tosylate (Chapter 20, exp. 20.5.4) in 30 ml of THF is added over 15 min. During this addition the temperature is kept between –25 and –35 C. A two-layer system is formed. The temperature is allowed to rise to –10 C, then the mixture is poured into 300 ml of a solution of 50 g of ammonium chloride to which 40 ml of 36% HCl (Note) has been added. Seven extractions with Et2O are carried out. The combined extracts are washed with 100 ml of a saturated solution of ammonium chloride to which 10 ml of 20% ammonia solution has been added (for removing traces of copper salts) and are subsequently dried over magnesium sulphate. After the greater part of the solvents has been distilled off at 760 Torr through a 30-cm Vigreux column, the remaining liquid is distilled to give 3,4-hexadienenitrile, bp 56 C/ 15 Torr, in 75% yield. t-Butyl 3,4-hexadienoate, MeCH¼C¼CHCH2COO-t-Bu, is prepared in a fair yield by a similar procedure starting from MeCOO-t-Bu and 1-methyl-2propynyl-4-methylbenzenesulphonate, HCCCH(Me)OTs.

Note No cyanide should be used for removing the copper salts, since the nitrile is probably very base-sensitive (isomerisation to a conjugated diene).

12.4.11

2,3-Alkadienenitriles from the reaction between acetylenic bromides and alkali cyanide in the presence of catalytic amounts of copper(I) cyanide

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml

250

12.

ACETYLENIC AND ALLENIC DERIVATIVES

12.4.11.1 Procedure (Note 1) In the flask are placed 20 ml of ethanol, 5 ml of water, 6 g of finely powdered CuCN and 0.20 mol of 3-bromo-1-butyne (Chapter 20, exp. 20.1.5). The mixture is warmed to 55 C and a solution of 13 g of KCN in 30 ml of water is added dropwise or in small portions. Care is taken to avoid complete dissolution of the copper cyanide (Note 2). The temperature of the mixture is maintained close to 60 C throughout the period of addition. The conversion is terminated by heating the mixture for a further 30 min at 65–70 C with vigorous stirring. After cooling to rt, 150 ml of ice water is added and the product is extracted seven times with small portions of Et2O. The extracts are combined and washed twice with saturated ammonium chloride solution. After drying over magnesium sulphate, most of the Et2O is distilled off at normal pressure through a 30 or 40-cm Vigreux column. Distillation of the remaining liquid gives 2,3-pentadienenitrile , bp 39 C/15 Torr, in 90% yield. 2,3-Butadienenitrile, H2C¼C¼CHCN, is obtained by a similar procedure from propargyl bromide and potassium cyanide [29]. Notes 1.

The product has lachrymatory properties and may cause blisters on the skin. 2. If the addition is performed at too fast a rate, all of the copper cyanide may dissolve temporarily. The free KCN, present in the solution, may cause partial resinification of the allenic cyanide. 12.4.12

CuCl-catalysed isomerisation of 3-phenyl-3-chloro1-propyne to 1-(3-chloro-1,2-propadienyl)benzene

Scale: 0.10 molar; Apparatus: 100-ml round-bottomed flask and thermometer, manual swirling or magnetic stirring 12.4.12.1 Procedure (cf. [30]) To a solution (Note 1) of 2 g of copper(I) chloride (commercial product) and 4 g of dry lithium chloride in 15 g of dry THF is added with swirling 0.10 mol of 3-phenyl-3-chloro-1-propyne (prepared from the corresponding alcohol and

12.4

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251

SOCl2, cf. Chapter 20, exp. 20.1.5). The refractive index nD (Note 2) of the solution rises during 40 min of warming at 40 C from the initial value of 1.487 to a maximum of 1.505. The solution is then poured into 100 ml of 4 N hydrochloric acid. After vigorous shaking, the product is extracted with a 1:1 mixture of Et2O and pentane. The extracts are washed with water and dried over magnesium sulphate. Concentration under reduced pressure gives 1-(3-chloro-1,2-propadienyl)benzene in more than 90% yield. The NMR spectrum shows that no starting compound is present and that the purity is satisfactory. Attempts to distil the allene lead to extensive polymerisation. Notes 1. 2.

Obtained by briefly heating the mixture under reflux. After placing the solution on the prism, the apparatus should be closed immediately because evaporation of the THF will give rise to too high values.

12.4.13

Copper bromide-catalysed isomerisation of propargyl bromide to bromoallene

Scale: 1.0 molar; Apparatus: 250-ml flask with gas inlet-thermometer combination and reflux condenser

12.4.13.1

Procedure [cf. 31]

A mixture of 10 g of copper(I) bromide, 35 ml of dry THF and 20 g of anhydrous lithium bromide is heated gently until a clear solution has formed, then 1.0 mol of freshly distilled propargyl bromide (Chapter 20, exp. 20.1.1) is added. The mixture is heated under reflux for 3 h. The temperature in the boiling solution, initially 87 C, is then dropped to the minimum value of 82.5 C. NMR spectroscopy indicates that the ratio of bromoallene and propargyl bromide is 70:30 (Note 1). After cooling to rt, the mixture is shaken vigorously with a cold (0 C) solution of 20 g of NaCN in 500 ml of water. The heavy lower layer is separated as sharply as possible. The aqueous layer (warning) is extracted twice with 30-ml portions of high-boiling petroleum ether (bp >170 C). The extracts and the undiluted liquid are combined and

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ACETYLENIC AND ALLENIC DERIVATIVES

transferred (without drying) into a 250-ml three-necked flask provided with a dropping funnel, a mechanical stirrer and a thermometer combined with an outlet. The solution is cooled to 10 C and a mixture of 0.6 mol of diethylamine and 40 ml of water is added over 10 min with vigorous stirring, while keeping the temperature between 10 and 5 C (Note 2). Stirring is continued for an additional 15 min at þ5 C. The mixture is then poured into 500 ml of cold (0 C) 2 N hydrochloric acid. After vigorous shaking, the organic layer is separated off. The aqueous layer is extracted twice with 70-ml portions of petroleum ether. The combined solutions are washed (Note 3) seven times with l00-ml portions of 2 N HCl, saturated with ammonium chloride and then dried over magnesium sulphate and transferred into a 1-litre distillation flask, equipped for distillation at water-aspirator pressure (Figure 1.10). By gradually heating the solution under 10–15 Torr, bromoallene condenses in the receiver cooled at –75 C. The evacuation is terminated as soon as petroleum ether begins to distil (bp > 50 C/15 Torr). The contents of the receiver are freed from traces of petroleum ether by repeating the procedure in the same apparatus, but keeping the temperature of the heating bath below 40 C so that the small amount of petroleum ether remains in the distillation flask. The receiver now contains pure bromoallene, the yield being 50–60%. Notes 1. 2.

This ratio corresponds to the equilibrium value. This operation is necessary to remove the propargyl bromide. At higher temperatures bromoallene also reacts with the amine. 3. The washing procedure is necessary to remove the dissolved THF. Warning: The aqueous layer should never be poured into a waste container for acids.

12.4.14

Copper bromide-catalysed isomerisation of 3-bromo-1-nonyne to 1-bromo-1,2-nonadiene

Scale: 0.10 molar; Apparatus: 100 ml two-necked round-bottomed flask with inlet and reflux condenser

12.4

EXPERIMENTAL SECTION

12.4.14.1

253

Procedure

A mixture of 40 ml of dry THF, 6.0 g of anhydrous LiBr, 2.5 g of CuBr and 0.10 mol of 3-bromo-1-nonyne (Chapter 20, exp. 20.1.4) is heated under reflux. The solid material disappears after a short time. The refractive index ( nD) of a sample, taken from the liquid after cooling to 50 C, which is 1.460 after dissolution of the solids, rises to the maximum value of 1.466 after refluxing for 2.5 h (Note). After 3 h the mixture is cooled to rt and poured into a solution of 10 g of ammonium chloride and 5 g of NaCN (or KCN) in 100 ml of water. The mixture is shaken vigorously, then five extractions with Et2O are carried out. The combined extracts are dried over magnesium sulphate and subsequently concentrated under reduced pressure. Careful distillation of the residue affords 1-bromo-1,2-nonadiene, bp 90 C/15 Torr, in 75% yield. The small first fraction contains some starting compound. Note In order to obtain reliable values, the determination should be carried out very quickly: A few drops are placed on the prism and the apparatus is closed immediately, otherwise the THF will evaporate and a too high value is measured. 12.4.15

1-(3-Bromo-1,2-propadienyl)benzene by CuBr-catalysed reaction of 1-phenyl-2-propyn-1-ol with concentrated aqueous hydrogen bromide

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 12.4.15.1

Procedure [32]

To a mixture of 50 ml of 47% hydrobromic acid, 0.03 mol of copper(I) bromide, 0.1 mol of ammonium bromide and 0.1 g of copper bronze (reduces traces of Cu(II) to Cu(I)) is added 0.10 mol of 1-phenyl-2-propyn-1-ol (Chapter 5, exp. 5.2.2) dissolved in 30 ml of pentane at 0 C in 3 min. After stirring for 2 h at this temperature, 150 ml of pentane and 200 ml of ice water are successively added. The pentane layer is shaken with 25-ml portions of 47% aqueous HBr until the aqueous layer remains colourless. The pentane solution is dried over magnesium sulphate and then concentrated under reduced pressure. High-vacuum distillation affords 1-(3-bromo-1,2-propadienyl)benzene,

254

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bp 50 C/0.01 Torr, in 80% yield. In view of the low thermal stability of the compound too high bath temperatures should be avoided. 12.4.16

1-Bromo-3-methyl-1,2-butadiene by CuBr-catalysed reaction of 2-methyl-3-butyn-2-ol with concentrated aqueous hydrogen bromide

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml 12.4.16.1 Procedure [32] A mixture of 50 ml of 48% HBr, 10 g of commercial CuBr, 8 g of ammonium bromide, 0.5 g of copper bronze (reduces traces of Cu(II) to Cu(I)) and 0.20 mol of 2-methyl-3-butyn-2-ol is stirred for 15 min at 40 C. After cooling to rt, the upper layer is separated as sharply as possible and is transferred into a 250-ml flask containing 10 g of sodium hydrogen carbonate. After shaking, the flask is fitted with a short column connected to a condenser and a receiver cooled at –75 C (Figure 1.10). By evacuating with the water aspirator (10–15 Torr) and heating the flask at up to 50 C the bromoallene condenses in the receiver. The yield of pure product is 75%. 12.4.17

1-Bromo-1,2-butadiene by CuBr-catalysed reaction of 3-butyn-2-ol with concentrated aqueous hydrogen bromide

Scale: 0.40 molar; Apparatus: Figure 1.1, 500 ml 12.4.17.1 Procedure [cf. 32] To 200 ml of 48% hydrobromic acid is added 0.40 mol of phosphorus tribromide (Note 1). The mixture is agitated vigorously, while the temperature is kept between 20 and 30 C by cooling in a water bath at 10–15 C. After 1 h the lower layer has disappeared completely. The solution is cooled to 0 C, then 0.40 mol of ammonium bromide, 0.10 mol (Note 2) of copper(I) bromide (commercial product), 2 g of copper bronze, 140 ml of redistilled pentane and 0.40 mol of 3-butyn-2-ol (Note 3) are successively added. The mixture is

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EXPERIMENTAL SECTION

255

stirred for 5 h at 0 C and subsequently for 18 h at rt. After separation of layers, two extractions with 50-ml portions of pentane are carried out. The combined solutions are washed with water and dried over magnesium sulphate. Most of the pentane is distilled off at normal pressure through a 40-cm Vigreux column, keeping the bath temperature below 100 C. The remaining liquid is carefully distilled through an efficient column, giving 1-bromo-1,2-butadiene, bp 60 C/160–170 Torr, in 60–75% yield. The product contains a small amount (< 5%) of 3-bromo-1-butyne, HCCCH(Br)Me.

Notes 1.

2. 3.

The concentration of the aqueous HBr solution is increased by the reaction of phosphorus tribromide with water. If available in a cylinder, a corresponding amount of gaseous HBr may be introduced into the 48% solution at 0 C. In Ref. 32 an equivalent amount of CuBr is used. This compound is commercially available as a 55% aqueous solution. The water can be removed by saturation of the solution with anhydrous potassium carbonate. The upper layer is dried over a small amount of potassium carbonate and distilled, bp 40 C/35 Torr.

12.4.18

1-Iodo-1,2-butadiene by reaction of 3-butyn-2-ol with triphenylphosphite-methiodide in N,N-dimethylformamide

Scale: 0.10 molar; Apparatus: 250-ml two-necked round-bottomed flask, magnetic stirring 12.4.18.1

Procedure [33]

A solution of 55 g of triphenyl phosphite methiodide in 100 ml of dry DMF is heated at 100 C (bath temperature) and 0.10 mol of 3-butyn-2-ol (commercially available) is added in 2 min by syringe. After stirring for 30 min at 100 C, the mixture is cooled. On the flask are placed a 20-cm Vigreux column and the column is connected with a condenser and a receiver. The DMF and the iodoallene distil between 40 and 50 C/15 Torr. After addition

256

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of 200 ml of water to the distillate, four extractions with small amounts of Et2O or pentane are carried out. The extracts are washed with water and dried over magnesium sulphate. The residue, remaining after evaporation of the solvent under reduced pressure is distilled through a short column, affording 1-iodo-1,2-butadiene, bp 40 C/15 Torr, in 75% yield.

12.4.19

1-Iodo-3-phenylpropadiene by CuI-catalysed reaction of 1-phenyl-2-propyn-1-ol with concentrated aqueous hydrogen iodide

Scale: 0.10 molar; Apparatus: 250-ml round-bottomed flask, magnetic stirring 12.4.19.1 Procedure [33] A mixture of 40 ml of 50% hydroiodic acid, 0.03 mol of copper(I) iodide, 0.1 mol of ammonium iodide, 0.2 g of copper bronze, 0.10 mol of 1-phenyl2-propyn-1-ol (Chapter 5, exp. 5.2.2) and 20 ml of pentane is vigorously stirred for 1 h at 0–5 C (bath with ice water). Ice water (200 ml) is then added and the product is extracted three times with 50-ml portions of a 1:1-mixture of pentane and Et2O. The combined organic solutions are washed with water, dried over magnesium sulphate and subsequently concentrated under reduced pressure. The weight of the residue corresponds to 90% yield of the 1-iodo-3phenylpropadiene. High-vacuum distillation gives the pure product, bp 70 C/ 0.01 Torr, in 60% yield. Due to its low thermal stability much of the product polymerises during the distillation.

12.4.20

Allenic alcohols from the reaction between lithium alanate and chlorine-containing acetylenic alcohols

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml, reflux condenser instead of the thermometer

12.4

EXPERIMENTAL SECTION

12.4.20.1

257

Procedure [34]

To a solution of 0.20 mol of 4-chloro-2-butyn-l-o1 (see Chapter 5, exp. 5.2.8) in 150 ml of dry Et2O is added a solution of 0.22 mol of lithium alanate in 250 ml of Et2O. The addition is performed at a rate such that the Et2O gently refluxes. A thick white suspension is formed. The mixture is warmed for an additional 30 min under reflux and is subsequently cooled by complete immersion of the flask in a bath with ice water. Ice water ( 20 ml) is added dropwise with vigorous stirring until the refluxing of the Et2O has ceased. The ethereal layer is decanted and the white slurry is extracted ten times with small portions of Et2O. The combined extracts are dried well over magnesium sulphate, after which the greater part of the Et2O is distilled off at normal pressure through a 40-cm Vigreux column. Distillation of the residue (using a single receiver, cooled at 0 C, Figure 1.10) gives 2,3-butadien-1-ol, bp 38 C/12 Torr, in 75% yield. In a similar way are prepared: 3,4-pentadien-2-ol, H2C¼C¼CHCH(Me)OH, bp 65 C/50 Torr, in 70% yield from 5-chloro-3-pentyn-2-ol, ClCH2C CCH(Me)OH, (for the preparation of this compound from LiCCCH2Cl and acetaldehyde see the general procedure in Chapter 5, exp. 5.2.2) and 1-phenyl-2,3-butadien-1-ol, H2C¼C¼CH–CH(Ph)OH, bp 100 C/2 Torr, in 85% yield from 4-chloro-1-phenyl-2-butyn-1-ol, ClCH2CCCH(Ph)OH.

12.4.21

Allenic alcohols from the reaction between acetylenic alcohols containing an ether group and lithium alanate

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre, reflux condenser instead of thermometer 12.4.21.1

Procedure [35]

To a solution of 0.24 mol of lithium alanate in 500 ml of Et2O is added 0.20 mol of the acetylenic alcohol (Note) at a rate such that the gentle reflux of the Et2O is maintained. After the addition, the mixture is warmed under reflux for an additional 1 h, then it is then cooled to rt. Water (25 ml) is then added dropwise with vigorous stirring until refluxing ceases. The ethereal layer is decanted and the slurry is extracted several times with Et2O. The combined ethereal solutions are dried over magnesium sulphate and subsequently

258

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concentrated under reduced pressure. Distillation of the residue through a 30-cm Vigreux column gives 4-methyl-2,3-pentadien-1-ol, bp 76 C/32 Torr, in 75% yield. In a similar way are prepared: 5-methyl-3,4-hexadien-2-ol, (Me)2C¼C¼ CHCH(Me)OH, bp 70 C/25 Torr, in 70% yield and 3-cyclohexylidene-2propen-1-ol, (CH2)5C¼C¼CHCH2OH, bp 110 C/18 Torr, in 70% yield. Note Prepared by converting 3-(1-ethoxyethoxy)-3-methyl-1-butyne, HC CCMe2OCH(Me)OEt into its lithium derivative, subsequently adding the required amount of dry paraformaldehyde and heating the mixture for 2 h under reflux (cf. Chapter 5, exp. 5.2.1). The acetal is prepared from 2-methyl-3-butyn-2-ol, HCCCMe2OH, and excess of H2C¼CHOEt in the presence of a small amount of p-toluenesulphonic acid (cf. Chapter 20, exp. 20.6.7). 12.4.22

Allenes by reaction of propargylic chlorides with zinc–copper in ethanol

Scale: 0.70 molar; Apparatus: 1-litre round-bottomed three-necked flask, equipped with a dropping funnel-thermometer combination, a mechanical stirrer and an efficient column, connected with a condenser and receiver cooled at –10 C. 12.4.22.1 Procedure A Zn/Cu couple, freshly prepared from 70 g of zinc and 130 ml of 100% ethanol (see exp. 12.4.23), are placed in the flask. Stirring is started and 0.20 mol of the 3-chloro-1-butyne (Chapter 20, exp. 20.1.5) is added. When the Zn/Cu couple is of good quality, the temperature begins to rise after a few minutes and 1,2-butadiene begins to distil. The remaining 0.50 mol of the chloride is added dropwise over a period of 30 min. The temperature of the reaction mixture is kept between 65 and 70 C, and the temperature in the head of the distillation column below 45 C by occasional cooling or heating. After the addition, the temperature of the reaction mixture is increased gradually. Heating and stirring are stopped when ethanol begins to pass over at 78 C. The distillate is carefully redistilled through the same

12.4

EXPERIMENTAL SECTION

259

column, using a cold receiver. 1,2-Butadiene distils between 20 and 35 C (bp 20 C/760 Torr) and is obtained in 80–85% yield (Note). In a similar way 3-methyl-1,2-butadiene, (Me)2C¼C¼CH2, bp 41 C, is prepared in 70% yield from 3-chloro-3-methyl-1-butyne, HCCCMe2Cl (Chapter 20, exp. 20.1.9).

Note Some batches of zinc powder gave yields of only 60%. The reaction then proceeded much more slowly, and heating (at 65–70 C) had to be continued for 2–3 h in order to achieve complete conversion.

12.4.23

Vinylidenecyclohexane by reaction of 1-chloro-1ethynylcyclohexane with zinc–copper in ethanol

Scale: 0.50 molar; Apparatus: Figure 1.1, 1 litre 12.4.23.1

Procedure

To a suspension of a zinc–copper couple in 150 ml of 100% ethanol, prepared from 80 g of zinc powder (see below), is added at rt 0.10 mol of 1-chloro-1ethynylcyclohexane (Chapter 20, exp. 20.1.10). After a few minutes an exothermic reaction starts and the temperature rises to 45–50 C (Note). When this reaction has subsided, the mixture is cooled to 35–40 C and the remaining 0.40 mol of the chloride is added over a period of 15 min, while maintaining the temperature around 40 C (occasional cooling). After the addition stirring is continued for 30 min at 65 C, then the mixture is cooled to rt and the upper layer is decanted. The black slurry of zinc is rinsed five times with 50-ml portions of Et2O. The alcoholic solution and the extracts are combined and washed three times with 100-ml portions of 2 N HC1, saturated with ammonium chloride. After drying over magnesium sulphate, the greater part of the Et2O is distilled off at normal pressure through a 40-cm Vigreux column. The remaining liquid is distilled at 15 Torr through the same column. The (single) receiver is cooled in an ice-bath (Figure 1.10). Vinylidenecyclohexane, bp 32 C/ 15 Torr, is obtained in 85% yield.

260

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Note A prompt start occurs when the Zn/Cu couple is of good quality. If the reaction does not start at rt, the mixture should be warmed stepwise (first to rt, then to 30 C, etc.) until a further rising of the temperature is observed. 12.4.23.2 Preparation of the zinc–copper reagent Finely powdered zinc (70 g, Merck, Darmstadt, Germany) is transferred into a 500-ml conical flask. Dilute hydrochloric acid is prepared by mixing 50 ml of concentrated (ca 36%) acid with 500 ml of water. The zinc powder is swirled vigorously by hand for 30 s with one-third of the dilute hydrochloric acid (Note), then water (200 ml) is added in order to stop the evolution of hydrogen. The liquid is decanted from the zinc, which is treated subsequently with a second portion of 200 ml of dilute acid in the same way for 30 s. This treatment is carried out (after addition of water and decanting) for a third time with the remaining dilute acid. After decanting the acid solution, the zinc is shaken twice with 100-ml portions of distilled water, which are decanted from the zinc. The flask is then provided with a mechanical stirrer and a third portion of 100 ml of distilled water is added. Stirring is started at a rate such that all zinc powder is homogeneously suspended. A solution of CuSO4 (5 g) in 100 ml of distilled water is added to the stirred suspension in 10 s (experienced persons can do these operations by hand). Stirring is then stopped and the powder is allowed to precipitate. The supernatant liquid is cautiously poured off. Distilled water (100 ml) is added and the same procedure is repeated. After a third treatment with CuSO4 the powder is washed successively three times with 75-ml portions of distilled water, three times with 75-ml portions of 96% ethanol and three times with 75-ml portions of 100% ethanol. The activated zinc powder obtained in this way is used directly. It is transferred, together with the third portion of 100% ethanol into the reaction flask.

Note From our first experiments with Zn–Cu couples prepared from different batches of zinc powder we found that the results (yield, and sometimes purity) of the allene preparations varied considerably from one batch to another. After many experiments we concluded that there is some connection between the results and the behaviour of the zinc during the treatment with hydrochloric acid and CuSO4. A smooth reaction and good results were predicted and obtained whenever the evolution of hydrogen started immediately after addition of dilute acid, causing the powder to move slowly up and down when swirling was stopped for a while. After washing with water the

12.4

EXPERIMENTAL SECTION

261

powder was still finely divided. The results were less satisfactory when during the treatment with acid; the formation of porous spongy clusters of powder took place. During the evolution of hydrogen the powder remained on the bottom of the flask. Further we had the impression that the treatment with CuSO4 solution did not result in a satisfactory fixing of the copper on the zinc particles. Although we cannot give an explanation for the varying results, we believe that the structure of the powder (possibly the size of the particles) has a considerable influence on the results of the allene syntheses. It also seems important to remove the water completely during the washing with ethanol. Traces of water can remain when aggregates of zinc are formed during the treatment with acid or by inefficient washing with ethanol. 12.4.24

1,2,4-Hexatriene by reaction of 5-bromo-3-hexen-1-yne with zinc–copper in hexanol

Scale: 0.20 molar; Apparatus: 1-litre three-necked round-bottomed flask, equipped with a dropping funnel, a gas-tight mechanical stirrer and a 40-cm Vigreux column connected to a condenser and receiver cooled at –75 C (cf. Figure 1.10). Between the receiver and the water aspirator is placed a tube filled with KOH pellets 12.4.24.1

Procedure

A Zn/Cu couple is prepared from 70 g of zinc powder (see preceding exp.). The black slurry is transferred into the reaction flask. After the greater part of the absolute ethanol has been poured off from the zinc, the zinc is rinsed at least ten times with small portions of dry Et2O. The Et2O is then decanted, 100 ml of hexanol is added and the flask is connected to the other parts of the distillation apparatus. The Et2O and traces of ethanol are subsequently removed by evacuating the apparatus (the receiver being cooled at –75 C) and heating the reaction flask. This operation is stopped when 10 ml of hexanol has passed over. The receiver and condenser are cleaned and the apparatus is again evacuated (10–15 Torr). Stirring is started and the flask heated until the hexanol starts to reflux in the lower part of the column. From the dropping funnel is added over 20 min 0.20 mol of the bromide (Chapter 20, exp. 20.1.8). The reaction is very vigorous and external heating is not necessary. A mixture of 1,2,4-hexatriene and hexanol condenses in the receiver (Note 1). The

262

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conversion is completed by heating, so that 5–10 ml of hexanol distils at 55– 60 C/15 Torr. The contents of the receiver are ‘redistilled’, using the apparatus shown in Figure 1.10, collecting the vapour of the hexatriene in a receiver cooled at –75 C. The yield of this hydrocarbon is 75–85% (with comparable amounts of the (Z)-and (E)-isomer). The compound can be distilled at normal pressure (bp 78 C/760 Torr), but some polymerisation occurs (Note 2). Notes If the temperature in the top of the column rises above 50 C, the addition should be interrupted. 2. We have carried out this synthesis also in ethanol as a solvent but the results were not reproducible. Although a series of experiments with zinc powder from one flask gave reasonable results (60–78% yields), a new bottle with the same batch number gave low yields of impure products. The main impurity is probably 1,4-hexadiene, H2C¼CHCH2CH¼CHMe, possibly resulting from reduction of the 1,2,4-triene by the zinc. The advantage of using hexanol is that the triene can be removed directly from the reaction mixture, so that no further reduction can occur.

1.

12.4.25

Copper(I) chloride-catalysed reaction of propargyl alcohol with propargyl chloride in aqueous medium. Preparation of 4,5-hexadien-2-yn-1-ol

Scale: 0.25 molar; Apparatus: Figure 1.1, 500 ml 12.4.25.1 Procedure [36] Methanol (70 ml), 25% aqueous NH3 solution (50 ml), freshly distilled propargyl alcohol (0.50 mol) powdered CuCl (1.5 g, technical grade) and hydroxylamine HCl (2 g) are placed in the flask. The air in the flask is completely replaced by nitrogen. A mixture of 0.25 mol of propargyl chloride and 40 ml of methanol is added dropwise over 1 h, while keeping the temperature between 25 and 30 C. After an additional 45 min a solution of 5 g of KCN or NaCN in 150 ml of water is added with vigorous stirring. Subsequently 10 extractions with Et2O are carried out. The combined ethereal solutions are

12.4

EXPERIMENTAL SECTION

263

washed once with saturated aqueous NH4Cl and are subsequently dried over MgSO4. After complete removal of the solvent and other volatile compounds (some HCCCH2OH) under reduced pressure, almost pure 4,5-hexadien-2-yn1-ol, H2C¼C¼CHCCCH2OH, is obtained in 80% yield. If desired, the compound can be distilled in a high vacuum, using a short column and a single receiver, cooled to below –20 C. Prior to carrying out the distillation, 40 ml of paraffin oil (Note) should be added. 2-Methyl-5,6-heptadien-3-yn-2-ol, H2C¼C¼CHCCC(Me)2OH, (undistilled), is obtained in 70% yield by a similar procedure from 2-methyl-3-butyn-2-ol, HCCC(Me)2OH, and HCCCH2Cl.

Note The addition of some paraffin oil minimises the risk of a vigorous decomposition in the last stage of the distillation. Polymeric substances remain as dispersion in the oil. 12.4.26

Methyl propargyl ketone by zinc chloride-catalysed reaction of allenyl tributyltin with acetyl chloride

Scale: 0.20 molar; Apparatus: Figure 1.1, 250-ml two-necked, round-bottomed flask with thermometer and outlet, magnetic stirring 12.4.26.1

Procedure [38]

In the flask are placed 0.20 mol of tributyl(1,2-propadienyl)stannane (Chapter 7, exp. 7.2.7) and 0.20 mol of freshly distilled acetyl chloride. The mixture is cooled to –15 C and 300 mg of powdered anhydrous zinc chloride is added. After stirring for 30 min at –10 to –15 C, the cooling bath is removed and the temperature is allowed to rise gradually in 1.5 h to rt (occasional cooling may be necessary). The flask is then equipped for a vacuum distillation. A stopper and a 30-cm Vigreux column are placed on the flask. This column is connected with a condenser and a receiver, cooled at –15 C. Between the receiver and the water aspirator is placed a tube filled with anhydrous calcium chloride. The apparatus is evacuated at 10–15 Torr and the flask gradually heated until the temperature in the top of the column has risen to 60 C. A dark residue, chloro(tributyl)tin, remains in the distillation flask. The contents of the

264

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receiver are redistilled in a partial vacuum of 40 Torr. 4-Pentyn-2-one, bp 50 C, is obtained in 70% yield. 12.4.27

Allenic sulphides from the copper halide-catalysed reaction between propargylic halides and lithium thiolates

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 12.4.27.1 Procedure [37] Freshly distilled thiophenol (0.12 mol) is added at –20 C to a solution of 0.12 mol of BuLi in 75 ml of hexane and 120 ml of THF. Subsequently, a solution of 1.5 g of CuBr and 3 g of anhydrous LiBr in 20 ml of THF is added with cooling below 0 C. 3-Chloro-3-methyl-1-butyne (0.10 mol) is added over a few minutes at –15 C, after which the cooling bath is removed. After 30 min the light-brown solution is heated under reflux for 15 min (Note), then cooled to rt and poured into a solution of 5 g KCN, 5 g NaOH and 20 g of NH4Cl in 150 ml of water. After vigorous shaking and separation of the layers three extractions with Et2O are carried out. The combined organic solutions are dried over potassium carbonate and subsequently concentrated under reduced pressure. 1-Phenylthio-3-methyl-1,2-butadiene, bp 75–80 C/0.5 Torr, is obtained in 70% yield. The product contains 2–6% of the acetylenic isomer 1,1-dimethyl-2-propynyl phenyl sulphide, HCCC(Me)2SPh. Propargyl chloride, HCCCH2Cl, gives a mixture of 85% allenic and 15% acetylenic sulphide, when using catalytic amounts of CuBr. Note Heating for a longer period will probably result in a decrease of the amount of acetylenic isomer, due to its isomerisation under the influence of PhS CuBrLiBr (cf. [37]).

REFERENCES 1. P. P. Montijn, E. Harryvan and L. Brandsma, Recl. Trav. Chim., Pays-Bas 83, 1211 (1964). 2. J. G. A. Kooyman, H. P. G. Hendriks, P. P. Montijn, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 87, 69 (1968). 3. H. G. Viehe and M. Reinstein, Angew. Chem., Int. edn. 3, 506 (1962).

REFERENCES

265

4. H. G. Viehe (ed.), Chemistry of Acetylenes. Marcel Dekker, New York, 1969, p. 868. 5. R. A. van der Welle and L. Brandsma, Recl. Trav. Chim., Pays-Bas 92 667 (1973). 6. J. F. Normant, A. Alexakis and J. Villieras, J. Organometal. Chem. 57, C 99 (1973); A. Alexakis, A. Commerc¸on, J. Villieras and J.-F. Normant, Tetrahedron Lett., 3935 (1978). 7. D. J. Pasto, R. H. Shults, J. A. McGrath and A. Waterhouse, J. Org. Chem. 43, 1382 (1978). 8. J.-L. Moreau and M. Gaudemar, J. Organometal. Chem. 108, 159 (1976). 9. G. Tadema, P. Vermeer, J. Meijer and L. Brandsma, Recl. Trav. Chim., Pays-Bas 95, 66 (1976). 10. L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas, 85, 734 (1967). 11. P. Vermeer, J. Meijer and L. Brandsma, Recl. Trav. Chim., Pays-Bas, 94, 112 (1975). 12. P. Rona and P. Crabbe´, J. Am. Chem. Soc. 91, 3289 (1969). 13. H. Kleijn, C. J. Elsevier, H. Westmijze, J. Meijer and P. Vermeer, Tetrahedron Lett., 3101 (1979). 14. A. Alexakis, I. Marek, P. Mangeney and J.-F. Normant, Tetrahedron Lett. 30, 2387 (1999). 15. P. R. Ortiz de Montellano, J. Chem. Soc., Chem. Comm., 709 (1973). 16. J. H. Wotiz, J. Am. Chem. Soc. 73, 693 (1951). 17. G. F. Hennion and J. J. Sheehan, J. Am. Chem. Soc. 71, 1964 (1949). 18. T. L. Jacobs, E. G. Teach and D. Weiss, J. Am. Chem. Soc. 77, 6254 (1955). 19. M. Sipenhou Simo, A. Jean and M. Le Quan, J. Organomet. Chem. 35, C23 (1972). 20. H. G. Kuivila and J. C. Kochran, J. Am. Chem. Soc. 89, 7152 (1967). 21. Ya. I. Ginsburg, J. Gen. Chem. USSR 10, 513 (1940); M. Bertrand, Bull. Soc. Chim. France, 461 (1956). 22. M. Biollaz, W. Haefliger, E. Velarde, P. Crabbe´ and J. H. Fried, J. Chem. Soc., Chem. Comm., 1322 (1971). 23. W. J. Bailey and C. R. Pfeifer, J. Org. Chem. 20, 95 (1955). 24. T. L. Jacobs and R. D. Wilcox, J. Am. Chem. Soc. 86, 2240 (1964). 25. J. Meijer, K. Ruitenberg, H. Westmijze and P. Vermeer, Synthesis, 551 (1981). 26. J. Meijer and P. Vermeer, Recl. Trav. Chim., Pays-Bas 93, 183 (1974). 27. H. Westmijze and P. Vermeer, Synthesis, 390 (1979). 28. R. A. Amosand and J. A. Katzenellenbogen, J. Org. Chem. 43, 555 (1978). 29. P. Kurtz, H. Gold and H. Diesselnko¨tter, Liebigs Ann. Chem. 624, 1 (1959). 30. O. J. Muscio, Y. M. Yun and J. B. Philip, Tetrahedron Lett., 2379 (1978). 31. T. L. Jacobs and W. F. Brill, J. Am. Chem. Soc. 75, 1314 (1953). 32. P. M. Greaves, M. Kalli, Ph.D. Landor and S. R. Landor, J. Chem. Soc. (C), 667 (1971). 33. C. S. L. Baker, Ph. D. Landor, S. R. Landor and A. N. Patel, J. Chem. Soc., 4348 (1965). 34. W. J. Bailey and C. R. Pfeifer, J. Org. Chem. 20, 1337 (1955); Ph.D. Landor, S. R. Landor and E. S. Pepper, J. Chem. Soc. (C), 185 (1967). 35. J. S. Cowie, Ph. D. Landor and S. R. Landor, J. Chem. Soc., Chem. Comm., 541 (1969); A. Claesson, L.-I. Olsson, C. Bogentoft, Acta Chem. Scand. 27, 2941 (1973). 36. A. Sevin, W. Chodkiewicz and P. Cadiot, Tetrahedron Lett., 1953 (1965). 37. A. J. Bridges, Tetrahedron Lett., 4401 (1980). 38. Unpublished results from the author’s laboratory.

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13 Aminoalkylation of Acetylenic Compounds

13.1

INTRODUCTION

The reaction of phenylacetylene with formaldehyde and secondary amines was reported in 1933 [1]. Aliphatic 1-alkynes, which are less acidic than phenylacetylene, react sluggishly.

The formation of the acetylenic tertiary amines may be visualised as a nucleophilic attack of the acetylide anion on the imonium ion R12 NþCH2, which is in equilibrium with the (dialkylamino)methanol R12 NCH2OH. These compounds are easily formed at room temperature or slightly elevated temperatures from secondary amines and polymeric formaldehyde (paraformaldehyde). The reaction of R12 NCH2OH with acetylenes is usually carried out at 100 C in an organic solvent such as dioxane. Acetylenes with a conjugated unsaturated system, RCH¼CHCCH or RCCCCH, arylacetylenes, ArCCH, and ethynyl sulphides, HCCSR, react more easily than do alkylacetylenes. In the latter compounds the ethynyl proton is less ‘mobile’. The reaction times, which are quite long for alkylacetylenes, can be shortened to one or a few hours by using a small amount of a copper salt (Cu(OAc)2, CuCl, CuBr) [2]. This forms a copper(I) compound with the acetylene. The copper acetylide is often visible as a yellow solid during the reaction. This solid disappears or is replaced by a red suspension of copper, when the conversion has finished. It is advisable to use no, or only a slight excess of the secondary amine and paraformaldehyde, because the presence of R12 NCH2OH may give rise to difficulties during the purification of the aminoacetylenes (partial 267

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decomposition of the aminomethanol during distillation) especially in the cases of more volatile representatives. The yields of the copper-catalysed Mannich reactions with acetylenic derivatives are usually high. The reactions with volatile acetylenes (especially gases) require a more careful performance than the ones with boiling points higher than 60 C. A too quick addition may lead to incomplete conversion due to lowering of the attainable temperature in the reaction mixture. Acetylene and (dialkylamino)methanol react under pressure to give N,N-dialkyl 2-butyne-1,4-diamines, R2NCH2CCCH2NR2, as the main product [2]. If the usual procedure is followed with acetylenic alcohols, yields are often low due to preferential reaction of the hydroxyl group [3,4] or formation of N,N-acetals, H2C(NR)2 [5]. An efficient procedure for Mannich coupling with acetylenic alcohols has been developed in the author’s laboratory [6]. Ethoxyacetylene, HCCOEt, does not give the normal Mannich reaction [7]. Many examples of dialkylaminoalkylation can be found in the monographs [8,9] and in a review [10].

13.2 13.2.1

EXPERIMENTAL SECTION

Preparation of (dimethylamino)methanol and (diethylamino)methanol

Scale: 0.30 molar; Apparatus: 250-ml two-necked, round-bottomed flask, equipped with a stopper (which is temporarily removed during the addition of the amine) and a combination of a thermometer and an outlet; magnetic stirring. 13.2.1.1

Procedure

Pure dioxane (25 ml) and powdered paraformaldehyde (9 g, corresponding to 0.30 mol of the monomer) are placed in the flask. Liquefied dimethylamine ( 0.10 mol, mixed with 10 ml of dioxane and cooled to 0 C), or diethylamine ( 0.10 mol) is added at rt. The temperature of the mixture rises gradually to 45 C. After cooling to rt, a second portion of 0.10 mol of the amine is added. When the ensuing exothermic reaction has subsided, the remaining 0.10 mol of the amine is added at rt. The conversion is completed by heating the mixture for 30 min at 50 C. A slightly turbid solution is formed.

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269

Other aliphatic or cycloaliphatic secondary amines are converted into the condensation products by a similar procedure.

13.2.2

Mannich reactions with gaseous acetylenes

Scale: 0.30 molar; Apparatus: 500-ml three-necked, round-bottomed flask, equipped with a long gas inlet tube, a gas-tight mechanical stirrer and a reflux condenser. The inlet tube is connected with a trap containing the liquefied acetylene, and the top of the condenser with a trap placed in a bath at –78 C. All connections are fixed well and are made gas-tight. 13.2.2.1

Procedure

Powdered copper(I) bromide (2 g) is added to the solution prepared in exp. 13.2.1. The flask is heated in an oil bath at 100–105 C. The trap containing the acetylene (0.40 mol, excess) is placed in a bath at 0–5 C (in the case of propyne) or rt (in the case of butyne and vinylacetylene). During the introduction of the acetylene, which takes 30 min, the mixture is agitated vigorously in order to achieve efficient absorption of the gaseous acetylene. As soon as the trap has become empty, the two traps are interchanged. As a rule, only a small amount of unconverted alkyne appears to be present in the second trap. The introduction of gas and heating at 100 C are continued until the amount of condensed acetylene in the second trap has become very small (< 0.1 mol). The brown suspension (in some cases yellow) is then cooled to rt. Although it is possible to isolate the product via an aqueous work-up (Note 1), we prefer the following procedure. The reaction flask is equipped for a vacuum distillation, using a short Vigreux column, condenser and single receiver cooled in a bath at <–40 C (cf. Figure 1.10). The apparatus is evacuated using a water aspirator (10–20 Torr) and the reaction flask warmed in an oil bath (initially rt), until the distillation has stopped completely. After some cooling, nitrogen is admitted. A small brown residue remains in the reaction flask. The distillate, a mixture of dioxane, water ( 0.3 mol) and the desired product, is vigorously shaken with 15 g of K2CO3 in order to absorb the water. After suction filtration through sintered glass and thorough rinsing of the K2CO3 with Et2O, a very careful distillation (Note 2) through an efficient column is carried out. The amines N,N-diethyl-2-butyn-1-amine, R1 ¼ Et, R ¼ Me, bp 45 C/12 Torr; N,N-diethyl- 2-pentyn-1-amine, R ¼ R1 ¼ Et, bp 63 C/10 Torr; and

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N,N-diethyl-4-penten-2-yn-1-amine, R ¼ H2C¼CH, R1 ¼ Et, bp 68 C/10 Torr, are obtained in high yields (mostly > 70%). Notes 1.

In the case of the lower homologues, which have a reasonably good solubility in water, several extractions with Et2O have to be carried out. The presence of insoluble copper compounds may give rise to difficulties with the separation of the layers. 2. In view of serious foaming, a relatively big distillation flask is used.

13.2.3

Mannich reactions with liquid acetylenes

Scale: 0.30 molar; Apparatus: 250-ml two-necked round-bottomed flask equipped with a dropping funnel and a reflux condenser and a magnetic stirring bar. 13.2.3.1

Procedure

After addition of 2 g of finely powdered CuBr, the solution of R12 NCH2OH (exp. 13.2.1) is heated up to 70 C (bath temperature). The reactive acetylenic compound (HCCCCR, HCCCH¼CHR, (Het)arylCCH, HCCSR, 0.31 mol) is added over 20 min, while keeping the temperature between 70 and 80 C. The conversion is completed by heating the mixture (brown suspension) for 30 min at 90 C, after which it is cooled to rt. In the other cases, the mixture of R12 NCH2OH and dioxane is heated in a bath at 85 C and the acetylene is added in portions over 30 min. Subsequently, the bath temperature is raised to 100–110 C. After an additional period of 2–2.5 h the reaction mixture is cooled to rt. In all cases the reaction mixture is poured into 500 ml of water, after which a sufficient number of extractions with Et2O are carried out. The organic solutions (washing is not carried out) are dried well over K2CO3 (shaking or stirring with 20 g of K2CO3 for 15 min, then suction filtration and rinsing of the drying agent with Et2O). The isolation is carried out as described in the preceding procedure. Yields are generally higher than 70%.

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EXPERIMENTAL SECTION

271

Examples of compounds prepared by this method: N,N-dimethyl-2-heptyn-1amine, n-BuCCCH2NMe2, bp 60 C/12 Torr; N,N-diethyl-2-heptyn-1-amine, n-BuCCCH2NEt2, bp 86 C/12 Torr; N,N-diethyl-4-hepten-2-yn-1-amine, EtCH¼CHCCCH2NEt2, bp 92–98 C/12 Torr ((E):(Z) 1:1); (Z)-N,Ndiethyl-5-ethylthio-4-penten-2-yn-1-amine, EtSCH¼CHCCCH2NEt2, bp 142 C/12 Torr (short Vigreux column); N,N-diethyl-2,4-nonadiyn-1-amine, n-BuCCCCCH2NEt2, bp 90 C/0.5 Torr (20-cm Vigreux column); 4methoxy-N,N-dimethyl-2-butyn-1-amine, MeOCH2CCCH2NMe2, bp 60 C/ 15 Torr; N,N-diethyl-4-methoxy-2-butyn-1-amine, MeOCH2CCCH2NEt2, bp 77 C/15 Torr.

Note Volatile acetylenes, such as 1-pentyne and methyl propargyl ether, should be added in small portions, especially in the beginning, otherwise it takes rather long before the required reaction temperature of 90 C is reached. 13.2.4

Mannich reactions with acetylenic alcohols

Scale: 0.30 molar (acetylenic alcohol); Apparatus: 500 ml round-bottomed flask with reflux condenser and thermometer; mechanical or magnetic stirring.

13.2.4.1

Procedure [6]

A solution of (dialkylamino)methanol, R1NCH2OH, in 35 ml of dioxane, prepared on 0.40 molar scale (excess, exp. 13.2.1) is cooled to –10 C, after which 10 ml of a 1:1 (by weight) mixture of 96% sulfuric acid and water is added with manual swirling (lower yields are obtained if more is added). Subsequently 1 g of powdered CuBr and 0.30 mol of the acetylenic alcohol are added. The mixture is heated under gentle reflux for 20 min. The greenish-yellow slurry soon disappears and the reaction mixture turns dark red to brown. After cooling to rt, 120 ml of Et2O is added followed by 20 g of anhydrous potassium carbonate. After vigorous shaking, the brown supernatant layer is decanted from the brown slurry. The extraction operation is

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repeated at least 10 times with small amounts of Et2O (cf. hint in Chapter 1, Section 1.3). The combined extracts are dried over a smaller amount of potassium carbonate and subsequently concentrated under reduced pressure. Distillation of the rather viscous liquids through a short column gives 4-(dimethylamino)-2-butyn-1-ol, Me2NCH2CCCH2OH, bp 110 C/15 Torr, and 5-(dimethylamino)-3-pentyn-1-ol, Me2NCH2CCCH2CH2OH, bp 115 C/ 15 Torr, in excellent yields. Good results are obtained also with other R12 NCH2OH.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

C. Mannich and F. T. Chang, Chem. Ber. 66, 418 (1933). W. Reppe et al., Liebigs Ann. Chem. 596, 1 (1955); 601, 81 (1956). C. M. McLeod and G. M. Robinson, J. Chem. Soc. 1470 (1921). J. E. Fernandez, C. Powell and J. S. Fowler, J. Chem. Eng. Data 7, 600 (1963). R. L. Salvador and D. Simon, Can. J. Chem. 44, 2570 (1966). Unpublished results from the author’s laboratory. J. F. Arens, D. H. Koerts and P. Plieger, Recl. Trav. Chim., Pays-Bas 750, 1454 (1956). H. Hellmann and G. Opitz, -Aminalkylirung. Verlag-Chemie, Weinheim, 1960, p. 95. B. Reichert, Die Mannich Reaktion. Springer-Verlag, Berlin, 1959, p. 39. V. Ja¨ger, in Houben-Weyl, Methoden der Organischen Chemie, Band 5/2a. Thieme-Verlag, Stuttgart, 1977, p. 545.

14 Cross-coupling between 1-Alkynes and 1-Bromo-1-alkynes

14.1

INTRODUCTION

The Cu(I)-catalysed cross-coupling between 1-alkynes and 1-bromoalkynes was published for the first time in 1957 [1].

This synthesis of unsymmetrically substituted butadiynes is one of the most useful and versatile methods in acetylenic chemistry [2–5]. This reaction, usually referred to as Cadiot–Chodkiewicz coupling, has been found particularly useful in syntheses of naturally occurring poly-unsaturated compounds [6]. About the mechanism little is known. Copper acetylides are likely intermediates. The present chapter is mainly based on the reviews [1–5] and own experimental data. The Cadiot–Chodkiewicz coupling gives access to a wide variety of unsymmetrically substituted butadiynes, RCC–CCR1. Some hetero-substituted acetylenes do not survive the conditions of the coupling. For example, ethynyl(trimethyl)silane, Me3SiCCH, and ethynyl(trialkyl)stannanes, R3SnCCH, undergo C-heteroatom cleavage under the influence of the amine present in the coupling mixture. However couplings with 2-bromoethynyl(triethyl)silane, BrCC–Si(Et)3, have been successfully carried out [9]. Acetylenic phosphines, R2PCCH, cannot be used, because of strong P–Cu complexation. In the review on this cross-coupling [2] a number of representative asymmetric couplings reported in literature are arranged according to the nature of the acetylene RCCH. 273

274

14.

CROSS-COUPLING BETWEEN 1-ALKYNES . . .

The thermodynamic acidity of the acetylene (pK) and the ease with which it couples with the bromoalkyne seem to be related. Acetylenic hydrocarbons with a non-conjugated triple bond, e.g. 1-hexyne, HCCn-Bu, are less reactive than arylacetylenes, e.g. ethynylbenzene, PhCCH, presumably because the intermediary copper alkynylides, e.g. n-BuCCCu, are formed less easily. Whereas PhCCH and 1-bromo-1-butyne, EtCCBr, gave the unsymmetrical acetylene 1-phenyl-1,3-hexadiyne, PhCCCCEt, in a good ( 70%) yield, 1-(2-bromoethynyl)benzene, PhCCBr, and 1-butyne, EtCCH, reacted under similar conditions to give the unsymmetrical and symmetrical product diphenylbutadiyne, PhCCCCPh, in comparable amounts. From the reaction (at 30 C) between 1-octyne, C6H13CCH, and 1-bromo-1-butyne, EtCCBr, the coupling product 3,5-dodecadiyne, C6H13CCCCEt, was isolated in a modest ( 50%) yield [10]. The formation of appreciable amounts of homo-coupling products may become a serious problem in larger-scale preparations of RCCCCR1 in which both R and R1 contain long carbon chains. We succeeded in obtaining good (> 65%) yields of cross-coupling products from EtCCBr and the alcohols HCC(CH2)nOH with n ¼ 1, 2, 4, 5 and 7 by carrying out the reactions at suitable temperatures (see Table 14.1). However 10-undecyn-1-ol, HCC(CH2)9OH, and bromobutyne gave yields of maximally 45% and 25% of 10,12-pentadecadiyn-1-ol, EtCCCC(CH2)9OH, when performed at 30 to 35 C and 15 to 20 C, respectively, homo-coupling of EtCCBr being the main reaction. An unfavourable factor in the case of HCC(CH2)9OH might be the slight solubility of the copper derivative, which appears as a white suspension upon addition of copper(I) halide. Most of the other acetylenic derivatives investigated form almost colourless solutions with copper(I) halide. The presence of an alcoholic function in the acetylene is said to be favourable, whereas variations in the structure of the bromoacetylene, R1CCBr, are reported to have little influence upon the results. In the general procedure the bromoacetylene (mixed with a solvent) is added dropwise to a well-stirred mixture of the acetylene, water or an organic solvent, aqueous ethylamine, hydroxylamine HCl and a catalytic quantity (1 to 5 mol%) of copper(I)chloride or bromide. The ethylamine serves to neutralise the hydrobromic acid produced in the coupling. The use of a large ( 70 mol%) excess is recommended [2]. If the acetylene contains a COOH group, more ethylamine has to be used. Bromoacetylenes containing a COOH group are most conveniently added as a solution of their sodium or ethylamine salts. The function of the hydroxylamine salt is to reduce any Cu(II), which might be formed by the presence of traces of oxygen, to Cu(I), and which may give rise to oxidative dimerisation of the acetylene RCCH.

14.1

INTRODUCTION

275

Methanol, ethanol and water are the most frequently used solvents. For reactions with compounds that are slightly soluble in these solvents, diethyl ether, tetrahydrofuran, N,N-dimethylformamide or N-methyl-2-pyrrolidinone may be used. The coupling reaction is usually very fast at concentrations of the order of 0.5 to 1 mol/litre and can be easily followed by observation of the heating effect. Most couplings in the presence of ethylamine proceed at a convenient rate within the temperature range 10–35 C, but the rate may decrease strongly if the temperature is lowered by 10 to 20 degrees. ‘Optimum temperatures’ depending upon the nature of the acetylene are recommended [2]. These are 15–25 C for non-conjugated acetylenes, RCCH, and 30 C for enynes, RCH¼CHCCH, and diynes, RCCCCH. If the product is neutral or contains weakly basic groups (NH2, R2N), a small amount of alkali cyanide is added prior to carrying out the work-up. This converts Cu(I) into the inactive complex. If relatively much methanol or ethanol has been used, it seems practical to remove these solvents under reduced pressure before carrying out the extraction procedure. Carboxylic acids can be isolated after treatment with mineral acid. After addition of the bromoacetylene (no cyanide should be added!) methanol or ethanol are removed in vacuo, the neutral by products that might have formed are removed by extraction. Finally, dilute acid is added to liberate the coupling product. 1-Bromo-1-acetylenes are far more reactive than 1-chloro-1-acetylenes, while 1-iodo-1-acetylenes have not been used because they very readily undergo homo-coupling. However, some examples of successful cross-couplings between 1-iodoacetylenes and acetylenic compounds have been reported more recently [7,8]. Conditions similar to the ones applied for coupling between acetylenes and sp2 halides (Chapter 16) were applied.

An unsymmetrically substituted compound RCCCCR1 can, in principle, be obtained by two alternative couplings:

The decision about the alternative to be followed depends upon a number of factors, such as yield, accessibility and stability of the reaction partners and ease of purification of the product. If, for example, 1-phenyl-1,3-hexadiyne, PhCCCCEt, is to be prepared, route a is preferred (PhCCH þ BrCCEt), since couplings with more acidic acetylenes give better results.

276

14.

CROSS-COUPLING BETWEEN 1-ALKYNES . . .

For the preparation of, for example HOCMe2CCCCCH2NMe2, the combination of BrCCCMe2OH and HCCCH2NMe2 is better than HCCCMe2OH þ BrCCCH2NMe2, since the latter bromide is expected to be very unstable. Under the catalytic influence of Cu(I) the bromoacetylene may be converted into the symmetrical product (homo-coupling):

Cu2þ is reduced to Cuþ by the hydroxylamine present in the solution. Ammonia is said to favour this homo-coupling, whereas primary amines repress it. The possibility of this undesired reaction can be further reduced by using Cu(I) salts in small amounts, by slow addition of the bromoacetylene with efficient stirring and by a careful control of the operating temperature (low is better, but not always). The use of large amounts of primary amine (more than the usual excess) involves the risk of addition across the triple bond of the bromoacetylene [3].

14.2

EXPERIMENTAL SECTION

Note: All reactions are carried out under inert gas. 14.2.1

General remarks and some observations

We have carried out several couplings on a 0.05 to 0.10 molar and in some cases larger scale with readily available 1-bromo-1-alkynes and acetylenes (Table 14.1). The amount of copper halide (we always used copper(I) bromide) was ca. 5 mol%, while ethylamine was used in a large excess (15 g 70% aqueous solution for 0.10 molar-scale reactions). The solvent for our reactions was methanol. For the coupling of propargyl alcohol with the lower bromoalkynes we also did experiments with water–methanol mixtures, but the results were similar to those obtained with methanol as the only solvent. The bromoalkyne was added as a solution in methanol. The reaction can be easily followed by temperature observation, provided that the concentration of the acetylene, R1CCH, is not too low (between 0.5 and 1 mol/litre). Addition of a few drops of a methanolic solution of bromoalkyne to a mixture of the acetylenic partner, methanol and the other

14.2

EXPERIMENTAL SECTION

277

reagents usually causes the temperature to rise by several degree celsius within the temperature range 10–40 C. When the addition is stopped, the temperature does not further rise. The couplings with propargyl alcohol are exceptions on this rule: the heating effect during addition of the bromoalkyne is weak below 40 C. This lower reactivity might be due to a poor solubility of the copper acetylide, CuCCCH2OH. It appears as a yellow suspension upon addition of the copper halide. In couplings with 1-butyne and its homologues also a yellow suspension or tubidity was visible, but in these cases the heating effect was strong. It is, in general, advisable to carry out the reactions at temperatures as low as possible, but with maintenance of the prompt temperature response after addition of a small amount of the bromoalkyne or after interruption of the addition. It seems furthermore important to stir efficiently during the addition of the acetylenic bromide, as too high concentrations of this may give rise to homo-coupling. It may be noted from the table that the results of some couplings can be considerably improved if carried out at lower temperatures. Higher temperatures may be more favourable when the intermediary copper acetylide has a low solubility. Another possibility to improve results is to use excess of the bromoalkyne, or of the acetylene if this is readily accessible or cheap, e.g. 2-propyn-1-ol, HCCCH2OH, and 2-methyl-3-butyn-2-ol, HCCC(Me)2OH. In the case of acetylenic alcohols with a long carbon chain one may decide to use an excess of the bromoalkyne in the hope that the alcohol will be completely converted into the desired product, thus circumventing a laborious purification procedure. 14.2.2

General procedure for the Cadiot–Chodkiewicz coupling

Scale: 0.10 molar; Apparatus: 250-ml round-bottomed, three-necked flask equipped with a dropping funnel, gas inlet and thermometer-outlet combination; magnetic stirring. 14.2.2.1

Procedure

In the flask are placed 0.10 mol of the acetylenic derivative, 15 g of a 70% aqueous solution of ethylamine (EtNH2), 5 g of hydroxylamine HCl and 50 ml of methanol. The air in the flask is thoroughly replaced by inert gas, then 0.7 g of finely powdered copper(I) bromide is added. In the case of propargyl alcohol and aliphatic 1-alkynes and some other acetylenes a yellow suspension is formed, while 1,3-diynes may give a red suspension. A mixture of 0.10 mol of the bromoalkyne (Chapter 9) and 25 ml of methanol is added dropwise over 40 min with efficient stirring and maintaining the temperature at the level indicated in Table 14.1 (occasional cooling in ice). Ten minutes after the

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14.

CROSS-COUPLING BETWEEN 1-ALKYNES . . . Table 14.1

Cadiot–Chodkiewicz cross-couplingsa Reactants C6H13CCH, BrCCEt PhCCH, BrCCEt EtCCH, BrCCPh HOCH2CCH, BrCCEt HOCH2CCH, BrCCEt HOC(Me)2CCH, BrCCEt HO(CH2)2CCH, BrCCEt HO(CH2)2CCH, BrCCEt HO(CH2)4CCH, BrCCEt HO(CH2)4CCH, BrCCEt HO(CH2)4CCH, BrCCEt HO(CH2)7CCH, BrCCEt HO(CH2)9CCH, BrCCEt HO(CH2)9CCH, BrCCEt HO(CH2)9CCH, BrCCEt ROCH2CCH, BrCCC5H11b EtSCH2CCH, BrCCEt EtSCH2CCH, BrCCEt Et2NCH2CCH, BrCCEt RO(CH2)2CCH, BrCCEtb 5% excess EtCCBr RO(CH2)4CCH, BrCCEt Et2N(CH2)2CCH, BrCCEt Et2N(CH2)2CCH, BrCCEt (EtO)2CHCCH, BrCCEt EtSCH¼CHCCH, BrCC–t-Bu H2NC(Me)2CCH, BrCCEt H2NC(Me)2CCH, BrCCEt

Temp. (in C) 30–35 or 15–20 44–48 25–30 45–50 25–45 20–25 25–28 9–11 15–17 28–32 42–47 25–30 45–50 35–40 15–20 30–35 15–18 40–45 30–35 17–20 17–20 25–30 10–13 24–27 30–35 37–40 11–13

Yield (in %)

Add. time (in hours)

% Excess RCCH

1

20

1 0.75

20 20 20 20 20 15 15

55 70 45 86 71 81 74 87 69 57 45 64 36 45 25 >80 80 70 >80 74 80 <10 55 77 >80c 43c 67c

15

1 1

15 15 20 1.2 1.2

a Reactions carried out in the author’s laboratory on a scale of at least 50 mmol; products were isolated by fractional distillation at 10 to 15 Torr, products with long carbon chains in a high vacuum. For other couplings see the Refs. [1,2]. b R ¼ OCH(Me)OEt. c Undistilled products, purity 95%.

addition, a solution of 2 g of NaCN or KCN in 10 ml of water is introduced. After removing the greater part of the methanol on the rotary evaporator, the remaining liquid is extracted with Et2O. After drying over magnesium sulphate or potassium carbonate (in the case of amino compounds) and concentration of the solution under reduced pressure, the remaining liquids are distilled in a vacuum. Products with systems of more than two conjugated triple bonds should not be distilled.

