The Chemistry of Heterocyclic Compounds, Imidazole and Its Derivatives

I M I DAZ 0 L E and Its Derivatives Part I

KLAUS HOFMANN Professor of Biochemistry, iltediccrl School, Unilrersity of Pithtncrgh

1 9 5 3

INTERSCIENCE PUBLISHERS, INC., NEW YORK INTERSCIENCE PUBLISHERS LTD., LONDON

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IMIDAZOLE and Its Derivatives Part I

This is the sixth volume publiskd i n the sm*es THE CHEMISI'RY OF HETEROCYCLIC COMPOUNDS

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THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS A SERIES OF MONOGIlAPHS

ARNOLD WEISSBERGER, Consultiny Iid,ilor

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I M I DAZ 0 L E and Its Derivatives Part I

KLAUS HOFMANN Professor of Biochemistry, iltediccrl School, Unilrersity of Pithtncrgh

1 9 5 3

INTERSCIENCE PUBLISHERS, INC., NEW YORK INTERSCIENCE PUBLISHERS LTD., LONDON

LTBRARY OF CONGRESS CATALOG CARD NUMBER &3-7158

ALL RIGHT8 RWERVED. Thie book or any part thereof must not Iw reproduced without prmiesion of the puhlhher in writing. Thia applies epecifically to phohtat and microfilm reproductions.

INTIZRBCIENCE PUBLISHEIS, INC., 250 Fifth Avonue, New York 1, N. Y. For ( 3 r d Britain and N o r t h Irelad: Interscience Publiehers L a , London ISBN 0-470-37653-8 ISBN 13: 978-0-47037653-9

This book is dedicated to the memory of FRANK LEE PYMAN

a pioneer in imidawle chemistry

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The Chemistry of Heterocyclic Compounds The chemistry of heterocyclic compounds is one of the most complex branches of organic chemistry. It is equally interesting for ita t-heoretical implications, for the diversity of its synthetic procedures, and for the physiological and industrial significance of heterocyclic compounds. A field of such importance and intrinsic difficulty should be made as readily accessible as possible, and trhelack of a modern detailed and comprehensive presentation of heterocyclic chemistry is t.herefore keenly felt. It is the int.ention of the present serics to fill this gap by expert presentations of the various branches of heterocyclic chemistry. The subdivisions have been designed to cover the ficld in its cntirety by monographs which reflect the importance and the interrelations of the various compounds, and accommodate the specific interests of the authom.

Research Laborcrtories Eastman Kodak Cornpang Rocheater, New York

ARNOLD WEISSBERGER

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Preface /micluZole and Zls Deririatitres (Part I ) summarizes the chemistry of thc, imidasoles, imidazolines, imidszolidinm, aid benzimidszoles and their s Derivatives,” preents derivatives. Section 1, “Chemistry of C I ~ s e and a critical evaluation of the synthetic methods, and the fundamental physical and chemical aspects of these compounds. Brief descriptions of the pharmacological properties of some of the biochemically important derivatives are also included. Section 2, “Systematic Survey and Bibliography, ” contaim a comprehensive noncritical surrey of the pertinent literature. Names, melting points, melting points of some derivatives, and i ~ y a r s 1919 to 1950. literature references are given. The survey ~ * o v ethe Substances that were prepared before 1919 and were not mentioned in the literature covered are not listed ; Beilsteh’s H a d ~ 6 C should h be consulted for informationabout these compouuds. The subject is treated hi this fashiou with the iiiteiktion of preseiiting a readable account of the fiindamentuls, yet ut the same time attempting a comprehensive coverage of the entire field. With but few exceptions the original articles have served a~ the source. The Chemical Abstracts reference is listed, in addition to the primary reference, for any article not consulted in the original. In some instances, data from the older literature have been reevaluated in the light of more recent concepts, and a number of reaction mechanisms are tentatively presented. Most of these interpretations are based on analogies with better understood examples, and must remain qeculative until quantitative information is forthcoming; they are given with the aim of stimulating inquiry into the theoretical aspects of imidaeole chemistry. Many friends and colleagues have aided in the preparation of the book, and the author is greatly indebted to them. Miss Anne Bridgwater abstracted the literature for the compound tables and organized Section 2. Dr. R. S. Tipaon read the entire manuscript slid made many valuable suggestions. My sincere thanks are also due to Drs. M.F. Dull and 8. 11. Sax,and Mr. F. Tausig for their help in checking literature references, and for reading tlw proofs. Pittsburgh,.Pennsylvania May, 1953

K.H.

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Contents l’mfwe .................................................................

ix

Section f

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CHEMZSTRY OF CLASSES AND DERIVATIVES

I General Properties and Structure of the Imldezoles. . . . . . . . . . . . . . . . . . .

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A Somenclat.uro. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... 1% Physical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Boiling and 3lcltirig Points . . . . . . . . . . . . . . . . 3 Solubility ............................... 4. Molecular Weight nncl Dnprrc of .4.s~wintion 5. V i o s i t y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Dipole bfonionts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ... . . 7 Spwtrascopic Propcrtien . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (x) Ultravinlrt AlwqBtinii Spwtrn . . . . . . . . . . . . . . . . . . . . . . . . . . [b) Ramarr Spectra.. . . . . . . . .......................... (c) Clicmilumiiiesi.ciicc!..... 8 Micrcn?lluncousPhgsind Prnpwt.ics. . . . . . . . C. Chomical Propcrticn ......................... 1. Basic Strength . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Pneutioricirlic Character . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 C%cmical StRldity arid r\mmat.ic!Charnctcr . . . . . . . . . . . D. St.iuctural Considcmtions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I . The C!la&cd Iiniclnnolc Forinu1.r . . . . . . . . . . . . . . ......... ...................................... 2 Currcnt Vims .... E. Tautomcrio Charrictcr . . . . . . . . . . . . ..................

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10 10 11

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XI The Alkyl- and hrylimidazoles. . . . . . . . . . . . . . . . .

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3

5 5 5 7

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3

. ........ . 3. The Wcidcmhagon Synthmis .......... . . . . . . . . . . . . . . . . . . . . . . .

4 Formation from Carbohydrates ..............................

5. Formation from Z ( ~ ~ ~ n i i d a e o I a t h i o and n e s Mthiohylnntoiiiina . . G Formation from I m i d a z o l ~ h o x y l i cAoi& .............. i Formrrtion from PImidrnolinetl . . . . . . . . . . .............. 8 ~ i s c c ~ l a n wPrWdurccr us ..... .............. I3. Properties and Chemical Behavior. . . . . . .................... 1. Gcncnl Propcrtirs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2. Acylation . . . . . . . . . . . . . . . . . . . .................... 3. Alkyhtion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

xi

11

11 11 13 13 13 15 16

li 17

19

20

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.4 Syiit.hot.ic P r w d u r m . . . . . . . . . . . . . . . . . . . . . . . 1 Intmluction . . . . . . . . . . . . . . . . . . . . . . . . . 2 Tlw Rrwbi.szcwski Syntliesis . . . . . . . . . . . . . . . .

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c

33

38

39 41 42 42 43 45 46 47 40

sii

C~OlltelltR

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111 The 0x0- and Iiydroryimidamles and Their Sulfur Ailalugues . . . . . . .

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.4 The Oxoimidasalrs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Imicisral~~rl~os.~lilt~li~tl~.s ... . . . . . 2 Imidxmlc?Kctriiicw . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . 3. Imidazolo~tt+s and Tliioiicbs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(a) Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

(I> Structural ) Coneitlerations Itt.lgtrdiiigthe 2(3H)-Iniid:izalon~~ and Thionca.... ...................... (c) 2(3H)-Iniid:ixola . (d) 2(3H)-Itiiidt~zn1c ( 0 ) 2(.H)-Iaiiclrrzolono~ . . . . . . . . . . . . . . . . . . . . . . . . . . . . ( f ) 4(5H) (or S(4H))-Imitl:txoloiii~~ . . . . . . . . . . . . . . . ;. . . J3 . The I I y ~ x y . z l k y l i n i i c ~ s n..... lt~. ... . . . . . . . . . . 1 ..onoliydrosyrtlkpliniirl.sal. .......................... (a) lIydrosymetliylitiiidazciIcn. . . . . . . . . . . . . . . . . . . . . . (I)) 4(or 5)-(2-H~ilroxycttiyl)I1iii~.i~til~ . . . . . . . . . . . . . .

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2. I’olyh~drox3~alkylimid.o1~.. . . . . . . . . . . . . . . . . . . . . . . (a) -#(or6)-Polyliycl~sy.~lkyliniict~olc~~ . . . . . . . . . . . . . (I)) l-Pol~~h~~.rospnlkgliinitlneolcg .....................

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IV The Haloaenoimidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . 13romoimi&zoles..... ......................................

. ..................................... 2. Propert.ies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 I’repnrrrtive Met

. . .

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l3 Chloroiinidazoles.... ..................... C Chloroalkylimidaroles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1) Imloimidazoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Preparative Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Propertit*s.................................................

V The Nitro.. Arylazo.. and Aminoimidazoles ..........................

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A Xitroimiilssoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Synthetic Mctliocls a i d Orientation of the Xitro Croup . . . . . . . . . 2 Properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R Arylneoimidazolw 1 Formtion and Orientation of the A r y h Group . . . . . . . . . . . . . . . 2 Application 01the Diazo Twt to the Identification and Ihtimnt.ion of Imiclasoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Pmpertiw . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C AminoimidR7,olm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2-Aminaimidrzalcs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 4(ar 5)-Aminoimidazolrs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . L) lfistamine . . . . . . . . . . . . . . . . . ........................ 1 Discovery, Distrilmtion ature, and l%armscologiral Effects. . 2 Isolation from Natural Jfatorials ....... 3 Quantitative Ehtimation of Ifstaminc . . (a) Biological Methods ........................... (b) Colorimetric Methods ........................... 4 Formation by Microorganisms...............................

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Ill 111

111 117 119

121

122

In 123

127 121

127 131 136 136

139 139 141

141 142 143

I43 145 146 146

147 149

\I: The Nitro.. Arylazo.. and Aminolmidazolea (continuad)

. 7. Structural Analogues of Hi&aniino

5 Preparative Methods ........................................

6. Physical and Chomical l’iopwtic6. . . . . . . . . . . . . . . . . . . . . . . . . . . .

........................... Position Isomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (1)) Ring-SulBtitution Products . . . . . . . . . . . . . . . . . . . . . . . . . . . ( e ) :V->fonoalkyl- niid :V-Dialkylliistamine Derivativts. . . . . . . (ti) lliitamine Annlogues Yoerming Iqge? or Shorter Aliphatic Side [?hain8 .......................................... 8. Pharrnndogicd Specificity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (ti)

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VI The Imidazolecarboxylic and Sulfonlc Adds. . . . . . . . .

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158 158 160 163

lfM 16.5

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A . Tinitla~ok!carl~xylic Aeicb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. l-Imidn.~olecr~r~~osylic heidtj. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 ZIrniclnsolecnrlmsylic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4(or 5)-Iini~zolccarboxJ.iicAcids. . . . . . . . . . . . . . . . . . . . . . . . . . 4 4,~Imiclnxoleclirnrk~s~lic Acids . . . . . . . . .................. 5. 4(or 5)-tirnino-j(or 4)-Irnidazolecurl~oxylic Acids . . . . . . . . . . . . . (a) Occurrence nnd J f e t k r d of Prcpnrrrtion . . . . . . . . . . . . . . . . (l ), Coiivetuioii into I’uriiies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G JIistidine .................... ......................... (a) Discovery. l)i&ril)utioii it .It.UI‘C, autl Sttuctulr? . . . . . . . . . 0))Noniencl;rt.~iu.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (c) Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (cl) Qunrrtitntive Estitn.rtioii . . . . . . . . . . . . . . . (e) Synthesis rnid Rcsolutioii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (f) Pli.y&ul and Chemical Yrolwbics . . . . . . . . . . . . . . . . . . . (g) Structural Anrilogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Iniiclatolwulfonic Aci& ............................... I Structural Cowiden ................................ 2. 1-Imidwolesulfonic .4ck 1s. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 ZIrnidszolerrulforiic:Acids . . . . ..... ............... 4 4(or 5)-Imid~xolt~ulfo1iic Acids . . . . . . . . . . . . . . .....

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150 153

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.Inoimidazolldlnes,and Imidazolidinen ............................

1’11 The Imidazolinee, 2-Imidazolidonee. 2-1midazolidinethiones, 2-Im-

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175 175 176 176

178 179 179 182 184

181

188

188 194 197

203 206 206 206 200

207 213

A Komenclnture . . . . . . . . . ..... ......................... 213 U 2-lmidnrolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 1. Synthetic Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 2. General Properties and Structural eneideratioiis . . . . . . . . . . . . . . 219 3. Acylat.ion ................................................ 221 1. Alkyhtion . . . . . . . . . . .............................. 223

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5 Prwtical Applications

rnincologioul Actioii

C. ZIiiiiclnxolidories .................................................

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1 Syritfietic Methods and Prolwrtirs. . . . . . . . . . . . . . . . . . . . . . . . 2 Ikxthioliiotin s i d Its k i l o g i e x . . . . . . . . . . . . . . . . . . . . . . 1) ZIiiiidslcolitliii.tIiion.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E ZImiiioiiiii.zolitIi~i. ...........................................

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. F. frnitlrtxolitliiiw. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

226

2x 231

234

238

242

XiV

Contents

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VIII The Bemimidamlea.............................................. 247 A Nomenclature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.47 B GeneralPrope-rties ........................................... 1 Boiling Points. Melting Points. and Dcgrw of &mi&.n ... 2. Pmdouoidic Character..................................... 249 3. Basic Strength and Eleotmnic Structure ........ 4 Ultraviolet Absorption Spectra . . . . . . . . . . . . . . . . 5. Chemical Proporties ........................................ 254 6. Tautomeric Clitinwter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 C. Synthetic Proodurer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . 258 2 Formation fmni Acyl: . . . . . . . . . . . . . . . . 258 3. Formntion from ~ ~ I i t t r ~ y l e r i t ~ l i ::nit1 i ~ i ~C:irl)osylic i i i ~ ~ ~ Acids, Avid Anhydrides, Esters. or Amidw ............................... 200 4 . Formation [rum o-l’henyleneclinrnincs and h’it.r.ihw.. . . . . . . . . . . . . 2625 6. Formation fmni o-Phcnylent~cliamii~crc niid Iiiiiiio 1l;tJvtrrc o r I n i i i i o Tliiouthers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 0. Fornlcrtiou from o-Plienyle~ieclia~iii~~e~ autl AIdt41ycIc~or Kcttoricw . 267 7 Miscellaneous Procedures................................... 211 D. Tlro 1-AcS.lbeaziniiiluzolen irnd the BuJiilwrgerIlc:rcl.iori . . . . . . . . . . . . . . 273 E . The Alliyl- ant1 Aryllm~izimi~Lazoles and 1.3-Dialkyll~c.i1siiiii1Itrzcrliui1i Salts........................................................... 276 F. The 0x0- aud EiydrosylJe~inii~zolcn :nit1 Their Sulfur A ~ i : t I o ~ i i i : ~ 1. “Osunhylro Baw!~” ar “Ox~~crixiniicltrxol~“ .............. 2 2(3H)-Benzimiduzolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 3. 2(3H)-13etuimidazolethion.. ................................. 291 4 . 1IJdrusy~rllrylbet.i.iid.oleN ................................. 293 (:L) I-(l)olyhydro~yalkyI)berlziriiill:~i)l~~ (I-ClycosylLeuiiIlidusoles) ............................................... 293 (b) Z(Moiioli~O.clroxyalb;yl)l~enzimi~zolc. . . . . . . . . . . . . . . . . . . . 296

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Z(Altlo~~lyl~ydrosyt~lky~)l~c~nsi~d~zolt?rr .... ((1) Altlnrodiiiensimida ole.. . . . . . . . . . . . . . . . . . . (i Tlic I I t d o ~ ~ i ol ~ i ei n~ i da~ ...... ol es . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. ..-Iklogenobensimida.o.e. ................................. 2. 2-Chloroknzirni&zoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. U=hlomnlkylbcnzimi~asole..... ......... I1. The Nitro- and Anlinobeiidmidnzolcs. ................ 1. Nittdmwimidnzoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Aminohenaimidazolcs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (a) Bz-Aminobeneimidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (11) ZArninobeneimidaaoles. . . . . . ................. (c) Aminoayl- and Arninoar.li~i.irziiiii.zoie. ............... I. TIIOJ3enziniidazolecarbo~licand Sulforiic Acids. . . . . . . . . . . . . . . . . . . . 1 Carboxylic Acids ................................ 2 Sulfonic Acids ............................................. (c)

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300 300 302 303 304 304 308

308

309 310

313 317

Section 2. SYSTEMATIC SURVEY AND BIBLIOGRAPHY Key to Al)l)rc:vicit.ionw.. . . . . . . . . . .

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. . . . . . . . . . . . . . . . . . . . . . . . . 326

I. Imidazoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . 327

A. Alkyl- r ~ i i t lArylinridrzol(%.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 . . . . . . . . 330 13. Alkyl- and Arylimiclncolium Sii1t.s. . . . . . . . . . . . . . . . . . . C. 0x0- and Hydrosyimidamlos and Their Sulfur 1. 2(3H)-Imidazoloncs. . . . . . . . . . . . . . . . . . (a) Alkyl- nml Ar~l-2(3H)-imici~olones.. .. . . (I))0s-, I.lvdrosynlkyl-, RIKI Hydrosy (c) I~lalognriortlkyl-,Aniinonlkyl-, and Sulfoalk~E.2(3H)-imiclnzolonw. .. . .. ... . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 ((1) 2(3H)-Imid~~IoiicrarI ~osylicAcids. . . . . . . . . . . . . . . . . . . . . . 332 (e) Cnrhsyrlkyl- and ~arhos~.nryl-2(3H)-in~itIa~olo1i~. . . . . . . 332 (f) C h t ~ ~ x rmcl y - Cnrbo~yalkyl-2(3H)-irnidasoloncsContnining Additions1 Functional Croups. . . . . . . . 2. 5(4H)-Imidazolonos. . . . . . . . . . . . . . . . . . . . . 3. 4(5H) (or 5(4H))-Imid~~obtios. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334 4. 2 ( 3 H ) - I m i c l n s ~ ~ t h i(ZXlerclrrptoin~iclr~~olc.~). o~i~ . . . . . . . . . . . . . . . 336 (a) Alkyl- and Ar3’1-2(.7H)-imiditxol~thialrc.a.. . . . . . . . . . . . . . . . 336 (la) 2(3H)-Imitl~olcthicmc.sContaining AdcIit.icmi1 Ihiic.t.iorial Grou............................................... 337 ( 0 ) 2(3H)-In~idao;ol~t.hioncxnrl~s~lic ~ n t lCarl)osya.lkyl-

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.

2(3H)-imidaeolethiori~s.. . . . . . . .

. . . . . . . . . . . . . . . . . . 388

. . . . . . . . . . . . .. . . , . 339 .i 4(5H) . (or 5(4A))-Imidasolethionc,s. . . . 6. Mono- and Polyhydroxyalkyl- and J r y t l m s ~ n r ~ l i m i ~ l ~ o l ~ , Their Ethers and Halogeno Derivativr?.. . . . . . . . . . . . . . . . . . . . . . 340 7. Mercaptoalkyl- and Mercaptoarylimida7alcs.. . . . . . . . . . . . . . . . . . 341

8. Imidaeolecarhoxaldehydcs and Ketones. . . . . . . . . . . D. Halogenoimidssoles.. .. . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . 1. Hdogcno-, Halogenmlkyl-, and Walogenoarylimidazoles. . . . 2. Halogenated 61ks.I- and Arylimidazolium Salts.. . . . . . . . . . E. Nitroimidazoks.. . .. . .. ..... .. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . 1. Nitro- and Nit.mnrylimidaaoles. . . .. . 2. Nitwlkyl- anti Nitroarylimidn7mlc~ tional Groupv.. . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Nitroalkyl- and Nitroarylimidamlium Salts. . . . . . . . . . . . . . . . . . . F. Arylazoimidaeoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... C . Aminoimidades. . . . 1. Amino-, .4minonlkgl-, and Aminoarylimidazoles. . . . . . . . . . . . . . . . 2. Amino-, Aminoalkyl-, and Aminoarylimidazoles C a n t h i n g Additional Functional Groups.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . i t Cyano- and Isocyamtoimidaxdcs. . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . .

.

342 345

346 346 347

350 361

I . I midazoler (cordinmi) . .

.

1 TinidsxciIrrtlrrt~sylic ht.itla . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 . %Ioiitwirrlxxylic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . bi) .itkg1- ant1 A ~ l i n i i t 1 : i x a l ~ : r r l ~ ~Acitls ylic . . . . . . . . . . . . . (13) Imidazolecrrrl>oxylic AaicLs Containing kldit.ianltl Fu tional Groups ........................................ (c) Carboxyalkyl- awl C ~ r r b o s ~ a r y l i m i d xIncluding ol~~ Those Containing .4 dditional Functional Grnirps . . . . . . . . . . . . . . . . (1) r&iat.idiiic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (2) i ~Cisticline l ................................ (3) oirHist.idiiic. . . . . . . . . . . . . . . . . . ............. (4) HiRtidiiie PcptidrR . . . . . . . . . . . . . . . . . . . . . 2 Dicarboyylic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (a) Alkyl- and .4r~limiclrrsol~?clicnrl.s~lic! .\cidx . . . . . . . . . . . . . . (1)) Imidazalociiaarhos~lic Acids Cnnt..thing Acitlit.ioii:rl F’urtctianal Croup ......................................... (c) C a r b o x ~ : ~ l k y l i m i d ~ s o l ~ n ~ ~Aeitl~ o s ~ l i cIlielutlirig Those C h i t h i n g Aclditicmsl Functionnl Grnups. . . . . . . . . . . . . . . . J 1micl:raoleuulfinic slid Sulfoiiie .4rids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I< Imidmolo Arscnicale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I Isoimitiazolcs....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 I Iek!rnring-Sul)Rtit.utcll ImitLi7xhs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Funin 1hivat.ivm. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Tlric~plieiic? Ihriv:rt.ivt*s.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Tliirrxolr Ihriv:tt.ivtw. .......................... 4 Pyridiiic hrivntivw . ............................... 3 Pilinritliiic~Dt~riv:rtivt~s . . . . . . . . . . . . . . . . . . . . . . . . . 6 Morphnliiw Dc-riv.rtivcs. . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 l’yriniitliiic 1)t.riv:i.tivt-s. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Quiriolinc 1h~riv.itivw. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Acritliiio Dc?riv.rtivt!s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Y I3i- mtl I%iinimiciaxoltw ... ..............................

.

.

. .

..

.

. .

. . . . .

.

.

.

I1 Imidazolines..............

.

.......

.....

.

352

3.53 355 358 358 359

360 361

362 363 363 363 3(W

3rd 364 364

364

36.;

3115 3% 36 3(15

366 367

A 2-Tmid.i.soli~ic ..s .................... ....................... Mi 1 Alkyl- :ind Aryl-2......................... 3f11 2 :\lkyC ant1 Aryli:nitl:~soli~iiuni Brlk ........................... 360 3 Alkyl- :riitl Aryl-2-imicI.w~linw(hnttrining Achlitiniial Piiric.tioiinl

. . . <:mu1m ................................................... 4. ZIinit Inxnlirinanrl~nsylic :ind Bulfniiie .4t!itl .. .......

. ............. C. CImidazoliiita . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1) . I TetttrorinK-8iJ)Nti~t~~l 2-Imit lxzoli . . . . . . . . . . . . . . . . . . . . . . . . 1. Fumn Dcrivlttives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Ttiiophriic 1)crivst.ives. . . . . . . . . . . . . . . I1 3-Imidnroli1ita..............................

3.

I IPN

3. Triaxolv Ihtivntivw . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 . l’yritlinc J>orivnt.ivrR.. . . . . . . . . . . . . . . . . 5 . Piperitliiiti Dttrivntive. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Thianeplithetic I)t.rivativcn . . . . . . . . . . . . . . . . . . . . . . IC 3% ant1 Di-%imitlasolinrs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

aao

371 372 372 372 352

372 358

373 3 3

CoiiknLs

.

xvii

I11 ImidazoUdines. ....................................................

.\.

Alkyl- and Ar?.liriiidnnolidint.x.....................................

. Yittivt itmil( hwtps C . HekmrinpSulwtJ tuttwl Imidazoliclincn . . . . . . . . . . . . . . .: . . . . . . . . . . . . . . 1. F u n n h r i v n t i w s .............................................. 2. Triazole hrivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Biaimidazolidines................................................ IV. Imidamlidones. Imidazolidlnethiones. and 2-Jminoimidazolidines.. 1% Alkyl- 1 ~ l i t 1Ar?.liniid,r7~lifli1i~~ Chit:iitiiiiK Atltlit i o t i : ~I

.

.\ 2-Imidazoliclones (Ethylcneurcas) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Alkyl- and Aryl-Zimidardidonea .............................. 2. Alkyl- and Aryl-2-imidazolidones Containing Additionn1 Functionnl Gmups .............................................. 3. ZImi~lnrolidonec~rhoxylicAcids and Carboxynlkyl-Zimictseolicbnw Including Those Containing Additional Functional Gmups . 13. 4 and 5-Imitlasoliclones.......................................... C. 2-Imidazolidinethiow (Ethylenethioureas) . . . . . . . . . . . . . . . . . . . . . . . . D. 4Imi(Jszolidinethiones ........................................... E. 2-11nitioimiclazolitIi~ies(Ethylenegunnidinm)........................

V Benzimidamlea .....................................................

. . .

. .

37.3 353 Xi4

37.5 355

375 316 356

376

31g

376 377 378

378 379 379

379

A Alkyl- and Arylhonzimidazolea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 13 AlkyE and Arylbenzimidazoliuni Salts ............................. 382 C Oso- and HyclroxyhenzimidRzolcs and Their Sulfur Analogucw ......... 382 1 2(3H)-Benzimidazoloncs (ZII~dros~I~.xiaimids~oles, o-Phenylene-

.

UlWbS) .................................................... 382 (a) hlkyl-2(3H)-l~ciiziinicl~zolonr~ Iiiclucling Those Containing Ackiitioiinl Functional Cmups .......................... 382 (11) 2(3H)-Benzimiclaaolon~a~~os~lic Acids sntl Cnrhosyalkyl............................... 2(3H)-f~nzimida~olon~~ 3&7 2. 2(3H)-Benzimidseolet.hionw (ZJicrcnl,to.erizimiLnzol.. o-Phenylenetliioun) ...................................... 383 3. Monw and Polyhydrosyalkyl- and ~I~clro~~ar~1Iieiiximitlnzolcs, Their Ethers and Halogen Derivatives ........................ 384 (a) Hydroxy-. Irydroxyalkyl-. and H~~droxgnr~~ll~enzi~d.olea, Their Ethers and Sulfur Analngues...................... (I)) Hydroxy-. Hydroxydkyl-. and H y c l ~ . ~ ~ n r y l b c ~ i r n i ~ ~ z o l ~ Cantaining Halogen ................................... 386 (c) Polyhydnxyalkylbonaimidazoles........................ 386 4 Benzimidazolecsrbo?uIlde.d.s. Iietones. and Quiiionctcr . . . . . . . . . 381 D Halogeno-. Halogenoalkyl-. and Hal~norrrJ.ll~e~imiclazole~. ......... 388 I3 Nitro-. Kitroalkyl-. and Nitroarylhenzimidaznlea Including T h m Containing Additional Funct.ionnl Croups ............................ 388 F Aminobeneimidarol............................................. 389 1. Amino-. Aminodkyl-. sncl .eninoalrlI.nrirni~ a.oles. . . . . . . . . . . 389 2 Amino-. Aminoalkyl-. and Aminoar~~lhensimidarol~ Containing Additional Functional Croups............................... 392 394 G Cyanohenzimidazol.............................................

. . .

.

.

.

sviii

.

\? Ikrisimidaxolt-s( w n h t t c d )

11. H ~ ~ i i z i t ~ ~ i t l : t . ~ o I ~At-ids r b ~ s ~ l i i. :. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 . \lonwri.rbosylic

AcMi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . :rncl A r ~ l l ~ c : ~ i s i i i ~ i t h s o l ~ At:idn ~ ~ r l ~ Iitcludinr s~li~! Thorn Containing klditiond Functional Croups . . . . . . . . . . (b) Carbosyrlkyl-, C:rrrlxwydkxnyl-, and (:rrrl,os\.sr?rlltcrtximiClazolcs..... .......................... 395 2. Dicarhoxylir. :\(.ids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 I IJrtrximidunolc~ulfonicAcids, Sulfn.ilkyl-, and Sulfortl.3.lbeiIziniicfRzolc~s. 398 J . l~ndmidnrolcAmtiia.ils ..................... . . . . . . . . . . . . . . . . . 398 li. 2.3-Mhydmlw~iraimitlrmolc.s( l ~ ~ ~ ~ i ~ i n i i c l ~. ~. ~ t l. i. i.i.~. ~. .s .) . . . . . . . . . 399 1.. 1 Ictcmrin~-~iih.sf.ittiirvl Ik?nximiclszoli*s ............................ 399 I . 1hir:in 1hriv:it iws . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3w 2. Tlriojihciic I )c*riv:iiivc.?c . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 3. I’yrrolc 1)rriv:rt.ivc.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 .b 1’yr:ixoltr I)criv.iiivi.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3w A . Iiyriiliiic! I)c!riv.it.ivia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . -100 t i l’i~~~*rieli~ic I>c*riv:it ivw . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 i. > forplioliI tc 1hriv:it iw!: . . . . . . . . . . . . . . . . . . 400 X . S:irithyl Dc1riv:i.iivc.s.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MO 9. 1 ’ l r t l ~ : t I i ~ l f)i*riv:ti ~~ ivv . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 10. 1iril:crin :nit1 Irtclolo I )e!riv:it.ivcr.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . m 1 1. Quiniiliitc 1)c.riv:i.t.ivc.s.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 12 Ik.iiacnli:isc~ijiiti! 1hiv.it.ivc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 13. h c ~ t ! i i : ~ ~ i J ~ f 1hiriv:rt . I i ~ ~ ~ i ivc ~ ~ .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 11 Hi-? IX-,: ~ i i c lI.ixl~criaiinicI.ize.lr.. . . . . . . . . . . . . . . . . . . . . . . . . . -101 (8)Alkyl-

.

.

.

. .

8

.

Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

401

Suhject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

421

SECTION 1 Chemistry of Classes and Derivatives

This Page Intentionally Left Blank

..

CHAPTER I

General Properties and Structure of the Im idazoles A. Nomenclature

This book deals with the chemidry of the ring system depicted below wliich has been designated as glyoxaline, imidazole, iminazole, or 1,3diazole by various workers. As a starting point for the following discussion it is essential to sct forth the rules whicli govern the naming and numbering of this ring system. Debus ( l ) ,tile discoverer of tlie parcnt compound, prepared it from glyoxal and ammonia and, to indicate its source, proposed the name glyoxaline. This name is still uscd in thc modern literature, especially by British workers. The name imidazole, uscd in the dresent monograph, is due to Hantzseh (2). He classified as azoles the five-membered p l y heteroatomic ring systems containing at least one tertiary nitrogen. The term imidazole implies a five-membered, heterocyclic ring system containing, in addition to a tertiary nitrogen, an imino group; just 8s the names oxazole, and thiazole designate five-membered ring systems containing in addition to a tertiary nitrogen an oxygen or sulfur atom.

The correct numbering of the imidazole ring is shown above. The imino nitrogen receives position 1, and the numbering follows around the ring so as to assign the smallest. possible number to the tertiary nitrogen, which is designated as position 3. The substituted nitrogen represents the starting point, for the numbering of the N-substitiited imidazoles. The designation of a substituent in position 2 offers no problem because of the symmetrical location with respect to the nitropens. The naming be-

:;

Chemistry of Classes and ncrivfitivrs

4

soiiieahnt more coniplcx, Iiowcvcr, wlicii a subst itirent is introduced in(o the 4- or 5-pasitioa. Depending iipoii tho position of t h iinino Iiydrogcn such A cu~iipoi~ncl must bc clcsigndcd as cithcr a 4- or H 5-nionosubstitntcd jniidszole, thc tautomoric cliatactcr of the imidazoles (see Section WJWS

E) precluding :t definite assignincnt of structurc. Such compounds are designated as 4 (or 5) -monosubstitutcd imidszoles.

k A siniilar situation exist.s in tlic case of the 4- and 5-disiibstituted and the more highly substituted iniidazoles. The following examples will serve to illustrate this point.

-

4 (or 5)-Methyl-5(or I)-ethylimidasole

H I

H

H

H

I H

2,4(or 2,5)-Dimethyliniidazole

H 2-Meth yl-4(or~)-ethylimi&~zole

A

2,4 (or P,5)-Dlmethyl-5 (or 4J-nitroiniidadc

Substitution of the iinino hydrogen eliininates the possibility of tautomerisni, and ct definite assignment of structure becomes possible, as illustrated below.

1,4-Dimethylimidnzole

1,S-DirnethyIimidamle

The sclieine outlined here will be used systeinatically throughout tliir monograph. Additional remarks regarding the naining of certain special types of imidazolcs will be found in the respectkc sections. The nomenclature used conforms to the rulcs of Chetr~icalAbstracts.

B. Physical Properties 1. Introduction

The consideration of structurc inust be based on physical as well 8s chemical properties. It thus seems logical to summarize first the physical properties of tlie iniidazoles. Whenever possible, tliis will be donc from tlie point of view of coinparison, since pertinent inforination on other hctcrocyclic, ring systems will :tit1 in 1inderst:mding tlie iinitlazole problem. 2. h i l i n e and Melting Points

'l'.ABLE I. Boiling Points of s Numhr of Five-Membcred Heterocyclic Compounds B.p., OC. (760 mm.)

Compound

-__

Furan ......................................... 32 Pyrrole ....................................... 131 Pymzole ...................................... 187 1,2,3-Triazole .................................. 204 Imicluzolc ..................................... 2.56 1,2,4-Triwolc .................................. !260 I

- -_.-

-

Tnble I summarizes tlie boiling points of a nmnbcr of five-membered licterocyclic compounds and illustrates the unusually high boiling points

G

Chemistry of Classes and Derivatives

of iiuidazole and 1,2,4-triazolc. Pyrscole also boils rather high in coio-

parison with furan, and yyrrole, dthougli it does not differ. significantly froin them in inolecular weight. Tile boiling point of iniidazole is strikingly lowered by the introduction of 8 methyl group into the 1-position, but is not significantly affected by the introduction of a inctliyl group into the 4(or Ti)-position. Even tlic introduction of an amyl group, which doubles the niolecular weight, results in a substance boiling lower than the parent ring system. Tliesc results demonstrate that the free iinino hydrogen is, to a certain degrec, responsible for the observed high boiling points of imidazoles (Table 11).

.

TARLE 11. Effert of Snbstitiients on the Boiling Point of Imidawlc Compound

B.IL,'C. (?!XI mni.)

Imidazole ...................................... 258 198 I-Methyl- ..................................... 4(or !j)-Methyl- ............................... 264 1-Propyl- ..................................... 223 1-Amyl- ....................................... 245 1$-Dimethyl- ................................. 205 1-Ethyl-%methy I- ............................. 211 1-Methylb-clilowi- ............................ 202 1-Methyl-4-chlqro- ............................ 245 200 1,4-Dimethyl- ................................. 1,SDimethyl- ................................ 220 1-Phenyl- ...................................... 277 2-Phenyl- ...................................... 340

Table 111 suniinarizes the melting points of a nuinber of imiclazolcs. ITcrc again it will be noted that the introduction of substitucnts into 1 . 1 ~ I -]wition of the imidazole ring hns a striking lowering effect. TAl3T.E 111. IIclting Points of a Number of Tmidnmles ('mtq~ountl

Imidazola ....................................... I-Methyl- ...................................... 2-Methyl- ....................................... 4(or Fi)-MeiItyl- ................................. 1-Phenyl- ....................................... 2-Phenyl- ....................................... 4(or I)-Ptic~nyl- ................................. ....................................... I-Ben& 2-Benzyl- ........................................ 4(or S)-Bengyl- ................................ 4.5-DiphenyL. ................................ 2-Methyl-4,5dipheuyl- ......................... l-Methyl-4,6-diphenyl- ..........................

!bf.p..

oc. 90

-6 140-141 55-56 13

148-149 133-134 71-72

125-126

82-84 228 240

158

3. s%luhility

Tlic sulultility o l iiiricl:txolc is high ia poltrr :rncl low in I I O I I - ~ I O ~ ~ U solvents. At rooiii temperature it is so cxtremely soluble in water that quantitative data on its solubility have not been obtained. The base is somewhat soluble in benzene ; however, at room temperature its solubility in this solvent is rather limited. Cyclohexane is a poor solvent. 4(or 5 ) Methylimidazole exhibits good solubility in benzene. The N-substituted imidazoles are in general much more soluble in non-polar solvents than are the imidazoles with a free imino hydrogen. Quantitative figures on the solubilities of imidazole in benzene and in dioxsne, and of 4(0r 5)-methylimidazole in benzene, are given in Tables I V and V. TABLE IV.Solubility of Imirlszole in Bcnxcne and in Dioxane (3) 1.1

Temp., "C.

ihxt-ne

----

_.--_--

eM.7 4 1.o 42.2 42.8 448 45.7 478 40.0 51.2 .i1.8 52.9 56.2

_t

Molnli~y

0.198 0.268

0.486

0.888 1.196 1.524 2.38 3.00 4.03 5.38 6.77 9.23

Ihxnnr

'renrp., T.

14.7 17.9 21.9 23.0 32.7 38.0 39.4 46.8 55.8

Molslity

3.62 429 4 9.3 6.17 7 48

9.46 10.5 143 19.3

TAHIJ! V. Solnbility of 4(0r 5)JiethyIimitlnzole in Renzene (3) Temperature. T.

I _

---

32 16.8 21.1 25.4 3.3 31.4

Molnlitp

4.57 6.0i

687 7.44 8.24 8.54

4. Molecular Weight and Degree of Association

._ -. -

The determination of the molecular weight of iiiiidazolc and of 4(or 5)methylimidazole by the vapor-density method indicates that tliese compounds are not associated in the gaseous state (4,5). The theoretically expected molecular weight of 68.0 is found for irnidazole by the use of Vietor Jfeyer's vapor-density method at a temperatiire of 306" (3). However, when thc inoleculnr weights of these compounds are determined

Chemistry of Clnsaca nncl Dcrivs t.ivrs

8

11ythe cryoscopic'or cl)ullioinetqi.ir~ iii&wis in non-polar snlveiif s, striking deviationP from ideal behavior isre abserved. Most unusual in t,hk respect is the cryoscopic behavior of 4 (or 5 ) -mctliylimidazole in hpnsenc: solution. A t I\ conccntmtion of 0.6 7n (nz = molalikyy)this stihRtance ex-

I

1

I

I

I

I

I

I

1 2 3 4 5 6 7 CONCENTRATION. 9. mols. x IO'*/IOO g. of solution

I

8

Pig. 1. Associution-concentration curves of a number of iniidnaoles in napht.halcne (6): t 1) imidazolc; (2) 2,4~trimetliylin~idozole ; (3) benzimidiizole; (4) I-c.r~il~etho?rybenzirnidaeoIe;(5) 1-niethgl-4.5diphen~limidnxolc. y p r e n t molecular weight Association factor. a = formula weight

hibits an sppsrcnt molecular weight of 1500. Tliis represents almost twenty times thc cxpected formula weight of 82. At liiglier concentrations R slight rise in the apparent molecular weight is notcd, which reaches a maximum a t a concentration of 1 n z and slowly decreases a t still higher concentratsions. Similar behavior is observed with imidazolc, which exhibits~a normal molecular weight only in highly dilute solution.

I. General Properties and Structure of Imidazoles

9

The cryoscopic behavior in naphthalene of a great number of imidasoles and benzimidazoles parallels that observed with imidazole and 4 (or 5 )-methylimidazole. Of importance is the fact that substitution of the imino hydrogen by alkyl, aryl, acyl, or carbethoxy groups invariably leads to compounds exhibiting little association (6). A set of typical association-concentration curves for a number of imidaeoles obtained by the cryoscopic method in naphthalene is illustrated in Figure 1. Ebulliometric molecular weight determinations in boiling benzene also yield abnormal results. For example, 4 (or 5 )-metliylimidazole a t a concentration of 0.4 m exhibits an apparent molecular weight of 190, which is approximately twice the formula weight. Imidazole is also appreciably associated in boiling benzene, since at a concentration of 0.4 m a molecular weight of 250 is observed (approximately four times the formula weight). It is of interest to note that imidazole in aqueous solution exhibits a normal molecular weight which changes little with increasing concentration. TABLE VI. Viscosity of I3enzenc Solutions of 1micl:izolr and 4(or 5)-MetliyIimidazole (3) Compound (tonap., "C.)

vvlcOs1ty

0.073

0.W8 0.0649

.................................. 0.036

Iinidazole (30")..

Imidnzolc ( 5 0 " )....................................

0.146 0.146 0.416 0.483

........ 0.040

4tor 5)-Methylimidazole (30")......... ... ..

4(or 5i)-Methylimidazole(50').

Specif0

Molality

0.080

0.242 0249 0.476 0.493 0.607 1.075 1362 2.w 2.848 3.738

..................... 0.242

0.249 0.475 0.493

0.801

0.0106

0.0410 0.1500 0.1686 0.0071

0.0354 0.1 187 0.127; 02926

0.3262 0.4113 0.7801 0.9911 1.6524 2.3138 3.1560 0.0910 0.0030 02140 02370 0.3079

All these findings point to a high degree of trstiociation of the itiiidazoles in non-polar solvents; that the association is dependent on the presence of a free imino hydrogen is evidenced by the low degree of association of tlie N-substituted imidazoles and benzimidasoles. 5. Vlecosity

Tlie specific viscosities of benzene solutions of iniidszole and 4(or 5 ) ~uetlryliiiiidazoleare given in Table VI (p. 9). Solutions of pyrrole or of pyrazole in benzene have approximately the same viscosity as tlic pure solvent, and negligible variation of the specific viscosity with increasing concentration is observed. This suggests little association. Tlie specific viscosity of solutions of iiiiidazolc and 4(or 5 ) -methylimid~bsolc,011 t Iic other band, increases with incrciising concentration (see Table IT),n bcliuvior pointing to tlie pwacnce of long-chin aggregates. 6. Dipole Moments

Most valuable infornintion on the fine structure of organic niolcculcs iiiay be gained from an exact knowledge of tltcir dielectric properties, sincc tlic magnitude of tlic dipolc iuotiiciits is iaciicntivc of the cliarge distribution within their structures. Unforttinatcly tlie esperjmental 11i:iterial 011 iinidazolcs is rather limited, clipole moments being avni1al)Ie only for imidazole, 4 (or 6) -iiietliyliinidnzole, l-riietliyliii~i~l:rgolc,uticl h i i ziinidazole. Tlie results are sumninrized in Table VII.

Again tlie high degree of ussocitation of the imidazolcs containing R free iiriino group in non-polar solvents reflccts itself in the dipolc?moments. Thus the mornent of I -methylimidazolc witen iiieasured in bctizenc solution is little dependent on the concentnrtion, in contrast to that, of iiiriclazolc ~vl~icli v:iric?s t,o R consiclcr:rldc extent as illiistr:\ted in T:hIc VTTT.

I. General l’rolwrtics

a i d Strtvt.urc of Iniitlnzolcs

11

TABLE VITI. Variation (with Conccntration) of thc Dipolc IIonimit of Imitlnxole in Benwne (7) Mole fmtion of cnlute

--

Dipole moment. Debye unib

o.oo5051 0.001140 O.OOO233

5.02 4.42

3.93 7. Spectroscopic Properties

(a) Ultraviolet Absorption Spectra

The siiiiple iinidazoles fail to exhibit selective absorption in the ultmviolet region t8,9,. Sclcctivc absorption is observed in iniidazolcs in wliicli thc iniidltzole ring is conjugated with a carbonyl group, such as in the imidazolecarhoxaldehydes and irnidazolecarboxylic acids. Also, certain functional derivatives such as the imidazoletliiones exhibit characteristic absorption maxima in the ultraviolet region. The spectra of these coiiipounds will be found in the appropriate sections.

( b ) Ranian Spectra The Raman spectra of various iiiiidazoles have been investigated, and thc reader is referred to the original literature on this subject (10).

( c ) Chemiluminescence A nunibcr of arylimidaroles exhibit chemiluminescence when exposed the action of an oxidizing reagent in alkaline milieu. This interesting phenomenon was first observcd by Radzisrewski (11) who found that a solution of 2,4,5-triphenylimidazoIc (lophine) in potassium hydroxide emitted light when it was shaken with air. He was struck by the intense light production and described his observation as follows: “The phenomenon becomes rather spectacular on a large scale; I employed 100 g. of lophine and 300 g. of potassium hydroxide in alcohol for my experiments. The devclopmcnt of light was so intense that it was possible to see the faces of the observers at a distmce of two to three feet, and at a distance of two and one half to fivc ccntinieters the numbers and hands of a pocket watch could be recognized.” The addition of an oxidizing agent to n solution of lopliine in alkali brings about a marked increase of the cheniilumincscence. Optimal effects are obt-ainedwhen a solution of lopliine in ethanol, methanol, acetone, or ’ dioxane is treated with an oxidizing reagent such as hypohalite, pota,.~slllni to

Y

13

TABLE IX.Density, Refractive Index, and Molar Refractivity of Iniidazole und Derivatives at Various Temperature* (3,171 Imidazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . .

4(or +Methyl-.

.. . . . . . . . . . . . .

Temperature

Density. dd

95.0 100.9 110.0 153.0 205.0 14.3 18.0

1.0360

(0, OC.

Compound

.

. , .... . . . .

.,.

50.0

60.0

1-Methyl- . . . . . . . . . . : . . . . . . . . . . . . . . . . . . . . . . . . . . ................................ I-ISoamyl-. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . l,%Dimethyl-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-Ethyl-%methyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-Methylb-chloro- .. .. . . . , . . . . . . . . . . . . . . , . , . . . . I-Methyl-4-chloro-.. . . . . . . . . . . . . . . . . . . . . . . . . . . l-Ethyl-%methyl-5-chlo~~. .. . . . . . . . . . . . . . .. . . . l-Ethyl-%mthybhbr+. . . . . . . . . I-Phenyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I

70.0 110.0 153.0 20.5 19.6 19.7 16.1 21.8

20.5 17.7 19.8 19.8 16.8 15.4

-

1.om 0.9920 0.9370 1.M16 1.0360 1.0160 1 .m 1 0.9691

.oom

0.9380

1.0325 0.9i05 0.9427

''C

1.48075 1,47625

-

1,50367 1.50115 1.a922 1 ,48627 1.-18227 I

1.2500

1.4885B 1,47671 1.47114 1.48665 1.4a301 1.50630

1.1415 1.1598 1.139i

1. m o 1.49519 1.a364 1.59335

1.m 0.9807 1.2561 1 .a83

1 SO783

"He

(UjP

1.48428 1.48006

-

fiF

1.49442

1.48W

-

I

1 ,50774 1.50572 1.4BfI8 1.48!494 1.48553

1.51750 1.51499 1.50284 1.49982 1.4953S

-

I

1.43244 1.48021 1.47425 1.49024 1.48660

1 ,51009 1.51181 1.51308 1.49888 1.50223 1.59999

1.50157 1 .WQ

1.4m5 1.49926 1.49516 1.51958 1.52121 1,52259 1.50731 1.51088 1.61650

.w,

ferricyanide, hydrogen peroxide, or hemoglobin (12-15). 9 variety of substituted aryliinidazoles such as 2,4,5-trb (p-methylphenyl) - , 2,4,5tris (p-methoxyphenyl)-, and 2,4,5- tris (p-chlorophenyl)-hidasole, or substances like 4,5-diphenyI-2-methyl-, 4,5-diphenyl-2-ethyl-, 4,5-diphenyl-2-isopropyl-, and 4,5-diphenyl-2- (p-methoxyphenyI) -imidazole cxhibit clieniiluiiiinescence under the above-mentioned conditions ( 16). Ainarine (2,4,5-tiiphenyl-2-iinidasoline)behaves similarly (14). Imidnzole exhibits a weak degree of chemiluminescence upon exposure to hydrogen peroxide (12). The emitted light exhibits a continuous specti-um ranging from 48006OOO A, with a maximum at 5300 A. 8. Miscellaneous Physical Properties

Information on refractive indexes, densities, molar refractivities, surface tensions, heats of fusion, and heats of solution of imidaaole and 4(or 5)-methylimidazole is suinmarized in Tables IX, X, and XI. TABLE X. Surface Tension of Imidazola and 4(or 5)-Methylimidarole (3) Comwuad

Imidazole

..........................

4(ori)-Methyl-

....................

Temperature, "C.

Surface trmsion, dynidcni.

110.0 150.0 205.0 20.0 66.0 110.0 153.0

36.82

33.85

30.05 38.70 3621 32.36 29.28

TABLE XI. Heat of Fusion 2nd Heat of Solut.ion in Benzene at Varying Concentrations of 4 (or 5 )-3Iethylimidazole (3) molity

Heat of solution. eal./mole (21')

0.13 0.22

-3210 -2170

-

Heat of fusion, cal./mole

-2840

-

C. Chemical Properties 1. Basic Strength

Iinidazole is a monoacidic base having the ability to form crystalline salts with acids. The melting points of a nuiiiber of characteristic imidazoliwn salts are listed in Table XII. The basic nature of the imidazoles is due to the ability of the pyridine nitrogen t o accept a proton. Substituents influence the basic strength of imidazole in the inanner illustrated in Table XIII. The introduction of methyl groups into the

'I'.iHLE S I I . Alr4ting Points of %It

.

B

Xiimbt-r of Imidnnole Salts Mp., OC.

Xitrate ................... 118 Chloroaurate ............. tlec. 100 Chloroplatinate ........... clec. 200 Dimolybdatc ............. Picrate .................. 208-212 Flavianate ............... 224-220 Dilituratc ................ Acid oxaliitr .............. 232,252,225 Acid tartrutc .............. 202 Benzoate ................. w

..

. . . _ I

iniirlazole ring increases its basic strength. This is explicable in terins of the electron-releasing properties of the inctliyl group, which tends to increase the electron density about the pyridinc nitrogen. The situation parallels that observed in the pyridine series, where the basic strength of a-picoline is also higher than that of the parent ring system (33). This increase in basic strength has been attributed to a combined inductive and resonance effect (hyperconjugation). Siinilur considerations may apply to 2-methyliinidarole, where hyperconjugated states of the type depicted below are indicated. The introduction of a methyl group into tlie 4( or 5 )position of the iniidazole ring also increases tlic basic strength, but tlic

effect is lcss pronounced than that of the 2-nietliyl group. Syiiiiiictry considerations iiiiglit ofler mi cxplanation for this different-c. Tile 2-mcthyliinidazolium ion represents a highly symmetrical structure with two equivalent contributions, in contrast to the 4(or 5 )-metliyliinidcizolium ion methyl with two non-equivalent contributions. The introduction of group into both the 2- and the 4(or 5)-position causes u further incrcasc in basic strength. Electron-attracting groups such as tlie plieiiyl group, the nitro group, or a halogen, decrease the basic strength. A few qualitativc observations on tlic basic strength of N-nlkylnitroimidsroles are of interest. A coiiipsrison of 1-methyl-5-nitroiinidazole and 1,2-dimethyl-5-nitroimidazole with their respective 4-nitro derivativcs indicates that tlie 5-nitro compounds are the stronger bases (34%). It

I. General Properties and Structure of Imidaaoles TABLE XIII. Basic Strength of a Number of Imidazoles (30,32,32a) Compound

Imidazole 1-Methyl%Methyl4(or WMethyl2,4(or 2,5)-Dimethyl2,4,5-Trimethyl2-Phenyl4(or ti)-Phenyl4(or S)-Hydroxyrnethyl4(or S)-Carboxy4(or S)-Carbethoxy4(or S)-BromoHistamine

PKa

6.95; 6.W 7.26 7.88 7.52 8.36 8.88. 6.39

15

--

6.00

6.38 8.08'

3.06'

3.80. 5.98'

Measurementa in 233 per cent aqueous ethanol at 30'.

seems logical that the structure' in which the nitro group is located in close proximity to the electron-donor system (pyridine nitrogen) should represent the weaker base. CH L

CHa I

I

H-C' N'f-CHI

O&-F'N'f-CH,

H-C-N 1,2-Dimethyl-5-nitroimidazole (stronger base)

II OnN-C-N

1,2-Dimethyl-4-nitroimidazole (weaker base)

2. Pseudoacidic Character

In addition to its basic nature, imidazole also exhibits weakly acidic (pseudoacidie) properties. It forms aalts with metals of the general structure shown below. Most important among the salts is the sparingly solu-

ble silver salt, which is precipitated when imidazole is brought into contact with ammoniacal silver solutions. In the presence of ammonia, insoluble salts with cobalt and einc are also obtained (36,37). The reaction of imidazole with a Grignard reagent results in the formation of an imidasole magnesium halide (38,39).

Chemistry of Classes and Derivatives

16

H

The pseudoacidic nature of iiiiidttzole depends upon tlie preseiice of an unsul),staitutediinino group, and iniidazoles having this structural requirement forni sparingly soluble silver stilts in the presence of aminoniiical silver solutions. Many imitfazoles foriu insoluhlc salts witli cuprous ion in the prcsence of animonia (40). Iinidazole dissolves in liquid aiiinioni:i, forming H clear solution from wliich it is regencrated on cvaporntion of tlir aolvcnt. The addition of iiictals or of nietal :iniidcs to sueli a solutioii i*csulteiii riilt forination. Tfie sodiuiii, potnssiuiii, cdc:iu~ii, niid magnesiuiri sitlts ttrc obtained in this iiiann~r. Tlicsc stilts ;ire unstahlc in the prcsc.iic.c of wiLtw, :rnd hydrolyze with tlic ioriiiation of iiiiidnzolc iriid inctullic. Iiyli.oxitlcs (41 ) . A coinpariaon of the c*oiiiluctaiiccof liquid miinoiri:i sohitions of iiiiirliizole and of pyrrole deiiionstrates the former coiii~~oriiitl to rcprcscnt the stronger acid. Elcrtroiicg~ttivcsubstituents increase tlic nridic. propertics of tlic iiiiidazolcs by tlcc*rcxsiiigthe electron density itl)out tlic ~~yrrolc nitrogen. J.ol)liiiic is ;L st rongcr acid tliuii iiiiit1:izoIt~. I A c iliridiwdc, lopliiiic foriiis salts ul)oii tinatiiicnt with metals or iiictal :tiiiidcs in liquid iiiiiiiionia solution (41). 2,4,5-Tril~roiiioiii~idaz~le is a strong enough avid to dissolve in tiqueous sodium c:irl)onate solution (42). 3. Chemical~Stabilityand Aromatic Character

Altliougli a detailed discubsion of tlic clicniical behavior of tlic iiiiiclazoles will represent the subject of Iiltcr cliaptcrs, it seems pertinent to suiii . tiiarizc briefly a numlm of their kcy propertics prior to consideration of structure. Outstanding is tlic pronounced cliciiiicitl stiil)ility of tlic iinidazolcs. 'I'licy are rcsistant to tlic most drastic trcatntcnts with :scitls anti 1)asca. Kxposure of iinidazolus to the action of 11ydrogc.uiotlidc i r k teiiiiwrzttr1rcs up to 300" Iias little effect, and the iniidnzolc- ring 1-csistsclttulytiv hydrogenation to it reinarkablc degree. A number of I)enziiiiidazoles, such us !&inethyl-, 2-ctliyl-, and 1,2-dimcthyl-bensin~id~zole, in tlie presence ol' Adains cstulyst and glacial acctir acid undergo hydrogenation iii tlw !)cnzcnc portion with the foi-nintionof the rorresponding tetrahydro derivntiws. The iinirlirzolc portion roirirriiis unuffcctcd (43-45).

I. General Proprtics and St.nicturc of Imidnzolcs

H H

17

I

€I--& +N H’ ‘C’

H H’ Lophine undergoes catalytic hydrogenation over Willstiitter platinum catalyst in glacial acetic acid?and is converted into 2,4,5-tricyclohexyl-2imidazoline (46). Imidazole is stable toward chromium trioxidc (a), but is readily attacked by pot.assium permaneanate and hydrogen peroxide with the formation of oxamide (47,481). Benzoyl peroxide in cliloroform solution also attacks imidazole readily with the formation of urea and aninionia (49). The imidazoles undergo typical “aromatic” substitution. They can be halogenated (see Chapter IV),nitrated (see Chapter V, Section A-1), sulfonated (see Chapter VI, Section B ) , and hydroxymethylated (see Chapter 111, Section B-1-(a)), and exhibit the abi1it.y to couple with diazotized aromatic amines to form azo dyes (see Chapter V, Section B-1). Despite t.he presence of an “imino” group they fail to react with nitrous acid.

D. Structural Considerations

1. The Classical Imidazole Formula

As has been stated previously, the discovery of irnidazole dates back to the year 18.58 when Debus (1) obtained the compound for tlic first time. He recognized the basic nature of the substance and esta1)lishetl the correct empirical composition as C3H4Nl,but did not propose a structural formula. Although this represented the first description of the parent ring system, imidazole derivatives had been known prior t o 1858. For example, 2,4,5-triphenylimidazole (lophine) was initially synthesized by Laurent (50) in 1845. Recognition of the close chemical relation between lophine and imidazole was of a later date. The first chemical study of iniidazolc was carried out by Wyss (42), wlio substantiated the work of Debus and established a number of fundamental points about its general behavior. He recognized the amphoteric nature of the coinpound, and although lie was able to alkylate the base, he failed to achieve its acylation. The great stability of imidazole toward hydrogen iodide, and the formation of a tribromo derivative, also were reported by this investigator. Based on these findings, MTyss proposed the structural formula: 0

Chemistry of Classes and Derivatives

18

Imidamle (Wyss, 1877)

Most fruitful for the further dcvclopinent of the constitutional problem was the suggestion by Radzisxcwski (51) that lophine may be an imidazole derivative. Considerable progress on the constitution of this latter compound had already been made a t that time. Based on t-hc partial structure advanced by Fischcr and Trosclike (52), Japp and Robinson (53)in 1882 proposed the currently accepted, classical structmc of lophine. Almost simultaneously Radziszewski (51) prepared lophine

Fischer, 1880

Japp, 1882

Proposed structures for lophine

Radeiszewski, 1882

by the interaction of benzil and benzaldehyde with ammonia and, based on this synthesis, proposed a structure for lophine which differed from the Japp formulation in the distribntion of the double bonds. He also postulated for imidazole a formula not containing an imino function, since in his opinion only such a structure was capable of explaining the failure of imidazole to undergo acylation and its inertness towards nitrous acid. These views were not shared by Japp who put forth an imidazole formula

Radziszeaski, 1882

H

Japp, 1882 Proposed structures for imidamlc

with an arrangement of the double bonds analogous to that proposed for lophine (54). Japp accepted Radziszewski’s suggestion that imidazole representa the parent ring system of Iophine but pointed out that his formula was better suited to explaining the chemical behavior of the com-

I. General Properties and Structure of Imidazoles

19

pound. He reasoned, for example, that. the structure proposed by Radziszewski would be expected to form a tetrabromo derivative, whereas imidazole had been shown by Wyss to be brominated with the formation of a tribromoimidazole. Also, he felt that his structure was better suited to explaining the great stability of imidasole toward hydrogen iodide. Although the Japp formulation was later shown to represent the correct classical structure of imidazole, neither Japp nor Radsiszewski presented conclusive evidence for the correctness of their postulated formulas. It remained for Bamberger (55) to furnish the most convincing piece of evidence for the structure of imidazole when he oxidized benzimidazole to 4,5-imidazoledicarboxylicacid and by decarboxylation of this compound obtained imidazole.

dxH

H

H

H I

oxidation-

HOOC 2. Current View8

Any theory concerning the structure of the imidazoles must offer plausible explanations for the following characteristic features of this class of compound: (1) Their pronounced “aromatic” properties, as reflected in great cliemical stability, saturated character, and typically aromatic substit ution behavior. (2) The pseudoacidic nature of the imino hydrogen. (3) The high degree of association in non-polar solvents and the idge dipole moments. (4) Many other properties as discussed in succeeding chapters. The classical formula of Jspp fails to satisfy these criteria and thus is not a suitable representation of the imidazole molecule. The azoles are, without exception, substances exhibiting a typical “aromatic” behavior. Their much more pronounced polar character differentiates them markedly from benzene and from other five-membered lieterocyclic compounds, such as furan, pyrrole, and thiophene. This polarity reflects itself in unusually high boiling and melting points, increased water solubility, and high dipole moments. Despite these differences in fundamental behavior, explanations similar to thoae,currently in use for characterizing the state of the benzene molect~leitlay he profitahly applied t.0 these heterocyclic systems. The

20

Chemistry of Classes and Derivatives

properties of benzene are linked to a characteristic six-electron resonance system. The azoles and many other lieterocyclic ring systems contain similar electronic configurations, as illiist,rnted below : €1

H

H I

N

H

T"yH

H

Pyrrole

N

Tliiazole

111 coiitxast to tlic situation in lm~zciie,wlicre circli imd,liiiic groiii) ooiit*ributesone T electron, tlie different ring partners in tlie Iic!terocyclic: coiiipounds do not make equal contributions to tlie resonance systeui. Thc i i i c t h e groups and the tertiary nitrogen contribute one electron each, in contrast to tlie imino group and atoms sucli as oxygen or sulfur, which are the source of two electrons. Pertinent in connection with the present discussion is ti consideration of the pyrroles and the pyridines. Pyrrole is best represented as a resonuiice hybrid to which tlic classical structure A and two pairs of syminctrical structures B and C m:dx significant contributions (56). This foriiiui:it.ion, which receives support. flwn hond-distancc n i e a ~ ~ i r ~ i ~ i (57 c n t)s :uid clipolc nioiiicnt t b t . a (hb) , offers a pkiusiblc explanation for tlic!

H H

t ,

H A

H

€1

I

B

H

H C

chemical behavior of pyrrolc. Its acidic character, for example, may be tlic result of the illustrated T electron distribution which places a positive vhargc o i i tlic iiniiio nitrogen, tlius facilitating the release of a proton. Pyiwlitliiw, tlic r:hirtrtetl ittrdogt1c of pyrrok, wliic.11 lacks this resonnncc system, I)eliiiws likr :L typi(.:il sc9c~oiitl:wyiainiiic.

a

The acidic nature of the imidazolcs is explicable in a similar manner, and the imino nitrogen will be referred to as the pyrrole nitrogen. Characteristic for the aaoles is the presence in their molecules of a tertiary nitrogen which endows them with basic properties. The properties of this nitrogen are strikingly similar to those of the nitrogen in pyridinc. Accordingly, this function will be designated AS the pyridinc nitrogen. The presence of an electronegative nitrogen in pyridine is responsible for the characteristic behavior of its ring system. Sincc it seems reasonable to assume that the tertiary nitrogen in the azoles will exert a similar influence, a brief consideration of fundamental pyridine chemistry is in order. Using its affinity for electrophilic reagents as the criterion, pyridine is less reactive than benzene. Pyridine fails to undergo the Friedel-Crafts yeaction, and extremely drastic conditions are required to bring about its sulfonation, nitration, or halogenation. Another characteristic property of pyridine is its ability to undergo nucleophilic substitution, as exemplified by its transformation into 2-aminopyridine by treatment with alkali amides. I n contrast t o electrophilic reagents which attack the pyridine ring in the 3- and 5-positions, substitution by nucleophilic reagents occurs predominantly in the 2-, 6-, and (to a lesser degree) in the 4-position. These experimental findings indicate a higher electron density in the 3and 5-positions as compared to the 2-, 6-, and 4-positions, and a general deactivation toward electrophilic substitution. Pyridine may be represented by a' resonance hybrid with contributions from two KekulB-type structures A and B and from structures C, D, and E. These latter contributions picture the electron drift toward the nitrogen atom, which is responsible for the low reactivity toward electrophilic substitution.

A

B

C

D

E

The presence in the imidazole structure of an acidic pyrrole nitrogen and a basic pyridine nitrogen explains the amphoteric nature of these compounds. Qualitatively, the imidazoles may be regarded as a "cross" between a pyridine and a pyrrole. Thus one could expect a deactivating influence toward electrophilic reagents caused by the pyridine nitrogen, which to a certain degree is offset by the electron-releasing properties of

n

Chemistry of Clrrsses and Derivatives

the pyrrole nitrogen. The chemical behavior of the imidazoles is in agreement with this admittedly crude picture. A comparison of the dipole moments of a number of azoles, as recorded in Table XIV,shows that tetrazole, 1,2,4-triseole, and imidazole exhibit the largest moments of the group. It is of interest to note that

TABLE XIV. Dipole Moments a.nd Dissociation Constants of a Number of Azalea (7)

D Pyrazole ................. 157 Thiazole ................. 1.84 1,2,3-Triazole ............. 1.77 1,2,4-Triaz.ole ............. 3.17 Imidazole ................ 3.84 Tetmole ................ 6.11

PKa

Compound

2.53 2.53

.-

----

-

2%

8.95

-

--

these ring systems embody a common structural element, namely two nitrogens separated by a methine group. This particular arrangement inust, in part, be responsible for their highly polar character. Azoles which do not contain this particular arrangement, such as 1,2,3-triazole and pyrazole, have considerably smaller moments. Contributions from n typical amidine-type of resonance system to the state of the imidazoles, t,hc 1,2,4-triazolesl and the tetrasoles, are thus indicated. These contributions done, however, are not capable of explaining the acidic nature of the

H-C\ /

B

N-

..

N-

@

c--c

//

H I

N-

"-%.N. 8

imidazoles, as will be apparent froin a coinlxtrison of the properties of the imidazoles with those of :he 2-imidazolincs. Thesc lnttcr cornponiuls. also possessing an amidine-type resonance system, are n e i t h r ninpitot(8ric. nor do they exhibit the pronounced association whirl1 is so typical of t l w imidazoles (6).

*

I. General Properties and Structure of Imidamles

23

From an inspection of Table XIV it will be apparent that there is little correlation between the relative magnitudes of the dipole moments and the basic dissociation constants in the mole series. For example, the moments of 1,2,4-triazole and of imidazole are of the same order of magnitude, but their dissociation constants are markedly different. This observation is in disagreement with the postulated amidine resonance which predicts an especially high negative charge on the pyridine nitrogen in azoles exhibiting a high dipole moment. Although it is impossible with the experiinentrzl material on hand to offer a definite explanation for the high basicity of the imidazoles, there seems to be little doubt that the amidine-type resonance and the highly symmetrical nature of the imidseoliuin ion must be important contributine factors. Two non-equivalent structures A and B contribute to the state of the uncharged molecule. These would be expected to differ in their energy content.

B A

B

The addition of a proton to the pyridine nitrogen leads to the formabion of the positively charged imidazolium ion .~.hich receives contributions from two exactly equivalent structures. The higher stabilization (“addi-

lional ionic resonance effect”) of the imiduzoliuin ion as compared to the uncharged molecule might be expected to increase the basio strength. A final decision regarding evaluation of the structure of the imidazoles must await the establishment of the bond distances and bond angles, In analogy to other, more thoroughly investigated, heterocyclic ring systems, imidazole may be represented a8 a resonance hybrid with contributions from structures shown on p. 24. A set of similar contributions in which the functions of the nitrogens are reversed may account for the other tautomer (59). This formulation could account for the acidity, the

Chemistry of Classes and Derivatives

24

aromatic character, the substitution I)eliavior, and the high dipole 1110111ent of imidazole. The classical formula will be employed throughout this book as a representation of t,lie imidazole molccule. The relation between degrcc of resonance and clieinicrrl stability iii the imidazole series is well illustratcd by a comparison of the stability toward hydrolysis of tlie imidazoles with that of tlie 2-imidazolines and the imidazolidines. The highly stabilized iiniclazole ring withstands Iieating at 180’ with concentrated hydrogen ohloridc. The 2-iinidazolino ring. which still retains the nniidine-type resoiiance systein, hydrolyzes wit1I the formation of a monoucylated etliylenediainine on short refluxing witli dilute mineral acid. The imidazolidine ring unstabilizcd I)y resonance is highly labile, and on short exposure to coId dilutc mineral :wids, is Iwokeii with the formation of an aldehyde and ethylenediumine.

H

€I

I

H H

Imidazole

-

2-linidazolinc Decreasing stability

ir--

x

Iiiiidazolidiric

Inquiry into tlic physical Iwopertim of tlic iiiiic1:teolcs Iius rcvcalct I n high degree of association for tlicsc coniyouncls i i i ~ion-polar solvents. Tliis property, wliicli depends on the presence of ;I free iiiiino hydrogen, is explicable in tcrins of hydrogen bonding between the pyridinc. nitrogen of one inoleculc and t.he iniino hydrogen of another. The rcsulting hydrogen-bonded ~nncroinolcculcsmay be visualized in t l i c b n i i w

I. General Proprrties and Structure of Imidamles

25

ner shown below (6). Such a formulation offers a plausible explanation €or the non-association of the imidazoles in polar solvents. The size and

1

x l -

.**N’N-H*.N’

H H

H

H

x x w x i I - i H H H

N-H.*N

X-H**N

N-H..N

N-H..N

H

H

H

H

H

1

I

H

H H H - . H - - N ~ N . . M - ~ ~ ~ . . E Z - \NN . . I I - A N . . E I - - N

H

N-H...

H

H

R

H N..H-NAN...

I H- tH tH -H iH HH H H H K H H H H

H

shape of the aggregates are unknown; however, the observed increase of the specific viscosity with concentration of benzene solutions of imidazole indicates the presence of long-chain polymers. Certain imidrtzoles such as 2-to-hydroxyphenyl) -4,5-diphenylimidezole, 2-(o-liydroxyphenyl j benzimidazole, or 2- (o-aminophenyl) benzimidazole exhibit little association in noa-polar solvents, despite the presence of a free imino group. This observation is explicable in terms of intramolecular hydrogen bonding. The formation, through hydrogen bonding, of a quasi-six-membered ring between the ortho substituent and one of the imidazole nitrogens, as illustrated for 2-(0-hydroxyphenyl) benzi-

midazole, may successfully compete with the formation of the abovementioned association complexes. The coplanar structure for 2- (ohydroxyphenyl) benzimidazole receives support from spectroscopic evidence (60). The introduction of a hydroxyl group into the meta or para positions of 2-phenylbenzimidszole causes little change in the ultraviolet absorption spectrum. The spectrum of 2- (o-hydroxyphenyl) benaimidazole, on the other hand, is markedly different,

26

Chemistry of Classes and Derivatives

E. Tautomeric Character

Imidazoles containing a free imino hydrogen and a substituent in the 4- or 5-position, or two dissimilar substituenta in these positions, might be expected to occur in the isomeric forms illustrated below. These isomeis differ in the position of the imino hydrogen which may be

H

H

attached to either of the two nitrogen atoms. The removal of this hydrogen or the addition of a proton to the pyridine nitrogen leads to the formation of ions in which the possibility for isomerism has been lost. Both forms are thus transformed into identical salts.

Many attempts to prepare such pairs of isomeric imidazoles have resulted in failure, and only one compound is obtained where the synthetic routes employed might have led to the formation of isomers. For example, 2-amino-3-pentanone and 3-amino-2-pentanone afford the same 4(or 5 )methyl-5 (or 4) -ethylimidazole when they are subjected to the WohlMarckwald imidaeole synthesis (61,62). (See Chapter 11, Section A-5.) The separate existence of t-woisomeric forms of a given imidazole contain-

-

l:fr H I

I. General Properties and Structure of ImidszoIes

27

ing an imino hydrogen has been claimed from time to time. Most of these cases were later interpreted in terms of polymorphism rather than tautomerism. A classical example is the compound 2,4(or, 2,5)-diphenylimidazole. This substance exists in two forms melting at 168' and 1 9 3 O , respectively. The lower melbing modification results from the condensation of a-aminobenzyl cyanide with bemaldehyde and also from the treatment of 2,6diphenyloxazole with ammonia (63),while the higher melting form is obtained from the reaction of benzamidine with m-bromoacetophenone or by the interaction of a-hydroxyacetophenone with benzaldehyde in the presence of ammoniacal cupric acetate (40,64). Both modifications afford identical salts from which either form of the base can

1 L

be regenerated. Short boiling of the higher melting base with ethanol

leads to the formation of the lower melting compound (65). This experimental evidence indicates polymorphism rather than isomerism (6). The finding that only one isomer is obtained by synthetic procedures which should have resulted in the formation of two is explicable in terms of tautomerism. It doea not, however, establish the tautomeric character of the imidasoles, as a difference in stability of the two isomers might also favor the formation of only one compound. The virtually tautomeric character of 4 (or 5 )-methylimidaaole follows from its behavior on methylation, leading to the formation of a mixture, separable by distillation, of 1,&dimethyl- and 1,4dimethylimidazole (66,67). Thus the compound reacts as if it were a mixture of 4-methyl- and 5-methylimidseole.

28

Chemistry of Classes and Derivatives

CH, 1,5-Dimethylimidnzolo

1 ,.l-DimcthylimidnzoIc

Iiiiidazoles containing a, free iiiiino lrytlrogcn arc thus virtually bausystem and react like tautoriieric iiiixtures of the two possible Corms. Their reaction Iwoducts arc not ncccssurily obtained in equal parts but in proportions wliicli differ froiii eonipound to conipound. The ratios of isomers resulting froni the metliylation of u number of iinidazoles under a variety of experiinental conditions are given in Table XV. It will 1)c noted that the nature of the suhstituents on tlic ii~idazolcring and also the experimental conditions uscd, litivc a pronounccd effect on the course of the reaction. Elcctronegtttivc sulwtitucnts. suc*li as tlic nitro group. halogen, the carhoxy group or tlic nldclipdc groiip, d i w t tlic methyl grorrl) predominantly to the adjacent iiitrogcn ntoiii wlicn iiictliyl sulfate is usctl as the alkylating agent. The dirccting inflwwc of electroncgativc subt oiiicric

stituents is less pronounced when irictiiyl sulfate and alkali are employed in the alkylation. The methylation of imidazoles with methyl iodide via the silver salts leads in many instances to entirely different results. The pronounced effect of certain substituents on the tautomeric behavior of the imidazoles is little understood, and speculation on this point would seem premature since the experimental material at hand is rather limited. The highly asfiociated character of the imidazoles may tx connected with their tautomeric behavior. In Section D-2these association complexes were formulated as hydrogen-bonded macromolecules. The interaction of such a complex structure with a given reagent may give rise to the formation of isomers and thus simulate intramolecular tautomerism. Such a mechanism may be operative in non-polar solvents only, since association is negligible in polar solvents. TABLE XV. Ratios of Isomers Formed on Methylation of Imidaaoles under Varying Conditions" Methylation pwcediire LfelSO4

Compound

hfe&Or

and alkali

A g salt

with Me1

Disaomethane

Refu

4(or 5)-Methylimidaeole. . . . . . . . . . . 1 :2.2b 4(or 5)-Cyanomethyl. . . . . . . . . . . . . . 1:6 4(or 5)-Phengl-. . . . . . . . . . . . . . . . . . . 4(or 5)-Bromct. . . . . . . . . . . . . . . . . . . 34:I. 4(or 5)-Nitm.. . . . . . . . . . . . . . . . . . . 350:1 4(0r 5)-Ndro-%methyl-. ........... 50: 1 4(or 5)-ivilr&(or 4)-methyl-. . . . . 233: 1 4(or 5)-ivdro-5(or 4)-bromo-. ....... 1,5* 4(or 5)-Ndro-5(or 4)-(pnitrophenyl)1,5* 4(or 5)-Bf&(or 4)-methyl-. ..... 1,5* 1,5* 4(or 5)-&omcr-5(or 4hphenyl- ...... 4(or 5)-Nilr&(or 4)-methyl-%brom+ 1 ,5* 45: 1 2,4(0r 2,6)-DibomA(or 4)-methyl-. 4(or 5)-Nitw5(or 4)-styryI-. ....... 4(0r 5)-Imidezolecarboxaldebyde.. .. 1 ,5* 4(or 5)-Methylb(or 4)-imidazolecar1,5* boxaldehyde.................... Methyl 4(or S)-imidaaolecarboxylate. 1,5* Methyl .G(or 6)-zitr&(or 4)-imidazolecsrhoxylate ............... 4(or 5)-Nilm5(or 4)-imidazolec~rboxamide ................. : .....

-

-

The 6guree represent the ratios of the 1,5 to the 1,4 isomers. Starred figurw

(*) indicate the preaence of only one isomer. The dmipation of the isomers in the

0

disubstituted imidazoles is b a d on the relative position of the italicized substit uent and entering methyl group. * Methylation with methyl iodide in benzene.

30

Chemist.ry of Classes and Derivatives

It seems more plausible t.hat prototropic changes of the type illufitrated are involved, especially since both tautomers are derivable from common ions.

H

Although it is not possible at present to account fully for the tautoineric nature of the imidazoles, there seems to be little doubt that this phenomenon is due to intermolecular reactions between two or more molecules. It does not involve the intramolecular shift of a proton from one nitrogen to the other, as visualized by earlier investigators.

Bibliography 1. Debus, H., Ann. 107, I!N (1858). 2. Hbnbsch, A., &id. 9.19, 1 (1888).

3. Huckel, W., Datow, J., and Simmerebadi. E.,2. p h p . Ctcern. lS6A, 129 (1940). 4. Goldschmidt, H., Rcr. 14, 1844 (1881). 5. Wallach, O., An.%.214, 309 (1882). 6. Hunter,L., and Marriott, J. A., J . Chem. SOC.19&, 777. 5. Jensen, K. A., and Friediger, A., Ygl. Danske Videnskab. Selskab, Mul. jvx. Medd. 20 (No.20), I (1943). 8. Hunter, G., Biochent. J. ,$O, 1183 (I=). 0. Cavalieri, L. F., Bendich, .\., Tinker, J. P.,nnd Brown, G. B., J. Am. Cliem. Soc. 70,3815 (1918). 10. Kohlrausch, K. W. F.. and Sckn, R.. Ber. 71, 985 (1938). 11. Radziscewski, B., ibid. 10, 70 (1877). 12. Traatz, M., &. p h p Chrm. 5?.((6 (lm5). 13. Weiser, H. B., J . phys. C h ~ n i22, . 439 (1918). 14. Rhatnagar. S. S., and Mathur, K. G., 2. phys. C h . 169A. 454 (1932). 15. Cottman, E. W.,Moffett, R. B., and Moffett, S. M., Proc. Indint~rA c d . Sci. 47. 124 (1937). 16. Cook, A. H., and Jon-,

D.G.. J . Chem. &c. IS41,278. 17. von Auwers. K..and Ern~t.W.,2. phu8. Chom. 1%. 217 (1E6). 18. Heller, G., Ber. 37, 3112 (1904). 19. Gerngrw, O., ibirf. 46, 1908 (1913). 20. Parrod, J., Ann. chim. phyx. 1.9. 205 (1933). 21. Leiter, L., J . B i d . Chem. 64. 125 (1!325). 22. Fargher, R. G.,and Pyman, F. L., J . Chrm. Pnr. 115, 317 (1919). 23. Pnrrod, J., Bull. snr. chini. Fmnre 61, 1424 (1932).

.

I. General Properties and Structure of Imidamles 24. John, W., Bet. 68, 2283 (1935). 25. Redemann, C. E., and Niemann, C., 1. Am. Chem. SOC.69,690 (1940). 26. Langley, W. D.,and Albrecht, A. J., J . Bwl. Cltem. 10% 129 (1935). 27. Frey, 2. S., Compt. rend. roS, 759 (1939). 28. Frey, Z.8, Ann. chim. phus. 18, 5 (1943). 29. Horn, F., 2. physiol. Chem.2m,111 (1932). 30. Dedichen, G., Ber. .W,1831 (1908). 11. Wallach, O., aid. 26, 644 (1882). 32. Kirby, A. H. My and Keuberger, A , Bwchem. J . 32, 1146 (1938). 32a. Cowgill, R. W., and Clark, W. M., J . Biol. Chem. 198, 33 (1962). 33. Brown, H. C., and Barabae, G. K., J . Am. Chem. SOC.69, 1137 (1947). 34. Forayth, W.G., and Pymsn, F. L., J . Chem. SOC.137, 573 (1925). 35. Hazeldine, C. E., Pyman, F. L., and Winchester, J., axd. fS,1431 (1924). 36. Windaue, A , and Knoop, F., Ber. 88,1166 (1905). 37. Feigl, F.,and Gleich, H., Monakh. 49, 385 (1928). 38. Oddo, B., and Mingoia, Q., Gmz. chim. ital. 68, 673 (1928). 39. Oddo, B., and Mingoia, Q., W.68,684 (19as). 40. Weidenhagen, R., and Remnann, R, Ber. 68, 1963 (1936). 41. Strain, H. H.,1. Am. Chem. Soc. 49, 1995 (1927). 42. Wyss, G, Bet. 10, 1385 (lS77). 43. Hartmann, M., and Panierllon, L., Helu. Cirim. Actn 91, 1692 (1938). 4-1. Weidenhagen, R., and Wegner, H., Ber. 71, 2124 (1938). 45. Winans, C. F., and Adkina, H., 1. Am. Chem. SOC.66, 4167 (1933). 46. Waser, E., and Gratsos, A., Hela. C h h . Acta 11, (1928). 47. Radzieeedi, B., Ber. 17, 1289 (1884). 48. Pinner, A., and Schwam, R., aid. 86. 2441 (1902). 49. Botwinnik, M. M., and Prokofjev, M. A., J. prnkf. Chem. 1.48, 191 (1937). 50. Laurent, A., ibict. 36, 455 (1845). 61. Radakeewaki, B., Ber. 16, 1 4 s (1882). 52. Fischer, E.,and Troechke, H.,ibid. 13, 708 (1880). 63. Japp, F. R., and Robinson, H.H.,ibid. 16, 1288 (1882). 54. Japp, F. R.,&id. 26, 2410 (1882). 55. Bamberger, E., Ann. ZJ3,267 (1893). 53. Pauling, L.,and Sherman, J., J. Chem. Phys. I , 606 (1933). 37. Schomaker, V.,and Pauling, L., J . Am. Chem. Soc. 61, 1769 (1939). 58. De Vries Robles, H .,Rsc. tmu. h i m . 6S, 111 (1939). 59. Hill, T.L.,and Branch, G. E. K.,SciencS 91, 145 (1940). 60. Wiegand, C., and Merkel, E., Arm. 667,242 (1947). 61. Gabriel, S., and Posner, T.,Ber. 27, 1037 (1894). 62. Jianecke, E., ibid. 39, 1095 (1899). 68. Minovici, 8. S.,ibid. 99, a097 (1896). 64. Kunckell, F., &id. 34, 637 (1901). G5. Burtlee, R, and Pyman, F. L., J. Chem. Soc. I B , 361 (1923). 66. Pyman, F. L., &id. 97, 1814 (1910). 67. Pyman, F. L.,&id. ldf, 2616 (1922). 68. AUsebrook, W. E., Gulland, J. M.,and Story, L. F., ibid. 1949, 232. 09. Hubball, W., and Pyman, 8'. L.,ibid. 1928, 21. 70. Pyman, F. L., aid. M,2172 (1911). 71. Sakami, W., and Wileon, D. N.,J. BWZ. Chem. 164, 215 (1944). 72. Bhagwat, V. K.,and Pyman,F. L.,J . Chem. Soc. 1157, 1832 (1925).

31

This Page Intentionally Left Blank

CHAPTER I1

The Alkyl- and Arylimidazoles A. Synthetic Procedures 1. Introduction

In addition to their usefulness for the preparation of alkyl- and arylimidazoles, some of the procedures described in this section have been successfully applied to the synthesis of imidaaoles containing additional functional groups or heterocyclic substituents. It seems appropriate to summarize them in the present section because their widest application lies in the preparation of alkyl- and arylimidazoles. 2. The Radziszewskl Synthede

An imidazole synthesis involving the condensation of a dicarbonyl compound with an aldehyde and ammonia was discovered almost simultaneously by Japp (1) and Radziszewski (2). The former investigator reacted benzil with p-hydroxybenzaldehyde and ammonia, and obtained 4,5-diphenyl-2-p-hydroxyphenylimidazole;while the latter prepared 2,4,5-triphenylimidazole (loyhine) by reacting benzil with benzaldehyde and ammonia. The method carries Radziszewski's name because he ex-

q

=

o

(3\

CEO

-

+"".O=x-j NHs

3/ \

N

Lophine

tended it t o the preparation of simpler imidazoles and demonstrated its general applicability. It occurred to him that the formation of imidazole from glyoxal and ammonia, as discovered by Debus (3), might proceed in a manner similar t o the lophine synthesis, imidazole formation being due to tlie interaction of (tiiiiuonia, glyoxal, and foriiialdehydc. The formaldehyde, he reasoned, might arise from the cleavage of the glyoxal

33

34

Chemistry of Classes and Derivatives

under the influence of ammonia. In order to test this hypothesis he reacted a mixture of glyoxal and ammonia with a number of aldehydes and aldehyde ammonias, and obtained 2-substituted imidazoles (4-7). The 2-substituent in the imidazoles was representative of the aldehyde employed. The Radziszewski synthesis has found some use in the preparation of substituted imidazoles (8-12). H

The condensation of an a-kctoaldehyde with ammonia and formtrldehyde leads to the formation of a 4(or 5)-1nonosubstitutcd imidazole. Examples arc the formation of 4(0r 5 )-methyl- and of 4(or 5 )-phenylimidaeole from methyl- and phenylglyoxal and formaldehyde (13-15). The formation of 2,4 (or 2 3 ) -dimethglimidaaole from methylglyoxal and acetaldehyde represents an example of the combination of a n a-ketoaldehyde with a higher aldehyde (13). An a-diketone may be combined with formaldehyde or a higher aldehyde to give either a 4,5-disubstituted or a 2,4,5-trisubstituted imidazole (16). The conventional method for bringing about these condensations involves the use of alcoholic ammonia. This older technique is highly unsatisfactory in many instances, since the desired imidazoles are obtained in relatively small yields. Negligible amounts of 4,5-diphenylimidazole are realized from the reaction of benzil with formaldehyde in ethanolic ammonia (15,17). On the other hand, almost quantitative yields of this compound result when the condensation is carried out in glacial acetic acid, with ammonium acetate as the source of ammonia and hexamethylenetetramine as that of the formaldehyde (18). Replacement of the hexamethylenetetraniine by paraldehyde, acetaldehyde, propionaldehyde, isobutaldehyde, salicylaldehyde, and anisaldehyde affords excellent yields of the corresponding 2-substituted 4,5-diphenylimidszoles. Acrylaldehyde, crotonaldehyde, and cinnamaldehyde fail to give imidazoles (19). Substitution of the conventional alcoholic ammonia by glacial acetic acid and ammonium acetate represents a distinct improvement over the older technique (18). The formation of lophine (IV) from benzil (I), ammonia, and benzaldehyde may involve the production of a diamine intermediate (11),its condensation with banzil yielding a product of structure (1111, followed by a rearrangement (lS,20).

11. .41kyl- and Arylimidamles

35

(IV)

The ammonolysis of beneil under a variety of experimental conditions results in the formation of lophine (21-26). Practically quantitative yields are realized when the diketone is subjected to the action of ammonium acetate in glacial acetic acid (18). The reaction between benzil and ammonia in alcoholic solution affords mainly three products, N-desylbenzamide, 2,4,5-triphenyIoxazole, and 2,4,5-triphenylimidazole (lophine).

N-Desylbenzamide

2,4,5TriphenyloxazoleIe

2,4,5Triphenylirnidarole

N-Desylbeneamide seems to be the precursor of the other two compounds. Its formation from bemil and ammonia may proceed as in equation (1), page 36. Once formed, the N-deaylbeneamide-may either undergo cyclodehydration with the formation of 2,4,5-triphenyIoxazole, or it may react with ammonia to give lophine. The latter reaction occurs very readily upon treatment of N-desylbenzamide with ammonium acetate and glacial acetic acid. N-Desylformamide and N-deaylacetamide give 4,5-diphenylrespectively, in practically imidaeole and 2-methyl-4,5-diphenylimidaeole, quantitative yields when exposed to the action of ammonium acetate in glacial acetic acid (1837). See equation (2), page 36. An alternative explanation for the formation of the various products resulting from the ammonolysis of bemil was formulated by Japp (24). He postulated the reaction as an initial fission of a molecule of benzil, with the formation of a molecule of benaaldehyde and a molecule of either

Chemistry of Clnsses and Derivnt.ivre

36

W

R- H, or CHI ctliyl tjcnzoatc or bcnzttmiclc. Tlic conhination of the l)enzultleliyde with aiii~noniaand snotlicr ~riolcculcof IBcnzil ttwourita, :wortling to this view, for tlic foritiirtion of t Iic lopliinc. The smnronolyais of hcnzil rcprcscnts a coiiiplcs rwvtiori, :inti I)ot11 j):itlnviiys i i ~ opcrntc y siiii~ilt:irii!o~isl~. ITndcr tlw influcncc of :uiiiiioniit, cii:wctyl is t r:uirfoiwictl into 2,4,5t riii~ctliyliiiiidszolc (28,29,46) . \\'lictliw iiiiirLrzolc foriiiat,ioii is in this (*tts(i the rwult of elcan-agc of tlic t1i:tc~tylinto acrtaiiiidc anti :icc~t:rlrlcliydc, tlic I:it.tcr rinrlergoing iiiii~latzolc for1ii:rtioii with :i scc*ontl iiioicciile of rliscctyl, or wliet.licr iL iiirchmisiii s i i i i i l w to t l i v on19 ciisviissccl in tlic caw of henzil is involved, rriiiains to I)(! cliwidwted. Sniall amounts of 2-iiicthpl-4,ii-ctipilien~limid;laolcrcwilt frola tlic interaction of Imzoin with tiiniiiotiiiiin acctstc in glacial acetic acid (27). The major products of this reaction arc ainarone and dihydroamarone.

11. Alkyl- and Arylimidazoles

Amarone

Dihydrosmarone

37

IEMethyl4,bdiphenylimidasole

The formation of these products may proceed through the desylamine and N-desyiacetamide stages as shown below. Self-condensation of the desylainine may afford dihydroamarone, which undergoes dehydrogena-

/

tion to give arnaronc. As has been stated above, interaction of the N-desylacetamide and animonia gives 2-methyl-4,5-diphenylimidszole. In the presence of formic acid, this sequence of reactions leads to the forination of 4,5-diphenyliaiidazole, aiiiaroxie foriiiation being negligiblr under tliese conditions. N-1)euylfolniwiiide sreiiin to I ) e the key interiiiediate in tlie process (27). Although tlie Rsdeiszewski synthesis has been applied to the preparation of a variety of iniidazoles, it is rat.her limited in scope. One of its

38

Chemistry of Clssses and Derivativa

serious limitations lies in the daculty in obtaining the necessary starting materials, especially those required for preparation of the more complex imidazoles. Also, in many instances it affords poor yields, and very frequently leads to the formation of mixtures of imidazoles which are difiicult to separate. 3. The Weidenhagen Synthesis

Weidenhagen developed an imidarole synthesis representing a great improvement over the older, Radziszewski method (30-32). This procedure is based upon the observation that a-hydroxyketones under the influence of ammoniacal cupric acetate solutions are quantitatively oxidized to the corresponding dicarbonyl derivatives. Carried out in the presence of an aldehyde, this process results in imidazole formation. The reaction may be visualized as occurring through the following sequence of steps. The cupric ion first oxidizes the hydroxyketone to a ketoaldehyde or a diketone, and thereby is converted into cuprous ion. The dicarbonyl compound under the influence of the ammonia condenses with the aldehyde, thus producing an imidazole which precipitates from the reaction mixture in the form of a sparingly soluble cuprous complex. Decomposition of this salt by means of hydrogen sulfide yields the free imidazole. Carried out in the presence of mineral acids this decomposition leads to the formation of the respective imidazole salts.

In practice, mixtures of the reactants are usually heated for a short time, whereupon the cuprous complex of the imidazole separates. The salt is collected, washed, and decomposed, giving the free imidazole which is obtained in a high degree of purity. The acetyl derivatives of hydroxyketones, or, in some cases, the corresponding a-halogenoketones, may .be substituted for thc hydroxyketones. The ammonia causes hydrolysis of

11. Alkyl- and Arylimidazoles

39

these substances to the hydroxyketones which, in turn, undergo oxidation and imidazole formation. For example, 4 (or 5) -methylimidazole may be prepared from hydroxyacetone acetoxyacetone, or chloroacetone.

B Acyloins may also serve as starting materials (33,34). Compounds such as acetoin, benzoin, or furoin undergo imidasole formation on treatment with an aldehyde and ammoniacal cupric acetate solutions. The formation of 2,4,S-t.ri-(2-furyl) imidasole from furoin and furfural demonstrates that even highly sensitive aldehydes may serve in this synthesis. The simplicity of operation, and the high yields usually obtained, characterize this imidazole synthesis as a most useful procedure. The iiw of a rather mild oxidizing agent allows the introduction of sensitive groups into the starting materials prior to their conversion into imidazoles. Formation of undesirable side products (resulting from the self-condensation of the dicarbonyl compound) represents a disadvantage of the method. Such side reactions become prominent when higher, leas reactive aldehydes are employed. The procedure is thus not applicable to the preparation of imidazoles containing higher aliphatic suhstituents in the 2-position. 4. Formation from Carbohydrates

The formation of 4(or 5)-methylimidasole from D-glucose under the influence of zinc hydroxide and ammonia was discovered in 1905 by Windaus and Knoop (35). This reaction captured the interest of chemists, since they expected that study of this transformation might aid in clarification of the biosynthesis of the imidazole ring. I n their first experiments, Windaus and Knoop (35) added zinc hydroxide and ammonia to a solution of *glucose, and kept the mixture at room temperature for six weeks. The resulting insoluble zinc salt wan

collected, decomposed with hydrogen sulfide, and 4(or 5 )-methylimidazole way isolated as the oxalate. D-Mannose, D-fructose, L-sorbose, D-xylotle, and L-arabinose also yield appreciable amounts of 4 lor 5)-methylimidazole under similar conditions, while maltose, lactose. and n-galactosc afford only traces of the compound (36,311. Important, to elucidation of thc intermedintc steps in this rewtioli is the observation that the addition of acetaldehyde to the reaction niixtuw leads to the forinat.ion of L inixturc of 4(0r Ti)-methyl- and 2,4(or 2,5)dimethylimidazole. The addition of formaldehyde increascs the yield of 4(or 5)-methylimidazole (38). There is ample evidence (13,14,39) to substantiate the view, first expressed by Windaus (351, that the initial step represents a breakdown of the D-glucose molecule with the formation of methylglyoxal. The methylglyoxal thus formed reacts with ammonia and formaldehyde to yield thc final prodmts (Radziszewski synthesis) The following observations support this scheme: (I) methylglyoxal reacts with zinc hydroxide plus ammonia and formaldehyde to give 4(or 5 ) methylimidasole ; ( 2 ) the reaction of methylglyoxnl wit 11 acctnldehydc plus zinc hydroxide and ammonia affords 2,4(or 2,s)-tliinetliyliinidazole ; (3)methylglyoxal can be isolated from tlic D - ~ ~ U C O S zinc C hydroside-minionia reaction mixture in tlic form of its p-nitrophcnylosazonc or its tlisemirarbazone. Tlic finding that mctliylglyoxrtl fails to give 4(or 5 )iiiethylimidazole on treatment with zinc liydroxide-nmiiionia slio~rsthat it, cannot, be the source of the formaldehyde. Thc reaction wliicli leads to the forination of 4(or 5 ) -inetliylimidrteolc froin gliirow iiisy tlws he

Isolation of a mixture of 4(or 5)-methyl- and of 2,4 (or 2,s) -dimethylimidazoles from the reaction of ~-rhamnosewith zinc hyrlroxide-ammonia indicates a breakdown of this sugar into methylglyoxal plus a mixture of acetaldehyde and formaldehyde. Thc interaction of these compounds would be expected t o afford the observed mixture of imidazoles (40). The transformation of D-glucose into 4(or 5 ) -methyliniidazole by the above procedure represents one of the most convenient methods known for the

11. Alkyl- and Arylimidazoleu

41

preparation of this imidazole. The reaction time may be greatly shortened and the yields increased, if the synthesis is carried out a t 100°C. rather than a t room temperature (13). 5. Formation from 2(3H)-ImidazoIethiones and Mthiohydantoins

One of the most important routes to alkyl- and arylimidazoles involves the desulfurization of alkyl- or aryl-2 ( 3 H )-imidazolethiones. These reH I R-YNY-S R’-C-N 1

I

.c-

H

H I R-C‘ N‘7-SH H

R’-C-N

I

H

I R - p p i R‘-C-N

actions will be treated in connection with the discussion of the 2 ( 3 H ) imidazolethiones (see Chapter 111, Section A-3-d) . The availability of a great variety of 2(3N)-imidazolethiones, and the ease with which they are convertible into imidazoles either by oxidation or by hydrogenolysis, make t.liis method one of the most important synthetic tools in the imidasole field. I n this connection, it is of interest to note that treatment with Raney nickel brings about the conversion of dithiohydantoins into imidazoles (41,B). In contrast to the procedures previously dis-

42

Chemistry of C l m and Derivatives

cussed, these syntheses are not applicable to the preparation of imidazoles containing substituents in the 2-position. 6. Formation from ImidszolecarboxylicAcids

Many 2-alkyl- or 2-awl-substituted imidazoles cannot be satisfactorily prepared according to the Raciziszewski method. These imidazoles are available through the decarboxylation of suitably substituted 4,5-imidazoledicarboxylic acids, prepared according to the Maquenne procedure (43) (see Chapter VI, Section A-4). Decurboxylation niay be effected by heating tlic conipounds above their melting points, or by reflwing their aniline solutions. The moat convenient procedure for the preparation of imidazole involves the decarboxylation of 4,5-imidszoledicarboxylic acid, in the presence of LI copper-chroniiwn oxide catalyst (44-48).

B HOOC-~HNY-R HOOC-C-N

A

- 2coa

H-CHNY-R

H-LN

7. Formation from 2-Imldazolinea

2-Imidarolines have served as the starting niaterials for the prepasstion of I-mono- or 1,2-dialkylimidazoles (49). Aroinatization of the ring is effected by dehydrogenation with nickel hydrogenation catalysts in the liquid phase at a temperature of 300°C. This method, although excellent for the preparation of certain alkyluted irnidazoles, docs not seem applicable to the preparation of more complex irnidazoles bccausc of the rather drastic conditions used to bring about the dehydrogenation.

In contrast to the alkyliniidazolineu (which require rather drastic conditions for their conversion into imidazoles) , certain arylitnidazolines are transformed into arylimidazoles with remarkable ease. Amariric . (2,4,5-triphenyl-2-imidazoline)is an outstanding example. It is quantitatively converted into lophine (2,4,5-triphenylimidarole) when iodine or potassium amide are added to itu solution in liquid ammonia (2OOpO). Mild oxidation with chromium trioxide in acetic acid also brings about the conversion of amarine into lophine (51-53).

11. AIkyI- and Arylimidazoies

43

8. Miscellaneous Procedures

In addition to the previously mentioned, generally applicable procedures, there are a number of other methods which have been used to prepare imidazoles. One of these reactions involves the interaction of benzamidine with an a-halogenoketone. This method has been successfully applied to the preparation of 2,4(or 2,5)-diphenylimidazole and to the synthesis of 2-phenyl-4(or fi)-rnethylimidrtaolr: iA4$5).

R-

-

X halogen

The formation of lophine by the interaction of benzoin with benzamidine also belongs t.o this class of reactions (56).

The reaction between an a-aminonitrile and an aldehyde may result. in thc formation of an imidazole. An example of this reaction is the formation of 2,4 (or, 2,5) -diyhenylimidazole from a-aminobenzyl cyanide and benzaldehyde (57).

The condcnsation of an a-aminoketone hydrochloride with an imiioether produces a mixture of an oxazole and an imidasole (55). The exposure of oxszoles to aqueous ammonia at high temperatures may residt in imidazole formation. The first conversion of an oxazole into an imidazole was reported as early as 1888 by Lewy (58), who transformed 2-methyl-4-pheny loxazole into 2-methyl-4 (or 5) -phenylimidazole+ (59) *"him compound is recorded in Beihein's Handbilch (4th ed., Vol. B,p. 190) aa %phenyl4(or Fi)-methylimidarole, but later NRS shown to be 2-methyl4(or S)-phenylimidazoIe (55,591.

44

Chemistry of Classes and DerivaEived

by trcutiiig the compound wit,ll aqucous aniaionia at 220-230" for sixteen hours. 2,5-Diphenyloxazole is converted into 2,4 (or 2,5)-diphenylimid-

mole under similar conditions (57). These conversions give poor yields, and offer little advantagc as prel)artttivc mcthocls. It is of interest to note, however, that alkyl- ;ind :~iyloxazole-4-carboxylicacids nrc converted in good yields into alkyl- and arylimidazoles when heated with aqueous ammonia a t a temperature of 150°C. Coinpounds such as 2-methyloxazole-4-carboxylic acid or 2-n-amyloxazolc-4-carboxylic acid afford 2-methyl- and 2-n-nmylimidazole, respectively (55,60). Thc carboxyl group facilitates the replacement of the ether oxygen by the imino group, possibly through the following elcckronic mechanism (55). The preparation of 2-plienyl-4 (or 5 )-ii~eth?rliniidszoleby smmonolysis p"

R-5"F-R' N-C-H

1

R" I -C0Ny - R '

I- COZ

of the readily available 2-phenyl-5-mcthyloxazolc-4-carI~oxylic*:wit I represents a convenicnt routc to this compound. A number of procctlurcs cq)cciaIly suitcd to thc prepttrtrtion of lopliiliv (2,4,5-triplienyli1~iid~~zolc) a n d of lopliinc derivatives deserve inention a t this point. Lophine is fornicd when liydrobcnattinide is lieated at 300°C. This reaction, which was investigated by Laurent in 1845, led to the discovery of lophine (15,61,62). Amarine (2,4,5-triphenyl-2-imidazoiine)represents an intermediate, and it becomes the major reaction product when hydrobenzamide is heated at 12.5-130°C. (63-67),or, preferably, when

11. AlkyI- and Arylidazoles

45

potassium ainide is added to a solution of hydrobenzamide in liquid ammonia (20). This conversion of hydrobenzamide into amarine may by a reaction involve the initial formation of 2,4,5-triphenyl-3-i1nidazoline coinparable to that leading to the production of benzoin from benzaldeliyde. Through a rearrangement, the 2,4,5-triphenyl-3-imidazoIine changes into the more stable amarine (20). The pronounced tendency of amarinc to undergo dcliydrogenation to lophine has been mentioned.

The conversion of 2,4,6-triplienyltriaeine (kyaplienine) into lophine by reduction with zinc dust in acetic acid was discovered by Radziszewski (2). The formation of 2!4,5-triplienylimidazoles from 2,4,64riphenyltriazines is a general reaction and represents a useful procedure for tlic preparation of substituted lophines (19j. The reaction kyapheninee lophine is reversible; the addition of iodine to a solution of lophine in liquid ammonia leads to the forinatiou of kyaphenine (20). A possible scheme for these convcrsions is shown in equation ( l ) ,page 46. Treatment with aqueous ammonia a t 200-230O converts N-desylbenzsnilide into N-phenyllophine (1,2,4,5-tetraphenylimidazole)(68,69). See equat.ion (2), page 46.

B. Properties and Chemical Behavior 1. Genetal Properties

The slkyl- and aiylimidazoles possessing a free iiiiino hydrogen arc arnphoteric compounds forming salts both with acids and with metals; the picrates and acid oxalat.es represent. especially suitable derivatives belonging for cliaractcrization purposes. The alkyl- and a~-yli~tiidazoles to this group are solids exhibiting a high degree of chemical stability.

Chemistry of Classes and Derivatives

46

H

H

Lopliinc

2-

x13,

b

Jiyaphcninc

Their chemical behavior closely parallels that observed with imidasole, md requires little additional comment. The methyl-substituted imidaeoles :&reslroi~gcrbases tliun imidarole. The introduction of phenyl groups into tlic iiiiicitrsole nucleus weakens the basic oiiaracter and increases tlic pseudoacidic properties (see Table XlIl ) . Tlic rrlkyl- and arylimidazoles csliibit a positive Yauly reaction (scc Chapter V, Section 13) provided t h y coiituin a free imino hydrogen :~ndat least onc frec iuethine goup. Lophine (2,4,5-triphenylimidarole) deserves special comment as the oldest, and most carefully investigated, representative of the arylimidaaoles. The compound melts at 275O, distils without decomposition, and exhibits great chemical stability, especially under acid conditions. The addition of metals or metal aniides to its solution in liquid ammonia results in the formation of salts (70). These hydrolyze when dissolved in water with the formation of lophinc and a metal hydroxide. Exposure

11. Alkyl- and Arylimidazoles

.

47

to hydrogen iodide at 300" brings about a slow conversion of lophine into benzoic acid (71); treatment with sodium in alcohol leaves the compound unchanged (53). Catalytic liydrogenation over IVillsGtter platinum in glacial acetic acid transforms lophine into 2,4,5-tricyclohexy1-2imidazoline (72). This behavior is rather unusual, since the imidazole ring in most of the other alkyl- or arylimiduzoles is resist,nnt to catalytic hydrogenation even at high temperatures and pressures (73). Lophine in sodium hydroxide solution in the presence of air undergoes slow decomposition into benzoic acid and anunonia; the process is accompanied by chemiluniinescence (62) (see Chapter I, Section B-7-43). Drastic oxidation with chromium trioxide in glacial acetic acid affords a mixture of benzeinide and dibenzamide (52). The direct nitration of lophine with

concentrated nitric acid at the boiling teuiperature results, in the formation of 2,4,5-triS(p-nitrophenyl)imidazole, a compound which exhibits considerably less stability toward alkali than does lophine (74).

2. Acylation

The observation that the simple iniidazoles are not readily acylated (75) is not too surprising if it is remembered that the irnino group in thc?iC compounds possesses the acidic character associated with a pyrrole nitrogen and not the basic properties of a secondary amino group (see Chapter I, Section C-2). The'study of the acylation of imidazoles is complicated by the property of a number of these substances to undergo ring fission under the influence of scylating reagents and alkalis. Under very carefully controlled experimental conditions, however, it is possible to obtain N-monobcnzoyl derivatives (76). Imidazole, 4 (or 5 ) -methylimidazole, 4,5-climet~1iylimidazoleJand methyl 4 (or 5 ) -methyl4 (or 4) -

Chemistry of Classes and Derivatives

88

imidazolecarboxylate form the corresponding N-benzoyl derivatives when two moles of base are reacted with one mole of benzoyl chloride in benzene solution. The second mole of base serves as the acceptor of the Iiydrochloric acid formed during tlie acylation reaction. The N-benzoyl derivatives are crystalline, low-melting compounds which undergo hydrolytic debenzoylation on exposure to moist air with the formation of the benzoic acid salts of the respective imidazoles. The henzoylation of imidazoles according to the Schotten-Baumann reaction does not usually result in the formation of N-benzoyl derivatives but brings about the fission of the imidazole ring. This reaction was discovered during attempts to benzoylate benzimidazole, and, in recognition of its discoverer, is frequently referred to as the Bainberger reaction (77). The reaction of imidazole with benzoyl chloride and alkali a t low temperature results in the formation of 1,2-diLenzamidoethylene and formic acid (78,79). Tlie intermediate steps leading to the ultimate cleavage of the imidazole ring have been investigated with benzimidazole and will be discussed in Chapter VIII, Section D. The 1abilit.y under the conditions H

I

H-c.N-(;-H II H-C-N

H

H-F

H-C-N-CO

+ HCOO-

H

of the Scliotten-Bauiuann berizoylatioii of the otherwise liiglily stable imidazole ring is remarkable indeed. The ability t20 bring ntmut t,lw rupturc of the iinidazole ring is not limited to benzoyl chloride. Thus 4 (or 5)-metliylimiduzole is converted I -~)ropcnc and formic acid when it is into 1,2-di-isovaleryla1i~idoshaken with isovaleryl cliloridc in the presence of sodium hydroxide (80). The reaction of imidazole iiiagnesium bromide with benzoyl chloride also results in ring fission with the forination of 1,2-dibenzamidoethyIene (81). Acetic anhydride in tlie presence of sodium acetate fails to bring about cleavage of tlie iniiduzole ring (80,82). Tlie property of undergoing ring fission on trcatnicnt with benzoyl chloride and alkali is not common to all the imidazolcs. Alkyliniidazoles such as 4 (or 5 )-methyl-, 4(or 5 )-ethyl-, or 4,5-di1iietliyliiiiiclazoleundergo cleavage (83,84), while the N-dkylimidazoles resist the action of bcnzoyl chloride and alkali (85,86). Electronegat,ivc sul)&t,ucnt,s on tltc ring ] " ~ e n t .the fission process: sucli rompoiiiids as 4 (or 5 )-nitwilnidnzolo (B), 4(or S)-imi-

11. Alkyl- and Arylimidszoles

49

dazolecarboxaldehyde (SO), or 4 (or 5 ) -imidazolecarboxylic acid (87) remain unchanged when they are subjected to the action of benzoyl chloride and alkali, while 2-phenyl- and 2-p-nitrophenylimidazole are converted into their N-benzoyl derivatives (88). The benzoylation of 2,4,5-tribromoimidazole also results in the formation of a N-benzoyl defivative (89). The above-mentioned 1,2-dibenzamidoethyIene derivatives may serve as the starting materials for the preparation of 2-substituted imidazoles. The reaction of 1,2-dibenzainido-l-propene with propionic anhydride a t 180" results in the formation of 2-ethyl-4(or 5 ) metliylimidazole, whilc its rcaction with acctia anhydride affords 2,4( or 3 5 ) -dimet hylimidwiole (90).

Imidazole and its alkyl derivatives fail to undergo C-acylation in the presence of acyl chlorides or acid anhydrides and aluminum chloride. In this respect they behave like pyridine, wliiah also fails to undergo the Friedel-Crafts reaction. 3. Alkylation

The first observation of the replacement of the imino hydrogen of imidazole by alkyl groups was made by Wyss (75). He prepared N-ethylimidazolium bromide and N-benzylimidazolium chloride by the treatment of imidazole with ethyl bromide and benzyl chloride, respectively, and iiberated the corresponding free alkylimidaeole from these salts by treatment with silver oxide. Further studies (7,91-95) have

amply demonstrated that imidazoles containing a free imino group readily undergo N-alkylation under a variety of conditions. Reaction with alkyl halides followed by treatment with alkalis or interaction of their silver salts with alkyl halides are good preparative methods. Imidazoles react with dimethyl sulfate or diazomethane to give N-methyl derivatives (49,86,95-101).

Clicmistry of Classes and Derivat.iws

50

'I'he N-alkyl- and nrylimidazoles arc basic suhstaims since they have lost the pseudoacidic properties associated with the imino hydrogen. They are highly stable, distillable liquids, and form crystalline salts with acids. The picrates and chloroplatinates are well suited for characterisation purposes. The marked changes in physical behavior which accompany the -1'-alkylation have been mentioned previously (see Chapter 'I 1 . Rather interefiting is thc behavior of l-met,hyliniidRrc,lc.. 'Phis cumpound undergoes R rearrangement with thc formation of 2-methyliinid;tzolc when it is passed through tb rcrl-hot tube (38,93). This rernlls the c11, I

H-C-N

A

€I I

-cyNxf

-CH

H H-C-N

similar hchavior of N-methylpyrrole, which also rearranges with the formation of a C-methyl compound under similar conditions. The reaction is not successful with higher N-alkylimidaroles. I t is important to note that the bemyl group in N-benzylimidazoleu i w i he removed by reduction with sodium in liquid ammonia, resulting in regcnrration of the free imino group (102). This behavior of thc .V-hcnzylimidazoles is significant from the synt.hetic point of view. The N-monoalkylimidazoles have the ability to add a molecule of 311 d q - 1 halidc. with the formation of dialkylimidazolium salts. Two possible 1wys in which this addition may occur cnn be vimalixed. Either thc alkyl halidc adds to the non-nlkylated nitrogen with formation of R 1,3-dialkylimidazoIium salt (I),or it may combine with the suhstitatcd nitrogen, thas forming R 1.1-didkyIimidaxolinm salt (IT). Heating XR I

H -c " II H -C-N

~ -H

X-

011-

A

S = hrlogcn

R I

NIfz IICOO-

+

XI12 I

R'

II. Alkyl- and Aryhidazolea

51

one mole of such salts with sodimn or potassium hydroxide solution brings about a complete fission of the imidasole ring with the formation of two moles of primary amine and one of formic acid (85,91,103,104). This behavior of the quaternary salts shows that they are 1,3-dialkylimidasolium salts and not 1,l-dialkylimidazolium salts. A 1,l-dialkylimidasolium salt would not be expected to yield two moles of primary amine on decomposition with alkali. The intermediate steps leading to the disruption of the imidaeolium salts have not been studied in the case of the simple imidazoles, but have been well investigated in the 1,3-dialkylbensimidasoliumseries. It would seem logical to assume that similar mechanisms are operative in both instances and that the results obtained with the benzimidasoles (see Chapter VIII, Section E) are also applicable to the simpler molecules. When heated, the 1,3-dialkylimidaeoliu halides decompose into one molecule each of a N-inonoalkylimidasole and one molecule of an alkyl halide. The stability of the nitrogen-alkyl bond depends on the nature of the alkyl group and also on the character of other ring substituents. For example, 1-methyl-3-ethylimidazolium iodide affords 1-ethylimidasole and methyl iodide. l-Methyl-3-benzylimidasolium iodide dissociates

with the formation of 1-methylimidazole, the benzyl moiety leaving the molecule in the form of benzyl iodide (105-107). This finding is in general agreement with the observed ease with which the hensyl group is removed from other molecules. An electronegative substituent in the 4(or 5)-position of a 1,3-dimethylimidasolium salt weakens the adjacent nitrogen-alkyl bond. The 4 (or 5)-chloro-, bromo-, or nitro-] ,3-dimethylimidazolium iodides decompose with the exclusive formation of l-methyl-4-chloro-, bromo-, or nitroimidasoles,respectively. This reaction has preparative potentialities.

52

Chemistry of

Classes and

Derivatives

The influence of a phenyl group is less pronounced, as evidenced by the behavior of 1,3-dimethyl-4 (or 5 )-phenylimidazoliuin iodide. Heat decomposes this compound into a mixture of isomers containing a small amount of 1-methyl-5-phenylimidazoleand a larger quantity of l-methyl4-phenylimidaeole (106). Bibliography

1. Japp, F. R.,and Robinson, H . H.,Bet. 16, 1268 (1882). 2. Radziszewski, B., ibid. 16, 1493 (1882). 3. Debus, H.,Ann. Im, 199 (1868). 4. Radziszewski, B., Ber. 16, 2706 (1882). 5. Behrend, R.,and Schmitz, J., Ann. ,9777,310 (18%). 6. Radziszewski, B., and Seul. L., Ber. 17, 1291 (1884). 7. Radziszewski, B.,ibid. 16, 487 (1883) 8. Radziszewski, B., iba. 16, 747 (2883). 9. Karcz, M., Momtsh. S, 218 (1887). 10. Riegcr, 5.. i b 2 . 9, 603 (1888). 11. Windnus, A., and Vogt, W., BET.40, 3691 (IW7). 12. Jolin. W.,ibid. 64 2283 (1935). 18. Bernhnuer, K., Z . physiol. Chem. 183, 67 (1929). 14. Gulland, J. M.,and Macrae, T.F., J. Chenr. Soc. 10S9, W2. 15. Pinner, A., Ber. 35,4131 (1902). 16. Japp, F. R., and Wynne, W. P., J. Chena. Soc. 49, 462 (1886). 17. Japp, F. R.,ibid. 61, 557 (1887). 18. Davidson, D.,Weiss, M.,and Jelling, M., J. Org. Cheni. I , 319 (1837). 19. Cook, A. H., and Jones. D. G., J. Chem. Sor. 19.j1, 278. 20. Strain, H. H.,J . Am. Chcm. SOC.49, 1558 (1927). 21. Zinin, N.,Ann. 34, 186 (1840). 22. Lnurent, A., J. prokl. Clrcw. 36, 461 (1845). 23. Ilenius, M.,Ann. 237,339 (1885). 24. Jnpp, F. R.,and Wynnc. W. P., J . Clrena. SOC.40,473 (1886). 25. Struin, H.H.,J . Am. C1ir.n~SOC.69,820 (1930). 26. tcslic, W. B., and W:ii.l, C . W.,J . Orq. Chem.7 , W (1942). 27. Davidson, D.,Weiss, M., 2nd Jelling, M., ibg. 9,325 (1937). 28. von Pechmann, H., Ber. 21, 1411 (1888). 29. Fittig, R.,Daimler, C., and ICeIler, H.. Ann. $49, 182 (1888). 30. Weidenhagen, R.,and Herrmnnn, R., Bcr. GS, 1953 (1935). 31. Weidenhagen, R.,and Herrmnnn, R., 2. angew. Chem. 48,506 (1935). 32. Weidenhagen, R., and Rienacker, H., nsr. 7% 57 (1939). 33, Weidenhagcn, R.,Herrmnnn, R., and Wegner, H.,ibid. 70, 570 (1937). 34. Bernhauer, K.,and Hoffmnnn. R., J. prakt. Chem. (2) 149, 321 (1937). 35. Windaus, A., and Knoop, F.. Bcr. $9, 1166 (19051. 36. Windaus, A., &id. 40, 799 (1907). 37. Iuouye, K.,&idd.40, 1890 (1907). 38. Windsus, A.,&id. M,3886 f 1906). 39. Sjollcma, B. J., and I b u , A. J. H., J<(-c. lrau. c l t b t . $6, 180 ( l ! W . 40. Windniis, A., and lillrif+. A., %. plrysiol. Cltr.rit. $2, 276 (1914).

