Catalytic C(sp3)-H Trifluoroethylation of Amino Acids and Carboxylic Acids.

Integrating of the trifluoroethyl (-CH2CF3) group into the organic compounds by activating the distal C(sp3)-H bond is a challenging but crucial task in organic chemistry. This transformation imparts unique physicochemical properties to the compounds, such as enhanced lipophilicity, metabolic stability, and altered electronic characteristics. In this study, we unveil a new palladium-catalyzed method to directly introduce the trifluoroethyl group into amino acid and carboxylic acid derivatives. Remarkably, this method effectively activates the ß-C(sp3)-H bond across various substrates at room temperature. Utilizing mesityl(2,2,2-trifluoroethyl)iodonium triflate as a trifluoroethyl source, our approach selectively targets the distal ß-C(sp3)-H bonds of amino and carboxylic acids, ensuring high chemoselectivity and enabling the straightforward synthesis of a diverse array of important γ-trifluoromethyl amino acid and carboxylic acid derivatives. Furthermore, the practical applicability of this methodology is demonstrated through its scalability for gram-scale synthesis.

Organophotoredox Catalysis: Switchable Radical Generation from Alkyl Sodium Sulfinates for Sulfonylation and Alkylative Activation of C-C Bonds of Cyclopropenes.

Generating alkyl radicals from the sulfonyl radicals remains challenging in synthetic chemistry. Here, we report an efficient photocatalyzed strategy using alkyl sodium sulfinates as both sulfonylating and alkylating reagents by controlling the reaction temperature. This methodology provides a versatile protocol for synthesizing diastereoselective sulfonylated cyclopropanes and poly-substituted styrene derivatives. This methodology is successfully demonstrated with a wide variety of cyclopropenes and alkyl sulfinates, showcasing its broad substrate scope, high diastereo- and E/Z selectivity, and yielding good to excellent yields.

Organophotocatalyzed Alkyl/Arylsulfonylation of Vinylcyclopropanes.

Allyl sulfones are an essential pharmacophore in many bioactive compounds. To combat their synthetic barrier, we report a practical, straightforward organophotocatalyzed methodology for accessing miscellaneously functionalized allyl sulfone derivatives using inexpensive and bench-stable sodium sulfinate salts under mild conditions. This photo-catalyzed radical sulfonylation provides access to a variety of allyl sulfones in good to excellent yields with high E : Z selectivity. A wide range of vinyl cyclopropanes, as well as aryl/hetero and alkyl sodium sulfinates, were tolerated and reliable in gram-scale synthesis. Later on, further functionalization of allyl sulfones was demonstrated. A plausible mechanism for radical sulfonylation is proposed from the control experiments.

Organophotocatalyzed Mono- and Bis-Alkyl/Difluoroalkylative Thio/Selenocyanation of Alkenes.

Organophotocatalyzed three-component 1,2-difluoroacetyl/alkyl/perfluoroalkylative thio/selenocyanation of styrene derivatives under stoichiometric, transition metal-, oxidant-, and additive-free, and mild redox-neutral conditions is reported. Organophotocatalyst 4CzIPN operates the overall radical-polar-crossover mechanistic cycle via initial oxidative luminescence quenching, and the key intermediates were experimentally detected. Selective mono-alkylative thiocyanation of alkenes using dibromoalkanes is also demonstrated. This one-pot synthetic methodology is suitable for primary, secondary, and tertiary alkyl halides and also extended for double alkylative thiocyanation of the dibromoalkanes with excellent yields.

Diastereoselective Hydroacylation of Cyclopropenes by Visible-Light Photocatalysis.

An efficient and general strategy for the hydroacylation of cyclopropene is disclosed for synthesizing various 2-acylcyclopropane derivatives under mild reaction conditions. High functional group tolerance of this protocol features a novel route to access a divergent synthesis of acylated cyclopropane in a diastereoselective manner by photoinduced decarboxylation of α-ketoacid followed by acyl radical addition to cyclopropene. Additionally, the regioselective addition of acyl radical at the least substituted olefinic carbon center with trans-selective fashion makes this protocol more appealing toward natural product development.

Metal-Free Photoredox Four-Component Strategy to 1,3-Functionalized BCP Derivatives.

