The simple solvent-free synthesis of 1H-quinazoline-2,4-diones using supercritical carbon dioxide and catalytic amount of base

Article abstract of DOI:10.1016/j.tetlet.2004.07.152

Using scCO₂ as a reactant and a solvent, 1H-quinazoline-2,4- diones were synthesized in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2004.07.152

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7073–7075
The simple solvent-free synthesis of 1H-quinazoline-2,4-diones
using supercritical carbon dioxide and catalytic amount of base
Takumi Mizuno,* Toshiyuki Iwai and Yoshio Ishino
Osaka Municipal Technical Research Institute, 1-6-50, Morinomiya, Joto-ku, Osaka 536-8553, Japan
Received 28 June 2004; revised 22 July 2004; accepted 26 July 2004
Available online 13 August 2004
Abstract—Only supercritical carbon dioxide (scCO2) as a reactant and a solvent, and catalytic amount of base (DBU (1,8-diazabi-
cyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), DabcoÒ (1,4-diazabicyclo[2.2.2]octane), and triethylamine) affor-
ded 1H-quinazoline-2,4-diones in good to excellent yields from 2-aminobenzonitriles. 6,7-Dimethoxy-1H-quinazoline-2,4-dione,
which is a key intermediate of medicines (Prazosin, Bunazosin, and Doxazosin) was synthesized successfully in a 97% yield, using
0.1equiv of DBU under scCO2 (10MPa) at 80°C.
Ó 2004 Elsevier Ltd. All rights reserved.
Substituted 1H-quinazoline-2,4-diones 1 have been
interesting for their biological activities. For example,
6,7-dimethoxy-1H-quinazoline-2,4-dione (1b) is a key
intermediate for the production of the following medi-
cines (Prazosin (MinipressÒ),1 Bunazosin (DetantolÒ),2
and Doxazosin (CardenalinÒ)3) (Fig. 1). These medi-
cines, which are effective a1-adrenergic blocker, are use-
ful for antihypertensives. 7-Chloro-1H-quinazoline-2,4-
diones (1d) is also a key intermediate of medicines (FK
366 (ZenarestatÒ) and KF31327). FK 366 (ZenarestatÒ)
O
O
N
N
CH3O
CH3O
N
N
Prazosin
NH2
HCl
H
O
CH3O
CH3O
N
NH
1b
O
O
O
N
O
O
N
N
CH3O
CH3O
N
N
CH3O
CH3O
N
N
Doxazosin
N
Bunazosin
NH2
NH2
HCl
Figure 1. 6,7-Dimethoxy-1H-quinazoline-2,4-dione (1b) is a key intermediate of Prazosin (MinipressÒ), Bunazosin (DetantolÒ), and Doxazosin
(CardenalinÒ).
Keywords: Supercritical carbon dioxide; Carbonylation; Cyclization; Quinazolines; Quinazolidinones; DBU.
*
Corresponding author. Tel.: +81 6 6963 8051; fax: +81 6 6963 8049; e-mail: tmizuno@omtri.city.osaka.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.152

7074
T. Mizuno et al. / Tetrahedron Letters 45 (2004) 7073–7075
Table 1. Effect of pressure and bases (0.1equiv) for synthesis of 1a
showed the effect for an aldose reductase inhibitor, and
was produced for a remedy of complications of diabetes
mellitus,4a,b and KF31327 was developed as a heart dis-
ease remedy and an impotence medicine.5
Entry
Pressure (MPa)
Base
Yield (%)
1
20a
10a
10a
6.0
3.0
10a
10a
10a
10a
10a
10a
DBUb
DBUb
DBUb,c
DBUb
DBUb
DBNd
Dabcoe
Et3N
88
91
69
89
76
86
89
70
0
2
3
The conventional syntheses of 1 are carried out by
anthranilic acid with urea,6a,b anthranilamide with phos-
gene,7 and anthranilic acid with potassium cyanate8 or
chlorosulfonyl isocyanate.9 However, these synthetic
methods are considerably limited because of high toxic-
ity of the reagents or the use of drastic conditions.
