Cycloaddition reactions of benzyne

Derivatives of the naphthalen-l,4 -imine ring system (2) have become available only since the discovery of cycloaddition reactions of benzyne, on the one hand, and the recent rapid development of isoindole chemistry on the other. 

There is some evidence that the cycloaddition reaction of benzynes with 1-substituted pyrroles may proceed in two steps via a zwitterionic intermediate and that the reaction is thermally reversible, for although 1-methylpyrrole yields the [w4 + w2] adduct (258) with... 

Cycloaddition reactions of benzyne with cyclic olejms, Benzyne reacts with cyclo-hexadiene to give, as the main products, hydrocarbons (l)-(4). The first (I) arises by 2 + 4 cycloaddition, (2) and (3) arise by ene cycloadditions, and (4) is a result of 2 + 2 cycloaddition. Addition of catalytic amounts of silver fluoroborate exerts a marked effect in this case (1) becomes almost the exclusive product. Silver ton, however. 

Metal-Catalyzed Carbonylative Cycloaddition Reactions of Benzyne. 142... 

Scheme 23 Stereospecific [2+2] cycloaddition reaction of a benzyne 3.2.2 Reactions of Cycloalkynes...

The reactions of benzyne with enol-ethers and enol-acetates have been much studied very recently 115-118). We were not surprised therefore to isolate a product derived from the attack of tetrafluorobenzyne on the bis-enol-ether (75). This product is derived from a (2 + 2) n cycloaddition and the available evidence suggests that this product has the structure (78). 

The 7r-nature of the central bond in bicyclo[1.1.0]bulane is aptly demonstrated by its cycloaddition reaction with benzyne in 1,2-dichloroethane, from which two compounds 29 and 30 were isolated in moderate yield in a ratio of 6 1. The structures of the major and the minor compounds were identified as 3-phenylcyclobutene (29) and benzobicyclo[2.2.1]hex-2-ene (30), respectively.44 Deuterium labeling experiments showed that both products resulted from attack on bicy-clo[1.1.0]butane from the endo side.44... 

After [2n+2n] cycloaddition reaction of imine 271 and benzyne 272, the formed benzazetidine 273 underwent ring opening into its valence tautomer 274. Moisture attacked the tautomer 274 to give oxazepine 275. This method yielded 60-68% of the bicyclic 1,4-oxazepine 275. One extra mole of benzyne led to the formation of N-phenylated 276 (Scheme 48) <2003T6067>. 

Triptycene is the Diels-Alder cycloaddition product from the reaction of benzyne with anthracene (compound A). Although anthracene is aromatic, it is able to undergo cycloaddition at the center ring with a dienophile because the adduct retains the stabilization energy of two benzene rings. 

The reaction of benzyne with aromatic aldehydes proceeds via nucleophilic attack of the carbonyl oxygen onto the benzyne to give the zwitterionic intermediate 172 followed by cyclization to the benzoxete intermediate. Cycloreversion then forms an ortho-quinone methide, which undergoes a [4+2] cycloaddition with a second molecule of the benzyne to form the xanthene (Scheme 56) <20040L4049>. 

Benzyne probably forms from acetylene by cycloaddition reaction of acetylene and diacetylene, concerted or stepwise (Woodward and Katz, 1959 Woodward and Hoffmann, 1965a, b) ... 

Cycloaddition reactions with alkynic compounds are illustrated by the reaction of methyl propiolate with (78) to form (79), and by the reaction of benzyne with (78) to form (80)... 

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>. 

Benzyne undergoes [4+2]-cycloaddition reactions in which it acts as a dienophile. The Diels-Alder reaction of benzynes give fused- or bridged-ring systems. 

Reaction of benzynes with acyclic dienes generally gives Diels-Alder products in poor yields because of competitive [2 + 2] cycloadditions and ene-type processes (Scheme 113). The product distribution, obtained from 2,3-dimediyl-l,3-butadiene (484)," is more characteristic of a two-step mechanism than of a concerted addition. Widiout pursuing this argument, it tqrpears diat the extremely poor yield of [4 + 2] cycloadduct (485) results from die very fast reaction of benzyne with the transoid diene (484). Bond formation at C-1 coupled with a hydrogen transfer (- 487) or cyclobutane ring closure (-> 486) seems to occur rapidly before diene (484) can adopt the s-cis conformation. 

