Synthesis of 2-aminoquinoline-3-carboamides and pyrimido[4,5-b]quinolin-4-ones through copper-catalyzed one-pot multicomponent reactions

Article abstract of DOI:10.1002/asia.201402962

Pyrimido[4,5-b]quinolinones have attracted considerable interest from both chemical and medicinal scientists as these compounds display remarkable antimicrobial, anti-inflammatory, antitumor, antiallergy, analgesic, and antioxidant activities. The importance of pyrimido[4,5-b]quinolinones has stimulated enormous efforts to develop efficient methodologies for their synthesis. Herein, we disclose a novel synthetic protocol toward pyrimido[4,5-b]quinolin-4-ones through Cu(OAc)₂-catalyzed one-pot four-component reactions of 2-bromobenzaldehydes, aqueous ammonia, cyanoacetamides and aldehydes. The synthetic procedure combines amination/condensation/cyclization/dehydrogenation reactions in one pot, allowing synthesis of complex compounds in a simple and practical manner. Compared with literature procedures, the synthetic strategies developed herein showed advantages such as readily available and economically sustainable starting materials, structural diversity of products, good functional group tolerance, and a remarkably simple operation process.

Full text of DOI:10.1002/asia.201402962

DOI: 10.1002/asia.201402962
Communication
Multicomponent Reactions
Synthesis of 2-Aminoquinoline-3-carboamides and Pyrimido[4,5-
b]quinolin-4-ones through Copper-Catalyzed One-pot
Multicomponent Reactions
Xin-Ying Zhang,* Xiao-Jie Guo, and Xue-Sen Fan*[a]
be prepared by reduction of o-nitrobenzaldehydes. As a result,
Abstract: Pyrimido[4,5-b]quinolinones have attracted con-
siderable interest from both chemical and medicinal scien-
up to three separate operations are involved in the prepara-
tion of pyrimido[4,5-b]quinolinones starting from cheap com-
tists as these compounds display remarkable antimicrobi-
mercial reagents (Scheme 1).
al, anti-inflammatory, antitumor, antiallergy, analgesic, and
antioxidant activities. The importance of pyrimido[4,5-
b]quinolinones has stimulated enormous efforts to devel-
op efficient methodologies for their synthesis. Herein, we
disclose a novel synthetic protocol toward pyrimido[4,5-
b]quinolin-4-ones through Cu(OAc)2-catalyzed one-pot
four-component reactions of 2-bromobenzaldehydes,
aqueous ammonia, cyanoacetamides and aldehydes. The
synthetic procedure combines amination/condensation/
Scheme 1. Currently used multistep preparation of pyrimido[4,5-b]quinolin-
4-ones.
cyclization/dehydrogenation reactions in one pot, allow-
ing synthesis of complex compounds in a simple and
practical manner. Compared with literature procedures,
the synthetic strategies developed herein showed advan-
Compared with step-by-step transformations, one-pot multi-
tages such as readily available and economically sustaina-
component reactions (MCRs) usually enable the construction
ble starting materials, structural diversity of products,
of complex molecules from simple and readily available start-
good functional group tolerance, and a remarkably simple
ing materials and offer higher atom economy and better over-
operation process.
all yields owing to the avoidance of separation and purification
of the intermediates. As a result, MCRs have been used exten-
sively in the construction of different chemical libraries.[9,10] In
Pyrimido[4,5-b]quinolinones are an important class of substan-
particular, copper-catalyzed MCRs with CÀN bond formation as
ces with potent antimicrobial,[1] anti-inflammatory,[1,2] antitu-
a key step are emerging as a highly efficient approach toward
mor,[3] antiallergy,[4] and analgesic activities.[1] So far, the
pyrimido[4,5-b] quinolinone scaffold is usually constructed
through condensation of 2-aminoquinoline-3-carboamides
with carbonyl or carboxylate compounds.[1,3–8] While this syn-
thetic strategy is reliable, the required 2-aminoquinoline-3-car-
boamides are commercially not available and are usually ob-
tained via condensing cyanoacetamides with o-aminobenzal-
dehydes. Furthermore, o-aminobenzaldehydes are still of limit-
ed commercial availability or quite expensive and thus have to
N-heterocyclic compounds.[11,12] In this regard, we have recently
developed a one-pot four-component cascade reaction leading
to pyrazolo[1,5-c]quinazolines and a one-pot three-component
reaction affording quinolizines with copper-catalyzed amina-
tion of aryl halides as an initiating step by using aqueous am-
monia as a cheap and convenient nitrogen source.[13] Encour-
aged by the above results, we proposed an alternative synthe-
sis of pyrimido[4,5-b]quinolin-4-ones through copper-catalyzed
one-pot four-component cascade reaction of the commercially
available o-bromobenzaldehyde (1), aqueous ammonia (2), cya-
noacetamide (3), and aldehyde (4) as shown in Scheme 2.
