Isatoic anhydride, reaction with amines

The use of activated anthranihc acid derivatives facUitates the preparation of the amides in those cases where the amines are either umeactive or difficult to obtain. Thus, reaction of (87-1) with phosgene gives the reactive the isatoic anhydride (89-1). Condensation of that with ortho-toluidine leads to the acylation product (89-2) formed with a simultaneous loss of carbon dioxide. This is then converted to the quinazolone (89-3) by heating with acetic anhydride. Reaction with sodium borohydride in the presence of aluminum chloride selectively reduces the double bond to yield the diuretic agent metolazone (89-4) [99]. 

A similar rapid microwave one-pot synthesis of substituted quinazolin-4-ones was also reported, which involved cyclocondensation af anthranilic acid, formic acid (or an orthoester) and an amine under solvent-free conditions (Scheme 3.37)61. A complimentary approach was adopted to synthesise 4-aminoquinazolines in very good yields, involving the reaction of aromatic nitrile compounds with 2-aminobenzonitrile in the presence of a catalytic amount ofbase (Scheme 3.38)62. The reactions were performed in a domestic microwave oven and required only a very short heating time. A microwave-assisted synthesis of a variety of new 3-substituted-2-alkyl-4-(3H)-quinazolinones using isatoic anhydride, 2-aminobenzimidazole and orthoesters has also been described (Scheme 3.38)63. 

Isatoic anhydride can be used as a versatile synthon for the synthesis of a diverse set of molecules. The isatoic anhydride can be reacted with amines, amides, hydrazides, isothiocyanates, diketo substrates, aminoacids, amino-, thio or hydroxy anilines, as well as in a three-component reaction with aldehydes and amines to form a large set of diverse pharmacophores. 

The 2,3-disubstituted 4(3//)-quinazolinones 306 are often prepared by reaction of amines with isatoic anhydride 305 as exemplified by Scheme 167 <2005SC279>. 

Amidine and amine groups may be joined together to form this triazepinone ring by heating the compound with methanolic sulphuric add for 3h. The reactant is obtained by stirring isatoic anhydride (review of reactions [3008]) with an amidrazone (formally, a hydrazone of a carboxamide). 

Some indirect applications of this reaction have been made. Isatoic anhydride (119) was converted to anthranilamide by ammonia in dimethyl-formamide addition of phosphoryl chloride converted this amide to 2-dimethylaminomethyleneaminobenzonitrile (analog of 118), which methyl-amine converted to 4-methylaminoquinazoline (see 1). It is remarkable that this was done in one vessel without isolation of intermediates and in good overall yield.158 Again, isatin-3-oxime (120) with phosphoryl chloride and dimethylformamide gave 2-dimethylaminomethyleneaminobenzonitrile, which was cyclized to 4-aminoquinazoline with ammonium acetate and to... 

When treated in water with ammonia, 2-aminobenzamide is quickly and quantitatively formed, and organic amines react similarly. These amino-benzamides can be used in all the syntheses described in Section VII,A. Conditions can be arranged so that a further reaction proceeds spontaneously, as when 5,7-dichloroisatoic anhydride gives a moderate yield of 6,8-dichloroquinazoline-2,4-dione when gently refluxed in aqueous ammonia for 1 hr.251,377 Isatoic anhydride can easily be N-alkylated or N-arylated with the appropriate halide or tosylate and potassium carbonate or sodium hydride.378... 

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],... 

In an extension of the Niementowski synthesis, it was found that 4-quinazolones could be also be synthesized via an isatoic anhydride intermediate/ Isatoic anhydride has been prepared from anthranilic acid using either phosgene or ethyl chlorocarbonate. Clark and Wagner reported that when isotoic anhydride 38 was heated with a primary amine and triethyl orthoformate, 39 was formed. The reaction likely proceeds by way of initial attack of the amine on the carbonyl group at the 4-position of 38 to form the corresponding anthranilamide followed by ring closure with triethyl orthoformate. If triethyl orthoformate is not added to the reaction mixture, the anthranilamide that is formed can be isolated and used as an intermediate for the synthesis of quinazolones by various methods. ... 

The mono- and disubstituted quinazolin-4(3/7)-one derivatives were firstly synthesized under solvent-free conditions by one-pot three-component reaction of isatoic anhydride, ortho ester, and anunonium acetate or an aliphatic and aromatic primary amine in the presence of SSA (Salehi et al., 2005) (Scheme 5.8). After completion of the reaction, the crude mass was diluted with hot ethanol and filtered. The filtrate was concentrated and products were purified by recrystallization from ethanol. Solvent-free... 

A set of benzo[d][l,3,2]diazaborinin-4(lfl)-ones 124, boron-containing quinazolinones, were prepared in a solvent-free, two-step, one-pot reaction starting with the condensation of isatoic anhydride and amines to give 2-aminobenzamides, followed by reaction with boronic acids (Scheme 43) (2013SC2936). 

Mechanistically, this tiansformation is probably initiated by the reaction between the primary amine and isatoic anhydride to give a carbamic acid derivative that spontaneously decarboxylates to afford anthranylamide derivative 69. The reaction of the latter with the carbonyl component affords the corresponding imine, which imdergoes a final intramolecular 6-endo-trig cyclization to give the final product, as summarized in Scheme 1.37 [57],... 

A convenient method for the synthesis of 3-substituted quinazolin-4(3H)- ones using the convergent reactions of formic acid, a primary amine, and isatoic anhydride under solvent-free conditions and with brief microwave irradiation is described. 

Dabiri et al. reported the s mthesis of 2-methylquinazolinones 167 (Scheme 92) in the presence of 1-methylimidazo-lium trifluoroacetate [HMIM] [TFA]. In reaction optimization studies, the authors found that the two steps could be carried out in a general and efficient one-pot process to afford a variety of 2-styryl quinazolinones. The tactic involved the addition of 0.1 g of [HMIM] [TFA] to a reaction mixture consisting of isatoic anhydride, amine, and triethyl orthoacetate in a ratio of 1 1 1 at 80 °C for 5 h, followed by treatment of the reaction mixture with 1 equivalent of an aromatic aldehyde under continued heating at 80 °C for 4-7 h to afford 2-styryl-substituted 4(3H)-quinazolinones 167 in good yield [258]. 

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