Arynes generation

A variety of substituted aromatic compounds have been prepared through addition of anionic nucleophiles to arynes generated from readily accessible precursors.1 Most of the laboratory preparations start with aryl halides. The coupling yields are usually good to modest (equations 13-15) but can be poor (equation 16).83 Sometimes, a dramatic improvement in reaction efficiency can be achieved by the change of the base/solvent pair or other reaction conditions. For instance, in arylation of phenoxides and benzenethiolates, a switch over to DMSO as the solvent boosted the yield considerably (equation 17).86 Another example, illustrative of this point, is the reaction of N-methylpyrrolidone with aryl halides where an acceptable yield could not be obtained under a variety of conditions except with LICA in THF (equation 18).71... 

Arynes, generated in situ from o-silylaryl triflates (229), undergo ene reaction with alkynes (230) possessing propargylic hydrogen in the presence of KF-18-crown-6 in... 

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>. 

More remarkable are the reactions between ketone enolate ions and arynes generated by a complex base. Products derived using the aprotic solvent system differ considerably from those involving enolate ions in ammonia. In the protic solvent the aryl anion resulting from the addition of an enolate ion to an aryne is protonated and continued reaction is thereby prevented. Such protonation does not occur in the aprotic medium further reactions occur by intramolecular addition of the aryl anion to a carbonyl group, Scheme 5. Products obtained from acyclic ketones include... 

A recent synthesis of anthraquinones involves the base-catalyzed addition of phthalides to arynes (generated from the corresponding aryl bromide and lithium diisopropylamide), as outlined in Scheme 6.54... 

Julia et al. have employed intramolecular reactions of arynes generated from indoline derivatives for closure of a six-membered ring linking the 3-and 4-positions. Thus, 103 is obtained from 102 by treatment with sodium... 

Aryne generation. The desilylative route (e.g., by CsF) is the most expedient method for generation of arynes. 1,2-Functionahzation of arenes from 2-trimethylsilylaryl triflates is readily achieved as long as noninterfering co-reactants are used. Thus trapping by organoazides leads to benzotriazoles, by phenyhodonium diacyhnethyhdes leads to... 

Two interchangeable fluoride ion sources used in aryne generation from o-trimethylsily-laryl triflates are CsF and TBAF. Many henzannulated heterocycles are now conveniently prepared via cycloaddition reactions of arynes. 3-Indazolecarboxylic esters are accessible from such a reaction. ... 

Arylxanthenes are formed when electron-rich aromatic aldehydes react with an excess of arynes. Initial nucleophilic attack by the carbonyl oxygen atom on the aryne generates a benzoxete which isomerises to an o-quinone methide. A [4-i-2]cycloaddition with the aryne completes the sequence <040L4049>. 

If the benzobarrelene has been prepared from an aryne generated from 5-amino-[3,3]paracyclophane , this may well be a route to arynes. 

Tosylate can function in place of halogen as the leaving group in aryne generation. The method has been most successfully applied to naphthynes " as in the following example ... 

In addition to recovered 456 (38%) there was obtained monoadduct 457 and, in very low yield, bis-adduct 458. Additional 458 (11%) could be obtained by resubjecting 457 to the aryne-generating conditions. Hydrogenation and thermolysis converted 458 to 459 in essentially quantitative yield. In these reactions, the 3,6-dibromoanthranilic acid functions as a synthetic equivalent for 1,3,5-benzatriyne, albeit the overall yield of 458 is very low. 

An attempt to develop a multigram synthesis of458 provoked a reinvestigation of aryne generation from polyhalobenzenes k The main results are the following. Hexabromobenzene, BuLi (1 equiv) and furan give monoadduct 460 via 3,4,5,6-tetrabromobenzyne further metallation occurs at the 2-Br (and with 2 equiv of BuLi, at the 2,3-bromines, as established by low-temperature proton quenching) and elimination... 

A high yield synthesis of diaryl ethers involves nucleophilic attack by phenoxide on arynes generated from iodobenzenes. The arynic nature was established with substituted iodobenzenes ( -MePhI and phenol, for example, gave 35% m-tolyl phenyl ether as well as 25% of t -tolyl phenyl ether). Diaryl sulfides were similarly prepared from thiophenols and iodoarenes. 

A convenient one pot route to various biphenyls [12], p-terphenyls [13] as well as m-terphenyls [6], starting from suitably substituted polyhalobenzenes, was developed in our laboratories in the mid 1980s. The protocol involves a tandem aryne generation - nucleophilic capture sequence and is described in detail here only in conjunction with the synthesis of m-terphenyls. 2,6-Dichloroiodoben-zene 14 is frequently employed as the polyhalobenzene required for the m-terphenyl synthesis. It is readily prepared from commercially available... 

An interesting new addition to the methods available for constructing arylthiophenes is the addition of thienyllithium to arynes generated from aryl triflates and LDA <93JOC4722>. Both ipso-and c/ne-substitution are possible. o-Tolyl triflate gave the ortho- and we/a-substituted products in the ratio 43 57, but 2-methoxyphenyl triflate gave exclusively the weta-substituted product. 

Unsymmetrically substituted anthraquinones have been synthesised through addition of the isobenzofuranone 52 to arynes generated in situ from haloarenes, the regioselectivity of the reaction being controlled by substituents in the aryne moiety [61]. This approach is unlikely to allow regiospecific synthesis of anthracyclinones other than 11-deoxy analogues, but the unsubstituted phthalide 51 has been condensed with 68 to give 69, a precursor of 4-demethoxydaunomycinone 6. 

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