Arynes from Aryl Anion Intermediates

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.  

Replacement of the ortho hydrogen of an aryl halide with another elec-trofugic group leads to many additional precursors of o-haloarylanions and in some cases arynes. Several of the more effective in the latter category (32b-32f) are summarized in Table 1 and in the following scheme  

Particularly useful have been the o-dihalobenzenes (32b), which permit the generation of arynes without the use of organometallic or strongly basic reagents. A recent variant traps the initially formed anion (33) as its TMS derivative (32f), which then can be converted to the aryne 1 with the nonbasic and nonnucleophilic KF.  

Replacement of the halogens of the above precursors with different nucleofugic groups generates another set of aryne sources (32g-321) which once again probably react via the o-substituted anions (34). 

The mechanistically most ambiguous of the above precursors are those (32d and 321) containing carboxylate as the electrofugic group. In neither case has an anionic intermediate (35) been demonstrated although it has been considered. In fact, such evidence as is available better supports the intermediacy of the zwitterion 36 or one of its valence tautomers 37 or 38. 

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The second example of a cine-substitution of a thiophene involves the reaction of arylthiolates with 3,4-dinitrothiophene (331) or 3-nitro-4-phenylsul-fonylthiophene (332) to give the 2,4-substituted products 333. Both an elimination-addition mechanism via the aryne (334) or an abnormal addition-elimination (AEa) mechanism (Section II.2.A.e) via the Meisenheimer complex (335) have been considered for these reactions. The former is unlikely for several reasons including the lack of precedence for aryne formation from aryl nitro compounds (Section II. 1) under these reaction conditions and the fact that addition of the nucleophile ArS" to the aryne (334) would have to proceed via the 3-thienyl anion (336) rather than via a more stable 2-thienyl anion such as 320 as would be expected. Contrariwise, cine-substitution by the AEa mechanism is favored by the ability of the complex (335) to stabilize the negative charge by delocalization to both the NO2 group and the a position of the thiophene ring." As in the pyrrole series (Section III.2.B) the actual mechanism appears to be more complex, however, involving several addition and elimination steps via 337, which was recently isolated from the reaction (X = NO2) and shown to go to the product 333 under the reaction conditions. It therefore appears that neither of the cine-substitutions of thiophene described in this Section proceeds via an aryne intermediate. 

The preceding reactions dealt with the use of chiral auxiliaries linked to the electrophilic arene partner. The entering nucleophile can also serve as a chiral controller in diastereoselective SjjAr reactions. This approach was successfully employed for the arylation of enolates derived from amino acids. To illustrate the potential of the method, two examples have been selected. Arylation of Schollkopf s bislactim ether 75 with aryne 77 as electrophilic arylation reagent was demonstrated by Barrett to provide substitution product 81 with good yield (Scheme 8.18) [62, 63]. Aryne 77 arises from the orf/jo-lithiation of 76 between the methoxy and the chlorine atom followed by elimination of LiCl. Nucleophilic attack of 77 by the lithiated species 78 occurs by the opposite face to that carrying the i-Pr substituent. Inter- or intramolecnlar proton transfer at the a-face of the newly formed carbanion 79 affords the anionic species 80. Subsequent diastereoselective reprotonation with the bulky weak acid 2,6-di-f-butyl-4-methyl-phenol (BHT) at the less hindered face provides the syn product 81. Hydrolysis and N-Boc protection give the unnatural arylated amino acid 82. The proposed mechanism is supported by a deuterium-labeling experiment. Unnatural arylated amino acids have found application as intermediates for the construction of pharmaceutically important products such as peptidomi-metics, enzyme inhibitors, etc. [64, 65]. 

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