Electrochemical Synthesis of Quinazolinones by the Metal-Free and Acceptor-Free Dehydrogenation of 2-Aminobenzamides

Article abstract of DOI:10.1055/s-0040-1707248

An efficient approach has been developed for the construction of quinazolin-4(3 H)-ones by the selective anodic dehydrogenative oxidation/cyclization of benzylic chlorides and 2-aminobenzamides. The method features acceptor-free and metal-free dehydrogenation of amines to imines; a subsequent intermolecular addition provides the products in moderate to good yields.

Full text of DOI:10.1055/s-0040-1707248

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
A
en
Synlett
Y. Yao et al.
Letter
Electrochemical Synthesis of Quinazolinones by the Metal-Free
and Acceptor-Free Dehydrogenation of 2-Aminobenzamides
Yan Yaoa
Xiu-Jin Menga
Qing-Hu Teng*a,b
Yan-Yan Chen*c
a
State Key Laboratory for Chemistry and Molecular Engineering of
Medicinal Resources, School of Chemistry and Pharmaceutical
Sciences, Guangxi Normal University, Guilin 541004, P. R. of China
qinghuteng@163.com
b
Guangxi Key Laboratory of Electrochemical and Magnetochemical
Function Materials, College of Chemistry and Bioengineering, Guilin
University of Technology, Guilin 541004, P. R. of China
Pharmacy School, Guilin Medical University, Guilin 541004, P. R. of
c
China
chenyy269614@163.com
Received: 02.06.2020
Accepted after revision: 26.07.2020
Published online: 19.08.2020
O
N
N
N
O
N
OMe
OH
OMe
S
O
N
DOI: 10.1055/s-0040-1707248; Art ID: st-2020-l0330-l
H2N
N
NH
NH2
F
Abstract An efficient approach has been developed for the construc-
tion of quinazolin-4(3H)-ones by the selective anodic dehydrogenative
oxidation/cyclization of benzylic chlorides and 2-aminobenzamides.
The method features acceptor-free and metal-free dehydrogenation of
amines to imines; a subsequent intermolecular addition provides the
products in moderate to good yields.
Afloqualone
Nolatrexed
Isaindigotone
Cl
O
N
N
O
H
N
N
N
N
N
Key words quinazolinones, electrochemical synthesis, aminoben-
zamides, benzylic chlorides, metal-free
N
O
NC
Methaqualone
CP-465
Rutaecarpine
Figure 1 Selected examples of biologically active quinazolinones
Quinazolinones are an important class of nitrogen-con-
taining heterocyclic compounds, widely present in natural
products and pharmaceutical agents that present diverse
1
2
3
zamide to provide the desired quinazolinones.10 Li and co-
workers reported a valuable synthesis of quinazolinones
through the cross-coupling of methylarenes with 2-amino-
benzamide promoted by DTBP/TsOH.11 However, these
transformations rely on catalysis by transition metals and
oxidation by stoichiometric quantities of oxidants, both of
which are environmentally unfriendly. Therefore, it is still
highly desirable to develop green methods for the synthesis
of quinazolines.
biological activities, such as antibacterial, antiviral, anti-
4
5
inflammatory, and antitumor activities (Figure 1). Be-
cause of the wide range of applications of quinazolinones,
much effort has been devoted to the exploration of efficient
methods for their construction.
2-Aminobenzamide has been widely used as a precur-
sor for preparing quinazolinones. In conventional methods,
quinazolinones are commonly prepared through coupling
6
7
of 2-aminobenzamide with aldehydes, carboxylic acids, or
8
acyl halides. However, these methods involve harsh condi-
Acceptor-free dehydrogenation is considered an import-
ant synthetic approach in terms of atom economy and envi-
ronmental effects.12 The functionalization of amines by ac-
ceptor-free dehydrogenation has attracted widespread re-
cent attention, and several methods based on catalysis by
tions or require substrates that are not readily available.
Some recent studies have resulted in the development of
methods to overcome these drawbacks. A cascade reaction
of 2-aminobenzamides with benzylic alcohols gave the de-
14
15
sired quinazolinones in good yields under catalysis by tran-
precious transition metals such as Ir,13 Ru, or Os have
been developed. However, the high cost and toxicity of pre-
cious transition metals cannot be ignored.
