Alkylation of Nitrogen-Containing Heterocycles via In Situ Sulfonyl Transfer

Abstract

A convenient synthesis of N-substituted heterocycles from primary and secondary alcohols and N-sulfonyl heterocycles is described. The reaction proceeds through sulfonyl transfer and in situ formation of activated alcohol derivatives. The formation of alkyl sulfonates as transient intermediates mitigates challenges associated with isolation of these reactive species. N-Sulfonyl heteroarenes were found to be stable over prolonged time, and efficiently coupled to a variety of alcohols.

Key words

pyrazoles - sulfonyl transfer - N-heterocycles - S_N2 reaction - alkylation

• References and Notes


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• 13 See the Supporting Information for further experiments examining regioselectivity. General Procedure for Alkylation of Heterocycles through Sulfonyl Transfer (Procedure 2, SI): The alcohol (0.6 mmol, 1 equiv), sulfonylpyrazole (0.72 mmol, 1.2 equiv) and Cs₂CO₃ (0.72 mmol, 1.2 equiv) were weighed into a vial. The vial was fitted with a stirring bar and a screw cap with a septum. MeCN (2 mL, 0.3 M) was added, the vial was sealed and heated overnight at 90 °C. No special precautions to exclude air or moisture were taken. After a 16–18 h reaction time, the reaction was diluted with NH₄Cl (aq) and EtOAc and, extracted into EtOAc. The aqueous phase was washed with EtOAc (2 ×). The combined organic phases were washed with brine, dried over MgSO₄, filtered, and concentrated to give the reaction crude. The crude was purified through column chromatography to give the final product (typically 4-g cartridge, EtOAc and heptanes as solvents). tert-Butyl 4-[2-(4-Cyano-1H-pyrazol-1-yl)ethyl]piperazine-1-carboxylate (3a): yield: 78%; colorless oil (solidified over time); mp 75–76 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.92 (s, 1 H), 7.72 (s, 1 H), 4.21 (t, J = 6.2 Hz, 2 H), 3.31–3.37 (m, 4 H), 2.75 (t, J = 6.0 Hz, 2 H), 2.36 (br m, 4 H), 1.39 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 154.5, 142.0, 134.8, 113.4, 91.9, 79.7, 57.0, 52.8, 50.1, 43.4 (br), 28.3. IR (neat): 3124, 2974, 2929, 2861, 2816, 2233, 1687, 1544, 1421, 1364, 1249, 1169, 1128, 1005 cm^–1. HRMS (ESI): m/z [M + H⁺] calcd for C₁₅H₂₄N₅O₂: 306.1925; found: 306.1926. tert-Butyl 4-{2-[4-(Trifluoromethyl)-1H-pyrazol-1-yl]ethyl}-piperazine-1-carboxylate (3c): yield: 67%; colorless solid; mp 66–68 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.75 (s, 1 H), 7.65 (s, 1 H), 4.22 (t, J = 6.2 Hz, 2 H), 3.37 (br t, J = 5.1 Hz, 4 H), 2.78 (t, J = 6.4 Hz, 2 H), 2.38 (br t, J = 4.7 Hz, 4 H), 1.42 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 154.6, 136.7 (q, J = 2.4 Hz), 128.9 (q, J = 3.7 Hz), 122.5 (q, J = 265.6 Hz), 113.3 (q, J = 38.1 Hz), 79.6, 57.3, 52.9, 50.1, 43.4 (br m), 28.3. ¹⁹F NMR (376 MHz, CDCl₃): δ = –56.27 (s, 1 F). IR (neat): 2976, 2926, 2856, 2816, 1686, 1574, 1458, 1404, 1366, 1232, 1170, 1114, 1005, 968 cm^–1. HRMS (EI): m/z [M + H⁺] calcd for C₁₅H₂₄F₃N₄O₂: 349.1846; found: 349.1849. 