A Type of Chiral C2-Symmetric Arylthiol Catalyst for Highly Enantioselective Anti-Markovnikov Hydroamination.

The development of chiral hydrogen donor catalysts is fundamental in the expansion and innovation of asymmetric organocatalyzed reactions via an enantioselective hydrogen atom transfer (HAT) process. Herein, an unprecedented type of chiral C2-symmetric arylthiol catalysts derived from readily available enantiomeric lactate ester was developed. With these catalysts, an asymmetric anti-Markovnikov alkene hydroamination-cyclization reaction was established, affording a variety of pharmaceutically interesting 3-substituted piperidines with moderate to high enantioselectivity. Results of the designed control experiments and theoretical computation rationalized the origin of stereocontrol and disclosed the spatial effect of the moiety of chiral thiols on the enantioselectivity. We believed the facile synthesis, flexible tunability, and effective enantioselectivity-controlling capability of these catalysts would shed light on the development of versatile chiral HAT catalysts and related asymmetric reactions.

Ligand-Controlled Regiodivergent Alkoxycarbonylation of Trifluoromethylthiolated Internal Alkynes.

Controlling the regioselectivity for the alkoxycarbonylation of unsymmetric internal alkynes is challenging. Herein, a palladium-catalyzed ligand-controlled regiodivergent alkoxycarbonylation of internal trifluoromethylthiolated alkynes was achieved. A series of α- or ß-SCF3 acrylates from the same trifluoromethylthiolated alkyne were obtained with moderate to high yield and regioselectivity.

Chiral phosphoric acid-catalyzed transfer hydrogenation of 3,3-difluoro-3H-indoles.

A convenient and efficient method for the synthesis of optically active difluoro-substituted indoline derivatives starting from the corresponding 3H-indoles by chiral phosphoric acid-catalyzed transfer hydrogenation was developed. Using Hantzsch ester as the hydrogen source under mild reaction conditions, the target products can be obtained with excellent yield and enantioselectivity.

Synthesis of Chiral α-Aryl Ketones by Photoredox/Nickel-Catalyzed Enantioconvergent Acyl Cross-Coupling with Organotrifluoroborate.

Photoredox/nickel-catalyzed enantioconvergent acyl cross-coupling of carboxylic derivatives with racemic secondary organotrifluoroborate was developed for the synthesis of an enolizable chiral α-aryl ketone under mild neutral conditions. Moderate to high yields and good enantioselectivities were achieved.

Parallel Paired Photoelectrochemical Bromination of Alkylarenes with Electrochemical Pinacol Coupling.

A paired electrochemical method for paralleling benzylic bromination of alkylarenes under irradiation with reductive pinacol coupling in a divided cell has been developed. A variety of benzyl bromides at the anode and pinacols at the cathode were obtained simultaneously in moderate-to-high faradaic efficiency. This parallel paired electrochemical protocol showed a broad substrate scope and high chemoselectivity as well as high synthetic and faradaic efficiencies.

Nickel/Titanocene-Catalyzed Electrophilic Acylation Coupling of Styrene Oxides.

The cross-coupling of epoxides with acyl chlorides or anhydrides by a nickel/titanocene dual catalytic system is established. A variety of synthetically useful ß-hydroxy ketones were obtained in good to high yields by using modified pyridine-oxazoline ligand. The reaction proceeds via the cooperation of titanocene-catalyzed ring-opening of epoxides and nickel-catalyzed acylation of the benzylic radical intermediate.

Pairing Electrocarboxylation of Unsaturated Bonds with Oxidative Transformation of Alcohol and Amine.

A parallel paired electrosynthetic method, coupling electrocarboxylation incorporating CO2 into ketone, imine, and alkene with alcohol oxidation or oxidative cyanation of amine, was developed for the first time. Various carboxylic acids as well as aldehyde/ketone or α-nitrile amine were prepared at the cathode and anode respectively in a divided cell. Its utility and merits on simultaneously achieving high atom-economic CO2 utilization, elevated faradaic efficiency (FE, total FE of up to 166 %), and broad substrate scope were demonstrated. The preparation of pharmaceutical intermediates for Naproxen and Ibuprofen via this approach proved its potential application in green organic electrosynthesis.

