J Org Chem. 2023 Mar 23. doi: 10.1021/acs.joc.2c02771. Online ahead of print.
ABSTRACT
Within the scope of developing a new route to an active pharmaceutical ingredient intermediate, we had need of a fluorinated indazole. Although an established route was in place, it was undesirable due to safety and selectivity concerns. A concise and improved route was developed to form the desired indazole, which takes advantage of an electronically directed metalation/formylation sequence followed by condensation with methyl hydrazine to form a hydrazone and culminates in a copper-catalyzed intramolecular Ullmann cyclization. The Ullmann reaction was plagued with difficulties ranging from poor reactivity to thermal hazard concerns, but use of high-throughput screening, statistical modeling, and an unusual isolation method for fine chemicals, safe and optimal conditions were found that produce high-purity isolated material in excellent yields at a laboratory scale.
PMID:36951763 | DOI:10.1021/acs.joc.2c02771
