Oxidative Synthesis of Quinazolinones under Metal-free Conditions

Article abstract of DOI:10.1002/jhet.2562

A metal-free procedure for the synthesis of quinazolinones under oxidative conditions has been developed. In the presence of DABCO and TBHP, the desired products can be obtained in moderate yields with 2-fluorobenzaldehydes and 2-aminopyridines as the substrates.

Full text of DOI:10.1002/jhet.2562

Month 2015
Oxidative Synthesis of Quinazolinones under Metal-free Conditions
a,b
a,b
Jian-Bo Feng and Xiao-Feng Wu *
a
Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, People’s Republic of China
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
b
*
E-mail: xiao-feng.wu@catalysis.de
Additional Supporting Information may be found in the online version of this article.
Received June 4, 2015
DOI 10.1002/jhet.2562
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A metal-free procedure for the synthesis of quinazolinones under oxidative conditions has been devel-
oped. In the presence of DABCO and TBHP, the desired products can be obtained in moderate yields with
-fluorobenzaldehydes and 2-aminopyridines as the substrates.
2
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
EXPERIMENTAL
As the development of our society, the concept of “Sus-
tainable Development” has been accepted and raises the
demand of “Green Chemistry” [1]. Under this background,
the establishment of metal-free synthetic procedures will
be under current interests.
On the other hand, the syntheses of N-heterocyclic com-
pounds have attracted general attention for their wide and
distinct pharmaceutical activities [2]. Among the known
N-heterocycles, quinazolinones is a class of representative
example, which is reported with various activities in-
cluding anticancer [3], anti-inflammation [4], antibacterial
In a 25-mL pressure tube equipped with a stirring bar,
2-fluorobenzaldehyde (1 mmol), 2-aminopyridine (1.5mmol),
and DABCO (2 equiv.) were added in DMF (2 mL); then,
TBHP (70wt % in H O; 2 equiv.) was injected by syringe.
2
After that, the tube was closed and heated up to 120°C for
14 h. When the reaction is completed, cool the reaction mix-
ture to room temperature. The reaction was quenched with
distilled water, and the solution was extracted with ethyl ace-
tate. The combined organic phases were washed with
saturated NaCl solution and dried over Na SO . The crude
2
4
product was purified by column chromatography (ethyl
[5], and anti-diabetes [6]. Regarding the importance of
acetate/pentane= 1:4).
quinazolinones, numerous elegant methods have been
developed for their preparation [7]. In the transition
metal-catalyzed methodologies, good to excellent yields
of the desired products can be obtained with Pd, Ru, Ir,
Cu, and Fe as the catalysts. However, besides the high
costs of these catalytic systems, the heterocyclic products
are usually contaminated by the metals. Furthermore, in
the known oxidative procedures, oxidants like KMnO4,
N,N′-dicyclohexylcarbodiimide, and TBHP together with
catalyst are usually required. In our group, we were
succeeded in developing several new procedures for the
synthesis of quinazolinones as well, such as palladium-
catalyzed carbonylation of aryl bromides with 2-
aminobenzamides [8] and metal-free procedures with
aldehydes and 2-aminobenzamides and analogs as the sub-
strates [9]. As our continuing interests on this topic, we
wish to report our new results on the metal-free synthesis
of quinazolinones from 2-fluorobenzaldehydes and 2-
aminopyridines here.
RESULTS AND DISCUSSION
The first set of reactions was performed with solvents
testing (Table 1, entries 1–4). We using 2-fluorobenzaldehyde
and 2-aminopyridine as the model substrates; in the
presence of TBHP and DABCO, different solvents were
tested. Gratingly, 28% of the desired product was produced
in DMF, while only low yield of the product was formed in
the other tested solvents. To our surprise, the yield dropped
dramatically when TBHP in decane was applied as the ox-
idant (Table 1, entry 5). In the other tested oxidants,
cumene hydroperoxide gave similar yield of the desired
product (Table 1, entry 6). Notably, full conversion of
2-fluorobenzaldehyde was detected in all the cases.
2-Fluorobenzoic acid, 2-Fluorobenzamide, and non-
characterizable compounds are the by-products in general.
