Stereocontrolled Aldol Reaction of N-Acylpyrazoles with Aldehydes Using LDA or MgBr2-DIEA

The aldol reaction of 1-acyl-3,5-dimethylpyrazoles (1) was kinetically controlled with syn stereoselectivity through lithium enolate intermediate using LDA.On the contrary, the anti stereoselective aldol reaction of 1 was caused by the action of DIEA in the presence of MgBr2 under the thermodynamic control.In the formation of sy11-aldol products using 3-phenyl-I-menthopyrazole as a c h i d auxiliary, the diastereoselectivity was observed up to 81% de with the predominant configuration of 2's form.Recently we have been much interesting in the chemistry of N-acylpyrazoles, especially Z-acyl-3-phenyl-lmenthopyrazoles as the c h i d synthetic intermediate.'By the treatment with various nucleophiles, Nacylpyrazoles were converted into the corresponding a m i d e ~, ~ esters: ketones4 and P-keto esters?Moreover, N-acylpyrazoles were allowed to react with LDA or LiHMDS to generate lithium enolates, which were the key intermediates for a-alkylati~n,~ a-sulfenylation7 and a-acylation.@In the case of using 2acyl-3-phenyl-I-menthopyrazoles, the highly diastereoselective a-alkylation and a-acylation were accomplished by the diastereofacial attack of akyl halides and acyl halides respectively on the lithium enolate, which was rigidly fixed by the intramolecular chelation between lithium and N-1 a t ~r n .~. ~ The subsequent a-acylated products were easily converted into the chiral N-methyl fi-keto amides in spite of the enolizahle compounds.For the further extension of the utilities of N-acylpyrazoles as the synthetic intermediate, a wide variety of the stereoselective reactions on the acyl moiety of N-acylpyrazoles are highly desired.Also we are longing to improve the reactions of N-acylpyrazoles under the more mild, efficient and convenient conditions.Here, we report the aldol reactions on the acyl moiety of N-acylpyrazoles with aldehydes, especially the diastereoselective aldol reactions using a new chiral auxiliary, 3-phenyl-lmenthopyrazole.When 1-propanoyl-3,s-dimethylpyrazole (la) was treated with LDA followed by benzaldehyde, 1-(3'hydroxy-2'-methyl-3'-phenyl)propanoyl-3,5-dimethylpyrazole (2a) was obtained in good yield as the synlanti isomeric mixture.From the NMR spectrum, the sydanti ratio was found to he 85 : 15.