Trifluoromethyl bicyclo[1.1.1]pentanes (BCPs) have attracted significant attention from the scientific community and pharmaceutical industries due to their advantageous physicochemical properties as arene bioisosteres. Initial photoredox perfluoroalkylation of [1.1.1]propellane triggers the tandem reaction to the perfluoroalkyl BCP radical followed by Giese addition to an in situ generated electron-deficient alkene by Knoevenagel condensation in a four-component fashion to form 1,3-functionalized BCPs. This strategy provides easy access to various 1,3-functionalized perfluoroalkyl BCP derivatives with the added advantage of nitrile group as a functional handle to diversified transformations. This methodology offers scalability and late-stage derivatization of drug molecules with high chemoselectivity.

Photoinduced Cascade Difluoroalkylative Ring-Opening of Vinyl Cyclopropanes.

Here, we report a facile and efficient method for the difluoroalkylation of vinyl cyclopropanes (VCPs) using visible-light organophotoredox catalysis. This strategy exploits the interplay of α-amino alkyl radical-mediated halogen-atom transfer (XAT) reaction. The broad substrate scope, excellent functional group compatibility, operational simplicity, inexpensive CF2 precursors, and high efficiency make this protocol promising for the cost-efficient synthesis of allylic difluoroalkylated derivatives.

Visible-Light-Driven Organophotocatalyzed Multicomponent Approach for Tandem C(sp3)-H Activation and Alkylation Followed by Trifluoromethylthiolation.

A visible-light-driven organophotocatalyzed multicomponent approach has been developed for tandem direct C(sp3)-H activation and alkylation followed by trifluoromethylthiolation in a one-pot operation. We report a completely metal-free, tandem, three-component approach for the difunctionalization of activated alkenes via the photoinduced radical pathway. This protocol allows the formation of two new C(sp3)-C(sp3) and C(sp3)-SCF3 bonds using a bench-stable, easy-to-handle trifluoromethylthiolating reagent under mild reaction conditions. The generosity of this reaction is shown with a library of C(sp3)-H donors and alkenes derivatives. The reaction conditions can tolerate a wide variety of functional groups. Gram-scale synthesis using environmentally benign and straightforward conditions highlights the synthetic advancement of the methodology. Further functionalization of the final product is also successfully demonstrated.

Visible-Light-Driven Organophotocatalyzed Mono-, Di-, and Tri-C(sp3)-H Alkylation of Phosphoramides.

A photocatalytic metal-free, visible-light-driven, highly atom-economic, direct multiple α-C(sp3)-H alkylation of phosphoramides and thiophosphoramides is demonstrated under environmentally benign conditions. Economically viable and commercially available Eosin-Y is used as an HAT photocatalyst for mono-α-C(sp3)-H alkylation of phosphoramide derivatives. Remarkably, di- and tri-C(sp3)-H alkylation of phosphoramides and thiophosphoramides using an acridinium photocatalyst is reported with good yield and selectivity. Mechanistic studies reveal that monoalkylation of phosphoramides by Eosin-Y follows the HAT mechanism, whereas di- and tri-C(sp3)-H alkylation by the acridinium photocatalyst follows the SET mechanism.

Ammonium Chloride-Mediated Trifluoromethylthiolation of p-Quinone Methides.

Ammonium chloride-mediated trifluoromethylthiolation of p-quinone methides is reported using inexpensive and bench stable AgSCF3 as a nucleophilic trifluoromethylthiolating (-SCF3) reagent. This method is an efficient strategy for the construction of the benzylic C(sp3)-SCF3 bond to synthesize trifluoromethylthio-diarylmethane derivatives by 1,6-conjugate addition/aromatization under mild reaction conditions without any metal catalyst, oxidants, or additives. This is the first report of trifluoromethylthiolation of p-quinone methides. In addition, di-trifluoromethylthiolation of δ-chloro-p-quinone methide and scalability are demonstrated.

Metal-Free Visible-Light-Promoted Trifluoromethylation of Vinylcyclopropanes Using Pyrylium Salt as a Photoredox Catalyst.

Visible-light-induced metal-free trifluoromethylation of activated, carbocyclic, and unactivated vinylcyclopropanes via a ring-opening reaction using the Langlois reagent (CF3SO2Na) is reported to synthesize allylic trifluoromethylated derivatives. Allylic trifluoromethylation was achieved by a photo-oxidative single electron transfer (SET) process at an ambient temperature and under metal-free conditions and visible-light irradiation using pyrylium salt as a photoredox catalyst. The reported methodology has an operational simplicity, broad substrate scope, high functional group tolerance, and scalability.