Palladium-Catalyzed Cross-Coupling Reaction of a Sulfoximine with Aryl Dichlorides under Microwave Irradiation

Abstract

A new procedure for N-arylation of aryl dichlorides with a sulfoximine, utilizing a palladium-catalyzed microwave-assisted reaction, has been developed. Only the monosulfonimidoyl arenes were obtained in good to excellent yields.

Key words

sulfoximine - coupling reaction - microwave irradiation - palladium

References and Notes

• For some examples and leading references, see:
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13

General Procedure for Coupling of Sulfoximines with Aryl Dichlorides - Procedure A To 5 mL of toluene in a 10 mL microwave tube was successively added aryl dichlorides (1.0 equiv), (R)-sulfox-imine (4.0 equiv), rac-BINAP (7.5 mol%), Pd(OAc)₂ (5 mol%) and Cs₂CO₃ (1.4 equiv) under N₂ atmosphere. The reaction mixture was stirred at r.t. for 30 min, then irradiated under vigorous stirring for 1.5 h at 135 °C (constant temperature) and 200 W (irradiation power). The reaction was cooled down and diluted with CH₂Cl₂, filtered through a pad of Celite^® and concentrated in vacuo. The residue was purified by flash chromatography. Procedure B To 5 mL of toluene in a 10 mL microwave tube was successively added aryl chloride (1.5 mmol), (R)-sulfox-imine (0.3 mmol), rac-BINAP (7.5 mol%), Pd(OAc)₂ (5 mol%) and Cs₂CO₃ (0.42 mmol) under N₂ atmosphere. The reaction mixture was stirred at r.t. for 30 min, then irradiated under vigorous stirring for 1.5 h at 135 °C (constant temperature) and 200 W (irradiation power set). The reaction was cooled down and Pd(OAc)₂ (5 mol%), rac-BINAP (7.5 mol%) was added again under N₂ atmosphere. The reaction mixture was again treated under the same conditions. Then the reaction was cooled down and diluted with CH₂Cl₂, filtered through a pad of Celite^® and concentrated in vacuo. The residue was purified by flash chromatography. Procedure C To 5 mL of toluene in a 10 mL microwave tube was successively added aryl chloride (1.0 equiv, (R)-sulfoximine (4.0 equiv), Pd(OAc)₂ (5 mol%), tri(tert-butyl)phosphane (15 mol%) and Cs₂CO₃ (1.4 equiv) under N₂ atmosphere. The reaction mixture was stirred at r.t. for 30 min, then heated in the microwave reactor with vigorous stirring for 1.5 h at 135 °C (constant temperature) and 200 W (irradiation power). The reaction was cooled down and diluted with CH₂Cl₂, filtered through a pad of Celite^® and concentrated in vacuo. The residue was purified by flash chromatography (30-40% EtOAc-hexane).