REFERENCES

279 REFERENCES

1. W. Chodkiewicz, Ann. de Chimie (Paris), 819 (1957). 2. P. Cadiot and W. Chodkiewicz, in Chemistry of Acetylenes (ed. H. G. Viehe). Marcel Dekker, New York, 1969, p. 597. 3. G. Eglinton and W. McCrae, in Adv. in Org. Chem. Interscience Publ., New York, 1963, Vol. 4, p. 252. 4. T. F. Rudledge, Acetylenic Compounds. Reinhold Book Corp., New York, 1968, p. 256. 5. U. Niedballa, in Houben-Weyl, Methoden der Organischen Chemie, Band 5/2a. Thieme-Verlag, Stuttgart, 1977, p. 931. 6. F. Bohlmann, C. Zdero, H. Bethke and D. Schumann, Chem. Ber. 100, 1553 (1968). 7. J. Wityak and J. B. Chan, Synth. Commun. 21, 977 (1991). 8. G. Linstrumelle, personal communication. 9. R. Eastmond, D. R. M. Walton, J. Chem. Soc., Chem. Comm., 204 (1968). 10. Unpublished results and observations from the author’s laboratory.

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15 Copper Halide-Catalysed Oxidative Coupling of Acetylenes

15.1

METHODS, SCOPE AND LIMITATIONS

The original procedure [1] using pre-formed copper acetylide has evolved to a number of variants in which the acetylene is oxidised with oxygen or air in the presence of catalytic amounts of copper(I) halide. The overall equation is:

Instead of introducing oxygen, copper(II) salts can be used in stochiometrical amounts. Copper seems to have an unique role. Salts of cobalt and iron are not capable of catalysing the coupling. The various coupling methods have been reviewed [2,3]. A wide variety of acetylenic compounds have been oxidatively ‘dimerised’. Several examples are mentioned in the reviews. Especially in procedures on a small scale relatively large amounts of copper salts have been used, often much more than stochiometrically required. Depending on the acidity of the ethynyl proton in RCCH, the nature of R and other factors, the oxidative coupling may be carried out in an organic solvent or in aqueous medium, following the general procedures a and b. a.

Introduction of oxygen into a vigorously agitated mixture of a 1-alkyne, RCCH, and an organic solvent containing a catalytic amount (up to 10 mol%) of copper(I) halide [4]. In order to solubilise the copper salt, pyridine or TMEDA (formation of the bidentate complex) is used. The amine also facilitates the (reversible) proton removal from the 1-alkyne. Pyridine can be used as solvent, though many chemists will prefer the nonsmelling DMF. The easily removable acetone is particularly attractive [4,5]. Aryl- or hetaryl-acetylenes, (Het)ArCCH, enynes, R1CH¼CHC CH, diynes, R1CCCCH, and triethylsilylacetylene, Et3SiCCH, react 281

282

15.

COPPER HALIDE-CATALYSED OXIDATIVE . . .

very smoothly under the influence of CuX pyridine or CuX TMEDA complexes and yields are generally excellent. Also acetylenic tertiary alcohols, HCCC(R1)(R2)OH, react satisfactorily, but for primary alcohols and the acetylenic amines HCCC(R1)(R2)NH2 the aqueous procedure b is more suitable. Acetylenes without conjugation, e.g. aliphatic 1-alkynes [7], and also 2-ethynyl-1-methylpyrrole [6], react sluggishly, but addition of the more strongly basic 1,8-diaza[5.4.0]bicycloundec-7-ene (DBU) greatly facilitates their oxidative coupling [6,7]. b. Reaction of oxygen with a mixture of the acetylene and an aqueous solution of ammonium chloride containing copper(I) halide. The amount of copper halide is generally much larger than that used in method a. This method can be used for the oxidative couplings of primary (HC C(CH2)nOH), secondary (HCCCH(R)OH) and tertiary alcohols [8], HCCC(R1)(R2)OH), acetylenic carboxylic acids [8] (e.g. 4-pentynoic acid, HCCCH2CH2COOH), and amines [9] (e.g. N-t-butyl-2-propyn-1amine, HCCCH2NH-t-Bu). Successful conversion of butenyne, HC CCH¼CH2, into 1,7-octadien-3,5-diyne, H2C¼CHCCCCCH¼CH2, has been achieved by using diethyl ether as a co-solvent [8]. Oxidative couplings of methyl 10-undecynoate, HCC(CH2)8COOMe, 1-penten-4-yne, H2C¼CHCH2CCH, 1-alkyn-o-ols, HCC(CH2)nOH, 5-hexyn-2-one, HCCCH2CH2COMe, 2-penten-4-yn-1-ol, HCCCH¼ CHCH2OH, have been carried out in water or alcohol-water mixtures [10–14]. As the oxidative couplings proceed smoothly over a wide pH range, acid- as well as base-sensitive acetylenes can be dimerised with satisfactory results. Acetylenic amines can be coupled as their HCl salts. A number of heterosubstituted acetylenes do not give the coupling products, due to the presence of strongly complexing groups [15] in ethynylphosphines, HCCPR2, C-heteroatom cleavage [15] in ethynyl(trialkyl)stannanes, HCCSnR3, and led analogues, HCCPbR3, or reactions involving strongly activated triple bonds [16], e.g. HCCOEt (however, cf. [22]). Several attempts to couple methyl propiolate, HCCCOOMe, and 2-propyn-1-amine, HCCCH2NH2, have failed [17]. Under basic conditions the order of the reaction rates of oxidative couplings is found to be parallel with the expected order of acidities of the acetylenes [18,19]. Thus, enynes RCH¼CHCCH, and diynes, RCCCCH, reacted faster than do acetylenes with a non-conjugated triple bond. Discussions on the various mechanistic proposals can be found in the reviews [2,3,20]. Our rather extensive experience with oxidative couplings shows, that none of the various solvents gives generally satisfactory results. Many acetylenic derivatives can be successfully coupled in pyridine, which is a good

15.2

EXPERIMENTAL SECTION

283

complexing agent for copper compounds. However, some couplings of acetylenic compounds containing polar groups such as OH and C¼O do not give optimal results in pyridine, while the work-up may be laborious. Application of DMF, acetone or other volatile organic solvents provides complementary possibilities for oxidative couplings. Water is a suitable solvent for couplings of the lower acetylenic alcohols such as HCCCH2OH. Also some more lipophilic acetylenes have been successfully coupled using a two-phase system of water and an organic solvent [8]. In a number of cases the coupling may stop or proceed very sluggishly due to formation of a slightly soluble copper compound. The only general advice that we can give is to try another solvent. Aryl- or hetarylacetylenes (except 2-ethynyl-1-methylpyrrole), enynes (R1CH¼CHCCH) and diynes (R1CCCCH) very readily ‘dimerise’ and the choice of the solvent is determined only by considerations involving the ease of the work-up.

15.2

EXPERIMENTAL SECTION

For a summary of the various experimental procedures and some procedures from literature see Table 15.1. 15.2.1

Oxidative coupling of propargyl alcohol in aqueous medium

Scale: 0.50 molar; Apparatus: Figure 1.9, 500 ml, with long gas inlet tube 15.2.1.1

Procedure

After completely replacing the air in the flask by oxygen, the rate of introduction of oxygen is adjusted at 100 ml/min. The flask is charged with 100 ml of a cold ( 5 C) saturated aqeous solution of ammonium chloride and 5 g of finely powdered copper(I) chloride (technical grade may be used). After addition of 4 g of freshly distilled propargyl alcohol (under gentle stirring) at rt, the colour of the mixture (first green) becomes very light. The rate of stirring is increased in order to effect intensive mixing of the solution with oxygen (high turbulence). The mixture is brought at 30 C, after which the temperature gradually rises to above 35 C. By occasional cooling the temperature is maintained in the region of 40 C. When the green colour begins to return, a second portion of 4 g of propargyl alcohol is added (stirring is temporarily stopped). The remainder

284

15.

COPPER HALIDE-CATALYSED OXIDATIVE . . . Table 15.1

Copper(I) chloride-catalysed oxidative coupling of acetylenic compounds* Acetylenic compound HCCCH2OH HCCCH2OH HCCCH(Me)OH HC¼CCMe2OH HCCCH2CH2OH HCCCH2OMe (Z)-HC–CCHCHOMe HCCAr HCCSiEt3 HCCO–t-Bu HCCCH(OEt)2 HCCCH2SEt 2-Ethynylpyridine

Reaction conditions

NH4C1, H2O, 40 TMEDA, acetone, 40 TMEDA, acetone, 45–50 TMEDA, acetone, 45–50 TMEDA, acetone, 45–50 TMEDA, acetone, 40–50 TMEDA, acetone, 45–50 TMEDA, acetone, 45–50 TMEDA, acetone, air, rt, 6 h TMEDA, acetone, rt, 1 h TMEDA, DMF, 45-50 TMEDA, DMF, 40 TMEDA, MeOCH2CH2OMe, 35 pyridine, rt pyridine, 40–45 HCC(CH2)4OH HCCEt DBU, pyridine, 30–35 HCC–t-Bu DBU, pyridine, 35–40 HCCSiMe3 DBU, pyridine, 35–40 2-Ethynyl-1-methylpyrrole DBU, pyridine, 35–40 HCC(CH2)2COOH NH4C1, acetone, H2O, 0 HCCCMe2NH2 HC1 NH4C1, H2O, 50 HCCCH2NH–t-Bu NH4C1, 2 M HCI, 55, 6 h HCCCH2CH¼CH2 NH4Cl, HCI (diluted) HCC(CH2)3OH NH4C1, HCI (diluted) HCCCCSiEt3 Same conditions, 1.5 h HCCSEt NH4OH (conc.), MeOH, rt, 1 h

Refs. and notes

Ref. 5; excellent yield Ref. 22; high yield

Ref. 21; 1 h, 79% yield

Ref. 8; quant. yield Ref. Ref. Ref. Ref. Ref.

9; >100 mol % CuCl 11; excellent yield 11; 100% yield 5; excellent yield 16

*Temperatures in C.

of the 0.50 mol is added in 4-g portions over 1.5 h. Stirring (at 40 C) after addition of the last portion is continued for an additional period of 30 to 45 min. The green suspension is cooled to rt, after which six to eight extractions with a 1:3 mixture of THF and Et2O are carried out (first twice with 100-ml portions, for the other extractions 50-ml portions). The light-brown extracts are combined and stirred during 30 min with 50 g of anhydrous potassium carbonate. After filtration and thorough rinsing of the drying agent with the Et2O–THF mixture, the solution is concentrated under reduced pressure. The remaining light brown solid is powdered (mortar) and subsequently heated at 50 C (with occasional manual swirling) in a vacuum of < 1 Torr in order to remove the last traces of solvent. The yield of pure product is greater than 85%.

15.2

EXPERIMENTAL SECTION

15.2.2

285

Coupling of 3-butyn-2-ol using copper(I) chloride TMEDA in acetone

Scale: 0.50 molar; for the equipment see exp. 15.2.1 15.2.2.1

Procedure [4]

After filling the flask with oxygen, 90 ml of acetone, 3.2 g of TMEDA, 3.2 g of finely powdered copper(I) chloride and 5 g of of 3-butyn-2-ol (commercially available) are introduced with intervals of a few seconds and with stirring at a moderate rate. The flow of oxygen is adjusted at 100 ml/min and very vigorous stirring is started (intensive mixing of the solution with oxygen). The mixture is heated to 45 C. The temperature of the green-blue solution rises to over 50 C within a few min. Occasional cooling is applied to keep the temperature between 45 and 50 C. When the temperature has begun to drop (without cooling) and the colour of the solution has become darker, a second portion of 5 g of the acetylenic alcohol is added. The remaining amount is introduced in 5 g-portions over approximately half an hour. When after addition of the last portion the temperature begins to drop, the reaction mixture is heated in a bath at 45 C. After an additional half an hour most of the acetone is removed under reduced pressure (rotary evaporator). The residue is treated with 100 ml of a saturated solution of ammonium chloride containing some ammonia, after which five extractions with Et2O are carried out. The combined extracts (washing is not carried out) are dried over anhydrous potassium carbonate. After concentration in vacuo (in the last stage a high vacuum is applied) a viscous light-brown oil remains, which slowly solidifies upon standing at rt. The 1H-NMR-spectrum (4.45 and 1.42 ppm) indicates that the product has a satisfactory purity. The yield is almost quantitative. 2-Methyl-3-butyn-2-ol, HCCCMe2OH (0.15 mol, added in one portion), is converted into 2,7-dimethyl-3,5-octadiyn-2,7-diol by a similar procedure, using 70 ml of acetone, 1.2 g of CuCl, 1.2 g of TMEDA. The work-up is carried out by adding aqueous NH4Cl (20 g in 500 ml) containing a small amount of ammonia. The solid diol is obtained in almost 100% yield. For the oxidative coupling of 3-butyn-1-ol, HCC(CH2)2OH, (0.15 mol) 80 ml of acetone and the same amounts of CuCl and TMEDA are used. After the reaction has finished, 5 ml of water is added, and the acetone is removed under reduced pressure. The greenish residue is extracted five times with Et2O. The extract is dried over potassium carbonate, which adsorbs

286

15.

COPPER HALIDE-CATALYSED OXIDATIVE . . .

dissolved copper compounds. After thorough removal of the ether under reduced pressure, 3,5-octadiyn-1,8-diol remains as a viscous liquid (yield 100%) slowly solidifying at rt. Similar procedures (on a 0.10–0.15 molar scale) are applicable for 2-propyn1-ol, HCCCH2OH, 3-methoxy-1-propyne, HCCCH2OMe, (Z)-1-methoxy1-buten-3-yne, HCCCH¼CHOMe, 2-t-butyl-1-buten-3-yne, HC CC(t-Bu)¼CH2, ethynylbenzene, PhCCH, 2-ethynylthiophene and 2-ethynylfuran. In procedures on a larger scale the substrate is added portionwise. In the cases of ethynyl(trimethyl)silane, Me3SiCCH, and 3-ethylthio-1propyne, HCCCH2SEt, the reaction stops in an early stage. With 3,3diethoxy-1-propyne, HCCCH(OEt)2, the reaction at 45 C proceeds rather slowly [17]. 15.2.3

Oxidative coupling of 3,3-diethoxy-1-propyne using CuCl TMEDA in DMF

Scale: 0.15 molar; Apparatus: Figure 1.9, 500 ml, oxygen is introduced at a rate of 100 ml/min.

15.2.3.1

Procedure

After completely replacing the air by ogygen, 110 ml of DMF, 1.5 g of freshly powdered copper(I) chloride, 5 g of TMEDA and 0.15 mol of freshly distilled 3,3-diethoxy-1-propyne, are introduced with intervals of a few seconds. A greyish suspension is formed. After starting very vigorous stirring, the temperature rises to above 40 C within a few minutes. Occasional cooling may be necessary. After the exothermic reaction has subsided (dropping of the temperature) the mixture is stirred for an additional 20 min at 40 C. The bluish-green solution is then treated with 500 ml of water and five extractions with a 1:1 mixture of Et2O and pentane are carried out. The combined extracts are washed with water and dried over anhydrous potassium carbonate. After removal of the solvent under reduced pressure pure 1,1,6,6-tetraethoxy-2,4-hexadiyne remains as an almost colourless liquid. Yield 95%. Ethyl propargyl sulphide, HCCCH2SEt, is converted ( 85% yield) into 1,6-bis(ethylthio)2,4-hexadiyne by a similar procedure.

15.2

EXPERIMENTAL SECTION

15.2.4

287

Oxidative coupling of 5-hexyn-1-ol in pyridine

Scale: 0.20 molar; Apparatus: Figure 1.9, 500-ml; oxygen is introduced at a rate of 100 ml/min. 15.2.4.1

Procedure

5-Hexyn-1-ol (0.20 mol) is dissolved in 110 ml of pyridine and 1 g of finely powdered copper(I) chloride is added with stirring at a moderate rate. The green solution is then stirred vigorously and the temperature rises within 15 min to 40 C. The temperature of the mixture is kept between 40 and 45 C by occasional cooling. After the exothermic reaction has subsided and the temperature has begun to drop, the mixture is stirred for another half an hour at 40 C, during which period the colour gradually becomes darkgreen. The greater part of the pyridine is removed on the rotary evaporator. The remaining liquid is treated with a sufficient amount of cold (0 C) dilute aqueous hydrochloric acid (4 N). The solution is extracted four times with Et2O. The combined extracts are washed with water and subsequently dried over magnesium sulphate. After removal of the solvent in vacuo small amounts of the starting compound are distilled off in a high vacuum. The residue (yield 85%) is almost pure 5,7-dodecadiyn-1,12-diol. It solidifies after cooling to rt.

15.2.5

Oxidative coupling of 2-ethynylpyridine

Scale: 0.20 molar; Apparatus: Figure 1.9, 500 ml, without dropping funnel; oxygen is introduced at a rate of 100 ml/min. 15.2.5.1

Procedure

A mixture of 0.20 mol of 2-ethynylyridine, 2.0 g of finely powdered copper(I) chloride and 100 ml of pyridine is vigorously stirred, while keeping the temperature of the mixture between 15 and 20 C (if the temperature is allowed to

288

15.

COPPER HALIDE-CATALYSED OXIDATIVE . . .

rise above 30 C, much brown tarry material is formed). After 1.5 h the dark mixture is poured into 300 ml of water. The mixture is extracted four times with small portions of chloroform. The combined extracts are dried over anhydrous potassium carbonate, after which the solvent is removed under reduced pressure. The last traces of solvent are removed in an oilpump vacuum (< 0.5 Torr). The remaining solid (mp 119–120 C) is pure di(2-pyridyl)butadiyne. Yield 80%. Oxidative couplings of phenylacetylene, 2-ethynylfuran 3-ethynylpyridine, 2-ethynylthiophene, 5,5-dimethyl-1,3-hexadiyne, t-BuCCCCH, and N,Ndiethyl-2-propyn-1-amine, HCCCH2NEt2, are successfully carried out by similar procedures at 35 C. Stirring and introduction of oxygen are stopped when the temperature begins to drop fast and the colour of the mixture has become very dark-green or greenish brown. Yields are generally excellent. 15.2.6

Oxidative coupling of 1-butyne catalysed by CuCl and 1,8-diaza[5.4.0]bicycloundec-7-ene (DBU)

Scale: 0.50 molar; Apparatus: Figure 1.9, 1-litre. The outlet is connected to a cold trap (–78 C); oxygen is passed through the flask at a rate of 100–150 ml/min. All connections are made gas-tight. 15.2.6.1

Procedure

After the air in the flask has been completely replaced by oxygen, 250 ml of pyridine, 2 g of finely powdered copper(I) chloride and 3 ml of DBU are introduced. The mixture is cooled to 10 C and 0.50 mol of 1-butyne (liquified in a cold trap, –70 C) is added. Vigorous stirring with introduction of oxygen is started. The temperature of the mixture gradually rises, but is kept between 25 and 30 C by occasional cooling in a bath at –10 C. When the reaction has subsided, the contents of the cold trap are returned into the flask (usually not more than a few ml). Stirring at 35 C is then continued for an additional period of 30 min. The dark-green solution is poured into 1 litre of ice water, after which ten extractions with small (first portion 70 ml, subsequently 30 ml) portions of pentane are carried out. The combined extracts are washed with cold dilute hydrochloric acid and subsequently dried over magnesium sulphate. Most of the pentane is distilled off at normal pressure through an efficient column. The remaining liquid is distilled in vacuo. 3,5-Octadiyne, bp 40 C/15 Torr, is obtained in greater than 75% yield.

15.2

EXPERIMENTAL SECTION

15.2.7

289

Oxidative coupling of 2-ethynyl-1-methylpyrrole catalysed by CuCl and DBU

Scale: 0.05 molar; Apparatus: Figure 1.9, 250 ml; magnetic stirring; oxygen flow: 100 ml/min. 15.2.7.1

Procedure [6]

A mixture of 0.05 mol of 2-ethynyl-1-methylpyrrole, 50 ml of pyridine, 1 g of finely powdered copper(I)chloride and 2 g of DBU is vigorously stirred. The temperature of the mixture, initially 20 C, rises to above 35 C, but is kept between 35 and 40 C by occasional cooling. After the temperature has begun to drop, stirring is continued for an additional half an hour at 30–35 C. The mixture is poured into 500 ml of water, after which five extractions with Et2O are carried out. The combined extracts are dried over anhydrous potassium carbonate and subsequently concentrated in vacuo . The last traces of pyridine are removed in a high vacuum of < 0.5 Torr 1-methyl-2-[4-(1-methyl-1H-2-yl) 1,3-butadiynyl]1-1H-pyrrole remains as a light-brown solid. Yield > 80%. In the absence of DBU no reaction takes place. t-Butylacetylene is ‘dimerised’ with an excellent yield by a similar procedure to give white crystals [7].

15.2.8

Oxidative coupling of ethynyl(trimethyl)silane

Scale: 0.10 molar; Apparatus: Figure 1.9, 500 ml; oxygen is introduced at a rate of 100 ml/min. 15.2.8.1

Procedure

After completely replacing the air in the flask by oxygen, 50 ml of DMF, 2 ml of pyridine, 1 g of finely powdered copper(I) chloride and 0.10 mol of trimethylsilylacetylene are placed in the flask. Vigorous stirring is started, causing

290

15.

COPPER HALIDE-CATALYSED OXIDATIVE . . .

the temperature to rise within a few minutes from 20 to 40 C. Occasional cooling is necessary to keep the temperature between 35 and 40 C. After the temperature has begun to drop (from 40 C) stirring is continued until the colour of the mixture has become brown. The mixture is poured into 500 ml of ice water, after which four extractions with small portions of pentane are carried out. The combined organic solutions are washed with cold (0 C) 2 M hydrochloric acid in order to remove traces of pyridine and subsequently dried over magnesium sulphate. After evaporation of the pentane in vacuo bis(trimethylsilyl)butadiyne remains as light-brown crystals. Yield 80%. Using CuCl in pyridine or CuCl TMEDA in acetone, poor results are obtained.

15.2.9

Oxidative coupling of the HCl–salt of 2-methyl-3-butyn-2-amine

Scale: 0.20 molar; Apparatus: Figure 1.9, 250 ml; oxygen is introduced at a rate of 100 ml/min. 15.2.9.1

Procedure

Concentrated, aqueous hydrochloric acid (36%) is added dropwise at 0 C to a mixture of 0.20 mol of 2-methyl-3-butyn-2-amine and 150 ml of a saturated aqueous solution of ammonium chloride until the pH has become 6. Finely powdered copper(I) chloride (8 g) is introduced, after which the mixture is warmed to 45 C. A yellowish solution is formed. The flask is insulated in cotton wool and very vigorous stirring is started. The temperature rises within half an hour to above 50 C. Stirring is stopped when the temperature has dropped to 30 C, then 30 ml of a concentrated aqueous solution of ammonia and 100 ml of water is added to the light green suspension. The blue solution is extracted seven times with Et2O. The ethereal solutions are dried (without washing) over anhydrous potassium carbonate and subsequently concentrated under reduced pressure. Pure 2,7-dimethyl-3,5-octadiyne-2,7-diamine remains as a light-brown solid. Yield 85%. Under similar conditions 2-propynylamine, HCCCH2NH2, gives an amorphous red solid [17].

REFERENCES

291 REFERENCES

1. C. Glaser, Justus Liebigs Ann. Chem. 154, 137 (1870); Chem. Ber. 2, 422 (1869). 2. G. Eglinton and W. McCrae, Adv. in Org. Chem., Methods and Results, Interscience Publishers, New York, 1963, Vol. 4, p. 225. 3. P. Cadiot and W. Chodkiewicz, in Chemistry of Acetylenes (ed. H. G. Viehe). Marcel Dekker, New York, 1969, p. 597. 4. A. S. Hay, J. Org. Chem. 27, 3320 (1962). 5. R. Eastmond, T. R. Johnson and D. R. M. Walton, Tetrahedron 28, 4601 (1972). 6. S. F. Vasilevsky, H. D. Verkruijsse and L. Brandsma, Recl. Trav. Chim., Pays-Bas 111, 529 (1992). 7. L. Brandsma, H. D. Verkruijsse and B. Walda, Synth. Commun. 21, 137 (1991). 8. W. Reppe et al., Justus Liebigs Ann. Chem. 596, 72 (1955). 9. D. A. Ben Efraim, Tetrahedron 29, 4111 (1973). 10. J. P. Riley, J. Chem. Soc., 2193 (1953). 11. S. Paul and S. Tchelitcheff, Bull. Soc. Chim. France, 417 (1953). 12. J. B. Armitage, C. L. Cook, N. Entwistle, E. R. H. Jones and M. C. Whiting, J. Chem. Soc., 1998 (1952). 13. J. Cologne and Y. Infarnet, Bull. Soc. Chim. France, 1914 (1960). 14. I. Heilbron, E. R. H. Jones and F. Sondheimer, J. Chem. Soc., 1586 (1947). 15. P. Cadiot and W. Chodkiewicz, in Chemistry of Acetylenes (ed. H. G. Viehe). Marcel Dekker, New York, 1969, p. 601. 16. J. F. Arens, H. C. Volger, T. Doornbos, J. Bonnema, J. W. Greidanus and J. H. van der Hende, Recl. Trav. Chim., Pays-Bas 75, 1459 (1956). 17. Unpublished observations and results from the author’s laboratory. 18. F. Bohlmann, H. Schoenowsky, E. Inhoffer and G. Graw, Chem. Ber. 97, 794 (1964). 19. L. G. Fedenok, V. M. Berdnikov and M. S. Svartsberg, Zh. Org. Khim. 9, 1781 (1973); 10, 922 (1974); 12, 1395 (1976). 20. L. I. Simandi, in The Chemistry of the Triple-Bonded Functional Groups, Supplement C, Part 1 (ed. S. Patai). John Wiley, Chichester, New York, 1983, p. 529. 21. U. Fritzsche and S. Hu¨nig, Tetrahedron Lett., 4831 (1972). 22. E. Valenti, M. A. Perica˜s and F. Serratosa, J. Am. Chem. Soc., 7405 (1990).

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16 Transition Metals-Catalysed Couplings of Acetylenes with sp2-Halides

16.1

INTRODUCTION

In 1975 Japanese investigators reported on the coupling of acetylene and some derivatives with a number of sp2-halides under the joint influence of palladium(II) chloride and copper(I) iodide [1]. In the same year, two other research groups had communicated similar couplings under different conditions, using only palladium catalysts [2,3]. Such like sp to sp2-couplings were earlier only possible under forced conditions [4].

In this Scheme, R1 may represent an aryl, hetaryl, (cyclo-)olefinic group or an allenic system. As to the nature of R there are practically no limitations. In the case of acetylene itself, the product is a disubstituted acetylene RCCR. By far most of the couplings are performed under the joint catalytic action of a palladium complex and a copper(I) halide. The solvent is usually an amine, which also serves to bind the hydrogen halide eliminated. Useful alternatives are the reactions of metallated acetylenes, RCC–ZnCl or RCCMgX, with sp2-halides (R1X) [5,6].

The preliminary communications on these catalytic methods were followed by a large number of papers. A number of selected procedures are described in the monograph [7] and in reviews [8]. The most commonly used procedures for the fully catalytic cross-couplings consist of the reaction between a free acetylene and an olefinic or (het)aryl halide in the presence of a palladium compound, usually Pd(PPh3)4 or PdCl2 (PPh3)2, and a copper(I) halide (CuBr or CuI) using an aliphatic or cyclo-aliphatic amine as solvent. The initial 293

294

16.

TRANSITION METALS-CATALYSED. . .

formation of bis(triphenylphosphane) dialkynyl palladium(II), decomposing into bis(triphenylphosphane) palladium(0) and the ‘dimeric’ acetylene, has been suggested [1] (cf. [2]). The coordinatively unsaturated Pd species and the olefinic or aryl halide form the oxidative addition product. This undergoes nucleophilic attack by the acetylide anion. Reductive elimination finally affords the disubstituted acetylene. If Pd(PPh3)4 is used, the oxidative addition may take place first, then the nucleophilic substitution, reductive elimination, etc. may follow [3]. Detailed mechanisms are not yet available. The latter representation is supported by the following observations: a.

Addition of a relatively large excess of triphenylphosphane, more than two equivalents with respect to the amount of the Pd-catalyst, causes the reaction to slow down or to stop (repressing the substitution of phosphane ligands by other organic groups) [9]. b. In piperidine, pyrrolidine and diisopropylamine the reaction proceeds markedly faster than in more weakly basic amines such as diethylamine [1,10] (less easy formation of acetylide in the latter solvent). While it has been noticed that copper(I) halide considerably facilitates the couplings in amines, it is not known in what stage it intervenes in the reaction. A likely assumption is that a copper alkynylide is formed, which reacts with the oxidative adduct Pd(X)R1(PPh3)2 to give Pd(CCR)R1(PPh3)2. In this respect, a comparison may be made with the Pd(0)-catalysed reactions of alkynylzinc chlorides with vinylic or (het)aryl halides [5].

16.2

SCOPE AND LIMITATIONS

The Pd/Cu-catalysed cross-coupling reaction has a very broad scope. There are only a few limitations. The reaction first seemed to be restricted to activated halogenides, such as 1,1- or 1,2-dichloroethene [11] and a compound with the system C(Cl)¼N [12], but later [13] it was shown that even vinylic chlorides with the structure RCH¼CHCl react smoothly at room temperature in the presence of copper(I) iodide and the weakly liganded palladium compounds PdCl2 (MeCN)2 and PdCl2 (PhCN)2. In these couplings the relatively strongly basic piperidine was used as a solvent. Strikingly, the more commonly used complexes Pd(PPh3)4 and PdCl2 (PPh3)2 were found to be much less efficient catalysts in couplings with olefinic chlorides. On the other hand, for cross-couplings with olefinic iodides Pd(PPh3)4 turned out to be the most efficient catalyst. The procedures summarised in Tables 16.1a–c illustrate the synthetic potential of the coupling methods.

16.2

SCOPE AND LIMITATIONS

295

Table 16.1a Pd/Cu-Catalysed cross-couplings of ethynyl(trimethyl)silane with sp2-halides sp2-Halidea 3-Bromo-5,6-dihydropyran (5-Bromo-3,4-dihydro -2H-pyran) 3-Bromo-5,6-dihydropyran (5-Bromo-3,4-dihydro -2H-pyran) 3-Br,4-Bromothiophene

2-Bromofuran

3-Bromopyridine

4-Bromoacetophenone [1-(4-Bromophenyl)-1 -ethanone] 2-Iodo-1-methylpyrrole

1-Bromo-2-chlorobenzene

1-Bromo-2-fluorobenzene 4-Bromoanisole (1-Bromo-4-methoxybenzene) 4-Bromo-dimethylaminobenzene (4-BromoN,N-dimethylaniline) 2 Br, 3-Bromofuran

a

Reaction conditionsb 35 ml Et2NH, 400 mg PdC12 (PPh3)2, 150 mg Ph3P, 0.10 mol 3-Br-5,6-DHP, 0.12 mol Me3SiCCH; 100 mg CuI; ! reflux þ 4 h 40 g piperidine; 0.10 mol 3-Br-5,6-DHP, 0.12 mol Me3SiCCH, 150 mg Pd(PPh3)4, 120 mg Ph3P; 120 mg CuI; ! reflux þ 30 min 0.20 mol 3,4-dibromothiophene, 500 mg PdCl2 (PPh3)2, 200 mg Ph3P; 30 g Et2NH (100 mol% excess), 0.10 mol Me3SiCCH; 150 mg CuI; reflux ! 80 C 250 ml Et3N, 0.40 mol 2-Br-furan, 700 mg PdCl2 (PPh3)2, 500 mg Ph3P; 0.40 mol Me3SiCCH; 400 mg CuBr; ! reflux þ 1 h 250 ml Et3N, 0.30 mol 3-Br-pyridine, 800 mg PdC12 (PPh3)2, 600 mg Ph3P, 0.35 mol Me3SiCCH; 400 mg CuBr; ! reflux þ 1 h 50 ml Et3N, 0.20 mol 4-BrC6H4C(¼O)Me, 600 mg PdCl2 (PPh3)2, 400 mg Ph3P, 0.23 mol Me3SiCCH; 300 mg CuI; ! 80–85 C þ 3 h 100 ml Et3N, 0.25 mol 2-iodo-l-methylpyrrole, 0.30 mol Me3SiCCH, 600 mg PdCl2 (PPh3)2; 250 mg CuBr; ! 75 C þ 3 h 90 g piperidine, 0.20 mol 1-BrC6H4–2-C1, 0.24 mol Me3SiCCH; 600 mg Pd(PPh3)4; 300 mg CuBr þ 1 g LiBr in 10 ml THF; ! reflux þ 40 min same amounts; ! reflux þ 30 min 75 g piperidine, 0.10 mol 1-BrC6H4–4-OMe, 300 mg PdCl2 (PPh3)2, 500 mg Ph3P, 0.12 mol Me3SiCCH; 300 mg CuI; ! reflux þ 2 h 75 g piperidine, 0.10 mol 4-BrC6H4NMe2, 500 mg PdCl2 (PPh3)2,1000 mg Ph3P, 0.14 mol Me3SiCCH, 400 mg CuI; ! reflux þ 2 h 70 ml Et3N, 0.05 mol 2,3-dibromofuran, 0.05 mol Me3SiCCH, 150 mg Ph3P; ! , 75 C þ 15 min; ! rt; 70 mg CuBr þ 500 mg LiBr in 5 ml THF; ! reflux þ 1.5 h [60% yield of 3-Br-2-CC(SiMe3)-furan]

The atom(s) in bold/cursive is (are) substituted by one (two) acetylenic group(s). The various operations or additions to be carried out are separated by a semicolon; the arrow ( ! ) sign means: ‘bring at, or – in some cases – allow the mixture to reach the desired (e.g. reflux) temperature’; additional reaction times are indicated with the plus (þ) sign and number of minutes or hours.

b

296

16.

TRANSITION METALS-CATALYSED. . . Table 16.1b

Pd/Cu-Catalysed cross-couplings of acetylenic alcohols with sp2-halides* Reactantsa

Reaction conditionsb

HCCCH2OH and H2C¼CH(Me)Br

150 ml Et2NH, 0.20 mol 2-propyn-1-ol, 500 mg Pd(PPh3)4, 300 mg CuBr; rt ! 45 C; 0.25 mol 2-bromopropene over 30 min at 45 C; ! reflux þ 1 h HCCCH(Me)OH and 50 ml Et2NH, 0.10 mol 3-butyn-2-ol, 0.15 mol H2C¼CH(Me)Br 2-bromopropene, 250 mg Pd(PPh3)4, 200 mg CuI; reflux þ 30 min HCCCMe2OH and 50 ml Et2NH, 0.10 mol 2-methyl-3 -butyn-2-ol, EtOCH¼CHBr 300 mg Pd(PPh3)4, 250 mg CuI; 0.06 mol 1-bromo-2-ethoxyethene at rt; ! 40 C; add another 0.05 mol the bromide over 15 min; after exothermic reaction, reflux þ 1 h HCCC(Me)2OH and 50 ml Et2NH, 0.10 mol 2-methyl-3-butyn-2-ol, (E )-CICH¼CHCl 0.5 mol (E)-1,2-dichloroethene; 200 mg PdCl2 (PPh3)2, 100 mg CuI; rt ! reflux þ 2 h HCCCH2OH and 10 ml Et3N, 0.08 mol 2-propyn-1-ol, 0.05 mol 1-bromo1-BrC6H4–4-NO2 4 nitrobenzene, 20 ml C6H6,, 200 mg PdCl2 (PPh3)2, 200 mg PPh3; 200 mg CuI; ! reflux þ 2 h HCCCH2OH and 0.10 mol 1-bromo-1-cyclooctene, 400 mg Ph3P, 1-Br-1-cyclooctene 200 mg PdCl2 (PPh3)2; ! 30 C þ 30 min; 100 ml i-Pr2NH, 0.10 mol 2-propyn-1-ol; 250 mg CuBr þ 1.5 g LiBr in 10 ml THF; ! reflux þ2 h HCCC(Me)2OH and 100 ml Et3N, 0.10 mol 2,5-dibromothiophene, 0.25 mol 2,5-Dihromothiophene 2-methyl 3-butyn-2-ol, 400 mg Ph3P, 300 mg PdCl2 (PPh3)2; 200 mg CuBr; rt; ! , 80 C þ 2.5 h 100 ml Et3N, 0.20 mol 1-bromo-4-fluorobenzene, HCCC(Me)2OH and 1-Br–C6H4-4-F 400 mg Ph3P, 400 mg Pd(PPh3)4, 0.25 mol 2-methyl-3-butyn-2-ol; 250 mg CuBr þ 1 g LiBr, 10 ml THF; ! reflux þ 3 h HCCC(Me)2OH and 100 ml Et3N, 0.30 mol 2-methyl-3-butyn-2-ol, 1-Br–C6H4–4-OMe 0.22 mol 1-bromo-4-methoxybenzene; 300 mg Ph3P, 200 mg CuBr; ! –80 C þ 4 h HCCC(Me)2OH and 40 ml Et3N, 0.25 mol 1-bromo-4-chlorobenzene; 1-Br–C6H4–4-Cl ! 30 C; 400 mg Pd(PPh3)4, 200 mg Ph3P; 0.20 mol 2-methyl-3-butyn-2-ol; after 15 min, 250 mg CuBr þ 1 g LiBr in 10 ml THF; ! reflux þ 1.5 h HCCC(Me)2OH and 0.30 mol 2-bromofuran, 300 mg Pd(PPh3)4; rt, 15 min; 2-Bromofuran 90 ml Et3N, 0.40 mol 2-methyl-3-butyn-2-ol, 200 mg Ph3P, 200 mg CuBr þ 1 g LiBr in 10 ml THF; ! 85 C; ! 93 C þ 1 h (Continued)

16.2

SCOPE AND LIMITATIONS

297

Table 16.1b Continued Reactantsa HCCC(Me)2OH and 1-Br,2-Bromobenzene HCCC(Me)2OH and Me2C¼CHBr

Reaction conditionsb 100 ml Et2NH, 0.05 mol 1,2-dibromobenzene, 0.07 mol 2-methyl 3-butyn-2-ol, 300 mg Pd(PPh3)4, no CuBr; ! reflux þ 14 h (yield 55%) 50 ml Et2NH, 0.10 mol 2-methyl-3-butyn-2-ol, 0.15 mol 1-bromo-2-methyl-1-propene; 250 mg Pd(PPh3)4, 200 mg CuI; ! 1 h reflux

*For meaning of superscript a and b cf. Table 16.1a.

Table 16.1c Other Pd/Cu-catalysed cross-couplings* Reactantsa HCCCSH11 and BrCH¼CH2 HCCSiMe3 and BrCH¼C¼CMe2

HCCC6H13 and (E)-ClCH¼CHCl HCC–n-Bu and ClC(Cl)¼CH2 HCCCCMe and 2-Iodothiophene HCCCH2NMe2 and 1-BrC6H4-4-F

Reaction conditionsb 150 ml Et2NH, 0.20 mol 1-heptyne, 300 mg CuBr; 500 mg Pd(PPh3)4; ! 45 C; 0.25 mol 1-bromoethylene in 30 min; 45 C þ 1 h 75 ml Et2NH, 0.12 mol ethynyl(trimethyl)silane, 0.10 mol 1-bromo-3-methyl-1,2-butadiene; 300 mg Pd(PPh3)4; 200 mg CuBr; ! 35 C þ 30 min (50 ml Et2O added) 50 ml Et2NH, 0.10 mol 1-octyne, 50 g (E)-1,2-dichloroethene; 450 mg Pd(PPh3)4, 450 mg CuI; ! 30 C ! reflux þ 1.5 h amounts of reactants same as in case of 1,2-dichloroethene; 600 mg PdCl2 (PPh3)2 and 450 mg CuI were used 80 ml Et3N, 0.05 mol iodide, 0.06 mol 1,3 pentadiyne; 200 mg PdCl2 (PPh3)2, 200 mg Ph3P, 100 mg CuI; ! 40 C þ 1 h (2-bromofuran and 2-bromothiophene gave tars) 0.10 mol 1-bromo-4-fluorobenzene, 400 mg Ph3P, 200 mg PdCl2 (PPh3)2; ! 30 C 30 min; 100 ml i-Pr2NH, 0.10 mol N,Ndimethyl-2-propyn-1-amine; 250 mg CuBr þ 1.5 g LiBr in 10 ml THF; ! reflux þ 3.5 h (Continued)

298

16.

TRANSITION METALS-CATALYSED. . . Table 16.1c Continued

Reactantsa

Reaction conditionsb

HCCCH2OR and 1-BrC6H4-4-F [R ¼ CH(Me)OEt]

HCCH and 2 equiv. 4-BrC6H4C(¼O)Me

HCCH and 2 equiv. 4-IC6H4Me HCCH and 2 equiv. 2-Bromopyridine HCCH and 2 equiv. 2-Iodothiophene HCCH and 2 equiv. 3-Iodothiophene HCCH and 2 equiv. 2-I-1-Me-imidazole

0.10 mol 1-bromo-4-fluorobenzene, 400 mg Ph3P, 200 mg PdCl2 (PPh3)2; ! 30 C þ 30 min; 100 ml i-Pr2NH, 0.10 mol 3-(1-ethoxyethoxy)-1-propyne; 250 mg CuBr þ 1.5 g LiBr in 10 ml THF; ! reflux þ 3.5 h 100 ml Et2NH, 0.05 mol 1-(4-bromophenyl)-1-ethanone; acetylene during 10 min; 100 mg PdCl2 (PPh3)2; 200 mg PPh3, 100 mg CuI; ! reflux þ 30 min, introduction of HCCH same as in exp. with 4-BrC6H4C(¼O)Me, reaction time 3 h same as in exp. with 4-BrC6H4C(¼O)Me, reaction time 2 h same as in exp. with 4-BrC6H4C(¼O)Me, reaction time 2 h (2-bromothiophene reacts very slowly) same as in exp. with 4-BrC6H4C(¼O)Me, reaction time 4 h 60 ml Et3N, 0.05 mol 2-iodo-1-methylimidazole, 200 mg PdCl2 (PPh3)2, 180 mg Ph3P; 100 mg CuI; ! 55 C þ 1.5 h introduction of acetylene

*For meaning of superscript a and b cf., Table 16.1a.

16.3

RELATIVE RATES OF COUPLING

As expected, aryl chlorides are considerably less reactive than the corresponding bromides and iodides. The difference in reactivity between p-chloro- and p-bromobenzonitrile, for example, is of the order of 400 [3]. In general, vinylic halides react more easily than do aryl halides, while in hetaryl halides the halogen atom is substituted by an acetylenic group faster than in the analogous aryl halides [9,14]. A halogen in the a-position of a heteroatom is considerably more reactive than a more remote halogen atom [15]. Already in one of the first papers on Pd-catalysed cross-couplings with acetylenes the influence of substituents in the aryl halide on the reactivity of the halogen atom is mentioned [3]. Relative rates of a number of para-substituted

16.4

REGIOCHEMISTRY

299

aryl halides in the catalysed reaction with 1-heptyne in triethylamine at room temperature and at elevated temperatures have been determined [14]. Electron-donating substituents such as OMe and NH2 make substitution less easy, whereas CN and CH¼O groups facilitate the couplings. The same conclusion was made earlier [12]. In our experiments p-bromoanisole and p-bromo-N,N-dimethylaniline reacted less easily than did bromobenzene [9]. The relative rates are more or less parallel to those observed with oxidative additions of Pd(PPh3)4 to aryl halides. It has been noticed that alkylacetylenes are less reactive than phenylacetylene [2]. Such differences will not be observed when using more strongly basic amines such as piperidine, and during performance of the reactions at elevated temperatures. Alkyl substituents on the double bond retard the reactions with acetylenes. Thus, whereas vinyl bromide reacts under very mild conditions, substitution of bromine in 1-bromo-2-methyl-1-propene, Me2C¼CHBr, requires heating at 70 C or higher temperatures [9]. We found that 3-bromofuran and 3-bromothiophene react rather sluggishly. 3-Bromopyridine, however, showed a high reactivity, comparable with that of the 2-isomer [9].

16.4

REGIOCHEMISTRY

Highly selective substitution of 2-bromine in 2,3-dibromofuran, 2,3-dibromothiophene and 2,5-dibromopyridine has been observed [15]. Reaction of tetraiodothiophene with two equivalents of ethynyl(trimethyl)silane in diisopropylamine led to specific displacement of the 2- and 5-iodine atoms [16]. If 1,2-dibromo-4-nitro- and 1,2-dibromo-3-nitrobenzene and one equivalent of an alkyne interact in the presence of Pd(0) and Cu(I), the bromine atom in the para- and ortho-position is substituted much faster than the meta-bromine atom, so that mono-alkynylation products can be obtained in excellent yields. In similar reactions with the analogous N-(dibromophenyl)acetamides the meta-bromine atom was substituted slowly, but specifically [14]. Successful mono-displacements in 1,2-dibromobenzene have been reported [17]. The coupling reactions were carried out in n-propylamine, t-butylamine or diethylamine, the only catalyst being Pd(PPh3)4. Disubstitution could be achieved by using more acetylene and heating for longer times. Using Cu(I) as a co-catalyst the reaction times for disubstitution were much shorter. We could effect a satisfactory mono-substitution in 3,4-dibromothiophene and in the 2,5isomer by using a 100 mol% (or more) excess of the dibromides [9]. Using a large excess of 1,2-dichloroethene one of the chlorine atoms can be replaced by an alkynyl group [11]. This reaction proceeds with retention of configuration

300

16.

TRANSITION METALS-CATALYSED. . .

(cf. [13]). The excess of 1,2-dichloroethene can be reduced considerably.

The reactivity differences between the halogens are sufficiently large to allow regiospecific performance of the reactions between acetylenes and 1-bromo4-chlorobenzene, 1-bromo-4-iodobenzene and 2-bromo-1,1-dichloroethylene [18]. In the acetate and t-butoxycarbonyl derivatives of 2,4-diiodophenol the p-iodine atom is selectively replaced by an acetylenic group in Pd0/CuIcatalysed couplings with acetylenes in triethylamine at room temperature [19].

16.5

SYNTHETIC APPLICATIONS OF THE CROSS-COUPLING REACTIONS WITH ACETYLENES

The versatility of the acetylenic group in synthetic transformations together with its generally successful coupling to sp2-carbon atoms in aliphatic and (hetero)aromatic systems under mild conditions gives rise to several useful synthetic applications. In continuation on the preliminary communications mentioned several papers with well-described experimental conditions for the Pd- or Pd/Cucatalysed cross-couplings have appeared. Part of these is directed on the synthesis of alkynes with a terminal acetylenic function. A frequently applied strategy is coupling of the halogen compound with ethynyl(trimethyl)silane or 2-methyl-3-butyn-2-ol, followed by base-catalysed removal of the Me3Si-group or elimination of acetone [12,15,20,21].

In the synthesis of 1,3-diynylamines [18], an arylacetylene is coupled with 2-bromo-1,1-dichloroethylene, BrCH¼CCl2, after which the product, 1,1-dichloro-4-aryl-1-buten-3-yne, ArCCCH¼CCl2, is treated with LiNR2 to give 4-aryl-N,N-dialkyl-1,3-butadiyn-1-amine, ArCCCCNR2. A number of (Z)-enynes, RCH¼CHCCH (R ¼ aryl or hetaryl) have been synthesised by a succession of coupling between 1-ethylthio-1-buten-3-yne, HCCCH¼CHSEt, and ArBr or HetarylBr, partial reduction of the triple

16.6

PRACTICAL ASPECTS OF THE COUPLING REACTIONS

301

bond in 1-ethylthio-4-(het)aryl-1-buten-3-yne, (Het)aryl–CCCH¼CHSEt and elimination of ethanethiol from the reduction product (Het)arylCH¼CHCH¼ CHSEt with sodamide in liquid ammonia [22]. Applying the Pd/Cu-catalysed cross-coupling method with ethynyl(trimethyl)silane in combination with base-catalysed removal of the trimethylsilyl group, a variety of di- and polyethynylarenes and -hetarenes have been synthesised [16]. Although, in general, the fully catalytic method seems more practical than the zinc halide method [5], the latter may have distinct advantages when gaseous or unstable acetylenes are to be coupled. Palladium/copper mediated cross-couplings have been widely used in synthesis of structurally or biologically interesting acetylenic compounds and (hetero)cyclic compounds [8].

16.6 16.6.1

PRACTICAL ASPECTS OF THE COUPLING REACTIONS

Performance of the reactions and isolation of the products

Most of the Pd- or Pd/Cu-catalysed couplings can be easily performed. In the usual procedures, the desired amounts of catalysts and additives are added to a mixture of the acetylene, the sp2-halide and an amine (sometimes with a co-solvent). The mixture is stirred under inert gas (oxygen may cause ‘dimerisation’ of the acetylene or other reactions) at room temperature or with heating ‘until GLC or TLC indicates complete conversion’. Temperature control during performance of the reaction is only necessary in the case of very fast reactions and volatile halides such as vinyl bromide and in the case of gaseous acetylenes. The progress of the reaction can be qualitatively followed from the suspended amine salt (precipitating salt in the supernatant layer after temporarily stopping the stirrer). Another way, applicable in the cases of volatile acetylenes such as ethynyl(trimethyl)silane (bp 52 C at atmospheric pressure), provided that the amine is much less volatile, is to observe the temperature in the reaction mixture if the reflux is held constant. If no further increase of the temperature is observed, the conversion is (nearly) finished. We often observed that during heating the mixtures up to reflux the solution turned brown in the beginning, but became light yellow at somewhat higher temperature. Especially in slow reactions or in reactions with propargyl alcohol the brown colour may become more intensive and sometimes the reaction mixture may become black due to the formation of metallic palladium. If the latter stage has been reached, the conversion has stopped. In some cases this decomposition could be prevented by adding a

302

16.

TRANSITION METALS-CATALYSED. . .

limited amount of triphenylphosphane at the moment of beginning development of a brown colour (Pd ‘in statu nascendi’). We therefore advice to keep ready a solution of triphenylphosphane before starting the reaction. The amount should not exceed (in weight) half of the amount of Pd(PPh3)4 or be the same as the amount of PdCl2(PPh3)2. At higher concentrations of triphenylphosphane the reaction is slowed down or may even stop. Very often, however, triphenylphosphane is added already in the beginning if bivalent palladium is used. In some cases, metallic palladium was formed upon addition of the Pd- and Cu-catalysts. This seemed to be caused by reaction of the Pd-compound with the copper salt when the rates of their dissolution were to low due to slight solubility in the amine (especially diisopropylamine) or to insufficient powdering (or coagulation of the particles) of the catalysts. The following general procedure for performing Pd/Cu-catalysed couplings and the work-up may be followed (not absolutely necessary in the case of smooth reactions). The sp2-halide is first warmed for a short time at 40–60 C with Pd(PPh3)4 or the mixture of PdCl2(PPh3)2 and PPh3 without or with a very small amount of the amine until dissolution is complete (formation of the oxidative addition complex), then (more of) the amine and the acetylene are added and finally the copper salt. This is preferably added in a dissolved form, e.g. 200 mg of Cu(I) halide on 1 g of anhydrous lithium bromide in 5 ml of THF. This order of charging the reaction flask with reagents, solvents and catalysts was shown to give satisfactory results [9]. After cooling the reaction mixture to room temperature, either a ‘dry’ or an aqueous work-up may be carried out. In the first case a sufficient amount of diethyl ether or in the case of a sufficient solubility of the product-pentane or hexane (or together with ether) is added. Subsequently the amine salt is filtered off on a sintered-glass funnel (G-1, with suction) and rinsed well with the organic solvent. Complete conversions should afford near to the theoretically expected amount of dried salt. The filtrate is concentrated under reduced pressure and the residue subjected to a flash distillation at very low pressure, using a short column. If there is a great risk of decomposition of the product under the influence of Pd and Cu-remnants, the crude product is dissolved in an organic solvent and the solution filtered through a short column of aluminium oxide or silica gel in order to remove traces of catalysts. Purification by crystallisation or distillation may then follow. In the aqueous procedure of work-up, water and pentane or diethyl ether is added successively, followed by extraction, washing with water, drying and evaporation of the solvents under reduced pressure. The isolation of the product is carried out as described above. Distillation of products from catalysed cross-coupling reactions involves the risk of decomposition under the influence of remnants of catalysts,

16.6

PRACTICAL ASPECTS OF THE COUPLING REACTIONS

303

particularly in the case of reactions of olefinic halides with propargyl alcohol or in the case of acetylenes with a conjugated system of double or triple bonds (e.g. 1,3-diynes). The distillation should therefore not be carried out with amounts larger than 5 g, using a short and wide column (B-29 joints).

16.6.2

Choice of the solvent and catalysts for coupling reactions

The most frequently used solvents are diethylamine, triethylamine and piperidine. The volatile diethylamine is applied in reactions that proceed readily at room temperature or slightly elevated temperatures. It has been found that at room temperature couplings in the absence of copper salts are much faster in piperidine or pyrrolidine than in more weakly basic amines like diethylamine or triethylamine [23]. Similar differences were found when a copper halide was used as a co-catalyst. They may be explained on the basis of the assumption that the active form of the acetylene in the reaction is the acetylide. In the more strongly basic amines this is formed more easily. Couplings with less reactive sp2-halides such as 3-bromothiophene, 1-bromo-4-methoxybenzene and 1-bromo-N,N-dimethylaniline can be successfully carried out in a short time at temperatures in the range 110–115 C, using piperidine as a solvent. An additional advantage is the higher attainable temperature with this solvent [24]. In di- and poly-alkynylation reactions with aryl and hetaryl di- and poly-halides, diisopropylamine was used as a solvent [16]. An explanation for this choice of solvent is not given. With diisopropylamine we obtained better results in the reaction of 1,3-dibromobenzene with two equivalents of ethynyl(trimethyl)silane than in piperidine. Whereas the reaction of 1-bromo1-cyclooctene with propargyl alcohol in triethylamine gave rise to the formation of an intractable mixture and low yields, a satisfactory result was obtained when applying diisopropylamine (see experimental section). The most commonly used catalytic system is a combination of a palladium catalyst and copper(I) bromide or iodide, as proposed in the pioneering report [1]. The Pd-catalyst may be either Pd(PPh3)4 or PdCl2(PPh3)2, in the latter case often combined with two molar equivalents of additional triphenylphosphane. In general, there is no or little difference in activity between the two variants. In both cases the catalysts can enter the catalytic cycle. Although in some procedures carried out at elevated temperatures the copper salt is omitted, this does not seem to have special advantages. We found that also at temperatures above 60 C the reaction proceeded much faster in the presence of copper halide. Others found a molar ratio of 2:3 for Pd(PPh3)4 and CuBr to be optimal for reactions carried out at room temperature [14].

304

16. 16.7

TRANSITION METALS-CATALYSED. . .

EXPERIMENTAL SECTION

Several cross-couplings performed in the author’s laboratory are summarised in Tables 16.1a–c. General Note: All reactions are carried out under nitrogen. 16.7.1

Pd/Cu-catalysed cross-coupling of propargyl alcohol with vinyl bromide

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml, in a later stage the thermometer is replaced with a reflux condenser. Although a variety of aliphatic secondary and tertiary amines may be used as a solvent and scavenger of the hydrogen halide, diethylamine is preferably applied for couplings that proceed very readily. This amine is easily removed after completion of the reaction either in a dry work-up after filtration, or by addition of much water, in which it dissolves completely. The dry work-up is recommended if the product is soluble in water to some extent. 16.7.1.1

Procedure

Diethylamine (100 ml), propargyl alcohol (0.20 mol, freshly distilled under a pressure of 200 Torr) and finely powdered copper(I) bromide (0.3 g) or copper(I) iodide (0.5 g) are successively placed in the flask. After stirring for 15 min at 20–25 C, a suspension of 0.5 g of Pd(PPh3)4 (Note 1) in 10–20 ml of Et2O is added in one portion. Subsequently, a mixture of 0.30 mol (excess) of vinyl bromide (Note 2) and 50 ml of dry Et2O (cooled initially at –10 C) is added in 5 equal portions over 45 min. After introduction of the first portion the temperature gradually rises to 35–40 C, while salt begins to separate from the solution. During the further additions the temperature of the suspension is maintained (occasional cooling or warming) between 40 and 45 C. Since the suspension becomes rather thick, 75 ml of Et2O is added gradually. After an additional hour (a gentle reflux is maintained) the suspension is cooled to rt and then filtered on a sintered-glass funnel. The salt is rinsed well with dry Et2O. Upon cooling to –20 C a small amount of salt precipitates from the Et2O solution. The supernatant solution is decanted from the salt (the latter is rinsed with a small portion of Et2O) and subsequently concentrated under reduced pressure (temperature heating bath

16.7

EXPERIMENTAL SECTION

305

not higher than 30 C). The remaining yellow brown liquid is subjected to a flash distillation at < 1 Torr, using a 20-cm Vigreux column, and the distillate is collected in a single receiver cooled in a bath at <–40 C (Figure 1.10, Note 3). Redistillation at water-aspirator pressure gives the 4-penten-2-yn1-ol, bp 67 C/15 Torr, in at least 80% yield.

Notes 1. 2.

3.

Using smaller amounts of Pd(PPh3)4 and CuBr or CuI, the reaction presumably will also proceed smoothly. A quick test for the presence of non-volatile compounds (polymer) is allowing 1 ml of vinyl bromide to evaporate (bp 15 C) on a watch glass (in a well-ventilated hood). If no residue remains, no purification is necessary. Under these mild conditions – temperature of the heating bath not higher than 35 C – the risk of decomposition of the compound under the influence of the catalysts is small. If, however, the reaction is carried out on a larger scale and more catalyst is needed, it is advisable to precipitate the greater part of the catalysts. This may be done by adding a relatively large amount of a mixture of pentane and Et2O (ratio>5) to the reaction mixture.

