Rearrangement of 4-imino-(1H,4H)-3,1-benzoxazine-2-ones to 2,4- quinazolinediones via an isocyanate carboxamide intermediate

Article abstract of DOI:10.1016/S0040-4039(00)00803-0

Reaction of 3-arylimino-2-indolinones 1 with m-chloroperbenzoic acid in CH₂Cl₂ or methanol at 0°C leads to the corresponding 3-aryl-2,4(1H,3H)- quinazolinediones 4 and (2-arylcarbamoyphenyl)carbamic acid methyl ester 5, respectively.

Full text of DOI:10.1016/S0040-4039(00)00803-0

Tetrahedron Letters 41 (2000) 5265±5268
Rearrangement of 4-imino-(1H,4H)-3,1-benzoxazine-2-ones
to 2,4-quinazolinediones via an isocyanate carboxamide
intermediate
Javad Azizian,* Morteza Mehrdad,* Khosrow Jadidi and Yaghob Sarra®
Department of Chemistry, Faculty of Sciences, Shahid Beheshti University, Shahid Chamran Highway,
Evin 19834, Tehran, Iran
Received 13 March 2000; accepted 16 May 2000
Abstract
Reaction of 3-arylimino-2-indolinones 1 with m-chloroperbenzoic acid in CH2Cl2 or methanol at 0ꢀC
leads to the corresponding 3-aryl-2,4(1H,3H)-quinazolinediones 4 and (2-arylcarbamoyphenyl)carbamic
acid methyl ester 5, respectively. These conversions proceed through 4-arylimino-(1H,4H)-3,1-benzoxazin-
2-one 2 and its ring-opened isocyanate carboxamide isomer 3 as key intermediates. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: benzoxazines; carbamates; quinazolinones; rearrangements.
The synthesis of 3-aryl-2,4-quinazolinediones are of current interest from both pharmacological
and chemical aspects.1 These compounds are prepared by various methods.2 Most of these
methods involve rearrangement of di€erent starting materials.3
Recently, we have reported the preparation of 3-arylimino-2-indolinones 1 and their applications
for the synthesis of several types of heterocyclic systems.4 As a continuation of this work, we wish
to report the rearrangement and mechanism of the formation of 3-aryl-2,4(1H,3H)-quinazoline-
diones 4 from oxidation of isatin-3-imines 1 with m-chloroperbenzoic acid (m-CPBA).
When 3-arylimino-2-indolinones 1a±d reacted at 0ꢀC with m-CPBA in CH2Cl2 the expected
N-aryl-2,4-quinazolinediones 4a±d were obtained. This oxidation had been reported with hydrogen
peroxide in alkaline solution.5 The product 4 was easily separated on silica gel from impurities by
dry ¯ash chromatography.6 The impurities were unstable compounds and decomposed during the
separation process. However, when these impurities were heated in methanol, (2-arylcarbamoy-
phenyl)carbamic acid methyl ester 5 was obtained in low yield. When imine 1 was treated with
m-CPBA in methanol, carbamate 5 was also obtained in high yield (Scheme 1). The results are
summarized in Table 1. On the other hand, when carbamate 5 was heated to its melting point,
ring closure occurred, and the quinazolinediones 4 were obtained.
* Corresponding authors. Fax: +00 98 21 240 3941; e-mail: m-mehrdad@cc.sbu.ac.ir
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00803-0

5266
Scheme 1.
Table 1
The preparation and yield of 3-aryl-2,4(1H,3H)-quinazolinediones 4 and (2-arylcarbamoylphenyl)-
carbamic acid methyl ester 5 and N-methyl-4-(p-tolylimino)-(1H,4H)-3,1-bezoxazine-2-one 7
A possible mechanism for the conversion of 1 to 4 is through 4-imino-(1H,4H)-3,1-benzoxazin-
2-one 2 as a product of Baeyer±Villiger oxidation followed by rearrangement of 2 to the isocyanate
carboxamide intermediate 3 as proposed in Scheme 1. Recently, a similar rearrangement was
reported for 4-imino-4H-3,1-benzoxazines to 4-quinazolinones via amidine carboxamides.7
The separation and puri®cation of 2 was not possible; 2a is the only example that has been
reported as a likely intermediate; however, the authors were not sure of the actual structure of
2a.12 The formation of intermediates 3 by a ring-opening has not been reported. However, the
intermediates have previously been obtained by a variety of methods. N-Aryl-2,4-quinazoline-
dione 4 has been obtained through this intermediate by: (i) the pyrolysis of 1-phenyl-5-(o-carboxy-
phenyl) tetrazole;13a (ii) the reaction of isatoic anhydride with SOCl2 or PCl5 and then treatment

