2-aryl benzimidazoles

Benzimidazole, IV-aryl-reactions, 5, 448-449 Benzimidazole, 2-aryl-1-methyl-reactions,... 

Chichibabin reaction, 5, 409-410 sulfonation, 5, 429 synthesis, 5, 160, 161, 457-498, 496 tautomerism, 5, 365 toxicity, 1, 139 UV spectra, 5, 356, 357 2H-Benzimidazoles 3,3-dioxides synthesis, 6, 407 2V,7ST-dioxides reactions, 5, 456 Benzimidazoles, aryl-oxidation, 5, 433 Benzimidazoles, nitro-mass spectra, 5, 359 reduction, 5, 441 Benzimidazole-2-sulfonic acids reactions... 

Benzimidazole, 2-amino-5-bromo-l-methyl-diazo coupling, 5, 429 Benzimidazole, 2-amino-6-bromo-1 -methyl-diazo coupling, 5, 429 Benzimidazole, 2-amino-1-ethyl-alkylation, 5, 438 Benzimidazole, 2-amino-1-methyl-acylation, 5, 438 bromination, 5, 429 tautomerism, 5, 368 Benzimidazole, 4-amino-2-methyl-diazo coupling, 5, 429 Benzimidazole, 2-aroyl-mass spectra, 5, 360 Benzimidazole, 1-aryl-metallation, 5, 448 reactions... 

Dmitrofluorobenzene also serves as an arylation agent for a wide vanety of biologically useful amines including aromatic amines [5b], ammo acids [57], and ammocarbohydrates [55,59] Weak nucleophilic amines such as benzimidazole [60] and fluoroamines [61] can also be arylated (equation 30)... 

Other patent reports covering PDF inhibitors from structural classes different from those discussed above include hydrazides (43) [118], aryl-substituted pyrrolidines (44) [119], benzimidazoles (45, 46) [120-121], hydantoins (47) [122] and oxo-pyrrolidines (48) [123], A prodrug approach utilising PDF has been published by Pei, and patents have been published by NewBiotics, but in this case the compounds of interest are used as substrates rather than inhibitors (49) [124-126]. 

Following the pioneering work by Alterman, several microwave-assisted palladium-catalyzed aminations have been reported for a number of different substrates, using different types of palladium sources and ligands. The examples shown in Scheme 6.59 include bromoquinolines [124], aryl triflates [125], and intramolecular aminations in the synthesis of benzimidazoles [126]. In all cases, the use of micro-wave irradiation dramatically reduced the required reaction times and in many cases also improved the yields. Several authors have also found that the microwave-driven reaction required significantly less catalyst than its conventionally heated counterpart [126]. 

Scheme 7.21 Copper(ll)-mediated N-arylation of polymer-bound benzimidazole.

Utilizing the same aryl fluoride linker on conventional MeOPEG polymer, these authors also presented a microwave-accelerated liquid-phase synthesis of benzimidazoles (Scheme 7.70) [79]. This bicydic pharmacophore is an important and valuable structural element in medicinal chemistry, showing a broad spectrum of pharmacological activities, such as antihistaminic, antiparasitic, and antiviral effects. 

The cyclization to the desired head-to-tail linked bis-benzimidazoles could also be performed utilizing aryl or alkyl isothiocyanates with N, N -dicyclohexylcarbodiimidc (DCC) [82]. Upon completion, the insoluble N,N -dicyclohexylthiourea formed had to be removed by filtration and the desired PEG-bound products were precipitated by the addition of diethyl ether. The results were essentially the same as those of the cyclizations with the above mentioned aldehydes. 

In addition to palladium catalysts, Co(OAc)2 shows a catalytic activity for the arylation of heterocycles, including thiazole, oxazole, imidazole, benzothiazole, benzoxazole, and benzimidazole.78 As shown in Scheme 6, the catalytic system Co(OAc)2/9/Cs2C03 gives G5 phenylated thiazole, while the bimetallic system Co(OAc)2/CuI/9/Cs2C03 furnishes the G2 phenylated thiazole. The rhodium-catalyzed reaction of heterocycles such as benzimidazoles, benzoxazole, dihydroquinazoline, and oxazoline provides the arylation product with the aid of [RhCl(coe)]2/PCy3 catalyst.79 The intermediacy of an isolable A-heterocyle carbene complex is proposed. 

Arylations of amines and nitrogen-containing heterocycles require the presence of a copper catalyst, usually 10% copper(ll) acetate. For example, the reaction of 4-MeC6H4Pb(OAc)3 with the benzimidazole 20 affords the arylation product 21 in 98% yield.39 40 Similarly, the arylation of the amino groups of heteroaromatic compounds 22 and 23 gives rise to the corresponding products 24a and 25 in good to excellent yields (Equations (7)-(9)).41 42... 

The two-phase alkylation reactions have been extended to the acylation of simple heteroaromatic systems. Generally, the required conditions are milder than those employed for the alkylation reactions, but an excess of the acylating agent is usually required, owing to its facile hydrolysis in the basic media. Thus, benzimidazole and its 2-alkyl and 2-aryl derivatives have been benzoylated [46], and pyrrole and indole have been converted into a range of A-acyl [47, 48] and A-sulphonyl derivatives [48-53] (Table 5.35 and Table 5.36). 

Imidazole was converted by hydrogenation over platinum oxide in acetic anhydride to 1,3-diacetylimidazolidine in 80% yield, and benzimidazole similarly to 1,3-diacetylbenzimidazoline in 86% yield [480. While benzimidazole is very resistant to hydrogenation over platinum at 100° and over nickel at 200° and under high pressure, 2-alkyl- or 2-aryl-substituted imidazoles are reduced in the benzene ring rather easily. 2-Methylbenzimidazole was hydrogenated over platinum oxide in acetic acid at 80-90° to 2-methyl-... 

A facile method for the synthesis of N-substituted 2-benzimidazolinones 142 has been developed by Romero et al. (96TL2361) using A-substituted ureas 139, which are cyclized to 142 with IBTA as an oxidant. The reaction probably proceeds via intermediates 140 and 141. Besides the iV-alkyl or aryl substituent, presence of the 1-methoxy group is necessary for the success of this cyclization. Another benzimidazoles synthesis involves cycli-zation of N-phenyl-C-alkyl formimidamides with IBD [95JCS(P1)615]... 

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. 

Thermolysis of the thiadiazole (164) leads to elimination of isocyanate and sulfur giving the triazine derivative (167). If the thermolysis is carried out in the presence of phenols 2-aryl-benzimidazoles (168) are produced <85JCS(P1)1007>. The S—N bond of (157) is readily cleaved with both N- and C-nucleophiles. Thus, treatment of (157) with an excess of amine gives the sulfenamide (169) (Scheme 39) and reaction of (157) with active methylene compounds leads to derivatives of type (170) (Scheme 39) which on heating furnish (171). Cyanide ion inserts into the S—N bond of (164), probably via the intermediate (172) which immediately recyclizes to give the thiadiazinone (173) (Scheme 40) <85JCS(P1)1007>. 

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