16.7.2

2,6-Dimethyl-5-hepten-3-yn-2-ol from 1-bromo-2-methyl-1propene and 2-methyl-3-butyn-2-ol

Scale: 0.10 molar; Apparatus: Figure 1.1, 250 ml, the dropping funnel is omitted

16.7.2.1

Procedure

To a mixture of 50 ml of diethylamine, 0.10 mol of 2-methyl-3-butyn-2-ol and 0.15 mol of 1-bromo-2-methyl-1-propene are successively added 250 mg of Pd(PPh3)4 and 200 mg of copper(I) iodide. The mixture is heated for 1 h under reflux and then cooled to rt. After filtration on a sintered-glass funnel

306

16.

TRANSITION METALS-CATALYSED. . .

and rinsing the salt with pentane, the filtrate is cooled to –20 C. The clear liquid is decanted from the precipitate (salt) and concentrated under reduced pressure. Flash distillation (bp 40 C/0.3 Torr) affords 2,6-dimethyl-5hepten-3-yn-2-ol, in 85% yield. In the case of propargyl alcohol the reaction proceeds sluggishly, while the solution becomes very dark due to the formation of Pd.

16.7.3

(E )-1-chloro-1-decen-3-yne from (E )-1,2-dichloroethene and 1-octyne

Scale and Apparatus: same as in exp. 16.7.2 16.7.3.1

Procedure

To a mixture of 50 ml of diethylamine, 0.10 mol of 1-octyne and 50 g (large excess) of (E)-1,2-dichloroethylene are added 450 mg of Pd(PPh3)4 and 450 mg of copper(I) iodide. After warming to 30 C, the reaction starts and a few minutes later salt is formed. The mixture is kept under reflux for 1.5 h, then the salt is filtered off on a sintered-glass funnel and rinsed with Et2O or pentane. The dark solution is concentrated under reduced pressure and the residue dissolved in 40 ml of pentane. Flash chromatography on neutral Al2O3 followed by evaporation of the solvent and distillation gives the enyne, bp 60 C/6 Torr, in 80% yield.

16.7.4

Other cross couplings, using similar conditions

The procedure below has been applied for the preparation of (Z)-5-chloro4-penten-2-yn-1-ol, ClCH¼CHCCCH2OH, (Z)-6-chloro-6-hexen-3-yn-1-ol, ClCH¼ CHCCCH2OEt, (Z)-1-chloro-5-etyhoxy-1-penten-3-yne, ClCH¼CHC C(CH2)2OH, (Z)-5-chloro-N,N-dimethyl-4-penten-2-yn-1-amine, ClCH¼CHC CCH2NMe2, 1-[(Z)-chloro-3-buten-1-ynyl]benzene, ClCH¼CHCCPh, 4-(4nitrophenyl)3-butyn-1-ol, 4-NO2–C6H4–CC(CH2)2OH, and several other derivatives with a conjugated system of unsaturated units [25].

16.7

EXPERIMENTAL SECTION

16.7.4.1

307

Procedure

To a stirred solution of Pd(PPh3)4 (1.164 g,1 mmol), (Z)-1,2-dichloroethene (3.917 g, 40.4 mmol), n-butylamine (2.93 g, 40.1 mmol) and propargyl alcohol (1.142 g, 20.4 mmol) in benzene (35 ml) is added CuI (388 mg, 2.05 mmol). The reaction is slightly exothermic. After keeping the mixture for 4 h at rt, a saturated aqueous solution of ammonium chloride is added, followed by dilute hydrochloric acid (just enough to neutralise the excess of n-butylamine). The product is isolated in 70% yield by chromatography of the extract over silica gel (elution with pentane–Et2O 6:4).

16.7.5

1,2-Bis(4-acetylphenyl)ethyne from acetylene and 4-bromoacetophenone

Scale: 0.05 molar; Apparatus: 500-ml round-bottomed, three-necked flask (vertical necks), equipped with a gas inlet tube, an efficient mechanical stirrer and a reflux condenser.

16.7.5.1

Procedure

Diethylamine (100 ml) and 0.05 mol of 4-bromoacetophenone are placed in the flask and acetylene is passed (200 ml/min) through the stirred mixture during 10 min, then 100 mg of PdCl2(PPh3)2, 200 mg of triphenylphosphane and 100 mg of copper(I) iodide (finely powdered) are successively introduced. The mixture is heated under gentle reflux during 30 min, while continuing the flow of acetylene at a rate of 100 ml/min. TLC then indicates complete conversion. After an additional 1 h the mixture is cooled to rt, water is added and the product is extracted with Et2O. The ethereal solution is washed with water and filtered through SiO2. After evaporation of the Et2O under reduced pressure the almost pure product (85% yield) remains. Recrystallisation from benzene gives the pure product, mp 195–196 C, in 80% yield.

308 16.7.6

16.

TRANSITION METALS-CATALYSED. . .

1-Nitro-4-(trimethylsilylethynyl)benzene from 1-bromo-4-nitrobenzene and ethynyl(trimethyl)silane

Scale: 0.10 molar; Apparatus: 500-ml round-bottomed, three-necked flask, equipped with a nitrogen inlet, an efficient mechanical stirrer and a combination of a reflux condenser and a thermometer. 16.7.6.1

Procedure

1-Bromo-4-nitrobenzene (0.10 mol), diethylamine (120 ml) and ethynyl(trimethyl)silane (0.12 mol) are placed in the flask. To the stirred mixture are added Pd(PPh3)4 (1.0 g) (or PdCl2(PPh3)2, 0.8 g) and copper(I) iodide (0.5 g) or copper(I) bromide (0.4 g). The mixture is stirred for 1 h at 35 to 40 C, after which 200 ml of a 1:1 mixture of Et2O and pentane is added at rt. The salt is filtered off on a sintered-glass funnel and rinsed well with the Et2O–pentane mixture. The solution is washed with water in order to remove traces of salt, then dried over MgSO4 and concentrated under reduced pressure. The product (brown crystals) obtained in an excellent yield, is purified by flash chromatography on neutral Al2O3 and subsequently crystallised from a 2:1 mixture of pentane and Et2O, mp 95–97 C. 16.7.7

3-(4-Nitrophenyl)prop-2-yn-1-ol from 1-bromo-3-nitrobenzene and propargyl alcohol

Scale: 0.05 molar; Apparatus: 250-ml round-bottomed, three-necked flask equipped with a gas inlet, a magnetic stirring bar and a reflux condenser. 16.7.7.1

Procedure

A mixture of 0.05 mol of 1-bromo-3-nitrobenzene, 0.08 mol of propargyl alcohol, 10 ml of triethylamine, 20 ml of benzene, 200 mg of PdCl2(PPh3)2, 200 mg of CuI, and 200 mg of Ph3P is heated under reflux for 2 h. After cooling to rt the salt is filtered off on a sintered-glass funnel and rinsed well with Et2O. The amount of dried salt is 90% of the theoretically expected one. The organic solution is concentrated under reduced pressure and the residue

16.7

EXPERIMENTAL SECTION

309

dissolved in 50 ml of Et2O. The ethereal solution is subjected to flash chromatography on neutral Al2O3. Evaporation of the Et2O gives 3-(4-nitrophenyl)2propyn-1-ol in 95% yield. Recrystallisation from carbon tetrachloride gives 85% of pure product, mp 95–96 C. 16.7.8

4-(4-Methoxyphenyl)-2-methyl-3-butyn-2-ol from 1-bromo-4-methoxyenzene and 2-methyl-3-butyn-2-ol

Scale: 0.10 molar; Apparatus: cf. exp. 16.7.7, 250 ml 16.7.8.1

Procedure

A mixture of 0.10 mol of p-bromoanisole, 0.12 mol of 2-methyl-3-butyn-2-ol, 50 ml of triethylamine, 300 mg of PdCl2(PPh3)2, 150 mg of CuI and 200 mg of PPh3 is heated at 85–90 C for 4.5 h. The salt is filtered off on a sintered-glass funnel and rinsed with Et2O. The dried salt weighs 15 g (18 g corresponds to 100% yield). After removal of the solvents under reduced pressure, the residue is diluted with 50 ml of Et2O and the solution filtered through a 4 cm thick layer of neutral Al2O3 on a sintered-glass funnel. Evaporation of the Et2O, followed by crystallisation from pentane gives pure 4-(4-methoxyphenyl)-2methyl-3-butyn-2-ol, mp 49–50 C, in 60% yield. 16.7.9

3-(2-Thienyl)-2-propyn-1-ol from 2-bromothiophene and propargyl alcohol

Scale: 0.10 molar; Apparatus: same as in exp. 16.7.8 16.7.9.1

Procedure

A mixture of 0.10 mol (16.3 g) of 2-bromothiophene. 0.12 mol (7.0 g) of propargyl alcohol, 40 ml of benzene, 15 ml of triethylamine, 350 mg of PdCl2(PPh3)2, 200 mg of copper(I) iodide and 300 mg of triphenylphosphane is heated for 3 h at 75 C. After a work-up as described in the preceding exp., 3-(2-thienyl)-2-propyn-1-ol, bp 100 C/0.5 Torr, is obtained in 80% yield.

310 16.7.10

16.

TRANSITION METALS-CATALYSED. . .

4-(4-Dimethylaminophenyl)-2-methyl-3-butyn-2-ol from p-bromoaniline and 2-methyl-3-butyn-2-ol

Scale: 0.10 molar; Apparatus: cf. exp. 16.7.9 16.7.10.1 Procedure A mixture of 0.10 mol of p-bromo-N,N-dimethylaniline, 0.12 mol of 2-methyl3-butyn-2-ol, 100 ml of triethylamine, 300 mg of PdCl2(PPh3)2 and 150 mg of copper(I) iodide is heated for 7 h at 90 C. After cooling to rt the product (mp 88–89 C, after crystallisation from a 1:1 mixture of Et2O and pentane) is obtained in 70% yield by a dry work-up as described above for the coupling with p-bromoanisole.

16.7.11

1,3-Bis(trimethylsilylethynyl)benzene from 1,3-dibromobenzene and ethynyl(trimethyl)silane

16.7.11.1 Procedure [16] 1,3-Dibromobenzene (0.05 mol), 500 mg PdCl2(PPh3)2 and 800 mg of triphenylphosphane are placed in the flask. The mixture is warmed to 30–35 C under swirling until much of the solid has dissolved, then 75 ml of diisopropylamine, 0.12 mol of ethynyl(trimethyl)silane and a solution of 400 mg of copper(I) bromide and 1.5 g of anhydrous lithium bromide in 10 ml of THF are successively added and the mixture is brought to reflux. A thick suspension is formed very soon. After about 1 h the temperature in the flask does not rise further than between 80 and 85 C. After an additional half an hour the mixture (light brown) is cooled to rt and 150 ml of pentane and 200 ml of water are successively added. The aqueous layer is extracted three times with pentane. The combined organic solutions are washed four times with water and subsequently once with 2 M cold hydrochloric acid. After drying over anhydrous MgSO4,

16.7

EXPERIMENTAL SECTION

311

the solution is concentrated under reduced pressure to give the solid, almost pure product, in essentially quantitative yield. When piperidine is used as a solvent, the yield is by 25% lower. 16.7.12

3-(1-Cyclooctenyl)-2-propyn-1-ol from 1-bromo-1-cyclooctene and propargyl alcohol

Scale: 0.10 molar; Apparatus: cf. preceding experiments 16.7.12.1

Procedure

A mixture of 1-bromo-1-cyclooctene (0.10 mol), 400 mg of triphenylphosphane and 200 mg of PdCl2(PPh3)2 is warmed for 30 min at 30 C with occasional swirling (or stirring), then 100 ml of diisopropylamine, 0.10 mol, freshly distilled at 100 Torr) of propargyl alcohol and a solution of 250 mg of copper(I) bromide and 1.5 g of anhydrous lithium bromide in 10 ml of THF are added. The mixture is brought to reflux. After 2 h the suspension is cooled to rt, and a mixture of 100 ml of Et2O and 100 ml of pentane is added, followed by 300 ml of water. After vigorous shaking and separation of the layers, the aqueous layer is extracted twice with the Et2O–pentane mixture. The combined organic solutions are washed with water and dried over anhydrous MgSO4. The liquid remaining after concentration of the solution in vacuo is subjected to distillation through a very short column. 3-(1-Cyclooctenyl)-2-propyn-1-ol, bp 115 C/0.5 Torr, is obtained in 60% yield. There is much brown viscous residue. Poor results are obtained from the reactions in diisopropylamine of HCCCH2OH with 1-bromo-4-methoxybenzene and 1-bromo-4-fluorobenzene. In an early stage metallic Pd is formed, after which the conversion is very slow. In the case of triethylamine as solvent a dark slurry is deposited on the bottom of the flask and the reaction stops. 16.7.13

1-Methoxy-4-(trimethylsilylethynyl)benzene from 1-bromo-4-methoxybenzene and ethynyl(trimethyl)silane

312

16.

TRANSITION METALS-CATALYSED. . .

Amounts of catalysts and solvent are the same as in the preceding exps. After 7 h of refluxing the product, bp 125 C/15 Torr, is isolated in 75% yield (in piperidine the period of reflux is 2 h only, Table 16.1a). 16.7.14

4-(3-Furyl)-2-methyl-3-butyn-2-ol from 3-bromofuran and 2-methyl-3-butyn-2-ol

Scale: 0.20 molar; Apparatus: same as in preceding experiment 16.7.14.1 Procedure A mixture of 0.20 mol of 3-bromofuran, 100 ml of diisopropylamine, 20 ml of piperidine, 0.25 mol of 2-methyl-3-butyn-2-ol, 1.5 g of PdCl2(PPh3)2, 200 mg of triphenylphosphane and 200 mg of copper(I) bromide (added as a solution with 1 g of anhydrous lithium bromide in 10 ml of THF) is heated under reflux for 5 h. After a work-up with pentane and water, the organic solution is dried over anhydrous magnesium sulphate and subsequently concentrated in vacuo. The remaining liquid is dissolved in Et2O and the solution filtered through a short (3–4 cm) layer of neutral Al2O3. 4-(3-Furyl)-2-methylbut-3-yn2-ol, bp 80 C/0.5 Torr, is obtained in 75% yield. 16.7.15

1-Ethynyl-1-cyclooctene starting from 1-bromocyclooctene and ethynyl(trimethyl)silane

Scale: 0.20 molar; Apparatus: 500-ml round-bottomed, three-necked flask, equipped with a nitrogen inlet-thermometer combination, a reflux condenser and a mechanical stirrer. 16.7.15.1 Procedure 1-Bromo-1-cyclooctene (0.20 mol), Pd(PPh3)4 (600 mg) and triphenylphosphane (300 mg) are placed in the flask. After swirling for a few minutes, 90 g of piperidine, 0.24 mol of ethynyl(trimethyl)silane and a solution of 300 mg of copper(I) bromide and 1.0 g of anhydrous lithium bromide in

16.7

EXPERIMENTAL SECTION

313

10 ml of THF are added. The mixture is brought to reflux while stirring at a moderate rate. After 5 min (a constant rather strong reflux is maintained by gradually increasing the bath temperature) the temperature (initially 90 C) has risen to 110 C. After an additional 15 min the mixture is cooled to rt, and pentane (100 ml) and water (200 ml) are added to the salt mass. The aqueous layer is extracted three times with small portions of pentane. The combined organic solutions are washed twice with cold 2 M hydrochloric acid and subsequently dried over anhydrous MgSO4. The liquid remaining after concentration of the solution under reduced pressure is diluted with a solution of 2 g of NaOH in 30 ml of methanol. The solution is heated for 15 min at 50 C. Water (100 ml) is added, after which three extractions with 50-ml portions of pentane are carried out. The dried (MgSO4) extracts are concentrated under reduced pressure. 1-Ethynyl-1-cyclooctene, bp 75 C/15 Torr, is obtained in 80% yield. 16.7.16

2-Ethynylthiophene starting from 2-bromothiophene and 2-methyl-3-butyn-2-ol

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml, reflux condenser instead of thermometer for the coupling; 1-litre round-bottomed flask for the elimination of acetone. 16.7.16.1

Procedure [26]

A mixture of 2-bromothiophene (0.20 mol), 200 mg of Pd(PPh3)4 and 200 mg of PPh3 is stirred or swirled for 30 min at rt, then 100 ml of triethylamine, 0.22 mol of 2-methyl-3-butyn-2-ol and 100 mg of CuBr þ 1 g of anhydrous LiBr in 10 ml of THF are successively added. The mixture is heated for about 1 h under gentle reflux, then it is cooled to rt and 200 ml of water and 100 ml of pentane are added. The aqueous layer is extracted twice with pentane. The combined organic solutions are washed several times with water in order to remove the triethylamine as completely as possible. After drying over magnesium sulphate, the solution is concentrated in a 1-litre round-bottomed flask

314

16.

TRANSITION METALS-CATALYSED. . .

under reduced pressure. Small amounts of the acetylenic alcohol are removed in a high vacuum. The crude product is mixed with 50 ml of paraffin oil and 2 g of powdered KOH is added. The flask is equipped for a vacuum distillation, the receiver being cooled in a bath at –70 C (Figure 1.10). After evacuating the system (7–20 Torr), the flask is heated in a bath at 200 C. The elimination of acetone is accompanied by strong foaming. After about 45 min the flask is cooled to rt and air is admitted. The contents of the receiver are distilled to give 2-ethynylthiophene, bp 38 C/15 Torr, in 80% overall yield. 2-Ethynylfuran, 1-chloro-4-ethynylbenzene and 1-ethynyl-4-fluorobenzene can be obtained in high overall yields by similar procedures. Reaction conditions of the Pd/Cu-catalysed couplings are summarised in Table 16.1.

16.7.17

Reaction of 2,3-dibromothiophene with 2-methyl3-butyn-2-ol. Selective substitution of the bromine atom at the 2-position

Scale: 0.10 molar; Apparatus: 500-ml three-necked, round-bottomed flask, equipped with a combination of gas inlet and thermometer, a magnetic stirring bar and a reflux condenser. 16.7.17.1 Procedure In the flask are placed 0.10 mol of 2,3-dibromothiophene, 75 ml of triethylamine and 0.10 mol of 2-methyl-3-butyn-2-ol, then 250 mg of PdCl2(PPh3)2 and 130 mg of triphenylphosphane are introduced. The mixture is stirred for 15 min at 35 C, after which a solution of 130 mg of copper(I) bromide and 1 g of anhydrous lithium bromide in 10 ml of THF is added. The mixture is stirred for 2 h at 55–60 C, and subsequently for 1 h at 80 C. After cooling to rt, the mixture is diluted with 150 ml of pentane and then poured into water. The aqueous layer is extracted four times with Et2O. The combined organic solutions are dried over potassium carbonate and subsequently concentrated under reduced pressure. The remaining oil is dissolved in 100 ml of Et2O and the solution filtered through a 3-cm thick layer of neutral Al2O3 on a sintered-glass funnel. After evaporation of the Et2O, the product is distilled (bp 120 C/0.5 Torr) through a short Vigreux column. The distillate,

16.7

EXPERIMENTAL SECTION

315

solidifying upon standing at rt is pure mono-substituted product, yield 70%, mp 41–42 C. Reaction of 2,5-dibromothiophene with 2-methyl-3-butyn-2-ol under similar conditions gives only satisfactory yields of mono-substitution product if a 100 to 200 mol% excess of the dibromo compound is used. Most of the excess can be recovered by distillation.

16.7.18

Pd(0)-catalysed reaction of an alkynylzinc chloride with iodoheteroaromates

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 16.7.18.1

Procedure

A solution of Me3SiCCLi (0.12 mol) in THF (50 ml) and hexane (77 ml) is prepared by adding BuLi in hexane to a mixture of Me3SiCCH and THF (Chapter 3, exp. 3.9.4). Subsequently a solution of 0.12 mol of anhydrous zinc chloride in 50 ml of THF is added at 0 C followed by a solution of 1 g of Pd(PPh3)4 in 20 ml of THF and 0.10 mol of the iodo compound. The cooling bath is removed and the temperature allowed rising. If the flask is insulated in cotton wool, 40 C may be reached. After an additional 2 to 3 h (at 30–35 C) the solution is cooled to rt and pentane (300 ml, Note 1) and a saturated aqueous solution of ammonium chloride (150 ml) are successively added with vigorous stirring. After separation of the layers, the aqueous layer is extracted with pentane. The combined solutions are washed five times with 200-ml portions of water (Note 1) and subsequently dried over MgSO4. The brown liquid remaining after concentration of the solution in vacuo is first subjected to a flash distillation (see Figure 1.10) at 0.1 Torr or lower pressure (Note 2). The contents of the receiver are redistilled. 1-Methyl-2-(trimethylsilylethynyl)pyrrole, bp 70 C/0.5 Torr, and 2-(trimethylsilylethynyl)furan, bp 30 C/0.5 Torr, can be obtained in greater than 70% yields by this procedure. MeCCCCZnCl and 2-iodothiophene react under similar conditions to give the expected coupling product, bp 70 C/0.5 Torr, in an excellent yield. The additional time of heating at 35 C in this case is 30 min.

316

16.

TRANSITION METALS-CATALYSED. . .

Notes 1.

The addition of a relatively large amount of pentane causes precipitation of part of the catalyst, which adheres to the glass wall of the separating funnel. Another part precipitates when the THF is removed in the wash procedure. The precipitate dissolves readily in acetone. 2. Under the mild conditions of this distillation, the chance of decomposition of the product under the influence of traces of Pd-compounds is small. 16.7.19

Pd(0)-catalysed reaction of an alkynylzinc chloride with (het)aryl bromides

Scale: 0.10 molar (RBr) or 0.05 molar (2,5-dibromothiophene); Apparatus: Figure 1.1, 500 ml 16.7.19.1 Procedure A solution of 1 g of Pd(PPh3)4 in 20 ml of THF is added to the solution of Me3SiCCZnCl (0.12 mol) in THF and hexane (see exp. 16.7.18). The bromo compound (0.10 mol, or 0.05 mol in the case of 2,5-dibromothiophene) is added in one portion at 30 C. The flask is insulated in cotton wool. In the cases of hetaryl bromides, the reaction is clearly visible from a gradual rise of the temperature to 45 C over about half an hour, dibromothiophene reacts very fast and the temperature of the mixture rises to 60 C within 15 min. At this stage the thermometer is quickly replaced with a reflux condenser. Aryl bromides (1-bromonaphthalene, 1-bromo-2-chlorobenzene, 1-bromo-3-fluorobenzene) react more slowly and the heating effect is hardly visible in spite of the insulation. The reactions with the heteroaromates are completed by heating the solutions under reflux for an additional 2.5 h (for 2,5-dibromothiophene 0.5–1 h is sufficient), in the cases of the bromoaromates at least 4 h reflux is necessary (an additional amount of catalyst may be added to shorten the reaction time). An atmosphere of nitrogen is carefully maintained during the reactions. The work-up is carried out in a manner similar to that described in the preceding experiment. The following compounds are obtained by this procedure in yields of at least 70% (3-bromopyridine gives the lowest yield): 1-(trimethylsilylethynyl)naphthalene, bp 110 C/0.5 Torr (a careful distillation is necessary to separate unconverted bromonaphthalene from the

REFERENCES

317

product); 1-chloro-2-(trimethylsilylethynyl)benzene (from 1-bromo-2-chlorobenzene), bp 116 C/15 Torr, (in this case, 2 g of Pd-catalyst is used); 3-(trimethylsilylethynyl)thiophene, bp 72 C/0.5 Torr; 3-(trimethylsilylethynyl)pyridine, bp 60 C/0.5 Torr; 2,5-bis(trimethylsilylethynyl)thiophene (solid, not further purified, 1H NMR shows a satisfactory purity); 1-fluoro-3-(trimethylsilylethynyl)benzene (qualitative experiment, purification not carried out). C6H13CCCH¼CH2, bp 70 C/15 Torr, is prepared in 80% yield from C6H13CCZnCl and H2C¼CHBr; the bromide is added in 30% excess at 35 C. The reaction is brought to completion by stirring for 3 h at 40–45 C and 30 min at 60 C.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett. 4467 (1975). H. A. Dieck and R. F. Heck, J. Organometal. Chem. 93, 259 (1975). L. Cassar, J. Organometal Chem. 93, 253 (1975). R. D. Stephens and C. E. Castro, J. Org. Chem. 28, 3313 (1963). A. O. King, E. Negishi, F. J. Villani, Jr. and A. Silveira, Jr., J. Org. Chem. 43, 358 (1978). H. P. Dang and G. Linstrumelle, Tetrahedron Lett., 191 (1978); H. Hopf and M. Theurig, Angew. Chem., Int. Ed. (Engl.) 33, 1099 (1994). R. F. Heck, Palladium Reagents in Organic Synthesis. Acad. Press, London, 1985, p. 299. V. N. Kalinin, Synthesis, 413 (1992); R. Rossi, A. Carpita and F. Bellina, Org. Prep. Proced. Int. 27, 127 (1995). Unpublished observations and results from the author’s laboratory. M. Alami, F. Ferri and G. Linstrumelle, Tetrahedron Lett., 6403 (1993). V. Ratovelomanana and G. Linstrumelle, Tetrahedron Lett., 315 (1985); D. Guillerm, G. Linstrumelle, Tetrahedron Lett., 315 (1981); V. Ratovelomanana, A. Hammoud and G. Linstrumelle, Tetrahedron Lett., 1649 (1987). W. B. Austin, N. Bilow, W. J. Kelleghan and K. S. Y. Lau, J. Org. Chem. 46, 2280 (1981). M. Alami and G. Linstrumelle, Tetrahedron Lett., 6109 (1991). R. Singh and G. Just, J. Org. Chem. 54, 4453 (1989). J. W. Tilley and S. Zawoiski, J. Org. Chem. 53, 386 (1988). T. X. Neenan and G. M. Whitesides, J. Org. Chem. 53, 2489 (1988). G. Just and R. Singh, Tetrahedron Lett., 5981 (1987). A. Lo¨ffler, G. Himbert, Synthesis, 125 (1990). R. W. Bates, C. J. Gabel and J. Ji, Tetrahedron Lett., 6993 (1994). C. Huynh and G. Linstrumelle, Tetrahedron 44, 6337 (1988). S. Takahashi, Y. Kuroyama, K. Sonogashira and N. Hagihara, Synthesis, 312 (1980). M. Fossatelli, A. C. H. T. M. van der Kerk, S. F. Vasilevsky and L. Brandsma, Tetrahedron Lett., 4229 (1992). M. Alami, F. Ferri and G. Linstrumelle, Tetrahedron Lett., 6403 (1993). L. Brandsma and H. G. M. van den Heuvel, Synth. Commun. 20, 1889 (1990). G. Linstrumelle et al., Tetrahedron Lett., 3543 and 5335 (1994). A. G. Mal’kina, L. Brandsma, S. F. Vasilevsky and B. A. Trofimov, Synthesis, 589 (1996).

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17 Base-Catalysed Isomerisations of Acetylenic Compounds

17.1

INTRODUCTION

Interaction between an acetylenic compound and a catalytic amount of a base can give rise to isomerisation to an unsaturated system with the same number of p-electrons. The result is often a (pseudo-) equilibrium mixture of the starting compound and isomeric acetylenes or allenes. The composition of the mixture is determined by the relative thermodynamic stabilities of the isomers. Under more forcing conditions a conjugated diene or polyene is formed, provided that the carbon chain is sufficiently long, while in some cases cyclic compounds are the end products. Since it is, in general, very difficult to separate the isomeric compounds, the synthetic importance of the base-catalysed isomerisations is restricted to conversions that afford predominantly one product. The ratio of the isomers in the equilibrium mixture may vary strongly with the substituents. Reaction of N,N-diethyl-2-propyn-1-amine, HCCCH2NEt2, with t-BuOK in DMSO gives an equilibrium mixture [1] of 80% of N,N-diethyl-1-propyn-1-amine MeCCNEt2 and 20% of N,Ndiethyl-1-allenamine, H2C¼C¼CHNEt2. Under similar conditions the dimethylamino compound, HCCCH2NMe2, is converted into a mixture consisting of 10% of N,N-dimethyl-1-propyn-1-amine, MeCCNMe2 and 90 of N,N-dimethyl-1-allenamine [2], H2C¼C¼CHNMe2. 1-Propargylpyrrole, HCCCH2-1-pyrrolyl, prepared in situ from pyrrole, potassium hydroxide and propargyl chloride in dimethylsulphoxide, isomerises completely to 1-allenylpyrrole under the reaction conditions [6]. The base-catalysed isomerisation of 3-alkoxy-1-propynes, HCCCH2OR, to alkoxyallenes, H2C¼C¼CHOR, can be easily brought approximately by warming with solid t-BuOK [3]. Attempts at further conversion into 1-alkoxy-1-propynes, MeCCOR, have resulted in decomposition [1]. 2-Propynyl sulphides, HCCCH2SR (R ¼ alkyl or aryl), can be completely converted into 1-propynyl sulphides, MeCCSR, under mild conditions (NaOEt in liquid ammonia [4] or in ethanol [5]). 319

320

17.

ISOMERISATIONS OF ACETYLENIC COMPOUNDS

Compounds with the structure HCCCH2CH2R, in which R may represent alkyl, aryl or a variety of other groups, isomerise smoothly to the 2-alkyne systems, MeCCCH2R, upon treatment with t-BuOK in DMSO at 20 C or slightly elevated temperatures [1]. In addition to the reactions mentioned, many other isomerisations of acetylenic compounds with a conjugated or non-conjugated unsaturated system have been carried out. The experimental procedures in this chapter are a selection of conversions that, in our opinion, are useful from a preparative point of view. A number of base-catalysed isomerisations are summarised in Table 17.1. The isomerisation conditions in the procedures described below result from an extensive experience in this field. So-called contrathermodynamic isomerisations, brought about by treatment of a substrate with equivalent amounts of a very strongly basic reagent and subsequent protonation of the alkali metal intermediate, are treated in Chapter 3.

17.2 17.2.1

EXPERIMENTAL SECTION

Isomerisation of 1-alkynes to 2-alkynes

Scale: 0.30 molar; Apparatus: 500-ml round-bottomed two-necked flask with stopper and thermometer-outlet combination; stirring is carried out magnetically; addition by syringe or – in the case of 1-butyne – by pouring the cold liquefied gas into the flask. 1-Alkynes are smoothly converted into 2-alkynes under the influence of a catalytic amount of t-BuOK in DMSO at temperatures between 20 and 40 C. Using 10 mol% of base and concentrations of the alkyne between 1 and 5 mol/litre of DMSO, the conversion is complete within 30 min. From the modest enthalpy difference of 1- and 2-alkynes (roughly 5 kcal/mol) and the heat capacity of the solvent and alkyne (0.5 cal/ C/g), a rough estimate can be made of the amount of heat evolved in the isomerisation of 0.5 mol of a 1-alkyne to the 2-alkyne in 150 ml of DMSO. This leads to the conclusion that the 1-alkyne can be added over a short period. Cooling in a water bath at 10–15 C will be sufficient to keep the temperature of the solution between 25 and 40 C. In the case of the volatile 1- and 2-butyne, the temperature should not be allowed to rise above 30 C. There is little risk of a further isomerisation into a conjugated diene in this temperature range.

17.2

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321

Table 17.1 Base-catalysed isomerisations of acetylenic compoundsa Acetylenic compound HCCCH2Alky1 HCC(CH2)9OH HCCCH2NMe2 HCCCH2NEt2 HCCCH2N-morpholyl Me2NCH2CCCH2OMe HCCCH2N-pyrrolyl HCCCH2N-imidazolyl HCCCH2N-pyrazolyl HCCCH2OMe HCCCH2O-t-Bu HCCCH2OCH(Me)OEt EtOCH2CCCH2OEt EtOCH(Me)CCCH2OMe EtOCH2CCCH(OEt)2 n-PrCCCH(OEt)2 MeCCCH(SEt)2 HCCCH2SEt HCCCH2CH¼CH2 HCCCH2CCH HCCCH¼CHCH2R H2C¼C(Me)CCCH2OMe H2C¼CHCCCH2NEt2 H2C¼C(Me)CCCH2NEt2 HCCCCCH2NEt2 HCCCH2C(¼O)Et HCCCH¼CHCH2CN a

Reaction conditionsb t-BuOK, DMSO, 30 t-BuOK, DMSO, 30 t-BuOK, DMSO, 30c t-BuOK, DMSO, 50–55d t-BuOK, THF, 40–45 t-BuOK t-BuOH, THF, 40 KOH, DMSO, 45e t-BuOK, liq. NH3, 33 t-BuOK,1iq. NH3, 33 t-BuOK, DMSO, 30 ! 55f t-BuOK, no solvent, 55 t-BuOK, DMSO, 30–35f t-BuOK, liq. NH3, 33 t-BuOK, liq. NH3, 33 t-BuOK, DMSO, 30–35 t-BuOK, DMSO, rt ! 40 NaOEt, liq. NH3, 33g NaOEt, liq. NH3, 33 NaOH, EtOH, 35 PhOLi, MeOH, rt ! 50 t-BuOK, DMSO, rt, 1 min t-BuOK, HMPT, 25 t-BuOK, DMSO, 30–35h t-BuOK, DMSO, 30–35 t-BuOK t-BuOH, HMPT, 10 NaHCO3, H2O, rt K2CO3, H2O, EtOH, 60–80

Isomerisation product MeCCAlkyl MeCC(CH2)8OH H2C¼C¼CHNMe2 MeCCNEt2 H2C¼C¼CHN-morpholyl Me2NCH¼C¼CHCH2OMe H2C¼C¼CHN-pyrrolyl H2C¼C¼CHN-imidazolyl H2C¼C¼CHN-pyrazolyl H2C¼C¼CHOMe H2C¼C¼CHO-t-Bu H2C¼C¼CHOCH(Me)OEt EtOCH¼C¼CHCH2OEt EtOCH(Me)CH¼C¼CHOMe EtOCH¼C¼CHCH(OEt)2 EtCCCH2CH(OEt)2 MeCH¼C¼C(SEt)2 MeCCSEt H2C¼C¼CHCH¼CH2 H2C¼C¼CHCCH MeCCCH¼CHR H2C¼C(Me)CH¼C¼CHOMe MeCH¼CHCCNEt2 Me2C¼CHCCNEt2 MeCCCCNEt2i H2C¼C¼CHC(¼O)Et H2C¼C¼CHCH¼CHCN

All reactions were carried out in the author’s laboratory. Temperatures in C. c 10% MeCCNMe2 present in the equilibrium mixture. d 20% H2C¼C¼CHNEt2 present in equilibrium mixture. e The acetylenic isomer is formed in situ from pyrrole, KOH and propargyl chloride [6]. f DMSO is added in relatively small amounts [1]. g Ref. 8. h 15% of N,N-Diethyl-l-penten-3-yn-l-amine, MeCCCH¼CHNEt2, is formed [7]. The two isomeric products can be separated by distillation. i Using DMSO, yields are much lower [1]. b

322 17.2.1.1

17.

ISOMERISATIONS OF ACETYLENIC COMPOUNDS

Procedure

Dry DMSO (100 ml) and t-BuOK (3 g) are placed in the flask. Stirring is started and the solution is brought at a temperature of 20 C. Liquefied 1-butyne (0.30 mol, Chapter 10, exp. 10.2.3) or 1-hexyne (0.30 mol, Chapter 4, exp. 4.5.8) is added in portions of 5 g with intervals of 3 to 5 min, while keeping the temperature of the mixture between 25 and 30 C (bath at 15 C). After an additional 30-min period of stirring at 30 C the 2-alkynes are isolated. In the case of 2-butyne the flask is connected (via a vacuum tube) to a trap cooled in a bath with liquid nitrogen. The connection is made in such a way that during the evacuation with the water aspirator, the vapour of 2-butyne enters the large annular space of the trap: in this way, clogging being avoided. During the evacuation, the temperature of the bath is gradually raised to 50 C. Air is then admitted to the system and the solid 2-butyne is allowed to melt. Subsequent distillation at atmospheric pressure using a short Vigreux column and a receiver, cooled below 0 C gives pure 2-butyne, bp 27 C, in >75% yield. For the isolation of 2-hexyne, the reaction flask is equipped for a vacuum distillation: 40-cm Vigreux column, condenser and receiver cooled in a bath at 70 C (Figure 1.10). The system is evacuated (water aspirator) and the flask gradually heated, until the DMSO begins to reflux in the column. Redistillation of the contents of the receiver at atmospheric pressure gives 2-hexyne, bp 85 C, in 90% yield. The IR spectrum shows the absence of 1-hexyne. 2-Heptyne and 2-octyne can be isolated in a similar way. In the case of less volatile 2-alkynes it is more convenient to dilute the reaction mixture with water (500 ml) and to extract with pentane.

17.2.2

Isomerisation of 10-undecyn-1-ol to 9-undecyn-1-ol

Scale: 0.10 molar; Apparatus: 250-ml round-bottomed flask and thermometer; manual swirling

17.2.2.1

Procedure

10-Undecyn-1-ol (0.10 mol) is added in one portion to a solution of 2 g of t-BuOK in 200 ml of dry DMSO. The temperature rises from 20 to 30 C within 1 to 2 min and a white precipitate is formed. The mixture is subsequently heated to 80 C and held at this temperature for 2 min. The precipitate

17.2

EXPERIMENTAL SECTION

323

dissolves completely. After cooling to rt, the solution is poured into 500 ml of water and six extractions with a mixture (1:1) of Et2O and pentane are carried out. The combined organic solutions are washed twice with water and subsequently dried over MgSO4, after which the solvent is removed under reduced pressure. Distillation of the remaining liquid through a short Vigreux column gives 9-undecyn-1-ol, bp 100 C/15 Torr, in >90% yield.

17.2.3

Isomerisation of N,N-diethyl-2-propyn-1-amine to N,N-diethyl-1-propyn-1-amine

Scale: 0.30 molar; Apparatus: 250-ml round-bottomed flask and thermometer; manual swirling Treatment of a propargylic tertiary amine, HCCCH2NR2, with a catalytic amount of a basic reagent under suitable conditions generally affords an equilibrium mixture of the allenic amine, H2C¼C¼CHNR2, and the 1-propynylamine, MeCCNR2. This cannot be separated into the components by distillation because of the small difference in boiling points. There is, however, a considerable difference in thermal stability of the yneamines and allenic amines. If a mixture of N,N-diethyl-1-propyn-1-amine, MeCCNEt2, and N,N-diethyl-1-allenamine, H2C¼C¼CHNEt2, is heated for approximately half an hour at a temperature above 100 C, all allenic amine has dimerised. The yneamine survives this treatment and can be obtained in a good yield by vacuum distillation. Unfortunately, there are only a few cases in which the yneamine is the main component in the equilibrium mixture. Amines, HC CCH2NR2, having one or both groups R ¼ Aryl give the yneamines in high yields.

17.2.3.1

Procedure

N,N-Diethyl-2-propyn-1-amine (0.30 mol, Chapter 20, exp. 20.2.2) is added in one portion to a solution of 5 g of t-BuOK in 50 ml of dry DMSO. The temperature rises in a few minutes to above 45 C but is kept between 50 and 55 C by occasional cooling (with manual swirling) in a water bath at 10 C. After 30 min the flask is equipped for a vacuum distillation (wateraspirator pressure, 40-cm Vigreux column, condenser and single receiver, cooled in a bath at 10 C, Figure 1.10) and the products are quickly distilled

324

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ISOMERISATIONS OF ACETYLENIC COMPOUNDS

off from the dark solution. The distillation is stopped after a few millilitres of DMSO have passed over (bp 80 C/15 Torr). The distillate is heated (under N2) for 30 min in a bath at 120 C. After cooling to below 30 C, the yneamine is distilled through an efficient column and collected in a single receiver, cooled in a bath at 0 C (Figure 1.10). N,N-Diethyl-1-propyn-1-amine, bp 27 C/ 12 Torr, is obtained in 75% yield. The residue, a mixture of DMSO and the dimer of the allenic amine, is discarded. If the compound is stored in a wellclosed and dry bottle, no deterioration occurs at rt. 17.2.4

N,N-Dimethyl-1-allenamine from N,N-dimethyl-2propyn-1-amine

Scale: 0.10 molar; Apparatus: 100-ml round-bottomed flask and thermometer; manual swirling

17.2.4.1

Procedure

A clear solution of 10 mmol of t-BuOK and 10 mmol of t-BuOH in 10 ml of dry DMSO is prepared by warming the mixture at 50 C. The solution is then cooled to 17 C and added to 5.0 g of N,N-dimethyl-2-propyn-1-amine (Chapter 20, exp. 20.2.3), in the 100-ml flask. The air in the flask is quickly replaced by inert gas and the mixture is kept at 23 C for 10 min (occasional cooling in a bath of 15 C may be necessary). During this period the flask is occasionally swirled by hand. The flask is then connected to a distillation apparatus (see Figure 1.10), consisting of a 30-cm Vigreux column, condenser and receiver, cooled at 78 C. Between the receiver and the water aspirator is placed a tube filled with KOH pellets. The system is evacuated and the distillation flask gradually warmed at 80 C. After this operation nitrogen is admitted. The receiver contains reasonably pure (90–95%) N,N-dimethyl1-allenamine, yield 85–90%. The NMR spectrum indicates the presence of 5–10% of N,N-dimethyl-1-propyn-1-amine, MeCCNMe2 (Note). The product can be stored under pure nitrogen at 25 C for at least 24 h. The equilibrium mixture consists of 20% of MeCCNMe2 and 80% of H2C¼C¼CHNMe2. The isomerisation method is therefore unsuitable for the preparation of the yneamine. In the case of the isomerisation of N,N-diethyl2-propyn-1-amine, HCCCH2NEt2, the equilibrium ratio, allenic amine:yneamine, is 1:4 (cf. exp. 17.2.3).

17.2

EXPERIMENTAL SECTION

325

Note All operations of the isolation procedure must be carried out without delay. The distillation apparatus must be made perfectly dry, as allenic amines are extremely water-sensitive.

17.2.5

1-(1,2-Propadienyl)morpholine from 4-(2-propynyl)morpholine

Scale: 0.10 molar; Apparatus: 200-ml round-bottomed, three-necked flask provided with a gas inlet, a thermometer and a gas outlet; magnetic stirring

17.2.5.1

Procedure

In the flask is placed 0.10 mol of the 4-(2-propynyl)morpholine (cf. Chapter 20, exp. 20.2.2). The air in the flask is replaced by nitrogen and a solution of 10 mmol of t-BuOK in 10 ml of THF is added. The mixture is warmed at 40 C. A weakly exothermic reaction is observed and the temperature rises to 45 C. After 1–2 min the gel originally present (presumably the potassiated acetylenic amine) has disappeared almost completely and a brown solution has formed. The refractive index of the solution (Note 1) is measured after intervals of 2 min. After the maximum value (nD 1.464) has been reached, heating at 40 C is continued for another 2 min. t-Butylalcohol (10 mmol) is then added (Note 2) and the mixture is cooled to rt. The THF is removed in a wateraspirator vacuum and the residue is distilled (bp 30–40 C) in a high vacuum (pressure < 0.5 Torr), the (single) receiver being cooled at 0 C (Figure 1.10). Towards the end of the distillation the temperature of the heating bath is increased to 60–70 C in order to minimise the hold-up. The yield of 1-(1,2propadienyl)morpholine is 85%. The NMR spectrum indicates the presence of 4% of 4-(1-propynyl)morpholine, MeCC-Morpholine. The product rapidly turns yellow upon exposure to the air and polymerises at rt within a few hours. A similar procedure with 1-(2-propynyl)piperidine (reaction temperature 45–55 C) leads to a mixture of 92% of the 1-(1,2-propadienyl)piperidine and 8% of the 1-(1-propynyl)piperidine. During the high-vacuum distillation the receiver is cooled at –30 C. The product mixture, bp 30 C/0.5 Torr, is obtained in a yield of 80%.

326

17.

ISOMERISATIONS OF ACETYLENIC COMPOUNDS

The equilibrium mixture obtained in this isomerisation under the influence of t-BuOK in DMSO consists of 70% of allenic and 30% of yneamine. Base-catalysed isomerisation is therefore not a suitable method to prepare the 1-(1-propynyl)piperidine.

Notes 1.

A small sample is taken by means of a Pasteur pipette and the liquid is placed on the prism. Care should be taken that no evaporation of THF takes place as this will result in measuring of a too high refractive index. 2. Conversion into 1-(1-propynyl)morpholine is repressed by the addition of t-BuOH, which forms the less active 1:1 complex with t-BuOK. If the isomerisation with t-BuOK is carried out in DMSO, an equilibrium mixture of 80% of the allenic amine and 20% of the yneamine is formed after 1–2 min at 30 C.

17.2.6

Isomerisation of N,N-diethyl-4-penten-2-yn-1-amine to N,N-diethyl-3-penten-1-yn-1-amine

Scale: 0.10 molar; Apparatus: 500-ml round-bottomed flask and thermometer (manual swirling) The conditions for the base-catalysed isomerisation of N,N-diethyl-4-penten2-yn-1-amine, H2C¼CHCCCH2NEt2, are similar to those applied in exp. 17.2.3. The work-up cannot be carried out in the same way, because the bp of the product is too close to that of DMSO. An aqueous work-up seems risky, since enyne amines have shown to be water-sensitive [1]. The somewhat peculiar manner in which the product is isolated is based on the fact that DMSO is slightly soluble in the non-polar pentane. Extraction with this solvent alone presumably would be not very effective, therefore a 1:1 mixture of pentane and Et2O is used. The small amount of DMSO, which is co-extracted, can be easily removed by strongly cooling the extract, during which operation the DMSO crystallises out. Interestingly, the isomerisation with t-BuOK also gives a small amount of the amine with the reversed order of the double and triple bond. Its boiling

17.2

EXPERIMENTAL SECTION

327

point is by 20 to 30 C higher than that of the predominant product and careful fractional distillation results in a satisfactory separation of these isomers. 17.2.6.1

Procedure

N,N-Diethyl-4-penten-2-yn-1-amine (0.10 mol, prepared by Mannich reaction of vinylacetylene, Chapter 13) is added in one portion to a solution of 3 g of t-BuOK in 45 ml of dry DMSO. The temperature (initially rt) rises within 1 to 2 min to 35 C, but is kept between 30 and 35 C by occasional cooling (with manual swirling) in a water bath at 10 C. After 30 min the brown reaction mixture is extracted eight times with a 1:1 mixture of Et2O and pentane (1 70 ml, 7 40 ml). The combined extracts are cooled to 80 C (with continuous swirling). Fifteen minutes after this temperature has been reached, the cold mixture is quickly filtered on a sintered-glass funnel (with suction) and the DMSO on the filter rinsed with a very limited amount of the cold (80 C) Et2O–pentane mixture. After concentration of the extract in vacuo, the remaining liquid is carefully fractionated through an efficient column to give N,Ndiethyl-3-penten-1-yn-1-amine, MeCH¼CHCCNEt2 ((E):(Z) 70:30), bp 70–75 C/12 Torr, in 80% yield. The small brown residue consists mainly of N,N-diethyl-1-penten-3-yn-1-amine, MeCCCH¼CHNEt2. N,N-Diethyl-4-methyl-4-penten-2-yn-1-amine, H2C¼C(Me)CCCH2NEt2, bp 70 C/12 Torr, is converted by a similar procedure into N,N-diethyl4-methyl-3-penten-1-yn-1-amine, (Me)2C¼CHCCNEt2, bp 90 C/12 Torr, with an excellent yield. Amines with a longer carbon chain, e.g. N,N-dialkyl-4-hexen-2-yn-1-amine, MeCH¼CHCCCH2NR2, give 1,3,5-trienylamines, e.g. N,N-dialkyl-1,3,5hexatrien-1-amine, H2C¼CHCH¼CHCH¼CHNR2, under the isomerisation conditions described above [7].

17.2.7

N,N-diethyl-1,3-pentadiyn-1-amine from N,N-diethyl-2,4-pentadiyn-1-amine

Scale: 0.20 molar; Apparatus: Figure 1.1, 250 ml, addition by syringe When N,N-diethyl-2,4-pentadiyn-1-amine, HCCCCCH2NEt2, is subjected to the isomerisation conditions of exp. 17.2.4, a vigorous reaction takes place and a very dark solution is formed from which only tarry products can be isolated. A moderate yield of N,N-diethyl-1,3-pentadiyn-1-amine,

328

17.

ISOMERISATIONS OF ACETYLENIC COMPOUNDS

MeCCCCNEt2, is obtained, when the basic catalyst is ‘poisoned’ by addition of t-butyl alcohol (ratio t-BuOK/t-BuOH 1:3 by weight). Replacement of DMSO by HMPT, however, gives good results, provided that during the isomerisation the temperature is carefully maintained around 10 C, and the concentration of the base is not too high. Since HMPT and pentane or Et2O are completely mixable, a ‘dry’ extraction procedure as described in exp. 17.2.4 cannot be applied. Fortunately, the diyne amine appears to be reasonably stable at pH > 9 in water at ambient temperature, so that the compound can be isolated by the usual extraction procedure. 17.2.7.1

Procedure

(Note) Dry HMPT (40 ml) is placed in the flask. A solution of 1 g of t-BuOK and 3 g of t-BuOH in 5 ml of HMPT is added and the mixture is cooled to 7 C (ice-water bath). A mixture of 0.10 mol of N,N-diethyl-2,4-pentadiyn-1-amine, (Chapter 3, exp. 3.9.33) and 15 ml of dry HMPT, pre-cooled to 5 C, is added in 5 equal portions with intervals of 3 min. The temperature of the dark mixture is maintained between 8 and 12 C (occasional cooling). Ten minutes after this addition, a same amount of the solution of the basic catalyst in HMPT is added and stirring at 10 C is continued for an additional 10 min. The very dark solution is then poured into 300 ml of ice water and seven extractions with a 1:1 mixture of Et2O and pentane are carried out as quickly as possible. The combined solutions are washed twice with ice water and dried over K2CO3. The liquid remaining after concentration of the solution in vacuo, is distilled through a short Vigreux column and the distillate collected in a single receiver cooled in a bath at 0 C (Figure 1.10). N,NDiethyl-1,3-pentadiyn-1-amine, bp 50 C/0.1 Torr, is obtained in 75% yield. Note Possibly, good results are obtained also when using t-BuOK in DMSO, provided that more than one equivalent of t-butyl alcohol is used to ‘tame’ this base. 17.2.8

Methoxyallene from 3-methoxy-1-propyne

Scale: 1.0 molar; Apparatus: 500-ml two-necked, round-bottomed flask, provided with a reflux condenser and a thermometer

17.2

EXPERIMENTAL SECTION

17.2.8.1

329

Procedure

In the flask is placed 1.0 mol of dry freshly distilled 3-methoxy-1-propyne (Chapter 20, exp. 20.6.1). A solution of 5 g of t-BuOK in 35 ml of DMSO is added with manual swirling. The temperature of the mixture gradually rises from 25 C and after about half an hour a gentle reflux starts. The reaction may be followed by taking small samples of the reaction mixture at intervals of 10 min and determining the refractive index. After refluxing has subsided, the mixture is heated for an additional 30 min in a bath at 70 C (the maximum value of nD is 1.427). The flask is cooled to rt and equipped for a distillation: 30-cm Vigreux column, condenser and receiver. Most of methoxyallene is distilled off at 760 Torr, care being taken that the temperature of the heating bath remains below 90 C. A small amount of allenic ether may be obtained by evacuation (water-aspirator pressure, receiver cooled in a bath at 70 C, Figure 1.10). Pure methoxyallene, bp 52 C/760 Torr, is obtained in > 85% yield.

17.2.9

t-Butoxyallene from 3-t-butoxy-1-propyne

Scale: 0.50 molar; Apparatus: Figure 1.1, 250 ml, no dropping funnel is used

17.2.9.1

Procedure

In the flask are placed 0.50 mol of freshly distilled and dry (Note 1) 3-(tbutoxy)-1-propyne (Chapter 20, exp. 20.6.8) and 4 g of powdered t-BuOK. The mixture is warmed to 54 C and is kept at this temperature (Note 2) by occasional cooling or warming until the refractive index (nD) has increased to 1.444 (70 min, Note 3). The flask is then connected to a 40-cm Vigreux column, condenser and receiver, cooled at 75 C (Figure 1.10). A few boiling stones are added and most of the liquid is distilled at 15–20 Torr. The bath temperature is gradually increased to 60 C. When the distillation has stopped, nitrogen is admitted and the receiver is replaced with an empty one. The last traces of the allenic ether are subsequently distilled off from the brown mass at 0.5 Torr or lower pressure, while the flask is warmed in a bath at 50 C and the receiver is cooled at 75 C (Figure 1.10). The yield of tert-butoxyallene is at least 90%.

330

17.

ISOMERISATIONS OF ACETYLENIC COMPOUNDS

Notes 1.

If not kept under nitrogen in well closed bottles, 3-(t-butoxy)-1-propyne is gradually converted into 3-(t-butoxy)-1-propynyl hydroperoxide, HCCCH(OOH)O-t-Bu, even during storage at 20 C. Small amounts of this peroxide as well as moisture will lead to inactivation of the base. As a result, the isomerisation is very slow or does not take place. The presence of hydroperoxide appears from an increase of the nD and from a KI test: brown colour after shaking a small sample with an aqueous solution of KI. This colour disappears if shaking is continued for some minutes. The impure 3-(t-butoxy)-1-propyne can be freed from hydroperoxide by adding some paraffin oil and subsequently distilling the product at <1 Torr, using a receiver cooled at 70 C (Figure 1.10) and keeping the bath temperature below 30 C. 2. Especially at temperatures higher than 60 C further conversion of the allenic ether to 1-(t-butoxy)-1-propyne, MeCCO-t-Bu, takes place. This ether splits off isobutene under these conditions and the resulting ketene. 1-propen-1-one, MeCH¼C¼O, reacts with the allenic ether and the 1-propynyl ether. The yield of t-butoxyallene is then much lower. 3. Although the nD of the pure allenic ether at 20 C is 1.4418, the final value for the reaction mixture is higher, since the t-BuOK partly dissolves in the allenic ether.

17.2.10

1-Ethoxyethoxyallene starting from propargyl alcohol and ethoxyethene

Scale: 1.0 molar; Apparatus: Figure 1.1, 500 ml 17.2.10.1 Procedure In the flask is placed 100 g of freshly distilled ethyl vinyl ether. After cooling to –25 C, a solution of 100 mg of p-toluenesulphonic acid in 5 ml of THF is added, immediately followed by 5 ml of the total amount of 1.0 mol of freshly distilled (bp 50 C in a partial vacuum) propargyl alcohol. After the evolution of heat (rising of the temperature by several C) has ceased, the

17.2

EXPERIMENTAL SECTION

331

remainder of the alcohol is added in 5-ml portions with intervals of a few minutes, care being taken that the temperature of the solution remains between 20 and 10 C. After the addition the temperature is allowed rising to 5 C and kept at this level for an additional 15 min. A solution of 0.10 mol of t-BuOK in 100 ml of DMSO is then added and the mixture is brought at 25 C. The temperature is allowed rising, but is kept between 35 and 40 C by occasional cooling. Stirring is stopped when, after subsiding of the weakly exothermic reaction, the temperature has dropped again to below 32 C. A solution of 30 g of ammonium chloride in 300 ml of water is added, after which the organic layer is washed five times with 50-ml portions of ammonium chloride solution of the same concentration. The combined washings are extracted once with 50 ml of pentane and this extract is washed three times with water. The combined organic solutions are dried over potassium carbonate, after which 1-ethoxyethoxyallene, bp 40 C/15 Torr (receiver cooled in a bath at 0 C), is isolated in an excellent overall yield. 17.2.11

Isomerisation of 1,4-bis(alkoxy)-2-butynes to the corresponding allenes

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml, no dropping funnel, no inert gas 17.2.11.1

Procedure

In 150 ml of anhydrous liquid ammonia (water content<0.1%) 8 g of t-BuOK is dissolved. 1,4-Dimethoxy-2-butyne (Chapter 20, exp. 20.6.2) (0.20 mol) is poured into the solution. The reaction mixture is stirred for 25 min after which 20 g of powdered ammonium chloride is introduced over 5 min. The ammonia is removed by placing the flask in a water bath at 40 C. Water (200 ml) is then added and five extractions with 40-ml portions of pentane are carried out. The combined solutions are freed from t-BuOH by shaking four times with 100-ml portions of water. The washings are combined and subsequently extracted twice with small amounts of pentane. The extracts are shaken two times with water. After drying the solution over potassium carbonate, the greater part of the pentane is distilled off on a water bath at 70 C at normal pressure through an efficient column. The remaining liquid is carefully fractionated to afford 1,4-dimethoxy-1,2-butadiene, bp 38 C/15 Torr, in 85% yield.

332

17.

ISOMERISATIONS OF ACETYLENIC COMPOUNDS

The isomerisation of 1,4-diethoxy-2-butyne proceeds more slowly. A mixture of 0.20 mol of t-BuOK, 0.20 mol of the bis-ether and 250 ml of liquid ammonia is stirred for 2 h, then solid ammonium chloride (20 g) is added portionwise and the ammonia is removed by evaporation. 1,4-Diethoxy-1,2butadiene, bp 59 C/15 Torr, is obtained in an excellent yield. 4-Ethoxy-1-methoxy-2-pentyne, EtOCH(Me)CCCH2OMe (obtained by reaction of 3-methoxy-1-propyne, HCCCH2OMe, with BuLi followed by addition of 1-chloro-1-ethoxyethane, MeCH(Cl)OEt), can be converted into 4-ethoxy-1-methoxy-1,2-pentadiene, EtOCH(Me)CH¼C¼CHOMe, by stirring a mixture of 0.10 mol of t-BuOK, 0.10 mol of the bis-ether and 300 ml of liquid ammonia for 4 h. The allenic ether, bp 52 C/15 Torr, is obtained in an excellent yield. Conversion of 1,1,4-triethoxy-2-butyne, EtOCH2CCCH(OEt)2, into 1,4,4-triethoxy-1,2-butadiene, EtOCH¼C¼CHCH(OEt)2, with 80% yield is achieved by adding 1.5 g of powdered t-BuOK in 5 portions with 3-min-intervals to a solution of 0.10 mol of the substrate in 40 ml of DMSO. After 15 min at 30–35 C the product, bp 92 C/15 Torr, is isolated via an aqueous work-up. 17.2.12

1,2,4-Pentatriene from 1-penten-4-yne

Scale: 0.30 molar; Apparatus: 250 ml one-necked flask and thermometer 17.2.12.1 Procedure [9] Sodium hydroxide (8.0 g) is dissolved in 100 ml of 96% ethanol (Note 1) and 0.30 mol of freshly distilled 1-penten-4-yne (Chapter 19, exp. 19.1.7) is added at 35 C. After swirling, the refractive index (Note 2) of the solution is measured (nD 1.387). The solution is kept at 35 C for 45 min, by which time the refractive index (nD) had reached its maximal value (1.396) (Note 3). The flask is equipped for a distillation and the product is distilled off, together with a small amount of alcohol and water, and collected in a receiver, cooled below 0 C (Figure 1.10). The distillation, which takes 15 min (Note 3), is stopped when the temperature in the head of the column has reached 78 C. The distillate is transferred into a small separating funnel and shaken three times with 20-ml portions of a cold (–10 to 5 C) concentrated ammonium chloride solution. The upper layer is dried over a small amount of magnesium sulphate. The refractive index (nD) is 1.470, corresponding to pure 1,2,4-pentatriene.

