Arynes 1,3-dipolar cycloaddition

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. 

Di- and tri-aryne equivalents other than explored. Bistriazole 466 was synthesized as a with lead tetraacetate (LTA) in the presence of various dienes give bis-adducts in good yield (mainly 70-90%, 17 examples). The main advantages over tetrahalobenzenes 440 is that dienes with functionality that might not survive BuLi can be tolerated, as shown in examples 467-469 (the latter a bis-l,3-dipolar cycloaddition). The regioselectivity in these cycloadditions is also striking. The major disadvantage is that precursor 466 requires a multistep synthesis. 

Despite its obvious attractiveness as a potential route to isoindoles and benz-fused isoindoles, no new examples of the dipolar cycloaddition of munchnones and arynes have been reported since the first report by Kato and co-workers. This area is ripe for further exploration, particularly because many new mild methods for generating arynes and hetarynes have been developed since 1976. 

In 1953, Robert s experiments on the conversion of C-labeled chlorobenzene with KNH2 into aniline gave strong support to the intermediacy of ortho-benzyne in this and related reactions. Additional direct evidence for the existence of ortho-benzyne was provided by the observation of its IR spectrum, sohd-state dipolar NMR spectrum, and NMR in a molecular container, and by UV photoelectron spectroscopy. Even at low temperatures, arynes are extraordinary reactive. The reactions of arynes can be divided into three groups (i) pericyclic reactions, (ii) nucleophilic additions, and (iii) transition-metal catalyzed reactions. The pericyclic reactions can be divided into several categories such as Diels-Alder reactions, [2-f2] cycloadditions, 1,3- and l,4-dipolar cycloadditions, and the ene reactions. Arynes react with practically aU kinds of nucleophiles. More recently, the transition-metal catalyzed reactions of arynes have been studied, in particular those involving palladium. 

An intramolecular 1,3-dipolar cyloaddition protocol involving as key step in situ desilylation of azido alkyne 176, coupled with microwave irradiation, successfully furnished triazolobenzoxazepine 177 (13TL6005). A tandem 1,3-dipolar cycloaddition/N—O single bond insertion process between quinoline N-oxides and aryne precursors afforded pentacyclic oxazepino[4,5-(j]quinolines 178 with, in most cases, concomitant formation of the corresponding 2-(2-hydroxyphenyl)quinolines (13BCJ615). 

A wide variety of reagents have been used in 1,3-dipolar cycloadditions with arynes. For example, a general method for the preparation of Al-unsubstituted indazoles 27 and 1 -arylindazoles 28 by the [3+2] cycloaddition of aiynes generated from o-(silyl)aryl triflates and diazomethane daivatives has been developed. The selective formation of 27 or 28 depends on the relative amounts of the... 

Also in this field, Larock et al. have described that sydnones 29 undergo [3+2] dipolar cycloadditions with arynes affording 2//-indazoles 30 nndo" mUd reaction conditions. These heterocyclic derivatives are formed by a spontaneons extmsion of CO from the initial cycloadduct (Scheme 12.19) [30]. The same authors have developed a simple route to pyrido[l,2-f>]indazoles 31 via an aryne [3+2] cycloaddition with A(-tosylpyridininm imides and subsequent flnoride-induced elimination of the tosylate anion (Scheme 12.19) [31]. 

In an efficient procedure, indazoles 12 are obtained under mild conditions by 1,3-dipolar cycloaddition of arynes and diazoalkanes [450] ... 

SCHEME 6 1,3-dipolar cycloaddition of in situ-generated nitrile imines and aryne [26]. 

Nitrones are stable, easily available, isolable, and are known to participate in 1,3-dipolar reactions with various dipolarophiles. The 1,3-dipolar cycloaddition of a,p-xmsaturated nitrones 26 with arynes generated from 25 under basic conditions leading to the formation of benzoisoxazoline derivatives 27 was developed by Danishefsky and coworkers (Scheme 14) [37]. Additionally, they applied this methodology to the synthesis of oxa[3.2.1]octane core of... 

SCHEME 14 1,3-dipolar cycloaddition of a, 3-unsaturated nitrones with arynes [37]. 

Larock et al. 27 examples, 56-95% SCHEME 15 1,3-dipolar cycloaddition of various nitrones with arynes [38]. 

SCHEME 76 1,3-dipolar cycloaddition of pyridine N-oxides with arynes [103]. 

T. Jin, Y. Yamamoto, An efficient, facile, and general synthesis of IH-indazoles by 1,3-dipolar cycloaddition of arynes with diazomethane derivatives, Angew. Chem. Int. Ed. 46 (2007) 3323-3325. 

F. Shi, R. Mancuso, R.C. Larock, 1,3-Dipolar cycloaddition of arynes with azomethine imines synthesis of l,2-dihydropyrazolo[l,2-a]inda-... 

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