Highly efficient synthesis of 1H-quinazoline-2,4-diones using carbon dioxide in the presence of catalytic amount of DBU

Article abstract of DOI:10.1016/S0040-4020(02)00279-X

The first example of chemical fixation of carbon dioxide in the presence of catalytic amount of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or DBN (1,5-diazabicyclo[4.3.0]non-5-ene) was developed. Carbon dioxide easily reacted with 2-aminobenzonitriles under

Full text of DOI:10.1016/S0040-4020(02)00279-X

TETRAHEDRON
Pergamon
Tetrahedron 58 '2002) 3155±3158
Highly ef®cient synthesis of 1H-quinazoline-2,4-diones using
carbon dioxide in the presence of catalytic amount of DBU
p
Takumi Mizuno and Yoshio Ishino
Osaka Municipal Technical Research Institute, 1-6-50, Morinomiya, Joto-ku, Osaka 536-8553, Japan
Received 16 February 2002; accepted 6 March 2002
AbstractÐThe ®rst example of chemical ®xation of carbon dioxide in the presence of catalytic amount of DBU '1,8-diazabicyclo[5.4.0]-
undec-7-ene) or DBN '1,5-diazabicyclo[4.3.0]non-5-ene) was developed. Carbon dioxide easily reacted with 2-aminobenzonitriles under
mild conditions '1 atm, 20 8C), assisted by excess amount of DBU or DBN to give corresponding 1H-quinazoline-2,4-diones in excellent
yields. Also, catalytic amount of DBU or DBN is effective for the synthesis of 1H-quinazoline-2,4-diones. Using catalytic amount of DBU
w
0.05 equiv.), 7-chloro-1H-quinazoline-2,4-diones which is a key intermediate of medicines 'FK366, Zenarestat and KF31327) was
pressure of 10 atm at 808C. q 2002 Elsevier Science Ltd. All rights reserved.
'
synthesized successfully in a 90% yield under the CO
2
1. Introduction
We report here the full results of our investigations on a
convenient synthesis of 1H-quinazoline-2,4-diones 1 from
Use of chemical ®xation of carbon dioxide on the ®ne
chemicals production is of importance for both the environ-
mental problems of global warming and the effective
utilization of chemical resources. Carbon dioxide is also
2-aminobenzonitriles 2 by the chemical ®xation of carbon
dioxide under mild conditions '1 atm, 208C) in the presence
of excess amount of DBU '1,8-diazabicyclo-[5.4.0]undec-7-
ene) or DBN '1,5-diazabicyclo[4.3.0]non-5-ene). Further-
more, we established the ®rst example of chemical ®xation
of carbon dioxide in the presence of catalytic amount of
DBU or DBN.
7
,8
an attractive C building block in organic synthesis as it is
1
highly abundant, inexpensive, nontoxic, and non¯ammable.
However, due to the inert nature of carbon dioxide, ef®cient
catalytic processes for chemical ®xation remain signi®cant
synthetic challenges.
2. Results and discussion
We developed a new chemical ®xation of carbon dioxide to
form substituted 1H-quinazoline-2,4-diones 1 which is
useful for the synthesis of medicine intermediates. Substi-
tuted 1H-quinazoline-2,4-diones 1 have been interesting for
their biological activities. For example, 7-chloro-1H-quin-
azoline-2,4-diones '1g) is a key intermediate for the produc-
Our initial studies showed that successful synthesis of
1H-quinazoline-2,4-dione '1a) from 2-aminobenzonitrile
'2a) with 3.0 equiv. of DBU in DMF was performed at
w
tion of the following medicines. FK 366 'Zenarestat )
showed the effect for an aldose reductase inhibitor, and
was produced for a remedy of complications of diabetes
mellitus, and KF31327 was developed as a heart disease
1
a,b
2
remedy and an impotence medicine 'Fig. 1). The conven-
tional syntheses of 1 are carried out by anthranilic acid with
3
a,b
urea, anthranilamide with phosgene, and anthranilic acid
4
5
with potassium cyanate or chlorosulfonyl isocyanate.
6
However, these synthetic methods are considerably limited
because of high toxicity of the reagents or the use of drastic
conditions.
Keywords: carbon dioxide; carbonylation; cyclyzation; catalytic; quinazo-
lines; quinazolidinones.
p
Corresponding author. Tel.: 181-6-6963-8057; fax: 181-6-6963-8049;
e-mail: tmizuno@omtri.city.osaka.jp.