17.2

EXPERIMENTAL SECTION

333

The yield is 85–90%. The compound can be stored for a limited period (a few weeks) at –25 C.

Notes 1. 2.

3.

With NaOH in methanol the isomerisation is markedly slower. A small amount (0.1–0.2 ml) of the solution is sucked into a Pasteur pipette and the refractive index is measured immediately. The liquid should be transferred between the prisms in such a way that there is no opportunity for evaporation as this would result in measuring of a too low value. The ultimate result is a mixture of 1,2,4-pentatriene, H2C¼C¼ CHCH¼CH2, and 3-penten-1-yne, HCCCH¼CHMe (9:1). Since the refractive index of these compounds is between those of vinylallene and allylacetylene, longer reaction times will result in a decrease of the nD. Although, the further conversion of vinylallene under the described reaction conditions is much slower, it is safer to keep the reaction time and the time used for the distillation as short as possible.

17.2.13

1,2-Pentadien-4-yne from 1,4-pentadiene

Scale: 0.10 molar; Apparatus: 100-ml round-bottomed flask and thermometer 17.2.13.1

Procedure [1]

Lithium (0.10 mol) is dissolved in 100 ml of methanol and 0.11 mol of pure phenol is added (Note 1). From the obtained solution of lithium phenolate, 15 ml is mixed at rt with 0.10 mol of freshly distilled 1,4-pentadiyne (Chapter 4, exp. 4.5.31). The refractive index (nD) determined immediately after mixing is 1.381 (Note 2). The mixture is then rapidly warmed to 48 C and kept at this temperature for 15 min. The nD is now 1.391 (Note 3). Water (100 ml) is then added and three extractions with 20-ml portions of high-boiling petroleum ether (bp>180 C) are carried out. The organic solution is washed with 1 N hydrochloric acid and subsequently dried over magnesium sulphate. The extract is warmed in a distillation apparatus, using a water aspirator vacuum

334

17.

ISOMERISATIONS OF ACETYLENIC COMPOUNDS

of 10–15 Torr. The vapour of the yneallene is collected in a receiver cooled at 75 C (Figure 1.10). As soon as the petroleum ether begins to pass over, nitrogen is admitted to the apparatus. This evacuation procedure is repeated once with the contents of the receiver, now with only slight external heating, so that the petroleum ether does not boil. In the receiver is collected 3.5 g of product, consisting of a 9:1 mixture of 1,2-pentadien-4-yne and 1,3-pentadiyne. This is the best result obtained from several experiments, using various solvents and bases. Sodium phenolate gave considerably more 1,3-pentadiyne, and with lithium p-nitrophenolate as a base the isomerisation to 1,2-pentadien-4-yne was too slow.

Notes 1.

A slight excess of phenol is used. With a stoichiometric amount the solution may be too strongly basic so that the further isomerisation will become too fast. 2. A very exact determination is not possible because of the dark brown colour of the solution. 3. Heating for longer periods gives more 1,3-pentadiyne.

17.2.14

Isomerisation of 3-ethylthio-1-propyne to 1-ethylthio-1-propyne

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre Base-catalysed isomerisation of 2-propynyl sulphides, HCCCH2SR, has been carried out in ethanol at slightly elevated temperatures. The intermediary allenic sulphides, H2C¼C¼CHSR, were found to isomerise relatively slowly to 1-propynyl sulphides, MeCCSR, under the influence of sodium ethoxide [5]. We observed an extremely fast isomerisation of propargylic sulphides to 1-propynyl sulphides in boiling liquid ammonia (33 C) using sodium ethoxide as a catalyst [4]. This base can be prepared by adding an equivalent amount of ethanol to a solution of sodium or a suspension of sodamide in liquid

17.2

EXPERIMENTAL SECTION

335

ammonia. Sodium ethoxide prepared in this way is not solvated by ethanol, which explains its high reactivity. Alternatively, a catalytic amount of tBuOK (commercially available) may be added to a mixture of a propargyl sulphide and liquid ammonia. The propargyl sulphides can be conveniently prepared in situ by adding propargyl chloride to an ammoniacal solution of sodium alkanethiolate, formed by adding the thiol to a solution of sodium in liquid ammonia. Thiols often contain small amounts of disulphides formed by oxidation. For the preparation of thiolates from thiols and sodium in ammonia it is not necessary to remove the disulphide by distillation (complaints about the stench!), as also the disulphide is converted by the alkali metal into thiolate. Methanethiol is very volatile (bp 6 C) and it is experimentally not very attractive to prepare a solution of sodium methanethiolate in liquid ammonia from the thiol. This solution is conveniently obtained, however, by adding the commercially available dimethyl disulphide, MeSSMe, to the double equivalent amount of sodium in liquid ammonia (MeSSMe þ 2 Na ! 2 MeSNa).

17.2.14.1

Procedure

Anhydrous liquid ammonia (300 ml) is placed in the flask and 0.25 mol of sodium is added in pieces of 0.5 g. After 10 min ethanethiol is added dropwise over 20 min, while cooling the reaction mixture between 35 and 40 C. After the blue colour has vanished, 0.20 mol of propargyl chloride is added over 15 min, likewise with cooling below the bp of ammonia. Salt separates immediately from the solution. After an additional 25 min, a solution of 5 g of tBuOK in 50 ml of liquid ammonia (prepared by adding the base to ammonia in a small round-bottomed or conical flask) is cautiously poured into the reaction flask (Note). The mixture is vigorously stirred for 5 min, after which the ammonia is allowed to evaporate overnight (Figure 1.7). Water (200 ml) is added with vigorous stirring. After dissolution of the salt, four extractions with small portions of pentane are carried out. The combined organic solutions are washed three times with water and subsequently dried over MgSO4. The greater part of the pentane is distilled off at atmospheric pressure (40-cm Vigreux column, bath temperature not higher than 90 C). Distillation of the remaining liquid, using a single receiver cooled in a water bath at 0 C (Figure 1.10) gives 1-ethylthio-1-propyne, bp 30 C/15 Torr, in 80% yield. 1-Methylthio-1-propyne, MeCCSMe, bp 70 C/100 Torr, is obtained in slightly lower yield (between 70 and 75%) from MeSNa and HCCCH2Cl. The required solution of 0.20 mol of MeSNa is obtained by adding 0.10 mol of dimethyldisulphide, MeSSMe, to a solution of 0.20 mol of sodium in 300 ml of liquid ammonia, cooled to between –35 and –40 C.

336

17.

ISOMERISATIONS OF ACETYLENIC COMPOUNDS

Note If no t-BuOK is available, a solution of 0.10 mol of sodium ethoxide in 100 ml of liquid ammonia may be added. This solution is obtained in a 1-litre roundbottomed flask by cautious addition of 0.10–0.13 mol of absolute ethanol to a solution of 0.10 mol of sodium or to a suspension of 0.10 mol of sodamide in 150 ml of ammonia.

17.2.15

Isomerisation of 1-(phenylthio)-3-propyne to 1-(phenylthio)-1-propyne

Scale: 0.30 molar; Apparatus: 1-litre round-bottomed, three-necked flask, provided with a dropping tunnel, a mechanical stirrer and a reflux condenser

17.2.15.1 Procedure [5] A solution of 0.30 mol of sodium ethoxide is prepared by dissolving 0.30 mol of sodium in 300 ml of 100% ethanol. Thiophenol and propargyl chloride (0.30 mol) are successively added over 15 min without external cooling. Five minutes later a solution of sodium ethoxide in 100 ml of 100% ethanol, prepared from 3 g of sodium, is run in. The suspension is heated under reflux for an additional 1 h. The reaction mixture is cooled to rt and subsequently poured into 500 ml of ice water. The product is isolated by extracting five times with Et2O, washing the extract with water, drying over magnesium sulphate and concentrating the extract in a water-aspirator vacuum. Distillation through a short column gives 1-(phenylthio)-1-propyne, bp 100 C/1 Torr, in an excellent yield.

17.2.16

1,1-Diethoxy-3-heptyne from 1,1-diethoxy-2-heptyne

Scale: 0.10 molar; Apparatus: 250-ml round-bottomed flask and thermometer, manual swirling

17.2

EXPERIMENTAL SECTION

17.2.16.1

337

Procedure (cf. [13])

A solution of 1 g of t-BuOK in 8 ml of DMSO is added at rt to a mixture of 0.10 mol of 1,1-diethoxy-2-heptyne and 30 ml of DMSO. The temperature rises by a few degrees only. After 10 min a second portion of the solution of t-BuOK in DMSO is added. After warming the solution for 15 min at 40 C, 150 ml of ice water is added, followed by extraction with Et2O. The extracts are dried over magnesium sulphate after washing with water. Careful distillation of the residue remaining after removal of the solvent under reduced pressure gives the isomeric acetal, 1,1-diethoxy-3-heptyne, bp 91 C/10 Torr, in 70% yield. The small first fraction consists mainly of 1-ethoxy-1-hepten3-yne, n-PrCCCH¼CHOEt.

17.2.17

3-Vinylidene-1-cyclohexene from 1-ethynylcyclohexene

Scale: 0.10 molar; Apparatus: Figure 1.1, 250 ml, without dropping funnel

17.2.17.1

Procedure (cf. [10])

In the flask are placed 40 ml of dry HMPT and 3 g of finely powdered t-BuOK. The mixture is warmed until all suspended material has dissolved, then 7.5 g of t-BuOH and 0.10 mol of 1-ethynylcyclohexene are successively added. Immediately after these additions, the temperature is adjusted at 55 C. After stirring for 10 min at 54–56 C (Note) the brown mixture is poured into 200 ml of ice water and 5 extractions with pentane are carried out. The extracts are washed with water, dried over magnesium sulphate and then concentrated under reduced pressure. The isomerisation product, 3-ethenylidene-1-cyclohexene, is collected between 35 and 40 C/17 Torr in 80% yield. The contamination of ethylbenzene may vary between 5 and 20% (Note).

Note Heating for longer periods or at higher temperature gives more ethylbenzene.

338 17.2.18

17.

ISOMERISATIONS OF ACETYLENIC COMPOUNDS

Sodamide-catalysed isomerisation of 2-alkynyl ethers to allenic ethers

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml, no dropping funnel is used 17.2.18.1 Procedure [11] The 2-alkynyl ether (0.20 mol) is added in a few seconds to a suspension of 0.40 mol (excess) of sodamide in 250 ml of liquid ammonia. After 15 min the thermometer is replaced with a powder funnel and 30 g of powdered NH4Cl is added as quickly as possible. The ammonia is removed by placing the flask in a bath at 40 C. Water is added and extraction with Et2O or pentane is carried out. The extracts are dried and concentrated under reduced pressure. Careful distillation of the remaining liquid gives 1-ethoxy-4,4-dimethyl-1,2-pentadiene, bp 46 C/15 Torr, in > 80% yield. The ethers RCCCH2OEt, R ¼ i-Pr, c-Pentyl and c-Hexyl, can be converted into the corresponding allenic ethers with high yields, but purities are between 80 and 90% only. With potassium amide the predominating reaction is 1,4-elimination of ethanol with formation of R12 C¼CHCCH through the intermediary cumulenes, R12 C¼C¼C¼CH2 (R12 C ¼ Me2C, (CH2)4C, (CH2)5C, cf. [12]). This elimination is not possible with the t-butyl derivative. 17.2.19

4,5-Hexadien-3-one from 5-hexyn-2-one

Scale: 0.20 molar; Apparatus: 100-ml round-bottomed flask closed with a rubber stopper 17.2.19.1 Procedure A mixture of 0.20 mol of the crude 5-hexyn-3-one (purity 80%, Chapter 20, exp. 20.4.3), 5 g of sodium hydrogen carbonate and 10 ml of water is shaken vigorously at rt on a vibrator (or agitated vigorously with a mechanical stirrer). The isomerisation is followed by determining the refractive index of the upper layer (shaking or stirring is interrupted for a few minutes). When this has

17.2

EXPERIMENTAL SECTION

339

reached its maximum value (1.464) (Note) shaking or stirring is stopped and the mixture is extracted five times with small portions of diethyl ether. The extracts are dried (without washing) over magnesium sulphate and, after removing the solvents in a water-aspirator vacuum, 4,5-hexadien-3-one is distilled, bp 35–40 C/15 Torr, yield 85%. The product may contain 15% of an unknown impurity.

Note The reaction time at rt is 2–3 h. At 40 C the isomerisation is finished within 30 min. With a dilute (1 g per 10 ml) aqueous solution of K2CO3 only 5 min is required. 17.2.20

2,4,5-Hexatrienenitrile from 5-bromo-3-penten-1-yne and potassium cyanide

Scale: 0.10 molar; Apparatus: 250-ml f1ask. Figure 1.1, no dropping funnel is used 17.2.20.1

Procedure

In the flask is placed 2.0 g of copper(I) cyanide, 15 ml of water, 25 ml of ethanol and 0.10 mol of 5-bromo-3-penten-1-yne (see below). The mixture is heated to 60 C and a solution of 0.11 mol of potassium cyanide in 40 ml of water is added over 20 min, while keeping the temperature between 60 and 65 C (occasional cooling may be necessary). After the addition the mixture is heated for an additional 10 min at 80 C, then cooled to rt and 200 ml of water is added. The reaction product is extracted seven times with Et2O. The combined extracts are washed once with a concentrated NH4Cl solution and dried over magnesium sulphate. Removal of the Et2O by evaporation in a wateraspirator vacuum gives 9 g of a residue, consisting of equal amounts of 3-hexen-5-ynenitrile and 2,4,5-hexatrienenitrile. This mixture is dissolved in

340

17.

ISOMERISATIONS OF ACETYLENIC COMPOUNDS

25 ml of Et2O and 2 g of potassium carbonate is added. The temperature rises in a few minutes from 20 to 30 C. The mixture is shaken for an additional 15 min (by hand or mechanically) and is subsequently poured with swirling into 50 ml of 2 N hydrochloric acid saturated with ammonium chloride. After separation of the layers, two extractions with Et2O are carried out. The combined ethereal solutions are washed once with 50 ml of concentrated NH4Cl solution and dried over magnesium sulphate. Removal of the solvent and subsequent distillation through a 30-cm Vigreux column affords the pure 2,4,5-hexatrienenitrile (equal amounts of (E)- and (Z)-isomers), bp 55 C/15 Torr, in a high yield. Note Prepared by addition of the required amount of PBr3 at –10 C to an ethereal solution of 2-penten-4-yn-1-ol, HC¼CCH¼CHCH2OH (Chapter 4, exp. 4.5.14), to which 5 ml of pyridine has been added. After standing for 2 h at rt, the mixture is poured into water. 5-Bromo-3-penten-1-yne, bp 40 C/ 15 Torr, is obtained in 75% yield.

REFERENCES 1. Unpublished observations and results from the author’s laboratory. 2. H. D. Verkruijsse, H. J. T. Bos, L. J. de Noten and L. Brandsma, Recl. Trav. Chim., Pays-Bas 100, 244 (1981). 3. S. Hoff, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 87, 916 (1968). 4. L. Brandsma, H. E. Wijers and J. F. Arens, Recl. Trav. Chim., Pays-Bas 82, 1040 (1963). 5. G. Pourcelot and P. Cadiot, Bull. Soc. Chim. France, 3016 (1966). 6. O. A. Tarasova, F. Taherirastgar, H. D. Verkruijsse, A. G. Mal’kina, L. Brandsma and B. A. Trofimov, Recl. Trav. Chim., Pays-Bas 115, 145 (1996). 7. W. G. Galesloot, M. J. A. de Bie, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 89, 575 (1970). 8. G. A. Wildschut, J. H. van Boom, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays-Bas 87, 1447 (1968). 9. J. Grimaldi and M. Bertrand, Bull. Soc. Chim. France, 947 (1971). 10. J. P. C. M. van Dongen, A. J. de Jong, H. A. Selling, P. P. Montijn, J. H. van Boom and L. Brandsma, Recl. Trav. Chim., Pays-Bas 86, 107 (1967). 11. J. H. van Boom, P. P. Montijn, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays Bas 84, 31 (1965). 12. P. P. Montijn, H. M. Schmidt, J. H. van Boom, H. J. T. Bos, L. Brandsma and J. F. Arens, Recl. Trav. Chim., Pays Bas 84, 271 (1965). 13. R. Mantione, M. L. Martin, J. Martin and H. Normant, Bull. Soc. Chim. France, 2912 (1967).

18 Allenic Compounds by 2,3- and 3,3-Sigmatropic Rearrangements

18.1

2,3-SIGMATROPIC REARRANGEMENTS

An excellent method for the preparation of allenyl sulphoxides consists of reacting a propargylic alcohol with a sulphenyl chloride in the presence of triethylamine. The initially formed product undergoes a 2,3-sigmatropic rearrangement at low temperatures to afford the allenic sulphoxide. The formation of the strong S–O bond is the driving force. Yields are generally high [1–6] (Scheme 1).

Analogous reactions between propargylic alcohols and sulphinyl chlorides [7–9] or trivalent phosphorus chlorides [10–19], exemplified by Schemes 2 and 3, respectively, are known.

341

342

18. 18.2

2,3- AND 3,3-SIGMATROPIC REARRANGEMENTS 3,3-SIGMATROPIC REARRANGEMENTS

Schemes 4–10 represent approaches to the acetylenic starting systems and their subsequent thermal rearragements [20–31]. There are several other examples of 3,3-sigmatropic rearrangements affording an allenic system [32–39]. This can be isolated as a relatively stable compound, but in many cases one is concerned with a short-living molecule, which polymerises or cyclises, unless it is trapped with a reactive reagent. Rearrangements of allenic compounds to acetylenic isomers are less investigated [40].

18.3

EXPERIMENTAL SECTION

18.3 18.3.1

343

EXPERIMENTAL SECTION

Methyl 1,2-propadienyl sulphoxide from propargyl alcohol and methanesulphenyl chloride

Reaction Scheme 1, R1 ¼ H, R2 ¼ Me Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre 18.3.1.1

Procedure

To a mixture of 200 ml of dry dichloromethane, 0.22 mol of dry propargyl alcohol and 0.22 mol of dry triethylamine a solution of 0.20 mol of methane– sulphenyl chloride (Note 1) in 60 ml of dichloromethane is added with occasional cooling between –95 and –100 C. After the addition, which takes 10 min, 10 g of methyl iodide (Note 2) is added and the cooling bath is

344

18.

2,3- AND 3,3-SIGMATROPIC REARRANGEMENTS

removed. When the temperature has reached –20 C, the salt is filtered off on a sintered-glass funnel (G-2) and rinsed well with dichloromethane. To the residue remaining after evaporation of the solvent in a water-aspirator vacuum is added 100 ml of dry Et2O in order to precipitate some remaining salt. Filtration and subsequent removal of the Et2O under reduced pressure gives pure methyl 1,2-propadienyl sulphoxide in 100% yield as an oily liquid.

Notes Prepared by adding 0.10 mol of dimethyl disulphide, MeSSMe, at –30 C to a solution of 0.10 mol of chlorine in dichloromethane and subsequently raising the temperature to 0 C. 2. Traces of unconverted triethylamine might cause partial isomerisation of the allenyl sulphoxide to the propargyl sulphoxide. The methyl iodide is added to ensure that no triethylamine remains.

1.

18.3.2

Phenyl 1,2-propadienyl sulphoxide from benzenesulphenyl chloride and propargyl alcohol

Reaction Scheme 1, R1 ¼ H, R2 ¼ Ph Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml 18.3.2.1

Procedure

In the flask are placed 0.22 mol of the propargyl alcohol, 0.22 mol of triethylamine and 200 ml of dichloromethane (Note 1). To this mixture a solution of 0.20 mol of benzenesulphenyl chloride in 75 ml of dichloromethane (Note 2) is added in 10 min with occasional cooling between –90 and –100 C. Five minutes after this addition 10 g of methyl iodide is added (Note 3) and the cooling bath is removed. When the temperature has reached 10–15 C, the mixture is poured into 200 ml of water to which 2 ml of 36% HCl has been added. After vigorous shaking, the lower layer is separated. The aqueous layer is extracted with 50 ml of dichloromethane. The combined organic solutions are washed with water and dried over magnesium sulphate. The oily residue remaining after evaporation of the solvent under reduced pressure appears to be reasonably pure phenyl 1,2-propadienyl sulphoxide. The yield is almost quantitative. Small amounts of diphenyl disulphide, which are sometimes present, can be removed by shaking the oil with 50 ml of pentane. The disulphide is extracted in this way. The n20 D of phenyl 1,2-propadienyl sulphoxide, PhS(¼O)CH¼C¼CH2, obtained after this purification is 1.6180.

18.3

EXPERIMENTAL SECTION

345

1,2-Butadienyl phenyl sulphoxide, PhS(¼O)CH¼C¼CHMe, n20 D 1.5993, is obtained by a similar procedure from 3-butyn-2-ol, HCCCH(Me)OH, and benzenesulphenyl chloride, PhSCl.

Notes 1. 2.

3.

All reagents and solvents must be thoroughly dry. Prepared by adding at –20 C a cold (–30 C) solution of 7.2 g (0.10 mol) of chlorine in 20 ml of CCl4 to 0.10 mol of diphenyl disulphide in CH2Cl2. After the addition, which is carried out in 15 min, the temperature is allowed to rise to 0 C. See exp. 18.3.1, Note 2.

18.3.3

Methyl 3-methyl-1,2-butadienyl sulphone from 2-methyl-3-butyn-2-ol and methanesulphinyl chloride

Reaction Scheme 2, R ¼ Me Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml for the preparation of the sulphinate; 250-ml two-necked flask with a thermometer and a reflux condenser for the rearrangement.

18.3.3.1

Procedure

To a mixture of 0.10 mol of dry 2-methyl-3-butyn-2-ol (commercially available), 0.12 mol of dry triethylamine and 150 ml of dry dichloromethane 0.12 mol of methanesulphinyl chloride is added over 10 min with cooling at –50 C. The cooling bath is removed and after 15 min a mixture of 3 ml of 36% HCl and 200 ml of water is added with vigorous stirring. The lower layer is separated, washed with water and dried over magnesium sulphate. The residue remaining after evaporation of the solvent under reduced pressure is dissolved in 80 ml of xylene. The solution is heated under reflux for 15 min, then the xylene is distilled off at 10–20 Torr. The residue is warmed for a few minutes with 75 ml of dry Et2O. After cooling to 20 C, the brown solution is decanted from the small amount of insoluble material. Evaporation of the Et2O under reduced pressure gives reasonably pure methyl 3-methyl-1,2-butadienyl sulphone as a brown oil, in a yield of 85%. 2-Propynyl methanesulphinate, HCCCH2OSOMe, did not rearrange upon heating at 130–140 C in xylene.

346 18.3.4

18.

2,3- AND 3,3-SIGMATROPIC REARRANGEMENTS

1,2-Propadienyl diphenylphosphinate from propargyl alcohol and chlorodiphenylphosphane

Reaction Scheme 3, R ¼ Ph Scale: 0.10 molar; Apparatus: 500-ml, three-necked, round-bottomed flask with thermometer, mechanical stirrer and outlet; addition by syringe. 18.3.4.1

Procedure

To a mixture of 100 ml of dry dichloromethane, 0.10 mol of propargyl alcohol and 0.11 mol of triethylamine is added in 3 min, a solution of 0.10 mol of diphenylphosphinous chloride, Ph2PCl, in 75 ml of dichloromethane with cooling between –80 and –90 C. The cooling bath is removed. When the temperature has reached rt, the reaction mixture is poured into a solution of 2.5 ml of 36% HCl in 100 ml of water. After vigorous shaking and separation of the layers, the aqueous layer is extracted twice with 25-ml portions of dichloromethane. The combined solutions are washed twice with water, dried over magnesium sulphate and then concentrated under reduced pressure giving almost pure 1,2-propadienyl diphenylphosphinate as a white solid, mp 98–100 C, in almost 100% yield.

18.3.5

N,N-Diethyl-2-methyl-3,4-pentadienamide from the boron trifluoride-catalysed reaction of propargyl alcohol with N,N-diethyl-1-propyn-1-amine

Reaction Scheme 4 Scale: 0.10 molar; Apparatus: 250-ml round-bottomed flask and reflux condenser. 18.3.5.1

Procedure

To a mixture of 65 ml of dry benzene and 0.10 mol of freshly distilled N,Ndiethyl-1-propyn-1-amine are added 3 drops of BF3-etherate and 0.12 mol of dry propargyl alcohol is added to the reddish solution in 5 min. The temperature rises in 5–10 min to 45 C, remained at this level for 10 min and then begins to drop. The mixture is warmed to 60 C. The temperature rises in a few minutes to 85 C. This level is maintained by occasional cooling. After the exothermic reaction (3,3-sigmatropic rearrangement) has subsided, the mixture is heated for an additional 10 minute at 80 C, then the benzene is removed under reduced pressure. The red residue is practically pure carboxamide (NMR). Distillation through a 10-cm Vigreux column gives

18.3

EXPERIMENTAL SECTION

347

pure N,N-diethyl-2-methyl-3,4-pentadienamide, bp 70 C/0.5 Torr, in 85% yield. A small brown residue remains.

18.3.6

6-Methylhepta-4,5-heptadien-2-one from the acid-catalysed reaction of 2-methyl-3-butyn-2-ol with methyl isopropenyl ether

Reaction Scheme 5 Scale: 0.50 molar; Apparatus: Figure 1.1, 500 ml; after the addition of 2-methoxy-1-propene the dropping funnel is replaced with a thermometer and a reflux condenser is placed on the flask. 18.3.6.1

Procedure

In the flask are placed 1.50 mol (large excess) of 2-methoxy-1-propene (commercially available) and 0.10 mol of (dry) 2-methyl-3-butyn-2-ol (also commercially available), and in the dropping funnel 0.40 mol of the latter compound. The mixture is cooled to 0 C and 100 mg of anhydrous p-toluenesulphonic acid is added with stirring. An exothermic reaction starts immediately and the temperature rises by several degrees. When this reaction has subsided, the mixture is cooled to 10 C and the remaining 0.40 mol of the acetylenic alcohol is added from the dropping funnel over 15 min, whilst keeping the temperature between 10 and 20 C. The apparatus is then modified as indicated above and the solution is heated under reflux. In order to maintain refluxing the bath temperature has to be increased gradually. After 2 h the temperature in the boiling liquid has become constant ( 95 C). The brown solution is cooled, then the volatile components (mainly 2,2-dimethoxypropane) are removed on the rotary evaporator. Subsequent distillation of the remaining liquid through a 30-cm Vigreux column gives 6-methyl-4,5-heptadien-2-one, bp 65 C/15 Torr, in 75% yield (Note). There is 8 g of viscous residue.

Note This yield is lower than that reported in the literature. In our procedure no lowboiling petroleum ether is used as co-solvent so that the temperature of the boiling reaction mixture can become considerably higher. This may give rise to the formation of polymeric products and tars. Our reaction time is much shorter than that in the literature. The reaction with 2-propyn-1-ol, HCCCH2OH, and 3-butyn-2-ol, HCCCH(Me)OH, failed.

348 18.3.7

18.

2,3- AND 3,3-SIGMATROPIC REARRANGEMENTS

Ethyl 3,4-pentadienoate from the acid-catalysed reaction of propargyl alcohol with ethyl orthoacetate

Reaction Scheme 7, R ¼ H Scale: 0.50 molar; Apparatus: 500-ml three-necked flask equipped with a dropping funnel, a thermometer dipping in the liquid and an efficient column connected to a condenser and receiver. 18.3.7.1

Procedure

A mixture of 0.50 mol of 1,1,1-triethoxyethane, 3 g of propionic acid and 0.22 mol of propargyl alcohol is gradually heated in an oil bath. When 5 ml of ethanol has passed over (between 75 and 85 C), another amount of 0.30 mol of propargyl alcohol is added dropwise over a period of 15 min. When the temperature of the liquid in the reaction flask has reached 150 C, the heating bath is removed and the liquid is allowed to cool to 120 C. The ethanol in the receiver is placed in the dropping funnel and mixed with 2 g of propionic acid, after which the flask is heated again. The mixture of ethanol and acid is added gradually in 20 min. After the greater part of the ethanol has been distilled off ( 50 g), the internal temperature can rise to 155 C. This temperature is maintained for 30 min, The contents of the flask are allowed to cool to rt. Very careful fractionation gives ethyl 3,4-pentadienoate, bp 54 C/17 Torr, in 60% yield. 18.3.8

Ethyl 3,4-pentadienedithioate from the reaction of ethyl ethanedithioate with lithium amide and propargyl bromide

Reaction Scheme 6 Scale: 0.30 molar; Apparatus: Figure 1.1, 1 litre for the preparation of the enethiolate; 1-litre round-bottomed, three-necked flask with mechanical stirrer and two open necks for the reaction of the enethiolate with propargyl bromide. 18.3.8.1

Procedure

Ethyl ethaneditioate (0.31 mol, prepared from MeMgBr, CS2 and ethyl bromide [41]) is added over a few minutes to a suspension of 0.30 mol of lithium amide in 250 ml of liquid ammonia (Chapter 2, exp. 2.3.1) with cooling at –50 C. After an additional 5 min the resulting solution (50 C) of the enethiolate is cautiously poured over 5 min through one of the open necks of the other reaction flask, while keeping the temperature between –50 and –60 C. This flask contains a solution of 0.40 mol (excess) of propargyl bromide in 250 ml of liquid ammonia, cooled to –60 C which has been made just before

18.3

EXPERIMENTAL SECTION

349

(Note 1) by adding propargyl bromide to the ammonia pre-cooled at –60 C. Four minutes after the addition of the enethiolate to the solution of propargyl bromide 10 g of powdered ammonium chloride is added. After stirring for an additional 1 h (without cooling) the reaction mixture is poured onto 300 g of finely crushed ice on the bottom of a large beaker. Extraction with pentane (at least 5 times) is carried out as quickly as possible. The extracts are kept below 0 C and are washed three times with 1 N hydrochloric acid in order to remove dissolved ammonia (Note 2). After drying over magnesium sulphate, the combined organic solutions are concentrated under reduced pressure to a volume of 50 ml, care being taken that the bath temperature remains below rt. The remaining pale yellow solution is brought to 35 C. The ensuing exothermic reaction is kept under control by occasional cooling so that the temperature does not rise above 45 C. When, after about half an hour, the reaction has subsided, the flask is heated for 30 min in a bath at 55 C. Removal of the pentane under reduced pressure gives an orange liquid, being almost pure ethyl 3,4-pentadienedithioate. The yield is at least 75%.

Notes 1.

2.

Propargyl bromide reacts very fast with boiling liquid ammonia, therefore the reaction of it with the enethiolate should be carried out without any delay. For efficient cooling a bath with liquid nitrogen is indispensable. Since ammonia may catalyse cyclisation of the allenic dithioate to a derivative of 2H-thiopyran, it seems desirable to neutralise it.

18.3.9

Ethyl 3,4-hexadienoate from the acid-catalysed reaction of 3-butyn-2-ol with ethyl orthoacetate

Reaction Scheme 7, R ¼ Me Scale: 0.45 molar; Apparatus: same as for exp. 18.3.7 18.3.9.1

Procedure

In the flask are placed 100 g of 1,1,1-triethoxyethane and 2 ml of propionic acid. From the dropping funnel, which contains 0.45 mol of 3-butyn-2-ol (commercially available), is added 10 g of this acetylenic alcohol. The flask is heated in an oil bath. The temperature of the boiling liquid, which initially is 113 C, rises to 130 C in 20 min, while ethanol distils off at 76–80 C. The remainder of the acetylenic alcohol is added dropwise over 30 min. After heating for 40 min 50 g of ethanol has passed over and the temperature of the

350

18.

2,3- AND 3,3-SIGMATROPIC REARRANGEMENTS

liquid in the distillation flask has risen to 150 C. Heating at this temperature is continued for an additional 30 min. After cooling to 30 C, the remaining liquid is carefully distilled. After the first fraction, consisting mainly of 1,1,1triethoxyethane, has passed over, ethyl 3,4-hexadienoate distils at 65 C/ 15 Torr, and is obtained in 70% yield. 18.3.10

Synthesis of 2,2-dimethyl-3,4-pentadienal starting from propargyl alcohol and 2-methylpropanal

Reaction Scheme 9 Scale: 0.50 molar; Apparatus: Figure 1.1, 500 ml with long gas inlet tube for the first reaction; 500 ml round-bottomed three-necked flask with thermometer, mechanical stirrer and reflux condenser for the elimination of hydrogen chloride and the 3,3-sigmatropic rearrangement. 18.3.10.1 Procedure Gaseous hydrogen chloride is introduced into a mixture of 0.52 mol of propargyl alcohol and 0.50 mol of freshly distilled 2-methylpropanal while keeping the temperature of the mixture between –10 and 0 C. The introduction of gas is stopped when copious fumes of HCl escape from the outlet. After standing for 1–2 min at 0 C, the clear upper layer is decanted from the small turbid aqueous layer. The latter is extracted (shaking followed by decanting) four times with 20-ml portions of pentane. The main portion and the extracts are dried over a small amount of magnesium sulphate. Subsequently, the pentane is removed on the rotary evaporator keeping the bath temperature at 25 C. The residue (weight 70 g), crude 3-(1-chloro-2-methylpropoxy)1-propyne, is mixed with 120 g of N,N-diethylaniline and the mixture is heated at 100 C (internal). A weakly exothermic reaction starts during which the temperature rises gradually. Some cooling (water bath) is applied in order to keep the temperature between 100 and 105 C. Twenty minutes after the exothermic reaction has ceased the mixture is heated. The diethylaniline salt of HCl, which has deposited on the glass wall, dissolves. The reaction mixture is heated under reflux for 10 min (temperature of the reaction mixture 165–170 C but soon dropping to 150–155 C). The mixture is cooled to 80 C and 300 ml of ice water is added. After shaking (until the salt has dissolved) and separation of the upper layer, the aqueous layer is extracted once with 30 ml of pentane. The extract and the upper layer are combined and washed five times with water. After drying over magnesium sulphate, the mixture is distilled in a weak flow of nitrogen through a 30-cm Vigreux column. The fraction passing over between 110 and 175 C/760 Torr is redistilled through

REFERENCES

351

the same column giving 2,2-dimethyl-3,4-pentadienal, bp 132 C, in 65–75% yield (towards the end of the distillation and after cooling, a partial vacuum is applied to minimise the hold-up). Starting from propionaldehyde 2-methyl-2,4-pentadienal, H2C¼CHCH ¼C(Me)CH¼O, is obtained in an impure state and in moderate yield. Its precursor, 2-methyl-3,4-pentadienal, H2C¼C¼CHCH(Me)CH¼O, is present in traces only. 18.3.11

Silver perchlorate-catalysed rearrangement of 1,1-dimethyl2-propynyl acetate to 3-methyl-1,2-butadienyl acetate

Reaction Scheme 10 Scale: 0.10 molar; Apparatus: 100 ml round-bottomed flask and thermometer 18.3.11.1

Procedure

To a mixture of 0.10 mol of 1,1-dimethyl-2-propynyl acetate (Chapter 20, exp. 20.5.1) and 20 g of dry dichloromethane is added at rt 0.60 g of silver perchlorate. The mixture is swirled for 2–3 min. The perchlorate dissolves completely and the solution becomes turbid. The temperature rises gradually to 30 C and the solution turns brown to black. After standing for 2 h (Note) the solution is poured into 100 ml of water to which 4 ml of concentrated ammonia solution has been added. After vigorous shaking, the organic layer is separated and combined with two dichloromethane extracts. The combined solutions are dried over magnesium sulphate and subsequently concentrated under reduced pressure. Distillation of the remaining brown liquid through a short Vigreux column gives the almost pure 3-methyl-1,2-butadienyl acetate, bp 60 C/20 Torr, in 55% yield. A rather large residue is left behind. Note Longer reaction time gives rise to lower yields and more polymer. With 1-ethynylcyclohexyl acetate (1-acetoxy-1-ethynylcyclohexane) 50% conversion is effected after 2 h. Addition of more AgClO4 results in a vigorous decomposition.

REFERENCES 1. H. Altenbach and H. Soicke, Liebigs Ann. Chem., 1096 (1962). 2. L. Horner and V. Binder, Liebigs Ann. Chem. 757, 33 (1972).

352 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.

18.

2,3- AND 3,3-SIGMATROPIC REARRANGEMENTS

E. M. G. A. van Kruchten and W. H. Okamura, Tetrahedron Lett., 1019 (1962). S. Braverman and Y. Stabinsky, Isr. J. Chem. 5, 125 (1967). A. J. Bridges and J. W. Fischer, J. Chem. Soc., Chem. Comm., 665 (1982). S. Joganathan and W. H. Okamura, Tetrahedron Lett., 4763 (1982). S. Braverman and H. Mechulam, Tetrahedron 30, 3883 (1974). C. J. M. Stirling, J. Chem. Soc., Chem. Comm., 131 (1967). G. Smith and C. J. M. Stirling, J. Chem. Soc., (C), 1530 (1971). A. P. Boiselle and N. A. Meinhardt, J. Org. Chem. 27, 1828 (1962). A. N. Pudovik and I. M. Aladzheva, J. Gen. Chem. USSR 33, 700 (1963). A. N. Pudovik, I. M. Aladzheva and L. N. Yakovenko, J. Gen. Chem. USSR 35, 1214 (1965). A. Sevin and W. Chodkowiecz, Tetrahedron Lett., 2975 (1967). A. Sevin and W. Chodkowiecz, Bull. Soc. Chim. France, 4016 (1969). W. Welter, H. Hartmann and M. Regitz, Chem. Ber. 111, 3068 (1978). M. Huche´ and P. Cresson, Tetrahedron Lett., 9433 (1972). M. Huche´ and P. Cresson, Bull. Soc. Chim. France, 800 (1975). V. M. Ignat’ev, B. I. Ionin and A. A. Petrov, J. Gen. Chem. USSR 37, 1807 (1967). P. S. Macomber and E. R. Kennedy, J. Org. Chem. 41, 3191 (1976). J. Ficini, N. Lumbroso-Bader and J. Pouliquen, Tetrahedron Lett., 4139 (1968). G. Saucy and R. Marbet, Helv. Chim. Acta 50, 1158 (1967). J. Meijer, P. Vermeer, H. J. T. Bos and L. Brandsma, Recl. Trav. Chim., Pays-Bas 93, 26 (1974). J. K. Crandall and G. L. Tindell, J. Chem. Soc., Chem. Comm., 1411 (1970). H. J. Monteiro and J. B. Sidall, U.S. Patent 3,737,452 (1973). C. A. Henrick and J. B. Sidall, U.S. Patent 3,770,783 (1973). C. A. Henrick and J. B. Sidall, U.S. Patent 3,801,611 (1973). C. A. Henrick, W. E. Willy, D. K. MsKean, E. Baggiolini and J. B. Sidall, J. Org. Chem. 40, 8 (1975). K. A. Parker and R. W. Kosley, Jr., Tetrahedron Lett., 341 (1976). K. A. Parker, J. J. Petraitis, R. W. Kosley, Jr. and S. L. Buchwald, J. Org. Chem. 47, 389 (1982). D. K. Black and S. R. Landor, J. Chem. Soc., 6784 (1965). D. G. Oelberg and M. D. Schiavelli, J. Org. Chem. 42, 1804 (1977), and refs. mentioned therein. R. A. van der Welle and L. Brandsma, Recl. Trav. Chim., Pays-Bas 92, 667 (1973). J. Meijer and L. Brandsma, Recl. Trav. Chim., Pays-Bas 91, 578 (1972). P. J. W. Schuijl, H. J. T. Bos and L. Brandsma, Recl. Trav. Chim., Pays-Bas 88, 597 (1969). L. Brandsma and P. J. W. Schuijl, Recl. Trav. Chim., Pays-Bas 88, 30 (1969). L. Brandsma and H. J. T. Bos, Recl. Trav. Chim., Pays-Bas 88, 732 (1969). L. Brandsma and D. Schuijl-Laros, Recl. Trav. Chim., Pays-Bas 89, 110 (1970). D. Schuijl-Laros, P. J. W. Schuijl and L. Brandsma, Recl. Trav. Chim., Pays-Bas 91, 785 (1972). J. Meijer, P. Vermeer, H. J. T. Bos and L. Brandsma, Recl. Trav. Chim., Pays-Bas 92, 1067 (1973). P. J. W. Schuijl and L. Brandsma, Recl. Trav. Chim., Pays-Bas 88, 1201 (1969). J. Meijer, P. Vermeer and L. Brandsma, Recl. Trav. Chim., Pays-Bas 92, 601 (1973).

19 Miscellaneous Reactions of Acetylenic and Allenic Compounds

19.1

19.1.1

ELIMINATION REACTIONS RESULTING IN ADDITIONAL UNSATURATION

2-Methyl-1-buten-3-yne from 2-methyl-3-butyn-2-ol and acetic anhydride

Scale: 1.0 molar; Apparatus: 1-litre round-bottomed, three-necked flask, equipped with a dropping funnel, a mechanical stirrer and a 40-cm Vigreux column, connected to a condenser and a receiver, cooled at –20 C; stirring is carried out at a moderate rate; all connections should be made gas-tight. 19.1.1.1

Procedure

The flask is charged with 1.3 mol of acetic anhydride and 7 g of p-toluenesulphonic acid monohydrate (or, if available, the anhydrous acid). 2-Methyl-3butyn-2-ol (1.0 mol, commercially available) is added over 10 min with some cooling. The flask is then quickly heated until the enyne begins to pass over. Further heating is carried out in a controlled way, so that the enyne does not distil too fast. The greater part should pass over below bp 60 C. With increasing bath temperature the reaction mixture turns very dark. When, after 45–60 min, the temperature in the head of the column indicates 100 C, heating is stopped. The distillate is washed twice in a small separating funnel with 10–15 ml of a cold KOH solution in order to remove traces of acetic acid. Redistillation from 5 g of anhydrous MgSO4 gives pure 2-methyl-1-buten-3-yne, bp 35 C/760 Torr, in 60–70% yield. The compound should be stored in a refrigerator (–20 to –30 C). Under these conditions polymerisation is slow. 353

354

19.

REACTIONS OF ACETYLENIC/ALLENIC COMPOUNDS

19.1.2

1-Ethynyl-1-cyclohexene from 1-ethynylcyclohexanol and phosphoryl chloride in pyridine

Scale: 0.50 molar; Apparatus: Figure 1.1, 1 litre 19.1.2.1

Procedure

A mixture of 0.50 mol of 1-ethynylcyclohexanol (commercially available) and 90 ml of pyridine (dried over KOH) is heated to 100 C. A mixture of 33 ml of phosphoryl chloride and 40 ml of pyridine is then added over 15 min, while stirring at a moderate rate. The temperature of the reaction mixture is kept between 105 and 110 C by occasional cooling or temporarily increasing the rate of stirring. After the addition heating at 105–110 C is continued for 15 min. The mixture is cooled to below 75 C (partial solidification), and 400 ml of ice water is poured into the flask. After vigorous stirring, the layers are separated and five to seven extractions with small portions of a 1:1 mixture of Et2O and pentane are carried out. The combined organic layers are washed with cold 3 N hydrochloric acid in order to remove pyridine. After drying over MgSO4, the greater part of the solvent is distilled off at atmospheric pressure through a 40-cm Vigreux column. Distillation of the remaining liquid in vacuo (using a single receiver cooled in an ice bath, Figure 1.10) gives 1-ethynyl-1-cyclohexene, bp 38 C/12 Torr, in an excellent yield. 1-Ethynyl-1-cyclopentene, bp 55 C/120 Torr, and 1-ethynyl-1-cycloheptene, bp 52 C/12 Torr, are obtained in high yields from the ethynylcarbinols. The enynes polymerise slowly on storage in a refrigerator.

19.1.3

3,1-Enynes by 1,2-elimination of p-toluenesulphonic acid from propargylic tosylates using KOH in a water–DMSO mixture

Scale: 0.30 molar; 1-litre round-bottomed, three-necked flask, equipped with a dropping funnel-gas inlet combination, a mechanical stirrer and a 20-cm

19.1

ELIMINATION REACTIONS

355

Vigreux column, connected to a condenser and 250-ml (single) receiver, cooled in an ice bath; all connections should be made gas-tight.

19.1.3.1

Procedure

Potassium hydroxide (110 g) is dissolved in 120 ml of water and 40 ml of DMSO. After the air in the flask has been completely replaced by nitrogen, the solution is heated in a bath at 100–110 C. When the temperature of the solution indicates 90 C, the flow of nitrogen is adjusted at 100 ml/min and 1-vinyl-3-butynyl-4methylbenzenesulphonate (0.30 mol, for the preparation cf. Chapter 20, exp. 20.5.4) is added over 10–15 min to the efficiently stirred solution. During the reaction, a mixture of 1,3-hexadien-5-yne and water passes over, after about half an hour only water. Remaining traces of the dienyne may be forced into the condenser by vigorously introducing nitrogen during a few seconds. The contents of the receiver are shaken with anhydrous MgSO4 ( 5 g) in order to remove the water. The receiver is subsequently equipped for a vacuum distillation (20-cm Vigreux column, condenser, receiving flask, cooled in a bath at –70 C, Figure 1.10). The apparatus is evacuated using a water aspirator (10– 20 Torr). A mixture of (E)- and (Z)-1,3-hexadien-5-yne, (E) / (Z) ratio 1), is collected in the receiver. The yield is usually greater than 80%. Other volatile enynes, e.g. 3-penten-1-yne, HCCCH¼CHMe, and 3-hexen1-yne, HCCCH¼CHEt, can be prepared in > 80% yields in a similar way from the corresponding tosylates. Comparable amounts of the (E)-and (Z)-isomers are obtained. These compounds can be redistilled at atmospheric pressure: HCCCH¼CHMe, bp 44–51 C/760 Torr; HCCCH¼CHEt, bp 73–78 C/760 Torr. 19.1.4

3,5-Heptadien-1-yne from 5-hepten-1-yn-4-ol in a one-pot procedure using p-toluenesulphonic chloride and potassium hydroxide as reagents

Scale: 0.25 molar; Apparatus: for the preparation of the tosylate a 1-litre roundbottomed, three-necked flask, equipped with a powder funnel, a mechanical stirrer and a thermometer; for the preparation of the enyne the powder funnel is replaced with a gas inlet and the thermometer by a reflux condenser.

356

19.

REACTIONS OF ACETYLENIC/ALLENIC COMPOUNDS

3,5-Heptadien-1-yne is less volatile and presumably more stable than 1,3hexadien-5-yne. Distillative separation at atmospheric pressure from Et2O should therefore be possible without involving the risk of polymerisation or decomposition. This allows the preparation of 1-(2-propynyl)-2-butenyl-4methylbenzenesulphonate and its conversion into 3,5-heptadien-1-yne in the same pot, using Et2O as solvent. Other enynes having bp >100 C/760 Torr can be prepared in a similar way.

19.1.4.1

Procedure

A mixture of 0.25 mol of 5-hepten-1-yn-4-ol, 350 ml of Et2O and 0.35 mol (excess) of tosyl chloride is placed in the flask. After dissolution of the tosyl chloride, the solution is cooled to –5 C (dry ice-acetone bath). Freshly, machine-powdered KOH (140 g) is added in 5-g portions over 15 min to the vigorously stirred mixture while maintaining the temperature between 10 and 0 C. The air is then completely replaced by nitrogen and the cooling bath is removed. At 15 C an exothermic reaction starts, and after an additional 10–15 min the Et2O begins to reflux. The mixture is heated for another 1 h under reflux. After cooling to rt, the thick slurry is poured into 500 ml of ice water and the flask rinsed with a small amount of ice water. After vigorous shaking and separation of the layers, the aqueous layer is extracted three times with small portions of Et2O. The combined organic solutions are washed with saturated aqueous ammonium chloride and subsequently dried over MgSO4. The greater part of the Et2O is then distilled off (under a slow stream of N2) at atmospheric pressure through an efficient column. The temperature of the heating bath is kept between 80 and 90 C in the last stage of this distillation. After cooling to rt, the remaining liquid is carefully distilled in a partial vacuum, giving 3,5-heptadien-1-yne, bp 30–40 C/40 Torr, ((E)/(Z)-ratio 40:60, the double bond between C-5 and C-6 has the (E)-configuration), in an excellent yield. 1-(1-Buten-3-ynyl)benzene, HCCCH¼CHPh ((Z)/(E)-ratio 55:45), bp 55 C/0.4 Torr, is obtained in an excellent yield from 1-phenyl-3-butyn-1ol, HCCCH2CH(OH)Ph, by a similar procedure.

19.1.5

6-Ethynyl-2,3-dihydro-4H-pyran from 3-bromo-2-ethynyl tetrahydro-2H-pyran and t-BuOK in tetrahydrofuran

19.1

ELIMINATION REACTIONS

357

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml 19.1.5.1

Procedure

3-Bromo-2-ethynyltetrahydro-4H-pyran (0.10 mol, Chapter 4, exp. 4.5.20) is added over 15 min to a solution of 0.20 mol (excess, Note) of t-BuOK in 150 ml of THF. During this addition the reaction mixture is kept between –10 and –20 C. After an additional 15 min the temperature is allowed to rise to 10–20 C. Finally, the suspension is warmed to 40 C. A solution of 25 g of NH4Cl in 200 ml of water is then added with vigorous stirring. After separation of the layers, three extractions with Et2O are carried out. The combined organic solutions are washed three times with water and subsequently dried over MgSO4. After concentration of the solution under reduced pressure, the remaining liquid is distilled through a 20-cm Vigreux column to give 6-ethynyl-2,3-dihydro-4H-pyran, bp 54 C/10 Torr, in 90% yield. From other alkynyl bromoethers, for example 4-bromo-3-ethoxy-1-butyne, BrCH2CH(OEt)CCH, HBr can be eliminated by a similar procedure. In this example 2-ethoxy-1-buten-3-yne, H2C¼C(OEt)CCH, the synthetic equivalent of 3-butyn-2-one, MeC(¼O)CCH, is obtained. The ethereal extract obtained as described above is concentrated under normal pressure, after which the enyne ether is distilled at water-aspirator pressure. Note The t-BuOH formed in the elimination gives the 1:1 complex with t-BuOK, which is much less active. 19.1.6

2-Ethoxy-2-penten-4-yne from 5-bromo-4-ethoxy-1-pentyne and sodamide

Scale: 0.50 molar; Apparatus: Figure 1.1, 1 litre for the reaction with allenylmagnesium bromide; 3-litre wide-necked round-bottomed flask with stirrer for the dehydrohalogenation (Figure 1.5).

358 19.1.6.1

19.

REACTIONS OF ACETYLENIC/ALLENIC COMPOUNDS

Procedure [1]

A solution of 0.50 mol of 1,2-dibromo-1-ethoxyethane in 100 ml of Et2O, prepared by addition of 0.50 mol of bromine to a mixture of 0.70 mol of ethyl vinyl ether and Et2O at 40 C, is added over 30 min to a solution of allenylmagnesium bromide in 400 ml of Et2O prepared from 0.70 mol of propargyl bromide (Chapter 2, exp. 2.3.9). During this addition the temperature of the reaction mixture is kept between –5 and –15 C. After an additional 30 min the reaction mixture is poured into 250 ml of an aqueous solution of 50 g of ammonium chloride. After extraction and drying over magnesium sulphate, most of the Et2O is removed under reduced pressure. The remaining more concentrated solution in 100 ml of Et2O is added over 15 min to a suspension of 1.2 mol of sodamide in 1 litre of liquid ammonia. The reaction is very vigorous. After the addition most of the ammonia is removed by placing the flask in a bath at 40–50 C. To the remaining dark brown slurry is cautiously added a solution of 50 g of ammonium chloride in 200 ml of water, followed by extraction (4 times) with pentane. After drying, most of the solvent is distilled off at normal pressure through a 30-cm Vigreux column. 2-Ethoxy2-penten-4-yne, bp 42 C/17 Torr, is obtained in 60% yield. A contamination of 10%, presumably 1-ethoxy-2-ethynylcyclopropane, is present. A considerable non-volatile residue is left behind. Similar procedures may be carried out with the homologues RCHBrCHBrOEt obtained from 1-ethoxy-1-alkenes, RCH¼CHOEt, and bromine.

19.1.7

4,1-Enynes by elimination of bromine and ethoxy groups from 5-bromo-4-ethoxy-1-alkynes with zinc in dimethylsulphoxide

Scale: 0.50 molar; Apparatus: Figure 1.1, 1 litre with a gas-tight mechanical stirrer, an evacuable dropping funnel, and a reflux condenser instead of the thermometer. The top of the condenser is connected with a trap cooled in a bath at –78 C (preferably liquid nitrogen, in that case the connection is made in a way such that the vapour of the volatile product can enter the large annular space).

19.2

REMOVAL OF PROTECTING GROUPS

19.1.7.1

359

Procedure [2]

In the flask are placed 250 ml of DMSO, 70 g of technical-grade zinc powder and 5 g of potassium iodide. The system is evacuated using the water aspirator and the pressure is adjusted at 50 Torr. The bromoether 5-bromo-4-ethoxy1-pentyne or 5-bromo-4-ethoxy-1-hexyne (0.50 mol, prepared as described in exp. 19.1.6, and freed from any Et2O) is added over 30 min to the gently refluxing DMSO. After the addition heating is continued for another 2 h (if after half an hour no condense is present in the trap, the pressure should be increased so that the temperature of the reaction mixture can rise). The contents of the trap are washed twice with 10 ml portions of ice water in order to remove some DMSO and ethanol formed from EtOZnBr and some water present in the DMSO. A very small amount of magnesium sulphate is added, after which the enyne is distilled. 1-Penten-4-yne, bp 42 C and 4-hexen1-yne, bp 76 C, (E)/(Z) 1, are obtained in 70% yields. About 10% of 1,2,4-pentatriene, H2C¼C¼CHCH¼CH2 or 1,2,4-hexatriene, H2C¼C¼ CHCH¼CHMe, formed from the allenic bromoethers 5-bromo-4-ethoxy-1,2pentadiene (R ¼ H) or 5-bromo-4-ethoxy-1,2-hexadiene (R ¼ Me), BrCH(R) CH(OEt)CH¼CH2, is present. The allenic compounds can be removed by reaction with maleic anhydride.

19.2 19.2.1

REMOVAL OF PROTECTING GROUPS

1,3-Diynes by potassium hydroxide-catalysed elimination of acetone from the corresponding diyne carbinols

Scale: 0.10 molar; Apparatus: Figure 1.10, 250 ml (Note) 19.2.1.1

Procedure

2,7,7-Trimethyl-3,5-octadiyn-2-ol (0.10 mol, obtained by Cu(I)-catalysed coupling between an excess of 2-methyl-3-butyn-2-ol, HCC(Me)2OH, and 1-bromo-3,3-dimethyl-1-butyne, t-BuCCBr, followed by thorough removal of the excess of the acetylenic alcohol at 1 Torr, see Chapter 14) is mixed with 50 ml of paraffin oil and 2 g of finely powdered KOH (vigorous shaking for a few seconds), after which the flask is equipped for a distillation in vacuo (10–20 Torr). The system is evacuated and the flask heated

360

19.

REACTIONS OF ACETYLENIC/ALLENIC COMPOUNDS

during 2 h in a bath at 160–170 C. The contents of the receiver (cooled in a dry-ice acetone bath) are washed 5 times with 5-ml portions of 3 N hydrochloric acid in order to remove the acetone, and are subsequently transferred to a 100-ml round-bottomed flask containing 0.5 g of magnesium sulphate. The rather volatile 5,5-dimethyl-1,3-hexadiyne is isolated in almost quantitative yield in a strongly cooled receiver (Figure 1.10) by distillation at 10–20 Torr and condensation. The extremely unstable 1-(1,3-butadiynyl)benzene, PhCCCCH, can be obtained in a good yield by a similar procedure from the Cadiot– Chodkiewicz coupling product 2-methyl-6-phenyl-3,5-hexadien-2-ol, PhC CCCCMe2OH. An essential condition is that during heating with KOH-paraffin oil the pressure is lower than 0.01 Torr. A very short (<5 cm) column and a few centimetre long condenser should be used. The parts of the distillation set-up should have a diameter of at least 1.5 cm (B-29 ground-glass joints) and the connection with the vacuum pump as short as possible. Aryl- and hetaryl-acetylenes, Het(aryl)CCH, for example 2-ethynylthiophene, 2-ethynylfuran and 1-ethynyl-4-fluorobenzene are accessible in high yields from (Het)arylCCCMe2OH using this procedure [3]. These compounds can be prepared by Pd/Cu-catalysed coupling between (Het)aryl-Br and HCCCMe2OH (Chapter 16). Note The elimination of acetone is accompanied by rather strong foaming. For this reason a relatively big flask (with a short neck) should be used. 19.2.2

19.2.2.1

General procedure for the base-catalysed desilylation of silylated acetylenes

Procedure

A solution of 0.10 mol of the silylated acetylene and 2 g of potassium hydroxide in 50–100 ml of methanol is heated for 15 min at 50 C, then most of the methanol is removed under reduced pressure if the free acetylene has bp >50 C/10 Torr. In the other cases the solution is diluted with 300 ml of water, followed by extraction with (preferably) pentane. For base-sensitive acetylenes (polyynes with a conjugated system of triple bonds, which easily add methanol in the presence of bases, or compounds

19.2

REMOVAL OF PROTECTING GROUPS

361

with the systems HCCCH2CC and HCCCH2C¼C, which may undergo base-catalysed isomerisation to conjugated systems) the AgNO3–methanol method [4] may be applied. Other mild reagents for desilylation are potassium fluoride–H2O and 18-crown-6 [9]. A general method for the preparation of (Het)arylCCSiMe3, consisting of Pd/Cu-catalysed coupling between ethynyl(trimethyl)silane, HCCSiMe3, and (Het)aryl halides, is described in Chapter 16. 19.2.3

19.2.3.1

Acid-catalysed conversion of O-protected alcohols into the free alcohols

Procedure

The protected alcohol (0.10 mol) is mixed with 30–50 ml of methanol and a few drops of concentrated hydrochloric acid are added. The mixture is heated for 10 min at 50–60 C. In the case of non-volatile (bp >60 C/15 Torr) alcohols the greater part of the methanol is removed on the rotary evaporator after neutralisation of the HCl with a very small amount of aqueous ammonia. The alcohol is then isolated (mostly in quantitative yield) applying the usual operations in the work-up. In the case of rather volatile alcohols the reaction mixture is diluted with a sufficient amount of water prior to carrying out the work-up. A similar procedure of deprotection may be followed with tetrahydropyranyl-protected alcohols. 19.2.4

Acid-catalysed conversion of acetylenic acetals into the aldehydes

Scale: 0.10 molar; Apparatus: 250-ml round-bottomed flask and thermometer

362

19.

