Arynes nucleophilic addition

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. 

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. 

The classification within this section is based on the structural (rather than the mechanistic) relationship between the starting materials and products. Mechanistically, all of the reactions considered in this section involve nucleophilic substitution as the first step, except for aromatic substitution via the aryne mechanism, which involves elimination followed by nucleophilic addition. 

The reaction proceeds by (1) organometallic exchange, followed by (2) aryne formation, and (3) a regiospecific nucleophilic addition of the aryl Grignard to the aryne. These steps can occur or recur in tandem fashion to form from one to six new carbon-carbon bonds in a single operation [33,34]. Subsequently, the method was extended to alkenyl and alkynyl Grignards [35 Eq. (13)] and trimethylsilylvinyl Grignards [36]. 

The regioselectivity of the reaction ( 100% ipso-substitution) is in favour of a nucleophilic substitution mechanism. However on this basis the arynic (elimination-addition) mechanism can be excluded. 

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... 

With few exceptions arynes used in the nucleophilic additions discussed so far are generated either by removing with base an aryl proton adjacent to a leaving group (Type A2, Section III.A.2), or by decomposing an anthranilic acid derivative (Type Bl, Section III.A.3). Reactions described in the remainder of this section are initiated instead by metal-halogen exchange (Type Al, Section IILA.l). 

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...

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. 

Arynes react readily with simple alkenes to give either benzocyclobutenes or substituted benzenes (Scheme 7.31). The formation of benzocyclobutenes by [2+2] cycloaddition reaction of the aryne to the alkene proceeds best for strained and electron-rich carbon-carbon (C=C) double bonds. For example, dicyclopentadiene reacts to give the ex o-isomer of the corresponding four-membered ring in good yield. The addition to cyanoethene (acrylonitrile) and the reaction with the electron-rich ethoxyethene (ethyl vinyl ether) gives the cyano- and ethoxy-benzocyclobutenes in 20% and 40% yields, respectively. The latter reaction almost certainly involves nucleophilic addition of the enol ether to the electrophilic aryne followed by coUapse... 

Scheme 7.36 shows a further example of the use of aryne in alkaloid synthesis, involving intramolecular nucleophilic addition reaction as a key step in the synthesis of lysergic acid ester. 

The reactions of arynes can be divided into three groups (i) pericyclic reactions, (ii) nucleophilic additions, and (iii) transition-metal catalyzed reactions. 

The major application of arynes in synthesis is in the construction of polycyclic systems using either the Diels-Alder or intramolecular nucleophilic addition reactions. 

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. 

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