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JOHN B. WRIGHT Rsesarch Laboratories, The Upjohn Company, Kalamazoo, Michigan
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....... I. Introduction.. ............................ ....... 398 1 . Synthesis of benzimidazoles.. . . . . . . . . . . . . . 1 ............................ 401 A. From o-phenylenediamines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 1. By reaction with carboxylic acids . . . . . . . . . . . . . . . 401 a. Monobasic acids.. . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 b. Dibasic acids.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408 2. By reaction with acid anhydrides.. . . . . . . . . . . . . . . . . . . . .411 a. Anhydrides of monobasic acids.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411 b. Anhydrides of dibasic acids.. . . . . . . . . . . . . . . . . . . . . . . . .416 3. By reaction with esters. . . . . . . . . . . . . . . . . . . . . . . . 418 4. By reaction with amides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423 5. By reaction with acid ch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428 6. By reaction with lactones.. . . . . . . . . . . . . . . . . . . . 428 7. By reaction with nitriles a. Reaction with cyanogen bromide. b. Reaction with other nitriles.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431 8. By reaction with aldehydes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434 9. By reaction with ketones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439 a. Ketones containing one carbonyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439 b. Ketones containing two or more carbonyl groups. .................... 440 10. By reaction with potassium hydroxide and chloroform 11. By reaction with imino-ethers and imino-thioethers.. . 12. By reaction with amidines and guanidines.. ............................ 444 13. Preparation of 2(3H)-benzimidazolones (or 2-hydroxybenzimidazoles) . . . 446 14. Preparation of 2(3H)-benzimidazolethiones (or 2 15. Preparation of 2-aminobenzimidazoles. . . . . . . . . B. From monoacyl- and diacyl-o-phenylenediamines. . . . . . . . . . . . . . . . . 456 C. By reduction of acylated o-nitroanilines.. . . . . . . . . D. From o-aminoazo compounds ; the preparation of N-(ary1amino)benzimid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462 . . . . . . . . . . . . . . . 464 F. Benzimidazole derivatives of sugars.. . . . . . . . . . . . . . . . . . . . 464 G. iLPseudobases”. . . ................................. 466 1. Structure.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466 2. Preparation.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468 H.Miscellaneous syntheses.. . ................................. 470 I. Syntheses from other benz ................................. 474 1 1 Physical properties of benzim 1. ......... ...................... 475 ................................. 477 , . , . , . , , . , , , , , . 477 1. Reactions involving the nitrogens a t the 1- and 3-positions. . . . . . . . . . . . . 477 a. Alkylation.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477 b. Acylation.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481 c. The action of Grignard reagents on benzimidazoles.. . . . . . . . . . . . . . . . . 481 397
JOHN B. WRIGHT
d. Benzimidazoles in the Mannich reaction.. ........................... 482 e. Metal derivatives of benzimidazoles. . . . . . . . . . . . . 2. Reduction of benzimidazoles; hydrogenated bensi genation of reduced benzimidazoles.. ................................. 484 3. Cleavage of the imidazole ring.. ....................................... 486 489 4. Halogenation.. ........................................................ 5. Nitration.. ............................................................ 495 6. Miscellaneous reactions. ..................... 495 groups.. ................. B. Reactions involving substit 1. Reactions involving the 2-methyl (or methylene) group 2. Reactions of 2-benzimidazolecarboxylic acids. .......................... 502 3. Reactions of 2-(~-haloalkyl)benzimidazoles. .............. . . . . 503 4. Reactions of 2(3H)-benzimidazolones (or 2-hydroxybenzimidazoles) . . . . . 505 5. Reactions of 2(3H)-benzimidazolethiones 6. Reactions of 2-aminobenzimidazoles. . . . . 7. Reactions of o-benzoylene-2,l-benzimida .......................................... 517 nzimidazole nucleus VI. Biological action of be VII. Uses of benzimidazoles VIII. References.. . . . . . . . . . .
I. INTRODUCTION The benzimidazoles contain a phenyl ring fused to an imidazole ring, m indicated in the structure for benzimidazole (I).
This important group of substances has found practical applications in a
number of fields. Recently the interest in benzimidazole chemistry has been revived somewhat by the discovery that the 5,6-dimethylbenzimidazolemoiety is part of the chemical structure of vitamin Bu. Historically, the first benzimidazole was prepared in 1872 by Hoebrecker (327), who obtained 2,5(or 2,6)dimethylbenzimidazole (11) by the reduction of 2-nitro-4-methylacetanilide (111).
CHEMISTRY OF THE BENZIMIDAZOLES
Several years later Ladenburg (446)obtained the same compound by refluxing 3 ,4-diaminotoluene with acetic acid.
Since compounds of this type were formed by the loss of water, they were called “anhydrobases” in the very early literature. It was subsequently shown (335, 339, 343) that “anhydrobases” of this type were formed only by compounds i n which the nitrogen-containing groups were ortho to each other; that the ring formed was an imidazole ring was indicated by certain reactions of benzimidazoles, such as the fact that imidazoledicarboxylic acid may be obtained, although in small yield, by the oxidation of benzimidazole (40).
The benzimidazoles are known also as benziminazoles or benzoglyoxalines. They have been named also as derivatives of o-phenylenediamine, especially in the early literature. Thus, benzimidazole according to this nomenclature would and 2-methylbenzimidazole would be be called methenyl-o-phenylenediamine Also, they have been named as derivatives called ethenyl-o-phenylenediamine. of the grouping composing the imidazole portion of the ring. Thus, for example, benzimidazole has also been called o-phenyleneformamidie) and 2 (3H)-benzimidazolone (IV) and 2(3H)-benzimidazolethione (V) are known also as o-phenyleneurea and o-phenylenethiourea, respectively.’
The numbering system for the benzimidazoles is aa follows:
Occasionally the 2-position is designated as the p-position.
1 For examples in which benzimidazoles have been named as benzene derivatives ma references 166,192,193, and 751.
5. 6 (or 2 .4. 7 ) a t first to be isomers are in reality tautomers. 5 .6 t C' H N ~ @ H (&) VI VI1 Thus.7) 2. This may be depicted as follows (172)': H This tautomerism is analogous to that found in the imidazoles and amidines. 6 (or 5 . may be considered as cyclic analogs of the amidines. 6 . This may be illustrated with 5(or 6)-methylbenzimidazole : CH3flrY kq. 5-methylbenzimidazole (VI) is a tautomer of 6-methylbensimidazole (VII).7) 4. 6 . although two nonequivalent structures can be written.4. 4 . the second number or group of numbers being placed in parentheses. The benzimidazoles. WRIQHT Benzimidazoles which contain a hydrogen atom attached to nitrogen in the 1-position readily t. In designating such tautomeric compounds two numbers or sets of numbers are usually given designating the positions of the substituent group (or groups). 7 ) 2 . 5 (or 6. 7 ) 4 . 5 . only one compound is known. 6 . According to this convention the compound designated by the pair VI-VI1 is written 5(or 6)-methylbenzimidazole. 4 . 5 . 4 (or 2. 6 . 7 ) 2.automerize. 7 (or 4 . 7 ) 2. in fact. . and both structures (VI and VII) represent the same compound. 6 (or 2 . 7 ) 4 .7 (or 2 . 5 .6 (or 5 . In table 1 are illustrated the equivalent tautomeric pairs in benzimidazole derivatives. 7 ) 2 .5 (or 2 . 6 .5 (or 2 . Because of this tautomerism in benzimidazoles certain derivatives which appear TABLE 1 Equivalent tautomeric pairs in benziniidazole derivatives POSITION OF SUBSTITUEKT GROUP(S) I N FIRST TAUTOMER POSITION OF SUBSTITUENT GROUP(S) I N SECOND TAUTOMER DESIGNATION 4 (or 7 ) 5 (or 6 ) 2 . 6 ) 4 .400 JOHN B. 5 . 4 .
FROM O-PHENYLENEDIAMINES 1.g. etc. By reaction with carboxylic acids a. naphthimidazoles. The reaction is carried out usually by heating the reactants together on a steam bath.5-dimethylbenzimidazole and 1. 1.6-dimethylbenzimidazole are separate and distinct compounds. or by heating in a sealed tube. SYNTHESIS BENZIMIDAZOLES OF Practically all syntheses of benzimidazoles start with benzene derivatives possessing nitrogen-containing functions ortho to each other. usually in very good yield. benzobisimidazoles. such tautomerism is not indicated and isomeric forms exist. Monobasic acids o-Phenylenediamines react readily with most carboxylic acids to give 2-substituted benzimidazoles. Acetic acid gives a 68 per cent yield of 2-methylbenzimidazole (107). 11. As is evident from this table. The present review is concerned only with the chemistry of the benzimidazoles. Walther and von Pulawski (736) report that aromatic acids containing a nitro group in the ring lead to almost complete carbonization because of the . the starting material possesses the function designated by formula VIII. A. The acids that have been used in this general reaction are listed in table 2. also included are selected papers that have appeared in the literature in 1950. a wide variety of acids have been employed. and concentrations as + RCOOH - + 2z H0 low as 25 per cent formic acid have been used successfully. Those compounds which contain a fused phenyl and imidazole ring m part of a higher condensed system (e. by heating together under reflux or at an elevated temperature. Thus. that is. The literature is reviewed through Volume 43 (1949) of Chemical Abstracts. The use of anhydrous acid is not necessary.) are not included.CHEMISTRY OF THE BENZIMIDAZOLES 401 When the group attached to the nitrogen in the l-position is larger than hydrogen. phenanthrimidazoles. VI11 In the following discussion the synthetic methods have been grouped in the main according to the starting material used. Benzimidazole may be prepared in 8385 per cent yield by using 90 per cent formic acid (107)..
.... ... . .... ..... . . ... .. .... (107.. .. 576..... . 616) (127.. .. . . CHaCHzCHCH(CH8)COOH ..... . .. . . .. ... . .. .... .. . . .. . . . . . CH.. .... .. . ....... . ..sCOOH .. . .. ... .. ..166. . .. 661) (613) (613.... .... .. ..... .. .615... . . 577) (174) (174) (671) (671) (205. . 321. . . . .616. . . .. . . . ... .. . . . 613... . . .. ... .. . CHSOCOOH .. . .. ...... .. .. . ... .. .ClCHzCOOH . . . 577. (Cd3s)zCHCOOH .. . 661) (613) (613) (613) (613. ... .. .. . ... 581. CH... ... .361. .. . ... . . .. ... ... . . .... . . .... ... . . . . n-CioH2iCOOH . .. . .. . .. n-ClrH2&OOH ... . .. ... . . .. .. 307... . . ....... . . . 312....127... .. .. .. . . .. . . n-CilH2sCOOH . . ... .. .... 581... ... . . . . . ... CzHsCOOH ... ... ... 572... ... . 576.... . . .. ..... 661) (613) (127... n-CsHiiCOOH .... . . ..... ... . (127. .. 615) (412) 671) .. 576... . 358) (204. . . . ..... .... . .... 613. . CHaCHClCOOH .. 616. ... . ... .. . .572. ..... .. . . .... ... .. . . .. . . II . CHsCOOH ..... . .... ... . . CHOHCO d-CHaCHOHCOOH . . 613.. .. . ... . 560... . ... ... .. .. ... ... . 661) (613) (613.... )~CH~(CHI)ICOOH .. ... .... . 613. .... .. . . .. ... . . .. CH&H&HOHCOOH . .. . .. 356. . . . .. . .IsCOOH. .. . ... . . ... . ... . 576. . .. . ... . 127. .. ... . . . ... . CJIICHOHCOOH .(CH. . . 572...... . . . . . . . . 661) (127. . ..... 307.. n-C7HisCOOH . . . . . . .. . ... .... . .. .... .. . . 2-CHSCHOHCOOH . 307. . .. . . . . ...307..... ...... . . . .. . ... . . n-CgHioCOOH . . . . ... ....... . 127. . . . CJ3sCHOHCHzCO (Cas)& (0H)cOo I (661) (93.. . . ... ... . ... . .. . ..... . . .. CeHsCHtCH&OOH . .... . . ........ . . .. ... .. . . 613) (127... . .. .. . .. .. ... . .. .. .... ....... .. .. ... .. Ct& a-CloH7COOH ...... .... . . . 615.. . . . . ... Csf. . 737) (307.... .. . . . . .. ... 446. . . 661) (613) (613) (613) (613....... . n-CsHiaCOOH .... .... .. 205) (256) (109... 572. .. .. ...... . .402 JOHN B WRIOET . . . . ... . . .. n-CilH&OOH .. . . . .. 728. .... CHnOHCOOH .. .. .... . .. .. ... CH.. .. ... . . ... . . .... .... ...... . .. . . . ... . . 671) (634) (415) (317.... . .. . ... . n-ClrH. .. .. . . . ..... ...... .. . .. .. . dAsHiiCOOH . 356.. . 730) (107. . 738) (356.. . . . . .. . .. n-CeHi7COOH .... . .. .. n-CdHgCOOH .... . .. . . 623) (207) 0 C&CHsCH(C&)CHsCHtCOOH . . .. . .... .. .. . .....572. . . ... . (CHs)rC (0H)COOH ....... ... ... ... ... .. ..... .. . . .. . HSCHzCOOH . .. . . . . . CcHsCHiCOOH .... .... . . ...... CtHsOCOOH . ... . ..... 572. .... .. .. TABLE 2 Monobmic carboxylic acids used i n the synthesis of benzimidazoles ACID' HCOOH . . . ... . . n-ClrH&OOH .. ... ....... . ... 415..
. .. . . . . . . .. . . .. 0 9 ' 0 CHI C 0OH. . .. . . . . .. . . . . . . . . . . . . . . . . . * . . . . . . . . CJ3bOCH&OOH. . . . . . . . . . . . . . . . . . .. . .. . 162) . . .. . . . . . . . .. . . . .. . .B. . .. .... . . . . . . . . . . @CH&OOH. . . CH(CJ%)r C I ~ ~ O C H . . d ? C H & O O l 3 .. . . . . . . . ~ .. . . .. (161. . . . . . . (C. .. . .. . .. . . . . . . . (160. . . . ~ O C H I C O O H . . . . . . . .. p . .. . . . . . .O d C~HICHICOOH. .. . . . CHnOH OH CaHg (74) I CO-0 . . . . . . . . . .. . . .. . . .. . .. . . . . . ... . . . . . ... .. . . . . . . . . . . . . .. . . . . . . .H. . .. . ... .. .. .-CHCH .C H ~ C ~ H ~ O C H I C O O H . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .CHEMISTRY OF THE BENZIMIDAZOLES 403 TABLE 24ontinued ACID* nrrznwast COOH. . . . . . . . . . . C O O. . 162) ocrq CII. . . . . . . . . ... . .. . . . CH(CE4)i .. . . . .)nCClCOOH. . . . . . . .. . . . .
. . a seven-membered ring compound (IX) is apparently formed (24): I x Glycine and phenylglycine give no reaction (356). . . . . especially with the simpler acids. . . . . oxidative effect of the nitro group at the high temperatures employed in the reaction. CsHsCONHCH. only representative references are given. . . . . . . . . . . . . . . . . . . . . . . . . . Anthranilic acid gives only a dyestuff (120). . . . Instead. . . . . . . . . . . . . . . . . . . . . P-HzNCaHrCOOH . * Acids derived from sugars are not included in this table. . .COOH . . . . . . . . . . . . . . Several dithio acids have been used in this reaction. . . . Benzimidazole derivatives of sugars are treated in a separate section (page 464). WRIGFlT TABLE 2 4 o n c l u d e d Am C ' o -0zNC sHaCH2COOH . . . . . . . . . . . . . . . . . . . . . . . . p-H2NCcHdCH&OOH. . . . . . . . . . . . . . . . . t Owing to the large number of references in some cases. . . Dithiobenzoic acid with o-phenylenediamine gives about a 55 per cent yield of 2-phenylbenzimidazole (767). Benzimidazolethiol is obtained a~ a by-product in this reaction : . . . . . . . Acrylic acid does not give 2-vinylbenzimidazoie. . . Phthalimidoacetic acid gives an amorphous product containing no oxygen. . . . .404 JOHN B. . . . . . . . . . .
2. . 279. of which they may be considered as cyclic analogs. carbalkoxy (183). and aryloxy groups. 652).CHEMISTRY O F T H E BENZIMIDAZOLES 405 Similarly. 577). A wide variety of o-phenylenediamines have been used in this general reaction. and alkylsulfonamido (6) groups. 8-Aminotetrahydroquinoline. A large number of ring-substituted o-phenylenediamines have been used successfully. sulfonamido (5). Ghosh (271. arsonic acid (64. iodine). 1. a-dithionaphthoic acid gives a 71 per cent yield of 2-a-naphthylbenzimidazole and p-methyldithiobenzoic acid gives 2-p-tolylbenzimidazole in 60 per cent yield (767). Acid hydrolysis of XI with concentrated hydrochloric acid (272) gives the corresponding acid. for with formic acid gives 4-imidazo-(ij)-tetrahydroquinoline (307). bromine. 647. nitro (577). with formic acid gives 1-methylbenzimidazole (253) : + HCOOH + @! \ N/ I CH3 N . 576. acetyl (113). example. and tertiary). 617). example. 361. 272) has condensed o-phenylenediamine with thioacetylcarbonic acid derivatives to obtain 2-substituted benzimidazoles : @" + H z HOOCNHCSCH(C0OCzI)z + @( C l: H C 00C 2 HS 1 X @ : + HOOCNHCSCHCOCHa I -+ COOCzHz Q-* ' + 2Hz0 JCHCOCH3 N I H COOCzH5 XI Both X and XI on heating with 15 per cent alcoholic potassium hydroxide solution give 2-methylbenzimidazole. alkoxy."-Disubstituted o-phenylenediamines give "pseudo bases" (cf. 8-Aminotetrahydroquinoline and related compounds act as N-alkyl-o-phenylenediamines(55. halogens (chlorine. page 468). 726).3-Triaminobenzene gives 4(or 7)-aminobenzimidazoles (17. aryl. 377. N-Monosubstituted o-phenylenediamines lead to l-substituted bensimidafor zoles. 307. cyano (112). Among the substituent groups in the phenyl ring of the o-phenylenediamines that have been used are various alkyl. carboxylic acid (274. secondary. Treatment of N-methyl-o-phenylenediamine. amino groups (primary. 329.
while benzoic acid gives only a trace of 2-phenylbenzimidazole (572). 581) introduced an important modificat.ion iu the reaction of o-phenylenediamines with organic acids to give benzimidazoles in the use of dilute mineral acid (usually about 4 N hydrochloric acid) in the reaction mixture. 577. Phillips' conclusion concerning the monoacyl-o-phenylenediamine as the necessary intermediate in the reaction has been confirmed by Roeder and Day (633). Since diacyl-o-phenylenediamines zoles under the same conditions. I + HCOOH --$ &!z + H S 2&0 \ / CHz \ / C Hz The corresponding compounds derived from indoline derivatives do not appear to have been prepared.406 JOHN' B. with aqueous hydrochloric acid in an evacuated tube (615). Good yields may be obtained with aromatic acids. 576. The monoacyl derivatives passed readily into the corresponding benzimidazoles on heating also gave benzimidawith dilute mineral acid. Diamines which are very easily oxidized may be converted to benzimidazoles by fission of the components at 180°C. These authors also showed that monoacyl-o-phenylenediamines not do yield benzimidazoles under anhydrous conditions unless there is at least one hydrogen on each of the two nitrogen atoms. They showed that o-amino-Nmethylacetanilide (XII) did not undergo ring closure under anhydrous conditions. Good yields are obtained with aliphatic acids. however. (615. WRIGHT G: CH. it was concluded that the latter reaction involved as the first step the hydrolysis of the diacyl derivative to the monoacyl derivative.486. The mechanism of the reaction of organic acids with o-phenylenediamines Phillips (578)concluded that the monoacyl has been studied (287. o-Diaminobenzimidazoles react with carboxylic acids to give benzobisimidaBoles (442): These compounds may be obtained also from tetraaminobenzenes by treatment with organic acids in the presence of dilute mineral acids (579). Phillips (572. by carrying out the reaction in a sealed tube at about 180-185°C.616).578. In some cases this permits the reaction to take place at a lower temperature and has permitted the preparations of compounds that were formed either not at all or in low yields when the components were heated together without the use of mineral acid. . derivative was the necessary intermediate for the reaction.633). whereas benzimidazole formation occurred when water was present.
633): H ____--_.CHEMISTRY OF THE BENZIMIDAZOLES 407 The reaction was explained as involving first the hydrolysis C Ha refluxed in dry p-cymene --+ No ring closure xu: Irefluxed in imoist p-cymene CH8 o the acetyl group and then reacetylation on the other nitrogen atom and subsef quent removal of water a~ indicated above. These and other experiments indicate that the reaction for the ring closure in general probably involves the splitting out of water by losing the oxygen of the acetyl group and one hydrogen from each of the two nitrogens (287. In contrast to the behavior of XII.486)as probably proceeding according to equation 1.\ &Ha + Ha0 The complete reaction has been considered (172. . 1>CH R xm McCoy and Day (486)have pointed out that other reactions leading to benzimidazoles may be considered aa involving an intermediate of the type XI11 which .! ip' \ N=C-CI& + ' 0. the isomeric N-methyl-N'-acetyl-o-phenylenediamineunderwent ring closure readily when refluxed in dry xylene. @ -H --_-_ N 1I I.
b. the products in most cases are bisbenzimidazoles (666). When two or more moles of the o-phenylenediamine are heated with one mole of the dibasic acid. therefore (616).408 JOHN B. The role of hydrochloric acid in the reaction has been studied (616). the reaction in this case being carried out in a sealed tube. Addition of a small amount of water gave a 30 per cent yield of 2-phenylbenzimidazole. that the free diamine is responsible for the reaction and that the hydrochloride salt of the diamine will react only under conditions which permit its hydrolysis first to the free diamine. The conversion of aliphatic acids to benzimidazoles by reaction with o-phenylenediamines has been used BS a method for characterizing aliphatic acids (127. 613. The conclusion was drawn. The catalytic action of hydrochloric acid is explained as activation of the carboxyl group by addition of a proton to oxygen. Dibasic acids When dibasic acids are caused to react with o-phenylenediaminesthe products formed depend on the mole ratio of the reactants and the experimental conditions. When the reaction was carried out with o-phenylenediamine as the free base. . The final step in the reaction involves the removal of HY. The concentration of hydrochloric acid j n the reaction was also varied and the optimum concentration was found to be 25 per cent. etc. NR2. The intermediate in the reaction is the addition product formed by the entry of the unshared electron pair of one nitrogen into the carbonium ion of the acid radical: 0e R-C-OH e II 5 OH + H+ R-&-OH e o-Phenylenediamine dihydrochloride gave no reaction with benzoic acid under anhydrous conditions. 661). a 65 per cent yield of 2-phenylbenzimidazole was obtained. NH2. WRIGHT in the general case may be considered as in XIV.HNR. where Y = OH.€1. forming a carbonium ion with electron deficiency at the carbon atom.
