A Practical Synthetic Pathway to Polysubstituted Tetrahydropyridines via Multicomponent Reactions Catalyzed by BF₃·OEt₂

Abstract

BF₃·OEt₂-catalyzed solvent-free synthesis of tetrahydropyridines has been developed through a one-pot multicomponent reaction of aldehydes, anilines and Brassard’s diene under mild reaction conditions. A gram scale synthesis was achieved in 62% yield. A two-step condensation pathway (firstly aldol and then aza Diels-Alder condensation) was proposed.

Key words

BF₃·OEt₂ - tetrahydropyridine - multicomponent reaction - aldol condensation - aza Diels-Alder condensation

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13

A Typical Procedure for Synthesis of 4a.
Brassard’s diene (0.7 mmol) and BF₃·OEt₂ (0.1 mmol) were successively added to a mixture of benzaldehyde (0.2 mmol) and aniline (0.2 mmol). The reaction mixture was stirred for 8 h at r.t., and then quenched with sat. aq NaHCO₃ (10 mL), extracted with CH₂Cl₂ (3 × 10 mL). The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography with eluent of hexane-EtOAC (10:1, v/v) to give the desired product 4a as white crystal (mp 162-164 °C) in 85% yield. ¹H NMR (400 MHz CDCl₃): δ = 10.27 (s, 1 H), 7.25-6.31 (m, 19 H), 5.10 (d, J = 4.8 Hz, 1 H), 3.92 (s, 3 H), 3.76 (s, 3 H), 3.71 (s, 3 H), 2.91 (m, 1 H), 2.76 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 168.5, 159.8, 159.5, 156.4, 146.8, 145.8, 144.5, 137.8, 129.6, 129.1, 128.8, 125.9, 125.8, 119.0, 118.8, 116.2, 113.0, 112.9, 112.7, 111.7, 110.9, 97.5, 58.1, 55.1, 55.0, 33.4. HRMS (ESI): m/z calcd for C₃₃H₃₂N₂O₄ [M + Na⁺]: 543.2254; found: 543.2242.

15

The mixture of aldehydes and anilines will generate imines 7 in situ: see ref. 2c-e.