Benzyne generation from

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... 

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). 

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>. 

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. 

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). 

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 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... 

Diazo compounds have also been used as precursors in the preparation of pyrazoles and indazoles. The copper-promoted cycloaddition reaction of lithium acetylides 18 with diazocarbonyl compounds 19 provided a direct and efficient approach to the synthesis of pyrazoles 20 <07AG(I)3242>. A facile, efficient, and general method for the synthesis of 1-arylated indazoles 22 and A-unsubstituted indazoles 23 by the 1,3-dipolar cycloaddition of benzynes, generated from 21, with diazomethane derivatives has been reported <07AG(I)3323>. Reaction of diazo(trimethylsilyl)methylmagnesium bromide with aldehydes or ketones gave 2-diazo-2-(trimethylsilyl)ethanols, which were applied to the synthesis of di- and trisubstituted pyrazoles via [3+2] cycloaddition reaction with ethyl propiolate or dimethyl acetylenedicarboxylate <07S3371>. 

Dibromopyrrole 1084 (R = Br) and benzyne generated from anthranilic acid and isoamyl nitrile gave dibromo-derivative 1086, the metallation of which led to product 1087 (Scheme 211) <20050L1003>, which was later successfully used in a cyclotrimerization reaction. 

Naphthalene oxides. The Diels-Alder reaction of 1,4-diacetoxybutadiene (1) with benzyne (generated from o-benzenediazonium carboxylate, 1, 46) gives the diacetate of l,4-dihydronaphthalene-cis-l,4-diol (2) in 53% yield. The product is converted into 3 by reaction with hydrogen peroxide and catalytic amounts of osmium tetroxide. The monotosylate of 3 is converted into 4 by treatment with base. This epoxy diol has the stereochemistry found in the carcinogenic epoxy diols formed as metabolites of aromatic hydrocarbons. The dimesylate of 3 is converted into the syft-diepoxide 5. 

Arylideneoxazolones 139a behaved as imines in [2+2] cycloaddition with benzyne, generated from benzenediazonium carboxylate, to afford mainly benzoxazepine-2-ones 144, through ring-opening of the cycloadduct 143, followed by water addition <03T6067>. 

An unusual 1,3-cycloaddition of benzyne across a C=N-Se grouping in a 1,2,5-selenadiazole leads to the formation of the isoselenazole ring. The benzyne, generated from anthranilic acid, reacts with 3,4-diphenylselenadiazole 81 to afford 3-phenylbenzisoselenazole 82 as confirmed by mass spectrometry and the detection of benzonitrile, but the reaction has no practical synthetic value (Scheme 28) <1988J(P1)2141>. 

Benzo-fused isoquinuclidines have been synthesized via benzyne (generated from anthranilic acid) addition to the appropriate N-substituted-A -alkyl-2-pyridones to produce benzomorphan-type analgesics (e.g., 28a,b) [28,78]. 

Prepared by the method of Dilthey, the reagent is more efficient than tetraphenyl-cyclopentadienone as a reagent for trapping benzyne generated from diphenyl-iodonium carboxylate. In experiments with equimolar quantities of reactants, the yields of tetraarylnaphthalenes isolated by chromatography were 19 and 57%, respectively. 

Reaction with benzyne. Benzyne generated from diazotized anthranilic acid reacts with phenylacetylene to give the two hydrocarbons formulated. Surprisingly, it reacts with ethoxyacetylene to form 2-ethoxyphenylacetylene. 

Wittig found phenyl azide useful also as a reagent for trapping benzyne generated from a new precursor prepared from sodium o-aminobenzenesulfinate. A solution of this salt and sodium nitrite in the least amount of water was stirred at —15° and... 

Reaction of (134) with benzyne, generated from o-fluorobromobenzene and n-butyllithium, gave... 

Acyclic dienes bearing Oppolzer s sultam auxiliary 261 have been utilized in the synthesis of functionalized 1,4-dihydronaphthalenes <05JA15028>. Cycloaddition of dienes 261 with benzynes, generated from 2(trimethylsilyl)phenyl triflate 263 using cesium fluoride, provides cycloadducts 263 with excellent diastereoselectivities. 

Intramolecular addition to benzyne generated from the Schiff base of aniline and... 

Aryne interconversion, involving the transfer to benzyne of two hydrogen atoms from adjacent positions of another aromatic compound, is apparently possible at high temperatures (see discussion of thiophen, Section V,B). 1,4-Abstraction of hydrogen atoms by benzyne is the most probable explanation of the aromatization of the Diels-Alder adducts of benzyne and some styrene derivatives under the relatively mild conditions used for benzyne generation from o-bromofluorobenzene or benzenediazonium-2-carboxylate (4) (Scheme 4).24... 

Benzoselenadiazole (128) behaves as a heterodiene toward dimethyl acetylenedicarboxylate, with which it gives the quinoxaline 124 and selenium. But 128 reacts differently with benzyne (generated from 4 or from 9) to give the 1,2-benzisoselenazole derivative 132 (88%) and a small amount of a cis,trans stereoisomer of 132.82 The analogous adduct 131 is obtained in lower yield from benzyne and 2,1,3-benzothiadiazole (127). The structure of these benzyne adducts is strikingly reminiscent of 135, which is obtained from a photochemical addition of dimethyl acetylenedicarboxylate to 126 via a nitrile oxide intermediate.84 However, for reasons given elsewhere,82 a nitrile selenide is unlikely to be an intermediate in the formation of 132, which is better explained by the mechanism outlined in Scheme 16. As in the case of thiophen (Section V,B), this is a 1,3-cycloaddition (in one or two steps) of benzyne to the heterocycle, enabled by the use of d orbitals on the sulfur or selenium atom. 

The earliest example is the addition of benzyne (generated from 4 or by diazotization of anthranilic acid in situ) to N-phenyl sydnone (3-phenyl-l,2,3-oxadiazolium 5-oxide, 138)88 spontaneous loss of carbon dioxide from the intermediate adduct 139 gives 2-phenylindazole (140). Later workers have obtained 140 in higher yield (73%) and the corresponding 2,3-disubstituted indazoles from two other sydnones using benzyne generated by oxidation... 

Benzyne (generated from 7 or from 9) also reacted with l,3-dithiolan-2-thione (163) to give l,3-benzodithiole-2-thione (164) (9-13%).92 Evidence for... 

The reaction of benzyne with pyridine has been studied only at 690°C (benzyne generated from phthalic anhydride).96 The main condensable products in order of decreasing abundance were naphthalene, phenyl-pyridines (three isomers), bipyridyls, and quinoline. It is necessary to consider two modes of 1,4-cycloaddition, followed by rearomatization, to account for the formation of naphthalene (Eq. 4) and quinoline (Eq. 5), respectively. 

Benzyne is also formed almost quantitatively on oxidation of l-aminobenzotriazole with NBS (2 equivalents) in the presence of tetracyclone, 1,2,3,4-tetraphenylnaphthalene is obtained in 88% yield. In the absence of a trap, o-dibromobenzene is obtained in 52% yield. No dimer is formed. Bromine is known to be an efficient scavenger of benzyne generated from this precursor.3... 

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