Then the effects of bases were checked. Among all the tested
©
2015 HeteroCorporation

J.-B. Feng and X.-F. Wu
Vol 00
Table 1
Table 2
Metal-free quinazolinones synthesis: 2-aminopyridines testing.
a
a
Metal-free quinazolinones synthesis: optimization.
b
Entry
Oxidant
Base
Solvent
DMF
DMSO
DMAc
1,4-Dioxane
DMF
DMF
DMF
DMF
DMF
Yield (%)
b
Entry
1
2
3
Yield
c
1
2
3
4
5
6
7
8
9
TBHP
TBHP
TBHP
TBHP
TBHP
CHP
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
28 (26)
48
6
7
9
d
3
26
DTBP
BPO
Trace
Trace
5
2
52
H
2
O
2
e
10
11
12
TBHP
TBHP
TBHP
DMF
DMF
DMF
23
c,f
83 (81)
21
g
a
Reaction conditions: 2-fluorobenzaldehyde (1, 1 mmol), 2-aminopyridine
2, 1.5 mmol), TBHP (70 wt % in H O; 2 equiv.), DABCO (3 equiv.),
(
2
solvent (2 mL), 18 h.
b
3
4
48
52
GC yield, using hexadecane as the internal standard.
Isolated yield.
c
d
e
5.5 M TBHP in decane.
DABCO (2 equiv.), 10 h.
DABCO (2 equiv.), 14 h.
f
g
DABCO (2 equiv.), 24 h.
t
bases [K CO , K PO , KO Bu, DBU, 1,5-diazabicyclo[4.3.0]
2
3
3
4
non-5-ene, and N,N-diisopropylethylamine (DIPEA)],
DABCO was still proven to be the best base. Interestingly,
the reaction time was found to be important for the outcome
of this transformation. Shortened reaction time gave non-
complete conversion, while the decomposition of the product
was observed in the reaction with prolonged reaction time
5
6
38
30
(
Table 1, entries 10–12). Reaction temperatures were tested
as well, but no better results can be obtained. At this stage,
1% of the product can be isolated in DMF, at 120 °C with
8
DABCO (2 equiv.) as the base and TBHP (2 equiv.) as the
oxidant (Table 1, entry 11).
With the best reaction conditions in hand, we started the
scope and limitation testing subsequently (Tables 2 and 3).
Various functional group substituted 2-aminopyridines were
tested at the beginning. Moderate yields of quinazolinones
can be isolated from the corresponding 2-aminopyridines.
Methyl, chloro, and fluoro are tolerable under this reaction
conditions. However, 2-aminopyridine with functional groups
like bromo, cyano and nitro can only give traces of the
corresponding product under standard conditions. This phe-
nomenon might be due to the reduced electron density on
NH–Ar anion and subsequently decreased the ability of nucle-
ophilic substitution with 2-F–Ar. This situation cannot be
improved by varying the reaction temperature and time. On
a
Reaction conditions: 2-fluorobenzaldehyde (1, 1 mmol), 2-aminopyridine
2, 1.5 mmol), TBHP (2 equiv.), DABCO (2 equiv.), DMF (2 mL), 14 h,
20 °C.
(
1
b
Isolated yield.
the other hand, steric effect acts as another important role for
this transformation. Only the non-cyclized amide was isolated
when 6-methylpyridin-2-amine was applied as the reaction
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Oxidative Synthesis of Quinazolinones under Metal-free Conditions
Table 3
Metal-free quinazolinones synthesis: 2-fluorobenzaldehydes testing.
Then, different 2-fluorobenzaldehydes were reacted with
a
2-aminopyridine. As shown in Table 3, low to moderate of
the corresponding quinazolinones were isolated. Compared
with 2-fluorobenzaldehyde, the substituted substrates re-
sulted decreased yields that can be explained as follows:
(1) nucleophilic substitution can be favored by electron-
withdrawing substituents, while this can lead the aldehyde
to be activated and the trend to be oxidized to the acid; (2)
electron-donating substituted aldehydes are more stable in
oxidative conditions, but this can increase the difficulty in
nucleophilic substitution.