. . . .. . . it is possible to obtain benzimidazole acids. . 28 50. . . . . . . . . ... . . . Malonic acid with o-phenylenediamines gives o-phenylenemalonamides (504. . . ... . . . . p-(2-Benzimidazo1e)propionic acid may be obtained by heating equimolecular amounts of o-phenylenediamine dihydrochloride. Oxalic acid with N-substituted o-phenylenediamines is reported to give only starting material TABLE 3 Dibasic acids f r o m which bisbenzimidazoles have been obtained ACID YIEIB REFERENCES per C M i l Succinic. . . .. 30 . . . .. . . .. . .. . ... . . 507. . . . .. . . . .. . Fumaric... . .. . . . 666. . .. . . . .. .CHEMISTRY OF THE BENZIMIDAZOLES 409 The dibasic acids from which bisbenzimidazoles have been obtained are listed in table 3. .3-dihydroxyquinoxalines (573.. Maleic. . . . 665. . . . .. . . . 148) (577). and sodium carbonate to 1SO"C. . (507). .. /"CEO NHC=O \ CHCHI / When equimolecular amounts of o-phenylenediamines and dibasic acids are used. 666. . .. .. . 666) (666) (666) (666) (666) (666) (149) (126) (145. 576. . . . . .. Adipic.. . . 695) (418. . . . . . . . Oxalic acid gives 2.. . .. . . . . . .. .. . . . . . . . . .. . 574. . . . . . . 576. . . . ... 5S3. .. . 575. . . . / + a . . . .. . ... ... . Glutaric. 585. .. Pimelic. .. . . . . . succinic acid.. . .. . . 666). .. .... 46 62 56 63 60 (152.. .. . 667) in good yield: "WO + HOOCCHZCOOH + ~ H Z NH/CO The same product is formed when equimolecular amounts of the two components are used (507). . Isosuccinic acid gives the analogous product in poor yield (507): HOOC HOOC \ CHCH.
l-benzimidazole (89).2'diaminosuccinanilide (XV) (574). give a 60 per cent yield of (tetrachloro-obenzoylene)-2. C1 A 76 per cent yield may be obtained by carrying the reaction out in nitrobenzene aa a solvent (89). @ 2 -2HC1 + Na.4diaminophenylamenic acid is reported to give only starting material (576). Succinic acid with 3. Under the vigorous conditions of the reaction the benzimidazole acid first formed loses an additional mole of water. . Equimolecular amounts of tetrachlorophthalio acid and o-phenylenediamine when heated gradually to 250°C.410 JOHN B WRIGHT . \ CHz CHI C 0OH Equimolecular amounts of o-phenylenediamine and succinic acid when heated with 4 N hydrochloric acid are reported to give ~-(2-benzimidazole)propionic acid and 2.Coa_. The same product has been obtained by treatment of XV with hot 4 N hydrochloric acid (575). @z :: xv 8-(2-Benzimidazole)propionic acid on further condensation with o-phenylenediamine gives the bisbenzimidazole (575).
and N-phenyl-o-phenylenediamines. It waa formerly thought that o-phenylenediamine8 yield .CHEMISTRY OF THE BENZIMIDAZOLES 411 From the reaction between quinolinic acid and o-phenylenediamine are oband tained a . Dibasic acids of this type that have been used in the synthesis of benzimidazoles are listed in table 4.l-benzimidazole 2-@-pyridyl)beneimidasole(90) : co Dibasic acids containing one carboxylic acid group and one sulfonic acid group react with o-phenylenediamines to yield benzimidazolesulfonic acids. 2./3-picolinoylene-2. Using oxalic acid. fumaric (148) : acid is reported to condense with N-isopropyl-o-phenylenediamine HCH( CH3)z + HOOCCH CHCOOH /I + The reaction of acids containing three or more carboxyl groups with o-phenylenediamines does not appear to have been investigated. Anhydrides of monobasic acids The reaction of acid anhydrides and o-phenylenediamines wl lead to benil zimidazoles or to N . Phillips (577) obtained only starting material with N-methyl. N-Substituted o-phenylenediamines have been used also in the reaction with dicarboxylic acids.N'-diacylphenylenediamines (510) depending on the conditions employed. However. By reaction with acid anhydrides a.
How- . usually in good yield.412 JOHN B. this was shown (16) to be incorrect. however. Practically the only acid anhydride that has been used in the preparation of benzimidazoles has been acetic anhydride. Time appears to be a decisive TABLE 4 Benzimidazolesulfonicacids ~ ~~ ACID USED O-PHENYLENEDIAMINE USELl PPODUCI !EPZPBNCL HOaSCH(CzH5)COOK HOsSCH (CzH5)C 0 OH H0a SCH(CH3)CHz COOH H03SCH(CsH7)COOH (d-form) (Z-f orm) factor and if the refluxing is continued long enough benzimidazoles may be obtained. WRIQHT benzimidazoles with acids and diacyl derivatives with acid anhydrides (510).
Excellent results have been obtained by employing the modification of Phillips (570. 469. the mixed formic-acetic anhydride (70) and benzoic anhydride (120.2-dimethylbensimidazole (601.2-dimethylbenzimidazoles (590. + 2(CHaC0)20 + 0: . 2-methylbenzimidazole may be obtained in 93. 601. and m-amino-N . 656). or acetic acid (164). N-Substituted o-phenylenediamines lead to 1-substituted benzimidazoles and N . 735.2-dimethyl-5chlorobenzimidazole (594).3 per cent yield from o-phenylenediamine and acetic anhydride on heating with 15 per cent hydrochloric acid (729). N . 2dimethylbenzimidazole.N-dimethyl-1 .4-triaminobenzene gives 5-acetamido-l . N. 518.N-Dimethyl-N’-acetyl-o-phenylenediamine acetic anwith hydride also gives 1. 4-chloro-2-aminodimethylaniline when heated with excess acetic anhydride at 145-160°C. gives 1.2. the types being similar to those diamines mentioned previously in connection with the syntheses from carboxylic acids. + (CHaCOhO + 0 --N + CHzCOOCHa \ ‘\&Ha CHs Similarly. 583) involving the addition of dilute mineral acids (usually about 4 N hydrochloric acid) to the reaction mixture. Good . 553). 594. N-dimethyl-p-toluidine as a by-product (590). 577. Thus. 656). which on hydrolysis yields 5-amino-1.CHEMISTRY OF THE BENZIMIDAZOLES 413 ever. N’-disubstituted o-phenylenediamines lead to “pseudo bases”.2-dimethylbenzimidazole(595): I + HzO I CHs CHsCOOCHa + CHaCOOH The reaction of o-phenylenediamines with acetic anhydride has been carried out with acetic anhydride alone or with acetic anhydride to which has been added sodium acetate (116. o-Phenylenediamine when heated under reflux for several hours with acetic anhydride is completely converted to 2-methylbenzimidazole (16) : @ . Thus. 763) have also been used successfully. 580. N-Dimethylo-phenylenediamines when heated with acetic anhydride give 1.N-dimethyl-p-toluidine gives 5-methyl1. mineral acids. c1/ \ ‘ \ JCHa + 3CHsCOOH A wide variety of o-phenylenediamines have been used in this reaction. N . discussed separately in a later section.2-dimethylbenzimidazole with m-acetamido-N.
* . WRIQHT xo u 0 g 0 E! E! xo 0 ? 8 0 u ? u. ta.414 JOHN B. z+g I / Id d R 0 o/ z \g g/ \8 0 u - 8 d u - .
CHEMISTRY OF THE BENZIhfIDAZOLES 415 h Y ff v 9 e 0 /\ O 0 (yJ 0 0 / \ 0 .
o-benzoylene-2. with prevention of the return of the evolved water. succinic anhydride with o-phenylenediamine gives /3-(2-benzimidazole)propionic acid (XVI) and phthalic anhydride gives o-(2-benzimidazole)benzoic acid (XVII). the products obtained are diphthaloyl-o-phenylenediamine. Direct heating of equimolecular amounts of o-phenylenediamine and phthalic anhydride to 140-150°C. Heating the components in alcoholic solution gives the o-substituted benzoic acid (XVII) (143. 669). In several cases amides (11. and phenylenedibenzimidazole (XIX) (614). 580. Anhydrides of dibasic acids The anhydrides of dibasic acids react as monobasic acids. XVIII Tetrachlorophthalic anhydride behaves similarly (89). WRIGHT results have been obtained also with substituted o-phenylenediamines (577.l-benzimidazole (XVIII) (88).l-benzimidazole (XVIII).416 JOHN B. . 583. for example. 509) have been obtained as byproducts. gives o-benzoylene-2.When o-phenylenediamine and phthalic anhydride are heated to 120-130°C. or phthalanils (73. 143. XVI XVII Anhydrides of dibasic acids that have been condensed with o-phenylenediamines to give benzimidazole acids of this type are listed in table 5. b. 508). The reaction of o-phenylenediamines and phthalic anhydride has been investigated rather extensively under varying conditions. 238).
Succinic anhydride and o-phenylenediamine at 180°C. (736) or to 290°C. behave similarly (736). Equimolecular amounts of diphenylmaleic anhydride and o-phenylenediamine when heated under reflux in alcohol give an 85-90 per cent yield of N-(2-aminopheny1)diphenylmaleimide (83). (467).l-benzimidaaole (XVIII) and o-phenylenediamine (614) and from o-phenylenediamine and phthalic anhydride by heating to 180°C. homophthalic. and diphenic acida has also been investigated. This substance cyclizes on heating: Homophthalic acid anhydride and diphenic anhydride react somewhat analogously (82): co HOOCCH~ OC-CHt I I . The action of o-phenylenediamine upon the anhydrides of diphenylmaleic.CHEMISTRY OF THE BENZIMIDAZOLES 417 XIX The latter product (XIX) may be obtained also from o-benxoylene-2.
7-trimethylenebenzimidazole: .6)-dimethylbenzimidazole. Equimolecular amounts of 3. A good yield of 2-methylbenzimidazole may be obtained by allowing a mixture of o-phenylenediamine and ethyl acetate to stand (378).5(or 2. at 225°C. 3 By reaction with esters .4-tetrahydroquinoline.H C l \ \ / + 2H20 + CzHsC1 The product is not further alkylated by the ethyl chloride formed (538).2.418 JOHN B. give 84 per cent of 5(or 6)-methylbenzimidazole hydrochloride (544). It has been reported (59) that high-pressure hydrogenation of 6-methoxy-8aminoquinoline in ethyl acetate solution using 25 per cent Raney nickel gives. a 40 per cent yield of 5-methoxy-2-methyl-l . this method has not been used frequently. c H 8 E I .4-diaminotoluene dihydrochloride and ethyl formate when heated in a sealed tube for 3 hr. Reaction of o-phenylenediamines with esters also yields benzimidazoles. and poor yields of benzimidazoles would probably be obtained from esters of acids of higher molecular weight (544). Ethyl acetate under the same conditions gives only a poor yield of 2.3. in addition t o the expected 6-methoxy-8-amino-l . however. WRIGHT + \ (71 per cent yield) + HOOC 0 ’ 4 150°C. von Niementowski (537) first investigated the reaction of esters and o-phenylenediamines to give benzimidazoles.
684. For example. Diethyl oxalate reacts with o-phenylenediamine to yield quinoxalines. however. olive oil (284. benzimidazoles have been obtained. The benzimidazole formed is cleaved to 2-benzylbenzimidazole with alcoholic potassium hydroxide (654). fish oil (686). . 689). when heated under reflux with diethyl oxalate. 688). castor oil (284. Vulpinic acid (XX) gives a benzimidazole with o-phenylenediamine. Ethyl and methyl methacrylate fail to react with o-phenylenediamine a t reflux temperatures (24). N=CCH3 Ethyl cyanoacetate with o-phenylenediamine gives a 70 per cent yield of 2-cyanomethylbenzimidazole (166).3 per cent yield of 2. Ethyl a-hydroxyisobutyrate gives a 93. coconut oil (685). gives the expected quinoxaline with 1-phenyl-2-carbethoxy-5-nitrobenzimidazole a byaa product (626).(2'-hydroxyisopropyl)benzimidazole and ethyl 3-ethoxypropionate gives an 82 per cent yield of p-ethoxyethylbenzimidazole (145). such as coco fat (284. linseed oil (284. and various other glycerides of saturated and unsaturated acids (284). 687).CHEMISTRY OF THE BENZIMIDAZOLES 419 CH2 CH3 I II / \CH2 I CH~COOC~HS . in several cases. xx alcoholic 0- I I c=o A number of patents have been issued for the preparation of 2-substituted benzimidazoles from o-phenylenediamines and various naturally occurring fats and oils. 693). Ethyl w-diethylaminobutyrate is reported to undergo condensation with o-phenylenediamine in the presence of copper sulfate to give the copper salt of 2-(diethylaminopropyl)benzimidazole (364). 2-amino4-nitrodiphenylamine.
4-tetrahydroquinoline reacts with ethyl acetoacetate under acidic conditions to give a product analogous to XXI (308): . however. depending upon whether the reaction is carried out under acidic.420 JOHN B.2. it has been pointed out (663) XXI that this second reaction. 8-Amino-l. owing to the fact that impure ethyl acetoacetate was probably used. apparently carried out under neutral conditions. Under acidic conditions ethyl 6-(2-aminoani1ino)crotonate is formed (XXI) from ethyl acetoacetate and o-phenylenediamine (663). or basic conditions. probably was carried out in reality under acidic conditions. the corresponding acid may be obtained (627): I CaHs Esters of fumaric acid are reported to lead to the bisethylene compound (145) : @: ' HCCOOR ROOCCH II + 2ROH + 2H20 + [ @ C H != ] 2 The reaction of ethyl acetoacetate with o-phenylenediamines can lead to several products. WRIGHT CsHs By treating the same diamine with diethyl oxalate and sodium ethoxide in alcoholic solution and allowing the reaction mixture to stand for several days.3. neutral. This substance is also obtained when equimolecular amounts of the reactants are shaken together (324).
663): By carrying out the condensation of o-phenylenediamine and ethyl acetoacetate under neutral or basic conditions. 308. Sexton (663) obtained a mixture of two other products: XXIII XXIV XXIII is the major product under neutral conditions (71-72 per cent) and XXIV is the major product under basic conditions (64 per cent).n .324. Monti ( 1 ) i 53.CHEMISTRY OF THE BENZIMIDAZOLES + NH2 NH CHaCOCHzCOOCZHs --+ yN:Hz ' 421 CH2 (H !Z ' \ / HNC=CHCOOCzHs CHa I XXII Both XXI and XXII on heating are converted to 2-methylbeneimidazolea (241.
By using other 0-keto esters and o-phenylenediarnines under basic conditions. Both XXIII and XXV on treatment with strong acids are converted to 2-hydroxybenzimidazole and acetone (513. obtained 2-aminoacetylacetanilide (XXV). when heated under reflux in ethanol.COOCzHs (2 moles) - XXV TABLE 6 8-Acylmethyl. . + COCHa CH.8-aroylmethylbenzimidazoles and R-t- + v * N H R'COCHzCOOCiHs + R- (R = H. CH3.663). Cl) DIAhUh'E R ' PRODUCT which is probably an intermediate in the formation of XXIII and XXIV. Ethyl a-chloroacetoacetate and o-phenylenediamine. WRIORT carrying out the reaction with two mole-equivalents of ethyl acetoacetate under basic conditions (a trace of pyridine).COCH. These products are listed in table 6. other products analogous to 2-benzimidazoleacetone (XXIV) have been obtained (662).422 JOHN B. give 2-methylbenzimidazole hydrochloride in high yield (65).
in most cases the first product isolated was not the benzimidazole but rather the ethylisoformalide of the diamine. . 705. A. 4 . 706) . However. however. these reactions are discussed in Section 11. 13. undergoes ring closure readily upon treatment with hot.475). very dilute hydrochloric acid. The reaction of o-phenylenediamines with urea and related compounds is discussed in Section 11. This method was investigated because several of the diamines used by these authors were acid sensitive. the use of ethyl orthoformate has been investigated more fully by Mamalis. and Sturgeon (474. ' @ : Sugar HC(OCz&)S G e c H o C z H 6 H dilute HC1 (-Cz&OH) --j I ' 0 \ -N \N/ I Sugar Lgar The latter product. Several N-tetracetyl-Dglucose)-0-phenylenediamines and o-phenylenediaminetriacetylpentosideswere converted to 1-substituted benzimidazoles by this general method. Esters of chloroformic acid lead to 2(3H)-benzimidazolones (703.5(or 2. A. Very recently. Ethyl orthoformate was first used for the preparation of benzimidazoles by von Walther and Kessler (732). By reaction m'th amides Relatively few amides have been used for the synthesis of benzimidazoles. good yields have been obtained in most cases. The amides that have been used are listed in table 7.CHEMISTRY OF THE BENZIMIDAZOLES CHsCOCHC1COOC*Hs3 0-i " 423 *HCI \ \ /CH3 o-Toluylenediamine and ethyl a-chloroacetoacetate lead to 2. 13.6)-dimethylbenzimidazole (13). Petrow. however. These authors prepared 1-phenyl-5-nitrobenzimidazole by the reaction between ethyl orthoformate and 4-nitro-2-aminodiphenylamine. These authors found that o-phenylenediamines or N-alkylated o-phenylenediamines may be converted to the corresponding benzimidazoles in almost quantitative yield by the use of an excess of ethyl orthoformate at an elevated temperature or in a solvent such as ethanol or ethyl acetate.
424 JOHN B. WRIGHT h v 8 f h v v s n v 9 .
CHEMISTRY OF THE BENZIMIDAZOLES 425 ! . - V x" V u .
426 JOHN B. WRIQFfl! h v 2 .
CHEMISTRY OF TEE BENZIMIDAZOLES 427 82 5 0 z=\ a u R n. 4 z-\ u I 5-s ij 0 - 5 0 u 8 0 u % z 0 6 R .
Benzoyl chloride. 6. 344). 13. Phthaloyl chloride on gentle warming gives 2-(benzimidazoleS')benzoic acid and other products (485).2-(1'-methyltrimethy1ene)benzimidazole (103). . The reaction of lactones with o-phenylenediamines was first studied by Bistrzycki and Schmutz (loo).4-diaminotoluene in benzene solution yields 2. Valerolacetone when refluxed with o-phenylenediamines gives only a small yield of 1. By reaction with acid chlorides The action of acid chlorides on o-phenylenediamines leads to benzimidazoles or monoacylated or diacylated o-phenylenediamines. Table 8 lists the compounds that have been prepared by the reaction of acid chlorides and N-substitu ted o-phenylenediamines. l-tert-Butyl3 . 6 By reaction with lactones . phenylacetyl chloride. p-Toluoyl chloride with o-phenylenediamine in benzene solution is reported to give only a small yield of 2-tolylbenzimidazole (128. depending upon experimental conditions. The Schotten-Baumann procedure leads to diacylated o-phenylenediamines. this is one of the methods for cleavage of the imidazole ring of benzimidazoles. Acetyl chloride with 3 .6)-dimethylbenzimidazole if the reaction is carried out without cooling and diacetyl-o-phenylenediaminewhen the reaction is cooled (80).4diamino5-nitrobenzene heated with acetyl chloride on a water bath is reported to give 5(or 6)-tert-butyl-7(or 4)-nitro-2-methylbenzimidazole(395).5(or 2 . most reactions have been carried out with N-substituted o-phenylenediamines. The action of phosgene on o-phenylenediaminesis discussed in Section 11. Since benzimidazoles which possess no grouping in the l-position may undergo acylation with acid chlorides.. who investigated several ?-lactones of alcohol acids and phenol acids. Most reactions between o-phenylenediamines and acid chlorides to give benzimidazoles have been carried out with aroyl chlorides. A.by heating under reflux. WRIGHT Equimolecular amounts of o-phenylenediaminedihydrochloride and thiobenzamide when heated to 240-250°C. The reactions are carried out usually by heating the components together at about 200-22OoC. give an almost quantitative yield of 2-phenylbenzimidazole (562). and benzenesulfonyl chloride when heated in benzene solution give only acylated o-phenylenediamines (80). &s a matter of fact. or by heating on a steam bath in the presence of pyridine or a similar basic substance.428 JOHN B.
This lactone reacts analogously with 3. [QZl] CH2 OH Phenolphthalein is reported to react in a somewhat analogous manner (102): Biphthalyl and dihydrodiphthalyl with o-phenylenediamine at 280-290°C. with o-phenylenediamine gives a quantitative yield of 2-(2’-hydroxybenzhydryl)benzimidazole (104).CHEMISTRY OF T E E BENZIldIDMOLES 429 CHsCH-CH2 2-Hydroxydiphenylacetic acid lactone when heated at 120-130°C.Ibenzimidazole hydrochloride in about 80 per cent yield. . there is some doubt about the structure of this compound.4-diaminophenetole (105). however. Phthalide with o-phenylenediamine hydrochloride is reported to give o-benzylene-2.in a sealed tube are reported to give phenylenedibenzimidazole (XIX) (467).
F.HBr The reaction is carried out by mixing equimolecular amounts of the reactants in aqueous suspension (466. By reaction with nitriles a.A. . 2-aminobenzimidazole may be prepared from cyanogen bromide and o-phenylenediamine: @:+ @.430 JOHN B. Pellizzari (564) has obtained benzimidazole derivatives by treatment of o-aminophenylurea with cyanogen bromide : . Lactones of acids derived from sugars are discussed in Section 1 .ONH2 BrCN BrCN -o : i HCN HZ .. WRIGHT Pulvinic acid lactone (XXVI) and p . 1 7. for example.586). moist air or water bO"2 XXVII o-Phenylene-a-guanylurea (XXVII) is unstable and tends to hydrolyze to 2-aminobenzimidazole. Reaction with cyanogen bromide Cyanogen bromide will react with o-phenylenediamines to yield 2-aminobenzimidazoles in good yield.p'dimethoxypulvinic acid lactone yield : benzimidazoles (654) XXVI Phthalophenone and the lactone of 2-hydroxy-5-methyltriphenylaceticacid are reported not to undergo reaction with o-phenylenediamine (100). Other methods for the synthesis of 2-aminobenzimidazoles are discussed in Section 11. 15.
