Synthesis of 1,3,4-Trisubstituted Pyrazoles from α-(1,3-Dithian-2-yl) Enamine Ketones via [4+1] Cyclization

Shugang Wang; Yongguang Li; Xihe Bi; Qun Liu

doi:10.1055/s-0034-1378858

Synlett, Table of Contents

Synlett 2015; 26(13): 1895-1899
DOI: 10.1055/s-0034-1378858

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Synthesis of 1,3,4-Trisubstituted Pyrazoles from α-(1,3-Dithian-2-yl) Enamine Ketones via [4+1] Cyclization

Shugang Wang

^aDepartment of Chemistry, Northeast Normal University, 5268 Renmin Street, Changchun 130024, P. R. of China Email: liuqun@nenu.edu.cn

^bCollege of Chemistry, Jilin University, 2519 Jiefang Road, Changchun 130023, P. R. of China

,

Yongguang Li

^bCollege of Chemistry, Jilin University, 2519 Jiefang Road, Changchun 130023, P. R. of China

,

Xihe Bi

^aDepartment of Chemistry, Northeast Normal University, 5268 Renmin Street, Changchun 130024, P. R. of China Email: liuqun@nenu.edu.cn

,

Qun Liu*

^aDepartment of Chemistry, Northeast Normal University, 5268 Renmin Street, Changchun 130024, P. R. of China Email: liuqun@nenu.edu.cn

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Abstract

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Abstract

A novel method for the synthesis of 1,3,4-trisubstituted pyrazoles from α-(1,3-dithian-2-yl) enamine ketones and primary amines, involving copper(II)-catalyzed oxidative N–N coupling, has been developed. This unprecedented [4+1] approach is versatile in the synthesis of N-aryl, N-benzyl and N-alkyl pyrazoles, and provides an alternative to the conventional [3+2] methods.

Key words

enamine ketones - primary amines - copper(II) - catalysis - N–N coupling - [4+1] cyclization

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References

References and Notes

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17 General Procedure for the Synthesis of α-(1,3-Dithian-2-yl)enamine Ketones (1a): To a 25.0-mL round-bottomed flask, dithiane (10.0 mmol), NH₄OAC (3.85 g, 50.0 mmol) and EtOH (5.0 mL) were added successively. The mixture was stirred at 70 °C. Solid in the flask dissolved into liquid gradually, and a clear solution was obtained. Continuous heating made the solution muddy, and finally solid was precipitated from the solution. The solvent was removed and the residue was cooled. The residue (crude product) was washed with cool EtOH to obtain pure product 1a. Selected Spectral Data of 4-Amino-3-(1,3-dithian-2-yl)pent-3-en-2-one (1aa): yield: 92%; white solid; mp 163–164 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.70–1.83 (m, 2 H), 2.39 (s, 3 H), 2.49 (s, 3 H), 2.81–2.86 (m, 2 H), 2.94–3.01 (m, 2 H), 5.22 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.40, 25.25, 28.74, 33.86, 48.14, 104.64, 167.15, 195.09. General Procedure for the Synthesis of 1,3,4-Trisubstituted Pyrazoles (4b): To a solution of α-(1,3-dithian-2-yl) enamine ketones 1a (1.0 mmol) and primary amine (1.0 mmol) in MeCN (10.0 mL), CuBr₂ (0.1116 g, 0.5 mmol) and Et₃N (0.1518 g, 1.5 mmol) were added. The reaction mixture was warmed to 60 °C and stirred until the staring material was consumed (monitored by TLC). Upon cooling to r.t., the reaction mixture was filtrated and washed with CH₂Cl₂. The filtrate was concentrated in vacuo and purified by column chromatography over silica gel to give product 4b. Selected Data:
1-[3-Methyl-1-(4-methylphenyl)-1H-pyrazol-4-yl]ethanone (4ba): 91% yield; white solid; mp 101–103 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.40 (s, 3 H), 2.47 (s, 3 H), 2.57 (s, 3 H), 7.25–7.28 (d, J = 8.4 Hz, 2 H), 7.54–7.57 (d, J = 8.4 Hz, 2 H), 8.25 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.26, 20.98, 28.65, 119.38, 122.37, 130.08, 130.84, 136.99, 137.25, 151.71, 192.49. HRMS (ESI, TOF): m/z [M + H]⁺ calcd for C₁₃H₁₅N₂O: 215.1186; found: 215.1179.