Homophthalic Acid and Anhydride

HOMOPHTHALIC ACID AND ANHYDRIDE (a-Toluic acid, o-carboxy-, and 2-benzopyran-l,3-dione) 

Submitted by Oltvek Gsummitt, Richard Egan, and Alien Buck. Checked by R. L. Shriner and Walter R. Knox. 

Eomophlhalic acid. A solution of 243 g. (0.83 mole) of technical potassium dichromate in 3.6 1. of water and 1330 g. (725 ml., 13 moles) of concentrated sulfuric acid is prepared in a 5-1. three-necked flask fitted with a sealed mechanical stirrer, a thermometer, a 100-ml. dropping funnel, and a reflux condenser. 

Homophthalic anhydride. A mixture of 60 g. (0.33 mole) of dry homophthalic acid and 33.7 g. (31 ml., 0.33 mole) of acetic anhydride in a 200-ml. round-bottomed flask fitted to a reflux condenser by a ground-glass joint is refluxed for 2 hours. The mixture is cooled to about 10° for 30 minutes, and the solid anhydride is collected on a Buchner funnel with the aid of suction. It is washed with 10 ml. of glacial acetic acid and pressed, and as much of the solvent as possible is removed by suction. hc product is spread out on a porous i)latc for several hours 

Indene of approximately 90% purity may be obtained from the Koppers Company, Pittsburgh, Pennsylvania, or United Gas Improvement Company, Philadelphia, Pennsylvania. The practical grade of the same purity from the Eastman Kodak Company may also be used. If the material is dark colored, it should be redistilled and the fraction boiling from 180° to 182° should be used. 

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The first direct approach to a pentacyclic system, based on the condensation product 101 of tryptamine with a homophthalic acid or anhydride, was introduced by Clemo and Swan and extended to reduced and substituted homophthalates. Esterification of... 

Homophthalic acids are acylated by acid anhydrides in the presence of pyridine, producing 4-acylisochroman-l,3-diones (494) (80CB3927). Rearrangement to a 3-alkylisocoumarin-4-carboxylic acid (495) occurs in acid solution and may be accompanied by decarboxylation. 

The oriAo-benzoyl-benzoic acids readily yield anthraquinone and its derivatives (see p. 82). It may be noted that o-benzoyl-benzoic acid itself, with benzene and aluminium chloride, yields phthalophenone the same compound is made directly from phthalic anhydride by increasing the amount of the latter or by adding acetic anhydride. The same holds for p-toluoylbenzoic acid and ditoluoylphthalide. (Am. Soc., 43, 1965 J. C. S., 122, 539.) (For the use of carbomethoxylbenzoyl chlorides and of homophthalic anhydrides in these reactions, see Am. Soc., 43, 1950.)... 

Fulveneallenes and benzocyclobutenones from homophthalic acid anhydrides... 

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). 

A convenient and efficient route to isocoumarins has been described starting from readily available substituted indan-l-ones, which are first converted to the enol form with trifluoroacetic anhydride, then cleaved with ozone. Isocoumarin-4-carboxylic acid is easily prepared from homophthalic acid by addition of Vilsmeier reagent followed by hydrolysis. 

In a facile and rapid stereoselective, three-component, one-pot reaction, a series of cis-isoquinolonic acids 132 were synthesized using silica supported sulfuric acid to catalyze the reaction between homophthalic anhydride 133 with different aldehydes 134 and amines 135. This three-component cyclocondensation offers a variety of advantages including high yields, easy experimental work-up, and the use an inexpensive, non-toxic, readily available, and recyclable catalyst <06JHC187>. 

The ionic liquid [BMIM]BF4 was found to efficiently catalyze the three-component coupling reactions of aldehydes, amines, and homophthalic anhydride under ambient conditions to give the corresponding c/ -isoquinolonic acids in excellent yields with... 

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). 

Multi-component reactions were also utilized for the synthesis of isoquinolines. Yadav et al. reported the reaction of homophthalic anhydride 125, benzaldehyde 126, and anilines 127, under neutral conditions, in the presence of iodine in dichloromethane at room temperature to afford the desired cfs-oxoisoquinolinecarboxylic acid derivatives 128 in high yields <07S3191>. 

