A simple and convenient copper-catalyzed tandem synthesis of quinoline-2-carboxylates at room temperature

Article abstract of DOI:10.1021/jo901101v

(Chemical Equation Presented) We developed a simple and convenient copper-catalyzed method for the synthesis of quinoline-2-carboxylate derivatives through sequential intermolecular addition of alkynes onto imines and subsequent intramolecular ring closur

Full text of DOI:10.1021/jo901101v

pubs.acs.org/joc
A Simple and Convenient Copper-Catalyzed Tandem Synthesis of
Quinoline-2-carboxylates at Room Temperature
He Huang, Hualiang Jiang, Kaixian Chen, and Hong Liu*
Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Shanghai Institutes for Biological Sciences, and Graduate School, Chinese Academy of Sciences, 555
Zuchongzhi Road, Shanghai 201203, China
hliu@mail.shcnc.ac.cn
Received May 25, 2009
We developed a simple and convenient copper-catalyzed method for the synthesis of quinoline-2-
carboxylate derivatives through sequential intermolecular addition of alkynes onto imines and
subsequent intramolecular ring closure by arylation. The efficiency of this system allowed the
reactions to be carried out at room temperature.
Introduction
for the preparation of quinox ligands which were widely
applied in asymmetric catalysis.2a-2d In particular, 2-quino-
linecarboxylic acid 4 has been shown to be a promising
ligand for the ruthenium-catalyzed dehydrative allylation
of alcohols.2e As a consequence of their unique chemical and
biological properties, quinoline-2-carboxylates have at-
tracted wide interest from pharmaceutical and synthetic
materials. Traditionally, the quinoline-2-carboxylate frame-
work has been prepared through oxidative reactions of
2-methylquinolines,5 2-carbonylquinolines,6 and 4-oxo-1,4-
dihydroquinolines7 in the presence of strong oxidants or the
hydrolyzation of 2-cyanoquinolines8 with bases. In addition,
the Doebner-von Miller reaction is also a useful method to
construct quinolines.9 Although these methods are effective,
harsh reaction conditions are necessary, and some depend on
the availability of the requisite substituted quinoline deriva-
tives.5-8 Many starting materials are also sometimes difficult
to prepare, so more convenient and efficient approaches
The quinoline-2-carboxylate framework is a motif com-
mon to biologically active compounds and valuable syn-
thetic intermediates (Scheme 1).1-4 For example, kynurenic
acid 11a is a useful agent for the potential control of neuro-
degenerative disorders; compound 21b can be used as a
potent 5-hydroxytryptamine antagonist; and compound 31c
is a potent lead compound for inhibiting the binding of
Insulin-like Growth Factor (IGF) to IGF-binding proteins.
In addition, quinoline-2-carboxylates are key intermediates
*To whom correspondence should be addressed. Phone: þ86-21-
50807042. Fax: þ86-21-50807088.
(1) (a) Manfredini, S.; Vertuani, S.; Pavan, B.; Vitali, F.; Scaglianti, M.;
Bortolotti, F.; Biondi, C.; Scatturin, A.; Prasad, P.; Dalpiaz, A. Bioorg. Med.
Chem. 2004, 12, 5453. (b) Horchler, C. L.; McCauley, J. P.; Hall, J. E.;
Snyder, D. H.; Moore, W. C.; Hudzik, T. J.; Chapdelaine, M. J. Bioorg. Med.
Chem. 2007, 15, 939. (c) Zhu, Y. F.; Wang, X. C.; Connors, P.; Wilcoxen, K.;
Gao, Y. H.; Gross, R.; Strack, N.; Gross, T.; McCarthy, J. R.; Xie, Q.; Ling,
N.; Chen, C. Bioorg. Med. Chem. 2003, 13, 1931.
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Masson, S. Tetrahedron 2004, 60, 9263. (b) Muller, P.; Chappellet, S. Helv.
Chim. Acta 2005, 88, 1010. (c) Park, S. W.; Son, J. H.; Kim, S. G.; Ahn, K. H.
Tetrahedron: Asymmetry 1999, 10, 1903. (d) Zhang, Y.; Sigman, M. S. J. Am.
Chem. Soc. 2007, 129, 3076. (e) Saburi, H.; Tanaka, S.; Kitamura, M. Angew.
Chem., Int. Ed. 2005, 44, 1730.
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5476 J. Org. Chem. 2009, 74, 5476–5480
Published on Web 07/02/2009
DOI: 10.1021/jo901101v
r
2009 American Chemical Society

Huang et al.
