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.

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.

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.

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.

Desulfonylation via Radical Process: Recent Developments in Organic Synthesis.

As the "chemical chameleon", sulfonyl-containing compounds and their variants have been merged with various types of reactions for the efficient construction of diverse molecular architectures by taking advantage of their incredible reactive flexibility. Currently, their involvement in radical transformations, in which the sulfonyl group typically acts as a leaving group via selective C-S, N-S, O-S, S-S, and Se-S bond cleavage/functionalization, has facilitated new bond formation strategies which are complementary to classical two-electron cross-couplings via organometallic or ionic intermediates. Considering the great influence and synthetic potential of these novel avenues, we summarize recent advances in this rapidly expanding area by discussing the reaction designs, substrate scopes, mechanistic studies, and their limitations, outlining the state-of-the-art processes involved in radical-mediated desulfonylation and related transformations. With a specific emphasis on their synthetic applications, we believe this review will be useful for medicinal and synthetic organic chemists who are interested in radical chemistry and radical-mediated desulfonylation in particular.

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.

Three-Component Bisannulation for the Synthesis of Trifluoromethylated Tetracyclic Aza-Aromatics through Six C(sp3)-F Bond Cleavage and Four C-N Bond Formation.

An unprecedented and expeditious tandem bisannulation of polyfluoroalkylated tetralones with benzamidines to access various fluoroalkyl tetracyclic [1,3]-diazepines through multiple C-N bond formation and C(sp3)-F bond cleavage is reported. The process features high regio-/chemoselectivities, broad substrate scope, good functional group tolerance, procedural simplicity, mild reaction conditions, and scale-up synthesis. Mechanistic studies showed that the distinctive fluorine effect of polyfluoroalkyl tetralone plays a vital role for the aza-tetracycle construction.

Titanium(IV)-Mediated Ring-Opening/Dehydroxylative Cross-Coupling of Diaryl-Substituted Methanols with Cyclopropanol Derivatives.

A titanium(IV)-mediated ring-opening/dehydroxylative cross-coupling of diaryl-substituted methanols with a cyclopropanol derivative was developed. The reactions proceeded efficiently to provide synthetically useful γ,γ-diaryl esters in moderate to good yields, which could be applied to the functionalization of complex molecules derived from bioactive fenofibrate and isoxepac and the synthesis of a precursor of Zoloft.

Metal-free [3 + 2 + 1] annulation of allylic alcohols, ketones, and ammonium acetate: radical-involving synthesis of 2,3-diarylpyridine derivatives.

A three-component [3 + 2 + 1] annulation strategy for the synthesis of biologically and pharmaceutically active 2,3-diarylpyridine derivatives by using a series of allylic alcohols, ketones, and ammonium acetate as substrates has been developed. The method proceeds efficiently under metal-free conditions, and the desired heterocycles could be obtained in a site-specific selectivity manner with good functional group tolerance.

Preparation of Alkyl Indium Reagents by Iodine-Catalyzed Direct Indium Insertion and Their Applications in Cross-Coupling Reactions.

An efficient method for the synthesis of alkyl indium reagent by means of an iodine-catalyzed direct indium insertion into alkyl iodide in THF is reported. The thus-generated alkyl indium reagents effectively underwent Pd-catalyzed cross-coupling reactions with various aryl halides, exhibiting good compatibility to a variety of sensitive functional groups. By replacing THF with DMA and using 0.75 equiv of iodine, less reactive alkyl bromide could be used as substrate for indium insertion with equal ease.

Lead-Mediated Highly Diastereoselective Allylation of Aldehydes with Cyclic Allylic Halides.

Lead was found to efficiently mediate the allylation reactions of carbonyl compounds with cyclic allylic halides in the presence of stoichiometric amounts of lithium chloride and a catalytic amount of GaCl3 (20 mol %), leading to the desired homoallylic alcohols in modest to high yields with excellent diastereocontrol (>99:1 syn/anti) and good functional group tolerance. In contrast, the use of either 2-pyridinecarboxaldehyde as the carbonyl substrate or ( E)-cinnamyl bromide as the allylating agent produced the corresponding product with reversed diastereoselectivity (>99:1 anti/syn).

