Aryne Intermediates Research Articles

Basicity‐Controlled Reactivity of meta‐OTf‐Substituted Diaryliodonium Salts for Direct Arylation or Diels‐Alder Cycloaddition of Pyrrole Derivatives

AbstractIn this study, we explored the reactivity of meta‐trifluoromethanesulfonate (OTf) substituted diaryliodonium salts under alkaline conditions. Two distinct pathways with direct arylation of pyrrole derivatives and Diels‐Alder cycloaddition via aryne intermediates, have been found upon the relative alkalinity strength of potassium carbonates or hydroxides. This approach offers a straightforward and efficient route to synthesize heterocyclic aromatics under mild reaction conditions with tolerance of various functional groups.

Synthesis of cyclic organosilicon compounds by palladium-catalyzed reactions of 2-silylaryl triflates

Abstract 2-Silylaryl triflates are widely employed as effective aryne precursors in organic synthesis, but their use as substrates for the synthesis of organosilicon compounds by retaining their silicon substituents is another attractive usage of these reagents. In particular, cyclic compounds with a silicon atom in the ring are promising candidates for various biologically active substances and optoelectronic functional materials. In this context, new synthetic methods for silicon-containing cyclic compounds have been actively investigated through the development of palladium-catalyzed reactions of 2-silylaryl triflates without generating aryne intermediates. As a result, selective synthesis of various silacyclic compounds has been achieved via C–H and/or C–Si bond activations as well as intramolecular exchange between these bonds and C–Pd bonds that are formed as reaction intermediates. An overview of this topic is described, including the mechanistic insights.

Bromothiolation of Arynes for the Synthesis of 2-Bromobenzenethiol Equivalents.

A new method to synthesize o-bromobenzenethiol equivalents through aryne intermediates is disclosed. Various o-bromobenzenethiol equivalents are prepared by the bromothiolation of aryne intermediates with potassium xanthates. Aryl xanthates serve in the synthesis of diverse organosulfurs involving phenothiazines and thianthrenes by further transformations.

Synthesis of [2.2]Paracyclophane-Fused Heterocycles via Palladium-Catalyzed C-H Activation/Annulation of [2.2]Paracyclophanecarboxamides with Arynes.

[2.2]Paracyclophane-fused heterocycles represent an important scaffold. Traditional approaches often suffer from tedious synthetic routes, and the development of catalytic synthesis of them remains in its infancy. Herein, by employing highly strained aryne intermediates as partners, we have developed a concise protocol by palladium-catalyzed C-H activation/annulation from [2.2]paracyclophanecarboxamide substrates. [2.2]Paracyclophane-fused quinolinone products are obtained in good yields (up to 84%). Furthermore, the utility of the process has been shown through the synthesis of [2.2]paracyclophane-fused heterocyclic catalysts.

One-pot formal [3 + 2] annulation of 2-pyridinyl-substituted p-quinone methides and arynes for the synthesis of 3-aryl pyrido[1,2-a]indoles.

An efficient and metal-free method for the synthesis of 3-aryl pyrido[1,2-a]indoles from aryne intermediates and 2-pyridinyl-substituted p-QMs was successfully developed under ambient conditions. The reaction offered a novel and practical protocol to access some diverse functional molecules in good to excellent yields. The proposed mechanism indicated that the reaction proceeded via a formal [3 + 2] cycloaddition step.

Asymmetric Cycloaddition Reactions of Aryne Intermediates with a Chiral Carbon-Carbon Axis: Syntheses of Axially Chiral Biaryl Compounds.

An asymmetric synthesis via an axially chiral arylaryne intermediate was developed. A cycloaddition reaction with various arynophiles was used to obtain chiral biaryl compounds while preserving the enantiomeric excess (ee) of a precursor even though the reaction proceeds through an arylaryne intermediate, whose chirality decreases on a time-dependent basis. High chiral transfer from a precursor to a product was observed not only at low temperature (-78 °C) but also at room temperature.

Transformations of 6-[4-(methylthio)phenyl]-3-(2-pyridyl)-1,2,4-triazines in the reaction with an aryne intermediate

Transformations of 6-[4-(methylthio)phenyl]-3-(2-pyridyl)-1,2,4-triazines in the reaction with an aryne intermediate

Oxidative Cycloaddition Reactions of Arylboron Reagents via a One-pot Formal Dehydroboration Sequence.

Arylboron compounds are widely available and synthetically useful reagents in which the boron group is typically substituted. Herein, we show that the boron group and ortho-hydrogen atom are substituted in a formal cycloaddition reaction. This transformation is enabled by a one-pot sequence involving diaryliodonium and aryne intermediates. The scope of arylboron reagents and arynophiles is demonstrated, and the method is applied to the formal synthesis of an investigational drug candidate.

