Straightforward access to 2-iminoisoindolines via three-component coupling of arynes, isocyanides and imines

A three-component coupling reaction of arynes, isocyanides and N-tosylaldimines has been developed to offer modest to high yields of diverse 2-iminoisoindolines in one step. Intermediacy of arynes in the coupling has been verified by the reaction of unsymmetrical arynes.     

Chemo- and regioselective assembly of polysubstituted pyridines and isoquinolines from isocyanides, arynes, and terminal alkynes

We have disclosed a general and efficient synthetic strategy for polysubstituted pyridines and isoquinolines with high chemo- and regioselectivity. In this methodology, 1-alkynyl imines act as the key compound to undergo a sequential alkynyl imine-allenyl imine isomerization/aza-Diels-Alder reaction/aromatization. In the first place, 1-alkynyl imines were formed in situ by a highly selective multicomponent reaction of isocyanides, arynes, and terminal alkynes and reacted with another molecule of arynes or terminal alkynes to furnish target heterocyclic products in a highly efficient and atom-economic manner. On the other hand, we attempted to prepare 1-alkynyl imines by other approaches to undergo a similar reaction sequence to afford polysubstituted pyridines and isoquinolines with a wider range. Different from the first approach, the second approach utilized the preprepared 1-alkynyl imines to introduce the related different substitutents into the final products: arynes or terminal alkynes bearing substituents different from those of 1-alkynyl imines have been successfully applied for the synthesis a wide variety of pyridines and isoquinolines with diversity.     

Highly efficient route to fused polycyclic aromatics via palladium-catalyzed aryne annulation by aryl halides

Polycyclic aromatic and heteroaromatic hydrocarbons have been synthesized in high yield by two different processes involving the Pd-catalyzed annulation of arynes. The first process involves a Pd-catalyzed annulation of arynes by 2-halobiaryls and related vinylic halides. The second process utilizes a Pd-catalyzed double annulation of arynes by simple aryl halides. Both processes appear to involve the catalytic, stepwise coupling of two very reactive substrates, an aryne and an organopalladium species, to generate excellent yields of cross-coupled products.     

Recent advances in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions using arynes

This tutorial review is aimed at highlighting recent developments in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions utilizing a versatile class of reactive intermediates, viz., arynes, which hold the potential for numerous applications in organic synthesis. Key to the success of the resurgence of interest in the rich chemistry of arynes is primarily the mild condition for their generation by the fluoride-induced 1,2-elimination of 2-(trimethylsilyl)aryl triflates. Consequently, arynes have been employed for the construction of multisubstituted arenes with structural diversity and complexity. The versatile transition-metal-free applications of arynes include cycloaddition reactions, insertion reactions and multicomponent reactions. In addition, arynes have found applications in natural product synthesis. Herein, we present a concise account of the major developments that occurred in this field during the past eight years.     

苯炔参与的去芳构化反应研究进展

去芳构化反应是有机化学热点研究领域之一,可从二维平面分子出发构筑高官能团化的三维立体分子.近年来,苯炔作为一类高活性中间体被有机化学家们广泛用于去芳构化反应研究中,并取得了一系列创新成果.从含氮芳杂环同苯炔的去芳构化反应、苯炔与双烯体的[4+2]环加成去芳构化反应以及苯炔以其它途径参与的去芳构化反应三个方面,对机理进行...     

Synthesis of 3-substituted indazoles from arynes and N-tosylhydrazones

Readily available, stable, and inexpensive N-tosylhydrazones react with arynes under mild reaction conditions to afford 3-substituted indazoles in moderate to good yields. The reaction appears to involve a dipolar cycloaddition of in situ generated diazo compounds and arynes.     

Transition-Metal-Free α-Arylation of β-Keto Amides via an Interrupted Insertion Reaction of Arynes

Direct α-arylation reactions of secondary β-keto amides with arynes, generated by fluoride-induced elimination of ortho-silyl aryltriflates, are described. The transformation proceeds via an interrupted insertion reaction of arynes and leads to densely functionalized aromatic compounds exhibiting a chiral 'all carbon' quaternary center under transition-metal-free conditions. An organocatalytic asymmetric version of the reaction also proved possible, affording the proof of concept that arynes can be involved in enantioselective transformations.     