Tetrahydroisoquinolonic acids are formed in good yields and enhanced rates from three-component coupling reactions of benzaldehydes, amines, and homophthalic anhydride. The key feature of this approach is the use of ionic liquids <03T1805>. 

Homophthalic anhydride has been obtained by heating the acid alone," and by refluxing with acetyl chloride or with acetic anhydride."... 

Homophthalic anhydrides in synthesis of heteroeycies 84KGS1587. Metallation as key step in heterocyclic synthesis 83S957. a-Methylamino acids—heterocyclic derivatives, synthesis of 85MI21. Polysubstituted heteroeycies in syntheses of bi- and polycyclic systems ... 

In view of the emerging importance of the ionic liquids as novel reaction media, Yadav and his coworkers explored the use of ionic liquids as promoters for the synthesis of c -quinolonic acids. The reactions of various aldehydes, amines, and homophthalic anhydride were studied in different ionic hquids (Fig. 12.5) [4], Among these ionic liquids, [bmim][BF ] was found to be superior in terms of yields, reaction rates, and reusability. 

Ring expansion of homophthalic anhydride 114 on reaction with N-i- r-N-methylhydrazine in acetic acid resulted in the 2,3-benzodiazepinedione derivative 115 in moderate yield. The combination of the less hindered nitrogen (NCH3) and the more reactive carbonyl group in 114 may explain the regioselectivity observed. Functionalisation of C5 by the azido group then led ultimately via the amine 116 and the peptide 117 to the 2,3-benzodiazepine-1,4-diones 118. These final compounds were designed to act as peptidomimetics at the carboxy terminus of hydroxyamides one such compound 118 (R =... 

Isoquinoline derivatives are an important family of natural products. They have diverse biological activities and are used, for example, as bronchodi-lators, skeletal muscle relaxants, and antiseptics. The solid-phase synthesis of a 43,000-compound tetrahydroisoquinoline 2 combinatorial library has been reported by Griffith et al. [32]. The library was synthesized by a three-step procedure. An imine was formed by reacting a substituted benzaldehyde with a methylbenzhydrylamine (MB HA) resin-bound amino acid. Imine formation was driven to completion using trimethylorthoformate as a dehydrating reagent. Treatment of the imine with homophthalic anhydride provided the desired tetrahydroisoquinoline (Fig. 3a). 

Thalactamine (15 R = H) and its 6,7-dimethoxy-analogue have been synthesized from the appropriately substituted homophthalic anhydride, e.g. (14) this, with phosphorus oxychloride and dimethylformamide, gives the acid (15 R = CO2H), which can be decarboxylated. The peptide alkaloid amphi-bine (17) has been synthesized by the condensation of the primary amine (16) with N-benzyloxycarbonyl-L-valylglycine, followed by removal of the N-benzyloxy-carbonyl group... 

Homophthalic anhydrides can be prepared by the dehydration of homoph-thalic acid with add chloride, acid anhydride, phosgene, thionyl chloride, benzene sulfonyl chloride, ketene, phosphorous pentoxide, dicyclohexyl-carbodiimide, or J -carbonyldiimidazole. However, these methods are not always effective for the acid-sensitive and/or unreactive homophthaUc acid derivatives. We developed a very mild and efficient method for obtaining homophthaUc anhydrides using (trimethylsilyl)ethoxyacetylene [9] (Scheme 1). Thus the treatment of homophthaUc acid 1 with (trimethylsi-lyl)ethoxyacetylene 2 in inert solvents such as methylene chloride, 1,2-di-chloroethane, and acetonitrile gave the homophthaUc anhydride 3 in a quantitative yield accompanied by ethyl trimethylsilyl acetate as the only side product. The high purity homophthaUc anhydride 3 could be obtained for the next cycloaddition reaction just by evaporation to remove the reaction solvent and the formed ethyl trimethylsilyl acetate. The method is quite useful, and was also applicable to the syntheses of hetero-homophthalic anhydrides 4. 

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