5267
with 1 equivalent of amine;13b (iii) the reaction of N-mesyloxy phthalimide with aniline and triethyl-
amine;13c and (iv) the reaction of imino-phosphorane with carbon dioxide.9 However, none of
these authors have proved the structure of their intermediates. A hydrogen shift and formation of
isocyanate 3 must be considered for the rearrangement of 2 into 4. This isocyanate intermediate
3 can cyclize spontaneously to give 4, or methanol attacks the isocyanate to generate carbamate 5.
In support of the proposed mechanism, when N-methyl-3-(p-tolylimino)-2-indolinone 6 was
treated in CH2Cl2 or MeOH with m-CPBA under the same reaction condition, the new com-
pound N-methyl-4-(p-tolylimino)-(1H,4H)-3,1-benzoxazin-2-one 7 was obtained (Scheme 2). In
this case, the formation of an isocyanate is impossible (Table 1).
Scheme 2.
The preparation of 3-phenyl-2,4(1H,3H)-quinazolinedione 4a from oxidation of 1a is representa-
tive. The imine 1a (2 mmol) in CH2Cl2 (25 ml) was cooled to 0ꢀC in an ice-bath and m-CPBA (2.4
mmol) dissolved in the same solvent (25 ml) was added dropwise to a vigorously stirred solution.
After 45 min at 0ꢀC, some of the product 4 was precipitated and was ®ltered, and the ®ltrate was
poured into water. Dichloromethane (50 ml) was added and the organic layer was separated,
washed (1 M Na2SO3, 2 M NaHCO3) and dried (Na2SO4). The rest of product 4 was obtained by
evaporation of solvent at low pressure. The pure product 4a was easily separated on silica gel by
dry ¯ash chromatography using hexane/ethyl acetate6 or the crude product was recrystallized
from methanol.
Satisfactory mass and 13C NMR spectra were obtained for 4, in good agreement with the
1
reported values.14 The structures of 5a±d and 7 are supported by H and 13C NMR. HH COSY
and CH COSY provided additional support for assignments of protons and carbons of structures
4,15 516 and 7.17
Due to the simplicity of the experimental one-pot procedure and mild conditions, the synthesis
of various compounds 4, 5 and 7 by this method is ecient. Compounds 4 and 5 have been tested
against Mycobacterium avium, which is the most common systematic bacterial infection complicating
AIDS, but were not found to be active.1a Recently, it was reported that the replacement of the
oxygen in the heterocyclic ring resulted in a decrease or loss of antimycobacterial activity.1b There-
fore, the new compound 7 may be an active substance in this regard and will be tested in due course.
Acknowledgements
We thank the Vice President of research a€airs at the Shahid Beheshti University for ®nancial
support. Professors I. Yavari and A. Sha®ee are appreciated for their consultations. Finally, we
gratefully acknowledge Professor A. Khodai for helpful suggestions.