1-[2-(Pyridin-4-yl)ethyl]-1H-pyrazole-4-carbonitrile (3e): yield: 66%; off-white solid; mp 99–101 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.45 (d, J = 5.9 Hz, 2 H), 7.77 (s, 1 H), 7.58 (s, 1 H), 6.94 (d, J = 6.2 Hz, 2 H), 4.37 (t, J = 6.8 Hz, 2 H), 3.16 (t, J = 6.8 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 149.8, 145.8, 142.3, 134.4, 123.6, 113.0, 91.7, 52.7, 35.1. IR (neat): 3121, 3069, 3032, 2994, 2954, 2233, 1603, 1544, 1462, 1438, 1417, 1385, 1358, 1158, 999 cm^–1. HRMS (EI): m/z [M + H]⁺ calcd for C₁₁H₁₁N₄: 199.0978; found: 199.0978. 1-[(3S,6R)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-3-yl]-1H-pyrazole-4-carbonitrile (3k): yield: 90%; colorless solid; mp 113–114 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.92 (s, 1 H), 7.82 (s, 1 H), 7.28–7.40 (m, 5 H), 4.88–4.93 (m, 1 H), 4.82 (t, J = 4.7 Hz, 1 H), 4.79 (d, J = 11.3 Hz, 1 H), 4.70 (d, J = 4.7 Hz, 1 H), 4.59 (d, J = 11.7 Hz, 1 H), 4.37 (dd, J = 10.5, 5.5 Hz, 1 H), 4.26 (dd, J = 10.2, 2.0 Hz, 1 H), 4.12 (td, J = 6.6, 4.7 Hz, 1 H), 3.91 (dd, J = 9.0, 6.2 Hz, 1 H), 3.80 (dd, J = 9.4, 7.0 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 142.6, 137.4, 133.4, 128.4, 127.9, 127.8, 113.0, 92.8, 87.3, 81.1, 78.5, 72.8, 72.5, 71.0, 68.4. IR: 3121, 3065, 3031, 2928, 2878, 2234, 1544, 1495, 1454, 1388, 1359, 1324, 1211, 1134, 1099, 1082, 1058, 1021, 984 cm^–1. HRMS (EI): m/z [M + H⁺] calcd for C₁₇H₁₈N₃O₃: 312.1343; found: 312.1342. tert-Butyl 4-{2-[5,6-Dichloro-2-(methylthio)-1H-benzo[d]-imidazol-1-yl]ethyl}piperazine-1-carboxylate (9): yield: 89%; pale yellow solid; mp 122–123 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.68 (s, 1 H), 7.31 (s, 1 H), 4.08 (t, J = 6.6 Hz, 2 H), 3.38 (t, J = 4.7 Hz, 4 H), 2.75 (s, 3 H), 2.66 (t, J = 6.6 Hz, 2 H), 2.42 (br s, 4 H), 1.43 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 155.5, 154.5, 142.7, 135.5, 125.6, 125.4, 119.2, 109.9, 79.6, 56.4, 53.2, 43.4 (br), 42.2, 28.3, 14.7. IR (neat): 2974, 2932, 2861, 2815, 1687, 1457, 1428, 1363, 1300, 1245, 1168, 1127, 1091, 1050, 1005, 864 cm^–1. HRMS (ESI): m/z [M + H⁺] calcd for C₁₉H₂₇Cl₂N₄O₂S: 445.1226; found: 445.1229. tert-Butyl 4-[2-(3-Acetyl-1H-indol-1-yl)ethyl]piperazine-1-carboxylate (13): yield: 88%; yellow solid; mp 107–108 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.34–8.40 (m, 1 H), 7.81 (s, 1 H), 7.32–7.37 (m, 1 H), 7.26–7.32 (m, 2 H), 4.23 (t, J = 6.6 Hz, 2 H), 3.41 (br t, J = 4.3 Hz, 4 H), 2.77 (t, J = 6.4 Hz, 2 H), 2.50 (s, 3 H), 2.42 (br s, 4 H), 1.46 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 192.8, 154.5, 136.6, 135.3, 126.1, 123.1, 122.5, 122.4, 116.9, 109.5, 79.6, 57.1, 53.0, 44.5, 43.5 (br), 28.3, 27.4. IR (neat): 2975, 2932, 2861, 2814, 1684, 1641, 1527, 1461, 1419, 1389, 1365, 1291, 1243, 1220, 1167, 1127, 1003, 921 cm^–1. HRMS (ESI): m/z [M + H⁺] calcd for C₂₁H₃₀N₃O₃: 372.2282; found: 372.2278.