41. Cook, A. H.,Heilbron, I., and Levy, A. L., J . Chew&.Soc. 19.47, 15%. 42. Cook, A. H.,Heilbfon, I., and Levy, A. L., iW.19@, 201. 43. Maquenne, M.,Ann. chim. phys. (6) 94, 522 (1891). 44. Dedichen, G.,Ber. 39, 1831 (1906). 45. Pauly, H.,and Gundemann, K.,ibid. 4 , 3999 (1W). 46. Fargher, R. G., and Pyman, F. L., J. Chem. Soc. 115. 217 (1919). 47. Jones, R. C.,J. Am. Chem. Soc. 71, 844 (1949). 48. Organic: Synthmar, Vol. 22, John Wiley-and Sons, In(*., New York, 1942, p. 05. 49. Kyridea, L. P., Zienty, F, B., Steshly, G.W., and Morrill, EI. L., J . Org. Chem. 19, 577 (1947). 50. Strain, H. H.. J. Am. Chem. SOC.62, 1216 (1930). 51. Fischer, E., Ann. 511,217 (1882). 52. Fischer, E.,and Troschke, H., Bcr. IS, 706 (1880). 53. Biltz, H.,and Krebs, P., Ann. 391, 210 (1912). 64. Kunckell, F., Ber. $4, 637 (1901). 55. Cornforth, J. W., and Huang, H.T., 1. Cl~etn.SOC.1948, 1980. 56. Kulisch, V., Monatsh. 17, 300 (1896). 57. Minovici, 9. S., Ber. 99, 2097 (1896). 58. Lewy, M., ibid. g1, 2192 (1888). 59. Cornforth, J. W.,and Huang, H. T., J . Chem. SOC.1948, 731. 60. Cornforth, J. W., and Cornforth. R. H., ibid. 1047, 96. 01. Laurent, A., J . prukt. Chem. 36, 455 (1845). 62. Radziszewski, B., Ber. 10, 71 (1877). 63. Laurent, A., Compt. rend. 19, 353 (1844). 64. Laurent, A., Ann. 69, 359 (1844). 65. Fownes, G.,ibid. 64,363 (1845). "3. Bertngnini, C., &id. 88, 127 (1853). 67. Bhatnagar, S. S.,and Matkur, K. G., Z. physik. Chem. A169, 464 (1932). 68. Everest, A. E., and McCombie, H., J. Chem. Soe. $9, 1746 (1911). 69. Everest, A. E.,and McCombie, H., ibid. 99, 1752 (1911). 70. Strain, H.H., J. Am. Chem. SOC.4.9, 1995 (1927). 71. Japp, F. R., Ber. 16,2410 (1882). 72. Waser, E.,and Gratsos, A,, Helv. Chim. dcta 11, 944 (1928). 73. Winans, C. F., and Adkins. IF., J. Am. Chem. SOC.66, 2051 (1933). 74. TrSger, J., and Thomas, H., J. p m k t . (IhPm. (2) 110, 42 (1925). 75. Wyss, G..Ber. 10, 1365 (1877). 76. Gemgross, O.,&id. 48, 1908 (1913). 77. Bamberger, E.,Ann. 878, 267 (1893). 78. Ruggli, P., Ratti, R., and Henzi, E., Ifelu. Chim. Acta 19, 332 (19'29). 79. Ruggli, P.,and Henzi. E., &id. 19. 302 (1929). 80. Windaus, A., Dorries. W., and Jensen, H.,Ber. 61,2745 (1921). 81. Oddo, B.. and Mingoia, Q.,Gazz. ch.im. ilnl. 58, 573 (1928). 82. Heller, G.,Ber. 37, 3112 (1904). 83. Windaus, A., &bid. @, 758 (1909). 84. Gemgross, O.,&id. 46, 1913 (1913). 85. Pinner, A., and Schwsrz, R., ibid. 36, 2441 (1902). $6. Pyman, F. L.,J. Chem. SOC.1Z1, 2016 (19B). 87. Windsus, A.,Ber. 43,499 (1910).

54

Chemistry of Classes and Derivatives

88. Grant, R. L.. and Pyrnsn, F. L.. J . Chem. Snc. 11.9, I%X? flml). 89. Ruggli, P., Ilelv. Chim. Acta 3, 559 (lm). 90. Windsus, A., and Langenbeck, W.,Ber. 66: 3706 (1922). 91. Wallach, O.,Ann. 3f4, 267 (1882). 92. Wallach, O.,Ber. 26,644 (1882). 93. Wallach, O., ibid. 26, 634 (1883). 94. Dankowa, T. F., Genkin, E. I.. and Preobrazhenskii, N. A., J . Gen. Chem. (U.Is. 8. R.) IS, 189 (1945); Chsm. Abstracts @, 1800. a.Allsebrook, W. E., Gulland, J. M., and Story, L. F., 3. Chem. Soc. IS@, 232. 9. Haseldine, C. E., Pyman, F. L, and Winchester, J., &id. 126, 1431 (1924). !l7. Forsyth, W. G., and m a n , F. L., M.I%",673 (1925). (98. Hubball, W,,and m a n , F. L, &id. I=, 21. 99. Pyman, F. L., .W,1814 (1910). 100. ForsytJi. R., and Pymun, F. L, ibid. lW, aB7. 101. Baxter, R. A., and Spring, F. S, &id. 1946, 232. la.Jones, R. G.,J . Am. Chem. Sac. 71, 383 fi949). 103. Shepard, E. R., nnd Shonle, H. A., ibid. 69,2269 (1947). 104. Rung, F.,and Behrend, M., Ann. e72, 28 (1892). 105. Samin, J., Helv. Chim. Acta 6. 370 (1923). 106. Gamin, J., and Wegmann, E., ibid. 7, 720 (1924). 107. von A I I W P ~K., , snd MRIISS,W.,Ber. 61, 2411 (1928).

CHAPTER I11

The 0x0- and Hydroxyimidazoles and Their Sulfur Analogues A. The Oxoimidazoles

1. Imidazolecatboxaldehydea

4(or 5) -Imidarolecarboxaldehyde multa from the oxidation with concentrated nitrio acid of 4(or 5)-hydroxymethylimidaeole (14). Nitric acid oxidation of 4(or 5)-methyl4 (or 4) -hydroxymethyl- and of 1,4-dimethyl-5-hydroxymethylimidaeoleleads to the formation of 4 (or 5 )

-

H

’

I

I

CHZOH

€I I

I

c=o I

H

methyl-5 (or 4) -imidazolecarboxaldehyde and 1,4-dimethyl-5-imidaeolecarboxaldehyde, respectively. 4 (or 5)-Imidazolecarboxaldeliydeis a colorless crystalline solid melting at 173-174”, forming such salts as an acid oxslate, a picrate, a nitrate, and a hydrochloride. The aldehyde is not oxidized by air, fails to reduce ammoniacal silver nitrate solution, and forms a red dye with diazotized sulfanilic acid. It affords typical carbonyl derivstivcs such as an oxime, a phenylhydrazone, a 2,4-dinitrophenylliydrazonc, a semicarbasone, UII anil, and a bisulfite addition compound. Wit11 hydrogeu oyyanide, tr cyanohydrin is obtained, which dissociates readily with the regeneration of the starting materials. 4 (or 5 )-Imidazolecarboxaldehyde resists acetalieation and fails to react with methyl magnesium iodide. The aldehyde condenses readily with malonic acid to form 4 (or 5 )-imidazolemethylenemalonic acid (7). Its ability to undergo the Perkin azlactone synthesis and its capacity to condense with a number of active-methylene compounds, renders the aldehyde R vdiiahle synthetic intermediate (see

Chemistry of Classes and Derivatives

56

Chapter VI, Section A-6-e (3,6). The observation that the aldehyde fails to undergo the Cannizzaro reaction, and the finding that it does not afford tlie expected imidazolc analogue of benzoin wlien exposed to the action of aqueous potassiuni cyanide, indicate a deviation from the behavior of B typical “aroinatic” aldchyde. Indeed, the suggestion was offered that 4 (or 5 )-imidazolecarboxaldehyde inay be better represented by the tautomeric hydroxyniethylene rather than the aldehyde forinula (3). Tlie infrared absorption spcct~ruinof tlic aldehyde fails to support.

I C=O

II

C 4 H

1

I

H

H

this view. Tlie spectrum exhibits a band in the region of 1654-1696 crn.-l, wliicli is cliarscteristic for aroinatic nldcliydcs, and fails to reveal an absorption ~uuxiinuiiiin tlic 3ooe3FjOo c ~ n . - Iiydroxyl-stretching ~ region. 4(or 5 )-Hydroxy~itctItyliaiiduzoleesltil)its tlic cxpectcd liydroxyl absorpultraviolet absorption spectra of t ion at, around 3003fioo c t i ~ - ~Tlte . Q 4(or 5)-ii~iidazolecarl~ox:Itdcllyde and of its cation are shown in Figure 2. It will be noted that tlie aldehyde sltows a pronounced inaxiinum at $ & 2560 A. wltich is :&sent in tlic spcctruni of its ion. This maxiniuni is duc to conjugation of the carbonyl group with tlie ring, since imidaeolc fails to display selcctivc absorption in the ultraviolet, region. Structures sticl~ r

**

‘

.

I1

H

I C=O

c-O:Q

1.1

H

I

it

I

H

1 I

C-0:” I

Ii

‘

111. 0x0- and Hydroxiimidrtaolcs and sulfur Analogues

------

0.7

I

2200

57

in 95% ethanol in ethanol containing hydrochloric acid

----2400

----------____________ 1

2600 WAVE LENGTH, A

2800

3000

Fig. 2. Ultrnviolet absorption spectrum of 4(or ~)-imidazolt3cnrbox~Ideh~de.

as those on page 56 may be responsible for the absorption maximum. The addition of a proton to the pyridine nitrogen increases the electronattracting power of the imidaeole ring, thus interfering with the drift of electrons toward the oxygen. The main contributing structure in the case of the cation may be the one illustrated. The conjugation between the ring and the carbonyl group is thus suppressed in the ion,. and the selective absorption is obliterated (8). Although this interpretation may H

i.

I

1

cI =o H

explain the behavior of the aldehyde, it would seem that additional experimental material will be necessary to get a clearer picture of its fine structure.

Chemistry of Classes and Derivatives

58

Thc iiietliylation of 4(0r 5 )-imidarolecarboxaldehyde solely with tlimet.hy1 sulfate loads to t hc formation of 1-methyl-5-imidazolecarboxH I

1

. c 4 =ti n ii c-It I C=O I 11

11

F *”$--i

C-NH

I

r:=o

-H

I 11

I

c=o I

H

:rldehyde as the major reaction product (3,4). This behavior of the :rldehyde is in sword with the obscrv:ition that imidnsoles possessing electron-attracting groups in t.he 4(or 5 )-position arc xnethylated on the djacent nitrogen atom when subjected to the action of dimethyl srilfrrte in the absence of nlknli (see Chapter I, Section E). This mctlrglntion proceeds with ratlicr poor yields, and 1-dkyl-5iinidarolecarl~osalrlcl~~~e~ arc more convenicntly obtained by application of the McFadyen-Stevens aldehyde synthesis to suitahly substituted I -:~lk~l-5-imidssol~~~~nrbo~lates. Preparation of the altlehydeR by this metaliotlinvolves convcrsion of the carhoxylatcs into the respective hydwzides, followd by phenylsulfonation to give the corresponding 1-alkyl-

I

COOEt J

CHIOH

I

If

111. 0x0- and Hydroxyhnidazoles and Sulfur Analogues

59

5-imiclazolecarboxyphenylsulfonhydrazides. Heating of the yhenyleulfonliydrazides in glycerol solution leads to the formation of the aldehydeti in yields of jo-so%. The reaction fails with tlie phenylsulfouylligdrazide of 4 (or 5 J -iiiiiJuaolecarboxylic acid (9). The 1-alkylutcd-j-iniidazolccarboxaldehydes forin phenylhydrazones; on catalytic hydrogenation in the preBence of Adam catalyst and a trace of ferric chloride the aldehydes are converted into l-alkyl-substituted 5-hydroxymet1iylittiidar;oles. 1 Methyl-5-imidazolecarboxaldel1ydecondenses readily with 2-t Iiio-3-acetylhydantoin with the formation of 5- (l-methyl-5-imidazoleinethylene)2-thiohydantoin, and reacts with malonic acid to give l-methyl-5H

CHa I H-c/~u;.,c=

+ /

HaC,

COOH

COOH

-

I N-CH

I3 I

o=c-Ny=s I

C-NH

/ COOH

illlidtrzoieinetiipleiieriialonicacid. Both these condensatiotis proceed with cxcelleiit, yields (.4,9). The iniidazolecarboxaldehydes with a iuetliylatetl ring nitrogen, such as 1-methyl-S-imidrrzolecarboxaldeliydeand 1! 4 4 metl~yl-5-iiiiidazolecarboxaldehyde undergo the Cannizzaro reaction with the forii~ationof the expected mixture of a hydroxymetliyliinidazole and nu iinidiizolecarboxylic acid (3). 2. Imidazole Ketones

Iinidaaole ketones are compounds not readily available, because imidaroles fail to undergo the Friedel-Crafts synthesis. A few representatives of tlie group have been prepared by indirect methods. 2-Imidazolephenyl ketone results when 2-benzylimidazole is oxidized with chromium trioxide. Hydrogenation converts the ketone into 2-imidazole phenyl

Chemistry of Classes and Derivatives

60

carbinol (10). 4 (or 5 )-Methyl-5 (or 4) -acetylimidazole is prepared from isonitrosoacetylacetone by the method illustrated below (11). It forms a semicarbazone. 0

0

II

-c--C”

N--OH

I

1 I

Ha-,

c=o

H-C

,dHsCI-

I

HCI

HsC’

H&’

c=o

1

K*CNS-

H

H

0

1

O I U N HIC -C - $‘ ’V-SH HSC C-N

-

3. Imidazolones and Thiones

( a ) Nomenclature

Imidszoles in whicli a hydroxyl group is directly attached to tlic imidazole ring, such as 2-hydroxyimidazole and 4 (or 5)-hydroxyimidazole, are t.automeric systems; they are usually referred to as imidazolones. The existence, within this imidazolone class of iinidazoles, of a numbcr of additional tautomeric forms requires the adoption of a rather complex system of nomenclature. The accepted procedure is based on an assignment of the position of the “extra” hydrogen atoin. Two classes of 2iinidazolones have to bc cliffcrcntiatcd, namely the 2(3H)- and tlic 2 (511)-imidnzolonc!s. 13otli t h s e typw may tautoinerize in the manner illustrated. The 4-iinidaxoloncs bcliavc as though they were composed of H I

H-F/N*~H H-C-N

-

€I I

H-%HNT=O H-C-NH

Tautomeric forms of Z(tH)-imidazolonc (2-hydroxyimidawlc)

H I

4 -

HC-N

&yNyOH HC-N

Tautoriicric forins of 2(BI/)-i1nitlazoloiic(2-l~ydroxyisoi1nidawlc)

-

a mixture of a 4(5H) -imidazolone and of a 5 ( 4 H )-imidazolone. Because it is impossible to assign a definite structure to such compounds, they are classified as 4 ( 5 H ) (or 5 (4H) ) -imidazolones. Substitution of the imino hydrogen 1imit.s the poseihilit3pfor tsritomerism to the one-ol type, per-

H

H

H

Tautomeric forms of 4(5H)(or 5(4H))-imidazolone

mitting a definite assignment of structure. A similar system of nomenclature applies to the imidazolethiones.

*

( b ) Structural Considerations regarding the 1(5H)-Imidazolones and Thiones The electronic structure of the 2(3H)-imidazolones and of their sulfur analogues, the 2 ( 3 H )-imidazolethiones, represents a highly complex problem. Its discussion must remain speculative until more information is obtained, especially on bond distances and dipole moments. As has been mentioned in the preceding section, two tautomeric forms, the imidazolone (thione) and the 2-hydroxyimidazole (2-mercaptoimidazole) structures, have to be considered. A comparison of the melting points of the 2(3H)-imidazolones and thiones with those of the corresponding imidazoles (Table XVI) demonstrates that the introduction of oxygen or sulfur into the 2-position of an imidazole results in a marked elevation of the melting point. This suggests the presence in the solid state of salt-like, zwitter-ionic structures. Con-

TABLE XVI. Melting Points of a Number of 2(3H)-Imidazolones and Thiones Compound

M.p..

OC.

2(3H)-Imidazolone ...................................... 250-251 Diacetyl derivative ................................... 105-106 4(or 5)-Methyl-2(3H)-imidazolone 202-204 Diacetyl derivative 78-80 2 (3H )-Imidazolethione ................................... !2!&227 4(or 6)-Methyl-2(3H)-imi~~olethione .................... 245-240 S-Methyl ether ....................................... 136-137 90 Imidazole 4(or 5)-Methylimidaeole 56-56

....................... ....................................

............................................... .................................

I

62

Chemistry of Clnascs nncl Derivatives

Irihtions from striwtures A to C may be considered. Changes such as ibcyl&ion or alkylation which interfere with the “urea resonance” markedly lower the melting points.

’

I n solution thc 2 (3H) -imidazolones exhibit a positive ferric chloride test, suggesting the presence of a phenolic hydroxyl group. This property of the imidazolones points to significant contributions from the 2-hydroxyimidaeole structure, which readily arises from the 2 ( 3 H )-imidaeoIone structure by a protonic shift from nitrogen to oxygen. -9 hybrid with major contributions froin structures D to G may be considered for this tantomer. It is conceivable that in solution there exists a tauto-

‘ 8

H-.$-~*?

H- C-N

-x-H

G

X=OorS

meric equilibrium between tlic imidazolone and t lie 2-hyd~o?ryimid~tzole forms so that all the illustrated structures may hare significance. A similar situation prevails in the case of the 2 (311)-imidseolethionerr. The property of the 2(3H)-imidazolones to undergo C-acylation in the presence of an acyl chloride and aluminum chloride may he diie to contributions such as F and G, which increase the electron clcnsity at positions 4 and 5. The 2 ( 3 H )-imidazolones and thionea are acidic substances, which have lost the characteristic basic properties of the imidazoleo. They

111. 0 x 0 - and Hyclroxyimidnmles and Sulfur .4nalogues

63

dissolve readily in dilute alkali with the formation of salts. 2(311)-Imidazolethione dissolved in liquid ammonia is capable of reacting with two atoms of sodium, demonstrating that it contains two acidic hydrogens (12). The rate of reaction of these two hydrogens differs markedly, suggesting the initial displacement of the thiol hydrogen followed by the loss of the imino hydrogen. Indeed, the reaction of the monobasic ion with henzyl chloride leads to the formation of 2-bS-benzylmercaptoimidazole. The 2-S-alkylmercaptoimidazoleaare basic compounds forming salt* wikh acids. Electronically, they may be regarded as hybrids with contributions from structures H to K. Their remarkable reactivity toward X I

B1

R I

K

electrophilic substitution (ease of nitration in position 4 or 5 ) may be the result of contributions from such structures as J and K (see Section A-3-d- (3))

.

(a) d(SH)-ImidazoEones (1) Synthqtic Methods

The interaction of the hydrochloride of an a-aminoaldehyde, an a-aminoketone, or an a-amino-8-ketoester wit.h IL salt of cyanic acid such as sodium, potassium, or ammonium cyanate, represents a convenient route to 4(or 5 )-monosubstituted and 4,&disubstituted 2( 3 H )-imidasolones, or 4 (or 5 )-substituted 2 (3H)-imidazolone-5(or 4) -carboxylates. See equation ( I ) , page 64. Saponification of the imidazolonecarboxylatesresults in the formation of imidazolonecarboxylic acids which are readily decarboxylated to give 4(or 5)-monosubstituted 2(3H)-imidazolones. See equation (2), page 64. This synthesis is applicable to the preparation of a wide variety of 2(3H)-imidasolones (13-!2!2), and is usually carried out by dissolving the hydrochloride of the a-aminocarbonyl derivative in water and adding an

64

H

I

b

R-CpF R' -C-N

=L

0

I

H

H

+ CNO-

I

c

H-$"T=O R-C-N

J

O , C ' R I

I

H

H

H

H

H

I

H

H

H

equivalent amount of sodium or potassium cyanate. Short warming of the solution completes the reaction. The resulting iinidazolones are conveniently purified either by recrystallization or sublimation. This method is also valuable for the preparation of 2(3N)-imidazolones containing additional functional groups. The formation of the hydrochloride of 4 (or 5 )-aminomethyl-2 ( 3 H )-imidazolone from the interaction of diaminoacetone dihydrochloride with one equivalent of potassium cyanate is illustrative (23).

,

NHS+CICHI

,c=o I -CI+HjN-CHr

K*CWO-

H I

- c a y =0

€I n -CI+HjN-CH,-C-N

1

H

The replacement of the salts of cyanic acid by alkyl- or arylisocyanates leads to the formation of nitrogen-substituted 2 ( 3 H )-imidazolones (24-28).

111. 0x0- and Hydroxyimidazoles and Sulfur Analogues

65

The reaction between the hydrochloride of a n a-aminocarbonyl compound and a salt of cyanic acid proceeds in two distinct steps. The initial phase involves the combination of the reactants with the formation of an a-ureidocarbonyl compound; this in turn loses the elements of water to give the final product. The reaction can be arrested after the first step

if the acetal of an a-aminoaldehyde is employed. a-Aminoacetal hydrochloride, for example, reacts with potassium cyanate to form a-ureidoacetal. This compound is converted into 2 (3H)-imidazolone upon exposure to mineral acid (29,30).

EtO,

OEt I

C-H I

Cg2

KHs+

-

OEt EtO, I +ch'oC-H I HSC-

H

NHs

1

I

cko I

N I H

HI

L

H-S' H-C-N

N 1

'

H

The disadvantage of this pro,cedure as a method for the preparation of 2(3H)4midazolone lies in the fact that the a-ureidoacetaldehyde formed during the acid hydrolysis of the a-ureidoacetal has a tendency to undergo a n intermolecular condensation with the formation of polymers, thus decreasing the yield of the monomeric 2 ( 3 H )-imidazolone. This polymerization may be suppressed by hydrolyzing the ureidoacetal at room temperature in highly dilute solution. Under these experimental conditions the 2(3H)-imidazolone is obtained in high yields and is conveniently separated from small amounts of polymeric material by sublimation in vacuo. A practical procedure for the preparation of 4,5-disubstituted-2 (3H j imidazoloncs involves the condensation of acyloins with urea. Acyloins

-

Chemistry of Classes and Derivatives

66

of the aliphatic, aroiuatic, and heterocyclic series may be employed in this synthefjis. The condensation of hnzoiu, and of furoin, with urea affords 4,5-diphenyl-2 ( 3 H )-imidazolone and 4,5-di (2-furyl) -2 (311)-imidazolonc, respectively (31-35).

R"

1

H

In contrast to tlie acyloins of tlie aliphatic series (which fail to react with sub.stituted urctis) , benzoin rcwts with sym-dhnethyl- or diphenylt 311)-imidazolo~ic or 1,3,4,5urea to form 4,6-diphenyl-l,3-ctimeth~l-2 tetraplienyl-2 (311)-iiiiitluzoloiic, rewpectivcly. Proni tlie stidpoint of yield it is advantageous to perform t h e condensations in glacial acetic acid (36-38). Two additioiial procedures for the 8ynthexis of 2 (3N)-imidazolone, wlricli in the lust nnalytiis may be regurded :I* condenstitions of n a-liydroxyaldeliyde with urea, also deserve inention. The first of these involves lieating a mixture of diliydroxymaleicacid and urm. It is asauiuecl thut the diliydroxymaleic acid undergoes decnrboxylation with forniatioii of dihydroxyucrylic acid, and that this acid condenxes with urea to givc 2 (3M)-iniiil:i~olone-4-c~r~~lic acid. Decarboxylation of thc latter co111pound :~ffordsthe 2(3H) -imidazoloue (39). HO, ,COOH C

c

HO'A\COOH

H

H

111. 0x0- and Hydrosyimidn7~lcsand Sulfur .4nnlogues

07

Thc second reaction is rather similar and involves the treatment of

a mixture of t.artaric acid and urea with fuming sulfuric acid. The reaction

product in this instance is 2 (3H)-irnidazolone-4-carboxyoxylic acid. Dihydroxyacrylic acid is again assumed to be an intermediate in the reaction (30,40). -imidazolone-4 (or 5)-carboxylate inAnother route to ethyl 2 (3H) volvt?~the desulfurizat4ionwith Raney nickel of ethyl 4-thiohydantoin-5carhoxylate (41). I

-

=*-Q=,

EtOOC-C8

I

H

I

E d t

A '

Imidazolone formation has also been observed as the result of the hydrolytic cleavage of certain heterocyclic ring systems. Thus the hydrolysis, by means of dilute sodium hydroxide, of a number of derivat.ives of dihydro uric acid leads to the formation of 2(3H)-imidazolones. For example, 7,Mimethyldihydro uric acid on hydrolysis with dilute sodium hydroxide affords 1$-dimethyl8 (3H)-imidazolone-4-carboxyoxylic acid ; this on heating undergoes decarhoxylation with the formation of 1,3-dimethyl-2 (3H)-imidazolonc. Under similar experimental conditions 4,7,9-trimethgldihydro uric acid affords 1,3,4-triniethyl-2(3H)4midazolone-Bcarhoxylic acid and through decarlmxylation 1,3,4-trimethyl2 (3H)-imidseolone (211. Sec equntion ( 1 , page 68. A number of uracil derivatives arc converted into imidaeolones when they are treated with acids or alkalis. 1,3-Dimethyl-5-aminouracil-4carboxylic acid, for example, giwu 1,3-dimethyl-2 (3H) -imidasolone-4carboxylic acid when exposed to the action of hot, dilute sodium hydroxide (42). Drastic hydrolysis with hydrobromic acid converts 4- (U-ethoxyethyl) uracil into 4,5-dimethyl-2 (3H)-imidazolone, while 4- (U-ethoxyethyl) -5-methyluracil yields Pmethyl-B-ethyl-2 (3H) 4midazolone under similar conditions (43,M). These pyrimidines are,apparently, hydrolyzed

68

Chemistry of Clusses and Derivatives

to open-chain urea derivatives in which the amino group undergoes an intramolecular reaction to form the corresponding imidazolones. (2) General Properties

The 2 ( 3 H )-irnidaxolones are high-melting, well-crystallized solids. The lower members of the series sublime in vacuo, thereby offering a eonvenient method for their purification. They are stable to acid hydrolysis, and may be treated with hydrochloric or liydrobromic acids a t temperatures of 1 5 0 - 1 6 0 O without undergoing any observable change. They exhibit characteristic absorption maxima in the ultraviolet region (45a). (3) Acyhtion

The 2 ( 3 H )-imidazolones undergo N-acetylation upon treatment with acetic anhydride or with mixtures of acetic anhydride and sodium acetate. Depending upon the severity of the conditions mono- or diacetylated products may be obtained. Although strict proof is lacking, i t is generally assumed that both acetyl groups are located on the nitrogen atoms. NAcylation also occurs when a 2(3H)-imidazolone is exposed to the action

111. 0x0- and Hydroxyimidaaoles and Sulfur Analogues

69

of an acid chloride in the presence of pyridine. The acyl groups are readily removed with the regeneration of the starting material when the acyl derivatives are subjected to the action of dilute alkali (36,4547). The property of a number of 2 (3H)-imidazolones to undergo FriedelCrafts acylation in the 4(or 5’)-position on treatment with acid chlorides in the presence of aluminum chloride is of both theoretical and practical importance. Compounds such as 2 (3H) -imidazolone, 4 (or 5)-methyl- , and 4 (or 5)-ethyl-2 (3H)-imidazolone are readily ncylated when treated with acid chlorides and aluminum chloride in nitrobenzene solution. Acid chlorides such as acetyl-, benzoyl-, chloroacetyl-, or 8-carbethoxyvaleryl chloride and others may serve as acylating agents (30,46).

H I

R-py-0 H - C Y

H

P

CIC-R’

Alct

H I

R-YY==O

R’-f-c-I. 0 H

It should be noted that imidazole or 4(or 5)-methylimidazole fail to react with acyl chlorides in the presence of aluminum chloride. The reactivity of the 2 (3H)-imidazolones is thus clearly due to the activating influence of the oxygen function (see Section A-3-b). The dzering behavior of the imidazoles and the 2 (3H)-imidazolones in the FriedelCrafts reaction has a parallel in the tliiazole series. Thiazole and 4inethyltliiazole fail to undergo acylation when treated with acetyl chloride and aluminum chloride; on the other hand, 2-hydroxy- or 2-mercaptotliiazole are readily acylatd under these conditions (48). (4) Alkylation

In contrast to the 2 ( 3 H )-imidazolethiones, which are alkylated on the sulfur atom with the formation of thioethers (32), the 2 (3H)-imidazolones are alkylated on the nitrogen atoms with the formation of 1,3-dialkyl-2(312)-imidazoloncs. Methylation by means of dimethyl sulfate and alkali converts 2 (3H)-imidazolone-4-carboxylicacid, into 1,3-dimethyl-2 (3H) imidszolonc-4-rsrboxylicacid (40). The positions of the methyl groups in the methylated product follow from the identity of the latter with 1,3-dimethyl-2 (3H)-imidazolone-4-carboxylic acid (obtained by the alkaline hydrolysis of 7,9-dihydro uric acid) (21). Decarboxylation of the acids obtained by both procedures affords 13-dimethyl-2 (3H)-imidazolone.

-

H-qs=

Chemistry of Classes and Derivatives

70

'iHi

H I

HW-fT-0 H-CON

~

t

~

HhOO H-C-7 C ~ -$3Y ~ 'o

c

CHI

---c A

H-C-

I

+ co;

CHa

(5) Halogenation

The more highly unsaturated character of the 2 (3H)-imidarolone~as compared to the iuiclazoles is clearly evident from their different behavior on bromination. In contrast to 4,5-diphenyliuid~zoleJaliich is substituted in the 2-position on bromination (49), 4,5-diplienyl-2 (3H)-imidazolonc adds bromine at the 4,5-double bond. The resulting 4,5-diphenyl-4,5dibromo-2-imidarolidone is highly reactive, undergoes further bromination, and thus escapes isolation. A8 is to be expected the solvent influences the course of tlie brominntion of the 2 (3H) -imidszolones. Bromination of 4,5-tiiplrenyl-2 ( 3 H )-imiclurolone in lmiling clilorofom solution gives a coiiipountI foimulthxl as 4-bro1ii0-4,%bis p - t)ronioplienyl)-2-imiduxolidonc. This substance is unstable and, on lieuting tcbore 100' or on boiling with water, loses s inolecrilc of hydrogen bromide with tlie formation of 4,S-bis (p-bromoplienyl ) -2 (a//)-iiiiidazolone. The pofiitionof the lialogeiis in the fiml prodrid followti froni the results of it* osiilatioii with cliroiniuin t rioside, lcatliiig to the format ion of sytn.-bis (p-browobetizoyl) -urea.

Br

111. 0x0- and Hydroxyimidnxoles and Sulfur Analogies Br

Br

Br

I

I

Br

Q Br

i1

f

&o 4

6

Q

The 4,5-bis (p-hroinophenyl)-2( 3 N )-iinidaeolone lins tlie ability to add a molecule of bromine to give 4,.5-his (p-broinoplicnyl)-4,5-dibromo24midaeolidone. The broniine atoms in the 4,5-position in this compound :Lre highly reactive and are readily displaced by hydroxyl groups when the compound is treated with water, 4,5-bis (p-bromophenyl)-4,5-dihydroxy-2-imidaaolidone being the reaction product. The observation that both tlie 4.5-l)is ( p-hroinophcnyl) -4,.i-diliydroxy- and the 4,j-bis (p-broiaopbenyl) -4,Bdihro1no-2-imidasolidonesreact readily with urea to form hexahydro-2$-dioso-7,8-bis(p-bromophenyl)imidaz[ d]imidazole (R.I. 604) establiphes the position of the lRbile bromine atoms (43). -imidarolone in boiling glacial accBroinination of 4,5-cliphcnyl-2 (3H) tic acid followed by treatment with boiling water affords p,p’-dibromobenxil. Here again, 4,5-bis (p-hromophengl)-4,5-dibromo-2-iniidazolidone represents the initial reaction product. This material under the influencc of the water undergoes a displacement reaction with the formation of the labile 4,5-bis (p-bromophenpl)4$-dihydroxy-2-imidaaolidone; this hydrolyzes to give the p,p’-dihromobenail (5081). See equation top 11. 72. Bromination in alroholic solution of 4,5-diphenyl-2 ( 3 H )-imidaaolone proceeds in an entirely different manner. Under these experimental conditions, one observes the forniation of a mixture of stereoisomeric 4.5-di-

72

6

r

Br-C-N-H

30-C-N--B

Br-(+j$Ti

IO-C-N--E

-

Br

"0

I

.

8

$=(

Br

O=

Br

plienyl-4,5-dialkoxy-2-iinid~zolidones.A plausible mechanism for this reaction is illustrated below (52).

111. 0x0- and Hydroxyimidazoles and Sulfur Analogues

73

The reaction of 4-methyl-5-carbethoxy-2 ( 3 H )-imidazolone with bromine in carbon tetrachloride solution leads to the formation of 4-bromomethyl-5-carbethoxy-2 (3H)-imidazolone (47). N-Bromosuccinimide converts a number of 4(or 5)-methyl-2 (3H)imidazolones or their 1,bdiacetyl derivatives into the corresponding bromomethylimidazolones. These me useful intermediates for synthetic work because of the high reactivity of the halogen atom. The halogen in these bromomethyl derivatives undergoes facile displacement upon reaction with an alkoxide ion, acetate ion, benzoate ion, sulfite ion, or amines. Ac

Ac

AC

I

+ X-

R-C-Y

1

XHiC- !-I?=" Ac

Ae

I AC

+Br-

(6) Oxidation

2 (3H)-1inidazolone and its substitutioii products are readily attacked by. oxidizing agents such as chromium trioxide, potassium permanganate, or nitric acid, and, depending upon the nature of the substituents, are converted into different products. Chromium trioxide oxidation of 2(3H) imidazolone-4-carboxylic acid leads to the formation of parabanic acid. 1,3-Dimethyl-2 (3H)-iinidazolone-4-carboxylic acid and 1,3,4-trimethyl2 ( 3 H )-imidazolone-5-carboxylic acid are converted into 1,3-dimethylparabanic acid (21,40).

-

-

2 ( 3 H )-1midazolones containing arouiatic groups in the 4 (or 5) or in the 4- and 5-positions are readily attacked by chromium trioxide with the formation of N,N'-diacylated wetas. 4(or 5) -Plienyl-2 (3H)-imidaeolone

chemistry of claeses and Derivativea

14

affords AT-formyl-N’-benzoylurea, while 4,5-diphenyl-2 (3H) -imidaaolone is converted into Np-dibenzoylurea (14~5,4532).

0

0

0

The addition of concentrated nitric acid to a glacial acetic acid solution of 4,5-diphenyl-2(3H) -imidazolone, followed by dilution of the reaction mixture with water, leads t o the addition of two hydroxyl groups to the 4,5-positions with the formation of 4,5-diphenyI-4,5-dihydroxy-2imidazolidone. The same glycol is obtained when the 4,S-diphenylimidasolone is subjected to permangsnate oxidation in acetone solution (52m).

9

Treatment with concentrated nitric acid converts 4,5-diphenyl-2 (3H)imidazolone into 3,3’-dinitrobenzil, while its reaction with a mixtuR of concentrated nitric acid and sulfuric acid reaults in the formation of 4,4’dinitrobenzil. The latter reaction is a useful method for the synthesis of 4,4’-dinitrobenzil (which cannot be obtained by the direct nitration of benzil because of the ineta-directing effect of the carbonyl groups) (54)

-

111. 0x0- and Hydroxyimidazoles and Sulfur -4na~ogucs

75

(7) Reduction

The 2 (311)-iuiidazolones are readily convertible into 2-iinidazolidones.

This differentiates thefn markedly from the imidazolea which resist reduc-

tion under even the most drastic conditions. 4,5-Diphenyl-2(3H) -imidaaolone is converted into 4,5-diphenyl-2-imidazolidoneby treatment with . 4 i u m and ethanol (55). High-pressure! hydrogenation over nickel vat nlysts at temperatures of 150-!NOo transforms 4,6-diplienyl-2 (8H)imidaeolonc into 4,5-dicyclohexyl-2-imidazolidone(38). Iieduvtion oyer Raney nickel at elevated temperatures and high pressures (56:57), or low-pressure hydrogenation in the presence of noble-imidinetal catalysts, are suitable methods for the conversion of 2 (3H) nzolones into 2-imidazolidones (30,46,58,59)(see Chapter VII, Section C! . Acetylation increases the unsaturated character of the 2(3H) -imidazolones and renders them more susceptible to reduction. Imidaeolonecsrboxylates such as ethyl 4-methyl-2 ( 3 H )-imidazolone-5-carboxylateare resistant to low-presm hydrogenation. Increased stabilization due to cross conjugation between the carboxy group and the ring may account for their higher stability. The conversion of 4-methyl-5-benzoyl-2 (3H)-imidazolone into 4methyl-6-(hexahydrobenzyl)-2-hidsz;olidone by hydrogenation over Adams catalyst proceeds in three distinct steps; these differ markedly in their respective rates. The initial phase involves the conversion of the keto group into a methylene group with the formation of 4-methyl-5benzpl-2 (3H)-imidazolone. This subdance undergoes further reduction

0

76

Chemistry of Classes and Derivatives

with the formation of 4-methyl-5-liexahydrobenzyl-2 (3H)-imidazolone. The saturation of the imidazolone ring proceeds a t the slowest rate. It is possible to arrest the reaction at these intermediate stages and to isolate and characterize the various products (46). Hydrogenation over Adams catalyst in glacial acetic acid of C-acylated 2(3H)-imidazoIones in which the acyl group is aliphatic in nature leads to the formation of the corresponding alkyl-substituted imidazolidones, while their diacetyl derivatives are converted into the respective 4- ( 1-hydroxyalkyl) -2-iiniclazolidonc,.;.

3x2

R I

H-C-N

H

I F=o H-C-A-€I

R'--AH*

acetyiotion

€I-! c=o -Ac +

II

H-~-A-A~

0

R'-CH

AH

The reduction of 4,5-disubst.ituted 2 (3H)-imidazolones niay lead to the formation of geometrical isomers. Hydrogenation over Adams catalyst in glacial acetic acid tends toward the formation of cis isomcrs, while reduction over Raney nickel in alcoholic solution results in the formation of cistrans mixtures.

R-C-N

I

I \

/ / /%=o

R--~'-N'

I

H

111. 0x0- and Hydroxyimidasoles and Sulfur Analogues

77

(8) Stability of 2(3EI)-Imidazolonecarboxylic Acids

2 (3H)-Imidazolone-4-carboxylic acid is a rather stable compound, but it undergoes decarboxylation (with the formation of 2 (3H) -imidazolone) in the presence of copper powder at temperatures of 250300". Its esters cannot be prepared by treatment of the acid with alcoholic hydrogen chloride. Esterification occurs readily, however, when a solution of the acid in concentrated sulfuric acid is poured into alcohol (40). The 4hydroxymcthyl- and 4-et hoxymethyl-2 (3H )-imidazolone-5-carboxylic acids exhibit similar stability. These acids are readily obtained from their esters by hydrolysis. The ethoxymethyl acid forms a stable acid chloride when treated with tliionyl chloride (30). A number of 2(3H)-imidazolonecarboxylic acids are highly unstable and cannot be prepared by the hydrolysis of their respective esters. For example, ethyl 4-methyl-2 (3H)-imidazolone-5-carboxylateor ethyl 4ethyl-2(3H) -imidazolone-5-carboxylate treated with aqueous barium hydroxide are decarboxylated to 4-methyl- or 4-ethyl-2 (3H)-imidazolone (30,57). Several other imidazolonecarboxylic acids exhibit a similar instability. Attempts to esterify such substances as 1,3-dimethyl-, 1,3,4-trimethyl-, or 1,3-dimethy1-4-pheny1-2 (3H)-imidazolone-5-carboxylic acid by refluxing with ethanolic hydrogen chloride lead to decarboxylation. The reaction of their silver salts with methyl iodide is a convenient method for the preparation of their niet.hy1 esters. All these acids undergo rapid decarboxylation on heating above their melting points (21).

(a) 2 ($HI-Itniduzolethiones (2-Mercaptoimidazoles, 2-Thiolimidazobs) (1) Synthetic Methods

The oldest method for the preparation of 2 (3H)-imidasolethiones involves the hydrolysis of an alkyl- or arylthioureidoacetal with mineral acid. It was by the use of this procedure that Wohl and Marckwald (60) obtained 1-phenyl-2 (3H)-imidazolethione, the first representative of this class of compounds. The required alkyl- or arylthioureidoacetals result from the reaction of aminocetal with alkyl- or arylisothiocyanates, or from the combination of isothiocyanatoacetal with aliphatic or aromatic amines (61,62). See equation ( l ) ,page 78. An alternate route to hi-substituted 2 (3H)-imidazolethiones involves condensation of an N-substituted aminoacetal hydrochloride with potassium thiocyanate, followed by acid hydrolysis of the resulting asymmetrically substituted thiourea. The N-substituted aminoacetals are obtained by reacting cliloroacetal with amines. The synthesis of 1-benzyl-2 (3H)imidazolethione serves as an illustration (63). See equation f2), page 78.

Chemistry of Classes and Derivatives

78

-

R

' NCS I

EtO\ ,OEt

YH HN-R

H2C,&=8 I

f

R H&

6

H-C-N

I

In eertsiu imtaiicerj Iiydrdysis of substituted thiuureidowetuls with dilute iiiiiieral acid 1c:rtls to tlic ionnation of tlduzolines rntlier tlian to 3 ( 3 H )-imidazolethionea. TIius, short hydrolysis with 5 N Iiyclroclilorie acid eotivcrts a-methyltliiourcidopropion~cetal into a mixturc of 2-inctliylamino-4-11i~tbyI-5-etlioxy-2-thiuzoline with a small proportion of 1,4dimethyl-2 (31f1 -imictuzolethiouc~. Proloiiged hydrolysis of the scetal it)creases the yield of the imidaeolethione at the expense of the thiazoline. The thiasoline, on more drastic hydrolysis with concentrated hydrochloric acid, affords a mixture of lJ4-dimethyl-2 (3H)-imidazolethione, 1,4-di1nethyl-2-ethplinercaptoimidasole, and 2-methylamino-4-methylthiazole. The folloniiig wheme may account for the formation of these various products. Tho initial phase of the liydrolysis of the acetal may well involve the Eorinnt2ionof n l ~ c ~ n i : ~ ~ this ~ c t :in~ Itiirn , undergoing ring closrire

111. 0x0- and Hydroxyimidamles and Sulfur Analogues

79

to give the ethoxythiaroline. TJoss of the elements of ethanol from this

intermediate may explain the formation of the 2-methylamino-4-methylthiarole. The conversion of the 2-methylamino-4-methyl-5-ethoxy-2thiacoline into 1,4-dimethyl-2 (3H)-imidarolethione seems t o involve an initial hydrolysis to the hemiacetal followed by an imidazole ring-closure, possibly by way of the 5-ethoxy-2-imidarolidinethionestage. The 5ethoxythiarolines may be the normal intermediates in the conversion of thioureidoacetals into 2 (3H) -imidazolethiones (64). EtO,

OEt

76 BT-CHs

HS-CVC=S I

H I

- EOH The reaction between aminoacetal and thiocyanic acid results in the formation of thioureidoacetal, and this, on heating, loses two molecules of ethanol to give 2 ( 3 H )-imidazolethione, the series parent compound (65).

A most versatile method for the preparation of 2 ( 3 H )-imidaBoletliiones involves the interaction of an a-aminoketone with thiocyanic acid.

80

Chemislry of Classes and Derivatives

In practice a salt of the a-aminoketone, usually the hydrochloride, is heated in aqueous solution with sodium, potassium, or ammonium thiocyanate. The sparingly water-soluble 2 (3H)-imidaaolethiones separate in crystalline form. The reaction seems to involve the initial formation of an a-thioureidoketone which loses the elements of water to give the 2 ( 3 H )-imidaxolethione (16-lS,22,~26,ss-sS,71,72). This synthesis has found application in the preparation of 4(or 5 ) monosubstituted and of 4,s-disubstituted 2 (3H)-imidazolethiones, Aminoinetliylketones of the general structure (I) serve as the precursors for the syntheses of the former type (69,701, wlrile a-aininoketones of tlie general structure (11) are the starting mcrterials for the preparation of the latter.

The 4 (or 5 )-iiionosubstituted-2 (311j 4midaroletliiones are also available froin the reaction of =-aiuinoeldcliydes and tliiocyanic acid. Tlie necessary a-alainoaldeliydcs arc prcpared by sodiuin-amalgam reduction in acid solution of a-ainino acid esters; usuitlly they arc not isolated, but arc! dircctly converted into tlic 2 (311)-iiiiicIuzolct~liioncs(12,73-77). Nuaicrous examples of tlicsc gcncrul ~iicthodb:will bc found throughout this monograph.

Especially noteworthy is the formation of 1-alkyl- or l-aryl-substituted 2 (3H)-imidazolethione-5-carboxylates from the reaction of the sodio derivatives of N-alkyl- or N-aryl-N-forinyl-C-liydroxymettlyleneglycinates with sodium thiocysnate in the presence of hydrochloric acid. Sodio cthyl N-formyl-C-hydroxyinetliyleneglycinate is converted into ethyl 2 (3H)-imidazolethione-4-carboxylateunder these conditions (78).

111. 0x0- and Hydroxyimidamles and Snlfur Analogies

+ R-N-CHI-COOCHa HCOOCHa

H-b=O

81

HC-Or

n

R-N-C-COOCHI I H-C=O

H

HII

R- H, alkyl or aryl The condensation of an a-amino-8-ketoester with thiocyanic acid leads to the formation of a 4 (or 5)-substituted 2 (3H)-imidatolethione-5 (or 4) carboxylate. Hydrolysis converts such an ester into a 4 (or 5)-substituted 2 (3H) -imidatolethione-5(or 4)-carboxylic acid, which is readily decarboxylated with the formation of a 4(or 5)-monosubstituted 2(3H) imidatolethione (64,79).

-

The heating at temperatures of 150-200” of alcoholic solutions of an acyloin and thiourea, or of an acyloin and ammonium thiocyanate represents another route to 4,&disubstituted 2 (3H)-imidaeolethiones (31-34).

2-Benzylmercaptoimidazoles, available from the condensation of ahalogenoketones and S-benzylisothiourea, may serve as the starting materials for the preparation of 2 (3H)-imidatolethiones. Thus, phenacyl bromide reacts with S-benzylisothiourea in the presence of sodium bicarbonate to form 4 (or 5)-phenyl-2-benzylmercaptoimidazole,and this on

Chemistry of Clnsscs nnd Dcrivntivcs

82

treatment with acetyl iodide in glacial acetic acid is converted into 4(or 5)phenyl-2(311) -imidazolethione (80). Sodium in liquid ammonia (81) or aluminum bromide in benzene also effect the cleavage of 2-henzylinercaptoimidazoles to 2(3H)-imidazolet.hiones (12). C-S-CHrO

\

HN'

Dl

[

H

el

-1 --S€ H I -

I H

-"S]-H -N-H

Certain 5-aminothiazoles rearrange readily into 5-amino-2 ( 3 H )irnidazoletliiones when exposed to the action of dilute alkali. This remarkable reaction, discovered by Heilbron and co-workers (82), is rather broad in scope and has opened the way to the synthesis of certain substituted 2 (3H)-imidazolethiones not readily available by the more conventional procedures. A few typical examples may serve to illustrate this method. Aminoacetonitrile combines readily with alkyl- or arylisothiocyanates to form 2-alkyl- or 2-arylamino-5-aminothiazoles. With methylisothiocyanate 2-methylamino-5-aminothiazoleis obtained. This thiasole rearranges into l-methyld-amino-2 ( 3 H )-imidazolethione when it is subjected to the action of hot, aqueous sodium carbonate solution (83).

H

The reaction between aminoacetonitrile and carbethoxyisothiocyanate results in the formation of 2-carbethoxyamino-5-aminothiazole. Treatment with dilute sodium carbonate solution transforms this thiarole into 4(or 5)-carbethoxyamino-2 (3H) -imidazolethione. 4-Alkyl- or 4-aryl-substituted 5-amino-2-carbethoxyaminothiazoleswhich are readily available from the interaction of substituted aminoacetonitriles with car-

III. 0x0- and Hydroxyimidaeoles and Sulfur Analogues

83

bethoxyisothiocyanate rearrange tqo4 (or 5)-alkyl- or 4(or 5)-aryl-substituted 5 (or 4)-carbethoxyamino-2 (3H)-imidaaolethiones (84,85).

IVV~~~C+COOEt-

HI HtN-Cfs~-N400Et

B-

-

f

N.,CO,*HN~'SJH R-b--r-cooEt

H

Substitution of the carbethoxyisothiocyanate by beneoylisothiocyanate leads to the formation of the respective beneamidothiaeoles and 2 (3H) imidasolethiones. ThuE, 2-benzamido-4-methyl-5-aminothiazoleresulting from the reaction of a-aminopropionitrile and benzoylisothiocyanate is rearranged to 4(or 5 )-methyl4 (or 4) -benzamido-2 ( 3 H )-imidaeolethione by dilute sodium carbonate solution.

-

It is of interest to note that the 2-alkylamino- or 2-arylamino-substituted 5-aminothiazoles rearrange to l-alkyl- or 1-aryl-substituted 5amino-2 (3H)-imidazolethiones, while the 2-acylamido-5-aminothiazoles are converted into 4(or 5)-acylamido-2(3H) -imidasolethiones. The acyl group in the final product is attached to the more basic nitrogen. The method is also applicableto the preparation of the ester and amide of l-methyl-5-amino-2 (3N)-imidarolethione-4-carboxylic acid. This synthesis involves the reaction of ethyl a-aminocyanoacetate with methyl-

TABLE XVII. Light Absorption of a ISumber of 2(3H)-Imidazolethiones+ Compound

00 l b

A (mcU).A*

2(3H)-Imidazolethione ..........................................................2,580 4(or 5)-Benzamido- ........................................................ 2.670 2 m 3.050 4(or 5)-Carbethoxyamino- .................................................. 2.690 1-Hydroxymethyl- .......................................................... 2.550 4(or 5)-Methyl- ............................................................ 2.580 2.730 2.670 I-Methyl-&amino1-9IethyI-5-amino-4-carbethoxy- ............................................ 2.280 2.690 3.0i 0 l-hlethyl-5-amino-4-carboxamidc+ 2.880

......................................................... ........................................... .............................................

4(or 5)-Methyl-5(or 41-bromo4(or 5)-Methyl-5(or rl)-csrbethoxyam*no-

3.030

2.7 00 ................................... 2,230 2.670 OF 5)-MethyM(or 4)dimethylaminomethyI- ............................... 2.660 4(or 5)-Phenyld(or 4)-carbethoxyamino- .................................... 2.690 2.960 2-Acetylmerrapto-4(or li)-methylimidazole ...................................... 3.250 Ergothioneine .................................................................. 2.580 4-Methyl- ..................................................................2.600 2-Carbethoxymcrcaptohistidinedihydrochloride .................................. 2.400 2-Mereapto-4-methylhistidine 2.800 2-Methylmercapto-4-methylhistidine methylester dihydrochloride ................. 2.550

...................................................

* e = molar extinction coefficient.. Ch = chloroform. W = water. Et

IP

ethanol

.

14.600 17.100 17.100 6800 13.850 15.OOO 14.800 14.800 13.550 9.050 lo.050 22. 100 9.975

18.925 16.200 6.250 14.300 16.OOO 15.775 15.775 11.700

IS.OOO

15.600 9.400

15,300 7.800

.

Solvent

Ref

W

(12)

Et Et W W

(84)

Et

(83)

Ch

(85)

(12)

(l2)

a

8.

p

8

%

Et

(83)

Et

(83)

Et Et

(85) (12)

Et Ch W

(85) (12) (88)

Et

w w

(92)

W

(87) (88)

W

(87)

(87)

*

g,

3.

isothiocynnate to give 2-methylaniino-4-carbethoxy-5-aminothiazole,and rcarrangcinent of tlic lattcr by exposure to dilute sodium carbonate to yield ethyl l-iiicthyl-5-aiiiino-2( 3 H l -imidazolethione-4-carboxylate. A similar scqucnce of reactions lcads from a-aminocyanoacetamide to l-methylN-F

-

S * ~ = ~ - ~ ~ H~N-F’ I

EtOOC-C-NHa

EtOOC-C-N

I H‘

H s-F--N-CH~ ’

t E~OOC-C-LNH NMOJ

H ~ ~ ~ w - c H ~

5-amino-:! (3H)-imidazolethione-4-carhoxamide (83,86). (2) General Properties’

The 2 (3H)-imidasolethiones are well-crystallized, high-melting, colorless to faintly yellow solids exhibiting characteristic ultraviolet absorption spectra. The locations and extinction coefficients of the major hand(s) of a number of 2 (3H)-imidazolethiones are summarized in Table XVII. The 2(3H) -imidazolethiones dissolve in aqueous alkalis with the‘ formation of stable salts. The monosodium salt of 4,5-diphenyl-2(3H)imidazolethione has been isolated in crystalline form (33). Most 2(3H)imidasolethiones are too weakly basic to form stable salts with mineral or picric acids. Addition of auric chloride to a solution of a 2 (3H)-imidasolethione results in the formation of a deep red solution. The color is not stable and fades as the auric chloride reacts with the sulfur atom. The final product of the reaction is a yellow colored, polymeric auromercaptoimidazole of the general structure:

Platinum or gold chlorides react with l-mebhyl-2(3H) -imidasolethione to form red addition compounds of the composition 2 base PtCL and 1 base AuCls, respectively. With mercuric chloride crystalline chloromercurimercaptoimidazolesare obtained (61,66,79). A characteristic property of the 2(3H)-imidasolethiones is the formation of deep yellow colors when sulfur dioxide is passed through their aqueous solutions. Crystals of a 2 (3H) -imidazolethione acquire a deep

+

* See Section A-3-b.

+

86

Chemistry of Classes and Derivatives

yellow to orange color when they are exposed to dry sulfur dioxide. The formation of labile addition compounds between sulfur dioxide and the Z(31f)-imidazolcthioncs is rcsponsihle for these colors (12,79). In contrast t.0 the imiclazolcs wliich couplc with diazotizcd sulfanilic acid in wcakly alkaline solut8ionwith tlic formation of rcd dyes (Pauly diazo reaction), certain 2 (311)-iinidszolcthiones afford yellow solutions under these conditions. The addition of strong alkali to such solutions produces deep-red to magenta colors. The color reaction was first observed by Hunter while studying ergothioneine and is usually referred to as the Hunter diazo test (88-90). In order to respond to the test a 2 ( 3 H ) iinidazolethione must possess a free imino group, an unsubstituted sulfur atom, and a hydrogen at.omor a replaceable group such a s a carboxy group in positions 4 or 5. The test is not too specific as a number of 2(3H)imidazolethiones exhibit the normal Pauly test; examples are 4(or 5 ) bemamido-2 ( 3 H )-imida.zolethione and 4 (or 5 )-methyl-2 ( 3 H )-imidazolethioned (or 4) -carboxylic acid (79,84). The 2 ( 3 N )-imidazolethiones instantaneously decolorize a potassium permanganate solution.

-

' (3) Acyktion and Alkyktion

The acylation with acetic anhydride in pyridine solution of a 2 ( 3 H ) imidazolethione results in the formation of an S-scetyl derivative. The acetyl derivatives are readily hydrolyzed to the corresponding 2 ( 3 H )imidazolethionesby treatment with water or alcohol. Ethyl chloroformate converts the 2 ( 3 H )-imidazolethiones into S-carbethoxy derivatives (12, 87).

H-C-Y-H

The 2 (311)-imidazolethiones undergo thioether formation with remarkable ease under conditions which fail to convert ordinary rnercaptans into their thioethers. The esterification of 4(or 5)-methyl-2 ( 3 H )-imidaaolethione-5 (or 4) -carboxylic acid with methanolic hydrogen chloride affords in addition to the normal eater a large proportion of methyl 2methylmercapto-4(or 5)-methyl-5 (or 4) -imidazolecarboxylate (79).

111. 0x0- and Hydroxyimidasoles and Sulfur Analogues

87

More important from the preparative standpoint is the formation of thioethers by treatment of the alkali salts of 2 (3H) -imidazolethiones with alkyl halides (33,911, or the reaction of a 2(3H)-imidazolethione with one equivalent of sodium in liquid ammonia followed by the addition of one equivalent of an alkyl halide. 4 (or 5)-Methyl-2 (3H)-imidazolethione is S-benzylated with excellent yield by the latter method (12).

The properties of the thioethers differ markedly from those of the 2 (3H) -imidazolethiones. They are basic compounds forming well-crystallised salts with mineral or picric acids. Those possessing the necessary structural features (see Chapter V, Section B-1)exhibit a positive Pauly reaction. The 8-alkylmercaptoimidasoleswith a free 4- or 5-position undergo nitration with great ease. Dilute nitric acid converts 2methylmercaptoimidaeole into 4 (or 5 )-nitro-2-methylmercaptoimidazole. 4 (or 5 )-Bromo-2-bensylmercaptoimidazolereacts with 3% nitric acid to form 4 (or 5 )-nitro-2-bennyImercaptoimidaeole sulfoxide, the bromine atom being displaced by the nitro group (see Section A-3-b) (61,92). 2Bensylmercapto-4(or 5 )-methylimidazole reacts with N-bromosuccin-

h i d e in the presence of catalytic amounts of benzoyl peroxide to give 2-bencylmercapto-4 (or 5 )-methyid (or 4) -bromoimidazole (92) and forms 2-benzylmercapto-4 (or 5) -methyl-5 (or 4) -N,iV-dimethylaminornethylimidazole when subjected to t,he action of formaldehyde and dimethylamine in gIacia1 acetic acid (12).

s8

Cliciiiistry of Classes and Dcrivativcs

(4) Oxidation

Most important from tlie practical point of view is the observation by Wohl and Marckwald (61,65,66) that exposure to dilute nitric acid converts the 2 (3H)-imidazolethiones into imidazoles. This Wolil and Marckwald synthesis (which has been applied to the preparation of a wide variety of imidaaoles) was directly responsible ior some of the most important advances in the field (16-18,67,68). The first successful syntheses of histamine and histidine are based on this reaction (see Chapter V, Section D-5, and Chapter VI, Section A-6-e) . The oxidative desulfunzation of a 2 (3H)-imidazolethione involves the initial formation of a 2-imidazolesulfinic acid, followed hy fission of the carbon-sulfur linkage with the formation of an imidazole and sulfur dioxide. H

-

HF"'c~-sH I

IIX'OI

HC-N

H I H~-F-SO~H HC-N

H I

- HYNT-H HC-N

+ so*

The 2-i1nidazolesulfinic acids are highly unstable coiiipounds, and only one representative, 4 (or 5 )-inetl1yl-2-imiduzolesulfinicacid, lias been obtained in pure form. This acid results from a carefully controlled hydrogen peroxide oxidation of 4(or 5 )-methyl-2 (311) -iiiiidazolethione. The sulfinic acid is a very sensitive coinpound which undergoes dccomposition to 4(or 5)-methylimidazole and sulfur dioxide on short exposure to dilute sulfuric acid. On standing at. room temperature it rearranges to tlie sulfite salt of 4(or 5)-methylimidazole. For inany years tlie 2-imiduzolesulfonic acids have bcen regarded as tlie intermediates in tlie conversion of 2(3H b -iinidazoletl~ionesinto imidazoles. This view is untenaljlc sincc tlie known 2-imidazolesulfonic acids are liiglily stable toward acid liydrolyais (see Chapter VI, Section B-3) (79,93). The conversion of certain 2 ( 3 H )-iinidazolethiones int.0 tlie corrcsponcling imidazoles by dilute nitric acid may be accompanied by undesirablc aide reactions. 4 (or 5 )-Aminomethyl3 (3H) -imidazolethione represents a typical example. This substance is transformed by nitric acid into 4(or 5)-hydroxymethylimidazoleand not into tlie expected 4(or 5)-aminomethylimidazole. Thc nitrous acid resulting from tho oxidation-reduction reaction deaminates the initially forined aminomethyl derivative. 4 (or 5)-Aminometliylimidazolo is readily obtained when the oxidative desulfurization is effected by ferric chloride or by ferric sulfate. Ferric salts are in many instances the reagents of choice for the convcrsion of 2 ( 3 H )-imidazoIethiones into imidazoles (69,73,94).

111. 0x0- and Hydroxyimidnzolcfi and Siilfiir Analogties

89

Oxidation of 2 (3H) -imidaxolethiones with iodine results in the formation of disulfidcs. A solut.ion of iodine in potassium iodide converts 4(or 5 )-methyl-2 ( 3 H )-iinidasolctliione into the corresponding disulfidc periodide (33,79,95). N-Bromosucciniinide also brings about the conversion of 2 ( 3 H )imidazolethiones into disulfides. 4(or B)-Methyl-2 (3N) -imidazolethione, for example, is transformed into di-[4(or 5) -methyl-5 (or 4) -bromo-2imidszole] disulfide when subjected to the action of two equivalents of this reagent in aqueous solution (92). The disulfides are high-melting, yellow solids which iail t o exhibit characteristic absorption bands in the 21003600 A. rcgion. They are soluble in dilute hydrochloric acid and passage of a stream of sulfur dioxide through such a solution brings about their reduction to 2 (3H1-imidazolethiones (79,92).

H

2

I HC/~-~--SH

HLN

H

H

H ~I ~ - ‘ - s -I s - ~ ~ Y ~ oxidation SOI

H -N

-CH

More drastic oxidation of the 2 (3H)-imidasolethiones with hydrogen peroxide or with potassium permanganate results in the formation of 2imidazolesulfonic acids (see Chapter VI,Section B-3). Chromium trioxide oxidation converts 4,!j-diphcnyl-2 ( 3 H )-imidazolethione into hi,”-dibenzoylurea (33). (5) Behavior toward Raney Nickel

The exposure of a 2(3H)-imidazolethione to the action of Raney nickel in alcoholic solution results in smooth replacement of the sulfur atom by hydrogen with the formation of an imidazole. This reaction has been applied to the synthesis of a wide variety of imidazoles and seems to be superior to the older Wohl-Marckwald method (83-85,96). (6) Pharmacological Activity

A number of 2 (3H) -imidazolethiones, because of their pronounced antithyroid activity, have found application in clinical medicine. The discovery by McGinty and Bywater (97,98) of the antithyroid activity of benzimidazolethione was the first recognition of the pronounced pharmacological activity of the imidazolethiones. Stanley and Astwood (99) recognized the high antit.hyroir1 activity of 2 (3H)-imidazolethione and found that in man this subst.ance exhibits ten times the activity of thiouracil. A number of other 2(3H)-imidazolethiones, such as the 4(or 5)-

!lo

Chcrnistry of Classes and Derivatives

methyl- and the 4(or 5) -n-propyl derivatives, also exhibit the same effect (70). 1-Methyl-2 (3H)-imidazolethione with an activity approximately one hundred tiincs that of thiouracil is the most potent compound of the series (100). Tlic S-carhcthoxy dcrivetivc of 1-mcthyl-2 (3H)-imidazolethione also posscsscs a high dcgrec of h,itliyroid activity in man (101,102). This latter compound offers the advantage of not possessing the bitter taste characteristic of the free 2 (311)-imidazolethiones. (7) Erpothionelne

Ergothioneine (thioneine, 2-mercaptohistidine betaine) is the only 2(3H)-imidazolethione thus far recognized as a constituent of plant and animal tissues. The base was first isolated from ergot (103,104) and later shown to be a constituent of blood (105,106). H

1 HC”-(i=S d-XH I HZC CHI I 1 H.$qN--C-COOI I HSC H Ergothioneine

Ergothioneine melts at 290°, has the elementary composition C~HIII-

02N& and forms a stable dihydrate and monohydrochloride. The base

is optically active ([=II, 47O in water) and exhibits a positive Hunter diazo test. Mercuric chloride, silver oxide, potassium bismuth iodide, and phosphotungstic acid form precipitates with ergothioneine. With sulfur dioxide a yellow color is produced, and treatment with iodine results in the formation of a disulfide. Ergothioneine is readily soluble in water, sparingly soluble in cold ethanol, and insoluble in chloroform and benzene. The constitution follows from the formation of one mole of trimethylamine and one mole of 2(3HI -imidazolethione-4(or 5)-acrylic acid on heating one mole with 50% potausium hydroxide, and from the conversion into hercynine (histidine betaine) on oxidation with ferric chloride (73, 107). The synthesis (88) of ergothioneine from L-histidine is illustrated on page 92. L-Histidine methyl ester is converted into methyl ~-2,4,5-tribenzamido-4-pentenoate by treatment with benzoyl chloride and sodium car-

+

111. 0x0- and Hgdroxyimidazoles and Sulfur Analogues

-

H I HVa-$!=S

OH-

C-NH

H I

HSaF=S

A

I

91

C-NH I CH If C-COO-

k

+

CHi I N-CHa I CHa

H I H-Y~-~-H C-N i HJ2 CHt I 1 H&-W+-C-COOI 1 HaC H

bonate (108,109) (see Chapter VI, Section A-6-f), and the latter compound on exposure to methanolic hydrogen chloride affords methyl L-2,5dibenzamino-4-keptopentanoate ( 110). Hydrolysis of this compound with concentrated hydrochloric acid results in the formation of ~-2,5diamino-4-ketopentanoic acid dihydrochloride. This dihydrochloride reacts with one equivalent of potassium thiocyanate to give 2-mercapto~Aiistidine (111). Protection of the sulfur by carbethoxylation, and methylation with methyl iodide and silver oxide, followed by removal of the blocking carbethoxy group by hydrolysis with hydrochloric acid completes the synthesis. This synthetic ergothioneine i s in every respect identical with the natural material. A number of analogues of ergothioneine are available through similar reactions (87). See equation (1), page 92. The biological significance of ergothioneine remains to be established. (e)

S(5H) -ImidazOlones

Biltz’s (52) isoimidazolones may be regarded as representatives of the class of the 2 (5H) -imidazolones. The removal of a molecule of alcohol from 4,5-diaryl-4,5-dialkoxy-2-imidazolidonesprovides a synthetic route to 4,5-diaiyl-5-alkoxy-2 (5H 1-imidazolones (isoimidazolones). The conversion is readily effected by heating the diaryldialkoxy-2-imidazolidones above their melting points. See equation (2), page 92. Substitution of one of the imino hydrogens in the diaryldialkoxy-2-imidazolidoneby an alkyl group does not interfere with the reaction. The process is reversible.

Chemistry of Classes and Derivatives

92

-

p0

CXS-

CHI MeOOC-C-K-C

I I II H H 0

-

H I HTNT=S C-NH

CICOOEt

I CHt 1 HOOC-C-NH, I H

H I

HY"fC-N

I H$"f-fi-COOEt C-N

CHJ

Aslo

AHZ I HOOC-C-NH, I

H

-

S COOEt

it

Hz+ YH, -OOC-C-NC-CH~ I I

6 I 6

H

H CH,

EtO-C-q-lI EtO-C-N-€I F=O

A

H+

1i I

H$"*Y=S C-NH I H K CHj -OOC-i-A%CH1 I 1 H CHj

8

EtO- -N-H

I

$=O

+ EtOH

(2)

111. Oso- nnd Hydrm~imirlnzolrsSiilfiir Annlogiirs

9.3

as the addition of a trace of mineral acid to an alcoholic solubion of an iaoiinidazolone results in the regeneration of the starting material. Oxidation with clwoinic acid convcrts tlic isoirriidazolones inta sum-diaroyltircas. Rcductiori with zinc (lust in acetic acid or with sodiuin aiiialgaiii leads to the forination of 4,5-diaiyi-2-iniidln;olidones. ( f ) 4 ( b H ) (or 6(4H))-hidazolones (1) Synthetic Methoda

The first representative of this class of imidazoles, the compound 2phenyl-4(or 5 ) -benzylidene-4(5H) (or 5 (4N) ) -imidaaolone, was obtained by Ruhemrrnn and Cunnington (112) from the sodium ethoxide catalyzed reaction of ethyl phenylpropiolate and bemamidine hydrochloride. A more generally applicable procedure for the synthesis of these imidazolones H

HN\ ,NHz C

involves the condensation of equimolar proportions of an amidine and an ester of an a-amino acid. The reaction of glycine ester with an amidine leads to the formation of a 2-monosubstituted 4(5H) (or 5(4H))-imidazolone, while the use of other a-amino acid esters affords 2,4(or 2,5)-disubstituted 4 (5H) (or 5 (4H)1-imidazolones. The reaction proceeds

-

R

I H- C-COOEt I NHS HN=C-NHt

+

L

R

I N-f:y=O

HNFrN R'

rapidly on mixing the components a t room temperature and in some instances is so violent that cooling is necessary. The method is applicable to the preparation of a great variety of imidazolones since the groups R and R' may be aromatic or aliphatic in nature (113-115). The condensation in the presence of a base of an a-ketoaldehyde with an amidine is another route to 2,4 (or 2,5) disubdituted 4 (5H)(or 5 (4H) ) -imidazolones. An example of this reaction is the formation of 2-phenyl-4(or 5)-methyl) -imidazolone from methylglyoxal and henzamidine 4 (5H) (or 5 (4H)

-

Chemistry of Classes and Derivatives

94

(115-118). This reaction seems to proceed through the stage of a 4,5dihydroxy-2-imidaroline in the inaniicr indicatcd bclow.

Closely related to this synthesis is the formation of 2-phenyl-4(or 5 )-arylidene-4 (511) (or 5 (4111) -imidarolones from the interaction of benrnmidine-glyoxal with aromatic aldehydes. The addition of potassium hydroxide to a mixture of glyoxal and benramidine hydrochloride results in the format.ion of a labile, basic substance which may be represented either as an open-chain compound or, preferably, as a 2-phenyl4,5-dihydroxy-2-imidazoline (benzamidine-glyoxal) (115). This benzamidineglyoxal addition compound dissociates in aqueous solution, and the addi0 0 II II H-C--C-H Ii,N\C,NH

+

-

OH OH I 1 €I-y,I-€I HNtC’N

YH B

Or

H-C-C-€1 I HN@H

tion of phenylhydraaine leads to the formation of glyoxalphenylosazone. In the presence of a n aromatic aldehyde and sodium or potassium hydroxide this substance is converted in good yields into a 2-phenyl-4 (or 5) arylidene-4(5H) (or 5 (4H) ) 4midazolone. Using the more plausible 4,5dihydroxy-2-imidaroline formulation for the bemamidine-glyoxal complex as the basis, this reaction may be formulated in the manner illustrated below. Under the influence of the base, the dihydroxyimidaaoline is assumed to lose a molecule of water with the formation of the highly reac-

-

111. 0x0- and Hydroxyimidszoles nnd Sulfur Analogues

95

tive 2-phenyl-4(5H) (or 5(4H) )-imidazolone, which in turn undergoes an aldol-type condensatioc with the aldchydc to give the final product. The d d i t y to undergo this type of condciirstion is a typical property of 4(5H)(or 6 (411)) -imidazoloncfi, siiicc tlic proxiiuity of thc carbonyl group activates thc adjacent mcthylcnc group. Nu~ncroiis2-plicnyl-4(or 5)-arylidene-4(51-1) (or 5 (411)) -iinidnzoloncu are ncccssiblc by this method (119122). The dehydration of a-acylamido-B-phenylacrylic acid amides (readily available from the reaction of aelactones with ammonia) represents another route to 2-phenyl-4(or 5)-arylidene-4(5H) (or 5 (4H) )imidazolones. The synthesis of 2-phenyl-4 (or 5 )-benzylidene-4 ( 5 H ) (or 5 (4H)) -imidazolone serves as an illustration of the method. The reaction of hippuric acid with benzaldehyde in the presence of a mixture of acetic anhydride and sodium acetate leads to the formation of benzoyl-acinnamic aelactone (4-beneylidene-5-oxazolone) . This substance is readily converted into the smide of a-benzamido-j3-phenylacrylicacid by exposure to aqueous ammonia, and the amide under the influence of hot dilute sodium hydroxide loses a molecule of water with the formation of 2-phenyl-4 (or 5 ) -beneylidene-4(5H)(or 5 (4H) ) 4midaeolone. Numeroue other szlactones are convertible into the corresponding imidarolones ac-

H

8

A OH-

cording to this scheme (123-126). It is of interest to note that treatment with hot dilute sodium hydroxide converts the amide of a-beneamidoisobutyric acid into 2-phenyl4,4 (or 5,5) -dimethyl-4 (5H)(or 5 (4H) ) -imidaeolone, while similar treatment of the amides of bensoylglycine and benzoylalanine leads to hydrolysis of the carboxamide linkage (127,128).

Certain amides and the anilide of a-benzamido-8-phenylacrylicacid are not conrcrtible into the respective iinidazolones by treatment with hot alkali. Here, more drastic treatment such as heating in vucuo nt temperatures of 170-200' is required to bring about tlic ring closure. The reaction is not generally applicable as heating of the isopropylamide of a-benzamido-p-phenylacrylic acid results in the regeneration of bcnzoyl-8-aminocinnamic azlartone and not in the formation of the A expected l-isopropyl-2-phenyl-4-benzy lidened (4H) -imidazolone. similar situation prevails in the case of a nutnher of acylated dehydrophenylalanyl dipeptide esters. Heating in v u m o at 170' converts henzoyldehydrophenylalanylglycine ethyl ester into l-carbethoxymethyl2-phetiyl-4-henzylidene-5-iniidazolone. The same treatment converts such compounds RS hcnzoyldcli~droplien~l~lanylalanine ctliyl ester or

8

henzoyldehydrophenylalanylleucineethyl ester into benzoyl-a-einnatnic azluctone and the rcspcctirc aininoncid cstcr (129,130).

The anilide of a-benzamido-p- (o-nitrophenyl) acrylic acid is readily converted into 1,2-diphenyl-4 (o-nitrobeneylidcne)-5-imidazolone when subjected to the action of phosphorus oxycliloridc (131).

111. 0x0- and Hydroxyimidszoles and Sulfur Analogues

97

The reaction between hippuramide and phosphorus pentachloride leads to the formation of hippuronitrile and not to the formation of 2phenyl-4(5H) (or 5(4H))-imidazolone (132,133). 4 (5H)(or 5 (4H) ) -1midazo1one-2-carboxylic acid results from the oxidation of diketopiperazine with alkaline hypobromite. The compound couples with diazotized aniline, is extremely unstable, and in the presence of alkali decomposes with liberation of hydrogen cyanide (134). (2) Structural Considerations and Properties

'

In addition to many plausible contributions in the resonance sense, four tautomeric forms of the 4(5H) (or 5(4H))-imidazolones have to be considered (see Section A-3-a). These are the result of the presence of an amidine and a keto-enol system in these molecules. The available chemical evidence suggests the importance of both the imidazolone and the hydroxyimidazole forms. The dibenzoyl derivatives which result when 2-methyl-4(5H) (or 5(4H))-imidazolone or 2-benzyl-4(5H) (or 5 ( 4 H ) ) imidazolone are treated with benzoyl chloride in pyridine solution must arise from the enolic form and may possess either of the two structures shown below (113,114) :

ff--JLo-l-$

HC-N

8 --B

c=o

HC-N

--R

R = - C H ~ or -cH.-(-J

Similarly, the acetyl derivative of 2-phenyl-4 (or 5)-methyl-4 (5H) (or 5 (4H)-imidazolone is best regarded as an 0-acetyl derivative arising

98

Chemistry of Classes and Derivatives

from the hydroxyimidazole form. The basic nature of the acetyl derivative supports this view (115).

H73a

r&c-c-o1 I 0

The observations that 4(5H) (or 5 (411)) -imidazolones possessing an unsubstituted methylene group couple with dimotized aromatic amines, and form beneylidene derivatives on treatment with benzaldehyde are best explained in terms of the keto form, the activation of the methylene group being due to the electron-attracting effect of the neighboring carbonyl group and possibly of the tertiary nitrogen atom (113,114).

Y The 4(5H) (or 5(4H) ) -imidcxoloncs are aniphoteric compounds having the ability to form salts with both acids and metals. 2-Phenyl-P(or 6)-methyl-4(5H) (or 5(4N) )-imidazolone, for example, forms a silver salt when treated with silver nitrate and also has the ability to give a sparingly soluble picrate (115). The amidine part of the molecule must be responsible for the basic properties, while the acidic character may be due to the enolic hydroxyl group. The acidic character of the 2-phenyl4(or 5)-arylidene-4(5H) (or 5 (4H)) -imidazoloncs is not explicable in terms of enolization. A plausible formulation for the anions of these compounds is illustrated:

The 4(5H) (or 5(4N)) -imidaeoloncs exhibit less chemical stability than the 2 (311)-imidaroIones. Treatment with strong acids or alkalis brings about fragmentation of their molecules. 2-Benzyl-4(6H) (or 5(4H)) imidazolone cleaves with the formation of phenylacetic acid, ammonia,

-

111. 0x0- and nydroxyimidazoles and Sulfur Analogues

99

and glycine, while 2-phenyl-4(or 5)-methyla (5H) (or 5(4H) ) -imidazolone affords bensoic acid, ammonia, and alsnine (114,115).

H’c-w3 77

O==C-N

0

Ha\’NHa H\ H 0 - 6 0 0 4 3 - 0 H NHI -

The 4 (or 5) -arylidene-4(5H) (or 5(4H) ) -imidal;olones exhibit characteristic U.V. absorption spectra and are readily reduced either catalytically or by sodium amalgam in acetic acid solution. Both the exocyclic and the ring double bond are saturated. The conversion of 2-phenyl-4(or 5) -benzylidene-4(5H) (or 5 ( 4 H ))-imidazolone into 2phenyl-4-benzyl-5-imidazolidone is illustrative (122,129).

B. The Hydroxyalkylimidazoles 1. Monohydroxyalkylimidazolea

( a ) HydrozymethyZi.midazoZes

The direct hydroxymethylation of suitably substituted imidazoles represents a convenient route to hydroxymethylimidazoles. The ability to undergo hydroxymethylation upon treatment with formaldehyde is a common property of many imidazoles. Although imidazole itself reacts with formaldehyde, it fails to afford a defined reaction product. Ring substituents either prevent the reaction or exert a directing influence, which guides the hydroxymethyl group into the 4(or 5)- or the 2-position. 4(0r 5)-Alkyl- or 4 (or 5) -halogen-substituted imidazoles (such as 4 (Or 5)-methyl- or 4(or 5)-brombimidazole) are hydroxymethylated in the 5(or 4)-position, while in general the I-substituted imidazoles form the

Chrmistry of Clnsws and Derivntiva

1 0

H

H I R-T"F-H H-C-N

P-

H-F~T-H

€I-C-N

I R - ~ ~ - H HOB&-C-N

CHaO

R I

H-~~~-cH,oH H-C-N

respective 2-hytlroxymethyl derivatives. Compounds which exhibit this behavior are 1-methyl-, 1-benzyl-, 1,5-diinethyl-, 1-methyl-5-chloro-, and 1-methyl-5-bromoimidazole (63,135-143). An exception is l,4dimetliylimidazole which is hydroxymethylated in the 5-position (144, 145). The orientation of the hydroxymethyl group is usually established by conversion of the hydroxymethyl derivatives into methylimidazoles of known structure by reduction with hydrogen iodide and red phosphorus (63,135,136). The halogen atom in hydroxymethylated halogenoimidazoles is replaced by hydrogen during these reductions. l-Methyl-2liydroxymcthyl-5-cl1loroimid~zole, for example, affords 13-dimethylimidazole. CHI I C~-SJ'~+CA~OH H-C-N

C&

I

H-F~T-CH, H-C-N

As a typical electrophilic substitution reaction, hydroxymethylation is inhibited by electronegative substituents such as the nitro group or the phenyl group, and is facilitated by the electron-releasing methyl group. Compounds such as 4(or 5 )-nitro-, 4-nitro-l-methyl-, 5-nitro-l-methyl-, or 2-phenyl-4(or 5)-methylimidazole fail to react with formaldehyde (115,144). A halogen atom in the 4(or 5)-position interferes with the hydroxymethylation reaction as judged by the behavior of 4(or 5)bromoimidazole, which affords a poor yield of 4(or 5)-bromo-5(or 4)hydroxymethylimidarole on treat.ment wit.h formaldehyde. 1-Methyl5-chloro (or bromo) imidazoles are hydroxymethylated in the 2-position with excellent yields, while 1-methyl-4-chloroimidazole is recovered unchanged in an amount of 60% (144). l-Met~hyl-4,5-dibromoimidazole fails to be hydroxymethylated (141).

111. 0x0- and Hydroxyilnidurolesrand Sulfur Anttlogucs

101

A number of methods for the preparation of those liydroxymethylimidazoles which are not obtainable by direct hydroxymethylation must be mentioned at this point. The l-substituted 5-hydroxymethylimidasoles, for example, cannot be prepared by hydroxymethylation of 1substituted imidazoles, since the substituent in position 1 directs the hydroxymethyl group into the 2-position. These imidazoles are readily available by reduction of the esters of l-substituted 5-imidaeolecarboxylic acids with lithium aluminum hydride. Also the reduction of suitably 1substihted 5-imidazolecarboxaldeliydes over Adams catalyst in the presence of traces of fcrric chloride provides a route for their synthesis (9).

Of theoretical interest is the foimation of 2-phenyl-4 (or 5 )-methyl-

5 (or 4) -hydroxymetliyli~nidazole. This compound results from the

treatment with hydrochloric acid of the addition compound of diacetyl and benzamidine. Diacetyl and bensamidine combine in aqueous solution in the presence of sodium acetate to give a compound which is beat formulated as 2-phenyl-4,5-dimethyI-4,5-dihydroxy-2-imidazoline.The formation of a beneylidene derivative on treatment of the substance with benzaldehyde is in accord with this formulation. This imidaeoline is a rather unstable substance which dissociates into diacetyl and benzamidine upon refluxing with water. Boiling with hydrochloric acid converts the compound into the hydrochloride of 2-phenyl-4 (or 5 )-methyl4 (or 4) hydroxymethylimidaeole. It seems logical to assume that dehydration of the dihydroxyimidazoline leads to the initial formation of a methylene derivative which, in turn, undergoes an anionotropic shift with the formation of the final product, possibly by way of the chloromethyl derivative (115,146148). See equation (1), page 102. A number of hydroxymethylimidaeoles deserve special mention because of their use as intermediates in the synthesis of other imidaeole .derivatives.

102

Chemistry of Classes and Derivatives

l-Benzyl-2-hydroq1nethylirnidazoleresults in practically quantitative yield from the reaction of 1-benaylimidaaole with formaldehyde. It is a viscous oil forming a crystalline picrate which melts at 132-133O. Oxidation with potassium permanganate converts 1-benayl-2-hydroxymethylimidaaole into 1-benayl-2-imidaaolecarboxylic acid, while its reaction with thionyl chloride lends to the formation of the hydrochloride of 1-beneyl-2-cl~lorometl~ylimidazole. The latter substance is a valuable intermediate in the synthesis of various histamine and histidine analogues (63) (see Chapter V, Section D-7, and Chapter VI, Section A-6-g). bHydro~~inethyZi~nu1~~ole is obtained from 1-benzyl-2-hydroxymethylimidaeole by debenzylation with sodium in liquid ammonia (63). The oily compound forms a crystalline picrate and hydrochloride. 4-(or 6 )-HydroxymsthylimidazoZe was originally prepared by treatment of 4 (or 5 )-aminomethyl-2 ( 3 H )4midaaolethione with dilute nitric acid (149). The best method for its preparation involves the interaction

XII.

0x0- and Hydroxyimiclazolcs and Sulfur Analogues

103

of D-fructose with formaldehyde in the presence of ammoniacal cupric acetate (150-152). 4(or 5)-Hydroxymethyliiiiidazole melts a t 93-94" and is best isolated in the form of its crystalline picrate. The substance is readily soluble in water and ethanol, is sparingly soluble in ether and other organic solvents, and f o r m precipitates with iiiercuric chloride, ammoniacal silver nitrate, or zinc hydroxide solutions (149). Treatment with phosphorus pentachloride (149) or preferably with thionyl chloride, converts 4 (or 5) -hydroxymethylimidazole into the hydrochloride of 4 (or 5 ) -chloromethylimidazole (5,9).

( b ) 4(or 5)- (~-H.ydro~~ethyZ)imi~nzoZe (Histaminole) Histaminole, the most important representative of the hydroxyethylimidaeoles, is the deamination product of histamine (153,154) Two

.'

B

routes for the synthesis of this coinpound are of importance. The first involves the reduction of a-amino-y-butyrolactone with sodium amalgam in acid solution and treatment of the hydrochloride of the resulting aminoaldehyde with potassium thiocyanate. The 4 (or 5) (2-hydroxyethyl) 2 (3H) -imidazolethione which is thus obtained is converted into histaminole either by oxidation with dilute nitric acid or by reductive desulfurization with Raney nickel (96,155). This synthesis is of limited ap-

-

-

plicability, however, since a-amino-7-butyrolactone is not easily accessible and because the initial reduction requires the use of large quantities of sodium amalgam. A superior method of preparation involves the reaction of 1,4-dihydroxybutanone-2 with formaldehyde and ammonia

104

Chcmistxy of Clxs,m and &rivnf.ivcs

under the conditions of the Weidenhagen synthesis. This method is simple, and the starting material is readily available froin 1,4-butynediol (156).

4 (or 5)- (2-Hydroxyethyl) imidazole crystallizes from chloroform in hexagonal plates of m.p. 92O. It is readily soluble in acetone, ethanol, and water, but is sparingly soluble in ether or benzene. It forms a characteristic picrate, chloroplatinate, and picrolonate, and is readily converted into the hydrochloride of 4(or 5)- (2-chloroethy1)imidazole by treatment with thionyl chloride (155). 2.

Polyhydroxyelkylimidmles

(a) 4 (or 6)-Pol?Jh~~rox?jnlk?/l~~~~azoles

A variety of imidazole derivatives are formed when ammoniacal cupric acetate solutions of carbohydrates are aerated at room temperature for prolonged periods of time (157-161). Of special interest is the formation of 4 (or 5 )- (D-urubino-tetrahydroxybutyl)imidazole from Dglucose, pmannose, and 4-fructose. This compound exhibits the typical imidazole reactions, such as silver salt formation, and gives a positive response to the Pauly diazo test. Decisive elucidation of its chemical constitution is the finding that oxidation with nitric acid transforms the compound into a mixture of 4(or 5)-imidazoleglyoxylic acid and 4(or 5)-imidazolecarboxylic acid. See equation (1) , page 105. A similar product is obtained by the reaction of D-glucosamine with thiocyanic acid, followed by oxidative removal of the sulfur from the resulting ~-nrctbin~-imidazolethione. Oxidation converts the comtetrahydroxybutyl-2 (3H) pound into 4(or 5)-imidazolecarboxylic acid (162). The formation of an identical 4 (or 5) (D-arubino-tetrahydroxybutyl)imidazole from Dglucose, wmannose, and D-fructose, points to D-glucosone as the common intermediate. Indeed the reaction of D-glucosone with ammonia and formaldehyde produces the same 4 (or 5) (D-arnbino-tetrahydroxybutyl) imidazole.

-

-

III. 0x0- and Hydroxyimidazoles and Sulfur Andogues

105

=-Ci=O H-C-OH

H-f-OH HgOH

PI

D-ClUCOSe

H0-i-H €I-C-OH H- -OH

t&OH

D-Mannose

__c

HO-A-* I H-C-OH H-L-OH I CHtOH D-Gfucosone

HO-LH

cu++

___*

CHto

I

H-Y-oH

H-~-OH

CHrOH 4(or 5)- wncqingtetrahydroxy(bUtyl~~daaol~

I

CHlOH

I

OXid6(iOn


Ir0-VH H-C-OH H-&-OH I CHIOH D-FruCtose

(1)

H-q

5’f-H

I3-F”j”f-H

CI-N C=O I

C-N I tOOH

COOH I(ur 5)-Imiduzolc glyoxylic acid

4(or 5)- ImidamIe

carboxylic acid

( 6 ) 1-Pol~hy~roxyalkyZimi~zoZes

Representatives of this class of compound are obtained by the interaction of imidazole silver with polyacetylglucosyl halides. Thus the reaction of imidaeole silver with tetra-0-acetyl-a-D-glucosyl bromide in boiling xylene results in the formation of l-tetra-O-acetyl-&D-glucopyranosylimidaeole. Deacetylation with sodium methoxide in methanolic solution affords l-p-D-glucopyranosylimidazole ( 163) :

Chemistry of Classes and Derivatives

-"-I--%. - "-7"

106

Kawhfe-

H-

H -I-Br

T'I-

(CHOAC), 0 H-C I CH~OAC

'2

-N

H-C-N

FH &-€I

A-H dI H b o H-C------J I CH~OAC

d H h 0

H-AI CHaOH

The silver salt of 4 (or 5 )-metliylimidarole reacts with tetra-0-acetyla-D-glucopyranosyl bromide to form 1-tetra-0-acetyl-&wglucopyranosyl5-methylimidarole. The constitution of the product follows from its conversion into 1,4-dimethylimidazole by the following steps: quaternirstion with methyl iodide, conversion to the hydrochloride by exchange reaction with 'silver chloride, and removal of the carbohydrate residue by hydrolysis with concentrated hydrochloric acid a t 150" (164).

J."

then HCI

Bibliography

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5. Turner, R. A., Huebner, C. F., and Schole, C. R., J . Am. Chem. SOC.72, 2801 (1949). 6. Deulofeu, V., and Mitta, A. E. A., J Org. Chem. 24, 915 (1949).

111. 0x0- and Hydmxyimidazoles and Sulfur Annlogacs

107

7. Barger, G., and Dakin. H. D., Biochern. J . 10, 376 (1916). 8. Turner, R. A., J. Am. Cham. Soc. 71, 3412 (1949). 9. Jones, R. G.. and McL~iiglilin.I<. C., ibid. 71, 2444 (1949). 10. Sonn, A., and Greif, P., B w . 66, 1900 (1933). 11. Ochiai, E., Tamamarlii, Y., md E;agrZ'*Iwa, F., ibirl. 73, 28 (1940). 12. Heath, H.,Imvson, A., ant1 Rimington, C., J. Clcem. SOC. 1951, 2217. 13. Rupee,H., Ber. 97, 588 (18W). 14. Gabriel, S., and Posner, T., *id. 1037 (1894). 15. Rupe, H.,ibid. $8, 251 (1895). 16. Kunne, H.,ibid. 98, 2036 (1895). 17. Belw-Bregowelri, L., ibid. 30, 1515 (1897). 18. Jiinecke, E., &id. Sg, 1095 (1899). 19. Kolshorn. E.,ibid. 31, 2474 (1904). 20. Widman, O., and Wahlberg, E., &id. 44, M65 (1911). 21. Biltz, H., and Biilow, H., Ann. .bsr, 103 (1927). 22. Dakin, H. D., and West, R., J. BWZ. Chem. 78, 757 (1928). 23. Franchimont, A. P. N.. and Dubsky, 1. V, Rec. trav. chim. SO, 186 (1911). 24. Ryan, H.,Ber. 32, 2129 (1898). 25. Sonn, A., ibid. 40, 4666 (1901). 26. Hildesheimer, A., &id. 43, 2796 (1910). 27. Brazier, 5. A., and McCombie, H.,J. Chem. Soc. 102, 2352 (1912). 28. McCombie, H., and Scarborough, H. A.. &id. 103, 66 (1913). 29. Marckwald, W., Ber. 96, 2354 (1892). 30. Duschinsky, R., and Dolan, L. A., J . -4m.Chem. SOC.68, 2350 (1946). 31. Anschutz, R., and Oeldermann, H., -4nn. 261, 129 (1890). 32. Anschiitz, R., and MiWer, H.,ibid. ,?84,25 (1894). 33. Anschutr, R., and Schwickerat, K., ibkd. 984,9 (1894). 34. Baese, A., and Klinger, H., Ber. 32, 1217 (1898). 35. Sircar, A. C.,and Guha, 5. C., 1. Indian Chem. SOC.13, 704 (1938). 36. Bilta, H., Ber. 40, 4799 (1907). 37. Organic Syztheses, Col. Vol. 11, John Wiley and Sons, Inc., New York, 1943, p. 231. 38. Winsns, C. F., and Adkins, H., J. Am. Chem. Soc. 66, 4167 (1933). 39. Fenton, H.J. H., and Wilks, W.A. R., J. Chem. SOC.96, 1329 (1909). 40. Rilbert, G. E., J . Am. C h m . Soc. 64, 3413 (1932). 41. Cook, A. H., Heilbron, I., and Hunter, G. D.,1. Chem. Soc. 1949, 1443. 42. Beythien, R., Ann. 9139, 214 (1912). 43. Johnson, T. B, and Hadley, S. E.,J . Am. Chem. SOC.39, 1715 (1917). 44. Johnaon, T. B., and Hadley, 8. E.,&id. 39, 1919 (1917). 45. B i b , H., Bet. 42, 1754 (1908). 45a. Dither, K., Ferger, M. F., and du Vigneaud, V., 1.BioL Chem. 164, 19 (1946). 46. Duschinsky, R., and Dolan, L. A., J. Am. Chem. SOC.6?',2079 (1945). 47. Duschinsky, R., and D o h , L. A., ibid. 70, 657 (1948). 48. Ochiai, E.,and Nagasawn, F., Ber. 79, 1470 (1939). 49. Lamb, I. D., and Pyman, F. L., J . Chem. 8oc. 225, 706 (1924). 80. Biltt, H., Ber. 0, 1761 (1908). 51. Biltt, H., Am. Sss, % !d! (1SOg). 52. Bilta, H.,&id. $68, 156 (1909). 63. Bilts, H, Ber. 4,167 (1908). 51. Chattaway, F. D., and Coulson, E. A., J. Chem. Soc. 1928, 1361.

n,

la$

Chamistw of Clwes and Drriva.t.ivcs

55. Biltz, H., Ann. 391, 169 (1912). 56. Wood, J. L.,nnd du Vigneuud, V., J. d i n . Chem. Soc. 67,210 (1945). 57. McKennis, Jr., H., and du Vigneaud. V., ibirl. 6s. 832 (1sQ6). 58. Dumhinsky, R., Dolan, L. A.,-Randall, L. O.,and Lchmann, G., ibid. 69, 3150

(1947). 59. Duschidy, R., and Dolan, L. A., Emil C. BureU Jubilee Volume, F. HoffmannLa Roche & Co., Ltd., Basel, 1946, p. 164. 60. Wohl, A., and Marckwald, W., Ber. 89, 568 (1889). 61. Wohl, A., and Marckwald, W.,&id. 22, 1353 (1889). 62. Easson, A. P. T., and Pyman, F. L., J. Chem. h c . 1X3.9, 1808. 63. Jones, R. G., J. Am. Chem. SOC.71, 383 (1949). 64. Biirtles, R., Pyman, F. L., and Roylance, J., J . Chpm. Srw. 1%‘. 581 “25). 65. Marckwald, W.,Bcr. 26, 2354 (1892). 66. Gabriel, S., and Pinkus, G., &id. B,2197 (18%). 67. Gabriel, S., and Posner, T.,W. 97, 1141 (1894). 88. Gabriel, S., 41, 1928 (1908). 69. Jackson, A. O., and Marvel, C. S., J. B i d . Chem. 105, 191 (1933). 70. Jackman, M., Klenk, M., Fishburn, B., Tullar, B. F., and Archer, S., J . Am. Chem. SOC.70, 2884 (1948). 71. Tamamushi, T., J . Pharm. SOC.Japan 63,359 (1933); Chem. Abstracts 27, 3934. 72. Tamamushi, Y.,ibid. 63,766 (1933); Chem. Abstracts 98, 3406. 73. Akabori, 8.. Bet. 86, 151 (1933). 74. Akabori, S., and Numano, S., &id, 66, 159 (1933). 75. Akabori, S., and Numano, S., J. Chem. SOC. Japan 65, 200 (1932); Chem.

im.

Abstracts 97, 292.

76. Akabori, S., and Kaneko, T., ibid. 63, 207 (1932); Chem. Abstracts D,293. 77. Akabori, S., and Numano, S., ibid. 63,213 (1932): Chrm. AbRtrnct.9 97, 293. 78. Jones, R. G., J . Am. Chem. SOC.71, 844 (1949). 79. Balaban, I. E., and King, H., J. Chem. Soc. 1997, 1858. 80. Dodson, R. M.,J . Am. Chem. SOC.70, 2753 (1948). 81. Dessert, A. M.,U. S. Patent No. 2,519,310. 82. Heilbron, I., J. Chem. SOC.1949, 2099. 83. Cook, A. H., Downer, J. D., and Heilbron, I., ibid. 19.48, 2028. 84. Cook, A. H.,Downer, J. D.. and Heilbron, I., &id. 19/18, 1262. 1340. 86. Capp, C. W., Cook, A. H., Downer, J. D., and Heilbron, I., ibzil. 86. Cook, A. € Heilbron, I., I., and Smith, E., ibid. 1949, 1440. 87. Heath, H., Lawson, A., and Rimington, C., &id. 1.961, 2220. 88. Heath, €Lawson, I., A., and Rimington. C., ibid. 1962,2215. 89. Hunter, G., ibid. 1930, 2343. W.Hunter, G., Biochern. J . 2% 4 (1928). 91. Cohen, A., King, H.,and StrangewayR, W. I., 1. Chem. Soc. 19
liI. 0x0- and Hydruxyiuiiduzolw and Sulfur halogum

109

99. Stmley, M. M., and Astwood, E. B., Rndorrinologu 41, 66 (1947). 100. Stanley, M. M., and Astwood, E. B., ibid. &, 588 (1949). 101. Rimington, C., and Searle, C . E., Lancet 1961 11, 619. 102. Lamn, A., and Barry, G., M.1961 XI, 621. 103. Tanret, C., J . pharm. chim. 80, 146 (1909). 104. Tanret, C., Compt. rend. l@, 222 (1909). 105. Benedict, S. R., Newtan, E. B., and Behre, J. A., J . Biol. Chem. 67, 267 (1928). 106. Newton, E. B., Benedict, 8. R., and Dakin, H. D.,ibid. 73, 367 (1927). 107. Barger, G., and Ewins, A. J., J. Chem. SOC.99, 2336 (1911). 108. Kassel, A, and Edlbacher, S., 2. physiol. Chem. 93, 396 (1915). 109. Tesar, C., and Rittenberg, D., J . Biol. Chem. 170, 35 (1947). 110. Windaus, A., Dorries, W., and Jensen, H., Ber. 64,2745 (1921). 111. Ashley, J. N., and Harington, C. R., J. Chem. SOC.lfAW,2586. 112. Ruhemann, S., and Cunnington, A. V., &id. 76, 954 (1899). 113. Finger, H.,J. prakt. Chem. (21, 76, 93 (1SCn). 114. Finger, H.,and Zeh, W.,ibid. (21, Sa, 60 (1910). 115. Cornforth, J. W., and Huang, H. T.,J . Chem. Soc. 1948,731. 116. Fisher, H.J., Ekeley, J. B., and Roneio, A. R., J . Am. Chem. SOC.64, 1434 (1942). 117. Waugh, R. C., Ekeley, J. B., and Roncio, A. R., ibid. 64,2028 (1942). 118. Cole, J. O., and Romio, A. R., ibid. 66, 1584 (1944). 119. Ekeley, J. B., and Ronsio, A. R., &id. 67, 1353 (1936). 120. Ekeley, J. B., and Elliott, J. L.,ibid. 68, 163 (1936). 121. Ekeley, J. B., and Ronsio, A. R., ibid. 69, 1118 (1937). 122. Williams, D. L., Symonds, F. L.,Ekeley, J. B., and Ronzio, -4. R.,&id. 67, 1157 (1945). 123. Erlenmeyer, Jr., E., Ber. 33, 2038 (1900). l24. Erlenmeyer, Jr., E., Ann. 387, 265 (1904). 125. Erlenmeyer, Jr., E., and Matter, O., &id. 337,271 (1904). 126. Erlenmeyer, Jr., E., and Wittenberg, F., &id. 337, 294 (1904). 127. Mohr, E., J. prukt. Chem. (21, 81, 49 (1910). 128. Mohr, E., &id. (2), 81,473 (1910). 129. Granacher, C.,'and Gulbas, G., Helv. Chim. Acla 10,819 (1927). 130. Griinacher, C., and Mahler, M., ibid. 10, 246 (1927). 131. Narang, K. S., and Ray, J. N., J. Chem.SOC.1931, 976. 132. Karrer, P., and Griinacher, C., Helv. Chim. Acta 7 , 763 (1924). 133. Kjaer, A., Acta China. &and. 3, 647 (1949). 134. Goldschmidt, S., and Steigerwald, C., Ber. 68, 1346 (1926). 135. Windaus, A., iW. 42, 768 (1909). 136. Ewins, A. J., and Pyman, F. L., J. Chem. SOC.99, 339 (1911). 137. Ewins, A. J., &id. 99, 2052 (1911). 138. Swash, J., Helv. Chim. Acta 6, 377 (1923). 139. Sarasin, J., ibid. 7, 713 (1924). 140. Balaban, I. E., and Pyman, F. L., J . Chem. SOC.le6, 1564 (1924). 141. Sonn, A., Hotes, E., and Sieg, H., Ber. 6'7, 963 (1924). 142. Sonn, A., Hotcs, E., and Sieg, H.,W .67, 2134 (1924). 143. Erlenmeyer, H.,Waldi, D., and Sorkin, E., Helv. Chim. Acta $1, 32 (1948). 144. Grindley, R., and Pyman, F. L., J. Chem. Soc. 19m, 3128. 145. Jowet, H.A. D., J . Chem. Soc. 87, 405 (1905).

110

Chemistry of Classes and Derivatives

146. Diels, O.,and Schleich. K., Ber. qS, 1711 (1916). 147. Diels, O.,ibid. 61,965 (1918). 148. Diels, O.,and Salomon, C., ibid. 69, 43 (1919). 149. Pyman, F. L.,J . Chem. SOC.99, 668 (1911). 160. Weidenhagen, R.,and Herrmann, R., Ber. 68, 1953 (1935). Ul.Dacby, W. J., Lewis, H. B., and Totter, J. R., 3. Am. Chem.Soc. 84,463 (1942). 162. Organk sgnnlhese8, Vol. 24, John Wiley and Sons, he.,New York, 1944, p. 64. 163. Windam, A, and Opits, H., Ber. &, 1721 (1911). 154. Wrede, F., and H o b , P., Arch. ges P h y h l . (Plliigers) 234, 432 (1934); Chem. Abstracls aS, 5477. 155. Garforth, B., and Pyman, F. L., J . Chem. SOC.1936,489. 156. Huebner, C.F.,J . Am. Chem. SOC.73, 4667 (1961). 167. Parrod, J., BuU. 8oc. chim. France (4) 63, 198 (1933). 168. Parrod, J., &id. (4) 61, 1424 (1932). 169. Parrod, J., Compt. rend. 900, 1049 (1935). 180. Parrod, J., and Garreau, Y., &id. 193, 890 (1931). 161. Girard, P., and Parrod, J., Ann. physiol. physicochim. bbl. 7 , 295 (1931). 162. Pauly, H.,and Ludwig, E., 2.physiol. Chem. 1.91, 170 (1922). 183. Bergmann, E.,and Heimhold, H., J . Chem. SOC.1 M , 505. 164. Gulland, J. M.,and Macrae, T. F., &id. 19S?662.

.

CHAPTER IV

The Halogenoimidazoles A. Bromoimidazoles 1. Preparative Method8

The imidazoles undergo bromination with remarkable ease. The addition of bromine to an ethereal or chloroform solution of imidazole results in the formation of a tribromo derivative (13)which is capable of forming a silver salt. The silver salt reacts with methyl iodide to give l-methyl-2,4,5-tribromoimidarole,identical with the bromination product of 1-methylimidazole (3). This sequence of reactions establishes the structure of the tribromo derivative as 2,4,5-tribromoimidaeole and

w

demonstrates that substitution of the imino hydrogen does not interfere with the brominstion of the imidazole nucleus. In general it is found that the number of bromine atoms which arc capable of entering the ring of a given imidazole is a direct measure for the number of free methine groups. The 1-substituted imidaaoles form tribromo derivatives. Compounds such as 2-methyl-, 4 (or 5)-methyl-, lJ4-dimethyl- 1,5-dimethylimidaeole, and ethyl 4 (or 5)-imidazolecarboxylate are converted into dibromo derivatives. The bromination product of 2-methylimidaeole is designated in the older Iikrature as a tri-

111

112

Chemistry of Clasws and Derivatives

bromo derivative (4) ; in reality the compound is the hydrobromide of 4,5-dibromo-2-methylimidazole ( 5 ) . Substances such as 4,5-diplienyl-, 4 (or 5 ) -methyl-5 (or 4) -nitro-, 1-ethyl-2-methyl-5-chloroimidazole, and ethyl 4 (or 5 ) -methyl4 (or 4) -imidaaolecarboxylate are brominated with the formation of monobromo derivatives ( 6 9 ) . The bromination of a number of imidazoles with limited amounte of bromine at low temperatures (-10’ .to-20’) may lead to the formation of partially brominated products. Although not important from the preparative standpoint, this experimental technique clarifies in a qualitative manner tlie relative rates of bromination at different locations on the imidaaole ring. The application of this technique to imidazole results in the foEmation of a small quantity of 4,5-dibromoimidazole in addition to 2,4,5-tribroinoiinictazole and iinidaaoliuin bromide (2).

. . The structurc of the dibroino derivative follows froin its nonidcntity with 2,4 (or 2,5) -dibromoimidazole which is readily obtained by bromination of ethyl 4(or 5)-iinidazolecarboxylate to give ethyl 2,4 (or 2,5) -dibromo-5 (or 4) -itnidaaolecarhoxylate followed by saponification and decarboxylation (2,lO).

B y’

Br--S/

HOOC-C-N

N‘C-Br II

/

A

HI N U r - r ‘f-Br H-C-N

+ COr

Low-temperature bromination of 1-methylimidazolo takes a course similar to that observed with imidazole ; l-methyl-2,4,5-tribromoimidazole is the major product, and a small quantity of l-methyl-4,5-dibromoimidazole is also formed (3,ll). The latter compound also results from the methylation of 4,5-dibromoimidazole, a correlation establishing the orientation of the bromine atoms.

IV. 13dogenoimidm-h

113

Treatment of sgm-dimethyloxamide with phosphorus pentabromide represents another route to 1-methyl-4,5-dibromoimidazole(11). Low-temperature bromination with an equimolar amount of bromine converts 4 (or 5 )-methylimidazole into a mixture of 4 (or 5)-methyl4 (or 4)-bromoimidazole (34"/o ) and 2,4(or 2,5)-dibromo-5 (or 4) -methylimidazole (12%) (12J3).

.

The constitution of the monobromo derivative follows from ita nonidentity with 4 (or 5 ) -methyl-2-bromoimidazole,which is readily prepared by brominating ethyl 4 (or 5 )-methyl4 (or 4) -imidaaoIecarboxylate and eliminating the carbethoxy group by hydrolysis, and decarboxylation (9). H I EtOOC-C"y-H HaC-6-N

I HOOC-CM~T-B~ H,c-~--N

A

A

B

EtOOC-CONT-Br H,c-&-N

H I H-C>-f-Br H,c-&-N

'

+ COr

The reaction between 1,4-dimethylimidazole and an equimolar amount of bromine leads mainly to the formation of 6-bromo-l,4dimethylimidaaoleand a small amount of 2,6-dibromo-l14-dimethylimidazole. Under identical conditions 13-dimethylimidazole affords mainly 2,4-dibromo-l,5-dimethylimidazoleand a little 4-bromo-1,5-dmethylimidaaole (9). Both monobromo derivatives react readily with bromine

114

Chemistry of Classes 3nd Derivatives

to give 2,5-dibromo-l,Pdirnethyl- and 2,4-dibromo-l,bdirnethylimida2018, respectively.

4 (or 5)-Phenylimidazole in the presence of an equimolar quantity of bromine in chloroform solution is converted into a mixture of 4(or 5)brornod(or 4)-phenylimidaeole (64%) and 2,4(or 2,5)-dibromo-5(or 4)phenylimidasole (11%) (14). The finding that permanganate oxidation converts the dibromo derivative into benzoic acid demonstrates that both bromine atoms are attached to the imidazoje portion of the molecule. The non-identity of the monobromo derivative with 2-bromo-4 (or 5)-phenylimidazole, prepared from ethyl 4(ot 5)-phenyl-5 (or 4)-imidazolecarboxylate by bromination and elimination of the carbethoxy group, establishes the position of the halogen atom (14). The introduction of a carboxyl group into the ring does not interfere with the ability of imidazoles to undergo bromination. A number of instances of the bromination of imidaaolecarboxylates have been mentioned. The halogenation of 4 (or 5) -imidasolecarboxanilide provides another example. This compound is brominated in glacial acetic acid with the formation of a mixture of equal parts of 4(or 5)-imidasolecsrboxylic acid p-bromoanilide and of 2,4 (or 2,5)-dibromo-5 (or 4) -imidazolecarboxylic acid p-bromoanilide. A small amount of 4(or 5)-bromo-5 (or 4) -imidazolecarboxylic acid p-bromoanilide is also formed (15). Hydrolysis with hydrogen bromide at 150”cleaves the 2,4(or 2,5)-dibromo5 (or 4) -imidazolecarboxylic acid p-bromoanilide with the formation of p bromoaniline, 2,4 (or 2,5) -dibromoimidazole, and 2-bromoimidazole. This is the only method available for the preparation of 2-bromoimidazole (15).

IV. Halogenoimidazoles

115

1lUr 150.

H

H

I Br-C' NF-Br + H-8-N

B*r

H-C'?-Br

+

I

H-LN + co,

Nitroimidaroles are also capable of undergoing bromination. 4(or 5)-Methyl-5 (or 4) -nitroimidarolc is brominated in aqueous solution with the formation of 2-bromo-4(or 5)-methyl-5 (or 4) -nitrohidasole (&9) *

If

I

""-E"'S-*

HSC-

-N

A

H

OS-fi-Br

IF&-

-N

4-Nitro-l,5-dimethylimidaroleabsorbs bromine with great ease and is converted into 2-bromo-4-nitro-l,5-dimethylimidaeole. The isomeric 5-nitro-1,4-dimethylimidarole,on the other hand, fails to react with bromine, thus representing one of the rare examples of an imidasole possessing a free methine group which fails to undergo bromination. The expected bromination product is readily prepared by methylating 2-bromo4ior 5)-methyl-5(or 4)-nitroimidasole (9). See equation (1), page 116. The fact that 4-nitro-l,5-dimethylimidaroleis brominated readily in contrast to 5-nitro-l,4-dimethylimidarole,which is non-reactive, indicatea that the nitro group in the latter substance is more effective in withdrawing electrons from the 2-position. The interpretation is in agreement with the observation that the bromine atom in 5-nitro-li4-dimethyl2-bromo-, but not that in 4-nitro-l,5-din1ethyl-2-bromoimidarole, is displaced by sulfite ion with the formation of the corresponding sulfonic

116

Chemistry of Classes and Derivatives

acid (9). Tlic following electronic interpretation iiiuy sccouiit for this bcliavior.

8 It is of interest to note that thc 4(ur 5)-substituted iiiiidazoles al€orrl ttppreciablc amounts of partially Iialogcnatcd products when they are brominated with a limited quantity of bromine. They differ markedly from imidazole and its 1-methyl- and 2-methyl- derivatives, which are converted into the fully brominated tri- and dibromo derivatives under similar conditions and which afford only traces of partially brominated imidazoles. The rate of bromination in the 4(or 5)-position exceeds that in the 2-position, as illustrated by the behavior of 4(or 5)-methyl- and 4 (or 5 )-phenylimidazole which are brominated with the formation of the respective 5(or 4) - and not of the 2-monobromo derivativcs. As has bcen mentioned, the direct broinination with molecular hromine converts 1,4-dirnethyliinidazole into a mixture of 5-bromo-1,4dimethylimidazole and 2,5-dibromo- 1,4-dimethylimidatole. Bromina-

IV. Hdo~noimirl~mnlcs

117

tion with cyanogen bromide leads to the cxclusive formation of 2-homo1,4-diinetliylimidazole (16). CHa I

cur

I H - ~ ~ T - B ~ HSC-C-N 2. Properties

The halogen atoms in the bromoiinidazoles exhibit the typical behavior of “aromatic” halogen. They fail to react with zinc and hydrochloric acid and arc not displaced on treatment with such reagents as diethyl malonste, hydroxyl or cyanide ions. Treatment with sodium amalgam removes the halogen from 2,4,5-tribromoimidazole with the formation of imidasole (1). Heating of the halogenoimidazoles with hydrogen iodide and red phosphorus is frequently used for the preparation of the halogen-free bases. The introduction of halogens decreases the basic strength of the imidasoles and increases their pseudoacidic charactcr (see Table XIII) . 2,4,5-Trihromoimidazole dissolves in aqueous sodium carbonate and forms a hydrochloride which hydrolyzes upon cxposure to water. Of both practical and theoretical importance is the behavior of the bromoimidazoles t.oward sulfite ion. Refluing of a bromoimidazole with aqueous or ethanolic sodium sulfite solutions may either remove the halogen reductively or displace it with the formation of a sulfonic acid. The position of the halogen and the nature and position of other substituents on the ring determine the course of the reaction. 2,4,5-Tribromoimidazole is converted into a mixture of 4(or 5 ) bromoimidazole, 4,5-dibromoitnidazole, 4 (or 5 )-bromo-5 (or 4) -imidazolesulfonic acid, and imidazole (2). 2-Bromo-4(or 5 )-methylimidazole is

fI

H A

-H

H

H-rNbf-H I

‘Br-

-N

+

’$ Br-g“g-H

HOS-

+N I

H-F’~H H-C-N

Chemistry of Clnsws 2nd Dcrivntivcs

118

easily reduced by sodium sulfite to give 4(or 5 )-methylimidazole (9) ; and 2-methyl-4,!j-dibro1noimidazole hy the samc treatment is converted into 4(or 5 )-bromo-2-inetl~ylimidazolcin 82% yield ( 5 ) . 2,4(or 2,5) -Dihromoimidszole affords 4(or 5 )-I)ro~nc,imidazolc(2). The general behavior of I~lwaoimiclazolestoward sulfi te ion may be summarized as follows. In iinidazoles containing a free imino group a bromine atom in the 2-position is readily replaced by hydrogen (except in the case of 2-bromo-4(or 5 )-nitro4 (or 4)-methylimidazole). One of the two bromine atoms in 4,5-dibromoimidazole is also replaceable by hydrogen, but less readily. A single bromine atom in the 4(or 5)-position is stable as exemplified by the behavior of 4 (or 5 )-bromoimidazole (11) and 4 (or 5)-bromo-2-methyliniidazole. Replacement of the bromine by the sulfonic acid group is observed only with 2,4,5-tribroinoimidazole, which in addition to other products yields 4 (or 5 )-bromod (or 4) -imidazolesulfonic acid. The introduction of an electronegative substituent such as a nitro group into the 5(or 4)-position of a 4(or 5)-bromoirnidazole alters the behavior toward sulfite ion. The bromine is readily displaced with the formation of the respective sulfonic acid. The conversion of 4(or 5 ) bromo-5 (or 4) -nitroimidazole into 5(or 4) -nitro-4(or 5 )-imidazolesulfonic acid is an example (11). It. is plausible to assume that the electron-attracting nitro group withdraws electrons from the 4 (or 5 )-position, thus facilitating attack by the nucleophilic sulfite ion. Although readily displaced by sulfite ion, the bromine in 4(or 5)-bromod(or 4-nitroimida-

H B ' 0tN-flT-H I

Br-C-N

I

-

H I O-N==TNF-H I Br-C--N

H

:&e

1

sol-

_ . )

B l o - N - ~ ~ ~ I -0S-C-N

+ Br-

zole is not reactive toward cyanide and diethyl malonate ions. A carboxyl group in the 5(or 4)-position fails to activate the halogen in the 4(or 5)position (10). In 1-methylimidazoles the bromine in the 2-position is less readily replaced by hydrogen. 2,5-Dibromo-1 ,4-dimethylimidazole is only slowly, and 2,4-dibromo-lJ5-dimethylimidazolenot perceptibly, attacked by prolonged boiling with sodium sulfite. Halogen atoms in the 2-position in 1-methylimidazoles are readily displaced by a sulfonic acid group when a nitro group occupies the 5-position. An example is the con-

N. Halogenoimidamles

119

version of 2-bromo-5-nitro-l,4-dimethylimidazoleinto 5-nitfo-lJ4dimethyl-2-imidazolesulfonicacid (9).

