Cross-Electrophile Couplings of Benzyl Sulfonium Salts with Thiosulfonates via C-S Bond Activation.

A zinc-mediated cross-electrophile coupling of benzyl sulfonium salts with thiosulfonates via C-S bond cleavage was achieved. The reductive thiolation proceeded well under transition metal-free conditions to afford the desired benzyl sulfides in good yields, exhibiting both broad substrate scope and good functionality tolerance. In addition, the reaction could be applied to the use of selenosulfonate as an effective selenylation agent and be subjected to scale-up synthesis.

Magnesium-Mediated Cross-Electrophile Couplings of Aryl 2-Pyridyl Esters with Aryl Bromides for Ketone Synthesis through In Situ-Formed Arylmagnesium Intermediates.

Aryl 2-pyridyl esters could efficiently undergo cross-electrophile couplings with aryl bromides with the aid of magnesium as a reducing metal in the absence of a transition-metal catalyst, leading to the unsymmetrical diaryl ketones in modest to good yields with wide functionality compatibility. In addition, the reaction could be easily scaled up and applied in the late-stage modification of biologically active molecules. Preliminary mechanistic study showed that the coupling reaction presumably proceeds through the in situ formation of arylmagnesium reagents as key intermediates.

Chemo-, regio-, and stereoselective tetrafunctionalization of fluoroalkynes enables divergent synthesis of 5-7-membered azacycles.

Alkyne annulation has been widely used in organic synthesis for the construction of azacycles with unique structural and physicochemical properties. However, the analogous transformation of fluoroalkynes remains a challenge and has seen limited progress. Herein we report a 1,2,3,4-tetrafunctionalization of polyfluoroalkynes for the divergent construction of 5-7-membered (E)-1,2-difluorovinyl azacycles. The use of the fluorine atom as a detachable "activator" not only obviates the use of any transition metal catalysts and oxidizing reagents, but also ensures the [3-5 + 2]-annulation and defluorinative functionalization of fluoroalkynes with high chemo-, regio-, and stereoselectivities. This method exhibits a broad substrate scope, good functional group tolerance, and excellent scalability, providing a modular platform for accessing fluorinated skeletons of medicinal and biological interest. The late-stage modification of complex molecules, the multi-component 1,2-diamination of fluoroalkyne, and the synthesis of valuable organofluorides from the obtained products further highlight the real-world utility of this fluoroalkyne annulation technology.

Combining (CH2O)n and (NH4)2CO3 as a Formamidine Equivalent for "Four-in-One" Synthesis of Fluoroalkylated 2-H-Pyrimidines.

Multicomponent reactions hold the potential to maximize the synthetic efficiency in the preparation of diverse and complex molecular scaffolds. An unprecedented formal [3+1+1+1] annulation approach for the one-step synthesis of fluoroalkylated 2-H-pyrimidines commencing from perfluoroalkyl alkenes, paraformaldehyde, and ammonium carbonate is described. By harnessing readily accessible (CH2O)n and cheap (NH4)2CO3 as a formamidine surrogate, this method effectively replaces traditionally preformed amidines with a pyrimidine assembly. The multicomponent reaction proceeds in a step-economical, operationally simple, metal-free, and additive-free manner, featuring a broad substrate scope, excellent functional group compatibility, and scalability. The potential for the synthetic elaboration of the obtained 2-H-pyrimidine is further demonstrated in the alkylation and vinylation of its C2 position.

Sulfonylation of Pyridyl Phosphonium Salts with Sulfinate Salts in Aqueous Media for the Synthesis of 4-Pyridyl Sulfones via C-P Bond Cleavage.

A Na2S2O8-initiated sulfonylation of pyridyl phosphonium salts with sulfinate salts in aqueous media has been developed for facile access to 4-pyridyl sulfones. The reactions, which employed pyridyl phosphonium salts as efficient pyridylation agents via C-P bond activation, showed both broad substrate generality and good functional group compatibility. In addition, the scale-up synthesis and the late-stage modification of pharmaceutically active complex molecules (e.g., loratadine, bisacodyl) could also be successfully realized.

Nickel-Catalyzed Reductive Amidation of Aryl Fluorosulfates with Isocyanates: Synthesis of Amides via C-O Bond Cleavage.

