Amino- and Alkoxybenziodoxoles: Facile Preparation and Use as Arynophiles.

We report here on the facile synthesis of amino- and alkoxy-λ3-iodanes supported by a benziodoxole (BX) template and their use as arynophiles. The amino- and alkoxy-BX derivatives can be readily synthesized by reacting the respective amines or alcohols with chlorobenziodoxole in the presence of a suitable base. Unlike previously known nitrogen- and oxygen-bound iodane compounds, which have primarily been employed as electrophilic group transfer agents or oxidants, the present amino- and alkoxy-BX reagents manifest themselves as nucleophilic amino and alkoxy transfer agents toward arynes. This reactivity leads to the aryne insertion into the N-I(III) or O-I(III) bond to afford ortho-amino- and ortho-alkoxy-arylbenziodoxoles, iodane compounds nontrivial to procure by existing methods. The BX group in these insertion products exhibits excellent leaving group ability, enabling diverse downstream transformations.

A Strategy Based on "Ambident Anthracene" for the Synthesis of Higher-Order Iptycenes.

An efficient method for the synthesis of higher-order iptycenes using an "ambident anthracene" building block is presented. For that purpose, an iterative elongation strategy involving the ring-opening of an endoxide to give a highly reactive anthranoxide, followed by a Diels-Alder reaction with an aryne was used. The method systematically provides higher-order iptycenes, including trideciptycene, which is currently the iptycene with the longest chain to have been synthesized. X-ray crystallography revealed interesting structures in which solvent molecules fill the cavities of these iptycenes, thus creating a "honeycomb" structure with the solvent molecules arranged in tubular spaces.

Functionalization of Siloxanes with Arynes Generated from o-Triazenylarylboronic Acids.

Herein, we report the functionalization of polyhedral oligosilsesquioxanes (POSS) and related siloxanes with arynes. Using o-triazenylarylboronic acids as aryne precursors and silica gel as the activator, the transformation of siloxane bearing various arynophilic moieties on the side chains was achieved with high yields without touching the siloxane core. This method was applied to the conjugation of POSS and pharmaceutical cores using an aryne derived from the synthetic intermediate of cabozantinib. Furthermore, orthogonal dual functionalization of POSS was realized by combining the aryne reaction with Huisgen cyclization.

Recent Progress on Multi-Component Reactions Involving Nucleophile, Arynes and CO2.

Carbon dioxide (CO2) is a non-toxic, abundant and recoverable source of carbon monoxide. Despite its thermodynamically stable and kinetically inert nature, research on CO2 utilisation is ongoing. CO2-based aryne reactions, crucial for synthesising ortho-substituted benzoic acids and their cyclisation products, have garnered significant attention, and multi-component reactions (MCRs) involving CO2, aryne and nucleophilic reagents have been extensively studied. This review highlights recent advancements in CO2 capture reactions utilising phenylalkyne reactive intermediates. Mechanistic insights into these reactions are provided together with prospects for further development in this field.

Palladium(0)-catalyzed aryne annulation: a powerful strategy for the synthesis of thio-bridged compounds.

A method for the construction of various thio-bridged compounds is developed using readily available o-(trimethylsilyl)aryl triflates as a source of aryne precursor, catalyzed by simple Pd(dba)2/dppe complex. This operationally simple and modular protocol allows thio-bridged compound via C(sp2)-C(sp2) and C(sp2)-C(sp3) bond formation in promising yields with a broad substrate scope. The key part is in situ generation of an aryne from o-(trimethylsilyl)aryl triflates and their subsequent intermolecular annulation.

Regiocontrol Using Fluoro Substituent on 3,6-Disubstituted Arynes.

The effect of fluoro substituent on the regioselectivity of several reactions of 3,6-disubstituted arynes was studied. These arynes contained another inductively electron-withdrawing substituent other than fluorine. A reasonable degree of regiocontrol was achieved in the (3 + 2) cycloaddition reaction of 3,6-disubstituted aryne containing both fluorine and bromine atoms with benzyl azide. Furthermore, the insertion reaction of aryne into Sn-F σ-bonds and the three-component coupling reaction involving the insertion of aryne into C=O π-bonds also led to the high degree of regiocontrol.