Synthesis of 5-[4-(arylsulfanyl)phenyl]-2,2′-bipyridines using aryne intermediates

A convenient method for the preparation of 5-aryl-2,2′-bipyridines with para -arylsulfanyl group in an aromatic substituent was proposed. The synthesis was performed using in situ generated aryne intermediates without the use of complex experimental procedures and expensive reagents/catalysts. The structure of one product was confirmed by XRD data. This approach is a new variant for the preparation of 5-aryl-2,2’-bipyridines with an extended conjugation system.

Meta‐OTf‐Substituted Diaryliodonium Salts Enabled Diels‐Alder Cycloadditions of Furans via Aryne Intermediates**

AbstractArynes are highly reactive intermediates that may be trapped with arynophilic reagents. However, the generation of benzyne necessitates stringent reaction conditions. The cycloaddition reaction of traditional benzyne precursors including diaryliodonium salts with arynophiles under strongly basic conditions encounters the limitations in tolerance of labile functional groups. To overcome this issue, the modulation of diaryliodonium structures are considered by incorporation of specific groups for activation of vinical C−H bond, enabling the generation of aryne intermediates in cycloaddition reactions under mild conditions. In this study, we reported meta‐trifluoromethanesulfonate (OTf) substituted diaryliodonium salts as benzyne precursor, in which the activation of C−I bond and selectively deprotonation of neighboring C−H bond generate highly reactive aryne intermediates for cycloaddition reactions with furans. This approach offers a simple and efficient method for synthesizing bridged ring compounds under mild reaction conditions with good functional group tolerance.

Ligand-Induced Regioselectivity in Metal-Catalyzed Aryne Reactions Using Borylaryl Triflates as Aryne Precursors.

The utility of reactions using unsymmetrically substituted aryne intermediates can be negatively impacted by issues with regioselectivity as these reactions are substrate controlled. This leaves no avenues for improving regioselectivity without altering the substrate which has led to numerous reports about how to enhance or reverse this regioselectivity in metal-free aryne reactions by changing the electronics. To the best of our knowledge, no such studies exist for systems with metal-bound aryne intermediates, which often suffer from worse regioselectivities. Herein we report a means of achieving regioselectivity in a metal-catalyzed aryne difunctionalization via catalyst control. Through the use of an unsymmetrical ligand environment, selectivity can be induced (up to 9:91 r.r.). These investigations demonstrate that catalyst design can influence selectivity in metal-catalyzed aryne reactions.

Arynes in Natural Product Synthesis

Abstract: Arynes are a unique class of intermediates used in synthetic organic chemistry, and research interest has been intensely focused on their peculiar reactivities. Arynes have been researched for almost a century. However, difficulties in monitoring these reactive species, as well as difficulties in creating synthetically viable techniques for their synthesis and trapping, have restricted their application. A key tactic for achieving the racemic and enantiopure total synthesis of a broad variety of natural compounds or their structural derivatives. The chemistry of arynes has advanced significantly over the past thirty years, particularly in the field of transition metal carbon- carbon and carbon-heteroatom bond-forming mechanisms. The field’s fast growth is largely attributable to the development of mild aryne production processes. To create a natural product with complex organic molecules, the role of aryne intermediates was non-replaceable. These organic substances are often used in medicine, therapies, or as raw material for the synthesis of other substances. Moreover, they may perform important biological tasks. There are numerous methods for synthesizing natural compounds including total synthesis, semi-synthesis, and biosynthesis. Total synthesis is the process of creating natural products entirely chemically from basic precursors as well as it can be produced in large quantities and can reveal information about its biological activity. One of the developments in Arynes’ chemistry is the chemical rearrangements brought about by this electrophilic intermediate. It is not feasible to use conventional methods in a single step. This review article discusses how arynes are used to create natural products. Arynes has a wide range of functionality in the field of scientific research. The evolution of this method has made a tremendous change in the total synthesis of natural products. Benzynes enabled creative synthesis in mild conditions. The transformation has expanded to investigate various reaction classes such as nucleophilic addition, (4+2), and (2+2) cycloaddition strategies and metal-catalyzed reactions are shown and explained in this article. This review will provide an idea about how the arynes act as an intermediate in those reaction mechanisms and enlighten the scope of these aryne intermediate.

Meta-Selective O-Arylation of Cyclic Diaryliodonium Salts with Phenols via Aryne Intermediates

Herein, we report a base-mediated, highly meta-selective O-arylation process of phenols and cyclic diaryliodonium salts without usage of transition metals. This novel and practical method was proved to be useful for the synthesis of iodine-containing meta-functionalized biaryl ethers in a broad functional group tolerance and environmentally friendly manner. Diversity-oriented transformations of the products were carried out to give various valuable functionalized biaryls. Preliminary mechanistic studies support the proposed aryne generation mechanism.