Thiol-Catalyzed Photodriven Stereoselective Hydrodifluoroacetylative Cyclization of Alkyne.

A metal-free protocol for visible-light-driven intramolecular hydrodifluoroacetylative cyclization of N-propargyl or N-homopropargyl-2-bromo-2,2-difluoroacetamide to α,α-difluorinated ß-substituted γ- or δ-lactam without an additional photosensitizer has been developed. By using thiol and Hantzsch ester as the catalyst and hydrogen donor, respectively, to implement a hydrogen atom transfer process, moderate to high (Z) selectivity was achieved. The results of a mechanistic investigation revealed the critical contribution of the thiol catalyst in attaining the stereoselectivity.

Pd-Catalyzed Enantioselective Hydroamidocarbonylation of α-Substituted Acrylamides to Chiral Succinimides.

With the aid of an innate amide group, an intramolecular Pd-catalyzed enantioselective hydroamidocarbonylation reaction of α-substituted acrylamides was developed, and a series of chiral 2-substituted succinimides were obtained in moderate to high yields and enantioselectivities. The generality of this approach was demonstrated by the carbonylation of both aryl- and alkyl-substituted acrylamides containing numerous functional groups.

Asymmetric Double Hydroxycarbonylation of Alkynes to Chiral Succinic Acids Enabled by Palladium Relay Catalysis.

A Pd-catalyzed asymmetric double hydroxycarbonylation of terminal alkynes was developed by using relay catalysis, providing a highly efficient route to chiral succinic acids (41 examples, 76-94 %, 94-99 % ee). Key to success was the combinatorial use of a Pd precursor with two distinct phosphine ligands in one pot. The synthetic utilities of this protocol were showcased in the facile synthesis of key intermediates for chiral pharmaceuticals.

Ni-Catalyzed enantioselective reductive arylcyanation/cyclization of N-(2-iodo-aryl) acrylamide.

A Ni/(S,S)-BDPP-catalyzed intramolecular Heck cyclization of N-(2-iodo-aryl) acrylamide with 2-methyl-2-phenylmalononitrile was developed to give oxindoles with good enantioselectivities. We found that utilizing such an electrophilic cyanation reagent could tackle the deleterious effect of the coordinative cyanide ion in the asymmetric alkene arylcyanation.

Diastereoselective Alkene Hydroesterification Enabling the Synthesis of Chiral Fused Bicyclic Lactones.

Palladium-catalysed diastereoselective hydroesterification of alkenes assisted by the coordinative hydroxyl group in the substrate afforded a variety of chiral γ-butyrolactones bearing two stereocenters. Employing the carbonylation-lactonization products as the key intermediates, the route from the alkenes with single chiral center to chiral THF-fused bicyclic γ-lactones containing three stereocenters was developed.

Palladium-Catalyzed Asymmetric Hydroesterification of α-Aryl Acrylic Acids to Chiral Substituted Succinates.

A palladium-catalyzed asymmetric hydroesterification of α-aryl acrylic acids with CO and alcohol was developed, preparing a variety of chiral α-substituted succinates in moderate yields with high ee values. The kinetic profile of the reaction progress revealed that the alkene substrate first underwent the hydroesterification followed by esterification with alcohol. The origin of the enantioselectivity was elucidated by density functional theory computation.

Asymmetric Alkoxy- and Hydroxy-Carbonylations of Functionalized Alkenes Assisted by ß-Carbonyl Groups.

As a fundamental type of carbonylation reaction, the alkoxy- and hydroxy-carbonylation of unsaturated hydrocarbons constitutes one of the most important industrial applications of homogeneous catalysis. However, owing to the difficulties in controlling multi-selectivities for asymmetric hydrocarbonylation of alkenes, this reaction is typically limited to vinylarenes and analogues. In this work, a highly efficient asymmetric alkoxy- and hydroxy-carbonylation of ß-carbonyl functionalized alkenes was developed, providing practical and easy access to various densely functionalized chiral molecules with high optical purity from broadly available alkenes, CO, and nucleophiles (>90 examples, 84-99 % ee). This protocol features mild reaction conditions and a broad substrate scope, and the products can be readily transformed into a diverse array of chiral heterocycles. Control experiments revealed the key role of the ß-carbonyl group in determining the enantioselectivity and promoting the activity, which facilitates chiral induction by coordination to the transition metal as rationalized by DFT calculations. The strategy of utilizing an innate functional group as the directing group on the alkene substrate might find further applications in catalytic asymmetric hydrocarbonylation reactions.

