Chalcones to Functionalized Azetidines via Anion-Induced Cyclization Using Task-Specific Ionic Liquids

Abstract

The first example of the application of task-specific ionic liquids (TSIL) to a new and practical synthesis of functionalized azetidines is reported. Aza-Michael addition of diethyl N-arylphosphoramidates to chalcones affords diethyl N-aryl-N-(1,3-diaryl-3-oxopropyl)phosphoramidates, which undergo cyclization to functionalized azetidines. The cyclization is induced by anions (NCS^-, PhS^-) of TSIL and gives excellent yields with high diastereoselectivity in a one-pot procedure. The use of KSCN or PhSNa instead of the corresponding TSIL, [bmim]SCN or [bmim]SPh, resulted in significantly lower yields of products. After isolation of the product, the ionic liquid could be recycled for further use.

azetidines - Michael addition - chalcones - ionic liquids - phosphoramidates

References and Notes

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<A NAME="RG37407ST-39">39</A>

General Procedure for the Synthesis of Diethyl N -Aryl- N -(1,3-diaryl-3-oxopropyl)phosphoramidates 3 [25] To a solution of diethyl N-arylphosphoramidate 2 (5 mmol) in dry benzene (5 mL) was added dropwise a solution of NaH (120 mg, 5 mmol) in dry benzene (10 mL) with stirring at r.t. After the addition was complete and evolution of hydrogen gas(effervescence) had ceased, the reaction mixture was stirred at 60 °C for 30 min and then cooled to r.t. Next, a solution of chalcone 1 (5 mmol) in dry benzene (5 mL) was added and the reaction mixture was stirred at 50-60 °C for 3 h. The solvent was evaporated under reduced pressure, the residue washed with H₂O and recrystallized from n-hexane to afford an analytically pure sample of 3.
Physical Data of a Representative Compound
Compound 3a: white crystals yield 87%, mp 186-187 °C. IR (KBr): ν_max = 3052, 2990, 1692, 1605, 1582, 1456 cm^-1. ¹H NMR (400 MHz, CDCl₃/TMS): d = 1.23 (t, 6 H, J = 7.5 Hz, 2 Ž Me), 3.06 (dd, 1 H, J = 12.9, 8.5 Hz, 2-H_a), 3.38 (dd, 1 H, J = 12.9, 3.5 Hz, 2-H_b), 4.16 (q, 4 H, J = 7.5 Hz, 2 Ž OCH₂), 4.65 (dd, 1 H, J = 8.5, 3.5 Hz, 3-H), 7.08-7.43 (m, 13 H_arom), 7.81-7.89 (m, 2 H_arom). ¹³C NMR (100 MHz, CDCl₃/TMS): d = 16.3 (Me), 41.7 (CHPh), 50.3 (CH₂O), 69.9 (CH₂CO), 126.5, 127.5, 128.3, 129.4, 131.4, 132.7, 133.4, 134.2, 135.5 (3 Ž Ph), 193.2 (CO). MS (EI): m/z = 437 [M⁺]. Anal. Calcd (%) for C₂₅H₂₈NO₄P: C, 68.64; H, 6.45; N, 3.20. Found: C, 68.92; H, 6.74; N, 3.07.

<A NAME="RG37407ST-40">40</A>

General Procedure for the Synthesis of Functionalized Azetidines 5 A mixture of adduct 3 (5 mmol) and [bmim]SCN or [bmim]SPh (4, 7.5 mmol) with a few drops of distilled H₂O was taken in a 50 mL round-bottomed flask and stirred for 3-4 h at r.t. (for [bmim]SCN) or at 60-65 °C (for [bmim]SPh). After completion of the reaction as indicated by TLC, the product was extracted with Et₂O (3 × 20 mL), dried over anhyd MgSO₄, filtered, and evaporated to dryness. The crude product 5 thus obtained was recrystallized twice from n-hexane to afford an analytically pure sample.
Physical Data of Representative Compounds
Compound 5a: white crystals, yield 81%, mp 98-99 °C. IR (KBr): ν_max = 3082, 2965, 2892, 2813, 2132, 1604, 1495, 1451, 753, 706 cm^-1. ¹H NMR (400 MHz, CDCl₃/TMS): δ = 2.75 (dd, 1 H, J = 11.3, 8.7 Hz, 3-H_a), 3.05 (dd, 1 H, J = 11.3, 6.6 Hz, 3-H_b), 4.90 (dd, 1 H, J = 8.7, 6.6 Hz, 4-H), 7.11-7.43 (m, 15 H_arom). ¹³C NMR (100 MHz, CDCl₃/TMS): δ = 41.1 (3-C), 55.7, 78.5 (2-C, 4-C), 111.7 (SCN), 123.6, 124.5, 125.3, 126.7, 129.8, 130.7, 131.6, 132.4, 133.5, 134.3, 139.0, 141.7 (3 × Ph). MS (EI): m/z = 342 [M⁺]. Anal. Calcd (%) for C₂₂H₁₈N₂S: C, 77.16; H, 5.30; N, 8.18. Found: C, 76.81; H, 5.53; N, 8.39.
Compound 5g: white crystals, yield 82%, mp 58-59 °C. IR (KBr): ν_max = 3073, 2968, 2896, 2818, 1600, 1492, 1456, 758, 696 cm^-1. ¹H NMR (400 MHz, CDCl₃/TMS): δ = 2.79 (dd, 1 H, J = 11.3, 8.7 Hz, 3-H_a), 3.10 (dd, 1 H, J = 11.3, 6.6 Hz, 3-H_b), 4.92 (dd, 1 H, J = 8.7, 6.6 Hz, 4-H), 7.01-7.53 (m, 20 H_arom). ¹³C NMR (100 MHz, CDCl₃/TMS): δ = 41.2 (3-C), 55.9, 79.0 (2-C, 4-C), 123.5, 124.6, 125.3, 126.3, 127.2, 128.0, 129.8, 130.6, 131.5, 132.6, 133.4, 134.5, 135.8, 138.2, 139.7, 141.3 (4 × Ph). MS (EI): m/z = 393 [M⁺]. Anal. Calcd (%) for C₂₇H₂₃NS: C, 82.40; H, 5.89; N, 3.56. Found: C, 82.76; H, 5.52; N, 3.85.