Through a Benzyne Intermediate

Elimination-addition goes through a benzyne intermediate, and the nucleophile can add to either benzyne C, so both 3- and 4-bromotoluene should give mixtures of products if this mechanism is operative. 

The synthesis of 273 proceeds through a benzyne intermediate (Scheme 55) <2005TL7443>. An enzymatic cyclization has also been reported (Scheme 56) <1990TL6907>. 

This evidence that benzyne is at least one of the intermediates in acetylene pyrolysis has many implications. However, as the ratios of products from acetylene and hexafluorobenzene differ appreciably from those obtained from phthalic anhydride, it might be best at this point to call acetylene a benzynoid precursor. Additional data will be needed and are being accumulated to determine to what extent acetylene reactions proceed at high temperatures through a benzyne intermediate (Fields and Meyerson, 1967a). 

Three papers have appeared in the past two years on catalysts that are either supported on polymers or are heterogeneous. Djakovitch first reported animation reactions catalyzed by palladium particles immobilized on metal oxide supports, as well as by palladium complexes contained in NaY zeolites [172]. In most cases, these reactions were conducted at high temperatures, generally 135 °C. When NaOtBu was used as the base, competing amination through a benzyne intermediate was observed. Thus, para meta regioselectivity was not high, and reaction yields were modest. 

The reaction of an aryl halide with potassium amide proceeds through a benzyne intermediate. Ammonia can then add to either end of the triple bond to produce the two methylanilines observed. 

Beller s palladacycle (12) catalyzes the arylation of N-methylaniline and di-n-butylamine with an activated aryl chloride, Eq. (48) [70]. As was observed in the reactions of cyclic amines, significant amounts of the regioisomeric product was formed, indicative of reaction through a benzyne intermediate. 

In the same way, 2-bromo-2 -hydrazino-diphenyl sulfide cyclizes to AT-amino-phenothiazine (also through a benzyne intermediate) (78JHC1137). Other syntheses of phenothiazine derivatives by an Ullmann-type cyclization were reported earlier (50JA888, 81JHC759, 57USP2769002). 

Synthesis Predictions. LHASA suggested that carbaryl could be synthesized by reaction of N-methylcarbamic acid witii either 1- or 2-chloronaphthalene in the presence of strong base. The literature reference that LHASA provided and associated with this route indicates that the reaction proceeds through a benzyne intermediate. LHASA failed to suggest the commercial route (68) that proceeds via... 

S. Dixon, X. Wang, K.S. Lamb, M.J. Kurth, Solid-phase synthesis of quinoxaline, thiazine, and oxazine analogs through a benzyne intermediate, Tetrahedron Lett. 46 (2005) 7443-7446. 

An intriguing approach to the synthesis of 1,2-diiodoarenes was proposed to proceed through a benzyne intermediate that was trapped by elemental iodine to generate a diiodo species (Scheme 7.94) [153]. The chemistry occurred under mild conditions, and moderate yields of the target compounds were obtained. The method appeared to be a general approach to these compounds, and the biggest limitation could be the availability of the substrates. 

A mixture of sodamide, bromoanisole, and l-methoxy-2-methyl-l-(trimethylsilyl-oxy)-l-butene were reacted at room temperature at a 50 millimolar scale. After some two horns, with slight emission of ammonia, the reaction suddenly became exothermic, with violent gas emission and on one occasion a fire. This was a modest scale-up of a literature procedure for synthesis of 2-alky lbenzoic acids, via a benzyne intermediate. It is advised that this reaction be employed only on smaller scale, with safety precautions. The reaction must pass through a benzocyclobutane intermediate, this, or another, high energy species might accumulate and then decompose. 

For the formation of indoles 2 and 3 we assumed that amines 1 first reacted with fBuLi at -110°C to give N-(2-lithioallyl)amines 4, through halogen-metal exchange 23 this was confirmed by deuteration and isolation of the deuteriated amine 5 a (Scheme 2). Intermediate 4, which is stable for several hours at —110 °C, probably undergoes proton-abstraction ortho to the fluorine atom by the additional equivalents of fBuLi when the temperature is raised to — 40 °C giving the intermediate 6. The subsequent elimination of LiF produces a benzyne intermediate 7, which is efficiently... 

In this context aryllithiums are also able to carbolithiate a benzyne moiety, and so we have also described the preparation of several phenantridine, dibenzopyran and diben-zothiopyran derivatives 383. In these cases y-functionalized organolithiums, derived from bromides 382, afford the corresponding and regiospecifically functionalized six-membered benzofused N-, O- or S-heterocycles through a 6-exo cyclization reaction onto a benzyne intermediate (Scheme 101)161b. 

Evidence supporting the bcnzyne mechanism has been obtained by studying the reaction between bromob izene and the strong base potassium amideCKNHj) in liquid NHn solvent. When bromobenzene labeled with radioactive at the Cl position is us, the substitution product has the label scrambled between Cl and 02. The reaction must therefore proceed through a symmetrical intermediate in which Cl and C2 are equivalent— a requiremer.r that only benzyne can meet. 

O-Phenylation of tertiary alcohols can be realized through reaction with pentaphenylbismuth (4), a benzyne intermediate being involved. r rf-Butyl phenyl ether (80) was also obtained in rather low yields in the reaction of triphenylbismuth diacetate with rerr-butyl alcohol used as solvent in the presence of potassium carbonate or by reaction of triphenylbismuth dichloride with lithium ten-... 

The C-labeling experiments of Roberts in 1953 put the existence of ortho-benzyne as an intermediate beyond doubt when it was found that treatment of 1-i C-chlorobenzene with potassium amide in liquid ammonia gave a 1 1 mixture of 1- and 2- C labeled aniline. The reaction had clearly proceeded through a symmetrical intermediate ortho-benzyne. The overall process whereby a nucleophile apparently enters ortho to the leaving group is referred to as cine substitution (Scheme 7.10). 

Special NAS reactions can take place without electron-withdrawing groups on the ring. These require extreme conditions and likely go through what is called a benzyne intermediate (explored further in the Exercises section of this ChemActivity). 

Halobenzenes undergo nucleophilic aromatic substitution through either of two mechanisms. If the halobenzene has a strongly electron-withdrawing substituent in the ortho or para position, substitution occurs by addition of a nucleophile to the ring, followed by elimination of halide from the intermediate anion. If the halobenzene is not activated by an electron-withdrawing substituent, substitution can occur by elimination of HX to give a benzyne, followed by addition of a nucleophile. 

After a new (and unusual) mechanism, such as the benzyne mechanism for nucleophilic aromatic substitution, is proposed, experiments are usually designed to test that mechanism. A classic experiment supporting the benzyne mechanism used a radioactive carbon label. Examination of the mechanism shown in Figure 17.6 shows that the carbon bonded to the leaving chlorine and the carbon ortho to it become equivalent in the benzyne intermediate. Consider what would happen if the carbon bonded to the chlorine were a radioactive isotope of carbon (l4C) rather than the normal isotope of carbon (I2C). If we follow the position of the radioactive carbon label through the mechanism of Figure 17.6, we find that the label should be equally distributed between the carbon attached to the amino group in the product and the carbon ortho to it. 

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