ALDOL ADDITIONS OF PINACOLONE LITHIUM ENOLATE WITH KETONES - REACTIVITIES GOVERNED PREDOMINANTLY BY FIELD EFFECTS

The relative reactivities of representative alpha- and beta-heterosubstituted acyclic, cyclic (five- and six-membered), and aromatic ketones with the lithium enolate of pinacolone in diethyl ether at -78-degrees-C were determined. The order of reactivities of monosubstituted acetones (MeCOCH2X) is X = Cl > OTBDMS > OMe > SMe > NMe2 > CH2SMe > H > Me and spans a range of 10(4). Excellent correlation was obtained for MeCOCH2X when log (k(X)/k(Me)) was plotted against sigma(I)(X) (r = 0.996, rho = 6.62), demonstrating the overwhelming importance of substituent field/inductive effects in the rate enhancement. Similar linear relationships were also observed for aromatic ketones (r = 0.993, rho = 7.61) as well as five-membered (r = 0.997, rho = 6.87) and six-membered ring (r = 0.998, rho = 6.92) cyclic ketones. Thiacyclopentanone and 3- and 4-thiacyclohexanones were unique among the substrates studied in departing significantly from the correlations shown by all other types of substrates. Similarities of the reactivities for 3-oxacyclohexanone vs cyclohexanone and of 3-oxacyclopentanone vs cyclopentanone to that for methoxyacetone vs butanone established that chelation has no role in the very large rate enhancements observed. The synthetic utility of this effect for regioselective additions was demonstrated by the exclusive addition of pinacolone lithium enolate to the 2-carbonyl in MeCO(CH2)3COCH2OSiMe2t-Bu. Steric retardation by alpha-methyl and alpha-methoxy groups was nearly absent in cyclopentanones, small in acyclic ketones, and considerable in cyclohexanones.