M. Bilodeau. D.A. Evans A Survey of Soft Enolization techniques Chem 115 Horner-Wadsworth -Emmons reaction Lewis Acid -Tertiary Amine Enolizations i-PrCHO, 1 equiv oEt MecN 1.2 equiv 了 pKa 19.2( DMSO), K,counterion Base= DIPEA, 7 h, 97%, >50: 1E:Z pKa 12.2( Diglyme), Li counterion R'3N-MLn NHCbz NHCbz 85%+ 10% recovered aldehyde a Acidity of a-protons enhanced by coordination of Lewis acid Conventional methods of deprotonation(NaH)resulted in epimerization I This allows the use of mild bases to depronate substrate I A critical issue in the success of procedure of enolization is the Rathke, Nowak J. Org. Chem. 1985, 50, 2624-2626 reversible Lewis acid/amine base association R3N MLn R3NLn a Many reactions surveyed here dont rely on complete enolization of the carbonyl substrate. If the electrophile can withstand the reaction conditions it can access an equilibrium concentration of the enolate R= i-Pr, 40% yield R= n-CaH13, 100% yield 22A-02 Ketone Acidity 11/1/01 3: 41 PMR3N MLn R3N + MLn ■ Many reactions surveyed here don't rely on complete enolization of the carbonyl substrate. If the electrophile can withstand the reaction conditions it can access an equilibrium concentration of the enolate. pKa 19.2 (DMSO), K+ counterion pKa 12.2 (Diglyme), Li+ counterion LiCl, 1.2 equiv Base, 1.0 equiv i-PrCHO, 1 equiv MeCN 1.2 equiv rt Horner-Wadsworth-Emmons Reaction. Base = DBU, 5 min, 99%, >50:1 E:Z Base = DIPEA, 7 h, 97%, >50:1 E:Z Above conditions using DIPEA 24 h, rt 85% + 10% recovered aldehyde Conventional methods of deprotonation (NaH) resulted in epimerization (Overman JACS 1978, 5179). R= i-Pr, 40% yield R= n-C6H13, 100% yield 1 equiv MgBr2, 1.2 equiv Et3N, 1.1 equiv RCHO, 1 equiv THF rt Rathke, Nowak J. Org. Chem. 1985, 50, 2624-2626. El+ ■ Acidity of a-protons enhanced by coordination of Lewis acid. ■ This allows the use of mild bases to depronate substrate. ■ A critical issue in the success of procedure of enolization is the reversible Lewis acid/amine base association. Lewis Acid - Tertiary Amine Enolizations + MLn R'3N R'3N-MLn R'3N - + M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 R O Me Me O R MLn O MLn-1 R Me O R Me El O OEt (EtO)2P O R OEt O O OEt (EtO)2P O OEt O Me Me NHCbz CHO Me Me NHCbz OEt O 22A-02 Ketone Acidity 11/1/01 3:41 PM