Initially, 2-bromobenzaldehyde (1a) was treated with aque-
ous ammonia (2), cyanoacetamide (3a), and benzaldehyde
(4a) under the catalysis of CuI (0.1 equiv) in DMF. Unfortunate-
ly, this four-component reaction afforded a complicated mix-
ture, and the expected 2-phenylpyrimido[4,5-b]quinolin-4(3H)-
one (5a) was not obtained. Further attempts with regard to
different catalysts and solvents did not give satisfying results
as well. Considering that 2-aminoquinoline-3-carboamide (6a)
serves as a key intermediate in the formation of 5a, we went
[a] Prof. X.-Y. Zhang, X.-J. Guo, Prof. X.-S. Fan
School of Chemistry and Chemical Engineering
Collaborative Innovation Center of Henan Province for Green Manufactur-
ing of Fine Chemicals
Henan Key Laboratory for Environmental Pollution Control
Henan Normal University
46 Jianshe Road, Xinxiang, Henan 453007 (P. R. China)
Fax: (+86)373-332-6336
E-mail: xinyingzhang@htu.cn
xuesen.fan@htu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201402962.
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lene
diamine
(DMEDA),
N,N,N’,N’-tetramethylethylene
diamine (TMEDA), or 2,2-dime-
thylpropanoic acid (PivOH) did
not improve the yield of 6a
(Table 1, entries 10–15). On the
other hand, addition of K2CO3
or Cs2CO3 could increase the
Scheme 2. Proposed one-pot four-component reaction leading to pyrimido[4,5-b]quinolin-4-ones.
one step back to check whether 6a could be obtained from
the reaction of 1a with 2 and 3a. Thus, 1a was treated with 2
and 3a in the presence of CuI (0.1 equiv) in DMF for 6 h. To
our delight, it afforded 6a in a yield of 41% (Table 1, entry 1).
Encouraged by this preliminary result, thorough optimization
yield of 6a (entries 17, 18) while Na2CO3 or K3PO4·3H2O showed
no obvious effect (entries 16, 19). Upon further screening, to
our pleasure, we found that raising the reaction temperature
from 808C to 1008C could increase the yield of 6a from 55%
to 60% (Table 1, entries 17, 20). A temperature higher than
1008C showed an adverse effect (entry 21). Furthermore, it was
observed that raising the amount of Cu(OAc)2 from 0.1 equiv
to 0.2 equiv did not improve the reaction obviously (Table 1,
entry 22). On the other hand, no formation of 6a was observed
without a copper catalyst (Table 1, entry 23). In summary, treat-
ing 1a, 2, and 3a with 0.1 equiv of Cu(OAc)2 and 1 equiv of
K2CO3 in DMSO at 1008C for 6 h afforded 6a in a yield of 60%.
With the optimized reaction conditions in hand, the scope
and generality of this cascade reaction leading to 2-aminoqui-
noline-3-carboamides (6) were explored. Firstly, several 2-bro-
mobenzaldehydes (1) bearing different substituents were stud-
ied as possible substrates to react with 2 and 3a. The results
listed in Table 2 showed that they underwent this cascade re-
action successfully and produced the desired 2-aminoquino-
line-3-carboamides in yields ranging from 48% to 60%
(Table 2, entries 1–8). Various functional groups, such as fluoro,
chloro, trifluoromethyl, methyl, and methoxyl were well tolerat-
ed under the reaction conditions. Then, some N-substituted cy-
anoacetamides (3) were also tested. We were pleased to find
that propyl-, benzyl-, phenethyl-, and cyclopropyl-substituted
cyanoacetamides reacted with different 2-bromobenzalde-
hydes and aqueous ammonia smoothly to give N-substituted
2-aminoquinoline-3-carboamides in moderate yields (Table 2,
entries 9–16).