. In support of this mechanism Holljes and Wagner (330) showed that benzimidazoles could be prepared also from imino halides of the type indicated as an intermediate in the proposed mechanism. benziminobromide hydrobromide on brief warming with o-phenylenediamine gives 2-phenylbenzimidazole. This reaction has been studied by Holljes and Wagner (330). at this temperature ammonium chloride will undergo decomposition to regenerate additional hydrogen chloride and cause the reaction to proceed further.CHEMISTRY O F THE BENZIMIDAZOLES 431 b. who find that the reaction proceeds under acid conditions and probably involves hydrogen-ion catalysis. Reaction with other nitriles Nitriles when heated with o-phenylenediamine hydrochloride give 2-substituted benzimidazoles.HC1 + RCN @ + II H 2 NH RCCl N (1 Rc + 0-\@ O-C~HC 1 (NE c - CR -HC1 \ \ / NH II " The reaction is carried out usually at about 200°C. The following mechanism for this reaction is suggested (330) : . mCeH6 + COH6"3'HCI C Ha a . a more stable imino halide. h r N-Phenylbenzimino chloride. The first step in the reaction appears to be the rate-determining step. reacts aimilarly (330) : C=N CsHs iYH HiSlljes and Wagner found that in the absence of acid no reaction takes place. The reaction proceeds under anhydrous conditions and is therefore not due to the generation of acid or amide in situ. for example.
n n b c s W W X Z Z=U x" x .432 P I JOHN B WRIGHT .
: z x z z u .CHEMISTRY OF THE BENZIMIDAZOLE8 433 x” x=U z Z x RZ.--\W / R ‘4 I x Z=u.
\ N=CNH2 XXVIII 8. aryl.434 JOHN B. Since an oxidation is involved. This latter reagent waa first introduced by Weidenhagen (741).743. 744).4-diamino-1 . which possesses a structure comparable to that obtained from o-phenylenediamine and malonic acid.5-triazabenzepine (XXVIII) (l). by the use of other oxidizing agents such BS cupric acetate.3 . 741. 2. @+ Hr N=CNH2 Jj ' fCN +N -H > CN b . In the latter case. WRIGHT Nitriles that have been used in the synthesis of benzimidazoles are listed in table 9. and by means of hydrogen sulfide it may be readily decomposed to the free benzimidazole and cuprous sulfide. Dicyanimide with o-phenylenediamine gives a seven-membered ring compound. 743. This oxidation may be brought about by the air or. N-Alkylated o-phenylenediamines give very good yields of l-substituted benzimidazoles (489. although no imide hydrogen is present.763). B y reaction with aldehydes Under the correct conditions aldehydes may react with o-phenylenediamines to yield 2-substituted benzimidazoles. The cuprous salt of the benzimidazole separates.Cu2C12 + 4CH3COOH +- H20 NR / . more conveniently. By means of Weidenhagen's method excellent yields of 2-substituted benzimidazoles may be obtained. cuprous salts of the benzimidazoles are also formed first (743) : GR -2HC1 + R'CHO + \ \ 2(CHaCO0)2Cu --+ @\. Weidenhagen's method consists in reacting the diamine and aldehyde in water or alcoholic solution in the presence of cupric acetate or a similar cupric salt. The suUide may be removed readily by filtration. the reaction is best carried out under oxidative conditions. A large number of alkyl. and heterocyclic aldehydes have been used with uniformly good results (375.
and p-diamine dihydrochlorides.2HC1 + 2CaHbCHO + O $ b Z X + HCl (3) CH2CeH6 *HCI I This latter reaction (equation 3) may be used to distinguish o-diamino dihydrochlorides from m. Thiele and Falk (714) obtained a product which they thought to be o-benzylene-2 1-benzimidazole. The reaction is usually carried out by heating the diamine with the aldehyde to 120-160°C. When the reaction between o-phenylenediaminesand aldehydes is carried out in the absence of a specific oxidizing agent such 5s cupric acetate. However. 448. The reaction for the preparation of “aldehydines” was first discovered by Ladenburg (447. Betrabet and ) Chakravarti (74) claim that the structure assigned by Thiele and Falk is er- . In some cases “aldehydines” are the major product and in some cases 2-substituted benzimidazoles are the major product (320). since only the diamine dihydrochlorides of the ortho series evolve hydrogen chloride when heated for several minutes with a few drops of benzaldehyde (461)..CHEMISTRY OF THE BENZIMIDAZOLES 435 The cuprous salts formed can be decomposed with hydrogen sulfide in the usual way. 450) and the structure of the products elucidated by Hinsberg (316. The best yields of “aldehydines” are obtained usually by carrying out the reaction under acidic conditions. or the dry diamine dihydrochloride is heated with the aldehyde until the evolution of hydrogen chloride ceases (450). 320). This was assumed to form in a manner analogous to the preparation of “aldehydines” (equation 4 . 2-Substituted benzimidazoles are usually obtained along with the “aldehydine.” From the reaction between o-phenylenediamine dihydrochloride and phthalaldehyde. the reaction may lead either to 2-substituted benzimidazoles or to “aldehydines” (equation 2): + 2RCHO - rearrangement ---f -CHR CHzR XXIX In most cases the formation of “aldehydines” and 2-substituted benzimidazoles takes place simultaneously. Those “aldehydines” which have been prepared from o-phenylenediamines and aldehydes are listed in table 10. I @ H2 .
H CHa CHo H NOn H €3 H H CHs roneous and that their compound was instead the intermediary Schiff base shown in equation 4. @ H* ..HCI + OHC fx X" @ x NHi + RCHO __t I X&-Pi'CH*R I. 452) rearrangement --+ . WRIffHT TABLE 10 Preparation of aldehydines Xh-N or \ N/ IlR X"' R X X ' H H H H H H H H H H H H H H H H H H H H CHI H CHI CH: CHs H CHa CHsO NHz NO.436 JOHN B. CHiR X" x' \ XU' NYR X' " H H H H H H c 1 H H CHI0 H H H H H H H H H H H H H H H H H H H H H H H H H H H H I3 H (448.
CHEMISTRY O F THE BENZIMIDAZOLES
Aliphatic aldehydes in neutral solution with o-phenylenediamines may form substances which have the same empirical formulae as “aldehydines” but possess higher molecular weights and are probably dimers or polymers of “aldehydines” (323). Aromatic aldehydes react with o-phenylenediamines which are monosubstituted a t one nitrogen to form compounds which have been formulated aa either azomethines (XXX) or 2 )3-dihydrobenzimidazoles (-1).
1,2-Disubstituted benzimidazoles have been reported also a the product of this reaction (188, 210, 211, 215, 711). Fischer (210) obtained l-methyl-2and benzaldephenylbenzimidazole by heating N-methyl-o-phenylenediamine hyde in alcoholic solution; however, Weidenhagen, Train, Wegner, and Nordstrom (743) report that a different compound is obtained when the reaction is carried out with the use of cupric acetate according to Weidenhagen’s method. N )N’-Disubstituted o-phenylenediamines with aromatic aldehydes give com: pounds which have been formulated a 2,3-dihydrobenzimidazoles
QYJCOOH CHa I
Aldehydo acids react preferentially at the aldehydo grouping. Glycolic acid, for example, gives 2-benzimidazolecarboxylicacid (722).
Calcium glycolate reacts similarly (315, 318). Phthalic aldehydo acids (78, 668) and derivatives thereof (79, 81) react a t the aldehyde grouping to give (benzimidazole-2)benzoic acids. Terephthalaldehyde gives a bisbenzimidazole:
JOHN B. WRIGHT
TABLE 11 The reaction of o-phenylenediamines with ketones
(Product not isolated)
CH&OCHzC sH s
CHI and CsH&H,
CHEMISTRY OF THE BENZIMIDAZOLES
6-Methoxy-8-amino-l,2,3 4-tetrahydroquinoline reacts with heptaldehyde to give a 2-hexylimidazole (188):
By reaction with ketones2
a. Ketones containing one carbonyl group The reaction of o-phenylenediamines with a number of ketones has been investigated by Elderfield and Kreysa (188). The reaction occurs as indicated in equation 5 (188).
R-H or alkyl.
In several cases the product represented by R”H was isolated and identified. The results obtained by these workers are summarized in table 11 (188). From the results summarized in table 11 it appears that in the reaction of 6-methoxy-8-aminotetrahydroquinoline (and possibly other N-substituted o-phenylenediamines) with methyl ketones the larger alkyl group of the ketone is lost rather than the methyl group, whereas in the reaction of o-phenylenediamine with methyl benzyl ketone and, presumably, with l-diethylamino4-pentanone, elimination of the methyl group occurs to a major extent. The direct elimination of the alkyl group and of hydrogen (as R”H) from the intermay be assumed to be due to the gain in mediate benzimidazolines (-11) resonance stabilization on conversion to the benzimidazole (188). Ladenburg and Rugheimer (453) obtained 2-phenyl-5(or 6)-methylbenzimidazole by heating 3,4-diaminotoluene with acetophenone a t 180°C. for some time. Here again the methyl group is the one that is eliminated preferentially:
+ CI-4 + H20
2-Phenylbenzimidazole may be obtained also from benzoin and o-phenylenediamine dihydrochloride (394). If o-phenylenediamine is used as the free base, the product is 2 3-diphenylquinoxaline (394).
2 Note added in proof: The reaction of o-phenylenediamines with ketones has recently been studied more fully by Elderfield and McCarthy (J. Am. Chem. SOC.73,975 (1951)).
440 JOHN B.N-Diethyl-n-propylamine was detected in the reaction product. Dunn . A. In this reaction it appears that the pyridine ring is reduced before the azomethine grouping and the resulting reduced product rearranges to a benzimidazoline-type intermediate. The reaction of ethyl acetoacetate and other &keto mters with o-phenylenediaminea is discussed in Section 11.Kreysa.6dihydro-4-imidazo-(ij)-quinoline the major product from a reductiveas and l-diethylaminoamination reaction involving 6-methoxy-8-aminoquinoline 4-pentanone. Ketones containing two or more carbonyl groups o-Phenylenediamine and acetylacetone on gentle warming in alcohol or acetic acid solution react as indicated in equation 6. WRIGHT Elderfield. XXXIII . which yields an imidazole by rupture of a carbon-carbon bond (189) : N . b. and Humphrey5 (189) obtained 2-methyl-8-methoxy5. the type formed in the reaction of o-diamines with ketones (XXXII). 3.
but 2-amino-4-chlorodiphenylamine gives only a stilbazonium compound and no benzimidazole derivative (120). Dibenzoylmethane and o-phenylenediamine give 2-phenylbenzimidazole (261). The same product may be obtained also from diphenyltriketone (261). CtHdOH ozN@C.CHEMISTRY OF THE BENZIMIDAZOLES 441 Heating an aqueous solution of the hydrochloride of XXXIII under reflux gives 2-methylbeneimidazole and acetone (717).13i CHJ-p 02NQ-Jc6H6 + + CsHsCOOCrHs 2H \ N k S & c&-p 2-Amino-4-nitrodiphenylamine behaves similarly. acetophenone. v\N=CCHp I heat --$ +Ht 0 ()T7CH3 NH * HC1 + CHaCOCH3 Benzoylacetone reacts in an analogous manner (717). the intermediate compound of type XXXIII decomposing simultaneously to a mixture of 2-methylbenzimidazole. B y reaction with potassium hydroxide and chloroform Grassi-Cristaldi and Lambarbi (286. HC1. and acetone. C s%C 0 C OCcHe. CsHhCOCOCOCaH6 + p H 2 OH Dibenzoylphenylmethane and tribenzoylphenylmethane when heated with o-phenylenediamine in the presence of hydrochloric acid also give 2-phenylbenzimidazole (747). 727) report the preparation of benzimidazole by heating o-phenylenediamine with chloroform and potassium hy- . I O . Dibenzil when heated with an equimolecular amount of 4-nitro-2-amino-4'-methyldiphenylamine in an alcoholic solution containing slightly more than an equivalent amount of hydrogen chloride is reported to give 1-tolyl-5-nitro-2-phenylbenzimidazole (120). 2-phenylbenzimidazole.
WRIQHT A v 3 h n v 3 v 3 G G x G x E=u x i3 Y 8 u U 3 u 3 u .442 JOHN B.
CHEMISTRY OF THE BENZIMIDAZOLES 443 n h V V 3 z h W 2 8 B w 01 .
The following mechanism for this reaction.444 JOHN B. aa applied to formamidines.) are required.a-disubstituted benzimidazoles may be obtained by using N-substituted o-phenylenediamines (413). the resulting amidines (XXXIV) on treatment with acetyl chloride are converted readily to the corresponding benzimidazoles (413). on the other hand. Benzimidazoles that have been obtained from o-phenylenediamines and iminoethers or imino-thioethers are listed in table 12. R 3 H or CHs. When the reaction of o-phenylenediamines with imino-ethers is carried out in the absence of acid relatively high temperatures (about 130°C. However. WRIQHT droxide (dissolved in ethanol). 650). A side reaction leading to amidines (equation 8) limits the preparation of XXXIV 5-chlorobenzimidazoles by this method. has been suggested (486) : . This convenient method for the preparation of benzimidazole is related to the method involving the use of ethyl orthoformate (Section 11. 11.A. By reaction with amirlines and guanidines Amidines will react with o-phenylenediamines to yield benzimidazoles. Good yields of 1 . very good yields may be obtained at much lower temperatures if one f equivalent of acid is present. 12. 3). lower yields are obtained (413). o-Phenylenediamines and diethyl iminocarbonate in the presence of acid yield 2-ethoxybenzimidazoles (648. This reaction may be illustrated by the preparation of 2-phenylbenzimidazole from o-phenylenediamine and benzimino methyl ether (equation 7) (748). I three equivalents of acid are present. By reaction with imino-ethers and imino-thioethers The synthesis of benzimidazoles from imino-ethers or imino-thioethers and o-phenylenediamines has been investigated by King and Acheson (413).
In the absence of acid no 2-phenylbenzimidazole is formed (332).3 per cent yield of benzimidazole when heated at about 125°C. although additional evidence is needed on this point. Phenyl o-tolylacetamidine gives a 63. Dains (171) obtained benzimidazole in about 80 per cent yield by heating dichloromethylformamidine hydrochloride and o-phenylenediamine in benzene (equation 9).CHEMISTRY OF TRE BENZIMIDAZOLES 445 \ NH \ -"J--$ t + / H" Cz II C " 2 - / C-NH-CH I The work of Holljis and Wagner (330) would indicate that the reaction of amidines with o-phenylenediamines is acid catalyzed. HCI Diphenylformamidine gives an 85. Diphenylbenaamidine with o-phenylenediamine dihydrochloride gives a 46 per cent yield of 2-phenylbenzimidazole.6 per cent yield of 2-methylbenzimidazole when heated with o-phenylenediamine at 180°C. with o-phenylenediamine (729) : @: + CeHbN=CHNHCsHs --+ + 2CeHs"n Di(p4olyl)formamidine reacts similarIy with the liberation of two moles of p-toluidine. (729). Price and Reitsema (618) have reported the condensation of benzenesulfonamidoguanidines with o-phenylenediamine to give 2-(benzenesulfonamido)benzimidazoles (equation 10). 2-(Benzenesulfonamido) benzimidazole (XXXV) may XXXV .
Synthesis by the reaction of o-phenylenediamines with phosgene Phosgene with o-phenylenediamines gives 2(3H)-benzimidazones. 608). 13. Preparation of b@H)-benzimidazolones 2(3H)-Benzimidazolone (XXXVI) and 2-hydroxybenzimidaxole (or 2-be~aimidazolol) (XXXVII) are tautomeric substances. halogen (243. XXXVI XXXVII In certain reactions the oxygenated function in the 2-position behaves as though it were in the keto form. who prepared 2(3H)-benzimidazolone in this way. m-Nitro. carboxy (155. including those which contain alkyl (303). WRIQHT be obtained in this way in 56 per cent yield. By heating o-phenylenediamine and urea under . often in excellent yield. 649).OPTH+ \ \ NH /co 2NKC1 This general method has been used also for the preparation of substituted benzimidazolones (444. 706) groups on the benzene ring. b. The reaction is carried out usually in an organic solvent such as benzene. Phosgene is usually used in excess. gives 2(3H)-benzimidazolone (435). 193).303). a. @ Hz a 2HC1 + NHZCONHZ . This method was first used by Hartmann (303). 704. toluene. N-Monosubstituted o-phenylenediamines lead to l-substituted benximidazolones (421. arsonic acid (421). carbalkoxy (397).446 JOHN B. while in other reactions it behaves as a hydroxyl group. 192. or chloroform or an aqueous solution of the dihydrochloride salt of the diamine may be used.and p-aminobenzenesulfonamidobenzimidazoles may be prepared analogously from the corresponding substituted benzenesulfonamidoguanidines (618). alkoxy (157). and stibinic acid (360. From o-phenylenediamines and urea o-Phenylenediamine dihydrochloride when heated with urea at 130°C. @ : -2HC1 + COClz " A rather wide variety of o-diamines have been used successfully in this reaction.
(307). for some time (564). 1 0C 5° . with the liberation of two moles of aniline (462). -__ cO N H ~ Q J + NH + 3 " The same compound may be obtained by heating N-phenyl-N'-o-aminophenylurea at about 183°C. 2(3H)-Benaimidalones may be prepared also from o-aminophenylureas. FROM PHENYLURETHANS 2(3H)-Benzimidazolone was prepared by Rudolph (638) by heating o-aminophenylurethan above its melting point (equation 11): . The cyclization may be brought about by heating the reactants to about 150°C. for example.N-Diphenyl-N'-o-aminophenylureas also give 2 (3H)-benzimidazolones on heating. -%+ E C O N H z HC1 [@ COOH / ' NHz HCONH2 ] $-I: -E!+ \ COOH + NH4C1 \ / NH XXXVIII The intermediary o-aminophenylurea is cyclized under the acidic condition employed in the reduction. 769). Griess (290). Pelliaaari. These latter compounds are undoubtedly intermediates in the preparation of 2(3H)beneimidazolones from o-phenylenediamines and urea. for example.CONHC. e z i CsHE".HF. or above the melting point or the o-aminophenylurea may be heated with mineral acids (290. -+ - @. N . Mistry and Guha (512) obtained a 95 per cent yield of 2(3H)-benaimidaeolone. C. obtained 2(3H)-beneimidaaolone-4-carboxylic acid from N-(2-nitro-3-carboxyphenyl)urea reduction with tin and hydroon chloric acid.CHEMISTRY O F THE BENZIMIDAZOLES 447 reflux in amyl alcohol solution until the evolution of ammonia ceased. 2(3H)-Benzimidazolones have been obtained also from o-nitrophenylureas (290). obtained 2 (3H)-benzimidaeolone by heating o-aminophenylurea at 150°C.
N-[Carbo-0’-chlorophenoxy]-o-phenylenediamine (XL) behaves analogously (620.4-diaminobenzenearsenic or stibinic acids lead to l-substituted 2(3H)-benzimidazolones (359. WRIGHT Hager (300) obtained 5-amino-2(3H)-benzimidazolone by reducing 2. The cyclization may be brought about also by heating the solution.4-dinitrophenylurethan with tin and hydrochloric acid : H2Nfi-y + v\ . 1.3-Trimethylbenzimidazolium hydroxide. d. Several patents have been issued for the preparation of 5(or 6)-anenic acid (359.2. Pot=sium permanganate is usually used as the oxidizing agent. 706) derivatives of 2(3H)-benzimidazolones. 621) : XL The cyclization in this case takes place on attempted recrystallization of the substituted diamine (XL) from alcohol.4-diaminostibinic acid with enough chloroformic ester to react with one of the amino groups. These compounds may be prepared by treating 3 . N Monosubstituted-3. on oxidation with potassium permanganate in the cold is converted to 1.4-diaminophenylarsenic acid or 3. followed by cyclization of the resulting urethans by heating with dilute mineral acids or by heating with the material itself. 703) or 5(or 6)-stibinic acid (705. 706).co ” CzHsOH 2(3H)-benzimidazolone may be prepared also from N-carbophenoxy-o-phenylenediamine (XXXIX) (620. 621): @rCO 0CsHS XXXIX mf ” + CaHsOH This material i soluble in potassium hydroxide solution.448 JOHN B. 703. and cyclization to s 2(3H)-benzimidazolonemay be brought about by acidification of the potassium hydroxide solution with dilute mineral acids. By the oxidation of “pseudo bases” 1.3-Disubstituted 2(3H)-benzimidazolonesmay be prepared conveniently by oxidation of “pseudo bases” or the quaternary salts derived therefrom. + - . for example.3-dimethyl-2 (3H)-benzimidazolone (230).
CH3 cHo$H3 (21_ _ _ f KMnOl io1 CH3 XLI I I bH3 XLIII CH3 XLII .3 . 603.5-tetramethylbenzimidazolium chloride (XLI). CH3 CH3 CH3 C H3 I the phenyl ring of the benzimidazolium halide contains a methyl or other f alkyl group. obtained 1.3-dimethylbenzimidiazolium chloride with potassium permanganate (602). 3. this may be oxidized under the conditions of the reaction to a carboxy group (598. from 1 . Thus.5-trimethyl2(3H)-benzimidazolone (250). 3. 1 . for example. Pinnow and Samann (603) obtained a mixture of the expected product (XLII) and the corresponding acid (XLIII).3-dimethyl-2(3H)-benzimidazoloneby oxidizing 1.3-Disubstituted benzimidazolium halides also yield 2(3H)-benzimidazoolones under vigorous conditions of oxidation. 2 . 606).5-Trimethylbenzimidazolium hyciroxide on oxidation with potassium permanganate gives 1. Pinnow and SSimann. CH3 1.CHEMISTRY OF THE BENZIMIDAZOLES 449 Conversion to the 2(3H)-benzimidazolone may be brought about also by simply subjecting the pseudo base to distillation (230).
6dinitro-. but rather the nonacetylated product having hydrogen in the 3-position. 2(3H)-Benzimidazolones have been obtained in addition by treatment o f 2-chlorobenzimidazoles or 2-ethoxybenzimidazoles (648. o-nitro-N. e.N-diethylanilines. Manuelli and Recchi (478) obtained 2(3H)-benzimidazolone by heating o- . 3. is converted to l-methyl-3-acetyl-2 (3H)-benzimidazolone.N-dimethylaniline. When the above reaction is carried out with o-nitro-N . NH I C2H6 f. the products are not 2(3H)-benzimidazolones.2. the product waa not the 3-acetyl derivative.4 .6-trinitro-N . when heated under reflux for several hours with zinc chloride (0. or by the use of iron and hydrochloric acid (635. The acetyl group present in the other 2(3H)-benzimidazolones prepared may be conveniently removed by hydrolysis with dilute sodium hydroxide solution.6-trinitro-N . By treatment of I CHs This reaction has been carried out also. in good yields. by heating with water in a sealed tube. WRIGRT Silver oxide has been used also as an oxidizing agent in reactions of this type (249). 636). but rather 1. 650) or by treatment of 2-aminobenzimidazolea with barium hydroxide solution in a sealed tube or with nitrous acid (587).5 part) and acetic anhydride (2 parts). with 2. and 3.450 JOHN B .N-dimethylaniline. o-Nitro-N .4-tetrahydro-3keto-l-ethylquinoxalines(635.4.3. 636). 550). by treatment with chromic acid in acetic acid solution. or by heating with zinc dust (549.N-dimethylanilines to give the correspondingnitro2(3H)-benzimidazolones. 650) with concentrated hydrochloric acid (443. Miscellaneous methods 2(3H)-Benzimidazolone has been prepared also by the isomerization of l-hydroxybenzimidazolone by means of benzoyl chloride in cold sodium hydroxide solution.4-dinitro-.N-dimethylanilines with acetic anhydride and zinc chloride This reaction has been investigated by van Romburgh and Huyser (635.In the case of the 3 . 636).