19.2.4.1

REACTIONS OF ACETYLENIC/ALLENIC COMPOUNDS

Procedure

To a mixture of 4 g of 96% H2SO4 and 20 ml of water are successively added 40 ml of DMSO and 0.10 mol of 1,1-diethoxy-2-heptyne (Chapter 4, exp. 4.5.23). The mixture is heated for 15–20 min at 75 C with occasional swirling. After 5 min (at 75 C) the solution has become homogeneous. The solution is cooled to rt and subsequently poured into 150 ml of ice water, saturated with NH4Cl. The product is isolated by extraction with Et2O, washing the solution with saturated aqueous NH4Cl, drying over MgSO4 and distillation through a short Vigreux column. 2-Heptynal, bp 55 C/10 Torr, is obtained in an excellent yield. In the case of lower homologues, less DMSO should be used.

19.3

19.3.1

PARTIAL REDUCTIONS OF CONJUGATED SYSTEMS OF TRIPLE BONDS

Partial reduction of 3,5-octadiyne with activated zinc powder

Scale: 0.20 molar; Apparatus: 250-ml round-bottomed, three-necked flask, equipped with a gas inlet (for introduction of N2), a mechanical stirrer and a reflux condenser. There are several reports on the successful partial reduction of acetylenic compounds with activated zinc powder. The formation of (Z)-double bonds has been explained by assuming that after adsorption of the acetylene on the metal two electrons are successively transferred from the metal to the triple bond [5]. Protolysis of the resulting three-membered metallocycle, in which the double bond has the (Z)-configuration, finally gives the (Z)-olefinic compound. The reaction is usually carried out in ethanol. Non-conjugated triple bonds are not reduced unless they are in the terminal position or the molecule contains a OH group, an amino, ether or ester function. It has appeared that systems in which these functions are close to the triple bond (e.g. in the ‘propargylic’ position) are reduced more easily than the isomers in which the heteroatom-containing group is in a more remote position. In a series of homologues, the time required for complete conversion increases with increasing length of the carbon chain. These experimental facts support the adsorption mechanism.

19.3

PARTIAL REDUCTIONS OF CONJUGATED SYSTEMS

363

Triple bonds in conjugated unsaturated systems are reduced relatively easily. Depending upon the degree of activation of the zinc-powder, one or both of the triple bonds in a conjugated diyne can be reduced to a double bond. We have found that the reduction can be completely stopped at the stage of the enyne by using zinc that is activated by boiling with a small amount of 1,2-dibromoethane in ethanol. Further activation of the metal by addition of copper(I) bromide (added as a solution of CuBr LiBr in THF) leads to reduction of the second triple bond with formation of a conjugated diene. In the case of hydrocarbon-diynes, these partial reductions give almost pure (Z)-enynes and (Z,Z)-dienes.

19.3.1.1

Procedure [6]

Ethanol (100%, 60 ml) and zinc powder (50 g, Merck, analytical grade) are placed in the flask. 1,2-Dibromoethane (5 g) is added and the mixture is heated until refluxing begins. The heating bath is then removed. When the exothermic reaction (evolution of ethene and refluxing of the solvent) has subsided, an additional amount of 5 g of 1,2-dibromoethane is added. After this has reacted, the mixture is heated for an additional 10 min under reflux. The suspension is then cooled to 50 C, while introducing N2. 3,5Octadiyne (0.20 mol, Chapter 4, exp. 4.5.3) is then added over 10 min in two or three portions. The reaction is markedly exothermic and refluxing of the ethanol may ensue. After the reaction has subsided, the mixture is heated for an additional 2 h (technical zinc powder reacts less easily) under reflux while a weak flow of N2 is passed through the apparatus. The mixture is then cooled to rt, after which the suspended zinc is allowed to settle down. The supernatant layer is decanted and poured into a solution of 35 g of NH4Cl in 200 ml of water and 30 ml of concentrated aqueous ammonia. The zinc slurry in the flask is rinsed four times with 30-ml portions of hot ( 50 C) ethanol and the alcoholic solutions added to the hydrolysed mixture. Subsequently four extractions with pentane are carried out. The combined extracts are washed with 2 N hydrochloric acid and subsequently dried over MgSO4. The greater part of the solvent is then distilled off at atmospheric pressure through a 40-cm Vigreux column. After cooling to rt, the remaining liquid is distilled in vacuo and the distillate collected in a single receiver, cooled at 0 C (Figure 1.10). (Z)-3-Octen-5-yne, bp 40 C/15 Torr, is obtained in greater than 70% yield. (Z)-4,6-Decen-6-yne, n-PrCH¼CHCCn-Pr, bp 75 C/15 Torr, can be prepared in a similar way from 4,6-decadiyne. The period of reflux (5 h in the case of using the same molar amounts of reagents as above) can be shortened to 3 h if only 35 ml of ethanol is used.

364

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REACTIONS OF ACETYLENIC/ALLENIC COMPOUNDS

19.3.2

Regiospecific and stereospecific partial reduction of 1-trimethylsilyl-1,3-heptadiyne with activated zinc powder

Scale: 0.05 molar; Apparatus: 100-ml three-necked, round-bottomed flask, equipped with a gas inlet (for the introduction of N2), a magnetic stirring bar and a reflux condenser. Russian chemists have found that trimethylsilyl groups protect adjacent triple bonds against hydrogenation with poisoned Pd-catalysts [7]. A similar effect has been shown in reductions of trimethylsilylated 1,3-diynes with (activated) zinc powder [6]. One disadvantage of the zinc method is that the zinc salts present in the reaction mixture can cause cleavage of the C–Si bond. This was shown in a separate experiment in which a trimethylsilylated 1,3-diyne was heated with a solution of zinc bromide or chloride in ethanol [10]. It seems therefore important to keep reaction times of the reductions with zinc as short as possible and to activate the zinc powder with a limited amount of 1,2-dibromoethane.

19.3.2.1

Procedure

To a mixture of 30 g of zinc powder (Merck, analytical grade) and 30 ml of absolute ethanol is added 3.5 ml of 1,2-dibromoethane. The mixture is heated until an exothermic reaction (evolution of ethene and temporary reflux) starts. The activation is completed by heating the mixture for an additional 10 min under reflux. After cooling to about 50 C, 1,3-heptadiynyl(trimethyl)silane (0.05 mol, Chapter 7 for silylation methods) is added in one portion. The introduction of N2 is started and the mixture is heated for 30 min under reflux. After cooling to rt, the work-up is carried out in a way similar to that in exp. 19.3.1 (no aqueous ammonia is used). (Z)-3-Hepten-1-ynyl(trimethyl)silane, n-PrCH¼CHCCSiMe3, bp 75 C/20 Torr, is obtained in a high yield. (Z,Z)-1-(1-Ethylthio)-7,7-dimethyl-1,3-octadien-5-yne, EtSCH¼CHCH¼ CHCC-t-Bu (not distilled), is obtained from (Z)-1-(1-ethylthio)-7,7dimethyl-1-octen-3,5-diyne, EtSCH¼CHCCCC-t-Bu, by a similar procedure (1 h reflux). The starting compound is prepared by Cadiot–Chodkiewicz coupling of (Z)-1-ethylthio-1-buten-3-yne, EtSCH¼CHCCH, with 1-bromo3,3-dimethyl-1-butyne, BrCC–t-Bu (Chapter 14).

19.3

PARTIAL REDUCTIONS OF CONJUGATED SYSTEMS

19.3.3

365

Regiospecific and stereospecific partial reduction of 2,5-octadiyn-1-ol with activated zinc powder

Scale: 0.10 molar; Apparatus: 100-ml three-necked, round-bottomed flask, equipped with a gas inlet, a magnetic stirring bar and a reflux condenser. For the influence of a propargylic OH group see introduction of exp. 19.3.1. 19.3.3.1

Procedure

Zinc powder (30 g, Merck, analytical grade) is activated in 30 ml of 100% ethanol as described in exp. 19.3.1. 3,5-Octadiyn-1-ol (0.10 mol, Note) is added at 50 C, after which the mixture is heated under reflux for about 2 h. Nitrogen is introduced during this period. After cooling to rt, the reaction mixture (including the excess of zinc powder) is poured into a solution of 30 g of NH4Cl in 200 ml of water. The aqueous mixture is extracted seven times with Et2O. The combined extracts are washed once with a saturated solution of NH4Cl and subsequently dried over MgSO4. The liquid remaining after removal of the solvent under reduced pressure is distilled through a short Vigreux column. (Z)-2-Octen-5-yn-1-ol, bp 60 C/1 Torr, is obtained in an excellent yield.

Note 3,5-Octadiyn-1-ol can be prepared by removal of the protecting group from 1-(1-ethoxyethoxy)-3,5-octadiyne, EtCCCH2CCCH2OCH(Me)OEt. This compound is obtained by Cu(I)-catalysed reaction of 2-pentynyl-4-methylbenzenesulphonate, EtCCCH2OTs, with 1-magnesium bromide-3-(1-ethoxyethoxy)1-propyne, BrMgCCCH2OCH(Me)OEt (cf. Chapter 4, exp. 4.5.31).

19.3.4

Regiospecific and stereospecific partial reduction of O-protected diyne alcohols and acetals with a conjugated diyne system using activated zinc

366

19.

REACTIONS OF ACETYLENIC/ALLENIC COMPOUNDS

Scale: 0.10 molar; Apparatus: 100-ml, three-necked, round-bottomed flask, equipped with a dropping funnel-gas inlet combination, a magnetic stirring bar and a reflux condenser. Although treatment of diyne alcohols RCCCCCH2OH with activated zinc powder in ethanol results in specific reduction of the triple bond that is closest to the OH group, the reduction is not stereospecific. In the various experiments we found significant amounts of (E)-RCCCH¼CHCH2OH (up to 30%). It might be possible that a satisfactory stereoselectivity can be achieved by using non-activated zinc (with analytical zinc powder activated with dibromoethane the reaction is very fast). Satisfactory and reproducible results can be obtained, however, by carrying out the reduction with the protected diyne alcohol (either as the adduct with H2C¼CHOEt or as an O–SiR3 derivative, cf. [8]).

19.3.4.1

Procedure

Zinc powder (30 g, Merck, analytical grade) is activated with 1,2-dibromoethane (3.5 ml) in 100% ethanol (35 ml) as described in the preceding experiments. After cooling to 30 C, the protected diyne alcohol (0.10 mol, Chapters 14 and 20, exp. 6.7) is added in three equal portions over 5 min, while introducing N2. The temperature of the suspension rises fast and (as a rule) after some 10 min the ethanol begins to reflux: Spontaneous refluxing ceases after 5 to 10 min. The mixture is heated for an additional 30 min under reflux (for compounds with a longer carbon chain, see introduction of exp. 19.3.1). After cooling to rt and settling of the zinc powder, the supernatant solution is decanted and poured into 200 ml of an aqueous solution of 30 g of NH4Cl to which 10 ml of concentrated aqueous ammonia has been added. The zinc powder in the flask is rinsed three times with 20-ml portions of hot (40–50 C) ethanol, the ethanolic solutions being added to the NH4Cl-solution. The product is isolated by extraction with Et2O (five times), washing the organic solution with saturated aqueous NH4Cl, drying the solution over MgSO4 and concentrating the solution under reduced pressure. Removal of the protecting group, as described in exp. 19.2.3 gives (Z)-2decen-4-yn-1-ol, C5H11CCCH¼CHCH2OH, bp 80 C/0.5 Torr, in 80% yield. 1,1-Diethoxy-2,4-heptadiyne, EtCCCCCH(OEt)2,is converted into (Z)1,1-diethoxy-2-hepten-4-yne, EtCCCH¼CHCH(OEt)2, (yield 75%) by a similar procedure ( 45 min reflux, using the same molar amounts of reagents).

REFERENCES

367 REFERENCES

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

M. Bertrand and C. Rouvier, Bull. Soc. Chim. France, 220 (1968). J. Grimaldi and M. Bertrand, Bull. Soc. Chim. France, 947 (1971). A. G. Mal’kina, L. Brandsma, S. F. Vasilevsky and B. A. Trofimov, Synthesis, 589 (1996). H. Schmidt and J. F. Arens, Recl. Trav. Chim., Pays-Bas 86, 1138 (1967). F. Na¨f, R. Decorzant, W. Thommen, B. Wilhalm and G. Ohloff, Helv. Chim. Acta 58, 1016 (1975). M. H. P. J. Aerssens, R. van der Heiden, M. Heus and L. Brandsma, Synth. Commun. 20, 3421 (1990). B. G. Shakovskoi, M. D. Stadnichuk and A. A. Petrov, J. Gen. Chem., USSR 34, 2646 (1964). W. Oppolzer, C. Fehr and J. Warneke, Helv. Chim. Acta 60, 48 (1977). R. Diercks and K. P. C. Volhardt, J. Amer. Chem. Soc. 108, 3150 (1986). Unpublished results and observations from the author’s laboratory.

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20 Transformation of Functional Groups in Acetylenic and Allenic Compounds

20.1 20.1.1

ACETYLENIC HALOGEN COMPOUNDS

Propargyl bromide from propargyl alcohol and phosphorus tribromide

Scale: 3.0 molar; Apparatus: 1-litre round-bottomed, three-necked flask, equipped with a dropping funnel, a mechanical stirrer and a reflux condenser. The most convenient way to prepare 3-bromo-1-propyne on a laboratory scale consists of converting the corresponding alcohol with phosphorus tribromide in the presence of a small amount of pyridine. The formation of the bromide proceeds through a number of intermediates. In the first step 2-propynyl dibromophosphite, HCCCH2OPBr2, and HBr are formed, which react further to HCCCH2Br and HOPBr2. The reaction with dibromophosphinous acid, HOPBr2, proceeds in a way that is analogous to the first step. The nucleophilic attack of bromide on propargylic carbon in the bromophosphites, resulting in the formation of propargyl bromide, is catalysed by pyridine. This binds part of the HBr, thus converting it into the more nucleophilic Br. In addition to propargyl bromide, appreciable amounts of 2,3-dibromo-1-propene, H2C¼C(Br)CH2Br, are formed, especially when no solvent is used. The formation of this compound may be visualised as an electrophilic addition of HBr to the triple bond in HCCCH2OH or some intermediate, followed by reaction with PBr3. Diethyl ether suppresses this electrophilic addition by forming the oxonium complex Et2OþH Br with HBr. It is possible to obtain propargyl bromide in high yields by slowly adding PBr3 to a strongly cooled mixture of propargyl alcohol and diethyl ether and subsequently allowing the 369

370

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

temperature to rise very slowly. In the procedure described below, the reaction is carried out in refluxing ether, giving 3-bromo-1-propyne in 70% yield. In the published procedure [1] propargyl alcohol is added dropwise to phosphorus tribromide containing a small amount of pyridine. We experienced this procedure as inconvenient because much HBr escapes from the reaction mixture during the addition of the alcohol. Warning: Contact of 3-bromo-1-propyne (and homologues) with the skin causes a painful irritation. It is absolutely necessary to wear protective gloves and to work in a well-ventilated hood. 20.1.1.1

Procedure

A mixture of 3.0 mol of 2-propyn-1-ol, 400 ml of dry Et2O and 10 ml of pyridine is placed in the flask. Phosphorus tribromide (1.1 mol) is added dropwise over 1.5 h without cooling, while stirring at a moderate rate. After the addition, the reaction mixture is heated for an additional 1 h under reflux. The greater part of the Et2O is then quickly distilled off (during 45 min) at atmospheric pressure through a 40-cm Vigreux column, keeping the bath temperature below 100 C. The remaining liquid is cooled to rt, after which the volatile components are distilled off in a water-aspirator vacuum (10 to 20 Torr). The vapours are condensed in a single receiver, cooled in a bath at 50 C, or lower temperature (Figure 1.10). The distillation is stopped when (at a pressure of 10–20 Torr) the temperature in the head of the column rises above 35 C. Redistillation at 760 Torr using an efficient column gives the main portion of 3-bromo-1-propyne, passing over at 80–95 C. The residue is mainly 2,3-dibromo-1-propene, H2C¼C(Br)CH2Br. Fractional distillation of the ethereal distillate (see above) gives an additional small amount of 3-bromo-1-propyne, bringing the yield at 70%. Pure 3-bromo-1-propyne, bp 84 C/760 Torr, is obtained by redistillation. 5-Bromo-3-penten-1-yne, HCCCH¼CHCH2Br, bp 40 C/15 Torr, ((E):(Z) 85:15), is obtained in 70% yield by a similar procedure from the corresponding alcohol (Chapter 4, exp. 4.5.14). During the addition of PBr3 the solution turns very dark. 5-Bromo-3-penten-1-yne is a very lachrymatory compound. Contact of the liquid or vapour with the skin has a similar effect as in the case of 3-bromo-1-propyne and other acetylenic bromides. 20.1.2

Homologues of 3-bromo-1-propyne from propargylic alcohols and phosphorus tribromide

20.1

ACETYLENIC HALOGEN COMPOUNDS

371

Scale: 0.90 molar; Apparatus: Figure 1.1, 1 litre 20.1.2.1

Procedure (for introduction and warning see exp. 20.1.1)

A mixture of 0.90 mol of the acetylenic alcohol, 250 ml of dry Et2O (Note 1) and 5 ml of pyridine is cooled to 35 C. Phosphorus tribromide (0.32 mol) is added dropwise over 45 min, while keeping the temperature between 25 and 35 C (Note 2). The reaction mixture is stirred for an additional 2 h at 20 to 25 C, after which the temperature is allowed to rise over 2 h to rt. After heating the reaction mixture for 30 min under reflux, a saturated aqueous solution of NaCl is added with vigorous stirring. After separation of the layers, one extraction with a small portion of Et2O is carried out. The organic solution is dried over MgSO4, after which the greater part of the solvent is distilled off at atmospheric pressure through a 40-cm Vigreux column or removed under reduced pressure (in the case of less volatile bromo compounds). Careful distillation of the remaining liquid gives the bromo compounds 1-bromo-2-butyne, MeCCCH2Br, bp 60 C/80 Torr; 1-bromo-2-pentyne, EtCCCH2Br, bp 38 C/10 Torr and 1-bromo-2-heptyne, n-BuCCCH2Br, bp 72 C/12 Torr in high yields.

Notes 1. 2.

When smaller amounts of Et2O are used, yields are lower and more of the dibromo compound (cf. exp. 20.1.1) is formed. If the addition of PBr3 is carried out under reflux (cf. exp. 20.1.1), yields are by 5 to 10% lower.

20.1.3

3-Bromo-3-methyl-1-butyne from 2-methyl-3-butyn-2-ol and phosphorus tribromide

Scale: 0.30 molar; Apparatus: Figure 1.1, 500 ml 20.1.3.1

Procedure (cf. exps. 20.1.1 and 20.1.2)

Phosphorus tribromide (0.11 mol) is added dropwise over 20 min to 0.30 mol of (neat) 2-methyl-3-butyn-2-ol, while keeping the temperature between 10 C

372

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

and rt. During the addition, which is carried out over 15 min, the solid on the glass wall (2-methyl-3-butyn-2-ol) gradually melts. Fifteen minutes after the addition, 100 ml of water is added with vigorous stirring. The organic layer is dried over a small amount of MgSO4 and subsequently transferred into a 500-ml round-bottomed flask which is equipped for a vacuum distillation using an efficient column, a condenser and a single receiver cooled in a bath at 10 C (cf. Figure 1.10). The product passing over below 45 C/15 Torr, a mixture of 3-bromo-3-methyl-1-butyne and 2,3-dibromo-3-methyl-1-butene, H2C¼ C(Br)Me2Br, is carefully redistilled in the same apparatus. The fraction having bp up to 30 C/15 Torr, is practically pure 3-bromo-3-methyl-1-butyne. The yield is 50% (Note).

Note It should be possible to obtain higher yields by adding PBr3 at low temperatures to a mixture of the alcohol and Et2O and gradually raising the temperature (cf. exp. 20.1.2).

20.1.4

3-Bromo-1-nonyne from the corresponding tosylate and lithium bromide

Scale: 0.30 molar; Apparatus: 1-litre two-necked, round-bottomed flask, equipped with a mechanical stirrer and a reflux condenser. The procedure for 3-bromo-1-nonyne illustrates an excellent method for the preparation of primary and secondary propargylic bromides [2]. The preparation of the tosylates as well as the conversion into the bromides are very clean reactions giving high overall yields. Purification by distillation is not necessary if the proper conditions are applied for the preparation of the tosylates and their conversion into the bromo compounds. For these reasons, this method is more suitable than the PBr3-method for the preparation of propargylic bromides with a low volatility or low thermal stability. Propargylic iodides may be prepared similarly, using NaI in acetone or ethanol. It should be noted that the substitution is regiospecific, i.e. 1,3-substitution (‘propargylic rearrangement’) does not take place at all.

20.1

ACETYLENIC HALOGEN COMPOUNDS

20.1.4.1

373

Procedure

A solution of 0.40 mol of anhydrous lithium bromide in 150 ml of dry acetone is added to a mixture of 0.30 mol of 1-hexyl-2-propynyl-4-methylbenzenesulphonate (cf. exp. 20.5.4) and 100 ml of acetone. After refluxing for 1 h, 600 ml of ice water is added to the suspension and eight extractions with small (1 150 ml, 7 50 ml) portions of pentane are carried out. The combined extracts are washed with water and subsequently dried over MgSO4. After removing the pentane under reduced pressure, the remaining liquid is distilled through a 30-cm Vigreux column to give 3-bromo-1-nonyne, bp 82 C/15 Torr, in an excellent yield. 20.1.5

4-Bromo-1-butyne from the corresponding tosylate and lithium bromide in DMSO

Scale: 0.50 molar; Apparatus: Figure 1.10, 1 litre, a 40-cm Vigreux column is used This method for the conversion of tosylates into the corresponding bromides, a variant of the preceding procedure, is more suitable for rather volatile bromides (bp < 55 C/15 Torr) because the isolation is more convenient (no frequent extraction, no time-consuming distillation). It should further be noted that the PBr3 method fails for homopropargylic bromides, such as 4-bromo-1-butyne, HCCCH2CH2Br. 20.1.5.1

Procedure

3-Butynyl-4-methylbenzenesulphonate (0.50 mol, freed from traces of Et2O by evacuation, cf. exp. 20.5.4) is added with manual swirling to a solution (partly suspension) of 0.70 mol of anhydrous lithium bromide in 250 ml of DMSO. The apparatus is evacuated (water aspirator) and the flask heated in an oil bath. The volatile acetylenic bromide is trapped in the strongly cooled (–40 C) receiver (Figure 1.10). The temperature of the bath is gradually raised until DMSO begins to distil (bp 80 C/15 Torr). The distillation is stopped when about 20 ml of DMSO has passed over. The contents of the receiver are washed three times with 30-ml portions of water in a small dropping funnel and the lower layer is subsequently dried over a small amount of MgSO4. Pure 4-bromo-1-butyne, HCCCH2CH2Br, (distillation is not necessary) is

374

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TRANSFORMATION OF FUNCTIONAL GROUPS

obtained in a greater than 80% overall yield, starting from the acetylenic alcohol. 3-Bromo-1-butyne, HCCCH(Me)Br, is obtained in an excellent yield by a similar procedure starting from 3-butyn-1-ol, HCCCH(Me)OH. This alcohol is commercially available as a 50% solution in water. The alcohol can be freed from the water by saturating the aqueous solution with K2CO3 and subsequently drying the upper layer over K2CO3. 3-Chloro-1-butyne, HCCCH(Me)Cl, bp 74 C/760 Torr, can be prepared analogously, using anhydrous lithium chloride. For the preparation of 6-bromo-1-hexyne, HCC(CH2)4Br, from 5-hexyn1-ol by the same method a more efficient column is used instead of the Vigreux column. The distillation is stopped when about 50 ml of DMSO has been collected in the receiver (cooled at 0 C). The wash procedure gives pure 6-bromo-1-hexyne in 80% overall yield. Acetylenic bromides with boiling points in the region of 80 C/15 Torr or higher may be prepared by heating the solution of LiBr and the tosylate in DMSO for 1 h at 70–80 C and subsequently adding water to the reaction mixture. The bromo compound is then isolated via extraction with Et2O. It is, however, also possible to prepare less volatile bromides by heating the corresponding tosylates with a 10 to 20% excess of anhydrous LiBr in refluxing acetone or THF, as described in exp. 20.1.4.

20.1.6

1,4-Dichloro-2-butyne from 2-butyn-1,4-diol and thionyl chloride

Scale: 2.0 molar; Apparatus: Figure 1.1, 3-litre The reaction of primary or secondary alcohols with thionyl chloride is a general method for preparing the corresponding chloro compounds. In the first step a chlorosulphite, ROSOCl, is formed, from which SO2 is eliminated in a relatively slow step. This decomposition is facilitated by a tertiary amine, e.g. pyridine. The ammonium salt RO-SONþCl, formed from the chlorosulphite, e.g. 1,4-bis[chlorosulphinyloxy]-2-butyne, is subsequently attacked on carbon (in R) by Cl. Since nucleophilic substitutions on propargylic carbon

20.1

ACETYLENIC HALOGEN COMPOUNDS

375

proceed more easily than on carbon in saturated compounds, it may be expected that the conversion of propargylic chlorosulphites into the chlorides will take place under relatively mild conditions. The thionyl chloride method can be applied successfully to prepare primary and secondary acetylenic chlorides. The isolation and purification of volatile chlorides is less convenient (contamination with SOCl2) than in the cases of higher-boiling compounds (simple distillation from the reaction mixture). The tosylate method (exp. 20.1.5) seems more attractive for the preparation of chlorides such as 3-chloro-1-butyne, HCCCH(Me)Cl, (bp 74 C/760 Torr) and 1-chloro-2-butyne, MeCCCH2Cl (bp 101 C/760 Torr), on a modest (up to 0.5 molar) scale. For the preparation of ‘non-propargylic’ chlorides from the corresponding alcohols, e.g. 6-chloro-1-hexyne, HCC(CH2)4Cl from 5-hexyn-1-ol, HCC(CH2)4OH, the reaction conditions are expected to be comparable with those necessary for the formation of saturated alkyl chlorides (refluxing for a few hours). Warning: 1,4-Dichloro-2-butyne is a skin-irritating compound. It is advisable to wear protective gloves during the experiment.

20.1.6.1

Procedure

Powdered butynediol (2.0 mol, technical grade, light brown colour) and pyridine (15 ml) are placed in the flask. Thionyl chloride (4.3 mol, pre-cooled at 40 C) is added in a number of portions over 30 min. During this addition, the flask is cooled in a bath at 30 to 40 C. The addition is accompanied by abundant evolution of hydrogen chloride. As a result, the net heating effect is very small. Temperature control in the first stage of the addition is therefore not very essential. Stirring becomes more easy when the greater part of the thionyl chloride has been added and part of the butynediol has dissolved. After the addition, stirring at 0 to 10 C is continued for an additional 2 h, then the flask is placed in a large (10 to 15 litre if available) bath with ice and ice water. The gas outlet is connected with a tube, loosely filled with CaCl2-lumps. The stirrer is replaced with a stopper. After 12 h the brown reaction mixture is poured into a 1-litre round-bottomed flask, which is equipped for a vacuum distillation, using an efficient column, a condenser and a single receiver, cooled in an ice bath (cf. Figure 1.10). The system is evacuated (water aspirator) and the temperature of the heating bath (during the first hour of the evacuation rt) is gradually raised to 40 C. When the pressure has dropped to below 40 Torr, the bath temperature is raised until dichlorobutyne begins to pass over. Exhaustive distillation of the remaining viscous brown residue (partly pyridineHCl) should not be attempted because decomposition may ensue (Note). Careful redistillation

376

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

affords 1,4-dichloro-2-butyne, bp 57 C/12 Torr, in 80% yield. If purified butynediol (recrystallised from a 3:10 mixture of THF and Et2O) is used, yields may be higher than 90%. 1,4-Dichloro-2-pentyne, MeCH(Cl)CCCH2Cl, bp 60 C/12 Torr, is prepared in a similar way from 5-chloro-3-pentyn-2-ol, MeCH(OH)CCCH2Cl. This alcohol is obtained from lithiated propargyl chloride, LiCCCH2Cl, and acetaldehyde (Chapter 5, exp. 5.2.2).

Note Treatment of the residue with water, followed by extraction with Et2O gives an additional small amount of product.

20.1.7

1,6-Dichloro-2,4-hexadiyne from 2,4-hexadiyne-1,6-diol and thionyl chloride

Scale: 0.30 molar; Apparatus: Figure 1.1, 500-ml

20.1.7.1

Procedure (for warning see preceding experiment)

2,4-Hexadiyne-1,6-diol (0.30 mol, Chapter 15, exp. 15.1.1) and pyridine (3 ml) are placed in the flask. Thionyl chloride (0.70 mol, pre-cooled to 30 C) is added in 10-g portions over 20 min, while cooling the flask in a bath at 30 C. Stirring is started as soon as possible. After the addition the cooling bath is removed and the temperature of the reaction mixture is allowed to rise over 4 h (occasional cooling is applied if the temperature rises too fast) to þ30 C. The flask is then placed in a bath at 4045 C. The equipment is removed and the flask is evacuated using a water aspirator. After about 1 h, the evacuating operation is terminated and Et2O (200 ml) is added to the remaining brown liquid. The solution is vigorously shaken with a mixture of 200 ml of ice water and 20 ml of pyridine. After separation of the layers, two extractions with Et2O are carried out. The combined organic solutions are successively washed with 3 N HCl and water and then dried over MgSO4.

20.1

ACETYLENIC HALOGEN COMPOUNDS

377

The Et2O is removed under reduced pressure and the remaining liquid distilled through a short Vigreux column to give pure 1,6-dichloro-2,4-hexadiyne, bp 50 C/0.2 Torr, in an excellent yield. The compound should be stored at 20 C.

20.1.8

5-Chloro-3-hexen-1-yne and 5-bromo-3-hexen-1-yne from 4-hexen-1-yn-3-ol and concentrated aqueous HCl or HBr

Scale: 0.50 molar; Apparatus: Figure 1.1, 1 litre 20.1.8.1

Procedure [cf. 3]

4-Hexen-1-yn-3-ol (0.50 mol, Chapter 5, exp. 5.2.4) is added over 30 min to 250 ml of a concentrated aqueous solution of HCl (37%) or HBr (Note), while keeping the temperature at 20 C or 5–10 C, respectively. The heating effect is weak. After an additional 30 min (at the temperature indicated), 250 ml of ice water is added. The product is extracted six times with a 1:1 mixture of Et2O and pentane (a sufficient amount of solvent should be used for the first extraction of the bromo compound in order to effect a satisfactory separation of the layers). The combined organic solutions are washed with water and subsequently dried over MgSO4. The greater part of the solvent is then distilled off at atmospheric pressure through an efficient column, keeping the bath temperature below 80 C. Distillation of the remaining liquid in vacuo through the same column gives the chloride 5-chloro-3-hexen-1-yne, HCCCH¼CHCH(Cl)Me, ((Z)/(E) 30:70), bp 55–60 C/50 Torr, and the bromide 5-bromo-3-hexen-1-yne, HCCCH¼ CHCH(Br)Me, ((Z)/(E) 30:70), bp 44–50 C/10 Torr, in yields of 70 and 90%, respectively. 1-Penten-4-yne-3-ol, H2C¼CHCH(OH)CCH, and concentrated HBr give, in 60% yield, a 30/70 mixture of 3-bromo-1-penten-4-yne, HCCCH (Br)CH¼CH2 and 5-bromo-3-penten-1-yne, HCCCH¼CHCH2Br.

Note The solution of HBr is obtained by stirring a mixture of 250 ml of 48% HBr with 50 g of PBr3 at 20 C until the solution has become homogeneous.

378 20.1.9

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

3-Chloro-3-methyl-1-butyne from 2-methyl-3-butyn-2-ol and concentrated aqueous HCl in the presence of copper(I) chloride

Scale: 0.50 molar; Apparatus: 1-litre wide-necked, conical flask and thermometer.

20.1.9.1

Procedure [cf. 4]

Concentrated aqueous HCl (37%, 200 ml) powdered NH4Cl (50 g), copper(I) chloride (10 g, technical grade) and copper bronze (2 g, Note 1) are placed in the flask. The mixture is cooled to 20 C and 0.50 mol of 2-methyl-3-butyn-2-ol (commercially available) is added over a few minutes with manual swirling. Subsequently gaseous HCl (40 g, weight increase) is introduced over 10 min with manual swirling, while keeping the temperature below 10 C (Note 2). The flask is then placed in a bath at 10 C. After 1 h (occasional swirling by hand) 300 ml of ice water is added. The layers are separated as completely as possible. The upper layer, crude 3-chloro-3-methyl-1-butyne, HC CCMe2Cl, (45 to 48 g), is swirled with 10 g of anhydrous K2CO3 (Note 3) in a 500-ml round-bottomed flask. This flask is equipped for a vacuum distillation using a 40-cm Vigreux column, a condenser and a single receiver cooled in a bath at 70 C (Figure 1.10). A tube filled with CaCl2 lumps is placed between the distillation apparatus and the water aspirator. The apparatus is evacuated (10 to 20 Torr) and the flask containing the crude chloro compound and the drying agent warmed in a bath at 30 to 40 C. Careful redistillation of the contents of the receiver through an efficient column gives 3-chloro-3-methyl1-butyne, bp 75–79 C/760 Torr, in 70 to 75% yield, with a purity of 95%.

Notes We presume that the metal serves to re-convert CuCl2, formed by oxidation, into CuCl. 2. At higher temperatures the tertiary chloride undergoes a rearrangement under the influence of CuCl giving a chloride with a conjugated diene system. This isomer has a considerably higher refractive index. 3. Traces of HCl or CuCl are neutralised or adsorbed.

1.

20.1

ACETYLENIC HALOGEN COMPOUNDS

20.1.10

379

1-Chloro-1-ethynylcyclohexane from 1-ethynylcyclohexanol and concentrated aqueous HCl in the presence of copper(I) chloride

Scale: 0.50 molar; Apparatus: 1-litre three-necked, round-bottomed flask, equipped with a mechanical stirrer, a powder funnel and a thermometer.

20.1.10.1

Procedure (for literature see exp. 20.1.9)

A mixture of concentrated HCl, CuCl, copper bronze (see Note 1 of exp. 20.1.9) and NH4Cl is prepared in a 1-litre conical flask as described in the preceding experiment. Gaseous HCl ( 40 g, weight increase) is then quickly introduced at 15 C (see exp. 20.1.9). The cold mixture is poured into the reaction flask. 1-Ethynylcyclohexanol (0.50 mol, commercially available) is then added over 2 min with stirring and cooling between 5 and 10 C. Stirring at 0 to 5 C is continued for an additional 1 h. Ice water (just enough to effect dissolution of the salt) is then added, followed by 50 ml of pentane. After separation of the layers, one extraction with a small amount of pentane is carried out. The combined organic solutions are dried over MgSO4 and subsequently concentrated under reduced pressure. Careful distillation of the remaining liquid through an efficient column gives 1-chloro-1ethynylcyclohexane, bp 55 C/15 Torr, in high yields.

20.1.11

‘Contrathermodynamic’ formation of propargyl iodide from the bromide and sodium iodide in absolute ethanol

Scale: 0.50 molar; Apparatus: 1-litre f1ask, provided with a mechanica1 stirrer and a reflux condenser. 20.1.11.1

Procedure

A solution of 0.60 mol of dry sodium iodide in 350 ml of 100% ethanol (Note 1) is heated to about 70 C. Freshly distilled propargyl bromide (Note 2)

380

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

(0.50 mol) is added over 10 min. After heating for 20 min at 70–75 C, the white suspension is cooled to rt and 500 ml of water is added, then the product is extracted five times with 60-ml portions of high-boiling petroleum ether (bp >190 C). The combined extracts are washed with water and dried over magnesium sulphate. The propargyl iodide is isolated from the extract by heating this at 10–15 Torr in a distillation apparatus, using an efficient column and a single receiver cooled at 30 C (Figure 1.10). The distillation is stopped when the temperature in the top of the column has risen above 50 C. Redistillation of the contents of the receiver in the same apparatus gives 3-iodo-1-propyne, bp <25 C/15 Torr, (receiver cooled at 30 C), containing about 10% of iodoallene. Notes 1.

In another experiment, performed on the same scale, 96% ethanol (instead of 100%) and sodium iodide, containing 3–4% of water, was used. Ethanol, 175 ml 96%, appeared to be sufficient to dissolve 90 g of this quality of NaI. The reaction with propargyl bromide, HCCCH2Br, gave no trace of iodoallene, but instead some ( 10%) HCCCH2Br was still present in the crude product. This amount will probably increase if more water is present since then the equilibrium cannot completely shift to the right. 2. Propargyl chloride gives comparable amounts of propargyl iodide and iodoallene. Propargyl tosylate will probably yield a product that is free from the allene.

20.1.12

Zinc chloride-catalysed conversion of 2-alkynyl ethers into the corresponding chlorides

Scale: 0.40 molar; Apparatus: Figure 1.1, 250 ml, magnetic stirring. 20.1.12.1 Procedure Powdered anhydrous zinc chloride (1 g) is added to 0.40 mol of the 2-alkynyl ether. Freshly distilled acetyl chloride (0.50 mol, excess) is added over 15 min.

20.2

ACETYLENIC AMINO AND IMINO COMPOUNDS

381

The mixture gradually turns brown, the temperature rises to 50–55 C and is maintained at this level by occasional cooling. After the exothermic reaction has subsided, the mixture is heated for an additional 1.5 h at 50 C. A saturated aqueous solution of ammonium chloride (50 ml) is then added with vigorous stirring. The upper layer is vigorously stirred at rt for 15 min with a solution of 40 g of KOH in 150 ml of water in order to remove the methyl acetate (this operation is not necessary when non-volatile acetylenic chlorides are to be prepared). After drying the upper layer over a small amount of magnesium sulphate, distillation is carried out, if R ¼ Me or Et, under normal pressure. 1-Chloro-2-butyne, R ¼ Me, bp 101 C/760 Torr, and 1-chloro-2-heptyne, R ¼ n-Bu, bp 55 C/12 Torr, are obtained in at least 80% yield. Note The chlorides are not accessible by reaction of the corresponding alcohols with PCl3, since the intermediary phosphites do not readily react with HCl. Alternative procedures for acetylenic chlorides are given in exps. 20.1.5 and 20.1.6.

20.2 20.2.1

ACETYLENIC AMINO AND IMINO COMPOUNDS

Propargylamine from propargyl bromide and liquid ammonia

Scale: 1.0 molar; Apparatus: Figure 1.1, 1 litre for the ammonolysis; 2-litre round-bottomed, three-necked flask, equipped with a thermometer, a mechanical stirrer and a powder funnel, for the addition to sodamide. 1-Amino-2-propyne (propargylamine) can be obtained in a fair overall yield by alkylation of phthalimide with propargyl bromide in DMF followed by

382

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

treatment of the product with dilute sulphuric acid and final addition of alkali hydroxide [43]. The alternative syntheses may be summarised as conversion of propargyl bromide or propargyl alcohol into some derivative (for example a tosylate or hexamethylenetetramine salt [44]) and a subsequent treatment of this intermediate, ultimately resulting in the formation of either the free amine or some salt. Although in some cases impressive yields (of the final step) have been reported, the syntheses are, in general, very laborious. The use of reagents with relatively high molecular weights in some syntheses makes performance on a larger scale inconvenient. It may be expected that propargylamine is smoothly ammonolysed in liquid ammonia. A qualitative experiment shows that this is indeed the case. Five millilitres of the bromide are added to 50 ml of boiling ammonia. When after 30 min the solution is poured onto 100 g of finely crushed ice, no under layer is visible. Repetition of this operation after an interaction time of ten minutes still does show the presence of some propargyl bromide. These experiments give useful information with respect to the additional reaction time in a synthetic procedure. A serious problem is the subsequent reaction of propargyl bromide with the corresponding amine presumed to occur in equilibrium with the primarily formed propargylammonium bromide. This reaction, which affords dipropargylamine, proceeds (like in the case of saturated-alkyl halides) much more easily than the preceding reaction of propargyl bromide with ammonia. In order to suppress this undesired reaction, the use of a large excess of liquid ammonia seems desired. The next problem to be solved is to prevent entraining of the volatile propargylamine with the evaporating ammonia. In an earlier performed synthesis of propargylamine the ammonia was allowed to evaporate completely. The amine was isolated in yields of 40% only [42]. In the procedure described below this problem is effectively solved by reaction of propargyl bromide with liquid ammonia followed by addition to an excess of sodamide in liquid ammonia. In this way, the amine is fixed as the sodium compound. After complete evaporation of the ammonia, the amine can be liberated by addition of water, just enough to effect a smooth dissolution of the solid.

20.2.1.1

Procedure

Freshly distilled propargyl bromide (1.0 mol) is added dropwise over 1 h to 800 ml of anhydrous liquid ammonia in the 1-litre round-bottomed, threenecked flask. During the addition the temperature of the reaction mixture is kept between 33 (bp of ammonia) and 36 C (bath with dry ice and acetone), while nitrogen is introduced at a rate of 100 ml/min. After an

20.2

ACETYLENIC AMINO AND IMINO COMPOUNDS

383

additional 45 min (at 36 C) the resulting solution is cooled to between 60 and 70 C in a bath with liquid nitrogen. The solution is subsequently poured in a number of portions over 10 min through the powder funnel to a suspension of 2.2 mol of sodamide in 500 ml of liquid ammonia. During this addition the temperature is carefully kept below 50 C by cooling with liquid nitrogen. After this operation the cooling bath and the equipment are removed. On the outer necks are placed stoppers. The middle neck is connected with a drying tube filled with KOH pellets. In order to ensure the constant presence of a protecting atmosphere of ammonia in the last stage of the evaporation, the drying tube is placed on a level below the bottom of the flask (cf. Figure 1.7). When, after one night, liquid ammonia is no longer present, the flask is placed in a bath at 30 C and evacuated (water aspirator) until the pressure has dropped to below 10–20 Torr (this operation takes about 1 h). Inert gas (preferably argon) is then admitted and the flask is equipped with a dropping funnel (on the middle neck), a reflux condenser filled with dry ice and acetone (‘cold finger’-type) and a gas inlet. The flask is placed in a bath at 0 C (or, preferably, at lower temperature). Nitrogen or argon is slowly introduced and water (200 ml) is added over 30 minutes, in the beginning dropwise, but in a later stage, when the intensity of reflux (some ammonia) in the cold finger has subsided, portionwise. At the end, the flask is vigorously swirled by hand for a few minutes in order to achieve complete contact of the solid with the water. The flask is then equipped for a distillation under atmospheric pressure (20-cm Vigreux column, condenser and receiver cooled in a bath at 0 C). The flask is immersed in an oil bath and heated until the temperature in the head of the column has reached 100–102 C. The distillate, a mixture of propargyl amine and water, is saturated with KOH pellets (or, if available, machine-powdered KOH) and a redistillation is carried out, now collecting all liquid passing over below 95 C. After addition of KOH pellets and vigorous shaking, a final distillation is carried out giving the almost pure amine, distilling between 75 and 85 C, n20 D 1.4492. Yields are between 60 and 65%. 20.2.2

Propargylic tertiary amines from propargyl bromide and aliphatic or cycloaliphatic secondary amines

Scale: 0.50 molar (HCCCH2Br); Apparatus: Figure 1.1 , 1 litre

384

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

Nucleophilic substitutions on propargylic or allylic carbon atoms generally proceed more easily than substitutions with halides in which the unsaturated system is absent or more remote from the halogen atom. This also holds for reactions with amines. The initial product in the reaction of propargyl bromides with an aliphatic or cycloaliphatic amine R2NH is the ammonium salt HCCCH2NR2 HBr. Since secondary amines are stronger bases than tertiary amines, it may be expected that HBr will be largely transferred to the secondary amine. Thus, in order to achieve a complete conversion of propargyl bromide, it will be necessary to use an excess of at least 100 mol% of the secondary amine. The reactions proceed at a convenient rate in diethyl ether and the ethereal solutions of the propargylic tertiary amines can be separated from the HBr salt of the secondary amine by filtration. If desired, the secondary amine used in excess can be recovered by treating the salt with concentrated aqueous KOH. Propargyl bromide reacts sluggishly with the bulky diisopropylamine (yields are low).

20.2.2.1

Procedure [5,6]

Propargyl bromide (0.50 mol) is added over 20 min to an efficiently stirred mixture of 1.10 mol of the amine (dried over KOH) and 500 ml of dry Et2O. A suspension of salt is formed almost immediately. When the temperature of the mixture has reached 35 C, the thermometer is replaced with a reflux condenser. The reaction is brought to completion by heating the suspension for an additional hour under reflux. The suspension is then cooled to 0 C, after which the salt is filtered off on a sintered-glass funnel and rinsed well with dry Et2O. In the case of pyrrolidine, an oily precipitate may be formed: instead of carrying out the filtration, the supernatant solution is decanted and the precipitate is thoroughly rinsed with pentane. In all cases, the greater part of the solvent is distilled off at atmospheric pressure through a 40-cm Vigreux column (bath temperature not higher than 100 C), after which the remaining liquid is carefully fractionated through an efficient column. The following amines can be prepared by this procedure. N,N-diethyl-2-propyn-1-amine, HCCCH2NEt2, bp 60 C/150 Torr, yield >70%; 1-(2-propynyl)pyrrolidine, HCCCH2–N(CH2)4, bp 42 C/10 Torr, yield >70%; 1-(2-propynyl)piperidine, HCCCH2–N(CH2)5, bp 62 C/ 10 Torr, yield >85%; 4-(2-propynyl)morpholine, HCCCH2N(CH2)2O (CH2)2, bp 75 C/10 Torr, yield >85%. (E)-N,N-Diethyl-2-penten-4-yn-1-amine, E-HCCCH¼CHCH2NMe2, bp 70 C/80 Torr, can be obtained in a high yield from (E)-5-bromo-3-penten-1yne, HCCCH¼CHCH2Br, and dimethylamine (2.5 mol equivalents) in Et2O by a similar procedure.

20.2

ACETYLENIC AMINO AND IMINO COMPOUNDS

20.2.3

385

N,N-Dimethyl-2-propyn-1-amine from propargyl bromide and dimethylamine

Scale: 0.50 molar (HCCCH2Br). Apparatus: Figure 1.1, 1 litre; stirrer: Figure 1.2. 20.2.3.1

Procedure (for introduction see preceding exp.)

Dimethylamine (1.1 mol) is liquefied in a cold trap and subsequently poured into 250 ml of high-boiling petroleum ether (bp >170 C), pre-cooled at 5 C. Propargyl bromide (0.50 mol) is then added dropwise over 45 min, while maintaining the temperature between 0 and 10 C. A thick suspension is gradually formed. After the addition, the temperature is allowed to rise to 35 C (occasional cooling may be necessary). After an additional 1.5 h (at 35 C, warming may be necessary) the dropping funnel and thermometer are replaced with stoppers and the flask is equipped for a vacuum distillation (cf. Figure 1.10: 40-cm Vigreux column, condenser and single receiver, cooled in a bath at 70 C). A tube filled with KOH pellets is placed between the receiver and the water aspirator. The system is evacuated (10–20 Torr) and the flask gradually heated until the petroleum ether begins to pass over. The contents of the receiver are carefully redistilled at atmospheric pressure through an efficient column N,N-Dimethyl-2-propyn-1-amine, HCCCH2NMe2, bp 82 C/ 760 Torr, is obtained in greater than 80% yield.

20.2.4

1,4-Bis(diethylamino)-2-butyne starting from 1,4-dibromo-2-butyne

Scale: 0.25 molar; Apparatus: Figure 1.1, 500 ml for the preparation of dibromobutyne; for the conversion into the amine the thermometer is replaced with a reflux condenser. Warning: Dibromobutyne is a skin-irritating and lachrymatory compound. Protective gloves of suitable quality should be used; the experiment should be carried out in a well-ventilated hood.

386 20.2.4.1

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

Procedure

2-Butyne-1,4-diol (0.25 mol, technical grade) is powdered and subsequently placed in the flask, containing 100 ml of Et2O. Phosphorus tribromide (50 g, slight excess) is added dropwise over 45 min with cooling in a bath with ice and ice water. After the addition, the cooling bath is removed and stirring is continued for an additional 2 h (gentle refluxing may temporarily occur). Ice water (300 ml) is then added and the lower (organic) layer is dried (without washing) over MgSO4. The aqueous layer is extracted twice with 40-ml portions of Et2O. The combined ethereal solutions are added over 30 min to a mixture of 1.3 mol of diethylamine (dried over machine-powdered KOH) and 150 ml of Et2O. The thick suspension is heated for an additonal 1 h under reflux, after which it is poured into 200 ml of an aqueous solution of 75 g of KOH. The upper layer is dried (without washing) over K2CO3 together with four ethereal extracts. The Et2O and excess of diethylamine are removed under reduced pressure and the remaining liquid distilled from a 500-ml flask (a relatively big flask is used in view of foaming during the distillation). N1,N1,N4,N4-Tetramethyl-2-butyne-1,4-diamine, bp 110 C/10 Torr, is obtained in 65% yield based on butynediol. 20.2.5

N,N-Diethyl-5-hexyne-1-amine from the corresponding tosylate and diethylamine

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre, reflux condenser, stirrer and thermometer 20.2.5.1

Procedure

5-Hexynyl-4-methylbenzenesulphonate (0.20 mol, prepared as described in exp. 20.5.4), dioxane (60 ml, dried over KOH) and diethylamine (0.5 mol, dried over KOH) are placed in the flask. The mixture is heated for 2 h under reflux. The temperature of the refluxing liquid rises by about 10 C over the first period of 1 h, but remains constant during the rest of the time. After stopping the stirrer, a two-layer system is visible. The mixture is cooled to rt and then cautiously poured into a mixture of 50 ml of concentrated HCl and 50 ml of ice water. Three extractions with Et2O are then carried out in order to remove impurities. The extracts are washed twice with 10-ml portions of water, the washings being added to the main portions of the aqueous solution. This is subsequently

20.2

ACETYLENIC AMINO AND IMINO COMPOUNDS

387

heated and evacuated (rotary evaporator) in order to remove as much as possible of the dioxane. This operation is terminated when the volume of the solution has decreased to about 70 ml. After cooling to below 10 C, NaOH pellets (40 g) are added in ten equal portions with vigorous stirring and cooling in a bath with ice water. The amine is then extracted five times with Et2O and the extracts dried over K2CO3 (without preceding washing). After concentration of the ethereal solution under reduced pressure, the remaining liquid is carefully distilled through an efficient column. N,N-Diethyl-5-hexyne-1-amine, bp 73 C/14 Torr, is obtained in greater than 80% yield.

20.2.6

2-Heptyne-1-amine from 1-bromo-2-heptyne and hexamethylenetetramine

The procedure [7] for 2-heptyne-1-amine, n-BuCCCH2NH2, starting from 1-bromo-2-heptyne, n-BuCCCH2Br, gives good results.

20.2.7

2-Methyl-3-butyne-2-amine from 3-chloro-3-methyl-1-butyne and sodamide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre stirrer: Figure 1.2 The mechanism of this remarkable reaction, in which a halogen atom in an acetylenic tertiary halide is substituted with high yields by the nucleophilic group NH2, is not completely clear. Probably the ethynyl hydrogen atom is abstracted in the first step by the strongly basic amide. The results from solvolysis experiments carried out with tertiary acetylenic bromides suggest that the intermediary sodium-3-chloro-3-methyl-1-butyne, NaCC–CMe2Cl, loses NaCl to give the carbene :C¼C¼CMe2. This species is attacked by NH3 or NaNH2.

20.2.7.1

Procedure [8] (cf. exp. 20.2.1 for the isolation)

To a suspension of 0.50 mol of sodamide in 400 ml of liquid ammonia 3-chloro3-methyl-1-butyne (0.20 mol, exp. 20.1.9) is added dropwise over 10 min. A thick brown suspension is formed. The ammonia is allowed to

388

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

evaporate overnight (see Figure 1.7). The last traces of ammonia are removed by evacuating the flask for about half an hour. Nitrogen is then admitted and the flask is equipped with a gas inlet (for introduction of N2), a dropping funnel and an outlet, connected (via a plastic tube) to a cold trap (–70 C). Water (120 ml) is cautiously added over 15 min from the dropping funnel, while N2 is passed through the apparatus. It is desired to immerse the flask in a bath with ice water. After the addition of the water, the flask is swirled in order to bring the aqueous mixture into contact with the solid on the glass wall. After all solid material has dissolved, the contents of the trap are poured into the flask. The flask is then equipped with a 40-cm Vigreux column, which is connected to a condenser and a 250-ml receiver, cooled at 20 C. The flask is heated in an oil bath until the thermometer in the head of the column indicates 100 C. During this distillation, some gaseous ammonia escapes from the receiver. The liquid in the receiver is saturated with KOH (portionwise addition of pellets with manual swirling and cooling in an ice-water bath). The receiver is then equipped for a vacuum distillation (Figure 1.10) using a 30-cm Vigreux column, a condenser and a 250-ml receiver cooled at 70 C. The volatile amine is collected in this strongly cooled receiver by subjecting the mixture of KOH, water and the amine to a flash distillation at water-aspirator pressure (temperature of the heating bath not higher than 60 C). The liquid collected in the receiver still contains small amounts of water. These can be removed by adding machine-powdered KOH (15–20 g) and repeating the flash distillation operation. Redistillation of the contents of the receiver gives 2-methyl-3-butyn-2-amine, bp 83 C/760 Torr, in 60% yield. 20.2.8

1-Ethynylcyclohexanamine from 1-chloro-1-ethynylcyclohexane and sodamide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre stirrer: Figure 1.2 20.2.8.1

Procedure (cf. preceding exp.)

The tertiary chloride (0.20 mol, see exp. 20.1.10) is added dropwise over 15 min to an efficiently stirred suspension of 0.50 mol of sodamide in 400 ml of liquid

20.2

ACETYLENIC AMINO AND IMINO COMPOUNDS

389

ammonia. The reaction is very vigorous and occasional addition of small amounts of Et2O may be necessary to suppress frothing (cooling of the reaction mixture to below the bp of ammonia also is effective). The ammonia is allowed to evaporate overnight (Figure 1.7), after which 200 ml of Et2O is added. The mixture is then hydrolysed by cautiously adding (with swirling) 300 ml of ice water. After dissolution of the solid material and separation of the layers, three extractions with Et2O are carried out. The ethereal solutions are dried (without preceding washing) over K2CO3 and subsequently concentrated under reduced pressure. Distillation of the remaining liquid gives 1-ethynylcyclohexanamine, bp 54 C/15 Torr, in excellent yield.

20.2.9

1-Propargylpyrrole from pyrrole, potassium amide and propargyl bromide

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml

20.2.9.1

Procedure [9]

Freshly distilled pyrrole (0.20 mol) is added over a few seconds to a solution of 0.20 mol of potassium amide (Chapter 2, exp. 2.3.1) in 150 ml of liquid ammonia, cooled at 60 C. After 1 min 0.22 mol of propargyl bromide is added over a few minutes, likewise at 60 C. After this addition the reaction mixture is stirred for 15 min at 50 C, then the cooling bath is removed and the ammonia is removed by placing the flask in a bath at 40 C (the equipment is removed). The remaining mass is extracted five times with dry, warm Et2O. The combined organic solutions are concentrated under reduced pressure. Careful distillation through an efficient column gives 1-propargylpyrrole, bp 60 C/10 Torr, in 70% yield. The higher boiling fraction consists of 2-propargylpyrrole, 1,2- and 1,3-di(propargyl)pyrrole. Using lithium amide or sodamide instead of potassium amide, the yield of 1-propargylpyrrole is moderate and the purity less. 1-Propargyl-1,3-imidazole and 1-propargylpyrazole can be prepared with high yields from the azoles, potassium amide and propargyl bromide.

390

20.

20.2.10

TRANSFORMATION OF FUNCTIONAL GROUPS

Acetylenic imines (general method, not checked) [48]

20.2.10.1 Procedure To a solution of 0.03 mol of the acetylenic aldehyde in 10 ml of dry Et2O was added dropwise an equimolar amount of the amine. Heat was evolved while the reaction mixture became turbid. After an additional 10 min (at rt) the aqueous layer was separated off and the ethereal solution was dried over magnesium sulphate. After removal of the Et2O (water spirator), the remaining liquid was distilled in vacuo or crystallised from benzene, Et2O or pentane. Yields were generally higher than 70%.

20.3

20.3.1

ACETYLENIC AND ALLENIC NITRILES, THIOCYANATES AND ISOTHIOCYANATES

Preparation of 2-alkynenitriles from 1-bromo-1-alkynes and copper(I) cyanide in the presence of lithium bromide

Scale: 0.20 molar (RCCBr); Apparatus: Figure 1.1, 250 ml, magnetic stirring

20.3.1.1

Procedure

The 1-bromoalkyne (0.20 mol, Chapter 9, exps. 9.2.3–9.2.5), dry THF (80 ml) and dry, powdered copper(I) cyanide (0.25 mol) are placed in the flask. The mixture is warmed to 40 C and a solution of 6 g of anhydrous lithium bromide in 20 ml of THF is added. As a rule, the reaction starts within a few minutes (heating to 50–55 C may be necessary) and (with stirring at a moderate rate) the temperature may rise above 60 C. Occasional cooling is applied to keep the temperature between 65 and 70 C. After the reaction has subsided, the mixture is heated for an additional half an hour at 65–70 C. Most of the solid has then passed into solution. The solution is poured into 200 ml of a cold (0 C) aqueous solution of 20 g of KCN (or 15 g of NaCN) and 30 g of NH4Cl. After vigorous shaking, the solution is extracted four times with Et2O. The combined ethereal solutions are washed with concentrated aqueous NH4Cl and subsequently dried over MgSO4. After removal of the solvent under reduced

20.3

ACETYLENIC AND ALLENIC NITRILES

391

pressure, the remaining liquid is first subjected to a flash distillation in a high vacuum and the distillate collected in a strongly cooled (<30 C, Figure 1.10) receiver. Redistillation gives the nitriles in 75% yield. Examples of nitriles, which have been obtained by this procedure: 3-phenyl2-propynenitrile, PhCCCN, bp 95 C/15 Torr, the distillate solidifies at rt; 3-(1-cyclohexenyl)-2-propynenitrile, 1-cyclohexenyl–CCCN, bp 100 C/ 15 Torr; 2-heptynenitrile, BuCCCN, bp 56 C/15 Torr. Warning: The aqueous layers should not be poured into a waste container for acids.

