Copper-catalyzed direct amination of quinoline N-oxides via C-H bond activation under mild conditions

Article abstract of DOI:10.1021/ol500183w

A highly efficient and concise one-pot strategy for the direct amination of quinoline N-oxides via copper-catalyzed dehydrogenative C-N coupling has been developed. The desired products were obtained in good to excellent yields for 22 examples starting from the parent aliphatic amines. This methodology provides a practical pathway to 2-aminoquinolines and features a simple system, high efficiency, environmental friendliness, low reaction temperature, and ligand, additives, base, and external oxidant free conditions.

Full text of DOI:10.1021/ol500183w

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Direct Amination of Quinoline N‑Oxides via C−H
Bond Activation under Mild Conditions
Chongwei Zhu,† Meiling Yi,† Donghui Wei,† Xuan Chen,† Yangjie Wu,*,† and Xiuling Cui*,†,‡
†Department of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied
Chemistry of Henan Universities, Zhengzhou University, Zhengzhou 450052, P. R. China
‡School of Biomedical Sciences, Engineering Research Centre of Molecular Medicine of Chinese Education Ministry, Xiamen Key
Laboratory of Ocean and Gene Drugs, Institute of Molecular Medicine of Huaqiao University, Fujian, Xiamen 361021, P. R. China
S
* Supporting Information
ABSTRACT: A highly efficient and concise one-pot strategy
for the direct amination of quinoline N-oxides via copper-
catalyzed dehydrogenative C−N coupling has been developed.
The desired products were obtained in good to excellent yields
for 22 examples starting from the parent aliphatic amines. This
methodology provides a practical pathway to 2-aminoquino-
lines and features a simple system, high efficiency, environmental friendliness, low reaction temperature, and ligand, additives,
base, and external oxidant free conditions.
2-Aminoquinolines exist widely in pharmaceuticals and bio-
logical activity antagonists. Some representative examples are
shown in Figure 1. Compound A is a novel potent antagonist
Scheme 1. Synthesis of 2-Aminoquinolines
Figure 1. Two examples illustrating the importance of the compounds
with 2-aminoquinoline moiety.
that selectively modulates native TRPC4/C5 ion channels and
has a wide use in physiological and pathophysiological studies;1
B is an antagonist of the MCH-1R for the treatment of obesity.2
Their high incidence of pharmacological activity has stimulated
many research efforts to prepare such a core. The condensation
of 2-chloroquinoline with amines catalyzed by Co/DPPP3 or
Ni(II)-(α-Aryl)/IPr4 or promoted by microwave1,5 could
provide 2-aminoquinolines (eq 1, Scheme 1). The 2-
mercaptoquinoline could also be served as a substrate to
build 2-aminoquinoline through two steps (eq 2, Scheme 1).6
There are some disadvantages with these procedures, such as
requirement of the expensive starting materials (2-choloroqui-
noline, 2-mercaptoquinoline), harsh reaction conditions, and
low efficiency. Hence, development of a simple, highly efficient,
and atomic-economic method to synthesize 2-aminoquinolines
is highly desired.
bond from Yu and co-workers,9 copper-catalyzed dehydrogen-
ative C−N coupling has been increasingly attractive due to its
cheapness and abundance on the earth.10 However, the
protected or activated amines were usually employed as
substrates since the high electron density of nitrogen atom in
the parent amines could strongly coordinate with the catalyst
and reduce the electrophilicity of metal, which hindered the C−
H bond cleavage.11 Therefore, the parent amines were
employed rarely as substrates for C−H amination. Cu-catalyzed
direct amination of azoles at 140 °C under 1 atm O2 were
reported by Mori.12 The Chang, Daugulis, and Warren groups
also reported their elegant work on copper-catalyzed direct
dehydrogenative C−N coupling from parent amines. However,
a stoichiometric amount of oxidant, such as silver salt or TBHP,
was required.13 In our previous work, we successfully realized
the olefination, sulfonylation, alkylation, and acetoxylation of
quinoline N-oxides via metal-catalyzed C−H bond activation.14
Transition-metal-catalyzed C−N bond formation via C−H
bond activation has become a powerful and efficient method
due to its atom economy.7 Palladium, copper, rhodium, or
ruthenium was usually reported as a catalyst in the literatures.8
Since the pioneering work on the direct amination of Carene−H
Received: November 29, 2013
Published: March 14, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
In our continuing effort to develop versatile C−X (X = C, O, S,
N) bond formation of quinoline N-oxides, we embarked on the
development of C−N bond formation. Herein, we present an
extremely simple and highly efficient copper-catalyzed synthesis
of 2-aminoquinoline via a direct C−H amination of quinoline
N-oxides using the parent amines as substrates at 50 °C and
under ligand, additives, base, and external oxidant free
conditions (eq 3, Scheme 1).