Entry
1
1
3
Yield
8
Additionally, 2-bromobenzaldehyde and 2-nitrobenzaldehyde
were tested as substrates with 2-aminopyridine under the same
reaction conditions; 36% and 10% yields of the quinazolinone
were produced (Scheme 1). Remarkably, no reaction occurred
when 2-fluorobenzoic acid was applied as the starting material.
By using 2-aminophenol as the reaction partner, good yield of
the desired dibenzo[b,f][1,4]oxazepin-11(10H)-one can be
achieved (Scheme 2). Based on these experiments, a possible
reaction pathway has been proposed. As shown in Scheme 3,
the reaction starts with amide formation via oxidative
amidation. Then the rearrangement of the C¼N occurred
and followed by nucleophilic substitution to give the final
product.
2
3
4
5
6
7
22
46
11
33
16
15
CONCLUSIONS
In summary, we have explored the possibility of using
2
-aminopyridines and 2-fluorobenzaldehydes as starting
materials for quinazolinone synthesis. In the neutral sub-
strate, excellent yield can be achieved, while this transfor-
mation is very sensitive to the electron properties and steric
character of the substrates.
EXPERIMENTAL
General comments.
All reactions were carried out
under air. Reactions were monitored by TLC analysis
precoated silica gel plates with fluorescent indicator
(
UV254, 0.2 mm) and visualized with 254nm ultraviolet
light. Chemicals were purchased from Aldrich, Alfa-
Aesar (Ward Hill, MA, USA) and, unless otherwise
noted, were used without further purification. All
1
13
compounds were characterized by H NMR and
C
NMR spectroscopy and recorded on Bruker AV 300 and
AV 400 spectrometers. GC was performed on Agilent
a
Reaction conditions: 2-fluorobenzaldehyde (1, 1 mmol), 2-aminopyridine
2, 1.5 mmol), TBHP (2 equiv.), DABCO (2 equiv.), DMF (2 mL), 14 h.
Isolated yield.
6
890 chromatograph with a 30-m HP5 column.
(
b
General procedure for the synthesis of quinazolinone. In
a 25-mL pressure tube equipped with a stirring bar,
2-fluorobenzaldehyde (1 mmol), 2-aminopyridine (1.5 mmol),
and DABCO (2 equiv.) were added in DMF (2 mL), then
partner (Table 2, entry 3). Quinolin-2-amine was tested with
-fluorobenzaldehyde as well, but only trace of the desired
product was detected, which may due to the steric issue.
2
TBHP (70wt % in H O; 2 equiv.) was injected by syringe.
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J.-B. Feng and X.-F. Wu
Vol 00
Scheme 1. Metal-free quinazolinones synthesis from 2-bromobenzaldehyde and 2-nitrobenzaldehyde.
Scheme 2. Oxidative synthesis of dibenzo[b,f][1,4]oxazepin-11(10H)-one.
6
Scheme 3. Proposed reaction mechanism.
(
101MHz, DMSO-d ) δ 157.84 (d, J= 2.1 Hz), 153.40,
151.02, 147.74, 145.62, 134.98, 128.81–128.01 (m), 126.82,
1
26.48, 125.57, 115.06, 112.05, 111.63.
3
-Methyl-6H-pyrido[1,2-a]quinazolin-6-one [7a].
1H NMR
300MHz, DMSO-d ) δ 8.69 (dd, J= 7.4, 0.7 Hz, 1H), 8.26
ddd, J=8.2, 1.6, 0.6 Hz, 1H), 7.87 (ddd, J= 8.5, 6.9, 1.6Hz,
H), 7.68 (ddd, J=8.4, 1.2, 0.6Hz, 1H), 7.46 (ddd, J= 8.1, 6.9,
.2 Hz, 1H), 7.29 (dt, J=2.0, 1.1Hz, 1H), 6.91 (dd, J=7.5,
6
(
(
1
1
13
1.8 Hz, 1H), 2.38 (d, J=1.2 Hz, 3H). C NMR (101MHz,
6
DMSO-d ) δ 158.19, 148.55, 147.35, 146.36, 134.89, 126.65,
1
1
26.52, 125.68, 127.47–126.16 (m), 124.45, 123.05, 115.95,
15.38, 20.78.
