Isochromanes, formation

Enediynes are of interest because of their ability to cleave DNA. The 10-membered oxadiyne (5) cycloaromatises to the isochroman (6) <96TL2433> and a biradical intermediate is proposed to account for the formation of an isochroman from an acyclic enediyne <96TL5397>. 

As with five-membered heterocycles, phosphorus pentasulfide may replace a ring oxygen atom by sulfur, or it may effect replacement in an acyclic precursor and then bring about cyclization. Thus isochroman-l-one (99) is converted into thioisochroman-l-thione (100) under the same conditions a 3-arylisocoumarin( 101) produces a 3-ary 1-1-thioisocoumarin (102) only, with no replacement of the ring oxygen atom.122 A typical example of thiation, followed by cyclization, is the formation of 2-alkyl- or 2-aryl-3,l-benzo-thiazine-4-thiones (103) from /V-acylanthranilic acid esters (104) by treatment with phosphorus pentasulfide in boiling xylene.122... 

Carboxybenzyl aryl ketones are formed together with the isocoumarin when homophthalic anhydride (isochroman-l,3-dione) is used to acylate aromatic molecules under Friedel-Crafts conditions (51JOC1064) and the 7-methoxy derivative behaves in a similar fashion (66JIC615). Some care in the choice of Lewis acid is necessary in view of the formation of the tropone derivative (504) in the acylation of hydroquinone (Scheme 181) (55JCS2244). 

Bromophenyl)ethanol undergoes a palladium-catalyzed carbonylation which results in the formation of isochroman-l-one (79H(12)92l). It is considered that the reaction involves formation of an aryl-palladium complex (624) through insertion of the zerovalent palladium complex (623) into the aryl halide. Insertion of carbon monoxide followed by reductive elimination of the metal as a complex species leads to the isochromanone (Scheme 242). 

In a related manner, sodium 2-bromobenzoates have been converted into 2-allylbenzoic acids. A palladium-catalyzed cyclization involving nucleophilic attack of the carboxylate on the palladium-complexed alkene yielded an isocoumarin. However, in situ catalytic hydrogenation results in the formation of an isochroman-l-one. 

Formation of the isochroman system is considered to trigger the synthesis of the dibenzopyran (17, X = H2) by the acid catalysed cyclisation of c/s-enediynes (16, X = H2). In a similar manner, the carboxyl function in (16, X = O) promotes cylisation to a dihydropyranone derivative which is followed by a Myers cycloaromatisation to the dibenzopyranone (17, X = O) (95TL9165). 

Table 26 Addition of various formates to laudanosine 551 furnishing isochromans 552 (Scheme 119)...

Table 28 Formation of tetrahydropyrans 600 by Lewis-acid-mediated nucleophilic addition to resin bound isochromans 599...

Vinylnorcaradiene derivatives 1175 undergo a photochemical reaction resulting in the regioselective cleavage of one of the cyclopropyl a-bonds and the formation of isochroman-3-ones (Equation 457) <1997CC1973>. 

A three-component Pd-catalysed reaction involving a 3-iodophenyl ether, an alkyl halide and an electron-deficient alkene proceeds with the creation of three new C-C bonds resulting in the formation of chromans (Scheme 14). When applied to benzylic ethers, isochromans are formed <03OL4827>. 

Aryl-l,3-dioxolanes undergo a TiCU-promoted Pictet-Spengler rearrangement to give 4-hydroxyisochromans. Bulky substituents at C-2 and C-4 of the dioxolane moiety result in formation of the cw-l,3-disubstituted isochroman while the 2,4-dimethyl derivative affords mainly the tran -diastereomer <04TL411>. 

In most cases dialkyl peroxides arise from the alkyl hydroperoxides formed as primary products this is so in autoxidation of isochroman,333 phthalan,334 2-methyl-l,3-dioxolane,344 and tetrahydroacenaphthacene.345 Formation of dialkyl peroxides from alkyl hydroperoxides can occur under the influence of acids, and in this ionic dimerization 333,334 hydrogen peroxide is also formed ... 

Benzylic oxidation. Dihydroisobenzofuran and isochroman are readily converted to the lactones. Solvent effects are manifested in the cleavage of styrenes, since EtOAc favors the formation of aldehydes, whereas in THF, the major products are the benzoic acids. 

Reaction with homophthalic acid. If the reaction of homophthalic acid with POCI3 and DMF is carried out at 0°, the major product is the isochromane-1,3-dione (2). If the reaction is conducted at 100°, the major product is the iso-quinolone (3). Treatment of (2) with hydrochloric acid in methanol results in formation of the methyl ester of isocoumarin-4-carboxylic acid (4). 

Other 0-heterocyclic ring formations from substructure F (Figure 6.4) concern the preparation of isochromanes [104] or the study of the effect of ether versus ester tethering during the cyclization [105]. 

Scheme 6.36 Formation of chromans and isochromans by an intermolecular carbopallada-tion sequence followed by electrocyclic ring closure and aromatization.

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