Direct access to anthranilic acid derivatives via CO2 incorporation reaction using arynes

CO2 was found to be directly convertible into anthranilic acid derivatives of great synthetic value through a three-component coupling using arynes and amines. Zwitterions arising from nucleophilic attack of amines to arynes serve as key intermediates in the coupling.     

Cyclotrimerization reactions of arynes and strained cycloalkynes

The use of arynes and related species as substrates in metal-catalyzed cycloaddition reactions leads to structurally interesting products. Palladium-catalyzed cyclotrimerization of arynes provides a new method for the synthesis of polycyclic aromatic hydrocarbons. For instance, the chemoselective formal [2 + 2 + 2] cocycloaddition of 2,3-triphenylynes with alkynes affords extended triphenylenes, which are good candidates to behave as liquid crystals. Cotrimerization of benzyne and electron-deficient alkenes selectively affords dihydrophenanthrenes or ortho-olefinated biaryls depending on the catalytic system employed. The use of 2,2'-bis(diphenylphosphino)-1,1'-binophythyl (BINAP)-based palladium(0) catalysts in the cocyclotrimerization of 7-methoxynaphthalyne and dimethyl acetylenedicarboxylate affords an enantiomerically enriched tetrasubstituted pentahelicene, the first example of a metal-catalyzed enantioselective reaction involving arynes. Strained cyclic alkynes can also participate in the palladium-catalyzed cyclotrimerization reactions, which again lead to structurally interesting products.     

The facile insertion of β-keto sulfones to arynes： The direct preparation of polysubstituted ortho-keto benzyl sulfones

One novel carbon-carbon bond insertion reaction of arynes has been developed. By this reaction β-keto sulfones can insert the triple bond of arynes to prepare polysubstituted ortho-keto benzyl sulfones.     

ortho-Difunctionalization of arynes by LiZnEt2(TMP)-mediated deprotonative zincation/elimination of aryl triflates

Generation of arynes from aryl triflates has been achieved using lithium diethyl(tetramethylpiperidyl)-zincate base LiZnEt₂(TMP), via a directed ortho-deprotonative zincation and subsequent elimination of the triflate group. The aryne formation has been demonstrated by the cycloaddition reaction with diene and insertion reactions with ureas. Furthermore, the nucleophilic addition of LiZnEt₂(TMP) to arynes was observed in the absence of external aryne partners, offering a new cascade strategy for diverse difunctionalization of arynes.     

The facile insertion of β-keto sulfones to arynes: The direct preparation of polysubstituted ortho-keto benzyl sulfones

One novel carbon-carbon bond insertion reaction of arynes has been developed. By this reaction β-keto sulfones can insert the triple bond of arynes to prepare polysubstituted ortho-keto benzyl sulfones.     

Uncovering the Neglected Similarities of Arynes and Donor–Acceptor Cyclopropanes

Arynes and donor–acceptor (D–A) cyclopropanes are two classes of strained systems having the potential for numerous applications in organic synthesis. The last two decades have witnessed a renaissance of interest in the chemistry of these species primarily because of the mild and robust methods for their generation or activation. Commonly, arynes as easily polarizable systems result in 1,2‐disubstitution, whereas D‐A cyclopropanes as polarized systems lead to 1,3‐bisfunctionalization thereby showing striking similarities. Transformations with 1,2‐ and 1,3‐dipoles afford cyclic structures. With arynes, emerging four‐membered rings as intermediates might react further, whereas the analogous five‐membered rings obtained from D–A cyclopropanes are most often the final products. However, there are a few cases where these intermediates behave surprisingly differently. This Minireview highlights the parallels in reactivity between arynes and D–A cyclopropanes thereby shedding light on the neglected similarities of these two reactive species.     

A novel multicomponent reaction of arynes, beta-keto sulfones, and michael-type acceptors: a direct synthesis of polysubstituted naphthols and naphthalenes

A novel multicomponent reaction of arynes, beta-keto sulfones, and Michael-type acceptors is presented, providing an efficient method for the synthesis of polysubstituted naphthols and polysubstituted naphthalenes. Further investigation suggests that the tandem reaction may proceed via a sequential nucleophilic attack to arynes, intramolecular nucleophilic substitution followed by a Michael addition, and a ring closure-elimination process.     

