β-Lactam-Synthon-Interceded Facile Synthesis of Functionally Decorated Thiohydantoins

Abstract

Base-promoted facile synthesis of thiohydantoins has been described via intramolecular amidolysis of C-3 functionalized 2-azetidinones. This approach provides a convenient and rapid access to diversely functionalized thiohydantoins compared to conventional protocols.

Key words

β-lactam synthon - thiohydantoin - intramolecular amidolysis

• References and Notes

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• 26 Typical Procedure for the Preparation of Thiourea 2: To a stirred solution of 2-isothiocyanateazetidin-2-one 1 (1 mmol) was added a solution of the amine (1 mmol) in anhyd acetone (20 mL). The reaction mixture was allowed to stir at r.t. for 15–20 min and the reaction progress was monitored by TLC. The solvent was removed in vacuo resulting in a solid that was recrystallized from Et₂O to yield the desired product 2. 1-(2-Oxo-4-styryl-1-p-tolylazetidin-3-yl)-3-phenylthiourea (2a): white solid; mp 156–157 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.35 (s, 3 H, Me), 4.64 (dd, J = 4.8, 6.4 Hz, 1 H, H2), 4.92 (dd, J = 4.8, 7.2 Hz, 1 H, H1), 6.08 (dd, J = 6.4, 15.6 Hz, 1 H, H3), 6.61 (d, J = 15.6 Hz, 1 H, H4), 6.80–7.02 (m, 5 H, ArH), 7.06 (d, J = 8.1 Hz, 2 H, ArH), 7.12 (d, J = 8.1 Hz, 2 H, ArH), 7.16–7.32 (m, 5 H, ArH), 7.82 (d, J = 7.2 Hz, 1 H, NH, D₂O exch.). ¹³C NMR (75 MHz, CDCl₃): δ = 20.6, 59.0, 63.4, 120.0, 123.3, 124.8, 125.5, 126.2, 127.3, 127.8, 128.1, 128.8, 129.6, 133.1, 134.9, 137.4, 139.4, 170.5, 178.1. MS: m/z = 414 [M⁺]. Anal. Calcd for C₂₅H₂₃N₃OS: C, 72.61; H, 5.61; N, 10.16. Found: C, 72.51; H, 5.57; N, 10.22.
• 27 Typical Procedure for the Sodium Methoxide Mediated Synthesis of 3-Aryl/Alkyl-5-(3-phenylallylidene)-2-thioxoimidazolidin-4-ones 4: To a stirred solution of thiourea 2 (1 mmol) in anhyd MeOH was added a solution of sodium methoxide (1 mmol) in anhyd MeOH. The reaction mixture was allowed to stir at r.t. for 50–60 min and the progress of the reaction was monitored by TLC. On completion, the precipitated crude product was filtered and recrystallized from EtOAc–hexane (60:40) to yield 3-aryl/alkyl-5-(3-phenylallylidene)-2-thioxoimidazolidin-4-one 4 as yellow crystals. 3-Phenyl-5-(3-phenylallylidene)-2-thioxoimidazolidin-4-one (4a): yellow solid; mp >220 °C. ¹H NMR (300 MHz, CDCl₃): δ = 6.54 (d, J = 11.7 Hz, 1 H, H1), 7.00 (dd, J = 11.7, 15.0 Hz, 1 H, H2), 7.18 (d, J = 15.0 Hz, 1 H, H3), 7.32–7.80 (m, 10 H, ArH), 12.63 (s, 1 H, NH, D₂O exch.). ¹³C NMR (75 MHz, CDCl₃): δ = 112.5, 113.9, 114.2, 120.8, 125.6, 125.9, 127.2, 127.4, 128.9, 129.0, 134.8, 138.6, 161.3, 175.0. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₄N₂OS: 307.0827; found: 307.0838. Anal. Calcd for C₁₈H₁₄N₂OS: C, 70.56; H, 4.61; N, 9.14. Found: C, 70.50; H, 4.56; N, 9.19