Palladium-Catalyzed Cyclization of a Pyryne Precursor to Higher Pyrenylenes.

The palladium catalyzed cyclotrimerization of ortho-silylaryl triflates as aryne precursors is meanwhile an established method to synthesize polycyclic aromatic hydrocarbons (PAHs) with triphenylene cores. During the palladium-catalyzed reaction of a pyrene with an o-silylaryl triflate moiety in the K-region higher homologues with central eight- and ten-membered rings (the pyrenylenes) were found, besides the expected trimer and a protocol was developed to isolate all members of this series. This unprecedented new class of PAHs was fully investigated by all means, including X-ray diffraction of single-crystals, UV/Vis and fluorescence spectroscopy and theoretical calculations. Supported by density-functional theory (DFT) calculations, a mechanism of all higher cyclooligomers is proposed.

Aryne-Enabled C-N Arylation of Anilines.

Anilines are potentially high-value arylating agents, but are limited by the low reactivity of the strong C-N bond. We show that the reactive intermediate benzyne can be used to both activate anilines, and set-up an aryl transfer reaction in a single step. The reaction does not require any transition metal catalysts or stoichiometric organometallics, and establishes a metal-free route to valuable biaryl products by functionalizing the aniline C-N bond.

Uncovering the hidden reactivity of benzyne/aryne precursors utilized under milder condition: Bonding and stability studies by EDA-NOCV analyses.

Arenes [C6 H3 R(TMS)(OTf); also called benzyne/aryne precursors] containing inter-related leaving groups Me3 Si (TMS) and CF3 SO3 (OTf) on the adjacent positions (1,2-position) are generally converted to their corresponding aryne-intermediates via the addition of fluoride anion (F- ) and subsequent elimination of TMS and OTf groups. This reaction is believed to proceed via the formation of an anionic intermediate [C6 H4 (TMS-F)(OTf)]- . The EDA-NOCV analysis (EDA-NOCV = energy decomposition analysis-natural orbital for chemical valence) of over 35 such precursors of varied types have been reported to reveal bonding and stability of CAr Si and COTf bonds. EDA-NOCV showed that the nature of the CAr Si bond of C6 H3 R(TMS)(OTf) can be expressed as both dative and electron sharing [CAr Si, CAr →Si]. The CAr OTf bond, on the other hand, can be described explicitly as dative [CAr ←OTf]. The nature of CAr Si bond of [C6 H4 (TMS-F)(OTf)]- exclusively changes to covalent dative σ-bond CAr →S(Me)3F on the attachment of F- to the TMS group of C6 H4 (TMS)(OTf). Introduction of σ-electron withdrawing group (like OMe, NMe2 , and NO2 ) to the ortho-position of the TMS group of functionalized arynes C6 H3 R(TMS)(OTf) prefer to have a covalent dative σ-bond (CAr →Si) over an electron-sharing covalent σ-bond (CAr Si). If this σ-electron withdrawing group is shifted from ortho-position to meta- and para-positions, then the preference for a dative bond decreases significantly, implying that the electronic effect on the nature of chemical bonds affects through bond paths. This effect dies with distance, similar to the well-known inductive effect.

S-(Trifluoromethyl)Benzothioate (TFBT): A KF-Based Reagent for Nucleophilic Trifluoromethylthiolation.

S-(Trifluoromethyl)benzothioate (TFBT) has been developed as an inexpensive, bench-stable, and user-friendly trifluoromethylthiolation reagent, which can be easily synthesized by using KF as the only fluorine source. By using TFBT, trifluoromethylthiolates with various counterions can be readily obtained. The synthetic application of TFBT was demonstrated by trifluoromethylthiolation-halogenation of arynes, bis(trifluoromethylthiolation)-halogenation of 1,2-benzdiynes, nucleophilic substitution of alkyl halides, deoxytrifluoromethylthiolation of alcohols, and cross-coupling with aryl and vinyl boronic acids.

