We succeeded in synthesizing five different types of multiply arylated alkanes from diarylketones in a single step. The key for this method is the generation of diarylphosphinates via a phospha-Brook rearrangement of ketones with phosphine oxide.

1-Azaspirocyclic compounds have gained attention in chemistry and drug discovery fields. In this manuscript, the development of a Pd-catalyzed dearomative azaspirocyclization of bromoarenes bearing an aminoalkyl group with N-tosylhydrazones is described. The present method enables azaspirocyclization with the introduction of carbon substituents, achieving the convergent synthesis of 1-azaspirocycles. This method allowed furan, thiophene, and naphthalene cores to generate the corresponding 1-azaspirocycles. The obtained azaspirocycles from furans were further elaborated via an acid-catalyzed rearrangement to afford 1-azaspirocyclopentenones.

A Ni-catalyzed aryl sulfide synthesis through an aryl exchange reaction between aryl sulfides and a variety of aryl electrophiles was developed. By using 2-pyridyl sulfide as a sulfide donor, this reaction achieved the synthesis of aryl sulfides without using odorous and toxic thiols. The use of a Ni/dcypt catalyst capable of cleaving and forming aryl-S bonds was important for the aryl exchange reaction between 2-pyridyl sulfides and aryl electrophiles, which include aromatic esters, arenol derivatives, and aryl halides. Mechanistic studies revealed that Ni/dcypt can simultaneously undergo oxidative additions of aryl sulfides and aromatic esters, followed by ligand exchange between the generated aryl-Ni-SR and aryl-Ni-OAr species to furnish aryl exchanged compounds.

Transition metal-catalyzed cross-coupling between aryl halides and nucleophiles is one of the most reliable C-C and C-heteroatom bond forming reactions. However, preparation of haloarenes usually requires multi-step operation, making the whole cross-coupling process inefficient. Nitroarenes, synthesized by a single-step nitration of arenes, can be attractive alternatives as electrophiles in cross-coupling methodology, but inherent inertness of C(sp 2)-NO 2 bonds toward metal catalysts has been a bottleneck of general denitrative transformations. Recently, we have overcome this obstacle and achieved direct activation of Ar-NO 2 bonds by using Pd/BrettPhos catalysis. Herein, we describe the development of denitrative couplings by Pd/BrettPhos catalyst and its unique suitability from a mechanistic point of view. Deep understanding of reaction mechanism also enabled us to design more active Pd/NHC system.

A Pd-catalyzed dearomative three-component C-C bond formation of bromoarenes with diazo compounds and malonates was developed. Various bromoarenes ranging from benzenoids to azines and heteroles were transformed to the corresponding substituted alicyclic molecules. The key to this reaction is the generation of a benzyl-palladium intermediate, which reacts with malonates to form a Pd-O-enolate species. Strikingly, the present method enabled rapid access to multi-substituted alicycles through subsequent elaboration of dearomatized products. This journal is

Functionalization of arenes is a topic of central importance in diverse fields ranging from medicinal chemistry to materials science. Metal-catalyzed cross-coupling and nucleophilic aromatic substitution are among the most reliable methods to access functionalized arenes. In these reactions, haloarenes are often used as a versatile synthetic platform to introduce various functional groups. However, haloarenes are typically prepared from the corresponding nitroarenes through the classic sequence of reduction, diazotization, and halogenation. Thus, haloarene cross-coupling can become a multistep transformation overall. To avoid this lengthy sequence, the direct utilization of nitroarenes has the potential to significantly streamline synthetic processes and, therefore, has attracted attention in the chemistry community from the vantage points of atom- A nd step-economy. In this Review, we comprehensively cover advances in transition-metal-catalyzed denitrative reactions of nitroarenes.

Aromatic rearrangement reactions are useful tools in the organic chemist’s toolbox when generating uncommon substitution patterns. However, it is difficult to precisely translocate a functional group in (hetero) arene systems, with the exception of halogen atoms in a halogen dance reaction. Here, we describe an unprecedented “ester dance” reaction: a predictable translocation of an ester group from one carbon atom to another on an aromatic ring. Specifically, a phenyl carboxylate substituent can be shifted from one carbon to an adjacent carbon on a (hetero) aromatic ring under palladium catalysis to often give a thermodynamically favored, regioisomeric product with modest to good conversions. The obtained ester moiety can be further converted to various aromatic derivatives through the use of classic and state-of-the-art transformations including amidation, acylations, and decarbonylative couplings.