14

Data for Selected Compounds
Compound 3 (procedure A): colorless liquid, yield 42%. IR: 3064, 3019, 2925, 1589, 1474, 1286, 1200, 1090 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 8.06-8.03 (m, 2 H), 7.60-7.53 (m, 3 H), 7.31 (dd, J = 7.9, 1.5 Hz, 1 H), 7.19 (dd, J = 7.9, 1.5 Hz, 1 H), 6.97 (td, J = 7.5, 1.5 Hz, 1 H), 6.82 (td, J = 7.5, 1.5 Hz, 1 H), 3.25 (s, 3 H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 142.1, 139.0, 133.4, 129.8, 129.5, 128.5, 127.1, 123.9, 122.7, 45.6. HRMS: m/z calcd for C₁₃H₁₂ClNOSNa [M + Na]⁺: 288.0220; found 288.0228. [α]_D ²⁵ 12.25 (c 2.4, CHCl₃).
Compound 5 (procedure B): colorless liquid, yield 92%. IR: 3060, 3015, 2949, 2921, 1732, 1585, 1442, 1298, 1262, 1176, 1033 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.98-7.96 (m, 2 H), 7.60-7.57 (m, 1 H), 7.53-7.50 (m, 2 H), 6.99-6.95 (m, 2 H), 6.89-6.86 (m, 1 H), 3.96 (s, 3 H), 3.18 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 167.7, 144.1, 138.4, 133.5, 130.6, 130.2, 129.5, 129.4, 128.5, 122.0, 120.2, 52.4, 45.6. HRMS: m/z calcd for C₁₅H₁₄ClNO₃SNa [M + Na]⁺: 346.0275; found: 346.0266. [α]_D ²⁵ 95.30 (c 5.06, CHCl₃).
Compound 7 (procedure B): colorless liquid, yield 93%. IR: 3064, 3019, 2933, 2230, 1580, 1450, 1298, 1217, 1094, 1045 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 8.01-7.99 (m, 2 H), 7.63-7.61 (m, 1 H), 7.58-7.54 (m, 2 H), 7.10 (t, J = 8.2 Hz, 1 H), 7.00 (dd, J = 8.2, 0.9 Hz, 1 H), 6.90 (dd, J = 8.1, 0.9 Hz, 1 H), 3.31 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 150.9, 138.0, 137.1, 133.9, 133.2, 129.8, 128.2, 121.9, 119.7, 115.5, 108.5, 46.1. HRMS: m/z calcd for C₁₄H₁₁ClN₂OSNa [M + Na]⁺: 313.0172; found: 313.0168. [α]_D ²⁵ 226.61 (c 4.51, CHCl₃).
Compound 9 (procedure B): yellow solid, yield 75%; mp 203-204 °C. IR: 3064, 3007, 2925, 2361, 2340, 1674, 1572, 1331, 1241 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 8.25-8.21 (m, 3 H), 7.83 (dd, J = 7.6, 1.2 Hz, 1 H), 7.73-7.52 (m, 6 H), 7.45 (t, J = 7.9 Hz, 1 H), 3.36 (s, 3 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 182.5, 182.3, 146.3, 138.9, 138.0, 136.6, 136.2, 133.9, 133.5, 133.4, 130.1, 129.5, 129.2, 128.6, 126.4, 124.9, 121.4, 45.8. HRMS: m/z calcd for C₂₁H₁₄ClNO₃SNa [M + Na]⁺: 418.0275; found: 418.0288. [α]_D ²⁵ 414.83 (c 2.67, CHCl₃).
Compound 11 (procedure A): colorless oil, yield 92%. IR: 3075, 3025, 2945, 1597, 1493, 1457, 1346, 1291 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.94-7.93 (m, 2 H), 7.63-7.54 (m, 3 H), 7.36 (d, J = 8.5 Hz, 1 H), 7.11 (d, J = 1.7 Hz, 1 H), 6.89 (dd, J = 8.5, 1.6 Hz, 1 H), 3.26 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 149.8, 138.3, 133.8, 132.4, 129.8, 128.3, 127.9 (q, J = 4.9 Hz), 125.2, 124.3, 122.2, 120.6 (q, J = 31.4 Hz), 120.3, 46.3.
Compounds 13/14 (procedure A): colorless oil, yield 85%. IR: 3048, 2937, 1595, 1495, 1446, 1331, cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 8.04-8.00 (m, 2 H), 7.65-7.54 (m, 4 H), 7.41-7.00 (m, 2 H), 3.30 (s, 3 H). ¹³C NMR (125 Mz, CDCl₃): δ = 145.8, 142.9, 138.4 (138.5), 133.8 (133.7), 130.1, 129.7 (129.6), 128.4 (128.5), 126.9 (q, J = 3.9 Hz), 124.1 (q, J = 3.7 Hz), 122.8, 120.0 (q, J = 3.9 Hz), 119.0 (q, J = 3.9 Hz), 46.1 (45.8).
