PROGRESS IN
HETEROCYCLIC CHEMISTRY Volume 18
Related Titles of Interest Books CARRUTHERS: Cycloaddition Reactions in Organic Synthesis CLARIDGE: High-Resolution NMR Techniques in Organic Chemistry FINET: Ligand Coupling Reactions with Heteroatomic Compounds GAWLEY & AUBÉ: Principles of Asymmetric Synthesis HASSNER & STUMER: Organic Syntheses Based on Name Reactions KATRITZKY: Advances in Heterocyclic Chemistry KATRITZKY & POZHARSKII: Handbook of Heterocyclic Chemistry, 2nd Edition LEVY & TANG: The Chemistry of C-Glycosides LI & GRIBBLE: Palladium in Heterocyclic Chemistry, 2nd Edition (in Press) MATHEY: Phosphorus-Carbon Heterocyclic Chemistry: The Rise of a New Domain McKILLOP: Advanced Problems in Organic Reaction Mechanisms OBRECHT: Solid Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries PELLETIER: Alkaloids; Chemical and Biological Perspectives SESSLER & WEGHORN: Expanded Contracted and Isomeric Porphyrins WONG & WHITESIDES: Enzymes in Synthetic Organic Chemistry Major Reference Works BARTON, NAKANISHI, METH-COHN: Comprehensive Natural Products Chemistry BARTON & OLLIS: Comprehensive Organic Chemistry KATRITZKY & REES: Comprehensive Heterocyclic Chemistry I CD-Rom KATRITZKY, REES & SCRIVEN: Comprehensive Heterocyclic Chemistry II KATRITZKY, METH-COHN & REES: Comprehensive Organic Functional Group Transformations SAINSBURY: Rodd’s Chemistry of Carbon Compounds TROST & FLEMING: Comprehensive Organic Synthesis Journals BIOORGANIC & MEDICINAL CHEMISTRY BIOORGANIC & MEDICINAL CHEMISTRY LETTERS CARBOHYDRATE RESEARCH HETEROCYCLES (distributed by Elsevier) PHYTOCHEMISTRY TETRAHEDRON TETRAHEDRON: ASYMMETRY TETRAHEDRON LETTERS Full details of all Elsevier Science publications, and a free specimen copy of any Elsevier Science journal, are available on request at www.elsevier.com or from your nearest Elsevier Science office.
PROGRESS IN
HETEROCYCLIC CHEMISTRY Volume 18 A critical review of the 2005 literature preceded by two chapters on current heterocyclic topics Editors
GORDON W. GRIBBLE Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA and
JOHN A. JOULE The School of Chemistry, The University of Manchester, Manchester, UK
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For information on all Elsevier publications visit our website at books.elsevier.com Printed and bound in The Netherlands 07 08 09 10 11
10 9 8 7 6 5 4 3 2 1
v
Contents Foreword
x
Editorial Advisory Board Members
xi
Chapter 1:
1
The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives
Heui-Yeon Kim and Cheon-Gyu Cho, Department of Chemistry, Hanyang University, Seoul, Korea 1.1 1.2 1.2.1 1.2.2 1.2.3 1.3 1.4 1.5
Overview of the Diels–Alder chemistry of 2-pyrone 3,5-Dibromo-2-pyrone [4+2] Cycloadditions of 3,5-dibromo-2-pyrone Synthesis and cycloadditions of substituted monobromo-2-pyrones Intramolecular Diels-Alder cycloadditions of 2-pyrones Conclusion Acknowledgements References
Chapter 2:
1 6 6 14 21 24 24 25
Recent developments in the chemistry of nucleosides
27
Jean-Luc Girardet and Stanley A. Lang, Valeant Research & Development, 3300 Hyland Avenue, Costa Mesa, California, USA. 2.1 2.2 2.2.1 2.2.1.1 2.2.1.2 2.2.1.3 2.2.1.4 2.2.1.5 2.2.2 2.2.2.1 2.2.2.2 2.2.2.3 2.2.3 2.2.3.1 2.2.3.2 2.3 2.4 2.5
Introduction Sugar chemistry Hydrogen and oxygen substitutions Modifications at C-1’ Modifications at C-2’ Modifications at C-3’ Modifications at C-4’ Modifications at C-5’ Ring-oxygen substitution Substitution with carbon Substitution with sulfur Substitution with nitrogen Nucleosides with bicyclic sugars Spiro nucleosides Bicyclic nucleosides Combinatorial approaches Conclusion References
Chapter 3:
27 28 29 29 29 32 33 34 38 38 40 41 42 42 44 46 49 49
Three-membered ring systems
Part 1:(2004)
55
Albert Padwa, Emory University, Atlanta, Georgia, USA and Shaun Murphree, Allegheny College, Meadville, Pennsylvania, USA 3.1.1 3.1.2 3.1.2.1 3.1.2.2 3.1.3 3.1.3.1 3.1.3.2 3.1.4
Introduction Epoxides Preparation of epoxides Reactions of epoxides Aziridines Preparation of aziridines Reactions of aziridines References
55 55 55 62 69 69 74 78
Part 2:(2005)
81
Stephen C. Bergmeier and Damon D. Reed, Department of Chemistry & Biochemistry, Ohio University, Athens, Ohio, USA 3.2.1 3.2.2 3.2.2.1 3.2.2.2 3.2.3
Introduction Epoxides Preparation of epoxides Reactions of epoxides Aziridines
81 81 81 87 95
Contents
vi 3.2.3.1 3.2.3.2 3.2.4
Preparation of aziridines Reactions of aziridines References
Chapter 4:
95 97 103
Four-membered ring systems
106
Benito Alcaide, Departamento de Química Orgánica I, Facultad de Química, Universidad Complutense de Madrid, Madrid, Spain and Pedro Almendros, Instituto de Química Orgánica General, CSIC, Madrid, Spain. 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8
Introduction Azetidines and azetes Monocyclic 2-azetidinones (β-lactams) Fused polycyclic β-lactams Oxetanes, dioxetanes, oxetes and 2-oxetanones (β-lactones) Thietanes, β-sultams, and related systems Silicon and phosphorus heterocycles. miscellaneous References
Chapter 5:
Five-membered ring systems
Part 1.
Thiophenes and Se/Te Analogues
106 106 109 113 115 118 118 120
126
Tomasz Janosik and Jan Bergman, Department of Biosciences at Novum, Karolinska Institute, Novum Research Park, Huddinge, Sweden, and Södertörn University College, Huddinge, Sweden 5.1.1 5.1.2 5.1.3 5.1.4 5.1.5 5.1.6 5.1.7 5.1.8
Part 2.
Introduction Thiophene ring synthesis Reactions of thiophenes Non-polymeric thiophene organic materials Thiophene oligomers and polymers Thiophene derivatives in medicinal chemistry Selenophenes and tellurophenes References
126 126 130 135 137 141 143 144
Pyrroles and benzo derivatives
150
Erin T. Pelkey, Hobart and William Smith Colleges, Geneva, NY, USA. 5.2.1 5.2.2 5.2.2.1 5.2.2.2 5.2.2.3 5.2.3 5.2.3.1 5.2.3.2 5.2.3.3 5.2.4 5.2.4.1 5.2.4.2 5.2.4.3 5.2.5 5.2.5.1 5.2.5.2 5.2.5.3 5.2.5.4 5.2.6 5.2.6.1 5.2.6.2 5.2.6.3 5.2.6.4 5.2.7 5.2.7.1 5.2.8
Part 3.
Introduction Synthesis of pyrroles Intramolecular approaches Intermolecular approaches Transformation of other heterocycles Reactions of pyrroles Substitution at nitrogen Substitution at carbon Functionalization of the side-chain Pyrrole natural products and materials Natural products Macrocycles and oligopyrroles Non-oligomeric materials Synthesis of indoles Intramolecular approaches Intermolecular approaches Transformation of other heterocycles Oxindoles, azaindoles, and carbazoles Reactions of indoles Substitution at nitrogen Substitution at C–2/C–3 Functionalization of the benzene ring Functionalization of the side-chain Indole natural products Natural products References
150 150 151 153 155 156 156 157 159 160 160 161 162 163 163 166 167 167 169 169 170 175 176 177 177 178
Furans and benzofurans
Xue-Long Hou, Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China, Zhen Yang, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, Department of Chemical Biology, College of Chemistry, Peking
187
vii
Contents
University, Beijing, China, Kap-Sun Yeung, Bristol-Myers Squibb Pharmaceutical Institute, Wallingford, CT, USA, and Henry N. C. Wong, Department of Chemistry, Institute of Chinese Medicine and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis, The Chinese University of Hong Kong, Hong Kong, China and Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, Shanghai, China. 5.3.1 5.3.2 5.3.2.1 5.3.2.2 5.3.3 5.3.3.1 5.3.3.2 5.3.3.3 5.3.3.4 5.3.4
Part 4.
Introduction Reactions Furans Di- and tetrahydrofurans Synthesis Furans Di- and tetrahydrofurans Benzo[b]furans and related compounds Benzo[c]furans and related compounds References
187 188 188 192 194 194 199 203 209 210
With more than One N Atom
218
Larry Yet, Albany Molecular Research, Inc., Albany, New York, USA. 5.4.1 5.4.2 5.4.3 5.4.4 5.4.5 5.4.6 5.4.7
Part 5.
Introduction Pyrazoles and ring-fused derivatives Imidazoles and ring-fused derivatives 1,2,3-Triazoles and ring-fused derivatives 1,2,4-Triazoles and ring-fused derivatives Tetrazoles and ring-fused derivatives References
218 218 225 232 236 240 241
With N and S (Se) atoms
247
Yong-Jin Wu, Bristol Myers Squibb Company, Wallingford, Connecticut, USA and Bingwei V. Yang, Bristol Myers Squibb Company, Princeton, New Jersey, USA 5.5.1 5.5.2 5.5.2.1 5.5.2.2 5.5.2.3 5.5.2.4 5.5.2.5 5.5.2.6 5.5.2.7 5.5.2.9 5.5.2.10 5.5.3 5.5.3.1 5.5.3.2 5.5.3.3 5.5.3.4 5.5.4 5.5.5 5.5.6 5.5.7
Part 6.
Introduction Thiazoles Synthesis of thiazoles and fused derivatives Synthesis of thiazolines Synthesis of 2-imino-thiazolidine and thiazoline derivatives Reactions of thiazoles and fused derivatives Reactions of thiazolines Thiazole intermediates in synthesis Thiazolium-catalyzed and -mediated reactions Thiazole-containing drug candidates New thiazole-containing natural products Isothiazoles Synthesis of isothiazoles by ring-formation Reactions of isothiazoles Isothiazoles as auxiliaries in organic syntheses Biologically interesting isothiazoles Thiadiazoles and selenadiazoles 1,3-Selenazoles, 1,3-selenazolidines and 1,3-tellurazoles Acknowledgement References
247 247 247 252 254 255 257 258 261 264 265 265 265 268 268 270 271 272 273 273
With O and S (Se, Te) atoms
276
R. Alan Aitken and Lynn A. Power, University of St Andrews, UK. 5.6.1 5.6.2 5.6.3 5.6.4 5.6.5 5.6.6 5.6.7 5.6.8
Part 7.
1,3-Dioxoles and dioxolanes 1,3-Dithioles and dithiolanes 1,3-Oxathioles and oxathiolanes 1,2-Dioxolanes 1,2-Dithioles and dithiolanes 1,2-Oxathioles and oxathiolanes Three heteroatoms References
276 279 282 282 283 283 283 284
With O and N atoms
289
Stefano Cicchi, Franca M. Cordero and Donatella Giomi, Università degli Studi di Firenze, Italy. 5.7.1 5.7.2
Isoxazoles Isoxazolines
288 291
Contents
viii 5.7.3 5.7.4 5.7.5 5.7.6 5.7.7 5.7.8
Isoxazolidines Oxazoles Oxazolines Oxazolidines Oxadiazoles References
Chapter 6:
Six-membered ring systems
Part 1.
Pyridines and benzo derivatives
294 298 300 304 306 307
310
Heidi L. Fraser, M. Brawner Floyd, and Darrin W. Hopper, Chemical and Screening Sciences, Wyeth Research, Pearl River, New York, USA 6.1.1 6.1.2 6.1.2.1 6.1.2.2 6.1.2.3 6.1.3 6.1.3.1 6.1.3.2 6.1.4 6.1.4.1 6.1.4.2 6.1.5 6.1.5.1 6.1.6
Introduction Pyridines Preparation of pyridines Reactions of pyridines Pyridine N-oxides and pyridinium Salts Quinolines Preparation of quinolines Reactions of quinolines Isoquinolines Preparation of isoquinolines Reactions of isoquinolines Piperidines Preparations of piperidines References
310 310 310 313 319 322 322 326 328 328 331 333 333 346
Part 2.
Diazines and benzo derivatives
352
Part 3.
Triazines, tetrazines and fused ring polyaza systems
353
Pilar Goya and Cristina Gómez de la Oliva, Instituto de Química Médica (CSIC), Madrid, Spain. 6.3.1 6.3.1.1 6.3.1.2 6.3.1.3 6.3.2 6.3.3 6.3.3.1 6.3.3.2 6.3.4 6.3.5 6.3.6
Part 4.
Triazines 1,2,3-Triazines 1,2,4-Triazines 1,3,5-Triazines Tetrazines Fused [6]+[5] polyaza systems Triazino and tetrazino [6+5] fused systems Purines and related structures Fused [6]+[6] polyaza systems Miscellaneous fused polyaza systems References
353 353 353 357 359 361 361 363 368 369 371
With O and/or S atoms
376
John D. Hepworth, James Robinson Ltd., Huddersfield, UK and B. Mark Heron, Department of Colour and Polymer Chemistry, University of Leeds, Leeds, UK. 6.4.1 6.4.2 6.4.2.1 6.4.2.2 6.4.2.3 6.4.2.4 6.4.2.5 6.4.2.6 6.4.2.7 6.4.2.8 6.4.3 6.4.3.1 6.4.4 6.4.4.1 6.4.4.2 6.4.5 6.4.5.1 6.4.6 6.4.6.1 6.4.7
Introduction Heterocycles containing one oxygen atom Pyrans [1]Benzopyrans and dihydro[1]benzopyrans [2]Benzopyrans and dihydro[2]benzopyrans Pyrylium Salts Pyranones Coumarins Chromones Xanthones and xanthenes Heterocycles containing one sulfur atom Thiopyrans and analogues Heterocycles containing two or more oxygen atoms Dioxins and dioxanes Trioxanes Heterocycles containing two or more sulfur atoms Dithianes and trithianes Heterocycles containing both oxygen and sulfur in the same ring Oxathianes References
376 377 377 380 382 383 384 386 389 390 391 391 393 393 394 395 395 396 396 396
ix
Contents
Chapter 7:
Seven-membered ring systems
402
John B. Bremner, Institute for Biomolecular Science and Department of Chemistry, University of Wollongong, Wollongong, NSW, Australia and Siritron Samosorn Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok, Thailand. 7.1 7.2 7.2.1 7.2.2 7.2.3 7.2.4 7.3 7.3.1 7.3.2 7.3.3 7.4 7.4.1 7.5 7.6 7.7
Introduction Seven-membered systems containing one heteroatom Azepines and derivatives Fused azepines and derivatives Oxepines and fused derivatives Thiepines and fused derivatives Seven-membered systems containing two heteroatoms Diazepines and fused derivatives Dioxepines, dithiepines and fused derivatives Miscellaneous derivatives with two heteroatoms Seven-membered systems containing three or more heteroatoms Systems with N, S and/or O Seven-membered systems of pharmacological significance Future directions References
Chapter 8:
402 402 402 406 411 412 412 412 418 419 425 425 426 427 427
Eight-membered and larger rings
430
George R. Newkome, The University of Akron, Akron, Ohio, USA. 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 8.10 8.11 8.12 8.13 8.14 8.15 8.16 8.17 8.18 8.19 8.20
Index
Introduction Carbon-oxygen rings Carbon-nitrogen rings Carbon-sulfur rings Carbon-silicon rings Carbon-selenium rings Carbon-oxygen/carbon-nitrogen rings Carbon-nitrogen-oxygen rings Carbon-nitrogen-sulfur rings Carbon-phosphorus-sulfur rings Carbon-phosphorus-nitrogen rings Carbon-selenium-nitrogen rings Carbon-sulfur-oxygen rings Carbon-nitrogen-sulfur-oxygen rings Carbon-nitrogen-metal rings Carbon-phosphorus-metal rings Carbon-oxygen-nitrogen-metal rings Carbon-sulfur-nitrogen-metal rings Carbon-phosphorus-oxygen-metal rings Referencees
430 431 433 436 437 438 438 438 439 440 440 440 441 442 442 443 443 443 443 444
449
x
Foreword This is the eighteenth annual volume of Progress in Heterocyclic Chemistry, and covers the literature published during 2005 on most of the important heterocyclic ring systems. References are incorporated into the text using the journal codes adopted by Comprehensive Heterocyclic Chemistry, and are listed in full at the end of each chapter. This volume opens with two specialized reviews.
The first, by Heui-Yeon Kim and Cheon-Gyu Cho covers ‘The Diels-Alder
cycloadditions of 3,5-dibromo-2-pyrone and its derivatives'. The second, by Jean-Luc Girardet and Stanley Lang discusses ‘Recent developments in the chemistry of nucleosides’. The remaining chapters examine the 2005 literature on the common heterocycles in order of increasing ring size and the heteroatoms present. In the previous volume, Vol. 17, it was not possible to include a chapter on ‘Three-membered rings’ so this volume has two chapters on this topic: 3.1 covers the literature of 2004 and 3.2 covers the publications of 2005. ‘Diazines and benzo derivatives’ does not appear in this volume; Volume 19 will include two reviews of this topic, one covering the literature of 2005 and one that of 2006. The Index is not fully comprehensive – it includes only systematic heterocyclic ring system names. Thus, wherever a pyrrole is discussed, that would be indexed under 'pyrroles'; wherever 'pyrido[3,4-b]indoles' are mentioned an indexed entry under that name will be found; similarly 'aceanthryleno[1,2-e][1,2,4]triazines', 'azirines', '2H-pyran-2-ones', '1,2,4-triazoles', etc., etc. are listed. But, subjects like '4-ethyl-5-methylpyrrole', '5-acylazirines', '6-alkyl-2H-pyran-2-ones', '3alkylamino-1,2,4-triazoles', are not listed as such in the Index. 'Diels-Alder reaction' or 'Heck coupling' etc., are also not indexed. However, additionally this year, the Contents pages list all the subheadings of the chapters which we hope will considerably improve accessibility for readers. We are delighted to welcome some new contributors to this volume and we continue to be indebted to the veteran cadre of authors for their expert and conscientious coverage. We are also grateful to Joan Anuels of Elsevier Science for supervising the publication of the volume. We hope that our readers find this series to be a useful guide to modern heterocyclic chemistry. As always, we encourage both suggestions for improvements and ideas for review topics. Gordon W. Gribble John A. Joule
xi
Editorial Advisory Board Members Progress in Heterocyclic Chemistry 2005 - 2006 PROFESSOR M. BRIMBLE (CHAIRMAN) University of Auckland, New Zealand
PROFESSOR D. ST CLAIR BLACK University of New South Wales Australia
PROFESSOR H. HIEMSTRA University of Amsterdam The Netherlands
PROFESSOR M.A. CIUFOLINI University of British Columbia Canada
PROFESSOR D.W.C. MACMILLAN California Institute of Technology USA
PROFESSOR T. FUKUYAMA University of Tokyo Japan
PROFESSOR M. SHIBASAKI University of Tokyo Japan
PROFESSOR A. FÜRSTNER Max Planck Institut Germany
PROFESSOR L. TIETZE University of Göttingen, Germany
PROFESSOR R. GRIGG University of Leeds UK
PROFESSOR P. WIPF University of Pittsburgh USA
Information about membership and activities of the International Society of Heterocyclic Chemistry (ISCH) can be found on the World Wide Web at http://webdb.uni-graz.at/~kappeco/ISHC/index.html
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1
Chapter 1 The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives Heui-Yeon Kim and Cheon-Gyu Cho* Department of Chemistry, Hanyang University, Seoul, Korea
[email protected]
1.1
OVERVIEW OF THE DIELS-ALDER CHEMISTRY OF 2-PYRONE
As one of the classical 1,3-dienes investigated by Diels and Alder <31A257>, 2pyrones are synthetically useful synthons which can provide various carbocyclic frameworks in the single chemical operation called the Diels-Alder cycloaddition <92TL9111; 99AC47>. However, due to the inherent partial aromatic character, the parent unsubstituted 2-pyrone 1 itself does not undergo cycloadditions as readily as do other cyclic 1,3-dienes. Cycloadditions often require high reaction temperatures which can cause concomittant CO2 extrusion from the bicyclolactone 2, furnishing dihydrobenzenes or aromatized products 3 (Scheme 1). Scheme 1. Diels-Alder cycloaddition of 2-pyrone 1 O 6
O
5
O 3
4
1
R
R
O
R
R
- CO2
heat
R 2
R
3
The reaction sequence in Scheme 1 is a viable synthetic protocol, utilized in the synthesis of various aromatic natural products including lasalocid A <83JACS1988>, rufesine <84JOC4050>, juncusolare <84JOC4033>, among many others. The initially formed bicyclolactone 2 has further synthetic utility, because of the stereochemically controlled rich functionality resulting from the cycloaddition reaction. Some notable applications can be found in total syntheses of taxol <95JACS634>, shikimic acid <86JACS7373>, natural/unnatural sugars and a series of vitamin D3 analogs <95OS231>. Various strategies have been developed to arrest the cycloadditions at the bicyclolactone stage. Performing the reactions in the presence of a Lewis acid or under high pressure can lower the reaction temperature to allow the isolation of the bicyclic lactones. In some cases, using geometrically constrained dienophiles or templates like phenylboronic acid have effectively suppressed the CO2 extrusion. A more widely applicable strategy is matching the electronic demand of the dienophile with that of the 2-pyrone by means of substitution on the 2-pyrone unit, narrowing the energy gap of the frontier orbitals involved in the cycloaddition.
2
H-Y. Kim and C-G. Cho
The cycloadditions of the parent 2-pyrone 1 are not only sluggish, but also often nonselective with respect to both regiochemistry (syn/anti) and stereochemistry (endo/exo). Scheme 2 shows the structures of the four possible isomers. Scheme 2. Regio- and stereochemistry of cycloadducts O
O
O
Z
O
O
O
+
O
Z
+
O
O
O
+
Z
Z syn-endo
syn-exo
Z anti-endo
anti-exo
2-Pyrones with either an electron-donating or -withdrawing substituent can undergo faster and more selective reactions than the parent 2-pyrone 1. Therefore, substitution of 2-pyrone has become an important area of investigation. Some selected examples are shown in Scheme 3, where equations 1 and 2 represent normal electron demand and inverse electron demand cycloadditions, respectively. Scheme 3. Electronic matching of the cycloaddition components O
O + EDG
O
CO2R
O O
EDG CO 2R
(eq. 1)
EDG = -SPh, -OH
O + EWG
normal electron demand D-A
OR
inverse electron demand D-A
O O
EWG OR
(eq. 2)
EWG = -CO2Me, -SO2Ph
The cycloadditions of 2-pyrones bearing various electron-donating and electronwithdrawing groups with electronically matching dienophiles have been thoroughly discussed in reviews by Posner and co-workers in 1992 <92TL9111> and 1995 <99A47>. The DielsAlder reactions of 2-pyrones with unactivated dienophiles are generally non-selective and will not be discussed in this review. The 2-pyrones 4 and 5 with a bromine atom substituted at the C3 or C5 position, respectively, are particularly versatile 1,3-diene synthons, which can readily undergo [4+2] cycloadditions to give the cycloadducts 6 and 7 with high regio- and endo/exo selectivity under milder conditions than the parent 2-pyrone (Scheme 4) <91TL5295; 92TL7839>. They are viable synthetic equivalents of the parent 2-pyrone as the bromine atom can be reductively removed after cycloaddition. Additionally, they exhibit ambident enophilic character and are capable of undergoing both normal and inverse electron demand cycloadditions.
3
The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives
Scheme 4. Diels-Alder cycloadditions of 3-bromo-2-pyrone 4 and 5-bromo-2-pyrone 5 O O
O
Z
Br
Br
O
Z = EWG or EDG
4
O O
Z
O
Br
Z
6
O
Br
5
Z
7
Additionally, the position of the substituent on the 2-pyrone ring is an important factor in the enophilic reactivity of 2-pyrone, as clearly demonatrated by Liao and coworker (Scheme 5) <00OL2049>. Scheme 5. Cycloadditions of 2-pyrone carboxylates O O
O
O
9, MeOH
CO2Me 8
rt, 8 h
O
MeO
O
CO2Me
O
13
rt, 10 h
MeO 2C
82%
12 O
O
5, MeOH
MeO 2C O
14
53%
O
O
O
MeO2C
reflux, 10 h MeO2C
O
5, MeOH
11
O
9 O
O
MeO 2C
10 O
80%
O
O
O
reflux 15
O
O
5, MeOH
MeO2C
No Reaction
16
O
O
3-Methoxycarbonyl-2-pyrone 8 and 5-methoxycarbonyl-2-pyrone 11 undergo cycloadditions with 2-methoxyfuran 9 more readily than 4-methoxycarbonyl-2-pyrone 13. On the other hand, no reaction was observed with 6-methoxycarbonyl-2-pyrone 15, even after prolonged heating in MeOH or MeCN (Scheme 5). The lack of reactivity of 15 was attributed to the steric repulsion of the C6-methyl ester with the incoming dienophile during the formation of the corresponding transition state. This conclusion is based on semiempirical calculations of the transition states leading to the DA product 16 (AM1 and PM3). Table 1. Cycloadditions of 4-halo-2-pyrones. O O
O
CO2Me 50 - 70 oC
X
14 d
entry
2-pyrone
1 2 3
17 (X = Cl) 18 (X = Br) 19 (X = I)
X
O
O
X CO2Me
5-endo
O
O X
CO Me 6-endo 2
O
5-exo
5-endo:6-endo:5-exo:6-exo 41:48:2:9 44:45:4:7 39:47:6:8
O CO2Me X
O
6-exo
CO2Me
combined yield 70% 78% 93%
4
H-Y. Kim and C-G. Cho
In a similar context, Afarinkia and coworkers have shown that 2-pyrones with a Cl, Br or I substituent at the C4 position have marginal enophilic reactivity, only undergoing cycloadditions with electron-deficient dienophiles <05JOC1122>. For example, the reaction of 4-bromo-2-pyrone 18 with excess methyl acrylate provided a mixture of syn/anti and endo/exo isomers in 78% combined yield after heating at 50 – 70 °C for two weeks with no solvent (Table 1). By increasing the temperature, the reaction of 18 with methyl acrylate provided the bicyclic lactone, which underwent CO2 extrusion, to afford a cyclohexadiene intermediate. A second cycloaddition reaction then occurred with the dienophile to furnish barrelenes 20 (Scheme 6). Scheme 6. Formation of barrelenes 20 O
O
O
Z 100
Br 18
oC
Br
O
Z
Z
Z
Z
Z
Br
Br
20
Z = CO2Me
The cycloadditions of 5-aryl-2-pyrone 21 and 6-aryl-2-pyrone 24 with vinylene carbonate 22 further demonstrate the importance of the substitution pattern of the 2-pyrone (Scheme 7) <00TL4955; 00TL7583>. While the cycloaddition of 21 furnished the cycloadduct 23, the reaction of 24 with vinylene carbonate could not be arrested at the cycloadduct stage and only the phenol 25 was isolated, in low yield. Scheme 7. Diels-Alder cycloadditions of 5-aryl-2-pyrone and 6-aryl-2-pyrone O O
O
Ar 21
100 oC
O +
O
O O
22
O O
5d 87%
Ar =
23
MeO
O
OMe OH O
O
O +
Ar' 24
Ar' =
O O 22 O
110
oC
10 d
O
32%
O
25
O
An additional example can be found in the cycloadditions of 5-(indol-2-yl)-2-pyrone 26 with various electron-rich and electron-poor dienophiles reported by Passarella and coworkers (Scheme 8) <00T5205>. While the normal electron demand cycloadditions with electron-deficient dienophiles proceeded under solely thermal conditions, reactions with electron-rich dienophiles required the presence of SiO2 or lanthanide shift agents, such as Eu(FOD)3 and Pr(FOD)3.
5
The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives
Scheme 8. Cycloadditions of 5-(indol-2-yl)-2-pyrone 26 O O
O
O
catalyst +
Z
5 h to 7 d
NSEM
Z NSEM
Z = CHO, COMe, OR, SR
26
27
The highly substituted 6-aryl-2-pyrones 28 react with acetophenones 29 in a stepwise base-induced formal cycloaddition reaction. The reaction proceeds via a sequential Michael and aldol reaction in the presence of an alkali metal hydroxide. In this case, the formal cycloadduct 31 extrudes CO2, providing the diene 32, which subsequently undergoes dehydration to afford aromatic products 33 (Scheme 9) <03TL3363>. Scheme 9. Formal stepwise cycloadditions of 6-aryl-2-pyrones 28 O
R
O O
+ Y
29
O
KOH
X
DMF
Y
O
X O
O
Y
28
X
O
OH
R' R
R' X
Y
R
30
31 R' Y
OH
- CO2
X - H2 O
R
32
R
R'
R' 33
The cycloaddition of 3-hydroxy-2-pyrone 34 with an electron-deficient dienophile can be catalyzed by triethylamine as illustrated in Scheme 10 <95TL5939; 00TL8317>. Reaction with methyl acrylate provided cycloadduct 37 as a mixture of endo/exo-isomers (11:1) in 98% yield after 12 h at ambient temperature. No cycloaddition was observed when the reaction was conducted in the absence of base. Scheme 10. Base-catalyzed Diels-Alder cycloaddition of 3-hydroxy-2-pyrone 34 O
O
Et3N
O
O CO2Me
O
O
O HNEt3
O
OH 34
O
35
Et3NH
36
CO2Me
- Et3N
O OH 37
CO2Me
6
H-Y. Kim and C-G. Cho
The asymmetric Diels-Alder cycloadditions of 2-pyrones have recently attracted much attention. Albeit much remains to be explored, a few successful strategies have been reported, which have been systematically addressed in a recent review <99AC47>. We have found that 3,5-dibromo-2-pyrone 38 undergoes both normal and inverse electron demand cycloadditions more readily than mono-bromo-2-pyrones and these reactions proceed with greater regio- and stereoselectivity (Scheme 11). Moreover, bromides can be selectively functionalized to generate an array of new 2-pyrone synthons, exhibiting much greater applicability than their mono-bromo counterparts. This review is focused on the chemistry of 3,5-dibromo-2-pyrone and derivatives thereof. Scheme 11. The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone O O
O
O
Z = electron donating or withdrawing group
Z Br endo-adduct
Br 38
Br
Z
+ Br
O
1.2
3,5-DIBROMO-2-PYRONE
1.2.1
[4+2] Cycloadditions of 3,5-dibromo-2-pyrone
O
+
Br Z
Br exo-adduct
3,5-Dibromo-2-pyrone was first reported by Pirkle and coworkers <69JOC2239> in 1969, and was prepared from 2-pyrone 1, via either a 3-step sequence that involved two successive brominations, followed by elimination of HBr, or a four-step process comprised of a bromination, HBr elimination and photochemical bromination reaction, followed by a second HBr elimination (Scheme 12). Scheme 12. Preparation of 3,5-dibromo-2-pyrone 38 reported by Pirkle and coworkers O O
O
Br2
O
O
O
O
Et3N
Br
Br
Br
Br + Br
Br Br
Br
Br2 heat
1
O
38
O Br
Et3N O Br
- HBr
O
O Br
Br2 hv
Br Br
O
O Br
No synthetic applications of 38 had since been reported, presumably due to its difficult preparation. We found that it can be efficiently prepared in single step from the commercially available coumalic acid 39 (Scheme 13) <01TL1065; 02JOC290>, in which coumalic acid undergoes concomitant aromatic bromination and bromo-decarboxylation reactions <97JOC199; 94JOC3543>.
The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives
7
Scheme 13. One-step synthetic protocol for 3,5-dibromo-2-pyrone from coumalic acid O HO2C
O
CCl4, MeCN (2:1) 39
O
NBS (3 eq), LiOAc, Bu4NBr
O
Br
65 - 76%
Br 38
Both 3-bromo-2-pyrone 4 and 5-bromo-2-pyrone 5 can also be prepared from 2-pyrone-3carboxylic acid 40 and coumalic acid 39 in one step, albeit in moderate yields, utilizing the same protocol, varying only the equivalents of NBS employed in the reaction (Scheme 14). Scheme 14. Synthesis of 3-bromo-2-pyrone 4 and 5-bromo-2-pyrone 5 O
O CO2H
40
O HO2C
CCl4, MeCN (2:1) 42%
O Br
4
O
same as the above
O 39
O
NBS (1.2 eq), LiOAc, Bu4NBr
35%
Br
O 5
The results of the DA cycloadditions of 3,5-dibromo-2-pyrone 38 are summarized in Table 2 <02JOC290>. Only the endo products are shown for clarity (a; 5-endo, b; 5-exocycloadduct). Except for the entries 2, 6 and 9, using toluene as the solvent generally provided better results than CH2Cl2 with respect to chemical yields, endo/exo ratios and reaction rates. 3,5-Dibromo-2-pyrone proved to be more reactive than either 3-bromo-2pyrone or 5-bromo-2-pyrone in both normal and inverse electron demand cycloadditions. For example, 3,5-dibromo-2-pyrone with methyl methacrylate, methyl crotonate and benzyl vinyl ether provided 41a, 47a and 51a in 84%, 82% and 69% yields (entries 1, 7 and 11), while the same reactions with mono-bromo-2-pyrones 4 or 5 gave the corresponding cycloadducts in 30 – 40% yields under the same reaction conditions. The two bromine atoms act in an additive manner to enhance the reactivity. Because 5-bromo-2-pyrone had been previously shown to be more reactive than 3-bromo-2-pyrone <92TL9111>, the reactivity order of the bromo-2-pyrone series is the following: 3,5-dibromo-2-pyrone > 5-bromo-2-pyrone > 3bromo-2-pyrone. Notably, the cycloaddition of 3,5-dibromo-2-pyrone is more stereoselective than monobromo-2-pyrone counterparts 4 and 5. For instance, cycloadditions with acrylonitrile and benzyl vinyl ether provided the cycloadducts 44 and 51 in endo/exo ratios of 76:24 and 100:0 (entries 4 and 11), respectively, while 5-bromo-2-pyrone 5 afforded the corresponding cycloadducts in ratios of 54:46 and 67:33, respectively. Intriguingly, the cycloadditions with dimethyl fumarate and dimethyl maleate furnished an identical mixture of two diastereomers, in slightly different ratios (entries 8 and 9 in Table 2). Comparison of the coupling patterns of their 1H NMR spectra to other structurally related bicyclolactones, as well as performing decoupling experiments, established the relative stereochemistry of 49a and 49b, which was ultimately confirmed by their single crystal X-ray crystallographic analyses (Figure 1).
8
H-Y. Kim and C-G. Cho
Table 2. Reaction of 3,5-dibromo-2-pyrone with various dienophiles. entry
dienophile
endo:exo
conditions
O
O 1
OCH3
toluene, 100
oC,
5h
94:6 Br
2
CH2Cl2, 50 oC, 12 h
H
O toluene, 100 oC, 5 h
toluene, 100 oC, 12 h
42a
71%b
43a
84%
44a
90%
45a
92%
46a
84%
47a
82%
48a
80%
49a (same as 48a)
79%
O CO2Me Br O
O COMe
O CN O
O
O
N Et
toluene, 100 oC, 12 h
76:24 Br O O
O 6
OCH3
CH2Cl2, 100 oC, 24 h
86:14 Br
OCH3
toluene, 100 oC, 4 d
MeO2C
CO2Me
toluene, 100 oC, 3 d
MeO2C
CO2Me
toluene, 100 oC, 3d
Me
O CO2Me
Me O CO2Me O Br
52:48
CO 2Me CO2Me
Br 9
NEt
O Br
62:38 Br
8
Br O
O Br
O 7
CH2OH
O Br
76:24 Br
5
Br
O Br
94:6 Br
CN
84%
O
95:5 Br
3
41a
O
O
4
yielda
endo-adduct
64:36
O O Br 10
OEt
CH2Cl2, 50 oC, 2 d
86:14 Br
50a
75%
51a
69%
OEt O O Br
11
OBn
toluene, 100 oC, 3d
100:0 Br
OBn
a) total isolated yield (endo + exo), b) the cycloadduct was reduced with NaBH4
The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives
9
Figure 1. ORTEP representations of the X-ray crystal structures of 49a and 49b, respectively.
Apparently, the stereochemistry of dimethyl maleate was not preserved during the cycloaddition, implying that the cycloaddition proceeded in a stepwise, rather than a concerted fashion <98BKCS957>. Monitoring the reaction progress by TLC and GC indicated the appearance of dimethyl fumarate from the reaction mixture comprised of 3,5dibromo-2-pyrone and dimethyl maleate after a few hours. The concentration of dimethyl fumarate increased during the course of the reaction, and slowly decreased as the cycloaddition progressed. Additionally, no cis-trans isomerization was observed when dimethyl maleate was heated alone in toluene. Although not isolated, 1H NMR and GC analysis of the reaction mixture indicated the existence of cis-disubstituted bicyclolactones. Based upon this evidence, the cycloaddition of 3,5-dibromo-2-pyrone with dimethyl maleate is reversible, proceeding through zwitterionic intermediates, 49-endo-1 and 49-exo-1, in which C-C bond rotation takes place to afford sterically less congested 49-endo-2 and 49exo-2, respectively (Scheme 15). The reverse reactions from 49-endo-2 and 49-exo-2 would then furnish dimethyl fumarate.
Scheme 15. Proposed mechanistic pathways O +O
Br CO2Me
Br MeO
O
O
Br O 49-endo-1
+O
+O
BrO OMe CO2Me 49-endo-2
O +O
Br CO Me 2
Br CO Me 2
O Br 49-exo-1
OMe
Br MeO
O 49-exo-2
Because of the higher reactivity, 3,5-dibromo-2-pyrone can undergo the D-A cycloaddition with sterically hindered silyl enol ethers as summarized in Table 3 <02TL8193>.
10
H-Y. Kim and C-G. Cho
Table 3. D-A cycloaddition of 38 with silyl enol ethers dienophile
entry
cycloadduct
conditions
O Br
1 Br
52a
53a Br
OTMS
Br
54a
55a OTMS
Br
tol, 100 oC, 24 h
99:1
86%
tol, 100 oC, 48 h
99:1
73%
tol, 100 oC, 24 h
99:1
89%
tol, 100 oC, 72 h
35:65
85%
O OTMS O Br
5
85%
O OTBS O Br
4
93:7
O OTMS O Br
3
tol, 100 oC, 24 h
O OTBS O Br
2 OTBS
combined yield
O
OTBS
OTMS
endo:exo
56a Br
OTMS
The reactions provided tricyclolactones 52a – 56a in good yields and endo/exo selectivity except entry 5, in which the formation of the exo-isomer prevailed. The resultant cycloadducts can be readily manipulated into bicyclic triols as exemplified with 54a. Reductive removal of tertiary alkyl bromide (vide infra) and reductive cleavage of the lactone afforded 58 in good overall yield (Scheme 16).
Scheme 16. O O
O Br
Bu3SnH
O
HO H
LAH/THF
AIBN/benzene Br
54a
OTBS
88%
Br Br
57
OTBS
84%
H
OTBS
H OH 58
The bromine atoms present in the cycloadducts (Table 2) can be independantly functionalized. Treatment of cycloadduct 41a with 2.4 equiv of Bu3SnH removed both vinyl and tert-alkyl bromides to furnish 59 in 75% yield (Scheme 17), while reaction with 1.2 equiv of Bu3SnH removed only the tertiary alkyl bromide at the bridgehead (C4) to afford 60 in 74% yield. The vinyl bromide can be readily functionalized utilizing Pd-catalyzed coupling reactions <02TL5591>.
11
The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives
Scheme 17. Selective functionalizations of cycloadduct 41a O O H
59
O
O Bu3SnH (2.4 eq)
H
O
AIBN, PhH, reflux
CO 2Me
Br
75%
41a
Bu3SnH (1.2 eq)
Br CO2Me
AIBN, PhH, reflux 74%
H
O Br
CO2Me
60
"Pd" CO 2Me
PhSnBu3 or PhB(OH)2
82% O
MeO2C
CO2Me
61
O
O Br
O
O Ph
62
TMS
SnBu3 65%
60-72%
Br CO2Me
O
Br
O
O
CO2Me
63
86%
64
TMS
Br CO2Me
As seen in 61 and 63, various 1,3-diene functionalities can now be readily incorporated into the bicyclolactone. Summarized in Table 3 are the results of the cycloaddition of 63 with various dienophiles <02TL5591>. Notably, cycloaddition proceeded in a highly regio- and stereoselective fashion to provide, in all cases, virtually a single diastereomer out of four possible isomers <01OL2949>. Interestingly, the reaction of nor-Br-bicyclic diene 66 with Nethylmaleimide afforded a mixture of two diasteromers 67-endo and 67-exo in a ratio of 62:38 (Scheme 18, representations in an alternative orientation for clarity). Table 4. Cycloadditions of 63 with various dienophiles entry
dienophile
cycloadduct
conditions
O
CO2Me
MeO2C O
100 oC, 8 h
1
EtN NEt
100 oC, 30 h
O O
O
O 100 oC, 48 h
O
O
70%
CO2Me Br CO2Me
65b
66%
Br CO2Me
65c
58%
O
O 4
O
O
O
3
O
O
O
Br 65a
MeO 2C
CO2Me
2
yield
100 oC, 24 h
O
O
Br CO2Me
65d
61%
12
H-Y. Kim and C-G. Cho
Scheme 18. Cycloaddition of nor-Br bicyclic diene 66 O H
O
Z
+
Et N
100 oC, 30 h 66%
O
66
O
O
O
H H
Z = CO2Me
O
H
H
+
O
NEt
O
O
H H Z O 67-endo (62 : 38)
H H Z NEt 67-exo O
Although it is not entirely clear, there may be a steric repulsion between the bridgehead Br and the carbonyl group of the incoming dienophile (N-ethylmaleimide), which destabilizes the corresponding exo-transition state. Another interesting effect of having a bridgehead Br is that it prevents the aromatization of the initially formed cycloadduct. The nor-Br cyclic diene 66 furnished aromatized cycloadducts 68 and 69, in which the cycloadduct was dehydrogenatively aromatized by the excess dienophile, in each case (Scheme 19, representations in an alternative orientation for clarity). In constrast, the same reaction with 63 bearing the bridgehead Br stopped at the initial cycloaddition stage (entries 1, 3, Table 4). Scheme 19. Cycloadditions of nor-Br bicyclic diene 66 MeO2C H
O
MeO 2C
100 oC, 8 h, 70%
MeO2C
CO 2Me
O
O
O
O
CO2Me
O
H O
O
CO2Me 68
O
66 o
100 C, 48 h, 58%
O
H
CO 2Me
69
The reaction of 38 with styrenes 70 provided aryl-substituted bicyclolactones 71 with good endo/exo selectivity (Table 5, actual ratios not shown) <02BKCS1021>. Table 5. Cycloaddition of 38 with styrenes O O
O +
Br entry 1 2 3 4 5 6 7 8
Br
70 70a (Ph) 70b (2-BrC6H4) 70c (4-BrC6H4) 70d (2-MeOC6H4) 70e (4-MeOC6H4) 70f [[2,3-(MeO)2C6H3] 70g [2,4-(MeO)2C6H3] 70h [3,4-(MeO)2C6H3]
O
toluene Ar
Ar
100 oC
70
38 time
71 (yield)
entry
5h 15 h 12 h 6h 5h 12 h 3h 10 h
71a (90%) 71b (96%) 71c (79%) 71d (87%) 71e (86%) 71f (99%) 71g (90%) 71h (94%)
9 10 11 12 13 14 15 16
Br
Br 70
71 time
70i [1,4-(MeO)2C6H3] 5 h 70j [1,3,4-(MeO)3C6H2] 8 h 70k (4-Me2NC6H4) 6h 70l (4-MeCONHC6H4) 9 h 70m (2-pyridyl) 13 h 70n (3-pyridyl) 7h 70o (4-pyridyl) 9h 70p (2-thienyl) 5h
71 (yield) 71i (85%) 71j (80%) 71k (98%) 71l (99%) 71m(60%) 71n (93%) 71o (82%) 71p (94%)
13
The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives
The mixture of endo/exo cycloadducts were directly treated with base to trigger a one-pot, three-step reaction sequence, involving lactone opening, HBr elimination and aromatization to give the corresponding biaryl compounds 74 in good yields (Scheme 20) <02BKCS1021>. The resultant biaryls can be readily applied to the generation of the sartan class of therapeutics such as irbesartan, losartan, valsartan, candesartan and temisartan, currently used as angiotension II antagonists. Scheme 20. One-pot, three-step synthesis of 2-carboxy-biaryls O
Br
R Br
O
R NaOMe
71
- HBr
Br MeO2C
R
R
CO2Me
OH HO Br 72
- H2 O
Br 73
CO2Me
Br 74
The tribromocycloadduct 71b (Scheme 21) can be used in the synthesis of novel polycyclic skeletons. Stille coupling reaction with excess vinyltributyltin installed both diene and dienophile groups, which underwent intramolecular Diels-Alder (IMDA) cycloaddition in a tandem fashion to furnish 76 as a single diastereomer in 65% yield <03JOC10191; 96CR167>. Scheme 21. Tandem coupling-IMDA cycloaddition of 71b. excess
Br Br
Br O
O
H
SnBu3 Pd(PPh3)4, tol reflux
71b
Br
O
Br
O
O
O
75
76
R1 Br Br
Br O O
+
71b R2
O O
R1
Br
"Pd" O
M
R1
Br
R2
O O
79
M
Br "Pd"
O
M = SnBu3 or B(OH)2
R2
78
R1 H Br
80
Because the initial oxidative addition of Pd(0) is faster with the aryl bromide than the vinyl bromide, the vinyl groups can be selectively coupled to give 78, by using one equivalent of organo-stannane or boronic acid. Coupling with a second equivalent of organo-
14
H-Y. Kim and C-G. Cho
stannane or boronic acid provided 79, which also underwent an IMDA cycloaddition reaction in the same pot affording benzotetracyclolactones 80.
1.2.2
Synthesis and cycloadditions of substituted monobromo-2-pyrones
Palladium-catalyzed coupling reactions of 38 (Scheme 22) take place regioselectively at C3. Subsequent studies have shown that the oxidative addition of the catalytically active “Pd(0)” occurs faster at this carbon because of its lower electron density, relative to C5, indicated by the 13C NMR spectrum <05CC431; 00ACR314>. Scheme 22. Regioselective Pd-catalyzed coupling reactions of 3,5-dibromo-2-pyrone O
O 113.8
100.0
Br
Br
+
O
"Pd"
"R" (electrophiles)
R
Br
38
O
81
Sonogashira coupling with various alkynes 82 (Scheme 23) generated an array of 3alkynyl-5-bromo-2-pyrones 83 in good yields <02OL1171>. Under these conditions, no C5alkynylated 2-pyrone products were observed. Scheme 23. Sonogashira coupling reactions of 3,5-dibromo-2-pyrone O Br
O Br
O
Pd(PPh3)2Cl2, CuI, Et3N
O
R
+
dioxane, rt
82
Br
38
R
83
R = TMS, TIPS, Ph, CH2OH, CH2Ph, n-Bu, 1-cyclohexenyl, (CH2)4
Scheme 24. Cycloadditions of 3-(TMS-ethynyl)-5-bromo-2-pyrone O CO2Me O
TMS
Br 83a
O
O
Br
CO2Me 84-endo (87:13) O
OBn
84-exo O
TMS
O
O
+
toluene/100 oC 71%
Br
Br
OBn 85-endo
(74:26)
Br
TMS CO2Me
+
toluene/100 oC 63%
O
O
TMS
85-exo
TMS OBn
15
The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives
The resultant 3-alkynyl-5-bromo-2-pyrones 83 are potent ambident dienes, undergoing cycloadditions with both electron-rich and electron-poor dienophiles. As exemplied in Scheme 24, 3-[(trimethylsilyl)-ethynyl]-5-bromo-2-pyrone 83a underwent efficient cycloaddition with benzyl vinyl ether, as well as with methyl acrylate, to afford the corresponding cycloadducts 84 and 85, respectively. Cycloaddition of 3-ethynyl-5-bromo-2-pyrone 86 (Scheme 25) with 2-substituted styrenes provided cycloadduct 87-endo, which have been elaborated to polycarbocycle 9 0 <03TL4439> via a carbopalladation/trapping process <03OL845; 89JACS3454>. During this process, oxidative addition of “Pd(0)” occurs regioselectively at the aryl carbon, which then undergoes an addition reaction across the triple bond. The vinyl palladium 89 was subsequently trapped with either organotins or organoboronic acids to give 90. Opening of the lactone ring with NaOMe then furnished a series of tetrahydrofluorenes. Scheme 25. Cyclocarbopalladation of 87-endo O
O
Br
R'
X
Br O
heat
R'-M, "Pd"
Br O
O 86 +
H
O
87-endo PdL2
R'-M
X X = Br, I, OTf
PdL2X
Br O O
90
M = SnR3, B(OH)2
PdL2I
H Br O
88
89
O
Similarly, the Pd-catalyzed stannylation of 3,5-dibromo-2-pyrone 38 (Scheme 26) provided 3-(trimethylstannyl)-5-bromo-2-pyrone 91 exclusively. Coupling with various arylhalides furnished a series of 3-aryl-5-bromo-2-pyrones 92 in good yields <02TL5779>. Scheme 26. Synthesis and coupling reactions of 3-(Me3Sn)-5-bromo-2-pyrone 91. O
Br 38
O
Pd(PPh3)4, (Me3Sn)2
Br
THF, 100 oC, 2 h 67%
O Br
O SnMe3
91
ArX, CuI Pd(PPh3)2Cl2 DMF, 50 oC, 3 h X = I, Br
O Br
O Ar
92
Ar = Ph, 4-O2NC6H4, 2-O2NC6H4, 2-MeO2CC6H4, 4-MeOC6H4, 4-FC6H4, 3-IC6H4, 4-NCC6H4, 4-MeCOC6H4, 4-PhCOC6H4, 1-naphthalenyl, 2-thienyl, 3-quinolinyl
We also found that the C3 carbon of 38 (Scheme 26) can be selectively coupled with various organotin reagents 93 to produce the 3-substituted pyrones 81 in good yields <02TL5779>.
16
H-Y. Kim and C-G. Cho
Scheme 27. The Stille coupling reactions of 3,5-dibromo-2-pyrone 38 O
O +
Br
Br
O
Pd(PPh3)4, CuI
R-SnBu3
Br
toluene, 100 oC
93
R
81
38 R =
EtO
O
O
MeO2C
N
(Z = CN, OMe, CO2Me)
Z
The ambident enophilic character of the resultant 3-aryl-5-bromo-2-pyrone 81 was demonstrated by the easy cycloadditions of 3-phenyl-5-bromo-2-pyrone 94 (Scheme 28) with both methyl acrylate (MA) and benzyl vinyl ether (BVE), affording the corresponding cycloadducts 95 and 96 in good yields with varying endo/exo selectivity. Scheme 28. D-A cycloadditions of 94 with MA and BVE. O CO 2Me O
O
tol, 100 oC, 7 h 87%
O
O
Br
O
+
CO2Me 95-endo (>99:1)
Br
95-exo
O Br
OBn
94
O
O
tol, 100 oC, 12 h 99%
Br
CO2Me
O
+ OBn
96-endo
(70:30)
Br
OBn
96-exo
Stannylated 2-pyrones 91 and 98 (Scheme 29) are competent 1,3-dienes, reacting with methyl acrylate to afford the stannylated bicyclolactones. However, 91 and 98 do not react with the electron-rich dienophile BVE. Scheme 29. Cycloadditions of 91 and 98. O
O SnMe3
O
CO2Me tol, 100 oC, 24 h
Br 91
97%
O
Br 97-endo
SnMe3
CO2Me tol, 100 oC, 24 h 54%
SnMe3
O
CO2Me 97-exo
(90:10)
O SnMe3
98
SnMe3 CO2Me +
Br
O O
O
O
O SnMe3 CO2Me
Br 99-endo
O
+ (68:32)
SnMe3 CO2Me
Br 99-exo
17
The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives
2-Pyrone derivatives containing a 2-pyridyl substituent at C3 can undergo Lewis-acid catalyzed DA cycloadditions with electron-rich dienophiles. Shown in Scheme 30 is the ZnBr2 catalyzed cycloaddition of 100 with BVE. After 48 hours at -20 °C, the reaction afforded endo-cycloadduct 102 as only product in 81% yield. Scheme 30. ZnBr2-catalyzed D-A cycloaddition of 100 with BVE. O
N
Br
O
ZnBr2 (0.1 eq)
O
O Br
CH2Cl2 -20 oC
100
O
ZnBr2 N
OBn 81%
101
O Br
102
N OBn
Under the reaction conditions, 3-(2-furyl)-5-bromo-2-pyrone and 3-(2-thienyl)-5-bromo2-pyrone also undergo ZnBr2-catalyzed D-A cycloadditions with BVE, but not as readily as does 100. After 12 hours at ambient temperature, cycloaddition products were produced in 30 - 40% yield. Mono-coordinating Lewis acids, such as BF3 etherate, did not promote the reaction. Additionally, no cycloaddition products were observed with electron-deficient methyl acrylate under identical reaction conditions. The 3-(2-pyridyl)-5-aryl-2-pyrones 103a – 103d (Scheme 31) also underwent smooth ZnBr2-catalyzed cycloaddition reactions with BVE to give the endo-cycloadducts 104a – 104d with no detectable amount of exo-adduct in each case. Scheme 31. ZnBr2-catalyzed D-A cycloaddition of 103a – 103d with BVE. O
O
N ZnBr2, THF
O
+ R 103a - 103d
R=
OR' R' = Et, Bn N
O
N
rt, 48 h 55 - 73% endo:exo > 99:1 O
R
OR' 104a -104d
S
The Pd-catalyzed amination reactions <98AC(E)2046; 01JOC2560> of 3,5-dibromo-2pyrone 38 provided an array of structurally novel 2-pyrones with primary and secondary, aromatic and aliphatic amines at C3 in a highly regioselective manner (Scheme 32) <03TL95>. The 3-amino-5-bromo-2-pyrones 106 were expected to favor normal electron demand cycloadditions, compared to the parent 3,5-dibromo-2-pyrone, because of the presence of the electron-donating amino group. Summarized in Table 6 are the results of the cycloadditios of 3-phenylamino-5-bromo-2-pyrone 106a with various electron-deficient dienophiles (only exo-adducts were shown for clarity) <04TL1683>. Attempted cycloaddition of 106a with electron-rich BVE gave only traces of cycloaddition products, even after prolonged heating at 100 oC. Unlike the parent 3,5-dibromo-2-pyrone or other 2-pyrone derivatives, 3phenylamino-
18
H-Y. Kim and C-G. Cho
Scheme 32. Pd-catalyzed amination reactions of 3,5-dibromo-2-pyrone O
O
Br
R-NH2
Br
toluene, 110 oC, 0.5 - 5 h
Br
NH2
106
NH2
NH2
NH2
N
N
Me
NH2
NH2
NH2
NH
O NHR
105
38
R-NH2 =
O
Pd(OAc)2, xantphos, Cs 2CO3
+
NH
MeO
NH
nPrNH2
MeN
nBuNH2
Me
Et2NH
-5-bromo-2-pyrone 106a favors the formation of exo-cycloadduct. A simple molecular modeling study suggested that the aryl group imposes an additional steric repulsion with the incoming dienophile, destabilizing the otherwise favorable endo-transition state. Table 6. D-A cycloadditions of 106a with various electron-deficient dienophiles. entry dienophile
% yield entry dienophile (endo:exo)
exo-adduct O
O 1
OCH3
O
O
O NHPh CO2Me
95 (47:53)
6
O NHPh CO2Me
OCH3
107b
Br
Br
O O 2
O NHPh COCH3
CH3 Br
3
Br O 4
O O 5
81 (53:47)
O NHPhO
NEt
OCH3 Br
O
O
NEt 110b
O NHPh CO2Me Me
Ph(4-Br) Br CO2Me
8 MeO2C
109b
O
Br
7
108b
O O NHPh CN
CN
85 (18:82)
84 (44:56)
9
% yield (endo:exo)
exo-adduct
Br
CO2Me CO2Me Br
Me O
80 (46:54)
112b
O NHPh Ar
83 (76:24)
O
113b O NHPh CO2Me 81 (10:90) CO2Me 114b O 84 (30:70) O NHPh CO2Me CO 2Me 115b
84 (48:52)
111b
It is noteworthy that the stereochemistry of dimethyl maleate was preserved during the cycloaddition to give cis-disubstituted cycloadducts (entry 9). The cycloaddition of the parent 3,5-dibromo-2-pyrone with the same dienophile was shown to proceed in a stepwise fashion to produce trans-disubstituted cycloadducts (cf. entry 9, Table 2). Contrary to previous results (cf. Table 2), the reactions in CH2Cl2 gave uniformly better results than in toluene, in terms of
19
The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives
both reaction rates and product yields. Lactone ring opening with NaOMe provided a series of conformationally constrained α-amino acid derivatives <01T6429; 95JACS7904>. In general, the endo/exo stereochemistry of the 2-pyrone cycloadduct can be assigned by the chemical shift of the C5-methine proton. The C5 proton of exo-cycloadduct normally appears at higher field than the proton of endo-cycloadduct, because of the anisotropic shielding effect of the olefin bridge. The trend of the chemical shift in the case of the 3-(Nanilino) derivatives 107b – 115b is completely reversed; the C5-proton of exo-cycloadduct 107b resonates at lower field than that of endo-cycloadduct 107a. The unusual downfield shift of the proton in the exo-adduct is believed to be due to the anisotropic deshielding effect of the neighboring phenyl group. A simple MM2 calculation study suggested that Hb lies in the deshielding cone of phenyl ring. O O
O
H N
O
Ha 3.04 ppm CO2Me
Br
107a-endo
H N CO2Me Hb 3.58 ppm 107b-exo
Br
Figure 2. 1H NMR chemical shifts of Ha and Hb. The 2-pyrone 116 (Scheme 33), containing the weakly electron-donating carbamate group at C3, has been reported to undergo cycloadditions with alkynes in refluxing decalin or tetralin, providing aniline derivatives 118 upon elimination of CO2 and aromatization <04JOC3193>. Scheme 33. Cycloaddition of 116 with various alkynes
R2
O
O
R1
R3 +
NHCOPh 116
R4
NHCOPh R4
O tetralin
- CO2
NHCOPh O R4
heat R1
R2
117
R1
R3
R3 R
2
118
Because of the special effect of Cu(I) <90JOC5359; 96JACS2748; 06OL1109> and solvent, the Pd-catalyzed Stille coupling reactions of 38 can be altered to take place at C5, rather than C3, as shown in Table 7 <03JACS14288>. Table 7. Regiocontrolled Stille coupling reactions O Br
38
entry 1 2
O Br
+ PhSnBu3
O
conditions Br
94
conditions Pd(PPh3)4, CuI (0.1 eq), toluene, 100 oC Pd(PPh3)4, CuI (1.0 eq), DMF, 50 oC
O Ph
O +
Ph
119
O
O Br
+
Ph
O
120
Ph
time
94
119
120
0.5 h 2h
94% trace
trace 75%
trace trace
20
H-Y. Kim and C-G. Cho
Suzuki coupling reactions of 38 also proceed in a highly regiocontrolled fashion to provide either C3-coupled or C5-coupled products, depending on the reaction conditions (Table 8) <04SL2197>.
Table 8. Regiocontrolled Suzuki coupling reactions O Br
O Br
38
O
conditions
+ PhB(OH)2
Br
Ph
94
entry conditions Pd(PPh3)4, K2CO3, toluene, 100 oC Pd(PPh3)4, CuI (1.0 eq), Na2CO3, DMF, 50 oC
1 2
O
O
+
Ph
O
119
Br
O +
Ph
O
120
Ph
time
94
119
120
4h 4h
81% trace
trace 89%
trace trace
A series of 5-substituted-3-bromo-2-pyrones can be thus readily synthesized as summarized in Figure 3. The resultant 2-pyrones are expected to be potent ambident dienes as exemplified by the cycloadditions of 5-phenyl-3-bromo-2-pyrone with methyl acrylate and benzyl vinyl ether (Scheme 34).
Figure 3. 5-Subsituted-3-bromo-2-pyrones O
O
O
Br 121
O
122 O
O S
Br 126
nBu
Br
O O
Me
Z 131: Z = CO 2Me 132: Z = CN, 133: Z = OMe
Me
134
125 O
N
O
O
Br 129
O Br
Br
124
O Br
O F
O
135
O Br
130 O
Br F
O
TMS
128 O
O
O Br
Ph
123
O
O Br
O
Br
127 O
O
Br
OEt
O
O
O
O Br
136
21
The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives
Scheme 34. Cycloadditions of 119 with MA and BVE O CO2Me
Br
O
O
O
Ph
85%
CO 2Me 137-endo
Br
Ph
O
OBn tol, 100 oC, 12 h 89%
Ph
CO2Me
137-exo
O
119
1.2.3
(90:10)
Br
O
+
o
tol, 100 C, 12 h
O
O Br
O
+ OBn
138-endo
(80:20)
Ph
Br OBn
138-exo
Intramolecular Diels-Alder cycloadditions of 2-pyrones
The intramolecular Diels-Alder (IMDA) cycloadditions <05CR4779; 02AC(E)1668> of 2-pyrones have not been exhaustively explored, due to the lack of synthetic methods to incorporate requisite tethered dienophiles. Only a few examples can be found in the literature and they have been employed mostly in the synthesis of aromatic compounds. 2-Pyrone-6-carboxylate 139 (Scheme 35) was shown to undergo an IMDA reaction to afford dihydrobenzofuranone 141, upon elimination of CO2 from the initially formed cycloadduct 140 <85CL151>. Analogously, the amide 142 produced 143, which was a key intermediate in syntheses of the natural products (±)-reserpine and (±)-yohimbine <87JACS6124>. Scheme 35. IMDA cycloadditions of 139 and 142 O
O O
O
O
toluene 150 oC
R 139
O
140
O
O 141
OMOM
O BnN
R
66-72%
R - CO2
O
O
O
heat
(±)-reserpine H
93% OMOM
142
N Bn
O 143
(±)-yohimbine
Narasaka and coworkers have reported the IMDA reaction of 3-hydroxy-2-pyrone 34 (Scheme 36) with 4-hydroxy-2-butenoate 144, which was temporarily tethered with phenylboronic acid, to provide a single cycloadduct 147 in 75% yield <91S1171>. This elegant strategy was further elaborated by Nicolaou and coworkers for the synthesis of 151 as the C-ring intermediate in their initial synthetic endeavors towards the total synthesis of taxol <92JCS(CC)1118; 95JACS624>.
22
H-Y. Kim and C-G. Cho
Scheme 36. Temporarily tethered IMDA cycloadditions OH
144
O
O
O
CO2Me
o OH PhB(OH)2, 80 C
34
MeO2C
OH O
O 145
O B
B
Ph
146 CO 2Me
MeO2C O
o OH PhB(OH)2, 80 C
34
149
OH
O
OH
75%
O
O O B Ph O
147
B O
CO2Me
O
Ph
O
CO2Me
O
O
O
O
148
O
Ph
O
O
OH
MeO
O 61%
OH
O
150 CO2Me
151
O
ZnBr2-catalyzed IMDA cycloaddition of the 2-pyrone 152 (Scheme 37), tethered with a chiral enol silaketal, provided (+)-153-exo in 74% yield, along with a small amount of (-)153-endo <95JOC1617>. In this case, the E-geometry of the dienophile was not preserved during the cycloaddition, as in the cycloaddition of 3,5-dibromo-2-pyrone with dimethyl maleate (cf. entry 9, Table 2), implying a stepwise reaction mechanism. The isolated exo product (+)-153 was used as the key intermediate for the asymmetric total synthesis of a 2alkyl-vitamin D3 analog. Scheme 37. IMDA cycloaddition of a silaketal dienophile O
O O
O
O
OO ZnBr2 O Si(i-Pr)2
O
O O O Si (i-Pr)2
O
-30 oC, 4 d
(+)-152
(+)-153-exo
74%
O O
O
O O Si(i-Pr)2
+
(-)-153-endo 15%
Similarly, the 2-pyrone tethered with a chiral alkyl silane 154 (Scheme 38) was found to undergo IMDA cycloaddition to afford dihydrobenzenes 156 as a mixture of two diastereomers (de = 36%) in a combined yield of 78% after 2.5 hours at 140 °C <98TL4261>. Scheme 38. IMDA cycloaddition of 154 with alkyl silane tether O
O R'N Me R Si
O
O
o
140 C 2.5 h
154
O
O
- CO2 Me
O R'N
Si R
155
R'N Me
Si
R
156
23
The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives
With the establishment of the regioselective Pd(0)-catalyzed coupling of 3,5-dibromo-2pyrone, dienophilic groups can be readily tethered to the 2-pyrone unit. Various alkynes 157 (Scheme 39) bearing a terminal acrylate were successfully coupled regioselectively at the C3 position to generate the 2-pyrones 158 with good regioselectivity and chemical yields. The Sonogashira coupling reaction of the alkyne is faster than the possibly competing Heck reaction of the acrylate under these reaction conditions. Heating in toluene at 110 °C overnight provided IMDA-produced tricyclolactones 159 <04TL5857>. While 158a gave a mixture of endo/exo-adducts (60:40), 158b, 158c and 158d afforded only the corresponding endo-adducts with no detectable exo-cycloadducts. It is postulated that the alkynyl tether in 158a is not long enough to allow the proper orbital overlap for an endo-transition state. Scheme 39. Preparation and IMDA cycloadditions of tethered 2-pyrones 158. O Br
O
PdCl2(PPh3)2 CuI
n +
O
O
O
O
n
O O
PhMe
O
Br
Br 38
157a (n = 1) 157b (n = 2) 157c (n = 3) 157d (n = 4)
O
110 oC
Et3N, DMF, rt
n
O Br
overnight
158a (n = 1): 73 % 158b (n = 2): 78 % 158c (n = 3): 69 % 158d (n = 4): 73 %
O 159a: 31% (60:40) 159b: 51% (100:0) 159c: 55% (100:0) 159d: 66% (100:0)
The IMDA cycloadditions of the systems containing a substituted acrylate, i.e. 160 (Scheme 40), also afforded the corresponding cycloadducts 161, in much lower yields after prolonged reaction times (48 hours). Scheme 40. IMDA cycloaddition of 2-pyrones 160. O
3
O O
PhMe
O
O
R
160a: R = Me 160b: R = Ph
3
O R O
110 oC Br
Br
O
161a: R = Me, 32% 161b: R = Ph, 34%
In the cases of 10- and 11-membered macrocyclic bis-lactones, 159c and 159d (Scheme 41), the selective lactone ring opening with NaOMe occurred on the more strained [2,2,2]bicyclic lactone to provide 162c and 162d. For the 9-membered homolog 159b, opening of the macrolactone was competitive, furnishing 163b, due to the inherent ring strain. Scheme 41. Selective lactone opening reactions with NaOMe. O O Br
n O
O 159b (n = 2) 159c (n = 3) 159d (n = 4)
NaOMe MeOH, 0 oC
MeO 2C Br HO
O O 162b ~0% 162c 99% 162d 99%
n
MeO2C Br
n OH
+
HO
CO2Me 163b 99% 163c 0% 163d 0%
24
H-Y. Kim and C-G. Cho
Palladium-catalyzed coupling reactions of 38 (Scheme 42) with the alkynyl acrylamide 164 also took place regio- and chemoselectively to generate 165 in good yields. IMDA reaction of 165a gave the cycloadduct in less than 10% yield, forming an 8-membered lactam, while those with longer tethers (165b – 165d) furnished tricyclolactams 166b – 166d in good yields with exclusive endo-selectivity. Scheme 42. Synthesis and IMDA cycloadditions of 2-pyrones tethered with acrylamide O Br
O
+
O
NH
O
NH
O
PhMe
Br 164a (n = 1) 164b (n = 2) 164c (n = 3) 164d (n = 4)
NH
overnight
165a (n = 1): 80% 165b (n = 2): 85% 165c (n = 3): 70% 165d (n = 4): 76%
n
O
110 oC
Et3N, DMF, rt
Br 38
O
n
O
PdCl2(PPh3)2 CuI
n
Br
O 166a: 10% (50:50) 166b: 46% (100:0) 166c: 53% (100:0) 166d: 69% (100:0)
The IMDA reaction of pyrone 167, which bears a chiral tether proceeded in a highly diastereoselective fashion to provide 168a-endo in 68% yield (95% based on a 72% conversion of 167), upon heating at 110 °C in toluene (Scheme 43) <06AG(E)>. Scheme 43. Highly Diastereoselective IMDA cycloaddition of 167 O
O
O
3
O
O
Me
H
110 oC
167
1.3
3
toluene
68 %
Br
O Br
O O
Me +
H
Br O O
O
3
O
168-endo
169-endo
single diastereomer
not observed
Me
H
CONCLUSION
Known since the days of Diels and Alder, 2-pyrones have proven to be versatile 1,3-diene synthons, especially with the incorporation of electronic matching of the cycloaddition partners. First reported almost forty years ago, 3,5-dibromo-2-pyrone had remained largely unexplored until the disclosure of a convenient one-step synthetic protocol. Subsequent studies have shown 3,5-dibromo-2-pyrone is a reactive 1,3-diene and proceeds with greater stereoselectivity in D-A cycloadditions than mono-bromo-2-pyrones. It also exhibits ambident enophilic character, undergoing both normal and inverse electron demand D-A cycloadditions. Additionally, Pd-catalyzed coupling reactions can occur selectively at either the C3 or C5 by simply controlling the reaction conditions. Considering the recent advances in the chemistry towards, and of, substituted-2-pyrones, further expansion of its versatility for diversity- and target-oriented synthetic endeavors seems certain. 1.4
ACKNOWLEDGMENTS
The authors thank the Korean Science and Technology Foundation (KOSEF, R01-2006000-11283-0) for support of our program on the Diels-Alder cycloadditions of 3,5-dibromo-
The Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone and its derivatives
25
2-pyrone and its derivatives. Mr. Douglas C. Beshore at University of Pennsylvania and Dr. Todd D. Nelson at Merck Co. are thanked for their helpful suggestions. 1.5
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O. Diels, K. Alder, Ann. 1931, 490, 257. W.H. Pirkle, M. Dines, J. Org. Chem. 1969, 34, 2239. R.E. Ireland, R.C. Anderson, R. Badoud, B.J. Fitzsimmons, T.J. McGarvey, S. Thaisrivongs, J. Am. Chem. Soc. 1983, 105, 1988. 84JOC4033 D.L. Boger, M.D. Mullican, J. Org. Chem. 1984, 49, 4033. 84JOC4050 D.L. Boger, C.E. Brotherton, J. Org. Chem. 1984, 49, 4050. 85CL151 M. Noguchi, S. Kakimoto, S. Kajigaeshi, Chem. Lett. 1985, 151. 86JACS7373 G.H. Posner, D.G. Wettlaufer, J. Am. Chem. Soc. 1986, 108, 7373. 87JACS6124 S.F. Martin, H. Rüeger, S.A. Williamson, S. Grzejszczak, J. Am. Chem. Soc. 1987, 109, 6124. 89JACS3454 Y. Zhang, E. Negishi, J. Am. Chem. Soc. 1989, 111, 3454. 90JOC5359 L.S. Liebeskind, R.W. Fengl, J. Org. Chem. 1990, 55, 5359. 91S1171 K. Narasaka, S. Shimada, K. Osoka, N. Iwasawa, Synthesis 1991, 1171. 91TL5295 G.H. Posner, T.D. Nelson, C.M. Kinter, K. Afarinkia, Tetrahedron Lett. 1991, 32, 5295. 92JCS(CC)1118 K.C. Nicolaou, J.J. Liu, C.-K. Hwang, W.-M. Dai, R.K. Guy, J. Chem. Soc., Chem. Commun. 1992, 1118. 92TL7839 G.H. Posner, K. Afarinkia, Tetrahedron Lett. 1992, 33, 7839. 92TL9111 K. Afarinkia, T.D. Nelson, M. Vinader, G.H. Posner, Tetrahedron Lett. 1992, 48, 9111. 94JOC3543 A. Graven, K.A. Jorgensen, S. Dahl, A. Stanczak, J. Org. Chem. 1994, 59, 3543. 95JACS624 K.C. Nicolaou, P.G. Nantermet, H. Ueno, R.K. Guy, E.A. Couladouros, E.J. Sorensen, J. Am. Chem. Soc. 1995, 117, 624. 95JACS634 K.C. Nicolaou, J.-J. Liu, Z. Yang, H. Ueno, E.J. Sorensen, C.F. Claiborne, R.K. Guy, C.-K. Hwang, M. Nakada, P.G. Nantermet, J. Am. Chem. Soc. 1995, 117, 634. 95JACS7904 C. Bisang, C. Weber, J. Inglis, C.A. Schiffe, W.F. van Gunsteren, I. Jelesarov, H.R. Bosshard, J.A. Robinson, J. Am. Chem. Soc. 1995, 117, 7904. 95JOC1617 G.H. Posner, C.-G. Cho, T.E.N. Anjeh, N. Johnson, R.L. Horst, T. Kobayashi, T. Okano, N. Tsugawa, J. Org. Chem. 1995, 60, 1617. 95OS231 G.H. Posner, K. Afarinkia, H. Dai, Org. Synth. 1995, 73, 231. 95TL5939 H. Okamura, T. Iwagawa, M. Nakatani, Tetrahedron Lett. 1995, 35, 5939. 96CR167 J.D. Winkler, Chem. Rev. 1996, 96, 167. 96JACS2748 G.D. Allred, L.S. Liebeskind, J. Am. Chem. Soc. 1996, 118, 2748. 97JOC199 S. Chowdhury, S. Roy, J. Org. Chem. 1997, 62, 199. 98AC(E)2046 J.F. Hartwig, Angew. Chem. Int. Ed. 1998, 37, 2046 98BKCS957 C.-G. Cho, G.H. Posner, Bull. Korean Chem. Soc. 1998, 19, 957. 98TL4261 P. Coelho, L. Blanco, Tetrahedron Lett. 1998, 39, 4261. 99AC47 B.T. Woodard, G.H. Posner, Adv. Cycloaddit. 1999, 5, 47. 00ACR314 C. Amatore, A. Jutand, Acc. Chem. Res. 2000, 33, 314. 00OL2049 C.-S. Chen, C.-C. Liao, Org. Lett. 2000, 2, 2049. 00T5205 D. Passarella, G. Lesma, M. Martinelli, A. Silvani, M. Cantò, J. Hidalgo, Tetrahedron 2000, 56, 5205. 00TL4955 K. Afarinkia, J. Berna-Canovas, Tetrahedron Lett. 2000, 41, 4955. 00TL7583 L. László, I. Kádas, T. László, Tetrahedron Lett. 2000, 41, 7583. 00TL8317 H. Okamura, H. Nagaike, T. Iwagawa, M. Nakatani, Tetrahedron Lett. 2000, 41, 8317. 01JOC2560 M.H. Ali, S.L. Buchwald, J. Org. Chem. 2001, 66, 2560. 01OL2949 S.R. Chemler, U. Iserloh, S.J. Danishefsky, Org. Lett. 2001, 3, 2949. 01T6429 F. Clerici, M.L. Gelmi, A. Gambini, D. Nava, Tetrahedron 2001, 57, 6429. 01TL1065 C.-G. Cho, J.-S. Park, I.-H. Jung, Tetrahedron Lett. 2001, 42, 1065. 01TL8193 C.-G. Cho, Y.-W. Kim, W.-K. Kim, Tetrahedron Lett. 2001, 42, 8195. 02AC(E)1668 K.C. Nicolaou, S.A. Snyder, T. Montagnon, G. Vassilikogiannakis, Angew. Chem. Int. Ed. 2002, 41, 1668. 02BKCS1021 S.-H. Min, Y.-W. Kim, S. Choi, K.B. Park, C.-G. Cho, Bull. Korean Chem. Soc. 2002, 23, 1021. 02JOC290 C.-G. Cho, Y.-W. Kim, Y.-K. Lim, J.-S. Park, H. Lee, S. Koo, J. Org. Chem. 2002, 67, 290.
26 02OL1171 02TL5591 02TL5779 02TL9015 03JACS14288 03JOC10191 03OL845 03TL3363 03TL4439 03TL95 04JOC3193 04SL2197 04TL1683 04TL5857 05CC431 05CR4779 05JOC1122 06AC(E) 06OL1109
H-Y. Kim and C-G. Cho J.-H. Lee, J.-S. Park, C.-G. Cho, Org. Lett. 2002, 4, 1171. H.-S. Lee, D. Kim, H. Won, J.H. Choi, H. Lee, C.-G. Cho, Tetrahedron Lett. 2002, 43, 5591. J.-H. Lee, W.-S. Kim, Y.-Y. Lee, C.-G. Cho, Tetrahedron Lett. 2002, 43, 5779. W.-S. Kim, H.-J. Kim, C.-G. Cho, Tetrahedron Lett. 2002, 43, 9015. W.-S. Kim, H.-J. Kim, C.-G. Cho, J. Am. Chem. Soc. 2003, 125, 14288. S.-J. Pang, S.-H. Min, H. Lee, C.-G. Cho, J. Org. Chem. 2003, 68, 10191. B. Salem, P. Klotz, J. Sluffert, Org. Lett. 2003, 5, 845. D. Sil, A. Goel, V.J. Ram, Tetrahedron Lett. 2003, 44, 3363. S.-H. Min, S.-J. Pang, C.-G. Cho, Tetrahedron Lett. 2003, 44, 4439. J.-H. Lee, C.-G. Cho, Tetrahedron Lett. 2003, 44, 95. K. Kranjc, B. Stefane, S. Polanc, M. Kocevar, J. Org. Chem. 2004, 69, 3193. K.-M. Ryu, A. Gupta, J.-W. Han, C.H. Oh, C.-G. Cho, Synlett 2004, 2197. W.-S. Kim, J.-H. Lee, J. Kang, C.-G. Cho, Tetrahedron Lett. 2004, 45, 1683. J.-T. Shin, S. Shin, C.-G. Cho, Tetrahedron Lett. 2004, 45, 5857. A. Zapf, M. Beller, Chem. Commun. 2005, 4, 431. K.-i. Takao, R. Munakata, K.-i. Tadano, Chem. Rev. 2005, 105, 4779. K. Afarinkia, M.J. Bearpark, A. Ndibwami, J. Org. Chem. 2005, 70, 1122. J.-T. Shin, S.-C. Hong, S. Shin, C.-G. Cho, Angew. Chem. Int. Ed. 2006, submitted Y. Wang, D.J. Burton, Org. Lett. 2006, 8, 1109.
27
Chapter 2
Recent developments in the chemistry of nucleosides Jean-Luc Girardet and Stanley A. Lang Valeant Research & Development, 3300 Hyland Avenue, Costa Mesa, CA 92626
[email protected],
[email protected]
2.1
INTRODUCTION
Nucleosides have been at the forefront of heterocyclic research since they have been identified more than one hundred years ago. It is the work of Emil Fisher and Phoebus Levene at the end of the nineteenth century that contributed to the discovery of what was called at the time the building blocks of life. Several books present in detail the synthesis of nucleosides and their heterocyclic bases and sugar moieties <88MI1; 91MI1; 94MI1; 01MI1>. Most, if not all, nucleoside research in present days is focusing on the quest for bioactive molecules, and this is most certainly due to the important interactions between these types of molecules and living cells <90MI1; 97MI1> and the therapeutic advantage associated with them. In the past four decades, numerous nucleoside analogs were approved by the American Food and Drug Administration (FDA) to treat various cancers and viral infections, including seven over the past eight years: capecitabine (anticancer) in 1998 <99ARMC317>, abacavir sulfate (antiviral) in 1999 <00ARMC331>, tenofovir disoproxil fumarate (antiviral) in 2001 <02ARMC257>, adefovir dipivoxil (antiviral) in 2002 <03ARMC347>, emtricitabine (antiviral) in 2003 <04ARMC337>, azacitidine (anticancer) in 2004 <05ARMC443> and entecavir (antiviral) in 2005. Some of these drug compounds, like capecitabine and azacytidine, incorporate only one or two chemical modifications as compared to a natural ribo- or deoxyribonucleoside. Others, like adefovir, tenofovir and abacavir, are heavily modified. Research on the chemical modifications of the sugar moiety of nucleosides has explored many other modifications, ranging from simple methylation of the ribose sugar to multiple ring systems as seen in many spironucleosides. This chapter will review the recent developments in nucleoside research both in term of chemistry and potential medical use. We will first review modifications brought to the ribose or 2’-deoxyribose moiety of a nucleoside, from C-1’ to C-5’ (nucleoside nomenclature). We will then look at publications on ribose replacement with unnatural sugars, including carba, thia and aza sugars, and then we will review the literature on bicyclonucleosides published in recent years. This chapter will be concluded with a review of recent articles on nucleoside synthesis on solid support, and the challenges associated with this technique applied to nucleoside synthesis.
28
J.-L. Girardet and S.A. Lang
O
O N
O N
NH
N
F
O
N tenofovir disoproxil
N
O
H2N
O
OH
HO
O
O N
S
NH2 N
HO
F
N
N
O
O N
adefovir dipivoxil
2.2
N
O N
O
H2N N
O
O
P O O
N
O O
H2N
abacavir O
N
N
H2N
capecitabine
O
O N
NH
HO OH
N
N
O
O
O P O O
OH
OH emtricitabine
azacitidine
SUGAR CHEMISTRY
In the past few years, sugar modifications have taken a more important role in the chemistry of nucleosides and nucleotides. These ribose or 2’-deoxyribose chemical modifications can be classified in three main categories: addition of a substituent to an unmodified sugar in place of a hydrogen, substitution of a methylene group or oxygen atom, and finally, replacement of the natural sugar by an either unnatural or heavily modified one. All three of these strategies proved successful recently, and allowed the advancement of various nucleoside or nucleotide analogs to the clinic: valopicitabine, the valine ester prodrug of 2’-C-methylcytidine, is scheduled to enter phase III clinical trial in early in 2006 for the treatment of hepatitis C virus (HCV) infections, entecavir was approved in 2005 for the treatment of hepatitis B virus (HBV) infection and a New Drug Application (NDA) has been submitted in January 2006 for telbivudine, or Ldeoxythymidine, also for the treatment of HBV infections. OH
OH
O N
O OH O
NH2
HO
O
N
O
N
HN
N
O
O N
O
HO N
OH
NH
H2N
NH2 valopicitabine
entecavir
telbivudine
29
Recent developments in the chemistry of nucleosides
2.2.1
Hydrogen and Oxygen substitutions
Keeping the core ribose or 2’-deoxyribose intact, and substituting one hydrogen or oxygen with a different atom has been quite popular in the past 5-6 years. These modifications bring minimum changes to the overall conformation of nucleosides, thus increasing the chances of enzymatic recognition and biological activity. Several nucleoside analogs currently in clinical trial belong to this category. 2.2.1.1 Modifications at C-1’ Only a few C-1’ modifications have been reported in the past few years, one of the reasons being the difficulty of obtaining any stereoselectivity at this anomeric position. Cappellacci <02JMC1196> reported the synthesis of 1’-C-methyladenosine 4 starting from the lactone 1 in 6 steps with chiral separation after the last step. A different approach was followed by Kodama <00TL3643; 01CEJ2332; 02JOC7706> who introduced stereoselectively a phenylseleno group at the 1’ position of a nucleoside, followed by formation of the samarium enolate 6 and aldehyde condensation to give 7. A similar strategy was applied to synthesize compound 5 <02TL5657>. No significant antiproliferative activity was reported for any of these analogs. 1) NaH, BnBr, THF BnO
O
HO
O O Ph
2) MeLi, Et2O 3) Ac2O, DMAP, pyr
O 1
1) NH3
2) HCOONH4 10% Pd/C, MeOH, reflux
O Ph
O 2
N
CH3 N OH
HO
EtAlCl2, OAc MeCN
NH2
HN
S
HO
N
HO
O
Cl N
N
3 N NH2
N
OH OH
N
N
5 H N
O O
N SePh
O
N
N CH3
O Ph
N
4
O TIPDS
Cl
N
O
HO
N
CH3
N
O
HO
O
O 6
H N
O O
1) SmI2/THF 2) (CH2O)n 3) NaBH4, MeOH 4) TBAF, THF
O
HO
O
N OH
HO OH 7
2.2.1.2 Modifications at C-2’ A great deal of chemistry was published recently on chemical modifications at the C-2’ position of ribonucleosides. This sudden surge in interest is most certainly due to reported antiHCV activity of 2’-C-methylribonucleosides bearing a purine heterocyclic base. Several routes for the synthesis of the 2’-C-methyl, 2’-C-ethynyl and 2’-C-ethyl sugar were recently reported by Harry-O’kuru <97JOC1754>, Girardet <00JMC3704> and Eldrup <04JMC5284; 04JMC2283>. The reaction of the protected sugars 8, 11, 14 and 17 with 6-chloropurine yielded the protected
30
J.-L. Girardet and S.A. Lang
2’-C-substituted-purine nucleoside, which, after ammonia treatment, afforded 19 in the case of R being an ethyl group. Hattori also published the synthesis of 2’-C-ethynylcytidine with very low stereoselectivity for the β face (8% versus 68% for arabino compound) <98JMC2892>. Also obtained was the 2’-deoxy-2’-C-methylcytidine which derived from 2’-C-methylcytidine through a deoxygenation reaction at the 2’-hydroxyl group <03JOC6799>. A process chemistry article on the synthesis of 2’-methyl sugar and 2’-methyladenosine was published recently by Merck <04JOC6257>. Several publications also reported similar modifications applied to 3-deazapurine analogs <05SL1586; 05TL3883>, thiazole-4-carboxamide adenine dinucleotide analogs <05BMC2045>, toyocamycin and sangivamycin analogs <05BMCL725>, triciribine analogs <04BMCL3517>, as well as a series of 6-substituted purine nucleoside analogs <05BMCL709>. Dess-Martin periodinane, BzO DCM, rt
O
BzO
OBz BzO OH
TIPDS
1) RMgBr, THF, rt
OMe
2) TBAF, THF, rt
O 11
1) RMgBr, THF, rt
O OMe O 14 O OAc Et OBz
17
R OBz
10 1) Ac2O, DMAP, O O HO AcO OMe NEt3, DCM OAc 2) Ac2O, R R HO AcO AcOH, H2SO4, OH OAc rt 12 13 O
HO
2) BzCl, DMAP, DCM 3) H2, Pd/C
DCBO
AcO
OBz
2) BzCl, BzO DMAP, NEt3
O
O
BzO
O
9
O
DCBO
OBz
BzO
8 O
1) MeTiCl3 or RCeCl2 BzO
O
TMSOTf, DBU, MeCN BzO
OMe
HN
15
O Et OBz N
AcO Cl
N
N
2) Ac2O, AcOH, H2SO4, rt
R OBz
HO
N N
1) BzCl, DMAP, DCM BzO
18
N
NH3/dioxane HO
O OAc R OBz
AcO 16
O N
Cl N
Et OH N
HO 19
N NH2 N
A number of fluoroalkyl substitutions were also described in the past few years. Several 2’-Ctrifluoromethyl ribonucleosides were synthesized <01OL1025>; the chemical scheme involved the formation of protected sugar 20 by action of trimethyl(trifluoromethyl)silane on ketone 9. Glycosydation proceeded with the bromo sugar 21, and three 2’-C-trifluoromethyl pyrimidine ribonucleosides were obtained as exemplified with compound 23. More recently, 2’-Cdifluoromethyl uridine was synthesized through a slightly different approach <05JOC7902> involving the use of difluoromethyl phenyl sulfone, followed by hydrogenation of 24 and condensation of silylated uracil. The desired nucleoside 27 was obtained after treatment of 26 with methanolic ammonia.
31
Recent developments in the chemistry of nucleosides
1) CF3SiMe3, TBAF (5%), BzO OBz THF, rt 2) TBAF, rt BzO
O
BzO BzO
O OBz CF3 OBz
O 9
30% HBr in AcOH, 80 oC BzO
Br CF3 OH
BzO
20
21
O
O N
O
BzO
N
O
HO
R1
N
N
NH3, persilylated BzO CF3 CF3 HO R2 OH OH MeOH, 4 oC nucleobase, 22 23 R1=OH or NHBz HgO/HgBr2, benzene or R2=H or Me tol, reflux
O
BzO
O
OBz
PhSO2CF2H, LiHMDS, THF, -78 to 0 oC BzO
BzO
24 O O
BzO
H N
OBz
2) BzCl, CF2SO2Ph BzO DMAP, NEt3, OH DCM, rt H N
O O
O
HO
N
persilylated BzO CF2H nucleobase, OH SnCl4, 26 MeCN, reflux
O
2
OBz
BzO 9
1) 5% Na-Hg, Na2HPO4, MeOH, THF, BzO H , 0 oC
O
O
R2
R1 R1=OH or NH 2 R2=H or Me
NH3, HO MeOH, 4 oC
CF2H OBz 25
O
N
CF2H OH 27
Finally, 2’-C-fluoromethyl uridine was synthesized starting from uridine 28 that was protected with a di-tert-butylsilyl group and oxidized at the 2’-position to give the still protected nucleoside 29 <03OL807>. A Wittig reaction with methyltriphenylphosphonium bromide, followed by a series of protection/deprotections, afforded compound 31. Once again, only examples of pyrimidine nucleosides were given. H N
O O
HO
N
2) DessMartin periodinane, DCM
HO OH 28 O O
O Si
N
O CH2 30
O 1) Cl2SitBu2, AgNO3
MEM N
O
H N
O O
O Si
N
1) methyltriphenyl O phosphonium bromide, K tert-pentoxide, ether 2) MEM-Cl, DIEA, DCM
O O 29
1) MCPBA, DCM 2) KF/HF 3) Ac2O, pyridine 4) B-bromocatecholborane, DCM, rt 5) guanidine/guanidine HCl, MeOH, DCM
O HO
O
N
CFH2 OH
HO 31
H N
O
32
J.-L. Girardet and S.A. Lang
Clark reported the synthesis of 2’-deoxy-2’-fluoro-2’-C-methylcytidine 33 <05JMC5504>. The fluorination proceeded through inversion of configuration of the 2’-hydroxyl group. Elimination product was also observed, as well as 2’-C-methylcytidine. Enzyme-assisted synthesis of 2’-deoxy-2’-fluoroguanosine was reported <99NN687>, while various 2’-deoxy-2’fluoro-D- and L- nucleoside analogs were reported by Shi <05BMC1641>. O O
O Si
N
O NHBz
N
2) DAST, tol, -20 oC 3) NH3 / MeOH
O O
O
HO
1) MeLi, -78 oC
N
NH2
N
HO F 33
32
2.2.1.3 Modifications at C-3’ No significant antiviral activity has been reported for nucleosides bearing a 3’-Cmodification, but several compounds in this class have been shown to posses antitumor properties, the most successful of them being 3’-C-ethynylcytidine (ECyd) <99NN811>. This modified sugar was prepared from D-xylose following a scheme published by Hattori <96JMC5005>. Addition of trimethylsilylacetylene to 34 proceeded stereoselectively to yield sugar 35 after deprotection of the trimethylsilyl group. Glycosidation with cytosine, followed by deprotection with methanolic ammonia afforded compound 38 (Ecyd). A variation in which the benzoyl protecting group was replaced by a tert-butyldimethylsilyl group was later published by Nomura <02T1279>. 3’-Ethynyladenosine was also synthesized via the same chemistry route <00BMCL139>. Several analogs of Ecyd have been prepared with modified nucleobases, including pyrido[2,3-d]pyrimidines <00JMC3704> and various aza- and deazapyrimidines <05BMC1249>. In that first example, the ethynyl group was condensed via a Grignard reaction with ethynyl magnesium bromide. Reverse stereoselectivity (addition from α face) was obtained when the reaction was performed on the 3’-oxonucleoside. A butadiynediyl dimer of the same nucleoside 38 was reported by Jung <03OL383> and was synthesized via palladium coupling of the two ethynyl moieties. The C-3’-allenyl uridine was synthesized using Crabbe reaction <01NNNA1775>.
D-xylose
1) TMSCCH, BuLi, THF, -78 oC BzO
O
TBSO
O O 34
O
2) TBAF, THF, rt 3) BzCl, pyr, rt
1) HCl 20%, MeOH, rt
O O
HO
O 35
O BzO
N persilylated BzO nucleobase, OBz 37 SnCl4, MeCN, reflux
HO
N
O
NH2
N NH3, MeOH
HO 38
OH
O
OAc 2) BzCl, DMAP, BzO o OBz pyr, 100 C 36 3) H2SO4, AcOH
O N
O
BzO
NH2
33
Recent developments in the chemistry of nucleosides
Several 3’-C-methyl nucleosides were also described <00JMC3704; 05JMC4983>. Application to nicotinamide analogs was described <04BMCL4655>. Their synthesis involved intermediates similar as 34 and a Grignard reaction using methylmagnesium bromide. All five natural ribonucleosides were described with a 3’-C-trifluoromethyl group, following a synthesis involving D-xylose as starting material <95NN185; 03NNNA2195>. Their 3’-deoxy version was published by Sharma, and involved a Barton deoxygenation to remove the 3’-hydroxyl group <00NNNA757>. 2.2.1.4 Modifications at C-4’ Modifications at the 4’ position of ribo- and deoxyribonucleosides have drawn attention in the past few years due to several reports of anti-HIV activity and, more recently, anti-HCV activity. Nomura <99JMC2901> described the synthesis of a series of 4’-C-modifications involving the diol intermediate 40. Interestingly, dimethoxytrityl chloride was selective for the 4’-Chydroxymethyl group. This selectivity was also reported by Gunic in his synthesis of 4’-modified analogs of toyocamycin <01BMC163>. 2’-Deoxycytidine and 2’-deoxyuridine derivatives were described, as well as several alkylated uridines <05S1467>. The same chemical strategy was later followed by Kohgo <04NNA671> for the synthesis of 4’-C-ethynyl and cyano modifications of 2’-deoxypurine nucleosides. Haraguchi published a variation involving a 4’,5’unsaturated nucleoside <03OL1399>. In this article, compound 43 was oxidized to its epoxide which was then opened to yield 44. The synthesis of 4’-C-methyl ribonucleosides bearing the five natural heterocyclic bases was published by Griffon and followed previously published procedures <03NNNA707>. Several 4’-C-hydroxymethyl derivatives of various nucleosides were also synthesized <00JMC3704; 01BMC163; 01NNNA747; 01NNNA649>. O N
O
HO
N TBSO 39
1) EDC.HCl, NaBH4, benzene, EtOH DMSO NHBz 2) HCHO, NaOH, dioxane
OTBDPS 1) DMTCl, pyr. rt 2) TBDPSCl, DMF, imid, rt 3) AcOH 80%, rt
NHBz
TBSO 40 OH
O N
O
R
NHBz
TBSO
N
NH2
HO 41
42
O
1) DMDO, DCM, -30 oC
NH
O N
O 2) TMSCN
43
N N
N N
TBDMSO
O O
HO
O
O
HO
OH
OH NC
R= Me, Et, vinyl, Clvinyl, CN, ethynyl O NH
O N
O
TBSO 44
The synthesis of 4’-C-trifluoromethyl derivatives followed a different scheme. Starting from D-ribose, the key intermediate 48 was obtained in five high yielding steps. The stereoselectivity
34
J.-L. Girardet and S.A. Lang
at this stage was 4:1 D-ribo/L-lyxo. The fully acylated sugar 49 was condensed with various heterocyclic bases following a classical Vorbrüggen procedure. Another 4’-fluorinated sugar was obtained by Jung <01JOC2624>. His synthetic strategy involved the formation of the tert-butyl ester 52 followed by an electrophilic addition at the C-4. This reaction delivered the desired deutero compound 53 with a decent yield (43%), but unfortunately, in the case of a fluoro substitution with N-fluoro-benzenesulfonimide, the reaction only yielded the undesired stereoisomer 54 in 48% yield. The removal of the 4’-hydroxymethyl group has also been investigated, using D-erythrose as starting material, yielding the corresponding erythronucleoside <05JMC6430>.
D-ribose
1) DMP, H+ TBDMSO
PDC,
iPrPPh3+I-, BuLi
O
Ac2O, O sieves O OH 46 OTBDMS
OH 2) TBDMSCl, imidazole
TMSCF3, TBAF
1) BzCl, TEA 2) O3 3) TFA
O O OH OH
F3C
2'-deoxythymidine
O
4) Ac2O, pyr
O
1) persilylated nucleobase, TMSOTf
OBz O F3C
OAc
AcO
48 1) MMTCl, Et3N OH 2) TPSCl, ImH O 3) Amberlyst 15 O
4) TEMPO
45
49
2) NaCN, MeOH
OAc
OH
NH O
5.5 eq LDA HO 4.5 eq tBuLi AcOD, MeOD
53
O NH N
O
HO 52 OtBu
NH N
O
OH
1) tBuOH, OtBu EDCI, DMAP O O 2) TBAF
O
D
N
HO
TPSO
O
O
NH
F3C
51 OtBu
O O
50
O N
O O O 47 OTBDMS
O
O
F 5.5 eq LDA 4.5 eq tBuLi NFSI
NH
O
O
N
O
HO 54
2.2.1.5 Modifications at C-5’ Nucleosides modified at their 5’-position can generally not be phosphorylated by cellular nucleoside kinases. This characteristic is sometimes used to design receptor agonists or antagonists without the risk of incorporation of the modified nucleoside into DNA or RNA. The first example of these compounds is capecitabine in which the 5’-hydroxyl group is replaced by a hydrogen atom. Many examples of 5’-deoxynucleosides were published in the past few years <00JMC2438; 04JMC5773; 05JMC7808>, including some incorporating a fluoro atom at C-5’ <05BMCL3361>. Some research involved attaching a phosphonate group to the 5’-carbon to mimic a natural phosphate group, but without the liability of poor enzymatic stability. In the later
35
Recent developments in the chemistry of nucleosides
category, Koh recently published the synthesis of several adenosine monophosphate mimics <05JMC2867>. In this example, diphenyl(triphenyl-phosphoranylidene) methylphosphonate was reacted with the 5’-aldehyde of 55 to yield 56 after reduction of the double bond. Chen used a slight variation of this coupling to make cytidine phosphonate derivative 60 <02JOC9331> as well as the corresponding arabino derivative <02PSS1783>. Several other derivatives of uridine and cytidine have also been described by Jung <00BMC2501>. O O
HO
1) DMSO, DCC, TFA / pyr
N
N BzO 55
OBz N
N
NHBz 2) (PhO)2P(=O)CHPPh3 3) H2, PdC, MeOH
O O N HO 57
OH N
1) NH3, MeOH
N
NHBz 2) H2, PdC, N MeOH
1) NaH, BnOH, DMSO, rt
N
N
NHBz
BzO 56
N
O N O
NHAc 59
HO P HO
OBz N
O N
N
N NH2
HO
1) DMSO, EDC, TFA / pyr
O
O
O
O
BnO P BnO
HO
PhO P PhO
2) LHMDS, HP(=O)(OEt)2, THF, -78 oC 3) TMSBr, DCM, 0 oC to rt, then MeOH
58
OH N
N
OH O HO N O P HO N O HO OH 60
NH2
The synthesis of 5’-C-alkyl and alkenyl nucleosides was reported by Wang <98NN1033; 00JMC2566>. It involved oxidation of the 5’-hydroxyl group of 61, followed by a Grignard reaction with allylmagnesium bromide to give 64 when R is an allyl group, or a Wittig reaction and epoxide formation, followed by nucleophilic ring-opening to yield 64 when R is a cyano group or an amino group. The 5’-deoxy-5’-N-hydroxylaminopyrimidine and purine nucleosides were synthesized via Mitsunobu reaction with benzyloxycarbonyl- and tert-butoxycarbonylprotected hydroxylamine, as exemplified with compound 65 <99JOC9289>. Deprotection via hydrogenation and acidification afforded nucleoside 66 in excellent yield. A carboxylic derivative of all four natural ribonucleosides 67 was synthesized by using TEMPO/BAIB as oxidant <99JOC293>. From this carboxylic acid intermediate, Umino reported the synthesis of N-alkylcarboxamido compounds via displacement of a nitrophenol ester intermediate, made by condensing nitrophenol in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, with the desired alkylamine to yield compound 68 <01JMC208>.
36
J.-L. Girardet and S.A. Lang
O HO
O
1) DMSO, DCC, TFA / pyr
NH
O N
O NH
O
O
N 2)CH3PPh3 3) MCPBA
TBDMSO 61
62
DMSO, DCC, TFA / pyr
NH3 / MeOH or KCN R
O NH
O
O
N
O
O
TBDMSO 64
PPh3, DBAD BocN DMF / THF adenosine CbzO BocNHOCbz HO
O
OH N
O
R=allyl, CN, NH3
1) H2, PdHN C HO NH2 2) HCl HO
N
N
65
N
O
N
N
NH2
66
OH N
N
O
O B 67 (B = A)
O
67
NH N
63
O
O O
HO
AllylMgBr
TBDMSO
HO
O
TBDMSO
1) 4-nitrophenol 2) RNH2 3) 80% TFA
O
HN R HO
N
NH2
68
B = A, U, C, G
N
OH N
N
A series of more than twenty 5’-deoxy-5’-thio-substituted adenosine derivatives, as exemplified with 65, was described by Kung <05BMCL2829>. The synthesis of these thio derivatives involved 5’-deoxy-5’-chloro as starting material. The article also described the synthesis of 71 obtained from aldehyde 70 following a Wittig reaction with benzyltriphenyl phosphonium chloride. Specific 5’-deoxy-5’-thiocyanates were prepared using the von Braun cyanogen bromide reaction <02JOC1898>. Several 5’-epimuraymycin analogs were synthesized <03BMCL3345; 05T11850>. The synthesis of 5’-deoxy-5’-aziridine derivative of adenosine was described in eight steps from adenosine <05JOC5833>. This synthesis involved two Mitsunobu reactions: one for the amine condensation to give 73, and one for the ring cyclization to yield the target compound 75. O O
RS
N
N NH2
HO OH N 69
O
H
N
O
N 70
O
N
N N(Bz)2
O
N
N NH2
HO OH N
N 71
N
37
Recent developments in the chemistry of nucleosides
EtO O
HO
O
N
N N
O
N
72 EtO
O
N H
O
N
N NH2
74
N
N
1) TFA 2) Et3SiCl, NEt3 3) PhSH, K2CO3
N
N
NH2
O
N
O
N
73
1) LAH 2) PPh3, DEAD, THF
TESO TESO
O
N Ns
O
PPh3, DEAD, THF
NH2
O
NH EtO Ns
O
N
N
N
3) TBAF, TMSOMe, THF
NH2
HO OH N
75
N
Aziridines were also described by Comstock <02T6019>. Lui described the synthesis of 5’functionalized adenosine 78 using rhodium (II) catalyzed 1,3-dipolar addition <01OL2273>. Some unique 5’-deoxy-5’-thiomethyl amino acid derived adenosine derivatives were described by Kehraus <04JMC2243>. 5’-Deoxy-5’-(iodomethylene)adenosine was synthesized by reaction of a sulfone-stabilized phosphonate on a protected adenosine, followed by stannylsulfonylation and iododestannylation to yield compound 79 <06JMC2096>. Several sugar-modified enyne analogs were synthesized by a Sonogashira coupling as shown in 81 <04JMC5251>. The Z analog 82 was also synthesized and is described in the same article. The synthesis of 80 was referenced. One example of DNA methyltransferase click chemistry was published by Weller <05OL2141>. O O
H2N
N O
76 OEt MeO O O
N
N
O
N
80
N
N OO
O
N
N
77
N
I
O
N Me HO
O
O
N N2
O
O O
1) ethyl vinyl ether, Rh2(pfbm)4, tol 2) TFA/H2O; Pd/C, EtOH, NH4COOH NHCbz
O
chloride, toluene, N2 4) MsN3, TEA
N
N
O
N
N NH2
78
I
1) (CH3CO)2, pyr MeO 2) Rapoport's reagent, DCM NH2 3) methyl malonyl
OH N
NH2
HO OH N
N
79
1) TMS-acetylene, CuI, (PPh3)2PdCl2, N DEA
N
N
O N
NH2 2) TBAF, THF HO 3) TFA, H2O
O
N
N NH2
OH N 81
N
N NH2
HO OH N
N 82
N
38
J.-L. Girardet and S.A. Lang
2.2.2
Ring-oxygen substitution
The success of entecavir has boosted the research on carbocyclic nucleosides; three main substitutions exist: oxygen for carbon, oxygen for sulfur and oxygen for nitrogen, the latest being the least popular in term of number of publications. 2.2.2.1 Substitution with carbon Nucleosides with a carbocyclic “sugar” have gained more attention with the success of entecavir as an anti-hepatitis B agent. The synthesis of entecavir itself is already well documented <97BMCL127; 03T9013; 04TL739>. Its 3’-deoxy analog has also been described <04TL739>. Trost published a very nice palladium-catalyzed enantioselective synthesis of several carbanucleosides, with the key step being a palladium(0)-catalyzed enantioselective allylic amination of cis-3,5-dibenzoyloxycyclopent-2-ene with the desired nucleobase <00JACS5947>. Two convergent approaches start from cyclopentenol and lead to carbocyclic analogs of 2’-deoxythymidine, 5-fluoro-2’-deoxyuridine and 5-bromovinyl-2’-deoxyuridine <03NNNA683; 03S2101>. Takagi published the synthesis of 5’-methylenearisteromycin <05OBC1245> because of its similarity with entecavir. The synthesis involved a stereoselective intramolecular radical cyclization as the key step to construct the carbocyclic structure. (+)Aristeromycin 90 was synthesized in eleven steps from compound 83, with the key reaction being a one-pot ring expansion of cyclobutanone 84 <00JOC1865>.