Monoacetylacetanilide yields 2(3H)-beneimidaeolone. ~ x4+Lo + \ \ / 0 -NH CH.O C H co CH. also. which readily undergoes hydrolysis to 2(3H)benzimidazolone (468).HCl 4 heat in 3 dry state OPTH \ \" . From XLV. 2 (3H)-Beneimidazolonehas been obtained by the rearrangement of the sodium salt of 2-aminobenehydroxamic acid (XLIV) (660) : @H o2 :c + NaOH + @?NOH I NH20H.CHEMISTRY O F T H E BENZIMIDAZOLES 451 phenylenediamine dihydrochloride with urethan in the presence of molten sodium acetate. may be obtained l-carboanilido2(3H)-beneimidaeolone (XLVI). obtainable from phthalyl diazide and methyl alcohol.COCHa XH Elbs (186) obtained 5-methyl-2(3H)-beneimidazoloneby the electrolytic reduction of o-nitro-p-methyllactanilide in acid solution. on heating in toluene yields l-carbomethoxy-2(3H)benzimidazolone (468) : COOCHa XLV The analogous 1-carbethoxy derivative may be obtained in the same manner. by treatment with aniline followed by heating of the resulting 2-(carboanilidoamino)benzoyl azide in toluene. on cleavage with strong acids (513): @N.co + NaOH ONa XLIV The potassium salt of the dibenzoyl derivative also rearranges to 2(3H)-benzimidazolone. I CONHCe Ha XLVI I . 2-(Carbomethoxyamino)beneoyl azide (XLV).
2-benzimidazolethiol. analogous to 2(3H)-benzimidazolone and 2-hydroxybenzimidazole. Before 1937 the name in Chemical Abstracts was 2-benzimidazolemercaptan. Preparation of d(3H)-benzimidazolethiones I 2(3H)-Benzimida~olethione~ 2-mercaptobenzimidazole are tautomeric suband stances. 142). WH \ \ /c=s YH t - o-Y \ \ /C+H SH . C&OH ~ 0 / ' NHCOOCzH6 "COO CzH5 2NNaOH ' 6"" \ \ " P O XLVII 2(3H)-Benzimidazolones have been obtained also as by-products from the reaction of phthalyl anhydrides and sodium azide in the presence of sulfuric acid (141. which on treatment with 2 N sodium hydroxide solution gives 2(3H)benzimidazolone (176). WRIGHT 0''" CON3 Phthalyl azide reacts with two moles of ethanol to give o-phenylenediurethan (XLVII). no solvent/ o s @' + Hz / I c=s OCzH6 XLIX I CZHS&S&OC~H~ XLVIII \ CiHrOH I c=o OGHS 14. 2-thiobenzimidazolone. Other names found in the literature are o-phenylenethiourea. and o-phenylenethiocarbamide.452 JOHN B. Guha and Dutra have investigated the reaction between o-phenylenediamine and ethyl xanthoformate (XLVIII). l-Thiocarbethoxy-2(3H)-benzimidazolone (XLIX) is obtained when the reaction is carried out without solvent a t room temperature and l-carbethoxy-2(3H)-benzimidazolethione (L) is obtained in ethanolic solution.
However. The reaction is carried out usually by heating the reactants in alcoholic solution with or without the addition of alkali to the reaction mixture. 252. in some cases. or. phenyl (179)) anilino (215). 383).4-diaminotoluene. 242. This reaction has been studied by Jacobson and Hugershoff (384). sulfonamido and N substituted sulfonamido (6. c. 358). / XHz QH2 I n many cases the reaction has been carried out on N-aryl-o-phenylenediamines. at lower temperatures when heated for longer periods of time. 3 4-Diaminophenylarsenic acid and carbon disulfide give 2(3H)-benzimidazolethione-5-arsenic disulfide and arsenious sulfide (197). respectively. d.405). 381. itself. (436).CHEMISTRY O F THE BENZIMIDdZOLES 453 a. 2(3H)-benzimidazolethiones containing hydrogen (5. 383). 3 4-Diaminobenzenearsonic acid and thiophosgene gave a 78 per cent yield of 2(3H)-benzimidazolethioned-arsonic acid (195). halogen (139. 176. has been prepared by this method (139. The reaction apparently involves rearrangement + - + cs2 OPTH \ \” /cs + H2S . ) b. including those containing alkyl (139. 381. 380. 294. 382. From hydrazo compounds and carbon disulfide 2 (3H)-Benzimidazolethiones may be prepared also by heating hydrazo compounds with carbon disulfide a t about 150°C. 6. an alkyl (213). 2(3H)-Benzimidazolethione. 489). 29) groups and sodium 3.in general. 2(3H)-Benzimidazolethiones that have been prepared from o-phenylenediamines and thiourea are listed in table 13. o-Phenylenediamines containing substituent groups in the phenyl ring have been used. 380. From o-phenylenediamines and thiourea This reaction is analogous to the preparation of 2(3H)-benzimidazolones from o-phenylenediamines and urea. Synthesis from o-phenylenediamines and carbon disulfide 2(3H)-Benzimidazolethiones. 215. From o-phenylenediamines and thiophosgene Billeter and Steiner (76) obtained 2(3H)-benzimidazolethione and 5-methyl2(3H)-benzimidazolethione by the action of thiophosgene on o-phenylenediamine and 3. 292.4-diaminosulfonate (358). Excellent yields have been obtained by carrying out the reaction in amyl alcohol and heating under reflux until the evolution of ammonia becomes negligible (512). may be prepared very conveniently by this method. 242. or a dialkylaminoalkyl (489) group in the 1-position have been prepared also by this method. 2(3H)-Benzimidazolethione may be prepared by this method by heating o-phenylenediamine dihydrochloride and thiourea t o 170-180°C. 382. so that the products of the reactions are l-aryl-2(3H)-benzimidazolethiones (179.
2 20. CH 3 (3851 (389) (387 ) (391) (390) .4 15. This reaction.2 22. however. is not a general reaction (384).0 R R’ R“ R”! REFERENCE CzHs0 CzHsO CzHsO CzHsO CzH SO H H H CHa H H CH 8 H H CHa H €I CHa CH.454 JOHN B. TABLE 13 d ( 9 H )-Benzimidazolethiones .0 48.0 25.from o-phenylenediamines and thiourea R R’ YfELD REFERENCES ) ccnl n H CHa n-C4H0 H H H H “Excellent” 67. WRIGHT of the hydrazo compound to an o-aminodiarylamine under the conditions of the reaction and the reaction of the resulting diamine with carbon disulfide in the normal manner.2 7.
13. The preparation of l-carbethoxy-2(3H)-benzimidazolethione(292). 2 (3H)-Benzimidazolethiones have been prepared also from o-phenylenediamine dihydrochlorides and ammonium thiocyanate. a). L ACN I (('&form") .N \ ' \w&HCN 4% L:)( IBSN NH H 2 AN LI A number of interesting products can be prepared from 2-aminobenzimidazole and its precursor (LI) in this latter reaction. 4-methyl (459). 586) has been mentioned previously (Section 11. A solution of the two substances is usually evaporated to dryness on a steam bath and then heated for a short time. using ethyl xanthoformate. Some of these transformations are indicated below : CN LI I A . has been mentioned previously in Section 11. 16. 7. Preparation of 2-aminobenzimidazoles The preparation of 2-aminobenzimidazolesby the action of cyanogen bromide on o-phenylenediamines (466. 0 . f.CHEMISTRY OF THE BENZIMIDAZOLES 455 Benzimidazolethione-5-arsonic may be prepared by the same general method acid (198) from 3. By this general method 2(3H)-benzimidazolethione (242. 259) and the 5-chloro (242).N IL. A. and 5-methyl (458) derivatives of 2(3H)-benzimidazolethione have been prepared.4-diaminobenzenearsonicacid. A. 2-Aminobenzimidazoles may be prepared also by the action of cyanogen bromide (or cyanogen chloride) on phenylhydrazines (569) : CaH6NHNH2 CNBr ---t + C ~ H S N " ~C N B ~ CN .
2-Arylaminobenzimidazoles may be prepared by the act. 569). 567. Aniline has been used instead of ammonia with 2-chloro-5(or 6)-nitrobenzimidazole to yield 2-anilino-5(or 6)-nitrobenzimidazole (443). 566. 2-Aminobenzimidazoles may be prepared also by the action of ammonia on 2-chlorod(or 6)-nitrobenzimidazole (443) or 2-benzimidazolesulfuric acid (370). 410. The two benzimidazoles on hydrolysis with potassium hydroxide solution yield 2-aminobenzimidazole. 568. on o-phenylenediamine dihydrochloride. . WRIGHT The dicyano derivative (LI) reacts also with amines (ammonia. and hydrazine) to form tricyclic derivatives containing a melamine ring. 411) : + CsHsN=C=NCsHs H* 210-220"C4 QiIkHc6 Ha + CBHSNH~ 2-(Benzoylamino)benzimidazole and 2-(cinnamoylamino)benzimidazole have been prepared by the action of benzoyl cyanamide (588) and cinnamoyl cyanamide (589).N/~Hcoc6H~ + 2CzHaSH 2-Carbethoxyaminobenzimidazole may be prepared in 97 per cent yield by heating molar quantities of o-phenylenediamine and the methyl ether of thiocarbonyldiurethan in alcoholic solution (521) : NC 0 OCz Hs CH3SC I NHCOOC2Hs A I/ [Z [2 + NH CHBSH + NHzCOOC2Ha B . Other primary and secondary amines (370) and hydrazine (368.372) or substituted hydrazines have been used in place of ammonia with 2-benzimidazolesulfuric acid.456 JOHN B. monoacyl-o-phenylenes are probably involved rn intermediates in the synthesis of benzimidazoles from o-phenylenediamines and organic acids (578. FROM MONOACYL. 633) and related compounds. These and other transformations in this series have been studied extensively by Pellizzari (565. aniline.ion of diarylcarbodiimides on o-phenylenediamines (406. 408.AND DIACYL-0-PHENYLENEDIAMINES As mentioned previously. 2-Benzoylaminobenzimidazolehas been prepared also by the action of the diethyl ester of benzoylimidedithiocarbonic acid on o-phenylenediamine (749): @+ H z NCOCeHs Cz Hs SC Cz Ha I/ * / --N (). respectively.
Acetic anhydride has also been used to effect ring closure. thus. / ---+ . A relatively large number of monoacyl. employing the use of dilute (about 4 N ) hydrochloric acid (62. formed by the splitting out of a dialkylamine residue (3. 570.581). Ring closure to benzimidazoles may be effected by heating the material itself. In attempts to prepare the corresponding 2-(dialkylaminoethyl)benzimidazoles in an analogous way. the only products obtained are benzimidazoles with an unsaturated group in the 301). N-(o-Carboxybenzoy1)-o-phenylenediamine when heated under reflux in an alcoholic alkaline solution gives o-(2-benzimidazole)benzoic acid : COOH 2-Dialkylaminomethylbenzimidazoles may be prepared from the corresponding monacyl-o-phenylenediamines (3.577. are transformed into benzimidazoles by heating by a t a relatively high temperature (137).571.and aryl-benzimidazoles have been prepared by utilizing the various methods outlined above. Diacyl derivatives. by distillation. A relatively large number of 2-substituted alkyl.641). 344. 2-position.576.or by distillation (80. Alkaline conditions have been used also (379. or by heating under reflux an alkaline alcoholic solution of the monoacyl derivative. 477. in general.by heating with acids either under pressure a t a relatively high temperature (137.578. 2-Cinnamylbenzimidazoles may be prepared from dicinnamoyl-o-phenylenediamines(437). 106).and diacyl-o-phenylenediamineshave been converted to benzimidazoles by the general method of Phillips. 182). Hal1 and Turner (301) obtained 5(or 6)-chloro-2-propenyIbenzimidazoIein an attempted cyclization of p-chloro-o-amino-P-piperidinobutyranilide: CHB HCOCHZCHX CHZCHz \ CHZCHZ \ CH. by heating in the presence of mineral acid or acetic acid. keeping the material in the fused state for some time (42.CHEMISTRY OF THE BENZIMIDAZOLES 457 Benzimidazoles may be prepared from monoacyl-o-phenylenediamines directly. 736).578). or by heating under reflux with dilute mineral acids or acetic acid.
343). This general method has been used frequently for the preparation of 2-arylbenzimidazoles. Under anhydrous conditions no benzimidazole is formed unless one hydrogen is available on each nitrogen atom. 335. This method has been used extensively for the preparation of benzimidazoles and. WRIQHT 1. C. under the conditions of the reduction the resulting diamine immediately undergoes cyclization to the benzimidazole (327. 339.3-Triacetylaminobenzeneon ring closure gives 2-methyl-4(or 7)-acetylaminobenzimidazole (1. The reducing agents generally employed are tin and hydrochloric or acetic acid. together with the method involving the action of carboxylic acids of ophenylenediamines. 2. studies of these workers indicate that in the removal of water from monoacyl-o-phenylenediamines to yield benzimidazoles one atom of hydrogen must come from each of the two nitrogen atoms.458 JOHN B. and stannous chloride and hydrochloric acid.5) : LII Further cyclization of the resulting compound (LII) to form a tricyclic structure with two imidazole rings does not appear to take place. BY REDUCTION OF ACYLATED O-NITROANILINES Acylated o-nitroanilines when reduced with tin and hydrochloric acid or similar reducing agents yield monoacyl-o-phenylenediamines by reduction of the nitro group in the normal manner. __f ()I!~~~ \ ‘’ h Reference has already been made to the studies of Roeder and Day (634) and Green and Day (287) on the mechanism of the formation of benzimidazoles from The monoacyl. Other means that have been .and diacyl-o-phenylenediamines.2. especially. probably constitutes one of the methods that have been most used. however.2’-Diacetylaminodiphenylamines ring closure give 1-(2’-acetylaminoon phenyl)-2-methylbenzimidazoles(721).
Thus. halogen (30.5-dimethylbenzimidazole : C Ha This reaction may be brought about also with sodium sulfite (18 per cent yield) (472). and catalytic reduction with palladium catalyst in acetic acid solution (432). . 463. It appears to involve first the reduction of the nitro group to a nitroso group followed by the removal of water (472). which accounts for the low yields of benzimidazoles usually obtained. 594. carbalkoxy (184. N-methyl-2-nitro-4-methylacetanilide reduction yields 1. HCl CHa I CHa 1-Substituted derivatives have been observed also by von Pinnow (591.CHEMISTRY OF THE BENZIMIDAZOLES 459 used satisfactorily include electrolytic reduction in acidic solution (118). zinc dust and aqueous acetic acid (581). 3-nitro-4-dimethylaminotoluene on reduction with tin and dilute hydrochloric acid gives some 1. the second f nitro group is reduced to an amino group during the reaction (345. 597.31. 529) : Sn concd. 185). on For example. 592. and cyanomethyl (66) groups remain intact. I the acylated o-nitroaniline contains an additional nitro group. N-Substituted acylated o-nitroanilines lead to 1-substituted benzimidazoles. such as ferrous oxalate. 593. is also reported (740). iron and dilute hydrochloric acid (31). 433. The use of oxygen acceptors. 526. 600. or platinum oxide in ether solution under acidic conditions (2).2. reduction ____t cH8@2 (CHa)2 A competing reaction involves the further reduction of the nitroso group.5trimethylbenzimidazole (2. 185. 593). 464. Carboxy (400).605) among the products of the reduction of o-nitrodimethylanilines. 733).
4-diaminotoluene dihydrochloride and trichloroacetic acid.or acylacetyl-o-nitroanilines on reduction under acidic conditions yield 2-aroylmethyl.2-dibenzimidazolylethylene (147). 2-Nitro-4-ethoxysuccinanilic acid (LIV) on reduction with tin and acetic acid gives only a very poor yield of 5(or 6)-ethoxybenzimidazole-2-propionic acid (144). 185). Aroylacetyl.460 JOHN B. WRIGHT Trichloroacetyl-4-methyl-2-nitroaniline with tin and hydrochloric acid undergoes hydrolysis (340) to 3 . respectively (662.2'-Dibenzimidazoles (LIII) may be obtained from the substituted oxamide derivatives (341. 4-Crotonoylamino-3-nitrotoluene yields 3-propenyld(or 6)-methylbenzimidazole. Salicyloyl-o-nitroaniline is converted readily to 2-(o-hydroxyphenyl)benzimidazole (347).and 2-acylmethylbenzimidazoles. 352) : LIII Dialkylaminoacetyl derivatives of o-nitroaniline on warming with tin and hydrochloric acid are converted to 2-(dialkylaminomethy1)benzimidazoles(184. 2-Nitro-4-methylsuccinanilic (LV) on reduction under anhydrous conditions acid . 2 . 663). cH3@~COCH=CHCHI -+ The maleoyl derivative of o-nitroaniline on reduction with tin and hydrochloric acid gives 1. The double bond is not reduced in the reaction.
679.4. 618.104.22.168)-tetramethylbenzimidazole is obtained (679) : CHs CH.CHEMISTRY O F THE BENZIMIDAZOLES 46 1 employing tin and acetic acid saturated with hydrogen chloride gives a tricyclic compound through the loss of two moles of water (342): CH3/ s- NO2 Sn HCOCH2CH2COOH CKCOOH. 680). 533.7-trimethyl-2-benzimidazole)propionic acid (2): LVI Several examples occur in the literature in which o-dinitrobenzenes have been used as starting materials for the synthesis of benzimidazoles. zene (LVI) is reported to give ~-(1. von Niementowski (30. 536. 528.6tetraethylbenzene by heating the latter under reflux with a solution of stannous chloride in a mixture of hydrochloric and acetic acids (676): When this reaction is carried out with 1. These substances on reduction with stannous chloride and hydrochloric acid in the presence of acetic acid give 2-methylbenzimidazoles (676.4.2-dinitro-3.2-dinitro-4-bromo-3.5. Thus.7(or 2.6. s a t u r a t e z with HCl cH3(J3 CHz N \CO--bH. LV Catalytic reduction of d-N-succinoyl-1-methylamino-:!4-dimethyl-6-nitroben.7-tetraethylbenzimidazole may be prepared from 1. 548) first showed that among the .6-trimethylbenzene the bromine is removed and 22.214.171.124. 2-methyl4.6. 530.
yields of “oxbenzimidazoles” aa high as 6&70 per cent may be obtained (57.g. or treatment with potassium permanganate in warm sulfuric acid solution or with ferrous sulfate in ammonium hydroxide solution. As mentioned previously. sometimes. von Niementowski (533) obtained “oxbenzimidazoles” also in the following manner : Br “Oxbenzimidazoles” are converted to the corresponding benzimidazoles by treatment with acetic anhydride. in boiling acetic acid) with the shifting of a hydrogen atom to form N-arylaminobenzimidazoles. This isomerization is analogous to that involved in the preparation of “aldehydines. FROM 0-AMINOAZO COMPOUNDS: THE PREPARATION OF N. 548).(ARYLAMINO)BENZIMIDAZOLES o-Aminoazo compounds react with aldehydes to form Schiff baaw in the normal manner.” The correct structure of the products was first elucidated by Fischer (226. however. LVIII. . compounds which contain an oxygen atom. D.. These compounds have been called “oxbenzimidazoles” and for the simplest case correspond to either of the following structures (LVII. WRIQHT reduction products of acylated o-nitromilines are found. + RCHO -+ 0 -0-j / N=CHR N-NCsHs LX \ \N NHCsHs I The resulting Schiff bases (LX). “oxbenzimidazoles” may be isomerized readily to 2(3H)-benzimidazolones. 58. LVIX) : OH LVII LVIII LVIX When an alcoholic ammonium sulfide solution is used as the reducing agent.462 JOHN B. readily isomerize (e. distillation with zinc dust or soda lime.227).
N-Arylaminobenzimidazoles may be prepared also by treating l-chlorobenzimidazoles with arylamines (226).CHEMISTRY OF THE BENZIMIDAZOLES 463 The reaction is carried out usually by heating the o-aminoazo compound and aldehyde in acetic acid. formic acid. 552) (226. 228. alcoholic hydrogen chloride. 227. 552) (224) (226) 0- H * The starting material in this case was Chrysoidine: Reduction of these compounds with hydriodic acid or zinc and hydrochloric acid leads to benzimidazoles by the removal of the arylamino residue in the 1-position (227). TABLE 15 N . 227. 227.(Ary1amino)benzimidazoles + R ~ RCHO + R"\ "o-'. 278) (227)* (227). pyridine. . 226. 552) (226. The N-(ary1amino)benzimidazoles that have been prepared by this general method are listed in table 15. \x/ KHAr R' R ' I H H CzHs n-CsH11 CsHa CsHs CsHs CsHs o-HOCsHc o-HOCsH4 0-C1C s c H 0-0zNCoHc 2 " C sH sC=N 0-HOC eHcC=NH H H H H H (754) (275) (276) (277) (755) (133. (225) * (223) (228) (226. or alcoholic solution.
8. 293). and lead tetraacetate.The correct structure for the products obtained was deter- . However. for example. 214. or by heating under reflux an alcoholic or ethereal solution of the Schiff base. The use of lead tetraacetate in benzene or acetic acid solution gives benzimidazoles in excellent yield. FROM SCHIFF BASES The preparation of benzimidazoles and aldehydines from Schiff bases of o-phenylenediamines has been discussed previously in Section 11.392). The use of the latter two reagents has been investigated by Stevens and Bower (700. 292. A. The oxidation involved has been attributed to the presence of air (323). These authors suggest that in an inert atmosphere the formation of benzimidazoles may occur as indicated in equation 11. this conversion takes place in an inert atmosphere. cupric acetate. who have studied this reaction in detail. Their method consists in the evaporation of an aqueous solution of an aldose and an o-phenylenediamine. by prolonged standing of a solution in the air. (11) The conversion of monoalkylidene-o-phenylenediamines benzimidazoles may to be brought about also with chemical oxidizing agents such as mercuric oxide (117.464 JORN B. BENZIMIDAZOLE DERIVATIVES O F SUGARS 1 . The Schiff bases are undoubtedly intermediates in this latter reaction. The conversion of monoalkylidene Schiff bases to benzimidazoles involves oxidation and the reaction can be brought about. WRIGHT E. 701). as shown by Crippa and Moffei (169). Benzimidazoles containing a sugar residue in the %-position The preparation of benzimidazoles from various sugars and o-phenylenediamines was first investigated by Griess and Harrow (291. Green and Day (289) obtained 2-phenyld(or 6)-methylbenzimidazolein about 80 per cent yield from 3-benzalamino-4-acetaminotoluene and from 4-benzalamino-3-acetaminotoluene by heating with nitrobenzene and alcoholic potassium hydroxide solution : CH3 / N=CHCEHb ()“COCH3 C&”i alcoholic KOH heat ~ F.