Aryne Generation from o-Triazenylarylboronic Acids Induced by Brønsted Acid.

We report aryne generation from 2-triazenylarylboronic acids using an activator such as Brønsted acids, Lewis acids, and solid acids. With the use of (±)-Camphorsulfonic acid [(±)-CSA], the aryne precursors provided cycloadducts with a range of arynophiles in high yields. Aryne generated under the acidic conditions underwent chemoselective cycloaddition with a furan in the presence of a basic arynophile, namely an amine. Hammett plot analyses revealed that an aryne generation mechanism induced by (±)-CSA is distinct from the mechanism induced by silica gel.

The Aryne Phosphate Reaction.

Condensed phosphates are a critically important class of molecules in biochemistry. Non-natural analogues are important for various applications, such as single-molecule real-time DNA sequencing. Often, such analogues contain more than three phosphate units in their oligophosphate chain. Consequently, investigations into phosphate reactivity enabling new ways of phosphate functionalization and oligophosphorylation are essential. Here, we scrutinize the potential of phosphates to act as arynophiles, paving the way for follow-up oligophosphorylation reactions. The aryne phosphate reaction is a powerful tool to-depending on the perspective-(oligo)phosphorylate arenes or arylate (oligo-cyclo)phosphates. Based on Kobayashi-type o-silylaryltriflates, the aryne phosphate reaction enables rapid entry into a broad spectrum of arylated products, like monophosphates, diphosphates, phosphodiesters and polyphosphates. The synthetic potential of these new transformations is demonstrated by efficient syntheses of nucleotide analogues and an unprecedented one-flask octaphosphorylation.

Aryne 1,4-Disubstitution and Remote Diastereoselective 1,2,4-Trisubstitution via a Nucleophilic Annulation-[5,5]-Sigmatropic Rearrangement Process.

Both aryne 1,4-disubstitution and 1,2,4-trifunctionalization were accomplished from tertiary amines bearing a penta-2,4-dien-1-yl moiety. These transformations could directly incorporate a C-N and a C-C bond para to each other on an aryne intermediate via a sequential nucleophilic addition and [5,5]-sigmatropic rearrangement. When arynes bearing 3-tethered electrophiles were employed, a cascade regioselective nucleophilic addition, intramolecular cyclization, and remote diastereoselective [5,5]-sigmatropic rearrangement process was observed. Our density functional theory (DFT) calculations revealed that hydrogen-bonding interactions between two C-H hydrogens on the penta-2,4-dien-1-yl chain and the oxygen anion generated upon N-nucleophilic annulation reaction in the [5,5]-sigmatropic rearrangement step is responsible for the remote diastereoselective control in this reaction system.

Thermodynamically Stable o-Quinodimethane: Synthesis, Structure, and Reactivity.

Thermal isomerization of cyclobutaphenanthrene to o-quinodimethane was investigated. Sterically congested substituents or electron-donating substituents on the four-membered ring promoted the ring-opening, affording o-quinodimethane in a relatively stable form. Isolation of the newly prepared o-quinodimethane allowed its structural elucidation and investigation of its potential reactivities. Dual [4+2] cycloaddition of an aryne and o-quinodimethane afforded tetrabenzopentacene, demonstrating the synthetic application of the isolated compound.

Regioselective Synthesis of 1,2,3,4-Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts*.

Herein, the synthesis of 1,2,3,4-tetrasubstituted benzenoid rings, motifs found in pharmaceutical, agrochemical, and natural products, is described.[1] In the past, the regioselective syntheses of such compounds have been a significant challenge. This work reports a method using substituted arynes derived from aryl(Mes)iodonium salts to access a range of densely functionalized 1,2,3,4-tetrasubstituted benzenoid rings. Significantly, it was found that halide substituents are compatible under these conditions, enabling post-synthetic elaboration via palladium-catalyzed coupling. This concise strategy is predicated on two regioselective events: 1) ortho- deprotonation of aryl(Mes)iodonium salts to generate a substituted aryne intermediate, and 2) regioselective trapping of said arynes, thereby improving previously reported reaction conditions to generate arynes at room temperature and in shorter reaction times. Density functional theory (DFT) computations and linear free energy relationship (LFER) analysis suggest the regioselectivity of deprotonation is influenced by both proximal and distal ring substituents on the aryne precursor. A competition experiment further reveals the role of arene substituents on relative reactivity of aryl(Mes)iodoniums as aryne precursors.

