Metal and phosgene-free synthesis of 1H-quinazoline-2,4-diones by selenium-catalyzed carbonylation of o-nitrobenzamides

Article abstract of DOI:10.1016/j.tetlet.2010.01.040

1H-Quinazoline-2,4-diones were efficiently synthesized by selenium-catalyzed carbonylation of o-nitrobenzamides under relatively mild conditions. In situ-generated carbonyl selenide (SeCO) is proposed to initiate the catalytic carbonylation. Thus, a concise transition metal and phosgene-free synthetic route to potentially bioactive-substituted 1H-quinazoline-2,4-dione derivatives has been developed.

Full text of DOI:10.1016/j.tetlet.2010.01.040

Tetrahedron Letters 51 (2010) 1500–1503
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal and phosgene-free synthesis of 1H-quinazoline-2,4-diones
by selenium-catalyzed carbonylation of o-nitrobenzamides
Xiaowei Wu a,b, Zhengkun Yu a,
*
a Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, Liaoning 116023, China
b College of Life Science, Dalian Nationalities University, 18 Liaohe West Road, Dalian, Liaoning 116600, China
a r t i c l e i n f o
a b s t r a c t
Article history:
1H-Quinazoline-2,4-diones were efficiently synthesized by selenium-catalyzed carbonylation of o-
nitrobenzamides under relatively mild conditions. In situ-generated carbonyl selenide (SeCO) is proposed
to initiate the catalytic carbonylation. Thus, a concise transition metal and phosgene-free synthetic route
to potentially bioactive-substituted 1H-quinazoline-2,4-dione derivatives has been developed.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 8 December 2009
Revised 8 January 2010
Accepted 12 January 2010
Available online 18 January 2010
O
O
Quinazoline-2,4-dione template features a urea unit and occurs
in many bioactive molecules.1 1H-Quinazoline-2,4-diones and
their derivatives have usually been used as antibacterial agents,
receptor antagonists, and inhibitors.2 Conventional synthetic
routes to substituted 1H-quinazoline-2,4-diones include the reac-
tions of acyl azides or amines with triphosgene, o-aminobenza-
mides with phosgene, isatoic anhydride with amines, anthranilic
acids with ureas, and the reactions of potassium cyanates, isocya-
nates, and anthranilates with N-aryldithio carbamates.3–6 How-
ever, these methods are considerably limited due to the high
toxicity of the reagents or use of the extreme conditions although
some modifications have been made by employing urea dianions,
supercritical carbon dioxide, solid state synthesis conditions, and
transition metal catalysis.7,8 Nonmetal elements sulfur and sele-
nium have been known to catalyze the reductive carbonylation
of nitroaromatics to form ureas.9 In this area, much work has been
directed to selenium-catalyzed carbonylation of nitroaromatics for
the synthesis of ureas, but little attention has been paid to the syn-
thesis of cyclic urea derivatives.9,10
Through our ongoing studies on selenium-promoted cataly-
sis,11–13 we found that the oxidative carbonylation of benzamide
and reductive carbonylation of 2-methoxy-5-nitropyridine can be
coupled in a one-pot reaction, producing N-pyridyl-N0-benzoylurea
(A) in 34% yield (Scheme 1).11a Intrigued by the structural similar-
ity of o-nitrobenzamide, we reasonably envisioned its reduction/
carbonylative cyclization to form 1H-quinazoline-2,4-dione under
CO atmosphere. Herein, we report efficient transition metal and
phosgene-free synthesis of substituted 1H-quinazoline-2,4-diones
(2) by selenium-catalyzed carbonylation of o-nitrobenzamides (1)
with CO Eq. 1.
R'
cat. Se
-2 CO2
R'
O
N
N
+ 3 CO
R
R
H
ð1Þ
NO2
N
H
1
2
In our initial studies, the carbonylation of N-phenyl-o-nitroben-
zamide (1b) was carried out with 3.0 MPa CO in the presence of
5 mol % selenium catalyst and Et3N in toluene at 160 °C in a fashion
similar to the synthesis of A,11a forming the desired product 2b in
<80% yield as well as considerable amount of unknown tar mixture
Eq. 2. In THF, the same reaction afforded 2b in 91% isolated yield
(entry 2, Table 1). Then, screening the reaction conditions was car-
ried out by means of the carbonylation of 1b as a model reaction
(Table 1). Using THF as the solvent and increasing the reaction
temperature improved the reaction efficiency, leading to the best
result at 170 °C to produce 2b in 95% yield (entries 1–3). The reac-
tion at 180 °C generated 2b in a lower yield (81%), demonstrating
the decomposition of the desired product under overheating. In
other solvents, for example, benzene, toluene, dioxane and DMF,
2b was formed in 79–90% yields (entries 5–8). The presence of
water in the system retarded the reaction, suggesting that the
hydrogen necessary for the formation of the desired product, that
CONH2
O2N
OMe
+
N
cat. Se
Et3N
3.0 MPa CO
toluene, 160 oC
-CO2
CONHCONH
OMe
N
A, 34%
* Corresponding author. Tel./fax: +86 411 8437 9227.
E-mail address: zkyu@dicp.ac.cn (Z.K. Yu).
Scheme 1. A coupled oxidative and reductive carbonylation.11a
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.040

