Efficient Parallel Synthesis of Privileged Benzopyranylpyrazoles via Regioselective Condensation of β-Keto Aldehydes with Hydrazines

摘要

In this study, the practical construction of a pilot library with benzopyranylpyrazole, a novel core skeleton synthesized through the recombination of privileged structures, benzopyran and pyrazole, was successfully conducted through the efficient utilization of solution-phase parallel synthesis using solid-phase reagents and solid-phase parallel synthesis. We have also developed a novel procedure for the synthesis of benzopyranylpyrazoles via regioselective condensation of substituted hydrazines with β-keto aldehydes. The diversity of this core skeleton was expanded by the regioselective introduction of alkyl- and aryl-substituents at the R~1 diversity point on the pyrazole moiety and by the introduction of piperazine on the benzopyran substructure, which provide the R~2 diversity point. Lastly, the introduction of a nitro group on the benzopyran moiety was found to accelerate the nucleophilic aromatic substitution of piperazine and provide the R~3 diversity point at the aniline moiety through the reduction of the nitro group. In this pilot library, we only focused on the diversification at the R~1 position with either the R~2 or R~3 position, and thus maximized the diversity through the rational selection of building blocks using chemoinformatics. Overall, a 192-member benzopyranylpyrazole pilot library was constructed with an appending potential for further diversification. The average purity of the library is 87%.