Enantioselective Bromolactonization of Deactivated Olefinic Acids­: Studies Toward the Synthesis of Brominated Isochroman-1,4-diones

^† These authors contributed equally to this work.

Abstract

Enantioselective bromolactonization using an amino-carbamate­ catalyst to generate brominated isochroman-1,4-diones is described. Excellent yields and moderate enantioselectivities were achieved.

Key words

isochroman-1,4-diones - bromolactonization - organocatalysis - enantioselectivity - deactivated olefins

• References and Notes

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• 8 Representative Procedure for Generating α,β-Unsaturated Ketone 4a : To a solution of keto acid A (3.0 mmol, 1.0 equiv) in acetic acid (6 mL) was added pyrrolidine (0.1 mL, 1.2 mmol, 0.4 equiv) and formaldehyde solution (36.5–38% in H₂O, 1 mL, 13.2 mmol, 4.4 equiv) at room temperature. The mixture was then stirred for 48 h at 85 °C. After evaporation of the acetic acid, water and EtOAc were added. The organic layer was washed with water, dried over magnesium sulphate and filtered. Concentration of the organic layer afforded the crude product, which was further purified by flash column chromatography (hexane/EtOAc) to give the corresponding α,β-unsaturated ketone 4a. Yield: 427.5 mg (75%); yellow solid; mp 125–126 °C; ¹H NMR (CDCl₃, 300 MHz): δ = 10.84 (br/ s, 1 H), 8.09–7.33 (m, 4 H), 5.80 (s, 1 H), 5.30 (s, 1 H), 2.07 (s, 3 H); ¹³C NMR (CDCl₃, 75 MHz): δ = 199.2, 170.9, 145.9, 142.7, 133.2, 130.8, 129.4, 127.8, 127.7, 127.6, 17.4; HRMS (TOF⁻): m/z [M – 1]^– calcd for C₁₁H₉O₃: 189.0562; found: 189.0561
• 9 Representative Procedure for Generating Isochroman-1,4-dione 5a : To a solution of α,β-unsaturated ketone 4a (38 mg, 0.2 mmol, 1.0 equiv) and catalyst 15s (14.6 mg, 0.03 mmol, 0.15 equiv)in toluene (8 mL), at 15 °C, in the dark under nitrogen was added NBS (46 mg, 0.26 mmol, 1.3 equiv). The resulting mixture was stirred at 15 °C and monitored by TLC. The reaction was quenched with saturated Na₂SO₃ (1 mL) at 15 °C and then was allowed to warm to room temperature. The mixture was diluted with water (3 mL), extracted with EtOAc, dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/EtOAc) to yield the corresponding isochroman-1,4-dione 5a. Yield: 53.1 mg (99%); yellow oil; [α]_D ²⁵ = 4.9 (c 1.0, MeOH, 73:27 er); ¹H NMR (CDCl₃, 300 MHz): δ = 8.32–7.83 (m, 4 H), 3.99 (dd, J ₁ = 9.0 Hz, J ₂ = 93.0 Hz, 2 H), 1.78 (s, 3 H); ¹³C NMR (CDCl₃, 75 MHz): δ = 192.3, 160.9, 135.9, 134.7, 130.7, 130.6, 126.6, 126.4, 87.6, 37.4, 25.4; HRMS (TOF⁺): m/z [M + H]⁺ calcd. for C₁₁H₁₀BrO₃: 269.1377; found: 269.1378; HPLC (Daicel Chiralcel AD-H; i-PrOH/hexane = 10:90, 1.0 mL/min, 254 nm): t ₁ = 8.6 min (major), t ₂ = 9.5 min (minor)