9
sition metals. In the presence of the I /DMSO catalytic sys-
2
tem, ketones as substrates coupled with 2-aminoben-
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2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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Y. Yao et al.
Letter
Table 1 Optimization of the Synthesis of 2-Phenylquinazolin-4(3H)-
one (3a)
best electrolyte, and gave 3a in 52% yield (entries 2 and 3).
Among various solvents examined, MeCN was found to be
optimal, providing an 80% yield (entries 2 and 4–7). When
the temperature was decreased to 80 °C, the yield of 3a re-
mained at 80%, whereas a lower yield was obtained at 70 °C
(entries 8 and 9). Increasing or decreasing the constant cur-
rent reduced the yield markedly, providing 3a in yields of
a
RVC
Pt
O
O
NH2
NH2
NH
Ph
+
Ph
Cl
solvent, temp.
electrolyte
N
1
a
2a
3a
54 and 45%, respectively (entries 10 and 11). When the re-
action of 1a and 2a was carried out under an argon atmo-
sphere, it proceeded smoothly to form quinazolinone 3a in
Entry Solvent
Constant current Temp
Yield
(%)
b
(
mA)
(°C)
7
6% yield (entry 12). Finally, the optimal conditions were
1c
2
H
H
H
O–1,4-dioxane (1:1)
O–1,4-dioxane (1:1)
O–1,4-dioxane (1:1)
10
10
10
10
10
10
10
10
10
7.5
15
10
90
90
90
90
90
90
90
80
70
80
80
80
36
52
44
33
0
2
2
2
identified as MeCN as solvent, containing Bu NBF as an
4
4
electrolyte, with RVC as the anode and Pt as the cathode, in
an undivided cell at a constant current of 10 mA, and at
80 °C.
With the optimal reaction conditions in hand, we inves-
tigated the scope of the 2-aminobenzoamides and halides
3d
4
2
MeCN–H O (1:1)
5
H
2
O
6
EtOH
0
(Scheme 1). The presence of various halogens on the ben-
7
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
80
80
45
45
54
76
zene ring of the benzylic chloride led to a slight drop in
yield, and quinazolones 3b–d were obtained in yields of
8
9
58–64%. Unfortunately, benzylic chlorides with highly elec-
10
tron-deficient substituents (CF or NO ) failed to give the
3
2
corresponding quinazolinones 3e and 3f. When benzylic
chlorides bearing electron-donating methoxy or methyl
groups on the benzene ring were used, products 3g–j were
obtained in yields of 71–75%. 2-(Chloromethyl)naphthalene
(2k) reacted smoothly, generating quinazolinone 3k in 73%
yield. 2-Aminobenzoamides bearing various substituents,
such as methoxy, methyl, or halo groups, gave the corre-
sponding products 3l–p in moderate yields of 59–68%. 2-
11
2e
1
a
Reaction conditions: RVC anode (100 PPI, 1 × 1 × 1.2 cm), Pt plate cathode
1 × 1 cm), undivided cell, constant current: 10 mA, 1a (0.5 mmol), 2a (0.6
mmol), Bu NBF (10 mol%), solvent (6 mL), 80 °C, 6 h.
Isolated yield.
(
4
4
b
c
No electrolyte.
d
e
4 4
10% Et NBF was used.
Under Ar (1 atm).
(
Methylamino)benzamide also gave the desired product 3q
in 72% yield.
To demonstrate the practicability and scalability of this
Organic electrosynthesis is an environmentally friendly
synthetic strategy due its use of electrons as redox re-
agents. The application of organic electrosynthesis in ac-
ceptor-free dehydrogenation recently attracted our atten-
protocol, we carried out an acceptor-free and metal-free
dehydrogenation of 2-aminobenzamide at an 8 mmol scale
under the standard condition, giving 3a in 70% yield
(Scheme 2).
To explore the reaction mechanism, control experi-
ments were performed. When the reaction of 1a and 2a
16
tion. In this respect, an anodic oxidation sequence of alco-
hols/aldehydes/benzyl ethers with ortho-
aminobenzamides has been applied in the preparation of
17
quinazolinones. Furthermore, in our previous work, we
reported an electrochemical metal-free synthesis of
quinazolinones by coupling of alkenes with 2-aminoben-
was conducted in MeCN with 10 mol% Bu NBF4 at 80 °C
4
without electrolysis, only trace amounts of 3a and 5a were
detected by GC/MS, and 4a was obtained in 50% yield, indi-
cating that 4a is a key intermediate (Scheme 3, eq. 1). Elec-
trolysis of 4a under the standard conditions gave 3a in 90%
yield (Scheme 3, eq. 2).
