ORGANIC CHEMISTRY. Catalytic asymmetric hydroamination of unactivated internal olefins to aliphatic amines

Abstract

Catalytic assembly of enantiopure aliphatic amines from abundant and readily available precursors has long been recognized as a paramount challenge in synthetic chemistry. Here, we describe a mild and general copper-catalyzed hydroamination that effectively converts unactivated internal olefins—an important yet unexploited class of abundant feedstock chemicals—into highly enantioenriched α-branched amines (≥96% enantiomeric excess) featuring two minimally differentiated aliphatic substituents. This method provides a powerful means to access a broad range of advanced, highly functionalized enantioenriched amines of interest in pharmaceutical research and other areas.

Fig. 1. Proposed asymmetric hydroamination of unactivated internal olefins to access enantioenriched branched aliphatic amines

(A) Advantageous properties of the reaction profile. (B): DFT-calculated activation barriers for the hydrocupration of olefins 1a–d. Energies are computed at the M06/SDD-6-311+G(d,p)/SMD(THF) level with geometries optimized at the B3LYP/SDD-6-31G(d) level. (C): Proposed catalytic cycle. (D): Optimization studies. Reactions were performed using 4 (0.60 mmol), 5 (0.20 mmol), (MeO)₂MeSiH (0.60 mmol), Cu(OAc)₂ (5 mol %), L (5.5 mol %) in THF (1.0 M) at 45 °C for 36 h. Yields were determined by GC analysis using dodecane as the internal standard.

Fig. 2. Substrate scope of the copper-catalyzed enantioselective hydroamination of internal olefins

(A): Asymmetric hydroamination of 2-butene with a variety of electrophilic amines. (B): Scope of symmetrical internal olefins. (C): Deuterium Incorporation. (D): Regioselectivity in the hydroamination of unsymmetrical internal olefins. Yields refer to isolated yields on the average of two runs. Enantiomeric excesses were determined by chiral HLPC analysis or using Swager’s protocol (37). * Yield in parentheses was determined by ¹H NMR analysis. † Reaction was performed on a 5 mmol scale with 1 mol % Cu(OAc)₂, 1.1 mol % (S)-DTBM-SEGPHOS and 2 mol % PPh₃. ‡ Ph₂SiD₂ was used in lieu of (MeO)₂SiMeH. d.r. = diastereomeric ratio.

Fig. 3. Diversification of pharmaceutical agents

Conditions: a. 5 mol % Cu(OAc)₂, 5.5 mol % (S)-DTBM-SEGPHOS, (MeO)₂MeSiH, internal olefin, THF, 45 °C. b. (R)-DTBM-SEGPHOS was used instead of (S)-DTBM-SEGPHOS. TFP = 2-(5-trifluoromethyl)pyridyl.

Fig. 4. Transition state structures of the enantioselectivity-determining hydrocupration step

Energies are computed at the M06/SDD-6-311+G(d,p)/SMD(THF) level with geometries optimized at the B3LYP/SDD-6-31G(d) level.