Aromatic or Chiral Heterocycle - Balance between 1,3-Oxazoline-2-thione and 1,3-Oxazolidine-2-thione

Abstract

1,3-Oxazoline-2-thiones (OXT) and bis-1,3-oxazol­idine-2-thiones (bis-OZT) were selectively prepared depending on the conditions and starting materials used, and then underwent some N- and S-selective reactions.

hydroxyketones - 1,3-oxazoline-2-thione - 1,3-oxazol­idine-2-thione

References and Notes

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10

(4 R ,9 S )-4- tert -Butyldimethylsilyloxymethyl-3,8-dioxa-1,6-diazaspiro[4.4]nonane-2,7-dithione ( 5) Bis-OZT (S)-4 (1.01 g, 4.59 mmol) was dissolved in DMF (7 mL), TBDMSCl (1.99 g, 13 mmol) and imidazole (0.63 g, 9.3 mmol) were added and the reaction was stirred for 4 h at r.t. When the reaction was complete, the mixture was hydrolysed and extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with H₂O, brine and then dried over MgSO₄. After flash chromatography on silica gel (petroleum ether-EtOAc, 7:3), compound 5 (1.53 g) was obtained quantitatively as a solid; mp 154-157 °C; [α]_D ²⁵ +30 (c 1.0, MeOH). ¹H NMR (CDCl₃, 250 MHz): δ = 0.07 (s, 3 H, CH₃), 0.09 (s, 3 H, CH₃), 0.85 (s, 9 H, t-Bu), 3.89 (dd, 1 H, ² J = 10.8, ³ J = 7.0 Hz, CH_aH_bOSi), 3.96 (dd, 1 H, ² J = 10.8, ³ J = 6.5 Hz, CH_aH_bOSi), 4.60 (d, 1 H, ² J = 11.3 Hz, H_9a), 4.64 (d, 1 H, ² J = 11.3 Hz, H_9b), 4.87 (t, 1 H, ³ J = 6.8 Hz, H₄), 10.94 (s, 1 H, NH), 10.99 (s, 1 H, NH). ¹³C NMR (CDCl₃, 62.5 MHz): δ = -5.7 (CH₃), -5.6 (CH₃), 17.7 [(CH₃)₃ C], 25.6 [(CH₃)₃C], 59.3 (CH₂OSi), 76.0 (C₉), 81.3 (C₅), 83.9 (C₄), 186.6 (C₂ or C₇), 187.8 (C₂ or C₇). MS (IS+): m/z = 335.3 (M + H)⁺. Anal. Calcd for C₁₂H₂₂N₂O₃S₂Si: C, 43.08; H, 6.63; N, 8.37. Found: C, 42.85; H, 6.57; N, 8.31.

11

(4 R ,9 S )-2,7-Bisbenzylthio-4- tert -butyldimethylsilyloxy-methyl-3,8-dioxa-1,6-diazaspiro[4.4]nonane-1,6-diene (7); Typical Procedure Bis-OZT 5 (0.12g, 0.4 mmol) was dissolved in DMF (3 mL) and the solution was cooled to 0 °C. NaH (60%, 36 mg, 0.9 mmol) and BnBr (108 µL, 0.9 mmol) were added successively. After 3 h at r.t., the reaction mixture was hydrolysed and extracted with EtOAc (2 ×). The collected organic phases were washed with H₂O, brine and dried over MgSO₄. After the solvent was removed, the crude was purified on silica gel (petroleum ether-EtOAc; 95:5) to afford compound 7 (0.145 g, 2.82 mmol, 79% yield). [α]_D ²⁵ +9 (c 1, CH₂Cl₂). ¹H NMR (CDCl₃, 250 MHz):
δ = 0.07 (s, 3 H, CH₃), 0.08 (s, 3 H, CH₃), 0.89 (s, 9 H, t-Bu), 3.87 (dd, 1 H, ² J = 10.9, ³ J = 6.2 Hz, CH_aH_bOSi), 3.96 (dd, 1 H, ² J = 10.9, ³ J = 6.8 Hz, CH_aH_bOSi), 4.15 (d, 1 H, ² J = 9.1 Hz, H_9a), 4.28 (s, 4 H, 2 × CH ₂Ph), 4.32 (t, 1 H, ³ J = 6.6 Hz, H₄), 4.56 (d, 1 H, ² J = 9.0 Hz, H_9b), 7.28 (m, 10 H, H_Ar).
¹³C NMR (CDCl₃, 62.5 MHz): δ = -5.3 (2 × CH₃), 18.3 [(CH₃)₃ C], 25.9 [(CH₃)₃C], 36.4 (2 × CH₂Ph), 61.2 (CH₂OSi), 78.5 (C₉), 88.0 (C₄), 98.0 (C₅), 127.7-136.4 (C_Ar), 168.5 (C₂ or C₇), 168.9 (C₇ or C₂). MS (IS+): m/z = 515 (M + H)⁺. Anal. Calcd for C₂₆H₃₄N₂O₃S₂S: C, 60.66; H, 6.66; N, 5.44. Found: C, 60.37; H, 6.62; N, 5.42.