18
zamides. We therefore speculated the N-substituted 2-
aminobenzamides might undergo dehydrogenation/cy-
clization through electrocatalytic anodic oxidation. Here,
we report an electrochemical synthesis of quinazolinones
by coupling of 2-aminobenzamides and halides in one pot.
Initially, the reaction of 2-aminobenzamide (1a) and
The reaction was then examined by cyclic voltammetry
(CV) (Figure 2). An oxidation peak was observed for the re-
benzyl chloride (2a) in H O–1,4-dioxane (1:1) with reticu-
action of 1a at E = +1.155 V vs. SCE, in the region of 0.0–3.0 V
2
p
lated vitreous carbon (RVC) as the anode and Pt as the cath-
ode in an undivided cell at a constant current of 10 mA pro-
vided quinazolone 3a in 36% yield (Table 1, entry 1). De-
lighted with this result, we then optimized the reaction
conditions, and the results of our optimization study are
summarized in Table 1. The addition of an electrolyte led to
a significant increase in yield; Bu NBF was found to be the
vs. Ag/AgCl, while this peak was markedly weakened (Fig-
ure 2, curve b).1 The cyclic voltammogram for the reaction
7a
of 2a showed an oxidation peak at E = +2.567 V (Figure 2,
p
curve c). However, a mixture of 1a and 2a showed an oxida-
tion peak at E = +1.155 V with a slightly decrease in the
p
catalytic current (Figure 2, curve d). These results indicate
that 1a and 2a are not directly oxidized at the anode to par-
4
4
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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Y. Yao et al.
Letter
RVC
Pt
O
O
N
NH2
NH2
NH
R1
R2
Cl
R1
+
Bu4NBF4 (10 mol%)
MeCN, 80 °C
R2
1
3
2
O
N
O
N
O
O
O
O
NH
NH
NH
NH
NH
NH
N
NH
NH
NH
N
N
N
3f, 0%
O
3
a, 80%
3b, 60%
F
3c, 64%
Cl
3d, 58%
Br
3e, trace
CF3
NO2
O
O
O
O
O
MeO
NH
NH
NH
NH
N
N
N
N
N
N
3
g, 75%
OMe 3h, 74%
3i, 71%
3j, 74%
3k, 73%
3l, 68%
O
O
O
O
O
F
Cl
Br
NH
NH
NH
NMe
N
N
N
N
N
3m, 61%
3n, 63%
3o, 65%
3p, 59%
3q, 72%
Scheme 1 Synthesis of 2-substituted quinazolinones 3a–q. Reagents and conditions: RVC anode (100 PPI, 1 × 1 × 1.2 cm), Pt plate cathode (1 × 1 cm),
undivided cell, constant current: 10 mA, 1 (0.5 mmol), 2 (0.6 mmol), Bu NBF (10 mol%), MeCN (6 mL), 80 °C, 6 h. Isolated yield are reported.
4
4
ticipate in the reaction. To clarify the mechanism of the re-
Based on the above results, a plausible mechanism for
the formation of quinazolinones was proposed (Scheme 4).
The coupling of 1a and 2a generates an intermediate 4a
that loses an electron to the anode surface to generate the
cationic radical A. After release of a proton, intermediate A
is transformed into radical B. Further anodic oxidation of B
produces imine C, and subsequent intramolecular cycliza-
tion gives 5a. Finally, 3a is formed through anodic oxidation
of 5a. Protons are reduced to hydrogen at the cathode to
complete the cycle.
action, a CV study of the coupling product 4a was carried
out, and the result showed a slightly higher oxidation po-
tential than that of 1a (Figure 2, curve e), but with an addi-
tional marked increase in the catalytic current; this provid-
ed further confirmation that 4a is an intermediate in this
electrocatalytic cascade reaction.
