2-Phenyl-2,3-dihydrobenzo[d]thiazole: A Mild, Efficient, and Highly Active in situ Generated Chemoselective Reducing Agent for the One-Pot Synthesis of 5-Monoalkylbarbiturates in Water

Abstract

A metal- and catalyst-free reductive alkylation protocol for the one-pot synthesis of 5-monoalkylbarbiturates from barbituric acids and aldehydes using the in situ generated chemoselective reducing agent 2-phenyl-2,3-dihydrobenzo[d]thiazole from 2-aminothiophenol and benzaldehyde is described. The notable advantages of the protocol are operational simplicity, mild reaction conditions, high yield, short reaction time, and simple workup and purification process which make it highly attractive.

Key words

5-monoalkylbarbiturates - benzothiazoline - transfer hydrogenation - aqueous media - metal- and catalyst-free

• References and Notes

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• 24 General Procedure for the Synthesis of 5-Monoalkylbarbiturates 4aa–cp A mixture of barbituric acid 1 (1 mmol) and aldehyde 2 (1 mmol) was refluxed in 5 mL of water for an appropriate time until the generation of 5-arylidenebarbituric acid as indicated by TLC. Next 2-aminothiophenol (3, 1 mmol) and benzaldehyde (2a, 1 mmol) were added, and the reaction mixture was further refluxed for an appropriate time. On completion of the reaction as indicated by TLC the reaction mixture was allowed to cool to room temperature and was extracted with EtOAc (3 × 10 mL). After drying with anhydrous Na₂SO₄ and evaporation under reduced pressure, the crude product was purified suitably either by recrystallization from a DCM/EtOH (1:1) solvent mixture or column chromatography on silica gel using EtOAc/hexane (2:8) as the eluent to afford 5-monoalkylbarbiturate 4. 5-Benzylpyrimidine-2,4,6(1H,3H,5H)-trione (4aa) White solid; 0.191 g (88%); mp 209–210 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.22–3.24 (m, 2 H), 3.87–3.90 (m, 1 H), 7.05–7.24 (m, 5 H), 11.17 (s, 2 H) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 33.3, 49.3, 126.7, 128.3, 128.9, 137.4, 150.6, 170.0 ppm. IR (KBr): ν_max = 3234, 2939, 1716, 1681, 1581 cm^–1. ESI-MS: m/z calcd for C₁₁H₁₀N₂O₃ ⁺: 218.07; found: 219.0 [M + H]⁺. Anal. Calcd (%) for C₁₁H₁₀N₂O₃: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.70; H, 4.46; N, 13.02. 5-Cinnamyl-6-hydroxypyrimidine-2,4(1H,3H)-dione (4ah) Pale yellow sticky solid; 0.195 g (80%). ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.68 (d, 2 H, J = 7.2 Hz), 5.99–6.09 (m, 1 H), 6.27 (s, 1 H), 6.41 (d, 1 H, J = 15.9 Hz), 7.19–7.31 (m, 5 H), 11.28 (s, 2 H) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 43.0, 75.0, 121.5, 126.2, 127.7, 128.4, 128.7, 134.3, 136.5, 150.0, 171.6 ppm. IR (KBr): ν_max = 3234, 3030, 2974, 1734, 1680, 1616, 1560 cm^–1. ESI-MS: m/z calcd for C₁₃H₁₂N₂O₃ ⁺: 244.08; found: 245.0 [M + H]⁺. Anal. Calcd (%) for C₁₃H₁₂N₂O₃: C, 63.93; H, 4.95; N, 11.47. Found: C, 64.08; H, 5.07; 11.29. 1,3-Dimethyl-5-(thiophen-2-ylmethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4cn) Pale yellow solid; 0.226 g (90%); mp 118–119 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.20 (s, 6 H), 3.72 (s, 3 H), 6.76–6.77 (m, 1 H), 6.85–6.88 (m, 1 H), 7.12–7.13 (m, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 28.4, 30.7, 50.4, 125.2, 127.0, 127.2, 136.4, 151.0, 167.7 ppm. IR (KBr): ν_max = 2976, 1672, 1589 cm^–1. ESI-MS: m/z calcd for C₁₁H₁₂N₂O₃S⁺: 252.06; found: 253.0 [M + H]⁺. Anal. Calcd (%) for C₁₁H₁₂N₂O₃S: C, 52.37; H, 4.79; N, 11.10. Found: C, 52.22; H, 4.94; 10.98. 1,3-Dimethyl-5-(naphthalen-1-ylmethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (4cp) White solid; 0.266 g (90%); mp 153–154 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.92 (s, 6 H), 3.91 (s, 3 H), 7.22 (t, 1 H, J = 6.9 Hz), 7.33 (t, 1 H, J = 7.8 Hz), 7.47–7.53 (m, 2 H), 7.75 (d, 1 H, J = 8.4 Hz), 7.82 (d, 1 H, J = 8.1 Hz), 7.94 (d, 1 H, J = 8.4 Hz) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 28.1, 34.7, 50.8, 123.2, 124.9, 125.8, 126.3, 127.7, 128.6, 128.9, 131.4, 131.5, 133.7, 150.9, 168.6 ppm. IR (KBr): ν_max = 3953, 1695, 1658, 1560 cm^–1. ESI-MS: m/z calcd for C₁₇H₁₆N₂O₃ ⁺: 296.12; found: 297.1 [M + H]⁺. Anal. Calcd (%) for C₁₇H₁₆N₂O₃: C, 68.91; H, 5.44; N, 9.45. Found: C, 68.76; H, 5.60; N, 9.63.
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