Benzimidazole, 1-methyl-, basicity

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-... 

Pyrrolo[l,2-a]benzimidazoles [181] (R = H, Me, Ph R = Me, CH2Ph), unsubstituted at the 1- and 3-positions, protonate in trifluoroacetic acid exclusively on C-1 (Alekseeva et al., 1972b). A methyl substituent in the 1-position leads to mixtures of C-1 and C-3 protonated forms, the relative amounts depending on the presence and nature of substituents at C-3. Without a C-3 substituent, the extent of protonation at the position is 81%, but decreases to 18% in the 3-methyl- and 3-phenyl derivatives the basicity of the derivatives increases simultaneously. 

Ife RJ, Dyke CA, Keeling DJ, Meenan E, Meeson ML, Parsons ME, et al. 2-[[(4-Amino-2-pyridyl)methyl]sulfinyl]-benzimidazole H+/K+-ATPase inhibitors. The relationship between pyridine basicity, stability, and activity. /. Med. Chem., 1989, 32(8), 1970-1977. 

Imidazoles react with chloroform at high temperature to form azines by carbene insertion and trichloromethyl radicals behave similarly, but carbenes do not always induce ring expansion. In alkaline medium, chlorodifluoromethane converts benzimidazole and its 2-methyl analogue into the 1-difluoromethyl derivatives 365. Dichlorocarbene under basic conditions N-alkylates benzimidazole, and 1-methylbenzimidazole couples under the influence of the same reagent (Scheme 69), perhaps involving initial attack of the carbene at N(3). 

The effects of substituents on the basic nature of imidazole are summarized in Section 4.02.1.3.4. Tables 1 and 2 list the basic pKa values of some representative imidazoles and benzimidazoles. From these it can be seen that methyl and other alkyl substituents exert a weak, base-strengthening inductive effect which is additive. Aromatic substituents decrease basic strength, while groups attached to these aryl rings exert their normal behavior. In fact, Hammett studies have permitted prediction with reasonable accuracy and correlation of p/Ca values for a variety of imidazoles. In a study of meta- and para-substituted 1-phenylimidazoles Pozharskii <70CHE194) has shown not only that 1-phenylimidazole is a... 

The use of phase-transfer catalysis in the alkylation of imidazoles and benzimidazoles has already proved its value in ether, 18-crown-6 catalysis gives 64-86% yields of JV-methyl products with basic aqueous solutions of the heterocycles and alkyl halides (79TL4709, 76BSF1861, 80JOC3172). 

It is a general rule that imidazoles and benzimidazoles are resistant to Friedel-Crafts reactions. This is not surprising since such basic compounds must be markedly deactivated in the presence of Lewis acids. Imidazolin-2-ones appear to be an exception and apparently possess sufficient activation to react. Reactions between imidazoles and Af-methylfor-manilide and phosphoryl chloride are also unproductive. With 4,5-diphenylimidazole, phenyl isocyanate at 80 °C gives products of both N- and C-substitution, but in boiling nitrobenzene only the latter (86) is formed. 2-Methyl-4-phenylimidazole gives (87) under the same conditions, and 1,3-diphenylimidazolium perchlorate is transformed by potassium t-butoxide into a ylide which reacts at C-2 with phenyl isothiocyanate. Sufficient activation is present in l-methyl-2-phenyl-4-phenylaminoimidazole for it to react by substitution at C-5 with acetic anhydride (71JOC3368). 

The kinetics and mechanism of the transalkylation reaction between 2-alkoxy-1-methyl-benzimidazoles and thiophenol have been studied. The results demonstrate a rapid protonation of the azole followed by an 5n2 reaction which forms the benzimidazolinone. The basicity of the benzimidazole and the pH both affect the reaction rate (Scheme 126). The corresponding sulfur analogue, l-methyl-2-methylthiobenzimidazole, does not react with thiophenol, probably because of the poor electron-donating ability of the sulfur atom of thiophenate (71 JCS(B)2299). 

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]. 

Abe et al. reported that the imidazol [l,2-a]pyridine moiety of the basic framework of a class of the non-peptide bradykinin B2 receptor antagonists (11, Figure 15.14) could be successfully replaced by several heterocyclic bioisosteres. Among those, the l-methyl-2-methoxy-l//-benzimidazole, 2-methylquinoxaline and 2-methylquinoline derivatives showed potent B2 binding affinities against both human and guinea pig B2 receptors (Figure 15.14). 

The binuclear iron(III) complex [Fe2(HPTP)(p-OH)(N03)2](C104)2 (1) with HPTP = A W,7W,-tetrakis(2-pyridyl methyl)-2-hydroxy-1,3-diamino-propane [5], reacts with H2O2 to yield a blue species [6], The crystal structure of (1) and its interaction with montmorillonites (MMT) has been reported [7]. The occlusion of [Fe2(HPTP)(p-OH)] complexes in new families of hexagonal mesoporous materials such as MCM-41 and HMS will be described elsewhere [8], Related HPTB complexes, with benzimidazole instead of pyridine, have their tripodal N atoms tmns to strong basic peroxo-ligands, the benzimidazole ligands perpendicular to the Fc203 plane and tmns to each other on every iron [9]. 

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>. 

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