CHEMISTRY OF THE BENZIMIDAZOLES 465 mined later (321. however. such as a mixture of hydrochloric and phosphoric acids (517). 671). xylonic acid reacts with o-phenylenediamine in the presence of zinc chloride and hydrochloric acid to give anhydro-d-xylobenzimidazole (354. the yields obtained are poor and in many cases quinoxalines are obtained as by-products. by employing the use of cupric acetate as an oxidizing agent. Benzimidazoles containing sugar residues in the 2-position have been used as a means of resolving racemic tartaric acid (306. the products in these cases being dibenzimidazoles (471). 353. The general procedure mentioned above is applicable to saccharic acids. occasionally in good yield (175. in the presence of zinc chloride and hydrochloric acid the products are “anhydro” derivatives formed by the loss of an additional mole of water in the sugar portion of the 2-sugar-substituted benzimidazole (353). 518) : Epimerization appears to be possible a t higher temperatures (517). 631. 630.g. 321. 72. Uronic acids can be converted to saccharic acids (e. 298. Haskins and Hudson (306) and Moore and Link (516. 558. When the reaction is carried out at 180°C. Thus. good yields of benzimidazoles may be obtained. 71. 501. This general method has been used rather extensively to prepare benzimidazole derivatives substituted in the 2-position with a sugar residue (60. 425. 517. This reaction has been investigated by several other investigators (319. 709) and potassium acid tartrate (709). The reaction is carried out usually by heating the aldonic acid and o-phenylenediamine in the presence of a mineral acid. 517) carried out this reaction by first oxidizing the aldose to an aldonic acid and treating the resulting acid with an o-phenylenediamine. Aldoses may be condensed directly with o-phenylenediamineto give benzimidazoles. Richtmeyer and Hudson (631) have enunciated the so-called “benzimidazole rule. 651).. They form hydrochlorides and picrates readily and may be precipitated from solution as the copper salt (516).” which relates the stereochemical configuration of the hydroxyl group in the 2(or a)-position of the aldonic acid with the optical rotation of the derived benzimidazole. 517). benzimidazole derivatives have been reported to be superior to hydrazones and osazones (516). . according to the method of Weidenhagen (741). with hydrogen bromide and bromine) and identified as the dibenzimidazoles (471). For the characterization of sugars. In this way. 559. Epimerization depends also on the concentration of mineral acid used in the reaction (61). 302. 651).
WRIGET in the 1-position These may be prepared from N-monosubstituted-o-phenylenediamines in g. The arguments for the carbinol structure (LXI) appear to have been developed on the following assumptions: “Pseudo bases” may be synthesized from benzimidazolium iodides by reaction with sodium hydroxide. The resulting “pseudo base” is not strongly basic. These o-diamines may be caused to undergo ring closure by one of the conventional methods for the preparation of benzimidazoles (121. 404). Structure “Pseudo bases” possess either the structure LXI or the structure LXII.466 JOETN B. The amide . is volatile in steam. 403. CHa W . “PSEUDO BASES” 1. Several 1-sugar-substituted 2-hydroxybenzimidazoles have been obtained as by-products in the synthesis of flavins. Benzimidazoles containing a sugar residue which the substituent is a sugar moiety.S u g a r G. 401). These compounds were obtained by ring closure of N-sugar-substituted N’-carbalkoxy-o-phenylenediamines (194. hence the product could not be the benzimidazolium hydroxide and it was assumed (251. consequently. R“ Rl R’ LXI The reaction may be reversed by treatment in the cold with acid. 532) that it must possess the carbinol structure (LXI). LLpseudo bases” in the literature have been assigned this structure. &-TxR1’ \ or dOH COR I R’ R’ LXII LXI Until recently the evidence was very much in favor of the 2’3-dihydrobenzimidazolol (LXI) structure. and is soluble in ether. 402.
but it appeared to be less likely because of the ease with which the product may be converted to the bensimidazolium halide by treatment with acid. These spectra indicate the presence of an amide linkage. in addition. Smith. in order to avoid confusion with the literature.CHEMISTRY OF THE BENZIMIDAZOLES 467 structure (LXII) was considered. Rasmussen. different products would have been obtained: CH8 LXIVa CH3 CH3 LXVa I n view of this recent work it would appear that the evidence was in favor of the amide structure (XLII) for these compounds. LXIV If the compounds had possessed the 2. chemical evidence which would also indicate the amide structure. these authors showed that LXIV on treatment with propionic anhydride and LXV on treatment with acetic anhydride gave the same compound (LXXIII). the carbinol structure (LXI) is used throughout the present review. .3-dihydrobenzimidazolol structures (LIVa and LXVa). Very recently. which would indicate structure LXII rather than LXI. However. for example. The authors present. and Ballard (674) investigated the infrared spectra of these compounds.
299.609.3-dimethyl-2. with formic (229) : acid gives the formate of 1. in some cases. may be cleaved by vigorous treatment with alkalis to regenerate the diamine and aliphatic acid.584) or acetic anhydride (229. Thus. accordingly. N . Preparation As mentioned previously.468 JOHN B.3-trimethyl-2-hydroxy-2 ) . They may be obtained also by treatment of N . WRIGHT When benzimidazolium halides are heated with freshly precipitated silver oxide the products obtained are insoluble in ether and are. 2.734).3-dihydrobenzirnidazolol CH3 ) I 0 The preparation from N ”-disubstituted o-phenylenediamines and aliphatic acids is a reversible reaction since the product. 551. also gives 1. “pseudo bases” may be prepared by treatment of 249. the corresponding benzimidazolium hydroxides : R” R” I R’ R’ I These substances are transformed into “pseudo bases” by treatment with alkali. ”-disubstituted o-phenylenediamines with aliphatic acids (229. o-Methylamino-a-methylphenylhydrazine treatment with acetic anhydride on 3-dihydrobenzimidazole (424).2.532. benzimidazolium halides with alkali (241.N’-dimethyl-o-phenylenediamine when heated at 140OC.581. Tinkler (718)reports that neutral “pseudo bases” on standing for some time become strongly alkaline.665). On the basis of this fact and of ultraviolet spectral studies and electrical conductivity measurements it appears that benzimidazolium hydroxides and “pseudo bases” are in equilibrium : 3 ” R” \ R” OH- \N/CR I * R‘ RJ In contradistinction to this it has been reported recently (674)that benzimidazolium hydroxides in the absence of ezcess soluble alkali are quite stable and are not transformed into pseudo bases as reported by Tinkler.
0-y \ I 4- CsH6COCl 4.5-0.HzO -+ I I \@H COCsH6 LXVI LXVI on treatment with ethanol and hydrochloric acid is reported to give the corresponding 2-ethoxy analog (268) : .3-dihydrobenzimidazole(267).CHEMISTRY O F THE BENZIMIDAZOLES 469 CH3 Shriner and Boermans (665) obtained the same compound from phenylenemalonamide: l-Benzoylbenzimidazole on treatment with one mole of benzoyl chloride and 0.3-dibenzoy1-2-hydroxy2.1 mole of water in a benzene-ether mixture gives 1.
3-dihydrobenzirnidazole reported is (230) to give mostly 1-methylbenzimidazole with 1. As mentioned previously.5-tetramethy1-2-hydroxy-2. Reduction with sodium in absolute ethanol or zinc dust in alkaline solution also cleaves the imidazoline ring (251) : Distillation of 1.3-dircethy1-2(3H)-benzimidazolone among the by-products. 2(3H)-benzimidazolones may also be obtained by oxidation of “pseudo bases”. 256): LXVII . H. in a sealed tube (20).3-dihydrobenzimidazole shows Liebermann’s reaction and reacts with sodium nitrite and sulfuric acid with cleavage of the imidazoline ring: This reaction is explained readily if the amide structure (LXII) for the “pseudo base” is assumed. WRIGHT Fischer (251) reports that 1 2 3.3-dimethyl-2-hydroxy-2.470 JOHN B. MISCELLANEOUS SYNTHESES 2-Phenylbenzimidazole has been obtained by the rearrangement of o-aminobenzophenone oxime: This reaction may be carried out by heating o-aminobenzophenone and hydroxylamine hydrochloride in alcoholic solution at 130-140°C. Benzylidine-o-aminophenylhydrazone (LXVII) gives 2-phenylbenzimidazole in quantitative yield when warmed with dilute mineral acids (255.
in .2-dirnethylbenzimidazole 73 per cent yield (423). Reduction of the acetyl derivative of LXVIII with zinc dust and acetic acid gives 1.CHEMISTRY OF THE BENZIMIDAZOLES 47 1 Guha and Ray (297) obt'ained 2-phenylbenzimidazole in a similar manner from the corresponding o-nitro analog: 2-Methylbenzimidazole may be prepared in the same way (295): CHsCHOj S n -j HCI @ZNH2 THK\'=CHCH3 2-Phenylbenzimidazole may be obtained by heating @-(2-aminophenyl)benzylhydrazine in aqueous alcoholic sulfuric acid solution (257) : Analogs containing an a-sulfonic acid group also yield 2-phenylbenzimidazole (258). 1-Methylbenzimidazole has been prepared from o-(methy1azo)methylaniline (422) : @ZH3 LXVIII + HCl --+ 0-J \ + NHdC1 \NI CH3 1-Methylbenzimidazole has been obtained also from the acetyl derivative of LXVIII (423).
to give 2-anilinobenzimidazole (173) : may be prepared in an an2-p-Tolylamino.3-dihydrobenzimidazole (521).C=N C 00C2 Hs . @El The preparation of 2-phenyld(or 6)-chlorobenzimidazole by heating 2. + @:: CH~SC=NC~HE~ HNCsH6 I -0-N ' . . The whole alloxan residue is oxidized away in the process. with concenin trated hydrochloric acid and ethanol has been reported (178).!kHCsH5 NH + CH. WRIGHT N-Formyl-N.and 2-o-tolylaminobenzimidazoles alogous manner (173).3-oxo-6-chloroquinazoline a sealed tube a t 150°C. N'-dibenzoyl-o-phenylenediamine when heated a t 180-200°C. gives 1-benzoylbenzimidazolein addition to other products (759) : CHO o-Phthalimidoazo derivatives on reduction give a mixture of 2-benzimidazoleo-benzoic acids and benzoylenebenzimidazoles (167) : COOH co o-Phenylenediamine reacts smoothly with methyldiphenylisothiourea at 140°C.SH + CsH6NH2 + C H ~ S C H ( N H C O O C ~ H S-+ )~ Y .472 JOHN B.4diphenyl-2. Rudy and Cramer (639) report that alloxan 2-dimethylaminoanil (LXIX) on oxidative degradation with hydrogen peroxide is converted to 1-methylbenzimidazole. o-Phenylenediamine when heated in alcoholic solution with a molecular amount of the methyl ether of thiocarbonyldiurethan gives 2-carbethoxyimino2. Q .
!b& CeHs 1 .494. YOz HCOR ____$ + R”NHa NO2 NOz .497. (12) R’ R” in most of the cases studied was an aryl group.N’-Dibenzenesulfonyl-o-phenylenediamine (LXX) when treated with methylene iodide in the presence of sodium ethoxide is reported to give 1.493. or C2Hs.\ /I CG LXIX N . The general reaction is illustrated in equation 12: RO/ 6 R’ H& O.492. CHs.. By means of this general reaction a large number of benzimidazoles have been prepared.499. for example.498. + RQ HO or t .500) has studied the preparation of 1.CHEMISTRY OF THE BENZIMIDAZOLES 473 NH oxidative degradation . R’ R = H.R’ = NO2 or H.Bdisubstituted benzimidazoles by means of the reaction between primary amines and acylated o-nitroanilines in which the nitro group is labilized by the presence of other groups in the benzene ring. in many cases in good yield . l-phenyl-2-methyl-4.3dibenaenesulfonylbenzimidazoline (326) (LXXI) : LXX Meldola in a series of papers (491.7-dinitro-6-hydroxybenzimidaaole may be prepared in this way in yields of 84-91 per cent (495) : CH3 NOz + CsHaNHz --+ HO\ OzN 61N ‘ ~.
g.474 JOHN B. for several hours gives 2-benzimidazolecarboxylic acids (367). 372) by using hydrazine or a substituted hydrazine (e. 2-benzimidazolesulfonic acid on treatment with 2 per cent hydrochloric acid at 150°C. phenylhydrazine). 369) . for example. . gives 2-hydroxybenzimidazole. 370. These acids may be obtained in yields as high as 90 per cent from 2-mercaptobenzimidazoles by oxidation with potassium permanganate in dilute alkaline solution (200) : Treatment of these sulfonic acids with alkali cyanides and water by heating at 150°C. 372). 2-Hydrazinobenzimidazoles may be obtained in an analogous way (368. 372) claim also that these reactions may be carried out with l-substituted 2-benzimidazolesulfonic acids.. M I G H T I . 2(3H)-Benzimidazolones may be prepared also from 2-benzimidazolesulfonic acids (366. 369. 367. The patents cited above (366. SYNTHESES FROM OTHER BENZIMIDAZOLES Several patents have been issued describing the preparation of various 2substituted benzimidazoles from benzimidazole-2-sulfonic acids. Treatment of 2-benzimidazolesulfonic acid with ammonia or primary or secondary amines yields 2-aminobenzimidazoles (370): + ~ R R ' - Q:lhRRt + Hs0 + Sot 2-Aminobenzimidazole may be prepared in this way in good yield by using ammonia and heating the reactants for 2 hr. It is claimed that 2-hydrazinobenzimidazolesmay be obtained also from hydrazines and 2(3H)-benzimidazobnes or 2-halogen-substituted benzimidazoles in a manner analogous to the method from 2-benzimidazolesulfonic acid (368. at 120-130°C.
Benzimidazoles with the imide nitrogen &e. . . and 2-aminobenzimidazole (4). .. the solubility in nonpolar solvents is increased . like those of the imidazoles (629). The relative basicity of the benzimidazole ring has been determined also by an indirect qualitative method involving comparison of the spectrum of a cyanine dye containing the benzimidazole ring as a constituent with cyanine dyes derived from other basic substances. . .3). . . . . . 239 2(3H)-Benzimidazolone . 170 61 176 294 112 2. . . . Benzimidazoles are also sufficiently acidic to be generally soluble in aqueous alkali and form N-metallic compounds. being somewhat less basic than the imidazoles. . Benzimidazole. . . Conversely. is easily soluble in ether.’* = 12. . . . . seem to be due to stabilization of the ion by resonance.. 308 2(3H)-Benzimidazolethione. . . 4 Reference 712. 111. .2-Diphenylbenzirnidazole. . . . 2-Methylbenzimidasole . . . . 1-Methylbensimidazole. . . . . 292-293 Benzimidazoles are also distillable. values have been determined for benzimidazole (4. . . . . The acidic properties of the benzimidazoles. . for example. . . . . The method involves a measurement of the deviation in A. . With the introduction of other nonpolar substituents in various positions of the benzimidazole ring. T i appears to be due to the fact that benzimidazoles containing hydrogen in the 1-position are associated.. . thus. Benzimidazoles are weakly basic. Benzimidazole distills unchanged above 300°C... . 1. . . . . hydrogen in the 1-position) are usually more soluble in polar solvents and less soluble in organic solvents. 2-aminobenzimidazole is soluble in water. . . . the introduction of polar groupings into the molecule increases solubility in polar solvents. =nNG mum ‘C. . 203 .CHEMISTRY O F THE BENZIMIDAZOLES 475 A large number of benzimidazolecarboxylic acids have been prepared by the oxidation of substituted groups of benzimidazoles.. . . Benzimidazole.30.5(or 2. . . .. . for example. . The pK. . is soluble in hot water but difficultly soluble in ether and insoluble in benzene and ligroin. 398. 2-Phenyl-5(or6)-methylbenzimidazole. . . 712) (pKLl = 5. . .6)-Dimethylbeneimidazole. . 2-Phenylbenzimidazole. 2-methylbenzimidazole. . . . . . . 658. . they are in general soluble in dilute acids. Accordingly. pK. 2-methylbenzimidazole (658). which is assumed to be due to the basicity of the heterocyclic structure. . .. From this table it will be noted that the introduction of a substituent hs into the 1-position in general lowers the melting point. . PHYSICAL PROPERTIES BENZIMIDAZOLES OF The melting points of a number of the simpler benzimidazoles are listed in table 16.. . TABLE 16 Melting points of benzimidazoles BEN-AZOLE YLLTING mIm BENZMDAZOLF.. . . . T. . . .
08 D (710).476 JOHN B. 353. WRIGHT The solubility of benzimidazoles in alkaline solutions depends on the particular compound in question. or amino group are not highly associated. LXXIII Such internal chelation is possible in a number of 2-substituted benzimidazoles. 191. Hunter and Marriott (357) determined the molecular weight of a number of benzimidazoles from freezing-point data in naphthalene solution over a range of concentrations. 726. The infrared spectra of “pseudo bases” have been studied (674). The strength of this bond is evidently enhanced by resonance of the benzimidazole nucleus. Hughes and Lions (356) found that 2-aminomethylbenzimidazole (LXXIV) and benzimidazole-2-methylmercaptkn (LXXV) coordinate with copper and other metals to give complexes of the type shown in formula LXXX (page 483). such as potassium carbonate solution. 751). It would appear that a majority of the molecules possess the internal chelate structure (LXXIII). Substances such as 2-benzoylbenzimidazole (LXXII) occupy an intermediate position. aryl. 1-methylbenzimidazole. The dipole moment of benzimidazole has been determined. the values that have been obtained being 3. . 698. acyl. 2-Benzimidazoleca~boxylic acids are e d y soluble in dilute acids. carbalkoxy. These spectra indicate the presence of an amide linkage in these substances. 2(3H)-Benzimidazolone is difficultly soluble in dilute sodium hydroxide solution. and 2-methylbenzimidazole have been studied (420). 121. 273. Evidence for such internal chelation has been obtained also from ultraviolet absorption data (752). being less highly associated than other benzimidazoles unsubstituted in the 1-position. It is insoluble in dilute hydrochloric acid but is readily soluble in slightly warmed concentrated hydrochloric acid. Those substances which are substituted in the 1-position by an alkyl.93 D (in dioxane) (396) and 4. Evidence was obtained indicating molecular association through N-H-N bonds in those compounds possessing an unsubstituted NH grouping. 750. The more acidic benzimidazoles may be soluble in less basic solutions. The Raman spectra of benzimidazole. LXXIV LXXV The ultraviolet absorption spectra of several benzimidazoles have been determined (69.
599. may be converted conveniently to benzimidazolium iodides with lead hydroxide. yield l-alkylbenzimidazoles and. The periodides. REACTIONS OF THE BENZIMIDAZOLE RING The benzimidazole ring possesses a high degree of stability. thus. 231.CHEMISTRY O F THE BENZIMIDAZOLES 477 IV. monoacetate. 499. 718). Alkyl iodides are usually used and. The benzimidazole ring is also quite resistant to reduction. For the preparation of benzimidazolium halides the reaction is carried out usually by heating the benzimidazole (or N-substituted benzimidazole) with an excess of alkyl halide in methanol under pressure a t a temperature of about 110-150°C. periodides are obtained as by-products or as the exclusive product.3-dialkylbenzirnidazolium halides. Benzimidazole does not couple to indazole in the presence of alkaline benzene diazotate. 645. 217. upon alkylation with alkyl halides. 349. Fischer. tetrahydro. a mixture of isomers may be ob- . 602. give mostly l-methylbenzimidazole hydroiodide (217). Reactions involving the nitrogens at the 1. When the benzimidazole contains a substituent group. 239. 245. especially by 0. monopicrate. CHEMICAL PROPERTIES BENZIMIDAZOLES OF A . nor by vigorous treatment with hot hydrochloric acid or with alkalis. R The alkylation of benzimidazoles has been studied quite extensively (49. Thus. a. 313.and 3-positions Benzimidazoles form salts with acids readily. Oxidation cleaves the benzene ring of benzimidazole only under vigorous conditions. however. Benzimidazole. however. mononitrate. Benzimidazole gives a negative test with sodium nitroprusside and alkali. l-alkylbenzimidazoles may be the main product. in some cases. etc. for example. When the alkylation reaction is carried out at a lower temperature with one equivalent of alkyl halide. 592. 1. 218. benzimidazole readily forms a monohydrochloride. 222. equimolecular amounts of benzimidazole and methyl iodide in methanol a t 90-100°C. (208). The alkylation has been carried out with various alkyl and aralkyl groups. 334. Benzimidazole also forms a salt with 2-nitro-l. under more vigorous conditions. 1 . 212. is not affected by concentrated sulfuric acid when heated under pressure to 270°C. 220. 2(3H)-Benzimidazoolethione gives a red color with these reagents (561). 248. Alkylation Benzimidazoles.and hexahydrobenzimidazoles in which the benzene ring is reduced may be prepared by catalytic reduction under certain conditions.3-indanedione (724) and with copper azide (154). 219. 500.
7(or 1.6. 1.IfJijcH8 \ CHa LXXVII AH8 LXXVI I Both LXXVI and LXXVII on further treatment give the same compound (m. for example. losing ethyl chloride to give 2 .): namely.' caHQN \ CHJ IICH N/ + CH.2.6 .6)dimethylbenzimidazole (249).6)-dimethylbenzimidazole (247).5.3.5-trimethylbenzimidazole (LXXVI) and 126.96.36.199)-Tetramethylbenzimidazole when heated under reflux with methyl iodide in benzene solution gives the methiodide (111).2 . When the reaction is carried out in xylene with the addition of metallic sodium. 1. 1. WRIGHT tained.7(or 2 .2.5(or 2 . CHa@CHsI I CHs Fischer (221) has postulated that in the preparation of benzimidazolium iodides methyl iodide adds first to the double bond of the imidazole ring to give a 2-iodo-3-methyl derivative.p.3.6)-dimethylbenzimidazoleon prolonged treatment with methyl iodide at room temperature gives a mixture of l12.6)-tetramethylbenzimidazoliumiodide (221).6-trimethylbenzimidazole (LXXVII) (220).2 .3.478 JOHN B. The fact that the same compound is obtained indicates the tautomeric state of the benzimidazole ring system.2.3-Dialkylbenzimidazolium iodides on heating under diminished pressure lose the elements of alkyl iodide to give 1-alkylbenzimidazoles.5(or 2 .7)-hexamethylbenzimidazolium iodide is obtained. Thus. + CHaI . which then undergoes rearrangement to the stable benzimidazolium iodide.2. The corresponding N-ethyl compounds behave analogously.3. 2 . 1. I .6-trimethylbenzimidazole (LXXVII) (as the hydrochloride salts) on vigorous heating split out methyl chloride to give the same compound: namely.4 .5(or 2. 2 .3diethylbenzimidazolium iodide loses ethyl iodide to yield 1-ethylbenzimidazole (19) in 80 per cent yield.4.5-Trimethylbenzimidazole (LXXVI) and 1.5(or 1. 221OC.5 .4. 1 . 2 .
