Benzyne nucleophilic addition

Other examples of the ElcB pathway are benzyne formation from C6HsF (cf. p. 174), reversal of simple nucleophilic addition to 0=0, e.g. base-induced elimination of HCN from cyanohydrins (20 cf. p. 212),... 

A way forward might be to form the imine 7.3 [and hence its enamine tautomer 7.4] by reacting the phenylamine 7.2 with cyclohexanone (Scheme 7.18). Then to generate the benzyne anion 7.5 by treating the tautomers with sodamide and sodium fcr/-buloxide in THF. Cydization to the required indole 7.1 occurs through nucleophilic addition to the benzyne, followed by protonation during work-up. 

L in Scheme 11.3) departs. Nucleophilic addition to the intermediate benzyne (step D) is readily explained by perturbative MO arguments. The extra and orbitals of benzyne are compared to those of ethylene in Figure 11.7. The aromatic n system is not involved in the special properties of benzyne. The third benzyne n bond is due to the overlap in fashion of the two sp2 hybrid orbitals which lie in the nodal plane of the intact 6 electron system. Two factors contribute to a very low LUMO for benzyne. First, the sp2 hybrid orbitals are lower in energy than the 2p orbitals from which the ethylene orbitals are constructed. Second, the intrinsic interaction between the two sp2 orbitals is less than the normal / cc since the orbitals have less p character and are tipped away from each other. The low LUMO of benzyne makes the molecule a strong Lewis acid, susceptible to attack by bases, and a reactive dienophile in Diels-Alder reactions, as we shall see later. 

A similar but conceptually distinct approach to difunctionalization of terminal alkynes consists of sequential carboboration-palladium-catalyzed cross-coupling 137 equation (33) illustrates that this method also provides alkenes of high stereochemical purity by net syn Markovnikov addition. Benzyne-contain-ing molecules can act as highly activated substrates for vicinal difunctionalizations initiated by nucleophiles 138-140 thus, nucleophilic addition-electrophilic trapping can serve as an alternative to sequential directed metallation for the production of 1,2-disubstituted and 1,2,3-trisubstituted aromatic systems (equation 34).141... 

Although there is ample evidence for nucleophilic additions to benzyne la> and some other unstable angle strained cycloalkyne intermediates 15,27,31,205 207), only a few addition reactions to isolable angle strained cycloalkynes are known which can be classified as nucleophilic. Hydroxylamine and hydrazine add to (31) to yield the corresponding oxime and hydrazone, resp. 208). 

The electrophilicity of benzyne (90) is 1.95 eV, a value that falls within the range of strong electrophiles in the w scale.102 This value, which is larger than that evaluated for acetylene (32), to = 0.54 eV, allows to explain the reactivity of the benzyne derivatives towards nucleophilic additions. The electrophilicity of the fused four-membered... 

The analysis of the local electrophilicity at the fused four-membered benzyne derivative 91 indicated that the strained substituent present on the C3 position breaks the symmetry of benzyne (90), and the Cl carbon atom becomes slightly more electrophilic than the C2 one. This result is in agreement with the regioselectivity observed in the nucleophilic additions to 91 (see Scheme 15). 

Cyclopropyllithium may engage itself in various types of reactions depending on the properties of the aromatic compound. When fluorobenzene is the aromatic substrate, benzyne formation followed by hydride transfer is believed to take place, but if the aromatic compound is a diazine or a substituted or annulated pyridine, the first step is nucleophilic addition of cyclopropyllithium to the nitrogen-containing ring of the aromatic nucleus. The predominance... 

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... 

Nucleophilic addition of dienolates to substituted benzynes is followed by closure of a six-membered ring to form naphthalene derivatives.31... 

Dibenzofurans can be constructed using benzyne chemistry, by nucleophilic addition of o-iodophenols to benzyne (generated by treatment of silylaryl triflate with CsF), followed by the Pd-catalyzed intramolecular arylation . 

Addition of nucleophiles such as ammonia or alcohols or their conjugate bases to benzynes takes place very rapidly. These nucleophilic additions are believed to involve capture of the nucleophile, followed by protonation to give the substituted benzene. ... 

Nucleophilic addition of dienolates to substituted benzynes is followed by... 

In 1953, Robert s experiments on the conversion of C-labeled chlorobenzene with KNH2 into aniline gave strong support to the intermediacy of ortho-benzyne in this and related reactions. Additional direct evidence for the existence of ortho-benzyne was provided by the observation of its IR spectrum, sohd-state dipolar NMR spectrum, and NMR in a molecular container, and by UV photoelectron spectroscopy. Even at low temperatures, arynes are extraordinary reactive. The reactions of arynes can be divided into three groups (i) pericyclic reactions, (ii) nucleophilic additions, and (iii) transition-metal catalyzed reactions. The pericyclic reactions can be divided into several categories such as Diels-Alder reactions, [2-f2] cycloadditions, 1,3- and l,4-dipolar cycloadditions, and the ene reactions. Arynes react with practically aU kinds of nucleophiles. More recently, the transition-metal catalyzed reactions of arynes have been studied, in particular those involving palladium. 

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. 

Keywords Benzyne C-H functionalization Heteroaromatic A(-oxides Metal-free reactions Nucleophilic addition Organocatalyst Radical reactions... 

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