RVC
Pt
In conclusion, an efficient electrocatalytic cascade reac-
tion of 2-aminobenzamides and benzylic chlorides has
been developed that provides quinazolin-4(3H)-ones in
O
O
NH2
NH2
NH
Cl
+
Bu4NBF4 (10 mol%)
MeCN, 80 °C
N
19
moderate to good yields. For this approach, a mechanism
1
a
2a
9.6 mmol, 1.21 g
3a
involving an acceptor-free dehydrogenation of amines to
imines promoted by electrocatalytic anodic oxidative has
been proposed.
8
mmol, 1.09 g
70%, 1.24 g
Scheme 2 Synthesis of 3a on a gram scale
O
O
O
O
NH2
NH2
NH
Cl
NH2
+
Bu NBF4 (10 mol%)
MeCN, 80 °C
NH
4
+
+
N
H
N
N
H
(1)
(2)
2
a
1a
3a, trace
4
a, 50%
5
a, trace
O
RVC
Pt
O
N
NH2
NH
N
H
Bu NBF4 (10 mol%)
4
MeCN, 80 °C
3a, 90%
4a
Scheme 3 Controlled reactions for exploring the reaction mechanism
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
Synlett
Y. Yao et al.
Letter
AD19110027), Guangxi Funds for Distinguished Experts and State Key
Laboratory for Chemistry and Molecular Engineering of Medicinal Re-
sources (CMEMR2019-A03), and Guangxi Science and Technology
Base and Talents Program (AD18281035, AD18281028) for financial
support.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707248.
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References and Notes
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Figure 2 Cyclic voltammograms of reactants and their mixtures in
.01 M Bu NBF /MeCN on a glassy carbon disk working electrode (di-
0
4
4
ameter: 3 mm) with a Pt disk and Ag/AgCl (MeCN) as the counter and
reference electrode, respectively, at a scan rate of 100 mV/s. (a) Back-
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zamide + benzyl chloride, (e) 2-(benzylamino)benzamide.
(
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(
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O
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NH2
Ph
NH
Ph
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Ph
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–
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5a
3a
–
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NH2
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H
B
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2
–
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2 e–
+
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(
NH2
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2013, 15, 378. (b) Mohammed, S.; Vishwakarma, R. A.; Bharate,
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H
NH2
4
a
2a
1a
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cathode
5223.
Scheme 4 Plausible mechanism
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Funding Information
We thank the National Natural Science Foundation of China
(
(
(
21861006), Ministry of Education of the People’s Republic of China
IRT_16R15), Natural Science Foundation of Guangxi Province
2016GXNSFEA380001,
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2019, 21, 5517. (b) Huang, C.; Huang, Y.; Liu, C.; Yu, Y.; Zhang, B.
2016GXNSFGA380005,
2018GXNSF-
Angew. Chem. Int. Ed. 2019, 58, 12014. (c) Xu, F.; Long, H.; Song,
J.; Xu, H.-C. Angew. Chem. Int. Ed. 2019, 58, 9017. (d) Huang, C.;
Qian, X.-Y.; Xu, H.-C. Angew. Chem. Int. Ed. 2019, 58, 6650.
BA281151), Guangxi Key R&D Program (No. AB18221005), Science
and Technology Major Project of Guangxi (AA17204058-21), Guangxi
Science and Technology Base and Special Talents (guike
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2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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Y. Yao et al.
Letter
(
e) He, M.-X.; Mo, Z.-Y.; Wang, Z.-Q.; Cheng, S.-Y.; Xie, R.-R.;
with a condenser, an RVC (100 PPI) anode, and a Pt plate (1 × 1
cm) cathode. The flask was opened to air and MeCN (6 mL) was
added. Electrolysis was carried out at 80 °C (oil-bath tempera-
ture) at a constant current of 10 mA until the substrate was
completely consumed (TLC). The mixture was then cooled to rt,
and the solvent was removed under reduced pressure. The
residue was purified by chromatography (silica gel, EtOAc–PE).
2-Phenylquinazolin-4(3H)-one (3a)
Tang, H.-T.; Pan, Y.-M. Org. Lett. 2020, 22, 724. (f) Meng, X.-J.;
Zhong, P.-F.; Wang, Y.-M.; Wang, H.-S.; Tang, H.-T.; Pan, Y.-M.
Adv. Synth. Catal. 2020, 362, 506. (g) Wang, Z.-Q.; Hou, C.;
Zhong, Y.-F.; Lu, Y.-X.; Mo, Z.-Y.; Pan, Y.-M.; Tang, H.-T. Org. Lett.
