Aryl halides aryne generation

Much of the early work on arynes was undertaken using the aryl halide-strong base route (equation 6), but a variety of other procedures, discussed below, are also available. In practice, the choice of the method of generation is often governed by the nature of the reaction to be carried out subsequently. Since arynes are transitory intermediates used in situ, the conditions employed for their formation have... 

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 are generated from aryl halides by reaction with strong bases. The final outcome of the reaction is substitution of the halide. 

The reaction of strong bases with aryl halides results in the generation of an aryne through loss of HX, Arynes can also be formed by reaction of aryl halides with lithium and organolithium compounds. 

Aromatic substitution reactions that proceed by the elimination-addition mechanism are not widely used synthetically, as a very strong base (pIsTb — 35) is required to generate the aryne intermediate by /3-elimination of HX. In addition, there is regiochemical ambiguity for unsymmetrical aryl halides. Even benzyne itself is much more readily prepared by several other methods. 

Scheme 7.5 summarizes the common methods of aryne generation, although the examples are limited to ortho-benzyne. Because of their extreme reactivity, arynes must be generated in situ. When an unactivated aryl halide is treated with a very strong base, an elimination reaction is possible, generating aryne. 

Arynes with their reactive triple bond would be expected to participate readily in cycloaddition reactions. However, as demonstrated in the previous section, the addition of nucleophiles is extremely facile, and therefore reactions with non-nucleophilic reagents cannot usually be observed unless the aryne is generated in the absence of nucleophiles. In practice this usually means that routes involving the treatment of aryl halides with nucleophilic bases cannot be used. The first cycloaddition reaction of ortho-benzyne, the Diels-Alder reaction with furan was observed in 1955 by Wittig and used 2-fluorobromobenzene as the precursor. The cycloadduct was obtained in almost 90% yield, and the reaction has formed the basis for numerous synthetically useful Diels-Alder cycloadditions involving arynes. Tetrabromobenzene reacts with butyllithium to give the diaryne intermediate with furan to form a tetrahydroanthracene. The mixture of syn and anti conformers can be separated based on differences in methanol solubility (Scheme 7.26). 

Aryl halides upon treatment with strong base generate arynes. 

Since the aryllithiums are highly polar and very strong bases, several side-reactions are possible. Certain aryl halides can undergo the elimination of HX to generate the aryne intermediates that may produce an isomeric biaryl via nucleophilic addition to the adjacent carbon atom, Scheme 4. 

By far the most common and historically oldest aryne generation method involves the elimination of hydrogen halides from aryl halides (32a) in the presence of strong bases (Table 1). " In many cases o-haloarylanions (33) can be trapped as intermediates, although often the elimination of halide ion to the aryne (1) is either too rapid to allow their detection or perhaps concerted. The effect of halogen, metal, and substituents on this reaction has been well studied. ... 

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