Arynes electrophilicity

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. 

Arynes are intermediates in certain reactions of aromatic compounds, especially in some nucleophilic substitution reactions. They are generated by abstraction of atoms or atomic groups from adjacent positions in the nucleus and react as strong electrophiles and as dienophiles in fast addition reactions. An example of a reaction occurring via an aryne is the amination of o-chlorotoluene (1) with potassium amide in liquid ammonia. According to the mechanism given, the intermediate 3-methylbenzyne (2) is first formed and subsequent addition of ammonia to the triple bond yields o-amino-toluene (3) and m-aminotoluene (4). It was found that partial rearrangement of the ortho to the meta isomer actually occurs. 

The chemistry of dehydrobenzene, the parent aryne, has become well established during the past almost twenty years 4>. It is essentially the chemistry of a short lived (half-life ca. 10-4 sec.), and highly electrophilic intermediate. It reacts with a large number of nucleophiles, and undergoes cyclo-addition reactions with a wide variety of compounds. A number of observations have led us, and others, to concentrate our efforts on the tetrahalogenobenzynes. It seemed reasonable to predict that the presence of four electron withdrawing substituents on the aryne (1) would result in a significant increase in the electrophilicity compared with that of benzyne. 

Overlap between these orbitals will, on spatial grounds, be very poor, and the resultant bonding correspondingly weak arynes are thus likely to be highly reactive towards nucleophiles (and electrophiles), though they are found not to be entirely unselective in this. 

The group R1 can be allyl, acyl, or alkynyl, and arynes can also act as the acceptors. The catalysts are usually Ni(cod)2, or ligated palladium. The mechanisms are not understood in detail, but a catalytic cycle involving the product of oxidative addition, Sn-M-R1, is thought to be involved. The stannylalkenes that are formed can then be subjected to reaction with electrophiles (e.g., AczO or RCH=0), or to coupling reactions in the presence of transition metals (e.g., the Stille reaction). 

The reactive zwitterions arising from the nucleophilic attack of imines 479 on the benzyne generated in situ from 2-(trimethylsilyl)phenyl triflate 478 proved to be an appropriate molecular scaffold for the capture of CO2 with sufficient electrophilicity to yield 2-aryl-3,l-benzoxazin+-ones 480 (Equation 53). Both substituents of the C=N bond affected the course of the reaction considerably the best yields were achieved by using imines with electron-rich or neutral aryl groups on the carbon, and benzyl or nonbranched chain alkyl substituents on the nitrogen atom. With substituted derivatives of 478, the unsymmetrically substituted arynes led to regioisomeric products <2006JA9308>. 

Dry diazodicyanoimidazole is highly explosive, however one can work safely with its solutions. When heated to 80°C in solution, 26 loses nitrogen, generating a highly electrophilic intermediate (Scheme 12) (73JA2695). Its chemical characteristics more resemble carbonium ions than aryne or carbodiimide. 

Most of the reports in the literature discuss electrophilic substitution of 1,3,6-triazacycl[3.3.3]azine (80) and the 2-methyl, 4-cyano and 4-ethoxycarbonyl derivatives. Electrophilic bromination occurs preferentially at the 4-position (if available), and subsequently at the 9- and 7-positions. These data support the electron charge density calculations (see Section 2.20.2) (73ACS3264). Nitrations are carried out using copper(II) nitrate and acetic anhydride. The central nitrogen is completely non-basic, and in the triazacycl-azines protonation occurs initially at position 6 (80) (77ACS(B)239). Ceder and Vernmark have reported that piperidine reacts with (81) via the aryne intermediate the A-E cine-substitution mechanism is an attractive alternative (equation 40). 

If the moeity adding to the aryne carries a suitably placed electrophilic center, cyclization with the initially formed anion can occur as observed in the synthesis of dibenzothiophene (60).92 Of wider synthetic import in this context is enolate addition to arynes. Here, after the initial ring closure many types of products can be formed (Scheme ll).35 However, with some substrates, a particular reaction course can predominate 93 94 for example, reaction of cyclodecanone with bromobenzene provides an efficient method for benzo-annulation and ring expansion. Similarly, high yields of benzocyclobutenols can be obtained from the monoketals of ot-diketones.9s... 

Ethers do not exhibit marked nucleophilicity towards arynes but readily enter into reaction with more electrophilic halogenated analogs like (121). In the betaine derived from (121) and ethyl ether, a proton... 

