Synthetic Optimization and Structural Limitations of the Nitrile Aldol Reaction

In an effort to further optimize and to define the structural limitations of the nitrile aldol reaction, several studies were undertaken. Lithiated phenylacetonitrile 1 was demonstrated to exhibit diastereoselectivity for addition to benzaldehyde higher than that of other metalated phenylacetonitriles. With a view toward practical lab-scale synthesis of aldols derived from lithiated arylacetonitriles, the effects of reaction concentration and quenching method on isolated yields of the anti -aldols were readdressed. Secondary aldehydes give reasonable recrystallized yields of anti -aldols at reaction concentrations as high as 0.1 M; pivalaldehyde gives good results at concentrations up to 0.3 M. Thirdly, the aldol reaction of lithiated 1 with para -substituted benzaldehydes 6b − g was then studied; increasing electron-withdrawing power of the para substituent was found to cause a marked decrease in diastereoselectivity. Finally, the aldol reactions of two aliphatic nitriles (isovaleronitrile 4 and tert -butylacetonitrile 5 ) were studied. Suprisingly, aldol diastereoselectivity of aliphatic nitriles is not uniformly anti -selective, and selectivities overall are lower than those afforded by arylacetonitriles.