JOCArticle
TABLE 1. Optimization of the Catalysis Conditionsa
SCHEME 1. Representative Quinoline-2-carboxylates in Med-
icinal Chemistry and Organic Synthesis
entry
catalyst
CuI
solvent
yield 7a/8 [%]
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
dioxane
furan
toluene
DMSO
DMF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0/0
0/78
0/73
0/59
87/0
15/0
28/0
37/0
0/27
0/81
54/0
31/0
64/0
52/0
85/0
Cu(OAc)2
Cu(acac)2
Cu(tmhd)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
3b
4c
would be helpful. In recent years, transition metal-catalyzed
coupling reactions have emerged as a powerful tool for the
synthesis of heterocyclic compounds.10 Chan et al. have
developed silver- or copper-catalyzed efficient alkynylation
of R-imino ester with arylacetylenes.11 These methods pro-
vide an effective route to propargylic amines, which are key
intermediates to the construction of quinoline derivatives.
Recently, Fujiwara et al. reported an efficient synthesis of
quinolin-2(1H)-ones by using PdII via the activation of
aromatic C-H bonds for addition to C-C multiple bond-
s.12a Also, an efficient synthesis of 2,4-disubstituted quino-
line derivatives from N-aryl-2-propynylamines has been
reported by Takai and Kuninobu in which AuI and CuI were
used together.12b By using AuCl3/CuBr catalysis, Wang
described a sequential catalytic process for the synthesis of
quinolines through a three-component reaction of alde-
hydes, amines, and alkynes.12c Although these approaches
provide efficient access to quinolines, there is considerable
room for improvement. For example, an aryl or alkyl group
at position 2 of the quinoline ring is predominant in these
protocols. To the best of our knowledge, there is no example
of constructing a quinoline-2-carboxylate framework under
5d
6
7
8
9
10
11e
12f
13g
14h
15i
aReaction condition: phenylacetylene (100 μL), N-PMP R-iminoethyl
glyoxylate (2.0 equiv), catalyst (0.2 equiv), solvent (2 mL), room
c
temperature, reaction time (16 h). bacac = acetylacetonate. tmhd =
2,2,6,6-tetramethyl-3,5-heptanedione. dOTf = trifluoromethanesulfo-
nate. e10% mol Cu(OTf)2 was used. f4% mol Cu(OTf)2 was used. g1.0
equiv of N-PMP R-iminoethyl glyoxylate was used. hReaction time
(10 h). iReaction time (24 h).
ligand-free copper catalysis at room temperature. The nu-
merous advantages of copper catalysts make them highly
attractive for chemical synthesis from environmental and
economic points of view.13 Herein, we report a straightfor-
ward and practical copper-catalyzed tandem reaction for the
efficient synthesis of quinoline-2-carboxylates via activation
of C-H bonds under mild conditions, wherein the Grignard-
type imine addition is followed by a Friedel-Crafts alkeny-
lation of arenes with alkynes. The method only requires one
metal catalyst, which is both simpler and less costly than
those methods that use two metals for both steps. These
reactions represent an environmentally friendly and atom-
economical concept when performed under mild conditions.
The 2-carboxyl group makes this method particularly ap-
pealing, since this substituent can be used for further syn-
thetic manipulations.
(10) For recently reported methods or reviews for the synthesis of
substituted quinolines, see: (a) Cui, S. L.; Wang, J.; Wang, Y. G. Tetrahedron
ꢀ
2008, 64, 487. (b) Istvan, S.; Ferenc, F. Synthesis 2009, 775. (c) Ghorbani-
Vaghei, R.; Akbari-Dadamahaleh, S. Tetrahedron Lett. 2009, 50, 1055. (d)
Vander Mierde, H.; Van Der Voort, P.; Verpoort, F. Tetrahedron Lett. 2009,
50, 201. (e) Ghassamipour, S.; Sardarian, A. R. Tetrahedron Lett. 2009, 50,
514. (f) Qi, C. M.; Zheng, Q, W.; Hua, R. M. Tetrahedron 2009, 65, 1316. (g)
Likhar, P. R.; Subhas, M. S.; Roy, S.; Kantam, M. L.; Sridhar, B.; Seth, R.
