Diastereo- and Enantioselective CuH-Catalyzed Hydroamination of Strained Trisubstituted Alkenes

Abstract

Amine-substituted cyclobutanes and cyclopropanes are important substructures in biologically active compounds. Moreover, many of the cycloalkane units bear multiple substituents and stereocenters. Therefore, synthetic methods that produce polysubstituted aminocyclobutanes and aminocyclopropanes in a highly diastereo-and enantioselective manner are of importance. Herein, we describe the diastereo-and enantioselective synthesis of various types of polysubstituted aminocyclobutanes and aminocyclopropanes through CuH-catalyzed hydroamination of 1-substituted cyclobutenes and cyclopropenes. These strained trisubstituted alkenes exhibit much higher reactivity compared to their unstrained analogues in the initial hydrocupration step of the reaction. Moreover, an interesting reversal of regioselectivity was observed in the hydroamination of 1-aryl-substituted cyclobutenes compared to the cyclopropene analogues. The origins of the enhanced reactivity of strained trisubstituted alkenes as well as the differences in the regio-and enantioselectivity between reactions with cyclobutenes and cyclopropenes were investigated computationally.

Catalytic asymmetric hydrometallation of cyclobutenes with salicylaldehydes

“…4,5 Most existing catalytic asymmetric approaches for cyclobutane synthesis rely either on ring-closure, [6][7][8][9][10][11][12][13] or the functionalization of pre-formed four-membered rings using activating or directing groups. [14][15][16] Direct addition reactions to unactivated cyclobutenes are rare, [17][18][19] but attractive as they offer a modular entry to functionalized cyclobutanes and are generally not limited to specic substitution patterns.…”

Earth-Abundant 3d Transition Metal Catalysts for Hydroalkoxylation and Hydroamination of Unactivated Alkenes

“…A strategy to achieve such reactivity is to rely on the release of the ring strain energy of stained trisubstituted olefins. Early last year, the group of Buchwald reported the diastereo-and enantioselective CuH-catalyzed hydroamination of 1-aryl and alkyl-substituted cyclobutenes, and 1-phenyl, 1-alkyl, 1-silyl substituted cyclopropenes leading to the C-N bond formation with different regioselectivity according to the substitution and ring size (Figure 26) [167]. Markovnikov regioselectivity was noticed for 1-arylcyclobutenes while anti-Markovnikov regioselectivity was observed for all other substrates.…”

Enantioselective Functionalization of Prochiral Cyclobutanones and Cyclobutenones

“…Enantioselective functionalizations of cyclobutene derivatives, including asymmetric allylic substitutions of cyclobutenes, 26 desymmetrization of cyclobutenes, 27 hydroamination of cyclobutene, 28 and conjugate addition of cyclobutene-1-carboxylate, 29 have been developed. Herein we would like to focus on cyclobutenones only.…”