2,2-Difluoroethylation of Heteroatom Nucleophiles via a Hypervalent Iodine Strategy.

The 2,2-difluoroethyl group is an important lipophilic hydrogen bond donor in medicinal chemistry, but its incorporation into small molecules is often challenging. Herein, we demonstrate electrophilic 2,2-difluoroethylation of thiol, amine and alcohol nucleophiles with a hypervalent iodine reagent, (2,2-difluoro-ethyl)(aryl)iodonium triflate, via a proposed ligand coupling mechanism. This transformation offers a complementary strategy to existing 2,2-difluoroethylation methods and allows access to a wide range of 2,2-difluoroethylated nucleophiles, including the drugs Captopril, Normorphine and Mefloquine.

Programmable Deuteration of Indoles via Reverse Deuterium Exchange.

Methods for selective deuterium incorporation into drug-like molecules have become extremely valuable due to the commercial, mechanistic, and biological importance of deuterated compounds. Herein, we report a programmable labeling platform that allows access to C2, C3, or C2- and C3-deuterated indoles under mild, user-friendly conditions. The C2-deuterated indoles are accessed using a reverse hydrogen isotope exchange strategy which represents the first non-directed C2-deuteration of indoles.

A Guide to Directing Group Removal: 8-Aminoquinoline.

The use of directing groups allows high levels of selectivity to be achieved in transition metal-catalyzed transformations. Efficient removal of these auxiliaries after successful functionalization, however, can be very challenging. This review provides a critical overview of strategies used for removal of Daugulis' 8-aminoquinoline (2005-2020), one of the most widely used N,N-bidentate directing groups. The limitations of these strategies are discussed and alternative approaches are suggested for challenging substrates. Our aim is to provide a comprehensive end-users' guide for chemists in academia and industry who want to harness the synthetic power of directing groups-and be able to remove them from their final products.

Copper-Catalyzed Chan-Lam Cyclopropylation of Phenols and Azaheterocycles.

Small molecules containing cyclopropane-heteroatom linkages are commonly needed in medicinal chemistry campaigns yet are problematic to prepare using existing methods. To address this issue, a scalable Chan-Lam cyclopropylation reaction using potassium cyclopropyl trifluoroborate has been developed. With phenol nucleophiles, the reaction effects O-cyclopropylation, whereas with 2-pyridones, 2-hydroxybenzimidazoles, and 2-aminopyridines the reaction brings about N-cyclopropylation. The transformation is catalyzed by Cu(OAc)2 and 1,10-phenanthroline and employs 1 atm of O2 as the terminal oxidant. This method is operationally convenient to perform and provides a simple, strategic disconnection toward the synthesis of cyclopropyl aryl ethers and cyclopropyl amine derivatives bearing an array of functional groups.

Protodepalladation as a Strategic Elementary Step in Catalysis.

Protodepalladation is the redox-neutral conversion of a C-Pd(II) bond to a C-H bond promoted by a Brønsted acid. It can be viewed as the microscopic reserves of Pd(II)-mediated C-H cleavage. In the context of catalytic reaction development, protodepalladation offers a means of converting organopalladium(II) intermediates to organic products without a change in oxidation state at the metal center. Hence, when integrated into catalytic cycles, it can be a uniquely enabling elementary step. The goal of this Review is to provide an overview of protodepalladation, including exploration of different reactions types, discussion of literature examples, and analysis of mechanistic features. Our hope is that this review will stimulate other researchers in the field to pursue new applications of this underexploited step in catalysis.

Tridentate Directing Groups Stabilize 6-Membered Palladacycles in Catalytic Alkene Hydrofunctionalization.

Removable tridentate directing groups inspired by pincer ligands have been designed to stabilize otherwise kinetically and thermodynamically disfavored 6-membered alkyl palladacycle intermediates. This family of directing groups enables regioselective remote hydrocarbofunctionalization of several synthetically useful alkene-containing substrate classes, including 4-pentenoic acids, allylic alcohols, homoallyl amines, and bis-homoallylamines, under Pd(II) catalysis. In conjunction with previous findings, we demonstrate regiodivergent hydrofunctionalization of 3-butenoic acid derivatives to afford either Markovnikov or anti-Markovnikov addition products depending on directing group choice. Preliminary mechanistic and computational data are presented to support the proposed catalytic cycle.