B. Chloroimidazolee

Some of the earliest investigations in the imidaeole field dealt with the chemistry of the chloroimidaeoles which result when symmetrically substituted oxamides are subjected to the action of phosphorus pentachloride. Wallach, the discoverer of this reaction, named the compound resulting from the reaction of sym-dimethyloxamide and phosphorus pentachloride “chloroxalmethylin” and that resulting from sym-diethyloxamide “chloroxalethylin” (3,6,17-22). The imidazole nature of these compounds followed from their conversion into 1-methylimidazole and 1ethyl-2-methylimidazole, respectively, by treatment with hydrogen iodide and red phosphorus. The position of the chlorine atoms was established in 1924, although the compounds had been known since 1874. “Chloroxahethylin” is 1-methyl-5-chloroimidazole and “chloroxalethylin” is 1-ethyl-2-methyl-5-chloroimidaeole(1133).

120

Chemistry of Classes and Derivatives

The Wallach procedure for the preparation of chloroimidazoles is limited to these two cases. Higher oxamides either fail to give imidaaoles on treatment with phosphorus pentachloride,. or they give extremely poor yields (3). Although neglected for inany years, "chloroxalmethylin" and "chloroxalethylin" have recently become of some importance as useful starting materials for the preparation of certain purines (23,24) (see .Chapter VI, Section A-5-b). Another route to chloroimidazoles involves the tyatment of certain acylated derivatives of glycine with phosphorus pentachloride. Benzoylglycine ctliylsniide is converted into l-etl~yl-2-phenyl-5-cliloroiinidazolc, while benroylglycinc anilide affords 1,2-diphenyl-5-cliloroimidazolc, (25,261. I

H-C-N

2,4 (or 2,5) -Dicliloroinidazole is obtained froiii tlic trcirtriicnt of 2,4 (or 2,5) -dibroinod- (or 4) -imidazolccarboxylic acid p-bromoanilidc with conccntrated liydrocliloric acid at 150' (15). The introduction of a nitro group into thc 4(or 5)-position of a 5(or 4) -chloroiinidazole renders the otherwise inert halogen atom displaceable by cyanide ions, sulfite ions, or amines. An cxample is 1-methyl-Cnitro5-chloroimidaaole, which is converted into l-inetliyl-4-nitro-5-cyanoimidazole when refluxed with sodiuin cyanide. Treatment with etlianolic ammonia at 140' or refluxing with aqueous sodium sulfite converts 1methyl-4-nitro-5-cliloroimidaeole into l-inetliyl-4-nitro-5-arninoi1nidarole and l-methyl-4-nitro-5-imidazolesulfonicacid, respectively (1193, 27)-

IV. Hdogenoimidazolcs

121 CHI

I

YH;

Cl-C3T-H Oa-6-N

/ xn,

_____)

\

N-C-~~-Y-H OrK-C-N

YH*

H ~ N - ~ M ~ ~ H O*K-C-N CHI I -OS-$'"-f-H OZN-C-N

C. ChloroaUcylimidamlea The chloroalkylimidazoles are obtained in the form of their crystalline hydrochlorides when hydroxyalkyliinidazoles (Chapter 111, Section B-1) are subjected to the action of phosphorus pentachloride or, preferably, of thionyl chloride (28-35). The covalent.ly bound chlorine is highly reactive and is readily displaceable by nucleophilic reagents. This property renders the chloroalkylimidazolium chlorides most valuable as intermediates for the incorporation of an imidazolealkyl group into another molecule. Examples of such. reactions will be found in Chapter V, Sections D-7-12 and d and Chapter VI, Section A-6-e and g) . Two important representatives of this class are 4 (or 5 ) -chloromethyl- and 4 (or 5) (2-chloroethyl) imidazolium chloride.

-

Chemistry of Classes and Derivatives

122

D. Iodoimidazoles

1. Preparative Method6

The behavior of imidazoles toward iodine differs markedly from that toward bromine, as only those imidazoles containing a free Xino group are capable of undergoing iodination. Imidazole reacts readily with iodine to form 2,4,5-triiodoimidazole (36,37). Alkylimidaeoles such as 2-methyl- or 4 (or 5 )-methylimidazole are converted into 2-methyl-4,5diiodoimidazole and 4 (or 5) -methyl-2,5 (or 2,4)-diiodoimidazole respectively. 4 (or 5)-1midaeolecarboxylic acid yields 2,4,5-triiodoimidazole with elimination of GOn (38). The reaction between iodine and an imidazole is catalyzed by alkali and proceeds at optimal rates in the presence of sodium carbonate or sodium hydroxide. A procedure well suited for the preparation of 2,4,5-triiodoimidarole of a high degree of purity involves the addition of a solution of iodine in hexane to a soluton of imidazole in sodium hydroxide (39). The imino hydrogen is also capable of undergoing substitution by iodine. 2,4,5-Triiodoimidazole reacts with an excess of iodine to give l,2,4,5-tetraiodoimidaeole,while the iodination of 2,4,5-trimethylimidaaole leads to the formation of l-iodo-2,4,5-trimethylimidaeole(37). The iodination of imidazole with suboptiinal amounts of iodine results in the formation of a mixture of 2,4(or 2,5)-diiodoimidazole and 2iodoimidaeole. The structure of the monoiodoimidazole follows from the fact that its bromination affords 4,5-dibromo-2-iodoimidazolewhich differs from 2,4 (or 2 3 ) -dibrcmo-5 (or 4) -idoimidazolc, the iodination product of 2,4(or 2,5) -dibromoimidazole (13).

7 H-Q 3T - H

I1

on-

H-C-N

H

I H-S3'f-Br Br-C-N

H

H

It

I H - C ~ ~ C - I Hn n + I-C-N H-C-N

,

'i' H

I I N 1-rN\~-~r-not --..-L Br-C' 'C-I Br-C-N identical Br-C-N

The iodination of 4(or 5)-methylimidazole with a limited amount of iodine yields 2-iodo-4 (or 5 )-methylimidazole. The orientation of the iodine atom follows from the observation that bromination affords the

IV. Halogenoimidazolea

123

same 2-iodo-4 (or 5)-methyld(or 4) -bromoimidazole resulting from the iodination of 4(or 5 )-methyl-5(or 4) -bromoimidarole (13).

I Br-il"'F-H HaC-C-N

These studies demonstrate that the rate of iodination in the 2-position exceeds that in the 4(or 5)-position. This is in marked contrast to the behavior on bromination where the 4(or 5 ) -position is attacked preferentially. The observation that iodination depends upon the presence of a free imino group and that it is catalyzed by alkali points to fundamentally different mechanisms for the bromination and iodination of imidazoles. The bromination ie best regarded as an electrophilic substitution in contrast to the iodination which seems to involve a primary substitution by iodine of the imino hydrogen followed by a base-catalyzed rearrangement of the resulting N-iodoimidazole (39).

2. Propelrtleo

The C-iodinated imidaroles are amphoteric compounds, forming salts with metals and acids. The basic character of the imidazole system is markedly decreased by the introduction of iodine, while the pseudoacidic nature becomes more pronounced. This behavior is in accord with the general observation in the imidazole series (Chapter I, Sects. C-12) that the introduction of electronegative substituents brings about an increase in the pseudoacidic character at the expense of the basic properties. The N-iodoirnidazoles fail to dissolve in acids and alkalis, and decompose on heating with the liberation of iodine. The highly 'iodiiated imidaroles react with aqueous sodium sulfite and are converted into partially iodinated products. In contrast to the behavior of the bromoimida-

Chemistry of C

124

h and Derivatives

zoles, where a bromine atom in position 2 is more reactive toward sulfite ion than a bromine in position 4(or 5 ) , one observes that an iodine atom in the 2-position is more resistant toward sulfite ion than one attached to the 4(or 5)-position. It will be recalled that the reaction between 2,4,5tribromoimidazole and sodium sulfite leads to the formation of 4,5-dibromd- and 4 (or 5)-bromoimidazole. 2,4,5-Triiodoimidaz;ole, on exposure to sodium sulfite, is converted into a mixture of 2,4(or 2,5)diiodoimidarole and 2-iodoimidazole (13).

B I-C-

H 1

I-C-N Bibllography

If

H-$/MN-f-I 1 HI-C-N

1. Wys, C., Bcr. 10, 1385 (lS77). 2. Balaban, I. E.,and Pymnn, F. I,., J. Clwtr. Soc. iff, 947 (1'322). 3. Wallach, O.,Ber. 10. 534 (1883). 4. Radsiscewski, R., ibid. 16, 2706 (1882). 5. Light, L., and Pyman, F. L., 1. Cheni. SOC.121, 2626 (1922). 6. Walhch, O., Ann. 914,257 (1882). 7. Lamb,I. D., and Pyman, F. L., 1. Chem. Soc. f%, 706 (1924). 8. Windaus, A., Bar. &, 758 (1909). 9. Pyman, F. L., and Timmis, G. M., J. Citcm. ,%c. f23, 494 (1923). 10. Balaban, I. E., ibid. 1.938, 2423. 11. Balaban, I. E., and Pyman, F. L., &id. 1.96, 1564 (1924). 12. Pyman, F.L., ibicl..87,1814 (1910). and I. Arauner. , E.. J . prnk.!. Chntn. (2) 118,33 (1928). 13. Pauly, € 14. Forsyth, W. G., and Pyman, F. I.., J . Cliem. Sun. ffl, 573 (1926). 15. Ring, H.,und Murch, W. 0.. ibdd. f23, 621 (1!323). 16. Langenbcrk, W.,J . p m k t . Chcm. (2) If& 77 (1W). 17. Wallach, O., Bor. 7 , 326 (1874). IS. Wallach, O.,Ann. 184, 1 (1876). 19. Wallach, O.,ibid. 184, 121 (1816). 20. Wallach, 0.. and Oppenheim, F., Bar. 10, 11% (1877). 21. Wallach, O.,Ann. 924, 193 (1882). 22. Wallach, O., Ber. 16, 644 (1882). 23. Saraain, J., and Wegrnann, E., Helv. Chim. Acln 7 , 713 (1924). 24. Mann, F.G.,and Porter, J. W. G., J . Chom. SOC.13.46, 751. 25. Karrer, P., and Gfinacher, C., Helv. Chim. Acta 7 , 763 (1924). 26. Griinaeher, C., Sclielling, V., and Schlatter, E., a i d . 8, 873 (1925). 27. Balaban, I. E.,J. Chem. Soc. 1930, 268. 28. Pyman, F. L., ibid. 90, 668 (1911). 29. Garforth, B., and Pyman, F. I,., &id. 2936, 489. 30. Albertaon, N. F., and Archer, S., J . Am. Chem. SOC.6'7, 308 (1945).

IV. Hnlogenoimidnsoles 31. Erlenmeyer, H., Waldi, D., and &%rkin,E., Helv. Chim. Acln 31, 32 (1948). 32. Jones, R. G., J . Am. Chem. SOC.71, 383 (1940). ,33. Jones, R. C., and McLauglilin, X. C., ibici. 71, 2444 (1949). 34. Turncr, R. A., Huebncr, C . F., and Sclrolc, C.H.,ibid. 71, 2801 (1949). 35. Turner, R. 9.,ibitf. 71, 3476 (1949). 36. Pauly, H., and Gundermsnn, I<., Hvr. 41, 3999 (1908). 37. Pauly, H., ibid. &, 2243 (1910). 38. Weidenhagen, R., Herrmann, R.,and Wegner, € M. I., 70, 570 (1937). 39. Brunings, K. J., J . Am. Chcm. Soe. 09, 205 (1947).

125

This Page Intentionally Left Blank

CHAPTER V

The Nitro-, Arylazo-, and Aminoimidazoles A. Nitroimidazoles

1. Synthetic Methods, and Orientation of the Nitro Group

The treatment of an imidaeole with a mixture of fuming nitric and sulfuric acids or the exposure of the nitrate of an irnidazole to the action of hot concentrated sulfuric acid are practical procedures for the preparation of mononitroimidaeoles. Polynitroimidasoles are unknown. The entering nitro group occupies, without exception, the 4- or 5-position, and imidaroles in which these positions are substituted, such as 4$-dimethyl(1) and 4,5-dibromoimidasole (2), or 4,5-imidaroledicarboxylic acid (1) fail to undergo nitration. Imidaeole is nitrated with the formation of 4 (or 5)-nitroimidazole (1,3,4). 2-Methylimidasole affords 2-methyl-4 (or

B

I:

B 5)-nitroimidaeole ( 5 ), while 4 (or 5 )-methylimidaeole is converted into 4(or 5 )-methyl4 (or 4) -nitroimidaeole (1 $3). 2,4 (or 2,5) -Dimethylimidmole is readily nitrated to give 2,4 (or 23) -dimethyl4 (or 4) -nitroimidseole (6). Substitution of the imino hydrogen by a methyl group does not interfere with the ability of an imidaeole to undergo nitration. It must be kept in mind, however, that nitration of a N-methylixnidarole may lead to the formation of a l,4- or a 1,5-isomer; both these possibilities are usually realized, with the 1,4-isomer predominating. 1-Methylimidaeole

Chmistry of Clnmas and Dcrint,iws

12s

is nitrated with the formation of a mixture composed mainly of l-methyl4-nitroimidazole and a smallcr quantity of the 1,5-isonieridc ( 5 ) . CHa

"-E".f-" H-

I

-N

HN4

CH, 1

CN3 I

H-T~X-H

O,N-G~\F-H 4- H-C-N

OrN-

-

More

Iass

The nitration of 1,2-dirncthylimidazolc yields a large amount of 12dimethyl-4-nitroimidazolc and n smaller quantity of l$-dimethyl-5nitroimidasole (7). 1,4-Dimet11ylimidazole is nitrated to give 1,4-dimethyl-5-nitroimidazole, while 1,5-dimethyl-4-nitroimidazole ensues from 1,5-dimethylimidazole (8). Halogenated iinidazoles are also capable of undergoing nitration. 4 (or 5)-Bromoimidazole is converted into 4 (or 5 ) -bromo-5 (or 4) -nitroimidasole and 2'4 (or 2,5) -dibromoimidazole affords 2,4(or 2,5)-dibromo-5(or 4) -nitroiinidazole (2). Both l-methyl5-chloroimidazole and 1-ethyl-2-n1ethyl-5-chloroimidasoleare converted into the corresponding 4-nitro derivatives (9,lO). 2-Methyl-4(or 5)brornoimidazole is nitrated with the formation of 2-methyl-4 (or 5 )bromo-5 (or 4) -nitroimidazole ( 11) . Bot'h 1-methyl-5-bromoimidazole and 1-methyl-4-bromoiinidaaole are readily nitrated giving l-methyl5-bromo-4-nitro- and 1-methyl-4-bromo-5-nitroimidazole, respectively (2).

Imidazolecarboxylic acids fail to be nitrated, and the nitroimidazolecarboxylic acids must be prepared by other methods. Certain imidazoles undergo oxidation when subjected to the action of concentrated nitric acid. 4 (or 5 )-Hydroxymethylimidazole, for example, is converted into a mixture of 4 (or 5 ) -iinidazolecarboxaldehydeand 4 (or 5 ) 4midazoleenrboxylic acid (12) (see Chapter 111,Section A-1). The exclusive 4(or 5)-nitration of imidazole and its derivatives may be due to: ( 1 ) the electron distribution in the imidazolium ion, and ( 8 ) a higher stability of the transition state for 4(or 5)-substitution. The 2-position, because of its location between two powerful electron-at.tracting nitrogen atoms is, most likely, more electron-deficient tlmn tlic 4(or 5)position. Such a charge-distribution would be expcct.ed to facilitate the attack of the KO,.+ion a t the 4(or 5)-position. An inspection of the H-C-%H

V. Nitro-, Arylazo-, and Aminoimidazolcs

129

transition states for 2- or 4-substitution suggests a higher degree of Stabilization for the latter state, since it receives contributions from the amidine resonance (structures A, 13, and C) , The 2-transition state lacks this stabilization. These views are in disagreement with those expressed

X 1

H-C-3-H

I

bH H--E-RLH A

- H-C-Y-H X I

FH H--b-N--H 0

B

X

H - cI - ~ Q ~

I

H-C=&H C

4Transition state

H

2-Tmnsition state

by Dewar (13) who maintains that imidaaoles are substituted predominantly at the 2-position because “in the transition state for ‘l-substitut.ion the nitrogen atoms are at the ends of the mesomeric cation, while in the 4-transition state one nitrogen occupies a central position.” Y I

H-C-Y-H H-C=N&.$-A

I

2-Transitioii state &Transition state Transition states for 2-or &ul>Stitution in imidazolcs, according to Dewar

An inspection of the rat.her extensive material on the substitution behavior of the imidazoles, as presented in these pages, demonstrates that substitution t.akes place equally readily at the 4 (or 5) or the 2-position. Consequently, Dewar’s “theoretical” treatment is of little significance. The nitrates of the phenyl-substituted imidazolea undergo nitration in the phenyl nucleus upon exposure to the action of concentrated sulfuric acid at 100’. The nitro group enters predominantly the para position of the benzene ring. A number of examples may serve to illustrate this point. 1-Phenylimidasole affords 1-(p-nitrophenyl)imidazole in 58% yield (14), while 2-phenylimidazole is converted into a mixture of 2-(p-

-

130

Chemistry of Classes and Derivatives

’

-

nitrophenyl) -I 50%, 2- (o-nitrophenyl) -I 1.5% ,’ I and 2- (n-nitrophenyl) imidazole, 0.2 % respectively (15). 4 (or 5) -Phenylimidazole affords 69% of 4(or 5)-(p-nitrophenyl)- and 25% of 4(or 5)-(o-nitrophenyl)imidazole (16).

NO* 25%

69%

Fuming nitric acid converts 2-plicnyl-4 (or 5 ) -metliylimidazole into 2- (p-nitrophenyl)-4 (or 5 )-methyld(or 4) -nitroimidazole (17). The

nitrates of the nitrophenylimidazoles undergo further nitration when they are treated with hot, concentrated sulfuric acid, the second nitro group entering the 4(or 5)-position of the imidazole nucleus. The conversion of the nitrate of 4 (or 5) (p-nitrophenyl) imidazole into 4 (or 5) (p-nitrophenyl) -5 (or 4) -nitroimidaeole (16) and the transformation of the nitrate of 4- (p-nitrophenyl) -1-methylimidazole into 4- (p-nitrophenyl) -5-nitro1-methylimidazole (5) may serve as illustrations.

-

-

V. Nitro-, Arylazo-, and Aminoimidn7nlcs

131

The substitution behavior of the phenyliinidaeoles demonstrates that the imidazoliuni ion is nitrated at a lower rate than the phenyl nucleus, and that the imidacolium group directs the entering nitro group predominantly into the para position. The incorporation of carboxyl groups into the 4,5-position of the imidazole moiety of 2-phenylimidacole brings about a change from a predominantly para to a predominantly mets nitrated compound (see Table XVIII) . The 2-imidazolinium group is also a powerful meta director. TABLE XVIII. Orientation of the Nitro Group in Certain Nitrated 2-Phenylimidazoles (15,lS) Composition of nitro D ~ U C ~(%) S

Compound nitrated

..................................

Pan.

Meta

50

0.2 84.4

2-Phenylimidasole 2-Phenyl-2-imidazoline 2-PhenyWor Wmidscolecarboxylic acid 2-PhenylJ1,5-imidseolediearbo~licacid ..........

.............................. ............ 52 :... 19

19

52

2. Propertiea

The nitroimidaeoles are high-melting, colorless, crystalline compounds. Those possessing a free imino group dissolve in alkali hydroxides, alkali carbonates, and ammonia to form yellow solutions containing the respective nitroimidacole anion. The sodium salt of 4(or 5)-nitroimidazole is obtained in crystalline form when nitroimidaeole is dissolved in hot 20% sodium hydroxide and the solution is allowed to cool (19). The yellow nitroimidaeole anion may be represented as a hybrid having the major contributions shown below. 0

O-N-j-$; II

H-C-N

-

-@ : . o_"=vFH

H-

EN

-

0 04-1-4 H-C-, p .-

The introduction into the imidaeole ring of the electronegative nitro group markedly decremes the basic strength (see Chapter I, Section C-1) .

132

Chemistry of Clns..s and Derivatives

4 (or 5 )-Nitroimidazole fails to form a stable hydrochloride or picrate. It dissolves in concentrated hydrochloric acid, but is regcnerated unchanged wlien tlic solution is diluted with water (1). Giiiiilur bcliavior is observed with 4 (or 5 )-broiiio-Ci(or 4) -nitroiinidazole (2). l-l\iIethylti-nitroimidazole is a stronger base than 1-methyl-4-nitroiinidazole as evidenced by the finding that the former, but not the latter, forms a stable hydrochloride and picrate. A possible explanation for this difference in basicity is found in Chapter I, Section C-1. It is of interest that the 1,4-isomeride exhibits a greater chemical stability than does the 1,5-compound. This is shown hy tlie fact that heating of 1,3-dimethyl4 (or 5 ) -nitroimidazolium iodide (resulting from tlie reaction of methyl iodide with either I-methyl-4-nitro- or 1-methyl-5-nitroimidazole) C ~ U S C S elimination of methyl iodide to give 1-methyl-4-nitroimidazole ( 5 ) .

I-

In Chapter IV, Section -4-2, mention was made of the fact that an adjacent nitro group facilitates the displacement by sulfite ion of an otherwise inert halogen in the 4(0r 5)-position on the imidazole ring. A inethyl group in the 4(or 5)-position is also activated by a neighboring nitro group, as evidenccd by the ability of this methyl group to condense with benealdehyde to form a styrylnitroimidarole. The simplest example of this reaction is the formation of 4(or 5 )-styryl-5 (or 4) -nitroimidazole from 4(or 5)-rnethyl-!j(or 4)-nitroimidasole and benzaldehyde (20). The condensation proceeds with optimal yields a t temperatures of 150160' in the presence of piperidine (21). N-Methylimidazoles such as 1,4-

dimethyld-nitro- or I .5-dimethyl-4-nitr6imidazole also condense with benzsldehyde to give the respective styrylimidazoles (21). The former compound may serve as the example for a discussion of plausible electronic explanations for both the activation of the methyl

V. Nitro-, Arylaao-, mid Aminoiuiidazolw

133

group and the base-catalyeed condensation with benaaldehyde. The first step in the condensation reaction may involve the formation of the 1,4dimethyl-5-nitroimidazole anion by the removal of a proton from the 4-methyl group by the base B (piperidine). The nitro group, because of its tendency to remove electrons from the methyl group (hyperconjugation), facilitates this process:

"I

e:6:

CH:

I

O-N=C' .f-H 1 H C-N

*:y He

!

-

-

BH+

The condensation of the 1,4-diinethyl-5-nitroimidazoleanion with benaaldehyde to give the intermediate carbinol may proceed through the following intermediate steps: 0

0-N-f"f-H I

CHa

1

J" -*

'3 H-$-0:

6

-

CHa 0 1 0-X-Er"'E;H II

8

H:gN

H-

....-

-0:-

+BH*

0

O*:--FNT-H+ R $a

-'

8

H:CO

H-

-OH

The base-catalyzed elimination of water froin the carbinol may involve the initial removal of a proton from the "activated" methylene group followed by the expulsion of a hydroxide ion. See equation (1), page 134. It should be noted that the behavior of the methyl group in the nitromethylirnidaroles closely parallels that of the methyl group in a-picoline and N-methyl-a-picolinium ion, where similar mechanisms are indicated (22-24).

As has been mentioned in Chapter IV, Section A-2,the bromine atom in 5-nitro-l,4-dimethyl-2-bromoimidazoleis readily displaceable by suI-

134

Chemistry of Classes and Derivativm

4 0

n

H-7

1I

-

BH+

p -N

+ OH-

fite ion to give the corrcsponding 2-sulfonic acid. This suggests the possibility that the 2-methyl group in 1,2-dimethyl-5-nitroirnidazolemay be capable of undergoing a base-catalyzed condensation with benzaldehyde. This, however, is not the case, as both 5-nitro-l,2-dimethylimidazoleand 4-nitro-l,2-dimethylimidazolefail to react with benzaldehyde (7). Oxidation with potassium permanganat-e in acetone solution converts the yellow, high-melting styrylimidacoles into the corresponding nitroimidazolecarboxylic acids and bencoic acid. Compounds such as 4 (or 5 ) nitro-5(or 4)-imidazolecarboxylic acid, l-methyl-5-nitro-4-imidazolecarboxylic acid, or 1-methyl-4-nitro-5-imidazolecarboxylic acid are readily available through this route (ZO$l). See equation (1),page 135. The constitution of the nitroimidazoles is determined from their behavior on reduction with stannous cliloride in the presence o€ hydrochloric

-

V. Nitro-, Arylnzo-, and Aminoimidnzoles

-. o"-rNx-H H I

135

B

H-Ctl H-S

0

acid. In some instances this t.reatment results in the formation of an aminoimidasole; in most cases, however, it brings about a complete fragmentation of the imidazole nucleus into ammonia and other nitrogenous degradation products (25). The location of the nitro group in the original compound follows from the nature of these fragments. The reduction by this procedure of 4(or 5)-nitroimidazole results in the formation of glycine, formic acid, and ammonia (26). The existing evidence suggests that this fragmentation proceeds in the manner illustrated, with 4 (5H) (or ,5(4H))-imidasolone as an intermediate (27). The location of the

nitro group in 1-methyl-5-nitroimidasole follows from its conversion into glycine,methylamine, and ammonia by treatment with stannous chloride and hydrochloric acid (5). A different mode of fission is observed with 2-methyl-4(or 5)-nitroimidaeole and 1,4-dimethyl-5-nitroimidasole. The former compound affords acetamidine (26), while the latter is converted into a mixture of ~~-N-methyl-2-aminopropamidine, m-alanine, methylamine, and ammonia (8).

k

k

Chcmistxp of Clnsws nnrl Derivatives

136

B. Arylazoimidazoles 1. Formation and Orientation of the Arylam Group

Most imidazoles possessing a free iiiiino group and Ihydrogen atom or a free carboxyl group in positions 2, 4, or 5 couple with diazotised aromatic amines with the formation of deep-colored szo-dyes (Pauly diazo reaction). Coupling occurs in alkaline milieu only and is usually carried out by adding a solution of a diazonium salt to a solution of an iinidazole in sodium carbonate. Although discovered earlier (3,2281, the diazo reaction was extensively investigated for the first time by Burian (29) who formulated the coupling products as N-azo derivatives. The instability of these products toward mineral acid and the fact that only imidazoles possessing a free imino group have the ability to couple led him to this conclusion. Pauly (30), and especially Pyman and his group, elucidated the structure of the coupling products as C-azo derivatives and established the oricntation of the arylazo group in a great variety of arylazoimidazoles. Iinidazole couples with phenyldiazonium chloride with the formation of a large amount of 2-phenylazoimidazole and a sinall quantity of 2,4,S-tris- (plrcnylazo)imidnzolc (1 ). Otlicr ~ryldinzoniumchlorides also

T

H-~~T-H H-C-N

(-J+XCl-

TE

OH-

.c

H-~~-c--N=N H-C-k

+

attack imidazole with tlie predominnnt formation of tlic respective 2nrylazoimidnzolcs. Tlic naturc of the. azo componcnt cxcrts a distinct influcnrc upon thc yield, as illustrated in Table XIX. Tinidaeoles in whiclt the 2-position is blockcd by an alkyl or aryl group couple into tlie 4 (or 5)-position. Examples are 2-methyl- and 2-phenylimidaz~le,both of which undergo coupling with the formation of 4(or 5)-arylazo derivatives (1). 4 (or 5) -Methylimidazole reacts with diazotized aniline to give approximately equal amounts of 2-phenyIazo-4(or 5)-methyl-, 5 (or 4) phenylaeo-4 (or 5 )-methyl-, and 2,4 (or 2 3 ) -his (phcnylazo)-5(or 4)-

V. Nitro-, Arylazo-, and Aminoimidazulcs

137

methylimidazole (1). Halogenoimidazoles such as 2-bromo-4 (or 5) methyl- or 4(or 5)-methyl4 (or 4 ) -bromoimidazole afford the expected arylazo derivatives (32). TABLE XIX. Yields of 2-Arylazoimidazoles on Coupling of Imidazole kith Various Aryldiazonium Chlorides (31) Comwund coupled

%PhenyIasoimidazole

24o-Tolylazo)-

Yield (96)

............i............ 74

...............................

%(p-Toly1azo)- ............................... 2-(p-Bromophenyl~o)2-(o-Methoxyphenylazo)2- (p-Et hoxypheny1aeo)- ...................... 2-(p-Sulfophenyho)- ........................

....................... .....................

26 84

85 10

64 52

The behavior of the imidazolecarboxylic acids toward diazotized aromatic amines deserves special mention. A number of these compounds couple normally, while their esters or anilides fail to give a positive diazo test. Table XX summarizes a series of acids exhibiting this abnormal behavior. Acids in which the carboxyl group ia not directly attached to the iinidazole ring, such as 4(or 5)-imidazoleacetic acid or TABLE XX. Imidazolecarboxylic Acids Exhibiting Abnormal Behavior toward Aryldiazonium Salts (33) %Methyl-4(or 5)-imidaeolecarboxylic acid 2-Ethyl-4(or 5)-

2-Phenyl-Q(or 5)4(or 5)-Methyl-B(or 4)4(or 5)-Imidazolecarboxylic acid

4 (or 5 )-imidazolepropionic acid, produce colors regardless of whether tlie

free acids or the esters are used (12,33). 4,5-Imidazoledicarboxylicacid couples readily with diartotized sulfanilic acid with the formation of 2- (psulfophenylazo) -4,5-imidazoledicarboxylicacid. The reaction is accompanied by some decarboxylation (1,29). 2-Phenyl-4,5-imidazoledicarboxylic acid reacts readily with p-bromopheny ldiazonium chloride with the elimination of one of the carboxyl groups to give 2-phenyl-4(or 5 )- (p-bromophenylazo) -5(or 4) -imidazolecarboxylic acid. The same coupling product ensues from the reaction of p-bromophenyldiazonium chloride and 2-phenyl-4 (or 5 )-imidasolecarboxyIic acid. 2-Methyl-4,5imidazoledicarboxylic acid exhibits similar behavior (34).

TABLE XXI. Rr Values and Diazo Colors on Filter Paper of a Number of Imidaaoles (37,38) ~~~

Compound

Imidamle..................................................... %Methyl-. ................................................... 4(or 5)-Hydroxymethyl-. ....................................... 4(or 5)-(!&HydroxyethyI)-. .....................................

Solvent Sptemo

Solvent &atem b

SB m d V rhnct

0.88

0.58

0.68 0.70

0.75 -

-

0.66

-

-

0.56 0.50

Diw Color

-&

Yellow'

Red' Redf Oran& Red' Red'

0.30 0.10-0.28 Histamine; 4(or 5)-(ZAminoethyl)-.............................. 0.65 0.60 4(Or 6>(2-Ethylaminoethyl)-. ................................... 0.75 Red' 4(or 5>(2-Dimethylaminomethyl)-............................... 0.76 Red' 4(or 5)-(%n-Propylaminomethyl)-. ............................... 0.79 Red' 4(0r S>(%DimethyIsminOethyl)-. ............................... Redd 0.82 4(0r 5)-(2-Diethylaminomethyl)-. ............................... Red' 0.86 4(or 5)-(%Piperidinomethyl)-................................... 0.90 Red' 4(or 5)-(%Piperidinoethyl)-..................................... Redd 0.94 4(or 5)-(2-Benaylmethylsminoethyl)-. ............................ Yellow* 0.29 0.23 4(or S)-ImidazoIecarboxylic acid................................. Blue' 4(or 5 ) - h i n G ( o r 4)-imidazolecarboxamide. ..................... 0.52 0.51 Red' 0.27 0.26 4(or 5)-Imidsaolelactic acid. .................................... Red' 0.31 0.31 4(or 5)-Imidazolepyruvic acid. .................................. Red' 0.69 0.34 4(or 6)-Imidaeoleacrylic acid.. .................................. 0.12 Red* Histidiie. .................................................... 0.n Red' 0.75 0.45 Histidine methyl ester.. ........................................ Red* 0.24 0.06 Carnosine. ................................................... Red' 0.10-0.28 0.65 Histidinol .................................................... Red 0.26 Ergothioneine................................................. 0.27 Red' 0.15 0.23 %Memaptohistidine............................................ 0.56 2(3H)-Imidazolethione ........................................ Orange" Yellow' 0.83 2-Hydroxyethyl-4-phenyl-2(3H)-imida8olethione ................... With 1 n-propanol-1 N acetic acid. c n-Butnnol saturated with ' M I% aqueoue pyridine. 3: a 3: 1 n-propanol-O.2N ammonia: diaeotized p-bromoaniline. With diazotized dfanilic acid.

-

-

I

-

-

I

-

-

-

V. Nitro, Arylnzo-, and Aminoimirlazdcs

139

The nitroimidasoles fail to give a positive Pauly test. 2. Application of the Diazo Teat to the Identification and Estimation of Imidazolea

The Pauly diazo test provides a basis for the identification and in some instances the quantitative estimation of imidazoles. The nonspecificity of the test and the fact, apparent from the preceding discussion, that many imidazoles fail to couple with diazotized aromatic amines limit the usefulness of the method. The application of the diazo reaction to the quantitative estimation of histamine and histidine will be discussed in Section D-3- (b) and Chapter VI,Section A-6-d- (2). The Pauly test provides a convenient method for localizing imidarole spots on a paper chromatogram. Imidazoles are readily separable by paper chromatography, and spraying of the developed chromatografn with a solution of a diaeotieed aromatic amine followed by sodium carbonate results in the development of colored imidasole spots (35-38). The R, values, i.e., the ratio of the distance travelled by the substance t o that travelled by the solvent front, of a number of imidazoles and the color characteristics of the resulting diazo spots are summarized in Table XXZ. As little as 0.3 microgram of an imidasole is readily detectable by this technique. 3. Properties

The arylazoimidazoles are orange to brown colored, crystalline, highmelting compounds. They are sparingly soluble in watep, dilute aqueous ammonia, or sodium carbonate, but dissolve to some extent in sodium hydroxide. They dissolve readily in hydrochloric acid, and evaporation of such solutions affords the crystalline hydrochloridee. The stability of the tlirglazoimidazoles toward boiling, dilute hydrochloric acid raries considerably. 2-Phenylazoimidazole, for example, is rather reeiatant

Chemistry of Clns.scs and Dcriva.tivw

140

-

toward boiling 10% hydrochloric acid, while 4(or 5)-methyl-5 (or 4) phenylazoimidazole is rapidly destroyed. The arylazoimidazoles dissolve in concentrated sulfuric acid to give brightly colored solutions. The solutions of the monoarylazo compounds arc orange to magenta in color, while those of the bis- and tris- (arylazo) imidazoles arc green and of higher color intensity. The orientation of the arylazo group in the 2-arylazoimidazoles follows from the nature of their reduction products. The reduction of 2-phcnylazoimidazolc with zinc dust and acetic acid leads to the formation of 2-imino-4-imidazolidone (glycocyamidine) and aniline. The same treatment converts 2-phenylazo-4 (or 5) -methylimidazole or 2- ( p -

Y

B

H

H

ii

bromophenylazo) -4 (or 5 ) -methylimidazolc into 2-imino-5-methyl-4imidazolidone (alacreatinine) (1,3940). Reduction of arylazoimidazoles with stannous chloride in hydrochloric acid takes an entirely different course from that observed in the zincdust reduction. Arylazoimidazoles in which the para position on the benzene ring is unsu1)stituted undcrgo a lwnzidine-type rearrangcment and tire convcrt.cc1 into 2-nmino-4 (or 5 ) - (p-aminophenyl) imidazoles.

2-Aminoimidazole becomes the major reaction product when psubstituted 2-arylazoimidazole,s are reduced by stannous chloride in hydrochloric acid, The behavior of 2-phenylazoimida~ole and of pbromophenylazoimidazole serve as illudxations. The former compound

V. Nitro-, Arylam-, and Aniioiniiclseoles

141

-

undergoes the benzidine-type rearrangement to give 2-amino-4 (or 5 ) (paminopheny1)imidazole in the form of its dihydrochloride in 65% yield, while the latter is converted into the monohydrochloride of 2-aminoimidasole in 56% yield (131).

C. Aminoimidazoles 1. 24rninolmidazolea

As has been mentioned in the previous section, tlie 2-aminoi~nidazoles are readily obtained by the reduction of para-substituted 2-phenylazoimidazoles with stannous chloride in the presence of hydrochloric acid (1,31).. The yields which are realized with a variety of arylazoimidazoles are summarized in Table XXII. 4,5-Dimethyl-2-aminoimidasole results when 4,5-dimethyl-2- (p-broinop11enyl~o)iinidasoleis simiiarly reduced (39)*

TABLE XXII. Yield of 2-Aminoimidamle from the Stannous Chloride Reduction of a Number of pma-Substituted 2-PhenylamimidamIes (31) Aryluzo derivative

.

2-Am+3imiduole Yield (%)

............... 56 15 ......................26 .........................43

2-(p-Bromophenylseo)imidazob k(p-TolyIaso)- ............................... %(p-Etboxyphenylazo)%(p-Sulfophenylaao)-

2-Aminoimidasole is a monoacidic base exhibiting pronounced chemical stability. It remains unchanged when refluxed with acids or alkalis and forms well-crystallized salts with acids. The free base has not been obtained in crystalline form. Acetylation and benzoylation convert 2-aminoimidazole int.0 the respective monoacyl derivatives] which exhibit a positive Pauly test.. 2-Aminoimidaeole fails to undergo diazotixation when treated with nitrous acid, but is converted into a nitroso derivative. These properties demonstrate that 2-aminoimidazole fails to behave l i e an “aromatic” amine, and that it is best regarded as a guanidine derivative] the 2-aminoirnidazolium ion receiving major contributions from the

142

Chemistry of Classes and Derivatives

structures shown below, with the positive charge evenly distributed among all three nitrogem.

2. 4(0r 5)-Aminoimidazoles

The free 4 (or 5 ) -aminoimidazole is a highly unstable compound which has thus far not been isolated in pure form. The reduction of 4(or 5 )-nitroimidazole with sodium amalgam in methanol at low temperature provides a method for the preparation of a methanol solution of the base. The addition of mercuric acetate to such a solution brings about the precipitation of the mercury salt of 4(or 5)-aminoimidaaole, which may be converted into the crystalline dihydrochloride by treatment with hydrogen sulfide and hydrochloric acid (41). The reduction of 4 (or 5 )-nitroimidazole with stannous chloride in the presence of liydrochloric acid and acetic anhydride (reductive acetylation) results in the formation of tlic crystallinc acetyl derivative of 4 (or 5)-aminoiinidazole (41).

B

B

Two dcrivtrtivcs of 4(or 5)-aminoiinidaeole,namely 4(or 5)-yanidoimidazolc and 4 (or 5 ) -urcidoimidazole, are of importance as hydrolytic products of tlic purine base guanine (42). The 4(or 5)-ureidoimidazolc

V. Nitro-, Arylazo-, and Amiioimidamles

143

is readily obtained when the crude methanol solution of 4(or 5 ) -aminoiinidazole, resulting from the sodium amalgam reduction of 4(0r 5 )-nitroiinidazole, is treated with potassiuni cyanate and acetic acid (43). 4 (or 5 )-Carbomethoxyaminoirnidazole and 4 (or 5)-carbethoxyaminoirnidaaole, two well-crystallized, high-melting, stable derivatives of 4 (or 5)-aminoimidazole, result from the Curtius degradation of 4(or 5 ) irnidszolecarboxylic acid (44). Their hydrolysis to 4(or 5 )-aminoimidazole has not yet proved feasible. 4(or 5 )-Methyl-5 (or 4) -aminoimidazolc exhibits a greater stability than the parent compound. Stannous chloride reduction of 4 (or 5)-methyl4 (or 4) -nitroimidazole provides a convenient method for the preparation of its crystalline dihydrochloride (25,226). Small amounts of the hydrochlorides of 4-amino-l,5-dimethyl- and 5amino-l,4-dimethylimidazole are obtained, in addition to ring fission products, when the corresponding nitrodimethylimidazoles are reduced with stannous chloride (8). The properties of the 4(or 5)-aminoimidazoles differ markedly from those of the isomeric 2-aminoirnidazoles. They are highly unstable, diacidic bases forming crystalline dihydrochlorides and picretes. Short exposure to room temperature of an aqueous solution of the dihydrochloride of 4(or 5 )-aminoimidazolo leads to its decoinposition with the formation of black pigments. The dihydrochloride of 4(or 5 )-methyl5 (or 4) -aminoimidazole exhibits higher stability. An aqueous solutioii of this salt can be evaporated to dryness in vacuo without causing destruction of the material. 4 (or 5 )-Aminoimidazole undergoes deamination and ring fission under the conditions of the Van Slyke amino-nitrogen determination (41). The behavior of 4 (or 5 )-methyl4 (or 4)-aminoimidazole toward nitrous acid differs markedly from that of the parent compound. Here normal diazotization takes place, and the resulting diazonium salt couples with a-naphthol or resorcinol (25). 4 (or 5)-Methyl-5 (or 4) -aminoimidazole is readily acetylated and benzoylated, and forms a benzylidene derivative on treatment with benzaldehyde (25,26). Acid hydrolysis causes fragmentation of 4 (or 5 )-acetamidoimidazole with the formation of glycine, ammonia, formic and acetic acids (41). The close parallelism between this process and that involved in the reductive fragmentation of 4 (or 5) -nitroimidazole (see Section A-2) is apparent. 4 (or 5 )-Aminoimidazole and 4 (or 5 )-yanidoimidazole produce blue colors with diaeotized sulfanilic acid.

-

D. Histamine

1. Discovery, Distribution in Nature, and Pharmacologlcal Effects

The most important representative of the aminoalkylimidazoles is the substance histamine. Histamine was discovcred in 1907 by Win-

144

Chemistry of Classes and Derivatives

daus and Vogt (45), who prepared it synthetically by the Curtius degradation of 4(or 5) -imidazolepropionic acid. This classical synthesis of histamine established its chemical structure as 4 (or 5) - (2-aminoethyl) imidazole. Its discoverers were not aware of the powerful physiological

‘

effects of the base, and the compound aroused little interest until 1910, when histamine was shown to bc a constituent of ergot (46,47). In the same year it was demonstrated by Ackermann (48) that putrefactive bacteria could produce histamine from histidine. Shortly thereafter, Mellanby and Twort (49) reported that organisms usually present in tlie intestinal tract of man and animals could effect the decarboxylation of histidine and that histamine was a normal constit,uent of tlie intestinal contents. Histaminc is usually found alien histidine-containing materials are attacked by bacteria. I n 1911 Barger and Dale (50) isolated histamine from the intestinal mucosa, and in 1919 Abel and Kubota (51) reported its occurrence in the pituitary gland. The classical investigation of Best, Dale, Dudley, and Thorpe (52) established beyond question that histamine is a norinal constituent of many tissues. Its distribution is not uniform throughout various tissues of a given animal species, nor is it uniforin for a given tissue in various species. Rcpreseritative figures for the histamine content of various tissues and body fluids are found in Guggcnheiln’s excellent treatise (53). The various physiological actions of histamine are: (1) its stiinulating action upon smooth muscles; (2) its dilating effect upon the capillaries; (3)its stimulation of glands. The histamine sensitivity of various organs and of the same organ in different species differs greatly. Thus the rabbit ileum responds in vitro to a dose only several hundred times that needed to cause an excellent contraction of the ileum of the guinea pig. The uterus of all species studied is contracted by histamine, except that of the rat which is relaxed (54). Numerous pathological conditions such as peptone shock, experimental anaphylaxis, allergic diseases in man, surgical shock, toxemia and shock in severe, burns, toxemia in pregnancy, and inflammation have

V. Nitro-, Arylam-, and Aminoimidazoles

146

been linked to histamine. It is far beyond the scope of this monograph to discuss these various biological and medical aspects; the reader is referred to a number of excellent reviews on the subject (53,55,56). 2. Isolation from Natural Materials

Histamine, as has been mentioned previously, is a normal constituent of animal tissues, and several isolations of the base from animal sources are on record (50,51,57-59). Best, Dale, Dudley, and Thorpe (52) established in a most convincing manner the presence of histamine in alcoholic extracts from ox liver and ox lung in amounts sufficient to account for the vasodilator activity of these extracts. Pure samples of histamine dipicrate were isolated, and the progress of the purification was followed by biological assay. The isolation scheme was based on the Kossel-Kutscher silver method. The fresh tissue is minced and immediately extracted with alcohol. The alcohol extracts are evaporated to a small volume, and fat is romoved by ether extraction. The basic constituents are then precipitated with phosphotungstic acid and are regenerated from the phosphotungstates by treatment with barium hydroxide. This is followed by a silver-barium hydroxide precipitation, and the silver precipitate, containing the histamine, is decomposed with hydrogen sulfide. The silver sulfide is removed by filtration, and solid barium hydroxide is added to the filtrate, which is then evaporated. The dried residues are extracted with ethanol, and the histamine is precipitated as the dipicrate from the ethanol extract. Several modifications of this general scheme have been used to isolate histamine. It seems advantageous, for example, to separate the initial phosphotungstic acid precipitate into an acetone-soluble and an acetoneinsoluble fraction prior to its decomposition. The histamine phosphotungstate is acetonesoluble and is thus separated from basic constituents forming acetoneinsoluble phosphotungstates (60-62). Hot water extracts of tissues have been employed as the starting point for the isolation of histamine. The extracts are clarified by tannic acid precipitation and are then carried through the phosphotungstic acid and silver precipitations. The filtrates from the decomposition of the silver precipitates are directly treated with flavianic acid to give a crude histamine difiavianate which is purified by recrystallization (63-65). The amount of histamine actually isolated is usually small compared to the amount originally present in the tissue extracts, as determined by biological assay. Toxemic pregnancy urine contains large amounts of histamine, and several isolations of the base from this source have been recorded. The

146

Chemistry of Classes and Derivatives

isolation from t h s c urincs involves an initial precipitation witah zinc: hydroxide. The zinc hydroxide precipitate is decomposed with hydrogen sulfide, and the ensuing alkaline solution is extracted with amyl alcohol. The histaiiiine passes into the amyl alcohol layer, from which it is recovered by extraction with dilute sulfurio acid. Precipitation as the diflavianate and recrystallization complete the process (66). In two isolations amounts of 34.6 and 62.5 mg. of histamine diflavianate were ohtsined from 7.7 and 8.5 liters, respectively, of toxemic pregnancy urine. 3. Quantitative Estimation of Histamine

( a ) Biological Methods

The spasmogenic effect of histamine on smooth-muscle preparations and its lowering cffect on the blood prcssrire of the anesthetized cat provide the basis for the quantitative biological estimation of histamine (56,67,68). The biological assays are carried out on tissue extracts, and a variety of procedures linvc hccn suggcsted for the purification of histamine extracts for this purpose. Alcohol cxA.raCts, which mere freed of fat by ether extraction, were originally used. Such cnide tissue extracts contain substrmccas which interfere with the biological assay. Acid hydrolysis destroys the biological activity of the interfering substances without seriously affecting the biological activity of histamine. Consequently, hydrolysis of tissues with hydrochloric acid has been used in the preparation of extracts for the quantitative determination (69). The Code method (70) for the biological estimation of histamine in blood involves the preparation of a trichloroacetic acid filtrate and hydrolysis with hydrochloric acid. The hydrochloric acid is removed by repeated evaporation with alcohol, and the resulting dry residue is extracted with small amounts of water. The water extracts are filtered and assayed. Rather advantageous is the application of electrodialysis to the extraction of histamine. A three-cell electrodialyzer, patterned after the apparatus described by Foster and Schmidt (71), is employed. The middle compartment is separated by parchment or collodion membranes from the cathode and anode cells. The tissue mince is placed in the center compartment, and the other cells are filled with distilled water. Under the influence of a direct current the histamine passes quantitatively into the cathode chamber, while histidine and other compounds which interfere with the biological assay remain in the center compartment (72-74). Another micro-method for the extraction of histamine from blood is based on extraction and adsorption procedures. This method offers

V. Nitro-, Arylazo-, and Amiioimidazoles

147

distinct advantages as far as speed and accuracy are concerned, when the estimation of histamine in amounts of less than two microgram is desired. An aqueous Iiistainine-containing extract from tissues is shaken with n-butanol under conditions which assure a quantitative extraction, &A, at a pH of 12.5-13 in the presence of sodium sulfate and trisodium phosphate. The histamine is then selectively removed from the n-butanol extract by a cation-exchange medium and is eluted from the adsorbent by extraction with 0.4 N hydrochloric acid. A cellulose aoid succinate, prepared by treatment of cotton with succjnic anhydride, sodium acetate, and glacial acetic acid, serves as the cation-exchange medium. The final eluate is neutralized with sodium hydroxide and is then ready for histamine determination either by biological assay or by paper chromatography (75). A modification of this method especially adapted for the determination of histamine in whole blood uses Amberlite IRC-50 as a selective adsorbing agent. (76).

( b ) Colorimetric Methods The colorimetric estimation of histamine is based on the Pauly diazo reaction (301,i.e., the capacity of imidazoles to form azodyes upon exposure to diazotied aromatic amines in the presence of sodium carbonate. The reaction is not specific for histamine. Numerous imidazoles and a great variety of other organic compoiinds, such as phenols, aromatic amines, tyrosine, tyramine, pyrroles, and indoles, which may be present in natural extracts, form colors with the Pauly reagent. In order to adapt the diazo reaction to the quantitative estimation of histamine in natural extracts, it is essential to remove these interfering compounds quantitatively prior to the colorimetric determination. Such a purification is rather dficult to achieve without incurring serious losses of histamine. Despite these limitations the method has been used in certain instances (69). The determination of histamine in bacterial cultures and its estimation in b l d will be described to illustrate the principle of the procedure. The methods are based on the observation that histamine can be quantitatively extracted from alkaline solution by such organic solvents as nbutanol, isobutyl alcohol, or n-amyl alcohol. Histidine is not extracted under these conditions (77). A bacterial culture, to be analyzed for histamine, is alkalied by the addition of sodium carbouttte, and tlic histamine is extracted with a iuixture of chloroform and amyl alcohol. Back-extraction with dilute sulfuric acid affords a solution containing histamine, ammonia, and volatile amines. These latter compounds have to be removed, since they interfere with tlie colorimetric determination. To this end the sulfuric

148

Chemistry of Classes and Derivatives

acid extract is neutralized with sodium carbonate and is rendered alkaline by the addition of borax. Boiling for five to eight minutes dispels the ammonia and thc volatile bases, and the solution is then ready for the colorimetric estimation (78). The colorimetric histamine deterinination in blood involves a similar scheme. The blood samples are deproteinized by the addition of trichloroacetic acid, and the filtrates are alkalized by the addition of sodiuiii hydroxide. The alkaline solutions are then extracted with ether, which removes interfering bases but f,ails to extract the histamine. The ctliereal extracts are discarded, and tlie histamine is extracted froin tlie aqueous pliasc with aniyl alcohol. Back-extraction with dilute hydrochloric acid affords a solut*ion containing Iiistaiiiinc hydrochloride. Following conccntration snd neutralization, thc solution is ready for the colorimetric detcnnination (79), Small amounts of histanline can IN readily identified by paper chromatography. This teclinique is well suited for t-lie selective separcttion of the base froni closely related iiiiidazoles and impurities. The identification of histamine by this inetliod rests on the development on a paper strip of x colored band of esttrblislied Rl value (see Section’B-2). The Rl values of liistaiiiinc, nc.et.~lhi~:tsiiiinc, and liistidiiie differ widely. :ind the sul)stances :ire Iwictily scl)alwl)lcin h: uiiidiiiienaional chroinatogr&ill. In tlie solvent niixture, tr-butaiiol rtrturated with 10% aqueous aiiiiiioiiia, tlie RI value of histaiiiine is 0.56. wliilc that of ~r-acetylliistaikiinc is 0.71. The liistidine band iwnains prcicticdly stationary in tliis systeiii. Tlle devcloped cIii*uinatograiiis are dried and are then drawn tlirougll B so1ut.ion of diazotizcd p-broinoaniline for the development of the colored bands. Since small variations of the experimental conditions may affect the Rl values, it is desirable to run strips of pure histamine simultaneously with tlie chroiiintograms of the unknowns. The quantitative estimation of histamine by this method involves the comparison of the color intensity of the liiataniine band in an unknown sample witli the color intcnsities of bands derived from graded amounts of histamine. Tlie results obtained by this inetliod agree well with those of biological determinations on identical samples. Amounts of histamine in excess of one millimicrogram are readily detected (36, 80). Various aryldiazonium salts may be employed in the colorimetric estimation of histamine. The original Koessler and Hanke method (81) uses diazotieed sulfanilic acid. The color is first yellow, then red; it, reaclics its maximum intensity in four to five minutes, and tlien begiiis to fade. The quantitntivc cvnluutioii is based on a coinparison with color standards, prepsred froni iriixt ures of inethyl orange and congo red

V. Nitro-, Arylazo-, sncl .4minoimidnxoles

149

indicator solutions (78). Amounts of histamine as small as ten millimicrograms can be determined. Tho instability of the sulfanilic acid dye represents a serious drawback. This difficulty is overcome by the use of diazotized p-nitroaniline or p-hromoaniline. The dyes which result when these diazo components are coupled with histamine are soluble in n-butanol or isobutyl nlcohol. Thc color is stabilized in these organic solutions and can be ineasured with a photoelectric colorimeter (79,82). Traces of copper, cobalt, or nickel interfere with the Pauly reaction. These metmaisform complexes with the histamine and thus prevent the coupling reaction (83). 4. Formation by Microorganisms

The ability of microorganisms to bring about the conversion of histidine into histamine was first observed by Ackermann (48). He was able to demonstrate a 50% conversion of histidine to histamine by a culture isolated from a piece of contaminated pancreas. The decarboxylation of hist.idine by microorganisms hap since been studied by numerous investigators (84-92). A large number of coliform organisms have the ability to decarboxylate histidine with the formation of histamine in high yield. The activity of such cultures increases with age and reaches a maximum between the fourteenth and sixteenth hours of incubation, after which it falls steadily to the forty-eighth hour. The ability of the organisms to decarboxylate histidine is increased by the presence in the medium of fermentable carbohydrates. The decarboxylase activity of cultures grown in the absence of carbohydrate is rather low. Cultures which are grown in the absence of amino acids also fail to develop the ability to decarboxylate histidine. The decarboxylase activity has a sharp maximum at pH 4. Organisms grown a t pH 7 are low in decarboxylase activity, while those g r o w ~a t pH 4-5 or in the presence of D-glucose are highly active. The increased activity of cultures grown in the presence of D-glucose is the result of the fall in pH caused by the formation of acids during the fermentation. Washed cell suspensions of coliform organisms decarboxylate histidine with practically quantitative yields under anaerobic as well as aerobic conditions. The addition of mglucose to such preparations has no effect on the rate. of decarboxylation. In addition to the coliform organisms, numerous other microbial forms such as those of the Protewr and CZostricZilrin groups have the ability to decarboxylate histidine. Here the pH maximum for decarboxylation lies at 2.5-3.0, and the above-mentioned dependence upon the presence in the medium of fermentable carbohydrate for maximum activity is also observed. These organisms are capable of bringing about the

150

Chemistry of Classes and Derivatives

decarboxylation of histidinc under both aerobic and anaerobic conditions. The activity to decarboxylatc histidine is due to a specific histidinc decarboxylase. The histidine deerrrhoxylase of a strain of CZoRtridiwti. welchii (Typc A) has been partially purified (93). Animal tissues also have the ability to decarboxylate histidine with the formation of histamine (fJ4-97). 5. Preparative Methods

Histamine is prepared commercially by the bacterial decarboxylatiori of histidine. The base is formed in high yields and is usually isolated in the form of its dipicrate. This salt ia then converted into the dihydrochloride or diacid phosphate for marketing purposes. The picratc method has certain disadvantages. Histamine dipicrate is sparingly .soluble, and large volumes of solvents have to be used in its purification and conversion to other salts. This difficulty is avoided by the use of 3,4dichlorobeneenesulfonic acid (98) as the precipitating reagent. Histamine bis-3,4-dichlorobemenesulfonate is precipitated in practically quantitative yields when the sulfonic acid is added to a histidine fcrinentation mixture. The salt is readily purified by recrystallieation and serves as a convenient starting material for the preparation of other liistaminc salts (99). I n addition to its formation by the biological decarboxylation of histidine, histamine is also formed when histidinc is treated with acids at clevated temperatures. For example, heating of histidine in concentrated liydrochloric or 20% sulfuric acid at temperatures of 2(i5-27Oo affords histaminc in yields of 20-25%. Similarly, heating of histidinc hydrochloride with potassium hydrogen sulfate at 265-270°, or heating of N-beneoylhistidine in the dry state at a temperature of 240" in vamco followed by hydrolysis of the ensuing N-beneoylhistaminc (loo),lead to histamine formation. Besides these methods, 8 number of synthetic proccdurev for the preparation of the base may be mentioned. The classical Windaus synthesis, which led to the discovery of histamine, involves the conversion of ethyl 4(or 5) -hidasolepropionate into its hydraeide by treatment with hydraeine, and reaction of the hydrszide with ethanolic hydrogen chloridc and amyl nitrite to give the corresponding aeide. Decoinposition of thc aeide by refluxing with ethanol affords N-cnrbethoxyhistnmine, which is converted into histamine hydrochloride by hydrolysis with concentrated hydrochloric acid (46). See equation (11, page 151. Diaminoacetone, available from citric acid, scrrcrt ns the atarting material for the first Pymm synthesis of histm-h (101). Its dihydrochloride, on treatment with an equivalent amount of ammonium or po-

V. Nitro-, Arylaeo-, and Aminoimidaeoles

++

151

2Cl-

Histaminedihydroehloride

tassium thiocyanate, is converted into 4(or 5) -aminomethyl-2 (3H)-imidazolethione. Oxidation of this imidazole with dilute nitric acid leads to the formation of 4 (or 5 )-liydroxyinetliyliinidazole, which is converted into 4 (or 5 )-cyanomethylimidazole through the chloromethyl derivative. The cyanomethylimidazole, upon reduction with sodium in ethanoI, affords histamine. 4 (or 5 ) -1midazoleacetic acid and 4 (or 5 )-methylimidaeole are the by-products in the process. Under optimal conditions (102) it is possible to obtain 165 g. of histamine dihydrochloride from 4530 g. of

152

Chemistry of Classes and Derivatives

citric acid by this process. In the last analysis this method involves the conversion of 4 (or 5) -hydroxymethyliniidazole into histamine ; this intermediate is more readily available from D-fiwctose (103) (see Chapter 111,Section B-1-a). Closely related to this conversion of hydroxymethylimidazole into histamine is the preparation of the base by direct ammonolysis of 4 (or 5) (2-chloroethyl) imidazole. This reaction proceeds in high yields (104). Essentially two routes for the conversion of L-glutamic acid into histamine are known. The first of these involves the transformation of diethyl glutamate into a-amino-7-carbethoxybutyraldehydehydrochloride and its conversion with ammonium thiocyanab into ethyl 2 ( 3 H )-imidrtzolethione4 (or 5 )-propionate. This 2(311)-imidaeolethione is in turn transformed into ethyl 4 (or 5 )-imidarolepropionate by oxidation with ferric chloride.

[Ej COOEt

1:: I

COOEt

.1

Histamine

The exchange of the carbcthoxy group of this ester for an amino group inay be accoiiiplishcd according to the Windaus scheme (45,105). In the second procedure L-glutuiiiic acid is converted into ethyl u,ydiaminobutyrate which is reduced to give a,r-disniinohutyraldehyde. Exposure of the dihydrochloride of this aldehyde to one equivalent of amiiioniuiii tliiocyanate leads to the formation of 4(or 5 ) - (2-aniinoethyl) 2 (3H)-imidazolethione (2-iiicrcty)toliistaalinc), and by oxidative dcsulfurization to histamine (106,107).

V. Nitro-, Arylazo-, and Aminoimidazoles

163

Another histamine synthesis uses 2-butyne-I,4diol as the starting material. This compound is converted into 1,4-dichloro-2-butyne by treatment with thionyl chloride in pyridine. The replacement of the chlorine atoms by phthalimido groups leads t o the formation of 1,4diphthalimido-2-butyne, which is readily hydrated to give 1,4-diphthsiimido-2-butanone. The dihydrochloride of 1,4-diamin0-2-butanone, resulting from the acid hydrolysis of 1,4-diphthalimido-2-butanone,reacts with one equivalent of potassium thiocyanate to give 4(or 5 ) - (2-aminoethyl) -2 ( 3 H )-imidazolethione. The final step involves the oxidative desulfurization of the 4 (or 5 j - (2-aminoethyl)-2 (3N) -imidaeolethione by means of ferric chloride to give histamine (108).

roH I

- H I

C

I

CHrOH

6

4

C

I

.:zcn CHIC1

l-

-
l-

FHpCl

c R C

A

O=

02c-

o=c

From the practical point of view these methods are of little importance, since they are unable to compete successfully with the much more economical decnrboxylation of the readily accessible histidine, 6. Physical and Chemical Propertie@*

Free histamine was obtained for the first time by Pyman, who treated an aqueous solution of histamine dihydrobromide with an excess of sodium

* In order to d8eerentist.e the primary amino group from the ring nitrogens, it is customary to designate this nitrogen as the N-position.

Chemistry of Claws and Derivatives

154

carbonate, cvaporated the solution to dryness, and rxtracted the base from the inorganic salts with chloroform. The base is much more conveniently prepared by passing a solution of its dihvdrochloride t.hrough a column of the ion-exchange resin, Amberlite IRA-400 (109,110). Histamine crystallizes in clear, wedge-shaped plates, melts at 83-84", and distils at 209-210" at 18mm. pressure. It is highly deliquescent, very soluble in water and ethanol, readily soluble in hot chloroform, but sparingly soluble in cold chloroform, and insoluble in ether. As a diacidic base it has the ability to form well crystallized salts, the most important ones being listed in Table XXIII. Histamine exhibits no characteristic absorption maximum in the ultraviolet region, in accord with the general absorption behavior of imidazoles not possessing a carbonyl function in conjugation with the imidazole ring (111) . TABLE XXIII. Melting Points of a Number of Histamine Salts Salt

M.p., OC.

Monohydrochloride ........................... 193 Dihydrochloride .............................. 244-248 Monohydrobromide .......................... 182-183 Dihydrobromide .............................. 284 Di(acid phosphate) ........................... 132133 Dinitrate ..................................... 14%160 Chloroaurate' . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200-216 Iodobismuthate ............................... Chloroplatinate ............................... dec.200 Iodoplatinate ................................. Phosphotungatate ............................. Silicotungstate ................................ Monopicrate .................................. 233-234 Dipicrate, .................................... 238-242 Dipicrolonate ................................. 268 Diliturate ..................................... 260 Monoflavianate" ............................... Di5vianate .................................. -263 Disozoidolat$ ................................. 241 Bis-Znitroindane-1,3dionate ................... Bis-3,4-dichlorobenzenesulfona~............... 225-227 D i a m i n o q u i n a t e ....................

-

-

-

-

Referenma

(112) (46.102,1O5,112) (109) (101) ( 109) (112) (48.113.114) (115) (45) (116) (116) (11s) (100)

(45,100-102) (46) (116) (63,117) (63,66)

(118) (118) (99) (118)

.For the behavior of this compound on treatment with water, see Strack snd Schwaneber (120). ,For crystalfogra hic data on thia compound, see Tabhashi, Yaginuma, and Hayakawa ( 1 2 8 Bnd Yaginuma and Hayakawa (la). *For cryatatlographic data, consult Wanag and Dombrowski (118). 'Sosoidolic acid IS 2,6diiodophenol-4-sulfonic acid.

V. Nitro-, Arylazo-, and Aminoimidazoles

155

The addition of copper sulfate to a water solution of the base causes the formation of a dark blue complex (123).. The addition of alkali to a water solution of a histamine salt containing cobaltus nitrate results in the formation of a dark blue precipitate and in high dilution of a violet color. The color is sensitive to oxidizing agents and to air. Other imidasole derivatives such as pilocarpine or anserine fail to produce a color. Carnosine and histidinc form yellow solutions when tested in the presence of sir but fail to develop color when tested under anaerobic conditions. 4,5Iinidazoledicarboxylic acid produces a pink precipitate, while imidasole forms a blue precipitate which is not decolorized on exposure to air. The identification of small rrmounta of histamine by this Zimmermann test (124) is best carried out in evacuated Thunberg tubes. The reaction is not very sensitive; less than 0.5 mg. of histamine will not respond. Nickel ions also complex with histamine (83). Histamine forms a brownish red color with bromine (Knoop test) (125-130). Refluxing of histamine with acetic anhydride or with mixtures of acetic anhydride and sodium acetate leads to the formation of N-acetylhistamine. Depending upon the conditions wliicli are employed, the bensoylation of histamine may result in tlic forxustion of different products. Benzoylation by the Schotten-Bsumann procedure under carefully controlled conditions or by treatment. of histamine base in chloroform with somewhat less than one equivalent of bensoyl chloride leads to the formation of X-benzoylhistamine. This monobenzoyl derivative couples normally with diazotized aromatic smines to form monoaeo-dyes. Treatment of one mole of the N-bensoyl derivative with an additional mole of benzoyl chloride in benzene results in the formation of a dibensoyl derivative, the second benzoyl group substituting the imino hydrogen of the imidazole nucleus. As is to be expected, this compound fails to couple wit.h aryldiRzonium salb (112,132).

Chemistry of Classes and Derivatives

156

The reaction between a n excess of benroyl chloride and histamine in the presence of strong alkali aff or& 1,2,4-tribensamidobutene-l,the imidarole ring undergoing fission during the process. Isovaleryl chloride under similar conditions converts histamine into 1,2,4-triisovaierylamidobutene-1 (133,134). H I

CH? I CHa-KHr

0 ii-&-ci KaOH *

Pc=o I

H-YNH 11 C--\T-C-R I *I CHr H 1 CHr-X-C-R

+HCOO-

A8

Histamine reacts readily with such reagents as potassium cyanate, phenyl isocyanate, or cyanamide to form N-carbamyl-, N-phenylcarbamyl-, and N-guanylhistamines, respectively (131). Two types of reaction products may arise from the interaction of histamine with aldehydes. The primary reaction products resulting from the normal interaction of the primary amino group with the aldehyde are of the Schiff-base type. They are yellow to orange colored compounds which undergo catalytic hydrogenation in the presence of noble metal catalysts to form N-alkylated histamines. Anisaldehyde, for example, reacts readily with histamine t o form the yellow colored N-(p-niethoxybenxylidene)histamine, which is smoothly converted into N- (p-methoxybenzyl) histamine when hydrogenated over n palladium catalyst (131).

The reaction between histninine and an aldehyde may, under certain conditions, lead to the formation of bicyclic compounds. The simplest example of this type of reaction involves the condensation of histamine with formaldehyde in the presence of hydrochloric acid. The only isolable

V. Nitro-, drylaro-, and Aminoimidamles

157

product of this reaction is the compound 1-imidaror cltetrahydropyridine (R.I. 764) (135).

CH*O

l-Imida~o[c]tetrahydmpyridine (R.I. 764)

The reaction between histamine and pyridoxal may be influenced by varying the reaction conditions to give either a Schifl base or a bicyolic condensation product. N-Pyridoxylidene histamine results in ethanol solution in the presence of sodium carbonate, while condensation in the presence of sodium hydroxide aff or& 4- (2-methyl-3-hydroxy-5-hydroxymethyl-4-pyridyl) -1-imidazor c] tetrahydropyridine. The two products are readily distinguishable. The former substance is bright yellow and undergoes hydrogenation with the formation of I\'-pyridoxylhistamine, whereas the latter is colorless and fails to absorb hydrogen (136).

H

Histamine is smoothly deaminated with the formation of 4(or 5)(2-hydroxyethyl)imidazole when treated with barium nitrite and mineral acid (137,138).

158

Chemistry of Classes and Derivatives 7. Structural Analogues of Histamine

The pronounced physiological activity of histamine lias provided the stimulus for chemical and phannacological investigations on its structural analogues. These studies have to a certain degree clarified the specific structural requirements endowing a compound with histamine-like activity. During the classical era of histamine research which had its origin with the discovery of the physiological activity of the base, it was mainly the pioneering work of Pyman and his collaborators that provided the synthetic methods for the preparation of histamine analogues for pharmacological testing. These earlier investigations were disappointing from s practical standpoint, since it was soon discovered that modification of the histamine molecule invariably led to compounds with inferior physiological activity or substances that were completely inactive. As a consequence, there was little active interest in histamine analogues for many years. The discovery of the antihistaminics, is., compounds having the ability to antagonize histamine both in vitro and in vivo, and the recognition of their important clinical applications in numerous allergic manifestations resulted in a renewed interest in histamine analogues. The metabolite-antimetabolite concept, it was reasoned, might be applied to histarnine, and histamine analogues by virtue of their structural relationship to histamine might exhibit antihistaminic properties. Indeed, a few of the structural analogues were found to possess weak antihistaminic action. However, none of the analogues has thus far become of practical importance as s n antihistaminic agent. A more detailed account of the preparative methods employed and of the relationships between chemical structure and histamine-like activity will be given in the following sections. (a,) Position

Isomem

The two position-isomers of histamine, namely 1- (2-aminoethyl) imitiasole (I) and 2-(2-aminoethyl)imidazole (111, are known. The synthesis of the physiologically inact,ive 1-(2-aminoethyl) imidazole involve8 the

V. Nitro-, Arylsm-, and Aminoimidszoles

159

alkylation of imidazole silver r i t h 2-bromoethylphthalimide in boiling xylene, followed by renioval of the phthalyl group from the ensiling 1-(2phthrtlimidoet~hyl)imidarolewith hydrazinc (139).

O=

P\ c/ = o N

ar

0-c, ,c-0

kH¶ I

CHt

Br

AH8

L

H-q

A'f-H

H-C-N

2- (2-Aminoethyl)jmidaaole is readily obtainable froui 1-benzylimidaeole. Hydroxymethylation of 1-benzylimidazole leads to the formation of 1-benzyl-2-hydroxymethylimidazole, and through the l-benzyl-2chloromethylimidazole hydrochloride this compound is converted into 1benzyl-2-cyanomethylimidazole. Reduction of the nitrile with lithium aluminum hydride affords 1-benzyl-2- (2-aminoethyl) imidazole and on debenaylation with sodium in liquid ammonia 2- (kaminoethyl)iinidaeole (140).

160

Chemistry of Chms and Deriwt.ives

( b ) Ring-Substitution Products The four ring-methyIated histamines, 1-methyl-5- (2-aminoethyl) imidazole (111), l-methyl-4-(2-aminoetl~yl)imidazole(IV) , 2-methyl-4 (of 5)-(2-aminoethyl~imidttzole(V),and 4(or 5)-methyl-5(or 4)-(2-aminoethyl) imidazole (VI) , have been synthesized. The Pyman histamine

synthesis provides the basis for the preparation of the two ring-nitrogen mcthylated compounds. The methylation of 4 (or 5 )-cysnoinethyliinidazole affords a mixture from which it is possible to isolate l-methyl-4cyanomethyliinidazole in 43 “/o yield and 1-methyl-5-cyttnomethylimidazole in 15% yield. Sodimn ethanol reduction of these isomeric nitriles affords 1-methyl-5- (2-aininoct~hyl) and 1-inethyl-4- (2-aininoet.hy1)imidazole, respectively. The corresponding dimethylimidazoles, i.e., 1,4- and 1,fi-dimethylimidazole, and t,hc respective mettiylimidazoleacetic acids, i.e., 1-methyl-4- and 1-methyl-5-imidazoleacetic acid, are the by-product,s of the reaction (141 ) .

-

V. Nitro-, Arylazo-, and Aminoimidazoles

161

Although adequate for the preparation of 1-methyl-4- (2-aminoethyl) imidazole, this method is not satisfactory when the preparation of 1methyl-5- (Zaminoethyl) irnidaaole is desired. The isolation of the 1methyl-5-cyanomethylilnidaeoie from the methylation mixture is rather tedious, and the yields reported by Pyman have not been substantiated. This difficulty is avoided by preparing 1-methyl-5-cyanomethylimidazole from ethyl 1-methy1-5-irnidazolecarboxylate. Reduction of this ester with lithium aluminum hydride affords 1-methyl-5-hydroxymethylimidazole, which is readily converted into the desired nit.rile through l-methyl5-chloromethylimidazoIe hydrochloride. The nitrile is identical with the

YHa HJ~-C€IS--CH*--F

1-H

&

H-C-

lCN-

YHa

,N - c - c H , - ~ ~ - H H-

-

compound prepared according to Pyman. The ring nitrogen-substituted histamines fail to give the Pauly reaction (142). 4 (or 5 )-Methyl4 (or 4 j - (2-aminoethyl) iinidazole is readily available from 4(or 5)-methyl4 (or 4) -hydroxymethylimidazole via 4(or 5)methyl-5 (or 4) -chlorornethylimidazole hydrochloride and 4 (or 5)-methyl5(or 4)-cyano1nethylimidazole(62,1431.

1,2,4-Tribenaamidobutene-1,the product of the Schotten-Baumann benaoylation of histuinine, may serve ns the starting niaterial for the

I 62

Chemistry of Classes and Derivatives

-

preparation of 2-methyl-4 (or 5 ) (2-aminoethyl) imidseole. Treatment with acetic anhydride a t 150’ converts the compound into 2-methylN-beneoylhistamine, which is converted into 2-methyl-4(or 5 )- (2-aminoethyl) imidaeole by acid hydrolysis (131). The compound has also been prepared from 2-methyl-4 (or 5 )-hydroxymethyl-5 (or 4) -imidazolecarhoxylic acid in the manner shown below (244). The reported properties of 2-niethylhistaminc dihydrocliloride prepared by both methods agree.

H I

H-SH~F-CH~ C-N

I I

CHI CHI-SIII

+

c1-

H I

t

A

Y I

HOOC--~M~\F-CH,

__.c

C-N

\

C-N

B

h more generally applicable method for the preparation of 2-alkylor 2-aryl-substituted histamine derivatives involves the interaction of suitably %-substituted 4(or 5 ) (2-chloroethyl)imidazole hydrochlorides with ammonia. The required halides arc readily avsilablc from 2alkyl- or 2-awl-substituted 4 (or 5 ) (2-hydroxyethyl) imidaeoles resulting from the reaction of an aldehyde with 1,4-dihydroxybutanone-2 in the presence of ammonia and cupric acetate (37).

-

-

V. Nitro-, Arylazo-, and Aminoimidasoles

(1-1 N-.Mononlkyl-

16.3

and N,2V-nirtllc?ilhBtrr.mine Derivatives

-

The hydrochloride of 4(or 5 ) (2-chloroet Iiyl) imidazole serves as the key intermediate for the prepwittion of reprcsentatives of this class of compounds. As has been stated previously (see Chapter IV,Section C), the covalently bound chlorine in this suhstsnce is highly reactive and is readily replaced by ammonia, primary or secondary amines. In practice, an ethanolic solution of the halide is treated with an excess of an ainine in a sealed tube at a temperature of loo",and after removal of the unreacted amine the alkylaminoethylimidazole is precipitated as the clipicrate. Refluxing of the halide with an excess of the amine in n-propanol may also be used in order to avoid the use of pressure tubes (104,145).

I-(${ - H-rN-f-" +

Cl-

H I

R

HJ-R' A

AHz -N R

I I CHr-N-R'

CHI-CI

An alternate route to the N-alkylatcd histamines, which is especially useful when the preparation of 2-alkyl- or 2-aryl-substituted 4(or 5)(2-alkylaminoethyl) imidazoles is desired, employs hydroxymethyl vinyl ketone as the starting material. This ketone adds secondary amines with the formation of aminohydroxy ketones. These are not isolated, but are allowed to react directly with an aldehyde and ammonia according to the Weidenhagen process (see Chapter 11, Section A-3) to give the desired imidazole. Such compounds as 4 (or 5) - (2-piperidinoethyl)imidazole, 2ethyl-4 (or 5 ) (2-piperidmoethyl)imidazole, or 2-phenyl-4(or 5 )- (2piperidinoethyl)imidazole are readily prepared in this manner (37).

-

CHaH b-0 +-€I R

I CHI +HN-R'

-

NHa CHXOH f ;>C-Rtt NHa

I Hi-N-R'

Y

H-cJ"+R'~ I

-

GI*+

1

C-N C&

R I I CHr-N-R'

The aminoalkylimidazoles are diacidic bases forming characteristic dipicrates and dihydrochlorides, which are employed in their isolation and characterization. With the exception of the ring nitrogen-substituted compounds, they give a positive Pauly reaction.

Chemistry of Classee and Dcrivatiws

164

( d ) Histamine Analogues Possessing Longer

Chains

M"

Shorter Aliphatic Side

4 (or 5 )-Aminomethylimidazole, the simplest representative of this class of imidazoles, was obtained for the first time by Windaus and Opitr (137) by the Curtius degradation of 4(or 5)-imidaeoleacetic acid. The substance also results from the oxidation of 4(or 5 )-aminomethyl2(3N)-imidazolethione with ferric chloride or from the treatment of 4(or 5 )-chloromethylimidarole hydrochloride with ammonia (141). A superior method for its preparation involves the catalytic hydrogenation of the oxime of 4 (or 5 )-imidazolecarboxaldehyde in the presence of two equivalents of hydrogen chloride, the dihydrochloride being obtained under these conditions (146). 1

H-%/~-~H HOOC-CHt-C-N

H I H-CYN\7=S U HzN CH 2-C-N-H

-

H I

H-~~T-II H-C-C-N II

N-OH

-

4(or 5 ) - (Dialkylaminomcthyl) imidasoles are obtained from 4(or 5 ) chloromethylimidarole hydrochloride and secondary amines. The reaction proceeds in good yields, and thc resulting tertiary amines are isolated in the form of their dipicrates or dihydrochlorides. The 4(or 5 )- (moncalkylaminomethyl) imidazoles arc not readily obtained in this manner. A practical procedure for their preparation involves the catalytic debenzylation of 4 (or 5 ) (benzylslkylaminomethyl) imidaroles. The dihydrochlorides of compounds such as 4(or 5 )-(methylaminomethyl) -, or 4(0r 5 )- (ethylaminomethyl) imidaeole are readily obtained by catalytic hydrogenation of 4 (or 5 )- (benzylmethylaminomethyl) and 4 (or 5 ) (benzylethylaminomethyl) imidaeole, respectively, in the presence of a palladium catalyst and hydrochloric acid. Hydrogen- . olysis of 4 (or 5 )- (dibenzylaminomethyl) imidazole under the above-mentioned conditions affords 4 (or 5 ) (benrylaminomethyl) imidazole (146, 147).

-

-

-

-

V. Nitro-, Arylazo-, and Aminoimid:izolee

165

++ zc1-

Among the various known histaniine derivatives containing additional methylene groups in the aliphatic side chain, the compounds 4(or 5)-(3aminopropyl) and 4 (or 5 )- (4-aminobutyl) imidazole may be mentioned. These may be obtained from arginine and lysine, respectively (148,149).

-

H I

3-H

€I 3 -$

C-N

I (CH:)a I

NHa J(or 5)-(3-Aminopropyl)iidatole

H I

P--Ba'v-H --N

I (YHJ' NHa 4(or 5)-(~-Aminobut?rl)imidatole

8. Pharmacological Specifcity

Three physiological effects of histamine provide the biological basis for studies on the relationships between chemical structure and physiological activity in the histamine series: ( 1 ) its spasmogenic effect upon smooth muscle preparations; (8) its depression of blood prmsure in the anesthetized cat; (3) its stimulatory action on certain glands. A given structural alteration of the histamine molecule will not necessarily elicit 2% comparable effect in all these tests, and a histamine analogue may have little effect upon the blood pressure of the cat, but may be highly active when assayed on the guinea pig uterus. Also the response of the guinea pig uterus and the guinea pig ileum to a given compound may vary significantly. N-Methyl- and N-ethylhistamine provide good examples to illustrate this point. N-Methylhistamine is half as active as histamine when assayed on the cat, but exhibits twice its activity as far as its effect on the guinea pig uterus is Concerned. Its stimulating effect on gastric secretion in the human parallels that of histamine. X-Ethylhistamine, on the other hand, has only 5% of the activity of histamine on the cat and the guinea pig uterus, but is 75% as active when tested on the guinea pig ileum (146,150-153).

166

Chemistry of Clrtsses and Derivatives

It is thus important to compare the biological activity of a series of histamine analogues in terms of one and the same test system. The pharmacological testing of numerous histamine derivatives and analogues has led to the recognition of certain critical structural elements. The presence of a free primary, secondary, or tertiary amino group in the side chain is essential for histamine activity. Acylation of the primary amino group destroys the biological activity. Compounds such as N-acetylhistamine, N-benzoyllistamine, or substances in which histamine is linked to peptide structures through its primary amino group are devoid of histamine activity (154,155). N-Acetylhistamine is of special interest in this connection since it represents a metabolic product of histamine. The compound is present in the urine of the dog and man following the oral adtuinistration of histamine and thus seems to be a physiologically important “detoxified” form of histamine (36,110,131). Aldehydes bring about a complete inactivation of histamine. Their effect is pH dependent and must be attributed to either the formation of Schiff bases or of 1-imidaro-[c]-tetraliydropyridine derivatives (see Secbioti D-6) (135,156-158). A number of N-alkyl and N,N-dialkyl derivatives of histamine are biologically active. Using the contracting effect 011 the guinea pig ileum ILS the criterion for physiological activity, it may be generally stated that the activity of these compounds is inversely proportional to the size of the alkyl group. N-Methylhistamine is highly active, S-ethylliistaminc possesses 75% of the activity of histamine, while the N-propyl derivative iu only 5 “/o as active. NJV-Dibeneylhistamine possesses no histamine activity. This compound is weakly antihistaminic in its action, i.e., it has the capacity to suppress the action of histamine on the guinea pig ileum (145). NJV-Dimethylhistamine exhibits approxiinately 20% the activity of histamine when assayed on the cat, while its effect upon the guinea pig uterus is approximately 30% that of histamine. The substance possesses 75% of the activity of histamine as far as its effect on the guinea pig ileum is concerned. N-Trimethylhistamine has no histamine activity (145,150).

A high order of histamine activity depends upon the presence of the 2-aminoethyl side chain; shortening or elongation of the side chain markedly decreases the biological activity. The next lower homologuc of histamine, 4(or 5) -aminomethylimidaaole, is inactive (62). Its Nmono and NJV-dialkyl derivatives show a variable physiological response. Some of the compounds such as 4 (or 5) -methylaminomethyl-, 4 (or 5) -dimethylaminomethyl-, and 4 (or 5) -ethylaminomethylimidarole

V. Nitro-, Arybzo-, mid Aminoimidazoks

167

possess a low ordcr of Iiistsmine activity, while others such as 4(or 5 ) dibenzylaminoniethylimidtlzolehave the ability to antagonize hid rtminc. Their antihistaininic properties are not very pronounced (146, 153). Substitution of the ring hydrogens in histamine by methyl groups exerts a pronounced effect upon the physiological activity. 2-Methylhistamine is the most active of these methylated products. Its effect upon the guinea pig ileum is 30% that of histamine, while it is only 15% as effective when assayed on the cat (152). 4(or 5)-Methyld(or 4)-(2arninoethy1)irnidasole is a compound of low activity. It is only 0.5% as active as histamine when tested on the guinea pig uterus (62). It is of interest to note that the two ring-nitrogen methylated histamines differ in their biological activity. 1-Methyl-4- (2-aminoethyl)imidazole possesses 6% the activity of histamine on the guinea pig ileum and is 274 as active in depressing the blood pressure in the cat, while its isomer, 1-methyl-5- (2-aminoethyl)imidasole, is completely devoid of histamine activity. The substitution of the imidazole ring by such other groups as in 4 (or 5 )- (Zaminoethyl)-2 (3H)-imidazolethione leads to inactive coinpounds (159,160). The two position-isomers of histamine, 1-(2-aminoethy1)imidazole (53) and 2-(2-aminoethyl)imidazole (152), are completely inactive. The presence of the imidazole ring is not essential for histamine activity. Several compounds in which the 2-aminoethyl side chain is attached to other heterocyclic ring systems possessing aromatic character exhibit histamine-like activity (152, 161). All the highly active compounds possess the structural element I. in which the portions -X=C-

I

nntl

--.V-C-

ll

- I

are part of the resonance-stabilized aromatic system. The presence within a moleeule of this fragment does not imply that the compound must possess

R

=N-C-CHt-CIIz--I;J n ‘ I

Chemistry of Classes and Derivatives

168 \

liiettrniine activity. Other striictmal rcquirenients also have to be satisfied. In addition to the presence of the fragment I, the size and shape of the aromatic nucleus seeins to play an important part. The most highly active compounds are those possessing a small, unsubstituted nucleus. The observation that 2- (2-aminoethyl) pyridine possesses histamine activity in contrast to 3- (2-aininoethy1)pyridine and 4- (2-aminoethyl) pyridine, which are pIiysio1ogically inert, led to the postulation that intramolecular hydrogen bonding between the primary sniino group and

H~K -CH?

2-(2-Aminoetligl)pgndine

3-(2--4minoethyl)pyridinc

.I-(2-An~iiioethyl)pyridine

the pyridine nitrogen in the cation is an essential prerequisite for histamine activity (162,163). Such hydrogen-bonded structures may be written for the 2- (2-aminoethyl)pyridine, but not for the other two compounds. The physiologically active forms of the histamine cation, according to

2-('2-Aminoetliyl)pyridinecation

tliis view, are to be represented by the following hydrogen-bonded structures.

Histamine cation, according to Kieinnnn and Hays

The compound 2-(2-arninoethyl) iinidazole provides just as favorable a structure for hydrogen bonding 8s does the histamine itself. However,

V. Nitro-, Arylam-, and Aminoimidazoles

169

the compound is completely devoid of histamine activity. The occurrence under physiological conditions of hydrogen bonding between two basic

2-(2-Arninoethyl)imidamle cation

ccntera is highly improbsble, and there seems t o be little basis for assuming the existence of a relationship between hydrogen bonding and histsmine activity. 1. 2. 3. 4. 5.

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170

Chemistry of Classes and Derivatives

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V. Nitro-, Arylazo-, and Aminoimidazoles

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i 7 . Iiwmler, K.K.,and Hanke, M. T., W .39, 521 (1919). 78. Eggerth, A. H., Litwan, R. J, and Deutsch, J. V., J. Bml. ,W, 187 (1939). 79. Rnraud, JI Renevois, L., Mandillon, G., and Ringenbach, G.,Cmnpl. rend. 92% 760 (1946). 80. Urbach, K. F., and Giscafrd, L., Proc. SOC.Ezptl. Biol. Med. 68, 430 (1948). 81. Koessler, K. K.,and Hanke, M. T., J. BbZ. Chem. 39, 497 (1919). 82. Gebauer-Fuelnegg, E., 2. phyeiol. Chem. 191, 222 (1930). 83. Eichler, O., and Meyer, G., Naturwisenschajten 1948, 93. 84. Koessler, K. K., and Hanke, M. T., J. BWZ. Chem. SS, 539 (1919). 85. Hanke, M. T., ahd Koessler, K. K., ibid. 60, 131 (1922). 86. Hanke, M. T., and Koesler, K. K., &id. 69, 835 (1924). 87. Hanke, M. T., and Koessler, K. K.,ibitl. 69, 855 (1024). 88. Eggerth. A. H,1. Bact. 37,205 (1939). 89. Gale, E. F., Biochem. J . 34, 392 (1940). 90. Gale, E. F.,ibid. 36,66 (1941). 91. Gale, E. F., “The Bacterial Amino Acid Decarboxylases,” in Advwtca in Enzymology, Vol. VI, Interscience Publishers, Inc., New York, 1946, p. 1. 92. Schales, 0.. “Amiuo Acid Decarboxylases,” in Vol. 11, Part I, of J. B. Sumner and K.Myrbiick, editors, The Enzynes, Academic P m ,Inc., New York, 1951, p. 216. 93. Epps. H . M. R., Bwchem. J . 39, 42 (1945). 94. Werle, E., Biochem. Z. MS, 292 (1936). 95. Werle, E., &id. 891, 105 (1937). 96. Werle, E., and Krautaun, K.,ibid. 256, 315 (1938). 97. Werle, E., ibid. $04,201 (1940). 98. Vickery, H. B., J. Bwl. Chem. 1&, 77 (1942). 99. Galat, A., and Friedman, H. L., J. Am. Chem. SOC.71, 3976 (1949). 100. E w h , A. J., and Pyman, F. L., J . Chern. SOC.99, 339 (1911). 101. Pyman, F.L.,ibid. 99,868 (1911). 102. Koeesler, K. K., and Hanke, M . T., J. Am. Chem. SOC.40, 1716 (1918). 103. Organic Syntheses, Vol. 24, John wiley and Sons, Inc., New York, 1944, p. 64. 104. Garforth, B.,and Pyman. F. L.,J . Chem. Soc. 1936,489. 105, Akabori, 9, Bet. 66, 151 (1933). 108. Akabori, S., and Numano, S., J. Chem. SOC.Japan 63,213 (1932) ;Chem. Ahatracta

sr, 293.

107. Akabori. S., and Numano, S., Bull. Chem. SOC.Japan 11, 214 (1936); Chetn.

Aht-

30,6988.

108. Fraser, M. M., and Raphael, R. A., 1. Chem. Soc.2962, nS. 109. Pyman, F. L.,&id. 202,630 (1912). 110. Tabor, H., and Mosettig, E., J. Biol. Chem. 280,703 (1949). 111. Lewis, B., Gebauer-Fuehegg, E., and Fanner, C. J., J . Am. Chem. Snc. 66, %)% (1933). 112. Qerngrw, O., 2. physiol. C h . 108, 50 (1919). 113. Ackermann, D., &id. eeS, 46 (1934). 114. Horn, F., 2.p h y h l . Chetn. 207, 111 (1932). 11s. van Itallie, L.,and Steenhauer, A. J., Phann. IVeckblad 62, 429 (1925). 116. Redemann, C. E., and Niemann, C., 1. Am. Chem SOC.68,590 (1940). 117. Langley, W. D., and Albrecht. A. J., J. Biol. Chem. fO8,7%) (I=). 118. Wan&, G., and Dombrowski, A., Bet. 76,82 (1942).

Clianistry of Classes nnd Derivatives

172

119. Garrwu. Y., C ~ ~ t t pr to .d . %I, 1515 (1935). 120. Strack, E..aud Schwaneberg, H.,Bcr. 68. 1038 (1935). 121. Takahashi, G., Yaginumn. T., and Hayskiwn. K., Prop. Ittip. rlctirl. Tokvo 7, 57 (1931); Cheni. A bstrncts 26, 2973. 122. Yaginumn, T.,and Rayakaws, K..J. SOC.. Chem. h i d . , Jnpccn :tf (Suppl. binding), 215; Chcnr. Abstrcicl.9 67, 5397. 123. Axmwhcr, I:., Biochewt. %. 984,339 (1936). 124. Zimmermann, W.,%. &sad. C h i & .lS6,260 (lm). 125. Knoop. F.,Britr. C h o u . Ph~xiol.IJnlh. If, 356 (1908). 126. Hunter, C.,Biochem. J. 16, 637 (1922). 127. Hunter, G.,ibid, IS, 640 (1922). 128. Hunter, G.,ibid. 19, 25 (1925). 129. Hunter, C.,ibid. 19, 34 (1925). 130. Hunter, C.,&id. 10, 42 (1925). 131. van der Merwe, P., Z. physiol. Chcna. 177,301 (I!)%). 132. Diemair, W.,and Fox, H.. Ber. 71, 2493 (1938). 133. Windaus, X., Dijrricu, IV., and Jeosen, H.,&id. 64, 2745 (1021). 134. Winduua, A., and Lingenbeck, W., ibid. 66,3706 (1922). 135. Friinkel. S.,:ind Zciincr, K.,Biochenr. %. 110, 234 (1920). 136. Heyl, D.,Luz, E., Harris, S. A., and Folkers, I<., J . A M . Chent. Soc. 70, 366i) (1948).

137. Windtius, A, and Opitz, H.,Ber. .jj, 1721 (1911). 138. Wredc, F., and Holtz. P., Arch. gcx. Phll.\.iol. (Pfliigerx) $9.4, 421 (1934); Chem. Absllncts 28, 5477. 139. Lur’e, S.I., Kulesliova, M.C., and Iiocltetkov, N. K.,J . Gm. Chmz. W . S. S. R . ) 9, 1933 (1939); Chert&.Abstracls 84, 4387. 140. Jones, R. G.,J. Am. Chem. Soc. 71, 383 (1949). 141. Pyman, F.L., J. Chem. SOC.09,2172 (1911). 142. Jones, R.G.,and McLaughlin, I<. C., 1. A m . Chem. Soc. 71, 2444 (1949). 143. Erlenmcyer, H.,Waldi, D., and Sorkin, E.,Helv. Chim. Arln 31, 32 (1948). 144. Tamamushi, Y.,J. PIiorni. Sac. J n l w ~53, 1080 (1033); CIirni. Ahztrnrla 2!), 7328.

145. Huebner. C. F.,T~irner,H. A, :ml Srholz, C. R., J . Ant. Ckern. Soc. 71, 3942 (1949). 146. Turner. H. A.. Hiichrr. C. F., :mi Sdiolz. C . It., ;bit/. 71. W1 (1WI)). 147. Turner, R. J., ibid. 70, 3523 (1948). 148. Akabori, S., and Kaneko. T..J. Chcwr. Soc. J n p m 6d. 207 (1932); Chwti. Abstracts 27, 293. 149. Akabori, S.,cind Knneko, T., Bull. Chem. h. Jnprut If. 208 (1936); Clirtn. Abstracts 30, 59%. 150. Vartainen, A., J. Phnrniacol. 64,265 (1935). 161. Schnedorf. J. G..and Ivy, A. C., Proc. Soc. Expll. B i d . Wed. 32,777 (1m5). 152. Lee, H.M..and Jones, R. G., J. Phnri)anrol. 96, 71 (1949). 153. Graver. R. N.. Harrrtt. W..Ciirnwon. A., and Hcrrdd. K.. Arch. Inlrrantl. P~iort~iororly,rrtntic. 87, 33 (1951). 164. Rocha c Silva. M., J. Plinnmcol. 77, 198 (1943). 155. Rochn c Silvri, M.. J . AlIrr{/v 16. 399 (1944). 156. Dale, H.H.,and Dudley, H.W., J . Phmmacnl. 18, 103 (1921).

V. Nitro-, Aryluo-, 157. 158. 159. 160. 161. 162.

niid Aninoiiniclazoles

1%

Kamimura, S.,Hukuoka Actu Med. $3, 1269 (1940) ; Cheni. Abstracls 36, 1338. Kendall, A. I., J . ZnJ. Dis. @, 689 (1927). McDonagh, J. E.R.,Lancet, 284, 989 (1933). ’ Pyman, F. L.,J . Chena. SOC.1030,98. Rosiere, C. E., and Grossman, M.I.,Science 223,651 (1951). Walter, L. A., Hunt, W. H., and Fosbinder, R. J., J . Am. Chena. Soc. 68, 2771

(1941). 163. Niemann, C., and Hays, J. T., ibid. 64,2288 (1942).

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CHAPTER VI

The Imidazolecarboxylic and Sulfonic Acids A. ImidazolecarboxylicAcids 1.

1-ImidazolecarboxylicAcids

The reaction between imidazole magnesium bromide and ethyl chloroformate leads to the formation of ethyl 1-imidazolecarboxylate. Ethyl 4- or 5-methyl-1-imidazolecarboxylate is similarly prepared from 4 (or 5)-methylimidazole magnesium bromide (1). The interaction between imidazole magnesium bromide and ethyl chloroformate does not give ethyl 2-imidazolecarboxylate as had been claimed by Odd0 and Mingoia (23). 1-Imidazolecarboxylic acid is an unstable compound (carbamic acid) which loses carbon dioxide with the greatest of ease to give imidazole. Its ethyl ester is a distillable basic liquid forming a crystalline picrate. The ester also loses carbon dioxide when heated at 250-260°, and is converted into 1-ethylimidacole. Ethyl 4- or 5-methyl-1-imidazolecarboxylrate under similar conditions affords a mixture of 1-ethyl-4-methylimidazole and 4 (Or 5 )-methylimidazole (1).

HfxH+ H

COZ

+ EtOH

2. 2-ImidazolecarboxylicAcids

A convenient method for the preparation of 2-imidazolecarboxylic acid involves permanganate oxidation of 1-benzyl-2-hydroxymethylimidarole, followed by debemylation of the resulting 1-benzyl-2-imidazolecarboxylic acid with sodium in liquid ammonia (4). The acid melta at

176

Chemistry of CILWS and Derivatives

KSInO,

.

CI H 2 0 H-(NICOOH H

Nn,

~

liquid NHS

H I H - ~ ~ C O O H

H

163-164' with the evolution of carbon dioxide to give imidazole. The oxidation of 2-styryl-4 (or 5 )-1nethylimidazole (prepared from inethylglyoxsl, amiuonia, and cinnumaldehydc) with bariuiii permanganate leads to the formation of 4 (or 5 )-rnethyl-2-imidazolecarboxylic acid. This acid is an amorphous powder which melts a t 160-165' with the evolution of carbon dioxide to give 4 (or 5 )-methylimidazolc (1).

?.

4(0r 5)-Imidazolecarboxylic Acids

4(or 5)-Iinidazolecarboxylic acid was fist obtained by Knoop ( 5 ) :is a degradation product of the ainino acid histidine. It is forikied iii sniull yicltl when D-glucose is exposed to the action of ainmonincal cupric. acetate solution (6). Two prtictical proccdureu for the preparution of 4 (or 5 )-iniitl~zolccarl~oxylic acids are of importance. Thc first of t l m c involves tlic oxidtttioii of 4 (01' 5 )-hydroxymctliylimidazolc, or of suitably substituted 41or 5 ) -Iiydroxyaietliglimidazoles, with nitric acid or potns-

I"'

-

VI. Imidazolecsrboxylicand Sulfonic Acids

177

sium permanganate (7-9). The second consists in the partial decarboxylation of 4,5-imidazoledicarboxylic acid, or of a 2-substituted 4,5imidazoledicarboxylic acid, in boiling aniline (10). The resulting 4 (or 5 ) imidazolecarboxanilides are readily convertible into respective 4 (or 5)imidazolecarboxylic acids by acid hydrolysis. The oxidative desulfurization of 1-alkyl- or 1-aryl-substituted 2 (3H)-imidazolethione-5-carboxylates (see Chapter 111, Section A-3-d- (4) ) with dilute nitric acid provides a preparative route to 1-alkyl- or 1-aryl-substituted 5-imidazolecarboxylates (11). Ethyl 2(3H)-imidazolethione-4(or 5)-carboxylate affords ethyl 4 (or 5)-imidazolecarboxylate on treatment with dilute nitric acid.

-

Sfl2-CEt p.

HN

-

P

H * ? y E t

HXOZ

R I

H

~

~

~

O

R- H.alkyl or aryl

O

E

t

The chemical behavior of 4(or 5 )-imidazolecarboxylic acid serves to illustrate the general properties of this class of imidazoles. 4(or 5)Imidazolecarboxylic acid melts at 286" with the evolution of carbon dioxide to give imidazole. It forms a stable sodium salt and, as a base, is capable of yielding salts with acids, e.g., a hydrochloride, a nitrate, and a picrate. Exposure to methanolic or ethanolic hydrogen chloride converts the acid into the respective ester hydrochlorides from which the free esters may be liberated by treatment with potassium carbonate (7). Heating with ammonia or primary amines in methanol converts the methyl and ethyl esters of 4(or 5)-imidazolecarboxylic acid into the corresponding amides (9,12). 4(or 5 )-Imida~olecarboxamidefails to undergo the Hofmann reaction when subjected to the action of alkaline hypobromite (12). Hydrazine hydrate converts ethyl 4 (or 5 )-imidazolecarboxylate into the hydrazide, and this, on exposure to nitrite, affords the azide. Refluxing with ethanol transforms the azide into 4(or 5)carbethoxyaminoimidaaole (13). 4 (or 5)-Hydroxymethylimidazolesare formed when 4(or 5)-imidasolecarboxylates are reduced with lithium aluminum hydride (14). 4(or 5)-1midazolecarboxylic acid reads with phosphorus pentachloride to form an amorphous acid chloride which re-

178

Chemistry of Clrtsses and Derivatives

acts readily with primary and secondary amines to give the corresponding amides (9). Treatment with iodine in alkaline solution brings about, the decarboxylation of 4 (or 5)-imidazolecarboxylic acid, with the formation of 2,4,5-triiodoimidazole (15). The behavior of the irnidasolecarboxylic acids and esters toward diazotized aromatic amines is discussed in Chapter V, Section B. 4(or 5)-Imidasolecarbo?rylic acid exists predominantly as the zwitter-ion (16).

4(or

4.

Zwitter-ion of 5)-imidaaolecarboxylic acid

4,5-Imidazoledicar~xyorylic Acids

4,5-Imidasoledicarboxylic acid and its 2-alky l- and 2-ary l-derivatives are prepared according to the iMaquenne procedure (10,17-20). This method which is, in the last analysis, a modification of the Radsiszewski procedure (see Chapter 11, Section .4-2) iiivolves the int'eraction of tartaric acid dinitrate with ammonia and an aldehyde to give a 2substituted 4,5-imidazoledicarboxylic acid. With formaldehyde, 4,5imidazoledicarboxylic acid is obtained. The Maquenne synthesis proceeds with high yields in most instances, and thus provides a convenient route to 4,5-imidasoledicarboxylic acids.

4,5-Imidasoledicarboxylic acid melts at 280° with evolution of carbon dioxide to give imidazole (see Chapter 11,Section A-6). It is practically insohble in most of the common organic solvents; sparingly soluble in cold water; but somewhat soluble in hot water, from which it may be conveniently recrystallied. 4,5-Imidazoledicarboxyoxylia acid is capable

VI. Imidazolecarboxylic and Sulfonic Acids

179

of forming both a mono- and a disodium salt. When titrated with 0.1 N sodium hydroxide (phenolphthalein as indicator), the acid requires only 87 per cent of the calculated amount of base for neutralization. Partial evaporation of the neutralized solution causes the monosodium salt to precipitate, while the disodium salt stays in the mother liquors and can be precipitated by the addition of alcohol (21-23). A mono- and a diammonium salt of 4,5-imidazoledicarboxylic acid are known. The acid salt remains when an aqueous ammonia solution of the dicarboxylic acid is evaporated to dryness; addition of ethanol to a solution of the acid in concentrated ammonia brings about precipitation of the diammonium salt. This salt is unstable and on standing at room temperature loses a molecule of ammonia to give the iiionoaiiiinonium salt. 4,5-Imidazoledicarboxylie acid forms stable wid salts with many amines. Most of these salts are highly water-soluble and thus are of little use for charact,erization purpoees (2324). The 4,5-imidazoledicarboxylic acids are best represented by zwitter-ionic structures akin to that of 4 (or 5 )-imidazolecarboxylic acid. The carboxyl groups illustrated for 4,bimidazoledicarboxylic acid and its 2-alkyl- or 2-aryl-derivatives exhibit normal functional behavior in many reactions. Esterification occurs readily on treating with ethanolic or methanolic hydrogen chloride, or on pouring solutions of the acids in concentrated sulfuric acid into alcohols (25). The esters are basic compounds having the capacity to form salts with acids. As typical imidazoles they afford sparingly soluble silver salts. The 4,5-imidazoledicarboxylic acids form acid chlorides when exposed to the action of phosphorus pentacliloride (in phosphorus oxychloride as solvent), and these react normally with aniline to give thc respective dianilides. Amides are readily prepared by heating the methyl esters with alcoholic ammonia. Treatment with phosphorus oxychloride converts them into the corresponding dinitriles (26-29). Exposure of 4,5-imidazoledicarboxylic acid to an excess of diazoinetliane in ether, or treatment of methyl 4,5-imidazoledicarboxyistewith sodium metlioxide and methyl iodide, leads to the formation of methyl 1-methyl-4,5-imidazoledicarboxylate which is transformed into its diainide upon expoaure to alcoholic ammonia at 120' (25). 5. 4(or 5)-Amino-S(or 4)-Imidazolecarboxylic Adds

(a) Occurrence and Methods of Preparation 4(or 5 )- h i n o d (or 4) -imidazolecarboxamide, the most important reyresent,ative of this claas of iinidazoles, accumulates in the culture medium of Esclaerichiu coli during sulfonarnide bacteriostasis, and seems

180

Chemistry of Classes and Derivatives

to be an intermediate in the biosynthesis of purines. It has the ability to replace purines as growth promoters for a number of microorganisms, and has been shown by radioactive-tracer techniques to be converted into purines by .such biological systems as pigeon-liver lioniogenate (3032). Many years prior to its isolation from a natural source, 4 (or 5)-amino5 (or 4) -imidnzolecarboxaniide was prepared by Windaus and Langenbecli (33) by catalytic reduction of 4 (or 5)-nitrod (or 4) -imidazolecarboxamide (see Chapter V, Section A-2). Alternate methods for the preparation of the amide have since been devised (34,35). A one-step process

i:

fi d(or 5)-Amino5(or d)-imidazolectirboxumide

involves the interaction of aiiiinocyanoacetamide and formamidine Iiydrochloride in boiling met llano1 (35). 4 (or 5 )-Amino-5 (or 4) -imidazolecarboxainide melts at. 1&169", and forms a hydrochloride and a picratc

(melting st 255-256" and 237-238') respectively). In contrast to iitost other imidazoles, which form red dycs on coupling with diazotiaed aromatic aniincs, 4 (or 5)-timinod (or 4 ) -iniidazolecarboxaniide forms darkhlue colors with these reagents (see Chapter V, Scction B-2). 1-Methyl-5-chloroin~idazole(see Chapter IV, Section B) may serve as the starting material for the prcparatioii of l-metliyl-4-amino-5imidazolecarboxylic acid and its esters and aniidcs. Nitration converts this substance into l-iiiethyl-4-nitro-,i-chloroimidazolc,which undergoes a displacement reaction on exposure to potassiuin cyaiiidc to give 1methyl-4-nitro-5-cyanoimidazole. Acid hydrolysis converts the cyano which is highly derivative into l-methyl-4-nitro-5-imidazolecarboxainide, resistant to further hydrolysis. For conversion into l-inethyl-4-nitro-5imidazolecarboxylic acid, treatment with concentratd sulfuric acid and sodium nitritc is necessary !36,37). l-hletl1yl-4-riitro-;S-ii~iictaeolecnl.t)oxylic :wid, through its acid oliloride, is readily c.onvcrtil)lc into miirtes.

VI. Imidazolecarboxylic and Sulfonic Acids

181

and these, oti reduction, afford the respective l-methyl-4-amino-5-imidazolecarhoxamides. The esters and amides of 1-met.hy1-Camino-5-imida-

zolccarboxylic acid form crystalline picrates and hydrochlorides. Ethyl 1-methyl-5-amino-4-imidazoleearboxylate is readily available from ethyl sminocyanoacetate. This ester condenses with methylisothiocyanate to give ethyl 5-amino-2-methylamino-4-thiazolecarboxylatc, which rearranges in the presence of boiling aqueous sodium carbonate -imidazolethions-4-carboxylate. Dcinto ethyl 1-methyl-5-amino-2 (3H) sulfurization with Raneg nickel gives ethyl l-methyl-5-a1nino-4-imidazolecsrboxylate (38). HaC-N=C

//

s

+

YEN

H*N-y-COOEt

A

H H,C-NI'TNH. I COOEt

H

The interaction of ethyl aminocyanoacetate with imino ethers or imino thioet.her hydrochlorides represents a convenient method for the preparatsion of 2-substituted ethyl 4 (or 5 ) -amino-6 (or 4) -imidazolecar-

182

Chemistry of Classes and Derivatives Et(j) NH R-C*+ C=N

I

H3-C-COOEt

-

1 H.

H I

A

---..c

R alkyl or aryl p

boxylates. With formsrnidine hydrochloride, ethyl 4 (or 5 )-amino-5 (or 4) -imidazolecarboxylate is obtained (39). These imidazoles form picrtttcs and monoacetyl derivatives, and condense with 1,cnzaldehydc to give benzylidene derivatives. They ('an be diasotiaed. (b) Conver&n into Acrines

Sarasin and Wegrnann (36) recognized the potentialities of the 4(or 5 )-amino4 (or 4) -imidazolecarboxamides as starting materials for the

synthesis of purines, and pcrforincd the first conversion of an imidazole into a purine. They heated l-methyl-4-amino-Fi-i1nidaaolecsrhoxamidc with diethyl carbonate to obtain 7-inethplxanthine. This original syn-

iI

7-Methylwnt hine

thesis was later improved so~nen~hat hy replacing t . 1 diethyl ~ rsr1)onat.c with ethyt chloroformate (37). l-Substituted purincs arc oi)ttrincd hy this method when substituted amides of 4(or 5 )-uminod(or 4) -imidasolccarboxylic acid are employed as the starting materials. An example is the formation of l-ethpl-7-metl1ylxanthine from ethyl ch1oroform:rtc and the ethyl amide of l-rnethyl-4-amino-5-imidazolecarboxylicacid.

These reactions require rather drastic conditions, and are thus not readily adaptable to the synthesis of purines containing sensitive substitu-

VI. Imidamlecarboxylic and Sulfonic Acids

183

ents. A further modification designed to overcome these limitations replaces the ethyl chloroformate with phenylthioformyl chloride. 5Amino-2-methylthio-1-methyl-4-imidazolecarboxamide, for example, reacts with this reagent to give 5- (phenylthioformamido)-1-methyl-2methylthio-4-imidazolecarboxamide. Heating in the dry state, or refluxing in pyridine solution, converts this compound into 8-methylthio-9-methy1xsnthine; thiophenol is liberated in the process (40).

'

CHI

NHt

-

c1 I

CHr H I I

It

II

0

0 CHI El

H&-S$$)=ON'

'63H

II

0 S-AIethylthio-9-methyhnthine

The 4 (or 5)-ureido-5 (or 4)-imidazolecarboxylates are other intermediates for the preparation of purines. Xanthine results, for example, when 4(or 5) -ureidod(or 4)-imidazolecarboxylic acid is heated with 6 N hydrochloric acid. The required ureido derivative is readily obtained by treating the hydrochloride of methyl 4 (or 5)-amino-5 (or 4) -imidazoleearboxylate with potassium cyanate, and saponifying the resulting wter (411.

H I

COOMe *OH-

H t

dbH

H I

H I

HYJKF=O+HX, N SI'H C

8

Xanthine

Closely related to this method of preparation is the conversion of alkylureidoimidazolecarboxylates into purines. Ethyl l-methyl-5methylureido-2 (3H ) -imidazolethione-4-carboxylate (readily available from ethyl l-methyl-5-amino-2 (3H)-imidazolethione-4-carboxylateand methyl isocyanate) is smoothly converted into 1,9-dimethyl-8-thiouric acid when cxpoeed to the action of dilute sodium hydroxide (3942).

Chemistry of Classes and Derivatives

1‘s-4

CHz

I

C‘

II

0 OEt

0

4,5-Iiuidszoledicarboxaii~icleatid its ~i-glycosidesare otlier valuable starting iusterials for the synthesis of purines and iiucleosides. 4,6-Imidazoledicarboxamide is converted into xant.hine when exposed to the action of alkaline Iiypobroiiiite (25), 1-~letl1yl-4,5-iniidazoledicar~oxaiiiidc H I -COXHI

II

0

Xantliinc

6 9-hletliylatnthine

uiider siinilur coiiclitioiis aflorcls 9-nietliylsaat Iiinc. Thcse hasic observations opened the \\-upto t lie syiiilieeis of nuclciisidcs. TIN syiitliesis of santliosine (9-~-u-ril)ofiir:InosylsHatliiiic) scrvcs to illndi*iltct.lre gcncrnl proccrlurc. The silwr salt of lrictli~l4,~-i111i~lueolcilir.ul.bosylate re:rcts with 2,3,5-tri-O-nret,vI-u-u-1.il.~ofuruiioayI diloridc in boiling sylene to give an oily ester glycosidc wlrich is convertctl into thc cryvsttdline 1-(8-u-ribofuranosyl)-4,bimidazoledicarboxainide by exposure to alcoholic sinmonia. Alkaline liypobromite converts this diainide into xnnthosinc! (4345). See equation (1), p ~ g e185. 6.

Histidine*

(~Amino-rl(or5)-lmidazolepropionicAcid, B-(4(or 5)-Imidazole)-alanine)

( n i T)iscover!/~Distribrrtioti

ill

A--(ittire,( i d Strridrrre

The amino acid, L-histidine, is a norinal constituent of inost proteins, from which it. is liberated by liydrolysis with acids. 111 1896 histiiliiri* 4

Biochemical aspects of liist.icIiuc nro suiirmrwized in Giiggcniicirn’s t wiitisc (53).

VI. Imidazolecarboxylic and Sulfonic Acids

185

U

0

Xanthosine

was discovered practically siniultaneously by Kossel (46) and Hedin

(47). The former investigator isolated the base from an acid hydrolyzate of the protamine, sturin; the latter obtained it from hydrolyeates of a number of common proteins. In addition to its occurrence in proteins, small amounts of the amino acid are found in such natural materials as mushrooins, geminating seeds, ineat extract, Swiss cheese, sweat, urinc, and blood (53). The dipeptide 8-alanyl-L-histidine (carnosine)? is a normal constituent of mamiualian muscle. The histidine content of a number of proteins is shown in Table XXIV, page 186. The correct structure of histidine was postulated by Pauly (50),who based his argument mainly on the observation that histidine, like many other simple imidazoles, has the capacity to form colored solutions with diaeotized sulfaniiic acid. Knoop and Windaus (531) provided chemical evidence in support of Pauly's structure. The starting point for their

CHI I HS--~+-COOH

I

€I Histidme (Pa* 1904)

classical investigations was the compound 4 (or 5 )-irnidazolelactic acid (oxydesaminohistidine) previously obtained by Friinkel (52) from the reaction of histidine with silver nitrite. They reduced this compound with hydrogen iodide and red phosphorus, and obtained 4(or 5)-imidazolepropionic acid. This degradation product was identical with a t For a comprehensive review on carnosine see reference (54).

Chemistry of Classes and Derivatives

I86

.

T.4HT,E XXIV Histidine Content of Aldolase

8

Niimber of Proteins' (48)

.....................................

4.21

....................................... 3.00 Chymotrypinogen ........................... 1.23 Ctostridium botulinum toxin (type .\ ) ......... 1.03 Colostrum pseudoglobidin ..................... 2.20 Edeatin ..................................... 2.90 Casein

Fibrinogen (human) .......................... 2.60 Gelatin ..................................... 0.73 Gliadin ...................................... 1.82 ~-GlobuIin (human) .......................... 2.5 Hemoglobin (horse) ........................... 8.71 Insulin ....................................... 4.91 p-Lactoglobulin .............................. 1.58 Myoglobin (horse) ............................ 8.50 Myosin ...................................... 2.41 Ovalbumin .................................. 2.35 Pepsin ....................................... 0.9 Ribonuclease ................................. 4.22 Serum albumin (bovine)...................... 3.80 Serum albumin (human)..................... 3.50 Silk fibroin ................................... 0.36 Sturin ....................................... 12.9'' Tobacco mosaic virus........................ 0.00 Triase phosphate dehydrogenaw ............... 5.01 Tropomyosin ................................ 085 Wool Keratin ................................ 1.05 Zein ......................................... 1.32

.

.

Values in g amino acid per 100 grams

.

'Reference 49

synthetic specimen of 4 (or 5)-imidazolepropionic acid prepared from p.carhoxyethylglyoxa1. ammonia. and formaldehyde by the Radriszewski method (see Chapter 11. Section A.2)

.

