Facile and efficient synthesis of quinazoline-2,4(1H,3H)-diones through sequential hydrogenation condensation

Article abstract of DOI:10.1080/00397911.2018.1439173

The heterocyclizations from various methyl (2-nitrobenzoyl)carbamates to substituted quinazoline-2,4(1H,3H)-diones under hydrogenation conditions were investigated in this study. In the presence of p-toluenesulfonic acid monohydrate in methanol, various q

Full text of DOI:10.1080/00397911.2018.1439173

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Facile and efficient synthesis of
quinazoline-2,4(1H,3H)-diones through sequential
hydrogenation condensation
Peng-Xu Wang, Ya-Nan Wang, Zi-Yun Lin, Gang Li & Hai-Hong Huang
To cite this article: Peng-Xu Wang, Ya-Nan Wang, Zi-Yun Lin, Gang Li & Hai-Hong Huang (2018):
Facile and efficient synthesis of quinazoline-2,4(1H,3H)-diones through sequential hydrogenation
condensation, Synthetic Communications, DOI: 10.1080/00397911.2018.1439173
To link to this article: https://doi.org/10.1080/00397911.2018.1439173
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https://doi.org/10.1080/00397911.2018.1439173
Facile and efficient synthesis of quinazoline-2,4(1H,3H)-diones
through sequential hydrogenation condensation
Peng-Xu Wanga,b, Ya-Nan Wanga, Zi-Yun Lina,b, Gang Lia,b , and Hai-Hong Huanga,b
aState Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica,
Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, P. R. China; bBeijing Key
Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking
Union Medical College and Chinese Academy of Medical Sciences, Beijing, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 3 December 2017
The heterocyclizations from various methyl (2-nitrobenzoyl)
carbamates to substituted quinazoline-2,4(1H,3H)-diones under
hydrogenation conditions were investigated in this study. In the
presence of p-toluenesulfonic acid monohydrate in methanol, various
quinazoline-2,4(1H, 3H)-diones were obtained in good to excellent
yields within 12 h. The reaction was proposed to proceed through the
cascade reactions of nitro reduction and condensation.
KEYWORDS
Cascade reaction;
heterocyclization;
hydrogenation
condensation; quinazoline-
2,4(1H,3H)-dione
GRAPHICAL ABSTRACT
Introduction
Heterocycles are of special interest and significant importance in the search for new
biologically active scaffolds in the pharmaceutical industries. Among different types of
the nitrogen containing heterocycles, quinazolinones and quinazolinediones have attracted
great attention due to their diverse pharmacological activities, such as anticancer,
anticonvulsive, anti-inflammatory, and antihypertensive activities, etc.[1–7] Owing to the
widespread applications of the quinazolinedione skeleton, substantial efforts have been
made to the chemical derivatization on the scaffold. Thus, various synthetic methods have
been developed to construct substituted quinazolinediones, with the most common
method as the heterocyclization of 2-aminobenzoic acid with urea above 150 °C (method
A, Scheme 1)[8] or metal-catalyzed condensation (methods B–E, Scheme 1),[9–12] and
several other conditions (methods F–H, Scheme 1).[13–15] Among these methods, it is
obviously that the introduction of 2-position carbonyl group was crucial to the
CONTACT Gang Li
ligang@imm.ac.cn; Hai-Hong Huang
joyce@imm.ac.cn
Institute of Materia Medica, Peking
Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, P. R. China.
Color versions of one or more figures in this article can be found online at www.tandfonline.com/lsyc.
Supplemental data (full experimental detail, 1H NMR, 13C NMR, and HR-MS spectra) can be accessed on the
publisher’s website.
© 2018 Taylor & Francis

