Pyridone functionalization: regioselective deprotonation of 6-methylpyridin-2(1H)- and -4(1H)-one derivatives
journal contributionposted on 12.10.2016, 08:46 by Beatriz Fernandez D.-R., Mark ElsegoodMark Elsegood, Gary Fairley, Gareth PritchardGareth Pritchard, George WeaverGeorge Weaver
Selective functionalization at the α-methyl group of 1-substituted pyridin-2(1H)- and 4(1H)-ones (2- and 4-pyridones) can be achieved by appropriate choice of base. n-Butyllithium was found to effect clean 6(2)-methyl deprotonation of 1-benzyl-2- and -4-pyridone derivatives, while potassium hexamethyldisilazide (KHMDS) was the preferred reagent for methyl deprotonation of the corresponding 1-methyl-2- and -4-pyridones. Deprotonation proceeds smoothly at –78 °C, and the resulting anions react readily with a wide range of electrophiles (aldehydes, ketones, alkylating reagents, and an azo compound) under precise temperature control to form usefully functionalized 2- and 4-pyridones and quinolizinones.
We thank AstraZeneca and Loughborough University for financial support, and the Engineering and Physical Sciences Research Council (EPSRC) UK National Mass Spectrometry Facility at Swansea for mass spectra.