Nickel-Catalyzed Enantioselective Reductive Arylation of Common Ketones.

A nickel complex of chiral bisoxazolines catalyzed the stereoselective reductive arylation of ketones in high enantioselectivity. A range of common acyclic and cyclic ketones reacted without the aid of directing groups. Mechanistic studies using isolated complex of a chiral bis(oxazoline) (L)Ni(Ar)Br revealed that Mn reduction was not needed, while Lewis acidic titanium alkoxides were critical to ketone insertion.

Cobalt-Catalyzed Enantioselective Reductive Arylation, Heteroarylation, and Alkenylation of Michael Acceptors via an Elementary Mechanism of 1,4-Addition.

Cobalt complexes with chiral quinox ligands effectively promote the enantioselective conjugate addition of enones using aryl, heteroaryl, and alkenyl halides and sulfonates. Additionally, a cobalt complex with a strongly donating diphosphine, BenzP*, successfully catalyzes the asymmetric reductive arylation and alkenylation of α,ß-unsaturated amides. Both catalytic systems show broad scopes and tolerance of sensitive functional groups. Both reactions can be scaled up with low loadings of cobalt catalysts. Experimental results and density functional theory (DFT) calculations suggest a new mechanism of elementary 1,4-addition of aryl cobalt(I) complexes.

Cobalt-Catalyzed Enantioselective Cross-Electrophile Couplings: Stereoselective Syntheses of 5-7-Membered Azacycles.

Cobalt complexes of chiral pyrox ligands catalyzed enantioselective reductive couplings of nonconjugated iododienes with aryl iodides or alkenyl bromides. The reaction enabled stereoselective syntheses of 5-7-membered azacycles carrying quaternary stereocenters. Mechanistically, cross-electrophile selectivity originated from selective coupling of alkylcobalt(I) complexes generated after cyclization with aryl iodides.

Nickel-Catalyzed Enantioselective Reductive Arylation and Heteroarylation of Aldimines via an Elementary 1,4-Addition.

Nickel catalysts of chiral pyrox ligands promoted enantioselective reductive arylation and heteroarylation of aldimines, using directly (hetero)aryl halides and sulfonates. The catalytic arylation can also be conducted with crude aldimines generated from condensation of aldehydes and azaaryl amines. Mechanistically, density functional theory (DFT) calculations and experiments pointed to an elementary step of 1,4-addition of aryl nickel(I) complexes to N-azaaryl aldimines.

Metal-catalyzed asymmetric heteroarylation of alkenes: diverse activation mechanisms.

This review summarizes the state-of-the-art in transition metal-catalyzed asymmetric alkylation of heteroarenes using alkenes (covering literature from 2000 to late 2021). Based on elementary reactions on metals for substrate activation, these reactions are broadly classified in several categories: (A) concerted oxidative addition of heteroaryl C-H bonds on rhodium(I) and iridium(I), (B) ligand-to-ligand hydrogen transfer (LLHT) on low-valent 3d metal complexes of nickel and cobalt, (C) different ways for deprotonation of heteroaryl C-H bonds by late transition metal complexes, especially palladium, including electrophilic aromatic substitution and a related mechanism, base-assisted intramolecular electrophilic substitution, concerted and nonconcerted metalation deprotonation, (D) σ-bond metathesis by d0 early transition metal complexes, (E) electrophilic activation of olefins by Pd(II), Pt(II) and Au(I), and (F) metal hydride insertion of aryl olefins and dienes. The demand to achieve enantiocontrol in the heteroarylation reactions has also driven innovation in chiral ancillary ligands, exemplified by extremely bulky, chiral N-heterocyclic carbenes for nickel catalysts, bulky monodentate oxazolines for Wacker-type reactions and chiral cyclopentadienyl ligands for half-sandwich complexes of scandium.

Cobalt-Catalyzed Asymmetric Deuteration of α-Amidoacrylates for Stereoselective Synthesis of α,ß-Dideuterated α-Amino Acids.

A cobalt-catalyzed deuteration of amidoacrylates using deuterated methanol afforded α,ß-dideuterio-α-amino esters in excellent enantiomeric ratios (mostly >95 : 5) and almost complete deuteration (99 %). The new protocol was used to prepare dideuterio-α-amino acid fragments in some drugs. Furthermore, the stereoselective deuteration was applied in a concise synthesis of dideuterio l-DOPA.

Nickel-Catalyzed Enantioselective Reductive Conjugate Arylation and Heteroarylation via an Elementary Mechanism of 1,4-Addition.

A nickel complex of isoquinox promoted enantioselective conjugate arylation and heteroarylation of enones using aryl and heteroaryl halides directly. The reaction was successfully applied to stereoselective syntheses of ar-turmerone, chiral fragments of (+)-tolterodine and AZD5672. Mechanistically, experiments and calculations supported that an arylnickel(I) complex inserted to enones via an elementary 1,4-addition.

Enantioselective Synthesis of Chiral Carboxylic Acids from Alkynes and Formic Acid by Nickel-Catalyzed Cascade Reactions: Facile Synthesis of Profens.

We report a stereoselective conversion of terminal alkynes to α-chiral carboxylic acids using a nickel-catalyzed domino hydrocarboxylation-transfer hydrogenation reaction. A simple nickel/BenzP* catalyst displayed high activity in both steps of regioselective hydrocarboxylation of alkynes and subsequent asymmetric transfer hydrogenation. The reaction was successfully applied in enantioselective preparation of three nonsteroidal anti-inflammatory profens (>90 % ees) and the chiral fragment of AZD2716.

