Base-mediated [3+2]-cycloannulation strategy for the synthesis of pyrazolo[1,5-a]pyridine derivatives using (E)-β-iodovinyl sulfones

Pyrazolo[1,5-a]pyridines continue to occupy a special place in medicinal chemistry, but the direct construction of 3-sulfonyl analogues remains unexplored. Under basic conditions, pyridinium-N-amine and the corresponding dipolar aminide played a vibrant role in [3 + 2]-cycloaddition using (E)-beta-iodovinyl sulfones. K2CO3-mediated tandem cycloannulative-desulfonylation of (E)-beta-iodovinyl sulfones with 1-aminopyridinium iodide is realized to access 2-substituted pyrazolo[1,5-a]pyridines in good to high yields. An essential modification of the dipolar N-tosylpyridinium imide allows the first preparative synthesis of 3-sulfonyl-pyrazolo[1,5-a]pyridines in moderate to high yields. Of note, the metal-free protocol features a broad substrate scope with good functional group tolerance and compatibility. The efficacy of the process was proved with gram-scale reactions, and a plausible mechanism is also presented based on concrete results.

Automated summary

Pyrazolo[1,5-a]pyridines continue to play an important role in medicinal chemistry, but the direct synthesis of 3-sulfonyl analogues has not been explored. In this study, a method for the synthesis of 2-substituted pyrazolo[1,5-a]pyridines was developed using (E)-beta-iodovinyl sulfones and 1-aminopyridinium iodide. Additionally, a modification of the dipolar N-tosylpyridinium imide allowed for the preparation of 3-sulfonyl-pyrazolo[1,5-a]pyridines. The metal-free protocol demonstrated a wide substrate scope and good functional group tolerance.