Nucleophilic FluorinationNi-catalyzed Cross Coupling

Nucleophilic Fluorination


An expansive array of medicines, agrochemicals, and materials contain fluorine due to the unique chemical properties that the element confers on organic molecules. One of the chief obstacles to the discovery and production of these compounds is the availability of synthetic methods for carbon–fluorine (C–F) bond formation. The most abundant and inexpensive fluorine sources, nucleophilic fluoride salts, typically suffer from low solubility, high hygroscopicity, and strong Brønsted basicity, rendering them recalcitrant reagents for chemical synthesis. Nevertheless, our laboratory has recently identified two strategies that achieve mild and efficient nucleophilic fluorination using transition metal catalysis. These stereoselective methods represent exciting platforms for the invention of a wide spectrum of chemical transformations. Through mechanistic studies, we are interested in assembling a better understanding of the properties and reactivity of transition metal fluorides. Ultimately, our efforts may enable the discovery and manufacture of novel pharmaceuticals, materials, and small-molecule tracers for positron emission tomography (PET).


Ni-catalyzed Cross Coupling


NiTransition metal-catalyzed cross coupling, recently awarded the Nobel Prize in Chemistry, has revolutionized the way that chemists assemble carbon–carbon (C–C) bonds. These reactions typically involve halogenated aromatic electrophiles, which represent a small subset of the reaction partners used in organic synthesis. Our laboratory is interested in developing new cross-coupling reactions with classic aliphatic electrophiles in organic synthesis, including epoxides, aziridines, N,O-acetals, and acetals. Achieving cross coupling with these electrophiles poses a number of challenges, including the relative inertness of the Csp3–O or Csp3–N bond undergoing activation and the propensity of the resulting organometallic intermediate to decompose by β-H elimination. To overcome these challenges, we have identified a dual activation strategy wherein the organometallic partner of the cross-coupling reaction promotes C–O or C–N oxidative addition by Lewis acid complexation. In turn, the organometallic partner is activated toward transmetalation by Lewis base association. In the context of this strategy, we have pursued the intriguing possibility that the cross-coupling reactions may be initiated by an oxidative insertion into the C=N or C=O π system of iminium and oxocarbenium ions rather than by the process of oxidative addition into a C–X σ bond. This unusual alternative should enable the design of a wide range of synthetic methods for the preparation of amines and ethers. In addition to methodology development and mechanistic investigations, an important objective of this program is to demonstrate the utility of the chemistry by applications that permit rapid and efficient access to biologically active natural products and medicinal agents.