Table 1. Optimization for the formation of 2-aminoquinoline-3-carboa-
mide (6a).[a]
Entry Cu source Solvent Ligand
Base
T [8C] Yield [%][b]
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuBr
CuCl
CuCl2
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DMF
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
41
37
33
45
44
36
41
42
48
41
46
45
49
48
43
40
55
52
44
60
57
62
–
dioxane
iPrOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
9
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
DMAP
l-Proline
1,10-phen
DMEDA
TMEDA
PivOH
–
–
–
–
–
–
–
–
Na2CO3
K2CO3
Cs2CO3
K3PO4·3H2O 80
Having confirmed that 2-aminoquinoline-3-carboamides (6)
could be smoothly formed via the reaction of 1, 2, and 3, we
proceeded to try our proposed synthesis of pyrimido[4,5-b]qui-
nolinone as shown in Scheme 2 again, yet following an alterna-
tive operational method. Thus, instead of treating the mixture
of 1a, 2, 3a, and 4a with copper catalyst, 1a, 2, and 3a were
firstly treated with Cu(OAc)2 and K2CO3 in DMSO at 1008C for
6 h, and then benzaldehye (4a) was added. The resulting mix-
ture was stirred at 1008C under air for 2 h. Subsequent workup
of the reaction gave the desired pyrimido[4,5-b]quinolin-4(3H)-
one (5a) in a yield of 46% (Scheme 3).
Encouraged by this promising result, the generality for the
synthesis of 5 was studied with different 2-bromoaldehydes
(1), cyanoacetamides (3), and aldehydes (4). The results listed
in Table 3 showed some notable features: 1) 2-bromobenzalde-
hydes of various substitution patterns took part in this cascade
process smoothly and produced a series of pyrimido[4,5-b]qui-
nolin-4(3H)-ones (5) in reasonably good yields; 2) in addition
to cyano-acetamide (3a), its N-substituted analogues were also
suitable for this reaction; 3) aryl aldehydes (4) with either elec-
Cu(OAc)2 DMSO
K2CO3
K2CO3
K2CO3
K2CO3
100
Cu(OAc)2
Cu(OAc)2
–
DMSO
DMSO
DMSO
110
100
100
[c]
[a] The reactions were run with 0.5 mmol of 1a, 0.5 mmol of 3a,
0.1 mmol of additive, 0.05 mmol of catalyst, 0.5 mmol of base, and 1 mL
of 26% aqueous ammonia (2) in 2 mL of solvent in a sealed tube for 6 h.
[b] Isolated yield. [c] 0.1 mmol of Cu(OAc)2.
of the reaction conditions was then carried out. Firstly, 1,4-di-
oxane, iPrOH, or DMSO was tried as the reaction medium
(Table 1, entries 2–4). Among them, DMSO gave a better yield
of 6a while iPrOH and 1,4-dioxane were less effective com-
pared with DMF. Experiments with different copper salts
showed that Cu(OAc)2 was more effective than CuI, CuBr, CuCl,
CuCl2, or Cu(OTf)2 for this reaction (Table 1, entries 4–9). In the
next stage, the effect of several additives was also studied by
using Cu(OAc)2 as catalyst and DMSO as solvent. It was found
that addition of 4-dimethylaminopyridine (DMAP), l-proline,
1,10-phenanthroline hydrate (1,10-phen), N,N’-dimethylethy-
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tron-donating or electron-with-
drawing group reacted smooth-
ly with the in situ-formed 2-ami-
noquinoline-3-carboamides to
give 5; 4) no obvious steric
effect was observed with ortho-
substituted aryl aldehydes; and
5) in addition to aryl aldehydes,
butyraldehyde was also com-
patible to give 5n in 44% yield.
To elucidate the reaction
mechanism, some control ex-
periments were carried out
(Scheme 4). Firstly, 6a was treat-
ed with 4a in DMSO at 1008C
for 6 h in the absence of
Cu(OAc)2 and K2CO3. From this
reaction, 2-phenyl-2,3-dihydro-
pyrimido-[4,5-b]quinolin-4(1H)-
one (7) was obtained in a yield
of 36% along with trace
amount of 5a. In the presence
of 0.1 equiv of Cu(OAc)2, on the
other hand, 5a and 7 were
formed in 30% and 21% yield,
respectively. With 1 equiv of
K2CO3, the starting materials
were consumed in 2 h, and 7
was obtained in a yield of 80%.
Notably, in the presence of
0.1 equiv of Cu(OAc)2 and
1 equiv of K2CO3, 5a was
formed in a yield of 85%. When
the reaction was carried out
under nitrogen instead of air at-
mosphere, it mainly afforded 7.
