Benzimidazoles, from o-phenylenediamine

Condensation reactions. The nitroaldol reaction and formation of benzimidazoles from o-phenylenediamine and aldehydes are ctirried out in silica gel support with microwave irradiation. The latter preparation also includes nitrobenzene or dimethyl sulfoxide for dehydrogenating the initial condensation products. 

Recently, Sharghi et al. (2011) also investigated the assembly of 2-aryl/2-heteroaryl benzimidazoles from o-phenylenediamines and aromatic aldehydes using Cu nanoparticles on activated carbon (CuNPs/C) as the reusable heterogeneous catalyst (Scheme 4.45). The substrates can directly condensate at room temperature to... 

Benzimidazole ring-bearing heterocyclic compounds are important in pharmacology and medicinal chemistry. The synthesis of benzimidazoles from o-phenylenediamines and carboxylic acids or nitriles needs harsh conditions. Hence, the synthesis of benzimidazoles can be accomplished with < -phenylenediamines and aldehydes. Benzimidazole derivatives were synthesized by the reaction of o-phenylenediamine with either aldehydes or nitriles in the presence of SSA as a cheap and readily available heterogeneous catalyst in refluxing ethanol (Sadeghi and Nejad, 2013) (Scheme 5.16). The protocol is beneficial in terms of short reaction time, high yield, and operational simplicity. Salehi et al. (2006) synthesized... 

Preparation of mercapto-benzimidazole from o-phenylenediamine and thiocyanate... 

Methyl benzimidazol-2-ylcarbamate (47), known as carbendazim, and some of its derivatives such as benomyl (48), are potent broad spectrum systemic fungicides (B-77MI10703). They are synthesized straightforwardly from o-phenylenediamine (b-... 

At about the same time, a group at Oxford reported their synthesis of a benzimidazole analogue of FA (290, R = H) (Scheme 3.53) [48, 156]. Initially, they envisioned that (290) could be obtained from acylation of glutamic acid with (288). The requisite acid chloride (288) was readily obtained in three steps from o-phenylenediamine via (286) and (287). Unfortunately, the extreme insolubility of (288) rendered it inactive towards basic solutions of glutamic acid or glycine. Therefore, an alternative approach was developed in which the chloromethylbenzimidazole (286) was used to alkylate (31) to yield (289), from which (290, R = H) was obtained following careful saponification. Repetition of this latter reaction sequence with 5-chloro-2-chloromethylbenzimidazole, available from 4-chloro-o-phenylenediamine dihydrochloride and chloroacetic acid, afforded (290, R = Cl) [156],... 

The 2-(oMo-polyhydroxyalkyl) benzimidazoles are weak bases derived from o-phenylenediamine by condensation with an aldonic or closely related hydroxy acid. The present review includes substances of this type containing hydroxylated side chains of one to seven carbon atoms in length. Typical is the benzimidazole from D-glucose via D-gluconic acid. The side chain is attached at position 2 of the benzimidazole nucleus,... 

XVII). The result was completely satisfactory, for the reaction produced a 70% yield of the 2-benzimidazolecarboxylic acid (XVI), which on subsequent decarboxylation by heating at 190° produced benzimidazole (IX), identical with the synthetic material from o-phenylenediamine... 

Benzimidazole has been prepared from o-phenylenediamine by the action of chloroform and alcoholic potassium hydroxide and of formic acid, and by the reduction of o-nitroformanilide. Less serviceable methods include the interaction of o-phenylene-diamine and dichloromethylformamidine or formoacetic anhydride, and the thermal decarboxylation of benzimidazole-2-carboxylic add. The procedure described was developed from that of Wundt. ... 

The synthesis of2-substituted-benzimidazoles 80 and 1,2-di-substituted benzimidazoles 82 from o-phenylenediamines 79 and 1,2-di-substituted benzenes 81, respectively, are shown in the tables below. A one-pot four-step tandem synthesis of various 1,2-di-substituted benzimidazoles from 2-nitrofluorobenzenes was disclosed (14TL4697). 

The synthesis of 2-substituted-benzimidazoles 61 and 1,2-disubstituted-benzimidazoles 63 from o-phenylenediamines 60 and 1,2-disubstituted-benzenes 62, respectively, are shown in the tables given below. 

