Stereoselective Synthesis of Densely Substituted Tetrahydroquinolines by a Conjugate Addition Nitro-Mannich Reaction with Carbon Nucleophiles

Dedicated to my friend and mentor Professor Steven V. Ley for his guidance and inspiration

Abstract

Conjugate addition of an alkyl group to a series of 2-imino-nitrostyrenes and then addition of trifluoroacetic acid initiates a nitro-Mannich cyclisation to give cis,cis-2,3,4-substituted tetrahydroquinolines in good yield and high diastereoselectivity.

Key words

amines - stereoselective synthesis - cyclisation - imines - quinolines

• References and Notes


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• 14 A solution of 5 (0.25 mmol) and Cu(OTf)₂ (5 mol%) in Et₂O (2.5 mL) was cooled to –78 °C over 30 min. A solution of ZnEt₂ (0.375 mL of a 1.0 M solution in hexanes, 1.5 equiv) was added and the mixture stirred for up to 1 h and then stirred for up to 2 h at r.t. The resulting suspension was recooled to –78 °C over 30 min, and TFA (2.5 equiv) was added dropwise, stirred for up to 1 h and then stirred for up to 1 h at r.t. The reaction was then quenched with sat. aq NaHCO₃ (50 mL), extracted with EtOAc or CH₂Cl₂ (3 × 30 mL), the combined organic layers washed with brine (100 mL), dried (Na₂SO₄), and concentrated in vacuo to give the crude tetrahydroquinoline 6. Purification by column chromatography gave the pure tetrahydroquinoline 6. Analytical Data for 6a Yield 44 mg, 62%; R_f  = 0.33 (1:1 CH₂Cl₂–hexanes). IR (neat): ν_max = 3416 (NH), 1545 (NO), 1368 (NO) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.32–7.45 (m, 5 H, ArH), 7.08–7.16 (m, 2 H, ArH), 6.82 (t, J = 7.5 Hz, 1 H, ArH), 6.68 (dd, J = 7.9, 1.3 Hz, 1 H, ArH), 4.98 (app. t, J = 2.9 Hz, 1 H, CHNO₂), 4.76 (d, J = 3.3 Hz, 1 H, CHPh), 4.25 (s, 1 H, NH), 3.20 (ddd, J = 8.3, 5.3, 2.4 Hz, 1 H, CHEt), 1.69–2.01 (m, 2 H, CH ₂CH₃), 1.12 (t, J = 7.4 Hz, 3 H, CH₂CH ₃). ¹³C NMR (151 MHz, CDCl₃): δ = 142.5 (ArC), 138.1 (ArC), 129.4 (ArCH), 129.1 (ArCH), 129.1 (ArC), 127.6 (ArCH), 126.8 (ArCH), 121.2 (ArCH), 118.8 (ArCH), 114.7 (ArCH), 86.8 (CH), 54.6 (CH), 41.8 (CHEt), 30.7 (CH₂CH₃), 11.6 (CH₂ CH₃). ESI-MS: m/z (%) = 234 (100) [M – H₃NO₂ ⁺], 45) [M + H⁺]. HRMS: m/z calcd for C₁₇H₁₉N₂O₂: 283.1447; found: 283.1448.
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