-Fluoro-N-(6-methylpyridin-2-yl)benzamide [8b]. 1H NMR
2
6
(300 MHz, DMSO-d ) δ 10.69 (s, 1H), 8.00 (d, J=8.2Hz,
After that, the tube was closed and heated up to 120 °C for
4 h. When the reaction was completed, cool the reaction
1H), 7.81–7.63 (m, 2H), 7.57 (dddd, J=8.6, 7.2, 5.3, 1.8Hz,
1H), 7.39–7.22 (m, 2H), 7.03 (dd, J=7.5, 1.0Hz, 1H), 2.42
(s, 3H). 13C NMR (101 MHz, DMSO-d ) δ 163.18, 160.38,
157.90, 156.66, 150.96, 138.54, 130.11 (d, J=2.7Hz),
126.68–121.90 (m), 119.22, 116.03 (d, J= 22.2 Hz), 110.99,
23.57.
1
6
mixture to room temperature. The reaction was
quenched with distilled water, and the solution was
extracted with ethyl acetate. The combined organic
phases were washed with saturated NaCl solution and
dried over Na SO . The crude product was purified by
4-Methyl-6H-pyrido[1,2-a]quinazolin-6-one [8b].
1H NMR
2
4
6
column chromatography (ethyl acetate/pentane = 1:4).
(300MHz, DMSO-d ) δ 8.98 (ddd, J= 7.5, 1.4, 0.7 Hz, 1H),
8.47 (dd, J= 8.6, 0.9 Hz, 1H), 8.26 (dd, J= 7.9, 1.7 Hz, 1H),
7.92 (ddd, J=8.8, 7.2, 1.7Hz, 1H), 7.82–7.58 (m, 2H), 6.97 (t,
1
6
H-Pyrido[1–9]quinazolin-6-one [8b].
H NMR (300MHz,
6
DMSO-d ) δ 8.80 (ddd, J=7.3, 1.5, 0.9Hz, 1H), 8.31 (ddd,
J= 8.1, 1.6, 0.6Hz, 1H), 7.91 (ddd, J=8.5, 6.9, 1.6Hz, 1H),
13
J= 7.0 Hz, 1H), 2.40–2.30 (m, 3H). C NMR (101 MHz,
6
7
.82–7.62 (m, 2H), 7.59–7.43 (m, 2H), 7.07 (ddd, J=7.6,
DMSO-d ) δ 165.11, 151.55, 137.54, 136.01, 133.32, 132.15,
6
13
6
1
.4, 1.4 Hz, 1H). C NMR (75MHz, DMSO-d ) δ 158.25,
48.18, 147.35, 135.16, 135.00, 126.69, 126.42, 125.78,
24.94, 115.68, 113.19.
128.31, 127.86, 127.67, 121.02, 116.29, 112.37, 18.46.
2-Chloro-6H-pyrido[1,2-a]quinazolin-6-one [8b].
1H NMR
6
1
(300MHz, DMSO-d ) δ 8.78 (dd, J= 2.4, 0.7Hz, 1H), 8.30
(ddd, J= 8.1, 1.7, 0.6Hz, 1H), 7.93 (ddd, J=8.5, 7.0, 1.6 Hz,
2
-Fluoro-6H-pyrido[1,2-a]quinazolin-6-one [8b].
