Rhodium-Catalyzed Asymmetric Hydrogenation of N-(1-benzylpiperidin-3-yl)-enamides: An Efficient Access to Valuable Enantioenriched 3-Aminopiperidine Derivatives

Abstract

An efficient synthetic entry to enantioenriched 3-aminopiperidine derivatives using rhodium-catalyzed asymmetric hydrogenation of N-(1-benzylpiperidin-3-yl)enamides is described. This method provides an atom-economical and attractive route to both enantiomers of the valuable 3-aminopiperidine moiety, which is an important structural unit that can be found in many natural products and pharmaceutical drugs encompassing a broad range of biological activities. Under optimized reaction conditions, the targeted 3-aminopiperidine derivatives were obtained in high yields up to 92% and with enantiomeric excesses up to 96% after a single crystallization.

Key words

rhodium - asymmetric hydrogenation - enamide - synphos - 3-aminopiperidine

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• 14 Typical Procedure for the Asymmetric Hydrogenation of 1a The rhodium complex [Rh(cod)₂]⁺BF₄ ^– (3.0 mg, 0.0074 mmol, 1% mol) and the (S)-SYNPHOS ligand (0.0081 mmol, 1.1% mol) were placed in a tubular reactor under argon. THF was added (3 mL), and the solution was stirred at room temperature for 30 min after three vacuum/argon cycles. The enamide 1a (1 equiv) was then added in one portion, and the reactor was put in a stainless steel autoclave after three vacuum/argon cycles. The hydrogenation was performed at 50 °C under 20 bar of hydrogen pressure for 40 h. After careful releasing of the hydrogen gas, the reaction mixture was concentrated under vacuum, and the residue was purified by flash column chromatography on silica gel to give the 3-aminopiperidine derivative (R)-2a. N-(1-Benzylpiperidin-3-yl)benzamide [(R)-2a] White solid; yield 270.5 mg (92%); mp 133 °C; R_f = 0.4 (EtOAc); [α]_D ²⁰ +2.6 (c 1, MeOH). ¹H NMR (300 MHz, CDCl₃): δ = 7. 79 (t, J = 7.8 Hz, 2 H), 7.55–7.39 (m, 3 H), 7.39–7.18 (m, 5 H), 6.87 (s, 1 H), 4.28 (s, 1 H), 3.58 (d, J = 13.0 Hz, 1 H), 3.47 (d, J = 13.1 Hz, 1 H), 2.60–2.70 (m, 2 H), 2.52–2.13 (m, 2 H), 1.63–1.80 (m, 2 H), 1.61–1.42 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 155.6, 136.7, 129.1, 128.5, 128.3, 128.2, 128.1, 127.3, 66.5, 63.0, 58.2, 53.4, 46.7, 29.3, 21.8. MS (CI, NH₃): m/z = 295 [M + H]⁺. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₉H₂₂N₂ONa⁺: 317.1630; found: 317.1624. The enantiomeric excess of (R)-2a was determined by SFC (Chiralcel AD-H, scCO₂/MeOH = 90:10 + 0.1% Et₃N, 4 mL/min, P = 150 bar, λ = 215 nm): t _R (S) = 5.76 min (minor), t _R (R) = 7.17 min (major, ee 92.5%), upgraded to 96% ee after a single crystallization in EtOH.