Synlett 2012; 23(14): 2087-2092
DOI: 10.1055/s-0032-1316584
letter
© Georg Thieme Verlag Stuttgart · New York

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

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
› Author Affiliations
Further Information

Publication History

Received: 29 April 2012

Accepted after revision: 06 June 2012

Publication Date:
03 August 2012 (online)


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.

Supporting Information

 
  • 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; Rf = 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; Rf = 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; Rf = 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%; Rf = 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.