Rhodium-catalysed syn-carboamination of alkenes via a transient directing group

Abstract

Alkenes are the most ubiquitous prochiral functional groups--those that can be converted from achiral to chiral in a single step--that are accessible to synthetic chemists. For this reason, difunctionalization reactions of alkenes (whereby two functional groups are added to the same double bond) are particularly important, as they can be used to produce highly complex molecular architectures. Stereoselective oxidation reactions, including dihydroxylation, aminohydroxylation and halogenation, are well established methods for functionalizing alkenes. However, the intermolecular incorporation of both carbon- and nitrogen-based functionalities stereoselectively across an alkene has not been reported. Here we describe the rhodium-catalysed carboamination of alkenes at the same (syn) face of a double bond, initiated by a carbon-hydrogen activation event that uses enoxyphthalimides as the source of both the carbon and the nitrogen functionalities. The reaction methodology allows for the intermolecular, stereospecific formation of one carbon-carbon and one carbon-nitrogen bond across an alkene, which is, to our knowledge, unprecedented. The reaction design involves the in situ generation of a bidentate directing group and the use of a new cyclopentadienyl ligand to control the reactivity of rhodium. The results provide a new way of synthesizing functionalized alkenes, and should lead to the convergent and stereoselective assembly of amine-containing acyclic molecules.

Figure 1. Carboamination Reactions

a, Transition metal catalyzed difunctionalization of alkenes. b, Available carboamination reactions in organic synthesis. c, Rh(III)-catalyzed intermolecular syn-carboamination of alkenes. Ar, aromatic; M_CAT, metal based catalyst; Ph, phenyl; Phth, phthalimide.

Figure 2. Working hypothesis: Tuning of the directing group to influence reactivity

Ligands on Rh omitted for clarity. Ar, aromatic; L, exogenous nucleophile.

Figure 3. Applications of the carboamination reaction

a, General conditions for carboamination of 1,2-disubstituted alkenes. b, Effect of substituents on the N-Enoxyphthalimide. c, Probe of reaction stereospecificity. d, Functionalization of 1,2-disubstituted alkenes. e, Functionalization of mono-substituted alkene. f, Derivatization of the carboamination adduct: Formation of pyrrolidine. Ac, acetyl; Ad, adamantyl; Bn, benzyl; Boc, tert-butoxycarbonyl; Cy, cyclohexyl; Cp, cyclopentadienyl, Et, ethyl; iPr, isopropyl; Me, methyl; Phth, phthalimide; Ph, phenyl; rt, room temperature; tBu, tert-butyl; TBS, tert-butylsilyl.

Figure 4. Reaction mechanism: study and proposal

a, Crossover experiment. b, Probe of the formation of 5aa. c, Reactivity of a secondary amide in the carboamination reaction. d, Proposed mechanism for the carboamination reaction. Ligands on Rh and phthalimide substituents omitted for clarity. Ad, adamantyl; Cp, cyclopentadienyl, Me, methyl; Ph, phenyl; Phth, phthalimide; tBu, tert-butyl; rt, room temperature.