Benzocyclobutene derivative synthesis

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. ... 

Cases exist, such as the natural or commercial preparation of provitamin D from provitamin D (Sect. 1) or the ring opening of cycIohexa-2,4-dienones to their dieneketene seco-isomers (Sect. 2), in which the photoreaction has the advantage. There are other instances such as the preparation of reactive or//(o-quinodimethane derivatives as intermediates in steroid synthesis ) (Sect. 3), in which either pliotoenoKzation or thermal seco-isomeriza-tions of appropriate benzocyclobutene derivatives may be used equally weU. 

Two approaches to convergent steroid syntheses are based on the thermal opening of benzocyclobutenes to the o-quinodimethane derivatives (see p. 80 W. Oppolzer, 1978 A) and their stereoselective intramolecular Diels-Alder cyclizations. T, Kametani (1977 B, 1978) obtained (+ )-estradiol in a six-step synthesis. The final Diels-Alder reaction occurred regio- and stereoselectively in almost quantitative yield, presumably because the exo transition state given below is highly favored over the endo state in which rings A and D would stcrically inter-... 

A similar synthesis starts from commercially available 1,5-hexadiyne and 2-methyl-cyclopent-2-enone. The benzocyclobutene is obtained from a bis-acetylene in a cobalt-catalyzed reaction. It rearranges regio- and stereoselectively to a 3-deoxy steroid derivative. The overall yield from the cyclopentenone was 40% (R.L. Funk, 1977). 

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). 

Further examples of the use of the hDA reaction in dihydropyran synthesis include the formation of the fused pyrans 18 from vinylallenes 17 and aldehydes (Scheme 8) <00TL6781> and a trans-fused dihydropyran containing a phosphonate group 19 . A total synthesis of the 11-oxa steroid system is based on an intramolecular Diels-Alder reaction involving an orthoquinodimethane derived from a benzocyclobutene (Scheme 9) <00TL1767>. 

This type of preparation of 1,2-diazepines has been reported earlier involving the dipolar cycloaddition of sydnones with benzocyclobutene <1996CHEC-II(9)113>. This method could be further exploited by the use of the correct hydrazone derivative (1,3-electrophile, nucleophile) with a,/3-unsaturated ketone (1,4-electrophile, nucleophile) for the synthesis of 1,2-diazepines. 

Until now, only few attempts were made to apply the ortho photocycloaddition to organic synthesis. Particular interest lies in the field of compounds possessing interesting biological activity (Sch. 22). The cyclohexane-1,3-dione carboxylic acid derivative 110 can be used as core structure of new herbicides [27,51,84]. Benzocyclobutenes 75a,b obtained... 

The availability of benzocyclobutenes from cocycloadditions of 1,5-hexadiynes and hindered alkynes has been elaborated into an iterative synthesis of a variety of novel polycyclic biphenylene derivatives. 

The reports in the organic sections of this review are now considered. Irradiation of valerophenone is well known to yield both acetophenone and cyclobutanols by a Norrish Type II process but Zepp et al. report that the latter product (cis trans ratio 2.4 1) is more efficient in aqueous systems than hydrocarbons. Such ketones as 1 readily undergo the Type II process in the solid phase and from a detailed study involving the use of chiral auxiliaries as counter ions of its carboxylate derivative, Leibovitch et al. conclude that the ionic chiral auxiliary approach is a viable general method for asymmetric synthesis. Crystals of the ketone 2 are apparently photostable at room temperature but when finely ground or at elevated temperatures intramolecular hydrogen abstraction and formation of the benzocyclobutene 3 occurs (Ito et al), and the same workers also note that irradiation of S-4 at 4 °C in the solid state and at 34% conversion gives the SS product 5 with a diastereoselectivity of 99%. 

The dipolar cycloaddition of sydnones (l,2,3-oxadiazolidin-5-one derivatives) (108) with benzocyclobutene (109) has been used to synthesize 3 f-2,3-benzodiazepines (110). This synthesis involves a cycloaddition-extrusion-ring-expansion sequence, and with other mesionic compounds, for example the thiazolium-4-olate (111), primary cydoadducts (112) were isolated (Scheme 13)... 

Magnus and his group have discovered a new method of cyclization via quinodimethane intermediates, which avoids the problems associated with the well known methods involving benzocyclobutenes, dihydrothiophen dioxides, etc. The discovery was made after the observation that when the trimethylsilyl derivative (173) was treated with fluoride ion cyclization did not occur, only (174) was isolated. The cyclization to (175) is affected in good yield by heating (174) with acetic anhydride, and although the method is being developed for synthesis of Aspidosperma alkaloids, it promises to have much wider application. 

Cyclization.—Earlier work on the cobalt-catalysed synthesis of the strained 4,5-bistrimethylsilylbenzocyclobutene (29), an o-xylene synthon, has been extended to the synthesis of naphthalenes and polycyclic systems. The basis of the reaction involves the (7 -C5H5)Co(CO)2 catalysed cyclodimerization of bistrimethylsily-lacetylene (BTMSA) with 3-substituted hexa-l,5-diynes to give benzocyclobutenes (29) as intermediates. With 3-alkoxy derivatives (29 R = OMe or OSiMea), further reaction with BTMSA produces the naphthalene (30 = SiMe3), which... 

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