obtained in the presence of 10 mol % of CuI in toluene at 50
°C with 4 equiv of amines by prolonging the reaction time to
15 h. However, 8 equiv of amines was employed to shorten the
reaction time. The yield decreased to 86% and 70% when the
temperature was reduced to 40 and 30 °C, respectively (entries
21−22, Table 1). After surveying the reaction parameters, the
optimal reaction conditions were determined: CuI (10 mol %),
amine (8.0 equiv), toluene, 50 °C, under air.
The condensation of quinoline N-oxide 1a with piperidine 2a
was initially chosen as a model reaction to screen the various
reaction parameters (Table 1). To our delight, the desired
With the optimized reaction conditions in hand (entry 18,
Table 1), the scope of substrates for this transformation was
investigated (Schemes 2 and 3). A series of representative
Table 1. Optimizing Reaction Parameters for the
Condensation of Quinoline N-Oxide 1a with Piperidine 2a
Scheme 2. Copper-Catalyzed Amination of Quinoline N-
Oxide with Various Amines
a
a
b
entry
catalyst (equiv)
solvent
amine (equiv)
yield (%)
1
Cu(OAc)2 (0.2)
Cu(OTf)2 (0.2)
CuBr2 (0.2)
CuBr (0.2)
CuCl (0.2)
CuI (0.2)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
8.0
7.0
6.0
4.0
8.0
8.0
8.0
8.0
8.0
85
2
84
3
83
4
80
5
89
6
94
7
NiCl2·6H2O (0.2)
Pd(OAc)2 (0.2)
CoCl2 (0.2)
CuI (0.2)
NR
NR
NR
80
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
CuI (0.2)
CH3CN
DMSO
DCE
78
CuI (0.2)
NR
NR
trace
85
CuI (0.2)
CuI (0.2)
DMF
CuI (0.2)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CuI (0.2)
82
CuI (0.2)
75
CuI (0.1)
91
CuI (0.08)
CuI (0.05)
CuI (0.1)
86
a
Reaction conditions: 1a (0.2 mmol), 2 (1.6 mmol), CuI (10 mol %),
78
b
c
d
toluene (1.5 mL), 50 °C, 7 h. 12 h. 9 h. 20 h. Isolated yields based
c
86
on 1a.
d
CuI (0.1)
70
a
Reaction conditions: 1a (0.2 mmol), solvent (1.5 mL), 50 °C, 7 h.
Isolated yield based on 1a. 40 °C. 30 °C. NR = no reaction.
b
c
d
amines were tested with quinoline N-oxide 1a in Scheme 2.
Cyclic amines readily underwent conversion to the desired
products. Piperidine and pyrrolidine could provide the products
3aa and 3ab in 91% and 86% yields, respectively. 2-
Methylpiperidine, 2-arylpyrrolidine, and benzopiperidine were
also suitable substrates for this transformation and provided the
corresponding products in 45%, 86%, and 88% yields,
respectively (3ac−ae, Scheme 2). Morpholine and 1-methyl-
piperazine, with two heteroatoms, were smoothly coupled with
quinoline N-oxide, affording the desired products 3af and 3ag
in 93% and 44% yields, respectively. Moreover, acyclic
secondary aliphatic amines could also be employed for this
conversion to smoothly provide the corresponding products
3ah, 3ai, and 3aj (Scheme 2). Diallylamine and dibenzylamine
gave 3ak and 3al in 27% and 25% yields, which might be caused
by the lower nucleophilicity of diallylamine and dibenzyl-
amine.15 No desired products were obtained when primary
amines, aromatic amines, or amides were employed under the
standard reaction conditions.