20.3.2

2,3-Decadienenitrile from corresponding bromo compound and copper(I) cyanide in the presence of lithium bromide

Scale: 0.10 molar; Apparatus: 100-ml two-necked flask, provided with a magnetic stirring bar and a reflux condenser 20.3.2.1

Procedure

A mixture of 0.15 mol of dry CuCN (commercially available), 6 g of anhydrous LiBr, 0.10 mol of 1-bromo-1,2-nonadiene (Chapter 12, exp. 12.4.14 ) and 25 ml of dry THF is heated to 90 C and kept at that temperature for 30 min. The reaction mixture gradually becomes homogeneous. After cooling to about 50 C the brown solution is poured into a vigorously stirred solution of 30 g of sodium cyanide and 30 g of ammonium chloride in 200 ml of water, to which 100 ml of Et2O has been added (for warning cf. preceding exp.). The reaction flask is rinsed with warm (40 C) THF and the solution obtained is also hydrolysed. After separation of the layers, the aqueous layer is extracted three times with Et2O. The combined ethereal solutions are washed with concentrated ammonium chloride solution, dried over magnesium sulphate and subsequently concentrated under reduced pressure. Rapid distillation of the residue through a 25-cm Vigreux column gives 2,3-decadienenitrile, bp 110 C/15 Torr, in 62% yield. The nitrile dimerises or polymerises upon prolonged heating. 1-Bromo-3-methyl-1,2-butadiene, Me2C¼C¼CHBr, and copper cyanide give 4-methyl-2,3-pentadienenitrile under similar conditions.

392 20.3.3

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

3-Alkynenitriles from 1-bromo-2-alkynes and copper(I) cyanide

Scale: 0.40 molar; Apparatus: Figure 1.1, 500 ml Nitriles with the system –CCCH2CN cannot be prepared from the corresponding propargylic bromides or tosylates and alkali cyanide, because the basic cyanide causes a smooth isomerisation to allenic nitriles (C¼C¼ CHCN). The use of copper(I) cyanide allows the substitution reaction to be carried out under non-basic conditions. Since copper(I) cyanide is poorly soluble in THF, the reaction proceeds sluggishly in this solvent and prolonged heating at elevated temperatures presumably will be necessary. Anhydrous LiBr forms a complex with CuCN that is soluble in THF, thus creating favourable conditions for the conversion. Indeed, a sub-stochiometrical amount of LiBr appears to cause a smooth reaction. In addition to the main product, a small amount of the 1,3-substitution product, the allenic cyanide, RC(CN)¼C¼CH2, is formed. The two isomers can be satisfactorily separated by fractional distillation. 20.3.3.1

Procedure

Anhydrous lithium bromide (0.1 mol) is dissolved in 100 ml of dry THF. Dry, powdered CuCN (0.47 mol) and the bromoalkyne (0.40 mol) are successively added, after which the suspension is warmed to between 40 and 60 C. An exothermic reaction starts gradually and occasional cooling is necessary to keep the reaction mixture between 70 and 80 C. The greater part of the suspension disappears and a brown solution is formed. After heating for an additional 30 min at 75–80 C, the hot (cooling may result in partial solidification) solution is cautiously poured into a vigorously stirred solution of 50 g of NH4Cl in 250 ml of 4 N hydrochloric acid (in another three-necked flask), which is kept between 0 and 5 C. The first flask is rinsed with the aqueous layer. The product is isolated by extraction with a 1:1 mixture of Et2O and pentane (five to seven times). The combined organic solutions are washed with saturated aqueous NH4Cl and subsequently dried over MgSO4. The liquid remaining after removal of the solvent in vacuo is first subjected to a flash distillation at <0.5 Torr, using a short Vigreux column and a single receiver cooled in a bath at 50 C (Figure 1.10). Redistillation of the contents of the receiver through an efficient column gives 3-pentynenitrile, MeCCCH2CN,

20.3

ACETYLENIC AND ALLENIC NITRILES

393

bp 47 C/15 Torr, in 60% yield (the small first fraction is mainly 2-methyl2,3-butadienenitrile, MeC(CN)¼C¼CH2) and 3-octynenitrile, BuCCCH2 CN, bp 84 C/15 Torr, in 70% yield (the first fraction of 5 g consists mainly of 2-butyl-2,3-butadienenitrile, BuC(CN)¼C¼CH2). 20.3.4

4-Pentynenitrile from 3-butynyl tosylate and sodium cyanide in DMSO

Scale: 0.50 molar; Apparatus: Figure 1.1, 1 litre 20.3.4.1

Procedure

Dry, powdered sodium cyanide (40 g, excess; KCN is not sufficiently soluble), DMSO (200 ml) and 3-butynyl tosylate (0.50 mol, cf. exp. 20.5.4) are placed in the flask. The mixture is gradually heated to 70 C. A rather strong exothermic reaction occurs and occasional cooling may be necessary. After an additional half hour (at 70 C) the mixture is cooled to rt and then poured into 400 ml of saturated aqueous NH4Cl. Twenty (Note) extractions with Et2O (2 100 ml, 1 50 ml, the other portions 30 ml) are carried out. The combined organic solutions are washed twice with 100-ml portions of saturated aqueous NH4Cl and subsequently dried over K2CO3. The Et2O is then removed under reduced pressure. Distillation of the remaining liquid through an efficient column gives 4-pentynenitrile, bp 60 C/10 Torr, in high yields.

Note The presence of DMSO enhances the solubility of the nitrile. The method can also be applied to prepare other nitriles with the general structure RC C(CH2)nCN (n >2). In these cases the extraction procedure is less laborious. 20.3.5

2-Heptynenitrile from the corresponding carboxamide and phosphorus pentoxide

Scale: 0.20 molar; Apparatus: 1-litre round-bottomed flask

394 20.3.5.1

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

Procedure

The powdered crystalline 2-heptynamide (0.20 mol), paraffin oil (250 ml), some drops of anti-foaming liquid and 130 g of P2O5 are successively placed in the flask. The mixture is vigorously shaken during 1–2 min, so that a homogeneous slurry is formed. The flask is then equipped for a distillation in vacuum (Figure 1.10), the receiver being cooled in a bath at –60 C. After evacuating the apparatus (<0.1 Torr), the flask is heated in an oil bath, initially at 150 C, later at 200 C. When the distillation has stopped, inert gas is admitted and the brown hot mass is cautiously (spatula) broken up in smaller particles. Repetition of the heating operation gives an additional small amount of the nitrile. Redistillation gives pure 2-heptynenitrile, bp 56 C/15 Torr, in 70% yield. 20.3.6

2-Propynyl thiocyanate from propargyl bromide and potassium thiocyanate

Scale: 0.20 molar; Apparatus: Figure 1.1, 250 ml; no dropping funnel, reflux condenser instead of a thermometer. 20.3.6.1

Procedure

A vigorously stirred mixture of 0.30 mol of potassium thiocyanate, 30 ml of water and 0.20 mol of propargyl bromide is heated for 30 min in a bath at 90 C. After cooling extraction with Et2O is carried out. The ethereal solution is dried and concentrated under reduced pressure. 2-Propynyl thiocyanate, bp 65 C/15 Torr, is obtained in 90% yield. 20.3.7

Propargyl isothiocyanate from propargylamine and thiophosgene

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml The reaction of primary amines with (commercially available) thiophosgene is a convenient preparative method for isothiocyanates. The reaction is

20.4

ACETYLENIC ALDEHYDES, KETONES AND . . .

395

quite general and gives good yields. The amino group attacks on the thiocarbonyl carbon atom with primary formation of a compound with the structure RNHC(¼S)Cl. This intermediate may either eliminate HCl under the influence of the amine with formation of the isothiocyanate or may undergo a second substitution of Cl with formation of the thiourea derivative S¼C(NHR)2. The latter compound can also be formed by addition of RNH2 to the heterocumulene system of the isothiocyanate. These undesired processes can be largely avoided by keeping the concentration of the amine as low as possible during the reaction. Since part of the amine is inactivated by reaction with the HCl liberated, it is necessary to carry out the reaction in the presence of a basic reagent that neutralises the HCl, but does not react with thiophosgene. In the procedure for propargyl isothiocyanate, which should be generally applicable, we use aqueous potassium carbonate. At a later stage, aqueous KOH is added to complete the elimination of HCl from the intermediary N-(2-propynyl)carbamothioic chloride, HCCCH2NHC(¼S)Cl. 20.3.7.1

Procedure

A mixture of 0.11 mol of thiophosgene and 75 ml of dichloromethane is cooled to 5 C. A solution of 0.10 mol of potassium carbonate in 100 ml of water (5 C) is added. A mixture of 0.10 mol of propargylamine (exp. 20.2.1) and 20 ml of water is added dropwise over 15 min with vigorous stirring and maintaining of the temperature between 0 and 5 C. After an additional 10 min a cold (0 C) solution of 0.2 mol of KOH in 100 ml of water is added in one portion with cooling below 0 C and stirring is continued for an additional 15 min. The organic layer and three extracts (Et2O) are dried (without washing) over MgSO4 and subsequently concentrated under reduced pressure. Distillation of the remaining liquid through a 20-cm Vigreux column gives 2-propynyl isothiocyanate, HCCCH2N¼C¼S, bp 55 C/15 Torr, in 70% yield. Like most isothiocyanates, the compound is a strong lachrymator. Poor results are obtained when the addition is carried out in a reversed sense (Cl2C¼S to HCCCH2NH2, H2O, CH2Cl2 and KOH or K2CO3).

20.4

20.4.1

ACETYLENIC ALDEHYDES, KETONES AND CARBOXYLIC ACIDS

Propiolaldehyde, HCCCH¼O

A satisfactory procedure for propiolaldehyde, HCCCH¼O, from propargyl alcohol and chromic acid is described [10].

396 20.4.2

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

Ethynyl ketones from corresponding ethynyl carbinols and chromic acid

Our experiences with the procedure described in the literature [45] were satisfactory. For the preparation of 1-hexyn-3-one, HCCCOn-Pr, the original procedure is slightly modified: the solution of CrO3 is added over 45 min, while keeping the temperature between 10 and 15 C. After an additional 1.5 h (at 10 to 15 C) the mixture is extracted 8 times with Et2O and the combined extracts are washed with saturated aqueous ammonium chloride. The conversion of HCCCH(OH)Me into 3-butyn-2-one is carried out in the absence of acetone. Our yields are the same as those mentioned. 1-Phenyl-2-propyn-1-one, HCCCOPh, is prepared as follows: 1-Phenyl-2-propyn-1-ol (0.20 mol, Chapter 5, exp. 5.2.2) is added to a mixture of 200 ml of acetone, 60 ml of water and 23.1 g of 96% sulphuric acid cooled at 10 C. A solution of 14.7 g of CrO3 in 50 ml of water is added dropwise over 40 min, while maintaining the temperature between 10 and 15 C. After an additional 2 h (at rt) the greenish solution is poured into 1 litre of ice water and the product is extracted with Et2O (five times). The combined organic solutions are washed with concentrated aqueous ammonium chloride and dried over MgSO4. The solid remaining after removal of the solvent under reduced pressure is dissolved in 250 ml of refluxing pentane. The clear solution is decanted from a small amount of brown product and put in the refrigerator (25 C). Colourless crystals, mp 49–50 C, are obtained. The mother liquor is concentrated and cooled again, giving an additional small amount of crystals. The yield is about 90%.

20.4.3

5-Hexyn-3-one from 5-hexyn-3-ol and chromic acid

Scale: 0.30 molar; Apparatus: Figure 1.1, 1 litre

20.5

ACETYLENIC ESTERS, DITHIOESTERS AND . . .

20.4.3.1

397

Procedure [11]

In the flask is placed acetone (90 ml), 5-hexyn-3-ol (0.30 mol, Chapter 5, exp. 5.2.9) and pentane (100 ml). To the vigorously stirred mixture is added over 15 min a solution of 25 g of CrO3 in a mixture of 23 ml of 96% H2SO4 and 60 ml of water, while keeping the temperature between 0 and 5 C. Stirring at this temperature is continued for 30 min at 0 C, then the mixture is cooled to 10 C and ten extractions with small portions of a 1:1 mixture of Et2O and pentane are carried out. Care is taken to keep the temperature of the aqueous layer below 0 C. The combined extracts are washed twice with 50-ml portions of 1 N H2SO4 saturated with ammonium chloride and dried over magnesium sulphate. After removal of the solvents under reduced pressure, the remaining liquid is distilled in the apparatus shown in Figure 1.10, the receiver being cooled in a bath at 0 C. 5-Hexyn-3-one, bp 38 C/15 Torr, is obtained in 70% yield. The purity is 80%.

20.4.4

Propynoic acid, HCCCOOH

The results mentioned in the procedure described in the literature [46], involving oxidation of propargyl alcohol with CrO3 in an acetone–water mixture, could be reproduced.

20.5

ACETYLENIC ESTERS, DITHIOESTERS AND CARBOXAMIDES

20.5.1

General procedure for the preparation of acetylenic acetates

Scale: 0.30 molar; Apparatus: Figure 1.1, 500 ml

20.5.1.1

Procedure [12]

N,N-Diethylaniline (0.70 mol) and redistilled acetyl chloride (0.37 mol) are placed in the flask. The acetylenic alcohol (0.30 mol) is added over a few minutes while heating the mixture at 40 C. An exothermic reaction starts and the temperature rises to 120 C in a few minutes. Occasional cooling is

398

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

necessary to keep the temperature at that level. After the exothermic reaction has subsided, the mixture is heated for an additional 15 min at 130 C (immersion of the flask in the heating bath is necessary to prevent solidification of the reaction mixture on the glass wall). After cooling to 50 C (stirring has been stopped), a mixture of 300 ml of ice water and 30 ml of 36% hydrochloric acid is added. A small amount of Et2O is added, after which the mixture is vigorously shaken (or stirred). After separation of the layers, two extractions with Et2O are carried out. The combined organic solutions are washed with water and then dried over MgSO4. The liquid remaining after concentration of the solution under reduced pressure is distilled through a 30-cm Vigreux column. 1,1-Dimetyl-2-propynyl acetate, R ¼ H, R1 ¼ R2 ¼ Me, bp 45 C/ 27 Torr, and R ¼ H, R1R2C ¼ cyclohexyl, bp 87 C/15 Torr, are obtained in excellent yields. With primary and secondary alcohols the reaction presumably proceeds much more easily and a sufficient amount of a solvent e.g. Et2O, may be necessary. The reaction may be carried out in the refluxing solvent.

20.5.2

2-Propynyl propanedithioate from bromomagnesium propanedithioate and propargyl bromide

Scale: 0.30 molar; Apparatus: Figure 1.1, 1 litre

20.5.2.1

Procedure [13]

To a solution (partly suspension upon cooling) of ethylmagnesium bromide prepared from 0.35 mol of ethyl bromide and 0.45 mol of magnesium in 300 ml of THF is added with cooling at 0 C 0.30 mol of carbon disulphide. This addition is carried out over 30 min. After an additional 30 min at rt, 50 ml of HMPT (instead of this co-solvent DMSO, DMF, N-methylpyrrolidinone, or other strongly polar solvents may be tried) and 0.40 mol of propargyl bromide are successively added. The temperature rises slowly. After heating for 2 h at 50 C, the mixture is kept (without stirring) overnight at rt. Water (250 ml) is then added. After dissolution of the salt and separation of the layers, two extractions with pentane are carried out. The combined organic solutions are

20.5

ACETYLENIC ESTERS, DITHIOESTERS AND . . .

399

washed three times with saturated aqueous ammonium chloride and are subsequently dried over magnesium sulphate. The red liquid remaining after removal of the solvents under reduced pressure is distilled at the lowest possible pressure (<1 Torr) to give 2-propynyl propanedithioate, bp 50 C/0.5 Torr, in 70% yield. For distillation at >5 Torr higher bath temperatures are required and as a result a 3,3-sigmatropic rearrangement to 1,2-propadienyl propanedithioate, EtC(¼S)SCH¼C¼CH2, and subsequent decomposition of this allenic dithioester take place.

20.5.3

General procedures for the preparation of acetylenic methanesulphinates and methanesulphonates

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre Esters of acetylenic alcohols and methanesulphinic and methanesulphonic acid have been used as synthetic intermediates in our laboratory, mainly for SN20 -like substitution reactions leading to allenic derivatives [14]. Although pyridine is recommended as solvent for the preparation of these esters [15], the procedure given in this experiment, which uses dichloromethane as solvent and a relatively small excess of triethylamine or pyridine, seems more simple. Yields are generally excellent as in the case of the acetylenic p-toluenesulphonic esters (exp. 20.5.4). Also acetylenic tertiary alcohols RCCC(R1)(R2)OH have been successfully converted by this procedure into the 1,1-dialkyl-2-propynyl methanesulphinates. The esters from tertiary alcohols and methanesulphonic acid, MeSO2OC(R1)(R2)CCR, are unstable at rt and can only be prepared at low temperatures in an organic solvent from the lithium alkoxides and MeSO2Cl.

20.5.3.1

Procedure

Methanesulphinyl chloride [16] (0.25 mol), or methanesulphonyl chloride (0.25 mol, commercially available) is added dropwise over 10–15 min to a mixture

400

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

of the acetylenic alcohol (0.20 mol), dry dichloromethane (300 ml) and dry triethylamine (0.35 mol). After the addition, which is carried out at 50 C, the temperature is allowed to rise to 0 C. Ice water (200 ml) is added with vigorous stirring to the white suspension. The aqueous layer is extracted twice with small portions of dichloromethane. The combined organic solutions are dried over MgSO4 and subsequently concentrated under reduced pressure, while keeping the bath temperature below 70 C. The last traces of solvent may be removed in a high vacuum (bath temperature 30 to 40 C). Yields of the products (purity >95%) are usually greater than 90%. If not used directly, the esters should be stored in the refrigerator (20 C).

20.5.4

General procedure for the preparation of acetylenic 4-methylbenzenesulphonates

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre; a powder funnel is used instead of the dropping funnel Esters of arenesulphonic acids are prepared by reaction of the corresponding alcohol with the arenesulphonyl chloride in the presence of a basic reagent, which has the function of activating the alcohol and binding the hydrogen chloride. The reaction is often carried out with pyridine, which is used as solvent. In the procedure for tosylates of primary aliphatic alcohols, described in A. I. Vogel, A Textbook of Practical Organic Chemistry, an aqueous solution of sodium hydroxide is used. Esters of primary alcohols are formed more easily than secondary-alkyl esters, while tertiary alcohols cannot be esterified under the usual conditions. The procedure described below is quite general and uses finely, freshly machine-powdered KOH, which is added to a solution of the primary or secondary (acetylenic) alcohol and a 10–15% molar excess of tosyl chloride in Et2O, kept around 0 C. The excess of tosyl chloride is destroyed during the reaction with the excess of KOH. Side- and subsequent reactions (‘saponification’ of the ester by KOH and 1,2-elimination of 4-methylbenzenesulphonic acid from the ester) can be suppressed by keeping the temperature of

20.5

ACETYLENIC ESTERS, DITHIOESTERS AND . . .

401

the reaction mixture below 5 C. This procedure can be carried out within 2 h and generally gives excellent (often almost quantitative) yields of the tosylates. Purification of acetylenic tosylates by distillation, which is risky because of the limited thermal stability of the esters, is not necessary because the ‘crude’ products have a satisfactory purity (>95%) for further synthetic work. If not used immediately, the tosylates should be stored in the refrigerator, where deterioration is negligible. Warning: Tosyl chloride may irritate the skin; protective gloves should be worn.

20.5.4.1

Procedure

4-Methylbenzenesulphonyl chloride (0.22 mol in the case of primary alcohols or 0.24 mol for secondary alcohols) is dissolved in 400 ml of Et2O. The alcohol (0.20 mol) is then added and the mixture is cooled to between 5 and 10 C (bath with dry ice and acetone). Freshly and finely machine-powdered KOH (100 g) is added with efficient stirring. The addition is initially carried out in 5-g portions with intervals of 2 min. The evolution of heat is considerable and efficient cooling is necessary to maintain the temperature between 5 and 0 C (for primary alcohols) or between 0 and þ5 C (for secondary alcohols). After about 20 g of KOH has been added over the first 20 min, the remainder is added over an additional 10 min. The mixture is then stirred for half an hour or 1 h at the temperature indicated in the cases of primary or secondary alcohols, respectively. The work-up is carried out by pouring the mixture into 500 ml of ice water (the solid remaining in the flask is quickly hydrolysed with ice water) and subsequently added to the bulk of the solution. After vigorous shaking, the layers are separated. The organic layer and two ethereal extracts are dried over MgSO4, after which the ether is thoroughly removed under reduced pressure, keeping the temperature of the heating bath below 80 C. Yields are usually greater than 90%. The following variant, which uses a very concentrated aqueous solution of NaOH, also may be applied. Propargyl alcohol (0.10 mol) and tosyl chloride (0.12 mol) are dissolved in 100 ml of Et2O. A solution of 7 g (excess) of technical-grade KOH in the minimal amount (4 ml) of water is added dropwise over 15 min with vigorous magnetic stirring, while keeping the temperature of the mixture at 10 C. After an additional 30 min at 0 C the work-up is carried out. Small amounts of tosyl chloride still may be present in the product. The yield is almost quantitative.

402 20.5.5

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

Conversion of ethyl 2-heptynoate into the corresponding carboxamide

Scale: 0.20 molar; Apparatus: 250-ml round-bottomed, two-necked flask with mechanical stirrer and thermometer-outlet combination. 20.5.5.1

Procedure

A mixture of 0.20 mol of ethyl 2-heptynoate, 200 ml of a concentrated solution of ammonia in water and 100 ml of methanol is vigorously stirred at rt until it becomes homogeneous. After standing for an additional period of about 4 h at rt, methanol and water are removed under reduced pressure. The crystalline residue is dissolved in 200 ml of a 1:4 mixture of pentane and Et2O. The lower layer is extracted twice with small portions of this mixture. The combined organic solutions are dried over magnesium sulphate and subsequently concentrated under reduced pressure. The yield of pure crystalline 2-heptynamide is quantitative.

20.6 20.6.1

ETHERS

3-Methoxy-1-propyne from propargyl alcohol, NaOH and dimethyl sulphate

Scale: 3.0 molar; Apparatus: 2-litre round-bottomed, three-necked flask, equipped with a dropping funnel, a gas-tight mechanical stirrer, an efficient reflux condenser and a thermometer, combined with the reflux condenser or dropping funnel. 20.6.1.1

Procedure [17]

A cold (0–10 C) solution of 180 g of sodium hydroxide (Note 1) in 300 ml of water is placed in the flask. Propargyl alcohol (3.0 mol) is added over 10 min

20.6

ETHERS

403

at rt, after which dimethyl sulphate (250 g) is added at a rate such that the temperature is maintained between 50 and 55 C (some cooling may be necessary). This addition takes about 2 h. After the addition the mixture is heated under reflux for 2 h. The reflux condenser is then replaced with a 40-cm Vigreux column, which is connected to an efficient condenser and a receiver, cooled at 0 C. The propargylic ether is distilled off as quickly as possible, while the temperature of the heating bath is gradually raised. The distillation is stopped when the thermometer in the head of the distillation column indicates 95 C. In order to remove some methanol, the contents of the receiver are washed three times with cold aqueous NH4Cl in a small separating funnel. The upper layer is dried over a small amount of MgSO4. Yields are generally higher than 70%. Redistillation (under N2) may be carried out (bp 61 C/760 Torr, but is not necessary. The product must be stored under N2 in a perfectly closed bottle, placed in the refrigerator (20 C) (Note 2). 3-Ethoxy-1-propyne, HCCCH2OEt, bp 80 C/760 Torr, is obtained in a similar way (yields >70%) using Et2SO4. During the addition of this reagent, the temperature of the reaction mixture is maintained between 60 and 70 C. The reaction is brought to completion by heating the reaction mixture for 2 h under reflux.

Notes 1. 2.

The use of potassium hydroxide is less convenient since a very thick suspension of K2SO4 is formed. Auto-oxidation with formation of 1-methoxy-2-propynyl hydroperoxide, HCCCH(OOH)OMe takes place very readily. Samples that have been stored for a few days at rt under air (instead of N2) contain detectable amounts of the hydroperoxide. The presence of this compound appears most convincingly by shaking 1 ml of the ether with an aqueous solution of KI. A brown colour is developed immediately, but disappears when shaking is continued (due to addition or some other reaction with I2). The presence of much hydroperoxide (after prolonged storage at rt or even in the refrigerator) appears from a considerably higher refractive index. Samples that show a positive KI test, should never be redistilled at atmospheric pressure. A good qualitative test consists of shaking 2 to 3 ml with t-BuOK. If a dark brown colour is developed and much heat is evolved (in that case the refractive index at rt is considerably higher than 1.40), the sample should be poured into the waste container (after dilution with an equal volume of acetone). One of the coworkers in our laboratory had an extremely vigorous explosion during a distillation of a large (500 g)

404

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

amount of HCCCH2OMe, which had been stored for a few weeks at rt (not under N2). Samples that contain small amounts of hydroperoxide (nD< 1.403, slight evolution of heat upon shaking with t-BuOK) can best be purified by adding a small amount of paraffin oil (20 ml on each 100 ml of HCCCH2OMe) and subsequently ‘distilling’ the volatile ether at 10 to 20 Torr. The vapour is condensed in a strongly cooled receiver (cf. Figure 1.10).

20.6.2

1,4-Dimethoxy-2-butyne from 2-butyne-1,4-diol, NaOH and dimethyl sulphate

Scale: 1.0 molar; Apparatus: Figure 1.1, 1 litre

20.6.2.1

Procedure [18]

A solution of 1.0 mol of 2-butyne-1,4-diol in 160 ml of water is placed in the flask. Sodium hydroxide pellets (100 g, Note) and dimethyl sulphate (2.5 mol) are added in turn in 20 equal portions over 1.5 h. During the addition the temperature of the reaction mixture is kept between 30 and 40 C (occasional cooling). After the addition, the mixture is heated for an additional 3 h in a bath at 90 C. Ice water (150 ml) is then added and, after cooling to rt, five extractions with Et2O are carried out. The organic solutions are dried (without washing) over K2CO3, after which they are concentrated in vacuo. Distillation of the remaining liquid through a 40-cm Vigreux column gives 1,4-dimethoxy2-butyne, bp 54 C/12 Torr, in yields of at least 80% (depending on the quality of butynediol). 1,4-Diethoxy-2-butyne, EtOCH2CCCH2OEt, bp 76 C/12 Torr, is prepared in a similar way, with comparable yields. The bis-ethers should be stored under N2 in the refrigerator.

Note If potassium hydroxide is used, a very thick suspension of potassium sulphate is formed making efficient stirring difficult.

20.6

ETHERS

20.6.3

405

Di-(2-propynyl) ether from propargyl alcohol, propargyl bromide and NaOH

Scale: 0.50 molar; Apparatus: 1-litre three-necked, round-bottomed flask, equipped with a powder funnel, a mechanical stirrer and a combination of thermometer and outlet; after the addition of NaOH, the powder funnel is replaced with a stopper 20.6.3.1

Procedure

Propargyl alcohol (0.70 mol) and propargyl bromide (0.50 mol) are placed in the flask. Freshly and finely machine-powdered sodium hydroxide (30 g) is added in small portions with vigorous stirring (small amounts of THF may be added if stirring becomes difficult). The heating effect is rather strong so that occasional cooling is necessary to keep the temperature between 60 and 70 C. When the reaction has subsided, the mixture is heated for an additional 1 h in a bath at 70–80 C. After cooling to rt, 500 ml of ice water is added with vigorous stirring. The product is extracted with Et2O and the extract washed with water. After drying the organic solution over MgSO4, most of the Et2O is distilled off at normal pressure. The remaining liquid is distilled through a 30-cm Vigreux column to give di-(2-propynyl) ether , bp 67 C/85 Torr, in an excellent yield.

20.6.4

O-Methylation of an acetylenic tertiary alcohol with dimethyl sulphate

Scale: 1.0 molar; Apparatus: Figure 1.1, 1 litre Tertiary and secondary alcohols are less acidic than primary alcohols. Methylation of 2-methyl-3-butyn-2-ol, HCCCMe2OH, with Me2SO4 and alkali hydroxide in aqueous medium, analogous to the procedure for HCCCH2OMe (exp. 20.6.1), is therefore expected to give a poor result. In the aprotic DMSO, however, the concentration of the alkoxide HCCC (Me)2OK will be sufficient, while the alkylation will proceed smoothly in this

406

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

strongly polar solvent. Undoubtedly, part of the dimethyl sulphate will react with KOH to give methanol (which may further react to dimethyl ether). Therefore, an excess of Me2SO4 and KOH is used. The procedure for the tertiary propargylic ether seems to be generally applicable. If alkyl groups other than methyl or ethyl are to be introduced, modification of the reaction conditions will be necessary. For example, for the preparation of 1-butoxy-2-propyne, HCCCH2OBu, powdered KOH may be added portionwise to a heated mixture of HCCCH2OH (excess), butyl bromide and DMSO. The volatile butyl propargyl ether can be isolated from the reaction mixture by evacuation. In the cases of higher-boiling ethers, isolation can be carried out after addition of water and extraction with Et2O or pentane. Methylation or ethylation of primary alcohols can also be performed in Et2O.The procedure may consist of adding the alkylating reagent (MeI or Me2SO4, EtI or Et2SO4) to a mixture of the primary alcohol, excess of finely powdered KOH and Et2O (or THF, cf. exp. 20.6.11). 20.6.4.1

Procedure [19]

DMSO (technical grade, 250 ml) and machine-powdered KOH (1.5 mol) are placed in the flask. 2-Methyl-3-butyn-2-ol (1.0 mol, commercially available) is added over a few minutes. Subsequently 1.0 mol of dimethyl sulphate is added dropwise with vigorous stirring, while keeping the temperature in the region of 60 C (45 min). After the exothermic reaction has ceased, stirring and heating at 60 C are continued for an additional half an hour. The flask is then equipped for a vacuum distillation using a 40-cm Vigreux column, a condenser and a single receiver cooled in a bath at 70 C (Figure 1.10). The system is evacuated (water aspirator) and the flask heated in a bath at 70 C. The volatile ether condenses in the strongly cooled receiver. The contents of the receiver are washed twice with saturated aqueous ammonium chloride and are subsequently dried over MgSO4. Pure 3-methoxy-3-methyl-1-butyne, HCCC (Me)2OMe, is obtained in 65% yield. Distillation is not necessary. 20.6.5

O-Methylation of an O-lithiated acetylenic tertiary alcohol with methyl iodide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre

20.6

ETHERS

407

Although the procedure for the O-methylation of 2-methyl-3-butyn-2-ol (exp. 20.6.4) gives a fair yield, it is less suitable for the O-methylation of alcohols that are not available in large amounts. In such cases there is need for a very clean high-yield method. The procedure for the O-methylation of ethynylcyclohexanol is illustrative. 1-Ethynylcyclohexanol is O-lithiated quantitatively by BuLi in a mixture of THF and hexane. Since O-alkylations of lithium alkoxides in solvents of moderate polarity proceed very sluggishly (even in the case of methyl iodide), a sufficient amount of the polar DMSO has to be added as a co-solvent. The methylation with methyl iodide can then be accomplished under relatively mild conditions and there is no indication for decomposition of the intermediary lithium alcoholate into LiCCH and cyclohexanone. 20.6.5.1

Procedure

THF (140 ml) is added to a solution of 0.21 mol of BuLi (Note) in 133 ml of hexane with cooling below 0 C. A mixture of 0.20 mol of 1-ethynylcyclohexanol and 20 ml of THF is then added at 25 C, followed by 75 ml of dry DMSO. Five minutes later, 0.32 mol (excess) of methyl iodide is added in one portion at 0 C. The mixture is successively stirred for 1 h at 10 C and 1 h at 45 C, then it is poured into 400 ml of a saturated aqueous solution of NaCl. The aqueous layer is extracted three times with Et2O. The combined organic solutions are washed four times with brine and are subsequently dried over MgSO4. The greater part of the solvent is then distilled off at atmospheric pressure through a 40-cm Vigreux column. Careful distillation of the remaining liquid through an efficient column gives 1-ethynyl-1-methoxycyclohexane, bp 56 C/18 Torr, in an excellent yield.

Note The excess of BuLi is used to compensate for losses due to the presence of traces of oxygen and moisture. 20.6.6

Methylation of an in situ prepared acetylenic lithium alcoholate with methyl iodide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre

408 20.6.6.1

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

Procedure [20]

A suspension of 0.20 mol of MeCCLi in 126 ml of hexane and 140 ml of THF is prepared (Chapter 3, exp. 3.9.4). To this suspension is added at 0 C a solution of 0.10 mol of anhydrous lithium bromide (Note) in 40 ml of THF. The mixture is then cooled to 40 C and 0.20 mol of cyclohexanone is added over 10 min, while maintaining the temperature between 35 and 45 C. After the addition, the cooling bath is removed and the temperature allowed rising to 5 C. Methyl iodide (0.28 mol) and dry DMSO (75 ml) are then successively added. The temperature rises to about 35 C, while salt separates from the solution. After heating for an additional 1.5 h at 50 C, two clear layers have formed. Ice water (500 ml) is added and, after separation of the layers, the aqueous layer is extracted four times with Et2O. The combined organic solutions are washed four times with saturated aqueous NH4Cl and are subsequently dried over MgSO4. Removal of the solvent in vacuo followed by careful distillation through a 30-cm Vigreux column gives the 1-methoxy-1(1-propynyl)cyclohexane, bp 80 C/12 Torr, in greater than 80% yield. Note The LiBr is added to solubilise part of the propynyllithium. If no LiBr is added, the coupling with ketones is slower and part of the ketone is converted into the enolate. In the cases of soluble lithium alkynylides, the addition of LiBr is not necessary. 20.6.7

Protection of the OH group in alcohols with ethyl vinyl ether

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml Although many organic chemists still use 3,4-dihydro-2H-pyran for the protection of OH groups [21,22], protection with ethyl vinyl ether has distinct advantages. Ethyl vinyl ether [23] is much cheaper than the cyclic ether, and chemists working in a university will perhaps find the advantage of the easier protection and deprotection more important. Furthermore, 1H NMRspectroscopic analysis of the addition products from ethyl vinyl ether in many cases will be easier. The reaction of alcohols (and phenols) with ethyl vinyl ether proceeds readily at temperatures in the region of 0 C. For obtaining good yields (often almost

20.6

ETHERS

409

quantitative) it is essential to use water-free alcohols and to keep the temperature below 0 C during the protection reaction. The use of an excess of ethyl vinyl ether allows the reaction to be completed within 30 min, irrespective of whether primary, secondary or tertiary alcohols are used. It should be pointed out that the reaction is by no means limited to acetylenic alcohols. Traces of acid, which often adhere to the glass, should be neutralised. This can be done most easily and effectively by rinsing the glass with gaseous ammonia or a solution of an aliphatic amine in acetone. 20.6.7.1

Procedure

Freshly distilled ethyl vinyl ether (0.3 to 0.4 mol, excess) is cooled to 25 C and 70 mg of p-toluenesulphonic acid (monohydrate or anhydrous) dissolved in 1 ml of THF is added with efficient stirring. The dry alcohol (0.20 mol) is then added portionwise over about 15 min, while keeping the temperature between 20 and 15 C (a cooling bath at 70 C is indispensable, since it provides the necessary flexibility in controlling the temperature). After the addition, the mixture is stirred for an additional 15 min at 5 to 0 C. Then an additional 50 mg of p-toluenesulphonic acid is added while watching the temperature attentively. If, without external cooling, no significant rise of the temperature is observed, a solution of 2 g of K2CO3 in 5 ml of water is added with vigorous stirring (for 1 min). The organic layer is dried over K2CO3, 1 ml of diethylamine is added, after which the solution is concentrated under reduced pressure. As a rule, the remaining liquid needs not be distilled because the purity is higher than 95%. Distillation (if desired) is often accompanied by foaming; it is therefore advisable to use a distillation flask of 500 ml. Impure or water-containing alcohols often react sluggishly (no distinct rise of the temperature upon addition of 5 g of the alcohol in one portion to the vinyl ether). It is then tempting to add more acid catalyst, but this may result in a sudden rise of the temperature and development of a brown colour. Purification by distillation is then difficult and yields are considerably lower. Solid alcohols, for example 2-butyne-1,4-diol, HOCH2CCCH2OH, can best be added as a solution in a small amount of Et2O or THF. 20.6.8

3-(t-Butoxy)-1-propyne by acid-catalysed addition of propargyl alcohol to isobutene

410

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

Scale: 1.5 molar; Apparatus: Figure 1.9, 500-ml; the gas inlet and outlet are connected to a cylinder with isobutene and a washing bottle filled with paraffin oil, respectively; all connections are made gas-tight 20.6.8.1

Procedure [24]

Concentrated sulphuric acid (1.5 to 2 ml) is added with efficient stirring to 1.5 mol of propargyl alcohol (freshly distilled under reduced pressure). The alcohol is then warmed to 35 C and isobutene is introduced at a rate such that a weak flow (10 to 20 ml/min) is emitted from the outlet. The temperature of the vigorously agitated reaction mixture is kept between 40 and 45 C (occasional cooling, later occasional warming). The flow of isobutene should be continuously controlled: in the beginning the rate of absorption increases with the temperature due to the higher rate of reaction, when the reaction subsides the rate of absorption decreases. After about 1.5 h (depending inter alia upon the efficiency of stirring) the reaction begins to subside and the temperature to drop. Stirring at 40 to 45 C is then continued for another 1.5 h, while introducing isobutene at a rate of 50 ml/min. The light-brown solution is poured into 500 ml of ice water, containing a sufficient amount of KOH. After vigorous shaking in a small separating funnel, the upper layer is dried over K2CO3 and subsequently distilled. 3-(t-Butoxy)-1-propyne, bp 70 C/90 Torr, is obtained in 70% yield. The compound should be stored under nitrogen in a well-closed bottle at 20 C (cf. note 2 of exp. 20.6.1).

20.6.9

Conversion of acetylenic chlorohydrines into oxiranes

Scale: 0.20 molar; Apparatus: 1-litre round-bottomed flask, equipped with a powder funnel, a mechanical stirrer and a thermometer-outlet combination; after the addition of KOH, the powder funnel is replaced with a stopper

20.6.9.1

Procedure

Freshly distilled chloroacetone (0.20 mol) is added over a few minutes to a solution (or suspension) of 0.20 mol of the lithiated acetylene in 140 ml of

20.6

ETHERS

411

THF and 126 ml of hexane (Chapter 3, exp. 3.9.4) with cooling between 80 and 90 C. Five minutes after the addition the mixture is poured into 300 ml of an aqueous solution of 5 g of NH4Cl. In the cases of lithium alkynylides with slight solubility, stirring is continued at 80 C for an additional 15 min before hydrolysing the mixture. After separation of the layers, extraction of the aqueous layer with Et2O and drying of the organic solutions over MgSO4 the solvent is removed in vacuo and the remaining liquid distilled. The distilled chlorohydrine (0.20 mol) is mixed with 200 ml of Et2O, and 50 g of finely, freshly machine-powdered KOH is added over 30 min with efficient stirring, while maintaining the temperature between 5 and 15 C. After an additional half an hour the mixture is poured into water. The organic layer and the ethereal extract of the aqueous layer are dried over K2CO3, after which the solvent is removed under reduced pressure. In the case of the volatile 2-methyl-2-(1-propynyl)oxirane (bp 50 C/60 Torr), the greater part of the Et2O is distilled off under atmospheric pressure. Yields are mostly excellent.

20.6.10

O-Silylation of acetylenic tertiary alcohols

Scale: 0.10 molar; Apparatus: 500-ml round-bottomed three-necked flask, equipped with a dropping funnel, a mechanical stirrer and a reflux condenser

20.6.10.1

Procedure [25]

In the flask are placed 0.10 mol of 1-ethynylcyclohexanol, 120 ml of dry Et2O, 0.11 mol of dry triethylamine and 5 ml of DMSO (or 3 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene). Freshly distilled chloro(trimethyl)silane (0.12 mol, mixed with 20 ml of Et2O) is added over 20 min with vigorous stirring. A thick precipitate is formed. After the spontaneous reflux of the Et2O has subsided, the mixture is heated for 1 h under reflux. Ice water is then added, followed by extraction with Et2O, drying over magnesium sulphate and removal of the solvents under reduced pressure. 1-Ethynylcyclohexyl trimethylsilyl ether, bp 76 C/17 Torr, is obtained in an excellent yield. Other tertiary alcohols can be silylated by a similar procedure.

412 20.6.11

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

O-Methylation of alcohols with methyl iodide and potassium hydroxide

Scale: 0.30 molar; Apparatus: 500-ml round-bottomed, three-necked flask equipped with a powder funnel, a mechanical stirrer and a reflux condenser

20.6.11.1 Procedure A mixture of 0.30 mol of 2-penten-4-yn-1-ol (Chapter 4, exp. 4.5.15), 0.60 mol of methyl iodide and 50 ml of Et2O is warmed to 35 C. Machine-powdered KOH (60 g) is added in 5 portions (with temporary cooling below reflux temperature) over 30 min with vigorous stirring. Immediately after addition of each portion the powder funnel is replaced with a stopper. When the ensuing gentle reflux has ceased, the next portion of KOH is added. After stirring for an additional 1 h (with heating under reflux) ice water is added and two extractions with small portions of Et2O or pentane are carried out. The dried organic solution is concentrated under reduced pressure (bath temperature <25 C) and the remaining liquid distilled to give 1-methoxy-2-penten-3yne, bp 38 C/10 Torr, in a high yield. This experimental procedure can also be applied to O-methylate or -ethylate other primary alcohols. As alkylating reagents alkyl iodides or dialkyl sulphates can be used.

20.7 20.7.1

ACETYLENIC SULPHIDES AND THIOLS

Methyl 2-propynyl sulphide from sodium methanethiolate and propargyl chloride

Scale: 0.50 molar; Apparatus: Figure 1.1, 500 ml

20.7

ACETYLENIC SULPHIDES AND THIOLS

20.7.1.1

413

Procedure [26]

Sodium hydroxide (0.60 mol) is dissolved in 40 ml of water and 150 ml of methanol is added. Methanethiol (0.60 mol) is condensed ( 60 C) in a cold trap and 30 ml of cold (20 C or lower temperature) methanol is added. This cold mixture is added over 15 min to the vigorously stirred solution of sodium hydroxide while keeping the temperature between 0 and 10 C. Subsequently 0.50 mol of propargyl chloride (or bromide) is added dropwise over 20 min while keeping the temperature between 0 and 10 C. Salt separates immediately from the solution. After stirring for an additional half an hour at 15 C, 500 ml of an aqueous solution of 10 g of KOH is added (to prevent stench due to hydrolysis of the excess of sodium methanethiolate). The mixture is extracted ten times with small portions (total amount 500 ml) of high-boiling (bp >170 C/760 Torr) petroleum ether. The combined extracts are washed twice with water and subsequently dried over MgSO4. The solution is brought in a 1-litre round-bottomed flask, which is equipped for a vacuum distillation using an efficient column (Figure 1.10). The apparatus is evacuated using a water aspirator, the receiver being cooled in a bath at 70 C. The flask is heated in a water bath, which is gradually brought at a temperature of 80 C. The evacuation is terminated when the petroleum ether begins to reflux in the top of the column. The contents of the receiver are subjected again to the distillation-condensing procedure, now keeping the temperature of the ‘heating’ bath below 15 C. Methyl 2-propynyl sulphide is collected in 85% yield. Ethyl 2-propynyl sulphide and phenyl propargyl sulphide can be prepared from the corresponding sodium thiolates and propargyl chloride or bromide. In the case of EtSCH2CCH, the reaction conditions are similar to those described above. Pentane is used as extraction solvent. The greater part of the solvent is distilled off at normal pressure through an efficient column, after which the product is distilled at a pressure of 50 to 100 Torr. In the preparation of phenyl 2-propynyl sulphide, PhSCH2CCH, a 10% excess of propargyl halide is used. The product is extracted with a 1:1 mixture of Et2O and pentane. The solvent is removed under reduced pressure and the sulphide distilled at 0.5 to 1 Torr. 20.7.2

1,4-Bis(methylthio)-2-butyne from sodium methanethiolate and 1,4-dichloro-2-butyne

Scale: 0.20 molar; Apparatus: Figure 1.1, 500 ml

414 20.7.2.1

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

Procedure

A solution of 0.45 mol of MeSNa in 40 ml of water and 150 ml of methanol is prepared as described in the preceding experiment. 1,4-Dichlorobutyne (0.20 mol, exp. 20.1.6) is added over 15 min, while keeping the temperature between 0 and 10 C. After an additional period of 30 min, during which the temperature is allowed to rise to rt, the suspension is poured into a solution of 5 g of KOH in 500 ml of water. The product is extracted with a 1:1 mixture of Et2O and pentane, the extracts are washed with water, dried over MgSO4 and subsequently concentrated under reduced pressure. 1,4-Bis(methylthio)-2butyne, bp 116 C/14 Torr, is obtained in 80% yield. 20.7.3

(Z )-1-Ethylthio-1-buten-3-yne from ethanethiol and butadiyne

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre 20.7.3.1

Procedure

Ethanethiol (0.20 mol, freshly distilled) is added over 10 min to a solution of 0.20 mol of butadiynylsodium (Chapter 3, exp. 3.9.26) in 300 ml of liquid ammonia with cooling at 40 C. After an additional 10 min the thermometer is replaced with a powder funnel and 15 g of powdered ammonium chloride is added in small portions over 15 min. After this addition the cooling bath is removed. After standing for 2–3 h 150 ml of Et2O and 150 g of finely crushed ice are successively added with stirring. After separation of the layers, three extractions with Et2O are carried out. The organic solution is dried over magnesium sulphate and subsequently concentrated under reduced pressure. (Z)-1Ethylthio-1-buten-3-yne, bp 64 C/12 Torr, is obtained in an excellent yield. 20.7.4

1,1-Bis(ethylthio)-2-butyne by zinc chloride-catalysed substitution of the ethoxy groups in the corresponding acetal by ethylthio groups

Scale: 0.10 molar; Apparatus: 250 ml two-necked round-bottomed flask equipped with a mechanical stirrer and a reflux condenser

20.7

ACETYLENIC SULPHIDES AND THIOLS

20.7.4.1

415

Procedure

In the flask are placed 0.10 mol of 1,1-diethoxy-2-butyne (Chapter 4, exp. 4.5.23) and 8 g of anhydrous zinc chloride. Freshly distilled ethanethiol (0.30 mol, large excess) is added in 5 portions over 20 min through the reflux condenser. After this addition a second portion of 8 g of zinc chloride is added and the mixture is heated for 30 min in a bath at 45 C. It is then poured into 100 ml 3 N hydrochloric acid. After vigorous shaking and separation of the layers one extraction with Et2O is carried out. The organic solution is dried over magnesium sulphate and subsequently concentrated under reduced pressure. In order to absorb the ethanethiol, a tube filled with KOH pellets and a trap cooled at 70 C are placed between the water aspirator and the flask containing the ethereal solution (Note). 1,1-Bis(ethylthio)-2-butyne, bp 80 C/0.6 Torr, is obtained in 80% yield. Note Attempts to remove the excess of ethanethiol by shaking the ethereal extract with a KOH solution are likely to result in isomerisation to 1,1-bis (methylthio)-1,2-butadiene, MeCH¼C¼C(SEt)2. 20.7.5

2-Propyne-1-thiol from propargyl bromide and potassium hydrosulphide

Scale: 0.30 molar; Apparatus: Figure 1.9, 500 ml; long inlet tube; after introduction of hydrogen sulphide the reaction is carried out under inert gas.

20.7.5.1

Procedure

Hydrogen sulphide is introduced into a vigorously stirred solution of 60 g of KOH in 60 ml of water. The temperature, initially between 0 and 10 C, is gradually lowered to 30 C. After complete dissolution of the suspended dipotassium sulphide at this temperature (formation of potassium hydrogen sulphide) propargyl bromide (0.30 mol) and 200 mg of a radical inhibitor are added and introduction of inert gas (200 ml/min) is started. After very vigorous stirring during 1.5–2 h at 2 to þ2 C, 50 ml of water (saturated with inert gas) is added. The layers are separated as completely as possible. A radical inhibitor (200 mg) is added to the upper layer and the liquid is transferred into a 200 ml round-bottomed flask filled with inert gas and

416

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

containing a few grams of magnesium sulphate. The flask is equipped for a vacuum distillation (Figure 1.10), the receiver being cooled in a bath at 70 C. The system is evacuated (10–20 Torr) and the flask warmed in a bath gradually heated to 70–80 C. Almost pure 2-propyne-1-thiol is collected in the receiver. The yield is between 40 and 50%. A considerable residue of di(2-propynyl) sulphide is left behind. Some polymerisation takes place during storage at 20 C, even in the presence of a radical inhibitor. 2-Butyne-1-thiol, MeCCCH2SH, is obtained in >70% yield by a similar procedure. The mixture of KSH, water and 1-bromo-2-butyne, MeCCCH2Br, is stirred for 3 h at 35 C. There is a small residue of di(2-butynyl) sulphide.

20.7.6

2-(Propargylthio)thiophene from in situ prepared lithium mercaptothiophene and propargyl bromide

Scale: 0.10 molar; Apparatus: Figure 1.1, without dropping funnel, addition by syringe. 20.7.6.1

Procedure

Thiophene (0.13 mol) is added in one portion to a solution of 0.10 mol of BuLi in 63 ml of hexane and 70 ml of THF cooled at 10 C, after which the cooling bath is removed. After stirring for an additional 15 min at rt, the solution is cooled to 35 C and 3.2 g (0.10 mol) of powdered sulphur is added in a few seconds. The mixture is stirred for an additional 30 min at 20 C, then 20 ml of methanol (Note 1) is added followed by 0.12 mol of propargyl bromide. After having allowed the temperature rising to between 0 and rt, the reaction mixture is heated for 30 min at 40 C. Ice water (200 ml is added and two extractions with Et2O are carried out. The organic solution is washed with water and then dried over magnesium sulphate. The liquid remaining after removal of the solvents under reduced pressure is distilled in a high vacuum, keeping the temperature of the heating bath below 90 C (Note 2). 2-Thienyl propargyl sulphide, bp 50 C/0.5 Torr, is obtained in an excellent yield. The reaction with selenium gave the analogous 2-thienyl propargyl selenide, but with tellurium the allenyl telluride H2C¼C¼CHTe-2-Thienyl was the only product [47]. This compound is not the result of a base-catalysed isomerisation, but is formed directly in a 1,3-substitution of bromine.

ACETYLENIC AND ALLENIC SULPHOXIDES . . .

20.8

417

Notes 1.

2.

The desired product easily isomerises to the allenic sulphide under the catalytic influence of the thiophenethiolate. This is solvated by methanol making it less active as a catalyst. At temperatures higher than 100 C a 3,3-sigmatropic rearrangements sets in, ultimately resulting in the formation of 2H-thieno[2,3-b]thiopyran [41].

20.8

20.8.1

ACETYLENIC AND ALLENIC SULPHOXIDES, SULPHONES, SULPHINAMIDES AND SULPHONAMIDES Conversion of 1-ethylthio-1-propyne into the sulphoxide

Scale: 0.05 molar; Apparatus: Figure 1.1, 250 ml, the dropping funnel is omitted. 20.8.1.1

Procedure [27]

Sodium periodate (0.07 mol) is dissolved in 60 ml of water and a mixure of 0.05 mol of 1-ethylthio-1-propyne (Chapter 17, exp. 17.2.14) and 15 ml of MeOH (Note) is added. The solution is agitated vigorously, while keeping the temperature between 40 and 45 C (initially rt). After one hour the white suspension is cooled to rt and 100 ml of water is added. The solution is extracted seven times with chloroform and the combined extracts are dried (without washing) over MgSO4. Concentration under reduced pressure (the last traces of CHCl3 are removed at <0.1 Torr) gives pure ethyl 1-propynyl sulphoxide, in almost quantitative yield. Note In the cases of the higher homologues, more methanol should be used or the reaction should be carried out at a higher temperature. 20.8.2

Conversion of 1-ethylthio-1-propyne into the sulphone

Scale: 0.10 molar; Apparatus: Figure 1.1, 500 ml

418

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

Warning: Contact of the skin with 33% H2O2 gives very painful white spots. Rubber gloves should be worn and the face should be protected.

20.8.2.1

Procedure (cf. [28])

A mixture of 0.10 mol of 1-ethylthio-1-propyne (Chapter 17, exp. 17.2.14) and 100 ml of glacial acetic acid is heated to 95 C, then 36 ml of 33% hydrogen peroxide is added over 15 min, while keeping the temperature between 95 and 100 C. After an additional 1 h the solution is cooled to rt. Water (200 ml) is added and the solution is extracted ten times with small portions of chloroform. The combined extracts are dried (without washing) over MgSO4 and subsequently concentrated under reduced pressure (see preceding exp.). Ethyl 1-propynyl sulphone is obtained in an excellent yield. Di(1-propynyl) sulphone, (MeCC)2SO2 (mp 103–104.5 C after crystallisation from a Et2O–pentane mixture), is prepared in a similar way from di(1-propynyl) sulphide with a yield of 75%.

20.8.3

Conversion of 1-methylthiopropadiene into methyl propadienyl sulphoxide

Scale: 0.10 molar; Apparatus: Figure 1.1, 250 ml (without dropping tunnel) 20.8.3.1

Procedure

A mixture of 100 ml of water and 0.10 mol of methylthiopropadiene (Chapter 3, exp. 3.9.39) is placed in the flask and 24 g of sodium periodate is added in five portions at intervals of 4 min. The mixture is agitated vigorously and the temperature is kept between 25 and 30 C by occasional cooling. After 1 h twenty extractions with 10-ml portions of chloroform are carried out. The combined extracts are dried (without preceding washing) over magnesium sulphate. Removal of the chloroform by evaporation under reduced pressure gives the reasonably pure (>95%) methyl propadienyl sulphoxide in more than 90% yield.

20.8

ACETYLENIC AND ALLENIC SULPHOXIDES . . .

20.8.4

419

Conversion of 1-methylthio-1,2-pentadiene into methyl 1,2-pentadienyl sulphoxide

Scale: 0.15 molar; Apparatus: Figure 1.1, 250 ml, without dropping funnel 20.8.4.1

Procedure

A mixture of 0.15 mol of 1-methylthio-1,2-pentadiene (Chapter 3, exp. 3.9.39), 100 ml of water, 40 ml of methanol (Note) and 0.18 mol of NaIO4 is vigorously stirred. The temperature rises gradually, but is kept between 30 and 35 C by occasional cooling. After 1.5 h 500 ml of water is added to the white suspension and ten extractions with 30-ml portions of chloroform are carried out. The extracts are dried (without preceding washing) over magnesium sulphate. Evaporation of the solvent under reduced pressure (the last traces at 0.5–1 Torr) gives methyl 1,2-pentadienyl sulphoxide as a viscous oil in almost quantitative yield (purity 96%). The compound solidifies during storage in a refrigerator. Note This co-solvent is used in order to increase the solubility of the allenic sulphide.

20.8.5

Conversion of methyl propadienyl sulphoxide into methyl propadienyl sulphone

Scale: 0.05 molar; Apparatus: 250-ml flask with a thermometer and a reflux condenser

20.8.5.1

Procedure

A mixture of 100 ml of glacial acetic acid, 15 ml of 30% hydrogen peroxide and 0.05 mol of allenyl methyl sulphoxide (exp. 3) is heated for 30 min at 100 C. The colourless solution is cooled to rt and poured into 300 ml of ice water. The sulphone is isolated by extracting the solution twelve times with 20-ml portions of chloroform, drying the combined extracts over NaHCO3 and thoroughly

420

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

removing the solvent under reduced pressure. The residue is practically pure sulphone, yield 80%. The product solidifies during storage for a few days at rt. 20.8.6

Oxidation of 1-alkyne-1-sulphinamides with 3-chlorobenzenecarboperoxoic acid

Scale: 0.03 molar 20.8.6.1

Procedure [29]

3-Chlorobenzenecarboperoxoic acid (0.10 mol, large excess) is added portionwise to an ice-cold solution of N-phenyl-1-hexyne-1-sulphinamide(R ¼ n-Bu) in 70 ml of chloroform. After standing overnight at rt, the thick precipitate of m-chlorobenzoic acid is filtered off. The clear orange solution is washed with aqueous sodium bicarbonate. After drying over potassium carbonate, the solvent is removed under reduced pressure. The crude N-phenyl-1hexyne-1-sulphonamide- is purified by chromatography (SiO2) to give a pale yellow oil in 70% yield. 20.9

20.9.1

DIMETALLATED ACETYLENIC COMPOUNDS AND THEIR FUNCTIONALISATION Preparation of dilithiated 2-methyl-1-buten-3-yne and its regioselective functionalisation with c-hexyl bromide and oxirane

Scale: 0.10 molar; Apparatus: Figure 1.1, 1 litre

20.9

DIMETALLATED ACETYLENIC COMPOUNDS

421

Treatment of 2-methyl-1-buten-3-yne with an excess of BuLi or BuLi TMEDA does not give rise to double deprotonation, but to a slow addition with formation of an adduct. With the super basic reagent BuLit-BuOK in a mixture of THF and hexane, dimetallation can be accomplished in a short time at low temperatures [30,31]. The high efficiency of the dimetallation appears from the excellent yield (>90%) of trimethyl[3-(trimethylsilyl)methyl]-3-buten-1-ynyl]silane, Me3SiCCC(CH2SiMe3)¼CH2, obtained by quenching with Me3SiCl. Addition of anhydrous lithium bromide converts the dipotassium compound into the dilithio derivative, which can be used for regiospecific functionalisations.

20.9.1.1

Procedure

A solution of 0.10 mol of freshly distilled 2-methyl-1-buten-3-yne (Chapter 19, exp. 19.1.1) in 60 ml of THF is cooled to 80 C (occasional cooling in a bath with liquid N2). Solutions of 0.22 mol of BuLi in 140 ml of hexane and 0.22 mol of t-BuOK in 60 ml of THF, are successively added over 20 min with cooling between 75 and 85 C. A yellow suspension is formed. After stirring for an additional 30 min at 70 C, the cooling bath is removed and the temperature allowed rising to þ5 C. After an additional 10 min at 5 C (Note), a solution of 0.22 mol of anhydrous LiBr in 60 ml of THF is added at 20 C with vigorous stirring. The colour of the suspension changes into light yellow.

Note The 0.02 mol excess of BuLit-BuOK is destroyed by reaction with THF to give ethene and H2C¼CHOK. The reaction of dilithiated 2-methyl-1-buten-3-yne with cyclohexyl bromide is an exceptional case of a successful alkylation with a cyclohexyl halide. In reactions with most nucleophilic species, dehydrohalogenation is the main process. Although the reaction conditions for the cyclohexylation are similar to those of other alkylation reactions, the mechanism might differ from the usual SN2 mechanism in that a single electron transfer (S.E.T.) is involved. It is not possible to predict whether the reaction of a particular nucleophilic species with cyclohexyl halide in an organic solvent or in liquid ammonia will give a good yield of the cyclohexyl derivative or result in dehydrohalogenation of the cycloalkyl halide. Reaction with acetylides, RCC, and sp2-nucleophiles, C¼C (vinylic, aromatic or hetero-aromatic ‘anions’) only give rise to elimination of hydrogen halide.