3-sulfonyloxyaryl(mesityl)iodonium triflates as 1,2-benzdiyne precursors with activation via ortho-deprotonative elimination strategy

Benzyne has long captivated the attention of chemists and has gained numerous synthetic achievements. Among typical benzyne generation methods, removal of two vicinal substituents from 1,2-difunctionalized benzenes, i.e., Kobayashi’s protocol, are prevailing, while ortho-deprotonative elimination from mono-substituted benzene lags far behind. Despite the advantages of atom economy and ready achievability of precursors, a bottle neck for ortho-deprotonative elimination strategy resides in the weak acidity of the ortho-hydrogen, which normally demands strong bases as the activating reagents. Here, an efficient aryne generation protocol is developed, where ortho-deprotonative elimination on 3-sulfonyloxyaryl(mesityl)iodonium triflates occurs under mild conditions and the generated 3-sulfonyloxyarynes can serve as efficient 1,2-benzdiyne synthons. This array of 1,2-benzdiyne precursors can be conveniently prepared with high functional group tolerance, and densely substituted scaffolds can be accessed as well. Carbonate and fluoride salts are found to serve as efficient activating reagents, which are the weakest bases used in ortho-deprotonative elimination strategies. Particularly, this scaffold has predictable chemoselective generation of the designated aryne intermediates. The success of this ortho-deprotonative elimination protocol sets up a unique platform with a broad spectrum of synthetic applications.

Asymmetric reactions involving aryne intermediates.

Although arynes are usually considered fleeting intermediates, they are highly valuable synthons because they enable the introduction of aromatic rings and the simultaneous formation of new bonds at two sites. Although catalytic reactions using transition metals are excellent method for constructing complex polycyclic aromatic molecules in a single step, the use of asymmetric catalysis for the capture of arynes remains a crucial goal for the progress of aryne chemistry. Catalytic asymmetric reactions of arenes are challenging, requiring sufficient interactions between the neutral and highly reactive short-lived aryne intermediates in a stereo-controlled fashion. In addition, spontaneous decomposition, as well as side reactions, has hindered their development and, until recently, highly enantioselective reactions using arynes had remained elusive. This Review highlights asymmetric reactions using arynes, featuring diastereoselective, enantioselective and catalytic enantioselective reactions.

Migrative Thioamination of Aryne Intermediates Generated from o-Iodoaryl Triflates

AbstractMigrative thioamination of aryne intermediates takes place using various o-iodoaryl triflates and sulfilimines. The selective migration realizes the facile synthesis of a broad range of highly functionalized o-thioaminated diaryl sulfides. We succeeded in the ring expansion of cyclic sulfilimines enabling us to prepare eight- and nine-membered organosulfurs from dibenzothiophene- and thianthrene-type sulfilimines, respectively.

Synthesis of Arynes via Formal Dehydrogenation of Arenes

Arynes offer immense potential for diversification of benzenoid rings, which occur in pharmaceuticals, agrochemicals, and liquid crystals. However, accessing these high-energy intermediates requires synthetic precursors, which involve either harsh conditions or multistep syntheses. The development of alternative methods to access arynes using simpler substrates and milder conditions is necessary for a more streamlined approach. Here, we describe a two-step formal dehydrogenation of simple arenes to generate arynes at a remote position relative to traditionally reactive groups, e.g., halides. This approach is enabled by regioselective installation and ejection of an "onium" leaving group, and we demonstrate the compatibility of simple arenes (20 examples) and arynophiles (8 examples). Moreover, through direct comparison, we show that our formal dehydrogenation method is both more functional group tolerant and efficient in generating arynes than the current state-of-the-art aryne precursors. Finally, we show that aryne intermediates offer opportunities for regioselective C-H amination that are distinct from other methods.

Multisubstituted naphthalene synthesis from 4-hydroxy-2-pyrones through [4+2] cycloaddition with o-silylaryl triflates

An efficient synthetic method for multisubstituted naphthalenes from 4-hydroxy-2-pyrones through cycloaddition with aryne intermediates is disclosed.

Arynes as synthetic linchpins towards the construction of diversely functionalized natural product skeletons.

Arynes are a privileged class of reactive intermediates in synthetic organic chemistry, and their unusual reactivities have been the subject of engrossing research interest. Recently, there are many reports on novel aryne-based synthetic innovations as a linchpin approach to accomplish the total synthesis of structurally diverse natural products or their derivatives in a racemic and enantiopure fashion. This review provides an overview of the literature on synthetic strategies, employing arynes as crucial intermediates to construct architecturally intriguing bioactive natural products/derivatives in a period of 2019 to 2022. This study highlights the need to investigate the effective synthesis and search for new biological uses of highly functionalized natural product skeletons.

Cyclic Diaryl λ3-Chloranes: Reagents and Their C-C and C-O Couplings with Phenols via Aryne Intermediates.

Hypervalent chloranes are a class of rare and poorly explored reagents. Their unique electronic properties confer reactivity that is complementary to that of the common iodanes and emerging bromanes. Highly chemo- and regioselective, metal-free, and mild C-C and C-O couplings are reported here. Experimental and computational mechanistic studies elucidate the unprecedented reactivities and selectivities of these systems and the intermediacy of aryne intermediates. The synthetic potential of these transformations is further demonstrated via the post-functionalization of C-C and C-O coupling products obtained from reactions of chloranes with phenols under different conditions.