Stereodivergent Palladium-Catalyzed C-F Bond Functionalization of gem-Difluoroalkenes.

We herein describe a stereodivergent C-F bond functionalization of gem-difluoroalkenes. Using trisubstituted ß,ß-difluoroacrylates, both E and Z monofluoroalkene products can be obtained with excellent diastereoselectivities. The design of two different reaction manifolds, i.e., Pd(II)- versus Pd(0)-catalyzed cross-coupling of boronic acids, is the key to stereocontrol.

Rhodium(I)-Catalyzed Defluorinative Bisarylation of Monofluorodienes with Boronic Acids.

We herein describe a Rh(I)-catalyzed bisarylation reaction of monofluorodienes using arylboronic acids. Two aryl groups are installed in the trisubstituted (E)-alkene products in one step with excellent diastereoselectivities. An intriguing reaction sequence of Rh(I)-catalyzed 1,6-addition followed by defluorinative coupling is proposed for product formation.

Addition of Carboxylic Acids to gem-Difluoroalkenes for the Synthesis of gem-Difluoromethylenated Compounds.

We herein describe a straightforward protocol for the synthesis of carboxylic esters containing a gem-difluoromethylene unit. Readily available carboxylic acids can act as nucleophiles to add regioselectively to tetrasubstituted or trisubstituted ß,ß-difluoroacrylates (formal hydroacetoxylation) for the construction of RCO2-CF2 bonds. Thermal conditions are sufficient without the use of catalysts or additives.

Stereoselective Palladium-Catalyzed Hiyama Cross-Coupling Reaction of Tetrasubstituted gem-Difluoroalkenes.

We herein describe a diastereoselective Pd(0)-catalyzed Hiyama cross-coupling reaction of gem-difluoroalkenes. The use of organosilicon reagents in this reaction is advantageous over other organometallic reagents by allowing the introduction of a wide range of functional groups, including challenging alkyl groups. Also conveniently, the additive TBAF was not required for (hetero)aryl-substituted difluoroalkenes.

Synthesis of Difluoromethylated Alkenes via Copper-Catalyzed Protodefluorination of ß-(Trifluoromethyl)styrenes.

Under typical copper-catalyzed hydroboration conditions, ß-(trifluoromethyl)styrenes demonstrate unusal reactivities by forming difluoromethylated alkenes via a net protodefluorination process. This is also distinct from trifluoromethyl alkenes with alkyl substituents where defluoroborylation products predominate.

Stereoselective Palladium-Catalyzed C-F Bond Alkenylation of Tetrasubstituted gem-Difluoroalkenes via Mizoroki-Heck Reaction.

A highly diastereoselective Pd(0)-catalyzed Mizoroki-Heck reaction of gem-difluoroalkenes is described. Unlike previously reported C-F bond functionalization with organometallic reagents, this reaction takes place between two different alkenes to achieve a formal C-F and C-H bond cross-coupling via a distinct pathway. Monofluorinated 1,3-diene products can be synthesized with control of the geometry of each alkene and good functional group tolerability.

Three-Component Domino Acylation/Trifluoromethylation of Bicyclic Amidines.

We herein describe a three-component reaction involving bicyclic amidines such as DBN/DBU, acyl fluorides, and TMSCF3 for access to a novel class of N-acyl trifluoromethylated bicyclic aminals. Under mild and operationally simple conditions, bicyclic amidines can undergo difunctionalization (acylation/trifluoromethylation) using readily available reagents. Further Lewis acid-promoted nucleophilic ring-opening can lead to diverse products with quaternary carbon centers containing CF3. The corresponding pentafluoroethylation is also achieved by using TMSC2F5.

Palladium-Catalyzed Stereoselective Defluoroborylation of gem-Difluoroalkenes with Unsymmetrical Diboron: Access to Tetrasubstituted Monofluorinated Vinyl-B(dan) Derivatives.

