Tandem Difluoroalkylation‐Arylation of Enamides Catalyzed by Nickel

A nickel‐catalyzed three‐component reaction for the synthesis of difluoroalkylated compounds through tandem difluoroalkylation‐arylation of enamides has been developed. The reaction tolerates a variety of arylboronic acids and widely available difluoroalkyl bromides, and even the relatively inert substrate chlorodifluoroacetate. The significant advantages of this protocol are the low‐cost nickel catalyst, synthetic convenience, excellent functional‐group compatibility and high reaction efficiency.     

Nickel‐Catalyzed Difluoroalkylation of (Hetero)Arylborons with Unactivated 1‐Bromo‐1,1‐difluoroalkanes

A nickel‐catalyzed cross‐coupling between (hetero)arylborons and unactivated 1‐bromo‐1,1‐difluoroalkanes has been developed. The use of two ligands (a bidentate bipyridine‐based ligand, 4,4′‐ditBu‐bpy, and a monodentate pyridine‐based ligand, DMAP) offers a highly efficient nickel‐based catalytic system to prepare difluoroalkylated arenes which have important applications in medicinal chemistry.     

Synthesis of 1‐Difluoroalkylated Isoquinolines via Palladium‐Catalyzed Radical Cascade Difluoroalkylation–Cyclization of Vinyl Isocyanides with Bromodifluoroacetic Derivatives

A general method was developed for the synthesis of 1‐difluoroalkyl isoquinolines via the palladium‐catalyzed radical cascade difluoroalkylation–cyclization of vinyl isocyanides with bromodifluoroacetic derivatives. The difluoroalkylated cyclization products were readily converted to various other valuable gem ‐difluoro‐containing compounds.     

The ortho‐Difluoroalkylation of Aryliodanes with Enol Silyl Ethers: Rearrangement Enabled by a Fluorine Effect

Presented herein is an intriguing effect of fluorine, and it allows difluoroenol silyl ethers to couple with aryliodanes in a redox‐neutral manner to afford ortho‐iodo difluoroalkylated arenes. The remaining iodide group provides a versatile platform for converting the products into various valuable difluoroalkylated arenes. The reaction shows excellent functional‐group compatibility and broad substrate scope. A DFT mechanistic study suggests that the fluorine effect facilitates a subtle nucleophilic attack of the oxygen atom of enol silyl ethers onto aryliodanes, therefore leading to a rearrangement.     

Selective Methylation of Arenes: A Radical C−H Functionalization/Cross‐Coupling Sequence

A selective, nonchelation‐assisted methylation of arenes has been developed. The overall transformation, which combines a C?H functionalization reaction with a nickel‐catalyzed cross‐coupling, offers rapid access to methylated arenes with high para selectivity. The reaction is amenable to late‐stage methylation of small‐molecule pharmaceuticals.     

Palladium‐Catalyzed Intramolecular CH Difluoroalkylation: Synthesis of Substituted 3,3‐Difluoro‐2‐oxindoles

The synthesis of 3,3‐difluoro‐2‐oxindoles through a robust and efficient palladium‐catalyzed C? H difluoroalkylation is described. This process generates a broad range of difluorooxindoles from readily prepared starting materials. The use of BrettPhos as the ligand was crucial for high efficiency. Preliminary mechanistic studies suggest that oxidative addition is the rate‐determining step for this process.     

Palladium‐Catalyzed Intramolecular C?H Difluoroalkylation: Synthesis of Substituted 3,3‐Difluoro‐2‐oxindoles

The synthesis of 3,3‐difluoro‐2‐oxindoles through a robust and efficient palladium‐catalyzed C H difluoroalkylation is described. This process generates a broad range of difluorooxindoles from readily prepared starting materials. The use of BrettPhos as the ligand was crucial for high efficiency. Preliminary mechanistic studies suggest that oxidative addition is the rate‐determining step for this process.     

Bulky Diamine Ligand Promotes Cross‐Coupling of Difluoroalkyl Bromides by Iron Catalysis

Although iron‐catalyzed cross‐coupling of Grignard reagents with alkyl halides has been well established, the adoption of the reaction for fluoroalkylations has not been reported because traditional catalytic systems often lead to defluorination reactions. Described herein is the investigation of an iron‐catalyzed cross‐coupling between arylmagnesium bromides and difluoroalkyl bromides with modified N,N,N′,N′‐tetramethyl‐ethane‐1,2‐diamine (TMEDA) as a ligand. The use of this bulky diamine, in which a butylene is substituted at one carbon atom of the ethylene backbone in TMEDA, enables the iron‐catalyzed difluoroalkylation under mild reaction conditions with a wide range of difluoroalkyl bromides, including vulnerable bromodifluoromethane, thus providing a general and cost‐efficient route for applications in medicinal chemistry.     

