N-Alkoxy-4-methyl-5-(p-anisyl)thiazole-2(3H)thiones - New Precursors for Visible Light- or Thermally-Induced Alkoxyl Radical Reactions in Synthesis

Abstract

Visible light-initiated or thermally induced N-O homolysis of hitherto unknown 4-methyl-5-(p-anisyl)-substituted N-alkoxythiazolethiones furnishes alkoxyl radicals, which have been applied in the diastereoselective synthesis of bicyclic tetrahydro­furan rac-5 (5-exo-trig cyclization), formation of erythrose derivative 8 (β-C,C cleavage), and the preparation of bromoalcohol 10 (via selective 1,5-H-translocation), optionally under tin-free conditions.

alkoxyl radical - cyclization - fragmentation - hydrogen atom transfer - thiazolethione

References

1 For a review see: Hartung J. Gottwald T. pehar K. Synthesis   2002.  p.1469 ; and references cited therein

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3 Hartung J. Gallou F. J. Org. Chem.  1995,  60:  6706 

4a Pasto DJ. Cottard F. Tetrahedron Lett.  1994,  35:  4303 

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12

Hartung, J.; Gottwald, T.; pehar, K. unpublished results.

13

Satisfactory analytical data were obtained for all new compounds in this study: N-hydroxy-4-methyl-5-(p-anisyl)thiazole-2(3H)thione, thiazolethiones 1, 3a-d, rac-4, 7, 9, and products 6, 8 and 10 from alkoxyl radical reactions.

14

N-Ethoxy-4-methyl-5-(p-methoxyphenyl)thiazole-2(3H)thione(3a): A suspension of N-hydroxy-4-methyl-5-(p-anisyl)thiazole-2(3H)thione (279 mg, 1.10 mmol) in CH₃OH (2 mL) was treated with a solution of tetraethyl-ammonium hydroxide in CH₃OH (0.73 mL, 1.5 M, 1.10 mmol). The solvent was evaporated and the remaining salt was freeze-dried. The residue was taken up in dry DMF (2 mL) and treated with ethyl iodide (2a, 156 mg, 0.07 mL, 1.00 mmol). The reaction mixture was stirred for 12 h at 20 °C. Afterwards, H₂O (7 mL) and Et₂O (5 mL) were added and the phases were separated. The aq phase was extracted with Et₂O (2 × 5 mL). The combined organic phases were dried (MgSO₄) and concentrated in vacuo to provide an oil which was crystallized from CH₃OH to furnish 180 mg (0.64 mmol, 64%) of thione 3a: pale yellow solid, mp 133 °C, R_f = 0.34 [petroleum ether/Et₂O = 2:1, (v/v)]. ¹H NMR (400 MHz, CDCl₃): δ = 1.46 (t, 3 H, ³ J = 7.1 Hz), 2.33 (s, 3 H), 3.84 (s, 3 H), 4.53 (q, 2 H, ³ J = 7.1 Hz), 6.94 (m_c, 2 H), 7.24 (m_c, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 12.1, 13.2, 55.4, 72.2, 114.6, 119.3, 122.6, 129.9, 132.2, 159.9, 178.8. UV/Vis (EtOH): λ_max (lg ε) = 334 nm (4.46), 253 (3.85), 226 (4.20); MS (EI, 70 eV): m/z (%) = 281.1 (68) [M⁺], 237.0 (100) [C₁₁H₁₁NOS₂ ⁺], 178.1 (31) [C₁₀H₁₀OS⁺], 146.1 (36) [C₁₀H₁₀O⁺], 77.0 (18) [C₆H₅ ⁺], 39.9 (12) [C₃H₄ ⁺]. C₁₃H₁₅NO₂S₂ (281.39): calcd C, 55.49; H, 5.37; N, 4.98; S, 22.79. Found: C, 55.29; H, 5.52; N, 4.92; S, 22.32.

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20 Chittenden GJF. Carbohydr. Res.  1992,  242:  297 

21

Synthesis of 1,6-cis-8-bromomethyl-7-oxabicyclo[4.3.0]nonane rac-(5): [19] (i)Preparative scale. A degassed solution of rac-N-(cis-2-allylcyclohexyloxy)-4-methyl-5-(p-methoxyphenyl)thiazole-2(3H)thione rac-(4) (188 mg, 0.50 mmol) and BrCCl₃ (934 mg, 4.71 mmol, 0.46 mL) in dry benzene (3 mL) was irradiated for 30 min in a Rayonet^® photoreactor equipped with 350 nm-light bulbs. The solvent was partially removed and the residue was purified by column chromatography [SiO₂, solvent: petroleum ether/Et₂O = 5:1 (v/v)] to provide 76.7 mg of bromomethyl-substituted tetrahydrofuran rac-5 as colorless oil (0.35 mmol, 70%, 6,8-cis:6,8-trans = 72:28); R_f = 0.77 [SiO₂, solvent: petroleum ether/Et₂O = 5:1 (v/v)].(ii) NMR-Experiment: A degassed solution of thiazolethione rac-(4) (18.8 mg, 0.05 mmol) and BrCCl₃ (93.4 mg, 0.47 mmol, 0.05 mL) in dry C₆D₆ (0.28 mL) was irradiated for 15 min with visible light (Osram^® Power Star HQI/D, 250 W). After completion of the photoreaction (TLC-control), the yield of rac-5 (8.98 mg, 41.0 µmol, 82%, 6,8-cis: 6,8-trans = 72:28) was determined by integrating its NMR resonances versus added anisole as internal standard in C₆D₆ (0.5 mL).

22

4-Methyl-5-(p-anisyl)-2-(trichloromethylsulfanyl) thiazole(6): R_f = 0.77 [SiO₂, petroleum ether/acetone = 4:1, (v/v)]. ¹H NMR (250 MHz, CDCl₃): δ = 2.59 (s, 3 H), 3.86 (s, 3 H), 6.99 (d, 2 H, J = 7.5 Hz), 7.41 (d, 2 H, J = 7.5 Hz). ¹³C NMR (63 MHz, CDCl₃): δ = 16.3, 55.4, 114.4, 123.0, 130.6, 141.6, 150.3, 160.1, 182.5. UV/Vis (CH₃CN): λ_max
(lg ε) = 324 nm (4.33). MS (EI, 70 eV): m/z (%) = 354.8 (15) [M⁺], 236.0 (100) [C₁₁H₁₀NOS₂ ⁺], 177.0 (42) [C₁₀H₉NOS₂ ⁺]. C₁₂H₁₀Cl₃NOS₂ (354.70): calcd C, 40.64; H, 2.84; N, 3.95; S, 18.08. Found: C, 40.47; H, 2.77; N, 3.75; S, 17.52. HR-MS: calcd 352.9269, found 352.9269.

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