Organosulfur compounds have long played a vital role in organic chemistry and in the development of novel chemical structures and architectures. Prominent among these organosulfur compounds are those involving a sulfur(IV) center, which have been the subject of countless investigations over more than a hundred years. In addition to a long list of textbook sulfur-based reactions, there has been a sustained interest in the chemistry of organosulfur(IV) compounds in recent years. Of particular interest within organosulfur chemistry is the ease with which the synthetic chemist can effect a wide range of transformations through either bond formation or bond cleavage at sulfur. This review aims to cover the developments of the past decade in the chemistry of organic sulfur(IV) molecules and provide insight into both the wide range of reactions which critically rely on this versatile element and the diverse scaffolds that can thereby be synthesized.

Bond-Forming and -Breaking Reactions at Sulfur(IV): Sulfoxides, Sulfonium Salts, Sulfur Ylides, and Sulfinate Salts.

The synthesis of biaryls from benzyne intermediates offers an alternative strategy to conventional metal-catalyzed cross-coupling approaches. The concept is as old as benzyne itself, being the basis of Wittig's seminal observations on biphenyl synthesis from phenyl lithium and fluorobenzene in 1940. In the intervening 75 years, the transformation has grown to encompass a remarkable scope of reaction classes, and continues to develop as new benzyne precursors enable inventive biaryl syntheses under mild conditions. This review will cover all aryne methods relevant to biaryl synthesis, drawing together key ideas from the older literature involving halobenzene precursors, with a more comprehensive coverage of modern methods using 2-(trimethylsilyl)phenyl triflates and tri-ynes as the source of benzyne. Collectively, we hope to highlight the power of aryne chemistry to access a huge range of biaryl structures from a versatile and highly customizable set of substrates.

Synthesis of biaryls using aryne intermediates

The total syntheses of polycyclic natural products by exploiting an aryne as the key reactive species are reviewed. A short introduction summarizes the basic reactivities of aryne species as well as the methods for its generation. In the main part, early examples and the recent reports (mainly 2012–present) on the use of arynes in multistep syntheses are described.

Aryne-based strategy in the total synthesis of naturally occurring polycyclic compounds.

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.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.201909213

Uncovering the Neglected Similarities of Arynes and Donor-Acceptor Cyclopropanes.

Recent developments in aryne chemistry are reviewed with a particular focus on synthetic methods. This includes an overview of the precursors of arynes and their activators; the generation of aryne...

The Renaissance and Bright Future of Synthetic Aryne Chemistry

One of the most distinct characters of aryne chemistry over other synthetic methodologies is its ability to simultaneously functionalize the vicinal two positions of a benzene ring with diverse combinations of substituents. Moreover, the functionalization of the remaining four positions can be also achieved through multiaryne equivalents, in which more than one triple bond is generated on the different locations of the same benzene ring. This tutorial review summarizes the applications of benzdiyne and benztriyne equivalents from the standpoint of synthetic organic chemistry as well as in the preparation of polycyclic aromatic functional frameworks.

Aryne multifunctionalization with benzdiyne and benztriyne equivalents

Arynes are among the most active organic intermediates and have found numerous applications in expeditious preparation of substituted arenes. In the past 20 years, chemists have witnessed a resurgence in aryne chemistry, which is mainly attributed by the extensive utilization of Kobayashi's method, a fluoride-induced removal of the TMS group with concomitant departure of its ortho OTf group on o-silylaryl triflates. Nowadays, o-silylaryl triflates are the most frequently employed aryne precursors. This review provides an overview of the history of Kobayashi's method, its methodological achievements, and its applications in the synthesis of natural products, bioactive molecules, and polycyclic aromatic hydrocarbons.

o-Silylaryl Triflates: A Journey of Kobayashi Aryne Precursors.

An aryne precursor with a potential to perform domino aryne chemistry was proposed and synthesized. The reaction of this reagent with benzothioamide derivatives could afford 2,4-disubstituted benzothiazole with sequential incorporation of C–S, C–N, and C–C bonds on the consecutive three positions of the aryne precursor.

