Electrophilic Coupling of Arynes

Both xanthones and thioxanthones are available through CsF-promoted coupling of arynes with salicylates and thiosalicylates. The synthesis proceeds through sequential intermolecular nucleophilic substitution and intramolecular electrophilic cyclisation (Scheme 39) <07JOC583>. The Pd-catalysed annulation of 3-iodoflavone with the same triflate results in the dibenzo[a,c]xanthone (Scheme 39) <07JOC223>. 

Methyl thiosalicylate provides both electrophilic and nucleophilic sites for annulation of arynes generated from silylaryl triflates in the presence of CsF. An initial intermolecular nucleophilic coupling to afford a diaryl sulfide 529 is followed by an intramolecular electrophilic cyclization and thioxanthones result. The use of THF as solvent suppresses the competitive proton abstraction which leads to methyl 2-thiophenoxybenzoate (Scheme 211) <2005OL4273>. 

Coupling of 2,3-dihydrofuran with alkene-zirconocene <2004AGE3932> or aryne-zirconocene <2005SL2513> complexes and subsequent addition of an electrophile provided rA-disubstituted homoallylic alcohols, as illustrated in Equation (130). An insertion//3-elimination pathway that involved the formation of an oxazirconacyclooctene intermediate was proposed for the reaction mechanism. 

A one-pot coupling protocol of arynes with ortho-heteroatom-substituted benzoates to prepare xanthones, thioxanthones, and acridones has been reported by Zhao and Larock (Equation 12.30) [50]. The coupUng presumably proceeds by a tandem intermolecular electrophihc coupling of the aryne with the orthoheteroatom-substituted benzoates and subsequent intramolecular electrophilic cyclization. Proton abstraction by the aromatic carbanion intermediate is a major competing reaction in this cyclization. This side reaction is, however, largely suppressed by employing tetrahydrofuran (THF) as the solvent... 

Another important aspect of aryne chemistry that has found application in benzo-fused heterocycles synthesis is MCRs, which generally include the first addition of nucleophiles to arynes and subsequent interception of the aryl anion intermediate with other electrophiles. If the nucleophile and electrophile are not part of the same molecule, the overall process is a unique multicomponent coupling, where the aryne is inserted between the other two coupling partners to afford the final product 85 (Scheme 39). This highly efficient transition-metal-free methodology has been applied to the S5mthesis of valuable benzo-fused heterocycles and has foxmd application in natural product synthesis. 

The group R1 can be allyl, acyl, or alkynyl, and arynes can also act as the acceptors. The catalysts are usually Ni(cod)2, or ligated palladium. The mechanisms are not understood in detail, but a catalytic cycle involving the product of oxidative addition, Sn-M-R1, is thought to be involved. The stannylalkenes that are formed can then be subjected to reaction with electrophiles (e.g., AczO or RCH=0), or to coupling reactions in the presence of transition metals (e.g., the Stille reaction). 

In spite of their high total energy, arynes in general are selective towards different nucleophiles thus benzyne selectively captures the anion of acetonitrile in the presence of an excess of the dimethylamide ion used to generate both it and the benzyne. Nucleophilicity towards benzyne, determined by competition experiments, is in the order RLi RS- > R2N RO and I- > Br > Cl, which is an order of softness. The low energy of the LUMO of benzyne, coupled with its being uncharged, makes it a soft electrophile. 

---