1- Substituted 4-acylimidazoles

Catalytic reduction of iminoethers derived from 4-aminoisoxazoles (85TL3423, 87JOC2714) or 4-amino-5(477)-isoxazolones (91S127) leads to a-(acylamino)enaminones (231) which cyclize in the presence of bases to form 4-acylimidazoles (Scheme 34). Treatment of the enaminone with a primary amine incorporates a substituted amino function in the (3-position with concomitant expulsion of ammonia and allows access to 1-substituted and 1,2-disubstituted 4-acylimidazoles in 75-92% yields (87JOC2714). 

Y/ .v-(3-Lactains have also been obtained by the Staudinger reaction carried out between divinylimine and /V-acylimidazoles possessing an electron-withdrawing group (EWG) in a position [111]. This latter were prepared by treatment of a-EWG substituted carboxylic acids with 1,1-carbonyldiimidazole. 

Much work in the review period has concerned enantioselective substitution in five-membered heterocyclics. The enantioselective alkylation of some pyrroles by unsaturated 2-acylimidazoles catalysed by the bis(oxazolinyl)pyridine-scandium(in) triflate complex (31) has been reported.39 Compound (33) is formed in 98% yield and 94% ee from the 2-acylimidazole (32) and pyrrole at —40 °C. A series of enantiomer- ically pure aziridin-2-ylmethanols has been tested as catalysts in the alkylation of /V-mclhylpyrrolc and (V-methylindole by ,/l-unsalura(cd aldehydes.40 Enantiomeric excesses of up to 75% were observed for the alkylation of /V-mcthylpyrrole by ( >crotonaldehyde using (2.S ,3.S )-3-mclhylazirin-2-yl(diphenyl)methanol TFA salt as catalyst to form (34). 

The conjugate addition of carbonyl anions catalysed by thiazolium salts (via umpol-ung) that is fully operative under neutral aqueous conditions has been accomplished. The combination of a-keto carboxylates (157) and thiazolium-derived zwitterions (e.g. 160) in a buffered protic environment (pH 7.2) generates reactive carbonyl anions that readily undergo conjugate additions to substituted o /3-unsaturated 2-acylimidazoles (158) to produce (159). The scope of the reaction has been examined and found to accommodate various a-keto carboxylates and /3-aryl-substituted unsaturated 2-acylimidazoles. The optimum precatalyst for this process is the commercially available thiazolium salt (160), a simple analogue of thiamine diphosphate. In this process, no benzoin products from carbonyl anion dimerization were observed. The resulting 1,4-dicarbonyl compounds (159) can be efficiently converted into esters and amides by way of activation of the A-methylimidazole ring via alkylation.181... 

The quaternization of 1-substituted imidazoles is usually easy unless steric factors intervene, or strongly electron-attracting groups are present, for example, 1-acylimidazoles can only be alkylated at N(3) with powerful alkylating agents such as methyl fluorosulfonate or trialkyloxonium fluoroborates. Trimethyloxonium fluoroborate does not methylate 1-dimethylaminosulfonylimidazole. Regiospecific synthesis of 3-substituted L-histidines can be achieved by alkylation of Ar-/-butoxycarbonyl-l-phenacyl-L-histidinc methyl ester at N(3), followed by reductive removal of the phenacyl group (Scheme 15). 

Most of the reactions and properties of 1-substituted imidazoles have been discussed earlier in this review. Apart from the utilization of the readily removable benzyl substituent in synthetic procedures leading to 2-substituted imidazoles, perhaps the mostexciting advances have stemmed from the reactions of the 1 -acylimidazoles (imidazolides) which are extremely reactive in such nucleophilic reactions as hydrolysis and alcoholysis.12 The use of such compounds as N,N -carbonyl-diimidazole in peptide synthesis is now commonplace. The silicon-nitrogen bond in N-trimethylsilylimidazoles is also extremely reactive, so reactive that it is attacked by a-halogenocarboxylic esters.361... 

Acylation reactions which lead ultimately to 2-acylimidazoles will be discussed as electrophilic substitutions at ring carbon atoms (Section 4.07.1.4.6) in spite of the almost certain intermediacy of the iV-acyl compounds. 

Such synthetic approaches can only be valid if the other heterocycles are readily available, or if their transformations lead to imidazoles difficult to make by other means. It is certainly important to be able to aromatize imidazolines since a number of ring-synthetic procedures lead to reduced imidazoles. 4-Aminoisoxazoles are sources of a-acylaminoenaminones which cyciize with bases to give 4-acylimidazoles. Oxazole-imidazole conversion has largely historical importance, but it is also implicated in some ring-synthetic procedures (e.g. the Bredereck method, see Chapter 5). Transformations of benzofuroxans into 2-substituted benzimidazole iV-oxides have some synthetic importance. Few, if any, ring contractions appear to have major application. 

Analogous reactions in the aliphatic series cyclize alkylenediamines in which one amino group has been acylated (i.e., a-(acylamino)enaminones). These substrates can be made by catalytic reduction of 4-aminoisoxazoles <85TL3423, 87JOC27l4> or 4-amino-5(4W)-isoxazolones <91S127>. These a-(acylamino)enaminones (188) cyclize in the presence of bases to form a wide range of 2-substituted 4-acylimidazoles. If the isoxazole has no A-substituent, treatment of the enaminone with... 

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