OEt
hν
N + (CO)5Cr
O
O EtO
OBn
Ph 83
O
Ph
Ph
OBn 1) H2, [Rh(COD)dppb]BF4, DMF
N 84
OBn ClCO2Et
OCO2Et
2) DIBAL Ph 86
87
88
OH
Pd(PPh3)4 N
NH2 N
Ph 85
Ph
OH
N
OBn
HN
O N
O
O 1) LDA
Ph
N
O
OBn O O
2) Li2CO3
2) Li2CO3 Ph
OBn
1) TMS(O)I, NaH, O Sc(OTf3), DMF
BnO
O
1) BCl3
N NH2
89
N
N
2) OsO4
N HO 90
N NH2
OH
N
N
N
A different approach was used by Ainai, starting from azidopentane 91 <04JOC655>. (-)Aristeromycin 94 was obtained after building the adenine ring from the reduced form of 93. A third approach published consisted of building a carbocycle from D-ribose, and condensing the
39
Recent developments in the chemistry of nucleosides
chloropurine base via a Mitsunobu coupling <04JOC3993>. Yang also described the synthesis of 5’-homoneplanocin <05JMC5043> and the synthesis of (-)-3-deazaaristeromycin <04TL8981> through a similar route. A new chiral synthesis of 6’-β-fluoroaristeromycin was described using cis-4-acetoxy-2-cyclopentene-1-ol as starting material <05TL7535>. Enzymatic resolution of (±)-1-acetoxy-4-(nitromethyl)-2-cyclopentene provided the desired starting material for the synthesis of carbanucleosides and 5’-nor-1’-homo carbanucleosides <02T9889>. 1) Me2C(OMe)2, MeOOC PPTS
O N3
2) RuCl3.3H2O, NaIO4, then CH2N2
HO OH
N3
O
91
1) LAH 2) TEA, BuOH, 130 oC Cl NH2
O
N
92
NH2
NH O
Cl
N
O
Cl N
93
N
OH
1) (EtO)2CHOAc, reflux, pTsOH
OH O N
2) NH3, EtOH, 90 oC
OH
N
MeOOC NH2
HO 94
OH N
OH
HO
NHPf
N
N
N
H 95
96
OH N N H
Carbapentostatin 96 was synthesized via a one-pot, two steps preparation of the key aldehyde 95 followed by homologation and ring formation by Dieckmann cyclization <03JOC109>. The synthesis of carbocyclic analogs of other compounds of interest, like 2’-methyl nucleoside, was very recently published by Gosselin, starting from 2-cyclopenten-1-one to yield compound 97 <06T906>. Fluoroneplanocin A was synthesized via an electrophilic vinyl fluorination reaction to lead to compound 98 <03JMC201>. Isomers of neplanocin A and 2’-deoxyneplanocin A were also described <05TL1927>. Several methacarba analogs of purine nucleosides were synthesized <00JMC2196>, as shown with adenine analog 99. Jacobson also described more about the design of these analogs <05JMC8103>. Roy published an interesting occurrence during the attempted synthesis of 5’-noraristeromycin <05OL3889>. Several analogs with modified adenine bases were described <99JOC2240>. Lee prepared the novel apio carbocyclic nucleoside analog 100 in a stereoselective manner <05JOC5006>. AMP579, or compound 101, was obtained following an highly stereoselective route involving the condensation of an alkyl sulfonamide with a pyridine synthon <00JOC8114>. Hong described the synthesis the novel carbocyclic analog of 4’-hydroxy nucleoside 102 starting from D-lactose, in thirteen steps <02JOC6837>. Various purine and pyrimidine L-ribofuranoside analogs have been prepared in similar routes starting from (+)-cyclopentanol <99JOC4173>. OH
OH
O
OH
F
NH N HO
O
N
N
N NH2
HO 97
OH
98
OH N
N
N NH2
HO 99
OH N
N
40
J.-L. Girardet and S.A. Lang
NHEt OH N
O
N
N NH2
HO 100
OH N
OH N
S H N
HO
N
101
HO
Cl
N
N NH2
HO
OH N
102
OH N
N
Several new cyclohexenyl carbocycles have been described by Vijgen and Wang <00JMC736; 05JOC4591>. In these examples, the double bond is mimicking the ring oxygen, between C-1’ and C-4’. Condensation of the heterocyclic base was achieved via Mitsunobu reaction. Ueno synthesized benzene analogs in which the purine or pyrimidine base is built from an amino substituent on the benzene ring <05JOC7925>. 2.2.2.2 Substitution with sulfur The popularity of thionucleosides does not match that of carbonucleosides; nonetheless, some interesting chemistry has been published in the past 5 years. One way to synthesize stereoselectively these thionucleosides is via the Pummerer reaction <00JACS7233>. Compound 106 (R/S = 2.7:1), obtained in thirteen steps from the protected ribose 103, was treated with the nucleobase uracil in the presence of trimethylsilyl trifluoromethane sulfonate and triethylamine to yield the nucleoside 107. Final deprotections afforded the desired thionucleoside 108. A variation was recently reported starting from L-arabinose <06TL591>. Another technique for making thionucleosides relies on stereoselective electrophilic glycosidation as exemplified with the reaction of compound 109 with an heterocyclic base and phenylselenium chloride to yield nucleoside 110 <02JOC5919>. Derivatives bearing 4’-thio and 5’-uronamide were described by Jeong <03JMC3775; 06JMC273>. 1) TBDMSCl 2) DIAD, PPh3, 1) 4N HCl, 1) TIPDSCl2 pNitrobenzoic HO OH S O BnO BnO 2) diMeOBzCl dioxane acid OH OMe 2) NaBH4, 3) NaOMe 3) mCPBA BnO HO BnO MeOH 4) TBAF OBn OH OBn 5) MsCl 104 105 103 6) Na2S 7) BCl3 O O O NH NH S 1) TMSOTf, TEA O S S O HO N O N O TIPDS NH TIPDS 1) NH4F, MeOH HO O O O 2) NH3, MeOH ODMBz ODMBz OH NH 108 106 107 O
O O DTPS O 109
S
PhSeCl, CH3CN N
TMSO
N
O DTPS O
OTMS
NH
S N SePh 110
O
41
Recent developments in the chemistry of nucleosides
Several D- and L-β-3’-fluoro-2’,3’-unsaturated-4’-thionucleosides were synthesized by using (diethylamino)sulfur trifluoride on the ketone intermediate 111, followed by a key elimination reaction on the gem-difluoro compound 115 to yield nucleoside 116 bearing the five natural heterocyclic bases <04JMC1631>. The 2’-fluoro derivatives were also described via a slightly different route involving elimination of a phenylselenyl group <02JMC4888; 02OL305; 03JMC389>. Haraguchi described the synthesis of several novel 2’-β-carbo-substituted 2’deoxy-4’-thionucleosides made from 4-thiofuranoid glycals <04OL2645>. OTol
OTol O OMe
2'-deoxy-D-ribose O
OMe
DAST, F F DCM
1) BaCO3, TBAI, MeCN AcO 2) Hg(OAc)2, Ac2O, AcOH
S F F
113
HO
O HN
S
O
HO
O tBuOK, THF
N
F
NH
HN O
S N F
F
O
114
SBn F
112
1) BSA, TMSOTf 2) NH3, MeOH
SBn
F
2) Tf2O, lutidine
111 TolO
OTol OTf
1) BnSH, BF3.OEt2
O
115
NH
116
O
Trifluoromethyl substituted nucleoside 118 was synthesized from α-trifluoromethyl-α,βunsaturated ester 117 <02JOC1016> in eight steps involving the usual Pummerer rearrangement. Compound 119 was synthesized from L-xylose via 2-deoxy-2-C-difluoromethylene-4-thiosugar as a key intermediate <02OL529>. HO
O
COOEt N CF3 O
O
S
H2N
N
S
HO
N
N
O
NH2
HO 117
118
F3C
F
F
119
2.2.2.3 Substitution with nitrogen Very few publications on the synthesis of azanucleosides surfaced in the past 4-6 years. Qiu <05JOC3826> described the synthesis of azanucleoside 121 in fourteen steps from trans-4hydroxyproline 120. The same group published several other articles on various fluorinated derivatives as exemplified with compound 122 <02CCCC1267; 04BMC277; 04S334>. Compounds 123 and 124 were synthesized stereoselectively from a five-membered endocyclic enecarbamate using phenylselenyl bromide as promoter. L-nucleoside derivatives like 125 were described by Varaprasad <99T13345>. HOOC
H N
120
OH
HO F2HC HO
H N
O NH N
121
OH
H N
HO O
O NH N
122
CFn
O n = 1,2,3
42
J.-L. Girardet and S.A. Lang
O
H N
HO
NH N
O
O NH
N
R R = H or Me
123
O
H N
HO
O
O
OH
N OH
R R = H or Me
124
H N
HN
HO 125
2.2.3 Nucleosides with Bicyclic Sugars Nucleosides with a bicyclic sugar ring are often called conformationaly restricted or locked. The two major conformations of natural nucleosides are C-3’-endo and C-2’-endo. The formation of a second ring induces a restriction of the pseudorotational cycle of the ribofuranose puckering. The application of bicyclic nucleosides goes from the synthesis of modified oligonucleotides to enzyme inhibitors. 2.2.3.1 Spiro Nucleosides The 2',5'-bis-O-(tert-butyldimethylsilyl)- β -D-ribofuranosyl]-3'-spiro-5''-(4''-amino-1'',2''oxathiole-2'',2''-dioxide) or TSAO nucleoside series has been prolific in the past few years after the synthesis of the very first TSAO in 1992 and the description of its potent anti-HIV-1 activity. Aza analogs were described by Nguyen Van Nhien <03NNNA939; 05JMC4276>, and involved a cyclization of intermediate 128 with lithium diisopropylamide in tetrahydrofuran. Several N-3substituted analogs were described <03NNNA947; 05JMC6653>, as well as various substitutions at the 4’’-N-amino group of the spiro moiety <01NNNA707; 05JMC1158> and at the 3’’-C position <02JMC3934>. Some derivatives that lack the 4’’-amino group were synthesized <99NN675; 01NNNA711>. A generic structure for these modifications is shown in compound 130. OTBS
NH N
BnO
O
O 126 OTBS NH
N
S NH OTBS O 128
3) MeSO2Cl, pyr, DMAP
O
O
O
O NC
O
O
S O OTBS O O TSAO-T OTBS
1) Ti(OiPr)4, NH3, MeOH 2) TMSCN
O
O
H2N
O
LDA, THF H2N
O
O BnO NC O HN O S O 127 O R2 HN
O NH
O N
S NH OTBS O 129
OTBS
O
O N
O R1 O
R3 N O
S O OTBS O 130
The synthesis of the 4’-spiroannulated ribonucleoside was accomplished by elimination of the 2’-phenylthio group of compound 132 via a controlled oxidation with Davis oxaziridine reagent,
43
Recent developments in the chemistry of nucleosides
followed by heating in xylene to induce a thermal elimination of phenylsulfenic acid <03JOC8614>. Compound 133 was obtained after dihydroxylation with osmium tetroxide. Paquette published the synthesis of 4’-spiroannulated 2’-deoxyribonucleosides to be used as building blocks for DNA synthesis <04JOC7442>. Obtaining stereoselectivity during the Lewisacid promoted glycosidation was challenging, with both anomers of 135 being obtained. In the case of ribonucleosides, the β anomer was obtained selectively <01OL4039; 01OL4043>. The carbocyclic analogs were obtained <05JOC1597; 05S3209>, as well as the thionucleoside analogs in both ribo and 2’-deoxyribo series <03JOC8625; 04JOC7442; 05JOC5655>. Compounds 136 and 137 were synthesized from the same 2’-oxo sugar intermediate <03NNNA1313>. The synthesis of compound 139 was accomplished via Darzens reaction with lithiated methyl bromoacetate on intermediate 138 <00NNNA775>. The reaction was highly stereoselective and high yielding. The synthesis of the spiro[2,3]hexane carbocyclic compound 140 was achieved via enzymatic resolution <04OL2531>.
O O
NH O
OTBS
OTBS
O
O O
OH
134
HO
O
OTBS NH
O N O
1) LiCHBrCOOMe O
2) RNH2
O
O
O
N
N
O
O
137
N
O
139
N NH2
N
OTBS RHN
O
O
HO
NH
NH
O HO
O
O
OTBS 138
OH NH
136
O
O
OH 133
N
NH2 N
135
NH
HO
O O
TBSO
O
O N
2) OsO4, NMO 3) TBAF, THF
N
OH
PhO2S Ph 1) xylene, pyr.
SPh 132
131 SPh
OTBS
O N
OTBS O O N
OTBS
N
140
Spironucleosides at the C-1’ position have also been described. Their resemblance with natural nucleosides seems distant, but they are still categorized as such. 5-Epithiohydantocidin spironucleosides were prepared from glycosylaminoesters and furanoid methyl isothiocyanatoulosonates <06T97>. The spironucleosides 143 and 147 containing the barbituric acid moiety were synthesized from optically active precursors 141 and 144 <02JOC1302>, with compound 143 considerably more stable against ring opening than 147. The related 2’deoxyhydantoin 148 was synthesized via a Horner-Wadsworth-Emmons condensation of the phosphonate with the erythrose derivative, affording a mixture of six isomers that was
44
J.-L. Girardet and S.A. Lang
subsequently cyclized <00EJOC1831>. The 1,4-diazepine derivative 149 was synthesized from a novel cyclopeptide intermediate <04T2213>.
OMe OMe O
O
O
OH
OTBS O
1) (CH2O)n, AcOH, H2SO4
OMe
1) urea, tBuOK
O NH
O 2) TMSCl OMe 2) TMSCl, HO NH TBSO 3) resolution MeOH O O 4) TBSCl 141 142 143 O O NH NH O O H2, PdC OH Br2 Na2CO3 O O OH O NH NH O O O O O O O NH 145 146 144 O N O H O OH O O O NH HN O O O O NH O NH N NH HO HO O O H O O O 147 148 149
2.2.3.2 Bicyclic Nucleosides In recent years, the conformational restriction of nucleoside analogs has been well studied, especially in oligonucleotides and also for enzymatic studies. One of the most described bicyclic ring system has been the 2,5-dioxabicyclo[2.2.1]heptane as shown in compound 152. It was synthesized by intramolecular cyclization of 150 to yield 151, which, after condensation with thymine, gave compound 152 as a mixture of α and β anomers. A stereoselective route involving the nucleoside formation, followed by intramolecular cyclization was published later and yielded the pure β anomer 154 <01JOC8504>. The same bicyclo ring structure 155, but based on the xylo sugar was described by the same author <00JOC5161; 05EJOC2297>. Several more analogs with various heterocyclic bases and substitutions were published, including diaminopurines <04BMC2385; 04JOC3711>, 3’-C-ethynyluridine (EUrd) and 3’-Cethynylcytidine (ECyd) analogs <05BMC1249> and 3’-C-hydroxypropyl derivatives <04JOC6310>.
BnO
O
MsO
SPh
NaH, DMF
O
OH
HN
O HO
O
O 151
NH
O
SPh BnO
BnO 150
H N
O
OBn
N 1) HMDS HO 2) H2, PdC
O 152
O
45
Recent developments in the chemistry of nucleosides
OMs
O
MsO
1) NaH, DMF 2) NaOBz
NH
O N
O
OH
O
HO
NH
O N
3) H2, PdC 4) NH3
BnO
O
HO
NH
O
HO
O
N
O
HO
153
O
O
154
155
Several other bicyclic systems were described in the past few years. The 1’,2’-oxetane constrained adenosine was synthesized in thirteen steps from compound 156 <04JACS11484>. The key step was the intramolecular cyclization of compound 158 after deprotection of its 2’hydroxyl group. A 4,7-dioxabicyclo[4.3.0]nonane skeleton was described, the key step being the cyclization of 161 in the presence of sodium hexamethyldisilazide to give compound 162 in 73% yield. Nucleoside 162 was subsequently deprotected with para-toluene sulfonic acid <06JOC1306>. A 2’,3’-oxetane ring as in 163 was described by Sharma <05JOC4918> and involved a ruthenium-mediated cleavage of a double bond, followed by a substitution at C-2’ to give the arabino configuration. The β anomer was described earlier with a 3’-azido group <01JOC4878>. OTol
OTol 1) HCl, MeOH 2) MsCl
O O O O
O
HMDS, SnCl4
O Br
3) 90% TFA AcO 4) Ac2O 5) 30% HBr
156
N
OTol
OMs OAc 157
H N
N N
O
N
AcO OAc 158
N
NHBz N
N OMs
NHBz NHBz
N 1) NH3, MeOH 2) TIPDSCl2 3) NaHMDS
O
O TIPDS O
N
N
O
HO HO
O 160 OBn
O NH
O N
N N
159 HO
N
N O
OTs OBn
NH2
N
NaHMDS O
NH
O
O
OH
O N
O NH
O N
O
O
HO
BnO OMOP 161
BnO
OMOP 162
O 163
The 2-oxabicyclo[3.1.0]hexane nucleoside 166 was obtained via a Simmons-Smith type cyclopropanation reaction of intermediate 164, followed by glycosidation with several natural heterocyclic bases <05JOC6891; 05NNNA383>. A restricted version of puromycin built on a bicyclo[3.1.0]hexane template was synthesized by Choi via Mitsunobu coupling of a 3-azidosubstituted carbocyclic moiety with 6-chloropurine to give compound 167 <02OL589>.
46
J.-L. Girardet and S.A. Lang
OBn
OH
OBn O O
ZnEt2, CH2I2, tol
165
N
N
O
N(Me)2
H2N
OH 166
O
164
HO NH
N
O
O
2.3
O O
O
N
N
167
COMBINATORIAL APPROACHES
Nucleoside chemistry is traditionally labor intensive and the output of compounds is consequently relatively low. In order to overcome these limitations, several groups have implemented a parallel or combinatorial approach to speed up the synthesis process; this chapter will only discuss the use of solid support for the synthesis of nucleoside libraries, not for the purpose of oligonucleotide synthesis. Chang <05BMC4760> attached a purine dichloride to a Merrifield 3,4-dihydropyran resin, followed by sequential displacement of the two chloro atoms by various amines. The purine heterocyclic bases were then condensed with D,L-ribofuranosides following a classical Vorbrüggen method to yield nucleosides of general formula 171. 2,6-dichloropurine, CSA, DCM, 60 οC
N
N O
O
O
O 169
R1
Cl N
168
N
HN
Cl
N
N R2
N 170
OH 1) HMDS, (NH4)SO4, reflux 2) Tetra-O-acetylribose, TMSOTf, DCE, rt 3) NH3/MeOH
O N
N R1
HO OH N N 171 R2
Gunic <04NNNA495> and Koh <04NNNA501> condensed nucleosides 172, 173 and 174 with a Merrifield 4-methoxytrityl chloride resin. These three nucleosides were already bearing one or two reactive groups ready for further chemical modifications. To prevent side reactions on the highly activated 2- and 6-positions of the purine heterocycle, the only acceptable nonnucleophilic base that could be used for the condensation of the nucleoside with the resin was 2,6-lutidine. Halogen atoms were displaced with various amines and phenols. The authors also described palladium-catalyzed carbon-carbon coupling reactions on their scaffolds. Nucleosides 179, 180 and 181 were released from their support using hexafluoroisopropanol at room temperature, to yield libraries of 1,300 disubstituted and 760 trisubstituted purine nucleosides.
47
Recent developments in the chemistry of nucleosides
MMTr
O
HO
N
N
MeO
OH N 172
OH N 176
N
175 MMTr N
N OH N
R1 O
O
O
HO
N
173
177
F
OH N
NO2
NO2
R1 O
AcO
N
N
N F
R1 O
N
N
2,6-lutidine, THF, rt
O
HO
AcO
N I
Cl
R1 O
Cl
HO
I
HO
N
N
Cl
HO
O
O
N Cl
AcO
N Cl
AcO
OAc N N 174 H2N
OAc N 178
N
HN MMTr
176
177
178
R1 O
HO
HO
N
N
R2
HO OH N 179
R3
O
R1 HO
N
N
O OH N 180
R4
N
N
HO
N
O
O
HO OH N
NH 181
NH
R4
A similar approach was adopted by Epple, who combined the use of Nanokan technology developed by IRORI with a macroporous solid support to synthesize a 25,000 member library from compounds 186 and 187 <03JCC292>. The 5’-hydroxyl group was converted, via a Mitsunobu reaction, into an azido group which was subsequently reduced. The resulting 5’deoxy-5’-amino group was condensed with various carboxylic acids, isocyanates, isothiocyanates and sulfonyl chlorides to lead to a diverse 5’-amino substituted library. The 5’azido group was also reacted with disubstituted alkynes to yield a variety of 1,2,3-triazolyl compounds. A 2’,3’-acetal linkage of the nucleoside to the solid support proved to be compatible
48
J.-L. Girardet and S.A. Lang
with the chemistry involved, and was conveniently cleaved with 5% trifluoroacetic acid-5% water in dioxane at 50 °C.
H
O
O Br
H
O
MeO
OEt K2CO3, DMF, 20h, 50 oC
OH 182
OMe
TMOF, TsOH, MeOH, 5h, rt O O 183
O O 184
OEt
OEt
OH uridine, TsOH, DMF, 15h, 70 mbar, 50 oC
O N O
OEt
N NH
Cl N
O
O
O
R
N
O
O
N
N Cl
N
O
185
N
186
O
O
Compound 188 <03T2297> was obtained by condensation of an aminoglycoside attached on solid support with 2,4,6-trichloro-1,3,5-triazine; this intermediate led to a library size of 1,200 compounds after displacement of the 3- and 5-chloro atoms with various primary and secondary amines and cleavage from the support with 2% trifluoroacetic acid in dichloromethane. Compound 189 was synthesized in a similar way as 176 and 177; it led to a library of more than one thousand nucleosides via substitution of its triisopropylphenyl sulfonyl group <03JCC851>. Very similar compounds were obtained through Sonogashira and Stille reaction to yield 5substituted 2’-deoxyuridine derivatives after release from their base-labile solid linker <04JCC717>.
O
R
N N
O
O
O
O
Cl
O NH
MMTr O
N N
Cl
MMTr O
N
O NH 187
N N
R1
TBDMSO O
O O
188
OTBDMS
189
OMe
OTPS R2
A different strategy was used by Golisade, in which the acyl sulfonamide 192 was used to derivatize the 2’-deoxy-2’amino position of nucleoside 193 <00JCC537>. A library of 30 compounds is reported, with yields ranging from 87 to 98%, and purity between 85 and 98%
49
Recent developments in the chemistry of nucleosides
without the need for chromatography. The derivatization of a 2’,5’-dideoxy-5’amino nucleoside has also been reported; it involves an Ugi reaction with the primary amine while the 2’-hydroxyl group is attached to a polystyrene butyl diethylsilane resin. A 1344 member library based on formula 197 was synthesized <05TL8497>.
O S NH2 O 190
DIC, DIPEA, DMAP, THF, RCOOH
O
HO
N
N NH2 N
193
O NH
O
H2N
N
O
R2COOH R3NC
N
N
O O R S N O R' 192
R1CHO
O O R S N O R' 192
O
HO
THF, 55 oC
HO NH2 N
(Me)3SiCHN2, THF O O R or BrCHCN, NMP, DIPEA S NH O 191
NH2
HO O
R3
H N
NH N
N
R
194
R1
O
N O
R2
HF/pyridine
195
NH N
O R
O
O
O
HO 196
R
None of these libraries of nucleosides have been reported to yield any valuable antiproliferative activity thus far, but it is believed that these compounds will be tested over and over again against multiple targets in the future. 2.4
CONCLUSION
The field of nucleoside chemistry research has been very active since the start of the new millenium. Scores of publications have appeared in the literature, and several new compounds showed enough promise to enter clinical trials. It is likely that this trend will continue for the years to come, as the imagination of scientists and researchers seems to have no limit when it comes to designing novel modifications of molecules known for more than a century. 2.5 88MI1 90MI1
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50 91MI1 94MI1 95NN185 96JMC5005 97MI1 97BMCL127 97JOC1754 98JMC2892 98NN1033 99ARMC317 99JMC2901 99JOC293 99JOC2240 99JOC4173 99JOC9289 99NN675 99NN687 99NN811 99T13345 00ARMC331 00BMC2501 00BMCL139 00JOC1831 00JACS5947 00JACS7233 00JCC537 00JMC736 00JMC2196 00JMC2566 00JMC2438 00JMC3704 00JOC1865 00JOC5161 00JOC8114 00NNNA757 00NNNA775 00TL3643 01MI1 01BMC163
J.-L. Girardet and S.A. Lang
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Recent developments in the chemistry of nucleosides
01CEJ2332 01JMC208 01JOC2624 01JOC4878 01JOC8504 01NNNA649 01NNNA707 01NNNA711 01NNNA747 01NNNA1775 01OL1025 01OL2273 01OL4039 01OL4043 02ARMC257 02CCCC1267 02JMC1196 02JMC3934 02JMC4888 02JOC1016 02JOC1302 02JOC1898 02JOC5919 02JOC6837 02JOC7706 02JOC9331 02OL305 02OL529 02OL589 02PSS1783 02T1279 02T6019 02T9889 02TL5657 03ARMC347 03BMCL3345 03JMC201 03JMC389 03JMC3775 03JOC109
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52 03JOC6799 03JOC8614 03JOC8625 03JCC292 03JCC851 03NNNA683 03NNNA707 03NNNA939 03NNNA947 03NNNA1313 03NNNA2195 03OL383 03OL807 03OL1399 03S2101 03T2297 03T9013 04ARMC337 04BMC277 04BMC2385 04BMCL3517 04BMCL4655 04JACS11484 04JCC717 04JMC1631 04JMC2243 04JMC2283
04JMC5251 04JMC5284
04JMC5773 04JOC655 04JOC3711 04JOC3993 04JOC6257
04JOC6310 04JOC7442
J.-L. Girardet and S.A. Lang
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Recent developments in the chemistry of nucleosides
04NNNA495 04NNNA501 04NNNA671
04OL2531 04OL2645 04S334 04T2213 04TL739 04TL8981 05ARMC443 05BMC1249 05BMC1641
05BMC2045 05BMC4760 05BMCL709 05BMCL725 05BMCL2829
05BMCL3361 05EJOC2297 05JMC1158 05JMC2867 05JMC4276 05JMC4983 05JMC5043 05JMC5504
05JMC6430
05JMC6653 05JMC7808 05JMC8103 05JOC1597 05JOC3826
53
E. Gunic, R. Amador, F. Rong, J. W. Abt, H. An, Z. Hong, J.-L. Girardet Nucleosides, Nucleotides & Nucleic Acids 2004, 23, 495. Y.-h. Koh, M. B. Landesman, R. Amador, F. Rong, H. An, Z. Hong, J.-L. Girardet Nucleosides, Nucleotides & Nucleic Acids 2004, 23, 501. S. Kohgo, K. Yamada, K. Kitano, Y. Iwai, S. Sakata, N. Ashida, H. Hayakawa, D. Nameki, E. Kodama, M. Matsuoka, H. Mitsuya, H. Ohrui Nucleosides, Nucleotides & Nucleic Acids 2004, 23, 671. L. Bondada, G. Gumina, R. Nair, X. H. Ning, R. F. Schinazi, C. K. Chu Org. Lett. 2004, 6, 2531. K. Haraguchi, N. Shiina, Y. Yoshimura, H. Shimada, K. Hashimoto, H. Tanaka Org. Lett. 2004, 6, 2645. X.-L. Qiu, F.-L. Qing Synthesis 2004, 334. C. Taillefumier, S. Thielges, Y. Chapleur Tetrahedron 2004, 60, 2213. E. Ruediger, A. Martel, N. Meanwell, C. Solomon, B. Turmel Tetrahedron Lett. 2004, 45, 739. M. Yang, J. Zhou, S. W. Schneller Tetrahedron Lett. 2004, 45, 8981. S. Hedge, M. Schmidt. Annual Reports in Medicinal Chemistry; Elsevier: San Diego, 2005; pp 443. P. J. Hrdlicka, J. S. Jepsen, C. Nielsen, J. Wengel Bioorg. Med. Chem. 2005, 13, 1249. J. Shi, J. Du, T. Ma, K. W. Pankiewicz, S. E. Patterson, P. M. Tharnish, T. R. McBrayer, L. J. Stuyver, M. J. Otto, C. K. Chu, R. F. Schinazi, K. A. Watanabe Bioorg. Med. Chem. 2005, 13, 1641. P. Franchetti, L. Cappellacci, M. Pasqualini, R. Petrelli, V. Jayaprakasan, H. N. Jayaram, D. Boyd, M. Jain, M. Grifantini Bioorg. Med. Chem. 2005, 13, 2045. J. Chang, C. Dong, X. Guo, W. Hu, S. Cheng, Q. Wang, R. Chen Bioorg. Med. Chem. 2005, 13, 4760. Y. Ding, J.-L. Girardet, Z. Hong, V. C. Lai, H. An, Y.-h. Koh, S. Z. Shaw, W. Zhong Bioorg. Med. Chem. Lett. 2005, 15, 709. Y. Ding, H. An, Z. Hong, J.-L. Girardet Bioorg. Med. Chem. Lett. 2005, 15, 725. P.-P. Kung, L. R. Zehnder, J. J. Meng, S. W. Kupchinsky, D. J. Skalitzky, M. C. Johnson, K. A. Maegley, A. Ekker, L. A. Kuhn, P. W. Rose, L. A. Bloom Bioorg. Med. Chem. Lett. 2005, 15, 2829. T. D. Ashton, P. J. Scammells Bioorg. Med. Chem. Lett. 2005, 15, 3361. B. R. Babu, Raunak, N. E. Poopeiko, M. Juhl, A. D. Bond, V. S. Parmar, J. Wengel Eur. J. Org. Chem. 2005, 2297. S. deCastro, E. Lobaton, M.-J. Perez-Perez, A. San-Felix, A. Cordeiro, G. Andrei, R. Snoeck, E. DeClercq, J. Balzarini, M.-J. Camarasa, S. Velazquez J. Med. Chem. 2005, 48, 1158. Y.-h. Koh, J. H. Shim, J. Z. Wu, W. Zhong, Z. Hong, J.-L. Girardet J. Med. Chem. 2005, 48, 2867. A. NguyenVanNhien, C. Tomassi, C. Len, J. L. Marco-Contelles, J. Balzarini, C. Pannecouque, E. DeClercq, D. Postel J. Med. Chem. 2005, 48, 4276. P. Franchetti, L. Cappellacci, M. Pasqualini, R. Petrelli, P. Vita, H. N. Jayaram, Z. Horvath, T. Szekeres, M. Grifantini J. Med. Chem. 2005, 48, 4983. M. Yang, S. W. Schneller, B. Korba J. Med. Chem. 2005, 48, 5043. J. L. Clark, L. Hollecker, J. C. Mason, L. J. Stuyver, P. M. Tharnish, S. Lostia, T. R. McBrayer, R. F. Schinazi, K. A. Watanabe, M. J. Otto, P. A. Furman, W. J. Stec, S. E. Patterson, K. W. Pankiewicz J. Med. Chem. 2005, 48, 5504. S. H. Boyer, B. G. Ugarkar, J. Solbach, J. Kopcho, M. C. Matelich, K. Ollis, J. E. Gomez-Galeno, R. Mendonca, M. Tsuchiya, A. Nagahisa, M. Nakane, J. B. Wiesner, M. D. Erion J. Med. Chem. 2005, 48, 6430. M.-C. Bonache, C. Chamorro, S. Velazquez, E. DeClercq, J. Balzarini, F. R. Barrios, F. Gago, M.J. Camarasa, A. San-Felix J. Med. Chem. 2005, 48, 6653. B. C. Bookser, B. G. Ugarkar, M. C. Matelich, R. H. Lemus, M. Allan, M. Tsuchiya, M. Nakane, A. Nagahisa, J. B. Wiesner, M. D. Erion J. Med. Chem. 2005, 48, 7808. K. A. Jacobson, Z.-G. Gao, S. Tchilibon, H. T. Duong, B. V. Joshi, D. Sonin, B. T. Liang J. Med. Chem. 2005, 48, 8103. R. Hartung, L. A. Paquette J. Org. Chem. 2005, 70, 1597. X.-L. Qiu, F.-L. Qing J. Org. Chem. 2005, 70, 3826.
54 05JOC4591 05JOC4918 05JOC5006 05JOC5655 05JOC5833 05JOC6891 05JOC7902 05JOC7925 05NNNA383 05OL2141 05OL3889 05OBC1245 05S1467 05S3209 05SL1586 05T11850 05TL1927 05TL3883 05TL7535 05TL8497 06JMC273 06JMC2096 06JOC1306 06T97 06T906 06TL591
J.-L. Girardet and S.A. Lang
S. Vijgen, K. Nauwelaerts, J. Wang, A. VanAerschot, I. Lagoja, P. Herdewijn J. Org. Chem. 2005, 70, 4591. P. K. Sharma, M. Petersen, P. Nielsen J. Org. Chem. 2005, 70, 4918. J. A. Lee, H. R. Moon, H. O. Kim, K. R. Kim, K. M. Lee, B. T. Kim, K. J. Hwang, M. W. Chun, K. A. Jacobson, L. S. Jeong J. Org. Chem. 2005, 70, 5006. L. A. Paquette, S. Dong J. Org. Chem. 2005, 70, 5655. S. G. Petersen, S. R. Rajski J. Org. Chem. 2005, 70, 5833. J. Gagneron, G. Gosselin, C. Mathe J. Org. Chem. 2005, 70, 6891. J.-D. Ye, X. Liao, J. A. Piccirilli J. Org. Chem. 2005, 70, 7902. Y. Ueno, T. Kato, K. Sato, Y. Ito, M. Yoshida, T. Inoue, A. Shibata, M. Ebihara, Y. Kitade J. Org. Chem. 2005, 70, 7925. J. Gagneron, G. Gosselin, C. Mathe Nucleosides, Nucleotides & Nucleic Acids 2005, 24, 383. R. L. Weller, S. R. Rajski Org. Lett. 2005, 7, 2141. A. Roy, S. W. Schneller Org. Lett. 2005, 7, 3889. C. Takagi, M. Sukeda, H.-S. Kim, Y. Wataya, S. Yabe, Y. Kitade, A. Matsuda, S. Shuto Org. Biomol. Chem. 2005, 3, 1245. G. Rangam, N. Z. Rudinger, H. M. Müller, A. Marx Synthesis 2005, 1467. R. Hartung, L. A. Paquette Synthesis 2005, 3209. K. Sakthivel, P. D. Cook Synlett 2005, 10, 1586. F. Sarabia, L. Martin-Ortiz Tetrahedron 2005, 61, 11850. X.-q. Yin, S. W. Schneller Tetrahedron Lett. 2005, 46, 1927. K. Sakthivel, P. D. Cook Tetrahedron Lett. 2005, 46, 3883. X.-q. Yin, S. W. Schneller Tetrahedron Lett. 2005, 46, 7535. D. Sun, R. E. Lee Tetrahedron Lett. 2005, 46, 8497. L. S. Jeong, H. W. Lee, K. A. Jacobson, H. O. Kim, D. H. Shin, J. A. Lee, Z.-G. Gao, C. Lu, H. T. Duong, P. Gunaga, S. K. Lee, D. Z. Jin, M. W. Chun, H. R. Moon J. Med. Chem. 2006, 49, 273. M. Rapp, T. A. Haubrich, J. Perrault, Z. B. Mackey, J. H. McKerrow, P. K. Chiang, S. F. Wnuk J. Med. Chem. 2006, 49, 2096. M. Sekiguchi, S. Obika, Y. Harada, T. Osaki, R. Somjing, Y. Mitsuoka, N. Shibata, M. Masaki, T. Imanishi J. Org. Chem. 2006, 71, 1306. J. Fuentes, B. A. B. Salameh, M. A. Pradera, F. J. Fernandez de Cordoba, C. Gasch Tetrahedron 2006, 62, 97. G. Gosselin, L. Griffe, J.-C. Meillon, R. Storer Tetrahedron 2006, 62, 906. Y. Yoshimura, T. Kuze, M. Ueno, F. Komiya, K. Haraguchi, H. Tanaka, F. Kano, K. Yamada, K. Asami, N. Kaneko, H. Takahata Tetrahedron Lett. 2006, 47, 591.
55
Chapter 3.1
Three-membered ring systems (2004) Albert Padwa Emory University, Atlanta, GA 30322
[email protected] Shaun Murphree Allegheny College, Meadville, PA 16335
[email protected]
3.1.1
INTRODUCTION
Three-membered heterocycles are invested with a special allure that is derived from their apparent simplicity and spartan architecture. Yet these systems are multifaceted, and the literature continues to provide evidence of their diversity, both in terms of preparative routes and subsequent transformations. These smallest of heterocycles also exhibit a synthetically very useful balance between stability and reactivity. Thus, they are often employed as versatile and selective intermediates. With the potential to introduce two adjacent chiral centers with high atom economy, this methodology rightly deserves a place of prominence in synthetic organic chemistry. The utility of epoxides, for example, in the enantioselective synthesis of oxygensubstituted quaternary carbon centers has been the subject of a recent review <04COC149>. The following is not an exhaustive compilation, but rather a sampling of highlights from the past year’s literature with an emphasis on synthetic utility. The organization follows that of previous years. 3.1.2
EPOXIDES
3.1.2.1 Preparation of Epoxides An important preparative methodology which has developed rapidly over the last few years is the (salen)Mn mediated epoxidation of alkenes (the Jacobsen-Katsuki epoxidation). While the practical utility of this protocol is indisputable, the mechanistic underpinnings have been the matter of some debate. Adding to this ongoing dialectic is a result from a recently published DFT study, which suggests the salen ligand itself is involved in the transition state of the
56
A. Padwa and S. Murphree
epoxidation. In one outcome on a rather complex reaction surface, a covalent bond is formed beween the carbon atom of the substrate and the oxygen atom of the salen framework <04OL59>. A novel immobilized (salen)Mn catalyst has been constructed by incorporating a chiral sulfonato-salen complex into a zinc-aluminum layered double hydroxide (LDH) host. The active catalyst is proposed to exist as an intercalated species spanning the interlayer space (i.e., 1). The complex was shown to promote the selective epoxidation of limonene 2 with molecular oxygen at room temperature in the presence of pivaldehyde and N-methylimidazole under Mukaiyama conditions. The activity of the catalyst is stable even after multiple cycles, and no leaching of manganese has been observed <04CC554>. Recent mechanistic studies suggest that the epoxidation proceeds via the in situ formation of a peracid (i.e., perpivalic acid) through autoxidation of the aldehyde, which subsequently serves as an oxygen donor during the epoxidation <04JOC3453>.
SO3O N
1 O2 (75 psi)
O Mn
N
100% conversion 90% chemoselectivity 55% de
pivaldehyde (2.5 eq) N-MeI (0.5 eq) 25°C
Cl O 2
3
SO3-
1
Metal mediated epoxidation is remarkably diverse, with many types of ligand systems being represented. For example, a cytochrome P450 BM-3 mutant (139-3) has been developed using directed evolution, which exhibits high activity towards epoxidation of several non-natural substrates. Thus, exposure of styrene 4 to BM-3 variant 139-3 in phosphate buffer containing methanol and NADPH resulted in the quantitative conversion to styrene oxide 5. For terminal aliphatic alkenes, however, allylic hydroxylation is the predominant process <04T525>. O
cytochrome P450 BM-3 139-3
100% yield
phosphate buffer / MeOH NADPH 4
5
Highly efficient small molecular P450 mimics have also been developed. The sterically stabilized metalloporphyrin [Mn(TDCPP)Cl] 6 catalyzes the mild and highly diastereoselective epoxidation of protected cyclohexenol derivative 7 using hydrogen peroxide as the terminal oxidant. The preference for trans-epoxides is rationalized on the basis of non-bonded
57
Three-membered ring systems (2004)
interactions between the allylic substituent on the substrate and the bulky porphyrin ligand; diastereoselectivies increase with steric demand of the substituent <04OL1597>. The same metalloporphyrin has been shown to catalyze the epoxidation of aromatic substrates, which has implications not only in the realm of synthetic methodology, but also with respect to the toxicology of environmental polycyclic aromatic hydrocarbons. Thus, phenanthrene 9 is converted to epoxide 10 in excellent yield in three hours with a catalyst loading of 0.3 mol% <04CC608>. OTBDMS Cl
Cl
H2O2
N
Cl N
Cl
N
O
aq NH4HCO3 CH3CN 25°C
Cl
Mn
OTBDMS
6
N
7
Cl
100% conversion 88% yield 33:1 trans/cis
8
Cl
6 Cl
H2 O 2
Cl
100% conversion 91% selectivity
NH4OAc CH3CN-CH2Cl2 25°C
6
O
9
10
Conventional wisdom holds that these epoxidation reactions occur via oxygen atom transfer directly from the catalyst via the metal-oxo species. As a result of their studies of the structurally similar Mn-corroles, Goldberg and co-workers have proposed that at least a secondary pathway might exist in which the metal-oxo species activates the terminal oxidant through simple Lewis acid catalysis (cf. 12). This hypothesis, which is supported by 18O labeling experiments, would explain the long-recognized but poorly understood impact of the terminal oxidant on the course of these epoxidations <04JA18>. t-Bu
t-Bu
N
t-Bu
t-Bu N
N
MnIII
N N
N
MnV
(Cz)
O
N
t-Bu
t-Bu
O PhIO
Ph
I 12
t-Bu
t-Bu 11 (Cz)
MnIII
oxygen to be transferred
58
A. Padwa and S. Murphree
Metal-catalyzed epoxidations can also work quite efficiently even with very simple ligand systems. For example, 1-octene 13 is converted to its corresponding epoxide in practically quantitative yield within 5 min upon exposure to peracetic acid in the presence of the Mn(II)bipyridyl complex at 0.1 mol% catalyst loading <04OL3119>. O
[MnII(bipy)(CF3SO3)2]
99% conversion 94% yield
CH3CO3H CH3CN 25°, 5 min
13
14
Metal-catalyzed epoxidations are becoming important on the industrial scale, since the ability to use molecular oxygen as the terminal oxidant offers considerable operational and environmental benefits. The crucial feedstock propylene oxide 16 can be produced using molecular oxygen and a catalytic system of palladium(II) acetate and a peroxo-heteropoly compound in methanol <04CC582>. A discussion of some quantum chemical calculations with regard to the industrially relevant peroxometal epoxidation catalysts has recently appeared in the literature <04SCR645>. O2 [(hexyl)4N]3{PO4[W(O)(O2)2]4}
O
Pd(OAc)2 MeOH 100°C (autoclave)
15
43% conversion 82% selectivity
16
In the realm of epoxidations without the use of transition metals, dioxirane-mediated processes are among the most versatile. While the use of stoichiometric amounts of even the simplest dioxiranes can still be experimentally cumbersome, novel catalytic systems continue to emerge. For example, the PEG-immobilized trifluoroacetophenone 17 is a convenient dioxirane precursor that is highly active, soluble in both water and organic solvents, and easily recoverable and reusable. In the presence of Oxone, this ketone mediates the efficient epoxidation of sensitive substrates, such as the BOC-protected aminostyrene 18 <04TL6357>. O
MeO
O
O
n
17
O
17 Oxone
CF3 BocHN 18
water / dioxane 90% yield
BocHN 19
These ketone precursors can also serve as chiral auxiliaries. The dioxirane from the fructosederived ketone 20 converts trisubstituted and trans-disubstitued alkenes (e.g., 22) to the corresponding epoxides in very good yields and enantioselectivities, but is less effective for terminal and cis-disubstituted substrates. Fortunately, the oxazolidino analog 21 exhibits a complementary scope, providing high enantioselectivities for these latter olefins (e.g., 24). The stereochemical outcome of the reaction has been rationalized on the basis of a spiro transition
59
Three-membered ring systems (2004)
state <04ACR488>. Very mild homogeneous conditions have been elaborated for the in situ generation of dioxiranes from ketones using a buffered Oxone solution <04ACR497>. TMS O O
O
O O
O
O
O
N Ar
Ph 23
22
O
O
O
Oxone 96% ee
Ph
TMS
O
20
O
O 20
20
21
Oxone 91% ee
Ph
Ph 25
24
Page and co-workers have reported a noteworthy advance in asymmetric epoxidations of unfunctionalized olefins using chiral iminium salts, such as 26. In the presence of Oxone neutralized with sodium carbonate, the iminium salt is converted to the corresponding oxaziridium salt, which serves as the oxygen transfer agent. Yields are moderate to good, and enantioselectivities are highly variable, but can reach as high as 95%, as exemplified by the epoxidation of 1-phenyl-3,4-dihydronaphthalene 27. Effective catalyst loadings can also be remarkably low, as shown in the conversion of 1-phenylcyclohexene 29, which proceeded in 91% ee with only 0.5 mol% of the catalyst <04OL1543>. Anhydrous conditions have also been optimized for this system <04JOC3595>. Ph
BPh4 O N
27
Ph
26 (5 mol%) Oxone (2 eq) Na2CO3 CH3CN / H2O
O 66% yield 95% ee
28
O Ph
Ph
26
29
26 (0.5 mol%) Oxone (2 eq) Na2CO3 CH3CN / H2O
Ph
O 65% yield 91% ee
30
Remarkably, simple chiral ammonium salts such as 31 can induce modest enantiomeric excess in the Oxone-mediated epoxidation of trisubstituted alkenes. While no in-depth mechanistic models have been proposed, the mode of action is believed to be through the formation of chiral salts with Oxone itself <04AGE1460>.
60
A. Padwa and S. Murphree
Ph Ph N
Cl
H
H
Oxone
Ph
Ph
H
H
O
O OH
S O 31
Ph
N
O
Ph
31 (10 mol%) Oxone (2 eq) NaHCO3 CH3CN / H 2O
29
O
30
32
93% yield 41% ee
The same kind of associative event lies at the heart of the catalytic asymmetric epoxidation of enones using the interesting binaphthyl derived spiro ammonium salt 33, which serves as a phase transfer catalyst as well as chiral auxiliary. Using sodium hypochlorite in a biphasic system, this catalyst mediates the high-yielding epoxidation of a variety of electron-deficient trisubstituted and trans-disubstituted olefins with excellent enantioselectivity, as represented by the conversion of enone 34 to the corresponding epoxy ketone 35 <04JA6844>. Ph
Ph
Ph
Ph OH O
Br
33 (3 mol%)
N
Ph
OH Ph
34 Ph
13% NaOCl toluene 0°C 3.5 d
O
O Ph 35
99% yield 92% ee 33
Ph
Ph
Another commonly employed approach for the enantioselective epoxidation of enones is the Juliá-Colonna procedure, which utilizes basic hydrogen peroxide as an oxygen source and polyleucine as a chiral auxiliary. Practical improvements to this protocol have recently been reported. In one modification, poly-(L)-leucine is stirred in a biphasic mixture of water/toluene with tetrabutylammonium bisulfate as a phase-transfer agent. The polyamino acid appears to be the species that consumes hydrogen peroxide from the aqueous medium and serve as a source of oxygen in the organic phase. These reaction conditions accomplished the notable feat of preparing the epoxysulfone 37 in high yield and good optical purity <04TL5073>. Investigators at Bayer reported very similar conditions using silica supported poly-(L)-leucine, which was shown to epoxidize trans-chalcone 38 in excellent yield and enantiomeric excess <04TL5069>.
61
Three-membered ring systems (2004) poly-(L)-leucine (1 mol%) H2O2 / NaOH Bu4NHSO4 toluene RT
TolO2S 36
O
O
37
O
Si supported poly-(L)-leucine
Ph
H2O2 / NaOH TBAB toluene
Ph 38
89% conversion 76% isol'd yield 70% ee
TolO2S
> 99% conversion 92% ee
O
Ph
Ph 39
γ-Hydroxy-α,β-unsaturated esters were shown to undergo diastereoselective epoxidation in the presence of lithium t-butylperoxide, in which the delivery of the epoxide oxygen is guided by the solvent system. Thus, in coordinating solvents such as THF, the predominant product (i.e. 41) is anti; conversely, non-polar solvents such as toluene lead to syn diastereoselectivity. Interestingly, temperature exerts practically no influence on the stereochemical outcome over the range of -80° – 50°C <04TL5359>. O OEt
O
t-BuOOLi
O
O OEt
OH
+
OEt
OH 40
OH
syn-41
anti-41 Solvent
anti
syn
THF
75
25
40%
toluene
32
68
53%
O
yield
Thus far, discussion has centered around the reaction of alkenes with a source of electrophilic oxygen as a route to epoxides [the C=C + O protocol]. However, a second general approach is represented by the reaction of carbonyl compounds with amphophilic carbon centers [the C=O + C protocol]. For example, sulfonium ylides are known to convert aldehydes and ketones to epoxides; much recent work has focused on asymmetric induction using this methodology, a topic which has been the subject of a concise review in the past year <04ACR611>. As an illustration, the D-mannitol derived chiral sulfide 42 serves as a useful chiral auxiliary in the sulfonium methylide epoxidation of aldehydes to provide terminal monosubstituted oxiranes (e.g., 44) in fair to excellent yield and good enantiomeric excess <04CC1076>. Ph
O
Cl
Ph
O
O O
S 42
O
CH2Cl, DME 25°C
Cl 43
Cl
42 Et2Zn, CH2ICl
O 96% yield 76% ee
Cl 44
Aldehydes can also be converted to enantioenriched chiral epoxides through the Darzens reaction. Thus, haloimides (e.g., 47) react with benzaldehyde in the presence of a novel phase transfer catalyst 45 derived from BINOL to give 1,2-disubstituted epoxides in good yields with
62
A. Padwa and S. Murphree
high enantioselectivity, and fair diastereoselectivity. The protocol can be applied to both aromatic and aliphatic aldehydes with low catalyst loadings <04TL1845>. O MeO N 2 Br N
MeO 46
45 (2 mol%)
+
RbOH·H2O (2.4 eq) CH2Cl2, 25°C, 1d
O Br
NPh2 O 48 82% yield 60% ee cis/trans 8:1
NPh2
45
O
47
Finally, carbenoid species can be used as the carbon donor in aldehyde epoxidations. Thus, the rhodium carbenoid derived from the cyclic diazoamide 49 and rhodium(II) acetate reacts stereoselectively with aryl aldehydes to provide spiro-indolooxiranes 50 with Z-stereochemistry. The reaction is believed to proceed via the formation of a carbonyl ylide 51, which undergoes stereospecific thermal conrotatory electrocyclization to form the observed epoxide <04SL639>. N2
O O
+
Rh2(OAc)4
O
N
OMe
1,2-dichloroethane 60°C
Ph
84% yield
N O
Ph OMe 49
50
46
OMe O N Ph
H O 51
3.1.2.2 Reactions of Epoxides The hydrolysis of epoxides is a well-known reaction which can be exploited for various synthetically useful outcomes. Chiral nonracemic epoxides can be prepared from their racemates through the salen-mediated hydrolytic kinetic resolution (HKR). Racemic epichlorohydrin 53 was resolved in the presence of catalyst 52 and a slight excess of water under solvent-free conditions. The catalyst counterion exerts a significant effect on the course of the reaction, presumably due to competitive addition onto the epoxide, an effect which is evident in apparent reaction rates, but not enantioselectivities. Less nucleophilic counterions, such as tosylate, lead to more rapid resolution and lower catalyst loading requirements <04JA1360>.
63
Three-membered ring systems (2004)
52 (0.2 mol%) N
N Cl
Co O
t-Bu
t-Bu
O OAc t-Bu
H2O (0.7 eq)
O
0-4°C, 16 h
t-Bu
O
Cl
OH +
55
54
53
OH
Cl
42% yield (50% max) > 99% ee
52
Chiral diols have been prepared from the desymmetrization of the corresponding meso epoxides using epoxide hydrolases (EHs). As a general trend, microbial EHs tend to prefer the generation of (R,R)-diols, as demonstrated by the desymmetrization of cis-stilbene oxide 56. However, a recently reported variant (BD9126) exhibits the opposite enantioselectivity. This nice complement to existing methods provides good to excellent ee's, albeit at reaction rates typically two orders of magnitude less than the (R,R)-producing enzymes <04JA11156>. A new palladium-catalyzed ring opening of epoxyacrylate derivatives mediated by boric acid gives the corresponding diols 59 with net retention of configuration at both epoxide carbon centers, providing a nice complement to osmium dihydroxylation methodology. The reaction is believed to proceed through the intermediacy of cyclic boronates (e.g., 60) <04CL764>. O Ph
Ph 56
Ph
EH BD8877 (0.5 wt%)
HO
OH
phosphate buffer 5% CH3CN 22°C, 48 h
Ph
Ph
B(OH)3 Pd(PPh3)4
O CO2Et 58
57
HO Ph
THF 25°C 10 min
CO2Et OH
Ph
83% yield 99% ee
92% yield 98% de
59
CO2Et O
B
O 60
OH
Epoxides also suffer nucleophilic attack by amines, forming ethanolamine derivatives. This reaction can take place under a variety of conditions and with the influence of several catalysts. Styrene oxide 61 undergoes ring opening in the absence of catalyst under strictly thermal conditions (90°C in a sealed tube) to give predominantly the amino-alcohol 62, the product of attack at the more substituted (α) position <04SC2393>. The reaction time can be reduced by using a combination of catalytic bismuth(III) trifluoroacetate and brief microwave irradiation, as
64
A. Padwa and S. Murphree
illustrated in the reaction of 61 with p-bromoaniline, which requires only 40 sec of heating in a conventional microwave to provide 62 as the exclusive product in 90% yield <04CL304>. The reaction temperature can also be lowered (to room temperature) by the addition of 5 mol% lithium bromide as a catalyst. Under these conditions, the regioselectivity appears to be dependent upon the attacking nucleophile. Thus, p-chloroaniline engages in exclusive attack at the α-position, whereas piperidine gives an almost equimolar mixture of products 62 and 63 <04EJOC3597>. In contrast, the use of nickel(II) acetate as catalyst leads to an extremely high regioselectivity with piperidine, favoring the α-product 62 <04SL846>. Interestingly, indium bromide promotes the opposite regiochemistry. Thus, treatment of styrene oxide with p-tertbutylaniline and 1 equiv of indium tribromide gives exclusively aminoalcohol 63 in 75% yield. In this protocol, attempts to use substoichiometric amounts of catalyst led to lower yields and significant amounts of a 2:1 adduct of epoxide to amine <04TL7495>. H N R1 R2 conditions (see table)
O Ph
R1
N
R2 OH
Ph
61
OH +
R1 N
Ph
62
R2
63
amine
R1
R2
catalyst (loading)
solvent
time
temp
yield
62:63
reference
ethanolamine
HOCH2CH2-
H-
none
neat
3h
90°C*
99%
90:10
<04SC2393>
p-bromoaniline
(p-Br)Ph-
H-
Bi(TFA)3
CH3CN
40 s
MW
90%
100:0
<04CL304>
p-chloroaniline
(p-Cl)Ph-
H-
LiBr (5 mol%)
neat
5h
RT
100%
100:0
<04EJOC3597> <04EJOC3597>
piperidine
-(CH2)5-
LiBr (5 mol%)
neat
5h
RT
98%
42:58
piperidine
-(CH2)5-
Ni(OAc)2·2H2O
neat
12 h
50°C
99%
96:4
<04SL846>
InBr3 (1 eq)
CH2Cl2
12 h
RT
75%
0:100
<04TL7495>
p-t-butylaniline
(p-tBu)Ph-
H-
*sealed tube
Similar conditions have been applied to the ring-opening of meso epoxides using amines. Bismuth triflate catalyzes the reaction of cyclohexene oxide 64 with p-bromoaniline under aqueous conditions to provide the β-aminoalcohol 65 in 84% yield. In this particular case, the water solubility of the starting materials required the use of a micellar solution of sodium dodecyl sulfate (SDS); however, more soluble amines could be employed in water and bismuth triflate alone <04TL49>. A lanthanide variant has also been reported. Thus, treatment of 64 O
OH
p-bromoaniline conditions (see table)
Br
N H
64
65
conditions
time
temp
yield
reference
Bi(OTf)3 (10 mol%), SDS (40%), H2O
9h
25°C
84%
<04TL49>
SmI2(THF)2 (10 mol%), CH2Cl2
18 h
25°C
76%
<04TL7749>
with p-bromoaniline and 10% samarium iodide in methylene chloride solution provides the product 65 in 76% yield. An interesting aspect of the latter protocol is that the chiral bisbinaphthoxy iodo samarium catalyst 66 has been shown to effectively desymmetrize meso
65
Three-membered ring systems (2004)
epoxides, as illustrated by the conversion of the cyclohexadiene oxide 67 to the nonracemic aminoalcohol 68 <04TL7749>.
O
66 (10 mol%) CH2Cl2 25°C 18 h
O 67
66
OH
o-methoxyaniline
O
Sm I · (THF)2
N H
OMe
68
100% conversion 60% yield 68% ee
Chromium(salen) catalysts (e.g., 69) are also useful in desymmetrizing meso epoxides. Thus, cis-stilbene oxide 70 is converted to the (S,S)-aminoalcohol 71 in the presence of catalytic quantities of 69 in methylene chloride solution open to the atmosphere. The addition of small quantities of triethylamine was found to dramatically increase enantioselectivities (by almost 25%). This catalytic system also promotes an efficient aminolytic kinetic resolution (AKR) of racemic epoxides with C2-type symmetry <04OL2173>.
N
O
N
t-Bu
O
O
t-Bu
Ph
Cl t-Bu
Ph
Et3N (11 mol%) 25°C, 40 h
70
t-Bu
NHPh
69 (10 mol%)
Cr
Ph
Ph OH 71
98% yield 90% ee
69
Another very useful method of introducing nitrogen during epoxide cleavage is based on the azide nucleophile. This approach was used in the regioselective ring-opening of the optically pure aryl epoxide 72, a key step in the synthesis of (-)-cytoxazone 74, a cytokine modulating natural product isolated from Streptomyces. The regioselectivity is substrate dependent: terminal epoxides are attacked preferentially at the less substituted position, whereas benzylic positions tend to be more electrophilic in the case of aryl epoxides. The regioselectivity is attributed to the potassium ions found in mesoporous 4Å molecular sieves used as a catalyst <04TL7355>. O O
N3 CO2Et
4Å sieves CH3CN 25°C, 1.6 h
MeO
72
CO2Et
NaN3 OH
MeO
73
HN
3 steps 67%
O OH
MeO
74 (-)-cytoxazone
66
A. Padwa and S. Murphree
This type of ring-opening by heteroatomic nucleophiles can also occur in an intramolecular fashion, leading to new heterocycles. For example, vinyl epoxide 75 undergoes 6-endo cyclization in the presence of a rhodium catalyst to give the trans-hydroxypiperidine derivative 76 under extremely mild conditions. The olefinic moiety is crucial, as the reaction proceeds through the initial coordination of the π-bond and nitrogen lone pair, followed by the formation of an enyl or π-allyl intermediate. This double coordination is believed to govern both the regioselectivity and stereoselectivity of the process <04TL4193>. OH [Rh(CO)2Cl]2 (2 mol%)
O
THF 25°C 30 min
CO2Et
NH Cbz
83% yield N
CO2Et
Cbz
75
76
Epoxides can serve as competent electrophiles in the alkylation of a variety of carbanions, as illustrated by the ring opening of cyclohexene oxide (64) with the dianion of phenylacetic acid (77) to produce the γ-hydroxy carboxylic acid 78. In this protocol, the dianion is generated using n-butyllithium and a substoichiometric quantity of a secondary amine; lithium chloride is also used as a Lewis acid additive to activate the secondary epoxide toward nucleophilic addition. Primary epoxides undergo addition without the use of catalyst—in these cases, the nucleophile attacks at the less substituted position <04EJOC2160>. Ph OO
64
+
LiCl (1 eq) Ph
-O
HO
CO2H 83% yield
Et2NLi (10 mol%) THF, 25°C, 3 h
77
78
A similar transformation can be carried out under milder conditions by taking advantage of silyl ketene acetals, a masked form of the carboxylate dianion. When epichlorohydrin 53 was treated with the ketene acetal 79 in the presence of titanium(IV) chloride, a regioselective epoxide ring opening occurs at the less substituted carbon. Treatment of the crude reaction mixture with catalytic p-toluenesulfonic acid promoted a lactonization to the γ-butanolide 80 in high overall yield <04T8957>. OTMS
O
Cl
53
+
OMe 79
O TiCl4 CH2Cl2 / hexane -60° --> -30°C
cat. p-TsOH
O
CH2Cl2 25°C, 3 h 80
Cl
83% yield
Other carbon nucleophiles also tend to attack at the less substituted position of an unsymmetrical epoxide. This holds true for cyanide, which can be conveniently prepared in situ from methyllithium and acetone cyanohydrin 82. In a one-pot reaction, the epoxy ether 81 is
67
Three-membered ring systems (2004)
converted to hydroxy nitrile 83 in 80% yield <04TL7201>. Similarly, alkyllithium reagents attack the unsubstituted carbon of terminal epoxides, and when an excess of base is present, the intermediate alkoxides undergo elimination to form alkenes. Thus, when decyl epoxide 84 is treated with the vinyl lithium derivative 85 in the presence of lithium tetramethylpiperidine (LTMP), diene 88 is produced exclusively in the E-geometry in very good yield. The mechanism involves an initial deprotonation of the epoxide by LTMP, followed by nucleophilic attack of the carbenoid oxiranyl anion by the vinyllithium 85. The dilithio species 87 suffers elimination to provide the observed alkene <04JA12250>. O
OH
OPh
+
MeLi THF Δ 20 min
CN
81
82
O C10H21
OH NC
OPh
80% yield
83
LTMP (2 eq)
+
Li
84
hexane 0° -> 25°C 2h
85
85% yield
C10H21 88
OLi 84
O
LTMP C10H21
85
Li
88
C10H21 Li 87
86
The fascinating carbenoid character of the epoxide anion is also manifested in an intramolecular cyclopropanation reaction, in which the anion adds across a tethered olefin to provide bicyclo[3.1.0]hexanols (e.g., 92). The reaction is remarkably chemo- and diastereoselective. No C-H insertion is observed, and yields are generally very good. The stereochemical outcome is rationalized on the basis of a trans-lithiation, as well as the geometric constraints imposed by the [3.1.0] bicyclic system <04JA8664>. In the absence of wellpositioned double bonds, the oxiranyl anions can undergo another well-known reaction of carbenes, namely a 1,2-hydride shift. In the case of these substrates, the rearrangement leads to the formation of an enolate anion. Treatment of the cyclohexyl alkynyl epoxide 93 with an excess of n-butyllithium leads to an oxiranyl anion at the allylic site (i.e., 94). This intermediate undergoes a formal 1,2-hydride shift to provide the enynolate 96, which undergoes double distal protonation during acidic work-up to form the allenone 98 in 64% yield <04OL3509>. O O
OH
O
LTMP (2 eq)
:
80% yield 99% ee
t-BuOMe 0° -> 15°C 8h (S)-89
90
91
(1S,2S,5R)-92
68
A. Padwa and S. Murphree
O
O
:
O n-BuLi (2.2 eq)
H H
H
H
THF -78° -> -20°C
93
H
94
95 1,2-shift
H
O ·
O H
64% overall
H
O
2 ·
HCl / H2O
98
H
H
97
96
Lithiated epoxides are more commonly trapped by electrophiles, generating elaborated oxiranes. In this arena, Hodgson and co-workers <04OL4187> have optimized the lithiation of nonstabilized terminal epoxides with sec-butyllithium assisted by diamine ligands, such as dibutylbispidine (DBB, 99) or (-)-sparteine 100. The oxiranyl anions thus formed engage in smooth nucleophilic addition onto aldehydes to form epoxyalcohols (e.g., 101); the same conditions can be used for the stannylation of epoxides (e.g., 84 → 102). Similarly, epoxydisilanes 103 can be accessed through two sequences of deprotonation followed by treatment with chlorotrimethylsilane <04SL1610>. H N Bu
Bu s-BuLi 99
PhCHO
O
99 C10H21
H N
H 100
Ph
75% yield
101
H
N
OH
C10H21
N
H
O
H
s-BuLi 99
Bu3SnCl
s-BuLi 100 84
O C10H21
SnBu3
78% yield
SiMe3
61% yield
102 Me3SiCl (two iterations)
O C10H21
SiMe3 103
Epoxides undergo a variety of interesting and synthetically useful rearrangements to provide carbonyl compounds. The siloxycyclopentyl epoxide 104 (derived from the DMD oxidation of the corresponding tetrahydropyridine) underwent Lewis acid-catalyzed ring expansion to provide spiroketone 105 as a single diastereomer, suggesting a synchronous reaction mechanism <04JOC5676>. In a similar vein, the dichlororuthenium(IV)-porphyrin catalyst 106 promotes the rearrangement of terminal epoxides (e.g., 108) to aldehydes (e.g., 109). The epoxides themselves are prepared by oxidation of terminal alkenes (e.g., 107) with 106 in the presence of the stoichiometric oxidant 2,6-dichloropyridine N-oxide (Cl2pyNO), thereby representing a novel
69
Three-membered ring systems (2004)
conversion of terminal alkenes to aldehydes <04AGE4950>. Ruthenium catalysts also promote other unusual cyclizations of epoxides, such as the rearrangement of enynyl epoxide 110 to the cyclohexa-2,4-dienone 111 <04JOC7700>, and the cyclization of o-ethynylphenyl epoxide 112 to the alkylidene indanone 113 <04JA6895>. Both processes are thought to proceed through a ruthenium-ketene intermediate. TBSO O
TiCl4 (1.1 eq)
OTMS
96% yield
CH2Cl2 -78°C 30 min
N Ts
OH O
TBSO N Ts
104
105
Cl Cl
Cl
Cl
N
Cl
Ru
N
Cl
N
N
Cl
Cl
Cl
Cl 106
O
106 (2 mol%) Cl2pyNO (1 eq) CDCl3 25°C / 30 min
MeO 107
O
Me Ph
O
106
99% yield MeO
MeO 108
109
Me
TpRuPPh3(CH3CN)2PF6 (10 mol%)
Ph
toluene 100°C 12 h
92% yield
O
110
111 O TpRuPPh3(CH3CN)2PF6 (10 mol%)
F
F O
toluene 100°C 12 h 112
3.1.3
91% yield
113
AZIRIDINES
3.1.3.1 Preparation of Aziridines One method widely used for the synthesis of aziridines is the addition of nitrenes to olefins. Along these lines, sulfonamides serve as convenient nitrene precursors, which can be converted
70
A. Padwa and S. Murphree
using commercially available iodobenzene diacetate in the presence of various transition-metal catalysts. A copper(I) catalyst derived from the Evans chiral bis(oxazoline) ligand 114 was found to promote the high-yielding aziridination of styrene 4 with good enantioselectivity <04TL3965>. Chang and co-workers have developed a copper-catalyzed variant that requires no external ligand. Instead, a pyridyl nitrogen onboard the sulfonamide moiety serves as an internal ligand (i.e., 118), which in turn increases the efficiency of the aziridination <04OL4109>. Several unsaturated sulfonamides (e.g., 120) were shown to undergo a very facile intramolecular aziridination in the presence of a rhodium catalyst to provide tricyclic aziridines (e.g., 121) <04 JOC6377>. SO2NH2 +
114 (6 mol%) [Cu(CH3CN)4]ClO4 (5 mol%)
NO2
115
116 94% yield 75% ee O
O N
t-Bu
N t-Bu
114
PhI(OAc)2 Cu(tfac)2(3 mol%) N
CH3CN 25°C, 12 h
SO2NH2
4 N
N
SO2
118
SO2NH2
N
O2 S
[Cu] N
117
PhI(OAc)2
119 84% yield
O2 S
Rh2(OAc)4 MgO, CH2Cl2 120
O2 S
PhI(OAc)2 benzene
O2N 4
N
N
91% yield
121
Other interesting catalyst systems include copper(II) acetylacetonate (acac) immobilized in ionic liquids such as 1-n-butyl-3-methylimidazolium tetrafluoroborate (bmimBF4), which facilitates catalyst recycling and also appears to accelerate the reaction. Thus, transmethylstyrene 122 was converted to the corresponding tosyl aziridine 123 within 10 min using (tosylimino)phenyliodinane as the nitrogen donor <04SL525>. Bromamine T 125 is also a convenient, stable, and commercially available nitrene precursor. The perfluoroaryl iron porphyrin catalyst 124 is effective in promoting aziridination of a wide spectrum of alkenes in fair to good yields, as illustrated by the conversion of styrene 4 to the corresponding N-tosyl aziridine 126, which is believed to proceed through a mechanism involving an iron-nitrene intermediate <04OL1907>. A fluorinated aryl ligand is also at the heart of a chiral ruthenium(salen) catalyst 127 designed for the purpose of effecting enantioselective aziridination
71
Three-membered ring systems (2004)
Ts PhI=NTs Cu(acac)2 bmimBF4 25°C 10 min
122 F
F
F F
N
87% yield
Ph
Me 123
F
F
F
F N
F N
F
Fe N
O2 S
F N
Cl
+
F F
F F F
F
Br
N Na
4
125
NTs 124 (5 mol%) CH3CN 5A mol sieves 25°C, 12 h
F F
124
126 80% yield
F
F Ar = N
N Ru
O O Ar Ar
Me NTs
TsN3
F
127 (9 mol%) 4A mol sieves CH2Cl2 25°C, 24 h
Br
128
79% yield 90% ee
Br
129
CO 127
of olefins using sulfonyl azides as nitrene precursors. Thus, p-bromostyrene 128 provides the corresponding aziridine 129 in the presence of tosyl azide and catalyst 127. Enantioselectivities can reach as high as 99%, and the protocol also works well when tosyl azide is substituted with nosyl azide <04CC2060>. In the case of electron-deficient olefins, other methodologies are also available. For example, the dicyanoalkene 130 (derived from the Knoevenagel condensation of malononitrile with acetaldehyde) undergoes a facile aza-Michael addition of ethyl nosyloxycarbamate in the presence of calcium oxide to give a β-aminocarbanion intermediate 131, which quickly cyclizes to the corresponding dicyanoaziridine 132 in excellent yield <04SL1083>. When trifluoromethylacrylates are used as substrates, the intermediate Michael adducts can be isolated in >95% yield <04OL197>. Some degree of enantioselectivity has been observed when Cinchona alkaloids are used as catalysts in the reaction <04T8073>. An electrophilic variant is represented by the copper-catalyzed addition of N,N-dichloroarylsulfonamide across electrondeficient olefins such as methyl acrylate 133. The resulting β-chloroamines, which exhibit stereochemistry resulting from net anti addition, can be cyclized by treatment with sodium hydroxide to provide tosyl aziridines (e.g., 135) in good overall yield <04SC1337>.
72
A. Padwa and S. Murphree
An intriguing electrochemical aziridination is based on the selective anodic oxidation of Naminophthalimide (136, oxidation potential +1.60 V) in the presence of olefins. Thus, trans-hex4-en-3-one 137 is converted to the corresponding aziridine 138 in acetonitrile solution using a platinum electrode at a constant potential of +1.80 volts. The reaction mixture is buffered using triethylammonium acetate, since the cathodic process reduces proton to hydrogen gas. The use of platinum at the anode is critical, as graphite electrodes yielded no aziridination products <04PAC603>. NC
EtO2C NC N ONs
NsONHCO2Et
NC
CaO CH2Cl2 25°C, 2 h
Me
NC
Me
130
Me
CH3CN 25°C, 24 h
Cl
133
132
NHTs
aq Na2SO3
98% yield
NC
131 TsNCl2 Cu(acac)2 (8 mol%)
CO2Me
CO2Et NC N
CO2Me
Ts N
aq NaOH
CO2Me
134 O
135 O
O O
N NH2
+ 1.80 V (vs Ag)
+
Et3N·HOAc CH3CN 25°C, 4 h
O 136
80% yield
THF
N N
93% yield
O
137
138
Just as epoxides can be prepared from carbonyl compounds, aziridines can be accessed through the addition of amphophilic carbon centers onto imines, and sulfur ylides are frequently used as carbon donors in this regard. Thus, S-allyl tetrahydrothiophenium bromide 139 is smoothly deprotonated with strong base to provide an ylide which adds to a variety of Nprotected imines. For the N-tosyl aldimine 140 derived from isovaleraldehyde, the corresponding vinyl aziridine 141 is formed in fair yield as a mixture of stereoisomers <04TL1589>.
NTs
S Br
139
140
139 n-BuLi THF -78°C
Ts N
58% yield cis/trans 1:2
141
When chiral t-butylsulfinylimines (e.g., 142) are used as substrates, a highly stereoselective aziridination ensues, providing the heterocycles in good yield and good to excellent diastereomeric excess <04OL2377>. This approach of leveraging chirality at the imine nitrogen to impart enantioselectivity has also been used to advantage in the preparation of chiral heterosubstituted aziridines. Thus, when 2-(1-chloroethyl)-4-methyl-thiazole 145 is
73
Three-membered ring systems (2004)
deprotonated with LDA and treated with the chiral aldimine 144, the aziridinyl thiazole derivative 146 is produced in excellent yield and diastereoselectivity <04T1175>. O S
S
139 t-BuOLi
N
O
N
78% yield cis/trans 17:83
THF 25°C 142
143
Ph
OMe Ph
S
Me
N
Cl
+
N
Me
Ph
LDA THF -78°C
Me S
OMe N
90% yield > 96% de
H Ph
N
144
Me
145
146
Chiral induction can also be quite effective when the locus of asymmetry is attached to the sulfur ylide itself. The sulfonium salt 147 derived from Eliel's oxathiane can be used to deliver a benzylic center to tosylimines (e.g., 148) and efficiently produces phenylaziridines with a very high degree of asymmetric induction. The method is amenable to gram-quantity synthesis, and the chiral auxiliary can be easily recovered. In general, cis/trans mixtures are obtained, depending upon the steric bulk of the imine substituent <04JOC1409>.
NTs O
S Ph
OTf 147
148
147 phosphazene base
Ts N
CH2Cl2 -78° 30 min
Ph 149 80% yield 98.7% ee
As a complement to the base-catalyzed ylide approach, the Johnston group has developed a Bronsted acid-catalyzed direct aza-Darzens protocol for the synthesis of N-alkylaziridines. Ethyl diazoacetate 151 serves as an acetate enolate synthon under acidic conditions, engaging in [2+1] annulation with N-alkyl aldimines (e.g., 150) to provide the corresponding aziridine 152 with very high cis-selectivity. The conditions are mild enough that acid-catalyzed ring-opening of the products is not observed <04JA1612>. Ph N MeO2C 150
Ph
N2 +
TfOH (25 mol%) CO2Et
151
CH3CH2CN -78°C
86% yield cis/trans > 95:5
N MeO2C
CO2Et 152
74
A. Padwa and S. Murphree
3.1.3.2 Reactions of Aziridines One of the most widely encountered reactions of aziridines is the nucleophilic ring-opening of the heterocyclic ring. This has been the subject of a recent thoroughgoing and excellent review, to which the reader is directed <04T2701>. The interesting highlights of the previous year can be divided into the two categories of carbon-based nucleophiles and heteroatomic nucleophilic centers. Alkynylation of aziridines can be effected through the copper-catalyzed ring opening with acetylides. For example, lithium phenylacetylide engages in smooth nucleophilic attack of N-tosyl-7-azabicyclo[4.1.0]heptane 153 in the presence of copper(I) triflate to provide the cyclohexyl alkyne 154 in excellent yield <04SL1691>. Similarly, the lithium dimethyl cyanocuprate engaged in nucleophilic attack of the less substituted carbon on 1-pentyl-Ntosylaziridine 155 to give N-tosyl-octane-3-amine 156. In this system, the use of alkyllithium reagents led to eliminative pathways <04T3637>. However, there are other reports of productive ring-opening by lithiates. Treatment of 6-aza-3-oxabicyclo[3.1.0]hexane 157 with (trimethylsilyl)methyllithium led to the formation of an intermediate ring-opened dianion 158 which subsequently underwent elimination to form the functionalized allylic amine 159 <04CC2234>. Key to the success of this protocol is the formation of the aziridinyl anion, which has considerable carbenoid character. A fascinating example of this property is seen in the desymmetrization of the bicyclic tosyl aziridine 160 mediated by sec-butyllithium and (-)sparteine 100. The initially formed anion 161 behaves much like an amino carbene (i.e., 162) which engages in a transannular C-H insertion to give the bicyclo[3.3.0]octane derivative 163. Interestingly, the absolute configuration of 163 is the opposite of the alcohol formed from the corresponding rearrangement of the analogous alcohol <04HCA227>. NHTs Ph
NTs
Li
153 Ts N
NTs
Li2CuCN(Me)2
157
Me3SiCH2Li THF -78° -> 0°C
Ph
154
Et2O -78°C 25°C 12 h
155
O
96% yield
CuOTf (10 mol%) Et2O, 25°C, 45 h
63% yield 156
NTs O
NHTs
HO
NHTs SIMe3
SIMe3 158
159
92% yield
75
Three-membered ring systems (2004)
NTs
C-H insertion
NTs
s-BuLi
NTs
100
H
NHTs
:
69% yield 75% ee
H 160
162
161
163
Aziridines can be opened with a variety of heteroatomic nucleophiles. Silica-supported phosphomolybdic acid (PMA-SiO2) is effective in promoting the ring-cleavage of tosyl aziridines by a variety of nucleophiles. Thus, the azide anion preferentially attacked at the benzylic position to provide the azidoaminoalcohol 165, whereby the regioselectivity can be rationalized in terms of partial positive charge stabilization <04SL1719>. A different type of selectivity is observed in the magnesium bromide mediated opening of hydroxymethyl aziridines. In these systems, the delivery of the nucleophile (i.e., bromide) is under chelation control, as demonstrated in the conversion of aziridine 166 to the bromo aminoalcohol 167 <04SC85>. In the absence of Lewis acid catalysts, heteroatomic nucleophiles tend to attack at the sterically least hindered center. Such is the case when the the butylaziridine 168 is treated with tributylphosphine, a strong nonbasic nucleophile which smoothly opens the heterocyclic ring. The initial adduct undergoes rapid proton transfer to provide a betaine 169 which can serve as a Wittig reagent. The addition of benzaldehyde leads to an olefination/elimination sequence to afford the diene 170 as a mixture of E/Z isomers <04JOC689>. NTs Ph
N3
NaN3 OH
Ph
PMA-SiO2 CH3CN / H2O (9:1) 25°C, 1 h
164
OH NHTs 165
Boc
NHBoc
N BnO
OH
MgBr2
BnO
168
PBu3 (1.2 eq) benzaldehyde t-BuOH reflux
OH
Et2O 25°C
95% yield
Br 167
166 Ts N
93% yield
NHTs PBu3 169
PhCHO Ph 170 74% yield (E,E):(E,Z) 84:15
Another interesting and synthetically useful behavior of aziridines is their tendency to open thermally to azomethine ylides, a process which can also be facilitated by Lewis acid catalysts. These reactive intermediates can be trapped by a variety of dipolarophiles to give new heterocyclic species. Methyl vinyl ethers convert aziridines such as 172 into a pyrrolidine derivative (i.e., 174) in the presence of a zinc(salen) Lewis acid catalyst 171 <04JA2294>. Similarly, nitriles (e.g., 175) lead to the formation of 2,4-disubstituted 1H-imidazolines (e.g., 176) under the catalysis of boron triethyloxonium tetrafluoroborate <04TL1137>. Under almost
76
A. Padwa and S. Murphree
identical conditions, the aziridine-Lewis acid complex can be trapped with π-nucleophiles, such as a tethered olefin, to provide fused bicyclic pyrrolidines (e.g., 178) <04TL5011>. Ph N Ph
CO2Et
171 (20 mol%)
Ph
toluene 45°C 76 h
CO2Et
Ph
OMe
Ph N
Me
CO2Et
N
Ph
CO2Et
CO2Et
172
CO2Et
Me
173
OMe
174 76% yield dr = 1.3:1
N Ph
N Zn Cl Cl
Ph
171
NTs Et3OBF4
+ 126
CN
N H Ts 177
67% yield
176
Me Me
N NTs
175 Me
H
Ph
CH2Cl2 25°C
Et3OBF4
Me NTs
CH2Cl2 0°C
75% yield
178
The (salen)chromium complex 179 was shown to promote the insertion of carbon dioxide into aziridines (e.g., 180) to yield the corresponding oxazolidinones (e.g., 181), whereby the substrate is treated with CO2 under high pressure (Parr reactor) in the presence of catalytic quantities of 179 and dimethylaminopyridine (DMAP) <04OL2301>. Considerably milder conditions have been reported independently, in which lithium bromide serves as catalyst in a medium of Nmethylpyrrolidone (NMP). For example, aryl aziridine 182 was converted to oxazolidinone 183 in 79% yield over 24 hours. Use of the more polar and higher boiling solvent allows for delivery of CO2 using a balloon at atmospheric pressure. Electron-donating substituents tend to accelerate the reaction <04TL1363>.
77
Three-membered ring systems (2004)
N
N N Pr
Cr O
t-Bu
O
t-Bu
Cl t-Bu
180
t-Bu
N
DMAP (2 mol%) CH2Cl2 100°C, 2 h
O
NTs
Ts N
LiBr (20 mol%)
MeO
CO2 (1 atm) NMP 100°C, 24 h
182
Ph Ph
P
(CO)2Cl Rh Ph P Ph
Ph
Ph Ph
O
79% yield
P
(CO)2Cl Rh Ph P Ph
O
HN
N
O
N O
Ph
181
183
N
Ph P Cl(OC)2Rh
O
75% yield
179
MeO
Pr
179 (5 mol%) CO2 (400 psi)
NH
N
P
P Ph
O
Ph
NH
Ph P Ph Rh(CO)2Cl Ph
O 184
t-Bu N Ph 185
CO (400 psi)
Ph
t-Bu N
benzene O 186 99% yield
In a similar vein, a resin-supported rhodium-complexed dendrimer 184 has been shown to promote the carbonylative ring expansion of aziridines to β-lactams, as illustrated by the conversion of the N-t-butyl aziridine 185 to the corresponding lactam 186 in almost quantitative yield. The supported catalyst, which shows reactivity comparable to the solution-phase variety, is easily recovered by filtration and exhibits no significant loss of activity upon recycling.
78 3.1.4
A. Padwa and S. Murphree
REFERENCES
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A. Padwa, A. C. Flick, C. A. Leverett, T. Stengel, J. Org. Chem. 2004, 69, 6377. L. Ming-Yuan, R. J. Madhushaw, R. -S. Liu, J. Org. Chem. 2004, 69, 7700. Y. G. Abashkin, S. K. Burt, Org. Lett. 2004, 6, 59. D. Colantoni, S. Fioravanti, L. Pellacani, P. A. Tardella, Org. Lett. 2004, 6, 197. P. C. Bulman Page, B. R. Buckley, A. J. Blacker, Org. Lett. 2004, 6, 1543. W. -K. Chan, P. Liu, W. -Y. Yu, M. -K. Wong, C. -M. Che, Org. Lett. 2004, 6, 1597. R. Vyas, G. -Y. Gao, J. D. Harden, X. P. Zhang, Org. Lett. 2004, 6, 1907. G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, M. Massaccesi, P. Melchiorre, L. Sambri, Org. Lett. 2004, 6, 2173. A. W. Miller, S. T. Nguyen, Org. Lett. 2004, 6, 2301. D. Morton, D. Pearson, R. A. Field, R. A. Stockman, Org. Lett. 2004, 6, 2377. A. Murphy, A. Pace, T. D. P. Stack, Org. Lett. 2004, 6, 3119. A. Denichoux, F. Ferreira, F. Chemla, Org. Lett. 2004, 6, 3509. D. Leca, A. Toussaint, C. Mareau, L. Fensterbank, E. Lacôte, M. Malacria, Org. Lett. 2004, 6, 3573. H. Han, I. Bae, E. J. Yoo, J. Lee, Y. Do, S. Chang, Org. Lett. 2004, 6, 4109. D. M. Hodgson, N. J. Reynolds, S. J. Coote, Org. Lett. 2004, 6, 4187. T. Matsumoto, H. Masu, K. Yamaguchi, K. Takeda, Org. Lett. 2004, 6, 4367. Y. D. Y. L. Getzler, V. Mahadevan, E. B. Lobkovsky, G. W. Coates, Pure Appl. Chem. 2004, 76, 557. A. Caiazzo, S. Dalili, C. Picard, M. Sasaki, T. Siu, A. K. Yudin, Pure Appl. Chem. 2004, 76, 603. G. Righi, S. Catullo, Synth. Commun. 2004, 34, 85. U. K. Nadir, A. Singh, Synth. Commun. 2004, 34, 1337. G. Huerta, G. Contreras-Ordoñez, C. Alvarez-Toledano, V. Santes, E. Gómez, R. A. Toscano, Synth. Commun. 2004, 34, 2393. M. D'hooghe, N. De Kimpe, Synlett 2004, 271. M. L. Kantam, V. Neeraja, B. Kavita, Y. Haritha, Synlett 2004, 525. S. Muthusamy, C. Gunanathan, M. Nethaji, Synlett, 2004, 639. P. -Q. Zhao, L. -W. Xu, C. -G. Xia, Synlett 2004, 846. F. Chemla, F. Ferreira, Synlett 2004, 983. A. Fernández-Mateos, L. M. B. R. Rabanedo Clemente, A. I. R. Silvo, R. R. González, Synlett 2004, 1011. S. Fioravanti, A. Morreale, L. Pellacani, P. A. Tardella, Synlett 2004, 1083. D. M. Hodgson, E. H. M. Kirton, Synlett 2004, 1610. C. -H. Ding, L. -X. Dai, X. -L. Hou, Synlett 2004, 1691. G. D. Kishore Kumar, S. Baskaran, Synlett 2004, 1719. E. T. Farinas, M. Alcalde, F. Arnold, Tetrahedron, 2004, 60, 525. L. De Vitis, S. Florio, C. Granito, L. Ronzini, L. Troisi, V. Capriati, R. Luisi, T. Pilati, Tetrahedron 2004, 60, 1175. X. E. Hu, Tetrahedron 2004, 60, 2701. D. M. Hodgson, C. R. Maxwell, T. J. Miles, E. Paruch, I. R. Matthews, J. Witherington, Tetrahedron, 2004, 60, 3611. M. D'hooghe, I. Kerkaert, M. Rottiers, N. De Kimpe, Tetrahedron 2004, 60, 3637. S. Fioravanti, M. Gabriella Mascia, L. Pellacani, P. A. Tardella, Tetrahedron 2004, 60, 8073. V. Maslak, R. Matovic, R. N. Saicic, Tetrahedron, 2004, 60, 8957. T. Ollevier, G. Lavie-Coupin, Tetrahedron Lett. 2004, 45, 49. L. Bohé, M. Kammoun, Tetrahedron Lett. 2004, 45, 747. B. A. Bhanu Prasad, G. Pandey, V. K. Singh, Tetrahedron Lett. 2004, 45, 1137. W. Medjahed, A. T. Zatla, J. K. Mulengi, F. Z. Baba Ahmed, H. Merzouk, Tetrahedron Lett. 2004, 45, 1211. B. Kaboudin, H. Norouzi, Tetrahedron Lett. 2004, 45, 1283. A. Sudo, Y. Morioka, F. Sanda, T. Endo, Tetrahedron Lett. 2004, 45, 1363. L. G. Arini, A. Sinclair, P. Szeto, R. A. Stockman, Tetrahedron Lett. 2004, 45, 1589. S. Arai, K. Tokumaru, T. Aoyama, Tetrahedron Lett. 2004, 45, 1845. H. -L. Kwong, D. Liu, K. -Y. Chan, C. -S. Lee, K. -H. Huang, C. -M. Che, Tetrahedron Lett. 2004, 45, 3965.
80 04TL4193 04TL4405 04TL5011 04TL5069 04TL5073 04TL5347 04TL5359 04TL5991 04TL6003 04TL6357 04TL7201 04TL7355 04TL7495 04TL7749
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81
Chapter 3.2
Three-membered ring systems (2005) Stephen C. Bergmeier and Damon D. Reed Department of Chemistry & Biochemistry, Ohio University, Athens, OH, USA
[email protected] and
[email protected]
3.2.1 INTRODUCTION Three-membered heterocyclic ring systems continue to receive attention from organic chemists. These heterocyclic ring systems provide a useful combination of reactivity, utility and stability. This review is not a comprehensive review but rather covers a selection of interesting and synthetically useful transformations. Some themes that have emerged in the past year include the use of supported reagents, aqueous reactions and solvent free reactions. The organization of this chapter follows that of previous years. Several reviews on specific topics in aziridine or epoxide chemistry have been published in the past year. Two recent reviews have focused on advances in the metal catalyzed asymmetric epoxidation. One review focuses on Cr and Mn(salen) complexes <05CRV1563>. The other review focuses on the broader topic of homogenous and heterogeneous asymmetric epoxidation reactions <05CRV1603>. The coverage of these reviews is roughly to the end of 2004. A review on the use of chiral auxiliaries in epoxidation reactions has been published <05SL1047>. The review focuses on the epoxidation of several select substrates. The use of enzymatic transformations including the opening of epoxides has been reviewed <05MI181>. A recent review has covered asymmetric ring opening reactions of epoxides <05MI1>. The synthesis and reactions of lithiated epoxides has been the subject of a recent review <05SL1359>. A review on the synthesis of α,β-diamino acids that covers some syntheses from aziridines has been published <05CRV3167>. 3.2.2 EPOXIDES 3.2.2.1 Preparation of Epoxides The development of methods for metal-catalyzed epoxidations continues at a rapid pace. Mechanistic studies of the Jacobsen-Katsuki epoxidation have rationalized the enantioselectivity as arising from a competition of approach vectors <05JA13672>. The development of Mn-catalyzed epoxidation methods have provided useful methods for the stereocontrolled epoxidation of olefins. Evidence for a peroxy-Mn complex as a key intermediate in high valent manganese catalyzed epoxidations has been proposed <05JA17170>. From a synthetic perspective, a Mn-porphyrin catalyst has been developed for erythroselective epoxidations <05JOC4226>. This epoxidation catalyzed by Mn-porphyrin is highly
82
S.C. Bergmeier and D.D. Reed
substrate dependent. As shown below, reaction of 1 with Mn(2,6-Cl2TPP)Cl and oxone provides a reasonable yield of erythro-2 when R = COOMe. However, when R = OTBS or OAc the yields drop precipitously. R Mn(2,6-Cl2TPP)Cl, oxone, NH4OAc Ph
O
CH3
1
Ph
R
O CH3
R
Ph
erythro-2 6 R = CO2Me, 70% yield R = OTBS, <5% yield 1 R = OAc, 35% yield
CH3 threo-2 1 1
The use of Ru catalysts for selective epoxidations has also been explored. The Ru(2,6Cl2TPP)CO catalyst with dichloropyridine N-oxide as the stoichiometric oxidant provides good levels of stereocontrol for the synthesis of threo-amino epoxides, 4 <05MI29>. The use of the manganese system, Mn(2,6-Cl2TPP)Cl, on amine 3 provides a 1.4:1 mixture of the 4erythro: 4-threo isomers in 88% yield after 1 hour <05JOC4226>. BocHN Ph
O
BocHN
Cl2PyNO, Ru(2,6-Cl2TPP)CO
Ph
3
32% yield >99% threo 4
The epoxidation of olefins has been reported using an interesting tri-pyridyl catalyst 7 <05OL987>. Yields of the corresponding epoxides are generally quite high. An advantage of this epoxidation system is the use of hydrogen peroxide as oxidant. Chiral Ru analogs of 7 were used to carry out asymmetric epoxidations in which the ee reached only 54%.
N O 5
30% H2O2 t-AMOH 7, 0.005 eq.
N
O
O
O
N
N
N Ru
O
O
O 6 81% yield
O
O 7
Methyltrioxorhenium (MTO) has proven to be a useful oxidant for a number of reactions. A problem with the use of MTO in epoxidation is the acidity of the reagent, which leads to diol formation. Several different methods have previously been reported in an attempt to solve this problem. The use of microencapsulated Lewis base adducts of MTO appears to be a good solution <05T1069>. Another modification of MTO is (PPh3)2[Re(NCS)6] with H2O2 as an oxidant <05TL339>. Janda and co-workers have found that the enantioselectivity of the Sharpless epoxidation reaction can be reversed when utilizing a tartrate ester of polyethylene glycol <05JOC1728>. The work described here is based on earlier reports <02CC118, 04JOC2042> in which conflicting results were obtained with PEG-tartrate esters. In the current study, the molecular weight of the polyethylene glycol used has a significant effect on which epoxide enantiomer is produced. Using the usual Sharpless epoxidation conditions on alcohol 8, the (2S,3S)
83
Three-membered ring systems (2005)
enantiomer, 9, was obtained in 96% ee. A number of polyethylene glycol esters of tartaric acid were then prepared and used in the epoxidation reaction. Polyethylene glycol up to a MW of 350 all gave the expected epoxide, 9. A polyethylene glycol of MW 550 gave an epoxide with an ee of only 5%, while the next higher MW polyethylene glycol, MW 750, gave epoxide 10 with an ee of 67%. Increasing the size of the polyethylene glycol to MW 2000 gave 10 in 75% ee. The rationale for this change in the preferred enantiomer is not clear but the authors have hypothesized that it may be due to a change in aggregation of the ligand to the metal. O
O
L-DIPT, 96% ee OH
OH 9
PEG-DIPT, MW 350 75% ee
OH
8
10 PEG-DIPT, MW 2000 75% ee
A method for the polymer supported epoxidation of olefins has been reported <05TL1643>. The resin supported phthalate, 11, was oxidized to peracid 12 through oxidation with H2O2 or a urea-H2O2 complex. The reaction was most conveniently carried out by mixing 11, the urea-H2O2 complex and the olefinic substrate. Simple filtration then provides a wide variety of epoxides in excellent yield. This reagent system provides all of the typical advantages of supported reagents as well as an improved safety profile of the supported peracid. O O
nO
11
R2
R1 13
O
O
30% H2O2 or O urea-H2O2 complex O
O 1) 11, urea-H2O2 complex 2) filtration R1 14
O n
O
CO2H O
12
OH
O
R2
R1 n-C6H13 Ph Ph CH2OH
Yields(%) R2 95 H 75 H 80 CH2OH 90 H
Walsh and co-workers have developed a one-pot method for the synthesis of hydroxyepoxides via an initial synthesis of an allylic alcohol followed by an asymmetric epoxidation <05JOC1262, 05JA14668, 05JA16416>. This reaction provides an improvement in overall yields over the typical kinetic resolution reaction. The method involves an initial asymmetric addition to the aldehyde followed by a diastereoselective epoxidation reaction. O O H 15
O
OH
ZnEt2, Ti(OiPr)4, O2, 17 16
90% yield 99% ee 20:1 dr (erythro:threo)
N OH 17
Several methods for the epoxidation of α,β-unsaturated carbonyl compounds have been reported. The use of amino acid derivatives or peptides as chiral ligands for epoxidation continues to be an active area of investigation. The use of silica bound poly-L-leucine, 21, with sodium percarbonate appears to be an excellent route to enantiomerically pure keto
84
S.C. Bergmeier and D.D. Reed
epoxides, 19 <05TL5665>. Interestingly, the diphenylprolinol/t-BuOOH system 22, provides enantioenriched ketoepoxides of opposite configuration, 20, albeit with lower enantiomeric excess <05OL2579>. The use of the related 3,5-(CF3)2Ph prolinol catalyst 23 with H2O2 as oxidant provides epoxy aldehyde 19 (R1 = Ph, R2 = H) in excellent yield and enantiomeric excess <05JA6964>. Significantly this is one of the few routes to epoxy aldehydes. O
O Catalyst
R1
R2 19 (2S,3R)
O R1
or
R2 18
O
Yields R1 = R2 = Ph, 94% yield, 93% ee (2S,3R) R1 = R2 = Ph, 72% yield, 75% ee (2R,3S) R1 = Ph, R2 = H, 80% yield, 96% ee (2S,3R) R1 = R2 = Ph, 95% yield, 99% ee (2S,3R) R1 = R2 = Ph, 99% yield, 97.6% ee (2R,3S)
21 22 23 24 25
O
R1
R2 20 (2R,3S)
CF3 Si-AMP-(L-Leu)n, Na2CO4 21
HN HO
OCH3 Br
N
N
HN
t-BuOOH 2
Ph
TMSO 22
F
O H
N
2
23
Br
O H
H2O2 CF3
OCH3
N
H2O2 24
HO HO
OH OH La(Oi-Pr)3, Ph3PO 25
The use of a variety of chiral catalysts for the asymmetric epoxidation of α,β-unsaturated ketones has produced some interesting results. The use of a bis-quinoline catalyst, 24, and H2O2 as oxidant provides the desired epoxide 19 <05AG(I)1383>. A heterogeneous version of Shibasaki’s BINOL catalyst provides a very nice method to overcome some of the disadvantages inherent in the use of polymer supported version of the BINOL catalysts <05AG(I)6362>. The heterogeneous catalyst 25 provided (2R,3S)-epoxide 20 in excellent yield and with high enantioselectivity. The use of polyethylene glycol supported BINOL catalyst for example, provides the expected epoxide in good yield but with only 45% ee <05MI59>. The Baylis-Hillman reaction is a highly useful and general method for the synthesis of allylic alcohols. A method to convert the product of a Baylis-Hillman reaction to an epoxidized α,β-unsaturated ketone has been reported <05TL8895>. Iodosobenzene and KBr
Three-membered ring systems (2005)
85
initiate the reaction through the oxidation of the allylic alcohol to ketone 27. The resulting α,β-unsaturated ketone is then epoxidized with PhIO. OH CO2Me
Ph
O
PhIO, KBr
CO2Me
Ph
26
O
PhIO
CO2Me O
Ph
27
85% yield
28
The epoxidation of gem-deactivated olefins is a vexing problem in organic chemistry. While the epoxidation of α,β-unsaturated carbonyl compounds is well studied, the inclusion of an additional electron stabilizing group makes epoxidation much more difficult. The use of m-CPBA/K2CO3 provides an excellent solution to this problem in the epoxidation of the sulfone ester 29 <05JOC4300>. O
O TolO2S
m-CPBA, K2CO3
O 29
TolO2S
OEt
O
O
30
OEt
77% yield
A report on selective epoxidations of α,β-unsaturated carboxylates that uses the hydrophobicity of the substrate and reagent to provide largely a single product <05JA10812>. Reaction of a mixture of two carboxylates, 31 and 32, with oxaziridine 33 provides 34 as the major product. While this is a mechanistic study and reactions were carried out to only 5% completion, it does suggest that high levels of chemoselectivity can be accomplished through hydrophobic interactions between reagent and substrate. BF4 O
O Ph
O
+ H3C
31
O 32
33 oxone D2O
N CH3 O
O
O
O
Ph
O
H3C
98.1 34
O O
1.9 35
The selective capture of one isomer of interconverting allylic azides by epoxidation has been investigated <05JA13444>. Allylic azides 36 and 37 exist as a 70:30 equilibrium mixture. Upon treatment with m-CPBA, one isomer, 36, can be captured as the epoxide 38. As might be expected, the more substituted double bond of the mixture is epoxidized. N3
N3
m-CPBA, K2CO3, H2O
O N3
(70:30) 36
37
85% yield
38
A very interesting sulfur ylide approach to epoxides has been reported <05JOC4166>. In this method, a catalytic amount (10 – 20 mol%) of a C2 symmetric thiolane, 40, with a controlled topology is used to generate ylide 41. Reaction with an aryl aldehyde provides epoxide 42 via a catalytic transfer of benzylidene in generally excellent yields with good ee.
86
S.C. Bergmeier and D.D. Reed
A Darzens reaction has been used to generate trans-epoxides <05SL842>. Reaction of electron deficient p-substituted benzylammonium chlorides with benzaldehyde provides the trans-epoxide 46 in excellent to moderate yield as a 99:1 mixture of trans:cis epoxides.
O
O CHO
O
O
O
200 mol% BnBr NaOH
Ph
S 42
S 39
66% yield trans/cis 90:10 R,R/S,S 97.5:2.5
40 41
N
Cl
O
N
KOt-Bu, PhCHO
N
Ph
N
F3C
46 F3C
43
100% yield
CF3
44 45
The ring closure of halohydrins to form epoxides is a well known reaction. The ability to generate enantiopure halohydridns has been addressed through a biocatalytic approach <05MI1827>. The biocatalytic hydrogen-transfer reduction of prochiral α-chloroketones has been reported using lyophilized cells of Rhodococcus ruber DSM 44541 to provide chlorohydrin 48 in 99% conversion and with 99% ee. A subsequent cyclization reaction then provides epoxide 49. A strategy that uses whole cells of R. ruber as a base stable biocatalyst at pH >12 yields the epoxide in a single step, again with 99% conversion and 99% ee. O Cl
OH C6H13
47
R. ruber lyophilized cells pH 7.5, 30 ˚C
Cl
C6H13 48
KOH pellets pH > 12 30 ˚C
O
H C6H13 49
R. ruber lyophilized cells KOH pellets, pH ~13 30 ˚C
Enzymatic approaches to epoxidation are potentially quite powerful in that they avoid harsh reaction conditions and can provide high levels of enantioselectivity. Monooxygenases catalyze the activation of molecular oxygen and its addition to a variety of substrates. Monooxygenases are cofactor-dependent enzymes which restrict their use in epoxidation reactions. The use of direct electrochemical regeneration of monooxygenases appears to be a solution to the use of these enzymes in epoxidation reactions <05JA6540>. This approach uses the FADH2-dependent oxygenase component (StyA) of styrene monooxygenase (StyAB) from Pseudomonas sp. VLB120 coupled with cathodic reoxidation to epoxidize a series of styrene derivatives with excellent enantioselectivities.
87
Three-membered ring systems (2005)
A problem with enzymatic reaction systems is the inherent substrate specificity of the enzyme. An interesting approach to enzymatic epoxidation has been reported that overcomes this limitation <05T6009>. This approach combines the in situ enzymatic generation of H2O2 with the broad substrate specificity of a catalytic chemical system. Glucose oxidase catalyzes the conversion of β-D-glucose to gluconolactone and H2O2. Reaction of an olefin with glucose oxidase provides the epoxide through reaction with the generated H2O2. Both water soluble olefins as well as hydrophobic olefins such as 50 can be epoxidized. Hydrophobic olefins require the use of an additive such as t-BuOH or SDS to solubilize the olefin in the reaction medium. The enzyme has been immobilized on silica gel as well. glucose oxidase 0.2 M glucose, O2 pH 7.0 phosphate 50 Additive 10% t-BuOH 5 mM SDS
O
51 % Conversion 45 65
3.2.2.2 Reactions of Epoxides The reactions of epoxides are largely exemplified by nucleophilic attack on the epoxide ring. Both carbon and heteroatom nucleophiles are widely used. The use of carbon nucleophiles provides an excellent route for the preparation of highly substituted alcohols. The literature is replete with examples of organolithium and Grignard reagents used to open epoxides. In recent years the use of additional metals (e.g. B, Al, Ti, Pd) to modulate the ring opening in interesting and useful ways has been reported. The reaction of cyclohexene oxide with aryllithium reagents in the presence of both a Lewis acid (BF3•OEt2) and a Lewis base (sparteine) provides the ring opened product in excellent yields with moderate enantioselectivity <05EJO1354>. Reaction always occurs at the (S)-carbon of the oxirane. Other meso-epoxides gave excellent yields but with a lower enantioselectivity. H N O
N OH H
ArLi, BF3•OEt2 52
Ar = 2-Me-Phenyl, 91% yield, 65% ee Ar = 4-OMe-Phenyl, 95% yield, 40% ee Ar = 3-CF3-Phenyl, 90% yield, 60% ee
Ar 53
Regiocontrol in the ring opening of unsymmetrical epoxides is synthetically important. The ring opening of epoxides at the more substituted carbon is generally difficult yet potentially valuable synthetic transformation. The use of titanium reagents provides one solution to this problem.
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S.C. Bergmeier and D.D. Reed
OMOM
ClTi(OPh)3
O
HO OMOM
MgCl 54
55 O
ClTi(OPh)3 MgCl
t-BuO2C
46% yield
49% yield OH
t-BuO2C
56
57
The reaction of a wide variety of functionalized epoxides containing esters, amides and acetals with chlorotitanium triphenoxide and allylmagnesium chloride provides exclusive reaction at the more substituted carbon <05T6726>. The use of protected chiral epoxides, 54 and 56, with the same reagent system provides a facile route into chiral quaternary centers, 55 and 57. The use of organoaluminum reagents also provides a useful solution to the regioselective ring opening of epoxides <05TL797>. The use of diethylpropynylalane with diastereomeric epoxides will provide different ring-opened products depending on the relative stereochemistry of the alcohol and epoxide. The anti-hydroxy epoxide, 58, leads to nucleophilic ring-opening at the carbon distal to the alcohol to provide 59. The syn-hydroxy epoxide, 60, provides the product of nucleophilic ring opening at the proximal carbon of the epoxide providing 61 in 39% yield.
AlEt2 TIPSO OH
78% yield 89:11
TIPSO
O
OH
OH
59
58
OH AlEt2
TIPSO OH
O
39% yield 15:85
TIPSO OH
60
61
Epoxides of α,β-unsaturated ketones can undergo a ring opening/arylation reaction under Heck conditions <05JOC4720>. Epoxide 62 undergoes an initial Pd-catalyzed rearrangement to a 1,2-cyclohexanedione which then undergoes a Heck arylation reaction to form 63. O
O O
62
Pd(OAc)2, PPh3, i-Pr2NEt Δ or MW Ar Br
OH Ar
Ar = 3-(NMe2)-Ph, 71% yield Ar = 4-(CF3)-Ph, 33% yield Ar = 4-(acetyl)-Ph, 40% yield Ar = Ph, 72% yield
63
Epoxides derived from 1,6-anhydro-β-D-glucopyranose undergo a quite interesting rearrangement to generate substituted allylic alcohols <05EJO2841, 05EJO4557>. Treatment of epoxide 64 with MeLi and CuCN initiates an epoxide to allylic alcohol rearrangement to
89
Three-membered ring systems (2005)
generate intermediate 65. Intramolecular delivery of the methyl group provides the final product 66 in 92% yield.
