Desymmetrization of difluoromethylene groups by C-F bond activation.

Tertiary stereogenic centres containing one fluorine atom are valuable for medicinal chemistry because they mimic common tertiary stereogenic centres containing one hydrogen atom, but they possess distinct charge distribution, lipophilicity, conformation and metabolic stability1-3. Although tertiary stereogenic centres containing one hydrogen atom are often set by enantioselective desymmetrization reactions at one of the two carbon-hydrogen (C-H) bonds of a methylene group, tertiary stereocentres containing fluorine have not yet been constructed by the analogous desymmetrization reaction at one of the two carbon-fluorine (C-F) bonds of a difluoromethylene group3. Fluorine atoms are similar in size to hydrogen atoms but have distinct electronic properties, causing C-F bonds to be exceptionally strong and geminal C-F bonds to strengthen one another4. Thus, exhaustive defluorination typically dominates over the selective replacement of a single C-F bond, hindering the development of the enantioselective substitution of one fluorine atom to form a stereogenic centre5,6. Here we report the catalytic, enantioselective activation of a single C-F bond in an allylic difluoromethylene group to provide a broad range of products containing a monofluorinated tertiary stereogenic centre. By combining a tailored chiral iridium phosphoramidite catalyst, which controls regioselectivity, chemoselectivity and enantioselectivity, with a fluorophilic activator, which assists the oxidative addition of the C-F bond, these reactions occur in high yield and selectivity. The design principles proposed in this work extend to palladium-catalysed benzylic substitution, demonstrating the generality of the approach.

gem-Difluoroallylation of Aryl Halides and Pseudo Halides with Difluoroallylboron Reagents in High Regioselectivity.

We report the palladium-catalyzed gem-difluoroallylation of aryl halides and pseudo halides with 3,3-difluoroallyl boronates in high yield with high regioselectivity, and we report the preparation of the 3,3-difluoroallyl boronate reactants by a copper-catalyzed defluorinative borylation of inexpensive gaseous 3,3,3-trifluoropropene with bis(pinacolato)diboron. The gem-difluoroallylation of aryl and heteroaryl bromides proceeds with low catalyst loading (0.1 mol % [Pd]) and tolerates a wide range of functional groups, including primary alcohols, secondary amines, ethers, ketones, esters, amides, aldehydes, nitriles, halides, and nitro groups. This protocol extends to aryl iodides, chlorides, and triflates, as well as substituted difluoroallyl boronates, providing a versatile synthesis of gem-difluoroallyl arenes that we show to be valuable intermediates to a series of fluorinated building blocks.

Copper-Catalyzed Defluorinative Borylation and Silylation of gem-Difluoroallyl Groups.

Stereodefined (Z)-fluoroalkenes are bioisosteres of amides and synthetic precursors to value-added fluorinated compounds, but their stereoselective synthesis remains challenging. Herein, we report a copper-catalyzed formal SN2' defluorinative borylation of 3-substituted 3,3-difluoropropenes to form 3-fluoroallylboronic esters in high yields with excellent Z/E ratios. The primary 3-fluoroallylboronic esters undergo several synthetic sequences involving SE2' substitutions, SN2' substitutions, and sigmatropic rearrangements to provide tertiary allylic fluorides.

Printable Ultrathin Metal Oxide Semiconductor-Based Conformal Biosensors.

Conformal bioelectronics enable wearable, noninvasive, and health-monitoring platforms. We demonstrate a simple and straightforward method for producing thin, sensitive In2O3-based conformal biosensors based on field-effect transistors using facile solution-based processing. One-step coating via aqueous In2O3 solution resulted in ultrathin (3.5 nm), high-density, uniform films over large areas. Conformal In2O3-based biosensors on ultrathin polyimide films displayed good device performance, low mechanical stress, and highly conformal contact determined using polydimethylsiloxane artificial skin having complex curvilinear surfaces or an artificial eye. Immobilized In2O3 field-effect transistors with self-assembled monolayers of NH2-terminated silanes functioned as pH sensors. Functionalization with glucose oxidase enabled d-glucose detection at physiologically relevant levels. The conformal ultrathin field-effect transistor biosensors developed here offer new opportunities for future wearable human technologies.