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14

OXT Formation; General Procedure Compound 14 (0.17 g, 0.54 mmol) and KSCN (1.5 equiv, 0.08 g) were dissolved in H₂O. The solution was cooled to -5 °C then HCl (1 equiv) was added. The solution obtained was maintained at 60 °C for 24 h then extracted with EtOAc (3 ×). The organic phases were further washed with H₂O (3 ×), brine and dried over MgSO₄. The residue obtained after solvent removal was purified by column chromatography (petroleum ether-EtOAc, 7:3). OXT 2f was obtained in 60% yield as a pale yellow oil; [α]_D ²⁵ -60 (c 1, MeOH). ¹H NMR (250 MHz, CDCl₃): δ = 1.79 (br s, 1 H, OH), 3.77 (dd, 1 H, J _7b,7a = 11.8, J _7b,6 = 3.8 Hz, H-7b), 3.95 (dd, 1 H, J _7a,7b = 11.8, J _7a,6 = 3.8 Hz, H-7a), 4.32 (t, 1 H, J _6,7a = 3.8, J _6,7b = 3.8 Hz, H-6), 4.37-4.63 (AB system, 2 H, = 11.7 Hz, H-8a, H-8b), 7.26 (s, 1 H, H-5), 7.30-7.43 (m, 5 H, C-H_Ar), 10.72 (s, 1 H, N-H). ¹³C NMR (CDCl₃, 62.5 MHz): δ = 64.5 (C₇), 70.3 (C₆), 71.4 (C₈), 128.1 (C₄), 128.2, 128.5, 128.8 (CAr), 134.5 (C₅), 136.5 (Cq_Ar), 179.7 (C₂). Anal. Calcd for C₁₂H₁₃NO₃S: C, 57.35; H, 5.21; N, 5.57. Found: C, 56.90; H, 5.17; N, 5.53.

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17

N-Alkylation; Typical Procedure A solution of 4-methyl-13-oxazoline-2-thione (2a; 0.100 g, 0.869 mmol) in DMF (4 mL) was cooled to -5 °C (ice-salt bath); Et₃N (0.25 mL), E-BPSE (0.27 g) and Bu₄NBr (cat.) were then added. After stirring at r.t. for 24 h, the reaction mixture was hydrolysed, then extracted with EtOAc (3 ×). The combined organic phases were washed with H₂O (3 ×), brine and dried over MgSO₄. The solvent was removed and the residue was purified by column chromatography (cyclohexane-acetone-CH₂Cl₂, 2:1:2). Compound 20 was isolated in 93% yield; mp 102-104 °C. ¹H NMR (250 MHz, CDCl₃): δ = 2.24 (s, 3 H, Me), 7.08 (s, 1 H, H-5), 7.53-7.59 (m, 2 H, CH_Ar), 7.62-7.64 (m, 1 H, CH_Ar), 7.70 (d, 1 H, J = 13.8 Hz, H-2′), 7.91-7.94 (m, 2 H, CH_Ar), 8.38 (d, 1 H, J = 13.8 Hz, H-1′). ¹³C NMR (CDCl₃, 62.5 MHz): δ = 8.9 (CH₃), 120.2 (C_{2 ′}), 126,4 (C₄), 127.5, 129.5, 131.7 (C_Ar), 132.3 (C₅), 133.7 (C_{1 ′}), 140.4 (C_qAr), 177.1 (C₂). Anal. Calcd for C₁₂H₁₁NO₃S₂: C, 51.23; H, 3.94; N, 4.98. Found: C, 50.93; H, 3.92; N, 5.01.