Cycloadditions of benzyne

There is some evidence for the formation of unstable benzazetidines from [2 + 2] cycloaddition of benzyne to imines (75BCJ1063). A novel formation of a benzazetidine is reported in the solvolysis of the exo iV-chloro compound (297). Neighbouring group participation by the benzene ring leads to the cation (298), which is intercepted by methanol to give the benzazetidine (299) (81CC1028). 

The 2+2 cycloadditions of benzyne to cis- and trani-propenyl ether gave cis- and fran -benzocyclobntanes as the main products, respectively [ 117,118], Stereospecific [2+2] cycloaddition reactions were observed between the benzyne species generated by the halogen-Uthium exchange reaction of ort/io-haloaryl triflates and the ketene silyl acetals (Scheme 23) [119],... 

Cycloaddition of benzyne intermediates with aminothiazadienes provide access to substituted 2,4-diamino-4//-l,3-benzothiazines 196 in high yields. The benzynes are prepared by the treatment of (phenyl)[o-(trimethylsilyl)aryl]-iodonium triflates with 1.5 equiv of tetrabutylammonium fluoride (Scheme 20). Interestingly, 3-substituted-l,2-benzisothiazoles 197 are obtained when 4 equiv of tetrabutylammonium fluoride is used <2005H(65)1615>. 

Incidentally, a 1,3-cycloaddition of benzyne to thiophene has been postulated (81CC124) to account for the small, but reproducible amount of benzo[ >]thiophene formed in this reaction (Scheme 79). Reactive alkynes have been successfully used as dienophiles to cycloadd with thiophenes benzene derivatives are obtained after extrusion of sulfur from the adduct (Scheme 80) (72TL605, 72TL1909, 73CB674). 

The AuCl-catalysed 4 + 2-cycloaddition of benzyne with o-alkynyl(oxo)benzenes produced anthracene derivatives having a ketone in the 9-position, in good to high yields under mild conditions.118 Hypervalent iodine compounds, [5-acyl-2-(trimethyl-silyl)]iodonium triflates, readily yielded acylbenzynes which could be trapped with furan.119 Both DMAD and benzyne reacted with borabenzene to yield substituted borabarrelenes and borabenzobarrelenes, respectively.120... 

A DFT study of the 2 + 2/4 + 2-cycloaddition of benzyne with thiophene to produce 1-naphthyl- and 2-naphthyl phenyl sulfides led to a modification of the originally proposed reaction pathway.1 The reaction of an E-Z mixture of 7-benzylidenecycloocta-1,3,5-triene (1) with TCNE yields a mixture of 2 + 2- [(2) and (3)], 4 + 2- [(4) and (5)], and 8 + 2- (6) cycloadducts. The presence of pentadienyl and homotropylium zwitterions accounts for the products isolated (Scheme l).2... 

A report of 2 + 2- and 4 + 2-cycloadditions of benzyne and thiophene provides several reaction paths to account for the 1-naphthyl and 2-naphthyl phenyl sulfide products. A DFT study of these paths shows that some presumed reaction intermediates are not stable entities. A new reaction path adapting a portion of the literature paths but with a lower activation free energy, is described.2 The 4 + 2 path crosses over from (5) and joins the 2 + 2 path with structure (6). The paths appear to proceed by both 2 + 2 and 2 + 4-additions with equal facility. 

Cyclobutanefullerenes (four-membered rings fused to 6,6 junctions) are typically formed upon [2+2] cycloadditions. Basically these types of cycloadditions are less common, with the first reported example being the thermal [2+2] cycloaddition of benzyne to C60 [49,50]. 

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>. 

The [2+2] cycloaddition of benzyne 61 to substituted thiophenes (Equation 3) is a general method to trap such reactive intermediates. Usually, the adducts 62 are postulated rearrangement and addition of a second equivalent of benzyne gives 1- and/or 2-substituted naphthyl sulfides 63 <2003JOC70, 2005JP0477>. 

PjTToles have also been subjected to [4 + 2] cycloadditions of benzynes. A(-Trimethylsilylpynole (512) is particularly suitable for such additions subsequent mild desilylation furnished 1,4- hydronaphthalen-1,4-imines, e.g. (514), in yields ranging from 30 to 53% (Scheme 120). ... 

Cycloaddition of benzyne (478) to (the less aromatic) anthracene provides a well-known approach to triptycene (524). More recently, this type of reaction was extended to elegant syntheses of iptycenes, e.g. (526), using 1,2,4,5-tetrabromobenzene (525) as a 1,4-benzadiyne equivalent (Scheme 123). ... 

The tetrakis(methylidene)-7-oxabicyclo[2.2.1]heptane (527) offers an interesting route to linear poly-annulated ring systems, e.g. 4Klemethoxydaunomycinone (641), via a sequence of two Diels-Alder reactions (Scheme 124). Monoadduct (528) could be isolated and subjected to the [4 + 2] cycloaddition of benzyne. An alternative synthesis of anthracyclinone analogs starts with the Diels-Alder addition of 3-methoxybenzyne to a derivative of the bis-cisoid tetraene (527). ... 

A synthetic approach to the class of tq)oriAine alkaloids centers on [4 + 2] cycloadditions of benzynes to the cisoid 1,3-diene (531), which contains one double bond as part of a benzene ring (Scheme 125). 2 ... 

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>. 

The aforementioned cycloaddition of benzyne to 1,2,5-selenadiazole followed by extrusion of selenium, although of no synthetic value, is another example of ring transformation to isoselenazole (Scheme 28). 

