Arynes, functionalization

Arynes in general are the subject of a chapter in a volume of Patai and Rappoport s series The Chemistry of Functional Groups (Gilchrist, 1983). The formation of arynes from diazonium salts is treated in three chapters of two volumes of the same series (Wulfman, 1978 Hegarty, 1978 Zollinger, 1983 a). 

New Diels-Alder reactions of 3-vinylindoles with an aryne selective access to functionalized [a]anellated carbazoles [145]... 

Fluoro-o-benzyne (41) has also been isolated in cryogenic matrices by photolysis of the corresponding phthalic anhydride. The C=C stretching vibration of 41 has been observed at 1866 cm Compared to the parent, the triple bond length is only modestly increased according to DFT calculations (Fig. 16.2). Note, however, that the observed frequency shifts upon fluorine substitution in 4 are not reproduced at the B3LYP or BLYP level of theory (Fig. 16.2). Thus, the performance of different DFT functionals to account for the properties of o-arynes still remains a matter of debate,and casts some doubts on the results of certain DFT studies. 

Species such as 5 and 6 are called benzynes (sometimes dehydrobenzenes), or more generally, arynes, and the mechanism is known as the benzyne mechanism. Benzynes are very reactive. Neither benzyne nor any other aryne has yet been isolated under ordinary conditions,34 but benzyne has been isolated in an argon matrix at 8 K,35 where its ir spectrum could be observed. In addition, benzynes can be trapped e.g., they undergo the Diels-Alder reaction (see 5-47). It should be noted that the extra pair of electrons does not affect the aromaticity. The original sextet still functions as a closed ring, and the two additional electrons are merely located in a tt orbital that covers only two carbons. Benzynes do not have a formal triple bond, since two canonical forms (A and B) contribute to the hybrid. 

Many stable metal complexes of arynes are known but in most of their reactions of synthetic interest, the yields are poor. For example, thermolysis of titanocene (Cp2TiPh2) at 80-100 C gives rise to a tita-nium-benzyne complex which reacts with molecular nitrogen to afford aniline with low efficiency.29 However, procedures are available for in situ generation of zirconium complexes (14) and for their coupling reactions to synthesize functionalized aromatic compounds in preparatively useful yields (Scheme I).30 Whether such complexes should be regarded as ir-bonded benzynes or o-bonded o-phenylenes, remains a debatable point.31... 

Arynic substitution is a versatile technique of functional group transformation in aromatic systems and has found varied applications in preparation of simple compounds and in multi-step synthesis.3 4,3 The present section comprises examples illustrative of its synthetic scope. Attention is also drawn to some allied strategies which, when used in conjunction with the nucleophilic coupling of arynes, have opened convenient routes to complex natural products. 

Polyhalogenated arenes can function as diaryne equivalents via the tandem sequence illustrated in Scheme lO.90-91 The predominant meta addition to aryne (59) can be ascribed to steric hindrance, while in addition to (58) both steric and electronic effects favor the observed regioselectivity. 

The very reactive arynes have also been used as dienophiles in Diels-Alder cycloadditions with vinyl heterocycles and are included here, after the acetylenic esters, because of the similarity of their reactive functions. This reaction is of considerable importance because of its application in the synthesis of polycyclic compounds. 

The preferred site of deprotonation of di- or polysubstituted arenes is not easy to predict. In 1,3-disubstituted benzenes in which both substituents facilitate ortho-metalation, deprotonation will usually occur between these two groups [181, 365, 408, 416-419] (Scheme 5.45). Dialkylamino groups, however, can sometimes deactivate ortho positions (fourth reaction, Scheme 5.45), but this does not always happen [181, 420], 3-Chloroanisole [411] and 3-fluoroanisole [421] are deprotonated by organolithium compounds between the two functional groups, but the lithiated arenes dimerize readily at -78 °C, presumably via intermediate aryne formation (last example, Scheme 5.45). 

Two different carbon functional groups can be introduced simultaneously into 1,2-positions of aromatic skeletons based on a novel insertion reaction of arynes (101) into a carbonyl-cyanomethyl a-bond of a-cyanocarbonyl compounds (102) to produce 1,2-disubstituted aromatics (103).134... 

The iodine-magnesium exchange on ort o-iodoaryl sulfonates leads, after warming up, to the formation of functionalized arynes, which can be trapped by dienes or nucleophiles (Scheme 17).45,46 Hetaryl iodides react with 7-PrMgCl in THF giving the corresponding magnesium compounds in excellent yields (Scheme 18).47,47a,47b... 

The extra election pair involved in the aryne does not affect the aromaticity of the species. The original sextet still functions as a closed ring, and the two additional electrons are merely located in a tt orbital that covers only two carbon atoms. 

Arynes and heteroarynes are reactive intermediates derived formally by the removal of two adjacent hydrogens from, respectively, a carbocyclic or a heterocyclic aromatic ring. Prototypical examples are benzyne (1) and 3,4-didehydropyridine (2). Since these molecules contain a partial triple bond, they are properly regarded as -ynes and, as will be seen, undergo many reactions typical of that functionality, modified by the inherent strain caused by their nonlinearity. 

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 ... 

Pyrroles, like furans, undergo [4+2] cycloadditions with arynes. For good yields, however, it is important to have some functionality other than hydrogen attached to the nitrogen. A variety of 7-azabenzonorbornenes have been prepared in this way 54... 

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. 

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. 

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