2-Substituted benzimidazoles, formation

Microwave-assisted intramolecular C - N bond formations have also been studied. Substituted benzimidazoles were easily prepared from the corresponding M-(2-bromophenyl)imidoformamides by Brian et al. (Scheme 102) [ 104]. The protocol involved the use of a combination of Pd2 (dba)3 and PPha in a mixture of DME and water using NaOH as the base at 160 °C. It was apphca-ble for electron poor, neutral and rich as well as sterically hindered amidines. The fastest reactions were obtained with an electron withdrawing substituent... 

A variety of methods have been developed for the preparation of substituted benzimidazoles. Of these, one of the most traditional methods involves the condensation of an o-phenylenediamine with carboxylic acid or its derivatives. Subsequently, several improved protocols have been developed for the synthesis of benzimidazoles via the condensation of o-phenylenediamines with aldehydes in the presence of acid catalysts under various reaction conditions. However, many of these methods suffer from certain drawbacks, including longer reaction times, unsatisfactory yields, harsh reaction conditions, expensive reagents, tedious work-up procedures, co-occurrence of several side reactions, and poor selectivity. Bismuth triflate provides a handy alternative to the conventional methods. It catalyzes the reaction of mono- and disubstituted aryl 1,2-diamines with aromatic aldehydes bearing either electron-rich or electron-deficient substituents on the aromatic ring in the presence of Bi(OTf)3 (10 mol%) in water, resulting in the formation of benzimidazole [119] (Fig. 29). Furthermore, the reaction also works well with heteroaromatic aldehydes. 

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],... 

The 2-halo-substituted benzimidazoles, then, more or less readily react with ammonia, amines and hydrazines (80AHC 27)241,70AHC(12)103,74CRV279), It is likely that the formation of the 2-pyridinium compound (123) when cycloheptimidazolin-2(l//)-one reacts with phosphoryl chloride in pyridine occurs via the 2-chloro intermediate (Scheme 56). The sulfur function of benzimidazole-2-sulfonic acid can be displaced by amino or alkylamino groups. 

The reaction between o-phenylenediamine and an equimolar amount of an aromatic or heterocyclic aldehyde has been shown to proceed by initial formation of a monoanil (74). In the presence of oxidizing agents (e.g. nitrobenzene, which also acts as the solvent) this can form the 2-substituted benzimidazole. With two moles of aldehyde the bis-anil (75) forms, giving rise to a 1,2-disubstituted benzimidazole (Scheme 42). This aldehyde route to benzimidazoles is particularly suited to the synthesis of compounds with a heterocyclic group (e.g. 2-thienyl-, 2-pyridyl-) at C-2. Reaction of 2,2,4,4-tetrakis(trifluoromethyl)-l,3-dithietane with o-phenylenediamine gives 2,2-bis(trifluoromethyl)benzimidazoline (7430785). 

Although the direct oxidation of the parent compounds with organic peracids has not proved fruitful, benzimidazole N-oxides can be made by the action of boiling hydrochloric acid on o-nitro-N, A-dialkylanilines, although prolonged treatment results in the formation of a chloro-substituted benzimidazole (B-73MI40800). 

A palladium-catalyzed W-arylation reaction provided a novel synthesis of benzimidazoles 5 from (o-bromophenyl)amidine precursors 4 under microwave irradiation. The route was found to be flexible with respect to various substituents and allows for the preparation of highly substituted benzimidazoles, including W-substituted examples (Scheme 1) [23]. The method was later improved and optimized to achieve the rapid formation of benzimidazoles in high yield [24]. It has been found that 50% aqueous dimethyl ether (DME) is an optimal solvent for the reaction and that catalyst loading of palladium can be reduced to 1 mol %. 

The parent compoimd, benzimidazole, is a crystalline solid with a melting point of 169-171 °C. Benzimidazoles, like imidazoles, exist as a tautomeric pair of compounds. The tautomerism of 1//-benzimidazoles is sufficiently rapid that the compormds are observed as a single species on the NMR timescale at room temperature. 1//-Benzimidazoles with substituents at the 4(7) or 5(6) positions appear to be a single compound rather than a tautomeric mixture however, replacement of the NH proton with an alkyl group or other substituent results in formation of a pair of regioisomeric compounds. Thus, regiospecificity is a consideration in the synthesis of all Y-substituted benzimidazoles that bear any substituents at the C4-C7 positions. 

Intramolecular N-arylations of amidines 83 led to benzimidazoles 84 mediated by potassium hydroxide (140L536). Multi-substituted benzimidazoles 86 were obtained from amidines 85 via iodine(III)-promoted oxidative C(sp )-C(sp ) and C(sp )-N bond formation (140L2822). Direct... 

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). 

Ribofuranosyl derivatives of substituted benzimidazoles have been found to have virus inhibitory activity (44)-From glucosone, compounds with quinoxaline structures may be produced (4S), In the presence of hydrazine and o-phenylenediamine, 1-deoxy-1-p-toluino-D-fructose or -D-tagatose is converted to a quinoxaline compound in the pH range 6 to 8 by a mechanism similar to osazone formation 46),... 

It is knowm that the triethylphosphite-induced deoxygenation of aromatic nitro compounds or// o-substituted with a Schiff base group leads to the formation of benzimidazoles and benzopyrazoles, depending on the isomer of the Schiff base used [42-47]. By carbonylation of 2-nitro-N-(phenylmethylene)benzeneamine derivatives (20) at 220 °C and 50 atm in benzene as solvent and Ru3(CO)i2 as catalyst, the corresponding 2-substituted benzimidazoles (21) have been obtained in good yields (eq. 10) (Table 7) [48] ... 

On lowering the temperature to 170 °C (run 2), the conversion dropped to 82 % and also the selectivity in 21a decreased to 34 %. The use of a coordinating solvent such as CH3CN (run 4), gave complete conversion with good selectivity in 21a even at 170 C. At hi er temperature in CH3CN (220 °C, run 5), 2-methylbenzimidazole (21d) was obtain as a side product. The formation of this compound could be explained by the reduction of o-nitroaniline (23) to afford o-phenylenediamine. Such a diamine is known to react with nitriles to give 2-substituted benzimidazoles [49]. 

A plausible (simplified) mechanism includes primary Cu-promoted formation of an N-arylated amidine (13), its hydrolysis ( 14 by H2O resulting from reaction of the amidine hydrochloride with CS2CO3) and cychzation of 14 to 12 with elimination of NH3. (c) N-Arylamidines 16 undergo oxidative cydization via C-N bond formation to give 2-substituted benzimidazoles by reaction with O2 in AcOH-catalyzed Cu(OAc)2 [420] ... 

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