Enantioselective Construction and Transformations of Poly­functionalized 3,4-Dihydro-2H-thiopyrano[2,3-b]quinolines

Abstract

We developed an enantioselective organocascade Michael/Henry reaction in the presence of a bifunctional organocatalyst to construct chiral polyfunctionalized 3,4-dihydro-2H-thiopyrano[2,3-b]quinolines. The resulting optically active products with three contiguous stereocenters, one quaternary and two tertiary, were obtained in moderate to good yields and with good to excellent enantioselectivities. Remarkably, the resulting products were readily converted into polyfunctionalized optically active furo[2′,3′:4,5]thiopyrano[2,3-b]quinoline, 3,4-dihydro-2H-thiopyrano[2,3-b]quinoline 1-oxide and 2,3-dihydro-4H-thiopyrano[2,3-b]quinolin-4-one derivatives.

Key words

Domino reaction - Michael addition - Henry reaction - thiopyranoquinolines - polyheterocycles - cascade reaction

• References and Notes


For selected examples of the Michael/Henry reaction
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• 12 (3aS,4R,11bR)-2-Amino-3a-nitro-4-phenyl-3a,11b-dihydro-4H-furo[2',3':4,5]thiopyrano[2,3-b]quinoline-3-carbonitrile (4aa): Typical Procedure A mixture of 3aa (42 mg, 0.10 mmol), malononitrile (20 mg, 0.30 mmol), and DBU (0.10 mmol) in THF (1 mL) was stirred at r.t. for 2 d. The product was directly purified by flash chromatography (silica gel, 10% EtOAc–PE) to give a white solid; yield: 27 mg (67%, >99% ee); mp 213–215 °C; [α]_D ²⁵ +16.37 (c 0.5, THF). HPLC: Chiralpak OD column (15% i-PrOH–hexanes, 1 mL/min); t _major = 22.07 min, t _minor = 28.92 min. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.43 (s, 1 H), 7.99 (dd, J = 8.2, 1.4 Hz, 1 H), 7.88–7.83 (m, 1 H), 7.76 (ddd, J = 8.4, 6.8, 1.5 Hz, 1 H), 7.68–7.62 (m, 2 H), 7.56 (ddd, J = 8.1, 6.8, 1.3 Hz, 1 H), 7.45–7.34 (m, 3 H), 6.72 (d, J = 5.7 Hz, 1 H), 6.15 (dd, J = 11.4, 2.5 Hz, 1 H), 5.54–5.45 (m, 2 H). ¹³C NMR (151 MHz, DMSO-d ₆): δ = 156.3, 147.1, 141.3, 134.8, 131.9, 131.0, 130.0, 129.6, 129.1, 128.1, 127.3, 126.5, 126.5, 125.9, 125.9, 112.6, 110.8, 91.9, 75.2, 70.5, 45.7. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₁H₁₅N₄O₃S: 403.0865; found: 403.0854
• 13 (2R,3R,4R)-3-Bromo-3-nitro-2-phenyl-3,4-dihydro-2H-thiopyrano[2,3-b]quinolin-4-ol 1-oxide (6aa); Typical Procedure A mixture of 3aa (42 mg, 0.10 mmol), and m-CPBA (26 mg, 0.15 mmol) in THF (1 mL) was stirred at 0 °C for 5 h. The product was purified directly by flash chromatography (silica gel 1% MeOH–CH₂Cl₂) to give a white solid; yield: 37 mg (84%, 99% ee); mp 206–208 °C; [α]_D ²⁵ +93.71 (c 0.5, THF). HPLC: Chiralpak OD column (15% i-PrOH–hexane, 1 mL/min); t _major = 20.68 min, t _minor = 12.46 min. ¹H NMR (600 MHz, DMSO-d ₆): δ = 8.68 (s, 1 H), 8.26 (d, J = 7.8 Hz, 1 H), 8.21 (d, J = 8.3 Hz, 1 H), 7.97 (qd, J = 7.3, 3.8 Hz, 1 H), 7.85–7.81 (m, 1 H), 7.77 (s, 1 H), 7.72–7.69 (m, 2 H), 7.54 (dd, J = 3.8, 2.6 Hz, 3 H), 6.43 (s, 1 H), 6.19 (s, 1 H). ¹³C NMR (151 MHz, DMSO-d ₆): δ = 158.8, 147.0, 137.0, 132.4, 132.1, 130.6, 130.5, 130.3, 129.7, 129.3, 129.0, 128.9, 128.3, 106.8, 75.3, 68.8. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₈H₁₄BrN₂O₄S: 432.9852; found: 432.9854.