A new and direct route to 3-fluoromethyl substituted pyrazol-4-acrylates via Pd-catalyzed C-H activation

Direct C4-H activation of 3-fluoromethyl pyrazoles followed by an oxidative coupling with acrylates, which is perhaps the most direct method for the synthesis of 3-fluoromethyl substituted pyrazol-4-acrylates of biological interest, remains challenging. Here, the first example of the straightforward olefination via Pd-catalyzed C4-H activation of both C3-CF3 and C3-CF2H substituted pyrazoles is reported. The reaction of various C3-CF3 substituted pyrazoles with acrylates proceeds smoothly in the presence of Pd(OAc)2 and Ag2CO3, whereas olefination of C3-CF2H substituted pyrazoles requires the addition of benzoquinone. A further computational study reveals that reactivity of the pyrazolyl substrates employed are strongly impacted by the substituents of different nature on their C1 or C5 position, which is in good agreement with the experimental data.

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