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

Ping Liu; Qian-Qian Xu; Chao Dong; Xinsheng Lei; Guo-qiang Lin

doi:10.1055/s-0032-1316584

Synlett, Table of Contents

Synlett 2012; 23(14): 2087-2092
DOI: 10.1055/s-0032-1316584

letter

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

Authors

Ping Liu

Department of Chemistry and School of Pharmacy, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China, Fax: +86(21)51980128 Email: leixs@fudan.edu.cn Email: lingq@sioc.ac.cn
Qian-Qian Xu

Department of Chemistry and School of Pharmacy, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China, Fax: +86(21)51980128 Email: leixs@fudan.edu.cn Email: lingq@sioc.ac.cn
Chao Dong

Department of Chemistry and School of Pharmacy, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China, Fax: +86(21)51980128 Email: leixs@fudan.edu.cn Email: lingq@sioc.ac.cn
Xinsheng Lei*

Department of Chemistry and School of Pharmacy, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China, Fax: +86(21)51980128 Email: leixs@fudan.edu.cn Email: lingq@sioc.ac.cn
Guo-qiang Lin*

Department of Chemistry and School of Pharmacy, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China, Fax: +86(21)51980128 Email: leixs@fudan.edu.cn Email: lingq@sioc.ac.cn

Abstract

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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

Full Text

References

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.

Supplementary Material

Supporting Information (PDF)