Benzyne: generation

This section describes the more important methods by which benzyne is generated for capture by heterocyclic compounds it is not a comprehensive account of all known routes to benzyne (for which see Refs. 1 and 2). The importance of a variety of precursors and conditions for benzyne generation is to provide compatibility with heterocyclic co-reactants having widely differing properties. 

The use of sodium amide or potassium amide in liquid ammonia with bromo- or chlorobenzene leads inevitably to the capture of benzyne by its reaction with ammonia. However, the utility of bromo- or chlorobenzene as a benzyne precursor is extended to ethereal solvent systems by employing the conjugate base of a hindered secondary amine (diisopropylamine, 2,2,6,6-tetramethylpiperidine) which can be formed in situ from the amine and alkyllithium. Alternatively, butyllithium itself is used with the halogeno-benzene, and pentafluorobenzene and butyllithium are the usual source of tetrafluorobenzyne. In all of these reactions the aryne is generated by decomposition of an o-halogenoaryl anion at temperatures below 0°C. 

The formation of benzyne via o-FC6H4MgBr from o-bromofluorobenzene and magnesium is closely related in mechanism to the base-induced eliminations, but the reaction conditions for the Grignard method (in refluxing tetrahydrofuran) are often more convenient. Benzyne is also produced from o-bromofluorobenzene and butyllithium, and hexachlorobenzene is the usual precursor for generation of tetrachlorobenzyne (Eq. 1). 

Elimination of Stable Molecules from o-Disubstituted Benzenes 

The triazene 6, also derived from anthranilic acid, is more stable than 4 and can safely be stored in quantity. Benzyne, carbon dioxide, and dimethylamine are formed by decomposition of 6 in chlorobenzene at reflux temperature, or in benzene at 80°C in the presence of trichloroacetic acid.13 Benzyne is also produced on pyrolysis of diphenyliodonium-2-carboxylate (7) in various solvents at 160-220°C.14 

Elimination of Stable Molecules FROM o-Disubstituted Benzenes 

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Benzyne, generated from diphenyliodonium 2-carboxyIate, reacts with various thiophenes by addition to the sulfur and /3-carbon to give, after loss of an acetylene moiety, benzo[Z)]thiophenes in low (<4%) yield (Scheme 52) (81CC124). 

In a sequence of cycloaddition and cycloreversion, 3-phenyl-l, 2,4-triazine 1-oxides react with benzyne, generated from 2-aminobenzoic acid (see Houben-Weyl, Vol. 5/2 b, p 622 ff), to give 2-phenyl-l, 3-benzoxazepines in moderate yield.419... 

Another surprising feature appears in the reactions of certain alkyl-benzenes with tetrabromo- and tetraiodo-benzyne generated by the aprotic diazotisation of the corresponding anthranilic acids S9K While only one product (41, X = Br or I, R = H or Me) was obtained in the reactions with benzene or -xylene, three products, (42, X = Br or I, R = Me, Pr1, or But), (43, X = Br or I, R = Me, Pr1, or But) and a naphthalene derivative a> were obtained in reactions with toluene, cumene (isopropylbenzene), and f-butylbenzene. 

Products derived from intermediate zwitter-ions have been obtained in the reactions of benzynes with tertiary amines 1>. Benzyne generated by the reaction of -butyl-lithium with fluorobenzene interacts with AT.Af-dimethylaniline to yield iV-methyl diphenylamine and AT-ethyl diphenylamine 132,133). Using the reaction of chlorobenzene with n-butyl-lithium to generate benzyne resulted in the formation of increased amounts of 2-A7,AT-dimethylaminobiphenyl 132,133)... 

It is known that benzenediazonium-2-carboxylate decomposes to give benzyne via the zwitter-ion (128) 161>. We therefore checked that benzyne is involved in our reactions by carrying out reactions with cinnamaldehyde using benzyne generated from benzothiadiazole-1,1-dioxide 162), diphenyhodonium-2-carboxylate i 3,164)( weil as fr0m anthranilic acid165). Flavene was isolated from each reaction and hence our reactions do involve aiynes and are not arynoid 13 8). 

The [2+4] cycloaddition proceeds with retention of dienophile configuration, as was clearly demonstrated by carrying out the reaction with /ra .r-l, 2-dicyanocthync leading to 148 (Scheme 58). When benzyne generated in situ was utilized, reactions gave rise to 1-borabenzobarrelene derivatives 149 and 150 (Scheme 59). 

