Catalytic Epoxidation of Carbonyl Compounds via Carbonyl Ylides: from Racemic to Enantioselective.

Transition metal-catalyzed epoxidation of carbonyl compounds through carbonyl ylides represents a highly effective method for synthesizing a diverse range of valuable epoxides. This review offers an in-depth overview of the latest developments in inter- and intramolecular epoxidation reactions involving metal carbenes and carbonyl compounds, encompassing both racemic to enantioselective transformations. These catalytic epoxidations are reviewed by highlighting their product selectivity, diversity and applicability, and the related mechanistic rationale is showcased where possible.

Palladium-Catalyzed Heck/Suzuki Tandem Reaction of (Z)-1-Iodo-1,6-dienes and Organoboronic Acids.

The Heck/Suzuki tandem reaction has emerged as an essential strategy for the synthesis of complex molecules. Herein, an efficient palladium-catalyzed Heck/Suzuki tandem reaction of (Z)-1-iodo-1,6-dienes with organoboronic acids is described, providing various tetrahydropyridines in good to excellent yields under mild reaction conditions. The key to the success of this approach is the avoidance of the intramolecular second Heck insertion occurring prior to the transmetalation step. In addition, the asymmetric version of this reaction is investigated to deliver chiral tetrahydropyridine in excellent yield with promising enantioselectivity.

Asymmetric formal C-C bond insertion into aldehydes via copper-catalyzed diyne cyclization.

The formal C-C bond insertion into aldehydes is an attractive methodology for the assembly of homologated carbonyl compounds. However, the homologation of aldehydes has been limited to diazo approach and the enantioselective reaction was rarely developed. Herein, we report an asymmetric formal C-C bond insertion into aldehydes through diyne cyclization strategy. In the presence of Cu(I)/SaBOX catalyst, this method leads to the efficient construction of versatile axially chiral naphthylpyrroles in moderate to excellent yields with good to excellent enantioselectivities. This protocol represents a rare example of asymmetric formal C-C bond insertion into aldehydes using non-diazo approach. The combined experimental and computational mechanistic studies reveal the reaction mechanism, origin of regioselectivity and stereoselectivity. Notably, the chiral phosphine ligand derived from synthesized axially chiral skeleton was proven to be applicable to asymmetric catalysis.

Pd(0)-Catalyzed Asymmetric 7-Endo Hydroacyloxylative Cyclization of 1,6-Enyne Enabled by an Anion Ligand-Directed Strategy.

Despite diversity in reaction mechanisms, the palladium-catalyzed cyclization of 1,6-enyne generally proceeds in a 5-exo manner. Herein, we report the development of a Pd(0)-catalyzed hydroacyloxylative cyclization of 1,6-enyne in either 7-endo-trig or 6-exo-trig fashion when paired with an appropriate dihaloacetic acid reactant, such as F2HCCO2H and Cl2HCCO2H. Using the combination of Pd2(dba)3 and a chiral phosphine ligand, the hydroacyloxylative cyclization of 1,6-enyne bearing a 1,1-disubstituted alkene moiety readily gives highly enantiopure seven-membered heterocycles while the reaction of those having a 1,2-disubstituted alkene affords six-membered rings with moderate enantioselectivity. Preliminary experimental studies suggest a reaction mechanism featuring an unusual E-to-Z vinyl-Pd(II) isomerization and alkene trans-oxypalladation, which is proven to be governed by the rationally selected carboxylate.

Pd0 -Catalyzed Asymmetric Carbonitratation Reaction Featuring an H-Bonding-Driven Alkyl-PdII -ONO2 Reductive Elimination.

Reductive elimination of alkyl-PdII -O is a synthetically useful yet underdeveloped elementary reaction. Here we report that the combination of an H-bonding donor [PyH][BF4 ] and AgNO3 additive under toluene/H2 O biphasic system can enable such elementary step to form alkyl nitrate. This results in the Pd0 -catalyzed asymmetric carbonitratations of (Z)-1-iodo-1,6-dienes with (R)-BINAP as the chiral ligand, affording alkyl nitrates up to 96 % ee. Mechanistic studies disclose that the reaction consists of oxidative addition of Pd0 catalyst to vinyl iodide, anion ligand exchange between I- and NO3 - , alkene insertion and SN 2-type alkyl-PdII -ONO2 reductive elimination. Evidences suggest that H-bonding interaction of PyH⋅⋅⋅ONO2 can facilitate dissociation of O2 NO- ligand from the alkyl-PdII -ONO2 species, thus enabling the challenging alkyl-PdII -ONO2 reductive elimination to be feasible.

Enantioselective Copper-Catalyzed Formal [2+1] and [4+1] Annulations of Diynes with Ketones via Carbonyl Ylides.

Carbonyl ylides have proven to be powerful synthons for the efficient construction of various valuable O-heterocycles, and the formation of carbonyl ylides by the reaction of metal carbenes with carbonyls has attracted increasing attention over the past decades. However, a catalyst-controlled highly enantioselective reaction of carbonyl ylides from metal carbenes is extremely challenging. Herein, we report a novel copper-catalyzed asymmetric formal [2+1] and [4+1] annulations of diynes with ketones via carbonyl ylides. Importantly, this protocol not only represents the first example of successful asymmetric epoxidation via carbonyl ylides, but also constitutes the first reaction of vinyl cations with carbonyl compounds. This method leads to the divergent, practical and atom-economical synthesis of a range of chiral oxiranes and dihydrofurans in moderate to excellent yields with generally excellent enantioselectivities and diastereoselectivities via remote-stereocontrol strategy.

