Benzocyclobutenes 3- substituted

As exemplified in the present procedure, the reaction has been optimized and extended in scope it affords functionalized benzocyclobutenes as well as substituted isoquinolines in high yields. Benzocyclobutenes have been used as intermediates in the synthesis of many naturally occurring alkaloids, - steroids,polycyclic terpenoids,and anthracycline antibiotics. The traditional routes leading to the preparation of benzocyclobutenes have been... 

With substituted benzocyclobutene-1.2-diones other derivatives are available.36 Radical intermediates seem to be involved in the reaction process.37... 

This reaction can be applied to substituted benzocyclobutenes. For example, the reaction has been used to form an array of five linear rings containing most of the functionality for the antibiotic tetracycline. 

Benzenesulfonic anhydride, 46, 88 Benzocyclobutenes, 1-substituted, from addition of a side-chain carban-ion to an aryne bond, 48, 55 Benzofuran, 46,28 Benzoic acid, 2-phenylethyl ester,... 

Cyclization by addition of a side-chain carbanion to an aryne bond has been proposed as the method of choice for synthesis of the versatile 1-substituted benzocyclobutene system.7 This general procedure now has been modified to permit convenient large-scale preparations utilizing a commercially available base, a minimum amount of liquid ammonia, and distillation for isolation of the product. 

The monomers described so far have all been prepared by starting with 4-bromobenzocyclobutene, 2. A different approach to the preparation of monomers begins with the parent hydrocarbon benzocyclobutene 1 by carrying out electrophilic aromatic substitution reactions [36]. Benzocyclobutene readily undergoes a Friedel-Crafts benzoylation reaction with a variety of substituted acid chlorides (Fig. 7). 

Table 2. Ring opening temperature of 1-substituted benzocyclobutenes...

An investigation established a relationship between the intensity of the [M - C02] ion in the spectra of substituted isochroman-3-ones (29) and the yield of the corresponding benzocyclobutene (29a), obtained from flash vacuum pyrolysis of (29 equation 5) (77JOC2989). 

The //////-substituted benzocyclobutenes 601 undergo bond reorganization under mild conditions to form ortho-quinone dimethide intermediates 602, which function as dienes in an hDA reaction with aldehydes to afford all syn-substituted isochromans 603 in excellent yield (Scheme 129) <2000AGE1937>. 

Other benzo-fused carbocycles could be prepared in moderate yield by a similar strategy. Isomerically pure 3-substituted benzocyclobutenes or 5-substituted tetralins, 211, were prepared by a five-step sequence from the appropriate a-(2-fluorophenyl)-[Pg.101]

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... 

A relatively new route to benzocyclobutenes, without the involvement of o-quinodimethanes, is the cobalt-catalyzed co-oligomerization of bis(trimethylsilyl)acetylene with 1,5-hexadiynes, (580) + (581) - (582) (Scheme 133). Despite its elegance, and the potential to modify the silyl groups, this method suffers from limitations in providing benzocyclobutenes with well-defined substitution patterns. In this... 

It thus follows that benzocyclobutenes are readily accessible, relatively inert and reliable masked o-quinodimethane equivalents. With 7-substituted derivatives (586), thermal unmasking takes place at a rate which varies widely with the nature of the substituent R (Scheme 134, Table 34). ... 

Table 34 Approximate Temperature for Complete Ring Opening of 7-Substituted Benzocyclobutenes ...

A major initial limitation of the benzocyclobutene approach to o-quinodimethanes was the lack of efficient, large-scale syntheses for many specifically substituted derivatives. Fortunately, recent developments have lemov much of this impediment. Q>nceptually, the synthesis of benzocyclobutenes from aromatic precursors can be envisaged in only a limited number of ways. These include [2 -i- 2] cycloadditions involving benzynes and alkenes, intramolecular cyclization on to a benzyne, cyclizations involving arene anions, and electrocyclic closure of o-quinodimethanes. Benzocyclobutene derivatives can also be prepared by aromatization of bicyclo[4.2.0]octanes. Detailed discussion of variations to these approaches can be found in the cited reviews. The cobalt catalyzed co-oligomerization of 1,5-hexadiynes with al-kynes, especially bis(trimethylsilyl)acetylene, has also been employed for the preparation of specifically substituted benzocyclobutenes. In the latter case the cyclobutenes are often not isolated but converted directly to o-quinodimethanes and subsequent products. ... 

Stevens and Bisacchi have carefully examined the trailing of benzynes, generated fiom a number of aryl bromides and sodium amide in THF, with 1,1-dimethylethylene and report procedures which afford 6 6% yields of 1,1-dimethoxycyclobutenes, e.g. (131). These compounds are hydrolyzed quantitatively to the corresponding benzocyclobutenones (132). Excellent regioselectivity was obtained with unsym-metrical benzynes derived from methoxy substituted bromobenzenes due to the polarized nature of the benzyne intermediate. Steric effects also influence regioselectivity o-bromotoluene afforded a 3 1 mixture of 3-methyl- and 6-methyl-benzocyclobutene. 

The diazotization of anthranilic acid, a classic route to benzyne, when carried out in the presence of vinyl acetate, vinyl ethers or 1,1-dichloroethylene gives the expected benzocyclobutenes in about 40% yield. Despite the rather moderate yields this method represents a convenient route to multigram quantities of the parent compounds, benzocyclobutenol and benzocyclobutenone. The latter is easily converted to benzocyclobutene-1,2-dione. The diazotization sequence applied to 2-amino-3,6-dimeth-oxybenzoic acid and 1,1-dichloroethylene results in a 80% yield of 3, imethoxycyclobuten-l-one. Trapping of benzynes with other ethylene derivatives, and especially more substituted alkenes, has given generally poorer, variable results. ... 

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