product 3aa was obtained in 85% isolated yield in the presence
of Cu(OAc)2 (20 mol %) in toluene at 50 °C under air (entry
1, Table 1). The product 3aa was identified by MS, NMR
spectra, and X-ray diffraction. Inspired by this result, some
catalysts were screened (entries 2−9, Table 1). Copper salts,
such as Cu(OAc)2, Cu(OTf)2, CuBr2, CuBr, CuCl, and CuI,
could provide 80−94% isolated yields (entries 1−6). CuI was
slightly superior to the others and proved to be the best catalyst
(entry 6, Table 1). No desired product was observed when
NiCl2·6H2O, Pd(OAc)2, or CoCl2 was used as a catalyst
(entries 7−9). The solvent also played a crucial role. Among
the solvents tested (toluene, THF, CH3CN, DMSO, DCE, and
DMF), toluene was proved to be the best for this trans-
formation (entries 6, 10−14, Table 1). The loading of catalyst
and amine was also screened. The reaction could proceed
smoothly in the presence of 10 mol % of CuI and 8 equiv of
amine (entries 15−20, Table 1). A yield of 91% could also be
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Organic Letters
Letter
To investigate the reaction mechanism, the following
controlled experiment was performed (eq 5). The copper-
Scheme 3. Copper-Catalyzed Amination of Quinoline N-
Oxides with Piperidine
a
catalyzed coupling of 1a with 2a was conducted under nitrogen
atmosphere and obtained the product 3aa only in 16% yield.
This result suggested that O2 might act as an oxidant in this
catalytic system.
Based on the results obtained and literature reports,17
plausible pathway was proposed as shown in Scheme 4.
a
Scheme 4. Plausible Reaction Mechanism
a
Reaction conditions: 1 (0.2 mmol), 2a (1.6 mmol), CuI (10 mol %),
toluene (1.5 mL), 50 °C, 9 h. Isolated yields based on 1.
We next investigated a range of N-oxide derivatives with
piperidine under the optimized conditions (Scheme 3).
Excitingly, quinoline N-oxide substituted with 4-methyl, 4-
methoxy, 4-chloro, 3-bromo, 6-methyl, 6-bromo, and 6-nitro
reacted smoothly with piperidine and provided the desired
product in excellent yields (3ba−ha, Scheme 3). Electron-
donating and electron-withdrawing groups in quinoline N-
oxides did not significantly influence on this transformation. 4-
Bromoquinoline N-oxide gave monoaminated product 3ia and
diaminated product 3ja in 65% and 31% yields, respectively.
2,8-Diaminated quinoline N-oxide 3ka was obtained as a main
product (80% yield) for 4-nitroquinoline N-oxide. However, 6-
methoxyquinoline N-oxide only delivered the desired product
in 27% yield (3la), probably because the electron-donating
group (−OCH3) reduced the activity of C2−H bond of the
quinoline N-oxide. 8-Methylquinoline N-oxide with steric
hindrance and pyridine N-oxide were limited to this catalytic
system. Only a trace amount of product was detected (3ma,
3na). Notably, isoquinoline N-oxide, quinoxaline N-oxide, and
1,10-phenanthroline N-oxide could proceed efficiently and
afford the corresponding products in 86%, 90%, and 65% yields,
respectively (3oa, 3pa, 3qa, Scheme 3).
First, the 2-carbon of the quinoline N-oxide was attacked by
copper and afforded intermediate I.14b,18 Then, the high
electron density of nitrogen atom of the aliphatic amines could
smoothly coordinate with copper atom and give intermediate II
easily. Being surrounded by high electron density of the donor
atom could make Cu(I) be oxidized into Cu(III) complex III
by O2 from air. Finally, Cu(III) complex expedited C−N bond
formation and delivered directly the target product by reductive
elimination. CuI was regenerated to continue the catalytic cycle.
The feasibility of the mechanism was also verified by density
functional theory (DFT) (see the Supporting Information).