Palladium(II)-Catalyzed Directed anti-Hydrochlorination of Unactivated Alkynes with HCl.

A regioselective anti-hydrochlorination of unactivated alkynes is reported. The reaction utilizes in situ generated HCl as the source of both the Cl- and H+ and is catalyzed by palladium(II) acetate, with loadings as low as 25 ppm. Removable picolinamide and 8-aminoquinoline bidentate directing groups are used to control the regioselectivity of the chloropalladation step and stabilize the resulting alkenylpalladium(II) intermediate for subsequent protodepalladation. This method provides access to a broad array of substituted alkenyl chlorides in excellent yields and with high regioselectivity. The products from this transformation were successfully derivatized via Stille coupling to a variety of trisubstituted alkene products. Reaction progress kinetic analysis was performed, shedding light on a possible mechanism for this catalytic process.

Cross-Coupling of [2-Aryl-1,1,2,2-tetrafluoroethyl](trimethyl)silanes with Aryl Halides.

The synthesis of arylCF2CF2SiMe3 and their reactivity in cross-coupling reactions with aryl iodides and aryl bromides to afford a range of 1,1,2,2-tetrafluoro-1,2-arylethanes is reported. The use of pyridine as an alternative to phenanthroline, and the ability to carry out the reaction at 60 °C or room temperature are the key features of this Cu-Ag mediated cross-coupling methodology. The chemistry is compatible with (hetero)aryl halides, offering a platform to develop products of interest in material and medicinal chemistry.

Recruitment and Immobilization of a Fluorinated Biomarker Across an Interfacial Phospholipid Film using a Fluorocarbon Gas.

Perfluorohexane gas when introduced in the air atmosphere above a film of phospholipid self-supported on an aqueous solution of C2F5-labeled compounds causes the recruitment and immobilization of the latter in the interfacial film. When the phospholipid forms a liquid-condensed Gibbs monolayer, which is the case for dipalmitoylphosphatidylcholine (DPPC), the C2F5-labeled molecule remains trapped in the monolayer after removal of F-hexane. Investigations involve bubble profile analysis tensiometry (Gibbs films), Langmuir monolayers and microbubble experiments. The new phenomenon was utilized to incorporate a hypoxia biomarker, a C2F5-labeled nitrosoimidazole (EF5), in microbubble shells. This finding opens perspectives in the delivery of fluorinated therapeutic molecules and biomarkers.

Catalytic decarboxylative fluorination for the synthesis of tri- and difluoromethyl arenes.

Treatment of readily available α,α-difluoro- and α-fluoroarylacetic acids with Selectfluor under Ag(I) catalysis led to decarboxylative fluorination. This operationally simple reaction gave access to tri- and difluoromethylarenes applying a late-stage fluorination strategy. Translation to [(18)F]labeling is demonstrated using [(18)F]Selectfluor bis(triflate), a reagent affording [(18)F]tri- and [(18)F]difluoromethylarenes not within reach with [(18)F]F2.

Trifluoromethylation of allylsilanes under photoredox catalysis.

A new catalytic method to access allylic secondary CF3 products is described. These reactions use the visible light excited Ru(bpy)3Cl2·6H2O catalyst and the Togni or Umemoto reagent as the CF3 source. The photoredox catalytic manifold delivers enantioenriched allylic trifluoromethylated products not accessible under Cu(I) catalysis.

Catalytic hydrotrifluoromethylation of unactivated alkenes.

A visible-light-mediated hydrotrifluoromethylation of unactivated alkenes that uses the Umemoto reagent as the CF(3) source and MeOH as the reductant is disclosed. This effective transformation operates at room temperature in the presence of 5 mol % Ru(bpy)(3)Cl(2); the process is characterized by its operational simplicity and functional group tolerance.