4
5
6
7
8
9
Pyridine
K2CO3
None
10
11
0
0
We recently reported a convenient synthesis of 1H-quin-
azoline-2,4-diones 1 from 2-aminobenzonitriles 2 by the
chemical fixation of carbon dioxide under mild condi-
tions (0.1MPa, 20°C) in the presence of an excess
amount of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
or DBN (1,5-diazabicyclo[4.3.0]non-5-ene) using DMF
as a solvent.10a,b Furthermore, we also found that a
catalytic amount of DBU or DBN has the exceptional
ability for the chemical fixation of carbon dioxide to
give 1 in excellent yields under 1.0MPa at 80°C in
DMF or DMSO.11 However, these reactions need
DMF or DMSO as an organic solvent.
a Supercritical state of CO2.
b 1,8-Diazabicyclo[5.4.0]undec-7-ene.
c DBU (0.05equiv) was used.
d 1,5-Diazabicyclo[4.3.0]non-5-ene.
e 1,4-Diazabicyclo[2.2.2]octane.
A variety of conditions of pressure and bases was inves-
tigated for the synthesis of 1a under solvent-free at 80°C
for 4h (Table 1). Under supercritical state of CO2 (10.0–
20.0MPa) and 6.0MPa of CO2, 1H-quinazoline-2,4-
dione (1a) was given in excellent yields (88–91%) in the
presence of catalytic amount of DBU (0.1equiv) (entries
1, 2, and 4). However, using a less amount of DBU
(0.05equiv) and low pressure of CO2 (3.0MPa) lowered
the yield of 1a (entries 3 and 5).
Carbon dioxide is an attractive C1 building block in or-
ganic synthesis as it is highly abundant, inexpensive,
nontoxic, and nonflammable. However, due to the inert
nature of carbon dioxide, efficient processes for chemical
fixation almost remain significant synthetic challenges.
Also, use of supercritical carbon dioxide as a substitu-
tion for organic solvents is of great important, because
of both for the toxicity for human and the environmen-
tal problems of organic solvents.12a–c
DBU, DBN, and DabcoÒ as bases gave the best results
of synthesis of 1a (91%, 86%, and 89%, respectively) (en-
tries 2, 6, and 7). Surprisingly, triethylamine afforded
1H-quinazoline-2,4-dione (1a) in fairly good yield
(70%) (entry 8). However, other bases (pyridine,
K2CO3, and none) did not give the product (1a) at all
(entries 9–11).
Therefore, if solvent-free synthesis of substituted 1H-
quinazoline-2,4-diones 1 from 2-aminobenzonitriles 2
using only supercritical carbon dioxide and catalytic
amount of base is established, it would be one of the
ideal organic reactions.
These results agreed with the reported carbonylation
reaction with carbon dioxide using DBU, where a
CO2–DBU complex formed from carbon dioxide and
DBU was considered to be an active species for carbox-
ylation.17a–d
With our goal in mind, we now developed a new simple
solvent-free synthesis of substituted 1H-quinazoline-2,4-
diones 1, which include medicine intermediates, using
supercritical carbon dioxide as a reactant and a solvent,
and catalytic amount of base (DBU, DBN, DabcoÒ
(1,4-diazabicyclo[2.2.2]octane), and triethylamine).13
Several 1H-quinazoline-2,4-diones (1a–d), which include
the key intermediates (1b and 1d) of medicines, were
synthesized similarly in good to excellent yields, from
the corresponding 2-aminobenzonitriles (2a–d) with car-
bon dioxide in the presence of 0.1–0.2equiv of DBU or
triethylamine under supercritical CO2 conditions
(10MPa, 80°C) (Scheme 2). However, 6-nitro-1H-qui-
At the outset, our trial showed a successful result of syn-
thesis of 1H-quinazoline-2,4-dione (1a) with supercriti-
cal carbon dioxide. 2-Aminobenzonitrile (2a) easily
reacted with scCO2 at 10MPa, 80°C for 4h in the pres-
ence of DBU (0.1equiv). Finally, 1H-quinazoline-2,4-
dione (1a) was given in 91% yield (Scheme 1).15
H
R1
R2
NH2
CN
R1
R2
N
O
cat. base
+
scCO2
10 MPa, 80 oC, 4 h
NH
2a-e
1a-e
O
Scheme 2. 1a, R1 = H, R2 = H, DBU (0.1equiv): 91%, Et3N
(0.1equiv): 70%; 1b, R1 = CH3O, R2 = CH3O, DBU (0.1equiv): 97%;
1c, R1 = H, R2 = Cl, DBU (0.1equiv): 54%, DBU (0.2equiv): 96%,
Et3N (0.2equiv): 86%; 1d, R1 = Cl, R2 = H, DBU (0.1equiv): 64%,
DBU (0.2equiv): 67%; 1e, R1 = H, R2 = NO2, DBU (0.1equiv): 0%,
DBU (0.5equiv): ca. 20%.
