Trifluoromethylation Of Alkenes Research Articles

Chemodivergent alkylation of trifluoromethyl alkenes via photocatalytic coupling with alkanes.

gem-Difluoroalkenes and trifluoromethyl alkanes are prominent structures in biologically active compounds. Radical alkylation of α-trifluoromethyl alkenes represents a useful strategy to access these structures. However, reported methods have relied on the use of pre-functionalized radical precursors and examples involving the use of simple hydrocarbons as coupling partners are elusive. Here we report a chemodivergent methodology based on the direct activation of C(sp3)-H bonds enabled by HAT photoredox catalysis. This protocol provides an efficient platform for preparing both gem-difluoroalkenes and trifluoromethyl alkanes from ubiquitous hydrocarbon feedstocks, including gaseous alkanes. Importantly, chemoselectivity is easily achieved by simple modification of reaction conditions and/or additives.

Photochemical Defluorinative Alkenylation of Trifluoromethyl Alkenes with Organoboronic Acids

We have developed a photo‐catalyzed defluorinative two‐component coupling reaction of trifluoromethyl alkenes and organoboronic acids, providing a straightforward and efficient route for the synthesis of functionalized gem‐difluorinated 1,4‐dienes. Both the chemical yields and functional group tolerance are generally good.

Base-Mediated Regioselective [3 + 3] Annulation of Alkylidene Malononitriles with Trifluoromethyl Alkenes via Dual C-F Bond Cleavage.

A base-mediated regioselective [3 + 3] annulation of alkylidene malononitriles with trifluoromethyl alkenes was described. The reaction proceeds through sequential intermolecular SN2' and intramolecular SNV-type cyclization by cleaving dual C-F bonds in a trifluoromethyl group, which discriminate multiple carbon-nucleophilic sites using a single base. Various bicycles bearing a monofluorocyclohexene motif were assembled from readily available starting materials under mild conditions via a one-pot cascade approach.

Synthesis of β‐Trifluoromethylated Ketones by Photocatalyzed Deoxygenative Coupling of Aromatic Acids with α‐CF3‐Substituted Styrenes

Abstractα‐Trifluoromethyl alkenes are versatile CF3‐containing feedstocks. They have been widely used to construct gem‐difluoroalkene scaffolds through β−F elimination. The application of α−CF3 alkenes as trifluoromethylating reagents has been less explored. Herein, we report an efficient route for the synthesis of β‐trifluoromethylated ketones from readily accessed α−CF3 styrenes and aromatic carboxylic acids under photoredox catalysis. The reactions proceed by phosphoranyl radical promoted deoxygenation of aromatic acids, generating acyl radicals for subsequent hydroacylation of α−CF3 styrenes. The valuable trifluoromethyl‐containing compounds could be produced in good yields under mild conditions.

Synthesis of gem-Difluorohomoallyl Amines via a Transition-Metal-Free Defluorinative Alkylation of Benzyl Amines with Trifluoromethyl Alkenes.

A mild and transition-metal-free defluorinative alkylation of benzyl amines with trifluoromethyl alkenes is reported. The features of this protocol are easy-to-obtain starting materials, a wide range of substrates, and functional group tolerance as well as high atom economy, thus offering a strategy to access a variety of gem-difluorohomoallyl amines, which are extensively distributed in pharmaceuticals and bioactive agents, with excellent chemoselectivity. The primary products can be further transformed to a diversity of 2-fluorinated pyrroline compounds.

Picking Two out of Three: Defluorinative Annulation of Trifluoromethyl Alkenes for the Synthesis of Monofluorinated Carbo- and Heterocycles.

The increasing demand of organofluorine compounds in medicine, agriculture, and materials sciences makes sophisticated methods for their synthesis ever more necessary. Nowadays, not only the C-F bond formation but also the selective C-F bond cleavage of readily available poly- or perfluorine-containing compounds have become powerful tools for the effective synthesis of organofluorine compounds. The defluorinative cross-coupling of trifluoromethyl alkenes with various nucleophiles or radical precursors in an SN 2' manner is a convergent route to access gem-difluoroalkenes, which in turn react with nucleophiles or radical precursors via an SN V-type reaction. If the SN V reactions occur intramolecularly, the dual C-F bond cleavage of trifluoromethyl alkenes allows facile assembly of monofluorinated cyclic skeletons with structural complexity and diversity. In this personal account, we summarized the advances in this field on the basis of coupling and cyclization partners, including binucleophiles, alkynes, diradical precursors and radical precursors bearing a nucleophilic site. Accordingly, the annulation reactions can be achieved by base-mediated sequential SN 2'/SN V reactions, transition metal catalyzed or mediated reactions, photoredox catalysis, and the combination of photocatalytic reactions with SN V reaction. In the context of seminal works of others in this field, a concise summary of the contributions of the authors is also offered.

