Diastereodivergent Synthesis of Bromoiminolactones: Electrochemical and Chemical Bromoiminolactonization of α-Allylmalonamides

Published as part of the Cluster Electrochemical Synthesis and Catalysis

Abstract

A diastereodivergent synthesis of N-substituted iminolactones by bromoiminolactonization of α-substituted α-allylmalonamides is reported. Whereas bromocyclization under conventional chemical conditions provided cis-bromoiminolactones, electrochemical conditions exhibited complementary diastereoselectivity to afford the trans-products. A variety of substituents on the nitrogen atoms and an α-position of the malonamide were tolerated under both sets of conditions to afford the corresponding iminolactones in excellent yields and high diastereoselectivities.

Key words

diastereodivergent synthesis - electrochemical synthesis - N-bromosuccinimide - iminolactones - malonamides - bromoiminolactonization

• References and Notes

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• 23 Bromoiminolactonization of Compounds 1; General Procedure under Chemical Conditions NBS (178 mg, 2.0 equiv) was added to a solution of 1 (0.5 mmol) in toluene (6 mL), and the mixture was stirred at rt until all the starting material was consumed (TLC). The reaction was quenched with sat. aq Na₂S₂O₃, and the resulting mixture was extracted with EtOAc. The combined organic layers were dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, hexane–EtOAc] to afford 2 and 2′. Bromoiminolactonization of Compounds 1; General Procedure under Electrochemical Conditions In a beaker-type undivided cell, substrate 1 (0.5 mmol), Et₄NBr (322 mg, 2.0 equiv), Zn(OTf)₂ (18.2 mg, 10 mol%), and 2,2′-bipyridine (7.8 mg, 10 mol%) were dissolved in CH₂Cl₂ (6 mL), and the mixture was stirred for 20 min. The reaction vessel was fitted with a Pt plate electrode (1.0 × 2.0 cm²), and 4 F/mol of electricity was supplied under constant-current conditions (20 mA). The reaction was then quenched with sat. aq Na₂S₂O₃ and the resulting mixture was extracted with CH₂Cl₂. The combined organic layers were dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, hexane–EtOAc] to afford 2 and 2′. (cis)-5-(Bromomethyl)-3-ethyl-N-phenyl-2-(phenylimino)tetrahydrofuran-3-carboxamide (2b) (Prepared under Chemical Conditions) Colorless oil; yield: 187 mg (93%). IR (ATR): 692, 756, 1198, 1445, 1487, 1551, 1599, 1686, 3065 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 10.66 (s, 1 H), 7.59 (dd, J = 8.5, 1.2 Hz, 2 H), 7.39–7.32 (m, 4 H), 7.26–7.24 (m, 2 H), 7.18–7.14 (m, 1 H), 7.13–7.09 (m, 1 H), 4.76–4.69 (m, 1 H), 3.50 (d, J = 5.4 Hz, 2 H), 2.79 (dd, J = 13.9, 8.0 Hz, 1 H), 2.48 (dd, J = 13.7, 6.8 Hz, 1 H), 2.19–2.05 (m, 2 H), 1.10 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 163.0, 144.5, 137.8, 128.9, 128.7, 124.8, 124.1, 123.2, 119.5, 78.1, 56.5, 35.0, 34.9, 33.7, 9.25. HRMS (EI): m/z [M]⁺ calcd for C₂₀H₂₁ ⁸¹BrN₂O₂: 402.0766; found: 402.0763. (trans)-5-(Bromomethyl)-3-ethyl-N-phenyl-2-(phenylimino)tetrahydrofuran-3-carboxamide (2b′) (Prepared under Electrochemical Conditions) Colorless oil; yield: 146 mg (73%). IR (ATR): 692, 756, 1198, 1443, 1489, 1541, 1599, 1684, 3323 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.49 (s, 1 H), 7.56 (d, J = 8.3 Hz, 2 H), 7.37–7.33 (m, 4 H), 7.23 (t, J = 9.0 Hz, 2 H), 7.16–7.10 (m, 2 H), 4.62–4.56 (m, 1 H), 3.66 (dd, J = 10.7, 4.8 Hz, 1 H), 3.57 (dd, J = 11.2, 3.9 Hz, 1 H), 3.34 (dd, J = 13.2, 6.3 Hz, 1 H), 2.32–2.22 (m, 1 H), 2.10–1.96 (m, 2 H), 1.05 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 167.0, 163.6, 145.1, 137.7, 129.0, 128.7, 124.6, 124.3, 123.1, 119.3, 78.6, 58.3, 34.0, 33.6, 33.1, 9.5. HRMS (EI): m/z [M]⁺ calcd for C₂₀H₂₁ ⁸¹BrN₂O₂: 402.0766; found: 402.0763.