Nucleophilic Addition to Arynes

AU the examples discussed to date have involved ortho-benzyne itself, and have simply served to illustrate the range of nucleophiles that react. However, one needs to know what happens when unsymmetrical arynes are attacked by nucleophiles. 

Steric effects only become important when either the attacking nucleophile or the substituent ortho to the aryne bond is very bulky. An example of this effect can be seen in the increased regioselectivity of addition of Hthium piperi-dide to 3-isopropylbenzyne over 3-methylbenzyne. Likewise in the addition to 3-methylbenzyne, KNH2 adds to both ortho- and meta-positions in approximately 

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It seems that the repulsive steric interactions play a more dominant role in regioselectivity of aryne reactions than is sometimes realized. In fact, it has been argued that in nucleophilic addition to arynes, the transition state is reached early, while the incipient bond is still very much extended. Consequently, steric effects were considered not to be of great importance.80 81 It should, however, be noted that the dehydro bond orbitals are so oriented that the optimal approach trajectory for the nucleophile lies in the... 

In addition of organometallic reagents to some arynes, prior counterion complexation with the substituent can direct the incoming group to the ortho position (kinetic control). Addition of alkyllithiums to oxazolinyl (OXZ) aryne (51) to give the ortho product (52) is explained in this manner. In contrast, lithium dialkylcuprates add to the aryne (51) exclusively at the meta position. This is ascribed to thermodynamic control of the reaction, which results in the formation of the more ligated and stable adduct (S3).i2 Control of nucleophilic addition to arynes by complex-induced proximity effects has not been explored with substituents other than OXZ,83 but has considerable synthetic potential if it can be achieved, say through solvent manipulation. 

Although there are some mechanistic uncertainties, there is evidence that the reaction occurs via two successively formed arynes produced after metal-halogen exchange at both iodines. If arynes were formed independently at each halogen pair, one would expect a mixture of m- and p-terphenyls as products. It is thought that the regioselectivity in the nucleophilic additions to aryne intermediates 638 and 639 is a consequence of the need to keep the two carbanionic sites on the benzene ring remote (i.e. para) to each other. 

Nucleophilic Addition to Arynes Followed by Heck-Type Coupling (Pd[0])... 

Scheme 52 Synthesis of carbazoles 32 by nucleophilic addition to arynes and subsequent cyclization by intramolecular Heck-t3q>e coupling of the diarylamines 221...

Elimination-addition mechanism (Section 23.8) Two-stage mechanism for nucleophilic aromatic substitution. In the first stage, an aryl halide undergoes elimination to form an aryne intermediate. In the second stage, nucleophilic addition to the aryne yields the product of the reaction. 

The nucleophilic addition of the mesoionic compound 41 was further investigated upon addition to arynes <20030BC978> (Scheme 8). In this case the process stops at a single addition of the anion to the aryne to form 45 and workup under aqueous conditions led to the formation of the tetrazolium-5-olate 46. 

Benzyne also reacts with compounds containing nucleophilic carbon atoms such as enolates and aryl anions. Intramolecular nucleophilic addition to an aryne by the ortho ring carbon atom of another benzene ring substituted... 

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. 

Only one or/Ao-aryne 533 is possible in a thiazole ring. Its intermediacy was first considered in the reaction of 4>halothiazoles (534) with methoxide ion as a possible rationale for the surprisingly similar reactivity of these compounds and the 2- and 5-halo isomers. This hypothesis was consistent with the small element effect, the rapid base-catalyzed exchange of the 5-proton, and the exclusive formation of the normal substitution product 535 as would be expected if nucleophilic addition to the aryne 533 was determined by the stability of the resulting anion 536 with the negative charge adjacent to the sulfur atom. The fact that the 5-phenyl derivative 537, which cannot form an aryne 533, reacts at a comparable rate to 534 rules out the possibility of an elimination-addition mechanism, however. 

Heterocyclic compounds may show a higher tendency than carbocycles to react with nucleophiles according to the addition-elimination mechanism than via arynes. 

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... 

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