Photoinduced Triphenylphosphine and Iodide Salt Promoted Reductive Decarboxylative Coupling.

The transient electron donor-acceptor (EDA) complex has been an emerging area in the photoinduced organic synthesis field, generating radicals without exogenous transition-metal or organic dye-based photoredox catalysts. The catalytic platform to form suitable photoactive EDA complexes for photochemical reduction reactions remains underdeveloped. Herein, a general photoinduced reductive alkylation via the EDA complex strategy is described. A simple yet multifunctional system, triphenylphosphine and iodide salt, promotes the photoinduced decarboxylative hydroalkylation, and reductive defluorinative decarboxylative alkylation of trifluoromethyl alkenes, to access trifluoromethyl alkanes and gem-difluoroalkenes. Moreover, decarboxylative hydroalkylation can be applied to more kinds of electron-deficient alkenes as a general Giese addition reaction.

Photoredox-Catalyzed C(sp3)–H Difluoroallylation of Amides

AbstractA photoredox-catalyzed, bromine-radical-mediated C(sp3)–H difluoroallylation of amides is disclosed. This modular approach exploits the hydrogen atom transfer (HAT) ability of photooxidatively generated bromine radicals to convert both cyclic and acyclic amides into the corresponding α-amino alkyl radicals that then are coupled with readily available trifluoromethyl alkenes. This method is distinguished by its mild conditions, broad substrate scope (30 examples), and the use of a simple HAT reagent, namely sodium bromide (NaBr). This strategy offers a promising paradigm for the incorporation of carbonyl isosteres into saturated aliphatic amines.

Regioselective difluoroallylation of alkylidene malonates with trifluoromethyl alkenes: synthesis of gem-difluoro-1,5-dienes and their [2 + 2] photocycloaddition

The synthesis of gem-difluoro-1,5-dienes via regioselective SN2′-type reactions of alkylidene malonates with trifluoromethyl alkenes and their subsequent [2 + 2] photocycloaddition for the formation of bicyclo[2.1.1]hexanes are described.

Hydroazidation of trifluoromethyl alkenes with trimethylsilyl azide enabled by organic photoredox catalysis.

Herein, we report an organic photoredox-catalyzed hydroazidation of trifluoromethyl alkenes with user-friendly trimethylsilyl azide (TMSN3), enabling a direct access to a broad range of valuable β-CF3-azides with exclusive selectivity under mild reaction conditions. The synthetic utility of this reaction was demonstrated by the late-stage modification of complex drug derivatives, scale-up of the reaction and diverse further derivatizations of the β-CF3-azide product.

Multi-substituted trifluoromethyl alkene construction via gold-catalyzed fluoroarylation of gem-difluoroallenes.

An unprecedented fluoroarylation of 1,1-difluoroallenes with a cost-effective nucleophilic fluoride reagent and aryldiazonium salts is reported. This visible light promoted gold-catalyzed reaction allows a stereo- and regioselective incorporation of both the fluorine atom and aryl group, enabling a straightforward construction of multi-substituted trifluoromethyl alkenes. Under the mild reaction conditions, a nice tolerance of diverse functional groups is achieved. The high regioselectivity for fluorine-incorporation is rationalized by considering the thermodynamic driving force of trifluoromethyl group formation, whereas the counterintuitive stereoselectivity that aryl is installed on the side of the bulkier γ-substituent is interpreted by alleviating the increasing 1,3-allylic interaction in the gold-coordinated allene intermediate en route to the product.

Photoredox Enabled Defluorinative Benzylation of Trifluoromethyl Alkenes with Alkylarenes.

Herein, we report a photoredox enabled defluorinative benzylation of trifluoromethyl alkenes with readily available alkylarenes, which provides convenient access to a series of structurally valuable benzylated gem-difluoroalkenes under mild reaction conditions. The synthetic value of this protocol has been demonstrated by the transformations of several substrates bearing drug moieties, gram-scale reactions, and various further derivatizations of the gem-difluoroalkene products. The preliminary mechanistic investigations suggest a reaction pathway with rate-determining benzyl C-H bond cleavage of toluene followed by benzylic radical formation.