X. Wu, Z. Yu / Tetrahedron Letters 51 (2010) 1500–1503
1501
Table 1
Screening the reaction conditions of 1ba
O
O
cat. Se
base
Ph
Ph
O
N
N
(2)
+ 3 CO
H
solvent
-2 CO2
NO2
N
H
1b
2b
Entry
Solvent
Base (equiv)
Temp (°C)
PCO (MPa)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
THF
THF
THF
THF
Benzene
Toluene
Dioxane
DMF
Toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
None
150
160
170
180
170
170
170
170
130
170
170
170
170
170
170
170
170
170
170
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
1
2
12
12
12
12
12
12
12
12
12
8
10
11
24
11
11
11
11
11
11
81
91
95
81
79
82
83
90
17
73
91
95
88
9c
10
11
12
13
14
15
16
17
18
19
Et3N (2)
Et3N (4)
DBU (2)
Et3N (4)
Et3N (4)
43
94
11
41
94
THF
a
b
c
Conditions: 1b, 1.212 g (5 mmol); Se powder, 0.020 g (0.25 mmol); solvent, 50 mL.
Isolated yield of 2b.
Water (500 mmol) was added.
is, 2b, comes from the intramolecular hydrogen transfer of the
amide moiety in 1b (entry 9). Controlling the reaction time to
11 h was crucial to complete the reaction and avoid decomposition
of the product (entries 10–13). The carbonylation of 1b did not oc-
cur without the Et3N base, and four equivalents of the base were
necessary to accomplish the reaction (entries 3, 14–16). The other
organic base DBU did not efficiently promote the expected reaction
(entry 17).
A lower CO pressure (1.0 MPa) disfavored the reaction, while a
relatively high CO pressure (3.0 MPa) was not really necessary that
the 2.0 MPa seemed to be the suitable pressure of CO (entries 3, 18,
and 19). Thus, the conditions for the carbonylation of 1b were opti-
mized to: 5 mol % Se as the catalyst, 4 equiv Et3N as the base pro-
moter, THF as the solvent, 2.0 MPa CO at 170 °C for 11 h. It should
be noted that after the carbonylation was completed, the resultant
reaction mixture was stirred in air at ambient temperature for 1–
2 h to recover the Se powder catalyst which can be reused without
loss of the catalytic activity.
cases, N-aryl-o-nitrobenzamides underwent the carbonylation
more efficiently than their N-alkyl analogues, suggesting that the
N-substituents provide different levels of stabilization to the reac-
tion intermediates. The carbonylation of o-nitrobenzamides bear-
ing substituent(s) on their aryl backbones produced 1H-
quinazoline-2,4-dione products in good to excellent yields. Reduc-
tive carbonylation of 2-nitro-5-methoxybenzamides (1q–u)
formed the desired products 2q–u in 90–95% yields, respectively.
However, when the substituent on the aryl backbone is adjacent
to the nitro group such as the 2-methyl substituent in 1v, the yield
of 2v was decreased to 85% due to the increased hindrance as com-
pared with that of 2e (95%). The electron-withdrawing group, for
example, chloride, on the aryl backbones of 1w–y obviously re-
tarded the reactions, resulting in lower yields for the desired prod-
ucts 2w–y (78–82%) as compared with those of 2b (94%) and 2l
(86%). Both the chloride substituents on the aryl backbone and
the N-aryl moiety deactivated the substrate, leading to product
2z in a very poor yield (14%).
Next, the methodology was extended to prepare 1H-quinazo-
line-2,4-dione derivatives under the optimized conditions (Table
2).18 The reductive carbonylation of o-nitrobenzamide (1a) pro-
duced 1H-quinazoline-2,4-dione (2a) in 95% yield. For N-aryl-o-
nitrobenzamides 1b–e, their corresponding products 2b–e were
obtained in excellent yields (92–95%). When the N-aryl groups
were o-halophenyls, the reactions of 1f and 1g only afforded the
desired products 2f and 2g in poor yields (17–18%). With bulky
1-naphthyl on the N-aryl moiety, product 2h was formed in 77%
yield. The low reaction efficiency for 1f–h is attributed to the elec-
tron-withdrawing property and sterical hindrance from the N-aryl
substituents in the substrates. In the cases where the N-aryl moie-
ties were N-heteroaryls such as 4- and 2-pyridyls, the desired
products were only obtained in moderate yields (56–66%), also
revealing that the electronic property of the N-aryl group plays
an important role in the formation of the target product. The reac-
tions of N-alkyl-o-nitrobenzamides formed products 2k–n in good
yields (81–89%), while the carbonylation of N-allylic 1o and N-ben-
zylic 1p gave products 2o and 2p in better yields (90–91%). In most
A reaction mechanism is proposed for the carbonylation of
o-nitrobenzamides as shown in Scheme 2. It has been well docu-
mented that selenium reacts with carbon monoxide to form
carbonyl selenide (SeCO)14 which then promotes the carbonylation
of nitroaromatics, amines or anilines.9b,11b In our case, the in situ-
generated species SeCO initially interacts with o-nitrobenzamide 1
to form nitrene B, release selenium and aid in the generation of
CO2. Species B reacts with another molecule of SeCO to form isocy-
anate C8d,9b,11b,15 which is further transformed to afford the desired
product 2 via intramolecular hydrogen transfer. It is noteworthy
that the base, triethylamine, is essential for the present sele-
nium-catalyzed carbonylation of 1 and has been suggested to sta-
bilize the in situ-generated catalytically active species SeCO during
the reaction.16,17
In conclusion, we have developed an efficient synthetic route to
1H-quinazoline-2,4-diones by means of Se-catalyzed carbonylation
of o-nitrobenzamides. Due to the easy availability of o-nitrobenza-
mides, the present protocol is potentially applicable in the synthe-
sis of quinazoline-2,4-dione drug intermediates.