The stereoselective C-F bond borylation of tetrasubstituted ß,ß-difluoroacrylates has been achieved. In contrast to the previously used B2pin2 reagent, which only led to dimerization products, this work employs the unsymmetrical diboron reagent (pin)B-B(dan) under the palladium(0)-catalyzed conditions to access novel boronamides containing the monofluorinated vinyl-B(dan) functionality. These compounds can cross-couple directly with gem-difluoroalkenes without reactivation in Suzuki-Miyaura reactions to afford vincinal difluoro 1,3-dienes with modular control of the substituents.

Interrupted Click Reaction with CuCF2CF3 Reagent: Synthesis of 5-Pentafluoroethyl 1,2,3-Triazoles.

We herein describe a three-component interrupted click reaction to synthesize novel 5-pentafluoroethyl 1,2,3-triazoles in one step from readily available terminal alkynes and azides. The key reagent [CuCF2CF3], prepared from the low-cost gas pentafluoroethane, demonstrates an orthogonal reactivity in facilitating cycloaddition rather than previously reported radical reactions. Reaction conditions are mild by using air as a green oxidant.

Palladium-Catalyzed Stereoselective Defluorosilylation of gem-Difluoroalkenes for the Synthesis of Tetrasubstituted Monofluorinated Vinylsilanes.

Stereoselective synthesis of tetrasubstituted vinylsilanes is a challenging task. We herein report a novel palladium(0)-catalyzed defluorosilylation of ß,ß-difluoroacrylates to access tetrasubstituted vinylsilanes containing the monofluoroalkene motif in excellent diastereoselectivities (>99:1). This is our first example of C-heteroatom bond formation from the C-F bond under such a Pd catalytic manifold.

Radical Fluorosulfonyl Heteroarylation of Unactivated Alkenes with Quinoxalin-2(1H)-ones and Related N-Heterocycles.

The incorporation of sulfonyl fluoride groups into molecules has been proved effective to enhance their biological activities or introduce new functions. Herein, we report a transition-metal-free and visible-light-mediated radical 1-fluorosulfonyl-2-heteroarylation of alkenes, which could allow access to a series of SO2F-containing quinoxalin-2(1H)-ones, which are a critical structural motif widely present in a number of biologically active molecules. Further application of the method to the modification of other heterocycles and drug molecules as well as ligation chemistry via SuFEx click reactions is also demonstrated.

Copper-Catalyzed Visible-Light-Induced Allylic Difluoromethylation of Unactivated Alkenes Using Difluoroacetic Acid.

We herein describe a straightforward allylic difluoromethylation reaction of unactivated alkenes. Compared to cross-couplings of prefunctionalized allylic substrates for the construction of allylic CF2H bonds, this reaction employs readily available alkenes as substrates under mild conditions. Difluoroacetic acid is used as an inexpensive and easy-to-handle source of CF2H radical under visible light irradiation with PIDA. The copper catalyst plays an important role of diverting the reaction pathway toward allylic difluoromethylation as opposed to previously found hydrodifluoromethylation.

Stereoselective Rhodium(I)-Catalyzed C-F Bond Arylation of Tri- and Tetrasubstituted gem-Difluoroalkenes with Boronic Acids.

We herein describe a highly diastereoselective rhodium(I)-catalyzed C-F bond functionalization of gem-difluoroalkenes with arylboronic acids. In contrast to previously developed Pd(II)- and Pd(0)-catalyzed methods, the Rh(I)/BINAP catalytic system enabled the C-F bond arylation of both trisubstituted ß,ß-difluorostyrenes and tetrasubstituted ß,ß-difluoroacrylates in >99:1 dr toward the synthesis of valuable monofluoroalkenes. Experimental and computational studies suggested a plausible migratory insertion/ß-F elimination mechanism with the [Rh(I)-Ar] species.

Rhodium(I)-Catalyzed Defluorinative Coupling of Boronic Acids with Monofluoroalkenes.

We herein describe a highly selective Rh(I)-catalyzed defluorinative coupling of boronic acids with (E)-ß-monofluoroacrylates. In contrast to previous methods, the trisubstituted (Z)-alkene products were obtained in excellent dr with an inversion of double bond geometry. Experimental and computational studies established that Rh(I)-facilitated ß-F elimination is favored over competing ß-H elimination and protodemetalation.

