4H-l,3-Benzoxazin-4-ones

The enzyme catalyzes the hydrolysis of an amide bond linkage with water via a covalent enzyme-inhibitor adduct. Benzoxazinones such as 2-ethoxy-4H-3,l-benzoxazin-4-one [41470-88-6] (23) have been shown to completely inactivate the enzyme in a competitive and stoichiometric fashion (Eigure 5). The intermediate (25) is relatively stable compared to the enzyme-substrate adduct due to the electron-donating properties of the ortho substituents. The complex (25) has a half-life of reactivation of 11 hours. 

The reported examples of this ring system were obtained by the reaction of 2-ureidobenzonitrile (89JPR537) or 2-alky 1-4H--3, l-benzoxazin-4-one (84CPB2160) with anthranilic acid nitrile to give 6-aIkyI-13//-quinazolino[3,4-a]quinazolin-13-ones (546). 

The key step in the process is the thermal rearrangement of (2) to a 3-aryl-2-phenyl-4(3H)-quinazolinone (3). This 1,3-0 to N aryl migration was first observed by Tschitschi-babin and Jeletzky. This rearrangement proceeds at useful rates in the temperature range 275-325° it can be carried out neat, but the reaction is generally cleaner when run in heavy mineral oil. The final step consists of hydrolysis to the aniline and 2-phcnyl-4H-3,l-benzoxazine-4-one (4). This reaction can be carried out by alkaline... 

Selective biotransformation reactions on (i)-benzoxazines 01PAC167. Synthesis and reactions of 2-hetero (RO-, RS- or RR N)-4H-3,l-benzoxazin-4-ones 00JHC1369. 

Amino-4H-3,l-benzoxazin-4-ones from o-isocyanatocarboxylic acid chlorides... 

N- (Phenylcarbamyl) anthranilic acid treated 1 hr. at 80-100° with polyphosphoric acid l,2-dihydro-2-phenylimino-4H-3, l-benzoxazin-4-one (Y ca. 100%) treated 1 hr. at 150° with polyphosphoric acid 3-phenyl-2,4-quinazolinedione (Y 80%). M. Kurihara and N. Yoda, Tetrah. Let. 1065, 2597 Bull. Ghem. Soc. Japan 39, 1942 (1966). 

A soln. of 4-diloro-N-trifluoroacetylanthranilic acid and SOCl in dry benzene refluxed 12 hrs. 7-chloro-2-trifluoromethyl-4H-3,l-benzoxazin-4-one (Y 93%) dissolved with methyl 5-methoxy-2-methyl-2,3-dihydroindole-3-acetate in dimethyl sulfoxide, and heated 12 hrs. on a steam bath methyl l-(2-trifluoroacetamido-4-dilorobenzoyl)-5-methoxy-2-methyl-2,3-dihydroindole-3-acetate (Y 82%). F. e. s. D.R. Olson, W.J. Wheeler, and J.N. Wells, J. Med. Chem. 17, 167 (1974). 

A diflerent sequence afforded the biologically active 2-vinyl-4H-3,l-benzoxazin-4-ones 33 through the palladium-catalyzed reaction of o-iodoaniline 32 with unsaturated halides or triflates in the presence of K2CO3 and a catalytic amount of Pd(PPh3)4 under an atmosphere of carbon monoxide (Scheme 9.12) [41,42]. 

Cacchi, S., Fabrizi, G. and Marinelli, F. (1996) A novel one-pot palladium-catalysed synthesis of 2-substituted-4H-3,l-benzoxazin-4-ones. Synlett, 997-998. 

Arcadi, A., Asti, C., Caselli, G Marinelli, F. and Ruggirei, V. (1999) Synthesis and in vitro and in vivo evaluation of the 2-(6 -methoxy-3, 4 -dihydro-l -naphthyl)-4H-3,l-benzoxazin-4-one as a new potent substrate inhibitor of human leucocyte elastase. Biorganic ei Medicinal Chemistry Letters, 9, 1291-1294. 

When acid chlorides were used instead of cumulenes in the reaction with o-iodoanilines 3 and carbon monoxide (20atm), 2-substituted-4H-3,l-benzoxazin-4-ones 8 were obtained in good to excellent yields, also in the absence of a phosphine ligand [23]. The reaction is believed to proceed via in situ amide formation from o-iodoaniline and acid chloride, followed by oxidative addition to Pd(0), CO insertion, and intramolecular cyclization (Scheme 13.3). 

Azarifar and Sheikh [120] explored a convenient approach to 2,2 -(l,4-phenylene)bis[l-acetyl-l,2-dihydro-4H-3,l-benzoxazin-4-one] derivatives (169) employing the one-pot condensation of 2-aminobenzoic acids with benzene-l,4-di-carboxaldehyde under ultrasound irradiation conditions. The reactions proceeded smoothly in the presence of an excess of AC2O in the absence of any other catalyst and solvent affording the respective products in high yields (Scheme 44). 

SCHEME 44 Synthesis of 2,2 -(l,4-phenylene)bis[l-acetyl-l,2-dihydro-4H-3,l-benzoxazin-4-one] derivatives (169). 

Inata H and Matsumura S (1987) Chain extenders for polyesters. V. Reactivities of hydroxyl-addition-type chain extender 2,2 -bis(4H-3,l-benzoxazin-4-one), J Appl Polym Sci 34 2609-2617. 

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