Benzynes 2+2 cycloadditions

The aporphinoid alkaloid PO-3 (129) was also prepared by intermolecular benzyne cycloaddition between 1-methylene isoquinolines 148 and arynes derived from 147 (Scheme 53). The alkaloid was finally isolated by means of preparative thin layer chromatography (91JOC2984). 

The propensity of furans for benzyne cycloadditions is illustrated by its fourfold application to the four furan units of (495), providing the unusual macrocycle (496) in 84% yield in one synthetic operation (Scheme 115). The benzyne/furan adducts are also useful precursors for naphthalene derivatives. For example, adduct (489) (Scheme 114) was readily converted into a-naphthol (490) by treatment with acid. ... 

Hoye and co-workers (ref. 92) later reported the total synthesis of ancistrobrevine B (228), isolated from Ancistrocladus abbreviatus (ref. 93) and korupensamine C (229), isolated from Ancistrocladus korupensis. The approach to these natural products also utilised a benzyne cycloaddition to construct the naphthalene moiety. Thus, treatment of the amide 222 and bromide 230 with lithium cyclohexylisopropylamide furnished naphthalene 231 in low yield (Scheme 30). 

In a new synthesis of the cyclindrocarine group of alkaloids, it has been shown that when the spirocyclic ammonium ion (99) generated in situ from the amine (97) and the chloroaldehydoester (98) is heated,it generates the intermediate (100) which then undergoes intramolecular Diels-Alder reaction to (101) further elaboration of (101) then produces cyclindrocarine (102).30 The unusual benzyne cycloaddition (103) ... 

Benzyne cycloadditions have been useful in synthesizing sterically crowded naphthalenes . Recent examples include 1,2,4-tri- -butylnaphthalene 207 from cyclopentadienone 206 Tetra- -butylcyclopentadienone, however, turned out to be inert toward benzyne. The synthesis of 210 could be accomplished by adding benzyne to tetra-r-... 

Methoxybenzyne and 2-acetoxyfuran gave a mixture of both regioisomeric adducts in unspecified yield or ratio. On the other hand, benzyne cycloaddition to 246 occurs exclusively syn to the spirocyclopropane functionality a result that has been rationalized... 

Furancarbonamides 248 give good yields of cycloadducts with benzyne. Reduction and flash vacuum pyrolysis of 249 led to isobenzofurans, which were again subjected to benzyne cycloaddition to form 250, of potential interest as CNS-active agents. 

Decomposition of 294 in eleven substituted thiophenes established that [4+2] and [2+2] benzyne cycloaddition occur, but that the former predominates For example, 2-methylthiophene gave 24% of 1-methylnaphthalene [4+2] and only 2% of 2-methylnaph-thalene [2+2], as shown. Small yields (< 4%) of benzo[Z ]thiophenes formed in these reactions may arise from a 1,3-dipolar addition mechanism initiated by benzyne attack on sulfur... 

An intramolecular benzyne cycloaddition to a styrenic diene has been used to simultaneously construct two carbon-carbon bonds of the central ring of a phenanthrene moiety, in a new approach to aristolactam alkaloids 679. Treatment of jE -alkene 677 (R =... 

Rickborn and co-workers ° ° isolated the cycloadduct 164 from 4-phenylox-azole through careful manipulation of the experimental conditions (Fig. 3.50). They generated benzyne at 0°C from 1-aminobenzotriazole and lead tetraacetate. Compound 164 was stable at room temperature but, on heating, eliminated benzo-nitrile to give isobenzofuran 162, which could be trapped with A -methylmaleimide to afford a quantitative yield of the tetracyclic derivative 166 as an 88 12 mixture of endo and exo isomers. The cyclic aminal 164 was also sensitive to acid and rearranged to 4-hydroxy-3-phenyl-isoquinoline 165 on exposure to silica gel or a catalytic amount of trifluoroacetic acid. The benzyne cycloadditions were also carried out on 4-(4-nitrophenyl)oxazole and 4-(4-methoxyphenyl)oxazole. A fourfold rate increase was seen for the cycloaddition of the nitrophenyl-substituted oxazole relative to the methoxyphenyl analog, indicating a concerted process with little contribution from a polar intermediate. 

The Suzuki group subsequently reported a dual benzyne cycloaddition protocol starting from bis(sulfonyloxy)diiodobenzene 183 [100], which can be viewed as a synthetic equivalent of 3-methoxy-l,4-benzdiyne (184). When 183 was treated with 1.05 equiv. of n-BuLi in the presence of ketene silyl acetal 175 at -95 °C, a benzyne intermediate was generated on the iodo-triflate side of the arene, affording the mono-cycloadduct 185 in 11% yield (Scheme 12.51). 

Two examples have been reported of reactions which are the reverse of the isomerizations described so far, in that they involve a reduction in the number of carbon-carbon 7r-bonds and an increase in the number of carbon-carbon a-bonds. Photolysis of cyclo-octa-2,6-dienone (49) in the presence of copper(i) compounds gives the tricyclic ketone (50). The other example is a step in the silver(i)-catalysed benzyne cycloaddition. ... 

Hydroxy-THISs react with electron-deficient alkynes to give nonisol-able adducts that extrude carbonyl sulfide, affording pyrroles (23). Compound 16 (X = 0) seems particularly reactive (Scheme 16) (25). The cycloaddition to benzyne yields isoindoles in low- yield. Further cyclo-addition between isoindole and benzyne leads to an iminoanthracene as the main product (Scheme 17). The cycloadducts derived from electron-deficient alkenes are stable (23, 25) unless highly strained. Thus the two adducts, 18a (R = H, R = COOMe) and 18b (R = COOMe, R = H), formed from 7, both extrude furan and COS under the reaction conditions producing the pyrroles (19. R = H or COOMe) (Scheme 18). Similarly, the cycloadduct formed between 16 (X = 0) and dimethylfumarate... 

Its Strained triple bond makes benzyne a relatively good dienophile and when benzyne IS generated in the presence of a conjugated diene Diels-Alder cycloaddition occurs... 

Give the structure of the cycloaddition product formed when benzyne is generated in the presence of furan (See Section 11 22 if necessary to remind yourself of the structure of furan )... 

The reactions of pyrroles with dienophiles generally follow two different pathways involving either a [4 + 2] cycloaddition or a Michael-type addition to a free a-position of the pyrrole ring. Pyrrole itself gives a complex mixture of products with maleic anhydride or maleic acid and with benzyne reacts to give 2-phenylpyrrole rather than a product of cycloaddition (Scheme 47). 

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 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). 

Further mechanistic evidence comes from trapping experiments. When bromobenzene is treated with KNH2 in the presence of a diene such as furan, a Diels-Alder reaction (Section 14.5) occurs, implying that the symmetrical intermediate is a benzyne, formed by elimination of HBr from bromobenzene. Ben-zyne is too reactive to be isolated as a pure compound but, in the presence of water, addition occurs to give the phenol, in the presence of a diene, Diels-Alder cycloaddition takes place. 

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... 

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