Synthesis of β-Carbonyl α-Iminoamides by Double Insertion of Isocyanides into Aldehydes.

An unprecedented trimethylsilyl trifluoromethanesulfonate (TMSOTf)-promoted selective double insertion of isocyanides into aldehydes was developed, providing an efficient protocol for synthetically challenging β-carbonyl α-iminoamides. The given approach is applicable for a diverse selection of readily accessible aldehydes, along with isocyanides serving as essential precursors for "amide" and "imine" scaffolds. The versatile transformations of the given products were demonstrated, and the pivotal intermediates for the plausible mechanism were identified.

Cu-mediated enantioselective C-H alkynylation of ferrocenes with chiral BINOL ligands.

A wide range of Cu(II)-catalyzed C-H activation reactions have been realized since 2006, however, whether a C-H metalation mechanism similar to Pd(II)-catalyzed C-H activation reaction is operating remains an open question. To address this question and ultimately develop ligand accelerated Cu(II)-catalyzed C-H activation reactions, realizing the enantioselective version and investigating the mechanism is critically important. With a modified chiral BINOL ligand, we report the first example of Cu-mediated enantioselective C-H activation reaction for the construction of planar chiral ferrocenes with high yields and stereoinduction.

Triple-Consecutive Isocyanide Insertions with Aldehydes: Synthesis of 4-Cyanooxazoles.

An efficient TMSOTf-promoted selective triple consecutive insertions of -butyl isocyanide into aldehydes has been developed, affording pharmacological interesting 4-cyanooxazoles in high yields in a one pot manner. The given method encompasses a wide range of substrates with -butyl isocyanide serving as sources of critical "CN" and "C-N═C" moieties. The versatile transformations of the resulting 4-cyanooxazoles were demonstrated.

Pd-Catalyzed umpolung asymmetric allylic alkylation of hydrazones to vicinal tertiary and quaternary chiral carbon centers.

Diastereo- and enantioselective construction of vicinal tertiary and quaternary carbon centers is a great challenge in synthetic chemistry. Herein, we report a facile and efficient protocol to construct vicinal tertiary and quaternary chiral carbon centers in high yields with high regio-, diastereo- and enantioselectivities Pd-catalyzed umpolung asymmetric allylic alkylation of hydrazones with monosubstituted allyl reagents by using Kündig-type chiral N-heterocyclic carbene as the ligand. The control experiments revealed that the reaction proceeds the inner-sphere mechanism.

Palladium-Catalyzed Asymmetric (3 + 2) Cycloaddition of Vinyl Epoxides with Substituted Propiolates. Enantioselective Formation of 2,3,4-Trisubstituted 2,3-Dihydrofurans.

Alkynyl esters are viable dipolarophiles for the palladium-catalyzed asymmetric (3 + 2) cycloaddition with vinyl epoxides. The chiral dihydrofurans are obtained in high yields and high values. The use of a chiral benzylic substituted ,ligand is essential.

Regio- and enantioselective umpolung gem-difluoroallylation of hydrazones via palladium catalysis enabled by N-heterocyclic carbene ligand.

The enantioselective construction of C-CFR (R: alkyl or fluoroalkyl) bonds has attracted the attention of synthetic chemists because of the importance of chiral fluorinated compounds in life and materials sciences. Catalytic asymmetric fluoroalkylation has mainly been realized under organocatalysis and Lewis acid catalysis, with substrates limited to carbonyl compounds. Few examples using transition-metal catalysis exist, owing to side reactions including decomposition and isomerization of fluoroalkylating reagents.

Synthesis of Poly-Substituted Pyridines via Noble-Metal-Free Cycloaddition of Ketones and Imines.

An eco-friendly and noble-metal-free formal [4+2] cycloaddition reaction was developed for the efficient synthesis of biologically interesting poly-substituted pyridines from easily available ketones and imines, whereby two sequential C-C bonds are formed. The given approach features a unique synthetic strategy of imines and ketones with wide substrate scope, good functional group tolerance, mild conditions and operational simplicity, which represents a more direct pathway to synthesize poly-substituted pyridines than traditional methods.

PdCl/DMSO-Catalyzed Thiol-Disulfide Exchange: Synthesis of Unsymmetrical Disulfide.

Unsymmetrical disulfides have been effectively prepared through thiol exchange with symmetrical disulfides employing a simple PdCl/DMSO catalytic system. The given method features excellent functional group tolerance, a broad substrate scope, and operational simplicity. This reaction is especially useful for late-stage functionalization of bioactive scaffolds such as peptides and pharmaceuticals.