Benzyne generated in situ by diazotization of anthranilic acid adds readily to aminides 172 to provide cycloadducts 171. Introduction of a nitro group into para position of the phenyl ring on the nitrogen terminus of the 1,3-dipole (X2 = N02) stabilizes the system and results in higher yields of product 171 (70% vs. 50% forX2 = H). Electron-deficient imines react also with aminides 172, but the yields of isolated adducts 173 are relatively low (10-26%) (Scheme 19) <2003ARK(vii)110>. 

Benzocyclobutenone was first prepared from 1 -bromobenzocyclobutene by hydrolysis followed by chromium trioxide oxidation.3 More recent procedures involve hydrolysis of 1,1-dichloro- or 1,1-dimethoxybenzocyclobutene which in turn have been obtained through cycloaddition of the appropriate 1,1-disubstituted ethylenes to benzyne generated either from anthranilic acid through diazotization5 6 or from bromobenzene through sodium amide treatment.7.3 Benzocyclobutenone has... 

Benzyne generated from 2-carboxybenzenediazonium chloride reacted with sulfur monochloiide to give dibenzothiophene 13 (8-10%) and thiantherene 14 (26-35%) (1989SUL83). A mechanism involving the addition of sulfur mono-chloride to benzyne with the formation of betaine 15 followed by the elimination of SCI2 to afford benzothiirene 16 and a further reaction with another benzyne molecule or dimerization to thianthrene 14 is given in Scheme 8. 

Various 1-(1-naphthyl)-1,2,3-triazoles with electron-withdrawing groups at the 4- and/or 5-pos-itions (e.g. (135)) are synthesized from 1-azidonaphthalene and alkynes <87JCS(P1)413>. l-(Naphthyl)-benzotriazoles (127) are prepared by cycloaddition of the appropriate 1-azidonaphthalenes to benzyne or substituted benzynes, generated from 3-methylanthranilic acid. l-(l-Naphthyl)-naphthotriazole is similarly prepared by cycloaddition to 2,3-dihydronaphthalene. 1,3-Dipolar cycloadditions of 8-azidoquinolinone with benzyne and DMAD give benzotriazoles and triazoles (e.g., (130)), respectively <87JCS(Pi)403>. 

Benzotriazole and its derivatives are usually obtained by diazotization of o-phenylenediamines as discussed in Section 4.01.8.3 and in CHEC-1 <84CHEC-i(5)722>. Substituted o-phenylenediamines (e.g., 849) similarly give 1-substituted benzotriazoles (850) upon treatment with NaNOz (Equation (87)) <92JHC1519>. 1-Arylbenzotriazoles are alternatively synthesized from the cycloaddition of an aryl azide to benzyne or substituted benzynes, generated from the diazotization of anthranilic acid or its appropriately substituted derivatives (Scheme 169) <86CC399,87JCS(Pl)403, CHEC-i>. 

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>. 

Benzyne, generated in situ from anthranilic acid, has been successfully used as a dipolarophile in reaction with triazolium-l-aminides 170a and 170b. The reactions carried out in refluxing dimethoxyethane over 25 min produced indolo-1,2,3-triazoles 171a and 171b, respectively (Equation 32) <2003ARK110>. 

Photoexciting 1,4-dibromobenzene in a molecular beam with 307-nm pump pulse photons leads to sequential loss of both bromine atoms within 100 fs the excited dibromide has a lifetime of 50 fs and the monobromide of 80 fs. The p-benzyne generated decays relatively slowly, showing a lifetime of 400 ps. It presumably leads to (Z)-3-hexene-l,5-diyne through a valence isomerization of the sort associated with the Bergman rearrangement. 

Intramolecular addition to benzyne generated from the Schiff base of aniline and o-chlorobenzaldehyde is thought to involve addition of an amide anion to the C=N bond [163]. This mechanism indicates donor accentuation of the ortho carbon. 

Diels-Alder reactions of oxazoles afford useful syntheses of pyridines (Scheme 53) (74AHC( 17)99). A study of the effect of substituents on the Diels-Alder reactivity of oxazoles has indicated that rates decrease with the following substituents alkoxy > alkyl > acyl >> phenyl. The failure of 2- and 5-phenyl-substituted oxazoles to react with heterodienophiles is probably due to steric crowding. In certain cases, bicyclic adducts of type (359) have been isolated and even studied by an X-ray method (87BCJ432) they can also decompose to yield furans (Scheme 54). With benzyne, generated at 0°C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, oxazoles form cycloadducts (e.g. 360) in essentially quantitative yield (90JOC929). They can be handled at room temperature and are decomposed at elevated temperatures to isobenzofuran. 