O
O
O H
B
O
MeLi CuCN
64
O 92% yield
O OTs Li Cu Me Me 65
OTs
O
O
HO
Me 66
Control of SN2 versus SN2’ additions to vinyl epoxides continues to be of interest. The usual group of alkynyl lithium reagents generally provided a mixture of the SN2 and SN2’ products <05EJO3946>. However when lithio-ethoxyacetylene was used, the SN2 product 68 was the major product (98:2). Changing the metal to aluminum provided a shift to the SN2’ product 69 in a similar 98:2 ratio as a mixture of E and Z-isomers. OH EtO Li BF3•OEt2
OTBS
62% yield SN2/SN2' 98:2
68 OEt
OTBS
O 67
EtO
AlEt2
EtO
OH OTBS
55% yield SN2'/SN2 98:2 E/Z 70:30
69
An alternate approach to regiocontrol in the ring opening of unsaturated epoxides is found in the initial ring opening of unsaturated epoxides with a transition metal prior to a coupling reaction <05MI5260, 05TL6705>. The reaction of vinylepoxide 70 with pincer catalyst 73 and an arylboronic acid provides the SN2’ product 71 in an 11:1 ratio.
73, PhB(OH)2
O 70
Ph HO
Ph
HO
PhSe 72
71 94% yield
Pd Cl 73
SePh
Propargylic oxiranes can undergo a similar SN2’ type reaction <05TL6705>. Ring opening of oxirane 74 with palladium followed by coupling to an aryl boronic acid provides the allenic alcohol 75 as a single stereoisomer.
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S.C. Bergmeier and D.D. Reed
Pd(PPh3)4
CH3
OH
B(OH)2
•
O
75
CH3
Ph
O
74
92% yield
Ph
Ph
Pd2(dba)3•CHCl3, dppb
54% yield O
HO
CH3
76 CH3
The reaction of the same propargylic oxirane with a different catalyst and nucleophile provides radically different product <05TL3669>. Treatment of 74 with a phenol in the presence of a Pd2(dba)3 provides 76, the product of simple addition across the triple bond. It is interesting to note that no reaction of the epoxide ring occurs. The intramolecular ring opening of oxiranes with carbon nucleophiles is an excellent method for the construction of a number of novel molecules. A tandem base-promoted ringopening/Brook rearrangement/allylic alkylation of silyl epoxides provides the silyl enol ether 81 in very good yield <05JOC10515>. Reactions in which the cyclopropane derivatives are formed have also been reported <05T3349>. O
NaHMDS
CN
t-BuMe2Si
O t-BuMe2Si
77
O t-BuMe2Si
CN
78
t-BuMe2SiO CN
79
t-BuMe2SiO
R X
R = H, 73% yield R = Me, 63% yield
CN
80
CN
81 R
The acid catalyzed rearrangement of epoxides to form an aldehyde or ketone is a useful and commonly used reaction <05TL1269, 05T2541, 05JOC10747, 05TL89, 05JOC6537>. An interesting application of this reaction involves the in situ rearrangement of an epoxide to an aldehyde followed by reaction with an allenylstannane, 84, to generate alkyne 85 <05JOC6541>. None of the products that might arise from reaction of the allenylstannane with the epoxide were observed. Fused ring epoxides (e.g. cyclohexene oxide) were unreactive. OH O O
BF3•OEt2
Ph
CHO
Bu3Sn TMS
Ph 82
83
•
N
O
O
Ph 84
Ph
TMS
Ph
85
N
Ph
79% yield syn/anti >95:5
O Ph
Another interesting variation on this common rearrangement involves trapping the intermediate oxonium ion with an external nucleophile <05TL2311>. Treatment of epoxide 86 with ZrCl4 and a homoallylic alcohol generates intermediate 87. Cyclization and trapping
91
Three-membered ring systems (2005)
of the carbocation with chloride provides the isolated product 89. A number of homoallylic alcohols and epoxides were examined to provide a number of examples of 89 in excellent yields.
O
ZrCl4
O
Ph
Ph
Ph
Ph
Ph
Ph ZrCl3
O
Ph
O
Ph
87% yield
87 86
Cl 88
HO
89
The ruthenium-catalyzed cyclization of epoxy iodoalkynes shows a very intriguing solvent dependence <05OL1745>. The authors rationalize this solvent dependence as a result of two different ruthenium intermediates. In a polar solvent such as DMF an iodovinylidene species is formed followed by attack of the epoxide oxygen to eventually lead to naphthalene 91 in 88% yield. A nonpolar solvent such as benzene favors the formation of a p-iodoalkyne ruthenium species. Attack of this species by the epoxide oxygen leads to formation of oxepin derivative 92 in 78% yield. O TpRuPPh3(CH3CN)2PF6
O OH
90
I DMF (yields) Benzene (yields)
I 91 88% 12%
I 92 1% 78%
Radical cyclizations of epoxides initiated by Ti are versatile reactions for the formation of carbocycles and heterocycles <05JA14911>. While not truly a nucleophilic ring opening, these reactions provide similar products as a typical nucleophile ring opening reaction. The titanium-catalyzed intramolecular cyclization of 93 was studied <05S1405>. The use of sulfoximines and phosphine oxides as the leaving group (LG) were examined. The sulfoximines proved to be more difficult to prepare and gave poorer yields in the cyclization reaction than the corresponding phosphine oxides. Ts N
O
R2
LG 93
R
1
O LG = R1 = R2 = Me 40% yield S TsN p-Tol
Ts N
Cp2TiCl2, Mn HO 94
R1
R2
O P LG = Ph Ph
R1 = R2 = Me 80% yield
The metal catalyzed ring opening of epoxides followed by reaction with CO or CO2 to form β-lactones and carbonates is a useful reaction that continues to attract attention. In an expansion of previous work, Coates and co-workers have developed an improved catalyst, 99, for the carbonylation of epoxides <05JA11426>. These reaction conditions are compatible with a wide variety of side chains, including those bearing Lewis basic functionality. Interestingly, the cyclopentene oxide 97 was readily converted to the β-lactone 98 in excellent yield.
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S.C. Bergmeier and D.D. Reed
O O
O
99, 900 psi CO
O
R R
95
96 R = Et, 99% yield R = t-Bu, 99% yield R = CH2OTBS, 99% yield R = CH2OCH2CHCH2, 88% yield R = CH2OAc, 99% yield
N
N Cr N
N
O
O
99, 900 psi CO 99% yield
O
O 98
97
Co(CO)4
99, [(OEP)Cr(THF)2][Co(CO)4]
An interesting reaction for the synthesis of cyclopropanes makes use of a tungsten carbonyl compound as the electrophile <05JOC5852>. An initial conjugate addition of lithiated epoxide 101 onto tungsten carbonyl 102 leads to intermediate 103, which then does an intramolecular ring opening of the epoxide to provide cyclopropane 104. H3CO
O
W(CO)5 O
Ph 100
s-BuLi, TMEDA
73% yield
O
Ph Li 101
HO Ph Ph 104
Ph
Ph
OCH3
Ph
102
103
W(CO)5
pyridine N-oxide
OCH3
HO Ph Ph 105
O
W(CO)5 Li
83% yield
OCH3
α-Lithiated epoxides constitute an alternative to carbenes for a variety of reactions. The homo-dimerization of α-lithiated epoxides has been found to provide an excellent route to 1,4-diols <05OL2305>. R
O
OH LTMP
R
R 106
107
OH
R = t-Bu, 86% yield R = CH2OTr, 51% yield R = cC6H11, 51% yield (+ 26% of the cis isomer) R = n-C5H11, 43% yield (+ 19% of the cis isomer)
Vicinal amino alcohols are highly useful molecules. Vicinal amino alcohols find use as synthetic intermediates, ligands for metal catalyzed reactions, and as biologically interesting molecules. It is not surprising that considerable effort has gone into the synthesis of useful vicinal amino alcohols as well as the development of new and improved methods for their synthesis. Pericàs and coworkers have elucidated a facile and inexpensive route to determining the enantiomeric excess of primary amines. A regioselective and enantioselective epoxide ring opening of 108 with BF3 followed by lithium tert-butoxide catalyzed epoxide closure yielded 109, which was utilized as a resolution reagent. Through the use of 20 mol% of 109 relative to an amine, an ee determination could be performed on 110 via NMR without further purification <05OL3829>.
93
Three-membered ring systems (2005)
O OTs
Ph
NH2
1. BF3•OEt2 70% yield 2. t-BuOLi, THF 90-100% yield
F Ph
108
O
R1
F
R1 R2 LiClO4, THF MW, 75 °C
Ph OH 110
109
N H
R2
The microenvironment created by cyclodextrins can be used to overcome the low reactivity of epoxides. Rao and coworkers have shown that in situ formation of an epoxide/β-cyclodextrin complex in water, followed by amine addition yields regioselective epoxide openings <05SL506>. Several substituted epoxides and aromatic amines were examined with isolated yields in the range of 80-90%. NH2
O OH
Ph HN
β-CD, H2O, rt,
OH
92% yield
OH 111
112
Most methods for the ring-opening of epoxides require some type of acid catalyst. A potentially very useful ring-opening process has been reported that takes place in water and requires no catalyst <05OL3649>. In this reaction, the epoxide and amine are simply mixed in water for 5 – 24 hours and the resulting β-amino alcohol, 114, is then isolated in excellent yields. It is worth noting that aliphatic amines will preferentially react in the presence of aryl amines in this reaction system. O H2O, rt, R2
113
H N
R1
HO
R1 N R2
114
R1 R2 Yield(%) -(CH2)492 -(CH2)593 H n-Bu 84 Et Et 86
The search for improved catalytic systems for epoxide opening reactions has yielded a number of methods to improve this reaction. The use of 10 mol% of Cu(BF4)2 has been found to catalyze the ring-opening of epoxides with amines under solvent free conditions <05TL2675>. Both aliphatic and aromatic amines provide excellent yields of the β-amino alcohols. Scandium triflate has also been found to catalyze the ring-opening of epoxides with both aromatic and aliphatic amines in the absence of solvent <05TL9029>.
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S.C. Bergmeier and D.D. Reed
O
PhNH2
R1
PhHN
R2
OH
R1
R2
O
116
115
Sm I
O 117
R1, R2 (CH2)4 (CH2)4 (CH2)4 (CH2)4 (CH2)4 Ph, Ph
Reference <05TL2675> <05TL9029> <05TL8229> <05MI93> <05OL1023> <05OL4593>
Catalyst %Yield (ee) Cu(BF4)2 97 Sc(OTf)3 92 BiCl3 89 Ce-W10O36 100 117 79 (91) 118 89 (91)
N
N
OH
HO
Sc(OSO3C12H25)3
118
The use of BiCl3 is an interesting catalyst for the opening of epoxides with aryl amines <05TL8299>. When the ring opening reaction is carried out in acetonitrile, a chlorohydrin is the primary product. Changing the solvent to cyclohexane provides excellent yields of the βamino alcohol 116. Ammonium decatungstocerate (IV) polyoxometalate has been shown to be an effective heterogeneous catalyst for the ring opening of epoxides with arylamines <05MI93>. The conversion of meso epoxides to β-amino alcohols in high enantiomeric excess continues to be a rich area of research. The samarium binol catalyst 117, generates β-amino alcohols in excellent yield with good asymmetric induction (91%) <05OL1023>. The combination of a chiral bipyridal ligand and scandium tris(dodecylsulfate), 118, provides a method to open meso epoxides in water <05OL4593>. This catalytic system provides the amino alcohols in excellent yield and with good enantioselectivity. A one-pot epoxidation/azide-opening sequence has been developed <05JA2147>. A samarium-BINOL-Ph3AsO complex is used as a catalyst for enantioselective epoxidations of α,β-unsaturated amides. Upon addition of TMSN3 a new samarium azide complex is generated which regioselectively opens the epoxide to form 120. This method has also been extended to thiols and cyanide. O
N3 Sm(O-i-Pr)3, (S)-BINOL, Ph3As=O (1:1:1) Me3SiN3, TBHP in decane, THF, MS 4A, rt
N
O N
99% yield 99% ee
OH
119
120
The syn-opening of epoxides is a challenging reaction pathway to access. The use of arylborates, 122, may provide a general non-catalyzed route to such a reaction manifold <05CC1426>. Treatment of epoxide 121 with borate 122 provides 123 in 63% yield. The reaction occurs through an initial activation of the epoxide with the boron followed by synnucleophilic attack of the phenolic oxygen. This reaction occurs with some N-Boc aziridines as well although both syn and anti-opened products are obtained. OH O O
63% yield
O BOn-Bu
OH
O 121
122
123
Three-membered ring systems (2005)
95
Carboxylic acids are well known nucleophiles for opening epoxides and aziridines. Recently the stereoselective epoxide ring opening has also been achieved via palladium catalyzed formal 1,4 addition <05TL7243>. OH
O AcOH, Pd(Ph3)4
AcO OTES
OTES Ph
Ph
Ph
67% yield 94% ds
Ph 125
124
A tandem aldol/intramolecular enol cyclization of epoxyaldehydes to form α-furyl carbinols, 127, has been reported <05TL5467>. Only isopropyl methyl ketones or t-butyl methyl ketones have been shown to work in this reaction. The corresponding N-Boc aziridine aldehyde 127 (X = N-Boc) has also been used to generate an α-amino furan in excellent yield. H
X Bu2BOTf/DIPEA, DCM, 0 °C to 25 °C
X n-Pr
CHO
O
126
n-Pr
O
X Yield (%) O 71 N-Boc 72
127
3.2.3 AZIRIDINES 3.2.3.1 Preparation of Aziridines A general solution for the formation of aziridines by addition of nitrogen across an olefin has yet to be firmly established. Several examples of the transition metal mediated aziridination of olefins have been reported in the past year. The use of the rhodium catalyst, Rh2(cap)4, TsNH2 and NBS provides a number of aziridines in good to excellent yields <05OL2787>. Another rhodium catalyst, Rh2(pfm)4, (pfm = perfluorobutyramide) has been shown to catalyze the aziridination of olefins using TsNH2 and PhI(OAc)2 <05TL4031>. An advantage of the Rh2(pfm)4 catalyst system is the reported ability to use a variety of sulfonamides (e.g. nosyl, trichloroethoxysulfonyl) in the aziridination reaction. A cobalt porphyrin catalyst system that uses bromamineT as the nitrogen source provides excellent yields of aziridines <05OL3191>. A simple copper complex has been shown to catalyze aziridination as well <05JOC4833>. This reaction system uses PhINTs as the nitrogen F source and requires a borate, NaBAr 4, to remove the anionic ligands creating a coordinatively unsaturated cationic copper species. A key feature of all of these methods is that the olefinic substrate is the limiting reagent. This is an important feature of being able to use these methods in synthetically significant settings.
96
S.C. Bergmeier and D.D. Reed Ts N
R2
R1
R1
128 Catalyst
129
R2
Yield (%)
1 mol% Rh2(cap)4, NBS, TsNH2
R1 1 mol% Rh2(pfm)4, PhI(OAc)2, TsNH2
N Rh
R1 = Ph, R2 = H, 77% = n-C4H9,
R2
= H, 77%
R1 = Ph, R2 = H, 73%
Rh2(cap)4
R1 = n-C3H7, R2 = CH3, 44% 5 mol% Co(TDClPP), bromamine T
R1 = Ph, R2 = H, 83%
5 mol% (py)2CuCl2, NaBArF4, PhINTs
R1 = Ph, R2 = H, 97%
O Rh
R1 = n-C7H15, R2 = H, 56% R1 = n-C4H9, R2 = H, 49%
A rhodium-catalyzed route to bicyclic aziridines 131 from N-tosyloxycarbamates has been reported <05JA14198>. Several olefins were tested in this intramolecular process with yields ranging between 62-79%. O O O
N H
OTs
K2CO3, Rh2(OAc)4, Acetone, 25 °C
H
O
N
79% yield 131
130
The use of N-aminophthalimide as a nitrogen source in aziridination reactions has been examined. One of the problems associated with N-aminophthalimide as a nitrogen source is the need for a strong oxidant. The use of electrochemical catalysis with N-amino phthalimide has proved to be an effective and mild route for aziridination <05JOC932>. Both electronrich and electron-poor substrates worked well in this reaction.
MeO2C O
N
+ 1.80 V (vs Ag), MeCN, rt, NEt3H+ OAcCO2Me
NH2 132
O
O
133
N
O
92% yield trans
N MeO2C
134
CO2Me
The synthesis of aziridines from imines and sulfur ylides has been reviewed in previous editions of PHC and is a well-known reaction. A current study reveals that telluronium ylides add to α,β-unsaturated imines through a Michael addition-elimination to the olefin followed by a second equivalent of telluronium ylide addition to the imine, which subsequently eliminates to form aziridines 137 and 138 in a ratio of 13:1 <05JA12222>.
97
Three-membered ring systems (2005) Ph 1. NaHMDS
Te TMS
2. Ph
N
135
Ph Ph N
Ph
Ph N
TMS
TMS
TMS
136
137
TMS
138
82% yield 137/138 13:1
A new example of the aza-Payne rearrangement has been used to prepare βhydroxyaziridines <05OL3267>. The epoxy imine 139, is prepared by a sequential epoxidation and imination. Reaction of 139 with a series of alkyl lithium reagents initially adds to the imine which then does an aza-Payne rearrangement to form the hydroxyaziridine 140. While the method generally suffers from poor yields, the one step nature of the transformation lends greatly to its appeal. OH O N
t-Bu
R-Li N
139
140
R t-Bu
R = Me, 35% yield R = n-Bu, 47% yield R = Ph, 65% yield R = PhC≡C, 33% yield
3.2.3.2 Reactions of Aziridines In the synthesis of poison-frog alkaloid (-)-205B, a three-component Linchpin coupling was used to form a complex intermediate, 144, in a single step <05OL3247>. Lithiation of 141 followed by addition of epoxide 142, warming the reaction and then addition of aziridine in THF and DME to trigger the Brook rearrangement leads to 144. 1. t-BuLi, Et2O, -78 °C → -45 °C 2. Et2O, -78 °C → -20 °C S
S
3. THF/DME, -78 °C → 0 °C
OBPS
S
N Ts O
TBS O
O
O
142
141
O
OBPS
S OTBS NHTs
53% yield 144
143
The homologation of aziridines to allylic amines is an attractive process to a very useful class of molecules. Reaction of N-protected aziridines with excess dimethylsulfonium methylide provides the homologated allylic amines in excellent yields <05OL3295>. H 3C SO2t-Bu N R
145
S CH2 (300 mol%)
NHSO2t-Bu
H 3C R
146
R = CH2OTr, 90% yield R = (CH2)2CHCH2, 99% yield R = (CH2)4Cl, 98% yield R = CH2Ph, 99% yield
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S.C. Bergmeier and D.D. Reed
The gadolinium•149 complex was used to catalyze the enantioselective desymmetrization of an assortment of aziridines <05JA11252>. The substitution on the nitrogen was critical to obtaining optimal yields and enantioselectivity. The use of N-tosyl aziridine gave 148 in only 24% ee while changing to the p-nitrobenzoyl gave 148 with an 87% ee. Aziridines have also been opened through the use of nucleophilic catalysis <05OL3509>. Several nucleophilic catalysts were examined for the preparation of cyanoamides, 148, and the optimal choice was TMEDA (20 mol%). This represents a significant departure from the more typical acid catalysis used for aziridine ring opening.
N R 147
H N
Gd(Oi-Pr), TMSCN, 149 R = Ts, 58% yield, 24% ee R = 4-NO2-PhCO, 94% yield 87% ee or
Ph R
Ph
CN 148
P O HO
O
O
F
HO
F
149
TMEDA, KCN, R = Ts, 57% yield
1,2-Diamines are another highly useful class of molecules with potent biological activity and use as synthetic intermediates and metal ligands. The ring-opening reactions of aziridines with amines and azide provides a facile route for the synthesis of 1,2-diamines. The use of microwave induced Montmorillonite K-10 clay catalyzed opening of tosylaziridines provides an environmentally friendly route to 1,2-diamines 151 and 152 <05TL2083>. In general, these ring-opening reactions are regioselective with both arylamines and aliphatic amines participating equally well. Particularly interesting is the opening of aziridine 150 (R1 = Me, R2 = CO2Me) at the most substituted carbon to provide diamino ester 151. Ts R1 R3 Yield (%) R2 3HN 3 TsHN R NHTs NHR 97 N MW, K-10 H Me Ph R1 93 H Me PhCH R3-NH2 2 R1 R2 R1 R2 R2 PhCH2 92 H Ph 150 85 151 152 Ph Me CO2Me
Ratio (151:152) only 152 10:90 90.10 only 151
A dynamic kinetic asymmetric transformation (DYKAT) of racemic vinyl aziridine 153 yielded the enantiopure imidazolidinone 154 <05OL823>. This transformation was the initial step in a total synthesis of (+)-pseudodistomin D. (η3-C3H5PdCl)2, 155 DMB N AcOH, DCM
DMB N
O N DMB
O
O NH HN
O 153
154 O OCN
88% yield 94% ee
PPh2 Ph2P 155
The ring opening of unactivated aziridines is difficult due to the inertness of these ring systems. The use of AlCl3 to catalyze the ring opening of aziridine 156 by NaN3 has proven
99
Three-membered ring systems (2005)
surprisingly effective <05TL4407>. The authors report complete inversion at the carbon bearing the azide. Given the acidic reaction conditions, it is also interesting to note that the reaction was carried out on a several hundred gram scale without any difficulties! Me
Ph N
Ph
H
AlCl3 (cat.), NaN3, EtOH:H2O (50:50), pH 4
Me
CO2Et
N H
86% yield N3
CO2Et 156
157
The silicon β-effect has been exploited to convert aziridines to 2-imidazolines and oxazolidines <05JA16366>. This reaction presumably goes through siliranium ion 159, which can then react with an electrophile to form 160 or 161. It has also been shown that zinc dihalides are effective in catalyzing the formation of 160, but require elevated temperatures <05TL4103>. SiPh2t-Bu N Me
MeCN Ts N
SiPh2t-Bu
BF3•Et2O DCM, rt
F3B
O O S N
p-Tol
158
N Ts 160, 90% yield
SiPh2t-Bu
SiPh2t-Bu R 159
O
EtCHO
Et N Ts 161, 90% yield cis/trans 67:33
An interesting copper catalyzed phenol opening of aziridine 163 yielded an intermediate, 164, for the synthesis of ustiloxin D <05OL5325>. This reaction is quite unique in that the phenol is reacting at a highly congested carbon and that none of the SN2’ addition is observed. OBn
CO2Bn
HO Boc
N Ns
N 162
O
O
OH
OBn N H
CO2t-Bu
CuOAc DBU Toluene
O Ns
CO2Bn
HO 163
Boc
NH
N
N H
CO2t-Bu
90% yield
164
In a very neat reaction sequence, N-methylaziridines have been shown to be useful directing groups for ortho-metallation <05OL3749>. Reaction of 165 with s-BuLi followed by trapping with a carbonyl compound provides alcohol 167. Subsequent intramolecular aziridine ring opening provides isobenzofuran derivative 168.
100
S.C. Bergmeier and D.D. Reed
CH3 N
OH
CH3
Li
N
s-BuLi, -78 °C
acetone
165
167
166 O
NHCH3
TFA
CH3 N
95% yield
168
Ring-opening reactions of aziridines (and epoxides) typically require the use of a Lewis acid to catalyze the reaction. β-Cyclodextrins (β-CD) are very useful in creating microenvironments in which aziridines can be opened using mild conditions. The reaction of aziridines with β-CD and sulfur nucleophiles such as thiocyanate <05SL489> or thiophenols <05TL6437> provides a mild route to such ring-opened compounds. TsHN
Ts N
SPh
β-CD, H2O, PhSH, 50 °C
β-CD, H2O, KSCN, rt
TsHN
SCN
78% yield
90% yield 169
170
171
Several thiazolidines were synthesized via titanium tetrachloride catalytic cyclization <05JOC227>. The reaction proceeds via an intramolecular attack on the nitrile by the aziridine nitrogen to provide bicyclic aziridinium intermediate 173. Subsequent ring opening by chloride yields thiazolidine 174. O Cl
N 172
N
Cl 1. TiCl4, MeCOCl, DCM, rt 2. NaHCO3, rt
N
NH
SCN Ar
Cl N
Me 96% yield
S 174
S
Cl 173
An interesting SN2/formal [3+2] cycloaddition route for the synthesis of substituted indolizidines has been reported <05OL5545>. This reaction requires both an electron withdrawing group on the alkyne and an aromatic ring on the aziridine. The reaction goes through an initial N-alkylation of the aziridine with iodide 175 followed by a Michael addition/rearrangement to generate indolizidines 179 - 181.
101
Three-membered ring systems (2005) H N
176
Ph racemic K2CO3, MeCN, 60°C, 24hr
95% yield racemic
179 Ph
EtO2C
>99% ee Ph K2CO3, MeCN, 50°C, 16hr
I
OBn N
H N
177
CO2Et
Ph
EtO2C
BnO
92% yield >99% ee N 180
175
Cl K2CO3, MeCN, 65°C, 24hr H N
178
83% yield 94% ee
EtO2C
95% ee
181
N Cl
The regioselective oxidation of aziridines to α-tosylamino ketones has been accomplished via N-Bromosuccinimide (NBS) and cerium(IV) ammonium nitrate <05TL4111>. Both styryl aziridines, 182, and aliphatic aziridines, 184, have been oxidized. A related report uses β-cyclodextrins in addition to NBS to catalyze the same transformation <05TL1299>. These reaction conditions also work well for epoxides to provide the corresponding α-hydroxy ketones. Ts N Ph
O
CH3CN:H2O (9:1), CAN, NBS
NHTs
Ph 182
92% yield
183
184
O
CH3CN:H2O (9:1), CAN, NBS
N Ts
185
H NHTs
84% yield
The transformation of aziridines that do not involve ring opening are rare due to the reactivity of the aziridine ring. Considering the somewhat more difficult synthesis of aziridines (relative to epoxides), the ability to convert one aziridine into another represents a significant expansion of the scope of any aziridine synthesis. The deprotection of N-protected aziridines continues to be a problematic process. Many methods used to deprotect N-protected aziridines results in cleavage of the aziridine ring. The use of ozone to deprotect N-benzhydryl aziridines, 186, has been reported <05OL2201>. While the yields of this method were modest, this is an important new method for such deprotections. Ph
Ph N
Ph
CO2Et 186
1. O3, DCM, -78 °C 2. NaBH4, MeOH
H N Ph
60% yield CO2Et
187
102
S.C. Bergmeier and D.D. Reed
The Darzens reaction of the oxazoline 188 with a series of aldimines has been shown to form aziridine 190 in good yields and diastereoselectivity <05T3251>. Deprotonation of the aziridine to form the aziridinyl anion and subsequent reaction with an electrophile provides the highly substituted aziridines 191 in moderate yields. The diphenylphosphinyl group on the nitrogen provides optimal yields in the lithiation reaction.
1. LDA, -98 °C, THF
N Cl
O
2.
188
Ph
Me
Me
191
E
Electrophile Yield (%) 50 MeI 58 BnBr 24 PHCHO
H
66% yield dr 90:10
189
s-BuLi, -98 °C TMEDA Electrophile
N POPh2 N Ph O
O P Ph Ph N
N POPh2 N Ph O
190
Terminal aziridines were deprotonated with LTMP and directly treated with a variety of electrophiles to provide substituted aziridines, 193 <05OL1153>. In all cases, the products had the trans geometry about the aziridine ring. Related work on the lithiation of carboxylate substituted aziridines <05AG(I)6169> and aziridinium ions <05MI1294> was also reported.
THF, -78 °C, Electrophile
O S O N C5H11
H
O S O N C5H11
N Li
192
Electrophile TMSCl PhCHO DMF CO2
R 193
Yield (%) 86 38 63 63
R SiMe3 CHOHPh CHO CO2Me
2-Aziridinemethanols were resolved using porous ceramic (Toyonite)-immobilized lipase (PS-C II) <05JOC1369>. This report is significant in that few examples of the lipasecatalyzed reaction for such 2-aziridinemethanols having two stereogenic centers at β– and γcarbons are known, and none of these types of resolutions with aziridine derivatives without N-protection have been reported. Ph
H N
H
Me OH
Me 194
H N
Ph
OH H
195
lipase PS-C II Acetone -40 °C
Me
H N
Ph
OAc H
Ph
H N
H OH
Me
196
197
90% ee
87% ee
Kimpe et. al., have found that (2-bromomethyl)-N-alkyl aziridines react with organocuprate reagents to provide largely the product of bromide displacement, 199 <05SL931>. Most aliphatic organocuprates (e.g. R = Me, n-Bu) provide good yields of the displacement product 199. When R = allyl, the sole product is 200 (40%), presumably via a competing electron transfer or metal-halogen exchange reaction which then leads to ring opening.
103
Three-membered ring systems (2005) Ph
Ph R2CuLi, Et2O
N
R
N
Br
R
198
Yield (199:200) R 76:0 Me 54:10 n-Bu
N H
199
200
Aziridine 2-carboaldimines, 201, have been used to provide ready access to a variety of diamines <05T9281>. A number of nucleophiles were added to imine 201 to provide products 202 and 203. Grignard reagents and a ketene silyl acetal added to the imine in very good yields when catalyzed with BF3•OEt2. The Strecker product, R = CN, was obtained in very good yield but with only moderate diastereoselectivity by reaction with TMSCN and BF3•OEt2. Ph
PMB N
Me
N
Ph
BF3•OEt2 Nucleophile
Me
Ph
PMB N
HN
Me
PMB N
HN
R H
R
H
201 Nucleophile MeMgBr TMSCN OMe
H
202 Yield (%) Ratio (202:203) 86 99:1 99 69:31
203 R CH3 CN CO2Me
87 OTMS
In addition to the nucleophilic addition reactions of 201 shown above, the imine can also participate in cycloaddition reactions <05T9281>. Keto-piperidine 205 could be prepared in very good yield through a Diels Alder reaction of 201 with Danishefsky’s diene. The observed stereoselectivity was rationalized through a chelation controlled transition state with re-face preference. Ph Me
PMB N
N
BF3•OEt2 OMe OTMS
H
204
Ph PMB N N Me O H 205
201
Ph PMB N N Me 81% yield 71:29
O H 206
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Three-membered ring systems (2005)
05OL3829 05OL4593 05OL5325 05OL5545 05S1405 05SL489 05SL506 05SL842 05SL931 05SL1047 05SL1359 05T1069 05T2541 05T3251 05T3349 05T6009 05T6726 05T9281 05TL89 05TL339 05TL797 05TL1269 05TL1299 05TL1643 05TL2083 05TL2311 05TL2675 05TL3669 05TL4031 05TL4103 05TL4111 05TL4407 05TL5467 05TL5665 05TL6437 05TL6705 05TL7243 05TL8229 05TL8895 05TL9029
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106
Chapter 4 Four-membered ring systems Benito Alcaide Departamento de Química Orgánica I. Facultad de Química. Universidad Complutense de Madrid, 28040-Madrid. Spain
[email protected] Pedro Almendros Instituto de Química Orgánica General, CSIC, Juan de la Cierva 3, 28006-Madrid, Spain
[email protected] ______________________________________________________________ 4.1
INTRODUCTION
Strained four-membered heterocycles have received considerable attention for a variety of reasons. In addition to being key scaffolds in natural products as well as in compounds of biological and industrial interest, the use of four-membered rings as starting materials to prepare many different substances provides the motivation to explore new chemistry based on these compounds. Oxygen- and nitrogen-containing heterocycles, in particular β-lactams, dominate the field in terms of the number of publications. This chapter covers selected relevant aspects in this area. 4.2
AZETIDINES AND AZETES
A combined experimental and computational study of the photopreparation of fused 2,3-dihydroazetes 1 has been performed <05JOC7744>. The hybrid azetidine-oxadiazole based compound 2 has been identified as a potent sphingosine-1-phosphate-1 (S1P1) receptor agonist with minimal affinity for the S1P2 and S1P3 receptor subtypes <05JMC6169>. Cyclohexylglycine amides of various fluorinated azetidines have been prepared, displaying unexpectedly strong activity against dipeptidyl peptidase IV <05BMCL4770>. It has been reported that the intramolecular catalytic aldol cyclodehydration of 1,6-dialdehydes to the corresponding cyclopentene carbaldehydes can be promoted by azetidine-2-carboxylic acid 3 <05T267>. The preparation of palladium(II) complexes having sterically congested azetidines as ligands has been described <05JOM2306>. Combinatorial libraries of nonbiological polymers and drug-like peptides have been synthesized from unnatural amino acids such as azetidine-2-carboxylic acid, by exploiting the broad substrate specificity of ribosomes <05JA11727>. N
X N 1 (X = F, Cl, Br)
CO2H
N O
CO2H N H
N 2
3
107
Four-membered ring systems
Practical five- or six-step syntheses of both enantiomers of azetidine-2-carboxylic acid 3 have been developed starting from commercially available α-methylbenzylamine <05JOC9028>. Azetidine-2-carboxylic acid analogs possessing various heteroatomic side chains at the 3-position have been synthesized and designed to serve as tools for studying the influence of conformation on peptide activity <05MI298>. The asymmetric synthesis of 3substituted azetidine-2-carboxylic acids has been performed from hydrazones <05S3508>. The stereoselective synthesis of the cis-conformationally constrained glutamate analogue 5 containing an azetidine framework has been accomplished in seven steps in 15% yield from (S)-N-tosyl-2-phenylglycine. The key steps in the synthesis involved an N–H carbenoid insertion promoted by Cu(acac)2, and a Wittig olefination of an azetidin-3-one 4, followed by a highly stereoselective rhodium-catalyzed hydrogenation <05SL1559>. A set of ten azetidinic amino acids 6, that can be viewed as C-4 alkyl substituted analogues of trans-2carboxyazetidine-3-acetic acid and/or conformationally constrained analogues of (R)- or (S)glutamic acid, have been synthesized in a diastereo- and enantiomerically pure form from unsaturated amino esters through a straightforward three-step sequence <05OBC3926>. Ph
CO2H NHTs
i
O
Ph N
ii
iii
N
iv
Ts
4 (35%)
CO2Et
CO2H
HO2C
v
N H R 6 (31–45%)
vi
H
R
N Bn
5 (44%)
CO2H
HO2C
CN
Key: i) (a) (COCl)2; (b) CH2N2. ii) Cu(acac)2. iii) (a) Ph3PCHCO2Et; (b) H2, Rh/C. iv) (a) RuO4; (b) CH2N2; (c) LiOH; (d) Na/C10H8. v) LiHMDS. vi) (a) 6N HCl; (b) H2, Pd/C. Cyclization of a γ-azido-α-bromocarboxylic acid resulted in a synthesis of the 3,3dimethoxyazetidine-2-carboxylic acid 7 <05TL525>, which after reduction gave the corresponding 3,3-dimethoxy-2-(hydroxymethyl)azetidine. A practical synthesis of 2′deoxymugineic acid 8 has been developed via reductive alkylation of azetidine-2-carboxylic acid 3 with aldehydes <05TL1419>. β-Amino alcohols possessing an E vinylsilane moiety have been cyclized in the presence of N-bromosuccinimide to afford diastereoisomerically pure polyfunctional azetidines 9, which can be transformed into enantiopure β-amino alcohols with a Z vinylic bromide moiety <05TL8023>. CO2H MeO MeO
Br CO2H N3
i ii
MeO MeO
CO2H
CO2H
N
TMS
N
H 7 (41%)
R H
H
N
CO2H OH 8
Br
N H
Ph
HO 9 (38–64%)
Key: i) Ph3P, Et3N. ii) NaOH, THF–H2O, Δ. R = alkyl, aryl. Azetidine derivatives 10 were formed in an attempted aza-Baylis–Hillman reaction of N-tosylated imines with ethyl 2,3-butadienoate in the presence of DABCO <05JOC9975>. It has been reported that basic treatment of a bromoallene bearing a sulfonamide moiety gave azetidine 11 as the major product <05AG(E)1513>. Irradiation, in benzene or acetonitrile solution, of 3-allyl or 3-benzyl-2-acyl disubstituted perhydrobenzoxazines yielded azetidin-3ol derivatives in moderate chemical yields (50–60%) and good to excellent diastereoselection (64–96%) <05JOC1408>. Sterically congested 1-azabicyclo[1.1.0]butanes have been added to hydrazoic acid at 0–5 ºC to give 3-azidoazetidines in good to excellent yields <05HCA1658>. It has been proved that chelated ester enolates are suitable nucleophiles for 1,4 additions to nitroalkenes and that the intermediates formed are highly reactive and undergo clean cyclization to azetidine oxime esters 12 <05OL2643>. A practical
108
B. Alcaide and P. Almendros
chemoselective deprotection of allylic amines including azetidines catalyzed by Grubbs’s carbene has been reported <05S668>. R CO2Et CO2Et
H
i
ArCH=NTs +
Br
N
Ar
O N
ii N
NHTs
Ts 10 (45–69%)
Ts 11 (76%)
O
N t-BuOOC
Ts 12
Key: i) DABCO, C6H6, RT. ii) NaH, DMF. It has been observed that the [2+2] cycloaddition between ethyl vinyl ether and cyclic ketene imines afforded bicyclic azetidines 13 <05EJO3781>. The unusual tricyclic structure 14 has been isolated as a minor component from the reaction of benzonitrile oxide and a vinyl imidazole <05S2695>. The cis,cis,cis,cis-[5.5.5.4]-1-azafenestrane borane complex 15 has been efficiently prepared using a Mitsunobu reaction as key cyclization step <05AG(E)3732>. The preparation of 1,2-diazetidines from quadricyclane by the 2σ+2 σ+2π cycloaddition with azodicarboxylates has been explored in water <05AG(E)3275>. Thus, when a mixture of DMAD and quadricyclane is vigorously stirred, the reaction is complete within a few minutes at ambient temperature. Azeto[1,2-a]imidazoles are prepared by a formal intramolecular [2+2] cycloaddition of imino-ketenimines in which an ethylene chain links the nitrogen atoms of both functionalities, bearing a methyl and a phenyl group on the terminal carbon atom of the heterocumulene <05T1531>. The ring strain present in 2-aza-1phosphabicyclo[2.1.0]alka(e)nes has been calculated at the G3(MP2) level using homodesmotic reactions <05JOC8110>. The mode selectivity in the intramolecular [2+2] cyclization of ketenimines bearing N-acylimino units to give azeto[2,1-b]pyrimidinones 16 has been studied by ab initio and DFT calculations <05JOC1340>. It has been reported that the reaction of azetidinecarboxylate esters with metallocarbenes generated spiroazetidinium ylides, whose [1,2]-shift by the ester-substituted carbon furnished ring-expanded pyrrolidine products <05OL2949>. The preparation of an (E)-α,β-unsaturated ester bearing a terminal tosylamino group through the Arndt-Eistert reaction of L-N-tosyl-azetidine 2-carboxylic acid has been explored <05SC2535>. 2-tert-Butyldiphenylsilylmethyl-substituted azetidines 17 react efficiently with nitriles to generate tetrahydropyrimidine products 18 <05JA16366>. A new entry to enantiopure 3-aminopyrrolidines has been developed using a boron trifluoridemediated rearrangement of 2-aminomethylazetidines <05OL5861>. The regioselective opening of azetidinium ions with nitrogen and oxygen nucleophiles has been discussed <05SL1666>. The stereocontrolled synthesis of amino hydroxyalkyl diphenylphosphine oxides has been achieved starting from (2S,3S)-N,N-dibenzyl-3-hydroxy-2-methylazetidinium bromide <05TL4381>. The stereocontrolled synthesis of functionalized organosulfur compounds of a general formula: Bn2NCH(CH3)CH(OH)CH2SX [where: X = SO3Na or SP(S)(OR)2] was achieved by a regioselective opening of enantiomerically pure (2S,3R)- and (2S,3S)-N,N-dibenzyl-2-hydroxy-3-methylazetidinium bromides <05TA1577>. R1 R1
S
CF3 CN CF3
N
– O2N Ph
N N
BH3 +N
N
13
14
Key: i) R5CN, BF3.OEt2.
15
16
TBDPS
R2 R3 R4
N
H
H
N O H
EtO
O
i N Ts
Ph 17
TBDPS N
R5 N
Ts
18 (60–65%)
109
Four-membered ring systems
4.3
MONOCYCLIC 2-AZETIDINONES (β-LACTAMS)
A review on the synthetic utility of thioisomünchnones including β-lactam formation has appeared <05ACR460>. Bacterial resistance to β-lactam antibiotics has been reviewed <05CRV395>. A review on the drug-resistant bacteria including to β-lactam antibiotics deserves to be mentioned as well <05OBC959>. A report reviewing the preparation of enantiopure β-amino acids utilizing β-lactam derivatives has appeared <05MI001>. Effects of the C-3/C-4 ring substituents on anti-MRSA (methicillin-resistant Staphylococcus aureus) activity in N-methylthio-β-lactams, a new family of antibacterials, have been explored <05BMC6289>. Synthetic routes to novel 1-(2,3,4-tri-O-acetyl-alpha-Larabinopyranosyl)azetidin-2-ones revealing antimicrobial activity have been described <05NNN1277>. The synthesis and in vitro evaluation of β-lactam-based inhibitors of intestinal cholesterol absorption has been described <05JMC6035>. The novel azetidinyl γlactam based peptide 19, showing a preference for the β-turn conformation, has been synthesized using the Kinugasa reaction <05OBC4050>. Azapeptidomimetics containing sterically-congested β-lactam rings have been prepared by Mitsunobu cyclization of serine/homologated serine-azaalanine derivatives <05T10277>. Improved antiviral activity in structurally modified phenylalanine-derived 2-azetidinones bearing a 4-carboxylate moiety has been reported <05JMC2612>. A theoretical study of the cycloaddition reactions of ketene and N-silyl-, N-germyl-, and N-stannylimines to furnish β-lactams has been performed at the B3LYP/6-311+G(d,p) theory level <05JPC11022>. A combined theoretical and experimental study on the formation of silylated β-lactams from silylketenes through Lewis acid promoted [2+2] cycloaddition has been reported <05EJO2599>. The effect of aqueous media in the preparation of β-lactams 20 by multi-component reactions has been evaluated <05T11456>. A facile method for the synthesis of 4-hetaryl substituted β-lactams has been reported from substituted thienopyrimidinones <05IJC(B)2367>. 4-Phosphono-β-lactams 21 have been synthesized via a three-step sequence, including final formation of the C3–C4 bond through a phosphorus-stabilized carbanion <05S3603>. O O O
R1
NH N
CO2CHPh2
HN Ph
HO2C
Ph N O
Ph 19
R2
R1 R2 NH2
N O
R2
O
i R3
N H
20 (77–97%)
R4
N O
O P(OR3)2 R1
21
Key: i) R3CHO, R4NC, LiCl (aq 2.5 M). Synthetic sequences for 3-hydroxy-4-substituted β-lactams using biocatalytic reductions to install the desired chirality have been developed <05TA4004; 05MI33>. The dynamic kinetic resolution of 3-oxo-4-phenyl-β-lactam by recombinant E. coli overexpressing yeast reductase Ara1p has been achieved <05TA2748>. A series of 4ferrocenyl-β-lactams has been synthesized in good yields by a one-pot reaction of achiral and planar-chiral ferrocenylimines with substituted acetic acids <05EJO3326>. The synthesis and structure of trans-(+)-(3S,4S)-3-amino-4-ferrocenyl-1-p-methoxyphenylazetidin-2-one has been recorded <05JST60>. A diastereoselective synthesis of cis-3-alkyl-1-benzyl-4ethoxycarbonyl-β-lactams 22 has been developed by galvanostatic electrolysis of MeCN– Et4NPF6 solutions and subsequent addition of a N-(ethoxycarbonyl)methyl-N-benzyl-2bromoalkylcarboxamide <05TL8517>. The synthesis of β-lactams 23 through the [2+2] cycloaddition of chlorosulfonyl isocyanate (CSI) to alkoxyallenes derived from ethylidene
110
B. Alcaide and P. Almendros
and benzylidene erythritols and threitols have been described <05EJO429>. A highly regioand stereoselective synthesis of β-lactams containing spiropyrrolidine moieties has been achieved using [3+2] cycloaddition methodology <05T8512>. O Ph
i N
R
EtO2C
CO2Et
R
Br
N
R1
Ph
O
O
O
R1
ii
O
O
O
O
HN
R2O
R2O
22 (75–90%)
H
O
23 (66–87%; d.e. = 50–65%)
Key: i) CH3CN-Et4NPF6. ii) (a) CSI, Na2CO3; (b) Red-Al. It has been observed that the bis(trimethylsilyl)methyl group is an effective Nprotecting group and site-selective control element in rhodium(II)-catalyzed reaction of diazoamides to form β- and/or γ-lactams <05JOC8372>. It has been demonstrated that water is an efficient solvent for the Rh2(OAc)4 catalyzed intramolecular C–H insertion of a range of diazo substrates to yield 2-azetidinones <05CC391>. A catalytic system based on [RuCl2(pcymene)2] has been developed for the stereoselective cyclization of α-diazoacetamides to βlactams 24 by intramolecular carbenoid C–H insertion <05OL1081>. A solid-phase synthesis of 1,3,4-trisubstituted β-thiolactams 25 has been described <05SL1563>. The antiMarkovnikov addition of N–H amides including β-lactams to terminal alkynes has been performed <05AG(E)4042>. 2-Azetidinones 26 in which a new chiral center is generated at the benzylic carbon, have been prepared by photochemical treatment of α-oxoamides in the crystalline state <05JA3568>. O O
O
R1
EtO
R1
N R2
N2
R2
R1
CO2Et N
O
N
R2
CO2Me
S
24 (12–99%)
R*
O
i
N
O
N
O
R*
25
OH
ii O 26
Key: i) 2.5 mol% [RuCl2(p-cymene)2]. ii) hν. The synthesis of difluoro-β-lactams 27 using ethyl bromodifluoroacetate in the presence of a rhodium catalyst has been executed <05TL7679>. A mechanistically based study of bifunctional catalyst systems in which chiral nucleophiles work in conjunction with Lewis acids to produce β-lactams in high chemical yield, diastereoselectivity, and enantioselectivity has been reported <05JA1206>. It has been demonstrated that a planarchiral azaferrocene derivative of 4-(pyrrolidino)pyridine is an excellent catalyst for the enantioselective coupling of ketenes and N-triflyl imines, providing trans-β-lactams 28 <05JA11586>. An anionic, nucleophilic catalyst system that provides a diastereoselective route to trans-disubstituted β-lactams has been introduced <05OL3461>. N N R1
R3 R2
F i
F
R2 R1 N
O
R3
O C
Tf N H
+
R1
Ph
ii R2
27 (35–93%)
Ph
R2
R1 N
O
Tf
28 (60–89%; e.e. = 63–99%)
N Me
Fe
Me
Me Me
Key: i) BrCF2CO2Et, [RhCl(PPh3)3]. ii) 10% catalyst.
Me
111
Four-membered ring systems
N-Allenyl-β-lactams have been obtained via metal catalyzed <05OL2117> or base promoted <05TL6029> C–N amidation of NH-β-lactams. The cyclization of β-amino esters to α-methylene-β-lactams has been achieved <05SL2035>. The formation of the αalkylidene-β-lactam framework by the palladium-catalyzed intramolecular selenocarbamoylation of alkynes with carbamoselenoates has been achieved <05JA9706>. The PdCl2-catalyzed cyclocarbonylation reaction of propargylic amines with CuCl2 and benzoquinone afforded (E)-α-chloroalkylidene-β-lactams 29 <05JOC2588>. 1,3,4Trisubstituted 2-azetidinones have been prepared by diastereoselective and π-facially selective Lewis acid-catalyzed intermolecular Diels-Alder reactions of 3-butadienylazetidin2-ones <05EJO2397>. The synthesis of 3-(2'-amino)-β-lactams has been accomplished using diastereoselective allylic azide formation and isomerization reactions <05OL533>. The reaction of α-bromo-β,γ-unsaturated β-lactams with m-chloroperbenzoic acid to find experimental conditions for the exclusive formation of epoxides or bromide 1,3-shift has been studied <05SL2204>. In situ generated organozinc reagents of 3-alkenyl-3bromoazetidin-2-ones have been reacted with aldehydes to give alcohol derivatives <05S61>. The introduction of hydroxyl- or keto- functionalities into the C3·side chain of azetidin-2ones via allylic bromide rearrangement, followed by supported reagent substitution has been documented <05MI136>. Using a halogen–lithium exchange reaction on 4-aryl-3,3-dichloro2-azetidinones 30 followed by treatment with alkyl halides as electrophiles, the synthesis of cis-3-alkyl-3-chloro-4-arylazetidin-2-ones 31 has been accomplished <05S193>. The synthesis of trans-β-lactams from imines and a salicylamide-derived carboximide has been described <05S725>. Carbamoyl radicals have been generated from oxime oxalate amides, and the kinetics of their 4-exo cyclizations onto C=C and C=NO bonds, leading to β-lactamcontaining species, have been studied by EPR spectroscopy <05OL155>. It has been reported that silver acetate-promoted cycloaddition between (3RS)-phenyl-(4RS)-cinnamoyl-2azetidinone and nitrilimines gives 4-(4,5-dihydropyrazol-5-yl)carbonyl-2-azetidinones 32 as the major products <05T2413>. The liquid-phase synthesis of β-lactams from poly(ethylene glycol)-supported aldehydes has been developed <05S530>. The stereoselective synthesis of bis-β-lactams via Staudinger reaction of ketenes with bisimines derived from C2-symmetric 1,2-diamines has been described <05T2441>. R2 Cl NHR3 R1
i
R1
R2
Cl
N Ar N
R2
Cl
Cl
R3 H
Ph
N O
R3
29 (32–80%)
N O 30
R1
N O
R1
31 (23–57%)
Ph
H H O
ii
R2
CO2Me
N O
PMP 32
Key: i) 5 mol% PdCl2, CuCl2, benzoquinone, CO (300 psi). ii) (a) n-BuLi, THF, –78 °C; (b) R3X, THF,–78 °C to RT. PMP = 4-MeOC6H4. It has been reported that a Pd-Cu bimetallic catalyzed oxycyclization of α-allenols– cross coupling reaction sequence leads to functionalized β-lactams 33 <05CEJ5708>. A remarkable ring contraction to the indole spiro-β-lactam moiety has been described en route to the chartelline alkaloids <05AG(E)3714>. A Ru-catalyzed metathesis sequence with oxanorbornene precursors has been used for the synthesis of spiro-β-lactams tethered to tetrahydrofuran rings <05HCA1387>. The preparation of spirodienone β-lactams through cyclization of alkyl hydroxamates mediated by phenyliodine(III) bis(trifluoroacetate) has been documented <05JOC10271>. Spiranic 2-azetidinones 34 have been produced by the reaction of diphenylketene with isocyanides at low concentration <05OBC4246>. It has been
112
B. Alcaide and P. Almendros
uncovered that the Smiles rearrangement goes through a four-membered spiro intermediate on radicals derived from N-(α-xanthyl)acetanilides or N-(α-xanthyl)acetylaminopyridines <05OL3817>. 1,3-Thiazolidine-derived spiro-β-lactams 35 have been stereoselectively synthesized by means of a Staudinger ketene–imine reaction starting from optically active NBoc-1,3-thiazolidine-2-carboxylic acid derivatives and imines <05TA3371>. The synthesis of spirocyclic β-lactams through the cyclization of lithiated pyridine and quinoline carboxamides has been achieved <05OL3673>. R2 OH
R3
MeO2C
R3
O
R3 Ph Ph
i N O
N
R2 O
R1
N
R1
N O
33 (56–58%)
Ph O
S N
Ph
O
COR2 Ph
O
R1
35
Ph R
34
Key: i) methyl acrylate, Pd(OAc)2, LiBr, PPh3, Cu(OAc)2, K2CO3, O2, MeCN, RT. β-Lactams have been utilized as synthons for the preparation of a wide variety of compounds. 3-Methyl-4-thienyl-azetidin-2-one has been used in the preparation of the isoserine chain of taxanes <05TL3411>. The 1,3-dipolar cycloaddition reaction involving αalkoxy β-lactam acetaldehyde-derived azomethine ylides gave, with excellent diastereoselectivity, highly functionalized 2-azetidinone-tethered prolines, which were directly used for the first preparation of azabicyclo[4.3.0]nonane (indolizidinone) amino esters 36 from β-lactams <05JOC8890>. The stereoselective synthesis of a (R)-β-amino acid pharmacophore via a β-lactam intermediate has been discussed <05JOC1949>. Starting from the bicyclic β-lactam cis-7-azabicyclo[4.2.0]oct-4-en-8-one, novel routes have been developed for the synthesis of 2-amino-4-hydroxycyclohexanecarboxylic acid and its 3hydroxy-substituted analog <05EJO4017>. The dihydrobenzopyran skeleton has been prepared from β-lactams <05TA971>. A β-lactam related to salinosporamide A and omuralide has afforded a bicyclic pyrrolidine by methanolic base treatment <05JA15386>. An efficient synthesis of 2,3-aziridino-γ-lactones from β-lactams has been accomplished <05SL2370>. Acid-catalyzed tandem intramolecular azetidinone ring opening followed by aziridine ring formation via elimination of a mesylate group is the key step in this synthesis. The ring expansion of β-lactams to γ-lactams has been achieved via N-acyliminium intermediates <05JOC3369> and induced by electrophiles <05JOC8717>. The cleavage of the N1–C4 bond of 4-(4'-hydroxyphenyl)-azetidin-2-ones has been used to synthesize compounds to mimic tyrosine in peptide-based drug design research <05TL3715>. The synthesis of γ-lactam derivatives through N1–C4 one carbon ring expansion of β-lactam derivatives has been described <05TL1755>. The first organocatalytic N1–C4 bond breakage of the β-lactam skeleton has been used for the preparation of enantiopure 5-aryliminopyrrolidin-2-ones 37 from 4-(arylimino)-methyl-azetidin-2-ones <05OL3981>.
MeO O
H H
OR2 H
N
HN R1
R6
R3 R4 R5 CO2Me
R1HN
OR2 H
MeO
N
R3
i
O
R4 R5
R6 CO2Me
R1
R1 H H N O
36 (55–71%)
Key: i) MeONa, MeOH, RT. ii) 20 mol% TBACN, MeCN, RT.
NR3
ii NR N R2 37 (44–70%)
O R2
3
113
Four-membered ring systems
FUSED POLYCYCLIC β-LACTAMS
4.4
The enzyme-catalyzed reactions involved in formation of the bicyclic clavam and carbapenem nuclei, including β-amino acid and β-lactam formation, have been reviewed and compared with those involved in penicillin and cephalosporin biosynthesis <05CC4251>. The synthesis of deuterium labelled L- and D-glutamate semialdehydes, their evaluation as substrates for carboxymethylproline synthase, and their implications for carbapenem biosynthesis have been investigated <05CC1155>. The totally synthetic bicyclic β-lactam 38 related to salinosporamide A and omuralide has showed potent proteasome inhibition activity <05JA15386>. It has been reported that ceftriaxone 39, in addition to its classical antibacterial activity, offers neuroprotection by increasing glutamate transporter expression <05NAT73>. The crystal structure of the Stenotrophomonas maltophilia L1 enzyme in complex with the hydrolysis product of the 7α-methoxyoxacephem, moxalactam has been reported <05JA14439>. Ab initio quantum mechanical/molecular mechanical (QM/MM) calculations, augmented by extensive molecular dynamics simulations, describing the serine acylation mechanism for the class A TEM-1 β-lactamase with penicillanic acid as substrate have been reported <05JA15397>. The complete mechanism of acylation with benzylpenicillin, using a combined quantum mechanical and molecular mechanical (QM/MM) method (B3LYP/6-31G+(d)//AM1-CHARMM22) has been modelled <05JA4454>. Structure-activity correlations have been deduced in an investigation of the hydrolytic cleavage of penicillin G mediated by different dinuclear zinc complexes <05CEJ5343>. The mechanism of action of C6-(N1-methyl-1,2,3-triazolylmethylene)penem 40 toward class C β-lactamases has been investigated and the crystal structure of Enterobacter cloacae 908R β-lactamase complexed with 40 has been reported <05JA3262>. Hybrid QM/MM molecular dynamics simulation and density functional theoretical (DFT) calculations of the dizinc metallo-β-lactamase CcrA from Bacteroides fragilis in a complex with the cephalosporin nitrocefin showed that the substrate β-lactam is directed towards the active site dizinc center through the interactions of aminocarbonyl and carboxylate with the two active site zinc ions and two conserved residues, Lys167 and Asn176 <05JA4232>. H2N
O
H N
S
OH O
Cl
NH
Me
N H
Me
O
N N O
N N N
S N
Me N N
S
O HO
38
N
N
O
S O
OH
CO2–
O
39
40
The 3-chloromethyl cephalosporin 41 has been used for the preparation of nitrocefin 42 via Finkelstein and Wittig reactions <05JOC367>. The bicyclic β-lactam 43, a simple C3 homologue of sulbactam, has been prepared and evaluated as an improved inhibitor of class C β-lactamases <05JOC4510>. H N
S O
S N
i–iii Cl
O
H N
S O
S
NO2
N
N
O O
OPMB 41
O
O
S
O O
OPMB
NO2
CH2CO2H 43
42
Key: i) (a) NaI; (b) PPh3. ii) KOSiMe3, 2,4-dinitrobenzaldehyde. iii) (a) TFA; (b) DMSO.
114
B. Alcaide and P. Almendros
The acid-base properties of cephalosporins, such as cefalotin, cefazoline, and cefalexin, have been studied <05RJGC1513>. Vancomycin-cephalosporin hybrids have been achieved using chemoenzymatic strategies <05OL1513>. A practical synthesis for the largescale production of the new carbapenem antibiotic ertapenem sodium has been developed <05JOC7479>. The new iminosugars 1-oxabicyclic β-lactam disaccharides have been synthesized as inhibitors of elongating α-D-mannosyl phosphate transferase <05OBC1043>. A new approach to the synthesis of tazobactam 44, which belongs to a class of penicillanic acid sulfones, has been achieved using an organosilver compound <05S442>. 6Aminopenicillanates have been N-acylated via a domino addition–Wittig alkenylation sequence to give the corresponding 6-(E-2′-alkenoyl)amides 45 <05TL1127>. The intramolecular nitrone-alkene cycloaddition reaction using 2-azetidinone-tethered alkenylaldehydes as starting materials has been introduced as an efficient route to prepare bridged tricyclic β-lactams 46 <05EJO1680>. Bicyclic aza-β-lactam intermediates have been postulated on the ring expansion of pyroglutamates <05OL1117>. O
O S
N
N N
H 2N
N O
S N
O
CO2H
Me
i
H N
R2
N
O
Me CO2R1
S
O
44
Me Me CO2R1
N O
45 (50–77%) 2
R3 N
R2O H H
46
O ( )n
n = 1–3
o
Key: i) Ph3P=C=C=O, R CHO, THF, 60 C. Different-sized fused bicyclic β-lactams of non-conventional structure such as 47, have been obtained from 4-oxoazetidine-2-carbaldehydes through a novel carbonyl– bromoallylation/Heck reaction sequence <05JOC2713>. Six-, seven-, or eight-membered bicyclic 2-azetidinones have been prepared through triphenyltin hydride-promoted intramolecular free radical cyclization of β-lactam-tethered bromodienes <05S2335>. The reaction of 4-acetoxy-2-azetidinones with organoindium reagents generates 4-(1-substituted allenyl)-2-azetidinone derivatives, which have been cyclized to the corresponding bicyclic βlactams by Au(III) catalysis <05AG(E)1840>. o-Halogenophenyl- and o-halogenobenzyl-4alkenyl-β-lactams have been used for the regio- and stereoselective preparation of benzofused tricyclic β-lactams 48, including benzocarbapenems and benzocarbacephems, via intramolecular aryl radical cyclization <05T2767>. 2-Azetidinone-tethered haloarenes have proved to be appropriate substrates for the synthesis of fused or not fused β-lactam-biaryl hybrids by aryl-aryl radical cyclization and/or rearrangement <05T7894>. The microwaveinduced Staudinger reaction between ketenes generated from α-diazoketones and cyclic imines has been shown as a suitable method for the synthesis of polycyclic β-lactams <05JOC334>. Synthetic and computational studies on intramolecular [2+2] sulfonyl isocyanate-olefin cycloadditions to yield bicyclic β-lactam-sulfonamide hybrids has been documented <05T5615>. H H R O
CHO
N PMP
OAc H
R i O
N PMP
47 (60–65%)
R
R3
2 1R H
R
2 1R H
R3
ii N O
N
( )n
O X
( )n
48 (30–70%)
(n = 0, 1; X = Br, I)
Key: i) (a) 2,3-Dibromopropene, Sn, BiCl3, THF–H2O, RT; (b) Ac2O, RT, CH2Cl2; (c) Pd(OAc)2, PPh3, K2CO3, DMF, Δ. ii) Bu3SnH, AIBN, C6H6, reflux.
115
Four-membered ring systems
4.5 OXETANES, LACTONES)
DIOXETANES,
OXETES
AND
2-OXETANONES
(β-
The first fullerene-based slow-release system of paclitaxel for liposome aerosol delivery to the lungs have been synthesized <05JA12508>. A series of C-3’-cyclopropanated taxols has been synthesized and assayed for microtubule stabilization and cytotoxicity against two cell lines <05EJO3962>. A new family of 14β-amino taxanes, the study of antitumor in vitro and in vivo activity of which is underway, has been prepared <05T7727>. The key step in the synthesis of a C,D-seco-paclitaxel derivative has been a free radical fragmentation of an oxetane-taxine alcohol <05TL5049>. The enantioselective synthesis of the taxol CD ring unit, a fused bicyclic oxetane, has been achieved starting from an enantiopure building block, the enantiomer of those previously utilized in the synthesis of the A ring unit <05JOC3484>. A facile one-pot synthesis of 7-triethylsilylbaccatin III has been accomplished <05SL817>. A second-generation, highly abbreviated route for elaboration of the oxetane D-ring in a fully functionalized taxane has been achieved <05JOC732>. An investigation of the photoactivated cationic ring-opening frontal polymerization of a series of 3,3-disubstituted oxetanes has been carried out with the aid of a novel technique, optical pyrometry <05MI12109>. Atom transfer radical polymerization of 3-ethyl-3-(acryloyloxy)methyloxetane has been carried out <05MM3596>. An oxiranyl ether has been transformed into enantiopure oxetane 49 by a base promoted rearrangement process <05TA3841>. The addition of suitably protected pentaerythritols to polymer supported sulfonyl chloride with subsequent alkoxide formation and intramolecular cyclization to generate oxetanes has been described <05TL643>. Stereodifferentiation in the photochemical cycloreversion of diastereomeric methoxynaphthalene-oxetane dyads has been observed <05JOC1376>. A novel synthesis of pyrimidine furanosyl nucleosides such as 50 <05SL1683>, as well as a practical large scale synthesis of suitably protected 1’,2’-oxetane locked purine and pyrimidine nucleosides for incorporation in oligo-DNA or -RNA by solid-phase synthesis <05OBC4362> have been reported. The fluoride-mediated intramolecular cyclization reaction of enol triflates has been used for the synthesis of fused bicyclic oxetanes 51 <05TL1169>. O H
O H
i Bn2N
Bn2N
OBn
N
O Ph OH
HO
N
O
H O
TfO
OTBS R
O ii
R H H
HO O
49 (47%)
51 (91–92%)
50
Key: i) LDA, t-BuOK, THF, –75 oC. ii) TBAF, THF, RT. A model compound containing a thymine oxetane moiety linked to a flavin chromophore has been investigated regarding (6-4)-photolyase activity <05CC3430>. The origin of a large temperature dependence of regioselectivity observed for [2+2] photocycloaddition (Paternò-Büchi reaction) of 1,3-dimethylthymine with benzophenone and its derivatives to afford isomers 52 and 53 has been studied <05JOC2522>. A six-step approach to the tetracyclic core of merrilactone A, that uses an intramolecular Paternò-Büchi photoaddition to install the key oxetane ring has been described <05OL3969>. The reaction between glycosyl iodide donors and oxetane has been mentioned as a useful strategy for the formation of β-glycosides <05TL6727>. The addition of methyl substituents to the oxetane precursor for the conversion of a carboxylic acid in a commonly used [2.2.2]-bicyclic orthoester, significantly increased the ease of orthoester formation and its resistance to hydrolysis <05OL499>. Ketone enolate opening of oxetanes followed by oxidative cleavage
116
B. Alcaide and P. Almendros
provides an access to medium-sized lactones <05OL4301>. The 5-exo openings of oxetanes by hydroperoxides proceed rapidly and stereospecifically to furnish 1,2-dioxolanes 54 <05OL4333>. O Me O
O Me
N N Me
i
Me O
N
O
Me
Me
O N H Ar Me
Ar
+ O
52
Me Ar
N
R1 O
Ar N H Me
ii
C6H13
O
1 MeO O O R OH
C6H13 R2
R2 54 (72–77%)
53
Key: i) hν, Ar2C=O, from –40 to 70 oC. ii) O3, MeOH, CH2Cl2, –78 oC. A bicyclic oxete intermediate has been postulated in the intramolecular AgSbF6mediated alkyne-carbonyl metathesis <05OL2493>. It has been reported that the [2+2] cycloaddition reaction of 1-acetylisatin with alkynes gives spirooxetes 55, which upon spontaneous ring opening gave the corresponding α,β-unsaturated aldehydes <05JOC3850>. A series of new dioxetanes derived from bisphenol A has been synthesized by photopolymerization <05MI1697>. Recent developments of dioxetane-based chemiluminescent substrates have been reviewed from the viewpoint of relationships between the structure of dioxetanes and the properties of chemiluminescence <05BCJ1899>. Baseinduced decomposition of bicyclic dioxetanes bearing a 3-aminophenyl or 2-phenylindol-6-yl moiety with accompanying emission of light has been reported <05CL718>. Dioxetanes 56 bearing a phenyl moiety substituted with a methylene or methine having an electronwithdrawing group have been synthesized <05T9569>. Bicyclic dioxetanes bearing a 4(benzothiazol-2-yl)-3-hydroxyphenyl or 4-(benzoxazol-2-yl)-3-hydroxyphenyl group were synthesized. These dioxetanes underwent base-induced decomposition with accompanying emission of light with high efficiency in NaOH/H2O as well as in tetrabutylammonium fluoride (TBAF)/acetonitrile. Base-induced decomposition of dioxetanes bearing a 3hydroxyphenyl moiety substituted with a proton-donating group at the 4-position has been observed <05TL4871>. The chemiluminescence profile for base-induced decomposition, in aprotic and in aqueous media, of bicyclic dioxetanes bearing a 4-(benzoazol-2-yl)-3hydroxyphenyl moiety has been studied <05TL6075>. It has been reported that photocatalytic oxygenation of tetraphenylethylene with oxygen occurs efficiently via electron-transfer reactions to produce selectively a 1,2-dioxetane, which may suffer a photocatalytic cleavage of the O–O bond to afford benzophenone <05OL4265>. Singlet oxygen, from the reaction of superoxide with hydrogen peroxide, has been trapped in the form of a stable dioxetane and its chemiluminescence has been quantified <05JA8954>. Mechanistic insights in charge-transfer-induced luminescence of 1,2-dioxetanones 57 with a substituent of low oxidation potential has been investigated <05JA8667>. A synthesis of multisubstituted vinylsilanes has been achieved from β-silyl-β-lactones 58 <05CC2477>. The Kulinkovich protocol has permitted access to a cyclopropyl diol starting from βbutyrolactone <05OL516>. Enantiocontrolled synthesis of α-methyl amino acids via the organocuprate opening of Bn2N-α-methylserine-β-lactone has been described <05OL255>. R1 O
R2
O O
t-Bu
O N Ac 55
Key: i) O2, PPh3, hυ.
R3 O
i
O O
Me
R3
t-Bu 56
O
O
R4
O
57
Bn
O 58
SiMe3
117
Four-membered ring systems
The total synthesis of amphidinolide P has been accomplished using a β-lactone precursor <05JA17921>. A simplified synthesis of (R)-(–)-muscone using a ring-opening reaction of (R)-(+)-β-methyl-β-propiolactone has been achieved <05TA3176>. Salinosporamide B, a new cytotoxic bicyclic lactone has been isolated from a marine actinomycete <05JOC6196>. The total synthesis of salinosporamide A 59 has been accomplished <05JA8298>. An efficient, stereocontrolled synthesis of a potent omuralidesalinosporin hybrid for selective proteasome inhibition has been reported <05JA8974>. A new synthetic route for the enantioselective total synthesis of salinosporamide A and biologically active analogues <05OL2699>, as well as a simple enantiospecific syntheses of the C(2)-diastereomers of omuralide and 3-methylomuralide have been described <05OL2703>. The utility of the ammonia-free Birch reduction of electron-deficient pyrroles for the total synthesis of the 20S proteasome inhibitor, clasto-lactacystin β-lactone has been demonstrated <05CEJ4227>. An expeditious synthesis of nocardiolactone, a simple monocyclic β-lactone, has been accomplished <05SL1477>. The synthesis, structure, and reactivity of unexpectedly stable spiroepoxy-β-lactones 60 obtained by epoxidation of 4alkylidene-2-oxetanones have been reported <05JA16754>. Bis-diazoacetates have been transformed into spiro-β-lactones by chiral dirhodium(II) carboxamidates <05OL5035>. The synthesis and enzymatic resolution of tropic acid lactone have been achieved <05TA3892>. A two-step synthesis of optically active 3-amino-3-alkyl-2-oxetanones that involves cyclization of N-Boc-α-alkylserines under Mitsunobu reaction conditions has been reported <05TL6239>. The PdCl2-catalyzed cyclocarbonylation of 2-alkynols with CuCl2 has been demonstrated as a mild and efficient methodology for the regio- and stereoselective synthesis of (Z)-α-chloroalkylidene-β-lactones 61 <05JOC2568>. Chromium(III) octaethylporphyrinato tetracarbonylcobaltate has been proved to be a highly active, selective, and versatile catalyst for the carbonylation of epoxides to β-lactones <05JA11426>. Acid chlorides and aromatic aldehydes react in the presence of a stoichiometric amount of a tertiary amine and catalytic amounts of a cinchona alkaloid derivative and a Lewis acid to produce β-lactones with high diastereo- and enantioselectivity <05OL1809>. β-Hydroxy acids can readily be converted into β-tosyloxy acids (hydroxyl group activation) in moderate to excellent yields via the O,O-dianions generated by treatment with methyllithium, thus making it possible to prepare anti α,β-disubstituted β-lactones directly from the syn aldols <05CC1906>. The preparation of α,α,β-trisubstituted β-lactones has opened the way to living anionic ring-opening polymerization of these monomers <05MI25>. A bicyclic βlactone intermediate has been postulated during the iodolactonization of a 3,4-disubstituted 2,5-dihydrofuran <05TL4859>. Cyclobutene fused β-lactone species have been proposed in the photolysis reactions of 4-acyloxy-2-pyrones <05T8059>. Improved efficiency and expanded scope for the asymmetric synthesis of bicyclic β-lactones via the intramolecular, nucleophile-catalyzed aldol lactonization have been reported just by the use of pyridinium salts different to the original Mukaiyama reagent <05JOC2835>. Cl
R1 O
R
59
H O OH
i
R
O
R O O
O
NH O
R
O 60 (40–80%)
R1
OH R2 R3
X
R2 R3
ii O O
61 (52–91%)
Key: i) dimethyldioxirane, MgSO4, CH2Cl2, RT. ii) 10 mol% PdCl2, 5 equiv. CuCl2, CO (20 atm), THF, 30 oC. X = Cl, Br.
118 4.6
B. Alcaide and P. Almendros
THIETANES, β-SULTAMS, AND RELATED SYSTEMS
A novel one-step synthetic route for the construction of fully substituted pyrazol-4-ols by the condensation-fragmentation-cyclization-extrusion reactions of thietanone 62 with 1,2,4,5-tetrazines has been reported <05JOC8468>. 4-Hydroxy-5,5-dimethylimidazolines tethered at N1 to an aryl sulfide undergo an unprecedented acid-catalyzed domino reaction, involving double methyl transposition, heterocyclization, isomerization of thiazetidinium ions 63 and, finally, π-cyclization <05OBC3937>. Two flavin-containing oxetane and thietane model compounds for the (6–4) photolyase catalyzed repair process have been prepared and it was shown that both are efficiently cleaved by a reduced and deprotonated flavin. A flavincontaining thietane model compound 64 for the (6–4) photolyase catalyzed repair process has been prepared <05OBC1937>.
O
R1 N
Ph
O HN
O
N
S
O
O HN
i N
Ar
62
Ph
N
O
S
S Ph
O
t-BuOOC 63
R2
NH
64 (27%, R2 = flavin)
Key: i) (a) thiobenzophenone, hυ, MeCN, RT; (b) TFA, RT; (c) R2CH2NH2, HOBt, TBTU, Et3N, DMF, RT. The asymmetric synthesis of cis-3,4-disubstituted β-sultams 65, based on the oxidation of 1,2-aminothiols with H2O2 and ammonium heptamolybdate has been achieved <05S1807>. Different transition-state structures for the reactions of β-lactams and their sulfonyl analogues β-sultams with serine β-lactamases have been reported <05JA17556>. It has been discovered that the 3-oxo-β-sultam 66 is unusual in that it inhibits elastase by acylation resulting from substitution at the carbonyl center, C–N fission, and expulsion of the sulfonamide <05JA8946>. R1
NHMoc R1
R2 SBn
i
O
HOEnz O
R2 O
S N
O
H
65 (17–59%)
C–N fission S N Ph
O
H2O
CO2H O O
S
NHCH2Ph
66
o
Key: i) (a) Li/NH3, –33 C; (b) H2O2, (NH4)6Mo7O21, MeOH, RT; (c) NaOAc, CH2Cl2, RT; (d) COCl2, DMF, RT; (e) HBr–AcOH, CH2Cl2, RT; (f) Et3N, 0 oC. 4.7
SILICON AND PHOSPHORUS HETEROCYCLES. MISCELLANEOUS
It has been reported that from the perspective of ring strain, 1,2-dimetalacyclobutanes and 1,3-dimetallabicyclo[1.1.1]pentanes in which the bridgeheads and bridges are composed of different Group 14 elements (Si, Ge, Sn) are realistic synthetic targets <05CEJ5067>. The treatment of cyclotetrasilene 67, the structure of which was elucidated by X-ray crystallographic analysis, with excess iodine leads to the loss of one Sit-Bu3I molecule to afford a cyclotetrasilane <05AG(E)7884>. Irradiation of a solution of anti-
119
Four-membered ring systems
dodecaisopropyltricyclo[4.2.0.02,5]octasilane in the presence of C60 and CS2 has resulted in the formation of the adduct 68, bearing a dithiadisilolane fused cyclotetrasilane moiety <05AG(E)7567>. It has been reported that the reduction of 1,1-dichlorocyclotetrasilane with lithium metal gave the first fused bicyclic disilene <05JA15376>. Experimental results have demonstrated that the conversion of zirconacyclobutene–silacyclobutene derivatives 69 into zirconacyclohexadiene–silacyclobutenes 70 occurs through a novel cleavage of a C–C bond in the zirconacyclobutene skeleton and a C–Si bond in the silacyclobutene skeleton <05CEJ1895>. t-Bu3Si
Si
Si
I Si t-Bu3Si
Sit-Bu3
Si I Sit-Bu3
C60
67
Ph Sit-Bu3 S Si Si Sit-Bu 3 S Si Si Sit-Bu3 Ph Sit-Bu3 68
Ph Ph SiMe2 Cp2Zr
Ph
R2
i R1
R2
69
R1
SiMe2 Zr Cp2
Ph
70 (66–90%) o
Key: i) (a) 50 C, 1 h; (b) THF, reflux, 6 h. An eight-membered heterocycle has been obtained through the dimerization of an oxasiletane <05CEJ2954>. Siletanylmethylstannane 71 has been synthesized and characterized <05CC3047>. The tetrasilacyclobutadiene (tBu2MeSi)4Si4 has been used as a new ligand for transition-metal complexes <05JA5768>. It has been shown that the parasiletanylbenzyl ether is a peroxide-cleavable protecting group for alcohols and phenols <05TL3283>. 1,2-Oxaphosphetanes 72 bearing three phenyl groups directly bound to the phosphorus atom have successfully been isolated for the first time as stable crystals in a typical Wittig reaction of cyclopropylidenetriphenylphosphorane with activated carbonyl compounds <05TL8949>. Calculations of the phosphorus NMR chemical shielding of some oxaphosphetanes have been carried out <05T12343>. Ab initio and density functional investigations on the deoxygenation of a cis-2,3-dimethylepoxide by PPh3, has revealed a mechanism involving oxaphosphetane formation thereby ruling out the formation of a betaine intermediate <05TL4087>. Copper-mediated homocoupling of sterically hindered 2-(2,4,6tri-tert-butylphenyl)-1-trialkylsilyl-2-phosphaethenyllithiums has afforded 1,2bis(trialkylsilyl)-3,4-diphosphacyclobutenes (1,2-dihydrodiphosphetenes) 73 through a formal electrocyclic [2+2] cyclization in the P=C–C=P skeleton <05JOC3537>. Calculations on two parent P4H2 cyclic isomers has revealed that the tetraphosphacyclobutene isomer is 10.7 kcal mol–1 less stable than the tetraphosphabicyclobutane isomer <05AG(E)7729>. The protonation of the diradicaloid heterocycle 1,3-diphosphacyclobutane-2,4-diyl with trifluoromethanesulfonic acid resulted in the cyclic bis(phosphanyl)carbenium ion 74 <05AG(E)1405>. Imidazoline-functionalized diphosphane manganese complexes have been obtained <05AG(E)102>. Non-stoichiometry induced by differential oxygen/lone pair occupation in chiral bicyclic 1,1 -binaphthoxy cyclodiphosphazanes has been described <05CC5396>. A new synthesis of the [1,3,2,4]diselenadiphosphetane (Woollins Reagent) 75, and its use in the synthesis of novel P–Se heterocycles, including a spirocyclic heterocycle exhibiting a four-membered P2SeC ring have been reported <05CEJ6221>. It has been reported that W(CO)5-complexed 2-phosphabicyclo[1.1.0]butanes valence-isomerized to 3phosphacyclobutenes via 1-phosphabutadienes at elevated temperatures <05AG(E)6580>.
Si
SnBu3 71
Ph Ph P Ph O
Mes p-C6H4X
MeO
O 72
P P Mes 73
SiMe2R
Me3Si
SiMe2R
Mes
Mes P
P + TfO– 74
Mes = 2,4,6-t-Bu3C6H2
Se Se P Ph Ph P Se Se 75
120
B. Alcaide and P. Almendros
The dimerization of a cyclo-1σ4,3 σ2,4 σ2-triphosphapentadienyl radical and the evidence for phosphorus–phosphorus odd-electron bonds have been communicated <05AG(E)5497>. A review on the reactions and applications of titanium imido complexes including four-membered heterocycles has appeared <05ACR839>. A review on hypervalent iodine chemistry, including the use of 1,2-iodoxetane-1-oxide, has been published <05AG(E)3656>. The chromium- and manganese-salen promoted epoxidation of alkenes including the viability of metallaoxetane intermediates has been reviewed <05CRV1594>. A review on group-selective ring-closing enyne metathesis including metallacyclobutene intermediates deserves to be mentioned as well <05CEJ6118>. The structure of the dinuclear compound 76 has been determined by X-ray analysis <05JA14369>. The new fourmembered-ring compounds, trans -2,4-dichloro-1,1,2,4-tetrakis(di-tert butylmethylsilyl)[1,2,4]metalladigermetanes 77 and 78 have been obtained through the ring expansion of cyclic digermenes <05AG(E)6378>. The X-ray diffraction analysis of an auraoxetane has been accomplished <05AG(E)6892>. The reactivity of rhodium-triflate fourmembered rings with diphenylsilane has been studied <05CEJ2983>. Formation of oxatitanacyclobutane 79 and its metathesis type degradation have been documented <05OBC2914>. The reaction of a stable aluminacyclopropene with aromatic azides has resulted in an end-on azide insertion to yield aluminaazacyclobutenes 80 <05AG(E)5090>. The in-plane bishomoaromaticity in tetranitrogen dianions has been studied <05AG(E)2433>. The mechanisms of the rearrangements and stereoinversion of azametallacyclobutenes 81 generated via [2+2] cycloaddition of allenes and imidozirconium complexes have been studied <05JA1752>. The structures of two different four-membered heterocycles containing yttrium have been determined by X-ray analysis <05JA16788, 05CC5922>. A unified orbital model of delocalized and localized currents in monocycles, from annulenes to azaboraheterocycles such as 82 has been reported <05CEJ1257>. The structures of derivatives of the simplest polyhedral carborane anion has been estimated to be at the borderline between twoand three-dimensional aromatic compounds <05AG(E)1643>. Structural and spectroscopic demonstrations of agostic C–C interactions in electron-deficient metallacyclobutanes have been reported <05JA16426>. A bicyclic metallacyclobutene intermediate has been postulated during the cyclopolymerization of dimethyl dipropargylmalonate catalyzed by MoCl5 <05CC5208>. The synthesis of dimeric palladacycles has been achieved <05EJO4277>. The molecular estructure of an essentially planar NaOZnN ring has been determined <05JA13106>. The X-ray diffraction analysis of a Ti=N–Ti=N four-membered heterocyclic ring system has been published <05JA12796>. Ru S S Mo O S 76
R Cl R M Ge R Cl Ge R 77 (M = Si), 78 (M = Ge) Re = SiMe-t-Bu2
4.8
R Cp2Ti O R1 R2
R3 Ar 79
R Al N
R4 N N
R
ZrCp2 N Ar 81
H
H N B B N
H
H 82
80
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Chapter 5.1
Five-membered ring systems: thiophenes and Se/Te analogues Tomasz Janosik and Jan Bergman Department of Biosciences and Nutrition, Karolinska Institute, Novum Research Park, SE141 57 Huddinge, Sweden, and Södertörn University College, SE-141 04 Huddinge, Sweden
[email protected] (T. J.),
[email protected] (J. B.)
5.1.1 INTRODUCTION The objective of this chapter is to highlight the developments in thiophene-, selenophene-, and tellurophene chemistry, reported during the period of January to December 2005, with particular emphasis on ring synthesis and reactivity. Since many of the current advances in this field focus on thiophene containing oligomeric or polymeric organic materials for various applications, sections devoted to these types of structures are included, along with a selection of the recent developments in the design of thiophene based, biologically active molecules. Several specialized review articles of interest have appeared during the reporting period of this chapter, for instance summarizing the recent achievements in the area of fused thiophene containing systems, namely thienothiophenes <05RCR217>, and dithienothiophenes <05T11055>. The synthesis and reactivity of thioaurones has also been summarized <05H(65)451>. A survey of the regioselective cross-coupling reactions of multiply halogenated thiophenes has been included in a more general review covering similar transformations of numerous other heterocyclic systems <05T2245>. The recent advances in research on thiophene based materials <05AM1581>, as well as the developments in the field of light-emitting polythiophenes <05AM2281>, have also been covered. In addition, some aspects of photochromic polymers based on dithienylethenes have been discussed <05EJO1233>. 5.1.2 THIOPHENE RING SYNTHESIS A variety of new thiophene ring syntheses, including useful new variants of some wellestablished methods have appeared during the year 2005. For example, a microwave-assisted variant of the Gewald thiophene synthesis allows preparation of a series of 2-aminothiophene3-carboxylic acid derivatives 1 under solvent free conditions in good to excellent yields from the acyclic (R1 = Me, R2 = COMe or CO2Et) or cyclic [R1/R2 = –(CH2)3– or –(CH2)4–] ketones 2, cyanoacetic acid derivatives 3 (R3 = OMe, OEt, NH2, NHPh, and derivatives thereof) and elemental sulfur <05SC1351>. A fully substituted 2-aminothiophene has also
127
Five-membered ring systems: thiophenes and Se/Te analogues
been prepared by bromination of 2-phenyl-1,1,3-tricyanopropene with NBS, and subsequent treatment of the resulting intermediate with NaSH <05SC2251>.
R2
R1
NC
O
R1
51-95%
O
2
R2
S8, morpholine, Al2O3 MW, 160 W, 10 min
R3
COR3 S
NH2
1
3
A number of densely substituted 3-aminothiophene derivatives, including several fused systems, have been obtained by cyclization reactions of suitable acrylonitriles or similar precursors with ethyl mercaptopyruvate in the presence of a base, as illustrated by the conversion of the pyridine-1-oxide 4 into the pyridothiophene 5 <05JHC661>. Similar annulations involving 2-amino-4,6-dichloropyrimidine-5-carboxaldehyde and methyl mercaptoacetate leading to thieno[2,3-d]pyrimidine derivatives have also been reported <05JHC1305>. CN Cl
HSCOCO2Et Et3N, EtOH rt, overnight
Cl
76%
N O
Cl
NH2 CO2Et
O
N
S
O
5
4
It has been demonstrated that vinamidinium salts, which have previously been used for the construction of pyrroles, may also serve as useful starting materials for the synthesis of 2,4disubstituted thiophenes. Thus, heating of the salts 6 with methyl mercaptoacetate 7 in DMF afforded useful yields of the thiophenes 8 <05TL1319>. R
R O
ClO4 MeO Me2N
DMF, reflux
SH
56-87%
NMe2 6
7
S
CO2Me
8
A potentially useful one-pot procedure for the conversion of suitable aryl thiols to benzo[b]thiophenes or napththo[2,1-b]thiophenes in the presence of silica supported acidic and basic reagents has been devised, as exemplified by the synthesis of the system 9 from 2naphthalenethiol 10 <05SL2739>. A stepwise variant of the same theme has been employed in a synthesis of 6-bromo-1,2,3,4-tetrahydrodibenzothiophene, a partner for a Suzuki coupling leading to a chromene-4-one containing inhibitor of DNA-dependent protein kinase <05JMC7829>.
128
T. Janosik and J. Bergman O SH
Cl
Na2CO3/SiO2, PPA/SiO2 PhCl, 135 °C, 6 h 87%
S
10
9
Treatment of suitable 1,4-diketones or their equivalents with Lawesson’s reagent is a useful route to thiophene derivatives, which has been utilized in the conversion of the lactones 11 into the benzo[c]thiophenes 12. The substrates 11 are available for instance by halogen– metal exchange in 2-bromobenzoic acid, followed by introduction of Ar1CHO, and acidic work-up <05TL4225>. On the other hand, cyclization of aryl-4-(2′-thienyl)-4oxobutanamides with Lawesson’s reagent in refluxing toluene has been shown to furnish mixtures of 1-aryl-2-(2′-thienyl)pyrroles and 5-anilino-2,2′-bithiophenes, except in a few cases, where exclusive formation of pyrrole products was observed <05S199>. A microwave assisted approach to thiophenes based on cyclization of 1,4-diketones with Lawesson’s reagent has also been described <05EJO5277>. In a related approach starting from a precursor containing all the necessary carbon atoms, nucleophilic displacement of the halogen atoms in 3,4-bis(bromomethyl)-1,6-methano[10]annulene with Na2S, and subsequent dehydrogenation of the resulting ring system, provided access to the structurally interesting 1,6methano[10]annuleno[3,4-c]thiophene <05TL7311>. 1. Ar2MgBr, THF 2. NH4Cl (aq.) 3. Lawesson's reagent (1/2 equiv.)
Ar1
O
O
40-66%
11
Ar1
S
Ar2
12
Various diynes, as well as acetylenes, have also been utilized as precursors to thiophene derivatives. In one example illustrating a ruthenium-catalyzed cyclization of a series of sulfones into 3,4-disubstituted 2,5-dihydrothiophene-1,1-dioxides, the starting material 13 could be converted to the product 14 in good yield <05OL2097>. A mechanistic study of base-catalyzed cyclizations of some related dipropargyl sulfone precursors into thiophenes has led to the identification of allene intermediates <05JOC10166>. Iodocyclization of 2-(1alkynyl)thioanisole derivatives has been applied to the syntheses of benzo[b]thiophenes <05JOC9985>, and extended thieno-fused benzo[b]thiophene systems <05TL8153>. Treatment of a diazo-containing diacetylene precursor with Na2S·9H2O provided a mild synthetic route to a bis(diazo) compound incorporating a central thiophene unit in connection with the investigation of its photoproducts <05OBC431>. O [CpRu(CH3CN)3]PF6 (10 mol%) aq. acetone, 60 °C
O S O
76%
13
S O O 14
129
Five-membered ring systems: thiophenes and Se/Te analogues
Addition of SO2 to the allenes 15 has been demonstrated to give the thiophene derivatives 16. The regio- and stereoselectivity of these reactions was corroborated by a computational study <05OL1565>. The formation of tetrahydrothiophene 1,1-dioxides has also been observed during radical annulations using SO2 as a radical acceptor/donor <05JOC10854>. OR3
R 3O
Me R2
Me
SO2, hexanes
•
S
80-81%
H
R2
R1
O O
R1
15
16
An exclusive formation of the trans-product 17, an intermediate in a synthesis of (+)biotin, was unexpectedly observed during radical cyclization of the precursor 18. This outcome was rationalized in terms of steric interference between the TBS-ether and the adjacent N-benzyl group in the intermediate radical species 19 <05T9273>. O
O Bn N
Bu3SnH, AIBN, PhH reflux, 4 h
N Bn
Bn N
O Bn N
N Bn
SPh S
N Bn OTBS
53%
S
OTBS 18
S
OTBS
17
19
Addition of electron deficient alkenes, such as tetracyanoethylene to the dipole 20, generated by addition of diazomethane to methyl [(dialkoxy)phosphinyl]dithioformates, gave the tetrahydrothiophene 21 in good yield. The application of cyclic dipolarophiles, such as maleic anhydride or N-phenylmaleimide in similar cycloadditions, provided access to the corresponding fused tetrahydrothiophene systems <05HCA2582>. SMe (Oi-Pr)2P O
S
NC
CN
NC
CN
THF, Et2O, -65 °C to rt 75%
20
NC CN NC CN MeS S (Oi-Pr)2P O 21
Conversion of the precursor 22 by initial cleavage of the xanthate unit, and subsequent acid-induced cyclization provided a route to the dihydrothiophene 23. Similar cyclization of substrates where the pivaloyl group was replaced with TBDPS or acetyl groups gave considerably lower yields of the corresponding dihydrothiophenes <05TL8053>. OMe 1. ethylenediamine, EtOH, rt, 1 h
MeO MeO2C
S 22
OEt S
OPiv 2. TFA, CH2Cl2, rt, 1 h 89%
MeO2C OPiv S 23
130
T. Janosik and J. Bergman
In an approach relying on directed metalation, exposure of the functionalized benzamides 24 to LDA, and subsequent reactions of the resulting intermediates with aldehydes, provided the thioaurones 25 in good yields <05T9007>. An alternative thioaurone synthesis has been accomplished by treatment of 4-acetyl-2-oxo-benz[1,3]oxathiole derivatives with aldehydes in the presence of piperidine acetate in DMSO <05T8648>. R1 CONEt2
1. LDA (2.1 equiv.), THF, -10 to 0 °C, 1 h 2. R2CHO, 0 °C, 2 h 3. 2 N HCl 75-92%
SMe 24
R1
O
R2
S
R1 = H, OMe, SMe R2 = Ph, 2-thienyl, 4-ClC6H4, CH=CHPh
25
Other miscellaneous cyclization reactions leading to interesting thiophene derivatives include a thermal conversion of a 2,2′-bis(N,N-dimethylthiocarbamoyloxy)-1,1′-binaphthyl into a dinaphtho[2,1-b:1′,2′-d]thiophene (a heterohelicene) <05S1109>, solution-phase parallel synthesis of a 1140-member ureidothiophene carboxylic acid library <05JCC253>, and an unexpected cyclization occurring upon metalation of diphenylsulfone, followed by introduction of (–)-fenchone and subsequent aqueous workup <05T10449>. Heating of the 1,3-dithiole 26 with dimethyl acetylenedicarboxylate (DMAD) was demonstrated to give a 1:1 mixture of the isomeric fused thiophenes 27 and 28, resulting from a cycloaddition reaction, followed by a rearrangement. A mechanistic rationale for this outcome was also suggested <05OL791>. CO2Me S Cl S
S Cl
CO2Me
S DMAD xylene, Δ 55%
CO2Me
S S
MeO2C
26
CO2Me 27
CO2Me
MeO2C MeO2C S
CO2Me S
CO2Me
S 28
5.1.3 REACTIONS OF THIOPHENES Metalation reactions are very useful tools for the synthetic manipulation of thiophenes, and have consequently been well studied and used extensively over the years. New applications emerge continuously, providing access to new derivatives, as well as further insight into these valuable processes. Thus for instance, a series of thiophenes 29 was selectively deprotonated at C-2 by exposure to lithium tributylmagnesate in the presence of TMEDA, giving good to excellent yields of the products 30 after subsequent quenching with suitable electrophiles (I2, 4-anisaldehyde, 3,4,5-trimethoxybenzaldehyde). It should be noted that TMEDA plays an important role in this reaction by enhancing the reactivity. The intermediate magnesates may also be subjected to palladium catalyzed couplings with aryl- or heteroaryl halides <05T4779>. It has also been demonstrated that chlorothiophenes may be converted to the corresponding thienylzinc chlorides using zinc in the presence of a cobalt catalyst <05SL2171>. A remarkable temperature effect was observed during metalation of 2bromothiophene followed by quenching with e.g. aldehydes, giving 5-alkylated 2bromothiophenes at –78 °C, whereas at room temperature, exclusive formation of 2,4-
131
Five-membered ring systems: thiophenes and Se/Te analogues
dibromo-5-alkylated products was noted, as a result of a halogen transfer/halogen dance process <05TL3315>. Various metalation reactions at C-2 of thiophenes, and subsequent quenching with silyl chlorides, have been employed as the key steps during construction of polymer-supported organosilicon reagents for solid-phase synthesis <05EJO3900>. Studies on the solution structure and chelation properties of 2-thienyllithium reagents derived from 3(N,N-dimethylaminomethyl)thiophene and 3-(methoxymethyl)thiophene have established that in THF–Et2O mixtures at low temperature, the amino derivative exists as a chelated dimer (99%), in contrast to the ether, which exhibited a considerably lower level of dimerization (< 10%) <05JOC7520>. Mechanistic aspects of iodine–lithium exchange in 2-iodo-5methylthiophene have also been studied <05CJC1577>. Lithiation of (R)dihydrobenzo[b]thiophene 1-oxide at C-2, followed by homo-coupling with CuCl2 gave a 1:1:1 mixure of three diastereomeric 2,2′-bi(benzo[b]thienyl) 1,1′-dioxides <05EJO552>. Lithiation methodology has also been applied to the synthesis of a helicene incorporating 11 fused thiophene rings <05JA13806>. 1. Bu3MgLi (1/3 equiv.) TMEDA, THF, rt, 2 h
R
S
2. electrophile, then H2O
R
S
60-96%
29
E
30
E = I, CH(OH)(4-MeOC6H4), CH(OH)[3,4,5-(MeO)3C6H2] R = H, Cl, OMe
An excellent example of the applicability of metalation reactions in the synthesis of fused thiophenes is the preparation of the pentacyclic system 31, which was obtained over several steps from the thienothiophene 32, via the intermediates 33 and 34 as outlined below <05JA10502>. The parent pentacyclic system of 31 has also been prepared using a similar sequence involving metalation reactions from a brominated thieno[3,2-b]thiophene, and was used for the construction of organic field effect transistors <05JA13281>. Halogen-lithium exchange reactions have also been employed for the synthesis of, for instance, 3,4thiophenedicarboxaldehyde, which served as a starting material for the construction of thieno[2,3-f:5,4-f′]bis[1]benzothiophene <05JOC4502>, and various thiophene- or benzo[b]thiophenesulfonyl chlorides, which was effected by treatment of the intermediate lithiated heterocycles with SO2, followed by N-chlorosuccinimide <05BMCL617, 05BMC3927>. 1. BuLi, THF
S
Br 2. TIPSCl
Br
S
3. LDA, THF
Br
68%
S
S
S S
34
95%
33
S S
(Bu3Sn)2S, Pd(PPh3)4 PhMe
S
32 TIPS
TIPS
TIPS
1. BuLi, THF 2. CuCl2 52%
TIPS
S
S S
S
TIPS
S 31
The halogen–metal exchange technique has also been used during preparation of the thiophene-based phosphaquinomethanes 35, which were obtained in excellent overall yields by lithiation of the precursor 36, followed by dehydration of the intermediate carbinols <05JA8926>.
132
T. Janosik and J. Bergman
t-Bu
1. t-BuLi 2. Ar2CO 3. CuSO4, PhH
t-Bu
t-Bu
P H
S
Br
P
t-Bu
Ar S t-Bu
Ar
85-90%
36
t-Bu
35
As evident from several examples outlined above, thiophenes metalated at C-2 are relatively stable synthetic intermediates, in contrast to C-3 metalated thiophenes, which may undergo ring opening or participate in halogen dance reactions. An unusual ring opening reaction, which does however not proceed via a halogen–metal exchange, occurs upon treatment of 2-fluoro-3-arylbenzo[b]thiophenes with organolithium reagents. This is demonstrated by a representative example below, wherein the substrate 37 underwent ringopening yielding the alkyne 38, resulting from an initial nucleophilic addition of butyllithium onto the sulfur atom rendering the organometallic intermediate 39, followed by formation of the carbene 40, and a final rearrangement involving migration of the aryl moiety <05SL247>. A carbenoid species, namely 2-benzo[b]thienylchlorocarbene, has also been generated and identified as an intermediate resulting from photolysis of a diazirine precursor, and was shown to rearrange to a 2,3-didehydro-2H-thiopyran derivative, an example of a highly strained cyclic allene <05OL4467>. Ph F
Ph
1. BuLi, THF -40 °C, 1 h
S
S Bu
37
Ph
Ph F
C
Li
S Bu
39
H+ 66%
SBu 38
40
It has been established that thiophenes undergo regiospecific oxidative cyanation at C-2 with TMSCN, as illustrated by the general transformation of 41 into 42 <05OL537>. Conversion of 3-bromobenzo[b]thiophene to benzo[b]thiophene-3-carbonitrile has been accomplished by treatment of the substrate with Zn(CN)2 in the presence of a catalytic system consisting of Pd/C, Zn dust, Br2, and PPh3 in N,N-dimethylacetamide <05TL1849>. R S 41
R
TMSCN, PhI(OCOCF3)2 BF3·OEt2, CH2Cl2, rt 42-79%
S
CN
R = Me, Ph, OMe n-hexyl, cyclohexyl
42
The latter reaction is an example of a number of transition metal-catalyzed reactions for the functionalization of thiophene derivatives which have been reported during 2005, for instance leading to various aminothiophene derivatives. Thus, practical conditions for the copper catalyzed amination of 3-bromothiophenes or 2-bromothiophenes 43 with a variety of different secondary amines (e.g. where R2R3NH = Et2NH, piperidine, morpholine, etc.) leading to the corresponding 3-amino- or 2-aminothiophene derivatives 44, respectively, have been established <05T903>. A study on the Buchwald–Hartwig amination of multiply substituted bromothiophenes with aniline derivatives using Cs2CO3 as the base demonstrated that good results can generally be obtained using electron-rich anilines, whereas reactions
133
Five-membered ring systems: thiophenes and Se/Te analogues
involving anilines possessing electron-withdrawing groups give lower yields and require higher catalyst loadings <05S2373>. Palladium-catalyzed amination of 3,3′-dibromo-2,2′bithiophene with alkylamines constitutes an improved synthesis of N-alkyl substituted dithieno[3,2-b:2′,3′-d]pyrroles <05T687>. In addition, thiophene-3-boronic acid has been shown to participate in a copper-catalyzed coupling with di-tert-butyl azodicarboxylate, giving 1,2-bis(tert-butoxycarbonyl)-1-(3-thienyl)hydrazine in excellent yield <05JOC8631>. R2R3NH, K3PO4·H2O Cu (5 mol%), CuI (5 mol%)
R1 S
Br
R1
N,N-dimethylethanolamine, 80 °C
43
NR2R3
S
31-81%
44
It has been shown that C–H bond activation in bromothiophenes may be readily achieved by palladium catalysis in the presence of the reagent combination AgNO3/KF, for instance as illustrated by the synthesis of the 2,2′-bithiophene 45 from 2-bromothiophene 46, providing access to a variety of brominated thiophene derivatives suitable for further functionalization <05OL5083>.
Br
PdCl2(PhCN)2 (3 mol%) AgNO3, KF, DMSO, rt
S
81%
S
S
Br
Br
46
45
Further recent applications of the classical palladium catalyzed reactions in thiophene functionalization encompass preparation of 2-(pentafluorophenyl)thiophenes from the corresponding 2-bromothiophenes under Suzuki conditions <05S1589>, Stille coupling of 5tributylstannyl-2-aminothiophene derivatives with mono- and dibromoarenes <05S610>, and double Suzuki coupling of a thiophene-2-boronic acid with N-phenyldiiodomaleimide <05T4585>. Coupling of bromothiophenes with butadiynylstannanes as the key step en route to indenothiophene systems has also been described <05TL1233>. In addition, selective cisaddition of 2-substituted thiophenes at C-5 to alkynes, catalyzed by a dinuclear palladium complex has been performed <05TL7515>. A series of thiophene based diphosphine ligands for asymmetric hydrogenation have been prepared by a sequence featuring a palladium catalyzed coupling of a thienylmagnesium bromide with a vinyl triflate <05TL7397>. Suzuki coupling of the diboronic acid ester 47 with two equivalents of the benzodithiophene 48 gave the (Z)-ethene 49 in good yield, which was further annulated to the tetrathia[7]helicene 50 by irradiation <05SL1137>. It should also be added that Suzuki, Stille and Kumada couplings are highly useful tools in the preparation of various thiophene-containing organic materials (Cf. sections 5.1.4 and 5.1.5). S
O B Bu
S
B O
O O
Pd(PPh3)4 (3 mol%) 2 M Na2CO3 PhMe, EtOH, 65 °C, then reflux 83%
S
S
S
S
hν, PhMe rt
S
S
70%
S
S
I Bu
Bu 48
47
49
50
134
T. Janosik and J. Bergman
Acccess to benzo[b]thiophenes substituted at C-3 by oxygen or nitrogen has been gained by nucleophilic displacement reactions, as illustrated by the synthesis of the 3-amino benzo[b]thiophene-1-oxides 51 (Z = O, CH2, NMe) from the bromide 52 and appropriate amines <05JOC3569>. Substitution with amines at the 5-position of 4,7dioxobenzo[b]thiophenes or their corresponding 5,6-dichloro derivatives has been used as a route to 5-arylamino-4,7-dioxobenzo[b]thiophenes with antifungal properties <05BMCL2617>. Z Br
N
Z
S
PhMe, 80 °C 85-94%
N H
O
S O
52
51
Several studies involving thiophene derivatives as partners in Diels–Alder reactions have appeared recently. It is well established that simple thiophenes do not participate in cycloaddition reactions, but may however be converted to useful 4π-components by Soxidation. This fact has been nicely exploited in, for example, the conversion of the thiophene 1-oxide 53 into system 54 <05TL4165>. Diels–Alder reactions have also been performed using thiophene 1,1-dioxides possessing electron-withdrawing groups (SO2Me) as dienophiles <05T10880>, and (E)-2-nitroethenylthiophenes, in which case the thiophene ring contributes with one double bond to the diene component, giving for instance naphtho[2,1-b]thiophene derivatives upon addition to benzoquinones <05JHC1149>. t-Bu
t-Bu S O
O
O t-Bu S
100 °C 87%
O
O
t-Bu
O 54
53
Oxidation of the 5-hydroxybenzo[b]thiophenes 55 with IBX gave the unstable intermediate o-quinones 56, which were not isolated, but subjected directly to Diels–Alder reactions with the dienes 57, producing the tricyclic systems 58 <05T9097>. Ar
HO
IBX, DMSO rt, 6 h
O
Ar
O
R
O
R
S 56
2. DDQ, PhH, reflux, 10 h 78-86%
Ar
O
NHAc 57
PhH, 45 °C, 16 h
S 55
1.
AcHN R
S R 58 R = Me, Et
In a different approach to fused benzo[b]thiophenes, taking advantage of the thermal decomposition of DMSO as a source of formaldehyde, the starting material 59 was converted to the product 60, along with minor amounts of the dehydrogenated system 61 by means of a modified Pictet–Spengler reaction <05TL2465>.
