Tetrafluoroisopropylation of alkenes and alkynes enabled by photocatalytic consecutive difluoromethylation with CF2HSO2Na.

Direct assembly of complex fluorinated motifs from simple fluorine sources is an attractive frontier of synthetic chemistry. Reported herein is an unconventional protocol for achieving tetrafluoroisopropylation by using commercially available CF2HSO2Na as a convenient source of the tetrafluoroisopropyl [(CF2H)2CH] group, which finds widespread applications in life science and material science. Visible-light-induced hydrotetrafluoroisopropylation of alkenes and carbotetrafluoroisopropylation of alkynes have been thus developed. Various structurally diverse α-tetrafluoroisopropyl carbonyls and cyclopentanones are selectively constructed under mild conditions. A photocatalytic triple difluoromethylation cascade, driven by consecutive reductive radical/polar crossover processes, leads to the direct assembly of a tetrafluoroisopropyl moiety from CF2HSO2Na. This C1-to-C3 fluoroalkylation protocol provides a practical strategy for the rapid construction of polyfluorinated compounds that are otherwise difficult to access, thus significantly enhancing the boundary of fluoroalkylation chemistry.

Fluorine-Effect-Enabled Photocatalytic 4-Exo-Trig Cyclization Cascade to Access Fluoroalkylated Cyclobutanes.

Cyclobutanes are popular structural units in bioactive compounds and versatile intermediates in synthetic chemistry, but their synthesis is challenging owing to high ring strain. In this study, a novel method for highly regio- and diastereoselective synthesis of fluoroalkylcyclobutanes bearing vicinal quaternary and tertiary stereocenters is realized by a photocatalytic 4-exo-trig cyclization cascade of thioalkynes or trifluoromethylalkenes. Density functional theory calculations reveal that a unique fluorine effect, arising from hyperconjugative π→σ*C-F interactions, accounts for the regio-reversed radical addition at the sterically hindered alkene carbon, which facilitates an unprecedented 4-exo-trig ring closure. This chemistry enables the direct and controllable construction of medicinally valuable quaternary-carbon-containing cyclobutanes from readily available raw materials, nicely complementing the existing methods.

Controllable Synthesis of Cyclopenta[b]indolines via Photocatalytic Fluoroalkylative Radical Cyclization Cascade of Ynamides.

A de novo method for direct construction of cyclopenta[b]indolines via a photocatalytic fluoroalkylative radical cyclization cascade of ynamides has been established, which proceeds via a sequence of radical addition, 1,5-HAT, 5-endo-trig cyclization, intramolecular arylation, and oxidative deprotonation. This protocol allows for the controllable assembly of a tricyclic architecture with three contiguous stereocenters, showcasing its high efficiency, compatibility, and regio- and diastereoselectivity for accessing pharmacologically significant fluoroalkylated cyclopenta[b]indolines. It represents one of the very few examples of tetrafunctionalization of alkynes.

Cu-catalyzed cascade difluoroalkylation/5-endo cyclization/ß-fluorine cleavage of ynones.

A copper-catalyzed, redox-neutral cascade difluoroalkylation/5-endo annulation/ß-fluorine cleavage of ynones is developed, providing a direct and stereoselective method to access synthetically important α-monofluoroalkenyl cyclopentanones. Mechanistic studies suggest an unprecedented CuII-assisted ß-fluorine fragmentation, which may be valuable for the challenging but important C-F bond activation. Moreover, the in situ generated difluorocarbene was found to serve as an effective reductant for the regeneration of copper(I) catalyst, thus avoiding the addition of external reductants.

[3+2] Cycloaddition of alkyl aldehydes and alkynes enabled by photoinduced hydrogen atom transfer.

[3+2] Cycloaddition is a step- and atom-economic method for the synthesis of five-membered rings. Despite the great success of 1,3-dipolar cycloadditions, the radical [3+2] annulation of alkynes remains a formidable challenge. Herein, a photoinduced decatungstate-catalyzed [3+2] cycloaddition of various internal alkynes using abundant aliphatic aldehydes as a three-carbon synthon is developed, producing elaborate cyclopentanones in 100% atom economy with excellent site-, regio-, and diastereoselectivity under mild conditions. The catalytic cycle consists of hydrogen atom abstraction from aldehydes, radical addition, 1,5-hydrogen atom transfer, anti-Baldwin 5-endo-trig cyclization, and back hydrogen abstraction. The power of this method is showcased by the late-stage elaboration of medicinally relevant molecules and total or formal synthesis of (±)-ß-cuparenone, (±)-laurokamurene B, and (±)-cuparene.

Recent advances in difunctionalization of alkenes using pyridinium salts as radical precursors.

