Catalytic asymmetric addition of an amine N-H bond across internal alkenes

Abstract

Hydroamination of alkenes, the addition of the N-H bond of an amine across an alkene, is a fundamental, yet challenging, organic transformation that creates an alkylamine from two abundant chemical feedstocks, alkenes and amines, with full atom economy^1-3. The reaction is particularly important because amines, especially chiral amines, are prevalent substructures in a wide range of natural products and drugs. Although extensive efforts have been dedicated to developing catalysts for hydroamination, the vast majority of alkenes that undergo intermolecular hydroamination have been limited to conjugated, strained, or terminal alkenes^2-4; only a few examples occur by the direct addition of the N-H bond of amines across unactivated internal alkenes^5-7, including photocatalytic hydroamination^8,9, and no asymmetric intermolecular additions to such alkenes are known. In fact, current examples of direct, enantioselective intermolecular hydroamination of any type of unactivated alkene lacking a directing group occur with only moderate enantioselectivity^10-13. Here we report a cationic iridium system that catalyses intermolecular hydroamination of a range of unactivated, internal alkenes, including those in both acyclic and cyclic alkenes, to afford chiral amines with high enantioselectivity. The catalyst contains a phosphine ligand bearing trimethylsilyl-substituted aryl groups and a triflimide counteranion, and the reaction design includes 2-amino-6-methylpyridine as the amine to enhance the rates of multiple steps within the catalytic cycle while serving as an ammonia surrogate. These design principles point the way to the addition of N-H bonds of other reagents, as well as O-H and C-H bonds, across unactivated internal alkenes to streamline the synthesis of functional molecules from basic feedstocks.

Fig. 1. Catalytic asymmetric hydroamination of unactivated internal alkenes.

a, Long-standing challenges and previous strategies for catalytic hydroamination of unactivated internal alkenes. b, Alkene isomerization that leads to a mixture of constitutional isomeric products. c, Design of a cationic iridium catalyst and an ammonia surrogate based on 2-aminopyridine to achieve asymmetric hydroamination of internal alkenes. OA, oxidative addition. RE, reductive elimination.

Fig. 2. Development of asymmetric hydroamination of unactivated internal alkenes with 2-amino-6-methylpyridine as an ammonia surrogate.

a, Identification of suitable ammonia surrogates to enable hydroamination of unactivated internal alkenes. b, Identification of reaction conditions to achieve asymmetric hydroamination and to suppress alkene isomerization. ^aCombined yield. ^bNo reaction. ^cDefined as A/(A+B+C). ^d4-Selectivity defined as 1/(1+1’+1”). ^eConditions: 2.5 mol% [Ir(coe)₂Cl]₂, ligand, NaBARF, toluene, 100 °C. ^fConditions: 5 mol% [L*Ir(COD)]X, toluene, 120 °C. ^gin 2-MeTHF.

Fig. 3. Scope of internal alkenes that undergo the hydroamination.

a, Scope of asymmetric hydroamination of acyclic internal alkenes. b, Scope of hydroamination of simple cycloalkenes and of asymmetric hydroamination of substituted cyclic alkenes. c, Products from removal of the 2-(6-methyl)pyridyl group. ^a2.5 mol% catalyst. ^b7.5 mol% catalyst. ^c20 mol% catalyst. ^dConditions: 2.5 mol% [Ir(coe)₂Cl]₂, 7.5 mol% (S)-DTBM-SEGPHOS, 6 mol% NaBARF, 1,4-dioxane, 120 °C. ^eConditions: PtO₂, HCl, H₂ (1 atm); NaBH₄, THF/EtOH. ^fEnantioselectivities were determined after conversion to the original hydroamination product by palladium-catalyzed cross coupling of the primary amine with 2-bromo-6-methylpyridine.

Fig. 4. Mechanistic study of the hydroamination.

a, Deuterium-labeling experiments. b, Experiments to reveal kinetic orders of each reaction component. c, Competition experiments using 2-amino-6-methylpyridine and 2-aminopyridine. d, Transition-state structures of alkene migratory insertion computed by DFT. Single-point energies were computed at the M06/6–311+G(d,p)/SDD/SMD(1,4-dioxane) level of theory with structures optimized at the B3LYP/6–31G(d)/SDD level. The ligand used for the calculations is (S)-TMS-SEGPHOS. The hydride is located trans to the amido ligand in the lowest-energy transition state (TS-1a) that leads to the (R)-enantiomer but is located trans to the pyridyl group in the lowest-energy transition state (TS-2a) that leads to the (S)-enantiomer.