Substituted benzimidazole

Synthesis and Anti-Microbial Evaluation of Benzimidazole-1-Substituted Hydrazide Derivatives... 

Benzimidazoles substituted with an alkylamine at position 2 have a venerable history as Hi antihistaminic agents. The standard starting material for many benzimidazoles consists of phenylenediamine (40-1), or its derivatives. Reaction of that compound with chloroacetic acid can be rationalized by invoking initial formation of the chloromethyl amide (40-2). Imide formation with the remaining free amino group closes the ring to afford the 2-chloromethyl benzimidazole (40-3). Displacement of... 

Lescop, C., Belorizky, E., Luneau, D. et al. (2002) Synthesis, stmctures, and magnetic properties of a series of lanthanum(III) and gadolinium(lll) complexes with chelating benzimidazole-substituted nitronyl nitroxide free radicals. Evidence for antiferromagnetic Gd - radical interactions. Inorganic Chemistry, 41, 3375-3384. 

A variety of fragmentations has been noted in the mass spectra of benzimidazoles substituted by ketone functions at C-2. Some of these involve rearrangements such as those illustrated in Scheme 9. 

The SCF calculations (Section 4.06.2) predict the sequence of electrophilic attack in benzimidazole as 7 > 6 > 5 > 4, although positions 4 and 7, and 5 and 6 are tautomerically equivalent in iV-unsubstituted benzimidazoles. Substitution appears to occur with greatest facility in the 5- (or 6-) positions. Bromination in acetic acid of 2-amino-l-methylben-zimidazole occurs at C-6. It can be seen from Table 5 (Section 4.07.1.4.5) that aqueous bromination of benzimidazole itself occurs most readily at C-5, followed by C-7, as it does in the 1- and 2-methyl analogues (78JCS(P2)865). Some of the experimental results are summarized in Scheme 93. Chlorination of both benzimidazole and 2-methylbenzimidazole give the 4,5,6-trichloro product. Nitration and sulfonation, too, occur most readily at position 5 with either sulfuric or chlorsulfonic acids being effective in the latter reaction. 

This section is limited to a description of the synthesis of imidazoles substituted by carboxyl or carboxylate at the 2-, 4- and 5-positions, and benzimidazoles substituted at C-2. 

WangXA, CianciCW, YuK-Letal (2007) Respiratory syncytial virus fusion inhibitors. Part 5 optimization of benzimidazole substitution patterns towards derivatives with improved activity. Bioorg Med Chem Lett 17 4592-4598... 

Benzimidazoles substituted in position 1, e.g. 1-methylbenzimidazole, react with n-butyllithium at low temperature to give 2-lithio compounds. At room temperature, the reaction proceeds as follows ... 

Acid-catalyzed cyclocondensation of 2-acylmethyl-lH-benzimidazole 225 with aromatic aldehydes and urea furnished C5-benzimidazole substituted DHPM 226 (Scheme 86) (03CHE455). 

Magnetism of metal-nitroxide compounds involving bis-chelating imidazole and benzimidazole substituted nitronyl nitroxide free radicals 05CCR(249)2591. 

FIGURE 11 Synthesis of benzimidazole-substituted fluoroquinolone derivatives. 

S. Jubie, R. Rajeshkumar, B. Yellareddy, G. Siddhartha, M. Sandeep, K. Surendrareddy, H.S. Dushyanth, K. Elango, Microwave assisted synthesis of some novel benzimidazole substituted fluoroquinolones and their antimicrobial evaluation, J. Pharm. Sci. Res. 2 (2010) 69-76. 

Hiiekel m.o. ealenlations fail badly with benzimidazole. Loealisation energies for the free base and the eation indicated C(4) to be the most reactive position towards electrophilic attack, - and led to the false conclusion that substitution involved the free base, the orientation being controlled by charge densities. 

Firefly lucifenn is an example of an azole that contains a benzene ring fused to the five membered ring Such structures are fairly common Another example is benzimidazole present as a structural unit m vitamin B12 Some compounds related to benzimidazole include purine and its ammo substituted derivative adenine one of the so called het erocychc bases found m DNA and RNA (Chapter 28)... 

The TT-electron distribution in benzimidazole favors substitution at the 4-position in the conjugate acid, at the 4- and 5-positions in the neutral molecule, and at the 2-position in the conjugate base. These results do not explain the apparently exclusive substitution at the 5-position in nitration. There is thus no general agreement between the rr-electron distribution and the chemical reactivity. 

The localization energies for electrophilic substitution in benzimidazole predict that all three reactive forms should undergo substitution in the 4-position. This does not explain the formation of the 5-nitro compound or that of the 2-deutero compound. It is doubtful whether any electrophilic substitution occurs preferentially in the 4-position. 

The reactivity of these compounds is somewhat similar to that of the azolonium ions, particularly when the cationic species is involved. However, although the typical reaction is with nucleophiles, the intermediate (20) can lose the iV-oxide group to give the simple a-substituted azole (21). Benzimidazole 3-oxides are readily converted into 2-chloroben-... 

Substituted imidazoles can be acylated at the 2-position by acid chlorides in the presence of triethylamine. This reaction proceeds by proton loss on the (V-acylated intermediate (241). An analogous reaction with phenyl isocyanate gives (242), probably via a similar mechanism. Benzimidazoles react similarly, but pyrazoles do not (80AHC(27)24l) cf. Section 4.02.1.4.6). 

Irradiation of l//-indazoles under nonacidic conditions resulted in isomerization to benzimidazoles and also ring opening to isomeric benzonitriles. With 1-substituted benzimidazoles and sensitized irradiation, nitriles were formed, but these are only minor products with other substitution patterns 67HCA2244, 64TL2999). Irradiation of benzimidazoles leads to oxidative dimerization. 

Benzimidazole, l-methyl-2-trichloromethyl-substitution reactions, 5, 432 Benzimidazole, naphthoyl-, 1, 327 Benzimidazole, 5-nitro-alkylation, 5, 390 Benzimidazole, 6-nitro-1-oxide... 

H-Benzimidazole, 2,2-pentamethylene-reduction, 5, 423 Benzimidazole-2-carbaldehyde oximes, 5, 436 Benzimidazolecarbaldehydes oxidation, 5, 437 Benzimidazole-2-carbamates 5-substituted as anthelmintics, 1, 202 Benzimidazole-1-carboxylic acid, 2-amino-methyl ester reactions, 5, 453... 

A series of substituted benzimidazoles and pyrroles was protected and deprotected using this methodology. 

The formation of quaternary salts by the action of the common quatemizing reagents on 1-substituted imidazoles and benzimidazoles (29) to give salts of type 30 is well known. Only N-3 possesses a free... 

Other advances in the use of IR spectroscopy are (1) The substitution of sulfur by selenium, for comparison with the spectra of benzimidazole-, benzoxazole-, and benzothiazole-2-thiones 72 (80AJC279). (2) The use of IR, as a quantitative tool to determine the association (homo- and heterodimers) of thia- and oxa-diazolin-5-thiones and -5-ones 73 (80NJC527). 

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. 

Benzimidazole Equivalent position /fj- = 1 is little affected by substitution in... 

Stabilization of a metal-substituted derivative of a minor tautomeric form of the Ugand was reported for the complexes of mixed benzothiazo-line-benzimidazole (388 —> 389) (71ZOB1370 98POL381) and benzothia-zoline-pyridine ligands (390 —> 391/392) (Scheme 144) (77JA7704). 

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