N-Heterocyclic Carbene Catalyzed [2+2] Cycloaddition of Aryl Isothiocyanates and Nitroolefins: An Efficient Synthesis of β-Thiolactams

Abstract

The first example of a convenient N-heterocyclic carbene (NHC) catalyzed synthesis of β-thiolactams via [2+2] cycloaddition of aryl isothiocyanates and nitroolefins is reported. The protocol affords β-thiolactams in excellent yields with high diastereoselectivity in favor of the cis isomer. Operational simplicity, excellent yields of products, efficient synthesis, and no by-product formation are the salient features of this synthetic protocol. Two possible catalytic pathways, initiated by the addition of NHC to aryl isothiocyanates or nitroolefins, are discussed.

Key words

N-heterocyclic carbenes - nitroolefins - aryl isothiocyanates - β-thiolactams - stereoselective synthesis - cycloaddition reactions

References and Notes

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21

General Procedure for the Synthesis of 3-Nitro-1,4-diarylazetidine-2-thiones 4: A flame-dried round-bottom flask was charged with benzimidazolium salt 3a (0.20 mmol), β-nitroolefin 1 (1.0 mmol), aryl isothiocyanate 2 (1.0 mmol) and THF-t-BuOH (10:1, 5 mL) under positive pressure of nitrogen followed by addition of DBU (0.20 mmol) by using a syringe. The resulting solution was stirred for 6-8 h at room temperature (Table  [²] ). After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-EtOAc, 9:1) to afford analytically pure cis-4.
Characterization Data of Representative Compounds cis -4: Compound cis-4a: Yield: 86%; yellow solid; mp 135-137 ˚C. IR (KBr): 1621, 1605, 1556, 1460, 1232 cm^-¹. ^¹H NMR (400 MHz, CDCl₃/TMS): δ = 4.43 (d, J = 5.6 Hz, 1 H, 4-H), 4.82 (d, J = 5.6 Hz, 1 H, 3-H), 6.78-7.31 (m, 10 H, ArH). ^¹³C NMR (100 MHz, CDCl₃/TMS): δ = 61.1, 107.3, 121.6, 123.2, 126.8, 127.3, 128.3, 129.1, 138.5, 141.4, 199.9. MS (EI): m/z = 284 [M]⁺. Anal. Calcd for C₁₅H₁₂N₂O₂S: C, 63.42; H, 4.25; N, 9.86. Found: C, 63.71; H, 4.56; N, 9.72. Compound cis-4d: Yield: 87%; yellow solid; mp 146-148 ˚C. IR (KBr): 1619, 1600, 1565, 1465, 1240 cm^-¹. ^¹H NMR (400 MHz, CDCl₃/TMS): δ = 4.61 (d, J = 5.7 Hz, 1 H, 4-H), 5.10 (d, J = 5.7 Hz, 1 H, 3-H), 6.84-7.31 (m, 5 H, ArH), 7.86 (d, J = 8.4 Hz, 2 H, ArH), 8.33 (d, J = 8.4 Hz, 2 H, ArH). ^¹³C NMR (100 MHz, CDCl₃/TMS):
δ = 62.4, 105.7, 122.7, 123.8, 126.9, 127.5, 128.8, 140.8, 145.3, 147.6, 198.1. MS (EI): m/z = 329 [M]⁺. Anal. Calcd for C₁₅H₁₁N₃O₄S: C, 54.75; H, 3.37; N, 12.77. Found: C, 54.57; H, 3.66; N, 12.41. Compound cis-4h: Yield: 84%; yellow solid; mp 125-127 ˚C. IR (KBr): 1623, 1603, 1560, 1456, 1243 cm^-¹. ^¹H NMR (400 MHz, CDCl₃/TMS): δ = 4.50 (d, J = 5.4 Hz, 1 H, 4-H), 4.90 (d, J = 5.4 Hz, 1 H, 3-H), 6.79-7.68 (m, 12 H, ArH). ^¹³C NMR (100 MHz, CDCl₃/TMS): δ = 60.8, 106.4, 110.4, 118.2, 120.3, 121.5, 122.8, 124.2, 125.6, 126.7, 127.1, 127.5, 128.0, 136.1, 140.4, 143.4, 199.5. MS (EI): m/z = 334 [M]⁺. Anal. Calcd for C₁₉H₁₄N₂O₂S: C, 68.30; H, 4.22; N, 8.39. Found: C, 68.66; H, 4.42; N, 8.09. Compound cis-4k: Yield: 86%; yellow solid; mp 147-149 ˚C. IR (KBr): 1628, 1610, 1568, 1462, 1238 cm^-¹. ^¹H NMR (400 MHz, CDCl₃/TMS): δ = 4.61 (d, J = 5.6 Hz, 1 H, 4-H), 5.18 (d, J = 5.6 Hz, 2 H, 3-H), 6.97-7.54 (m, 7 H, ArH), 7.82 (d, J = 8.5 Hz, 2 H, ArH), 8.10 (d, J = 8.5 Hz, 1 H, ArH). ^¹³C NMR (100 MHz, CDCl₃/TMS):
δ = 61.9, 105.3, 112.1, 118.4, 120.6, 121.7, 122.5, 124.6, 125.7, 126.7, 127.4, 127.8, 136.4, 140.8, 143.7, 144.1, 200.1. MS (EI): m/z = 379 [M]⁺. Anal. Calcd for C₁₉H₁₃N₃O₄S: C, 60.20; H, 3.45; N, 11.09. Found: C, 60.35; H, 3.75; N, 10.77.