difluoromethylating

Difluoromethylating refers to chemical transformations that introduce a difluoromethyl group (–CF2H) into organic molecules. The difluoromethyl group is a valuable fluorinated motif in medicinal chemistry and agrochemistry because it can influence lipophilicity, acidity, metabolic stability, and hydrogen-bonding properties, while often acting as a bioisostere of hydroxyl or methylene groups.

Radical difluoromethylation is a common approach in which difluoromethyl radicals (CF2H•) are generated from reagents such as sodium difluoromethanesulfinate (Langlois reagent) under oxidizing or photoredox conditions. These radicals add to arenes, heterocycles, or alkenes to form difluoromethylated products, enabling late-stage functionalization of complex molecules.

Organometallic cross-coupling is another strategy, utilizing difluoromethyl zinc or copper reagents to form C–CF2H bonds by coupling with aryl or vinyl halides under transition-metal catalysis. These methods expand the scope to a wide range of substrates and permit installation of the CF2H group under relatively mild conditions.

Difluoromethylation via difluoromethylating reagents involves sources such as difluoromethyltrimethylsilane (TMSCF2H), which, upon fluoride activation, generates difluoromethyl anion equivalents for nucleophilic difluoromethylation of carbonyl compounds. This route can yield difluoromethylated alcohols or ethers.

Electrophilic difluoromethylation uses CF2H sources such as difluoromethyl sulfonium salts to difluoromethylate nucleophiles, including amines and heteroatoms, broadening the chemistry to N-, O-, and S-difluoromethylations.

Applications and challenges: The difluoromethyl group is widely used in drug discovery to tune pharmacokinetic properties. Challenges include reagent availability and cost, controlling regio- and chemoselectivity, and safety due to volatile or reactive difluoromethyl sources. Ongoing work aims to improve substrate scope, selectivity, and operational simplicity.

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