In summary, we have developed an extremely simple and
highly efficient protocol for the direct amination of quinoline
N-oxide and its analogues with secondary aliphatic amines
based on copper-catalyzed C−H bond activation. This method
features with a simple system, high efficiency, atomic economy,
environmental friendliness, low reaction temperature, and
ligand, additives, base, and external oxidant free conditions.
Further investigations on the applications of products are in
process in our laboratory.
The 2-aminoquinoline N-oxides were easily reduced by
16
PCl3 and delivered the corresponding 2-aminoquinolines in
ASSOCIATED CONTENT
* Supporting Information
■
excellent yields (eq 4), showing that this protocol through
dehydrogenative C−N coupling is practical for the construction
of 2-aminoquinoline skeleton.
S
Experimental details and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wyj@zzu.edu.cn.
*E-mail: cuixl@zzu.edu.cn.
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Organic Letters
Letter
(14) (a) Wu, J. L.; Cui, X. L.; Chen, L. M.; Jiang, G. J.; Wu, Y. J. J.
Am. Chem. Soc. 2009, 131, 13888. (b) Wu, Z. Y.; Song, H. Y.; Cui, X.
L.; Pi, C.; Du, W. W.; Wu, Y. J. Org. Lett. 2013, 15, 1270. (c) Chen, X.;
Zhu, C. W.; Cui, X. L.; Wu, Y. J. Chem. Commun. 2013, 49, 6900.
(d) Wu, Z. Y.; Pi, C.; Cui, X. L.; Bai, J.; Wu, Y. J. Adv. Synth. Catal.
2013, 355, 1971.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the NSF of China (21102133,
21172200) and the NSF of Henan (082300423201).
■
(15) Li, Y. M.; Xie, Y. S.; Zhang, R.; Jin, K.; Wang, X. N.; Duan, C. Y.
J. Org. Chem. 2011, 76, 5444.
(16) Wenkert, D.; Woodward, R. B. J. Org. Chem. 1983, 48, 283.
(17) (a) Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.;
Ribas, X. Chem. Sci. 2010, 1, 326. (b) Capdevielle, P.; Sparfel, D.;
Lafont, J. B.; Cuong, N. K.; Maumy, M. J. Chem. Soc., Chem. Commun.
1990, 565. (c) Beletskaya, I. P.; Cheprakov, A. V. Organometallics
2012, 31, 7753. (d) Shi, Z. Z.; Zhang, C.; Tang, C. H.; Jiao, N. Chem.
Soc. Rev. 2012, 41, 3381.
(18) (a) Zhang, M. L.; Zhang, S. H.; Liu, M. C.; Cheng, J. Chem.
Commun. 2011, 47, 11522. (b) Wu, X. F.; Anbarasan, P.; Neumann,
H.; Beller, M. Angew. Chem., Int. Ed. 2010, 49, 7316.
REFERENCES
■
(1) Miller, M. J.; Shi, Y. M.; Zhu, M. K.; Tian, J. b.; Stevens, A.; Wu,
M.; Xu, J.; Long, S. Y.; Yang, P.; Zholos, A. V.; Salovich, J. M.; Weaver,
C. D.; Hopkins, C. R.; Lindsley, C. W.; McManus, O.; Li, M.; Zhu, M.
X. J. Biol. Chem. 2011, 286, 33436.
(2) Clark, D. E.; Higgs, C.; Wren, S. P.; Dyke, H. J.; Wong, M.;
Norman, D.; Lockey, P. M.; Roach, A. G. J. Med. Chem. 2004, 47,
3962.
(3) Toma, G.; Fujita, K.; Yamaguchi, R. Eur. J. Org. Chem. 2009, 27,
4586.
(4) Fan, X. H.; Li, G.; Yang, L. M. J. Org. Chem. 2011, 696, 2482.
(5) Appukkuttan, P.; Van der Eycken, E. Eur. J. Org. Chem. 2008, 7,
1133.
(6) Poola, B.; Choung, W.; Nantz, M. H. Tetrahedron 2008, 64,
10798.
(7) (a) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev.
