Isatoic Anhydride1

[118-48-9]  · C8H5NO3  · Isatoic Anhydride  · (MW 163.14)

(reacts with either electrophiles or nucleophiles; derivatives have been widely used in pesticides, dyes, pigments, flavors, fragrances, pharmaceuticals, and miscellaneous industrial chemicals)

Alternate Name: 2H-3,1-benzoxazine-2,4(1H)-dione.

Physical Data: mp 233 °C; bp 350 °C.

Solubility: sol most organic solvents.

Form Supplied in: gray-brown powder; commercially available.

Handling, Storage, and Precautions: store in a dry, cold area. Use in a fume hood; gradually decomposes at high temperature upon exposure to air and water, and generates toxic gases (CO, NO, CO2).

Reactions with Electrophiles.

N-Substituted isatoic anhydrides can be obtained by reacting isatoic anhydride with various electrophiles (CH2N2, Me2SO4, MeI, RSCl) as shown in eq 1.1-3 Aromatic substitution of isatoic anhydride usually occurs at the 6-position, as shown in eq 2.4 However, the 8-substituted isatoic anhydride is obtained when the 6-position is already occupied (eq 3).5

Reactions with Nucleophiles.

Due to the different reactivity of the carbonyl groups, various nucleophiles react with isatoic anhydride at either the C-2 or C-4 position under controlled conditions.1 In principle, C-4 acts like an anhydride and is more reactive than C-2, which is closer to a carbamate in reactivity. In contrast, ionization can transform isatoic anhydride into 2-carboxyphenyl isocyanate, which reacts with nucleophiles only at C-2.1,6 Under the influence of acid or base catalysts, isatoic anhydride reacts with H2O, ROH, and RSH at C-4 to give the corresponding anthranilic acid, anthranilate ester, and anthranilate thioester, respectively.6,7 A less hindered primary amine (n-butylamine) also attacks C-4 to produce the corresponding anthranilamide (path a, eq 4). A bulky amine (t-butylamine) reacts through path b to give o-ureidobenzoic acid because C-2 is relatively unhindered relative to C-4.8 However, N-substitution (N-methylisatoic anhydride) blocks C-2, and all nucleophiles attack at the 4-position.9 In addition, highly nucleophilic species, such as carbanions, attack the C-4 carbonyl group and release a CO2 molecule.1

Solvent effects are also important in reactions of isatoic anhydride with nucleophiles. In general, polar aprotic solvents increase the yield of anthranilamide significantly.10 For example, the yield of the reaction of t-butylamine with isatoic anhydride is raised to 74% in DMF from 9% in water. In addition, the concentration as well as the ratio of the reactants is important.11 For example, the highest yield of anthranilamide was obtained by reacting 5 equiv of ammonia with a 2 M solution of isatoic anhydride (eq 5). Increasing the concentration of the substrate or changing the ammonia:substrate ratio decreased the yield of anthranilamide. Polymeric side products were formed when only 0.5 equiv of ammonia were used.

Formation of Heterocycles.

The preparation of nitrogenous heterocycles from isatoic anhydride has been reported.1 For example, the reaction of a derivative of isatoic anhydride with a lithium enolate gave a quinoline-type alkaloid (eq 6).12 The reactions of isatoic anhydride with amides, ureas, thioureas, isocyanates, and thiocyanates produce quinazolinones in one step (eq 7).1,13 The synthesis can also be carried out in a stepwise fashion. The displacement of the 3-oxygen of isatoic anhydride by an amine or hydrazine results in evolution of CO2 gas. The reaction of the product o-aminobenzoylhydrazine with an orthoester, chloroformate, or phosgene also gives a quinazolinone (eq 8).1,14 Treatment of the intermediate N-(2-aminobenzoyl)-a-amino ester with nitrous acid generates a benzotriazine (eq 9).15 On the other hand, ethyl glycinate reacts with isatoic anhydride to give a moderate yield of benzodiazepinone in the presence of pyridine (eq 10).16 A benzotriazepinone was produced directly from the reaction of benzoylhydrazine with isatoic anhydride (eq 11).17

