Benzocyclobutene, cycloaddition reactions

Benzocyclobutene, when generated by oxidation of its iron tricarbonyl complex, can function as the dipolarophile in 1,3-dipolar cycloaddition reactions with arylnitrile oxides (Scheme 113).177 Unfortunately the synthetic versatility of this type of process is limited because of the unreactivity of other 1,3-dipolar species such as phenyl azide, benzonitrile N-phenylimide, and a-(p-tolyl)benzylidenamine N-oxide.177... 

Malacria and coworkers346 prepared phyllocladane and kaurane types of diterpenes by means of [3 + 2]/[2 + 2 + 2]/[4 + 2] cascade reaction sequences. A representative example of such a reaction sequence has been outlined in equation 171. The five-membered ring of 598 was built by a 1,3-dipolar cycloaddition between 596 and an all-carbon 1,3-dipole generated from 597. The reaction of 598b with 568h afforded benzocyclobutene 599. The intramolecular [4 + 2] cycloaddition afforded diastereomers 600 and 601 in a 5 1 ratio. It is noteworthy that the exocyclic double bond in 598b neither participates in the [2 + 2 + 2] cycloaddition reaction nor isomerizes under the reaction conditions applied. 

From this work, the authors concluded that the reaction of two benzocyclobutene groups with each other is exothermic to the extent of 221.7 12.5 kJ. By comparison, the reaction of one mole of benzocyclobutene moieties with one mole of double bonds in a Diels-Alder fashion is exothermic by 184.1 12.5 kJ. Thus, the thermal dimerization of benzocyclobutenes is thermodynamically favored over the cycloaddition reaction of a benzocyclobutene with a double bond by about 37-38 kJ. By contrast, the authors found that for monomers that could react either by a benzocyclobutene dimerization or by a benzocyclobutene - double bond cycioaddition (e.g. monomer 13 in Table 3) the reaction products appeared to be dominated by the cycioaddition pathway. From this data, it was concluded that the Diels-Alder reaction was kinetically... 

In the presence of very reactive dienes, such as o-quinodimethanes, even electron-rich dienophiles, such as oxime ethers, can be reacted, as exemplified in Ae intramolecular cycloaddition of (143 Scheme 65), which is created in situ by an initial (2 + 2 -t- 2] cycloaddition reaction of (140) with (141) and subsequent electrocyclic ring opening of the resulting benzocyclobutene (142). This strategy has been applied recently to a novel isoquinoline synthesis. 

Scheme 2.11. Determination of the rate constants of the cycloaddition reaction of o-quinodimethane based on the product analysis depending on the delay time between the first 248-nm laser irradiation and second 308-nm laser irradiation. o-Quinodimethane was generated by the first 248-nm laser pulse irradiation. The cycloaddition reaction with maleic anhydride (path 1 with the rate constant of k ) and the dimerization (path 2 with the bulk rate constant of k2) were quenched by the photochemical conversion of o-quinodimethane into benzocyclobutene with the second 308-nm laser pulse irradiation.

Arynes react readily with simple alkenes to give either benzocyclobutenes or substituted benzenes (Scheme 7.31). The formation of benzocyclobutenes by [2+2] cycloaddition reaction of the aryne to the alkene proceeds best for strained and electron-rich carbon-carbon (C=C) double bonds. For example, dicyclopentadiene reacts to give the ex o-isomer of the corresponding four-membered ring in good yield. The addition to cyanoethene (acrylonitrile) and the reaction with the electron-rich ethoxyethene (ethyl vinyl ether) gives the cyano- and ethoxy-benzocyclobutenes in 20% and 40% yields, respectively. The latter reaction almost certainly involves nucleophilic addition of the enol ether to the electrophilic aryne followed by coUapse... 

Only a few facts about the chemical reactivity of the parent [6]radialene (5) are known - certainly because it is not easyto handle - but they reveal its character as a triple 1,3-diene system (catalytic hydrogenation, triple 1,4-addition of Br2, [4+2] cycloaddition reactions [5, 6]). Much more is known about the alkyl-substituted radialenes 113 and 72, in particular due to the detailed investigations of Hopf and coworkers [88]. Because of the presence of three hexa-2,4-diene subunits in the latter radialenes, it is not surprising that isomerization pathways via sigmat-ropic and electrocyclic reactions exist. Thus, in a gas-phase thermolysis of 113, products 125-129 were formed in relative yields that depended on the reaction temperature (e.g., 127 was the major product at 260 C and 129 at 360 °C). The mechanistic scenario includes the isomerization 113 125 by three consecutive 1,5-H shifts, and the sequence 127 128 129 [88]. The permethylated [6]radi-alene (72) is thermally much more stable than 113 the product mixture obtained from its pyrolysis at 350 "C was dominated by benzocyclobutene 130 (an analog of 127), which, however, could be isolated in only 17% yield [88] (Scheme 4.27). 