Compound 16 (procedure B): colorless liquid. IR: 3068, 3002, 2937, 2876, 1683, 1576, 1443, 1286, 1213 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 10.72 (s, 1 H), 8.01-7.97 (m, 2 H), 7.63-7.53 (m, 3 H), 7.09-6.93 (m, 2 H), 6.89 (dd, J = 7.6, 1.3 Hz, 1 H), 3.28 (s, 3 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 191.5, 149.2, 138.5, 135.0, 133.7, 133.5, 129.7, 128.2, 126.6, 123.8, 121.3, 45.9. HRMS: m/z calcd for C₁₄H₁₂ClNO₂SNa [M + Na]⁺: 316.0169; found: 316.0168. [α]_D ²⁵ 169.09 (c 4.53, CHCl₃).
Compound 17 (procedure B): colorless solid; mp 145-147 °C. IR: 3060, 2929, 2847, 1597, 1429, 1286, 1221, 1204 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 8.21 (d, J = 10.1 Hz, 1 H), 7.90-7.86 (m, 2 H), 7.64-7.57 (m, 3 H), 7.38-7.09 (m, 3 H), 6.46 (d, J = 10.1 Hz, 1 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 146.5, 141.0, 134.6, 133.5, 133.4, 131.8, 129.1, 128.8, 123.4, 120.9, 114.1, 110.5. HRMS: m/z calcd for C₁₄H₁₀ClNOSNa [M + Na]⁺: 298.0064; found 298.0064. [α]_D ²⁵ -261.48 (c 1.22, CHCl₃).
Compound 20 (procedure B): colorless solid; mp 190-192 °C. IR: 3043, 1605, 1442, 1303, 1172 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.90-7.89 (m, 2 H), 7.64-7.62 (m, 2 H), 7.56-6.59 (m, 3 H), 7.29 (dd, J = 7.7, 1.3 Hz, 1 H), 6.96 (t, J = 7.7 Hz, 1 H), 6.43 (d, J = 9.7 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 141.9, 141.0, 138.2, 133.5, 132.2, 129.0, 128.9, 128.3, 127.5, 120.0, 117.4, 111.1. HRMS: m/z calcd for C₁₄H₁₀ClNOSNa [M + Na]⁺: 298.0064; found: 298.0067. [α]_D ²⁵ -415.7 (c 1.12, CHCl₃).
Compound 21 (procedure C): colorless liquid, yield 14%. IR: 3047, 3015, 2921, 1593, 1540, 1454, 1278 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 8.19-8.15 (m, 2 H), 7.93-7.89 (m, 2 H), 7.66-7.31 (m, 8 H), 7.03 (dd, J = 7.8, 1.3 Hz, 1 H), 6.89 (t, J = 15.3 Hz, 1 H), 6.33 (d, J = 9.7 Hz, 1 H), 3.17 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 142.3, 141.1, 140.2, 139.3, 137.4, 133.0, 132.7, 128.9, 128.8, 128.7, 128.6, 128.0, 124.2, 120.0, 116.8, 109.5, 45.0. HRMS: m/z calcd for C₂₁H₁₈N₂O₂S₂Na [M + Na]⁺: 417.0702; found: 417.0715. [α]_D ²⁵ -96.36 (c 0.88, CHCl₃).

15

Compound 19 was not characterized, but the corresponding primary alcohol was a colorless liquid. IR: 3440, 3056, 2913, 1589, 1437, 1282, 1209, 1180 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 8.30-8.26 (m, 2 H), 7.70-7.59 (m, 3 H), 7.39-7.26 (m, 2 H), 7.04 (t, J = 7.8 Hz, 1 H), 4.77 (dd, J = 12.1, 4.6 Hz, 1 H), 4.52 (dd, J = 12.1, 7.0 Hz, 1 H), 3.81 (t, J = 6.9 Hz, 1 H), 3.15 (s, 3 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 140.3, 139.3, 138.3, 133.7, 130.7, 129.5, 129.4, 129.3, 128.3, 124.7, 62.6, 43.4. HRMS: m/z calcd for C₁₄H₁₄ClNO₂SNa [M + Na]⁺: 318.0326; found: 318.0323. [α]_D ²⁵ -11.24 (c 1.53, CHCl₃).