Figure 1. 7-Chloro-1H-quinazoline-2,4-dione '1g) is a key intermediate of
FK 366 'Zenarestat ) and KF31327.
w
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020'02)00279-X

3156
T. Mizuno, Y. Ishino / Tetrahedron 58 '2002) 3155±3158
room temperature '208C) under a CO atmosphere '1 atm)
2
for 24 h. The pure carbonylation and cyclization easily
proceeded under mild conditions to give 1H-quinazoline-
2,4-dione '1a) in a 97% yield 'Scheme 1).
A variety of bases was investigated as catalysts for this CO2
xation under similar mild conditions for 24 h 'Table 1).
®
Scheme 1.
DBU '1,8-diazabicyclo[5.4.0]undec-7-ene) or DBN '1,5-di-
azabicyclo[4.3.0]non-5-ene) gave the best results of syn-
thesis of 1a '97, 94%, respectively) 'entries 1 and 4).
However, a shorter reaction time '6 h) lowered the yield
of 1a '57%) 'entry 2). Also by use of severe reaction con-
ditions '10 atm, 808C), 1a was obtained quantitatively
Table 1. Effect of bases '3.0 equiv.) for synthesis of 1a
Entry
Base
Yield %
a
1
2
3
4
5
6
7
8
9
DBU
97
57
98
94
0
0
0
0
0
b
DBU
DBU
DBN
'98%) after a short reaction time '1 h) 'entry 3). However,
other bases 'Dabco
c
w
d
'1,4-diazabicyclo[2.2.2]-octane),
K CO , triethylamine, NaOH, NaHCO , pyridine, and
e
Dabco
CO
Et
NaOH
NaHCO
2
3
3
K
2
3
none) did not give the product '1a) at all 'entries 5±11).
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
3
N
3
1
1
0
1
Pyridine
None
0
0
9
a±c
considered to be an active species for carboxylation.
a
b
c
d
e
1
,8-Diazabicyclo[5.4.0]undec-7-ene.
Several 1H-quinazoline-2,4-diones '1a±d) were synthe-
sized similarly from the corresponding 2-aminobenzo-
nitriles '2a±d), substituted by either an electron donating
group or electron withdrawing groups, with carbon dioxide
in the presence of 3.0 equiv. of DBU under mild conditions
6
1
1
1
h.
0 atm, 808C, 1 h.
,5-Diazabicyclo[4.3.0]non-5-ene.
,4-Diazabicyclo[2.2.2]octane.
'1 atm, 208C) in excellent yields 'Scheme 2). Xanthine '1e)
was obtained from 5-amino-4-cyanoimidazole '2e) in 52 %
yield under 30 atm, 1208C for 4 h.
Excess amount '3.0 equiv.) of DBU or DBN showed the
effective chemical ®xation of carbon dioxide to synthesize
1
H-quinazoline-2,4-diones '1a±d) from 2-aminobenzo-
nitriles '2a±d) under mild conditions '1 atm, 208C).
However, from the viewpoint of application of the present
reaction to actual industrial production of 1, an ef®cient
catalytic process 'using catalytic amount of DBU) for
chemical ®xation of carbon dioxide is very signi®cant.
Therefore, effect of catalytic amount of DBU was examined
for the synthesis of 1H-quinazoline-2,4-dione '1a) from
2-aminobenzonitrile '2a) with carbon dioxide as a model
'Table 2). Under 1 atm, 208C, more than 1.0 equiv. of
DBU was necessary to obtain quantitative yields of 1a
'entries 1±3). However, using 0.1 equiv. of DBU under
Scheme 2.
Table 2. Effect of reaction conditions for synthesis of 1a
Entry
Base
Amount of base equiv.