Enantioselective Three-Component Coupling of Heteroarenes, Cycloalkenes and Propargylic Acetates.

Asymmetric coupling proceeds efficiently between propargylic acetates, cycloalkenes and electron-rich heteroarenes including indoles, pyrroles, activated furans and thiophenes. 2,3-Disubstituted tetrahydrofurans and pyrrolidines are produced in trans configuration and excellent enantiomeric ratios. The reaction proceeds via Wacker-type attack of nucleophilic heteroarenes on alkenes activated by allenyl PdII species.

Enantioselective Intermolecular Heck and Reductive Heck Reactions of Aryl Triflates, Mesylates, and Tosylates Catalyzed by Nickel.

Nickel-catalyzed intermolecular Heck reaction of cycloalkenes proceeds well with aryl triflates, mesylates and tosylates in excellent enantiomeric ratios. The asymmetric reductive Heck reaction also works with a 2-cyclopentenone ketal, which is equivalent to conjugate arylation of the enone itself.

Asymmetric Wacker-Type Oxyallenylation and Azaallenylation of Cyclic Alkenes.

Palladium-catalyzed three-component carboetherification of cyclic alkenes proceeded to give trans adducts exclusively with excellent enantioselectivity through a Wacker-type pathway. The reaction is also applicable to other oxygen nucleophiles, such as water, phenols, and carboxylic acids, as well as some electron-poor aryl amines.

Asymmetric Three-Component Heck Arylation/Amination of Nonconjugated Cyclodienes.

Substituted cyclohexylamines are becoming increasingly important in drug discovery. Asymmetric Heck insertion/amination of nonconjugated cyclodienes proceeds to give 5-aryl cyclohexenylamines with good enantioselectivity and exclusive trans configurations. Primary and secondary anilines, indoline, and benzylamines are suitable amines. The weakly donating diphosphite Kelliphite forms a deep unsymmetrical pocket, which is essential for stereoselective anti attack of amines.

Asymmetric Reductive and Alkynylative Heck Bicyclization of Enynes to Access Conformationally Restricted Aza[3.1.0]bicycles.

Conformationally restricted azabicycles are becoming increasingly important in medicinal research. Asymmetric Heck bicyclization of enynes proceeds to give medicinally useful aza[3.1.0] and aza[4.1.0] bicycles with excellent enantioselectivity. The key organopalladium species after bicyclization can be trapped by silanes and terminal alkynes.

Asymmetric Stepwise Reductive Amination of Sulfonamides, Sulfamates, and a Phosphinamide by Nickel Catalysis.

Asymmetric reductive amination of poorly nucleophilic sulfonamides was realized in the presence of nickel catalysts and titanium alkoxide. A wide range of ketones, including enolizable ketones and some biaryl ones, were converted into sulfonamides in excellent enantiomeric excess. The cyclization of sulfamates and intermolecular reductive amination of a diarylphosphinamide were also successful. Formic acid was used as a safe and economic surrogate of high-pressure hydrogen gas.

Copper-Catalyzed Asymmetric Arylation of N-Heteroaryl Aldimines: Elementary Step of a 1,4-Insertion.

Copper complexes of monodentate phosphoramidites efficiently promote asymmetric arylation of N-azaaryl aldimines with arylboroxines. DFT calculations and experiments support an elementary step of 1,4-insertion in the reaction pathway, a step in which an aryl-copper species adds directly across four atoms of C=N-C=N in the N-azaaryl aldimines.

Palladium-Catalyzed para-Selective Alkylation of Electron-Deficient Arenes.

Intermolecular alkylations of electron-deficient arenes proceed with good para selectivity. Palladium catalysts were used to generate nucleophilic alkyl radicals from alkyl halides, which then directly add onto the arenes. The arene scope and the site of alkylation are opposite to those of classical Friedel-Crafts alkylations, which prefer electron-rich systems.

Palladium-Catalyzed Enantioselective Arylation of Racemic Ketones to Form Bridged Bicycles via Dynamic Kinetic Resolution.

Enantioselective α-arylation of racemic ketones containing existing α'-stereocenters is reported for the first time via base-induced dynamic kinetic resolution. Bridged bicyclic rings are formed in good ee values, which are difficult to obtain otherwise. Furthermore, reactions in DMSO-d6 resulted in extensive deuteration of both α- and α'-positions in the products, thus supporting a pathway involving rapid, reversible deprotonation of ketones under catalytic conditions.

Nickel-Catalyzed Direct Synthesis of Aryl Olefins from Ketones and Organoboron Reagents under Neutral Conditions.

Nickel-catalyzed addition of arylboron reagents to ketones results in aryl olefins directly. The neutral condition allows acidic protons of alcohols, phenols, and malonates to be present, and fragile structures are also tolerated.

Asymmetric Intermolecular Heck Reaction of Propargylic Acetates and Cycloalkenes to Access Fused Cyclobutenes.

An asymmetric Heck annulation of propargylic acetates with several types of cyclic olefins affords highly strained cyclobutenes in high enantioselectivity.

Nickel-Catalyzed Asymmetric Reductive Heck Cyclization of Aryl Halides to Afford Indolines.

A nickel-catalyzed asymmetric reductive Heck reaction of aryl chlorides has been developed that affords substituted indolines with high enantioselectivity. Manganese powder is used as the terminal reductant with water as a proton source. Mechanistically, it is distinct from the palladium-catalyzed process in that the nickel-carbon bond is converted into a C-H bond to release the product through protonation instead of hydride donation followed by C-H reductive elimination on Pd.