422

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

It is shown in Chapter 4 that lithium acetylides do not react at rt with oxirane in a THF–hexane mixture. In contrast, the allylic site in dilithiated 2-methyl-1-buten-3-yne is smoothly hydroxyethylated at temperatures in the region of 50 C. 20.9.1.2

Procedure [40]

Cyclohexyl bromide (0.10 mol) or a mixture of 0.13 mol of oxirane and 30 ml of THF is added dropwise over 15 min to the suspension of 0.10 mol of dilithiated 2-methyl-1-buten-3-yne with cooling between 40 and 50 C. After an additional 15 min the cooling bath is removed and the temperature is allowed to rise to 10 C. Ice water (200 ml) is then added with vigorous stirring and the layers are separated. The aqueous layer is extracted four and eight times respectively, with Et2O. The organic solutions are dried (without washing) over MgSO4 and subsequently concentrated in vacuo. Careful distillation of the remaining liquid through a 30-cm Vigreux column gives: 1-(2methylene-3-butynyl)cyclohexane, HCCC(CH2-c-C6H11)¼CH2, bp 70 C/ 10 Torr, in 70% yield, and 4-methylene-5-hexyn-1-ol, HCCC(CH2CH2 CH2OH)¼CH2, bp 71 C/10 Torr, in 90% yield.

20.9.2

Dilithiation of phenylacetylene and subsequent regioselective formylation

Scale: 0.10 molar; Apparatus: Figure 1.1, 1 litre Abstraction of a proton remote from the ethynyl group is possible if this proton is sufficiently activated. Examples are the dimetallations of phenylacetylene [32–34], 1-naphthylacetylene [35], 1-ethynylpyrrole [36] and isopropenylacetylene [37,38]. Regioselective functionalisations at the most strongly

20.10

COPPER(I) BROMIDE-CATALYSED FORMATION

423

basic centre with a number of electrophiles have been successfully carried out. Lithiated acetylenes react very slowly at 70 C with DMF. However, lithiated arene and hetarene derivatives in most cases add very quickly to DMF at these low temperatures [39]. A difference in basicity may explain the specific reaction of the ortho-aryl negative centre in dilithiated phenylacetylene with DMF.

20.9.2.1

Procedure

THF (100 ml) is added to a solution of 0.22 mol of butyllithium in 140 ml of hexane, cooled to 50 C. Phenylacetylene (0.10 mol) is added over 10 min to the solution, while keeping the temperature below 20 C. The solution is then cooled to 65 C and a solution of 0.12 mol of potassium tert-butoxide in 100 ml of THF is added dropwise over 30 min, while maintaining the temperature of the red suspension between 60 and 65 C. After completion of the addition, the cooling bath is removed and the temperature is allowed to rise to 0 C. A solution of 0.13 mol of anhydrous lithium bromide in 40 ml of THF is then added over a few seconds with vigorous stirring. The colour changes to pink. The mixture is cooled to 90 C and DMF (0.15 mol, excess) is added over 5 min. The mixture is stirred for an additional 10 min at 65 C, after which the light-yellow to nearly white suspension is cautiously poured into a vigorously stirred mixture of 1 litre of ice water and 40 ml of 36% aqueous HCl. After standing for 15 min, the layers are separated and four extractions with pentane are carried out. The combined organic solutions are washed with a saturated solution of NH4Cl and subsequently dried over MgSO4. The light yellow liquid remaining after removal of the solvent under reduced pressure is distilled through a 20-cm Vigreux column at oil-pump pressure (1 Torr or less). The use of an air condenser is recommended. The solid distillate is crystallised from a 4:1 mixture of pentane and Et2O to give 2-ethynyl benzaldehyde, mp 67 C, in 55% yield.

20.10

COPPER(I) BROMIDE-CATALYSED FORMATION OF 2-PROPARGYLHETARENES

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre

424

20.

TRANSFORMATION OF FUNCTIONAL GROUPS

20.10.1.1 Procedure [42] A solution of 0.20 mol of 2-thienyllithium in 140 ml of THF and 126 ml of hexane is prepared from thiophene and BuLi as described [19]. Magnesium bromide etherate (0.25 mol, Chapter 2, exp. 2.3.10) is added at rt. A solution of 2 g of copper(I) bromide and 4 g of anhydrous lithium bromide in 15 ml of THF is added at 0 C, after which the mixture is cooled to 80 to 90 C. Propargyl bromide (0.25 mol ) is added dropwise over 15 min at 90 C, then the cooling bath is removed and the temperature of the suspension is allowed rising to 0 C. A solution of 20 g of ammonium chloride in 100 ml of water is cautiously added with vigorous stirring and cooling in an ice-water bath. The aqueous layer is extracted once with pentane. After drying over magnesium sulphate, the solvents are removed under reduced pressure (temperature of the water bath not higher than 35 C). Distillation of the remaining liquid gives 2-(2-propynyl)thiophene, bp 60 C/12 Torr, in 75% yield. The product contains a few percent of the allenic isomer. The analogous 2-furyl- and 1-methyl-2-pyrrolyl derivatives are prepared by similar procedures. In the case of the furyl compound, the greater part of the solvents is distilled off under atmospheric pressure prior to the vacuum distillation. In both cases a small contamination of the allenic isomers is present. The required Grignard compounds can be prepared via the lithium derivatives [19] as described above. Under similar conditions alkylmagnesium halides give practically pure allenic derivatives, while in reactions with arylmagnesium halides comparable amounts of acetylenic and allenic substitution product are obtained [42]. As mentioned in Chapter 4, the Cu(I)-catalysed reaction between acetylenic Grignard compounds and propargyl bromide or tosylate gives predominantly acetylenic coupling products.

REFERENCES 1. M. Gaudemar, Ann. Chim. (Paris), 151, (1956). 2. G. Eglinton, J. B. Armitage and M. C. Whiting, J. Chem. Soc., 3650 (1950); 2005 (1952). 3. I. M. Heilbron, E. R. H. Jones, R. N. Lacey, J. Y. McCombie and R. A. Raphael, J. Chem. Soc., 77 (1945). 4. G. F. Hennion and A. P. Boisselle, J. Org. Chem. 26, 725 (1961). 5. J. H. Biel and F. diPierro, J. Am. Chem. Soc. 80, 4609 (1958). 6. H. D.Verkruijsse, L. J. de Noten, H. J. T. Bos and L. Brandsma, Recl. Trav. Chim. Pays-Bas 100, 244 (1981). 7. I. Marszak and M. Koulkes, in Bull. Soc. Chim. France, 93 (1956). 8. G. F. Hennion and E. G. Teach, J. Am. Chem. Soc. 75, 1653, 4297 (1953). 9. L. Brandsma, O. A. Tarasova, N. A. Kalimina, A. I. Albanov, L. V. Klyba and B. A. Trofimov, Zh. Org. Khim. 38, 1115 (2002).

REFERENCES 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48.

425

J. C. Sauer, Org. Synth., Coll. Vol. IV, 813 (1963). J. le Gras, Compt. Rend. Acad. Sc. (Paris) 263, 1460 (1966). G. Saucy, M. Marbet, H. Lindlar and O. Isler, Helv. Chim. Acta 42, 1945 (1959). J. Meijer, P. Vermeer, H. J. T. Bos and L. Brandsma, Recl. Trav. Chim., Pays-Bas 92, 1067 (1973). G. Tadema, R. H. Everhardus, H. Westmijze and P. Vermeer, Tetrahedron Lett., 3935 (1978); H. Westmijze and P. Vermeer, Synthesis, 390 (1979). C. S. Marvel and V. C. Sekera, Org. Synth., Coll. Vol. 3, 366 (1955). I. B. Douglass and R. V. Norton, J. Org. Chem. 33, 2104 (1968). W. Reppe et al., Liebigs Ann. Chem. 596, (1955). G. F. Hennion and F. P. Kupiecki, J. Org. Chem. 18, 1601 (1953). L. Brandsma and H. D. Verkruijsse, Preparative Polar Organometallic Chemistry. SpringerVerlag, 1987, Vol. 1, p. 111. P. E. van Rijn, S. Mommers, R. G. Visser, H. D. Vekruijsse and L. Brandsma, Synthesis, 459 (1981). D. N. Robertson, J. Org. Chem. 25, 931 (1960). C. B. Reese, in Protecting Groups in Organic Chemistry (ed. J. F. Omiie). Plenum Press, 1973, p. 104. B. P. Gusev and V. F. Kucherov, Izvest. Akad. Nauk, Otd. Khim., 1062, (1962); Chem. Abstr. 57, 16383 (1962). R. Mantione, Bull. Soc. Chim. France, 4523 (1969). R. G. Visser, H. J. T. Bos and L. Brandsma, Recl. Trav. Chim., Pays-Bas 99, 70 (1980). G. Pourcelot and P. Cadiot, Bull. Soc. Chim. France, 3016, 3025 (1966). N. J. Leonard and C. R. Johnson, J. Org. Chem. 27, 282 (1962). W. E. Truce, H. E. Hill and M. M. Boudakian, J. Am. Chem. Soc. 78, 2760 (1956). H. A. Selling and H. J. Mak, Synth. Commun. 6, 129 (1976). W. Kulik, H. D. Verkruijsse, R. L. P. de Jong, H. Hommes and L. Brandsma, Tetrahedron Lett., 203 (1983). P. A. A. Klusener, W. Kulik, H. D. Verkruijsse and L. Brandsma, J. Org. Chem. 52, 5261 (1987). H. Hommes, H. D. Verkruijsse and L. Brandsma, J. Chem. Soc., Chem. Comm., 366 (1981). H. Hommes, H. D. Verkruijsse and L. Brandsma, Tetrahedron Lett. 22, 2495 (1981). H. Hommes, H. D. Verkruijsse, R. L. P. de Jong and L. Brandsma, Recl. Trav. Chim. PaysBas, 104, 226 (1985). J. C. Hanekamp, P. A. A. Klusener and L. Brandsma, Synth. Commun. 19, 2691 (1989). A. G. Mal’kina, O. A. Tarasova, H. D. Verkruijsse, A. C. H. T. M. van der Kerk, L. Brandsma and B. A. Trofimov. Recl. Trav. Chim. Pays-Bas 114, 18–21 (1995). W. Kulik, H. D. Verkruijsse and R. L. P. de Jong, Tetrahedron Lett. 24, 2203 (1983). P. A. A. Klusener, W. Kulik and L. Brandsma, J. Org. Chem. 52, 5261 (1987). Chapters 5 and 6 in Ref. 19. P. A. A. Klusener, W. Kulik and L. Brandsma, J. Org. Chem. 52, 5261 (1987). L. Brandsma and D. Schuijl-Laros, Recl. Trav. Chim. Pays Bas 89, 110 (1970). Unpublished results from the author’s laboratory. C. Gloset and R. Coupe, Bull. Soc. Chim. France, 2464 (1963). A. Marszak-Fleury, Ann. Chim., Paris 13, 656 (1958). K. Bowden, I. M. Heilbron, E. R. H. Jones and B. C. L. Weedon, J. Chem. Soc., 39 (1946). V. Wolf, Chem. Ber. 86, 735 (1953). L. Brandsma, E. H. Mørkved, O. Bjørlo, V. A. Potapov and S. V. Amosova, Sulphur Lett. 23, 215 (2000). I. V. Suvorova, M. D. Stadnichuk and K. S. Mingaleva, Zh. Org. Khim., 817 (1983); cf. A. I. Borisova, M. M. Demina, A. S. Medvedeva, I. D. Kalihman and N. S. Vyzankin, Zh. Org. Khim., 1310 (1983).

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Appendix A: 1H- and 13C-NMR Chemical Shifts of Acetylenic, Allenic and Cumulenic Compounds

NMR data of acetylenic compounds* Acetylenic Compound HCCH HCCAlkyl HCCNEt2 1-(HCC)-2-Bu-pyrrole 1-(HCC)-2-formylpyrrole HCCOMe HCCF HCCSEt HCCSCH¼CH2 HCCC(¼O)H HCCCN HCCCOOEt HCCC(¼O)Me HCCCH2Cl HCCCH2Br HCCCH2NH2 HCCCH2OMe HCCCH2OPh HCCCH2SMe HCCCH2OH HCCCH2SH HCCCH2NMe2 HCCCH¼C(SMe)2 HCCC(Me)¼C(SMe)2 HCCC(SMe)¼C(SMe)2 HCCC(OMe)¼C(SMe)2 HCCC(NMe2)¼C(SMe)2

d (HC)

Solvent

1.89a 1.75a 2.30a 2.97 3.06 1.33a 1.38a 2.64 3.11 3.42a 2.48a 2.75a 3.18a 2.40a 2.53 2.26 2.37 2.01 2.19 2.33 2.08 2.09 3.25 3.34 2.65 3.48 3.33

CCl4 CCl4 CCl4 CDCl3 CDCl3 CCl4 CCl4 CCl4 CCl4 CCl4 CCl4 CCl4 CCl4 CCl4 CDCl3 CDCl3 CCl4 CCl4 CDCl3 CCl4 CCl4 CDCl3 CDCl3 CCl4 CCl4 CCl4 CCl4

d (C1)

d (C2)

Solvent

59.23

73.05

CDCl3

74.97 70.40 74.48

78.83 85.01 79.43

CDCl3 CDCl3 CDCl3

70.93 73.84

79.79 83.14

CDCl3 CDCl3

72.94

75.51

CDCl3

(Continued)

427

428

APPENDIX A NMR data of acetylenic compounds* (Continued)

Acetylenic Compound MeOCH2CCn-C7H15 MeCCSSiMe3 t-BuCCSSiMe3 MeCCSSMe t-BuCCSSMe HCCPh HCC-1-Naphthyl HCC-2-Fluorophenyl HCC-2-Hetaryl HCC-1-pyrrolyl HCCCH2-1-pyrrolyl t-BuCCC(Me)¼CH2 HCCC(Me)¼CH2 (E)-HCCCH¼CH-2-Pyridyl (Z)-HCCCH¼CH-(Het)aryl (E)-HCCCH¼CHNEt2 (Z)-HCCCH¼CHNEt2 (Z)-HCCCH¼CHOMe (E)-HCCCH¼CHOMe EtOCCCH¼CH2 4-Me–C6H4SO3CCMeb t-BuOCCSiMe3c Me2(t-Bu)SiOCCt-Bud MeOCCCH2CMe2OH HCCCCHa HCCCC-Alkyl HCCCC-2-Thienyl HCCCC-Ph HCCCCCCMe Te(CCMe)2 MeTeCCTeMe ICCCH2SiMe3 ICCC5H11

d (HC)

Solvent

3.03 3.43 3.29 3.18–3.20 2.72 2.25

CDCl3 CDCl3 CCl4 CCl4 CDCl3 CDCl3

2.86 3.12 3.37–3.49 2.42 2.53 2.84 2.58

CDCl3 CDCl3 CDCl3 CCl4 CCl4 CCl4 CCl4

1.8 2.10 2.50 2.30 1.87

d (C1)

d (C2)

Solvent

75.58 62.92 62.72 71.94 67.38 77.23

87.09 80.49 93.54 97.24 105.37 83.72

CDCl3 CDCl3 CDCl3 CCl4 CCl4 CDCl3

76.98

82.38

97.4 76.1

80.2 84.7

CDCl3 CDCl3

98.9 129.7 106.55 85.5 93.01

38.5 44.1 39.92 40.3 32.2

CDCl3 CDCl3 CDCl3 CDCl3 CDCl3

CCl4 CCl4 CDCl3 CCl4 CCl4 31.4

109.3 66.41 2.39 92.2 7.5 94.8

CDCl3 CDCl3 CDCl3

*Strikingly high or low d-values are underlined; most of the spectra have been recorded from compounds prepared in the author’s laboratory. a J. Dale in Chemistry of Acetylenes, H. G. Viehe (ed.), Marcel Dekker, New York, 1969. b P. J. Stang, B. W. Surber, J. Am. Chem. Soc. 107, 1452 (1985). c E. Valenti, M. A. Perica˜s, J. Org. Chem. 55, 395 (1990). d P. J. Stang, K. A. Roberts, J. Am. Chem. Soc. 108, 7125 (1986).

APPENDIX A

429 NMR data of allenic compounds*

Allenic compound H2C¼C¼CH2 H2C¼C¼CHCCH H2C¼C¼CMe2 H2C¼C¼CHPh H2C¼C¼CHOMe H2C¼C¼CHOPh H2C¼C¼CHCH2OMe H2C¼C¼C(OMe)[CH(Me)OEt] EtOCH¼C¼CHOEt H2C¼C¼C(OMe)SMe H2C¼C¼CHSMe H2C¼C¼CHNMe2 H2C¼C¼CH-1-pyrrol H2C¼C¼CHF H2C¼C¼CHCl H2C¼C¼CHBr H2C¼C¼CHI H2C¼C¼CHCOOR (R ¼ CH(Me)OEt H2C¼C¼CHCOOH Me2C¼C¼CHC(¼O)TMS MeCH¼C¼CHCH2CN MeCH¼C¼CHCN H2C¼C¼CHCN H2C¼C¼CHNC H2C¼C¼CHCH2PPh2 1

d (H1)

d (H3)

4.49 5.43

6.71

6.80 (CCl4) 5.35 (CCl4) 5.11 5.80 5.16 5.95 5.40 6.77

5.24

5.62

5.28

5.64 5.60

4.80

5.36

d (C1)

d (C2)

d (C3)

74.8 77.3 72.1 78.8 91.07 88.9 75.2 90.6

213.5 217.7 207.3 210.0 201.40 203.1 209.8 198.9

74.8 74.8 93.4 94.4 123.05 117.9 88.3 135.7

90.7 81.3 84.9

193.6 206.1 203.1

133.0 90.0 111.9

93.9 84.5 83.8 78.3

200.2 207.9 207.6 208.0

129.8 88.8 72.7 35.3

80.0 99.3 89.7 92.1 80.7 86.1

217.7 213.2 205.8 215.9 218.7 210.1

88.1 100.2 82.2 67.0 67.4 86.1

*For most of the H-NMR spectra CDCl3 was used as a solvent. The shifts of protons directly attached to the allenic carbon atoms are found between 5.0 and 6.8 ppm. By far most of the 13C-NMR spectra have been recorded from neat samples. The solvent effects are generally less than 1 ppm. The chemical shifts (relative to TMS) of the central carbon atom of the allenic system are between 190 and 210 ppm, of the exterior carbon atoms between 80 and 120 ppm for most derivatives. Strikingly high or low d-values are underlined. NMR data for more than 200 allenic compounds have been published by R. A. H. M. Janssen, R. J. J. Ch. Lousberg, M. J. A. de Bie in Recl. Trav. Chim. 100, 85 (1981).

430

APPENDIX A NMR data of butatriene derivatives

Cumulenic compound H2C¼C¼C¼CH2 H2C¼C¼C¼CHMe H2C¼C¼C¼C(Me)(Et) Me2C¼C¼C¼CMe2 H2C¼C¼C¼CHOMe H2C¼C¼C¼CHSMe EtOCH¼C¼C¼CHOEt H2C¼C¼C¼C(Me)OMe H2C¼C¼C¼C(TMS)OMe Me2C¼C¼C¼CHOMe Me2C¼C¼C¼C(TMS)OMe Me2C¼C¼C¼C(SnMe3)OMe H2C¼C¼C¼CHNMe2 Me2C¼C¼C¼CHNMe2 Me2C¼C¼C¼C(TMS)NMe2 a

d (H1) 5.06 4.8

d (H4)

d (C1)

d (C2)

d (C3)

d (C4)

5.33 5.6

95.8

170.3

170.3

95.8

107.4 76.4

153.0 167.4

153.0 136.3

107.4 129.2

73.2 77.8 99.4 100.8 99.7 67.3 93.2 96.1

165.5 169.9 160.1 160.6 160.6 162.2 156.6 157.5

138.8 140.3c 137.2 142.6c 144.9 127.6 133.0 129.4

132.0 141.9c 124.5 141.6c 140.6 122.8d 116.7d 141.8d

4.70 6.75 4.93 6.25 6.18 and 6.43b 4.42 6.45

3.90

6.18 5.79

Compounds prepared in the author’s laboratory; CDCl3 was used as a solvent, for the H-NMR spectra of the hydrocarbons, CCl4 was used. b Assumed to be E and Z isomers. c These values possibly have to be interchanged. d Solvent C6D6. 1

Appendix B: Class–Compound–Method Index

INSTRUCTIONS FOR SEARCHING A limited number of simple and in the opinion of the author (potentially) useful compounds are tabulated in the List of Selected Compounds. The Class–Compound–Method Index includes all compounds and methods in this Book. The compounds, exemplifying the various synthetic methods, are arranged according to classes, in alphabetical order. If many compounds are listed in a group, the arrangement is indicated. For each class of compounds, the method of preparation is indicated in the second column. General methods (indicated with general structures containing the symbol R or by ‘‘illustrates general method’’ in the first column) as well as specific reactions are tabulated. If relevant, the crucial operations in a procedure are separated by a semicolon. The classes of compounds listed as follows: CLASS OF COMPOUND Acetals Acid Halides Alcohols Aldehydes Amines Carboxamides and Sulphur Analogues Carboxylic Acids Epoxides (Oxiranes) Esters (Sulphinates, Sulphonates, Acetates, Acetylenic Carboxylates) Ethers

431

432

APPENDIX B

Halogen Compounds Heteroaromatic Compounds Hydrocarbons Ketones Nitriles and Nitroalkynes Selenides and Tellurides Silicon, Tin and Phosphorus Compounds Sulphides Sulphur Compounds (miscellaneous) Thiols LIST OF SELECTED COMPOUNDS Compound

Chap. Sect. Exp.

Compound

Chap. Sect. Exp.

HCCMe HCCEt HCCBu HCC–t-Bu MeCCMe HCCCH2CCH HCCCH2CH2CCH HCCCH¼CH2 HCCC(Me)¼CH2 HCC-1-Cyclohexenyl HCCCCH HCCCCMe HCCPh HCC-2-Furyl HCC-2-Thienyl HCC-2-Pyridyl HCCOEt HCCCH2OMe HCCCH2OCH(Me)OEt HCCC(OMe)¼CH2 HCCCH¼C(Me)OEt H2C¼C¼CHOMe HCCCH(OEt)2 HCC(CH2)2OH

10.2.3 10.2.3 4.5.8 10.2.1, 4 17.2.1 4.5.32 3.9.24 10.2.6 19.1.1 19.1.2 10.2.7 4.5.2 10.2.2 16.7.16 16.7.16 3.9.21 3.9.28 20.6.1 20.7.7 19.1.5 19.1.6 17.2.8 3.9.21 4.5.16

HCC(CH2)4OH HCC(CH2)9OH HCCCH2NH2 HCCCH2NEt2 MeCCNEt2 Me2NCCNMe2 H2C¼CHCCNMe2 HCCC(¼O)Me HCCSiMe3 MeCCSiMe3 HCCCH2Br ClCH2CCCH2Cl Me3SiCCCH2Br MeCCBr PhCCBr HCCCOOH MeCCCOOH MeCCCOOMe MeCCCN PhCCCN H2C¼C¼CHCOOH H2C¼C¼CHS(¼O)Me H2C¼C¼CHSO2Me Cyclooctyne

4.5.33 3.9.43 20.2.1 20.2.2 17.2.3 10.2.11 10.2.13 20.4.2 7.2.1 7.2.2 20.1.1 20.1.6 7.2.4 9.2.4 9.2.3 20.4.4 6.4.1 6.4.2 20.3.1 20.3.1 6.4.13 20.8.3 20.8.4 10.2.9

APPENDIX B

433

CLASS Compound

Method

Chap. Sect. Exp.

ACETALS HCCCH(OR)2 (R ¼ Me, Et) RCCCH(OEt)2 (general method) MeSCCCH(OMe)2 [(EtO)2CHCC]2 EtCCCCCH(OEt)2

BrCH2CH(Br)CH(OR)2 þ 3 NaNH2, liq. NH3; H2O RCCMgBr þ HC(OEt)3, Et2O

3.9.21

LiCCCH(OMe)2 þ MeSCN, THF HCCCH(OEt)2 þ O2, DMF, TMEDA–CuCl (catal.) HCCCH(OEt)2 þ BrCCEt, EtNH2, H2O, MeOH, CuBr (catal.) RCCCCCH(OEt)2 þ Zn, EtOH

8.2.3 15.2.3

(Z)-RCCCH¼CHCH(OEt)2 (R ¼ Alkyl) RCCCH2CH(OEt)2 RCH2CCCH(OEt)2, t-BuOK, DMSO

4.5.23

14.2.2, Table 19.3.4 17.2.16

ACID HALIDES EtCCC(¼O)Cl EtCCCOOH þ SOCl2 (illustrates general method)

6.4.8

ACIDS, ACID AMIDES (see carboxylic acids, carboxamides) ALCOHOLS Orders: Alcohols with HCC > non-terminal CC Compounds with non-conj. CC > conj. CC > (Het)aryl–CC > C¼C¼C Compounds with system CC–C¼C > C¼C–CC > CC–CC > (Het)aryl–CC Compounds with system CCCOH > CCC2OH > CCC3OH, etc. For systems CCCC see also Tables 16-1a, b, c in Chapter 16. Some compounds are present under headings of other functionalities. a. Primary HCC(CH2)2OH HCC(CH2)3OH HCC(CH2)4OH HCC(CH2)9OH

HCCLi þ oxirane, liq. NH3; H2O tetrahydrofurfuryl chloride þ 3 NaNH2, liq. NH3; H2O HCCLi þ Br(CH2)4OR, liq. NH3; deprotection (R ¼ CH(Me)OEt) C8H17CCCH2OH þ KNH(CH2)3NH2, H2N(CH2)2NH2; H2O

4.5.16 3.9.27 4.5.33 3.9.43

(Continued)

434

Compound RCCCH2OH (general method) RCC(CH2)2OH (R ¼ alkyl) RCC(CH2)4OH (R ¼ alkyl) MeCC(CH2)8OH MeSCCCH2OH MeSCC(CH2)2OH Me3SiCCCH2OH RCCCCCH2OH (R ¼ alkyl, aryl) EtCCCC(CH2)nOH (n ¼ 1, 2, 4, 7, 9) (HOCH2CC)2

[HO(CH2)2CC]2 [HO(CH2)4CC]2 p-NO2–C6H4–CCCH2OH PhCC(CH2)2OH Thienyl-2-CCCH2OH (Z)-EtCCCH2CH¼ CH–CH2OH HCCC(R)¼CH2 (R ¼ CH2CH2CH2OH) (E)-HCCCH¼CHCH2OH

APPENDIX B

Method

Chap. Sect. Exp.

RCCLi þ (CH2O)n, THF or Et2O; H2 O RCCLi þ oxirane, liq. NH3; H2 O RCCLi þ Br(CH2)4OR1, liq. NH3, DMSO; H2O; deprotection (R1 ¼ CH(Me)OEt) HCC(CH2)9OH þ t-BuOK, DMSO LiCCCH2OLi þ MeSCN, liq. NH3; H2O LiCC(CH2)2OLi þ MeSCN, liq. NH3; H2O LiCCCH2OLi þ 2 Me3SiCl, Et2O; Hþ; H2O 1. RCCCCLi þ (CH2O)n, THF or Et2O; H2O 2. RCCBr þ HCCCH2OH, EtNH2, H2O, MeOH, CuBr (catal.) EtCCBr þ HCC(CH2)nOH, CuBr (catal.) EtNH2, H2O, MeOH 1. HCCCH2OH þ O2, H2O, NH4Cl, CuCl (catal.) 2. HCCCH2OH þ O2, acetone, TMEDA CuCl (catal.) HCC(CH2)2OH þ O2, acetone, TMEDA CuCl (catal.) HCC(CH2)4OH þ O2, pyridine, CuCl (catal.) p-NO2–C6H4–Br þ HCCCH2OH, Et3N, PPh3, PdCl2(PPh3)2, CuI PhCCLi þ oxirane, THF þ DMSO; H2O 2-Br-Thiophene þ HCCCH2OH, Et3N, PdCl2(PPh3)2, PPh3, CuI EtCCCH2CCCH2OH þ Zn, EtOH

5.2.1

LiCCC(CH2Li)¼CH2 þ oxirane, THF; H2O NaCCH þ epichlorohydrine, liq. NH3; H2O

20.9.1

4.5.16 4.5.33

17.2.2 8.2.2 8.2.2 7.2.12 5.2.1 14.2.2, Table 14.2.2, Table 15.2.1 15.2.2 15.2.2 15.2.4 16.7.7 4.5.18 16.7.9 19.3.3

4.5.15

(Continued)

APPENDIX B

Compound

435

Method

(E)-MeCCCH¼CHCH2OH þ 2 KNH2, liq. NH3; H2O 2-MeCC–THP þ 2 NaNH2, liq. NH3; H2O (THP ¼ tetrahydropyranyl) (Z)-BuCCCH¼CHCH2OH BuCCCCCH2OR þ Zn, EtOH; deprotection [R ¼ CH(Me)OEt] H2C¼CHCCCH2OH 1. H2C¼CHCCLi þ (CH2O)n, THF; H2O 2. BrCH¼CH2 þ HCCCH2OH, Et2NH, Et2O, CuI, Pd(PPh3)4 H2C¼C(Me)CCCH2OH H2C¼C(Me)CCLi þ (CH2O)n, THF; H2O MeCH¼CHCCLi þ (CH2O)n, MeCH¼CHCCCH2OH THF; H2O 1-Bromocyclooctene þ HCCCH2OH, Cyclooctene-1-CCCH2OH (i-Pr)2NH, PPh3, PdCl2 (PPh3)2, CuBr H2C¼C¼CHCH2OH ClCH2CCCH2OH þ LiAlH4, Et2O; H2O H2C¼C¼CH(CH2)2OH HCCCH¼CHCH2OH þ LiAlH4, Et2O; H2O PrCH¼C¼CHCH2OH H2C¼CHCCCH2OH þ EtLi, Et2O; H2O Me2(RO)CCCCH2OH þ LiAlH4, Me2C¼C¼CHCH2OH Et2O [R ¼ CH(Me)OEt] EtCH¼C¼CH(CH2)4OH 2-HCC-tetrahydropyranyl þ EtMgBr, Et2O, CuBr H2C¼C¼C(OMe)(CH2)2OH H2C¼C¼C(OMe)Li þ oxirane, Et2O; H2O RCH¼C¼C(Na)SEt þ oxirane, RCH¼C¼C(SEt)(CH2)2OH liq. NH3; H2O H2C¼C¼CHCCCH2OH HCCCH2Cl þ HCCCH2OH, NH4OH, CuCl H2C¼C¼CHCCC(Me)2OH HCCCH2Cl þ HCCC(Me)2OH, NH4OH, CuCl HCCCH¼CH(CH2)2OH (Z/E 9) HCCCH¼CH(CH2)4OH

Chap. Sect. Exp. 3.9.37 3.9.35

19.3.4 5.2.1 16.7.1 5.2.1 5.2.1 16.7.12

12.4.20 3.9.46 3.9.45 12.4.21 12.4.9 4.5.28 4.5.26 12.4.25 12.4.25

b. Secondary HCCCH(R)OH (R ¼ H2C¼CH, MeCH¼CH)

HCCLi þ RCH¼O, liq. NH3, 75 C; NH4Cl

5.2.4

(Continued)

436

Compound HCCCH(R)OH (general methods) HCCCH2CH(R)OH (general method) HCCCH2CH(Ph)OH (illustrates general method) HCCCH2CH(R)OH (general method) ClCH2CCCH(R)OH BrCCCH(R)OH [HOCH(Me)CC]2 H2C¼C¼CHCH(R)OH (general method) H2C¼C¼C(OMe)CH(R)OH

APPENDIX B

Method 1. HCCLi TMEDA þ RCH¼O, THF; H2O 2. HCCMgBr þ RCH¼O, THF; H2O LiCCH, liq. NH3! DMSO; R-oxirane; H2O HCCLi, liq. NH3 ! DMSO; styreneoxide; H2O 1. H2C¼C¼CHMgBr þ RCH¼O, Et2O; H2O ClCH2CCLi þ RCH¼O, Et2O; H2O KOBr þ HCCCH(R)OH, H2O HCCCH(Me)OH þ O2, acetone, TMEDA CuCl (catal.) ClCH2CCCH(R)OH þ LiAlH4, Et2O

Chap. Sect. Exp. 5.2.2 5.2.5 4.5.17 4.5.17 5.2.9 5.2.2 9.2.3 15.2.2 12.4.20

H2C¼C¼CH(Li)OMe þ RCH¼O, THF; H2O

5.2.10

1. HCCLi þ R1R2C¼O, liq. NH3; H2O (C(CH2)n ¼ cycloalkane ring) 2. HCCH þ t-BuOK þ R1R2C¼O, THF 3. HCCH þ KOH, DMSO 4. HCCH þ KOH, 1,2dimethoxyethane HCCLi þ H2C¼CHC(¼O)Me, liq. NH3; H2O HCCMgBr þ b-ionone, THF; H2O HCCCCC(Me)2OH þ LiAlH4, THF; H2O HCCCCLi þ Me2C¼O, THF; H2O MeCCLi þ cycloalkanone, THF þ LiBr; H2O Me2NCH2CCLi þ cycloalkanone, THF þ LiBr; H2O KOBr þ HCCC(Me)2OH, H2O EtOCCLi þ Me2C¼O, THF; H2O Me2C¼CHBr þ HCCC(Me)2OH, Et2NH, Pd(PPh3)4, CuBr

5.2.11

c. Tertiary HCCC(CH2)nOH (n ¼ 5, 6) (n ¼ 4, 5, 6) (n ¼ 5, 6) (n ¼ 5, 6) HCCC(Me)(CH¼CH2)OH HCCC(Me)(b-ionyl)OH (E)-HCCCH¼CHC(Me)2OH HCCCCC(Me)2OH MeCCC(R1)(R2)OH (R1R2C ¼ cycloalkyl) Me2NCH2C C–C(R1)(R2)OH BrCCC(Me)2OH EtOCCC(Me)2OH Me2C¼CHCCC(Me)2OH

5.2.6 5.2.7 5.2.12 5.2.4 5.2.5 3.9.47 5.2.3 5.2.2 5.2.2 9.2.3 5.2.2 16.7.2

(Continued)

APPENDIX B

Compound t-BuCCCCC(Me)2OH

437

Method t-BuCCBr þ HCCC(Me)2OH, CuBr (catal.), EtNH2, H2O, MeOH

[HOCMe2CC]2

HCCCMe2OH þ O2, acetone, TMEDA CuCl (catal.) RCCC(Me)2OH (Het)aryl-Br þ HCCC(Me)2OH, Et3N, PPh3, Pd(PPh3)4, CuBr or CuI (R ¼ 2-Furyl, 2-Thienyl, 3-Br-2-Thienyl, p-F–C6H4–, p-Cl–C6H4–, p-Me2N–C6H4, p-MeO–C6H4) 3-Bromofuran þ HCCC(Me)2OH, 3-Furyl–CCC(Me)2OH (i-Pr)2NH, PPh3, PdCl2(PPh3)2, CuBr Th-3-Br-2-CCCMe2OH 2,3-Dibromothiophene þ HCCC(Me)2OH, Et3N, Pd(PPh3)4, CuBr H2C¼C¼CHCCC(Me)2OH HCCCH2Cl þ HCCC(Me)2OH, NH4OH, CuCl (catal.) H2C¼C¼C(OMe)C(R1R2)OH H2C¼C¼C(Li)OMe þ R1R2C¼O, THF; H2O

Chap. Sect. Exp. 14.2.2, Table 15.2.2 16.7.8, 16.7.10, 16.7.16 16.7.14 16.7.17

12.4.25 5.2.10

ALDEHYDES HCCCH2OH þ CrO3, H2O, Hþ 1. RCCLi þ DMF, THF or Et2O; H2O, Hþ 2. RCCCH(OEt)2 þ H2O, Hþ o-HCC–C6H4–CH¼O Benzene þ 2 BuLi.t-BuOK, THF; LiBr, DMF; H2O, Hþ (CH2)5C¼C¼CHCH¼O (CH2)5C¼C¼CHLi þ DMF, (CH2)5C ¼ cyclohexane ring) THF; Hþ, H2O 3,3-sigm. rearr. of Me2C¼ H2C¼C¼CHC(Me)2CH¼O CHOCH2CCH HCCCH¼O RCCCH¼O (general methods)

20.4.1 6.4.3 19.2.4 20.9.2 6.4.15 18.3.10

AMINES AND IMINES Orders: HCC > non-terminal CC > primary > tert. amine > CC–N > CC–C–N > non-conjugated > conjugated CC > C¼C¼C > C¼C¼C¼C HCCCH2NH2 HCCC(Me)2NH2

HCCCH2Br þ liq. NH3; NaNH2; H2O 20.2.1 HCCC(Me)2Cl þ 2 NaNH2, liq. NH3; H2O 20.2.7 (Continued)

438

Compound HCCC(CH2)5NH2 [(CH2)5C ¼ cyclohexane ring] HCCCH2NMe2 HCCCH2NR2 [NR2 ¼ N(alkyl)2, pyrrolidino, piperidino, morpholino] HCCCH2-1-pyrrolyl HCCCH2-1-imidazolyl HCCCH2-1-pyrazolyl HCC(CH2)2NEt2 HCC(CH2)4NEt2 RCCNR12 (general method) MeCCNEt2 PhCCNMe2 R2NCCNR2 (R ¼ Me, Et) RCCCH2NH2 RCCCH2NR12 (R and R1 ¼ alkyl) MeCCCH2NEt2 HOCH2CCCH2NMe2 HO(CH2)2CCCH2NMe2 MeOCH2CCCH2NR2 (R ¼ Me, Et) Et2NCH2CCCH2NEt2 HCCCH¼CHNR2 HCCCH¼CHCH2NMe2 H2C¼CHCCNR2 (R ¼ Me, Et) MeCH¼CHCCNEt2 Me2C¼CHCCNEt2 1-Cyclohexenyl–CCNEt2 H2C¼CHCCCH2NEt2 EtSCH¼CHCCCH2NEt2

APPENDIX B

Method

Chap. Sect. Exp.

HCCC(CH2)5Cl þ 2 NaNH2, liq. NH3; H2O

20.2.8

HCCCH2Br þ 2 Me2NH, petr. ether HCCCH2Br þ 2 R2NH, Et2O

20.2.3 20.2.2

Pyrrole þ KNH2, liq. NH3; HCCCH2Br Imidazole þ KNH2, liq. NH3; HCCCH2Br Pyrazole þ KNH2, liq. NH3; HCCCH2Br MeCCCH2NEt2 þ KNH2, liq. NH3; H2O HCC(CH2)4OTs þ Et2NH, dioxane RCCOEt þ LiNR12 , Et2O

20.2.9 20.2.9 20.2.9 3.9.37 20.2.5 12.4.1

HCCCH2NEt2 þ t-BuOK, DMSO ClCCPh þ LiNMe2, Et2O ClCH¼C(NR2)2 þ KNH2, liq. NH3

17.2.3 12.4.2 10.2.11

RCCCH2Br þ hexamethylene tetramine; NaI; K2CO3 RCCH þ R12 NCH2OH, CuBr

20.2.6

LiCCCH2NEt2 þ MeI, liq. NH3 þ HMPT Me2NCH2OH (excess) þ HCCCH2OH; 50% aqueous H2SO4; CuBr Me2NCH2OH (excess) þ HCC(CH2)2OH, 50% aqueous H2SO4; CuBr MeOCH2CCH þ R2NCH2OH, CuBr

4.5.1 13.2.4

BrCH2CCCH2Br þ 4 Et2NH, Et2O H2C¼CHCCNR2 þ KNH2, liq. NH3; NH4Cl HCCCH¼CHCH2Br þ Me2NH, Et2O MeOCH2CCCH2NR2 þ t-BuOK, THF H2C¼CHCCCH2NEt2, t-BuOK, DMSO H2C¼C(Me)CCCH2NEt2, t-BuOK, DMSO 1-Cyclohexenyl–CCCl þ LiNEt2, Et2O H2C¼CHCCH þ Et2NCH2OH, Cu(OAc)2 or CuBr Et2NCH2OH þ HCCCH¼CHSEt, CuBr

13.2.3

13.2.4 13.2.3 20.2.4 3.9.36 20.2.2 10.2.13 17.2.6 17.2.6 12.4.2 13.2.2 13.2.3 (Continued)

APPENDIX B

Compound

439

Method

Chap. Sect. Exp.

EtSCH¼CHCCCH2NEt2 þ 2 NaNH2, liq. NH3; H2O EtCCCCC(Me)2NH2 HCCC(Me)2NH2 þ EtCCBr, EtNH2, H2O, MeOH, CuBr (catal.) EtCCCC(CH2)nNEt2 EtCCBr þ HCC(CH2)nNEt2, CuBr (catal.), EtNH2, H2O, MeOH (n ¼ 1, 2, 4) [H2NC(Me)2CC]2 HCCC(Me)2NH2.HCl þ O2, H2O, CuCl (catal.), NH4Cl; NH4OH Et2NCH2CCH þ O2, pyridine, CuCl (catal.) (Et2NCH2CC)2 H2C¼C¼CHNMe2 HCCCH2NMe2, t-BuOK t-BuOH, DMSO H2C¼C¼CH-N-Morphol. HCCCH2-N-Morphol., t-BuOK, THF BuCH¼C¼CHNMe2 BuCCCH2NMe2 þ BuLi; t-BuOK, THF; t-BuOH H2C¼CHCCCH2NEt2 þ EtLi, Et2O; H2O PrCH¼C¼CHCH2NEt2 MeOCH¼C¼CHCH2NMe2 MeOCH2CCCH2NMe2 þ BuLi, THF; H2O H2C¼C¼C¼CHNMe2 H2C¼CHCCNMe2 þ BuLi; t-BuOK, THF; t-BuOH Me2C¼C¼C¼CHNMe2 Me2(MeO)CCCCH2NMe2 þ BuLi, THF; t-BuOH RCCCH¼O+R1NH2, Et2O, rt RCC–CH¼NR1 HCCCCCH2NEt2

3.9.33 14.2.2, Table 14.2.2, Table 15.2.9 15.2.5 17.2.4 17.2.5 3.9.42 3.9.45 3.9.40 3.9.48 3.9.32 20.2.10

CARBOXAMIDES AND SULPHUR ANALOGUES RCCC(¼O)NH2 (illustrates general method) RCCC(¼O)NHPh (illustrates general method) RCCC(¼O)NMe2 (illustrates general method) RCCC(¼S)NHR1 (illustrates general method) H2C¼C¼C(Me)C (¼O)NEt2

RCCCOOMe þ NH4OH, MeOH

20.5.5

RCCLi þ PhN¼C¼O, THF; Hþ, H2O

6.4.10

RCCLi þ Me2NC(¼O)Cl, THF

6.4.9

RCCLi þ R1N¼C¼S, THF; Hþ, H2O

6.4.11

MeCCNEt2 þ HCCCH2OH, benzene, BF3 (catal.); heat (3,3-sigm. rearr.)

18.3.5

HCCCH2OH þ CrO3, H2O, Hþ RCCLi þ CO2, THF, then H2O, Hþ

20.4.4 6.4.1

CARBOXYLIC ACIDS HCCCOOH RCCCOOH (general method)

(Continued)

440

APPENDIX B

Compound

Method

RCCCH2COOH (R ¼ alkyl) HCC(CH2)8COOH H2C¼C¼CHCOOH t-BuCH¼C¼CHCOOH HOOCCH¼C¼CHCOOH HOOCC(Me)¼C¼CHCOOH

Chap. Sect. Exp.

RCH2CCCOOH þ 2 NaNH2, liq. NH3; NH4Cl; Hþ, H2O H2C¼CH(CH2)8COOH þ Br2; NaNH2, liq. NH3; H2O, Hþ H2C¼C¼CHLi þ CO2, THF; Hþ, H2O t-BuCH¼C¼CHLi þ CO2, THF; Hþ, H2O LiCCCH2Li þ CO2, THF; KOH, H2O; Hþ, H2O LiCCCH(Li)Me þ CO2, THF; KOH, H2O; Hþ, H2O

3.9.38

MeCCLi þ ClCH2C(¼O)Me, THF; H2O; solid KOH, Et2O

20.6.9

MeC(¼O)Cl þ HOR þ PhNEt2 (þ Et2O)

20.5.1

3.9.22 6.4.13 6.4.13 6.4.14 6.4.14

EPOXIDES Me Me O

(illustrates general method) ESTERS Acetates MeC(¼O)OR (general method)

Acetylenic and Allenic Carboxylates RCCCOOR1 (general method) Me2C¼C¼CHCOOMe MeCH¼C¼CHCH2COO–t-Bu RCH¼C¼CHCH2COOEt (R ¼ H, alkyl)

RCCLi þ ClCOOR1, Et2O

6.4.2

MeCOOC(Me)2CCH, AgClO4 (catal.), CH2Cl2 HCCCH(Me)OTs þ CuCH2COO–t-Bu, THF HCCCH(R)OH þ EtCOOH (catal.) þ MeC(OEt)3

18.3.11 12.4.10 18.3.7, 9

Sulphinates MeS(¼O)OR (general method)

MeS(¼O)Cl þ HOR þ Et3N, CH2Cl2

20.5.3

(Continued)

APPENDIX B

Compound

441

Method

Chap. Sect. Exp.

Sulphonates ArylSO2OR; (general method) MeSO2OR (general method)

ArSO2Cl þ HOR þ solid KOH, Et2O

20.5.4

MeSO2Cl þ HOR þ Et3N, CH2Cl2

20.5.3

ETHERS Orders: CCO > CC(C)nO; HCC > RCC; non-conjugated > conjugated CC > C¼C¼C > C¼C¼C¼C HCCOR (R ¼ Me, Et) HCCOEt RCCOEt (R ¼ prim. alkyl) MeCCCH2CCOEt Me3SiCCOEt H2C¼CHCCOEt HCCCH2OR (R ¼ Me, Et) HCCCH2O–t-Bu HCCCH2OR [R ¼ CH(Me)OEt] HCCCH2OCH2CCH HCCC(Me)2OMe

ClCH2CH(OR)2 þ 3 NaNH2, liq. NH3; H2O (Z)-BrCH¼CHOEt þ KOH LiCCOEt þ MeI or RBr, liq. NH3 MeCCCH2OTs þ BrMgCCOEt, THF, CuBr LiCCOEt þ Me3SiCl, THF EtOCH2CH¼C¼CHOEt þ BuLi LiBr, Et2O HCCCH2OH þ NaOH þ Me2SO4 or Et2SO4, H2O HCCCH2OH þ isobutene, H2SO4 HCCCH2OH þ H2C¼CHOEt Hþ

3.9.28 10.2.5 4.5.7 4.5.32 7.2.2 10.2.12 20.6.1 20.6.8 cf. 20.7.7

HCCCH2OH þ HCCCH2Br þ KOH 20.6.3 HCCC(Me)2OH þ Me2SO4 þ 20.6.4 KOH, DMSO HCC–C(OMe)(CH2)5 20.6.5 HCC–C(OH)(CH2)5 þ BuLi, [(CH2)5C ¼ cyclohexane ring] THF; DMSOþ MeI 2-(HCC)–THP HCCMgBr þ THP-2-Cl, THF 4.5.20 (THP ¼ tetrahydropyranyl) 2-(HCC)–3-Br–THP HCCMgBr þ 2,3-dibromo-THP, 4.5.20 THF HCCCH(OEt)CH2Br HCCMgBr þ BrCH2CH(Br)OEt, THF 4.5.20 H2C¼C¼CHMgBr þ HCCCH2CH(OEt)CH2Br 19.1.6 BrCH2CH(Br)OEt, Et2O 2-(RCC)-3-Br–THF RCCMgBr þ 2,3-dibromo-THF 4.5.20 (R ¼ alkyl) (THF ¼ tetrahydrofuran) C7H15CCCH2OMe LiCCCH2OMe þ C7H15Br, 4.5.14 THF, DMSO (Continued)

442

Compound ROCH2CCCH2OR (R ¼ Me, Et) ROCH2CCCH2OR [R ¼ CH(Me)OEt] EtOCH(Me)CCCH2OEt (illustrates general method) R1CCC(R2)(R3)OMe (generally applicable) R1CCC(R2)(R3)OSiMe3 MeCCCH2CH(Me)OEt MeCCCH2CH(Me)OEt HCCCH¼CHOEt HCCCH¼CHOR [R ¼ OCH(Me)OEt] HCCC(Me)¼CHOEt HCCCH¼C(Me)OEt HCCC(OMe)¼CHR (R ¼ H, Me) HCCC(OEt)¼CH2 6-HCC-2,3-Dihydropyran HCCCH¼CHCH2OMe EtCCCC(CH2)nOR [n ¼ 2, 4; R ¼ CH(Me)OEt] (MeOCH2CC)2 (MeOCH¼CHCC)2 H2C¼C¼CHOMe H2C¼C¼CHO–t-Bu H2C¼C¼CHOCH(Me)OEt H2C¼C¼C(OMe)R (R ¼ alkyl or PhCH2)

APPENDIX B

Method HOCH2CCCH2OH þ NaOH þ R2SO4, H2O HOCH2CCCH2OH þ H2C¼CHOEt, Hþ EtOCH2CCLi þ MeCH(Cl)OEt, Et2O, or THF R1CCLi þ R2R3C¼O, THF; MeI, DMSO R1CCC(OH)R2R3þ Me3SiCl þ Et3N, Et2O, DMSO LiCCCH2OCH(Me)OEt þ MeI, liq. NH3 LiCCCH2OCH(Me)OEt þ MeI, THF, DMSO EtOCH2CCCH2OEt þ 2 NaNH2, liq. NH3; H2O ROCH2CCCH2OR þ 3 NaNH2, liq. NH3; H2O EtOCH¼C¼C¼CHOEt þ MeMgBr, Et2O, CuBr BrCH2CH(OEt)CH2CCH þ 2 NaNH2, liq. NH3; H2O H2C¼C¼C(OMe)CH(R)OMe þ 2 NaNH2, liq. NH3; H2O HCCCH(OEt)CH2Br þ t-BuOK, THF 5-Br-6-CCH–DHP þ t-BuOK, THF HCCCH¼CHCH2OH þ MeI þ KOH, Et2O RO(CH2)nCCH þ BrCCEt, EtNH2, H2O, MeOH, CuBr (catal.) MeOCH2CCH þ O2, TMEDA CuCl (catal.), acetone HCCCH¼CHOMe þ O2, acetone, TMEDA CuCl (catal.) HCCCH2OMe, t-BuOK, DMSO HCCCH2O–t-Bu, t-BuOK HCCCH2OCH(Me)OEt, t-BuOK, DMSO H2C¼C¼C(OMe)Li þ RBr, THF–HMPT

Chap. Sect. Exp. 20.6.2 cf. 20.6.7 4.5.19 20.6.6 20.6.10 4.5.4 4.5.5 3.9.29 3.9.29 12.4.6 19.1.6 3.9.34 19.1.5 19.1.5 20.6.11 14.2.2 15.2.2 15.2.2 17.2.8 17.2.9 17.2.10 4.5.25

(Continued)

APPENDIX B

Compound RCH¼C¼CHOMe (general method) RCH¼C¼CHOEt (general method) RCH¼C¼CHOEt (R ¼ i-Pr, t-Bu, c-alkyl) Et(Me)C¼C¼CHOt-Bu (illustrates general method) Et(R)C¼C¼CHOEt (illustrates general method) ROCH2CH¼C¼CHOR (R ¼ Me, Et) EtO(Me)CHCH¼C¼CHOMe H2C¼C¼C(OMe)CH(R)OEt H2C¼C¼C¼CHOEt EtOCH¼C¼C¼CHOEt Me2C¼C¼C¼CHOMe

443

Method

Chap. Sect. Exp.

RCCCH2OMe þ BuLi þ t-BuOK, THF, HMPT; H2O RMgCl þ HCCCH(OEt)2, Et2O, CuBr RCCCH2OEt, NaNH2, liq. NH3

3.9.49

EtCCCH(Li)Ot-Bu þ MeI, THF

4.5.30

RCCCH(OEt)2 þ EtMgBr, Et2O, CuBr ROCH2CCCH2OR, t-BuOK, liq. NH3 MeOCH2CCCH(Me)OEt, t-BuOK, liq. NH3 H2C¼C¼C(Li)OMe þ RCH(Cl)OEt, Et2O or THF EtOCH2CCCH2OEt þ 2 EtLi, Et2O; H2O EtOCH2CCCH(OEt)2 þ 2 BuLi, Et2O; H2O Me2C(OMe)CCCH2OMe þ 2 BuLi, Et2O; H2O

12.4.5

12.4.5 17.2.18

17.2.11 17.2.11 4.5.30 3.9.30 3.9.31 3.9.50

HALOGEN COMPOUNDS Orders: Cl > Br > I; CCX > CC(C)nX; HCC > RCC RCCCl (general method) RCCBr (general method) RCCBr (general method) RCCBr (R ¼ Me, Et) RCCBr (general method) HOCH(Me)CCBr HOC(Me)2CCBr RCCI (general method) HCCCH2Br

1. RCCLi þ PhSO2Cl, THF

9.2.1

2. PhCCLi þ Cl2, Et2O 1. RCCLi þ Br2, Et2O (or THF)

9.2.8 9.2.2

2. RCCH þ KOBr, H2O

9.2.3

3. RCCH þ KOBr, H2O þ petr. ether

9.2.4

4. RCCLi þ BrCN, THF or Et2O

9.2.5

HOCH(Me)CCH þ KOBr, H2O HOC(Me)2CCH þ KOBr, H2O RCCLi (or Na) þ I2, liq. NH3 or THF

9.2.3 9.2.3 9.2.6, 7

HCCCH2OH þ PBr3, Et2O (pyridine)

20.1.1 (Continued)

444

Compound HCCCH2I HCCCH(Me)Cl HCCCH(Ph)Cl HCCCH(Me)Br HCCCH(C6H13)Br HCCC(Me)2Cl HCCC(Me)2Br HCC–C(Cl)(CH2)5 [C(CH2)5 ¼ cyclohexane ring] HCC(CH2)2Br HCC(CH2)4Cl HCC(CH2)4Br RCCCH2Cl (general method) RCCCH2Br (R ¼ alkyl) ClCH2CCCH2Cl BrCH2CCCH2Br Cl(Me)CHCCCH2Cl HOCH2CCCH2Cl HO(Me)CHCCCH2Cl MeOCOCCCH2Cl MeSCCCH2Cl Me3SiCCCH2Cl Me3SiCCCH2Br MeCCC(Me) (OH)CH2Cl C6H13CCCH¼CHCl BuCCC(Cl)¼CH2 HCCCH¼CHCH2Br HCCCH¼CHCH(Me)Cl HCCCH¼CHCH(Me)Br ClCH2(CC)2CH2Cl H2C¼C¼CHBr MeCH¼C¼CHBr MeCH¼C¼CHI C6H13CH¼C¼CHBr

APPENDIX B

Method

Chap. Sect. Exp.

