Isatoic anhydride formation

A more highly oxidized derivative of quinazoline forms the heterocyclic moiety of a compound with CNS activity. Condensation of the aminopropylpiperazine 141 with isatoic anhydride gives the anthranilamide 142. Reaction of that amide with phosgene gives directly the heterocyclic ring. (The reaction may proceed by initial formation of the carbamoyl chloride ... 

The reaction of maleic anhydride with trimethylsilyl azide was reported to provide l,3-oxazine-2,6-dione in good yield. Control of the temperature proved essential in order to avoid a violent, exothermic reaction this could readily be accomplished by running the reaction in methylene chloride at 0°C <19950PP651>. Similar transformations of 3-substituted phthalic anhydrides 546 resulted in formation of 8- 547 or 5-substituted 548 isatoic anhydrides (Equation 66). The ratio of the regioisomeric products was strongly influenced by the substituent X while nitro and acetylamino derivatives 546 (X = NO2, NHAc) gave exclusively the 8-substituted isomers, only the 5-substituted product was formed from 3-aminophthalic anhydride 546 (X = NH2) <1998JOC6797>. 

Isatoic anhydride itself (91-1), when allowed to react with the primary amine (91-2), gives the corresponding amide (91-3), again with the expulsion of carbon dioxide. Treatment of the intermediate with phosgene results in the formation of a quinazolodione ring. There is thus obtained the serotonin blocking compound doperidone (91-4) [101], which is described as a sedative. 

Isatoic anhydride has been prepared by prolonged refluxing of a mixture of anthranilic acid and ethyl chlorocarbonate,2 a reaction usually accompanied by formation of considerable monoethyl or/and diethyl isatoate or by action of phosgene upon anthranilic acid in a solution the acidity of which is moderated by occasional addition of sodium carbonate.2 The method described is based upon a patented procedure 3 in which, under conditions not fully specified, phosgene is passed into a solution of anthranilic acid hydrochloride with no subsequent adjustment of the acidity. 

Isatoic anhydride reacts with ethyl -aminocrotonate (9a) or 4-aminopent-3-en-2-one (9b) to give 2-methylquinazolin-4(3//)-one (43-57%), the formation of which can be rationalized as proceeding through the loss of ethyl acetate or acetone from the intermediate 10 by a retro-Claisen or retro-aldol type elimination, respectively. ... 

Isatoic anhydrides 11 are transformed with ammonia into quinazoline-2,4(li/,3i/)-diones 12 with concomitant formation of the corresponding anthranilic acids -or anthranil-amides. The reaction lacks generality and has seldom been used for the synthesis of quin-azoline-2.4(177,37f)-diones. 

Isatoic anhydride (Fig. 45) is an example of a compound which inactivates serine proteases by formation of a stable acyl enzyme. Chymotrypsin is stoichio-metrically modified by isatoic anhydride with the incorporation of one anthrani-loyl group, as indicated by the absorbance spectrum of the derivatized enzyme (Moorman and Abeles, 1982). The anthraniloyl moiety is proposed to result from acylation of the active site serine followed by decarboxylation of the resulting carbamate (Fig. 45). The inactivation is irreversible by virtue of the electron-donating effect of the amino substituent of the benzoyl group, which is known to decrease dramatically the rate of deacylation of benzoylchymotrypsin (Caplow and Jencks, 1962). Substitution of the isatoic anhydride nucleus results in increased selectivity for trypsinlike proteases over chymotrypsin (Gelb and Abeles, 1986). 

Mandelaldehyde, PhCH(OH)CHO, can be condensed with 7V-phenyl-ethanolamine under acid catalysis to afford the 5,6-dihydro-1,4-oxazine (393) (80%) none of the isomeric oxazolidine is formed.""" Oxidation of isatins with peroxodisulphate gives excellent yields of 2,3-dioxo-benzo[Z>]-l,4-oxazines (394), in contrast to the formation of isatoic anhydrides by oxidation with a peroxide." Benzo[f>]-l,4-oxazines that are functionalized with methylene at position 2, i.e. (395), are obtained in good yields by the mercuric-oxide-promoted cyclization of o-(propargylamino)phenols." ... 

Data published after 1979 on the chemical transformations of 2H-3,l-benzoxazine-2,4-diones (isatoic anhydrides), leading to the formation of other heterocyclic compounds, are reviewed, classified, and analyzed. 

The wide range of chemical transformations characteristic of isatoic anhydrides is due largely to their ability to eliminate a CO2 molecule with the formation of highly reactive imino ketones, as illustrated below for the case of the unsubstituted anhydride 1. 

The present review contains data on the synthesis of various nitrogen-containing heterocyclic systems based on isatoic anhydrides that have appeared in the press since 1980. It covers both the direct transformations of these anhydrides into such systems and processes leading at the first stage to the formation of anthranilic acid derivatives that are then transformed into the heterocyclic compounds in one or several stages. It is important that such transformations result in the formation of new heterocyclic systems. 

In contrast to the data presented above, the formation of compounds containing a six-membered heterocycle based on isatoic anhydrides has been discussed very widely in the literature. This has given rise to the need to divides this material into several subsections. 

Many examples of the formation of new six-membered rings containing a nitrogen atom in the reaction of isatoic anhydrides with ketones, diketones, various ether derivatives, lactones, and organometallic compounds are known. Thus, the anhydrides 2 and 34 condense with acetophenones and co-methoxyacetophenones in the presence of lithium diisopropylamide at low temperatures with the formation of derivatives of quinolone 35 [17, 18],... 

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],... 

Formation of six-membered rings with nitrogen and oxygen or sulfur atoms. Almost all the papers on the transformations of isatoic anhydrides leading to the formation of new six-membered rings with two different heteroatoms have been devoted to the synthesis of derivatives of 3,1-benzoxazine. There is only one paper in which the production of a derivative of 3,1-benzothiazine is described. 

At high temperatures the isatoic anhydrides 227 react with the carboxylic acid halides 228 in the absence of bases with the formation of derivatives of 3,l-benzoxazin-4-one 229 [138],... 

The reaction of isatoic anhydride 1 with acetic or benzoic anhydride resulted in the formation of 2-methyl-3,l-benzoxazin-4-one (yield 84%) [142] or 2-phenyl-3,l-benzoxazin-4-one [143] respectively. 

This part examines syntheses based on isatoic anhydrides in which polycyclic systems containing two new condensed heterocycles are formed in one or two stages. Some examples of the formation of such compounds are also discussed in parts 2.1, 2.2, and 3. 

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. ... 

Another example of an isothiocyanate participating in a [4+2] cycloaddition reaction as a dienophile is the formation of the tetrahydroquinazoline derivative 183 from isatoic anhydride 182 and methyl isothiocyanate... 

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