Substitution 3- substituted benzocyclobutenes

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. 

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. 

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

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... 

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. ... 

While the electrocyclic ring opening to o-quinodimethanes is the major reaction pathway in the irradiation of substituted benzocyclobutenes (cf. Example 6.14), the irradiation of unsubstituted benzocyclobutene yields 1,2-dihydropentalene (119) and 1,5-dihydropentalene (120) as major products. The mechanism shown with prebenzvalene (118) as primary photochemical intermediate has been proposed to explain the formation of the isomeric dihydropentalenes (Turro et al.. 1988). Supporting calculations that yield the same mechanism for the benzene-to-fulvene transformation have been published (Dreyerand Klessinger, 1995). 

One of the early unsuccessful approaches to benzocyclopropenes consisted of the ring contraction of an appropriately substituted benzocyclobutene. When 2-bromobenzocyclobutene was reacted under the conditions of the Favorskii rearrangement (sodium methoxide), ring opening to methyl 2-(methoxymethyl)benzoate occurred rather than ring contraction to methyl benzocyclopropene-1 -carboxylate (1). ... 

In a series of papers, Kametani and co-workers reported that o-quinodi-methanes are sufficiently reactive dienes to combine with neutral, elec-ton-rich cyclic and acyclic imines to produce Diels-Alder adducts.64-67 In all cases, the o-quinodimethane was generated by thermal opening of a substituted benzocyclobutene. Several examples of the transformations which could be effected are shown in Scheme 2-X. 

Substituted benzocyclobutenes, indans, and tetralins can be synthesized in good yield by the related co-oligomerization of a,cobalt-catalysed reaction of a,a>-diynes is their reac-... 

The use of quinone methides in the synthesis of spirobenzylisoquinolines has been extended by Kametani and his colleagues who have utilized substituted benzocyclobutenes as precursors for o-quinodimethides. They converted the known benzocyclobutene 10 to the amide 11 which upon treatment under Bischler-Napieralski conditions furnished the known spirobenzyliso-quinoline 13 probably via the o-quinodimethide 12 ° ... 

The versatile benzocyclobutene synthesis using the dicarbonyl-r) -cyclopenta-dienylcobalt-catalysed acetylene cyclizations has also been applied in a synthesis of (170). Reaction of the acetylene (171) with hexa-l,5-diyne gave the substituted benzocyclobutene (172) which was converted into (170). Use of bistrimethylsilyl-acetylene in the cyclization gave the benzocyclobutene (173). The trimethylsilyl groups are replaceable by electrophiles, and do not impair the ability of the benzocyclobutene to function as an o-xylylene synthon. Reaction of (173) with maleic anhydride gave the adduct (174) quantitatively. 

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... 

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,... 

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). 

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