HCCCH2Br þ NaI, EtOH (100%) HCCCH(OTs)Me þ LiCl, DMSO HCCCH(OH)Ph þ SOCl2 HCCCH(Me)OTs þ LiBr, DMSO HCCCH(C6H13)OTs þ LiBr, acetone HCCC(Me)2OH þ HCl, NH4Cl, CuCl, H2O HCCC(Me)2OH þ PBr3 HCC–C(OH)(CH2)5 þ HCl, NH4Cl, CuCl, H2O

20.1.11 20.1.5 12.4.12 20.1.5 20.1.4 20.1.9

HCC(CH2)2OTs þ LiBr, DMSO LiCCCH2Li þ Br(CH2)3Cl, THF; H2O HCC(CH2)4OTs þ LiBr, DMSO RCCCH2OMe þ MeC(¼O)Cl, ZnCl2 (catal.) RCCCH2OH þ PBr3, Et2O (pyridine)

20.1.5 4.5.21 20.1.5 20.1.12 20.1.2

HOCH2CCCH2OH þ 2 SOCl2, pyridine HOCH2CCCH2OH þ PBr3, Et2O MeCH(OH)CCCH2Cl þ SOCl2, pyridine ClCH2CCLi þ (CH2O)n, Et2O; H2O ClCH2CCLi þ MeCH¼O, Et2O; H2O ClCH2CCLi þ ClCOOMe, Et2O ClCH2CCLi þ MeSCN, Et2O ClCH2CCLi þ Me3SiCl, Et2O þ DMSO BrCH2CCLi þ Me3SiCl, Et2O þ DMSO MeCCLi þ ClCH2C(¼O)Me, THF

20.1.6 20.2.4 20.1.6 5.2.8 5.2.2 6.4.1 8.2.3 7.2.3 7.2.4 20.6.9

ClCH¼CHCl (excess) þ HCCC6H13, Et2NH, Pd(PPh3)4, CuBr H2C¼CCl2 (excess) þ HCCBu, Et2NH, Pd(PPh3)4, CuBr HCCCH¼CHCH2OH þ PBr3, Et2O HCCCH(OH)CH¼CHMe þ HCl, H2O HCCCH(OH)CH¼CHMe þ HBr, H2O HOCH2(CC)2CH2OH þ SOCl2, pyridine HCCCH2Br, CuBr LiBr (catal.), THF HCCCH(Me)OH þ HBr, NH4Br, H2O, CuBr (catal.) HCCCH(Me)OH þ (PhO)3PþMeI, DMF HCCCH(C6H13)OH, CuBr LiBr (catal.), THF

16.7.3

20.1.3 20.1.10

Table 16.1c 20.1.2 20.1.8 20.1.8 20.1.7 12.4.13 12.4.17 12.4.18 12.4.14

(Continued)

APPENDIX B

Compound PhCH¼C¼CHCl PhCH¼C¼CHBr PhCH¼C¼CHI Me2C¼C¼CHBr H2C¼C¼CH(CH2)3Cl

445

Method PhCH(Cl)CCH, CuBr (catal.), LiBr, THF HCCH(Ph)OH þ HBr, NH4Br, H2O, CuBr (catal.) HCCCH(Ph)OH þ HI, NH4I, CuI (catal.), H2O HCCC(Me)2OH þ HBr, NH4Br, H2O, CuBr (catal.) H2C¼C¼CHLi þ Br(CH2)3Cl, THF–HMPT

Chap. Sect. Exp. 12.4.12 12.4.15 12.4.19 12.4.16 4.5.24

HETEROAROMATIC COMPOUNDS (a few compounds with hetaryl substituents can be found under Alcohols, Amines and Sulphides) Hetaryl-2-MgBr þ HCCCH2Br, 2-HCCCH2-Hetaryl (Thienyl, Furyl, 1-Methylpyrrolyl) THF, CuBr (catal.) 1-Me-2-(CCSiMe3)-Pyrrole 1-Me-2-I-Pyrrole þ Me3SiCCZnCl, THF, Pd(PPh3)4 1-(HCC)-Pyrrole 1-(ClC¼CHCl)-Pyrrole þ 2 MeLi, Et2O; H2O Hetaryl–CC–Hetaryl Pd/Cu-catalysed coupling [2- and 3-Pyridyl 3-Thienyl, 2-(1-Imidazolyl)] [1-Me-Pyrrole-2-CC]2 1-Me-2-(HCC)-Pyrrole þ O2, pyridine, DBU, CuCl (catal.) [2-Furyl–CC]2 1. 2-(HCC)-Furan þ O2, pyridine, CuCl (catal.) 2. 2-(HCC)-Furan þ O2, acetone, TMEDA CuCl (catal.) [2-Thienyl–CC]2 1. 2-(HCC)-Thiophene þ O2, pyridine, CuCl (catal.) 2. 2-(HCC)-Thiophene þ O2, acetone, TMEDA CuCl (catal.) 2-Pyridyl–CCH 2-Pyr–CH¼CH2 þ Br2; NaNH2, liq. NH3; H2O [2-Pyridyl–CC]2 2-Pyridyl–CCH þ O2, pyridine, CuBr (catal.) [3-Pyridyl–CC]2 3-Pyridyl–CCH þ O2, pyridine, CuBr (catal.) 3-Pyridyl–CCSiMe3 3-Br-Pyridine þ Me3SiCCZnCl, THF, Pd(PPh3)4 2-Furyl–CCSiMe3 2-I-Furan þ ClZnCCSiMe3, THF Pd(PPh3)4

20.10 16.7.18 3.9.44 Table in Chap. 16 15.2.7 15.2.5 15.2.2 15.2.5 15.2.2 3.9.21 15.2.5 15.2.5 16.7.19 16.7.18

(Continued)

446

Compound

APPENDIX B

Method

2-Thienyl–CCCCMe 2-I-Thioph. þ Me3Si(CC)2ZnCl, THF, Pd(PPh3)4

Chap. Sect. Exp. 16.7.18

HYDROCARBONS Orders: terminal CC > non-terminal CC; non-conjugated CC > conjugated CC > ArylCC > C¼C¼C > C¼C¼C¼C HCCR (R ¼ Me, Et) HCCR (R ¼ prim. alkyl) HCCR (R ¼ c-alkyl) HCC–t-Bu, i-Pr HCCCHBu2 HCCCH2-c-Pentyl HCCCH2Ph HCC(CH2)2Ph HCC(CH2)2Ph MeCCMe MeCCC6H13 (illustrates general method) Cyclooctyne HCCCH2CH¼CH2 HCCCH2CH¼CHMe RCCCH2CH¼CH2 HCCCH2CCH HCC(CH2)2CCH

BrCH2CH(Br)R, solid KOH, phase transfer

10.2.3

1. HCCLi (Na) þ RBr, liq. NH3 2. HCCLi þ RBr, liq. NH3!DMSO Cl2CHCH2R þ 3 NaNH2, liq. NH3; H2O 1. BrCH2CH(Br)-t-Bu þ t-BuOK, DMSO 2. Cl2CHCH2-t-Bu or MeC(Cl)2-t-Bu þ KOH (solid), phase transfer BuMgCl þ BuCH¼C¼CHOMe, Et2O, CuBr c-PentylMgCl þ H2C¼C¼CHOMe, Et2O, CuBr H2C¼C¼CHOMe þ PhMgBr, Et2O, CuBr LiCH2CCLi þ PhCH2Cl, THF; H2O H2C¼C¼CHCH2Ph þ BuLi, Et2O; H2O HCCEt þ t-BuOK, DMSO HCCCH2C6H13 þ t-BuOK, DMSO

4.5.8 4.5.12 3.9.25 10.2.1 10.2.4

1-Bromo-1-cyclooctene þ LDA, THF 1. HCCMgBr þ H2C¼CHCH2OTs, THF, CuBr 2. HCCCH2CH(OEt)CH2Br þ Zn, DMSO HCCCH2CH(OEt)CH(Me)Br þ Zn, DMSO RCCMgBr þ BrCH2CH¼CH2, THF, CuBr HCCMgBr þ HCCCH2OTs, THF, CuBr H2C¼CH(CH2)2CH¼CH2 þ 2 Br2; NaNH2, liq. NH3; H2O HCCNa þ Br(CH2)nBr, liq. NH3

10.2.9 4.5.31

HCC(CH2)nCCH (n ¼ 4, 5, 6) HCCCH2CCR HCCCH2OTs þ RCCMgBr, THF, CuBr (R ¼ Me, Bu, C5H11) HCCCH¼CH2 (E)-ClCH2CH¼CHCH2Cl þ solid or aq. KOH, phase transfer HCCCH¼CHR HCCCH2CH(OTs)R þ KOH, H2O (R ¼ alkyl)

12.4.6 12.4.6 12.4.3 4.5.21 3.9.41 17.2.1 17.2.1

19.1.7 19.1.7 4.5.31 4.5.32 3.9.24 4.5.13 4.5.32 10.2.6 19.1.3

(Continued)

APPENDIX B

Compound (E)-HCCCH¼ CH-c-Hexyl HCCCH¼C(CH2)5 HCCC(Me)¼CH2 HCCC(CH2R)¼CH2 (R ¼ Cyclohexyl) 1-(HCC)-cyclopentene 1-(HCC)-cyclohexene 1-(HCC)-cycloheptene RCCCH¼CH2 (R ¼ alkyl) (Z)-RCCCH¼CHR (R ¼ alkyl) HCCCH¼CHCH¼CHR (R ¼ H, Me) HCCCCH HCCCCMe HCCCCR (R ¼ Et, Pr, Bu, C6H13) HCCCC-t-Bu HCCCCPh MeCCCCMe RCCCCR (R ¼ alkyl) EtCCCCPh PhCCCCPh HCCCCCCH t-Bu(CC)4-t-Bu HCCPh HCC-p-fluorophenyl HCC-p-chlorophenyl

447

Method MeCCCH¼C(CH2)5 þ KNH2, liq. NH3; H2O [C(CH2)5 ¼ cyclohexane ring] MeCC-1-cyclohexenyl þ KNH2, liq. NH3; H2O HCCC(Me)2OH þ p-tol. sulph. acid, Ac2O LiCCC(CH2Li)¼CH2 þ c-HexylBr, THF (CH2)4C(OH)CCH þ POCl3, pyridine (CH2)5C(OH)CCH þ POCl3, pyridine (CH2)6C(OH)CCH þ POCl3, pyridine RCCH þ BrCH¼CH2, Et2NH, Et2O, CuI, Pd(PPh3)4 RCCCCR þ Zn, EtOH HCCCH2CH(OTs)CH¼CHR þ KOH, H2O or Et2O ClCH2CCCH2Cl þ KOH, H2O, DMSO ClCH2CCCH2Cl þ 3 NaNH2 þ MeI, liq. NH3 ClCH2CCCH2Cl þ 3 NaNH2 þ RBr, liq. NH3 or liq. NH3 þ DMSO t-BuCCCCC(Me)2OH þ KOH PhCCCCC(Me)2OH þ KOH ClCH2CCCH2Cl þ 4 NaNH2 þ 2 MeI, liq. NH3 1. RCCH þ O2, pyridine, DBU, CuCl (catal.) 2. ClCH2CCCH2Cl þ 4 NaNH2 þ RBr, liq. NH3 EtCCBr þ PhCCH, CuBr (catal.) EtNH2, H2O, MeOH 1. PhCCH þ O2, pyridine, CuCl (catal.) 2. PhCCH þ O2, acetone TMEDA CuCl (catal.) ClCH2(CC)2CH2Cl þ t-BuOK, THF t-BuCCCCH þ O2, pyridine, CuCl (catal.) BrCH2CH(Br)Ph þ NaOEt, EtOH HO(Me)2CCC-p-Fluorophenyl, KOH HO(Me)2CCC-p-Chlorophenyl, KOH

Chap. Sect. Exp. 3.9.37

3.9.37 19.1.1 20.9.1 19.1.2 19.1.2 19.1.2 Chap. 16, Table 16.1 19.3.1 19.1.3, 4 10.2.7 4.5.2 4.5.6, 9 19.2.1 19.2.1 4.5.3 15.2.6 4.5.3 14.2.2, Table 15.2.5 15.2.2 10.2.8 15.2.5 10.2.2 19.2.1 19.2.1 (Continued)

448

Compound

APPENDIX B

Method

PhCCPh p-Me–C6H4CCC6H4–Me

PhCH(Br)CHBr þ NaOEt, EtOH Pd/Cu-catalysed coupling

H2C¼C¼CH2 H2C¼C¼CHMe H2C¼C¼CH-n-Bu (illustrates general method) H2C¼C¼CH-t-Bu H2C¼C¼CHCH2Ph H2C¼C¼CHCH¼CH2 H2C¼C¼CHCH¼CHMe

H2C¼C(Cl)CH2Cl þ Zn, EtOH HCCCH(Me)Cl þ Zn/Cu, EtOH HCCCH2OMe þ BuMgCl, Et2O, CuBr

3-Vinylidene-1-Cyclohexene H2C¼C¼CHCCH H2C¼C¼C(Me)Ph H2C¼C¼C(CH2)5 H2C¼C¼C¼CH2 H2C¼C¼C¼CHMe Me2C¼C¼C¼CMe2 Cyclonona-1,2-diene Cyclodeca-1,2,3-triene

HCCCH2Cl þ t-BuMgCl, THF, CuBr PhCH2CH¼CH2 þ [:CBr2]; BuLi, Et2O HCCCH2CH¼CH2, NaOH, EtOH HCCCH¼CHCH(Me)Br þ Zn/Cu, hexanol HCC-1-Cyclohexenyl, t-BuOK t-BuOH, HMPT HCCCH2CCH, LiOPh, MeOH MeCCCH2OTs þ PhCu, THF HCC–C(Cl)(CH2)5 þ Zn/Cu, EtOH [(CH2)5C is cyclohexane ring] ClCH2CCCH2Cl þ Zn, DMSO MeCH(Cl)CCCH2Cl þ Zn, DMSO Me2C¼C¼CMe2 þ [:CCl2]; BuLi, Et2O Cyclooctene þ [:CBr2]; BuLi, Et2O 1,2-Cyclononadiene þ [:CCl2]; BuLi, Et2O

Chap. Sect. Exp. 10.2.2 Table in Chap.16 10.2.15 12.4.22 12.4.3 12.4.4 11.2.1 17.2.12 12.4.24 17.2.17 17.2.13 12.4.8 12.4.23 10.2.16 10.2.17 11.2.4 11.2.2 11.2.3

KETONES HCCC(¼O)R (R ¼ alkyl, Ph) RCCC(¼O)R1 (general method) RCCC(¼O)R1 (general method) RCCC(¼O)R1 (general method) RCCC(¼O)Me (R ¼ alkyl, >C¼C<, 1-cyclohexenyl) RCCC(¼O)Ph (R ¼ alkyl) Ar–CC–Ar [Ar ¼ p-MeC(¼O)–C6H4] HCCCH2C(¼O)Me

HCCCH(OH)R þ CrO3, H2O, acetone, Hþ RCCLi þ (R1CO)2O, Et2O

20.4.2

RCCLi þ ZnCl2, THF; R1C(¼O)Cl

6.4.7

RCCLi þ ZnCl2, THF, Pd(PPh3)4; R1C(¼O)Cl RCCLi þ MeC(¼O)NMe2, THF or Et2O; H2O, Hþ

6.4.8

RCCLi þ PhC(¼O)NMe2, THF or Et2O; H2O, Hþ HCCH þ p-MeCO–C6H4–Br, EtNH2, PPh3, PdCl2(PPh3)2, CuI H2C¼C¼CHSnBu3 þ MeC(¼O)Cl, ZnCl2 (catal.)

6.4.5

6.4.6

6.4.4

16.7.5 12.4.26

(Continued)

APPENDIX B

449

Compound HCCCH2C(¼O)Et H2C¼C¼CHC(¼O)Et BuCH¼C¼CHC(¼O)Me Me2C¼C¼CHCH2C(¼O)Me

Method HCCCH2CH(OH)Et þ CrO3, H2O, acetone, Hþ HCCCH2C(¼O)Et, NaHCO3, H2O BuCH¼C¼CHLi þ MeC(¼O)NMe2, THF; Hþ, H2O H2C¼C(Me)OMe þ HCCC(Me)2OH, p-tol. sulph. acid (catal.); 3,3-sigm. rearrangement

Chap. Sect. Exp. 20.4.3 17.2.19 6.4.15 18.3.6

NITRILES AND NITROALKYNES RCCCN (general method) BuCCCN (illustrates general method) RCCCH2CN (R ¼ alkyl) HCCCH2CH2CN H2C¼C¼CHCN RCH¼C¼CHCN MeCH¼C¼CHCN Me2C¼C¼CHCN MeCH¼C¼CHCH2CN H2C¼C¼CHCH¼CHCN t-BuCCNO2

1. RCCBr þ CuCN, LiBr, THF

20.3.1

2. BuCCC(¼O)NH2 þ P2O5

20.3.5

RCCCH2Br þ CuCN, LiBr, THF

20.3.3

HCCCH2CH2OTs þ NaCN, DMSO HCCCH2Br þ KCN, H2O, CuCN (catal.) RCH¼C¼CHBr þ CuCN, LiBr, THF HCCCH(Me)Br þ KCN, H2O, CuCN (catal.) Me2C¼C¼CHBr þ CuCN, LiBr, THF HCCCH(Me)OTs þ CuCH2CN, THF HCCCH¼CHCH2CN, KCN, H2O t-BuC(I)¼CHNO2 þ solid KOH

20.3.4 12.4.11 20.3.2 12.4.11 20.3.2 12.4.10 17.2.20 10.2.10

SELENIDES AND TELLURIDES MeCCSeEt EtCCSeCH2Cl EtSeCCSeEt H2C¼CHCCSeMe MeCCTeEt H2C¼CHCCTeMe (RCC)2Te (general method)

MeCH(Br)CH2Br þ 3 NaNH2, liq. NH3; Se; EtBr EtCCLi þ Se, THF; BrCH2Cl HCCSeNa þ EtBr; NaOEt, liq. NH3 (E)-ClCH2CH¼CHCH2Cl þ 3 NaNH2 þ Se; MeI, liq. NH3 MeCH(Br)CH2Br þ 3 NaNH2 þ Te; EtBr, liq. NH3 (E)-ClCH2CH¼CHCH2Cl þ 3 NaNH2 þ Te; MeI, liq. NH3 4 equiv. RCCLi þ TeCl4, THF

8.2.5 8.2.6 8.2.5 8.2.4 8.2.5 8.2.4 8.2.11

(Continued)

450

Compound

APPENDIX B

Method

Chap. Sect. Exp.

SILICON, TIN AND PHOSPHORUS COMPOUNDS (for some Si-compounds see under other headings) HCCMgBr þ Me3SiCl, THF MeCCLi þ Me3SiCl, Et2O BrMgCCMgBr þ 2 Me3SiCl, THF EtOCCLi þ Me3SiCl, Et2O ClCH2CCLi þ Me3SiCl, THF þ DMSO BrCH2CCLi þ Me3SiCl, Et2O þ DMSO LiOCH2CCLi þ 2 Me3SiCl, THF; H2O, Hþ Me3SiCCLi þ DMF, then H2O, Hþ H2C¼CHCCLi þ Me3SiCl, Et2O RCCCCSiMe3 þ Zn, EtOH 1-Br-Cyclooctene þ Me3SiCCH, piperidine, Pd(PPh3)4, PPh3, CuBr 1-F–C6H4-3-CCSiMe3 1-F–C6H4–4-Br þ Me3CCZnCl, THF, Pd(PPh3)4 1-Cl–C6H4-2-CCSiMe3 1-Cl–C6H4–2-Br þ Me3SiCCZnCl, THF Pd(PPh3)4 4-MeO–C6H4–CCSiMe3 4-MeO–C6H4Br þ HCCSiMe3, (i-Pr)2NH, PPh3, PdCl2(PPh3)2, CuBr 4-NO2–C6H4–CCSiMe3 4-Br–C6H4NO2 þ HCCSiMe3, Et2NH, CuI, Pd(PPh3)4 1-Naphthalene–CCSiMe3 1-Br–Naphthalene þ Me3SiCCZnCl, THF Pd(PPh3)4 C6H4-1,3-(CCSiMe3)2 1,3-Dibromobenzene þ HCCSiMe3, (i-Pr)2NH, PPh3, PdCl2(PPh3)2, CuBr HCCSiMe3, O2, pyridine, DMF, (Me3SiCC)2 CuCl (catal.) Me2C¼C¼CHCCSiMe3 Me2C¼C¼CHBr þ HCCSiMe3, Et2NH, CuBr, Pd(PPh3)4 HCCCH2SiMe3 H2C¼C¼CHMgBr þ Me3SiCl, Et2O RCCCH2Li þ Me3SiCl, THF RCCCH2SiMe3 HCCCH2CCSiMe3 HCCCH2OTs þ BrMgCCSiMe3, THF, CuBr LiCCCH(Bu)Li þ 1 Me3SiCl; H2O HCCCH(Bu)SiMe3 HCCCH(Ph)SiMe3 LiCCCH(Ph)Li þ 1 Me3SiCl; H2O HCCCH(SMe)SiMe3 LiCCCH(SMe)Li þ 1 Me3SiCl; H2O H2C¼C¼C(Bu)SiMe3 Me3SiCCH2OTs þ BuCu, THF ROCH¼C¼C(R1)SiMe3 R1CCCH(Li)OR þ Me3SiCl, THF ¼ ¼ ¼ Me2C C C Me2C¼C¼C¼C(NMe2)Li þ Me3SiCl, C(NMe2)SiMe3 THF HCCSiMe3 MeCCSiMe3 Me3SiCCSiMe3 EtOCCSiMe3 ClCH2CCSiMe3 BrCH2CCSiMe3 HOCH2CCSiMe3 O¼CHCCSiMe3 H2C¼CHCCSiMe3 (Z)-RCH¼CHCCSiMe3 1-Cyclooctenyl-CCSiMe3

7.2.1 7.2.2 7.2.5 7.2.2 7.2.3 7.2.4 7.2.12 6.4.3 7.2.2 19.3.2 16.7.15 16.7.19 16.7.19 16.7.13 16.7.6 16.7.19 16.7.11 15.2.6 Table 16.1 7.2.7 7.2.9 4.5.32 7.2.13 7.2.13 7.2.13 12.4.7 7.2.9 7.2.10

(Continued)

APPENDIX B

Compound HCCSnBu3 EtOCCSnBu3 HCCCCSnBu3 H2C¼C¼CHSnBu3 HCCPBu2 (HCC)2PPh (MeCC)3P H2C¼C¼CHP(¼O)Ph2

451

Method HCCMgBr þ Bu3SnCl, THF EtOCCLi þ Bu3SnCl, Et2O LiCCCCH þ Bu3SnCl, THF H2C¼C¼CHMgBr þ Bu3SnCl HCCMgBr þ Bu2PCl, THF PhPCl2 þ 2 HCCMgBr, THF 3 MeCCMgBr þ PCl3, THF HCCCH2OH þ Ph2PCl þ Et3N, CH2Cl2

Chap. Sect. Exp. 7.2.1 7.2.2 7.2.6 7.2.7 7.2.14 7.2.15 7.2.16 18.3.4

SULPHIDES Orders: CCS > CC(C)nS; HCC > RCC; non-conjugated CC > conjugated CC > C¼C¼CSR HCCSR (R ¼ Me, Et) HCCCH2SR (general method) HCCCH2S-2-thienyl MeCCSR (R ¼ alkyl or Ph) RCCSR1 (general methods) RCCSCH2Cl (generally applicable) ClCH2CCSMe RSCCSR (R ¼ Me, Et) RSCCSR RSCH2CCCH2SR (R ¼ Me, Et) (RCC)2S (R ¼ alkyl, SiMe3) (Z)-HCCCH¼CHSR (R ¼ Me, Et) t-BuCCCCCH ¼CHSEt t-BuCC(CH¼CH)2SEt H2C¼CHCCSR (R ¼ alkyl)

BrCH2CH(Br)SR þ 3 NaNH2, liq. NH3; H2O 3.9.21 HCCCH2Cl (or Br) þ RSNa, EtOH or MeOH Thiophene þ BuLi, THF; S8; HCCCH2Br HCCCH2SR þ NaOEt, liq. NH3 or EtOH 1. RCCLi (or Na) þ S8, liq. NH3; R1Br 2. RCCLi þ R1SSR1, R1SCN or R1SSO2R1, THF, Et2O or liq. NH3 RCCSLi þ BrCH2Cl, THF

20.7.1 20.7.6 17.2.14, 17.2.15 8.2.4 8.2.1, 3 8.2.3

ClCH2CCLi þ MeSCN or MeSSO2Me, Et2O 1. HCCNa þ RSCN, liq. NH3

8.2.12

2. ClCCLi þ RSSR, liq. NH3 ClCH2CCCH2SR þ RSNa, EtOH

8.2.13 20.7.2

RCCLi þ SCl2, Et2O

8.2.10

HCCCCNa þ RSH, liq. NH3; NH4Cl

20.7.3

EtSCH¼CHCCH þ t-BuCCBr, CuBr (catal.) EtNH2, H2O, MeOH EtSCH¼CHCCCC–t-Bu þ Zn, EtOH 1. RSCH2CCCH2SR þ t-BuOK, THF or liq. NH3

14.2.2

8.2.3

19.3.2 10.2.14

(Continued)

452

Compound H2C¼CHCCSR (R ¼ alkyl) MeCCCCSMe [EtSCH2CC]2 H2C¼C¼CHSPh RCH¼C¼CHS-alkyl (-Ph) (R ¼ H or alkyl) PrCH¼C¼CHSEt Me2C¼C¼CHSPh R1CH¼C¼C(R3)SR2 (R1 ¼ H, alkyl, R2, R3 ¼ alkyl)

APPENDIX B

Method 2. (E)-ClCH2CH¼CHCH2Cl þ 3 NaNH2 þ S; RBr, liq. NH3 MeCCCCLi þ MeSSO2Me, liq. NH3 HCCCH2SEt, O2, DMF, TMEDA CuCl (catal.) HCCCH2Cl þ PhSLi, THF, CuBr LiBr (catal.) RCH2CCS-alkyl (-Ph) þ NaNH2, liq. NH3; H2O H2C¼CHCCSEt þ EtLi, Et2O; H2O HCCC(Me)2Cl þ PhSLi, THF, CuBr LiBr (catal.) R1CH2CCSR2 þ NaNH2þ R3Br, liq. NH3

Chap. Sect. Exp. 8.2.4 8.2.1 15.2.3 12.4.27 3.9.39 3.9.45 12.4.27 4.5.26

SULPHUR COMPOUNDS (MISCELLANEOUS) (for tosylates and sulphinates see under esters) RCCCH(SEt)2 HCCCH2SCN HCCCH2N¼C¼S

RCCCH(OEt)2 þ EtSH, ZnCl2 (catal.) HCCCH2Br þ KSCN, H2O HCCCH2NH2 þ Cl2C¼S, KOH, H2O CH2Cl2 HCCC(Me)¼C(SMe)2 MeCCCH2Li þ t-BuOK, THF; CS2; MeI H2C¼C¼CHMgBr þ PhN¼S¼O, Et2O; HCCCH2S(¼O)NHPh Hþ, H2O ¼ HC CC(Me)2S( O)NHPh LiCH¼C¼CMe2 þ MgBr2; PhN¼S¼O, (predominant product) THF, Et2O; Hþ, H2O HCCCH(Et)S(¼O)NHPh LiCH¼C¼CHEt þ PhN¼S¼O, (only product) THF; Hþ, H2O ¼ HC CCH(t-Bu)S( O)NHPh LiCH¼C¼CH–t-Bu þ MgBr2, THF; PhN¼S¼O; Hþ, H2O (predominant product) MeCCS(¼O)Me MeCCLi þ MeS(¼O)Cl, THF (illustrates general method) MeCCS(¼O)Et MeCCSEt þ NaIO4, H2O, MeOH MeCCSO2Et MeCCSEt þ H2O2, MeCOOH (RCC)2S¼O 2 RCCLi þ SOCl2, Et2O (R ¼ alkyl, Me3Si) (MeCC)2S þ H2O2, MeCOOH (MeCC)2SO2 t-BuCCS(¼O)NHPh t-BuCCLi þ PhN¼S¼O, THF; Hþ, H2O t-BuCCSO2NHPh t-BuCCS(¼O)NHPh þ m-Cl–C6H4COOOH, CH2Cl2 MeCCSSiMe3 MeCCSLi þ Me3SiCl, Et2O

20.7.4 20.3.6 20.3.7 6.4.17 6.4.18 6.4.18 6.4.18 6.4.18 8.2.9 20.8.1 20.8.2 8.2.10 20.8.2 6.4.12 20.8.6 8.2.8 (Continued)

APPENDIX B

Compound

453

Method

BuCCSC(¼O)Me BuCCSC(¼O)OMe HCCCH2SC(¼S)Et

BuCCSLi þ MeC(¼O)Br, Et2O BuCCSLi þ ClCOOMe, Et2O EtMgBr þ CS2, then HCCCH2Br, THF H2C¼C¼CHCH2CSSEt H2C¼C(SLi)SEt þ HCCCH2Br, liq. NH3; 3,3-sigmatropic rearrangement ar rt H2C¼C¼C(Me)C(SMe)¼NMe MeCCCH2Li þ MeN¼C¼S, THF; MeI

Chap. Sect. Exp. 8.2.7 8.2.7 20.5.2 18.3.8

6.4.16

(þ other examples of regioselective reaction between allenic$acetylenic anionic species and isothiocyanates and subsequent S-alkylation affording allenic thioimidates) H2C¼C¼CHS(¼O)Me H2C¼C¼CHS(¼O)Ph MeCH¼C¼CHS(¼O)Ph H2C¼C¼CHSO2Me MeCH¼C¼CHSO2Me

1. H2C¼C¼CHSMe þ NaIO4, H2O 2. HCCCH2OH þ MeSCl þ Et3N, CH2Cl2 HCCCH2OH þ PhSCl þ Et3N, CH2Cl2 HCCCH(Me)OH þ PhSCl þ Et3N, CH2Cl2 H2C¼C¼CHSMe þH2O2, MeCOOH HCCCH(Me)OH þ MeS(¼O)Cl þ Et3N, CH2Cl2

20.8.3 18.3.1 18.3.2 18.3.2 20.8.4 18.3.3

THIOLS HCCCH2SH MeCCCH2SH

HCCCH2Br þ NaSH, H2O MeCCCH2Br þ NaSH, H2O

20.7.5 20.7.5

This Page Intentionally Left Blank

Appendix C: Complementary Subject Indexes 1.

REACTION TYPES

Chap. Sect. Exp. O-Alkylation Ammonolysis

Autooxidation Conjugate addition Cadiot-Chodkiewics coupling Dehalogenation

Dehydration (O)-Deprotection

Disproportionation

Elimination of water Elimination of chlorine Elimination of Br and OEt of p-tol. sulphonic acid of HBr with PhNEt2 of HBr with t-BuOK of HBr with NaNH2 in liq. NH3 Enolate formation Ethynylation (of ketones)

of acetylenic alcohols of propargyl bromide of acetylenic esters, RCCCOOR1 of propargylic ethers of alkyllithium to enynes meaning of preparation of acetylenes of 1-(1,2-dichlorovinyl)pyrrole of ClCH2CCCH(R)Cl of ClCH2C(Cl)¼CH2 of acetylenic tert. alcohols of trimethylsilyl ethers of acetals ROCH(Me)OEt or –THP with formation of alcohols of ethynylmagnesium bromide of ethylselenoacetylene of ethynylphosphines see dehydration see dehalogenation from RCHBrCH(OEt)CH2CCH from RCH(OTs)CH2CCH from BrCH2CHBrOEt from RCHBrCH(OR)CCH from BrCH2CH(OEt)CH2CCH

20.6.1–6 and 11 20.2.1 20.5.5

in reactions of RCCM with ketones using HCCH and KOH using HCCH and t-BuOK

5.1

20.6.1; 17.2.9 3.6; 3.9.45 Chap. 14 3.8; Table 3.5 3.9.44 10.2.16, 17 10.2.15 20.1.1, 2 7.2.12 19.2.3

3.1 8.2.5 3.2

19.1.7 19.1.3, 4 3.9.23 19.1.5 19.1.6

5.2.7, 12 5.2.6 (Continued)

455

456

APPENDIX C

Chap. Sect. Exp. Exchange of metals

Favorsky reaction Fritsch-Wiechell-Buttenberg rearrangement Isomerisation, acid-catalysed Isomerisation, CuX-catalysed Mannich reaction Metal–metal exchange Oxidative addition Phase-transfer catalysis

Propargylic rearrangement Proton transfer (O)-Protection of alcohols Protolysis

Reduction of triple bonds Reductive elimination Removal of protecting group Replacement of Li by other metals Retro-Favorsky reaction O-Silylation Tele-eliminations Transmetallation O-Trimethylsilylation

literature survey Li ! ZnCl Li ! MgX Li ! Cu MgBr ! Cu Li ! K in ethynylation of ketones in formation of R2NCCNR2 from (R2N)2C¼CHCl and KNH2 of a-functionalised allenic ethers and sulphides to conjug. dienes of acetylenic halides to halogenoallenes meaning of see under exchange of metals in Pd/Cu-catal. cross-couplings in formation of 1-alkynes from halogen compounds and KOH in generation of dihalocarbenes mechanism of from DMSO to alkali acetylide from DMSO to metall. allenes using H2C¼CHOEt using Me3SiCl of alkali acetylide by DMSO of metallated allenes by liq. NH3 of metallated allenes by DMSO partial, using acivated zinc partial, using lithium alanate in Pd/Cu-catal. cross couplings with formation of 1-alkynes with formation of alcohols see Exchange of metals in prepn. of acetylenes by elimin. of acetone catalysed by KOH of acetylenic tert. alcohols survey of of DMSO by alkali acetylide and metallated allenic compounds of acetylenic tert. alcohols

3.10 3.9.4 3.9.9 12.4.10 12.4.7, 8 3.9.42, 49 5.2.7, 12 10.1; 10.2.11 4.5.25, 26 12.4.12–14 Chap. 13 16.1 10.2.3, 4, 6 11.2.1–4 12.3 4.1 4.1; 3.5 20.6.7 20.6.10 4.1 3.5 4.1; 3.5 19.3.1–4 3.6; 3.9.47 16.1 19.2.2 19.2.3; 7.2.12

20.2.1 20.6.10 10.1 4.1 20.6.10 (Continued)

APPENDIX C

457

Chap. Sect. Exp. Wittig-rearrangement Zipper reaction

2.

of LiCCCH(Li)OR in conversion of disubst. acetylenes to 1-alkynes

3.9.13 3.7; 3.9.43

REAGENTS, INTERMEDIATES AND SOLVENTS (cf. Chap. 2)

Chap. Sect. Exp. Acetyl bromide, MeC(¼O)Br Acetyl chloride, MeC(¼O)Cl Acyl halides, RC(¼O)X Acetic anhydride

Alkyl chloroformates, ClCOOR Allylbenzene, PhCH2CH¼CH2 Allyl bromide, H2C¼CHCH2Br

Allylic halides Aliquat Alkanesulphenyl chlorides, RSCl 1-Alkyl-1-iodo-2-nitroalkene, RC(I)¼CHNO2 Allenyl 2-thienyl telluride, H2C¼C¼CHTe–Th Allylbenzene, PhCH2CH¼CH2 Allyl bromide

Benzenesulphenyl chloride, PhSCl Benzyl chloride Boron trifluoride

reaction with RCCSLi in prepn of acetylenic acetates in reactions with RCCZnCl use in elimin. of water from HCCCMe2OH in prepn. of RCCC(¼O)Me in prepn. of RCCCOOR1 in reaction with RCCSLi preparation of, and addition of dibromocarbene to Cu-catal. reaction with RCCMgX reaction with PhMgBr reaction with Mg to 1,5-hexadiene behaviour towards RCCM use as phase-transfer catalyst in preparation of RCCS(¼O)R’ in preparation of nitroalkynes

8.2.7 20.5.1 6.4.7, 8 19.1.1

formation of

20.7.6

preparation of in preparation of 1,5-hexadiene in preparation of allylbenzene in preparation of 1,4-enynes in preparation of allenic sulphoxides in preparation of ClCCR reaction with LiCCCH2Li use in reactions with oxiranes and oxetanes

11.2.1 3.9.24 11.2.1 4.5.31 18.3.2 9.2.1 4.5.21 4.2

6.4.6 6.4.2 8.2.7 11.2.1 4.5.31 11.2.1 3.9.24 4.1 10.2.4, 6 18.3.1 10.2.10

(Continued)

458

APPENDIX C

Chap. Sect. Exp.

1-Bromo-3-chloropropane 1-Bromo-1-cyclooctene (Z)-1-Bromo-2-ethoxyethene, BrCH¼CHOEt N-Bromosuccinimide Carbon disulphide Chloroacetaldehyde acetals, ClCH2CH(OR)2 a-Chloroethers, RCH(Cl)OR1 Chlorobutatriene, ClCH¼C¼C¼CH2 4-Chloro-1,3-butadiene, ClCH¼CHCH¼CH2 Chlorohexapentaene, ClCH¼C¼C¼C¼C¼CH2 Chloroketene aminals, ClCH¼C[NR2]2 m-Chloroperbenzoic acid N-Chlorosuccinimide 2-Chlorotetrahydropyran Chromic trioxide, CrO3 Copper(I) chloride Copper(I) halides Copper(I) chloride, TMEDA Copper(I) cyanide, CuCN Cyanogen bromide Cumulenic amines, H2C¼C¼C¼CHNR2 Cumulenic ethers, RCH¼C¼C¼CHOR1 1,2-Cyclooctadiene Cyclopropane derivatives 1,2-Diaminoethane, H2NCH2CH2NH2

in addition of HCCCH2OH to MeCCNEt2 reaction with LiCCCH2Li preparation of preparation of

18.3.5

in preparation of RCCBr in reaction with RCCCH2Metal in reaction with RMgBr used for prepn of HCCOR

9.1 6.4.17 20.5.2 3.9.28

preparation of interm. in 1,4-elim. of HCl from 1,4-dichloro-2-butyne interm. in preparation of vinylacetylene from dichlorobutene intermediate in reaction of t-BuOK with ClCH2(CC)2CH2Cl preparation of

4.5.19 10.2.7

in preparation of a sulphonamide in preparation of RCCCl preparation of in prepn. of acetylenic ketones, HCCCOOH and HCCCH(¼O) in preparation. of 1,4-enynes and 1,4-diynes as catalysts in 1,3-substitutions in oxidative coupling of RCCH in preparation of acetylenic and allenic cyanides in preparation of RCCBr preparation of water-sensitivity of

20.8.6 9.1 3.5.20 20.4.1–4

Chap. 12 15.2.2, 3 12.4.11; 20.3.1–3 9.2.5 9.2.5 3.9.48

oxygen-sensitivity of

3.9.30

as intermediate in 1,4-eliminations from cyclooctadiyne and NaNH2 precursors for allenes as solvent in Zipper reaction of disubstituted acetylenes

3.3 11.2.9 11.2.1–4 3.7

4.5.21 10.2.9 3.9.23

10.2.6 10.2.8 10.2.11

4.5.31, 32

(Continued)

APPENDIX C

459

Chap. Sect. Exp. 1,3-Diaminopropane, H2N(CH2)3NH2 Diaza[5.4.0]bicycloundec-7-ene (DBU) 1,2-Dibromoethane a,b-Dibromoethers, RCH(Br)CH(Br)OR1 2,3-Dibromotetrahydropyran 1,2-Dibromobutane 1,2-Dibromopropane Dibutylamine 1,1-Dichloroalkanes, RCH2CHCl2

1,4-Dichloro-2-butene, ClCH2CH¼CHCH2Cl

2,3-Dichloro-1-propene, H2C¼C(Cl)CH2Cl Diethylamine N,N-Diethylaniline, PhNEt2

Dihalogenocarbenes, :CX2 1,1-Dihalogenocyclopropanes Diisopropylamine N,N-Dimethylacetamide N,N-Dimethylbenzamide Dimethylcarbamyl chloride, Me2C(¼O)Cl N,N-Dimethylformamide Dinitrogen tetroxide DMPU (N,N-dimethylpropyleneurea) Dioxane Epichlorohydrine, ClCH2–oxirane

as solvent in Zipper reaction of disubstituted acetylenes use in oxidative couplings of 1-alkynes use in activation of Mg use in preparation of activated Zn selective substitution of a-Br preparation of reaction with RCCMgBr in preparation of 1-butyne in prepn. of MeCCSeR, -TeR dehydrobromination of use in cross-couplings preparation of elimination of HCl from in prepn. of HCCCH¼CH2

3.7; 3.9.43 15.2.6, 7 2.3.7, 8 19.3.1–4 4.5.20 4.5.20 4.5.20 10.2.3 8.2.5 8.2.5 16.7.4 3.9.25 3.9.25, 10.2.4 10.2.6

in prepn. of H2C¼CHCCSR, Se and Te analogues in preparation of allene

10.2.15

as solvent in cross-couplings in prepn. of acetylenic acetates in purification of TMSCl in preparation of BrCH¼CHOEt addition to double bonds in preparation of allenes use as solvent in cross-couplings for introduction of MeC¼O groups for introduction of PhC¼O groups in reaction with RCCLi

16.7.1–6 20.5.1 2.2 3.9.23 11.2.1–4 11.2.1–4 16.7.11–14 6.4.4 6.4.5 6.4.9

for introduction of CH¼O groups preparation of addition to t-butylacetylene as substitute for HMPT

6.4.3, 15, 20.9.1 10.2.10 10.2.10 2.1

as solvent in aminomethylation reaction with alkali acetylide

13.1 4.5.15

8.2.4

(Continued)

460

APPENDIX C

Chap. Sect. Exp. Epoxides Ethyl chloroformate, ClCOOEt Ethylthiocyanate, EtSCN Ethyl vinyl ether, EtOCH¼CH2 Ferric nitrate a-Halogenoethers, RCH(X)OR1 Heterocumulenes 1,5-Hexadiene, [H2C¼CHCH2]2 1,2-Hexadien-5-yne, H2C¼C¼CHCH2CCH Hexamethyldisiloxane, Me3SiOSiMe3 Hexamethylenetetramine 1,2,4,5-Hexatetraene [H2C¼C¼C]2 Hydrogen bromide (gaseous) Hydrogen peroxide-acetic acid Hydrogen sulphide Hydroperoxides Hydroxylamine HCl Hypobromite Hypohalite Iron(III) nitrate Isothiocyanates, RN¼C¼S

4.2 þ exps. 6.4.2 8.2.7 8.1 8.2.2

reactivity towards organometallics in prepn. of acetylenic esters reaction with RCCSLi for introduction of EtS groups preparation of (cf. MeSCN) see under vinyl ethyl ether use in prepn. of alkali amides high reactivity of meaning of preparation of from HCCCH2Br and Mg

2.3.1 4.3 6.2 3.9.24 2.3.9

hydrolysis product of Me3SiCl

2.2

use in prepn. of RCCCH2NH2 from HCCCH2Br and Mg preparation of, from PBr3 in preparation of sulphones in preparation of thiols of HCCCH2OR

20.2.6 2.3.9 4.5.33 20.8.2, 5 20.7.5, 6 17.2.9; 20.6.1 Chap. 14 9.2.3 9.1 2.3.1 Table 6.1, 6.4.16

use in Cadiot-Chodk. Coupling preparation and use of

catalyst in prepn. of alkali amides regioselective reaction with RCCCH(Li)X (X ¼ alkyl, OR, NR02 ) and metallated allenes Lithium alanate (LiAlH4) addition to alcohols with a conjugated enyne or diyne system in prepn. of allenic alcohols Lithium bromide (anhydrous) solubilisation of LiCCR assistance in reaction of lithiomethoxyallene with oxirane as solubiliser for CuBr in THF, e.g. as solibiliser for some LiCCR as solubiliser for CuCN Mercury chloride use in prepn. of H2C¼C¼CHMgBr Methyl isothiocyanate, MeN¼C¼S reaction with organometallics Methyllithium LiBr or LiI preparation of Methyl methanethiosulphonate, for introduction of MeS groups MeSSO2Me

3.9.46 12.4.20, 21 5.1 4.5.28 16.6.1 5.2.2 20.3.1–3 2.3.9 6.4.11, 16 2.3.6 8.1

(Continued)

APPENDIX C

461

Chap. Sect. Exp. Methanesulphinyl chloride, MeS(¼O)Cl

Methanesulphonyl chloride, MeSO2Cl Methyl trioctylammonium chloride Methyl thiocyanate, MeSCN Oxetanes Oxiranes Palladium chloride (MeCN)2 Palladium chloride (PhCN)2 Paraffin oil

Peracetic acid, MeCOOOH Phenyl isocyanate, PhN¼C¼O Phenylsulphinyl amine, PhN¼S¼O Phosphoryl chloride-pyridine, POCl3-pyridine Phosphorus pentoxide Phosphorus tribromide Phosphorus trichloride Piperidine Potassium t-pentoxide, KO–C(Me)2Et Potassium thiocyanate, KSCN Pyrrole Sodium hydrogen carbonate Sodium periodate, NaIO4 Sulphenyl chlorides, RSCl

preparation of

20.5.3

use in preparation of sulphinates in preparation of RCCS(¼O)Me in preparation of allenic sulphones use in preparation of sulphonates

20.5.3 8.2.9 18.3.3 20.5.3

use as phase-transfer catalyst for introduction of MeS groups preparation of reaction with RCCLi reactivity towards organometallics preparation from chlorohydrines activity as catalyst activity as catalyst in redistillation of aged comp. use in retro-Favorsky reaction as conductor of heat

10.2.4, 6 8.1 8.2.2 4.2 4.2 þ exps. 20.6.9 16.2 16.2 1.3 20.2.1 see under distillation 20.8.2, 5 6.4.10 6.4.12, 18

in preparation of sulphones reaction with RCCLi reaction with metallated 1- and 2alkynes and allenes in elimination of water from acetylenic tertiary alcohols drying agent use in prepn. of nitriles in prepn. of acetylenic bromides use in preparation of HBr gas in preparation of (CH3CC)3P as solvent in Pd/Cu catalysed cross-couplings homologue of t-BuOK in prepn. of HCCCH2SCN in synthesis of 1-ethynylpyrrole in synthesis of 1-propargylazoles catalyst in isomerisation of HCCCH2C(¼O)Et in preparation of sulphoxides see methanesulphenyl chloride and Benzenesulphenyl chloride

19.1.2 2.2 20.3.5 20.1.1–3 4.5.33 8.2.16 16.7.15, Table 16.1a 2.2 20.3.6 3.9.44 20.2.9 17.2.19 20.8.1–4

(Continued)

462

APPENDIX C

Chap. Sect. Exp. Sulphur dichloride, SCl2 TEBA, Et3PhN–Cl Tellurium Tellurium tetrachloride, TeCl4 Telluroethers Tetraoctylammonium chloride Tetramethylallene, Me2C¼C¼CMe2 Tetrahydrofurfuryl chloride, THF-2-CH2Cl 2-Thienyl propargyl selenide, 2-Thiophene-SeCH2CCH 2-Thienyl allenyl telluride, 2-Thiophene-TeCH¼C¼CH2 2-Thienylmagnesium bromide Thionyl chloride, SOCl2 Thiophene Thiophosgene, Cl2C¼S p-Toluenesulphonic acid p-Toluenesulphonyl chloride, Me–C6H4SO2Cl Tosyl chloride Trialkynylaluminium, (RCC)3Al Triethylamine

Triphenylmethane Triphenylphosphane Vinyl ethyl ether, H2C¼CHOEt

Zinc chloride

in preparation of (RCC)2S use in generation of :CBr2 influence of modification on reactivity in preparation of (RCC)2Te oxygen sensitivity use as phase-transfer catalyst preparation of preparation of

8.2.11 8.2.4, 5 10.2.3, 4 11.2.4 3.9.27

formation of

20.7.6

formation of

20.7.6

preparation of in prepn. of acetylenic chlorides in preparation of (RCC)2SO lithiation of in prepn. of HCCCH2N¼C¼S catalyst in protection of ROH with vinylic ethers in preparation of tosylates

20.10 20.1 8.2.10 20.7.6 20.3.7 20.6.7

in preparation of tosylates in introduction of sec. and tert. alkyl groups solvent in cross-couplings

20.5.4 4.1

in reactions of acetyl. alcohols with RSCl, RSOCl and R2POCl in prepn. of methanesulphonates and methanesulphinates use as indicator in preparation of RCCNa in liq. ammonia stabiliser for Pd complexes use for Hþ-catalysed protection of OH groups catalyst in prepn. of RCCCH2Cl from RCCCH2OMe

8.2.10 11.2.1–4 8.2.4

20.5.4

16.7.7–10 16,17 18.3.1–4 20.5.3 3.9.2 Chap. 16.7 4.5.33, 20.6.7 20.1.12

(Continued)

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463

Chap. Sect. Exp.

Zinc-activated by 1,2-dibromoethane Zinc–copper couple Zinc in DMSO Zinc in EtOH–H2O

3.

in prepn. of HCCCH2COMe from H2C¼C¼CHSnBu3 in prepn. of RCCCH(SEt)2 from RCCCH(OR0 )2 use in partial reductions

20.4.26

preparation and use in generation of allenes from propargylic halides in prepn. of H2C¼C¼C¼CHR in prepn. of HCCCH2CH¼CHR in prepn. of H2C¼C¼CH2

12.4.22–24

20.4.7 19.3.1–4

10.2.16, 17 19.2.17 10.2.15

EXPERIMENTATION TECHNIQUES (cf. Chapter 1 )

Activation of metals a.

Magnesium

The usual way to activate magnesium for Grignard syntheses consists of adding a few crystals of iodine to the mixture of magnesium turnings covered with Et2O or THF. When the brown colour has disappeared, more solvent is added and the addition of the halogen compound is started. Alternatively, a few millilitres of 1,2-dibromoethane may be added and the temperature is allowed to rise. After the exothermic reaction, accompanied by evolution of ethene, has ceased, more of the solvent is added and the preparation of the reagent is started. If the solvent is not sufficiently dry or other impurities are present, a white suspension may be formed during the activation and the preparation of the reagent has to be repeated with dry and pure solvents. For the preparation of some Grignard reagents a stronger activation is required. If the magnesium is activated as described above, the subsequent reaction between (for example) propargyl bromide and the reagent, H2C¼C¼CHMgBr, with formation of ‘Wu¨rtz-coupling’ products predominates. Good results can be obtained if the magnesium is first stirred for about half an hour with a solution of a small amount of mercury(II) chloride in Et2O (Chapter 2, exp. 2.3.9).

b.

Zinc

Zinc powder also can be activated by halogens and by 1,2-dibromoethane. Zinc treated with dibromoethane in ethanol can be used for the partial reduction of

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APPENDIX C

triple bonds. A number of procedures are described in Chapter 19, Sect. 19.3. Additional treatment with a solution of copper(I) bromide and lithium bromide in THF results in a further activation, allowing the reduction of systems with conjugated triple bonds –CC–CC– to (Z, Z)-dienes (Chapter 19, Ref. 6). For the preparation of a zinc–copper couple the metal is successively treated with dilute hydrochloric acid and copper sulphate in water. The couple can be used for the preparation of allenes from acetylenic halides with the system CC–C–X. A detailed description of the activation as well as several applications can be found in Chapter 12, Sect. 12.4.

Addition a.

Of ammonia-sensitive reagents

Methyl iodide reacts very fast with ammonia, as vapour as well as liquid. An essential condition for a good result of a methylation of an anionic substance in liquid ammonia is that the contact between methyl iodide and liquid ammonia is made via the shortest possible way. This means that the reagent does not flow along the glass wall (as in the case of the traditional flask with non-vertical necks) and the dropping funnel ends just above the liquid ammonia. During the addition of methyl iodide nitrogen is passed through the dropping funnel in order to prevent contact of methyl iodide with the ammonia vapour. Occasional cooling of the reaction flask at a temperature below the boiling point of ammonia will reduce the vapour pressure of ammonia. The standard apparatus Figure 1.1 should be used. For reactions on a small scale with a short addition period, the addition may be carried out by syringe, keeping the end of the needle just above the liquid ammonia. Examples are the procedures (4.5.1–4.5.4) in Chapter 4. In the procedure (Chapter 20, Sect. 20.2.1) for propargylamine, HCCCH2NH2, by ammonolysis of propargyl bromide in liquid ammonia similar conditions are applied. Preceding contact of the bromide with the ammonia vapour is avoided in order to prevent formation of dipropargylamine, (HCCCH2)2NH, by subsequent reaction of HCCCH2NH2 with propargyl bromide due to the relatively high concentration of the latter reagent.

b.

Inverse-order addition

Carboxylations are traditionally carried out by pouring the solution of the organometallic intermediate onto a mixture of powdered dry ice and an organic solvent. By applying this inverse-order addition technique, using a large excess of carbon dioxide, further reaction of the carboxylate,

APPENDIX C

465

RC(¼O)OM, with the organometallic compound, RM, is avoided. Alternatively, one may add the solution of RM in portions to a very cold saturated solution of gaseous carbon dioxide in THF as in the procedures for allenic carboxylic acids Chapter 6, Sects. 6.4.13 and 6.4.14. The normal order of addition, i.e. introduction of gaseous CO2, gives excellent results in the case of the less strongly basic RCCLi (Chapter 6, Sect. 6.4.1). Acylations with acetic anhydride, [MeC(¼O)]2O, and dimethylcarbamyl chloride, Me2NC(¼O)Cl, are preferably carried out by adding the solution of the lithium alkynylide, RCCLi, to a solution of an excess of the acylation reagent (Chapter 6, Sects. 6.4.6 and 6.4.9). In the procedure (Chapter 18, Sect. 18.3.8) for H2C¼C(SEt)SCH2CCH, the solution of the enethiolate H2C¼C(SEt)S– in liquid ammonia is added to a strongly cooled mixture of HCCCH2Br and liquid ammonia. If the reactants would be combined in the normal sense, the product would undergo a base-catalysed isomerisation to H2C¼C(SEt)SCCMe under the influence of the enethiolate.

Cooling The use of a cooling bath with a dry ice–acetone mixture or with liquid nitrogen instead of a reflux condenser for reactions in liquid ammonia is mentioned in Chapter 1, Sect. 1.2. Frothing during reactions in liquid ammonia can be effectively suppressed by (temporary) strong cooling of the reaction mixture to below the boiling point of this solvent. Strong cooling may also be applied during addition of methyl iodide to a solution of some intermediate in liquid ammonia (see above).

Drying of reaction products and extracts For drying of extracts containing amines potassium carbonate can be generally recommended. Magnesium sulphate has weak Lewis-acid properties and it may be assumed that amines will be adsorbed. For removal of water from propargylamine (Chapter 20, Sect. 20.2.1), which is completely miscible with water, (machine-) powdered KOH seems more effective than potassium carbonate. Special cases are the mixtures of Mannich reactions containing amines R1CCCH2NR2. These contain water, dioxane and copper salts. The usual work-up by addition of water and extraction with Et2O sometimes gives rise to difficult separation of the layers. A satisfactory way of working up consists of shaking the reaction mixture with an amount of

466

APPENDIX C

potassium carbonate sufficient to fix the water and subsequently extract the resulting slurry with Et2O (Chapter 13, Sect. 13.2, exps. 13.2.2–13.2.4). Alcohols with the structures ROCH(Me)OEt or RO-tetrahydropyranyl may decompose during distillation under the influence of traces of acid adhering to the glass. Their extracts should be dried over potassium carbonate.

Distillation (cf. extraction) As mentioned in Chapter 1, Sect. 1.3 relatively big flasks should be used if strong foaming occurs during a distillation. Redistillation of aged products with an unsaturated system involves the risk of a vigorous decomposition or even explosion in the last stage, especially in the case of propargylic ethers, HCCCH2OR, which can form hydroperoxides with traces of oxygen if not stored carefully for a long period. If a test with a potassium iodide solution shows the presence of relatively small amounts of hydroperoxide, a certain amount of paraffin oil is added, after which the propargylic ether is redistilled in a vacuum and condensed in a strongly cooled receiver (cf. Figure 1.10). The non-volatile hydroperoxide remains as a dispersion or emulsion in the paraffin oil and the danger of an explosion is minimised (Chapter 20, Sect. 20.6.1). Paraffin oil can also serve as a conductor of the heat supplied by the bath during a vacuum distillation of a product from solid side products of the reaction. Examples are the procedures for allenic amines, R1CH¼C¼CHNR2, (Chapter 3, Sect. 3.9.42) and cumulenic amines, H2C¼C¼C¼CHNR2, which have to be distilled off from the solid alkali t-butoxide. The usual aqueous work-up would lead to immediate reaction of these compounds with water. In the reaction of compounds RC(Me)2OH, in which R represents an acetylenic group, with solid KOH or NaOH, giving RH (retro-Favrsky reaction, Chapter 19, Sect. 19.2.1) and in the preparation of alkynenitriles, RCCCN from the carboxamides RCCC(¼O)NH2 and P2O5 (Chapter 20, Sect. 20.3.5) the paraffin oil has a similar function. In the phase transfer reagent-catalysed elimination of hydrogen halide from halogen compounds (Chapter 10, Sects. 10.2.3, 10.2.4 and 10.2.6) the volatile acetylene is distilled off from a mixture of the halogenide, the catalyst, a large amount of powdered potassium hydroxide and high-boiling petroleum ether. As in the case of paraffin oil, the petroleum ether has the function of a heat conductor. For distillations in a high vacuum (less than 1 Torr) wide glass joints (B29) and a very short column ( 5-cm) should be used.

APPENDIX C

467

Extraction As extraction solvents for products with high volatility (bp < 110 C/760 Torr) we recommend high-boiling solvents (bp > 170 C/760 Torr), for example a petroleum ether fraction. The volatile product can be conveniently isolated by mild heating of the extract in vacuum and collecting the product in a strongly cooled receiver (Figure 1.10). If the product is sufficiently stable, it may be redistilled at atmospheric pressure. For unstable products the evacuation– condensation operation under low pressure is repeated. In this manual several examples are described, inter alia for the stable 1-alkynes in Chapter 4, Sect. 4.5.8 and for the extremely unstable HCCCCCCH in Chapter 10.2.8.

Filtration Extracts are usually filtered through filter paper in a funnel. If very fine particles are suspended or much drying agent is present in the solution, the filtering operation may take a relatively long time due to clogging of the pores in the paper. If the air is humid, ice crystals may collect on the paper caused by quick evaporation of the volatile solvent. We generally recommend the use of sintered-glass funnels on which the drying agent can be quickly filtered off by suction. If there is some risk of clogging due to the presence of very fine particles, the sintered glass in the filter may be covered by a layer of 2 cm of some drying agent or of the filter agent celiteR. The filtration of solutions of potassium amide in liquid ammonia, which may contain small particles of potassium is mentioned in Chapter 2, Sect. 2.3.1.

Protonation In most cases the free acetylene, allene or cumulene is obtained from the alkali metal derivative by addition of water. This way of protonation results in addition of water in the case of allenic amines, R1CH¼C¼CHNR2, (Chapter 3, Sect. 3.9.42) or cumulenic amines, H2C¼C¼C¼CHNR2 (Chapter 3, Sect. 3.9.48). t-Butyl alcohol has been successfully applied as protonating agent. The allenic or cumulenic amine can be distilled off from the alkali t-butoxide in a high vacuum. Solid ammonium chloride is used to liberate compounds with a very good solubility in water from their metallic intermediates in liquid ammonia. After evaporation of the ammonia the desired product can be isolated by extraction of the salty residue with ether (Chapter 3, Sect. 3.9.27) or by dissolving the

468

APPENDIX C

salt in the minimum amount of water (Chapter 5, Sect. 5.2.4), making the timeconsuming continuous extraction procedure unnecessary.

Working up a.

Aqueous work-up

In many procedures water or an aqueous solution of acid or some salt is added to the reaction mixture. If this results from reaction with a Grignard reagent, much heat is evolved during the hydrolysis, especially when Et2O has been used as a solvent involving the risk that part of the reaction mixture gets lost. Hydrolysis therefore has to be carried out by (cautious) addition of the reaction mixture to water or an aqueous solution of ammonium chloride. In the procedure for allenic sulphides, R1CH¼C¼CHSR, the intermediate R1CH¼C¼C(Na) R1CH(Na)CCSR, obtained by reaction of R1CH2C CSR with NaNH2 in liquid NH3, is quenched to give the free allenic sulphide by pouring the ammoniacal solution onto crushed ice (Chapter 3, Sect. 3.9.39). Addition of water to the solution of the intermediate in liquid ammonia would give rise to (partial) isomerisation of the allenic sulphide to the starting compound R1CH2CCSR catalysed by not hydrolysed intermediate. For the isolation of volatile products from ammoniacal reaction mixtures a similar quench procedure is applied. After addition of some high-boiling solvent, the reaction mixture is poured onto crushed ice. Following the usual procedure-addition of water after having allowed the ammonia to evaporate-would result in considerable loss of the product. In this book several procedures describe this way of working up (e.g. Chapter 4, Sects. 4.5.2 and 4.5.8). In the procedure for acetylenic ethers, HCCOR, from the acetals ClCH2CH(OR)2 and sodamide in liquid ammonia (Chapter 3, Sect. 3.9.28), hydrolysis after complete evaporation of the ammonia would involve the risk of an explosive decomposition of the metallated ethynyl ethers, NaCCOR. For this reason, the reaction mixture is quenched by rapid addition of crushed ice (after addition of high-boiling petroleum ether) when relatively much ammonia is still present. Volatile compounds prepared by a reaction in THF can be isolated by adding high-boiling petroleum ether, repeatedly washing the organic solution with water in order to remove the THF and finally heating the petroleum ether solution under reduced pressure. The vapour of the product is condensed in a strongly cooled receiver. Examples of this procedure are Chapter 7, Sect. 7.2.1, Chapter 10, Sect. 10.2.8 and Chapter 12, Sect. 12.4.4.

APPENDIX C

469

For products resulting from a reaction with lithium aluminium hydride the usual aqueous work-up by addition of relatively large amounts of water may give rise to problems with the separation of the aqueous layer (containing suspended Al(OH)3) and the organic layer. An easy way consists of adding a relatively small amount of water (preferably dissolved in THF), just sufficient to form a slurry along the glass wall and subsequently extracting this slurry with Et2O, as in the procedures 3.9.46, 3.9.47, and 12.4.20. b.

Dry work-up

Examples of a dry work-up for water-sensitive and water-soluble compounds are mentioned under Protonation. Evaporation of solvents under reduced pressure In a model experiment 20 g of a stable compound with bp 50 C/15 Torr was dissolved in 150 ml of THF and 200 ml of Et2O. The solvents were removed under water-aspirator pressure using a rotary evaporator and a heating bath at 45–60 C. After 20 min the greater part of the solvents had been removed. Exhaustive distillation of the remaining liquid at 15 Torr gave only 17 g of the compound. Apparently, 15% of the compound has been entrained with the vapour of the solvents. For more volatile compounds the loss may be at least 20%. Such losses can be limited by distilling off the greater part of the solvent(s) under atmospheric pressure before using the rotary evaporator. If the compound has a low thermal stability, slow evaporation on the rotary evaporator using a bath at 20–25 C may be considered.

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