The first successful Diels-Alder addition of thiophene appears to have been with tetrafluorobenzyne (66CC143). The adduct apparently loses sulfur, resulting in the isolation of the tetrafluoronaphthalene in 40% yield (Scheme 78). Other thiophene derivatives (69T25) and fluorinated benzynes <71JCS(C)604) have been similarly reacted. Subsequently it was found (80H 14)647) that unsubstituted benzyne, generated from diphenyliodonium-2-carboxylate, could be trapped with thiophene to form naphthalene in 33% yield. The earlier failure to add thiophene to benzyne generated by other methods must have been due to intervention of side reactions. Thiophyne also has been similarly trapped to yield benzo[A]thiophene (see Section 3.14.2.2). 

There has been a summary of the use of insertion reactions of arynes into a-bonds to prepare nrt/io-disubs tituted arenes. A key to the success of these processes is the ability to generate benzyne under mild conditions by the reaction of readily available o-(trimethylsilyl)phenyl triflate with fluoride ions.61 Reaction of amines and their derivatives with benzynes generated in this way has been shown to be an efficient method for the production of N-arylated derivatives, as illustrated in Scheme 8. The method also works well in the O-arylation reactions of phenols and carboxylic acids 62... 

The formation of 1,2,3-benzotrithiole with very low yield (1.3%) was detected by gas chromatography-mass spectrometry (GC/MS) in a mixture of other polysulfides produced by the reaction of elemental sulfur with benzyne generated either by treatment of o-(X>(, 111 with BuLi in Et20 at —60 °C, or by decomposition of benzenediazonium-... 

Phenanthridinones.1 Benzyne, generated in situ by Pb(OAc)4 oxidation of 1-aminobenzotriazole (l),2 undergoes [4 + 2]cycloaddition to cyclic vinyl isocyanates to form phenanthridinones. 

Okuma et al. <1998CL79, 2000BCJ155, 1999J(P 1)2997, 2005H(65)1553> published a series of papers describing reactions of various thioketones with benzyne generated from 2-trimethylsilylphenyl trifluoromethanesulfonate 96, phenyl[2-(trimethylsilyl)-phenyl]iodonium trifluoromethanesulfonate 97, or benzenediazonium-2-carboxylate 98, which led to the formation of benzothietes. Compounds 96-98 are good precursors of benzyne, but not in the... 

Benzynes generated from silylaryl triflates 803 react with ortho-hydroxy benzoates via a tandem nucleophilic coupling-electrophilic cyclization process to afford xanthones in good yield (Scheme 224) <2005OL4273>. 

Benzyne generated at room temperature from phenyl[2-(trimethylsilyl)phenyl]iodonium trifluoromethanesulfo-nate has been trapped in a [4+2] cycloaddition reaction with diarylthiones. The initial product, a 6-aryl-477 dibenzo[, r/]thiopyran, is accompanied by 6-aryl-67/-dibenzo[, r/]thiopyran arising by 1,3-prototropic aromatization of the cycloadduct (Equation 114). The use of sterically congested thiones, such as thiopivalophenones, results in competition from a [2+2] cycloaddition and 2/7-benzo[A]thietes are the sole products <2000BCJ155>. 

Benzyne generated from 2-iodophenyl 4-chlorobenzenesulfonate by treatment with tropropyl magnesium chloride at low temperature adds to the magnesium thiolate derived from thiosalicylic acid 530 to form thioxanthone. The carboxyl function behaves as an electrophile towards the intermediate aryl magnesium species and an intramolecular cyclization ensues (Scheme 212) <2005AGE4258>. 

The reaction of the sodium derivative of methylpyrazine with alkyl halides in liquid ammonia gives good yields (44-81%) of mono-alkylated products phenylation has been achieved by reaction with benzyne (generated from bromobenzene and sodamide in liquid ammonia) and gives 53% benzylpyrazine.178 The alkylation of the sodio derivative of 2-methoxy-3-methylpyrazine with methyl iodide, and of the product with ethyl bromide, gives 2-methoxy-3-sec-butylpyrazine (25) a constituent of galbanum oil.31... 

Benzyne, generated either by oxidation of 1-aminobenzotriazole with lead tetraacetate or by decomposition of benzenediazonium-2-carboxylate, was efficiently trapped by (2) to give 88% of the 1,2-benzisoselenazole (26) however, it was trapped in only 5-10% yield by (1). The series of adducts analogous to (26), prepared from benzyne and substituted benzoselenadiazoles (81JCS(P1)607), occurred via attack of the benzyne at the selenium atom followed by reorganization of the intermediate according to Scheme 6. Benzyne addition to dimethylthiadiazole produced methyl derivatives of quinoline and 1,2-benzisothiazole (82CC299). 

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