Copper-Catalyzed Tandem Reaction of 2-Aminobenzamides with Tertiary Amines for the Synthesis of Quinazolinone Derivatives

Article abstract of DOI:10.1055/s-0036-1588881

We developed a copper-catalyzed tandem reaction of 2-aminobenzamides with tertiary amines for the formation of quinazolinone derivatives. The strategy includes two steps (cyclization and coupling) performed in one pot. A number of substrates reacted well under standard conditions to give the corresponding quinazolinone derivatives in moderate to good yields.

Full text of DOI:10.1055/s-0036-1588881

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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
letter
A
W. Xu et al.
Letter
Synlett
Copper-Catalyzed Tandem Reaction of 2-Aminobenzamides with
Tertiary Amines for the Synthesis of Quinazolinone Derivatives
Wei Xu
O
O
1) Cu2O/PCy3
CHCl3, 100 °C
Xiao-Rui Zhu
R1
R3
NHAr
NAr
R3
Peng-Cheng Qian
Xing-Guo Zhang
Chen-Liang Deng*
+
N
R2
NH2
2) DDQ, r.t., 1 h
N
R1, R2, R3 = H, alkyl
21 examples
up to 91% yield
College of Chemistry and Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. of
China
dcl78@wzu.edu.cn
Received: 05.07.2016
Accepted after revision: 21.08.2016
Published online: 09.09.2016
A variety of convenient methods for the preparation of
the quinazolinone skeleton from a range of starting materi-
als have been fully explored. These include the Niemen-
towski reaction (fusion of anthranilic acids with amides),7
the oxidative cyclization of anthranilamides with primary
alcohols,8 the iodine-catalyzed oxidation of 2-aminoben-
zamides with benzyl alcohols,9 the condensation of imidate
esters with anthranilic acid,10 the di-tert-butyl peroxide
catalyzed oxidation of 2-aminobenzamides with toluene
analogues,11 and the microwave-assisted dehydrative cy-
clization of diamides.12 In the past decades, the transition-
metal-catalyzed C–N bond-forming reaction has emerged
as a powerful strategy for synthesizing quinazolinones ow-
ing to its step- and atom-economies. Processes for the syn-
thesis of quinazolinones involving catalysis by Pd,13 Ru,14
Cu,15 Ir,16 or Ag17 are widely reported in the literature. De-
spite their many advantages, these methods suffer from one
or more limitations, including complicated starting materi-
als, acid- or base-sensitive substrates, excessive oxidants, or
harsh reaction conditions. Therefore, the development of
efficient and readily performed methods that do not in-
volve the assistance of acids or bases is still highly desir-
able. Here, we report an ambient and efficient copper-cata-
lyzed tandem reaction of 2-aminobenzamides with tertiary
amines for the synthesis of quinazolinone derivatives under
aerobic conditions (Scheme 1).
DOI: 10.1055/s-0036-1588881; Art ID: st-2016-w0432-l
Abstract We developed a copper-catalyzed tandem reaction of 2-am-
inobenzamides with tertiary amines for the formation of quinazolinone
derivatives. The strategy includes two steps (cyclization and coupling)
performed in one pot. A number of substrates reacted well under stan-
dard conditions to give the corresponding quinazolinone derivatives in
moderate to good yields.
Key words copper catalysis, tandem reactions, aminobenzamides,
tertiary amines, quinazolinones
Quinazolinones are an important class of heterocyclic
compounds1 that are present in many natural products;
they are also widely used as pharmaceuticals due to their
remarkable biological and therapeutic activities, such as
anticancer,2 antitubercular,3 antiallergy,4 hypotensive,5 and
protein tyrosine kinase inhibitory activities6 (Figure 1).
O
Cl
O
N
OH
N
OH
N
Cl
N
Et
cloroqualone
O
diproqalone
O
H2N
Ph
O
N
O
N
1) [Cu]/ligand
R1
R3
CHCl3, 100 °C
NHAr
N
NAr
R3
N
+
N
R2
F
NH2
2) DDQ, rt.,. 1 h
N
afloqualone
(E)-bogorin
R1, R2, R3 = H, alkyl
Figure 1 Structures of several pharmaceutically relevant quinazoli-
nones
Scheme 1 Copper-catalyzed tandem reaction for the synthesis of
quinazolinones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 48, A–G