The imidazole nature of histidine received further support from a series of degradation steps leading to its ultimate conversion into imidszole. Oxidation of 4(0r 5)-imidazolelactic acid with nitric acid gave

VI. Imidazolecarboxylic and Sulfonic Acids

187

4(or 5) -imidasolepyruvic acid, and this compound, on further oxidation with hydrogen peroxide in glacial acetic acid, was converted into 4 (or 5 ) -imidazolecarboxylic acid, which, by decarboxylation, gave imidazole.

- 4 5 )-iinidazoleThese degradation studies pointed to ~ ~ a m i n o(or propionic acid as the most plausible structure for histidine. This coiiipound was synthesieed in 1911 by Pyman (55) and was found to bc identical with the natural amino acid. Histidine possesses an asymmetric carbon atom and consequently may occur in an L- or a D-form. The configuration of the naturally occurring form of histidine is that of an L-a-amino acid since it has the same configuration as L-aspartic acid of established stereostructure. The stereochemical correlation of the two amino acids involves the following steps. L-Histidine methyl ester is treated with benzoyl chloride and sodium carbonate to give methyl ~-2,4,5-tribenzamido-4-pentenoate(see Section f ) Ozonolysis converts this material into dibemoyl-L-asparagine, and this compound, on exposure to methanolio hydrogen chloride, is transformed into benzoyl-baspartic acid, benzoic acid, and ammonia. The melting point and optical rotation of this beneoylaspartic acid are identical with those of the benzoyl-L-aspartic acid prepared from Luapartic acid (56).

.

H+

COOH I

H0OC-k-N-C I , , H H Uonmgl-Laspart.ic acid

Clieniistry of Classes and Derivntivw

188

( b ) Nomenclot tire 4 s a 4(or 5 ) -iiionosubstitutccl iiiiidasolc, histidine exhibits tuutonierisui and Iience, in soinc of its rcactioiir;, uiny I~clittvc.like t i cwiiiposite of two coinpounds( see Chapter I, Section E). It Ilns Lecoiiie customary to naiiic conipountls enibodying the general structure (I) a* 1-sul)dituted Iiistidines, wIiile rutwtanrcs of tlic general forinuln (I11 are kiio\vii iis 3-d)stitutcd histitiitics.

%iJ, l*

CH,

X-R

I

IIOOC-C-XHt

I H

Histidine derivatives arising froiii tlic acylatioii or alkylation of oiic of the ring nitrogem, wlicre tlic position of tlie entering aubstitucnt is not cstablisl~ed,arc clrsignirtcct :is 1 {or 3)-rul)atitutctl Iiistitlines. Substit.uents on tlic priniiiry :mino group ;ire tlifrrcntiatcv1 froin tliosc on the ring nitrogens by nnining tliein as S-substitucnts. ( c ) IsoZatioji

Becf- or liorsc-blood plntclct pustc or co~iiiircrciiilIieiuoglobin scwc convcnie~it starting :niiterisls for tlw isolation of histidinc. TIic coininoil isolation prt~ccdurcs (57-60) arc iiiodifications of u inetliod described in 1903 hy Friiiikel (52). The blood-plstclct pa& (Iietnoglobin) is hydrolyzed with hydroclilorir mid, and the cxcctis of the hydrolyzing agent cvnpor:tted. Nu~iiinand ferric salts :ire rciriovcrl hy neutralization followccl by trctrtnicnt with cllttr(*oiil,t ~ i i t l t Iic lristidinc is precipitntcd with iiiewiiric c.liloriclc in tlic presciicc of sotliuiir twhonattx. Thc iiierwric cotiiplcs is dr.c*o~iipo~cti with Iiytli~ogi~n sultitlc, :inti tlic liistidinc S Iry~lrocliloridcfroill the filtrate. isoli~tctl~ L the A pwticultirly siiiiplc and efficient iiictliotl rccrwtly clescribed (611 cniploys 3,4-dichlorobenzenesulfonic acid as a dec*tivc precipitating reerystalagent for liistidine. Histidine l~is-3,4-tliclrlorol~enzcncaulfonlttc lizes out \viien :IU excess of tlic wlfoiiir acid is irclded to i k Iiyclrolyznte of 1iemoglol)iii i r t u pH of 1.2 to 1.6. ‘l’lrc crude siilt (soiiietinws rontamiis rc:itlily Iw-ifieci hy iiated wit 11 lciicinc 3,4-clinlilorol~c1~~~~1ie~iiI~o1i;iic~~ recrystal lisation. ab

1’1. Imidnzolecxrhos~licand Sdfonic -4cids

189

Sn~ullquantit,ies of liistidino liavc :dso been ohtained I)y c!hroniatopnpliy of protein hydrolyzrltcs 011 columns of the ion exchanger Dowex-50. Acctatr I)uffers in the pH range 5 to 7 are amploy4 as eluting agents; (62).

Free Iiistidino c*rystallizcwwlien awinonia and ethanol :ire added to :rn aqueous solution of its hydrochloride (63). It is also readily prepared from its bis-3,4-dichlorobenzenesulfonate (61) . Preparation of the base from the latter salt involves its decomposition wit.h barium hydroxide a t pH 7.2 The resulting precipitate of barium 3,4-diclilorobenxcnesulfonate dihydratc is filtered off , the excess of barium ions removed with sulfuric acid, and the histidine crystallized by the addition of alcohol to the concentrated filtrate. ( d ) Qziantitntive Estinlntion (1) Cravimetric Proceduree

Fractionation of the basic miino acids I liexone bases) with silver ions was introduced in 1896 by Hedin (47), and was developed into a quantitative procedure for the estimation of arginine, histidine, and lysine in protein hydrolyzates by Kossel and Kutscher (64). Their historically important “silver-baryta method” will be outlined since it provides the foundation for most of the gravimetric, and some of the colorimetric histidine determinations. The protein is hydrolyzed with sulfuric acid, and the hydrolyzate neutralized with bariuin hydroxide. The barium sulfate is removed by filtration, and arginine and histidine are precipitated siinultaneously in the foiin of their silver salts by adding silver sulfate and barium hydroxide in excess to the filtrate. The silver salt is suspended in dilute sulfuric acid, the silver precipitated with hydrogen sulfide, and the filtrate neutralized with barium hydroxide. An excess of silver nitrate is added, and the histidine-silver is selectively precipitated by careful addition of barium hydroxide. Failure of the supernatant to form a precipitate upon addition of ammonia indicates complete precipitation of the histidine. Arginine-silver is obtained from the filtrate by addition of a large excess of solid barium hydroxide. The histidine-silver is decomposed with hydrogen sulfide, and the nitrogen content of the dlver-free filtrate is determined by the Kjeldahl method. The histidine content of the solution is computed from its nitrogen content. (The arginine content is similarly determined on the filtrate arising from decomposition of the arginine-silver precipitate with hydrogen sulfide.) Dctermination of the lysine in the mother liquors (from the initial arginine-histidine-silver precipitate) involves acidification with sulfuric acid, renioval of the silver ions with hydrogen

Chemistry of Clswes and Derivatives

190

sulfide, and precipitation of thc lgsinc with phosphotungstic acid. The lysine phospliotungstate is t lien decomposed with barium hydroxide, and the amino acid isolated and weighed as the dipicrate. Kosei and Patten (&5), realizing that the histidine-silver as prepared in the original procedure was contaminated with other amino acids, thereby contrihuting non-histidine nitrogen to the final solution, introduced an additional purification step. They reprecipitated the histidine with mercuric sulfate (Hopkins’ reagent) prior to the final nitrogen determination. A number of refinements of the original Kossel procedures have been recommended. Thew variants rely on a preliminary precipitation of the histidine by silver ions, but differ in the purification steps and the methods used in the final estimation. Careful control of the hydrogenion concentration during separation of the histidine from the arginine is of key importance for the success of the method. Histidine-silver is precipitated practically free of arginine a t a pH of 7.0 to 7.4 (bluegreen to bromthymoi-blue indicator). Precipitation on the acid side of this critical pH range leads to losses of histidine, while on tlie alkaline side histidine-silver contaminated with arginine-silver is obtained (6668).

The quantitative aspects of tlie silver precipitation technique have been evaluated by microbiological assay. It was observed that 97 per cent, of the total histidine, present in a casein hydrolyzste, accumulates in the silver precipitate, while 3 per cent escapes precipitation and remains in the mother liquor (69). As has been mentioned above, Komel computed the histidine content from the nitrogen content of the solution resulting from decomposition of the final silver or mercuric ion precipitate with hydrogen sulfide, and thus assumed that this filtrate contains only histidine-nitrogen. Extensive studies have shown that these final filtrates are frequently contaminated by other amino acids, so that their nitrogen content is not an accurate measure of the histidine content. It is therefore advantageous to precipitate the histidine from such solutions by selective reagents and to calculate tlie histidine content from the weights of the resulting precipitates. Three reagents, namely, flavianic acid, nitranilic acid, and 3.4-dichlo~ohenzenesiilfonic. acid, are employed for this purpose.

Flavianioacid

Nitranilic acid

3,+Dichlorobenzenesulfonicacid

VI. Imidnzolecarboxylic and Sulfonic .4ritls

101

Flavianic acid was introduced as a precipitant for arginine by Kossel

(701, and waa suggested as a convenient reagent for histidine by Vickery (68,71) ; it has since found extensive use for this purpose. Because of

the tendency of flavianic acid to form, with histidine, mixtures of the mono- and the diflavianate, the results obtained by its use are not reliable (72). Nitranilic acid (73) seems to be a more suitable precipitant for histidine. Block (74) has described a rather convenient method for the estimation of histidine based on use of this reagent. The procedure is quite simple, essentially involving hydrolysis of the protein with 8 N sulfuric acid, removal of the sulfuric acid with barium hydroxide, precipitation of the histidine at pH 7.4 with silver ions, decomposition of the silver precipitate, and weighing the histidine as the nitranilate. On studying the solubility of the salts of amino acids with a number of aromatic sulfonic acids, Doherty, Stein, and Bergmann (75) found that 3,4-dichlorobenzenesulfonic acid forms a sparingly soluble salt with histidine. This substance was, in turn, used as a specific reagent for the determination of histidine by Vickery and Winternitz (72). The bis3,4-dichlorobenzenesdfonateof histidine crystallizes excellently, and no tendency for the formation of the mono-3,4-dichlorobenzenesuifonate is observed. Its salts with other amino acids are more soluble, and are thus readily separable from the histidine bis-t,4dichlorobenzenesu1fonate. The determination of histidine with 3,4-dichlorobenzenesu1fonic acid proceeds as follows. The protein is hydrolyzed with !20 per cent hydrochloric acid, and the hydrochloric acid is then removed by vacuum distillation. The residue is dissolved in water, the solution clarified with Norit, and histidine-silver is precipitated by addition of silver nitrate followed by 1 N sodium hydroxide to pH 7.4. The histidine-silver is collected, washed, and decomposed with hydrochloric acid. The histidine in the filtrate is then precipitated with 3,4-dichlorobenzenesulfonic acid. This technique, possibly the most accurate gravimetric method for the estimation of histidine, affords values in agreement with those obtained by other methods. The gravimetric methods discussed in this section cannot compete with the elegant micromethods developed in recent years. Large amounts of protein (25 grams in the older, 5 grams in the later, methods) are required, and the numerous steps are time-consuming and lead to losses of histidine. The histidine figures obtained by gravimetric procedures are usually low. (2) Colorimetric Procedures

The fundamental observation by Pauly (50) that histidine forms a deeply colored solution with Ehrlich’s reagent (diaeotized sulfanilic acid) provides the basis for a colorimetric estimation of histidine. As

192

Chemistry of Clsssrs nncl Derivatives

pointed out prcviously (sce Chapter V, Section D-3-1)I , t h e diazo reaction is not specific for histidine. In protein Iiyclrolyxntes, it is iriainly tlie amino acid, tyrosine, which interferes with t hc coloriinetricdeep-purple color with l3lirlicli’s determination, sincc it also forins reagent. For qualitative pinpow? it is possible to dist inguislr tyrosinc from histidine if the mixture to be tested is either lwieoylntml (76) or subjected to the action of nitric acid (77) prior to tlic c.oloriiiictric test. Both treatments, of course, convert the tyrosine into derivatives whicli fail to react with the diazo reagent. Quantitative sepwation of tyrosiac and histidine must precede colorimetric estimation of histidine in a protein hydrolyzate, and phosphotungstic acid has been suggested for this purpose (78). The phosphotungstic acid precipitate contains the histidine, while tbe tyrosine rcmains in the filtrate. The pliosphotungstate is decomposed, and the diazo color of tlie filtrate taken as R measure of the histidine content. Sincc phosphotungstic acid precipitation of histidine is not quantitative, a silvcr ion precipitation at pH 7.4 is preferahlc for the initial purification (79,80). Precipitation with mcrcuric chloridc in the presence of borate buffer lias been suggested as s nienns of separating histidine from tyrosine on a micro s u d c . The prccipihte is then dissolved in sodium cyanide for colorimctrie cstiiuation (81). Tliesc prwedurcs suffer froin tlic tlisudvantage that a precipitat*ioii step (which may involvc losses of histicline) precedes the actual colorimetric determination, A inetliod avoiding this difficulty utilizes electroclialysis in a three-cell appsratus for tlic sc1):iration of the hasic timino acids (82,831. Arginine, histidine, and lysinc accuniulate in tlie catliode chamber, free from other amino acids. The electrodialysis leads to a quantitative, clean separation of tlv hasic amino itcids, and the resulting catliolyte is used, without further manipulation, for colorimetric determination of the histidine. Arginiiie and lysine do not interfere with this determination. A few words regarding the coloriiiictric technique are in order at this point. The available methods (81,84436) are, without exception, inodifications of the original Koessler-Hanke procedure (87) (see Chapter V, Section D-34)). The tendency of the diazo color to fade on standing is largely overcome if ethanol is adrlcd to the solutions imniediately following the development of color. Diazotieed sulfanilic acid is used as the diazo component, and coupling is carried out in the presence of sodium carbonate. The color is estimated in n photoelectric colorimeter, against a histidine standard. litts I)txm

11. Imidazolecarboxylic and Sdfonic Acids

193

The Knoop test provides the basis for another colorimetric method for determination of histidme. Knoop (88) observed that heating of a solution of histidine in bromine water results in the formation of a cherry-red color and finally a black precipitate. This reaction has been rleveloped into a quantitative procedure by Kapeller-Adler (89). The asential features of her method are as follows. A histidine-containing solution is acidified with sulfuric acid, and bromine in 33 per cent acetic acid is added until a yellow color is produced. The mixture is kept t i t rooin temperature for 10 minutes, when a solution of ammoniuiu ctrrboiiute in aminonia is added. Heating in a boiling water bath for 5 minutes Iwiugs about the formation of a deep-violet color. The sensitivity of the iwcation is 1 in 50,OOO. Such iiiiidazole derivatives as 4 (or 5 )-imidazoleacetic, 4 (or .5) -imidazolepropionic, 4 (or 5 )-iinidazolelactic acid, carnosine, and .V-ii~thylIristicline fail to respond to the reaction. l-Methylhistidine, the iinidaxole coiiiponent of anserine, forms a red-violet color exhibiting only 20 per cent of the color intensity of histidine. Histamine affords a yellow color. Tile Kapeller-Adler procedure cannot be applied to protein hydrolyzirtes without prior purification of the histidine. Mercuric- or silver-ion Itrecigitationrs Itcave been einployed for this purpose (89-91). (3) Microbiological Procedures

Certain niicroorganisins are unable to synthesize L-histidine, and fail grow wlien this substance is omitted from their culture medium. Such organisms are sensitive tools for the quantitative determination of Lhistidine. Within certain limits, a graded growth-response is obtained when increasing amounts of L-histidine are added to the medium for these organisms, and a standard curve, correlating growth with L-histidine content of the medium, can be constructed. The assay organisms coniinonly used are lactic acid producers, and acid production (as deterinined by titration) serves as a convenient measure of growth. %e growth-response of Streptococcus jaecalis to increasing amounts of Lliistidiiie is shown in Figure 3. The niarked growth-response to extremely siuall quantities of L-liistidine is noteworthy. The L-histidine content of an unknown saniplc can readily be determined. Graded amounts of the unknown are added to the culture medium of a histidine-requiring organism, and ti growth’ curve is obtained. Simultaneously, an L-histidine standard curve is iun. By comparing identical growth-levels on the two wrves, tlie L-liisticline content of the unknowii may be readily cdculilted. to

Chemistry of Classes and Derivatives

194

, 12.

-

II-

0

to. 2

E

9.

i8 .

8 ic

7-

* 6m

9 5,

0

4.

3.

2I. 0

5

(0

IS

20 2s go 35 L-Histidine, microgmmr

do

4ii

so

Fig. 3. Growth response of Slreplocuccw faecalk to L-histidine.

Three organisms, Leucon.outocmesenteroides P-60(69), Streptococcus ja.ecal& (92) ,and Lactobacillua jetmenti (93),are useful organisms for the estimation of L-histidine. The microbiological methods require very small amounts of assay material and, when carried out with the necessary precautions, are highly reliable and sensitive. Values obtained with one organism should always be checked by assays of the same sample with another organism. These assays have found application to the estimation of L-histidine in a great variety of natural materials. The microbiological methods outlined respond to L-histidine only, and care must be taken to prevent racemization during the preparation of samples for assay.

( e ) Synthesis and Resolution Two simple itnidazoles, namely 4 (or 5 )-chloromethylimidssolium chloride (see Chapter IV, Section C) and 4 (or 5 )4midaeolecarboxaldehyde (see Chapter 111, Section A-l), serve as convenient starting materials for the preparation of DL-histidine. I n his first classical synthesis, Pyman (55) condensed one equivalent of 4 (or 6)-chloromethylimidazolium chloride with two equivalents of sodio ethyl chloromalontrte, and converted the ensuing cthyl 4 (or 5 ) imidazolemethylchloromalonate into D L - u - c ~ ~ ~ o(or ~ o 5) - ~-iriudazolepro'

VI. Imidazolecarboxylic and Sulfonic Acids

195

pionic acid. Amination with aqueous ammonia at 110" transformed the latter compound into m-histidine. t

B

c1-

EtOOC-&-Cl

p+.-

AOOEt

cot

H

,<XH CHa

I

H-C-C1 kOOH

Superior procedures for the conversion of 4 (or 5)-chloromethylimidazolium chloride into m-histidine involve its condensation with sodio ethyl acetamidomalonate (94) or acetamidocyanoacetate (95). The resulting condensation products are converted into the amino acid by acid hydrolysis.

+

EtooC-pZ-*al

'[

R- -COOEt or -CN

-

Na+

&A

P+

"cp H I

CHa I

196

Chemistry of Classes and Derivatiws

Several methods are avai1al)lc for tlic coiivernioa of 4(ur 5 )-imidazoleearhoxaldehydc into m,-histidine. All these procedures are bascd on condensations of the aldehyde with compounds possessing active methylene groups. Imidazolecarboxaldehydeundergoes the Perkin aelactone synthesis when treated with hippuric acid in the presence of sodium acetate and acetic anhydride (7). The condensation product must be -oxformulated as either a 2-phenyl-4- (1-aeetyl-5-imidazolemethylene) saolone or R 2-phenyl-4- (1-acetyl-4-imidaeoleinetliylene) -oxazolone, since the position of the acetyl group, which enters the imidazole nucleus during the reaction, is not established. Treatment with sodiuiii carbonate simultaneously opens the aelactone ring and removes the acetyl group from this compound to give ~benzamido4(or5 ) 4midazoleacrylic acid, which is then converted into DL-histidine by reduction with sodium amalgam followed by hydrolysis with hydrochloric acid.

Imidaeolecarboxaldehyde condenses with hydantoin in the presence of sodium acetate and acetic anhydridc to give a diacetyl derivative of 5 44 (or 5 )-imidaoolemethylene]-hydantoin, possibly possessing the structure illustrated. Reduction with sodium amalgam, followed by hydrolysis with barium hydroxide, converts this compound into m-histidine (96). See equation (1) , page 197. An excellent histidine synthesis, affording an over-all yield of 64 per cent, involves the reaction of imidazolecarboxaldehydc witah 2-mer-

-

VI. Imidazolecarboxylic and Sulfonic Acids

..

H

OsC-H

+Ha HTCF=O

O=C--NH

$-H A e - I f k = OI O=C-NH

1'3;

H

CH: I

(1)

Ha-C-COOH I H

cupto-5-t.liiazc.me and reductive hydrolysis of t..e resulting 444(or 5 ) i1nidazole11ietliylene]-2-mercapto-5-thiazolone with hydrogen iodidc and red phosphorus (97).

Dithioliydantoin and 2-phenyl-4-etlioxynietliyleneoxazolone aerve ti3 starting materials for another histidine synthesis. These compounds condense in the presence of triethylamine and sodium niethoxido with the forination of niethyl a-lenzainido-2,4-di1~lel.capto-5-i1~iidazoleac1~late, which is couverted into S-benzoyl-uL-lristicliiic inethyl ester by treatment with Raney nickel. The latter rompound sffor& DL-histidine when hydrolyzed with hydrochloric acid (97). See equation (1) , pngc 199.

Two procedures are available for the resolution of DL-histidine, namely, fractional crystallization of its salts with D-tartaric acid (55,98) , and selective hydrolysis of DL-histidineamidc with an enzyme from hog kidney (99). This kidney ensyiiic has tlrc :tt)ility to hydrolyze L-histidineamide into L-histidine and ammonia, while D-histidineamide remains unattacked. Following the enzymatic hydrolysis, the L-histidine is separated froni the D-liistidineamide by suitable manipulations. (f) Physical and Chemical Properties

Free L-histidine crystallizes fyoin water in lustrous, pnrallel-sided. brittle plates which frequently foim rosettes ; the crystals w e ~.nliydrous. deeply striated, and have irregular eiids. The crystrzls ~vhirlisepmzte

Chemistry of Classes and Derivatives

198

T A B U XXV. Optical Rotations and Melting Points of Histidine and Some of Its Salts

.......................

DL-Hktidine 283-285 Monohydrochloride .............. 157 dihydrate ..... . ... . .... .. 117-1 19 Dihydrochloride . . . . . .... 235-238 Monopicrate (lH10) ... . .. . . 180-181 Dipicrate (2EO) . ... ... 105 *Histidine .......... ..... 237-288

.. ... ... .. . . . ... . . .........

.........

.............. 2!56 ............... 234 ....... ............... 287-288

Monohydrochloride D-Hydrogentartrate d3istidine' .

Monohy+rochloride

....

...........

254

251-252

Dihydrochloride ...... ... 172-1 73 *Hydrogentartrate L-Hydrogentartrate ,..... .. . ... . . 233-234 Bis-m-bromopicrolonate .. . . . . . . .- 216-218 2-Dibeneofuransulfonate , . . . .. . 240-241 Bis3,4dichlorobeneenesulfonatc: . . 281 Diliturate Monoflavianate .. . . . .. . . . . . . . .. . . 212-214 224-236 Diflavianata .... . . . . .. .. . . . .. . . 251-254 241-24'2 237-238 Mononasylate ... . . . . . . . . . .. . . .. . 206-207 Dinasylate .......... . ... . . . . .. . . 265 Nitranilate . .... .... .. Bis-(Znitro-1,3-indandionate) ... 269 Monopicrolonate ................. 232

.

[a]hin w a t e

M.u.. *C.

Compound

.. ..

..

Ref.

+393 (23)

+40.15 -t 0.88 (20) +398 (23)

-+39.6(25) 8.14 (20)'

+I33 (28) -38.1 (26) -40.70 (21) -39.65 (20) -3880 st 0.07E(25) -38.95 -C 0.06" (25) -39.7 (25) + 8.06 (2Olb 8.0(26Ib +13.6 (27) 7.61 (20) +188 (24) -12.1 (25)

+ +

..

.........

.. -

.

227-229

-

Dipicrolonate ... .. . ... .. . .... . ... Reineckate (4H10) ... ..... .. .... 218-!222 Dirufianate ... ...... .. .... 305 DisozoidolateZ .. .. . . . .. .. . .. . . . . 2 0 7 m

......

.

---

'The figures in pawnthesea represent the temperature t at which the measure-

ments are bken. 'Represett meaaurementa in water containing three equivelenta of hydrocfiloric acid. [a19 5893 A. 'Soeoidolic acid is diiodophenol-d sulfonic acid. Reference (63) should be consu!ted for detailed information on the optical properties and solubility of thAidme.

1W

VI. Imidamlecarbo?rylicand Siilfonic Acids

+

6-H

I C-H

EtO-C-€I

II

when ethanol is added to a concentrated aqueous solution of histidine are small, well-developed, rectangular plates (100). The specific rotations and melting points of L-and D-histidine and of some df their derivatives are shown in Table XXV. The melting points of DL-histidine and some of its salts are also included in the table. L-Histidine is soluble in water to the extent of 4.286 k 0.013 g. per 100 g. a t 25.10 -+- 0.05” (63). It possesses two basic centers-the primary amino group and the pyridine nitrogen of the imidazole ring, and two acidic functions-the carboxyl group and the pyrrole nitrogen on the irnidazole ring. -4s a consequence, it has the ability to form monoand dibasic salts with acids. The melting points of a number of its characteristic salts are given in Table XXV. Histidine exhibits three measurable dissociation constants (see Table SSVI), designated as pKI, pK2, and pKs, which have been assigned to the csrboxyI group, the

TABLE XXVI. Dissociation Constants of Histidinc and Some of Its Derivatives Compound

PKi

PK9

pKa

1.66 169 1.65

6.01 6.13 4.18 2.72

9.17 928 8.62 8.18 885

7.08

9.53

...................... 2(or rl)-Iodo-chistidine ......... 2,&Diiodo-~-hstidine........... LHistidine

N-Methylhistidine .............. 1.69 Carnosine ....................... 2.63 Anserine ........................ 2.66

6.48 6.88

9.54

PKI

Ref.

-

(122) ( 123) ( 124)

-

12.4 9.76

-

-

(124) (123) ( 123)

(123)

Chmiistry of Classes and Derivatives

200

imidazole portioii, and the primary amino group, respectively. Histidine has the ability to combine with cobalt to form a complex which combines reversibly with oxygen (125,126). The chemical helinvior of histidine is that expected of a compound cinbodying within its molecule an imidazole ring and a n =-amino acid grouping. It, exhibits a positive Knoop and Pauly test (imidazole portion), and a positive ninhydrin reaction (a-amino acid grouping). L-Histidine is raceinizcd by drnstic treatment with acids and, especially. alkalis; and, as a carboxylic acid, has the ability to form esters. The methyl cstcr dihydrochloridc forms when histidine is exposed t o methanolic hydrogen diloride (60,127). The free ester is obtained from the dihydrocliloricle with two equivalents of sodium methoxide in methanol. This ester, which ~ c r v c sas an important intermediate in thc synthesis of histidine peptitles (128-131), is readily converted into L-histidine anhydride (3,6-his-[4 (or 5 )-i1nidazolcmethyl]-2,5-piperaaincdione)by heating a t 100" (132,133) or, preferably, by exposing its solution in methanol to a temperature of 37" for tieveral days (134,135). Cold, dilute sodium hydroxide opens the diketopiperazinc ring of L-hietidine anhydride with the formation of a histidylhistidinc of undetermined stereo strurturc H

H CHI \/ C

MeOOC'

+

'NH,

N

4 YHz A

__t

o=@qH

HN'

' d HxNYcoo*e /\ / \ I

H

H i

H I

I

3

'C=O

I H Histidineanhydride

-

H CHI

O=C'

N

\/

1

HN,

C

'NH, ,COOH

C /\

I

H

Histidylhistidine

(132,135). The amides of L- and DL-histidine are readily prepared froin the respective methyl esters with nietltanolic ammonia (99,136). Acylating reagentas react readily with L-histidine, and essentially three types of reactions arc obscrved. These are: ( a ) acylation of the primary amino group, with forination of :in opticttlly active N-acyl derivative; ( b ) acylation of tlic primary amino group. t80give an optically

VI. Imidazolecarboxylicmid Sulfonic Acids

201

inactive (racemized) N-aoyl derivative; and (c) formation of a diacyl derivative having acyl groups attached to both the primary amino group and the imidazole nucleus. Examples of the first reaction are the formation of optically active :V-acctyl-L-histidine from L-histidine with one equivalent of acetic anhydride in glacial acetic acid (101), .and the formation of such acyl derivatives as N-benzoyl- (107,137,138), N-p-nitrobenzoyl- ( 133), and N-carbobenzoxy-Lhistidine (139) from the amino acid and the respective acyl chloride in dilute aqueous alkali. Slightly modified aoylating conditions bring about N-acylation and complete racemization of L-histidine. A racemized N-acetyl-DL-histidine reaults when L-histidine is treated with two or more equivalents of acetic anhydride in glacial acetic acid a t 100' (101), or when the amino acid is acetylated with acetic anhydride in pyridine (140). Treatment with ketene also brings about acetylation and racemization of L-histidine (140). Particularly striking is the complete racemization of the amino acid in the course of its acetylation by acetic anhydride in dilute aqueous sodium hydroxide (98). The forniation of N,l (or 3)-bis- (2-naphthylsulfony1)histidine froin the aiiiino acid and the sulfonyl chloride in dilute sodium hydroxide exemplifies the formation of a diacyl derivative of histidine (50). Under the ordinary conditions of the Schotten-Bauniann acylation procedure, introduction of a benzoyl group into the imidazole portion of histidine derivatives possessing 8 free carboxyl group is not possible. -V-Benzoylhistidine, for example, cannot be further benzoylated (107). A different behavior is observed with the methyl esters of N-acylliistidines. Here a second acyl group is readily introduced into the iinidaeole ring when one tnole-equivalent of the ester is treated with half H inole-equivalent of an acyl chloride in anhydrous benzene. N,1 (or 3 ) Dibenzoylhietidine methyl ester (107) and N-beneoyl-1 (or 3)-hippuiylhistidine methyl ester (141) are readily obtainable in this manner. The observation that these coinpounds fail t o exhibit a positive Pauly reaction points to the imidasole ring 8s the location of the second acyl group. It is of interest to note that the N,1 (or 3)-diacylhistidine methyl esters can serve as acplating agents for ainino acids. X-Benzoyl-1 (or 3)hippurylhistidine methyl ester, for example, reacts in aqueous solution with sodium glycinate, to give benzoyldiglycine, with the regeneration of N-benzoylhistidine methyl ester (141). L-Histidine methyl ester displays a behavior markedly different from that of L-histidine toward benzoyl cliloride and alkali. The ester reacts with Ilenzoyl chloride and aodiuiii carbonate to give ~-2,4,5-tribenzamido-

202

Chemistry of C l a w and Derivatives

4-pentenoate, a n important intermediate for the preparation of 2-mercapto-L-histidine and ergothioneine (142,143) (see Chapter 111, Section A-3-d (7) )

.

-

110

0

CH*

OH-

I I H

C - N - C a I CHt

MeOOC-C-N-C

MleOOC-C-NHr

I I I1 H H O

The trnilide of 4(or 5 )-i~~iiduzole~~ropiox~ic acid is altio clelrved by benzoyl chloride and alkali, with the formation of the anilide of 4,5dibenzamido-4-pentenoic acid, whereas 4 (or 5 ) -imida%olepropionic acid and ethyl a-chloro-4 (or 5)-imidazolepropionate are refractory to this treatment (144,145) (see Chapter 11, Section B-2). A mixture of l ( o r 3)-benzyl-~-llistidine (57V 1 and N,l(or 3 ) dibenzyl-L-histidine (8% ) is obtttiiied wliexi L-liistidine hydrochloride is ditiiuolved in liquid uliimonia and t lie solution treated witti 4 equivalents of sodium followed by 1.1 equivalents of beiizyl cliloricle. The finding that the imino group reacts in preference to the primary axuino group is a reflection of its higher acidity. The 1(or 3)-benzyt-~-liistidine serves HC an int>ermediatein the synthesis of N-tzlkylhistidines, sincc its substituent prcventa alkylation of the imiclazole ring and is readily rcxnovablc hy reduction with sodiuin in liquid ammonia (146).

H I

HfkH

&,, ( - p * - C I liquid Nits

CHi I HIN-C-COOH

I H

CHi

I

* CHI H&--C-COOH I

I

H (57%)

+

H<,y

CHI I OC€f,-Ii4--F--COOH

H H

(8%)

L-liistidiiic iii 0 3 S uqucous sodium l~icarbonutereacts with nxi c’xof n-butyl 2-cliloroetliyl sulfide to give a coinpound believed to possess the structure illustrated (147). cess

VI. Imidaeolecarboxylic and Sulfonic Acids

203

L-Histidine and a number of its derivatives are readily iodinated in dilute sodium hydroxide solution to give well-defined 2,4-diiodo derivatives. Examples are 2,4-diiodo-~-histidine (124), 2,4-diiodo-N-bemoylL-histidine ( 138), and 2,4-diiodo-N-p-nitrobenroyl-~-histidine (138). I.Histidine anhydride accepts four atoms of iodine to give a tetraiodo derivative ( 138). Iodination with one equivalent of iodine converts L-histidine into 2(or 4) -monoiodo-L-histidine (124). The introduction of iodine brings about a marked shift toward the acid side in the imidaeole dissociation (pKt) of histidine (see Table XXVI). ( 8 ) Structural Analogues

An optically active 1-methyl-Z(-) -histidine, presumably possessing t.he same configuration as L-histidine, occurs in the tissues of many animals in the form of the dipeptide /3-alanyl-Z(-) -1-methylhistidine (anserine) .* The most abundant source of anserine appears to be the tissues of domestic fowl, but the compound is also present in tissues of various ot.her birds, reptiles, fish, and mammals. Hydrolysis with barium hydroxide cleaves anserine into /3-alanine and 1-methyl-DL-histidine, while I-Methylhistidine

HaN -CH~-C€I~-C--N-~-C00H

888

Anaerine

A-

HrN-6

COOH

f

HiN-CHr- CHI-COOH &Ahnine

acid hydrolysis affords p a l a n h e and 1-methyl-Z(-) -histidine (148,149). The position of the methyl group in the 1-methylhistidine follows from

*For a comprehensive review on ansethe, we reference

(64).

Chemistry of Classes and Derivatives

204

convcrsioii of anserine into I ,5-diinethylimidazolc on distillation witoh soda-lime (148,150,151).

?H*

H~N-cH~-c-HN-~-

I

H

0 "

CHt

COOH

1-Methyl-m-histidine is synthesizable by methods akin to those employed for the preparation of DL-histidine. One synthesis employs 1methyl-5-imidazolecarboxaldehyde as the starting material (152). The aldehyde is condensed with 2-thio-3-acetylhydantointo give 5- (l-methyl5-imidazolemethylene)-2-thiohydantoin, which is converted into 1methyl-DL-histidine by treatment with hydrogen iodide and red phosphorus. The synthetic compound is identical with the 1-methyl-DLhistidine derived from anserine by barium hydroxide hydrolysis. 1-Methyl-5-chloromethylimidazolium chloride serves as the starting material for the synthesis of 1-methyl-DL-histidine via the acetamidomalonate route (see Section (e) ) . Starting with an appropriately substituted chloromethylimidazolium chloride this method is applicable to the synthesis of such 1-substituted DL-histidines as 1-isopropyl-, 1-phenyl-, 1-cyclohexyl-, and 1-benzyl-DL-histidine (14). ~~-~-Amino-2-imidazolepropionic acid, a position isomer of DL-histidine is prepared in the ma&; illustrated (4).

+

CI-

+

N-Methyl-m-histidine is obtained from methylamine and DL-a-

VI. Imidazolecarboxylic slid Sulfonic Acids

205

chloro-4 (or 5 ) -imidasolepropionic acid (resulting from tlie deainination of L-histidine with nitrite in concentrated hydrochloric acid) (1.53). An optically-active N-methyl-L-histidine ensues when .V-phenylsulfonyl-1 (or 3)-benzyl-L-histidine is methylated with methyl iodide, and the phenylsulfonyl and benzyl groups of the methylated compound are removed by reduction wit-li sodiuin in liquid ammonia (146). 2-Mercapto-~-histidinc! is an important intermediate for the synthesis of ergothioneine. Its prepamtion from L-histidine is discussed in Chapter 111, Section A-3-d- (7). A 2-inercapto-~-histidine-2-C~~ is obtained by this route if sodium C14-thiocyanate is used instead of potassium thiocyanate. The labeled 2-mercapto-~-histidine serves as an intermediate in the prepamtion of L-histidine-2-W (154). Two procedures for the preparation of 2-mercapto-~~.-histidine have been described (145,155). Oxidative desulfurization with ferric sulfate converts 2mercapto-L-histidine into L-histidine. Hercynine (histidine betaine, N-trimethylhistidine) occurs in the mushrooms Agavatus campestris and Boletus edulis (ref. (53), p. 243). It is obtained from ergobhioneine by oxidative desulfurizat.ion with ferric chloride (156).

Fe+++

____c

HaC CHI I I &C-% -C-COOHa& Ergothioneine

HsC CHI I I H~C--+N-C-COO-

&A

iI

Hereynine

A rather interesting constituent of the liver of the shark Ascanthias vulgaris is the compound L-spinacin, which may be synthesized by treatment of L-histidine with formaldehyde in concentrated hydrochloric acid solution (157). H

Spinach

Chemistry of Clasea and Derivatives

206

B. Imidazolesulfonic Acids 1. Structural Considerations

Representatives of the three possiblc position-isomeric irnidazolesulfonic acids, 1-imidazole-, 2-imidazole-, and 4 (or 5 ) imidazolesulfonic acid, are known. Altliougli pertinent information on the acid-base behavior of these substances is lacking, tliey are probably best regarded as zwitter-ions.

-

H

H SSulfonic acid

ldulfonic acid

2.

4(or 5)-Sulfonicmid

1-Imidazoleaulfonic Acid8

4 (or 5 )-Yhenylimidazole reacts with pyridinium-N-sulfonic acid to give the sparingly soluble 4(or 5 ) -plienyl-1-iiiiidazolesulfonic acid as a high-melting, crystalline solid (lii),which foimis a water-soluble potassium salt. Thc coiiipound fails to couple with diazot.ized aromatic amines, and is hydrolyzed by dilute iiiincritl acids with formation of the respective iniidazole and sulfuric acid. 3.

2-lmldazolesulfonic Acids

The oxidation of 2 ( 3 H ) -iiiiidazolethiones with hydrogen peroxide or ulkalinc periiianganate providcs ti convenient route to 2-imidazolcsulwid, 4(or 5 ) -methyl-2-hidfonic ibcida (158-161 ) . 2-I~iiidr~zolcsulfonic azolesulfonic acid, and 4,5-diplrciiyl-2-itnidaeolesulfonicacid have been H

H

prepared in this manner. These 2-imidazolesulfonic acids exhibit a high degree of stability toward acid hydrolysis, exceeding that of the corresponding 4 (or 5 ) -imidazolesulionic acids. Exposure to the action of hydrochloric acid (at 170" for three hours) resu1t.s in a 12 per cent liydrolysis of 2-iinidaeolesulfonic acid; 4 (or 5 )-imidazolesulfonic acid under these condition8 is coiiipletely hydrolyzed (162). This pronounced

I

m

VI. Imidazolecarbxylic and Sulfonic Acids

dsbility toward acids eliminates the possibility of the 2-imidazolesulfonic acids as intermediates in the oxidative desulfurization of the 2 ( 3 H )-imidazolethiones (see Chapter 111, Section A-3-d- (4) ) . 4.

4(or 5)-Imidazolesulfonic Acids

Direct sulfonation of imidazole with 50 to 60 per cent oleum at

160" results in the formation of 4(or 5)-imidazolesulfonic acid. A small

quantity of a disulfonic acid, possibly 4,5-imidazolediF;ulfonic acid, is also formed. The nonidentity of the monosulfonio acid with 2-imidazolesulfonic acid establishes the position of the sulfonic acid group (162,163). 4(or 5)-Methylimidazole, 4(0r 5)-bromoimidazole, and 2-methyI-4(or 5)-

H

H

H

bromoimidasole undergo sulfonation, the sulfo group entering the 4(or 5 ) position in all instances (162,164-1 66). On drastic sulfonation, 2methylimidazole is converted into a mixture of 2-methyl-4 (or 5)-imidaeolesulfonic acid (80%) and 2-methyl-4,5-imidazoledisulfonic acid (20%) (164). These examples, although limited in number, demonstrate that imidazoles( possibly as the imidazolium ions) are sulfonated solely in the 4(0r 5)-position. A possible explanation for the substitution by electrophilic reagents a t the 4(or 5)-position of the imidazoles is presented in Chapter V, Section A-1. The 4(or 5)-imidazolesulfonic acids are high-melting solids which are insoluble in most organic solvents but soluble in water. They form salts with cations, and may be liberated from their barium salts by the addition of the calculated quantity of sulfuric acid. 4(or 5 )-Imidazolesulfonic acid is hydrolyzed to imidazole and sulfuric acid when exposed to the action of concentrated hydrochloric acid at 170'. The sulfo group resists esterification on refluxing with ethanolic hydrogen chloride or on treating the sodium salt with methyl iodide. Sulfonyl chlorides cannot be obtained by treatment with phosphorus pentachloride. Bibliography

1. John, W.,Ber. 68, 2283 (1935). 2. Oddo, B.. and Mingoia, Q.,Gnaz. claim. ital. 69, 553 (1928). 3. Oddo, B.,and Mingoia, Q.,&id. 68, 584 (1928). 4. Jones, R. G., J . Am. C b n . SOC.71, 383 (1949).

Chemistry of Claases and Derivatives

208

5:Kpoop, F., Beitr. Chem. P h y k l . Path. 10, 111 (1901). 6. Windaus, A., and Ullricli, A., 2. plil/.uiol. Chem. % .I 366 (1914). 7. Pyman, F. L., J . Chem. SOC.109, 186 (1916). 8. Hubball, W., and Pyman, F. L., ibid. 131, 21 (1928). 9. Weidenhagen, R. and Wegner, H., Ber. 70, 2309 (1937). 10. Fargher, R. C., and Pyman, F. L., J . Chem. SOC.116, 217 (1919). 11. Jones, R. G., J. Am. Chem. SOC.71, 644 (1949) 12. Balaban, I. E.,J. Chem. SOC.1938, 2423. 13. Balaban, I. E., a i d . 1930, 268. 14. Jones, R. G., and McLaughlin, K. C., J. Am. Cltetn. SOC.7 1 , 2444 (1949). 15. Weidcnhagen, R., Herrmann, R., and Wegner, H.,Ber. 70, 570 (1937). 16. Cowgill, R. W.,and Clark, W. M., J. Bwl. Ckem. 198, 33 (1952). 17. Maquenne, M., Ann. chim. phys. $4, 622 (1891). 18. Dedichen, G., Ber. 39, 1831 (1906). 19. Pauly, H., and Gundermnnn, K., ibid. 41, 3999 (1908). 20. Organic Syntheses, Vol. 22, John Wiley and Sons, Inc., New York, 1942, p. 65. 21. Lehmstedt, K., Ber. 58, 1219 (1925). 22. Tamamushi, Y., J . PImrm. Soc. Japan 48, 851 (1928); Chcm. Abstracts 93, 1639. 23. Pauly, H., and Ludwig, E., 2. phy.riol. Chcm. 181, 165 (1922). 24. Tamamushi, Y., J . Pharm. SOC.Japan 48, 863 (1928); Chem. Abstracts B,1472. 25. Baxter, R. A., and Spring, F. S., J . Chem. SOC.1946, 232. 26. Tamamushi, Y., J. P h a m . SOC.Japan 63, 680 (1933); Chem. Abstructs rd8, 150. '27. Tamamushi, I-., J . Pharni. SOC.Japan 66, 1053 (1935); Chem. Abstrmk 31, 6654. 28. Tnmamushi, Y., J. Phann. SOC.J ~ p a 67, t ~ 1023 (1937); Chem. Abstrach 32, 3394. 29. Tamamushi, Y., J . Pliamn. SOC.Japan 68, 1 (1938); Chem. Abstracts 38, 3394. 30. Stetten, M. R., and Fox, C. L., Jr., J . Bwl. Chem. 161, 333 (1945). 31. Shive, W., Ackermann, W. W., Gordon, M., Getzendaner, M. E., and Eakin, R. E., J. Am. Chem. SOC.69, 725 (1947). 32. Schulmann, M. P.,Rriclianan. J. M., and Miller, C. S., FCdGtnlw?L Proc. 9, 226 (1950).

33. Windaus. A., and Langenbeck, W., Ber. 66, 083 (1923). 34. Shaw, E., and Woolley, D. W., J . BWZ. Chcm. 181, 89 (1949). 35. Cook, A. H.,Heilbron, I., and Smith, E., 1. Chem. SOC.1949, 1440. 36. [Jar&, J., and Wegmann, E.,Helv. Chim. Acta 7, 713 (1924). 37. Mann, F. G., and Porter, J. W. G., J. Chsm. SOC.1946, 751. 38. Cook, A. H.,Downer, J. D., and Heilbron, I., ibid. 1948, ao28. 39. Cook, A. H.,Davis, A. C., Heilbron, I. and Thomas, G. H.,ibid. 2949, 1071. 40. Cook,A. H., and Smith, E., ibid. 1949, 2329. 41. Ahbrook, W.E.,Gulland, J. M.,and Story, L. F., ibid. 19.49, 232. 42. Cook, A. H., Downer, J. D., and Heilbron, I., &id. 1949, 1089. 43. Baxter, R. A., and Spring, F. S., dbid. 1947, 378. 44. Baxter, R. A., McLean, A. C., and Spring, F. S., ibid. 19.48, 523. 45. Howard, G. A., McLean, A. C., Newbold, G. T., Spring, F. S., nnd Todd, A. R., ibid. 1949,232. 46. Kossel, A., 2.physiot. Ckem. 22, 176 (1896). 47. Hedin,S. G., ibid. 92, 191 (1896). 48. Tristram, G. R., in Advances in Prot& Chcwktry, Academic Press, Inc., New York, 1949, Vol. V, p. 83.

VI. ImidamIecarboxyiic and Sdfonic Acids

200

49. Iiosa~l.A. and Dtlkin, H. D., Z. phy&Z. Chem. 40, 566 (1W). 50. Pauly, H.. i 6 d $3, 508 (1904). 51. Knoop, F., and Windaus. A., Beitr. Cltem. P h u h l . Path. 7, 144 (1904). 52. Frilnkel, 8,Monatsh. 94,229 (1903). 53. Guggenheim, M., Die biopenen Amine, Fourth Edition, Verlag von Kmger, Basel, 1951; Interscience Publishers, Inc., New York; p. 409. 54. du Vigneaud, V., and Behrens, 0. K., Erg. Physiol. 41, 917 (1939). 55. Pyman, F. L., J . Chem. SOC.99, 1386 (1911). 56. Laugenbeck, W.,Ber. 6S, 227 (1925).

57. Hanke, M.T.,and Koessler, K. EL., J. BioZ. Chem. .bs, 621 (1920). E., Fleischmann, R., and Eon, W., Fementforschwlq 10, 446 ( 1929). 59. Vickery, H. B., and Leavenworth, C. S., J . Bwl. Chem. 78, 627 (1928). 60. Organic Swheses, COIL Vol. 11, John Wiley and Sons, Inc., New York, 1943,

68. .4bderhalden,

p. 830.

61. Vickery, H.B.,J . BWZ. Chem. 1@,77 (1943). 62. Him, C.H.W.,Moore, S., and Stein, W. H.,ibid. 196, 669 (1952). 63. Dunn, M. S.,Frieden, E. H.,Stoddard, M. P., and Brown, H.V., &id. I&, 487 (1942). 64. Kossel, A., and Kutscher, F., 2. physiol. Chem. 31, 165 (1900).

65. Kossel, A., and Patten, A. J., ibid. 38, 39 (1903). 68. Kossel, A., and Edlbacher, S., ibid. 110, 241 (1920). 67. Vickery, H.B.. and Leavenworth, C. S., J. BWZ. C h m . 68, 225 (1926). 68. Vickery, H.B., and Leavenworth, C. S.,&kZ. 76, 707 (1928). 69. Dunn, M.S.,Camien, M. N., Shankman, S.,and Rockland, L.B.,&id. 269, 663 ( 1945). 70. Kossel, A., and Groas, R. E., 2.physiol. Chem. 136, 167 (1924). 71. Vickery, H.B.,J. Biol. Chem. 71, 303 (1927). 72. Vickery, H. B., and Winternits, J. K., dbid. 166, 211 (1944). 73. Block, R.J., Ptoc. SOC.Exptt. Bwl. Med. flJ580 (1937). 74. Block, R. J., J . Biol. Chern. 133, 67 (1940). 75. Doherty, D.G., Stein, W. H.,and Bergmann, M.,&id. 136, 487 (1940). 76. Inouye, K.,Z.physiol. Chem. 83, 79 (1913). 77. Brunswik, H.,W .ffl, 268 (1923). 78. Hanke. M. T.,and Koeasler, K. K., J. BioZ. Chem. 49, 527 (1920). 79. Hanke, M.T.,&id. 66,475 (1925). 80. Hanke, M. T.,&id. 66, 489 (1925). 81. Lang, K.,2.physiol. Chem. B9,3 (1933). 82. Albanese, A. A., J. B i d . Chem. 134, 467 (1940). 83. MacPhenon, H.T.,Bwchem. J . 40, 470 (1946). 84. Jorpes, E., itrid. B,1507 (1932). 85. MacPherson, H. T., ibid. 96,59 (1942). 86. Lyman, C. M., Kuiken, K. A., and Hale, F.,1. Biol. Chem. 171, M3 (1947). 87. Koessler, K.K., and Hanke, M. T.,ibid. 39,497 (1919). 88. Knoop, F.,Beilr. Chem. Physiol. Path. 11, 396 (1908). 89. Kapeller-Adler, R., Bdochem. 2.B4, 131 (1933). 90. Block, R. J., J. BWE. Chem. 106, 457 (1934). 91. Csonka, F.A., &id. 109, 703 (1935).

210

Chemistry of Classes and Derivatives

92. Stokes, J. L., Gunnes, M., Dwyer, I. M., and Camell, M. C., &id. 160, I ( 1945). 93. Dunn, M. S., Shankman, S., and Catmien, M. N., ibid. 161, 669 (1945). 94. Albertson, N. F.,and Archer, S., J. Am. Chem. SOC.67,308 (1945). 95. hlbertaon, N.F.,and Tullar, B. F., ibid. 67, 502 (1945). 06. Deulofeu, V., and Mitta, A. E. A., J . Org. Chem. 14, 915 (1949). 97. Davis, A. C.,and Levy, A. L., J. Chem. SOC.1949, 2179. 98. du Vigneaud, V., and Hunt, M., J . B i d . Chmir. 116, 93 (1936). 99. Levintow, I,., Price, V. E., and Greenstein, J. P., ibitf. f&, 55 (1950). 100. Vickcry, H.B., and Lciivcnworth, C. S., ibid. 76, 701 (1928). 101. k!rgnann, M., and Zervas. L.,bluJchwtr. Z . 9U3, 280 (1928). 102. Ahilt*rhaIdcn, E.,and Weil, A.. %. physwl. Chcm. 77,435 (1912). 103. Viekory 8.B.,J. B i d . Chcm. I@, 77 (1042). 104. Cos, C.J., :tnd Berg, C. P., ibitf. 107, 497 (1934). 105. IGMcI, X., snd Muthcws, A., Z . phyniol. Cheat. 96, lY0 (1898). IM..ll)ili*rii:tldm, E., and Einbcc-k, H.. ibitl. ri?. 322 ( I!HJ!b). 107. Gcrngross, O., ibitl. 108, 50 (1919). 108. Ashley, J. N.,and Harington, C.R.. J . Chcnr. Soc.. I!Mf), 2586. 109. Smordinzew, I. A., Biochem. 2.922, 425 (1930). 110. Kiipfliniuincr, J., and Sporer, H.,%. physiol. Chwtc. 173, 245 (1928). 111. Ziniiiirriiiann, W.,and Cuthbertson, D. P., ibid. 206, 38 (1932). 112. Imscn, J., Witt, N. F., m d POC,C. Y., .Vlikroc.h~~rt&Xj, 1 (1948). 113. \Vc!ndlitnd, R.T.,m i l Smith, C. H., Pm:.N. I)nkolrt . 4 d . Sci. 5, 31 (1949). 114. Ac.kcrmun, D.,%. phyYiul. Chns.255, 46 (1934). 115. Rcdcmann, C. E.,and Niemann, C.,J. Am. Chem. SOC.62,590 (1940). 116. Langley, W.D.,and Albrecht, A. J., J. Bwl. Chem. 108,720 (1935). 117. Bergmann, M.,and Stein, W. H., ibid. lZ9, 609 (1939). 118. Dunn, R.,Inouye, I<., and Kirk, P. I,.. Mikrochemic 2 i , 154 (1939). 119. Zimnicrmunn, W.,Z.physiol. Chcm. lW, 180 (1930). 120. Brig], P.,ibid. 64, 337 (1910). 121. Ewinu, A. J., and Pyman, F. J,., J . Chent. Soc. g.9, 339 (1911). 122. Levy, M., J. Biol. Chcm. if)!), 361 (1935). 123. Dcutsch, A., and Eggleton, l’., Buiehem. J . S2, 209 (1938). 124. Rrunings, K.J., J. Am. Chsm. &JC. 69,205 (1N7). 125. Michaelis, I,., Arch. Bwchcm. 24, 17 (1917). 126. Burk, D., Hc:iron, J., Ctirolinr. T,., :ml Srlinili~.A . I. .. J . RirJ. ( ’ l i t ni. 166, 723 ( 1946). 127. Pischer, E.,and Conc, I,. H., Awc. 3G3, 107 (1908). 128. S i e r t , R. H.,and du Vigncuud, V., J . B i d . Chewa. 108, 753 (1935). 129. Hunt, M.,and du Vigneaud, V., ihitl. 124, 699 (1938). 130. du Vigneaud, V., and Hunt, M., ibid. 126,269 (1938). 131. Hunt, M.,and du Vigncaud, V., &id. 127” 43 (1939). 132. Fischer, E.,and Susucki, U..Ber. &S, 4173 (1905). 133. Pauly, H.,2. physsiol. Chon. G4, 75 (1910). 134. Abderhalden, E.,and Geidel, W., FermenlJorschung 18, 518 ( 19311. 135. Abderhalden, E., irnd Leincrt, F., ibid. 16, 324 (1937). 136. Zeile, I<.. and Pititli, P., 2.phyGol. Clwttt. 31S, 52 (1B3). 137. Friinkel, S.,Beilr. Chcwt. Phl/sioZ. I’olh. 8. 156 (1909).

VI. Imidazoleenrboxylic and Sulfonic Acids

21 1

Puuly. H., Ber. 43, 2243 (1910). Bcigmann, M., and Zervas, L.. ibid. 66, 1192 (1932). Ncuberger, A., Biochem. J . 3.9, 1452 (1938). 13crgmann, M., and Zervas, L., 2 physwl. Chem. 176, 145 (1928). Kosucl, A., and Edlbachcr, S., &id. 93, 398 (1915). Tessr, C., and Rittenberg, D., J . Biol. Chem. 170, 35 (1947). Windam, A,, Ber. 4.3, 499 (1910). Harington, C. R., and Ovcrhoff, J., Biochem. J. 97,338 (1933). du Vigneaud, V., and Behrenu, 0.K., J . Bwl. Chem. 117, !27 (1937). du Vigneaud, V., Stevens, C. M.,McDuffie, H. F., Jr., Wood, J. L., and McKennis, H.,Jr., J . Am. Chem. SOC.70, 1620 (INS). 148. Linnewch, W., Keil, A. W., and Hoppe-Seyler, F. A., 2. physiol. Chenr. 1S3. 11 ( 1929). 149. Linneweh, W., and Linneweh, F., ibid. 189, 80 (1930). 150. Keil, A. W., &id. 187, 1 (1930). 151. Pymnn, F. L., J. Chem. SOC.1980, 183. 152. Sakami, W., and Wilson, D. W., 1. Biol. Chem. 164, 223 (1944). 163. Fnrgher, R. G., and Pyman, F. L., J. Chem. SOC.119, 734 61921). 154. 13orsook. H., Deasy, C. L., Hsagen-Smit, A. J., Keighley, G., and Lowy, P. H.. J. Biol. Chem. 187, 839 (1950). 155. Dey, A. N., J. Chem. SOC.1937, 1166. 156. Barger, G., and Ewim, A. J., ibid. 99, 2336 (1911). 157. Ackermann, D., and Skraup, S., 2. physiol. Chem. 984, 129 (1919). 158. Anschiite, R., and Schwickerat, K., Ann. f84, 9 (1895). 159. B i b , W.,and Krebs, P., ibid. 391, 191 (1912). 160. Lamb,I. D., and Pynian, F. L., J . Chem. SOC.226, 706 (1924). 161. Balaban, I. E., and King, H., &id. 1927, 1858. 162. Barnes, G. R., and Pyman, F. L., ibid. 1.90, 2711 (1927). 163. Pymrtn. F. L., and Ravald, L. A., ibid. 117, 1429 (1920). 164. Light, L., and Pyman,F. L., ibid. 191, 2626 (19n). 165. Forsyth, R., Moore, J. A., and Pyman, F. L., ibid. 226. 919 (1924). 166. Balaban, I. E,, and Pymnn, F. I,., &id. 191, 947 (1922). 138. 139. 140. 141. 142. 143. 144. 145. 146. 147.

This Page Intentionally Left Blank

CHAPTER 1’11

The Imidazolines, 2=Imidazolidones,2-Imidazolidinethiones, 2-Iminoimidazolidines, and Imidazolidines A. Nomenclature

-

The degree of saturation of an aeole is designated by changing the eliding ole into oline and olirline for its dihydro and tetrahydro derivatives, respectively. This system applies to the di- and the tetrahydroimidaeoles which arc designated as imidaeolines,and imidaeolidines. Theory predicts the existence of three isomeric imidizolines, namely, the 2-iniidszolines (4,5-dihydroirniduzoles),the 3-imidaeolines (2,5-dihydroimidrtzoles), and the 4-imidneolines ~1,2-dihydroimidaeoles). H&-Y-H

I

H,C-R

cH

Nmidawline

HC’N 3-Imidazoline

4-Imida wline

Representatives of all three classes of imidazolines have been described. With the exception of the imidaeolidones, which can be prepared by hydrogenation of the imidaeolones, the hydrogenated imidneoles must be prepared by special synthetic methods.

B. 2-Irnidazolines

1. Synthetic Methods

This section deals with the preparation of 2-substituted 2-imidazolines and their substitution products. (The 2-unsubstituted 2-imidaeolines have received only scant mention in the literature.) The discovery of the 2-substituted 2-imidaeolines or “anhydrobases of the aliphatic series” dates back to the year 1888 when Hofmann (1) prepared 2-methyl-2imidazoline (lysidine) by heating N,N’-diacetylethylenediamine in R stream of dry hydrogen chloride. Ladenburg (21 prepai-ed the same ~0111-

2 14

Chemistry of Classes uncl Derivatives

pound by fusing two equivalents of sodium acetate with one equivalent of ethylenediamine dihydrochloride. A number of other simple 2substituted 2-imidazolines have been prepared by this same procedure (3,4). The important iiuidazoline syntheses use etliylenediaiuinc or one of its acyl or alkyl derivatives as the starting material. An excellent witli inagprocedure involves lieating of a r~r,M'-diar~letliylcne~irtiiiitle

C-0 I

R

nesiuin or sodium (5). This method is applicable to the synthesis of both 2-alkyl and 2-aryl substituted 2-imidazolines, but cannot be used for the preparation of the parent compound. The dehydration of Ninonoacylethylenediamines,either by heating alone or by heating with calcium oxide, provides nnotlicr practical routc to 2-substituted 2iniidazolines. The twiuired inoiioacylatcd ctli~lcneclirtniincs are pre-

pared in liigli yield froiii ethylenedisii~iiicand ii carboxylic: wit1 ibstcr (6-8). 2-Imidazolincs arc also obtained when u mixture of one cyuivulent oC II fatty acid and one half equivalent each of ethylcnediaminc and its diliydrochloride is heated a t 290-300O (9). The etliylencdiainiiic inay be replaced by its inono- or disubstituted alkyl-, aryl-, or srnlkyl deriwtives. More highly substituted 2-imidazolincs arc thus available vin this route. Thc foiination of 1,3-dibcnzyl-2-hc~,tudecyl-2-iiiii~azoliniui~i chloride from the interaction of N,N'-dibenzylethylenediainine and its dihydrochloride with stearic acid illustrates an application of this inetliod (see equation a t top of page 215). The reaction between N-(2-aminoisobutyl) -isopropy lamine and acetic acid to give 2,4,4-triinethyl- 1-isopropyl2-iinidazoline typifies a route to more highly substituted 2-imidazolines (equation (1), page 215). Imidazolinc formation k readily brought about by dissolving one equivalent each of the diolmine and the fatty acid in benzene and removing the water produced in tlic reaction by

VII. Imidazolines, ZImidamlidones,

+

etc.

215

A

HOOC- (CHJ 1'- CHa -C 1

azeotropic distillation. The resulting 2-imidazolines are purified by distillation. These highly substituted 2-imidasolines are frequently contaminated with higher boiling complexes composed of one equivalent of the imidazoline and one or two equivalents of the fatty acid. The complexes become the major reaction products when one equivalent of substituted diamine is reacted with three equivalents of a fatty acid under the described conditions. Alkali liberates the imidazolines from the addition compounds. The addition of two equivalents of fatty acid to one equivalent of imidszoline results in regeneration of the complexes which are insoluble in ether or petroleum ether. The fact that they exhibit rather low boiling points and contain two molecules of fatty acid per molecule of imidazoline argues against salt-like structures for these addition compounds (10).

216

Chemistry of Classes and Derivatives

Salts of ethylenediamine condense with nitriles at 220-250" to give 2-substituted 2-imidazolines (11). Sulfonates of ethylenediamine such as the bis-p-toluenesulfonate and the mono-p-toluenesulfonate are especially useful for this purpose. The initial reaction products are amidiniuni salts which undergo imidaxoline formation with the elimination of ammonium ion or ammonia. The amidinium salts are the sole products whcn salts of a N,N-dialkylethylene-

diamine are heated with a nitrile, since the alkyl substitucnts prevciit ring closure. 2-Diethylaminoetliylammonium p-toluencsulfonate, for example, reacts with phenyl cyanide to give N-(2-diethylaminoethyl) benaamidinium p-toluenesulfonate. The reaction of a dinitrile and two equivalents of ethylenediamine p-toluenesulfonate leads to the fornintion of a 2,2'-bi-2-imidazoline.

-

The methods discussed thus far require rather drastic conditions, and consequently, are not applicable to the synthesis of 2-imidazolines containing sensitive groups. The formation of 2-substituted 2-imidaaolinee from ethylenediamine and a thioamide or an imino ether hydrochloride proceeds under mild conditions and, although less direct than the previously discussed methods, provides the basis for the preparation of sensitive 2-imidazolines. The first example of the synthesis of a 2-substituted 2-imidazoline from a thioamide and ethylenediamine was described hy Forssel (12,13).

VII. Imidazoliies, %Imidazolidones, etc.

217

He prepared 2-phenyl-2-imidazoline from thiobenzamide and ethylene-

diamine. The formation of 2- (benzhydryloxymethyl)-2-imidazoline from benzhydryloxythioacetamide and ethylenediamine provides another example (14). The thioamides of dicarboxylic acids are readily, con-

+ HaNica

s

-

-

€1

I

A

vcrted into 2,2'-bi-2-itnidazoliiics when heated with an excess of ethylencdiamine or wlicn refluxed with ethylenediamine in ethanol ( 15).

The formation of 2-chloro1uethyl-2-imidazolinehydrochloride from ethylenediamine and chloroacetimino ethyl ether hydrochloride illustrates the formation of a 2-substituted 2-imidazoline from an imino ether hydrochloride. The reaction proceeds rapidly at ice-bath temperatures with excellent yields (16,17). The combination of hydroxyacetimino ethyl ether hydrochloride with ethylenediamine leads to the formation of 2hydroxymethyl-2-imidazoline hydrochloride, which is readily converted into 2-chioromethyl-2-imidazoline hydrochloride on treatment with thionyl chloride (16). 2-Chloromethyl-2-imidazolinehydrochloride is a key Hie-NHi

I

HiC-NHz

H,C-NH*

EtO, j2-CHI-CI Ha+

+

c1-

EtO,

I + $-CHl-OH HiC-NHi H a + c1-

-

-

218

Chemistry of Clssses and Derivatives

compound which serves to incorporate the 2- (2-iniidazolinemethyl) moiety into other molecules (14,18,19). In addition to the methods discussed thus far, there are a number of routes to 2-substituted 2-imidazolines which are not based on the use 6f ethylenediamine. Some of these deserve mention a t this point. For example, 2-methyl-4 (or 5 )-substituted 2-imidazolines are formed when a-acetamido nitriles are reduced over Raney nickel (20). 2-Phenyl2-imidazoline results in poor yield from the interaction of benzimino

ethyl ether and 2-bromoethylamine hydrobromide in the presence of sodium cthoxide (21). Small quantities of 2-benzyl-2-imidazoline are obtained when phenylacetamide is fused with 2-bromoethylamine hydroIwomide at 200°, or from reaction of the amide with ethylene dibromide :tnd ammonia at elevated tempcratures (22). 2-Substituted 1-aryl-2-imidazolines are not too readily available. One method of preparation involves the fusion of an N-acylallylamine with the hydrochloride of an aromatic amine. The formation of 12cliphenyl-5-methyl-2-imidazolinefrom N-benzoylallylamine and aniline hydrochloride is illustrative (23).

+ c1-

Another procedure uses N-2-chloroethylcarboxamides as starting materials. Treatment with phosphorus pentachloride converts them into the respective imino-chlorides, and these react readiiy with primary aromatic amines to give N-aryl-N’- (2-chloroethyl) -substituted amidinium chlorides which are smoothly converted into the 2-imidazolines upon exposure to alkali (24).

VII. Imidazolines, 2-Imidazolidones, etc.

219

2. General Properties and Structural Considerations

The 2-substituted 2-imidazolines are strong monoacidic bases, titratable with hydrochloric acid and not perceptibly associated in naphthalene solution (25). They are low melting, distillable solids, so1ul)le in most of the common organic aolvcnts. The lower members of the series dissolve in water to give strongly basic solutions. 2-Methyl-2-imidazoline forms complexes with salts of silver, copper, and cobalt ( 5 ) . The 2substituted 2-imidazolines forin salts with acids; the hydrochlorides, chloroplatinates, r-liloroaurates, and picrates having been most widely prepared. The hydrochlorides are hygroscopic and not well suited for characterization purposes (6,7). The picrates are the most desirable derivatives for identification. The 2-substituted 2-imidazolines react readily with phenyl isocyanate or phenyl isothiocyanate to form the respective N-phenylcarbamyl-, or N-phenylthiocarbamyl-2-imidazolines ( 6 9 6 ) . Some of the lower 2substituted 2-imidazolines, although reacting vigorously with phenyl isocyanate, fail to afford crystalline derivatives. 2-Phenyl-2-imidazoline forms L nitroso derivative upon t,reatment with nitrous acid (12). A highly characteristic property of the 2-substituted 2-imidazolines is their tendency to undergo hydrolysis with the formation of N-acylated ethylenediamines on treatment with alkalis or acids. Heating in aqueous solution is frcquently sufficient to bring about this transformation. The 2-aryl-2-imidaeolines are more resistant than the 2-alkyl-2-imidazolines

to hydrolysis. 2-Methyl-2-imidazoline, for example, is quantitatively converted into N-acetylethylenediamine when boiled with water for ten minutes. 2-Phenyl-2-imidazoline requires heating for one hour in 50 per cent ethanol for its hydrolysis into N-benzoylethylenediamine (6).

Chemistry of Classes and llerivativea

%Lo

It is generally observed that the salts of the 2-substituted 2-imidaeolines are more resistant to hydrolysis than are the free bases. Treatment in the liquid phase with nickel catalysts at temperatures of 350-400’ converts a number of 2-substituted and 1,2-disubstituted 2-imidaeolines into the corresponding imidazoles ( 8 ) (see Chapter 11, Section A-7). The 2-substituted 2-imidazolines exhibit considerably less chemical stability than the imidaeoles, possibly because they lack the “three electron-pair resonance sy&ein’’ endowing the imidazoles with “aromatic” properties. They still retain the typical amidine resonance with contributions from two non-equivalent structures, A and B. Their capavitp to add rr proton to give the 2-imidazolinium ion with tmwoexactly

H~c-N-H

I.>- .

H2C-N

-

H:c-$-H 111

,C-R

H2C-N:-

-

equivalent contributions, C and D, explains their basic character. The H z ~ - q +~H+ - ~ -* HIC-R

H aC -9-H

I.$-.

H2C-T- H

%-

+ H 2c I1 UF-K H $2- I\’- €I

I

2-i~~ii~i~ieoliniu1i~ ion, because of its highly syninietrical structure, is expected to exhibit a higher degree of chemical stability than the unchargctl molecule. Thus, the previously mentioned higher resistance toward hydrolysis of the sa1t.s of t.he 2-substituted 2-imidazolines finds a rcrrdy explanation. Exposure to a mixture of nitric and acetic ncids converts 2-methyl2-imidaeoline into 1,3-dinitr0-2-imidazolidone in poor yield. The nitrat,ion of 2-methyl-2-i1nidazolinium chloride takes a n entirely different (’oursc and affords H chlorine containing compound‘ believed to be 1,3dinit~o-2-chloroniet.liyl-2-aretoxyimida.loli~ine(27). HsC-5-H C-CH1 HzC-S

1

HKOi CH,COOH

___c

H&-q--NOz

1

c=o

H2C-k- NO,

VII. Imidazolies, 2-Imidadidonrs, et c.

221

3. AcyIation

Benzoylation according to the Schotten-Uaumann method brings about fission of the 2-imidazolines, and generally does not lead to the formation of N-benzoyl derivatives. Thus, treatment of 2-methyl-2-imidazoline with benzoyl chloride and sodium carbonate gives N,N'-dibenzoyl-Nacetylethylenediamine. Cold ethanolic potassium hydroxide transforms this triacylated ethylenediamine into an approximately fifty-fifty mixture of N-benzoyl-N'-acetylethylenediamine and N,N'-dibemoylethylenediamine. The latter substance is also obtained when 2-methyl-2-imidazoline is benzoylated in ihe presence of aqueous sodium hydroxide. The observation that hydrolysis of N,"-dibenzoyl-N-acetylethylenediamine affords a mixture of N,N'-dibemoylethylenediamine and N-benzoy1-N'acetylet.hylenediamine demonstrates that it is not necessarily the acid derived from the 2-substituent on the imidazoline ring which is expelled during the fission process. Thus, the relative strengths of the nitrogenacyl bonds in the intermediate triacyl derivative is the determining factor.

HsC-F-H C-CH, H&-A

I

6O I

~

C

NaOH

o

I

KOH in EtOH

a

Q

C-0

H

222

Chemistry of Classes and Derivatives

This fact is brought. out further when phenylsulfonyl chloride is used to open the 2-iniidazoline ring. Treatment of 2-methyl-2-imidazoline with this chloride in the presence of sodium carbonate leads to the formation of N,.~~'-diphenylsulfonyl-N-acetyletli~lenediamine.This compound is transformed into N,N'-diphenylsulfonylethylenediamine upon exposure to sodium hydroxide since the sulfonaniide bond is consideral>ly inore stable than the nitrogen-acetyl linkage 128,291. The heliavior of 2-

Q + CHSCOOnictliyl-2-iinidazolinc on benzoylation resembles that of imiduzole (see Chapter 11, Section B-2) and benzimidazole (see Chapter VIII, Scctioii D). Under special conditions, however, another course of events is observed. Treatment of 2-methyl-2-imidazoline with one equivalent of p-acetamidophenylsulfonyl chloride in water at 0-10" in the prescnce of one cquivalcnt of sodiuin hydroxide affords a mixture of products conI) -2-liydroxy-2hining 30 per cent of 1- (y-accta~nidopIicnylsulfony iiictliyliiaidazolidine, a considerable quantity of N-acetyl-N'- (p-acct~riiiidophenylsulfonyl) -ethylenediamine, and a small amount of N,N'-bisI p-acetainidophenylsul fony 1) -N-acctylcthy lenediamine. A practically quantitative yield of N-acetyl-M'- (p-acetamidophcnylsulfonyl)-ethylenediainine is obtained wlicn the reaction is performed at 60°. The 1-(p;wctamidophenylsulfony1) -2-hydrox y-Zinct~h ylimidasolidine is very unstal)le and undergoes rapid hydrolysis with thc formation of N-acetyl-N(p-acetaniidophenyIPulfonyl) cthylcnediamine upon treatment with dilute ni'ncral acid. 2-I~lethyl-2-iinidazolinc reacts with p-nitrophenylsulfonyl cliloridc in benzene solution followed by treatment with water t o give .V- ( p-nitroplieny lsulfonyl) -2-methyl-2-imidazoline which is hydrolyzed 1 o .V-acctyl-N'- (p-nitrophcnylsulfonyl ethylencdiamine in the prescnce of tliliitc iriincral acids 130).

VII. Imidazolines, 2-Imidamlidones, etc.

223

4. Al..ylction

The %-substituted 2-imidazolines undergo N-alkylation upon heating with alkyl halides in such solvents as benzene, toluene, n-butanol, or aqueous ethanol. The reaction is complex and, depending upon the experimental conditions, niay afford a variety of products. Rather low yields (30-40per cent) of 1,2-dialkyl-2-imidazolinesare obtained (8,31). The alkylation of 2-methyl-2-imidazoline with benayl chloride in refluxing benzene, for example, leads to the formation of a mixture of 2-methyl2-imidazoliniuin chloride, 1-benzyl-2-methyl-2-imidazolinium chloride, and 1,3-dibenzy1-2-methyliinitlazoliniuinchloride. The interaction of two equimolar portions of 2-methyl-2-imidazoline with one equimolar portion

+ Cl-

0

+Cl-

of dodecyl bromide in anhydrous benzene at reflux temperature, followed by treatment with cold aqueous alkali, affords a 40 per cent yield of 1-doctecyl-2-methyl-2-imidazolineand a substantial amount of Nj"-

2.4

Chemistry of Classes and Derivatives

didodecyl-iV-acetyletliylenediamine. The latter arises from the hydrolysis of the 1,3-didodecyl-2-methyl-2-imidazolinium salt which is present in tlie alkylation mixture. The addition of small amounts of water alters tlie course of the alkylation reaction. Under such conditions, one obtains substantial amounts of N,N'-didodecylethylcnediamine, in addition to tile aforeinentioned products. Alkylation of 2-substituted 2-imidazolines in the presence of potsssiuni carbonate results in the exclusive formation of quaternary compounds (31). These examples demonstrate a pronounced tendency of the 2-substitilted 2-imidazolines to alkylate beyond tlie 1,2-dialkyl-2-imidazoline stage to give 2-substitutecl-l,3-dialkyl-2-imidazoliniumderivativm. This bcltavior may be explained in terms of increased resonance stabilization of the %substituted 1,3-dialkyl-2-i1nidacoliniumions over the 1P-dialkyl2-imidacolinium ions. The latter ions receive contributions from two non-equivalent structures, A and B; the former from two equivalent form, C and D.

H2C-rj-R c,F-R' HzC-5- R

I

-

H C A-R * ;c--Iv

II,

H&-K-

R

1 , 2 , 3 1 ' i i a l k ~ i - ? - i i t i i d t t ~ ~ I i i i i uioii iii

T!ic interaction at teuipcraturcs of 100-1 10" between a 1,2-dialkyl2-iniidszoline and an alkyl halide in tlic presence or absence of a solvent results in the formation of a 1,2,3-trislkyl-2-imidazoliniumhalide (32). Hydrolysis with hydrochloric acid converts the 1,2-dialkyl-2-imidazolincs into N-n~onoalkylethylenediamincs;tlie 1,2,3-trialkyl-2-imidazoliiiiuiii derivatives are convcrt.ed into N,N'-dialkylethylencdiamines under t l i l w rotiditions (31). 5. Practical Applications and Pharmacological Action Tlte 2-imidazolines have found wide application in a number of fields ,Soiiie of the higher 2-alkyl-substituted 2-imidazolines exhibit surface-

active properties which make them useful as emulsifiers, textile aids, flot,ation itgents, and asphalt additives. Onc compound, preparcd from

VII. Imidseolines, 2-Imidazolidones, etc.

225

oleic acid and 2-aiiiinoethylethanolallline and marketed under tlie trade name Amine 220, has particularly desirable surface properties. It is a brownish-colored, oily liquid readily soluble in aqueous acids to give solutions with high surface sctivit.y (3334).

The product may be quaternised with the lower alkyl halides, sulfates, or sulfonates to give quaternary salts exhibiting desirable surface properties. The 2-alkyl-1- (2-acetamidoethyl)-2-imidazolines are softening agents for textiles (35-37). Some 2-imidazolines such as 2-methyl-ldecyl-, 2-methyl-l-dodecyl-, 2-methyl-l-tetradecyl-, 2-hendecyl-, 2hendecyl-1-methyl-, 2-hendecyl-l-ethyl-, and 2-hendecyl-l-amyl-2imidaaoline exhibit in vitro bacteriostatic activity against streptococci, staphylococci, pneumococci, and Shigella dysenteriae. Some of these compounds also exhibit a prolonged mild local anesthetic effect when applied to the rabbit cornea. 2-Tridecyl-2-imidasolineis highly toxic to the red spider, Tetranychos tekrius Linn6 (832). Of interest are the fungicidal properties of such compounds as 2heptadecyl-2-imidazoline (Fungicide 341) and 2-heptadecyl-1- (2-aminoethyl) -2-imidazoline. These substances find application as foliage fungicides for the control of apple scab and cherry leaf spot (38,39). Moat outstanding is the marked effect of the 2-aralkyl-2-imidazolines on the circulatory system and the peripheral vessels. It does not fall within the framework of this monograph to deal in detail with these pharmacological properties, and reference should be made to the original literature (19,40) and to a review paper by Schola (41). 2-Bensyl-2iinidazoline exhibits a marked dilating effect on the peripheral vessels and lowers the blood pressure. It finds medical applications as a circulatory stimulant under the trade name Priscoline. It is of interest to note that

Chemistry of Classes and Derivativa

2%

the replacement of the benzyl group in Priscoline by a l-naphthylmethyl group reverses the pliarinacological effects. 2- (l-Naphthylmethyl) -2iinidazoline is a potent vasoconstrictor marketed under the trade name Privine. Another inedically important 2-imidazoline is 2- (N-phenyI-NI~cnzyl~~ininoiiietliyl) -2-imidazolinc (Antistine) , an ant,ihistaininic agent, H*C-N--Ii

I HzC-N "

H&-q-H C-CHZ HaC-l(i

I

/ \

Priecolinc"

"

8 \ /

Privine"

"Antistine"

C. 2-Imidazolidones (Ethgleneureas, 2-Hydroxy-2-imidazolines) 1. Synthetic Methods and General Properties

W i c k syntlicsis o f 2-iinidarolidone from ethyleneditmine and diethyl carbonate (42), its formation on electrolytic reduction of parabanic acid (42a), or its production from ethylencdiainine and phosgenc (43) are of little significance when the preparation of the coinpound on a large scale is desired. A generally applicable proccdure for the large-scale production of 2-iiiiidazolidone involves heating of ethylenediamine with carbon dioxide or heating of N-(2-aminoet1iyl)carbamic acid. At pressures of 400-900 pounds per square inch and temperatures of 200-230°, yields of 2-imidazolidone of 95 per cent or better are realized. N-(2-Aminoethyl) rrtrbamic acid is obtained in the form of a whitc powder froin the interaction of etliylenedisminc and carbon dioxide (aqueous or anhydrous) in the presence of such solvents 8s ethanol! propsnol, or hutsnol (44).

VII. Imidazolines, 2-Imidazolidones, etc.

227

Another suitable method for the preparation of 2-imidazolidone, affording excellent yields on a laboratory scale, is based on the interaction of ethylenediamine with urea in the presence of water as a moderator (45). Also, the interaction of ethylene glycol with urea leads to the format.ion of 2-imidazolidone. The reaction is best carried out in two steps. First, a mixture of ethylene glycol and an excess of urea is heated gradually from 150 to 240' during a period of several hours. Ammonia and carbon dioxide are evolved and a brittle resinous solid is obtained. Hydrolysis with water at 250' converts this material into 2-imidazolidone. The direct synthesis of 2-imidazolidone from ethylene glycol, ammonia, and carbon dioxide under pressure at 250' affords a yield of 58 per cent (46).

Substituted 2-imidazolidones are readily obtained by catalytic hydrogenation of the corresponding 2 ( 3 H )-imidazolones (47-49). They may also be prepared from N-carbalkoxyethylenediamineseither by heating or by treatment with sodium ethoxide (50,51). Formation of a 24midazolidone from interaction of a B-acylamidoethyl carboxamide with a hypohalite in alkaline solution was discovered by Karrer and Schlosser (52). These investigators exposed acetyl-Lasparagine to the action of alkaline barium hypobromite, and obtained L-2-imidazolidone-4-carboxylic acid. Benzoyl-L-asparagine behaves similarly (53). H'C-(?o

}

NH:

H-C-NH I 1 HOOC C=O

I R

'

H 3C-q-

BaOClr

OH-

*

R = CH1or CSHI

H

H*

HzC-q-H

I c=o H-C-LH

H-c-~-H

-0oc

HOOC

__c

I

I

c=o

I

Alkaline hypobromite converts carbobenzoxy-L-asparagineinto t l carbobenzoxy-2-i1nidazolidone-5-carboxylicacid, readily convertible into L-2-imidazolidone-4-carboxylicacid by catalytic hydrogenation (54). Formation of the carbobenzoxy derivative in the last-mentioned reaction points to the l-acyl derivatives of the 2-imidazolidones as intermediates, and suggests the course of reaction shown on page 228. CP-Benzamido-pphenylpropionamide and benzoyl-8-alanine amide are converted into 4-phenyl-2-imidazolidone and 2-imidazolidone respectively, when exposed to the action of alkaline hypobromite (55,56). The interaction between N,N'-dialkyl- or N,N'-diarylethylenediamines and phosgene leads to the formation of 1,3-dialkyl- or 1,3-diaryl-2-imidazolidones(57,58).

Chemistry of Classes and Drrivn-tiwz

228 0 H+-C-NH? II

I

H-7-NH HOOC 0-0

-

I I I 0

HOOC C=O

0 I

H tC -q-H C=o H-c-~C-H I HOOC

I

+ CO.. + H&

2-luiitlasolidoiw is a colorlcss neutral solid which is odorless when 1~u1-e.It melts at 133.1' and may be dist.illed. Crystallized from aqueous solution, it is obtained as a hemihydrate which slowly effloresces at rooin temperature to the anhydrous form. There arc two crystalline modifications with a transition temperature a t about 80'. The solubilities of 2-imidazolidone in a number of solvents arc in Table XXVII. Drastic

TABLE XXVII. Solubilities of 2-Imidazolidone (46) --

- - - .___

solvc~i1l

__ -

Tcinp., 'C.

Water . . . . . . . . . . . . . . . . . . 8 Water ................... 35 Water ................... 56 Methanol . . . . . . . . . . . . . . . 64 Ethanol . . . . . . . . . . . . . . . . 25 n-Butanol ............... 25 Chloroform ............. 61 Apetone

Solubility'

_ I _ _ -

................

* Grams of anhydrous compound per

41 80 75 79

1%.

0

25 56

23

< 10 20 < 02 2 .w

100 g. of solution.

hydrolysis with acids or alkalis transforms 2-imidasolidone into ethylenectiainine (or its salts) and carbon dioxide.

VII. Imidazolines, 2-Imida.zolidones,etr.

229

Treatment with nitric acid in acetic anhydride leads to the formation of l ,3-dinitro-2-imidazolidone (59). l ,3-Dinitro-2-imidazoIidones are also formed when 2-nitramino-2-imidazolines are subjected to the action of either nitric acid or a mixture of nitric acid and acetic anhydride (59,60). Refluxing with water, or exposure t o 10 per cent aqueous sodium hydroxide, followed by acidification, converts the 1,3-dinitr0-2-imidazolidones into the corresponding open chain dinitramines. 1,3-Dinitro-4methyl-2-imidazolidone, for example, is converted into l&dinitraminopropane and carbon dioxide (60-63).

I /C=O HaC-h'- H

H2C-y-H

-

I

HNO,

HzC-F-NO, C=O HaC-i-NO?

HXOi

I

h- CHI

NOz I -NH

on -

H- C-N- NO2 I H,C

H-y- CHr

0,N-NH-c

then H+

__I_)

€I-C-NH I I HaC KO,

The hydrolysis of 2-nitramino-2-imidazolines with 10 per cent aqueccus sodium hydroxide affords excellent yields of the corresponding 2imidazolidones (124).

-

HaC-I$-R $-XH--SO1 H $2-N

on-

I

Ha'2-V-R C=O H *c-L H

I

+ NsO + HzO

The 4,5-dihydroxy-%imidazolidones deserve mention as intermediates in the preparation of certain hydantoins. They may be obtained from the reaction of an a-dicarbonyl compound and urea. The simplest exctmple of this reaction is the formation of 4,5-dihydroxy-2-imidazolidone froin glyoxal and urea (64).The formation of diethyl 4,5-dihydroxy-2imidazolidone-4,5-dicarboxylatefrom diethyl dihydroxytartrate and urea H-C=O

I

H-C=O

+

HIN,

F=O HZN

H9

- b

H-C-F-H

H- -N-H lc=O HO

and the production of 4-phenyl-4,5-dihydroxy-2-imidazolidonefrom phenylglyoxal and urea provide additional examples of this reaction (65,661.

230

Chemistry of Classes and Derivatives

Methylglyoxal combines with urea to give a mixture of 4-methyl-

4 (or 5 )-ureido-5 (or 4) -hydroxy-2-imidazolidone and hexahydro-2,5dioxo-7-methylimidaz [dlimidazole (parent ring system: imidaz [d] imid-

,

Lizole, R.I. 604) (67).

H H HO,I I H+ C-T

I +

HaC-C=O

H2N\ H&

c=o

-

!

N-d-h!

I I i H C H

H:

or

H I1 €1

i l l Y-C-?

o=c\

H2K

I

HO/x

I

2C=O

N”-&d I l l .H C II Ha

Hexahydro3,Sdioxo7-methylimidaz[d]imidazole

c=o

A

-A

H3

Y-C-h 8 1 \

c=o + o = q7 4

o=q

H-C=O

H H H I I I.

4,5-Dihydroxy-4,5-diphenyl-2-imidazolidone may be prepared by oxidation of 4,5-diphenyl-2 ( 3 H )-imidazolone with potassium permanganate or, preferably, with nitric acid (68,69). The interaction between an a-dicarbonyl compound and urea in the presence of acids or alkalis docs not usually result in the formation of a 4,5-dihydroxy-2-imidazolidonebut affords a hydantoin instead. Examples are the formation of hydantoin from the interaction of dihydroxytartaric acid and urea in the prcsence of hydrochloric acid (7O), the formation of 5-phenylhydantoin from phenylglyoxnl and urea (66),and finally the formation of 5&diphenylhydantoin from benzil and urea (71). The latter reaction occurs under the influence of ethanolic potassium hydroxide. Hydantoin formation proceeds through the 4,5-dihydroxy-2-imidazolidone stage. 4,5-Dihydroxy-2-imidazolidone, for example, affords hydantoin when it is exposed to hydrochloric acid (64); heating above its melting point converts 4-phenyl-4,5-dihydroxy-2-imidazolidoneinto 5phenylhydantoin (66). I n these instances the formation of the hydantoin involves a simple dehydration of the 4,5-dihydroxy-2-imida~olidones.

H

I

EO-LpH

c=o

HO-~-~-H

H

H*

VII. Imidazolines, ZImidarolidones, etc.

231

The formation of 5,5-disubstituted hydantoins from 4,5-disubstituted-

4,5-dihydroxy-2-imidazolidonesinvolves a pinacolic or benzilic acid shift. R R

"-7-1:; I

ao-pa

c==o O=C-N-H HO-C-L I H+

+ H20

R

a-Dicarbonyl compounds react with an excess of urea under neutral conditions with the formation of hexahydro-2,5-dioxoimidaz[ d ] imidazoles. This reaction also proceeds by way of the 4,5-dihydroxy-2-imidazolidones. Benzil, for example, affords hexahydro-7,8-diphenyl-2,5dioxoimidaz[d]imidazole when refluxed with an excess of urea in ethanol (71). Ethyl dihydroxytsrtrate reacts with an excess of urea in ethanol to give diethyl hexahydro-2,5-dioxoimidaz[ d ] imidazole-7,8-dicarboxylate (72). Acid hydrolysis converts a number of hexahydro-2,5-dioxoimidaz[d J imidazoles into hydantoins. The parent compound, for example, affords hydantoin and urea under these conditions (73).

-

2. Desthiobiotin and

Its Analogues

A 2-imidazolidone derivative of biochemical interest is the compound d-desthiobiotin (d-5-methyl-2-imidazolidone-4-caproicacid), which results from the desulfurization of d-biotin, the B-complex vitamin, with Raney nickel (74,75). Desthiobiotin contains two asymmetric carbon atoms, and consequently may occur in four optical isomers, forming two

Desthiobiotin

racemates. One of these, DL-dcsthiobiotin possesses a cis configuration; the other, DL-allodesthiobiotin, a trans configuration. m-Desthiobiotin is obtained when DL-biotin (76) or DL-epibiotin (77) are desulfurized with Raney nickel ; m-allodcsthiobiotin is the desulfurization product of DLallobiotin and of DL-epiallobiotin (76). See equation ( l ) ,page 232, In addition to its formation by desulfurization of DL-biotin, DLdesthiobiotin may be obtained by total synthetic procedures. The Wooddu Vigneaud synthesis (78) involves treatment of the hydrochloride of

Chemist,ry of Clnmes and Derivativw

232

0

/%

7%. r”

Jf

c-c I

H&

I CH,-R

II

Rancy Xi

Desthiobiotin

Biotin and Qiibiotin cis

Allodesthiobiotin

Allobiotin and Epiallobiotin botls

R--(CHz)(-COOH

7-amino-8-oxononunoic acid with potassiuin cyanate to give 5-iiictliyl2 (3H)-imidasolone-4-caproic acid, which is converted into DL-desthiobiotin by high pressure hydrogenation over Raney nickel at 100”. The m-desthiobiotin thus obtained is contaminated with m-allodesthiobiotin since high-pressure hydrogenation brings about both Cis and truns addition of hydrogen to 5-nict.liy1-2(3H)-imidaaolone-4-caproic acid. The reduction of R-methyl-2 (3N) -iinidazolone-4-caproic acid over Adams catalyst in glacial acetic acid leads to a predominantly ciu addition of hydrogen to giw it sterieally pirc m-desthiobiotin (48,79).

p rfjH,

C-CH

I

HzC

1

CHz- (CHz)r-COOH

CNO-

___c

0 II HNHC-~H L I HzC

C

I

I

CHz-(CHJ r-COOK

H t , 1’toI CHJC00H

I1

n

VII. Imidazolines, 2-lmidazoEdones, etc.

233

Several modifications of the original Wood-du Vigneaud synthesis, involving variations in the method of preparation of the 7-amino-8-0x0nonanoic acid have been described (79-81). A superior method for the preparation of Dx,-desthiobiotin is the very elegant Duschinsky-Dolan synthesis (48). It involves Friedel-Crafts acylation of 5-methyl-2 (3H) 4midazolone with harbethoxyvaleryl chloride to give 4- (8-carbethoxyvaleryl)-5-methyl-2 ( 3 H )-imidasolone, readily convertible into m-desthiobiotin ethyl ester by catalytic hydrogenation over Adams catalyst in glacial acetic acid. Saponification of the ester affords A nL-desthiobiotin of high purity. 0

0

Hf"H

II

It

Ft

Hi

HNM~YH

AlClj

+-7

___)

HP

I

O=C- (CH,) b-COOEt

Desthiobiotin

OH-

C-(CHa),-COOEt

II

lo

Ha, Ptck CHsCOOH

0 II HN RC"H

q.,/ 4., /

7-7

HaC

CH~-(CH*)~-COOEt

Essentially the same methods are applicable to. the preparation of desthiobiotin analogues (49,80,82,a).~~-2-Imidazolidone-4-caproic acid, an analogue in which the 5-methyl group of desthiobiotin is replaced by a hydrogen atom, may be prepared from the hydrochloride of 8-amino-imidazolone-4-caproic acid, followed by 7-oxooctanoic acid via 2 (3H) high-pressure hydrogenation over Raney nickel. Another route to this compound involves Friedel-Crafb acylation of -imidarolone with 8-carbethoxyvaleryl chloride to give 4- (8-carb2 (3H) ethoxyvaleryl) -2(3H) -imidazolone, which is converted into the ethyl ester of 2-imidazolidone-4-caproicacid by hydrogenation over Adam catalyst. Saponification of the ester gives ~~-2-imidazolidone-4-caproic acid. As cyclic urea derivatives, the various stereoisomeric desthiobiotins are hydrolyzed by exposure to barium hydroxide at elevated temperatures with the formation of the corresponding stereoisomeric 7,&diaminopelargonic acids and carbon dioxide. The desthiobiotins are regenerated

Chemistry of Classes and Derivatives

234

from the diaminopelargonic acids by trcatment with phosgene in the presence of alkali (76,s).

e

0 H Y ‘YH

H’i-’iH HsC CHI-R

hydro!ysia 3-----

phosgene

R = -(CHs),-COOH

HtN NHt H+-&H H&

I

+ COe

CHS-R

d-Desthiobiotin is a highly active growth factor for Saccharoiuyces cerevisiae. Its growth-promoting activity for Strain 139 is on a weight basis the same as that of d-biotin (75). A half-maximum growth increase is observed with one part of d-dcsbhiobiotin in 4.75 X lo**parts of Snell medium ( 8 5 ) . DL-Desthiobiotin exhibits just half the biological activity of the d-isomer, demonstrating that the I-isomer is devoid of I)iological activity (48,76). DL-Allodesthiobiotin is also inactive. In the biotin-deficient rat on an egg white diet, DL-desthiobiotin elicits a growth response which is 0.1-0.01 per cent that of d-biotin (86). The biological activity of d-desthiobiotin is not an intrinsic property of the desthiobiotin molecule, but is the result of its conversion by the yeast cell into a substance exhibiting the microbiological characteristics of d-biotin (most likely d-biotin) (87-89). Although d-desthiobiotin is a growth promoter for some 25 strains of S. cerevisiae, it fails to support growth of Lactobacillus casei, L. araliinosus, and Rhizobiuin trifolii on biotin-dcficicnt media (87,90). Presumably these organisms are unable to convcrt d-desthiobiotin into dhiotin. d-Desthiobiotin inhibits the growth of L. casei in the presence of suboptimal amounts of d-biotin. The ability to inhibit growth of S. cerevisiue, L. arabinosm, and L. casei by competing with d-biotin is a property common to many desthiobiotin analogues (48,49,83,87,90-92). Desthiobiotin seems to serve as a key intermcdiate in the biosynthest of d-biotin by organisms which are not dependent on an exogenous supply of this growth factor (89).

D. 2-Imidazolidinethiones (Ethylenethioureas, 2-Mercapto2-imidazolines) H8C-Y-H

I

K&-H

c-s

2-Imidazolidinethione

A

2-~lercapto-2-imidazoline

VII. Imidazolinm, 2-Imidazolidonesl etc.

235

The classical Hofmann process (93,94), involving thermal decomposition of a N-(2-aminoethyl) dithiocarbamic acid to give a 2-imidazolidinethione and hydrogen sulfide, provides a convenient method for the preparation of this class of compounds. The simplest example of the reaction is the formation of the parent compound from N- (2-aminoethg1)dithiocarbamic acid under t.he influence of heat. The required N-(Zaminoethyl) -dithiocarbnmic acids arc obtained from the combination of an ethylenediamine and carbon disulfide in a suitable solvent.

N,W-Dialkyl-, N,N’-diaryl-, and N,N’-diaralkylethylenediamines combine readily with carbon disulfide to give the respective dithiocarbamic acids; their decomposition leads to the formation of 1,3-dialkyI-, respectively (57,95l,&diaryl-, and 1,3-diaralkyl-2-imidslzolidinethiones, 98). The conversion of a N-alkyl-N- (2-alkylaminoethyl) dithiocarbamic acid into a 1,3-dialkyl-2-imidazolidinethionemay also be accomplished by way of the respective tetrahydro-1,2,5-thiadiazine-6-thiones, which are readily available from the dithiocarbamic acids by oxidation with iodine in aqueous potassium iodide. Under the influence of heat the tetrahydro-1,2,5-thiadiazine-6-thiones decompose into 2-imidazolidinethiones and sulfur (98).

s Another good mcthod for the preparation of 1,3-dialkyl- or 1,3-diaryl2-imidazolidinethiones involves heating of a N-formyl-N,N‘-dialkylor a N-formyl-N&’-diarylethy!cnediamine with sulfur (99,100). Ethyl ethylxanthoformate reacts with ethylenediamine to give N-carbethoxy-

236

Chemistry of Classes and Derivatives

P H&-NH

I

cI3 H*C-d\b I

R I

WlfW

A

*

H&-N

R

,c-S I

R

A?'-thiocarbethoxyethylenediamine which is converted into 2-imidazoiidinethione under the influence of concentrated hydrochloric acid with Ncarbethoxy-2-imidazolidinethioneas the intermediate (101). HrC-NHz HA-NHa

S I1 F-OEt S k-OEt II 0

H S I I1

- I

HtC -K-C-OEt H2C-X-C-OEt I II

H O

-9-H CS I

HaC-$-H

/

+ CO?-+ EtOH

Certain 2-uusubstituted 1;3-dit.\lkyliniidazolidines mrct with carbon disulfide in ethereal or alcoholic solution a t room temperature to give yellow addition compounds containing equimolar portions of the reactants. These addition compounds, possibly hexahydro-l13,6-thiadiazepine-2thiones, decompose under the influence of heat with the formation of 1,3-dia1kyl-2-imidazo1idinethionesand thioforinaldehyde (102).

The scope of the reaction is limited. I ,3-Diphenyl-2-imidazolidinc fails to react with carbon disulfide, and 2-substituted 1,3-dislkylimidazolidines combine with the reagent to give N-alkyl-iV- (2-alkglnminoetliyl ) dithiocarbamic acids. Polyamines of the type illustrated react with carbon disulfide with the formation of bis-dithiocarbaniic acids which decompose on heating into bis- (2-imidaxolidinethiones) and hydrogen sulfide (103-108).

VII. Iniidazolines, 2-Inii&zolidones, etc.

‘c-sII

1

237

-s-c‘

II S

2-Imidazolidinethione is a colorless solid (1n.p. 19&199”), sparingly soluble in cold, but readily soluble in hot water. It is moderately soluble in methanol, ethanol, ethylene glycol, pyridine, and acetic acid, and relatively insoluble in most other solvents. Complex salts are obtained with a number of metals (93,109). Treatment with mercuric oxide converts 2-imidazolidinethione into 2-imidazolidone (110). 2-Imidazolidinethione reacts readily with thiophosgene in chloroform to give 2,2‘thiodi-2-imidaaoline. This same compound results as the major reaction product when ethylenediamine ia treated with thiophosgene; small amounts of 2-imidazolidinethione are obtained as a by-product (111, 112). These reactions may proceed in the manner illustrated. When oxidized with 5,5-dibromohydroxyuracil (hypobromite) in boiling ethanol, Ii I

H

__c

+ H2C-Y-H I c-s-c, HzC-fi + HzC-N\-H

c=s

2;P’-Thiodi-’L-imidszoline

t

I-

CI

-

HtC-q-H

I

H2C-fi

C8:

1

H-p-

c-s-c-s-c,

N-CH,

2-irnidazolidinethione is converted into 2,2‘-thiodi-2-imidazoline ( 112). Iodine in aqueous potassium iodide solution transforms 2-imidazolidinethione into the dark red periodide of 2,2’-dithiodi-2-imidazoliniuni iodide, which decomposes when boiled with water with the formation of

238

Chemistry of Classes and Derivatives

2,2'-thiodi-2-imidazoline and iodine (113). 2,2'-ThiodiS-imidazoline is a basic compound forming crystalline salts with acids; thus, it gives a

sulfate, a hydrochloride, and a nitrate. The addition of ammonia to these salts liberates the free base as a colorless solid (112). 2-Irnidazolidinethione reacts readily with alkyl or aralkyl halides to give salts of the respective S-ethers. With bcnzyl chloride, 2-benzylmercapto-2-imidazolinium chloride is obtained (114). Z-hlethylmercapto-2-imidazolinium iodide, readily obtained from 2-imidazolidinethione and methyl iodide in boiling methanol, is a valuable intermediate for the preparation of 2-monoalkylamino- and 2-dialkylamino-2-imidazolines. These are readily obtained in the form of their hydroiodides when 2-methylmercapto-2-imidazoliniumiodide is heated with a moderate excess of a primary or secondary amine in an inert solvent. Methyl mercaptan is liberated in the reaction (115). H8C-T-H F=S Hs -N-H

-[ +

CHJ

Hz'2-Y-H ,C-S-CH3] H,c-~-H

I

+ I' +IIX<

:* [ I

IIIC-q-H ,R HIC-&-H CC .]-&S. R

+ I-

E. 2-Iminoimidazolidines (Ethyleneguanidines, 2-Amino2-imidazolines)

The reaction between ethylenediamine and cyanogen bromide leads

to the formation of the hydrobromide of 2-iminoimidazolidine (116). As it is a guanidine derivative, 2-iminoimidazolidine is a strong monoacidic

M.Imidazolines, 2-Imidazolidones, etc. +Br-C-N

- [ I- q - ~

H,C ,.jC:=XH] .~

239’

+ Br-

HZC-N AH

base, the 2-iminoimidazolidinium ion receiving contributions from structures A, B, and C. 2-Iminoimidazolidinium bromide is a highly watersoluble, hygroscopic compound which may be recrystallized from ethanol. HsC-lf-H C-NH, HP-~~+-H

1.

-

HaC -’y -H, dB,$=NH* HI -N-H

- 1:

H,C -N+-H C >--KHz HI -h-H

Treatment with silver sulfate converts the hydrobromide into the sulfate. The free base is obtained as B strongly basic syrup on treatment of the sulfate with barium hydroxide. It decomposes on heating with the formation of 2-imidazolidone and ammonia. 1,3-Disubstituted 2-iminoiniidazolidines are readily obtained in the form of their hydrobromides when a substituted p-bromoethylcyanamide is treated with a primary amine in ethanol (117).

Derivatives of =-amino acids may be employed in this synthcsis. Thus, p-bromoethylbutylcyanainide reacts with the ethyl cstcr of Ltyrosine to give a bicyclic lactam intermediate, which is convertiblc into 1-butyl-3- ( 1-carboxy -2 p-hydroxyplienyletliyl) - 2 - iminoimidazolidinium chloride by hydrolysis with hydrochloric acid (118). 1-Butyl-bcarboxymcthyl-2-iminoimidazolidine results from the reaction of p-bromoethylbutylcyanamide with sodium glycinate (118).

-

+ CI-

240

Chemistry of Classes and Derivatives

The preparation of 2-alkylamino-2-imidazolines (derived froin thc tautomeric 2-amino-2-imidaeoline form of 2-iminoimidaeolidine) involves the interaction of 2-methylmercapto-2-imidaeoline(see Section D) or of 2-nitrsmino-2-imidazoline with amines a t elevated temperatures (119. 119a). They are distillablc compounds forming well-defined monopicrates.

Ethylenediamine coinbincs with nitroguanidine in aqueous solution at 65-70' to give 2-nit~raniin0-2-imidul;olinc(120,121,124).

The combination of 1,2-diaminopropane and nitroguanidine leads to the formation of 4-methyl-2-nitramino-2-imidaeoline (120). 2-Nitramino-2-imidazoline undergoes nitration with the formation of the alkali soluble l-nitro-2-nitramino-2-imidasoline. The nitration may be carried out with mixed acid a t -10', by treating the nitrate of the nitramine with sulfuric acid, or by rcacting the 2-nitramino-2-imidazoline with one equivalent of nitric acid in acetic anhydride. Exposure to an excess of nitric acid in acetic anhydride converts 2-nitramino-2-imidazoline into 1,3-dinitro-2-iinidazolidonc.The same compound is also obtained when l-nitro-2-nitramino-2-imidazoline is treated with an excess of nitric acid (59).

H2C -q-XO: C=O H2C-k-X0g

I

+ S:O + H i 0

VII. Imidazolines, 2-lmidazolidones,etc.

241

l-Nitro-2-nitramino-2-imidazolineis an unstable compound; boiIing with water brings about its destruction in a short time. It is a very powerful explosive, exhibiting 1.3 times the power of T.N.T.in the 1)allistic mortar and 1.5 times in the Trauzl block. Ita brisance com1 )ares favorably with that of cyclonite (cyclotrimethylenetrinitramine). It is 2.8 times more sensitive to impact and 1.6 times more sensitive to impact friction than cyclonite. 1-Nitro-2-nitramino-2-imidazolineis a very dangerous substance; its instability, however, renders it useless as a practical explosive. The nitration of 4-methyl-2-nitramino-2-itnidazoline follows the pattern described for 2-nitramino-2-imidazoline. In the presence of two equivalents of nitric acid in acetic anhydride at - 5 O , 1-nitro-4- or 5methyl-2-nitramino-2-imidazoline is obtained ; exposure to seven equivalents of nitric acid in acetic anhydride favors the formation of 1,3dinitro-4-methyl-2-imidazolidone (60). l-Nitro-2-nitramino-2-imidazolinecombines with amines at low temperatures to give open-chain addition compounds (59,122). Certain

k open-chain nitroguanidine derivatives serve as precursors for the preparation of nitrated 2-iminoimidazolidines. 1-Nitro-2-iminoimidazolidinium chloride results in excellent yields when N-p-chloroethyl-N'-nitroguanidine is refluxed with water or preferably with 2-pentanol. N-/3-Bromoethyl-N'-nitroguanidine affords 1-nitro-2-iminoimidazolidiniumbromide under these conditions.

1-Nitro-2-iminoimidazolidinium nitrate is obtained from N-P-nitroxyethyl-N'-nitroganidine. Exposure to a mixture of nitric acid and acetic anhydride converts this salt into 1,3-dinitr0-2-imidazolidone (123). The reader is referred to a review article by McKay (124) for a debailed account of the chemistry of nitrated 2-amino-2-imidazolines.

242

Chemistry of Classes and Derivatives

F. Imidazolidines The 1,3-dialkyl-, 1,3-diaryl-, and 1,3-diaralkylimidazolidines are obtained when a suitably N,N’-disuhstituted ethylenediamine is treated 8

with an aldehyde in an inert solvent. With formaldehyde, 2-unsubstituted 1,3-disubstituted imidaaolidincs are obtained, whereas aldehydes of the aliphatic, aromatic, or heterocyclic series give the corresponding trisubstituted imidazolidines (57,98,12,5-129). Polyamines of the type

illustrated afford bis-imidazolidines upon treatment with benzaldehyde (103-105).

The imidazolidines are low-mclting, dist.illahlc compounds. They are sparingly soluble in watcr, but rcsdily soluble in inost of thc common organic solvents. Cold, dilute mineral ncids bring al)ont rapid hydrolysis of the imidazolidines into the respective N,N’-disubstitutcd ethylenediamine salts and an aldehyde. Thc imidazolidines witlistand treatment with cold dilute sodium hydroxide. 1,3-Dihcneyl-2-pheny1imidazolidinc €ails to react with methyl iodidc but. is converted into a mixture of benzamide and benzoic Rcid when exposed to aqueous potassium permanganate. Bibl‘ography

1. Rofmann, A. W.,Ber. 91,2332 (1888). 2. Ladenburg, A.. ibid. ??7,2952 (1894). 3. Klingenstein. E.,ibid. 98, l l i 3 (1895). 4. Baurnann, C.,ibid. 9S, 1176 (1895). 5. Chitwood, H. C., and Reid, E. E., J . Am. Chom. Soc. 67,2424 (1935). 6. Hill, A.J., and Aspinall, S.R.,ibid. 61,822 (1939).

VII. Imidnzolines, 2-Imidazolidones, etc.

243

7. Aspinall, 5. R.,ibid. 61,3195 (1939). 8. Kyrides, L. P., Zienty, F. B., Steahly, G.W., and Morrill, H. L., J . Org. Chem. 19,577 (1947). 9. Waldmann, E.,and Chwala, A., Ber. 74, 1763 (1941). 10. Riebeomer, J. L., J. Am. Chem. SOC.70, 1629 (1948). 11. Oxley, P., and Short, W . F., J. Chem. SOC.1947, 497. 12. Forssel, G.,Bet. #, 2132 (1892). 13. McClelland, E.W.,and Warren, L. A., J. Chem. SOC.1929,2621. 14. Djerassi, C., and Scholz, C. R., J. Org. Chem. 18,830 (1948). 15. Lehr, H., and Erlenmeyer, H.,Helv. Chim. Acta 87, 489 (1944). 16. Klarer, W , and Urech, E., ibid. 97, 1762 (1944). 17. Djerassi, C., and Schole, C. R., J . Am. Chem. SOC.69, 1688 (1947). 18. Dahlbohm, R., and Sjogren, R., Acta Chem. Seand. I, 777 (1947). 19. Urech, E.,Marxer, A., and Miescher, K., HeZu. Chim. Acta 33, 1386 (1950). 20. Hawkins, W.L., and Biggs, B. S., J. Am. Chem. SOC.71,2530 (1919). 21. Stoll6, R.,Merkle, M., and Hanusch, F., J. prakt. Chem. 140, 59 (1934). 22. Kubiczek, G.,and Smahel, A,, M m t s h . 80,389 (1949). 23. Clayton, 0. C., Be*. $8, 1665 (1895). 24. Partridge, M.W.,and Turner, H. A., J. Chem. Soc. 1949, 1308. 25. Hunter,L.,and Marriott, J. A., ibid. 1941, 777. 26. Henry, R.A., and Dehn, W . M., J. Am, Chem. Soc. 71,2297 (1949). 27. MacKenrie, J. C., Myers, G.S., Smart, G. N. R., and Wright, G. F.. Cart. .i Reeearch B.96, 138 (1948). 28. Ladenburg, A., Ber. 98,3088 (1895). 29. Aspinall, S. R.,J. Org. Chem. 6,895 (1911). 30. Zienty, F. B.,J. Am. Chem. SOC.6?',1138 (1945). 31. King, J. A., and McMillan, F. H., ibid. 6S, 1774 (1946). 32. Shepard, E.R.,and Shonle, H. A., ibid. 69,2269 (1947). 33. Carbide and Carbon Chemicals Corporation, U. S. patent No. 2267,965. 34. Carbide and Carbon .Chemicals Corporation, U. S. patent No. 2,268273. 35. Carbide and Carbon Chemicals Corporation, U. S. patent No. 2,355,837. 36. Richerds Chemical Works, U. S. patent No.2,200,815. 37. Richerds Chemical Works, British patent No. 549,328. 38. Wellman, R. H., and McCallan, S. E. A., Contrib. Boyce Thompson Inst. 1.5. 151 (1946) ; Chem. Abstracts 40,4470. 39. Thurston, H.W.,Jr., Harry, J. B., Lewis, F. H., Groves, A. B., and Taylor, C. F.,ibid. 14, 161 (1046); Chcm. Abstracts 40, 4470. 40. Hartmann, M.,and Xslcr, H., Arch. ezptl. Path. Pharniakol. 1.92, 141 (1939). 41. Scholz, C. R., Ind. Eng. Chem. S7, 120 (1945). 42. Fischer, E., and Koch. H., Ann. m9, 222 (1886). &a. Tafel, J.. and Reindl, L., Bet. 34, 3286 (1901). 43. Puschin, N.A., and Mitic, R. V., Ann. 63.9, 300 (1937). 44. Mulvaney, J. F.,and Evans, R. L., Ind. Eng. Chem. 40, 393 (1948). 45. Schweitzer, C. E.,J. Org. Chem. 16,471 (1950). 46. Schweitzer, C. E., ibid. 16,475 (1950). 47. Winans, C. F.,and Adkins, H.,J. Am. Chem. Soc. 66, 4167 (1933). 48. Duschinsky, R., and Dolan, L. A., ibid. 67,2079 (1945).

244

Chemist,ry of Classes and Derivat,ives

49. Duscbinsky, R., and D o h , L. A., &d. 68, 2350 (1946). 50. Funke, A., and Fourneau, J. P., Bull. soc. chim. Frame 9, 806 (1942). 51. Funke, A,, and Kornmann, P., &id. 1949,241. 52. Karrer, P., and Schlosser, A., Helv. China. Acta 6,411 (1923). 53. Harrer, P.,Escher, K., and Widmer, R., &id. 9, 301 (1926). 54. Schneider, F., Ann. 629, 1 (1937). 55. Kanewskaja, S. J., J. prakl. Chem. 13g, 335 (1932). 56. Kanewskaja, S. J., Ber. 69,286 (1938). 57. Lob, G., Rec. trav. chim. 66, 859 (1936). 58. Boon, W. R., J. Chem. SOC.1947,307. 59. McKay, A. F., and Wright, G. F., J. Am. Chew&.SOC.70,3990 (1948). 60. McKay, A. F., and Mancbester, D. F., ibid. 71, 1970 (1949). 61. Franchimont, A. P. N., and Klobbie, E. A., Rec. t.ruv. chim. 7, 12 (1888). 62. Franchimont, A. P. N., and Klobbie, E. A., ibid. 7, 236 (1888). 63. Francbimont, A. P. N., and Klobbie, E. A., dbid. 7,343 (1888). 64. Pauly, H., and Sauter, H., Ber. 6S, 2063 (1930). 65. Geiscnheimer, H., and Anschuts, R., Ann. S06, 38 (1899). 66. Fiscber, H. J., Ekeley, J. B., and Ronzio, A. R., J. Am. Chem. Soc. Gh, 1434 ( 1942). 67. Seeklcs, L., Rec. trav. chim. 4G, 77 (1927). 68. Biltz, H., Ber. 41, 167 (1908). 69. Biltz, H.,Ann. 368, 156 (1909). 70. Anschiitz, R.. ibid. ,964, 268 (1899). 71. Biltz, H., Ber. 41, 1379 (1908). 72. Anschutz, R., and Geldwmnnn, H., -4fi.r~Hf, 129 (1899). 73. Siemonsen. L., ibid. 333, 101 (1904). 74. du Vigneaud, V., Melville, D. B., Folkers. K., Wolf. D. E.. Mozingo, R., Keresztesy, J. C.,and Harris, S. A., J . Biol. Chem. 146, 475 (1942). 75. Melville, D. B., Dittmer, K., Brown, G. B., and du Vignenud, V.. Science 98, 497 (1943). 76. Harris, S. A., Mozingo, R.,Wolf. n. E.. Wilsou. A. N.. anti Folkcrs. I<., J . Am. Chem. SOC.(17, 2102 (1945). 77. Raker. l3. R., McEwen. W. L., :tnd Kinley. W. N., J . Org. Chenc. 18, 322 (1947). 78. Wood, J. I,., and du Vigneaud, V., J. Am. Chem. Sor. 6'7,210 (1945). 79. Swain, G., J. Chein. SOC.1948, 1552. 80. McKennis, H., Jr., and du Vignenud, V.. J . Am. Chem. SOC.68, 832 (1946). 81. Bourquin, J. P., Sehnider, O.,and Griissner, A., Helv. Chim. Acta 2.8, 528 (1945). 82. Dittmer, K., Ferger, M. F., and du Vigneaud, V., J. Biol. Chem. 164, 19 (1946). 83. Duschinsky, R.,and Rubin. S. H., J . Am. Chem. SOC.70, 2546 (1948). 84. Melville, D. B., ibid. Gt;, 1422 (1944). 85. Sncll, E. E.:Eakin, R. E., and Williams, R. J., ibbid. 69,175 (1940). 86. Rubin, S. H., Drekter, J,.. and Moyer. E. H.,Proc. Sor. Exptl. B i d . Med. 6s. 352 (1945). 87. Dittmer, K., Melville, L). B.,and du Vigneaud, V., Science 99,203 (1944). 88. Stokes, J. L., and Gunness, M., J. Biol. Chem. 167, 121 (1945). 89. Tatum. E. L., &id. 160,455 (1945). 90. Lilly. V. C., nnd Leoaian, L. H.. Science 99,205 (1944). 91. Dittmer. I(.. and du Vigneaud, V.,&id. 100, 12[) (1944).

VII , Imidazolines, 2-Imidxzolidones, ete.

