Accounting for Different Reactivities of Sulfinate and Thiosulfate Salts in Regioselective Azetidine Coupling via C–H Sulfenylation of Indoles

Abstract

The regioselective incorporation of azetidines into heteroaromatic compounds is reported via a formal C–H sulfenylation reaction. While sodium sulfinate salts undergo C3 sulfenylation of electron-rich indoles only, the corresponding thiosulfate salts have proved to be more generally useful. A mechanistic hypothesis for the different reactivities of sulfinate and thiosulfate salts is provided.

Key words

azetidines - coupling - indoles - C–H functionalization - thioethers

• References and Notes


For representative reviews on C–H activation, see:
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• 13 General Procedure A: Coupling of Azetidine Sulfinate Salt 1 to Indoles Iodine (1.0 equiv) was added to indole (1.0 equiv), PPh₃ (2.0 equiv), and sodium 1-(tert-butoxycarbonyl) azetidine-3-sulfinate (1, 2.0 equiv) in EtOH (0.5 mL) at r.t. The resulting solution was stirred at 70 °C for 1 d. All volatiles were removed in vacuo. Purification by recrystallization or by flash chromatography over silica gel, eluting with PE/EtOAc (0–30%) afforded the desired thioindoles. Synthesis of tert-butyl 3-[(1H-Indol-3-yl)thio]azetidine-1-carboxylate (2) Following general procedure A, 1H-indole (12 mg, 0.103 mmol), azetidine sulfinate salt (50 mg, 0.206 mmol), PPh₃ (54 mg, 0.206 mmol), and iodine (26 mg, 0.103 mmol) afforded the desired product as a brown gum (26 mg, 84%). ¹H NMR (400 MHz, CDCl₃): δ = 8.64 (br, 1 H), 7.79–7.75 (m, 1 H), 7.45–7.38 (m, 2 H), 7.31–7.21 (m, 2 H), 4.19–4.12 (m, 2 H), 3.92–3.84 (m, 2 H), 3.77 (tt, J = 8.0, 5.5 Hz, 1 H), 1.38 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 156.2, 136.3, 130.5, 129.7, 122.9, 120.8, 119.1, 111.6, 102.5, 79.6, 56.0 (br), 35.6, 28.3. FTIR (neat): ν_max = 3278 , (s), 305, (w), 2975, (m), 2882 , (m), 1675 (s) cm^–1. HRMS: m/z [M + H]⁺ calcd for C₁₆H₂₁N₂O₂S: 305.1324; found: 305.1319. Synthesis of tert-Butyl 3-[(5-Methyl-1H-indol-3-yl)thio]azetidine-1-carboxylate (3) Following the general procedure A, using 5-methyl-1H-indole (14 mg, 0.103 mmol), azetidine sulfinate salt 1 (50 mg, 0.206 mmol), PPh₃ (54 mg, 0.206 mmol), and iodine (26 mg, 0.103 mmol) afforded the desired product as a pale brown solid (32 mg, 97%); mp 119–120 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.57 (br, 1 H), 7.52 (s, 1 H), 7.33 (d, J = 1.5 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 7.08 (dd, J = 8.5, 1.5 Hz, 1 H), 4.16–4.10 (m, 2 H), 3.91–3.82 (m, 2 H), 3.74 (tt, J = 8.0, 5.5 Hz, 1 H), 2.48 (s, 3 H), 1.37 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 156.4, 134.7, 130.8, 130.0, 129.9, 124.4, 118.5, 111.4, 101.4, 79.7, 56.0, 35.4, 28.3, 21.5. FTIR (neat): ν_max = 3282 (br), 3060 (w), 2974 (m), 2930 (m), 2877 (m), 1675 (s) cm^–1. HRMS: m/z [M + Na]⁺ calcd for C₁₇H₂₂N₂O₂S: 319.1480; found: 319.1473. General Procedure B: Coupling of Azetidine Bunte Salt 13 to Indoles To a flame-dried Schlenk tube with a magnetic stirring bar was added indole (1.0 equiv), azetidine thiosulfate 13 (1.5 equiv), and iodine (20 mol%). The tube was closed with a rubber septum, and placed under an