1H NMR
300 MHz, DMSO-d ) δ 8.74 (ddd, J=5.3, 2.8, 0.7 Hz, 1H),
.29 (ddd, J= 8.2, 1.7, 0.6 Hz, 1H), 7.99–7.79 (m, 2H), 7.76
ddd, J=8.5, 1.2, 0.6Hz, 1H), 7.68–7.43 (m, 2H). 13C NMR
6
13
(
8
(
1H), 7.82–7.69 (m, 2H), 7.62–7.48 (m, 2H). C NMR
6
(75 MHz, DMSO-d ) δ 157.45, 147.78, 145.75, 135.73,
135.22, 127.59, 126.89, 126.74, 125.66, 123.88, 120.18, 115.72.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Oxidative Synthesis of Quinazolinones under Metal-free Conditions
6
9
-(Trifluoromethyl)-6H-pyrido[1,2-a]quinazolin-6-one [7a]. 1H
DMSO-d ) δ 157.47, 147.63, 146.89, 135.66, 135.13,
6
NMR (300MHz, DMSO-d ) δ 8.83 (ddd, J= 7.3, 1.5, 0.9Hz,
H), 8.48 (dt, J=8.4, 0.8Hz, 1H), 8.04 (dt, J= 1.7, 0.8 Hz,
H), 7.90–7.66 (m, 2H), 7.58 (ddd, J= 9.2, 1.4, 0.8 Hz, 1H),
.15 (ddd, J=7.3, 6.5, 1.4Hz, 1H). C NMR (75 MHz,
DMSO-d ) δ 157.92, 148.45, 147.95, 136.34, 134.33 (d,
129.03, 128.82, 126.53, 125.83, 125.30, 116.62, 113.73.
1
1
7
13
Acknowledgments. We thank the state of Mecklenburg-Vorpommern,
the Bundesministerium für Bildung und Forschung (BMBF) and the
Deutsche Forschungsgemeinschaft for financial support. In addition,
the research leading to these results has received funding from the
Innovative Medicines Initiative Joint Undertaking (CHEM21)
under grant agreement number 115360, resources of which are
composed of a financial contribution from the European Union’s
Seventh Framework Programme (FP7/2007–2013) and EFPIA
companies in kind contribution. We also thank Dr. C. Fischer, S.
Schareina, and Dr. W. Baumann for their excellent technical and
analytical support. We appreciate the general support from
Professor Matthias Beller in LIKAT.
6
J=32.1 Hz), 128.76, 126.71, 125.80, 123.92 (d, J=4.4Hz),
1
19.83 (d, J= 3.6 Hz), 118.05, 113.99.
7
-Chloro-6H-pyrido[1,2-a]quinazolin-6-one [7a].
1H NMR
300 MHz, DMSO-d ) δ 8.78 (ddd, J=7.4, 1.6, 0.9 Hz, 1H),
.85–7.71 (m, 2H), 7.65 (dd, J=8.4, 1.2Hz, 1H), 7.56–7.43
6
(
7
(
(
1
1
1
3
m, 2H), 7.09 (ddd, J = 7.4, 6.5, 1.4 Hz, 1H). C NMR
6
101 MHz, DMSO-d )
δ
156.18, 150.54, 147.87,
36.14, 134.40, 132.76, 126.93, 126.55, 126.24, 125.51,
13.50, 112.68.
-Methoxy-6H-pyrido[1,2-a]quinazolin-6-one [7a]. 1H NMR
9
6
(
8
1
(
1
1
300MHz, DMSO-d ) δ 8.78 (ddd, J=7.3, 1.6, 0.8Hz, 1H),
.20 (dd, J=8.8, 0.5Hz, 1H), 7.72 (ddd, J= 9.2, 6.5, 1.6 Hz,
H), 7.46 (dt, J=9.2, 1.1Hz, 1H), 7.22–6.92 (m, 3H), 3.93
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s, 3H). 1 C NMR (75MHz, DMSO-d ) δ 164.62, 157.48,
3
50.62, 147.89, 135.45, 128.39, 126.52, 125.40, 116.20,
12.93, 109.45, 106.26, 55.74.
1H NMR
10-Chloro-6H-pyrido[1,2-a]quinazolin-6-one [7a].
6
(
8
7
0
6
1
1
300MHz, DMSO-d ) δ 8.80 (ddd, J=7.3, 1.6, 0.9Hz, 1H),
.25 (dd, J= 8.1, 1.5Hz, 1H), 8.05 (dd, J=7.6, 1.5Hz, 1H),
.79 (ddd, J=9.2, 6.5, 1.6 Hz, 1H), 7.60 (ddd, J=9.2, 1.4,
.8Hz, 1H), 7.45 (dd, J=8.1, 7.6 Hz, 1H), 7.13 (ddd, J=7.3,
[
6
13
.5, 1.4 Hz, 1H). C NMR (75MHz, DMSO-d ) δ 158.03,
47.76, 144.55, 136.15, 134.77, 129.90, 126.67, 126.06,
25.96, 124.69, 117.20, 113.90.