Methyl thiosalicylate provides both electrophilic and nucleophilic sites for annulation of arynes generated from silylaryl triflates in the presence of CsF. An initial intermolecular nucleophilic coupling to afford a diaryl sulfide 529 is followed by an intramolecular electrophilic cyclization and thioxanthones result. The use of THF as solvent suppresses the competitive proton abstraction which leads to methyl 2-thiophenoxybenzoate (Scheme 211) <2005OL4273>. 

Zirconium-benzyne complexes have been used rather extensively in organic synthesis.8 45 For this purpose, one particularly important characteristic of zirconium-aryne complexes is that olefin insertion into the Zr—C bond occurs stereospecifically. Thus, when generated in situ, the zirconium-benzyne complex (45) reacts with cyclic alkenes to give exclusively the cis-zirconaindanes (46), which upon treatment with electrophiles provide access to a variety of m-difunctionalized cycloalkanes (47-49) (Scheme 5).46 For example, carbonylation of intermediate 46 affords tricyclic ketone 49, reaction with sulfur dichloride gives thiophene 48, and reaction of 46 with tert-butylisocyanide followed by I2 gives 47 via 50 and, presumably, intermediate 51 [Eq. (12)]. 

Four-membered carbocyclic ring systems are commonly formed by cycloaddition of electrophilic alkenes, ketenes and arynes to enamines. Since cycloaddition reactions of enamines are dealt with in Chapter 18 these reactions will only be mentioned briefly here. 

While not formal carbanions, arynes have been found to react with electrophilic centers. The first report of an aryne reacting with an epoxide has been published. While the yield of this reaction is not good, it suggests that this could be a viable route for the synthesis of benzofused heterocyclic ring systems <07SL1308>. 

Both xanthones and thioxanthones are available through CsF-promoted coupling of arynes with salicylates and thiosalicylates. The synthesis proceeds through sequential intermolecular nucleophilic substitution and intramolecular electrophilic cyclisation (Scheme 39) <07JOC583>. The Pd-catalysed annulation of 3-iodoflavone with the same triflate results in the dibenzo[a,c]xanthone (Scheme 39) <07JOC223>. 

In spite of their high total energy, arynes in general are selective towards different nucleophiles thus benzyne selectively captures the anion of acetonitrile in the presence of an excess of the dimethylamide ion used to generate both it and the benzyne. Nucleophilicity towards benzyne, determined by competition experiments, is in the order RLi RS- > R2N RO and I- > Br > Cl, which is an order of softness. The low energy of the LUMO of benzyne, coupled with its being uncharged, makes it a soft electrophile. 

Coupling of 2,3-dihydrofuran with alkene-zirconocene <2004AGE3932> or aryne-zirconocene <2005SL2513> complexes and subsequent addition of an electrophile provided rA-disubstituted homoallylic alcohols, as illustrated in Equation (130). An insertion//3-elimination pathway that involved the formation of an oxazirconacyclooctene intermediate was proposed for the reaction mechanism. 

Polyfluoroaryl-lithiums and, to a lesser extent, the Grignard reagents will decompose by a (3-elimination of metal fluoride, leaving an aryne whose properties are considerably affected by the remaining fluorine atoms. The highly electrophilic nature of these species leads to some reactions, e.g. with benzene derivatives, that are not shown by benzyne itself [228] (Figure 9.88). 

The aryne intermediate is usually written with a triple bond and a delocalized aromatic system, as shown in 3-44. The anion in the side chain reacts as a nucleophile with the electrophilic aryne. The resulting anion, 3-45, can remove a proton from ammonia to give 3-46. Because the product has been reached, we usually stop writing the reaction mechanism at this point. However, in the reaction mixture, amide will remove a proton from the carbon a to the cyano group of 3-46. Only during workup will the anion be protonated to give back 3-46. 

An aryne intermediate is unlikely to react as a nucleophile. Because of the high 5 character in the orbitals forming the third bond, arynes tend to be electrophilic, not nucleophilic. 

Substituted benzoMisothiazole d, d -dioxides 498 were synthesized through lithiation of 497 (X = H, F, Cl), aryne-mediated cyclization giving intermediates like 53a and subsequent quenching of aryllithium intermediates with various electrophiles (see Section 4.05.4.5) <1997T3615>. 

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