Conjugate Addition of Pyrazoles to Halogenated Nitroso- and Azoalkenes: A New Entry to Novel Bis(pyrazol-1-yl)methanes

Abstract

A new and versatile synthetic approach towards bis(pyrazolyl)methanes, based on 1,4-addition of pyrazoles to conjugated α-halogenated nitroso- and azoalkenes, is described. Tris(pyrazolyl)methanes can also be obtained by this methodology.

Key words

bis(pyrazolyl)methanes - conjugate addition - α-halogenated nitrosoalkenes - α-halogenated azoalkenes - tris(pyrazolyl)methanes

• References and Notes

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• 14 General Procedure for the Synthesis of Bis(pyrazolyl)methanes A mixture of oxime or hydrazone (3.5 mmol) in CH₂Cl₂ (35 mL), Na₂CO₃ (17.5 mmol) and pyrazole (10.5 mmol) was stirred for 16 h at r.t. Filtration of the insoluble material and evaporation of the solvent followed by flash chromatography (gradient elution with hexanes, CH₂Cl₂, EtOAc as appropriate) afforded the products. {[(4-Bromophenyl)-1-hydroxyimino]methyl}bis(1H-pyrazol-1-yl)methane (9a) Yield 67%; mp 159.1–160.7 °C (from hexanes). IR: ν_max = 3209, 2945, 1724, 1391, 1005, 771, 752 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 6.27 (s, 2 H), 7.38 (d, J = 8.4 Hz, 2 H), 7.52 (m, 4 H), 7.89 (d, J = 2.5 Hz, 2 H), 8.05 (s, 1 H), 11.75 (s, 1 H). ¹³C NMR (101 MHz, DMSO): δ = 75.05, 106.25, 122.17, 129.89, 130.29, 130.70, 130.79, 139.72, 149.51. ESI-HRMS: m/z calcd for C₁₄H₁₂BrN₅NaO: 368.01163 [M + Na⁺]; found: 368.01174. {[(4-Chlorophenyl)-1-hydroxyimino]methyl}bis(1H-pyrazol-1-yl)methane (9b) Yield 53%; mp 159.3–160.7 °C (from hexanes). IR: ν_max = 3179, 2862, 1734, 1648, 1595, 1516, 14922, 1426, 1394, 1323, 1262, 1093, 1055, 793 cm^–1.¹H NMR (400 MHz, DMSO-d ₆): δ = 6.27 (t, J = 2.1 Hz, 2 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.45 (d, J = 8.4 Hz, 2 H), 7.52 (d, J = 1.8 Hz, 2 H), 7.89 (d, J = 2.5 Hz, 2 H), 8.06 (s, 1 H), 11.75 (s, 1 H). ¹³C NMR (101 MHz, DMSO): δ = 75.09, 106.24, 127.86, 129.50, 130.06, 130.70, 133.40, 139.71, 149.43. ESI-HRMS: m/z calcd for C₁₄H₁₂ClN₅NaO 324.06281: [M + Na⁺]; found: 324.06274. {[Methyl-1-(tert-butoxycarbonylhydrazono)]methyl}-bis(1H-pyrazol-1-yl)methane (9c) Yield 57%; mp 147.2–148.9 °C (from hexanes). IR: ν_max = 3435, 3215, 2974, 1734, 1713, 1539, 1393, 1369, 1290, 1242, 1177, 1150, 1055, 847, 754 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.49 and 1.53 (s, 9 H), 1.93 and 2.09 (s, 3 H), 6.32 (dd, J = 2.5, 1.8 Hz, 2 H), 6.35 (t, J = 2.1 Hz, 1 H), 7.19 (br s, 1 H), 7.52 (s, 1 H), 7.60 (dd, J = 2.1, 0.6 Hz, 2 H), 7.62 (d, J = 2.1 Hz, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 12.80, 28.19, 76.79, 77.04, 77.30, 