2011, 40, 5068. (b) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed.
2009, 48, 6954. (c) Collet, F.; Lescot, C.; Dauban, P. Chem. Soc. Rev.
2011, 40, 1926. (d) Ramirez, T. A.; Zhao, B. G.; Shi, Y. Chem. Soc. Rev.
2012, 41, 931. (e) Zhang, X. P.; Lu, H. Chem. Soc. Rev. 2011, 40, 1899.
(f) Zhang, C.; Tang, C. H.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464.
(g) Partyka, D. V. Chem. Rev. 2011, 111, 1529. (h) Hartwig, J. F.
Angew. Chem., Int. Ed. 1998, 37, 2046. (i) Tsang, W. C. P.; Zheng, N.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (j) Hartwig, J. F.
Acc. Chem. Res. 1998, 31, 852.
(8) (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560. (b) Yoo, E. J.; Ma, S.; Mei, T. -S.; Chan, K. S. L.;
Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7652. (c) Huard, K.; Lebel, H.
Chem.Eur. J. 2008, 14, 6222. (d) Kim, M.; Chang, S. Org. Lett. 2010,
12, 1640. (e) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.; Yu, W.-Y.; Che, C.-
M. Angew. Chem. 2002, 18, 114. (f) Armstrong, A.; Collins, J. C.
Angew. Chem., Int. Ed. 2010, 49, 2282. (g) Shuai, Q.; Deng, G. J.;
Chua, Z. J.; Bohle, D. S.; Li, C.-J. Adv. Synth. Catal. 2010, 352, 632.
(h) Fiori, K. W.; Bois, J. D. J. Am. Chem. Soc. 2007, 129, 562.
(9) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790.
(10) (a) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932. (b) Li, Y.-X.; Wang, H.-X.; Ali, S.; Xia, X. -F.; Liang, Y. -M.
Chem. Commun. 2012, 48, 2343. (c) Huang, P. C.; Gandeepan, P.;
Cheng, C.-H. Chem. Commun. 2013, 49, 8540. (d) John, A.; Nicholas,
K. M. J. Org. Chem. 2011, 76, 4158. (g) Xia, Q. Q.; Chen, W. Z.; Qiu,
H. Y. J. Org. Chem. 2011, 76, 7577. (e) Santoro, S.; Liao, R.-Z.; Himo,
F. J. Org. Chem. 2011, 76, 9246. (f) Miyasaka, M.; Hirano, K.; Satoh,
T.; Kowalczyk, R.; Bolm, C.; Miura, M. Org. Lett. 2011, 13, 359.
(g) Shuai, Q.; Deng, G. J.; Chua, Z. J.; Bohle, D. S.; Li, C.-J. Adv. Synth.
Catal. 2010, 352, 632. (h) Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem.
Soc. 2011, 133, 5996. (i) Wang, X. Q.; Jin, Y.; Zhao, Y.; Zhu, L.; Fu, H.
Org. Lett. 2012, 14, 452. (j) Evans, R. W.; Zbieg, J. R.; Zhu, S. L.; Li,
W.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 16074.
(11) Zhao, H. Q.; Wang, M.; Su, W. Q.; Hong, M. C. Adv. Synth.
Catal. 2010, 352, 1301.
(12) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett.
2009, 11, 1607.
(13) (a) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew. Chem.,
Int. Ed. 2010, 49, 9899. (b) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S.
Angew. Chem., Int. Ed. 2009, 48, 9127. (c) Tran, L. D.; Roane, J.;
Daugulis, O. Angew. Chem. 2013, 125, 6159. (d) Gephart, R. T., III;
Huang, D. L.; Aguila, M. J. B.; Schmidt, G.; Shahu, A.; Warren, T. H.
Angew. Chem., Int. Ed. 2012, 51, 1. (e) Badiei, Y. M.; Dinescu, A.; Dai,
X. L.; Palomino, R. M.; Heinemann, F. W.; Cundari, T. R.; Warren, T.
H. Angew. Chem., Int. Ed. 2008, 47, 9961.
1843
dx.doi.org/10.1021/ol500183w | Org. Lett. 2014, 16, 1840−1843