245

!a.Dittmer, K.,and du Vigneaud, V., J. Biol. Chem. 169,63 (1947). 93. Hofmann, A. W., Ber. 6, 240 (1872). 94. Organic Syntheses, Vol. 26, p. 34, John Wiley and Som, hc., New York, 1946. :6. Newman, H,E., Ber. 94, 2191 (1891). 1)6. Ristenpart. E., ibid. 29, 2626 (1896). 97. Schinzel. T., and Benoit, G.. BuU. SOC. chim. France 0, 501 (1939). !M. Donia. R. A., Shotton. J. .4., Rentz, L. O., and Smith, G. E. P., Jr., J . Org. Chptti. 14, 946 (1949). W. Zienty, F. B., and Thielke, B.C., J. Am. Chem. SOC.67, 1040 (1945). 100. Zienty, F. B.. ibid. 68, 1388 (1946). 101. Guha, P. C., and Dutta, D. N., J. Indian Chem. SOC.6, 65 (1929); Clrem. Abstrcccls 33, 2952. 102. Donia, R. A., Shotton, J. A., Bents, L. O., and Smith, G. E. P., Jr., J . Org. Chew&.14,952 (1949). 103. van Alphen, J., Itec. lruv. chim. 66, 412 (1936). 104. van Alphen, J., ibid. 56, 669 (1936). 105. van Alphen, J.. ibid. 66,835 (1936). 108. van Alphen, J., ibid. 67,265 (1938). 107. van Alphen, J., M.68,544 (1939). 108. van Alphen, J., ibid. 69,31 (1940). 109. Morgan, G. T,, and Buntall, F. H., J . Chem. SOC.1998, 143. 110. Hlut, Arch. Pharnr. 940, 677 (1887). 111. Jaff6, M., and Eiihn, R., Rer. 9, 1663 (1894). 112. Johnson, T.B., and Edens,C. O., J . Am. Chem. SOC.63, 1058 (1941). 113. Johnson, T. R., and Edens. C. O., ibitl. 64,2706 (1942). 114. Walker, J., J. Chem. SOC.1949, 1996. 115. Aspinall, S. R., and Rianco, E. J., J . Am. Chem. SOC.7.9, 602 (1951). 116. Pierron, M. P., Ann. chim. phys. 11, 361 (1919). 117. Elderfield, R. C., and Hageman, H. A., J. Org. Chem. 14, 605 (1949). 118. Elderfield, R. C., and Green, M., ibid. 17,442 (1952). 119. McKay, A. I?., Ruchanan, M. N..and Grant, G. A., J. Am. Chem. SOC.71, 706 ( 1949). 119a. McKay, A. F., Coleman, J. R.,and Grant, G. A., ibid. 79,3205 (1950). 120. McKay, A. F., and Wright, G. F., ihid. 70,430 (1948). 121. Barton, 5.S., Hall, R. H., and Wright, G. F., ibid. 73,2201 (1951). 122. Hall, R. H., McKay, A. F., and Wright, G. F., ibid. 73,2205 (1951). 123. McKay, A. F., and Milks, J. E., iW. 73, 1616 (1960). 124. McKay, A. F., Chem. Revs. 61,301 (1952). 125. Moos, F.,Ber. 90,732 (1887). 126. Bischoff, C. A., ibid. S1, 3248 (1898). 127. Scholtz, M., and Jaross, K., ibirl. 34, 1504 (1901). 128. van Alphen, J.. REC..!mu. chim. 64,93 (1935). 129. Rameau, J. T h . L. B., ibid. 67, 194 (1938).

This Page Intentionally Left Blank

CHAPTER VIII

The Benzimidazoles A. Nomenclature

The ring system in which a benzene ring is fused to the 4,5-positions of imidazole is designated as benzimidazole. H I

Benzimidnzole R.Z. 777

The various positions on the benzimidazoIe ring are numbered in the manner indicated, with the imino function as number one. The general principles which guide the naming and numbering of the benzimidasoles are essentially those outlined during the discussion of the nomenclature of the simple imidazoles (see Chapter I, Section A). Benzimidazoles possessing a free irnino hydrogen are tautomeric systems. The two possible tautomeric forms of benzimidazole (and of those of its derivatives possessing a plane of symmetry) are identical, and a definite assignment of structure is possible. Examples are: %methyl-, li,b-dimethyl-, and 4,7-dimethylbenzimidazole.

a

I Ha 2-Methylbenzimidazole

4,7-Dimethylbeneiidazole

2448

Chemist.ry of Classes nncl Derivatives

Mono- and poly-substituted benzimidazoles not possessing a plane of symmetry may behave as though they were composed of two compounds, thus rendering impossible a definite assignment of structure. 4-Methylbenzimidazole, for example, is tautoineric with 7-methylbenzimidazole and, consequently, must be designated as 4(or 7) -methylbenziinidarole. A similar situation prevails in the case of Fi-nitrobenzimidazole which is tautoineric with 6- nitrobenzimidazole and, thus, is designated as 5 (or 6) -nitrobenzimidazole. The same considerations apply to the more highly substituted benzimidazoles. 4(or 7)-Methylbenzirnida~le

CHI

H

4-hlethyibenzimidazole

7-M ethyibenzimidazolc

5(or 6)-Nitrobcnzimidamole \

f

n 5-X itrobnzimidazole

GNitrobenzimidazole

Substitution of the iinino hydrogen eliminates the possibility for tautomerisrn, and a definite assignment of structure becomes possible. The numbering starts at the substituted nitrogen. Benzimidazoles possessing substituents in the benzene portion will be referred to as Bzbenzimidazoles.

B. General Properties 1. Boiling Points. Melting Points, and Degree of Association

The fundamental properties of the benzimidazoles, such as the melting and boiling point characteristics, the degree of association, the amphoteric nature, and tautomeric behavior parallel closely those of the simplc imidazoles discussed in Chapter I. In order to avoid unnecessary duplication these properties will receive only very brief consideration at this point.

VIII. Benzimidazolw

‘249

The benzimidazoles are high melting and high boiling solids. The parent compound melts at 170’. They are soluble in polar and sparingly soluble in nonpolar solvents. Detailed information on the melting points of a great number of benzimidazoles is available in Part 2. Benzjmidazoles possessing a free imino hydrogen are highly associated in nonpolar solvents. Substitution of the imino hydrogen markedly lowers the boiling and melting points, and the N-substituted benzimidazoles are not siwificantly associated. Benzimidazoles embodying the necessary structural prerequisites for intramolecular hydrogen bonding are likewise not markedly associated (1). 2. Pseudoacidic Character

The pseudoacidic character of benzimidazole and many of its derivatives is reflected in the ability to form salts with metals. Most important among these is the sparingly soluble silver salt which forms when a solution of silver nitrate is added to a solution of benzimidaaole in boiling water (24). It is a crystalline solid which dissolves readily in dilute mineral acids or acetic acid. Sparingly soluble precipitates are loo obtained with ammoniacal solutions of copper, cobalt, cadmium, and zinc ions. Substances such as 2-methyl-, 2-phenyl-, 2-methoxymethyl-, 2-ethoxymethyl-, 2-phenoxymethyl-, 2,5 (or 2,6) -dmethyl-, 5 (or 6) bromo-2-methyl-, and 5 (or 6) -nitro-2-methylbenzimidazole are capable of forming silver salts but fail to give precipitates with the other metal ions mentioned (4). The ability to react with Grignard reagents to give AT-magnesiumhalides also reflects the acidic nature of the bensimidaeoles ( 5 ) . Substitution of the imino hydrogen eliminates the pseudoacidic properties. A number of crystalline salts (such as a lithium, sodium, potassium, and barium salt) have been prepared by the addition of the appropriate metal amide to a solution of benzimidasole in liquid ammonia. These salts hydrolyze upon exposure to water with the regeneration of benzimidazole (6). Electronegative groups increase the acidic nature of the benzimidazoles. The nitrobenzimidasoles, for example, are strong .enough acids to dissolve in sodium carbonate or aqueous ammonia. 2-Methyl-4,6 (or 5,7) -dinitrobenzimidazole forms a stable ammonium salt (7,8). 3. Basic Strength and Electronic Structure

The bensimidazoles are predominantly basic compounds having the ability to form salts with acids. The basic properties result from the ability of the pyridine nitrogen to accept a proton.

150

Chemistry of Classes and Derivatives

Benzimidazole (PI(, 5.5) is a base considerably weaker than imidazole (pK, 7.0). This difference in basic strength is a reflection of the conjugation between the imidazole and benzene rings. Conjugation increases the number of contributing states in the resonance sense, thus enhancing the chemical stability of the molecule. Concurrently, it tends to remove electrons from the pyridine nitrogen, thus decreasing its proton afinity. Structures A to G may represent the major contributions to tho state of the bcnziinidazole system.

G

Structures D, E, and G picture the conjugation between the imidcrzole and benzene liortions which may be responsible €or the difference in basic strength between imidazole and benziniidazole. Table XXVIII summarizes the basic strength (in pK, units) of a varict.y of substitutcd benziniidazolcs, both in water nnd in 50 per cent aqucous ethanol (9). It may be seen that electron-re!easing groups increase the basic strength, while electron-attracting groups exhibit the opposite effect. Tlie influcnce of a given substitucnt varies markedly with its position on the benzimidazo!e ring. A methyl group in the 2-

VIII. Benzimidazoles

251

TABLE XXVIII. Basic Strength of Some Benzimidazoles (9) pKu values at 25 13 water

Substance

Benzimidazole 4(or 7bMethyl5(or 6)-Methyl4,6(or 5,7)-Dimethyl5,tkDimethyl2-Methyl%Ethyl2-n-Propy l2-IsopropylZterl-Butyl1-Methyl1-Ethyl1-n-PropylI-Isopropyll-n-ButylI-AlIy 11-Hydroxymethyl1-(2Hydroxyethyl)1&Dimethyll,t%Dimethyl2,5(or 2,6)-Dimethyl1,2,5-Trimethyl1,5,tkTrimethyl2,5,6-Trimethyl2-Phenyl2-Phenyl-5,&-dimethyl4 (or 7)-Met hoxy5(or 6bMethoxy5-Met!ioxy-l-methyl5(or 6)-Methoxy-2-methyl5-Methoxy-l,2-dimsthvl5(or 6)-Chloro5-Chloro-I-methyl6-Chloro-I-methyl5(or 6)-Chloro-2-methyC BChloro-12dimethyl4,G (or 5,7)-Dichlor05,fhDichloro5(or 6bNitro-

-

5-Nitro-l-methy l-

5(or 6)-Nitro-%inethyl-

.

%Amino-

5(or BbAmino-

5.48 5.67 5.81

-

5.98

0.19

0.20

-

623

-

5.57 5.62 5.46 5.74 531

-

5.44 520

_.

-

-

-

-

6.11

*

1OC.

In 605% ethanol

4.98 5.16 5.32 5.46 5.48 5.77 5.69 5.66 5.79 5.76 488 4.88 4.83 4.97 4.75 4.58 499 482 5.22 5.17 6.03

6.07 5.45 6.29 4.51 5.10 4.98 5.07 5.07 5.93 5.86

3.92 35 3.88 4.71 4.75 2.76 3.26 2.68 2.67 337 739

-

Table continued

. 25'2

Chemistry of Classes :rnd Drrivntium

TABLE XXVIII (continued) Subatance

5-Amino-l-meth yl5(or 6)-Arnino-%methyl-

1-p-WGlucopyranosyl-

l-p-~-Xylopyranosyl1-a-n-Arabopyranosy I1-a-L-Arabopyranos.vI-

l-p-D-Glucosyl-5-methyfl-p-o-Xyloay~5-rnethyl-

l-a-D-Arabinosyl-5-methyII-~-~-Glucosyl-fi,6-dime tIry ll-a-~-Arabinosyl-5,6dimethyll-p-o-Ribosyl-5,6-dimc thyl-

2-D-G~uco-pc~itahyclioxypent~l-

p f i valuea at 25 f 1'C.

In wator

6.37 6.81 4.01 3.92 4.22 4.09 4.32 4.17 4.33 4.63 4.68 4.70 5.28

In SO% ethanol

5.95

-

3.69

-

I

-

-

5.19

._

position exerts a more pronounced effect than one in the 5(or 6 ) - or the 4(or ?)-position. The marked effect of a 2-methyl group seems to be the result of the combination of an inductive and a hyperconjugative effect. Induction seems to be the dominant factor since such compounds as 2ethyl-, 2-isopropyl-, and 2-tert- butylbenzimidazole exhibit the saine basic strength as does the 2-methyl derivative. However, the ability of 2methylbenzimidazole to condense with aldehydes (see Section E) is suggestive of some hyperconjugation. Symmetry considerations may offer a plausible explanation for tlic observation that a methyl group in the 1-position fails to increase thc basic strength of benzimidazole. I n contrast to the a-methylbeneirnidazolium ion, which is highly symmetrical, the 1-methylbenzimidaeolium ion receives contributions from two non-equivalent structures. The resulting loss in resonance energy may off set the electron-releasing influence of the methyl group.

_.-

VIII. Benrimidsmies

i

2&?

4. Ultraviolet Absorption Spectra

The benzimidaroles possess characteriatic absorption spectra in the ultraviolet region which may be of use for their indentification (10-18). The spectra of benrimidazole, 5,6-dimethylbenzimidazoleand 1,5,6-trimethylbensimidarole in 0.01 N hydrochloric acid and 0.01 N sodium hydroxide are shown in Figures 4,5, and 6. It will be noted that the spectrum of each compound exhibits a number of bands in acid solution which are shifted in a characteristic manner in alkaline medium.

0.6

1 I

0.44

- in 0.01 NHCl

._.__ in 0.01 NNaOH

:’ Y

/I

WAVE LENGTH, A

Fig. 4. Ultraviolet absorption spectrum of beneimidaeole.

The difference in the electron distribution between the uncharged bcnzimidazole and the corresponding benzimidazolium ion (see previous Section) must be responsible for the marked shifts in the absorption spectra. This explanation is supported by the observation that the ultraviolet absorption spectrum of quaternary benaimidazolium ions such as 1,3,5,6-tetramethylbenzimidazolium ion is not dependent on pH. The possibility for proton addition is non-existent in this type of compound.

1 , 3 , ~ , 6 - T e t n r m e t h y l b n ~ ~ i ~ion ~lium

264

Chemistry of Classes and Derivatives 5. Chemical Properties

The most outstanding property of the benzimidazoles is their pronounced chemical stability (aromatic character). They are resistant to the most drastic treatments with acids and bases, and are not readily attacked by oxidizing reagents. Oxidation with permanganate converts a number of methylbenzimidazoles into the corresponding benzimidazolecarboxylic acids (see Section 1-1). Drastic oxidation with potassium permanganate removes the benzene portion of the ring with the formation of 4,5-imidazoledicarboxylicacid (7) (see Chapter I, Section D-l 1.

_-___-

in 0.01 NHCl in 0.01 NNoOH

WAVE LENGTH, A

Fig. 5. Ultraviolet absorption Npectnim of 5,&lirnetItylbcnzimidazole.

Bexuimidaeole is ufiaffected by drastic conditions of hydrogenation. Hydrogenation over platinum oxide in glacial acetic acid converts 2methyl-, 2-ethyl-, and 1,2-dimethglbenzirnidazoIeinto the corresponding tetrahydro derivatives (19). 2-Phenylbenzimidazole under these conditions is transformed into 2-cyclohexyl-4,5,6,7-tetrahydrobeneimidazole.

255

The chemical reactivity of benzimidazole is governed by the functional behavior of the nitrogens (salt formation, acylation, and alkylation) and its ability to undergo electrophilic substitution in the benzene ring. The benzimidazoles fail to couple with diazotized aromatic amines.

______ in

0.01 NHCl

in 0.01NNoOH

0.6-

*

E! x

i

0.4-

0

5 CI

0.2

-

I I I

I

i 0

I

WAVE LENGTH, A

Fig. 0. Ultraviolet absorption spectrum of 1,5,Btrimethylbenzimidazole. 6. Tautomedc Character

As has been mentioned previously, substituted benzimidazolea which do not possess a plane of symmetry, such as 5(or 6) -methylbenzimidazole, may occw.in two isomeric forms differing in the position of the imino hydrogen. Both forms are derivable from a common cation or anion.

256

Chemistry of Classes and Derivat,ives

- I{+

I

All attempts t o prepare such compound pairs have resulted in failure, and the same benzimidazole is obtained by synthetic methods which should have provided two isomers. This situation was first recognized by Kaiser in 1885 (20) when he attempted the preparation of the two possible isomers of 2-methyl-5 (or 6)-benzi~nidazolecarboxylicacid. He obtained one and the same benzimidazole from the reduction of 3-nitro-4-acetamidobenzoic acid or 4-nitro-3-acetamidobenzoic acid with tin and hydrochloric acid.

B

Similarly, the reduction of 4-nitro-3-acetamidoaniline and 3-nitro-4acetamidoaniline gave only one 2-methyl-5 (or 6) -aminobensimidasole (2132). The recognition that the two possible isomeric forms of a given benzimidazole are derived from a common ion suggested the possibility that such isomers may bc formed under neutral conditions. Day and Green (23) heated 3-amino-4-acet.amidotoluene and 4-amino-3-acetamidotoluene in dry cymene and again obtained one and the same 2,5(or 2,6) -dimethylbenzimidazole. See equation (1), page 257. The finding that only one compound is obtained by synthetic procedures which should have resulted in the formation of two isomers is explicable in terms of tautomerism. The tautomeric nature of 2,5 (or 2,6) -dimethylbenzimidazole was clearly established by Otto Fischer (24-26). This investigator methylated the compound and obtained a separable mixture of 1,2,5-trimethyl-

VIII. Renzimidamles

257

benzimidazole and 1,2,6-trimethylbenximidaxole. Both isomers on treatment with inethyl iodide were converted into one and the same methiodide.

1

methylation

Other Bx-substituted benximidazoles are converted into separable mixtures of isomers on methylation. The nature of the Bx-substituent exa marked effect on the course of the alkylation, and the two possible isomeric methylation products are not necessarily obtained in equal amounts. This is illustrated in Table XXUI. It will be noted that electron-attracting groups greatly favor the formation of 1,6-isomers when dimethyl sulfate is used as the alkylating agent. The effect is less pronounced when a combinat.ion of dimethyl sulfatc! and alkali is nsed.

258

Chemistry of Classes and

Derivatives

TABLE XXIX. Ratios of Isomers Formed on Methylation of Benzimidsl;olc:: under Varying Conditions* (3) Aletliylat 111: riagriit

1)mrimidnrole

3lC:SOc

5(or 6)-Me$yl2,s (or 2,6)-Dimet hgl5(or 6)-Bromo-2-met.hyl5(or 6)-Nitro-2-methyl-

AleiSOc and d k n b

1:l

10: 1 10: 1 50: 1 loo: 1

1: 1

2: 1 5:1

* The figures represent ratios of the I,0 to the 1.5 isomers. Explanations identical with those mentioned in connection with the treatment of the t.automeric nature of the simple imidazoles may explain the tautomeric behavior of the benzimidazolcs (SCC Chapter I, 8ect.ion El. C. Synthetic Procedures 1. Introduction

From the synthetic point of view, the benzimidazoles may be regarded as o-phenylenediamine derivativcs. Indeed, the important syntheses of the benzimidazole ring system utilize o-phenylenedismine or substituted o-phenylenediamines as starting materials. The methods to be described in the following section are applicable to the preparation of 1-alkyl- and 1-arylbenzimidazoles, and also to the synthesis of a wide variety of benzimidazoles containing substitucnts in the benzene portion (Ba-substituted benzimidasoles) . The reader is rcferred to later sections and to a review paper by Wright (27) for tlieir application to the preparation of specific compounds. 2. Formation from Acylated o-Nitromylaminee

The formation of a benzimidazole upon reduction of an acylated o-nitroarylamine is of both historical and practical interest. Hobrecker (28) in 1872 reduced 2-nitro-4-methylacetanilide with tin and hydrochloric acid and obtained 2,5- (or 2,6) -dimetkylbenzimidazole as tlie first representative of an “anhydrobase” in this series.

B

B

The method is a most versatile one since, by varying both the ary! amine- and acyl portions of an acylated o-nitroarylamine, it lends itsc

VIII. Benaimidazolea

259

to the preparation of a wide variety of benzimidazoles (29-31). The reduction of an acylated N-alkyl-o-nitroarylamineresults in the formation of a l-alkylbenzimidazole, whereas reduction of an acylated o-nitrodiarylamine affords a l-aryl-substituted benzimidazole. The formation of 1,2,5-trimethylbenzimidazole from 4-methyl-2-nitro-N-methyl-Nacetylaniline serves as an illustration of the former reaction (32,33), while the formation of 1-(p-tolyl)-2-phenyl-5-methylbenzimidazole from Nbenzoyl-2-nitro-di-p-tolylaminctypifies the latter (34,35).

Various reducing agents may be employed to bring about the conrersion of an acylated o-nitroarylamine into a benzimidazole. Tin and hydrochloric acid, or stannous chloride and hydrochloric acid are most widely employed. The benzimidazoles separate from the reaction mixture in the form of their sparingly soluble tin double salts, and these are readily converted into the respective benzimidazolium salts by treatment with hydrogen sulfide in mineral acid solution. The free benzimidaroles are liberated from these salts by the addition of ammonia. The reduction of an acylated o-nitroarylamine with iron powder in dilute acetic acid usually gives an acylated o-aminoarylamine and not a benzimidarole (3,3639). The formation of 2-methylbenzimidazole from o-nitroacetanilide represents one of the few examples where this reduction procedure favors formation of a benzimidazole (39). Although the majority of acylated o-nitroarylamines undergo benzimidazole formation upon reduction by tin and hydrochloric acid, 3nitro-4-crotonylamidotolueneunder these conditions does not produce the ring-closed compound, but yields a mixture of 4-amino-3-crotonylamidotoluene and 3-amino-4-crotonylamidotoluene. Other acylated onitroarylamines in which the acyl group is derived from an a,@-Unsaturated acid behave similarly (40).

Chemistry of Classes and Derivatives

2 0

Reduction of an o-dinitrobenzene derivative with stannous chloride in the presence of hydrochloric and acetic acids may produce a benzimidazole. The formation of 2,4,5,6,7-pentamethylbenzimidazole from 1$-dinitro-3,4,5,6-tetramethylbenzene is illustrative (41,42).

""w--. CHI

Hac+Noa CHI HaC NO?

7

HsC

CHaCOOB SOCI~, HCI

CH,

Another method for the conversion of an acylated o-nitroarylamine into a 2-substituted benzimidazole involves heating of the compound with ferrous oxalate at temperatures of 220-225". When applied to onitroacetanilide, 2-methylbenzimidazole results in 42 %J yield (43). The transformation of an acylated o-nitroarylamine into a benzimidazole may also be effected by electrolytic reduction (44),or by catalytic hydrogenation (33,45). The formation of a bensimidazole by this method involves the initial production of a monoacyl-o-phenylenediamine which loses the elements of water. The reduction of a 2-nitro-N~-dimetliylal.ylamine with tin and hydrochloric acid yields a mixture composed of a 1-methylbenzimidazolo and a N,N-dimethyl-o-phenylenediainine(46-51).

:& :

- C:-" E::; YHa

CHI HCI Sn

CHa I

+

Sodium sulfite reduction of a 2-nitro-N,N-dimetliylarylamine also brings about conversion into a 1-methylbenzimidazole (52). In this situation, benzimidazole formation seems t.0 proceed by way of the 2nitroso-NJV-dimethylarylamine stage and may involve elimination of the elements of water between the nitroso group and one of the N-methyl groups. The reaction has an analogy in the naphthimidazole series, where 1-nitroso-2-ethylaminonaphthaleneis converted into 2-methylnaphthimidazole under the influence of ethrrnolic hydrogen chloride (53,541* 3. Formation from o-Phenylenediamines and Carboxylic Acids,

Acid Anhydrides, Esters, or Amides

A bensimidasole synthesis of great practical importance involving the interaction of an o-phenylenediamine and a carboxylic acid was dis-

VIII. Benzimidazoles

261

covered by Ladenburg (55). He refluxed a glacial acetic acid solution of 3,4-diaminotoluene and obtained 2,5 (or 2,6) -dimethylbenzimidazole. Wundt (56) in 1878 prepared benzimidazole for the first time when boiling o-phenylenediamine in formic acid. A large number of benzimidazoles have since been synthesized by heating a mixture of an ophenylenediamine and t i rlrrboxylic acid (57-60). A superior method for the preparation of beiizilnidazoles involves refluxing an equiinolar inixture of an o-phenylenediamine and a carboxylic acid or an acid anhydride in dilute hydrochloric acid. (4 N Hydrochloric acid is usually employed.) This excellent method was developed by Phillips (3,22,39,61-63) and is frequently referred to as Phillips' benz-

iinidszole synthesis. In general it. is observed that aliphatic acids afford good yields of benzimidazoles, whereas with aromatic acids the yields are frequently poor. High yields of 2-arylbenzimidazoles are realized when nn equimolar mixture of an o-plienylenediamine and an aromatic acid is dissolved in dilute hydrochloric acid and heated at 180-190° in a pressure tube (64,65), The interaction of a dibttsic acid with o-plienylenediamine may give rise to different product8 depending upon the molar ratios which are employed. A bis-benzimidazole is usually obtained as the major product when two equivalents of o-phenylenediamine are heated with one equivitlent of a dibasic acid in the presence of dilute HCl (39,6643).

Succinic aeid serves as an example to illustrate other reaction products which may result when less than two equivalents of o-phenylenediamine are employed. Refluxing an equimo1a.r mixture of this mid with o-

262

Chemistry of Classes and Derivatives

phenylenediamine in 4 N hydrochloric acid results in the formation of 2,!2’-diaminosuccinanilide and 2-benzimidazolepropionic acid. Ethylenebis-benzimidazole becomes the major product when two moles of 0phenylenediamine are employed per mole of succinic acid. Both the 2,2‘-diaminosuccinanilide and the 2-benzimidszolepropionic acid are readily converted into ethylene-bis-benzimidazole (39).

The behavior of oxalic and malonic acids deserves special consideration since these acids do not afford bis-benzimidazoles upon heating with 4 N hydrochloric acid and o-phenylenediamine. Oxslic acid condenser with o-phenylenediamine to give 2,3-dihydroxyquinoxaline (39,61,66). whereas malonic acid affords the seven-membered ring compound 0phenylenemalonamide (39,61,69-71).

aNH’+Hoo! NHr

N,”-Dialkylated

Iio0

%-OH

o-phenylenediamines react with carboxylic acids

to give 1,3-dialkyl-2-hydroxybenzimidazolines(3,7275) (see Section E).

MI. Benaimidaaoles R

a:: I

+HOOC-R‘

RI

& * : : -

263

R

R

o-Phenylenediamine and substituted o-phenylenediamines combine readily with an acid anhydride to give either a N,N’-diacylated o-phenylenediamine or a bemimidszole. The course of the reaction depends on the structure of the o-phenylenediamine and the reaction time. Prolonged refluxing of an o-phenylenediamine with an acid anhydride frequently results in the formation of a benzimidazole, but short refluxing favors the formation of a N,”-diacyl-o-phenylenediamine. Short exposure of o-phenylenediamine to boiling acetic anhydride, for example, affords N,N’-diacetyl-o-phenylenediamine; 2-methylbensimidazole becomes the major reaction product when the diamine is refluxed with acetic anhydride for several hours. Prolonged refluxing with acetic anhydride converts 1,2,3-triaminobenaene into a mixture of 2-methyl-Q(or 7)acetamidobcnzimidazoleand 1,2,3-triacetamidobenzene (76). 2-Methylbenzimidazole results in practically quantitative yield when o-phenylenediamine is treated with a mixture of dilute hydrochloric acid and acetic anhydride (77). Prolonged exposure to heat, or distillation, converb many diacylated o-phenylenediamines into a mixture of a carboxylic acid and a benzimidaeole (78-80). A superior method, especially for the conversion of N,N‘-diacetyland N,N’-diformyl-o-phenylenediamines into benzimidazoles, involves refluxing with dilute hydrochloric acid. More drastic conditions, such as treatment with 70% sulfuric acid or with strong alkali at elevated temperatures, are required for the transformation of a N,N’-diaroyl-ophenylenediamine into a 2-arylbenzimidazole (22). o-Amino-Nfldimethylanilines are converted into 1,2-dimethylbeneimidazoleswhen they are refluxed with acetic anhydride (46,48,!50,81,82).

The interaction of an ester and o-phenylenediamine may lead to the formation of a benzimidazole. Heating a mixture of the dihydrochloride of 3,4-diaminotoluene with ethyl formate, for example, affords 5 (or 6) methylbeneimidazole hydrochloride (83). With ethyl acetate, a poor

-

264

Chrmistry of Classes :ind Derivatives

yield of 2,6(or 2,6) -dimethylbenzimidazole is obtained. o-Yheiiylenediamine combines readily with ethyl acetate to give 2-methylbeneimidazole (84). 2-Cyanomethylbeneimidaaole ensues froin the reaction of ethyl cyanoacetate with o-phenylenediamine (85). The interaction of an o-phenylenediamine with ethyl orthoformate represents an excellent. procedure for the synthesis of benzimidazoles (73,86,87). The inethod is of special importance for the synthesis of benziinidazoles c.ont.aining acid

H

sensitive groups, and has found application in the synthesis of l-glycosylbeneimidazoles (see Section F-4-a). The reaction between an acid amide and an o-plmylenediamine also results in the formation of a benzimidazole. 3,4-Diaininotoluene rcact~s with formamide to give 5 (or 6) -methylbenzimidazole; with acetamide, 2,s (or 2,6) -dimethylbenzimiclaeole is ohtrtind (83). Thc yields are god.

Formation of a benzimiciazole by the int eractioii of o-phcnylenediainine and a carboxylic acid, an acid anhydride, im ester, or an amide seems to involve a common mechanism with a monoacylated o-phenylencdiamine as the key intermediate. The behavior of monoscetyl- and diacetyl-o-phenylenediainine on heating in such anhydrous solvents as xylene or cymene supports this view. I n contrast to the former derivativc, which is converted quantititthe latter remains unchanged. 14,ssentively into 2-metl~yll~enzimidazolc, tially, two pathways may be considered for thc cliinination of water from the monoacylated o-phenylenediainines. Either the two hydrogens of one amino group may be involved (Scheme A), or both amino groups may contribute one hydrogen each (Scheme B). Scheme I3 is indicated to hc

VIII. Benzimidazoles

2 0

correct by the findings that o-amino-N-methylacetanilideremains unchanged when subjected to refluxing in dry xylene, whereas N-methyl-N'acetyl-o-phenylenediamine is quantitatively transformed into 1,2-dimethylbenzimidazole under these conditions (88).

A

xylem

no reaction

4. Formation from o-Phenylenedhminesand Nitriles

Heating the monohydrochloride of o-phenylenediamine with an aliphatic or an aromatic nitrile at 200" results in the formation of a 2substituted beneimidasole (77,89). o-Phenylenediamine, itself , fails to react with benzonitrile at 200O, indicating that benzimidazole formation depends upon the presence of acid. Forination of a mixture of an imino chloride and o-phenylenediamine may be the rate-determining step of the reaction. The combination of these two substances could lead to formation of the hydrochloride of an o-aminophenyl substituted amidine, which could lose the elements of ammonium chloride to give the 2substituted beneimidazole.

H

H

This scheme is supported by the observation that N-phenylbenzimino chloride reacts with o-phenylencdiamine to give 2-phenylbenzimidazole. The reaction proceeds through the N-phenyl-N'-o-aminophenylbenz-

266

Chemistry of Classes and Derivatives

amidine stage, and can actually be arrested at this point if the reactants are allowed to combine at low temperature. Heating of the N-phenyl-.Vo-aminophenylbenzamidine hydrochloride results in a quantitative conversion into 2-phenylbenzimidazole and aniline hydrochloride.

5. Formation from o-Phenylenediaminesand Imino Ethers or Imino Thioethers

The interaction between an o-phenylenediamine and a n imino ether, or an imino thioether provides another convenient route to a benzimidazole. The formation of 2-benzylbenzimidazole from o-phenylenediamine and phenacetimino methyl ether serves as an illustration (90,91).

The reaction is acid catalyzed. Heating of an equimolar mixture of o-phenylenediamine and phenacctimino methyl ether in methanol solution fails to bring about the formation of 2-benzylbenzimidazole, but heating the components a t 115' in the absence of a solvent results in slow evolution of ammonia with the formation of a small quantity of 2-benzylbeneimidaeole. The hydrochloride of the imino ether reacts rapidly with o-phenylenediamine in methanol to give 2-beneylbenzimidazole in 84 % yield. High yields of 2-benzylbenzimidaeole are likewise realized in the presence of two equivalents of hydrogen chloride, but the yield declines markedly when three moles of acid are employed. The following reaction mechanism offers a plausible explanation for these experimental findings.

VIII. Benzimidazolea

367

The initial phase of the reaction may involve a combination of the imino ether cation with the unshared electron pair of one of the amino groups of the o-phenylenediamine. The ensuing complex is, by the expulsion of an ammonium ion, converted into an o-arninophenyl substituted amidine which eliminates the elements of methanol to give the benzimidazole. The addition of more than two equivalents of acid to the reaction mixture would be expected to limit the availability of unshared electrons on the amino groups of the o-phenylenediamine and t.hw to interfere with the initial reaction step. The reaction is not a general one; certain chlorine-substituted ophenylenediamines fail to give benzimidazoles upon treatment with an imino ether hydrochloride. 6. Formation from o-Phenylenediaminesand

Aldehydes or Ketonee

Aldehydes react with o-phenylenediamine or substituted o-phenylenediamines with the formation of benzimidazoles (aldehydines). The reaction was discovered by Ladenburg, and is frequently referred to as the “aldehydine” synthesis (92-96). The chemical nature of the “aldehydines” was recognized by Hiasberg, who demonstrated that these substances are actually 12-disubstituted benzimidazoles. For example, the “aldehydine” resulting from the interaction of o-phenylenediamine and benzaldehyde is identical with the product of the alkylation of 2phenylbenzimidazole with benzyl chloride; thus, it must be l-benzyl-2phenylbenzimidazole (97,98).

268

Chemistry of Classes and Derivatives

Widely varying conditions have been used to bring about the formalion of benzimidazoles from o-phenylenediamine and aldehydes. Heating the components in alcohol or glacial acetic acid, or heating of o-phenylenediamine dihydrochloride with an aldehyde at temperatures of 120lGOo,may be mentioned. Frequently the reaction leads to the formation of a mixture of a 1,2-disubstituted and a 2-monosubstituted benzimidazole. In some instances the monosubstituted product is obtained as the major reaction product. The formation of 2-isopropyld (or 6) -methylbenzimidazole from 3,4-diaminotoluene and isobutyrsldehyde provides such an example (98,99). Synthesis of benzimidazoles from o-phenylenediamines and aldehydes seems to involve the initial formation of the respective Schiff bases. These are converted into benzimidazoles by way of an oxidative mechanism. The 2-monosubstituted benzimidazoles arise from monoalkylideneor monoarylidine-o-phenylenediamines, but bis-alkylidene- or bia-arylidenc-o-phenylenediamines must be regarded as the precursors of the 1,a-disubstituted benzimidazoles (aldehydines) . Under carefully controlled experimental conditions t hc inono- and dihenzylidine derivatives of o-phenylenediamine can be prcparcd and then converted into benzimidaeoles under a variety of cxperiinentsl conditions. Dibenaylidene-ophenylenediamine results from the reaction of one mole of o-phenylenediamine with two moles of benzaldehyde a t -20". The compound is unstable and gives rise to l-benzyl-2-phenylhenzimidazolewhen heated above its melting point or when an alcoholic soliltion is kept a t room temperature in the presence of air.

Conversely, monobenzylidene-o-phenylenediamine,obtained from t.hc rcaction of equimolar port.ions of o-phenylenediamine with benzaldehyde at low temperature, is transformed int,o 2-phenylbenzimidazole by heat-

VIII. Beneimidazoles

269

ing in the dry state at 100’ or by refluxing its solution in alcohol or ether in the presence of air. Refluxing the monobenzylidene derivatives in dilute hydrochloric acid solution in the presence of air also leads to benzimidazole formation (100-102). When heated at 180-230O under anaerobic conditions, inonoheiizylidene-o-phenylenediamine disproportionates into a iiiixture of 2-phenylbenzimidazole and inonobenzyl-ophenylenediamine, the ino~iobenzylidene-o-phenylenediamineserving as the hydrogen acceptor uiider these experimental conditions (103). The conversion of a monoalkylidene-o-phenylenediamine into a benzimidazole may also be brought about by such oxidizing agents as mercuric oxide (104-106) or lead tetraacetate (107,108). In its original form, the “aldehpdine” synthesis has many drawbacks, such as low yields and the formation of inseparable mixtures of monoand disubstituted benzimidazoles, A modification of the reaction, introduced by Weidenhagen (log), seems to diminish or eliminate these complications. The newer procedure involves the reaction of o-phenylenediamine with aldehydes in aqueous ethanol in the presence of cupric aceLate. 2-Substituted benzimidazoles form, and their cuprous salts separate from the reaction mixture in good yields. Essentially, two pathways, A and B, may be considered for the formation of a 2-substituted beneimidazole from o-phenylenediamine and an aldehyde. Scheme A regards the initial product as a benzimidazoline, and visualizes the oxidative step as a simple dehydrogenation, whereas Scheme B formulates the primary reaction product as a monoalkylideneor arylidene-o-phenylenediamine and pictures the oxidation step as a cyclodehydrogenation.

The interaction of o-phenylenediamine with formaldehyde deserves special mention. I n acid solution, this condensation leads to the formation of l-methylbenximidszole,identical with the product obtained by the alkylation of benzimidazole with methyl iodide (110,111). When carried out in alkaline medium, however, this reaction affords a product derived

270

Chemistry of Classes and Derivatives

froin four molecules of formaldehyde and two molecules of the base. This substance is unstable and undergoes hydrolysis when refluxed with dilute hydrochloric acid. It has been formulated in the manner illustrated (112). Condensation of o-phenylenediamine with acetaldehyde in

alkaline solutiou proceeds miilarly (101)In acid media 2-chloro-4,5-diaminotolueuecondenses with formaldehyde with the formation of l,6-dimethyl-5-chlorobenzimidazole. The constitution of this compound follows from the fact that it is also obtained from 6-chloro-3-methylamino-4-arninotolueneon treatment with formic acid. On the other hand, 2-chloro-4,5-diaminotoluenereacts with formaldehyde in alkaline solution to form an acid-labile product, believed to possess one of the two structures shown (112a).

o-Ylienylenediamine reacts with ketones to form 2-disubstituted benziinidazolines. These decompose under the influence of heat with the forination of a 2-substituted benzimidazole and a hydrocarbon. The gain in reaonance energy accompanying the aromatization process may be the driving force of the reaction, which involves the fission of a carbon to carbon bond (113,114). The decomposition of an unsymmetrically substituted benzimidazoline may lead to the formation of two different benziinidazoles depending upon whether the substituent R or the substituent R’ is eliminated preferentially.

H

MI. Bell!aimidaeoles

271

The course of the reaction follows from the structure of the resulting benzimidazoles and the nature of the eliminated hydrocarbons. Cenerally it is observed that the carbon-carbon bond is broken at that carbon atom having the greater degree of substitution, when an unsymmetrically substituted benzimidszoline is subjected to heat. 2-Methylbeneimidazole results from the interaction of o-phenylenediamine with methyl isopropyl, methyl isobutyl, and methyl tert-butyl ketones. NSubstitution of the o-phenylenediamine does not alter the course of the reaction. The same hydrocarbon is eliminated when a given unsymmetrical ketone reacts with either o-phenylenediamine or with a N-alkylor N-aryl-o-phenylenediamine. Methyl isopropyl ketone, for example, reacts with N-methyl-o-phenylenediamine to give 1,2-dimethylbenzimidazole and propane. As has been previously mentioned, propane is also eliminated when methyl isopropyl ketone interacts with o-phenylenediamine. The initial gas evolution temperature, i.e., the temperature at which a benzimidazoline decomposes with the liberation of gaseous hydrocarbon at a conveniently discernible rate, varies from compound to compound. Temperatures in the range of 200 to 260' are required to bring about the decomposition of the benzimidazolines derived from o-phenylenediamine, but lower temperatures, in the range of 100 to 150°, suffice to decompose a number of N-methyl-substituted benzimidazolines. The reaction is base catalyzed and may proceed according to the following mechanism.

7. Miscellaneous Procedures

Several less important procedures leading to benzimidazoles may be mentioned at this point. Benzimidazole arises from the interaction of o-phenylenediamine with chloroform and alkali, a procedure analogous to its formation from o-phenylenediamine and ethyl orthoformate (115). Certain o-aminophenylhydrazones under the influence of glacial acetic or hydrochloric acids are converted into 2-mbstituted benzimidazoles, a molecule of ammonia being liberated in the process. The formation of 2-phenylbonzimidazole from benzaldehyde o-aminophenylhydrazone serves as an illustration (116,117).

Chrmistry of Classes and Derivatives

272

Thc formation of l-methylbenziniiciszole from o-uiethylazo-i\-methylaniline under the influence of acid seems to be closely related to the above-mentioned reaction. It may involve the initial rearrangement of the methylazo compound into formaldehyde 0- (N-methylsmino) plienylhydrazone followed by ring closure with the elimination of ammonia (118). ?HZ

o-Aminoarylazo derivatives react readily with aldehydes to form S c h 8 bases; these isomerizc under the influence of glacial acetic acid with the formation of 2-substituted 1-aryiaminobenzimidazoles. The reaction resembles the “aldehydinc” synthesis. Treatment with hydrogen iodide, or zinc and hydrochloric acid, c0nvert.s the l-srylaminobenzimiduzoles into benzimidazoles (119-121 ) .

Q J”’

+

+NIX,

Ir

The interaction of a dithio acid with o-phenylenediamine may result in the formation of a benzimidazole. Dithiobenaoic acid, for example,

VIII. Benzimidazoles

n3

combines with o-phenylenediamine to form a mixture of 2-phenylbemiinidaeole and 2 ( 3 H )-benzimidaeolethione (122).

?

B

D. The 1-Acylbenzimidazolesand the Bamberger Reaction It was noted in Chapter 11, Section B-2 that imidazole undergoes

A'-acylation upon treatment with an acid chloride under carefully controlled anhydrous conditions. Acylat.ion by the Schotten-Baumsnn method brings about fission of the imidaeole ring with the formation of a 1,2-diacylarnidoethylene. The behavior of benzimidaeole toward acylating reagents closely parallels that observed with imidazole. Treatment under anhydrous conditions with acid chlorides or anhydrides results in the formation of 1-acylbenzimidazoles whereas acylation by the Schotten-Baurnann method brings about the fission of the imidaeole ring. A practical procedure for the preparation of 1-benzoylbensimidazole involves treatment of two equivalents of benzimidaeole with one equivalent of benzoyl chloride in benzene solution at low temperature. The second equivalent of bensimidazole ser'ves as a proton acceptor, and eventually separates from the reaction mixture in the form of the sparingly benzene-soluble benzimidaeolium chloride (123,124). See equation (1),page 274. The reaction between benzimidasole silver and beneoyl chloride provides another route to 1-beneoylbenzimidaeole (123). 1-Acetylbenaimidaeole may be prepared in a similar manner. Benzimidazole magnesium bromide readily reacts with aliphatic acid chlorides to give 1-acylbenzimidazoles. With beneoyl chloride, ring tission ensues and N,"-dibeneoyl-o-phenylenediamine is obtained (125). Refluxing of benzimidazole with an acid anhydride, followed by evaporation of the excess reagent 'under strictly anhydrous conditions is another procedure for the preparation of 1-acylbenrimidasoles. Refluxing of benzimidaeole with an acid anhydride followed by treatment with water brings about fission of the benzimidasole nucleus (126-128). The 1-acylbenzimidazoles are rapidly hydrolyzed with the formation of benzimidazole and a carboxylic acid when exposed to the action of dilute acids or alkalis. 1-Benzoylbenzimidazole is somewhat more stable toward hydrolysis than 1-beneoylimidaeole. Benzoylbenzimidaeole withstands treatment with cold sodium carbonate solution, but

Chemistry of Classes and Derivatives

274

+

0

+

c1-

c=o

&jI

[d€I]+ +

benzoylimidazole is readily hydrolyzed when exposcd to the action of moist air at room temperature (124). As has been stated previously, benzoylation by the Schotten-Buuinann procedure converts beazimidazole into N,N'-dibenzoyl-o-phenylencdiamine and formic acid (123). It seems remarkable, indeed, that the benzimidazole ring, which otherwise exhibits such a high degree of chemical stability, is cleaved by benzoyl chloride and dilute alkali a t icehath temperature. Essentially three products have been characterized as intermediates in the fission process (129). The reaction is initiated by conversion of the bemimidazole into 1-benzoylbenzimidazole (I). This suhstancr always accompanies the N,N'-dibenzoyl-o-phenylenediamine (VI) and may be isolated from the ether-soluble by-products. The exposure of 1benzoylbenzimidazole to the action of an equimolar quantity of benzoyl chloride and water under carefully selected conditions leads to the formation of a crystalline compound which has been formulated as 1,3-dibcnroyl-2-hydroxybenzimidazoline (pseudobase) (XI). Assigning of a pseudobase structure to this substance receives support from the observation that refluxing with ethanol brings about its conversion into 1,3-dibenzoyl-2-ethoxybenzimidazoline (111). To be readily displaceable is 3 characteristic property of the hydroxy group of the pseudobases. Exposure to hydrochloric acid converts the 1,3-dibenzoyl-2-hydroxybenz-

VIII. Benzimidazoles

a5

imidazoline into benzimidazolium chloride (IV) and benzoic acid, whereas under the influence of heat, the compound rearranges into N-formyl-N,N'dibenzoyl-o-phenylenediamine (V) The latter compound may be obtained directly from benzimidazole by benzoylation in the presence of sodium carbonate instead of sodium hydroxide. It is readily hydrolyzed to N,N'-dibenzoyl-o-phenylenediamine (VI) and formic acid.

.

6 6-0

&NO I

8 C=O

I

2 ! L a x H Ei'H +HcooI c=o

N-Acetyl- and IV-propionyl-N,iV'-dibenzoyl-o-phenylenediamine are obtained when 2-methyl-, and 2-ethylbenzimidazole, respectively, are subjected to the action of benzoyl chloride and dilute alkali (130). Hy-

276

Chemistry of Classes and Derivatives

droylsis with dilute acids or alkalis converts them into N,”-dibenzoyl-ophenylenediamine and the respective carboxylic acid. The conversion of the 1-benzoylbenzimidazole (I) into the pseudo base (11) may involve the following electronic mechanism. The attack of benzoyl chloride on (I) may lead to the formation of the 1,3-dibenzoylbenziniidazolium ion. In addition to other states, there are three structures (A, B, and C) which may be expected t o make significant contributions to the state of this ion. The location between two powerful electron-attracting nitrogen atoms renders position 2 electron deficient, thus facilitating attack at this location by a hydroxyl ion to give the pseudobase (11). See equation (1), page 277. The ability to undergo ring fission under the conditions of the Schotten-Baumann reaction is not a general property of all the benzimidazoles. In addition to benzimidazole and its 2-methyl- and 2-ethyl derivatives, the following benzimidazoles are subject to ring fission: 2ethyl-1-phenylbenzimidazole ( 130) ; 5 (or 6)-nitrobenzimidazole (123, 131,132); and 5 (or 6)-aminobenzimidazole (123,131,132). Such cornhydroxybenzimidazole ( 133); pounds as l-phenyl-2-methyl-4,7-clinitro-62-methyl-5 (or 6)-nitrobenzi~nidazole (131); 2-methyl-5,6-dinitrobenzimidazole (131) ; 2(3H)-benzimidazolone (131); 5(or 6)-nitro-2(3H)benzimidazolonc ( 131) , and 5,6-dinit.ro-2(3N) -benzimidszolone (131) arc’ resist.ant to the action of benzoyl chloride and alkali. Benzimidazolc reacts readily with aryl isocysnat,es to give 1-crylcarhamylhenziiiiidazolex (134).

E. The Alkyl- and Arylbenzimidazoles and 1,3-MalkylbenzimidazoliumSalts

Bz-Substituted alkyl- and arylbenzilnidazoles are prepared according to the general procedures outlined in Section C. Their chemical properties closely resemble those of the parent ring system and, consequently, require no additional comment a t this point. It is of interest to note that 5,6-dimethylbenzimidazole is a hydrolytic product of vitamin BIZ (17,135-137). Of special interest are the 2-inethylbenzimidazoles since the 2-methyl group in these compounds has a reactivity comparable to that of 2-methylpyridines and 2-methylquinolines, and so has the ability to condense with aromatic aldehydes to give 2-styrylbenzimidazoles (7). The condensation is brought about by heating a mixture of a 2-methylbenzimidazole and an aromatic aldehyde at 150-20O0, or by refluxing the reactants in glacial acetic acid. The formation of 2-styryl-5 (or 6)-methylbenzirnidazole from 2,5 (or 2,6) -dimethylbenzimidazole and benzaldehyde is illustrative. See equation (2), page 277.

VIII. Benzimidaxoles

277

9. C=O

I

Q I

Q

c=o

6 C=O

oxidation

(2)

Chemistry of Classes and Derivatives

278

The structure of the reaction product follows from its conversion by oxidation into 5(or 6) -methyl-2-benzimidazolecarboxylicacid. 2-Styrylbenzimidazole may also be obtained by treatment of N J V dicinnamoyl-o-phenylenediamines with ethanolic NaOH ; the same 5 (or 6) -nitro-2-styrylbenzimidazoleresults either from the condensation of 2-methyl-5 (or 6) -nitrobenzimidarole with benzaldehyde, or from 4nitro-N,N‘-dicinnamoyl-o-phenylenediamine with ethanolic sodium hydroxide (40,138,139).

In addition to its ability to condense with aldehydes, the 2-methyl group of 2-methylbenzimidazoles has also been shown to react with isatin (140) , phthalic anhydride (140,141) , and diethyl oxalate. 14Dimethylbenzimidazole? for example, condenses with diethyl oxalate to give a small quantity of ethyl 2-benrimidazolepyruvate. Sodium ethoxide serves as the condensing agent (142). CHI I

g g - C H l

+ Et00C-COOEt

KaOEt,

CHa 0 I ~,.-cH*-c-ccmEt

1,2,3-Trimethylbenzimidazolium’iodide undergoes a base-catalysed condensation with p-dimethylaminobenzaldehydeto form lJ3-dimethyl-2p-dimethylaminostyryylbenzimidazolium iodide. Piperidine serves as 8 convenient basic catalyst in this reaction (143). Attachment of the 2-methyl group to the electron-deficient 2-position seems to contribute to its reactivity. This effect alone, however, is not sufficient, since simple 2-methylimidazoles fail to condense with aldehydes. Conjugation between the imidazole and benzene rings is also important. The reactivity of the 2-methyl group may be explicable in terms of contributions A to D. The removal of a proton from the methyl

VIII. Benzimidazoles

279

group results in the .formation of an anion receiving major contributions from structures E to G.

Most likely, this anion is the reactive intermediate in the condensation. Its combination with the aldehyde results in the formation of a carbinol, and this by elimination of the elements of water is converted into the 2-styrylbemimidazole. A mechanism akin to that involved in the base-catalyzed condensation of 4 (or 5) -nitro-5 (or 4) -methylimidaeole with aldehydes (see Chapter V, Section A-2) may offer a plausible course for the base-catalyzed condensation of 1,2,3-trimethylbenzimidazolium iodide with benzaldehyde. The imino hydrogen in the bensimidaeoles is readily substituted by alkyl groups to give 1-alkylbenzimidazole. Heating with an equimolar quantity of an alkyl halide in the presence of methanol (24,!25,105,144149), treatment of a benzimidacole silver salt with an alkyl halide (3,137), or reaction with a dialkyl sulfate (3) provide convenient methods for the alkylation of benzirnidazoles. H

R

I

I

oikylation

The changes in physical properties and amphoteric character accompanying the substitution of the imino hydrogen have been discussed in Section B. The 1-alkylbenzimidasoles are basic substances which form crystalline salts with acids. They have the ability to add a molecule of an alkyl halide to give 1,3-disubstituted benzimidazolium salts. Heating of a bensimidaaole with two equivalents of an alkyl halide leads to

Chemistry of Classes and Derivatives

280

the formation of a 1,3-diczlkylbenzi1nidazoliuinsalt with identical subetituents on both nitrogens. The 1,3-dialkylbenziniidazoliumpicrates are well crystallized and are useful for characterization purposes. The 1,3-

P

dialkylbenzimidazolium iodides decompose on heating with formation of The nature of the alkyl group determines the course of the reaction. 1-Methyl-3-ethylbemimidazolium iodide, for example, decomposes into 1-ethylbenzimidazole and methyl iodide on heating a t 260-270°, whereas 1-methyl-3-benzylbenza 1-alkylbenzimidazole and an alkyl halide.

iinidazoliuni iodide eliniinstc~:. h w y l iotlitic under siniiliw conditions to give 1-methylbenzimidazole (150). Under the influence of hot dksli, tlie 1,3-dialkylbenziniidrtsoli~11ii salts undergo ring fission with the ioiiiistion of a iiiolecule of a ,V,N’dialkyl-o-phenylenediaiiiinc and n iiiolccule of a earboxylic acid. Tlic 2-unsubstituted 1,3-dialkylbenzimidazoles afford formic acid, ant1 t lie 2methyl-, 2-ethyl-, or 2-phenyl-l~3-dialkylbenzimidazolesyield acetic. propionic, and benzoic acid. respectively. This cleavage of 1,3-dialkylbenzimidazolium halides is a convenient method for the preparation of N,N‘-dialkyl-o-phenylenediainines. The conversion of 1,3-dimethylhenximidazolium iodide into Ar,~~’-dimethyl-o-pheny1enedi~inine itnd formic acid is a typical example.

The “ammonium bases” and the “carbinol bases” w e recognizsble intermediates in this fission reaction. Exposure of a n trqueoua solution of a 1,3-dialkylbenaimidazoli~imhalide to tlie action of silver oxide affords

VIII. Renrimidaroles

281

a strongly basic, electrically conducting solution containing an etherinsoluble l,3-dialkylbenzimidazolium hydroxide (“ammonium base”). Aqueous alkali catalyzes the rearrangement of this “ammonium base” into a “carbinol base.” The “carbinol bases” differ from the “ammonium bases” in their weakly basic character, their solubility in organic solvents, and their insolubility in water. Also, the ultraviolet absorption spectra of the “carbinol bases” differ markedly from those of the “ammonium

barn.’’

+

R d

i

-

OH-

H

R

R ”Carbinol base ’’

“Ammonium base

Thc “carbinol bases’’ were discovered by von Ticinentowski (32) , who formulated them as 2-hydroxy-1,3-dialkylhenziinidazolines,a view1)oint which was adopted by Otto Fischer in his extensive investigations (,25,74,145,146;148,151) of these compounds. This structure receives strong support from the observation that permanganate oxidation converts the “carbinol bases” into 1,3-dialkyI-2 (3H)-benzimidazolones (24, 51,74,152). Formation of the “carbinol bases” by the interaction of a N,N’dialkyl-o-phenylenedianiinewith a carboxylic acid also supports the 2hydroxybenzimidazoline formulation (3,74). The 2-hydroxybensimidazoline formula is not accepted universally, and some workers (153) R

a:: I

+HOOCH

RI

dT,H I1

,OH

R

t

R

N-R

oxidntioii

prefer to regard these compounds as N,~V’-dislkyl-i~-acyl-o-phenylenediamines. The infrared absorption spectra of the “carbinol bases” point to the presence of an amide linkage, a finding which is in disagreement with the 2-hydroxybenzimidazoline formulation. The following chemical evidence has been offered in favor of the I\r-,N’-dialkyl-N-acyl-o-phenylenediamine formulation.

282

Chemistry of Classes and Derivatives

1,2,3-Trimethylbenzimidazoliumiodide (I) is converted into its “carbinol base” (11) by treatment with alkali, and acylation of the latter compound with propionic anhydride in pyridine affords N,”-dimethyl-Nacetyl-.V’-propionyI-o-pllenylenediamine (111). The same N,”-dimethyl-N-acetyl-N’-propionyl-o-phenylenediamine (111) was obtained from 1,3-dimethyl-2-ethylbenzimidazoliumiodide (IV) by treatment with alkali followed by acetylation of the ensuing “carbinol base” (V) with acetic anhydride in pyridine. Two different esters (VI) and (VII), it was reasoned, should have resulted from “carbinol bases’’ possessing structures (VIII) and (IX).

CH,

CH*

This experimental evidence does not conclusively establish the N,IV’dialkyl-N-acyl-o-phenylenediaminestructure for the “carbinol bases,” since a 2-hydroxy-l,3-dialkyIbenzimidazolinemight undergo ring fission on treatment with an acid anhydride in pyridine to give a N,N’-dialkylN,N’-diacyl-o-phenylenediamine. Also, it is diflicult to understand the formation of 1,3-dialkyl-2 ( 3 H )-benzimidazolones from the oxidation of N,”-dialkyl-N-acy I-o-phenylenediamines. Actually, the two structures postulated are rather closely related and may represent an example of ring-chain tautomerism. The “carbinol

Vm. BenzimidszoIes

283

bases” may be a tautomeric mixture of both forms, a formulation which offers a plausible explanation for the observed experimental facts.

R

The transformation of the 1,3-dialkylbenzimidazoliumsalts into the “carbinol bases” is a reversible process; and exposure of these latter compounds to acids regenerates the former substances. It has thus not proved possible to prepare salts of the “carbinol bases.” R

r

R

K A freshly prepared aqueous solution of 2-hydroxy-l,3-dimethylbenzimidazoline is neutral, has a low conductivity and a characteristic ultravjolet absorption spectrum. On standing at room temperature, such a solution becomes strongly basic, and its spectrum changes to that of 1,3dimethylbenzimidazolium hydroxide. This transformation takes place slowly in water alone, but is effected immediately on addition of hydrochloric acid. 1,3-Dimethylbenzimidazolium chloride can be isolated from the reaction (184). 2-Hydroxy-2-ethyl-l,3-dimethylbenzimidazoline fails to exhibit this behavior. A solution of this substance in aqueous ethanol remains neutral and no change in its ultraviolet absorption spectrum is noticeable even on prolonged standing at room temperature (153). The conversion of 1,3-dirnethylbenzimidazoliumiodide into N,N’dimethyl-o-phenylenediamineand sodium formate may proceed according to the mechanism shown in equation ( l ) ,page 284. The transformation of the hydriodide into the “ammonium base” initiates the reaction. The proximity of the highly electron-attracting quaternary nitrogen atoms renders the carbon atom at position 2 of the 1,3-dimethylbenzimidszoliumion electron-deficient, and this carbon atom is consequently attacked by a hydroxyl ion with the formation of the “carbinol base.” Further hydrolysis brings about fragmentation of the molecule with the formation of N,iV‘-dimethyl-o-phenylenediamine and sodium formate.

Chemistry of Classes and Derivatives

284

Different “carbinol bases” hydrolyze a t widely different rates. Prolonged refluxing with alcoholic potassium hydroxide solution is required to bring about the hydrolysis of 1,3-dimethyl-2-phenyl-2-hydroxybenzimidazoline (25). Resistant “carbinol bases” may be cleaved by treatment with sodium and alcohol, or zinc dust in alkaline solution. Substituents in the benzene portion also have a pronounced effect on the hydrolysis rate. Electron-attracting group facilitate the hydrolysis. whereas electron-releasing substituents retard the fission process. This is well illustrated in Table SSX,which tabulates the stability of a number of 5 (or 6) -substituted 1,2,3-trimethyl-2-hydroxybenzimidazolinea toward 50% ethanolic potassium hydroxide. TABLE XXX. Stability of a Number of 5(or 6)-Substituted 1,2,3-Trimethyl2-hydroxybenaimidamlines toward 50 per cent Potassium Hydroxide at Room Temperature (3) S(or B)-SubatiLuent

--Me

-H

-Br -NOS

Time, min.

360 180 90

60

Yield of NJP-dimethyl-ophenylenediamine, o/o

45 45 50 50

F. The 0x0- and Hydroxybenzimidazoles and Their Sulfur Analogues 1. “‘Oxanhydro Baaee” or ‘‘OxbenzimidazoIea’*

The “oxbenzimidaaoles” or “oxanhydro bases” are a class of corn pounds differing from the benzimidazoles by the presence of one oxygeii atom in the irnidaaole ring. In its chemical inertness this oxygen resembles an ethereal oxygen. The “oxbenzimidazo1es” result from the

VIII. Benzimidazoles

285

reduction of acylated o-nitrosrylamines with tin and hydrochloric acid under mild conditions or, preferably, from their reduction with ammonium sulfide in alcoholic solution (32,165-159). The 2-alkyl-substituted “oxanhydro bases” are highly stable compounds which resist drastic treatment with concentrated hydrochloric acid or alkali. They are monoacidic bases having the capacity to forin well-crystallized salts. Zincdust distillation, or distillation over lime, transforms them into the corresponding benzimidazoles. The parent compound, “oxbenzimidazole,” is best prepared by the reduction of o-nitrofonnanilide with ammonium sulfide in alcoholic solution. The compound crystallizes in colorless needles melting at 210”. It is soluble in hot water, ethanol, and methanol, but sparingly soluble in ether or benzene. It dissolves in both acids and alkalis, and forms a hydrochloride, a chloroaurate, and a chloroplatinate. Treatment with benzoy-1 cliloride and alkali under the conditions of the Schotten-Bauinsnn procedure converts “oxbenzimidazole” into 2(3H)benzimidazolone. Heating of “oxbenzimidazole” with water or hydrochloric acid at 200”,or heating with zinc dust a t S O ” , alsoobrings about its conversion into 2(3H)-benzimidazolone. Essentially three structures h a w been posttilnted for “oxhenzimidazole.”

2. 2(3H)-Benzimidazolones (0-Phenyleneureas, 2-Hydroxybenzimidazolee)

Tautomerism between the 2 (3H)-benzimidazolone (A) and the 2hydroxybenzirnidazole structure (B) must be considered for this class of henzimidazoles. In addition to the benzirnidazole resonance contributions (see Section B-3) structures (C)to (F)may make significant contributions to their state. The same considerations apply to the 2(3H)benzimidazolethiones. N

H

Chemistry of Classes and Derivatives

286

Discovery of the 2 (3H) -bemimidaeolones must be credited to Rudolf (la), who prepared the parent compound for. the fist time in 1879. His method of synthesis involved the nitration of carbethoxyaniline to give o-nitro-N-carbethoxyaniline and its reduction to o-amino-N-carbethoxyaniline. This last compound, on heating in the dry state, eliminates the elements of ethanol to give 2(3H)-bensimidazolone. This general method is applicable to the preparation of a great variety of 2(3H) beneimidazolones.

A number of o-amino-N-carbophenoxyanilinesundergo benzimidazolone formation with the elimination of phenols wlien subjected to the action of dilute alkali. Acidification of the reaction mixture causes ]wecipitation of the 2 (3H) -beneimidaeolones (161). Dilute alkali converts N,N’-dicarbethoxy-o-phenylenediamine into 2 (3H)-beneimidazolone (162). Another important route to 2 (3H)-beneimidaeolones involves the interaction of an o-phenylenediamine with phosgene (13,78,131,163-167). 2 (3H)-Benzimidazolon& are also obtained when an 0-p henylenediamine is heated with urea (131,164,168). The

B

/

yield is practically quantitative when a mixture of o-phenylenediamine and urea is refluxed in amyl alcohol (169). The formation of a 2(3H)-

VIII. Benzimidssoles

287

benzimidazolone from an o-phenylenediamine and urea seems to proceed through the o-aminophenylurea stage, and indeed, o-aminophenylurea decomposes into 2 (3H)-benzimidazolone and ammonia when heated above its melting point (170). More highly substituted o-aminophenylureas such as N-(0-aminophenyl)4'-phenylurea, decompose on heating with the formation of 2(3H) -benzimidazolone and aniline (171,172).

In addition to thew more generally useful procedures, there are a number of other less valuable reactions yielding 2(3H)-benzimidazolones. One of these involves heating the dry potassium salt of o-aminobenzhydroxamic acid or treatment of the potassium salt of dibenzoyl oaminobenzhydroxamic acid with water (173). Phthalic acid diazide may serve as the starting material for the preparation of 2 (3H)-bensimidazolone. It reacts with ethanol to give the aside of o-carbethoxyaminobenzoicacid, which on heating in toluene solution loses nitrogen with formation of 1-carbethow-2 (3H)-bemimidazolone. Treatment with dilute alkali transforms the latter compound into 2 (3H) -benzimidazolone, carbon dioxide being lost in the process (174). The reaction of phthalic anhydride with hydrazoic acid in concen-

258

Chemistry of Classcs snd Derivatives

trated sulfuric acid also leads to the formation of 2(3H) -benzimidasolone (175,176). 2-Ethoxybensimidasole, prepared from o-phenylenediamine and diethylimino carbonate, is a derivative of the tautomeric 2-hydroxybensimidasole form of 2 ( 3 H )-benzimidazolone. Drastic hydrolysis with hydrochloric acid leads to its conversion into 2 (3M) -beneimidazolone (177). H

H

1,3-Dimethylbenzimidazolone results froai the oxidation with a h line permanganate of 1,3-dimethyl-2-hydroxybcnzirnidazolineor of 1,2,3trimethylbenzimidazolium iodide. The 2-methyl group in the latter compound is lost during the oxidation. The reaction seems to proceed through the 1,2,3-trimethyl-2-hydroxyimidazolinestage (24.51,74,152~.

1-

011-

CH j

A unique synthesis of nitrated l-methyl-2(3H~-benzimidazolones involves the reaction of o-nitro-N,N-dimethylanilines with zinc chloridtin acetic anhydride. 'Thc primary reaction products are the 3-acetyl derivatives of the 1-methyl-2 (3H)-benzimidazolones; these undergo hydrolysis on treatment with di1ut.e sodium hydroxide to give the final products. Formation of 5-nitro-1-methyl-2 (3H)-benzimidasolone froin 2,4dinitro-N,N-dimethylanilineserves to illustrate the reaction. The structure of the 5-nitro-1-methyl-2 (3H)-benzimidszolone follows clearly from its identity with the product of the reaction of phosgene with 2-amino-4nitro-N-methylaniline (166).

VIII. Benoimidazoles

289

Bz-Substituted 2 (3H)-benzimidazolones are prepared according to the general procedures outlined. 2,4-Dinitro-N-carbethoxyaniline,for example, is readily converted into 5-amino-2 (3H)-benzimidazolone by reduction with tin and hydrochloric acid and heating of the ensuing diamino compound (178).

2 (3H)-Benzimidazolone-4-carboxylic acid and 2 (3H)-benzimidaeolone-5-carboxylic acid result when 2,3-diaminobenzoic acid and 3,4-diaminobenzoic acid, respectively, are treated with phosgene (13,20,179, 180).

H

CI

SH,

O=C-CI

X-H

COOH

COOH

HOOC a

m

-

H

CI

XII?

,

O=C-CI

HOOC

2(3H)-Benzimidaeolone (melting pt. 311") exhibits a high degree of chemical stability. This is evidenced by its resistance to the action of concentrated hydrochloric acid at 200" and'its stability to distillation over

Chemistry of Classes and Derivatives

2 0

red-hot zinc dust. It is sparingly soluble in cold water or dilute hydrochloric acid, but dissolves readily in concentrated hydrochlorio acid or dilute alkali. A di- and a monosodium salt are known. The former precipitates when 25 per cent aqueous sodium hydroxide is added to a solution of 2 (3H)-benzimidazolone in sodium hydroxide, the latter is obtained in crystalline form when one equivalent of 10 per cent. aqueous sodium hydroxide is added to an ethanolic solution of 213H)benzimidazolone. Both salts hydrolyze upon exposure to hot water. 2(3H)-Benzimidazolone forms a silver salt. As a very weak base, it dissolves in concentrated hydrochloric acid, but is precipitated unchanged on dilution with water (181). Refluxing with acetic anhydride, or treatment with acetyl chloride in pyridine solution, converts 2 (3H)-bemimidazolone into 1,3-diacetylbenzimidazolone. A 1,3-dibenzoyl derivative is readily obtained when 2 (3H)-benzimidazolone is benzoylated with benzoyl chloride in pyridine, or from the interaction of its disodium salt with benzoyl chloride in benzene. These acyl derivatives are readily hydrolyzed by dilute acids or bases (131,181). Heating with methyl iodide converts 1-methyl-2 (3H) -benziniidaeolone into 1,3-dimethyl-2-benzimidazolone,identical with the compound resulting from pernianganate oxidation of 1,3-dimethyl-2-hydroxybenzimidazoline (51,74). Treatment with phosphorus oxychloride converts a number of 2 (3H)-benaimidazolones into the corresponding 2-chlorobenzimidazoies (131,166). The 2 (3H)-benzimidazolones undergo electroyhilic substitution a t the 5(or 6)-position. Exposure to a mixture of concentrated nitric and sulfuric acids converts 5-nitro-2 (311)-benziniidazolone into 5,6-dinitro2(3H~-benzimidazolone(131).

B

B

2 (3H)-Benzimidazolone reacts readily with succinic or glutaric anhydride in the presence of aluminum chloride to give 5- (3-carboxypropionyl) and 5- (4-carboxybutyryl) -2 ( 3 H )-benzimidszolone. Clemmensen reduction converts these keto-acids into 5- (3-carboxypropyl) and 5- (4-carboxybutyl) -2 (3H)-benzimidazolone, respectively. Their nonidentity with 4- (3-carboxyprapyl) - and 4- (4-carboxybutyl) -2 (3H)-benzimidazolone establishes the orientation in the Friedel-Crafts acylation. The 4-substitution products are readily prepared from the respective diaminocarboxylic acids and phosgene (13). Reduction over A d a m

-

-

Vm. Benzimidazoles

291

catalyst in glacial acetic acid converts 2 (3H)-benzimidazolones into ureylenecyclohexanes ( 13). Some of these, especially 7- (3,4-ureylene-

cyclohexane) butyric acid, have the ability to antagonize the growth promoting effects of biotin for a number of microorganisms.

7- (3A- U re) lenecy dohexsine) butyric acid

3. 2(3H)-Benzimidazolethiones (o-Phenylenethioureaa, 2-Mercaptobenzimidazolea, ZBenzimidazolemercaptans, 2-Benzimidazolethiols. 2-Thiobenzimidazolone, o-Phenylenethiocarbamides)

A variety of methods are available for the conversion of o-phenylenediamine into 2 ( 3 H )-bensimidazolethione. These include its interaction with potassium ethylxanthate (182), t.hiophosgene ( 183), thiourea (164, 169,184,185), carbon disulfide and alkali (105,?.49,185-194) , and ethyl ethylxanthoformate (195). Interaction between the dihydrochloride of

292

Chemistry of Classes and Dcrivativcs

o-phenylenediaminc with somewliat inore tlitrii two cquiv:rlciitb: of itiiirnonium thiocyanate is another convenient preparative method ( 196,197). Several of these general procedures have found application to the syn-

thesis of substituted 2(3H)-benzimidazolethiones. 2(3H)-Benzimidazolethione is a colorless solid (m.p. 312313") which dissolvea in dilute sodium hydroxide with the formation of a sodium salt. The sodium salt is also readily prepared by treating 2(3H) -benzimidazolethione with sodium ethoxide in ethanol; it is a white powder exhibiting an alkaline reaction (198). 2 ( 3 H )-BenzimidazoIetliione is insoluble in cold watcr and dilute mineral acids, but dissolvcs in hot wntcr or ethanol. It is sparingly soluble in other organic solvciits. One of the iiiost characteristic properties is its capacity to form sparingly watcr-soluble complex salts with such cations as those of Cu, Cd, Bi, Pb, Ag, Hg, Au, and Pd. In the presence of aiiiinoniuin hydroxide, cupric ion is quantitatively precipitated in the form of a dark-blue copper complex of the composition (C7HsNrS)CuOH. On ignition, this complex salt is converted quantitatively into CuO . Under similar conditions, Pb and Cd ions are precipitated as the coniplcx salts (C71i&S)PbOH and (C7Hr,NrS)CdOH.NHs,rcspcctivcly 199-203). Alkali or alkaline earth ions do not intcrfcrc in tlicsc rcvwtiotis. 2(31-1) -Bcnziiiiidazolctliiot~cis :L liiglily sclcctivc rcagciit for bisinutli, and is selective for Hg, Cd, Co, and Cu in thc absence of Ag. The blueMack coppcr and the bluish-green cobalt coniplcxes arc soluble in aqueous sodium hydroxide and can readily be separated from the white Hg and Cd precipitates which are insoluble. The Cd complex is soluble in acetic acid and is thus scparable from the insoluble Hg precipitate. 2(3H)Benzimidazoletliione is recommended as a specific reagent for palladium. The yellow-orange Pd complex is insoluble in dilute sodium hydroxide, in contrast t o the orange Bi precipitate which is soluble. Thus, with this reagent, palladium gives the only colored precipitate which is insoluble in caustic soda: dilution limit, L:25O,OOO (204). Oxidation with iodine transforins 2( 3 H )-benziiiiidazolethione into the disulfide (205). Alkaline potassium permanganate brings about its transformation into 2-benziinidazolesulfonic acid (2051 (see Section 1-2).

VIII. Benzirnidazoles

2x3

Methylation with dimethyl sulfate and alkali (194), or with methyl iodide in the presence of sodium ethoxide, leads to S-alkylation. 2(3H)Benzimidazolethione reacts readily with ethyl chloroacetate in the presence of sodium ethoxide to give 2-carhethoxymethylthiobenzimidazole (198,!206).

-

4. Hydroxyalkylbenzimidazoles

(a) 1 (Polyhydroxyalkyl)benzimiduzoles ( 1-C;773cos.lllbenzir,Lidazoles) A most important representative of this class of compounds is 1-a-Dribofuranosyl-5,6-dimethylbenzimidazolo(ribazole), a hydrolytic degradation product of vitamin BIZ. The structwe of ribazole is based on the following unequivocal synthesis. 2-Nitro-4,5-dimethylaniline is condensed with 5-O-trityl-~-ribofuranoseto give 2-nitro-4,5-dimethyl-N- (5‘-0- trityl-D-ribofuranosyl) aniline which is converted into 2-arnino-4,5-dimethylN-(5’-0-trityl-~-ribofuranosyl)aniline by catalytic hydrogenation. Condensation of the reduction product with formimino ethyl ether hydrochloride followed by acid hydrolysis t o remove the trityl group yields the crystalline 1-~-~-ribofuranosyl-5,6-dimethyIbenzimidazo~e. The synthetic material is identical with the product obtained from vitamin BIZ. It forms a picrate (137w7). See equation ( I ) , page 294. The interaction of the silver salt of a benzimidazole with a polyacetylglycosyl halide provides another preparative route to l-glycosylbenzimidazoles. Benzimidazole silver, for example, reacts with tetra-0acetyl-a-D-glucopyranosyl bromide to give 1-(tetra-O-acetyl-P-Pgluco-

Chemistry of Classes and Derivatives

294

CH:-OTr

I

H-C-OH H-t-0.

H-

I __c

NO:

7

H-C-OH

H-C-OH

H-C-OH

H-{-oH

H-

bI

HL+aNH& H rC

NO,

1

0

.&aNH H-C

I

HC

CHI-OH

\

J

CH,-OTr

I

I

_EtO,pC-H KHa CiH?RI

(11

H-C-OH H-

Ribamle

-

Tr Triphenylmethyl

pyranosyl) benzimidazoie. This reaction, which involves a Walden inversion from the a to the p anomer of the sugar residue, may be carried out in boiling xylene.

o-Nitroaniline or subst.itutedo-nitroanilines are of general importance as starting materials for the preparation of 1-glycosylbenaimidazoles. They combine with aldoses to give N-glycosyl-o-nitroanilines, and these are readily converted into N-(0-polyacetylglycosyi)-0-phenylenedi-

VIII. Benzimidazoles

295

amines by acylation and catalytic reduction. Ethyl orthoformate transforms this type of compound into N-(0-polyacetylglycosyl) -N'-ethoxymethylene-o-phenylenediamines which undergo ring closure on treatment with dilute hydrochloric (or, in some instances, picric) acid to give 1-(0-polyacetylglycosyl) benzimidazoles. The acetyl groups are readily removed by hydrolysis with 6 N hydrochloric acid (86,!208,!209). CHgOH

CHiOH

I

" 3 1

CHgOAc

0

(H-C-OH)

H-7

"-Fl I

1"1

CH~OAC

CHIOAC

H6 X HCI

The conversion of a N-glycosyl-o-phenylenediamineinto a l-glycosylbenzimidszole may likewise be brought about by the thioformamide route. N-Glycosyl-o-phenylenediaminesreact with sodium dithioformate to give N-glycosyl-N'-thioformamido-o-phenylenediamineswhich undergo benzimidazole formation upon exposure to pyridine at the boiling temperature (137). As typical benzimidazoles, the 1-glycosyl derivatives form CHSOH

-a H-C

+Hs>CH NHt S'

CHRH

I

NH 1c NH

s ,H

C&N

(H-C-OH) €3-C

0

'"I

&-H

' k

salts with acids. The frec bases are readily obtained from the hydrochlorides by passing their aqueous solutions through a column of a suitable ion-exchange resin, e.y., Amberlite IR-&. The l-glycosylbenzimidazoles are high-melting, crystalline solids exhibiting a rather remarkable stability toward acid hydrolysis. The synthesis of l-~-arabityl-2,6-dimcthylbenzimidazole may serve to illustrate a preparative route to 1-glycitylbenzimidazoles. The reductive condensation of 2-acetamido-5-metliylaniline with L-arabinose leads to the formation of 2-acetamido-5-methyl-W- (L-arabityl) -aniline which, under the influence of 10% hydrochloric acid, is converted into l - ( ~ arrtbityl) -2,6-dimethylbenzimidazole. The 1-glycitylbenzimidazoles are Irigli-melting, solid compounds whicli inay bc recrystallized froin hot

water They tare not perccpt.ibly attacked by 6 N hydrochloric acid a t 150" (210). ( b ) 9- (Monohydroxyulkyl)benzimiduzoles The reaction of a hydroxycarboxylic acid with o-phenylenediamine in thc prcscnce of dilute mineral acid (see Section C-3) is a convenient incthod for the preparation of 2- (hydroxyalkyl)benzimidazoles. Thus, glycolic, lactic, or rnandelic acids react with o-phenylenediamine to form the corresponding hydroxyalkylbenximidazoles (127,39).

Optically active hydroxy acids afford the corresponding optically active benzimidazoles. Thus D- and L-lactic acids condense with o-phenylenediamine in the presence of a mixture of hydrochloric and phosphoric acids to give the respectivc optically active 2- (1-hydroxyethyl) henzimidazoles (211).

VIII. Benairnidazoles

29i

Oxidation of 2-hydroxymethylbenzimidazole with alkaline potassium permanganate leads to the formation of 2-henzimidazolecarboxylic acid. Oxidation converts 2- (phenylhydroxymetliyl)benzimidazole into 2-benzoylbenzimidazole ( 137). The reaction of 2-hydroxymeth ylbenzimidaeole with thionyl chloride gives the highly reactive 2-chloromt?thylbenzimidazole hydrochloride (see Section G-3). 2-MercaptometIrylbenzimidnzoleJreadily prepared from o-phenylenediamine and thioglycolic acid, has the ability to form ehelates with it number of metals (212).

(c)

d- ( A Z d o p o ~ ~ h y d r o ~ ~benzirnidazobs ~lkyl)

The 2- (aldopolyhydroxyalky1)bcnzimidazoles* of the general structure (I) exhibit properties which render them highly valuable for the characterization of carbohydrates. They result from the condensation

of aldoses, aldonic acids, or aldonic acid laetoiics with o-phenylenediamiiic. The evaporation bf an aqueous solution containing an aldose and o-phenylenediamineleads to the formation of a mixture of products composed essentially of three components, namely, a benzimidazole, a S c M base, and a quinoxaline. The reaction was first investigated by Griess and Harrow (213-215), who failed, however, to recognize the imidazole nature of the major reaction product. The currently accepted structure *The knzirnidazole derivative of pglucose may serve to illustrate the nomenclature. Expressed in tlw most general terms, this compound is R 24pentaliydiossl,ei~tyi)beusiniidazole. In order to identify its carbohydrate portion with tlrrit of &glucose, tiic prefix n-gluco is inserted, thw leading to the name 2 4 0 gl~u.o-pentahydrox~entyl)bcnzimid,lcole. Othcr representatives of the series :we similarly designnted.

298

Chemistry of Classes and Derivatives

for the aldobenzimidazoles was proposed by Hinsberg (216) and estsblished by Ohle (217). Due to the complexity of the reaction, which involves oxidation and condensation steps, the direct conversion of aldoses into aldobenzimidazoles affords poor yields. These are improved for certain carbohydrates when cupric acetate is added to the reaction mixture (Weidenhagen procedure) (218,219). The best procedure for the conversion (in high yields) of aldoses into aldobenzimidazoles well suited for identification purposes was developed by Link and collaborators (14,218-220). It involves: ( 1 ) the oxidation of an aldose to the aldonic acid with hypoiodite in methanol solution, and ( 2 ) condensation of the latter coinpound with o-phenylenediamine in the presence of a mixture of hydrochloric and phosphoric acids a t 135" (Phillips procedure). The condensation of aldonic acid lactones with ophenylenediamine in the presence of hydrochloric acid is another good method (221). The 2- (aldopolyhydroxyalky 1) benzimidazoles crystallize well and their chemical behavior is that of typical imidazoles. They dissolve in hydrochloric acid to give non-mutarotrating solutions from which they are pccipitated by the addition of ammonium hydroxide. Crystalline salts are readily prepared with strong acids, the hydrochlorides and picrates being especially useful for chsract.erization purposes. The melting points, and optical rotations in citric acid solution, of a number of aldobenzimidazoles and their hydrochlorides and picrates are summarized in Table XXXI on page 299. As optically active basic compounds, the 2- (aldopolyhydroxyalky1)bcnzimidazoles are useful reagents for the resolution of racemic acids. An example is the resolution of DL-tartaric acid. The L-form of this acid forms 8 well-crystallized salt with 2- (D-gkico-D-gulo-hepto-hexshydroxyficxyl)benzimidazole, but the salt of its antipode fails to crystallize and remains in the mother liquors (221). The 2- (aldopolyhydroxyalkyl) benzimidazoles fail to reduce Fehling's solution. They dissolve in concentrated sodium hydroxide and are insoluble in alkali carbonates. Ammoniacal solutions of silver, zinc, and copper cause the formation of insoluble complex salts. The 2- (aldopolyhydroxyalkyl) -benzimidazoles undergo N-alkylation on trestment with alkyl halides, and are oxidized by potassium permanganate to 2-benzimidazolecarboxylic acid. Exposure benzimidazole in alkaline solution of 2- (D-galactopentahydroxypentyl) to ultraviolet light leads to the formation of a small amount of benzimidazole (224).

VIII.

TABLE XXXI. Properties of a Number of azoles

2- (Aldopolyhydroxyalkyl)beneimid-

Rewiniidazole

Carbohydmte

(1)

PAltrose

+-

PArabinoae

drabinme D-Digitoxose D-Erythrose L-Erythrose rpFucose D-Galactose L-Galactose *Glucose LGlucose D-GUIW PIdose PLyXOse

L-Lyxose o-Mannose L-Rhamnose D-Ribose D-Tahse D - XIoee ~

-

M+., "C.

+ -

-

+ ++

+-

++ -

+

198

235-230

235 207-209 177-178 177-178 248-249 246 250

215 21s 201 154-158 189 189 n7 207 190 190-191 141-143

299

Benzimidazoles

Hydrochloride

OD (2)

Picrate

M.P., "C.

M.P.,'C.

-48.1* -49.4 +492 -45.7 + 9.0 - 8.3 -41.2 +445 -44.1 + 9.0 - 9.0 +16.7* -192* -12.8

230 230 Oil

158 158 124-127

224-225 202-204

189-191 217

180

203

191

95-99

-22.0 +27,4

101-150 173-175 196-198

205 168 185-186

+20.0*

181-182

+22.5 -23.0*

Ref. Xo.

(221)

cnom,

(220)

(219) (222) (222) (219) (220)

(222) (220) (222) (221)

(221) (220)

(223) (220) (220)

(219) (221, (14)

(1) A plus sign indicates that the number 2 hgdroxyl group is on the right and a minus sign indicates that the hydroxyl group is on the left, when the aldonic acid is written in the usual vertical projection formula. (2) In 5% citric acid solution. * In 1 N hydrochloric acid.

When treated with ninc chloride in concentrated hydrochloric acid, one molecule of certain 2- (aldopolyhydroxyalkyl) benzimidazoles lose a molecule of water with the formation of 2- ( 1',4'-anhydropolyhydroxyalkyl.) benzimidazoles. This behavior is observed with D-x~ZO-, n-urubo-,

.fi p"y 0"

~ ~ - - C - - C - I- C -l - Cl H , O H

ZIIClt

N H OHH

D-Z~XO-, and D-ribobensimidazoIes, but undoubtedly also occurs with other representatives. The anhydro derivatives differ from the 2- (aldopolyhydroxyalky1)benzimidazoles in their ultraviolet absorption spectra and their behavior

300

Chemistry of CJa.ws and Derivat’ives

toward periodate. One mole of 2- (~-arabotctr~rliydroxybutyl) benzimidttzole, for example, consunies three moles of periodate with the formation of one mole of 2-benzirnidaeolecarboxaldehyde,two moles of formic acid, and one mole of formaldehyde, while one mole of its anhydro derivative reacts with four moles of the reagent to give a mixture of one mole of 2-benzimidazolecarboxylic acid, two moles of formic acid, and one mole of formaldehyde (14). Of particular interest to carbohydrate chemistry is the correlation between the stereo structure of an aldose and tile optical rotation of its bcnzimidazole derivative. This correlation is known as the “benzimidazole rule” (222). It states that “whenever the hydroxyl group on the second (or alpha) carbon atom of an aldonic acid is on the riglit in the conventional projection formula, the rotation of the derived benzimidazole is positive, and conversely, when the liydroxyl group is written on the left, the rotation of the benziinidazole derivative is negative.” A large number of carbohydrates have been shown to obey this rule which is a useful guide in confirming their configurations. ( d ) Aldarodibenzimidazoles

The oxidation of uronic acids with hypoiodite in methanol leads to the respective aldaric acids. These undergo condensation with two molecules of o-phenylenediamine in the presence of liydrochloric and phosphoric acids a t 1 3 5 O to form the well-crystallized, high-melting aldarodibenzimidazoles. The properties of these derivatives are similar to those of the 2-aldobenzimidazoles (225). Table XXXII summarizes tlic melting points and optical rotations in citric acid solution of three aldarodibenzimidazolcs and of their hydrochlorides and picrates. ‘I‘ARLE XXXII.I’ropcrtirs of Some .4ldnrodibcnzimitl,zzoLs (225) Dihpnrirnirlnrole

Hydrochloride

Picrate

Hexiironic acid

M.p.. ‘C.

.;b”

M.P., ‘C.

M.p., ‘C.

D-Cliwnronit! ihhlmnnuronic wGslacturonic

238

+603

298

0.o

267-258 256-251 318

211 24 1 250

250

- 1.3

L..

.-

G. The Halogenobenzimidazoles 1. Bz-Halogenobenzimidiamlea

Bz-Halogenobenzimidazolescontaining halogen at.oms a t estahlished positions are prepared hy the general methods outiincd in Section C.

VIII. Benzimidazoles

301

2,5-Dichloronitrobenzene, for example, may serve as the starting material for the preparation of 1-alkyl- or 1-aryl-5-chlorobenzimidazoles. The reactive 2-chlorine atom is displaceable by amine residues to give 2nitro-4-chloro-N-alkyi-, or 2-nitro-4-chloro-N-arylanilineswhich inay be reduced to the corresponding substituted o-plienylenedia~nines. Tliesc are readily converted into the I-alkyl- or 1-aryl-5-chlorobenziniidazoles by conventional methods (194).

The direct halogenation of benzimidazoles has received little attention, and in only a few instances has the position of a halogen entering the benaimidazole nucleus been established with certainty. The chlorination of 2-aminobenzimidazole has been thoroughly investigated. In the presence of hydrochloric acid and hydrogen peroxide, this substance is chlorinated in the 5(or 6)-position. The chlorination product is identical with the 2-amino-5 (or 6) -chlorobenzimidazole resulting from the reaction of 3,4-diaminochlorobenzene with cyanogen bromide (226).

Treatment of 2,5 (or 2,6) -dimethylbenzimidaeole with calcium hypochlorite leads to the formation of a monoohlorobenzimidasole in which the halogen is loosely bound. The compound regenerates the original bemimidazole on treatment with hydrochloric acid. Refluxing in benzene solution converts this substance into a chlorobenzimidaaole in which the halogen is firmly bound. The process seems to involve the initial substitution of.the imino-hydrogen by chlorine followed by a migration of the chlorine atom into the benzene ring. The rearranged chlorodimethylbenzimidazole may again be subjected to the same sequence of reactions, thus giving rise to a dichlorodimethylbensimidaaole. The process may be repeated until all the available positions on the benzene ring have been substituted by chlorine. The resulting trichlorodimethylbenzimidazole is

302

Chemistry of Classes and Derivatives

still capable of forming a N-chloro derivative on treatment with calcium hypochlorite. This substance remains unchanged when refluxed in benzene, and regenerates the trichlorobenzimidazole when subjected to the action of hydrochloric acid (2).

A number of substit u t d 1-phenylbenzimidazoles undergo chlorination in the presence of one equivalent of chlorine to give the corresponding 4chloro derivatives. l-PiienyI-2-met~hyl-5-acetsmido-, l-phenyld-hydroxy-, and l-phenyl-2-metliyl-5-liydroxybenzimidazoleare compounds exhibiting this behavior (227). 2-Methylbenzimidazole readily absorbs bromine in acetic acid solution to give polybromo derivatives of unknown structure in which the bromine is not firmly bound. Boiling in benzene solution, or heating with aniline rearranges these compounds into substances containing firmly bound bromine in the benzene portion of the molecule (228,229). Treatment of benzimidszole with iodine in the presence of alkali converts the compound into a monoiodobenzimidazole. The iodine is highly reactive and is liberated by treatment with dilute acetic acid. The compound is assumed to be 2-iodobenzimidazole (230). 2.

~-C~IWO~~IIZ~~~&ZOI~II

A few comments regarding the properties of the 2-chlorobenzimidazoles seem of interest since the reactivity of halogens in the 2-position differs markedly from that of halogens in the benzene portion of the ring system. 2-Chlorobenzimidazoles result from the treatment of 2 (3H) benzimidazolones with phosphorus oxychloride. The conversion of 5 (or 6) -nitro-2 (3H)-benzimidazolone into 2-chloro-5 (or 6) -nitrobenzimidazole is illustrative. The chlorine in this compound is capable of undergoing

-

VIII. Benzimidazoles

303

typical displacement reactions. Prolonged refluxing of 2-chlorod (or 6) nitrobenzimidazole with hydrochloric acid leads to the regeneration of 2 (3H)-benzimidazolone, whereas heating with aniline brings about its conversion into 2-anilino-5 (or 6) -nitrobenzimidazole. Heating with aqueous ammonia at 220' results in the formation of 2-amino-5 (or 6) -nitrobemimidazole (131,166). Halogens in the benzene portion of the benzimidazole ring are not displaced under similar conditions. The electron deficiency of the 2-position in the benzimidazoles seems to favor attack on that position by a nucleophilic reagent and thus may explain the displaceability of the chlorine in the 2-chlorobenzimidazoles. I n the example cited, the nitro group enhances the effect because of its electronattracting power.

3. 2-Chloroglkylbenzimidamlea

2-Chloromethylbenzi~dazole, because of its readily displaceable chlorine atom, serves as a convenient intermediate for the incorporation of the 2-benzimidazolemethy1 moiety into other molecules. The compound is readily prepared from o-phenylenediamine and chloroacetic acid, or better, from 2-hydroxymethylbenzimidazoleand thionyl chloride (212,231). Another method of preparation involves the interaction of

r+

HOOC-CH*-OH

-

H I

304

Chemistry of Clnsscs nntl Derivatives

o-phenylenediamine with chloroacetimino ethyl ether hydrochloride in ethanol (232). Exposure of 2-chlorometl~ylbenziidazole to the action of potassium iodide in acetone solution results in rapid displacement of the chlorine by iodine. The rate of the reaction exceeds that observed with ally1 chloride under comparable conditions. Short boiling with water converts 2-chloromethylbenzimidazole into 2-hydroxymethylbenzimidazolc. 2-Chloromethylbcnzimidazole fails to € o m a Grignard reagent, and its reaction with cyanide ion or ammonia leads to the formation of ill-defined products. It reacts with aliphatic amines to give 2-alkylaminomethylbenzimidazoles (see Section H-2-c) . l-Methyl-2-chloromethylbenzimidazole,on refluxing with potassium cyanide in aqueous ethanol, is transfornied into. 1-methyl-2-1)enziinidazolcacetamide, the initially formed nitrile undergoing further hydrolysis to t lie sinide under these conditions. 2-Chloromethylhenziniidazole dimerizes with the formation of a piperazine derivative wlicn it is subjected to the action of ethanolic sodium etlioxide (233,234). 2- (2-Chloroethyl) -

benzimidazole results from the interaction of #?-chloropropionic acid with o-phenylenediamine, or from the hydrolysis of 2- (2-etlioxyethyl) benzimidazole with concentrated hydrochloric acid. It is 8 highly unstable compound, undergoing epontaneous decomposition on standing at rootii temperaturc. Boiling wiBh water or dilute sodium hydroxide results in dehydrohalogenation with the formation of insoluble polymers (235).

H. The Nitro- and Aminobenzimidazoles 1. Nitrobenzimidazoles

Benzimidazole is nitrated in the benzene ring with the formation of 5(or 6) -nitrobenzitnidazole. The position of the nitro group follows from the non-identity of the compound with 4(or 7) -nitrobenzimidazole and its unequivocal synthesis from 3,4-diaminonitrobenzene and formic acid (7~6,146,227,236). 2-Methylbenaimidazole is nitrated with the forma-

B

VlII. Benzimidazoles

305

tion of 2-methyl-5 (or 6)-nitrobenzimidazole (146), whereas 5 (or 6)inethylbenzimidazole is converted into 5 (or 6) -methyl-6 (or 5)-nitrobemimidazole by nitration (146). The nitration of 2,5 (or 2,6) -dimethylbenzimidazole results in the forination of 2,5(or 2,6) -dimethyl-6(or 5 )-nitrobenzimidazole (146). The position of the nitro group htts heen itnequivocally established in all these examples. The observation that 1,3-dimetliyl-5(or 6)4trobenzimidazolium s i t s are subject to ring fission on treatment with hot alkali (see Section E) provides a convenient method for establiehmg the orientation of the nitro group in nitrobenzimidazoles (146). The behavior of 2-methyl-5 (or 6)nitrobenzimidaeole serves as an illustration. Treatment with methyl iodide and alkali converts this substance into the same N,N'-dimethyl-3,4diaminonitrobenzene as resultr, from 5(or 6) -nitrobenzimidazole under similar conditions. The nitro group must, therefore, occupy the same position in both compounds.

sra 7

CHI I

o*NcK:;

H I

S F

c-- OZN

CHa I

OZN

Coniparison with synthetic specimens, prepared from suitably oriented nitrobenzene derivatives, provides another route for establishing the position of the nitro group in nitrobenzimidazole. 3,4-Diaminonitrobenzene, tor example, reacts with acetic anhydride and dilute hydrochloric acid t.u give the same 2-methyl-5 (or 6)-nitrol)cnzimidazole as that obtained by clircct nitration of 2-methylbcn7,imid8l;olc (63).

B

B

During the discussion of the fine structure of benzimidazole (see Section B-3),it has been pointed out that conjugation between the benzene and the imidazole ring, as illustrated by structures A and B, may offer a plausible explanation for the difference in basic strength of the imidazoles and the benzimidazoles. These contributions, which depict an electron drift from the nitrogen atoms to the 5(or 6)-pouition on the benzene ring, may also explnin the reactivity of the 5 (or G) -position in benzimidazole toward clcctrophilic substitution. The effect will be lcss pronounced in the benziinidszolium ion (Structures C and D) ,which seems to be tlte reactive entity in the nitration process.

306

Chemistry of Classes and Derivatives

H

H

In contrast to 4(or 5)-nitroimidazole, which resists further nitration, it is possible to introduce a second nitro group into certain mononitrobenzimidazoles. Drastic treatment with a mixture of concentrated nitric and sulfuric acids converts 2-methyl-5 (or 6)-nitrobexuimidazole into 2metl~yl-5,6-dinitrobenzimidazole.The structure of the dinitro derivative follows from its conversion, by reduction and treatment with acetic acid, into 2,BdimethylbenzoC1,2,4,5]bisimidazole (131). (R.I. 1364). Its synthesis from 1,2,4,5-tetraaminobenzeneor from 1,3-diacetamido-4,6dinitrobenzene by conventional methods establishes the constitution of this bisimidazole (237). The nitration of 1,2-dirnethyl-5-nitrobenzimidazolc leads to the formation of 1,2-dimethyl-5,6-dinitrobenzimidazoleas

the major reaction product, accompanied by a small amount of 1,2dimethyl-4,5-dinitrobenzimidazole (227). 4 (or 7) -Nitrobenzimidazole is prepared from 2,3-diaminonitrobenzene and formic acid (16).

VIII. Benzimidazoles

307

The formation of 1-phenyl-2-methyl-4,7-dinitro-6-hydroxybenzimidazole by the interaction of 2,3,5-trinitro-4-acetamidophenoland aniline illustrates another route to nitrated benzimidazoles. The labile 3-nitro group in the 2,3,5-trinitro-4-acetamidoplienol is displaced by the aniline residue to give 2,5-dinitro-3-anilino-4-acetamidophenolwhich, in turn, loses the elements of water to form the final benzimidazole. A variety of

k0,

nitrated benzimidazoles have been prepared by this method (133,238-241). The nitrobcnzimidazoles are high-melting solid compounds, soluble in mineral acids and alkali hydroxides. They form salts with acids and are more acidic than the alkylbenzimidazoles (see Sections B-2,and B-3). The observation that 4 (or 7) -nitrobenzimidazole is more volatile, l e s ~ associated in phenanthrene solution, and a weaker acid than 5(or 6)nitrobenzimidazole points to significant contributions from internally hydrogen-bonded structures (242). .

308

Chemistry of Classes and Derivatives 2. Aminobenzimidazoles

(a) Rz-Atninobenzimid~zoles

The reduction of nitrobenzimidazoles, or the application of conventional benzimidaeole syntheses to polyaminobensene derivatives, provide practical routes for the prepamtion of Hz-aminobenrimidaroles (21,62,73, 168,242-245). Reduction of 8 (or 6) -nitrobenzimidazole with ferrous sulfate in the presence of hydrochloric acid leads to the formation of salts of 5(or 6)uminobenzimidazole (16,2361. 2-Methyl-5 (or 6) -aminohnzimidaeole is obtained in the form of its dihydrochloride by reduction of 2-methyl-5 (or 6) -nitrobenzimidazole, or on treatment of 3,Cdiacetamidoaniline with boiling 4 N hydrochloric acid (22). 4 (or 7)-Formamidobenzimidazole results from the reaction of 1,2,3trianiinobensene with formic acid. Hydrolysis with dilute hydrochloric acid converts the compound into the dihydrochIoride of 4(or 7)- aminobenzimidazole. The free base is liberated on addition of ammonia to the dihydrochloride (16,242). Bz-Polyaminobcnzimidazoles are prepared according t o the general methods mentioned above. 4,6 (or 5,7) -Diamino-2-metl1ylbenzimidaxole results on treatment of 1,2,3,5-tetraacetainidobenzenewith sulfuric acid (8). Reduction of 5,6-dinitrobenzimidazoleaffords 5,6-diaminobenzitnidazole (63,131). 5(or 6) -Aminobenzimidazole has the ability to form complex salts. The addition of ammonia to an aqueous solution of its tin double salt precipitates the complex salt (C7H7N3) zHCl.2H20 and not tlic free bnsr. This salt melts at 108.5-109O, and decomposcs on distillation. Treatinent. of the complex salt with concentrated sodiuni hydroxictc lilxrat(1s the f r w haso wliicli melts at 166.5-167O, and boils without decoinposition a t 216” (0.4 mill.). Siinilar complex salts containing bromide, iodide, nitratc, perchIorcito, and trichloroacetate ions are also known. In addition to tliesc 4 complex salts, the base forms a mono- and a dihydrochloride (132). The free Bz-aminobenzimidasoles are colorless, crystalline substances which darken on exposure to air. They are diacidic bases, forming characteristic salts with acids. Their functional behavior is that of “aromatic” amines. Diazotization of 2,5 (or 2,6) -dimethyl-? (or 4) -sminobenzimidazole leads to foriiiution of :I normal diazoirium salt wliic.11 couples with *odium p-n:iplrtlroxitlc (246). The Bz-aininol~cnsimidnzolcuform dinzoiiinino compounds upon reaction with cliazotised aromatic nmincs in nretic arid solution (227).

VIII. Rcnzimitlnzoirs

300

They react with acetic anhydride to give diacetyl derivatives, in which one acetyl group substit.utesthe imino hydrogen, the other being located on the amino group. These acyl groups are, of course, readily distinguishable by their different stabilities toward acid hydrolysis. Short treatment with dilute acetic acid at room temperature is usually sufficient to bring about removal of the acetyl group from the imidazole portion, thus leading to the formation of Bz-monoacetamidobenzimidaxoles. More drastic hydrolysis is required for removal of the second acetyl group (246). ( b ) 2-Aminobenzirnidazoles (0-Phenyleneguanidinss) The 2-aminobenzhnid~zoles,which result from the interaction of o-phenylenediamines and cyanogen bromide, differ markedly in their chemical behavior from the Bz-aminobenzimidazoles (226,247). Tautomerism between the 2-arninobenzimidazole and the o-phenyleneguanidine structure is indicated. As guanidine derivatives, the 2-aminohenz-

+

Br-

imidazoles are monoacidic bases forming salts of the general structure illustrated. Drastic hydrolysis with barium hydroxide at 180-190°,

or reaction with nitrous acid, transforms 2-aminobenzimidazole into 2(3N)-benzimidazolone. The compound exhibits a high degree of sta-

310

Chemistry of Classes and Derivatives

bility toward acid hydrolysis, most likely because of increased resonance stabilization of the highly symmetrical guanidinium ion. Benzoyl chloride in pyridine c0nvert.s 2-aminobenzimidazole into a monobenzoyl derivative, possibly 1-benzoyl-2-aminobenzimidazole. 2-Aminobenzimidazole reacts with arylsulfonyl chlorides to give alkali insoluble 1-arylsulfonyl-2-aminobenzimidazoles (226,248,249). These are rather labile, and short warming with alkali followed by acidification with acetic acid converts them into the respective arylsulf onic acid salts of 2-aminobenzimidazole.

H

10,

2-Arylsulfonylamidobenzimidazoles result from the interaction of o-phenylenediamine with arylsulfonylguanidines (249). The interaction

of o-phenylenediamine with diarylcarbodiimides (250) or with methyldiarylisotliiourcas (251) Icads to the formation of 2-arylaminobenzimidazoles. These are rather st,aI.de toward acid hydrolysis.

( c ) Aminoalkyl- and Aminoa.ryZbenzimnidazoles The simplest representative of this class of benzimidazoles, the compound 2-aminomethylbenzimidazole,is obtained in the form of its dihydrochloride when 2-benzitmidomethylbenzimidazole is hydrolyzed with

VIII. Bendmidazolea

311

concentrated hydrochloric acid. 2-Benzamidomethylbemimidazole is readily prepared from hippuric acid and o-phenylenediamine by the Phillips procedure (2 12). 2-Aminomethylbensimidazole offers possibilities HI

t- HOOC-CH1--N-CO

6>% ~ ~ - c H ~ - N - c o - Q 11 1

1 \

H I

/ \

as an analytical reagent since it has the ability to form coordination complexes with metals. 2- (2-Aminocthyl)benzimidazole results from the Hofmann degradation of 2-benzimidasolepropionamide (252), 2-Monoalkyland 2-dialkylaminomethylbenzimidazoles are readily prepared by the interaction of 2-chloromethylbenzimidazole with amines (212,231). 2- (1-Monoalkylaminoethyl)-, and 2- (1-dialkylaminoethyl)benrimidazoles are similarly prepared from 2- (1-chloroethyl)benzimidasole (88). An alternate route to 2-dialkylaminomethy1benzimidazoles utilizes 2chloroacetamidonitrobenzene as the starting material. This compound reacts with secondary amines to give 2-dislkylaminoacetamidonitrobeneene derivatives, which are converted into the 2-dialkylaminomethylbenzimidazoles by reduction and treatment with acetic anhydride and sodium acetate (253).

The synthesis of 1- (2-diethylaminoethyl)-5-methoxybenzimidasole typifies a generally applicable scheme for the preparation of 1- (dialkylis preaminoalkyl) benzimidazoles. 3-Nitro-4-p-tolylsulfonamidoanisole

Chemistry of Classes a.nd Derivatives

312

pared by nitration of 4-p-tolylsulfonamidoanisoleand is alkylated in the form of its sodium derivative with p-diethylaminoethyl chloride. The resulting 3-nitro-4-p-tolysulfon- (2-diethylaminoethylamino)anisole is detosylated by exposure to cold 90 per cent sulfuric acid to give 3-nitro-4(2-diethylaminoethylamino)anisole. The latter substance on reduction with Raney nickel followed by treatment with formic acid, undergoes ring closure to form 1- (2-diethylaminoethyl) -6-methoxyhenzimitlnzole (254). H

H

c FHt-CII CII Rs

N

H

Et I

2-

N- Et

z

The 1- (dialkylaminoalkyl) benzimidazoles are high-boiling oils, wliicli form crystalline dihydrochlorides, dipicrates, and dipicrolonates. They are ineffective against malaria parasites (91,25625'1). The preparation of 2-(aminoaryl) benzimidazoles follows conventional lines and requires no special comment. Of special interest is the chemical behavior of the 2-(o-aminophenyl) benzimidazoles, since they are readily convertible into tetracyclic compounds. Diazotization, for example, converts 2-(o-aminophenyl) benzirnidazole into a tetracyclic triazine, and its reaction with acid anhydrides, urea, or chloroform and alkali proceeds in the manner illustrated (83,158,229,258). It is of interest to note that 2-

VIII. Rmsiinidazoles

313

methyl-4 (or 7) -aminobenzimidazole does not exhibit similar behavior. Treatment with acetic anhydride, for example, leads to the formation of a 4(or 7)-acetamido derivative and not to a tetracyclic structure (76).

I. The Benzimidazolecarboxylic and Sulfonic Acids 1. Carboxylic Acids

The preparation of Bz-benzimidazolecarboxylic acids follows conventional patterns. Reduction with tin and hydrochloric acid converts 3-nitro-4-formamidobemoic acid into 5 (or 6) -benzimidazolecarboxylic acid (180), whereas refluxing of 2,$-diaminobe11zoic acid with formic acid leads to the formation of 4(or 7) -benzimidazolecarboxylic acid (259). Bemimidaaolecarboxylic acids are also obtained when methylsubstituted benzimidazoles are oxidized with potassium permanganate. Although of little practical importance, this behavior illustrates the pronounced chemical stability of the benzimidazole nucleus toward oxidation. Oxidation of 2,5 (or 2,6)-dimethylbenzimidazole aff ords 2-methyl-5 (or 6)benzimidazolecarboxylic acid. This structural assignment is justified because distillation with lime converts the acid into 2-methylbeneimidaaole. The isomeric 5(or 6)-methyl-2-benzimidazolecarboxylicacid is conven(7). iently obtained by oxidation of 5(or 6)-methyl-2-styr~llben~imida~ole More drastic oxidation of either 2,5 (or 2,6) -dimethylbenzimidaaoIe or of 2-methyl-5 (or G)-benziinidazolecarboxylic acid leads to the formation of 2,5 (or 2,6) -benzimidazoledicarboxylicacid. 4,5 (or 6,7) -Benzimidazole-

314

Chemistry of Classes and Derivatives

HOOC

dicarboxylic acid results from the oxidation of lJ2-naphthimidazole with cliromiuin trioxide in glacial acetic acid. As a 1,2-dicarboxylic acid it forms an anhydride when heated above its melting point, and is converted into an anil upon reaction with aniline (260). The benzimidazolecarboxylic acids with carboxyl groups in the benecne portion of the molecule differ strikingly from the 2-benzimidaeolecarboxylic acids in stability. The former derivatives exhibit great stability to heat, but the latter lose carbon dioxide with great ease. 2-Benzimiduzolecarboxylic acid results from the potassium permanganate oxidation of 2-styrylbenzimidazole (7) ,or, preferably, of 2-hydroxymethylbenzimidazole (85,127). Oxidation of 2-aldobenzimidazoles with permanganate also leads to the formation of 2-benzimidazolecarboxylic acid (14). 2-Benzimidazolecarboxylic acid melts at 174’ with the loss of carbon dioxide and the formation of benzimidazole. Its reaction with thionyl chloride leads to the formation of a bimolecular diketopiperazine derivative, dibeneimidazo- (1,2-~-1’,2’-d) -tetraliydropyrazine-6,13-dione. This compound serves RS a convenient starting material for the prepara-

VIII. Benzimidazobs

315

tion of functional derivatives of 2-benzimidazolecarboxylic acid. It reverts to the original acid OF. reaction with concentrated hydrochloric acid or sodium hydroxide. Treatment with ethanol results in the formation of ethyl 2-benzi~nidazolecarboxylate. The diketopiperasine reacts with ammonia or amines in aqueous solution to form amides of 2-benzimidazolecarboxylic acid.

The synthesis of carhxyalkylbenziniidazoles, such as 2-benzimidazoleacetic acid or 2-benzimidazolepropionicacid, offers no special problems. The former compound results from the hydrolysis of 2-cyanomethylbenzimidazole (851, and the latter is conveniently prepared by the interaction of o-phenylenediamine with succinic acid in the presence of dilute hydrochloric acid (see Section C-3) (70,252). 2-Benzimidazoleacetic acid also fails to form an acid chloride on treatment with thionyl chloride. Its esters and amides are readily prepared by conventional methods. A characteristic property of 2-benzimidazolepropionic acid is its capacity to lose a molecule of water to give an intramolecular lactam. This transformation is readily brought about by heating or by treatment with acetic anhydride (70,261).

Another class of benzimidaeolecarboxylic acids exhibiting a great tendency to form intramolecular lactams are the 2- (o-carboxypheny1)-

31B

Chemistry of Clusscs and Derivatives

benzimidazoles which result from the reaction of o-phthalaldehydic acids Heating with acetic anhydride converts 2- to-carboxyphenyl) benzimidazole into o-beneoylene-2,l-benr-

with o-phenylenediamino (262-265).

0

f-Jf:+Hoocn A

H-C

II

0

J

acebe aahydnda

o-Benzoylene-2,1-bensimidazole (R.Z.2271)

iinidazole (R.I. 2271) (266). o-Benzoylcne-2,1-benzimidal;oleis obtained as the major reaction product from the condensation of o-plienylenedismine with phthalic nnlrydrictc (2G7). or on rcduction wit.11 iron powder and acetic acid of o-nitropllthalanil (268). Its formation by oxidation of o-benzylene-2,l-bentimidasoleinsy also be mentioned (269).

VIII. Renzimidaxoles

317

On exposure to dilute acids or alkalis, o-benzoylene-2,l-benzimidazole is transformed into 2- (0-carboxyphenyl)benzimidazole. Esters of 2- (ocarboxyphenyl) benzimidazole are readily obtained by exposure of either o-benzoylene-2,1-benzimidacoleor the free acid to alcohols in the presence of mineral acids. The esters lose a molecule of alcohol upon exposure to heat, and are then converted into o-benzoylene-2,l-benzimidazole (266). 2. sutfonic Acids

The direct sulfonation of benzimidazole with sulfuric acid or chlorosulfonic acid is reported in the patent literature (270-276). Little information is available on the exact position of the sulfo group in the resulting materials. By analogy with the behavior of benzimidazole on nitration, substitution in the 5(or 6)-position is indicated. Sulfonamide derivatives of 5 (or 6)-benzimidazolesulfonic acid are obtainable from 3-nitro-4-aminobenzenesulfonyl chloride which reacts with ammonia or amines to form the respective sulfonamides. Reduction of the nitro group in these compounds leads to the respective diaminosulfonamides which may be converted into benzimidasoles by treatment with formic acid (193).

aoas

HZN-R-

R-IU

I

H

aNH

03

T

NOS

I

-

* -I

Oxidation with alkaline potassium permanganate converts 2 (3H) benzimidazolethione into 2-beneimidacolesulfonic acid (205). This compound withstands heating with concentrated hydrochloric acid at 170°, and thus exhibits the same stability toward acid hydrolysis noted earlier in the case of 2-imidazolesulfonic acid (see Chapter M,Section B-3). 2-Bemimidazolesulfonic acid is a high-melting solid, insoluble in organic solvents and moderately soluble in cold water. In accord with the observations on other imidazolesulfonic acids, it is not convertible into the sulfonyl chloride by treatment with phosphorus pentachloride (205).

Chemistry of Classes and Derivatives

318

1-Benzimidazolesulfonic acid results from the interaction of benzimidmole and pyridinium-N-sulfonic acid (277).

H

sorPyridinium-Nsulfonicacid

*

f

o-Phenylenediamine reacts with such compounds as a-sulfopropionic, -butyric, -valeric, and -phenylacetic acids to give the respective salts. Heating at 180" converts these salts into sparingly water-soluble 2- (l-sulfoalkyl) benzimidazoles. These form highly insoluble, hydrated salts with such metals as barium, cobalt, and nickel. "Zwitter-ionic'' structures are indicated for these sulfonic acids (191,278-281).

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822

Chemistry of Classes and Derivatives

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VIII.

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323

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324

Chemistry of Classes and Derivatives

242. Rabinowitz, J. L.,and Wagncr, E. C.. J. Am. Chem. Soc. 7’3,3030 (1951). 243. Kym, O.,Ber. 3.9, 2178 (1899). 244. Reissert, A., and Goll, G., ibid. 38,90 (1905). 246. von Walther, R., and Kessler, A., J. prakt. Chem. 69, 40 (1SOa). 246. Lindemann, H.,and Krause, H., ibid. 116, 256 (1927). 247. Pierron, P, A m . chim. phys. 16, 145 (1908). 248. Raizk, G. W., Clemence, L. W., and Freifelder, M., J. Am. Chem. Strc. 63, 2739 (1041). J . Org. Chem. f$269 (1947). 249. Price, C. C.,and Reitsema, R. H., 250. Keller, A., Ber. 94,2498 (1891). 251. Deck, J. F., and Dains, I?. B., J . Ant. Ckcm. SOC.66, 4986 (1933). 252. Chatterjee, B., J. C l m . Soc. 1999, 2965. 253. Ahmed, A., Narang, K. S., and Ray, J. N., J. Indian Chem. SOC.16, 152 (1938); Chem. Abstracts 3.9,7040. 254. King, F. E.,Beer, R. J. S., and Waley, S. G., J. Chem. Soc. 1946, 92. 255. Ochiai, E.,and Katada, M., J . Phama. SOC.Japan 60,543 (1940); Chem. Abstracts 36,1785. 256. Siminov, A. M.,J . Qen. Chem. (U.S. 8. R.) 10, 1688 (1940); Chem. Abstracts 36, 2870. 257. Clemo, G. R., :md Swan, G. A., J . Chem. Soc. 1044, 274. 258. Miklaszewski, R.,and von Niementowski, S.,Bet. $4. !2!353(1Wl). 259. Schilling, B., &id. 34, 902 (1901). 260. Fischer, 0..ibid. &?, 1312 (1899). 261. Betrabet, M.V., and Chakravarti, G. C., J . Zndian Chcm. Soc. 7, 191 (1930); Chem. Abstracts 2.4, 4516. 262. Bistrzycki, A., Ber. 91,2518 (1888). 263. Bistrzycki, A., ibid. 23, 1042 (1890). 264. Bistrzycki, A.. ibid. 24, 627 (1891). 265. Bistrzycki, A., and Cybulski, G., ibid. 2.6, 1984 (1892). 266. Bistrzycki, A,, and Lecco, A., Helv. Chim. Acta 4, 425 (1921). 267. Yorai-Kouhits. B. A., nnd Antoshul’skaya, M. M., 1. Gen. Ghc.rt8. ( I ? . S.S. R . ) lS, 339 (1943); Chem. Abstracts SS, 1234. 268. Hupe, H.,ant1 Tliiw, K. G., Bsr. &, 4287 (1909). 269. Thiclc. J., and Pall;, K. G., Ann. 347, 112 (1W). 270. Ciba Ltd., Swiss prrt.cntx 243,779-83,Chem. Abslraclx /ry, ,5426 (1949). 271. Griinacher, C.,U. S. patent 2,036,525; Chem. Abslrncls SO, 3546 (1938). 272. .hdeiXng. H.,and Jung, H., German patent 578,488; Chem. Abstmcts Z?’, 4349 (1933). 273. Schubert, M.,Ann. 668, 31 (1947). 274. Soci6t6 pour I’Industrie cliimique B Biile, Swiss patents l&3,005 and 164,730-6; Chem. Abstrmts k’8, 2918 (1934). 275. Soci6t,6 pour 1’Industrie cliimique Bale, British patent 403,977; Chem. Zenlr. 106, 2826 (1934). 276. Socikti: pour 1’Industrie chimique h BRle, French patent 45,611; Chem. Abstracts SO, 3910 (1936). 277. Weidenhagen, R., Herrmann, R., and Wegner, H., Bet. YO, 570 (1937). 278. Backer, H.J., Rec. trao. chim. 40, 582 (1921). 279. Backer, H.J., and De Boer, J. H., ibid. 43,420 (1924). 280. Backer, 19. J., and Rloemen, A., ibid. 45, 100 (1926). 281. Brust, J., ibid. 47, 153 (1928).