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1
White solid; yield: 88.8 mg (80%); mp 233–235 °C. H NMR (400
MHz, DMSO-d ):  = 12.52 (s, 1 H), 8.22–8.12 (m, 3 H), 7.84–
6
7.77 (m, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.53 (qt, J = 11.0, 5.2 Hz, 4
13
H). C NMR (101 MHz, DMSO):  = 162.80, 152.84, 149.28,
135.09, 133.26, 131.90, 129.12, 128.30, 128.03, 127.09, 126.39,
121.51.
3
61, 1761. (l) Mo, S.-K.; Teng, Q.-H.; Pan, Y.-M.; Tang, H.-T. Adv.
Synth. Catal. 2019, 361, 1756. (m) Pan, Y.-M.; Tang, H.-T.; Wang,
Z.-Q.; Li, Q.-Y.; Meng, X.-J. ZL 201810161249.9, 2019. (n) Feng,
E. Q.; Hou, Z. W.; Xu, H. C. Youji Huaxue 2019, 39, 1424. (o) Cao,
Z. C.; Liu, J. C.; Chu, Y. Q.; Zhao, F. M.; Zhu, Y. H.; She, Y. B. Youji
Huaxue 2019, 39, 2499. (p) Wu, Y. X.; Xi, Y. C.; Zhao, M.; Wang,
S. Y. Youji Huaxue 2018, 38, 2590. (q) Zhang, H. Y.; Tang, R. P.;
Shi, X. L.; Xie, L.; Wu, J. W. Youji Huaxue 2019, 39, 1837.
2-(4-Fluorophenyl)quinazolin-4(3H)-one (3b)
White solid; yield: 72.0 mg (60%); mp 240–242 °C. H NMR (400
1
MHz, DMSO-d ):  = 12.57 (s, 1 H), 8.25 (dd, J = 8.8, 5.6 Hz, 2 H),
6
8.15 (d, J = 6.4 Hz, 1 H), 7.84 (t, J = 6.8 Hz, 1 H), 7.73 (d, J = 8.1 Hz,
13
1 H), 7.55–7.50 (m, 1 H), 7.39 (t, J = 8.8 Hz, 2 H). C NMR (100
MHz, DMSO):  = 162.69, 151.86, 149.11, 135.15, 130.85 (d, J =
9.3 Hz), 130.10, 129.66 (d, J = 3.2 Hz), 127.92, 127.11, 126.32,
121.32, 116.11 (d, J = 22.0 Hz).
(
17) (a) Lin, D.-Z.; Lai, Y.-L.; Huang, J.-M. ChemElectroChem 2018, 16,
4
118. (b) Cao, L.; Huo, H.; Zeng, H.; Yu, Y.; Lu, D.; Gong, Y. Adv.
Synth. Catal. 2018, 360, 4764.
18) Teng, Q.-H.; Sun, Y.; Yao, Y.; Tang, H.-T.; Li, J.-R.; Pan, Y.-M.
ChemElectroChem 2019, 6, 3120.
2-(4-Chlorophenyl)quinazolin-4(3H)-one (3c)
(
White solid; yield: 81.9 mg (64%); mp 295.5–298 °C. 1H NMR
(400 MHz, DMSO-d ):  = 12.61 (s, 1 H), 8.21 (d, J = 8.7 Hz, 2 H),
6
(
19) Quinazolinones 3a–q; General Procedure
A mixture of the appropriate 2-aminobenzamide 1 (0.5 mmol),
benzylic chloride 2 (0.6 mmol), and Bu NBF (10 mol%) was
8.16 (d, J = 7.9 Hz, 1 H), 7.85 (t, J = 6.9 Hz, 1 H), 7.75 (d, J = 8.0 Hz,
1 H), 7.64 (d, J = 8.6 Hz, 2 H), 7.54 (t, J = 7.5 Hz, 1 H). 13C NMR
(100 MHz, DMSO):  = 163.04, 152.10, 149.31, 137.04, 135.45,
132.29, 130.37, 129.44, 128.27, 127.55, 126.62, 121.72.
4
4
placed in a 25 mL three-necked round-bottomed flask equipped
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2020. Thieme. All rights reserved. Synlett 2020, 31, A–E