Synthesis of Zaleplon

The synthesis of zaleplon (Scheme 15.3) starts by condensing acetophenone derivative 13 with dimethylformamide dimethylacetal (DMF-DMA) to provide enamine 14 (Mealy et ah, 1996 Dusza et al., 1987). A subsequent alkylation with ethyl iodide in the presence of sodium hydride gave 15. Zaleplon (2) is assembled by condensing amino-pyrazole 16 with enamine 15 in refluxing acetic acid. 

In 2010, Radi and coworkers reported the synthesis of isozaleplon, which is a regioisomer of the therapeutic drug Zaleplon to treat insomnia. The synthesis of isozaleplon featured the key C-C bond formation via direct arylation of the tautomerizable heterocycle with the arylboronic ester using PyBroP in the presence of PdCl2(PPh3)2 catalyst (10H1359). 

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