⁷Li/³¹P NMR Studies of Lithiated Arylacetonitriles in THF−HMPA Solution: Characterization of HMPA-Solvated Monomers, Dimers, and Separated Ion Pairs

The structures of lithiated phenylacetonitrile and 1-naphthylacetonitrile were studied in THF and HMPA−THF solution. In pure THF, 7Li NMR line width studies suggest that these species exist as contact ion pairs; HMPA titration studies confirm this conclusion. In the presence of 0.25−2 equiv of HMPA, HMPA-solvated monomeric and dimeric contact ion pairs are detected by 31P and 7Li NMR spectroscopy. Finally, at 4−6 equiv of added HMPA, 7Li NMR spectra provide direct evidence for the formation of HMPA-solvated separated ion pairs

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

HMPA Promotes Retro-Aldol Reaction, Resulting in Syn-Selective Addition of Lithiated 1-Naphthylacetonitrile to Aromatic Aldehydes

In HMPA−THF solution, lithiated 1-naphthylacetonitrile undergoes highly syn-selective addition to aromatic aldehydes, providing the first access to such syn-aldols. Syn-selectivity is also observed with two other arylacetonitriles. Aldolate equilibration and crossover experiments demonstrate that HMPA promotes retro-aldol reaction and that aldol diastereoselectivity under these conditions is thermodynamically controlled