Aryne Multicomponent Reactions by Directed C-H Activation.

Arylation via ortho C-H activation by the aid of directing groups has been explored recently by many researchers. Herein, a palladium-catalyzed C-H arylation using 8-aminoquinoline as a bidentate directing group has been developed. The reaction furnishes only C-H arylation, unlike previous methods where cyclization to corresponding isoquinolones is observed. More interestingly, sequential C-H functionalization was observed when methylacrylate and acrylonitrile was added; this led to C-H olefination with the aryl group, which was installed from the aryne precursor.

Highly Conjugated π-Systems Arising from Cannibalistic Hexadehydro-Diels-Alder Couplings: Cleavage of C-C Single and Triple Bonds.

We have investigated the cannibalistic self-trapping reaction of an ortho-benzyne derivative generated from 1,11-bis(p-tolyl)undeca-1,3,8,10-tetrayne in an HDDA reaction. Without adding any specific trapping agent, the highly reactive benzyne is trapped by another bisdiyne molecule in at least three different modes. We have isolated and characterized the resulting products and performed high-level calculations concerning the reaction mechanism. During the cannibalistic self-trapping process, either a C≡C triple bond or an sp-sp3 C-C single bond is cleaved. Up to seven rings and nine C-C bonds are formed starting from two 1,11-bis(p-tolyl)undeca-1,3,8,10-tetrayne molecules. Our experiments and calculations provide considerable insight into the variety of reaction pathways which the ortho-benzyne derivative, generated from a bisdiyne, can take when reacting with another bisdiyne molecule.

Transition-Metal-Free N-Arylation of Amines by Triarylsulfonium Triflates.

A simple and efficient method for transition-metal-free N-arylation of various amines by triarylsulfonium triflates is described. Both aliphatic and aromatic amines were smoothly converted at 80 °C in the presence of tBuOK or KOH to give the corresponding mono N-arylated products in good to high yields. The molar ratios of the reactants and the choice of bases had a big effect on the reaction. When a large excess of [Ph3 S][OTf] and tBuOK were employed for primary amines under the standard conditions, the bis(N-phenyl) products were predominantly formed. This method was also applicable to the synthesis of bioactive N-phenyl amino acid derivatives. The control experiments, the deuterium labelling study, and the presence of regioisomers of N-arylated products when using 4-substituted triarylsulfonium triflates suggested that the reaction might proceed through an aryne intermediate. The present protocol demonstrated that triarylsulfonium salts are versatile arylation reagents in the construction of CAr -N bonds.

CuI -Mediated Bromoalkynylation and Hydroalkynylation Reactions of Unsymmetrical Benzynes: Complementary Modes of Addition.

Benzynes formed by heating a suitable triyne (or tetrayne) substrate are shown to react with in situ generated alkynyl copper species. The latter are compatible with the polyyne substrates and two types of chemistries have been achieved: (i) 1-bromo-1-alkynes efficiently undergo net bromoalkynylation of the (unsymmetrical) benzynes and (ii) in situ generated alkynylcopper species give rise to hydroalkynylation products. The regiochemical preferences of these two modes of reaction are complementary to one another with respect to the position of alkynyl substituent in the final products.

Regioselective One-Pot Synthesis of Triptycenes via Triple-Cycloadditions of Arynes to Ynolates.

We developed the novel one-pot synthetic method of substituted triptycenes by the reaction of ynolates and arynes. This four-step process involves three cycloadditions and electrocyclic ring opening of the strained Dewar anthracene. Each of the three related but structurally distinct classes of nucleophiles (ynolate, enolate, and anthracenolate) reacts with o-benzyne in the same predictable manner controlled by chelation and negative hyperconjugation. The resulting functionalized C3 -symmetrical triptycenes hold promise in the design of functional materials.