78.60, 81.79, 105.00, 106.68, 130.11, 140.88. ESI-HRMS: m/z calcd for C₁₄H₂₀N₆Na O₂: 327.15385 [M + Na⁺]; found: 327.15400. {[Methyl-1-(tert-butoxycarbonylhydrazono)]methyl}-bis(1H-pyrazol-1-yl)methane (9d) Yield 57%; mp 147.2–148.9 °C (from hexanes). IR: ν_max = 3435, 3215, 2974, 1734, 1713, 1539, 1393, 1369, 1290, 1242, 1177, 1150, 1055, 847, 754 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.49 and 1.53 (s, 9 H), 1.93 and 2.09 (s, 3 H), 6.32 (dd, J = 2.5, 1.8 Hz, 2 H), 6.35 (t, J = 2.1 Hz, 1 H), 7.19 (br s, 1 H), 7.52 (s, 1 H), 7.60 (dd, J = 2.1, 0.6 Hz, 2 H), 7.62 (d, J = 2.1 Hz, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 12.80, 28.19, 76.79, 77.04, 77.30, 78.60, 81.79, 105.00, 106.68, 130.11, 140.88. ESI-HRMS: m/z calcd for C₁₄H₂₀N₆Na O₂: 327.15385 [M + Na⁺]; found: 327.15400. {[Phenyl-1-(tert-butoxycarbonylhydrazono])methyl}-bis(1H-pyrazol-1-yl)methane (9e) Yield 77%; mp 165.5–166.0 °C (from hexanes). IR: ν_max = 3360, 3213, 2976, 1753, 1485, 1394, 1225, 1153, 1092, 1045, 752 cm^–1. ¹H NMR (400 MHz, CDCl₃ + DMSO-d ₆): δ = 1.38 (s, 9 H), 6.24 (t, J = 2.1 Hz, 2 H), 7.15–7.31 (m, 2 H), 7.37–7.39 (m, 3 H), 7.51 (s, 2 H), 7.80 (s, 1 H), 7.92 (d, J = 2.4 Hz, 2 H), 9.09 (s, 1 H). ¹³C NMR (101 MHz, CDCl₃ + DMSO): δ = 13.69, 17.22, 39.12, 39.33, 39.54, 39.75, 39.96, 50.00, 50.11, 77.90, 78.23, 78.55, 100.43, 125.79, 126.00, 126.10, 127.22, 127.45, 127.85, 128.06, 128.24, 128.33, 128.59, 137.07, 150.75. ESI-HRMS: m/z calcd for C₁₉H₂₂N₆NaO₂: 389.16953 [M + Na⁺]; found: 389.16965. {[(4-Chlorophenyl)-1-hydroxyimino]methyl}bis(4-ethoxycarbonyl-1H-pyrazol-1-yl)methane (9f) Yield 46.5%; mp 93.7–95.2 °C (from hexanes). IR: ν_max = 3317, 2983, 1720, 1558, 1493, 1412, 1242, 1024, 884, 847, 794 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.26 (t, J = 7.1 Hz, 6 H), 4.20 (q, J = 7.1 Hz, 4 H), 7.43–7.54 (major) and 7.70–7.79 (minor, m, 4 H), 7.97 (s, 2 H), 8.30 (s, 1 H), 8.55 (s, 2 H), 12.01 (major) and 12.07 (minor, s, 1 H). ¹³C NMR (101 MHz, DMSO): δ = 13.98, 59.80, 75.06, 115.09, 127.99, 128.46, 129.88, 133.72, 134.39, 140.93, 161.54. ESI-HRMS: m/z calcd for C₂₀H₂₁ClN₅O₅: 446.12257 [M + H⁺]; found: 446.12257. [(1-Hydroxyimino)methyl]tris(1H-pyrazol-1-yl)methane (11) Yield 87%; mp 135.8–136.4 °C (from hexanes). IR: ν_max = 3297, 3129, 1515, 1424, 1386, 1323, 1270, 1247, 1200, 1101, 1085, 1045, 1016, 950, 907, 864 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 6.46 (t, J = 2.2 Hz, 3 H), 7.40 (d, J = 2.7 Hz, 3 H), 7.71 (d, J = 1.7 Hz, 3 H), 8.64 (s, 1 H), 11.97 (s, 1 H). ¹³C NMR (101 MHz, DMSO): δ = 88.58, 107.36, 131.08, 141.27, 145.02. ESI-HRMS: m/z calcd for C₁₁H₁₁N₇NaO: 280.09159 [M + Na⁺]; found: 280.09173.