Ball-milled prepared Fe3O4-FeSAs-NPs@NC catalyst synergistically facilitate the generation of reactive oxygen species for oxidative trifluoromethylation of alkenes

Heterogeneous catalysts have recently regarded as a promising chose for the thermally-driven generation of the reactive oxygen species (ROS) through catalytic reactions with molecular oxygen, which can facilitate this process by specific geometric and electronic structure. However, the oxidative trifluoromethylation of alkenes to α-trifluoromethylated ketones by CF3SO2Na is rarely reported in this system. In this work, we report a one-pot polymerization ball milling strategy to construct precursor, and then pyrolyze it to obtain specific carbon nanotubes matrix with Fe/Fe3O4 nanoparticles and single atoms Fe. Remarkably, the optimized catalyst (Fe3O4-FeSAs-NPs@NC-1) displays excellent catalytic performance, broad substrates and recyclability for this fluorination reaction via radical pathway. Based on characterizations and mechanistic studies, we discover that the coexistence of Fe/Fe3O4 and Fe-Nx not only synergistically facilitates the catalytic efficiency in altering the electronic structure of Fe sites, but also benefits the absorption of O2 and the ability of the thermally-driven generating ROS which can activate CF3SO2Na to CF3 radical. This work offers a method of designing Fe-based catalysts and also opens up a new thermal-heterogeneous catalysis way for the oxidative trifluoromethylation of alkenes.

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

Under typical copper-catalyzed hydroboration conditions, β-(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.

Visible Light Photoredox Aziridination of Chalcones

AbstractThe aziridination of chalcones with iminoiodinanes under photoredox conditions has been reported. The reaction proceeds through nitrene radical anion intermediate generated from iminoiodinanes. The trapping of nitrene radical anions by chalcones afforded trans‐aziridine products exclusively. The scope of the reaction in terms of both the substrates is considerably wide and in most of the cases trans‐3‐aryl‐aziridine‐2‐ketones were isolated in good yields. The reaction is challenging due to the electron‐deficient nature of the substrate, making this only the second example (after trifluoromethyl alkenes) of photocatalytic aziridination of electron‐deficient double bonds.

N-Heterocyclic Nitrenium-Catalyzed Photohomolysis of CF3SO2Cl for Alkene Trifluoromethylation.

N-Heterocyclic nitreniums (NHNs) have been utilized as Lewis acid catalysts to activate substrates with lone pairs. Alternative to their conventional applications, we have discovered that NHNs can also serve as charge transfer complex catalysts. Herein, we present another potential of NHNs by utilizing a weak interaction between NHNs and CF3SO2Cl. The method promotes CF3SO2Cl to undergo photohomolysis, resulting in the CF3 radical. Mechanistic studies suggested that the weak interaction could be due to the π-hole effect of NHNs.

Divergent Synthesis of Organofluorinated Molecules from Titanium Mediated Deoxygenation of Free Alcohols

Comprehensive SummaryAlcohols as among the most widely occurring organic compounds known, deoxygenative transformations of free alcohols as partners in radical addition reactions remain formidable challenges with great opportunities to achieve new and useful transformations. Herein, we report a protocol via C—O bond cleavage and C—C bond‐forming reaction of trifluoromethyl alkenes with free alcohols assisted by titanium reagents via a deoxygenative radical strategy, enabling the divergent synthesis for functional‐group‐rich organofluorinated compounds in high efficiencies. In this transformation, tertiary alcohols by Ti‐catalysis could be converted to trifluoromethyl alkanes without defluorination in acidic conditions, while benzyl alcohols are employed by Ti‐mediated activation to supply the gem‐difluoroalkenes with defluorination in the presence of a base. This protocol is applicable for a broad range of trifluoromethyl alkenes with good functional group tolerance and a variety of tertiary alcohols and benzyl alcohols (including primary, secondary, and tertiary alcohols), and is scalable to the gram level. Remarkably, the utility of this protocol is demonstrated by several derivatizations and late‐stage functionalization of drug molecules. The successful applications in scale up reactions and late‐stage functionalization of several drug molecules demonstrate its potential synthetic value in drug discovery settings.