Cycloaddition reactions of the C(3)=N bond of azirines are common (Scheme 45) <71AHC(13)45, B-83MI 101-03,84CHEC-I(7)47>. Azirines can participate in [4 + 2] cycloadditions with dienes including cyclopentadienones, isobenzofurans, triazines, and tetrazines. They also participate in 1,3-dipolar cycloadditions with azomethine ylides, nitrile oxides, mesoionic compounds, and diazomethane. Cycloadditions with heterocumulenes, benzyne, and carbenes are known. Azirines also participate in other pericyclic reactions, such as ene reactions. 

The reactions of benzyne are all additions to the formal triple bond of structure 1. The variety of such reactions can be clarified in terms of open-chain additions and cycloadditions, although the isolated products are in many cases derived from secondary decomposition of such primary adducts. The isolation or postulation of cycloadducts in very few cases provides any... 

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. 

Cycloaddition reactions were illustrated in CHEC-I by, for example, reactions of benzyne with pyridazine A -oxides and A -acetylimides (to give 2-hydroxy- and 2-acetylaminophenylpyridazines), inverse electron demand cycloaddition reactions of pyridazinecarboxylates with electron rich acetylenes (to give pyridines and benzenes) and dipolar cycloaddition reactions of a pyridazinone with... 

Useful reviews on redox transformations of thiophen derivatives (179 references), on the stereochemistry of carbonyl derivatives of five-membered heterocycles (257 references), on synthetic approaches to dihydrothiophens (135 references), and on biosteric thiophens" have been published. Aspects of thiophen chemistry have been treated in reviews on the synthesis of heterocycles by thermal [2 + 2] cycloaddition reactions of acetylenes and on aspects and perspectives of organic heterocyclic chemistry. A review comparing the chemistry of thieno[2,3-h]- and thieno [3,2-i ]-thiophen with that of benzo[ft] thiophen and quinoline has been published. In Advances in Heterocyclic Chemistry, the development of benzo[6] thiophen from 1968 to 1980 and of selenophen from 1970 to 1980 was presented. Other aspects of thiophen chemistry are treated in chapters on Dewar Heterocycles," on Cyclizations under Vilsmeier Conditions, on Polyfluoroheteroaromatic Compounds, and on Reactions of Benzyne with Heterocyclic Compounds. " Several dissertations treating various aspects of thiophen chemistry have appeared. " ... 

The formation of acridine in the reaction of benzyne with anthranil is thought to be a stepwise rather than a concerted (4 + 2)-cycloaddition.221 More interesting are the mercury sulfate-catalyzed cycloadditions of alicyclic ketones to anthranil in boiling xylene, which appear to involve the enol tautomers as indicated in Eq. (10).2 22 The yields of 2,3-cycloalkanoquinolines (163) range from 11% (n = 4) to 39% (n = 5). Phenylacetylene and diethyl maleate yield similar products. 

However, some failures in this general approach have been noted. The attempted cycloaddition-retro reaction of benzyne with the mesoionic 3-methyl-2,4-diphenylthiazolium-5-olate (26) is reported to give only very low yields of the expected isoindole.47... 

A new cathodic cyclodimerisation of 4-pyrones yields either (90) or (91) depending on conditions,88 2-Benzopyran-3-one has been isolated at low temperature and intercepted by NPM as the adduct (92) 88 high-pressure cycloaddition reactions of 2H-pyran-3-ones with a variety of dienophiles have been recorded.88 Cycloaddition reactions of furans and isobenzofurans continue to dominate this section. Dienophiles whose reactions with furan have been studied recently include phenylsulphonylpropadiene (giving predominantly the endo-adduct (93) 8b. benzynes (derived from aryloxazoli nesJ.8 and... 

The reaction of benzyne with enamines has been reinvestigated In the original study it was proposed that the two observed products from the reaction of benzyne with 1-pyrrolidinocyclohexene 362, (i.e. 364 and, after hydrolysis, 366) arose from a common dipolar intermediate 363 as shown. An alternative explanation is that 364 arises from a stepwise [2 + 2] cycloaddition as shown, but that 365 arises independently from a concerted ene reaction. If this hypothesis is correct, then there should in fact be two possible ene products, 367 and 368. Careful product analysis showed the presence of about 1% of previously unobserved 368, together with 15-25% of 367 and 15-25% of [2 + 2] product... 

One of the early examples of an intramolecular Diels-Alder reaction of benzynes involved cycloaddition to a furan that was tethered to the benzyne moiety . Diazoti-zation of anthranilic acid 669 gave in 86% yield the cycloadduct 670, which was subsequently converted to the o-naphthoquinone 671 (mansonone E 7 steps) as well as to the structurally related mansonones F and I and biflorin. ... 

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