Alkylation of imidazole

Ye et al. reported that the reduction of 2,4-dichlorophenyl-2-chloroethanone 1 with potassium borohydride in dimethylformamide to give 90% a-chloromethyl-2,4-dichlorobenzyl alcohol 2. Alkylation of imidazole with compound 2 in dimethyl formamide in the presence of sodium hydroxide and triethylbenzyl ammonium chloride, gave l-(2,4-dichlorophenyl-2-imidazolyl)ethanol 3 and etherification of 3 with 2,4-dichlorobenzyl chloride under the same condition, 62% yield of miconazole [9]. 

Whereas pyrrole was reported not to give N/H insertion by ketocarbenoids, such a reaction mode does occur with imidazole Copper-catalyzed decomposition of ethyl diazoacetate at 80 °C in the presence of imidazole gives ethyl imidazol- 1-ylacetate exclusively (93 %) small amounts of a C-alkylated imidazole were obtained additionally under purely thermal conditions 244). N/H insertion also takes place at benzimidazole 245 a). The reaction is thought to begin with formation of an N3-ylide, followed by N1 - C proton transfer leading to the formal N/H insertion product. Diazomalonic raters behave analogously however, they suffer complete or partial dealkoxycarbonylation under the reaction conditions 244) (Scheme 34). N-alkylation of imidazole and benzimidazole by the carbenoids derived from co-diazoacetophenone and 2-(diazoacetyl)naphthalene has also been reported 245 b>. 

Scheme 4.8 N-Alkylation of imidazole with alkyl halides under phase-transfer-catalysis conditions.

Reactions of Phosphonic and Phosphinic Acid Derivatives.—The reactions of phos-phonic and thiophosphonic amides and chlorides with carboxylic acid chlorides and amides have been discussed.101 Dialkyl alkylphosphonates and alkyl dialkylphos-phinates may be used for the iV-alkylation of imidazoles, triazoles, and pyrroles.105... 

Imidazolium salts that can be prepared by the first procedure, the alkylation of imidazole, are easy to obtain and often used for metal complex synthesis. Potassium imidazolide is reacted with the first equivalent of alkyl halide in toluene to give the 1-alkylimidazole. Subsequent alkylation in 3-position is achieved by addition of another equivalent of alkyl halide [Eq. (2)]. " A variant of this approach employs commercially available A-trimethylsilyl imidazole with 2 equiv of an alkyl chloride, under elimination of volatile MesSiCl. The drawback of these simple routes is the fact that only primary alkyl halides can be reacted in satisfactory yields because secondary and tertiary alkyl halides give substantial amounts of elimination by-products. 

The most common methods suitable for the synthesis of different azolium compounds will be discussed here. Two routes are particularly useful for the preparation of the imidazolium salts (1) substitution reactions at the nitrogen atoms of imidazole [25] and (2) multicomponent reactions for the generation of an Af,Af -substituted heterocycle which are particularly useful for the synthesis of imidazolium salts bearing aromatic, very bulky, or particularly reactive N,N -sub-stituents (Fig. 3a,b) [26]. Both methods offer the opportunity to produce unsym-metrically substituted imidazolium salts of type 1 either by stepwise alkylation of imidazole or by the synthesis of an W-arylated imidazole derivative followed by 77 -alkylation [27]. Nevertheless, the method of choice for the preparation of the imidazolium salts 1 is the 77,77 -substitution of imidazole. Several other methods for the preparation of imidazolium salts with previously unattainable substitution patterns have also been described [28, 29]. 

Further examples of alkylation of imidazole derivatives were recently reported by Galous et a/.145 The nature and importance of significant factors in phase transfer alkylation of pyrazole was studied by Elguero et al.146 Their conclusions are equivalent to those of Dehmlow and Lissel.147 The optimization method used by Elguero et al. (several parameters at a time) is different from the conventional procedure (one parameter at a time) and will probably find applications in the future for optimization of organic syntheses. 

The synthesis of the ligand system starts with the stepwise alkylation of imidazole using... 

There are numerous examples of quaternizing alkylations of imidazoles using such diverse reagents as alkyl, alkenyl or aralkyl halides, ethyl chloroacetate, phenacyl bromide or dimethyl sulfate. Since water is frequently held very tenaciously by imidazole quaternary salts the compounds are often best prepared in anhydrous conditions (e.g. dry benzene solvent in a dry nitrogen atmosphere) even though the reaction is commonly slower in non-polar solvents. 