These observations (Scheme 4)
together with the results listed
in Table 1 suggested that:
1) Cu(OAc)2 was not only indis-
pensable for the CÀN coupling
between 1 and 2 but also cru-
cial for the oxidative aromatiza-
tion of the in situ-formed 7 to
afford 5a; 2) K2CO3 acted as an
effective promoter in both the
formation of 6a and the cycliza-
tion of the in situ-formed 6a
with 4a to give 7; 3) air was the
stoichiometric oxidant for the
Table 2. Synthesis of 2-aminoquinoline-3-carboamides (6).[a]
Entry
1
1
3
Product (6)
Yield [%][b]
6a
6b
6c
6d
6e
6 f
60
2
3
4
5
6
7
8
57
53
54
50
56
52
48
6g
6h
9
6i
6j
61
60
10
11
12
6k
6l
48
43
oxidative aromatization of
7
toward 5a.
13
6m
41
Based on the above facts,
a plausible pathway for the for-
mation of 5a, 6a, and 7 is pro-
posed in Scheme 5. Firstly,
copper-catalyzed amination of
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2-bromoaldehyde (1a) with am-
monia (2) affords 2-aminoben-
zaldehyde (I). Base-promoted
condensation of I with cyanoa-
cetamide (3a) leads to 3-(2-ami-
nophenyl)-2-cyanoacrylamide
(II). Subsequent intramolecular
cyclization of II gives 2-amino-
quinoline-3-carboamide (6a). In
the next stage, base-promoted
condensation of 6a with ben-
zaldehyde (4a) affords 7. Cata-
lyzed by Cu(OAc)2 and promot-
ed by air, 7 then undergoes an
oxidative dehydrogenation to
afford 5a.
Table 2. (Continued)
Entry
1
3
Product (6)
Yield [%][b]
14
6n
6o
56
15
16
50
51
6p
[a] The reactions were run with 0.5 mmol of 1, 0.5 mmol of 3, 0.05 mmol of Cu(OAc)2, 0.5 mmol of K2CO3, and
1 mL of 26% aqueous ammonia (2) in 2 mL of DMSO in a sealed tube at 1008C for 6 h. [b] Isolated yield.
In summary, we have devel-
oped a convenient and eco-
nomical synthesis of 2-amino-
quinoline-3-carboamides
and
pyrimido[4,5-b]quinolin-4(3H)-ones via copper-catalyzed, base-
promoted one-pot multicomponent cascade reactions using
cheap commercial starting materials. It is particularly notewor-
thy that the synthetic procedure toward pyrimido[4,5-b]quino-
lin-4(3H)-ones combines amination/condensation/cyclization/
dehydrogenation reactions in one pot, allowing synthesis of
complex compounds in a simple and practical manner. Prelimi-
nary studies with regard to the
Scheme 3. Formation of 5a from a sequential one-pot reaction of 1a, 2, 3a,
and 4a.
reaction mechanism revealed
that the successful combination
of these single transformations
in one pot is largely due to the
multi functions of the copper
catalyst as well as the dual role
of the base promoter. Compared
with literature procedures for
the synthesis of the title com-
pounds, the synthetic strategies
developed herein showed ad-
vantages such as readily avail-
Scheme 4. Reactions of 6a with 4a under different reaction conditions.
able and economically sustaina-
ble starting materials, structural
diversity of products, good func-
tional group tolerance, and a remarkably simple operation pro-
cess.
Experimental Section
General procedure for the preparation of 2-aminoquinoline-3-
carboamides (6)
To
a tube containing a solution of 2-bromobenzaldehyde
1 (0.5 mmol) and cyanoacetamide 3 (0.5 mmol) in DMSO (2 mL)
were added Cu(OAc)2 (0.05 mmol), K2CO3 (0.5 mmol), and aqueous
ammonia (26%, 1 mL). Then, the tube was sealed, and the mixture
was stirred at 1008C for 6 h. After being cooled to room tempera-
ture, the reaction mixture was added to saturated brine (10 mL)
and extracted with ethyl acetate (10 mLꢁ3). The combined organic
Scheme 5. Plausible mechanism for the formation of 5a, 6a, and 7.
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Communication
evaporated under vacuum, and the crude prod-
uct was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate=1:1) to
afford pyrimido[4,5-b]quinolin-4-one derivative 5.
Table 3. Synthesis of pyrimido[4,5-b]quinolin-4(3H)-one (5).[a,b]
Acknowledgements
We are grateful to the National Natural Sci-
ence Foundation of China (21272058,
21172057), RFDP (20114104110005), PCSIRT
(IRT 1061) and 2012IRTSTHN006 for financial
support.