K.; Biswas, S. Org. Biomol. Chem. 2009, 7, 85. (h) Gabriele, B.; Mancuso, R.;
Salerno, G.; Ruffolo, G.; Plastina, P. J. Org. Chem. 2007, 72, 6873. (i)
Gabriele, B.; Mancuso, R.; Salerno, G.; Lupinacci, E.; Ruffolo, G.; Costa,
M. J. Org. Chem. 2008, 73, 4971. (j) Madapa, S.; Tusi, Z.; Batra, S. Curr. Org.
ꢀ
ꢀ
Chem. 2008, 12, 1116. (k) Kouznetsov, V. V.; Mendez, L. Y. V.; Gomez, C.
M. M. Curr. Org. Chem. 2005, 9, 141.
(11) (a) Ji, J. X.; Au-Yeung, T. L.; Wu, J.; Yip, C. W.; Chan, A. S. C. Adv.
Synth. Catal. 2004, 346, 42. (b) Ji, J. X.; Wu, J.; Chan, A. S. C. Proc. Natl
Acad. Sci. U.S.A. 2005, 102, 11196. (c) Shao, Z.; Wang, J.; Ding, K.; Chan, A.
S. C. Adv. Synth. Catal. 2007, 349, 2375.
Results and Discussion
(12) (a) Jia, C. G.; Piao, D. G.; Oyamada, J. Z.; Lu, W. J.; Kitamura, T.;
Fujiwara, Y. Science 2000, 287, 1992. (b) Kuninobu, Y.; Inoue, Y.; Takai, K.
Chem. Lett. 2007, 36, 1422. (c) Xiao, F. P.; Chen, Y. L.; Liu, Y.; Wang, J. B.
Tetrahedron 2008, 64, 2755.
(13) For recent reviews on copper-catalyzed reactions, see: (a) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (b) Ma, D. W.; Cai, Q.
A. Acc. Chem. Res. 2008, 41, 1450. (c) Reymond, S.; Cossy, J. Chem. Rev.
2008, 108, 5359. (d) Yamada, K.; Tomioka, K. Chem. Rev. 2008, 108, 2874.
(e) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887. (f) Poulsen, T. B.;
Jorgensen, K. A. Chem. Rev. 2008, 108, 2903. (g) Alexakis, A.; Backvall, J. E.;
Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev. 2008, 108, 2796. (h) Evano,
G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054.
Initially, we chose phenylacetylene 5a and N-PMP
R-iminoethyl glyoxylate (PMP=p-methoxyphenyl) 6a as the
model substrates to optimize the reaction conditions at room
temperature.14 As shown in Table 1, we tested various copper
catalysts in CH2Cl2. When the reaction was attempted with
(14) N-Aryl iminoethyl glyoxylates were prepared by a condensation
reaction through the ethyl glyoxylate and aromatic amines in CH2Cl2 at
temperature.
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TABLE 2. Copper-Catalyzed Synthesis of Quinoline-2-carboxylates
aReacted at 50 °C.
CuI as the catalyst, no conversion was observed. Under Cu-
(OAc)2, Cu(acac)2, and Cu(tmhd)2 catalysis, no desired pro-
duct was observed. Instead, the major product was ethyl
2-(4-methoxyphenylimino)-4-phenylbut-3-ynoate 8, which
was formed from the oxidation of propargylic amine (Table 1,
entries 2-4). However, switching to Cu(OTf)2 as the catalyst
resulted in ethyl 6-methoxy-4-phenylquinoline-2-carboxylate
7a in good yield (Table 1, entry 5). We also investigated the
effect of solvents (Table 1, entries 5-10). The choice of solvent
influenced both the activity and selectivity of the catalytic
system: the desired products were obtained when the reactions
were conducted in dioxane, furan, and toluene, albeit in lower
yield (Table 1, entries 6-8). The use of DMSO and DMF gave
27% and 81% oxidation product 8, respectively, and none of
the desired product (Table 1, entries 9 and 10). A satisfactory
result (i.e., 87% yield of desired product 7a) occurred when
CH2Cl2 was used (Table 1, entry 5). Then the amount of
catalyst required was also investigated. We were unable to
reduce the catalyst loading below 20 mol % (relative to the
phenylacetylene) without adversely affecting the product yield
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SCHEME 2. Copper-Catalyzed Three-Component Reactions
(Table 1, entries 5, 11, and 12). When 1.0 equiv of 6a was
performed, the reaction also works well but with a lower yield
(Table 1, entry 13). Finally, shortening reaction time to 10 h led
to a decrease in yield (Table 1, entry 14). No improvement was
observed when the reaction time was further prolonged
(Table 1, entry 15). Therefore, our optimal reaction conditions
for the synthesis of quinoline-2-carboxylates is as follows:
20 mol % of Cu(OTf)2 as the catalyst, CH2Cl2 as the solvent,
and carrying out the reaction at room temperature for 16 h. For
determining whether compound 8 was a possible intermediate,
we performed the reaction of isolated 8 under the optimal
reaction conditions, and observed no formation of product 7a.
