Methyl homophthalate

The carbanion derived from methyl homophthalate adds to 3a to provide a mixture of imidazolidine derivative 14a and its enaminic (aminostyrene) acyclic tautomer 14b. Likewise, a mixture of homologous perhydropyrimidine 16a and enamine (aminostyrene) 16b was formed by addition of the same carbanion to l-methyl-3-tosyl-tetrahydropyrimidinium cation (15). The stereochemistry of the products has been adequately established (85T3355). 

The products of the base-catalyzed Stobbe condensation of 3-formylindole and of 2-formylpyrroles undergo acid-catalyzed cyclization to yield l-hydroxycarbazole-3-carboxylic esters and 4-hydroxyindole-6-carboxylic esters, respectively (73JPR295, 74JPR386, 76JPR816). The analogous condensation of dimethyl homophthalate with 2-formyi-l-methylpyrrole and with 3-formylindole produces (443 Hetero= l-methyl-2-pyrrolyl, 3-indolyl), (444) and (445) under acidic conditions (76JHC83). 

A vigorous Claisen condensation ensues when a homophthalic ester and methyl formate are treated with sodium ethoxide and the active methylene group is formylated. Cyclization takes place with ease in acidic media to produce a methyl isocoumarin-4-carboxylate (50JCS3375). Hydrolysis under acid conditions is sometimes accompanied by polymerization, but the use of boron trifluoride in acetic acid overcomes this problem. Decarboxylation may be effected in the conventional manner with copper bronze, though it sometimes accompanies the hydrolysis. 

Methyl l-hydroxynaphthalene-2-carboxylate is formed in 19% yield when homophthalic anhydride and methyl propiolate are heated in toluene at 150° for 24 hours. 

R = H). Bromination gave the 4-bromo-derivative which afforded (16 R = CN) and (16 R = CHO) by successive cyanization and Raney nickel reduction/ The reported synthesis of the isoquinolone alkaloid thalactamine from 2,3.4-trimethoxyphenethylamine is unexceptional but an alternative synthesis involving bromination of 6,7-dimethoxy-2-methyl-l(2//)-isoquinolone followed by methan-nolysis in methanolic sodium methoxide is somewhat surprising/ A number of new methods for preparing AT-substituted l(2//)-isoquinolones include reaction of homophthalic acids with Vilsmeier reagentand borohydride reduction of homophthalimides. The effect of various substituents on the fluorescence of such isoquinolones has been studied. 

Hydroxyhomophthalates. Complete details are available for construction of benzene rings by condensation of 1, as the dianion equivalent of methyl acetoacetate, with various 1,3-dicarbonyl equivalents.1 The reaction has been extended to condensation of 1 with a 1,3,5-tricarbonyl unit to form 3-hydroxyhomophthalates. Thus when 1 (2 equivalents) is treated with trimethyl orthoformate (1 equivalent) in the presence of TiCl4, dimethyl 3-hydroxy-homophthalate (2) is formed in 68% yield. The reaction is believed to involve formation of the 1,3,5-tricarbonyl equivalent a, which then condenses with 1 to form 2. 

Artemidinal 4<5 can be readily synthesised from homophthalic anhydride (vide infra). Its syntheses from 3-methyl dihydroisocoumarin and 3-methyI isocoumarin are given below... 

Another interesting synthesis of the homophthalic anhydride involves lithiation of an amide and first introducing an ortho methyl group. Further lithiation leads to metalation at the aromatic methyl group. The organo metallic compound reacts with COj to furnish the anhydride. The synthetic sequence is shown below The whole sequence may be rendered into a one pot reaction, without isolating the aromatic methyl compound. 

Several 13-unsubstituted and 13-methyl-berbine alkaloids have been synthesised by reacting homophthalic anhydride with 3,4-dihydroisoquinolines followed by a sequence of reaction. Synthesis of (+) corydaline (57) involves the following steps... 

The synthesis of the homophthalic acid was a rather involved one, requiring as primary starting material /3-veratrylbutyric acid. It was necessary to block the 6-position with a bromine atom, ring-close to the corresponding 4-bromo-6,7-dimethoxy-3-methyl-l-indanone, and then treat the isonitroso derivative of this with p-toluenesulfonyl chloride in the presence of alkali. The resulting carboxy nitrile on hydrolysis and de-bromination with sodium amalgam afforded the desired acid. Similar syntheses are described in greater detail in the chapter on protopine and cryptopine. 

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). 

The formation of the isocoumarin skeleton in the total synthesis of achlisocoumarins I and II involved the cyclocondensation in neat conditions of a homophthalic acid with methyl 3-arylpropanoate or methyl ( )-... 

A mixture of equimolar amounts of homophthalic acid anhydride, veratriylidene-methylamine, and methylene chloride refluxed 10 min., and the resulting soln. allowed to stand 1 hr. at room temp. -> ( )-rran -4-carboxy-3-(3,4-dimethyoxy-phenyl)-2-methyl-3,4-dihydro-l(2H)-isoquinoline. Y 96%. F. e. s. M. A. Haimova et al.. Tetrahedron 33, 331 (1977) N-condensed N-heterocyclics s. M. Cushman, J. Gentry, and F. W. Dekow, J. Org. Chem. 42, 1111 (1977). 

Homophthalic acid allowed to react with Vilsmeier reagent (POClg-dimethyl-formamide) on a steam bath -> N-methyl-4-carboxy-l(2H)-isoquinolone. Y almost 80%. V. H. Belgaonkar and R. N. Usgaonkar, Tetrah. Let. 1975, 3849 Soc. Perkin 11977, 702. 

Benzenetriols on cyclocondensation with hydroxybenzoic acids gave 1,3-dihydroxyxanthones which were converted into various 0-derivatives containing carboxyl or amino groups.Several xanthones [e.g., (165)] have been synthesized by ring closure of the ketones (164) with ethanolic potash.Benzoxanthones are represented in nature by several compounds such as the quinone bikaverin. Several members of this class [e.g., (166)] were prepared by base-induced condensation of 2-hydroxyacetophenones with dimethyl homophthalates, and reduced benzoxanthanone (167) which is potentially of interest as an antitumour compound, was obtained by condensation of 2-methylchromone-3-carboxylic acid with methyl 4-oxocyclohexanecarboxylate. 

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