Synthesis of 2,4-dihydroxyquinazolines using carbon dioxide in the presence of DBU under mild conditions

Article abstract of DOI:10.1016/S0040-4039(99)02231-5

Chemical fixation of carbon dioxide was performed under mild conditions. Carbon dioxide (1 atm) easily reacted with 2-aminobenzonitriles at 20°C, assisted by DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) to give 2,4- dihydroxyquinazolines in excellent yields.

Full text of DOI:10.1016/S0040-4039(99)02231-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1051–1053
Synthesis of 2,4-dihydroxyquinazolines using carbon dioxide in
the presence of DBU under mild conditions
Takumi Mizuno,∗ Noriaki Okamoto, Takatoshi Ito and Toshiyuki Miyata
Osaka Municipal Technical Research Institute, 1-6-50, Morinomiya, Joto-ku, Osaka 536-8553, Japan
Received 26 October 1999; revised 19 November 1999; accepted 26 November 1999
Abstract
Chemical fixation of carbon dioxide was performed under mild conditions. Carbon dioxide (1 atm) easily
reacted with 2-aminobenzonitriles at 20°C, assisted by DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) to give 2,4-
dihydroxyquinazolines in excellent yields. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: carbonylation; cyclisation; quinazolines; quinazolinones.
Substituted 2,4-dihydroxyquinazolines 1 have been interesting for their biological activities. For exam-
ple, 7-chloro-1-carboxymethyl-3-(40-bromo-20-fluorophenylmethyl)-2,4(1H,3H)quinazolinone (FK 366,
Zenarestat®) was developed as an aldol reductase inhibitor for a remedy of complications of diabetes
mellitus.1 Generally, synthesis of 1 is carried out by anthranilic acid with urea,2 anthranilamide with
phosgene3 or carbon monoxide with sulfur,4 and anthranilic acid with potassium cyanate (Scheme 1).5
However, these methods are considerably limited because of high toxicity of reagents or use of drastic
conditions. We herein wish to report a new and convenient synthesis of 2,4-dihydroxyquinazolines 1
from 2-aminobenzonitriles 2 and carbon dioxide under mild conditions (1 atm, 20°C) in the presence of
DBU.
The typical procedure is as follows: The DMF solution (20 mL) containing 2-aminobenzonitrile 2a
(1.18 g, 10 mmol) and DBU (4.49 mL, 30 mmol) was vigorously stirred under carbon dioxide (1 atm)
at 20°C for 24 h. The reaction mixture was then poured into 1N HCl (200 mL) and deposited solid was
washed with toluene (100 mL) and diethyl ether (100 mL). 2,4-Dihydroxyquinazoline 1a (1.57 g, 97%)
was afforded as a pure form. Shorter reaction time (6 h) lowered the yield of 1a (57%).
A variety of base was examined for this carbonylation of 2a using carbon dioxide under similar reaction
conditions for 24 h. DBU and DBN (1,5-diazabicyclo[4.3.0]non-5-ene) brought about the good results
of synthesis of 1a (97%, 94%, respectively). However, other bases (Dabco™ (1,4-diazabicyclo[2.2.2]-
octane), triethylamine, pyridine, K2CO3, NaHCO3, NaOH, and none) did not give product 1a at all.6
∗
Corresponding author. E-mail: tmizuno@omtri.city.osaka.jp (T. Mizuno)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02231-5
tetl 16159

1052
Scheme 1.
Several 2,4-dihydroxyquinazolines 1a–c were synthesized similarly from corresponding 2-amino-
benzonitriles 2a–c with carbon dioxide in the presence of DBU in excellent yields. Xanthine 1d from 5-
amino-4-cyanoimidazole 2d was also afforded in 52% under severer reaction conditions (30 atm, 120°C,
4 h).
Scheme 2 shows a plausible pathway for the formation of 1a from 2a with carbon dioxide by DBU.
The carbonylation of 2a with carbon dioxide generates carbamate salt 3a in the presence of DBU. Then
nucleophilic cyclisation of 3a into 4a followed by rearrangement of 4a gives 5a. Then, hydrolysis of 5a
affords final product 1a.8
Scheme 2.
From a viewpoint of simple operation, mild conditions, good yields and high purities of products,
safety of reagents, and utilization of carbon dioxide, the present reaction may provide a useful method
for the synthesis of 2,4-dihydroxyquinazolines 1.
References
1. (a) Goto, S.; Tsuboi, H.; Kagara, K. Chem. Express 1993, 8, 761. (b) Kagara, K.; Goto, S.; Tsuboi, H. Japanese Patent 1989,
25767.
2. (a) Pastor, G.; Blanchard, C.; Montginoul, C.; Torrieilles, E.; Giral, L.; Texier, A. Bull. Soc. Chim. Fr. 1975, 1331. (b) Khalifa,
M.; Osman, A. N.; Ibrahim, M. G.; Ossman, A.-R.; Ismail, M. A. Pharmazie 1982, 37, 115.
3. Michman, M.; Patai, S.; Wiesel, Y. Org. Prep. Proced. Int. 1978, 10, 13.
4. Miyata, T.; Mizuno, T.; Nagahama, Y.; Nishiguchi, I.; Hirashima, T.; Sonoda, N. Heteroat. Chem. 1991, 2, 473.
5. Lange, N. A.; Sheibley, F. E. Org. Synth. 1943, 2, 79.
6. Carbonylation with carbon dioxide using DBU was reported,7 where a CO2–DBU complex formed from carbon dioxide and
DBU has been considered to be an active species for carboxylation.7a

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7. (a) Haruki, E. In Organic and Bio-organic Chemistry of Carbon Dioxide; Inoue, S.; Yamazaki, N., Eds.; Kodansha Ltd:
Tokyo, 1981; p. 5. (b) Haruki, E.; Arakawa, M.; Matsumura, N.; Otsuji, Y.; Imoto, E. Chem. Lett. 1974, 427. (c) Hori, Y.;
Nagano, Y.; Fukuhara, T.; Teramoto, S.; Taniguchi, H. Nippon Kagaku Kaishi 1987, 1408.
8. The formation of isocyanate as an intermediate might be impossible under mild conditions. Industrial urea synthesis in which
isocyanate is as a key intermediate is performed under high pressure and temperature.9
9. Mavrovic, I. In Kirk–Othmer Encyclopedia of Chemical Technology; Mark, H. F., Ed.; Interscience Publishers: New York,
1970; Vol. 21, p. 37.