SECTION 2

Systematic Survey and Bibliography

Key to Abbreviations Am. . . . . . . . . .Ammonium salt A t . . . . . . . . . . .Acetate Au . . . . . . . . . . .Chloroaurate C1.. . . . . . . . . . .Chloride CPt . . . . . . . . . .Chloroplatinate F . . . . . . . . . . . . Flavianate HBr ..........Hydrobromide HCl . . . . . . . . . .Hydrochloride HI.. . . . . . . . . . Hydroiodide H O x . ....... .Hydrogen oxalate I. .......... .Iodide

I t . . . . . . . . . . . . Iodate Ni. . . . . . . . . . .Nitrate 0%.. . . . . . . . . .Oxalate PCZ. . . . . . . . . .Perchlorate P i . . . . . . . . . . .Picrate P I . . . . . . . . . . . Periodate Po. . . . . . . . . . . Picrolonate PS. . . . . . . . . . .Picrylsulfonate S . . . . . . . . . . . . Styphnate Su. ......... .Sulfate

SYSTEMATIC SURVEY AND BIBLIOGRAPHY

..

Compound

.

.

Reference No

M.p o c

.

I IMIDAZOLES

.

A Alkyl- and Arylimidazolea

................

4(or 6)-allyld(or 4).methylimidaaole 4-allyl-1 .&dimetbyl. .............................. S-allyl.1.4-dimethyl. .............................. %myl- .........................................

4(or 5).amyl. .................................... 2-amy1-4(or 5).butyl.l-ethyl. ...................... 2.amYl.14ecYl. .................................. 2.amyl.l-dodecyl. ................................ 4(or 5).smyl.l-etbyl.~hexyl. ...................... 1-amyl-shendecyl-............................... 5-smyl-1-methyl- ................................ 29myl.l.pbe~l. ................................. I-bensyl2.benayl. ....................................... 4(or 5).bensyL 1.benryl-4.s-dimethyl.2.propyl. .................... 2-bensyI-l-ethyl-4(or 5)-phenyl- ................... l.bensyl.%methyl. ............................... Zbenryl.l.methy1. ............................... %bensyl4(or S)-methylb(or 4).phenyl. ............. l.bensyl.2.4.5-trimethyl. .......................... 4.S-bia(pmethylphenyl). .......................... I-but+ ........................................

....................................... ..................................

I-butyl-2.4.6-trimethyl-. ..........................

2-(hyclohexylpropyI). ........................... l-decyl.2-methyl. ................................ 1.2-diethyl. ..................................... 1.2-dimethyl. ....................................

599

71-72

-

-

599 599 168.152,141

. . . . .

409

38. Po 189.6-190.6 44.6 19.17 Pi 96 329

Po 143-144 71-72 128 84-85

.

Pi 166-157

Pi 163-164

Pi 111-112

210-212 81 275-276 Pi79.b-81.5 Pi 146 78-79

. .

Pi 181

1,kiimethyl.

....................................

1.Sdimethyl.

.................................... Ni 128-129

Au 138

Pi 168-189,

............................. 4.Sdimethyl. .................................... 2.4(or 2.5) -dimethyld(or 4).phenyl. ................ 2.4(or 2.5)-dimethyl.

4.6dimethyl.2-phe~l.

Ni 103.104 Pi 167.168.

...........................

327

. .

Au 227 92. Pi 142. HCl207 115-117.

.

HCL 305

224-227 HCl236-237 242. HCI 116-118

409 329 409 19.17 152 360 639.409. 136 19.17 436 329 360 136 121 436 488 695 436

409 409

601 590.601.49.300. sol.640 563.110.337.375, 306.460 683.110.337.434. 375 73.709.306.726. 391 243.74.712. 717 160.121 74. 166

828

Systematic Survey :ind Hibliogrsphg Compound

2.4(or 2.5);diphenylimidesole ......................

................................... 4.Sdiphenyl-2-ethyl-. ............................ 4.Sdiphenyl.l-ethyl.2.methyl. ..................... 4.&diphenyl.2ieopropyl. .......................... 2.4(or 2.5)-diphenyl.5(or 4).methyl. ................ 4.5-diphenyl-.

4.5diphenyl.l.methy1. .......................... 4,5diphenyl-2-met.hyl-........................... 2.4-diphenyl-1 (pmethylphonyl). .................. 4.5diphenyl.Zpropyl. ........................... 4.5dipmpyL. .................................. 4.5dipropyl.2-phenyl.

...........................

Zdodeoyl- ...................................... ldodecyl.2-methyl. .............................. lethyl.......................................... I-ethyl.2-methyl. ................................ 1-ethyJ4methyl. ................................ 2-ethyl4(or 6).methyl. ........................... 4(or S).ethyl.%methyl.

...........................

a-ethyl-rl(or S)-methylb(or 4).phenyl.

..............

2-ethyl-4(or 5).phenyl. ........................... 4(or 5)-(p.ethylpheny1)- .......................... 2-hendecyl-1-methyl-............................. 1-heptyl-%methyl-............................... 2-heptyl.l.methy1. ............................... 1-iaoamyl- ...................................... l.ieosmyl.2-niethyl. .............................. 4(or S).isohutyl. ................................. 1-imbutyl-%methyl- .............................. 2-impropyl-4(or 5).phenyl. ........................ 4(0r 5).(pisopropylpbenyl). ....................... I-methyl- ....................................... %methyl-.......................................

1-[(~~tsmidopheiiyi)~uifonyl) deriv ............ l-[(paminophenyl)sulfonyl] deriv................ 4(or 5).methyl. ..................................

.. .

M.p OC

.

193. HCl274-275 HOz 227. At 96 249. 232-233 Pi 235 229 HCl214-215 132-134

.

.

248

214-215. HCL 273-275 158 244

.

148 HCZ 91 HCI237-238 6558 HCI 154-156 17S-176. HC1 145-147 77-78

.

-

Pi 170 Pi 171 Pi 140 45. Pi 131. Ni 129 HCI 132. Oz 145 Pi 90-91

.

Ox 141

130-135

. .

HCI 200-203

Reference No

.

709. 108 411.712.717,121, 179.178.488. 489 179.148.489. 121 395 148 160.121 350

178,179,489.121 112.111 121 74 74

409 409

695.598.357 601.329 357 726

726 121

133 709 127-128. P i 197 717.712 409

-

Pi 103-104 Pi 148-149

72-73 Pi 151-152 180 114-115 Pi 186-187 Pi 158-159. 141-143 Pi 213. 0 2 160 93-94.5 228-2W 56.6, Pi 162-183.5. HC 118. 02 206

. .

409 409 598

801 19.17 601 709 717.712 598.095. 394

.

516.517.229.243 442.394.163. 360 440.442 440

709,73,393.568, 300.734.518.32. 616.300.367.391. 679.71 1

329

Imidaaoles Compound

l-methyl-2-nonylimidale ........................ 1-methyl-Zphenyl-...............................

l.methyl-4.phonyl.

...............................

1.rnethyl-5-phenyl.

...............................

2-methyl.l.phenyl. ............................... %methyl4(or 5).phenyl. .......................... 4(or 5).methyl.%phenyl. .......................... 4(or 6)-methyM(or 4).phenyl. ..................... 4(or 5)-methylb(or 4).phenyl.%propyl. ............. 2-methyl.l.propy1. ............................... 4(or 6).methyl.Z(2-phelurlvinyl). .................. 2-methyl.l.tetradecyl. ............................ 2-methyl-1 .4.S-triphenyl. ......................... 4(or S).(pmethylphenyl). ......................... 1.(pmethylphenyl).2.4.5-trimetby I. . . . . . . . . . . . . . . . . 4(or 5).(ZnaphthyI). ............................. l-oetyl. ......................................... Zpentadecyl-.................................... 1-phenyl- ....................................... Zphenyl- ....................................... 4(or 5).phenyl.

..................................

1-benxoyl deriv................................ l.phenyl.2.4.5-trimethyl. ......................... I-(Zpaenylethyl)-2.4,&.trimethyl-. . . . . . . . . . . . . . . . . . Z(3-phenylpropyl). .............................. 2.tetradecyl. .................................... 1,2.4,5-tetremethyl-. ............................. 2.(1.trid~~l). ................................. 2-tridml. ...................................... 1.2.S-trimethyl. ..................................

1,4.&-trimethyl-.

.................................

2.4.5-trimethyl-. ................................. 2.4.6-tripheny I. (lophino) .........................

.

. .

-

.

Fbfereaoe No

M.p., OC

409 46.255

Pi 133

Ni 126-127 Aa 189. HOz 136 110-111 Pi245 266.322 Ni 97 HBr 178-179 96-97. 258.322 Pi 138-139 Ni 176-177 Pi 145 153 161-162 709 181-182 367.156 186 HCI 192 121 HCZ135-140 121 Pi 142-143 601 236. Pi 248 367 Ni 168 409 197 178 116-117 712.717 Pi 210 Pi 123 436 170-171. Pi216. 712.717.289 Ni 186 HC2 219-220 173 87-88 409 Di" 82-86. 265.163 Pi 155-156 148-149 Pi 238. 332,243.703 N i 135. HOx 219 133-134. Pi216 144.200.2!44.32!. Ni 179 HCl180 708.132 ox 190 132 294 Pi 122 436 Pi 164 436 90-91 409 83-84 409 58. Pi 189 436 409 81-82 409 Pi208-209 300 Au 186-187 Pi218-219. 300 Au 201 Pi 163. He1310 243.712.717 27cI.5, Pi 235 712,717.178.170. 148.428.121.?4 H. 652.053

..

.

.

.

-

-

.

. .

.

-

.

..

.

330

Systematic Survey and Bibliography Compound

M.p

.

.. . O C

Reference No

B Alkyl- and Arylimidazolium Salts

3-allyl-l-decy1-2-methylimidasoliumbromide ........ 70-71.5 1.~llyl.3-hcptyl.2-methyl.. bromide ................ . Sallyl.l.methy1.Znonyl. bromide ................. 97-98 l.amyl3-bencyl.2.hendecyl.. bromide .............. 110-117 Zamyl4butyl.1.5diethyl.. chloride................ CPt 136 4(or 5).amyl.1.3-diethyl.2-hc.l. chloride........... 99. CPt 130 4(or 5)-amyl.l.3diethyl.2-hexyl.. iodide ............ 81 l.amyl.2.hendecyl.3.mcthyl.. iodide................ 3-bensyl.l-decyl.2-methy 1 bromide................ 87-88 Sbensyl.ldecyl.2-methyl.. chloride................ 112-114 3-bensyl.ldecyl.2.methyl.. iodide.................. 85.5-87 3.benzyl.2.hendecyl.l.methyl.. bromide ............. 185187 l.bensyl.2-heptyl.3-methyl.. bromide ............... 180-187 3.bensyl.l.heptyl.2-methyl.. chloride............... 141-142 3-bensyl.l.methy1.. bromide ....................... bbenryEl.mathyl.2-nonyl.. bromide ............... 193-195 3-benoyl.2methyl.l.tetraderyr.. bromide ............ 102-1 04 . l.butyl&thyl.. iodide ........................... . l.butyl-3-propyl.. iodide .......................... ldecyl.2.3-dimothyl.. bromide ..................... 83.6-85.5 108-109 l-decyl.2.3-dimethyl. iodide ...................... ldecy1-3-ethyl.2-methyl.. bromide ................. . ldecyl.2-methyl.3-(2.methylallyl).. chloride ........ 110-111 1.3-dibensyl-2-methyI-, chloride.................... 208 . 1.3dimethyl. iodide ............................. 1.3dimethyl.2hendecyl. iodide ................... 128-130 1.2dimethyl.3.heptyl.. iodide ..................... 80-81 108-109 1.3-dimethyl-2-heptyl-, iodide ..................... 127-123 1.3-dimethyl-%nonyl-. iodide...................... 1.5dimethyl.2-phenyl.. chloride ................... 272. Au 134 1.3-dimethyld(or 5).phenyl.. iodide................ 147-148 2.3-dimethyl.l-totradecyl.. iodide .................. 108-110 .. 3-ethyl.l.methyl.. iodide.......................... 3-ethyl.l.methyl.2.nonyl. iodide................... 81-82 . 3-ethyl.l-octyl.. bromide.......................... . l.ethyl-3-propyl.. iodide .......................... Zhendecyl.l.methyl.5(2-methylallyl).. chloride ..... 133-134 . 3-iaoamyl.l.methy1.. iodide ....................... . l.methyl-3.propyl.. iodide ........................ 4-methyl.1.2.3-triethyl. chloride................... 103 126.5 1.2.3,4-tetramethyl-, picrate .......................

.

.

.

.

.

.

.

.

.

.

622 622 622 622 329 329 329 622 622 622 622 622 622 622 598 622 622 695 696 622 622 622 022 329 598 622 622 622 622 46 322 022 696.598 622 173 695 622 598 695 329 494

C 0x0- and Hydroxyimidazoles and Their Sulfur Analogues

. 2(3H)-Zmidumlones

1

(a) Alkyl- and Ar~l-le(3R)imiaazolones 2(3s).imidaaolone ............................... 1.Sdiacetyl deriv ............................. 4-benoyl- ....................................... Pbensyl-6-methyl ...............................

251.5-252 105-106 241-243 270

880.207 3.30 207 172.206

.

Imidazoles Compound

331

..

M.p OC.

4-(ct~rclohexyhethyl)bmethyl-2(3H)-imidtuolone ... 368-360

4.S-dicyclohexyl. ................................. 4.&diethyl-. .................................... 1.3dimethyl-. ................................... 4.5-dimethyl- .................................... 1.3-dimethyl.Pphenyl. ............................ 4.6-diphenyl. .................................... 4.6dipropy 1. 1.3-diacetyl dcriv............................. Pethyl. ......................................... Pmethyl. ....................................... l(or 3)-acetyl deriv........................... 1.3-diacet.yI deriv............................. 4methyI-b-phenyl- ............................... 4phcnyl- ....................................... 1.3.rl-trimethyl.. ................................. (b) Ow..

287-289 293-294

-

.

