Uses of isatoic anhydrides

An interesting modification of Camps reaction was presented recently. It was based on the use of isatoic anhydride or benzoxazinones as active components for the in situ formation of intermediate amides, which were readily cyclized to the desired products. Thus, reaction of isatoic anhydride or benzoxazinones with malonates and/or ketoesters afforded libraries of quinoline compounds in high yields even at multikilogram scale. ... 

There are two important general types of reaction by which six-membered heterocycles containing two or more heteroatoms can be transformed into other six-membered heterocyclic systems, namely reactions which involve an ANRORC mechanism, and reactions which proceed by a Diels-Alder/retro-Diels-Alder type of mechanism. Transformation of 1,3-oxazinones and -thiazinones into pyrimidones (equations 193 and 194) has been extensively used, especially in the conversion of isatoic anhydride into quinazolinones (e.g. equation 195). 2,4-Diaryl-l,2,3,5-oxathiadiazines, which are readily accessible by reaction of sulfur trioxide with aryl isocyanates, are useful precursors to pyrimidines and 1,3,5-triazines (equation 196). 

The product is dried in air and then at 100°. The total yield is 118-123 g. (72-75%) of a white or nearly white product which decomposes at 237-240° cor. this material is pure enough for most purposes. It may be recrystallized from 95% ethanol (about 30 ml. per gram) or from dioxane (about 10 ml. per gram). The former solvent permits the higher recovery (89-90%) and, except for the large volume required, is to be preferred. The mother liquor may be used for recrystallization of several successive lots of isatoic anhydride. The purified compound decomposes at 243° cor. (Note 7). 

Azole approach. Aminolysis of isatoic anhydride using 3-hydroxyisothiazoles as the amino nucleophile provides a convenient method for preparing 9/f-isothiazolo[3,2-h]quinazolin-9-ones (134) (69AJC2497). 

The major use of phthalic anhydride is for ester derivatives used as plasticizers in the manufacture of flexible poly(vinyl chloride), e.g., wallpaper. The largest volume plasticizer is the di(2-ethylhexyl)phthalate. Other uses of phthalic anhydride are for unsaturated polyester and alkyd resins, for dye intermediates, and for isatoic anhydride (for the production of saccharin). 

Zhang and coworkers have developed the use of fluorous-tagged isocyanate as well as isatoic anhydride and acid chloride for the scavenging of amines for use in combinatorial as well as conventional chemistry (Figure 8.3) [30]. All reagents were readily prepared from commercially available sources, and the F-isatoic anhydride was prepared via a simple NaH-mediated alkylation of isatoic anhydride with per-fluoroalkyl halide. 

The importance of l,4-benzodiazepine-2,5-diones (BZDs) has increased due to their valuable pharmacological properties in the treatment of cancer, AIDS, hypertension, inflammation, pain, muscle tension, and depression. The green reaction of isatoic anhydrides with a-amino acids in the presence of the IL l-butyl-3-methyli-midazolium bromide gave 1,4- benzodiazepine-2,5-diones in excellent yields with no catalyst (Equation 4.45). The reaction work-up is simple and the IL was easily separated from the reaction and reused. The methodology was fairly general and numerous cyclic and acyclic a-amino acids were used to produce 1,4-benzodiaze-pine-2,5-diones [87]. 

The construction of six-membered rings with three nitrogen atoms on the basis of isatoic anhydrides has only been described for 1,2,3-benzotriazines. This method for the synthesis of the latter includes reaction of the anhydrides with primary amines and subsequent diazotization of the obtained amino amides, which dictates the use of initial isatoic anhydrides not containing substituents at the nitrogen atom. Thus, the action of sodium nitrite and hydrochloric acid on the amino amides 161, formed from the anhydrides 1, 10, 162 and imidazolylalkylamines, leads to diazotization and cyclization with the formation of derivatives 208 of benzo-l,2,3-triazin-4-ones (yields 36-85%) [96, 126],... 

The synthesis of rutaecarpine (26) itself from the sulphur analogue (27) of isatoic anhydride and 3,4-dihydro-/3-carboline is reported to proceed in 80% yield " however, the corresponding condensation with isatoic anhydride (25) is unsatisfactory, presumably owing to the instability of 3,4-dihydro-/3-carboline at the high temperature used. This may be circumvented by condensation of (25) with the more stable l-oxo-l,2,3,4-tetrahydro-/S-carboline (28), which affords rutaecarpine directly, a spontaneous dehydrogenation step obviously not being required in this reaction. ... 

The synthesis of 1,4-dihydropyridines (45) by four-component condensation reaction of 1,3-dicarbonyls (43), aldehydes (1), and ammonium carbonate (44) in an aqueous medium was reported at 60°C within 1.5-2.5 h (Scheme 9.11) (Tamaddon and Moradi 2012). ZnO nanoparticles can be used as a heterogeneous catalyst (Yavari and Beheshti 2011) for the one-pot three-component condensation of isatoic anhydride (46), amines (47), and aldehydes (48) to afford the corresponding 2,3-disubstituted quinazolin-4(l//)-ones (49) (Scheme 9.12). A short reaction time (3 h), solvent-free conditions, and an atom-economic nature are the significant advantages of the present method. The catalyst showed good recyclability without much loss of its catalytic activity. 

Under practically the same experimental conditions as those used to prepare NCAs of amino acids, phosphorus tribromide reacts with N-carbobenzoxyanthranilic acid to give nearly quantitative yields of isatoic anhydride [858]. 

Quinazolines and their spiro derivatives are also available via MCRs in water. The three-component condensation of isatoic anhydride, primary amines and aromatic aldehydes or isatin to give 2,3-dihydroquinazolin-4(l/f)-ones 67 or spiroox-indole derivatives 68 (Scheme 1.36) was performed in water using ethylenediamine diacetate (HDDA) as catalyst [56]. 

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

These formulae explain the scission products of the two alkaloids and the conversion of evodiamine into rutaecarpine, and were accepted by Asahina. A partial synthesis of rutaecarpine was effected by Asahina, Irie and Ohta, who prepared the o-nitrobenzoyl derivative of 3-)3-amino-ethylindole-2-carboxylic acid, and reduced this to the corresponding amine (partial formula I), which on warming with phosphorus oxychloride in carbon tetrachloride solution furnished rutaecarpine. This synthesis was completed in 1928 by the same authors by the preparation of 3-)S-amino-ethylindole-2-carboxylic acid by the action of alcoholic potassium hydroxide on 2-keto-2 3 4 5-tetrahydro-3-carboline. An equally simple synthesis was effected almost simultaneously by Asahina, Manske and Robinson, who condensed methyl anthranilate with 2-keto-2 3 4 5-tetrahydro-3-carboline (for notation, see p. 492) by the use of phosphorus trichloride (see partial formulae II). Ohta has also synthesised rutaecarpine by heating a mixture of 2-keto-2 3 4 5-tetrahydrocarboline with isatoic anhydride at 195° for 20 minutes. 

It was found inadvisable to use more than four molecules of form-amide [ (47) when R = H] per molecule of anthranilic acid and the condensation produces best results when the mixture is heated at 120 -130°C for 2 hr followed by further heating at 170°-180 C for 2 hr. Other variants of this reaction involve the use of ammonium o-acylaminobenzoates, anthranilic acid in the presence of nitriles and acetic anhydride, o-acetamidonitrile with acetic anhydride or hydrogen peroxide, anthranilic esters and aliphatic or aromatic amides or amidines, isatoic anhydride with amides or amidines, and anthranilic esters with aryl iminochlorides in acetoned The mechanism proposed by Bogert and Gotthelf has had experimental supporR and is represented in Scheme 12. 

It is clear from Table 44 that the E2/SN2 ratios observed for reactions of crown ether-separated KOt-Bu ion pairs will greatly depend on the type of substrate and solvent. Di Biase and Gokel (1978) have recently reported many examples of the use of this reagent either as a nucleophile [for example, in its reaction with benzyl chloride and in the reaction with isatoic anhydride (34)] or as a strong base [for example, in the basic oxidation of fluorene to 2-carboxybiphenyl (35)]. 

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