5268
References
1. (a) Waisser, K.; Machacek, M.; Dostal, H.; Gregor, J.; Kubicova, L.; Klimesova, V.; Kunes, J.; Palat Jr., K.;
Hladuvkova, J.; Kaustova, J.; Mollmann, U. Collect. Czech. Chem. Commun. 1999, 64, 1902±1924, and references
cited therein. (b) Waisser, K.; Dostal, H.; Kubicova, L.; Kaustova, J. Folia Pharm. Univ. Carol. 1998, 23, 139±140.
2. (a) Pawlewski, B. Chem. Ber. 1905, 38, 130±131. (b) Taub, B.; Hino, J. B. J. Org. Chem. 1961, 26, 5238±5239. (c)
Garin, J.; Melendez, E.; Merchan, F. L.; Tejero, T.; Villarroya, E. Synthesis 1983, 406±408. (d) Brown, D. J.
Quinazolines, Supplement 1; Wiley: New York, 1996; Chapter 4.
3. (a) Hurd, C. D.; Buess, C. M.; Bauer, L. J. Org. Chem. 1954, 19, 1140±1149. (b) Kurihara, M.; Yoda, N. Bull.
Chem. Soc. Jpn. 1966, 39, 1942±1948. (c) Olofson, R. A.; Vander Meer, R. K. J. Org. Chem. 1984, 49, 3377±3379.
(d) El-Tamany, E. H.; Salem, E. M.; Metwally, R. N.; El-Soghier, A. H. Egypt. J. Chem. 1997, 40, 339±351.
4. (a) Azizian, J.; Morady, A. V.; Jadidi, K.; Mehrdad, M.; Sarra®, Y. Synth. Commun. 2000, 30, 537±542. (b)
Azizian, J.; Jadidi, K.; Mehrdad, M.; Sarra®, Y. Synth. Commun., in press. (c) Azizian, J.; Sarra®, Y.; Mehrdad,
M.; Jadidi, K. Indian J. Chem. B. 2000, in press.
5. Jacini, G. Gazz. Chim. Ital. 1943, 73, 85±88. Chem. Abstr. 1944, 38, 5825.
6. Shusterman, A. J.; Mc Dougal, P. G.; Glasfeld, A. J. Chem. Educ. 1997, 74, 1222±1223.
7. He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397±1399.
8. Spence, T. W. M.; Tennant, G. J. Chem. Soc., Perkin Trans. 1 1972, 97±102.
9. Monia, P.; Alajarin, M.; Vidal, A. Tetrahedron 1989, 45, 4263±4286.
10. Winternitz, P.; Rapos, P.; Synak, J. Czech. Patent 128,433, 1968. Chem. Abstr. 1969, 70, 115176z.
11. Wagner, G.; Rothe, L. Pharmazie 1970, 25, 730±731.
12. Aurich, H. G.; Grigo, U. Chem. Ber. 1976, 109, 200±211.
13. (a) Behringer, H.; Fischer, H. J. Chem. Ber. 1961, 94, 2562±2566. (b) Iwakura, Y.; Uno, K.; Kang, S. J. Org.
Chem. 1966, 31, 142±146. (c) Imai, Y.; Ueda, M.; Ishimori, M. J. Polym. Sci., Polym. Chem. Ed. 1975, 13, 1969±
1977.
14. (a) Himottu, M.; Pihlaja, K.; Stajer, G.; Vainiotalo, P. Rapid Commun. Mass Spectrom. 1993, 7, 374±377. (b)
Petridou-Fischer, J.; Papadopoulos, E. P. J. Heterocyclic Chem. 1982, 19, 123±126.
15. Compound 4a: 1H NMR (500 MHz, DMSO) ꢀ (ppm), J (hertz): 11.55 (s, 1H, NH), 7.93 (dd, 1H, J=8.0, 1.5, 5-H),
7.67 (ddd, 1H, J=8.5, 7.5, 1.5, 7-H), 7.48 (dd, 2H, J=7.5, 7.0, 30, 50-H), 7.41 (ddd, 1H, J=7.0, 7.0, 1.5, 40-H), 7.32
(dd, 2H, J=7.5, 1.5, 20, 60-H), 7.23 (dd, 1H, J=8.5, 1.0, 8-H), 7.20 (ddd, 1H, J=8.0, 7.5, 1.5, 6-H). 13C NMR (125
MHz, DMSO) ꢀ (ppm): 162.2 (C-4), 150.1 (C-2), 139.8 (C-8a), 135.7 (C-10), 135.1 (C-7), 129.0 (C-20, 60), 128.7 (C-
30, 50), 128.0 (C-40), 127.5 (C-5), 122.4 (C-6), 115.2 (C-8), 114.3 (C-4a).
16. Compound 5a: 1H NMR (500 MHz, DMSO) ꢀ (ppm), J (hertz): 10.45 (s, 1H, NHCOOMe), 10.23 (s, 1H, NHCO-),
8.11 (d, 1H, J=8.5, 6-H), 7.84 (dd, 1H, J=7.5, 2.0, 3-H), 7.74 (d, 2H, J=8, 1.0, 20, 60-H), 7.53 (ddd, 1H, J=8.5,
7.0, 2, 5-H), 7.36 (dd, 2H, J=8.0, 7.5, 30, 50-H), 7.18 (dd, 1H, J=7.5, 7.0, 4-H), 7.13 (ddd, 1H, J=7.5, 7.5, 1, 40-H),
3.67 (s, 3H, OCH3). 13C NMR (125 MHz, DMSO) ꢀ (ppm): 167.1 (C-amide), 153.5 (C-carbamate), 138.6 (C-2),
138.5 (C-10), 132.1 (C-5), 128.8 (C-3), 128.5 (C-30, 50), 124.1 (C-40), 122.2 (C-4), 122.2 (C-1), 120.9 (C-20, 60), 119.7
(C-6), 52.0 (C-methyl).
1
17. Compound 7: H NMR (500 MHz, DMSO) ꢀ (ppm), J (hertz): 8.08 (dd, 1H, J=8.0, 1.5, 5-H), 7.66 (ddd, 1H,
J=8.5, 7.5, 1.5, 7-H), 7.29 (dd, 1H, J=8.5, 1.0, 8-H), 7.26 (ddd, 1H, J=8.0, 7.5, 1.0, 6-H), 7.15 (d, 2H, J=8.0, 20,
60-H), 7.04 (d, 2H, J=8.0, 30, 50-H), 3.38 (s, 1H, N-CH3), 2.28 (s, 3H, Ph-CH3). 13C NMR (125 MHz, DMSO) ꢀ
(ppm): 146.8 (C-2), 145.1 (C-4), 142.0 (C-8a), 139.6 (C-40), 134.0 (C-7), 133.2 (C-10), 129 (C-30, 50), 126.9 (C-5),
123.5 (C-6), 122.4 (C-20, 60), 114.4 (C-8), 114.1 (C-4a).