210

92 HC193-94

330-335 57-69 192-194 202-204 175 78-80 287-289 330-333

-

Reference No

206 725 725 79.330 492.491 79 510.126 209

207 206 200

206 172 207 79

~~~~~~~~~~, and H~drozyaryba(3H)irnidosolonss

Psoetyl-b-methyl-2(3H)-imidamlone ............... diacetyl deriv................................

...................................... 4-bensoyl. ...................................... 1.3discetyl deriv............................. 4benroyl-5-(bromomethyl)1.3-diacetyl deriv............................. 4bensoylJ-[ (dibenzy1amino)methylII(or 3)-aeetyl deriv........................... 4bennoylbmethyl. .............................. Pbensoyl-5 (nitromethyl)1.3diacetyl deriv............................. 4.5-bie(5-bromo-2-hydroxyphenyl)-................. P(b.bromovaleryl)bmethyl. ..................... bbutyryl-5-methyl. .............................. 4-caproyl........................................ 4oaproyl-5-methyl- .............................. osime

4-(chloroacetyl)-6-methyl-........................ 4.&bis(hydroxymethyl). tetraacetyl deriv............................... 4(3.4-aihy.xyphen).l-methyl. ................. P(p-hydroxybensy1)-6-methyl. .................... 4(1.2.3.Ptetrabydroxybutyl ). .....................

322 72-73 298 313-316 137-139

206

131-132

209

204-205

206 206 207 207

209

268

206

139-140 272-273 206-207 234-235 265-268 227-228 248-250

209

143-145 276-277 243-244

130-136

248

211 207 207

207 206

209 210 172 627

(e) Ralogenoalkyl.. Aminoalkyt.. and S~oalkyl-2(3H)imickrtolones

4.5bis(bromornethyl).2(361) .imidasolone I.&disoetyl deriv............................. C(bromomethy1)1.3di&yI deriv............................. 4-(bromomethyl)-5-methyl1.3 - d i i t y l deriv............................. 4-[(dibensylamino)methyl E l(or 3)-acetyl deriv........................... &(&sulSovaleryl)4methyl-.......................

108-110

209

80-81

209

84-89

209

174-176 209 Na sdt 332-334 211

.

~~

332

Systematic Survcy mid Bibliography

..

Couipound

.

M.p OC

(4b(SH)-Irnidcuoloncccrrboxylic Aeitb

................

2(3H)-imidaxolone4carboxylic mid ethylester .................................. l(or 3)-acetyl deriv......................... 1&dimethyl. .................................. methyl ester ................................ 1 3-dimethyl-5-p henyl- .......................... methyl eater ................................ 5-ethylethyl ester .................................. &methylethyl ester ..................................

.

...

.

195 228-230 127 217-218 124

330 143,361.330 143 79. 330 79 79 79

182-184

207

226-220

492.491.459.206. 207 206

261 256

l(or 3)gcetyI deriv ......................... 172-173 53-56 1.3discetyl deriv........................... &phenylethyl ester .................................. 215-217 179 1.3.5-trimethyl- ................................ methyl ester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88-89 2(3H)-imidsaolone-5-carboxylic arid 1-betuylmethyl eater ................................ 160-161 l-cyclohexyl230-282 mothyl ester ................................ 1-ieopropylmet.hyl eater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174-175

2(3H)-imidazolone-4-acetic acid &methylethyl eater .................................. 2(3H)-imidazolonc4hutyric acid &methylethyl ester .................................. 2(3H)-imidasolone4caproic acid . . . . . . . . . . . . . . . . . . &methyl- ..................................... ethyl eeter .................................. 1.3-diacetyl deriv ........................... methyl ester ................................. 2(3H)-imidasolon&-caprylic acid .................. 2(361)-imidaeolone4enanthic acid . . . . . . . . . . . . . . . . . &methylethyl eater .................................. 2(3H)-imid~olone4propionicacid a-carboxy-.................................... a-ieopropyl-5-methyIethyl ester .................................. 2(3H)-imida~olon&vderic acid ................... &methyl- ..................................... methyl eater ................................ 4-(pcarboxybenr.yl)-&rnethyl-2(3H)-imida~lone. methyl ester ................................

Reference No

206

207 79 79 361 361 361

249-250

459

218-219 178-179 169-170 194-196

459 196 656,97,729.206 200.459

193-195 169-170 228-229

97 196 190

186-189

459

253-255

209

118-120 242-244 214-210 194.5-197 336-338 256-258

150 97 97 650 656

.

200

105

333

Imidazoles Campound

.

M.p., O C

Reference No

V, Carbozp and Carbozydk&~(SH)-imidawlom Contcrining Additionul Funciional Groups

6-(aminomethyl)-2(3H)-imidamlo~aproicmid methyl ester ................................ HCL 186-188 c-amino-5-(aminomethyl)ethyl ester ............................... methyl ester ................................. HCll 176-178 &[(a or I)-bromo-6-carbo~ale~l]b-methyl2(3H)-imidasolone ethyl ester .................................... 178 1.3-diacetyl deriv............................. 90-92 6-(brornomethyl)-2(3~-imidarolone4carboxylicacid et.hy1 eater .................................... 220

4-(q-carboxycaprylyl)-5-methyl-2(311)-irnidasolone ethyl eater .................................... 4-(carboxycsrbonyl)-5-rnethyl- ..................... 4(a-carboxyisovaleryl)bmethylethyl ester .................................... 4 4 &carboxypropionyl)-i3-methylmethyl ester .................................. 4-(6-carboxyvaleryl)- ............................ P(~arboxyvsleryl)-5(b~omomethyl)ethyl ester 1,3-diacetyl deriv............................. methyl ester l(or 3)-aoetyI deriv........................... 1,3-diacetyl deriv............................. 1,3-dipropionyl deriv.......................... 4-(6-carbdxyvaleryl)-5-((dibenaylemino)methyl]-. . . . ethyl eater .................................... l(or 3)-ecet.yl deriv.......................... oxime ...................................... methyl aster .................................. oxime ...................................... 4-(6-carboxyvaleryl)-5-ethorymethyl)-.............. ethyl ester .................................... 1.34iacetyl deriv............................. 4-(licarboxyvaleryl)3-ethylethyl ester .................................... P(~.earboxyvsleryl)-5-[(guanylmercapto)methyl]~ methyl ester l&diacetyl deriv.............................

&(aaarboxyvsleryl)3(hydro~ethyl)ethyl ester O-.l&triacetyl deriv.......................... methyl ester 0-benmyl-1, 3-diacetyl deriv................... 4-(~rboxyvaleryl)&methyl- .................... ethylester .................................... l(or 3)-bemoyl deriv......................... 1.3-diaoetyl deriv............................. methyl estar................................... I,3-discetylderiv.............................

169

209 209 209

208 208 209.207 206

260

206

120-121

105

215 229-230

206

75-76.5

208

129-130 59-61 59-61 207-208 107-109 101-102 184-185 135136 191-192 214-217 100-101

209

209 208 a08

108-109

207

HBr 164-165

209

-

208

-

90-93 210-212 173-174 127-128 74-75 176-176 89-10

207

209 209

209

209 209 206 209

208

209 206.201 208 206

206

207

209

.

334

Systematic Survey and Bibliography

.. .

Compound

M.p

.

O C

.

4-(~boxyvaleryl)-5-methyl-2(3FZ)-imidasolonemethyl eater (contd) 1.3-dipropionyl deriv......................... 0550 oxime ........................................ 227 4-~rcsrbo.yvaleryl)~(a~fomethyl)ethyl eater .................................... Na Sai4 280-282 5-(ethoxymethyl)-2(3H)-imidasolon~c~~~lic acid 270 acid chloride.................................. 131-132 ethyl ester .................................... 179-180 148-149 I(or 3)-aeetyl derivative ...................... 1.3-discetyl derivative ........................ &(hydroxymethyl)-2(3H)-imidaaolon~c~boxylic acid ........................................ 200 ethyl ester .................................... 216-218 0-aeetyl derivative ........................... lbl-155 5-(auUomethyl)-2(3~-imidacolone-4-caproic acid .... Na Salt 262

.

2

.

209

208

209 207 207

207.209 207

2M

207 207 209

209

5(4H)-Imidawlones

I-anilino-2-methyl-5(4H)-imidaeolone.............. I.anilino-2.phenyl. ............................... I.ben%yl-4-benzylidene-%phenyl. ................... I-( N-berurylanilin.J)-2-phenyl-..................... a-beaeylphenylhydrssone ..................... 4-benrylidene-1.bensyloxy.2-phenyl. ................ 4benzylidene-l.2-diphenyl. ....................... 4benzylidene.l-ethyl.2-(p-methoxyphenyl). ......... 4.bensylidene-l-ethyl.2.phenyl. .................... 4-bensylidene-1-hydroxy-2-phenyl-. . . . . . . . . . . . . . . . . 4benzylidene-2-(p-methoxyphenyl).l.methyl. ....... 1,%limethyl-4.4-diphenyl-. ....................... 1.2-diphenyl-P(o-nitrobenzylidene)-. . . . . . . . . . . . . . . . 4.(p-ethoxybenzylidene).l.hydroxy.2.phenyl. ........ I.methyl4nitro- ................................

4-(3.4methylenedioxybenzylidene)-1 -+methylphenyl).2-phenyl. ............................ 4-(3.4.methylenedioxybe~ylidene).l.(pmethy 1. phenyl) .%phenyl. ............................ 4-be~ylidene-2-methyE5(4H)-imida~olone-l-a~tic acid .......................... N a Sat2 > ethyl ester .................................. 4-benzylidene-%phenyl-5(4Zf)-imidazolone-l-acetic acid ...................................... ethyl ester .................................. 4-carboxy-2-methyl-6(4H)-imidaeolone-l-m~on~cacid triethyl ester ................................

3

Reference No

200-206 178-186 143-144 147 110 122 180

613 291 613 507 019 291

110-112

291 019

613

103

291

200-207

163 171-172 178

231

291 85

.

Na Salt 320 K SaU 202

484 619 43

167

484

230

484

300 134

292 292

200-202 108-110

292 292

208-209

163

. 4(5H)(or5(4~)-Zmidaaolones

.

6(or 4)-(2-amino-5-bromophenyl)-2-methyl~(6H(or 5(4H)).imidacolone ..................... Ps'167 HCI 273 2423440 2-(paminophenyl)-5(or ().methyl. ................. 240 6(0r 4)-bensyl-2-phenyl1-benroyl deriv 170-177 692

-

..............................

~-

335

Imidamles

.. o c.

Compound

h1.p

5(or 4)-benrylidene-2-(po~phenyl)~(5~) (or 5331.5 (4H)-imidesolone 5(or 4).belusylidens2-(m-methylphenyl). ............ 258.5 5(or 4).bensylidene-2-(p.methylphenyl). ............ 310 5(or 4).be.liden.2-(2naphthyl). ................ 281 5(or 4)-be~lidene-2(p.nitrophenyl)-.............. 326 5(or 4).benoylidene.2.phenyl ....................... 284 2-(pben.yIideneaminophenyl)S(or 4).methyl. ....... At 156 5(or 4)-bromo-5(or 4)-(a-bromobensyl)-2-phenylo! form ..................................... 246-246 165-168 wform ..................................... 260-263 5(or 4)-bromo-5(or4).(a.a-dibromobensyl).2-phenyl. 5(or 4)-(4-bromo-2~y&orybenEylidene)-2-(~met~lphwl). .................................... 344.5-351.5 335 5(or 4).(4-bromo-2.hydrbensylidene).2.phenyI. 5(or 4)-bromo-%phenyl1-bensoylderiv.............................. 183-164 5(or 4)-(pbromobensyl)-zphenyE 1-bensoylderiv.............................. 212-213 5(or 4).(a.bromobenzylidene).%phenyl. ............ 230 HBr 265-266 5(or 4).(o-carboxybemylidene).2-phenyl. ............ 259-260 5(or 4).(o-c.orobeneylidene).a-phenyl. ............. 280 5(or 4).(p.chlorobenrylidene).2.phenyl. . . . . . . . . . . . . 305-306 5(0r 4).(2..ethoxybendene).2-( ..met4yl pheny1)- .................................... 250-251 6(or 4).(2.4-dimethoxybenensylidene).2.phenyl. ........ 248-249 5(or 4)-(2.Kdimethoxybensylidene)-%(m-methyL pheny1)-.................................... 229230 5(or 4).(3.4-dimethoxybemylidene).%(mmethy .1 pheny1)- .................................... 238-239 5(or 4).(2.5-dimethoxybensylidene).2.phenyl. ........ 268-269 5(or 4).(3,4-dimethoxybensylidene).2-phenyl. ........ 259-260 5(or 4).(pdimethyl8minobenaylidene).Zphenyl. ..... 277-278 2.5(or 2.4)-diphenyl. ............................. 251-252 acetyl deriv.................................. 174 166-167 5.5(or rl.d)-diphenyl. ............................. 5.5(or 4.4)-diphenyl.2-methyl. ..................... 228-229 1-acetyl deriv................................ 149-150 5(or 4).(pathoxybemylidene).%(m.rnethylphenyl). ... 237-238 5(or 4).(p-ethoxybensylidene).2.phenyl. ............ 292-29a 2-ethyId(or 4).phenyl. ........................... 165.167. Pi180.5-182 5(or 4).(m-forrnylbenaylidene).%phenyl............ 241 5(or 4).(pformyIbensylidene).!&phenyl. ............ 292 5(or 4).(o-hydroxybensylidene).Z(p-methylphenyl). .. 323.5-337 5(or 4)-(o-~dro.ybensylidene)-2-phenyl-........... 338 5(or4).(mhydro~benzylidene).Zphenyl. ........... 265-265.5 5(or 4).(2-hydroxy-3.6-.bromobensylidene).Zph.ny I. 311 5(or 4).(p-hydrorymethylbensy.dene).2.phenyl ..... 287-288 5(or 4)-(2-hydro.y-5-nitrobensylidene)-2-phenyl-..... 300 5(or 4)-(p~propy~ben6y~dene)-Z(tn-methylphenyl)-263-264 5(or 4 ) . ( p i a o p r o p y I b e ) . Z p h e n y I . .......... 246-247 S(or 4)-(o-metho.rbensylidene)-Z(~methylphenyl)-. m 2 7 3

...........................

.

Reference No

225

225 225

225 225

721.155.225.720 240

.

720 720 720

...

225 225

.

592 592 720 223 223 223 223 223 223 223 223 223 223 707 707

86

86 85

223 223 135

225 225 226 225

223

223 223 223 223 223 223

Systematic Siirvey and Bibliography

538

Compound

5(or 4)-(prnethoxybenzylidene)-2-(m-methylphenyl)4(5H)(or 5(4H).imidrusolono .................. 5(or 4).(o-methoxybensylidene).2.phenyl. ........... ........... 5(or 4).(prnethoxybenaylidene).2-phenyl. 5(or 4)-(4-methoxy-3-methylben~ylidene)-Z(mmethylpheny1)- .............................. 5(or 4).(4rnethoxy-3-methylbn~ylidene).Zphenyl. .. 2-methyl-5(or 4).plrenyl. ..........................

.. .

M.p oc

Reference No

227-229 283 307

223 225 225.155

237-239 223 253-264 223 190-191. 135 Pi185.5-186.5. HC1251-254 5(or 4).methyl.2.phenyl. .......................... 170,Pi 169-171 155 HCI .Ha0 170-172 170-172 acetyl deriv................................. 155 225 5(or 4).(prnethylbenaylidene).2.(gmethylphenyl). ... 295 5(or 4).(m.methylbeellcylidene).2.phenyl. . . . . . . . . . . . . 237-238 223 5(or 4).(p.niethylbensylidene).2.phenyl. ............ 319 225 5(or 4).(3.4.methylenedioxybenzylidcne)d.(m.methy I. phayl). .................................... 249 223 5(or 4).(3.4.methylenedioxybensylide,re).2.phenyl. ... 285-287 223 5(or 4).(m-~~itrobenzylidene).Z(pmetliylpliengl). . . . . 295 225 6(or 4).(m-nitrobenzylidene).2-phenyl. .............. 262 225 Zphenyl184 P i 182-IM 592 I-benzoylderiv .............................. methiodide ................................ 104 592 5(or 4)-phenyL%propyl- .......................... 215-230. 135 Pi 183.5-184, HCI 182-184 %phenyt-S(or 4)-[(psulfophenyl) hydraaono 11-benmylderiv.............................. 130 592 4(5H)(or 5(4H))-imidazolone-2-earboxylic acid . . . . . . 113 280 5.5(or 4.4)-diphenyl. ........................... 6540 85 Zamyl-rl(5H)(or 5(4H)) -imidatolone4(or 4)-carhoxylic acid ethyl eater................................... 230 152 2-benr;ylethyl ester ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 . 132 ncetyl deriv . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137.5 152 2-phenylethyl ester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 275 191 aeetyl deriv............................... 152

.

.

.

4

2(3H)-Imidazolethiones(2-Mercaptoimidazoles) (a) Alk& and Ar&%W)-imidaxdcUIioncs

2(3H)-imidazolethionc ............................ S-carbethoxymethylether ..................... S[(2-hydroxyethyl)carbnmylniethyl lether ...... 4(or 5)-allyM(or 4)-methyl ....................... 4(0r5).myl- .................................... 5-amyl-1-methyl................................ I.ben~y1. ...................................... 4(0r 5).bensyl. .................................. ..................... 4(or 5)-bensyL5(or 4)-111~t.hyl.

225-227 76 125-126 238-239 114-115 143-144 144-145 221-222 279-280

13.12 641

611

599 364.17,19 19.17 380 354J7.19 172

.

Imidazoles Compound

4(or 5)3erl.butyl.2(3H).imidnlolethione ............ 4(or 5).(cyclohexylmethyl). ....................... 4(or 5)-ayohpentyl. .............................. 1.4dimethyl. .................................... $-ethyl ether ......... ...

1.5dimethyl. .................................... 4.5dimethyl. .................................... S(4-pyridyl N-oxide) ether ................... S(PqUinoly1 N-oxide) ether and sulfono........ 4.klipheny1. S w t o n y l ether . . . . . ............ Sally1 ether ................................. Sbenaylether ............................... harboxymethyl ether ....................... S(Zhydroxyethy1) ether ..................... S(pnitrophenyl) ether ....................... Spmpyl ether ............................... &(2.4,6-trinitrophenyl) ether .................. 4.5diphenyl.l.(o-methylphenyl). ......... 4.6-diphenyl.l.(p-methylphenyl). .................. Sbensyl ether ............................... S(2. 4-dinitrophenyl) ether .. 4(or6)-hexyl- ................................... 4(or S).isobutyl. ................................. 4(or 6).iaopropyl. ................................ l.methy1. ....................................... 4(or 5).methyl. .................................. &thy1 ether ................................

1. . . . . . . . . . . . . 3.8’dithiobis [4(or 5)-11iethyli111idssolc 4-ma thyl-1-phenyl- ............................... 4(or 5)-methyl-5(or 4).phenyl. ..................... l-phenyl- ....................................... S-ethyl ether ................................ 4(or 5).phenyl. .................................. S-benzyl ether ............................... 4(0r S).propyl. .................................. 1.4.6-triphe~1. Sace.tony1 ether ............................. S(2.4-dini trophenyl) ether .................... S.(2.4, Gtrinitrophenyl) ether . . . . . . . . . . . . . . . . . .

337 M.D.,

ec.

234.2-235.4 331.2-232.5 218-220.8 21 1-212 Pi 105, HCl 136-127 261-262 270 190

236

150-151 181-182 186-186 216 167 209 174 180 288-289 318-320 191 233 115.2-116 188.P189.4 149.GlSO 143-144 24&245 09-71,

Pi 136-137,

A u 130-131

-

190-11)l 290-295 181-18’2

Pi 119-120 267.5, Pi 182,

HC1252 176.5-177.5, Pi 145-146.5 183-184 153-164

199-200

206-206

.

Reference N o

354 354 354 110 110

110 492. 491 352 362 78 78 78 78 78 78 78

78 78 78

78 78 354 354.19,17 354 219 47.12.13 47 359 110 172 110 110

LW. 132.!m4

200

364 78 78 78

(6) %(.9H)-ItniclazoleCh.iotres C ~ n h i i ~ i ~Additwrual cg Fitrbclhiual G T O U ~

4(or S)-acetyl-Li(or4)-lIiet~ly~-8(3~)-i111id;rzolet~1ioiic~ . . 808 4 ..5-rli~~lienyl.l.(pmetliox.y~~l1c11yl ). %benzyl ether ............................... 191-192 S-(2,4.&trinitrophenyyl) ether .................. 168 4(or 5)-(p-hydroxybenzyl)-5(or 4).methyl. .......... 273-275

495.009 78 78 172

Systematic Survey and Bibliography

338

Compound

1.(2-hydroxyethy1).2(3H)4mid~lethione . . . . . . . . . . 4(or 5).(2-hydroxyethyl). ......................... 4(or 5)-(%hydroxyethyl)-5(or 4).methyl. ............ 4(or I).hydroxymethyl. ........................... 4(or 5).(Zphenoxyethyl). ......................... 4(or S).(n.arabC.tetrshydroxybutyl). .............. 4-(~-arabino-tetrahydroxy butyl).l.allyl. ............ 4.(~-ur~bim-tetrahydroxybutyl).l.(pmethylphenyl). . 4(~-arahim-tetrahydroxybuty1)-1-phenyl- . . . . . . . . . . 5-(3-acetylthioureido)-4-eyano-l-methylSbenxyl ether. dichlom derivative ............ &methyl ether. dichloro derivative ............ 5-(3-acetylthioureido)-rl-cyano-l-phenylS-methyl ether. dichloro derivative . . . . . . . . . . . . 4(or 5)-aminol-aeetyl-N-bensoyl derivative ................. S-acetyl-N-benmyl derivative ................. N-benaoyl derivative ......................... S ldiacetyl-N-benwyl derivative .............. 5-amino-1.methyl. ............................... 4(or 5).(4aminobutyl). ...........................

.

4(or 5).(3.aminopropyl). .......................... 4(or 5).(3.gusnidinopropyl). ....................... &(.7-methylureido).l.rnethyl. ...................... 4.5diphenyl-1 (pnitrophenyl). ..................... 5-(cyanomethyl).l-ethyl4methyl. ................. 4(or 5)-(cyanomethyl)-5(or Q.methy1. .............. 1-phenacyl-cl-phenylS-bensylether ...............................

5-(3-acetylt hioureido)-l-methyl-2(3H)-imidasolethione4carboxylic acid amide S-benoyl ether ........................ amide S-methyl ether., ...................... 5-(3-acetylthioureido)-l-phenylamide. S-methyl ether ........................ 5-amino-1-methylamide ...................................... amide S-bensyl ether ........................ wide. S-methyl ether ........................ ethyl ester .................................. 5-amino-1-phenylarnide ...................................... m i d o &methyl ether ........................ I-methyl-5-(3-methylthioureido)amido. S-methyl ether ........................ l-methyl-5-(3-methylureido)ethyl ester .................................. l-methyl-6-(phenylthioformamido)w i d e &methyl ether ........................

.. . .

.

M.p

.

..OC.

Reference No

234-236

219 678.272 257 356 272 527.351. 290 290 290

226-228 22.5-226

150 150

232-233

150

249-250

138 138 138 138 139 15.16

151-152 193 201 203-204 172 168

. .

280

204 240 199 151 220.5-221.5, Pi 154-155 HCI 212-214

-

.

237.5 212 284 HI 170 146

16 16.15 139 78 663 663

143-143.5

200

192

150

199

150

204

150

251 225 176 211

139.147 150 149 139

229

150

154

150

193

150

242

140

300

149

339

Imidazoles

a

.

Compound

l-bensyl-2(3R)-imidasolethione-6-carboxylic acid methyl ester ................................ l-cyclohexylmethyl ester ................................ l-isopropylmethyl ester ................................ 1-methyl- ..................................... methyl eater ................................ 1-phenyl- ..................................... ethylester .................................. methylester ................................ 2(3H)-imidasolethione4(or 6)-carboxylic aaid ethyl ester .................................. methyleater ................................ 5(or 4)-methyl- ................................ S-uarborymethyl ether ....................... S-ethyl ether ................................ ethyl ester .................................. S-acetony1ether and semicarbaaone.......... &thy1 ether .............................. 5(or 4)-phenylethyl wter .................................. 2.2'4ithiobis [6(or 4)-methyU(or 6)-imidssoleoarboxylia acid ] diethyl ester ................................ 2(3li)-imidasolethione-l-acetia acid ................ 4.(wrabC6tetrshydroxybut~)-................ ethyl ester .................................. 6(0r 4)-methyl-2(3H)-imidasolethione-4(or 5)-acetic acid ...................................... amide ...................................... ethyl ester .................................. 2(3H)-imidasolethione-4(or5)-acrylic acid .......... 6(or 4)noethyl-2(3H)-imidasolethione-4(or 5)-caproic acid ........................................ 2(3R)-imidasolethione4(or 6)-carbamic acid ethyl eater .................................. 5-scetyl deriv 6(0r 4)-methyl-, ethyl ester 6(0r 4)-phenyl- ethyl eater 2(3H)-imidssolethione4(or 6)-propionia acid ........

.

.............................. ..................... ......................

M.p., O C

Referance No

174-176

361

171-172

361

148-149 207-208 193-194 198-200 188-190 224-226

361 361 361 301 361 361

184 190-191 240-241

361 361 47 134 47

188

179.180. RCI 189-190 229 140 144-146. Pi 135-136

491. 492

490

47.490

219

260

222-223 206-208 142-144 168-169

47 219 200 290

276 224 217-218

068 603

280-286

663.4.59 12

184

050

173 169

118 118 118 118 14.13,12

244

228 206-206.6

. 4(5H)(or 5(4H))-Imida%olethf~

5

6(0r 4).(2.gamethyl.heptenyl )-4(6H)(or 6(48))imidasolethione.............................. 2-methylb(or 4).nitro. ........................... 5(or 4)-phenyl- .................................. 4.4'(or 5.6')dithiobm[5(or 4).2. BdimethylS hepteny1)imidasole).......................... 4. 4'(or 6.5') -dithiobia[6(or 4)hexyliiidmole]........ 4.4'(or 5.5')-dithiobia[6(or 4).phenylimidepole]

......

93-96 HCZ 280 186

7 77

181-182 194495 227-228

7 6

6

6

.

340

Systematic Survey and Bibliography Compound

M.p.,

OC.

0

Reference No.

6. Mono-and Polyhydroxyalkyl-and Hydraryarylimidazoh, Their Ethers and

Halogeno Derivatives

4(or 5)-(wrubi~-tetrahydroxyhutyl)i~niclasole. .....

l l i 4 . HCZ 179, Pi 113

4,5-bis(%hydroxy-5-bromophenyl)- ................. 235-237 4,S-bis(p-methoxyphenyl)-........................ 183-184 2-(3,44imethoxypheny1)-4,&diphenyl-. ....... 2-(etho~ethyl)-5-chloro-l-methyl-......... I-&D-glucopyranosyl)- ............................ 217-218 tatr+O-acetyl deriv.. ........................ 206-208 1-(8-D-glucopyranosyl)~metIiyltetra-0-acetyl deriv.. ........................ 176 1-(8-o-gluropyranoayI)3,5.dLnethyl-.. . . . . . . . . . . . . Au 144-145 tetra-O-acetyl deriv. of iodide.. . . . . . . . . . . . . . . . 232 l-hydroxy-4.5-dimethyl-%(p-methoxyphenyl)3-oxide ..................................... 214 1-hydroxy-4,5-dirnethyl-2-(3,4-methyle11edioxyphenyl)3-oxide........................ .......... 224, HCl, 9HaO 194 l-hydrory4.5dimethyl-2-(p-methylpheayl)3-oxide. .................................... 230. HC1235 l-hydroxy4.5-dirnethyl-2-phenyl&side and benzoyl deriv.. . . . . . . . . . . . . . . . . . . . 130 %(a-hydroxybensy1)-............................. 199-201 4(or 5)-(phydroxybenzyl)-5(or 4)-methyl-. . . . . . . . . . 290 4(0r 6)-(3-hydroxybutyl)-. ........................ Pi 156, CPt 196 1-(2hydroSyethyl)-. ............................. 36-40, Pi 142-143 4(or 5)-(2-hydroxyethyl)-. ................ ... 92. Pi 144.

Au 148,

4(or 5)-(2-hydroxycthyl)-(~r 4)-methyl-. .. . 4(or 5)-[3-hydroxy4(phydroryphenoxy) plio . 4(or 5)-(2-hydroxy-5-methylphenyl)-. . . . . . . . . . . . . . . %(hydroxymethyl)-. ... ... 4(or 5)-(hydroxyrnethyl)-. ........................

CPt 175 96.5, Pi 157.5 Pi 183-184, 136-137 P i 151-152. HC1111-113 107-1023,

Pi 208,

HCZ 111-113, HBr 103-105, N i 84-85 4(or 5)-(hydmxymethyl)-5(or4)-brome.

. . . . . . . . . . . 118-117,

Pi 180, HCL 157 l-Dydro~methyl)-l-bensyl-.. . . . . . . . . . . . . . . . . . . . . Pi 132-133, HCl 159-160 6-(hydroWmetlryl)-l-bntyl-. . . . . . . . . . . . . . . . . . . . I 39-140 C(hydrorymethyl)-l-cyolo}iexyl- . . . . . . . . . . . . . . . . . . . 134-136 B(hydro.ymethyl)-l ,&dimethyl-. . . . . . . . 126-127. Pi 174

284,521,351,527, 519,517.516.377. 261,260 248 488,489 157 640 66 66

306 306 306 418 418

418 418 639 172 307 219 678,272,730 234,257 702 709 360 360,679,174.45, 23,284,159,355, 613.697.177,31, 22,391,712,709, 735.517.516.518, 519,522,283,362

300 360 302 362 300

Imidamles

. .

Compound

~(hydroxymethyl).l.5-dimethylimidaaole b(hydroxymethyl).l.Pdimethyl.

341

...........

..................

b(hydroxymethy1).l.isopropyl. .................... l.(hydroxymethyl)&methyl. ...................... 2.(hydroxymethyl).l.methyl. ...................... 2-OUrdroxymethyl).l.methyl.b.m. .............. 2-(hydrorymethyl).l.methyl.S-chlor. .............. 0-beruoyl deriv.............................. 2.(hydro w e t h y 1)-4(or 5).methyl. ................. b(hydroxymethyl).l-methyl. ...................... 4(0r 5)-(hydrosymethyl)-5(or 4).methyl. ............

...

4(or 5)-@ydroxymethyl)-5(or4).methyl.2-phenyl. &(hydroxymethyl).l.phenyl. ...................... 4(or 5).(+hydroxrphenyl). ........................ Z(o-hydroxyphenyl)4.5diphenyl. ................. Z(m-hydroxyphenyl)-P.5aiphenyl-................. bemoyl deriv.................................. 4(0r 5).(d.~.tetrahydroxy..yl}. ................ 4(or S)-(~-lyzo-tetr~yd~xybutyl)-2-(-(hydroxymethyl). .................................... l.(&L-rhamnopyranosyl). ......................... 2.3.4tri-0. acetyl deriv........................ 4(or 5).(pmethoxyphenyl). ....................... l.(pmethoxyphcnyl).2.4-diphenyl. ................. Z(p-methoxypheny1)-4.5-diphenyl. ................. 4(or 6)-(pmethoxyphonyl)-5(or 4).phenyl. .......... 4(or 5)-[2-(2-naphtbyloxy)ethyl 1. .................. 4(0r S).(%phenoxyethyl). .........................

2,4,&.tris(3,4-dimethoxyphenyl)-................... 2,4.s-tris(pmethoxyphenyl).......................

.

M.p OC

Refemnoe No

164-166.

300

126-127. Pi 167-168. HCll46. €I02 log-lfx 85-86 HCl92-94 116. Pi 130-137 143. Pi 105-166 120. Pi 161 HCl162 76 Pi 167 129. P i 8 2 113-114. Pi 108 180. HC1236-238 204 Pi 181 83-86 181 209 182

300.337

Pi 178-179

.

.

.

.

260

132 Pi 164 201 153-166 177-179 136-137 109-110 229 214-216 161-lS2 70. Pi 118-120. HCl136-137 91-95

362

486

300.040 49 300.43.800.640 640

618.616 337.362 234.43 156 362 709 148 676 676 273.517. 516

516.517.273 86 86 709 113 167.148 488 339 339.272

.

167 157

56-51

216

PO164-158

216 181

Pi 145-140. HClI25-128 Pt 200-201 Di HCl 227.0-229.6

679 696

146

114

. Mercoptoalkyl- and M e r c u p t o a r y l i m t l e s

7

l.&bia(2.mercaptoethyl)imidazolium chloride bis(Sbuty1) ether ............................ 1-(2-mercaptoethyl)iidszole S-butyl ether ................................ &(2hydroxyethyl) ether...................... 4(or 6)-(mercaptomethyl)8-bensyl ether ............................... Sbnitrophenyl) ether ....................... S-$uanyl ether ............................... Z(pmercaptophenyl)4(or 5)-phenylS-methyl ether ..............................

P a 144-140

677

Systematic Survey and Bibliography

342

.. .

Compound

8

.

Imidawiecorboxaldehydesand Ketones

4(0r 6).imida~olecarboxaldehyde ................... mil

.

Reference No

M.p OC

........................................

174. Ni 185. HCL 169 142-143 291-292 HCL 272 183-184 223-224 200 107 Pi 180-181 224 275 108 310 70-71 186-188 7O.Pi212-213

2.4-diiitrophenylhydrarone................... pnitrophenylhydrazone ...................... oxime semicarbasone............................... sodium biaulfitc deriv ........................ 5(or 4)-methyU(or 5)- ........................... anil pnitrophenylhydrazone ...................... 5(or 4)-methyl-%phenyl-4(or 5)- ................... 2.4-dinitrophenylhydrazone ................... l-cyclohexyl-b .................................. phenylhydrazone............................ 1.Pdirnethyl-5- .................................. I-ieopropyl b ................................... phenylhydrazone ............................ 110-118 1-methyl+ ..................................... 64.Pi 172-173. Ni 175 120-121 1-phenyl-5- ...................................... phenylhydrazone ............................ 207-209 3-amino4[4(or S)-imidazolyl]+butanone .......... Di HC1206-206 4(or 5)-(Zbensoylvinyl)imidazole .................. Pi 201 4.5-dibromo-2.imidazolyl phenyl ketone ............. 218-220 2-imidazolyl methyl ketone ........................ 80. Pi 204 Zimidasolyl phenyl ketone ........................ 161-162 4(or 5)-methylb(or 4)-imidarolyl aminomethyl ketone Pi 178 Di HCl335 4(or S)-rnethylb(or 4)-imidssolyl bromornethyl ketono HBr 223 4(0r 5)-methyl-6(or 4)-imidazolyl methyl ketone ..... 151. Ni 200 semicarbazone............................... 212 4(or S)-phenyl-2-imidnaolylphenyl ketone .......... 197-198 248 dibromo deriv............................... 2.4-dinitrophenylhydrarone................... 265 l-(l-methylbimidazolyl)-3-phenyl-1.3-propmedione 116.5-1 17.5

......................................

.

........................................

2.bromoimidazole 4(or 6).bromo-

609.495. 668 495.669 495.889 270

270 270 302

D. Halogenoimidazoles

.

Halogeenwlkyi. and Halogenoaryiimidades

................................

..................................

4(or 5)-brom&(or 4).(pbromophenyl). ............ 2-bromo-1. 4-dimethyl. ............................ K-bromo-1.4-dimethyl. ............................ 2.bromo4.S-diphenyl. ............................ 4(or S).bromo-Ziodo-

867 155 165 362 362 337 362 362 597.337. 362

068

.

. Halogeno..

337

362 302 172 337 639 498 639

.

1

730,079,159.22, 21.597. 337 337 186 730 337 337 337 337.007

............................

207. Pi 232. N i 137 130-131.Pi162 N i 135. HCI 102-185 192 51-52. HCl 240 02 90 205-206 Pi 181-182 174

.

.

388 48

496 415

508.250

411

525

ImidsZOleS Compound

....... ..........................

4(or 6)-bromo-%iodo5(or 4).methylimidasole

%bromO-rl(or 5).methyl.

4-bromo-I-methyl- ............................... 5-bromo-l-methyl- .

..............................

4(0r 5).bromo-2.methyl.

..........................

343

.. .

M.p

Reference No.

O C

147.148. HCl211 124-1 25. Pi 172-173 Ni 155. Pi 179 45-46. Pi190. Ni 155 HCl155. HOz 147

. .

162-163 Pi 161-183.

.

625 568

49 49 430

NZ 132 4(0r 5)-bromoJ(or 4).methyl. ..................... 5-bromo-l.methyl4phenyl. ....................... 2-bromO-rl(or 5).phonyl. .......................... 4(or S).bromo-Sphenyl. .......................... 4(0r 5)-brom&(or 4).phenyl.

..................

4(or 5).(pbmmophenyl). ......................... 4 (or 5)-(%bromopropyl)-5(or 4)methyl. ............ 4chloro-I.allyl. .................................. 6chloro-%(chloromethyl).l.methyl. ................

........................... hhloro-1&dimethyl. ............................

4-chloro-l.2-dimethyl-.

HC1187-188 _.

80-90. Pi 226 153 206-207 Pi 164-165 HCl118-119 242-245. Pi 188-189. Ni I27 142. P i 216 rOellO Pi 110-113 Pi 156-157 HCl167-168 93-94 Pi 167-168 Pi 175-176 133. P i 157-158 Pi 146-147 Pi 154-155 Pi 154

..

.

.

&chloro-l.2-diphenyl .(?) .......................... kchloro-l-ethyl. ................................. 4-chloro-l-ethyl.2.methyl. ......................... 6-chloro-l-ethyl.2-metbyl. ......................... 5ehl0ro-l~thyl-2-phenyl-(?) ...................... 05-67 Pi 160-161 4(0r 5)-(2-~hlo~iodopropyl)-S(or4).methyl.. or ... 94-95 4(or 5)-(3-chloro-%iodopropyl)-5(or 4)-methyIpchioro-1.isoamyl.. .............................. Pi 120-121 4-chloro-l.ieoamyl.%methyl. ...................... 4-chloro-l.iaobutyl.%methyl. ...................... Pi 141-142 P i 166-167 4-chloro-1-methyl- ............................... . bchloro-1-methyl- ............................... bhloro-Zmethyl-I-phenyl- ....................... Pi 176 4-chloro-2-methyl.l.propyl. ....................... Pi 152-153 ECll26 4(or 5).(2-chloroethyl). ........................... RCl141.5-143.5 4(or 5).(ohloromethyl). ........................... %(chloromethyl).l.bensyl. ........................ HCl181-182 HCll85-I87 5-(chloromethyl).l.benzyl. ........................ HC1199-200 5-(chloromethyl).1-cyclohexyl. ..................... HCll78-179 5-(chlorornethyl).l.ieopropyl. ...................... &(chloromethyl).l.methyl. ........................ ECl 166-167 4(or 5)-(chloromethyl)-S(or Q.methy1. .............. HCl218 4(or S)-(chlommethyl)-S(or 4)-methyl.%phenyl. ..... HCll8Z-183 Hc1173-174 5-(cllloromethyl).I.phenyl.

.

.

........................

568.525

256 256 264

256.4%

712. 717 599 598 640 601 640

367 598 601 468.293 367 699

600

801 601 598

394 293 601

272,678 679.23 300 362 362 362 362 234 166

362

344

Systematic Survey and Bibliography Compound

.. .

M.p OC

4(or b)-(pchlorophenyl) imidzwole . . . . . . . . . . . . . . . . . 147. Pi 219-220 2.4(or 2.5)dibromo- .............................. 193 4.6dibromc- .................................... 225. Ni 115. HCL 250 2.4-dibmmo-l.Bdimethyl- ......................... 125 2.6dibromo-l,4dimethyl-......................... 41-43 2.4(or 2.5) -dibrom&(or 4).iodo- ................... 181 4.5dibromo-2-iodo- .............................. 215.5 2.4(or 2.fi)dihrom&(or 4).methyl. . . . . . . . . . . . . . . . . 214-2 I 5 4.6-dibromo-l-methyl-. ........................... 78-80. Pi 148-149 N i 153. HCll79 4.Wibro1n0-2.methyl. ............................ 239-240 . HCl255 HBr 280 2. 4(or 2. 5)dibrom&(or 4).phenyl. . . . . . . . . . . . . . . . . 198-199 4.5-dibromo-2-phenyI-. ........................... 141.Pi 170-172. HCl 235-237. HBr 250-266 4(or 5)-(2.3-dibromopropyI)-5(or 4)-1llCthJ.l-. . . . . . . . . 116-117 2.4(or 2.5)-dichlom- .............................. 184-185 2.4(or 2.5)-diod04(or 4).1iiethyl. . . . . . . . . . . . . . . . . . . 191-192. HCI 220-222 2iodo- ......................................... 135-136. Pi 185. Ni 136.0s 220 2-iod0-4(0r 5)-methyl- ............................ 170-171. Pi 171 Oz 207 4(or 5)-iodo-%methyE............................ 144-145 2.4,S-tribromo- .................................. 221 1-bensoyl dcriv................................ 101-102 2.4.5-tribromo-l-methyl-. ......................... 93-94.5, HCl19o-2oo 2,4.5-triiodo-. ................................... 182-183 2.4.5triu(~~ci1lorophenyl)-. ....................... 2fis

.

.

2

Reference S o.

712.717

45.48 48

568.256 568.266 525 525 568 49 430 256 214 599

3aa

526

525 525 525 48 590 49 715.712 148

. Halogenated Alkyl- and Arylimidazolium Salts

4(or 5).broino-l. 3aimethylimidaiolium iodide ....... 5-chloro3.allyl.l.methyl.. bromide . . . . . . . . . . . . . . . . . 5-chloroSbensyl- 1.methyl. bromide............... S-ohloro-l.3-diethyI.2.mcthy 1 iodide............... 4-cNoro-1.3dimethyl.. iodide ...................... 5-chloro-l.3.dimethyl. iodide...................... 4-chloro-1.2-dimethyl-3-ethyl-. iodide............... 5-chloro.2.3.dimethyl.l-ethy 1 iodide............... 6-ohloro-l-ethyl-3.isoamyl.2.methyl.. iodide ......... Pchlom-l.ethyl-3.methyl.. iodidc .................. 5-chlorc3-ethyl.l.methyl. iodide .................. 5-chloro-l-ethyl.Zmethyl3.propy 1 iodide . . . . . . . . . . 5-chloro3.isoamyl.l.methyl. iodide................ 3.(pohlorobenayl).l-decyl.2.methyl.. chloride . . . . . . . I-(2.4-dichlorobenzyl)-2-heptyl-3-methyl-chlorida.... 3-(2.4-dichlorobensyl).l.hepty1.2.methyl.. chloride ...

..

.

.

.

. .

200-204 141-142 107-109 142-143 174-175 174-175 203-204 202-203

133-134 156-1.57 156-157 108-109 118-1 10 125-127 108-1 10 130-131

49 598 598 801 598

698 601 601 601 598 598 601 598 622 622 622

345

Imidazoles

.

R&uunoe N o

M.v., OC

Compound

E. Nitmimidazolee

.

. Nitro- and NitroarylimWzola

1

4(or 5).nitroimidaaole ............................ 4-nitro-1.Zdimethyl. ............................. 4-nitro-1.5-dimethyl.

............................. ............................

5-nitro-I .2-dimethyl.. i%nitro-l&dimethyl.

.............................

................................ &nitro-1-methyl- ................................ 4-nitro-1.methyl.

4(or 5).nitro-Zmethyl. ........................... 4(0r 5)-nitrob(or 4)methyl. ...................... methosulfato ................................ 4-nitro-l-methyl-B(2-phenylvinyl)-................ 5-nitro-l-methyl-4-(2-phenylvinyl)- ................ 4(0r 5)-nitro-5(or 4)-(pnitrophenyl)- ............... 4-nitro-5(pnitrophenyl)-l-methyl-................. &nitro-4-(pnitrophenyl)-l-methyl- ................. 4(or 5)-nitro-2-(pnitrophenyl)d(or 4)-methyl- ....... 4(or S)-nitro-S(or 4)-(2-~henylvinyl)-............... 1-(pnitropheny1)- ................................ 2-(o-nitrophenyl)- ............................... 2-(m-nitrophenyl)- ...............................

................................ 4(0r 5).(+nitrophenyl). ........................... I-bensoyl deriv .............................. 4(or S).(pnitrophenyl). ........................... 1-bensoyl deriv .............................. 2-(o-nitrophenyl)-4.5-diphenyl. .................... %(m-nitrophenyl)4.5-diphenyl-. ................... 2-(pnitrophenyl).

2.(pnitrophenyl)-a.sphenyl. .................... 4(or 5).(pnitrophenyl).2. 5(or 2.4)dphenyl. %(pnitrophenyl)-1-methyl- .......................

.........

4(o-nitrophenyl).l.methyl. 4-(pnitrophenyI).l.methyl.

....................... .......................

243.422

312413 182-183. HCI 215 100-161. P i 6688 138-139. P i 162-163 HCll95 57-58. P i 176. HCl188 135

77

563.77,20 77 563.20,77

55. Pi 153

600.322.49.266. 422. 26 322,256,422.26

248

243 26.243

HCll95 264

.

143-144 150-151 214-215 293 187 *209 248-249

303

20 26

26

294.496 322 322 496 727.26

256 HCI293-294 188-189. Pi 212 567 N i 153-154

204-206.

.

193-194 P i 245-246. N i 182 310-315. Pi202 N i 172 146. N i 168. HCI !203 loo-101 225. N i 200. RC1292 182 230 309 240 229 117-118 Pi 214-215. N i 186. Au 226 N i 182 195. Pi 268. N i 197

.

.

567

.

567 294 294 496.294 294 148 676.148. 167 148 148 45. 266 322 322

Systematic Survey and Bibliography

346

.

Compound

Reference No

h b . , OC

5-(pnitrophenyl)-l-methylimidtwole............... 171.172. Pi 184. Ni 213 2-(m-nitrophenyl)-4(or 5)-(pnitrophenyl-5(or 4)phenyl2.4.5-tria.(m-nitrophenyl). 2.4.6-trie.(pnitrophenyl).

..................................... ........................ .........................

2

322

148 157 676

256 126 147

. Nitroolkyl- and Nitroarylimidawles Containing Additional Functional Groups .................

4-nitro-..ino-l.methylimidssole 4(or 5)-nitro-5(or 4).(paminophenyl). .............. N-aoetyl deriv............................... 4(or 5)-nitrOS(or 4).bromo- ....................... 4nitro.2-bromo-1.5-d-dimethyl. ..................... 5-nitro-2-bromo-1&dimethyl. ..................... Pnitro-Sbromo-l.methy1. ........................ &nitr&bromo-l.methy1. ......................... 4(or 5)-nitro-2-broniod(or 4).methyl. .............. 4(or S)-nitrOS(or 4).bromo-%methyl. .............. 4-nitrob-chloro.l-ethyl.2-methyl. .................. 5-nitroPchloro-l-ethyI.2.rnethyl. .................. 4nitroS-chloro-1-methyl- ......................... 5-nitroPchloro-l.methy1. ......................... 4(or 5)-nitro-2.5(or 2.4)dibromo- .................. 4(or 5)-nitrOS(or 4).(phydroxyphonyl). ............ 4(or 5)-nitro-5(or 4).[2.(pmethoxyphenyl)vinyl]. .... 4(or 5)-nitr&(or 4)- [2-(3.4.methylenedioxyphenyl ). vinyl 1. ...................................... 2-(pnitrophenyI)-4(or 5).bromo- ................... 2.(o-Ntrophenyl)-4.5-dibromo-. or . . . . . . . . . . . . . . . . 2.(m-nitrophenyl)-4.5dibrom oZ(pnitrophenyl)-4.5ibromo- .................... 2-(o-nitrophenyl).l.liydroxy-4.5-dimethyl4-oxide .... 4(or 5)-(pnitrophenyl)-2-(o-hydroxyphenyl)-5(or 4)ph-I. .....................................

44 294 >280 294 279 48 179-180 688 67-68 HCL 187 415.588 180 HCL 155 49 49 105 220-221 588 268 430 88 488.601 67 601 147-148 600.49 77-78 600 >270 48 294 >300 298 727 303 XCL 250

..

288 222-223 181-182

254

220-222 150 HC1176

.

254 418

217

148

227 253 181 195-196 134-136

460 460 322 77 77 622 460

28

254

. Nitroalkyl- and NitroarylimidazolfumSalts

3

3-(2.4-dinitrophenyl)-1.4-dirnethylimidaaoIium chloride .................................... 8(2,4-dinitrophenyI)-1.5imethyl-.chloride......... 4(or 5).nitro-1.3.dirnethyl.. iodide.................. 4(or 6).nitro-1.2.3-trimethyl. iodide................ 4(or 5)-Ntro-l.3.5(or 1.3.O.trimethyl.. iodide ........ 3.(pnitrobonsyl).Zhendecyl.l.methyl.. chloride ..... 3-(2.4.6-trinitrophenyl).l.4-dimethyl.. chloride.......

.

.

-

179

F Arylazoimidazoles

........ .

4.6-bis(pbromophenylaco).2-methylirnid~le 2.4(or 2.5).bis(phenylaro ).5(or &.methyl. ........... 206 2-(pbromophenylaeo). ........................... 253 4(or 5).(pbromophenylaso). ...................... 191

242

243 243

243

.

Imidazoles

34i

..

M.R OC.

Compound

.

2-(pbromophenylaao)-4.5-dirnethylimidwole........ 213-214 HCi 135 2-(pbroniophenylazo)-(or 5).methyl. . . . . . . . . . . . . . . 225-226 4(or 5).(pbromophenylazo).2-methy& .............. 200 4(or 5)-(pbromophenylazo)-5(or 4).methyl. ......... 238 HCl188 4(or 5).(pbromophenylaao).2-phenyl. .............. 201 2-[m.(2. P d i y droxyphenylazo)phenyll-4.5.diphenyl. 222 216 Z(pethoxypheny1azo)- ........................... 194 2- [rn-(l-hydroxynaphthyleao)phenylJ-4.5-diphenyl. 2-[m.(2-hydro~ynaphthyl~o)phenyl]4.6diphenyl. ... 123 161 2-(o-methoxyphenylseo). .......................... 185-186 %(o-methylphenylam)- ........................... %(pmethylphenylazo). ........................... 235 152 4(or 5).(pmethylphenylao). ...................... 2-(pnitrophenylaao). ............................ 248 2-(phenyl-0). ................................... 190 %(phenylaso)-Q(or 5).methyl. ..................... 185 4(or 5).(phenylwo).2-methyl.. .................... 168 4(or 5)-(phenylazo)-5(or 4)methyl. ................ 240 >300 Z(pdfopheny1azo). ............................. 2.4. 6trie(pbromophenylazo)...................... 2.4,5-tris(phenyla%o)-............................. 200

.

..

...

-

.

Reference No.

i09

109 243 109

243 676 569 676 676 569 565 565 565 191 243 243 243 243 569

242

243

G Aminoimidazoles

1

. Amino-. Amirroalkyl.. and A m i n w r y l i m i d a w b

2-aminoimidwole ...............................

N-acetyl deriv............................... (paminophenylsullonyl) deriv................. N-benzoyl deriv.............................. 4(or 5)-aminO- ................................... N-acetyl deriv...............................

N-bensoyl deriv.............................. N-panyl deriv.............................. N-ureido deriv...............................

2-ami n d ( o r 5) .(4-amino-3-methylphenyl)- .........

.

hri 135-136. P i 236 HCll52 287 262 227 Di HCL 184 226. Pi 208. F 260 217 194-195 Pi 200. Hcl210

-

.

Di Pi 210 148. Di Pi 256

2-amind(or 5)-(parninophenyl). .................. diacetyl deriv................................ >300 4(0r 5)-amirIod(Or 4)-(paminophenyl)- ............. P i >300 HC1>300 _. benmylidene deriv............................. 2-amino-4(or 5)-(paminophenyl)-5(or O-methylPi 265. Di HCL >300 benzylidenederiv ............................ At 208 diacetyl deriv................................ 280. HCI 303 6amino-4-(psminophenyl)-l.methyl- .............. Di HCl>300 4(or 5)-amino-2-bensy1-5(or 4)-phe&l- ............. 199. P i 215. Hcl200 diacetyl deriv................................ 215 2-amino4.5dimethyl- ............................ Pi 246. HCl289 N-acetpl deriv............................... 210

.

....

243.669 243 29 243 240.349 349 138

345.346.344 345.346 565 243 243 294

294 243 243 243 322 137 137

109

109

348

Systematic Survey and Bibliography Compound

4-t~nino-1.5-ditiiethylimidasole .................... 5-aminu-1.4-diniethyl- ............................ 4(0r 5).arnino-2. 5(or 2.4)-diphenyl. ................. 2-amino4(0r 5).tnethyl. .......................... 5-amino-l.metliy1. ............................... 4(or 5)-aminod(or 4).niethyI. ..................... N-acetyl deriv............................... N-bensoyl deriv.............................. benrylidene deriv............................ N. l-diben~ylderiv.......................... N-phenylureide .............................. 4(or 5)-amino-2-rnethylb(or 4).phenyl. ............. 4(or B)-(paminoanilinomethyl)-5(or 4).methyl. ...... 4(or 5).(4-aminobutyl).

...........................

1.(2-aminoethyl). ................................ N-(~acetarnidophonylclfonyl) deriv. . . . . . . . . . . N-(pminophenylsulfonyl) deriv............... N-phthaloyl deriv............................ 2-(2.amin~thyl)-................................ 4(or 5)-(%aminoethyl)- (hiatnminc). . . . . . . . . . . . . . . .

..

.

Reference No

M.p o c

.

Pi220 HC1225 Pi 209 Pi 220 P i 186-185 101. Pi 177 P i 195. HCt 189 316 262 217 176 283

.

HCl238 Pi219-220 HCl257 51-53. Di Pi 197.5-198.6. Di Oz 168.5-170 218 228 157 155 Di Pi 213-214 Di HCl229-2.30 (See Table

.

XXIII)

N-aeetylhistamine............................... 147-148. Pi 181-183 N.(S-aminoarnyl). ............................... TstmPi216 N.(paminobenzoyl). ............................. 189-190 B(paminopheuy1azo)............. 241-243 N.benroy1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 N-(bensoylpheny1ruo)- ........... 186.5 Zbensyl- ....................... Di Pi 195. Di HCl245 N-cmbayl..................................... 148.Pi150 0s 153 NJ-dibenzoyl. ................................... N, N-dimethyl- .................................. Di Pi 233 Di HCll88 2-ethyl. ......................................... Di pi 219. Di HCI 209 N-thyl- ........................................ Di Pi 186. Di HC1 169 .. Di Pi 245. Di HC1208 hr-[2-(~iiyclrr~xy~liri~yI)cthyl I. . . . . . 157

.

I

.

.

Di Pi 208.5.

N-ieobutyryl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N-is~pr~pyl...............................

"('1 202-203 1 23

D i HCl 197.5-1W

.

563

563 137 109

139 710.240 710 710 240.710.494 710 710 137 275 15.16

441 441 441 441 380 12,504.18.20,2'i'L. 699.192 657@ 690 247 719 276 191 690 690 276 272

690 272 690 276

090 021

Imidazoles Compound

%rnercaptahiatamine ............................. N.(pmethoxyhenzyl). ............................ N.(pmethorybenllylidene). ....................... 1-methyl .......................................

-

%methyl- ....................................... 4(or 5)-methyl- .................................. N-methyl- ..................................... N.(3. Pmethylenedioxybensyl) .....................

349

.. .

M.p OC

Referenee No

Pi 225. HCl24S-249 Di Pi 213 186. Di Pi 222 Di Pi 199-201. HCl265-266 Di Pi 237 HCl217 DiHCl225-226

20.18. 584

. .

Di Pi 188

D i HCll76-177. Di HBr 167 Di Pi 195 Di HCl245 180 Di Pi 217 193 211-212

.

.

N.(3.4-methylenedioxybenzylidene). ................ N-(1-naphthylcarbamy1)- ......................... N.(pnitmbens~yl). .............................. Z(pnitropheny1aso). ............................. 251 2-phenyl- . ...................................... Di Pi 230 Di HCl240 Zphenylaao- .................................... 237 N.(phenylcarbamyl). ............................. 178 ;l'-trimethyl- .................................... Di HCl229 ........................................... Di Pi 212 2.(2-aminoethyl).l.bensylimidasole ................ 59-80. D i Pi 186-180 Di HCl224-226 Di HCl 196-198 l.(%sminoethyl).%methyl. ........................ N-(pecetamidophenylsulfonyl) deriv........... ai2-214 N-(paminophenylsulfonyl) deriv............... N-phthaloyl deriv............................ 161-162 !&(Zaminoethyl)-4(or 5).methyl. ................... D i HCL 262-284 N-benroyl deriv.............................. 206-208 4(or 5).(mminomethyl). ........................... Di HCL246-247 2-(aminomethyl)4(or 5).methyl. ................... DiHC1248-260 N-bensoyl deriv.............................. 186-186 2.(o-aminophenyl). ............................... 136-137. Pi 211-212. Di HCI 234-236 %(m-aminopheny1)-.............................. 202-203. Pi 218. Di HC1282 2.L-(paminophenyl). .............................. Pi 238. Di HCI 300 4(or S).(o-aminophenyl). .......................... 131.DiPi200, DiHGlW 4(0r li).(p-aminophenyl). ......................... 98. Di P i 240. Di HCI 310 N-acatyl deriv............................... 260-251 Z(o9minophenyl)4.5diphenyl. ................... 196

.

.

diSl5OdfOMt.8.

..............................

-

2-(nr-rrminophenyl)-4,5.dipbenyl-................... 295

690

690 362 690.664 234

272

690 690 690

247

719,377.378 690

377.719. 378 690

272 272 360 442 442 442 442 230 230 679 250 23Q 46

48 46 46 46.709. 496 709 148 676 148.676

.

350

Systematic Survey and Bibliography Compound

.

Reference No.

Map., OC

4(or 5).(p-aminophenyl).2. 5(or 2.4)diphenylimidazole l.(3-aminopropyl). ............................... 4(or 5).(3-arninopropyl). .......................... 4(or 5)-(Zaminopropyl)-5(or 4).methyl. .............

245 119. H a 2 2 2 Pi 244-244.5 ' LX Pi 2 29.230 Di HCl215-217 4(or 5)-(anilinomethyl)-5(or 4).methyl. ............. 183.Di HCl201 N-bensoylderiv.............................. 206 HCl235 4(or 5)-[(benzylamino)methyl j- .................... HCLUH).5-201 4(or 5)-[2-(bensylsthylamino)ethyl 1. ............... HBr 82-83 4(or 5)-[(beneylethylamino)methyl1. ............... HCI 208-209 4(0r 5).[2-(bensylrnethylamino)ethyl]. .............. HBT178-179 4(or 5).[(bencylmethylarnino)methyl]. .............. HC1229-230 4(or 5)-I(beneylphenylamino)methyl I. .............. 147-148 4.5-bis(aminomethyl)-%ethyt-. .................... 262 4.5-bis(aminomethyl).%methyl. .................... Di Pi 146. Tri Pi 218 HC1274 4(or 5).[p.p'.(bie(dimethylamino)l~enrhydryl]. ....... 190 4(or 5)-[2.diben~lamino)ct~l]-. . . . . . . . . . . . . . . . . . . Di HCl 155-156 4(or 5)-((dibensy1amino)methyl1. . . . . . . . . . . . . . . . . . . 148.5-149.5 4(or 5)-[2-(diethylamino)ethyl .1 . . . . . . . . . . . . . . . . . . . HCL 219-220 4(or 5)-[(diethylamino)methyl1. ................... Di HC1200 4(or 5)-[2-(diethylamino)propylI-5(or 4).methyl. . . . . Di Pi 178-179

148 441 16.15 599

4(or 5)+[2-(dimethylamino)ethyl 1. .................. Di Pi 215. Di HCl183-184 4(or 5)-[(dimethylarnino)rnethyl 1. .................. Di HCl 197-197.5 4(or 5).[2-(dipropylamino)ethyl]. . . . . . . . . . . . . . . . . . . Di Pi 190 4(or 5)-[2-(ethylamino)ethyl 1. ..................... Pi 185. Di HCl 102-163 4(or 5)-[(ethylamino)methyl .1 ..................... Di HCL 109-170.5 4(or 5).guanidino- ................................ Di Pi 216-217. Di HCl.288 4(or 5).(3.manidinopropyl). . . . . . . . . . . . . . . . . . . . . . . . 183.5-184, Ni 183.5-184, Pi 258 4(or 5)-[2-(iaopropylamino)ethyl .1 . . . . . . . . . . . . . . . . . Pi 176. HCl 195-196 4(0r 5).[(methylamino)methyl]. ................... Di HCL 198-199.5 4(or 5)-[(2-phenyletl~yl)aminomethyl]-5(or 4)-methyl- Pi 211. Di HC1 254 4(0r 5)-[2-(pmpylamino)ethyl1. .................... Di Pi 165. Di HClQ6-100

339

.

.

.

Di ACll99-ux)

2

. Amino..

276

275 679 339 679 339 679 679 660 605 337 339 679 339 679.677 599 679 339 339 679 344.407 10.15 339 679 275 339

Aminoalkyl.. and Aminoarylimidawles Containing Additional Functional Groups

4(or 5)-aminoS(or 4)-(2amino3-bro~nophenyI)-2phenylimidasole ........................... HCL 255. AL 161 242 242 triacetyl deriv...............................

-

Imidasolee Compound

351

.

M.E., O C

.

Reference No

%amino4(or 5)-(4-amino-3-methoxyphenyl)imida~ole P i 202. 669 Di HC1288 2- [(2-amino-6-bromophenyl) amino1. ................ 178 Di P i 226. 263 Di HC1246 4-amino4chloro-l.methyl. ........................ 600 bamino4-chloro-l.rnethyl. ........................ 600 2-(2-sminoethyl)b-choro-l.methyl. . . . . . . . . . . . . . . . . Pi 176 640 4(or 6)-[p(2-aminoethyl)phenoxymethyl .......... cpt 220 696 4(0r 5)-(2-amino-l-hydroxyethy1)-6(or 4).methyl. .... Pi 167.HCI 210 088 4(or 6)-(2-amin&hydroxypropyl)(histidinol)... Di HCl 193-195 373 N-bensoyl deriv.............................. 207.208. 373 HCl 178. Di OX 172-173 HC1183-183.4 233 trimethyl deriv (trimethylhistidinol)..... HI 190.8-197.1 ~(2-trimethylamino-3-hydroxypropyl).l.3-dimethy .1 (pentamethylhistidinol)...................... Di Pi 233 183.1-184.1. Di HC1204 0-acetylderiv............................... Di HCll11-113.5233 4(or 6).(aminomethyl).2. 6(or 2.4).dibromo- .......... 230 464 640 2-(anilinomethyl)S-chlore-l-met.hyl-. .............. 126-126. Pi 170-171 117 $(or 6)-f [benzyl(2-chloroethyl)amino]methyl~. ...... 194~194.5 117 4(or 61-1 [benzyl(2-hydroxyethyl)amino]methyl I. . . . . 696 4(or 6)-[(2-diethylaminoethoxy)methyl .1 ............ CPt 280 2[(dimethylamino)methyl]-6-ehloro-l.methyl. ....... HCl198 640 640 2-[(pethoxyanilino)methyl]-Cchloro-l-methS.I-. ..... 114-116 640 2-[(methylamino)methyl].6-chloro.l.methyl. . . . . . . . . Pi 178 464 4(0r 6).(thioureidomethyl).2, 6(or Z.l)-dibromo. . . . . . 252 Smethylether .............................. 220 464

-

.

.

-

H. Cyano- and Ieocyanatolmfdazolee

6-cyeno4amino-l-ethyl.2-methyfimidsaole .......... 162. HCl214 thyano-4-amino-l.methyl. ........................ 178. IiCl266-257 192.5-194 4(or 6)-cyano-%bensyl. ........................... boyano-l-ethyl.Zmethyl-4-nitro- .................. 70-71 141-142 6-cyano-l.methyl4nitro-......................... 114-116. %(cyanomethyl)-1-benzyl-........................ Pi 108-107 Z(cyanomethyl)bchloro-l.metbyl. ................ 128 Pi 156-167 b(cyanomethyl)-1-methyl........................ 4(or 6)-(cyanomethy1)-5(or 4).methyl. .............. HCl 180-161 4,Wicyano-2-e.thyl-. ............................. 185 4.6-dicyano-%methyl-............................ 2% 4.6-dicyauo-2-phenyl............................. 201 4(or 6).(%isocyanstoethyl). ....................... 186

469 469 164

446.488

600 360 840 362 234 006 606

332 682

Systematic Survey and Bibliography

352

.. .

I

.

Reference No .

hLp O C

Compound

ImidazolecarboxylicAcids

. MonocurboxylicAcids

1

(a)A&& and A ~ l i r n ~ ~A& ~ l i c

1-imidasolecarboxylic acid (1-naphthylanride) .......................... anilide...................................... ethylester .................................. 4,5dipheny lanilide...................................... 4(0r 5)-methylethyl ester . . . . . . . . 2-imidasolecarboxylic acid ........................ 1-benzyl- ..................................... 4(or 5)-methyl- ................................ ethyl eater .................................. 2-amyl-l-methylPiniidazolc~r~xylic acid .........

methyl ester ................................ l-cyclohexylmethyl ester ................................ hydracide ................................... phenylsulfonylhydraeide...................... 1,4-dimethyl-.................................. l-isopropylmethyl eater ................................ hydraside ................................... phenyleulfonylhydrsidc . . . . . . . . . . 1-niethyl ..................................... iiiethyl ester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . hydracide ................................... phenylaulfonylhydrazidc...................... l-phenylethyl ester . . . . . . . . . . . . . hydraside ................................... phenylsrilfnnylliydracidc. 4(or 6)-imidasolecsrboxylicacid . . . . . . . . . . . . . . . . . . .

-

amide ...............

..................

allylamide . . . . . . . . . . . ...................... diethylamide . . . . . . . ....................... diinethylaniide........................... di-rt-propylamidc . .

......................

238-239 114.5-115.5

-

326 326 367

210.5

326

Ni 116-117.

357

Pi 148-149 103-164 103-104 175 N i 124 121-123 42-43 66-67

360 360 367 357 152 162 162

03-64

361

90-91 175-176 165-186

361 362 362 337

205-2069

Pi 186-187

.

99-100 180-181

Pi 198-199

.

08-70 P i 171 188-189

812-213

80-81 159-160 184-186 283.Pi 195 215. Pi 228.

HC1220

361 362 362 337 337.361 362 362

361 362 362 361.48.735,159, 243,44.520,679 46.516

.

130. P i 171-172 717.715 Pi 158-159 717.715

Ox 166 90-91. P$200-202. 0s 204

BB-70. Pi 147-148.

0s 160-161

7'17. 715 715.717

353

Imidazolcs

.

Rsferenoe No

.

715.717

M.P., OC

Compound

4(or 6)-imidasolecarboxyliio wid (contd.) ethylamide ............................ methybide . . . . . . . . . . . . . . . . . . . . . . . . n-propylamide . . . . . . . . . . . . . . . . . . . . . . .

161.162

.

Pi 93-94 146 Pi 196

121.122. Pi 150 227-228 anilide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 Di P i 242 o-aminoruiilide. . . . . . . . . . . . . . . . . . . . . . . . . . Di HCl310 228 Pi 266 paminoanilidc . . . . . . . . . . . . . . . . . . . . . 273-274 pbromoanilide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . o-nitroanilide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 N i 196 pnitmanilide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307. N i 206. HCL H20 298 ethylester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157-158 acid chloride. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . aside . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 hydraside. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 237-238 phenyleul fonylhydrsaide. . . . . . . . . . . . . . . . . . . . . 2-smyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 Zamylb(or 4)-11iethylethyleater. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100-101 ZbnSylmethyl ester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214-216 262. Pi 196 aethyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . anilide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iga ethyl eatel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Pi 220-221 1-methyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262. Ni 180 Zmethyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HCL 268 anilide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 ethyl eater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 5(0r 4)-methyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . 222-223 N i 189 HC1231 220 hydrsaide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 phenyleulSonylhydraride . . . . . . . . . . . . . . . . . . 6(or 4)-methyl-%phenyl- . . . . . . . . . . . . . . . . . . . . .. . . 177 ethyl eater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... . 199-199.6 239 Zphenyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . anilide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 ... 189 ethyl eater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5(or 4)-phenylethyl eater ................................... 226

. .

.

.

-

.

-

-

.

..

-

(b) Zmidaw&wrbox&

716.717 716. 717 243.4s

46 46

388

46

46 361.146,47 717.715

44

362.44 362 152 166

136 244

244

244 337 243

243 244 243.337 667

667 156

156

244

244

244 256

Acida Conlainin0 Arldilwnal Fundwnal Group

&amino-l-methyl-4-imidsrrolecarboxylicacid

w i d e ......................................

ethylester .................................. 4-smino-l-Bthyl-~methyl-Simidasolecar~xylicacid

264. HClZS7

192. HC1203

.

139 139

w i d e ...................................... 166 HC1 195 468 ethyl smide ................................. Pi 176. HCI 169 446 4-amino-l-methyl600 amide ...................................... 184-186. RCl214-216

.

354

Systematic Survey and Bibliography Compound

4 - a m i n o - l - m e t h y l - 5 i n d a z o l ~ r ~ xacid ~ ~ ~(contd.) ethylamide ................................. m e t h y h i d e ................................ anilide ...................................... ethyl ester .................................. methyl eater ................................

C(dimethylsminop1-methylmethylamide ............................... iodomethylate ............................... C(methy1amino)-1-methyl-...................... methylamide (caffeidme)..................... benzoyl deriv.............................. nitroso deriv............................... 4-(methylarnino)-l-methyl-5-imidamlethionomethylamide (thiocaffeidine) ................. 5(or 4)-amind(or 5)-imidaeolecarboxylicacid w i d e ...................................... ethylester .................................. methyl ester ......... .................... 5(or 4)-amino-2-benzylethylester .................................. 5(or 4)-amino-2-methyla i d e ...................................... ethyl ester .................................. 5(or 4)-amino-%phenylethyl ester .................................. acetyl deriv ................................. beneylidene doriv., .......................... 5(or 4).(2.aminoethyl).2-methyl. ................. 5(or 4).(p-bromophenylaso).2-methyl. ............ 5(or 4)-(pbromophenylazo) .2.phenyl. . 5(or 4).bromo- ..............................

..........................

ethyl ester .................................. 2-bromob(or 4).methyl. ........................ ethyl ester .................................. 5(or 4).(chloromethyl).2.methyl. ................... 6(or 4).(ryanomethyl).%methyl. ................. 2.5(or 2,4)-dibromo-.............................. amide ...................................... p b r o m o d i d e ........ ............... ethyl ester .................................. 6(or 4).(hydroxymethyl).%methyl. .............. 5-nitro-l-methyl4imidazolocarboxylicacid ......... amide ......................................

..

.

M.P OC.

Refexears No

.

137.338. Pi 182 HC1 189-190 150. Pi 221 HC1222 HCll30 HCl 190 126-127. Pi 230. HCL 183

.

440

446.328 440

440 4 4 8 ’

98-99 106 Ni 215. HCl215 93 174 155

328.82. 83 328 82 82.83 82 82

104-105.

379

169.8-170.4.

020,147.727.023

Su 193-194. N i 182

Pi 240

.

137 180-181 Pi 235 HCI 210 727

Pi 221

137

.

HC1238-240 107 HCl213-214

147 137

218. Pi 224 HCl216 174 214 HCl237 160 210 205

137

245-246

170-171 234 153

-

224 225

256

257-258 147

-

105

234

.

137 137

004

242 242 45.388 388 388.45 568 568 004

004 45.48 45 388 48 602

20 20

Imidazoles

__

Compound

~nitro-l-ethyl-2-methyl-6-imidasdecar~xytic acid ... amide ...................................... ethylamide ................................. 4-nitro-l.methy1. ................................ a i d e ...................................... (29cetoxyethyl)amide ....................... (2bromoethyl) amide ........................ ethylamide ................................. (2-hydmxyethy1)amide ....................... methylamide ............................... anilide...................................... ethyl eater .................................. methyl eater ................................ acid chloride ................................ 6(0r 4)-nitrd(or 5)-imidsrolecsrboxyticacid ........ amide ...................................... methyl ester ................................

355 M.p

.. .

Reference No.

O C

139-141 272

446 468

172 267-268 109-110 154-166 146-146 148-149 196 191-198 101 128-129 62-62.5 302-303 291 212-213. He1215 248. su 230

600.328.20,446

86-88

.

%(m-nitrophenyl)-............................. E(pnitropheny1)- .............................. 288 Su 286 6-(3-acetylthioureido)-l-methyl4imid~olecark~oxylic acid 245 smide ...................................... 4-(l-methylthioureido)-l-methyl-5-imidasolecsrboxylic acid 197 methyhnids ............................... 6(or 4)-(3-methylthioureido)-4(or 5)-imidmleaarboxylic acid ethyl ester .................................. 163 6(or 4)-(3-methylthioureido)-l-bensylethyl eater ................................. 174 6(or 4)-(3-methylthioureido)-2-methylethyl ester .................................. 194 5(or 4)-(3-methylthioureido)-2-phenyl246 ethyl eater ........................ 5(0r 4)-(3-methylureido)-2phenyl181-182 ethyl ester .................................. 6(or 4)-ureido- ................................. . 213. Pi 208 methyl eater ................................

HC1208

.

446 000

446 446 446 446 328.446 446 328.446 20.446

446

26.727 727 26.727

507 567 150

83 137 137 137 137 137 26 26

(c) Carlmzyalkyl- a d Carboxgawlimiblea Including Those Containing Addiiional Fitnclional Grmrpa

4(or 6).(pcarboxyphenyl)imidaaole ................ 4(or 6).(p-~arboryphenyl)diiodo- ................... 4(or 5).(pcarboxyphenyl)iodo- .................... 1-hidesolemetic acid ............................ ethyl eater .................................. 2-bensyl- ..................................... (2-hydmxyethyl)amide....................... ethyl eater ..................................

308 234-235 240

2~i-a69 Pi 124-126 173-174 177-179 70-70.6

709 717 712.717 219 219 363 363 363

350

Systematic Survey and Bibliography Compound

..

M.P

.

.

Reference No

O C

I-imidasoleacetic acid ( c d . ) 5-chloro-2-phenylamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 ethyleeter .................... Pi 142 a-(l.mercaptoisopropyl).2.arnyl. . . . . . . . . . . . . . . . . . HCl 170 a-(I.mercaptoisopropyl).2.ben~l. . Pi 159460. HCL 174 a.(l.mercaptoisopropyl).2.(phydmxyhenzyl). ..... HCl 175-176 a.(l.meraaptoiciopmpyl).2-pentenyl. ... . . HCl 175 S-bensyl ether . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . 128 4(or 5)-imidaaoleaceticacid . . . . . . . . . . . . . . . . . . . . . . . 223. HCL 226-228 ethyleater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . acid chloride................................ HCll27 a-ammo- . . . . . . . . . . . . . . . . 254. Po 243 N-acetyl derivative .......................... 280 a-[(2.6-dinitro-3-methylphenyl)aminoj-. . . . . . . . . . . 270 a-oxo- (4(or 5)-imidadeglyoxylic acid) . . . . . . . . . . 4(or S)-imidaaoleacrylic acid (urocanic acid) . . . . . . . . . 231 N i 213.215. F 271 5-chloro-ls-oyano-a-etl~yl-l-n1ethyl-2-iniidasolebutyri~ acid ........................................ HC1250 (D-ar.ino.a.l9.y.trihydmxy )-4(or 5)-imidaeolebutyric acid. lactone ................................ N i 104 (&(hydroxymethyl)-aethyl-l-niethyl-4(or 5)-imidazolebutyric acid. lactone] (pilocarpine) ........ 34 Ni 178 HC1205.4. S 173-176 Pi 163-1G4

-

-

.

.

2-bmm0- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . nitro- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . isopilocarpine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-bromo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . nitro- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . neopilocsrpine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

isoneopilocarpine.............................. [@-(hydroxymethy1)-a-ethyl-(pilocarpidine)......... 2-mercapto- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . monoiodo- .................................... diiod0- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . isopilocarpidine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-mercap to-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8-(hydroxymethyl)-l-methyl- (pilosinino) . . . . . . . . . .

. .

He1 240

135-136 N i 158-159.8. Au 159 HCL 201 93-94 39-40

.

.

Pi 117.119. N i 9445 HCI 177 Pi 123-126. N i 105-108 128-129. NS 132.5-133. Au 124-126 207-208.5 161 192 Nd 114-114.5 207-208.5 N i 158.5-160

293 !a3

141.136 103.529.136

136 9.136 9 398. lS9

244 244 649 185 649 520 176,159.220.22. 21.221 640 520 444.259.657.569. 595.413.642.188. 558.508.698.447 258.129.296.739. 304.584.732.110 414 415

. .

546

558.842.188.544. 566.413 415 646

110

110 656.642.188.557. 659 669.666 525 525 544.188.842.558 544.668 545.205

Imidazoles Compound

367 M.D

.. ' c.

.

Reference No

[ B ( h y ~ ~ m e t h y l ) - ~ ~ p r o p y l - l - m e t h y6)-imil~(or dasolebutyric acid. laotone (isopropylpilosinine) ... Ni 138-139 [&(hydroxymethyl)- (pilosinidme) ................. Ni 117-118 [&(hydroxymethyl)-a-isopropyl- (isopropylpilosinidine) ..................................... 86-88 Ni 124.6-125.6 !&mercapto-................................... 202.5-2Q3 [&(hydroxymethyl)-a-ethyl- (pilocarpic acid). ...... chloropilocarpic acid ethyl eater .................................. N i 136 methyl ester ................................ 42-44 nitro- ........................................ 199 . chloronitro- ................................... [BOlydroxymethyl)-a~thylJl(orS)-imidamlepropionic acid, lactone] .......................... Ni 145-146 [&(hydroxymethyl)-a-ethyl-1-imidasolebutyric acid, lactone ] (N-DLisopilosylimidaole) ............. Pi 143-144 j&(hydroxymethyl)-a-ethyl-l-imidarolevderic acid, lactone] (N-Dbhomoisopilosylimidasole)........ Pi 133-134 4(or 6)-imidarolecarbsmic acid ethyl ester .................................. 181 Pi 210 N<143 methyl wter ................................ 175. Pi 243 5(or 4)-methylethyleater .................................. 167 5(or 4)-nitroe&yl ester .................................. 234 5(or 4)-phenylethyl eater .................................. 172 2-imidmolepropionic acid ethyl ester .................................. 103-104 a-amin o- ..................................... 254-255 a-amino-1-benayl- ............................. 216-217 a-amino-4-bromo-5-chloro-l-methyl............. Pi 231 Am 205-206

.

.

.

.

I-beDSYIethyl eater .................................. 4(0r 5)-imiddepropionic acid ....................

ethyl eater .................................. hydraside ................................... a-acetamidoa-cyanoethyl eater .................................. a-ecetyl-a-(zhydroryethrl)y-lactone ................................... w h l oro- ..................................... ethyl ester .................................. P-hydmxy- (4(or b)-imidsrolelsctic acid) ......... ethyl ester .................................. 5(or 4)-methylmethyl ester .................................. a-oxo- (4(m 6)-imidswlepyruvic acid) ............. 2.4-dinitrophenylhydramne ..................... a-amino-(histidine)

.

. CPf

486 s45 485

545 647 647 546 647 555 554

561 118.44 44 118

44 118

300 300 360 640

142-143

360 14.13,12,159,589, 393.397 244.12 12

100-103

24

H a 157

128 252.2%.221 245 159.443 244

212

208-209

ox 100

201

161-163 221 118-119

Pi 138

HCl241 240. HCl 192

687 51.101 101.668

358

Syst.cinatirSurvey :mil Uibliogriqhy Coinpound

.. oc.

b3.p

Reference No

.

(1) D-Histidine (eee Table XXV) (2) LHistidine (see Table XXV)

runide...................................... auhydride{3.&bis[4(or 5)-imidatoleiiiethyI j-2.6yiparaainedioneI......................... tetraiodo deriv ............................. N-(pacetamidophenylsulfony1)- . . . . . . . . . . . . . . . . . . . NSCetyl. ................................ ... 1(or 3)-acetyl-N-benaoylmethyl ester ................................ N-(paminophenylsulfon yl) .... methyl ester ................................ N-benroyl- ...................................... amide ............................... .. methyl ester ................................ N-bensoyl-1 (or 8 ) (N-bensoylglycy1)methyl ester ........ N-benroyl-bis(pnitrophen 0 ). . . . . . . . . . . . . . . . . . . methyl ester ....................... N-bensoyl-2.4(or 2.5).bie(phenylaao). . . . . . . . . . . . . . . methyl ester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N-bensoyl-1 (or 3)-[2-(butylmercapto)ethyl I. . . . N-benmyl-iodo- ................................. methyl ester ................................ l(or 3)benzyl. ................................. 1(or 3)-bensyl-N-methyl-N-(p-methylphenylsulfonyl)1(or 3).benayl..V.(p.methylphenylsulfonyl). ......... brom o- ......................................... .V. u.( a.bromoisocaproy1). . . . . . . . . . . . . . . . . . . . . . . . . .

~\r-D~(a-bromoisova~ery~)methyl ester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ~V-DL-(a-bromopropiony1)methyl ester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N-mrrbobenwxy-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .V.(chloroacetyl ). methyl ester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N-(8-chloropropionyl)methyl ester . . . . . . . . . . . . . ... .. N.1 (or 3)dibensoylmethyl eater ................................ N. 1(or 3)dibensyl. .............................. 2.4(or 2.5)diiodo- ................................ N.(3.5-dinitrobenzoyl). ..... ............. N.1 (or 3)disulfo- ................................ N-[p(2-hydroxy-l-naphthylaso)phenylsulfonyl I- ..... methyl ester ................................ N.(hydroxy~tyl). .............................. N.(o-hydroxybensylidene).

........................

Di HCl259

741

270-280

242-243 169

407.2.3.336.671 106 27 487.69

168 263-264 HCl218-225 249 234

71 27 71 276 67

157 162

71 191 191 191 191 216 191 191.55 212 212 212

.

159

208

. 217

. 208

190 248-249 118-122 198

. 116 . 117 171

. .

27G

86

1 1 2 2

2

a

200

65

.

2

.

2

10&109 193-1 95 HCl22Q 189

276 212 106 602

.

255-257 166-180

.

Btttcine Sat! 96-102

56 27

27 2 70

Imidasoles

359

.. .

.Compound

M.p

2(or 4).iodo-~hiatidine...........................

Reference No

O C

HCL 204-206 >310 Zmercepto- ..................................... 2-mercapto-betaine (ergothioneine, thioneine or 290 HCl208 thissine) ..................................

.

N-methyl- ......................................

.

.

-

methyl ester ................................

N-phthaloyl-1-methyl-........................... N-( pureidophenylsulfony1)-....................... N,l.3-tris[2-(butylmeroapto)ethyl J- ................

N-mtyl- ....................................... N-benmyl- ...................................... anilide......................................

arlactone ................................... 1-aoetyl deriv............................... methyleater ................................ 1-bensyl- ....................................... l-cydohexyl-.................................... l - i s o ~ r ~ p..................................... ~lZmeraapto-.....................................

...................................... bensoyl deriv................................

N-methyl-

1-methyl-....................................... I-phenyl- .......................................

.

348.308.420.670 218.722,543 212

.

-

(3) DbHistidine (see Table XXV) DL-Histidine.....................................

106 30

266 Di Pi 61 HCL 260. Di HCL 124-127 248-249. 186.436 Po 246 Ni 216 Di HCl206 63 202-204 448 486 740 191 617 376.704 296 196 376 187. 376 HC1238-240 376 229-231 27 HCI 187-188 216

....................................... methyleater ................................ N-(pmethylphenylsuUony1)-...................... Nsleoyl- ....................................... N-(pphenylazophenylcarhamy1)- .................. 1-phosphon0- .................................... N-phthaloyl .................................... ethyl aster .................................. bmethyl.

.

285. Di Pi 105 HCl 157 Di HC1236

.

148 248

250 215 183-184 150-151 239-240 235-237 223-224 >320 Di HCl204-206 270. Di Pi 132. Di HCl134-135 241 269-270. Di Pi 186 A'i 144-146 241-242

.

.

603,185.180.23. 24.213 69.213 180.69 180 407 180

180 362 362 362 189.314 245.186. 252 245 434,362.597 362

(4) Hbtidine Peptides

.................................... 157. SU 183 N-z~al~ny1-b methyl ester ................................ N-(~-carbobenmxy-balanyl)-b ................. 131 -ND-&DY~-L.................................... 163. Su 216

-

N-DLalanyl-L . ..................................

.

-

319.341 319 341 341

2

.

360

Systematic Survey and Bibliography Compound

M.p

..

.

O C

N.&danyl.L.histidin c. (bearnosine)................ 260. N i 223. H a 245 phenylcarbamyl deriv......................... ne N.(N.rbol.naoxy...alanyl).~. ................. 171 N.(A'.ph~phono-&alanyl).l.phosphono-~. . . . . . . . . . . H a 2 4 5 N-&alanyl-D- (n-carnosine)....................... 260 N-(N.earhoheneoXy.Bal8nyl).l. . . . . . . . . . . . . . . . . . 161 A'-&alanybl-methyl-rr (anseriae).................. 238-239 ethyl eater ................... ........... CPt 226-230 N-(NJVdimethyl-&alanyl)-l-ineth Au 92-90 N-asparagyl-.................................... h'.a.Wpal%ydD. ................................ 210 N-( N-carbobnzoxy-a-L-an 171 methyl ester .......... 95105 N.(8.L.aspartyl).L- . . . . . . . . N-(N~rboben90xy-8-rcaspartyl)-i.-.............. N-(dicarbethoxycystiny1)methyl ester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N.ulycy1.L- ..... ............... 155 HCL 175 amidc..... ...............

-

N-(N-carbolm

I.-.

...................

amide ...................................... iv.DL-histidylglycine.............................. N-(iV-acetyl-oLhistid~l)Rly~ine ethyl ester .................................. A'-bhistidyl-L- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . inethyl ester . . . . . . . . . . . . . .v.L-hitidyl.D L- . . . . . . . . . . . . . N-DL-hietidyl-Db ................................ N-(N-1-diulfohist.iclyl)-1-sulfohiatidine. . . . . . . . . . . . . N.Gleucy1.b ...... N-DL-leucyl- rc ................................... "D-IyByl-L- ..................................... N-(N.N'~icarbohensoxy-~-lysyl)-~~. methyl ester................................. 1v-prolyl- ........................... N.(N-carboxy.ctyroayl).L....................... N-(N,O-dicarbethoxy-L-t.ymyl)-Lmethyl ester .......................... N.DbVdy1.L- .................................... N-L-(&aminobutyryl)-t.-. ......................... N-(N-L-carboben.oxy-&aminobutyryl)-I,-. . . . . . . . . N-D-( @-aminobutyryl).t .......................... N.(N.Dc81bobnzoxy.~.minobutySvl).ir ......... N-(y-aminobutyry1)-L-.................. N.L-(&aminoisobutyryl).t ....................... N.D-(&aminoisobutyryl).L.......................

.

. . . . .

175 212-213 235 Po 213

.

182 310

.

Reference No

313.2,626,218 2.638 313.626 616 213 213 6.3

434

376

466 298

208 298 214 214 317 2.342 313 342 313 71 71 407.335,297,2 335 523 4

. 220 .

.

68

178

157-162 138-140 211-212 270

1 1.2 72 72 72 462 319

140 115 260 207 260 204 su 235 240 135

319 2 343 343 343 343 342 343 343

.

Su 205

. Dicarboxylic A d i s

2

(a) Alk& and ArylimSdacokdicarboqlicA d a

4.5-imidmoledic.tboxylic acid .....................

288.

K

Salt 281

243,736.659.512. 661

Imidamles Compound

361

.

Rsferenae No

M.P., OC

.

4.5-imideJoledioarborylic acid (cmdd.)

sdta

ammonium- ............................... 280 ammonium biimidasolate- . . . . . . . . . . . . . . . . . . 275

660 526 526 526 526 526 526 526 528 526 526 526 626 526 528 526 59

atrapine-.................................. 93

*butylsmine- .............................

aoniine- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

diethylamine- . . . . . . ....... ....... dimethylamine- ............................ ethylsmie- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . puanidine- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . khistidine- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . hydrasine- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

225-227

208-209

180 238-239 253-254 241-242 253-254 260 . . . . . . . . . . . . . . . . . . . . . . 245 methylamine- ............................. 240-245 piperidins ............................... 221-222 n-propylamine- ............................ 212 204-205 trimethylnmine- ........................... diamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . >360 dimethyl eater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200-203 Zirmyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 Zbnsyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 hthyl- ................... . . . . . . . . . . . . . . . 259. KW265 diamide ..................... . . . . . . . . . . 258 diethyl eater ................................ 94. HCl185 . 2-hexyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-iibutyl- . ........ .............. . %DL-%Op~OPyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 fbisopropyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . No SaU >300 R SaU 271 I-methyldiamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203-2643 2-methyl- . . . . . . . . . . . . ...................... 320-322 K Sau 271 diamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325

.

.

dianilide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . diethyl eater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . monoacid ohloride........................... monosnilide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-phenyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . diethyl eater . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zpropyl- .....................................

298

88 >300

. 27 1 190

Na W 3 0 0 . KSaU 253

59

141 039 243.736 666

666

.

736 736 554 736 59

442.243.736.660. 229.659 605 661

861 661 661 243.059.332 661 736

(b) I m M h * o x u t i c Acids Conluining A d d i t h d F i ~ d W n a Qroups l 2 - a m i n o - 4 . 6 i i n i d a r o l e ~ i ~ ~ acid ~ l i c. . . . . . . . . . . . . !&(m-arninophenyl). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.(pbromophenyleo). . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................... 2.(pbromophenylllyd.z.). !&(pSulfophenylam). ............................. 1-(&D-ambinopyranosyl)dIamide. . . . . . . . . . . . . . . . . .

245 -

250 203

-

216

243 242 242 242 243 60

:$ti2

System:tt.ie Survey . ant1 Bib1iogr:cpliy Compound

M.p..

OC.

1-(~ ~ o r a b i t c o ~ ~ r ~ t i ~ y l ) - 4 , ~ i i 1 i i d ~ o l e ~ i c a r b o x ~ l i c 215-216 Acid diamide.. ....... 132-133 triacetyl deriv.. ............................. 1-(&wribofuranouyl)218-220 diamide ...................................... 1-(&D-nbopyranosyl)215216 diamide...................................... triacetyl deriv.. ............................. 246-248 l-(&mxylopyranosyl)224-225 diamide ................ tS8-159 triacetyl deriv.. ............................. dimethyl eater triacetyl deriv.. . . . ... . . . . . . 166-107 l-(&wgIucopyrancmyl)332-233 diamide ...................................... 162-1fM tetraacetyl deriv.. ........................... dimethyl ester tetraacetyl deriv.. ........................... 123 l-(&D-msanopyranosyl)LW-2 10 diamide ...................................... tetraaeetyl deriv.. . . . . . . . . . . . . . . . . . . . . . . . . . . . 184-185 O-(m-Ntrophenyl)-. .............................. 279

Reference No.

60

60

336 57 57

60 60 00 00

60 Ro

57 57 242.50i

Futlclhal Group

4-carboxy-2-ruiiyl-I-iiiiid~zi~leart.1ic- wid . . . . . . . . . . . . diethyl ester. . . . dimethyl eater.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4-carboxy-2-benzyldiethyl ester. . . .

132-134 61 107

152 152

111-112

136

dimethyl eater.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4-carboxy-2-heiiayl-a-i~oprol,).litlrl,r-. ............ dimethyl enter.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4carboxy-2-niethyldiethyl ester. . . . ..............

106-107 324-225 117

I86 186 IXli

126- I a7

153 188

174 170

126-127 4-carboxy-a-(l-mercaptoisopropyl)-2-peiitcnyl-.. . . 195-198 5(or 4)-carboxy-2-methyl-4(or 5)-imidmleaeetic acid. 242 a-carboxy-l-mcthyl-5-imidaEoleacry)icacid. ......... 224-220 212 ..................... 228 I U%-lo1

dietliyl ester. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . u-carboxy-fi(or 4)-iitrtIigI-. . . . . . . . . . . . . . . . . . . . . .

!b!B

152

186 I a0

9.136

664 362 22.21 667

190 2:s

2IU

f%G;

120-121

:3w

159, Ni 173. IICl 179

82

u-c~r~xS'-u-ncwt,nrrrtidtrl -iiii.~.li~l-~-iiiiiilt~c~lr~Jr~i~iciiiir

acid dietliyl ester. ............................... 4 (.~-carboxy)methylatiiinoI- 1-~~ictliyl-Ci-iinidasolecarboxylic acid methylamide ...............................

363

Imidasoles M.p.,

Compound

.

.

oc

.

Reference No

J Imidazoleeullinicand Sulfonic Acids

..... .

4(or 5)-(2-carboxyethyl)-2-imidasolesdfinic acid 4(or S).methyl. ................................ 1-imidazolesulfonic acid ............................

4(or 5).(2-naphthyl). ........................... 4(or 5).phenyl. ................................ 2-imidasolesulfonic acid ........................... 1.4dimethyl-finitro- ........................... 4.6-diphenyI. .................................. 4(or 5).methyl. ................................ 5-bromo-l-methyl4imidasoleaulfonicacid 4-bromo-l-methyl-5-imidacolesulfonicacid .......... l.methyl4nitro- .............................. 4(or b)-imida&oleaulfonic acid ...................... 6(or 4).bmmo- ................................ 5 (or 4).bromo-2-methyl. ........................ flmethyl- ..................................... 5(or 4).methyl. ................................ b(or 4).(2-naphthyl). ........................... 6(0r 4).nitro- .................................. 5(or4)-phenyl4.5-imidasoledieulfonic acid ....................... hethyl. ..................................... 4(or 5)-(psulfophenyl)-2.5(or 2.4)diiodoimidaaole 2-(m9ulfophenyl)-4.5diphenylimidasole.

..........

................................

73 KWf 221-222 200-210

>300, KsaU 210

303 293 315418 280 284 256 254 307 280 268 279 n8

. 300

>300 .

280 327

... ........... .

.

13.12 47 717 712. 717 712.717 .54 568

411 47 49 49 49

566.%?

48 2.53.430 253 54 717 49 417 253 253

712.717 676

K Imidazole Arsenicals

4(or 5)-[(Parsono-2-aminophenyl)carbnmyl]imidacole 4(or 5)- [(4-sreono-2-nitrophenyl)carbt~myl 14(or 5).(parsonophenyl). ......................... 4(or 5).(parsonophenyl).2.butyl. .................. 4(or 5)-(parsonophenyl)-2-(3-~arbo~y4hydrorypheny1)- .................................... 4(or 5).(parsonophenyl).2-(paarboxyphenyl). ....... 4(0r 5).(psreonophenyl).2ethyl. .................. 4(or 6).(parsonophenyl).2-hexyl. .................. 4(or 5).(parsonophenyl).2-(pmethoxyphonyl). ...... 4(or 5).(psrsonophenyl).2-methyl. ................. 4(or 6).(paraonophenyl).2.(p.t.phenyl). 4(or 5).(parsonophieny1).2-phenyl. 4(or 5).(pamnophenyl).2.propyl. ................. 4(or 5).(panionophenylcarbamyl). * Unmeltgd a t t Needle form

.........

......... .................

.

.

.................

Q!20

327 a310 270

>300. HCL 307 320 316 t195-197 310 HCl270

.

>300

320-323 330. HC1303 260 280

46 46 713.46 713 713 713 713 713 713 713 713 713 713 46

.

L Isoimidazoles rt-hydraxy-2.4-diphenyl-4-isoimidacolc .............. ucetyl deriv................................... 2-amino-4-isoimidacole4aulfonicwid . . . . . . . . . . . . . . Zliydroxy-4 ~imimidaaolr-4-mlfonicacid ............

251-262 174 Am 172-174 225

707 707 224

224

.

f3ystemst.k Survey and Bibliography

364

X1.P..

ComDonnd

*c.

Zphenyl-4-boimidaaole4-sullonic acid. ............. 109 schlom-Z(pmethyIphenyl)-4-boimid~-4-one. .... 260-286 &chloro-2-phenyl-4-isoimidaaol-4one............... 215

Reference No.

224 466 466

M. Heteroring-SubstitutedImidazoles 1.

Furan Derivatives

4,5di-%furylirnidaaole.. ......................

162-163.

Pi 222-223,

4,6-ai-2-furyl-Z(m-hydroxyphenyl)-.. . . . . . . . . . . . . . . 4,5-di-Zfuryl-2-(phyd~~henyl)-. ............... 4.5di-Zfuryl-2-(p-nitrophenyl)-. . . . . . . . . . . . . . . . . . . 2-(2-furyl)-4(0r 6)-(parsonophenyl)-. . . . . . . . . . . . . . . 2-(Zfuryl)-4(or b)-phenyl-. . . . . . . . . . . . . . . . . . . . . . . 2,4,6-tri-2-f~&.

................................

4,6-di-2-furyl-2(5H)-imidaaolone. . . . . . . . . . . . . . . . . . . 4,&di-Zfuryl-2(5H)-imidssolethione. ............... 6(0r 4)-furfurylidene-2(~methylphenyl)-4(61(or 5(4H))-imidaaolone. . . . . . . . . . . . . . . . . . ......... 5(or 4)-furturylidene-2-phenyl-4(5~(or 6(4H))imidmlone .................................

HCl 190 286 236-236 176 297 180. Pi 204. HCl275-276 202, HCI 141 >290

-

717.712 028 628 628

713 712.717 717,712 628 628

310

226

293.6

155,225

2. Thiophene Derivatives l-decyl-2-methyl-3-(2-thenyl)imidaaoliumchloride.

,

.

150-152

622

3. Thiaaole Derivatives 4(0r 5)-(2-amino-4-thiazolyl)d(or 4)-methylimidmle. 210. HCL 253 315 acetylderiv 4(or 5)-(2-methyl-Pnislolyl)b(or 4)-methyl-. ...... 183, Pi 205. HC1225 4(0r 5)-(4-thicrmlyl)-6(or 4)-methyl-. ............... Pi 178 2-mercapt&[4(or 5)-imidaaolemethyleneM(4H)thiaaolone.................................. 258-260

...................................

4.

495,069 180

Pyridine Derivatives

Z(3-pyridyl)imidamlcde............................ 4(0r 5)-(%pyridyl)-. ............................. 4(or 6)-(3-pyridyl)-. ............................. 4(0r 6)-(2-pyridyl)-2(3H)-imidaaolethione.. . . . . . . . . . 4(0r 5)-(3-pyridyl)-2(3H)-imidasolethione.

..........

6(0r 4)-(3-pyridyl)-4(or 5)-imidasolecarboxylic acid. ethyl ester .................................. 5(or 4)-(3-pyridyl)Q(3H)-imidssolothione ethylester .................................. S-acetonyl ether..

495,669 495,669 495.660

.........................

.

196-198 112, Pi 207-208 117-118. Pi 285. Di Ni 200 247-248, Pi 194-195, HC1303 291-292. HCI 241-242 248 198

265 132 491.132.492

230-231.Pi193, HClll6 10s

492.491

132 132 49 1 492.491

497

Compound

M.P., OC.

S-(3-pyridyl)-2(3H)-imidazolone-4-csrboqicacid ethyl eater. ................................. 258 N-~3-(hydroxyrnethyl)-S-bydroxy-6-methyl4pyridylrnethylJhistamine............................ HCL 236-237 N-[3-(hydm~ethyl)-S-hydroxy-6-methyl-4-pyridylmethylene]hi~tamine ......................... 240-241

Reference No.

492.491 327 327

5. Piperidine Derivatives 4(or S)-(8-piperidyl)imidasole1

....................

N-benmyl deriv................................ 4(or 6)-[2-(1-piperidyl)ethylj-. .................... 4(or 5)-(1-piperidylmetbyl)-.

......................

Pi 227. HCl 188-190

492.491

CPl330 192 402,491 Di Pi 188-191, 339 Di HC1276-278 Di HCL 677.679 223.6-227.1

6. Morpholine Derivatives 4(or S)-[%(4-morpholinyl)ethyl]imidasole. .......... Di HCl238-243 339 4(or 5)-(4morpholinylmethyl)-. ................... Di HCl 173 677

7. Pyrimidine Derivatives 3-(4-amino-2-methyl-5-pyrimidylr11ethyl)-5(or 4)(Zhydroxyethyl)-rl(or5)-mcthylimidnaolium bromide (imidasoloaildogtie of Vitamin BI). . . . . 196-200 &(4-amino-2-methyI-S-pyrimidylmethyl)-5(or 4)hydroxymethyl)-rl(or5)-methylimidasolium bromide ....................................... 206-208 5-(S-isopropyl-5-barbiturylmethyl)4methyl-2(3~imidasolone 1,3-diacetylderiv............................... 189-191

234

2.34 209

8. Quinoline Derivatives 1-(6-methory-S-quinolyl)imidasole.. . . . . . . . . . . . . . . . 139-140, Pi 219-220. HCL 243-244 1-(&methoxy-&quinolyl)-2(3H)-imidawlethione. .... 297 120-121. l-(%quinolyl) .................................... HC1217-218 124-125. 1-(&quinolyl)-. .................................. Pi 197-198. HC1247-248 1-(2-~uinolyl)-2(3H)-imidacolethione............... 263-264 i-(8-quinolyl)-2(3H)-imidawlethione. .............. 304 S(0r 4)-(4-quinolylmethylene)-4(5H)(or S(4H))-imidasolone..................................... 304-305 2-[4(or S)-imidasolyl)-benso[f]c&olin&carboxylic acid ........................................ 300

219 210 219 219 219 299 337

9. Acridine Derivatives l-(&chloro-2-mcthoxy-Q-acridyl)imidasole ........... 227 1-[2-(&chlorrr2-methoxy-~~dylsmino)ethyl)-. .... 182, HCl250

441 441

366

Systematic Survey and Bibliography

’

M.P.,

Compound

OC

.

Z[~(~hloro-~etho~-~aeridylamino)ethy]106-1 12 4(or S).metbylimidasole ..................... Z[(gchloro-2-methoxy-9-~~dylamino)methyl ]150-154 4(or S).methyl. .............................. l.[.(s-chloro-~methoa1;4acn‘dyla.o)propyl].... 172 1-(2-etao.ys-nitro-s-acridyl)- ..................... 289

.

Reference No

230 230 441

441

N Bi- and Bieimidazolee 2.2 ‘.biimidaaole (glycodne) ....................... P i <270 . l-amind’-nitro1.1’-disminob.S’-dinitroPmet4yl................ . 4. 4’(or 5.6’)-dianilino-6,5‘(or 4.4’)dnitro- ........ . 4.4’(or 6.6’)-dibromo- .......................... 265-266 na 2b7-258 4.4’(or b,S’)dibromo-l.l‘-dimethyl-. ............. 188.5-198.5 4.4‘(or 5.5’)-dibromo-l. 1’dimethyl-5.5’(or 4.4 3.

...............................

.

dinitm ..................................... . 4.4’(or 6.6’)-dibromo-5. b’(or 4.4’)dinitro- ......... . 4.4‘-dietbyl.1.1’.5.5’-tetrsnitro- .................. 203

.

4.6-dihydro-5-iinitro-4’.methyl4methylene1 l ‘.S’-trinitromethyl deriv................................. 1.1’.ydrolry-4.4‘-dimethyl.5.5’.initro......... l.l’-dihydroxy.5.6’.ditro- ..................... l.l’.imethoxy-4.4’-dimethyl3.5’.nitro......... l.l’-dimethyl-4.4’.6.S’-fe.abromo............... 4.4’-dimethyl .i ,l’,S.S’-tetranitro-. ............... 1.5’dinitm- ................................... 4-etbyl-4’-metbyl-l,1’,5.5’-tctranitro-............. Il-ethyl-l,l’,5.5’-tetranitrct...................... 4-methyl-I .1’.6.5’-tetrsnitro- .................... 4.4’.6.S8-fetrabrorno- ........................... 4+4’.5.5‘.tetraebloro ........................... 4.5.4’.5’.fetrakie(phenylaso). .................... 1.1’.5.5’-tetranitm ............................. 1.1’.5-trinitro- ................................. 1.1’.3.3’.te.trsethy1.2.2 ’-biimidazolium diiodide..... AW’.bib(4H).imidcuolone ...................... 4.bdianilino-2.(S-anilino4phenylimino4~imidazo 1. Zy1)imidasole............................... 4.4’.hydrasobie[l.3-dimethyl.2(3H).imid.olonej ..... %imidmolyl ketone .............................. 4.4’(or S.S’).methylenebis[2. 5(or 2.4(-diphenylimid. d e ]....................................... 4.4’(or S.S’).(phenethylimin~imethylene).his [6(or

4)-metbylimidasole]..........................

1.1‘-pphenylenebis[2(3H).imidasolethion~ .5diphenylimidawle ] ...........................

4. 4’(or K.63.(phenyliminodimethylene)bis[b(or 4)metbylimidstola] ............................

127

. . 242 257-258 239-240 283 226 259 273-274

.

. 230-232 276 >300 244-245

421

421

422 423 423 423

423 423 422 422 422 421 422 423 422 421 422 422 422 423 423

.

421 421 421 421 347

347448 321

423 737

2bl

494

T&PI 176. CPt 270

27K

>340

78

199-200

275

.

500.501

.

~~

Imidazolines

367

.. .

Compound

.

Referonce No

M.p OC

.

I1 IMIDAZOLINES

.

.

A P-ImMa~oline~

1 Alkyl- and Aryl-2-imidasolines

. Pi 128.4

2.amyl.2-imidaaoline ............................. 2-amyl.l-decy1. .................................. Zamyl-l-dodet?yl................................ l.amyl.2-hendecyl. ............................... 2-amyl-4,4,5.5-tetramethyl-. ...................... Zhenthydr~l.................................... 2-bonzyl-.......................................

64

-

. . .

.

137. Pi 185 88,Pi 147 02 188-169

.

l.benzyl.2-methyl............................... 2-bensyl-1-me thyl-............................... 2-benayl.1.(pmethylphenyl). ...................... 2-bensyl-I-phenyl............................... 2-butyl-........................................ 2-(3-cyclohexylpropy1). ........................... 2-decyl......................................... l-decyl.2-methyl. ................................

130.31,409 409 409 409 577 31 136.399.S 16.31

408 136 524 524 515.130 409 130 79.5, Pi 82 409 Pi 129 1.5-diethyl.2.5-dimethyl. .......................... 130.320 2.4dimethyl.l.(l.3-dimet~hylbutyl)4ethyl. ......... 577 2.4 (or 2.5)-dimethyi-4(or 5)-ethyL . . . . . . . . . . . . . . . . . Pi 123.2-123.8 320 . I-mtyl deriv................................ 320 . 4.4-dimethyl-l,24iisopropyl-...................... 577 4.4-dirnethyl-2-heptadecyl-l-butyl-................. . 577 517 4.4-dimethyl-2-heptadecyl-l-aec-butyl-.............. . 4.4-dimethyl-2-heptadecyl-l-impropyl-. ............. . 577 4.4-dimethyl-2-heptadecyI-l-(m-methylphenyl)-...... 53-55 577 4.4-dimethyl-2-heptadecyl-l-phenyl-. ............... 39-40 577 . 4.Pdimethyl-l-isopropyl-......................... 577 4.4.dimethyl.l.isopropyl.2-amyl. ................... . 557 4.4-dimethyl.l.ieopropyl.2.butyl. .................. . 577 4,4dimethyl.l.isopropyl.2-ethyl. ................... . 577 4.4dimethyl.l.isopropyl.2-hendecyl. ............... . . 577 4.4-dimethyl.l.isopropyl.2-pentadecyl. .............. . 577 4.4-dimethyll. .bopropyl.2-phenyl. ................. . 577 577 4.4-dimethyl-l-isopropyl-2-propyl-................. . 4.4dimethyl.l.isopropyl.2-tridecyl. ................ . 577 100.103. Pi 190 480 4.5-dimethyl.2.phenyl. ........................... . 577 1-( 1.3-dimethylbutyl).4-ethyl.2-heptadecyl-4-methyl. 74-75 524 1.2-diphenyl. .................................... Pi 174-175 409 Zdodecyf-...................................... 87-88 . 409 l-dodecyl.2.methyl. .............................. 48. Pi 137.1 2-ethyl-......................................... 130.331 . l-ethyl-2-hendecyl............................... 40d Pi 103-104 4(or 5)-ethyl.2-methyl. ........................... 320.577 Pi161-162.5 5-ethyl-1,2.6-trimethyl-........................... 320 31 2-(l-ethylpropyl). ................................ 86 Pi 106. HCl245 1-(phenylcarbamyl)deriv..................... 133 31

Pi 172-174 Pi 170 Pi 188 41.4. Pi 126 I

.

.

.

Systematic Survey and Bibliography

368

.. .

Compound

M.p OC

%hendecyl.~imidasoline. . . . . . . . . . . . . . . . . . . . . . . . . . 2-handeoyl-1-methyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-heptsdecyl. ... Zheptyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-heptyl-%methyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zheptyl-1-methyl- . . . . . . . Zhexyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Z(1.ieoamylisohesyl). ... 1-(phenylcarbamyl) deriv. . . . . . . . . . . . . . . . . . . . . %methyl- Oyeidine) ..............................

82. Pi61.5 -

-.

94-95 60 Pi 104.8

-

46.2

103. Pi 125 82 107 Pi 205 HCI 171. HBr 158-160 126-126

.

.

l-(pnitrophenyfsulfonyl) deriv................. 1.methyl.Znonyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-methyl-2-phenyl-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pi 130 2-methyl.l.pheny1. ............................... Pi 146 2-methyl-l-tetradecyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Z(prnethylpheny1).

-

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183. Pi 203.

L(phenylcarbamy1) deriv. . . . . . . . . . . . . . . . . . . . . l-(pmethylphenyl)-2-phcnyl-. . . . . . . . . . . . . . . . . . . . . 2.(l.naphthyl). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Z(Znaphthy1). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I.(2.naphthyl).2-phenyl. .......................... Z(l.naphthylmethy1). . . . . . . . . . . . . . . . . . . . . . . . . . . . . Znonyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

..

.. ...........

HCl244 157 Pi 162-163 133.4-134, Pi 246 HCL 305-300 118. Pi 205 131. Pi 230 119.5. Pi 197. HCI 258-259 71.4, Pi 222 52.1 102.103. Pi 244. HC1234 156 104 158

.

1-(phenylcarbamyl) deriv. . . . . . . . . . . . . . . . . . . . . 1-(phenylthiocarbemyl) deriv . . . . . . . . . . . . . . . . . . 2.(pphenylbensyl). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-(3-phenylpropyl)............... 2-propyl. ........ . . . . . . . . . . . . . . . 35.3, Pi 129 2-tetradecyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92-93 211.213. 2,4.&tricyclohexyl. ............................... HCl268-270. 8 201.202. CPt 251-252 nitrow deriv. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 Z(1-trideceny1)- ................................. Ztridwyl- ...................................... 88-89

-

l-butyl-2,4.4-trirnethyl-........................... L-uec-butyl-2.4.4trimethyl-. ....................... l.isoproprl.2.4.et1hethyl. ....................... l.(m-methylphenyl).2.4.4-trimcthyl. ................ l.phenyl.2.4.4-trimethyl. .........................

.

-

2.4.5-triphenyl (amsrine) l-(l-naphthylcSrbamyl) deriv. . . . . . . . . . . . . . . . . . 164-155 t(phenyloarbamy1) deriv..................... 171-172 2.4.6-tris(Zphenylethyl)-. ........................ Pi 130-132

Rufemnoe No

.

701. 130 409 701 130 409 409 130 31 31 445.537,130.331, 28.389 742 409 651 051 409 331

331 524 515

515 524 515 130 130 703.254.615.331. 651 331 331 122 409 130 409 705.724

705 409 409 577 577 677 577 577 326 326 724

Imidazolines

369

.. .

Compound

B4.p o c

.

Alkyl- cmd ArylimidazoIinium Salts l-ainyl9-beiisyl-2hendecyl-2-iniidasoliniumbromide. .

.

Reference No

2

.

.

2.amyl.l-decyl-3-methyl. iodide ................... l.amyl.2.hendecyl-3-metliyl., iodide................ . 3-bensydl.d.yl.Zmethyl.. bromide................ 74-76 3-beneyl.l-d~ecyl.2.niethyl.. bromide.............. . 3.beneyl.2-hendecyl.l.methy1.. bromide............. . 3.bknsyl.l.heptyl.2.methyl. bromide............... . 3.bensyl.l.methyl.2.nonyl.. bromide. . . . . . . . . . . . . . . . l.bensyl.2-methyl9.tadecyl.. bromide . . . . . . . . . . . . 90-92 l.bensyl.2-methyl-3~oCtyl.. bromide................ 66-57 3-bensyl.%methyl.I.tetradecyl. bromide . . . . . . . . . . . 79-80 10a-104 l-decyl.2.3-dimethyl. iodide ...................... 2.a-dimethyI.l-dodecyl.. iodide .................... 120-121 1.3-dimethyl.2-heptyl.. iodide . . . . . . . . . . . . . . . . . . . . . 46-47 l.a-dimethyl-2-nonyl-. iodide ...................... 50-51 2.3-dimethyl.l.tetradecyl.. iodide .................. 120-121 I.methyl-3-(2-methyldlyl).2-nonyl.. chloride . . . . . . . . . . 2-methyl-3-(2-methylallyl).l.tetradecyl.. chloride . . . . . 1.2.3-trimethyl.. iodide ........................... 222

.

.

.

622 622 622 622

622 622

622

622

622 622 622

622 622 622 622 622 622 622 389

. Alkyl- and Aryl-2-Imldaaolinar Containing Additional

3

Functional Groups

2-amino-2-imidasoline N-(paminophenylsulfonyl) deriv............... 226.5-226.6 2-(paminobensyl). ................ . . . . . . . 124. Pi 138.5. Di Pi 195 %[(2-aminoethyl)amino E . . . . . . . . . . . . . . . . . . . . . . . . . Di Pi 199-200 2-[(2-aminoethyl)amio]-4(or b).methyl. . . . . . . . . . . . . Di Pi 200-201 %(amylamino). .................................. Pi 164-165.5 %(smylamino)-4(or 5).1iietliyl. . . . . . . . . . . . . . . . . . . . . Pi 14!2-143 2-(bensylamino). ........... .... . . . Pi 150.6-151.5 2-[(N-bnxyl)anilmomethyl I- ( . . . . . . . . . . . 123. HCl234 %(butylamino). ................................. Pi 173-174 Pi 136-137 2-(butylamjno)d(or S).methyl. ........... 4-(3-chlo~bonyl-l-rnethylureido)-l-methy tetraohloro- ................................. 136 or 143 2.(a.(Zdimethylaminoethoxy)bensylj. .... . . . . . HCl246-247 Pi 181-182 2-(faobutylamino). ............................... 2-(iibutylamino)-4(or S).methyl. .................. Pi 137-138 Z(%(l.~phthylsmino)ethylamino]. . . . . . . . . . . . . . . . . 176. Pi144.8-146.6 2-[(%phenylethyl)aminol. . . . . . . . . . . . . . . . . . . . . . . . . . Pi186.4-186.9 2-( bromomethyl). ......... ............... HBr 206-209 2.(l.~hl0r0ethyl). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64-65. HC2 213-214 2 4 1-chloroisopropy1)- . . . . . . . . . . . . . . . . . . . . . . . . . . . 122-124 2-(chloromethyl).

......

....

.

HCI 108

.

72-73 JICl202-204

-

2-(cNoromethyl).l.methyl. ........................ Z(pahl0roph~yl)............................... 187. Pz:206-206.6

321 515 453 463

453 453

453 310.122

463 453

674.80 672 453 453 453

453 392 392 392 392 392 515

370

Systematic Survey and Bibliography Compound

M.p.,

.

Reference N o .

ec!

l-(pohtorophenyl)-2-phenyl-%~midazoline .......... Pi 190 2-(a-OhlorOpropyl). ............................... HCl 146-148 2-[(4-chloro4-methylphenoxy)methyl]- ............. 221-223

3-(o-ehlorobensyl)-l-smyl-2-hendecyl-2-imidasolin-

-

ium, bromide................................ 3-(pohlorobe~l)-l-dodecyl-2-methyl-2-imidarolinium. chloride................................ 3-(o-chlorobenzyl)-2-heptyl-l-methyl-2-ini idarolinium bromide .................................... 104-105 %(bemhydryloxymethyl).2-imidaaoline ............. 102-103. Pi 205 HCE207-208 2-[3-(belubydryloxy)propyl I. ...................... H a 218 2-(bemyloxymethyl). ............................. 57-58.6. Pi 153-154 HC1 161 2- [(%biphenylyloxy)mothyl]-...................... HCI 115-116 2-[(4-biphenylyloxy)methyl]- ...................... HCI 225 2-[(a-oyclohexylbenz-yloxy)methyl]. ................ 86-87 Pi 131-132 HCl 180-180.5. l)i Oz 144-140 4.Sdihydroxy.2. 4(or 2.5)i)aiphenyl. ................. HCl282 diaaetyl deriv................................ IS1 4.b-dihydrory-l-(~hydroxyphenacyl)-2,5-diplienyl-. . 73-80 4.Sdihydroxy.2-phenyl. .......................... dicsrbanilate 1-bensoyl deriv.............................. 193-194 2-(3.4-dimethoxyphenyl)-. ........................ 158.5. Pi 206 2-[(2.5-dimethylphenoxy)methyl .1 . . . . . . . . . . . . . . . . . HC1 228.5-225.5 184-186 2-(a.hydroxybemyl). ............................. HC1 224-2% %(l.hydroX~thyl). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HCll78-174 o-bensoyl deriv.............................. HCI 1S5-1SfZ 2-(1.hydroxyimpropyl). ........................... HC'l 182-193 %(hydroxymethyl)-.............................. R9.-90. HCl 1.50- I5i 0-benroyl doriv.............................. 85-86 HCI 208-2 10 2-0lydroxymethyl).l.methyl. ...................... HCl 157-158 Z[o-(hydroxymethyl)phenyl 1-..................... 210-211 300. Pi 223 %(phydmxyphenyl). ............................. HC1246-247 2-[(2-iipr0pyl-SmethyIphenoxy)methyl ]- . . . . . . . . . . HC1223.5-225 2-[(&ieopropyl-2-methylphenoxy)methyl .1 . . . . . . . . . . HCl 176170 %[(o-impropylphenoxy)methyl1-. . . . . . . . . . . . . . . . . . . HCI 178.5-174.5 2-[(4-metho~ybe~hyd~I0~y)111ett1yl 1. . . . . . . . . . . . . . . Pi 143-145. HC'I 15(b161 P(pmethoxypheny1)- ............................ 140 1%30!) 2-[(4-methylbenrhydryloxy)methylJ-. . . . . . . . . . . . . . . 98-99. Pi 166-168. HCE 188-189

.

.

.

. .

.

.

.

.

524 392 197 622 622

.

622 122 23.310, 198.661 122 m11 128 122 1GH

707 707 707 165.225 592 515 197 672 392 893 392

392 302 302 76 515 197 197 197 169 51.5

1(if)

37I

Imitlazolines Compound

2.[(o-methylphenoxy)niethyl]-2-iniidamline . . . . . . . . . 2- [(m-methy1phenoxy)methyl 1. .................... 2-[(pmethylphenoxy)methyl I- .................... 2- [(a-1-naphthylhenzyloxy)methyl I. . . . . . . . . . . . . . . . k(phenoxymethy1). .............................. 2- ~(2-phenylet.hoxy)niethyl!-...................... 2- [(bphenylpropoxy)rnetliyl J- ..................... 2-(nitramino) .................................... 2-(nitramino)-4(or 5).methyl. ..................... 2.(nitrarnino).l.nitm- ............................ 2-(nitramino)-l-nitro-4(or 5).inetiiyl. . . . . . . . . . . . . . . . S(o-iiitrophenyl). ................................ 2-(m-&rophenyl). ............................... l.(pnitrophenyl).2.phenyl.

.......................

Z(mercaptomethy1)S-phcnyl ether ............................... 2-(o-mercaptophenyl). ............................ S-methyl ether .............................. o o’.dithiobis(2.phenyl).

..........................

2.(m-mercaptophenyl). ........................... S-methyl ether ..............................

m.m’dithiobis(2-phenyl)-. ........................ 2.(pmercaptophenyl). ............................ Smethyl ether .............................. p.p8-dithiohi(2-phenyl)-. ......................... 2.(o-thiocyanatophenyl). .......................... 2.(pthioeyanatophenyl). .........................

..

.

.

n1.p “C

Reference N o

HCI 200-202 HCl225-Y27 HC1 151-153 HCl204.205 Di Ox 126-128 HCI168-169.5 Pi 121 HCI 128 Pi 167.168. HCI 49-52 221-222 170.5 151-152 121.6-12.3 98. P i 185

197 197 197 169

.

.

P i 223. HCi 249.251 HI 207-209

.

197

561

561

455.456 455 456

454 515 254

177.6,

524

85-85.5. P i 127-128

. HCl184-I85

561

244. Pi 242

449.460 449.460

Pi 173-174

loo. P i 207.

.

HI 208

198 Pi 247-248. Di HBr 283 225-228

.

gp-ge

HI 262-264

193 290 156-158 HI 237 313 180 >265

.

. 2 - I m ~ w l i n e c a r l n ~ y land i c Sulfonic Acidr

449 450 450

450 450 450 450 451 451

4

2-benayl-a-isopropyl-2-imidasoline-l-actic acid ...... Zbensyl-2-imidsroline-4(or 5)-carboxylic: acid ....... .I-(inethylamino)-4.6aimethoxy.l.n~etli~I.2-imidaa oliiie-5-carboxylic acid methylamide ................................ 3-iinidsaoline-2-nialonicacid diethyl esler ................................ “iiiiida~line-2.ti.:i.ca..ylic acid 2-aininoetliyl arnide .......................... 2-[p-(methylaulfonyl)pheriyl J.2.iniidasdiiie .......... 2.(peulfamylbenzyl). ........................... Z(psulfamylpheny1). ..........................

211-213 302-304

136 136

164

82

1Oo-lOl

279

250-255 213.5 Pi 168.5 251

42-1 515 615 184.615

Systematic Survey and Bibliography

37’1

.. .

Compound

-

Reference No

M.p o c

2-[o-(eulfomercapto)phenyl J.2-irnidasoline ........ 228 2-[m-(sulfoinercapto)phenyl 1. .................... 246 %-[p(dfomercapto)phenyl]. .................... 248 %(p-aulfophenyIb.............................. >300

461 451

461

616

.

B 3-Imidazolines 2.~iphenyl-l-(pmethoryphenyi)-~-imidasoline3oxide....................................... 1-(pmethoxyphenyl)4(m-nitrophenyl)-2-phenyl-3oxide....................................... l-(pmethoxyphenyl)4phenyl-3-oxide.............. 2-methyl-l-(pmethylpheny1)4(m-nitrophenyl)-3oxide ....................................... I.(pmethylphenyl)4(m-nitrophenyl).3-oxide ....... l-(pmethylphenyl)4(m-nitrophenyl)-2-pbenyl-3oxide....................................... l.(pmethylphenyl)4phenyl3sxide ...............

.

109

113

206 187

113 118

225

189

113 113

224 223 .S

113 113

C 4-Imidazolines 2.6-diphenyl-l-hydroxy-3-(pinethylphenyl)4imid-

aroline .....................................

2,44iphenyl.l.(pniethylphenyl). .................. 1.2.3.4.6-pentaphenyl.............................

.

206 152-153 400-450. HCl>300

112 111 416

D Heteroring- Substituted 2- Imidazolines 1

. Furan Derivatives

2.4,5.tri(2-furyl)-2iiiiidatoliiie ..................... 2.4&trie(tetrahydrofuryl). ........................

117

054

Pi 202-203

724

HCl210-220 Pi 179-179.5

408

Pi 141-143.

578

-

578

. Thiophene Derivatives

2

2-(N.2-thenylanilinomcthyl).2-iinidaaolilie 2-[(ar-2-thienylhenxyloxy)methyl].

..........

.................

170

. Triazoole Derivatives

3

441-butyl44-dimethyl-2-imidssolin-2-yl)-%phenyl1,2.3.2H.triasole .............................

4-(4.4-dimethyl-1-isopropyl-2-imidasolin-Zyl)-2phenyl-.....................................

4 2.(%~ridyl).2.inii..z.iine 2.(3-pyridyl).

.

HCL 220-222

Pyridine Derivutives

........................

...................................

........

2-[(a-2-pyridyl-a-111etl~yli~nzyloxy)111etliyl 1.

98.5-99.Pi 235 515 11 1-1 I 1.5, 206.61.5 Pi 210.6, HCl249-251 Di Pi 203-205 170

IX OX 197-198

.

.

Imidsmlidines Compound

5

.

.

.

M.P., *C

Reference N o

Di Pi 113-1 14

204

. Piperidine Derivotives

4(or 5)-(l-piperidylmetIiyl)-~~ntadecyl-2-imidssnline .....................................

6

373

Thiamphthene Derivatives

2.(2-thianaphthenyhnethyl).2.imidazolh~ ........... HU 274-277 2.(3.thianaphthenylmethyl). ....................... HCl234-235

90 90

.

E Bi- and Di-2-imidazolines 2.2’.bi.2-imidaroline .............................. 2.2’-(4,4’-biphenylene)di- ......................... 2.2’4eoamethylenedi. ............................

290-298

.

.

.

424 615 412

181 Pi 223.234 HC1183 235 Dz Pi 228-229 162.5 185-187

515

.

516 615

8.2’-ethylenedi. ................................. 2.2‘(ethylenediimino)bis[4(or 5)-methyl-. . . . . . . . . . . . 2$’.hendecamethylen& ........................ 2.2’-octamethylenedi. ............................ 3.2’-pentamethylenedi-. . . . . . . . . . . . . . . . . . . . . . . . . . 2.2‘-tetramethylenedi-. ........................... 218.5-219, Di Pi 207 2.2’-trimethylenedi-. ............................. 2;2’.(vinylenedi.pphenylene)di. ...................

-

. IMIDAZOLIDINES

453

516 409.516 515 515.424

111

.

A Alkyl- and Arylimidazolidinee

-

2-amyl-1.3-dibenaylirnidasolidine................... I-bensyl-2.3-diphenyI-............................ 123 1.3-bis(2-ethylhexyl)-. ............................ 1.3-bie(~thylhexyI)-2-phenyl-.. . . . . . . . . . . . . . . . . . . 1.3.bia(2-ethylhexyl).%propyl. .......... . . . .. 1.3-bie(l-rnethylbutyI)-. .......................... 1.3-b~(l-~thylb~tyl)-2-ph~yl-. .................. 1.3-bis( l.methylbutyl).2.propyopyl . . . . . . . . . . . . . . . . . . . 1.3-bii(p-rnethylpheny1)-4.5-dimethyl. . . . . . . . . . . . . . . 1.3.bie(2-phenylethyl). .................... ... 1.3-bie(2-phenylethyl).zmethyC ................... 1.3.bie(2-phenyIethyl).2-phenyl. ................... 1.3-dialIyl....................................... 1.3-diiUyl-2-phenyl-.............................. 1.3-dially1-2-propyl-.............................. 1.3-diben~yL.................................... 27 1.3-dibexuyl-2-butyl-. ............................ 13 32 1.3-dibenryl-2ethyl-. ............................ 1.3-dibensyl-%hexyl-. ............................ 1.3-dibemiyl-2-iipmpyl. ......... , ................ 33 1.3-dibenryl-z(piaopropylphenyl)-................. 63 1.3-dibenxyl-Zmethyl-............................ 34 t.3-dibenzyl.2-(pmethylphenyl). ................... 88 I

-

438 293

202 202 202 202 202 202 481.479 574

574 674

202 202 202 438 438 438

438 438 438 438 438

3.4

Systematic Survey and Bibliography

I _ -

Conipound

1.3-dibenayI.2.phenylimid.o.diiie ...... 1.3-dibensyI. 2-(2-phenylvinyl) ..................... 1.3-dibensyl.2-propenyl. .......................... 1.3-dibensyl-2-propyl-............................ 1.3-dibutyl-........... 1.3-dibutyl. 2-phenylimid 1.3-dib~tyl-2-pr0pyl-.... 1.3-dicycloheryb. ................................ 1.3-dicyclohexyl-2-phenyl-. 1.3-dicyclohexyl-2-propyl-..... 1.3-diethyl-. ................ ............ 1.3-diethyl-%phenyl-. ..... 1.3-diethyl.2-propy I. . . . . . . 1..Miisobutyl.. .................................. 1.3-diiaobutyl-2-isopropyl-........................ I .3.diisobutyl.2-methy 1. 1.3diisobutyl.2-ph~nyl. . 1.3-diiaopropyl-........ 1.3-diiipropyl. 2.phcnyl I .3-diisopropyl.2.propyl.. . . . . . . . . . . . 4.5-dimethyl-l,3-diphenyl-. . . . . . . . . . . . . . . . . . . . . . . 1.3-diph~nyl-. ................................... 1.3-diphcnyl-2-propl\.I-. . . . . . . . . . . . . . . . . . . . .

1.2.3-tribensyl-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.5-triryrlohexyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

..

M.p OC .

Reference N o.

100 I17 85.6-86 11

682.438 142 142

438

-

. . . 59.2-S9.6 . . . . . . . 45-46 . .

.

99-100 124.6-124.8 SO 0-80.8

06-07 171 .172 HC1302, S 168.5, HBr 296 CPt 216.5-217 136.4-136.8 270-271, ifCl285

.

202 202 202 202 202 202 202 202 202 574 574

574

574 202 202 202 481 202 202 438 705

.

1.2.3-triphenyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.5-triphonyl-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

202 c14

B Alkyl- and Arylimidazolidines Containing Additionaf Functional Groups 1 .3.bis[2(benrsylide11eamirio)ethyl].2.~~l1eii~liriiirl~zol.i dine........................................ Z(o-chlorophenyl).l.3-dit.iisyI. ................... 2-(nr-chlorophenyl)-1.3-dihenzyl- . . . . . . . . . . . . . . . . . . . 2-(pchloropheiiyl)-l.3-dibencyl-. . . . . . . . . . . . . . . . . . . I .3-bia(p-methoxybenzyI)......................... 1.3-bis(p-methosybe~y~)-~~n~~l-. ................ 1.3-bis(pmethoxybensyI).2.(~nietlioxyp~ienyI ). . . . . . 1.3-bis(prnethoxybenzyI).2.inethyl. ................ l.~bia(pmethoxyben~yl).2-(3.~methyler1e~io~ y. phenyl). .................................... 1.3-bis(pmethoxybenzyl).2.phenyl. ................ 2-hydroxy-2-methyl1-(gacetamidophenylaulfonyl)deriv . . . . . . . . . . . . 2.(4-hydroxy-3.methoryphenyl).l.3-dibensyl. ........ 2-(o-hydroxyphenyl)-I .3-dibenzyl. . . . . . . . . . . . . . . . . . . 2.(ghydroxyphenyl).l.3-dibcnzyl. ................. 2.(pmethoxyphenyl).l.3.dibenrsyl. .................

86 96-97 93 110 30 68-69 73

7&-77

683 438 438 438 574 574 574 574

120 93-94

574 574

196-197 84-85

742 438 438 438 438

108

139

90

.

Imidazolidines

..

Compound

Z(p-methoxyphenyl).l.3-bw (2-phenylethyl)imidazolidine 2-(p-methoxyphenyl).l.3-diisobutyl. ................ 2-(3.4-methylenedioxyphenyl).l.3-dibeluyl. ......... 2.(3.4-methylenedioxyphenyl).l.3-diisobutyl. ........ 1.3-dinitro-2-(chloromethyl)-2-ethoxy-.............. 1.3-dinitro-2-(chlorornethyl)-2-hydrory-

0-acetyl doriv................................ 1.3-dinitro-2.(chloromethyl).2.methoxy ............. 1.3-dinitro-2(chloromethyl).2-propoxy. ............. 2.(nitramino).l.nitro-2-amino- ..................... 2-(nitramino)-l-nitro-2-(di hutylaniino). ............. 2.(nitramino).l.nitro-2-ethoxy. .................... 2-(nitramino).l.nitrc-2-propoxy. ................... P(nitramin0)-1 .nitro-2.(propylmino). ............. 2-(o-nitrophenyl)-1Bdibenayl-..................... 2-(m-nitrophenyl).l.3dibenzyl. .................... Z(p-nitn~phenyl)-1.3-dibenayl-.................... a(p-chlorophenylnso).1.3-diben.y1. 2.imidazolidiu. acetic acid ethyl ester .................................. 4-carboxy-a-(pchlorophenylaao)-l.3-dibenzylethyl ester ..................................

.

.

375

h1.p o c.

Hefernace No.

.

111-112 GI 130-130.5

574 574 438 574 445

164-164.5 157.5-158 93.4-93.8 184.8-185.3 75.&7 7.4 133.6-134 124.&125.5 122.4-122.7 91 95-96 101-102

445 445 446 456 456 456 456 456 438 438 438

88-89

142

137

142

.

C Heteroring- Substituted Imidazolidinea

.

1

Furun Derivatives

. . .

1.3-difurfurylimidazolidine. ...................... .. 1.3-dirurfuryl.2-(zfUryl). .......................... 1.3-difurIuryl-2-(pmethoryphenyl)-................ . 1.3-difurfuryl-2-methy1-. .......................... 1 .;Mifurfuryl.2-(S-methyl.2-furyl). ................. 1.3-difurfuryl-2-phenyl-.. . . . . . . . . . . . . . . . . . . . . . . . . . . 2-( &furyl)-l.3-his(pmethoxyben~yyl)-. . . . . . . . . . . . . . . 76 2-(2-furyl)-1.3-bis(2phenylethyl)-. ................. . 2-(2-Curyl)-1.3-dibensyl-.......................... 74 %(2-furyl)-l.3-diisobutyl.. . . . . . . . . . . . . . . . . . . . . . . . . . 2-[5-(hydroxymethgl)-2-furylJ-1 .?.bis(pniethox y. benzyl). .................................... 108 2.[54hydroxymethyl~.2-lurylj.l.3-dibenzyl. . . . . . . . . . 1 27 2-[S-hydroxymethyl)-2-furylEl .3diisobutyt.. ........ 56-67 Z(S-methyl.Zfuryl)-1.3-bia(pmethoxybensyl). . . . . . . 84 2-(5-methyl-2-furyl)-1.3-bis(2-phenylethyl)-. . . . . . . . . . 2-(5-methyl-2~furyl)-l.3-dibenzyl-. ................. 77-78 2-(S-methyI-2-furyl)-1.3-diieobutyl-................. .

. Tttoa~leDetiWtiWS

674 574 574 674 574 574 574 574 438 574 574 438 574 574 674 438 574

2

4-( l-butyl4.4-dimethyl-2-imid~olidyl)-~phenyl-

1.2.3.2H.triasole

............................. .

4-(4.4-dimethyl.l.iapropyl.2-imid~lidyl).2-phenyl. 4-[4.4-dimethyl.1.(p-methylphenyl).2.imida~0lidyll. ..

. .2.

phenyl-..................................... ~(4.4-dimethyl-l-phenyl-2-imidssolidyl)-2-phonyl-.

-

197-198

109-1 10

.. -

578 678 578 578

376

Systeiiiatic Survey and Bibliography

.. .

Compound

.

M.p OC

Raference No

.

.

D Bieimidazolidinea

1 1‘-decamethylenebis(3-bensyl-2-phenylimidazoli-

dine) .......................................

139 142

688

amlidinel ................................... 1.1‘-ethylenebis[3.bensyl.2-(3.4.methylenecliox y. pheny1)imidasolidineI ........................ l.l’-ethylenebis(3-benlcyl-2-phenylimidasolidine)..... 1.1’.trimethylenebis [3-bensyl-2-(pmethoxyphenyl)imidasolidine]............................... 1.l8.trimethylenebis(3.benzyl. 2.phenylimidazolidine) . bis[2-(3-butyl-2-imino-l-imida.colidyl)ethyl Isulfide....

165

884

170

684 684

...

1. 1’-ethylenebis[3-bensyl-2-(2-furyl)imida~olidineJ 1.I ‘-ethylenebie[3-bensyl-2-(p-methoxyphenyl)imid-

181

684

I10 685 123 686 Di HBr 204--206 227

.

IV IMIDAZOLIDONES. 1MIDAU)LIDINETHIONES. AND 2-IMINOIMIDAZOLIDINES

.

A 2-Imidazolidones (Ethyleneureas)

.

1 Alkyl- and Aryl-2-imidazolidones Mniidazolidone..................................

133.7

4-butyl.6-methyl-. ............................... P(cyclohenrylmethy1). ............................ 4-(cyclohexylmethyl).5-tnethyl. .................... 1,il-dibensyl. .................................... 4.S-dicydohexyl. ................................. 1.Miethyl. ............................. 4.5-diethyl-. .................................... 1.3-diisopropyl. .................................. 1.3-dimethyl. .................................... 4.5dimethyl. .................................... 1.3-dipropyl- .................................... 4-ethyl-5-rnethyl. ................................ 4-hexyl- ........................................ benwylderiv................................ Phexylb-methyl- ................................ Pmethyl. ....................................... Pphenyl- ....................................... acetyl deriv.................................

185-136 158-159 138-140 93 237-239 I

192-193

542.365.582.207 482 207 207

.

206

428 725 94

726

. . 191-196 .

94 206

167-17 1 113-1 14 112-1 13 124-125 120-123.5 160-161 159-160

207.581. 579 58 1.579 207 206.459 680,143,364.168 580

.

94

94

206

.

2 Alkyl- and Aryl-2-imidazolidonesContainingAdditional Functional Groups 4.(methylamino)-4.5-dihydroxy.l.methyl.2.iniid~o~ i. done ....................................... 443.Phis( bensy1oxy)phenyl1-1-methyl- ............. 4.5-dihydroxy-. .................................. 4.6-dihydroxy.l.5diphenyl. ....................... 4.5-dihydroxy4phenyl. .......................... 4-(3.CdihydroxyphenyI)-l-methyl-. I ............... 1.(3,4-dimethoxybensyyl). .........................

163. HCI 112 128-130 146 169-170

184

167-169

-

82 210 528 251 261

210 267

377

Inridazolidones Compound 1.(2-hydroxyethyl).2-imidmolidone ................ b-hydroxy-4-hydroperoxo-6-methylor . . . . . . . . . . . . . . . . 5-hydroxy4hydroperxo4methyl~(pmethoxyphenyl).1~thyl. ...................... 4.4-phenoxybutyld-methyl. ....................... t.a-dinitro-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3-dinitro4methyl. ............................. 4-(5idfoamyl)-5-methyl. ......................... 5-(l-methylureido)-4.S-dihydroxy-l-methyl-. . . . . . . . . 4-ureido5-hydroxy4-methylor ...................... 5-ureido-4-hydroxy-4-methyl-

.

3

M.p.,

*c.

.

Reference No

.

663

146

611

.

148-149 216-216.5 98.6-98.9

268 42 445.466

.

.

464 211 81

193

611

2-ImidazolidonecarimxylicAcids and Carboxyulkyl-timi&aaolidones Including Those Containing Additional Functional G m o s

5-phenyl-2-imidazolidone-l-carboxylicacid 160-161 ethyl eater .................................. ~ . imidazolidone-4-carboxyoxylic 2 acid . . . . . . . . . . . . . . . . . 190-191 1-carbobenxoxy deriv........................ 194 78 methyl ester ............. 199-201 DL-Zimidarolidone-4-csrboIylic dihydraside................................. bis(benay1idene hydraaide).................... 4,5aihydroxy ðyl eater ................................ 5-methyl-Zimidasolidone4acetioacid . . . . . . . . . . . . . . 5-methyl-2-imidarolidone-4-butyricacid . . . . . . . . . . . . Z-imidasolidone4caproic acid ..................... methyl ester .................... ........ h t h y l - ............. ........ thydroxy-54hydroXy ........ c.hydroxy-5-methyl-.... ........

-

5-methyl- (desthiobiotin) ntdesthiobiotin ............................... ethyl eater .................................. methyl ester ................................ ddeathiobiotin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . methyl ester ................................ DLdesthiodlobiotin. . . . . . . . . . . . . . . . . . . . . . . . . . . . methyl ester ................................ 2-imidasolidone-4-c.aprylia acid .................... !2-iidamlidone-4-enanthic acid.................... 5-methyl-..................................... 5-methyl-2-iiidasolidone-4-pelargonicacid .......... a-ieapropyl-5-methyl-2-imidasolidone-4-propionicacid

93 >350 310

. 159-100 139-140 145 88-89 173-174 120-122 Z m r e 149.150.

680 369.366.605

606 369 196 167 167 167

84 459 206 195,196.aO7 196 207

208 208

104-108

162-163 54-56 72 157-158 69-70 166 77 151-152 156-168 140-150 165-166.5 208-210

2071104.056,971 729.206.459 206 206.97 461a 215 316.41 315 196 196 459 206 105

Systematic Survey and Bibliography

358

Coiiipouad

2-imidasolidone-4-valeric acid ..................... ethyleater .................................. methyl ester ................................ 5-methyl- ..................................... methyl ester ................................ 4-[(4-carboxycyclohexyl) methyl ]-5-niethyl-2-imidasolidone................................... 4-(6-carboxyvnlcryl)-5-(hydroxy1iiethyl)-2-imidasolidone ....................................... 4-(6-carhoxyvrrleryl)~niethyl-.................... 4-(6-isoprop~~lS.harbituryliiic~hyJ)~riiet.liyl-. ....... diacet.yl derivat.ive. ..........................

.

.. .

.

Reference No

M.p OC

~

195.198

170 86-86.5 84.5-85 152-154 66-67

196

196 97 97

G5D

188-190

142-144 147-1 49 269-271 243-244

208 208

209 209

B 4- and 5-Imidazolidones 1.3-dianilino4imidagolidone...................... 173-175 Bbensyl.!&phenyl. .............................. .160-151. Pi 238 5.5dipheny1. .................................... 185.6-186.5 5.5-diphenyl.2.methyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . 180-181 195 diacetyl deriv................................ 2.5diphenyl-4.in:idasoIi.orie. 2.[.nrt.xylii. mid ....... 181 ethyl ester .................................. 148-149 4.4-diphenyl.l.niotliyl 5.i11iidasolidone. . . . . . . . . . . . . . (90 4-bensyl-2-phenyl-5-irnida~olidone-l-acetir acid ...... 158-160 a-isopropyl-3-@heriylacetyl)- (d~tliiobensS.lperii1211-213 lonicacid) ................................ methyl ester ................................ 104-106

.

131 619.291.721 85

85

85 285

285

86

292

530 530

C 2-Imidazolidinethiones (Ethylenethioureae) 2-imidaolidinethione ............................. 8-bensyl ether ............................... S-carbethoxymethyl ether ..................... S-carbomethoxyrnethyl ether . . . . . . . . . . . . . . . . . . S-carboxymethyl ether ....................... 2.2cthiodi-Z.imidaooline ..........................

198,

HCC 304-305 HC1 145-145.5 190

190

HCl223

218-220, Pi 223-224, HCl270-272

HI 284,

2.2'-dithiodi-2-imida~ioIine. ....................... 1.3-bis(2-othylhexyl)-~-iriiiclrrrnlidinethione. ......... 1,3-bm(l-methylbutyl)- ........................... l,3-dibe1&.................................... 1.3-dibUtyl- ..................................... 1.3-dicyclohexyl-. ................................ 1,3-diethyl-..................................... 1,3-diisopropy1- .................................. 4,6-diiethy I- .................................... 1,3-diphenyI- .................................... l-(%hydroxyethyl)- .............................. CmethylS-oarboxymethyl ether ....................... 2,2'-dithiob[4(nr S)-mctliyl-2-imidnsoline~.........

Pi 170-178

302.593.359.514 477 703 647.723 G47 359

.

:3m

PI 1 I9

359

-

201

_.

IH)

I

226.2 62.2 86.4 198

189-190 168.5

HCl215

PI 67

201

438

201, 743 201,744

201 201

738 743 614,615 359 359

.

Imidaeolidinet.hioIles, IiniiioimidasolidoiIrs. and Beuziinidamles

.. .

Compound

b1.p OC

Reference No.

~~li-nietIiyl-2-in1idnzolidinetl1ione-4~n~ro~c acid ..... 1. 1’-[2.2.bis(>thioxo- I. iiiiidaEolid.\lnietliyl)triniethylene]bia(2.iniidazolidinetbione) . . . . . . . . . . . . . . . . 1,3-l~~[~(2-thioxo-l-iinidaiolidyl)~~rop.vl 1. . . . . . . . . . . 1.1’.deaatnethyleritxli-. . . . . . . . . . . . . . . . 1.l’-ethylenedi.. ................................. 1.1’-ethylenebi~(3.b1isyl. ......................... l.l’.trimethylenedi. ..............................

147-148

104

>320 166-167

379

687

686 688 683 684 685

265 167 156

D . 4-ImidazoIidinethiones

%.6diethyl-2,5-ditnethyl4ui~idasolidinethione....... 67 2.5dihexy 1. ..................................... 104-105 ........................ 154. Pi 143 ........................ 204 163 Pi 212. 2.2-tlimethyl-5-phenyI. ........................... HC1182. HI 180 acetyl deriv................................. 213-214 bemyl deriv ................................ 236-237 61 S-methyl ether .............................. Zethyl.%methyl. ................................ 147 2.ethyl-2-methyl-Sptienyl-. . . . . . . . . . . . . . . . . 2-methyl.2.phenyl. ........................ 153-156 2,2,5.6-tetrnmethyl-. .............................

.

.

a

G

146 146 146 140

146

146

146 146 146 274

E 2-Iminoimidazolidinea(Ethyleneguanidines) 2.iminoimidaaolidine ............................. Xi 115. Pi 217. 542 HCI 120-1 22. HBr 125-1 26

.

I 3.bis(gari~ino~he11lylriulfoiipl) deriv. . . . . . . . . . . . ~-hiiino-4-(aniiiioniethyltetrabensoyl deriv............................ %iuiino-1.2-dihutyl-. ............................. ~-iniino-l-eth.vl~~(2-liydroxyethyl)-. ............... . 2.iniii1o-l.niethyl. ..........................

.

.

281 178-180

SIL

187

183.5

HBt 177-179 HBr 122-123

Pi 1947196

266 227 227 607

.

V BENZIMIDAZOLES

A Alkyl- and Arylbenzlmidazoles

Bcmimidesole ................................... l-(paeetaniidopheiiyIsulfonyl)deriv............ 1-acetyl deriv ................................

170-172 197-200 113.114 Pi 158. It 206 285-288 l - ( ~ ~ i i i i i i o ~ l i ~ ~ ~ i ~ lt~l aui vl ................ ~oiiyl) I -kneoyl dcriu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3. Pz- 215 1-but.yryl clrriv. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46. Pi 145 l - ( l - i i a ~ l i ~ . l i ~ l ~ ~ clerk ~ r l ~. .~.~. .i .i .~.l. ). . . . . . . . . 141 .5.142 I-(plieiiylc~~rrluiii~t) clrriv..................... IXi-IGt I-proyionyl dariv ............................. 125. Pi 228 149-150. 45.6, 7-tetrahydro deriv....................... Pi 189-190 1-bensoyl deriv 131-132

............................

.

640.646.609. 537

440

499.502

440

499

m.490 33; 3’W 503.502.499

716 716

380

Systematic Survey and Bibliography

.. .

Compound

2-amylbenaimidasole . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

612.708.717.649 334. 102 552

163-163.5.

Pi 282

2-bnshydryl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

218.219 HCl233-238 115-116.5. Pi 161-163 189. Pi 214-215 HCL 92-94. p h t h h t e 177

1-bensyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-benzyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-benryl-2-methyl4.5.6. 7.tetrahydro deriv . . . . . . . . . . . . . . . 2-benzyl.l.methy1. . . . . . . . . . . . . . . . . . . . . . . . &benzyl-S(or (%).methyl. . . . . . . . . . . . . . . . . . .

b r m n o e NO.

M.p OC

. . . 76. P i 143 . . . Pi 249 . . . 150-151.

HCl61-63 134 155-165.5 280 267 114-114.5 Pi 207. HCI 168.5-169.6 1.2.diniethyl. ........................... 112. P i 243 hgdrate 6 6 4 9 Pi 192 4,5.6.7-tetrahydro deriv. . . . . . . . . . . . . . . . . . . . . . . 1.5dimethyE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96. Pi 248-250. lartratc 185.2-185.9 l.Bdimethyl-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74-75 1.7-dimethyl-. . . . . . . . ........................ 68-70.5 2.4(or 2.7)aimethyl. . ........................ 168-169 2.5(or 2.6).dimethyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303-204 4.5,6,7-tetrahydro deriv. . . . . . . . . . . . . . 184 4.5(or 6.7)-dimethyl. . . . . . . . . . . . . . . . . . . . 196-197 5.6dimethyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204-205 %(2.6dimethyl-l,5-heptadienyl)-. . . . . . . . . . . . . . . . . . 102 2.4 (or 2.7) -dirnethyl-7 (or 4).isopropyl. . . . . . . . . . . . . . . 179.5-179.9 2-(1.2-diphenylvinyl)-. . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 109-109.5 2-dodecyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . l-dodecyl.2-methyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . l-ethyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160-162 Pi 218-219 ................................... 177. Pi 137 phlhnlale 1Ui l.benzyl.2.phenyl. ............................... 2-bUtyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-cyclohexyl. .................................... 4.5,6,7-tetrahydro deriv. . . . . . . . . . . . . . . . . . . . . . . 2-decyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2-diethyl-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

-

4.6.6. 7.tetrahydro deriv. . . . . . . . . . . . . . . . . . . . . I-ethyl-%methyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-e.thyl-l-methyl-. . . . . . . . . . . . . . . . . . . . . . . . . . 2-ethyl-5(or (I)-tiiethyl4.5.6,7-tetrabpdro cleriv. . . . . . . . . . . . . . . . . l-ethyl-2-phenyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . %ethyl-I-propyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

.

695.246 606,382.340.552, 228.689