H
O
NH2
CN
N
DBU (0.1 equiv.)
+
scCO2
NH
1a, 91%
10 MPa, 80 oC, 4 h
O
2a
Scheme 1.

T. Mizuno et al. / Tetrahedron Letters 45 (2004) 7073–7075
7075
G.; Ossman, A. R. E.; Ismail, M. A. Pharmazie 1982, 37,
115–117.
7. Michman, M.; Patai, S.; Wiesel, Y. Org. Prep. Proced. Int.
1978, 10, 13–16.
8. Lange, N. A.; Sheibley, F. E. Org. Synth. 1943, 2, 79–80.
9. Vorbrueggen, H.; Krolikiewicz, K. Tetrahedron 1994, 50,
6549–6558.
10. (a) Mizuno, T.; Okamoto, N.; Ito, T.; Miyata, T.
Tetrahedron Lett. 2000, 41, 1051–1053; (b) Mizuno, T.;
Okamoto, N.; Ito, T.; Miyata, T. Heteroat. Chem. 2000,
11, 428–433.
O
H
N
-
+
O
NHCO DBU H
NH
2
DBU
+
CO
2
O
C
N
C
N
-
+
N
DBU H
4a
3a
2a
+
-
H
N
DBU H
O
O
N
N=C=O
- DBU
OH
-
DBU H
N
NH
6a
5a
+
1a
N
OH
O
11. Mizuno, T.; Ishino, Y. Tetrahedron 2002, 58, 3155–3158.
12. (a) Brennecke, J. F.; Chateauneuf, J. E. Chem. Rev. 1999,
99, 433–452; (b) Baiker, A. Chem. Rev. 1999, 99, 453–474;
(c) Jessop, P. G.; Ikariya, T.; Noyori, R. Chem. Rev. 1999,
99, 475–494.
13. Yoshida et al. partially presented the synthesis of 1H-
quinazoline-2,4-diones from scCO2 and DBU based on
our reports10a,11 at an annual meeting of the Chemical
Society of Japan.14
14. Sato, A.; Yoshida, M. Proceedings of 81st spring meeting
of the Chemical Society of Japan, 2002; Vol. 1, p 367.
15. General procedure for synthesis of 1H-quinazoline-2,4-
dione (1a) using scCO2 and catalytic amount of DBU.
Into a 50mL stainless steel autoclave, 2-aminobenzonitrile
(2a) (1.18g, 10mmol) and DBU (0.15mL, 1.0mmol) were
placed with a magnetic stirring bar. The autoclave was
finally charged with carbon dioxide at 10MPa using
scCO2 reaction system (JASCO Corp.). The reaction was
carried out at 10MPa, 80°C for 4h with stirring. After
evacuation of carbon dioxide and cooling down, the
resulting solid was then poured into 1N HCl (100mL) and
washed with water (100mL) and t-butyl methyl ether
(100mL). 1H-Quinazoline-2,4-dione (1a) was obtained in
Figure 2. A plausible reaction pathway.
nazoline-2,4-diones (1e) was obtained from 2-amino-5-
nitro-benzonitrile (2e) in only ca. 20% yield18 even using
0.5equiv of DBU, because of low basicity of 2e.