Development of Dipolarophiles for Catalytic Asymmetric Cycloadditions through Pd-π-Allyl Zwitterions.

The development of new and efficient methodology for the construction of optically active molecules is of great interest in both synthetic organic and medicinal chemistry fields. To this end, the personal account summarizes our studies on the development of electron-deficient alkenes, allenes, and alkynes containing single activator as new dipolarophiles for Pd-catalyzed asymmetric cycloaddition reactions. These new dipolarophiles can participate in Pd-catalyzed asymmetric [3+2] and [4+2] cycloadditions through Pd-π-allyl 1,3- and 1,4-zwitterions in-situ generated by the reaction of Pd(0) catalyst with vinyl aziridines, vinyl epoxides, vinyl cyclopropanes, 4-vinyl-1,3-dioxan-2-ones, and vinyl benzoxazinanones.

Palladium-Catalyzed Asymmetric Decarboxylative [4+2] Dipolar Cycloaddition of 4-Vinyl-1,3-dioxan-2-ones with α,β-Disubstituted Nitroalkenes Enabled by a Benzylic Substituted P,N-Ligand.

The Pd-catalyzed asymmetric [4+2] cycloaddition reaction of an aliphatic 1,4-dipole with singly activated electron-deficient alkenes is realized for the first time, enabled by using a newly developed benzylic substituted P,N-ligand, affording tetrahydropyrans having three continuous chiral centers in high yields with high diastereo- and enantioselectivities. The rational transition states of the reaction as well as the role of the benzylic chiral center are proposed.

Silver-Assisted Oxidative Isocyanide Insertion of Ethers: A Direct Approach to β-Carbonyl α-Iminonitriles.

An efficient silver-assisted oxidative coupling of simple ethers with -butyl isocyanide was realized in the presence of DDQ. The direct synthesis of high density functional β-carbonyl α-iminonitriles was achieved in a single step with high yields through the synergetic cascade isocyanide insertion into C(sp)-H bond, where the isocyanide was used as crucial "CN" and "C═N" sources and the -butoxyl group acted as the carbonyl source. Diverse reactivity of β-carbonyl α-iminonitriles has been demonstrated.

Electron-Deficient Alkynes as Dipolarophile in Pd-Catalyzed Enantioselective (3 + 2) Cycloaddition Reaction with Vinyl Cyclopropanes.

The activated alkynes have been used successfully for the first time as the dipolarophile in the palladium-catalyzed asymmetric (3 + 2) cycloaddition, affording highly functionalized cyclopentenes in good to high yields with high chemoselectivities and good to high enantioselectivities. The introduction of an additional carbonyl group at the α-position of the alkynyl esters is the key to activating the carbon-carbon triple bond. The reaction process was investigated, and an inverse process of Pd-catalyzed (3 + 2) cycloaddition was observed.

Pd-catalyzed enantioselective cyclopropanation of nitriles with mono substituted allyl carbonates enabled by the bulky N-heterocyclic carbene ligand.

A highly efficient catalyst for Pd-catalyzed cyclopropanation was developed using a bulkier N-heterocyclic carbene ligand, with which the nitriles reacted with mono substituted allyl reagents to afford cyclopropanes in high yields with high cyclopropanation/allylation and enantioselectivities. The reasons for cyclopropanation were investigated and the usefulness of the products was demonstrated.

Trisubstituted alkenes with a single activator as dipolarophiles in a highly diastereo- and enantioselective [3+2] cycloaddition with vinyl epoxides under Pd-catalysis.

1,1,2-Trisubstituted alkenes with a single strongly electronic withdrawing activator, which are unreactive electron-deficient alkenes in transition metal-catalyzed [3+2] cycloaddition with vinyl three-membered heterocycles, were used in the Pd-catalyzed asymmetric cycloaddition of vinyl epoxides, affording multifunctionalized tetrahydrofurans in high yields with high diastereo- and enantioselectivities.

Diastereo- and Enantioselective Palladium-Catalyzed Dearomative [3+2] Cycloaddition of 3-Nitroindoles.

Diastereo- and enantioselective cycloaddition of 3-nitroindoles with vinyl aziridine was realized under Pd-catalysis using commercially available Walphos as the ligand, affording pyrroloindolines in high yields with high diastereo- and enantioselectivities. The reaction can be scaled up to a gram scale and the reaction products are easily converted to amino pyrroloindoline and other pyrroloindoline derivatives.

Highly Diastereo- and Enantioselective Palladium-Catalyzed [3 + 2] Cycloaddition of Vinyl Epoxides and α,β-Unsaturated Ketones.