Palladium‐Catalyzed Remote Aryldifluoroalkylation of Alkenyl Aldehydes

A palladium‐catalyzed three‐component reaction between fluoroalkyl bromides, arylboronic acids, and alkenyl aldehydes has been developed and provides facile access to 5‐, 6‐, or 7‐difluoroalkylated ketones under very mild reaction conditions. The resultant products can be smoothly converted into CF₂‐containing tetrahydronaphthalenes by a novel silver‐catalyzed intramolecular decarboxylative cyclization of 5‐aryl‐2,2‐difluoropentanoic acids.     

Nickel‐Catalyzed Reductive Coupling for Transforming Unactivated Aryl Electrophiles into β‐Fluoroethylarenes

We report herein a facile synthetic method for converting unactivated (hetero)aryl electrophiles into β‐fluoroethylated (hetero)arenes via nickel‐catalyzed reductive cross‐couplings. This coupling reaction features the involvement of FCH₂CH₂ radical intermediate rather than β‐fluoroethyl manganese species which provides effective solutions to the problematic β‐fluoride side eliminations. The practical value of this protocol is further demonstrated by the late‐stage modification of several complex ArCl or ArOH‐derived bioactive molecules.     

Palladium‐Catalyzed Difluoroalkylation of Aryl Boronic Acids: A New Method for the Synthesis of Aryldifluoromethylated Phosphonates and Carboxylic Acid Derivatives

The palladium‐catalyzed difluoroalkylation of aryl boronic acids with bromodifluoromethylphosphonate, bromodifluoroacetate, and further derivatives has been developed. This method provides a facile and useful access to a series of functionalized difluoromethylated arenes (ArCF₂PO(OEt)₂, ArCF₂CO₂Et, and ArCF₂CONR¹R²) that have important applications in drug discovery and development. Preliminary mechanistic studies reveal that a single electron transfer (SET) pathway may be involved in the catalytic cycle.     

Preparation of Vinyl Arenes by Nickel‐Catalyzed Reductive Coupling of Aryl Halides with Vinyl Bromides

This work emphasizes the synthesis of substituted vinyl arenes by reductive coupling of aryl halides with vinyl bromides under mild and easy‐to‐operate nickel‐catalyzed reaction conditions. A broad range of aryl halides, including heteroaromatics, and vinyl bromides were employed to yielding products in moderate to excellent yields with high functional‐group tolerance. The nickel‐catalytic system displays good chemoselectivity between the two C(sp²)‐halide coupling partners, thus demonstrating a mechanistic pathway distinct from other stepwise protocols.     

Nickel‐Catalyzed Difluoromethylation of Arylboronic Acids with Bromodifluoromethane

Although bromodifluoromethane (BrCF₂H) is a simple and readily available fluorine source, direct formation of difluoromethylated arenes with BrCF₂H has not been reported. Herein, we describe an efficient method to access difluoromethylated arenes through a nickel‐catalyzed difluoromethylation of arylboronic acids with BrCF₂H. The reaction exhibits high efficiency, good functional group tolerance and broad substrate scope, thus providing an efficient route for applications in drug discovery and development. Preliminary mechanistic studies reveal that a difluoromethyl radical is involved in the reaction.     

Aromatic Homologation by Non‐Chelate‐Assisted RhIII‐Catalyzed CH Functionalization of Arenes with Alkynes

Larger condensed arenes are of interest owing to their electro‐ and photochemical properties. An efficient synthesis is the catalyzed aromatic annulation of a smaller arene with two alkyne molecules. Besides difunctionalized starting materials, directed C? H functionalization can be used for such aromatic homologation. However, thus far the requirement of either pre‐functionalized substrates or suitable directing groups were limiting this approach. Herein, we describe a rhodium(III)‐catalyzed method allowing the use of completely unbiased arenes and internal alkynes. The reaction works best with copper(II) 2‐ethylhexanoate and decabromodiphenyl ether as the oxidant combination. This aromatic annulation tolerates a variety of functional groups and delivers homologated condensed arenes. Aside from simple benzenes, naphthalenes and higher condensed arenes provide access to highly substituted and highly soluble acenes structures having important electronic and photophysical properties.     

