Copper-catalyzed alkene diamination: synthesis of chiral 2-aminomethyl indolines and pyrrolidines

Abstract

Chiral vicinal diamines, including 2-aminomethyl indolines and pyrrolidines, are useful as ligands for catalytic asymmetric reactions and are also found as important components of bioactive compounds. Herein is reported the first copper-catalyzed alkene diamination that occurs with high enantioselectivity. The substrate range is the broadest yet reported for this kind of intra-/intermolecular reaction sequence both with respect to γ-alkenyl sulfonamide substrate and external amine nucleophile. The resulting products expand the availability of substituted 2-aminomethyl indolines and pyrrolidines, privileged compounds in asymmetric catalysis and medicinal chemistry. A unique solution to a challenging oxidation problem related to copper catalyst turnover is also presented.

Catalytic Asymmetric Radical Diamination of Alkenes

“…[1][2][3][4][5][6][7][8][11][12][13] In this regard, catalytic asymmetric diamination of unactivated alkenes with transition-metal or aryliodine(I) catalysts represents a straightforward and highly attractive method for creating such useful vicinal diamine scaffolds, given the facile accessibility of alkene starting materials. [14][15][16][17][18][19][20][21][22][23][24][25] However, the amine introduced by these asymmetric catalytic systems has to be masked by electron-withdrawing protecting groups, and direct incorporation of free alkylamine has so far remained elusive (Scheme 1A).…”

“…Two major factors have contributed to the lack of development of asymmetric alkene diamination with protection-free alkylamine. [14][15][16][17][18][19][20][21][22][23][24][25] On the one hand, the high affinity of a strongly Lewis-basic alkylamine for transition metal could lead to the formation of stable amine-metal complexes, thus resulting in poisoning of transition-metal catalysts. On the other hand, protection-free alkylamine is susceptible to oxidation under reported oxidative diamination reaction conditions.…”

“…On the other hand, protection-free alkylamine is susceptible to oxidation under reported oxidative diamination reaction conditions. [14][15][16][17][18][19][20][21][22][23][24][25] As a result, successful diamination of unactivated alkenes typically requires adequate electron-withdrawing protecting groups to suppress undesired strong ligation and amine oxidation, making these methods indirect for free amine synthesis and inconvenient for subsequent amine transformation (Scheme 1A).…”

A DFT Study on CuH‐Catalyzed Reductive Relay Hydroamination for Synthesis of Remote‐Chiral Amine

“…Recently, Buchwald, Harwtig, Chemler, Hirano and Miura, independently carried out excellent studies to achieve α‐ or β‐chiral aliphatic amines through Cu‐catalyzed Markovnikov and anti‐Markovnikov hydroamination, respectively. In contrast, as for γ‐ and δ‐stereogenic centers, a series of Cu‐catalyzed reductive relay hydroamination was described by Buchwald and coworkers .…”

Copper-promoted synthesis of 1,4-benzodiazepinones via alkene diamination

“…15–24 Such vicinal diamines have demonstrated significant utility as components of bioactive compounds, as well as in chemical synthesis, where they are useful as either ligands or catalysts in organic and organometallic transformations. 15,25,26 Our research group has developed copper-promoted 27–29 and copper-catalyzed 23 alkene diaminations for the synthesis of aminomethyl functionalized indolines, isoindolines, pyrrolidines, γ-lactams, cyclic ureas, cyclic sulfamides, tetrahydroisoquinolines and tetrahydroquinolines. While transition metal catalyzed cyclization reactions to form larger rings are generally more challenging than five-membered ring formation reactions, the successful precedent set by the palladium-catalyzed alkene difunctionalizations (Scheme 1) convinced us that formation of 1,4-benzodiazepinones via copper-facilitated alkene diamination should be feasible.…”