135
Five-membered ring systems: thiophenes and Se/Te analogues
NHAc
Cl
N Ac
Cl
DMSO, MW (140 W) reflux, 3 h
S
N
Cl
S
59
S
60 (62%)
61 (10%)
Other examples of preparative routes relying on reactions with electrophiles have been used in the syntheses of thieno[2,3-f][1,2,3,4,5]pentathiepin by treatment of tetrahydrothiophene with S2Cl2 in the presence of DABCO <05OBC3496>, and indium nonaflate [In(ONf)3] catalyzed annulation of the 2,2′-bithiophene 62 with methyl propargyl ether leading to the system 63 <05AG(E)1336>. Me Me Me
Me S
S
Me
MeO In(ONf)3 (30 mol%) Bu2O 40%
62
Me Me
Me S
S
Me
63
The generation and addition of a thienyl radical to an alkene has been used as a key step in the preparation of the linear tricyclic system 64, displaying trans-geometry, from the precursor 65. This reaction was carried out at high dilution <05SL1951>. H
S
BuSnH, AIBN, PhH, reflux, 8 h
Br
60%
H
S 65
64
Additional miscellaneous synthetic approaches to fused thiophene containing systems encompass syntheses of benzothieno[2,3-a]pyrrolo[3,4-c]carbazole derivatives <05TL907>, a thieno[3,2-a]carbazole by ring closing metathesis <05JOC10474>, trans-dihydrodiol derivatives of phenanthro[3,4-b]thiophene and phenanthro[4,3-b]thiophene <05JHC1345>, thieno[3,4-b]pyrrole derivatives by ring transformation of cyclic sulfonium ylides <05JHC717>, and partially saturated isoxazolo[3,4-d]thieno[2,3-b]pyridines by intramolecular nitrone cycloadditions <05T3525>. Finally, it should also be mentioned that several new macrocyclic compounds incorporating thiophene units have been prepared and studied, for instance a dithiaethyneporphyrin <05AG(E)5288>, 2,5-diamidothiophene based Schiff base macrocycles <05OL5277>, hybrid calixpyrroles <05JOC1511>, 21,23-dithiaporphyrins <05EJO2500, 05BMC2235, 05BMC5968>, heptaphyrins containing six meso links and a 2,2′-bithiophene motif <05OL5445>, dithiadiazuliporphyrins <05JA13108>, and core modified hexa- and octaphyrin derivatives <05JA11608>. 5.1.4 NON-POLYMERIC THIOPHENE ORGANIC MATERIALS The field of photochromic thiophene or benzo[b]thiophene containing ethenes exhibits continuous development in both synthetic and materials chemistry, as such compounds are
136
T. Janosik and J. Bergman
recognized as interesting materials for applications for optoelectronic devices, for example memories, switches, and displays. A new interesting application of these systems has been demonstrated by photoswitching of stereoselectivity in cyclopropanation reactions employing copper containing chiral 1,2-dithienylethene based bis(oxazoline) ligands <05AG(E)2019>. In an example based on reactivity-gated photochromism, the diene derivative 66, which cannot undergo a pericyclic photoreaction, may be activated by a Diels-Alder reaction with maleic anhydride, affording the 1,2-dithienylethene 67, which displays reversible photochromic behaviour upon irradiation, as illustrated by the conversion to 68 <05OL2969>. The syntheses and photochromic properties of numerous other 1,2-dithienylethenes have been described, for example systems containing fluorinated thiophene units <05EJO91>, naphthalene<05T6623>, spiropyran- <05T3719>, arylethynyl- <05JA13344>, and 2-(1,3-thiolpentane) substituents <05TL871>. In addition, the photochromic reactivity of 1,2-bis(2methylbenzo[b]thiophene-3-yl)perfluorocyclopentene derivatives bearing imino/nitronyl and nitronyl/nitroxyl groups has been studied <05OL3777>, as well as derivatives of dithia(dithienylethena)-phane <05EJO2771>, and systems featuring a central maleimide unit <05BCJ1145>. Cyclization and cycloreversion reactions of dithienylethene systems have also been accomplished by electrochemical oxidation <05OL3315, 05CEJ6414, 05CEJ6430>. It has also been demonstrated that the photochromic reactivity in dithienylethene single crystals depends upon the conformation of the ethane. Crystals composed of alternate layers of two different conformers displayed behaviour indicating that half of the molecules undergo photochromism upon irradiation at 366 nm <05AG(E)2148>. A dithienylethene featuring a thermally reversible naphthopyran moiety has been constructed, and was shown to exhibit four different states characterized by different absorption properties <05AG(E)5048>. In addition, it has been suggested that an ethene incorporating fused, extended chiral benzo[b]thiophene units undergoes ring closure to a single helical isomer <05JA7272>. O O
O
O
O
O
O
O
O
acetone, 65 °C
UV Vis
S
S
S
S
S 67
66
S 68
It should also be mentioned in connection with the dithienylethenes, that the fluorescent terthiophene 69 has been prepared in a convenient manner employing a Kumada coupling between 2,3-dibromothiophene and 2-bromo-3-methylthiophene, and was demonstrated to display photochromic behaviour upon irradiation by conversion to the ring closed, nonfluorescent form 70 <05TL5409>. S
S
S
S
69
254 nm >405 nm
S
S
70
137
Five-membered ring systems: thiophenes and Se/Te analogues
Suzuki coupling has been employed for the synthesis of the imidazole containing thiophene derivatives 71, as well as some isomers thereof, which were studied as their chargetransfer complexes with tetracyanoquinodimethane <05T6056>. The system 72 has been prepared along with several of its oligomers, and was subjected to studies probing its optical and electrochemical properties <05T3813>. Several new structures incorporating EDOT (3,4ethylendioxythiophene) units have been synthesized, for example 73 <05T3045>. The dye 74 has been prepared and used for in vivo optical imaging of amyloid aggregates in mouse brain tissue <05AG(E)5452>. Thienylpyrrole based donor–acceptor substituted diazo dyes have also been constructed and studied with regard to their solvatochromic and electrochemical properties <05T8249>. A synthesis of 1,4-bis(5-decyl-2,2′-bithien-5-yl)benzene has been reported, and the material was used for fabrication of high performance thin film transistors <05SM(149)231>. Intramolecular charge-transfer interactions in a series of thiophene containing tetrathiafulvalenes, for instance 75, have been studied <05JOC768>. In addition, the trifluoromethyl substituted 2,2′-bithiophene based system 76, as well as some related systems, have been examined as materials for organic field-effect transistors <05JA5336>. Bu
Bu
HN
S
N
n
Bu
Bu
NH N
S
S
71 n = 1 or 2
72 HO S
S
C6H13 O
S O
O
C6H13
S
O
MeS S
F3C
SMe
MeS N
N S
CN
74
73
S
CN S
S
S S
SMe S
CF3
76
75
5.1.5 THIOPHENE OLIGOMERS AND POLYMERS Many of the current developments in thiophene chemistry are focussed on the synthesis and properties of thiophene based oligomers and polymers, which are promising materials for a variety of different applications. Consequently, a considerable number of thiophene oligomers and related structures have been prepared and studied during 2005. For example, the cyclohexyl end-capped oligomer 77 has been synthesized by Stille coupling, and used in the construction of organic field-effect transistors <05CM3366>. Stille coupling has also been employed for the synthesis of oligothiophenes containing thermally cleavable solubilizing ester groups en route to self-assembly of ultra-thin oligothiophene films <05CM6033>. The electrochemical, magnetic and electrical properties of films based on various α,ω-end-capped sexithiophenes have been studied, compared, and discussed <05CM6492>. Oligothiophenes
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T. Janosik and J. Bergman
end-capped with carboxylate groups have been investigated as efficient photosensitizers <05EJO6272>, whereas terthiophenes substituted with ketone functionalities displayed some promising properties in organic field-effect transistor (OFET) applications <05JA1348>, in particular the system 78 <05JA13476>. Incorporation of hydrogen bonding motifs in oligothiophenes, as illustrated by the example 79, provided new building blocks for new photovoltaic devices <05OL3409>. A complex derived from the ligand 80 featuring ruthenium and osmium polypyridine chromophores, has been demonstrated to exhibit flow of excitonic energy to the osmium based unit <05CC802>. In addition, a series of quinquethiophenenophanes has been prepared and studied <05JA8082>. Oligothiophenes incorporating a central dithieno[3,2-b:2′,3′-d]pyrrole unit have been prepared, and were found to exhibit high fluorescence <05OL5253>. F
F
F S
S
F
S
F
S
O
O
S
S S
F
S 78
77
F F F
H N
O
O
HN O
O S
O
S
H N
O
O NH
S S
F
S
O
79 C4H9
S
S N N
S
C4H9
C4H9 C4H9
C4H9 C4H9 S
80
S
N N
A synthesis of the oligomer 81 displaying alternating thiophene and furan rings has been accomplished by repetitive Stille reactions. Several related structures were also prepared in a similar manner, and their properties were investigated and compared with the corresponding oligothiophenes <05JOC1147>. Other developments in this field encompass for instance studies of oligothiophene containing [1,10]phenanthroline derivatives <05OBC4143>, hybrid molecules composed of porphyrin and oligothiophene units <05OBC2075>, oligothiophenes substituted with oligoether groups <05OBC2008>, oligo(3-hexylthiophene)–perylene dyads <05OBC985>, or perylene–oligo(3-hexylthiophene)–perylene triads <05EJO3715> for photovoltaic applications, as well as octaethylporphyrin–dihexylbithiophene–fullerene compounds <05TL6961>. The extended system 82 has been prepared from a soluble silylated precursor using Stille coupling methodology <05OL3513>. It has been demonstrated that the oxygenated terthiophene-[4] S,S-dioxide 83, as well as several related compounds, may be prepared conveniently from the corresponding terthiophenes by treatment with the reagent HOF·CH3CN <05AG(E)7374>. In addition, a series of oligothienyl sulfides, for instance 84, have been prepared and studied <05CM2672>.
139
Five-membered ring systems: thiophenes and Se/Te analogues
S
S
S
S
S
O
O
O 81
t-Bu
S
S 82
O O S
O O S S
O O 83
S S
S
S S
t-Bu
S
S
O O 84
Stille coupling and related reactions are popular methods for synthesis of polymers and co-polymers of thiophene. This approach has for instance been used in the preparation of copolymers based on thiophene and 1,2,4-triazole/1,3,4-thiadiazole <05MAC1500>, pyridazine <05CM6060>, or vinylene units <05SM(150)297>, as well as carboxylate functionalized polythiophenes with increased stability towards air <05CM4892>. Co-polymerization of a bithiophene based monomer with an aromatic dibromide bearing an achiral side-chain under Stille conditions in a chiral nematic liquid crystal as the solvent, has been shown to give rise to chiral aggregation of the polymeric product <05AG(E)4323>. A microwave assisted synthesis of polythiophenes under Stille conditions has also been reported <05SM(148)195>. Polymerization of suitable metalated monomers using Ni(dppe)Cl2 as the catalyst (Kumada type coupling reactions) has also been used to prepare polythiophenes with chiral ether based substituents <05SM(153)125>, polythiophenes substituted with benzothiazole containing moieties, for instance 85 <05SM(152)197>, poly(3-alkoxythiophene)s <05MAC5554>, or alternating alkyl/perfluoroalkyl substituted polythiophenes, such as 86 <05MAC372>. The polymerization of 2,5-dibromo-3-alkylthiophene monomers using Grignard reagents and Ni(dppe)Cl2 has been suggested to proceed via a quasi-“living” chain growth mechanism <05MAC8649>, whereas a modification of this method has also proven to be useful for facile preparation of end-capped regioregular poly(3-alkylthiophene)s <05MAC10346>. An additional mechanistic study of Ni-catalyzed chain-growth polymerization has been published, wherein the process was suggested to involve a coupling reaction of 2-bromo-5thienylmagnesium chloride monomers with the polymeric chain via the nickel catalyst, which is thereafter transferred in an intramolecular manner to the terminal C–Br bond of the elongated chain <05JA17542>. A new class of boron-containing polythiophenes have been devised, for instance 87, and evaluated as chemosensors displaying changed absorption or emission properties upon binding of nucleophiles to the Lewis acidic boron moieties <05JA13748>. A fluorescent probe for detection of ATP based on a polythiophene with an ammonium salt functionality in the side chain has been developed <05AG(E)6371>, whereas a similar polymer was demonstrated to self-assemble with schizophyllan, a natural polysaccharide, to produce an insulated molecular wire <05JA4548>. It has also been established that thiophene may be polymerized under photochemical conditions using iodonium salts <05MCP1178>. Electrochemical conditions have been employed for the synthesis of terthiophene-based polymers with various substituents, for instance nitro- and amino groups <05SM(154)117>.
140
T. Janosik and J. Bergman i-Pr C8H17
S N
C6H13
S
S
S
n
S
C8F17
n 85
B
S
n C6H13
86
87
Conducting polymers of 3,4-ethylenedioxythiophene (EDOT) and related materials are widely studied, and the field continues to attract considerable attention. It has been reported that poly(3,4-ethylenedioxythiophene) (PEDOT) films with very high conductivities are formed upon oxidation with Fe(III) tosylate, provided that the acidity during the polymerization was controlled by addition of a basic inhibitor, for instance pyridine <05SM(152)1>. Highly conductive PEDOT films may also be prepared by high-concentration emulsion polymerization <05SM(149)211>. Electropolymerization of the monomer 88 resulted in a product which displayed lower oxidation potential and lower band gap than the corresponding polymers based entirely on EDOT or 3,4-ethylenedisulfanylthiophene units <05MAC6806>. The polymer 89, as well as several variants thereof along with related copolymers have been prepared and investigated <05MAC10379>. Moreover, an EDOT based polymer functionalized with ferrocene-containing oligonucleotides has been devised <05T3947>. A new facile synthesis of the thiophene-methine polymer 90 from 3,4ethylenedioxythiophene-2-carbaldehyde has also been described <05CC4187>. A study on the influence of the position and number of EDOT units in hybrid oligothiophenes has been performed, leading to increased understanding on tuning of the electronic properties of such systems <05CEJ3742>. It has also been shown that introduction of phosphine substituents into EDOT alters the electrochemical properties of the EDOT moiety, leading to irreversible oxidation <05CJC150>. O
O
C6H13 C6H13 O
S S 88
O
O
S S
O
O
O * S 89
* S
S
n 90
Several new examples of polymers incorporating fused thiophene units have also been reported recently. For instance, a stable semiconductor based on the polymer 91 has been prepared by Stille coupling of suitable monomers <05JA1078>. A water dispersible polymer has been obtained by oxidative polymerization of thieno[3,4-b]thiophene in the presence of poly(styrenesulfonic acid) in water <05SM(152)177>. Poly(3,6-dimethoxy-thieno[3,2b]thiophene) 92 has been designed as a possible alternative to PEDOT <05CC1161>. The poly(dithieno[3,2-b:2′,3′-d]pyrrole 93 and a related polymer with a chiral side-chain have been prepared, and were found to display high stability in both neutral and oxidized state <05MAC4545>, whereas several other derivatives of the system 93 have been included in a study of nitrogen-functionalized polythiophenes <05SM(152)137>.
141
Five-membered ring systems: thiophenes and Se/Te analogues C12H25 S *
S
S
C8H17 N
MeO S
*
S
n
OMe
n
93
92
91
5.1.6
S
S
n
S
C12H25
THIOPHENE DERIVATIVES IN MEDICINAL CHEMISTRY
During the year 2005, a considerable number of studies featuring thiophene derivatives in various medicinal and biological applications have been disclosed. A series of tetrasubstituted thiophenes, for instance 94, have been prepared and evaluated as potential anti-inflammatory agents <05BMC6685>, based on QSAR studies of a set of similar compounds, which led to the establishment of a three point pharmacophore <05BMC1275>. Tetrasubstituted thiophenes have also been evaluated as antagonists of the human glucagon receptor <05BMCL1401>. The quinuclidine containing molecule 95 has been identified as a ligand for the α7 nicotinic receptor without displaying cross-reactivity with the 5-HT3-receptor <05BMCL4727>. Likewise, the spiro-compound 96 is also an α7 nicotinic acetylcholine receptor agonist <05JMC2678>. A series of 2[(aminocarbonyl)amino]-5-acetylenyl-3thiophenecarboxamides has been evaluated as anti-inflammatory agents <05BMCL2870>. Screening of various 2,3-diarylthiophenes, prepared by palladium catalyzed coupling reactions, led to the identification of compound 97 as a selective EP1 receptor antagonist <05BMCL1155>. Several other thiophene derivatives incorporating heterocyclic substituents have been prepared and studied, for example 98, which is a non-zinc chelating MMP-12 (a matrix metalloproteinase) inhibitor <05BMCL3787>, and the apoptosis inducer 99 <05JMC5215>. Me EtO O
O
∗
NHEt
S
O
N
CO2Me
O N H
94
O
N
S
S
Cl
N
95
96 N
BnO
Cl
Cl CF3
N S
CO2H 97
H N
HO2C
N
Ph
S O
S
O N 99
98
Likewise, benzo[b]thiophenes have also been the subject of several biologically oriented studies. The structurally rather simple sulfonamide 100 was identified as a carbonic anhydrase inhibitor <05BMCL4872>, whereas methanesulfonate salts of the guanidine derivatives 101 displayed cardioprotective activity <05BMCL2998>. A series of 5-amidinobenzo[b]thiophene derivatives have been identified as dual inhibitors of factors IXa and Xa <05BMCL29>. The
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T. Janosik and J. Bergman
tetracyclic benzo[b]thiophene derivative 102, which was prepared by treatment of 3chlorobenzo[b]thiophen-2-carbonyl chloride with 4-cyanoaniline, followed by conversion of the cyano group into the amidine functionality and subsequent cyclization by irradiation, has been demonstrated to possess selective antitumor activity without inhibiting the growth of normal fibroblasts <05JMC2346>. In addition, a set of benzo[b]thiophenes 103 have been investigated as ligands for the estrogen receptor α, where the derivative with R = i-Pr displayed the highest affinity <05BMCL1505>, whereas a number of benzothieno[2,3b]indoles have been prepared and studied as selective estrogen receptor modulators <05BMCL2891>.
H2N
100 X N S
O
RN
NHi-Pr
S O O
H2NO2S
N
Cl NH2
O
NH
NH2
O
S
OH S
HO
101 X = NO2 or CN
102
103
Thiophenes fused to various heterocyclic rings, in particular pyridine, have also attracted some interest. A study on small molecule inhibitors of Src kinase, which is a potential target for several possible therapeutic areas, including cancer, has led to the discovery of several active compounds, for instance the thieno[3,2-b]pyridine system 104 <05JMC3891>. The tricyclic molecule 105 has been identified as a potent mGluR1 antagonist (IC50 = 3 nM), and displayed interesting efficiency in various animal pain models <05JMC7374>. Thieno[2,3d]pyrimidine derivatives, for instance the structure 106, have been investigated as tyrosine kinase inhibitors <05JMC6066>. Other studies of related interest focus on 4-oxo-4,7dihydrothieno[2,3-b]pyridines as non-nucleoside inhibitors of human cytomegalovirus <05JMC5794>, and structures based on the tetrahydropyrido[4′,3′:4,5]thieno[2,3d]pyrimidine skeleton as 5-HT1A /5-HT1B antagonists <05BMCL5567>. Cl MeN
HN
OMe CN
N S 104
N
Me
Cl
NH NMe2 N
N
S
N
O
Et
O 105
NH2 N N
S 106
NH
143
Five-membered ring systems: thiophenes and Se/Te analogues
5.1.7
SELENOPHENES AND TELLUROPHENES
Only a limited number of papers concerning new chemistry of selenophenes and tellurophenes have appeared during the year 2005. In an application of Woollins’ reagent ([PhP(Se)(μ-Se)]2, 107), a selenium analogue of Lawesson’s reagent, a series of 1,3diarylbenzo[c]selenophenes 108 have been prepared from the corresponding 1,3diarylbenzo[c]furans 109 <05TL7201>. 107 (1/4 equiv.) CH2Cl2, rt, 4 h
Ar1
Ar2
O
58-70%
Ar1
Se
109
Ar2
108
An interesting set of operations featuring a bromine–lithium exchange has been employed in a synthesis of the fused benzo[b]selenophene derivative 110 from the acetylenic precursor 111. The events leading to the final product involve formation of a 2,2′-bibenzo[b]selenophene intermediate, and a final oxidative cyclization yielding the central 1,2dichalcogenin ring. Several other related systems based on selenophene or thiophene were prepared using this methodology <05OL5301>. Br
Br
1. t-BuLi (4 eqiuv.), THF 2. Se (4 equiv.) 3. 1 M NaOH (aq.) 4. K3[Fe(CN)6] (aq.)
Se Se Se
62%
111
Se
110
Based on previous work by the same group, an approach to the parent benzo[1,2-b:4,5b′]dichalcogenophenes 112 was realized by a sequence involving lithiation of the bis(ethynyl)benzene 113, subsequent installation of the chalcogene atoms, cyclization, and finally desilylation of the intermediate products 114 <05JOC10569>. Heating of ferrocenylacetylene in refluxing benzene with Mo(CO6) or W(CO6) in the presence of elemental selenium has been reported to give 2,5-diferrocenylselenophene <05OM4793>. TMS Br
1. t-BuLi, Et2O, -78 C° to rt 2. E, rt 3. EtOH, rt
Br
R E
114a E = Se, R = TMS (65%) 114b E = Te, R = TMS (55%)
TMS 113
E R
TBAF, THF, rt
112a E = Se, R = H (93%) 112b E = Te, R = H (89%)
It has been demonstrated that 2-iodo-5-phenyltellurophene 115, available in 72% yield by treatment of 2-phenyltellurophene with butyllithium, followed by iodination, undergoes copper catalyzed coupling with alkyl- or arylthiols, providing the products 116 in good yields.
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T. Janosik and J. Bergman
Related reactions were also carried out successfully using 2-iodoselenophene as the substrate <05TL2647>. RSH, CuI (5 mol%) KOH, 1,4-dioxane, reflux
Ph
Te
I
77-90%
Ph
115
Te
SR
116
As a part of a study of stable hypervalent carbon compounds, the selenonium salt 117 has was prepared by treatment of the carbinol 118 with perchloric acid. A smiliar outcome was observed for several sulfur analogues <05JA5893>. Ph Ph
Ph
OH
MeSe
SeMe
118
HClO4, Et2O
Ph
MeSe
SeMe ClO4
117
Formation of the unstable 2,2′-biphenylenedimethylselenurane and the related tellurane was observed at low temperatures after treatment of dibenzoselenophene Se-oxide or 2,2′biphenylenedibromotellurane, respectively, with methyllithium. Both these species decomposed readily at room temperature into the corresponding dibenzochalcogenophenes <05TL8091>. Moreover, cationic selenophene containing expanded porphyrin-like macrocycles have been prepared and evaluated for selectivity towards a certain DNA quadruplex structure <05JA2944>. It has also been found that replacement of a thiophene unit with a selenophene in copolymers incorporating fluorinated phenylene units often leads to increasing hole mobility of the polymers <05CM6567>. 5.1.8 REFERENCES 05AG(E)1336 05AG(E)2019 05AG(E)2148 05AG(E)4323 05AG(E)5048 05AG(E)5288 05AG(E)5452 05AG(E)6371 05AG(E)7374 05AM1581 05AM2281 05BCJ1145 05BMC1275 05BMC2235 05BMC3927 05BMC5968
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F. Soki, J.M. Neudörfl, B. Goldfuss, Tetrahedron 2005, 61, 10449. V.G. Nenajdenko, A.M. Moiseev, E.S. Balenkova, Tetrahedron 2005, 61, 10880. T. Ozturk, E. Ertas, O. Mert, Tetrahedron 2005, 61, 11055. S. Pu, J. Xu, L. Shen, Q. Xiao, T. Yang, G. Liu, Tetrahedron Lett. 2005, 46, 871. J. Wang, N. Soundarajan, N. Liu, K. Zimmermann, B.N. Naidu, Tetrahedron Lett. 2005, 46, 907. T. Kawano, H. Inai, K. Miyawaki, I. Ueda, Tetrahedron Lett. 2005, 46, 1233. R.T. Clemens, S.Q. Smith, Tetrahedron Lett. 2005, 46, 1319. M. Hatsuda, M. Seki, Tetrahedron Lett. 2005, 46, 1849. C. Mésangeau, S. Yous, B. Pérès, D. Lesieur, T. Besson, Tetrahedron Lett. 2005, 46, 2465. G. Zeni, Tetrahedron Lett. 2005, 46, 2647. C. Peyron, J.-M. Navarre, N. Van Craynest, R. Benhida, Tetrahedron Lett. 2005, 46, 3315. J. Takayama, Y. Sugihara, T. Takayanagi, J. Nakayama, Tetrahedron Lett. 2005, 46, 4165. A.K. Mohanakrishnan, P. Amaladass, Tetrahedron Lett. 2005, 46, 4225. X. Li, H. Tian, Tetrahedron Lett. 2005, 46, 5409. N. Hayashi, A. Naoe, K. Miyabayashi, M. Miyake, H. Higuchi, Tetrahedron Lett. 2005, 46, 6961. A..K. Mohanakrishnan, P. Amaladass, Tetrahedron Lett. 2005, 46, 7201. S. Kuroda, M. Oda, M. Nagai, Y. Wada, R. Miyatake, T. Fukuda, H. Takamatsu, N.C. Tranh, M. Mouri, Y. Zhang, M. Kyogoku, Tetrahedron Lett. 2005, 46, 7311. R. Kadyrov, I.Z. Ilaldinov, J. Almena, A. Monsees, T.H. Riermeier, Tetrahedron Lett. 2005, 46, 7397. N. Tsukada, K. Murata, Y. Inoue, Tetrahedron Lett. 2005, 46, 7515. J.A. Wilkinson, N. Ardes-Guisot, S. Ducki, J. Leonard, Tetrahedron Lett. 2005, 46, 8053. S. Sato, M. Matsuo, T. Nakahodo, N. Furukawa, T. Nabeshima, Tetrahedron Lett. 2005, 46, 8091. C.-H. Wang, R.-R. Hu, S. Liang, J.-H. Chen, Z. Yang, J. Pei, Tetrahedron Lett. 2005, 46, 8153.
150
Chapter 5.2 Five-membered ring systems: pyrroles and benzo analogs Erin T. Pelkey Hobart and William Smith Colleges, Geneva, NY 14456
[email protected]
5.2.1 INTRODUCTION Pyrroles and indoles are likely the most studied and reported of all heterocyclic ring systems and there was a noticeable increase in citations this year compared to previous years. Pyrrole chemistry investigated by the Banwell (pyrrole alkaloids) <05COC1589> and Jacobi (phytochrome) <05SL2861> research groups has been reviewed. A number of indole review articles have been published that are based on the work of a number of leading research groups including: Borschberg (Aristotelia alkaloids) <05COC1465>, Gribble (electron-deficient and [b]fused indoles) <05COC1493>, Knölker (carbazole alkaloids) <05COC1601>, Takayama (Corynanthe alkaloids) <05COC1445>, and Umani-Ronchi (stereoselective alkylation reactions) <05SL1199>. A monograph detailing the preparation and reactions of 5,6-dihydroxyindoles and indole-5,6-diones was published <05AHC1>. A comprehensive review of the synthesis and elaboration of indoles utilizing palladium catalysts has appeared <05CR2873>. Additional review articles will be mentioned later in the text. 5.2.2 SYNTHESIS OF PYRROLES Intramolecular Approaches
Intermolecular Approaches
c type Ia N
c b
type IIab d
type Ib
N a H
N
N
b type IIac
type IIad
type IIbd
type Ic
type IIae
N N
N
eN a H
N N
151
Five-membered ring systems: pyrroles and benzo derivatives
In order improve the organization of this section, pyrrole syntheses have been categorized utilizing the systematic approach utilized by Sundberg <96CHEC-II119>. Intramolecular approaches (type I) and intermolecular approaches (type II) are classified by the number and location of the new bonds that describe the pyrrole ring forming step as shown opposite. 5.2.2.1 Intramolecular Approaches A few metal-mediated type Ia cyclizations have been reported. A gold(I)-catalyzed addition of an azide to a proximal alkyne was utilized to prepare 2,5-disubstituted pyrroles and higher functionalized pyrroles <05JA11260>. For example, treatment of azido alkyne 1 with a gold(I) catalyst led to the formation of pyrrole 2 presumably via gold(I) activation of the alkyne. In a related sequence utilized to prepare N-bridgehead pyrroles 3, silver nitrate was utilized to induce the addition of vinylogous carbamates onto pendant alkynes <05EJO505>. AuL R1 R2
(dppm)Au2Cl2 5% AgSbF6, CH2Cl2
R1 R2
R1
N
N3
N2
1
R2
N H 2
Treatment of hydrazonium salt 4 with palladium(0) led to the formation of pyrrole 5 via 5exo-trig amino-Heck cyclization <05H(65)273>. The reaction presumably proceeds by the oxidative addition of palladium(0) into an N-N bond. An oxidative addition into the N-O bond of benzoyloximes was the key step in the 5-endo-trig amino-Heck cyclization leading to 5-fluoro3H-pyrroles <05CC4684>. EtO2C
Ar Pd(PPh3)4, DMF, ∆ N
N
Me
Ar
NMe3
n
4
3 n = 1, 2, 3
N H 5
Treatment of azidoketones 8 with triphenylphosphine led to the formation of pyrrolidine 9 via a Staudiner-aza-Wittig reductive cyclization <05JOC4751>. The latter were converted into 2,3disubstituted pyrroles 10 upon heating. Azidoketones 8 were prepared by the novel condensation of 1,3-bis-silyl enol ethers 6 with azidoacetal 7. This sequence was exploited for the synthesis of a cyclododecyl-fused pyrrole. OMe N3 TMSO
OTMS R1
R2 6
7 TMSOTf
N3
R2
O
8
R2 O
PPh3 R1
O
R2
MeO
OMe
OMe
N H 9
O
∆ R1
N H 10
R1
152
E.T. Pelkey
A type Ib cyclization involving ketene-N,S-acetals led to the formation of highly functionalized pyrroles including 4-acetylpyrrole-2-carboxylates <05SC693> and 3,4diarylpyrroles <05TL475>. The latter are useful building blocks for the preparation of the lamellarin alkaloids. Another approach to the lamellarin framework involved a 1,5electrocyclization of azomethine ylides <05TL7531>. Ring-closing metathesis is an increasingly utilized strategy for the preparation of pyrroles via a type Ic cyclization process. A one-step process to pyrroles combined the ring-closing metathesis with the subsequent oxidative aromatization <05ARK(i)92>. The optimal reagents for this transformation were found to include the second generation Grubbs catalyst and tetrachloro-1,4-benzoquinone as the oxidant. Treatment of (bis)allyl carbamate 13 with Grubbs catalyst led to dihydropyrrole 14 which underwent an oxidative aromatization to pyrrole 15 upon treatment with DDQ <05OL2501>. The latter were further functionalized and evaluated as human lipoxygenase inhibitors. 13 was prepared in three steps from propargyl alcohol 11 via propargyl allyl amine 12. The key step involved a novel rhenium-catalyzed amination. In a separate report, an iridium catalyzed intramolecular cyclization involving propargyl allyl amine gave exocyclic dienes 16 which were subsequently converted into fused pyrroles via a cycloaddition/dehydrogenation sequence <05JA10804>. TMS
MeO2C OBn
TMS
N H
OBn
5% (dppm)ReOCl3
OBn
N
N
MeO2C
MeO2C
12
13
HO NH4PF6, MeCN
1. K2CO3 2. Lindlar, H2
11
R OBn
Grubbs' catalyst
OBn
DDQ
N
N
MeO2C
MeO2C
14
15
N Bn
CO2Et
16
Another type Ic approach combined a ring-closing metathesis followed by an elimination of a methoxy group to give the aromatized pyrrole system <05EJO1969>. Specifically, ring-closing metathesis of bis(allyl) sulfonamide 18 gave the corresponding dihydropyrrole which underwent conversion to pyrrole 19 after treatment with TFA. 18 was prepared utilizing a novel tandem cross-coupling between sulfonamide 17, methoxyallene, and iodobenzene.
+ NH Ts 17
Ph
Pd(PPh3)4, PhI OMe
N Ts 18
OMe
1. Grubbs-II catalyst 2. TFA
Ph
N Ts 19
153
Five-membered ring systems: pyrroles and benzo derivatives
A novel synthesis of [b]-fused pyrroles involved an intramolecular cyclization of enaminones (Knorr-type pyrrole synthesis) <05S3152>. Treatment of Weinreb amide 20 with two equivalents with thienyllithium led to intermediate ketone 21 which cycloisomerized into pyrrole 22 upon heating. O O
OMe N Me
O
O O
thienyllithium (2 equiv)
N H 20
S
S
N Li
N H 22
21
5.2.2.2 Intermolecular Approaches A one-pot Trofimov reaction (type IIac cyclization) has been developed <05ARK(vii)11>. Treatment of ketoximes with acetylene in the presence of superbase (KOH/DMSO) gave 2substituted and 2,3-disubstituted pyrroles. A type IIad cyclization of vinamidinium salt 24 with α-aminoacetophenone 25 in the presence of sodium hydride led to the formation of 2-keto-4-arylpyrrole 26 <05T1845>. The latter was utilized in a regiocontrolled preparation of the polycitone alkaloids. Vinamidinium salt 24 was readily available from phenylacetic acid 23 by a Vilsmeier-Haack type process. MeO
MeO POCl3, DMF then NaPF6
Me N Me
O OH 23
PF6
MeO
Me N Me 24
NaH, DMF OMe OMe N H
H3N TsO
O 25
O
26
The Paal-Knorr pyrrole synthesis, a type IIae cyclocondensation of 1,4-dicarbonyl compounds (or their synthetic equivalents) with primary amines, continues to figure prominently in the preparation of highly functionlized pyrroles. Selected recent applications of the Paal-Knorr synthesis include the preparation of the following: pyrrole-2-carboxamides 27 <05JOC1745, 05SL1405>, pyrrole amino acid derivatives 28 <05EJO5277, 05TL7069>, 2,3-diarylpyrroles (anticoccidial agents) <05BMCL3296>, 1,2-diarylpyrroles (COX-II inhibitors) <05H(65)1673, 05JMC3428>, oligopyrroles <05OL1887>, and bis(pyrrol-2-yl)arylenes <05JOC7996>. Bismuth nitrate <05TL2643> and iron(III) montmorillonite clay <05SC1051> have been investigated as novel catalysts for the Paal-Knorr pyrrole synthesis. A Nef reaction was utilized to transform γ-nitroketones into 1,4-ketoaldehyde substrates, which upon treatment with ammonium acetate provided 2,4-diarylpyrroles <05JOC5571>. A resin-anchored 1,4-diketone has been investigated as a protecting group for amines masking them as pyrroles on the solidphase <05OL565>.
154
E.T. Pelkey 2 Bz R CO2Me N H
H N R1
CO2Me
R3 N 4 R
R1
R2 Ar2
N
O
R3
27
28
R2
NHCBz
R1 N Ar1 29
Additional type IIae cyclizations have been reported between primary amines and four-carbon materials at the “1,4-dicarbonyl” oxidation level. Copper-mediated cyclizations of 2,7-ditosyl1,7-octadiene-3,5-diynes with anilines were utilized to produce tetraaryl-2,2’-bipyrroles <05H(66)319>. Pyrroles with chiral N-substituents have been prepared by the condensation between chiral primary amines and γ-chlorobutenones <05T3019, 05TA3170>. Treatment of αpropargyl ketoester 30 with amines in the presence of catalytic amount of trifluoroacetic acid (TFA) led to 1,2,3,5-substituted pyrroles 32 <05ARK(xv)105>. The reaction proceeds via the formation of an intermediate enamine ester (i.e., 31) followed by a 5-exo-dig cyclization onto the pendant alkyne. A two-step procedure utilizing the corresponding enamine nitriles provided 2aminopyrroles <05T10482>. EtO2C
RNH2, TFA (cat.) benzene, ∆
Ph
EtO2C
EtO2C
Ph
O
Ph
NH R 31
30
N R
Me
32
A novel type IIae approach to dihydropyrroles involved the ring opening of doubly electrondeficient cyclopropanes by amines <05OL2313>. For example, treatment of nitrocyclopropane 33 with aniline provided dihydropyrrole 35 by an intramolecular condensation of intermediate αaminoketone 34. Oxidation of 35 with DDQ provided pyrrole 36. An electrophile-induced ring opening of 1-chloro-1-cyclopropanecarboxaldehyde gave trichlorobutanals which were converted into 2-aryl-4-chloropyrroles <05T4631>. Ph
NO2 Ph O 33
aniline toluene, ∆
Ph Ph
NO2
NO2 NH
O
34
Ph
NO2 DDQ
Ph
N Ph 35
Ph
Ph
N Ph
Ph
36
Type IIbd cyclocondensation reactions between isocyanide-based reagents and electron deficient alkenes or alkynes provides a convenient synthetic approach to highly functionalized pyrroles. The cyclocondensation between tosyl methyl isocyanide (TosMic) and 1,2bis(benzenesulfonyl)ethene provided 3,4-bis(benzenesulfonyl)pyrrole 37 <05JHC333>. Additional pyrrole syntheses involving TosMic include the preparation of bicyclo[2.2.1]heptanefused pyrroles <05CM4622>, 3-ketopyrroles <05T2407>, and the total synthesis of
155
Five-membered ring systems: pyrroles and benzo derivatives
dictyodendrin B <05JA11620>. The regioselectivity of the cyclocondensation between methylTosMic and ethyl cinnamates was investigated <05OPP178>. Treatment of cyclopropylpropiolate 38 and isocyanide 39 with either potassium tert-butoxide or a copper thiolate catalyst gave cyclopropyl-substituted pyrrole-2,4-dicarboxylate 40 <05AG(E)5664>.
PhO2S
t-BuO2C
SO2Ph
t-BuO2C
38
CuSPh (cat.)
+ N H 37
Ph
39 Ph
EtO2C
41 +
dppp (cat.) CO2Et CN
44
CO2Me
40
EtO2C
CO2Et N H
N H
CO2Me
CN
Ph
Cu2O (cat.) N H
CO2Et
CO2Et
43
42
The regiochemical outcome of the pyrrole cyclocondensation can be reversed by utilizing a phosphine catalyst <05JA9260, 05TL2563>. While treatment of propiolate 41 and isocyanide 42 with a copper (I) catalyst led to the formation of pyrrole-2,4-dicarboxylate 43, the same reaction run with a catalytic amount of 1,3-bis(diphenylphosphino)propane (dppp) provided the regioisomeric product, pyrrole-2,3-dicarboxylate 44. The regiochemical outcome was explained by a 1,4-conjugate addition of phosphine onto the alkyne giving a zwitterionic intermediate which reverses the electronics of the alkyne (umpolong). 5.2.2.3 Transformation of other Heterocycles This last section will detail syntheses of pyrroles by the transformation of other heterocyclic systems. Ring contraction approaches to pyrroles have been reviewed <05COC261>. Boger reported an additional example of his reductive ring contraction of 1,2-diazines to pyrroles in a reported total synthesis of the marine natural product, ningalin D <05JA10767>. A novel pyrrole synthesis has been developed from 1,2-oxazines <05S3346>. The cycloaddition between nitroso dienophile 45 and 2,3-dimethylbutadiene gave 1,2-oxazine 46. Cleavage of the N-O bond followed by an oxidative cyclization gave pyrrole 48. Mo(CO)6 NaBH4
BocNHOH NaIO4
NHBoc O N
O N
Boc
Boc 45
OH
46
47
MnO2 N Boc 48
156
E.T. Pelkey
Pyrrole-3-carboxylates were obtained by the regioselective 1,3-cycloaddition reaction between 1,3-oxazolium-5-oxides (Münchnones) and α-acetoxyacrylates <05TL1061> under microwave irradiation. Finally, the condensation of 4-hydroxypyrrolidines with cyclic ketones in the presence of montmorillonite K10 under microwave irradiation provided an interesting route to 1-substituted pyrroles <05JOC1471, 05S1095>.
5.2.3 REACTIONS OF PYRROLES 5.2.3.1 Substitution at Nitrogen A modestly enantioselective pyrrole carbinol formation has been investigated <05SL2420>. Treatment of lithium pyrrolate with a ketoaldehyde in the presence of a chiral ligand preferentially led to the formation of pyrrole carbinol 49 (50% ee). A hydroxy-directed reduction of the ketone in the side chain by the addition of zinc borohydride provided 50 (88% de). Pyrrole carbinols serve as convenient precursors to aldehydes. A subsequent deprotective Horner-Wadsworth-Emmons reaction involving 50 and phosphonate ester 51 gave unsaturated ester 52. The regioselectivity (N- vs. C-3) of the intramolecular cyclization of 2-(prolinesubstituted)pyrroles has been examined <05TL249>. The regiochemical outcome was dependent on electronic factors and pH. This chemistry was utilized in the preparation of the rings embodied in pyrrole-2-carboxamide marine natural products such as dibromophakellin. An N-vinylation of pyrrole utilized a palladium-catalyzed coupling of pyrrole with vinyl triflates <05JOC8638>. For example, treatment of pyrrole and triflate 53 in the presence of palladium and the XPhos ligand gave N-vinylpyrrole 54. This chemistry was utilized in the preparation of the tricyclic mymicarin alkaloids <05OL4423>. O
O
H
OH
N Li
O
OH
N chiral bis(ether) ligand
OH
Zn(BH4)2 N 49
50 O
OTf + N H
O
O P OEt OEt
t-BuO
Pd2dba3 XPhos, K3PO4
NaH
51 N
OEt
OH
O
53
t-BuO O
OEt 54
52
157
Five-membered ring systems: pyrroles and benzo derivatives
5.2.3.2 Substitution at Carbon The electron-rich pyrrole moiety readily undergoes reactions with electrophiles predominantly at open α-positions. A regioselective nitrosation (sodium nitrite and HCl) of diarylpyrroles was utilized to prepare 2-nitroso-3,5-diarylpyrroles, useful building blocks for the preparation of novel azodipyrromethanes <05JOC5571>. The 2-alkylation and 2,5-dialkylation of pyrrole was investigated with primary alkyl bromides in an ionic liquid <05OL1231>. The Vilsmeier-Haack reaction is a useful method for the introduction of formyl groups onto a pyrrole ring. An attempt to convert 55 into 58 utilizing a Vilsmeier-Haack reaction failed due to the presence of the electron-deficient fused sulfolene ring <05TL2009>. A more forceful method was found that involved the treatment of 55 with benzodithiole 56 in the presence of acetic acid which gave bisadduct 57. Reduction of the dithiane groups with the reagent combination shown led to the desired diformylpyrrole 58. A novel formation of dipyrromethanes involved the acid-mediated condensation of pyrrole with the heterocyclic carbonyl equivalent, oxazinane <05T6614>. O
O
S
S
S
O
O
O
S
O 56
S
S
N H
AcOH S
55
N H 57
H
S
O S
HgO HBF4 – DMSO O
N H 58
H O
The introduction of electrophiles at the β-position of pyrroles can be accomplished with certain N-(substituted)pyrroles. Treatment of bulky N-tert-butylpyrrole with phosphorus bromide gave the corresponding 3-phosphinopyrrole <05CHE934>. The dibromination of 1tosylpyrrole with bromine liquid led to the formation of 3,4-dibromo-1-tosylpyrrole <05OL1003>. Interestingly, investigation of this reaction by GC-MS revealed that this product was formed via a rearrangement of a 2,5-dibromo-1-tosylpyrrole intermediate. An enantioselective alkylation of pyrrole with enones has been reported <05JA4154>. For example, treatment of N-methylpyrrole 59 with enone 60 in the presence of a catalytic amount (10 mol%) of bis(oxazoline) catalyst 61 provided chiral adduct 62. Different additives including iodine <05T11751> and an aluminum surfactant <05CC789> have been utilized to mediate the Michael addition of pyrroles to β-nitrostyrenes.
+ N Me 59
O
O
Et
OH O 60
+
N Cu t-Bu TfO OTf t-Bu 61 (cat.) N
N Me
OH Et
O
62
Fused heterocyclic 1,2,3,4,5-pentathiepins have been prepared by treatment of pyrroles and related heterocycles with disulfur dichloride in the presence of diazabicyclooctane (DABCO) <05OBC3496>. Thus, pentathiepin 64 was prepared from 2,5-dimethylpyrrole 63 using this
158
E.T. Pelkey
reagent combination. Interestingly, subjecting 64 to the same reaction conditions at room temperature led to the formation of bis(dithiolo)pyrrole 65 <05OL5725>. S S
S
S S
S2Cl2, DABCO, 0 °C Me
Me
N Bn
S
S2Cl2, DABCO, rt Me
63
N Bn
Me
S
64
S
S N Bn
S S
65
The substitution chemistry of 3,5-dichloro-2,4-pyrroledicarboxaldehydes has been investigated with different amine nucleophiles <05T5831>. Secondary amines preferentially form adducts with the formyl groups, while primary amines replace the 5-chloro group. The introduction of the cyano group onto the pyrrole ring was accomplished utilizing an hypervalent iodine reagent <05OL537>. Treatment of N-protected pyrrole 66 with trimethylsilyl cyanide in the presence of phenyliodine bis(trifluoroacetate) (PIFA) and boron trifluoride etherate provided 2-cyanopyrrole 67. The regioselective silylation of electron-rich heterocycles was reported using an iridium catalyst <05CC5065>. For example, treatment of pyrrole 68 with a tetrafluorodisilane in the presence of iridium catalyst 69 and a bipyridine ligand gave 3silylpyrrole 70. Br
Br
SiF2t-Bu
1/2[Ir(OMe)(COD)]2 69
TMS-CN, PIFA BF3-ether N Ts
N Ts
66
67
CN
N TIPS
N TIPS
dtbpy, (t-BuF2Si)2
68
70
Organometallic chemistry continues to provide regioselective methods for the α-, β-, and polyfunctionalization of pyrroles. An improved protocol for the Suzuki cross-coupling of a sterically crowded β-position was developed for a total synthesis of lamellarin D <05JOC8231>. A similar Suzuki cross-coupling sequence was utilized in a synthesis of the structurally related polycitone alkaloids <05T1845>. A double Suzuki cross-coupling of 3,4-dibromopyrroles was utilized to prepare 3,4-diarylpyrrole pyrroles (“open-chain lamellarin analogues”) <05TL2041>. A selective Suzuki cross-coupling reaction with 2,3,4-tribromopyrrole 71 and boronic acid 72 The preferentially led to the α-substitution product, 2-arylpyrrole 73 <05SL1957>. corresponding regioisomeric products were not detected. Br EtO2C
Br
N H 71
Br
(HO)2B
Pd(PPh3)4 Cs2CO3
+
t-Bu 72
Br EtO2C
Br
N H 73
t-Bu
159
Five-membered ring systems: pyrroles and benzo derivatives
A direct coupling of an unactivated pyrrole onto a pendant aryl iodide was utilized in a total synthesis of the natural product, (±) rhazinilam 76 <05OL5207>. Treatment of pyrrole 74 with palladium acetate in the presence of the DAVEPhos ligand provided pyrrole 75 containing a fused 9-membered lactam ring. A mechanism was proposed that involved an intramolecular nucleophilic attack by the pyrrole onto the Pd(II) center formed by the oxidative addition into the carbon-iodide bond. Removal of the MOM group and saponification followed by decarboxylation gave 76. A similar direct coupling of a pyrrole ring onto a pendant alkene (Heck reaction) was utilized in a total synthesis of the fused pyrrole moiety found in dragmacidin F <05JA5970>. The direct coupling of pyrroles to the α-position of carbonyl compounds was reported utilizing a copper catalyst for intermolecular coupling reactions and a ferrocene catalyst for intramolecular coupling reactions <05AG(E)609>. I MOM O
MOM N
Pd(OAc)2, K2CO3 DAVEPhos ligand
Et N
E
O
1. BCl3 O 2. NaOH then HCl
N Et N
(E = CO2Me)
74
H N Et
E
N rhazinilam (76)
75
Electron-deficient pyrroles undergo normal electron demand cycloadditions with dienes to give fused dihydropyrrole adducts <05CC1351, 05T7907>. Treatment of pyrrole 77 with 2,3dimethylbutadiene in the presence of zinc chloride at high pressure gave cycloadduct 78. The triflyl group proved to be essential. Tin seemed to be beneficial for the cycloaddition of 3bromo-4-stannylpyrroles leading to bicyclic adducts <05OL1003>. Cycloadditions of βnitrovinylpyrroles provided a route to indole-fused quinones <05JHC1149>. O
O
Me
N SO2CF3 77
Me Me
+
ZnCl2 high pressure (16 kbar)
N F3CO2S H
Me
78
5.2.3.3 Functionalization of the Side-Chain Gold-mediated asymmmetric Michael addition reactions onto α,β-unsaturated N-acylpyrroles were investigated <05JA514>. Selective Birch reductions were investigated with a number of electron-rich fused pyrrole substrates <05JOC2054>. Deprotonation of phenol 79 followed by treatment of phenoxide 80 with sodium metal in ammonia gave 81. The same reaction with the corresponding 7-methoxy derivative gave a mixture that contained over-reduced products.
160
E.T. Pelkey
NaH
HO
Na, NH3
NaO
N
HO
N
79
N
80
81
Pyrrolo[1,2-b]isoquinolines have been prepared by an intramolecular cyclization onto pyrrole Weinreb amides or morpholine amides <05T3311>. 5.2.4 PYRROLE NATURAL PRODUCTS AND MATERIALS 5.2.4.1 Natural Products The isolation, biological activity, biosynthetic studies, and syntheses of the pyrroloiminoquinone marine natural products 81 have been reviewed <05NPR62>. Total syntheses directed at members of this class of compounds, specifically the discorhabdins and makaluvamines, were the subject of a separate review <05COC1567>. Marine environments continue to be a primary source of novel pyrrole natural products. The first dimeric discorhabdin has been isolated from a New Zealand sponge Latrunculia sp. <05JNP1796>. Additional examples of the zyzzyanones, dipyrroloquinones, have been isolated from the Australian sponge Zyzzya fuliginosa <05JNP1424>. Additional examples of the lamellarin alkaloids were found in the Indian tunicate Didemnum obscurum <05T9242>. Microorganisms isolated from marine sediment collected in Alaska provided glaciapyrroles A-C, pyrrolosesquiterpenes <05JNP780>. An interesting non-bromopyrrole natural product, daminin 82, was isolated from the Mediterranean sponge Axinella damicornis <05T7266>. 82 demonstrated neuroprotective activity which prompted an independent total synthesis of the compound. The structurally related bromopyrrole natural product, laughine 83, was isolated from a Caribbean sponge Eurypon laughlini <05JNP327>. OMe H
R2
N
N H
O 81
N H N R1
O
N
CO2
N H N
O
82 R1 = H; R2 = H 83 R1 = Me; R2 = Br
84
Fermentation experiments with Streptomyces fumanus produced additional examples of the pyrrolomycins, chlorinated 2-benzoylpyrroles and structurally related pyrroles with demonstrated antimicrobial activity <05JNP277>. Pyrrole-2-carboxamide marine natural products continue to receive much synthetic attention. Synthetic studies directed at the hexacyclic pyrrole, palau’amine have been reviewed <05COC1551>. Separate racemic syntheses of dibromophakellstatin <05AG(E)2295, 05OL929> and asymmetric syntheses of agelastatin A <05OL621> and longamide B <05JOC9081> have been disclosed.
Five-membered ring systems: pyrroles and benzo derivatives
161
The total synthesis of the tripyrrole alkaloid, “butylcycloheptylprodiogiosin” 84, confirmed a structural assignment that had come under question <05AG(E)2777>. An enantioselective synthesis of the tricyclic myrmicarin alkaloids was reported <05OL4423>. As mentioned previously, a total synthesis of (±)-rhazinilam 76 was communicated <05OL5207>. Lamellarin natural products continue to inspire the development of new chemistry and many additional synthetic approaches were reported again this year and this topic was also the subject of a lengthy review article <05OPP413>. De novo pyrrole ring approaches to the lamellarins include the intramolecular cyclization of ketene-N,S-acetals <05TL475>, 1,5-electrocyclization of azomethine ylides <05TL7531>, and reductive ring contraction of 1,2-diazine <05JA10767>. Suzuki cross-coupling approaches that involve the selective functionalization of the pyrrole ring have appeared (vide infra) <05JOC8231, 05TL2041>. 5.2.4.2 Macrocycles and Oligopyrroles The synthesis, functionalization, and evaluation of pyrrole macrocycles (i.e., porphyrins) continues to be one of the most prolific areas in pyrrole research. Only a small fraction of the reports that have been published during the past year will be mentioned. Several reviews and accounts in this field have appeared including: nucleophilic substitution of porphyrins <05ACR733>, self-assembling porphyrins and chlorins <05ACR612>, fullerene-porphyrin conjugates <05ACR235>, benziporphyrins <05ACR88>, confused porphyrins <05ACR10>, dynamic supramolecular porphyrins <05T13>, and synthetic approaches to the linear tetrapyrrole, phytochrome <05SL2861>. A few synthetic approaches to porphyrins and related pyrrole macrocycles are highlighted here. A direct route to palladium porphyrins was disclosed and involved the dimerization of dipyrromethanes in the presence of palladium(II) reagents <05JOC3500>. Imine-substituted dipyrromethanes served as a building block for the preparation of zinc porphyrins <05JPP554>. The condensation of a phenanthroline dialdehyde with dipyrrylmethane produced a soluble (40 mg/mL) phenanthroline-“strapped” porphyrin bridged at the 10,20-meso positions <05TL139>. The preparation pentapyrrole macrocycle (sapphyrin) containing a novel benzene ring fusion has appeared <05AG(E)4053>. The functionalization of pyrrole macrocycles garners attention due to their potential in medicinal applications and materials science. A silver-promoted meso-meso dimerization of porphyrins was a key step in the preparation of a dibenzoporphyrin dimer that exhibited a large two-photo absorption cross section <05CC3782>. The preparation of meso-substituted porphyrins containing no β-substituents was reported <05CEJ3427>. Nucleophilic substitution reactions of bicyclo-fused porphyrins was useful for introducing meso-substituents allowing for the preparation of meso-substituted benzoporphyrins after a retro cycloaddition reaction <05H(65)879>. Retro cycloaddition chemistry was exploited for the preparation of watersoluble benzoporphyrins containing multiple carboxylate groups <05TL113>. Another approach to benzoporphyrins containing carboxylate groups involved the cycloaddition chemistry of fused 3-sulfolenoporphyrins <05TL2009>. The introduction of trimethylammonium groups <05JPP290>, cationic peptides <05CC4652>, and cobaltacarboranes <05CC1306> onto mesosubstituents was disclosed. A class of novel sulfur-bridge pyrrole macrocycles was discovered <05CC2122>. For example, treatment of dipyrromethane 85 with disulfur dichloride led to the formation of disulfide linked tetrapyrrole 86.
162
E.T. Pelkey
R
RR
R R
R S2Cl2 N H
N H
S
S
N H
N H
H N
H N
S
R
N H
NH
N H
R HN R
R S
85
NH
HN
CO2Et
EtO2C
R
R 86
87 (R = Et)
Synthetic approaches to α,α-linked quater-, penta-, and sexipyrroles (i.e., 87) have been developed starting from bipyrrole and tripyrrole intermediates <05OL1887>. This compounds could prove useful in the preparation of novel expanded porphyrins. Oligopyrrole macrocycles have found utility in molecular recognition, notably as anion sensors. Recent examples include meso-cyclohexyl calix[4]pyrroles <05MI1515>, meso-indanyl calix[4]pyrroles <05T10705>, mixed heterocycle “hybrid” calixpyrroles <05JOC1511>, mixed 2,6-diamidopyridine dipyrromethane macrocycles <05AG(E)7386, 05JA11442>, and chlorideselective calixdipyrromethanes <05CC540, 05CEJ2001>. The link between chloride transport and anti-cancer activity has been investigated with analogues of the prodigiosins (acyclic tripyrroles) <05AG(E)5989>. 5.2.4.3 Non-Oligomeric Materials Simple 2,5-bis(amido)pyrroles have been investigated as anion binding and membrane transport agents <05CC3761>. The anion binding profiles of thioamidopyrroles and amidopyrroles have been compared <05T4081>. Guanidinopyrrole 88 shows cooperativity in the binding of glutamate and not aspartate allowing for the differentiation of these closely related anions <05JA10486>.
N N NH2 H HN MeO2C
O
N NH2
NH2
NH3
88
N
N
B
N
F F 89
An active area of pyrrole materials science research involves the development of novel borondipyrromethene (BODIPY) for novel analytical applications and a small subset of the recently published work will be mentioned here. BODIPY derivatives have been developed for use as pH probes <05JOC4152>, chiral fluorescent labeling agents <05BCSJ464>, zinc(II)
163
Five-membered ring systems: pyrroles and benzo derivatives
imaging agents (i.e., 89) <05OBC1387>, photoreceptor protein detectors <05AG(E)2288>, fluoroionophores <05JA6956>, near-infrared absorbing dyes <05AG(E)1677>, and logic gates <05OL5187>. Structurally interesting BODIPY complexes containing Ru(II)-terpyridine <05CC4222> and azulene <05AG(E)6943> side chains have been reported. 5.2.5 SYNTHESIS OF INDOLES As with the corresponding section on pyrroles, indole syntheses have been categorized utilizing a systematic approach. Intramolecular approaches (type I) and intermolecular approaches (type II) are classified by the number and location of the new bonds that describe the indole forming step (2 examples shown below). In addition, the synthesis of oxindoles, azaindoles, and carbazoles will be treated separately. Intramolecular Approaches (type I) c d
Intermolecular Approaches (type II) c
type Ia d
b e N a H
c
type IIac d
b e N a H
b e N a H
5.2.5.1 Intramolecular Approaches A few type Ia reductive cyclizations leading to indoles have been reported. A palladium (II) trifluoroacetate catalyst was effective in the reductive cyclization of ortho-nitrostyrenes to 2substituted indoles <05T6425>. The Batcho-Leimgruber indole synthesis, the reductive cyclization of β-amino-2-nitrostyrenes, was utilized in a synthesis of 5-formylindole <05JHC137>. A partial reduction of a nitroarene provided a route to N-hydroxyindoles <05AG(E)3736>. Treatment of nitro ketoester 90 with tin chloride in the presence of a primary alcohol nucleophile provided N-hydroxyindole 93 via hydroxylamine intermediate 91. Br E O NO2 90
SnCl2 BnOH
Br
OBn E O NH
4 Å MS (E = CO2Me)
91
OH
N OH 92
OH E
N OH 93
E
A total synthesis of the herbindoles, structurally related cyclopent[g]indole natural products, utilized a type Ia condensation reaction <05OL1215>. Treatment of quinone imine 94 with cyclopentadiene produced cycloadduct 95 which cyclized to indole 96 in the presence of hydrochloric acid. The latter was elaborated into (±)-cis-trikentrin B 97.
164
E.T. Pelkey
MeO
O
OMe
O
1. cyclopentadiene NTs
HO
HO
2. HCl, THF
94
H
NHTs
N Ts
95
N H
96
97
An intramolecular Michael-type cyclization of 98 and subsequent trapping of the carbanion intermediate 99 with propyl iodide produced 2,3-disubstituted-1-methylindole 100 <05OL4641>. The indole ring was formed after elimination of sulfinic acid. SO2Ph Ph
SO2Ph
1. LiHMDS
NHMe
N Me
98
2. C3H7I
Ph
N Me
99
Ph
100
The iodocyclization reaction of o-ethynylanilines provides 3-iodoindoles, which are useful building blocks for the preparation of highly functionalized indoles. A solid-phase variation has been reported <05JCO809>. A solution phase example involved the treatment of Nmethylaniline 101 with iodine leading to 3-iodoindole 102 <05JOC9985>. A palladiumcatalyzed carbonylation/cyclization of 102 gave fused lactone 103. An iodocyclization of ocyclohex-2-enylanilines with N-iodosuccinimide provided hexahydrocarbazoles <05CJC63>. AcO
I
I2, CH2Cl2
OAc
O
PdCl2(PPh3), CO K2CO3, DMF
O
NH Me
N Me
N Me
101
102
103
Several examples of the metal-mediated cyclization of o-ethynylanilines (hydroamination) leading to 2-substituted indoles have appeared during the past year. Metals that have been utilized in this heterocyclization reaction include palladium <05T4035, 05T12330>, copper <05T10958>, and iridium <05OL5437>. The prepration of 3,4-fused indoles involved the palladium-mediated reductive cyclization of 2-(1-alkenyl)nitrobenzenes <05T3637>. An interesting metal-mediated tandem cyclization/cross-coupling reaction of o-(2,2dibromovinyl)anilines in the presence of boronic acids provided 2-substituted indoles in one step <05OL3549>. For example, treatment of aniline 104 and phenylboronic acid with palladium acetate in the presence of (S)-Phos ligand and potassium phosphate gave 2-phenylindole 105.
165
Five-membered ring systems: pyrroles and benzo derivatives
Br
PhB(OH)2 Pd(OAc)2, S-Phos K3PO4 • H2O
Br NH2
N H
104
105
Metal-mediated cyclization reactions of o-ethynylanilines performed in the presence of electrophiles provides highly functionalized indoles with new substituents introduced into the 3position. A gold-catalyzed tandem cyclization/conjugate addition of aniline 106 with methyl vinyl ketone produced 2,3-disubstituted indole 107 <05JOC2265>. The preparation of 3alkynylindoles involved the palladium-mediated tandem cyclization/cross coupling of oalkynyltrifluoroacetanilides and 1-bromoalkynes <05JOC6213>. A similar sequence with 3alkynyl-2-acetamidopyridines was utilized to prepare a 3-arylazaindole library <05JCO510>. Ph
O NaAuCl4 • H2O, ethanol
NH2
N H
O
106
107
Two type Ib approaches to indoles were reported involving tin-mediated radical cyclization reactions. Treatment of either 2-alkenylthioanilides <05H(66)241> or 2-(1-alkenyl) imidoyltellurides <05SL1893> provided 2,3-disubstituted indoles. The former precursor was also utilized in a synthesis of tetrahydro-β-carbolines. Heck cyclization reactions of o-halo-N-(2-alkenyl)anilines have proven useful for the development of type Ic approaches to indoles. Recent applications include the preparation of a 3-(2-hydroxyethyl)indole en route to the total synthesis of (-)-eudistomin C <05JA15038> and the preparation of 3,5,7-substituted indoles <05SL3071>. An asymmetric Heck cyclization reaction of triflate 108 led to dihydrocarbazole 109, which upon treatment with acid led to fused (iminoethano)carbazole 110 <05JA10186>. The latter was utilized in an enantioselective total synthesis of minfiensine. NHBoc Pd (OAc)2 chiral ligand
OTf
PhMe, 170 °C
N MeO2C 108
TFA, CH2Cl2 N MeO2C
NHBoc
109
N
N MeO2C Boc 110
Treatment of 3,5-dimethoxyaniline with α-chloroacetone in the presence of lithium bromide and sodium hydrogen carbonate gave 4,6-dimethoxy-2-methylindole in one step via a type Ic
166
E.T. Pelkey
cyclization of anilinoketone intermediate <05T77>. A type Ie copper-catalyzed amination leading to β-carbolin-1-ones was reported <05OBC911>. 5.2.5.2 Intermolecular Approaches The venerable Fischer indole synthesis, the acid-catalyzed type IIac cyclization of arylhydrazones leading to indoles, continues to find heavy use. A solid-phase Fischer indole synthesis of 2,3-disubstituted indoles involved a traceless silicon-based linker <05JCO130>. The Fischer indole synthesis was involved in the preparation of a variety of 2,3-fused indoles including indolo[2,3-a]carbazoles <05SL42, 05TL4839>, 4-oxocarbolines <05TL3831>, cycloalkyl[b]indoles <05JOC8385>, benzofuroindoles <05CBC1745>, and indeno[1,2-b]indol10-ones <05SC581>. The preparation of a 5,5’-bisindole involved a double Fischer indolization <05H(65)1679>. A few novel variations of the Fischer indole synthesis have been reported. A tandem hydroformylation/Fischer indolization reaction between terminal alkenes and arylhydrazines provided a route to tryptamines and homotryptamines <05JOC5528, 05OBC2335>. For example, treatment of phenylhydrazine 111 and piperazine 112 with a rhodium catalyst and the XANTPHOS ligand followed by aqueous sulfuric acid gave 3-homotryptamine 113. This chemistry was utilized in the preparation of three anti-migraine drug candidates <05JOC5528>. A titanium-catalyzed hydroamination of 1-silyloxy-4-pentynes with phenylhydrazines followed by Fischer indolization gave tryptophols, 3-(2-hydroxyethyl)indoles <05T7622>. A threecomponent approach to indoles involved bringing together nitriles (or carboxylic acids), aryl/alkyllithiums, and arylhydrazines <05T11374>.
N H
NH2
111
+
1. Rh(acac)(CO)2 XANTPHOS CO, H2, THF
N N O 112
N
OEt 2. aq. H2SO4
N
N H 113
OEt O
A review of the Bartoli indole synthesis (type IIac cyclization) has appeared <05COC163>. The Bartoli indole synthesis involves the addition of vinyl Grignards to nitroarenes. The Larock indole synthesis, the metal-mediated heteroannulation of o-haloanilines and alkynes, is another example of a type IIac approach to indoles. Recent examples include the preparation of benzene-ring substituted tryptophans <05SL2469>, 2-(α-mannosyl)tryptophans <05OBC687>, and a tryptophan derivative utilized in the preparation of the sarpagine indole alkaloids <05TL4219>. A Heck-reaction variation involved the coupling and subsequent cyclization of o-haloanilines and 1-bromo-1-arylethenes <05CEJ2276>. A variant involving the Stille coupling of a 1-(tributylstannyl)allene and N-acyl-2-iodoaniline followed by heteroannulation of the 2-allenylaniline intermediate provided 2,3-substituted indoles <05OL5793>. A three-component type IIae indole synthesis has been developed involving 1,2-dihaloarenes, arylalkynes, and anilines <05OL439, 05T11311>. For example, iodoarene 114 was converted to indole 116 in one-pot utilizing this three-step sequence: Sonogashira coupling, amination, and
167
Five-membered ring systems: pyrroles and benzo derivatives
base-mediated heteroannulation. In a related type IIae indole synthesis, the palladium-mediated double amination of vinyl triflate 117 with aniline gave tetrahydrocarbazole 118 <05AG(E)403>.
F3C
I
NH2
CuI, Cs2CO3 Pd(OAc)2 imidazolinium salt
Ph
F3C
F3C
Ph
Cl
F
Cl 115
114
N
t-BuOK
Ph
F
(same pot)
116 NH2
Pd2(dba)3, dpephos Cs2CO3, PhMe
F Br
OTf
+
F N Ph
117
118
5.2.5.3 Transformation of other Heterocycles An iodonium-mediated benzannulation approach to indoles starting from 3-alkynyl-2-pyrrolecarboxaldehydes has been reported <05ASC526>. For example, treatment of pyrrole 119 with iodine and styrene provided 4,5-disubstituted indole 120. The authors suggest a mechanism for this transformation. 2-Aminofurans have been converted into the ergoline indole alkaloids utilizing cycloaddition chemistry <05JOC6833>. Ph
O I2, K2CO3 CH2Cl2
Ph
+
H O
N Ts 119
Ph
Ph N Ts 120
5.2.5.4 Oxindoles, Azaindoles, and Carbazoles A stereoselective tandem Heck cyclization/cross-coupling approach to diarylindenyl oxindoles was reported <05JOC3741>. In the event, treatment of alkyne 121 with boronic acid 122 in the presence of Pd(0) and a copper(I) thiophene-2-carboxylate (CuTC) gave oxindole 124 as a single stereoisomer via Heck adduct 123. The stereochemistry of the products was assigned based on NOE experiments and in some cases, the reaction produced a mixture of stereoisomers. An approach to structurally related alkynylindenyl oxindoles involved a vinylpalladation reaction of 2-(alkynyl)phenylisocyanates <05AG(E)7718>.
168
E.T. Pelkey
Cl
Cl
Pd(PPh3)4 CuTC 4:1 THF/DMF
I N H
I
N
Cl
Cl
N
N H
122 B(OH)2
123
O Cl
121
Pd
O
N H 124
O
A radical cyclization approach to spiro-oxindoles was revealed <05OL151>. Treatment of ptrityloxybenzamide 125 with triethylborane and tris(trimethylsilyl)silane gave cyclohexadienone 126 via an ipso cyclization. The nucleophilic aromatic substitution of aryl fluorides was utilized in an asymmetric approach to spiro-pyrrolidone oxindoles <05JA3670>. O
OTr EtO
I
Et3B, (TMS)3SiH
N
EtO N O Boc 126
O
Boc 125
A microwave-mediated tandem enamine formation/intramolecular Heck reaction provided a general synthetic route to 4-, 5-, 6-, and 7-azaindoles <05S2571>. For example, treatment of 3amino-2-chloropyridine 127 with cyclohexanone in the presence of triethyoxysilane and pyridine p-toluenesulfonate (PPTS) gave 4-azaindole 129 via intermediate enamine 128. The Hemetsberger-Knittel reaction, the thermolysis of β-azidostyrenes, was utilized to prepare 5-, 6-, and 7-azaindoles <05SL2080, 05S2751>. A novel approach to 7-azaindoles involved a domino epoxide ring opening by an amine nucleophile followed by an intramolecular nucleophilic substitution onto a pyridine moiety <05SL1255>. A DBU-mediated intramolecular cyclization of o-(Boc-amino)alkynyl pyridines and diazines provided a general approach to azaindoles and diazaindoles <05SL3121>.
N
Pd(PPh3)4 Si(OEt)4, PPTS
Cl + NH2
127
O
pyridine
N
Cl N H 128
N N H 129
This paragraph details carbazole syntheses that involve the formation of new bonds to nitrogen. A direct C-H functionalization/amination of 2-acetaminobiphenyl compounds give carbazoles in one step <05JA14560>. For example, treatment of biphenyl 130 with palladium acetate and copper(II) acetate gave carbazole 131. A short synthesis of carbazoles involved the reductive cyclization of 2-nitrobiphenyl compounds mediated by triphenylphosphine
169
Five-membered ring systems: pyrroles and benzo derivatives
<05JOC5014>. An intramolecular addition reaction of an aryl Grignard onto a triazene moiety provided a unique entry into the carbazole ring system <05OL2543>. For example, the Grignard reagent derived from triazene 132 gave carbazole 133. Palladium-catalyzed bis-amination reactions of a 2,2’-dibromobiphenyl and a 2,2’-biphenylylene ditriflate were utilized to prepare the carbazole natural products murrastifoline-A <05H(65)1561> and mukonine <05JOC413>, respectively. A cascade benzannulation of 2-(enynyl)anilines mediated by sodium acetate and acetic anhydride provided carbazoles <05SL809>. Pd(OAc)2 Cu(OAc)2, NH
1. i-PrMgCl 2. heat
O2, PhMe
N O
O
Me 130
Me
Br
N N
I
N H
Br N
132
131
133
The final paragraph in this section details carbazole syntheses that involve the formation of CC bonds. Intramolecular Diels-Alder cycloaddition of ynamides provided a new route to [b]fused carbazoles <05OL2213>. An electrocyclization of 2,3-divinylindole intermediates produced functionalized carbazoles <05TL4045>. A domino alkynylation/palladium migration/C-H activation approach to 4-vinylcarbazoles was reported <05OL701>. For example, treatment of N-arylaniline 134 with diphenylacetylene in the presence of palladium acetate, cesium pivalate (CsPv), and bis(diphenylphosphino)methane (dppm) gave carbazole 136 via post-palladium migration intermediate 135. Ph
Ph I
Pd(OAc)2 dppm, CsPv N H
Ph
Ph
134
Ph
Ph Pd-I N H
N H
135
136
5.2.6 REACTIONS OF INDOLES 5.2.6.1 Substitution at Nitrogen Two synthetic approaches to N-(1’-alkylthioglucopyranosyl)indoles were developed <05TL8117>. Radical reduction of the thiol group of the orthothioamides preferentially gave the β-N-glycoside indoles. Treatment of β-carboline-1-carboxaldehydes with lithium ketene acetal provided canthin-6-ones by an intramolecular amidation of the aldol condensation intermediates <05S28>. The deprotection of N-pivaloylindoles was accomplished utilizing two equivalents of LDA <05SL107>. A hydride transfer mechanism from LDA to the carbonyl group of the pivaloyl group was postulated by the authors.
170
E.T. Pelkey
5.2.6.2 Substitution at C–2/C–3 The π-excessive indole ring readily undergoes substitution at C-3 with electrophiles. Two synthetic strategies to 3-thiocyanoindoles were developed and involved the treatment of indoles with ammonium thiocyanate in the presence of either oxone <05TL5831> or ferric chloride <05S961>. The regioselective halogenation of 2-heteroaryl-6-azaindoles leading to the corresponding 3-halo-6-azaindoles was accomplished utilizing copper(II) halides <05SL2400>. Treatment of indoles with allyl alcohols in the presence of palladium(0) and triethylborane gave 3-allylindoles <05JA4592>. The addition of allylic acetates (derived from the Baylis-Hillman reaction) to the 3-position of simple indoles was catalyzed by indium tribromide <05TL639>. The ring opening of aziridines by indoles was investigated in the context of the preparation of indole-based pancratistatin analogues <05JOC3490>. Electrophilic substitution reactions of electron-rich 4,6- <05T10490> and 5,7dimethoxyindoles <05T4989> was investigated in a series of reports. For example, treatment of 4,6-dimethoxyindoles with nitric acid gave either 7,7’-biindoles, 2,2’-biindoles, or 2-nitroindoles depending on the substitution pattern of the substrate <05T853>. The introduction of cyano groups to 4,6-dimethoxyindoles was also communicated <05T10501>. As in previous years, a large number of methods have been reported for the preparation of bisindolylarylalkanes and structurally related compounds. Catalysts that have been employed for the double condensation of indole derivatives with aromatic aldehydes leading to bisindolylarylmethanes include: rare earth (Yb, La, and Sm) perfluorooctanoates <05SL337>, hexamethylenetetramine-bromine <05SC1835>, zirconium(IV) chloride <05BKCS1962, 05S1949>, copper(II) bromide <05SC1997>, and benzoic hydrazide <05OBC4043>. The latter catalyst was also utilized in the double condensation reaction with ketones and non-aryl aldehydes. Alternate electrophiles that were investigated included N-tert-butanesulfinyl aldimines (catalyzed by iodine or amberlyst) <05TL1751> and hexamethylenetetramine (catalyzed by indium trichloride) <05S1779>. Treatment of indole-3-carbinols with indoles in the presence of ceric ammonium nitrate provided another method for the preparation of bisindolylarylalkanes <05T10235>. β,β-Bis(indolyl) ketones were prepared by treatment of indole with allylic acetates in the presence of scandium triflate <05OBC1933, 05OL5063>. Michael addition reactions of indoles to enones and nitroalkenes were investigated with the following catalysts: hafnium(IV) triflate <05SL2492>, iodine <05T11751, 05TL2479>, aluminum dodecyl sulfate trihydrate (ADS) <05CC789>, cerium(III) chloride-sodium iodidesilica <05JOC1941>, and samarium(III) triiodide <05TL3859>. 4,7-Dihydroindoles serve as convenient precursors to indoles but have the reactivity profile of pyrroles allowing for the introduction of electrophiles to the 2-position <05T2401>. For example, treatment of 4,7dihydroindole 137 with 2-cyclohexenone in the presence of bismuth(III) nitrate and pbenzoquinone gave indole 138 after oxidation of the intermediate Michael adduct. Treatment of 3-alkylindoles with electrophiles in the presence of bismuth(III) nitrate preferentially led to the formation of either the N-substituted or C-2-substituted products depending on the choice of solvent <05TL2915>. Aprotic solvents favored N-substitution while protic solvents favored C2-substitution.
171
Five-membered ring systems: pyrroles and benzo derivatives O
Bi(NO3)3, CH2Cl2
+
p-benzoquinone
N H 137
O
N H 138
A number of asymmetric Michael addition reactions to indoles have been reported. Work in this area by the Umani-Ronchi research group has been summarized <05SL1199>. Thiourea <05AG(E)6576> and bis-sulfonamide <05OBC2566> catalysts were employed in enantioselective additions of indoles to nitroalkenes. Asymmetric induction in the addition of indoles to alkyl trifluoropyruvates has been realized with a C2-symmetric 2,2’-bipyridyl copper(II) complex <05OL901> and also with cinchona alkaloid-based catalysts <05AG(E)3086>. The enantioselective Michael addition of indoles to enones utilized bis(oxazoline) catalyst 61 <05JA4154>. The preparation of a selective serotonin reuptake inhibitor, 5-cyanoindole 143, utilized an asymmetric Michael addition <05OL3437>. In the event, treatment of 5-iodoindole 139 with cyclic enal 140 in the presence of MacMillan’s imidazolidinone catalyst 141 gave Michael adduct 142 which was converted to 143 in 2 steps.
I
I
140 CHO O
N H 139
Me
N H
N Ph
N H 141
NC
142 O
CHO
N H
NMe2
143
Me
The Pictet-Spengler reaction, the condensation of tryptamine imines at the indole 2-position, provides an important synthetic strategy for the preparation of tetrahydro-β-carbolines. Aspects of this reaction that have been studied during the past year include adaptation to the solid-phase <05JCO458>, acid-mediated cyclization of tryptamine enamines <05H(65)1063>, application to the stereoselective synthesis of indolo[2,3-a]quinolizines <05EJO4179, 05JOC357>, and the use of thioortho ester electrophiles <05OL3701>. The latter provided 1-alkylthio-β-carbolines, convenient precursors to iminium electrophiles which were elaborated into 1-substituted-βcarbolines upon treatment with various nucleophiles. A multi-component reaction approach to tetrahydro-β-carbolines 146 involved bringing together alkynes, acid chlorides, tryptamines 144, and α,β-unsaturated acid chlorides <05OBC4382>. A Pictet-Spengler type cyclization of iminium intermediates 145 was presumably along the mechanistic pathway. A silicon-directed oxa Pictet-Spengler cyclization provided pyrano[3,4-b]indoles <05OL2043>.
172
E.T. Pelkey 1. Pd(PPh3)2Cl2 CuI, Et3N R3 2. R2
N H
+ R1
Cl
NH2
R4 3.
R5
O
O
R3
144 N
N H R2 O
O
N
N H R2 O
R4 R5
R1
Cl
R3
R4
R1
145
O
R5
146
Another classical approach to β-carbolines involves Bischler-Napieralski reaction of indoles, the intramolecular cyclization of iminium chlorides derived from tryptamides. Triphenylphosphite proved to be a mild reagent capable of promoting this reaction <05SL661>. The cyclization of ketene N,S-acetals derived from tryptamine produced push-pull β-carboline enamines <05SL309>. A novel synthetic route to the chartelline indolenine alkaloids employed an interesting ring contraction as the key step <05AG(E)3714>. In the event, removal of the Boc group of tryptamide 147 followed by an oxidative cyclization promoted by NBS provided spirocycle 149 via a ring contraction of intermediate adduct 148. Pummerer chemistry of 2-sulfides was investigated for the preparation of a variety of indolenine spirocycles <05JOC6429>. A transcyclization of a furoindoline derivative provided a synthetic entry into the indoline aminal framework found in oxaline and neoxaline <05OL941>. 1. 180 °C 2. NBS
O HN
N Boc N
Me N H
147
E
E = CO2Me
O
Br O N H
N
148
E N
Me N H
Me
N E
N
N
Me N H
Me
Me
149
Metal-mediated reactions continue to provide a diversity of strategies for the regioselective synthesis of highly functionalized indoles. A novel synthesis of 2-nitroindoles was realized by treatment of 2-haloindoles with silver nitrite. The presence of silver(I) was required as the same reaction with sodium nitrite provided no products <05TL1325>. An iron-catalyzed crosscoupling reaction of indole-3-cuprate with an aryl iodide provided 3-arylindoles <05AG(E)1654>. A copper-catalyzed Ullmann-type coupling of a 3-iodoindole substrate produced indeno[2,1-b]indol-6-one <05SC1845>. A carbonylative alkynylation of 3-iodoindoles provided a route to the meridianin alkaloids <05AG(E)6951>. For example, treatment of 3iodoindole 150 with TMS-acetylene in the presence of a palladium catalyst, copper iodide, triethylamine, and carbon monoxide provided 3-acylindole 151. Treatment of the latter with guanidine provided meridianin G 152. Sequential Sonogashira-Suzuki cross-coupling reactions of 5-bromo-3-iodoindoles were investigated for the preparation of 3-alkynyl-5-arylindoles (and
173
Five-membered ring systems: pyrroles and benzo derivatives
also 1,3-bis-alkynylindoles and 1,3-diarylindoles) <05S771>. Selective cross-coupling reactions of 3-indoleboronates and 3-indoleboronic acids with dihalopyrazines was the basis for a formal total synthesis of the bis(indole) dragmacidin alkaloids <05TL2423>.
I
TMS
N Boc 150
guanidine Na2CO3
O
Pd(PPh3)2Cl2 CuI, Et3N, CO
TMS
N Boc
CH3CN t-BuOH
151
N N
NH2
N H 152
Direct C-H activation processes are an increasingly important strategy for the preparation of functionalized indoles. A novel method for the direct C-2 arylation of indoles involved a rhodium-mediated cross-coupling of indole substrates with aryl iodides in the presence of cesium pivaloate <05JA4996>. The C-2 arylation of indoles was also investigated with N-alkylindoles where the regiochemical outcome seems to be due to a 1,2-migration of an intermediate palladium complex <05JA8050>. A solvent effect was observed in palladium-mediated Heck reactions of indoles <05AG(E)3125>. For example, treatment of indole with palladium acetate, tert-butyl peroxybenzoate, and n-butyl acrylate 153 preferentially gave either 3-vinylindole 154 or 2-vinylindole 155 depending on the solvent utilized. CO2n-Bu 153 Pd(OAc)2 N H 155 E = CO2n-Bu
E
CO2n-Bu 153 Pd(OAc)2
1,4-dioxane/AcOH t-BuOOBz
MeCN/AcOH t-BuOOBz
N H
E N H 154 E = CO2n-Bu
A directed palladation route to 2-vinylindoles was investigated with indole substrates containing directing groups <05CC1854>. Treatment of indole 156 with palladium(II) and methyl acrylate gave 2-vinylindole 158 via cyclopalladated complex 157. The ligated pyridine ring was found to be labile enough to allow the reaction to proceed to the product. CO2Me PdCl2 Cu(OAc)2, MeCN
N
N
N
156
H PdLn
N
N 157
CO2Me N
158
A copper-catalyzed coupling reaction between free N-H indole substrates and tetrahydroisoquinolines gave 1-(indol-3-yl)isoquinoline derivatives <05JA6968>. Metal-mediated C-H activation processes are useful for the annulation of the indole ring. Palladium-mediated intramolecular annulation reactions were utilized in the preparation of
174
E.T. Pelkey
naphthocarbazoles <05JMC1401> and azepino-fused indoles <05TL8177>. A tandem alkylation/arylation reaction was developed for the preparation of 1,2-fused indoles <05JA13148>. For example, treatment of indole 159 with iodobenzene 160 in the presence of palladium acetate gave fused indole 162. A multi-step mechanism was proposed and included a direct C-H annelation step (i.e., 161 to 162). Fused [a]carbazoles were prepared via a benzannulation of 2-aryl- and 2-heteroarylindoles with propargyl ethers in the presence of indium(III) nonaflate <05AG(E)1336>. Pd(OAc)2 tris-2-furylphosphine Cs2CO3, norbornene
N
Me
Me
N I
CO2Me
Me CO2Me 161
Br 159
Pd-Br
160
CO2Me
N
162
A few radical annulation approaches to fused indoles have been reported. 2-Indolylacyl radicals generated from selenoesters provided ellipticine quinones <05JOC9077>. A radical cyclization of haloacetamide derivatives was applied to the preparation of indolo[2,1d][1,5]benzodiazocines <05T941> and indolo[3,2-d][1]benzazepin-6-ones <05T5489>. 3,3Spiro-indolenines were generated using a halogen atom transfer radical 5-exo cyclization of trichloroacetamides <05CC4827>. Two different types of methods of generating pendant 1,3-dipoles that participate in intramolecular cycloaddition reactions leading to complex indole heterocycles were reported. The first method for preparing pendant 1,3-dipoles involves the cycloaddition of 1,3,4oxadiazole rings followed by extrusion of nitrogen and this was applied to the total synthesis of minovine <05OL741> and vindoline <05OL4539>. The second method involves a rhodium(II)catalyzed cyclization of γ−diazoimides <05JOC2206>. Different methods for the generation of indolo-2,3-quinodimethanes and subsequent cycloaddition have been reported. Indole-2,3-quinodimethane precursors include 3cyanomethyl-2-vinylindoles <05BMC2263> and furoindolones <05SL994>. A gold(I)-catalyzed tandem [3,3]-rearrangement/[2+2]-cycloaddition provided cyclobutanefused indolines <05JA16804>. For example, treatment of indole 163 with a gold/silver catalyst system gave tetracyclic indoline 164. O O N H 163
O Ph
n-Bu
AuCl(PPh3) / AgSbF6 CH2Cl2
O n-Bu N H H Ph 164
175
Five-membered ring systems: pyrroles and benzo derivatives
Spiro-oxindoles have been prepared in a few steps from indole-2,3-dione (isatin) <05JA11505>. Isatin 165 was converted into diazo derivative 166, which upon treatment with rhodium acetate dimer and piperylene gave spiro-cyclopropane 167. A mangesium-mediated ring expansion of the cyclopropane with aldimine 168 gave spiro[pyrrolidine-3,3’-oxindole] 169, a useful building block in a total synthesis of spirotryprostatin B. A titanium-catalyzed coupling of isatin with dihydropyrans gave complex spiro-oxindoles <05CC2621>. Me Me
X
1. N2H3Ts 2. NaOH
N MgI2, THF
N O 3. [Rh(OAc)2]2 H 165 X = O 166 X = N2
N H 167
O
N H 169
N
168
O TIPS
TIPS
A few methods have been investigated for the introduction of new stereocenters at C-3 of oxindoles. Palladium-catalyzed asymmetric allylation <05AG(E)308> and enantioselective fluorination <05JA10164> reactions have been published. A Mukaiyama aldol reaction of 2silyloxyindoles provided a novel diastereoselective route to 3,3-disubstituted oxindoles <05OL2795>. For example, treatment of 2-silyloxyindole 170 with chiral aldehyde 171 in the presence of a Lewis acid and pyridine base gave oxindole 172. Bn N NBn + N Bn 170
OTBDMS
OH
O H
O N
BF3-OEt2 2,6-di-tert-butyl-4-methylpyridine
Boc 171
O N Bn
O
N Boc
172
5.2.6.3 Functionalization of the Benzene Ring A synthesis of thiazolo[5,4-e]indoles from 5-aminoindoles was reported <05TL2865>. The key step was an NBS-mediated regioselective annulation of a 5-thiourea-substituted indole. An approach to benzocanthinones and related analogues involved a radical cyclization of halo-substituted 1-acylcarbazoles and 1-acylcarbolines <05T9102>. Metal-mediated processes are very useful for the preparation of benzene-ring functionalized indoles. Cross-coupling reactions of 5-trifloxyindoles <05JOC6519> and 5-bromovindolines <05H(65)165> have been reported. An intermolecular <05OL4087> and an intramolecular <05OL3421> palladium-catalyzed coupling reaction between 4-bromoindole substrates and cyclohexanone enolates was utilized in separate approaches to the welwitindolinone alkaloid skeleton. The preparation of a novel 2,2-bisindole-based macrocycle involves organometallic cross-coupling reactions to stitch it together <05AG(E)7926>.
176
E.T. Pelkey
An iterative directed-metallating approach to 4,5-substituted indoles starting from gramine was documented <05T6886>. Treatment of gramine 173 with tert-butyllithium and trimethylsilylmethylazide followed by Boc protection gave 4-aminoindole 174. Directed lithiation by the carbamate followed by treatment with DMF gave indole 175. 1. t-BuLi 2. TMSCH2N3 NMe2 3. Boc2O N TIPS 173
NHBoc
1. t-BuLi OHC NMe2 2. DMF
N TIPS 174
NHBoc NMe2 N TIPS 175
5.2.6.4 Functionalization of the Side-Chain A few notable examples of the functionalization of groups attached to the indole ring will be highlighted. The aza-cycloaddition between indole-2-imine 176 and allene 177 catalyzed by tributylphosphine gave 178 which upon treatment with acid gave bridged tetracycle 179 <05OL4289>. The latter was utilized in a formal total synthesis of the macroline alkaloids, alstonerine and macroline. A chiral auxiliary (chiral α-substituted benzyl group) attached to the indole ring allowed for an asymmetric cycloaddition between indole-2-imines and Danishefsky’s diene <05CHE1290>. The reaction between TosMic and indole-3-carboxaldehyde was explored and a number of different reaction outcomes were observed in addition to the expected 5-(indol3-yl)oxazole products <05T1793>. O
N Me 176
NNs
E
(E = CO2Et)
+ E 177
PBu3 CH2Cl2 N Me 178
Ns N
E E
H E
HCl N Me
N H
Ns
179
Novel chemistry involving 2-bromomethyl- and 3-bromomethylindoles was explored in two papers. An attempted metal-mediated coupling with a Grignard and a 2-bromomethylindole led unexpectedly to a dimerization reaction <05TL6983>. Bromomethylindoles were converted into the corresponding indolyl acetate derivatives utilizing a Stille carbonylation <05TL4577>. Ring-closing metathesis has been applied to the preparation of annulated indoles including indolo[2,3-a]carbazoles <05JOC10474> and azepino[4,3-b]indoles <05TL7881>. An interesting carbocationic cascade reaction was utilized as a key step in the total synthesis of cyclopiazonic acid 182 <05CC3162>. In the event, treatment of silyl ether 180 with triflic acid led to tetracycle 181 which was subsequently converted into 182.
177
Five-membered ring systems: pyrroles and benzo derivatives O NHNs
NNs
H
TBDPSO CO2Et
TfOH CHCl3
H
N Ts
H
CO2Et
HHO
N Ts
180
OH
N
N H
181
182
5.2.7 INDOLE NATURAL PRODUCTS 5.2.7.1 Natural Products The complexity and diverse biological activity of indole natural products continues to be a major driving forces in the development of new synthetic methods and novel indole-based medicinal agents. Several reviews of indole natural products have appeared including the following sub-topics: non-rearranged monoterpene indole alkaloids <05NPR73, 05NPR761> and synthetic approaches to reserpine <05CR4671>, Corynanthe alkaloids <05COC1445>, Aristotelia alkaloids <05COC1465>, and ergot alkaloids <05HCA1344>. New indole natural products continue to be isolated often in conjunction with the search for novel biologically active agents. Anti-cancer indole natural products that were isolated include schischkiniin (N,N’-linked bisindole 183) <05T9001> and a number of sulfinyl polybromoindoles <05JNP815>. A 3,7-diprenylated indole was discovered that showed modest anti-HIV activity <05P697>. Antibacterial indole natural products that were isolated include a 4,4’-linked bisindole 4,4’-linked bisindole <05JNP1277>, suaveolindole (indolosesquiterpene) <05JNP122>, and bisindole pyrazinones <05BMCL4927>. Indole natural products demonstrating cholinesterase inhibition included nostocarboline (β-carboline quaternary salt) <05JNP1793> and a series of iboga alkaloids <05BMC4092>. Finally, actinophyllic acid 184, a pyrrolo[1’,2’:1,2]azocino[4,3-b]indole, showed carboxypeptidase U/hippuricase inhibition <05JOC1096>. Other structurally interesting indole natural products that were isolated include gesashidine A (imidazole-substituted β-carboline) <05JNP1109>, koniamborine 185 (pyrano[3,2-b]indole) <05JNP1083>, and a number of sulfinyl polybrominated N,3’-linked bisindoles <05H(65)2675>.
N
N N H N O
N H
H N
183
N H
N H HO2C
O MeO
O
OH
N Me
O 184
185
O
178
E.T. Pelkey
Much attention has been directed at the total synthesis of indole natural products. Non-fused indole natural product targets that have been prepared include the following: meridianins (pyrimidine-substituted indoles, i.e., 152) <05AG(E)6951>, dragmacidin F (pyrazinonesubstituted indole) <05JA5970>, dragmacidin B and C <05TL2423> (bis-indole alkaloids), (+)hamacanthins A and B (bis-indole alkaloids) <05T2309>, and lottanongine (flavan-substituted indole) <05SL1311>. The total synthesis of the following tricyclic indole natural products have been reported: (±)-cis-trikentrin B 97 <05OL1215>, brassilexin (isothiazolo[5,4-b]indole) <05JOC1828>, murrastifoline-A [N,C9’-linked bis(carbazoles)] <05H(65)1561>, and mukonine (carbazole) <05JOC413>. Tetracyclic indole natural products that have relented to a total synthesis include: fischerindoles G and I <05JA15394>, eudistomin C 186 <05JA15038>, deplancheine (indoloquinolizidine) <05OBC2140>, cyclopiazonic acid 182 <05CC3162>, and the grossularines (imidazole-fused α-carbolines) <05AG(E)3280>. Pentacyclic indole natural products that have been the subject of synthetic efforts include: chartelline alkaloids (i.e., 149) <05AG(E)3714>, tangutorine <05TL8053>, (–)-reserpine <05JA16255>, rac-aspidospermine <05AJC722, 05OBC213>, ent-minovine <05OL741>, and ent-vindoline <05OL4289>. Bridged polycyclic indole natural products syntheses that have been investigated include: minfiensine <05JA10186>, avrainvillamide <05AG(E)3892>, stephadicin A 187 <05AG(E)606, 05TL9013>, garderine and gardnutine <05TL4219, (–)-vincamajinine <05JOC3963>, rac-alstonerine and rac-macroline <05OL4289>, and 6-oxoalstophylline 188 <05OL3501>. Finally, a magnesiummediated ring expansion of a 3,3-spiro-cyclopropyl indole provided a key step in the synthesis of the oxindole alkaloid, (–)-spirotryprostatin B <05JA11505>.
H Br
N H H2N
O
O
H N
HO
Me
N
O
O Me
S
186
N O H Me Me
N
MeO
N Me H
Me
H
H O
N H
O 187
188
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180 05CC3162 05CC3761 05CC3782 05CC4222 05CC4652 05CC4684 05CC4827 05CC5065 05CEJ2001 05CEJ2276 05CEJ3427 05CHE934 05CHE1290 05CJC63 05CM4622 05COC163 05COC261 05COC1445 05COC1465 05COC1493
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05T2309 05T2401
E.T. Pelkey
H. Suzuki, M. Adachi, Y. Ebihara, H. Gyoutoku, H. Furuya, Y. Murakami, H. Okuno, Synthesis 2005, 28. B. Witulski, J.R. Azcon, C. Alayrac, A. Arnautu, V. Collot, S. Rault, Synthesis 2005, 771. J.S. Yadav, B.V.S. Reddy, A.D. Krishna, C.S. Reddy, A.V. Narsaiah, Synthesis 2005, 961. J. Azizian, A.R. Karimi, Z. Kazemizadeh, A.A. Mohammadi, M.R. Mohammadizadeh, Synthesis 2005, 1095. P.K. Pradhan, S. Dey, V.S. Giri, P. Jaisankar, Synthesis 2005, 1779. Z.-H. Zhang, L. Yin, Y.-M. Wang, Synthesis 2005, 1949. N. Lachance, M. April, M.-A. Joly, Synthesis 2005, 2571. P.J. Roy, C. Dufresne, N. Lachance, J.P. Leclerc, M. Boisvert, Z. Wang, Y. Leblanc, Synthesis 2005, 2751. L. Calvo, A. Gonzáléz-Ortega, R. Navarro, M. Pérez, M.C. Sañada, Synthesis 2005, 3152. G. Calvet, N. Blanchard, C. Kouklovsky, Synthesis 2005, 3346. J.-B. Wang, Q.-G. Ji, J. Xu, X.-H. Wu, Y.-Y. Xie, Synth. Commun. 2005, 35, 581. G.L. Sommen, A. Comel, G. Kirsch, Synth. Commun. 2005, 35, 693. G. Song, B. Wang, G. Wang, Y. Kang, T. Yang, L. Yang, Synth. Commun. 2005, 35, 1051. M.B. Teimouri, H. Mivehchi, Synth. Commun. 2005, 35, 1835. G. Abbiati, V. Canevari, E. Rossi, A. Ruggeri, Synth. Commun. 2005, 35, 1845. L.-P. Mo, Z.-C. Ma, Z.-H. Zhang, Synth. Commun. 2005, 35, 1997. Y.-Z. Hu, Y.-Q. Chen, Synlett 2005, 42. C. Avendaño, J.D. Sánchez, J.C. Menéndez, Synlett 2005, 107. S. Chakrabarti, K. Panda, H. Ila, H. Junjappa, Synlett 2005, 309. L. Wang, J. Han, H. Tian, J. Sheng, Z. Fan, X. Tang, Synlett 2005, 337. A. Spaggiari, P. Davoli, L.C. Blaszczak, F. Prati, Synlett 2005, 661. S. Serra, C. Fuganti, Synlett 2005, 809. D. Mal, B.K. Senapati, P. Pahari, Synlett 2005, 994. M. Bandini, A. Melloni, S. Tommasi, A. Umani-Ronchi, Synlett 2005, 1199. H. Schirok, Synlett 2005, 1255. K. Hatakeyama, K. Ohmori, K. Suzuki, Synlett 2005, 1311. S. Werner, P.S. Iyer, Synlett 2005, 1405. M. Kotani, S. Yamago, A. Satoh, H. Tokuyama, T. Fukuyama, Synlett 2005, 1893. S. Schröter, T. Bach, Synlett 2005, 1957. T. Lomberget, S. Radix, R. Barret, Synlett 2005, 2080. F. Gallou, J.T. Reeves, Z. Tan, J.J. Song, N.K. Yee, S. Campbell, P.-J. Jones, C.H. Senanayake, Synlett 2005, 2400. D.J. Dixon, M.S. Scott, C.A. Luckhurst, Synlett 2005, 2420. Y. Jia, J. Zhu, Synlett 2005, 2469. M. Kawatsura, S. Aburatani, J. Uenishi, Synlett 2005, 2492. P.A. Jacobi, I.M. Adel Odeh, S.C. Buddhu, G. Cai, S. Rajeswari, D. Fry, W. Zheng, R.W. DeSimone, J. Guo, L.D. Coutts, S.I. Hauck, S.H. Leung, I. Ghosh, D. Pippin, Synlett 2005, 2861. N. Charrier, E. Demont, R. Dunsdon, G. Maile, A. Naylor, A. O'Brien, S. Redshaw, P. Theobald, D. Vesey, D. Walter, Synlett 2005, 3071. C. Harcken, Y. Ward, D. Thomson, D. Riether, Synlett 2005, 3121. A. Satake, Y. Kobuke, Tetrahedron 2005, 61, 13. K. Pchalek, A.W. Jones, M.M.T. Wekking, D.S.C. Black, Tetrahedron 2005, 61, 77. T. Keawin, S. Rajviroongit, D.S.C. Black, Tetrahedron 2005, 61, 853. J.B. Bremner, W. Sengpracha, Tetrahedron 2005, 61, 941. M. Chakrabarty, R. Basak, Y. Harigaya, H. Takayanagi, Tetrahedron 2005, 71, 1793. J.T. Gupton, R.B. Miller, K.E. Krumpe, S.C. Clough, E.J. Banner, R.P.F. Kanters, K.X. Du, K.M. Keertikar, N.E. Lauerman, J.M. Solano, B.R. Adams, D.W. Callahan, B.A. Little, A.B. Scharf, J.A. Sikorski, Tetrahedron 2005, 61, 1845. T. Kouko, K. Matsumura, T. Kawasaki, Tetrahedron 2005, 61, 2309. H. Çavdar, N. Saraçoglu, Tetrahedron 2005, 61, 2401.
Five-membered ring systems: pyrroles and benzo derivatives
05T2407 05T3019 05T3311 05T3637 05T4035 05T4081 05T4631 05T4989 05T5489 05T5831 05T6425 05T6614 05T6886 05T7266 05T7622 05T7907 05T9001 05T9102 05T9242 05T10235 05T10482 05T10490 05T10501 05T10705 05T10958 05T11311 05T11374 05T11751 05T12330 05TA3170 05TL113 05TL139 05TL249 05TL475 05TL639 05TL1061 05TL1325 05TL1751 05TL2009 05TL2041 05TL2423 05TL2479
185
V. Padmavathi, B.J.M. Reddy, B.C.O. Reddy, A. Padmaja, Tetrahedron 2005, 61, 2407. F. Aydogan, A.S. Demir, Tetrahedron 2005, 61, 3019. J. Ruiz, A. Ardeo, R. Ignacio, N. Sotomayor, E. Lete, Tetrahedron 2005, 61, 3311. B.C.G. Söderberg, J.W. Hubbard, S.R. Rector, S.N. O'Neil, Tetrahedron 2005, 61, 3637. P. Marchand, A. Puget, G. Le Baut, P. Emig, M. Czech, E. Günther, Tetrahedron 2005, 61, 4035. T. Zielinski, J. Jurczak, Tetrahedron 2005, 61, 4081. G. Verniest, S. Claessens, N. De Kimpe, Tetrahedron 2005, 61, 4631. G.C. Condie, M.F. Channon, A.J. Ivory, N. Kumar, D.S.C. Black, Tetrahedron 2005, 61, 4989. J.B. Bremner, W. Sengpracha, Tetrahedron 2005, 61, 5489. A.V. Zaytsev, R.J. Anderson, O. Meth-Cohn, P.W. Groundwater, Tetrahedron 2005, 61, 5831. I.W. Davies, J.H. Smitrovich, R. Sidler, C. Qu, V. Gresham, C. Bazaral, Tetrahedron 2005, 61, 6425. K. Singh, S. Behal, M.S. Hundal, Tetrahedron 2005, 61, 6614. T. Fukuda, H. Akashima, M. Iwao, Tetrahedron 2005, 61, 6886. A. Aiello, M. D'Esposito, E. Fattorusso, M. Menna, W.E.G. Müller, S. Perovic-Ottstadt, H. Tsuruta, T.A.M. Gulder, G. Bringmann, Tetrahedron 2005, 61, 7266. V. Khedkar, A. Tillack, M. Michalik, M. Beller, Tetrahedron 2005, 61, 7622. A. Chrétien, I. Chataigner, S.R. Piettre, Tetrahedron 2005, 61, 7907. M. Shoeb, S. Celik, M. Jaspars, Y. Kumarasamy, S.M. MacManus, L. Nahar, P.K. Thoo-Lin, S.D. Sarker, Tetrahedron 2005, 61, 9001. J.H. Markgraf, A.A. Dowst, L.A. Hensley, C.E. Jakobsche, C.J. Kaltner, P.J. Webb, P.W. Zimmerman, Tetrahedron 2005, 61, 9102. S.M. Reddy, M. Srinivasulu, N. Satyarayana, A.K. Kondapi, Y. Venkateswarlu, Tetrahedron 2005, 61, 9242. X.-F. Zeng, S.-J. Ji, S.-Y. Wang, Tetrahedron 2005, 61, 10235. A.S. Demir, M. Emrullahoglu, Tetrahedron 2005, 61, 10482. A.W. Jones, T.D. Wahyuningsih, K. Pchalek, N. Kumar, D.S.C. Black, Tetrahedron 2005, 61, 10490. T.D. Wahyuningsih, N. Kumar, S.J. Nugent, D.S.C. Black, Tetrahedron 2005, 61, 10501. X.K. Ji, D.S.C. Black, S.B. Colbran, D.C. Craig, K.M. Edbey, J.B. Harper, G.D. Willett, Tetrahedron 2005, 61, 10705. K. Hiroya, S. Itoh, T. Sakamoto, Tetrahedron 2005, 61, 10958. L.T. Kaspar, L. Ackermann, Tetrahedron 2005, 61, 11311. C.A. Simoneau, B. Ganem, Tetrahedron 2005, 61, 11374. C. Lin, J. Hsu, M.N.V. Sastry, H. Fang, Z. Tu, J.-T. Liu, Y. Ching-Fa, Tetrahedron 2005, 61, 11751. K. Hiroya, S. Matsumoto, M. Ashikawa, H. Kida, T. Sakamoto, Tetrahedron 2005, 61, 12330. A.S. Demir, A.C. Igdir, N.B. Günay, Tetrahedron: Asymmetry 2005, 16, 3170. T. Murashima, S. Tsujimoto, T. Yamada, T. Miyazawa, H. Uno, N. Ono, N. Sugimoto, Tetrahedron Lett. 2005, 46, 113. M. Koepf, F. Melin, J. Jaillard, J. Weiss, Tetrahedron Lett. 2005, 46, 139. N. Travert, M.-T. Martin, M.-L. Bourguet-Kondracki, A. Al-Mourabit, Tetrahedron Lett. 2005, 46, 249. P. Mathew, C.V. Asokan, Tetrahedron Lett. 2005, 46, 475. J.S. Yadav, B.V.S. Reddy, A.K. Basak, A.V. Narsaiah, S. Prabhakar, B. Jagadeesh, Tetrahedron Lett. 2005, 46, 639. G. Grassi, F. Foti, F. Risitano, D. Zona, Tetrahedron Lett. 2005, 46, 1061. S. Roy, G.W. Gribble, Tetrahedron Lett. 2005, 46, 1325. B. Ke, Y. Qin, Q. He, Z. Huang, F. Wang, Tetrahedron Lett. 2005, 46, 1751. S.H. Lee, K.M. Smith, Tetrahedron Lett. 2005, 46, 2009. C.A. Olsen, N. Parera, F. Albericio, M. Álvarez, Tetrahedron Lett. 2005, 46, 2041. N.K. Garg, B.M. Stoltz, Tetrahedron Lett. 2005, 46, 2423. B.K. Banik, M. Fernandez, C. Alvarez, Tetrahedron Lett. 2005, 46, 2479.
186 05TL2563 05TL2643 05TL2865 05TL2915 05TL3831 05TL3859 05TL4045 05TL4219 05TL4577 05TL4839 05TL5831 05TL6983 05TL7069 05TL7531 05TL7881 05TL8053 05TL8117 05TL8177 05TL9013
E.T. Pelkey
S. Kamijo, C. Kanazawa, Y. Yamamoto, Tetrahedron Lett. 2005, 46, 2563. B.K. Banik, I. Banik, M. Renteria, S.K. Dasgupta, Tetrahedron Lett. 2005, 46, 2643. M. Chakrabarty, T. Kundu, S. Arima, Y. Harigaya, Tetrahedron Lett. 2005, 46, 2865. S. Leitch, J. Addison-Jones, A. McCluskey, Tetrahedron Lett. 2005, 46, 2915. H. Suzuki, Y. Tsukakoshi, T. Tachikawa, Y. Miura, M. Adachi, Y. Murakami, Tetrahedron Lett. 2005, 46, 3831. Z.-P. Zhan, R.-F. Yang, K. Lang, Tetrahedron Lett. 2005, 46, 3859. A.K. Mohanakrishnan, R. Balamurugan, Tetrahedron Lett. 2005, 46, 4045. H. Zhou, D. Han, X. Liao, J.M. Cook, Tetrahedron Lett. 2005, 46, 4219. A.K. Mohanakrishnan, N. Ramesh, Tetrahedron Lett. 2005, 46, 4577. D. Alonso, E. Caballero, M. Medarde, F. Tomé, Tetrahedron Lett. 2005, 46, 4839. G. Wu, Q. Liu, Y. Shen, W. Wu, L. Wu, Tetrahedron Lett. 2005, 46, 5831. A.K. Mohanakrishnan, N. Ramesh, C. Prakash, Tetrahedron Lett. 2005, 46, 6983. M. Alongi, G. Minetto, M. Taddei, Tetrahedron Lett. 2005, 46, 7069. L. Töke, M. Nyerges, Tetrahedron Lett. 2005, 46, 7531. M.-L. Bennasar, E. Zulaica, S. Alonso, Tetrahedron Lett. 2005, 46, 7881. J. Wilkinson, N. Ardes-Guisot, S. Ducki, J. Leonard, Tetrahedron Lett. 2005, 46, 8053. T. Belhadj, P.G. Goekjian, Tetrahedron Lett. 2005, 46, 8117. L. Joucla, A. Putey, B. Joseph, Tetrahedron Lett. 2005, 46, 8177. A.W. Grubbs, G.D. Artman, R.M. Williams, Tetrahedron Lett. 2005, 46, 9013.
187
Chapter 5.3 Five–membered ring systems: furans and benzofurans Xue-Long Hou Shanghai–Hong Kong Joint Laboratory in Chemical Synthesis and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China.