A dearomative allylation of naphthyl cyanohydrins with allyl borates and allyl stannanes under palladium catalysis was developed. At the initial stage of this study, the dearomative reaction (C4 substitution of the aromatics) was competing with benzyl substitution. To circumvent this issue, the use of palladium and meta-disubstituted triarylphosphine as the catalyst in a 1:1 ratio was found to enhance the site selectivity, furnishing the desired dearomatized products. Further derivatizations of products were also successful.

We have developed a deoxygenative coupling of aromatic esters with diarylphosphine oxides/dialkyl phosphonates under palladium catalysis. In this reaction, aromatic esters can work as novel benzylation reagents to give the corresponding benzylic phosphorus compounds. The key of this reaction is the use of phenyl esters, an electron-rich diphosphine as a ligand, and sodium formate as a hydrogen source. Arylcarboxylic acids were also applicable in this reaction using (Boc)(2)O as an additive. Palladium/dcype worked to activate the acyl C-O bond of the ester and to support the reduction with sodium formate.

A catalytic ester transfer reaction of aromatic esters with aryl halides/arenols was developed. The present reaction can transfer an ester functional group from certain aromatic esters to haloarenes. This ester transfer reaction involves two oxidative additions-one from the C-C bond of the aromatic ester and one from the C-halogen bond of haloarenes-onto a nickel catalyst. The utilization of a Ni/dcypt catalyst capable of cleaving both chemical bonds was a key for the reaction progress. Furthermore, naphthol-based aryl electrophiles were also applicable to the catalytic system via C-O bond activation.

A decarbonylative cyanation of aromatic esters with aminoacetonitriles in the presence of a nickel catalyst was developed. The key to this reaction was the use of a thiophene-based diphosphine ligand, dcypt, permitting the synthesis of aryl nitrile without the generation of stoichiometric metal- or halogen-containing chemical wastes. A wide range of aromatic esters, including hetarenes and pharmaceutical molecules, can be converted into aryl nitriles.

A Ni-catalyzed decarbonylative methylation of aromatic esters was achieved using methylaluminums as methylating agents. Dimethylaluminum chlorides uniquely worked as the methyl source. Because of the Lewis acidity of aluminum reagents, less reactive alkyl esters could also undergo the present methylation. By controlling the Lewis acidity of aluminum reagents, a chemoselective decarbonylative cross-coupling between alkyl esters and phenyl esters was successful.

A Ni-catalyzed decarbonylative methylation of aromatic esters was achieved using methylaluminums as methylating agents. Dimethylaluminum chlorides uniquely worked as the methyl source. Because of the Lewis acidity of aluminum reagents, less reactive alkyl esters could also undergo the present methylation. By controlling the Lewis acidity of aluminum reagents, a chemoselective decarbonylative cross-coupling between alkyl esters and phenyl esters was successful.

Ni-catalyzed C-P bond formation was achieved using aromatic esters as unconventional aryl sources. The key to success was the use of a thiophene-based diphosphine ligand (dcypt). Several aromatic esters including heteroaromatics can be coupled with phosphine oxides and phosphates, providing aryl phosphorus compounds. The synthetic utility of the method was demonstrated by application of the present protocol to the sequential coupling reactions.

Transition metal-catalyzed cross-coupling reactions are a powerful method to form chemical bonds. Conventionally, haloarenes has been used as the most reliable aryl electrophiles in cross- coupling. Recent studies in the cross-coupling arena have enabled to employ unconventional but ubiquitous aryl electrophiles such as phenol and aniline. With this trend of organic synthesis, cross-coupling reactions using aromatic carboxylic acid derivatives such as esters as aryl electrophiles have gained considerable attention as a de novo and efficient method to construct C-C and C-heteroatom bonds. In order to realize this particular transformation, it is important to develop and design transition metal catalysts, those are active toward the scission of ester C-O bonds and decarbonylation. In this review, we describe the progress of catalytic decarbonylative cross- coupling of aromatic esters including chronological aspects and mechanistic considerations.