Figure 2 shows a plausible pathway for the formation of
1a from 2a with carbon dioxide aided by catalytic
amount of DBU. The carbonylation of 2a with carbon
dioxide generates a carbamate salt in the presence of cat-
alytic DBU. Then, nucleophilic cyclization of 3a into 4a,
followed by rearrangement of 4a by the way of isocya-
nate intermediate 5a, gives 6a. Finally, by the stabiliza-
tion of 6a, the final product (1a) is afforded. In this
reaction system, formation of isocyanate intermediate
5a assisted by o-cyano group seems to be important.
An industrial urea synthesis in which an isocyanate is
an intermediate, is performed under high temperature
conditions.19
In conclusion, a new simple solvent-free synthesis of
substituted 1H-quinazoline-2,4-diones 1, which include
medicine intermediates (Prazosin (MinipressÒ), Bunazo-
sin (DetantolÒ), Doxazosin (CardenalinÒ), FK 366
(ZenarestatÒ), and KF31327) from 2-aminobenzonitr-
iles was developed, using only supercritical carbon diox-
ide as a reactant and a solvent, and catalytic amount of
base (DBU, DBN, DabcoÒ, and triethylamine). The
present reaction seems to be one of the ideal synthetic
reactions.
a
91% yield (1.47g). 1H-Quinazoline-2,4-dione (1a):
mp > 300°C (>350°C16); IR (KBr) 3255, 3055,
1705cmÀ1 1H NMR (300MHz, d6-DMSO) 7.13–7.18
;
(m, 2H), 7.61 (t, J = 8Hz, 1H), 7.86 (d, J = 8Hz, 1H),
11.11 (s, 1H), 11.25 (s, 1H); 13C NMR (75MHz, d6-
DMSO) 114.3, 115.3, 122.3, 126.9, 134.9, 140.8, 150.3,
162.8; MS (m/z, %) 162 (M+, 100), 119 (48), 92 (17); Exact
MS calcd for C8H6N2O2: 162.0429. Found: 162.0408.
16. Beilstein 24, 373.
17. (a) Haruki, E. In Organic and Bio-organic Chemistry of
Carbon Dioxide; Inoue, S., Yamazaki, N., Eds.; Kodan-
sha: Tokyo, 1981; pp 5–78; (b) Haruki, E.; Arakawa, M.;
Matsumura, N.; Otsuji, Y.; Imoto, E. Chem. Lett., 1974,
427–428; (c) Hori, Y.; Nagano, Y.; Fukuhara, T.; Tera-
moto, S.; Taniguchi, H. Nippon Kagaku Kaishi, 1987,
References and notes
´
1408–1413; (d) Perez, E. R.; Silva, M. O.; Costa, V. C.;
1. Merck Index 1996, 12, 7897.
2. Merck Index 1996, 12, 1512.
3. Merck Index 1996, 12, 3489.
Rodrigues-Filho, U. P.; Franco, D. W. Tetrahedron Lett.
2002, 43, 4091–4093.
18. 6-Nitro-1H-quinazoline-2,4-dione (1e) could not be puri-
fied as a pure form, because of low solubility of 1e for
organic solvents. Yield of 1e was determined by 1H
NMR.
19. Mavrovic, I. In Kirk–Othmer Encyclopedia of Chemical
Technology; Mark, H. F., Ed.; Interscience: New York,
1970; Vol. 21, pp 37–56.
4. (a) Goto, S.; Tsuboi, H.; Kagara, K. Chem. Express 1993,
8, 761–764; (b) Kagara, K.; Goto, S.; Tsuboi, H. Japanese
Patent 25767, 1989; Chem. Abstr. 1989, 111, 97274.
5. Mohri, S. J. Synth. Org. Chem. Japan 2001, 59, 514–515.
6. (a) Pastor, G.; Blanchard, C.; Montginoul, C.; Torreilles,
E.; Giral, L.; Texier, A. Bull. Soc. Chim. Fr. 1975,
1331–1338; (b) Khalifa, M.; Osman, A. N.; Ibrahim, M.