Photoredox-catalyzed oxo-amination of aryl cyclopropanes

Abstract

Cyclopropanes represent a class of versatile building blocks in modern organic synthesis. While the release of ring strain offers a thermodynamic driving force, the control of selectivity for C-C bond cleavage and the subsequent regiochemistry of the functionalization remains difficult, especially for unactivated cyclopropanes. Here we report a photoredox-coupled ring-opening oxo-amination of electronically unbiased cyclopropanes, which enables the expedient construction of a host of structurally diverse β-amino ketone derivatives. Through one electron oxidation, the relatively inert aryl cyclopropanes are readily converted into reactive radical cation intermediates, which in turn participate in the ensuing ring-opening functionalizations. Based on mechanistic studies, the present oxo-amination is proposed to proceed through an S_N2-like nucleophilic attack/ring-opening manifold. This protocol features wide substrate scope, mild reaction conditions, and use of dioxygen as an oxidant both for catalyst regeneration and oxygen-incorporation. Moreover, a one-pot formal aminoacylation of olefins is described through a sequential cyclopropanation/oxo-amination.

Fig. 1

Synthetic elaboration of cyclopropanes and alkenes. a Reported strategies for ring-opening functionalization of cyclopropanes. b Hydroamination of alkenes by photoredox catalysis. c Oxo-amination of unactivated aryl cyclopropanes. d One-pot aminoacylation of alkenes

Fig. 2

Telescoped reactions and scale-up experiments. a One-pot formal aminoacylation of alkenes. b Additional products and their regioselectivity. c Gram-scale reaction to form 3aya. ^aThe isolated yield of the major isomer is listed. rr is regioisomeric ratio, represents the ratio of major isomer to the minor one. PC photoredox catalyst, DCE 1,2-dichloroethane, MS molecular sieves

Fig. 3

Mechanistic investigations. a Inhibition by TEMPO of the reaction between 1b and 2a. b Isolation of hydroperoxide intermediates and their conversion to the products 3. c Stern–Volmer fluorescence quenching study of 1a and 2a. d Experiments with enantiomerically enriched 1ao. DCE 1,2-dichloroethane, MS molecular sieves, DMAP 4-N,N-dimethylaminopyridine

Fig. 4

Proposed reaction mechanism. Single electron oxidation of aryl cyclopropane 1 gives cation radical intermediate I with an activated cyclopropane. Reaction with the nucleophile provides intermediate II, which reacts with dioxygen ultimately affording the product 3