Approach to 3-(Cyclo)alkylpiperidines through ‘sp³–sp³ via sp²–sp³’ Coupling

Abstract

The idea of introducing (cyclo)alkyl substituents at the C-3 atom of the piperidine ring, that is, formal sp³–sp³ retrosynthetic disconnection, is implemented through a two-step reaction sequence including directed ortho metalation of a pyridine derivative and the subsequent quenching with a carbonyl compound, followed by catalytic hydrogenation. This robust but very efficient method allows for multigram preparation of sp³-rich 3-(cyclo)alkylpiperidines, which are valuable building blocks for medicinal chemistry and other areas.

Key words

heteroaliphatic compounds - alicyclic compounds - lead-oriented synthesis - catalytic hydrogenation - piperidines

• References and Notes

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• 17 Representative Procedure for the Preparation of 2 1-(2-Bromopyridin-3-yl)cyclopentanol (2a)To a cooled (–78°С) solution of diisopropylamine (18.3 g, 25.4 mL, 0.181 mol) in absolute THF (700 mL), n-BuLi (69 mL, 23% in hexane, 2.5 M, 0.172 mol) was added dropwise under argon atmosphere. The mixture was stirred at –78 °C for 1 h, and a solution of 2-bromopyridine (23.1 g, 14.3 mL, 0.146 mmol) in dry THF (150 mL) was added dropwise over 20 min. The reaction mixture was kept at –78 °С for 90 min, and precooled (–78 °С) solution of cyclopentanone (26.6 g, 28 mL, 0.316 mol) in dry THF (70 mL) was added in one portion. The mixture was stirred at –78 °С for additional 80 min and quenched with sat. aq NaHCO₃ (140 mL) at –78°С, then warmed to r.t. and diluted with EtOAc (1 L). The organic phase was separated, washed with sat. aq NaHCO₃ (2 × 150 mL) and brine (200 mL), dried over Na₂SO₄, and concentrated in vacuo to give 22.5 g of residue. The product was purified by flash chromatography (gradient hexane–EtOAc as an eluent), followed by recrystallization from pentane. The sample of 2a of analytical purity was obtained by additional recrystallization from hexanes. Yield 14.2 g (40%); white needles; mp 80–82 °C (hexanes). MS (ESI): m/z = 242/244 [MH⁺]. Anal. Calcd for C₁₀H₁₂BrNO: C, 49.61; H, 5.00; Br, 33.00; N, 5.79. Found: C, 49.37; H, 5.27; Br, 32.74; N, 5.70. ¹H NMR (400 MHz, CDCl₃): δ = 8.22 (d, J = 3.6 Hz, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.31–7.19 (m, 1 H), 2.65 (br s, 1 H), 2.39–2.25 (m, 2 H), 2.18–2.05 (m, 2 H), 2.05–1.93 (m, 2 H), 1.91–1.80 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 147.5 (CH), 141.6 (C), 140.9 (C), 135.8 (CH), 122.18 (CH), 82.2 (C), 39.3 (CH₂), 23.7 (CH₂).
• 18 The detailed results on the optimization will be published in the upcoming full paper.
• 19 Representative Procedure for the Preparation of 1 3-Cyclopentylpiperidine (1a)A mixture of 10% Pd/C (5.0 g, 50% wet with H₂O for safety, unreduced), MeOH (400 mL), pyridine 2a (25.1 g, 0.103 mol), and concentrated aq HCl (2.5 mL, 0.03 mol), was placed in an autoclave and hydrogenated at 40 bar of H₂ and 85 °C for 64 h. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 24.6 g of the residue. It was dissolved in H₂O (150 mL), 20% aq NaOH (50 mL) was added, and the mixture was extracted with hexanes (2 × 80 mL). The combined organic phases were dried over NaOH and evaporated in vacuo. The crude product was distilled in vacuo (bp 94–96 °C/10 mbar) to give the product 1a; yield 13.8 g (87%); colorless liquid; bp 94–96 °C/10 mbar. MS (ESI): m/z = 154 [MH⁺]. Anal. Calcd for C₁₀H₁₉N: C, 78.37; H, 12.50; N, 9.14. Found: C, 78.03; H, 12.71; N, 8.96. ¹H NMR (400 MHz, CDCl₃): δ = 3.07–2.99 (m, 1 H), 2.97–2.89 (m, 1 H), 2.46 (td, J = 11.9, 2.9 Hz, 1 H), 2.21 (dd, J = 11.9, 10.4 Hz, 1 H), 2.04 (br s, 1 H), 1.85–1.77 (m, 1 H), 1.75–1.63 (m, 2 H), 1.63–1.48 (m, 3 H), 1.48–1.31 (m, 4 H), 1.20–1.10 (m, 1 H), 1.10–0.93 (m, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 51.9 (CH₂), 46.7 (CH₂), 44.0 (CH), 42.9 (CH), 30.2 (CH₂), 30.1 (CH₂), 30.0 (CH₂), 26.5 (CH₂), 24.9 (CH₂), 24.7 (CH₂).