[email protected] Zhen Yang Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry, Peking University, Beijing 100871, China.
[email protected] Kap-Sun Yeung Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, P.O.Box 5100, Wallingford, Connecticut 06492, USA.
[email protected] Henry N.C. Wong Department of Chemistry, Institute of Chinese Medicine and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis,† The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
[email protected] and Shanghai–Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai 200032, China.
[email protected] † An Area of Excellence of the University Grants Committee (Hong Kong).
________________________________________________________________________ 5.3.1 INTRODUCTION This article aims to review papers that were published in 2005 on reactions and syntheses of furans, benzofurans and their derivatives. Several reviews have summarized chemistry of furanoflavonoids <05NPR400> and furanoditerpenoids <05H(65)1221>, synthesis of substituted furans and benzo[b]furans by various organometallic reactions <05T2245; 05CL1068>, synthesis of morphine alkaloids <05SL388>, and synthesis of 2,5dihydrofurans <05OBC387>. Naphtho[2,3-c]furan-4,9-diones and their related compounds have also been reviewed <05T9929>. A feature article summarizes efforts in the electroorganic synthesis of 2,5-dialkoxydihydrofurans on solid phase employing polymer beads as supports <05S3654>. Like 2004, many new naturally occurring molecules containing tetrahydrofuran and dihydrofuran rings were identified in 2005. References on compounds whose biological activities were not mentioned are: <05HCA3225; 05JNP19; 05JNP435; 05JNP780; 05JNP1445; 05JNP1588; 05OL1877; 05OL3893; 05P1060; 05P2787; 05T8910>.
188
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
Articles on those naturally occurring compounds containing tetrahydrofuran or dihydrofuran skeletons whose biological activities were assessed are: <05CC2936; 05JNP194; 05JNP319; 05JNP915; 05JNP1051; 05JNP1125; 05JNP1175; 05JNP1394; 05JNP1656; 05OL2145; 05OL4733; 05P1163; 05P1707; 05P2734; 05T6561>. References on those furan-containing compounds whose biological activities were not mentioned are: <05BCJ1302; 05HCA2370; 05HCA2654; 05JNP7; 05JNP244; 05JNP787; 05JNP1314; 05OL5051; 05P1088; 05P1094; 05P1100; 05P2334; 05T845; 05T2655; 05T8699; 05T11032>. Naturally occurring compounds containing furan skeletons whose biological activities were assessed were mentioned in the following papers: <05JNP248; 05JNP413; 05JNP614; 05JNP706; 05P2298; 05T8382>. References of those benzo[b]furan- or dihydrobenzo[b]furan-containing compounds whose biological activities were not mentioned are: <05H(65)1471; 05H(65)2461; 05HCA23; 05HCA1034; 05HCA2554; 05JNP1175; 05JNP1723; 05P665; 05P669; 05P703; 05P1141; 05T8656>. References on those naturally occurring compounds containing benzo[b]furan or dihydrobenzo[b]furan skeletons whose biological activities were assessed are: <05EJO2708; 05H(65)267; 05H(65)871; 05H(65)1189; 05HCA2315; 05JNP43; 05JNP323; 05JNP1066; 05P487; 05P715>. 5.3.2 REACTIONS 5.3.2.1 Furans A number of novel cycloaddition reactions of furans were reported in 2005. A rare example of a Lewis acid-promoted intramolecular Diels−Alder reaction between a furan moiety and a trisubstituted allene, forming an oxa-bridged octalone that contains an exocyclic (E)-alkene as a single diastereoisomer, is shown below <05JA10834>. An intramolecular Diels−Alder reaction between a furan and a vinylsulfone provided a key exo-sultone intermediate for the synthesis of a C1’-C8’ segment during the total synthesis of pamamycin 621A and 635B <05AG(I)6231>. O C O
H
O
H Me2AlCl
O
−78 to −20 °C 80%
The [4+3] cycloaddition between 2-aminofuran and oxyallyl cations, followed by base-induced elimination of the resulting adducts, was used in the synthesis of 3aminotropones <05TL8475>. A chiral Lewis acid-catalyzed [4+3] cycloaddition between furans and nitrogen−stabilized oxyallyl cations derived from allenamides was developed. As depicted below, the C2 -symmetric salen-based ligand is the most effective in promoting this asymmetric cycloaddition reaction <05JA50>.
O
O N
+ O •
(9 equiv.)
Cu(OTf)2 (25 mol%) Catalyst (32 mol%) Dimethyldioxirane AgSbF6 Acetone–CH2Cl2 4Å MS −78 °C, 8−10 hr 99% ee 91%
O
O N
H
O N O
t
Bu Catalyst
N
OH HO tBu
t Bu
t
Bu
189
Five–membered ring systems: furans and benzofurans
A [6+4] cycloaddition between a furan and a tropone was successfully achieved for the first time in an intramolecular manner during the construction of the ABC-ring of ingenol, as depicted in the following scheme <05SL2501>. O O O MeO
Sit BuPh2 OCH2OMe
O
C6H6 reflux 65%
MeO
H Sit BuPh2 OCH2OMe
As shown in the following scheme, 2-butadienylfurans participate as 8π-components in the [8+2] cycloaddition with dimethyl acetylenedicarboxylate, giving oxygen−bridged 10membered rings <05OL1665>.
CO 2Me
+ O
O CO 2Me
1,4-Dioxane 80 °C, 10 hr 77%
MeO2C
CO2Me
Cu-Bisoxazoline-catalyzed asymmetric cyclopropanation of methyl 2-furoate with ethyl diazoacetate was a key step in the synthesis of the cis-fused 5-oxofuro[2,3-b]furan core of spongiane diterpenoids <05OL5353>. An interesting example of rhodium-catalyzed intramolecular addition of a diazoketone to furan affording a strained cyclobutenone, is illustrated below. Iodine-induced isomerization of the product provided the fused tricyclic dihydrofuran compound <05HCA330>. O
O
N2 O
O
Rh2(OAc)4 CH2Cl2 15 min CHO
I2 CH2Cl2 r.t., 1 hr 83% (2 steps)
O
The formation of an arene oxide intermediate, exemplified below, during the goldcatalyzed intramolecular reaction between furans and alkynes to form phenols was observed experimentally for the first time <05AG(I)2798>. O N Au Cl Cl NTs
NTs
NTs
O O
OH
The less well-studied 3-silyloxyfuran was shown to react with aldehydes in an aldol addition manner under Lewis acidic conditions. High syn-diastereoselectivity was obtained with bulky aldehydes <05OL387>. 4-Alkoxy-3-lithio-2-silyloxyfurans reacted with a variety of electrophiles to form 3-substituted tetronates after acidic hydrolysis <05SL2735>. Furans and 2-trimethylsilyloxyfuran are effective nucleophiles in the organocatalytic tandem
190
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
Michael addition/enamine chlorination reaction <05JA15051>. 2-Trimethylsilyloxyfuran reacted readily with chiral tungsten carbene complexes in a Mukaiyama−Michael addition manner to give the anti products selectively, as depicted in the example below <05AG(I)6583>. OMe (OC)5W
O
Me3SiO
O
+ O
OMe
O
PhMe −60 °C 92% anti : syn = 11 : 1 face selectivity = 38 : 1
O
W(CO)5
O
O
C-O Bond cleavage of 2-methoxyfurans by a catalytic amount of NaI followed by in situ alkylation produced butenolide derivatives in good yield as shown in the following example <05JOC1063>. CO2Me
+ Ph
O
CO2Me
NaI (10 mol%) I
OMe
Ph THF reflux, 10.5 hr 79%
O
O
Sodium chlorite in acidic aqueous medium was found to be an efficient oxidation system for the conversion of symmetrical 3,4-disubstituted furans to γ-hydroxybutenolides <05JOC3318>, and 2-substituted and 2,5-disubstituted furans to α,β-unsaturated dicarbonyl compounds <05SL1468>. 3-Alkoxy-2,5-diphenylfurans were oxidized by phenyltrimethylammonium tribromide to 2-alkoxy-3-furanones in alcohols, and to cis-2alkoxy-2-butene-1,4-diones in DMSO <05H(65)1347>. A regioselective oxidation via 2trimethylsilylfuran was employed in the synthesis of a β-lactam-based proteasome inhibitor <05JA15386> and a total synthesis of milbemycin G <05OBC3654>. As shown in the following example, a regioselective oxidation of 3-substituted furans (except 3-carboxylate) was achieved by using N-bromosuccinimide, followed by acidic hydrolysis of the 2,5diethoxy-2,5-dihydro intermediate, giving α-substituted γ-butenolides <05SL1575>. The regioselectivity was proposed to arise from the kinetic elimination of the more acidic C2 proton of this intermediate. NBS NaHCO3
BnO
O
EtOH−CHCl3 r.t.
BnO EtO
HCl O
OEt
H2O−Acetone r.t. 80%
BnO O
O
Photooxygenation of furanosyl furans can lead to either O- or C-furanosides, depending on the transformation of the intermediate endoperoxides <05JOC6503>. Photosensitized oxidation of 2-trimethylsilylfuran was used to construct the bis-spiroketal core of prunolides. As shown below, both the (Z)- and (E)-isomers provided the same 2:1 mixture of the trans and cis products <05OL2357>.
191
Five–membered ring systems: furans and benzofurans
SiMe3
1) O2, hv Rose Bengal MeOH 2 min
SiMe3
2) Silica gel 80%
MeO O O
O
MeO O O
O
MeO
O
MeO
An interesting example of performing the Achmatowicz oxidation of furfuryl alcohol and its aza-variant simultaneously on a furfuryl alcohol/furfuryl amine-containing substrate in the synthesis of aza-C-linked disaccharides was reported <05CC1646>. Oxidation of 2,5bis-hydroxyalkyl substituted furans using NBS was used as an approach to construct the trioxadispiroketal ring systems found in azaspiracid, pinnatoxins and pteriatoxins <05OL27>. A related example of intercepting the transient oxonium ion by a pendant hydroxyl group during the oxidative cleavage of a furan ring is shown below <05TL8439>. The ketone intermediate underwent further cyclization to provide the tetracyclic isochromene product. OH O
O HCl O
Br
Br
Br
EtOH reflux 57%
O
O
O
O
Oxidation of the furan moiety of the diterpene hispanolone was performed electrochemically in a solution of NH4 Br in MeOH, providing its spiro-tetracyclic derivative, and subsequently, the α-butenolide analog isoleopersin G <05JOC4538>. Electrochemical annulation of furan has attracted further interest in the synthesis of complex ring systems. This kind of anodic oxidation approach was employed in the construction of the [6-7-5] fused tricyclic core of guanacastepenes, obtained as a single diastereoisomer, as shown below <05OL3425>. The good reaction yield is consistent with the gem-dialkyl effect that is required for the efficient formation of the 7-membered ring in this type of electron transfer reaction <05JA8034>. RVC anode (0.2 mA) 2,6-Lutidine 0.06 M LiClO4
Ph2tBuSiO
Ph2t BuSiO H
20% MeOH−CH2Cl2 2.44 F/mol r.t., 17 hr OSitBuMe2 70%
O Ph2tBuSiO
MeO
O H OSit BuMe2
O
A one-step furan alkylation/eliminative cyclization between N-tosylfurfurylamine and electron-rich o-(3-hydroxypropyl)anilines under refluxing conditions in strong acids provided indole derivatives in modest yield, as depicted in the example below <05TL8443>. MeO
NHTs OH
MeO Et
+
H3PO4 O NHTs
AcOH reflux 30%
MeO
Ts N O
MeO Et
Me
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5.3.2.2 Di- and Tetrahydrofurans The addition of active methylene compounds to 2,3-dihydrofuran was promoted by catalytic amounts of AuCl3 -AgOTf, providing 2-substituted THF derivatives, as depicted in the scheme below <05OL673>. 2-Lithiated dihydrofurans were shown to lead to heterospiro cycloalkanones <05H(66)57>. O O
O
Ph
Ph
+
AuCl3−AgOTf
O
O
Ph
Ph
CH2Cl2 r.t. 58%
O
2,3-Dihydrofurans participated in a TiCl4 -promoted three-component reaction that involved the nucleophilic addition of a cyclic enol ether to an imino ester and subsequent reaction of the intermediate oxocarbenium ion with a silane reagent, forming interesting THF-containing amino acid analogs. A high diastereomeric ratio (d.r.) was obtained with 5substituted-2,3-dihydrofurans, as illustrated by the following example <05OL7>.
Ph
O
+ TsHN
CO2Et
TsHN H
TiCl4 MeCN (5 equiv.)
+ Me3Si
CH2Cl2 −78 °C 99:1 d.r. 84%
Ph
CO2Et
O
A full account of the Ru(PyBox)-catalyzed enantioselective 1,3-dipolar cycloaddition between 2,3-dihydrofuran and diazopyruvates, first described in 2004, was reported <05HCA1010>. 2,3-Dihydrofurans having a 3-acetyl group, e.g. benzocycloalka[1,2b]furans and spiro[furan-2(3H),1’-benzocycloalkane], underwent benzannulation via photoinduced cleavage of the dihydrofuran ring <05TL7303>. An example that produced a helicene-type compound is shown below.
O
O
hv 2M HCl O
MeCN Ar 61%
Related to the example described in 2004, another novel reaction of 2,3-dihydrofuran with zirconocene was reported. As shown in the scheme below, regioselective insertion of 2,3-dihydrofuran into aryne-zirconocene complexes, generated from aryllithiums, and subsequent reaction with electrophiles, provided 1,2-disubstituted products that contain a (Z)alkene <05SL2513>. I
Li
O
+
1. Cp2Zr(Me)Cl 2. I2 54%
OH
Further studies of the regioselective tandem ring opening/cross metathesis of 2-endosubstituted 7-oxanorbornenes with electron-rich olefins, a process first described in 2004, were reported. Reaction of the 2-exo isomer, like that of the 2-endo isomer, was also found to
193
Five–membered ring systems: furans and benzofurans
provide good regioselectivity (9:1) <05OL131>. An interesting example of tandem ring opening/ring closing metathesis of a 7-oxanorbornene, shown below, was used to prepare a key bicyclic cyclopentenone intermediate in a total synthesis of trans-kumausyne <05OL3493>. O
O
H2C=CH2 Cl2(PCy3)2Ru=CHPh (5 mol%)
O
H
CH2Cl2 r.t. 83%
H O
A related approach was used for the synthesis of an interesting tricyclic β-lactam <05HCA1387>. However, only the allylic ether starting material, shown below, was able to undergo the subsequent ring-closing step. O Bn
H2C=CH2 Cl2(PCy3)2Ru=CHPh (10 mol%)
O
CH2Cl2 r.t. 98%
N O
O N Bn
O
O
Palladium-catalyzed enantioselective Heck phenylation of 2,3-dihydrofuran to provide 2-phenyl-2,5-dihydrofuran was performed employing a chiral phosphite-oxazoline ligand derived from D-glucosamine <05OL5597>. Related furanoside-derived diphosphite ligands were used for the rhodium-catalyzed hydroformylation of 2,5-dihydrofuran to provide 3-formyltetrahydrofuran as the major product with modest enantioselectivity <05CC1221>. An efficient hydrophenylation of oxabicyclic alkenes was performed by using an oxazoline-derived palladacycle as the catalyst <05JOC6085>. Rhodium-catalyzed cyclopropanation of 8-oxabicyclo[3.2.1]oct-6-ene by diazocarbonyl compounds gave exoproducts <05TL2709>. A 3,4-dibromo-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one was found to be more reactive than bicyclo[2.2.1]heptenes towards the thermal Diels–Alder reaction with dienes, e.g. 1,3-butadiene <05OL423>. The ring opening of 7-oxabenzonorbornadienes with alkyl Grignard reagents was studied using spiro-phosphoramidite, (S,S,S)-SIPHOS-PE, as a chiral ligand. Although high anti-diastereoselectivity could be obtained, enantiomeric excess was only up to 88% <05JOC3734>. The Ni-catalyzed ring opening of 7oxabenzonorbornadienes with alkyl and allyl zirconium reagents in the presence of Zn provided 1,2-dihydronaphthalene products regio- and syn-selectively <05JOC9545>. The enantioselective ring opening of 7-oxabenzonorbornadienes with dialkyl zinc reagents as catalyzed by chiral palladium Fesulphos complexes to give 1,2-cis products were optimized such that 0.5 mol% of catalyst could be employed to achieve high enantioselectivity <05JA17938>. New reactions involving tetrahydrofuran radicals continued to be explored. An example is the reaction of two THF molecules with anilines to provide THF-substituted amino alcohols, as demonstrated in the following scheme <05T379>. A plausible mechanism involves the generation of an oxonium ion by oxidation of the initially formed THF radical. NH2
Me2Zn (12 equiv) air
+ OMe
O
MeO
O r.t. 73%
N H
OH
Ring opening of tetrahydrofuran to 4-iodobutanol was used as the starting point for a synthesis of the complex tetracyclic picrasane famework of triterpene quassinoids <05OL5601>. Acylative cleavage of tetrahydrofuran can be performed under iodine-
194
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
catalyzed conditions to give a 4-chlorobutyl ester <05TL8493>. This type of reaction can also be achieved in a regioselective manner by using Bi(III) halides as catalyst <05T4447>. An application to the synthesis of a tetralin is shown below. AcO
O
Ph
AcCl BiCl3 87%
The C2 hydrogen of substituted tetrahydrofurans was found to undergo 1,5-hydride migration to pendant electron-deficient alkenes <05JA12180> and aldehydes <05OL5429> under Lewis acid-promoted conditions, forming spiro-carbocycles and spiro-ketals respectively after subsequent cyclization. An example is illustrated below. CO2Et CO2Et
O OHC
CO2Et
BF3•Et2O O
CH2Cl2 r.t., 3 hr 96%
CO2Et O
5.3.3 SYNTHESIS 5.3.3.1 Furans A procedure to produce furyllithium species using lithium magnesates was reported <05TL7989>. Unusual regioselectivity was observed in the lithiation of 3-aryl- and 3styrylfurans using BuLi, in which lithiation occurred preferentially at the 2-position <05OL3347>. Several furan-containing natural products were synthesized, in which classical procedures were adopted in the furan ring formation <05JOC2250; 05SL511; 05SL1951; 05T2003; 05TL1713>. A highlight in the development in furan syntheses also appeared in 2005 <05AG(E)850>. Lewis acid catalyzed carbonyl-ene reaction of 2-methylene-2,3dihydrofuran, produced from the Kishner reduction of 2-furylhydrazone, reacted with aldehydes in the presence of a Lewis acid, affording 2-substituted furans as depicted below. It is worth noting that an optically active alcohol was provided when Ti(OiPr)4 /(S)-BINOL was the catalyst <05JOC2862>. PhCHO
O
OH
Yb(fod)3 96%
O
Ph
As can be seen in the scheme below, an interesting molecule, tetrakis(2furyl)methane, was synthesized from tri(2-furyl)methane using an aromatic nucleophilic substitution reaction as the key step <05CL910>. O O O
1. BuLi, iPr2NH DME, -78 °C
O
2.
O
Cl
O 34%
CO2Me
O O
O
1. 10% NaOH MeOH
2. Cu powder quinoline 73% CO2Me
O O
O
Ring-closing metathesis (RCM), one of the most powerful tools for ring-formation, has been employed to the synthesis of substituted furans. As shown below, a range of
195
Five–membered ring systems: furans and benzofurans
different substitution patterns and functional groups are compatible with this sequence <05EJOC1969>. 1. 10% Grubbs' catalyst CH2Cl2, heat
p-MeOC6H4
MeO2C Me
1. 10% Grubbs' catalyst CH2Cl2, heat
MeO2C
2. CF3CO2H 70%
Me
OMe
O
p-MeOC6H4
2. CF3CO2H 79%
OMe
O
MesN
O NMes
Cl
O
Ru Ph PCy3 Grubbs' catalyst Cl
A full paper describing the synthesis of 2,4-disubstituted furans in high yields through a novel oxidative cyclization-dimerization reaction between two different allenes was provided <05JOC6291>. Pr
Ph
PdCl2(MeCN)2 (5 mol%)
H
Ph
O
+ H
Me
COOH2 O
MeCN rt 90%
O Pr
Me
O
2,3-Disubstituted furans with different functionalities were synthesized through an acid-catalyzed elimination reaction of 2-alkylidenetetrahydrofurans, in turn, prepared via the cyclization of 1,3-bis-silyl enol ethers with 1-chloro-2,2-dimethoxyethane with high regioselectivity <05EJOC2074>. 2-Substituted furans and bicyclic furans can also be synthesized utilizing this methodology. OMe O Cl
CO2Et
DBU (2 equiv)
O
CF3CO2H
MeO
THF 20 °C 80%
CO2Et
CH2Cl2 20 °C 100%
O
CO2Et
Aldol reaction of α,β-aziridino- or α,β−epoxyaldehydes followed by an intramolecular enol cyclization in the presence of Bu2 BOTf/DIPEA provided 5-substituted2-furylamines and carbinols in good yields. The reaction proceeded in a one-pot manner <05TL5467>. X
Bu2BOTf DIPEA
O CHO
+
X
OH
O
CH2Cl2 0–25 °C O
X
X = NHBoc, 72% X = O, 75%
As illustrated in the following scheme, a two-step electrochemical annulation directed to polycyclic systems containing annulated furans has been extended to the formation of seven-membered ring fused furans <05JA8034>. Mechanistic insights were also provided.
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X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
1. Carbon anode i PrOH, LiClO4 2,6-Lutidine–MeCN
Me O
2. 1N HCl 61%
Me3SiO
O HO
Thermal reaction of cis-2-alken-4-yn-1-one afforded trans- and cis-1,2difurylethenes as well as a small amount of trimer in the presence of a weak acid. However, treatment of the same alkenynone with Et3 N and CHCl3 led to the formation of a triethylfurylammonium salt and an isobutenylfuran derivative <05JOC2576>. Ph PhPh
O
HOAc
Ph
Ph
CHCl3
O
Ph
O 62%
+
Ph
O O
+
OO 23%
6%
O Ph
O
Et3N
Ph
+
CHCl3
Ph
NEt3 Cl–
O 71%
+
Ph
O 24%
Synthesis of furans with chiral substituents with high diastereoselectivity was achieved by using an optically active electrophilic selenium reagent via a carboselenenylation reaction of simple aryl-conjugated alkenes <05AG(E)3588>.
Ph
Me
1. Ar*SeOTf 4A MS –78 °C
Me OMe Me
Me
2.
O
SeAr*
O 63% 84% de
Me
SeOTf OMe Ar*SeOTf
A mild and simple reaction of dimethyl acetylenedicarboxylate with ammonium ylides produced trisubstituted furans in good yields <05S391>. Reaction of acetylenedicarboxylate with α-bromoketones in the presence of DABCO gave similar products in good yields <05JOC8204>. It seems that the intermediate is the same in both reactions.
MeO2C
CO2Me
+ Me
O
N N
+
Br–
K2CO3 (200 mol%) MeCN 58%
MeO2C Me
CO2Me O
A 5-Endo-dig electrophilic cyclization reaction of 1,4-diarylbut-3-yn-1-ones with NBS, NIS or ICl afforded 3-halofurans in high regioselectivities and yields <05OL1769>.
197
Five–membered ring systems: furans and benzofurans Me Br
O
NBS O
Acetone 89%
Br
Me
Br
An example of the synthesis of 3-halofurans was provided by Müller <05CC2581>. As shown below, cross-coupling of acid chlorides with THP-protected propargyl alcohol derivatives gave rise to the corresponding alkynone, which underwent acid-assisted electrophilic addition of hydrogen halide with concomitant deprotection and cyclization, affording 3-halofurans. If RB(OH)2 was added into the reaction system before work-up, the reaction can provide Suzuki-coupled products in moderate yields. O Ph
OTHP
1. Pd(PPh3)4 (2 mol%) CuI (4 mol%) Et3N (100 mol%)
Cl
+
Cl
Ph
2. NaCl (200 mol%) PTSA (110 mol%) MeOH 60 °C 70%
Et
O
Et
Yamamoto demonstrated that in the presence of CuBr as catalyst, trisubstituted furans were generated employing similar starting materials <05JOC4531>, while Liu showed that 3-iodo-tetrasubstituted furans were produced using the same starting materials and I2 /K3 PO4 as reagent <05OL4609>. Ph CuBr (10 mol%)
MeOH I2 (110 mol%) K3PO4 (110 mol%)
DMF 80 °C 62%
CH2Cl2 r.t., 30 min 94%
O
O
iPrOH
OiPr
Ph
Ph
O I OMe
Gevorgyan reported a regiodivergent synthesis of halofurans via a 1,2-halogen migration of haloallenyl ketones catalyzed by AuCl3 <05JA10500>. The procedure provided 3-halofurans, some of which are not easy to access. Br
H
H15C7
CHO
Toluene 73%
Me
Br
AuCl3 (2 mol%) H15C7
O
A microwave-assisted synthesis of polysubstituted furans via the Paal–Knorr reaction was reported. Thus, furans were easily obtained in good yields by heating diketones under microwave irradiation in acid solution <05EJOC5277>. O
CO 2Me
Me O
CO2Me
Microwave EtOH–HCl, 100 °C, 4 min 84%
Me
O
Pr
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X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
Au-Catalyzed reaction of propargyl vinyl ethers furnished tri- and tetrasubstituted furans in high yields. The reaction proceeded through cyclization of 2-allenyl-1,3-dicarbonyl intermediates produced from propargyl-Claisen rearrangement <05OL3925>. (PPh3)AuCl (2 mol%) AgBF4
Me CO2Et
O
Me O
CO2Et
Me
Me
CH2Cl2 95%
Me
Me
CO2Et
Me
O
Another example concerning furan synthesis by gold-catalyzed cyclization was also reported. Reaction of (Z)-enynols using AuCl3 furnished fully substituted furans in high yields under mild reaction conditions <05OL5409>. Pr
Pr
Pr
AuCl3 (1 mol%) Me
PhCH2
CH2Cl2 92%
HO Ph
Pr O Me
Pd-Catalyzed three-component cyclization-coupling reaction of methyl acetoacetate, propargyl bromide or carbonate and aryl halides gave tetrasubstituted furans with high regioselectivities and good yields <05JOC6980>. ArI Pd(PPh3)4 K2CO3
O Me
CO2Me
+
OCO2Me
Me
CO2Me Ph
CO2Me
+
DMF 100 °C 50%
Ph
O
Me 99 : 1
O
Me
Multicomponent reaction of an imidazolinium salt with aldehydes and acetylenecarboxylates in the presence of NaH led also to tetrasubstituted furans in good yields. A plausible reaction mechanism was proposed <05OL2297>. CHO
Cl– t Bu + N
Ph
+
MeO 2C
+
toluene, 90∞C 58% F3C
N CF3
CO2Me
Ph
NaH
t Bu
O
N tBu
NHtBu
Similarly, reaction of a thiazolium salt with aldehydes and dimethyl acetylenedicarboxylate provided 3-amino tetrasubstituted furans in moderate to good yields. The substitution pattern differs from the reactions illustrated above <05JOC8919; 05OL1343>. CHO
CO2Me
+ NO2
Me
+ CO2Me
I–+ Me N S
CO2Me
MeHN NaH CH2Cl2 –78 °C 61%
O O2N
CO2Me
199
Five–membered ring systems: furans and benzofurans
An intramolecular Wacker oxidation of allyl hydroxypyridinone gave rise to furopyridinone derivatives in excellent yields <05JOC8055>. PdCl2 CuCl2 O2
Me
O Me
N
HO
Me Me
DMF–H2O 95%
O
Me
O
N
O O
Another procedure for the synthesis of furopyridinone derivatives was reported, in which, an imine derived from furfuraldehyde was used as the starting material as can be seen in the following scheme <05SL1006>. Cyclization of 2,5-disubstituted furans using TFAA afforded the tetracyclic lactam skeleton containing trisubstituted furans found in the alkaloid selaginoidine <05OL1339>. 1. CF2Br2 Active Pb Bu4NBr N
O
Ph
F
F
F
O
160 °C
O
N Ph
2. SiO 2 H2 O 53%
N
83% O
Ph
O
5.3.3.2 Di- and Tetrahydrofurans Williamson-type cyclic ether synthesis continues to be one of the most popular methods for the construction of tetrahydrofurans. Leaving groups used in these approaches are mesylate <05H(65)519; 05OL2627; 05OL4083; 05OL48819; 05TL325>, tosylate <05AG(I)580>, triisopropylbenzenesulfonate <05TA7; 05TL4287>, ammonium salts <05OL933>, water <05SL2391>, iodide <05TL4235> and iodonium salts <05T1061>. The scheme below depicts the use of a selenonium moiety as a good leaving group <05EJO543>. Ph CO2Me
HO
SeR R = Camphor
Ph
PhSeBr AgOTf
Ph CO2Me
+ MeCN O Se R r.t., 15 min TfO– H SePh 61%
O
CO2Me
Opening of epoxides has also been employed in the preparation of tetrahydrofuran frameworks <05OL2945; 05OL4867; 05SL1630>. The reaction illustrated below is a relevant example <05JA5806>. Moreover, electrophiles generated in an oxidative manner have been shown to serve as initiators in epoxide cascade cyclization routes to form polyethers <05TA3570>. O
O O
OSEM HO
H
O
O
H
OH
CSA
O
OSEM
CH2Cl2 r.t., 10 min HO 98%
H
O
H
O
H
OH
Hydroalkoxylation of alkenols catalyzed by acids <05HCA3055; 05OL4117>, silver(I) triflate <05OL4553>, palladium catalysts <05SL1609> and molybdenum catalysts <05CL790> has also been utilized in the formation of tetrahydrofurans. As can be seen
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X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
below, the Lewis acid catalyst tin(IV) triflate has also been shown to activate the double bond in a cycloisomerization reaction, forming a tetrahydrofuran ring <05CC2286>. On the other hand, cycloetherization of 1,4-butanediols catalyzed by a cationic platinum salt prepared in situ from PtCl2 and AgSbF6 also led to tetrahydrofurans <05SL152>. Sn(OTf)4 OH
MeNO2 reflux, 15 min > 98%
O
Another general route from which tetrahydrofuran rings can be generated is haloetherization <05AG(I)734; 05OL2837; 05SL421; 05S1237; 05TL6519>, which is used as the pivotal step in the total synthesis of cordiaquinones as shown below <05T9164>. OMe HO
NIS
I
O
OMe
MeCN 75% OMe
OMe
The configuration of the penta-tetrahydrofuranyl diol produced by a one-step RuO4 – catalyzed oxidative polycyclization of squalene was reported <05T927>. The total synthesis of neodysiherbaine also involved the use of a ruthenium-mediated oxidative cyclization step <05TL6629>. In addition, osmium tetroxide is known to catalyze the formation of tetrahydrofurans from the diene as shown in the following scheme <05AG(I)4766>. Geranyl acetate gave also a similar result <05TL1623>. An oxidative cyclization reaction was employed as the key step to synthesize 21,22-di-epi-membrarollin <05CC5636>, and to convert gardnerine to gardnutine <05TL4219>.
OBn
OsO4 Me3NO CSA CH2Cl2 88%
OHH
OBn
O
OH
The hydrolysis of the N,O-acetonide linkage of the butenolide below, followed by treatment with a mild base promoted conjugate addition led to the formation of the bicyclic lactone containing a tetrahydrofuran ring <05OL875>. Similar Michael approaches were also used by the same authors in their stereoselective synthesis of a novel carbamoyl oxybiotin <05TL6469> as well as by another group in the total synthesis of (+)-7-epi-goniofufurone <05SL2260>. NCbz O
O
O
1. HCO 2H CH2Cl2 0 °C
CbzHN
H
O O
2. NaHCO3 EtOAc-H2O 79%
O
H
A radical cyclization procedure is also a viable route for the formation of tetrahydrofuran skeletons <05CC1996; 05OL1597; 05OL3093; 05SL59; 05TL4859; 05TL7751>. A relevant example to show the versatility of radical cyclizations <05JA10396> is depicted below in the total synthesis of (–)-jimenezin <05TL6621>.
201
Five–membered ring systems: furans and benzofurans
C10H12 O
O
O
S
O
PhMe –30 °C 93%
I
O
O
S
••
••
Tol
C10H12
n-Bu3SnH Et3B
Tol
Conversions of γ-lactones <05OBC1670; 05OL5517; 05S3219; 05TL3249; 05TL5761; 05TL8199>, 2-acyloxytetrahydrofurans <05JA10879; 05OL3989>, 2methoxytetrahydrofurans <05TL7451> and 2-phenylthiotetrahydrofurans <05AG(I)6231> to tetrahydrofurans are direct approaches towards these molecules. The scheme below is an example <05TL6297>. DIBAL
t
BuPh2SiO H
O
Et3SiH BF3•Et2O
t
BuPh2SiO O CH2Cl2 –78 °C, 30 min
H
O
t
BuPh2SiO CH2Cl2 –78 to –5 °C 5 hr 86% (2 steps)
OH
H
O
Organometallic chemistry has also been widely utilized in preparing substituted tetrahydrofurans. Thus, (+)-goniothalesdiol and (+)-7-epi-goniothalesdiol have been synthesized employing as the pivotal step a standard Pd(II)-catalyzed carbonylation of unsaturated polyols <05T2471>. A palladium-catalyzed conversion of allenyl-aldehyde to tetrahydrofurans was also reported <05OL3733>. On the other hand, o-(1,6enynyl)benzaldehydes underwent rhodium(I)-catalyzed [3+2] cycloaddition to form tetrahydrofurans, presumably via dipolar carbonyl ylide intermediates <05CC4429>. Ru(COD)(COT) was employed to catalyze the codimerization of 2,3-dihydrofurans with α,βunsaturated esters to form 2-(1-alkoxycarbonyl)alkylidenetetrahydrofurans <05CC5100>. As in our previous reports in this series, many other organometallic protocols for realizing 2alkylidenetetrahydrofurans were recorded in 2005 <05CL160; 05JA5798; 05JA12466; 05JOC1505; 05OL779; 05OL2237; 05OL3093; 05OL5777; 05S3293; 05SL1889; 05TL1155>. A new stereoselective synthesis of tetrahydrofurans was achieved by palladiumcatalyzed reactions of aryl and vinyl bromides with γ-hydroxy terminal olefins <05JOC3099>. An example is illustrated in the following scheme. HO
Br
Pd2(dba)3 NaO-t-Bu dpe-phos
O
+ tBu
THF 65 °C 70%
tBu
In the presence of SnCl4 , allylsilanes were able to react with aldehydes in a [3+2] annulation to afford 2,5-trans-tetrahydrofurans with good diastereoselectivities <05JA10818>. (+)-Bullatacin <05OL4245>, virgatusin <05OL3685>, 3-vinylidene tetrahydrofurans <05OL3283> and several annonaceous acetogenins <05JOC8035> were all synthesized using similar strategies. 3-Methylenetetrahydrofuran rings can also be constructed from aldehydes and a palladium trimethylenemethane complex in a [3+2] manner <05OL641>. Similar conversions lead to the formation of 3-vinyltetrahydrofurans <05SL3148>.
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X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
SiMe2Ph C10H21
+ BnO
SnCl4 4Å MS CHO
OSitBuMe2
PhMe2Si tBuMe
CH2Cl2 –45 °C 93%
2SiO
O
H21C10
OBn
3-Oxidopyrylium betaine underwent [3+2] cycloaddition to various olefins to form bicyclic compounds embedded with tetrahydrofurans <05SL285; 05T3025>. A one-pot conversion of unprotected monosaccharides to benzylsulfonylmethylene C-glycosides via a Horner–Wadsworth–Emmons / ring closure procedure was recorded <05TL9043>. As shown in the scheme below, 2,5-disubstituted tetrahydrofurans were prepared with excellent diastereoselectivity via an Sn(OTf)2 -catalyzed cycloaddition of aldehydes to cyclopropanes containing donor-acceptor groups, presumably through 1,3-zwitterionic intermediates <05JA16014; 05JOC1057>. [3+2] Cycloaddition between cyclopropylmethylsilanes and α keto aldehydes also led to the formation of 2-silymethyl substituted tetrahydrofurans in good yields <05CL538>.
CO2Me CO2Me
+ PhCHO
CH2Cl2 r.t., 2.5 hr 100%
Ph
CO2Me CO2Me
Sn(OTf)2 Ph
Ph
O
2,3-Dihydrofurans can be conveniently synthesized via a standard carbonylcyclopropane rearrangement procedure <05OL4565; 05TL7345>, via reactions between halides and electrophilic olefins in the presence of DABCO and K2 CO3 <05T9140>, or from β-enaminoketones via a halophilic process <05TL5357>. Spiro[furan-2(3H),1’-(2benzocycloalkanes)] were obtained through Mn(III) oxidative reactions of methylenebenzocycloalkanes and 1,3-dicarbonyl compounds <05S731>. Alternatively, copper(II) acetate, CAN or manganese(III) acetate-mediated radical reactions alkenes and ketonic compounds also led to the formation of 2,3-dihydrofurans <05CL1588; 05OBC794; 05TL6227>. As shown in the following scheme, irradiation of the enone gave a 2,3dihydrofuran in good yield <05T3771>. Asymmetric synthesis of 2,3-dihydrofurans via a formal retro-Claisen photorearrangement has also been reported <05JA2725>. CO2Et
PMBN
CO2Et
NPMB
hν EtO2C
OMe
O
OMe
H O
EtO 2C
DMF 1 hr 86% MeO
OMe
Rhodium(II)-catalyzed reactions of diazodicarbonyl compounds with conjugated dienes provided a convenient route to 2,3-dihydrofurans as depicted below <05EJO1568>. MeO O
O OMe
N2
+ O
OMe
O
OMe
Rh2(OPiv)4 60 °C, 3 hr 87%
O
O
203
Five–membered ring systems: furans and benzofurans
2,5-Dihydrofurans are most conveniently constructed via RCM reactions starting from bis(allyl)ethers <05CC1860; 05JA17160; 05JA18024; 05SL2083; 05TL591>. As shown below, a sequence of palladium-catalyzed α-allenols cross-coupling spirocyclization reactions led to the formation of spirolactam derivatives with 2,5-dihydrofuran rings. A rhodium-catalyzed silicon-initiated carbonylative carbotricylization of enediynes provided polycyclic compounds with tetrahydrofuran frameworks <05JA17756>. HO
CO2Me
Me • O
CO2Me
Pd(OAc)2-PPh3 LiBr
O Me O
+ Cu(OAc)2-K2CO3 O2 MeCN 53%
N Me
N Me
2,5-Dihydrofuran skeletons can also be realized from 3-methylenetetrahydrofurans via a series of reactions <05EJO4852; 05TL4859>, from acid treatment of hexa-2,4-diene1,2diols <05TL5369>, and from alkylidenecarbenes as illustrated below <05TL7483>.
BuMe2SiO
H
t Me3SiC(Li)N2 BuMe2SiO
O
THF 0 °C 76%
O
OSiMe2t Bu
••
t
H O
O
5.3.3.3 Benzo[b]furans and Related Compounds Unexpected results were obtained when chromenone-based cyclophanes was treated with DBU to achieve HNO2 elimination, followed by DDQ oxidation to give benzo[b]furanbased cyclophanes as shown below <05TL8789>. DDQ oxidative conversion of (E)-β-[2hydroxyphenylethylene]benzeneethanol into 2-phenylbenzofuran was also reported <05H(65)1641>. In addition, an unusual rearrangement of substituted 2phenylbenzo[d]pyrrolo[3,2-b]pyrylium perchlorate to 2-phenylfuro[2,3-c]isoquinoline was observed <05SL1036>. Me Me
Me 1. DBU THF O
NO 2 O
2. DDQ 22 °C, 20 hr 28%
Me O
As depicted below, a procedure for the iodocyclization of acetoxy-containing 2-(1alkynyl)anisole and subsequent direct palladium-catalyzed carbonylation/lactonization was reported as an efficient entry to naturally occurring coumestan and coumestrol <05JOC9985>. A novel Pd(II)-mediated cascade carbonylative annulation of substituted ohydroxyphenylacetylenes to give benzo[b]furan-3-carboxylic acids was achieved in a one-pot reaction <05OL2707>.
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X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
MeO
OTs
OTs
OTs
I I2 O
O
CH2Cl2 78%
OAc
O
O
PdCl2(PPh3) (5 mol%) CO, K2CO 3 DMF, 60 °C 61%
OAc
O
O
O
A wide variety of benzo[b]furans was synthesized efficiently via a CuI-catalyzed ring closure of 2-haloaromatic ketones <05JOC6964>. CuI (10 mol%) K3PO4 (1.5 equiv)
EtO 2C
Br
CO2Et
DMF 105 °C, 12 hr 88%
O
O
A structurally diverse series of 2-aryl-3-aminobenzo[b]furans was made via an InCl3 catalyzed three-component reaction <05SL2047>. R2
O CHO R
1
+
R2
Hf(OTf)4 (5 mol%)
OH
+ TsNH2 R3
O R1
CH2Cl2 46%
R3 NHTs
Regio-isomeric naphthofurans and benzodifurans were made by a base-catalyzed cyclization reaction from their corresponding o-alkoxybenzoylarenes as shown below <05T545>. An innovative synthesis of dibenzofurans through a carbanion-induced ring transformation reaction was also described <05TL491>. PhOC
COPh K2CO3
NCH2CO
OCH2CN
DMF 60 °C 84%
O
O
NC
CN Ph
Ph
Cyclization reactions of vinyl radicals via 1,6-H atom transfer was applied to synthesize 2,3-disubstituted dihydrobenzofurans as depicted in the scheme below <05SL2603>. SmI2 mediated intramolecular radical cyclization was applied to the construction of the key intermediate for the total synthesis of (±)-cryptotanshinone <05T1863>. A similar type of cyclization strategy was employed in the solid-phase synthesis of benzo[b]furans <05SL477>. Highly efficient reduction of unactivated aryl and alkyl iodides by a ground-state, neutral organic electron donor to realize benzo[b]furans was also reported <05AG(I)1356>. ortho-Acylphenols were utilized to synthesize 2,3-disubstituted benzo[b]furans by treatment with n-Bu3 SnH/AIBN in the presence of ethyl propiolate <05S387>. CO2Et Br O
CO2Et
n-Bu3SnH AIBN C6H6 81%
O
205
Five–membered ring systems: furans and benzofurans
As shown in the following scheme, a SEM-ether derived phenyl acetylene was treated with PtCl2 in the presence of CO to give a benzo[b]furan, which was first subjected to desilylation, followed by Pd-catalyzed intramolecular etherification, affording the tetracyclic skeleton of pterocarpane family of phytoalexins <05JA15024>. A similar type of synthetic transformation was also applied to make a key intermediate in the total synthesis of vibsanol <05JA15022>. 2,3-Disubstituted benzo[b]furans were prepared under very mild reaction conditions by the Pd/Cu-catalyzed cross-coupling of various o-iodoanisoles and terminal alkynes, followed by electrophilic cyclization with I2 , PhSeCl, or p-O2 NC6 H4 SCl <05JOC10292>. Br
O
PtCl2 (5 mol%) CO (1 atm) PhMe 80 °C, 3 hr 75%
OSEM
SiMe3 1. HF C5 H5 N
O
2. Pd(OAc)2 Cs2CO3 (t-Bu)2P(2-biphenyl)
O Br
O
A direct one-pot synthesis of naphtha[2,3-b]furan-4,9-dione derivatives was recorded via C,O-dialkylation of β-dicarbonyl with 2,3-dichloro-1,4-naphthoquinones <05S1605>. O
O O
Cl
+ Cl O
Me
O
O Me
K2CO3 Me
Me MeCN 80 °C, 6 hr 99%
O O
An efficient asymmetric synthesis of substituted methyl 2-aryldihydrobenzo[b]furan-3-carboxylate was achieved by a rhodium-catalyzed C-H bond activation route in an excellent yield, and the generated product was an intermediate applicable to the total synthesis of (+)-lithospermic acid <05JA13496>. A similar type of framework existing in (±)-ε-viniferin was made through a biomimetic transformation by a Tl(NO3 )3 -mediated oxidative dimerization of resveratrol <05T10285>. CHO MeO2C O OMe
1. (R)-(–)-aminoindane C6 H6 reflux 99%
CHO CO Me 2 OMe
2. [RhCl(coe)2]2 (10 mol%) FcPCy2 (30 mol%) OMe PhMe OMe 75 °C, 20 hr 3. aq. HCl 88%
O OMe
OMe
An intramolecular Heck reaction was applied to the synthesis of the key intermediate for the stereoselective construction of the rigid morphine molecular framework as depicted in the following scheme <05T513>. On the other hand, an intramolecular Heck reaction was utilized for the assembly of structurally diverse functionalized benzo[b]furans <05SL1767>.
206
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
MeO
MeO
O
1. Pd(OAc)2 PPh3 THF
I N
O
N
2. K2CO3 n-Bu4NBr MeCN 125 °C 41%
CO2Et
CO2Et
The enantioselective synthesis of aflatoxin B2 was accomplished, and the key step in the synthesis is the asymmetric [3+2] cycloaddition to generate a dihydrobenzo[b]furan skeleton <05JACS11958>. Another similar type of [3+2] cycloaddition was employed to make functionalized furans and benzo[b]furans <05TL2185>. H PhPh N+ B
O MeO
H
+ O O
– O Tf2N
OH
OH
MeO
o-tol
H
MeCN–CH2Cl2 –78 °C to 23 °C 65%
O H
H
+ MeO O
O
H O
92% ee, 65%
90% ee, 32%
A Pd-catalyzed tandem reaction was developed to synthesize a group of interesting benzo[b]furans as depicted below <05CC271>. The Pd-catalyzed cyclization of propargylic carbonates was also applied to make 2,3-dihydrofurans and benzofurans <05T4381>. Furthermore, an oxidative cyclization procedure catalyzed by Pd(II) and pyridine in the presence of molecular oxygen was carried out on a variety of 2-allylphenols to form 2substituted as well as 2,2-disubstituted benzo[b]furans <05JA17778>. OH Bu
PdI2 CO KI–PPh3
CO2Me
MeOH 100 °C, 15 hr 91%
O
O
Bu
Functionalized benzo[b]furan-based heterocycles were made from Fischer carbene complexes and heterocycle-bridged enynes in good to acceptable yields <05TL2211>. Cr(CO)5 SiMe3 O CO 2Me
1. MeO Me dioxane 80 °C 2. H2SO4 (cat.) 89% (2 steps)
Me3Si
CO2Me
O
O CO2Me
As illustrated in the following scheme, in the first total synthesis of (S)-(+)-cacalol, the benzo[b]furan ring was assembled by a base-mediated condensation reaction <05H(65)319>. Other similar scaffolds were made by a procedure featuring an intramolecular Friedel–Crafts acylation and a subsequent methylation <05OL1765>. A
207
Five–membered ring systems: furans and benzofurans
Friedel–Crafts based cyclization reaction was also developed to realize the key intermediate for the synthesis of bergapten <05H(65)1985>. A structurally diverse series of 2-aryl-5substituted-2,3-dihydrobenzo[b]furans was made via a rapid and efficient base-mediated onepot reaction from o-nitrotoluene and aromatic aldehydes <05JOC3727>. OMe
OMe OCH2CO 2H Me
Me
Me
O
MeCO2Na
O
Ac2O 70%
Me
Me
Me
As illustrated, the asymmetric synthesis of the dihydrobenzo[b]furan was achieved by a base-induced epoxide ring-opening, a key step for the stereoselective synthesis of the potent anticancer agent psorospermin <05TL827>. Two epoxide ring-opening strategies were also applied to the stereoselective synthesis of (–)-(2R,10S)-megapodiol <05TA917>, and enantiomerically enriched dihydrobenzo[b]furans <05TL5239>. O
O
OMe
OBn
OBn MsO
O
Raney Ni K2CO3 EtOH 70%
O
OMe
O OBn Psorospermin
O H O
A novel and efficient synthetic method to form 4-acetoxy-2-amino-3arylbenzo[b]furans from 1-aryl-2-nitroethylenes and cyclohexane-1,3-diones was reported via a one-pot multi-step synthetic approach as shown in the scheme below <05OL1211>. Syntheses of tetrahydrofurobenzo[b]furans were achieved from 1,4-cyclohexanedione and pyruvic acid as starting materials <05JOC6171>. 4-Functionalized benzo[b]furans from 2,3dihalophenols was made in a straight-forward manner by using different 2,3-dihalophenols <05JOC6548>. Halogen-metal exchange/cyclization of iodoketones was utilized for the synthesis of 3-arylbenzo[b]furans <05SL2504>. Diastereoselective syntheses of 3functionalized 2,3-dihydrobenzo[b]furans were achieved from their corresponding allyl 2bromoaryl ethers by halogen-metal exchange/cyclization in the presence of optically pure sparteine as a chiral source <05CUJ5397>. An application of a coupling reaction was applied to benzofuran anions and monoketals, and was followed by BF3 •Et2 O mediated cyclization to afford a tetracyclic product <05TL7511>. O NO2
1. Et3N THF 12 hr
OAc
+ O
2. Ac 2O Et3N–DMAP THF 5 hr 70% (2 steps)
O
NO 2
A new domino reaction consisting of insertion, coupling-isomerization, and Diels–Alder reactions was developed to make spirocyclic benzofuranones in moderate to excellent yields <05AG(I)153>.
208
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
OMe
H Ph
O
I
O
PdCl2(PPh3)2 (5 mol%) CuI (2.5 mol%)
H
+ O
O OMe
Et3N PhMe reflux, 3 days 66%
Ph O O
A new method was developed for the formation of N-(2-aroylbenzofuran-3-yl)-2hydroxythiobenzamides from dithiazole and bromoacetylaryl derivatives <05H(65)1295>.
S S
S
O
S
Et3N DMF
N OH
O
MeOH 73%
O Ph
O 92%
NH NaOMe
N Ph
Br
S
O
OH Ph O
–O
A new type of benzo[b]furan was constructed by a bimolecular nucleophilic substitution reaction at the sp3 carbon atom, which was envisaged to proceed via a fivecoordinate carbon compound as a transition state <05OL2739>. pAn
pAn OMe
Br OMe
MeO
OMe
hv
OMe
O
Br–
49 %
S
pAn
+
S
S
In the biomimetic synthesis of rubicordifolin, its building block benzo[b]furan was generated by conversion of the unstable vinylquinone at room temperature to afford the desired product in 23% yield, together with the formation of natural product furomollugin <05JA2870>. A group of dihydrobenzo[b]furans could be made by the iridium(III)catalyzed tandem Claisen rearrangement-intramolecular hydroaryloxylation from their corresponding precursors aryl allyl ethers <05TL1237>. A similar type of benzo[b]furan formation was developed by a Pd(II)-catalyzed oxidative cyclization <05OL3355>. O
OH OMe CO2Me THF
OH
O
+
OH
OH CO 2Me
O
r.t. O
OH
CO2Me
+ 23% O Rubicordifolin
OH
24% O Furomollugin
An efficient synthesis of rocaglaols was accomplished by development of a novel synthetic approach for the synthesis of its key intermediate by α-arylation of ketones <05EJOC1731>. The Pd-catalyzed Suzuki coupling reaction was also applied to the syntheses of 2,3-disubstituted benzo[b]furans <05EJO3334>.
209
Five–membered ring systems: furans and benzofurans
Me2tBuSiOCH2 TfOSit BuMe2
O Br O
F
CH2OSit BuMe2
B(OH)2
Cl
Cl
Br Et3N PhMe 46%
PdCl2(PPh3)2 F Na2CO3 C6 H6 98%
O
F
O
New functionalized mono- and bisbenzo[b]furans as blue-light emitting materials were synthesized via Wittig reaction as shown below <05OL1545>. In addition, the Pdcatalyzed regio- and stereoselective furylthiolation of alkynes was employed to make highly conjugated benzofuran-based compounds <05SL1161>. Photochromic diarylethenes having benzofuran heteroaryl groups were synthesized. These compounds were shown to exhibit photochromic reactivity even in the single-crystalline phase <05JOC10323>.
P(O)(OiPr)2 MeO
CHO
OMe O
NaH OMe O OMe
OMe
O
+ THF 70% P(O)(OiPr)2 MeO
OMe OMe
OMe
As illustrated in the following scheme, a new strategy for the diastereoselective and convergent synthesis of pterocarpans was achieved via sequential RCM reaction and allylation of cyclic allylsiloxanes <05CC2689>. A similar method was also employed to make substituted benzo[b]furans via an isomerization-ring-closing metathesis strategy <05T7746>. MeO CHO
Grubbs' 1st generation catalyst Si O
CH2Cl2 reflux 76%
MeO
OPiv Si O
BF3•Et2O CH2Cl2 68%
O OPiv
5.3.3.4 Benzo[c]furans and Related Compounds Benzo[c]furan non-benzenoid analogs, namely heptaleno[1,2-c]furans, were generated in two steps from the corresponding heptalene-4,5-dicarboxylates, and underwent Diels–Alder cycloaddition reactions readily to form the corresponding 1,4epoxybenzo[d]heptalenes as illustrated below <05HCA1250>. Conversion of 1,3arylbenzo[c]furans to 1,3-diarylbenzo[c]selenophenes can be achieved for the first time by employing Woollins reagent <05TL7201>.
210
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
iPr
iPr
MeO 2C
i Pr
CO2Me
+ PhMe 120 °C, 3 hr
O
O
O MeO2C
CO2Me
MeO2C
55%
CO2Me
36%
Dihydrobenzo[c]furans can also be obtained via an intramolecular Diels–Alder cycloaddition via strained cyclic allenes as intermediates. An example is shown below <05SL2062>. The same group also reported an Ir-catalyzed enantioselective [2+2+2] cycloaddition of an octayne with a monoalkyne to form a chiral noviaryl in high chemical and optical yields <05CC6017>.
H O
O
O
C6H4Me2 reflux, 1 hr 88%
Another way in which dihydrobenzo[c]furans can be produced is through Ni(0)catalyzed [2+2+2] cocyclotrimerization of arynes with diynes, as depicted in the following scheme <05CC2459>. Similar ruthenium- <05CC4438> and rhodium-catalyzed reactions <05CC3971>, as well as a carbene-Zn catalyzed reaction <05OL3065> led to the formation of dihydrobenzo[c]furans. TfO O
NiBr2(dppe) Zn
+
O Me3Si
CsF MeCN 80 °C 71%
Acknowledgements: HNCW wishes to thank the Areas of Excellence Scheme established under the University Grants Committee of the Hong Kong Special Administrative Region, China (Project No. AoE/P–10/01) and an anonymous donor for financial supports. XLH acknowledges with thanks support from the National Natural Science Foundation of China, National Outstanding Youth Fund, the Chinese Academy of Sciences, and Shanghai Committee of Science and Technology. KSY thanks Dr. Nicholas A. Meanwell for support. 5.3.4 REFERENCES 05AG(I)153 05AG(I)580 05AG(I)734 05AG(I)850 05AG(I)1356
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X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
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05OL5409 05OL5429 05OL5517 05OL5597 05OL5601 05OL5777 05P487 05P665 05P669 05P703 05P715 05P1060 05P1088 05P1094 05P1100 05P1141 05P1163 05P1707 05P2298 05P2334 05P2734 05P2787 05S387 05S391 05S731 05S1237 05S1605 05S2188 05S3219 05S3293 05S3654 05SL59 05SL152 05SL285 05SL388 05SL421 05SL477 05SL511 05SL1006 05SL1036 05SL1161 05SL1468 05SL1575 05SL1609 05SL1630 05SL1767 05SL1889 05SL1951 05SL2047 05SL2062
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Y.-H. Liu, F-J. Song, Z.-Q. Song, M.-N. Liu, B. Yan, Org. Lett. 2005, 7, 5409. S.J. Pastine, D. Sames, Org. Lett. 2005, 7, 5429. M.C. Carreño, G. Hernández-Torres, A. Urbano, F. Colobert, Org. Lett. 2005, 7, 5517. Y. Mata, M. Diéguez, O. Pàmies, C. Claver, Org. Lett. 2005, 7, 5597. A. Dion, P. Dubé, C. Spino, Org. Lett. 2005, 7, 5601. K. Mikami, S. Kataoka, K. Aikawa, Org. Lett. 2005, 7, 5777. A.L. Anaya, M. Macías-Rubalcava, R. Cruz-Ortega, C. García-Santana, P.N. SánchezMonterrubio, B.E. Hernández-Bautista, R. Mata, Phytochemistry 2005, 66, 487. Y. Takenaka, N. Hamada, T. Tanahashi, Phytochemistry 2005, 66, 665. M.B. Machado, L.M.X. Lopes, Phytochemistry 2005, 66, 669. P.K. Tarus, P.H. Coombes, N.R. Crouch, D.A. Mulholland, B. Moodley, Phytochemistry 2005, 66, 703. A. Evidente, A. Andolfi, M. Vurro, M. Fracchiolla, M.C. Zonno, A. Motta, Phytochemistry 2005, 66, 715. A. Karioti, J. Heilmann, H. Skaltsa, Phytochemistry 2005, 66, 1060. M.K. Tchimene, P. Tane, D. Ngamga, J.D. Connolly, L.J. Farrugia, Phytochemistry 2005, 66, 1088. H. Feld, U.M. Hertewich, J. Zapp, H. Becker, Phytochemistry 2005, 66, 1094. P.H. Coombes, D.A. Mulholland, M. Randrianarivelojosia, Phytochemistry 2 0 0 5 , 66, 1100. R. Ahmad, K. Shaari, N.H. Lajis, A.S. Hamzah, N.H. Ismail, M. Kitajima, Phytochemistry 2005, 66, 1141. S.C.S.M. Hoelzel, E.R. Vieira, S.R. Giacomelli, I.I. Dalcol, N. Zanatta, A.F. Morel, Phytochemistry 2005, 66, 1163. C. Sridhar, K.V. Rao, G.V. Subbaraju, Phytochemistry 2005, 66, 1707. J. Coll, Y. Tandrón, Phytochemistry 2005, 66, 2298. J.-X. Cai, Z.-W. Deng, J. Li, H.-Z. Fu, P. Proksch, W.-H. Lin, Phytochemistry 2 0 0 5, 66, 2334. P.H. Coombes, D. Naidoo, D.A. Mulholland, M. Randrianarivelojosia, Phytochemistry 2005, 66, 2734. M. Suzuki, T. Kawamoto, C.S. Vairappan, T. Ishii, T. Abe, M. Masuda, Phytochemistry 2005, 66, 2787. K.-O. Kim, J. Tae, Synthesis 2005, 387. M.-J. Fan, L.-N. Guo, X.-Y. Liu, W.-M. Liu, Y.-M. Liang, Synthesis 2005, 391. R. Fujino, H. Nishino, Synthesis 2005, 731. S. Tojo, M. Isobe, Synthesis 2005, 1237. H.-Y. Hu, Y. Zhu, L. Wang, J.-H. Xu, Synthesis 2005, 1605. Z.-J. Yang, M.-J. Fan, W.-M. Liu, Y.-M. Liang, Synthesis 2005, 2188. E. Bourque, P.J. Kocienski, M. Stocks, J. Yuen, Synthesis 2005, 3219. J.J. Caldwell, I.D. Cameron, S.D.R. Christie, A.M. Hay, C. Johnstone, W.J. Kerr, A. Murray, Synthesis 2005, 3293. S. Nad, R. Breinbauer, Synthesis 2005, 3654. D.H. Cho, D.O. Jang, Synlett 2005, 59. T. Shibata, R. Fujiwara, Y. Ueno, Synlett 2005, 152. C.W.G. Fishwick, G. Mitchell, P.F.W. Pang, Synlett 2005, 285. J. Zezula, T. Hudlicky, Synlett 2005, 388. B.-Y. Wang, J.-W. Huang, L.-P. Liu, M. Shi, Synlett 2005, 421. C. Chevet, T. Jackson, B. Santry, A. Routledge, Synlett 2005, 477. C. Stock, F. Höfer, T. Bach, Synlett 2005, 511. I.V. Voznyi, M.S. Novikov, A.F. Khlebnikov, Synlett 2005, 1006. V.S. Tolkunov, O.V. Shishkin, R.I. Zubatyuk, I.F. Perepicjka, V.I. Dulenko, Synlett 2005, 1036. T. Hirai, H. Kuniyasu, S.; Asano, J. Terao, N. Kambe, Synlett 2005, 1161. S.P. Annangudi, M. Sun, R.G. Salomon, Synlett 2005, 1468. J.P. Cenñal, C.R. Carreras, C.E. Tonn, J.I. Padrón, M.A. Ramírez, D.D. Díaz, F. GarcíaTellado, V.S. Martín, Synlett 2005, 1575. M. Babjak, L. Remen, O. Karlubíková, T. Gracza, Synlett 2005, 1609. K. Oh, D. Cheshire, P.J. Parsons, Synlett 2005, 1630. D. Ma, Q. Cai, X. Xie, Synlett 2005, 1767. D.H. Kim, Y.K. Chung, Synlett 2005, 1889. S. Mal, S. Some, J.K. Ray, Synlett 2005, 1951. C.-X. Chen, L. Liu, D.-P. Yang, D. Wang, Y.-J. Chen, Synlett 2005, 2047. T. Shibata, R. Fujiwara, D. Takano, Synlett 2005, 2062.
216 05SL2083 05SL2260 05SL2391 05SL2501 05SL2504 05SL2513 05SL2603 05SL2735 05SL3148 05T379 05T513 05T545 05T845 05T927 05T1061 05T1863 05T2003 05T2245 05T2471 05T2655 05T3025 05T3771 05T4381 05T4447 05T6561 05T7746 05T8382 05T8656 05T8699 05T8910 05T9140 05T9164 05T9929 05T10285 05T11032 05TA7 05TA917 05TA3570 05TL325 05TL491 05TL591 05TL827 05TL1155 05TL1237 05TL1623 05TL1713 05TL2185 05TL2211
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
S.K. Chattopadhyay, K. Sarkar, S. Karmakar, Synlett 2005, 2083. K.R. Prasad, S.L. Gholap, Synlett 2005, 2260. D. Enders, A. Hieronymi, A. Ridder, Synlett 2005, 2391. J.H. Rigby, G. Chouraqui, Synlett 2005, 2501. G.A. Kraus, J.D. Schroeder, Synlett 2005, 2504. J. Barluenga, A. Fernández, L. Álvarez-Rodrigo, F. Rodríguez, F.J. Fañanás, Synlett 2 0 0 5 , 2513. H. Lin, A. Schall, O. Reiser, Synlett 2005, 2603. F.F. Paintner, L. Allmendinger, G. Bauschke, Synlett 2005, 2735. K. Miura, R. Itaya, M. Horiike, H. Izumi, A. Hosomi, Synlett 2005, 3148. Y. Yamamoto, M. Maekawa, T. Akindele, K.-i. Yamada, K. Tomioka, Tetrahedron 2 0 0 5 , 61, 379. L.-W. Hsin, L.-T. Chang, C.-W. Chen, C.-H. Hsi, H.-W. Chen. Tetrahedron 2 0 0 5, 61, 513. K.K. Park, J. Jeong, Tetrahedron 2005, 61, 545. H. Bousserouel, M. Litaudon, B. Morleo, M.-T. Martin, O. Thoison, O. Nosjean, J.A. Boutin, P. Renard, T. Sévenet, Tetrahedron 2005, 61, 845. T. Caserta, V. Piccialli, L. Gomez-Paloma, G. Bifulco, Tetrahedron 2005, 61, 927. A. Miura, H. Kiyota, S. Kuwahara, Tetrahedron 2005, 61, 1061. W.-G. Huang, Y.-Y. Jiang, Q. Li, J. Li, J, Y. Li, W. Lu, J.-C. Cai, Tetrahedron 2 0 0 5, 61, 1863. M. Kolympadi, M. Liapis, V. Ragoussis, Tetrahedron 2005, 61, 2003. S. Schröter, S.; C. Stock, T. Bach, Tetrahedron 2005, 61, 2245. M. Babjak, P. Kapitán, t. Gracza, Tetrahedron 2005, 61, 2471. M. Tene, P. Tane, B.L. Sondengam, J.D. Connolly, Tetrahedron 2005, 61, 2655. S. Celanire, F. Marlin, J.E. Baldwin, R.M. Adlington, Tetrahedron 2005, 61, 3025. C.M. Williams, R. Heim, P.V. Bernhardt, Tetrahedron 2005, 61, 3771. M. Yoshida, Y. Morishita, M. Fujita, M. Ihara, Tetrahedron 2005, 61, 4381. S.J. Coles, J.F. Costello, W.N. Draffin, M. B. Hursthouse, S.P. Paver, Tetrahedron 2 0 0 5 , 61, 4447. T. Teruya, K. Suenaga, S. Maruyama, M. Kurotaki, H. Kigoshi, Tetrahedron 2 0 0 5, 61, 6561. W.A. van Otterlo, G.L. Morgans, L.G. Madeley, S. Kuzvidza, S.S. Moleele, N. Thornton, C.B. de Koning, Tetrahedron 2005, 61, 7746. J. Wu, Q. Xiao, S. Zhang, X. Li, Z.-H. Xiao, H.-X. Ding, Q.-X. Li, Tetrahedron 2 0 0 5, 61, 8382. S. Cheenpracha, R. Srisuwan, C. Karalai, C. Ponglimanont, S. Chantrapromma, K. Chantrapromma, H.-K. Fun, S. Anjum, Atta-ur-Rahman, Tetrahedron 2005, 61, 8656. A. Fernández-Mateos, G.P. Coca, R.R. González, Tetrahedron 2005, 61, 8699. J.J. Fernández, M. L. Souto, L.V. Gil, M. Norte, Tetrahedron 2005, 61, 8910. Z.-J. Yang, M.-J. Fan, R.-Z. Mu, W.-M. Liu, Y.-M. Liang, Tetrahedron 2005, 61, 9140. A. Yajima, F. Saitou, M. Sekimoto, S. Maetoko, T. Nukada, G. Yabuta, Tetrahedron 2005, 61, 9164. M.J. Piggott, Tetrahedron 2005, 61, 9929. Y. Takaya, K. Terashima, J. Ito, Y.-H. He, M. Tateoka, N. Yamaguchi, M. Niwa, Tetrahedron 2005, 61, 10285. H. Gaspar, M. Gavagnin, G. Calado, F. Castelluccio, E. Mollo, G. Cimino, Tetrahedron 2005, 61, 11032. T.K. Chakraborty, G. Sudhakar, Tetrahedron: Asymmetry 2005, 16, 7. R. Sathunuru, J.-C. Quirion, Tetrahydron: Asymmetry 2005, 16, 917. V.S. Kumar, S.-Y. Wan, D.L. Aubele, P.E. Floreancig, Tetrahedron: Asymmetry 2 0 0 5, 16, 3570. N. Sudhakar, A.R. Kumar, A. Prabhakar, B. Jagadeesh, B.V. Rao, Tetrahedron Lett. 2005, 46, 325. A. Goel, M. Dixit, D. Verma, Tetrahedron Lett. 2005, 46, 491. D.J. Wallace, Tetrahedron Lett. 2005, 46, 591. M.K. Schwaebe, T.J. Moran, J.P. Whitten, Tetrahedron Lett. 2005, 46, 827. S. Jana, C. Guin, S.C. Roy, Tetrahedron Lett. 2005, 46, 1155. V.H. Grant, B. Liu, Tetrahedron Lett. 2005, 46, 1237. M. Friedel, G. Golz, P. Mayer, T. Lindel, Tetrahedron Lett. 2005, 46, 1623. J. Aslaoui, H. Li, C. Morin, Tetrahedron Lett. 2005, 46, 1713. E. Bellur, I. Freifeld, P. Langer, Tetrahedron Lett. 2005, 46, 2185. Y. Zhang, D. Candelaria, J. W. Herndon, Tetrahedron Lett. 2005, 46, 2211.
Five–membered ring systems: furans and benzofurans
05TL2709 05TL3249 05TL4219 05TL4235 05TL4287 05TL4859 05TL5239 05TL5357 05TL5369 05TL5467 05TL5761 05TL6227 05TL6297 05TL6469 05TL6519 05TL6621 05TL6629 05TL7201 05TL7303 05TL7345 05TL7451 05TL7483 05TL7511 05TL7751 05TL7989 05TL8199 05TL8439 05TL8443 05TL8475 05TL8493 05TL8789 05TL9043
217
R. Fujino, S. Kajikawa, H. Nishino, Tetraheron Lett. 2005, 46, 2709. T. Aslam, M.G.G. Fuchs, A. Le Formal, R.H. Wightman, Tetrahedron Lett. 2 0 0 5, 46, 3249. H. Zhou, D.-M. Han, X.-B. Liao, J.M. Cook, Tetrahedron Lett. 2005, 46, 4219. A.S. Veleiro, P.J. Taich, L.D. Alvarez, P.H. Di Chenna, G. Burton, Tetrahedron Lett. 2005, 46, 4235. T.K. Chakraborty, G. Sudhakar, Tetrahedron Lett. 2005, 46, 4287. S. Gowrisankar, K.Y. Lee, J.N. Kim, Tetrahedron Lett. 2005, 46, 4859. U. Bhoga, Tetrahedron Lett. 2005, 46, 5239. Y.-M. Wu, Y. Li, J. Deng, Tetrahedron Lett. 2005, 46, 5357. G.-L. Mao, C.-Y. Wang, J.-L. Chen, A. Muramatsu, Z.-F. Xi, Tetrahedron Lett. 2 0 0 5 , 46, 5369. G. Righi, R. Antonioletti, S. Ciambrone, F. Fiorini, Tetrahedron Lett. 2005, 46, 5467. M.I. Simone, R. Soengas, C.R. Newton, D.J. Watkin, G.W.J. Fleet, Tetrahedron Lett. 2005, 46, 5761. R. Çaliskan, T. Pekel, W.H. Watson, M. Balci, Tetrahedron Lett. 2005, 46, 6227. S. Kuwahara, M. Enomoto, Tetrahedron Lett. 2005, 46, 6297. C.S. Stauffer, A. Datta, Tetrahedron Lett. 2005, 46, 6469. F. Alonso, J. Maléndez, M. Yus, Tetrahedron Lett. 2005, 46, 6519. C.H. Hwang, G. Keum, K.I. Sohn, D.H. Lee, E. Lee, Tetrahedron Lett. 2005, 46, 6621. B. Lygo, D. Slack, C. Wilson, Tetrahedron Lett. 2005, 46, 6629. A.K. Mohanakrishnan, P. Amaladass, Tetrahedron Lett. 2005, 46, 7201. R. Fujino, S. Kajikawa, H. Nishino, Tetraheron Lett. 2005, 46, 7303. M. Honda, T. Naitou, H. Hoshino, S. Takagi, M. Segi, T. Nakajima, Tetrahedron Lett. 2005, 46, 7345. W.-H. Zhong, J. Xie, X. Peng, T. Kawamura, H. Nemoto, Tetrahedron Lett. 2 0 0 5, 46, 7451. M. Akiyama, Y. Isoda, M. Nishimoto, A. Kobayashi, D. Togawa, N. Hirao, A. Kuboki, S. Ohira, Tetrahedron Lett. 2005, 46, 7483. G.A. Kraus, J. Wei, Tetrahedron Lett. 2005, 46, 7511. N.T. Tzvetkov, J. Mattay, Tetrahedron Lett. 2005, 46, 7751. F. Mongin, A. Bucher, J. P. Bazureau, O. Bayh, H. Awad, F. Trécourt, Tetrahedron Lett. 2005, 46, 7989. J. Murga, E. Falomir, M. Carda, J.A. Marco, Tetrahedron Lett. 2005, 46, 8199. A.V. Butin, V.T. Abaev, V.V. Mel’chin, A.S. Dmitriev, Tetraheron Lett. 2005, 46, 8439. A.V. Butin, S.K. Smirnov, Tetraheron Lett. 2005, 46, 8443. A.M. Montaña, J.A. Barcia, Tetraheron Lett. 2005, 46, 8475. J.S. Yadav, B.V.S. Reddy, P.M.K. Reddy, M.K. Gupta, Tetraheron Lett. 2005, 46, 8493. L. Minuti, A. Marrocchi, I. Tesei, E. Gacs-Baitz, Tetrahedron Lett. 2005, 46, 8789. S. Jeanmart, R.J.K. Taylor, Tetrahedron Lett. 2005, 46, 9043.
218
Chapter 5.4 Five membered ring systems: with more than one N atom
Larry Yet Albany Molecular Research, Inc., Albany, NY USA
[email protected] __________________________________________________________________________ 5.4.1
INTRODUCTION
The synthesis and chemistry of pyrazoles, imidazoles, and 1,2,3-triazoles were actively pursued in 2005. Publications relating to 1,2,4-triazole and tetrazole chemistry were not particularly well represented this year. The solid-phase and combinatorial chemistry of these ring systems have not been heavily investigated as in past years. No attempt has been made to incorporate all the exciting chemistry or biological applications that have been published this year. 5.4.2
PYRAZOLES AND RING-FUSED DERIVATIVES
A review has been published on the stereoselective cycloadditions of nitrilimines as a useful tool in the synthesis of a number of enantiopure heterocycles containing the 4,5-dihydropyrazole ring <05H(65)2513>. Addition of hydrazines to 1,3-difunctional compounds is one of the most common methods employed for the preparation of pyrazoles. For example, several synthesis of pyrazoles have been reported where azide reagents are added to α,β-unsaturated systems. Reactions of trifluoroacetyl enol ether (thiophene) 1 with hydrazines afforded 3-(2-furyl) or 3-(2thienyl)pyrazoles 2 <05S2744>. A regiospecific one-pot synthesis of trifluoromethyl-substituted heteroaryl pyrazolyl ketones has also been disclosed <05JHC631, 05JHC1055>. 1,3,5Trisubstituted-2-pyrazolines 4 were obtained from chalcones 3 and phenylhydrazine under silica gel and microwave irradiation conditions <05JHC157>. An efficient and convenient synthesis of 3,5-diphenyl-1H-pyrazoles from chalcones by the action of hydrazine hydrate on chalconeepoxide followed by simultaneous dehydration has been reported <05SC1135>. Condensation of α-oxoketene N,S-acetals 5 with arylhydrazines provided 1,3,5-trisubstituted pyrazoles 6 <05JOC9644>. Furan-2,3-diones 7 reacted with various hydrazines to yield pyrazole-3-
219
Five membered ring systems: with more than one N atom
carboxylic hydrazides 8 in moderate yields <05JHC117>. Baylis-Hillman adducts 10, derived from aldehydes and 2-cyclohexen-1-one 9, reacted with hydrazines to give pyrazoles 11, which were oxidized to 2H-indazoles 12 <05TL5387>. A stereoselective five-step syntheses of 3,5dialkyl-3,5-dihydro-3,5-diphenyl-4H-pyrazol-4-ones has been published <05S2901>. OMe O
O (S) RNHNH2, CHCl3
CF3
F3C
(78-87%)
O (S) 1
R = H, Ph
O
PhNHNH2, silica gel
Ar1
Ar1
(60-85%)
Ar2 4
R1
ArNHNH2, NaH, DMF, 90 ˚C or
O
N
ArNHNH2, KOt-Bu, t-BuOH, 80 ˚C
NR2R3
MeS
(61-77%)
5
O
N Ar 6
NR2R3
O
R3NHNH2 (2 equiv)
O
R1 O
R1
7
O
various
= OEt, Ph;
R2=
Ph, Ar;
R3 = Ph, Ar
OH
R1CHO
R2
(45-65%)
O
O
ClCH2CH2Cl
R1
reflux
conditions
R2 N N
R2NHNH2·HCl
R1 = Ar, Me, CH(OMe)2 R2 = R3 = morpholinyl; Me, CH2Ar
O
R1
NHNHR3
PhH, reflux R2
2
Ph
3
R1
N
N N
microwave, 2-3 min
Ar2
N R
N R3
N 8
PhH, reflux
R1
R2 N N
DDQ (2 equiv) R1
(57-80%)
(47-54%) 9
10
R1 =Ph, Ar, n-C5H11 R2 = Ph, Ar, t-Bu
11
12
1,3-Diones and 1,3-dihalides can also be utilized as substrates for azide reagents in the preparation of pyrazoles. Primary aliphatic and aromatic amines 13 underwent electrophilic amination with oxaziridine 14 to give the corresponding N-Boc hydrazines which reacted further
220
L. Yet
with 3,5-heptadione 15 to give pyrazoles 16 in a one-pot synthesis <05OL713>. Pyrazoles and tetrahydroindazoles may be prepared by condensation of 1,3-diones and hydrazines under layered zirconium sulfophenyl phosphonate catalysis, in solvent-free conditions <05SL2927>. Microwave-assisted cyclocondensation of arylhydrazines 17 with alkyl dihalides or ditosylates 18 in aqueous media afforded 4,5-dihydropyrazoles 19 <05TL6011>. O NBoc 1. EtO2C
CO2Et
14
2. NaHCO3, then MgSO4
R NH2
3. TFA
13
O
R Me
O
4. Me
Me 15
N N
Me
R = Ph2CH2CH2, Bn, Ph(CH)Me, Ph, 4-CNPh
16
(36-59%) K2CO3, H2O ArNHNH2 17
+
microwave, 120 ˚C X
X 18
20 min (60-70%)
Ar N N
X =Cl, Br, I, OTs
19
Hydrazones are useful substrates in the preparation of pyrazoles. Enantioselective [3+2] cycloaddition of halohydrazones 21 with dipolarophile 20 in the presence of ligand 22 under Lewis acid conditions followed by reduction provided an entry to chiral dihydropyrazole scaffolds 23 in excellent yields and in good enantiomeric excesses <05JA8276>. Highly enantioselective synthesis of pyrazolidines 27 was obtained by the [3+2] acylhydrazone-enol ether cycloadditions of 24 and 25 in the presence of a chiral silicon Lewis acid 26 <05JA9974>. DABCO-catalyzed aza-Michael additions of hydrazones 28 to activated olefins 29 gave products 30 which underwent cyclization to 4,5-dihydropyrazoles 31 upon treatment with acid <05T7277>. Two-step one-pot microwave irradiation of 2-halobenzaldehydes or 2haloacetophenones 32 with phenylhydrazine yielded the aryl hydrazones, which were further cyclized to give 1-phenyl-1H-indazoles 34 via copper(I)-diamine-catalyzed N-arylation reactions in the presence of ligand 33 <05TL7553>. Condensation of χ-carboxy ester hydrazones 35 with Vilsmeier reagent yielded a general synthesis of 1,3-diaryl-4-pyrazoleacetic acid esters 36 <05JHC131>. Select C(α),N-phenylhydrazones were dilithiated with excess lithium diisopropylamide followed by condensation with methyl 2-(aminosulfonyl)benzoate and acid cyclization to afford new pyrazole-benzensulfonamides <05JHC1095>. 1,3-Disubstituted pyrazole-4-carbonitriles were prepared from enaminonitriles and hydrazonyl halides <05JHC1185>. Structurally novel chiral glycopyrazoles were obtained in good yields from the intramolecular [3+2] nitrilimine cycloaddition reactions of phenylhydrazone groups on carbohydrate-derived substrate <05T365>.
221
Five membered ring systems: with more than one N atom
O
O
O
R + Ph
N 20
N
i-Pr2NEt, CH2Cl2, 4Å MS, -78 ˚C
21
O N
Ph
HO
2. NaBH4, THF, H2O
Br (Cl)
O
R
1. 22 (10 mol%), Mg(NTf2)2 (10 mol%)
NHAr
N
N N
22
Ar
(91-98%, 79-99% ee)
23
R = H, Me, Et, Ph, CO2t-Bu
O N R
+
H
R
(66-85%, >95:5 %de)
25
24
O
HN N
PhMe, 23 ˚C
Ot-Bu
Ph
Ph
(S,S)-26 (1.5 equiv)
NHBz
Si
Ot-Bu
Me 26
27
R = PhCH2CH2, BnOCH2,
Ph
N Cl Me
i-Pr, Cy, t-Bu, 2-furyl
Ph
N
NHR1 +
28
DABCO (1 mol%)
R2
Ph
N
THF, 25 ˚C
29
(91-99%)
N R1 30
R1
5N HCl
R2
N N
DMF
R2
(31-99%)
31
R1 = Ph,Ts, COPh R2 = COMe, COPh
H (Me)
160 ˚C, 10 min
O
R
H (Me)
1. PhNHNH2, microwave, NMP 2. K2CO3 (2 equiv), CuI (5 mol%),
X
33 (10 mol%)
32
R 34
N N Ph
NHMe NHMe 33
(69-95%)
X = Cl, Br, I
N
NHAr2
Ar1
CO2R 35
POCl3 (3 equiv) DMF, 80 ˚C (66-95%) R = Me, i-Pr
Ar1 N
CO2R N Ar2 36
Tandem sequences have also yielded some interesting pyrazole structures. Four-component coupling of terminal alkynes 37, hydrazines 38, carbon monoxide and aryl iodides furnished pyrazoles 39 in the presence of palladium catalyst <05OL4487>. Fully substituted 1H-pyrazoles 42 were prepared from the condensation/fragmentation/cyclization/extrusion reactions of thietanone 40 with 1,2,4,5-tetrazines 41 <05JOC8468>. Reactions of isocyanides 43 and dialkyl acetylenedicarboxylates 44 in the presence of 1,2-diacylhydrazines 45 led to highlyfunctionalized pyrazolines 46 <05TL6545>.
222
L. Yet
R1
CO, ArI Pd(PPh3)2Cl2 (1 mol%) 25 ˚C R1= Ph, n-C6H13 R2 = H, Me (59-93%)
R2NHNH2
+ 37
38
R2 N N R1
Ar 39 Ar
HO Ph
O
N N +
S
KOH, ROH
Ar
Ar N N
40
N
RO
(9-56%)
N Ph
41
Ar
42 O O
R1
NC
+
R2O2C
43
CO2R2
+
R3
44 R1 = cyclohexyl, t-Bu; R2 = Me, Et R3 = Me, OEt
N H
acetone
H N
R3
25 ˚C (68-85%)
O
R3
O
N N
R2O2C
R3 NHR1
CO2R2
45
46
Diazo reagents have also been utilized in the preparation of pyrazoles. 1,3-Dipolar cycloaddition of 2-diazopropane with propargyl alcohols led to the regioselective synthesis of 3H-pyrazoles <05EJO3526>. Reactions of diazomethane or diazoethane with activated sulfoxides 47 in the presence of Yb(OTf)3 produced a stereocontrolled synthesis of bicyclic pyrazoles 48 <05JOC8942>. O
TolOS
O R1
OEt 47
R2CH2N2 Yb(OTf)2 THF, 25 ˚C
TolOS N N
O O
1 R2 R OEt 48
R1 = H, Me R2 = Me, Et (65-89%)
Several interesting reactions of pyrazole or pyrazolines have been noted in the literature. Efficient aromatization of 1,3,5-trisubstituted-2-pyrazolines 49 to pyrazoles 50 was achieved under microwave irradiation with silica-gel supported N-bromosuccinimide and solvent-free conditions or with bismuth(III) nitrate pentahydrate in acetic acid <05H(65)865, 05SC2581>. 3,5-Dimethylpyrazoles were efficiently halogenated by ultrasound irradiation using Nhalosuccinimides <05TL6833>. Pyrazolecarboxaldehydes reacted in the presence of triflic acid to generate electrophilic intermediates capable of reacting with benzene in condensation reactions <05TL2931>. An effective method for the kinetic resolution of racemic pyrazolinone imines via copper-catalyzed [3+2] cycloadditions with alkynes has been investigated with planar phosphaferrocene-oxazoline catalyst <05JA11244>. A simple procedure for the Boc-protection of 1H of 3-aminopyrazoles has been described where 3-acylaminopyrazole derivatives could be prepared in good yields <05TL933>. Fluoride-mediated nucleophilic substitution reactions of 1-
223
Five membered ring systems: with more than one N atom
(4-methylsulfonyl(or sulfonamide)-2-pyridyl)-5-chloro-4-cyanopyrazoles with various amines and alcohols occurred under mild conditions to provide 5-alkylamino and ether pyrazoles in moderate to high yields <05TL6887>. When the same conditions were applied to 2,4-dihydro3H-pyrazol-3-ones instead of 1,2-diacylhydrazine, 7-oxo-1H,7H-pyrazolo[1,2-a]pyrazoles were obtained <05T3963>. Reaction with dimedone 51 with 1-(2-alkenoyl)-4-bromo-3,5dimethylpyrazoles 52 catalyzed by DBFOX/Ph-nickel(II) perchlorate, 2,2,6,6tetramethylpiperidine (TMP) produced enol lactones 53 in high enantioselectivities via Michael additions followed by cyclization with removal of the pyrazole auxiliary <05OL979>. Reaction of pyrazolium and indazolium salts with silyllithium reagents led to a regioselective synthesis of silylated pyrazolines and indazolines <05EJO4663>. Ar1
silica gel-supported NBS (76-92%)
Ar2 N N Ph
Me
O
R
N N
microwave
50
O
O
51
Ph
R
Br
N
O
R,R-DBFOX/Ph, Ni(ClO4)2 N
Me
52
Ar2
Bi(NO3)3·5H2O, HOAc (94-99%)
49
+
Ar1
or
TMP, Ac2O, THF, 25 ˚C (62-94%, 89-98% ee)
O
Me
O
R = Me, Et, i-Pr, 2-furyl, CO2Me, Ph, c-C6H11
Me 53
Several reports of cross-coupling reactions of pyrazoles and indazoles have been reported. The palladium-catalyzed cross-coupling reactions of aryl iodides and 5-tributylstannyl-4fluoropyrazole 55 prepared from fluoro(tributylstannyl)acetylene 54 proceeded smoothly to give the corresponding 5-aryl-4-fluoropyrazole 56 in good yields <05CC2041>. Palladium-catalyzed cross-coupling of pyrazolyl triflates 57 with aryl boronic acids afforded highly substituted pyrazoles 58 <05JOC4188>. 5-Bromo-3-iodoindazole has been employed in sequential Sonogashira and Suzuki cross-coupling reactions <05S771>. 3-Trimethylsilylindazoles 59 underwent regioselective copper(II)-catalyzed cross-coupling to give 1-aryl-3trimethylsilylindazoles 60, which were deprotected to 1-arylindazoles 61 under basic conditions <05TL3771>. 4-Substituted and 3,4-disubstituted indazole derivatives were obtained by palladium-catalyzed cross-coupling reactions <05TL6161> and these compounds were further
F
SnBu3
-30 °C (98%)
54
F
F
CH2N2 Bu3Sn
N H 55
N
Ar-I, Pd(PPh3)4 (5 mol%) DMSO, 100 ˚C (59-94%)
Ar
N H
N
56
elaborated into other indazoles <05TL8218>. ω-Functionalized-3-alkylpyrazolo[1,5a]pyrimidines were prepared by Sonogashira couplings of 3-iodopyrazolo[1,5-a]pyrimidines
224
L. Yet
with propargylic and homopropargylic compounds <05S131>. 3-Chloro-1-phenyl-2-pyrazoline efficiently underwent Suzuki cross-coupling reactions with aryl boronic acids in good yields under microwave irradiation <05TL2631>. R1 N N R2
R1 N N
ArB(OH)2 (3 equiv), K3PO4 (3 equiv) PdCl2(dppf) (8 mol%), dppf (4 mol%)
OTf
R2
1,4-dioxane, 100 ˚C
R3
58
TMS
59
TMS
ArB(OH)2 (2 equiv), Cu(OAc)2 (1.5 equiv) pyridine (2 equiv), 4Å MS, CH2Cl2
N
R
R3
(71-92%)
57
R1= H, Me, Ph R2 = R3 = H, Me
Ar
air, 25 ˚C
N H
(84-98%)
KOH, EtOH reflux
N
R 60
N N Ar
R
(62-97%)
N Ar
61
Pyrazole-tethered Schiff base ligands 62 promoted Suzuki cross-couplings of aryl bromides and chlorides with phenylboronic acid efficiently under mild conditions <05TL15>. Chromiumtrioxide complex with 3,5-dimethylpyrazole 63 oxidation of cyclohexenecarbonitrile provided 3oxocyclohex-1-ene-1-carbonitrile <05S3179>. R1 N
N
R2
Me
CH=NAr 62 R1 = R2 = Me, t-Bu
Me HN N 63
Resin-immobilized β-ketoamides 64 reacted with hydrazines in the presence of Lawesson’s reagent followed by acidic cleavage to give 5-N-alkyl(aryl)amino pyrazoles 65 <05JCO584>. Resin-bound enamino keto diesters 66 reacted with hydrazines followed by acidic cleavage to give pyrazoledicarboxylic acid derivatives 67 <05EJO4621>. A library synthesis of pyrazoles by azomethine imine cycloaddition to the polymer-supported vinylsulfone has been reported <05CL438>. O
OMe
O
O R3
N R1
R2 64
R2
1. R4NHNH2, Lawesson's Reagent THF, pyridine, 55 ˚C 2. TFA, ClCH2CH2Cl, 25 ˚C
R1HN
R3 N R4 65
N
225
Five membered ring systems: with more than one N atom O
O
R2O
R1
O
2. TFA, CH2Cl2, 25 °C
NH2
R1
R2O2C
1. R3NHNH2, CH2Cl2, 25 °C
N
HO2C
O 66
N R3
67
Many reports of fused-pyrazole heterocycles have been published. A high throughput synthesis of pyrazolopyrimidines has been achieved by copper(I)-catalyzed cyclizations <05H(65)1821>. A simple synthesis of 6-phenylpyrano[2,3-c]pyrazol-4(1H)-ones has been reported <05S2583>. A solvent-free, one-pot synthesis of pyrano[2,3-c]pyrazole derivatives in the presence of potassium fluoride and grinding has been disclosed <05SC2509>. Reactions of 4-aryl-5-aminopyrazoles with aryl/heteroaryl aldehydes led to a versatile synthesis of pyrazolo[3,4-c]isoquinoline derivatives <05OBC932>. A convergent synthesis of substituted pyrazolo[1,5-a]pyridines has been achieved by a regioselective [3+2] cycloaddition of Naminopyridines with alkynes <05OL4753>. Indeno[1,2-c]pyrazole-4-ones were synthesized by oxidation of indenopyrazoles by treatment with a base and molecular oxygen <05TL7615>. A new entry to pyrazol[4,3-e][1,4]diazepines has been reported <05JHC675>. Substituted pyrazolo[4,3-d]pyrimidin-7-ones <05JHC1085> and several ferrocenylpyrazole derivatives <05JHC265> have been synthesized. A new 5H-pyrazolo[1,5-c][1,3,2]benzoxazphosphorine ring system has been disclosed <05JHC1143>. A facile synthesis of 1,6-dihydro-7Hpyrazolo[4,3-d]pyrimidin-7-ones <05JHC751> and pyrazolo[1,5-a]pyrimidines <05JHC925> have been reported. 4-Pyrazolyl-2-oxo-1,2,3,4-tetrahydropyrimidines were synthesized in good yields using pyrazole aldehyde, ethyl acetoacetate and urea in the presence of phosphotungstic acid <05JHC863>. New derivatives of purinyl homo-carbonucleoside of 2benzylcyclopenta[c]pyrazole have been prepared <05S925>. 5.4.3
IMIDAZOLES AND RING-FUSED DERIVATIVES
Microwave irradiation has been employed in several published syntheses of substituted imidazoles. Microwave irradiation of aromatic aldehydes 68 in the presence of alumina/ammonium acetate provided a simple synthesis of 2,4,5-triarylimidazolines 69 <05H(65)353>. Bridgehead aziridines 71 were synthesized in high yields and in high
Ar
alumina, NH4OAc Ar CHO 68
microwave, 2-5 min (53-80%)
N Ar
Ar 69
RCHO (2 equiv)
O
NH
Cl
Ph 70
NH4OAc, HOAc, n-PrOH microwave, 90 °C, 10 min (72-92%) R = Ar, t-Bu
H R
H N
71
Ph H
N
R
diastereocontrol by a three-component reaction of aldehydes, phenacyl chloride 70 and ammonium acetate in acetic acid under microwave irradiation <05SL1633>. 2-Aryl-4,5-
226
L. Yet
diphenylimidazoles 73 were prepared in good yields by a one-step condensation reaction of benzil 72, aromatic aldehydes and ammonium acetate in acetic acid under microwave irradiation <05SC1369>. Ph
O
ArCHO, NH4OAc (2 equiv)
Ph
N
Ph
N H
HOAc, microwave Ph
Ar
(70-98%)
O 72
73
Metal-mediated approaches to the synthesis of imidazoles have been reported. Palladium(II)catalyzed intermolecular 1,2-diamination of conjugated dienes with ureas led to 4-alkenyl-2imidazolones in good yields under mild conditions <05JA7308>. Palladium-catalyzed cyclization of O-pentafluorobenzoylamidoximes 74 furnished 1-benzyl-2-substituted-4methylimidazoles 75 <05OL609>. Direct copper(I)-chloride mediated reaction of nitriles 76 with α-amino acetals 77 followed by acidic reaction led to a variety of 2-substituted imidazoles 78 <05TL8369>.
N R
OCOC6F5
76
+
H 3C
N H 77
N
Et3N (5 equiv)
N Bn
R
DMF, 80 °C (30-72%)
74
R CN
Me
Pd(PPh3)4 (10 mol %)
75
R = Bn, Ph(CH2)2, CO2Me
OMe OMe
1. CuCl, 85 °C 2. TFA (32-96%)
N Bn
N N R
CH3
R = FCH2, Bn, Ar, alkyl
78
Multicomponent reactions have been described for several syntheses of imidazoles. Multicomponent reaction of amines 79, aldehydes 80 and isocyanides 81 gave a diverse range of highly substituted 2-imidazolines 82 <05JOC3542>. A novel three-component one-pot condensation between o-picolylamines 83, aldehydes 84 and isocyanides 85 led to a synthesis of 1H-imidazol-4-yl-pyridines 86 <05OL39>. Van Leusen three-component reaction of isocyanides 87, aldehydes 88 and amines 89 gave imidazole dienes 90, which underwent ringclosing metathesis reactions to provide fused bicyclic imidazoles 91 <05OL3183>. Similarly, fused imidazo azepine derivatives were also obtained by this sequential van Leusen/enyne metathesis reaction protocol <05TL9049> and fused triazolo-imidazole derivatives were prepared by sequential van Leusen/alkyne-azide cycloaddition reactions <05TL9053>.
227
Five membered ring systems: with more than one N atom
NC R1 NH2
+
+
R2CHO
R3
80
79
AgOAc (2 mol%)
R4
R3
CH2Cl2, 25 °C
R1 = H, i-Pr, t-Bu, CHPh2 R2 = H, i-Pr, t-Bu, Ar R3 = R4 = fluorene; Ar, H
N
R4
(5-91%)
81
R1 N
R2
82
R1
R2 N
H 2N N N
+
R1CHO
R2NC
+
84
83
InCl3 (0.5 equiv) MeOH, 25 °C, 16 h
R1 = i-Bu, n-Bu, c-C6H11, Ar R2 = ArCH2, n-Bu
N
(17-55%)
85
86
DMF
SO2Tol R1
NC
+
R2CHO
+
89
88
87
R3NH2
K2CO3
( )n
R1
(51-92%)
Grubbs'
N ( )m
N
(39-86%)
90
R1 = Ar, allyl R2 = (CH2)nCH=CH2, n = 0, 1 R3 = (CH2)mCH=CH2, m = 1, 2
catalyst
( )n
R1 N
N ( )m 91
A improved room temperature ionic liquid promoted rapid synthesis of 2,4,5triarylimidazoles from aryl aldehydes and 1,2-diketones or α-hydroxyketones has been described <05T3539>. A series of 2-aryl-substituted imidazolidines were prepared through the simple diamine transfer reactions between 2-alkyl-substituted imidazolidines and aromatic aldehydes under the catalysis of n-butylamine <05H(65)1829>. Diastereochemical diversity of imidazole scaffolds was obtained from substrate-controlled trimethylsilyl chloride mediated cycloaddition of azlactones <05OL5091>. α-Amino acids were converted to α-aminocarbonyl derivatives, then reacted with isothiocyanates to give N-substituted cyclic thioureas, and finally oxidative or reductive desulfuration afforded structurally diversed imidazoles <05T7315>. Reaction of various aldehydes 92 and 1,2-diamines 93 followed by N-bromosuccinimide treatment provided a mild and efficient one-pot synthesis of 2-dihydroimidazoles 94 <05TL2197>. Chiral technologies were employed in the efficient synthesis of imidazole-substituted δ-amino acids <05OL1931>. 2-tert-Butyldiphenylsilylmethyl-substituted aziridines 95 reacted efficiently with nitriles to form imidazolines 96 <05JA16366>. Magnesium bromide-catalyzed ring expansion reaction of chiral aziridine-2-carboyxlate proceeded regio- and stereospecifically to give enantiomerically pure 4-functionalized imidazolidin-2-ones <05CC3062>. R2 R1CHO 92
+
R2
H2N
NH2 93
NBS, CH2Cl2, 0 °C (69-99%)
R2
H N
R2
N 94
R1
R1 = Ar, alkyl, alkenyl R2 = H, Ph
228
L. Yet
Ts
N
TBDPS
R
R-CN, BF3·OEt2
N
CH2Cl2, 25 °C (82-90%)
95
TBDPS
Ts N 96
Several reports of the synthesis and chemistry of benzimidazoles have been published. 2,4Dinitro-N-acylanilines 97 were regiospecifically reduced at the C-2 position with Baker’s yeast to afford 2-amino-4-nitroacylanilines 98, which were then cyclized under acidic conditions to give 2-substituted-6-nitrobenzimidazoles 99 <05SL340>. A highly efficient and versatile method for the synthesis of benzimidazoles was achieved in one step via the sodium hyposulfite reduction of o-nitroanilines in the presence of aldehydes <05S47>. An efficient one-pot procedure for the preparation of aminobenzimidazoles from dinitroaniline derivatives has been described <05S17>. One-pot reductive carbonylation of 2-nitroanilines 100 in the presence of base led to 2-benzimidazolones 101 <05EJO1675>. Direct one-step synthesis of various benzimidazoles from phenylenediamines and aldehydes has been published using air as the oxidant in dioxane at reflux <05TL4315>. A microwave-assisted bismuth(III) chloride-mediated benzimidazole cyclization on solid support has been described <05SL1243>. Oxidative cyclization of 2,3-diaminobenzoic acid and aromatic aldehydes afforded 2-aryl-1Hbenzimidazole-4-carboxylic acids <05SC2395>. An efficient, microwave assisted synthesis of 1,2-disubstituted benzimidazoles has been reported using mercury chloride on polyethylene glycol support <05TL177>. 2-Nitroanilines were reacted with carboxylic acids in the presence of tin(II) chloride under microwave irradiation to give 2-substituted benzimidazoles <05TL6741>. H N
phosphate buffer
O NO2
O2N
H N
Baker's yeast
R
pH 7.5, 30 °C
NO2
CO (30 atm), Et3N
NH2
(66-92%)
R 100
98
PhMe, 4 h
N
HOAc, 60 °C
O NH2
O2N
(36-90%)
97
R
R N H
O2N
(80-94%) R = H, Me, i-Pr, CF3
99
H N O
R
N H 101
Imidazoles and fused-derivatives have participated in a myriad of cross-coupling reactions. 2-Thiomethylimidazolin-5-one 102 underwent efficient palladium-catalyzed cross-coupling reactions with boronic acids in the presence of copper(I)thiophene-2-carboxylate (CuTC) to give 2,4-disubstituted-2-imidazlin-5-ones 103 under microwave irradiation <05S25>. Coppercatalyzed coupling reactions provided access to sterically-hindered N-arylimidazoles <05EJO1637>. Ruthenium complexes catalyzed the ortho-selective direct cross-coupling reaction of 2-arylimidazolines with bromobenzene <05JOC3113>. Coupling of 1-aryl-1Himidazoles 104 with aryl iodides or bromides with a catalyst mixture of palladium(II) acetate and triphenylarsene in the presence of cesium fluoride provided a regioselective synthesis of 1,5-
229
Five membered ring systems: with more than one N atom
diaryl-1H-imidazoles 105 <05JOC3997>. Benzimidazole underwent a mild copper-catalyzed Narylation reaction with aryl halides in the presence of copper(I) triflate and 4,7-dichloro-1,10phenanthroline as the ligand <05TL2405>. L-Proline promoted Ullmann-type reaction of vinyl bromides 106 with imidazole in ionic liquids gave the corresponding N-vinylimidazoles 107 in good to excellent yields <05CC2849>. Newly-designed copper apatite catalysts were employed in the N-arylation of imidazole with chloro- and fluoroarenes <05JA9948>. 2,4Diarylimidazoles were prepared by Suzuki cross-coupling reactions of imidazole halides with arylboronic acids <05H(65)1975>. Suzuki cross-coupling reactions of 6-bromoimidazo[1,2a]pyridines have been developed <05H(65)2979>. CuI-catalyzed N-arylation of imidazoles and benzimidazoles with aryl bromides was achieved in a near-homogeneous system that utilized tetraethylammonium carbonate as base, 8-hydroxyquinoline as ligand and water as cosolvent <05JOC10135>. OMe
OMe N MeS
N Me
N
ArB(OH)2, Pd(PPh3)4 O
Ar
CuTC, DMF, microwave (31-80%)
102
O
N Me
103
Ar2X, Pd(OAc)2 (5 mol%) N
AsPh3 (10 mol%), CsF (2 equiv)
N Ar1
N
N
DMF, 140 °C (36-61%)
104
105
X = Br, I
Ar
CuI, K2CO3 [Bmim]BF4
106
(87-93%)
Ar2
N
imidazole, L-Proline Br
Ar1
N
Ar 107
2-(α-Substituted-amidoalkyl)imidazoles 109 were prepared from 1-substituted imidazoles 108 via the addition reaction of the imidazolium ylides to electron-deficient imines <05TL4789>. Versatile access to C-4-substituted 2-aminoimidazoles was obtained from hydropyridines via bromine-mediated oxidative conditions <05JOC8208>. Asymmetric hydrogenation of 1-aryl-2-imidazol-1-yl-ethanones offered a concise route to homochiral 1-aryl2-imidazol-1-yl-ethanols <05OPRD110>. Reductive lithiation of several 1,3-dimethyl-2arylimidazolidines led to interesting cleavage products depending on the substituents on the aryl ring <05T3177>. Mitsunobu alkylation of imidazole provided a convenient route to chiral ionic liquids <05TL631>. Palladium-catalyzed decarboxylation of allylic carbamates 110 afforded allylic imidazoles 111 <05SL2759>. The scope and limitations of the catalytic asymmetric rearrangement of epoxides to allylic alcohols were investigated using chiral lithium amide bases and lithiated imidazoles <05TL8315>. Bis(oxazolinyl)pyridine-scandium(III) triflate complexes catalyzed the enantioselective Friedel-Crafts alkylations of α,β-unsaturated 2-acylimidazoles <05JA8942>. A method for selective N-protection of hydroxyalkylbenzimidazoles using 2,2,2-
230
L. Yet
trichloroethylchloroformate applicable to various alkyl chain lengths has been developed <05TL6311>. Baylis-Hillman acetates 112 underwent nucleophilic substitution reactions with imidazole readily in aqueous THF solutions to afford the corresponding N-substituted imidazole derivatives 113 in good to excellent yields <05TL5233>. A series of 4,5-bis(alkyn-1yl)imidazoles were synthesized and their reactivities in photoinduced Bergman cycloaromatization reactions were determined <05TL1373>. Imidazolidin-2-one 114 was converted with dimethyl chlorophosphate to 2-chloro-2-imidazoline 115, which was reacted with aliphatic amines and anilines to afford 2-(N-substituted)-2-imidazolines 116 in a one-pot process <05SC2633>. N
1. PhCH=NR2, Boc2O,
N
ClCH2CH2Cl, 80 °C
N R1 108
NHR2
N Ph R1 109
2. TFA (47-95%)
R1 = Me, Bn, allyl R2 = Ts, PO(OPh)2, Boc, CBz
O O
N
Pd(PPh3)4 (5 mol%)
N
CH2Cl2, 25 °C
N
( )n
N
n = 1 (90%), n = 2 (71%) ( )n
110
111
N
imidazole OAc R
CO2Me
112
THF, H2O, 25 °C R = Ar, 2-furyl
HN
113
Cl
114
NH
CH2Cl2, reflux
CO2Me
R
(50-98%)
O ClP(O)(OMe)2, Et3N
N
N
NHR
RNH2 NH
R = alkyl, aryl (94-97%)
115
N
NH
116
Lithiation of 1-aryl-1H-imidazoles followed by quenching with electrophiles provided a route to 1,2-diaryl, 1-aryl-2-cycloalkyl- and 1-aryl-2-heterocycle-substituted imidazoles <05H(65)2721>. Isoprene-catalyzed lithiation of imidazole provided a synthetic route to 2(hydroxyalkyl)- and 2-(aminoalkyl)imidazoles <05T11148>. 2-Lithiobenzimidazoles were efficiently acylated with esters, lactones and lactams <05TL5081>.