Multiply arylated (hetero) arenes are intriguing structural motifs in functional molecules, such as natural products, pharmaceuticals and functional organic materials. In recent decades, many synthesis methods of multiply arylated (hetero) arenes have been reported. As a subclass of multiply arylated arenes, fully arylated (hetero) arenes have also flourished as a unique structural class in functional organic materials and biologically active compounds. Despite the successful application of fully arylated (hetero) arenes with different aryl substituents, the synthesis of such (hetero) arenes has not been explored compared to partially arylated arenes due to the difficulty of synthesizing sterically hindered and highly unsymmetrical aromatic cores. This review reports the synthesis of fully arylated (hetero) arenes bearing more than two different aryl substituents and categorizes this emerging topic by the type of (hetero) arene core, focusing on the methods employing cross-coupling reaction including direct C-H arylation.

A decarbonylative aryl thioether synthesis by nickel catalysis is described. After optimization of the reaction conditions, two air-stable Ni catalytic systems [Ni(OAc)2/PnBu3 and Ni(OAc)2/dppb] were identified. Using these catalysts, various aryl thioesters can be converted to the corresponding aryl thioethers in decarbonylative fashion.

Transition metal-catalyzed cross-coupling reactions are a powerful method to form chemical bonds. Conventionally, haloarenes has been used as the most reliable aryl electrophiles in cross- coupling. Recent studies in the cross-coupling arena have enabled to employ unconventional but ubiquitous aryl electrophiles such as phenol and aniline. With this trend of organic synthesis, cross-coupling reactions using aromatic carboxylic acid derivatives such as esters as aryl electrophiles have gained considerable attention as a de novo and efficient method to construct C-C and C-heteroatom bonds. In order to realize this particular transformation, it is important to develop and design transition metal catalysts, those are active toward the scission of ester C-O bonds and decarbonylation. In this review, we describe the progress of catalytic decarbonylative cross- coupling of aromatic esters including chronological aspects and mechanistic considerations.

© Georg Thieme Verlag Stuttgart, New York. Heteroaromatic esters were found to be applicable as an arylating agent for the Pd-catalyzed α-arylation of ketones in a decarbonylative fashion. The use of our in-house ligand, dcypt, enabled this unique bond formation. Considering the ubiquity and low cost of aromatic esters, the present work will allow for rapid access to valuable α-aryl carbonyl compounds.

Catalytic cross-coupling reactions of aromatic esters and amides have recently gained considerable attention from synthetic chemists as de novo and efficient synthetic methods to form C-C and C-heteroatom bonds. Esters and amides can be used as diversifiable groups in metal-catalyzed cross-coupling: in a decarbonylative manner, they can be utilized as leaving groups, whereas in a non-decarbonylative manner, they can form ketone derivatives. In this review, recent advances of this research topic are discussed.

We have achieved a synthesis of multiply arylated pyridines by using a [4 + 2] cycloaddition of 2,4-diaryl-5-chloroxazoles and cinnamic acids as a key reaction. The resulting hydroxytriarylpyridines can be derivatized into triarylpyridines, tetraarylpyridines and pentaarylpyridines by sequential cross couplings. This synthetic method allows for facile and rapid access to highly arylated pyridines with different aryl substituents. (C) 2017 Elsevier Ltd. All rights reserved.

Because diaryl ethers are present as an important motif in pharmaceuticals and natural products, extensive studies for the development of novel methods have been conducted. A conventional method for the construction of the diaryl ether moiety is the intermolecular cross-coupling reaction of aryl halides and phenols with a copper or palladium catalyst. We developed a catalytic decarbonylative etherification of aromatic esters using a palladium or nickel catalyst with our enabling diphosphine ligand to give the corresponding diaryl ethers. The present reaction can be conducted on grain scale in excellent yield. This reaction not only functions in an intramolecular setting but also allows for a crossetherification using other phenols.

A palladium-catalyzed decarbonylative alkynylation reaction of aromatic esters with terminal alkynes is reported. This reaction allows for halogen-free Sonogashira coupling, resulting in various aryl- and heteroarylalkynes. The utility of the reaction was demonstrated by orthogonal coupling reaction.

The first palladium-catalyzed decarbonylative coupling of phenyl 2-azinecarboxylates and arylboronic acids is presented. The key for the development of this decarbonylative coupling is the use of Pd/dcype as a catalyst. A wide range of 2-azinecarboxylates can undergo the present coupling reaction to afford 2-arylazines. By combination with previously reported nickel-catalyzed decarbonylative coupling, we achieved a chemoselective sequential decarbonylative coupling of pyridine dicarboxylate to synthesize 2,4-diarylpyridine.

