Cryogenic Organometallic Carbon–Fluoride Bond Functionalization with Broad Functional Group Tolerance

Abstract

The unique properties of fluorinated organic compounds have received intense interest and have conquered a myriad of applications in the chemical and pharmaceutical sciences. Today, an impressive range of alkyl fluorides are commercially available, and there are many practical methods to make them exist. However, the unmatched stability and inertness of the C–F bond have largely limited its synthetic value, which is very different from the widely accepted utility of alkyl chlorides, bromides, and iodides that serve everyday as “workhorse” building blocks in countless carbon–carbon bond forming reactions. This study demonstrates practical and high-yielding functionalization of the C–F bond under mild conditions, i.e., at temperatures as low as −78 °C, in short reaction times and with unconventional chemoselectivity. Cryogenic Csp³–F bond cleavage using fluorophilic organoaluminum compounds together with fast nucleophile transfer of intermediate ate complexes forge carbon–carbon bonds with unactivated primary, secondary, and tertiary alkyl fluorides alike. This method, which exploits the stability of the Al–F bond as the thermodynamic driving force, is highly selective toward Csp³–F bond functionalization, whereas many other functional groups including alkyl chloride, bromide, iodide, aryl halide, alkenyl, alkynyl, difluoroalkyl, trifluoromethyl, ether, ester, hydroxyl, acetal, heteroaryl, nitrile, nitro, and amide groups are tolerated, which is an unexpected reversal of long-standing main group organometallic and alkyl halide cross-coupling reactivity and compatibility patterns. As a result, the strongest single bond in organic chemistry can now be selectively targeted in high-yielding arylation, alkylation, alkenylation, and alkynylation reactions and used in late-stage functionalization applications that are complementary to currently available methods.