Facile Synthesis of Pyridones from Cyclopentenones

Keywords

pyridones - ¹⁵N-labelling - Beckmann rearrangement - silyl enol ethers - oxidative amination

Significance

2-Pyridones are found in a range of biologically active molecules and serve as both ligands for C–H activation reactions and as intermediates in the synthesis of functionalized pyridines. Several routes exist for the synthesis of 2-pyridones, including Knoevenagel-type condensations, rearrangements of pyridine N-oxides, and the Guareschi synthesis, though these are often lengthy, limited in scope and/or require harsh reaction conditions. The current report describes an operationally simple synthesis of 2-pyridones through the ring expansion of cyclopentenones that proceeds through the intermediacy of the corresponding silyl enol ether.

Comment

Proof-of-concept studies initially utilized the pre-formed silyl enol ether with increased steric bulk of the silyl moiety shown to be important for optimal yields to be obtained. The use of protic solvents was critical for the ring-expansion, with a mixed solvent system being utilized to enable direct transformation of the cyclopentenone to the 2-pyridone in a one-pot process. Model studies allowed identification of the most efficient oxidants and nitrogen sources with the reaction proceeding rapidly at ambient temperature. A range of cyclopentenones were successful substrates with 1-indanones interestingly displaying different regioselectivity in the process when compared to the traditional Beckmann rearrangement. The reaction was also effective for the synthesis of ¹⁵N-labelled pyridones, with mechanistic studies suggesting the intermediacy of N-iodonium aziridine derivatives.

Publication History

Article published online:
20 December 2024