5a, 46%
5b, 44%
5c, 42%
Keywords: 2-aminoquinoline-3-carboamides ·
copper catalysis · multicomponent reactions ·
one-pot reactions · pyrimido-[4,5-b]quinolin-4-
ones
5d, 47%
5e, 44%
5 f, 41%
[1] a) A. B. A. El-Gazzar, M. M. El-Enany, M. N. Mah-
moud, Bioorg. Med. Chem. 2008, 16, 3261–3273;
b) A. B. A. El-Gazzar, H. N. Hafez, G. A. M. Nawwar,
Eur. J. Med. Chem. 2009, 44, 1427–1436; c) E. Raja-
narendar, M. Nagi Reddy, S. Rama Krishna, K. Rama
Murthy, Y. N. Reddy, M. V. Rajam, Eur. J. Med. Chem.
2012, 55, 273–283.
5g, 49%
5h, 46%
5i, 54%
[2] a) O. A. El-Sayed, T. M. Al-Turki, H. M. Al-Daffiri, B. A.
Al-Bassam, M. E. Hussein, Boll. Chim. Farm. 2004,
143, 227–238; b) S. Mukherjee, M. Pal, Drug Discov-
ery Today 2013, 18, 389–398.
5j, 45%
5k, 44%
5l, 55%
[3] a) S. I. Alqasoumi, A. M. Al-Taweel, A. M. Alafeefy, E.
Noaman, M. M. Ghorab, Eur. J. Med. Chem. 2010,
45, 738–744; b) H. I. Ali, K. Tomita, E. Akaho, H.
Kambara, S. Miura, H. Hayakawa, N. Ashida, Y. Ka-
washima, T. Yamagishi, H. Ikeya, F. Yoneda, T. Naga-
matsu, Bioorg. Med. Chem. 2007, 15, 242–256;
c) H. M. Faidallah, S. A. F. Rostom, Eur. J. Med. Chem.
2013, 63, 133–143; d) H. I. Ali, K. Tomita, E. Akaho,
M. Kunishima, Y. Kawashima, T. Yamagishi, H. Ikeya,
T. Nagamatsu, Eur. J. Med. Chem. 2008, 43, 1376–
1389.
5m, 60%
5n, 44%
[a] The reactions were run with 0.5 mmol of 1, 0.5 mmol of 3, 0.05 mmol of Cu(OAc)2,
0.5 mmol of K2CO3, and 1 mL of 26% aqueous ammonia (2) in 2 mL of DMSO in a sealed
tube at 1008C for 6 h, and then treated with 0.75 mmol of 4 at 1008C under air for 2 h.
[b] Isolated yield.
[4] a) T. H. Althuis, S. B. Kadin, L. J. Czuba, P. F. Moore,
H. J. Hess, J. Med. Chem. 1980, 23, 262–269; b) T. H.
Althuis, P. F. Moore, H. J. Hess, J. Med. Chem. 1979,
22, 44–48.
[5] E. C. Taylor, N. W. Kalenda, J. Am. Chem. Soc. 1956, 78, 5108–5115.
[6] W. Chen, G. Jiang, Chem. J. Chin. Univ. 1990, 11, 532–533.
[7] R. M. Singh, N. Sharma, R. Kumar, M. Asthana, S. Upadhyay, Tetrahedron
2012, 68, 10318–10325.
[8] a) K. Wang, E. Herdtweck, A. Dçmling, ACS Comb. Sci. 2012, 14, 316–
322; b) D. K. J. Gorecki, E. M. Hawes, J. Med. Chem. 1977, 20, 124–128.
[9] a) A. Dçmling, Chem. Rev. 2006, 106, 17–89; b) B. B. Tourꢂ, D. G. Hall,
Chem. Rev. 2009, 109, 4439–4486.
layer was washed with brine and then dried over anhydrous
Na2SO4. The solvent was evaporated under vacuum, and the crude
product was purified by column chromatography on silica gel (pe-
troleum ether/ethyl acetate=1:2) to afford 2-aminoquinoline-3-car-
boamide derivative 6.
General procedure for the preparation of pyrimido[4,5-b]qui-
nolin-4-ones (5)
[10] a) H. H. Nguyen, T. A. Palazzo, M. J. Kurth, Org. Lett. 2013, 15, 4492–
4495; b) P. Salehi, D. I. MaGee, M. Dabiri, L. Torkian, J. Donahue, Mol. Div.