Benzimidazole and 2-methylbenzimidazole have been alkylated with esters of lauryl mcH3 NH + CHZClCOOH -+ Cj @ : H3 . Prolonged treatment with excess ethereal diazomethane fails to methylate either 2-benzylor 2-phenylbenzimidazole.6-isomeride is reduced. Benzimidazoles have been alkylated in the l-position also with dialkylaminoalkyl halides. 2. Aryl isocyanates react with benzimidazoles in the l-position (314). The same product may be obtained from benzimidazole and ethylene oxide (490). or nitro groups in the 5(or 6)-position and found that with methyl sulfate or methyl iodide as the methylating agent the formation of the l16-isomerideis favored.5-Dimethylbenzimidazole reacts analogously with ethyl chloroacetate in the presence of sodium ethoxide solution (52). With mixed benzimidazoles (i. Chloroacetic acid and chloroacetamide with benzimidazoles give (benzimidazole-1)acetic acid derivatives (203.5(or 2 .5(or 2.e. The silver salt of benzimidazole has been alkylated with N-(/3-bromoethy1)phthalimide (473). Benzimidazole with ethylene chlorohydrin in sodium hydroxide solution gives a 33 per cent yield of l-j3-hydroxyethylbenzirnidazole (490). either with or without the addition of a basic material such as sodium ethoxide (554. Methyl sulfate with or without the addition of alkali yields l-methylbenzimidazoles (356.6)-dimethylbenzimidazole (51). Benzimidazoles containing a sugar residue in the 2-position have also been alkylated in the l-position (353). With methyl sulfate in the presence of aqueous alkali the proportion of the 1. In toluene solution without the addition of sodium hydroxide. bromo. Treatment of benzimidazole with dichloroethylene or dibromoethylene gives a polymeric benzimidazolium halide.@ : I + CpHJ CaH6 CnHs This reaction has been studied by von Auwers and Mauss (18)..6)-Dimethylbenzimidazolewith benzyl chloride in ethanolic sodium ethoxide solution yields l-benzyl-2 . 581. Phillips (581) studied the alkylation of benzimidazoles containing methyl. Ethyl chloroformate in ether solution yields l-carbethoxybenzimidazoles (328). 673. with those containing different groups a t N-1 and N-3) the reaction proceeds less readily. 677). a 60-65 per cent yield is obtained. 669). 625) : kH2COOH 2 .CHEMISTRY O F THE BENZIMIDAZOLES 479 @ f: I CZHS I- ..
2. + I OH ---t NH I K SO3K SOsH Benzimidazole reacts with formaldehyde to give l-hydroxymethylbenzimidazole in very good yield (25). The alkyl group introduced into the 3-position is that of the alcohol used. I I .480 JOHN B. Chloral when heated in a flask with benzimidazole gives 1-lo.5(or 2. Benzimidazole undergoes cyanoethylation in the l-position in very good yield (371. (333) to give 1-cyano-2-phenylbenzimidazole Several patents (283. i reported among other products.6)-Dimethylbenzimidazolereacts analogously (44). C (CHa)2 SOaH LXXVIII C(CHa)zS03H LXXIX s 2-Phenylbenzimidazole.6)-dimethylbenzimidazole is added to acetone saturated with sulfur dioxide a product is obtained which has been assigned (333) the structure indicated by LXXVIII or LXXIX. when heated with excess cyanogen iodide. l-Dodecyl-2-methylbenzimidazole been obtained has in 58 per cent yield by the reaction between two moles of 2-methylbenzimidazole and one mole of dodecyl chloride (445). 691) describe the preparation of 1.@-trichloro-ahydroxyethyl]benzimidazole (32).@ .3-dialkylbenzimidazolium chlorides by heating l-alkylbenzimidazole hydrochlorides in alcoholic solution. 374): 0-f \ + CHz=CHCN -+ Nit &-J \ N AHzc H zm (l-Benzimidazo1e)sulfonic acid may be prepared in 69 per cent yield by the alkylation of the potassium salt of benzimidazole with pyridinium-N-sulfonic acid (742): CsHsN HSO. WRIGHT and cetyl alcohols (692). When 2. 373.5(or 2. ~.
Under other conditions. 309). 269.7-Tetrahydrobenzimidazoles may be smoothly benzoylated with benzoyl chloride in pyridine (745).6 . Odd0 and RalTa (556. N . decarboxylation occurring a t the same time: N-Formyl-N . on benzimidazole (43. c. 1-Acetylbenzimidazole has been prepared also by heating 2-benzimidazolecarboxylic acid with acetic anhydride (95). yields of N-acylbenzimidazole as high as 100 per cent may be obtained. when the excess of acid anhydride is not removed. (337). Acylation N-Acylbenzimidazolea may be prepared by the action of acid chlorides or anhydrides on benzimidazoles.5 . 555). N-Acylbenzimidazoles are generally relatively unstable when heated with aqueous solutions and tend to hydrolyze to benzimidazoles (43. l-Benzoyl-2-methylbenzimidazole been obtained (760) from the reaction between 2-methylbenzimidazole and benzoyl chloride in the presence of sodium hydroxide solution. 264. 4 . respectively. The action of Grignard reagents on benzimidazolea Grignard reagents react with the active hydrogen in the l-position of benzimidazole (555): + CnHsMgBr . i s reported (759) to give l-benzoylbenzimidazole in addition to other products. 264.N'-dibenzoyl-o-phenylenediamine on heating to 180-20O0C. 1-Benzoylbenzimidazole and l-acetylbenzimidazole may be prepared by the action of benzoyl chloride and acetyl chloride. 95.N'-diacyl-o-phenylenediaminesare obtained.265. 2-Methylbenzimidazole when heated with acetic anhydride gives l-acetyl-2has methylbenzimidazole (96). The reaction is usually carried out in the absence of water. It is reported that 2-phenylbenzimidazole is unaffected by benzoyl chloride at 160°C. l-Benzoyl and l-acetyl derivatives have been prepared aho by the action of these acid chlorides on the silver salts of benzimidazolea (53). If the excess acid anhydride is removed before the reaction product is poured into water. 557) have studied the reaction of acid anhydrides with benzimidazole under various conditions. In the presence of water and especially in alkaline solution (SchottenBaumann procedure) cleavage of the imidazole ring may occur.0-J I + cpHs MgBr .CHEMISTRY O F THE BENZIMIDAZOLES 48 1 b.
Benzimidazoles in the Mannich reaction Bachman and Heisey (25) have studied benzimidazoles in the Mannich reaction.C H ~ ' Morpholine gives a 97 per cent yield and diethylamine a 74 per cent yield of the corresponding Mannich base in the same reaction. 2-Ethylbenzimidazole and 1-phenylbenzimidazoledo not react. formaldehyde. + 2CHzO + 2CeH6"z -+ 0.N'-dibenzoyl-o-phenylenediamine (555). reaction with 2-alkylbenzimidazoles might occur at higher temperatures (25). however. I OJ I + MgClBr 'CH. 556) : a-. the main product being N . and piperidine give a 97 per cent yield of 1-(piperidinomethy1)benzimidazole. 1-carbethoxybenzimidazole is obtained (555. \ N + ClCOOCzH5 MgBr C OOCz Hs Benzoyl chloride gives 1-benzoylbenzimidazole as a by-product. 2(3H)-Benzimidazolethione with formaldehyde and aniline is reported (362) to give 1. Equimolecular amounts of benzimidazole. 2-Ethylbenzimidazole is less reactive and apparently does not react with formaldehyde in this manner (25). 556. With ethyl chloroformate.k"NHc6& H~ .3-bis (anilinomethyl)benzimidazole-2-thione.482 JOHN B. Attempts to use primary amines or higher aldehydes in place of formaldehyde in the reaction were unsuccessful. 557). Benzimidazole when used as the amine component with formaldehyde and 2nitropropane or pyrrole reacts abnormally to give a 95 per cent yield of l-hydroxymethylbenzimidazole. d. WRIGHT Benzimidazole-1-magnesium bromide ("magnesylbenzimidazole") reacts with aliphatic acid chlorides or anhydrides to yield 1-acylbenzimidazoles (555.NHC (.
2-Phenylbenzimidazole and 2-methylbenzimidazole form silver and mercury salts but no salts with copper. However. cobalt.5(or 2. 2(3H)-Benzimidazolone and 2-chlorobenzimidazole yield no metal derivatives. The ability of various benzimidazoles to form metal salts has been studied extensively by Feigl and Gleich (205). cadmium. 2(3H)Benzimidazolethiones form S-metal salts. A number of silver. other benzimidazoles may not form metal salts with all of the metals listed above.5(or 2. 2-Phenoxymethyl-. are reported (205) not to form metal salts with copper. for example.6-dimethylbenzimidazole.6)-dimethylbenzimidazole. insoluble in water and in most organic solvents. l-phenylbenzimidazole. l-Benzylbenzimidazole. however. 393). and silver. The salt-forming ability of 2-a-pyridyl.6)-Dimethylbenzimidazole. The N-so+um salt thus obtained is hydrolyzed with mater to regenerate 2.copper. Other benzimidazoles. mercurous chloride salts of l-phenylbenzimidazole and l-p-tolylbenzimidazole have been reported (46. such as 2-methylbenzirnidazole and 2phenylbenzimidazole. cobalt. however. mercury (mercurous chloride salt). A rather wide variety of metals form salts with benzimidazoles. have been prepared (205. Metal derivatives of benzimidazole The hydrogen in the l-position of benzimidazoles is sufliciently acidic to be replaced by metals and give N-metal benzimidazoles. 2. zinc.and 2-/3-pyridylbenzimidazoleswith metals has been investigated (455. gold. nickel. cobalt. or zinc (205). dissolve readily in aqueous sodium hydroxide solution (48). for example. and 1. The corresponding N-sodium salt may be prepared by adding an equivalent amount of sodium ethoxide. and then adding ether. 456). cadmium. The silver (48).CHEMISTRY O F THE BENZIMIDAZOLES 483 e. containing no hydrogen in the l-position. 2-ethoxymethyl-. and zinc salts of benzimidazole. 2-Aminomethylbenzimidazole coordinates with metals such as copper to give a complex of the following type (356): H2 N-+Cu+-NH2 I I LXXX (Benzimidazole-2)methylmercaptan coordinates with metals in an analogous way (356). and copper salts of various benzimidazoles are described (363) and are claimed to be of value as therapeutic agents. This mas first shown by Bamberger and Lorenzen (48). when treated in alcoholic solution with an ammoniacal silver nitrate solution yields the N-silver salt. . 672). and 2-methoxymethylbenzimidazoles give silver and mercury salts. cadmium.
or 2 . 5(or 6)-Ethoxy-2-methylbenzimidazole yields 2-methyltetrahydrobenzimidazole. 208).in good yield. Catalytic reduction of benzimidazole (305. first showed that certain benzimidazoles could be reduced to 4 . to cleave arylamino groups from benzimidazoles without affecting the . Hydrogenation of 2-(p-dimethylaminostyryl)benzimidazole with nickel at atmospheric pressure saturates only the olefinic linkage in the 2-position (640): Other benzimidazoles possessing an unsaturated side chain have been hydrogenated with nickel and hydrogen under high pressure to effect hydrogenation only in the side chain (285). . and 2-phenylbenziBenzimidazole and those midazole yields 2-cyclohexyltetrahydrobenzimidazole. however.&dimethylbenzimidazoles give the corresponding tetrahydrobenzimidazoles. Sodium in refluxing absolute alcohol also causes no reduction of the benzimidazole ring (108). the ethoxy group undergoing cleavage.5(or 2. in fact. 739. and 1. 193. The reduction is successful only with those benzimidazoles which contain a substituent in the 2-position. Hartmann and Panizzon (305). 746) is reported to give negative results. 2-methylbenzimidazole. benzimidazoles containing a substituent in the l-position (but not in the 2position) could not be reduced with platinum according to this method.benzimidazole ring in the process (227). 751). WRIGHT 1. 2Phenylbenzimidazole gives only 2-cyclohexylbenzimidazole. 2-ethyl-.5. Thus. dehydrogenation of reduced benzimidazoles Until very recently it was thought that the benzimidazole ring was stable t o reduction. with platinum in acetic acid solution at several atmospheres pressure (155. 746) even under high pressure with nickel as the catalyst (305. A number of 2(3H)-benzimidazolones containing substituents on the benzene ring have been reduced catalytically to hexahydrobenzimidazolea.484 JOHN B.7-tetrahydrobenzimidazolesin good yield with platinum (Adam’s catalyst) in acetic acid solution at atmospheric pressure. hydrogenated benzimidazoles. even for those compounds which also contain a substituent in the 2-position.s)dimethylbenzimidazole with red phosphorus and hydriodic acid even to 300°C. Treatment of benzimidazole. The presence of a substituent in the benzene ring of the benzimidazole hinders hydrogenation also.6 . gives no reduced product (47. 2-methyl-. Red phosphorus and hydriodic acid have been used. Reduction of benzimidazoles.
4).& \ / CH C=O I I "6 . Hexahydro-2(3H)-benzimidazolone may be obtained by the reaction between hexahydro-o-phenylenediamine and phosgene in sodium hydroxide solution (181). A number of hydrogenated benzimidazoles have been prepared also by chemical methods.3.CHEMISTRY OF THE BESZIMIDAZOLES 485 R = -(CHdnCOOH (where n = 0. Hexahydro-2(3H)-benzimidazolone may be obtained from 2(3H)-benzimidazole by this general method in 38 per cent yield (192). CH2 Hz C Hz C I co \ CH. Ha C Hz C /CHz\ CHhTHz CHz 2-Benzylhexahydrobenzimidazolemay be prepared by treatment of the same diamine with an imino-ether (694) : \ CHz / CH"z c1 (NaOH) + CHI -+ Tetrahydrobenzimidazoles may be prepared also by chemical methods.- I + c 1 \ -2HC1 Hz C /CHz\ CH-NH H. Weidenhagen and Wegner (745) prepared a series of 2-substituted tetrahydrobenzimidazoles by the reaction between aldehydes and 2-hydroxycyclohexanone. CHOH + RCHO cu+++ "a / f .
The imidazole ring may be cleaved in poor yield with benzoyl chloride and sodium hydroxide solution. acetaldehyde.757) as occurring a5 follows: .2-di(2-benzimidazolyl)ethanesto the corresponding ethylenes a t elevated temperatures in the presence of a mild oxidizing agent such aa ferric sulfate or mercuric acetate. WRIGHT This procedure is analogous to a method for the synthesis of imidazolas from the coraldehydes and acyloins. By using 4-methyl-2-hydroxycyclohexanone responding 5(or 6)-methyltetrahydrobenzimidazoles may be obtained (745).486 JOHN B. Tetrahydrobenzimidazoles may be prepared also from 1 2-cyclohexanedione. Attempted dehydrogenation of tetrahydrobenzimidazoles with palladium sponge does not give the corresponding benzimidazole but instead a compound of high molecular weight (745). This transformation has been postulated (266. Potassium permanganate completely destroys the molecule. In the presence of additional acid chloride and in the presence of water further reaction may occur and N N'-dibenzoyl-o-phenylenediaminea are obtained. 3. tetrahydrobenzimidazoles melt higher than the corresponding benzimidazoles and possess greater basicity. This compound when treated with benzylamine. 2-Methyltetrahydrobenzimidazolemay be prepared in an analogous way by using an excess of ammonia (470). and ammonia in ethanol yields 38 per cent of l-benzyl-2-methyltetrahydrobenzimidazole. 695) describe the dehydrogenation of a number of 1. Cleavage of the imidazole ring The imidazole ring of benzimidazoles may be readily cleaved by one of several methods : a. The benzimidazoline or 2.3-dihydrobenzimidazolestructure does not appear to have been established with certainty. Several patents (152. In general. Aroyl halides in the presence of water Benzimidazoles when treated with benzoyl chloride yield first N-benzoylbenzimidazoles.
By reactions involving "pseudo bases" Pseudo bases on vigorous treatment with alkaline reagents may be cleaved to N . ) .CHEMISTRY OF THE BENZIMIDAZOLES 487 COCaHg The benzoyl chloride addition product is hypothetical. In addition to N .COC1. With 1 3-dimethyl-2-hydroxy-2 . however. 122. 699) : + R R'COOH This reaction. 696.N'-dibenzoyl-o-phenylenediamines there may be formed as by-products l-benzoylbenzimidazoles and N N'-dibenzoyl-N-aryl-o-phenylenediamines (266. 757).3-dihydrobenzimidazole (LXXXI) cleavage occurs readily on refluxing with aqueous alkali. 698. 697. benzoylation according to the Schotten-Baumann procedure (benzoyl chloride in aqueous alkali) readily cleaves the imidazole ring (41. consequently. Benzimidazoles which have a substituent group in the l-position are cleaved in a similar manner (757): CsHE. ) b. however. H20+ I I p c o c e H 6 I COR R' R' These reactions may be carried out conveniently in alkaline solution. the other producta have been isolated. is not a general one and in certain cases it proceeds with difficulty or not a t all. 757).N'-dialkyl-o-phenylenediamines (558.
2-Hydroxy-l. 1. CIE LXXXII Other pseudo bsses containing a 2-aryl group have been cleaved in a similar manner.2. In the latter cases temperatures to 150°C. In general. CHs I CH3 This latter reaction is best explained if the psuedo base is considered as being in the amide form (cf.3-dihydrobenzimidazole (LXXXIII) has been cleaved also by treatment with sodium and alcohol or with zinc dust in alkaline solution (251).3-dihydrobenzimidazole hinders cleavage.488 JOHN B. page 467): . Treatment of LXXXIII with sodium nitrite in dilute CH3 LXXXIII sulfuric acid gives 3-acetylmethylamino-4-methylnitrosoaminotoluene (251).3-Dimethyl-2-phenyl-2-hydroxy-2 (LXXXII) may be cleaved by refluxing with aqueous-alcoholic potassium hydroxide solution (251). whereas an alkyl group on the benzene ring has a hindering affect (251. are required to effect cleavage. the presence of groups larger than hydrogen in the 2-position also .3. WRIGHT The presence of a nitro or bromo group in the 5-position facilitates cleavage.582).5-tetramethyl-2.
5(or 2. By treatment of 1-benzimidazoylmagnesium halides with aroyl chlorides Whereas acyl halides react with 1-benzimidazoyimagnesium halides to form l-acylbenzimidazoles.6)-dimethylbenzimidazoleis obtained : C l . aroyl halides react to form chiefly an open-chain diamine through rupture of the imidazole ring. l-chloro-2. By treatment with acid anhydrides Odd0 and Raffa (556.N’-diacetyl-o-phenylenediamine by the action of acetic anhydride and sodium acetate a t reflux temperatures (312).6)-dimethylbenzimidazole in an aqueous acid solution is treated with a saturated solution of bleaching powder at (35°C. Thus. When benzimidazole is heated with an excess of acetic anhydride and the reaction product poured into boiling water without first removing the excess anhydride the product is N . N ’ dibenzoyl-o-phenylenediamine. 1-benzimidazoylmagnesium bromide when treated with benzoyl chloride in ether solution gives mostly N . 4.N‘-diacetylo-phenylenediamine (556). The rupture of the imidazole ring has been postulated (555) as occurring as follows: Qj \ N MgBr + CsHsCOCl + I Q J COCsHs CsH6 C 0 Cl. Propionic anhydride and butyric anhydride react analogously (557). Halogenation When 2. with l-benzoylbenzimidazole and benzimidazole as side-products (555). Benzimidazole is also cleaved to N . I d. 557) have studied the action of acid anhydrides on benzimidazoles under a variety of conditions.CHEMISTRY O F THE BENZIMIDAZOLES 489 c.5(or 2.
490 JOHN B.mr 2-Methyl-6-bromobenzimidazole and 2-methyl-4-bromobenzimidazole under the same conditions give 2-methyl-2. When heated under reflux in benzene solution a rearrangement of the chlorine atom to the benzene ring takes place: Cl The N-chloro derivative of this compound may then be prepared by treatment again with bleaching powder : c H1a m " 3 c C H c 1 I C1 Treatment of the latter compound by refluxing in benzene solution rearranges the N-chlorine atom again into the ring. The addition of two moles of bromine to a cold acetic acid solution of 2-methylbenzimidazole gives a tetrabromo derivative: Br / -NBr 2Br2 ---t @H C3 l . QN6yH3.4.5-dimethylbenzimidazole) is obtained (50). ?-tribromobenzimidazole at steam-bath temperature adds bromine acrosa the 2.3-double bond.4 5 6-tetrachloro-2. 2-Methyl-4. even at relatively low temperatures. 2-Aminobenzimidazole may be chlorinated in the 5(or 6)-position in 95 per cent yield by treatment with hydrochloric acid and hydrogen peroxide (466).3.6. ) ) The bromination of 2-methylbenzimidazole has been studied by Baczynski and von Niementowski (30). The chlorinated products obtained in each case are listed in table 17. This process may be repeated until the totally chlorinated compound (1. The bromine atoms at the 2.6-tetrabromobenzimidazoline hydrobromide. WRIGHT The N-chloro compound loses chlorine quite readily.and 3-positions of the brominated products mentioned above may be removed by heating with . A number of 5-hydroxybenzimidazoles and 5-aminobenzimidazoles have been chlorinated with chlorine in acetic acid solution (260).
CHEMISTRY O F THE BENZIMIDAZOLES 49 1 TABLE 17 Chlorination of 6-hydroxy. Calculated amount of chlorine Excess chlorine .and 6-aminobensimidazoles STAPTING BBNZIUIDAZOLE CALOPINATING CONDITIONS PXODUCT Calculated amount of chlorine Calculated amount of chlorine 0 CII.
