D. A. Evans Kinetic Enolate Acylation: The Mander Reagent Chem 206 a Kinetic Acylation: Methyl Cyanoformate (1): a The Tetrahedral Intermediate 2; Why is it so stable? 78°c Me 2 LCN Enolate acylation with 1 is fast Intermediate 2 breaks down to product Consider this in the broader context of elimination reactions more slowly than the acylation step of the elcb classification where Under these conditions, proton transfer ither c or some heteroatom from product to enolate does not occur X might ous leaving groups such as CN, OR etc. OMe slow +X les: o Co, Me 84% I Data is available for the case where x= CN, or&Y= carbanion Stirling, Chem. Commun. 1975. 940-941 CO2 Me 65% FG base CFG 一 FG COmE leaving grp pKa log OTMS Mander Tet. Lett. 1983. 24. 5425 Me-Li H CO,Me CMe Mander, SynLett. 1990, 169 Above data makes the point that CN is a poor LG but it also leads one to the faulty conclusion that 2 should partition to acyl cyanide rather than methyl ester! R2Cu(CN Hashimoto, chem Lett. 1989. 1063 R2 LICN H23-03-Mander Reagent 11/5/00 8: 21 PM-78 °C fast D. A. Evans Kinetic Enolate Acylation: The Mander Reagent Chem 206 ■ Kinetic Acylation: Methyl Cyanoformate (1): + slow + LiCN 1 Enolate acylation with 1 is fast Intermediate 2 breaks down to product more slowly than the acylation step 2 Under these conditions, proton transfer from product to enolate does not occur. Mander Tet. Lett. 1983, 24, 5425 ■ Examples: LDA 1 84% 1 LDA 65% 75% LDA 1 1 Me-Li + isomer 7% Mander, SynLett. 1990, 169 1 R2Cu(CN)2Li2 82% Hashimoto, Chem. Lett. 1989, 1063 ■ The Tetrahedral Intermediate 2; Why is it so stable? 2 slow + LiCN Consider this process in the broader context of elimination reactions of the E1cb classification where: Y might be either C or some heteroatom X might be various leaving groups such as CN, OR etc. base – slow + X– + X slow – – base Data is available for the case where X = CN, OR & Y = carbanion: Stirling, Chem. Commun. 1975, 940-941 leaving grp (X) pKa H–X log kX kOPh –OPh 10 1 –CN 9.5 <-7 –C(Me)2-NO2 ~10 <-9 –OMe 16 -3.9 + LiOMe 2 + LiCN Above data makes the point that CN is a poor LG but it also leads one to the faulty conclusion that 2 should partition to acyl cyanide rather than methyl ester! O Li O CN R1 OMe R2 R2 O R1 OMe O X FG H R FG X FG X Y Y R Y H X R R R2 R R O R1 OMe O CN Li O R1 OMe O R R2 2 O R1 CN O O O NC OMe O R2 O R1 OMe O CN Li CO2Me Me OTMS Me CMe3 Me3C H R1 OLi R2 O R1 OMe O R2 Me O Me CO2Me O Me O CO2Me O Me Me O Me CO2Me O OTBS O CO2Me H23-03-Mander Reagent 11/5/00 8:21 PM