One-Pot Synthesis of Densely Substituted Pyrazolo[3,4‑b]‑4,7-dihydropyridines

We have achieved a facile synthesis of a combinatorial library of densely substituted pyrazolo­[3,4-b]-4,7-dihydropyridines the mimics of antigenital wart drug podophyllotoxinfrom 5-aminopyrazoles and 4-(methylthio) 4H-chromenes. The C(4) pyrazolyl 4H-chromenes, which also possess structural features of podophyllotoxin, were isolable intermediates in the two-step, one-pot condensation. The condensation took place in a one-pot, multicomponent manner when 3-oxo-3-phenylpropanenitriles, hydrazine (precursors for 5-aminopyrazoles) and 4-(methylthio)-4H-chromenes were heated in refluxing ethanol. The condensation, however, stops at 4H-chromene stage when methyl hydrazine or phenylhydrazine were employed. Our findings offer an opportunity for synthesis of a combinatorial library of podophyllotoxin mimics, thus paving the way for discovery of lead candidates for cancer treatment.