atmosphere of argon, followed by the addition of DMSO via syringe (2 mL). The septum was replaced by a Teflon^TM screw cap under argon flow. The reaction mixture was stirred at 80 °C for 12 h. After cooling to r.t., a saturated solution of Na₂S₂O₃ was added and the product extracted with EtOAc. The combined organic layers was washed with H₂O and brine, dried over MgSO₄, filtered, and then concentrated in vacuo. Purification by recrystallization or by flash chromatography over silica gel, eluting with PE/EtOAc (0–30%) afforded the desired thioindoles.
• 14 General Procedure B: Coupling of Azetidine Bunte Salt 13 to Indoles To a flame-dried Schlenk tube with a magnetic stirring bar was added indole (1.0 equiv), azetidine thiosulfate 13 (1.5 equiv), and iodine (20 mol%). The tube was closed with a rubber septum, and placed under an atmosphere of argon, followed by the addition of DMSO via syringe (2 mL). The septum was replaced by a Teflon^TM screw cap under argon flow. The reaction mixture was stirred at 80 °C for 12 h. After cooling to r.t., a saturated solution of Na₂S₂O₃ was added and the product extracted with EtOAc. The combined organic layers was washed with H₂O and brine, dried over MgSO₄, filtered, and then concentrated in vacuo. Purification by recrystallization or by flash chromatography over silica gel, eluting with PE/EtOAc (0–30%) afforded the desired thioindoles. Synthesis of tert-Butyl 3-[(2-Phenyl-1H-indol-3-yl) thio]azetidine-1-carboxylate (14) To a flame-dried Schlenk tube with a magnetic stirring bar was added indole (1.0 equiv), azetidine thiosulfate 13 (1.5 equiv), and iodine (20 mol%). The tube was closed with a rubber septum, and placed under an atmosphere of argon, followed by the addition of DMSO via syringe (2 mL). The septum was replaced by a Teflon^TM screw cap under argon flow. The reaction mixture was stirred at 80 °C for 12 h. After cooling to r.t., a saturated solution of Na₂S₂O₃ was added and the product extracted with EtOAc. The combined organic layers was washed with H₂O and brine, dried over MgSO₄, filtered, and then concentrated in vacuo. Purification by recrystallization or by flash chromatography over silica gel, eluting with PE/EtOAc (0–30%) afforded the desired thioindoles. Synthesis of tert-Butyl 3-[(5-Fluoro-1H-indol-3-yl)thio]azetidine-1-carboxylate (15) Following the general procedure B, using 5-fluoro-1H-indole (47 mg, 0.344 mmol), azetidine Bunte salt 13 (151 mg, 0.517 mmol), and iodine (17 mg, 0.069 mmol) the desired product was afforded as a white solid (81 mg, 73%); mp 161–162 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.21 (br, 1 H), 7.40–7.35 (m, 2 H), 7.30 (dd, J = 9.0, 4.5 Hz, 1 H), 6.98 (td, J = 9.0, 2.5 Hz, 1 H), 4.19–4.09 (m, 2 H), 3.86–3.79 (m, 2 H), 3.71 (tt, J = 8.0, 5.5 Hz, 1 H), 1.37 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 158.6 (d, J = 236.5 Hz), 156.3, 132.8, 132.4, 130.5 (d, J = 10.0 Hz), 112.5 (d, J = 9.5 Hz), 111.3 (d, J = 26.5 Hz), 104.0 (d, J = 24.0 Hz), 102.1 (d, J = 3.5 Hz), 79.9, 55.9, 35.4, 28.3. ¹⁹F NMR (377 MHz, CDCl₃): δ = 110.3. FTIR (neat): ν_max = 3267 (br), 3040 (w), 2979 (m). 2881 (m), 1675 (s) cm^–1. HRMS: m/z [M + Na]⁺ calcd for C₁₆H₁₉FN₂O₂S: 345.1043; found: 345.1042.