Generation, structure and reactivity of arynes: A theoretical study

The semiempirical AM1 SCF-MO method is used to study the benzyne mechanism for aromatic nucleophilic substitution of various m-substituted chlorobenzenes and 3-chloropyridine. The calculations predict that most of the fixed substituents studied here would induce the formation of 2,3-arynes through their electron-withdrawing resonance or inductive effects. The geometry and electronic structure of the 2,3- and 3,4-arynes investigated here, confirm the generally acceptedo-benzyne structure postulated for arynes. The sites of nucleophilic addition to arynes as predicted here are in fair agreement with expectation and experimental findings.     

Copper-catalyzed alkyne-aryne and alkyne-alkene-aryne coupling reactions

The efficient copper-catalyzed two-component coupling reaction of alkynes with arynes and the three-component coupling reaction of alkynes with allylic chlorides and arynes have been developed. Copper acetylide was postulated as a transient intermediate for the initiation of the coupling reactions.     

Synthesis of Heterocycles by Formal Cycloadditions of Isocyanides

Synthetic methodology for the synthesis of heterocycles is of continuous and high interest with applications in materials, catalysis, and medicines. Multicomponent reactions are suitable tools to efficiently generate chemically diverse sets of heterocycles with sufficient structural complexity. Especially isocyanides have proven to be particularly versatile building blocks in these one‐pot processes. Due to their electronic structure, isocyanides are able to act sequentially or simultaneously as a nucleophile and an electrophile. Traditionally, isocyanides are therefore frequently used in multicomponent chemistry. In the recent literature, numerous reactions have been reported that involve formal cycloadditions of isocyanides with conjugated heterodienes. This Focus Review aims at mapping this reactivity and at providing insight into the relationship between the various reported reaction partners and the observed reactivity modes.     

The Coordination Chemistry of Multidentate Isocyanide Ligands

In spite of the excellent ligation properties of isocyanides, until a few years ago there was only a small number of known multidentate ligands of this type. One of the reasons for this lack of interest, when compared to monodentate isocyanides, was the linear arrangement of the M? C?N? R group, which usually inhibits the formation of mononuclear chelate complexes and leads to the formation of multinuclear or polymeric metal complexes. In these, the multidentate ligand acts in a monodentate fashion towards each metal atom. Only recently has a series of polyisocyanides with large ligand backbones been synthesized successfully. Bidentate isocyanides can bridge two metal atoms or react to give chelates with only one metal center. Tripodal ligands form mono- or binuclear complexes, in which the largest organometallic rings observed to date occur (up to 36 atoms). This class of ligands promises to be interesting for the synthesis of stable, diagnostically important technetium complexes of the type [Tc(CNR) ₆ ]⁺. There also appear to be applications for tripodal isocyanides in catalysis. A facial, chiral Cr(CNR^*)₃ unit might be able to catalyze the hydrogenation or isomerization of prochiral double bonds. It is even possible to bind triisocyanides with suitable backbones to carbonyl trimetal clusters, thereby stabilizing them, or making selective cluster formation possible. Coordinated isocyanides can be transformed readily into carbene ligands, which, in the future, could lead to complexes with polycarbene ligation.     

Intramolecular aryne-ene reaction: synthetic and mechanistic studies

Although the chemistry of arynes is well developed, some challenges still remain. The ene reaction of arynes has not gained widespread use in synthesis as a result of poor yields and selectivity. A general, high yielding and selective intramolecular aryne-ene reaction is described providing various benzofused carbo- and heterocycles. Mechanistic data is presented, and a rationale for the resulting stereochemistry is discussed.     

Recent advances in reactions between arynes and organosulfur compounds

The recent progress made on transformations involving the reactions between aryne intermediates and organosulfur compounds has been reviewed. A wide variety of aromatic organosulfurs are now synthesizable by generating arynes in the presence of organosulfur compounds. Organosulfurs have distinctive reactivities with arynes, which depend on the sulfur atom’s valence state, that is, S(II), S(IV), and S(VI), as well as the presence or absence of other intra- or intermolecular reactive moieties. These novel transformations have enabled the diversity-oriented synthesis of unique aromatic organosulfurs that were once difficult to prepare by the conventional methods, paving the way for the development of molecules that are beneficial across numerous disciplines, including pharmaceutical science and materials science.