In this review, we summarise the recent applications of pyridinium salts in the radical-mediated difunctionalization of alkenes. Pyridinium salts are a privileged class of compounds that show great utility in natural products and synthetic chemistry. Various organic transformations of pyridinium salts, especially in radical chemistry, have been developed in recent years. We prepared this review based on the two distinguished properties of pyridinium salts in radical transformation: (1) pyridinium salts can easily undergo single electron reduction to deliver X radicals. (2) Pyridinium salts are highly electrophilic so that alkyl radical intermediates can easily add to the pyridine core. Based on the role of pyridinium salts in difunctionalization of alkenes, the main body of this review is divided into three parts: (1) using pyridinium salts as X transfer reagents. (2) Using pyridinium salts as novel pyridine transfer reagents. (3) Using pyridinium salts as bifunctional reagents (X and pyridine). The C2 and C4 selectivity during pyridylation is discussed in detail. We hope that this review will provide a comprehensive overview of this topic and promote the wider development and application of pyridinium salts.

Photocatalytic Sulfonylcarbocyclization of Alkynes Using SEt as a Traceless Directing Group: Access to Cyclopentenes and Indenes.

Cyclopentenes and indenes are important structural scaffolds in synthetic, medical, and material chemistry. Cyclization of alkynes via remote C-H functionalization is an appealing approach to construct these motifs due to its high efficiency and step-economy. Herein, a traceless directing group strategy was designed to reverse the regioselectivity of radical addition which enabled an unprecedented photocatalytic sulfonylcarbocyclization of terminal alkynes by forming C-C bond on inert C(sp3 )-H bond. It offers a facile access to decorated cyclopentenes and indenes under mild conditions. The resultant products could be converted into a set of valuable molecular scaffolds, including a key intermediate of AM-6226. Mechanistic experiments suggest a radical cascade pathway comprising a Markovnikov-type sulfonylation, 1,5-hydrogen atom transfer, 5-endo-trig cyclization, and ß-elimination. This study lays further groundwork for the use of anti-Baldwin 5-endo-trig radical cyclization in rapidly assembling five-membered carbocycles.

Radical Chain Isomerization of N-Sulfonyl Ynamides to Ketenimines and Its Application to Furan Dearomatization.

A radical chain isomerization of N-sulfonyl ynamides to isolable ketenimines is developed, featuring mild reaction conditions, a high efficiency, ∼100% atom economy, a broad substrate scope, and column chromatography-free workup in most cases. Meanwhile, an unprecedented dearomatization of furans is achieved by the radical chain isomerization-triggered aza-Claisen rearrangement, providing highly chemo-, regio-, stereo-, and diastereoselective access to functionalized quaternary nitriles.

Solvent-controlled photocatalytic divergent cyclization of alkynyl aldehydes: access to cyclopentenones and dihydropyranols.

Divergent synthesis is a powerful strategy for the fast assembly of different molecular scaffolds from identical starting materials. We describe here a solvent-controlled photocatalytic divergent cyclization of alkynyl aldehydes with sulfonyl chlorides for the direct construction of highly functionalized cyclopentenones and dihydropyranols that widely exist in bioactive molecules and natural products. Density functional theory calculations suggest that a unique N,N-dimethylacetamide-assisted 1,2-hydrogen transfer of alkoxy radicals is responsible for the cyclopentenone formation, whereas a C-C cleavage accounts for the selective production of dihydropyranols in acetonitrile and water at 50 °C. Given the simple and mild reaction conditions, excellent functional group compatibility, forming up to four chemical bonds, and tunable selectivity, it may find wide applications in synthetic chemistry.

Electrooxidative dearomatization of biaryls: synthesis of tri- and difluoromethylated spiro[5.5]trienones.

Radical spirocyclization via dearomatization has emerged as an attractive strategy for the rapid synthesis of structurally diverse spiro molecules. We report the use of electrochemistry to perform an oxidative dearomatization of biaryls leading to tri- and difluoromethylated spiro[5.5]trienones in a user friendly undivided cell set-up and a constant current mode. The catalyst- and chemical oxidant-free dearomatization procedure features ample scope, and employs electricity as the green and sole oxidant.

Transition-Metal-Free α Csp3 -H Cyanation of Sulfonamides.

This report describes the site-selective α-functionalization of sulfonylamide derivatives through the in-situ generation of imine intermediates. The N-F sulfonylamides, which could facilitate the elimination to generate imines, are coupled with TBACN to efficiently and mildly afford α-amino cyanides. Comparing with Strecker reaction, this transformation offers a complementary strategy to efficiently construct α-amino cyanides from direct α C-H functionalization of sulfonylamindes. The reaction is also characterized by broad substrate scope and flash chromatography column free workup. More importantly, the new two-electron pathway to generate imines through manipulation of the leaving group allows us to achieve excellent α site-selectivity.

Internal Alkyne-Directed Fluorination of Unactivated C(sp3)-H Bonds.