Moderne Magnesiumorganische Chemie. Neues von der Grignard‐Reaktion

Organomagnesium reagents can be employed for a variety of useful transformations, which are also of relevance for industrial processes. Recent protocols for syntheses of highly functionalized Grignard reagents highlight fascinating new perspectives for organic synthesis. Particularly, the addition of superstoichiometric amounts of LiCl allowed for the preparation of organomagnesium compounds, employing haloarenes or arenes at very mild reaction conditions. These highly functionalized Grignard reagents can be used as starting materials for transition metal‐catalyzed cross‐coupling reactions. New developments in the ligand design resulted in highly active palladium and nickel catalysts for efficient transformations of inexpensive chlorides or tosylates, as well as challenging fluorides. Economically attractive iron‐catalyzed coupling reactions of organomagnesium reagents bear great potential for further developments.     

Aromatic Homologation by Non‐Chelate‐Assisted RhIII‐Catalyzed C?H Functionalization of Arenes with Alkynes

Larger condensed arenes are of interest owing to their electro‐ and photochemical properties. An efficient synthesis is the catalyzed aromatic annulation of a smaller arene with two alkyne molecules. Besides difunctionalized starting materials, directed C H functionalization can be used for such aromatic homologation. However, thus far the requirement of either pre‐functionalized substrates or suitable directing groups were limiting this approach. Herein, we describe a rhodium(III)‐catalyzed method allowing the use of completely unbiased arenes and internal alkynes. The reaction works best with copper(II) 2‐ethylhexanoate and decabromodiphenyl ether as the oxidant combination. This aromatic annulation tolerates a variety of functional groups and delivers homologated condensed arenes. Aside from simple benzenes, naphthalenes and higher condensed arenes provide access to highly substituted and highly soluble acenes structures having important electronic and photophysical properties.     

Aryl Sulfonium Salts for Site‐Selective Late‐Stage Trifluoromethylation

Incorporation of the CF₃ group into arenes has found increasing importance in drug discovery. Herein, we report the first photoredox‐catalyzed cross‐coupling of aryl thianthrenium salts with a copper‐based trifluoromethyl reagent, which enables a site‐selective late‐stage trifluoromethylation of arenes. The reaction proceeds with broad functional group tolerance, even for complex small molecules on gram scale. The method was further extended to produce pentafluoroethylated derivatives.     

Metal‐Free,Initiator‐Free Graphene Oxide‐Catalyzed Trifluoromethylation of Arenes

The direct C−H trifluoromethylation of arenes catalyzed by graphene oxide (GO) under safe conditions is described. This strategy is metal‐free, initiator‐free, safe, and scalable. It employs a readily available CF₃ source and the reaction can be easily controlled to obtain a mono‐trifluorinated product. This method opens a new avenue for GO‐catalyzed chemistry.     

Palladium‐Catalyzed Dearomative syn‐1,4‐Carboamination with Grignard Reagents

A protocol for palladium‐catalyzed dearomative functionalization of simple, nonactivated arenes with Grignard reagents has been established. This one‐pot method features a visible‐light‐mediated [4+2] cycloaddition between an arene and an arenophile, and subsequent palladium‐catalyzed allylic substitution of the resulting cycloadduct with a Grignard reagent. A variety of arenes and Grignard reagents can participate in this process, forming carboaminated products with exclusive syn‐1,4‐selectivity. Moreover, the dearomatized products are amenable to further elaborations, providing functionalized alicyclic motifs and pharmacophores. For example, naphthalene was converted into sertraline, one of the most prescribed antidepressants, in only four operations. Finally, this process could also be conducted in an enantioselective fashion, as demonstrated with the desymmetrization of naphthalene.     

Palladium‐Catalyzed Dearomative syn‐1,4‐Oxyamination

A palladium‐catalyzed dearomative syn‐1,4‐oxyamination protocol using non‐activated arenes has been developed. This one‐pot procedure utilizes arenophile chemistry, and the corresponding para‐cycloadducts are treated with oxygen nucleophiles via formal allylic substitution, providing direct access to syn‐1,4‐oxyaminated products. The reaction conditions permit a range of arenes, as well as different O‐nucleophiles, such as oximes and benzyl alcohols. Moreover, this process was established in an asymmetric fashion, delivering products with high enantioselectivity. The dearomatized products are amenable to a multitude of further derivatizations ranging from olefin chemistry to C?H activation, giving rise to a diverse set of new functionalities. Overall, this dearomative functionalization offers rapid and controlled formation of molecular complexity, enabling straightforward access to functionalized small molecules from simple and readily available arenes.