Chromium(III)-Catalyzed Addition of Water and Alcohol to α,ß-Unsaturated Ketones for the Synthesis of ß-Hydroxyl and ß-Alkoxyl Ketones in Aqueous Media.

An efficient chromium(III) chloride-catalyzed Michael-type reaction of water or alcohol with α,ß-unsaturated ketones is developed. A variety of α,ß-unsaturated ketones effectively reacted with either water or alcohols to give the corresponding ß-hydroxyl ketones or ß-alkoxyl ketones in modest to high yields with excellent compatibility to various functional groups. The approach was further utilized for the preparation of synthetically useful compounds containing tetrahydrofuran skeleton.

Iron Catalysis for Modular Pyrimidine Synthesis through ß-Ammoniation/Cyclization of Saturated Carbonyl Compounds with Amidines.

An efficient method for the modular synthesis of various pyrimidine derivatives by means of the reactions of ketones, aldehydes, or esters with amidines in the presence of an in situ prepared recyclable iron(II)-complex was developed. This operationally simple reaction proceeded with broad functional group tolerance in a regioselective manner via a remarkable unactivated ß-C-H bond functionalization. Control experiments were performed to gain deep understanding of the mechanism, and the reactions are likely to proceed through a designed TEMPO complexation/enamine addition/transient α-occupation/ß-TEMPO elimination/cyclization sequence.

Aqueous Reaction of Alcohols, Organohalides, and Odorless Sodium Thiosulfate under Transition-Metal-Free Conditions: Synthesis of Unsymmetrical Aryl Sulfides via Dual C-S Bond Formation.

A transition-metal-free process for the synthesis of unsymmetrical aryl sulfides via dual C-S bond formation by a one-pot three-component reaction of alcohols, organohalides, and odorless sodium thiosulfate in water has been developed. In addition, the aryl sulfides could also be prepared by the reaction of the corresponding alcohols and Bunte salts under the identical conditions. This protocol provides a green and efficient manner for the construction of various unsymmetrical aryl sulfides.

TBAI-Catalyzed/Water-Assisted Double C-S Bond Formations: An Efficient Approach to Sulfides through Metal-Free Three-Component Reactions.

An aqueous catalytic method for double C-S bond formations that involves alcohol derivatives, organic halides, and sodium thiosulfate has been developed. A diverse range of functionalized sulfides, including pharmaceutical and biological derivatives, can be obtained in an efficient and eco-friendly manner under air. The mechanistic studies revealed that this tetrabutylammonium-iodide-catalyzed/water-assisted reaction generated a mercaptan species as the key intermediate.

One-Pot Synthesis of Allylic Sulfones, Ketosulfones, and Triflyl Allylic Alcohols from Domino Reactions of Allylic Alcohols with Sulfinic Acid under Metal-Free Conditions.

A metal-free tandem procedure by using a sulfonylation reaction of aryl allylic alcohols followed by an iodobenzenediacetate (PIDA)-promoted oxidative functionalization has been established. Allylic sulfones, γ-ketosulfones, and triflyl allylic alcohols have been constructed in a single operation. The methodology incorporates the sulfonyl (both aryl and triflyl) functionality with a simple work-up procedure.

One-Pot Synthesis of Allylic Sulfones, Ketosulfones, and Trifylallylic Alcohols from Domino Reactions of Allylic Alcohols with Sulfinic Acid under Metal-Free Conditions.

Invited for the cover of this issue is the group of Shun-Jun Ji and co-workers at Soochow University, (China). The image depicts a cheaper, low-toxic, eco-friendly benign and metal-free methodology incorporating the both aryl and trifyl sulfonyl functionality from allylic alcohols. Read the full text of the article at 10.1002/chem.201500469.

Metal-free oxidative radical addition of carbonyl compounds to α,α-diaryl allylic alcohols: synthesis of highly functionalized ketones.

A metal-free direct alkylation of simple carbonyl compounds (ketones, esters, and amides) with α,α-diaryl allylic alcohols is described. The protocol provides facile access to highly functionalized dicarbonyl ketones by a radical addition/1,2-aryl migration cascade. The regioselectivity of the reaction was precisely controlled by the nature of the carbonyl compound.