Tandem aryne reactions

One of the two reaction types which dominate the synthetic utility of arynes as reactive intermediates is cycloaddition. Cycloadditions can be subdivided into several categories. For example, benzynes undergo [4+2] and [2+2] cycloadditions as well as 1,3-dipolar cycloadditions, the ene reaction, and miscellaneous others. These reactions may occur in an inter- or intramolecular mode. Further, multiple and tandem aryne reactions can be used for multiple-bond construction in a single step. Each of these reaction types, as well as a few miscellaneous reactions, is discussed in the following sections. 

The scope of multiple and tandem aryne additions, which as we have seen are useful for forming two or more carbon-carbon bonds in a one-pot reaction, remains to be further explored. 

The reaction proceeds by (1) organometallic exchange, followed by (2) aryne formation, and (3) a regiospecific nucleophilic addition of the aryl Grignard to the aryne. These steps can occur or recur in tandem fashion to form from one to six new carbon-carbon bonds in a single operation [33,34]. Subsequently, the method was extended to alkenyl and alkynyl Grignards [35 Eq. (13)] and trimethylsilylvinyl Grignards [36]. 

Brown N, Luo D et al (2009) New synthesis of (-1—)-cis-trikentrin A via tandem indole aryne cycloaddition/Negishi reaction. Applications to library development. Tetrahedron Lett 50 7113-7115... 

Ackermann employed a different reaction order to meld 1,2-dihaloaryls together with anilines to access a series of carbazoles, including murrayafoline A (Scheme 2, equations 1 and 2) [23]. Jean and colleagues reported a tandem Suzuki/aryl-Heck protocol to prepare functionalized carbazoles and glycosinine (equation 3) [24]. Larock and Liu synthesized a series of carbazoles and the alkaloid muko-nine via an aryl-Heck reaction, which featured an aryne mediated preparation of the requisite diaryl amines [25]. Willis and coworkers reported an indole synthesis involving Heck arylation followed by double bond isomerization (equation 4) [26]. Urabe and colleagues described a similar aryl-Heck indolization from p-bromo-Al-aryl enamines giving 2-alkylindoles [27]. 

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... 

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