TABLE 174ontinued STAPTXNG BLNZIYIDAZOW CHLOPINATING CONDITIONS PPODUCP Calculated amount of chlorine Calculated amount of chlorine 1 CI Saturated with chlorine. 492 . followed by reduction of the keto chloride HO/ c1\ j --N / II SH Saturated with chlorine Mixture of dichlorinated and trichlorinated products 0 CH.
benzene.7-tetrabromobenzimidazole. Treatment with water in some cases removes the bromine atoms at the 2-and 3-positions but the second bromine removed enters the benzene ring.6(or 5. since this grouping in the brominated products still shows all the characteristic reactions of the 2-methyl group of benzimidazoles (30).and tribrominated 2-ethylbenzimidazoles (675). Bromination with two moles of bromine in cold alkaline solution gives 2-methyl-4. or aqueous potassium iodide solution to give brominated products containing bromine only in the benzene ring. thus. .6. followed by reduction of the keto chloride c1 NH c 1 Saturated with chlorine.6(or 5. Bromination of the latter product with one mole of bromine in alkaline solution gives a tribromo derivative (2-methyl-4 .6.7)-dibromo-2-methylbenzimidazole. followed by reduction of the keto chloride c1 " CH. 2.5. Exhaustive bromination of 2-methyIbenzimidazoleor any of its brominated products in alcoholic solution gives 2-methyl-4. 2-Ethylbenzimidazole on treatment with bromine water gives a mixture of di. Bromination in all of these caaes does not take place on the 2-methyl group. ?-tribromobenzimidazole).4-tribromo-2-methylbenzimidazoline on treatment with water gives 4. aniline. 2-Methylbenzimidazole on long standing with one mole of bromine in acetic acid solution gives 2-methyl-4(or 7)-bromobenzimidazole. followed by reduction of the keto chloride c1 NH Saturated with chlorine.3.7)dibromobenzimidazole.CHEMISTRY O F THE BENZIMIDAZOLES 493 TABLE 17-Concluded STAPTING BENZIMIDAZOLE C H W P I N A T U Q CONTJITIONS PPODUCI Saturated with chlorine.
4-diacetylaminophenol when treated with excess bromine gives 2-methyl-5. 4 . WRIGHT Treatment of 2.5(or 2.6)-dimethylbenzimidazole or 6(or 5)-bromo-2.5(or 2.494 JOHN B.7(or 4.g)dimethylbenzimidazole.6-dibromo analog may be obtained by bromination in acetic acid solution. in Bromination of 2-phenyl-5-acetylaminobenzimidazole the presence of sodium (260) acetate gives 2-phenyl-4-bromo-5-acetylaminobenzi~dazole : Br It is reported (311) that 3. HBr CHa/ -N @N’cH=CHc6 __3 Bra 2-Methyl-l-phenyl-5-hydroxybenzimidazole bromination in aqueous acetic on The acid solution leads to 2-methyl-l-phenyl-5-hydroxy-4-bromobenzimidazole.5(or 2. &HT Qil .6)-dimethylbenzimidazolewith bromine in acetic acid or carbon disulfide (534) or in chloroform (45) leads to either 4(or 7)-bromo2.6)-dibromo-6(or 5)-hydroxybenzimidazole: Treatment of benzimidazole in aqueous solution with the theoretical amount of iodine (N/10 solution) in the presence of sodium hydroxide gives a quantitative yield of 2-iodobenzimidazole (560). Br 5(or 6)-Methyl-2-styrylbenzimidazolehydrobromide on treatment with bromine in chloroform gives a perbromide which on refluxing in alcohol yields 8 product brominated in the side chain (206).
ring closure may occur also on the 6position if the 4-position is blocked.or 6-position. alt. 283. For example. 5-Aminobenzimidazoles form diazoamino compounds with aryldiazonium salts. 690). respectively (155. A number of patents describe “sulfonated benzimidazoles” obtained by the sulfonation of benzimidazoles with either sulfuric acid (150. Nitrobenzimidazoles that have been obtained by the nitration of benzimidazoles are listed in table 18. although halogenation may occur also on the opposite side of the hydroxyl group (6position). The benzimidazole nucleus is very stable to oxidation in that it is possible to carry out the oxidation of substituent groups without affecting the nucleus. In the Skraup reaction on 5-aminobenzimidazoles ring closure occurs preferentially on the 4-position. halogenation of 5-hydroxybenzimidazole takes place preferentially a t the 4-position. 2-Benzylbenzimidazole gives the corresponding triiodide under comparable conditions (736).or 7-position) especially if the 5. 683) or chlorosulfonic acid (682.QJ HOsS /’ -N H20 .CHEMISTRY O F THE BENZIMIDAZOLES 495 2-Phenylbenzimidazole on heating with six moles of iodine in an alcoholic solution is reported (348) to give a triiodide: This substance on heating under reflux in aqueous solution yields 2-phenylbenzimidazole hydroiodide. Nitration and halogenation may take + l : o + HdKh . however.or 6-position is blocked. In most cases nitration appears to take place preferentially a t the 5. Vigorous oxidation with a hot alkaline solution of potassium permanganate gives a small amount of 4. 363. 312).5-imidazoledicarboxylicacid (40). 655. the nitro group may also enter the 4.hough some analogies to naphthalene are apparent. 6 . Nitration The nitration of benzimidazoles proceeds readily. Benzimidazoles are mainly benzenoid in their reactions. 6. Treatment of benzimidazole with concentrated sulfuric acid gives 5-benzimidazolesulfonic acid (363). However. Fries (260) has investigated the benzenoid and naphthenoid characteristics of benzimidazoles. Miscellaneous reactions 2(3H)-Benzimidazolone reacts with succinic anhydride and glutaric anhydride in the presence of aluminum chloride to give P-(benzimidazoyl-5)propionicacid (13 per cent yield) and ~-(benzimidazoyl-5)butyricacid (5 per cent yield).
527) HtSOd KNOa warm on stean bath + (480) . 233. 726.496 JOHX B. 234) Q& J C NH @i \ II CHl Fuming HNOa CHa :696) I :338) Fuming "0s $35) Concentrated HiSOi KNOD warm on stean bath + NO2 (480) "01 (236. + HzSO. :33.702) "0s + HSSO. WRIGHT TABLE 18 Nitration of benzimidazoles STARTING BEWZIYIDAZOLE m A T I N G CONDITIONS PZODUCI PEPIPENCLS HNO.
5dinitro isomer waa obtained aa a by-product in 5 per cent yield.KNO: heat on steam bath NO9 HNO. ?-Dinitro-l. . 5 (or 6) -Chloro-?-nitro3- phenylben zimidazole “‘ 0 + H2SO I I CHi Fuming HNOI 5.2diphenylbenzimidazole C& CtHs *The 4.CHEMIBTRY O F THE BENZIMIDAZOLES 497 TABLE 184ontinued SR4XTING BZNZULIDAZOLE JITPAflNG CONDITIONS PPODUCI LERRtNczs “Os + H2SO KNOs %90°C. + HNOa + HzSO 5(or 6)-Chloro-?-nitrobenzimidazole NH HzSOi $.
I CK HNOa Crt CHI + HsSOd '5. \ N Fuming HNOJ. CH~ c0~0-j~~ HNO.498 JOHN B.p a CNCH ' Q .or 7-nitro derivative" NH "01 CaCOOH + CsHr CSHS Br I or Fuming HNOs '?-Nitro derivative" . "?-Nitroderivative" -5" to -10°C. c . WRIGHT TABLE 184untinued STARTING BENZIMIDAZOIZ -TINO CONDITIONS PPODWCI Fuming HNOI 5. ?-Dinitro-l-p-tolyl-2phenylbenzimidazole CtI4 CH .
$-position of naphthalene).CHEMISTRY OF THE BENZIMIDAZOLES 499 TABLE 1 8 4 o n c b d e d YITPATING CONDITIONS PRODUCT KNO. etc. place preferentially on the 5-position (corresponding to the . Benzimidazoles are unaffected by hydroxylamine.. + HISO./ ( p NOQ \ /co NH Dissolve in fuming HNO. such aa the conversion of an acid to its ester. Reactions involving the 2-methyl . Such reactions will not be considered in the following discussion but rather only these reactions which are characteristic of benzimidazoles. B. Chlorides of hydroxybenzimidazoles may lead to keto chlorides or an ortho-quinone (analogy to naphthalene). methylene group The methyl group of 2-methylbenzimidazoles is comparable in its activity to the methyl group of a-picoline. or methyl ketones and shows OT 1 . HISO‘ HNOi at low tempera ture (or) reflux with HNO. REACTIONS INVOLVING SUBSTITUENT GROUPS A number of reactions of benzimidazoles involve commonplace transformations. OtN\ CH. quinaldine. + NO2 Nitrous oxide (or: “?-Nitro derivative” cold HNO. 80-90°C.
2-Methylbenzimidazoles. because of its electron-attracting nature imparts a positive character to the carbon atom of the 2-methyl group. react with aromatic aldehydes in aldol-type condensations in a manner analogous to a-picoline and quinaldine (35). and alloxan (the alloxan is decomposed) (9). The benzimidazole ring.500 JOHN B. Phenanthraquinone condenses with 2-methyld(or 6)-nitrobenzimidazole in boiling acetic anhydride to form an abnormal product (439).for 2 hr. for example. Acenapthenequinone condenses in an analogous manner with 2methylbenzimidazole (9) : G CNH B H + o=y8 o=c \ Negative results are reported with benzil. 1. quinone. Isatin gives a normal condensation product (438) : 02NQJCH* + oc- Isatin condenses similarly with 2-methylbenzimidazole and 2-benzylbenzimidazole (8). A rather large variety of aromatic aldehydes and 2-methylbenzimidazoles have been condensed in this manner. The above reaction may be carried out by heating the two reactants together a t 200°C. WRIGHT most of the same reactions of these compounds.2-Dirnethylbenzimidazole when allowed to stand for 1 week with diethyl oxalate gives a small yield of condensed product (114) : . p-dimethylaminobenzaldehyde. In addition to 2-methylbenzimidazoles other benzimidazolm having a 2-alkyl or 2-aralkyl group have been used. like the pyridine and quinoline ring.
the keto and imino groups on the latter compound having been interchanged.CHEMISTRY O F THE BENZIMIDAZOLES 501 + @ C y H 3 : CHs I (COOCZH~)~ - Q. whereas 2-ethyl. however. The compound LXXXIV possesses a yellow color and is isomeric with indigo. Borsche and Doeller (115) have prepared the phthalone from l-phenyl-2methylbenzimidazole.c/coo NH \CO\ LXXXIV The evidence for this structure is based on the fact that 2-methylbenzimidazole yields a phthalone. 2-Methylbenzimidazoles like quinaldine react with phthalic anhydride at an elevated temperature to yield phthalones (36) : Phthalones from a number of 2-methylbenzimidazoles have been prepared in this way.ycH2 CHa I c0c00c Hs 1-Phenyl-2-methylbenzimidazole gives a poor yield of the corresponding condensation product after 4 days (115). he assigns this compound a somewhat different structure (LXXXIV): Q'.and 2-benzylbenzimidazoles do not. they assign their product the isophthalone structure : 2-Methyl-1-phenylbenzimidazoleon shaking with benzoyl chloride and sodium hydroxide solution reacts at the 2-methyl group (761): H: aJ c @ + c6% I CsHbCOCl NaoH @:ICH=COCOC6H5 LH6 LXXXV . however. van Alphen (7) prepared the phthalone from 2-methylbenzimidazole. )CH3 + 0::) Q.
reverts to 1-phenyl-2-phenacylbenzimidazole (761). for example. WRIQH7! l-Phenyl-2-phenacylbenzimidazole also gives LXXXV under the same conditions. analogous to the corresponding reactions in the a-picoline series. yields benzimidazole (94) : 5(or 6)-Methyl-2-benzimidazolecarboxylicacid is decarboxylated i a similar n manner by melting or by boiling the acid in acetic acid (39). Reactions of d-benzimidazolecarboxylic acids Benzimidazoles containing a carboxyl group in the 2-position readily undergo decarboxylation on heating. With excess thionyl chloride a yellow cyclic diamide containing no chlorine is obtained in 86 per cent yield: 0 c1 I! 0 Acidic or basic hydrolysis of this substance regenerates 2-benzimidazolecarboxylic acid. 2-Benzimidazolecarboxylicacid on heating above its melting point. apparently has not been studied. 2-Benzimidazolecarboxylicacid may not be converted to its acid chloride with phosphorus chlorides or thionyl chlorides (166). however. l-Phenyl-5-nitro-2benzimidazolecarboxylic acid and the corresponding ethyl eater may be decarboxylated by heating with concentrated hydrochloric acid in a sealed tube a t 150°C. (628). The replacement of one of the active hydrogens of the methyl group of 2methylbenzimidazoles by lithium or sodium. In such a c u e replacement of the hydrogen in the l-position might be expected first. Alcoholysis leads to 2-benzimidazolecarboxylic esters and treatment with ammonia or amines (primary or secondary) yields amides (166): . The product (LXXXV). with l-substituted benzimidazoles such substitution on the 2-methyl group might be possible. 2.502 JOHN B. on treatment with alcohol or on heating with 20 per cent hydrochloric acid.
Other 2-or-chloroalkylbenzimida- . 2-Chloromethylbenzimidssole (LXXXVI) and other 2-(a-haloalkyl)beneimi- LXXXVI dazoles are highly reactive. Structurally. 2-Chloromethylbenzimidazole is quantitatively hydrolyzed with boiling water in 30-60 min. Day. since they possess the same =CCH&l grouping. and Miller (670. they are related to allyl and benzyl halides.671). who find that these halides are more active than allyl and benzyl halides.CHEMISTRY OF THE BENZIMIDAZOLES 503 // (674% yield) OJCOOH 3 Reactions of W-(a-huloalky2)benzimidazoka . The reactivity of these benzimidazoles is probably due to the existence of such resonating structures as: -N -N -N \ C-CHt // and -N \ C-CH / + The chemical reactivity of these substances has been investigated by Skolnick.
356.504 JOHN B. 415.(a-chloroisopropyl) derivative is completely hydrolyzed by water a t room temperature.(a-chloroalkyl)beneimidazoles in this reaction have been determined (670). 698) : u. + E JCH1Cl ” . The Williamson reaction of 2-chloromethylbeneimidaeolewith sodium ethoxide leads not to 2-ethoxymethylbeneimidazole but rather to a product containing no oxygen.” + 2NaCl CH2 LXXXVII 24a-Chloroisopropyl)beneimidazole when refluxed in dry alcoholic solution in the presence of pyridine gives a good yield of 2-(a-ethoxyisopropyl)benzimidazole and hence reacts in a manner analogous to trityl chloride (triphenylmethyl chloride). 2-(a-Chloroalkyl)benzimidazoles react with primary and secondary amines to give 2-(a-aminoalkyl)beneimidaaoles(109. + 2NaOC2Hs @ilCHZCl .0-i 2 \ N/ CCH2Cl Na I CH2 + 2CzHoOH -+ 01 ‘yRNQ -’ \ N/ \ . WRIQHT eoles that were studied are hydrolyzed in a somewhat shorter time and the 2. 634. 2.(a-Chloroalkyl)benzimidazoles react alsa with potassium iodide in acetone solution to yield the corresponding 2-(a-iodoaJkyl)benzimidazoles. presumably LXXXVII (671).The reaction rates of several 2.
3 I I From the reaction between 2-a-chloromethylbenzimidazole and phenylmagnesium bromide. no product could be isolated (671). treatment of 2 (3H)-benzimidazolone . \ \N/CH2 CON& CH.CHEMSTRY OF THE BENZIMIDAZOLES 505 2-(a-Chloromethyl)benzimidazolereacts with p-aminobenzoic acid or its ethyl ester in alcoholic solution in the presence of a small amount of sodium iodide (415) : C1 + NH~DCOOH N d C2H60H* Various attempts to replace the chlorine of 2-(a-chloromethyl)benzimidazole by an amino group by reaction with ammonia are reported to give a mixture of products. Reactions of 2-(SH)-benzimi&azols 2(3H)-Benzimidazolones (or 2-hydroxybenzimidazoles) are extremely stable substances. 2 (3H)-Benzimidazolone is not split by treatment with benzoyl chloride in alkaline solution. I &HZ C1 CH. + KCN HzO* @ . for example. 2-(a-Chloroethy1)benzimidazole with ammonia gives a 36-42 per cent yield of di(a-benzimidazolylethy1)amine (634) : @-LCH(CH8)NHCH( NH CHa) HN KO 1-Methyl-2-chloromethylbenzimidazoleon treatment with potassium cyanide in acetone-water solution gives an 80 per cent yield of 1-methyl-2-benzimidazoleacetamide (671) : 0: . 4. with no 2-aminomethylbenzimidazoleisolatable (356). 2 (3H)-Benzimidazolones show many of the reactions of 2-hydroxypyridines and 2-hydroxyquinolines.
JOHN B. WRIGHT
with phosphorus oxychloride or phosphorus pentachloride yields the 2-chloro derivative (478) :
NH NH 2-Hydroxybenzimidazolea have been alkylated on the oxygen in good yields by treatment with chloroacetic acid in sodium carbonate solution (707) :
Heating of 2-ethoxybenzimidazoles with concentrated hydrochloric acid in a sealed tube cleaves the ether linkage to yield ethyl chloride and 2(3H)-benzimidazolone. 5-Ethoxy-2(3H)-benzimidazolone refluxing with acetic anhydride is conon verted to the 1,3-diacetyl derivative (187). 2(3H)-Benzimidazolone is converted to the 1,3-disodium salt with dilute sodium hydroxide solution. Treatment of the resulting disodium salt with benzoyl chloride yields 1,3-dibenzoyl-2(3H)benzimidazolone. 2 (3H)-Benzimidazolone with ethanolic sodium hydroxide solution gives a monosodium salt which dissociates on warming with water. Treatment of the monosodium salt with benzoyl chloride gives a mixture of 2(3H)benzimidazolone and 1,3-dibenzoy1-2(3H)-benzimidazolone. 2(3H)-Benzimidazolone also yields a silver salt, which on treatment with benzoyl chloride and acetyl chloride gives the 0-benzoyl and 0-acetyl derivatives of 2-hydroxybenzimidazole, respectively. Direct acetylation of 2(3H)-benzimidazolone gives 1,3-diacetyl-2(3H)-benzimidazolone(310). 2-(3H)-Benzimidazolone is reported (514) to give l-xanthyl-2(3H)-benzimidazolone with one mole of xanthydrol and the corresponding 1,3-dixanthyl derivative with two moles of xanthydrol. 2(3H)-Benzimidazolone on heating with an aqueous formaldehyde solution yields the corresponding 1,3-di(hydroxymethyl) derivative (515) :
CHEMISTRY OF THE BENZIMIDAZOLES
6 . 2(~H)-Benzimidazolethiones
2(3H)-Uenzimidazolethiones (or 2-mercaptobenzimidazoles)are generally stable substances and are soluble in dilute alkali. Alkylation occurs readily with replacement of the mercapto hydrogen to yield S-alkylated derivatives, and a number of these derivatives have been prepared (199, 201, 519, 651). 2(3H)-Benzimidazolethione, for example, may be alkylated with chloroacetic acid by refluxing in 2 N sodium hydroxide solution (202) :
Methylation may be brought out by the use of dimethyl sulfate in alkaline solution (489) :
2-Chlorobenzothiazole when refluxed in an alcoholic solution with 2(3H)benzimidazolethione yields 2-(benzothiazole-2’-mercapto)benzimidazolehydrochloride in 86 per cent yield (659).
Like 2(3H)-benzimidazolone, 2(3H)-benzimidazolethione is reported (514) to give l-xanthyl-2(3H)-benaimidazolethione with one mole of xanthydrol and the Corresponding 1,3-dixanthyl derivative with two moles of xanthydrol. Acetylation of l-phenyl-6-ethoxy-2 (3H)-benzimidazolethione by heating with acetic anhydride in the presence of molten sodium acetate gives the corresponding 2-thioacetyl derivative (386).
The corresponding l-p-tolyl analog reacts analogously (388). 2 (3H)-Benzimidazolethione is reported (270) to give only a monobenzoyl derivative (LXXXVIII),
JOHN B. WRIGHT
in contradistinction to 2(3H)-benzimidazolone, which gives also a 1,3-dibenzoyl derivative.
2(3H)-Benzimidazolethione is not desulfurized on treatment with hot alkaline lead soIutions (460). The mercapto group of 2-mercaptobenzimidazoles may be removed by treatment with iodine (0.5 N ) solution and sodium bicarbonate (196) :
Aqueous iodine solution (1 N ) yields the disulfide (199):
The mercapto group may be oxidized to the sulfonic acid group with alkaline potassium permanganate solution in good yields :
The resulting 2-benzimidazolesulfonic acid may be cleaved to benzimidazole with hydrochloric acid at 170°C. (199). 2-Benzimidazolesulfonyl chloride has been prepared by an oxidative chlorination of 2(3H)-benzimidazolethione (632). 2(3H)-Benzimidazolethione, like 2(3H)-benzimidazolone, gives a 1,3-dihydroxymethyl derivative on heating with an aqueous formaldehyde solution (515) : f 2CH20 +
2(3H)-Benzimidazolethione reacts with a number of cations to form metal derivatives (177, 201, 426, 427, 428, 429, 430, 431). A number of cations are precipitated quantitatively in this way and this reaction has been used aa a basis for their quantitative estimation.
Treatment with two moles of cyaaogen bromide in the presence of water and potassium bicarbonate or treatment with biuret a t 180°C. 2-Aminobenzimidazole is converted to 2(3H)-benzimidazolone upon heating with barium hydroxide and a little water to 180-190°C. I-Aminobenzimidazoles 2-Aminobenzimidazoles may exist also in the imide form: 2-Aminobenzimidazole is soluble in water and soluble in alkali. yields a tricyclic compound (586) : oc NH A tricyclic product is formed also by reaction with diethylmalonyl chloride in the presence of pyridine (170): \ / co oc C (CzHs)2 The ring in the latter compound may be opened with aqueous potassium hydroxide solution (170) : \ / co oc\ /co c (C2HS)z 2-Aminobenzimidazole is reported (569) to condense with m-nitrobenzaldehyde to form a Schiff base: . or by treatment with nitrous acid (587).CHEMISTRY OF THE BENZIMIDAZOLES 509 6 . Hypochlorous or hypobromous acid causes a series of color changes to take place (569).