© 2016, Springer International Publishing Switzerland.Catalytic C–H functionalization using transition metals has received significant interest from organic chemists because it provides a new strategy to construct carbon–carbon bonds and carbon–heteroatom bonds in highly functionalized, complex molecules without pre-functionalization. Recently, inexpensive catalysts based on transition metals such as copper, iron, cobalt, and nickel have seen more use in the laboratory. This review describes recent progress in nickel-catalyzed aromatic C–H functionalization reactions classified by reaction types and reaction partners. Furthermore, some reaction mechanisms are described and cutting-edge syntheses of natural products and pharmaceuticals using nickel-catalyzed aromatic C–H functionalization are presented.

<p>Dihalogenation of alkene is well known reaction undergoing in a stereospecific manner. Although enantioselective dihalogenation of alkene using chiral auxiliary was developed, the catalytic protocol remained as a challenging issue. This review summarizes recent progress of catalytic enantioselective dihalogenation of alkene.</p>

The Suzuki-Miyaura cross-coupling is a metal-catalysed reaction in which boron-based nucleophiles and halide-based electrophiles are reacted to form a single molecule. This is one of the most reliable tools in synthetic chemistry, and is extensively used in the synthesis of pharmaceuticals, agrochemicals and organic materials. Herein, we report a significant advance in the choice of electrophilic coupling partner in this reaction. With a user-friendly and inexpensive nickel catalyst, a range of phenyl esters of aromatic, heteroaromatic and aliphatic carboxylic acids react with boronic acids in a decarbonylative manner. Overall, phenyl ester moieties function as leaving groups. Theoretical calculations uncovered key mechanistic features of this unusual decarbonylative coupling. Since extraordinary numbers of ester-containing molecules are available both commercially and synthetically, this new 'ester' cross-coupling should find significant use in synthetic chemistry as an alternative to the standard halide-based Suzuki-Miyaura coupling.

The mechanism of the Ni-dcype-catalyzed C-H/C-O coupling of benzoxazole and naphthalen-2-yl pivalate was studied. Special attention was devoted to the base effect in the C-O oxidative addition and C-H activation steps as well as the C-H substrate effect in the C-H activation step. No base effect in the C(aryl)-O oxidative addition to Ni-dcype was found, but the nature of the base and C-H substrate plays a crucial role in the following C-H activation. In the absence of base, the azole C-H activation initiated by the C-O oxidative addition product Ni(dcype)(Naph)(PivO), 1B, proceeds via ΔG = 34.7 kcal/mol barrier. Addition of Cs2CO3 base to the reaction mixture forms the Ni(dcype)(Naph)[PivOCs·CsCO3], 3-Cs-clus, cluster complex rather than undergoing PivO- → CsCO3- ligand exchange. Coordination of azole to the resulting 3-Cs-clus complex forms intermediate with a weak Cs-heteroatom(azole) bond, the existence of which increases acidity of the activated C-H bond and reduces C-H activation barrier. This conclusion from computation is consistent with experiments showing that the addition of Cs2CO3 to the reaction mixture of 1B and benzoxazole increases yield of C-H/C-O coupling from 32% to 67% and makes the reaction faster by 3-fold. This emerging mechanistic knowledge was validated by further exploring base and C-H substrate effects via replacing Cs2CO3 with K2CO3 and benzoxazole (1a) with 1H-benzo[d]imidazole (1b) or quinazoline (1c). We proposed the modified catalytic cycle for the Ni(cod)(dcype)-catalyzed C-H/C-O coupling of benzoxazole and naphthalen-2-yl pivalate. (Chemical Equation Presented)

Nickel catalysis for biaryl coupling reactions has received significant attention as a less expensive and less toxic alternative to "standard" palladium catalysis. Here we describe recent developments in nickel-catalyzed biaryl coupling methodology, along with mechanistic studies and applications. In particular we focus on nickel-catalyzed coupling reactions in which "unreactive" bonds such as C-H, C-O, and C-C bonds are converted into biaryl moieties.

Nickel-catalyzed cross-coupling reactions have recently been receiving significant attention from the synthetic community as a way to construct carbon-carbon or carbon-heteroatom bonds, because nickel catalysts are less expensive and less toxic than palladium catalysts. We herein describe our recent developments in nickel-catalyzed biaryl coupling methodology, along with mechanistic studies and applications to the synthesis of natural products and pharmaceuticals. In particular, we focus on nickel-catalyzed direct coupling reactions in which "unreactive" bonds such as C-H, C-O, and C-C bonds are converted into biaryl moieties.