Benzimidazole acylation

NH-Benzimidazol Acyl-chlorid Reaktionsbedingungen Produkt 1 1 O 1 1 Schmp. [°C] Lite- ratur... 

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). 

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... 

Benzimidazole-2-carboxylic acid decarboxylation, 5, 435 Benzimidazole-3-carboxylic acid, 1-hydroxy-ethyl ester synthesis, 6, 407 Benzimidazoles acidity, 5, 50, 385, 386 acylation, 5, 71, 391, 402, 417 2V-alkyl-... 

As noted earlier (see Chapter 10), 4-acyl piperidines separated from benzimidazole by a three carbon chain often show antipsychotic activity. The heterocycle can apparently be replaced by a pyridopyrimidine ring. Thus alkylation of piperidine 41 with halide 42 affords pirenperone (43). ... 

An analogous sequence leads to the anthelmintic agent, etibendazole (50). Reaction of the benzophenone 47, which can be obtained by acylation of o-nitroaniline with g-fluorobenzoyl chloride, with ethylene glycol leads to acetal 48. Sequential reduction of the nitro group and cyclization of the resulting diamine (49) with N,N-dicarbomethoxy-S-methylthiourea gives the benzimidazole etibendazole (50) fl6]. 

As in the case of benzimidazole, a parallel synthesis of benzoxazoles was described. The authors report that mixing directly differently substituted o-amino phenols 193 with acylating agents 194 and heating at 200 °C for 10-15 min under microwave irradiation, a collection of benzoxazoles 195 was obtained (Scheme 70). With this reaction, a 48-member library of benzoxazoles with different substituents on the aromatic rings was obtained [125]. 

Three different microwave-assisted synthetic routes to benzimidazole derivatives are summarized in Scheme 6.205, involving the condensation of 1,2-phenylenedi-amines with either carboxylic acids (Scheme 6.205 a and b) [368, 369] or two equivalents of aldehydes (Scheme 6.205 c) [370], or by cyclization of N-acylated-diamino-pyrimidines mediated by a strong base (Scheme 6.205 d and e) [371, 372],... 

A variation of this method led to the generation of bis-benzimidazoles [81, 82], The versatile immobilized ortho-phenylenediamine template was prepared as described above in several microwave-mediated steps. Additional N-acylation exclusively at the primary aromatic amine moiety was achieved utilizing the initially used 4-fluoro-3-nitrobenzoic acid at room temperature (Scheme 7.72). Various amines were used to introduce diversity through nucleophilic aromatic substitution. Cyclization to the polymer-bound benzimidazole was achieved by refluxing for several hours in a mixture of trifluoroacetic acid and chloroform. Individual steps at ambient temperature for selective reduction, cyclization with several aldehydes, and final detachment from the polymer support were necessary in order to obtain the desired bis-benzimidazoles. A set of 13 examples was prepared in high yields and good purities [81]. 

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). 

Reissert compounds (>70%), derived from benzimidazole, phthalazine, quinoline and isoquinoline, have been prepared by a simple catalysed one-pot N-acylation of the appropriate heterocycle, followed by reaction with cyanide ion [e.g. 101-103],... 

Preferential reduction of a nitro group in the presence of a carbonyl group in 4-nitroacetophenone ISD, intramolecular rearrangements of o-nitro-benzanilides 32) intramolecular cyclizations of o-nitro-ferf-anilines to benzimidazol-1-oxides 153,154) cyclizations of acylated 2-nitrodiphenylamines to phenazine-l-oxides i ), intramolecular additions of nitro groups to double bonds 156) remarkably ef-... 

Starting from acylated 2-azidomethylbenzimidazoles (145), an additional imidazole ring can be condensed by transformation of the azido group with tri-n-butylphosphane into the appropriate iminophosphorane intermediate 146. After extrusion of phosphane oxide, cyclization occurs to the 1-substituted 4//-imidazo[l,5-a]benzimidazole 147 (Scheme 58) (89T1823 94S1197). 

Die Reduktion der Nitro-Gruppe in N-Acyl-2-nitro-anilinen kann ohne Isolierung der N-Acyl-o-diamino-arene mit dem Cyclisierungsschritt zum Benzimidazol kombiniert werden. Als Al-ternativen bieten sich folgende Methoden an ... 

Acyl-2-amino-benzimidazole werden durch Pyridin (100° 1 h) zu 2-Acylamino-benzimid-azolen umacyliert (s.a. S. 351, 3S6)447. 

Tab. 36 1-Acyl-benzimidazole durch Acylierung von NH-Benzimidazolen mit Carbonsaure-chloriden, -chlorid-hydroximiden,... 

Mechanisms of Hydrolysis of N-Acylimidazoles and N-Acyl-benzimidazoles, Ace. Chem. Res. 26, 325 (1993). 

T.H. Fife, Kinetic and Mechanistic Effects of Ease of C-N-hond Breaking in Amide Hydrolysis, The Mechanisms of Hydrolysis of N-Acylimidazoles and N-Acyl-benzimidazoles, Acc. Chem. Res. 26, 325 (1993). 

Akasaki and Ohno206 recently found that S-phenacyl-2-mercapto-benzimidazole (197) on treatment with benzoyl chloride did not give the expected N-benzoyl derivative but the benzimidazothiazole 198 in quantitative yield. Exploration of the mechanism revealed a complicated sequence of acyl migrations, which, though not yet fully elucidated, may have important biochemical implications, particularly on the mode of action of biotin. 

Habib and co-workers observed the rearrangement of 2-quin-oxalinone 4-oxides (219) on treatment with acetic anhydride to 1,3-diacetyl- or l-acetyl-3-acyl-2-benzimidazolones (220).219 Recently, the ring contraction of 2-azidoquinoxaline 1-oxide to 2-cyano-l-hydroxy-benzimidazole has been reported.220... 

Examples of the reaction of pyrroles and indoles in acidic media with 77-electron-excessive heterocycles are discussed in Section 3.05.1.2.2 and elsewhere. However, for comparison of the reaction conditions, it is of interest to note, for example, the reaction of indole with an acyl chloride in the presence of a 7r-electron-excessive heterocycle, such as thiophene or furan, to yield the 3-acyl-2-heteroarylindoline (78KGS561, 79KGS493), the reaction of pyrroles and indoles with imidazole and benzimidazole in the presence of acetic anhydride to yield the iV,iV -diacetylimidazoline derivatives of the indoles and pyrroles (80T2505), and the formation of 2-heteroaryl-3,3-dimethylindolines from the reaction of 3,3-dimethyl-3Ef-indoles with indoles or pyrroles (77S343). 

Well over 100 plant pathogens have become resistant to various fungicides under field conditions. Failure of the acyl alanines, benzimidazoles, thiophanates, carboxanilides, dicarboximides, hydroxypyrimidines, some organophosphates, and most of the antibiotics has occurred. In other cases, a moderate decrease in sensitivity without a rapid loss of disease control has been observed as in the case of sterol biosynthesis inhibitors (triazoles, pyrimidines, and imidazoles) and organophosphates. The most effective approach is to use fungicides having different modes of action in combination,... 

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, I, 202 Benzimidazole-l-carboxylic acid, 2-amino-methyl ester reactions, 5, 453 Benzimidazole-2-carboxylic acid decarboxylation, 5, 435 Benzimidazole-3-carboxylic acid, 1-hydroxy-ethyl ester synthesis, 6, 407 Benzimidazoles acidity, 5, 50, 385, 386 acylation, 5, 71, 391, 402, 417 N-alkyl-... 

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