231
Five membered ring systems: with more than one N atom
Imidazole-containing reagents have been utilized for various types of reactions. Carbamoylimidazolium and thiocarbamoylimidazolium salts 117 were found to be novel reagents for the synthesis of ureas, thioureas, carbamates, thiocarbamates and amides <05T7153>. Tetrakis(2-methylimidazol-1-yl)silane 118 was found to be a convenient dehydrating reagent for the synthesis of carboxamides and thioesters <05CL734>. N-Substituted 2-(2-bromophenyl)benzimidazoles 119 were useful ligands in the palladium-catalyzed Heck reactions <05TL661>. Imidazolium salt 120 was generated under basic conditions to its Nheterocyclic carbenes in reactions with enals; depending on the base, the reaction can give either olefin reduction or cis-disubstituted χ-lactones <05OL3873> or cis-disubstituted χ-lactams <05OL3131>. N-Heterocyclic carbenes derived from benzimidazolium salts 121 were effective catalysts for generating homoenolate species from α,β-unsaturated aldehydes <05OL905>. O (S) R1
N R2
N
Me I N CH3
Si N
R N
N 4
117
118
Br
N
Mes N
N Mes Cl
119
120
121
CH3 N I N CH3
R = n-Bu, Bn, Bz, Ts
A multi-step polymer-assisted solution phase strategy for the highly automated synthesis of 2-alkylthiobenzimidazoles and N,N ’-dialkylbenzimidazolin-2-ones has been reported <05JCO385>. A facile solid-phase synthesis of 1,2,4,5-tetrasubstituted imidazoles using sodium benzenesulfinate as a traceless linker has been developed <05JCO644>. A solid-phase synthesis of disubstituted 1,3-dihydro-2H-imidazol-2-ones has been reported <05SL1322>. The novel alkyl N-methyl-N-polystyreneamino-2-isocyanoacrylate resin 122 was employed for the synthesis of 1-substituted-imidazole-4-carboxylates 123 via a microwave-assisted catch and release methodology <05JCO905>. R1OC
R1OC N C N Me 122
R2NH2, n-BuOH microwave (80-98%)
N N R2
R1 = OMe, OBn, NHR R2 = ArCH2, alkyl
123
Many ring-fused imidazole derivatives have been synthesized by various methods. Domino Michael addition retro-ene reaction of 2-alkoxyiminoimidazolidines and acetylene carboxylates provided a synthesis of 2,3-dihydroimidazo[1,2-a]pyrimidin-5-(1H)-ones <05T5303>. A single step synthesis of 3,5-dialkyl-9-nitroimidazo[1,2-c]quinazolin-2(3H)-ones from simple carbonyl compounds, primary amines or amino acid methyl esters and 2-azido-5-nitrobenzonitrile has been published <05TL5778>. Diels-Alder reaction of azadienes and benzimidazole-4,7-diones afforded imidazo[4,5-g]quinoline-4,9-dione derivatives <05EJO1903>. Reaction between isocyanides and dialkyl acetylenedicarboxylates in the presence of 4,5-diphenyl-1,3-dihydro-2Himidazol-2-one provided a one-pot synthesis of 5H-imidazo[2,1-b][1,3]oxazine derivatives <05T2645>. Microwave irradiation was employed in the synthesis of 1-aryl-3-acetyl-1,4,5,6-
232
L. Yet
tetrahydrobenzimidazo[1,2-d][1,2,4]triazines, the first example of this novel ring system <05TL1725>. Imidazo[5,1-b]thiazol-3ones/thiazin-4-ones were synthesized and its reactivity explored for library generation <05JCO503>. Library preparation of 3-imidazo[1,2-a]pyridine3-yl-propionic acid derivatives involving Meldrum’s acid has been reported <05JCO530>. Ionic liquid-promoted reaction of ketones, [hydroxy(tosyloxy)iodo]benzene and 2-aminopyrimidine provided a one-pot synthesis of 2-arylimidazo[1,2-a]pyrimidines <05SC1741>. Imidazo[5,1f][1,2,4]triazin-4(3H)-ones as isosteres of purines have been synthesized <05JOC7331>. Multicomponent reaction of 2-aminopyridines, aldehydes and isocyanides catalyzed by scandium(III) triflate furnished a convenient one-pot synthesis of 3-aminoimidazo[1,2a]pyridines <05TL8355>. 1-Alkyl-2-aryl-1H-imidazo[4,5-b]pyridines were prepared from 2alkylamino-3-aminopyridines and aromatic aldehydes using air as an oxidant <05H(65)2189>. 1-Aryl-5-amino-4-cyanoformimidoyl imidazoles were reacted with methyl cyanoacetate to afford 3-aryl-6,7-dicyanoimidazo[4,5-b]pyridine-5-ones <05SL2429>. Solid-phase synthesis of imidazoquinazolinone derivatives with three points of diversity has been published <05T629>. Microwave irradiation of 3-nitro-5-fluoromethyl-o-phenylenediamine and aromatic anhydrides provided a convenient method for the synthesis of new trifluoromethyl-substituted 11Hisoindolo[2,1-a]benzimidazol-11-ones <05H(65)2329>. Palladium-catalyzed iminoannulation of 3-haloimidazol[1,2-a]pyridine-2-carbaldehyde in the presence of alkynes afforded dipyrido[1,2a;d’4’-d]imidazoles <05H(65)1071>. Three-component condensation of pyruvic acid, aromatic aldehydes and aminoazoles afforded synthesis of 5-aryl-5,8-dihydroazolo[1,5-a]pyrimidine-7carboxylic acids <05S2597>. Parallel microwave-assisted library of imidazothiazol-3-ones and imidazothiazin-4-ones has been described <05JCO947>. 5.4.4
1,2,3-TRIAZOLES AND RING-FUSED DERIVATIVES
A kinetic study of the rearrangement of several polysubstituted Z-arylhydrazones of 3benzoyl-5-phenyl-1,2,4-oxadiazole into 2-aryl-4-benzoylamino-5-phenyl-1,2,3-triazoles in dioxane/water has been published <05T167>. 1,2,3-Triazole has been found to be a safer and practical substitute for cyanide in the Bruylants reaction for the synthesis of tertiary amines containing tertiary alkyl or aryl groups <05TL5455>. Several triazole-linked glycosides have been prepared by copper(I)-catalyzed 1,2,3-triazole formation <05JOC4847, 05CC2852, 05TL2331>. 1,3-Dipolar cycloadditions have been the most common methods for the syntheses of various 1,2,3-triazoles. The first method involves the addition of azide reagents to terminal alkynes mostly mediated by copper metals. Copper(I) iodide promoted reaction of alkyl azides 124 and terminal alkynes 125 in the presence of iodine monochloride led to a regiospecific synthesis of 5iodo-1,4-disubstituted-1,2,3-triazole 126, which could be further elaborated to a range of 1,4,5trisubstituted-1,2,3-triazole derivatives <05S1314>. Azidomethyl pivalates and carbamates 127 underwent copper(I)-catalyzed 1,3-dipolar cycloaddition with terminal alkynes 128 to give triazoles 129, which were cleaved under basic conditions to give 1H-1,2,3-triazoles 130 <05SL2847>. Palladium-copper catalyzed reaction of benzyl azides 131 with acetylenes 132 provided a general synthesis of fused-isoindoline triazoles 133 <05TL8531>. The mechanism of the ligand-free copper(I)-catalyzed azide-alkyne cycloaddition reaction has been investigated in detail <05AG(I)2211>. Bitriazolyl compounds were synthesized via 1,3-dipolar cycloaddition of
233
Five membered ring systems: with more than one N atom
an azidotriazole with alkynes <05H(65)345>. Functionalized 1,4-disubstituted-1,2,3-triazoles have been prepared from terminal alkynes and azides from Cu(I) generated in situ from Cu(0) nanosize activated powder and amine hydrochloride salts <05TL2911>. The use of chiral Pybox ligands demonstrated the first asymmetric induction in the copper-catalyzed azide-alkyne cycloaddition process, both in kinetic resolution and desymmetrization of a series of 1,4disubstituted-1,2,3-triazoles <05TL4543>.
R1 N3
+
124
R1 N N N
CuI (1 equiv), Et3N
R2
ICl, THF, 25 °C
125
R2
I 126
(34-81%)
R1 = CF3CH2, CHF2CF2CH, Bn, n-C8H17 R2 = Ph, n-C4H9, CO2allyl, CONHallyl
CuSO4·5H2O (5 mol%)
O R1
O
N3
+
R2 128
127
NaOH
O
sodium ascorbate (30 mol%)
R1
O
N
t-BuOH, H2O, 25 °C 129
R1 = t-Bu, morpholinyl, NEt2 R2 = Ar, CH(OEt)2, (CH2)3CO2H
N
N R2
MeOH
HN
N
H2 O (60-98%)
130
N R2
R PdCl2(PPh3)2 (3 mol%)
I N3 131
R
+
CuI (7 mol%), Et3N (6 equiv) DMF, 115 °C
132
(28-63%)
N N N 133
Other metal-mediated reactions of azide reagents to terminal alkynes have also been reported. Indium(II) triflate catalyzed tandem azidation/1,3-dipolar cycloaddition of various ω,ω-dialkoxyalkynes 134 with trimethylsilyl azide yielded fused 1,2,3-triazoles 135 <05TL8639>. A new ruthenium-catalyzed process for the regioselective synthesis of 1,5disubstituted-1,2,3-triazoles has been developed <05JA15998>. OR1 X ( )n
OR1 R2
In(OTf)3 (5 mol%) TMSN3 (1.5 equiv) ClCH2CH2Cl, 50 °C (39-87%)
134
X ( )n R2
OR1 N
N N
135
X = O, NBn, NTs, CHCH2OBn n = 0, 1 R1 = Me, Et R2 = H, COPh
234
L. Yet
1,2,3-Triazoles can also be prepared from in situ formation of azides from halo compounds. For example, 1,4-disubstituted-1,2,3-triazoles 138 were obtained in excellent yields by a convenient one-pot procedure from a variety of aryl and alkyl iodides 136 and terminal alkynes 137 without isolation of potentially unstable organic azide intermediates <05SL2941>. Efficient one-pot synthesis of 1,2,3-triazoles from in situ formation of azides from benzyl and alkyl halides with alkynes has also been reported <05SL943>.
Ar-I
ascorbate, DMSO/H2O (5:1), 25 °C (38-99%) R = alkyl, TMS, aryl
137
136
N N N Ar
NaN3, 33, CuI, sodium
R
+
R
138
The second method involves the addition of azide reagents to propargyl substrates. A series of 4,5-disubstituted-1,2,3-triazoles 140 have been regiospecifically prepared directly from propargyl halides or tosylates 139 and sodium azide via the Banert cascade <05S1514>. Copper(I)-catalyzed three-component reaction with amines 141, propargyl halides 142 and azides 143 in water afforded (1-substituted-1H-1,2,3-triazol-4-ylmethyl)dialkylamines 144 <05T9331>. Three-component asymmetric copper-catalyzed reaction of aldehydes 145, bis(benzyl)amine 146 and trimethylsilylacetylene 147 afforded propargylamines 148, which underwent cycloaddition with benzyl azide to yield various chiral α-aminoalkyl-1,2,3-triazoles 149 <05SL2796>. Enantiomerically pure 3-substituted-5-amino-4-hydroxy-5,6-dihydro-4Hpyrrolo[1,2-c]triazoles were synthesized efficiently from the sequential reactions including a regioselective ring-opening of 1-aziridine-2-yl-propargylic alcohols by azidotrimethylsilane and the subsequent intramolecular 1,3-dipolar cycloaddition between alkyne and azide <05SL2187>. Copper-catalyzed coupling of bromoalkynes and organic azides resulted in the formation of bromo-containing trisubstituted 1,2,3-triazole derivatives in high yield and a regioselective manner <05SL3059>. NaN3, NH4Cl X R
dioxane, H2O, 75 °C (60-95%)
141
+
Br (Cl) 142
N
NH N3
R 140
139
R1R2NH
N
+
Ar
(CH2)nN3 143
R = H, Et, n-Pr, Ph, phthalimidoyl, CH2OH, CH2Cl X = Cl, Br, OTs
N
CuI (10 mol%), Et3N H2O, 25 °C (70-98%)
R2R1N
N
144
Ar N ( )n
235
Five membered ring systems: with more than one N atom RCHO 145
CuBr (5 mol%)
+ NHBn2 146 +
(R)-Quinap (5.5 mol%) PhMe, 25 °C (58-98%, 73-98% ee)
TMS
1. TBAF (91-99%)
NBn2
2. BnN3, Cu powder,
R TMS 148
147
Bn2N N Bn N N
R
t-BuOH, H2O (74-98%) R = benzothiophenyl, furanyl, cyclopropyl, i-Pr, n-Bu, t-Bu
149
The third method is the addition of azide reagents to activated olefins. Tetrabutylammonium fluoride-catalyzed [3+2] cycloaddition reactions of 2-aryl-1-cyano(or carbethoxy)-1-nitroethenes 150 with trimethysilyl azide under solvent-free conditions provided 4-aryl-5-cyano(or carbethoxy)-1H-1,2,3-triazoles 151 in good to excellent yields under mild conditions <05JOC6526>. Similarly, nitroalkenes or vicinal acetoxy nitro derivatives underwent a clean reaction with sodium azide in hot dimethyl sulfoxide to give the corresponding 1,2,3-triazoles in good yields <05S3319>. 1,2,3-Triazoles 154 were prepared in modest to good yields by cycloaddition of alkyl azides 152 onto enol ethers 153 under solventless conditions <05S2497>. TMSN3, TBAF3•H2O
NO2
Ar
CN (CO2Et) 150
R1
N3
+
152
R2
MeO
solvent-free conditions
neat, 200 °C
N N NH CN (CO2Et) 151
(70-90%)
(49-78%) 153
Ar
N N N R1
R2
R1 = alkyl, cyclohexyl, benzyl R2 = Ac, CN
154
Cycloaddition of aryl imines 155 with diazomethane followed by oxidation of the intermediate triazoline with potassium permanganate afforded 1-(4-methylsulfonylphenyl)-5aryl-1,2,3-triazoles 156 <05JHC33>. 1,2,3-Triazolo-3’-deoxycarbanucleosides and their analogs were prepared efficiently by palladium(0)-catalyzed reactions <05T11744>. Base-induced generation of aryl(1,2,3-triazol-1yl)carbenes from 1-[(N-phenylsulfonyl)benzohydrazonoyl)1,2,3-triazoles and their ring enlargement to 3-aryl-1,2,4-triazenes has been published <05H(65)279>. Ar N MeO2S
Ar
1. CH2N2, dioxane (50-74%) 2. KMnO4 (35-52%)
155
N MeO2S
N
N
156
1,4-Disubstituted-5-iodo-1,2,3-triazoles 157 underwent various Suzuki, Heck and Sonogashira cross-coupling reactions <05S2730>. A new class of triazole-based monophosphine (ClickPhos) ligands 158 has been found to be highly active catalysts for the Suzuki-Miyaura coupling and amination reactions of aryl chlorides <05OL4907>.
236
L. Yet
R1 N
N
N R2
I 157
Ph N
N
N PR2
Ar 158
A couple of reports on the solid-phase approaches to 1,2,3-triazoles have been published. 1,3-Dipolar cycloaddition of polyethylene glycol-supported azide with various dipolarophiles followed by acidic cleavage afforded 4- and 5-substituted-1,2,3-triazoles <05T4983>. Trimethylsilyl-directed 1,3-dipolar cycloaddition reactions in the solid-phase synthesis of 1,2,3triazoles have been developed <05OL1469>. Benzotriazole-mediated methodology publications continued in 2005. A very detailed recent review has been published which described extensively the synthesis and the broad utility of aminomethylbenzotriazoles, amidomethylbenzotriazoles, alkoxymethylbenzotriazoles and alkylthiomethylbenzotriazoles has been published <05T2555>. An account on acylbenzotriazoles has also been reported <05SL1656>. A concise benzotriazolyl-mediated synthesis of 9-methoxycepharanone A has been described <05T665>. 1-[1-(Benzotriazol-1yl)alkyl]-1H-benzotriazoles underwent deprotonation with n-BuLi to generate polyanions which react with electrophiles to allow preparation of highly functionalized benzotriazole derivatives <05T3305>. Lithiated heteroaryl(or aryl)methylbenzotriazoles were precursors for the synthesis of heteroaryl 1,2-diketones <05JOC3271>. Reaction of (Z)-1-aryl-3-hexen-1,5-diynes with sodium azide led to the synthesis of 1-aryl-1H-benzotriazoles via a novel tandem cascade reaction involving 1,3-dipolar cycloaddition reaction, anionic cyclization, and sigmatropic rearrangement <05OL475>. 1H-1,2,3-Benzotriazole-5-carboxaldehyde was prepared and utilized in reductive aminations with primary and secondary amines <05SC2587>. N-Tfa- and N-Fmoc-(α-aminoacyl)benzotriazoles were utilized as chiral C-acylating reagents under FriedelCrafts reaction conditions <05JOC4993>. Several benzotriazole sulfur reagents were prepared and used for thioacylations, thiocarbamoylations, alkyl/alkoxythioacylations, and aryl/alkylthioacylations <05JOC7866>. β-Lithiation of benzotriazolylvinyl ethyl ether led to synthesis of substituted α,β-unsaturated ketones, pyrazoles, isoxazoles, and 2,4,6-triarylpyrylium chlorophosphates <05S245>. N-Sulfonylbenzotriazoles were found to be advantageous reagents for C-sulfonylation <05JOC9191>. Carboxylic acids are converted into corresponding alcohols by chemoselective reduction of their benzotriazole amides with sodium borohydride <05SC2935>. Aromatic and aliphatic amines were reacted through a regioselective 1,4- or 1,2addition with N-cinnamoylbenzotriazoles to afford β-amino-N-acylbenzotriazoles or cinnamides, respectively <05SL3042>. 5.4.5
1,2,4-TRIAZOLES AND RING-FUSED DERIVATIVES
An account has been written on the mechanistic studies of the 1,2,4-triazoline-3,5-dione ene type reactions <05SL713>. Acetic hydrazides are useful precursors for the synthesis of 1,2,4-triazoles. For example, a convenient and efficient one-step, base-catalyzed synthesis of 3,5-disubstituted-1,2,4-triazoles 161 is obtained from condensation of nitriles 159 and hydrazides 160 under microwave
237
Five membered ring systems: with more than one N atom
irradiation <05TL3429>. Dimethylaminomethylene hydrazide 164, prepared from acetic hydrazide 162 and dimethoxymethyl dimethylamine 163, reacted with various amines under microwave irradiation in a one-pot three-component synthesis of 3,4-disubstituted-1,2,4-triazoles 165 <05H(651957>. K2CO3, n-BuOH
O R1 CN
+
R2
159
NHNH2
NHNH2
+
O
CH2Cl2 reflux
R1 = Ar, Het, HetCH2 R2 = Ar, Het, CH2Het
NH R2
161
Me2NCH(OMe)2
162
N
(34-83%)
160
O H3C
N
R1
microwave, 150 °C
H3C
163
H3C
RNH2, HOAc N
N H
NMe2
microwave
N N
(55-98%)
N
R
165
164 R = alkyl, benzyl substituted, aryl
Hydrazonyl chlorides have been employed in the synthesis of 1,2,4-triazoles. Intermolecular cyclization of hydrazonyl chlorides 166 with nitriles catalyzed by ytterbium(I) triflate afforded a series of 1,3,5-trisubstituted-1,2,4-triazoles 167 in good yields <05SC1435>. Dipolar cycloadditions between hydrazonyl chlorides 168 and nitriles in aqueous sodium bicarbonate in the presence of a surfactant provided mild conditions for the synthesis of 1-aryl-5-substituted1,2,4-triazoles 170 via intermediate 169 <05H(65)1183>. A series of 1,2,4-triazoles have been prepared by oxidative intramolecular cyclization of heterocyclic hydrazones with copper dichloride <05T5942>. RCN, Yb(OTf)3
Cl Ph
N
PhCl
NHPh (Ar)
N Ph (Ar)
N
(70-85%)
166
N
Ph
R
R = Me, Ph, Ar
167 MeO2C
HN
N
Cl CO2Me
168
R2
5% aq. NaHCO3 THAC, 25 °C
R1
N
N R1
N N
CO2Me
169 R1 = H, Me, R2 = CO2Et, CO2Bn, CCl3
CN
N
R2
(24-95%) R1 170
Oxadiazoles have been utilized in the synthesis of 1,2,4-triazoles. Condensation of highly reactive chloromethyloxadiazoles 171 with ethylenediamines 172 afforded amidines 173, which under reflux in methanol, gave [1,2,4]triazolo[4,3-a]piperazines 174 <05OL1039>. Reaction of
238
L. Yet
some fluorinated 1,2,4-oxadiazoles in the presence of methylamine or propylamine under photochemical irradiation in methanol or acetonitrile led to the corresponding fluorinated 1methyl- or 1-propyl-1,2,4-triazoles <05H(65)387>. R2 R1
H2N
O N N
Cl
R1
NHR3
O
172 R1
MeOH, -20 °C
HN
(54-74%)
171
N
NH N 173
R1 =
CF3, Ph; R3 = Me, Bn
R2
MeOH R3
R2
N
N
N
N
reflux (51-99%)
174
R3
R2
= Me, Ph
A novel and efficient synthesis of 2,5-substituted-1,2,4-triazol-3-ones where various alkyl, aryl, and heterocyclic groups can be introduced successfully at both the N2 and C5 positions has been described <05TL7993>. A practical synthesis of piperidine-/tropane-substituted 1,2,4triazoles has been reported <05SL1133>. Novel isonucleosides with 1,2,4-triazole-3carboxamide attachments were prepared from D-ribose and D-xylose <05SC2653>. Palladium-catalyzed reaction of bicyclic hydrazines 175 with allyltributylstannane 176 in ionic liquid provided a facile method for the synthesis of substituted 1,2,4-triazole-3,5dionecyclopentenes 177 <05SL2273>. Sonogashira coupling of 3-mercaptopropargyl-1,2,4triazoles 178 with various aryl iodides led to the regioselective synthesis of 6-benzylthiazolo[3,2b]1,2,4-triazoles 179 <05TL1607>. R N
O O
N N
N
O
R
SnBu3 176
[Pd(allyl)Cl]2,
N N H
Sc(OTf)3, dppe, [bmim]PF6, 60 °C R = Ph (90%) R = Bn (97%)
175
177
ArI, Pd(PPh)2Cl2, CuI N N R
N H 178
Ar
Et3N, DMF S CH2C≡CH
(48-81%) R = Me, Ph
O
R
N
N
N
S
179
4-Phenyl-1,2,4-triazole-3,5-dione 180 was found to be a novel and reusable reagent for the aromatization of 1,4-dihydropyridines under mild conditions <05TL5581>. 1-Benzylsulfanyl1,2,4-triazole 181 was an useful electrophilic sulfur source in the organocatalyzed αsulfenylation of aldehydes <05AG(I)94>.
239
Five membered ring systems: with more than one N atom N N O
N Ph
N O
N
N S Ph
181
180
Resin-bound phthalazines 182 were reacted with various hydrazides 183 followed by acidic cleavage in a solid-phase synthesis to afford [1,2,4]triazolo[3,4-a]phthalazines 184 <05TL3107>. 1,3-Dipolar cycloadditions between diethyl azodicarboxylate and the polymer-bound munchnones generated from the corresponding carboxylic acids provided a library of 3,5disubstituted-1,2,4-triazoles in excellent yields and in high purities <05SL1135, 05SL2595>. Polyethylene glycol resin thioureas 185 reacted with various arylhydrazides 186 followed by acidic cleavage to yield 3-amino-4,5-disubstituted-1,2,4-triazoles 187 <05TL5139>. A similar protocol using the same resin linker afforded 3,5-disubstituted-1,2,4-triazoles <05TL8479>. An efficient liquid-phase synthesis of strongly fluorescent tetraaryl-4,5-dihydro-1,2,4-triazoles via 1,3-dipolar cycloaddition of imines with nitrile imines generated in situ on soluble polymer support has been described <05S3535>.
N
R1 N N
Cl
O 1.
R2
HN NHNH2 183
N N
Et3N, xylene, 110 °C N
2. TFA, CH2Cl2, 25 °C
182
R1
R2
R1 = CH2Py, Bn, n-Pr R2 = Ar, Bn
N
184
(40-73%)
O O
CH3 O Ar1 N 185
S
1. NHAr2
Ar3
NHNH2 186
Hg(OAc)2, 25 °C
Ar3
Ar2 N
2. TFA, CH2Cl2, 25 °C
N N
(56-96%)
187
NHAr1
Several interesting 1,2,4-triazole fused-ring systems have been reported. Reaction of aryl nitriles with 4-amino-1,2,4-triazine-3-thiones in the presence of potassium tert-butoxide afforded 1,2,4-triazolo[1,5-d]-1,2,4-triazine-5-thiones <05JHC1021>. An improved method for the synthesis of 1,2,4-triazolo[4,5-a]pyrimidin-5-ones has been reported using microwave irradiation <05S2833>. Reaction of 3-alkyl-5-amino-1-phenyl-1,2,4-triazoles with N-cyanoimidates or with N-ethoxycarbonylimidates led to several novel 1,2,4-triazolo[4,3-a]triazines <05SC2467>. Arenecarbaldehyde-4-arylthiazol-2-ylhydrazones underwent ring closure with poly[(4diacetoxyiodo)styrene] to yield 3,5-diarylthiazolo[2,3-c]-s-triazoles <05SC1753>.
240 5.4.6
L. Yet
TETRAZOLES AND RING-FUSED DERIVATIVES
2,3-Diaryltetrazole-5-thiones were prepared and theoretical studies on atomic charge distributions were performed on these compounds <05JOC8322>. Several methods have been reported in the preparation of various tetrazoles. Aromatic amides 188 were converted to 1-aryl-5-methyl-1H-tetrazoles 189, which were reacted with 1,2dehydrobenzene to yield a series of 1-aryl-5-benzyl-1H-tetrazoles 190 <05TL2679>. Reaction of N-fluoropyridinium fluoride 192, generated in situ from substituted pyridines 191 with elemental fluorine, with a series of isonitriles and trimethylsilyl azide led to the formation of the corresponding tetrazol-5-yl-pyridines 193 <05TL4851>. A facile and efficient procedure was developed for a one-pot synthesis of fused 1,5-disubstituted tetrazoles 195 from cyclic ketones 194 and sodium azide in the presence of aluminum chloride in solvent-free media <05SC1115>. A four-component Ugi reaction with amines 196, aldehydes or ketones 197, and isocyanides 198 in the presence of azidotrimethylsilane afforded 1,5-disubstituted tetrazoles 199, which were cleaved with base to give 5-substituted 1H-tetrazoles 200 <05TL7393>. Nanocrystalline zinc oxide was found to be an efficient heterogeneous catalyst for the [3+2] cycloaddition of sodium azide with nitriles to afford 5-substituted-1H-tetrazoles in good yields <05ASC1212>. Synthesis of new tetrazole-substituted pyroaminoadipic and pipecolic acid derivatives has been reported <05EJOC326>. O H3C
N
1. PCl5 NHAr
2. HN3
H3C
188
N
N N Ar
1,2-dehydrobenzene
189
N
CH3CN reflux, 12-18 h
Ph
(60-78%)
N
N N Ar
190
R2NC F2, CHCl3
R1 N 191
TMSN3
R1
-60 °C R1 = H, Me, Cl, OMe, Ph, CO2Me
O
N F F 192
NaN3, AlCl3 50 °C , grinding ( )n
194
(51-95%) n = 0-3
(37-84%)
R1
R2 = n-Bu, t-Bu, Ar, Bn
N N N N ( )n 195
N 193
R2 N N N N
241
Five membered ring systems: with more than one N atom
O R1 NH2
+
R2
+
R3
197
196
R2 R3 R1HN
TMSN3 NC
RO2C R4
MeOH
RO2C
(37-92%)
198
R = Me, Et; R1 = Bn, (OMe)2CHCH2 R2 = Me, Ar, I-Pr; R3 = H, Me; R4 = Ph, CO2Me
N R4 199
N
N N
1. NaOEt or
R2 R3 R1HN
KOt-Bu HN
2. HCl (33-67%)
N
N N
200
An efficient protocol for the Suzuki-Miyaura synthesis of ortho-biphenyltetrazoles 203 from non-protected 2-bromophenyltetrazole 201 and boronic acids 202 using microwave irradiation in aqueous solvent has been published <05TL6529>. Linear Nω-tritylated ω-amino α ω thiobenzylamides and N ,N -ditritylated polyamino mono- and bisthioamides were efficiently converted to the corresponding tetrazole derivatives upon treatment with azidotrimethylsilane under Mitsunobu reaction conditions <05OL561>. 3β-Acetoxy-6β-(3,5-dioxo-4-phenyl-[1,2,4]triazolidin-1-yl)cholest-4-ene has been prepared from the reaction of cholesteryl acetate with 4phenyl-1,2,4-triazoline-3,5-dione in diethyl ether mediated by lithium perchlorate <05SC1059>. N N N NH Br
B(OH)2
PdCl2(dppf) (10 mol%)
N N N NH
Na2CO3, DME, H2O +
R
R
microwave, 115 °C (40-93%)
201
202
203
5-Pyrrolidin-2-yltetrazole 204 has been found to be a new, catalytic, and more soluble alternative to proline in a highly selective, organocatalytic route to chiral dihydro-1,2-oxazines <05OL4189> and as an asymmetric organocatalyst for Mannich, nitro-Michael and aldol reactions <05OBC84>. N
N H
N HN N 204
5.4.7
REFERENCES
05AG(I)794 05AG(I)2211 05ASC1212 05CC2041 05CC2849 05CC2852 05CC3062 05CL438 05CL734
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246 05TL2631 05TL2679 05TL2911 05TL2931 05TL3107 05TL3429 05TL3771 05TL4315 05TL4543 05TL4789 05TL4851 05TL5081 05TL5139 05TL5233 05TL5387 05TL5455 05TL5581 05TL6011 05TL6163 05TL6311 05TL6529 05TL6545 05TL6741 05TL6833 05TL6887 05TL7315 05TL7393 05TL7533 05TL7615 05TL7993 05TL8218 05TL8315 05TL8355 05TL8369 05TL8479 05TL8531 05TL8639 05TL9049 05TL9053
L. Yet H.-J. Wang, J. Keilman, C. Pabba, Z.-J. Chen, B.T. Gregg, Tetrahedron Lett. 2005, 46, 2631. A.A. Aly, R.M. Shaker, Tetrahedron Lett. 2005, 46, 2679. H.A. Orgueira, D. Fokas, Y. Isome, P.C.-M. Chan, C.M. Baldino, Tetrahedron Lett. 2005, 46, 2911. D.A. Klumpp, P.J. Kindelin, A. Li, Tetrahedron Lett. 2005, 46, 2931. J.Y. Hwang, H.-S. Choi, Y.-D. Gong, Tetrahedron Lett. 2005, 46, 3107. K.-S. Yeung, M.E. Farkas, J.F. Kadow, N.A. Meanwell, Tetrahedron Lett. 2005, 46, 3429. Y. Hari, Y. Shoji, T. Aoyama, Tetrahedron Lett. 2005, 46, 3771. S. Lin, L. Yang, Tetrahedron Lett. 2005, 46, 4315. J.-C. Meng, V.V. Fokin, M.G. Finn, Tetrahedron Lett. 2005, 46, 4543. C.A. Zificsak, D.J. Hlasta, Tetrahedron Lett. 2005, 46, 4789. A.S. Kiselyov, Tetrahedron Lett. 2005, 46, 4851. K. Asakawa, J.J. Dannenberg, K.J. Fitch, S.S. Hall, C. Kadowaki, S. Karady, S. Kii, K. Maeda, B.F. Marcune, T. Mase, R.A. Miller, R.A. Reamer, D.M. Tschaen, Tetrahedron Lett. 2005, 46, 5081. Y.-X. Zong, J.-K. Wang, G.-R. Yue, L. Feng, Z.-E. Song, H. Song, Y.-Q. Han, Tetrahedron Lett. 2005, 46, 5139. J. Li, X. Wang, Y. Zhang, Tetrahedron Lett. 2005, 46, 5233. K.Y. Lee, S. Gowrisankar, J.N. Kim, Tetrahedron Lett. 2005, 46, 5387. M. Prashad, Y. Liu, D. Har, O. Repic, T.J. Blacklock, Tetrahedron Lett. 2005, 46, 5455. M.A. Zolfigol, A.G. Choghamarani, M. Shahamirian, M. Safaiee, I. MohammadpoorBaltork, S. Mallakpour, M. Abdollahi-Alibeik, Tetrahedron Lett. 2005, 46, 5581. Y. Ju, R.S. Varma, Tetrahedron Lett. 2005, 46, 6011. S.E. Kazzouli, L. Bouissane, M. Khouili, G. Guillaumet, Tetrahedron 2005, 61, 6163. R.C. Woudenberg, E. Bryan Coughlin, Tetrahedron 2005, 61, 6311. N. Cousaert, P. Toto, N. Willand, B. Deprez, Tetrahedron Lett. 2005, 46, 6529. M. Adib, M.H. Sayahi, S. Rahbari, Tetrahedron Lett. 2005, 46, 6545. D.S. VanVliet, P. Gillespie, J.J. Scicinski, Tetrahedron Lett. 2005, 46, 6741. H.A. Stefani, C.M.P. Pereira, R.B. Almeida, R.C. Braga, K.P. Guazen, R. Cella, Tetrahedron 2005, 61, 6833. A. Shavnya, S.M. Sakya, M.L. Minich, B. Rast, K.L. DeMello, B.H. Jaynes, Tetrahedron Lett. 2005, 46, 6887. N. Xi, S. Xu, Y. Cheng, A.S. Tasker, R.W. Hungate, P.J. Reider, Tetrahedron Lett. 2005, 46, 7315. J. Mayer, M. Umkeher, C. Kalinski, G. Ross, J. Kolb, C. Burdack, W. Hiller, Tetrahedron Lett. 2005, 46, 7393. C. Pabba, H.-J. Wang, S.R. Mulligan, Z.-J. Chen, T.M. Stark, B.T. Gregg, Tetrahedron Lett. 2005, 46, 7553. Z.-F. Tao, T.J. Sowin, N.-H. Lin, Tetrahedron 2005, 61, 7615. J.Z. Deng, C.S. Burgey, Tetrahedron Lett. 2005, 46, 7993. L. Bouissane, S.E. Kazzouli, J.-M. Leger, C. Jarry, E.M. Rakib, M. Khouili, G. Guillaumet, Tetrahedron 2005, 61, 8218. S.J. Oxenford, J.M. Wright, P. O’Brien, N. Panday, M.R. Shipton, Tetrahedron Lett. 2005, 46, 8315. J. Schwerkoske, T. Masquelin,, T. Perun, C. Hulme, Tetrahedron Lett. 2005, 46, 8355. R.P. Frutos, I. Gallou, D. Reeves, Y. Xu, D. Krishnamurthy, C.H. Senanayake, Tetrahedron Lett. 2005, 46, 8369. X.-C. Wang, J.-K. Wang, Y.-X. Da, Z.-J. Quan, Y.-X. Zong, Tetrahedron Lett. 2005, 46, 8479. C. Chowdhury, S.B. Mandal, B. Achari, Tetrahedron Lett. 2005, 46, 8531. H. Yanai, T. Taguchi, Tetrahedron Lett. 2005, 46, 8639. V. Gracias, A.F. Gasiecki, S.W. Djuric, Tetrahedron Lett. 2005, 46, 9049. V. Gracias, D. Darczak, A.F. Gasiecki, S.W. Djuric, Tetrahedron Lett. 2005, 46, 9053.
247
Chapter 5.5 Five-membered ring systems: with N and S (Se, Te) atoms Yong-Jin Wua and Bingwei V. Yangb a Bristol Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492-7660, USA b Bristol Myers Squibb Company, PO Box 4000, Princeton, NJ 08543-4000, USA
[email protected] and
[email protected]
5.5.1 INTRODUCTION The study of thiazoles and their derivatives has continued to flourish primarily due to their importance as both synthetic targets and drug candidates. This review chapter focuses on the syntheses and reactions of these 5-membered heterocyclic ring systems containing nitrogen and sulfur (or selenium or tellurium) (reported during 2005). The importance of these π-rich heterocycles in medicinal chemistry and natural products is also covered. 5.5.2
THIAZOLES
5.5.2.1 Synthesis of Thiazoles and Fused Derivatives The Hantzsch reaction discovered in 1889 remains one of the most reliable routes to thiazoles and several applications of this reaction appeared during the past year <05JOC8991; 05JA15644; 05T1257>. This approach has been used twice to form both thiazole rings of the cyclopeptide dendroamide A <05H(65)95>. The first thiazolation of α-bromomethyl ketone 2 with thioamide 1 results in the formation of thiazole 3, which is converted into thioamide 4. This compound undergoes the second thiazolation with 5 to furnish oxazolyl bis-thiazole 6, a precursor to dendroamide A. i-Pr BocHN 1
NH2
+ Br
S
2
KHCO3; TFAA, Py; NH3
BocHN
OMe
N H
O
N S
O
Me N H
N
O
S 6
O
CO2Me
+
Me
Me N H
BocHN
i-Pr
N
5
i-Pr
65%
Me N H
Br
KHCO3; TFAA, Py; NH3
Me
O
O
83%
i-Pr
O
O
N O
CO2Me Me
BocHN
O
N S
N S
Me N H
3
OMe O
3 steps O
Me N H
4
NH2 S
248
Y.-J. Wu and B.V. Yang
Thiazoles can also be derived from 1,4-dicarbonyl compounds, which are available through the N-H insertion reaction of rhodium carbenoids <05JA15644>. For example, the dirhodium(II) carboxylate-catalyzed reaction of diazocarbonyl compound 8 in the presence of primary amide 7 leads to the formation of α-acylaminoketone 9, which is converted into thiazole 10 by treatment with Lawessons’ reagent. Thiazole 10 serves as one of the six thiazole building blocks in the total synthesis of thiopeptide antibiotic amythiamicin D. O BnO2C
N2
Me NH2
BocHN
CO2Me
BocHN
Rh2(OAc)4 74%
O
7
8
BnO2C
BnO2C
O 9
H N
CO2Me
O
Me
N
BocHN
P2S5
S
65%
10
CO2Me Me
Thiazoles can be prepared from thiazolines by oxidation with activated manganese dioxide. This approach has been applied to the synthesis of dimethyl sulfomycinnamate (11 to 12) <05JOC1389>, the polyoxazole-thiazole based cyclopeptide YM-216391 (13 to YM216391) <05CC797>, and didmolamides A and B (14 to 15) <05TL2567>. A facile preparation of thiazole 17 from thiazolidine 16 involves a bromination-elimination protocol <05JMC2584>. R S
NH
i-Pr
Ph
N
Me HN Fmoc
O
MnO2
N S 14
O
Me O
N
O
S
O 91% Allyl
O dimethyl sulfomycinamate
O N
NH
N
Me
S YM-216391
O
O N S 15
CO2Me O Allyl
HN Ph
O
N
N
13
HN Fmoc
R
N
NH
Ph MnO2
N
Et
55%
O H
NH
i-Pr
Et
N
O
O
N
N
Me
O
NH
O
R
12
N
NH
Me O
O
N
O
O
O
Me
11 (R = CO2Me)
S
80%
N
R
N
NaIO4, OsO4
S
79% N
O
N
MnO2
N Me
R
R N
S
48% 16
CO2Me
NBS
N Ph
S
17
A one-pot four-component solution phase procedure has been developed for the synthesis of 2,4,5-trisubstituted thiazoles 25 <05SL79>. The four components, the 3-substituted 3bromo-2-isocyanoacrylate 18, the ketone or aldehyde 19, the primary amine 20, and the thiocarboxylic acid 21, can vary broadly, thus producing thiazoles with five potential diversity points. Presumably, condensation of 19 with 20 generates imine 22, which reacts regioselectively with 18 and 21 via the Ugi pathway. The intermediate Ugi product 23 is in
249
Five-membered ring systems: with N and S (Se, Te) atoms
equilibrium with its mercaptoimine tautomer 24, which undergoes Michael addition followed by elimination of hydrogen bromide to afford thiazole 25. Replacement of 18 with 2isocyano-1,1-dimethoxyethane furnishes endothiopeptides 26, which are converted into thiazoles 27 directly using trimethylsilyl chloride and sodium iodide <05OBC3184>. R3R4C(O) (19) R2NH2 (20) R1C(O)SH (21)
NC
MeO2C R5
Br
R3
R4 R3 N R5
N S
O
R2
C
MeO2C
R1
N
R5
25
N
Br
SH 24
OMe
MeO
MeO2C
N
R5
Br
O
R2
MeO2C
R1
R5
4 3 H R R 2 N R N S OMe O R1 26
55-92%
R4 R3
R2
HS O R1 21
25-43%
+ 19 + 20 + 21
N 22
R4 R3
-HBr
NC MeO
R4
R5 Br 18
18
MeO2C
N
MeO2C
R2
N S
H
O
R1
4 3 H R R N R2 N S Br O R1 23
R3
TMSCl, NaI
N
66-91% (R4 = H)
R2
N S
27
O
R1
2-Cyanothiazoles 33 are prepared from N-vinyl-1,2,3-dithiazolimines 31, obtained from the reaction of 4,5-dichloro-1,2,3-dithiazolium chloride 29 with aziridines 28 <05H(65)1601>. Thermolysis of imines 31 brings about cyclization to give sulfur, hydrogen chloride and 2-cyanothiazoles 33, possibly by an electrocyclization and fragmentation process. Reaction of allenyl isothiocyanate 34 with a variety of nucleophiles (NuH) leads to 5-methylthiazoles 35 bearing a functionality at the C-2 position <05SL2920>.
R
Cl
H N
+ Ph
S
S N S
Cl
Cl
N
R
S 28 29 R = CO2Et, CO2NH2, C(O)Ph R Ph
H
Cl
S 32
CN
-H 75-90%
N
58-72%
Ph S
Ph
30 H
R
N
N
R Cl H
Ph
S 33
CN
S
N
31
C
N
Cl
NCS 34
-S -Cl
N
NuH 40-95%
Et3N
Me
S
Nu
35
The cyclocondensation of 1-alkynyl(phenyl)-λ3-iodanes with thioureas and thioamides is also a useful method for thiazole synthesis <05AG(E)6896>. For instance, reaction of iodane 36 with thiourea in the presence of triethylamine affords 2-aminophenylthiazole 38. When the same reaction is carried out in the absence of triethylamine, thiazole 38 is not formed; instead the isothiouronium mesylate 37•MsOH is isolated in 82% yield. Exposure of this mesylate to an aqueous solution of sodium bicarbonate produces 38 through an intramolecular 5-endo digonal cyclization. Presumably, methanesulfonic acid, generated
250
Y.-J. Wu and B.V. Yang
from iodane 36 during the reaction with thiourea, inhibits the intramolecular cyclization by formation of the mesylate 37•MsOH. The isolation and cyclization of 37•MsOH indicate that sulfide 37 is a reactive intermediate in the one-step synthesis of 38 in the presence of a base. The proposed mechanism involves Michael addition of thiourea to iodane 36 followed by a 1,2-rearrangement of the iminothio group in the alkylidene carbene 40 <05AG(E)6896>. Et3N, 54%
Ph
I 36
OMs S + H2N NH2 Ph
HN
82% Ph
NH2
S
NaHCO3 51%
37
NH2
N
S
Ph
38
-MsOH Ph S H2N
.
Ph
-PhI
HN
HN S
I Ph H2N
39
40
A convenient synthesis of 2-mercaptobenzothiazoles 44 features an exclusive orthoselective nucleophilic aromatic substitution reaction of ortho-haloanilines 41 and subsequent intramolecular cyclization of the intermediate O-ethyl carbonodithioates 43 <05JHC727>. 2Mercaptobenzothiazoles 44 are readily converted to the corresponding 2chlorobenzothiazoles 45 upon treatment with sulfuryl chloride. Y
X
R 41
NH2
S KS
42 OEt
Y
S
S
R
OEt
Y
SO2Cl2
Y
S
R
Cl
40-99%
N 45
44
43
X = Cl, Br, F; Y = CH, N
SH N
NH2
65-99%
S
R
A series of 2-aminothiazo[5,4-b]pyridines 47 are obtained from 2-hydroxy-3thioureidopyridines 46, which are readily prepared from the condensation of aryl isothiocyanates and 2-hydroxy-3-aminopyridine <05H(65)2729>. N
OH
ArNCS
NH2
25-90%
N
46
OH
TFA
S N H
NHAr
N
S NHAr
19-65%
N 47
Three new methodologies for the preparation of 2-substituted benzothiazoles have emerged. The first one involves manganese(III)-promoted radical cyclization of arylthioformanilides and benzoylthioformanilide 48 under microwave irradiation <05TL4345>. The second method uses a direct palladium-catalyzed arylation of benzothiazoles 51 with aryl bromides <05TL1349>. The third methodology provides a onepot synthesis of 2-aryl- and 2-alkyl-substituted benzothiazoles 57 from o-aminothiophenols 54 and β-ketoesters 55 using microwave irradiation <05H(65)2119>. The formation of 57 probably involves the nucleophilic addition of the thiol group to the keto group of the β-keto ester with subsequent elimination of ethyl acetate to give the intermediate adduct 56. 2-
251
Five-membered ring systems: with N and S (Se, Te) atoms
Substituted benzothiazoles are also prepared from ortho-aminothiophenol and carboxylic acids <05S2521>. R1
Mn(OAc)3•2H2O, HOAc, MW
S N H
.
R1
R2
H N
R
O
O
R2
NH2
54
S
Ar
-EtOAc
OEt
R2
S
MW
55
56
S
>96%
O
R1
R2
N 53
N 52
+ R1
R1
S
51 R = H, OMe SH
R2
N 50 50-88%
ArBr, Pd(OAc)2, P(t-Bu)3, Cs2CO3, CuBr, DMF 10-84%
S
S
.
N 49
R2
48 R1 = H, OMe, Cl, Br; R2 = Ar, C(O)Ph R
R1
S
NH2
R2
N
R1
57
R1 = H, Cl; R2 = alkyl, aryl
A series of 2-imidazolidin-2-one substituted benzothiazoles 62 are prepared from Oamidinylhydroxylamines 58 with aryl isothiocyanates 59 in moderate yields <05PJC115>. The reaction pathway has been proposed to proceed via iminocarbonyl sulfenamide 61, which undergoes spontaneous sulfurization of the aromatic ring with loss of 1aminocyclohexanecarbonitrile to furnish benzothiazole 62. NHR' H O N 58
p-R-PhNCS 59
Et3N
N
R'HN R
R
15% (R = H) 15% (R = OMe) 20% (R = Me)
R
S
N N 61
60
S N N 62
S
N
N N
-R'NH2
NHR'
O
NH
O
NC
NH
R' =
O
A regioselective synthesis of 6-substituted benzylthiazolo[3,2-b]1,2,4-triazoles 65 makes use of the Sonogashira coupling of 3-mercaptopropargyl-1,2,4-triazoles 63 with aryl iodides <05TL1607>. The intermediate coupling product 64 undergoes the Pd(II)-catalyzed intramolecular cyclization of the nitrogen at the 2-position onto the triple bond followed by base-induced aromatization. H
R
Ar
[(PPh3)2PdCl2], ArI, CuI, Et3N
N N N H 63
Ar
S
R
N N
48-78%
2
R S
N H 64
N N S
N 65
252
Y.-J. Wu and B.V. Yang
An elegant synthesis of the marine sponge derived β2-adrenoceptor agonist S1319 has been recently reported <05OL4697>. The key step for this approach is the formation of a 7lithiated-2,4-dialkoxybenzothiazole intermediate 68 obtained via a directedlithiation/benzyne-mediated cyclization reaction of phenylcarbamothioate 66. This process enables the rapid introduction of a highly functionalized substituent into the 7-position of the benzothiazolone nucleus to provide the benzylic alcohol 70 directly from 66. The incorporation of a tert-butyl ether residue is used as a means to sterically suppress a competing directed ortho-lithiation reaction at the 3-position, thus improving the efficiency of the pivotal ring-closing step. F
Li S
3
t-BuO
N H
S
t-BuLi
Oi-Pr
N t-BuO
O H
Me HO N CO t-Bu 2 69
N
HO
N t-BuO
68 NHMe
CO2t-Bu Oi-Pr
74%
t-BuO
Me
S
Oi-Pr N
Oi-Pr
67
66
S
7
TFA
S
49%
N H
O OH
70
S1319
A one-pot three-component reaction of 2-aminobenzimidazoles, aldehydes 71 and βketoesters 72 has been developed for the synthesis of 4H-pyrimido[2,1-b]benzothiazoles 75 <05BMCL5553>. The reaction presumably proceeds in two steps: Knoevenagel condensation of 71 with 72 produces 3-benzylidene-2,4-pentanedione 73; Michael addition of 73 with 2-aminobenzothiazole then generates 74, which cyclizes to 75. N
O NH2 +
S
Ar
O H
+
R
CO2Me
Ar N S
N OMe
S
72
71 H
Ar
O
O NH
R
74
53-77%
H
Ar N S
NH2
CO2Me R O 73
CO2Me R N 75
5.5.2.2 Synthesis of Thiazolines As described previously, thiazolines are versatile intermediates to thiazoles. In addition, thiazoline rings are structural motifs found in numerous natural products. Among a variety of methods for the construction of thiazolines, the cyclodehydration protocol is perhaps most popular. In the total synthesis of cyclopeptide YM-216391, (diethylamino)sulfur trifluoride (DAST) is used as the cyclodehydrating agent for the conversion of β-hydroxy thioamide 76 to thiazoline 13 <05CC797>. A similar strategy has been used in the construction of the thiazoline moiety in two independent total syntheses of halipeptin A (77 to 78; 79 to 80)
253
Five-membered ring systems: with N and S (Se, Te) atoms
<05AG(E)135; 05AG(E)4925>. A more recent protocol for the dehydrative cyclization of cysteine derivatives to thiazolines involves molybdenum (IV or VI) oxides as catalysts as exemplified by the formation of 82 from 81 <05OL1971>. O
O NH
i-Pr O
N N
Me
O
N N
89%
O
Me
OMe n-Pr 77 Me
S
N
NH
N
O
N
N
S
O H
Ph
76 Me
O
NH
O
S
Me
N
Et
HN
O H HO
Ph
O
DAST
Et NH
NH
i-Pr O
NH
O
O
13 Me
R
Me Me O
N H Me O N N Me S CO2Me Me S DAST OMe O Me Me O OH Me O 85% n-Pr O O N3 O Me N3 R = (CH2)2OTBDPS 78 Me Me Me OH
Me HN N H CO2allyl Fmoc 79
DAST 89%
Me
S
Me HN N R CO 2allyl Fmoc 80
N H
N CO2Me Me
Mo(IV) or Mo(VI) R oxide
SH
O
S N
CO2Me 81
R
96% R = Ph(CH2)2
CO2Me 82
In the total synthesis of didmolamides A and B, the thiazoline moiety is formed from the trityl protected cysteine 83 by a nucleophilic attack of the cysteine thiol group on the phosphorus-activated amide carbonyl group of the preceding residue (see 84) <05TL2567>. Me HN Fmoc
NH CO2allyl
Ph3PO, Tf2O 92%
O 83
STr
Me FmocHN (TfO)Ph3P
Me N
O
S Tr
CO2allyl
84
HN Fmoc
N
CO2allyl
S 85
A recent synthesis of dimethyl sulfomycinamate involves Wipf’s oxazoline-thiazoline conversion as the key step <05JOC1389>. Thus, the oxazoline formation is carried out from 86 using the Burgess reagent, and treatment of the resulting oxazoline 87 with hydrogen sulfide leads to ring-opening to give the thioamide 88, which is recyclized, once again using the Burgess reagent, to afford thiazoline 11.
254
Y.-J. Wu and B.V. Yang
MeO2C
Burgess reagent 63%
NH HO
R
O 86
MeO2C
NH HO
71%
R O 87
Burgess MeO2C reagent 87%
MeO2C
H2S, Et3N
N
S
R 88
N S 11
R
N
R = Me
N
O
CO2Me
5.5.2.3 Synthesis of 2-Imino-thiazolidine and Thiazoline Derivatives 2-Imino-thiazolidine 93 is prepared directly from the corresponding O-methanesulfonyl βamino alcohol hydrochloride 89 using potassium thiocyanate via aziridine intermediate 90 <05TL233>. Ring opening of 90 with potassium thiocyanate gives amines 91 and 92, which recyclizes to furnish the same cis imine 93.
Et
KSCN
NH3 Cl Et 89
Et b
OMs
a 90
Et
NH2
NH2
NH
Et
Et
+
SCN 91 path a
Et
Et SCN 92 path b
87%
Et
H N
Et
S 93
NH
A straightforward synthesis of 2-imino-1,3-thiazolidines 96 and 2-imino-1,3-thiazolines 99 has been developed by ring transformation of 1-arylmethyl-2-(thiocyanomethyl)aziridines 94 upon treatment with a catalytic amount of titanium(IV) chloride <05JOC227>. This reaction probably proceeds through the formation of a bicyclic aziridinium salt 95 resulting from a nucleophilic attack of the lone pair of nitrogen onto the electrophilic carbon atom of the thiocyano group, which is activated by the Lewis acid. Subsequently, this aziridinium intermediate 95 undergoes ring opening by chloride, furnishing a heterocyclic moiety. Although two possible pathways might occur, only the route leading to a five-memebred ring is favourable (route a), as no traces of 2-imino-1,3-thiazine 97 are detected (route b). Addition of an acid chloride to the same reaction generates the 2-(N-acylimino)-1,3thiazolidine 98, which is converted to the corresponding thiazoline 99 via base-induced dehydrochlorination. N TiCl4
Ar N
Ar N Cl
Ar N
S a
94 TiCl4, 84-96% AcCl N
N
98
KOt-Bu 61-69%
S
84-89%
NH
Ar N
a Cl
b 95
Cl
S 96
b
Ac S
TiCl3
N
Ar N Me
Ac
NH Ar
N
S
S 99
Cl 97
255
Five-membered ring systems: with N and S (Se, Te) atoms
A series of 1-acylimino-3H-thiazoline derivatives 104 are prepared by a one-pot threecomponent condensation of arylisothiocyanates 100, primary amines 101 and α-halocarbonyl derivatives 102 presumably via intermediates 103 <05TL419>. R2
O Ar NCS 100
+ R1NH2 + 101
O
S
Ar
R2
N
R3
O
R3
O X
36-95%
Ar
103
R3
N
R2
N
NH O
102
S
R1
104
R1
5.5.2.4 Reactions of Thiazoles and Fused Derivatives A practical synthesis of L-869,298, a potent phosphodiesterase-4 (PDE4) inhibitor, involves two regioslective deprotonations of thiazole at the 2- and 5-positions <05JOC3021>. Treatment of thiazole with LiHMDS gives clean formation of the C-2 anion, which reacts with hexafluoroacetone, and the resulting lithium alkoxide 105 is protected as the MOM ether 106. Deprotonation of 106 at the 5-position with n-BuLi followed by addition of nitrile 107 furnishes ketone 108, a key intermediate for the synthesis of L869,298. 5
S 2
LiHMDS; (CF3)2CO
N
S
CF3
N
OLi CF3
MOMCl
S
89%
N 106
105
O n-BuLi; CF3 RCN (107) S R CF3 87% OMOM N 108 O
CF3 CF3 OMOM
R= HF2CO
Direct lithiation of peptide thiazoles provides an efficient C5 diversification strategy <05OL299>. Thus, treatment of thiazoles 109a/b with 1.05 equiv of LDA, followed by reaction with a variety of electrophiles, affords 5-substituted thiazoles 110a/b without racemization. Of special note is that 1.05 equiv of LDA is sufficient even with N-trityl Lalanine-based thiazole 109b where a secondary amine is present. The thiazole lithiation approach even works in complex systems. For example, lithiation of ceratospongamide 111a and its epimer 111b with 4.2 equiv of LDA, followed by quenching with iodine, affords the 5-iodo thiazole adducts 112a and 112b, respectively, again without epimerization. 5
S R
N 109a/b
R CO2Me
a: R=
LDA; 61-97% electrophile
b:
E R=
S R
N 110a/b
CO2Me
O
S
N H
N N Boc Me
a: R b: S
N O
NH O
HN O
O N
N
Bn NHTr
Bn
O Et
Me
Me
111a/b R = H 112a/b R = I (70%)
256
Y.-J. Wu and B.V. Yang
Easy access to a series of 5-substituted 4-bromo-2-thiazolamine derivatives 116 is based on the halogen dance (HD) reaction <05JOC567>. Treatment of 4-bromothiazole 113 with 3.3 equiv of LDA at 0 °C brings about full conversion to the HD product 115, which is trapped with various electrophiles to give the 5-substituted thiazoles 116. For example, 4bromo-5-trimethylsilyl-thiazole 118 is obtained in 74% yield when 113 is exposed to LDA followed by addition of TMSCl as the electrophile. The HD reaction is completely blocked when thiazole 113 is added to a solution of 3.3 equiv of LDA in the presence of TMSCl at 80 °C, and the corresponding normal, anti-HD product product 117 is formed exclusively. In the process of the HD studies on bromothiazole 113, methylation of amide nitrogen was attempted <05JOC567>. Deprotonation with sodium hydride or LDA and subsequent quenching with methyl iodide or dimethyl sulfide (DMS) leads to the exclusive methylation
Br
Li
O
N N H
S 113
Br
t-Bu
LDA, TMSCl
67% TMS Br
LDA; TMSCl 74% Br
O
N N H
S 117
S 114
t-Bu
TMS
N Li
Br
halogen dance
O
N
LDA
Li
t-Bu
O
N N Li
S 115
electrophile
S 118
Br
O
N N H
E
t-Bu
t-Bu
46-93% O
N S 116
N H
t-Bu
of the ring nitrogen and not to the desired methylation of the amide nitrogen. Under optimized conditions, 3-methylthiazol-2(3H)-imine derivative 119 is obtained from 113 in quantitative yield. The pivaloyl group in 2,2-dimethylpropanamide 121 shows a great tendency to migrate into the 5-position of the thiazole ring under lithiation conditions even at low temperatures to form amide 123 via 5-lithiated thiazole 122 <05JOC567>. This migration must be an intermolecular process since for steric reasons an intramolecular migration is not possible. This represents the first intermolecular migration of a pivaloyl group whereas intramolecular migrations have been known in the literature. O
N Br
N H
S 113 N
S
O
N Ph 121
LiH; Me2S Br
t-Bu
S
N
N
t-Bu
119 (100%) N
LDA t-Bu
Me O N
Li
S 122
pivaloyl migration
O N Ph
t-Bu
O
Br
N S 120 (0%) Me
t-Bu
N
t-Bu
O
S
NHPh
123
Regioselective substitution of the bromine at the 2-position in 2,4-dibromothiazole with prenylmagnesium chloride 124 proceeds with complete allylic transposition to afford disubstituted thiazole 125 <05OL339>. This compound serves as the starting material for the total synthesis of (±)-mycothiazole. 2-Vinylthiazole 126 undergoes Michael-like addition with various amines to give 2-aminoethylthiazoles 127 <05TL2251>.
257
Five-membered ring systems: with N and S (Se, Te) atoms
S Br
4
2
Me Br
N
S
87% Me
+
Mg Br
124
Br
N Me Me 125
EtO2C
S
F 3C
N
EtO2C
RR'NH 11-79%
S
N F 3C R'RN 127
126
The reductive coupling of substituted α-iodomethylthiazoles with aliphatic aldehydes under samarium Barbier conditions provides an effective method for the direct incorporation of intact thiazole systems <05OL4099>. For example, β-hydroxybenzothiazole 131 is obtained in good yield from iodide 128 and isobutyraldehyde. The iodomethylene appendage may be positioned at the 2- or 4-position of the thiazole nucleus. In the case of 2-αiodomethylthiazoles such as 128, the reaction may proceed through a net two-electron reduction producing the N-metallo-enamine 129 for precomplexation in the six-membered array 130. However, this approach does not work for aromatic aldehydes due to competing pinacol coupling. S I
S
SmI2 N
S N SmI2
i-PrCHO
128
i-Pr
129
O
i-Pr
82% N Sm I
S
HO
N 131
130
A concise synthesis of the heterocyclic core of the thiazolyl peptide antibiotic GE 2270 features two Negishi and one Stille cross-coupling reactions <05AG(E)1199>. The first Negishi coupling of the pyridyl zinc chloride 133 with 2-bromothiazole 132 affords 2-pyridyl thiazole 134; The second one occurs regioselectively between pyridyl dibromide 135 and thiazolyl zinc bromide 136 to furnish a 6.5:1 mixture of the 6-substituted 2-bromopyridine 137 and the 2-substituted 6-bromopyridine in 78% yield. Finally, the Stille cross-coupling of the thiazolyltin 138 with pyridyl bromide 137 generates 139. This compound serves as an advanced intermediate for the synthesis of thiazolyl peptide GE 2270. ClZn
S Br
S R
PdCl2(PPh3)2 81% S
BnHN
N 133
Br
N 132
EtO2C
Br
N
N N Br 2 137
O
S
N
N Br O 134 (R = OEt) 135 (R = NHBn)
136
S CO2Me
SnMe3
Pd(PPh3)4 61%
BnHN O
AcO
N S
Ph NHAc
138
CO2Me
S
N
N AcO
N
PdCl2(PPh3)2 78%
S
6
S
BrZn
Br
S
N
N
CO2Me
N
N S
Ph NHAc
139
5.5.2.5 Reactions of Thiazolines It was reported that thiazoline 142 reacted stereoselectively with acyl Meldrum’s acid derivatives 140 under acidic conditions to give 6-acylpenams 144. Recent studies have
258
Y.-J. Wu and B.V. Yang
shown that the structure elucidation of these compounds was incorrect <05OL1019>. The new data indicate that instead of acyl β-lactams, 1,3-oxazinones 143 are formed stereoselectively. Presumably, the reaction pathway involves the [4+2] cycloaddition of acyl ketene 141 with thiazoline 142 instead of the [2+2] cycloaddition as previously assumed. OH
R
via R
O
O O
H
H O
+
Me Me 140
H
O
142
H H
R
S
O
N
38-93%
CO2Me
141 R = Ar, CH2Ar, alkyl
O
HCl (g)
N
C O
O
R
S
CO2Me
N
O
143 (38-81%)
S
CO2Me 144 (0%)
5.5.2.6 Thiazole Intermediates in Synthesis The utility of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is amply demonstrated in a recent enantioselective synthesis of apoptolidinone. This synthesis features three thiazolidinethione propionate aldol reactions for controlling the configuration of 6 of 12 stereogenic centers <05JA13810>. For example, addition of aldehyde 146 to the enolate solution of N-propionyl thiazolidinethione 145 produces aldol product 147 with excellent selectivity (>98:2) for the Evans syn isomer. Compound 145 also undergoes diastereoselective aldol addition with bisaryl aldehyde 148 to give the Evans syn product 149, which is converted to eupomatilone-6 in 6 steps <05JOC9658>. OMe
CHO OMe Bn N
146 OBn
145
TiCl4, (-)-sparteine, NMP, 90%
Me S S
O
Bn
BnO Me
N
S S
OMe
145, TiCl4, S OMe TMEDA
OHC O 147
OMe
Me N S
65%
OH
OMe
Bn
OMe
OMe O
OH
O 148 O
149
O O
Addition of the titanium enolate of N-acetyl-4-isopropyl-1,3-thiazolidine-2-thione 150 to the N-acyl iminium ions from 151 furnishes the corresponding Mannich-type adducts 152 and 153 with good diastereoselectivity <05JOC4214>. A similar diastereoselective addition of the titanium enolate derived from N-4-chlorobutyryl-1,3-thiazolidine-2-thione 154 to N-Boc2-methoxypyrrolidine 155 has been used to provide 2-substituted pyrrolidine 156, a key intermediate in the synthesis of (+)-isoretronecanol <05TL2691>. i-Pr
S
N S O 150
Me + AcO
R1 N 151
i-Pr
TiCl4, DIPEA O
anti/syn = 7/3 to 9/1 58-84%
N
S S
R1 N
O 152 (anti)
i-Pr
O
+
N
S S
R1 N
O 153 (syn)
O
259
Five-membered ring systems: with N and S (Se, Te) atoms
i-Pr
S
N
+ MeO
S O 154 (R2 = (CH2)2Cl)
i-Pr
TiCl4, DIPEA
Boc N
R2
Boc N
R2 N
S
84%
S
155
OH H
3 steps
N
O 156
(+)-isoretronecanol
The Ni(II) Tol-BINAP-catalyzed enantioselective orthoester alkylation of Nacylthiazolidinethiones 158 is carried out using 5 mol% of (S)-Ni(II) Tol-BINAP 157 to provide 159 in good yields and with excellent enantioselectivities <05JA10506>. (Tol)2 P OTf Ni P OTf (Tol)2
HC(OMe)3, BF3•Et2O, 2,6-lutidine 157 (5 mol%)
R S
N
R
S O 158
157
N
S S
OMe
O 159
63-92% yield 90-99% ee
OMe
Exo- and enantioselective 1,3-dipolar cycloaddition of nitrones 161 with 3-(2-alkenoyl)-2thiazolidinethiones 162 is carried out in the presence of a catalytic amount of binaphthyldiimine-Ni(II) complex, readily prepared in situ from diimine 160 and Ni(ClO4)2•6H2O <05OL1431>. R3
Cl
N N
160
R1
O
N
160-Ni(ClO4)2•6H2O (5-20 mol%)
H R2 161 +
Cl HO OH Cl
N
S
O R2 163 (exo)
exo/endo = >86/14 to 99/1 82-95% ee (exo)
R3
O N R1
S
R3 N
S
S
O 162
Cl
N
S
S
O N R1
O R2 164 (endo)
A new route to 3,4-disubstituted piperidines employs diastereoselective 1,4-addition of Nnicotinoyl thiazolidinethiones with aryl cuprates <05TL8673>. Treatment of the pyridinium salt, prepared from chiral nicotinic amide 165 and phenyl chloroformate, with O
S N
N
PhC(O)Cl, Ar2CuLi•LiBr S (166)
O
S
S N
N
Ph 170
Ph
Ph
PhC(O)Cl, Ph2CuLi•LiBr S (171) 81%
N N O
O
S
S
168 (>99% de)
Ph HO
172 (90% de)
Ar HO
Ph Ph
S
Ph Ph
S N
N
167
O
O
78%
O Ar2CuLi
165 O
Ar
N
N
Ar = p-F-Ph
Ph
S
Ph
N H
173
N H 169
260
Y.-J. Wu and B.V. Yang
cuprate 166 furnishes 1,4-dihydropyridine 168 with 99% diastereoselectivity. This high diastereoselectivity is rationalized by the addition of a nucleophile from the less sterically hindered side of the intermediary cation-π complex 167. Similarly, reaction of phenyl cuprate 171 with the nicotinic amide 170, the opposite enantiomer of 165, affords dihydropyridine 172 in 90% diastereoselectivity. Compounds 168 and 172 are converted to the 3,4-disubstituted piperidines 169 and 173, respectively. Thiazolyl thioglycosides such as 174 are used as glycosyl donors. Glycosylation of 174 with 175 using silver triflate as a promoter proceeds stereoselectively to give tetrasaccharide 176 in high yield <05TL433>. One advantage of using thiazolyl thioglycosides in glycosylation reactions is that the thiazolylthio moiety (S-Taz) is stable toward common protecting group manipulations involving strong bases. The synthesis of a series of C-glycosyl ketones from the corresponding Cglycosylbenzothiazoles is based on the use of benzothiazole as a carbonyl group equivalent <05JOC9257>. This process starts with the addition of 2-lithiobenzothiazole to sugar lactones such as L-fuconolactone 177, followed by reductive dehydroxylation of the resulting adducts OH
BzO BzO
OBz O
OBn OBn
OBz BzO BzO
O
175
O BnO
O OBz BzO BzO 174
BzO BzO
OBz O OBz BzO BzO
OMe
AgOTf >73%
O O
S
OBz
O O OBz BzO BzO
N S
O O
O
OBz OBn OBn 176
O BnO
OMe
178 to give the benzothiazolyl β-L-C-flucosides 179. A series of C-glycosyl ketones 180 are derived from 179 by a one-pot, three-step reaction sequence involving N-methylation of the thiazole ring by methyl triflate, addition of the N-methylbenzothiazolium salt with various Grignard reagents, and HgCl2-promoted hydrolysis of the resulting benzothiazolines. Me OBn
OBn 177
OBn
R1
N
O O
Li S >86%
Me OBn
O OBn
N OBn (R1
S
178 = OH) 179 (R1 = H)
MeOTf; R2MgBr; Me HgCl2 35-80%
OBn
H O OBn
C(O)R2 OBn
180
The (Marc) Julia-(Sylvestre) Julia coupling reaction involving alkylsulfonyl benzothiazoles remains one of the most effective methods for the stereoselective formation of olefins and several applications have been reported <05TL3127; 05AG(E)1221; 05CC110; 05OBC1372>. The power of this reaction is demonstrated in the total synthesis of (+)-SCH 351448 <05JOC6321>. Coupling of sulfone 181 with aldehyde 182 using NaHMDS in ether proceeds stereoselectively to give a 20:1 mixture of olefin 183 and its Z-isomer in 83% yield. Compound 183 is used as one of the two fragments in the synthesis of (+)-SCH 351448.
261
Five-membered ring systems: with N and S (Se, Te) atoms
CO2R O Me Me
OBn OTBS
R = (CH2)2TMS
181
CO2R O Me Me
+
S NaHMDS E/Z > 20/1
OHC
Me
O
O
Me O O N S
O
O
Me
182
83% O
Me
Me
O
O
O
Me
OBn OTBS 183
The stereoselectivity of the Julia-Julia olefination has been well documented, and as a rule of thumb, α-lithioalkyl benzothiazolyl sulfones deliver cis-olefins and α-lithiobenzyl benzothiazolyl sulfones provide trans-olefins <05SL289>. However, unexpectedly, high cisselectivity is observed in the Julia-Julia coupling reactions involving tributyltin-containing allyl benzothiazolyl sulfones <05SL289>. For example, reaction of sulfone 184 with aldehyde 185 using KHMDS results in a 96 : 1 mixture of 3,4-cis-olefin 186 and 3,4-transolefin 187. The origin of the high cis-selectivity observed remains to be established. Bu3Sn
O O S N
66% cis/trans = 96/4
S
184 Bu3Sn
Bu3Sn LiHMDS
CHO
SnBu3 3 4
Bu3Sn
3
185
186
+
SnBu3
4
187
The Julia-Julia coupling reaction has been extended to sugar derived lactones to furnish methylene exoglycals in good yields as exemplified by the conversion of lactone 188 to exomethylene derivative 190 upon treatment with lithiomethyl benzothiazolyl sulfone from 189 <05SL520>. This approach serves as an alternative to the Tebbe reagent commonly used for this type of transformation. OTES TESO TESO 188
O TESO
+ O
N S
O S Me O
LiHMDS; DBU 74%
189
OTES TESO TESO 190
O TESO
5.5.2.7 Thiazolium-Catalyzed and -Mediated Reactions The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the thiazolylalanine-derived catalyst 191 for asymmetric intramolecular Stetter reaction of α,β-unsaturated esters <05CC195>. However, these cyclizations proceed only in moderate enantioselectivities and yields even under optimized conditions. Thiazolium salt 191 has been used successfully for enantioselective intermolecular aldehyde-imine cross coupling reactions <05JA1654>. Treatment of tosylamides 194 with aryl aldehydes in the presence of 15 mol% of 191 and 2
262
Y.-J. Wu and B.V. Yang
equiv of pentamethylpiperidine (PEMP) delivers α-amido ketones 196 in good diastereoselectivities. Me
O Me
OBn
N H
NHBoc
192
O
191 S
Ar1
I
O
O
TolO2S
N Et
N H
O Ar1
R
194
CO2t-Bu
R 191, (20 mol%), DIPEA
R
H N
O
CO2t-Bu 39-47%
CHO
N
R = Ph, i-Pr
Ph
O 193
up to 81% ee
191 (15 mol%), Ar2CHO, PEMP Ar2
O
H N
R
Ar1
O 196 (up to 87% ee)
15-91%
195
N-Nicotinoyl thiazolidinethione 197 has been identified as an effective catalyst for kinetic resolution of sec-alcohols 198 to give 200 in good to excellent enantioselectivities <05TL2239>. Me Me N O
S N
N
OH S
t-Bu 197
(i-PrCO)2O, collidine, 197 (0.5 mol%)
R Me 198
OH R S Me 199
OC(O)i-Pr +
R R Me 200 (78-98% ee)
R = aryl, allyl, propargyl
The thiazolium-mediated three-component reaction of thiazolium salts 201, aryl aldehydes and dimethyl acetylenedicarboxylate provides a facile synthesis of 2-amino-2-arylfurans 202 <05OL1343>. The reaction pathway may involve the sequential nucleophilic addition of thiazol-2-ylidene 203 with the aldehyde and DMAD to form the spirocyclic intermediate 204 through the simultaneous formation of two C-C bonds and a C-O bond. Selective ring opening of the spirocyclic intermediate 204 followed by hydrolysis leads to 3-aminofuran 202 via 205. Y
CO2Me
S Me X 201
N R
Y S Me
..
+
ArCHO +
R = Me, Et, Bn X = Cl, Br, I Y = (CH2)2OH Ar H
N R 203 MeO2C
NaH 31-87%
CO2Me
CO2Me
S Me
O MeO2C
CO2Me
202
Y
O
Ar
RHN
Ar
N R MeO2C
SH
H O
Y CO2Me
204
R N
Me MeO2C 205
Ar O CO2Me
263
Five-membered ring systems: with N and S (Se, Te) atoms
5.5.2.8 Synthesis of Thiazole-Containing Natural Products O
Me O
N
i-Pr N H
O
Me S
O
N
Me
Me N H
S
O
HO O
NH
OMe
Me N H
S
Me
n-Pr O
H Me Me Me N Bn Bn Me O O NH O NH NH HN HN Me NH Me N HN S N N Me N O O O O Me Me N Me O S S S Me (CH2)2R dendroamide A didmolamide A didmolamide B halipeptin A (R = OH) halipeptin D (R = H) O S i-Pr CO2Me Me Me N N O HN X O O N H N N O O N O NH2 S N i-Pr N N H O NH N S N HN N S N S O O i-Pr OH N S N Me S S N HN S Ph bistratamide G (X = O) N H HN S O bistratamide H (X = S) i-Pr i-Pr HN N N N S O O O Me O NH amythiamicin D O H N O NH N N O Me MeHN S CH2OMe S O Me i-Pr O O H H O GE 2270 CO2Me N HN OH NH2 N S H S O O O N S N O latrunculin A O O H NH2 O H N N N Et N S N S H N Me Me N Me O N N Me H Me OH H Me O O N N NH H O S N Me S OH H2N O OMe HN NH 206 (dehydropiperidine HO core) O O N HN Me H OH OH MeO2C N N N Me S NH Me S O Me S Me Me HO OH thiostrepton mycothiazole N
N
N
O
O
During the past year, synthetic studies on epothilones A <05OBC3812>, B and D <05OL1311> and GE 2270 have been disclosed <05AG(E)1199>. In addition, there have been several reports on the synthesis of thiazole-containing natural products, including mycothiazole <05OL339>, latrunculin A <05AG(E)3462>, dendroamide A <05H(65)95>, didmolamides A and B <05TL2567>, bistratamides G and H <05BCJ1492>, halipeptins A
264
Y.-J. Wu and B.V. Yang
and D <05AG(E)135>, 05AG(E)4925>, YM-216391 <05CC797>, epothilones B and D <05OL1311>, and amythiamicn D <05JA15644>. Four new epothilones are also produced by genetic engineering of a polyketide synthase in Myxococcus xanthus <05JAN178>. Among members of the thiopeptide family of antibiotics, thiostrepton is an extraordinarily complex natural product that has been used as a topical veterinary antibiotic and also exhibits promising antimalarial and antitumor activity. Thiostrepton contains 10 rings, 11 peptide bonds, and 17 chiral centers, and it is recognized as the flagship of the thiopeptide class of antibiotics. The landmark synthesis of thiostrepton, first communicated in 2004, has been described in detail <05JA11159; 05JA11176>. Recent structure-activity relationship studies have culminated in the discovery of a biologically active thiostrepton fragment 206, the dehydropiperidine core <05JA15042>. Despite its relatively small size, this tri-thiazolecontaining fragment maintains, and in some instances surpasses, the biological properties of the parent natural product. Compound 206 represents a new lead for further exploration in chemical biology studies and drug discovery efforts. 5.5.2.9 Thiazole-Containing Drug Candidates Epothilones are thiazole-containing natural products that induce tubulin polymerization and stabilize microtubules as does another class of antimicrotubule drugs, taxanes. However, they have a distinct binding mode to tubulin, and they may be less susceptible to mechanisms of multiple drug resistance than taxanes. For this reason, significant efforts have gone into the investigation of epothilones for advanced cancer therapy, and these efforts have culminated in the development of five epothilones currently in human clinical trials for the treatment of various cancers: patupilone (phase III), ixabepilone (phase III), fludelone (phase I) <05DF737; 05AG(E)2838>, epothilone D (phase II), and BMS-310705 (phase I) <05COID616; 05BJU296>. With respect to epothilone D, the phase II prostate cancer trials were discontinued, but the metastatic breast cancer trials are still ongoing <05COID616>. S
S
Me
R
X
N O Me
Me
O OH Me Me O OH
S
Me
Me
O
N Me
Me patupilone (epothilone B) (R = Me, X = O) ixabepilone (BMS-247550) (R = Me, X = NH) BMS-310705 (R = CH2NH2, X = O)
Me
Me
O
Me O
N OH Me
Me O OH
Me epothilone D (KOS-862)
F3C
10
Me
9
O OH Me Me O OH
Me fludelone (KOS-1584)
Dasatinib is one of the most exciting thiazole-containing drug candidates in clinical trials. It inhibits five tyrosine kinase proteins, including BCR/ABL, the protein that accounts for abnormal cell growth in chronic myeloid leukaemia, and SRC, the proteins that may play a role in imatinib resistance. In Phase II clinical trials dasatinib shows promising activity for the treatment of imatinib-resistant chronic myelogenous leukaemia (CML) <05EOID89>. Other biologically significant thiazole analogs include isatoribine <05DF886>, lidorestat <05JMC3141>, TAK-715 <05JMC5966>, 207 <05JMC2167>, and 208 <05BMCL3081>. Isatoribine, a toll-like receptor 7 (TLR7) agonist, has been advanced to phase Ib studies for the treatment of hepatitis C virus (HCV) infection. Lidorestat is a potent and selective inhibitor of aldose reductase for the treatment of chronic diabetic complications. TAK-715 is
265
Five-membered ring systems: with N and S (Se, Te) atoms
an inhibitor of p38 mitogen-activated protein (MAP) kinase and the proinflammatory cytokine tumor necrosis factor-α (TNF-α), and it is being evaluated in clinical trials for the treatment of rheumatoid arthritis. Compound 207 blocks the production of interleukin (IL)-5, a primary eosinophil-activating and proinflammatory cytokine, and it may be useful in the topical treatment of allergic disorders. Compound 208 is a dual adenosine A2B/A3 receptor antagonist with therapeutic potential in the treatment of allergic diseases. O HN
F
HO
N
Me
HN
O
F
N
OH
lidorestat
F
NH
Me Me
N N
O
S S
O
HO
H N
O O
Cl N
N
N
H2N
HO2C
Cl S
S
Cl N
207
O Ph
CN
N
isatoribine
N
N
OH Me
N
H N
O
Me
NH
N Ph HO
N
Et
TAK-715
S
N
N
S
dasatinib
N
Me
N
208
N
5.5.2.10 New Thiazole-Containing Natural Products New thiazole-containing natural products include two structurally related cyclopeptides mechercharmycin A <05JAN289> and YM-216391 <05JAN27; 05JAN32>, and hectochlorin and deacetylhectochlorin <05JNP951>. O O
N
NH i-Pr
Me Et O
O O
Ph mechercharmycin A
5.5.3
N
NH NH Me Et O
N
N
S O
Ph
YM-216391
Me OR
Me O
N
i-Pr O
N
N
S
O
N
NH N
O
O
N
NH NH
O
O
O Me HO
S O
S
N
N O
O
O Me
Me
O
Me
Cl Cl
hectochlorin R = Ac deacetylhectochlorin R = H
ISOTHIAZOLES
5.5.3.1 Synthesis of Isothiazoles by Ring-formation Nitrile sulfides are well suited for the synthesis of isothiazoles incorporating the C=N-S unit via their 1,3-dipolar cycloaddition reactions with double or triple-bonded dipolarophiles. Benzonitrile sulfide 210 is readily prepared from decarboxylation of oxathiazolone 209 using microwave irradiation <05SC807>. Subsequent cycloadditions to dimethyl acetylenedicarboxylate (DMAD) and dimethyl fumarate afford 211 and 212, respectively. In the case of ethyl propiolate, a 1:1 regioisomeric mixture of phenylisothiazoles 213 and 214 is obtained.
266
Y.-J. Wu and B.V. Yang
Ph
O
160 °C
O
N S 209
Ph C N S 210
MW
CO2Me
211
N S
Ph CO2Et + N S 213
MeO2C
DMAD 56%
Ph
Ph
CO2Et
CO2Et N S 214
CO2Me CO2Me
Ph
CO2Me
N S
CO2Me
212
A tetrabutylammonium fluoride (4 equiv of Bu4NF)-promoted reaction between orthotrimethylsilyl-phenyliodonium triflates 215 and dialkyl-aminothiazadienes 216 provides a novel approach to 3-substituted benzisothiazoles 219 <05H(65)1615>. Interestingly, when 1.5 equiv of TBAF is used, the same reaction furnishes only benzothiazines 222. Formation of isothiazoles 219 presumably involves the trapping of a benzyne intermediate by a nitrile sulfide 218 generated in situ at high concentration of fluoride ion. The more frequently used methods for construction of isothiazoles (and its partially or completely saturated analogs) consist of cyclization of compounds containing preformed NC-C-C-S fragments with a S-N bond connection. For example, 4,6-dinitrobenzisothiazole 225 is prepared from sulfenyl chloride 224 upon treatment with ammonia <05MC200>. Further functionalization at 4-position is achieved by nucleophilic replacement at the 4-nitro group. S R1
N
N
TMS 4 equiv TBAF
+
R2 NMe2 215 1.5 equiv TBAF
216
NR1R2 N H
220
N
I Ph OTf
retro ene
S N
N Me
NR1R2 H
N
85-93%
N 2 R1 R 219
O2N
80-85%
N 222
NO2 SCl
SO2Cl2
Nu
NH3
N
54% O N 2 NO2 224
NR1R2
S
[1,3]-H
221 CHO
SBn
NO2 223
+
NR1R2 218
R1 R2 217
CHO O2N
S [3+2]
[4+2]
S
H
S N
S N
S 225
N O2N
S
226 Nu = SPh, OPh, N3
N-Aroylisothiazolium imines 230 are prepared by cyclocondensation of thiocyanobutenals 227 with aryl hydrazides 228 <05H(65)2705>. These imines are oxidized, and the resulting hydroperoxy sultams are reduced to give hydroxysultams 231. Under thermal conditions, these sultams undergo dehydration followed by 1,5-electrocyclization to give a novel series of heteropentalenes, the oxadiazolo-sultams 233.
267
Five-membered ring systems: with N and S (Se, Te) atoms
R1
CHO +
R2
HOAc, H2O2 18-53%
R1
Na2SO3•7H2O R2 69-95%
HO Ar N NH
S O2
O toluene, Δ
18-60%
N NH S Ar CN O 229
R2
H2NHN Ar 228
SCN 227
R1
R1
O
R1
O
-HCN
S O2
231
S
N N Ar
230 R1
Ar 38-95%
N N
R2
R2
O
O
Ar
N N
R2
S O2
232
233
Sultams can also be accessed by intramolecular cyclization of compounds containing preformed C-S-N-C-C fragments with a C-C bond formation as demonstrated in a one-pot synthesis of tricyclic sultam 236 <05SL577>. Tetrahydropyridine 235, obtained from N,Nbis(allyl)sulfonamide 234 by ring-closure-metathesis (RCM) followed by isomerization, undergoes radical cyclization in the presence of tris(trimethylsilyl)silane (TTMSS) to give tricycle sultam 236. O S
O
O
RCM; RuH
N
O
S
Br 234
N
Br 235
O
TTMSS, AIBN
S
O N
62%
236
Bicyclic sultam 241 is a sulfonyl analog of thiolutin, a commercially available antibiotic <05HCA1208>. A recent synthesis of 241 starts with the intramolecular Dieckmann condensation of diester 237 to give sultam 238. Subsequent methylation, bromination with NBS, and dehydration afford sultam bromide 240. Treatment of 240 with excess of hydrogen sulfide in the presence of triethylamine brings about nucleophilic displacement of both the methoxy group and the bromine by a thiol group, and the resulting dithiolate is oxidized in air to furnish bicyclic sultam 241. MeO
MeO2C
S
CO2Me HO CO2Me NaOMe; HCl SO2 SO2 87% N N H H MeO2C 237 238 O
N Me thiolutin
O
MeO Br
S
CO2Me
S N
MeO2C 241
SO2
SO2 N OH Me 239
Me
MeO H2S; O2 35%
CO2Me
MeO2C
H2SO4 (cat), Ac2O
NHAc
S
C(OMe)4 55% NBS 83%
92% CO2Me
SO2 N MeO2C Me 240 Br
The synthesis of isothiazoles involving hexamethyldisilathiane-based thionation has been reviewed <05SL1965>.
268
Y.-J. Wu and B.V. Yang
5.5.3.2 Reactions of Isothiazoles Thermal extrusion of sufur dioxide from spirobenzosultam 243 has been utilized in the synthesis of 2-aryl-dehydrothiopyrans 245 <05T8848>. Tandem alkylation-sulfanylation of benzo- and pyridosultams 242 with 4-bromobutyl thiocyanate gives sultams 243 that yields 245 after extrusion of sufur dioxide and [1,5]-hydrogen shift.
Y
R N O S O X 242
SCN
Br
NaOH
Y
R N O Δ S O -SO X S 2
R N Y
[1,5]-H 73-95%
X S
243
R NH X
Y
S
244
R = Me, i-Pr; X = CH, N; Y = H, Me
245
The regioselective cross-coupling reactions of multiple, halogenated heterocycles including isothiazoles have been reviewed <05T2245>. 5.5.3.3 Isothiazoles as Auxiliaries in Organic Syntheses Oppolzer’s camphor sultam is a well-known chiral auxiliary, and two elegant applications in the asymmetric [2,3]-sigmatropic rearrangement of ylides have been reported. One involves glycine-derived allyl ammonium ylides <05JA1066>, and the other employs sufur ylides <05JA15016>. The [2,3]-rearrangement of N’N’N’-allyldialkyl glycinoyl (2S)-sultam salts 246 is carried out with sodium hydride at 0°C, and the allyl glycine derivatives 248 are obtained with a high level of diastereoselectivity, in favour of the (2’R)-isomer (dr > 96 : 4). The reactions are predictable in terms of asymmetric control: (2S)-configured auxiliary delivers predominantly (2’R)-configured products, while the use of the (2R)-configured auxiliary gives (2’S)-products. This methodology has been applied to the synthesis of (R)(+)-allyl glycine 251 from sultam salt 249 via a three-step sequence: ylide rearrangement (dr = 32:1) (249 to 250), deallyation and saponification. Me
Me
O R1
N
R2 Br
N
NaH
Xs H
O
2
S 246 O O
64-99%
R1 N R2 247
10
O Br 249
Xs
NaH
H
N
2'
Xs +
O
H R1 N R2
Xs
O 250
2'
Xs
O
(2'S)-248
(2'R)-248
R1, R2 = allyl, Bn, Me; Xs = (2S)-camphor sultam
N
H R1 N R2
2'R/2'S = 96/4 to >99/1 Pd(PPh4)4, barbituric acid; LiOH
H
86% from 249
251 O
R
NH3 O
The sulfur ylides 254 used in the stereoselective [2,3]-sigmatropic rearrangement are generated by copper(I)-catalyzed Doyle-Kirmse reaction of aryl sulfides 253 and diazo compounds bearing Oppolzer’s camphor sultam auxiliary 252 in the presence of chiral diamine ligand (S, S)-259 <05JA15016>. These intermediate ylides undergo spontaneous
269
Five-membered ring systems: with N and S (Se, Te) atoms
rearrangements to give sulfides 255 with high diastereoselectivities. Interestingly, the asymmetric induction is dictated by the chiral auxiliary rather than the chiral ligand of the Cu(I) catalyst. Comparable diastereoselectivity is obtained with achiral diamine ligand 260. The reaction of propargyl 2-chlorophenylsulfides 257 with diazoacetamides 252 is also diastereoselective using either diamine ligand with only one exception observed, and allenes 258 are obtained in high enantioselectivities after reductive removal of the chiral auxiliary. Me
Me N O
S
O O 252
SAr
253
N2
XR
S
CuLn
O
SAr
R O
254
LiAlH4
255
R OH
256
82-99% ee (259) 70-94% ee (260)
Cl Cl
SAr Ar = o-Cl-Ph; R' = H, Me R
SAr
39-95% from 252
= (2R)-camphor sultam
R'
HO
SAr
XR
R
Cu(MeCN)4PF6 (20 mol%), ligand (22%); LiAlH4 65-95% yields 82-96% ee Cl
257
•
XR
Cu(MeCN)4PF6 (20 mol%), ligand (22%)
R
R = Me, aryl, propenyl, cinnamoyl R'
Ar
Cl
Cl
Cl
Cl
Cl 260
259
258
Acyclic dienes bearing Oppolzer’s sultam auxiliary 261 have been utilized in the synthesis of functionalized 1,4-dihydronaphthalenes <05JA15028>. Cycloaddition of dienes 261 with benzynes, generated from 2(trimethylsilyl)phenyl triflate 263 using cesium fluoride, provides cycloadducts 263 with excellent diastereoselectivities. Me
Me
TfO
Y
TMS
Z
O S
+
N
O O 261 R = Me, aryl
262 R
Y, Z = H, H; -OCH2O-
XR
CsF, MeCN
O Y
40-60% dr > 19 : 1
Z R
263 XR = (2R)-camphor sultam
Other applications of Oppolzer’s sultams in diastereoselective reactions include HornerWadsworth-Emmons reaction with a chiral phosphate in the synthesis of epothilones <05OL1311>, Lewis acid-catalyzed asymmetric halohydroxylation of α, β-unsaturated carboxylic acid derivatives <05TL3073>, phosphine-catalyzed [3+2] cycloaddition with 2butynoic acid derivatives <05T8120; 05JOC6369>, α−aminoacid preparation via hydroxyamination of acid derivatives <05T1181>, α-alkylserine preparation via alkylation of 2-phenyl-2-oxazoline-4-carboxylic acid derivatives <05JOC4158>, 1,3-dipolar cycloaddition in formation of 2-isoxazolines <05TA2257>, high-pressure Diels-Alder reaction of butadiene and chiral glyoxylates <05TA2897>, alkylation of glycine derivative for the preparation of the labeled proline in a 13C, 15N backbone-labeled C-terminal tripeptide amide fragment of the neurohypophyseal hormone oxytocin <05AA(29)151>, and an asymmetric 1,3-dipolar cycloaddition in a large-scale synthesis of (3R, 4R)-4-(hydroxymethyl)pyrrolidin-3-ol, a key
270
Y.-J. Wu and B.V. Yang
intermediate of the purine nucleoside phosphorylase inhibitor BCX-4208, currently in phase I clinical trials <05OPRD193>. Several novel chiral sultams and their applications as chiral auxiliaries in asymmetric reactions have appeared during the past year <05HCA2441>. For example, N-crotonyl bicyclic sultams 266a/b show excellent diastereoselectivities including endo selectivities in the Diels-Alder reactions with cyclopentadiene (92% and 98% de for 266a/b, respectively) <05TA761>. Sultams 266 are prepared from sultones 264 in three steps: nucleophilic ring opening with (S)-α-methylbenzylamine, phosphoryl trichloride-mediated cyclization of the resulting internal ammonium sulfonate salts to give sultams 265, and acylation with (E)-but2-enoyl chloride. O Bn N R
H O S H O2
264
1. (S)-α-methylbenzylamine
O Bn N
2. POCl3 3. separation
R
H NH S H O2 265
O
n-BuLi
Bn N
O N
S O Me R H 2 266a R = Ph 266b R = pyrenyl
Cl O
H
Me
5.5.3.4 Biologically Interesting Isothiazoles A chemical model using isothiazolidinones 269 has been developed to characterize the unusual chemical reactions involved in the redox regulation of protein tyrosine phosphatase 1B (PTP1B) activity <0JA10830>. Sulfenic acids 268 are readily converted to isothiazolidinones 269 during incubation under physiologically relevant conditions. This finding confirms that the sulfenic acid residue possesses sufficient electrophilicity to drive the cyclization reaction with a neighbouring amide group, thus generating a 3-isothiazolidinone analogous to that recently characterized at the active site of oxidatively inactivated PTP1B (shown in the scheme). The remarkable facile nature of the sulfenic acid chemistry, along with the fact that protein sulfenic acids are common intermediates generated during the oxidation of cysteine thiol residues in cells, suggests that the reversible formation of a protein-derived 3-isothiazolidinone residue represents a potentially general mechanism for redox “switching” of protein function. O
S
O NHR O
pH 7.5 37 °C
S
H R1 267a/b CO2Et
268a/b
O active
O
N H2O2 H SH PTP1B active site Cys215
O
NHR
S
OH
N H
OH sufenic acid
NR S
88% (a) 92% (b)
269a/b
O
inactive
N S 3-isothiazolidinone
a: R = Ph, R1 = H b: R =- CH2CO2Et, R1 = CO2Et
271
Five-membered ring systems: with N and S (Se, Te) atoms
5.5.4
THIADIAZOLES AND SELENADIAZOLES
The solid phase synthesis of benzo[1,2,3]thiadiazoles and benzo[1,2,3]selenadiazoles 273 starts with diazotation of anilines 270 using tert-butylnitrite followed by coupling of the resulting diazonium salts with piperazine resin (YH) to afford the triazene aryl halide resins 271. These triazenes are subjected to halide-lithium exchange and subsequent trapping with elemental sufur or selenium to give thiol or selenol resins 272. An alternative synthesis of the thiol resins 272 involves a palladium-catalyzed cross-coupling with triisopropylsilylthiol (TIPSSH) and subsequent deprotection with tetrabutylammonium fluoride. Cleavage of thiol or selenol resins 272 with trifluoroacetic acid results in spontaneous cyclization, yielding thiazdiazoles and selenadiazoles 273 <05OBC1835>. A solid phase synthesis of [1,3,4]thiadiazoles is also reported <05T5565>.
.
X R H2N
270
1. BF3 Et2O, t-BuONO 2. Py, YH 52-100%
n-BuLi, S8 or Se
X Y
N
R N
Y
271
HZ N
R N
X
TFA 10-63%
R
N N 273
272 N
X = Br, I; Z = S or Se; Y =
N
Benzo[c][1,2,5]thiadiazoles and benzo[c][1,2,5]selenadiazoles are frequently used as masked forms of o-phenylenediamine derivatives, which are unstable in air. For example, reduction of thiadiazole 274 with zinc powder gives diamine 275, which undergoes condensation with glyoxal to afford quinoxaline 276 in moderate yield <05JOC2754>. Similarly, reductive deselenation of 279 using hydrazine hydrate and Raney nickel furnishes the air-sensitive 5,6-diaminoindole 280. Treatment of 280 with selenium dioxide regenerates selenadiazoloindole 279 <05H(65)1939>. NHPh N S
NHPh
Zn, HOAc
NHPh
H2N
N
glyoxal 39%
H2N 275 NHPh
274 NHPh SeO2, HCl
H2N H2N 277
92% N Ac
N Se N
N 276
DDQ; Na2CO3 N 278 Ac
N
40%
N Se N
NHPh Ra Ni, NH2NH2 77%
N 279 H
SeO2 89%
H2N H2N
N 280 H
Reaction of [1,2,3]selenadiazole 281 with tetrakis(triphenylphosphine)platinum leads to the formation of a novel selenoplatinum catalyst 283 <05TL1001>. This complex has been used as a catalyst for the hydrosilylation of terminal alkynes. Both 3,3-dimethylbut-1-yne and trimethylsilylacetylene undergo regioselective and sterereoselective hydrosilylation with dimethylphenylsilane in the presence of 0.0002 mol% of 283 to afford (E)-285 in good yields. In the case of phenylacetylene, the hydrosilylation is regioselective; however, the stereoselectivity is reduced to 5:1 (E:Z).
272
Y.-J. Wu and B.V. Yang
Me
N N Se
EtO2C
Me
(Ph3P)4Pt
N
N PPh 3 Pt Se PPh3 282
EtO2C
281
R
R
PhMe2SiH
H
283 (0.0002 mol%) 284 R = t-Bu, TMS, Ph
+281 -N2
Me
N
N Pt Se Se
EtO2C
CO2Et
283 PPh3 80% (R = t-Bu) SiMe2Ph 74% (R = TMS) 76% (R = Ph) E/Z = 99/1 (R = t-Bu, TMS); (Z)-286 5/1 (R = Ph)
R
+ SiMe2Ph
Me
(E)-285
5.5.5 1,3-SELENAZOLES, 1,3-SELENAZOLIDINES AND 1,3-TELLURAZOLES A series of 2-amino-1,3-selenazole-5-carbonitriles 290 are readily prepared from selenazadienes 287 upon treatment with chloroacetonitrile in the presence of triethylamine <05JHC831>. Similarly, reaction of selenoazadiene 291 with chloroacetyl chloride generates acyl chloride 292, which is trapped with various amines to yield the corresponding amides 293.
R2
R1 N
Se
NC
N
Cl
R2
NMe2
N
Se N
Se
288
R1 N
CN
Se N
NMe2
63-91%
CN
N
Cl
292
R2
R1 N
Se N
R1R2NH
O
R1
N
40-82%
Se N
CN 290
289 NMe2
Cl
Se N
-Me2NH
O
Cl
NMe2
291
R2
N
Et3N
287
R1 N
N
R2
O
293
Several 2-imino-1,3-selenazolidine derivatives 295 and 297 are prepared in the same fashion as their 1,3-thiazolidine counterparts as described in section 5.5.2.3 from the corresponding O-methanesulfonyl β-amino alcohol hydrochlorides 294 and 296, respectively, using potassium selenocyanate <05TL233>.
R
NH3 Cl R
KSeCN 65-87%
R
H N
R
Se
NH
OMs 295 294 R = Me, Et, n-octanyl
R
NH3 Cl R2 1 296
OMs
KSeCN 77-84%
R1
H N
R2
Se
NH
297 R 1, R2 = Et, Et; -(CH2)4-
2,4,6-Trimethylbenzotellurazole 301 is obtained from 1-bromo-3,5-dimethylbenzene in four steps <05JHC243>. The bromide is treated with magnesium followed by tellurium powder, and the resulting ditelluride 298 undergoes a regioselective nitration to give nitrate 299. The nitro group is reduced to give amine 300, which is cyclized to give benzotellurazole 301.
273
Five-membered ring systems: with N and S (Se, Te) atoms
Me
Me
Me
Me
73%
Br Me
Te 300
298
36% 2
Te
75% 2
Me
299
Te
85% 2
Me
Ac2O, H3PO2
NH2 Me
Me
NaBH4
NO2
HNO3
Mg; Te
N Me Me
Te 301
5.5.6 ACKNOWLEDGMENT We thank Drs. Richard Hartz and Lorin Thompson for critical reading of this review. 5.5.7 REFERENCES 05AA(29)151 05AG(E)135 05AG(E)1199 05AG(E)1221 05AG(E)2838 05AG(E)3462 05AG(E)4925 05AG(E)6896 05BCJ1492 05BJU296 05BMCL3081 05BMCL5553 05CC110 05CC195 05CC797 05COID616 05DF737 05DF886 05EOID89 05H(65)95 05H(65)1601 05H(65)1615 05H(65)1939 05H(65)2119 05H(65)2705 05H(65)2729 05HCA1208 05HCA2441 05JA1066
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Five-membered ring systems: with N and S (Se, Te) atoms
05OL1019 05OL1311 05OL1343 05OL1431 05OL1971 05OL4099 05OL4697 05OPRD193 05PJC115 05S2521 05SC807 05SL79 05SL289 05SL520 05SL577 05SL1965 05SL2920 05T1181 05T1257 05T2245 05T5565 05T8120 05T8848 05TA2257 05TA2897 05TL233 05TL419 05TL433 05TL1001 05TL1349 05TL1607 05TL2239 05TL2251 05TL2567 05TL2691 05TL3073 05TL3127 05TL4345 05TL8673
. .
275
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276
Chapter 5.6 Five-membered ring systems: with O & S (Se, Te) atoms
R. Alan Aitken* and Lynn A. Power University of St. Andrews, UK (e-mail:
[email protected])
5.6.1
1,3-DIOXOLES AND DIOXOLANES
The selective protection of aldehydes with ethanediol to give the corresponding 1,3dioxolanes, while ketones remain unreacted, is achieved under solvent-free conditions using microwave irradiation with anhydrous CuSO4 on SiO2 <05MI151>, and reaction of carbonyl compounds with ethanediol to give 1,3-dioxolanes or with α-hydroxy acids to give 1,3dioxolan-4-ones occurs with 5 mol% iodine in THF <05TL2341>. A further report on the use of hexafluoroacetone as a protecting agent for α-hydroxy acids to give derivatives such as 1 has appeared <05ARK(vi)191>. New catalysts for the reaction of epoxides with acetone and other carbonyl compounds to form dioxolanes include Cu(OTf)2 <05MI221; 05SL854>, LiBF4 <05SC1441> and heteropolyacids <05MI1275>. Reaction of chiral amino epoxides such as 2 with acetone or other ketones in the presence of BF3 •Et2 O gives the dioxolane 3 in excellent yield and d.e. <05OL247>. A large number of new catalyst systems for the reaction of epoxides 4 with CO2 under mild conditions to give dioxolanones 5 have been developed including (CO)5 ReBr <05JOC381>, copper and manganese aza-macrocycles <05JMOC(226)199>, aluminium salen <05T12131>, polymer-supported gold nanoparticles <05JA4182> and zinc-substituted polyoxometalates such as Na1 2[WZn3 (H2 O)2 (ZnW9 O3 4)2 ] •48H2 O together with DMAP <04USP242903>. The cyclisation of hydroxyethyl ethers such Me Me
O
HO2C R
O CF3
6
I O
7
R
R1
O N O
8
CO2
O–Ti(OR2)3 CO2R2 O
O
O R
4
3
O R
O
O
N(Bn)2
2
HO O
O Bui
N(Bn)2
CF3
1
R
O
Bui
O
O
5 R1CHO
OH
O
1 * R
O
9
10
277
Five-membered ring systems: with O & S (Se, Te) atoms
as 6 to give dioxolanes 7 is achieved by photolysis in MeCN with iodine and polymersupported iodobenzene diacetate <05SL923>. Reaction with iodine in MeCN also allows Ndeprotection of N-allyloxycarbonyl amino acid derivatives by formation and hydrolysis of the dioxolane-2-imine derivatives 8 <05TL4403>. Reaction of the titanium vinyloxy alkoxides 9 with aldehydes produces hydroxyalkyldioxolanes and by introducing chiral ligands on Ti the process can be made asymmetric giving 10 in over 95% e.e. <05TA3848>. The bis(hydroalkoxylation) reaction of butynone 11 with ethanediol and 5% DMAP gives the valuable synthetic intermediate 12 in 81% yield <05CC227> and a range of ring-fused o-quinones 13 are converted into the benzodioxoles 14 in one step using cathodic reduction in CH2 Cl2 <05OL2567>. Further details of the reaction of 4-diazo-1,3-diketones 15 with aromatic aldehydes, ArCHO, to give bicyclic dioxolanes 16 by way of intramolecular carbonyl ylide formation have appeared <05ARK(xi)146> and the related anhydride-containing diazo compounds 17 form carbonyl ylides which add to alkenes RCH=CHR to give bicyclic dioxolanone products 18 <05TL1259>. Microwave irradiation of compound 19 with a range of isocyanides in DMF affords the iminodioxolanes 20 <05SC675> and bis(methoxycarbonyl)carbene similarly causes dioxolane formation from quinones and aldehydes to give products such as 21 <05T2849>. O
OH
HO
O
Me
H
11 R
R Ar
O O
NMe
O
MeN
O O
Me
O O
N2
15
O
O
O
O
O
O
Me
MeN
Me
12
O
O
O
O
O
19
20
Me N
14 O
Ar
16
Me O O N O
13 2
O
O Ar1
O
17
But
N2
O O
Ar1 R
O
O
18
Ar2
R
O
NMe
But MeO2C
O NR
OMe O CO2Me
21
Reaction of 6-benzoyl-2,3-dihydropyran 22 with triols results in protection as polycyclic acetals as exemplified by the product 23 formed with glycerol <05CC1883> and 2-acetyl-6-methyl-2,3dihydrofuran reacts similarly with a range of 1,2-diketones to give products such as MeCO O
Ph O O O
COPh
22
30
24
O Me
O
29
O O
O
O Me
O
28
Me
26
25 O Me Me O
O
But
H But
But R
O O
CHO
Me
23
OH O Ph
O
O
O
Me
O
O Me O
CO2Me (CH2)n
27 n = 2–4
278
R.A. Aitken and L.A. Power
24 <05CC2621>. Treatment of chiral dioxins 25 with m-CPBA followed by acid-catalysed ring contraction gives the chiral dioxolane aldehydes 26 whose absolute configuration has been determined by X-ray diffraction of camphanic acid derivatives <05TA3394>. A detailed analysis of the EI and CI mass spectra of dioxolane derivatives 27 has appeared <05MI1237> and the redox-induced conformational change resulting from oneelectron oxidation of bis(benzodioxole) 28 has been examined <05AG(E)2771>. The stereochemistry of various compounds of structure 29 has been studied in relation to their use in doping of liquid crystals and the relationship between CD spectra and 'twisting ability' has been explored <05JOC8009>. The X-ray structure of the dioxolanone 30 has been reported <04MIx121>. Reaction of substituted benzyl cyanides with 1,3-dioxolan-2-one and K2 CO3 at 150 °C affords the cyclopropane products 31 <05TL7247> and conjugate addition of 1,3-dioxolane to a chiral butenolide occurs photochemically to give 32 <04JOC7822> while cobalt-catalysed addition to methyl acrylate in oxygen gives 33 in 82% yield <05TL3687>. Treatment of the hydrazones of aromatic aldehydes, ArCH=NHNH2 , with 2-trichloromethyl-1,3-dioxolane, CuCl and ethylenediamine in DMSO affords the intermediates 34 which are readily hydrolysed to provide a useful synthesis of α-chlorocinnamaldehydes <05S605>. Chiral dioxolanes have again been of interest in asymmetric synthesis and the stereochemistry of 1,3-dipolar cycloaddition of nitrile oxides to E and Z isomers of 35 <05ARK(v)103> as well as Grignard reagent addition to 36 <05TL3103> have been examined. Alkylation at C-5 of the chiral 1,3dioxolan-4-one has been used to obtain a range of products 37 in high d.e. <05TL3815> and combination of hydroxyproline and tartrate-derived fragments has been used to obtain tricyclic compounds such as 38 <05TL7813>. A highly stereoselective ring expansion occurs upon treatment of dioxolanes such as 39 with TiCl4 to afford products 40 <05AJC565>. RO
O
CN
R
O
CHO
CO2Me
O O
O
36 Cl Me
39
O
Cl O
BnO
R
N
Me
MeO
40
OH
35 CO2Me
38 Me
Cl
O
CH–COR
O
O
O Me
O O
34
37
MeO
Me
ArCH
CO2H O
Me
O O
O
32
O
OH
33
But
O
31
O
O
NC Bu OH
41
Formation and regioselective ring opening of 1,3-dioxolane-2-thiones with NaCN has been used to obtain compounds such as 41 from the corresponding 1,2-diol <05TL161>. The stereochemistry of ring-opening of dioxolane 42 with Cl2 AlH has been examined <05TL1837> and erbium triflate is effective in catalysing cleavage of benzylidene acetals 43 <05OBC4129>. Mild and selective deprotection of sugar acetonides is achieved using polymer-supported FeCl3 <05S708> and chemoselective deprotection of 2-substituted-1,3-dioxolanes to give carbonyl compounds is achieved using 3% ceric ammonium nitrate in MeCN with an aqueous borate buffer, conditions which leave an enol triflate unaffected <05SL2195>. There have again been a number of important developments involving derivatives of TADDOLs 44. A range of new mono- and di-unsaturated TADDOL esters have been prepared <05S2491> and dimeric TADDOLs have been produced and used for molecular recognition of
279
Five-membered ring systems: with O & S (Se, Te) atoms
enantiomers <05TA635>. A TADDOL-titanium dichloride catalyst is effective for enantioselective 1,2-di-imination of alkenes <05CC2729> and a TADDOL catalysed addition of cyclohexanone enamines to nitrosobenzene giving products 45 has been described <05JA1080>. A thermal [2+2]-cycloaddition between coumarin molecules occurs with high regio- and enantioselectivity in a TADDOL inclusion complex under high vacuum <05CC2732>. A range of chiral imidazolium salts 46 have been prepared and characterised <05S2473>. F3C
O
Me
O
R
O O
R
O
R
Ar
Ph
43
42 F2C
O
Me
O
Me
O
Ar
O
OH OH
OH Me N Ph Me
O
N
O
N
+ NMe
(OTs–)2 + NMe
Ar Ar
F CF3 F CF3
45
44 O
47
BSA
NHMe
O NH
Me
O
NH2
46 MeO O
48
N N
S N
•2HCl O
O
N N
Cl
49
Et N N
N N
N
O
N
O
O
50
Crystalline inclusion compounds of 1,3-dioxolane with Ar4 Si (Ar = 3,5dimethoxyphenyl) have been examined by X-ray diffraction <05JA10008> and perfluorinated 2-methylene-1,3-dioxolane monomers such as 47 have been used for radical polymerisation <05MM9466>. A system involving attachment of 'Ecstasy-class' derivatives and immunogens to proteins to give structures like 48, followed by development monoclonal antibodies has been patented for the detection of illegal drugs <05EUP1498415>. Compounds such as 49 have been prepared and evaluated as haem oxygenase inhibitors <05BMCL1457> and compounds such as 50 have been patented as antifungal agents <05WOP40156>. 5.6.2
1,3-DITHIOLES AND DITHIOLANES
New catalysts for the reaction of carbonyl compounds with ethanedithiol to give 2-substituted 1,3-dithiolanes include Cu(BF4 )2 <05TL6213>, NaHSO4 on silica <05S250>, iodine on a natural phosphate rock <05JMOC(233)43> and TsOH with silica under heterogeneous conditions <05S1326>. The formation of regioisomeric 1,3-dithiolanes by cycloaddition of thiocarbonyl ylides to thiocarbonyl compounds has been further examined by theoretical <05EJO1505> and experimental <05EJO1519; 05EJO1604> methods and phosphonate substituted thiocarbonyl ylides have also been investigated in this reaction <05HCA2582>. Reaction of benzene-1,2-di(selenenyl bromide) with acidic methylene compounds has been used to obtain a range of 1,3-benzodiselenoles 51 <05SC1077>.
