Benzynes with nucleophiles

The principle of microscopic reversibility brings the above stereoelectronic effects back into play in the reactions of o-benzynes with nucleophilic trapping species (Figure 10.17). For example, control of relative stabilities of aryl lithiums by substitution allows selective preparation of halosubstituted biphenyls. In the... 

Very strong bases such as NaNH2 convert unactivated aryl halides into benzyne intermediates which react rapidly with nucleophiles to form the products of an apparently simple nucleophilic substitution. It is now clear that hetarynes are frequent intermediates in reactions of not too highly activated heteroaromatic halides. 

Figure 8-5. Reactions of halobenzene derivatives with nucleophiles, a) Unactivated compounds are extremely inert and only react by mechanisms that involve the formation of benzynes. b) The presence of the electron-withdrawing nitro group, which can stabilise an anionic intermediate by the delocalisation of the charge onto the electronegative oxygen atoms, allows facile nucleophilic substitutions.

Fluoride anion can both react with silylaryl triflate to generate benzyne and act as a base to abstract the hydrogen on the amide nitrogen to afford an anion that can attack the benzyne. Intramolecular nucleophilic attack on the carbonyl carbon (or... 

The reaction of benzyne with aromatic aldehydes proceeds via nucleophilic attack of the carbonyl oxygen onto the benzyne to give the zwitterionic intermediate 172 followed by cyclization to the benzoxete intermediate. Cycloreversion then forms an ortho-quinone methide, which undergoes a [4+2] cycloaddition with a second molecule of the benzyne to form the xanthene (Scheme 56) <20040L4049>. 

In summary, the benzyne mechanism operates when the halobenzene is unactivated toward nucleophilic aromatic substitution, and forcing conditions are used with a strong base. A two-step elimination forms a reactive benzyne intermediate. Nucleophilic attack, followed by protonation, gives the substituted product. 

Notice the symmetry in this mechanism. Benzyne is formed from an ortho carbanion and it gives an ortho carbanion when it reacts with nucleophiles. The whole mechanism from bromobenzene to aniline involves an elimination to give benzyne followed by an addition of the nucleophile to the triple bond of benzyne. In many ways, this mechanism is the reverse of the normal addition-elimination mechanism for nucleophilic aromatic substitution and it is sometimes called the elimination-addition mechanism, the elimination step... 

As already stated, aryl halides on treatment with a strong base such as KNH2 generates benzyne. The benzyne further reacts with nucleophile (NHJ) to give aniline. 

In addition to these cycloaddition reactions with nucleophilic Tr-donors, tetrafluoro-benzyne is very susceptible to more general nucleophilic attack. Biphenyl derivatives often occur as by-products in reactions of pentafluorophenyl-lithium, formed by addition to the benzyne [204, 229] (Figure 9.89). 

The reaction of halobenzenes with a strong base (e.g. NaNH2 in NH3) can lead to the elimination of HX and the formation of benzyne (in a synperiplanar elimination reaction). The new Jt-bond that is formed (by the overlap of two sp2-orbitals outside the ring) is very weak, and benzyne can react with nucleophiles or take part (as the dienophile) in Diels-Alder reactions (see Section 6.2.2.11). As benzyne is extremely... 

The reaction of benzyne with 1,4,2-benzodithiazine 618 to give a low yield of thianthrene 619 is probably initiated by nucleophilic attack of sulfur, as shown. 

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). 

Although the vast majority of stepwise polar additions to ortho-benzyne involve nucleophilic attack on the aryne, electrophilic attack is also possible provided that the aryne is generated by a method that does not involve strongly basic conditions. Few such additions are synthetically useful, with the exception of the formation of 1,2-dihalobenzenes by reactions of ortho-benzynes with halogens, although alternative mechanisms initiated by nucleophilic attack of halide may be envisaged. Radical reactions of ortHo-benzyne, on the other hand, are extremely rare. 

Grignard reagents are also shown to undergo anionic 1,3-cycloadditions with benzyne, leading to the fused system (33), but the reaction competes with nucleophilic addition and [2-1-2] cycloaddition reactions. 

Despite their high electrophilicity, arynes are discriminatory toward nucleophiles (33). An interesting reaction involving an additive rearrangement of benzyne with alkylidenetriphenylphosphoranes (34) is depicted as the following. 

Aromatic compounds with good leaving groups may eliminate to give a benzyne intermediate, which readily reacts with nucleophiles. 

Aryl thioethers s. Thioethers, ar. Arylthiomethylation 26,844 Aryl tridiloromethyl carbinols -, reactions with nucleophiles, review 22, 629 suppl. 26 Arynes s. Benzyne..., Hetarynes Ascaiite 11,963 suppl. 28 Asscher-Yofsi reaction 21,642 Assistance, intramolecular s. Neighboring group participation... 

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