B
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Letter
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We chose the reaction of 2-amino-N-phenylbenzamide
(1a) with triethylamine (2a) as a model reaction to opti-
mize the reaction conditions, and our results are summa-
rized in Table 1. Initially, we treated amide 1a (0.2 mmol)
with amine 2a (0.6 mmol) in the presence of Cu(OAc)2·H2O
(10 mol%) in CHCl3 at 100 °C for 24 hours under air, fol-
lowed by oxidation with DDQ under air for one hour. We
were delighted when we obtained a 61% yield of 2-methyl-
3-phenylquinazolin-4(3H)-one (3) (Table 1, entry 1). This
result encouraged us to pursue the search for optimal con-
ditions. Subsequently, a number of cupric and cuprous salts
{CuO, Cu(OTf)2, CuBr, CuI, [Cu(OTf)]2·PhH, and Cu2O} were
examined. All of these copper catalysts were active in the
transformation, but Cu2O was the most efficient (entries 2–
7). We also tested a series of solvents (CHCl3, DMF, DMSO,
MeCN, DCE and toluene) and we found that CHCl3 gave the
best results (entries 7–12). Interestingly, the yield of prod-
uct 3 increased when 10 mol% PPh3 was added to the reac-
tion mixture (entry 13). Consequently, we examined the ef-
fects of several ligands: PCy3, dicyclohexyl(2′,4′,6′-triisopro-
pylbiphenyl-2-yl)phosphine (X-Phos), dicyclohexyl(2′,6′-
dimethoxybiphenyl-2-yl)phosphine (S-Phos), t-Bu3P·HBF4,
N,N′-dimethylethane-1,2-diamine (DMEDA), and 1,10-
phenanthroline (1,10-Phen) (entries 13–19). This screening
revealed that PCy3 was more efficient than the other li-
gands. Finally, the scale of the reaction was increased to 1
mmol with satisfactory results (entry 20).
With this optimized procedure in hand, we explored the
scope of the reaction by screening a range of amides 1 and
tertiary amines 2 (Table 2). Generally, the reaction of alkyl
tertiary amines 2b–e proceeded quickly to provide the cor-
responding products in moderate to good yields (Table 2,
entries 1–4). The bulky substrate 2f was suitable for the
transformation and gave product 3 in 71% yield (entry 5).
Similar results were achieved when the tertiary amine 2g
was used as a substrate (entry 6). Unfortunately, the reac-
tion of amide 1a with tertiary amine 2h under the opti-
mized conditions was sluggish, giving product 3 only in 17%
yield (entry 7). Substrates 1b–d bearing electron-donating
groups on the aromatic ring also performed well, giving the
corresponding products 8–10 in 60–80% yields (entries 8–
10). Halogenated substrates 1e–j gave the corresponding
products 11–16 in yields ranging from 53% to 82% (entries
11–16). The N-alkyl compounds 1k and 1l reacted with 2a
to give products 17 and 18 in 32 and 48% yield, respectively
(entries 17 and 18). Gratifyingly, 2-(aminomethyl)aniline
(1m) successfully reacted with tertiary amine 2a to give 2-
methylquinazoline (19), albeit in a lower yield (entry 19).
The N-methyl tertiary amines 2i–p were also evaluated,
and all were found to be good substrates for conversion into
the target products in moderate yields. For example, tertia-
ry amines 2i–k reacted smoothly with 1a to give 3-
Table 1 Screening of the Reaction Conditionsa
O
O
1) [Cu]/oxidant
solvent, 100 °C
NHPh
Et
Et
NPh
+
N
NH2
2) DDQ, r.t., 1 h
N
1a
2a
3
Entry
[Cu]
Ligand
Solvent
Yieldb (%)
1
2
Cu(OAc)2·H2O
CuO
–
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DMF
61
58
63
47
62
65
68
27
28
trace
48
11
77
89
81
85
78
66
66
91
–
3
Cu(OTf)2
CuBr
–
4
–
5
CuI
–
6
[Cu(OTf)]2·PhH
Cu2O
–
7
–
8
Cu2O
–
9
Cu2O
–
DMSO
MeCN
DCE
10
11
12
13
14
15
16
17
18
19
20c
Cu2O
–
Cu2O
–
Cu2O
–
toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Cu2O
PPh3
Cu2O
PCy3
Cu2O
X-Phos
S-Phos
t-Bu3P·HBF4
DMEDA
1,10-Phen
PCy3
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
a Reaction conditions: (1) 1a (0.2 mmol), 2a (0.6 mmol), [Cu] (10 mol%),
ligand (10 mol%), solvent (2 mL), 100 °C, 24 h, under air; (2) DDQ (1 equiv),
r.t., 1 h, under air.
b Isolated yield.
c 1a (1 mmol), 2a (3 mmol).
phenylquinazolin-4(3H)-one (20) in 30–40% yield (entries
20–22). To our delight, 1,3,5,7-tetraazaadamantane (2l), a
commercially available tertiary amine, also served as an ef-
ficient substrate, giving product 20 in 53% yield (entry 23).
A similar result was obtained when trimethylamine (2m)
was used (entry 24). TMEDA (2n) also turned out to be
good substrate for the transformation, giving the target
products 20 and 21 in moderate yield (entries 25 and 26). A
28% yield of 20 was isolated when 1a reacted with diamine
2o under the standard conditions (entry 27). Interestingly,
treatment of 1a with Et2NMe (2p) under the optimized con-
ditions afforded product 3 in 23% yield, together with prod-
uct 20 in 50% yield (entry 21).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 48, A–G