2
P.-X. WANG ET AL.
Scheme 1. Representative strategies for the construction of quinazolinediones. Note: DMF,
dimethylformamide; THF, tetrahydrofuran.
construction of quinazolinedione with the key precursor reagents such as urea, DMF, CO,
and KOCN (Scheme 1).
Although above synthesis methods are very useful, many of them have drawbacks such
as involving harsh reaction condition, long reaction time, use of toxic and expensive
chemicals and low reaction yields. Herein, we wish to design a facile and efficient protocol
for the preparation of quinazoline-2,4(1H,3H)-diones through sequential hydrogenation
condensation under mild reaction conditions with a novel and simple method for the
introduction of 2-position carbonyl group. To our knowledge, this is the first time that
methyl (2-nitrobenzoyl)carbamates are used as the starting materials to construct
quinazolinediones under hydrogenation/condensation conditions.
Results and discussion
Initially, ethyl (2-nitrobenzoyl)carbamate (A) as an important substrate was conveniently
synthesized from 2-nitrobenzamide by the use of oxalyl chloride and C2H5OH, in which
the 2-position carbonyl was formed in advance. Then, Pd/C hydrogenation was proceeded
to reduce the nitro group. Finally, after 3 h hydrogenation at room temperature, removal of
Pd/C and evaporation of the solvent at 30 °C, we found that a mixture of nitro reduction
product (B) and trace quinazolinedione (1a) was formed according to the 1H NMR spectra
(Scheme 2). Interestingly, when a drop of DCl was added to the mixture of 1a and B in the
NMR tube and laid overnight, the compound B could completely convert to the target

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3
Scheme 2. Exploration of the synthesis of quinazolinedione 1a.
compound 1a. This result indicated that the acid could promote the cyclization process. It
is anticipated that quinazolinedione 1a could be directly prepared with a combination of
Pd/C and acid through hydrogenation from substrate A. Herein we report the development
of heterocyclization toward quinazolinediones through a cascade of nitro reduction and
condensation.
First, we screened the leaving group OR, solvent and acid that might affect the
heterocyclization (Table 1). The results displayed that the leaving group (OR) was crucial
for the reaction due to the steric hindrance effect. The use of methoxy group resulted in a
much higher yield (entry 1) compared to the ethoxy or phenoxy group (entries 2, 3), but
tert-butoxy group did not proceed cyclization (entry 4). When PTSA · H2O was used as the
=
catalyst, the reaction yields were increased from 61.8 to 82.4% (OR OC2H5, entry 2 vs
=
entry 6), and 60.1 to 76.7% (OR OPh, entry 3 vs entry 7), respectively. The results revealed
that PTSA · H2O could be favorable to the cyclization reaction. However, for the bulky
tert-butoxy group, the heterocyclization still did not occur even in the presence of
PTSA · H2O (entry 8). Second, with optimized leaving group OCH3 and PTSA · H2O in
Table 1. Optimization of reaction conditions.a
Yield (%)
Entry
R
Acidb
Solvent
1a
C
1
2
CH3
CH2CH3
Ph
CH(CH3)3
CH3
CH2CH3
Ph
CH(CH3)3
CH3
CH3
CH3
–
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
C2H5OH
THF
87.0
61.8
60.1c
–
88.1
82.4
76.7c
–
–
–
–
3
–
–
–
4
90.4
–
–
–
5
PTSA · H2O
PTSA · H2O
PTSA · H2O
PTSA · H2O
PTSA · H2O
PTSA · H2O
PTSA · H2O
6
7
8
88.7
–
9
83.3
–
–
10
11
NRd
NR
DME
aReaction was run at room temperature with H2 balloon for 3 h, evaporation of the solvent at 45 °C after removal of Pd/C.
The concentrate was washed with water to afford the product.
bUsing 5% of PTSA · H2O.
c1H NMR yield.
dNo reaction.
DME, dimethylether; PTSA, p-toluenesulfonic acid; THF, tetrahydrofuran.

