Synthesis of 2-Pyrazolines with a CF₃- and Alkyne-Substituted Quaternary Carbon Center via [3 + 2] Cycloaddition of β-CF₃-1,3-enynes and Diazoacetates

Abstract

Given the importance of both the CF 3 group and the alkyne moiety in synthetic/medicinal chemistry, we report here the first example of efficient synthesis of 2-pyrazolines with a CF 3 -and alkyne-substituted quaternary carbon center. This methodology has the advantages of high functional group compatibility, the avoidance of base and open-flask conditions, easily available and easy to handle reagent, and broad substrate scope. Notably, this protocol allows for the late-stage functionalization of biologically active molecules and the gram-scale synthesis.P yrazoline derivatives constitute an important class of nitrogen heterocyclic compounds in biological, medicinal, and synthetic chemistry. 1 The incorporation of a trifluoromethyl group (CF 3 ) into pyrazolines is often an effective way to enhance the metabolic stability and lipophilicity. 2 The 2pyrazolines with a quaternary CF 3 -substituted carbon contiguous to the NH moiety are particularly attractive synthetic targets because of their remarkable biological activities and their unique structural features. 3 Representative examples of such molecules are depicted in Figure 1. 1a,4 However, currently available synthetic routes to this class of compounds are not only rare but also suffer from an extremely narrow substrate scope and limited functional group compatibility (Scheme 1). The groups of Huisgen and Reissig reported the 1,3-dipolar cycloaddition reactions of electron-deficient olefins with diazo

Strategies and Methods for the Synthesis of 2‐Pyrazolines: Recent Developments (2012–2022)

“…Reactions were carried out between substituted diazo(thio)esters 84 and β ‐CF 3 ‐enynes 85 under open flask conditions in DMSO (Scheme 16c). The broad substrate scope of this approach enabled the practical synthesis of CF 3 ‐functionalized dihydropyrazoles 86 [37b] in high yields. Notably, diazoacetonitrile afforded the corresponding pyrazolines in 68% yield, whereas α ‐diazo amides, ketones, phenol esters, phosphonate, and trimethylsilyl diazomethanes failed as substrates.…”