Optimized Synthesis of 7-Aza-Indazoles by Diels–Alder Cascade and Associated Process Safety

16 April 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Although pyrimidines are not among the most reac-tive partners in intramolecular inverse-electron de-mand [4πs+2πs] reactions with alkynes, they could be activated under mild and practical conditions, leading to fused nitrogen-containing heterocycles. We report an optimized synthesis of a 5-iodo-7-aza-indazole by a one-pot Diels–Alder cascade that starts from a pyrimidine substituted in the 2-position by an (alkynyl)hydrazone. The safety of the process was carefully studied by DSC studies. Eventually, a selection of cross-coupling reactions of 17 was studied and allowed the introduction of carbon- and nitrogen-based nucleophiles at the C5-position in good to excellent yields.

Keywords

Hetero-Diels-Alder reaction
indazole
aza-indazole
cycloaddition
Process Chemistry
Safety evaluation
DSC studies
Cross-Coupling Reactions

Supplementary materials

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Supporting Information-v11
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