C
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Letter
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Table 2 Cu2O-Catalyzed Tandem Reaction of 1 with 2a
O
O
R1
R3
standard conditions
NHAr
NAr
R3
+
N
R2
NH2
N
1
2
3–15
Entry
1
Benzamide 1
Amine 2
Product
Yieldb (%)
O
Ph
Et
N
N
N
N
1a
2b
Pr3N
81
N
O
4
5
6
Ph
Pr
2
3
4
1a
1a
1a
2c
2d
2e
Bu3N
80
78
77
N
O
Ph
Bu
[Me(CH2)4]3N
[Me(CH2)5]3N
N
O
Ph
N
Pen
7
3
3
5
6
1a
1a
2f
DIPEA
71
65
2g
Et2N(CH2)2OH
7
1a
2h
2a
3
17
N
Et
OMe
OMe
O
O
8
1b
68
N
N
N
N
H
N
O
NH2
8
O
9
1c
2a
2a
60
80
N
H
N
O
NH2
9
O
10
1d
N
H
N
NH2
10
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 48, A–G

D
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Letter
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Table 2 (continued)
Entry
11
Benzamide 1
Amine 2
Product
Yieldb (%)
Cl
Cl
O
O
1e
2a
82
N
N
N
N
H
N
O
NH2
11
12
13
O
12
13
14
1f
2a
2a
2a
75
66
69
N
H
Cl
Cl
N
O
NH2
O
Cl
F
1g
1h
N
H
Cl
F
N
O
NH2
O
N
N
H
N
O
NH2
14
Br
Br
O
15
1i
2a
53
N
N
H
N
NH2
15
O
N
O
Cl
Ph
Cl
Ph
N
16
17
1j
2a
2a
72
32
N
H
NH2
16
17
O
O
Bu
Bu
Bn
N
1k
N
H
N
O
NH2
O
Bn
N
N
18
19
20
1l
N
2a
2a
2i
48
12
31
H
N
NH2
18
19
NH2
NH2
1m
1a
N
O
Ph
N
N
N
20
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 48, A–G