Enantioselective Hydroesterificative Cyclization of 1,6-Enynes to Chiral γ-Lactams Bearing a Quaternary Carbon Stereocenter.

A palladium-catalyzed asymmetric hydroesterification-cyclization of 1,6-enynes with CO and alcohol was developed to efficiently prepare a variety of enantioenriched γ-lactams bearing a chiral quaternary carbon center and a carboxylic ester group. The approach featured good to high chemo-, region-, and enantioselectivities, high atom economy, and mild reaction conditions as well as broad substrate scope. The correlation between the multiple selectivities of such process and the N-substitutes of the amide linker in the 1,6-enyne substrate has been depicted by the crystallographic evidence and control experiments.

Access to α-Cyano Carbonyls Bearing a Quaternary Carbon Center by Reductive Cyanation.

Reductive cyanation of tertiary alkyl bromides using electrophilic cyanating reagent and zinc reductant was developed, providing various α-cyano ketones, esters, and carboxamides containing a nitrile-bearing all-carbon quaternary center in good to excellent yields under mild reaction conditions. The corresponding reaction mechanism involving in situ generated organozinc reagent and reactivity distinction was elucidated by density functional theory computation.

Synthesis of Enantioenriched α,α-Difluoro-ß-arylbutanoic Esters by Pd-Catalyzed Asymmetric Hydrogenation.

Synthesis of optically active gem-difluorinated organic molecules attracts a great deal of interest due to their unique properties in pharmaceutical and agrochemical areas. Herein, a series of enantioenriched α,α-difluoro-ß-arylbutanoic esters were prepared in high yields (83-99%) with moderate to excellent enantioselectivities (≤97:3 er) by palladium-catalyzed asymmetric hydrogenation.

Nickel-catalyzed regio- and diastereoselective hydroarylative and hydroalkenylative cyclization of 1,6-dienes.

An unprecedented nickel-catalyzed hydroarylative and hydroalkenylative cyclization of unsymmetrically substituted 1,6-dienes with organoboronic acid was developed by using MeOH as the hydrogen source and employing commercially available Ni(η2-1,5-cyclooctadiene)2 as the catalyst. A series of biologically interesting cyclic products were afforded in moderate to excellent yields with high regio- and diastereoselectivities.

Recent progress in transition-metal-catalyzed hydrocyanation of nonpolar alkenes and alkynes.

Hydrocyanation is a powerful method for the preparation of nitriles which are versatile building blocks for the synthesis of amines, acids and amides. This review summarizes the research on transition-metal-catalyzed (asymmetric) hydrocyanation of nonpolar (or non-activated) alkenes and alkynes in the last decade. These studies involve the extension of HCN surrogates and unsaturated substrates, catalyst development as well as the improvement of the activity and multiple selectivities. The remaining challenges and personal future perspectives are presented at the end.

Synthesis of Carboxylic Acids by Palladium-Catalyzed Hydroxycarbonylation.

The synthesis of carboxylic acids is of fundamental importance in the chemical industry and the corresponding products find numerous applications for polymers, cosmetics, pharmaceuticals, agrochemicals, and other manufactured chemicals. Although hydroxycarbonylations of olefins have been known for more than 60 years, currently known catalyst systems for this transformation do not fulfill industrial requirements, for example, stability. Presented herein for the first time is an aqueous-phase protocol that allows conversion of various olefins, including sterically hindered and demanding tetra-, tri-, and 1,1-disubstituted systems, as well as terminal alkenes, into the corresponding carboxylic acids in excellent yields. The outstanding stability of the catalyst system (26 recycling runs in 32 days without measurable loss of activity), is showcased in the preparation of an industrially relevant fatty acid. Key-to-success is the use of a built-in-base ligand under acidic aqueous conditions. This catalytic system is expected to provide a basis for new cost-competitive processes for the industrial production of carboxylic acids.