SYNTHETIC OPTIMIZATION AND STRUCTURAL LIMITATIONS OF THE NITRILE ALDOL REACTION

In an effort to further optimize and to define the structural limitati ons of the nitrile aldol reaction, several studies were undertaken. Li thiated phenylacetonitrile 1 was demonstrated to exhibit diastereosele ctivity for addition to benzaldehyde higher than that of other metalat ed phenylacetonitriles. With a view toward practical lab-scale synthes is 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 recr ystallized 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 ben zaldehydes 6b-g was then studied; increasing electron-withdrawing powe r of the para substituent was found to cause a marked decrease in dias tereaselectivity. Finally, the aldol reactions of two aliphatic nitril es (isovaleronitrile 4 and tert-butylacetonitrile 5, were studied. Sup risingly, aldol diastereoselectivity of aliphatic nitriles is not unif ormly anti-selective, and selectivities overall are lower than those a fforded by arylacetonitriles.