436 382 551 718. 163 708.549.717. 334 316 316

549

714

541.398.583.714. 382.82.539 316 419.541.02 5 41.6 2 62

63 62.54 1.9I.295 716

62 D9.62 708.717 203

631

549

401)

695.714

032.539.102.689. 657.708.549.717 334 3Wt. Pi 146-14fi 81G.710 Pi '236-237 714 54.5-+x.[i, 714 Pi 'L31i-236 fW-205

Hs-88.5

Pi 212-212.5,

HI 168-169

.

710 714 714

.

Benzimidazoles Compound

S(or 6)-etlry1-2,4.U.i(or 2,4,5,7)-tctrsIiiethylbemimid~-

........

2-hendecyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Zheptadecyl-. ....... ....................... Zheptyl- ....................................... Zhexadecyl-. ................................... 1,2.4.5,6.7-hexamet.l1yl...........................

%hex+. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6,6,7-tatrshydro deriv.. .....................

............. Ziaobutyl-. .................. 4,6,6,7-tetrahydro deriv.. . . %hpropyl- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4,6.6,7-tetrshydro deriv.. . . ......... %hpmpyl-l-methyl-. ............................ 1-methyl-. ........... . . . . . . . . . . . . . . . . . . . . . . . . . . .

381 M.P.. OC.

Referanee No.

Lt6.6 107.6 93-94.6 144.5-146 03.5-94.5 105, Sn 268-251,

6a6 612,649 573,649,612 612,649 649

136-138 157-168. Pi 142-144 186-187

708,649,717 716

HI >350

636

717.708 716 228.Pi136 717,708,612,102 240-241,Pi90-93716 Pi 225-226 714 136.Pi 246-247, 398.539,714,62, nct 226-227 630,541.394,587 178,6179, 279,301.5i)6,509, %methyl-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pi 214. 637.540.708,549, phtlLdore 190, 717.394,700,583. HCL >300 163,353,334,68, 228.662,706,382. 689,539,102,541, 62.246 l-(phenylcsrbarnyl) deriv.. . . . . . . . . . . . . . . . . . . . 128-129 326 4,6,6,7-tetrahydro deriv.. . . . . . . . . . . . . . . . . . 224. Pi 185-186 316,436,736 91,641.246,62 l-methyl-2-phenyl-. 2-methyl-l-phenyl-.

...... ......

6(a 6)-methyl-2-(2-phenylet~l)-. .... 2-methyl-l-propyl-. .............................. 6(0r 6)-methyl-2-propyl4.6.6,7-tetrahydro deriv.. . . . . . . . . . . . . . . . . . . . . 2-methy14,6,6.7-tetrsethyl-....................... %(%rnthylbutyl)-.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . %-@methylphenyl)-.............................. %(l-naphthyl)-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Znonyl- ........................................

Zoctyl- ......................................... 2-pentadecyL. ......... 2,4,6,6,7-pentamethyl-. . ................. l-phenyl- ....................................... 2-phenyL. ... ........... 4,s,6.7-t&rshydm deriv.. 2-(2-phenylethyl]-

.....................

.................. ..........

HC12?+276 HCl82-83.5 Pi 218-219 183-184 241-242 158-159 266-269 271 127-127.5 139.5-140.5 264

98 290. HCI 306 290-291,Pi258. HCL 249-251 189-190. Hc1268-270

249,296.561

714 716

634

612 =.7= 552,733

549,612

649.462 649,612 636

589 537,271,718,708, 717,733,163,334, 682,303,248,246 716 340,561

3S?

Systematic Survey and Ribliography o c.

Compound

M.P.,

2-(Q-phenylheptadecyl) bemimidasole . . . . . . . . . . . . . . . 2-(2-phenylvinyl). ............................... 2-(2-phenylvinyl)-4.5.~.7.tetramethyl. .............. 1-n-propyl. ....................................... 2-n-propyl. ......................................

.

4.5,6.’i-tetrahydro deriv ....................... 2-tetradecyl. .................................... 1.2,4,5-tetramethyl-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.5.6-tetramethyl. .. .. 2.4.5. 7(or 2.4.6.7).tetrslnetliyl. . . . . . . . . . . . . . . . . . . . . 2-tridecyl- . .....................................

I.2,5-trimethyl-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.0-trimethyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1,2.7-trirnethyl-. . . . ......................... 1.4.5-trimethyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6,6-trimethyl-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................ 2.4. 5(or 2.6.i).triniethy I. . . . 2.5.6-trhnetliyI-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.vinyl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-vinyl- (polymer).

.

Reference No

201-202 278-279 Pi 204-206 157-159. Pi 124 185-186. Pi 115-1 16 08.5-99.5 144-145 164

233 105-105.5 142 122-127 146-147

549 62 G2

fj37

549

95-96

140-143 188-190 233-234 1% 194-195 CPt 240-245

.

%If)

.

381 717.708 635 695.714 549.7 17.334.708, 612.102 716

295.541. 02 295,541.62 62 62 62 62

62 461 11.34

B Alkyl- and Arylbenzimidazolium Salts

.

.

I.benzyl5-ethylhenzimMaso)iutii iodide . . . . . . . . . . . . 173.5-174.5 1.benzylY.methyl. iodide . . . . . . . . . . . . 158 225.227, I,.Midhgl-. iodide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pi 254-257 1..Mietbyl.2.riiethyl.. iodide . 200-202 I28 I .3-diniethyl.. sulfate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3-dimethyl.2-ethyl.. iodide . . . . . . . . . . . . . . . . . . . . . . 173-173.5 202-203 1.3-dipropyl-, iodide. I-ethylSmethyl.. iodide .......................... 192-193 l-ethyl-3.propyI. iodide . . . . . . . . . . . . . . . . . . . . . . . . . . 171.5-172 1.2,3-trimethyl-, chloride. 226-23 1 256-259 1,2,.2trimethyl-. iodide . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

1

695 G95 695 100 639 632 G95 695 095 624 f124

.

C 0x0- and Hydroxybenzimidazolee and Their Sulfur Analogues

2(3H)-Benzimidazolones(2.Hydrorybenzimidawles. o-Phenyleneureas)

(a) A l k u l - ~ ( $ H ) - b e t l s i m i ~Including ~a T h e e CmUainiW Addilbnnl Funelibnol Croups

S(RH).tanrimidacdone .........................

3 I2

0-acetyl deriv............................... 0-bemy1 deriv.............................. 1.3-diacetyl deriv............................. 1.3-dibenroyl deriv . . . . . . . . . . . . . . . . . . . . . . . . . . . hexahydro deriv.............................. 1-(phenylcarbainyl) clcriv ..................... 5-amino-1-methyl- ...............................

205 205 149 212-213 147-149 I97 HC1320-330

175.432.609.324. 302,571.1 19.570 46% 175.631.470. 324 324 324 324 281 432 692.fi93

383

Benzimidazoles Compound

&amino-l-rnethyl-2(3H)-bensimidaaolone . . . . . . . . . . . l-tarabityl-4.5dirnethyl-. ............ 1.3.bis(hydroxymethyl). .............. diacetyl deriv ................................ dibensoyl deriv .............................. 5.6-dinitml.methyl. ..... acetyl deriv. . . . . . . . . l.n.lyxityi.5.6-dimethyl. .. .................... 1-tmannomethylit.ylb,(I-dimethyl................. 4-nitro- ......................................... 5.nitro-1.methyl. ................................ acetyl deriv................................. 6-nitro-l.methy1. . . . . . . . . . . . . . . . . . acetyl deriv................................. l-o-ribityl-4.6dimethyl-..........................

.. oc.

M.p

He1348 247-248 164-165 143-144 165

216 219-220

-

800

175-176

185-186 248

Referenoe No.

693.692 372 472 472 472 692.693 692.698 368 697 120

692.693 692.693 692.693 693.692 371

(a) % ( ~ H ) - B e n t i m ~ ~ ~ ~Acids ~ r ~and m Cx ~a l r~ c~ ~ ~ l - a ( ~ H ) ~ r n ~ d ~

2(3H)-bensimidasolone-l-ear~xyliracid ethyl ester .................................. methyl eater ................................. 2(3t[)-bensimidas~one-4-carboxylic acid ............ methyl ester ................................ hershydro deriv............................. 2(3t[)-bensimidaeolone-5-aarboxylie acid ............ methyl ester ................................ hershydro deriv.............................. 2 ( 3 H ) - b e n s i m i d s r o l o 1 i ~ l - t h i o n ~ a r ~ acid x ~ l i.c. . . . . ethyl ester .................................. 2(3H)-benrimidasoloiie-6 acetic acid ethyl ester .................................. (2-hydroryethy1)aniide ....................... 2 (3H)-bensimidasolon&but.yric acid . . . . . . . . . . . . . . hexahydro deriv.............................. 2(3H)-benPimidazolone-5-butyric acid . . . . . . . . . . . . . . hexahydro deriv.............................. 2(3H)-bensirnidasolone-&valeric acid ............... hexahydro deriv.............................. 2(3H)-bensimidazolone-5.valericacid ............... hexahydro deriv..............; ............... 5-(y-~arboxybutyryl)-2(3H)-ben~ifnidszolone........ 5-(B-earboxypropionyI)-..........................

.

2

156 159

>305 280-263 204-205 >300 312-313 206-207 I

132-123 .XI8.209

245-246 'm-300

198-208

253.5-255 138-142 263-265 212-215 234-236

212-21 4 280-282 298

432 432 231 231

231

231

231 231

302 302

363 3&3 231 231 232.231 232.23 1 131 231 231 231 231 232.231

2(3H)-Benzimidamlethiones(2.Mercaptobeneimidamles. 0-Phenylenethioureas)

2(3H).bensimidazolethione

........................

S-(%bensothia~Iyl)ether ..................... S-bensoyl deriv.............................. 5-carbethoxymethyl ether ..................... S-earbomethoxymethyl ether ..................

309-10 or 312-313

405,401.402,404. 116.282.302.182. 673,374.733,Ma.

233-234 186-187 97 83

610

238

378 641.723. 647 047

Systematic Survey and Bibliography

384

Compound

M.P.,

2(3~>benrimidasolethione( c o d . ) kbosyxnethyl ether .......................

8-[(2-hydroxyethyl)carbtunyhnethyl] ether ...... &methyl ether .............................. m t y l d e r i v................................. 2.2‘dithiobisbensimidasole ...................... l e b u t y l - ....................................... 6(0r 6).broma- .................................. l.(pbmmophenyl)S-ethoxy. ...................... 6(0r 6)-chlom-................................... bchloro-l-(4-diethylsmino-l-methylbuty1)&methyl ether .............................. 5(0r 6)-ethoxy. .................................. 5(or 6).iodo- .................................... l.(p-iodophenyl)-6-methyl. ........................ S-methyl ether .............................. 5(or B).methoxy. ................................ l.methy1. ....................................... 5(or B).methyl. .................................. 5(or 6).nitro- .................................... 1,3-bis(hydmxymethyl). .......................... diaoetyl detiv................................ dibenwyl deriv.............................. 2(3H)-bensimidasolethione-l-r!arhoxylia acid ethyl eater .................................. 2(3H)-benrimidarolethioneS(or G)-rrulfonicacid pacetarnidoanilide ........................... paminoanilide .............................. o-hydroxyanilide.............................

.

.

O C

Reference No

190

238

201 200 230. HC2 210 100-101 300401 266 296-297

333

.

. 251-255 381 284-285 139-140 261-263 u)0-200.5

641

282

282.x17 116 116 366 116

458

>295

116 116 3m1 366 116 116 116

160-162 146-146 176-178

472 472 472

93-94

302

240-242 255

25

.

.

.

380

25

25

3 Mono- and Polyhydroxyalkyl- and Hydroxyarylbenrimidawles. Their Ethers and Halogen Derivatives

.

(a)H y d r o t p Hgdrox&kgI.

4.7dihydroxy.2.methyl.1.

.

and Hudro~aryl~snoimida&.

3-diphenylbensimida~olium

amtate

0.O’diaoetyl deriv........................... 5(0r 6)-ethoxy.%benzylbenzimidaaole

...............

6-ethory-5-methyl.l.(pmethylphenyl). . . . . . . . . . . . . . 1.(4-ethoxy-3-rnethylphenyl)-6-methyl. . . . . . . . . . . . . . 5 b r 6)-ethoxy.2-phenyl. .......................... 6(0r 6)-ethoxy.2-(2-phenylethyl).

..................

Theit Elkla and Sulfur A W u m

...

135-136 Pi ‘207 HC1259 162-163 HC1 189 102.5. Pi 228 Pi 186-187 51-63. H a 249-250 151-152. HCl216-217 158.5-157 203.7-204.4 154.5-155

2+ethoxyethyl). ............................... %(1-ethoxyisopropyl). ............................ !&(ethoxymethyl). ............................... 1-(4hydroxy-3-methoxybensyl)-2-(4-hydroxy-3224 methoxypheny1)-............................ 2-(4-hydroxy-3-methoryphenyl). ................... 221-222 1.hydroxy.2-methyl. ............................. 23 .1

309 551

356 366 651 561 34

629 246.629

718 708.717 264

Benzimidamoles

.

.. .

M.p

Compound

6(0r 6)-by&o.y-2-met4ylbmidarrde. ............ &hydroxy.%m~l.1.phenyl. ..................... Beetyl deriv................................. 6-hy&0.y-1-(p-methylphe11~1)-.................... aaetyl deriv................................. 1.(4hydroxy.methylphenyl)6-methyl. ............ 2-( I.hydmxy.2-naphthyl). ........................ 5-hydmxy.l.pbeny1. .............................. acetyl deriv................................. Z(a-hydroxybenry1) ............................. 1.(2.hydm~yetbyl). ..............................

nk2-(1-hydroxyethyl). ........................... acetylderiv................................. L%(1.hydroxyethyl). ............................

Referenos No

O C

L(hydmxymethy1)-..............................

2.(hyd~~ymethyl)............................... %(memaptomethyl). ............................. %(hydrorymethyl).I~ethyl. ...................... 2.[o-Ulydro.ethyl)phenyl]. ..................... Z(o-hydroxypheny1). ............................. 2-( 1.hydmmmpyl). ............................. 6(0r 6)-m&h04. ................................ 6(0r 6).methoxy.2-bensyl. ........................ 6(or 6).methoxy.Z-methyl. ........................

081

262 262 202-203. Pi209 637. 102 107-108 461 Pi 204 ECI18a-1&1. ca 189-180 179-181 637.193.629. 473 162-163 34 176-177. P i 131 193.102 ECl213-216 176-177. 193 ECI 213-216 163.6-15P 6 34 170-171 637 80 589.629 227.6-228 34.629 141-143 a3 171-172. P i 214 1(w,637.161.629

..

340 340

237-239

a53

22io-221 123. Pi I91

.

................

46 HCl176-178 141.6-142.6 Pi 191.6-192.6 103-105 149 142 HCl266-267 128-130. HCl239-241

.

%(methoxymethyl). .............................. 137 2-(prnethoxyphenyl). ............................ 228-230 4.6.6, 7.tetrabydro deriv....................... 236-238 Pi 211-212 2-.methoryphenyl).l.tbyl. ..................... 108-106.5 2-(pmethoxyphenyl)&methyl. .................... 118 2-(pmetho~henyI).lropyl. .................... 67.6-68

.

..............................

262 366

133

196-197 >265 244 88

168 106

6-metho.y-2-methyl-f-phenyl-..................... 6(0r B)-methoxy-B(or S).phenoxy.%methyl. ......... 5(or 6).methoxy.2-phenyl. ........................

k(phenoxymethy1).

262 262 262

.

Z(2-hydroxyethyl) ............................... 2-(1-hydro.yethyl)b-ethoXy-. ..................... 2-( l-hydroxyethyl).L.methyl. ...................... 2(I.hydro~prOpy1). ..........................

I.(3.4methylen~o..n.l).%(3.4meth~en.ioxy phenyl). .................................... 2.(3.4m&hylenedioxyph~yl)......................

277

187.6-188.6 243 141 239

.

D-%(lhydm~ethyl).............................

6(or 0).methoxy.2.(2-phenylethyl).

385

.

176 249 162

70 aM) 629

493

661 627

286 437 561 661

246.340 708. 717 716 714 714 714 718 708.717 246.340

386

Systematic Survey and Bibliography M.p

Coiiipound

4. 5(or 6.7)-dihydroy-B,7(or 4.5)-dichlorobenrimid.

scole .....................................

diacetyl deriv................................ 5.6dihydroxy4.7-dichloro-l.2dimethyl.............

.. .

Reference No.

O C

262

196

213 >300. HCI >300

262 262

diacetyl deriv................................ 200 4.5(or 6.7)-dihydroxy-6.7(or 4.5)-dichloro-2-1nethyl. .. HC1 >250 diacetyl deriv................................ 148 5.6-dihydmxy-4,7-dichIoro-2-tnetliyl-. .............. >300. HC1>300 diacetyl deriv................................ 207 4.5-dihydro~-6,7-dicliloro-2-methyl-l-phenyl-. ...... > 160 5hydroxy4bromo-2-methyl.l.phenyl. ............. 266 &hydroxy.l.(pbromophenyl). ..................... 295 ethyl ether .................................. 5-hydroxy~hloro-l.(o-chloropIienyl).2.methyl. ..... 250 5.hydmxy4chloro-l.(pchlorophenyl).2.methyl. ..... 270 acetyl deriv................................. 186 5l~ydroxy-Peliloro.2-titctliyl.l.p)leityl. . . . . . . . . . . . . . 287 acetyl deriv................................. 161 ;ihydroxy4cllloro-I.(~.ttiethylplietiyl). . . . . . . . . . . . . 217 5-hydroxy-4-chloro-l.phenyl. ...................... 220 5hydroxy-l-(ochlorophenyl)-2-met.hyl-............. 245 5hydro..l.(gohlorophenyl).2.methyl. ............ 225 5(or 6).hydroxy4. 6(or 5.?)-dibmmo-%methyl. ....... . 5hydro4..&librom..methyl.l.phenyl. .......... 190 5(or 6).hydroxy-4. 6(or 5.7)-dichloro- ............... >250 acetyl deriv................................. 212 5(or 6).hydroxy-4. 6(or 5.7)-dichloro-2-methyl. ....... HCL 250 5-hydroxy-4.6-diel~loro-%tt1ethyl-l-phet~yl-. . . . . . . . . . 216. He1283 acetyl dcriv................................. 183 5(or 61.hydroxy-4. 6(or 5.7)-dicliloro-..~~Iietiyl. . . . . . . . 240 2-(hydroxyrnothyl)-5(or6).cliloro. . . . . . . . . . . . . . . . . . m - 2 0 7

-

2.(~-erythro-trihydroxypropyl)bcn~imi~le ........ 2-(berwthto.trihydroxypropyl). .................... 1.rrcua.ityl.2.gditnethyl. ......................... a(tar.i.tetrahydn,xybutyl ). . . . . . . . . . . . . . . . . . . tetraacetyl deriv............................. Z-(l.Panhydro-w~bino-tetrahydroxybutyl)-....... isopropylidene deriv .......................... 2-(dyco-tetrahydroxybutyl)......................

2-(~~pz~~trahydro~b ...................... utyl) 2 - ( 1 . P a n h y D-t.hydr.xybutyl) ~ ........... %(D-rib&&ahydmWbtttyl)

......................

%(I .4.anhydro-n-~.tetr.hy.ir.xy.~~tyI)

...........

177-178 177-178 235-236 235 Pi 158 HCL 230 141-142 208 195-190 189 Pi 95-99. HCl 191 189

.

.

.

200-204.

Pi 132-138 191. Pi 184-186

HCl2OI-203 82-83.

Pi 120-126

262 2fJ2

262 262 262 263 262 368 356 262 262 262 262 262 262 262 262 262 325 262 262 262 263

262 262 263

166

575 575

:no

474.mfi

506

388

338 305.474 305 338

. 576,194,52.517 3RR

Benzimidazoles

3%

.

Compound

1-o-xylityl-2.B-dimethylbeluimidasole.............. 2.(~zt/lo.tetrahydrortybutyl)...................... 2-(Ian 4 .hy .d. o-.trshydroxybutyl) ........... 2-(I ,4-anhydrctP-zyro-tetrahydro.ybutyl)-l-ben~l-. . 2-(who-pentahydroxypenty1)- ................... 2-(~-gaCaclrrpentahydroxypentyl) .................. hexaacetyl deriv............................. 2-(r.~ahdo-pentahydmxypantyl).................. 2-(DLga.c(o-pentahydroxypentyf). ................ l-~-mrbityl-2.5-dimethyl-......................... 2.(o-glttco-pcntahydroxypentyl). ...................

2-(~-~lucu-pentahydrxyyent~) .................... 2-(o-o.iico-pentahydroxypentyl).l.bensyl. ........... 2-(o.onlo-pentahydrnxypentyl) ..................... 2.(~ido-yentahJrdroxypsntsl)...................... %(o-rnamo-peiitahydroxypentyl). .................. 2-(n-tu~o-pentaliydroxype1i tyl). .................... 2-(dt~ifozo-trihydroxypcnty1)- ................... %(L-ualuclomeChylo-tetrRhydrox.\.pentyl)-

.

M.p., OC

Reference No

179-180 141.143. HCll81-I82 221-223 215-217 198 246 P i 217 HC1202-204 179

370 338

.

.

250

233 226 215 Pi 203 HCL 180 215 188 201 164-156 227 P i 205 190-191 207-209 P i 124-127 Pi 248-249. Pi 189-191 HCl224-225

.

.

.

.

.

a(o-glucornellrylo-tetetnrhydrortypenty1). .............. 190 2-(Lmcmnomelhulrahydrorypentyl). ............ 210. P i 168. HCL173-175 2-(nqtlla.bmanno-hexahydroxyhexyl). ............. 218 a(D-olwo-D.ud.Yhe.1). ............... 215 2-(n-oiueo-Pido-hed~xyhe.yl)-............... 192 2-(Mnan~~aln-hexahydro.yhexyl) .............. 241 ~(o-oala-~Llo-heptahydroxS’heptyl) ............... 234-235 2 - ( ~ - o l u c o - ~ o a l a - ) i e p t ~ y ~ o ~ h e.............. ptyI) 246-247 2-(Dgluco-~-tolo-heptahydroxyhe~tyl) .............. 191-192

2.2’-(1,2,3,4-tetrahydmxytetramethylene)-dibensimidd

e

.

338

338 318 400.318.475,474 400 576 64

370 3 18.474. 4 7 6 575 475 318 318 474. 318 318 194

194 576 474.318 318 318

318

318 312 576 312

D-(goladomiccodibenrimidaaole.................. 298 P i 250.

489

n-mnnnatnitcosaocharo-..........................

439

P-snccharo- ...................................

4

.

. .

.

HCl.318 250 Pi 241 HCl.266-267 238 Pi 211. HCl267-268

439

Benximidawlecarboxaidehyies.Ketones. and Quinones

2-benrimidarolecarborsldehyde.................... 2.4-dinitrophenylhydraaone................... onme ...................................... 5(2-ben.imidaaolyl)-2,epentsnedione ..............

...

3-(2-bensimidasolyl)-4-(phenylimino).2.pentse 2-bensimidluolylmethylmethyl ketone............. 5(2mctliylbenaimid~olyl)methylketone........... 2.4-1iinitrophenylhydramne...................

235 309-31 1 213-215 138-139.

338 338 338 279

315-316 148

281 618 95 95

HCZ 243-244

190-191 N 7 .6

388

Systematic Survey and Rihliogmpliy Compound

MV.,

.

oc.

Reference Nu

4.7diox0-6(0r 5)-chloro-5(or Bbhydroxybensimidmole ....................................... 250 4.7diox06(or 5)-chloro-5(or 6).hydroxy.%methyl. . . . 250 4.5(or 6.7)dioxo-6,7(or 4.6)-dichlor~-. . . . . . . . . . . . . . . >280 N i 102 4.6diox06.7dichloro- 1.%dimethyl. . . . . . . . . . . . . . . . . >300 4.5(or 0,7)dioxo-0.7 (or 4.5)dichloro-%methy I. . . . . . . 280 4.5diox~.7dichloro-2.methyl.l.phenyl. . . . . . . . . . . . 229 4.5(or 6.7)dioxo-6.7(or 4.5)dichloro-2phenyI-. . . . . . . 305 HC1200 5.0aioxo-4.7dihydro-l.2dimethyl-4,4.7.i-~~~hl~ri~ 5.Bdioxo-4.idihydr~2.methyl4.4.7.7.tetrachloro- ... HCL 300 4(or 7)sxo-6(or 5)-chIo&(or 6)-hydroxy-2-methyl7(or 4).(phenylimino). ........................ 300 4(or 7)sxo-6(or 5)-chloroS(or G)-hydroxy-7(or 4)(pheny1imino)- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 5(or 6)-oxo-4.4,6.7(or 4.4.5.7)-tetrachlor~.phei.y1. ... HC1199

203

.

263 263

262 26a

2&3 263 262 262

263

263 263

.

.

D Halogeno.. Halogenoalkyl. and Halogenoarylbenzimidamles

5(or 6).bromobenriuiidamle ....................... 5-brorno-1.2-dimethyL.... ............ 6-bromo-1.2dimethyI. ............................ 5(or 6).bromo-Zmethyl. . . . . . . . . . . . . . . . . . . . . . . . . . . 2-(Zbromoethyl). .......................... 5(or 6)-chloro-...................................

137 141 180 215 227-220 124-1 26 Pi 215-216 5(or 6).chloro-2.(chloromethyl). . . . . . . . . . . . . . . . . . . . 140. Pi 195.196 HCl213-214 5-chloro-1.6dimethyl. ... . . . . . . . . . . . . . . . . 154 191 5(or 6)-ohlor0-6(or 5)-methyl. ..................... 100 5-chloroSmethyl.l.pi.enyl. . . . . . . . . . . . . . . . . . . . . . . . 210 5(or 6)-chloro-2.phenyl. ...... ..... HC1290-291 184-187 5(or 6)-chloro.2.l,rol~nyI. . . . . . . . . . . . . . . . . . . . . . . . . 288.5 4(or 7)-chloro%.5,6,i(or 2.4.5.(~)-tetrmiethyG. 250-251 5(or 6)-chloro-2.4.6. 7(or 2.4.5.7).totraniothyI. . 134.7-135.4 2 4 1.chloroethyl). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-(2-~hIo~&hyl).. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88.5-89. HCl180 2 4l-chloroethyl).l.methyl. ........................ 64-65 135.5-136.6 2-( 1-chloroisopropyl). ............................ 165 2.(chlommethyl). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.(chlon-~methyl).l-methyl. ...... . . . . . . . 94.5-95.5 %(o-chIorophenyl)-5(orG)-methyl . . . . . . . 160, Pi 189 144.&14 5.5 2-( 1-chloropropyl)-............................... Pi 196-197. l.(%iodoethyl). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HI 174-175 137-139 %(iodornethyl). . . . . . . . . . ......................

.

.

.

.

541 541 541

541

34

.

166.645

384.046 478 478.246 478 217. 651 311 637 637 629.5&334 3%. 34 629

629.34

340,92.629,.384 340.629 249 629 461 628

E Nitro.. NitroaUcyI. and Nitroarylbenzimidazolee Including Those Containing Additional Functional Groups

4,5-dinitro-l.2dimethylhensimidmole.............. 170 5.6dini~1.2-dimethyl........................... 232 2[2(2.edinitrophenyl)pinyl 1. ..................... 215 4(or 7).nitro- .................................... 238-239. Pi 184486

*

262 262 66 691

389

Bendmidazolea Compound

5(or 6).nitrobenaimidazole ........................ 4(or 7).nitro-2. 6(or 2.5)-dimethyl................... 5-nitro-1.2-dimethyl. ............................. 6-nitro.l.2.dimethyl. ............................. 5-nitro-1.2-diphenyl. ............................. 5(0r B).nitro-%methyf. ........................... 5nitm-l-methyl-2-phenyl-........................ 5nitro-2-methyl-I-phenyl........................

Reference No

203 Pi216

203.691 481 262.640.541 541 98 640.536.541 98 539 98

.

248 226 242 181 221 189 HC1202

-.

5-nitro-l-(pmethylphenyl)-2-phenyl-............... 177-178,

B(or 0).nitro-2.(p-nitrophenyl).

....................

5(or @.nitro-1.phenyl. ............................ S(or 0).nitro-2.phenyl. ............................ 2.(o-nitroknzyl). ................................ Z(pnitrobenzy1). ................................ 2-(o-nitrophonyI)................................. 2.(m.nitrophonyl). ............................... 2.(pnitrophenyl). ................................

HCl23S 358

.

206 217 215 261. HCl 291 207-208 329-330 HCl310 117.5-118 Z(m-nitropheny1)-l-ethyl-........................ 213-214 2.(p.nitrophenyl).l.niethyl. ....................... 5(or 6)-(2.4-dinitroanilino)-2-mcthyl-. .............. HCl325-320 156 a-form .................................... 241 &form ........................... 5-(2.4-dinitroanilino)-l-phenyl-. ................... 221 S-nitro-6-amino-l.2-dimethyl-. .................... 309 5(or 6)-nitr&(or 6)-anlino-2-tilct.t1~~-. . . . . . . . . . . . . . . 292 235 aeetylderiv................................. 5-nit~l.(3-nitro4anilinophenyl).2-methyl. . . . . . . . . 199 2.(o-nitrophenyl).l.(gmothylanilino).5-methyl. ...... S O Pi 182 1$30 nitroso deriv................................. Pi 174 2.(m.nitrophenyl).l.(pmethylanilino)-S-methyl. . . . . . 224.225 120 nitroao deriv................................. 2-(pnitrophenyl).l.(pmethylanilino)-5-methyl. ..... 186 5-nitro-2-cNoro-l.methyl. ......................... 202-203 6-nitro-ZcNoro-1-methyl-......................... S-nitr~l-(o-ahloropheny1)-2-met hyl-................ 140 5-nitro-l.(pehlorophenyI).2-mothyl. . . . . . . . . . . . . . . . 210 5nitro-l.(3.nitr~hlorophenyl).2-methyl. . . . . . . . . . 226 Bnitro-5-hydroxy-4-chloro-~methyl.l.phenyl. . . . . . . . 221 >250. HCIIOO 4(or 7)-nitr&(or S).methoxy. ..................... N i 204 5(or 6)-nitr&(or fi).methoxy. .....................

.

.

-

.

.

F Aminobenzimidazolee

1

.

M.p., OC.

648 539 203 340 340 708.717.350 708.717.648 648.708.717 714 714 643 043

202 640 540

262 249 249 249 249 249 692.693 693.092 262 262 262 262 385 493

. Amino.. Aminoalkyl..and Aminwrylbenzimidawles

2-aminobenzimidasole . ........................... N-(m-aminophenylsulfonyl) deriv.,. . . . . . . . . . . .

N-(paminophenylsulfonyl) deriv............... 1-(paminophenylsulfonyl) deriv ................ N-(m-nitrophenyWonyI)deriv................ l-(m-nitrophenylsulfonyl) deriv................ N-@henylsulfonyl) deriv...................... I-oarbamylderiv.............................

.

326 321-322 a1 1-212 299401 233-234 354-356 Pi 250-260

S31.427.560 580 600 572.560 600 580 880 531

Systematic Survey and Bibliography

390

Colapound

ALP., OC.

4(or 7)aminobensimidasole. . ,. . . . . . . . . . . . . . . . . . . . N-formyl deriv.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5(0r 6)-amino-.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6-an1ino-l-suilino-2-plienyl. . . .. . . . . . . . . . . .

. . . ..

diacetyl deriv.. . . . .. . . . . . .... . . . . . . .. . . . 4(or 7)-amin+2,6(or 2.5)dimethyL. . . . . . . . . . . . . . . . aeotyl deriv.. . . . . . . . . . . . . . . . . . . . . . . . . , , . . . .

.

.

NJ-diacetyl deriv.. . . . . . . . . . . . . . . . . . , . . . . . . . 4(or 7)-(29lnino-l-iiaphthylaso)-2,6(or 2,5)-dirnethyl4(or 7)-(2-hydroxy-l -naphthylaso)-2,6(or 2.5)dimethyl-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5-amino-I.2dimethyl-. . . . . . . , . acetyl deriv.. . . . . . . . . . . . %amino-l-methyl-. . . . . . . . . . . . . . . . . , . . . . . . . . . . . , .

.

.

120-121. P i >250 209 166.5-167. P i 205. HCI >210. Di HCl>300 228, P i 204, Po 186 105 IOU 160, Ni 125. HCL 235

-

HCI >2W 07-98

128 210 214 217 131 >300 213. HCL 310.912

214-215 2-(Zaminoethyl)-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pi 193, Di HCl270-272 %(3-aminoguanidino)-. . . . . . . . . . . . . . 195-195 %(aminomethyl)-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53. Di HCI 263 N-acetyl deriv.. . . . . . . . . . , . . . . . . , . . . . . . . . . . . . 200 N-benzoyl deriv.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 I-(o-aminopheny1)-%methylN-acetyl derivative. . . . . . . . . . . . . . . . . . . . . . . . 220 2-(o-arninophenyl)3(or @-methyl-. . . . . . . . . . . . . . . . . 190 %(m-aminophenyl)4(or @-methyl-. . . . . . . . . . . . . . . . 236 2-(paminophenyl)-S(or 6)-methy&. . . . . 124 2-(psminopbenyl)-1-phenyl-. . . . . . . . . . . . . . . . . . . . . 197 2- [(amylamino)methylI-. . , . . . . . . . . . . . . . . . . . . . . . . Di HCl 190-191 %anilia..................................... 188. HCl 151-152 1-anilino-5-(bensylidoneamino)-2-phenyl-.. . . . . , . . 242 n i t m deriv.. . . . . . , . . . . . . . .. . . . 110

. .

.

.

.

.

.

. . . . ... . . .. . . .

249

431 431

48 I 262

167 3!#

233

1-(2-aminoethyl)-

249

su 210

15.3

- .. . . . . . , . . . . . . . . . . . . . . . . . . . . . . .

691

691,644

43 1 431

250. HCL 825

Z(paminobensy1)

691

109

HCl281

-

acetyl deriv.. . . . . . . . . . . . . . . . . . . . . . . . 5-(piiitmphenylasin,ino) deriv.. . . . . . . . I-(2-amino-4-niethylphenyl)-2,5-dimethyl-

Reference No.

w2 128

694 094 ?j36 530

262.539 262.589 262 262 262 075 538 70 552,840 440 127 532

.340

340 340 675 249 240

249

m 02 183 249

249

391

Benrimidnzoles Compound

1-anilino-2-phenylbenenrimidazole . ..................

nitroso deriv................................. 2-(aniiinomethyl).. .............................. .(anilinomethyl).l.methyl. ....................... 2 41.(benr&unino)ethyl]. ......................... 2-I(benxylamino)methyI 1. ......................... B(bensylideneamino)-1-(pmethylpheny1)- . . . . . . . . . . 2-[1-(buty1amino)ethylI. .......................... 2.[(butylsmino)methyl]. ..... 2-[(ayclohexylamino)methyl I. ..................... 5.&diamino-l.2-dimethyl.......................... 4.5(or 6.7)-diamino-2.methy 1. diacetyl deriv................................ triacetyl deriv ............................... 5.6diamino-%methyl. .................... acetyl deriv................................. diacetyl deriv................................ 2-[l-(dibensylamino)ethyl 1. ....................... 2-[(dibenrylamino)methyl 1. ....................... 2-[l-(dibutylamino)ethyl 1. . . . . . . . . . . . . . . . . . 2-[(dibutylamino)methyl]. ........................ 2-[1-(diethylamino)ethylj - ........................ 2.[(2-diethylaminoethyl)amino). .. ........ 1- [(diethylamino)methyl]........................ 2-1(diethylarnino)methylj - ........................ 2-[(diisopropylamino)methyl]. ..................... 1-[2-(dimethylamino)ethyl 1-....................... 2- [l.(dimethyIamino)ethyl]. ....................... 1- [2-(dimethyl~o)ethyl I-2.isopropyl. ............ 1- [2-(dimethyJamino)ethylJ-%methyl. ..............

1-[2-(dimethylamino)ethyl j-2-phenyl..............

M.p.,

.

O C

Reference No.

.

211. Pi 199 P o 220 137 162 118

249.163 249 340 340 583

166.6-156.

HCl218-220 Di HCI 211-213 92 142 262 583 120.3-121.7, HC1171.8-172.7 Dd HCI 203-204 92 Di HCI 213-214 92 279 262 176 260

*

591 591

510 540 540 583

I

>300 >300 222.3-223.2 169 139.1-189.3 132 177.6178 126-128

92

583

92 583 333 33 170 645.92,ll 178-178.5 645 Di HC1234-236 531 683 208-210 DiPi236-236 731 Di HC1 731 238439.5 72.5-74. 731 Di Ha 234 132.5-133 645

-

2-[(dimethyismino)rnethyl J- ....................... 2-(pdimethylaminophenyl)-l-(pmethylanilino)-5249 Pi 177 methyl. ..................................... 249 2-[2-(pdimethylaminophenyl)ethylI. .. 594 187. Pi 198 2- [2-(pdimethylaminophenyi)vinyl1. ............... 256. Pc1232 594 2-[2-(pdimethylaminophenyl)vinyl].l.methyl. ....... HI 234 694 2-[(diphenylsrnino)methyl]- ....................... 340 215 2-[(dipropylamino)methyl1. ....................... 180.5-181 645 149-149.3, 2-[I-(ethy1amino)ethyl .......................... 583 HC1225.7-226 2-[(ethylarnino)methylJ- .......................... WRCl223-226 92 Zguanidincr-.................................... 264 Pi2aQ-270. 532.383.533 N i 228, Di HCl € 237 I & 2-guanidino-5.6dimethyl-......................... 191.Pi258-269 383 HCl266 2-guanidin&(or 6).methyl. ....................... Pi 264 383 Di HC7.228-229

.

.

.

.

.

Systematic Survey nnd Bibliography

392

M.p.,

Compound

2-(3-.opropylgu.iidiiio)benEiniid.olu

....

.

O C

168.Pi 263-264. Di HCl230-232

2-(3.iwopropylguanidiino)-5.6-1limethyl. . . . . . . . . . . . . . . Pi 245. HCl 138-141 2-(3&0propylpiauidino)-5(or 6).methyl. .. Pi 212. HCL 214-217 2.(3.methyl3.pheiiylguaiiidiiio). . . . . . . . . . . . . . . . . . . . 163 2-[(methylamino)methylk . . . . . . . . . . . . . . . . . . . . . . . . Di IICl207-209 2-(o-methylaniiino).. . . . . . . . . . . . . . . . . . . . . . . . . . 182. NCl89-90 2.(pmethylaniliiio). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207. HCi 174 I-(pmethylanilino)~methyl-2-piienpl. . . . . . . . . . . . . 231 nitmao deriv. . . . . . . . . . . . . . . . . . . . . . . . . 129 2 4N.methylanilinomethy1). . . . . . . . . . . . . . . . . . . . . . . . 202 2-(N-methylaniliiomethyl).l.metliyl. . . . . . . . . . . . . . . . 145 2-[(2-phenylethyl)sminomethyl)-. . . . . . . . . . . . . . . Di HCl23&-239 2-(3-phenyIguanidiao). . . . . . . . . . . . . . . . . . . . . . . . . 178 Ni 173-174 2.(tphenylureido). . . . . . .................... 250. HC1 193 'L-ureido- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-(2-anilinovinpl)-l j.diiiiethylbenaiiiiidaeoliuiii iodidc 27s 5-(dimethylamino).1.2.S.triiiiethyl. sitifate . . . . . . . . . . 255 2-[2-(~iiiietiiyla~1iiiioplie1iyf)vinylJ-l ..?-diethyl.. iodide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245-24i 2-[2(pdimethylariiiiioplreiiyl)vitiylj.1.8-dinietliyl.. iodide ...................................... >310

.

.

2

.

Rsferenee No 383

383 388

535 92 183 183

249.250

250

340

340 92 632 532 534.532 410 539 100

633

. Amino.. Amimalkyl.. and AminwrylbenximidawlesContaining Additional Functional Groups

5(or 6)-amino-4(or 7).broino.2.pheiiylIwnriitiiclazole . . 238-239 aeetyl deriv. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 2-amino-5(or 6).chloro- . . . . . . . . . . . . . . . . . . . 167.168.

262 282 427.645

1-(m-nitrophenylsulfonyl) deriv. . . . . . . . . . . . . . . . 216-218 5(or 6)-nmino-G(or 5)-chloroformyl deriv................................. 205 &smincechloro-2.methyl-l-plie~i-. . . . . . . . . . . . . . . 257 aoetyl deriv................................. 228 5.aminoSohlor~Zn~ethyl-l-phe~iyl-. . . . . . . . . . . . . . . 208

427

Ni 168. At 226-227

.........................

199

ethylpheny1)- . . . . . . . . . . . . . . 128 .......................... 209 formyl deriv. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 5-amino-Bchloro-l-(pettiylplrenyi~. formyl deriv................................. 105 143 5-amino-4-chloro-1.phenyl. . . . . . . . . . . . . . . . . . . . . . . . . aoetylderiv................................. 205 69mino-l.(whlorophenyl).2.methyl. . . . . . . . . . . . . . . 130 69mino-l.(p-chlorophenyl)-2-methyl. . . . . . . . . . . . . . . 170 I94 &phenylazimhio deriv . . . . . . . . . . . . . . . . . . . . . . . 5(or 6).amind, 6(or 5,7)-dirhloro325 fonnyl deriv.................................

262 262 262 202 262 262 262 262 262 262 262 262 262 262 262

.

393

Renzimidazoles h1.P

Compound

..

O C

.

2-(anilinomethyl)-5(or 6).chlorobeilzimidasolc . . . . . . . Pi214.215. . Di RCL 250-251 2-[(diethylamino)methyl]-5(0r 0)-chloro- . . . . . . . . . . . 150-151 l-[3-(diethylmnino)propyl]~hloro-2.methyl. . . . . . . . s 5 3 . 5 4 . Pi 105. Di Pi 239. Di PO235-236 1.[3-(diethylamino)propyl~chlm.2.methyI. . . . . . . . Di Pi 217. Di Po 230. Di HC1100-110 1.[3-(diethylemino)propyl]-5.gdichloro-2-me~l. .... Di Pi 226-228 2-guanidin&(or 6).chloro- ........................ 207.P i -201. Di HCl211 2-guanidino-5.6-dichloro-.......................... 244 Pi 319. HCL 287-290 %(%isopropylguanidino)-5(or f))-chloro-............. Pi 248. Di €€a 215-217 2-(3-isoprnpylguanidino)b.0aiohloro-. . . . . . . . . . . . . . 204. Pi 296. Di HCl224-225 l.(pmethyla11ilino).2.(o-chlorophenyl)-5-methyl. ..... 195. Pi 178-179 nitroso deriv................................. 124 6-amino-l-anilino-2-(~hydroxyphenyl) . . . . . . . . . . . . . . 177 4(or 7)-amino-5(or 6).ethoxy.kethyl. . . . . . . . . . . . . . 147 4(or 7)-amino-6(or 5).methoxy. . . . . . . . . . . . . . . . . . . . Pi 240 N-(p-methylphenylsulfonyl) deriv . . . . . . . . . . . . . . 248 5(or 6)-aminO-B(or 5).methoxy. .................... N-acetyl deriv. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310 4(0r 7)-[(2-diethylaminoethyI)amino~(or 5)methoryN-(pmethylphenylsulfonyl) deriv.............. 179-181 l-(%~ino9-bydroryphenyl)-2.S.dimethyl-, or 1.(2-runino4methylphenyl).5-hydroxy.%methyI. .... 248 N.O-discetylderiv............................ 243 1.(2-amin04hydroxyphenyl).5-methoxy.2.methyl. or l.(2amino-4-metholyphenyl)-5-hydroxy.2.methyl. ... 278 N.O-diacetyl deriv.............. 244 1-(2-amino4-methoxyph,henyl)-2.5-din1 l-(2-amino4methylphenyl)-5-methoxy-2-rnethylN-acetyl deriv................. 202 1.(2.amino4methoxyphenyl)-5-methoxy.2-methyI. . . 148 N-acetyl deriv............................... 236 2-(2aminoethyl)-5(or B)-ethoxy. . . . . . . . . . . . . . . . . . . . DiHCl251-252 19nilino-6-(0-hydroxybensylideneamino)-2-(0bydmxyphenyl). ........................... 242 nitroso deriv ................................. 125 2(3-butylguanidino).5.~~iIiii1etlloxy. . . . . . . . . . . . . . . . 116-120. Pi256. I>i HCl232 l.(rl-diethylaniiiitrl.iiiethyll,utyl)-t-iiietlioxy. . . . . . . . Pi 161 l.(edisthylaniiiicrl.in.thyl.ut.l).Diiietliox.. . . . . . . . ID$135 1’0 197 1-(edietbylamino-l-inrt~hglbnt~lf-~~~i~thox~~-% methyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Di Pi 198. Po 229

.

-

.

.

Reference No.

384 311 382 382 382 383 383

383 383 249 249 249 93 385 385 493 493 385 075 075 675 675 675 075 675 127 249 249 383 133

1:15

133

394

Systematic Survey and Bibliography Coiiipoiind

1-(4-dietliylaniino-l-methylhutyl)-R-methoxy-2methylbenzinlidamle......................... 1-[2.(diethylaiiiino)ethyl]-&tnethoxy- . . . . . . . . . . . . . . 4(nr 7)-[2-diethylatninwthyl(aminn)-G(or 5)-methoxy1-(2-diethylaminoetIiyl) IN-(ynietliylplienylnrilfonyl) deriv. ............. l-[.~(dietliylainino)~~rnpyl]-.5-~nethoxy-2-methyl-. ....

M:P., OC.

Referenw

Pi 192, Po 230 HCL 203

385

120 40, D i Pi 238-239 Pi 218-219

133

385 627.382

1-[3-(diethylaniino)propyl~-inethoxy-2-methyl-. .... 627 1-[3-(diethylamino)propyl ]+methoxy-2-(2-phenylDi HCC 234-236 627 vinyl)- ..................................... 1-[(3diethylaminopropyl)amino ]5(or 6)-methoxy-. .. 493 5(or 6)-[(3diethylaminopropyl)amino16(or 5)niethoxy- .................................. P i 206 483 l-(pdimethylaminophenyl)-6-ethoxy-............... 141-143 :150 l-(pdimethylaminophenyl)&thoxy-2-(o-hydroxypheny1)- .................................... 182-183 366 %guanidinob.%-dimethoxy-. ...................... 16.3. 383 HC1 HIO 285 2-guanidino-S(or 6)-1iiethoxy-...................... 203.P i 288-2658, 383 Di HCL 219-220 215, P i 278. 2-(3-isopropylgua1iidin0)-5.6-ditiicthox.v-.. . . . . . . . . 383 Di HCl. 244-246

-

2-(:3-iaopropylplrial,icliiio)-j(or 6)-ttietlinxy-.

.........

117-122

J’i 224-225, Di HCL 207 197- 19R

I -(p-iiietliylanilino)-0-(o-liydroxyplienyl)-.5-iiietli~~l-. .. diacetyl deriv.. .............................. 280 1-(2-amin&hydroxyphenyl)-chloro-Z.5-diniethyl-.or 1-(2-amino4-n~etliylpIienyl)-chloro-6liydroxy-2methyl-

-

I -(P-aniino-4-hydroxy~he1iyl)-cliloro-5-iiie~hoxy-~- 070 methyl-, or 1-~9amino-4-mct~n~~I,cnyl)-chlor1~~liy~lrox~-~methyl1-(4-diethyl~nino-l-1iictliyll~~1tyl)-~lil~~~~2-(~~ methoxyphenylb ............................ 1-(4-diethylamino-l-inctliylhutyl)-2-(pcliloropheiiyl)5-methoxp. ................................

G. Cyanobenzimldazoles l-cyano-Z(c.yaiioumitt~),)iisitiiidasole. . . . . . . . . . . . . . 2-(cyanoamitio)-................................. &(cyanoinethyl)-. ............................... 5(or 6)-(cyanometliyl)-. .......................... 5(or B)-(c?yanottietliyI)-~-iii~tliyl-. .................. 2-(pcyanophenyl)-. .............................. l-(m~anopheiiyl)-~-riicthyI-~~nil.ri~. ..............

-

-

209.7-210.7 158-150

%200

2cj BGO

No.

395

l3enzimiclaxolrs __ ....

... I__.._.._I_

.. . JI.".. OC .......

.............. Cniiiliniitrd

.

..............

__ --.. .-

Reference

.

No.

I3. BenzimidazolecarboxylicAcids

.

1

Monocarboxylic Acids

(a) Alkyl- and ArUlbentimidawlecarhozu~icAeiRe IncludinO Tho8e. Cdadning Atldirionnl Fiindional. Croups

I-benzirnidazolecarboxylicacid ethyl ester .................................. 2-hensirnid~olefarboxylicacid .................... ethylestar .................................. methyl eater ............................ arnide ......................................

........................

n-butylamide ................................ cyclohexylamido............................. dibutylarnide ....... ......... diethylamide ................................ dimethylamide ...............................

.............................

)arnide........................ (2-niethoxyethy1)amide....................... methylamide .......................... (4-morpholiny1)aniide......................... 1-methyl-..................................... 2-methyl-4(or 7)- ................................ Zethyl-S(or 6)ethyl eater .................................. 2-hexylethyl ester .................................. 7(or 4)-amino-2-methylb(or 6). .................... acetyl deriv................................. 5(or B)-chIoro-!& ................................. [3-(l-piperidyl)propyl] aniide.... 6(0r 5)-bromo-2-methyl-5(or 6)- ................... 6(or 5)-chloro-2-methyl- ........................ 6(or 5)-hydrory-2-methyl-4(or 7)- .................. $(or 5)-methoxy-2-rnethyl- ...................... 6(or 5)-(hydroxymethyl)-2-methyl-5(or 0) .lactone .... 7-ni tro-2-methyl-1-phenyl-5...................... 7(or 4)-nitro-2-methylb(or 6)-.....................

(a)

Carbozyclucyl.. Carhz&kan&.

.

107 Pi 178.

PC1 148

499

151.338 151 151 151 151 151 151 151

174 212.i-213.7 187.3 >300 172.4 180.5-181.5 269.5 101.2 124.5 223-224 210-211 219-220 138 246.5 181.2 98-99 >300

680 476

151

708.717

Hc1238-240

708.717 431

310 >375 159 173-174 323 324 dw 300-?50 300-305

.

. 289

805

151

151 151 151

151 151

151

431

166 166

287 288 238 229

406

433

431

and Carbozgar~lhcnn'midawlea

Zbensizuidasoleaaetic acid ........................ ethyl eater .................................. d d e ...................................... (2hydroxyethyl)aniide .......................

110 128.5-129.5 244-247 185-190

151 151 151

363

.

Systematic Survey m r l 13ibliogrnphy

306 ..

--.---I.---.

.. .

Conipound

%benrimidasolencetio wid (conid.) a-acetyl- ..................................... ethyleater .................................. anilide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-methylamide ...................................... 5(or G)-bensimidazoleacaticacid . . . . . ethyl ester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (2-hydroxyetliyl)a111ide ....................... Zniethyl- . . . . . . . . . ......... a.B.dipheny l..bensLnidazoleacrylic acid . . . . . . . . . . . ethyl &ter .................................. anilide...................................... &(2-bemimidamlylimolylimino) butyric acid . . . . . . . . . . . . . . 2-bendmidazolecorbamic acid ethyl ester................................... 2-[ (o-carboxyanilino)met~llbensimidaeole .................... methyl ester 2-[(pcarboxyanilino ...................

...

aridc . . . . . . . . . . ......................... ethyl ester . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . benzytidene hydraaide ....

M.P ‘C

Reference No

172.

281

128-129 255

281 281

239-240 HCL 240-242 65-66 160-162 218-219 186

629 363 363 363

HCL 290-291

. 278 >300

.

216

281. Pi 216

HCl268 150 248. Pi 210.

HCt 255 . . . 276. P i 224. HCt 283

.

2-[(pcerboxyariilino)methyl]b(or 6)-chlor+ ......... 237. P i 235 HQ 276 2-(2-carboxycyclohexyl)- .......................... 245-247 ethyl eater .................................. 163-164 2- [2-(2’-carboxy)diphenyl 1- ....................... 206-207 amide ...................................... 227 anilide........ 248 143 phcnylhydrazide............................. 157 2.(8-carboxy-l-naphthyl)- .... . . . . . . . . . . . 205-289 2-(&carboxy-l -naphthyl) -5(or . . . . . . . . . . . 278-275 2-(a-carboxyphenyl)- . . . . . . . . . . . . . . . . . . . 270 amide ................ . . . . . . . . . . . . . . . . . . 264 827 anilide................ 2-(o-carboxyphenyl)b(or G)-chloro- . . . . . . . 2-(o-carboxyphenyl)-5(or +methyl- . . . . . . . 2-(2-carboxy-3.4.5.~tetrachlorophenyl)-. . . . . . . . . . . . phenylhydraside............................. 2-(3-carbo~-l,2.2-trimethyicydoptyl). ... 2(3.carboxy-2.2.3-trimethylcyclopentyl)- ........... 2-(3-carboxy-l.2.2-trimethylcydopentyl )-5(or 6)methyl- ....................................

-

262 285 260-262 236 295 233 203

239-240

87 87 87 164

483

320

298

91

340 384.387

384 384

384 384 75 75 87 87 87 87 87 124 124 161.585

88 88

88 88

586.585

124

88 88

125 125

125

.

-

Benzimidaroles M.P.,

Compound

2-(3-carboxy-2.2,3-trimethylcyclopentyl)~(or 6)methylbensimidawle ............... B-(2-benaimidesolylaino)crotonic acid. ............ ~~-(2-bensirnidasolyl)-a,a-diethylmslonamic acid. . . . methyl eater. ............................... 6-(2-be~idawlyl)3,4-dihydroxy-2,&b~~rnethoxyphenyl)-2,4-pentadienoic acid y-lactone ................................... 5(2-bentimid~olyl)~,~ihydroxy-2,6aiphenylr-lactone ................................... 5-(2-bensimidaeolyl)-4-hydroxy-3-methoxy-2,~ diphenyl.y-laotone ....................... ........ 2-bensirnidazolepropionic acid. .................... ethyl ester. . . . . . . . . . . . . . . . . methyl ester ..................... amide ...................................... hydrtteide. . . . . . . . . . . . . . 5(or 6)-ethoxy-. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . methyl ester. ............................... amide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1,5,7-trimethyl-. ............................... l-methyl-2-benzirnid~olepyruvic wid ethyl ester. . . . . . . . . ...................... l-phenylethyl ester. .............................

N-1 p[~2-bensimidssolylrnethyl)amino]benaoyl}-DL methionine. .................................

2.

OC.

..

397 Reference No.

250-252 >300 214 I16

125

334

606

312

606

326 228.

606 537,127,75

HCI 236-237 137 144-145 259-260 288

181, HCl221 103 189 265-267

164 166 165

127

127 127

I27

1!27 127

I27 10

154-156

90

151-152.

96

195

384

Pi 185-186

Dicarboxylic Acids

2-benzirnidasolemalonic acid diethyl ester. ............................... 5,7(or 4.6)-dihydroxy-4,6(or 5,7)-bensimidaaoledicarboxylic acid diethyl eater. ............................... 6(or 5)-methoxy-2,4(or 2,7)-. ...................... N-(p[(2-bendrnidasolylrnethyl)amino~bensoyl]-.I glutamic acid (bendmidmole analogue of folio acid) ..................................... diethyl ester. ...............................

N- p [5(0r 6)-chloro-~benrimiolylmethyl)smino 1-

bensoyi 1-tglutamic acid. . . . . . . . . . . . . . . . . . . diethyl ester. ...............................

3'-I N-(2-ben.imidazolylmethyl) aulfanilyiJ-1-glutamio acid ......................................

218

279

131-132 290-295

429

167, HCl201

387,384 387.384

HCl 199-202 123, Pi 195, HCl219-220

384

125, Pi 179. RC1232

229

384

222

39s

Systematic Survey and Bibliography D1.P.. o c

Compound

.

.

Reference No

.

I Benzimidazolesulfonic Adds. Sulfdkyl.. and Sulfoarylbenzimidazoles

2-(paminophenyl)-l-phenyl-henaimidaaolesulfo1iic ncid ........................................ 1-benzimidazolesulfonicacid ....................... 2-benzirnidawleuulfonicacid ....................... 2-(rnethylsulfonyl)benzimidnzole................... 5(or G)-benzitiiidasolesulfonic acid amide ...................................... 2-methylatuide ...................................... d-a-methyl-2-bensimidawle$thaneuulfonic acid &a-methyl-2-ben~imidazoleGthanesdfonic acid ....... nba-methyl-2-benzimidazole6thanesulfonicacid . . . . . d-aethyl-2-henei111idasole1netlinnevulfonic ncid . . . . . . d-a-propyl- ................................... ur~a-ethyl-2-bnsiniida~olemetllanesuffonic acid ..... DL-a-ethylS(or 6)-rnethyl- ...................... nla-methyl- .................................. Dba-phenyi- .................................. nrpa.propyl. .................................. 5.[(pmt.thyl~ulfonyl)pheriyl]I~nzin.idazole ........

......

.

.

608

22 1-222 306 202

712 237 333

213-214

25

221

25 37

. . .

. . . I

>300

.

.

.

292 Pi 255

37

36 39

40

3938 38.39 35 107 40 114

J Benzimidazole Arsenicals

5(or 6)-[(3-u1ni11d-Iiydroxypllerl~l)nr~1io]hc1isimidazole ....................................... HCl 2Wl . . . . . . . . 277 5(or6)-artrono- .................................. 297 5(or 6)-arsono-2-aniino ........................... stc 210 5(or (i)-arxono-f3(or 5)-itt11ir10-2-111ethyl- . . . . . . . . ucetyl deriv................................. . 5-rraono-l-(crtrbamyl~nethyl),or . . . . . . . . . . . . . . . . . . . . O-arsono-l-(carbnmyImethyl)5(or 6)-arsono-2-(cnrbamy~met~iy~r11er~~~~~1)........ ... 5arsono-l-(carboxymethyl) or .................... 6-arsono-l-(carhoxyrnethyl)5(or 6)-araono-2-(cluboxymethylrneri.np.)......... . 5-rrsono-2,3dihydro-2-hydroxy -I ,2,btrimethyl-...... . >300 6-nrsono-1.2dimethyI-. ........................... 5(or 6)-arsono-2,7(or 2,4)-dimethyl- ................ . . 5(or 6)-srsono-2-ethyl- ................ 4(or 7)-arsono-%( 1-hydroxyethylb . . . . . . . . . . . . . . . . . . 5(or 6)-araono-2-( 1-hydroxyethyl) . . . . . . . . . . . . . . . . . . 5(or 6)-sreono-Z(I-hydroxyethyl)-l-phenyl- . . . . . . . . . _6(or 6)-anrono-2(3H)-bensimidaaolethione thiolacetmnide deriv.......................... 245 2,2’dithiobia[6(or 6)-araonobenzimidszoleJ.......... . 4(0r 7)-arsono-2-rnethyl-.......................... 280-282 275 6(or 6)-nrsono-2-methyl- ............ 5(or 6)-arsono-7(or 4)-methyl- ..................... 300 5(or 6)-arsono-2-methyl-6(or 6)-nitm- .............. >300 5-arsono-%methyl-l-phenyl, , ........... .

.

I

-

.... ......

241

538

01,538,235.2s

650 540

540 239

237 239 237.338 541 941 01 538

538

538

539 236,236.2dX 237 237

538

61.538.539 61 540

639.50

399

Rensimidnzolcs Conipound

S-armno-1-phenylbensimidamle .................... 5(or 8)-amono.2-Sulfo- ............................ s(or 8).thiosrso-2(3H).benzimidarolethione ......... 4.4‘(or 7.7’).arsenobisbensimidamle . . . . . . . . . . . . . . . . 5.5’(or 6.8’).ar~enobis- ............................ 5.5’(or 8.6’).arsenobia(l.(carbamylmethyl). ......... 5.5’(or 6.6’)-8raenobis[2-(carbamylmethylmereapto) . 5.5’(or 6.6’).arasnobh [l-oarboxymethyl) ............ 5.5’(or 8.8’).areenobia[2-(carboxyniethylmer.pto). .. 6.6’(or 6.8’).~rsenobia[2. 7(or 2.4)dimethyl. ......... 5.5‘(or 6.8’)-araenobis[2(3H)-bensimidazolethione J ... 4.4’(or 7.7’).arsenobia(2-methyl. ................... 5.5’(or 6.6’).arsenobis(2-methyl. ................... 5.5’(or 6.8’).arsenobis[7(or 4).methyl. .............. 5.5’(or 8.8’).areenobis(2-aulfo- ..................... 5.5’kmenobie[2(3H).benrimidaaofone J .............. 2(3R)-bensimidazolone-5-arainic acid ............... 2(3H)-bensimidasoloneb-arsonous acid ............

.

R1.P .. oc.

Reference No.

. .

539 237 235,236.238 538 81.538 239 237 239 237

. .

.

. . . . .

.

_ _ _ I

61

. . .

2.35 538 01.538 81 237

. . .

.

235

235 199

.

.

K 2.3.Mhydrobenzimidazoles (Benzimidazolines) 2.3dihydro-l.3-dimethyl.2-phenylbensimidasole

.

2.9-dihydmSmethoxy

.....

1-(p-methylphenylsulfonyljderiv............... 5.5‘-oxybia[6(2.3dihydro-5,&dimethyl-2-ctllylS propyl-l-bensimid~ly1)barbituricacid]........ 5.S8-oxybis [5-(2.3dihydro-3-methyl-l-bensimidaroly1)-..................................... 5.5‘-oxybia[S-(2,3-dihydro-2,5,&trimethyl-l-ben~ imidssolyl ...............................

.

95-96

398

119-120

226

384-388

587

365

588.587

348

587

L Heteroring- Substituted Benzimidnzoles

. Furan Derivatives

1

2.(2-furyl)benximidaole .......................... 4,5,8.7-tetrahydroderiv.......................

288-290

290-300.

P i BO-225 ............................. 56 2-(2-furyl).l.methyl. 2.(2.fury1).5-methyl.l.(p-methylanilino). ........... 227

.

2

714 250

Thiophene Derivatives

2-(2-thienyl)bensimidazole ........................ >280 2.6di-2-bensimidszo1y1-3.4-dibromothiophene. ...... 385

115 648

3. Pyrrole Deriwtive

.

2-[2-(2.5-dimethyl-l-phenyl-3-pyrryl)vinylEl 3diethylbensimidssolium iodide................. 238-238

4

338.708.717 718

. Pyrawle Derivative

4.(2.bensimidazolyl)-3-methyl.l.phenyl.6pyramlone

.

.

172-173 HCl 2U3-2R4

100

2U1

400

Systematic Survey and Bibliography Compound

M.P.. "C.

Reference No.

5. Pyrjdine Derivatives k(2-carboxy-3-pyridyl)henaimidarole ............... a i d e. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . adide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

246-247 260-268 316317

2-(3-pyridyl)-.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

310, HCL 296-298

-

88 88 88 88 426,426 425,88,552,426

6. Piperidine Derivatives 2-[1-(1-piperidyl)cthyljbenaimidazole.. . . . . . . . . . . . . . l-(l-piperid~lrnothyI)-.. . . . . . . . . . . . . . . . . . . . . . . . . 2-(1-pipridyln~etliyl)-.. . . . . . . . . . . . . . . . . . . . .

167-167.2 91.s-92.5

683 33 340,11,92

D i HC1204-206 Z(l-pipridylmethy1)5(orO)-chloro-.. . . . . . . . . . 103-104, 645,311 D i HC1>250, HCl24Q-251

7. Morpholine Derivatives 2-[t-(4-morpholinyl)ethylJl~n~i1niclnm~lc . . . . . . . . . . . . 196.8-197 583 1-(4-rnorpholinyImethyI)-.. . . . . . . . . . . . . . . . . . . . . . . 110.5-111.5 33 2-(4-morpholinyl1netIiyl)-......................... 2 11. 340.92 D i HCL 194-196

8. Xanthyl Derivatives I-(9-~anthyl)-2(3H)-benzimidazolone.. . 1,3-di-9-xanthyl-. ................................ f183-286 1-(9-xanthyl-2(3H)-benzimid~olcthio11e.. . . . . . . . . . . 952-254 -262 l$-di-!&xrmthyl-.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

471 471 471 471

9. Phthalide Derivative 3-(l-phenyl-2-benaimidnsolylnicthylene)phthulide., . . 380-281

96

10. Zndane and Zndole Derivatives 2-[2(3H)-hensimidazolylideno~1.3-indanedior1c. . . . . . >350, N i 184 3-(a-2-henaimid~olylbnzylidene)oxindole.. . . . . . . . . 204 3-(2-bcn~imidazolylmethylene)oxindole.. . . . . . . . . . . . >350

889 089

889

11. Quinolme Derivatives 2-(2,Pdimethyl-3quinolyl)biizimidasole.. . . . . . . . . . 328-330, P i 260. HCL >a00 2-(2hydroxy4rnethykulfo-3-quinolyl)-.. . . . . . . . . . . 29.3-295, HCZ >310

281

281

12. Bendhazepine Derivative 3-(Zbenairnidazolyl)-2.4-diinetIi~~l-I.&benzodinzepine.

>310. HCl > N O

281

Benzimidszoles

401 M.P..

Compound

OC.

Reference No.

13. Acenaphthene Derivative 2-(2-bensimidasolylmethylene)-l-aoenaphthenone. ... 295

M. Bi-, Di-, and Bisbenzimidazoles

2,2'-bibenrimidasole.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1,4-di-2-benzimidasolyE2,3-butanedione. ............ a-di-2-bensimidasdylthiourea..................... 1 , l '-benaylidenebs(2-~~lbensylbonsimidasole) ......... 2.2'-ethyleneb~benrimidesole..................... 2,2'-heptsmethylens.. . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2'-hexamethylens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2,2'-(iminodiethylidene)-. .. 5.5'-isopropylidenebia(2-methylbenzimidasole). ...... 2,2'-(1nethyliminodiethylidene)bis~nzimidazole.. . . . . 2,2'-octamethyIene-. . . . . . . . . . . . . . . . . . . . . . . .

...

2,2'-pntamethylene-.

...

.......

2,2'+phenylen@bensimidasole. . . . . . . . . . . . . . . . . 2,2'-pphenylene-. .......................... ... 2,2'-tetramethylenebinziniiclazole.. . . . . . . . . . . . . . . 2,2'-trimethylene-. . . . . . . . . .

...

-

>300 208 171 325-330. Di HCC 312-315 273-275, Di HCl269-272 203-266, Di HCl290-299 206.8-210.2, Di HCl230-270 225 205.1-205.0, Di HCC 234-231 277-279, L% HC1263-285 225-226, Di HC1270-272 412 >300 259-260, Di HCt 305-309 258-259, Di HCl270-273, Di methhdide 228

2-[3-(1,3-diethyl-2(3t-benaimidazolylidene)prop n y l ) - 1 , 3 d i e t h y l b s i ~ diodide. ~ ~ ~ . . . . 278-280 2- [3-(1,3-dimethyl%(3s)-benrimida~~~dene)(l-methyI-2-bonximida~olyl)isobutenylj1,3-dimethyl-3-benaimidamlium iodide..... ... 230 2- [3-(1,3-dimethyl-2(3H)-hensimidasolylidene)propeqyl~1,3-dimethylbensimidaioliumiodide...... 303

689 162

280 185 631

625

625 625 583 696

583

625 625 550

646 625 625,390

100

504

504,505

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634. Smitli, L. I., ant1 Grlsn, C . O.,J . A I N .Cltrrti. Svc. (2,2035-8 (1940). 635. Smith, L. I., and Harris, S. A., JhiJ. 57, 1289-92 (1935). 636. Smith, L. I., and Kiess, M. A.. h i t l . (if, 284-8 (1939). 637. Smith, L. I., and Moylc, C. L.,ibid. 68, 1-10 (1936). 638. Smorodinsev, I. A., Rws. Phu.uM1. J. 9, 285.97 (1919); Chcm. Abslracts 16, 2040. 639.Sonn, A., and Urcif, P., Uer. 63,l(900-3 (1033). 640. Sonn, A, Hoteu, E., and Sieg. H., ihicl. 67, 953-9, 2134 (1924). 641. Soper, Q. I?., Whitehead, C. W., Behrens, 0. K., Corse, J. J., find Jones, R. G., J. Am. Chem. SOC.70, 2849-55 (1948). 642. Spiith, E., and Kunz, E., Brr. &', 513-18 (1E5). 643. Stauble, M., Hclv. Chim. Acla 30,224-31 (1047). 644. Stiiuble, M., &id. $2, 135-45 (1949). 645. Stank, 15. A., Nai*Iiod, I?. C., ICwing, Ci. W.,and Gorrnnn, N. H., J. Am. Chcm. Sor. 10, 3406-10 (1948). 646. Steinkoyf, W., TAtsiiiunn, K.,Miillor, -4. H., and Wilhclm, H., Ann. 641, 260-82 (1939). 047. Stepticn, H. W.,:mil Wilson. V. J.. J . C/cc.ttr.Sor. 1.926, 2531-8. 648. Stephens, I?. F., and Bowcr, J. D., ibid. 1949, 2971-2. 049. Stclvart, C. Y..Ijittc.lt(,ttt. 17, 130-3 (1923). 650. Stickings, It. W. IC., J . Clrritc. Stw. I!/.%, 3131-4. 651. Stolle, It., Merkle, bl., and H;inuscli, F. J., J. prnbl. Chcm. 1.40, 59-64 (1931). 6,52. Strain, H. H., J. A w . C l t c t t t . Sot!. .$!I, 1558 (1027). G53. Strain, H. H., i l d . $9, 1995-2000 (1927). 654. Strain, H. H., ibid. 52, 1216-19 (1930). 655. Stumyf, P. I<.,and Green, D. E.. J . Bud. Chciri. fZ3,387-!N (1944). 656. Swain, G., J. Chem. SOC.1948, 15524. 657. Tabor, H., and Mosettig, E., J. Biol. Chem. lS0, 703-8 (1949). 658. Tamamushi, T., J. Phamz. SOC.Japan 53, 379-85 (1933); Chcm. AhsLrrtc1.q LV, 3934. 659. Tumamnslii, Y., ibid. dS, 851-63 (1928) ; Ckern. Abslrucls 2.3, 1639. 660. Turnainiulii, Y., ihirl. .$S. 863-8 (1928) ; C/ic!m. Abslrcictx 23, 1472. Ml. T:iinaniushi, Y., i b d . 5.j. .%O-r32 (1!)33); Chc*ur.Abdlnelx 18, 150. 662. Titmaniurlii, Y . . iM.5 4 664-8 (l!M) ; Ckcm. AhzLrcccb 28, 2004. 003. Tamnmuslii, Y., ibul. 5 4 765-75 (1933) ; Chcwi. AIizL~rrclxM.3406. 604.Tamamushi, Y.,ibicl. 63, 1080-8 (1933); Chem. Abslrcrcla 99,7328. 665. Tamamushi, Y., ibid. 66, 1053-60 (1935); Chem. Zenlr. 2.936, I, 2547; Cirvttt. Abstracts $1, 8654. 660. T:initimiishi, Y., ihid. 67, 1023-8 (1937) ; Chem. Abslracts 32, 3394. 667. l':tinnmushi, Y., ibid. 60, 184-8 (1940); Ckem. Abstracts 3.$,5447. 668. Taimmushi, Y., ibid. 60, 189-91 (1940); Chem. Ahxlrnclx Jj, 5446. 669. Ttiiiiiiniu~hi,Y., and Nngarrilwa, H., ibid. /i0, 12732 (1940) ; Ckmti. Abxt,nc/s 34, 5081. 070. T:inret, G., Compl. rend. 174, 827-30 (1922). 071. Tazawa, Y., Enzymnlngia 7, r21-4 (1939). 672. Tilford, C. H., van Campcn, %I. C.. Jr., and Slielton, R. S., J . Am. Cirrr. Soc. 72, 1885 (1949). 673. Todd, A. R., Bergel, F., and I.iariinullah, .4.. Ber. 69, 217-23 (1936). 674. Todd, A. R..:ind Whittuker, N., J. Clwnz. &w. 18,$(2,628-33. 675. Toiiilinuoii, M . I,., ibkl. 1M9, 158-03. a/.

Uibl iogrsphy

410

676. Triiger, J., snd Thomas, H., J. prakt. Chem. 110, 42-63 (19'25). 677. Turner, R.J., J. Am. Chem. Soc. 70, 3523 (1948). 678. Turner, R. A., ibid. 71,34768 (1949). 679. Turner, R. A., Huebner, C. F., and &hole, C. R., ibz'd. 71, 2801-3 (1919). 680. Usherwood, E.H., and Whitely, M . A., J. Chem. Sac. 1-94 106%8!l (1%3). 681. van Allen, J. A,, J. Am. Chem. SOC.69, 2913-14 (1947). 682. van Alphen, J., Rec. trav. chim. 64, 93-6 (1935). 683. van Alphen, J., &id. 66, 41218 (1936). 684. van Alphen, J., W.66, 869-74 (1938). 685. van Alphen, J., a i d . 66,835-40 (1938). 686. van Alphen, J., ibid. 66, 343-60 (1937). (1938). 687. van AIphen, J, &id. Sr, -76 688. van Alphen, J., ibid. 68,644-9 (1939). 889. van Alphen, J., ibid. 69, -97 (1940). 690. van der Merwe, P., 2.physiot. Chem. 177,301-14 (1928). 691. van der Want, G. M., Rec. trav. chinr. 67,45-51 (1948). 692. van Romburgh, P., and Huyser, H. W.,ibid. 49, 165-76 (1930). 6(W. van Romburgh, P., and Huyser, H. W., Verslag Akad. Wetenschappetr Anrsterdam 36, 665-70 (1926). 694. von Auwers, K., and Frese, E., Ber. 69, 539-55 (1926). 695. von Auwers, K.,and M a w , W., &id. 61, 2411-20 (1928). 696. von Braun, J., Anton, E., Haensel, W., Irmisch, G.,Michselis, R., and Teuffert, W., Ann. M)7,14-36 (1933). 697. von Euler, H.,EEarrer, P.,Malmberg, M.,Schopp, K.,Bene, F., Becker, B.. nntl Frei P.,Helv. Chim. A d a IS, 52235 (1935). 698. Wachamuth, H,, Natuwto. Tijdschr. a6, 71-81 (1943); Chem. Zentr. 1943, 11, 661; Chem. Abstracts 38, 4384. 699. Wads, M, Biochem. Z.260,47 (1933). 700. Waper, E.C.,J. Org. Chem. 6, 133-41 (1940). 701. Wddmann, E.,Chwala, A, and Martinn, A., Ber. 75, 1763-6 (1941). 702. Walker, J., J. Chen. SOC.1849,347-53. 703, Walker, J, &id. 19@, 1998-2002. 704. Wanags, G., and Veinbergs, A., Ber. 76, 1558-69 (1942). 705. Waaer, E.,and Gratsos, A., Helv. Chim. Acla 11, 944-64 (1928). 706. Waterman, H.C., and Vivian, D. L., J . Org. Chem. 14, 289-97 (1949). 707. Waugh, R. C , Ekeley, J. B.,and Roneio, A. R., 1. Am. Chem. SOC.6.$,2028-31 (1942). 708. Weidenbagen, R., Ber. 6D, 2303-72 (1938). 709. Weidenhagen, R.,and H m a n n , R., ibid. 6S, 1953-01 (1935). 710. Weidenhagen, R.,and Herrmann, R., i l d . 68, 2205-9 (1936). 111. Weidenhagen, R., and Herrmann, R., 2. Wirtschajtsgruppe Zuckerind. S6, 126. 30 (1935); Chem. Abstmcts 99, 7327. 712. Weidenhagen, R.,Herrmann, R., and Wegner, H., Ber. 70, 570-83 (1937). 713. Weidenlingen, R.,and Rieniicker, H. &id. 79, 57-67 (1939). 714. Weidenhagen, R.,Train, G., Wegner. H.,and Nonlstrijrn, L., ibid. 76, 1936-48 ( 1942). 715. Weidenhagen, R., and Wegner, H.,&id. 70,2304-18 (1937). 716. Weidenhagen, R.,and Wegner, H., i!kZ. 71, 2124-34 (1938). rl7. Weidenhagen, R., and Wegner. H., 2. TVirtschajt.qgruppe Zecckerind. 87, Tech. TI.,755-77 (1937); Clienr. Abstracts 32, 8416.

43

Systematic Survcy find Bibliography

718. Weil,S., and Mnrcinkowskn, H., Rocziriki Cheni. Id, 1312-19 (1934); Chewt. ADstraclx ¶?$ 69233. 719. Went, I., and Kesztyus, L.,Orvosolc Lapju NEpEycxzxe'yiigU 8, 257-87 (1946); Cheni. AbslmcL~42, 3062. 720. William,D.L.,and Ronsio, A. R., J . Am. Cken. Soc. SS, 647-9 (1946). 721. Williariis, I ) . I,. Syintmls, I,.. Ekt!h?y,J. IS., stid Ronxia, A. It., it&!. 07, 1157-9 (1945). 722. Williainsw, 8.W.,:md Mcldriiiii, X. U., U i i d w t t r . J . M ,815-16 (1932). 723. Wilson, F.J., Baird, W., Burns, It., Munro, A. M. rind Stephen H. W., J . Hoy. Tech. Coll. Glasgow 9, KO.1, 56-61 (19N); Cketti. Abslrucls 23, 5104. 724. Winam,C.I?., and Adkins, H.,J . Atn. Clicm. Soc. 6.5,2051-8 (1933). 725. Winam, C. I?., a n t 1 Adkins, € &id. I., 65,4167-76 (1933). 5%. Wind:ius, ti., nntl Langenbeck, W., B c r . 55, 3706-9 (1022). 727. Windaus, A.. and Langenbcck, W.,ibid. 6ri, 683-6 (1'323). 728. Wood, D.,Jr., :inti RerqLroin, F. W.,J . A.m. Chsnt. SUC. 55, 3314-18 (1933). 729. Wood, J. I,., ant1 du Vigneautl,V., &id. ri7, 210-12 (1945). 730. Wrctlc, P.. : r i d IIolLr, l'., Arch. 01:s.Z%pi*iol. (Pjliigers) 2.34, 4324 (1934); Clwllt. Absbi'ucla 28, 5477. 731. \+'right., J. I%.. J . Am. Chcttr. S I X . 71, 2W5-7 (KM9). 732. l\'iirtzcw. V., Ihttxk 'I'uls. I ~ I I ~ ~Id, I I L160-9 (193!3) ; Ck.uw. Ali.drncL3 33, 7958. i33. Wiiyls. H.,:iricl \.:in V:i(w:nIit~rgli, J., Birll. s ~ r chitti. . Brlg. .jS,3-9 (1939); Chtwi. A k d r ~ l Y..!,~ l9S1. 734. Y:iltiiI;l. .'l' : I I I C ~I<:iiill1t~, I<., Ilitll. A!/#..Ckcltb. NOC. Jtl/>(tn,i, 74-5 (1928); C ~ C I ~ . AiJslrtrrls g.j, 3509. 735. Y:ilnit:i. T..aiitl 1<:111iIii!, I<.. i i d . S, Slfi-tW, (l!W!) ; Ckctt~.rlbxlrncls m,1882. 736. Yllnw, C . A., Arkiv. K I , I I IJ .l d t t o d . acol. 9, KO.41, 20 pp.; Clieiti. Abslrucla Z.9, 11'.

589.

737. Podiitoiiii, E.,Miy:in:ig:i, I<.. RIM^ M:ig:ie, S., J . P h i f i t t i . SIN:.Jrcpan 627, 5-11 (1926); Clictti. Abal~*/tc:l.u 20, 2826. i38. Z:ililav6. I,,* Collcclirm Czcdttasluv. Choti. C I ~ I I I 9, ~ I10s-11 I ~ . (1930); Chem. ADslrucls 9.$,2431. 539. Zeeliiiism, l€.,Arck. cap. 1'11th. 1'ltrtt-n~. Sli, 342-72 (1920); Ckwi. Abstracts 16. 411. 740. Zeile, I<., ;I1111 UcLZcl, M., %. phyxiol. Ckt~ttc.s.;, 1-19 (1949). 741. Zeile, I<.. :inJ Piutti, P., d i d . ,913, 5244 (1933). 742. Zienty, I?. K,J . A.m. Ckoti. Soc. 67, 1133-40 0945). 743. Zient.y,It'. IS., ibL1. GS, 1388-9 (1046). 744. Zicnty, I?. I{.? :inti Thiclkc, It. C., &id. (i7, 1040-1 (1M5).

SUBJECT INDEX Index references arc to the text and to the general heads of the Systematic Survey and Bibliography. Individual compounds should also be sought in t,he nppropriate section of the Gystcmatie Survey. A Acetaldehyde, effect on carbohydrate synthesis of imidazoles, 40 reaction with methylglyoxal and ammonia, 34 4(or 5)-AcetarnidoimidazoIc, 142, 143 l-(p-AcetamidophenyhIfonyl)-2-hydroxy-2-methylimidazolidine, 222 Acetic anhydride, action on imidneole, 48 action on imidazolones, 68 Acetoin, reaction with ammonincnl CIIprous acetate and aldehydes, 39 Acctoxyacetone, reaction with ammoniaesl cuprous acetate and formaldchyde, 30 2-Acetoxy-2-chloromethyl-l,3-dinitroimidazolidone, 220 a-Acetoxyketones, reaction with ammoniacal cuprous acetate, 38 Acetylation of aminoimidazoles, 141-143 of histidine, 201 of 2(3R)-imidazolones, 68 1-Acetylbemimidazole, 273 N-Acetylhistamine, pharmacological properties, 166 synthesis, 165 N-Acetylhistidine, 201 2-Acetylmerclapto-4(or 5)-methylimidazole, 84 4(or 5)-.4cetylb (or 4)-methylimidasoIe, 60 Acid anhydrides, in benzimidaeole syntheses, 203 reaction with benzimidazole, 273 Acid-imidazoline complexes, 215 Acidity of b i m i d a r o l e s , 249 and electron distribution, 20 of histidine, 199 of imidasole, 15, 19 of 2(3R)-imidazolones, 62 of 4(6H)(or 5(4~))-imidnzolonrs,98 of iodoimidazoles, 123

of nitroiniidazoles, 131

of phenylimidrzoles, 46

of 2.4,5-tribromoimidnzole, 117 At-ids, effect on hydrogenated imidazoles, 24

cffect on imidazoles, 16 .kylaldehyde, reaction with b e n d and ammonia, 34 Acylation (see also Friedel-Crafts acylation) of aminoimitinzoles, 141 of beneimidiizoles, 273 of 2(3H)-henzimidazolone, 290 of histamine, 155 of histidine, 200 of imidazolc, 17, 47 of 2(3H)-imidazolethiones, 86 of 2-imidazolines, 221 of imidaeolonee, 62, 68 of oxbenzimidazole, 285 .4cyloins, reoction with ammoniwal CIIpric acetate and aldehydes, 39 reaction with urea, 85 Aggregation, 7-10, 25, 249 Air, effect on lophine solution, 11 Alacreatinine, 140 p-Alanyl-1-methylhistidine,see Anserine Aldaric wids, 300 Aldarodibentimidazoles, 300 Aldehydes in beneimidaeole syntheses, 267 reaction with a-nminonitriles, 43 reaction with henzamidineglyoxd. 94 reaction with glyoxal and ammonia, 34 reaction with histamine, 166 reaction with histidine, 205 reaction with u-hydroxy-ketones and ammoniacal cupric acetate, 38 reaction with 2-methylbensimidaeoles, 276 Aldehydines, 267 .\ldobenzimir?aeolrs,291 oxidation. B8,3 0 . 314

431

422

Subject Index

.\Idol vnndensatinn,

M A Idooyolylipdroxyalkyl)hcnzitiiicliizol(.e,

297 .\lkyl:itiom of bnriinidiizoles, 2557, 279 of imidazole, 17, 40 of imitlaeoles, 29 of 2(3N)-imidaeolethiones, 86 rd %iniidazolidinethiones, 238 of 2-iinidazolines, 223 of imidaeolonea, 69 Alkglimidaeolee. 33-54 I-Alkyl-5-imidazolecarboxaldehydes, 58. 204 2-S-AIkglme~c~aptoimirlnxnlrs. 63 .\llodesthiobiotin, 232 ~-Allylhenzimidaeole,251 Amarine, c.hemiluminesc.enre, 13 dehydrogenation. 42 osidation, 42 synthesis. 44 .imrironc, 36 Amidcs in Iwnziiniclnxolr synthmw. 261 .2midinrs. intrrmrdi:itc.s in formation of bensimidazolep, 266 intermediates in formation of 2-imid:izolinea, 216 rowtion with a-amino ostrrs, 93 Amidine resonance, 23, 220 Amidine system, 22 “Aminr 220,” 225 ?\ininnar~tal.wartion with cyanate, 65 irnration with thiocynnnte, 79 a-Aminoaldrliydrs. rcnrtinn with cgnnnte. 63 reaction with thiocyamte, 80 2-Amin&(nr 5)-(pnminophenyl)imidaeole, synthesis, 140 Aminobenzimidasales. survey, 389 2-Aminobenzimidazoles, 3O!l hnsirit-g, 251 chlorination. 301 4(or 7)-Aminobensimidazole. 308 5(or 6)-Aminohenzimidarole, beaicity, 261 henzoylstion, 276 complex salts of, 308 synthesis, 308 5-Amino-2(3H)-beniimidasolone, 289

a-Amma-l-bensoyn>waimidaz~le.310 ordminobenzyl cyanide, reartion with henmidehyae, n,43

l ( o r . ~ ) - ( ~ - A ~ i ~ i i t i ~ l ~ i i t y I ) i i i i i1sFi d~ole, 5-.~1nin~4-anrhothox~-I-iiirth~I-2(3H)iriiidaxolrt.tiinnr, 81 3-.\1iii1i~4~~~11.hc~s:ciiiitltr I-iiwt liy1-2(3N )imidnzolethione, 84 2-Amino-4,5-dimethglimidAzolo, 141 4Amino-lb-dimethylimidnzole, 143 5-Amino-1,4-dimethylimidazole, 143 a-Amino esters, reaction with amidincs 93 ~-(P-Aminoctlipl)henzinridnzole, 311 142-Aminnct hy1)-2-hephtIcr.$.l-2-imidaxoline. 225 4(or S)-(2-Amin~.11iy1)-2(311)-imidazolethinnc. rre 2-Mrrc.nptoliistnmine l-(Z.4niinoctIiyl)imidnralr. pharniac:ological properties. 167 bynt hrsis, 1.58 ?-(2-rZminocthyl)imitlrtxnle, pharmacological prolwrtics. 167 synthesis. 159 4(or 5)-(2-;\minoeth~l)imidarole,see Histrlminr 4(or .5)-(2.4minorthyl)-2~3H)-imidazolctliinne, I67 4-(2-.4minoethyl) -1-rnethylimidazole, pharmacological properties, 167 cynt heplis, 161 4(nr fi)-(%Aminnethyl)-2-methylirnitl axnle. 160 4(nr 5)-(2-Aminoethyl)b(nr 4)-mcthylimidnzole, phmnncolngicd prnpertips. 167 synthesis, 161

.~(2-Aminoethyl)-l-m~tli~limid~ole, phrnnacological prnperties, 167 synthesiS, 160 .4minoimidazole~,nirvev. 347 ZAminoimidnnole. 140, 141 4(or 5~-.r\minaimidamles.142 Nor 5)-Aminob(ar 4)-imidarole?carhoxamiden, conversion to purines, 182 detertion, 138 nrriimnre and WtheRis, 179 4(or 5)-AminoS(or rl)-irnidaxolecmboxvlic acids, 179 a-Amind(or 5)-imidazolepropionic acid. W P HiRtidine .5-Amino-2(3U)-imidniolethion~, rrt %Amino-2-imidarolines, 238

Subject Iiidex

4!Li

reaction with benzoin, 30 reactim with desylamides, 35, 37 reaction with diacetyl, 36 reaction with oxaaoles, 27, 43 reaction with oxazolones, 95 63 reaction with iniino ethers. 43 reaction with sugars, 39 .41nmonium base of LI benzimidazole, 281 reaction with thiocyanatc, 79 2-.4minomethylbenzimidazoles, synthesis, Amphoteric character of benzimidaaoles, 310 249 bdmino-1-niethylbenzimidazolc. 252 and electron distribution, 250, 252 3 0 1 . 6)-Amino-2-methylbcnzimidrzole, of imidaaoles, 15, 43 of 4(5H) (or 5(4H) )-imidazolones, 98 synthesis. 258. 308 4(or 5)-Aminomethylirnidrzole, p1inrin:iof iodoimidazoles, 123 c*ologic*ulpropertics, 168 1-Amylimidazole, 6 ZAmylimidazole, 44 *yntlieuis, 88. 164 4(or 5)-Aniino-5(or 4)-i11ethylimidazolu, 2-Amyloxazole-4-carbo.\ylic acid, reaction 143 with ammonia. 44 Analysis of imidaxoles, 139 5(or 6)-Amino-2-methylbenzimidazolc. 252 2 4 1',4'-Anhydropolgiiydroxyallryl) benzimidazoles, 299 4-Amino-l-methyl-5-imidazolecarbos?-dnilino-5(or 6)-nitrobenzimidasole, 303 amide, 182 2-(o-Anisylaeo)imidirzole. 137 4(or S)-Arninomethyl-2(3H)-imidazole2-~.~nisyl-4~iplienylimidazole, 13 thione, desulfurieation, 102, 164 Antmine, 203 reaction with nitric acid. 88,151 qyntlicsis nntl desulfiirizution, 151, 164 ,htiliist~~minics, 1%. 226 5-.~111ino-l-iiw tliyl-2(311 )-imidrzoleAntistine, 226 tliione, spwtruiii. 84 Antithyroid activity of 2(3H)-imidazolesynthesis, 82 tliiones. 89 ~i-Aiiiino-l-metliyl-2(3N)-imidazolc1-~-A~:ibity1-2,6-dirnethylbenzimida~ole, thionecarboxamide, 85 296 4 (or 5)-Am home thyl-2 (3H)-irnidazglone, 4 (01. 5)-(D-AmbinO- tetra hydroWbuty1)imidazole, 104 64 Aromatic character of henzimidrzoles, 254 5-Amino-l-methpl-%me thylmercapto-4imidazolecarboxamide, 183 of imidazolea, 16. 19 5-.4mino-l-methyl-4-nitroimidaaolc, 120 .\romatic substitution, 17 a-Arninonitriles, reaction with aldehydes, Arsenicals, mrvcy. 363, 398 Arylazoimidazoles, 136-141 43 2-.4minoS(or 6)-nitrobenzimidazole, 303 survey, 346 ,\rylimidazoles. 33-54 hinonitro-%imidazolines, 241 a-.4minopl1enylacetonitrile,reaction with .hociation of benzimidazolcs, 248 of imidasoles, 7. 19. 26 henmldehyde, Z.43 2-(o-Aminophenyl)benzimidazole, associeffect of concentration on, 9 ation. 25 and tautomerism, 28 syntlicsis, 312 and viscosity, 10 4 (or 5) 3-Aminopropyl )im idaaole. 165 .4slw~tone-imidaeoloneconversion, 95 .j-.4rninotliiazoles, reaction with alkali. 82 .\zlwtone synthesis of hiRtidine, 196 Amtnoniac;rl c*upriravetab, reiwtion with .\zu mupliiy, 136-141 (rec uho Pmily a-hyiroxyketones. 38 Ivst) Ammoni:r, reaction with aldehydes, 33 ;\zolcs. aromatic character, 10 rcnrtion with bend. 35 dipole moments, 22 a-Amino-p-ketoesters, reaction with cyanate, 83 reaction with thiocyanate, 81 a-Aminoketones, reaction with cyanate,

-

Azoles (continued) :

acylation, 273 aikylation, 2i9 basicity, 251 B dipole moment, 10 1Jumbergcr reaction, 48, 273 hydrogenation. 16 Basicity of benrimidazoles, 249, 251 idination, 302 of histidine, 199 nitration, 304 of imidazoles, 13, 15, 46 oxidation, 19 and symmetry of iinidtrzoli~rin ion, properties, 254 23 sdts, 249 of iluiduzolinium ion, 220 srilfonation, 317 of nitroimidazoles. 131 survey, 379 of tertiary nitrogen, 21 syntllesis, 258 13cnxaldehytle, reaction wii Ii a-:uninotautomerism, 255 bcnzyl ryanidc, 27. 13 ultraviolct absorption spectra, 263 rcaction with b e n d :ind :in1nioniii, 33 i3enzimidazole rule, 300 wiction with o-lr~iIlos~;ic~c~~opiii~nonc 2-Bensimidazoleacetic acid, 315 and :ttnmonia. 25 2-Benzimidmolecarboxamide, 315 reaction with 4(5N) (or B ( 4 t l ) biiiiiilBt.nsimidneoIecarboxyiic acids, 313 aeolones. !)8 survey, 395 reartion wit 11 tri1.l Iiyliiil r ~ ~ i ~ ~ ~ i ~ l : i z o2-l~eneimida~olec~irltosyiic it~s, acid, syn132-134 thesis, 297, 298, 314 reaction \villi r ~ - ~ ~ l ~ c ~ ~ i ~ l ~ ~ n c26; ~ t l i : i4(or i i i i i7)-lh~1rsirtiicl:izolec:1rl~oxylic i~~. acid, 313 I3enzaniidine, reaction with benzoin, 43 $(or 6)-~i~rrzii11itlaaolecnrhosylic acid, 313 acids, survey, reaction with o-bronioacetophenone, 25 I~r~izi~i~iti:i~i~lc~~ii~~:ut,o.uqrli~~ reaction with diacelyl, 101 397 reaction with etliylphenylpropiolate, 93 ?$(or 2,~)-~~~nziinidnzolcdicarboxylic reaction with a-hnlogenoketones, 43 :wid, 313 reartion with methylglpoxal, 93 t,5(or (1.7)-~cnziniid:izolctlicarbo~~c nenzamidine-~lyox;~I,(34 ncid, 313 4 (or 5)-lknm i t i i I~t ii niidazolc. 143 2-lk?iisiii1iduzoledisulfidc,Y32 a-lJmr:iiiiidit-I(~irR)-itiiitl:iroIc~:icrylia I~riizinii~l:ixolcinagnesiuni Immidt:, 249 acid, 1% rcaction witit acid chlorides, 273 4(01* 5)-l~rnz~11rri~l~-2(~//~-i1rii~I:1zolc2-Hc~nziit1id:rzolernercnl,tans.wc 2(3ff 1tliionc. 84 Bcnaimidazolethiones 2-Hcnziniidasole~~ropin1i:1micle, Hofinann 8-l~enz:iii1icloinc~lliylbrnziti1itl:izt~lc, 311 drgradation, 311 4 (or 5)-13cnzaniido-5(01~4)-methyl2--Bcnziiiiid:~zolcp1~opionic :wid, 262, 315 2(311)-iriiicl:izoI~tl~ion~, &,' I~cnzi~i~id:tzolrs~~lfonic witlzr. survey, 398 Renrenediazoniuin cliloride (scc tikc, P:iiily frst,) rr:irI ion with iniiclazoles, 2-~cnsiinid~olesulloirir :wid, 292, 317 5(or 6)-L(enzi1nid:itolcsi1lfonicacid, 317 136 J3cnzrnrsrilfonyl rlrloritlr, rrwtion with 8-l~~nsitiiidazoletliiols.sce 2(311)-Benzirn idazolethioues 2-inritliizolines, 222 1(31I)-Beuzimid~olethionee,291 2-(Benzliycl~~losyii~~tliyl)-?-iiiii~:~zolin~, oxidation, 317 217 Rensidine resrrringcnient, 140 Stlts, 292 survey, 383 IJcnail, reaction with alddiytlw : i i d : i ~ t i s.vuthesis, 27Z, ?!)I ntonin. 33 rwction with aiirtiioni:r, 35 ~oinenclature,8

Subject Index :tcylation. 2Ho Iwnzoyla tion. 2% sun%y, 382 synthesis, 286 2 (3H)-Benairn idn xolonc-4-m 14)oxy1ir acid, 289 2 (3H)-Benzimiclazolon~-ca Ibosy ii c acid, 289 Benzoin, reaction with ammonia, 36 reaction with smmoniaral cuprous arctate and aldehydes, 39 reaction with henznmidine, 43 reaction with urea, 66 I-BenzoyI-2-aminobenzimidazole,310 Benzoylstion of Zaminohenzimidacolr. 310 of 2-aminoimidazoles, 141 of 4(or fi)-amin&(or 4)-methylimidazsle, 143 of benzimidazoles, 273 of 2(3H)-benzimidazolones. 290 of histamine, 155 of hietidine, 201 of Zimidazolines, 221 I-Beneoylbenzimidazole, 273 2-Benzoylbenzimidazole, 297 N-Benaoyl-2,4-diiodohistidine, 203 I-Bencoyl-4,5-dimethylimidazole,47 n-Benzoylene-2,1-benzimidazole, 316 N-Benzoyl-1 (or 3)-hippurplhistidine methyt ester, 201 N-Benzoylhistamine, 155, 166 N-Benzoylhistidine, 201 methyl ester, 197 I-&nmylimidazole, 47 %Bmeoylimidazole, 59 X-&nzoyl-2-methylhistamine, 162 l-Benzoyl4or 5)-methylimidazoie, 47 5-Benzoyl-4-methgl-2-~3H)-imidaeolone, 75 4(or 5)-(BenzylnminomethyI)imidnaolc, 164

%Renzylbenzimidazole, 286 l-Benzyl-2-ehloromethylimidazole, 102. 159 l-Ben~yl-2-cynnomcthylimidazole, 150 o-Beneylene-2,1-benzimidaaole,316 4(or 5)-(Benzylethylaminomethyl)imidazole, 184 1-&nzylh istidine, 204

I (iir 3)-Beiizyiliid idiirt., 202

425

I - H e n z ~ . l - 2 - h g ~ ~ r o \ ~ ~ ~ ~ mlv, etii~~lin~i~:i debeneylt~tion.102 oxidation, 175 yynthesis. iW,15!) ?-J~mzylidc~nc-l-r:trh~~t Iioxymet hyI-2phenyl-j-iinidi~zalone, 96 4-Benzylidenc- 1-isopropyl-2-phenyl6(4H)-imidazolone, 96 4(or 5)-Benzylidene-Zphenyl-4(SH)(or 5(4H))-imidnzolone, reduction, 99 synthesis, 93-95 2-Bt?n~yl-2-imidazoline,pharmnc.ologira1 properties, 225 I-Benzylimidaaole, hydrosymethylation. 100, 159 melting point, 6 reduction, 50 synthesis, 49 2-Benzylimidnrole, oxidation, 5!l melting point, 6 4(or 5)-Benzylimidazole, 6 I-Renzgl-2-imicl~zolersrboxylicacid, 102 l-Benzyl-2(3H)-imidnzolethione,77 1-Benzylimidarolium chloride, 49 2-Ben&4(5H) (or 5(4H))-imidazolonc, benzoylation, 97 ring fission, 98 2-Benaylmercapto-4(or 5)-bromoimidazole, 87 2-Benzylmercapto-4(or 5)-bromo-5(or 4)methylimidazole, 87 2-Bcnzylmerrapto-t(or 5)-N,A7-dimethy1aminomethyl-5(or 4)-methylimidazole, 87 ?-S-Benzylmcrcaptoimidazole, 63 2-Benzylmercapto-2-imidazolinium chloride, 238 2-Benzylmercapto-4(or 5)-methyl-5(or 4)-bromoimidazole, 87 2-Benaylmercapto-4(or S)-methyl-ti(or 4)-N,N,-dimethylaminomethylimidaeole, 87 ZBenzylmercapto-4(or 5)-methylimidazole, 87 2-Benisylmercapto-4(or li)-nitroimidazole sulfoxide, 87 4 (or 5)-(2-Benzylmethylaminoethyl)imidazole, 138 4(or S)-(Benzylmethyiaminomethyl)imidazole, 164

426

Subject Index

2-Ibnzyl-l-liiat 1iylbcnziinicl:tzoliuin iodide, 280 1-ILneyl-2-iiie~thyl-2-itii idiizoliniiih I rlilc Iride, 223 3-BenEyl-l-methyliiiiid:izolium iodide, 51 4-Benzylb-methyl-2(3H)-imidazolone, i5 l-Beneyl-2-phenylbenzimidseole,267

2-Uroiiio-1,I-cliriict Ityl-~niti-oimidn~oI~, 119 ?--Rronio-l ,.5-tliriictli~l-.l-ni~~~1iiiii~l~iei~Ic~, 115

4(or 5)-Bronio-5(or I)-hydrosyinethylimidazole, 100 5(or 6)-Bromo-2-h~~droxy-1~8-trimcthyIhenzimidaeoline. 284 Ikomoimidazoles, I1 1-119 2-Bromoin1icl~zole, 114 4(or 5)-~ronioimniilazole,Itwieity. 15 hydroxymethyla tion, M ! methylation, 29 nitration, 128 adfountion, 207 synthesis, I17 4(or 5)-Uromo-5(or 4)-imidnso!ec.srltcisylic acid p-hromoaniliclc. I14 4(or 5)-Rromo-5(or 4)-irnidaroles11lfr~nic. arid, 117 5(or 6)-Rro1no-2-methylhcnzimidnsolc,

4-Benzyl-%phenyl-5-imidasolidone, 99 13iacety1, reaction with ammonia. 36 reaction with hcnzamidinc, 101 13i-imidmoles, survey, 366 ?.2'-Bi-%imidazoline. 216 13iological properties, 8ee Pharm:ic.ologica1 properties Iiiotin desuifurization, 231 l%ia-benzimidszolcs, 261 I%i.s[l(or 5)-bromo-5(or 4)-nie11ty1-2imidazole] disulfide. 89 4 ..i-nis(p-bromophenpl )-1.Ci-tl ihromo-2imiriazolidone, 71 4.5-Ris(pbromophenyl)-4.ri-clihpdro?ry2-imidluolidone, 71 268 7.RRis(p-bromophenngl) hcxnltydro-2.54-Bromomet hgl-5-rarbcthoxy-2 (311)imidazolonc, 73 ilio?roirnidaz[d]iniidnzol~.71 4,5-Bis(pbromophenyl)-2(3H)-imicl:~~o- Z-Rrorno-l(or 5)-mrthylimidaaolc, row pling, 137 lone, 70 reaction with milfite. 117 Risimidazo1t.s. siirt-cv, 366 3,6-Bis-[4(or 5)-imidazolemethyl]-2,fi4-Bromo-l-methylimidnzole, nitration, piperaeinedione. 200 I28 synthc.&, 51 nis-imidazolidincs, 242 4(or 5)-~~c~ino-2-methylimidnzolr, nitraRis-(Z-imidaeolidinethioncs), 236 tion. 128 nismiith. tirtertion. % stilfona t ion, 207 N.1 (or 3)-Ris-(2-napht hylsulfonyl) lrixt isynthesis, 118 dine, 201 4(or 5)-13rnmo-5(or 4)-mrthylimielaxole, Rlood. estimation of histnminc in. 148 roripling. 137 Roiling pointq. 5 iodination. I23 Bond angles. 23 mrtliylnfion. 2n Hond distanres, 23 q.nthcsis, 113 llromination of imidaxolcs. 11 1 .i-Rrom~l-methplimidnzol~,hyetmsgof imidruolonas. 70 mrlhylation. 100 of 2-methyll~enzimidaeolc.302 nitration. I28 4(or 5)-Rr0mn-2-bcnzylmerc.aptoimid4 ( c )r 5)-Bromo-5 (or 4)-m ct h y l-2 (311)azole. 87 imidazolet hione, 84 4-~romo-4,~bis~~~~romophrnyI)-2-imidl-I3rornomethyl-ti-carbthmy-2( 311) azolidone. 70 imidazolonc.. i3 ZRromo-1.4-dimethplimi~lnzole,117 P-Rromo-4(or 6)-mcthyl-5lor 4)-nit ro~ R r o m o - l ~ 4 f i m e t , h y ! i m i ~ ~ a1zI3o ~ ~ , imidazole, mrthplrttion. 29. 11.5 fi-Rromo-l,4-dimet hylimichzolc. 113 2-liromo-Nor 5)-mrfhyl-5(or 4)-nitrn4(or 5~-Rr0mc~lS-dimcthylimid:ieoli11m irnidaxolc. synthwia. 115 iodide, 51 4-Hrotnn-I-rnrthpl-~nitroimidaroltt,128

-

Subject Index

42;

2-Csrbethoxymer~pto-l-metllylimitlmole, 90 4-Carbethoxy-5-metby1-2(3Zf)-imidazolone, 73 2-Carbethoxymethylmercaptobenzimidazole, 293 I-Carbcthoxyrnethyl-2-phenyl-4-benzylidene-5-i1~idazolone,96 4- (&Carbethoxyvalery 1) -2 (3H)-imidazolone, 233 4- (&Carbethoxyvalei~l) -5-methyl-2 (311) imidnzolone, 233 Carbinol base of a benzimidseole, 281 N-Carbobenzoxyhistidine,201 l-C.srbobcnzoxy-2-imidsr;olidone-5cwboxylic acid, 227 Carbohydrates, identification, 297, 290 Carbohydrate synthesis of imidaroles, 39. 104 4(or 5)-Cnrl~omethoxyprminoimidazole, 143 5-(4-Carbo?rybn tgl)-2(3H)-benzimidamlone, 290 544-Cnrboxybutyryl) -2(3Zf )-bcnzimitlnzolone. 20 4(or 5bCa rboxyimidazole, 15 2-(o-Cnrboxy~henyI)benzi~d~oles, 315 5- (J-Carboxypropionyl)-2(3H)-benzimidazolone, 290 b(t-Carboxypropyl)-2(3N)-benzimidazolone, 290 Carnosine, color tests, 155 detection, 138 occurrence, 185 Chromatography (see ako Ion exchnngc. Paper chromatography) of protein . C hydrolysates, 189 Chelation, 25 Canizsaro resction, 56, 59 4(or 5)Carbethox,vnminoimidaaole, 143, Chemiluminescence. 11 Chloroalkylimidaroles, 121 177 4(or 5)-Carbetho~amino-2(3I~)-imidaz- 2-Cliloro~nzimidasole.290, 302 5(or 6LChlorobenzimidazole, 251 olethione. spectrum, 84 nz-Chlorobenzimidazolee,301 synthesis, 82 Chloroctimethylbenrimidazole, 301 41or 5)-CarbethwsaminoS(or 4).i-Cliloro-l,2-rlimethylbenrimidazole, 251 met.hyd.2~3H)-imidnrolethione. 84 4 (or 5)-Car~,etlimynmino-5(orI)-phen;yl- .5-Clrlorn-l.Wimethylbenzimidazole, 270 2(3II)-imidazolet.hion~, 81 4lor 5)-Chloro-l~-dimethylimidasoli11in N-Carbet hoxyhistamine. 150 iodide, 51 4(or 5)-Cnrhethox3rirnidasole,15 8-Cttloro-l~-ctiphenylirnidnzole.120 2-Carht?t,hoxymercnptohistidine, 81 2 4 l-Chloroethyl)benzimidarole, 311 4(or 5)-Bromo-2-methyl-S(or 4 ) 4 t r o imidarole, 128 5-Bromo-l-methyl-4-nitroimidacole,128 2-Bromo-4-nitro-l,&methylimidarole, 115 2-Bromo5-ni tro-l,4-dimethylimidaaole, 119 4(or 5)-Bromo-5(or 4)-nitroimidssole, methylation, 29 reaction with suliite, 118 synthesis, 128 2-(p-Bromophenylazo)-4,5-dimethylimidnzole, 141 2-(p-Bromophenylnzo)imidazole, reduction, 140, 141 synthesis, 137 2-(p-Bromophenylazo)-4 (or 51-methylimidszole, 140 4(or 5)-(pBromophenylazo)-2-p henyl5(or 4)-imidazolecnrboxylic acid, 137 2-Bromo-Q(or 5)-phenylimidszole, 114 4(or 5)-RromoJ(or 4)-phenylimidazole, methylation, 29 synthesis, 114 I\’-Rrornosuccinimide, reaction with ‘2bcnzylmercaptod(or 5l-methylimidnzole, 87 reaction with 2(3H)-imidaiolethion~, 89 reaction with 4(or 5)-methyl-2(3H)imidazolones, 73 1-n-Butylbenzimidazole, 251 2-~~~-Butylbenzimidaeole, 261 1-Butyl-3-carbo~ymethyl-2-iminoimidae. . olidine, 239

-

2-(2-CBloroe~liyl)bcnziinidazole,304 4(or 5)-(2-Chloroethyl)iinidaaole, ammonolysis, 152 reaction with amines, 163 synthesis, 104, 121 4 (or 5)- (ZChloroethyI) itnidwa 0 I’lull1 chloride, 121 4-Chloro-l-etl1yl-2-niethylimidazole, 12 5-Chloro-l-cthyl-2-metllylimi~~~eolc, bromination, 112 nitration, 128 properties, 12 synthesis, 119

Chloroxrlmethylin, 110 Clemmensen reduction, 290 Code method, 146 Colorimetric estimation of Iii&itmine, 147 of histidine, 191 Conductancu! of imidazole solution, I6 Copper stilts of iniiderulcs, 16, 38 of 2(3N)-bcnzimitl:izoletliione,292 Coupling, 136-141 (rec cthu Piruly tes.t) Cupric awtate in Leneimidaaole syntheses, 269 iu imidazolc syntheses, 38 Curtius degradation, 143, 144, 160, 164 5-Chloro-l-ethyl-2.i~ietliyl-4-ni~ roCyamtes, reaction with aminwirbonyl mnpounds, 63 imidazole, 128 ~hloro-l-ethyl-2-~~hc1iylii1iidaaulc. 120 Cyanide, action on iniiduaolccarboxuldc.i-Chloro-ZhydroxyiiicthgI-l-iiiet,hylhydes, 66, 56 imidatole, 100 Cy:inohneimidazoles, survey, 394 Chloroimidazoles, 119 Cyanoimidazolea, survey, 351 a-Chloro-cl(or 5)-imidncolepropionic. :u:itl, 2-Cy~non~ethy~bensirnidaeo~e, 284 4 (or 5)-C.vanomct.liylirnid:~eole, nieL1iyl:i194,205 2-ChloromethyIbcnziiiiicl:izolc,re:ic-tion tion, !B, 160 syn‘ntiiesid, 151 with amincs, 311 synthesis, 297, 303 4-C~anoi11ctlipl-l-i11ctli~liniidnzolc, 160 5-Chloro-l-inet.hylbenzinii~:izole, 251 ~-C~.nnoiiictli~l-l-iiictByli~~iidueole, 160 6-Chloro-l-niethyB~en~iniidazolc,231 4(or 5)-C.vanotuc~tligl-3(or4)-methyl5(or 6)-Chloro-2-methylbenzimidnzolc, itnidseole, 161 5-Cq.nnul-iiiethyI-4-nitroiiitidneole, 120, 251 4(or ~~-~~i~oroiiicthy~~i~i~t~tiao~c, nnitiio180 nolyeia, 164 l-C.vcloliesylhistidine,204 2-Cyclohcs~lJ1.5,6,5-1 ctr:iliydrobenriiiiidsynthesis, 121 4-Cliloro-l-iii1~~.li~liiiii~ln~ol~, liyilrosymole, 254 niethgl:rh~,100 u i ~ r u p ~iw, r l 12 synthcais. 51 Ih~lkylubionof :ilkylitniduzoleJ, 61 5-Cliloro-I-iiic~~Iiyli1iiitl:isol~~. Iiytlroxy1hl)wniinat ion of broinoin~idmolec. 11i incthylntion, 100 I)i~~:irbosyIasc :ic:ticity of microorginnitration. 128, 180 istiis. 14!) ~cc*rirhsylntionof imitlnro1ec~:irl~osylic propc:rtic!s, 12 synl 1ic.sis. 119 :ic~itlr.42. 178 ?-CIiloroiiicth~1-2-iiiiitl:ixolinc. 217 t-I~c~t~yl-2-iiir~liyI-2-iniicl:izolinc, 225 4(0r .5)-c~hlororiicthyliiiiid:izoliitiiicliloIhliyd~-ogcn:itionof amarine, 42 ride, conueision to Iiistidinc, 194 of iniitlaeolines, 42, 220 syntliais, 121 Drdhiolhtin. 231 ~ ~ ~ l i l o r ~ l - i i i c ~ ~ l i ~ l ~ - n i ~ . r ra:ic*o i ~ i i i ~1’)c.siilfririz:il.ion l:ieol~. of biotin. 231 I.iou wit-li iiiiitiioniu. 120 of dil Iiioliydmtoins, 41 rcwtioii wit.11 cpnidr. 120 c~l.liyl4-1 Iiioh~dnnloiri-ti-c.:uliosyl:ilc~. rtwtioti with siilfitr. I2t1 67 syntlwsiri, 1%. 180 ctf 8(3H)-iiiiitl:iaolt~~liio1i~s, ,4l. 8H. 11~2. 302 2-Chloro4Xor 6)-nitrol~c~nxiiiiitl:ieolt~. 103 Clilorosslel Iiylin, 119 of 2-1iirrc.rrplolii~~iciinc, 205

Subject Index . V - l ~ l ~ , . y f : l ~ ~ l ~ l a l I l 35. i I f ~ 37 ~.

Y- i h y lhen zam ide. 36

.~‘--DesJ.lh~nssnilidc. 45 LV-nC8.Vlf WJ11:1 IIUdP,

%,

Detection of iniicliirolcs, 139 Detoxifiontion o f histnminc, 166 Diacetyl, rewtion with ammonia. 36 renction with benzamidine, 101 l~-Diacotylbenzimidazolone,280 Diacetyl-2(3H)-imidsolone, 61 Dirtcetyl4or 5)-methyl-2(3H)-i1iiidazolone, 61 Dialkyliniiclrizolium salts, 50 5,6-Dinminoheneimidneole, 308 4,6(or 5.7)-Dinn~ino-Zmethylbziiiiidazolc, 308 Diazo coupling, 136-141 (see also Paiily test)

l$-Diazole, 3 Diazomethnnc, action on iniidneolrs, 29, 49 action on 4.5-imidazoIedic.:irbos~lic acid%,179 Dinzotization of Bz-Rminobenrimidnzolcs,

308

of 2-aminoimidazoles, 141 of 4(or 5)-amino-5(or 4)-methylimidazole, 143 of 2-(o-aminophenyl)benzimidazole, 312 Dibenaimidazo-(l, 2-a-l’,2’4)-tetrnl i ~ d r o ~ ~ y r ~ z i n c - 6 , l ~311 ione. l.3-Dibenzoyl-2-ethoxybenzimidaznline, 274 N,l(or 3)-Dibenzoylhistidine methyl cster, 201 1f-Diben~oy1-2-hydroxybenzimidneoline, 274 4(or 5)-(Dibeezylaminomethyl)imidazole, hydrogenation, 164 phnrmncologicnl properties, 167 synthesis, 164 1~-Dibenzyl-2-hept~tiecyl-2-imid~zolinhim chloride. 214 :V,N-Dibenaylhistsminc. 166 .+‘,l(or 3)-Dibenzylhistidine. 1,3-Dibe~~l-~methylimidn~~Iinium rhloride, 223 4,5-Dihromo4,5his p-bromophenyl) -2imidaaolidone, 71

429

~ ~ 4 - l ~ 1 l ~ ~ 1 ~ 1 i 1 ~ ~ - ~ , ~ ~ l i 1 1rear1~~tli~li111 tion with ailfitv. 11s synthesis, 113 %~~ibrom~l,4dimethyliniidusolt~, reaction with siilfitc?,11s synthesis, 113 4,5-Dibromo-4,6-diphenyI-Zimidnzolidone, 70 2,4(or 2,5)-Dibromoimidnsole, ioclinntinn. 122 nitration, 128 reaction with sulfite, 118 synthesis, 112, 114 4,5-Dibromoimidaeole, methylntion, 1If nitration, 127 synthesis, 112, 117 2,4(or 2,5)-Dibromo4(or 4)-imidaralecarhoxylic acid p-hromonnilide, reaction with hydrochloric arid, 120 synthesis, 114 2.4 (or 2,6)-Dibrom04(or 4)-iodoimidasole, 122 4,5-Dibromo-2-iodoimidazole, 1% 2.4(or 2,6)-Dibrorno-5(or 4bmethylimidasole. methylation, 29 synthesis, 113 4.5-Dibromo-l-nicthylimidazole, 100 4,5-Dibromo-2-methyIimida~ole, reaction with sulfite, 118 synthesis, 112 2,4 (or 26) -Dibromo-5 (or 4)-nitmimidaeolo, 128 2,4(or 2,5)-Dihromo-5(ar 4)-phenylimidazole, 114 a-Dicnrbonyl eompoiinds, reaction with urea, 22n 3.4-Dichlorohenzcnc~ulfonicarid as precipitant for histnminc. 160 8.3 precipitant for histidine, 188. 191 4.6(or 5,7)-Dic~hlorohrnzimidazole,251 S.B-J)ichlorob~nsiniidnzolc.251 I~iehlorodimethglhcnrimidnzole.301 2.4(or 2,6)-Dirhioroimidnzole, 120 k5-Dicyclohexyl-%imidazolone, 76 I .3-Dini tro-2-chlorome t hyl-2-acet.oxyimidezolidine. 220 Dielectric properties of imidazoles, 10 l-P2-Dietzhylaminoethyl -5-methoxyhenzimidazole, 311 4(or 5)-~ZDi~thylaminomsthyl)imi~azolP, 1.38

430

Subject Index

I ktliyl 1,~-ilili~~I1.oxy-2-iriiicliixnlidonc1111 rw-iolet absorption sped ruin, 254 1,7-Dimct~hylh~nzimidAIdiumhydroxide, 4,6-dicarhoxplate, 229 m 1.5-Di(2-furyI)-2(3ff )-imidazolonr. 66 1f-Dirnotliglt~c~1iri1riid~~0liu11i ioclitle. 2& Dihydmamarone, 36 l~~imetliylbenziiiii~azolone, 288, 290 Dihydroimidazoles,see Imidnzolines 2,6Dimethylbeneo[l~,4~]bisimidsEolo, Dihydro uric acid, 67 308 4.5-Dihydroxy-4,5-dimethyl-2-phenyl-24,5-Dimethyl-2-(pbromophcnylazo)imidazoline, 101 imidazole, 141 1,5-Dihydroxy-4~iphenyl-2-imidazoli1.6-Dimethyl&~hlorobenzimidoeole, 270 done, synthesis, 74, 230 4,5-Dihydro&2-iiidazolidone, dehydm- 7,9-Dimethyldihy(lrouric acid, 67 1,3-Dimethyl-2-~imetltylrmino-~t~~ltion, 230 benzimitlazolium iodide, 278 synthesis, a29 4,5-Di hydroxy-4-phenyl-2-imidazolidone, l~DimethylJ1.5-di~~h~nyl-2(3fZ)imidazolone, 66 dehydration, 230 l~Dimethpl-2eth3.l~nzirnid~zoliiim synthesis, 229 iodide, reaction with alkali, 280 4,5-Dihydmxy-2-phenyl-2-imidazoline,94 1,4-Dimethyl-2ethylmercaptoimidrzole, 2,4-Diiodo-N-be~o~lhistidine, 203 2,4-DiiodohistidineI 203 18 NJV-Dimethylhistamine, 166 2,4(or 2,S)-Diiodoimidazole, 122, 124 1,4-Dimethyl-5-hydrox~methylimidaeole, 2,4(or 2,5)-Diiod&(or 4)-methyl55 imidazole, 122 1,2-Dimethylimidazole. nitration, 128 4,5-Diiodo-2-methylimidnzole,I22 2,4Diiodo-N-.p-nitrobenrpvlhistidine,203 properties, 6, 12 4(or li)-(2Dimethylaminoethyl)imidsynthesis, 100 1,4Dimethylimidnzole. boiling point, 6 azole, 138 bromination, 111, 113 4.5-Dimethyl-2-aminoimidazole,141 4 (or 5)-(Dimethylaminomet hyl )im idhydroxymethyhtion, 100 nitration, 128 asole, detection, 138 synthesis, 27 pharmacologirnl properties, 166 1,5-Dimethylimidazoie, boiling point, 6 synthesis, 164 hromination, 111, 113 4(or 5)-Dim~thyl~minomethylb(or 4)hydroxymethylation, 100 methyl-2(3ff )-imidazolethione, 84 nitration, 128 1.3-Dimethyl-5eminouracil-4-carboxylic synthesis, 27 acid, 67 1.2-Dimethylbenzimidneole, hydrogena- 2,4(or 2,5)-Dimethylimidazole, bnsicity. 15 tion, 16. 254 nitration, 127 .synthesis, 263, 265, 271 synthesis, 34, 40. 49 1,5-Dimethylbeneimidszole, 251 I&Dimethglimidazole, nitration, 127 1.6-Dimethylbenzimidazole.261 ring fimion, 48 2,5(0r 2,6)-Dimethylhenaimidazolc, bmicity, 251 1,4-Dimethyl-5-imidazolec~rboxaldehyde, rhlorination, 301 Cannizzaro reaction, 59 methylation, 2S8 synthesis, 55 nit,ration, 305 1,4-Dmethyl-2(3R)-imidazolethione, 78 oxidation, 313 l~Dimethyl-2(3H)-imidazolone, 67, fM reaction with bmealdehyde. 276 1~Dimethyl-2(3R)-imidazolon~~rsynthesis, 256, 258. 281, 264 boxylic acid, oxidation, 73 4.6(or 6,7)-Dimethylbenzimidarole,251 aynthasie, 67, 69 5.&Dimethylbenzimidaaole..ba&city, 2(21 I~~methyl-2(3H)-imidssoloneboncnirrence, nS cshxylic aaid, 77

Subjec;t Iudbx

43 1

4~Di~~lirnyl-1,3-cliniethyl-2(311)iinidazolone, 66 4.5-Dipbenyl-Zethpiimidaaole, 13 j.,i-niphenylhydnntoin, 230 15 1SDiDhenyl-2phydroxyphenylimidreaction with bcnzaldehyde, 134 arole, 33 synthesis, 128 l~D~etliyl-5nitroiniidunrole, bmicily, 2,4(or 2,5)-DiphenyIimidsaole, polyinorphism, 27 15 *thesis, 43 reaction with benzaldehyde, 134 1,4-Dimethyl-6-nitroirnidazole, rcrwtion 4,5-Diphenylimidazole, bromination, 112 synthesis, 34 with benzaldehyde, 132 4,.5-Diphenyl-2-imidatolesulfonic acid, 206 seduction, 135 4.5-Diphenyl-2(3H)-imidsgolethione 85 synthesis, 128 1.5-Dimethyl-4-nitroimidnzole.13? 4,5-niphenyl-2(3H)-imidaaolon~,bromination, 70-72 2,4(or 2.5)-Dimcthyl-5(or 4)-nitsoimidarole, 127 oxidation, 73, 230 1,4-lXrnethylb-nitro-2-iiuid~oiczul~~~nic reduction, 75 arid, 115, 119 synthesis, 66 1,3-Dimethyl-4lor 5bnitroiqidazoliu 111 4,5-Diphenyl-Zisoprapylimidrrzole.13 4,5-Diphenyl-2-(p-methoxyplienyi)imiciiodide, dealkyiation, 51 synthesis, 132 azole, 13 1.3-Dirnethylparnbanio acid. 73 4,5-Diphenyl-2-methylimidazole.13 5,&Dimethyl-2-phenylhenzimidaaoie. 251 12-Diphenyl-&methyl-2-imiduo~nc, I,~Dimetliyl-2-phenyl-2-li~ci~xy~en~218 1,2-Diphenyl4( o-nitrohe~yliclene)-5iinidazoline, 284 lf-Diniethyl4or 5)-i~lic~i~yliiiiida~olium imidaaolone, 96 iodide, 52 2,5-Diphenyloxazole, rrac-tion with am4,4(or 5P)-Dimetliyl-2-yiicnylJ1(SII) (or monia, 27, 44 5(4H))-imidnzolone. 95 Dipole moments, of azoles. 22 1,3-Dimethyl4phenyl-2 (311biniidazoand dissociation constants, 23 ione-€i-carboxylic sritl. i 7 of imiduoles, 10, 19 5,5Diniethyl-l-a-~-ribofiiranoliyll~enzvariation with concentration. 11 imidazole, 293 Di..jfiociation constants, 15. 23, 199, 251 Dimethyl sulfate, action on iniitlnzoles. Disulfides of imidazoles. 89 49 Dithiohydantoin, convemion to histidine. 1.9-Dimethyl-S-thiowic avid. 183 197 o-Dinitrobenzene derivrrtives, retluction, demlfurkation, 41 2,5(or 2,6)-Dimethyl-6(or 6)-nitrObenZimidazole, 305 1,2-Dimethyl-4-nitroimidazole, basid y.

280

l-~odecyl-2-metiiyl-2-iiriitlnxc,liiic,p h r 5,&Dinitrobenzimidaole. 308 inncwlogicai prolwrtics. 2% B,~Dinitr~2(3H)-benriinicb~ulonc, bciisynthesis. 223 eoylation, 276 Duscliinuky-Dolan riyntliesis. 233 synthesis, 290 1.3-Dinitro-2-imidazoiidone.220. 2%). 240 E 1,3-Dinitro4methyl-2-imidarolidone, 241 Electrodialysis o f tiistaniinc, 146 1.2-Diphenyl-5-chioroimidazole.1%) of histidine, 192 4P-Diphenyl-4adiiilkory-2-iniid:lroliElectrolytic! rrtltwtiem of o-nitroacylaniclones, 72 4~Dipheny1-4,5-dil~r1~1111~2-iiiiicl:~~e~li-lides, 2W douo, i o Electron density, 14 4 ,~Diphenyl-4,~ctihydrc~sp-~-iniidazoli- Eleclron distribution :ind rrmphoteric. done, 74 n:itrirc, 21

4x3

Subject Iudex

Electropliilic substitution of iiilidazoles, 129 (res ako Bromination, etc.) Emulsifiers, !224 Ergothioneine, detection, 138 properties and synthesis, 90 spectrum, 84 Esterification of histidine, 200 of irnidazolwtlrbosyiic acids, 177 of imidazolcclicarboxylic acids, Ii9 Esters in benzimidiirole synthcscy. 263 %Ethoxybenziniidazolc, 288 4-~o-Ethoxyetliyl)-5-niethgluracil,67 2-(p-EtlioxpplicnyI:izo)iiiii~lazolc, rccliiition, 141 syntshcsis~137 M o r ~)-~2-l~1~li~l:iiiiiiioc~t.liyl)iiiii1l:izoli~. 138 Elliyl 4(or 5)-niiiino-5(or 4)-iniid:tzoli!c*iirboxglate, 182 4 (or 5)-( Ethylrminoiiietliyl ) imihzolr . 1,iinrriiiic.oloy;iclaI properties, 166. byntliesis, 164 IW.vl 5-~iiiin~-l-iii1~~liyl-4-i~i~icl~ieolc~:ir1iosylate, 181 151hyl 5-:iiiiino-l-ii1etliyI-2(311 )-iniid:izolct Iiione-4-c:irboxylate. reaction with methyl isocy:inatc, 183 syntli~sis~ 85, 181 l-Et.liyll,ciixiiiiidnzolc, 251 ?-litIiyll)c.nziiiiid:ieolo, h i c i t y , 251 l.~mzoyl:ition,275 hgtlrogcn:iI ion. 10, 254 Ktltyl 2-~~.iiaiiiiitl:ieolc~c:1irborylntc. 315 ICtIiyl 2-1ic!nzimid:ieolep~1.uvate.278 N-l~lhyliniitlazoliuin l~roniiclr,49 Ktliyl 2,4(or 2,5)-ctibromo-5(01*4)-iniid:trolcc!arboxylatc. 112 I~tliylenct~i~~~ueimitfarolc, 262 E1hylcnrdi:iniinc in imidnzolitliii~thioiic syntlicws. 235 in imid;izolitlonc synl,licscs, 226. 227 in 2-imid:izoline syntlicsrs, 214 in 2-iminoiiiiicl:isolitlinr!synt.limcx. 238 15thylenc ulyrol. rwc.1 ion wiih WP:~. '227 Rtliylene~iiiinidines.238 Et.hylenc~f.hio~ii.e~, 234 13t~hylt?~~I~1 Ir<*:I%226 1511iyI ~I-~~i.IiyI-~(:tN)-iiiiitl:izoliinc~-~r:vI,i,syl;rla:, 77

.V-Elhylhint;iininc, 105

l - l ~ ~ i ~ i ~ ~ ~ 49. t i ~51, ~ ~175 ~:iz~~~r,

Kiliyi ~ - r i ~ e t b y l - ~ ~ r i t . t ~ l ~ ~ l i i ~ ~ ~ i ~ l ~ ~ - ~ ~ . ~<;~ ~ ) -

imidnrolethionet4-carboxylatr. I%* I-Ethyl-7-nie~,liylxnnthine, 182 2-Ethyl-l-phenylhenzimidazole,276

l-Ethyl-2-pheny1-5-chhloroimidazolc,120 Ethyl 4(or 5)-phenyld(or 4)-imidazolemrboxylate, 114 2-Et hyl-4(or 5 )42-piperidinoet hyl ) imidazole, 163 Ethyl 4-tIiiohydantoin-li-carhoxylnte,67 Explosive propsrtiea of I-nitro-2-nitramino-2-imidazoline, 241 “Est.ra” hydrogen, 00

F

Ferric chloride test, 62 Ferric salts as oxidants for imidazolethianes, 88 Ravianic acid ns precipitant for histidine, 191 Flotation agents, 224 Formaldehyde (see ako Hydroxymethylation) effect on carbohydrate synthesis of imidaeoles, 40 reaction with li4-dihydroxybutanone-2 and ammonia, 103 reaction with Pfructose and ammonia, I03 reaction with histamine, 1&8 reaction with histidine, 206 reaction with imidazoles, 99 reaction with a-ketoaldehydes and ammonia, 34 4(or 7)-Formnmidobenzimidazole,308 Friedel-Crafts acylntion of 2(3H)-benzimidazolones, %I0 of imidnzoies, 49, 59 of 2(3H)-imidazolones, 09, 233 &Fructose, reaction with formaldehyde and ammonia, 103 reaction with zinc hydroxide and aminonia, 40 “Fungicide 341,” 225 Furan, 5, 20 Fitroin, reaction with nmmoniacal riiprone acetate and nldahgdwi, 39 reaction with wen, 66 Piision. bent, of, 13

(

;c*ometric.al isomenmi, tlt~stliiobiotii~,

231

imidnzolidonea, 76 I-&d3lucopyranosylimidazole, 105 D-GhicosaminP, reartion with thiocyanntr, 104

D-Ghicwe, reaction with zinc hydroxitlc and ammonia, 39 L-Glutnmic acid-histamine conversion, 152 1-Glycitylbenzimidazoles,296 Glycocyamidine, 140 I-Glycosylbe~imidazoles, 293 basicity, 252 Glyoxal, reaction with aldehydes and ammonia, 34 reaction with urea, 229 Glyoxaline, 3 Grignard reagent, see Imidaeole magnesium bromide 4(or 5)-Guanidoimidaeole, 142 H Halogenation of 2(3H)-imidaeolones. 70 Halogenobenzimidazoles, 300 survey, 388 Halogenoimidazoles, 11 1-123 survey, 342 a-Halogenoketones, reaction with :txiimonincnl cuprous acetate, 38 reaction with benaamidine, 43 Hent of fusion, 13 of solution, 13 2-IIendecyl-%imidazolines, 225 ZHeptadecyl-Zimidazolines, 225 Hercynine, 205 Heterocyclic ring systems, 20 4-Hexahydrobenzyl-5-5-methy I-2-imitlazolidone, 75 4-Herahydrobenzyl-5-metthyI-2(3H )imidaeolone, 76 Hexahydro-2,6-dioxo-7,8-bis(phromophen~l~i~nidaz[cllimidnzole, 71 Hesahydro-2,5-nioxoimidaz[dJimidaeolc~, 230,231

Histamine, 143-109 :ic:ylntion, 1&5 :indogues, 168 t d r i t . y , I5

4x4

Subject Index

JIistrtiiiinc (c*odinuctl): liioa8sny, 146 volor tests, 1&5 cleamination, 157 tletet*tion, 138, 148 detoxification, 160 formation, 149 iwlation, 145 pharmaeological properties, 143, 105 properties, 153 quantitative estimation, 146 reaction with aldehydes. I56 Sdts, 154 synthesis, 150 Histnmine activity of pyritlinc! drriv:itivea, 168 Histaminole, 103 Histidine, 184-205 :ic*ylation, 200 amides, 200 anhydride. 200 betnine. 205 i~i.F3.4-cliohlorohrnzenc~iilfonnte, 188, I91 color trsts, 155 (*onversion to ergothioneine, 90 decarboxylntion. 144, 149, 150 detertion, 138 isolation, 188 mpthyl ester. benzoylation, 201 detection. I38 nomenclsture, 188 ocwirrcnre, 184 properties, 197 quantitative estimation, 189 reaction with bromine, l!B

o f Iwiisiiiiidnzolc, 250 of %(311)-iirnritnid:ixolonc.s, 285

of imidaroles, 21 of imidaroiontxi, 62 of 2-methylbenzimitl~zolr. 279 of nitroimidsaole anion, 131 Hydantoin, reaction with 4(nr 5)-iinie. azolecarboxaldehyde, 196 synthesis, 230 Hydrogen, “extra,” 60 methine, determination, 111 position, in imidaeoles, 4, 26 cffed on acidity, 16 effect on boiling point, 6 efiect on solubility, 7 Hydrogen bonding, and histnriiinc :ictivity, 168 of imidaaolea, 26 Hydrogen M t , 62 Hydrogenation of arylimidmioles, 47 of benzimidaeoles, 254 of 2(3H)-benzimidnzolones, 291 of imidazoles, 16 or imidrzolecarboxnldeliyitrs.59 of 2(3H)-imidazolones, 75 of n-nitroacylmilides, 260 Hydrogenolysis of 2(3N)-imidazolethiones, 41 Hydrolysis of 1-acylbenzimidaxoles,!273 of imidaeoles, 24 of imidnzoledonic acids, 208 of %imidazolines, 219 Hydroxyalkylbenzimidasoles, 293 Rasicity, 252 Hydroxyalkylimidazoles, 99-106 reaction with thionyl chloride, 121 wits, 198 2-Hy~mxy~nsimidazoles, see 2(311)wparntion from arginine. 1 0 Brneimidnzolonrs sepnrntion from tyrosine, 192 2-Hydroxy-1 M i m e t hylbenzimitl;tsolinc., rtruvliire proof, 1&5 283 snrvey. 358 2-FIydroxy-13-dimethyl-2-phenyli )emsynlhesie, I94 imidnaoline, 284 Hi~tidine-2-C’*,205 I-~2-Hydroxyethyl)benzimidazole,251 Histidine-silver, 189 2-~1-Hydroxyethyl)benzimidszole,296 Histidinol, 138 4(or 6)-(%Hydroxyethyl)imidaeole, deHistidylhistidine. !XlO tection, 138 Hofmann degradation. 1 1 I properties and synthesis, 103 Hofmann process. 2% synt.hesis, 157 Hunter diaro test, 86 Hybrid StNcf Iit‘e of 2-st11ino~m~dtis0l~ri1ii 4(or 6)-(2-Hydroxyethyl)-2(3H)-imitlim, 142 azoletbione, 103

Subject Index

4-35

I ?-Hydr~~y~~~~1-l-I,l,crlyl-2(RII)-~rni~l.molethionc. 138 IC~ CJII i t i w t ion o f iniitlazoles, 1 . W I fydroxyiinidrrmles, 8cc 1inicl:izolmes Imiduole, detection, 138 2-Hydroxy-Zimidnzolines,SCC 2-lmidpreparation, 42 arolidones 4(or 5)-Imidazoleacetic acid, coupling. a-Hydroxyketones, reaction with ammoni137 ncal cupric acetate, 38 Cuirtius degradation, 164 I-Hydroxymethylb~nrimidarole, 251 detection, 138 2-Hydroxymethylbenzimid~zole, oxida4 (or 5)-Imidaeoleacrylic acid, 138 tion, 314 j%(4(or 5)-Imidazole)-alnnine, see Histisynthesis, 296, 304 dine 5-Hydroxymethyl-l,4-dimethylimidazale. Imidarolerarboxnld~hydes. redurtion. 101 66 4 (or 5)-1midasolerarboxaldehyde , ('on6-Hydroxy-2-met hyl-4.7-dinitro-l-phenylversion to hiatidine, 194 tx&midazole, 307 methylation, 29, 58 bmzoylation, 276 stability, 48 Hydroxymethylirnidazoles, 99 synthesis, 65, I28 2-Hydroxymethylimidarole, 102 ultraviolet absorption spectrum, 57 4 (or 5)-Hydroxymethylimidasole, ba4(or 5)-Imida~olecarboxamide,177 mcity, 15 4(or 6)-Imidazolerarboxanilide. brominadetection, 138 tion, 114 oxidation, 65, 176 s.ynthe&, 177 reaction with nit& acid, 128 5-Imidazolecsrboxylates. reduction, 101 synthesis, 88, 102. 151, 177 Imidazolecarboxylic arids, 175-205 I-Hydroxymethyl-2(3H)-imidazolethione. coupling, 137 84 decarboxylation, 42 2-Hydroxymethyl-2-imidazoline,217 nitration, 128 4(or 6)-Hydroxymethyl-B(ar 4)-rn~tliylsurvey, 352 imidasole, oxidation, 55 ultraviolet absorption spectra. 11 synthesis, 161 1-Imidarolecarboxylic acid, 175 5-Hydroxymethyl-I-methylimidrsole. 161 2-Imidazolecarboxylic acid, 175 4 (or 5 1-Hydrox.ymet h yl-2-me thgl-5 (or 4 )4(or 5)-Imidazolecarboxylic acid, coiiimidacolecarboxylic acid, 162 pling, 137 4 ( o r 5)-Hydroxymethyl4(or 4)-methylCartius degradation, 143 2-phenylimidazole, 101 detection, 138 4(or 5)-Hydroxy-4-methyl-5(or 4)-11wiodination, 122 icio-2-imidazolidone, 230 properties and synthesifi. 176 2- o-Hydroxgpheny I ) benzimidazole. 25 stability, 49 2- (o-Hydroxyphenyl)-4,.5-diphenylimidsynthesis, 104, 128. 176 mole. 25 4.5-Imidazoledirarboxamide, 184 2-~Hydroxyphenyl~.5-diphenylimiciiiniciasoledicarboxylic acids, survey, 360 azole, 33 2-Hgdroxy-l2,3,5(or 1,2,3.6)-tetrarn~f11.~1- 4.5-Imidazoledicarboxylic acid, coupling. 137 benrimiclaroline. 284 2-Hydroxy-1,2~-trimeth~~I~~imidrrzo- decarboxylation, 19, 42. 177 nitration, 127 line, 284 properties and synthesis, I78 2-Hydroxy-I,2%-trimethyl-5(or &nitrosynthesis, 19 benrimidaroline, 2% Tmidarole disulfidea, 89 Hyperconjugation, 14, I33 Hypobromite, reretion with arylnmido4(or 5)-Imidaaoleglyoxylic acid, 104 mrboxamides, 227 Trnidazole ketones, 69

436

Sribjent Index

2- 1iiiiiiiizoliduties, 2fi I(or 5)-Imid1izoielsctic. .wid. 1% Imidasole magnesium twnmidr, forin:*properties, 22R tion, 15 .*urvey, 376 reaction with benzoyl rhloride, 48 synthesis, 76, 226 reaction with ethyl chloroformate, 175 2-Imidazolidone-4-c~rproicacid, 233 4(or 5)-Imidazolcmethylenemalonic acid, 2-Imiclazolidonc-4-ctarhosylic :wid, 127 8-Tmitlnzolin~s.213-226 55 ZImidazale phenyl carbinol, 59 tlchydrogcnntion. -12 2-Imidaeole phenyl ketone, 59 IiyiIrolysiA. 24. 219 rcsonanrc systcni, 22 4(or 5)-Imidazolepropionic acid, couwrvry, 367 pling, 137 ?-(ZIiniriiirolinoiilethgl) compounds, synCurtius degradation, 144 t.hrris. 21s synthesis, 152, I85 4(or 5)-Imidaeolepy~ivicacid, drtwtion, Tinidnzoliniuiu group, directive influence 138 of. 131 synthesis, 187 Tmidazoliiini group. tlirective infltienre of, 2-Imidszo~esulfinicmide, 88 131 Jmictnzolesulfonic acids, 208 Imidnzoliiiiii ion. rcsonnnvc stabilization snwey, 363 of, 23 synthesis, 117-120, 206. 207 Iniidaroliuin salts, 13 2-Tmidaeolrsalfonic a d s , ns intennrdiprcpsrat.ion. 38 ntcs in desulfurization of imidnzole- linidazoloncs. 60-90 f hionw, 88, 207 ?~3//)-Iniitl:izolont~~. 63-77 synthesis, 89,206 Friedel-Crdts nvyl:ilioii. 89. 233 4(or 5)-Iniidazolesulfonic. ncitl. 207 osidntion, i 3 2(3H)-Imidazoletliione~.77-91 properties. 68-77 rodnetion, 75 acylation, 88 structure, 81 dkylation, 88 nntithyroitl activity. 8n survey, 330 dclec.t.ion, 138 synthrsis. ria46 dcsulfurization, 41, III) ?(5H )-Imitlnzoloiirs, 91 gold complex, 85 1(5U )(or 5/4N))-I~nid:~aolones, %%%I osidation, 88. 206 ?(3/1)-Imiti:irolano-4-c~:t~~roic acid. 233 properties. 86 ? ( 3 1 1 ) - J m i d n z o l o n ~ - c : i r l ~scicl, ~ ~ l i ~dr~ phRrmaeologirnl prolwrtirs, 89 i*nibosylntion.63. 7: reaction with N-~)roiiiosiicc.inimidr, fin iwlliylat ion. OD reaction with rt hyl c*lrloroformntr,86 osidation, 73 reaction with sulfiir diosidc. 8.5 synthesis. 08. 67 salts, 85 4 (511)(or 5(4//) )diiiitI:itolniic-~c~:irhosstructure. 61 ylie :u:id. 97 survey, 336 l-Imidaco[cl~ntraliy~lro~~y~itliiio, 157 .synthesis, 77, 79 Iminazolc, 3 ultraviolet ab.wrption spectra, 11, 84 Iminobenzimidnzolin~s,.WC 2-Aminohcn7,1(3H)-Imidaeolethione-4(or S)-acrylic imidazoles acid, 90 Imino ethers, in benzimidnzole syntlicscs. Imidazolidines, 242 268 hydrolysis, 24 reaction with a-niiiinokrtoneR, 43 survey, 373 rcartion with cIhy1cnrdi:minr. 217 2,4-Imidazolidinrdiona, .we Hyrlnntoin 2-Tminoimiclazoliilinr~.2.78 Tmidsaolidinpt hinnm, 234 mrvey, 370 mirvev. 378 3-Tminainiitl:ixalitliiiiiitii 1)rntiii~io.239

Subjcct ladex

437

L P-Iiiiino4imitluzolidone, 140 2-Imino-5-1iiethylJ1-imidseolidone,140 Lucc~se,resetion with zinc hydroide and Imino thioethers in beneimidazole synammonia, 40 theses, 286 Ladenburg aldeliydine synthesis, 287 Inductive effect, 14 Ladenburg synthesis, 261 Infrared absorption spectra, 56 Link reaction, 298 Intramolecular reactions and tautoiner- Lithium aluminum liydride reduction of ism, 30 l-benzyl-2.cyanometh~~limidazole, 169 Ictdination of benzimidazoles, 302 of imidazolecarboxylntes, 101, 161, 157 of histidine, 203 Laphine, acidity, I6 of imidazoles, 122 chemiluminescence, 11 %Iodobenzimidazole, 302 hydrogenation, 17 2(0r 4)-Iodohistidinc, 203 reactions, 46 lo~loimidaaoles,122 synthesis of, 17, 18, 33-35. 1 2 4 4 2-Iotloimid~zole,122, 124 1,ophine-kyapheninc intcrconwwion, 46 2-IotIo-4(or 5)-nieth~liniidazole.122 Lysidine, 213 l-Cotl~r2,4~tr.ii~iethylimidazolr, I22 Jon cxehangc in glycosylhnidazole, isoM lation, 296 Mil~~oiiiole~zlles. 25 in histamine isolation, 147, 154 Maltose, reaction with zinc Iiy~lroxide in histidine isolation, 189 find ammonia, 40 Ionic resonance effect, M u-Mannose, reaction with ziiw Iiytlroxidc I-Ieoiimylimidaeole, 12 iiiid ammonia, 40 Isoryavnnates, reaction with aminwrbonyl MMatjuenne procedure. 158 c.ompound8, 64 McFadyenStevcns syntlicsis, 58 Isoimidnzoles, survey, 363 Melting points, 6. 327-401 Isoimidazolones, 91 o f irnitlazoliu~nsd!s. 14 Isomerism of imidazoles, 26 of iniidiisolones, 61 I-Isopropylbeneimidaeole, 261 2-~fer~ptobrnziruiii~izolod, s e r ~2(311)2-Isopropylbenzimidaeole,251 Bcneimidazolethioncs I-Isopropylhistidine, 204 2-Isopropyl-5 (or 6)-methy lbenzimidneole, ?-?ulcrcnptohistamine, 152 2Mcrc:aptohistidinc, detertion, 138 268 synthesis, 91, 205 l-Isopropyl-2plienyI-4-benzglidene2-Mermptohktidinc-2-C”. 205 5(4H)-imidazolone, 96 ~~erenptoiinidazoles. nee Iniidazolr?t~liioric~~ l-Isopropyl-2,4,4-trimethyl-2-imidazoline, 2-~~ercnpto-2-irnidnzolines..see 2-hid214 ‘azolidinethiones 2-Mercaptomethylbcnzimi1iazole,295 K 2-Mercapto-4-methylhistidine.84 Mcsomerism, see Hybrid structure ICapeller-Adler procedure, I!% salts of irnidazoles, 15 Metal a-Ketoaldehydes, reactim with formaldeMetliinc group between nitrogens, ace hyde and ammonia, 34 Aniidine system Ketones in benzimidaeole syntheses, Mcthine hydrogen determination, 111 270 4(or 7)-Mcthoxybe~iniidasole, 251 Ketones, imidazole, 59 Nor 6)-Methoxybenzii~iiduzolc. 251 Knoop test, 19d .V-(p-Methoxy~nzyI)his~~iiiine, 168 lioewler-Hauke J I ~ ~ A . ~ I1.18, U ~ , 192 .V- (/rMet.ho~ybeuzylic~ene) Iiiatamine, 156 I \ ‘ o ~ ~ c : l - f ~ i i l l iniel t ~ r hod, 145 5-Mi4 hoxy-l.2-clinwlIiyll~~nziiiiitf:ixale, l~~:t.~~lit~ninr-lo~iltinc iii!crc.nii\.c.).siorr, 251

438

Subjeeh Index

2-~f.ictliylbenzitiiid~izole. bwicity, 251 6IMethoxy-l-methylbenzin~ida~ole, 251 5(or 6)-Methoxy-2-methylbenzimidazole, henzoylation, B 5 bromintttion, 302 25I hydrogenation, 16, 254 2-(u-Me thoxyphenylaro) ~KI idazole. 137 nitration, 304 4(0r 5)-MethylS(or 4)-acetyliniidazolc, reaction with aldehydes, 276 60 reaction with alkali, 280 2-II.letliylb(or 6)-atniuo~nziitiidasole, synthesis, 259-264, 271 synthesis. 256,308 4(or 7)-Methylbenzimidazolc, 251 l-MetliylS-amino-4-carbethoxy-2(3H)5(or 6)-Metliylbenriniidarolc, basicity, imidazolethione, 84 251 I-Methyl-5-aminoa-earboxamido-2(3/1)nietiiylation, 258 imidazolethione. 84 nitration. 305 1-Methyl-4-(Zatuinoethyl)iniidazol~~, synthesis, 263 pliurrnacological properties, 167 Syyulllesis, 160

1 - ~ J e t ~ ~ . v ~ - 2 ~ ~ c ~ n raiiiitfo. i r i i ~ :Kbl i~~~~~~ci1~

or 6 ) - l 1 e n s i i t i i c l : l z o I c ~ ~ l ~ ~ ~ ~ l i ~ . l-Methy~S-(2-rtiiinoetliyl)imitlaso~c, 2-M~c-t.liyl-5( :ic*id. 256. 313 pharmacologic.:il properties, 167 6(or 6)-Mrtliyl-2-1 ~ctisi 111id:izolccnrl~oxsyntlicsis. 160 gliv : i 4 . 278. 313 %Methyl4 (or .5)-C?-amint let 1 1 . ~ 1 iir ) I irlI-MetligI-2(311)-bt~nriniiclazolotic.2%) azole, 160 162 4(or 5)-Mcthy13(or 41-(2-~iiiiiiio(~tIiyl)- 2-MetliyI-.~-l~~nso.~lliiuttrttiinc. imidazole, pliariiiiiaologit.~tl proper- l-Methyl-5-benzoyl-2(3H)-imidasolonc., 75 ties, 187 ;\letiiyl I-benzoyl-4(or 5 )-metliyt-5(or 4 )synthesis. 101 imiduzolerarbox~lil(e. 47 4 (or 5 M Met Iiyluitiinoriic~tIiyl)iniichsole. l-~e~iyl-3-benzyl~~enz~1i1~~l:izo~~un~ io143 dide, 280 ~-Met~l~~~-~imino~i~ti~c~szo~ec.iir~~os1-MethylS-bt.nzylitnid:isoliuiniodide. 51 :iniide. 182 75 Methyl 4(or 5)-aniino-5(or 4)-ii1i:d:izol~- 4-Methgl-5-henzyl-2f3H)-it~1i~l~~olone. 4(or 5)->h-4hy1-2.5(or 2,4)-bis(pheny1carboxylate. 183 nzo)iiiiitlazolc. 1% l-Mrtti,vl-S-iimin~2-2(3H)-iiiuct:izolc~I-hlethyl-l-l)roriioimirtilzolc.nitration. thione. spectrum. 84 128 synthesis, 82 wntliesis. 51 l-Metliyt-5-:iminu-2(3H )-imid;izolvI-Methyt-5.broriioi1riitl~tzole.hydroxythione-4-c.nrhoxnmidr. 85 4(or 5)-(M~thylnminomctl~vl)iiiiid~tzolc, methytiition, 100 nitration. 128 pharmacological properties, 168 2-Mcthyl-4(or 5~-l~ro11ioiriiicl~tzolc, nitrliyntheais. 1fM tion. 128 hlethylation of henzitnidnzolw. 257 nilfonlttion, u)7 of 2f~H)-l~enrimitliixoIrtliii~n1~~, a3 4(or 5)-~~rtligl-~-l~~c1it1~1itiii1l:izol~. I I:{ of imicluzoles, 28. 21 4(or 5)-MrthyM(or 4 ) - t ~ r o i i i o i t i i i t l ~ z o I ~ ~ . of I-riie~1iy1-2(3H)-I1r~nsi11iicii1zot1~1it~, coupling, 137 290 idination, 123 of 4(or 5)-metliyliniitiaeole, 27 synthesis, 113 Methyl a-benzamido-2,edimerctlpto-j4(or 5bMethyl-Nor 4)-bromo-2(3H)imidazoleacrylate, 197 imidazolrthione, 84 4(or 5)-Methyl-S(or 4)-bctiz:rmitlol-h.lrtliyI-41~lani(r5-nitroi~nid~tzole, 128 2(3H)-imiduzott~tliionc. 83 Mvt li~lhfiizitiiiclazol~~, taiitoint.rir;lil. 24.1~ I - ~ M P IItyld-l~r~)~~1oJ1-ui troirnidazotc., IZX I-Mc~tliylt~~nziniid~tzulc, hsivity, 251 2-hI(~tIiy1-4(or.5)-brot1~-5(or4 )-nit 1.0.sytil tie&, ?69, 272 iiiii(l:uole, 128

Subject Index

439

iraction with zinc hydroxide, ammonia. 4(or .5)-MrlIiylb(or I)-c.arhdImxyand aldehydes, 40 amino-2(3ff )-iniiti:tzolethionc. 84 Mcthyl groups, effect on basic strength, 4-Methyl-5-carbethoxy-2 (311 )-intidazo13 lone, 73 4-MethylS-hexal~ydrobenz;vl-2-imidarl-Methyl-4-chloroimidazole, hydrowolidone, 75 methylation, 100 4-Methyl3-hexahyrlr~~~nzyl-2c3H )properties, 6, 12 imidasolone, 76 synthesis, 51 Mcthyi histamines, I60 l-Methyl-5-chloroimidaeolc, hydr0x.v2-Methylhiatamine, 167 methylation, 100 nitration, 128, 180 iV-Methylhistamine, 165 properties, 6, 12 1-Methylhistidine, occurrence, 203 synthesis, 119 synthesis, 204 1-Methyl-5-chloromethylimidazolium N-Methylhistidine, 204 chloride, 204 1-Methyl-2-hydroxymethylb-chlorol-Methyl-4-cyanomethylimidade, 160 imidasole, 100 l-Methyl-5-cyanomethylimidaeole, 160 l-Methyl-5-hydroxymethylimidasole,161 4(or 5)-MethylS(or I)-cyanomethyl4(or 5)-Methyl-S(or 4)-hydroxymethylimidazole, 161 imidaaole, oxidation, 55 ZMethyl-ldecyl-2-imidazoline, 225 synthesis, 99 l-Methyl4,5-rlibromoimidazole,hydroxy2-Methyl-4(or 5)-hydroxymethylb(or methylation, 100 4)-imidaaolecarboxylic acid, 162 synthesis, 112 Yethylimidazoles, rearrangement, M) ZMethyM,5-dibrornoimidazole, 118 1-Methylimidasole, basicity, 15 ZMethyl-4,5diiodoimids&ole,122 bromination, 111, I12 4(or 5)-Methyl-2,5(or 2,4)diiodoimidhydroxymethylation, 100 twoole, I22 nitration, 127 4(or 5bMethyl-Nor 4)-dimethylaminoproperties, 6, 10, I2 111c?tligI-2(3H)-imidasolot~hione, 84 synthesis, 49, 51, 119 2-Methyl-5,6-dinitrobimidazole, 2-Methylimidaaole. basicity, 14, 15 beneoylation, !276 bromination, 111 synthesis, 306 coupling, 136 4-Methyl-I ,3-dinitro-2-imidazoliclone, 241 detection, 138 l-Methyl4,5-diphenylimidrtsole, 6 iodination, 122 2-Methyl-4,5-diphenyiimidasole, melting melting point, 6 point, 6 nitration, I27 synthesis, 35 synthesis, 44 5-Methyl-1,2-diphenyl-2-imidazoline, 218 4(or 5)-Methylimidazole, bromination, 4-Methylergothioneine, 84 I l l , 113, 116 I-Methyl-3-ethylbensimidnaolium iodide, from carbohydrates, 39 280 coupling, 136 4(or S)-Mrthyl-5(01*4)ethylimidazole, 26 hydroxymethylation, 99 1-Methyl-3-ethylimidaoliumiodide, 51 iodination, I22 4-MethylJ-ethyl-2(3If)-irnidazolone, 67 methylation, 27, 29 Methylglyoxal, reartion with acetaldenitration, 127 hyde and ammonia, 34 properties, 6-15 reaction with hensamidine, 93 ring fission, 48 reaction with formaldehyde and amaulfonation, 207 monia, 34 synthesis, 34,39. 88 relrction with urea, 2-30 tnntomerimn, 27

440

Subject Index

I -Met.hyM-iiii i t I:ixctIccmrl ms:i I( lo1 iyela*, 59 conversion tn I-methylhistidinn, 2 04 4(or S)-Metbyld(or 4)-iniidaeolcc.:irhns-aldehydc. mathylation. 20 synthesis, 55 Methyl 4(or 5)-i1iiidssolce~r~oxylatc, methylation, 29 synthesis, 177 2-Methyl4or j)-iinidi~zolecnrbo?lic acid, 137 4(or 5)-Mrthpl-2-iiiiidsxolecsl.boxplic acid, 176 4 (or 5)-h'fetby& (or 4)-iniidnzo~cc~i+ )Oxylic: wid, 137 I-Mcthyl4.bimicl:ixoleclic~tirhos:iiiiiclr,184 ?-Mc!tliyl-4.5-ii~ridnzolctlicarholrylic wid, 137 2-Metli~l-1,Siiiiiclaeolctlis~l~onic acid, 207 4(or 5)-Mcth~liiiiidaxolcmagnesiiim broniiclc. 175 2-Methyl4 (or 5) -iniiclnroleRulfonic. wid.

207 4(or 6)-Mctli~l-2-i1iiitl:irolcai1lfinic~avid. 88 d(or 5)-Mctliyl-2-iii1icI:i~cilc~i1lfonic acid, 208 1-MethyM(3N )-imidnzolcthione, 85 4 (or 5)-MethyI-2(3H)-imidazolethione,61 alkylntion. 87

wid, 232 'J-MetliJ-hiwrr~Il,tunuidiceole, x7

2-Methylrnercapto-2-imidsaolinc. 240

2-Methylmercapt o-2-imidri zoliniunt iodide, 238 %Methyhercap toJ1-iirctliylliistidine methyl ester, 84 gMethylmercapto-4.methylxnntliine, 183 2-Methylmercaptd(or B)-nitroimidnzole, 87 Methyl l-iiietIi~I-4.biniiclnzoledicarboh;ylatc, 179 4(or 5)-Metliyl-2-11irlli~l1iincl.captoimiRazoic, 61 Methyl 2-inct hyInicrc:ipto-4(or 5)methyl-ti(or 4)-imidazolecnrboxyInt~. 86 1-Methyl-2-IIIC t hyluicrc~~ 11 10-5- ( pheny Ithioforiiinniido)-4-imidnzolec:ii~boxamidc, 183 6Metliyl8nietliyl~iiel.e;ll,tos;lntliin~,183 2-Mctliylnaplitliin1idasolc, 260 4-Mrthyl-2-niir:iininu-2-iiiiitlazolinc, 240 4- or 5.hletlipl-2-nilrnmino-1-nitro-2 iniidnzolinc. 241 I-Mctliyl-4-nitro-5-riiiiinoimidazolc,120

.

I-Mctliyl-5-nitrobenzimidazole,251

2-MethyI-S(or 6)-1iitrohenzimidrlsolc, bnsivity, 251 antithyroid activit,y, 89 Iimzoplation, 276 oxidation, 88 nirthplation, 258 rr:ic*(.ionwith ;\r-l,roiiiofluc.t.iniinidc. 89 nil rat ion, 306 rcwtiou with icdinr, 89 rrwtion with Iicnz:tldehgde, !278 spnctruiii, 84 rrduction. 308 t ( o r li)-Met.)i~l-2(3//)-iniicIntolcthionc?- synthesis. 305 &(or 4)-c~nrhorylic:icid, 86 5(or 6)-M~thgl4(or5)-nitrobenzimid~-MetIi;\-l-Ziiiiiclnrolidon~-caproic: acid. nzolc, 305 231 l-Mrtliyl-4-1iitro-5-c~liloroimidaeole, re2-Mei liyl-2-i1nidneolinc, hcnzoylntion, 221 nc-tion with nmmonin. 120 reaction with r*ynnidc. 120 prol'ortica. 219 reriction wit.h Imnrgl cliloridc, 223 rcwtion with siilfitc, 120 synthesis. 213 synthcais. 180 2-Methyl-2-iniid:izolinii1mcliloride. 223 i-Mrtl1~lJI-nitro-5-~ynnoimi~lnzoIe, 120, 2-h.iethylimidaeoliiim ion, 14 180 4(or S)-Metliglimiclraolium ion, 14 I-Metlipl-4-nitroimidazole, baaicity, 14, 2-MethgI-4(6?~)(or 5(4H) )-imidazolone. 132 97 Iigdrorymethylation, 100 4(or S)-M~t.hgl-2(3H)-imidazolonn, 61 synthc8is. 51, 128 acylstion, 69 l-l\lctli~l-Fi-nitroimidazolc,bsaicity, 14, Friedd-Crafts wylnt ion, 6% 23.3 I32 3.Methyl-2(8N)-imid~rolona4-csproic, hydroxynicthylntion, 1fW

reduction, 135 synthesis, 128 2-Methyl4or 5)-nitroiniidazole, niethylation, 29 reduction, 135 synthesis, 127 4(or S)-MethyW(or 4)-nitroimidazole, bromination, 112, 115 methylation, 29 reaction with benzaldehyde, 132 reduction, 143 synthesis, 127 l-l\iIethyl5-nitro-2(3H)-benziluid~olone, 288 I-Methyl4-nitro-5-imidazolecarboxamide, 180 Methyl 4(or 5)-nitrob(or 4)-imidazolecarboxylate, 29 l-Methyl-4-nitro-5-imidazolecarboxylic acid, 134, 180 1-Methyl-5-nit.ro-4-imidazolecarboxylic acid, 134 l-Methyl-4-nitro-5-imida~olesulfonic acid, 120 l-Methyl-S-nitro-4-(p-nitrophenyl)irnid=ole, 130 4(or 5)-Methyl-5(or I)-nitro-Z(pnitrophenyll-imidazole, 130 l-Methyl-4-(p-nitroplien~~l)imidazole, 130 2-Methyl-N-(p-nitrophenylsulfonyl)%imidnzoline, 222 2-Methyloxaeole-4-carboxylic acid, reaction witti ammonia, 44 4(or 5)-Met liyl-2-~1lienyla~oimidazole, reduction, 140 synthesis, 136 I-Methyl-4-phenylimidazole,52 1-Methyl-5-phenylimidnzole, 62 %MethylJI(or 5)-phenylimidaeolc, 43 4 (or 5)-~~ethyl-2-pbenylimidazolc,Iiydroxymetliglation, 100 nitration, 130 synthesis, 43 4(or S)-Metliyl-2-plien~l-4~5~)(or 5(4H))-imidezolone, acetylation, 97 .salts, 98 synthesis, 93 ?-Met.hylsl-plienylos;lzolc, rnwtiou wit11 ammonia, 43 5-Methyl-2-~11enylosazole-4-c.nrbox~lic .~ acid, reaction with ammonia, 44

CMetliy I-2-pheny I- 1-p- lolylbenzimidazole, 259 4(or 5)-Methyl-2-styrylimidtuola, 176 5(or 6)-Methgl-2~tyrylbenzimi~zole, oxidation, 313 synthesis, 276 2-Methyl-l-tetradecy1-2-iniidasdine, 225 4( or 6)-Methyl-Zthiolacetylimidaaole,84 l-Methyl-2,4,6-tribromoimidazole,111 4-Methyl4or 5)-ureidoS(or 4)-hydraxyZimidazolidone, 230 I-Methylximthine, 182 9-Methyhnthinc, 184 Microbiological estimation of hi*t.idine, 193 Microorganisnw effecting dec.:rrl~oxyl:ition of histidine, 149 Molrcdar weight determiniition, 7

I

N

2-(l-Naphthylmethyl)-2-in1idazoline,226 Nickel, b e y , see Dc,nlfuriaation Xnhydrin reaction of Iristidine, 200 2-Sit~mino-2.imidazoline~, hydrolysis, 229 reaction with amines, 240 synthesis, 240 2-Nitramino-l-nitro-2-imidamline,240 Xtranilic acid as precipitant for histidine, 191 Sitration of benzimidazoles, 304 of itnidazoles, 127-131 of Zhidaeolines, 220 of lophine, 47 Kitriles, in benaimidazole syntlieaes, 26; reaction with ethylenediaminc. 216 o-Nitroacylanilides, reduction. w8, 285 Nitrobensimidazoles, 304 acidity, 249 tautomerim, 248 5(or 6)-Sitrobenzimidazolc, Im4cit.y, 251 benzoylatian, 276 reduction, 308 5(or 6)-Nitr0-2(3H)-he~imidnzolone,

276

;\'-p-NitrobenzoyJlii~~,itline, 201 I-(o-Nitrobenzylidene)-I,~lil~lIt~rr~l~~ iriiidazolone, YS 4(or 5~-Sit~o-2-benxrliiicrc.~n~oir1~id:rzolc snlfoxidc, 87

442

Subject Index

2-p-Kitrophenylimidazole,acylation, 49 synthesis, 130 4(or 6)-(pSitrophenyl)imidaeole, nitrati-Nitro-l,2-dimethylimidazole,134 tion, 130 &Nitro-l,4-diniethylimidazole, I15 synthesis, 130 &Nitro-l,4dinietliyl-2-iinidaeole~ullonic c ( p Kjtroplienyl)-l-i~cthylimid:ieole,130 acid, 119 Z(p-Nitroyii~nyI)-4(or5)-methyl-5(or 4(or 5)-Nitm1,3-diii1etliylimiclszolium 4)-nitroimidazole, 130 iodide, 51 4(or 5)-(p-Xitrophenyl)-5(or 4)-nitroNitrogem, aunitming of, 3 imidazole, I30 Sitroiiniduzoltw. 121-335 4 4 ~~~itrophenyl)-5-nitro-l-nielliylimidNitroiruidazolea, basic strength of, 14 azole, 130 bromination, 115 voupling, 139 ~V-(p~itrophenylsulfonyl)-2-methylaurvey, 345 Zimidazoline, 222 4(or 5 ) - ~ i t ~ ~ i ~tia3iuit3,, i d ~ ~132 ~ l ~ , 5(0r 6)-Nitro-Zstyrylbenzimidazole,278 4 (or 6)-xitrob(or 4)-styryfimidazole, hydroxyinetliglfition, 100 metliylation, 29 methylation, 29 synthesis, 133 reduction, 135, 142 Komenclature, 3 stability, 48 2-(Aldopolyhydroxyalkyl)himidtjynthesis. 127 4(or Q)-Nitro-S(or 4)-iinidrtzolecarboxazolee, 2(n amide. niethyl;ition, 2!l henzimidasola, 241 reduction, 180 liistidine derivatives, 188 4(or 5)-Nitro+j (or 4 )-in1 idaso lecarboxy I ic iin idneolethiones, 60 imidazolidones, 213 mid, 134 8(or 4)-Nitr04(or 5)-iiiiiclrru,olc~~Ifonic~ imidarolinw, 213 acid, 118 imidaeolones, 60 I-Nitro-24minoimiditzolidinium cliloritlc, Sucleosides from i m i d a z o l e c h d h , 241 184 .~Nitro-l-iiirthyli~i~~i~iiniil~eolr, 251 Sumbering, 3 5(or 6)-Nit~o-2-iiictliyi~n~iiiii~:irol~~, basicity. 251 mrthylation, 258 0 5Nitro-l-nicthy1-2(31~) - ~ t ~ n t i i i i i c ~ : ~ x o ~ t ~ i i i ~ , 288 Opt i t ' d isomerism, desthiobiotin, 231 4 (or 5)-Nit ro-5( or 4 )-nietliyi-Zbroinollistidjne, 187 imidaznlr. 2!4 Oximliydro bases,284 4-Nit~ro-l-m~tliylirniil;ixolc.100 Oxaroles. reaction with ammonia, 43 Mor 5bSitrcr-2-nii~tIiy1iiiiiil:mnb. 21 Oxarole-4-c*arboxylic acids, reaction with Nor 5)-Niti*0-.5(or 1 hiidlt.~liiiii~l:t~c)l~~, 29 ammonia, 44 bNitro-l-metl~yliniiiInaoI~,100 Osazolon~, reaction with ammonia, %j 4(or 5)-Nitro-ZnictIiyIiiic~~cnptoiiiiiilazole, 87 Oxbenzimidaeoie, 284 I-NjtrbQ- or &lll,.t Iiyl-2-nitrilniin+2E.2- Oxidation of 2(311)-iinitlnrolethiones,88. imidaxoline. 24 I 206 l-~itro-2-nitrrti~iinti-~-ii1iicl;izc~linc~. 240 of 2(3H)-iiiiidi~oloncs, 73 of nicthplboneimidnzol~s,251.313 4(or b)-Nitr&f or 4 I-( p-ni txoplic~npl)of styrylimidnzoles, 134 imidazole. metliylnt.ion. 29 8.ynthesici. 130 Oxnimidnrolrs. .W l-(p-NitroDhenyl)imiclanolc, 129 Osgd~cinminoliistidinc,1&5 4(or 5)-iWitru4(or 4)-broiiioiiiiiitszole, 29 4-Nitro-l,2-dimethylimidazole,134 4-Nitro-l,5-dimethylimidazole,115

Subject Index

P

i’alludiuu~ tlckction. m 2 Paper rhromrrtographg, 139 for liistumine detection, 148 Parabanic acid, 73 Pauly test, 2-ap~lamidoi~idazol~s~ 14 1 benaimidazoles, 255 histamine, 147 histidine, 191 imidazoles, 46, 136, 139 2 (3H )-imidazolethiones. 86 4(5H)(or 5(4H))-imidaeolones, 98 polyhydroxyalkylimidazolw, 104 Periodate, reaction with 2-(aldopolyhydrowalkyt)&nzimidazola, 299, reaction with 2-( l’iQ‘-anhydropolyhydroxysllryl)benzimidszoles,299,300 Perkin azlactone synthesis, 196 Pharmacological properties of desthiobiotin, 234 of histamine, 143, 165 of 2(3H)-imidaeolethiones, 80 of 2-imidazoliies, 2.24 of ureylenecyclohexanes, 291 2-(pPhenetylazo)imidazole, reduction, 141 synthesis, 137 Phenolic properties of imidamlones, 62 2-Phenylazoimid~zole,reduction, 140 synthesis, 138 2-Phenylazo-4(or 5)-methyIimidazole, 140 1-Phenylbenzimidazoles, 302 2-Phenylbenzimidazole, basicity, 251 hydrogenation, 254 synthesis, 285-213

443

-1-1’11~~11~1-l,~-tliii~dros~-~-i1iiid:~olidonc, tichydration, 2.30 syntheRis, m

Sl’lir~~yld,fi-dili~~li~~~~~-~ M- i i i ~ i ~ l : i ~

2-~Irrn~I-fi.~tli11i~tl~~lb~nzi1nidezole. 251 a-Phenyl-4Sdimethyl-~hYd~xY-2imidnzoline, 101 2-Phmyl-4,4(or 5,5)-diniethyl-4 (5II)(or M4H) )-imidazolone, 95 o-Phenylenediamine in t)enzimidszolc syntheses, 258-273, 311, 316 in 2(3H)-benzimidneolethione synt hcsa, 291 in benzimidazolone syntheses, 286 in 2-chloromethylbenzirnidazolesynthcses, 303 o-Phewlene~anidines, 309 o-Phenylenethiocarbamides, S l o-Phenylenethiourem* m1 n-Phenyleneureas, 285 Phenylglyoxal, reaction with forrnaldehyde and ammonia, 34 5-Phenylhydantoin, 230 I-Phenylhistidine, 204 l-Phenylimidaeole, nitration, 129 properties, 0, 12 2-Phenylimidazole, acylation, 49 roiipling, 136 nitration, 129 properties, 6, 15 4(or 5)-Phenylimidazole, bromination. 114, 116 methylation, 29 nitration, 130 properties, 6, 15 2-(N-Phenyl-N-benzylaminomethyl)-!& reaction with p\.r.idiniiiin-N-;9iiIfoIii(! imidazoline, 226 acid, 208 2-Phenyl-4(or 5)-bensylidend(5H) (or synthesis, 34 5 ( 4 H ) )-imidazolone, reduction, 2-Phenyl-4(or 5)-irnidruolernrl~oxyli* synthesis, 93-95 acid, coupling, 137 2-Phenyl~-benzyl-5-imidazolidone, 99 nitration, 131 4(or 5)-Phenyl-2-bemyknereaptoimid- 2-Phenyl-4,6-imidneoledicart~oxylicacid, asole. 81 coupling, 137 2-Phenyl-4(or 5)-(pbromophenylluro)nitration, 131 5(or 4)-imidazolecarboxyli~ acid, 137 4(or 5)-Phenyl-l-imidaxolesulfonic acid. N-Phenylcarbamyl-Zimidazoline,219 206 4(or 5)-Phenyld(or 4)-carbethoxyamino- I-PhenyI-2(3H)-imidasolethione, 77 4(or 5)-Phen.vl-2(3H)-imidazolethion1!, 2(3li)-imidazolethione, 84 82 Phenyldiazonium chloride (see also Pauly test) reaction with imidazoles, 136 4-Phenyl-Zimidazolidone, 227

444

Subject Index

~ - l ’ l i i ~ t i ~ l - ‘ ~ i i i i i c j ~ r ~iiilrxti~iii. ~ l i i i ~ ~ , 131

synthesis. 217 S-Phenyl4rliH) fnr S(4H))-iniiiitwdotit., (3f

4(or 5)-h.uyl-2(3/f )-itiiic~:txci~oiic~, rd N-Pheny lloph ine, 45 I-Phenyl-2-methyM,7-dini tro-5hydroxybenzimidazolc, 307 henzoylation, 276 %Phenyld(or 5)-mcthylb(or 41-11~droxymetliylinudnsole, 101 ?-Phenyld(or 5)-methylimidnaolr. l i p droxymethylation, 100 nitration, I30 synthesis, 43 P-Phenyl-4(or 5)-methyl-4(bH)(or 5(4H))-imidazolonc, nrctylaition, 97 hydrolysis, 99 salts, 98 synthesis, 93 2-Phenyl-4(or 5)-(2-l,iperidinactliyl)imidazole, 163 Phenylsulfonyl rhloride, rcnction with 2imidazolines, 222 N-Phenylthiocarbamyl-Z-i~nicl:troline,219 Phenylthioureidoacetal, 77 Phillips synthesis, 261, 298 Phosphotungstic acid as histamine precipitant, 145 as histidine precipitnnt. 192 I-(2-Plithnlimidoetliyl)imicinzolc, 150 Phpiological propertica, src Pharmacologicnl properties Pi clrrtrons, 20 1’in:trolic. shift, 231 4 (or 6)-(2-Piperidinoctli.vI)itiiicinzole,dctertion, 138 synthesis, 163 l(or 5)-(ZPipcridinonirt.li~l)iniicinxolc, 138

1’ol:irity of neoles, 19 l-~o-Poly~rctylglycos~l) hcnzimicliixolcs, 295 Polyliydrox~Hlkylimidnzol~s. 104 Polymers, 25 Polymorphi.sm, 27 Prkoline, 2 5 Privine, !220 4 (or 5)-~2-I’rn~~yl~tiiiinoittr~ ltyl ) itn idnznlr, 1x3

l-f’roiiylbmriitiidHzolr, 261 ~Propylbenzimid~xol~~, 251 N-Propylhistmnine. plia r t w c-olo~ic.:~ I properties, IM I-Propylimidazolt:, 6, 12 4 (or 5)-n-Propyl-2 (3If -in1idazoIcthione, 90

Protein hydrolysis, 184 Proton shift, 30, 60 Pseudoacidic charactrr, sec Acidity Purines from aminoimidazolecnrboxnmides, 182 l’ymnn synthesis, 150 Pymzole, 5, 22 l’yridine, 20,21 I’yridine nitrogen, 21 .~’-P~ridoxylhistamine,157 S-Pyridoxylidene histamine, I57 Pyrimidines, conversion to imidnzolones, 67 Pyrrole, 5, 20 Pyrrole nitrogrn, 21 Pynwaldehydc, RCC Mrthylglyoual

0 Qualitative analysis of iniidszolrs, 130 Quantitative estini:ition of histamine, 146 of histidine, 189 of imidazoles, 139 Qiinterneriration, 49

R 1turtiiix:ition of hi..tidiiic, 201 Radionrtive Inbellisg, 2M Ihdaiszewski synthesis, 33 scope, 37 yield, 38 Rsman spectra, 11 Raney nickel, sre Desulfuriaation Reduction, of nrylnzoimidnmoles, 140 of o-dinitrohcnzcnc derivntircs, 280 of 5-imidneolecnrboxaldehydcs, 101 of 6-imidautlecarboxylates, 101 of 2(3H)-imidasoloncrt, 75 with lithium aluminum hydride, 101, 159, 161, I77 of o-nitroacylanilides, 258, 284 o f nitrohanzimirlnznlrs,

445

Subjeut Index d nitrohidazoles, 136, 142 of %phenyM(orb)-bensylidend(5H)(or [i(~))-imidasolone,89 Reductive acetylation of 4(or 5)-nitroimidazole, 142 Refractive index, 12 Resonance, 14 (see alao Hybrid structure) Resonance stabilization of imidaeolium ion, 23 ~-Rhamnose,reaction with zinc hydroxide and ammonia, 40 Ribazole, 293 l-a-p.Ribofursnosyl-5,~dimethylbeneimidazole, 293 I-(pD-RibofuranosyI )-4,&iruidttzoledicarboxamide, 184 Ring h i o n of 4(or 5)-acetamidoimidasole, 143 of bensimidaaoles, 274-276 of 2-hnzyl-4(5H) (or 5(4H))-imidazdone, 98 of 1f-dialkylbenzimidazolium salts, 280 of 1,3-dimetlylb(or 0)-nitrobenziniidnsolium salts, 305 of imidasoles, 48, 51 of nitroimidazoles, 135 of 2-phenyl-4(or 5)-methyl-4(5H) (or 5(4H))-imidarolonc, 99 S

Saccharodibenzilnidaaoles, 300 Saponification of 2(3H)-imitInzolone6(or 4)-carboxylntes, 63 Schotten-Baumann reaction, see Acylntion Solution, heat of, 13 Lsorbosc, reaction with zinc hydroxide and ammonia, 40 Spectroscopic properties, 11 !,-Spinach, 205 Stereoisomerisin. dcsthiobiotin, 231 histidine, 187 Structure of i n k h o l e , 17, 24 (see ulso Hybrid structurc) 2-Styiylbenzimidd~ol~, osictntion. 314 synthesis, 276 StyryIitiIid:tzoles, ositl..I I 1011. ’ 134

4(or 5)-$tyryl-B(or 4)-nitrohidazole, 132 Substituenta, directing influence of, 28 effect on association, 9 effect on bnsicity, 13 effect on methylation, 28 effect on tautomerism, 28 numbering of, 3 Sugars, identification, 297, 299 reaction with zinc hydroxide and animonia, 39 synthesis of imidazoles from, 39, 104 Sulfite, reaction with bromoimidaeolos, 117 reaction with iodoirnidazoles, 123 2-(l-Sulfoalkyl)beneimirnidazolc, 318 Sulfonation of bengimidazole, 317 of imidasole, 207 2-(p-Sullophenylsao)imiJuzole, reduction, 141 synthesis, 137

2-(pSulfophenylazo)~~-imidnsoledicarboxylio acid, 137 Surface active agents, 224 Surface tension, 13 Symmetry of imi&tzoliiim ion, 23

T Tsrtaiic acid, reaction with urea, 67 Tsutomerism, of 2-nniinol~enziii~idaeok~, 309 and association, 28 of benzimidazoles, 247, 255 of 2(3H)-benzirnidazoiones,285 effect of substituents, 28 of histidine, 188 of imidaeolee, 25 of irnidazolones, 60-63 of 4 G H ) (or 5(4H))-imidazolones, 97 and intramolecular reaction, 30 T:iutomers, numbering of, 4 Tertiary nitrogen, basic properties, 21 1-(Tetra-O-acetyl-B-D-glueopyl.unosy I) benzunidaeole, 293

-

I-Tot ru-O-Ycebl-lr-ngliicopy~:lnosyl

irnidazolr., 105

I-‘re1I : i ~ - : ~ C ’ C . I , ~ l - ~ - ~ g l U U U ~ l ~ I . : 1 D 1 ) R ~ I ~ 2-Styryl-S(or O)-iiic:~.lt~ll~c~iieiiiii~laei~1~, iiietliyliiiriclttrrule, 106 276 ‘I’c~ttuliydroiri~idaaolex, see Ii11id:i~~)lidi~~(~..

2-St,yryI-4(or ri)-metliyliinictazole, 170

1~,4,.~Ti?Lr:iii~~eiiiiiic~:iro~c, 122

446

Subject Index

1 , 3 , 5 , ~ T e t r a m e t h y l ~ ~ i m i d ~ o l i u m 12~Trimethylbenzimidazoliumiodidc, reaction with alkali, 282 ion, 263 reaction with p-diiethylaininobcnz1,2,4$-Tetraphenylimidazole, 45 aldehyde, 278 1J,4,5-Tetraphenyl-2(3H)-imidazolone, 4,7,9-Trimethyldihydro uric acid, 67 66 N-Trimethylhistamine, I66 Tetruzole, 22 S-Trimethylhistidine, 205 Thiazole, 20, 22 1~~-Triinethyi-2-liydroxybenzilnidazThioamides, reaction with ethylenedine, 284 diaminc. 216 basicity, 15 ?-Thiobenzimidamlones, .see 2(3N )-Benz- 2,4~Trimet~yliluidlarolc, iodination, 122 imidtrzolcthioncs synthesis, 36 Thiocyanate, reaction wit I i itininowetat, 1.3,4-Trimethyl-2(3H)-iniicl:czolonr.67 79 l~;J-Trimethyl-2(3H)-ii1iicl~zolont~~ reaction with a-aminoaltlr~liyclew.80 cwboxylit. nciel, asterifit*atiori,77 reaction with a-amino-&kctoentma, 81 oxitl:ition, 73 reaction with a-aininoketones, 79 synthesis, 67 reaction with o-glumsitmine, 104 ronrtion with o-plimylcndiaminc, 292 2,4,4-TrimetIiyl-1-~o~)ropyI-2-iniidiuolinc, 214 2,2'-Thiodi-2-imidwoline, 237 2,4b-Triphenyliiirid11zole, 8ee Lophinc Thioethers, 86 2,4,5-Triphenyl-2-iniidazoline,see AmaThioimidazoles, see Imidazoletliiones rine Thiourea. reaction with o-phenylene2.1.5Triphen~I3-iiiiida;coline,45 diamine. 291 2.4,5-Tris(~liloiti~~lienyl)imitlazoIe, 13 Z(o-Tol?Jlaso)ioiidazale,137 13 2-(~~-Tol~l~1rofiiiiitlrixolt~. rrcliwlian, 141 2,4.5Tris~p-riit~tIiosypIienyl)iinitlazole, 2,4,S-Tris(yiiict It~l~~licnyl)imidazole, 13 syntlieriis, 137 2,4~-Ti~s(p-nitro~~lirnyl)imidnzole, 47 I-p-Tolyl-2-pIion~I-;i-iilct Iiyll Penziinid2.4~Tris(phenglazo)irnidazole,138 nzolc, 259 2,4~Tri-ptolylimidilzoic,13 2A~Tri-~;ini~~limid:isolc, 13 Triazoles. 5, 22 U 2,l~-TribromoiiniducuIe, acidity, 16, 117 Ultraviolct :rlJaorption spectra of h e nrylation. 49 imitlazolcs, 253 reaction with sotliiim iimalglrm, 117 of Z(hydro~yphmngl)benzimidazoles, reaction with sulfilr, 117 25 synthcsiiris. I l l of imidnzoles, 11 2,4,5-Trihrnino-l-nic~Iiglimitlazolc, 111 of 4(or 5)-imid:ieolat~nrbns:iIdchyde,,513 TrichlorodinicthyIhcnzimidnsolr,301 of 2(3H)-imidaaoictl1ioncs. 85 2,4~Tric~yc~lolicxyl-~imid~zolinc, 47 2-Undccyl-2-imidazoline, 225 ?-TritIe~ryl-2-imidsaoline, 225 I'rnoils. conversion t o iinidazolones, 67 ~.4~Tri-~2-hiryl)irnidazule, 39 Urcn. in hydantoin syntheses, 230 2,4,5-Triiodoiniidazolc, rcuction with sulreaction with acyloins, 66 fitc. 124 reaction with dibromoimidnzolidoncs, synthesis, 122, 178 71 1,2,5-Trimettiylbenzimidazole, basicity, reaction with a-dicarbonyl compounds. 261 229 syntlirisi..;, 259 reaction with clhylvnedianiine. 2'27 l..j,~-'~riiii~~~Irylbcueiiiiitl;~xolc~, lxisit-ity, reaction with ethylem? glywl, %% 251 rcwtioii wit11 glpoxul. %B> iiltrwiolct absorption spcctruiii, 255 readion with nietliglglyuxd, DO 2,~,O'l'iiiiic.Lliylbcn~~1iiid:i~olc, 251 rriction with o-phenylenediamincs, 2%

Subject Indcs

447

1 (or 5)-Ureidoimidazole, 342 4 (or 5)-1Jreidod(or I)-imida nolec*:trboxylic acid, 183 Urcylenecyclohexanea, 291

yidtl. 39 \Yinda\ur synttiwis, 1.50 Wold-Marckwald synthesis, 20, 88 Wood-du Vigneaud synthesis, 231

V Vasoconstrictor, 226 Viscosity, cffect of association on, 10 Vitamin Bu hydrolysis, 276, 293

X Santhinc, 183 ~ S y l o s e ,remtion with zinc hydroxiclc and ammonia, 40

W

Wallach reaction, 119 Weidenhagen benziinidazole syntlmis, 269 Weidenhagen synthesis, 38, 104 scope, 39

Z

%iminermanntest., 165 Zinc hydroxide, reaction with methylglyoxal, ammonia, and aldehydes, 40 ieartion with sugars and ammonia, 39

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