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P.-X. WANG ET AL.
hand, the solvents were screened. We found that the use of C2H5OH resulted in a slight
lower yield than CH3OH (entry 9 vs entry 5), but no reaction in tetrahydrofuran (THF)
and dimethylether (DME) (entries 10, 11). The possible reason was that the hydrogenation
reaction was prone to occur in alcoholic solvents and CH3OH was proved to be the best
solvent for this tandem reaction.
Encouraged by this promising result, the scope of the method for substituted quinazo-
line-2,4(1H,3H)-diones was then investigated. To our delight, various substrates 2 could
smoothly undergo heterocyclization to afford substituted quinazolinediones 1 in good to
excellent yields. It was noticed that the substrates containing electron-donating groups
or halogen substituents generally gave higher yields (1a–j in Table 2) under the optimal
reaction conditions, while the substrates containing electron-deficient group like
trifluoromethyl gave very low yield (1k, entry 11). The disubstituted electron-donating
substituents provided a higher yield than the single substituents (1d vs 1e). Interestingly,
when the substrate 2i with fluoro group in the ortho position of nitro displayed the lowest
yield compared to its isomers with fluoro group attached to the different position on phe-
nyl ring. The possible reason is that the intramolecular hydrogen bond between fluoro and
amino reduced the nucleophilicity of amino group. To improve the yield of 1k, the reaction
temperature was raised from room temperature to 40 °C. The yield of 1k was increased
from 12.4 to 37.4% but the intermediate amine D still left (entry 12). With the continuous
efforts, the amount of PTSA · H2O was increased from 5 to 20% and also the reaction time
was prolonged from 3 to 12 h, the yield was raised to 67.0% without remaining of the
intermediate amine D (1k, entry 13).
To clarify the proposed reaction mechanism, we focused on the transformation of the
reaction intermediate D inspired by the result of 1k. When substrate 2k was treated with
Table 2. Heterocyclizations from methyl (2-nitrobenzoyl)carbamates 2a–k.
Entry
No.
R1,2,3,4
Time
Yield (%)
1a
1a
1b
1c
1d
1e
1f
R1,2,3,4 ¼ H
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
12 h
89.9
90.5
86.4
94.2
81.5
75.3
86.7
90.3
67.8
95.5
12.4d
37.4d
67.0
2a
R1,2,3 ¼ H; R4 ¼ CH3
R1,3,4 ¼ H; R2 ¼ CH3
R1,4 ¼ H; R2,3 ¼ OCH3
R1,3,4 ¼ H; R2 ¼ OCH3
R2,3,4 ¼ H; R1 ¼ F
3a
4a
5a
6a
7a
1g
1h
1i
R1,3,4 ¼ H; R2 ¼ F
8a
R1,2,4 ¼ H; R3 ¼ F
9a
R1,2,3 ¼ H; R4 ¼ F
10a
11a
12b
13c
1j
R1,3,4 ¼ H; R2 ¼ OCOCH3
R1,2,4 ¼ H; R3 ¼ CF3
R1,2,4 ¼ H; R3 ¼ CF3
R1,2,4 ¼ H; R3 ¼ CF3
1k
1k
1k
aReaction was run at room temperature with H2 balloon using 5% of PTSA · H2O.
bReaction was run at 40 °C with H2 balloon using 5% of PTSA · H2O.
cReaction was run at 40 °C with H2 balloon using 20% of PTSA · H2O.
d1H NMR yield; a mixture of 1k and intermediate amine D.
PTSA, p-toluenesulfonic acid.

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Scheme 3. Exploration of the possible mechanism of 1k production.
Scheme 4. Proposed mechanism for the synthesis of quinazoline-2,4(1H,3H)-dione 1a.
Pd/C hydrogenation without catalyst PTSA · H2O at room temperature, the intermediate D
was formed exclusively (Scheme 3). With the assistance of PTSA · H2O at 40 °C, the inter-
mediate D smoothly underwent intramolecular cyclization to afford quinazolinedione 1k.
A plausible mechanism based on our experiments is proposed in Scheme 4. First, the
ethyl (2-nitrobenzoyl)carbamate A is reduced to the intermediate E by Pd/C hydrogen-
ation. Then intramolecular cyclization of E generates the intermediate F in the presence
of PTSA · H2O. At last, removal of C2H5OH and hydrogen ion affords the desired product
1a by ammonolysis of ester process. The nucleophilicity of amino group in the intermedi-
ate E plays a key role in the intramolecular ammonolysis reaction. This could be the
possible reason why substrates with electron-donating groups generally gave higher yields.
Conclusion
In summary, we have described a novel and efficient method for a PTSA-catalyzed
reaction to prepare various quinazoline-2,4(1H,3H)-diones from substituted methyl
(2-nitrobenzoyl)carbamates through sequential hydrogenation condensation. The crucial
2-position carbonyl group of quinazoline-2,4(1H,3H)-diones is constructed using oxalyl
chloride as the key precursor reagent to avoid harsh reaction condition and expensive
chemicals. This approach has several advantages, such as no-column separation, mild reac-
tion conditions and high yields. Further explorations to broaden the scope and synthetic
applications of this efficient approach are currently underway in our group. This useful
method could potentially be complementary to the existing methods for the synthesis of
quinazoline-2,4(1H,3H)-diones.
Experimental
Melting points were determined on Yanaco MP-J3 microscope melting point apparatus. 1H
and 13C NMR spectra were recorded on Varian 400 or 500 MHz NMR spectrometer with
CDCl3 or DMSO-d6 as a solvent. ESI-HRMS data were measured on Thermo Exactive