Domino Aryne Precursor: Efficient Construction of 2,4-Disubstituted Benzothiazoles

An aryne 1,2,3-trisubstitution with aryl allyl sulfoxides is accomplished, featuring an incorporation of C–S, C–O, and C–C bonds on the consecutive positions of a benzene ring. The reaction condition is mild with broad substrate scope. Preliminary mechanistic study suggests a cascade formal [2 + 2] reaction of aryne with S═O bond, an allyl S → O migration, and a Claisen rearrangement.

Aryne 1,2,3-Trifunctionalization with Aryl Allyl Sulfoxides

Polysubstituted arenes are prevalent in numerous natural products, medicines, agrochemicals, and organic functional materials. Among methods to prepare polysubstituted arenes, pathways involving benzyne intermediates are particularly attractive given they can readily assemble highly diverse vicinal difunctionalized benzenes in a step-economical manner under transition-metal-free conditions. In order to incorporate more than two substituents on a benzene ring via a benzyne intermediate, methodologies involving benzdiyne and benztriyne have been developed, which significantly expand the current difunctionalization strategies in benzyne chemistry. In the past years, our group has been focusing on pushing the frontier of traditional benzyne chemistry and exploring new applications. In an aim to efficiently and conveniently construct polysubstituted arenes, we developed several aryne multifunctionalization strategies. The first strategy is through the 1,2-benzdiyne processes, which can be divided into a domino aryne approach and stepwise 1,2-benzdiyne approach. In our domino aryne study, we developed three domino aryne reagents as "sesquibenzyne" synthons, which are complementary in terms of reactivity and could adapt different modes of cascade transformations. By employing these domino aryne precursors, we were able to accomplish several cascade transformations, including double nucleophilic reactions, i.e., the reaction with carbonyl protected benzothioamides, 1,2-diamination, and 1,3-diamination. In addition, two cascade processes involving nucleophilic and pericyclic reactions, namely, domino aryne annulation via nucleophilic-ene cascade and domino aryne nucleophilic, Diels-Alder process, were successfully achieved as well. Meanwhile, with our desire to expand the scope of 1,2-benzdiyne transformations, we employed stepwise 1,2-benzdiyne tactics to access polysubstituted arenes. Depending on the property of the substituent on the C3-position of a benzyne intermediate, either an electron-withdrawing or electron-donating group, the incoming ortho groups were chosen accordingly. Consequently, we realized a [2 + 2] cycloaddition-Grob fragmentation process using 3-triflyloxybenzyne and a 1,2-benzdiyne process using 3-(trimethylsilyl)benzyne. Our second research strategy is to use single benzyne to access trisubstituted arenes, which represents a more atom- and step-economical protocol. With our deliberate design, we discovered a tandem benzyne S═O bond insertion/C-H functionalization process using single benzyne and aryl allyl sulfoxides, furnishing three chemical bonds of different types in a single process. This transformation is the first 1,2,3-trisubstitution example using single benzyne intermediate. At last, we developed an oxidative dearomatization strategy on Kobayashi benzyne precursors, which led to the preparation of various cyclohexenynone precursors with diverse substituents in highly efficient manner. In this study, we also demonstrated a new reaction mode of these cyclohexenynones with allyl sulfoxides, which involves a deeper utilization of the cyclohexyne triple bond. This work is the first example of successful connection of precursors of benzyne with cyclohexyne together, revealing a new research direction in the field of cyclohexyne.

Yang Li

Papers

Aryne multifunctionalization with benzdiyne and benztriyne equivalents

o-Silylaryl Triflates: A Journey of Kobayashi Aryne Precursors.

Domino Aryne Precursor: Efficient Construction of 2,4-Disubstituted Benzothiazoles

Aryne 1,2,3-Trifunctionalization with Aryl Allyl Sulfoxides

Strategies toward Aryne Multifunctionalization via 1,2-Benzdiyne and Benzyne