2-Aminobenzimidazole with acetic anhydride gives 2-acetylaminobenzimidazole (569) : Acetylation of 2-phenylaminobenzimidazoleswith acetic anhydride takes place either in the l-position or on the side-chain nitrogen in the 2-position. Price and Reitsema (618) have shown that LXXXIX on warming with alkali and acidification yields 2-aminobenzimidazole m-nitrobenzenesulfonate (XC): warm _____ with NaOH -.” 2-Aminobenzimidazole is chlorinated in the 5-position in 95 per cent yield to give 2-amino-b(or 6)-chlorobenzimidazole (466).@LH* \ N LO. CJ-LN02-rn LXXXIX It was thought formerly that reaction with sulfonyl chlorides occurred on the amino group in the 2-position . Treatment with several times the necessary amount of benzoic acid anhydride a t 120140°C. The condensation with formaldehyde is also complicated (170). and acidification xc On this basis. 2-p-Tolylaminobenzimidazoleswith nitrous acid give nitroso derivatives. benzaldehyde is reported not to give the normal Schiff base product.in fact. WRIGHT However.om (409). a salt structJre analogous to that of XC is suggested (618) for the compound previously reported (622) as 2-sulfanilamidobenzimidazole. thus. yields a dibenzoyl derivative (407). it has been shown (466) that 2-aminobenzimidazole on direct combination with sulfanilic acid gives a sulfonate salt corresponding in physical properties to the above-mentioned 2-sulfanilamidobenziidazole or “sulfabenzimidazole. 2-Aminobenzimidazole reacts with sulfonyl chlorides at the ring nitrogen to give 1-sulfonylbenzimidazoles (618) : O-tH + \ \ / NH 2 ~ -O 2 C 1 S O*N . 2-aminobenzimidazole is erroneously reported to give 2-sulfanilamidobenzimidazole on treatment with p-acetylaminobenzenesulfonyl chloride followed by hydrolysis of the acetyl group. .5 10 JOHN B. the nitroso group being either in the l-position or on the side-chain nitrogen at.
.CHEMISTRY O F THE BENZIMIDAZOLES 511 7. or by the reduction of o-phthalimidoazo derivatives (167). This substance may be obtained also by the reduction of N-(2-nitrophenyl)phthalimide with iron and refluxing acetic acid (643)) or sodium hydrosulfite and acetic acid. 713): ) o-Benzoylene-2. 637. KMnO. It may be obtained also by the oxidation of the Schiff base XCI (74. 644.l-benzimidazoleis known as ll-isoindolo-[2. For example. However. being yellow in color. l-benzimidazole through lactam formation (88. since the former name has been used almost exclusively in the literature. o-(2-benzimidazole)benzoic acid on heating to 280°C.l-benzimidazole possesses chromophoric character. 714). H+ + co HzO or by the oxidation of o-benzylene-1 . or on refluxing with acetic anhydride gives o-benzoylene-2. it is used also here.l-]benzimidazol-ll-one. 6 According to Chemical Abstracts nomenclature o-benzoylene-2. o-Benzoykne-b 1-benzimidazole6and relaled compounds I the side chain in the 2-position of a benzimidazole contains a reactive f group.2-benzimidazole (74). 614.. this grouping may react a t the nitrogen in the 1-position to yield a tricyclic compound.
8-naphthoic (XCIV) and the corresponding anhydride. give a good yield of a tetrachloro-o-benzoylene-2.l-benzimidazole : (73) H2 C H C 2 /CH2\ @JH2 \ (33.l-benzimidazole (637) are kIlOWn.2 / The 5-methyl analog has also been prepared (73). which on cyclization with acetic anhydride yields hexahydro-o-benzoylene3.8’-naphthalene-2.l-benzimidazole c 1 Quinolinic acid and o-phenylenediaminegive XCII (or XCIII) (90) : XCII XCIII Hexahydrophthalic anhydride and o-phenylenediaminegive 0. o-Phenylenediamine and tetrachlorophthalic acid when heated gradually to (89).4-diaminotoluene.b \ co- \ XCIV + @El C1/ COOH O i\ B 4- Cl()COOH c 1 C l co CH2\ ” \ CHCHZ LOOH /cH2 .l-benzimidazole 5-methyl analog (XCV) may be obtained (143) from o-phenylenediamine and 3. Q.lbenzimidazole (143) and 5-chloro-o-benzoylene-2.(benzimidaeole-2)hexahydrobenzoic acid. 5-methyl-o-benzoylene-2.1-benzimidazole.512 JOHN B. WRIGHT In addition to o-benzoylene-2. respectively. 1’. 250°C. By the use of l.
CHEMISTRY OF THE BENZIMIDAZOLES 513 By the use of diphenylmaleic anhydride (84). and diphenic anhydride (86) the corresponding compounds XCVI. and XCVIII.+ ' --N @i1CH2 CH2COOH N/lLCH.g. I $o & = XCVII co XCVIIa XCVIII By heating the diphthalimide XCIX with acetic anhydride Crippa and Galimerti (168) have prepared the diphenyl derivative (C): XCIX C /3-(2-Benzi1nidazole)propionicacid also undergoes lactam formation readily [e. \co PH2 o-Benzoylene-2. XCVII (or XCVIIa). by heating to 230-240°C. (503)] to give o-propionylene-1.2-benzimidazole : 23O-24O0C. Q i L C CsHs CO-C CeH6 XCVI I I/ 0-i \ \N+ co-ck.1-benzimidazole and its derivatives and the compounds discussed above which are structurally related to o-benzoylene-2.l-benzimidazole I . homophthalic acid anhydride (85). may be prepared. respectively..
87. The reaction of phthalide and o-phenylenediamine hydrochloride also gives the same compound in about 80 per cent yield (101). 642. the melting point of this compound checking that reported by Thiele and Falk: . H0 s co NH OOH Q-9 OOR O"NH2 CONHt o-Benzylene-2. 503. amines. (714).1-benzimidazole reported to be a colorless compound melting waa a t 210°C. 713). and hydrazines leads to amides and hydrazides (83. Alcoholysis leads to eaters through cleavage of the lactam ring and treatment with ammonia.514 JOHN B. WRIGFI" posseas the normal reactions of a lactam ring.1-benzimidazolepossesses the structure indicated by CI : CI The synthesis of this compound waa first reported by Thiele and Falk (714) from the reaction between o-phenylenediamine dihydrochloride and phthalaldehyde : o-Benzylene-2. The amide linkage may be hydrolyzed with either alkali or acid.
Betrabet and Chakravarti (74) have synthesized a compound which they claim to be o-benzylenebenzimidazole.+ CHZOH C H OH ~ The preparation of o-benzylene-1.These authors condensed phthalide and o-phenylenediamine in cold absolute ethanol and obtained o-hydroxymethyl-of-aminobenzanilide (CII) .2-benzimidazole (and its 5-chloro derivative) is reported also from a dihydrophthalazine derivative (637): COH Sn HCI or SnClr + NO* LaCOOH The melting point for this preparation also checks that reported by Thiele and Falk. However.CHEMISTRY OF THE BENZIMIDAZOLES 515 @. \ q . N CHsOH CHz CIE These authors claim that the compound obtained by Thiele and Falk waa in reality the Schiff bme. @ H C O P / NH2 - -2Ha0+ \ Q-. Dehydration of this compound with acetic anhydride or by fusion gave a compound which these authors claim melts a t 185°C.2HCl + @"'O CHz' 180-210~C..
1-benzimidazolestructure for Thiele and Falk's compound. WRIGHT In Beilstein the compound prepared by Thiele and Falk is indeed represented as the Schiff base and for the sake of consistency it is represented as such throughout the present review. The issue might be settled by the reduction of o-benzoylene-2.(o-Aminopheny1)benzimidazole reacts also with formic acid or formamide to give a tetracyclic compound (546) : + HCOOH 2 " --+ o:b \ N CH=N - 2-(o-Aminophenyl)benzimidazole on treatment with urea and thiourea gives tetracyclic compounds (547) : Treatment of o-(2-benzimidazo1e)benzoic acid methiodide with ammonium hydroxide or sodium acetate solution yields a betaine (646): . However. 2-(o-Aminophenyl)benzimidazoleon treatment with sodium nitrite and hydrochloric acid gives a quantitative yield of a tetra cyclic compound (545): " H2N- \ + 2Hz0 N-N Amyl nitrite in neutral solution gives the same product.516 JOHN B.lbenzimidazole to o-benzylene-2. 2. it would appear that the evidence is strong also for the o-benzylene-2.l-benzimidazole. possibly through the use of lithium aluminum hydride.
2-Benzimidazolecarboxylic acid may be conveniently prepared in good yield by the oxidation of 2-hydroxymethylbenzimidazole (166). Oxidation Benzimidazoles are stable to oxidation (34). By very vigorous conditions of oxidation (potassium permanganate in hot alkaline solution) it is possible to partially oxidize benzimidazole to obtain a small amount of imidazoledicarboxylic acid (40).CHEMISTRY OF THE BENZIMIDAZOLES 517 8. NH Because of the stability of the benzimidazole ring to oxidation it is possible to oxidize substituent groups without affecting the ring. 2-Benzimidazolecarboxylic acids may be obtained also by the oxidation of 2-styrylbenzimidazoles wit'h potassium permanganate in the cold (38) : I n some cases the acid obtained may immediately undergo decarboxylation under the conditions of the reaction so that the final product obtained is the benzimidazole (30): Br Br/ N B Br " Q. . By the oxidation of substituent groups a variety of benzimidazolecarboxylic acids have been prepared.which may be prepared by the action of glycolic acid on o-phenylenediamine. 5(or 6)-Methyl-2-benzimidazolecarboxylicacid has been prepared in an analogous manner from 5(or 6)-methyl-2-hydroxymethylbenzimidazole (97).
6)-Dimethylbenzimidazole is oxidized first a t the 5(or 6)-methyl group and finally a t the 2-methyl group to give 2.7-benzimidazoledicarboxylic acid as a by-product (189).518 JOHN B. cH30&~CH8 N=CCHa CIII HOOC . 702) : Oxidation of naphthimidazole with chromic acid in acetic acid gives 4. 2-p-Tolylbenzimidazole on heating with potassium dichromate in a mixture of acetic acid and sulfuric acid is oxidized at the methyl group (128.5benzimidazoledicarboxylic acid (206) : COOH Oxidation of the imidazole CIII gives 2-methyl-5-methoxy-7-benzimidazolecarboxylic acid in 70 per cent yield with a small amount of 5-methoxy-2. 351.5(or 2. 5(or 6)-Methyl-l-benzyl-2-phenylbenaimidazole readily oxidized to is l-benzyl-2-phenyl-5(or 6)-benzimidazolecarboxylic acid (449). WRIGHT 2-Methylbenzimidazoles and benzimidazoles containing a sugar residue in the 2-position (353) may be oxidized to 2-benaimidazolecarboxylicacids.5(or 2. 346.6)-benzimidaaoledicarboxylic acid (37): 5(or 6)-Methylbenzimidazole gives 5(or 6)-benzimidazolecarboxylic acid on oxidation. 2.
2-Benzoylbenzimidazole may be prepared by the oxidation of 2-(~-hydroxy: benzy1)benzimidazole with chromic acid in refluxing acetic acid (97) + NH NH 5(or 6)-Methyl-2-benzoylbenzimidazolehas been prepared in an analogous manner (98). very recently the 5.6-dimethylbenzimidazole-l-a-D-ribofuranoside (CV) (121). A 70 per cent yield of 2-benzimidazolealdehyde has been obtained in this manner from 2-(d-arabo)benzimidazole (353).CHEMISTRY O F THE BENZIMIDAZOLES 519 2 .6-dimethylbenzimidazole (CIV) (122. Vitamin BU on acid hydrolysis leads to the formation of three closely related substances designated components a. p. since the ac o m p m t on acid hydrolysis yields the @-componentand phosphate (164). 2-Benzjmidazolealdehyde may be prepared by treatment of 2-methylbenzimidazole with selenium dioxide (376) : This procedure is applicable also to the preparation of l-substituted 2-benzimidazolealdehydes (376). 132).6)-Benzimidazoledicarboxylicacid has been prepared by treatment of a mixture of 2.6-dimethylbenzimidazole moiety has been shown to be part of the structure of vitamin BIZ. 2-Benzimidazolealdehyde has been prepared also by treatment with periodic acid of benzimidazoles substituted in the 2-position with a sugar residue. 131. V. The phosphate moiety is undoubtedly attached to either Cz or Ca in the sugar residue . 123).5(or 2. NATURAL PRODUCTS CONTAINING BENZIMIDAZOLE THE NUCLEUS The benzimidazole nucleus does not appear to occur very widespread in nature. Component y is 5 . and y (68. Component @ is 5. However.3-diaminobenzoic acid and maltose (or lactose) with potassium permanganate (653). H CIV H cv The a-component is probably a phosphorylated derivative of CV.
520 JOHN B. Of interest is the fact that the 172-diamino-4. addition of cyanide ions to a solution of vitamin BIZ. However. Vitamin Biza does not contain this cyano group. 132).and 2-phenylbenzimidazolehave been studied pharmacologically by Auverman (14). vitamin BIZ has been assigned (123) the partial formula: VI. A “ninhydrin-reacting” fragment is also released from vitamin BZ durI ing hydrolysis (190). 2-p-Aminoethylbenzimidazole dihydrochloride is stated to exhibit no pressor action even in high doses (144) and has no histamine-like activity on the isolated guinea-pig ileum (454). 132) are also closely related struc1t* turally to vitamin BIZ. w. 5(or 6)-p-Aminoethylbenzimidazole and 2-methyl-5(or 6)-~-aminoethylbenzimidazole said to cause a rise in blood are pressure (481). 2-methylbenzimidazole. b-. and 7-components) obtained from vitamin BIZ (131. a number of 8-aminoethyl derivatives of benzimidazole have been studied. Vitamin BIZ contains also one cyano group bound coordinatively to the cobalt atom present (125). SOC. This has been identified as 1-amino-2-propanol (613. Am.. On the basis of available evidence. Benzimidazole is relatively nontoxic and has little effect on the blood pressure. Benzimidazole. appears in riboflavin as well as in 5. A large number of benzimidazole derivatives are reported to possess trypanosomicidal and spirocheticidal action and are active against diseases caused by ‘Note added in proof: It has recently been shown (Kacakn. WRIGHT (131). Vitamin B 2 . 5-dimethylbenzene moiety. E. A. Because of their relation to histamine.6-dimethylbenzimidazole and vitamin BIZ. BIOLOGICAL ACTION BENZIMIDAZOLES OF Benzimidazole and a number of derivatives of benzimidazole possess a variety of biological actions. et al.yields vitamin BIZ(399).: J. .(126) and vitamin BlZe(131. Vitamin Bizc on acid hydrolysis yields the same components (CY-. Chem. 78. 756). 335 (1951))that vitamin Bm is identical with vitamin B .
These may be looked upon as closed-ring analogs of Paludrine. 2(3H)Benzimidazolonestibonic acid derivatives are also reported to be useful for the treatment of diseases caused by protozoa. 669). 554. also.CHEMISTRY OF THE BENZIMIDAZOLES 52 1 protozoa.) 2 CVI NH N 4 NH NHCH( CHa) 2 CVII / \ The closed-ring analog (CVII) of Paludrine itself as well as other compounds of this general type are without activity or possess only slight activity. A number of benzimidazoles related to the active antimalarial Paludrine (CVI) have been prepared (1. A number of benzimidazoles have been prepared and tested as local anesthetics. 135). A number of 2-alkylaminomethylbenzimidazoles (109) and 2-(a-alkylaminoethyl)benzimidazoles (634) have been prepared. These compounds in most cases are derivatives of 2 (3H)-benzimidazolethione or 2(3H)-benzimidazolone containing an arseno. 2-benzimidazolepropionic acid. 5-ethoxybenzimidazole-2-propionic acid. or arsine oxide grouping on the benzene portion of the benzimidazole ring.489. these compounds are without antimalarial activity.488. NH NH C NH / \ C II NH / \ NHCH( CH.416. and 5-ethoxybenzimidazolylethylaminehave been prepared also for testing for antimalarial activity (144). Almost without exception. A number of benzimidazoles have been prepared and tested as antimalarials. arsonic acid. P-Benzimidazolylethylamine. 2- . and are claimed to be useful as antimalarials. 2-Diethylaminomethyl5(or 6)-chlorobenzimidazole and 2-piperidinomethyl-5(or 6)-chlorobenzimidazole also possess no antimalarial activity (301). 414). 2-Methyl-5(or 6)-ethoxybenzimidazole is reported to have no local anesthetic activity (158). In large part these have been benzimidazoles containing a diethylaminoalkyl grouping in the 1-position with other substituent groups in other positions of the benzimidazole ring (156. A number of compounds closely related to CVII and possessing the general structure G (where G = dialkylaminoalkyl group) have been prepared (134.
COOH I CVIII CIX (where n = 0. A number of these compounds are reported to have bacteriostatic properties (155). A number of benzimidazoles have been tested for goitrogenic activity (140. 23. 2-Ethoxymethylbenzimidazole. (CHt). 2phenoxymethylbenzimidazole. and 2-(p-aminobenzenesulfonamido)benzimidazole have been prepared (618). 720). have been investigated for antibiotic activity (21. 22. Octahydro-2-oxo-5-benzimidazolebutyricacid inhibits the stimulating effect of dloxybiotin in Lactobacillus arabinosus CH2 \H C-NH HOOC (CH2)a CH / I I I whereas stimulation due to d-biotin is virtually unaffected (21). WRIGHT Diethylaminopropyld(or 6)-phenoxybenzimidazole is reported to be a local anesthetic (619). 191. 155. 2(3H)-Benzimidazolonecarboxylic acids of the type of CVIII and CIX. . Benzimidazole shows anticonvulsant activity when administered in rather large doses (138. as well as the corresponding hexahydro derivatives obtained by reduction of the benzene nucleus in these compounds. 2-(Benzenesulfonamido)benzimidazole. 765). 129. 193. N-Benzoylbenzimidazole shows only a trace of anticonvulsant activity. 5-ethoxy-2-ethoxymethylbenzimidazole. 2-Benzimidazolesulfonamide is a carbonic anhydrase inhibitor (900. 6). 2-(m-nitrobenzenesulfonamido)benzimidazole. 2(3H)-Benzimidazolethione itself is markedly goitrogenic. 901). these compounds are derivatives of 2(3H)benzimidazolethione.522 JOHN B. N-Sulfanilyl-4-aminobenzimidazole has antibacterial activity against Pseudomonas aeruginosa (484). No mention of activity is made with respect to these compounds. 697. A number of 5-benzimidazolesulfonamides have been prepared (5.4). 624. while 2-aminobenzimidazole is devoid of activity (138). and 5-ethoxy-2-phenoxymethylbenzimidazole have antipyretic activity (67). 2-(maminobenzenesulfonamido)benzimidazole. In the main. 753). 1-Dimethylaminoethylbenzimidazole several related compounds containand ing substituent groups in the 2-position of the benzimidazole ring were found to possess only slight antihistaminic activity (763).3. This compound and several other compounds in this series possess an affinity for Avidin (765). 487.
CHEMISTRY O F THE BENZIMIDAZOLES
Several benzimidazole analogs of pteroylglutamic acid (folic acid) have been prepared in which the pterine ring is replaced by a benzimidazole ring. The compound CX, COOH
which is the benzimidazole analog of pteroylglutamic acid, and CXI,
Q N b H 2 N - aC o o H H CXI the benzimidazole analog of pteroic acid, have been prepared (180, 415, 417). CX has a low order of inhibitory activity against Streptococcus faecalis R. and Lactobacillus casei. The 5-chloro analog of CX has also been prepared (415). Its inhibitory power against L. casei is somewhat greater than that of CX (417). However, it has also been reported that CX in larger concentrations may replace folic acid as a growth factor (180). Compound CXII,
COOH n ” c IH c H z c H zc 0 OH
Q J + ~ H = S O ~ -
differing from CX only in the substitution of a sulfonyl group for a carbonyl group in the p-aminobenzoic acid moiety, has also been prepared. This compound was found to be a metabolite antagonist of pteroylglutamic acid (180). CXI when tested against Streptococcus faecalis R. was found to be inhibitory but less so than CX (417). A number of 5-(2-benzimidazolylmethyl)barbituricacid derivatives have been prepared (483). 2-[Benzyl(2-chloroethyl)aminomethyl]benzimidaxole been screened against has sarcoma 180 (664). Benzimidazole is reported to reduce skeletal muscle tone by acting on the central nervous system (281,282), and hence is similar in its action to Myanesin. Benzimidazole is also reported (208) to have satisfactory fungicidal properties. Benzimidazole inhibits the growth of several yeasts and bacteria. This action can be reversed by certain purines (762), and yeast nucleic acid (419). Benzimidazole also inhibits the production of vaccinia virus (719). The physiological actions of 2-guanidobenzimidazole (77) and of a number of tetrahydrobenzimidazoles (305) and 1,2-disubstituted benzimidazoles (743) have
JOHN B. WRIGHT
been studied. 2-Benzylhexahydrobenzimidazolehas been studied for blood pressure action (304). 2-Alkylmercurimercaptobenzimidazolederivatives are claimed to be active as disinfectants (708). 4-Aminobenzimidazole is claimed as a “pharmaceutical” (329). 5,6-Dimethylbenzimidazoleand salts thereof are claimed to be of value as growth-stimulating agents (124). Mamalis, Petrom, and Sturgeon (476) have prepared several benzimidazole analogs of tryptophan of the general type:
@i I 1
, -N ’
COOH CH2 CHNHz
These compounds show no biological activity against a variety of organisms.
VII. USESOF BENZIMIDAZOLES
A large number of patents describe benzimidazole derivatives of use in the textile industry as wetting, emulsifying, foaming, or softening agents or as dispersants for use in dyeing. In the main, these compounds are sulfonated benzimidazoles. Another use is in the treatment of fibers to improve whiteness of the undyed material or as an optical bleach. A number of aminobenzimidazoles have been used for ihe preparation of sulfur and azo dyes of use in the textile industry. Another use has been in the preparation of fluorescent dyes for use in such preparations as inks for marking clothes to be dry-cleaned. The mark becomes visible under ultraviolet light. 2-Mercaptobenzimidazole [2(3H)-benzimidazolethione] and several other benzimidazoles have found use in the photographing industry. These compounds reduce photographic “fog)’ and increase contrast and speed and hence have found use in photographic developing and fixing solutions. 2-Mercaptobenzimidazole has been found to be of value, too, as an antioxidant for rubber. This compound has been used also as a specific reagent for the detection of various metals. Several benzimidazole derivatives have found use in the preparation of sunburn preventatives. These compounds protect the skin by absorbing ultraviolet rays. 5-Methylbenzimidazole has been used as a camphor substitute. 2-Methylbenzimidazole is said to be of value as a polymerization inhibitor and initiator in isoprene. 1-Piperidinomethylbenzimidazolehas been claimed to be of value as a booster compound for use with antioxidants in rubber. A number of salts of benzimidazolesulfonic acid are said to be of value in preparations for the care of the mouth and teeth.
CHEMISTRY OF THE BEKZIMIDAZOLES
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