Synthesis of γ-Lactams by Mild, o-Benzoquinone-Induced Oxidation of Pyrrolidines Containing Oxidation-Sensitive Functional Groups

Abstract

The late-stage oxidation of substituted pyrrolidines offers good flexibility for the construction of γ-lactam libraries, and especially in recent years the methods for functionalization of pyrrolidine have been available. We reported a new strategy for oxidation of pyrrolidines to γ-lactams: reaction of pyrrolidine with an o-benzoquinone gives an N,O-acetal by direct oxidation of the α-C-H bond of the pyrrolidine ring, and then the N,O-acetal is further oxidized by the o-benzoquinone to the γ-lactam. Because the first oxidation occurs selectively at the α-C-H of the pyrrolidine ring, oxidation-sensitive functional groups (allyl-, vinyl-, hydroxyl-, and amino groups) on pyrrolidine ring are unaffected. The synthetic utility of this novel method was demonstrated by the facile syntheses of (S)-vigabatrin and two analogues.

Condensation-Based Methods for the C–H Bond Functionalization of Amines

“…This reaction was applied to the synthesis of (S)-Vigabatrin and analogues. 66 Quinone-mediated amine α-C−H bond functionalization reactions of primary, α-tertiary amines were developed by Dixon and coworkers (Scheme 36). 67 Condensation of a primary amine with 3,5-di-tert-butyl o-quinone provides an No-hydroxyaryl imine intermediate via a 1,5-proton shift.…”

“…This reaction was applied to the synthesis of (S)-vigabatrin and analogues. 66 Quinone-mediated amine -C-H bond functionalization reactions of primary, -tertiary amines were developed by Dixon and co-workers (Scheme 36). 67…”

Primary α-tertiary amine synthesis via α-C–H functionalization

“…The mechanism involves the condensation of a quinone co-factor with the primary amine substrate and a subsequent formal [1,5] H-shift from the α-position of the amine to generate a reactive imine, which is then hydrolyzed to afford the aldehyde product. Despite elegant early work on quinone-mediated amine oxidation by McCoy and Day,15 and Corey,16 the elucidation of the mechanism of this biotransformation has paved the way for increasing applications in contemporary synthesis17 with notable contributions from Stahl,18 Kobayashi,19 and Fleury20 in amine oxidation, from Qu,9a,21 and Clift7 a in amine functionalization, and from Lumb in heterocycle synthesis 22,23…”

Traceless Redox-Annulations of Alicyclic Amines

“… 5 In addition, activation of an ortho -methyl group has been achieved with heteroaryl substrates ( Scheme 1b ) 6 and highly electron-deficient o -tolualdehydes ( Scheme 1c ). 7 – 10 Here, we report the first redox-annulations of amines with ortho -(nitromethyl)benzaldehydes ( Scheme 1d ). In these reactions, the nitro group acts as a traceless activator as it can be removed in a subsequent step.…”