Palladium-Catalyzed Cascade Reactions of δ-Ketonitriles with Arylboronic Acids: Synthesis of Pyridines.

This study presents the first example of the Pd-catalyzed cascade reactions of 5-oxohexanenitrile with arylboronic acids, affording important synthon 2-methylpyridines that can be further translated through C(sp3)-H functionalization to construct pyridine derivatives. Furthermore, this chemistry allows 5-oxo-5-arylpentanenitrile to react with arylboronic acids to provide unsymmetrical 2,6-diarylpyridines. This protocol paves the way for the practical and atom economical syntheses of valuable pyridines with broad functional groups in moderate to excellent yields under mild conditions.

Syntheses of Pyrroles, Pyridines, and Ketonitriles via Catalytic Carbopalladation of Dinitriles.

The first example of the Pd-catalyzed addition of organoboron reagents to dinitriles, as an efficient means of preparing 2,5-diarylpyrroles and 2,6-diarylpyridines, has been discussed here. Furthermore, the highly selective carbopalladation of dinitriles with organoboron reagents to give long-chain ketonitriles has been developed as well. Based on the broad scope of substrates, excellent functional group tolerance, and use of commercially available substrates, the Pd-catalyzed addition reaction of arylboronic acid and dinitriles is expected to be significant in future synthetic procedures.

Nickel-Catalyzed Tandem Reaction of Functionalized Arylacetonitriles with Arylboronic Acids in 2-MeTHF: Eco-Friendly Synthesis of Aminoisoquinolines and Isoquinolones.

The first example of the nickel-catalyzed tandem addition/cyclization of 2-(cyanomethyl)benzonitriles with arylboronic acids in 2-MeTHF has been developed, which provides the facile synthesis of aminoisoquinolines with good functional group tolerance under mild conditions. This chemistry has also been successfully applied to the synthesis of isoquinolones by the tandem reaction of methyl 2-(cyanomethyl)benzoates with arylboronic acids. The use of the bio-based and green solvent 2-MeTHF as the reaction medium makes the synthesis process environmentally benign. The synthetic utility of this chemistry is also indicated by the synthesis of biologically active molecules.

Pd-Catalyzed tandem reaction of N-(2-cyanoaryl)benzamides with arylboronic acids: synthesis of quinazolines.

The synthesis of 2,4-disubstituted quinazolines by a palladium-catalyzed reaction of arylboronic acids with N-(2-cyanoaryl)benzamides has been developed with moderate to excellent yields. The method shows good functional group tolerance. In particular, halogen and hydroxyl substituents, which are amenable for further synthetic elaborations, are well tolerated. Moreover, the present synthetic route could be readily scaled up to gram quantity without difficulty. The mechanism possibly involves nucleophilic addition to the nitrile function, forming an imine intermediate followed by an intramolecular addition to the amide and dehydration to the quinazoline ring.

Palladium-Catalyzed Three-Component Tandem Process: One-Pot Assembly of Quinazolines.

The first example of the palladium-catalyzed, three-component tandem reaction of 2-aminobenzonitriles, aldehydes, and arylboronic acids has been developed, providing a new approach for one-pot assembly of diverse quinazolines in moderate to good yields. A noteworthy feature of this method is the tolerance of bromo and iodo groups, which affords versatility for further synthetic manipulations. Preliminary mechanistic experiments indicate that this tandem process involves two possible mechanistic pathways for the formation of quinazolines via catalytic carbopalladation of the cyano group.

Palladium-catalyzed tandem addition/cyclization in aqueous medium: synthesis of 2-arylindoles.

An efficient protocol to construct 2-arylindoles was developed through palladium-catalyzed tandem addition/cyclization of potassium aryltrifluoroborates with aliphatic nitriles in aqueous medium. The use of water as the reaction medium makes the synthesis process environmentally benign. A plausible mechanism for the formation of 2-arylindoles involving sequential nucleophilic addition followed by an intramolecular cyclization is proposed. Moreover, the utility of this catalytic tandem transformation was also demonstrated in an efficient gram-scale synthesis. This method provides an alternative synthetic tool for accessing a more diverse array of 2-arylindoles.

The Development of a Palladium-Catalyzed Tandem Addition/Cyclization for the Construction of Indole Skeletons.

A palladium-catalyzed tandem addition/cyclization of 2-(2-aminoaryl)acetonitriles with arylboronic acids has been developed for the first time, achieving a new strategy for direct construction of indole skeletons. This system shows good functional group tolerance and remarkable chemoselectivity. In particular, the halogen (e.g., bromo and iodo) substituents are amenable to further synthetic elaborations thereby broadening the diversity of the products. Preliminary mechanistic experiments indicate that this transformation involves sequential nucleophilic addition followed by an intramolecular cyclization.

Tandem Addition/Cyclization for Access to Isoquinolines and Isoquinolones via Catalytic Carbopalladation of Nitriles.

The first example of the palladium-catalyzed sequential nucleophilic addition followed by an intramolecular cyclization of functionalized nitriles with arylboronic acids has been achieved, providing an efficient synthetic pathway to access structurally diverse isoquinolines and isoquinolones. This methodology has also been successfully applied to the total synthesis of the topoisomerase I inhibitor CWJ-a-5 (free base).