The reaction of an alicyclic enamine with benzyne intermediate yields simple arylation products and/or 1,2-cycloaddition products, depending upon the reaction conditions 102). This is illustrated by the reaction of l-(N-pyrrolidino)cyclohexene with benzyne (86) (obtained from fluoro-benzene and butyl lithium or o-bromofluorobenzene and lithium amalgam), which produces benzocyclobutene 87 102). 

For the synthesis of estradiol methyl ether 4-319, the cydobutene derivative 4-317 was heated to give the orthoquinonedimethane 4-318 which cydized in an intramolecular Diels-Alder reaction [109]. The thermally permitted, conrotatory elec-trocyclic ring-opening of benzocyclobutenes [110] with subsequent intramolecular cycloaddition also allowed the formation of numerous complex frameworks (Scheme 4.70). 

Malacria and coworkers [274] used an intermolecular trimerization of alkynes to gain efficient access to the skeleton of the phyllocladane family. Thus, the Co-cata-lyzed reaction of the polyunsaturated precursor 6/4-4 gave 6/4-5 in 42% yield. Here, six new carbon-carbon bonds and four stereogenic centers are formed. The first step is formation of the cyclopentane derivative 6/4-6 by a Co-catalyzed Conia-ene-type reaction [275] which, on addition o f his( Iri me ill y I si ly 1) e thy ne (btmse), led to the benzocyclobutenes 6/4-7 (Scheme 6/4.2). The reaction is terminated by the addition of dppe and heating to reflux in decane to give the desired products 6/4-5 by an electrocyclic ring opening, followed by [4+2] cycloaddition. 

Replacing the hydrogen in 68 with a phenyl group leads to the secondary acetylenic monomer 70. It was believed that this disubstituted acetylene would suppress the reaction of acetylene with itself and insure that there was an acetylene functionality available for reaction with the o-quinodimethane at 200 °G The DSC of 68 showed the presence of a single exothermic peak at 263 °C which the authors felt was adequate evidence for the occurrence of a Diels-Alder reaction between the acetylene and benzocyclobutene. Unfortunately they did not report on any control experiments such as that between diphenylacetylene and simple benzocyclobutene hydrocarbon or a monofunctional benzocyclobutene in order to isolate the low molecular weight cycloaddition product for subsequent characterization. The resulting homopolymer of 68 had a Tg of 274 °C and also had the best thermooxidative stability of all of the acetylenic benzocyclobutenes studied (84% weight retention after 200 h at 343 °C in air). 

Many metal-catalyzed reactions are accelerated by light irradiation [88], In the case of the Vollhardt reaction [89], which is performed with conveniently available Co catalysts, the irradiation with visible light is included in the standard conditions. In a triple [2 + 2 + 2] cycloaddition, the nonaalkyne derivative 86 is transformed into the [7]Phenylene 87 (Scheme 5.17) [90]. Compound 87, containing six benzo-cyclobutene moieties, is a partial structure of the archimedene C12o 88. In this way a variety of similar benzocyclobutene structures such as helical phenylenes [91] can be built up. 

The cobalt(I)-mediated [2 + 2 + 2] cycloaddition of 1,5-diynes with mono-alkynes provides access to benzocyclobutene derivatives (Scheme 24). Thermal rearrangement of benzocyclobutenes into o-quinodimethane and subsequent Diels-Alder reaction with an alkene moiety allow the formation of a tricyclic compound. 

As depicted in Scheme 41, an intramolecular cycloaddition of the furan 2,3-double bond of a furan tethered to a cyano-substituted benzocyclobutene via an intermediate quinone dimethide was used for the synthesis of the tetracyclic core of halenaquinol and halenaquinone <2001SL1123, 2002T6097>. The reaction proceeded via an OT,7i9-transition state to produce the cycloadduct 72 exclusively. A related chemistry is shown in Equation (56), in... 

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