Copper-Catalyzed C-H (Phenylsulfonyl)difluoromethylation of Acrylamides: Scope, Mechanism, and Critical Role of Additives.

Herein, we report the Cu-complex catalyzed, native functional group-assisted, and TFA/NMF additives promoted (phenylsulfonyl)difluoromethylation of vinylic C(sp2 )-H bond of acrylamides. Using our in-home designed reagent, this reaction enables the construction of the C(sp2 )-CF2 SO2 Ph bond from simple C-H bond activation by copper catalysis under mild reaction conditions with total Z-selectivity. The versatility of utilized fluorinated group was illustrated by its conversion into value-added CF2 moieties as well as the remarkable =CHF residue. The performed experimental and computational mechanistic studies enabled to identify the true nature of active catalyst and substrate, as well as establish critical roles of TFA and NMF additives. In this reaction, the TFA acts as a promoter of the much-needed CuII /CuII →CuIII /CuI disproportionation, while the NMF facilitates the following ligand exchange and C-C coupling processes. We ruled out the generation of radical intermediates and established the C-H activation to be irreversible and the rate-determining step of the entire process.

Electrochemical Difluoromethylation of Electron-Rich Olefins.

The electrochemical difluoromethylation of electron-rich olefins (enamides and styrene derivatives) is disclosed. The addition of the electrogenerated difluoromethyl radical from the corresponding sodium sulfinate (i.e., HCF2SO2Na) to enamides and styrenes in an undivided cell allowed the formation of a large panel of difluoromethylated building blocks in good to excellent yields (42 examples, 23-87% yields). A plausible unified mechanism was suggested according to control experiments and cyclic voltammetry measurements.

C-H Electrophilic (phenylsulfonyl)difluoromethylation of (hetero)arenes with a newly designed reagent.

The synthesis of an original electrophilic difluoromethylating reagent was successfully achieved upon a straightforward protocol (3 steps). Like a Swiss army knife, this bench-stable reagent allowed the functionalization of various classes of compounds under mild and transition metal-free conditions. Hence, an efficient and operationally simple tool for the construction of C(sp2)-, C(sp3)- and S-CF2SO2Ph bonds was provided, expanding the chemical space of PhSO2CF2-containing molecules. Late-stage functionalization of bioactive molecules and the synthesis of PhSO2CF2- and HCF2-analogs of Lidocaine were also successfully achieved.

Radical-Promoted Distal C-H Functionalization of C(sp3 ) Centers with Fluorinated Moieties.

Due to their unique properties, fluorinated scaffolds are pivotal compounds in pharmaceuticals, agrochemicals, and materials science. Over the last years, the development of versatile strategies for the selective synthesis of fluorinated molecules by direct C-H bond functionalization has attracted a lot of attention. In particular, the design of novel transformations based on a radical process was a bottleneck for distal C-H functionalization reactions, offering synthetic solutions for the selective introduction of fluorinated groups. This Minireview highlights the major contributions in this blossoming field. The development of new methodologies for the remote functionalization of aliphatic derivatives with various fluorinated groups based on a 1,5-hydrogen atom transfer process and a ß-fragmentation reaction will be showcased and discussed.

Sulfamyl Radicals Direct Photoredox-Mediated Giese Reactions at Unactivated C(3)-H Bonds.

Alcohol-anchored sulfamate esters guide the alkylation of tertiary and secondary aliphatic C(3)-H bonds. The transformation proceeds directly from N-H bonds with a catalytic oxidant, a contrast to prior methods which have required preoxidation of the reactive nitrogen center, or employed stoichiometric amounts of strong oxidants to obtain the sulfamyl radical. These sulfamyl radicals template otherwise rare 1,6-hydrogen-atom transfer (HAT) processes via seven-membered ring transition states to enable C(3)-H functionalization during Giese reactions.

Catalytic and Asymmetric Process via PIII/PV═O Redox Cycling: Access to (Trifluoromethyl)cyclobutenes via a Michael Addition/Wittig Olefination Reaction.

In the present study, we report the first enantioselective and highly efficient phosphine-catalyzed process via a chemoselective in situ phosphine oxide reduction. Starting with 4,4,4-trifluorobutane-1,3-dione and dialkyl acetylenedicarboxylate substrates, highly functionalized fluorinated cyclobutenes were obtained in excellent yields and enantioselectivities. Using the same methodology, CF3-spirocyclobutene derivatives were also synthesized (34 examples, up to 95% ee).

Synthesis of Sulfur-Containing Exo-Bicyclic Dienes and Their Diels-Alder Reactions To Access Thiacycle-Fused Polycyclic Systems.

The stereocontrolled synthesis of unprecedented sulfur-containing exo-bicyclic 1,3-dienes is reported through a palladium-catalyzed reductive cyclization of sulfur-linked 2-bromoenynes. The fused bicyclic structure provides a better stability to the thiacyclic diene compared to the simple 3,4-dimethylenetetrahydrothiophene. Their reactivity toward several dienophiles has been investigated, and various original thiacycle-fused polycyclic systems have been obtained with high or total diastereoselectivity. Moreover, they are the first exo-bicyclic dienes used in Diels-Alder reactions. The relative configurations of four cycloadducts have been unambiguously assigned by X-ray crystallographic analysis. Mechanistic details of the cycloadditions have been examined by computational means.

Synthesis of N-Substituted Sulfamate Esters from Sulfamic Acid Salts by Activation with Triphenylphosphine Ditriflate.

A general approach to access sulfamate esters through preparation of sulfamic acid salts, subsequent activation with triphenylphosphine ditriflate, and nucleophilic trapping is disclosed. The method proceeds in modest to excellent yields to incorporate nucleophiles derived from aliphatic alcohols and phenols. This approach can be employed to furnish differentially substituted sulfamides.

Aerobic Copper-Mediated Domino Three-Component Approach to 2-Aminobenzothiazole Derivatives.

An unprecedented three-component reaction involving a 2,2'-diaminodiaryl disulfide, copper cyanide, and an electrophile is described. This transformation is based on an oxidative copper-mediated S-cyanation as a key step and involves a cyanation/cyclization/acylation domino sequence enabling a rapid and efficient synthesis of diversely substituted 2-aminobenzothiazole derivatives. Notably, this reaction proceeds via an original mechanism involving an intermolecular migration of the acyl group.

Recent advances in the chemistry of organic thiocyanates.

Organic thiocyanates are important synthetic intermediates to access valuable sulfur-containing compounds. In this review the different methods for their preparation and their synthetic applications will be presented. The literature of the last 15 years will be covered, highlighting selected recent advances in the chemistry of this class of compounds. We hope to offer chemists the tools to have a good grasp of this singular functionality and open the door to further progress in this chemistry.

Cyclocarbopalladation/cross-coupling cascade reactions in sulfide series: access to sulfur heterocycles.

Cyclocarbopalladation/cross-coupling cascade reactions were applied for the first time in a sulfur series and represent an efficient route to access sulfur heterocycles. Stille or Suzuki-Miyaura cross-coupling was successfully used as the final reaction. The products are original benzothiolane and isothiochromane scaffolds with a stereodefined tetrasubstituted exocyclic double bond. To illustrate the application of this method to the synthesis of bioactive molecules, a sulfur analogue of the anticancer agent tamoxifen was prepared as a potential selective estrogen-receptor modulator.