If you see a new six-membered ring containing two new bonds with a 1,3-relationship and a 77 bond, think Diels-Alder A six-membered ring fused to a benzene ring is often made by the [4 + 2] cycloaddition of an o-xylylene and a dienophile or by a [4 + 2] cycloaddition of benzyne and a 1,3-diene. 

Dipolar cycloaddition reactions lead to heterocyclic products, but our concern will be only with those in which a hetero-ring is already present in reactions involving benzyne. Heterocyclic (V-oxides (Section IX) and meso-ionic heterocycles (Section VI, B) provide most examples of this type, although there are some cases of apparent 1,3-cycloaddition of benzyne to heterocycles in which no formal 1,3-dipole is identifiable. 

Cycloaddition of benzyne and of tetrahalogenobenzynes also occurs with simple monocyclic benzenoid compounds, and at higher temperatures (e.g., if benzyne is generated from phthalic anhydride) adducts such as 24 may rearomatize by elimination of acetylene. 1,4-Cycloadducts of benzyne and heterocyclic substrates are sometimes isolable, but frequently they too react further by a variety of pathways to give secondary products (Sections V, VI, and VII). 

Cycloaddition of benzyne occurs in two cases of homo-Diels-Alder additions (e.g., to norbomadiene) reported in Ref. 1. 

A 1,6-cycloaddition was wrongly claimed to occur with benzyne and cyclo-heptatriene. The structure of the cycloadduct is reliably established as 25, and the isomer 26 derived from an ene reaction was also obtained.32 1,8-Cycloaddition of benzyne occurs with 8-cyanoheptafulvene (27) to give 28.3 3 It is clearly possible to envisage similar reactions occurring with heterocyclic compounds, although none has yet been reported. 

Diphenyl-l-azirine (29) and benzyne yield the 1 1 adduct 31 (50%) and 1 2 adduct 32 (14%).34 The formation of these indoles can be explained by assuming 1,2-cycloaddition of benzyne, reorganization of the strained intermediate 30, and some N-phenylation of 31 by further reaction with benzyne. 

Cycloaddition of benzyne to 3-diazooxindole (99) led, via rearrangement of the spiro adduct 100, to the condensed indazole derivative 101 (91%), the structure of which was confirmed by an independent synthesis.76... 

Benzo[c]cinnoline (114) (3%) was separated from a complex mixture of colored products obtained from the oxidation of 9 with active manganese dioxide formation of 114 suggests the stepwise loss of nitrogen, 10- 113-+ 1, and 1,4-dipolar cycloaddition of benzyne to 113.16 Oxidation of 9 with (diacetoxyiodo)benzene gave azobenzene (4%), 1-phenylbenzotriazole (112)... 

Pacquer et al. also recognized a second series of intensely colored 1 1 adducts, the trithiapentalenes 153, from benzyne and 5-aryl-l,2-dithiole-3-thiones (151).93 Although very little of 153 (Ar = Ph) was obtained (< 1%), p-anisyl, p-tolyl, and p-chlorophenyl compounds were formed in higher yields. Unsuccessful attempts to achieve the conversion 152 - 153 render more likely an independent pathway for the formation of 153, e.g., one involving an initial 1,2-cycloaddition of benzyne to the exocyclic C=S bond of 151. Derivatives of the related l,2,4-dithiazole-3-thione system 160 and benzyne also afford two series of 1 1 adducts 161 and 162 corresponding to 152 and 153, respectively.93... 

The latter pathway is relatively disfavored, as the requisite diene system includes a terminal nitrogen atom. The enthalpy term for the rearomatization of the intermediate adduct (166) will favor extrusion of hydrogen cyanide rather than acetylene, so that isoquinoline is formed in only trace amounts, if at all. Fields and Meyerson also consider mechanisms involving 1,2-cycloaddition of benzyne to pyridine to account for formation of the same... 

Hydroxypyridine (201) itself possesses latent 1,3-dipolar character because of tautomerism involving 1-protiopyridinium 3-oxide (202). Aprotic diazotization of anthranilic acid in the presence of 201 gives two heterocyclic products [196 (20%) and 203 (23%)] which were isolated in separate experiments run under almost identical conditions.103,105 Formation of the bis-adduct 196 must involve cycloaddition of benzyne to 202 and N-phenylation and there is some evidence from related additions to 2//-phthalazin-1 -one (208) that the steps occur in this order.3 7b Formation of the isocoumarin structure 203 apparently involves electrophilic substitution of 201 by the benzyne precursor 5, followed by lactonization. From 3-hydroxy-6-methylpyridine compounds analogous to 196 and 203 were also obtained (10 and 29%, respectively). 3-Hydroxyquinoline afforded only the corresponding isocoumarin 204 (20%) whereas 4-hydroxyisoquinoline gave 4-phenoxyisoquinoline (12%) and the bis-adduct 205 (12%) with benzyne.103,105... 

Decomposition of 4 in the presence of l,3,4-oxadiazin-6-one 4-oxides, 267 (R = Me, Et, Ph), leads to the formation of benzofurans 272, benzofuranones 273, and the cyclic anhydrides 271, all of which can be rationalized in terms of an initial 1,3-cycloaddition of benzyne to 267, 1,3-sigmatropic rearrangement of 268 - 269, and subsequent decomposition steps as outlined in Scheme 26.120 Formation of 271 requires a cycloaddition of the benzyne precursor 5 to the ketene intermediate 270, which is supported by the observation of a similar capture of 5 by diphenylketene. 

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