A Complementary Approach to 3,5-Substituted Pyrazoles with Tosylhydrazones and Terminal Alkynes Mediated by TfOH

Abstract

A complementary method for the preparation of 3,5-substituted pyrazoles in moderate to high yields has been explored via TfOH-induced addition of tosylhydrazones to the terminal alkynes. This acid-induced addition procedure might be an operationally safe alternative compared to typical 1,3-dipolar cycloaddition as there is no involvement of diazo compounds.

Key words

alkynes - tosylhydrazones - cycloaddition - heterocyclics - pyrazoles

• References and Notes

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• 20 General Procedure for the TfOH-Mediated Reaction of Tosylhydrazones with Terminal Alkynes To a solution of tosylhydrazones (0.5 mmol, 1.0 equiv) in dry DCE (2 mL) was added TfOH (0.5 mmol, 1.0 equiv) dropwise at r.t. under Ar atmosphere. After stirring for about 10 min, the alkynes (0.75 mmol, 1.5 equiv) were added. The reaction flask was refluxed for 12 h, and then it was cooled to r.t. and quenched with sat. Na₂CO₃ (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (PE–EtOAc = 4:1) to afford the corresponding products 3. In some cases, compound 4 can be obtained by basic Al₂O₃ (100–200 mesh) column chromatography (PE–EtOAc = 6:1). 3,5-Diphenyl-1H-pyrazole (3a) Yield: 78%; mp 197–199 °C; R_f = 0.31 (PE–EtOAc = 4:1); light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.71 (d, J = 7.3 Hz, 4 H), 7.25–7.38 (m, 6 H), 6.82 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 128.9, 128.2, 125.6, 100.1. ESI-LRMS: m/z = 221.2 [M + H]⁺. CAS registry no. 1145-01-3. 3-(4-Bromophenyl)-5-p-tolyl-1H-pyrazole (3p) Yield: 68%; mp 239–241 °C; R_f = 0.49 (PE–EtOAc = 3:1); white solid. ¹H NMR (400 MHz, DMSO-d ₆ with a drop of concd HCl): δ = 7.90 (d, J = 8.6 Hz, 2 H), 7.82 (d, J = 8.1 Hz, 2 H), 7.70 (d, J = 8.6 Hz, 2 H), 7.40 (s, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 2.36 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆ with a drop of concd HCl): δ = 147.3, 147.0, 138.9, 132.3, 130.0, 128.1, 126.9, 126.1, 122.2, 100.8, 21.3. ESI-LRMS: m/z = 313.0 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₆H₁₄BrN₂ ⁺ [M + H]⁺: 313.0340; found: 313.0337. 3-(4-Bromophenyl)-5-(4-fluorophenyl)-1H-pyrazole (3r) Yield: 52%; mp 228–229 °C; R_f = 0.58 (PE–EtOAc = 3:1); white solid. ¹H NMR (400 MHz, DMSO-d ₆ with a drop of concd HCl): δ = 7.95–7.99 (m, 2 H), 7.88 (d, J = 8.5 Hz, 2 H), 7.69 (d, J = 8.5 Hz, 2 H), 7.32–7.37 (m, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆ with a drop of concd HCl): δ = 162.6 (d, ¹ J _CF = 245.7 Hz), 146.9, 146.6, 132.3, 130.1, 128.2 (d, ³ J _CF = 8.4 Hz), 128.0, 127.1 (d, ⁴ J _CF = 3.1 Hz), 122.0, 116.3 (d, ² J _CF = 21.8 Hz), 100.91. ESI-LRMS: m/z = 316.9 [M + H]⁺. ESI-HRMS: m/z calcd for C₁₅H₁₁BrFN₂ ⁺ [M + H]⁺: 317.0090; found: 317.0062. 5-(4-Bromophenyl)-3-p-tolyl-1-tosyl-4,5-dihydro-1H-pyrazole (4p) Yield: 9%; R_f = 0.35 (PE–EtOAc = 5:1); light yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.74 (d, J = 8.2 Hz, 2 H), 7.56 (d, J = 8.1 Hz, 2 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.25–7.28 (m, 4 H), 7.19 (d, J = 8.0 Hz, 2 H), 4.84 (dd, J = 11.1, 9.3 Hz, 1 H), 3.49 (dd, J = 17.2, 11.3 Hz, 1 H), 3.05 (dd, J = 17.2, 9.2 Hz, 1 H), 2.39 (s, 3 H), 2.37 (s, 3 H). ¹³C NMR (400 MHz, CDCl₃): δ = 156.5, 144.2, 141.2, 139.9, 132.4, 131.8, 129.5, 129.4, 128.5, 128.5, 127.7, 126.8, 121.9, 64.5, 43.7, 21.6, 21.5. ESI-LRMS: m/z = 469.0 [M + H]⁺. ESI-HRMS: m/z calcd for C₂₃H₂₂BrN₂O₂S⁺ [M + H]⁺: 469.0585; found: 469.0587.