0-Fluoro-6H-pyrido[1,2-a]quinazolin-6-one [8b]. 1H NMR
(
[
1
6
[
(
8
7
300MHz, DMSO-d ) δ 8.82 (ddd, J=7.3, 1.6, 0.9Hz, 1H),
.12 (dt, J = 8.2, 1.1 Hz, 1H), 7.87–7.71 (m, 2H),
.65–7.58 (m, 1H), 7.48 (td, J = 8.0, 4.8 Hz, 1H), 7.13
ddd, J = 7.6, 6.5, 1.4 Hz, 1H). C NMR (75 MHz,
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(
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[
[
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DMSO-d ) δ 158.44–157.42 (m), 154.33, 147.73, 138.13
d, J= 12.8 Hz), 135.88, 126.61, 126.02, 124.47 (d, J=7.6Hz),
22.47 (d, J= 4.8 Hz), 119.54, 119.30, 117.63 (d, J=2.6Hz),
13.77.
-Methoxy-6H-pyrido[1,2-a]quinazolin-6-one [7a]. 1H NMR
(
1
1
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8
6
9
(
6
(
7
300MHz, DMSO-d ) δ 8.78 (ddd, J=7.4, 1.5, 0.9Hz, 1H),
.73 (dd, J=9.0, 0.5Hz, 1H), 7.68–7.60 (m, 2H), 7.56 (dd,
J=9.0, 3.0Hz, 1H), 7.50 (ddd, J=9.2, 1.4, 0.9Hz, 1H), 7.04
ddd, J=7.4, 6.4, 1.4Hz, 1H), 3.91 (s, 3H). C NMR
101MHz, DMSO-d ) δ 157.81, 156.60, 145.67, 143.21,
33.85, 128.61, 126.16, 126.07, 125.84, 116.24, 113.24,
04.97, 55.63.
2012, 14, 3800; (i) Watson, A. J. A.; Maxwell, A. C.; Williams, J. M. J
Org Biomol Chem 2012, 10, 240; (j) Zhou, J.; Fang, J. J Org Chem
011, 76, 7730; (k) Hikawa, H.; Ino, Y.; Suzuki, H.; Yokoyama, Y.
13
(
(
1
1
6
2
J Org Chem 2012, 77, 7046.
[8] (a) Li, H. Q.; He, L.; Neumann, H.; Beller, M.; Wu, X. F. Green
Chem 2014, 16, 1336; (b) Chen, J. B.; Natte, K.; Spannenberg, A.;
Neumann, H.; Langer, P.; Beller, M.; Wu, X. F. Angew Chem 2014,
126, 7709; (c) Wu, X. F.; Oschatz, S.; Sharif, M.; Beller, M.;
Spannenberg, A. Tetrahedron 2014, 70, 23.
1H NMR
8-Chloro-6H-pyrido[1,2-a]quinazolin-6-one [7a].
6
(
8
7
7
300 MHz, DMSO-d ) δ 8.79 (ddd, J=7.3, 1.6, 0.9 Hz, 1H),
.23 (dd, J=2.6, 0.5Hz, 1H), 7.91 (dd, J=8.9, 2.5Hz, 1H),
.84–7.68 (m, 2H), 7.54 (ddd, J = 9.2, 1.4, 0.9 Hz, 1H),
.11 (ddd, J = 7.3, 6.4, 1.4 Hz, 1H). 1 C NMR (101 MHz,
[
9] (a) Wu, X. F.; Oschatz, S.; Block, A.; Spannenberg, A.;
Langer, P. Org Biomol Chem 2014, 12, 1865; (b) Sharif, M.; Opalach, J.;
Langer, P.; Beller, M.; Wu, X. F. RSC Adv 2014, 4, 8; (c) Oschatz, S.;
Brunzel, T.; Wu, X. F.; Langer, P. Org Biomol Chem 2015, 13, 1150.
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet