Solvent-free synthesis of quinazoline-2,4(1H,3H)-diones using carbon dioxide and a catalytic amount of DBU

Article abstract of DOI:10.1055/s-2007-983808

An ideal reaction system, which is aimed at sustainable chemistry, was developed. Under solvent-free conditions, quinazoline-2,4(1H,3H)-diones were obtained in good to excellent yields from 2-aminobenzonitriles with only carbon dioxide (1 bar) and a catalytic amount of base (DBU or DBN). For example, 6,7-dimethoxyquinazoline-2,4(1H,3H)-dione, which is a key intermediate of several drugs (Prazosin, Bunazosin, and Doxazosin) was synthesized successfully in 97% yield [DBU (0.2 equiv), CO₂ (1 bar), 120°C]. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983808

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2524
PAPER
Solvent-Free Synthesis of Quinazoline-2,4(1H,3H)-diones Using Carbon
Dioxide and a Catalytic Amount of DBU
S
olvent-Free Sy
a
nthesis of
k
Q
uinazoline-
u
2,4(
1
H
,3
H
)-
m
diones i Mizuno,* Masatoshi Mihara, Takeo Nakai, Toshiyuki Iwai, Takatoshi Ito
Osaka Municipal Technical Research Institute, 1-6-50, Morinomiya, Joto-ku, Osaka 536-8553, Japan
Fax +81(6)69638049; E-mail: tmizuno@omtri.city.osaka.jp
Received 26 September 2006; revised 6 June 2007
Abstract: An ideal reaction system, which is aimed at sustainable
chemistry, was developed. Under solvent-free conditions, quinazo-
line-2,4(1H,3H)-diones were obtained in good to excellent yields
H
N
O
Cl
from 2-aminobenzonitriles with only carbon dioxide (1 bar) and a
catalytic amount of base (DBU or DBN). For example, 6,7-
dimethoxyquinazoline-2,4(1H,3H)-dione, which is a key intermedi-
NH
1d
O
ate of several drugs (Prazosin, Bunazosin, and Doxazosin) was syn-
thesized successfully in 97% yield [DBU (0.2 equiv), CO2 (1 bar),
120 °C].
Key words: carbon dioxide, carbonylation, cyclization, catalytic,
quinazoline, quinazolidinone
COOH
N
Cl
N
O
Br
O
N
HN
HO
H
N
N
Quinazoline-2,4(1H,3H)-dione derivatives 1 are of inter-
est because of their biological activity, and they have been
widely used as key structures in medicinal drugs. For ex-
ample, 7-chloroquinazoline-2,4(1H,3H)-dione (1d) is an
important intermediate in the synthesis of FK 366 (Zenar-
estat®) and KF31327. FK 366 (Zenarestat®) functions as
an aldose reductase inhibitor and was produced as a rem-
edy for complications of diabetes mellitus;1,2 KF31327
was developed as remedy for heart disease and as an im-
potence medicine3 (Scheme 1). Also, 6,7-dimethoxy-
quinazoline-2,4(1H,3H)-dione (1b) is a key intermediate
for the production of the following medicines: Prazosin
(Minipress®),4 Bunazosin (Detantol®),5 and Doxazosin
(Cardenalin®)6 (Scheme 2). These medicines, which are
effective a1-adrenergic blockers, are useful as antihyper-
tensives.
S
F
N
N
⋅2HCl
Et
FK366
KF31327
Scheme 1 7-Chloroquinazoline-2,4(1H,3H)-dione (1d) is an im-
portant intermediate of FK 366 (Zearestat®) and KF31327
lent yields under 10.1 bar at 80 °C in N,N-dimethylform-
amide or dimethyl sulfoxide.15 However, these reactions
require N,N-dimethylformamide or dimethyl sulfoxide as
an organic solvent.
Substituting supercritical carbon dioxide for organic sol-
vents is of great importance, both because of the toxicity
of these solvents for humans and the environmental prob-
lems associated with organic solvents. We have success-
fully synthesized quinazoline-2,4(1H,3H)-diones 1 in
excellent yields using supercritical carbon dioxide (101
bar, 80 °C), as a reactant and a solvent, in the presence of
DBU (0.1 equiv).16 However, experimentally, it is not an
easy procedure to perform using carbon dioxide at such a
high pressure.
The conventional syntheses of 1 were carried out starting
from anthranilic acid and urea,7,8 anthranilamide and
phosgene,9 and anthranilic acid and potassium cyanate10
or chlorosulfonyl isocyanate.11 However, these synthetic
methods are considerably limited because of the high tox-
icity of the reagents or the use of drastic conditions.
Therefore, if a solvent-free synthesis of substituted
quinazoline-2,4(1H,3H)-diones 1 from 2-aminobenzoni-
triles 2 using only carbon dioxide (1 bar) and catalytic
amount of base is established, it would be an ideal organic
reaction.
Recently, we reported a convenient synthesis of quinazo-
line-2,4(1H,3H)-diones 1 from 2-aminobenzonitriles 2 by
chemical fixation of carbon dioxide under mild conditions
(1 bar, 20 °C) in the presence of excess 1,8-diazabicyc-
lo[5.4.0]undec-7-ene
(DBU)
or
1,5-diazabicyc-
At first, we examined the synthesis of quinazoline-
2,4(1H,3H)-dione (1a) under solvent-free conditions from
2-aminobenzonitrile (2a) with carbon dioxide (1 bar, 20
°C) in the presence of DBU (1.0 equiv). Within 30 min-
utes, a white solid had formed, however, because of diffi-
culties in stirring the reaction mixture, 1a was formed in
low yields (1 h, 14% yield; 48 h, 39% yield) (Scheme 3).
lo[4.3.0]non-5-ene (DBN) using N,N-dimethylformamide
as the solvent.12–14 Furthermore, we also found that a cat-
alytic amount of DBU or DBN has exceptional ability for
the chemical fixation of carbon dioxide to give 1 in excel-
SYNTHESIS 2007, No. 16, pp 2524–2528
x
x.
x
x
.
2
0
0
7
Advanced online publication: 24.7.2007
DOI: 10.1055/s-2007-983808; Art ID: F16006SS
© Georg Thieme Verlag Stuttgart · New York

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PAPER
Solvent-Free Synthesis of Quinazoline-2,4(1H,3H)-diones
2525
O
O
N
N
MeO
MeO
N
N
prazosin
NH2
HCl
H
O
MeO
N
NH
MeO
1b
O
O
O
O
O
N
N
N
MeO
MeO
N
N
MeO
MeO
N
N
N
doxazosin
bunazosin
NH2
NH2
HCl
Scheme 2 6,7-Dimethoxyquinazoline-2,4(1H,3H)-dione (1b) is a key intermediate for the synthesis of Prazosin (Minipress®), Bunazosin (De-
tantol®), and Doxazosin (Cardenalin®)
H
N
H
N
O
NH2
CN
O
NH2
CN
DBU (0.2 equiv)
DBU (1.0 equiv)
1 bar, 20 °C
CO2
+
CO2
+
NH
NH
1 bar, 120 °C, 4 h
2a
1a: 83%
O
O
1a: 14% (1 h)
39% (48 h)
Scheme 5 Solvent-free synthesis of quinazoline-2,4(1H,3H)-dione
(1a)
Scheme 3 Quinazoline-2,4(1H,3H)-dione (1a) synthesis at 20 °C
This result agreed with the reported reaction with carbon
dioxide using DBU, where a DBU–CO2 complex formed
from carbon dioxide and DBU at room temperature was
considered to be an active species for carboxylation.17–20
This DBU–CO2 complex was readily thermally decom-
posed into DBU and carbon dioxide at ca. 65 °C
(Scheme 4).
entries 2 and 3). In this reaction system, a catalytic amount
of DBU was also effective for the synthesis of quinazo-
line-2,4(1H,3H)-dione (1a) (Table 1, entries 4–6); even
0.2 equivalents of DBU afforded an 83% yield of 1a.
However, using lower amounts of DBU or shorter reac-
tion times gave 1a in low yields (Table 1, entries 5 and 6).
In this solvent-free synthesis of quinazoline-2,4(1H,3H)-
dione (1a), DBN was also effective (Table 1, entry 7);
however, using other bases (DABCO, Et3N, K2CO3, or no
base) gave no 1a (Table 1, entries 8–11).
N+
20 °C
N
CO2
+
N
N
65 °C
Next, several quinazoline-2,4(1H,3H)-diones 1a–d,
which include the key intermediates 1b and 1d, were syn-
thesized in good to excellent yields with carbon dioxide (1
bar) and DBU (0.2 equiv) under similar solvent-free con-
ditions (Table 2). In these cases, higher reaction tempera-
tures (150 °C) afforded superior results to give 1a,c,d in
excellent yields (Table 2, entries 3, 7, and 9). Even when
quinazoline-2,4(1H,3H)-dione (1a) was synthesized on a
tenfold scale, it was obtained in excellent yields (84% and
97%) (Table 2, entries 2 and 3). Using DBN (0.2 equiv) in
place of DBU gave 6,7-dimethoxyquinazoline-
2,4(1H,3H)-dione (1b) in quantitative yield (Table 2, en-
try 5).
O
O–
Scheme 4 CO2–DBU complex
Hence, to avoid the solidification of DBU with carbon di-
oxide, a model solvent-free synthesis of quinazoline-
2,4(1H,3H)-dione (1a) was attempted at high tempera-
tures under carbon dioxide (1 bar) (Scheme 5, Table 1).
Surprisingly, an almost quantitative yield (95%) of
quinazoline-2,4(1H,3H)-dione (1a) was obtained under
solvent-free conditions (CO2, 1 bar, 120 °C), using only
1.0 equivalent of DBU (Table 1, entry 1). Lower reaction
temperatures slightly decreased the yield of 1a (Table 1,
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2526
T. Mizuno et al.
PAPER
Table 1 Influence of Temperature and Base on the Synthesis of 1a
Table 2 Synthesis of Various Quinazoline-2,4(1H,3H)-diones 1a–e
Entry Base
Equiv of base Temp (°C) Isolated yielda
(%)
Entry Reactant
2a–e
(mmol) (°C)
Temp
Isolated
yielda (%)
1
2
DBU
DBU
DBU
DBU
DBU
DBU
DBN
DABCO
Et3N
1
120
100
80
95
90
75
89
83, 51b
48
84
0
1
2
3
5
50
50
120
120
150
83
84
97
NH2
CN
1
3
1
2a
MeO
4
5
5
5
120
120
97
NH2
CN
4
0.5
0.2
0.1
0.2
0.2
0.2
0.2
120
120
120
120
120
120
120
120
100b
5
MeO
2b
6
6
7
5
5
120
150
74
97
NH2
7
Cl
2c
Cl
CN
8
9
0
8
9
5
5
120
150
54
93
NH2
10
11
K2CO3
none
0
CN
0
2d
c
a Reaction conditions: 2-aminobenzonitrile (2a, 591 mg, 5 mmol),
CO2 (1 bar), 4 h.
10
11
12
5
5
5
120
120
150
–
–
–
NH2
c,d
e
b Reaction time was 1 h.
O2N
CN
2e
a Reaction conditions: DBU (0.2 equiv), CO2 (1 bar), 4 h.
b DBN (0.2 equiv) was used in place of DBU.
c Complex mixture was obtained.
Due to its low basicity, 2-amino-5-nitrobenzonitrile (2e)
gave a complex mixture instead of the expected product,
6-nitroquinazoline-2,4(1H,3H)-dione (1e) (Table 2, entry
10) even when using 1.0 equivalent of DBU (Table 2, en-
try 11). At high reaction temperatures (150 °C), 2e readily
decomposed to form a black tar (Table 2, entry 12).
d DBU (1.0 equiv) was used.
e 2-Amino-5-nitrobenzonitrile (2e) decomposed.
Then, we examined the synthesis of quinazoline-
2,4(1H,3H)-dione (1a) from 2-aminobenzamide under
solvent-free conditions, however, cyclization did not pro-
ceed to give 1a (Scheme 7).
Scheme 6 shows a plausible pathway for the formation of
quinazoline-2,4(1H,3H)-dione (1a) from 2-aminobenzo-
nitrile (2a) with carbon dioxide aided by catalytic
amounts of DBU. The carbonylation of 2a with carbon di-
oxide generates a carbamate salt in the presence of cata-
lytic DBU. Then, nucleophilic cyclization of 3a into 4a,
followed by rearrangement of 4a by way of the isocyanate
intermediate 5a, gives 6a. Finally, stabilization of 6a
gives the final product 1a. In this reaction system, forma-
tion of isocyanate intermediate 5a assisted by the o-cyano
group appears to be important.
H
O
NH2
N
DBU (0.2 equiv)
CO2
+
NH
1 bar, 120 °C, 4 h
C(O)NH2
O
1a: 0%
Scheme 7 Solvent-free synthesis of 1a from 2-aminobenzamide
O
NHCO– DBU H+
H
O
N
NH2
DBU
+
CO2
O
C
N
C
N
N–
DBU H+
2a
3a
4a
DBU H+
H
N
–
N
O
O
N=C=O
OH
– DBU
N
NH
N–
OH
5a
6a
1a
DBU H+
O
Scheme 6 A plausible reaction path
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PAPER
Solvent-Free Synthesis of Quinazoline-2,4(1H,3H)-diones
2527
6-Chloroquinazoline-2,4(1H,3H)-dione (1c)
Also, an industrial urea synthesis in which an isocyanate
is an intermediate, was performed under high-temperature
conditions.21
Yield: 951 mg (97%); mp >300 °C (Lit.15 >300 °C).
IR (KBr): 3199, 3059, 1743, 1713, 1668, 1483, 1429, 1285, 828
cm–1.
1HNMR (300 MHz, DMSO-d6): d = 7.16 (d, J = 8.7 Hz, 1 H, CH),
7.65 (d, J = 8.7 Hz, 1 H, CH), 7.79 (s, 1 H, CH), 11.24 (s, 1 H, NH),
11.40 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 115.7, 117.5, 125.9, 126.2,
134.7, 139.7, 150.0, 161.8.
A new simple solvent-free synthesis of substituted
quinazoline-2,4(1H,3H)-diones 1, which include medici-
nal intermediates Prazosin (Minipress®), Bunazosin
(Detantol®), Doxazosin (Cardenalin®), FK 366 (Zenar-
estat®), and KF31327, from 2-aminobenzonitriles was de-
veloped, using only carbon dioxide (1 bar) as a reactant
and catalytic amount of base (DBU or DBN).
MS (EI, 70 eV): m/z (%) = 196 (100) [M+], 153 (73), 125 (26).
HRMS (EI, 70 eV): m/z [M+] calcd for C8H5ClN2O2: 196.0040;
The present reaction is aimed at green and sustainable
chemistry in fine chemicals production and from the
viewpoint of the chemical fixation of carbon dioxide (1
bar) and solvent-free reaction conditions it appears to be
an ideal reaction system.
found: 196.0037.
7-Chloroquinazoline-2,4(1H,3H)-dione (1d)
Yield: 911 mg (93%); mp >300 °C (Lit.15 >300 °C).
IR (KBr): 3306, 3054, 1743, 1686, 1618, 1431, 1287, 864 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.15–7.21 (m, 2 H, 2 CH),
7.86 (d, J = 8.4 Hz, 1 H, CH), 11.20 (s, 1 H, NH), 11.36 (s, 1 H,
NH).
13C NMR (75 MHz, DMSO-d6): d = 113.3, 114.6, 122.4, 129.0,
139.2, 141.9, 150.1, 162.0.
MS (EI, 70 eV): m/z (%) = 196 (100) [M+], 153 (91), 126 (49).
HRMS (EI, 70 eV): m/z [M+] calcd for C8H5ClN2O2: 196.0040;
Melting points were determined on a Mettler FP 5 instrument and
are uncorrected. FT-IR spectra were recorded on a Nicolet Magna-
1
IR 550 instrument. H and 13C NMR spectra were obtained on a
JEOL JNM-AL300 (300 MHz, 75 MHz) instrument with TMS as
internal standard. MS and HRMS were recorded on a JEOL JMS-
600 spectrometer. 2-Aminobenzonitriles 2a–f, 2-aminobenzamide,
bases (DBU, DBN, DABCO, K2CO3, and Et3N), and carbon dioxide
(99.8%) were used as purchased.
found: 196.0036.
Quinazoline-2,4(1H,3H)-dione (1a); Typical Procedure
To a 100-mL, 3-necked flask equipped with condenser were added
2-aminobenzonitrile (2a, 5.91 g, 50 mmol) and DBU (1.50 mL, 10
mmol) under argon together with a large magnetic stirring bar.
Then, CO2 (1 bar) was charged at 20 °C. The mixture was vigorous-
ly stirred under CO2 (1 bar) at 150 °C for 4 h. The resulting white
solid was then poured into 1 M HCl (100 mL) and washed with
t-BuOMe (200 mL) to give pure 1a; yield: 7.86 g (97%); mp
>300 °C (Lit.14–16 >300 °C).
References
(1) Goto, S.; Tsuboi, H.; Kagara, K. Chem. Express 1993, 8,
761.
(2) Kagara, K.; Goto, S.; Tsuboi, H. JP 1,025,767, 1989; Chem.
Abstr. 1989, 111, 97274.
(3) Mohri, S. J. Synth. Org. Chem., Jpn. 2001, 59, 514.
(4) Merck Index, 12th ed.; Merck & Co., Inc.: Whitehouse
Station NJ, 1996, 7897.
IR (KBr): 3254, 3056, 2847, 1720, 1705, 1670, 1617, 1444, 757
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.14–7.18 (m, 2 H, 2 CH),
7.62 (t, J = 7.7 Hz, 1 H, CH), 7.87 (d, J = 7.7 Hz, 1 H, CH), 11.10
(s, 1 H, NH), 11.24 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 114.3, 115.3, 122.3, 126.9,
134.9, 140.8, 150.2, 162.8.
(5) Merck Index, 12th ed.; Merck & Co., Inc.: Whitehouse
Station NJ, 1996, 1512.
(6) Merck Index, 12th ed.; Merck & Co., Inc.: Whitehouse
Station NJ, 1996, 3489.
(7) Pastor, G.; Blanchard, C.; Montginoul, C.; Torreilles, E.;
Giral, L.; Texier, A. Bull. Soc. Chim. Fr. 1975, 1331.
(8) Khalifa, M.; Osman, A. N.; Ibrahim, M. G.; Ossman, A. R.
E.; Ismail, M. A. Pharmazie 1982, 37, 115.
(9) Michman, M.; Patai, S.; Wiesel, Y. Org. Prep. Proced. Int.
1978, 10, 13.
MS (EI, 70 eV): m/z (%) = 162 (100) [M+], 119 (48), 92 (17).
HRMS (EI, 70 eV): m/z [M+] calcd for C8H6N2O2: 162.0429; found:
(10) Lange, N. A.; Sheibley, F. E. Org. Synth. Coll. Vol. II; John
162.0408.
Wiley & Sons: London, 1943, 79.
(11) Vorbrüeggen, H.; Krolikiewicz, K. Tetrahedron 1994, 50,
6549.
6,7-Dimethoxyquinazoline-2,4(1H,3H)-dione (1b)
Yield: 1.08 g (97%); mp >300 °C (Lit.14,15 >300 °C).
(12) The use of the chemical fixation of carbon dioxide in fine
chemicals production is of importance both in terms of the
environmental problems of global warming and the effective
utilization of chemical resources. Carbon dioxide is an
attractive C1 building block in organic synthesis as it is
highly abundant, inexpensive, nontoxic, and nonflammable.
However, due to the inert nature of carbon dioxide, efficient
processes for chemical fixation remain significant synthetic
challenges.
(13) Mizuno, T.; Okamoto, N.; Ito, T.; Miyata, T. Tetrahedron
Lett. 2000, 41, 1051.
(14) Mizuno, T.; Okamoto, N.; Ito, T.; Miyata, T. Heteroat.
Chem. 2000, 11, 428.
IR (KBr): 3470, 3375, 3296, 1708, 1651, 1626, 1468, 1438, 1266,
1100 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.77 (s, 3 H, CH3), 3.81 (s, 3
H, CH3), 6.66 (s, 1 H, CH), 7.24 (s, 1 H, CH), 10.88 (s, 1 H, NH),
11.06 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 55.7, 55.8, 97.7, 106.2, 107.2,
136.5, 145.0, 150.4, 154.9, 162.4.
MS (EI, 70 eV): m/z (%) = 222 (100) [M+], 207 (38), 164 (22).
HRMS (EI, 70 eV): m/z [M+] calcd for C10H10N2O4: 222.0641;
found: 222.0642.
Synthesis 2007, No. 16, 2524–2528 © Thieme Stuttgart · New York