Efficient Synthesis of Novel Polyfunctionalised 4,5′-Bithiazol-4′-ol Derivatives

Abstract

2-Thiazolin-4-one derivatives, obtained by reaction of tert-butyl (3-methoxy-1-methyl-3-oxoprop-1-enyl)diazenecarboxylate with aryl thioamides, were transformed into 5-bromoacetyl-4-hydroxythiazole derivatives by polymer-supported reagents and simple work-up procedures. The compounds thus synthesised were coupled with thioamides bearing valuable functional groups affording novel polyfunctionalised 4,5′-bithiazol-4′-ol derivatives.

1,2-diaza-1,3-butadienes - thioamides - nucleophilic addition - cyclizations - bithiazoles

References

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9

Representative Procedure for the Synthesis of 4, 5, 7 and 8.Preparation of 4b: Compound 3b (354 mg, 1 mmol), prepared as previously reported, [2a] was suspended in a (CH₃)₂CO-H₂O mixture (9:1, 10 mL) and heated under reflux in the presence of Amberlyst 15 (500 mg) for 18 h. The resin was filtered off, washed with THF (3 × 10 mL) and, after evaporation of the solvents under reduced pressure, the solid residue was treated with Et₂O and filtered in vacuo to obtain derivative 4b with a yield of 71%. [2b]
Preparation of 5b: To a magnetically stirred solution of 4b (240 mg, 1 mmol) in CHCl₃ (20 mL) was added tribromide on Amberlyst A-26 (1.36 g) and the reaction was allowed to stand at r.t. for 24 h (monitored by TLC). The fine solid suspended in the reaction medium was filtered and furnished the first crop of compound 5b. Then, the resin was washed with THF (4 × 20 mL) and the combined filtrates were evaporated under reduced pressure to afford an additional amount of brominated product in overall yield of 69%. Data for 2-bromo-1-(4-hydroxy-2′-methyl-2,4′-bi-1,3-thiazol-5-yl)ethanone 5b: dark yellow powder from CHCl₃, mp 194 °C (dec.). IR (nujol): 3397, 3070, 1643, 1590, 1548, 1540 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.72 (s, 3 H, CH₃), 4.58 (s, 2 H, CH₂), 8.17 (s, 1 H, Ar), 11.78 (br s, 1 H, OH, D₂O exch.). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 18.77, 33.88, 108.55, 120.97, 146.59, 164.67, 165.09, 167.99, 183.34. MS: m/z (%) = 320 (46) [ M⁺ - H], 318 (43), 238 (50), 225 (100). Anal. Calcd for C₉H₇BrN₂O₂S₂: C, 33.86; H, 2.21; N, 8.78. Found: C, 33.68; H, 2.35; N, 8.61. Preparation of 7i: α-Bromo ketone derivative 5b (319 mg, 1 mmol) was added to a solution of ethyl thiooxamate (6f, 133 mg, 1 mmol) in EtOH (40 mL). The mixture was heated under reflux for 10 h (monitored by TLC) during which time a yellowish precipitate was formed. After partial removal of the solvent the suspension was filtered yielding the desired product 7i. Data for ethyl 4′-hydroxy-2-methyl-4,2′:5′,4′′-ter-1,3-thiazole-2′′-carboxylate (7i): yellow powder from EtOH, mp 224-234 °C (dec.). IR (nujol): 3395, 3118, 1717, 1587, 1510 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.33 (t, J = 7.4 Hz, 3 H, CH₂ CH ₃), 2.71 (s, 3 H, CH₃), 4.37 (q, J = 7.4 Hz, 2 H, CH ₂ CH₃), 7.94 (s, 1 H, Ar), 8.07 (s, 1 H, Ar), 12.07 (s, 1 H, OH, D₂O exch.). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.03, 18.80, 62.21, 103.26, 116.67, 118.84, 147.61, 148.48, 156.35, 156.98, 159.23, 159.87, 167.27. MS: m/z (%) = 353 (20) [M⁺], 229 (35), 201 (100). Anal. Calcd for C₁₃H₁₁N₃O₃S₃: C, 44.18; H, 3.14; N, 11.89. Found: C, 44.06; H, 3.23; N, 11.76. Preparation of 7k: α-Bromo ketone derivative 5c (304 mg, 1 mmol) was added to a solution of 2-cyanothioacetamide (6d, 100 mg, 1 mmol) in EtOH (20 mL). The mixture was heated under reflux for 8 h (monitored by TLC) during which time brown needles precipitated. After cooling to r.t. the solid was filtered off yielding the bithiazole derivative 7k. Data for (4′-hydroxy-2′-thien-2-yl-4,5′-bi-1,3-thiazol-2-yl)acetonitrile (7k): brown crystals from EtOH, mp 220-223 °C. IR (nujol): 3140, 3088, 2255, 1580, 1554, 1511 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 4.60 (s, 2 H, CH₂), 7.17 (dd, J = 3.9 Hz, J = 4.9 Hz, 1 H Ar), 7.69 (dd, J = 1.6 Hz, J = 3.9 Hz, 1 H Ar), 7.70 (s, 1 H Ar), 7.72 (dd, J = 1.6 Hz, J = 4.9 Hz, 1 H Ar), 12.00 (s, 1 H, OH, D₂O exch.). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 21.39, 102.74, 113.57, 117.05, 126.83, 128.85, 129.09, 136.77, 146.08, 155.26, 158.49, 159.03. MS: m/z (%) = 305 (27) [M⁺], 196 (41), 168 (100). Anal. Calcd for C₁₂H₇N₃OS₃: C, 47.19; H, 2.31; N, 13.76. Found: C, 47.03; H, 2.47; N, 13.84. Preparation of 7m: α-Bromo ketone derivative 5a (298 mg, 1 mmol) was added portionwise to a stirred and heated solution of dithiooxamide (6g, 120 mg, 1 mmol) in EtOH (20 mL) monitoring, by TLC analysis, the disappearance of 5a before further addition. After reaction was complete (16 h) the solid formed was filtered off to furnish the bithiazole derivative 7m. Data for 4′-hydroxy-2′-phenyl-4,5′-bi-1,3-thiazole-2-carbothioamide (7m): brown powder from EtOH, mp >350 °C. IR (nujol): 3444, 3322, 3121, 1584, 1574, 1504 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.47-7.53 (m, 3 H, Ar), 7.86-7.88 (m, 2 H, Ar), 7.99 (s, 1 H, Ar), 9.70 and 10.17 (2 s, 2 H, NH₂, D₂O exch.), 11.90 (s, 1 H, OH, D₂O exch.). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 103.20, 121.46, 125.24, 129.42, 130.41, 132.95, 147.72, 159.78, 161.29, 167.89, 186.34. Anal. Calcd for C₁₃H₉N₃OS₃: C, 48.88; H, 2.84; N, 13.15. Found: C, 48.96; H, 2.76; N, 13.09. Preparation of 8: Dithiooxamide (6g, 120 mg, 1 mmol) was added portionwise to a heated and stirred solution of α-bromo ketone derivative 5a (596 mg, 2 mmol) in EtOH (40 mL). The reaction was monitored by TLC checking for disappearance of 7m before each addition of 6g. After reaction was complete (24 h) the solid precipitate was collected by filtration furnishing tetrathiazol-4,4′′′-diol derivative 8. Data of 2,2′′′-diphenyl-5,4′:2′,2′′:4′′,5′′′-quater-1,3-thiazole-4,4′′′-diol(8): brown powder from EtOH, mp >350 °C. IR (nujol): 3124, 2926, 1667, 1584, 1570, 1504 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.46-7.55 (m, 6 H, Ar), 7.94-7.98 (m, 3 H, Ar), 12.01 (s, 2 H, OH, D₂O exch.). Anal. Calcd for C₂₄H₁₄N₄O₂S₄: C, 55.58; H, 2.72; N, 10.80. Found: C, 55.46; H, 2.85; N, 10.69.

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