6
P.-X. WANG ET AL.
Orbitrap plus spectrometer. All solvents and reagents were obtained from commercial
suppliers and used without further purification.
General procedure for the preparation of methyl (2-nitrobenzoyl)carbamate (2a)
To a magnetically stirred solution of 2-nitrobenzamide (2 g, 12.04 mmol) in 1,2-
dichloroethane (15 mL) was added oxalyl chloride (1.8 mL, 20.47 mmol). The reaction
mixture was heated to reflux for 3 h under an atmosphere of argon. The solvent was eva-
porated under reduced pressure. The residue was dissolved in anhydrous acetonitrile
(30 mL). The mixture of CH3OH (10 mL) and anhydrous acetonitrile (10 mL) was slowly
added to the reaction mixture keeping the reaction under −10 °C. The reaction mixture was
stirred for 2 h keeping the reaction under −10 °C. The solvent was evaporated under
reduced pressure. The residue was washed with water, filtrated and dried to give a white
1
solid (2.27 g, 84.0%). mp 119–120 °C. H NMR (400 MHz, CDCl3) δ: 8.25 (dd, J1 ¼ 8.4 Hz,
J2 ¼ 1.2 Hz, 1H), 8.11 (brs, 1H), 7.75 (td, J1 ¼ 7.6 Hz, J2 ¼ 1.2 Hz, 1H), 7.66-7.62 (m, 1H),
7.45 (dd, J1 ¼ 7.6 Hz, J2 ¼ 1.2 Hz, 1H), 3.69 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ
167.2, 152.5, 145.1, 134.9, 132.6, 130.8, 128.5, 124.1, 52.7; ESI-HRMS m/z calcd for
C9H8N2O5Na (MþNaþ): 247.0325, found: 247.0325.
General procedure for the preparation of quinazoline-2,4(1H,3H)-dione (1a)
To a magnetically stirred solution of 2a (200 mg, 0.892 mmol) in CH3OH (50 mL) was
added 10% Pd/C (10% Pd loaded on Carbon wetted with ca. 55% water, 20 mg) and
PTSA · H2O (8.6 mg, 0.045 mmol). The reaction mixture was stirred under an atmosphere
of hydrogen at room temperature for 3 h. After filtration of Pd/C and concentration under
reduced pressure at 45 °C, 20 mL H2O was added to the residue and the mixture was stirred
at 0 °C for 1 h. After filtration, the product was dried to give a white solid (130 mg, 89.9%).
1
mp >250 °C; H NMR (500 MHz, DMSO-d6) δ: 11.26 (brs, 1H), 11.12 (brs, 1H), 7.89–7.87
(m, 1H), 7.64–7.61 (m, 1H), 7.17–7.15 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ 163.0,
150.5, 141.0, 135.1, 127.1, 122.4, 115.5, 114.5; ESI-HRMS m/z calcd for C8H7N2O2
(MþHþ): 163.0502, found: 163.0501.[8]
Funding
This work was supported by the National Natural Science Foundation of China under Grant
81703362; CAMS Innovation Fund for Medical Sciences under Grant CAMS-2016-I2M-1-010;
and Fundamental Scientific Research Fund of Chinese Academy of Medical Sciences under Grant
2016ZX350030.
ORCID
Gang Li
http://orcid.org/0000-0003-0924-7950
Hai-Hong Huang
http://orcid.org/0000-0003-1641-1309
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