Magnesium coordination-directed n-selective stereospecific alkylation of 2-pyridones, carbamates, and amides using α-halocarboxylic acids.
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.
Department of Chemical Process Research & Development, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA. yfang@amgen.com
Yuan-Qing
YQ
Fang
Matthew M
MM
Bio
Karl B
KB
Hansen
Matthew S
MS
Potter
Andrew
A
Clausen
D000478:Alkylation; D000577:Amides / Q000737:chemistry*; D002219:Carbamates / Q000737:chemistry*; D002264:Carboxylic Acids / Q000737:chemistry*; D006219:Halogens / Q000737:chemistry*; D006846:Hydrocarbons, Halogenated / Q000737:chemistry; D008274:Magnesium / Q000737:chemistry*; D015394:Molecular Structure; D011728:Pyridones / Q000737:chemistry*; D013237:Stereoisomerism
D000577:Amides; D002219:Carbamates; D002264:Carboxylic Acids; D006219:Halogens; D006846:Hydrocarbons, Halogenated; D011728:Pyridones; D008274:Magnesium