Organocatalytic Three-Component Acyldifluoromethylation of Vinylarenes via N-Heterocyclic Carbene-Catalyzed Radical Relay.

We herein describe an N-hetercyclic carbene-catalyzed three-component acyldifluoromethylation of vinylarenes, aldehydes, and NaSO2CF2H. This organocatalytic approach provides a practical route for the synthesis of pharmaceutically relevant α-aryl-ß-difluormethyl ketones without the need for transition metals or photocatalysts. The late-stage acyldifluoromethylation of drug analogues was also demonstrated. The reaction design employs NaSO2CF2H as the source of the CF2H radical in the presence of an oxidant for the radical relay.

Highly Selective C-F Bond Functionalization of Tetrasubstituted gem-Difluoroalkenes and Trisubstituted Monofluoroalkenes Using Grignard Reagents.

We herein describe selective C-F bond functionalizations of tetrasubstituted gem-difluoroalkenes and trisubstituted monofluoroalkenes using Grignard reagents without the transition metal catalyst. ß,ß-Difluoroacrylates react with Grignard reagents under mild conditions to afford tetrasubstituted (E)-ß-monofluoroacrylates. Experimental and computational studies revealed that the selectivity stems from the intrinsic reactivity difference between the (E)- and (Z)-isomers toward excess Grignard reagent, which leads to the resolution of the two products.

Enantioselective Pd-catalyzed dearomative reductive Heck and domino Heck-Suzuki reactions of 2-CF3-indoles.

Highly enantioselective palladium-catalyzed dearomative reductive Heck reaction and domino Heck-Suzuki reaction of 2-CF3-indoles have been developed. Using Pd(OAc)2/(R)-Synphos as the catalyst and Et3SiH as a hydride source, a variety of indolines bearing a 2-trifluoromethyl quaternary stereocenter were obtained via a dearomative reductive Heck reaction. Alternatively, using Pd(dba)2/phosphoramidite as the catalyst and Ar4BNa as a coupling partner, structurally diverse indolines containing two vicinal carbon stereocenters were afforded through the domino dearomative Heck-Suzuki reaction.

Construction of Carbon-Fluorine Bonds via Copper-Catalyzed/-Mediated Fluorination Reactions.

The construction of carbon-fluorine bonds is an important yet challenging task in organic synthesis. Transition metal-catalyzed/-mediated C-F bond forming processes have recently emerged as a viable strategy and provided access to value-added monofluorinated compounds. A dramatic increase in fluorination methods using inexpensive and earth-abundant copper can be seen in the past decade surpassing those using palladium and silver. This review discusses the recent development of Cu-catalyzed/-mediated formation of C(sp2 )-F and C(sp3 )-F bonds.

Palladium-Catalyzed Stereoselective C-F Bond Vinylation and Allylation of Tetrasubstituted gem-Difluoroalkenes via Stille Coupling: Synthesis of Monofluorinated 1,3- and 1,4-Dienes.

We herein describe a Pd-catalyzed stereoselective C-F bond vinylation and allylation reaction of tetrasubstituted gem-difluoroalkenes for the synthesis of valuable monofluorinated 1,3- and 1,4-dienes with excellent diastereoselectivities. Different from previously used Pd(PPh3)4, a catalytic system involving Pd(0) and dppe as the ligand was developed for Stille-type cross-coupling between gem-difluoroalkenes and vinyl- and allyltin reagents.

Nucleophilic Vinylic Substitution (SNV) of Trisubstituted Monofluoroalkenes for the Synthesis of Stereodefined Trisubstituted Alkenes and Divinyl Ethers.

We herein describe a nucleophilic vinylic substitution (SNV) of trisubstituted monofluoroalkenes with excellent stereocontrol (d.r. > 99:1). Starting from (E)-ß-monofluoroacrylates, various trisubstituted (E)-alkenes containing O/N/S-substituent groups at the vinylic position can be obtained under simple conditions. Furthermore, (E,E)-divinyl ethers can be generated through dimerization of the monofluoroalkenes, triggered by adventitious water in the reaction mixture.