Kazimierczuk and co-workers prepared several 2-(polyfluoroalkyl)benzimid-azoles from o-phenylenediamines using the corresponding polyfluoroacetic acid (Scheme 16) [24], Likewise, the reaction of o-phenylenediamine with difluoroacetic acid provided 2-(difluoromethyl)benzimidazole in 72 % yield [25], Several other research groups utilized similar conditions to prepare the targeted 2-(trifluoro-methyl)benzimidazoles [26]. 

Eapen and Tamborski prepared few 2-perfluoroaIkylbenzimidazoles from o-phenylenediamine (Scheme 17) [27]. While 2-pentafluoroethyl- and 2-heptafluor opropylbenzimidazole were prepared by heating o-phenylenediamine with the corresponding acid anhydride and carboxylic acids, respectively, a benzimidazole bearing a perfluoroalkyl ether at C-2 was prepared in a two-step procedure via a A -monoacyl derivatives of o-phenylenediamine. Likewise, a bis(benzimidazole) was prepared by the condensation of o-phenylenediamine with 0.5 equivalent of diethyl 2,2,3,3,4,4-hexafluoropentanedioate. 

Benzimidazoles.—Benzimidazoles with bulky substituents in position 2, e.g. (492 R = Bu or 1-adamantyl), are produced from o-phenylenediamines and carboxylic acids RCO2H at hydrostatic pressures of up to 8 kbar. The acid-catalysed cyclisation of AW-dialkyl-N -o-nitrophenyl-hydrazines (493 R = alkyl) usually leads to benzimidazoles (494) 2-substituted benzotriazoles (495), the corresponding 1-oxides, and the betaines (496) are also formed in certain... 

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. 

Anhydro-L-xylose, characterized as the benzimidazole derivative formed from the corresponding 2,5-anhydro-L-xylonic acid and o-phenylenediamine, has likewise been prepared92 by the action of one molar equivalent of periodic acid on 1,4-anhydro-D-glucitol. 

Apart from the chemistry of the 4-hydroxy derivative (see p. 126) relatively little investigation in this area has been conducted. Thiocoumarin-3-carbonyl compounds have proved to be effective precursors for the synthesis of the pharmaceutically useful 3-(2-benzimidazolyl) derivatives. Thus, on interaction of the 3-carboxamide with o-phenylenediamine or the 3-aldehyde with o-nitroanilines, the above benzimidazoles or their TV-oxides are formed. 

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... 

Ribose may be identified through the benzimidazole from ribonic acid, 2-(D-n6o-tetrahydroxybutyl)benzimidazole52 53 54 and its picrate and hydrochloride. However, caution must be used at two points in this procedure. In the first place, the customary oxidation of ribose with alkaline hypoiodite produces both ribonic and arabonic acids, the latter being formed by the alkali-induced epimerization of the former. While this epimerization may be avoided by using a buffered oxidizing mixture such as bromine-barium benzoate,65 there is, in the second place, further risk of epimerization during the condensation of the aldonic acid with o-phenylenediamine, particularly if there is insufficient acid present.9 10-11... 

The condensation of fatty acids with o-phenylenediamine has been carried out effectively by refluxing the components in 4 N hydrochloric acid.19 Moore and Link, in their second paper on the preparation of benzimidazoles,20 stated that this procedure gave less satisfactory yields with the aldonic acids, the yield from D-galactonic acid being only 24%. 

A word of caution at this point seems most desirable. In every case where a pure aldonic acid or its derivative has been heated with o-phenyl-enediamine and an excess of hydrochloric acid, only a single benzimidazole has been isolated. It is well known that aldonic acids are epimerized by heating them at temperatures above 100° with organic bases such as pyridine. The heating of an aldonic acid with o-phenylenediamine at 135-150° may also result in appreciable epimerization. Thus, Moore and Link20 reported that from the fusion of xylonic acid with o-phenylenediamine at 150°, in the absence of mineral acids, they could isolate the epimeric lyxo-benzimidazole. Barker, Farrar, and Gulland,21 in a more detailed study, proved conclusively that both D-ribo- and D-arabo-benzimidazoles were formed when the condensation of calcium D-ribonate with o-phenylenediamine was carried out in the presence of less than two molecular equivalents of hydrochloric acid, whereas with an excess of hydrochloric acid only the D-ribo-benzimidazole was obtained. It is important, therefore, in the condensation of o-phenylenediamine with an optically active acid at an elevated temperature that the reaction mixture always be kept on the acid side. 

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