280
R.A. Aitken and L.A. Power
Mild deprotection of 2,2-disubstituted 1,3-dithiolanes to give carbonyl compounds is achieved using catalytic HBr with an excess of H2 O2 <05JCR218> or NaHSO4 on silica <05S250> while treatment with the combination of Selectfluor® and pyridinium poly(hydrogen fluoride) results in direct conversion into gem-difluorides, Ar2 CF2 <05CC654>. Oxidative ring expansion of dithiolanes 52 to give dihydro-1,4-dithiins 53 can be achieved using iodoxybenzoic acid <05SL1483> or ButOCl <05SL2935> while treatment of 52 (R3 = H) with N-halosuccinimides gives halogenated products 53 (R3 = halogen) <05TL7331> and use of NBS in the presence of an anion source gives products 53 (R3 = CN, SCN or N3 ) <05EJO416>. Treatment of the corresponding N,N-diphenylhydrazone with Na2 PdCl4 results in cyclopalladation to afford 54 as determined by X-ray diffraction <05JOM(690)454>. Sequential treatment of acetylenic dithiolanes 55 with BuLi, an alkyl halide and a Grignard reagent provides a synthesis of tetrasubstituted allenes <05TL771> while the mechanistically intriguing reaction of dithiole 56 with diethyl acetylenedicarboxylate to give regioisomeric products such as 57 has been described <05OL791>. A simple anthracene/1,3-dithiol-2-thione compound has been introduced as a 280-for Hg2+ <05CC2161>. A detailed analysis of the EI and CI mass spectra of dithiolane derivatives 58 has appeared <05MI1237>. Se E1 R
Se E2
R1 S
R1
S
R2
2
51
53
MeO2C
S
S S
S
MeO2C MeO2C
Cl
56
S
57
S R2
R1
55
S Me
54
S S
S
Ph N Cl Pd N S Me
S
52 Cl
MeO2C
S
CO2Me
S
CO2Et CO2Et
(CH2)n
58 n = 2,3
A large number of new publications in tetrathiafulvalene (TTF) chemistry have appeared including reviews of TTF <05PS(180)1133> and its derivatives <05T3889>, salts of extended TTF derivatives <05CSR69> and substituted bis(ethylenedithio)TTFs <05JMAC347>. Theoretical (DFT) calculations on the role of alkylthio substituents on TTFs have appeared <05PS(180)1429> and a practical two-step synthesis of tetraselenafulvalene 59 has been described <05S2810>. New functionalised TTFs reported include the tetrasilyl compounds TTF(SiPh2 H)4 and TTF(SiMe2 H)4 <05SM(151)186>, the substituted pyrrolo-fused systems 60 <05S1251> and unsymmetrical dicyano TTFs 61 <05H(65)187>. The new TTF derivative Se Se
Se Se
59
R1 R2
R3 S
S
S
S
R
S
S
CN
MeS
S
S
CO2Me
R
S
S
CN
MeS
S
S
CO2Me
N R4 R5
60
61
O MeS
S
S
MeS
S
S
63
62 O
N H
N
R
S
S
N
R
S
S
N
64
O
N
S
N
S
65
S
S
S
S
281
Five-membered ring systems: with O & S (Se, Te) atoms
62 forms a ribbon structure with CuI <05EJI2339> and an electrochemical sensor for H2 PO4 – based on 63 has been reported <05CC4777>. New semiconducting benzoTTF salts have been prepared <05S1291> and a potentially hydrogen bonding diaminodibenzoTTF has been reported <05SM(152)433>. A range of pyrazine-fused TTFs have been reported including 64 <05SM(153)389> and 65 <05SM(153)437>. New cyanoethyl-containing donors include 66 <05JHC847> and 67 <05SM(150)317> and alkyl derivatives of BEDT-TTF 68 with R = hexyl for example show dramatically improved solubility properties <04MI443> and the alkyl compounds 69 (E = CN, CONH2 , CO2 Me; R = hexyl or decyl) have been prepared <05SM(149)219>. New fused ring donors include 70 <05JMAC4399> and 71 <05SM(154)261>. S
S
S
S
S
S
S
S
CN CN
R
S
S
S
S
S
S
Me
Se
Se
O
S
S
Me
Se
Se
O
68
66 S
S
Se
S
S
Se
R
CN CN
S
S
S
S
70 S
E
O
S
S
S
S
E
O
S
S
S
69
67
71
A variety of chiral TTFs such as the oxazoline compound 72 have been prepared <05JA5748; 05T10935; 05OBC2155>. New vinylogous TTF derivatives of general type 73 have been prepared for R1 = CN <05S2157>, R1 = CO2 Et, CN, COMe, CH2 OH and Me <05TL5499> and R1 = aryl <05SM(152)429> and the aza analogues 74 have also been reported <04TL8211; 05PS(180)1471>. The properties of compounds containing multiple and extended TTFs with a variety of spacers have been examined <05TL7871; 05EJO3660; 05SM(153)429>. New donor-acceptor compounds include 75 <05PS(180)1363>, 76 <05PS(180)1473>, a TTFspacer-perylenedicarboximide system <05JOC6313>, a TTF-oxophenalenoxyl system showing solvatochromism <05AG(E)7277> and a zinc porphyrin-based benzodithiole compound <05CC2433>. R N S
S
S
S
S
O
S
R
72
O
S S O
R2
S S
2
R1
S
S
Me
S
78
R2
S
R2
S R1
S
R1
S
N
R
S
R
S
CO2Me
N n
CN
S
S
CN
S
S
S
O
S
S
S
O
S
79
R2
S
R2
S
S
S
S
77
76 S
S
74 n = 1,2
73
CO2Me
75
Me
S
R1
S
S
S
S
S
S
S
S
80
S
S
S
S
282
R.A. Aitken and L.A. Power
A porphyrin containing four TTF units has been prepared <05JOC4988> and salts of TTF and various derivatives with benzenehexacarboxylic acid have been examined <05JMAC1317>. The first proton-conducting metallic ion radical salts are based on BEDTTTF <05AG(E)292> and the first radical cation salts of dihydro-TTF donor 77 with a mercurycontaining counterion have been reported <05SM(155)588>. Other partly saturated TTF analogues of interest include 78, 79 <05SM(154)277> and 80 <05SM(153)373>. Selfassembly of an organogelator based on a TTF-crown ether structure has been examined <05AG(E)7283> and various other applications based on combination of TTFs with crown ethers and/or calixarenes have been described <05JAP35952; 05PS(180)1475; 05JOC6254; 05CC1255>. 5.6.3
1,3-OXATHIOLES AND OXATHIOLANES
New catalysts for the reaction of carbonyl compounds with 2-mercaptoethanol to give 1,3-oxathiolanes include TaCl5 on silica <05SC3127> and bromodimethylsulfonium bromide <05JMOC(226)207> and the formation of oxathiolanes by reaction of epoxides with thiocarbonyl compounds catalysed by BF3 •Et2 O or SiO2 has been examined <04HCA2296; 05EJO1613; 05PS(180)1309>. The 2-hydroxyalkyl thiocyanates 81, readily derived from ring opening of the epoxide of a terminal alkene with SCN–, interact with carbocations derived from polycyclic alcohols to give 2-imino-1,3-oxathiolane products 82 (R2 = adamantyl, isobornyl) <05ARK(iv)199> and water-soluble 4-imino-1,3-oxathiolanes such as 83 have been prepared <05S2946>. Both the dibenzodioxadiselenafulvalene 84 and its Z-isomer have been prepared for the first time and their X-ray structures determined <04JOC9319>. Early work on the mode of attack of PhLi on the carbonyl compound of 85 has been re-investigated <04JOC8131> and a detailed analysis of the EI and CI mass spectra of oxathiolane derivatives 86 has appeared <05MI1237>. Copper catalysed reaction of oxathiolanes 87 with EtO2C–C(=N2 )SiEt3 results in net insertion into the C–S bond to give stereoisomers of the products 88 <05T43>. NR2 R
R
SCN
81 O
85
S
1
82
O Me O S
S
5.6.4
O
"R2 +"
OH 1
CO2Me (CH2)n
86 n = 2,3
H N+ O
S
N Me H
NAr
83
Se
O
O
O
Ar S
87
Se
84 Ar
O
EtO2C Et3Si
S
88
1,2-DIOXOLANES
Intramolecular reaction of oxetane-containing hydroperoxide derivatives leads to formation of 1,2-dioxolanes as exemplified by ozonolysis of 89 in MeOH to give 91 and HF treatment of 90 to give 92 <05OL4333>. Reaction of 'silylperoxyacetals' 93 with an alkene R3 R4 C=CH2 and SnCl4 also gives 1,2-dioxolanes 94 <05OL4617> and the cyclopropyl substituted 1,2-dioxolan-3-ones 95 have been prepared <05TL2757>.
283
Five-membered ring systems: with O & S (Se, Te) atoms
5.6.5
1,2-DITHIOLES AND DITHIOLANES
Complexes of 5-alkylthio-1,2-dithiole-3-thiones 96 with cyclodextrins have been examined <05ARK(xii)47> and dithiolethiones such as 97 have been patented as cyclooxygenase inhibitors <05WOP51941>. The 1,2-ditellurole containing compound 98 and an anthracene analogue have been examined as the basis for molecular conductors <05EJI3435>. Me O
R O O Me
O3
C6H13
R
R2
Me
R
OOSiEt3
1O
O
R
OOSiEt3
S
R1
O R R
3
S RS
Me
R
Me Ar1
Me
Me Te Te
S
96
Ar2
Te Te
97
2
95
S S
S
O O
R3
94
O Me
90
R4
2
EtO
5.6.6
Me Me
C6H13
91 R = OMe 92 R = Me
93
MeSO2
Et3SiOO
OH
MeOH C6H13
89 Me
1
HF
99
O S O
100
O S O
98
1,2-OXATHIOLES AND OXATHIOLANES
The 1,2-oxathiol-2-ones 99 are formed by reaction of Ar1 C≡CCH2 OH, Ar2 MgCl and SOCl2 <05BMCL2057> and the unexpected formation of benzoxathiolones 100 has also been reported in a study involving the ortho-directing effect of sulfoximines <05T8138>. The preparation of sulfuranes such as 101 has been described and benzoxathiolones such as 102 are also formed <05PS(180)1345>. The enantiomers of the benzoxaselenolone 103 have been separated by chromatography on a chiral stationary phase and the absolute configuration assigned by circular dichroism and correlation with the newly determined X-ray structure of the sulfur analogue 104 <05JOC5020>. The 1,3-dipolar cycloaddition of both nitrile oxides <05TA761> and nitrones <05TL173> to the oxathiole dioxide 105 has been examined, and the benzoxathiole dioxide 106 has been used as a thermal source of o-benzoquinonemethide for cycloaddition to maleimides <05T8419>. 5.6.7
THREE HETEROATOMS
Quinoline-containing 1,2,4-trioxolanes such as 107 have been patented as anti-malarial agents <05FRP2862304>. Further results on the reactivity of the novel 1,3,2-dioxathiolane-2thione containing the cyclic thionosulfite function have appeared <05HCA1451> and a convenient method for direct conversion of 1,2-diols into cyclic sulfates using sulfuryl chloride has been described <05TA3908>.
284
R.A. Aitken and L.A. Power
F3C
CF3
But F3C
O R R
S : O F3C
101
But
CF3
102 But O
S
108
04TL8211 04USP242903 05AG(E)292 05AG(E)2771 05AG(E)7277 05AG(E)7283 05AJC565 05ARK(iv)199 05ARK(v)103 05ARK(vi)191 05ARK(xi)146 05ARK(xii)47 05BMCL1457 05BMCL2057 05CC227 05CC654
05CC1883 05CC2161 05CC2433 05CC2621 05CC2729 05CC2732 05CC4777 05CSR69
But
O X O
103 X = Se 104 X = S
R
O
R
O
109
O S O2
O
106
105
SO2
O O O
NH
N
SO2 Cl
N
107
REFERENCES
04HCA2296 04JOC7822 04JOC8131 04JOC9319 04MIx121 04MI443
05CC1255
O S O
S S O But
5.6.8
CF3
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286 05OL791 05OL2567 05OL4333 05OL4617 05PS(180)1133 05PS(180)1309 05PS(180)1345 05PS(180)1363 05PS(180)1429 05PS(180)1471 05PS(180)1473 05PS(180)1475 05S250 05S605 05S708 05S1251 05S1291 05S1326 05S2157 05S2473 05S2491 05S2810 05S2946 05SC675 05SC1077 05SC1441 05SC3127 05SL854 05SL923 05SL1483 05SL2195 05SL2935 05SM(149)219 05SM(150)317 05SM(151)186 05SM(152)429 05SM(152)433 05SM(153)373 05SM(153)389 05SM(153)429 05SM(153)437 05SM(154)261 05SM(154)277 05SM(155)588
R.A. Aitken and L.A. Power
V.A. Ogurtsov, O.A. Rakitin, C.W. Rees, A.A. Smolentsev, P.A. Belyakov, D.G. Golovanov, K.A. Lyssenko, Org. Lett. 2005, 7, 791. B. Batanero, F. Barba, Org. Lett. 2005, 7, 2567. P. Dai, P.H. Dussault, Org. Lett. 2005, 7, 4333. A. Ramirez, K.A. Woerpel, Org. Lett. 2005, 7, 4617. M.A. Herranz, L. Sánchez, N. Martín, Phosphorus, Sulfur and Silicon 2005, 180, 1133. C. Fu, M. Blagoev, A. Linden, H. Heimgartner, Phosphorus, Sulfur and Silicon 2 0 0 5 , 180, 1309. J. Drabowicz, J.C. Martin, Phosphorus, Sulfur and Silicon 2005, 180, 1345. R.A. Aitken, S.J. Costello, N.J. Wilson, Phosphorus, Sulfur and Silicon 2 0 0 5, 180, 1363. R. Andreu, J. Garín, J. Orduna, Phosphorus, Sulfur and Silicon 2005, 180, 1429. R. Andreu, J. Garín, C. López, J. Orduna, E. Levillain, Phosphorus, Sulfur and Silicon 2005, 180, 1471. R. Andreu, M.J. Blesa, L. Carrasquer, J. Garín, J. Orduna, R. Alcalá, B. Villacampa, Phosphorus, Sulfur and Silicon 2005, 180, 1473. M.-J. Blesa, B.-T. Zhao, M. Allain, N. Mercier, M. Sallé, Phosphorus, Sulfur and Silicon 2005, 180, 1475. B. Das, R. Ramu, M.R. Reddy, G. Mahender, Synthesis 2005, 250. V.G. Nenajdenko, A.L. Reznichenko, O.N. Lenkova, A.V. Shastin, E.S. Balenkova, Synthesis 2005, 605. M.A. Chari, K. Syarnasundar, Synthesis 2005, 708. H. Gopee, K.A. Nielsen, J.O. Jeppesen, Synthesis 2005, 1251. L. Boudiba, L. Kaboub, A. Gouasmia, J.M. Fabre, Synthesis 2005, 1291. M.H. Ali, M.G. Gomes, Synthesis 2005, 1326. C. Jia, S.-X. Liu, A. Neels, H. Stoeckli-Evans, S. Decurtins, Synthesis 2005, 2157. M.Y. Machado, R. Dorta, Synthesis 2005, 2473. D.C. Gerbino, S.D. Mandolesi, L.C. Koll, J.C. Podestá, Synthesis 2005, 2491. K. Takimiya, H.J. Jeon, T. Otsubo, Synthesis 2005, 2810. B. Zaleska, M. Karelus, E. Zadora, H. Kruszewska, Synthesis 2005, 2946. M.B. Teimouri, Synth. Commun. 2005, 35, 675. P. Potaczek, K. Kloc, J. Mlochowski, Synth. Commun. 2005, 35, 1077. F. Kazemi, A. Kiasat, S. Ebrahimi, Synth. Commun. 2005, 35, 1441. S. Chandrasekhar, S.J. Prakash, T. Shyamsunder, T. Ramachandar, Synth. Commun. 2005, 35, 3127. P. Krasik, M. Bohemier-Bernard, Q. Yu, Synlett 2005, 854. T. Teduka, H. Togo, Synlett 2005, 923. V.G. Shukla, P.D. Salgaonkar, K.G. Akamanchi, Synlett 2005, 1483. N. Maulide, I. Markó, Synlett 2005, 2195. N.D. Arote, V.N. Telvekar, K.G. Akamanchi, Synlett 2005, 2935. M. Katsuhara, I. Aoyagi, H. Nakajima, T. Mori, T. Kambayashi, M. Ofuji, Y. Takanishi, K. Ishikawa, H. Takezoe, H. Hosono, Synth. Met. 2005, 149, 219. L. Boudiba, A.K. Gouasmia, L. Kaboub, O. Cador, L. Ouahab, J.M. Fabre, Synth. Met. 2005, 150, 317. F. Guyon, M.N. Jayaswal, H.N. Peindy, A. Hameau, M. Knorr, N. Avarvari, Synth. Met. 2005, 151, 186. M. Osada, T. Kumagai, M. Sugimoto, J. Nishida, Y. Yamashita, Synth. Met. 2 0 0 5, 152, 429. Y. Morita, E. Miyazaki, K. Fukui, S. Maki, K. Nakasuji, Synth. Met. 2005, 152, 433. J. Yamada, K. Fujimoto, H. Akutsu, S. Nakatsuji, H. Nishikawa, K. Kikuchi, Synth. Met. 2005, 153, 373. Naraso, J. Nishida, M. Tomura, Y. Yamashita, Synth. Met. 2005, 153, 389. S. Matsumoto, W. Matsuda, H. Fueno, Y. Misaki, K. Tanaka, Synth. Met. 2 0 0 5, 153, 429. S. Kimura, K. Yamashita, H. Suzuki, S. Ichikawa, H. Mori, Y. Nishio, K. Kajita, Synth. Met. 2005, 153, 437. H. Suzuki, S. Ichikawa, K. Yamashita, S. Kimura, H. Mori, Y. Nishio, K. Kajita, Synth. Commun. 2005, 154, 261. H. Nishikawa, H. Sekiya, D. Watanabe, T. Kodama, K. Kikuchi, I. Ikemoto and J. Yamada, Synth. Met. 2005, 154, 277. N.D. Kushch, A.V. Kazakova, L.I. Buravov, E.B. Yagubskii, S.V. Simonov, L.V. Zorina, S.S. Khasanov, R.P. Shibaeva, E. Canadell, H. Son, J. Yamada, Synth. Met. 2 0 0 5, 155, 588.
Five-membered ring systems: with O & S (Se, Te) atoms
05T43 05T2849 05T3889 05T8138 05T8419 05T10935 05T12131 05TA635 05TA761 05TA3394 05TA3848 05TA3908 05TL161 05TL173 05TL771 05TL1259 05TL1837 05TL2341 05TL2757 05TL3103 05TL3687 05TL3815 05TL4403 05TL5499 05TL6213 05TL7247 05TL7331 05TL7813 05TL7871 05WOP40156 05WOP51941
287
M. Ioannou, M.J. Porter, F. Saez, Tetrahedron 2005, 61, 43. V. Nair, S. Mathai, S.C. Mathew, N.P. Rath, Tetrahedron 2005, 61, 2849. A.A.O. Sarhan, Tetrahedron 2005, 61, 3889. S. Gaillard, C. Papamicaël, G. Dupas, F. Marsaise, V. Levacher, Tetrahedron 2 0 0 5, 61, 8138. K. Wojciechowski, K. Dolatowska, Tetrahedron 2005, 61, 8419. C. Réthoré, M. Fourmigué, N. Avarvari, Tetrahedron 2005, 61, 10935. M. Alvaro, C. Baleizao, E. Carbonell, M. El Ghoul, H. García, B. Gigante, Tetrahedron 2005, 61, 12131. S. Legrand, H. Luukinen, R. Isaksson, I. Kilpelaeinen, M. Lindstroem, I.A. Nicholls, C.R. Unelius, Tetrahedron Asymmetry 2005, 16, 635. H.-K. Zhang, W.-H. Chou, A.W.M. Lee, W.-Y. Wong, P.-F. Xia, Tetrahedron Asymmetry 2005, 16, 761. S. Flock, H. Frauenrath, C. Wattenbach, Tetrahedron Asymmetry 2005, 16, 3394. P. Maier, H. Redlich, J. Richter, Tetrahedron Asymmetry 2005, 16, 3848. M. Alonso, A. Riera, Tetrahedron Asymmetry 2005, 16, 3908. S.H. Jacobo, M. Adiyaman, C.-T. Chang, N.-I. Kang, W.S. Powell, J. Rokach, Tetrahedron Lett. 2005, 46, 161. L. Fang, W.-H. Chan, Y.-B. He, Tetrahedron Lett. 2005, 46, 173. H.-Y. Tu, Y.-H. Liu, Y. Wang, T.-Y. Luh, Tetrahedron Lett. 2005, 46, 771. M. Hamaguchi, N. Tomida, E. Mochizuki, T. Oshima, Tetrahedron Lett. 2005, 46, 1259. C. F. Morelli, A. Fornili, M. Sironi, L. Durì, G. Speranza, P. Manitto, Tetrahedron Lett. 2005, 46, 1837. B.K. Banik, M. Chapa, J. Marquez, M. Cardona, Tetrahedron Lett. 2005, 46, 2341. C. Singh, N.C. Srivastav, N. Srivastava, S.K. Puri, Tetrahedron Lett. 2005, 46, 2757. B. Dhotare, A. Chattopadhyay, Tetrahedron Lett. 2005, 46, 3103. T. Kagayama, S. Sakaguchi, Y. Ishii, Tetrahedron Lett. 2005, 46, 3687. P.-F. Xu, T. Matsumoto, Y. Ohki, K. Tatsumi, Tetrahedron Lett. 2005, 46, 3815. R.H. Szumigala Jr., E. Onofiok, S. Karady, J.D. Armstrong III, R.A. Miller, Tetrahedron Lett. 2005, 46, 4403. M. Guerro, D. Lorcy, Tetrahedron Lett. 2005, 46, 5499. R.C. Besra, S. Rudrawar, A.K. Chakraborti, Tetrahedron Lett. 2005, 46, 6213. V.R. Arava, U.B.R. Siripalli, P.K. Dubey, Tetrahedron Lett. 2005, 46, 7247. D. Dong, R. Sun, H. Yu, Y. Ouyang, Q. Zhang, Q. Liu, Tetrahedron Lett. 2 0 0 5, 46, 7331. A. Trabocchi, M. Rolla, G. Menchi, A. Guarna, Tetrahedron Lett. 2005, 46, 7813. R. Berridge, P.J. Skabara, R. Andreu, J. Garín, J. Orduna, M. Torra, Tetrahedron Lett. 2005, 46, 7871. M. Pinori, M. Lattanzio, D. Modena, P. Mascagni, PCT Int. Appl. WO 040156 (2005) [Chem. Abstr. 2005, 142, 447236]. I.-H. Cho, M.-Y. Chae, Y.-H. Kim, K.-J. Yeon, C.-S. Lyu, J.-H. Kim, S.-H. Jung, S.-W. Park, H.-C. Ryu, J.-Y. Noh, H.-J. Park, J.-E. Park, Y.-M. Chung, PCT Int. Appl. WO 051941 (2005) [Chem. Abstr. 2005, 143, 43881].
288
Chapter 5.7
Five-membered ring systems with O & N atoms
Stefano Cicchi, Franca M. Cordero, Donatella Giomi Università degli Studi di Firenze, Italy
[email protected]
5.7.1
ISOXAZOLES
The biological activity of substituted isoxazoles has made them a focus of medicinal chemistry and the significant pharmaceutical activity of several naturally occurring examples is well-documented <05CRV2723>. Moreover, the facile cleavage of the N−O bond of the isoxazole nucleus under simple reaction conditions is the reason for the numerous applications of this system as synthetic intermediates for the construction of molecular assemblies including different heterocycles and natural products <05CRV4237>. From a synthetic viewpoint, 1,3-dipolar cycloadditions (1,3-DCs) between alkynes and nitrile oxides are still widely exploited. The use of alkynylboronates as dipolarophiles provides a direct access to a wide variety of trisubstituted isoxazole 4-boronates with high levels of regiocontrol <05T6707>. Analogously, sequential [3+2] cycloaddition/silicon-based cross-coupling reactions allowed for the synthesis of 3,4,5-trisubstituted isoxazoles 5. Regioselective 1,3-DC reactions between alkynyldimethylsilyl ethers 1 and alkyl and aryl nitrile oxides 2, generated in situ from 1-nitropropane and N-hydroxybenzene carboximidoyl chloride, respectively, gave as predominant products after hydrolysis isoxazol-4-ylsilanols 3, converted into 4-arylisoxazoles 5 by treatment with a variety of aryl iodides 4 <05JOC2839>. I R1 +
N O 2
1. toluene or dioxane, Δ R2
EtOMe2Si
2. AcOH
1 R1 = Et, Ph
N
R1 HOMe2Si
O
4
R2
3 33-52% R2 = Me, Ph
R1 R3
N
O R2
Pd, base
R3 R3 = NO2, Me, OMe
5 33-78%
The use of catalysts in 1,3-DC permits significant improvements in yields and regioselectivity. A copper(I) catalyst, generated in situ from Cu(II) salts via reduction with sodium ascorbate or via operation of a Cu(II)/Cu(0) couple, allowed an easy access to 3,5disubstituted isoxazoles 8 as single regioisomers, through non-concerted 1,3-DC reactions of nitrile oxides, coming from imidoyl chlorides 6, with terminal alkynes 7 fortunately reacting
289
Five-membered ring systems with O & N atoms
as copper(I) acetylides. Computational studies revealed a stepwise mechanism involving unprecedented metallacycle intermediates, which appear to be common for a variety of dipoles <05JA210>. CuSO4.5H2O (2 mol%) sodium ascorbate (10 mol%)
OH
N
+ Ar
R
Cl 6
7 R = Ph, CH2OH, CO2H
1. H2NOH.HCl, NaOH CHO H2O/t-BuOH (1:1) Ph 9
KHCO3 (4.3 equiv) H2O/t-BuOH (1:1), rt
N
N
Ar
O R
8 74-98%
N O
O 10
Ph
Cu0/CuSO
2. TsN(Cl)Na.3H2O
Ph 4
(cat.)
11 68%
The same process was exploited in a convenient one-pot three-step procedure. The copper(I)-catalyzed regioselective synthesis of 3,5-disubstituted isoxazoles was performed in satisfactory yields (57-76%) from aldehydes and terminal acetylenes. Aldehydes were first converted to aldoximes, that were transformed without isolation to the corresponding nitrile oxides with chloramine-T trihydrate. The sequence is tolerant of most functional groups. Treatment of E-cinnamaldehyde 9 with 1-ethynylcyclohexene 10 gave isoxazole 11 with complete regio- and siteselectivity <05JOC7761>. N O O
AcO AcO
O
AcO
OAc OAc
N O
O
OEt
OAc
N
OAc
12
EtO
OAc
CO2R
O
13
Multivalent neoglycoconjugates were synthesized through 1,3-DC processes between alkyne sugars and/or nitrile oxide sugars. The divalent homo neoglycoconjugate 12 was isolated in 59% yield from nitroethyl and propargyl D-glucopyranosides <05T9338>. [3+2] Cycloadditions of pyridine-3-nitrile oxide with alkyl 4,4-diethoxy-3-p-tolylsulfinylbut-2enoates allowed a facile access to 3-(pyridin-3-yl)isoxazole-5-carboxylates 13, a useful scaffold for highly functionalized 3-(pyridin-3-yl)isoxazoles <05T4363>. Other synthetic approaches involve cyclocondensations of hydroxylamine with 1,3bielectrophiles. For instance, starting from conjugated alkynyl-carbonyl compounds 14, electrophilic cyclization allowed a facile access to a variety of 3,5-disubstituted-4-halo(or seleno)isoxazoles 16 in high yields under mild reaction conditions, by treatment of O-methyl oximes 15 with ICl, I2, Br2, or PhSeBr <05OL5203>. O R1 R2
py, Na2SO4 MeOH, rt
14
R
N
H2NOMe.HCl
OMe EX
R1 R2 15
+ NH2OH + CO + ArI
CH2Cl2, rt 55-100%
18
N
O R2
E
EX = ICl, I2, Br2, PhSeBr
16 N O
PdCl2(PPh3)2 (1 mol%) DMF/H2O
17 R, Ar = Ph, 4-MeOC6H4
R1
R
Ar
19 54-66%
290
S. Cicchi, F.M. Cordero, and D. Giomi
Though not proved, alkynyl-ketones could also be involved as reactive intermediates in the regioselective preparation of 3,5-diarylisoxazoles 19 through four-component coupling of terminal alkynes 17, hydroxylamine, carbon monoxide, and aryl iodides 18, in the presence of a palladium catalyst. The reaction proceeds at room temperature and an ambient pressure of CO in an aqueous solvent system <05OL4487>. W
OMe O NH2OH.HCl CX3 W 20
X = F, Cl W = O, S
R2 R1
SEt N H
23
R3
X3C
MeOH, Δ
W 98% H2SO4
O
HO
90-95%
N
X3C
50 °C 76-89%
21
N H
MeOH
CN
R3
R1 = n-Pr, n-Bu, Ph R2 = H, Et, n-Pr R1-R2 = (CH2)4
R2 N
R1
R3 = CN, CONH2
N
22
R2 NH2OH, H2O
O
O
+
O
R1
N H H2NOC
CN
24 56-89%
N NH2
25 3-5%
Cyclocondensation of trihalo-3-buten-2-ones 20 with hydroxylamine gave 3-(2-thienyl)and 3-(2-furyl)-5-trihalomethylisoxazoles 22, through dehydration of the 5hydroxyisoxazoline intermediates 21 <05S2744>. 5-Amino-3-(pyrrol-2-yl)isoxazoles 24 were selectively prepared by treatment of cyanoethylthio-ethenylpyrroles 23 with hydroxylamine in methanol, probably via replacement of the SEt group with a hydroxylamino moiety. With carbamoyl derivatives (R3 = CONH2) minor amounts of regioisomers 25 were also isolated and their formation was increased (1248%) by operating in the presence of aqueous NaOH <05T4841>. 4-Amino-5-benzoyl(or acetyl)isoxazole-3-carboxamides were prepared by cyclization of α-hydroxyimino nitriles Oalkylated with bromoacetophenone (or bromoacetone) in the presence of LiOH as base. Treatment of O-alkylated oximes with LiClO4 increased the purity of the target compounds <05RCB1189>. R ( )n N 26
R O
NH2OH.HCl
EtOH, Δ n = 1,3 R = Ph, 3-BrC6H4, 3-py, 4-py O
O N Ar
O
Ra-Ni, H2 CO2Me
rt
( )n N
O
H2N
NH2
O CO2Me
Ar
CO2Me 30
O
R1 = R2 = H O
Ra-Ni, H2 rt
NH2
Ar
O HN
Ar
NR1R2
33
CO2Me 31b
HN
32
MeOH, rt
O
Ar
31a
NR1R2
O
28 35-89%
R1R2NH
O N
R NH
O
27
Ar
29
( )n
N OH
O R1
=H
Ar
34
R2
N
CO2Me
291
Five-membered ring systems with O & N atoms
Structurally different 3-acyl-lactams 26 were reacted as 1,3-bielectrophiles with NH2OH in boiling EtOH to give 3-substituted-4-aminoalkylisoxazol-5-ones 28 as single regioisomers in satisfactory yields, through oximes 27 <05RCB220>. Hydrogenolysis in the presence of Raney-Ni of derivatives 29 and 30, coming from BaylisHillman adducts of 3-isoxazole carbaldehydes, generated enaminones 31a,b that underwent ring-closure reactions to afford substituted 2-pyrrolidinones 32, 1,5-dihydro-2-pyrrolones 33, and N-substituted pyrrolidines 34 in good yields <05JOC353>. Catalytic antibody 34E4 accelerates the base-promoted E2 elimination of substituted benzisoxazoles leading to salicylonitriles, also known as the Kemp elimination. GluH50 was identified as the catalytic base in 34E4, confirming predictions based on a homology model <05JA1307>. Moreover, the Kemp decarboxylation reaction for benzisoxazole-3-carboxylic acid derivatives has been investigated using QM/MM calculations in protic and dipolar aprotic solvents <05JA8829>. X 35 X=
SiMe3 N O
R1CN n-BuLi
X
THF −70 °C
R1
N
Li+ R2CN SiMe3
THF, rt
R3 X
NH2
R1
N
R2
Me2NCR3(OMe)2 140 °C
X
N
R1
36 N O
OEt
NH2 O
N Ph
N
N
MeCN/H2O, Δ
NH t-BuOK
N Ph
N
N
94% 37a
N
R2
37
OEt
Mo(CO)6
N
THF, Δ
N
O Ph
N
N
96% 38
N
39
N
Substituted isoxazolylpyrimidines 37 were synthesized through a four-component coupling reaction involving a functionalized silane 35, two types of aromatic nitriles, and an acetal, via amidine intermediates 36. Reductive opening of the isoxazole ring of 37a gave enaminone 38 converted to triazanaphthalene 39 in excellent yield by intramolecular cyclisation onto the pyrimidine with the tethered amino group <05OL4705>. The same reductive cleavage of the N-O isoxazole bond was exploited in the stereoselective total synthesis of the polyketide natural product tarchonanthuslactone <05OL5813>. Ring-opening of 3-bromoisoxazoles with either Mo(CO)6 or FeCl2.4H2O gave β-keto-nitriles in good yields <05LOC280>. Starting from aldehyde-containing 3-bromoisoxazoles, a tandem ring-opening/cyclocondensation allowed the synthesis of 1-benzoxepins <05SL259>. A Hantzsch 1,4-dihydropyridine selectively reduced the exocyclic double bond of 4arylmethylene- and 4-alkylidene-4H-isoxazol-5-ones with high efficiency to give 2Hisoxazol-5-ones <05SL1579>.
5.7.2 ISOXAZOLINES The use of isoxazolines as synthetic intermediates continues to be a valuable approach to different classes of molecules. Mapp et al. have reported a versatile and efficient synthesis of substituted β-amino acids (β-AA) through diastereoselective nucleophilic addition to enantiopure isoxazolines 40. In the C=N reduction with LiAlH4 in THF, the proximal hydroxymethyl substituent directed the hydride approach to the same side as the C-5 ring substituent, affording the amino diol 41 with high diastereoselectivity. In contrast, carbon nucleophiles were sterically driven and preferentially added on the opposite isoxazoline face. The facial selectivity was complete with
292
S. Cicchi, F.M. Cordero, and D. Giomi
cis-4,5-disubstituted isoxazolines 40 (R2 = H, R3 H). Eventually, intermediates 41 and 43 were transformed into the corresponding protected β-AAs 42 and 44 <05JA5376>. H NPG
R4 R1
HN R4
R3
OH R4M O BF3.OEt2 N H
O
3 R1 R
R1
CO2H 44 43 PG = Boc, Cbz 90-100% ds O
O
R2 = H R3 = H, Ph
O
R3
H R2
OH 1. LiAlH 4 THF
1 2. Boc2O R
R3 = H R2 = H, Et
40
O
O
O
Cl
NOH 45
N
rt 5d
O 46 40%
N O 47 27%
H N Boc
R1 R2
R2 OH 41 88-94% ds
CO2H 42
O O N H
O
OBn
2
O
O N
O Br
O 49 calafianin (revised structure)
CO2H
O
N O
O
+
Boc OH
O
O
O NEt3
HN
O 50
O O
NH2 48 (+)-furanomycin
The hydroximoyl chloride 45 obtained from mannitol was treated with NEt3 in 2methylfuran to give a mixture of two separable diastereomers 46 and 47 in a 3:2 ratio. The enantiopure furoisoxazoline 46 was then converted to the natural antibiotic (+)-furanomycin 48 and to some analogues of 48 <05EJO3450>. A synthesis and structural revision of calafianin 49, a spiroisoxazoline isolated from the sponge Aphysina gerardogreene, was described. In particular, a trans-relationship between the epoxy and isoxazoline oxygen atoms was established <05TL1083>. Intramolecular nitrile oxide cycloaddition (INOC) is a useful method for the synthesis of cyclic compounds including macrocycles, and the resulting cycloadducts are amenable to transformations with introduction of extra functionalities. This process was applied to the synthesis of medium and large-sized oxacyles (10-12 and 15-16-membered rings) starting from pseudooligopentose derivatives. In all cycloadditions a single product was obtained with complete stereo- and regioselectivity. Usually, bridged isoxazolines were formed with the exception of the smallest compound 50 which is a fused isoxazoline <05JOC8579>. O
H
OMEM
O
NaOCl
HON
O
rt
O
O 51
O
O
O
O O
N
OMEM 1. Mo(CO)6 O
O
O O CH2Cl2 96% dr = 2:1 dioxane 89% dr > 10:1 52
O
2. Burgess' reagent 3. TFA
OH
O O O
O
O
53 (+)-macrosphelide B
INOC was successfully employed in the total synthesis of the 16-membered macrolactone (+)-macrosphelide B 53. Interestingly, the cycloaddition of nitrile oxide generated in situ from 51 was more stereoselective in dioxane than in CH2Cl2 (dr 10:1 vs 2:1). The major isomer was then converted into 53 by reductive N-O bond cleavage, dehydration and MEM deprotection <05OL3159>.
293
Five-membered ring systems with O & N atoms
X
O
X
O
DIB
N
O NaOCl
CH2Cl2 0 °C rt 1h NOH
N O 55 80-90% X = H, 4-Me, 4-Cl, 4-Br, 2-NO2
54
O
O
O
H 2O 5 °C rt 18 h
NOH 56
O 57
O
O
97% dr = 4:1 O
N
Some benzopyrano- and furopyranoisoxazolines were prepared by treatment of suitable substituted aldoximes with diacetoxyiodobenzene (DIB). For example, 2allyloxybenzaldoximes 54 were smoothly converted into 55. The formation of an intermediate nitrile oxide which undergoes INOC was hypothesized <05S1572>. The use of water as a solvent for some INOCs was studied. In particular, benzaldoxime 56 was shown to have limited solubility in water, but on mixing with NaOCl gave a homogenous solution from which the dimeric species 57 precipitated in high yield <05S3423>. Multicomponent reactions (MCRs) were applied to the synthesis of substituted isoxazolines. For example, 64 was obtained by addition of nitro-alkene 60 and acrylate 61 to a solution of isonitrile 59 generated in situ by reaction of trimethylsilyl cyanide and isobutene oxide in the presence of Pd(CN)2 <05OL3179>. This cascade MCR is believed to occur through [1+4] cycloaddition of 59 with 60, subsequent fragmentation of 62 and 1,3-DC of nitrile oxide 63 with 61. Under microwave irradiation, reaction times could be reduced from several hours to 15 min, with comparable yields. Ph Pd(CN)2
NO2
58
NO2 a) N
O
65
OH OH
N
CO2Me Me3SiCN OTMS 61 N CH2Cl2 C LiClO4 60 °C MeCN 18 h 59 80 °C, 60 h
O
OTMS
60
O2N N O 66
O
Ph
Ph
HN
HN
N
O
N O
Ph
N 62
63
O
O
Ar b)
O
O2N
O
64 37%
O2N
CO2Me
Ar R
c) R Ar
N O 67
Ar = Ph, 4-NO2C6H4, 4-ClC6H4, 2-ClC6H4, 4-MeOC6H4
N O
O
68 59-86% R = H, COMe, CO2Et
Reagents and conditions: a) ArCHO (1 equiv), piperidine (0.1 equiv), EtOH, 60 °C, 2 h; b) MeCOCH2R (2 equiv), piperidine (1.9 equiv), 60 °C, 6 h; c) 1M HCl.
A one-pot 3-MCR for the preparation of spiroisoxazolines 68 was reported starting from 4nitroisoxazole 65, an aromatic aldehyde and a ketone. The reaction occurred with complete control of the relative configuration of the four new stereocenters, and only diastereomer 68 was isolated after recrystallization. 4-Nitroisoxazolines 68 were shown to be configurationally stable in the solid state but underwent a rapid C-4 epimerization in solution <05JOC8395>. The substrate specificity and mechanistic parameters of the 29G12 antibody-catalyzed 1,3DC of nitrile oxides with alkenes were recently investigated <05JOC7810>. Primary nitro-compounds activated by an α-EWG react with alkenes in the presence of a tertiary amine to afford 4,5-dihydroisoxazoles generally in higher yields compared to
294
S. Cicchi, F.M. Cordero, and D. Giomi
previously reported procedures <05TL7877>. Rehydrated Mg:Al 3:1 hydrocalcite was shown to be a suitable catalyst for the cyclization of ethyl nitroacetate and alkenes to 5-substituted 4,5-dihydro-3-isoxazolecarboxylates. The reaction, which occurred at 110 °C in the presence of catalytic amounts of iodine, is probably a SET-induced process <05TL6563>. The reaction of enantiopure cyclic nitrone 69 with alkynylzinc reagents led to a tandem addition/cyclization process affording 2,3-dihydroisoxazole derivatives 72 in high yields and with complete diastereoselectivity <05EJO2694>. t-Bu O
N
H
N
+
O 69
R 70
toluene 20 °C then NH4Cl
t-Bu
t-Bu
Me2Zn (1.3 equiv)
HO N
N
O N
R
N
O R
O
71
72
R = Ph 92% Bu 60% cyclohexen-1-yl 94% CH2Ot-Bu 90% CH2OAc 76% CH(OEt)2 78%
5.7.3 ISOXAZOLIDINES The 1,3-DC of nitrones with alkenes is the most common synthetic approach to isoxazolidines and offers several advantages including atom-economy, readily accessible starting materials, and control of regio- and stereochemistry. However, catalytic asymmetric nitrone cycloadditions still remains challenging. During the last year some new examples of chiral Lewis acid-catalysed 1,3-DC of nitrones and electron-deficient alkenes have been reported. The chiral binaphthyldiimine-Ni(II) complex prepared from 75 and NiClO4.6H2O in the presence of 4 Å molecular sieves catalysed the cycloaddition of acyclic nitrones 73 with 3-(2-alkenoyl)-2-thiazolidinethiones 74 with high enantio- and endo(alkyl)-selectivity <05OL1431>. R2 R1
N
73
O
S
O + R
N
S
O
+ R2 N N H R1 O R3 77 78 R1 = Me, Bn, Ph R2 = H, Me; Et; R3 = Me R2-R3 = (CH2)3
76
HO
R S
N
R2
CHCl3, rt 15-150 h
74 R1 = Ar, Bn, Me R2 = Ar, Et R = Me, Et, n-Pr, Ph
Ph
[75 + Ni(ClO4)2] R1 O N (5-20 mol%)
O
N
S
Cu(OTf)2 (30 mol%)
R1
t-Bu 79 (30 mol%) 4 Å MS CH2Cl2, rt 5-10 d
N
O
R2 H N
Ph R3 O 80 O 50- 89% dr = 99:1- 85:15 86-98% ee
Cl Cl
N
36-95% dr = > 99:1-86:14 82-95% ee O
Cl
75
t-Bu
HO
O
Cl
O N
N
79
The reaction of 77 and α,β-disubstituted acrylamides 78 mediated by Cu(OTf)2-79 afforded C-4 disubstituted isoxazolidines 80 with good diastereo- and enantioselectivity. In this case, the N-H imide template was chosen to accomplish rotamer control and improve reactivity by reducing A1,3 strain compared with traditional cyclic templates such as
295
Five-membered ring systems with O & N atoms
oxazolidinones <05OL2349>. High levels of regio- and stereoselectivity were observed in metal-catalyzed 1,3-DC of acyclic nitrones with α'-hydroxy enones. The reaction probably occurs through the formation of reactive 1,4-metal-chelated intermediates. The remarkable diastereo- and enantiocontrol could be obtained through two complementary approaches by using a camphor-derived α'hydroxy enone in combination with Cu(OTf)2 or an achiral enone such as 81 in combination with the bis(oxazoline)-Cu(II) catalyst 83. At the end, the hydroxylated auxiliary could be easily removed. For example, treatment with periodic acid released a carboxylic moiety as in 86 and 87 <05AG(E)6187>. O HO
+ Bn 81
O
Ph N
OH
Ph HO
Ph
a)
+ O
94%
82 b)
N Bn O 84 dr ≥ 98:2
93 : 7
O 85
O
c)
O Ph
Bn
N
O HO
OH
Ph
N Bn O 86 84% 94% ee
BocHN
O N
O
t-Bu
OH
N Cu t-Bu TfO OTf 83
87 84% 94% ee
Reagents and conditions: a) 83 (10 mol%), 4 Å MS, CH2Cl2, –20 °C; b) NaIO4, MeOH/H2O, rt; c) i. H2, Pd/C, (Boc)2O; ii. NaIO4, MeOH/H2O.
R Bn
N 88
OHC +
O
1. (S,S)-89 (10 mol%) R CH2Cl2, −40 °C, 14-40 h 2. NaBH4, EtOH
R = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 2-naphthyl, t-Bu, 2-methyl-1,3-dithian-2-yl
OH
N O Bn 90 76-94% 88-97% ee
O
Oi-Pr Ti
O
O
O
i-PrO
Ti O
(S,S)-89
The asymmetric 1,3-DC between nitrones 88 and acrolein catalyzed by the chiral bisTi(IV) oxide 89 afforded adducts 90 with complete endo-selectivity and good enantioselectivity (88-97% ee) <05JA11926>. The reaction of some acyclic and cyclic nitrones with methacrolein in the presence of catalytic amounts of Rh or Ir complex 92 was studied. Some intermediates involved in the process were isolated and characterized and, accordingly, a catalytic cycle involving [M]aldehyde, [M]-nitrone and [M]-adduct species was proposed. All reactions occurred with complete diastereoselectivity and good enantioselectivity. Cyclic nitrones such as 91 were added slowly to the mixture of aldehyde and 92 to avoid nitrone coordination to the metal <05JA13386>. Isoxazolidines are often used as synthetic precursors of different classes of compounds. Intramolecular cycloaddition of sugar-derived alkene-nitrones was applied to the synthesis of some chiral cyclopentenone building blocks and natural compounds as exemplified by the synthesis of (−)-neplanocin A 94 starting from D-ribose <05JOC6884>.
296
S. Cicchi, F.M. Cordero, and D. Giomi
CHO +
( )n N O
91
(7 equiv)
OTr O O
O
H
92 (5 mol%) 4 Å MS
92 = [(η5-C5Me5)M{(R)-1,2-bis(diphenylphosphino)propane}(H2O)](SbF6)2
( )nN O CHO n = 1, 2; M = Rh, Ir 93 quant ≥ 99% ds 86-92% ee
CH2Cl2, −25 °C 15 h
NH2
1. MeNHOH N O py 20 °C TrO 2. PhCl O 135 °C O 75%
N
OTr
Zn MeNH AcOH
OH
Et2O TrO 20 °C O 98%
O
O
OH
N
N
N
O
O
HO
OH 94
Denmark and Montgomery applied the tandem inter-/intramolecular [4+2]/[3+2] cycloaddition of nitro-alkene 95 and vinyl ether 96 to the synthesis of the highly strained azafenestrane.BH3 99 <05AG(E)3732>. Catalytic hydrogenation of nitroso acetal 97 afforded directly the amino alcohol 98 through two N–O bond cleavages and reductive amination. The reaction was carried out in wet ethyl acetate since the key intermediate 97 underwent a dyotropic rearrangement to aminal 100 in the more common solvent methanol. The same rearrangement was promoted by silica gel. O
NO2 + 95
Ot-Bu AlMe3
96
CH2Cl2 −78 °C
O
H
H2 Ra-Ni
H
H2O EtOAc
H 97 67%
dyotropic rearrangement O H
Ot-Bu
N
N
1. PPh3 DIAD CH2Cl2, 0 °C
OH HN H
H
BH3 N H
H
2. BH3.THF −78 °C rt
H 98 85%
H 99 87%
MeOH, rt H
R1O
R2
H
N
O N
( )n
O 101 n = 1-3
H 100 98%
N
N
O Ot-Bu
H
PMP
O
O ( )n
H 102 n = 0-1
Intramolecular 1,3-DC of 2-azetidinone-tethered alkenyl nitrones afforded novel tricyclic β-lactams, such as 101 and 102, amenable for further elaboration <05EJO1680>. Optically active tricyclic isoxazolidine 105, a precursor to (−)-rosmarinecine, was prepared from racemic hydroxy-nitrone 103 through a hydrolase-catalyzed kinetic resolution (KR). In particular, Candida antarctica lipase, fraction B (CAL-B), effectively catalysed the KR of (±)-103 in the presence of the acyl donor 104 in MeCN at 0-5 °C. The generated (R)-ester underwent a fast intramolecular 1,3-DC to 105 under the reaction conditions <05CC2369>. O
EtO
OH
CAL-B (300 wt%)
O N O (±)-103
+
O
OH
H
CO2Et + N MeCN N O O 5 °C, 12 h CO2Et (S)-103 105 60% 91% ee 104 (after recryst: 40% > 99% ee ) 28% 96% ee
HO
H
O
N
OH OH
(−)-rosmarinecine
297
Five-membered ring systems with O & N atoms
N
OH O
N
N H
OH
HN
N (+)-febrifugine
NH2
CO2H (−)-monatin
O
N
H
H
( )7 ( )4 O H pyrinodemin A (revised structure) N
( )6
CO2H
The strategy of 1,3-DC of nitrones with alkenes followed by suitable elaboration of the adducts was also applied to the synthesis of anti-malarial alkaloid (+)-febrifugine <05SL346>, natural sweetener (−)-monatin <05JOC4569>, cytotoxic marine sponge alkaloid pyrinodemin A <05T1127>, monocyclic and bicyclic iminosugar analogues as potential glycosidase inhibitors <05TA487; 05JOC1356; 05TA3897>, azabicyclo[X.Y.0]alkane amino acids as constrained dipeptide mimics <05JOC4124; 05JOC856; 05T8836>, and nucleoside analogues <05JOC8991; 05TA3865; 05S2695>. Intramolecular oxime-olefin cycloaddition (IOOC) is a useful approach to N-unsubstituted isoxazolidines. However, high temperatures are usually necessary to induce oxime tautomerization to nitrone. Tamura et al. reported the generation of N-boranonitrones 107 by treatment of O-t-butyldimethylsilyloximes 106 with two equiv of BF3.OEt2 at room temperature. Under the reaction conditions, the intermediate 107 smoothly underwent intramolecular cycloaddition to afford 108 after extractive work-up <05JOC10720>. Nitrone 1,3-DC reactions on solid-phase and the subsequent transformations of polymersupported isoxazolidines and isoxazolines have been reviewed <05CSR507>. The isoxazolidine ring was used as a scaffold for the design and construction of artificial small molecule activation domains. In particular, the amphipathic isoxazolidines 109 were shown to be nearly as active as the natural activation peptide ATF14 in in vitro transcription assays <05JA12456>. BF3.OEt2 (2.1 equiv)
N
TBSO
X
R1 R2
CH2Cl2 rt, 1h
O R1
BF2 N X R2
106
H H N X
O R1 R2 H 108
107
X R1 R2 Yield O H Ph 87% O Me Me 80% NCbz Ph H 92%
R3 O
R2 N
N
O
R1
N CO2H
N H 109
H
O O +
H 110
O
N
HN
111 = HX*
NH2 N
NH2 O
HN O 1. CH Cl 2 2 −78 °C O
N
N
H
2. TMSCHN2
R1 = Ph; R2 = CH2OH; R3 = CHMe2 R1 = Ph; R2 = CHMe2; R3 = CH2OH R1 = CH2OH; R2 = Ph; R3 = CHMe2
CO2Me
1. Cp2Zr(H)Cl
COX*
2. TBSOTf 2,6-lutidine
H 112 96% dr > 97.5:2.5 3. LiBH4,
H
OTBS OH
H 113 > 95% ee
The enantiopure isoxazolidine 111 proved to be a diastereoselective reagent for desymmetrisation of cyclic meso-anhydrides such as 110 (ds 96%) <05SL646>. Asymmetric 1,3-DC of ynolates with a nitrone derived from Garner’s aldehyde afforded 5isoxazolidinones in good yields and with high diastereoselectivity. The adducts were alkylated and converted to enantiopure β-amino acids, β-lactams and γ-lactams <05TA2821>.
298 5.7.4
S. Cicchi, F.M. Cordero, and D. Giomi
OXAZOLES
The continuing discovery of new natural compounds containing in their structure an oxazole ring, as well as the biological activity demonstrated by several derivatives of oxazole, has stimulated researchers’ activity on this ring system. Despite the large amount of literature already present, new methods for the synthesis and the elaboration of this heterocyclic ring are still being described. Some new valuable elaborations have been published, mostly aimed at the regioselective functionalisation of the oxazole nucleus. The direct arylation of ethyl 4oxazolecarboxylate was studied with the aim of optimizing the reaction for a regioselective arylation <05TL8573>: a proper choice of reaction conditions and ligands allowed a remarkable selectivity between the 2- and the 5-positions. While the so-called ‘halogen dance reaction’ had been reported for aromatic and heteroaromatic systems, it had never been described for the oxazole ring. This approach was used for an efficient transformation of 5-bromo-2-phenyloxazole, 114, into several 5substituted 4-bromo-2-phenyloxazoles 115 <05SL1433>. The electrophiles used were water, benzaldehyde, TMSCl, halogens, and CO2 affording the final compounds in good yields (6678%). It is well known that the lithiation of oxazole affords the lithium derivative of an open isomer proposed to be in tautomeric equilibrium with 2-lithiooxazole. Thus reaction with electrophiles often affords mixtures of products. However, it is possible to obtain excellent yields of 2-substituted oxazoles using a lithium magnesate <05JOC5190> as lithiating agent or triisopropylsilyl triflate as electrophilic reagent <05JOC9074>. The salts obtained from oxazole 116 or benzoxazole and lithium magnesate, although demonstrated to exist in the open chain form 118, underwent smooth reaction with electrophiles, as well as with aryl halides in Pd mediated coupling, to afford the corresponding 2-substituted oxazoles 119 and 120. On the other hand treating oxazole 116, with n-BuLi and quenching with TIPS-triflate afforded 2-silyl substituted oxazoles 121 providing a useful protection method for the C-2 of oxazole ring <05JOC9074>. Once the C-2 position is protected it becomes possible to introduce new substituents at C-4 by direct metallation and reaction with electrophiles. Finally, by simple acid treatment, the 2-silyl group is conveniently removed. LDA E+
N Br
N
1/3 Bu3MgLi rt
O 116
O 114
O
N
O
N TIPS
3. 1M HCl
O
Ph 115
O CN MgLi O O 118
N 117
1. THF, n-BuLi 2. E+
N E
MgLi O
N
1. THF, n-BuLi 2. TIPSOTf
O 121
Ph
Br
NC
CN ArX PdCl2(dppf)
N O
Ar
O 119 E+ N E
O
E
N
120
122
The efficient reaction of an electrophile with 2-lithiooxazole is also crucial to a new method for the production of poly-oxazoles <05OL3351>. The reaction of the lithium salt of
299
Five-membered ring systems with O & N atoms
several different 4,5-disubstituted oxazoles 123 with hexachloroethane afforded chemoselectively and in good yield the corresponding 2-chlorooxazoles 124. This is the starting point for a one-pot formation of a bis-oxazole 125 using TosMIC. This reaction can be performed in a two-step or in a one-pot fashion and the final product is the starting material for a new sequence of reactions to produce a tris-oxazole. The importance of this new approach to poly-oxazoles is confirmed by the publication of a review dedicated to polyoxazole-containing natural products <05S1907>. In a one-pot Friedel-Crafts/Robinson-Gabriel procedure it is possible to transform the oxazolone 126 into an oxazole bearing an aromatic substituent at C-5, like 128. The reaction proceeds in the presence of a Lewis acid, which catalyses the acylation, and a dehydrating reagent that favours the formation of the aromatic cycle <05JOC4211>. The use of microwaves allowed the optimisation of the transformation of oximes and acyl chlorides into trisubstituited oxazoles. Although the yields are seldom high, this represents a significant improvement with respect to the original method <05TL5463>. R2 1. n-BuLi, −78 °C N 2. C2Cl6 R1 O 61-98% 124
R2 N R1
O 123
R3 O
R2
R2
N R1
N 129
Cl O 130
+ CN
N
N
N
4 Å MS CH2Cl2 −40 °C
O 136
O N
R1
rt
SmI2, R2CHO, rt I
R1
O O
2. 10% CuI, 20% BF3 R3 H
N
O
128
O 131
R1
N
R3
O
1. R2COCl, 0 °C
R1 H + LiN(TMS)2 133
O
dehydrating R2 agent
Ph
O
R1
O
R3
Ph
+
N
125
127
O
R2
67-77%
N H
Lewis acid
126
Cl 2. HO2CCHO/H2O, K2CO3
R1
O
O
1. TosMIC (1.5 equiv) NaH (3.5 equiv), 0 °C
R3 R2
N
NaH
O
R2
N R1 135
134 R1
132 O
O N H
R3
N O
HO R2
O 137
Some multicomponent syntheses of trisubstituted oxazoles were described. α-Isocyano-αalkyl(aryl)acetamides, as 131 <05S161>, was demonstrated to be a useful starting material for a three-component reaction involving isoquinoline 129 <05SL532>. A four-component synthesis was also published starting from an aldehyde, a silylamide, an acyl chloride and a terminal acetylene derivative. The overall process is a modification of a four-component synthesis of a propargylic amide 134 which can be eventually isolated <05T11317>.
300
S. Cicchi, F.M. Cordero, and D. Giomi
Solid phase syntheses of oxazoles have also been addressed, searching for the best reaction conditions to perform the classical synthetic solution procedure on solid phase <05JCC644>. Trifluoroacetic anhydride TFAA was the reagent of choice in a traceless solid phase synthesis of oxazoles through a Robinson-Gabriel reaction of solid-supported α-acylaminoketones <05JCC463>. A Wang resin bound diazocarbonyl underwent the known Rh-catalyzed insertion with benzamide affording the solid-supported precursor for the synthesis of oxazoles <05TL5495>. Some new procedures for the introduction of the preformed oxazole ring into more complex structures were described mainly in studies aimed at the synthesis of natural product such as ajudazol A <05OL1063>, martefragin A <05JOC5840>, diazonamide A <05JOC7305>, cyclopeptide YM-216391 <05CC797>. An interesting application of the samarium Barbier reaction was applied using 4-(αiodomethyl)- or 2-(α-iodomethyl)oxazoles 136 with aliphatic aldehydes. This reaction is compatible with the presence of esters and common ether protecting groups <05OL4099>. The scope of the reaction is somewhat limited by the low yields obtained with α-alkoxy aldehydes.
5.7.5
OXAZOLINES
The biosynthesis of many naturally occurring oxazolines appears to involve the dehydrative cyclization of serine and threonine residues. Now, N-acylserines and Nacylthreonines 138 have been easily converted to oxazolines 139 employing molybdenum(IV or VI) oxides as highly effective catalysts in toluene, under Dean-Stark conditions. The present method, involving neutral conditions, can also be applied to the synthesis of a wide range of complex substrates <05OL1971>. HO O R1
N H
R2
R2
Mo(IV or VI) oxide (10 mol%)
R
PGHN R2 140 R = OH 141 R = I
N H
O
H N O
R1
toluene, Δ, (−H2O)
CO2Me
138 R1 = Ph O
O
R1
TPP, I2, imidazole CH2Cl2, rt
,
Cbz
H N
R2 = H, Me R2
N
CO2Me
139 86-99% O
1. DMF, rt 2. 0.1N NaOH (aq) TFA/H2O/TIPS
PGHN
= HN-Rink-PEGA800
O
H N
N O
NH2 R1
142 56-72%
Peptide-derived 2-oxazolines 142 were obtained through a mild and high-yielding solidphase synthesis. A two-step protocol involved the iodination of serine containing peptides 140, with the reagent system triphenylphosphine-iodine-imidazole, followed by in situ nucleophilic attack of the carbonyl oxygen from the next amino acid in the iodo derivatives 141. This approach was even exploited for the synthesis of a resin-bound 2-oxazoline ligand <05OL581>. o-Biphenyl-2-oxazoline-4-carboxylic acid tert-butyl ester 143 allowed high enantioselective synthesis of compounds 145 via phase-transfer catalytic alkylation in the presence of cinchona-derived catalyst 144. Hydrolysis of 145 (R = benzyl, 96% ee) afforded
301
Five-membered ring systems with O & N atoms
optically active (R)-(+)-benzylserine 146 <05OL1557>. Analogous 2-aryl-2-oxazoline-4carboxylic acid tert-butyl esters were exploited in catalytic Michael addition to acrylates to give (2S)-α-(hydroxymethyl)-glutamic acid with high enantioselectivity <05OL3207>. A convenient synthesis of unprotected 2-acetamido-2-deoxy-β-D-glucopyranosides 149 from N-acetyl-D-glucosamine 147 has been achieved by treatment of the reactive furanosyl oxazoline 148 with a variety of alcohols under acidic conditions <05OL4021>. Oxazolinouridine 150 was converted in five steps into silatranyl- and germatranyluridines 151a,b; these compounds are novel transition-state analogues (TSAs) for RNA hydrolysis with several advantages over existing TSAs <05OL1165>. N
CO2t-Bu
N
O
144 (10 mol%)
O
CO2t-Bu R R = Bn
OH
147
O
Ph
OH NHAc
O
ROH/p-TsOH
reflux 148
rt
O N
51-82%
O
N
N
O
149
OR
NHAc
O NH
O
144
HO HO
OH
O
DMTrO
F
OH O
77%
F
N
O acetone/FeCl3
O
HO HO
OH
(R)-(+)-146 98%
145 75-90% 90-96% ee
143
N F
12N HCl
CsOH, RX CH2Cl2, −40 °C
Br
CO2H
H2N
N HO
O
N
O O
N E O RO O
150
CCl3
O 151a E = Si; R = Et 27% 151b E = Ge; R = H 29%
The ortho position of the aromatic ring in 2-aryloxazolines has been selectively arylated and alkenylated with organic halides in the presence of a ruthenium(II)-phosphine complex, to give 1:1 and 1:2 coupled products <05JOC3113>. I N
a) Oxa 152
Oxa
83% dr 91:9
Oxa = O
153 Ph
H
H
H
Oxa 154
a) 65% dr 99:1
H
H
I
Oxa 155
Ph Oxa Ph 156
a) 98% dr 99:1
Oxa I 157
Reagents and conditions: a) Pd(OAc)2 (10 mol%), I2 (1 equiv), PhI(OAc)2 (1 equiv), CH2Cl2, rt-50 °C
The combination of a hindered oxazoline auxiliary, Pd(OAc)2, I2, and PhI(OAc)2 was shown to be a powerful protocol for the selective catalytic and asymmetric iodination of unactivated C-H bonds of methyl, cyclopropyl, and aryl groups: for instance, compounds 152, 154, and 156 were easily converted under mild conditions into iodo derivatives 153, 155, and 157 in good yields and excellent diastereoselectivity <05AG(E)2112>.
302
S. Cicchi, F.M. Cordero, and D. Giomi
New catalyst systems that display two hydrogen bond donating arms from a rigid oxazoline backbone of type 158 were prepared and applied to activate aldehydes in hydrogen bond promoted enantioselective hetero Diels-Alder reactions (ee up to 90%) <05OL5473>. R
O Ph Ph
O HN S O
N OH
O PR12
O
158
O
N
R2 R2
159
O
PPh2 N 161a R = H 161b R = Me
RO
Ph
P
O
Ph
R1
O R2 160
N H N t-Boc 162
N
N
R2
O O
O
R2
A new class of conformationally rigid phosphino-oxazoline ligands 159 has been synthesized via an efficient ortho-substitution of phenyl-glycinol; their catalytic potential has been demonstrated in the highly enantioselective Ir-catalyzed hydrogenation of alkenes, intermolecular Heck reactions, and Pd-catalyzed allylic substitution <05T6460>. The latter reaction was performed very efficiently achieving excellent reaction rates and enantioselectivity (ee up to > 99%) in the presence of new phosphite-oxazoline ligands 160 <05JA3646>. Phosphino-oxazolines 161a,b exhibited contrasting behavior in Pd- and Ircatalyzed allylic alkylations: catalyst with ligand 161a generally provided products with low ee or even racemate, whereas the presence of the methoxy-containing ligand 161b gave products with high ee (Pd > 99%, Ir = 82%). These differences could be ascribed to different conformations of the two ligands and in particular to an OH-metal hydrogen bond in the metal-olefin complex of 161a <05JOC9882>. A new set of stereochemically diverse oxazoline ligands derived from simple amino acids, such as 162, was prepared and employed in the Cr-catalyzed enantioselective addition of allylic halides to aldehydes in up to 95% ee <05OL1837>. O N Fe
R1 1. s-BuLi THF, −78 °C
O Fe
2. R22SiHCl 163
60-91%, > 90% de
O
Fe
N
Pd(OAc)2 R
benzene, rt
Fe
Fe
H2O/MeCN air, rt or 60 °C 43-91%
164
O
O
R1 [IrCl(C8H12)]2 (1 mol%)
N Si H2 R R2
R1
165
R
N O Pd O
OO Pd OO
O Pd O N R
166
N Si OH R2 R2
167 64-78%
Fe
O
Various ferrocene-based organosilanols 165 have been synthesized in two steps from chiral 2-ferrocenyl oxazolines 163. Diastereoselective ortho-lithiation with sec-BuLi followed by electrophilic attack with chlorosilanes gave diastereomerically enriched 164, which were oxidized in air with [IrCl(C8H12)]2 as catalyst to give, after purification, stereochemically homogeneous samples of 165. Their application in asymmetric phenyl transfer reactions to substituted benzaldehydes afforded products with high ee (up to 91%) <05OL1407>.
303
Five-membered ring systems with O & N atoms
4-Ferrocenyl oxazolines 166 gave ‘interannular cyclopalladation’ in good yields by treatment with Pd(OAc)2 to furnish a hitherto unknown type of metalated ferrocenes 167 in which the carbon-palladium bond is formed by using a carbon atom in the unsubstituted cyclopentadiene ring <05AG(E)1865>. Palladium(II) catalysts based on a 2-ferrocenyl oxazoline palladacyclic scaffold were synthesized and evaluated for enantioselective azaClaisen rearrangement <05JOC648>. The first solid-phase synthesis of chiral pyridine-2,6-bis(oxazoline) (Pybox) ligands has been cleanly and efficiently performed in quite satisfactory overall yields and purity on polystyrene support, via a five-step synthetic sequence <05JOC4556>. New enantiopure C2 symmetric bis(oxazolinyl)cage ligands 168 have been synthesized from 4,5-dicyanopyridazine in two steps: a first pericyclic domino process with cycloocta1,5-diene gave the dicyano tetracyclic cage skeleton that was converted to the final products by treatment with optically active β-amino alcohols <05TA3998>. 2-Aryl-5,5-bis(oxazolin-2-yl)-1,3-dioxanes 169 have been easily prepared in three steps from diethyl bis(hydroxymethyl)malonate, amino alcohols, and aromatic aldehydes. They have been used for the copper-catalyzed asymmetric cyclopropanation of styrene with ethyl diazoacetate in up to 99% ee for the trans-cyclopropane (maximum trans/cis ratio = 77/23) <05TA1415>. The same reaction performed on 2,5-dimethyl-2,4-hexadiene with tert-butyl diazoacetate in the presence of copper catalysts bearing ligand 170, prepared from arylglycines, exhibited remarkable enhancement of the trans-selectivity (trans/cis ratio = 87/13), with 96% ee for the trans product <05JOC3292>. Novel enantiopure C2 symmetric bis(oxazolines) 171 were obtained from tartaric acid and applied in the copper-catalyzed conjugate addition of diethylzinc to chalcone and 2cyclohexenone. The sense of induction was found to depend on the configuration of the stereogenic centers in the oxazoline rings and not in the 1,4-dioxane backbone <05TA2946>. Ar O O
O N
R
O
N R2
R
Ar =
N H O
N R
O
Ar
N R2
169 Ar =
O
O N
O
R 172
N
N
O N
R
NC O
173
N
Ar
O
OMe
O
R
170
R1
N N
O N
O N
168
O
O O O
OMe
171
R N O Cl Re N OPPhCl 3
R
174 R = 4-t-BuC6H4
Interesting metal-controlled reversal of enantioselectivity was observed in the asymmetric Henry reaction of α-keto esters catalyzed by tridentate bis(oxazoline) complexes of 172, by changing the Lewis acid center from Cu(II) to Zn(II) <05JOC3712>. The enantiopure C3 symmetric trisoxazoline 173 proved to be a suitable supporting ligand for scandium-catalyzed olefin polymerization whilst invoking sufficient stereocontrol over the substrate to induce a high level of tacticity in the polymer microstructure <05AG(E)1668>.
304
S. Cicchi, F.M. Cordero, and D. Giomi
An easy approach to optically active α-amino phosphonic acid derivatives was achieved in high yields and with up to 98% ee by enantioselective amination of β-keto phosphonates with azodicarboxylates, catalyzed by chiral bis(oxazolines) and Zn(OTf)2 <05JA5772>. (CNBox)Re(V)-oxo complex 174 was employed as catalyst for an ‘open-flask’ enantioselective reduction of phosphinyl imines and α-imino esters to give the corresponding amines in high yields and ee (up to > 99%) <05JA12462>. A cationic oxorhenium(V)oxazoline coordination complex catalyzed hydrogen production from hydrolytic oxidation of organosilanes <05JA11938>.
5.7.6
OXAZOLIDINES
The reaction of a halomethyloxirane, like 175, with benzylamine 176 in the presence of K2CO3 and NEt3 afforded the N-benzyl oxazolidin-2-one 178 very efficiently. A careful analysis of the reaction demonstrated that the final product was obtained through the ring contraction of the intermediate oxazinone 177 which was unstable in the reaction conditions <05JOC5737>. A modified Mg:Al hydrotalcite was revealed as an excellent catalyst for the conversion of α-hydroxy carbamates into the corresponding oxazolidin-2-ones. The reaction is performed in refluxing toluene affording the expected products in high yields (83-96%, 6 examples) <05OBC967>. Ph
BnNH2 176 O
K2CO3, NEt3
Br
O N
O
N
MeOH
175
O
Ph
O O
O
Ph
HO
Ph 180
179
HO
N Ph
O
N
178
177 OH
O
C
O Silica Gel MeCN
OTf N H
CO2H
N H
181
TsHNOCO
N
reflux 182
OCONHTs
183
O PhSe
Bz O CO2Et 186
1.m-CPBA 2. K2CO3
65%
98% ds
Ts N
[Pd(η3-C3H5)Cl]2 ligand
O O 185
184 HN
O
O OH
O Bz N 187
CO2Et
H2N
CO2H 188
Two detailed procedures for the practical preparation of chiral allenamide 179 <05OS147> and oxazolidin-2-one 180 <05OS112> were published. Transformation of α-amino acids, like proline 181, into substituted allylic alcohols allowed a highly stereoselective SN2' cyclization affording enantiopure oxazolidin-2-ones, like 183 bearing a vinyl group on C-5. This procedure was applied to a series of amino acids with good yields and selectivity
305
Five-membered ring systems with O & N atoms
<05SL2289>. The desymmetrization of meso-compound 184 is often used as a test-bed for new enantiopure ligands, and efficient desymmetrization was found with new bisphosphine ligands <05SL2067>. In a route to the synthesis of both enantiomers of 4-amino-3hydroxybutyric acid (GABOB, 188) the oxazolidin-2-one 187 was obtained through a transformation of β-hydroxyalkyl phenyl selenides <05S579>. Particularly significant is the extension to the synthesis of enantioenriched oxazolidin-2thiones of the reaction of isothiocyanate 189 with aromatic aldehydes. This reaction is catalysed by Mg(ClO4) and the asymmetric induction is provided by a pybox ligand <05AG(E)1543>. A different approach to enantioenriched oxazolidin-2-thione was provided by a kinetic resolution of racemic substrate with an organic catalyst. Compound 192 efficiently catalysed the methanolysis of N-acyl oxazolidinethiones 191 and afforded an efficient kinetic resolution of 191 with an s-factor up to 32 <05JA13502>. O O
O N
1. Mg(ClO4)2, (R)-Ph-pybox i-Pr2EtN, CH2Cl2
O NCS + H
189
Ar
O
O
EtO
Ar 2. MeMgBr, EtOH
HN S
190
64-95% 86-95% ee S OAc R 191 O
S OAc
O 192
N
Toluene, MeOH
OAc
O N
R
194 O
O 193
R3 H N
O R1NH2 + 195
R3 CO2 HO R2 CuCl (20%)
R1 N 197
196
R3 R2
O O
R2
O
[BMIm]BF4
NMe2 OH
OMe
+ R
192 CF 3
O TEAC R4 DMSO R4 N O 80 °C or CO2, e- R2
198 R1
O NH 2 N OR
R1 200
NEt3
O
R3
R1 199
O 2 N OR H2S, py
R1
NH 201
O R1
2 N OR
202
S
Several new methods for the synthesis of 5-methylene- and 4-methylene-1,3-oxazolidin-2ones were described. A three-component reaction, involving a primary amine, a tertiary propargylic alcohol and CO2, was performed in the presence of CuCl in an ionic liquid affording 4-methylene-1,3-oxazolidin-2-one 197. The reaction proceeded very efficiently and the use of an ionic liquid allowed milder reaction conditions <05JOC7376>. Two examples of the synthesis of 5-methylene-1,3-oxazolidin-2-ones were described. The first one is an application of triethylamonium carbonate (TEAC) which is known to be a powerful reagent for carboxylation of several organic substrates. Acetylenic amines 198 react with TEAC to afford the corresponding oxazolidin-2-ones 199 in high yields <05SL67>. The same products can be obtained using the acetylenic amines with CO2 in an electrochemical synthesis <05JOC7795>. The synthetic potential of 3-hydroxy-4-imino-oxazolidin-2-ones 201 was demonstrated by the easy transformation into other novel 4-functionalised oxazolidin-2-one
306
S. Cicchi, F.M. Cordero, and D. Giomi
derivatives 200 and 202 by simple heating in the presence of NEt3 or by treatment with H2S, respectively <05S1340>. N-Acyl-oxazolidin-2-ones, as 203, are widely used in aldol reactions, however an unprecedented use of the aldol adducts for a stereoselective synthesis of trisubstituted α,βunsaturated amides and acids was reported. The syn-aldol adduct 204 underwent clean elimination upon treatment with KHMDS and afforded the E-olefin 205 with a 97% ds. The reaction was wide in scope but with a loss in selectivity using α,β-unsaturated or chiral aldehydes <05OBC2976>. This synthetic approach found immediate application in the synthesis of semiplenamide C 206 <05TL5547>. Oxazolidin-2,4-diones 207, obtained from cyanohydrins, can be easily converted into the corresponding α-hydroxyamides 208 in a reaction that can be accelerated by microwaves <05T7247>. O
O
H
N
O
O BBN-OTf i-Pr2NEt
+
O
O
KHMDS HO
N
O
O
OH −78 °C
N H 205
204
203
77% O
O O
N
R2
OH MeONa Ar
Ar
H
207
O
H N
HO
HN
12
R2
206
208 O
Two new oxazolidin-2-one derivatives were synthesised and used in pharmacological studies resulting active compounds as agonist of acetylcholine receptor <05JMC2678> and as antithrombotic agent <05JMC5900>.
5.7.7 OXADIAZOLES Oxadiazole derivatives found application for the production of electron transporting material for blended-layer organic light-emitting diodes. Compound 209 was used to enhance electron injection in an emissive polymeric material <05JMAC194>. The oxadiazol-3-one derivative 210 was revealed as a potent and selective myocardial calcium channel modulator. It was developed through a a 3D QSAR model <05JMC2445>. The benzo[1,2,5]oxadiazole derivative 211 was used in a study of the interaction of urea derivatives with anions. The role of the oxadiazole moiety was to exert an electronwithdrawing effect and to act as a fluorescent probe during the complexation tests <05CEJ3097>. C12H25O
OC12H25 O
O
N N
N N 209 H N
S O
N O N
Br
O
O2N 210
H N O
N N O
211
NO2
Five-membered ring systems with O & N atoms
307
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308 05JOC4569 05JOC5190 05JOC5737 05JOC5840 05JOC6884 05JOC7305 05JOC7376 05JOC7761 05JOC7795 05JOC7810 05JOC8395 05JOC8579 05JOC8991 05JOC9074 05JOC9882 05JOC10720 05LOC280 05OBC2976 05OBC967 05OL581 05OL1063 05OL1165 05OL1407 05OL1431 05OL1557 05OL1837 05OL1971 05OL2349 05OL3159 05OL3179 05OL3207 05OL3351 05OL4021 05OL4099 05OL4487 05OL4705 05OL5203 05OL5473 05OL5813 05OS112 05OS147 05RCB220 05RCB1189 05S161 05S579 05S1340 05S1572 05S1907 05S2695
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Five-membered ring systems with O & N atoms
05S2744 05S3423 05SL67 05SL259 05SL346 05SL532 05SL646 05SL1433 05SL1579 05SL2067 05SL2289 05T1127 05T4363 05T4841 05T6460 05T6707 05T7247 05T8836 05T9338 05T11317 05TA487 05TA1415 05TA2821 05TA2946 05TA3865 05TA3897
05TA3998 05TL1083 05TL5463 05TL5495 05TL5547 05TL6563 05TL7877 05TL8573
309
A.F.C. Flores, S. Brondani, L. Pizzuti, M.A.P. Martins, N. Zanatta, H.G. Bonacorso, D.C. Flores, Synthesis 2005, 2744. K. Bala, H.C. Hailes, Synthesis 2005, 3423. A. Arcadi, A. Inesi, F. Marinelli, L. Rossi, M. Verdecchia, Synlett 2005, 67. M.G. Kociolek, N.G. Straub, J.V. Schuster, Synlett 2005, 259. A. Ashoorzadeh, V. Caprio, Synlett 2005, 346. G.C. Tron, J. Zhu, Synlett 2005, 532. A.C. Evans, D.A. Longbottom, M. Matsuoka, S.V. Ley, Synlett 2005, 646. P. Stanetty, M. Spina, M. D. Mihovilovic, Synlett 2005, 1433. Z. Liu, B. Han, Q. Liu, W. Zhang, L. Yang, Z.-L. Liu, W. Yu, Synlett 2005, 1579. D. Zhao, Z. Wang, K. Ding, Synlett 2005, 2067. W.D. Seo M.J. Curtis-Long, J.H. Kim, J.K. Park, K.M. Park, K.H. Park, Synlett 2005, 2289. S.P. Romeril, V. Lee, J.E. Baldwin, T.D.W. Claridge, Tetrahedron 2005, 61, 1127. J.L.G. Ruano, C. Fajardo, M.R. Martín, Tetrahedron 2005, 61, 4363. L.N. Sobenina, V.N. Drichkov, A.I. Mikhaleva, O.V. Petrova, I.A. Ushakov, B.A. Trofimov, Tetrahedron 2005, 61, 4841. D. Liu, Q. Dai, X. Zhang, Tetrahedron 2005, 61, 6460. J.E. Moore, M.W. Davies, K.M. Goodenough, R.A.J. Wybrow, M. York, C.N. Johnson, J.P.A. Harrity, Tetrahedron 2005, 61, 6707. T. Kurtz, K. Widyan, Tetrahedron 2005, 61, 7247. M. Salvati, F.M. Cordero, F. Pisaneschi, F. Bucelli, A. Brandi, Tetrahedron 2005, 61, 8836. F. Pérez-Balderas, F. Hernández-Mateo, F. Santoyo-González, Tetrahedron 2005, 61, 9338. D.A. Black, B.A. Arndtsen, Tetrahedron 2005, 61, 11317. S. Moutel, M. Shipman, O.R. Martin, K. Ikeda, N. Asano, Tetrahedron: Asymmetry 2005, 16, 487. J.G. Knight, P.E. Belcher, Tetrahedron: Asymmetry. 2005, 16, 1415. M. Shindo, K. Ohtsuki, K. Shishido, Tetrahedron: Asymmetry 2005, 16, 2821. M.T. Barros, C.D. Maycock, A.M. Faísca Phillips, Tetrahedron: Asymmetry. 2005, 16, 2946. P. Merino, T. Tejero, F.J. Unzurrunzaga, S. Franco, U. Chiacchio, M.G. Saita, D. Iannazzo, A. Piperno, G. Romeo, Tetrahedron: Asymmetry 2005, 16, 3865. M.I. Torres-Sánchez, P. Borrachero, F. Cabrera-Escribano, M. Gómez-Guillén, M. AnguloÁlvarez, M.J. Diánez, M.D. Estrada, A. López-Castro, S. Pérez-Garrido, Tetrahedron: Asymmetry 2005, 16, 3897. M. Cecchi, C. Faggi, D. Giomi, Tetrahedron: Asymmetry. 2005, 16, 3998. T. Ogamino, S. Nishiyama, Tetrahedron Lett. 2005, 46, 1083. P. Wipf, J.M. Fletcher, L. Scarone. Tetrahedron Lett. 2005, 46, 5463. M. Yamashita, S.-H. Lee, G. Koch, J. Zimmermann, B. Clapham, K.D. Janda, Tetrahedron Lett. 2005, 46, 5495. I.R. Davies, M. Cheeseman, D.G. Niyadurupola, S.D. Bull, Tetrahedron Lett. 2005, 46, 5547. A. Cwik, Z. Hell, A. Fuchs, D. Halmai, Tetrahedron Lett. 2005, 46, 6563. L. Cecchi, F. De Sarlo, F. Machetti, Tetrahedron Lett. 2005, 46, 7877. C. Hoarau, A. Du Fou de Kernadiel, N. Bracq, P. Grandclaudon, A. Couture, F. Marsais, Tetrahedron Lett. 2005, 46, 8573.
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Chapter 6.1
Six-membered ring systems: pyridines and benzo derivatives Heidi L. Fraser, M. Brawner Floyd and Darrin W. Hopper Chemical and Screening Sciences, Wyeth Research, Pearl River, NY, USA
[email protected],
[email protected] and
[email protected]
6.1.1
INTRODUCTION
The myriad of pyridine rings in natural products <05JNP319, 05JA15644, 05P1804> and pharmaceutically active compounds <05BMCL645, 05BMCL1055, 05JMC2045, 05EJM1163, 05JMC5749, 05JMC5780> have been a motivating factor for developing improved methods for their synthesis and examination of their reactivity. Chelucci reviewed the synthesis of chiral pyridyl-methylamines <05TA2353>. The synthesis of optically-active isoquinolines were highlighted in a review by Kaufman <05ASNH99> and the synthesis of quinolines has also been reviewed <05CORC141>. Due to their unique properties, pyridines and their benzo-derivatives have been of interest as metal ligands <05JOC2274, 05OBC3105, 05CC4672, 05SL99, 05TA3536> and supramolecules <05TL2361, 05CEJ5742>. They have also been used in other material science applications <05JOC4935, 05JOC1518>. Moberg published a review this year on the coordination chemistry and application of bispyridylamides in catalytic reactions <05CCR727>. This review includes a summary of the methods developed for the syntheses and reactions of pyridines, quinolines, isoquinolines, and piperidines that were disclosed in the literature in 2005. This chapter covers selected advances in the field and will serve as an update to the review published last year in this volume. 6.1.2
PYRIDINES
6.1.2.1 Preparation of Pyridines The [4+2] disconnection is a common approach for the synthesis of pyridines. Lipińska has presented an extensive report of Diels-Alder-retro-Diels-Alder reactions of 1,2,4-triazines with enamines to produce cycloalkylpyridines <05T8148>. Triazines have been used as efficient
311
Six-membered ring systems: pyridines and benzo derivatives
building blocks for both terpyridines <05TL1521> and bipyridines <05TL1791>. Enamines have also been used in cycloaddition reactions with 2-aza-butadienes to generate fluoroalkyl substituted pyridines <05T2779>. Specifically, cycloaddition reactions have been used in the preparation of pyridine-fused quinones <05EJO1903, 05TL7669>. Imidazo[4,5-g]quinoline quinones were prepared using a hetero Diels-Alder reaction between benzimidazole quinone as the dienophile and α,βunsaturated N,N-dimethylhydrozones <05EJO1903>. This sequence proceeded with good yield but poor regioselectivity. Dujardin, Collet and Guingant utilized this type of reaction in their convergent synthesis of the 5-aza-analoge of angucycline 1 <05TL7669>. The key step of the synthesis, shown in Scheme 1, is a cycloaddition reaction between a 2-aza-1,3-diene 2 and 2bromonaphthoquinone 3 bearing a C6’-substituted C-glycoside moiety yielding the desired pyridine-fused naphthoquinone 1. O
O
O MeCN
OAc +
AcO AcO
H
OH
61%
N
Br O
N
3
2
O
OAc AcO AcO
N H
OH
O 1
Scheme 1 Multiple groups have utilized microwave conditions to enhance hetero Diels-Alder reactions in the preparation of substituted pyridines. Shao reported microwave assisted hetero Diels-Alder reactions of a series of acetylenic pyrimidines that resulted in improved yields and broadened the utility to the preparation of pyrido-fused lactams <05TL3423>. Eycken and co-workers reported the Diels-Alder reaction of 2-pyrazinones under microwave conditions to obtain 2-pyridones and pyridines in good yield as illustrated in Scheme 2 <05JCO490>.
R1 N Cl
N
CO2Me CO2Me CO2Me
O N
O
N N R2
4 R1
R2
DMAD microwave
= 4-OMe-Bn, = 4-OMePh; 7, 89%; 6, 10%
R1 = Ph, R2 = 4-OMePh; 7, trace; 6, 76%
MeO2C Cl N
N O
-R1NCO
Cl
N
O
R1
O
N N N
R2 5
7 -ClCN
MeO2C
R1 N
R2
O
O CO2Me 6
Scheme 2
N N N
2 N R N N
312
H.L. Fraser, M.B. Floyd and D.W. Hopper
The reaction proceeds through initial Diels-Alder reaction of 2-pyrazinones 4 with an acetylene forming bicyclic intermediate 5. This is followed by spontaneous elimination of cyanogen chloride or an isocyanate to obtain 2-pyridone 6 and pyridine 7, respectively. Additionally, continuous flow reactors have been designed for microwave reactions, which improve the energy efficiency. The continuous flow microwave reaction was illustrated using a microwave assisted Bohlmann-Rahtz pyridine synthesis <05JOC7003>. The Bohlmann-Rahtz reaction is a classic pyridine synthesis that has been studied and modified in many ways. Bagley et al. has elaborated on his previous work and reported an iodine-mediated catalytic Bohlmann-Rahtz reaction of aminodienone intermediates <05SL649>. This modified process is reported to be rapid at ambient temperatures resulting in good yields. Moreover, Bagley and co-workers presented a one-pot, three-component Bohlmann-Rahtz reaction to synthesize 2,3,6-trisubstituted and 2,3,4,6-tetrasubstituted pyridines 8 and 9 from βketoesters 10 and alkynes 11 as shown in Scheme 3 <05JOC1389>. O
O
O
+
t-BuO
R2 R1
O 10
NH4OAc
t-BuO
EtOH, reflux
R2
N
24 hr
11
R1
8, R1 = Et, R2 = Me, 71% 9, R1 = H, R2 = Ph, 89%
Scheme 3 Another well-studied pyridine synthesis is the [2+2+2] metal mediated cycloaddition. These reactions are generally preformed with cobalt <05JA3473, 05SL1188, 05SL1758> as the metal catalyst; however, catalysis of this reaction has also been reported with nickel <05JA5030>, ruthenium <05JA605>, and rhodium <05OL4737>. Yamamoto et al. presented the use of a ruthenium catalyst for the [2+2+2] cycloaddition reactions of diyne 12 with both nitriles and isocyanates, to yield the pyridine 13 and pyridone 14, respectively, as illustrated in Scheme 4 <05JA605>. MeO2C NC CO2Et MeO2C
13, 87%
Cp*RuCl
MeO2C 12
O
N Pr
N
MeO2C
MeO2C
N
MeO2C
CO2Et
Pr O
14, 85%
Scheme 4 Müller and co-workers demonstrated the synthesis of pyridines using a one-pot, fourcomponent process they refer to as a coupling-isomerization-enamine additioncyclocondensation sequence (Scheme 5) <05EJO1834>. In a stepwise fashion, this sequence can be explained as an initial reaction of an electron-deficient halide 15 with a terminal alkyne 16,
313
Six-membered ring systems: pyridines and benzo derivatives
generating intermediate 17, which undergoes isomerization to the corresponding enone 18. Compound 18 then undergoes enamine cycloaddition and subsequent cyclocondenstion with ammonia to generate pyridine 20 as shown in Scheme 5. 4-CN-C6H4
Br
OH
1. 2% (Ph3P)2PdCl2, 1% CuI, NEt3, Δ
+
N
2.
N
CN 15
16
O ,Δ
20, 70%
3. NH4Cl, AcOH, Δ 4-CN-C6H4 H
O
OH
19 N NC
NC
17
18
O
O
Scheme 5 A nucleophile-induced ring transformation reaction of 2-pyranones was reported (Scheme 6) to result in a regioselective synthesis of 2-aminopyridines 21 or 2-pyridones 22 <05SL623>. Urea was used to generate ammonia as a nucleophile source. The reaction of 23 (R=CN) was initially examined under elevated temperatures and solvent-free conditions. This system yielded a mixture of both 21 and the pyridone equivalent of 23, in equal amounts. The reaction conditions were modified to yield 2-aminopyridine 21 selectively as shown in Scheme 6. However, the only reaction found to be selective for 2-pyridone 22 formation is where the cyano group was replaced with an ester, shown in Scheme 6. Compound 24 was converted to pyridone 22 in good yield. S
S NH2CONH2
Ar
N H
O
150 °C R = CO2Me
22, 70-80%
S R
Ar
O
O
NH2CONH2 pyridine, reflux
23, R = CN 24, R = CO2Me
R = CN
Ar
N
NH2
21, 82-92%
Scheme 6 6.1.2.2 Reactions of Pyridines Functionalized pyridines are important starting scaffolds for pharmaceuticals and nonlinear optics. Gros et al. have developed a new approach to the facile synthesis of various
314
H.L. Fraser, M.B. Floyd and D.W. Hopper
functionalized pyridines (Scheme 7). They have immobilized 2-chloro-5-bromopyridine on a Merrifield resin via a traceless silicon linker at the C-4 position <05JCO879>. The silicon linker was selected because of its stability under a wide range of conditions and it is easily cleaved with fluoride anions. The 2-chloro-5-bromopyridine was chosen due to its numerous reactive sites, which allow for the introduction of diversity via a wide range of chemical transformations. Compound 25 was examined under a variety of reaction types as summarized in Scheme 7-9. First, bromine-lithium exchange was utilized and yielded 2,5-disubstituted pyridine 26 in excellent yield. Ortho-lithiation was shown to yield only the trisubstituted pyridine 27. Lithiation at the 3-position was not observed due to steric hindrance of the tethered silyl group (Scheme 7). I 1. t-BuLi, THF
Si
2. I2, -78 °C Br Cl
Cl
26, 90%
3. TBAF
N
N
Br
1. LDA, THF 2. MeSSMe, -78 °C
25
Cl
3. TBAF
N
S
27, 91%
Scheme 7 Moreover, the group explored Sonogashira, Suzuki and Stille couplings of 25, where the reactivity of the C-Cl and C-Br bonds was shown to be similar. Scheme 8 illustrates an example of the Stille reaction accomplished with compound 25 yielding 2,5-diphenyl pyridine 28. Si Br Cl
Ph
1. PhSnBu3, K2CO3 DMF, Reflux 2. TBAF
N 25
Ph
N 28, 82%
Scheme 8 The chemistry of the C-Cl bond was examined further and the chlorine atom was found to undergo displacement with alkyl amines to give compound 29, which in turn was then subjected to a Sonogashira coupling and then cleaved from the resin to give 30 in good yield over three steps (Scheme 9). Si
Si
H N Br
Cl
N 25
Ph Br
DMF, 100 °C
N
N 29, 97%
1. PdCl2(PPh3)2, CuI piperidine, Reflux Ph 2. TBAF
Scheme 9
N
N 30, 89%
315
Six-membered ring systems: pyridines and benzo derivatives
Fernàndez and co-workers have also reported Suzuki reactions of resin bound pyridine. However in this case, the pyridine is immobilized via an amide bond of a nicotinic ester <05TL581>. Similarly, Schell et al. utilize resin bound nicotinic carboximidamides as a key intermediate in the synthesis of pyrido[2,3-d]pyrimidin-4-ones <05JCO96>. In addition to using resin bound pyridines as scaffolds for organic synthesis, several groups have engineered resin bound pyridine-based ligands to facilitate solid phase metal catalysis. Davies reported the universal immobilization of a chiral dirhodium catalyst, which demonstrates a broad array of enantioselective rhodium carbenoid reactions <05OL2941>. Portnoy and Mayoral concurrently developed solid phase pyridinebis(oxazoline) ligands, via a polystyrene support and by polymerization of a vinyl group incorporated at the 4-position of the pyridine ring <05JOC4556, 05JOC5536, 05AG(I)458>. Likewise, Kirschning and co-workers utilized polyvinylpyridine to immobilize the Grubbs III catalyst for metathesis reactions <05SL2948>. There are an immense amount of palladium coupling reactions in the literature; palladium couplings involving pyridines are no exception. Medicinal chemists routinely utilize palladiumcoupling reactions in the synthesis of biologically active targets <05JMC3930, 05BMCL4385, 05BMCL905, 05BMCL4703, 05BMCL2221, 05BMCL4589, 05JOC10342, 05JOC6034, 05JOC5215, 05JOC6933, 05EJM1087>, as well as in the generation of diverse libraries <05JCO526>. The synthesis of a pyridine containing liquid crystal was accomplished using a Buchwald, copper-catalyzed arylation and subsequent Sonogashira coupling reaction <05OL1027>. Likewise, Cid et al., as shown above in Scheme 10, <05OL5737> utilized both Negishi and Sonogashira palladium coupling reactions to obtain 33, which is a key intermediate in the synthesis of visual pigment A2E, a fluorophoric material. Dibromide 34 underwent a Negishi coupling to give bromide 35 in good yield. Sonogashira coupling of bromide 35 was subsequently accomplished in excellent yield to obtain key intermediate 33. TMS Negishi Coupling
Br
Sonogashira Coupling
Br
Pd(PPh3)4, THF, 25 °C, 83% N 34
ZnCl
Br
Pd(PPh3)2Cl2, CuI, NEt3 TMS
N
105 °C, 97%
TBSO
N
OTBS 35
33
OTBS
Scheme 10 The efficiency of palladium coupling reactions has also made them useful in industral process development <05OPRD646>. Bryce and Itoh concurrently exemplified Suzuki type coupling reactions with pyridines containing unprotected primary amines in good yield <05JOC388, 05TL3573>. Doucet and Santelli have examined the Suzuki coupling reaction of 3pyridineboronic acid 36, with a variety of aryl bromides, as shown below in Scheme 11 <05SL2057>.
316
H.L. Fraser, M.B. Floyd and D.W. Hopper Br
[Pd(C3H5)Cl]2/Tedicyp 1:2, K2CO3, xylene, 20 h, 130 °C B(OH)2 N
37
[Pd(C3H5)Cl]2/Tedicyp 1:2, K2CO3, xylene, 90 h, 130 °C
Ph
B(OH)2
N
36
N
39
40
38 98%
75% substrate/catalyst ratio:
Br
33:1
1000000:1
Scheme 11 These reactions were shown to give the desired adduct in good yield; however, in most cases better yields, with the use of lower substrate/catalyst ratios, were obtained with 3-bromopyridine 38 and arylboronic acids, as illustrated with phenylboronic acid 39 in Scheme 11 yielding pyridine 40 in excellent yield. Hiyama couplings of trimethylsilylpyridines under classical conditions have been unsuccessful. Gros and co-workers reported the use of chloropyridyltrimethylsilanes 41-43 as reactive partners in the Hiyama cross-coupling reaction <05OL697>. This reaction is spotlighted in Scheme 12. The silyl pyridines, 41 and 42, react with 4-iodoanisole 45 to yield 46 and 47, respectively. The electron withdrawing effect of chlorine on the pyridine ring increased the polarization of the C-Si bond thus favoring formation of the intermediate complex required for the cross-coupling reaction. Moreover, the presence of the pyridine nitrogen alpha to the trimethylsilyl group was a requisite to achieve cross coupling. Nevertheless, the Hiyama cross coupling of 43 was unsuccessful and resulted in only formation of the desilylated product 48. The authors attribute this result to the weaker complexation to the palladium in the requisite intermediate. The electronegativity for this compound was calculated and was found to be in line with this explanation. Cl Cl N
SiMe3
41 = 3-chloro 42 = 4-chloro 43 = 6-chloro
Pd(Ph3)2Cl2, CuI, TBAF DMF, 12 h, rt
N
I
O 45
N
Cl
O 46 = 3-chloro, 82% 47 = 4-chloro, 82%
Scheme 12 Other coupling reactions have capitalized on the participation of the pyridine nitrogen in the metal complex intermediates to achieve a successful reaction. 2-Substituted pyridines were found to undergo samarium iodide promoted coupling with aldehydes and ketones to afford (2hydroxyalkyl)pyridines <05OL3609>. Jun and co-workers have used a chelation strategy in the reaction of aldimines bearing the 3-picolin-2-yl group with various arylboronates in the presence of a ruthenium catalyst to furnish the ketimines in high yield <05CC1185>. Also utilizing a ruthenium catalyst, Oi and Inoue performed arylation of alkenylpyridines 49 with aryl bromides to afford 50, selectively, the generally less stable β-arylated (Z)-2-alkenylpyridine (Scheme 13) <05OL4009>. This geometric selectivity is in sharp contrast to that of the Mizoroki-Heck
317
Six-membered ring systems: pyridines and benzo derivatives
reaction (Scheme 13, vinyl pyridine 51). The authors attribute the selectivity to the unprecedented reaction pathway involving a nitrogen atom coordinated ruthenacycle. [Ru(η6-C6H6)Cl]2, PPh3, K2CO3 79%
N 49
50
N
NMP, 120 °C, 20 h, PhBr
Ph
Pd(OAc)2, PPh3, Et3N NMP, 120 °C, 20 h, PhBr
51
N
60%
Ph
Scheme 13 Nitropyridines have proven to be synthetically useful intermediates in the pharmaceutical industry <05EJM209, 05BMCL3701> and are themselves of interest in material science <05OBC3408>. However, their synthesis is not trivial due to the electron deficient character of the pyridine ring, which does not easily undergo electrophilic aromatic substitution. Bakke and Katritzky have both independently developed nitration methods that are not classically electrophilic in nature as shown in Scheme 14 <05JHC463, 05OBC538>. These reactions proceed through initial fomation of N-nitropyridinium ion, followed by migration of the nitro group from the 1-position to the 3-position via a [1,5] sigmatropic shift. The reaction conditions are illustrated with pyridine 52 in Scheme 14. Moreover, Bakke explored vicarious nucleophilic substitution of 3-nitropyridine 53 and substituted analogs with ammonia and amines. Scheme 14 shows the conversion of 3-nitropyridine 53 to 2-aminopyridine 54 in excellent yield. 1. N2O5/THF-SO2 2. H2O 77% N 52
1. conc. HNO3 (CF3CO2)O
NO2 N 53
NO2
NH(Et)2 KMnO4 93%
N
N 54
2. Na2S2O5 83%
Scheme 14 In contrast, Kuduk and co-workers have developed a denitration method for the synthesis of fluoro, hydroxyl and methoxypyridines <05OL577>. They have shown that the TBAF-promoted fluorodenitration of nitropyridines is a mild and efficient alternative to the classical two-step Balz-Schiemann procedure for the synthesis of fluoropyridines. The reaction was shown to be general with good yields for pyridines with nitro substitution at the 2- or 4-position. The 2chloro-4-nitropyridine 55 example is illustrated in Scheme 15 to give fluoropyridine 56 in moderate yield. To accomplish this reaction with 3-nitropyridines an electron-withdrawing group was required for efficient conversion. The methodology was extended to other commercially available tetrabutylammonium salts, specifically hydroxide and methoxide. The
318
H.L. Fraser, M.B. Floyd and D.W. Hopper
reaction of these salts with 2-chloro-4-nitropyridine 55 was used to obtain the hydroxyl 57 and methoxy 58 substituted pyridines, respectively. NO2
R TBA-R
56, R = F, 53% 57, R = OH, 46% 58, R = OMe, 95%
THF or DMF N
Cl
N
Cl
55
Scheme 15 New methods for lithiation of pyridines continue to be of interest. Both Comins and Fort observed selectivity for the lithiation of substituted pyridines with superbase (BuLiThe regioselectivity is dictated by the Me2NCH2CH2OLi) <05OL5457, 05T4761>. complexation of the pyridine nitrogen and is unaffected by the influence of a directing group present on the pyridine ring. This point is illustrated in Scheme 16, where all the isomers of piperazine substutited pyridines 59-61 are lithiated alpha to the pyridine nitrogen giving compounds 62-64 in excellent yield. The results observed yielded products previously unobtainable through lithiation chemistry. Additional work by Gros and Fort examined the lithiation of anisylpyridines with superbase <05T3261>. They observed pyridine directed metallation exclusively, allowing for the efficient preparation of a range of alpha functionalized pyridylphenols. TPP
1. n-BuLi-LiDMAE 20 °C to -78 °C toluene N 2. MeSSMe, THF -78 °C 59, 2-TPP 60, 3-TPP 61, 4-TPP
TPP TPP = S
N
N Tr
N LiDMADE = LiOCH2CH2NMe2
62, 6-TPP, 90% 63, 3-TPP, 90% 64, 4-TPP, 90%
Scheme 16
P N N
NO
CN
W
80%
N N B
N
N
N
NC N
W 66
H
AgOTf
NC
86%
N 67
65
Scheme 17 Harman et al. have demonstrated the dearomatization of 2-substituted pyridine via complexation with tungsten <05JA10568>. The dearomatization process renders the bound
319
Six-membered ring systems: pyridines and benzo derivatives
pyridine chemically similar to a 2-azadiene and these complexes smoothly undergo Diels-Alder reactions with electron deficient alkenes. Shown in Scheme 17, complex 65 reacts with acrylonitrile to yield 66 in 80% yield with a >20:1 ratio of exo to endo, respectively. Bicyclic compound 66 can be liberated from the metal by oxidation with silver triflate to give 67 in good yield. Kiplinger and co-workers have also demonstrated dearomatization of pyridines with metals <05CC2591>. In the case reported, thorium complexes mediated ring opening and dearomatization of pyridine N-oxides yielding the thorium oximate complexes. Many groups have also examined the free radical chemistry of pyridines. Zard and coworkers explored a radical Smiles rearrangement to access various substituted pyridylacetic acid derivatives <05OL3817>. Bennasar et al. reacted 2-indolylacyl radicals with tethered pyridines to give various ellipticine quinones <05JOC9077>. Melman and co-workers demonstrated a new one step free radical approach for the regiospecific preparation of 4-alkyl and 4-acylpyridine-2,6dicarboxylates, from pyridine-2,6-dicarboxylate <05EJO1397>. 6.1.2.3 Pyridine N-Oxides and Pyridinium Salts Pyridine N-oxides have received an increased amount of attention from medicinal chemists in the past year due to their biological activity. They are of interest for anti-HIV activity <05JAMC135>, and as peptidomimetic scaffolds of thrombin inhibitors <05BMCL2771>. Pyridine N-oxides are also of interest as phosphodiesterase IV inhibitors <05T6330> and as an isosteric replacement of substituted phenyl groups for high affinity 5-HT1A receptor antagonists <05BMCL883>. To date pyridine N-oxides have been under-represented in palladium coupling reactions. Chloropyridine-N-oxide has been shown to undergo an unprecedented Suzuki-Miyaura cross coupling reaction in the synthesis of phosphodiesterase inhibitors <05T6330>. Moreover, Fagnou and co-workers illustrated direct regioselective palladium-catalyzed arylation of the 2position of pyridine N-oxides with a variety of aryl bromides <05JA18020>. Scheme 18 shows the cross coupling of 4-bromotoluene with pyridine N-oxide 68 to yield the 2-toluylpyridine Noxide 69, which was subsequently reduced to give 70 in good yield. Pd(OAc)2, P(t-Bu)3-HBF4 N O 68
K2CO3, PhMe, 110 °C
Br
Pd/C, HCOONH4 N O
MeOH, rt 69, 91%
N 70, 84%
Scheme 18 Pyridine N-oxides have also received attention due to their catalytic properties, for example, they have been used as Lewis bases in aldol reactions <05JOC5235, 05SL2388>. Malkov and co-workers elaborated on the use of pyridine N-oxides as a catalyst for allylation of aldehydes with allyltrichlorosilanes <05OL3219>. Additionally, Higuchi et al. report a highly reactive Ru porphyrin/pyridine N-oxide system that shows unique reactivity for the oxidation of various
320
H.L. Fraser, M.B. Floyd and D.W. Hopper
amides <05JA834>. More specifically, this system was used for the oxidative conversion of Nacylproline to N-acylglutamate in excellent yield. Over the past year, there continues to be a constant stream of methods for the deoxygenation of pyridine N-oxides. Two groups have demonstrated facile deoxygenation with molybdenum complexes <05TL125, 05SL1389>, while Sandhu et al. have accomplished this transformation with ruthenium <05TL8737>. Nucleophilic addition remains the most utilized reaction of pyridinium salts. Addition generally occurs at the 2- or 4-position giving rise to 2- or 4-dihydropyridines, respectively. Charette et al. observed nucleophilic addition of organometallic reagents to the 2-position of Namidine pyridinium salts <05OL5401>. This chemistry is illustrated in Scheme 19 with amide 71. O 1. Pyridine, Tf2O
NH
2.