E
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Letter
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Table 2 (continued)
Entry
Benzamide 1
Amine 2
Product
Yieldb (%)
30
21
1a
2j
20
N
O
N
22
23
1a
1a
2k
2l
20
20
40
53
N
N
N
N
24
25
1a
1a
2m
2n
Me3N
20
20
50
58
Me2N(CH2)2NMe2
O
N
O
NH
26
1g
2n
38
NH2
NH2
21
27
28
1a
1a
2o
2p
Me2N(CH2)2NH2
Me2NEt
20
28
3 + 20
23 + 50
a Reaction conditions: (1) 1 (0.2 mmol), 2 (0.6 mmol), Cu2O (10 mol%), PCy3 (10 mol%), CHCl3 (2 mL), 100 °C, 24 h, under air; (2) DDQ (1 equiv), r.t., 1 h, under
air.
b Isolated yield.
To probe the mechanism of this reaction, we performed
a number of control experiments. First, we carried out the
reaction of 1a with trioctylamine (2q) under the standard
conditions to generate the target molecule 22 in 76% yield,
together with dioctylamine as a byproduct (Scheme 2, eq
1). The corresponding reaction of substrate 1a with butanal
(3aa) gave product 5 in 80% yield (Scheme 2, eq 2).
On the basis of these results and our other experimental
results,18 we propose the mechanism outlined in Scheme 3.
Initially, the tertiary amine undergoes decomposition cata-
lyzed by the copper compound and ligand to provide an al-
dehyde and a secondary amine byproduct.18d–f Subsequent-
ly, condensation of the aldehyde with amide A gives imine
B,18b,c,g which undergoes intramolecular addition to furnish
intermediate C. Finally, oxidation of C generates the target
molecule.
In summary, we have developed a copper-catalyzed tan-
dem reaction of 2-aminobenzamides with tertiary amines
for the construction of quinazolinone derivatives.19 Under
the optimized conditions, the reaction tolerates various
substrates, regardless of any electronic effects, to afford the
O
O
standard conditions
NHPh
NPh
(n-C8H17)2NH
(1)
+
(n-C8H17)3N
NH2
1a
N
n-C7H15
2q
22, 76%
O
O
NHPh
NPh
Pr
1) CHCl3, 100 °C, air, 12 h
2) DDQ, air, r.t., 1 h
PrCHO
(2)
+
NH2
N
1a
3aa
5, 80%
Scheme 2 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 48, A–G

F
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R1
R3
R1
NH
R2
Cu2O/ligand
N
R2
O
H2O
R3
H
O
N
O
N
O
O
oxidation
NAr
R3
addition
NHAr
R3
NHAr
NAr
R3
condensation
NH2
N
H
B
A
C
Scheme 3 Proposed mechanism
desired products in moderate to good yields. Further stud-
ies focusing on expanding the scope of the reaction are cur-
rently underway in our laboratory.
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Acknowledgment
We thank the National Natural Science Foundation of China (Nos.
21102104, 21272177), the Natural Science Foundation of Zhejiang
Province (Nos. LY14B020011, LY15B020002), the Foundation of Zheji-
ang Province Department of Education (No. Y201327597), and Wen-
zhou University for their financial support.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588881.
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(19) 2-Methyl-3-phenylquinazolin-4(3H)-one (3); Typical Proce-
dure
column chromatography [silica gel, hexane–EtOAc (3:1)] to give
a light-yellow solid; yield: 42.0 mg (89%); mp 147–148 °C. 1H
NMR (500 MHz, CDCl3): δ = 8.27 (dd, J = 8.0, 1.0 Hz, 1 H), 7.79–
7.76 (m, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.58–7.55 (m, 2 H), 7.53–
7.51 (m, 1 H), 7.49–7.46 (m, 1 H), 7.28–7.26 (m, 2 H), 2.26 (s, 3
H). 13C NMR (125 MHz, CDCl3): δ = 162.2, 154.3, 147.4, 137.7,
134.6, 130.0, 129.3, 128.0, 127.1, 126.7, 126.7, 120.8, 24.3. LRMS
(EI, 70 eV): m/z (%) = 236 (100), 235 (80), 221 (58), 143 (16), 77
(50).
A reaction tube was charged under air with 2-aminobenzani-
lide (1a, 0.2 mmol), Et3N (2a, 0.6 mmol), Cu2O (10 mol%), PCy3
(10 mol%), and CHCl3 (2 mL). The vessel was sealed, heated at
100 °C (oil-bath temperature) for 24 h, and then cooled to r.t.
DDQ (1 equiv) was added, and the mixture was kept at r.t. for 1
h. After filtration of the mixture and evaporation of the solvent
under reduced pressure, the crude product was purified by
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 48, A–G