Benzimidazoles nitration

Benzimidazole (viii) and indazole (ix) differ from the azanaphthalenes in being nitrated at the / -position [C(g)] of the carbocyclic ring. ... 

Phenylbenzimidazole is nitrated first at the 5-position with mixed acid, and subsequent reaction produces 5-nitro-2-(4-nitrophenyl)-and 5-nitro-2-(3-nitrophenyl)-benzimidazole. 2-Phenyl-, 2-(4-nitro-phenyl)- and 5-nitro-2-phenyl-benzimidazole are nitrated as their conjugate acids. ... 

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. 

Electrophilic bromination (and nitration) of pyrido[l, 2-a]benzimidazole (analogous to 132) cannot take place in the imidazole moiety. Initial substitution, using NBS as reagent, was shown to occur at the 8-position, and subsequently at C-4 and C-6 (90JOU1166). 

The photoaddition reaction of 2-phenylbenzimidazole with Michael acceptors was investigated <96JHC1031> as was the preparation and cycloaddition-reactivity of benzimidazole-2-carbonitrile oxide <96AJC199>. The nitration of 1-methylbenzimidazole was found to give only the 5- and 6-nitrated products as a mixture of isomers in 87% yield... 

The highly selective nitration of 6 set the stage for the installation of the benzimidazole as well as solving the problem of the biaryl ether formation, which would have been a challenge for existing transition metal-catalyzed technologies. 

Treatment of benzimidazole with ozone and N02 results in a complex mixture of mono- and di-nitrated benzimidazoles and triazoles. However, nitration of 5-nitrobenzimidazole 1209 under such conditions leads to two major products, benzotriazoles 1210 and 1211. The mechanism of ring conversion from benzimidazole to benzotriazole is not clear (Equation 29) <2004CPB570>. 

In much the same vein, nitration of 2,3-dimethylpyridine Al-oxide (49-1) affords the nitro derivative (49-2). The newly introduced nitro group is then displaced by the aUcoxide from 3-methoxypropanol to afford the corresponding ether (49-3). Proceeding much as above, the methyl group at the position adj acent to the nitrogen is converted to its chloride (49-5). Condensation with benzimidazol-2-thiol then affords rabeprazole (49-6) [52]. 

The unsymmetrical derivative, L2, in which one benzimidazole group is replaced by a 2-pyridyl moiety, and its complexes with europium and terbium have been further studied for their photophysical properties (37). The coordinated nitrate anions in the [ ( 2)( ) ]... 

Materials. Imidazole, benzimidazole, and glucosamine hydrochloride were obtained from the Eastman Kodak Co., and used without further purification, after drying for several days over anhydrous calcium chloride. Stock solutions of nickel nitrate and nickel chloride were analyzed by precipitation with dimethyl-glyoxime. Stock solutions of cadmium nitrate were analyzed gravimetrically by conversion to cadmium sulfate. 

A large number of imidazole (4) and benzimidazole (5) silver(I) complexes have been prepared.64 Early reports predicted that the site of complex formation of the imidazole molecule would be the pyridine nitrogen rather than the pyrrole nitrogen. However, the crystal structure of bis(imidazole)silver nitrate showed that the two pyrrole nitrogens were bound in almost linear arrangement (Ag—N 212.0, 213.2 pm, N—Ag—N, 1720).65... 

There are some known unsuccessful attempts to carry out alkylation (Mel, Me2S04), halogenation (tert-butyl hypochloride) and nitration of aromatic dihydrobenzodiazepines [7, 105]. Such attempts only resulted in the destruction of the seven-membered heterocycle. As a rule, these destructive processes are typical of dihydrodiazepine systems and often manifest themselves during the synthesis and study of these compounds. Therefore, the results of the destruction of a seven-membered heterocycle are most widespread and include its decomposition into ortho-diamine and carbonyl compounds (Scheme 4.43, reactions A and B) [105, 106] and benzimidazole rearrangement accompanied by splitting out of a methyl aryl ketone molecule (Scheme 4.43, reaction C) [117]. 

In the case of benzimidazole itself, nitration usually occurs at the 5-position (80MI1). Sterba and co-workers have studied the nitration of some arylbenzimidazoles and have showed that 2-phenyl benzimidazole, when treated with nitric acid sulfuric acid at 10°C, gives 6-nitro-2-phenyl-benzimidazole (75%). The 2-(3-nitrophenyl) and 2-(4-nitro phenyl) benzimidazoles similarly yield the 6-nitro products (57 and 97% respectively), and nitration of 6-nitro-2-phenylbenzimidazole gives the 2-(4-nitrophenyl) and 2-(3-nitrophenyl) products in 44% and 32.5% yields, respectively (65CCC1093). 

A frontier-orbital MO treatment of the regioselectivity of the nitration of ben-zotriazole, benzimidazole, their IV-methyl derivatives, and their protonated cations gives predictions in accord with experimental observations.19 The preferred nitration site of the 1//-tautomer of benzimidazole (10), for example, is predicted to be the 5(6)-position, as observed experimentally. 

Benzimidazole is nitrated to the position 5(6) [40-44], The same orientation is observed... 

In a boiling mixture of nitric (d 1.50) and concentrated sulfuric acids 2-chloroben-zimidazole gives 2-chloro-5,6-dinitrobenzimidazole in a 75-80% yield [67], In analogous conditions, benzimidazole and 2-alkyl substituted benzimidazoles are also transformed into 5,6-dinitro derivatives however, in this case simultaneous formation of 4,6-dinitro isomers, which can be separated by fractional crystallization, has been fixed [48, 68], 5(6)-Nitro-2-heterylbenzimidazoles (thiazolyl-4-, furyl-4-, and pyrrolyl-4-) having antihelminthic activity were obtained by nitration with sulfuric-nitric mixture on cooling [69],... 

On nitration of 1-substituted benzimidazoles 5- and 6-nitro isomers [84-91] are formed. At the same time the nitration of l-alkyl-5-tosylaminobenzimidazole with nitric acid in a solution of acetic acid leads to the formation of one isomer, the nitro group being involved in the position 4 (Scheme 2.7) [92],... 

Prevailing formation of the 7-nitro derivative was observed in the nitration of 4-fluoro- [95] and 4-ferf-butylbenzimidazole [96, 97], When the benzimidazole ring has its 4 and 6 positions substituted, the nitration proceeds across the C-4 or C-7 atom [98-101],... 

In a medium of bromine in acetic acid and nitric-sulfuric mixture the benzimidazole derivatives are nitrated only to position 4 [102], In this case the bromine is introduced into the position 5 or 6 (Scheme 2.10). 

Mechanism of the nitration of benzimidazoles has not been studied much, but there are weighty arguments to conclude that they are nitrated as conjugated acids [51, 103], Kinetic studies of the nitration of benzimidazole and some of its 2-substituted derivatives have confirmed that the protonated form is involved in the process [104], Recent results of quantum chemical studies of the nitration of ben-zazoles indicate the importance of the protonated benzimidazolium cations in the nitration process [43],... 

It has been noted that in the nitration of 2-phenylbenzimidazole, the rate of nitration into the benzimidazole 5 position is about three orders of magnitude higher than that of the phenyl ring [51]. 

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