Stereoretentive and regioselective selenium-catalyzed intermolecular propargylic C-H amination of alkynes

Abstract

Herein we report an intermolecular propargylic C-H amination of alkynes. This reaction is operationally convenient and requires no transition metal catalysts or additives. Terminal, silyl, and internal alkynes bearing a wide range of functional groups can be aminated in high yields. The regioselectivity of amination for unsymmetrical internal alkynes is strongly influenced by substitution pattern (tertiary > secondary > primary) and by relatively remote heteroatomic substituents. We demonstrate that amination of alkynes bearing α-stereocenters occurs with retention of configuration at the newly-formed C-N bond. Competition experiments between alkynes, kinetic isotope effects, and DFT calculations are performed to confirm the mechanistic hypothesis that initial ene reaction of a selenium bis(imide) species is the rate- and product-determining step. This ene reaction has a transition state that results in substantial partial positive charge development at the carbon atom closer to the amination position. Inductive and/or hyperconjugative stabilization or destabilization of this positive charge explains the observed regioselectivities.

Scheme 1. Common routes to propargylamines.

Scheme 2. Sulfonamide/sulfamate screen.

Scheme 3. Terminal and silyl-substituted alkyne substrate scope.

Scheme 4. Regioselective amination of internal alkynes.

Scheme 5. Relative rates of amination reactions.

Scheme 6. Reaction mechanism: (A) proposed mechanistic cycle, (B) stereoretention at alpha position, (C) kinetic isotope effects.

Scheme 7. (A) Effect of substitution on terminal alkynes. (B) Effect of substitution on regioselectivity of internal alkynes. (C) Bell–Evans–Polanyi plot for calculated ene reactions.