Diastereoselective Synthesis of γ-Lactams and δ-Lactams via a Conjugate Addition-Initiated Tandem Reaction

Abstract

β-Alkoxycarbonyl-γ-lactams and γ-alkoxycarbonyl-δ-lactams were synthesized via a conjugate alkylation/Mannich reaction/lactamization tandem reaction of unsaturated dicarboxylates with diethyl zinc and aldimines. The high yield, the ready availability of the reagents, and especially the high diastereoselectivity are promising characteristics of the approach that allows access to functionalized lactams.

Key words

tandem reaction - conjugate addition - Mannich reaction - lactamization - conjugate alkylation - diastereoselectivity

• References and Notes

• 1 Present address: Houbo College, Xinjiang Medical University, Karamay 834000, P. R. of China
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• 13 A Representative Procedure: Under a nitrogen atmosphere, ZnEt₂ (1.0 mol/L, 1.2 mL, 1.2 mmol) was added dropwise to a stirred solution of dimethyl fumarate (130 mg, 0.90 mmol) and imine 2a (109 mg, 0.60 mmol) in a 1:1 mixture of THF/toluene (2.0 mL) at room temperature, and the mixture was stirred for 6 h. Then the reaction was quenched by adding saturated aqueous ammonium chloride (2 mL), followed by adding dilute hydrogen chloride (2 mol/L, 2 mL). After phase separation, the aqueous phase was extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with aqueous sodium bicarbonate (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, 20:1–3:1) to give the lactam isomers. trans,trans-3aa: Colorless solid; mp 79–81 °C; R_f = 0.30 (EtOAc/PE, 10:90). ¹H NMR (500 MHz, CDCl₃): δ = 7.32 (d, J = 7.9 Hz, 2 H), 7.29–7.16 (m, 7 H), 7.04 (t, J = 7.3 Hz, 1 H), 5.44 (d, J = 7.5 Hz, 1 H), 3.74 (s, 3 H), 3.01–2.93 (m, 1 H), 2.90 (t, J = 8.6 Hz, 1 H), 2.09–1.97 (m, 1 H), 1.89–1.80 (m, 1 H), 1.05 (t, J = 7.4 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 173.86, 173.23, 139.88, 137.43, 129.10, 128.73, 128.29, 126.70, 125.49, 123.40, 64.08, 52.64, 52.55, 47.78, 23.65, 10.72. HRMS: m/z [M + Na]⁺ calcd for C₂₀H₂₁NO₃Na⁺: 346.1408; found: 346.1419. trans,cis-3aa: Colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 7.44 (d, J = 8.0 Hz, 2 H), 7.36–7.22 (m, 7 H), 7.08 (d, J = 7.2 Hz, 1 H), 5.42 (d, J = 3.7 Hz, 1 H), 3.75 (s, 3 H), 3.28 (dd, J = 8.4, 4.1 Hz, 1 H), 2.93 (dt, J = 14.0, 7.2 Hz, 1 H), 2.05–1.90 (m, 1 H), 1.61–1.47 (m, 1 H), 1.04 (t, J = 7.4 Hz, 3 H). HRMS: m/z [M + Na]⁺ calcd for C₂₀H₂₁NO₃Na⁺: 346.1408; found: 346.1413
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This does not conclusively rule out other mechanisms; for example, a radical-polar mechanism, as one referee suggested, might be triggered by radical initiator introduced adventitiously, see:
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• 19 CCDC 1896065 and 1896064 contain the supplementary crystallographic data for this paper (major isomers of 5a and 5h, respectively). The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.