Efficient Synthesis of Thiobenzanilides by Willgerodt-Kindler Reaction with Base Catalysts

Abstract

Willgerodt-Kindler reaction between anilines and benz­aldehydes readily proceeded in the presence of catalytic amount of Na₂S·9H₂O to give thiobenzanilides in moderate to good yields. The base catalyst was also available for preparation of primary thio­benzamide.

sulfur - catalysis - condensation - aromatic amines - thioamides

References and Notes

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9

Experimental Procedure (Table [1] , entry 9): Na₂S·9H₂O (216 mg, 15 mol%) was added to a mixture of sulfur (160 mg, 5 mmol as elemental sulfur) and aniline (0.55 mL, 6 mmol) in DMF (4 mL), and the suspension was stirred at 115 °C for 0.5 h under nitrogen. After the mixture was cooled to r.t., benzaldehyde (0.41 mL, 4 mmol) was added, and was stirred at 115 °C for 12 h under nitrogen. After cooling to r.t., the resulting solution was quenched with sat. aq NH₄Cl solution (50 mL) and extracted with CHCl₃ (50 mL). The organic fraction was thoroughly washed with H₂O (2 × 50 mL) and dried with anhyd Na₂SO₄. After concentration, the resulting crude product was purified by chromatography on silica gel with CHCl₃ to afford N-phenylthiobenzamide as a yellow powder (780 mg, 91% yield); mp 99 °C, lit.⁷ 99 °C.

10

N -(4-Methoxyphenyl)thiobenzamide (Table [2] , entry 2): yellow powder; mp 135 °C, lit.⁷ 135 °C.
4-Methoxy- N -phenylthiobenzamide (Table [2] , entry 3): yellow powder; mp 154 °C, lit.⁷ 153-154 °C.
4-Methoxy- N -(4-methoxyphenyl)thiobenzamide (Table [2] , entry 4): yellow powder; mp 148 °C, lit.⁷ 148 °C.
1,3-Bis(anilinothiocarbonyl)benzene (Table [2] , entry 5): yellow powder; mp 243-244 °C, lit.^2a 242-244 °C.


1,4-Bis(anilinothiocarbonyl)benzene (Table [2] , entry 6): yellow powder; mp 280-281 °C, lit.^2a 280-282 °C. N -(4-Nitrophenyl)thiobenzamide (Table [2] , entry 7): yellow powder; mp 145-146 °C, lit.¹³ 145 °C.
N -(4-Pyridyl)thiobenzamide (Table [2] , entry 8): yellow powder; mp 187-188 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.99 (s, 1 H), 9.59 (d, J = 6.4 Hz, 2 H), 8.00 (d, J = 6.4 Hz, 2 H), 7.78 (d, J = 7.6 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 2 H). ¹³C{¹H} NMR (100 MHz, DMSO-d ₆): δ = 199.35, 150.17, 146.64, 142.78, 130.99, 128.00, 127.37, 116.67. Anal. Calcd for C₁₂H₁₀N₂S: C, 67.26; H, 4.70; N, 13.07; S, 14.96. Found: C, 67.32; H, 4.52; N, 13.15; S, 14.88.
N -(3-Pyridyl)thiobenzamide (Table [2] , entry 9): yellow powder; mp 140-141 °C, lit.¹⁴ 140-141 °C.
N -(6-Quinolyl)thiobenzamide (Table [2] , entry 10): orange powder; mp 177-179 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.03 (s, 1 H), 8.90 (br, 1 H), 8.56 (br, 1 H), 8.38 (d, J = 8.0 Hz, 1 H), 8.05-8.11 (m, 2 H), 7.89 (d, J = 7.6 Hz, 2 H), 7.53-7.56 (m, 2 H), 7.49 (t, J = 7.6 Hz, 2 H). ¹³C{¹H} NMR (100 MHz, DMSO-d ₆): δ = 199.81, 151.99, 147.55, 144.08, 139.55, 137.49, 132.50, 130.65, 129.67, 129.29, 129.08, 128.86, 123.41, 123.00. Anal. Calcd for C₁₆H₁₂N₂S: C, 72.70; H, 4.58; N, 10.60; S, 12.13. Found: C, 72.62; H, 4.51; N, 10.60; S, 11.97.
4 - Cyano -N -phenylthiobenzamide (Table [2] , entry 11): orange powder; mp 130-131 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.01 (s, 1 H), 7.91-7.93 (br, 4 H), 7.83 (d, J = 8.0 Hz, 2 H), 7.44 (t, J = 8.0 Hz, 2 H), 7.29 (t, J = 8.0 Hz, 1 H). ¹³C{¹H} NMR (100 MHz, DMSO-d ₆): δ = 195.16, 146.14, 139.47, 131.96, 128.42, 127.95, 126.42, 123.74, 118.27, 112.54. Anal. Calcd for C₁₄H₁₀N₂S: C, 70.56; H, 4.23; N, 11.76. Found: C, 70.85; H, 4.45; N, 11.71.
N -Phenyl-2-pyridinethioamide (Table [2] , entry 12): orange-yellow powder; mp 45 °C, lit.¹⁵ 45 °C.

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12

Preparation of Thiobenzamide (Scheme [4] ): Na₂S·9H₂O (244 mg, 1 mmol) was added to a mixture of sulfur (160 mg, 5 mmol as elemental sulfur) and 28% aq NH₃ (3 mL, ca. 44 mmol) in DMF (4 mL), and the suspension was stirred at 115 °C for 0.5 h under nitrogen. After the mixture was cooled to r.t., benzaldehyde (0.41 mL, 4 mmol) was added, and stirred at 115 °C for 12 h under nitrogen. After cooling to r.t., the resulting solution was quenched with sat. aq NH₄Cl solution (50 mL) and extracted with CHCl₃ (50 mL). The organic fraction was thoroughly washed with H₂O (2 × 50 mL) and dried with anhyd Na₂SO₄. After concentration, the resulting crude material was purified by chromatography on silica gel with CHCl₃-Et₂O (100:0-20:80) to afford thiobenzamide as a pale yellow powder (270 mg, 49% yield); mp 118 °C, lit.^7b 117-118 °C.

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