2-Methyl-5 -substituted benzimidazoles

Not much information has been added in recent years to the earlier studies of tautomeric equilibria of benzimidazoles based on basicity measurements [76AHC(S1), p. 292]. For 5(6)- and 4(7)-substituted benzimidazoles and 2-methyl-5(6)-substituted benzimidazoles values are very close to 1, which indicates near equivalence in the stability of N1(H) and N3(H) tautomers. The tautomeric equilibria of 2-substituted (H, NH2, OMe, CN) 5-nitrobenzimidazoles and 4-nitrobenzimidazoles were analyzed with the use of semiempirical MINDO/3 and INDO methods. It was predicted that electron-releasing groups in position 2 shifted the equilibria to the 6-NO2 and 4-NO2 tautomers, respectively. 

By using basicity data, Ridd and Smith- showed that 5-nitro- and 5-chloro-benzimidazole and their 2-methyl analogs exist essentially as mixtures of equivalent amounts of 29 and 30, and, in agreement with this ratio, 5-substituted benzimidazoles form comparable amounts of 1- and 3-derivatives on alkylation,- showing earlier alkylation ratios- to be erroneous. There are, however, other factors which can lead to the predominance of one tautomeric form. Basicity measurements indicate that 31 is preferred to the alternative non-hydro-... 

Stump, G.L., Lynch, J.J., Macaulay, A., Wafford, K.A., Koblan, K.S. and Liverton, N.J. (2004) NR2B-selective N-methyl-D-aspartate antagonists synthesis and evaluation of 5-substituted benzimidazoles. Journal of Medicinal Chemistry, 47, 2089-2096. 

The intramolecular 1,3-dipolar cycloadditions of homochiral nitrilimines derived from methyl esters of glycine, L-alanine, L-phenylalanine, and (S)-2-phenylglycine produced enantiopure 2,3,3a,4,5,6-hexahydropyrrolo[3,4-c]pyrazoles in fair to good overall product yields.50 The thermal reaction of diphenylnitrilimine with N-substituted benzimidazoles (47) produced lV,AP-disubstituted o-phenylenediamines (51). The reaction involved two 1,3-dipolar cycloadditions with two nitrilimine moieties yielding adducts (48-50), followed by a ring opening of the azolic ring of (50) (Scheme 13).51... 

When o-phcnylenediamine reacts with aliphatic or aliphatic-aromatic ketones the initially formed benzimidazolines can be thermally decomposed, losing a hydrocarbon fragment to yield 2-substituted benzimidazoles [81, 131]. While this method does not appear to have major synthetic importance, the analogous reaction with a, 6-diketonc has some application [132]. Presumably it involves an acid-catalysed retro-Claisen condensation of the S-dicarbonyl compound. When acetylacetonc is used, acetone is formed. The process, then, offers an unambiguous approach to compounds such as 2-methyl-4-nitrobenzimidazoles (not available by direct nitration). Neither the numbers of substituents on the arylenediamine nor their natures appear to affect yields or reaction times significantly. 

Similar methods apply, and mixtures of products result when the original substrate is substituted in the fused benzene ring. Quatemization is more difficult because benzimidazole is less basic than imidazole. When 5(6)-substituted benzimidazoles are alkylated the product ratios depend on the resonance electronic effects of the substituent, e.g. methylation of 5(6)-nitrobcnzimidazolc gives a 1 1 ratio of 1,5 and 1,6 isomers. Substituents in the 4(7)-positions have increased electronic directing effects, and steric effects also come into play, e.g. methylation of 4(7)-nitrobenzimidazole in basic medium gives a 6 1 ratio of 1,4 to 1,7 isomers. And so, in designing a synthetic approach to a 1-alkyl-C-nitrobenzimidazole, aU of these factors need to be taken into account. It may be more valid to nitrate a 1-alkylbenzimidazole than to alkylate a C-nitrobenziinidazole [2]. 

Protected benzimidazoles are smoothly lithiated in the 2-position by LDA, n-hutyllithium and t-hutyllithium. Particularly useful are metallations of benzimidazoles protected by formaldehyde as hemiaminals, or as the 1-(lV,A -dialkylamino)methyl derivatives. Reaction with a variety of electrophilic reagents, followed by acid-catalysed deprotection under mild conditions, leaves the 2-substituted benzimidazoles [31, 32]. 

Pantoprazole Sodium. The active ingredient in Pro-tonix (pantoprazole sodium) is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-l (3.4-dimethoxy-2-pyridi-nyl)methyl sulfinyl -l/y-benzimidazole sesquihydratc (1.5 HjO). a compound with a molecular weight of 432.4. The benzimidazoles have weakly ba.sic (pyridine N. pK, 3.%) and acidic (benzimidazole N-H. pK 0.89) properties, which facilitate their formulation as salts of alkaline materials (Fig. 21-17). Pantoprazole sodium. sesquihydratc is a while to off-while crystalline powder and is racemic. Pantoprazole sodium sesquihydratc is freely soluble in water, very. slightly. soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane. The stability of Ihe compound in aqueous solution is pH dependent the rate of degradation increases with decreasing pH. At ambient temperature, the degradation half-life is approximately 2.8 hours at pH 5.0 and approximately 220 hours at pH 7.8. 

Amine-substituted benzimidazole was studied with regards to its emission spectra in various solvents71. The spectral shifts of l-methyl-6-aminobenzimidazole (65a) from ethyl acetate (peak at 330 nm) to pyridine (peak at 470 nm) are appreciable, but there appears to be no systematic dependence on the polarity or HBA/EPD properties the peak emissions are at 370 nm for hexane and 362 nm for formic acid, and in many solvents 65a emits at 354 nm. Substitution of V-p-tolyl instead of the amino group at the 6 position (65b) did not improve the solvatochromic performance. 

AT-substituted benzimidazoles 62 and 63 (Fig. 6) have been reported to show anti-hepatitis B virus activity, and thus several derivatives of novel benzimidazoles 62 and 63 have been prepared by Li et al. [53]. The precursor benzimidazoles readily undergo AT-substitution reactions with sulfonyl chlorides in dichloromethane using DMAP as a base, whereas methylation can... 

The effects of 5-substituents on basic deuterium exchange at the 2-methyl groups in series of 1,2-dimethyl-5-substituted benzimidazoles appear to be dominated by resonance effects. Donor groups such as amino and methoxy slightly weaken the methyl acidity acceptor groups such as nitro have pronounced acid-strengthening effects <84CHEl0ll>. 

Another route to merocyanine derivatives (308) proceeded via 2-ethoxymethylene-thiazolo[3,2-a]benzimidazol-3(2//)-one (307) with 1-methyl substituted nitrogen heterocycles (Scheme 7) <56JCS361, 55BRP730489, 56BRP743133, 56BRP749189, 57BRP785939). 

The first synthesis of SFs-substituted benzimidazoles was described in an Asahi Glass patent (04JPP059452). Protected N-acetyl-4-SF5-aniline (58) was converted into the protected nitroaniHne 59, which was then quantitatively deprotected to nitroaniline 60, reduction of which provided 1,2-diamino-4-SF5-benzene 61 in 100% yield. Condensation of diamine 61 with formamide or A/,N-(bis)methoxycarbonyl-S-methylisothiourea (62) resulted in the formation of the corresponding S-SFs-benzimidazole 63 or S-SFs-substituted methyl (2-benzimidazolyl)carbamate 64 (Scheme 15). 

Scheme 3.35 The reactions of methyl propargylate with 2-substituted benzimidazoles...

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