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Synlett 2018; 29(03): 349-353
DOI: 10.1055/s-0036-1591490
DOI: 10.1055/s-0036-1591490
letter
Accounting for Different Reactivities of Sulfinate and Thiosulfate Salts in Regioselective Azetidine Coupling via C–H Sulfenylation of Indoles
We are grateful to The Iraqi Ministry of Higher Education and Scientific Research and Al-Mustansiriyah University for financial support.Further Information
Publication History
Received: 06 September 2017
Accepted after revision: 16 September 2017
Publication Date:
20 October 2017 (online)
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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.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0036-1591490.
- Supporting Information
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References and Notes
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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): νmax = 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): νmax = 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 TeflonTM 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 TeflonTM 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 TeflonTM 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): νmax = 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.
For representative reviews on C–H activation, see: