Synthesis of 1-Acyl-3-piperidones and Ring Expansion of Methyl 3-Oxopiperidine-1-carboxylate with Ethyl Diazoacetate.

Abstract

Nipecotic acid and guvacine are potent .gamma.-aminobutyric acid uptake inhibitors. 1-Acyl-3-piperidone derivatives are useful in evaluating structural analogs of these drugs. The 1-acyl-3-piperidones were synthesized from pyridin-3-ol via a reaction sequence of general utility for the preparation of 1-acyl-3-piperidones. Pyridin-3-ol was converted into 1-benzyl-3-piperidone hydrobromide hydrate (3) via 1-benzyl-1,2,5,6-tetrahydro-3-pyridyl benzyl ether (2). Hydrogenolysis of 3 followed by treatments with the appropriate acylating agents gave 5a-d. Compound 3 was converted into 1-benzyl-3-piperidone (4). The 1-acyl-3-piperidones 5b,c were transformed into the corresponding 1-pyrrolidinyl enamines 6b,c. The boron trifluoride catalyzed reaction of 5b with ethyl diazoacetate gave a mixture of the 2 cyclic .beta.-oxoesters, ethyl 1-methoxycarbonyl-4-oxoperhydroazepine-3-carboxylate (8) and ethyl 1-methoxy-carbonyl-3-oxoperhydroazepine-4-carboxylate (9), which were separated via selective formation of the copper(II) chelate of 8. The structures of 8 and 9 were finally confirmed by conversion into the ketones methyl 4-oxoperhydroazepine-1-carboxylate (10) and methyl 3-oxoperhydroazepine-1-carboxylate (11), respectively. The amide rotation in the urethane groups of 5b-d, 6b,c and 11 was discussed on the basis of the 1H-NMR spectra.