With the assistance of nickel as catalyst, 2,2'-bipyridine (bpy) as ligand, and manganese as reducing metal, the reductive amidation of isocyanates with readily accessible aryl fluorosulfates could be successfully accomplished. The reactions proceeded effectively via C-O bond activation in DMF at room temperature, enabling the facile synthesis of a range of structurally diverse amides in moderate to high yields with broad functionality compatibility. In addition, the synthetic usefulness of the method was further demonstrated by applying the reaction in scale-up synthesis and the late-stage functionalization of complex molecules with biological activities.

Transition-Metal-Free Hydrodefluoroamination of Trifluoromethyl Enones for the Synthesis of α-Fluoroenamides.

A three-component strategy was developed to enable hydrodefluoroamination of ß-trifluoromethyl enones by selectively activating two C(sp3)-F bonds in the trifluoromethyl group. The method involved a sequence of carbonyl reduction, hydrodefluorination, and defluoroamination under transition-metal-free conditions. Synthetically useful (E)-stereospecific α-fluoroenamides were obtained in good yields with diverse functional group tolerance, which could be easily transformed into valuable organofluorides and heterocycles. The carbonyl auxiliary exerts both electronic and steric impacts on the CF3-alkenes, allowing for controllable and selective defluorination.

Silver-Promoted Three-Component Synthesis of Perfluoroalkenyl Pyrroles through Partial Defluorinative Functionalization of Perfluoroalkyl Halides.

A silver-promoted three-component heterocyclization of alkynes, perfluoroalkyl halides, and 1,3-dinucleophiles was developed for the efficient synthesis of privileged (E)-perfluoroalkenyl pyrroles. The reaction proceeded through a rationally designed sequence of radical perfluoroalkylation and intramolecular defluorinative [3 + 2]-heterocyclization. The utility of perfluoroalkyl halide as a perfluoroalkenyl reagent, by selective and controllable functionalization of two inert C(sp3)-F bonds at vicinal carbon centers on the perfluoroalkyl chain, provides a new reaction mode for the synthesis of value-added organofluorides starting from the easily available and low-cost fluorinated feedstock.

Palladium-Catalyzed Esterification of Aryl Fluorosulfates with Aryl Formates.

An efficient palladium-catalyzed carbonylation of aryl fluorosulfates with aryl formates for the facile synthesis of esters was developed. The cross-coupling reactions proceeded effectively in the presence of a palladium catalyst, phosphine ligand, and triethylamine in DMF to produce the corresponding esters in moderate to good yields. Of note, functionalities or substituents, such as nitro, cyano, methoxycarbonyl, trifluoromethyl, methylsulfonyl, trifluoromethoxy, fluoro, chloro, bromo, methyl, methoxy, N,N-dimethyl, and [1,3]dioxolyl, were well-tolerated in the reactions, which could be kept for late-stage modification. The reactions employing readily available and relatively robust aryl fluorosulfates as coupling electrophiles could potentially serve as an attractive alternative to traditional cross-couplings with the use of aryl halides and pseudohalides as substrates.

Hydroxylation of Aryl Sulfonium Salts for Phenol Synthesis under Mild Reaction Conditions.

Hydroxylation of aryl sulfonium salts could be realized by utilizing acetohydroxamic acid and oxime as hydroxylative agents in the presence of cesium carbonate as a base, leading to a variety of structurally diverse hydroxylated arenes in 47-95% yields. In addition, the reaction exhibited broad functionality tolerance, and a range of important functional groups (e.g., cyano, nitro, sulfonyl, formyl, keto, and ester) could be well amenable to the mild reaction conditions.

Iron-Mediated Reductive Amidation of Triazine Esters with Nitroarenes.

A reductive amidation of triazine esters with nitroarenes by using cheap iron as a reducing metal in the presence of TMSCl in DMF was developed. The reactions proceeded efficiently under transition metal-free conditions to give the corresponding amides in moderate to good yields with good functional group compatibility. Preliminary mechanistic investigations indicated that nitrosobenzene, N-phenyl hydroxylamine, azoxybenzene, azobenzene, aniline, and N-arylformamide possibly served as the intermediates of the reaction.

Combining Hydrodefluorination and Defluorophosphorylation for Chemo- and Stereoselective Synthesis of gem-Fluorophosphine Alkenes.

A chemo-, regio-, and stereoselective reaction of trifluoromethyl enones, phenylsilane, and phosphine oxides through a sequential hydrodefluorination and defluorophosphorylation relay is developed for the synthesis of distinctive gem-fluorophosphine alkenes. This multicomponent reaction occurred under transition-metal-free conditions with good functional group tolerance. Moreover, the preinstalled carbonyl auxiliary is important for tuning the reactivity of ß-trifluoromethyl enones, thereby enabling controllable and selective functionalization of two fluorine atoms in trifluoromethylated enones.