A silver-mediated internal alkyne-guided fluorination of unactivated C(sp3)-H bonds is described. The reaction provides a facile access to γ-fluorinated fluoroalkylated (Z)-alkenes from readily available alkynes in promising yields with excellent regioselectivity, stereoselectivity, and site selectivity.

Synthesis of Polysubstituted Pyrroles via Silver-Catalyzed Oxidative Radical Addition of Cyclopropanols to Imines.

A silver-catalyzed formal [3 + 2] cycloaddition reaction, with cyclopropanols as a C3 subunit and imines as a two-atom subunit, is developed. The reaction takes place under mild conditions and produces a broad array of polysubstituted pyrroles in medium to high yields. It represents the first example of oxidative radical addition to imines, thus offering a new choice for the direct C-H functionalization of imines.

AIBN-Induced Remote Trifluoromethyl-Alkynylation of Thioalkynes.

A novel α,α'-azobis(isobutyronitrile) (AIBN)-induced remote trifluoromethyl-alkynylation of thioalkynes with alkynyl triflones as both the trifluoromethyl and alkyne sources is described. Structurally diverse trifluoromethylated (Z)-enynes can be constructed with full control of regio-, stereo-, and site-selectivity, which serves as a highly selective method for the rapid construction of trifluoromethylated molecules.

Photocatalytic Remote Oxyfluoroalkylation of Heteroalkynes: Regio-, Stereo-, and Site-Selective Access to Complex Fluoroalkylated (Z)-Alkenes.

A visible-light-induced remote oxyfluoroalkylation, including ketofluoroalkylation and hydroxytrifluoromethylation, of heteroalkynes is developed with dimethyl sulfoxide (DMSO) and H2O as the oxygen source, respectively. It provides a facile access to complex fluoroalkylated (Z)-alkenes in satisfactory yields with excellent regio-, stereo-, and site-selectivity. The reaction involves an uncommon vinyl radical-induced intermolecular C(sp3)-H functionalization, thus offering a good platform for the development of remote difunctionalization of alkynes.

Silver-Promoted Decarboxylative Sulfonylation of Aromatic Carboxylic Acids with Sodium Sulfinates.

A novel and efficient synthesis of sulfones was developed via a silver-promoted decarboxylative sulfonylation reaction between aromatic carboxylic acids and sodium sulfinates for the first time. The approach features operational simplicity and good functional group compatibility and uses readily available starting materials. Furthermore, mechanistic studies reveal that the decarboxylative sulfonylation reaction is likely to proceed via a radical mechanism.

Photocatalytic 1,1-Hydrofluoroalkylation of Alkynes with a Concurrent Vicinal Acylation: An Access to Fluoroalkylated Cyclic Ketones.

A visible-light-induced 1,1-hydrofluoroalkylation of alkynes with a concomitant vicinal acylation is developed using tetrahydrofuran (THF) as the hydrogen atom source. Various fluoroalkylated cyclic ketones, such as indanones, chroman-4-ones, 2,3-dihydroquinolin-4(1 H)-ones, and 3,4-dihydronaphthalen-1(2 H)-ones, can be efficiently synthesized with excellent trans-diastereoselectivity. The reaction represents the first example of 1,1-hydrofluoroalkylation of alkynes, thus providing a novel method for the construction of fluoroalkanes.

Synthesis of Benzofulvenes via Cp*Co(III)-Catalyzed C-H Activation and Carbocyclization of Aromatic Ketones with Internal Alkynes.

A highly efficient and practical synthesis of benzofulvenes was developed via ketone-directed Cp*Co(III)-catalyzed sequential C-H activation, addition, cyclization, and dehydration cascade processes between simple aromatic ketones and alkynes. The reaction tolerates a variety of functional groups, and various benzofulvenes were efficiently synthesized in 42-92% yields.

Iron-catalyzed domino Knoevenagel-hetero-Diels-Alder reaction: facile access to oxabicyclo[3.3.1]nonene derivatives.

A Fe-catalyzed domino Knoevenagel-hetero-Diels-Alder reaction of alkenyl aldehydes and 1,3-diketones has been developed. It provides straightforward access to a series of oxabicyclo[3.3.1]nonene derivatives in promising yields with excellent diastereoselectivity and functional group tolerance. The resultant bridged dihydropyrans can be smoothly converted into chromene derivatives, thus highlighting the synthetic utility of this method.

Modular Synthesis of Alkylarylazo Compounds via Iron(III)-Catalyzed Olefin Hydroamination.

A novel Fe-catalyzed olefin hydroamination with aryldiazo sulfones for accessing alkylarylazo compounds has been successfully developed. Aryldiazo sulfones are used as radical acceptors, and N-N double bonds will be regenerated when an arene sulfonyl group leaves. The reaction features mild reaction conditions and a broad substrate scope, allowing access to many azo compounds that would be difficult or perhaps impossible to access using other methods.