OLi
OTf
N
2. LAH, THF
N
71 CH2Cl2, -78 °C
H
1. H2, Pd(OH)2, EtOH H
N
OH
72
H N
tetraponerine T4 38% overall yield
Scheme 19 Pyridinium salt 72 is generated by the treatment of the amide 71 with triflic anhydride in the presence of pyridine followed by treatment with the lithium enolate. Intermediate 72 was used to synthesize tetraponerine T4 in four steps in 38% overall yield. Comins and co-workers used addition of a zinc enolate to an N-acylpyridinium salt in the synthesis of (+)-hyperaspine <05OL5227>. Additionally, they have studied cuprate addition to N-acyl pyridinium salts of nicotine, where addition occurs selectively at the 4-position <05OL5059>. Donohoe and co-workers have altered the reactivity of the pyridinium salt <05OL435>. The addition of two electrons to a pyridinium salt 73 results in the formation of the nucleophile 74, which was quenched with MeI, NH4Cl, or EtI to give compounds 75, 76 and 77, respectively. The sequence is illustrated in Scheme 20. O
O I
N
CO2Me
O 1. RX, -78 °C , 3 h
Li, DBB, THF -78 °C
O
N
2. H3O+, -78 °C to RT
O
N
R
CO2Me
75, RX = MeI, 71% 76, RX = NH4Cl, 65% 77, RX = EtI, 59%
73 74
Scheme 20 Polymer supported pyridinium salts, such as Mukaiyama reagent, have proven very useful synthetic tools in the preparation of 2-oxazoline libraries <05JCO688> and in automatable esterification reactions <05TL2817>. Yamamoto et al. have examined the use of polymer supported boronopyridinium salts for the preparation of amides and esters in good to excellent yield <05OL5043, 05TL5047>.
321
Six-membered ring systems: pyridines and benzo derivatives
Kiselyov has examined the reactivity of in situ generated N-fluoropyridinium salts with isonitriles under multiple reaction conditions as shown in Schemes 21-23 <05TL2279, 05TL4487, 05TL4851>. The author suggests that the reaction begins with initial formation of a highly reactive carbene intermediate 78, generated by deprotonation at the 2-position of the Nfluoropyridinium salt 79. F2, CH2Cl2
PhNC
-60 °C
N
N X F 79
N F 78
N F 80
N
Ph
Scheme 21 The carbene intermediate 78 undergoes a reaction with the isonitrile to afford the isonitrilium ylide 80. It is the reaction environment of this ylide intermediate 80 that determines the product observed, as illustrated in Schemes 23 and 24. When the isonitrile is the only additional component of the reaction the intermediate ylide 80 eliminates fluoride. This is followed by hydrolysis to produce 2-pyridylcarboxamide 81 in 55% yield, as shown in Path A <05TL2279>. A Path H2O
-F N F 80
N
N F
Ph
N
Pa t h
Ph
H N
N
Ph
81, 55%
O
B
N3
Ph N N N N
N
82, 75%
Scheme 22 When the isonitrilium ylide 83 is generated in the presence of TMSN3, as shown in Path B, it eliminates fluoride, and then undergoes reaction with the in situ generated azide to give tetrazole 82 in 75% yield as illustrated in Scheme 22 <05TL4851>. H MeCN N F 78
-F N F 83
N
PhNC N
F
N
N
N
N
N
HN Ph
N Ph 84
85, 67%
Scheme 23 If the reaction is done with acetonitrile as a solvent under reducing conditions, the carbene intermediate 78 eliminates fluoride and reacts with the nitrile generating nitrilium ylide 83 as illustrated in Scheme 23. This intermediate, in turn, undergoes addition of isonitrile followed by subsequent cyclization to the imidazopyridinium intermediate 84 that is then reduced with sodium triacetoxyborohydride to give imidazopyridine 85 <05TL4487>.
322 6.1.3
H.L. Fraser, M.B. Floyd and D.W. Hopper
QUINOLINES
6.1.3.1 Preparation of Quinolines One of the more common ways to synthesize quinolines is through the Friedländer synthesis; as a result, there have been a number of variations and improvements published for this reaction. Chelucci et al. presented a version of the Friedländer synthesis where the condensation and azaannulation reactions were carried out in a one-pot process. Additionally, they were able to synthesize quinoline analogs that were regiospecifically functionalized on both the pyridine and benzo-fused rings (Scheme 24) <05TL767, 05TL3493>. 1. t-BuOK 1,4-dioxane rt, 1-7 h
CHO +
N
2. 3 N HCl reflux 1-4 h
O
NHBOC F
F
87
86
88, 88%
Scheme 24 Utilizing their method to synthesize regiospecific functionalized quinolines, Chelucci et al. prepared a variety of chiral ligands 89-91. They tested their ligands in palladium-catalyzed allylic substitutions employing [Pd(η3-C3H5)Cl]2 and ligand as the catalytic system resulting in high yields (90-95%) and moderate enantiomeric excess (69-74%).
N PPh2
N PPh2
89
N
90
PPh2
91
The incorporation of environmentally friendly methodology was also presented in a number of reports in 2005. A variety of substituted quinolines 92 and 93 were synthesized in good yield (87-94%) through a variation of the Friedländer reaction using NH2SO3H as a recyclable heterogeneous catalyst and under solvent free conditions (Scheme 25) <05TL7249>. Ishii et al. also reported a synthesis of quinoline derivatives under solvent free conditions using the oxidative coupling of 2-aminobenzyl alcohol with ketones in the presence of base and an irridium catalyst <05TL4539>. Ph O O
R1 Ph
NH2
+
O
O
R2 R2
or O
NH2SO3H (5 mol %) 70 °C , solvent free
N
0.5 - 1.5 h, 87-94%
Ph
92
R1
93 N
n
Scheme 25
n
323
Six-membered ring systems: pyridines and benzo derivatives
Other methods that utilized mild conditions and environmentally friendly catalyst via the Friedländer quinoline synthesis were also reported. In one reaction, Y(OTf)3 was used as the catalyst for the condensation of 2-aminobenzophenones 94 and ketones 95 in acetonitrile at room temperature resulting in 2,3,4-trisubstituted quinolines 96 in good to high yields (Scheme 26) <05TL1647>. In another reaction, FeCl3 or Mg(ClO4)2 were used in the same condensation of 2aminobenzophenones 94 and ketones 95 in EtOH at room temperature also resulting in 2,3,4trisubstituted quinolines 96 in moderate to high yields (Scheme 26) <05SL2653>. O
R4
R1 94
O +
R3
Catalyst, Solvent rt Y(OTf)3, CH3CN, 76-92% FeCl3, ethanol, 63-98% Mg(ClO4)2, ethanol, 42-99%
R3
R2
NH2
R1
R4
95
N 96
R2
Scheme 26 A variety of reactions that use water as a solvent were also reported. Many of these reports have the advantage of being environmentally friendly. The reaction of Schiff base 97 with 1,3dicarbonyl compounds 98 in water and catalyzed by benzyltriethylammonium chloride (TEBA) resulted in substituted quinoline derivatives such as 99 in good to high yields (Scheme 27) <05TL7169>. Cl
Cl
O
O
Cl
TEBA
+
N
Cl
O 98
97
NH
water 99, 99%
Scheme 27 A 1,3-dipolar cycloaddition with oxime 100 in water was reported to form the quinolineisoxazoline 101 shown in Scheme 28. One of the advantages of this reaction when it was run in water was that 101 precipitated out of solution. Additionally, no starting material remained after 48 h <05S3423>. N O
H N N H 100
OH
NaOCl, H2O Ph
48 h, rt
Ph H N H 101, 92%
Scheme 28 Furthermore, a novel hydrothermal aromatic alkylation of anilines with cyclic ketones and acyclic ketones was presented. Though the yields were low for this system, the fact that these
324
H.L. Fraser, M.B. Floyd and D.W. Hopper
reaction were run only in water at high temperature makes them operationally simple <05TL6953>. The optimization of these conditions would make it a very nice tool. A novel one-pot domino process was developed to synthesize substituted 1,2dihydroquinoline derivatives 102 with high regioselectivity using a silver catalyst <05OL2675>. Scheme 29 shows the proposed pathway, which starts with the hydroamination of alkyne 103 and aniline 104. This is followed by C-H addition with another alkyne 103 and C-H addition cyclization to give intermediate 105. The final step is another C-H addition with alkyne 103 yielding the desired product 102. The scope and mechanism of this one-pot process is still under investigation. R1 NH2 +
Hydroamination
R2
R1 103 (4 eq) AgBF4/HBF4 BF3·Et2O 160-190 °C R2
R1C6H4
R2
104(1 eq)
103
R1
N
R1
C-H addition
R1 = Me, F, H R2 = Me, F, Cl, H C6H4R1 H Me N C6H4R1 H H
R1
C-H addition Cyclization
C-H addition cat
H 102, 60-88%
R2
H Me N H 105
103
R1
H N
R2
R1 R1
Scheme 29 Rossi et al. have reported a palladium-assisted multicomponent reaction involving 2ethynylarylamines 106, aryl iodides 107, primary amines 108, and carbon monoxide that lead to a variety of substituted quinoline derivatives 109 as shown by the example in Scheme 30 <05JOC6454>. This is the first time this type of multicomponent cascade reaction was successful using primary amines; previously, only secondary amines were successful. HN F3C +
I + H2N
NH2 106
107
3
+ CO
Pd(OAc)2/TTP THF, 100 °C , 24 h
108
3
N
CF3
109, 99%
Scheme 30 In another multicomponent one-pot reaction, Lu et al. reported the first use of iodine as a catalyst to synthesize a variety of pyrano[3,2-c]quinolines <05SL2357>. They reported a threecomponent reaction involving aldehydes 110, anilines 111, and 2,3-dihydropyran 112 resulting in diastereomeric mixtures of tetrahydroquinolines 113:114 as shown in Scheme 31.
325
Six-membered ring systems: pyridines and benzo derivatives
Additionally the authors were able to optimize their conditions to provide good to high yields of both isomers (113 and 114) and moderate to high diastereomeric ratios of 113:114. O
NH2 +
R1
+ O
R2 110
111
112
I2 (30 mol%) CH3CN, rt R1, R2 = 4-CH3O 96% 113:114 = 3:97
O
R2
H H
H
NH
H R1
R2
H
O
NH
H 113
114
R1
Scheme 31 An electrophilic cyclization of N-(2-alkynyl)anilines was developed that allow the synthesis of a variety of substituted quinolines 115. Illustrated in Scheme 32 the cyclization of the propargylic aniline 116 by ICl afforded 117, which then could be converted to 115 under basic conditions. Ms N
116
Ms N
1.5 ICI, CH2Cl2 -78 °C , 1 h 80%
Ph
N I
117
Ph
10 NaOH, EtOH 50 °C , 12 h 92%
I 115
Ph
Scheme 32 In this method the initial iodocyclization of a variety of propargylic anilines can be accomplished and followed by palladium-catalyzed substitution reactions to provide further elaboration of the quinoline core at the 3-positions shown in Scheme 33 <05OL763>.
N Ph 118
R
B(OH)2 Ph PdCl2(PPh3)2 K2CO3, DMF-H2O 100 °C , 2 h R = 4-FC6H4 73%
N N
115 R
PdCl2(dppf), dppf KO-t-Bu, toluene-DMF I 100 °C , 36 h R = 2-NH2C6H4 65%
NH 119
Scheme 33 In a similar manner a series of substituted tetrahydroquinolines were synthesized using a Lewis acid catalyzed intramolecular halo-arylation. This process was shown to be a regio- and stereoselective method that provided products in moderate to high yield <05TL8599>. A series of 2-alkyl(aryl)thio-3H-quinolin-4-ones 120 were synthesized in a thermally induced cyclization <05OL5281>. Initially, the ketenimine 121 undergoes a [1,5] sigmatropic migration of the alkyl(aryl)thio group to form 122 followed by a 6π-electrocyclic ring closure resulting in the formation of 120, illustrated in Scheme 34.
326
H.L. Fraser, M.B. Floyd and D.W. Hopper O R1
O SR2
N 121
R3
toluene, reflux, 1 h 120
6π-ERC O R3 Ph
R1 N 122
Ph SR2
N
Ph
[1,5]-SR2
R3
R1 = H, R2 = 4-CH3OC6H4, R3 = Ph, 89 % 97 % R1 = Cl, R2 = 4-CH3C6H4, R3 = Ph, R1 = H, R2 = 2-IC6H4CH2CH2 R3 = Ph, 90 %
SR2
Scheme 34 The use of metal catalyzed processes to synthesize quinoline derivatives continued to be of interest. During the investigation of the [Ru(DMSO)4]Cl2 catalyzed α-alkylation of ketones by alcohols it was found that the reaction between 2-aminobenzyl alcohol and an alkyl aryl ketone resulted in 2,3-disubstituted quinoline derivatives in good to high yield <05TL3683>. Yamamoto et al. found an interesting intramolecular hydroamination of 123 that resulted in quinoline derivatives 124 during their investigation into palladium-catalyzed additions of nitrogen pronucleophiles to alkylidenecyclopropanes, shown in Scheme 35 <05JOC5932> R1
123
NH2
R2
R1 5 mol% Pd(PPh3)4 15 mol% P(O)n-Bu3 120 °C 70-86%
124
H N
R2
R1 = 4-Cl, 3-Me, H R2 = Ph, 2-ClC6H4, Me
Scheme 35 6.1.3.2 Reactions of Quinolines Functionalization of quinoline at the 2-position via the activation of the quinoline nitrogen was the focus of various reports in the last year. Yadav et al. reported that alkynes could be added to quinoline activated with ethyl chloroformate via C-H activation at room temperature to make 2-alkynyl-1,2-dihydroquinoline 125 <05TL8905>. The same group also reported the novel addition of indoles to quinoline activated with ethyl chloroformate using CeCl3·7H2O to provide 2-(3-indolyl)-1,2-dihydroquinolines 126 (Scheme 36) <05SL2811>. Similarly, Yoon et al. described a novel method for the synthesis 2-substituted-1,2-dihydroquinolines. The desired 2substituted-1,2-dihydroquinoline 127 was synthesized using the Petasis reaction through the in situ activation of quinoline with diethyl pyrocarbonate <05TL3053>.
327
Six-membered ring systems: pyridines and benzo derivatives
1. ethyl chloroformate CH2Cl2 2. CuI, i-Pr2NEt, CH2Cl2
N EtO
Ph
O
H
1. ethyl chloroformate CH3CN 2. CeCl3·7H2O
N
EtO
N H
1. diethyl pyrocarbonate CH2Cl2 2. B(OH)
125, 90%
N
Ph
O
NH
126, 85%
2
O O
N EtO
O
127, 96%
Scheme 36 A new phase-transfer catalyzed asymmetric glycolate aldol reaction was reported that provides diols in low to good yields, high de, and moderate to good ee as illustrated in Scheme 37. The recystallization of diol products could enrich the ee to 95%, additionally, the authors used 128 (R = Ph) to synthesize a known (S,R)-diol methyl ester to show utility of this new method <05OL3861>. TMSO DPMO
OMe
129 OMe
130 (20 mol%) RCHO, THF -55 °C , 24 h CsF, H2O
OH
O
R DPMO 128
OMe
OMe R = Ph, 76%, >99/1 de, 80% ee R = 2-OMeC6H4, 70%, >99/1 de, 77% ee R = Naphthyl, 69%, >99/1 de, 79% ee
HF2N N 130
F
F F
Scheme 37 The enantioselective hydrogenation of quinolines continues to be an area of interest. Recently, a new air-stable Ir-(P-Phos) complex ([Ir(COD)Cl]2/(R)-P-Phos/I2) was shown to reduce quinoline derivatives in high yield and high ee in THF at room temperature under an H2 atmosphere. The group also showed that this catalyst complex could be immobilized in polyethylene glycol dimethyl ether (DMPEG) in hexanes to give high yields and high ee. Additionally, the immobilized catalyst could be recaptured and reused with very little or no effect on yield or ee over eight catalytic runs <05CC1390>. Hayashi et al. presented a high yielding and highly enantioselective rhodium-catalyzed 1,4-addition of arylzinc reagents in the presence of chlorotrimethylsilane to furnish a variety of 2-aryl-2,3-dihydro-4-quinolones 131 (Scheme 38) <05OL5317>.
328
H.L. Fraser, M.B. Floyd and D.W. Hopper ArZnCl [RhCl(C2H4)2]2 (7.5 mol % Rh) (R)-binap (8.2 mol %)
O
N CO2Bn
R1
O
Me3SiCl (3.0 eq),THF, 20 °C , 20 h; then 10% HClaq R1 = H, 6-Cl, 5,7-OMe, 6,7-OCH2OAr = C6H5, 3,5-CH3C6H4, 2-CH3C6H4, 4-OMeC6H4, 4-FC6H4, 2-naphthyl
132
R1
N Ar CO2Bn 131 72-100% 86-99% ee
Scheme 38 Comins et al. presented the synthesis of 4-substituted-2-bromoquinolines in good yields via a regioselective lithium-halogen exchange of 2,4-dibromoquinoline and treatment with a variety of electrophiles (MeI, I2, TMSCl, PhCHO, H2O and DMF) <05TL6697>. The regioselectivity they found for the quinoline core was identical to that seen for the pyridine core. Collis and coworkers reported a study involving the Diels-Alder reaction of 7,8-quinolyne with furan dienes <05TL3653>. In an effort to extend their results using 7,8-quinolyne as a dienaphile, Collis and co-workers are investigating the effectiveness of the in situ generation of 7,8-quinolyne and its use in Diels-Alder reactions. Selvero and co-workers <05SL2755> presented an interesting synthesis of 2,4dialkoxyquinolines. Using an operationally simple mild and efficient one-pot process that employed silver carbonate as the base, they were able to synthesize a series of 2,4dialkoxyquinolines in good yield at room temperature. 6.1.4
ISOQUINOLINES
6.1.4.1 Preparation of Isoquinolines The synthesis of 6-amino-11,12-dihydrobenzo[c]phenanthridine 133 and 6-aminobenzo[c]phenanthridine derivatives 134 was accomplished in a very straightforward approach by the condensation of 2-methylbenzonitrile 135 with aromatic aldehydes 136 resulting in the 6amino-11,12-dihydrobenzo[c]phenanthridine derivatives 133. Dehydrogenation of the dihydro derivatives using DDQ yielded the 6-aminobenzo[c]phenanthridine derivatives 134 in Scheme 39 <05S1052, 05JMC2772, 05AG(I)635>. R
R O R
H 136
+
CN KO(t-Bu) DMPU
2 135
35-40 °C 11 - 55 %
N 133
NH2
DDQ 1,4-dioxane 14 - 38 %
N 134
NH2
Scheme 39 Rutjes and co-workers developed an efficient method to construct αvinyltetrahydroisoquinolines through a palladium-catalyzed allylic N,O-acetal
329
Six-membered ring systems: pyridines and benzo derivatives
formation/aromatic cyclization sequence. As illustrated in Scheme 40, the allylic N,O-acetals 137 lead to the allylic iminium ion 138 using a Lewis or protic acid catalyst followed by the cyclization to form the α-vinyltetrahydroisoquinolines 139 <05JOC5519>. R acid CH2Cl2
OBn N PG
R
R
R1
65 - 99%
N PG
137
R1
PG
N
138
139
Scheme 40 A variety of reports using organometallic reagents to construct assorted isoquinoline derivatives were described in the literature this year. Several substituted isoquinolines were synthesized through a nickel-catalyzed annulation of 2-iodobenzaldimines 143 with alkynes 144, illustrated in Scheme 41. The majority of the reactions in this paper involved imine 143 with a variety of alkynes to give the desired isoquinoline derivatives in good to high yield <05OL5179>. Similarly, 4-fluoroalkylated isoquinolines were synthesized using a palladium catalyzed (Pd(PPh3)4, Na2CO3, DMF, 100 °C, 8h) annulation reaction of fluoroalkylated alkynes with various 2-iodobenzylidenamine derivatives <05JOC10172>. In their report, Konno et al. used an assortment of trifluoromethylated alkynes and differently substituted 2iodobenzylidenamine derivatives to construct isoquinoline derivatives in good yields.
N I 143
+
R1
R2 144
NiBr2(dppe) CH3CN, Zn 80 °C
N R2 R1
140-142 140, R1, R2 = Ph, 92% 1 2 141, R , R = Et, 87% 142, R1 = CO2Et, R2 = Ph, 92% (86:6)
Scheme 41 Recently, the Pictet-Spengler cyclization was run in supercritical carbon dioxide/CO2expanded liquid media to make tetrahydroisoquinoline derivatives in good yields <05CC4465>. Additionally, a one-pot three-component cyclocondensation reaction, using the inexpensive and nontoxic KAl(SO4)2•12 H2O as a Lewis acid catalyst, was described by Azizian et al. The advantages of this method include high yields, the ability to recycle the catalyst and easy experimental workup <05JOC350>. Surprising to the authors, this method was stereoselective for the synthesis of cis-isoquinolonic acid 145, for which there was no evidence for the formation of trans-isoquinolonic acid (Scheme 42).
330
H.L. Fraser, M.B. Floyd and D.W. Hopper O O O
PhNH2 +
+
PhCHO
N
Lewis acid CH3CN, rt 88%
O
145
Ph
H Ph H CO2H
Scheme 42 Procter et al. presented an interesting fluorous-phase Pummerer cyclative-capture method for the synthesis of tetrahydroisoquinolinones and other nitrogen heterocycles <05AG(I)452>. Treating the desired glyoxamide 146 with C8F17CH2CH2SH results in hemithioacetal formation followed by activation with trifluoroacetic anhydride and treatment with BF3-OEt2. One of the advantages of the fluorous tag other than triggering the Pummerer cyclization is the ability to rapidly purify the products with fluorous solid-phase extraction (FSPE). Additionally, these tetrahydroisoquinolinones 148 can be further modified and the fluorous tag can be removed under mild conditions to form 149 as shown in Scheme 43. In another report, 1benzoyltetrahydroisoquinoline derivatives were synthesized by means of a Pummerer-type reaction using polymer-supported bis(trifluoroacetoxyiodo)benzene (PSBTI) followed by a Pictet-Spengler reaction starting from α-benzoyl sulfide and N-benzenesulfonyl-βphenethylamine <05H1881>. O R
N
RF O OMe
1. RF-SH, CH2Cl2, 18 hr 2. (CF3CO)2O, 1 h
O
3. BF3-OEt2, 1 h
R
OMe
146
S
OMe OMe
N
OMe 147
60%
OMe 85%
RF-SH
= C8F17CH2CH2SH R = n-pentyl Bn
R
RF Bn S
OMe
O
OMe N
OMe
LHMDS, THF -78 °C 7 h, BnBr
SmI2 76%
149
O R
OMe OMe
N 148
OMe
Scheme 43 Both 4-arylisoquinolinium perchlorates 150 and 4-arylisoquinolin-1-ones 151 were synthesized using a novel method that incorporated HClO4-FeCl3 for the first time as a cyclization catalyst and oxidation reagent <05SC2435>. Aminoketones 152 can be converted to the 4-arylisoquinolin-1-ones 151 in good to high yields via the 4-arylisoquinolimium perchlorates 150 as shown in Scheme 44
331
Six-membered ring systems: pyridines and benzo derivatives R3
R1 O R2
O HClO4-FeCl3 N rt; 16 h R 62 - 85% 152
R3
R3
R1
1. KOH N 2. K3[Fe(CN)6] R 93 - 99% ClO4-
O R2
R = Me, Et, n-Pr, n-Bu, Bn R1, R2, R3 = H, MeO
R1 N
O
R
R2
150
O 151
Scheme 44 6.1.4.2 Reactions of Isoquinolines The annulation reaction of 3,4-dihydroisoquinoline 1-carboxylate 153 and ethyl 4bromobutyrate 154, ethyl 3-bromopropionate 155 and ortho-bromomethyl benzoate 156 to make isoquinoline heterocycles 157-159 was reported (Scheme 45). This reaction was found to proceed best using 2 equivalents of potassium tert-butoxide (KO-t-Bu) as base in degassed DMF at -60 °C in good yields <05T5037>. In another report, C2-symmetric secondary amines were employed as organocatalysts for the diastereo- and enantioselective annulation reaction of 2-(5oxopentyl)isoquinolinium derivatives. In general, the yields that were reported were poor to good, the diastereoselectivities were high (d.r. ≥10:1) and the enantioselectivities were also high <05AG(I)6058>. O CO2Et Br
154 CO2Et
O N
O 153
Br
CO2Et
O
155
N
O
N
O
N
O
EtO2C 157, 69%
O KO-t-Bu, DMF -60 °C
O
CO2Et Br
EtO2C 158, 75%
O 156
O
EtO2C 159, 80%
Scheme 45 A variety of metal mediated or catalyzed reactions involving isoquinoline derivatives were reported in the literature over the past year. An efficient method for the reductive amination of tetrahydroisoquinoline was performed in the presence of Ti(Oi-Pr)4 and NaBH4 to make a variety
332
H.L. Fraser, M.B. Floyd and D.W. Hopper
of N-alkyl tetrahydroisoquinoline derivatives in good yields <05S2205>. Additionally, a copper catalyzed cross-dehydrogenative coupling (CDC) of indoles and tetrahydroisoquinolines in the presence of t-butyl hydrogenperoxide was presented. This method is highlighted by the fact that it was performed using unprotected indoles and the reaction was not sensitive to moisture <05JA6968>. Multicomponent reactions (MCR) were also highlighted in the literature. The reaction of dimethyl butynedioate 160 and benzylidenemalononitrile 161 in anhydrous THF with isoquinoline at room temperature gave a mixture of two diastereomers 162 and 163 (2:1) in 81% yield (Scheme 46) <05TL5333>. Isoquinoline was also used in a MCR that included methyl chloroformate and morpholinyl-α-isocyano-β-phenylpropionamide resulting in the synthesis of (1,3-oxazol-2-yl)-1,2-dihydro(iso)quinoline derivatives in moderate yields <05SL532>. CN CO2Me N
+
+
THF, Ar, rt 23 h, 81%
CO2Me 160
H
CN NC
N H
NC
CO2Me
CN
Cl
N H
CO2Me CO2Me
CN
2:1
162
161
H
CO2Me
163 Cl
Cl
Scheme 46 A novel cyclo-condensation was reported between 1,1-bis(trimethylsilyloxy)ketene acetals 164 and isoquinolinium salts 165 <05TL8997>. This reaction resulted in the carboxylic acid 166 in moderate to good yields. Ultimately, this isoquinoline derivative 166 was used to make a series of 7,8-benzo-9-aza-4-oxabicyclo[3.3.1]nonan-3-ones 167 shown in Scheme 47. OSiMe3
R2
R1
R2 Cl-
CH2Cl2 N
ClCO2Me 0 °C , 2 h
N
R2
OSiMe3 164
N
R3
H R1
165
R3 OH
166
O R2
I N H
167
I2 (2 eq) CH2Cl2 20 °C, 12 h
H R3
O O
R1
Scheme 47 Additionally, the photolysis of an isoquinoline salt resulted in the formation of 2-methyl-1(2,3,4,5,6-pentafluorophenyl)-1,2-dihydroisoquinoline via photoinduced transfer of C6F5
333
Six-membered ring systems: pyridines and benzo derivatives
<05JOC10653>. Within their report Neckers et al. propose a mechanism based on photoinduced electron transfer of the C6F5 group. 6.1.5
PIPERIDINES
In 2005 a review by Afarinkia and Bahar which covered work on azapyranose sugars from 1998 to 2004 was published <05TA1239>. A review by Lebreton and co-workers summarized recent advances in the total synthesis of piperidine azasugars was also published this year <05EJO2159>. 6.1.5.1 Preparations of Piperidines Harrity and co-workers have developed strategies for piperidine synthesis based on [3+3] cycloaddition reactions and have published a perspective on their and the work of other groups <05OBC1349>. The construction of 6-membered nitrogen heterocycles was included in a review of the [3+3] cycloaddition approach to natural product synthesis by Hsung and coworkers <05EJO23>. A stepwise formal [3+3] cycloaddition reaction entailed the generation of the dianion of 168, transmetalation with MgBr2, and addition of aziridine 169 to give intermediate 170. A Mitsunobu reaction to give 171 completed the sequence with an overall yield of >90% <05OL2993> (Scheme 48). This strategy was applied to other aziridines in the preparation of 3methylenepiperidine intermediates for the total synthesis of several Nuphar alkaloids <05JOC207>. Me OH 168
1. BuLi 2. MgBr2 3. NTs Bn
Me
Bn NHTs
OH
169
Ph3P DIAD 94%
Me
N Ts
Bn
171
170
90%
Scheme 48 The formal [3+3] cycloaddition of vinylogous amide 172 was effected with chiral amine salts to provide 173 enantioselectively (Scheme 49). These reactions were studied with respect to solvent, counterion, and temperature effects, and the probable mechanism and absolute configuration of the products were determined <05JOC4248>. O
O
NH
chiral amine salts 26-67%
O H N 173
172
Scheme 49
334
H.L. Fraser, M.B. Floyd and D.W. Hopper
Lewis acid-catalyzed ene cyclization reactions at low temperature have been shown to yield substituted piperidines with a high diastereomeric ratio <05TL6611>. Organolanthanidecatalyzed cyclization-silylation has been developed as a powerful strategy for the piperidine rings found in alkaloids. As a prototypical example, the simple diallyl amine 174 was cyclized to 175 in the presence of 5 mol % of the catalyst shown in Scheme 50 and a suitable silane terminator <05T2631>. SiHPhMe
Cp*LuMe.THF PhMeSiH2
MeN
MeN
83%
174
175
Scheme 50 A stereoselective synthesis of 2,3,5,6-tetra- and 2,3,4,5,6-penta-substituted piperidines was achieved from oxidative cleavage of 2-azabicyclo[2.2.2]octane Diels-Alder adducts 176 derived from dihydropyridine 177. Appropriate functional group interconversions of the amidine and ester functionalities in 176 ultimately gave densely functionalized piperidines such as 178 <05OL5773> (Scheme 51). O N
Ph
+
N
O
1.CH2Cl2, 25 °C 2. SOCl2, MeOH 95%
O
177
Ph
OBn
OH
N
OBn N
N H 178
CO2Me 176 CO2Me
OH
Scheme 51 The aza Diels-Alder reaction has been extensively examined as a route to 2-substitited 2,3dihydropyridin-4(1H)-one derivatives. The iodosiloxydiene 179, generated from 3-butyn-2-one and TMSI, was reacted with various N-aryl- and N-benzylimines, including the chiral examples 180 derived from (S)-α-methylbenzylamine. The product 181 was obtained in good yield with ~3:1 to 4.5:1 diastereoselectivity (Scheme 52) <05T11837>. In a solid-phase method, Rinkamide-Resin bound imines were prepared and reacted with Danishefsky’s diene 182 to provide dihydropyridin-4(1H)-ones after cleavage from the resin with TFA <05T205>. O
TMSO
Me + I
R
N 180
Ph
MgI2 CH2Cl2, 0 °C 61-85%
179
R
181
N Ph
Me
Scheme 52 A Yb(OTf)3-catalyzed three-component aza Diels-Alder reaction of a diene with aldehydes and benzhydrylamine to provide 2,5-disubstituted 2,3-dihydro-4-pyridones has been developed <05SL1018, 05T9594>. A catalytic asymmetric aza Diels-Alder reaction of acylhydrazones 183
335
Six-membered ring systems: pyridines and benzo derivatives
and Danishefsky’s dienes 182 and 184 to provide 185 has been developed (Scheme 53). The method was used in a synthesis of (S)-(+)-coniine 186 <05TL1803>. N R
H N H
Ar O
TMSO + OR1
183
H N
Ar Zr(OPr)4-"BINOL" catalyst toluene, 0 °C 53-90%
O
HN
N
R
O 185
182, R1 = Me 184, R1 = t-Bu
186
Scheme 53 Intramolecular iminoacetonitrile [4+2] cycloaddition has been exploited in the synthesis of quinolizidine alkaloids (Scheme 54). The intermediate 187 was generated by elimination of trifluoromethanesulfinate from 188 and underwent the desired aza Diels-Alder reaction to give 189. A series of steps which included reductive decyanation, alkylation with (Z)-3-bromo-1chloropropene, classical resolution, and Sonogashira coupling provided the alkaloid (-)-217A 190 <05OL3115>. H
NC
Cs2CO3
Me
NTf
85-92% 188
OSiR3
N NC
Me OSiR3 187
130 °C 36 h 55-59%
Me
H
OSiR3
N 189
Me
N CN
190
Scheme 54 The preparation and study of polyhydroxylated piperidines and indolizidines as glycosidase inhibitors continues to be an area of intense interest. Ingenious routes to these compounds from chiral, polyolefinic precursors which employ olefin metathesis as the key step have been devised. The diene 191 (known absolute configuration) on ring closing metathesis (RCM) gave 192, which was carried on to 193. The last substance displayed the opposite sign of optical rotation to natural 1-deoxygulononojirimycin, which necessitates a revision of its absolute configuration <05T1413> (Scheme 55). OH OBz
OBz "Ru" CH2Cl2, 25 °C N Boc 96% OTBDPS 191
N Boc 192
OTBDPS
HO
OH N H
OH
193
Scheme 55 The racemic 5-hydroxy-3-piperidene derivative 194, prepared by RCM of 195, was resolved to provide both enantiomers with >99% ee through lipase-catalyzed transesterification (Scheme
336
H.L. Fraser, M.B. Floyd and D.W. Hopper
56). These were converted to several target structures including all four isomers of 3,4,5trihydroxypiperidine <05JOC5207>. HO
HO
"Ru" CH2Cl2, 25 °C
N Boc
N Boc
99%
195
194
Scheme 56 Enantioenriched 196 was prepared by ring rearrangement metathesis (RRM) of 197. Through the agency of regio- and stereo-controlled hydroxylation reactions, (+)-castanospermine 198 and both isomers 199 of the pentahydroxylated indolizidine uniflorine-A of putative structure 200 were prepared as shown in Scheme 57 <05T8888>. N
HO OBn
AcN "Ru" OTBS CH Cl 2 2, reflux sat C2H4
BnO
Ac N
HO
HO
OH OH
H TBSO
93%
197
198
H
N
HO H
HO
HO
196
199
N
HO H HO
OH OH 200
OH OH
Scheme 57 Carbamate 201, available in both chiral forms, was converted to piperidine 202. The (-)-202 was converted to deoxymannojirimycin 203, and the antipode was converted to swainsonine 204 <05JOC2325> (Scheme 58). A similar reaction was accomplished with unprotected triols via RCM to give useful precursors of various indolizidines <05OBC2626>. HO
H N
O
"Ru" CH2Cl2, 25 °C 99%
HO
H N
O 201
202
HO O O
HO HO
HO
H
H O
OH NH 203
N
OH
204
Scheme 58 Bioactive piperidines of other types have been prepared expeditiously using the RCM methodology (Scheme 59). The N-acylallylamine 205 was subjected to RCM to give 206. Further transformations provided the (-)-enantiomers, 207 and 208 respectively, of the NK1 receptor antagonists (+)-CP-99,994 and (+)-L-733,060 <05TL8927>.
337
Six-membered ring systems: pyridines and benzo derivatives CF3 MeO
O NBn Ph
Ph
"Ru" CH2Cl2, reflux O 94%
205
CF3
Ph
N Bn
NH
206
N H
O
Ph
N H
207
Ph 208
Scheme 59 The tetraene 209 undergoes a double RCM reaction to provide a mixture of 210 and 211 (Scheme 60). Intermediate 210 is converted in three steps to the NK1 receptor antagonist 212. A detailed study of reaction variables has clarified the mechanistic details and allowed prediction of the stereochemical outcome <05TL591>. HO O
O
O
"Ru" various N Ts 209
Ph
O
+ N Ts
Ph
N Ts
Ph
N H
Ph
211
210
OCF3
212
Scheme 60 Other bicyclic piperidine derivatives have been prepared by olefin metathesis reactions (Scheme 61). The perhydroquinoline (+)-trans-195A 213 was synthesized via a RRM reaction of 214. The chirality transfer to the product 215 was essentially complete and permitted assignment of the absolute configuration to the natural product <05OL1227>.
o-Ns
N
214
"Ru" CH2Cl2, 50 °C sat C2H4 96%
Me H N o-Ns 215
N H H 213
Scheme 61 An interesting series of 2-trifluoromethyl-tetrahydropyridines was prepared by RCM of diene precursors, exemplified by the conversion of 216 to 217 in 98% yield with 98% de <05EJO1258> (Scheme 62).
338
H.L. Fraser, M.B. Floyd and D.W. Hopper F 3C * Ph
F3C *
"Ru"
N
CH2Cl2, 25 °C
Ph
98%
CH2OMe
N CH2OMe
216
217
Scheme 62 Access to piperidines through the intermediacy of 4-piperidones continues as a useful concept. A simple, diastereoselective route to 2,3,6-trisubstituted 2,3-dihydro-4-pyridones 218 from linear diketoester 219, aryl aldehydes, and ammonium acetate has been developed <05TL5511> (Scheme 63). O O
O
O CO2Me +
Me
Ar
NH4OAc
H
MeO2C
43-80%
219
Ar
N H 218
Me
Scheme 63 Certain “deactivated” aromatic aldehydes on reaction with acetone in NH3/MeOH gave 2,2dimethyl-6-aryl-4-piperidones <05TL8685>. A study of the enantioselective, copper/phosphoramidite-catalyzed conjugate addition of dialkylzinc reagents to Nalkoxycarbonyl-2,3-dehydro-4-piperidones has afforded the corresponding 2-alkyl-4-piperidones with enantiomeric excess in the range of 59 to 97% <05CC1711>. A double Mannich reaction of bis(alkoxymethyl)alkylamines 220 and cyclic β-ketoesters, for example 221, gave bicyclic products such as 222 in high yield as shown in Scheme 64 <05EJO2385>. O
O EtO
R N
CO2Et OEt +
MeSiCl3 MeCN, 25 °C
CO2Et
R N
75-79% 220
221
222
Scheme 64 O
O Me
88%
N MeO
O
N H MeO
BnO OBn
O
TiCl4 CH2Cl2, 0 °C
BnO OH
223
224
Scheme 65 Chiral imines have been shown to undergo intramolecular Mannich reaction to give the tetrasubstituted 4-piperidones <05JACS8398> (Scheme 65). A Mannich-type cyclization of
339
Six-membered ring systems: pyridines and benzo derivatives
ketal 223 to the cis-2,6-disubstituted 4-piperidone ketal 224 was a key step in the synthesis of (+)-abresoline <05TL2669>. Conditions for the intermolecular aza-double Michael reaction of acrylamides leading to functionalized 2-piperidones have been developed, as exemplified by the conversion of 225 to 226. Of particular interest was the use of a cross reaction of amide 227 with methyl acrylate to give 228. This 2-piperidone was readily converted to (+)-paroxetine 229 (Scheme 66) <05JOC3957>. O NHR
R N NHR
80-90%
225 O
O
226
Bn N
1. TBSOTf TEA 2. NaOMe
NHBn
O
TMSI HMDS
O H N O
CO2Me
O O
58%
F 227
F
228
F
229
Scheme 66 The reaction of diethyl aminomethylenemalonate 230 with ethyl acetoacetate catalyzed by HCl affords the 2-piperidone 231 instead of the 4-piperidone 232 as previously reported <05SC2993> (Scheme 67). EtO2C
CO2Et NH2
O Me
O
EtO2C
CO2Et
CO2Et Me
230
N H 231
O
N H
Me
232
Scheme 67 The synthesis of D-gluco-, L-ido-, D-galacto-, and L-altro-configured glycaro-1,5-lactams from tartaric acids was accomplished. The key conversion is exemplified by the formation of protected D-glucarolactam 233 from the azide 234 via lactamization of the primary amine formed on hydrogenation (Scheme 68). The same strategy was used in the other configurational series <05TL3619>.
340
H.L. Fraser, M.B. Floyd and D.W. Hopper O H N3
H2 Pd/CaCO3
O
EtO H
O
BnO
O
NH
HO BnO
EtOH 65%
OBn
OEt
O
OBn
234
233
Scheme 68 A SmI2-promoted reductive deamination of methyl prolinate derivative 235 to a δ-aminoester, followed by spontaneous recyclization to lactam 236, was exploited in the synthesis of several lupine alkaloids (Scheme 69) <05JOC499>. SmI2 THF/HMPA/MeOH
MeO 235
N H
0-25 °C 78%
CO2Me
MeO O
N H
236
Scheme 69 Among the interesting uses of N,S-ketene acetals discovered was the aza-annulation of 237 with 238 to provide the 2-piperidone 239 in 80% yield (Scheme 70) <05SL1437>. O2N O2N MeS Ph
NH
O
+ O
237
O
MeCN, Δ 8-10 h 80%
MeS Ph
238
OH N
O
O
239
Scheme 70 Heating a mixture of N-benzyl-γ-chloropropylamine 240 with conjugated alkynoates 241 in the presence of NaI and Na2CO3 affords substituted piperidines 242 in good yields, as shown in Scheme 71 <05JOC7364>. Cl + NHBn.HCl
n-C5H11
NaI Na2CO3
CO2Et
i-PrOH, reflux 241
91%
CO2Et N Bn
n-C5H11
242
240
Scheme 71 A stereoselective aldolization of 243 gave 244 in 78% yield. It was shown that the C-2 epimer was also formed, but this suffered dehydration and permitted a simple isolation of 244 (Scheme 72) <05OL4851>.
341
Six-membered ring systems: pyridines and benzo derivatives O
Me2PhSi
CHO
DBU
TsN MeO2C
O
Me2PhSi
OH TsN
78%
CO2Me
244
243
Scheme 72 Reaction of racemic aldehyde 245 with chiral 246 resulted in formation of the lactam 247 with 9:1 stereoselectivity in 78% yield. A dynamic kinetic resolution with epimerization of the labile stereocenter in 245 was proposed (Scheme 73) <05CC1327>. MeO
O
CHO
Ph
+
Et
H2 N
245
OCHPh2
Ph
OCHPh2
246
N
O
toluene reflux 78%
OH
O Et
247
Scheme 73 Piperidines with contiguous quaternary and tertiary stereocenters (for example 248) have been prepared in high enantiomeric purity by intramolecular conjugate addition of enolates generated from α-aminoacid (for example 249 derived from phenylalanine) derivatives (Scheme 74). An axially chiral enolate intermediate was proposed <05OBC1609>. Ph
CO2Et
CO2Et
Ph
BocN
CO2t-Bu
KHMDS
CO2t-Bu
BocN
66%, 97% ee
249
248
Scheme 74 The chiral Betti base 250, as a salt with L-(+)-tartaric acid, reacted with pentane-1,5-dial and benzotriazole to form diastereopure 251 in 92% yield. Sequential replacement of the Bt and aryloxy substituents of the piperidine ring with Grignard reagents, followed by hydrogenolytic removal of the chiral auxiliary, gave optically pure 252 (Scheme 75) <05JOC1897>. Bt Ph
NH2 OH
OHC
Ph
N
OHC
O
BtH 250
1. MeMgCl 2. RMgBr 3. H2
251
Scheme 75
86-89% overall
Me HN R 252
342
H.L. Fraser, M.B. Floyd and D.W. Hopper
The utility of cascade generation and intramolecular trapping of iminium ions by allylsilane groups has been demonstrated in the conversion of 253 and 254 to the configurationally pure quinolizidines 255 <05OL2031> (Scheme 76). Me3Si
OHC
2. TFA MeO OMe
253
H
1. MeCN, 4Å sieves
+
NH2
R = H, 75% R = CN, 79%
N
3. Et3SiH or NaCN
254
255
R
Scheme 76 A similar concept was used in the synthesis of the indolizidine alkaloid tashiromine <05SL2528>. Aliphatic aldehydes react with the chiral vinylsilane 256 in an InCl3-induced azasilyl-Prins reaction to provide 2,6-trans tetrahydropyridines 257. Hydrogenolysis gave the natural products (-)-solenopsin A (R = n-C11H23) and (+)-epi-dihydropinidine (R = n-Pr), 258 (Scheme 77) <05SL2101>.
Me
SiMe3 RCHO InCl3 NHBn MeCN 58-72% 256
H2 Me
N Bn
R
100%
Me
N H
257
R
258
Scheme 77 An intramolecular Pd(0)/benzoic acid-catalyzed hydroamination of acetylene 259 afforded the indolizidine 260 as a single diastereomer. Saturation of the double bond gave the alkaloid (-)209D <05TL2101> (Scheme 78). H N H n-C4H9 259
Pd(TPP)4 PhCO2H-TEA dioxane, 100 °C n-C4H9 74%
H N
260
Scheme 78 In the first total synthesis of pseudodistomin D 261, the 1,2-diamine 262 of known absolute configuration was prepared and cyclized to 263 by sequential hydroamination and in situ imine reduction. The absence of any pyrrolidine product formation was rationalized mechanistically (Scheme 79) <05OL823>. A high-yield intramolecular hydroamination protocol has been developed for sulfonyl-protected primary aminoalkynes and application to piperidine synthesis
343
Six-membered ring systems: pyridines and benzo derivatives
was demonstrated. A catalytic amount of Pd(TPP)4 and TPP was employed, and no carboxylic acid proton source is necessary <05JOC4883>. OR OTBS 3
3
NH2
262
NH2
1. AgOTs 2. NaBH3CN 52%
3
N H
3
263, R = TBS 261, R = H
NH2
Scheme 79 Ring expansion reactions of 2-substituted pyrrolidines, with the intermediacy of a bicyclic aziridinium ion, has provided new piperidines. Treatment of the chiral olefinic imine 264 with Br2, followed by reduction of the resultant ion 265 results in the formation of a separable mixture of spiromethylpyrrolidines and a single spiropiperidine 266 (23% yield), a precursor of (-)nitramine 267 (Scheme 80) <05SL1726>. OBn
N Bn H
OBn Br2 CH2Cl2
N
OR
Bn LAH
Br
0 °C 95%
N
23%
266 267, R=H
265
264
R
Scheme 80 Sequential treatment of the prolinol 268 with TFAA, Et3N, and NaOH resulted in isomerization to 269 in 70% yield and a dr > 95% (Scheme 81) <05SL1170>. Ph Ph OH N Me
Ph
OH
1. TFAA 2. TEA 3. NaOH 70%
268
N Me
Ph 269
Scheme 81 The strategy for piperidine formation which relies on generation of a primary amine in an acyclic precursor with a favorably disposed carbonyl group has been the subject of much interesting work. The conjugate addition of N-sulfinyl metalloenamines to enones gave 270, which were readily converted to piperidines 271 with favorable diastereoselectivity by sequential stereoselective reduction, N-deblocking, cyclization, and imine reduction (Scheme 82) <05JOC7342>.
344
H.L. Fraser, M.B. Floyd and D.W. Hopper
S
O
R2
N
1. L-Selectride or NaBH4-Ti(OEt)4
O
R1
2. HCl 3. base 4. DIBAL-H
R3 270
R2 * R1
N H
*
R3
271
Scheme 82 The cyclohexenone 272, derived from L-alanine, was subjected to hydrogenation to give a 2:1 mixture of cis- and trans-fused perhydroquinolines 273 <05T8264> (Scheme 83). O
Me
H
H2 Pd(OH)2
NBn2
90%
OAc
OAc
N H H
272
Me
273
Scheme 83 A synthetic method for aza-C-glycosides, exemplified by the conversion of 274 to 275, has been described. In this case the primary amino group generated undergoes a conjugate addition to an enone intermediate (Scheme 84) <05T11716>. N3
O
O
1. H2 2. NaOMe
OBnOBn
75%
274
HO
NH OBnOBn
O
275
Scheme 84 The Boc-derivatives of primary amines readily participate in piperidine ring-forming reactions when an electrophilic center is generated under suitable conditions. Reaction of acetonide alcohol 276 as shown in Scheme 85 gave the Boc-derivative of (+)-α-conhydrine 277 <05TL4091>. O OH N
Boc
MsCl Et3N
OH
-78 °C 88%
Boc
N 277
276
Scheme 85 Treatment of the olefin 278 with catalytic OsO4 and NaIO4 in the presence of 2,6-lutidine gave the carbinolamine 279, which was reduced to 280 as shown in Scheme 86 <05TL7221>.
345
Six-membered ring systems: pyridines and benzo derivatives
This protocol was used in the synthesis of both (2S, 3R)-3-hydroxypipecolic acid 281 and (2S, 3S)-3-hydroxypipecolic acid 282 from D-serine <05JOC10182> Boc NH
Ph
OsO4 NaIO4
TBSO
Ph
2,6-lutidine 69%
278
Boc N OH Et3SiH BF3.Et2O 85%
TBSO 279 OH
TBSO 280
OH
CO2H
N H
Boc N
Ph
N H
281
CO2H 282
Scheme 86 3-Hydroxypipecolic acid is a structural moiety found in many compounds of medicinal interest. Using Sharpless asymmetric oxidation techniques both enantiomers of the trans-form (283 and 284) of this compound were synthesized from 1,4-butanediol. The piperidine ringforming steps used (285 to 286 and 287 to 288) are shown in Scheme 87 <05JOC360>. Ph O
1. DDQ 2. MsCl
O
MsO
3. H2 4. Boc2O
N3
OTBS
283
OH N Boc
2. Boc2O
287
CO2H
N H
286
1. Ph3P THF-H2O
O
OH
OH
N Boc
59%
285
N3
OH
48%
OH
OTBS N H
288
CO2H 284
Scheme 87 Benzenesulfonylaldimines 289 underwent 3-hydroxyquinuclidine-catalyzed Morita-BaylisHillman reaction with diene 290 to give adducts 291 as an E/Z mixture. The E-isomers cyclized to functionalized piperidines 292 on treatment with base, while the Z-isomers did not. However, simultaneous irradiation with UV light at 300 nm effected photoisomerization to afford high yields of 292 from the 291 mixture (Scheme 88) <05OL2377>. HN N R
Ts
SO2Ph
catalyst
+ H
289
SO2Ph Ts
R
DMF 290
291
Scheme 88
K2CO3 DMF-H2O hν 72% overall
R PhO2S
Ts
N 292
346
H.L. Fraser, M.B. Floyd and D.W. Hopper
N-Tosylaldimines 293 reacted with excess allene 294 in the presence of tertiary phosphine promoters to give a mixture of 295 (major) and 296 (minor). The “normal” Morita-BaylisHillman adducts 297, which were formed on catalysis by DMAP, were not intermediates in the formation of the piperidines. A mechanistic rationale for the different reactions was presented (Scheme 89) <05OBC3686>. Ar
Ts N
Ar
296 Ts N
O NHTs Ar
294
DMAP 40-81%
N
O 297
Ts
Bu3P 52-94%
O
Ar
Ar 293
295
O
Scheme 89 6.1.6
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Six-membered ring systems: pyridines and benzo derivatives 05CC1390 05CC1711 05CC2591 05CC4465 05CC4672 05CCR727 05CEJ5742 05EJM209 05EJM1087 05EJM1163 05EJO23 05EJO1258 05EJO1397 05EJO1834 05EJO1903 05EJO2159 05EJO2385 05H1881 05JA605 05JA834 05JA3473 05JA5030 05JA6968 05JA8398 05JA10568 05JA15644 05JA18020 05JAMC135 05JCO96 05JCO490 05JCO526 05JCO688 05JCO879 05JHC463 05JMC2045 05JMC2772 05JMC3930 05JMC5749
347
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Six-membered ring systems: pyridines and benzo derivatives 05OL1227 05OL2031 05OL2377 05OL2675 05OL2941 05OL2993 05OL3115 05OL3219 05OL3609 05OL3817 05OL3861 05OL4009 05OL4737 05OL4851 05OL5043 05OL5047 05OL5059 05OL5179 05OL5281 05OL5317 05OL5401 05OL5457 05OL5737 05OL5773 05OPRD646 05P1804 05S1052 05S2205 05S3423 05SC2435 05SC2993 05SL99 05SL532 05SL623 05SL649 05SL1018 05SL1170 05SL1188 05SL1389 05SL1437 05SL1726 05SL1758 05SL2057 05SL2101 05SL2357 05SL2388 05SL2528 05SL2653 05SL2755 05SL2811 05SL2948 05T205 05T1413 05T2631
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350 05T2779 05T3261 05T4761 05T5037 05T6330 05T8148 05T8264 05T8888 05T9594 05T11716 05T11837 05TA1239 05TA3536 05TL125 05TL581 05TL591 05TL767 05TL1521 05TL1647 05TL1791 05TL1803 05TL2101 05TL2279 05TL2361 05TL2669 05TL2817 05TL3053 05TL3423 05TL3493 05TL3573 05TL3619 05TL3653 05TL3683 05TL4091 05TL4487 05TL4539 05TL4851 05TL5333 05TL5511 05TL6611 05TL6697 05TL6953 05TL7169 05TL7221 05TL7249 05TL7669 05TL8599
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352
Chapter 6.2
Diazines and benzo derivatives
Unfortunately, the chapter on diazines and benzo derivatives does not appear in this volume. We apologise for this omission. We anticipate that PHC 19 will include two chapters on this area; one to cover the literature of 2005 and one that of 2006.
353
Chapter 6.3
Triazines, tetrazines and fused ring polyaza systems Pilar Goya and Cristina Gómez de la Oliva Instituto de Química Médica (CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain e-mail:
[email protected]
6.3.1
TRIAZINES
6.3.1.1 1,2,3-Triazines Very few publications have dealt with 1,2,3-triazines. Worth mentioning is a report concerning pyrolysis of 1,2,3-triazines. FVP pyrolysis of 1-acylnaphtho[1,8de][1,2,3]triazines 1 gave exclusively the corresponding 2-substituted naphtha[1,8de][1,3]oxazines 2. These compounds were also obtained by static pyrolysis in lower yield and together with the corresponding (N-napthalen-1-yl)acylamides 3 <05T10507>. O N
N
N
O
R R
O
N
HN
R
pyrolysis
1
2
3
6.3.1.2 1,2,4-Triazines The synthesis of 6,6’-bis-(5,6-diethyl[1,2,4]triazin-3-yl)-2,2-bipyridyl, the first example of a new class of tetradentate reagent for the efficient separation of americium(III) and europium(III) has been described <05ICC239>. The synthesis and characterization (including X-ray) of Cd(II), Zn(II), Pb(II), Co(III) and Ni(II) complexes of 5-methoxy-5,6-diphenyl-4,5dihydro-2H-[1,2,4]triazine-3-thione have been reported <05POL1435>. The reactions of 3-amino-2-(2-alkylthio-4-chlorobenzenesulfonyl)guanidines 4 with 1,2dicarbonyl compounds have been reported. Depending on the structure of the 1,2-dicarbonyl
354
P. Goya and C. Gómez de la Oliva
reagent novel N-(1,2,4-triazin-3-yl)benzenosulfonamides 5, 1-benzenesulfonyl-3-(2oxobutane-3-ylidenoimino)guanidines 6 and N-(1,2-dihydroxycyclobuta[e]1,2,4-triazin-3yl)benzenosulfamides 7 were obtained <05EJM377> R2O HO
N
HO
N 7
O
H N N
X S 2 O O R O
O
R2 = H, Et
O H2N H2N
N
X
S NH O O
R1
N
R1
N
R1
O
Cl
H N
X S O O
N
5
4
H N
HN
R4
X=
R1 = aryl
R1
R1 = methyl
S
N 6
O
X S NH O O
R3
Ring enlargement of aryl(1,2,3-triazol-1-yl) carbenes, generated from 1-[N(phenylsulfonyl)benzohydrazonoyl-1,2,3-triazoles 8, into 3-aryl-1,2,4-triazines 9 has been described <05H279>. Ar R1
N
R2
N
O S N O
R1
NaH C6H6
Ar
N
R2
N
N
9
8
Nucleophilic addition of hydrazine to the electrophilic C(5) of 3-benzoyl-5-perfluoroalkyl1,2,4-oxadiazoles 10 followed by ring opening and ring closure with enlargement led to the Z-oximes of 3-perfluoroalkyl-6-phenyl-2H-1,2,4-triazin-5-ones 11 <05JOC3288>. O N R
NH2NH2
Ph N
O
DMF R = perfluoralkyl
10
OH N Ph
N N
R NH
11
NH O
N N
H N
NH
O
O 12
Me
H2N
NH MgSO4
H2N
O
DMF
N
NH
14 (68% yield) HN
NH N
13 O
N H
N
15 (18% yield)
Triazines, tetrazines and fused ring polyaza systems
355
Cyclocondensation of suitable ketoesters 12 and amidrazone 13 afforded para- and metasubstituted bis(indole)-1,2,4-triazinones 14 and 15 respectively, the structures were unambiguously established by X-ray analysis <05TL1997>. 5-(Indol-3-yl)-2,3-dihydro-1,2,4-triazine-3-thione was prepared, its X-ray structure determined, and used for the preparation of fused triazolo- and tetrazolotriazines <05RJO875>. Silyl substituted 1,2,4-triazin-5-ones have been obtained from α-silyl-α-keto esters and thiosemicarbazide <05TL4049>. Efficient synthetic routes for 2-, 4- and 6-aryl-1,2,4-triazine-3,5-diones have been reported. Cyclization of 2,6-difluorophenylpyruvic acid 16 with 2-aryl-5,5dimethyltriazolidin-3-one under acid conditions afforded 2-aryl-6-substituted-1,2,4-triazine3,5-dione 17, cyclization of 16 with N-arylthiosemicarbazide in refluxing hydrochloric acid, followed by hydrolysis under basic conditions, yielded 4-aryl-6-substituted-1,2,4-triazine3,5-diones 18. The Suzuki reaction of 6-bromo-2,4-disubstituted-1,2,4-triazine-3,5-diones 19 with a variety of arylboronic acids afforded 6-aryl-2,4-disubstituted-1,2,4-triazine-3,5-diones 20 <05BMCL4363>. H N
O
N F
F
N
ArHN
Ar
O
N NH O
Ar
O
N H
H2SO4 (cat) Δ
1. H2N
CO2H F
F
S
HCl/ Δ
N F
F
2. KOH/MeOH
17
Ar N
O
NH
Br
R N N X
1. ArB(OH)2/Pd(PPh3)4/aq Ba(OH)2/DME/C6H6/EtOH Δ
O N F
NH
18
16
O
O
R N
O Ar
N X
2. TFA/C6H6
19 X = F, CF3
O N F
20
Microwave irradiation has been used in each step of the transformation of acyl glycines into 6-benzyl-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-5-one and its 4-phenyl derivatives <05MI415>.
R HO O
1O
H N
X
N
O
O NH
N N
21 O
N N
H N
O N
X
N
R1
O 22
NH2R2
HN NH
MW
R1 R2HN
O
H N
X
N
O 23
O NH
356
P. Goya and C. Gómez de la Oliva
Novel mesoionic structures 22 have been obtained via the internal cyclization of thio- and amino-acid derivatives of 6-azauracil 21. These compounds undergo ring-opening reactions with amines to yield the respective 6-azauracil amides 23. <05TL5325>. Cycloadditions of 2-cyclopropylidene-1,3-dimethylimidazolidine with different aryl substituted 1,2,4-triazines have been studied. At low temperatures, zwitterions (formed by nucleophilic attack on the triazines) could be detected spectroscopically and, in some cases, isolated <05HCA1491>. Aromatization and ring cyclization of 3-amino-6-hydrazino-1,2,4triazin-2-one has been studied, including the X-ray analysis of the 3-ethyl derivative of the title compound <05JHC851>. Conversion of 1,2,4-triazines into pyrimidines via an aza-Diels-Alder reaction has been used for preparing diaryl-terpyridines <05TL1521>, heteroaryl bipyridines <05TL1791> and pyridylpyridines <05CL836>. α-Chloro-α-acetoxy β-keto esters 24 reacted with amidrazones yielding 1,2,4-triazines 25 or with an amidrazone and 2,5-norbornodiene in a one-pot aza Diels-Alder reaction to give pyridines 26 <05TL6111>. R2
O
EtO2C
R2 EtO2C
R2
O Cl OAc 24
R1
H 2N H2N
EtO2C
EtO2C
R1
N N
N
R2
26
25
N
R1
N
Two novel protocols have been developed for the direct conversion of 1,2,4-triazines 27 into highly substituted pyridines 28 via the inverse-electron demand Diels-Alder reaction: a microwave-assisted solvent-free route and a tethered imine-enamine approach <05JOC10086>. R4 R2
N
R3
N 27
R1
N
R5
R4 R5
N MW, solvent-free
R5 R1
R3 N 28
R2
N R4
N R5
toluene, Δ
R4
R2
N
R3
N
R1 N
27
Transformations of 1,2,4-triazine-4-oxides to pyridazines and triazolo[4,3-b]pyridazines by the action of substituted acetonitriles have been published <05MC31>. Experimental and theoretical studies of the Diels-Alder reaction of 5-acetyl-3-methylthio-1,2,4-triazine with cyclic enamines have been carried out <05T8148>. In applications of 1,2,4-triazine derivatives, the following can be mentioned: the synthesis and biological evaluation of 1,2,4-triazinylphenylalkylthiazole carboxylic acids esters as cytokine-inhibiting antedrugs with strong bronchodilating effects has been reported <05JMC2167>; aryl-1,2,4-triazine-3,5-diones have been studied as gonadotropin-releasing hormone antagonists <05BMCL4363>; a novel class of platinum(II) complexes with 2pyridyl-1,2,4-triazine derivatives have been identified with high anti-HIV activity <05MI57>.
Triazines, tetrazines and fused ring polyaza systems
357
6.3.1.3 1,3,5-Triazines Supramolecular helical mesomorphic materials with different proportions of 2,4,6triarylamino 1,3,5-triazine and (R)-3-methyladipic acid have been described <05JA458>. Bis-(hydroxyamino)triazines (BHTs) have been reported as a new, general and highly versatile group of tridentate iron(III) chelating agents <05CC5319>. Co(III) complexes of a 2,4-di(2’-pyridyl)-6-(p-R-C6H4)-1,3,5-triazine ligand have been synthesized and characterized <05EJI1223>. N-Substituted 1,3,5-triazacyclohexanes reacted with TiCl4 to give cationic complexes <05EIJ3217>. Combined crystallographic and computational methods have been used to study anion-π interactions in cyanuric acid <05CEJ6560>. The synthesis, optical and electrochemical properties of new π-conjugated polymers containing 1,3,5-triazine units have been reported <05MRC998>. Two series of multibranched compounds with vinylenes attached to the striazine core have been synthesized <05CL644>. A new synthetic strategy and the optical properties of high fluorescent triazine-amine conjugated oligomers have been described <05JOC9269>. The synthesis of calix[4]arene dimelamines with different functionalities and their selfassembly with barbituric and cyanuric acid to hydrogen-bonded nanostructures have been published <05OBC3727>. Unique ionophores of penta-crown ethers have been prepared by the reaction of 1,3,5-triacryloylhexahydro-1,3,5-triazine (TAHTA) with diaza 18-crown-6 followed by Michael addition, and their binding capabilities towards alkali metal cations studied <05SL2257>. New silver complexes of polydentate ligands including a derivative of pyrazol-1-yl-1,3,5-triazine have been reported <05EJI4370>. Two novel donor-acceptor phenylazomethine dendrimers with a s-triazine core and butoxybenzene units have been synthesized <05TL8861>. Three novel nitrogen-rich nanolayered, nanoclustered and nanodendritic carbon nitrides have been prepared from 4,4',6,6'-tetra(azido)azo-1,3,5-triazine (TAAT) <05AG(E)737>. The mechanisms of the cascade reactions of amino-substituted imidazoles, pyrroles, and pyrazoles with 1,3,5-triazines have been studied using MP2/6-311++G**//B3LYP/6-31G* calculations in both the gas phase and in solution <05JOC998>. The reaction of bis(silyl-substituted)methylithium with α-hydrogen-free nitriles 29 afforded directly 2,4,6-trisubstituted-1,3,5-triazine 30 <05H1425>. Me N (Me3Si)2(Me2NMe2Si)CLi
N
hexane
N N
Me 29 Me
30
Me
N-Pyrimidinyl-N'-aryl guanidines have been cyclized with keto esters to give 1,3,5triazine derivatives <05JGU303>. Trimolecular condensation of paraformaldehyde, primary amines and suitable isoxazolyl-N-arylthioureas 31 using montmorillonite K-10 in dry media, under microwave irradiation afforded the corresponding isoxazolyl triazinethiones 32 <05JHC711>.
358
P. Goya and C. Gómez de la Oliva R1 NH
R1 R2NH2 (CH2O)n K-10
S NH
Me N
Ph
N
S
R2
N
Me
MW
O
N
Ph N O 32
31
Aminotriazine derivatives 35 are available in two steps by treating chlorotriazines 33 with acid-labile benzylic amines including triphenylmethylamines, diphenylmethylamines or 2,4dimethoxybenzylamine 34, followed by deprotection using trifluoroacetic acid <05TL2005>. NH2
Cl N N
R
NH2
OMe
N
1. DMA, 70 °C, MW 2. TFA
R
N
R
OMe
33
N
R
N 35
34
1,3,5-Triazine-2,4,6-triamines 38 and 39 with symmetrical and asymmetrical substitution respectively can be obtained under microwave irradiation in solvent-free conditions by reaction of pyrazolylamines with cyanuric chloride 36 and 2-chloro-4,6-diamino-1,3,5triazine 37 respectively. In the latter case, the procedure can be adapted for the preparation of polymer-supported triazines, with application in supramolecular combinatorial synthesis <05MI649>. Cl N
NHR1 N
N
Cl
NH2R1 Cl
N
R1 =
36
R1 =
N
R1 =
N R1HN
N NHR1
N
N
38
N NHR2
N N 37
185 °C
N
Cl
R1HN
MW, 90 W, 10 min
NHR1
N N
MW, 90 W, 10 min
NH2R2
125-140 °C R2 =
N
N R1HN
N N
NHR1
39 N
The reactivity of 2-chloro-4,6-dimethoxy-1,3,5-triazines 40 has been investigated in Pd- or Ni-catalyzed cross-coupling processes with organostannanes, Grignard reagents, organoalanes and organozinc halides. All organometallic reagents considered formed new C– C bonds on the heteroaromatic ring and afforded the corresponding 2-alkyl-4,6-dimethoxy1,3,5-triazines 41 <05T4475>.
Triazines, tetrazines and fused ring polyaza systems
359
Cl N MeO
R R-M
N N 40
OMe
"Pd" or "Ni"
N MeO
N N
OMe
41
Several reports have dealt with pharmacological applications of 1,3,5-triazine derivatives: 2,4,6-trisubstitutted s-triazines as antibacterial <05BMCL1121>, antimalarial <05BMCL531> and as antimicrobial agents <05JIC83>; melamine-based nitro heterocycles have shown activity against trypanosomatid parasites <05JMC5570>; 1,3,5-triazine-2,4,6triones as antagonists of the gonadotropin-releasing hormone receptor <05BMCL693; 05BMCL3685> and 4,6-diamino-1,3,5-triazines as VEGF-R2 tyrosine-kinase inhibitors <05JMC1717>. 1-Aryl-4,6-diamino-1,2-dihydrotriazine and 2-(3,5-disubstituted-pyrazol-1-yl)-4,6trisubstituted triazines have been synthesized and evaluated as antimalarial agents <05BMCL4957; BMCL915>. The synthesis of 1,3,5-triazine-pyridine derivatives as potent cyclin dependent kinase inhibitors <05JMC4535>, and of novel sulfonamides incorporating 1,3,5-triazine moieties as carbonic anhydrase inhibitors have been reported <05BMCL3102>. The diaminodihydro-1,3,5-triazine moiety has been used as a protecting group for the aldehyde function in the selective conversion of an ester group into the corresponding carboxamide in vinylogous ester-aldehydes of imidazole. The carboxaldehyde group is regenerated by hydrolysis of the triazine moiety to provide vinylogous amide-aldehydes of imidazole as the final products <05TL6005>. 2-Chloro-4,6-dimethoxy-1,3,5-triazines have been employed as reagents for the synthesis of 4,4-dimethyloxazolines from carboxylic acids and 2-amino-2-methyl-1-propanol <05MI25>. A new generation of efficient coupling reagents useful for peptide synthesis were obtained by treatment of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl morpholinium (DMTMM) chloride with lithium or silver tetrafluoroborate <05JA16912>. Ferrocene-based chiral phosphine triazines have been described as a new family of highly efficient PN ligands for asymmetric catalysis <05MI541>. A novel polymer-type of dehydrocondensing reagent comprising chlorotriazine has been developed <05CC2698>. Amphiphilic dehydrocondensing agents, based on the 1,3,5-triazine system have been used to demonstrate that a large rate enhancement of bimolecular dehydrocondensation occurs in micelles <05AG(E)7254> 6.3.2
TETRAZINES
Several reports have dealt with the 3,6-bis(2-pyridyl)-1,2,4,5-tetrazine (bptz) ligand: reactions of bptz with first-row transition metals have been explored <05JA12909>; the synthesis and crystallographic study of a dinuclear iridium complex have been published <05ICA1317> and a new molecular propeller compound prepared from the reaction of bptz with Ag[AsF6] has been reported <05CC46>. New Mn(II) polymers with deprotonated hydroxytetrazine bridges have been described <05ICC524>. Mononuclear Ru(II) complexes of 3-amino-6-(3,5-dimethylpyrazol-1-yl)1,2,4,5-tetrazine have been studied <05POL333>. Self-assembly reactions of low-valent titanocene units and N-heterocyclic bridging ligands (including tetrazine) afforded noveltitanium based supramolecular squares <05CEJ969>.
360
P. Goya and C. Gómez de la Oliva
New tetrazines 42⎯46 bearing heteroatom substituents have been synthesized. The electrochemical and fluorescence properties of these compounds have also been reported <05CEJ5667>. N N N N
R1
Cl
N N R2
Cl
O N N
O N N
N N 42 R1 = R2 = Cl 43 R1 = Cl, R2 = OCH3 44 R1 = R2 = OCH3
45
N N Cl
O N N 46
The synthesis of 1,5-diisopropyl substituted 6-oxo-verdazyls 49 has been accomplished starting from 2,4-diisopropylcarbonohydrazide bis-hydrochloride 47. The introduction of isopropyl groups results in free radicals more stable and soluble than their methyl counterparts <05OBC4258>. O RCHO
N N NH2 NH2
NaOAc EtOH
2HCl
HN N R
O
N N
benzoquinone
R
O
HN N
47
N N
48
49
A simple, yet non-obvious method for the construction of pyrazol-4-ols 52 by a consecutive series of condensation-fragmentation-cyclization extrusion reactions of thietanone 50 with 1,2,4,5-tetrazines 51 has been described <05JOC8468>. O
Ph
N N Ar
S
Ar N N
50
51
KOR/ROH THF
H RO
Ar
O
N N Ar
Ph 52
Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate continues to be an important reagent in the inverse Diels-Alder reaction, and has been used in the synthesis of ningalin D <05JA10767>, dihydrodiol and diol epoxide of phthalazine <05T1545> and novel pyridazino-psoralen derivatives <05T4805>. Another example of inverse-electron demand reactions of 3,6-disubstituted 1,2,4,5tetrazines is with alkynyl boronic esters which provides a direct and regioselective method for the synthesis of pyridazine boronic esters <05AG(E)3889>. Unexpected azido-tetrazolo tautomerizations and irreversible tetrazolo transformation have been studied in a report dealing with 3,6-diazido-1,2,4,5-tetrazine (DiAT) for which an improved synthesis pathway is also provided. DiAT undergoes azido-tetrazolo equilibria in CD3OD, (CD3)2CO and CD3CN and transforms to tetrazolo isomer 53 in DMSO. The
361
Triazines, tetrazines and fused ring polyaza systems
transformation from 53 to 54 only occurs when the temperature is at least 80 ºC. <05JA12537>. N N N3
CD3OD (CD3)2CO CD3CN
N N 53
N N N3
N N DiAT
N
N N
N3 N N
N N N3
DMSO
N N
N
N N
80 °C
N N
DMSO
53
N
N N
N
N N
54
Two reports deal with the synthesis and antitumor activity of 3,6-disubstituted 1,4dihydro-1,2,4,5-tetrazine derivatives <05JCR(S)91; 05BMCL3174>. In the latter, semiempirical calculations and X-ray diffraction were used to establish the correct tautomeric structure 55. N NH
R2
R2
N N O
6.3.3
R1 55
FUSED [6]+[5] POLYAZA SYSTEMS
The number of publications in this category is considerable, even though purine and pyrimidine nucleosides have not been included. 6.3.3.1
Triazino and tetrazino [6+5] fused systems
The synthesis of 1,2,4-triazolo[1,5-d][1,2,4]triazine-5-thiones has been developed in a one pot reaction from 4-amino-1,2,4-triazine-3-thione-5-one and aryl nitriles <05JHC1021>. A novel method for the synthesis of imidazo[5,1-f][1,2,4]triazin-4(3H)-ones 57 has been reported by cyclization of N-aminoimidazoles 56, and the method applied for the synthesis of vardenafil <05JOC7331> O
H2N
O
R2
EtO N
N R1 56
H2N
O R3
R2
HN R3
N 57
N
N R1
362
P. Goya and C. Gómez de la Oliva
A novel one-pot three component synthesis of 1,2,4-triazino[3,4-b]thiazolones 60 has been described by condensation of mercaptotriazinones 58, 5-aryl-furan-2-carboxaldehyde 59 and chloroacetic acid <05SC333>. O O R1
H N N
SH
O
O
O
N
58
R2
O Cl
HO
O NaOAc Ac2O
59
R2
R1
S
N N
N 60
Reversible metathesis reactions of 6,7-dihydropyrazolo[1,5-d][1,2,4]triazin-4-ones and aliphatic aldehydes or ketones have been reported to generate thermodynamically controlled mixtures of heterocycles <05OL4483>. O
O R2CHO
N HN
R
N N
R1CHO
N HN
pH 4, 40 °C 3 days
R1 61
N N
R
R2 62
The palladium-catalyzed regioselective arylation of imidazo[1,2-b][1,2,4]triazine 63 afforded 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)-imidazo[1,2-b][1,2,4]triazin-7yl]biphenylcarbonitrile 65 <05JOC5938>. Br HO
N N
CN
N N F 63
1% Pd(OAc)2 1% PPh3 KOAc, DMAC 130 °C
F
HO
N N
N N CN
64 65
F
F
Some novel triazolo[4,3-a][1,3,5]triazines have been synthesized by cyclization of imidates with 3-allyl-5-amino-1-phenyl-1,2,4-triazoles <05SC2467>. Derivatives of 1,6polymethylene-1,3,5-triazinones have been prepared in the reaction of cyclic nitroenamines with isocyanates using a strong base <05M211>. The synthesis and reactions of 5nitromethyltetrazolo[1,5-f][1,3,5]-triazinones have been described <05KGS259; 05KGS582>. Novel sulfone-containing pyrazolo[5,1-d][1,2,3,5]tetrazines and pyrazolo[1,5a]pyrimidines have been synthesized <05JHC609>. Several fused heterocycles have been synthesized and evaluated in different pharmacological fields: imidazo[1,2-b][1,2,4]triazine has been used to prepare an α2/3 selective GABA agonist <05JOC5938>; pyrrolo[2,1-f][1,2,4]triazines as inhibitors of the tyrosine kinase activity of growth factor receptors, VEGFR-2 and FGFR-1 <05BMCL1429; 05JMC3991>; pyrazolo[3,4-c][1,2,4]triazin-4-yl thiosemicarbazides as antiamoebic <05MI255>; imidazolo[2,1-c][1,2,4]triazines as analgesic <05EJM127> and 1,2,4triazino[5,6-b]indole derivatives as antimalarial agents <05BMC2935>.
363
Triazines, tetrazines and fused ring polyaza systems
In a paper dealing with the comparison of different heterocyclic scaffolds as PDE5 inhibitors, imidazo[1,5-a][1,3,5]triazin-4-ones have been synthesized and also showed PDE5 inhibitory activity <05BMCL3900>. Novel diamino derivatives of [1,2,4]triazolo[1,5a][1,3,5]triazine have been described as potent and selective adenosine A2a receptor antagonists <05JMC2009>. Reaction of N-acylimidates with suitable amino derivatives of pyrazole, benzimidazole, triazole and tetrazole afforded the corresponding pyrazolo[1,5a][1,3,5]triazine, [1,2,4]triazolo[2,3-a][1,3,5]triazine and tetrazolo[1,5-a][1,3,5]triazine, some of which showed anticancer and high antioxidant activity <05AP365>. Derivatives of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-5-ones 66 designed as novel alkylating agents have been synthesized and showed antiproliferative activity <05JMC2859>. Reactions of 2-diazoindoles with alkyl or aryl isocyanates afforded derivatives of the new ring system [1,2,3,5]tetrazino[5,4-a]indole 67, some of which showed antiproliferative activity <05BMC295> R1 R1
N
R2
N
N N
O
O
66
6.3.3.2
N N N R2
N
67
Purines and related structures
A study of the coordination modes of organotin(IV) complexes with 6-thiopurine and related ligands has been published <05JOM1560>. Tautomerism in 5,8-diaza-7,9-dicarbaguanine (alloguanine) has been studied. An X-ray structure analysis of the title compound revealed that this purinoid exists in the crystal as the two tautomers which interact with each other in the mode of a reverse-Watson-Crick base pair <05HCA1960>. The two tautomeric forms of one-electron oxidized guanosine have been investigated. The energetically most stable form is 68, the less stable form is 69 and its tautomerization to 68 has an activation energy of 23.0 kJ mol-1 <05AG(E)6030>. O N N R
O N
N N 68
NH2
N R
NH N
NH
69
A microwave assisted solid-phase synthesis of trisubstituted 2-(2,6-purin-9-yl)acetamides has been described <05TL2873>. New trisubstituted purin-8-ones 71 have been synthesized starting from cheap and readily available 5-bromouracil 70 <05S2227>.
364
P. Goya and C. Gómez de la Oliva Br
HN O
R1NH2
O
N H 70
NHR1
HN
160 °C
O
O
N H
NHR1
N
POCl3/Et3N 120 °C
Cl
R2NH, HCl H2O, EtOH
Δ
R1 N
N
O
R3HN
N 71
N R2
NH2R3 MW
R1 N
N Cl
triphosgene Et3N, THF
O
0 °C - Δ
N R2
N
Cl
N
NHR1
N Cl
NHR2
N
Parallel synthesis of libraries of 2,6,8,9-tetrasubstituted purines have been reported, one proceeding via a sulfur intermediate <05JCC627> and another through the 2,8,9trisubstituted 6-chloropurine core <05JCA474>. New C(2) substituted 8-alkylsulfanyl-9-phenylmethyl-hypoxanthines have been prepared <05JHC743>. A highly regioselective and traceless solid-phase route to N(1)-N(7)-disubstituted purines 73 has been developed. The reaction involves coupling of 6-chloropurine 72 to the REM resin (Michael addition), oxidation, N(1)-alkylation, quaternization and product release through Hoffman elimination <05JCC734>.
N
N
X
N H
N
N
HCOOH
N
N
DMF
O
O
N
O Et(i-Pr)2 DMF
72
O
Cl
O
Cl
X = resin
N
HN N
N
O
O X
X R1Br
DBU
O O R1
R2 N
N
N
N 73
O NH3
R1
N
N N
R2Br
N
N
N N
N
O
O
DMF
Br O
R1
R2
O
X X
The mechanism of selective purine C(2)-nitration has been investigated and it was demonstrated that this reaction occurs in a three-step process. The reaction was developed with N-9-Boc protected 6-chloropurine 74 and a mixture of tetrabutylammonium nitrate and trifluoracetic anhydride. NMR studies at -50 ºC demonstrated that it involved formation and
Triazines, tetrazines and fused ring polyaza systems
365
radical rearrangement of an N(7)-nitramine intermediate I. At T > -40 ºC, I underwent a nitramine rearrangement, which generated a C(2)-nitro species that immediately eliminated TFA to give 2-nitro-6-chloro-9-Boc purine 75 <05JA5957>. Cl
Cl N
N N 74
CF3CO2NO2
N Boc
NO2 N
N
N Boc
N
Cl
O O
N
CF3
N
O2N
N N 75
N O I Boc
CF3
Cl
Cl N
NO2 N H O
N Boc
N
N N
O2N
TFA
H O O
II
N Boc
CF3
Three new unsubstituted or N-methylated derivatives of 2-amino-6,7,9-trimethylpurinium iodides have been prepared by quaternization of the corresponding 2-amino-6,7dimethylpurines. The compounds were studied by 15N NMR and one purinium salt also by Xray diffraction <05EJO3026>. A highly enantioselective catalytic conjugate addition of N-heterocycles including purines 76 to α,β-unsatured ketones and amides 77 has been developed to give 6,9-disubstituted purines 78 <05AG(E)2393> R1
R1
O N
N
N H
N 76
R3 R2 77 R3 = Me, NHCOPh
N
N
N
N R2
O R3
78
Reactions of various zirconacylcyclopentadienes bearing alkyl and aryl groups with 6alkynylpurines in the presence of Ni(PPh3)Br2 afforded the corresponding 6-arylpurines. Although the yields were low to moderate some of the purines showed interesting cytostatic activity <05CCC339>. A novel isomerization of 6,7-dihydrooxazolo[2,3-f]theophyllines 80 to 7,8-dihydro-6H[1,3]oxazino[2,3-f]theophyllines 81 has been described. Derivatives 81, a new class of compounds, can be obtained in a one-pot procedure by reacting of 8-bromotheophylline 79 with an aminomethyloxirane, without isolation of the oxazolopurine 80 intermediate. <05TL3561>.
366
P. Goya and C. Gómez de la Oliva
O Me
H N
N
O
N Br
n
O Me
O
N N Me 79
N
N
O
N
N Me
N
O
n
Me
O
N
N
N
O
80
n
O
N
N Me 81
By reacting 8-thionoadenine 82 with benzenediazonium tetrafluoroborates 83 in DMSO, 8-(arylsulfanyl)adenines 84 were obtained under mild aerobic conditions <05JOC717> NH2 N
N N
H N
BF4
rt
S N
N
83
82
N
N
X
S N
N
NH2
DMSO
84
OAc
X OAc
The first example of alkylation of underivatized xanthine with chloroacetic acid to yield a separable mixture of N-7- and N-9-(methylenecarboxyl)xanthine and conversion to a peptide nucleic acid monomer have been described <05SL1442>. Aldehydes, arylideneanilines, carboxylic acids and orthoesters have been used as onecarbon units for binding the two amino functions of 4-amino-1-alkyl-3-propylpyrazole-5carboxamide to give 1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-ones <05MC619; 05JHC751>. A modified efficient synthesis of variably substituted pyrazolo[4,3-d]pyrimidin-7-ones has been described using a pyrazole-5-carboxylic acid, which was selectively brominated at position 4 and then converted into the carboxamide. Microwave irradiation gave better yields in the conversion of the carboxamides to pyrazolo[4,3-d]pyrimidinones <05JHC1085>. New cyclopentene-containing pyrazolo[3,4-d]pyrimidines 88 have been prepared by reaction of Boc-protected 4-aminocyclopent-2-en-1-ols 85 with chloropyrazolopyrimidines 86 followed by cyclization with Pd(0) under basic conditions <05JOC2824>. O Ph
O Ph AcO
NHBoc
AcO
N N
NH
1. TFA 85a AcO
NHBoc Ph 85b Cl
2.
87a
N N Bn
O O
N
Ph N AcO
N
N 86 Bn
N
NH
N 87b
N
N
N N Bn 88a
Pd(OAc)2 PPh3
N N Bn
N
O Ph N
N N
N N Bn 88b
367
Triazines, tetrazines and fused ring polyaza systems
A new enzymatic process in which penicillin-G acylase from E. coli, catalyzes the Markownikov addition of 1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one 89 to vinyl ester 90 to obtain pyrazolopyrimidine 91 has been reported <05CC2348>. O
O O
HN
N N 89
N H
O
Penicillin-G acylase
HN
R
N
N
90
N O O
91
R
Carbodimides 92, obtained from aza-Wittig reactions of iminophosphorane and aromatic isocyanates, reacted with primary amines to give isolable intermediate guanidines 93. Cyclization afforded selectively regioisomer 94 with sodium ethoxide, whereas in its absence another regioisomer 95 was obtained <05CL1022>. O N
OEt
N N Ar1 92
N C N
RNH2
N N N Ar1
OEt O 2 HN Ar N
NH R
93
O EtONa
N
N
N N Ar1
N 94
Ar2 NH R
Ar2 O N
N
N
N Ar1
N 95
R NH Ar2
The purine ring system can be considered as a privileged structure in medicinal chemistry, so several reports have appeared in 2005 dealing with biological applications of purine and analogs. Among them we can mention: 2,9-disubstituted[1,2,3]triazol-2-yl-purin6-yl-amine derivatives as adenosine A2A receptor antagonists <05JMC6887>; xanthines as selective adenosine A2B receptors antagonists <05BMCL609>; ‘reversine’ 2-(4morpholinoanilino)-N-6-cyclohexyladenine and its 2-substituted derivatives as potent and selective A(A3) adenosine receptor antagonists <05JMC4910>; 6-substituted purines as inhibitors of 15-lipoxygenase <05AP159>; purine derivatives as potential ATP-competitive kinase inhibitors <05JMC710>; 8-arylsulfanyl adenine derivatives as inhibitors of the heatshock-protein-90 (Hsp90) <05JMC2892>; 8-substituted analogs of 3-(3-cyclopentyloxy-4methoxy-benzyl)-8-isopropyladenine as inhibitors of phosphodiesterase 4 (PDE4) <05JMC1237>; 2-phenylamino-6-oxopurines as inhibitors of Herpes simplex virus thymidine kinase <05JMC3919>; antimycobacterial activity has been reported for agelasine-E and analogs <05OBC1025> and for 9-aryl-6-(2-furyl)purines <05JMC2710> and oxygen substituted hydroxylamine analogs of theophylline have been screened for antibacterial activity <05IJC(B)2166>. The synthetic potential of a novel precursor of 2,6-diaminopurine CDK inhibitors, 2(benzylsulfanyl)-6-chloro-9-isopropylpurine, has been described <05EJO939>. Novel highly potent adenosine deaminase inhibitors containing the pyrazolo[3,4-d]pyrimidine ring system have been reported <05JMC5162>. The synthesis of substituted 6-phenylpyrazolo[3,4d]pyrimidines as potential adenosine A(A2) receptor antagonists has been published
368
P. Goya and C. Gómez de la Oliva
<05PHA732>. New pyrazolo[3,4-d]pyridazine derivatives have shown antibacterial and antifungal activities <05EJM401>. 6.3.4
FUSED [6]+[6] POLYAZA SYSTEMS
A number of pyrimido[4,5-d]pyrimidine analogs 98 have been synthesized from pyrimidine carboxylic ester 96 and N-arylidene derivatives 97. The cycloaddition reaction has been studied by a PM3 semiempirical method indicating the preference of the endo approach over the exo approach of the dienophile towards the diene fragments used <05T4237>. Ph CO2Me
HN S
R
N H 96
S toluene
N
Me
HN
N
Me
H N Me
Ph CO2Me R N
N 98
97
Novel pyrimido[5,4-d]pyrimidines have been prepared from (2-acetamido-1,2dicyanovinyl)ammonium chloride <05JCR(S)530>. An efficient one-pot synthesis of 3-(2-oxo)-chromen-3-yl)-6H-8H-pyrimido[4,5c]pyridazine 5,7-diones 101 by reaction of 3-acetylcoumarins 99 with alloxan monohydrate 100 in acetic acid followed by hydrazine hydrate has been reported <05JHC1223>. R1 O
R1 O
O
O O
R2
NH
O
Me
99
O NH2NH2
N H
O
O
O
R2
NH
AcOH
N
100
N
101
N H
O
The synthesis of piperazine-derived 2-furan-2-yl[1,2,4]triazolo[1,5-a]pyrazines was carried out using 3-amino-2-pyrazine carboxylate. The introduction of the piperazine to the pyrazine template was achieved through a pteridin-4-one intermediate <05H2321>. Tetraazafulvalenes 102 rearranged in the presence of K-10 to give strongly fluorescent 1,4,5,8-tetraazanaphthalenes of type 103 <05SL643>. Ar Ar
H N N H
N
N
N
N 102
H N N H
Ar
K-10
Ar
DMF 130 °C
Ar Ar
H N
N
N H
N 103
N
H N
N
N H
Ar Ar
Two previously unknown 1,3-dimethyllumazine derivatives 104 have been isolated from a parasitic fresh water leech, Limnatis nilotica. The structures of the compounds have been assigned by NMR and unambiguously confirmed by chemical synthesis <05JNP938>.
369
Triazines, tetrazines and fused ring polyaza systems
O Me
N
N
O
N Me
OH
O
H N
N H
n
N
n = 1, 2
O
104
The synthesis and heterocyclization of 7-alkynyl- and 6,7-dialkynyl-1,3dimethyllumazines have been reported <05KGS140>. A novel heterocyclic scaffold consisting of indole-fused pteridines has been obtained <05JCC813>. Several 2- and 4-substituted pteridines bearing different heterocycles in position 2 linked through a thioester group have been synthesized and claimed to be novel templates for anticancer chemotherapy <05BMC3513>. Parallel synthesis of pteridine derivatives as potent inhibitors for a hepatitis C virus RNA polymerase has been described <05BMCL675> 6.3.5
MISCELLANEOUS FUSED POLYAZA SYSTEMS
The synthesis of pyridazino[4',3',4,5]thieno[3,2-d][1,2,3]triazines have been accomplished <05PSS591>. An alternative route to the pyrazolo[4,3-e][1,2,4]triazolo[1,5c]pyrimidine system has been reported <05RJO916>. A novel tricyclic ring system tetrahydrobenzimidazo[1,2-d][1,2,4]triazine 107 has been synthesized from suitable benzimidazoles 105 using microwave irradiation <05TL1725>. N
Cl
O N
N H
Cl
105
N H
N
MW
Ar
N N
O
106
N Ar
107
New derivatives of 1,2,4-triazino[3,4]purine have been obtained by [4+2] cycloaddition of 8-diazotheophylline with dipolarophiles <05IJC(B)1064>. The photolysis of 3-diazo-4,5diphenylpyrazolo[3,4-c]pyridazine has been investigated and can lead to condensed 1,2,4triazines <05JCR(S)643>. The synthesis and some novel reactions of 8-chloro-2H-[1,2,4]triazine[3,4b][1,3]benzothiazole-3,4-dione including a ring contraction to the corresponding [1,2,4]triazolo-fused derivative have been reported <05JCR(S)632>. R2
H R1
H N N 108
NH N N
1. R2CHO HBF4 EtOH 2. Et3N
R1
N
N Me N
N 109
O
O
R2 H R1
N
O N N
N
N
N N 110
N
Me
O
370
P. Goya and C. Gómez de la Oliva
Selective synthesis and cycloaddition reactions of new azomethine imines 109 containing a 1,2,4-triazine ring have been reported. 4,5-Dihydro[1,2,4]triazolo[3,4c]benzo[1,2,4]triazines 108 with aromatic aldehydes gave stable iminium salts which were deprotonated to give new mesomeric betaines 109. These underwent 1,3-dipolar cyclization reactions affording tetra- and pentacyclic heterocycles 110 <05EJO3553; 05H1889>. Flash vacuum pyrolysis of some substituted [1,2,4]triazolo[3,4-c][1,2,4]benzotriazine derivatives 111 between 450 and 600 ºC has been studied. The only transformation observed was the unexpected valence bond isomerization of the angularly fused starting compounds to the isomeric linearly fused [1,2,4]triazolo[4,3-b][1,2,4]benzotriazine derivatives 112 <05T7489> R
N
N
N 111
R
450-600 °C
N
N
N N
N
N N
112
Substituted 6-chloropyrimidino[4,5-e][1,3,4]thiadiazine reacted with hydrazine hydrate to give the corresponding 6-hydrazino derivative which was transformed into various substituted [1,2,4]triazino[1,2-a]pyrimido[4,5-e][1,3,5]thiadiazines <05PS2477>. Novel 3-arylcyclohepta[4,5]imidazo[1,2-a][1,3,5]triazinones 114 and the corresponding imino derivatives 115 have been obtained by the abnormal aza-Wittig reactions. Compounds 114 and 115 are capable of oxidizing some amines to give the corresponding imine in a photo-induced autorecycling process <05T6073>. Related [4,5]pyrrolo[1,2a][1,3,5]triazinones show similar behaviour <05H1629>. N
N
2 ArNCO N PPh3
N
N
N
N
O 114
113
N
O
N N
Ar 115
N
O
NAr Ar
The reaction between [1,3,4]thiadiazolo[2,3-d][1,2,4]triazolo[1,5a][1,3,5]triazinium halides 116 and primary or secondary amines afforded highly substituted guanidines 118 and fused tricyclic bis([1,2,4]triazolo)[1,5-a:1’5’-d][1,3,5]triazinium halides 119. The reaction occurs through novel intermediate triazinium-imidothioate zwitterions 117 one of which was characterized by X-ray analysis <05T673>. N N
R2
N N
N N N R3
N
R2
R1
R1
I 116
S
R4R5NH R2
R2
N N
N N N R3
N
N R3
S R2
R5
N
R2
N N
S
118 R1 R1
N 4 R5 R
117
R4
R2
N N
N N N R3
N
I
119
N R4
R2
371
Triazines, tetrazines and fused ring polyaza systems
A methodology for the synthesis of analogs of asmarine, marine alkaloids with a unique tetrahydro[1,4]diazepino[1,2,3-g,h]purine 120 (THDAP) structure has been developed. Three cyclization methods were applied for the preparation of the 9,9-disubstituted 10-hydroxyTHDAP system: aminomercurization, iodocyclization and acid-catalyzed cyclization <05JOC199>. A series of 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5-diones 121 have been synthesized and identified as affinity central benzodiazepine-receptor ligands <05JMC2936>. R R1
R2 O
HO N N
N N
N
120 THDAP
X
N
N
N H 121
N O
New pyrazolo[2,1-f]purine 2,4-dione and imidazo[2,1-f]purine 2,4-dione derivatives have been identified as potent and selective human A3 adenosine receptor antagonists <05JMC4697> 6.3.6
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Triazines, tetrazines and fused ring polyaza systems 05JA12537 05JA12909 05JA16912 05JCC474 05JCC627 05JCC734 05JCC813 05JCR(S)91 05JCR(S)530 05JCR(S)632 05JCR(S)643 05JGU03 05JHC609 05JHC711 05JHC743 05JHC751 05JHC851 05JHC1021 05JHC1085 05JHC1223 05JIC83 05JMC710 05JMC1237 05JMC1717 05JMC2009 05JMC2167 05JMC2710 05JMC2859 05JMC2892 05JMC2936 05JMC3919 05JMC3991 05JMC4535 05JMC4697 05JMC4910
373
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Chapter 6.4 Six-Membered Ring Systems: With O and/or S Atoms
John D. Hepworth James Robinson Ltd., Huddersfield, UK Email:
[email protected]
B. Mark Heron Department of Colour and Polymer Chemistry University of Leeds, Leeds, UK Email:
[email protected]
___________________________________________________________________________ 6.4.1
Introduction
A whole issue of Chemical Reviews <05CR4235> devoted to natural product synthesis contains reviews on marine products. Progress in the synthesis of the marine polycyclic ethers includes a route to a trans-fused polycyclic ether scaffold <05TL2179>, work on ciguatoxin <05T7392, 05TL3991, 05TL8279, 05TL8285>, gambierol <05AG(E)6157, 05JA848, 05OL2441, 05OL4061>, the brevotoxins <05JA9246, 05OL4033> and gymnocins <05JA4326, 05TL3537>. Among the developments in spiroketal chemistry is a Pd-mediated spiroketal synthesis involving stereospecific Stille coupling <05T11910>, a route to chiral spiroketal skeletons <05TL2291> and a diastereocontrolled spiroketal synthesis related to the macrolide bafilomycin <05S644>. Several papers refer to the spiroacetal segments of spongistatins <05OBC2399, 05OBC2410, 05OBC2420> and to the macrolide itself <05AG(E)5433, 05OBC2431>. Macrolide chemistry which has been reported includes progress in the synthesis of spirastrellolide <05OL4121, 05OL4125, 05S3225>, bryostatin <05OL2149, 05OL2153> and stephacidin <05AG(E)606, 05AG(E)7670, 05TL9013>. Total syntheses of milbemycins <05OBC3636, 05OBC3654>, laulimalide <05AG(E)2756> and rhizoxin D <05SL491> have been published. A book on the advances in flavonoid chemistry since 1994 has been published <05MI1> and naturally-occurring pyran-2-one derivatives <05NPR369>, furanoflavonoids <05NPR400>, isoflavones <04JHC449> and isoflavonoids <05NPR504> have been reviewed. Total syntheses of the pyranone-based molecules rasfonin <05T1827>, spectinabilin <05OL2473>, gambogin <05AG(E)756> and methyl barbascoate <05JOC2250> and of various complex marine pyranones <05AG(E)4602> have been described. The use of a polyketide synthase <05JA12709> and an anthocyanidin synthase <05OBC3117> in synthesis has been reported. The photochromic properties of naphthopyrans <05PHC33> and spiropyrans <05CHE281> have been reviewed. Electronic materials which incorporate six-membered Oand S-heterocycles include derivatives of (2,6-dimethyl-4H-pyran-4-ylidene)propanedinitrile used as dopants for red organic LEDs <05JMAC2470>. Reviews of the organosulfur donor
377
Six-Membered Ring Systems: With O and/or S Atoms
molecules bis(ethylenedithio)tetrathiafulvenes <05JMAC347> and the use of 3,4-ethylenedioxythiophene in advanced π-conjugated systems <05JMAC1589> have been published. Reviews on metathesis <05AG(E)4490>, Pd-catalysed cross-coupling <05AG(E)4442>, hydroarylation of alkynes <05S167>, total synthesis <05JOC7007>, insect pathogenic fungi <05ACR813>, anti-inflammatory metabolites <05CSR355>, plant glycosyltransferases <05CEJ5486>, hetero Diels–Alder (DA) reactions <05CEJ5806>, [3+3]cycloadditions <05EJO23>, thionation of carbonyl compounds <05SL1965>, the Pauson–Khand reaction <05SL26>, microwave-assisted reactions <05CHE951>, radical cyclisations <05T10603> and singlet oxygen chemistry <05T6665> contain material relevant to this chapter. 6.4.2
HETEROCYCLES CONTAINING ONE OXYGEN ATOM
6.4.2.1
Pyrans
A Stille coupling of the vinyl iodides derived from furan-3-carboxaldehyde with the vinyl stannane 1 obtained from tetronic acid is accompanied by electrocyclic generation of a pyran ring when carried out in the dark. The polycyclic pyran product, the core unit of the diterpenoid saudin, is delivered as a single diastereoisomer <05OL2413>. I
O n-Bu3Sn
Pd(PPh3)4, CuI DMF dark
O + O
O
1
O
O
O
O
O O
O
O
O 60%
O
O
The Cu-promoted enantioselective oxidative dearomatisation of alkynylbenzaldehydes followed by a cycloisomerisation leads to azaphilones, fused 4H-pyrans (Scheme 1) <05JA9342>, while an alternative synthesis involves oxidation of a 1H-benzopyrylium salt derived from a substituted benzaldehyde (Scheme 2) <05JOC4585>. Treatment of azaphilones with primary amines results in cleavage of the pyran ring and the formation of vinylogous γ-pyridones. R
R HO
(i) CHO OH
O HO
O
R
(ii)
O HO
O
OH
Reagents: (i) Cu(MeCN)4PF6, (-)-sparteine, DIEA, DMAP, O2, -10 aq. buffer, MeCN, rt Scheme 1
O oC;
5 examples 44 - 72% (95 - 97% ee)
(ii) KH2PO4/K2HPO4
The enynones 2 provide 2-pyranylidene complexes with Cr and Mo carbonyls <05CL1068> and cyclopenta[b]pyrans 3 result from the reaction between readily available ethenylcarbene-chromium complexes and alkynes <05CEJ4132>. 2-Aryl-α,β-unsaturated aldehydes react with cyclopentadiene to give dihydrocyclopenta[b]pyrans in a stereoselective manner by way of a tandem Lewis acid-catalysed DA reaction and a retro-Claisen rearrangement. Competitive formation of the [4+2] cycloadducts is reduced by careful choice of the Lewis acid and by working at lower temperatures (Scheme 3) <05JOC6680>.
378
J.D. Hepworth and B.M. Heron
The analogous [c]-fused system has been obtained through an intramolecular Michael addition of a substituted oct-2-en-1,8-dial promoted by L-proline in DMSO <05JA3696>. MeO
(CH2)3OAc (i) S S (ii)
HO O
OMe O
Cl (CH2)3OAc
HO O
OH O
Cl (iv)
(CH2)3OAc (iii)
OH O Cl
Cl (CH2)3OAc
HO
ClO4
O
(CH2)3OAc O (vi)
O
(v)
(CH2)3OAc
O
NR 8 examples, OH O O 44 - 98% Reagents: (i) Hg(OAc)2, MeCN, H2O, (95%); (ii) AlCl3, CH2Cl2, reflux, (86%); (iii) SO2Cl2, CH2Cl2, (72%); (iv) AcOH, HClO4, rt; (v) Pb(OAc)4, rt, (51% two steps); (vi) RNH2, CH2Cl2, rt AcO
AcO
Scheme 2 R
R O
M(CO)5(THF) THF
R1
O Ar
O
OEt
M(CO)5 9 examples, 8 - 71%
2
R1
R2 THF
NR2
R1
O
3 OEt 26 examples, 5 - 90%
O
5 - 20 mol% MeAlCl2
+
R2
(CO)5Cr
-40 to -20 oC CH2Cl2
Ar R1
10 examples, 30 - 71%, 74 - 98% de
Scheme 3
Both Pd-catalysis and microwave irradiation promote a [2+2] cyclisation of 1,7-ynallene carboxylates 4 to the fused cyclobutena[c]pyran ring system <05CC5670>. CO2Et
O
•
4
PhMe, microwave (93%) or 5 mol% PdCl2(PPh3)2 PhMe (81%)
CO2Et
O
Two groups have reported the synthesis of the pentaketide epoxyquinols which differ in the approach to the epoxide 5, oxidation and subsequent electrocyclisation of which generates a 2H-pyran. Various dimerisation modes in which the pyran acts as either diene or dienophile then yield the epoxyquinols <05JOC79, 05TL547>. The reaction of this epoxide and a related cyclohexenone with reactive dienophiles circumvented the dimerisation and the cascade reaction produced the endo DA products <05JOC79>. O
O (i)
O
OH OH
5
O
O O
OH
O
O O
OH
(ii) O EWG R
O
EWG R
OH
11 examples, 45 - 76% Reagents: (i) MnO2, CH2Cl2, 0 oC then filtration and solvent removal at 0 oC (ii) neat dienophile, rt
379
Six-Membered Ring Systems: With O and/or S Atoms
The photochemistry and photophysics of 2,4,6-triphenyl-2H-pyran and -thiopyran have been studied <05JPP34>. Various trifluoromethyl derivatives of 3,6-dihydropyran have been obtained by a ringclosing metathesis (RCM) of 4-allyloxy-5,5,5-trifluoropent-1-enes and related compounds. In a similar manner, the Pauson–Khand reaction yields fused fluorinated pyrans <05S2253>. R1 R3
R2 F3C
R4
Grubbs' cat. I or II CH2Cl2
O
Co2(CO)8 NMO
Ph
Ph Grubbs' cat. II CH2Cl2 F3C O 50 oC
R3 Ph
F3C O F3C 3 examples, 42 - 70% O Ph
CH2Cl2 / THF F3C rt
O
F3C
R1
O
O
PCy3 Cl Ru CHPh Cl Ms N N Ms
PCy3 Cl Ru CHPh Cl PCy3
67%, (de>95%)<