An asymmetric [3 + 2] cycloaddition reaction of vinyl epoxides with α,β-unsaturated ketones, the single activated electron-deficient alkenes, has been achieved under Pd-catalysis in excellent diastereo- and enantioselectivity. The utilities of the protocol are demonstrated by transformation of the products into other useful chiral molecules. Density functional theory calculations rationalize the stereocontrol of the reaction.

Enantioselective Synthesis of Chromenes via a Palladium-Catalyzed Asymmetric Redox-Relay Heck Reaction.

A palladium-catalyzed asymmetric redox-relay Heck reaction of 4H-chromenes and arylboronic acids has been successfully developed. The reaction proceeded in moderate to good yields with good to high enantioselectivities. The resulting product is an advanced intermediate of bio-active compound BW683C.

Palladium-Catalyzed Asymmetric Allylic Alkylation of Alkyl-Substituted Allyl Reagents with Acyclic Amides.

A wide range of alkyl-substituted allyl reagents, as well as nonstabilized carbon nucleophiles, was successfully used for the first time in the palladium-catalyzed asymmetric allylic alkylation reaction, affording the corresponding allylic alkylated products in high yields with high enantioselectivities. The usefulness of the protocol has been demonstrated by the enantioselective synthesis of an important chiral building block and enantiomer of Dubiusamine A.

Synthesis of β,β-Disubstituted Indanones via the Pd-Catalyzed Tandem Conjugate Addition/Cyclization Reaction of Arylboronic Acids with α,β-Unsaturated Esters.

Under Pd catalysis with a newly synthesized electron-deficient heterocycle, 2-(4,5-dihydroimidazol-2-yl)pyrimidine (as the ligand), the reaction of α,β-unsaturated esters with arylboronic acids afforded a wide range of 3,3-disubstituted indan-1-ones bearing a quaternary carbon in high yields. Mechanistic studies revealed that the reaction involves a tandem conjugate addition/1,4-Pd shift followed by a cyclization.

Tandem Thorpe Reaction/Palladium Catalyzed Asymmetric Allylic Alkylation: Access to Chiral β-enaminonitriles with Excellent Enantioselectivity.

A new type of nucleophile, a 3-imino nitrile carbanion generated in situ by Thorpe reaction of acetonitrile with a base, was developed successfully and applied in a Pd-catalyzed asymmetric allylic alkylation with mono-substituted allyl reagents under Pd/SIOCPhox catalysis, affording β-enaminonitrile products in high yields with excellent regio- and enantioselectivities.

Palladium/N-heterocyclic carbene catalysed regio and diastereoselective reaction of ketones with allyl reagents via inner-sphere mechanism.

The palladium-catalysed allylic substitution reaction is one of the most important reactions in transition-metal catalysis and has been well-studied in the past decades. Most of the reactions proceed through an outer-sphere mechanism, affording linear products when monosubstituted allyl reagents are used. Here, we report an efficient Palladium-catalysed protocol for reactions of β-substituted ketones with monosubstituted allyl substrates, simply by using N-heterocyclic carbene as ligand, leading to branched products with up to three contiguous stereocentres in a (syn, anti)-mode with excellent regio and diastereoselectivities.

Palladium-catalyzed asymmetric intermolecular Mizoroki-Heck reaction for construction of a chiral quaternary carbon center.

Palladium-catalyzed asymmetric intermolecular Mizoroki-Heck reaction for the construction of a chiral quaternary carbon center is developed, affording 2,2-disubstituted 2,5-dihydrofurans in high yield with excellent enantioselectivity. The products are easily converted into the corresponding butenolides with retention of enantioselectivity.

Highly diastereo- and enantioselective palladium-catalyzed [3+2] cycloaddition of vinyl aziridines and α,β-unsaturated ketones.

A palladium-catalyzed asymmetric [3+2] cycloaddition reaction of vinylaziridines with α,β-unsaturated ketones, wherein the alkenes have a single activator, is realized in high diastereo- and enantioselectivity, thus affording 3,4-disubstituted pyrrolidines in high yields with excellent ee values. The introduction of a methyl group at C1 of the vinyl group the vinylaziridines greatly improves the stereochemistry of the reaction. A plausible transition state is proposed.

Pyridine-NHC: effective ligand in Pd-catalyzed cyclopropanation of esters with substituted allyl carbonates.

By consideration of the mechanism of Pd-catalyzed cyclopropanation and allylation, NHC-pyridine compounds were adopted as the ligand in Pd-catalyzed cyclopropanation of esters and monosubstituted allylic reagents. The corresponding cyclopropanes were afforded as major products in moderate to good yields with high cyclopropane/allylation selectivity.