Benzylimidazole using phase transfer catalysis

Other alkylating agents which have been used include diazomethane [2], trialkyl phosphates [11], alkoxypho.sphonium salts [12], dimethylformamide dialkyl acetals [13], trialkyl orthoformates [14], alkyl cyanoformates [15], dialkyl carbonates (less toxic) [16] and, where more powerful reagents arc needed, alkyl fluorosulfonates, trialkyloxonium tetrafluoroborates [17], alky] triflates and mesylates [18, 19]. 

When unsymmetrical imidazoles are alkylated, mixtures of isomeric products are usually formed, e.g. methylafion of 4(5)-methylimidazole gives about equal quantities of the 1,4- and 1,5-dimethylimidazoles under a variety of reaction conditions. The orientation of A-alkylation of such unsymmetrical imidazoles is controlled by a number of factors (reaction conditions, polar and steric natures of the substituent(s), the nature of the alkylating agent, solvent, tautomerism in the substrate) [2], An understanding of these factors can help with the preferential synthesis of one of the possible isomers (6) and 

As a rule of thumb one ean assume that reactions which are carried out in basic media involve the anion (5), which A -alkylates to give mainly the 1,4 isomer (6) if R is bulky or electron-withdrawing. In free base alkylations the tautomeric mixture (3) (4) reacts. An electron-withdrawing substituent (R) will ensure that much of the reaction will be with the major tautomer (3) even if that tautomer is the less reactive. The product mixture formed will have mainly 1,5 regiochemistry (7), e.g. 4(5)-nitroimidazole methylated in basic medium gives mainly l-methyl-4-nitroimidazole in neutral media l-methyl-5-nitroimidazole forms almost exclusively. Sterically demanding groups, however, favour the 1,4 isomer. Table 7.1.1 lists some other examples. 

When isomeric mixtures are formed they can usually be separated quite readily by column or radial chromatography, for example mixtures of 4- and 5-halogeno-1-methylimidazoles separate on an alumina column eluted with. 2% ethyl acetate in dichloromethane 1,4- and 1,5-dimethylimidazolcs use methanol-ethyl acetatc-dichloromethane-hexanes (1 4 5 40) and l-methyl-4-and -5-nitroimidazolcs are separated by 4% methanol in dichloromethane. Further purification is achieved by vacuum distillation in a Kugelrohr apparatus 21.  

The range of alkyl and substituted-alkyl blocking groups used in lithiation processes include benzyl, p-methoxybenzyl, t-butyl, trityl, alkoxymethyl, hydroxymethyl, SEM ([2-(trimethyIsilyl)ethoxy]methyl) and 

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