Iron-Catalyzed Oxidative C(sp³)–C(sp³) Radical Coupling Reaction between Thiohydantoins and O-Acetyloximes for the Synthesis of 1,3-Dibenzyl-3,4-dihydropyrrolo[2,3-d]imidazole-2(1H)-thione Derivatives

Abstract

A unified heteroannelation method to achieve the synthesis of 1,3-dibenzyl-3,4-dihydropyrrolo[2,3-d]imidazole-2(1H)-thione derivatives with an iron catalyst is proposed. The annelation reaction follows a C(sp³)–C(sp³) radical coupling between a thiohydantoin and an O-acetyloxime. The synthetic approach enables access to several alkynylated thiohydantoins and O-acetyloximes with controlled selectivity toward C(sp³)–C(sp³) coupling rather than C(sp³)–C(sp³)–O coupling in moderate to high yields. An optimization study has been carried out by changing the catalyst loading, oxidants, solvents, and temperature. Synthesized compounds were characterized through ¹H and ¹³C NMR and mass spectral studies.

Key words

Thiohydatoins - C(sp³)–C(sp³) coupling - pyrroloimidazoles - iron catalysis - acetyloximes

Publication History

Received: 19 February 2024

Accepted after revision: 08 April 2024

Accepted Manuscript online:
09 April 2024

Article published online:
24 April 2024

• References and Notes

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• 32 1,3-Dibenzyl-5-phenyl-3,4-dihydropyrrolo[2,3-d]imidazole-2(1H)-thione (3a); Typical Procedure Imidazolidinone 1a (0.39 g, 1 equiv) and O-acetyloxime 2a (0.44 g, 1.9 equiv) were dissolved in toluene (7 mL) in an oven-dried flat-bottomed flask equipped with a condenser and magnetic stirrer bar. FeBr₂ (0.0032 g, 0.15 mmol, 15.0 mol%) and Cs₂CO₃ (1.9 equiv) were added and the resultant mixture was stirred at 110 °C under N₂ for 7 h. On completion of the reaction (TLC; EtOAc–hexane, 3:4), the crude product was transferred onto crushed ice and the mixture was filtered, then subjected to solvent extraction with EtOAc (20 mL). The organic layer was separated, dried (MgSO₄), and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, PE–EtAc) to give a white solid; yield: 77%; mp 124–125 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.50 (s, 1 H), 7.51–7.48 (m, 5 H), 7.39–7.27 (m, 10 H), 6.33 (s, 1 H), 4.92 (s, 2 H), 4.83 (s, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 176.80, 142.35, 141.64, 137.92, 135.22, 134.69, 134.60, 133.62, 131.09, 130.67, 129.92, 128.98, 127.28, 127.11, 126.12, 100.46, 53.78, 49.26. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₅H₂₁N₃S: 395.5190; found: 395.5184. Anal. Calcd for C₂₅H₂₁N₃S: C, 75.92; H, 5.35; N,10.62. Found: C, 75.94; H, 5.36; N, 10.64.