Alkylation 2-acylimidazoles

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). 

The use of a,P-unsaturated 2-acylimidazoles [151] as the dienophile increased the practicality of the approach, since the imidazole group can be removed readily from the product. The substrate scope is quite broad substituents at the alkene moiety (e.g., alkyl, aryl and 2-furanyl) were very well tolerated, hi all cases good to excellent enantioselectivies and diastereoselectivities were obtained, i.e., 80-98% ee for the endo isomer and endo. exo > 94 6, in the case of the 4,4 -dimethyl-2,2 -bipyridine ligand [152]. Moreover, the D-A reaction was successfully performed on a preparative scale (1 mmol), making it attractive from a synthetic point of view. 

Andrus MB, Christiansen MA, Butler AW, Hill AR (2009) Synthesis of Kurasoin B Using Phase-Transfer-Catalyzed Acylimidazole Alkylation. Synlett 2009 653... 

Electroreduction of styrenes or alkyl methacrylates in the presence of aliphatic acid anhydrides or N-acylimidazoles with zinc anode brought about novel one-pot vicinal double C-acylation to afford the corresponding 1,4-diketones in good to high yields. This is an example of cross-coupling reaction with no use of halogenated compounds. 

Stetter and Lorenz reported in 1985 that a thiazolylidine catalyst could promote the addition of a-ketoacid derivatives (17) to activated olefins (18) with loss of CO2 to give 1,4-diketones (19)7 The reaction has been called biomimetic because of its resemblance to the family of biochemical transformations effected by thiamine diphosphate-dependent enzymes acting on pyruvate While the original report was limited to alkyl vinyl ketones, more recent work by Scheldt and co-workers has greatly expanded the scope of this reaction by employing a, 3-unsaturated 2-acylimidazoles as the activated olefin component. ... 

Trost and coworkers extended their protocol to 2-acylimidazoles after accomplished enantioselective decarboxylative allylation of this type of ketones, the heterocycle was cleaved under formation of y,8-unsaturated esters. Thus, this protocol can be considered an equivalent of the enantioselective allylic alkylation of carboxylic esters [55a]. For the same purpose, the decarboxylative allylation of Af-acyloxazolinones was developed. The allylation products were converted, under cleavage of the heterocycle, into carboxylic acids, esters, and thioesters in high enantiomeric purity [55b]. 

Yoshida et aL recendy reported the direct synthesis of branched alkenylbo-rons via a-selective hydroboration of terminal alkynes employing (pin)B-B(dan) (where dan = 1,8-diaminonaphthalene) in the presence of 2 mol% [(SIPr)CuCl] 212,6 mol% KOt-Bu and MeOH (3 equiv.). Given that the scope of the alkynes is broad, the method was extended to the synthesis of Bexarotene and LG100268, which are used to treat T-cell lymphoma and as retinoid X receptor. In a different study by the same group, 208 catalyzed the selective addition of alkyl hydrob-oranes to imidazofyl-o,p-unsaturated ketones at the Imposition. Interestingly, the 2-acylimidazole moiety could be replaced by esters or amides. ... 

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