One-Pot Synthesis of 1,4-Disubstituted Pyrazoles from Arylglycines via Copper-Catalyzed Sydnone–Alkyne Cycloaddition Reaction

Abstract

A robust method for constructing 1,4-pyrazoles from arylglycines was developed using the copper-catalyzed sydnone-alkyne cycloaddition reaction. The procedure offers a straightforward and general route to the pyrazole heterocycle through a three-step one-pot procedure.

Synthesis of aminopyrazoles from sydnones and ynamides

“…A popular approach is the use of Lewis acids, since via coordination to the sydnone, the reaction is favoured and the regioselectivity of the pyrazole products can be affected. 12,45 The use of copper promoters has also been shown to affect regioselectivity and facilitate the cycloaddition reaction, commonly referred to as a Cu-mediated Sydnone Alkyne Cycloaddition (CuSAC). 11,13 Based on these reports, we decided to undertake a screening of readily available copper catalysts and study their effect on the cycloaddition between ynamides and sydnones.…”

“…1 Previously reported attempts to try to address these issues include the use of alkynylboronates 9,10 or copper promoters to direct the regioselectivity of the sydnone-alkyne cycloaddition reactions. [11][12][13] Due to the high interest towards new routes to fully functionalised pyrazoles, which are known to possess biological activities, 14,15 we were interested in expanding the scope of the sydnone-alkyne cycloaddition reaction to increase the tolerance for activated and electron-rich alkynes. To do so, we developed the synthesis of 4-aminopyrazoles from cycloaddition reactions between sydnones and ynamides, which have not been reported to date.…”

Crystal structure of 3-(5-methyl-1-p-tolyl-1H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde, a rare Z′ = 3 structure, C20H17N5O

“…Compounds containing a pyrazole ring system [6][7][8][9][10] exhibit a wide range of biological applications. Hence, it has been shown that many derivatives show antimicrobial, fungicidal, anticancer and antioxidant activities [11][12][13][14].…”

Sydnone Cycloaddition Route to Pyrazole-Based Analogs of Combretastatin A4

“…31 These cycloadditions can be highly regioselective and offer access to a wide range of pyrazoles. 32,33,34,35,36,37 In the context of developing novel VDAs, we envisaged that the sydnone cycloaddition strategy could be exploited to access a broad range of pyrazole templated combretastatin analogs from similar starting materials (Scheme 1). However, we recognized that a number of synthetic challenges needed to be met in order to achieve this goal: (1) access to 1,5-substituted pyrazoles theoretically required high temperature cycloaddition with acetylene gas; (2) 4,5-disubstituted…”