Table 2
Synthesis of 1H-quinazoline-2,4-diones (2)a,b
O
O
Me
iPr
N
OEt
O
O
O
O
O
Ph
O
NH
N
N
N
N
N
Br
Cl
N
H
O
N
H
N
H
O
N
H
O
iPr
N
H
O
N
H
O
N
H
O
2a, 95%
2b, 94%
2f, 17%
2g, 18%
2c, 92%
2d, 95%
2e, 94%
O
O
O
O
O
O
N
N
O
Me
N
iPr
N
Et
O
n
Bu
N
N
N
N
N
N
O
N
H
O
N
O
N
H
N
O
N
H
O
N
H
O
H
H
H
2m, 81%
2k, 89%
2h, 77%
2l, 86%
2i, 66%
2j, 56%
2n, 82%
O
O
O
O
O
O
MeO
MeO
MeO
MeO
MeO
Ph
O
Ph
O
Et
N
N
Ph
NH
N
N
N
N
H
N
O
N
H
O
N
H
N
O
N
H
O
H
H
2o, 90%
2t, 94%
2p, 91%
2s, 93%
2q, 95%
2r, 92%
O
OEt
O
O
O
O
N
O
N
MeO
MeO
2u, 90%
Et
N
Cl
iPr
Ph
Ph
N
N
N
Cl
N
H
O
N
H
O
N
H
O
Cl
N
H
O
Cl
N
H
O
Cl
N
O
H
Me
2x, 78%
2y, 82%
2w, 80%
2z, 14%
2v, 85%
a
Conditions: substrate, 5 mmol; selenium, 0.25 mmol; Et3N, 20 mmol; THF, 50 mL; CO, 2.0 MPa; 170 °C, 11 h.
Isolated yields.
b

X. Wu, Z. Yu / Tetrahedron Letters 51 (2010) 1500–1503
1503
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R'
R'
N
H
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R
O
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R
SeCO
NO2
R'
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H
O
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H
1
R
2
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Acknowledgments
We are grateful to the National Natural Science Foundation of
China (20972157) and the National Basic Research Program of Chi-
na (2009CB825300) for support of this research.
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0.25 mmol), and 50 mL THF. The reactor was sealed, flushed three times with
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remaining carbon monoxide was evacuated. Stirring was continued in air for
1–2 h to precipitate selenium powder and then filtered. The recovered
selenium powder was rinsed with 5 mL THF. The combined filtrate
evaporated all the volatiles under reduced pressure. The resultant residue
was purified by silica gel chromatography (eluent/petroleum ether (30–
60 °C):EtOAc = 2:1, v/v), affording 2r as a white solid (1.229 g, 92% yield).
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Mp: 283–284 °C. IR (KBr), cmꢀ1: 3199 (85) [
(C@O)]. 1H NMR (DMSO-d6, 23 °C, 400 MHz): d 11.39 (s, 1H, NH), 7.44–7.15
m(N–H)], 1717 (30) and 1648 (40)
[m
(m, 8H, aromatic CH), 3.75 (s, 3H, OCH3). 13C{1H} NMR (DMSO-d6, 23 °C,
100 MHz): d 162.6 and 155.3 (Cq each, C@O), 150.5, 136.4, 134.5, and 115.5 (Cq
each), 129.6, 129.3, 128.6, 124.6, 117.4, and 109.2 (aromatic CH), 56.2 (OCH3).
MS (EI): m/z: 268.00 [M+] (100), 176.05 (36), 149.10 (78), 121.10 (38), 106.05
(68). Anal. Calcd for C15H12N2O3: C, 67.16; H, 4.51; N, 10.44. Found: C, 67.15; H,
4.52; N, 10.43. All the new products were characterized by NMR, MS, and
elemental analyses. The known compounds were identified by comparison of
their NMR features with those of the authentic samples or the reported NMR
data.