1. Coppla, G. M. S 1980, 505.
2. Sherwin Williams Technical Bulletin No. 152.
3. (a) Wang, C. H.; Feng, T. C.; Christensen, B. E. JACS 1950, 72, 4887. (b) Sherwin Williams Technical Bulletin. No. 14. (c) Kricheldorf, H. R. AG 1973, 85, 86 (AG(E) 1973, 12, 73).
4. (a) Piskov, V. B. et al. Khim.-Farm. Zh. 1973, 7, 8 (CA 1973, 79, 78 332). (b) Junge, H.; Quadbeck-Seeger, H. J. Ger. Offen. 1973, 2 206 863 (CA 1973, 79, 137 170). (c) Bertelson, R. C.; Becker, W. J. JHC 1966, 3, 422. (d) Sherwin Williams Technical Bulletin No. 7.
5. Adams, R.; Snyder, H. R. JACS 1938, 60, 1411.
6. (a) Staiger, R. P.; Miller, E. B. JOC 1959, 24, 1214. (b) Bunnett, J. F.; Naff, M. B. JACS 1966, 88, 4001. (c) Washburne, S. S.; Peterson, W. R. Jr.; Berman, D. A. JOC 1972, 37, 1738. (d) Hegarty, A. F.; Ahern, E. P.; Frost, L. N.; Hegarty, C. N. JCS(P2) 1990, 11, 1935.
7. (a) Niementowski, S.; Rozanski, B. CB 1889, 22, 1672. (b) Kolbe, H. JPR 1884, 30, 467. (c) Staiger, R. P.; Moyer, C. L.; Pitcher, G. R. CED 1963, 8, 454.
8. Staiger, R. P.; Wagner, E. C. JOC 1953, 18, 1427.
9. Coppola, G. M.; Mansukhani, R. I. JHC 1978, 15, 1169.
10. (a) Jacobs, R. L. JHC 1970, 7, 1337. (b) Heindel, N. D.; Five, W. P.; Lemke, T. F.; Carrano, R. A. JPS 1971, 60, 703.
11. (a) Sheibley, F. E. JOC 1938, 3, 41. (b) Clark, R. H.; Wagner, E. C. JOC 1944, 9, 55. (c) Sheibley, F. E. JOC 1947, 12, 743. (d) Staiger, R. P.; Wagner, E. C. JOC 1948, 13, 347.
12. Coppla, G. M. SC 1985, 15, 135.
13. (a) Cortez, R.; Rivero, I. A.; Somanathan, R.; Aguirre, G.; Ramirez, F.; Hong, E. SC 1991, 21, 285. (b) Reisner, D. B. et al. AF 1977, 27, 766.
14. (a) Reisch, J.; Usifoh, C. O.; Oluwadiya, J. O. JHC 1989, 26, 1495. (b) Kornet, M. J.; Varia, T.; Beaven, W. JHC 1983, 20, 1553.
15. (a) Susse, M.; Johne, S. HCA 1985, 68, 892. (b) Suesse, M.; Johne, S. ZC 1986, 26, 167.
16. (a) Kamal, A. JOC 1991, 56, 2237. (b) Mohiuddin, G.; Reddy, P. S. N.; Ahmed, K.; Ratnam, C. V. IJC(B) 1985, 24, 905. (c) Peña, M. R.; Stille, J. K. JACS 1989, 111, 5417. (d) Nagasaka, T.; Koseki, Y.; Hamaguchi, F. TL 1989, 30, 1871.
17. (a) Peet, N. P. S 1984, 1065. (b) Reddy, C. K.; Reddy P. S. N.; Ratnam, C. V. IJC(B) 1989, 27B, 568. (c) Reddy, C. K.; Reddy, P. S. N.; Ratnam, C. V. S 1983, 842.

Teng-Kuei Yang & Shun-Ming Hung

National Chung-Hsing University, Taichung, Taiwan

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