The use of phase-transfer catalysis in the alkylation of imidazoles and benzimidazoles has already proved its value in ether, 18-crown-6 catalysis gives 64-86% yields of JV-methyl products with basic aqueous solutions of the heterocycles and alkyl halides (79TL4709, 76BSF1861, 80JOC3172). 

Table 4 Ratios of Isomers Formed in Alkylation of Imidazoles ...

Although a number of such radical reactions are known, few promise much synthetic potential, Examples include the 2-phenylation of imidazole and benzimidazole by benzoyl peroxide, but both products are more readily obtained by other routes. Homolytic alkylations of imidazole and benzimidazole also occur at C-2, but usually give indifferent yields [10]. A potentially useful reaction is the synthesis of 2- and 4-trifluoromethylimidazoles from imidazoles and photochemically generated trifluoromethyl radicals. 1-Substituted imidazoles are largely substituted at C-5 in these reactions benzimidazole reacts initially at the 4-position [11-14]. 

However, the following are examples of direct electrophilic alkylation of imidazole. A two-step synthesis of marine natural product ageladine A 271 started from the commercially available histamine 269 and the pyrrole-2-carbox-aldehyde 268. The entire skeleton of the alkaloid was built in one step via a Pictet-Spengler type condensation. The reaction was accelerated by Lewis acid scandium triflate, although the reaction did proceed without a catalyst but at a slower pace (Scheme 68) <20060L4083>. 

Since N-acylation is a reversible process, it has allowed the regiospecific alkylation of imidazoles to give the sterically less-favored derivative, i.e., the 1,5-disubstituted derivative (e.g., 109 Scheme 22). ° The sequence followed is (1) acylation (2) alkylation (often with oxonium reagents) and (3) deacylation with alcohol, water, or base. The N-acylation of 2-substituted imidazoles using ethyl chloroformate, triethylamine, and acetonitrile gives JV-alkoxycarbonylimidazoles ° which can lose carbon dioxide to give the JV-alkyl derivatives. The reaction is of limited use in the synthesis of asymmetrically substituted imidazoles since, whereas 2-ethyl-4-methylimidazole gave >95% of l-carbethoxy-2-ethyl-4-methylimidazole, the subsequent decarboxylation afforded a 3 1 mixture of 1,2-diethyl-4-methyl and l,2-diethyl-5-methyl compounds. 

VAPOR-PHASE N-ALKYLATION OF IMIDAZOLES WITH ALCOHOLS OVER ZEOLITES... 

The N-alkylation of imidazoles with alcohols were carried out in the vapor phase over a series of zeolites. H-Y was found most active. Thus, a 100% yield of N-methyl- and N-ethylimidazole was obtained over H-Y at 553 K and 573 K, respectively. H-Y also showed a high activity for the alkylation of 2-methylimidazole with methanol or ethanol. In the methylation of 4(5)-methylimidazole, the products were 1,4- and 1,5-dimethylimidazole. The former was the predominant product over H-Beta(78%) and H-ZSM-5(72.5%), while the latter was the main product over H-Y(89% selectivity). The similar regioselectivity was also found in the ethylation of 4(5)-methylimidazole. 

The alkylation of imidazole with 1-propanol gave a 40% conversion of imidazole, N-n-propylimidazole was a sole product. The alkylation of imidazole with benzyl alcohol gave a low yield of l-benzylimidazole(2%). 

N-Alkylations of imidazole with alcohols over H-forms of zeolites are considered to be catalyzed by Bronsted acid. Thus, the allqrlation of imidazole over zeolites may proceed as follows ... 

Since N-acylation is a reversible process, it has allowed the regiospecific alkylation of imidazoles to give the sterically less-favored derivative, i.e., the... 

Examination of the mechanism of alkylation of imidazole and benzimidazole with phenacyl bromide suggests that the enhanced reactivity of the reagent is due to a special combination of field and conjugative effects <82JCS(P2)135>. 

Martin-Aranda, RM Rojas C er antes,. ML Lopez-Peinado, AJ dc Lopcz-Oonzalez, J. Alkaline carbons as base catalysts alkylation of imidazole with alkyl halides. Journal of Molecular Catalysis, 1993 85,253-264. 

A synthesis of imidazoles can be achieved by methoxymercuration of an alkene (2), which upon bromination followed by addition of formamidine gives the imidazole (5 R = H, = H, Me, Et, Pr, etc.-, or R = R = Me) (Scheme 1). The A -alkylation of imidazoles (and pyridazoles) through the use of phase-transfer catalysts has been reported. ... 

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