2012, 16, 231–240; c) C. Che, S. Li, Z. Yu, F. Li, S. Xin, L. Zhou, S. Lin, Z.
Yang, ACS Comb. Sci. 2013, 15, 202–207.
To
a tube containing a solution of 2-bromobenzaldehyde
[11] For selected reviews, see: a) C. Zhang, C. Tang, N. Jiao, Chem. Soc. Rev.
2012, 41, 3464–3484; b) I. P. Beletskaya, A. V. Cheprakov, Organometal-
lics 2012, 31, 7753–7808; c) Y. Liu, J. P. Wan, Chem. Asian J. 2012, 7,
1488–1501; d) J. X. Qiao, P. Y. S. Lam, Synthesis 2011, 829–856; e) D. Ma,
Q. Cai, Acc. Chem. Res. 2008, 41, 1450–1460; f) H. Rao, H. Fu, Synlett
2011, 745–769; g) G. Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008,
108, 3054–3131.
[12] For selected examples, see: a) Y. Lv, Y. Li, T. Xiong, W. Pu, H. Zhang, K.
Sun, Q. Liu, Q. Zhang, Chem. Commun. 2013, 49, 6439–6441; b) P. Sang,
M. Yu, H. Tu, J. Zou, Y. Zhang, Chem. Commun. 2013, 49, 701–703; c) T.
1 (0.5 mmol) and cyanoacetamide 3 (0.5 mmol) in DMSO (2 mL)
were added Cu(OAc)2 (0.05 mmol), K2CO3 (0.5 mmol) and aqueous
ammonia (26%, 1 mL). Then, the tube was sealed, and the mixture
was stirred at 1008C for 6 h. After being cooled to room tempera-
ture, the tube was opened, and aldehyde 4 (0.75 mmol) was
added. After being stirred at 1008C for 2 h, the reaction mixture
was added to saturated brine (10 mL) and extracted with ethyl
acetate(10 mLꢁ3). The combined organic layer was washed with
brine and then dried over anhydrous Na2SO4. The solvent was
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Liu, H. Fu, Synthesis 2012, 2805–2824; d) P. Sang, Y. Xie, J. Zou, Y.
Zhang, Org. Lett. 2012, 14, 3894–3897; e) X. Yang, Y. Luo, Y. Jin, Y. Liu, Y.
Jiang, H. Fu, RSC Adv. 2012, 2, 8258–8261; f) H. Zhang, Y. Jin, H. Liu, Y.
Jiang, H. Fu, Eur. J. Org. Chem. 2012, 6798–6803; g) A. V. Vypolzov, D. V.
Darin, S. G. Ryazanov, P. Lobanov, Chem. Heterocycl. Compd. 2011, 46,
1481–1485; h) V. L. Truong, M. Morrow, Tetrahedron Lett. 2010, 51, 758–
760; i) J. Zhang, C. Yu, S. Yang, C. Wan, Z. Wang, Chem. Commun. 2010,
46, 5244–5246; j) Y. Ohta, Y. Tokimizu, S. Oishi, N. Fujii, H. Ohno, Org.
Lett. 2010, 12, 3963–3965; k) Z. Wang, F. Yang, X. Lv, W. Bao, J. Org.
Chem. 2011, 76, 967–970.
[13] a) S. Guo, J. Wang, X. Fan, X. Zhang, D. Guo, J. Org. Chem. 2013, 78,
3262–3270; b) X. Fan, B. Li, S. Guo, Y. Wang, X. Zhang, Chem. Asian J.
2014, 9, 739–743.
Received: August 18, 2014
Published online on && &&, 0000
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Chem. Asian J. 2014, 9, 1 – 7
www.chemasianj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
&
Multicomponent Reactions
X.-Y. Zhang,* X.-J. Guo, X.-S. Fan*
&& – &&
Synthesis of 2-Aminoquinoline-3-
carboamides and Pyrimido[4,5-
b]quinolin-4-ones through Copper-
Catalyzed One-pot Multicomponent
Reactions
You have to be practical: Practical syn-
theses of 2-aminoquinoline-3-carboa-
mides and pyrimido[4,5-b]quinolin-4-
ones via Cu(OAc)2-catalyzed and K2CO3-
promoted one-pot multicomponent re-
actions of 2-bromobenzaldehydes with
cyanoacetamides and aqueous ammo-
nia/aldehydes were developed.
Chem. Asian J. 2014, 9, 1 – 7
www.chemasianj.org
7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