Direct Hydrodefluorination of CF3-Alkenes via a Mild SN2′ Process Using Rongalite as a Masked Proton Reagent

A concise and efficient hydrodefluorination process was developed for the synthesis of gem-difluoroalkenes. This reaction employs rongalite as a masked proton source and does not require any additional catalysts or reductants. Notably, trifluoromethyl alkenes having both terminal and internal double bonds are compatible with this process, allowing for a wider range of substrates. The successful late-stage functionalizations of pharmaceuticals and gram-scale syntheses were used to demonstrate the viability of this method.

Synthesis of gem-Difluorinated 1,4-Dienes via Nickel-Catalyzed Three-Component Coupling of (Trifluoromethyl)alkenes, Alkynes, and Organoboronic Acids.

Herein, a nickel-catalyzed defluorinative three-component coupling of trifluoromethyl alkenes, internal alkynes, and organoboronic acids is presented. The protocol provides a highly efficient and selective route for the synthesis of structurally diverse gem-difluorinated 1,4-dienes under mild conditions. Mechanistic studies suggest that C-F bond activation proceeds probably through the oxidative cyclization of trifluoromethyl alkenes with Ni(0) species, sequential addition to alkynes, and β-fluorine elimination.

Nickel-Catalyzed Ligand-Controlled Selective Reductive Cyclization/Cross-Couplings.

ConspectusThe use of quaternary stereocenters during lead candidate optimization continues to grow because of improved physiochemical and pharmacokinetic profiles of compounds with higher sp3 fraction. Pd-catalyzed redox-neutral alkene difunctionalization involving carbopalladation of alkenes followed by nucleophilic-trapping σ-alkyl-palladium intermediates has been developed as an efficient method to construct quaternary stereocenters. However, the low chemoselectivity and air sensitivity of organometallic nucleophiles, as well as their low availability and accessibility, limit the scope of application of this elegant strategy. Recently, Ni-catalyzed reductive cross-coupling has evolved into a privileged strategy to easily construct valuable C(sp3)-C bonds. Despite great progress, the enantioselective coupling of C(sp3) electrophiles still relies on activated or functionalized alkyl precursors, which are often unstable and require multiple steps to prepare. Therefore, Ni-catalyzed reductive difunctionalization of alkenes via selective cyclization/cross-coupling was developed. This strategy not only offers a robust and practical alternative for traditional redox-neutral alkene difunctionalization but also provides strategic complementarity for reductive cross-coupling of activated alkyl electrophiles. In this Account, we summarize the latest results from our laboratory on this topic. These findings mainly include our explorations in modulating the enantioselectivity and cyclization mode of reductive cyclization/cross-couplings.We will first discuss Ni-catalyzed enantioselective reductive cyclization/cross-coupling to construct valuable chiral heterocycles with quaternary stereocenters and focus on the effects of ligands, reductants, and additives and their roles in reductive cross-coupling. A wide range of electrophiles have been explored, including aryl halides, vinyl halides, alkynyl halides, gem-difluoroalkenes, CO2, trifluoromethyl alkenes, and cyano electrophiles. The synthetic potential of this approach has also been demonstrated in the synthesis of biologically active natural products and drug molecules. Second, we will detail how to tune the steric effects of nickel catalysts by modifying bipyridine ligands for regiodivergent cyclization/cross-couplings. Specifically, the use of bidentate ligands favors exo-selective cyclization/cross-coupling, while the use of a carboxylic acid-modified bipyridine ligand permits endo-selective cyclization/cross-coupling. We will also show how to activate the amide substrate by altering the electronic and steric properties of substituents on the nitrogen, thereby enabling the nucleophilic addition of aryl halides to amide carbonyls. Further investigation of ligand properties has led to tunable cyclization/cross-couplings (addition to the amide carbonyl vs 7-endo-cyclization) for the divergent synthesis of pharmacologically important 2-benzazepine frameworks. Finally, we serendipitously discover that modifying the ligands of nickel catalysts and changing the oxidation state of nickel can control the migratory aptitude of different groups, thus providing a switchable skeletal rearrangement strategy. This transformation is of high synthetic value because it represents a conceptually unprecedented new approach to C-C bond activation. Thus, this Account not only summarizes synthetic methods that allow the formation of valuable chiral heterocycles with quaternary stereocenters using a wide variety of electrophiles but also provides insight into the relationship between ligand structure, substrate, and cyclization selectivity.