Magnesium coordination-directed n-selective stereospecific alkylation of 2-pyridones, carbamates, and amides using
Yuan-Qing Fang1, Matthew M Bio, Karl B Hansen
1Department of Chemical Process Research & Development, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA. yfang@amgen.com
Abstract:
A general inversion-stereospecific, N-selective alkylation of substituted 2-pyridones (and analogues), amides, and carbamates using chiral α-chloro- or bromocarboxylic acids in the presence of KOt-Bu (or KHMDS) and Mg(Ot-Bu)(2) is reported. The resulting α-chiral carboxylic acid products were isolated by crystallization in good chemical yields and in high ee (>90% ee). Mechanistic evidence suggests that the reaction proceeds through 2-pyridone O-coordinated Mg carboxylate intermediates, which afford the product through an intramolecular S(N)2 alkylation.
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