Solvent
Pressure 'atm)
Temperature '8C)
Time 'h)
Yield %
1
2
3
4
5
6
7
8
9
1
1
1
1
1
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBN
3.0
1.0
0.5
0.5
0.1
3.0
0.5
0.1
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
1
1
1
1
20
20
20
20
20
80
80
80
80
80
80
80
80
80
24
24
24
48
48
1
24
24
6
24
24
24
24
24
97
96
64
77
21
98
96
94
84
91
46
71
93
76
1
10
10
10
10
10
10
10
10
10
0.1
0
1
2
3
4
0.05
0.01
0.05
0.05
0.05
DMSO
DMF

T. Mizuno, Y. Ishino / Tetrahedron 58 '2002) 3155±3158
3157
DBU. Then, nucleophilic cyclization of 4a into 5a, followed
by rearrangement of 5a, gives 6a. Finally, formation of
aromatic ring of 6a affords the ®nal product '1a). In this
DBU catalyzed reaction system which proceeds, even if
under 1 atm, 208C, the formation of isocyanate as an
intermediate from the carbamate salt '4a) might be
impossible. An industrial urea synthesis in which an iso-
cyanate is a key intermediate is performed under high
1
0
pressure and temperature.
3. Conclusion
Scheme 3.
Carbon dioxide smoothly reacted with 2-amino-benzo-
nitriles 2 under mild conditions '1 atm, 208C), assisted by
excess amount of DBU or DBN to give corresponding
1H-quinazoline-2,4-diones 1 in excellent yields. Also,
1H-quinazoline-2,4-diones 1 was synthesized in the
presence of catalytic amount of DBU or DBN effectively.
Moreover, 7-chloro-1H-quinazoline-2,4-dione '1g) which is
a key intermediate of medicines 'FK366, Zenarestat and
KF31327) was prepared in a 90% under 10 atm, 808C using
0.05 equiv. of DBU.
mild conditions, turnover number reached to 2.1 'entry 5).
Next, catalytic activity of DBU was tested under 10 atm,
8
08C. Surprisingly, 0.05 equiv. of DBU gave the excellent
yield '91%) of 1H-quinazoline-2,4-dione '1a) 'entry 10).
This is the ®rst example of chemical ®xation of carbon
dioxide in the presence of catalytic amount of DBU. More-
over, in the presence of 0.01 equiv. of DBU under 10 atm,
w
8
08C, turnover number rose to 46 'entry 11). DMSO was
similarly effective as a solvent, high yield of 1a '93%) was
obtained using 0.05 equiv. of DBU 'entry 13). However,
yield of 1a was lowered using THF '71%), because of
low solubility of 1a in THF 'entry 12). DBN '0.05 equiv.)
also showed excellent catalytic activity for the carbonyl-
ation of 2-aminobenzonitrile '2a) with carbon dioxide,
4. Experimental
4.1. General
1
'
H-quinazoline-2,4-dione '1a) afforded in good yield
76%) 'entry 14).
Melting points were determined on a Mettler FP 5 instru-
ment and were uncorrected. FT-IR spectra were recorded on
1
13
In the presence of 0.1 or 0.05 equiv. of DBU under 10 atm,
08C for 24 h, 1H-quinazoline-2,4-diones '1a,b,f and g)
a Nicolet Magna-IR 550 instrument. H and C NMR
spectra were obtained on a JEOL JNM-AL300 '300 MHz,
75 MHz) instrument. Chemical shifts were reported in ppm
relative to tetramethylsilane 'd-units). Mass and exact mass
spectra were recorded on a JEOL JMS-600 spectrometer.
2-Aminobenzonitriles 2, DMF, THF, DMSO, bases, carbon
dioxide '99.8%) were used as purchased.
8
were synthesized from the corresponding 2-aminobenzo-
nitriles '2a,b,f,g) substituted by functional group, with
carbon dioxide in excellent yields 'Scheme 3). However,
preparation of 1c in reasonable yield needed 0.5 equiv. of
DBU, because of low basicity of 2c substituted by nitro
group. 7-Chloro-1H-quinazoline-2,4-dione '1g) which is a
w
key intermediate of medicines 'FK366, Zenarestat and
KF31327) was also synthesized in a 90% under 10 atm,
4.2. Typical procedure for synthesis of 1H-quinazoline-
2,4-dione ꢀ1a) using excess amount of DBU
8
08C for 24 h using 0.05 equiv. of DBU.
A 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 208C for
24 h. The reaction mixture was then poured into 1 N HCl
'200 mL), and the solid that deposited was washed with
Fig. 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 '4a) in the presence of catalytic
Figure 2. A plausible reaction pathway.

3158
T. Mizuno, Y. Ishino / Tetrahedron 58 '2002) 3155±3158
toluene '100 mL) and diethyl ether '100 mL). 1H-Quinazo-
line-2,4-dione '1a) was obtained in a 97% yield '1.57 g).
808C for 24 h with vigorous stirring. After cooling down and
evacuation of carbon dioxide, the resulting mixture was then
poured into 1 N HCl '200 mL), and the solid that deposited
was washed with toluene '100 mL) and t-butyl methyl ether
'100 mL). 1H-Quinazoline-2,4-dione '1a) was obtained in a
91% yield '1.48 g).
1
1
1
IR 'KBr) 3255, 3055, 1705 cm ; H NMR '300 MHz,
H-Quinazoline-2,4-dione '1a). Mp.3008C '.3508C );
1
2
1
d -DMSO) d 7.13±7.18 'm, 2H), 7.61 't, Jˆ8 Hz, 1H),
6
1
3
7
NMR '75 MHz, d -DMSO) d 114.3, 115.3, 122.3, 126.9,
.86 'd, Jˆ8 Hz, 1H), 11.11 's, 1H), 11.25 's, 1H);
C
6
1
34.9, 140.8, 150.3, 162.8; MS 'm/z, %) 162 'M , 100),
1
1
1
4.3.1. 6-Chloro-1H-quinazoline-2,4-dione ꢀ1f). Mp.
2
1 1
19 '48), 92 '17); exact MS calcd for C H N O :
8
62.0429. Found: 162.0408.
3008C; IR 'KBr) 3200, 3060, 1745, 1715 cm ; H NMR
'300 MHz, d
-DMSO) d 7.16 'd, Jˆ9 Hz, 1H), 7.64 'd,
Jˆ9 Hz, 1H), 7.78 's, 1H), 11.24 's, 1H), 11.41 's, 1H);
6
2
2
6
1
3
4.2.1. 6,7-Dimethoxy-1H-quinazoline-2,4-dione ꢀ1b).
Mp.3008C; IR 'KBr) 3470, 1710 cm ; H NMR
C NMR '75 MHz, d -DMSO) d 115.7, 117.5, 125.9,
6
2
1
1
1
126.2, 134.7, 139.7, 150.0, 161.8; MS 'm/z, %) 196 'M ,
100), 153 '73), 125 '26); exact MS calcd for C H ClN O :
196.0040. Found: 196.0037.
'
'
300 MHz, d -DMSO) d 3.77 's, 3H), 3.81 's, 3H), 6.67
6
8
5
2
2
1
3
s, 1H), 7.24 's, 1H), 10.91 's, 1H), 11.08 's, 1H);
C
NMR '75 MHz, d -DMSO) d 55.7, 55.8, 97.8, 106.2,
6
1
07.2, 136.5, 145.0, 150.4, 154.9, 162.4; MS 'm/z, %) 222
M , 100), 207 '38), 164 '22); exact MS calcd for
4.3.2. 7-Chloro-1H-quinazoline-2,4-dione ꢀ1g). Mp.
1
21 1
'
C H N O : 222.0641. Found: 222.0642.
3008C; IR 'KBr) 3305, 3055, 1745, 1685 cm ; H NMR
'300 MHz, d -DMSO) d 7.17±7.19 'm, 2H), 7.85 'd,
1
0
10
2
4
6
1
3
Jˆ9 Hz, 1H), 11.24 's, 1H), 11.36 's, 1H); C NMR
4
3
.2.2. 6-Nitro-1H-quinazoline-2,4-dione ꢀ1c). Mp.
'75 MHz, d -DMSO) d 113.3, 114.7, 122.4, 129.0, 139.3,
6
2
008C; IR 'KBr) 3455, 1680 cm ; H NMR '300 MHz,
1
1
1
141.9, 150.1, 162.0; MS 'm/z, %) 196 'M , 100), 153 '91),
d -DMSO) d 7.26 'dd, Jˆ2,9 Hz, 1H), 8.38 'td, Jˆ2,9 Hz,
126 '49); exact MS calcd for C H ClN O : 196.0040.
2
Found: 196.0036.
6
8
5
2
1
3
1H), 8.50 'd, Jˆ2 Hz, 1H), 11.65 's, 1H), 11.71 's, 1H);
NMR '75 MHz, d -DMSO) d 114.4, 116.6, 123.0, 129.5,
C
6
1
41.8, 145.6, 149.9, 161.5; MS 'm/z, %) 207 'M , 100),
1
References
1
Found: 207.0271.
64 '27); exact MS calcd for C H N O : 207.0280.
8
5
3
4
1
. 'a) Goto, S.; Tsuboi, H.; Kagara, K. Chem. Express 1993, 8,
61±764. 'b) Kagara, K.; Goto, S.; Tsuboi, H. Japanese Patent
25767, 1989. Chem. Abstr., 1989, 111, 97274.
7
4.2.3. 8-Bromo-6-nitro-1H-quinazoline-2,4-dione ꢀ1d).
Mp.3008C; IR 'KBr) 3175, 3080, 1700 cm ; H NMR
2
1
1
2
. Mohri, S. J. Syn. Org. Chem. Jpn 2001, 59, 514±515.
'
300 MHz, d -DMSO) d 8.51 'd, Jˆ2 Hz, 1H), 8.60 'd,
6
1
3
3. '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. G.; Ossman,
A. R. E.; Ismail, M. A. Pharmazie 1982, 37, 115±117.
Jˆ2 Hz, 1H), 10.95 's, 1H), 11.89 's, 1H); C NMR
'
75 MHz, d -DMSO) d 108.6, 116.1, 122.1, 132.4, 141.7,
6
1
43.9, 149.5, 160.8; MS 'm/z, %) 287 '98), 285 'M , 100),
1
244 '39), 242 '40), 152 '35), 151 '35); exact MS calcd for
C H BrN O : 284.9385. Found: 284.9370.
4
. Michman, M.; Patai, S.; Wiesel, Y. Org. Prep. Proced. Int.
978, 10, 13±16.
8
4
3
4
1
5
6
. Lange, N. A.; Sheibley, F. E. Org. Synth. 1943, 2, 79±80.
. Vorbrueggen, H.; Krolikiewicz, K. Tetrahedron 1994, 50,
4
heating without melting and with partial sublimation );
.2.4. Xanthine ꢀ1e). Mp.3008C 'decomposition on
12
2
IR 'KBr) 3005, 1705 cm ;
1
1
6
549±6558.
. Mizuno, T.; Okamoto, N.; Ito, T.; Miyata, T. Tetrahedron Lett.
000, 41, 1051±1053.
H NMR '300 MHz,
d -DMSO) d 7.80 'brs, 1H), 7.98 's, 1H), 10.85 's, 1H),
7
8
9
6
1
3
1.57 'brs, 1H); C NMR '75 MHz, d -DMSO) d 106.7,
2
1
1
6
1
40.3, 148.3, 151.3, 155.4; MS 'm/z, %) 152 'M , 100), 109
. Mizuno, T.; Okamoto, N.; Ito, T.; Miyata, T. Heteroatom.
Chem. 2000, 11, 428±433.
'52), 54 '38); exact MS calcd for C H N O : 152.0334.
5 4 4 2
Found: 152.0332.
. 'a) Haruki, E. In Organic and Bio-organic Chemistry of
Carbon Dioxide, Inoue, S., Ed.; Kodansha Ltd: Tokyo,
1981; pp. 5±78. 'b) Haruki, E.; Arakawa, M.; Matsumura,
N.; Otsuji, Y.; Imoto, E. Chem. Lett. 1974, 427±428.
4
2
.3. General procedure for synthesis of 1H-quinazoline-
,4-dione ꢀ1a) in the presence of catalytic amount of DBU
'
Taniguchi, H. Nippon Kagaku Kaishi 1987, 1408±1413.
c) Hori, Y.; Nagano, Y.; Fukuhara, T.; Teramoto, S.;
In a 100 mL stainless steel autoclave, 2-aminobenzonitrile
2a) '1.18 g, 10 mmol), DBU '0.075 mL, 0.50 mmol), and
DMF '20 mL) was placed with a magnetic stirring bar under
an argon atmosphere. The autoclave was then ¯ushed three
times with carbon dioxide and ®nally charged with carbon
dioxide at 10 atm at 208C. The reaction was carried out at
'
10. Mavrovic, I. Kirk±Othmer Encyclopedia of Chemical
Technology; Mark, H. F., Ed.; Interscience Publishers: New
York, 1970; Vol. 21, pp. 37±56.
11. Beilstein, 1936, 24, 373.
12. Merck Index, 1996, 12, 10193.