Development of a Three-Component Iron-Catalyzed Difluoromethylation Reaction

/Abstract The incorporation of difluoromethyl (–CF2H) group has become a leading strategy in pharmaceutical development to enhance drug performance due to –CF2H’s unique and profound bioisosteric activity for hydroxyls, amines, and thiols as a result of its hydrogen bond ability. Presently, transition metal-mediated approaches for the direct incorporation of the –CF2H group is an attractive methodology in the context of selective late-stage functionalization of complex molecules. While there is an abundance of synthetic methods employing this approach for the formation of the traditional carbon(sp2)-CF2H bonds, general protocols for the formation of more challenging carbon(sp3)-CF2H bonds are still limited. Hence, there is an urgent and unmet need to develop new, sustainable, and efficient synthesis methods to accelerate the synthesis and evaluation of bioactive compounds containing C(sp3)-CF2H bonds. The hallmark of this proposal is the development of three-component iron-catalyzed difluoromethylation reactions mediated through iron metal for the formation of C(sp3)–CF2H bonds. To achieve this objective, I will put forward two strategies. The strategies differ not in the specific C(sp3)–CF2H bond that is to be formed, but in the distinct, yet complementary, mechanistic manifold of introducing the difluoromethyl group into the organic substrate. The first approach employs HCF2–X electrophiles as •CF2H radical precursors which can, through strategic manipulation of reaction conditions, engage with a “radical lynchpin” and subsequently C(sp3)–CF2H bond formation with a well-defined iron-species (Aim 1). The second strategy will implement the use of organozinc reagent, [(DMPU)2Zn(CF2H)2], as a nucleophilic source of –CF2H group to be transmetalated into the iron catalytic cycle as a complementary route to synthesize the C(sp3)–CF2H bond (Aim 2). To bolster these efforts, I plan to implement advanced spectroscopic techniques (Mössbauer spectroscopy and single-crystal X- ray diffraction) as well as computational chemistry to accelerate the development of three-component iron- catalyzed difluoromethylation reactions. While both approaches target the development of iron-mediated synthetic methods that permit the direct incorporation of the –CF2H group, the mode of introduction is different. In doing so, this research project will foster the growth in knowledge in iron catalysis. The long-term goal of this proposal is to expand the fundamental research of domestically manufactured metals in the U.S., such as earth-abundant iron, for the development of synthetic methods that permit expedient access to high-value molecules in an economical, sustainable, and safe manner all while fostering and refining our knowledge and understanding of it. Project Number: 1F32GM165088-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Lupita Aguirre | Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES, LOS ANGELES, CA | Award Amount: $75,880 | Activity Code: F32 | Study Section: Special Emphasis Panel[ZRG1 F04A-K (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11388739