Imine Domino Reactions Generate Novel Scaffolds: Fused Bisthiazolidines or Bisthiiranes

Abstract

Novel domino processes that involve sequential reactions via iminium ions derived from β-amino thiols or β-amino alcohols were developed to form bisthiazolidines or bisthiiranes, respectively. The heterocycles were synthesized from readily available starting materials, forming four new chemical bonds in one process without the use of metals. The regioselectivity of the transformation could be explained on the basis of calculations of the coefficients of the frontier orbitals.

Key words

bicycles - fused thiazolidines - thiiranes - cycloadditions - iminium ions

References and Notes

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11

Representative Procedure for the Preparation of Bisthiazolidines: Synthesis of anti -1a
To a stirred suspension of cysteamine˙HCl (3a, 0.32 g,
2.8 mmol) in EtOH (15 mL) was added Et₃N (0.39 mL, 2.8 mmol), 1,4-dithiane-2,5-dithiol 4 (0.51 g, 3.4 mmol), and
p-TsOH (0.025 g, 0.12 mmol). The mixture was heated at reflux for 2 h. Then, it was cooled and poured into a sat. solution of NaCl (15 mL), extracted with CH₂Cl₂ (5 × 30 mL), dried (Na₂SO₄), and filtered. The solvent was removed under reduced pressure, and the residue was purified by chromatography on SiO₂ (EtOAc-hexanes = 1:6) to afford 1a (0.42 g, 78%, anti/syn = 92:08) as an oil (anti-1a). ^¹H NMR (400 MHz, CDCl₃): δ = 4.97 (dd, J = 5.2, 3.7 Hz, 1 H), 4.24 (dd, J = 7.0, 6.0 Hz, 1 H), 3.54 (ddd, J = 11.6, 5.2, 0.5 Hz, 1 H), 3.48 (ddd, J = 11.5, 5.7, 4.8 Hz, 1 H), 3.21 (ddd, J = 11.5, 7.2, 6.6 Hz, 1 H), 3.12 (m, 1 H), 3.08 (m, 2 H), 2.82 (ddd, J = 13.6, 7.6, 7.0 Hz, 1 H), 2.65 (ddd, J = 13.6, 9.1, 6.0 Hz, 1 H), 1.84 (dd, J = 9.1, 7.6 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 74.5, 73.2, 57.1, 38.4, 33.5, 31.8. HRMS: m/z calcd for C₆H₁₂NS₃ [M + H]⁺: 194.0132; found: 194.0156.

12

Representative Procedure for the Preparation of Bisthiiranes: Synthesis of 2a To a stirred solution of ethanolamine (5a, 0.30 g, 4.1 mmol) in EtOH (8 mL) was added 1,4-dithiane-2,5-dithiol 4 (0.70 g, 4.9 mmol) and p-TsOH (3 mg, 0.17 mmol). The mixture was heated at reflux for 1.30 h, and stirred overnight at r.t. under N₂. Then, it was cooled and poured into a sat. solution of NaCl, extracted with EtOAc (5 × 30 mL), dried (Na₂SO₄), and filtered. The solvent was removed under reduced pressure, and the residue was purified by chromatography on SiO₂ (EtOAc-hexanes = 1:1) to afford 2a (0.48 g, 66%) as an oil. ^¹H NMR (400 MHz, CDCl₃): δ = 4.91 (d, J = 3.0 Hz, 2 H), 3.72 (m, 2 H), 3.35 (dd, J = 9.5, 3.0 Hz, 2 H), 3.25 (d, J = 9.5 Hz, 2 H), 2.72 (m, 1 H), 2.59 (m, 1 H), 2.39 (t, J = 9.9 Hz, 1 H, OH). ^¹³C NMR (101 MHz, CDCl₃): δ = 70.0, 60.5, 50.7, 43.9. HRMS: m/z calcd for C₆H₁₂NOS₂ [M + H]⁺: 178.0360; found: 178.0350.