Nickel-Catalyzed Direct Cross-Coupling of Unactivated Aryl Fluorides with Aryl Bromides.

A nickel-catalyzed direct cross-coupling of unactivated aryl fluorides with aryl bromides is realized. The one-pot reaction, which avoids the use of preformed and sensitive organometallic reagents, proceeds effectively via C-F bond cleavage at room temperature in THF in the presence of the phosphine ligand and magnesium powder (with or without TMSCl) to produce the desired biaryls in modest to good yields.

Na2S·9H2O Enabled Defluorodisulfuration and Hydrodefluorination of Perfluorobutyl Tetralones: Synthesis of Trifluoromethyl 1,2-Dithioles.

An unprecedented defluorocyclization of perfluorobutyl tetralones with Na2S·9H2O was developed for the synthesis of trifluoromethyl 1,2-dithioles, which provided chemists novel access to biologically and pharmaceutically relevant organofluorides. Successive C(sp3)-F bond functionalization at the perfluoroalkyl chain is vital for the formation of four C-H/C-S/S-S bonds and a five-membered S-heterocycle assembly. Cheap, weakly toxic, and odorless inorganic sulfide Na2S·9H2O acts as both a disulfurating precursor and a hydrodefluorinating reagent in this tandem multi-bond-interconverting reaction.

Selective and Controllable Defluorophosphination and Defluorophosphorylation of Trifluoromethylated Enones: An Auxiliary Function of the Carbonyl Group.

The auxiliary function of a carbonyl group in the tunable defluorophosphination and defluorophosphorylation of trifluoromethylated enones with P(O)-containing compounds was demonstrated. Controlled replacement of one or two fluorine atoms in trifluoromethylated enones while maintaining high chemo- and stereoselectivity was achieved under mild conditions, thus enabling diversity-oriented synthesis of skeletally diverse organophosphorus libraries─(Z)-difluoro-1,3-dien-1-yl phosphinates, (1Z,3E)-4-phosphoryl-4-fluoro-buta-1,3-dien-1-yl phosphinates, and (E)-4-phosphoryl-4-fluoro-1,3-but-3-en-1-ones─in good yields with excellent functional group tolerance.

Nickel-Catalyzed Direct Cross-Coupling of Aryl Thioether with Aryl Bromide.

A straightforward cross-coupling of aryl thioether with aryl bromide with the aid of nickel salt, magnesium, and lithium chloride in tetrahydrofuran at ambient temperature was accomplished. The one-pot reactions proceeded efficiently via C-S bond cleavage to produce the desired biaryls in modest to good yields, avoiding the use of pregenerated or commercial organometallic reagents.

Nickel-Catalyzed Direct Cross-Coupling of Aryl Fluorosulfates with Aryl Bromides.

A one-pot, direct cross-coupling of aryl fluorosulfate with aryl bromide, which is step-economical and avoids the use of a preprepared/commercial organometallic reagent, could be accomplished by performing the reaction in THF at room temperature in the presence of nickel catalyst, magnesium turnings, and lithium chloride, giving rise to the corresponding biaryls in moderate to good yields with reasonable functional group compatibility.

Dual Role of (NH4)2CO3 Enables Defluorinative Synthesis of ß-Fluoroalkylated Aminovinyl Ketones.

A modular multicomponent reaction of readily available fluoroalkyl alkenes, amidines, ammonium carbonate, and water was developed for the facile construction of ß-fluoroalkylated aminovinyl ketones, which provided chemists a novel access to value-added organofluorine compounds. The reaction proceeded regio-/stereoselectively under mild conditions and exhibited good functional group tolerance. Cheap, stable, and low-toxic inorganic salt (NH4)2CO3 was first found to act as both a nitrogen source and a carbonyl equivalent in the multi-bond-forming process.

Nickel-Catalyzed Direct Cross-Coupling of Diaryl Sulfoxide with Aryl Bromide.

The direct cross-couplings of diaryl sulfoxides with aryl bromides via C-S bond cleavage could be readily accomplished using nickel(II) as the catalyst, 1,2-bis(diphenylphosphino)ethane (dppe) as the ligand, and magnesium turnings as the reducing metal in THF, leading to the corresponding biaryls in moderate to good yields. The reaction exhibited a broad substrate scope and could be applied to a gram-scale synthesis. The "one-pot" reaction, which avoids the utility of presynthesized and moisture-labile organometallic compounds, is operationally simple and step-economic.