Having established suitable reaction conditions, we ex-
plored the scope and generality of the methodology starting
with alkynes (Table 2). As shown in Table 2, most substrates
examined under the standard reaction condition provided
moderate to excellent yields at room temperature. Several
functional groups, including halogens and electron-donating
or electron-withdrawing substituents on the aryl ring of
the alkynes, were tolerated well. Generally, the substituted
aromatic alkynes containing electron-neutral (Table 2, entry
1) or electron-rich groups, for example, substrates with
groups such as tert-butyl (Table 2, entry 2), methyl (Table 2,
entries 3 and 4), and methoxy (Table 2, entry 5) proceeded
well. Electron-withdrawing substituents, including fluoro
(Table 2, entries 6 and 7) and chloro groups (Table 2, entry
8), were tolerated, although with slightly weaker reactivity,
while 1-(4-ethynylphenyl)ethanone provided lower yields
(Table 2, entry 9). Notably, the alkynyl group was also
tolerated (Table 2, entry 10). A wide range of aromatic
alkynes readily participated in the reaction with the aniline
rings at ambient temperatures. However, the catalytic pro-
cess was unsatisfactory with aliphatic substrates, and a
higher temperature was necessary for achieving sufficient
conversion. The corresponding product was obtained in
moderate yields when temperature was raised to 50 °C
(Table 2, entry 11). We also found that compounds sub-
stituted by electron-donating or electron-neutral substitu-
ents such as methoxy, benzyloxy, or methyl groups at the
4-position on the phenyl ring attached to the nitrogen pro-
ceeded well. In each case, we obtained satisfactory product
yields from the catalytic reactions (Table 2, entries 12-18).
We were also pleased to observe that the present protocol
could be readily used in a three-component reaction12c,15 in
one pot. As shown in Scheme 2, ethyl glyoxylate 9 and aniline
10 reacted with alkynes 5 in the presence of a Cu(OTf)2
catalyst to afford quinoline-2-carboxylates 7 under mild
conditions (room temperature, 24 h). It is important to note
that good yields can be obtained for these reactions by using
representative aromatic alkynes and anilines as starting
materials (Scheme 2). Consistent with the results of previous
studies, the electron-neutral or electron-rich aromatic al-
kynes were found to be more efficient.
SCHEME 3. Proposed Mechanism
reaction mixture by mass spectrum and TLC analysis. We
then performed the reaction of isolated propargylic amines
under the optimal reaction conditions, and obtained the
desired quinoline-2-carboxylates. These results indicated
that the propargylic amines were intermediates in the cata-
lytic process. The subsequent cyclization step may then occur
directly through a Friedel-Crafts-type addition leading to
the desired products. Alternatively, the oxidation products
would be obtained under the specific reaction conditions.
Conclusions
In summary, we have developed a simple and practical
copper-catalyzed tandem Grignard-type imine addition/
Friedel-Crafts alkenylation of arenes with alkynes for the
efficient synthesis of quinoline-2-carboxylates via activation
of C-H bonds. We obtained the target products in high
yields from a variety of readily available alkynes and imines.
This new method only requires one copper catalyst, which is
both simpler and less costly than those methods with two
metals for both steps, and tolerates a variety of useful
functional groups. The system’s efficiency allowed the reac-
tions to be carried out at room temperature.
On considering the mechanism (Scheme 3), the first
generally proposed step is the formation of propargylic
amines. As proposed by Chan and co-workers,11 propargylic
amines were produced via an intermediate that was formed
by successive complexation of substrates to the metal center.
The propargylic amines were detected and identified in the
Experimental Section
General Procedure for the Synthesis of 7a (Table 2, entry 1).
A mixture of N-PMP R-iminoethyl glyoxylate (377 mg) and
phenylacetylene (100 μL) was dissolved in CH2Cl2 (2.0 mL).
(15) Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am.
Chem. Soc. 2009, 131, 4598.
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Subsequently, 0.2 equiv of Cu(OTf)2 was added to this mixture.
The reaction was then stirred at ambient temperature for 16 h.
The crude reaction mixture was concentrated and purified by
flash column chromatography (petroleum ether/ethyl acetate)
to yield the expected product. The data obtained are as follows:
1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=9.3 Hz, 1H), 8.09 (s,
1H), 7.57-7.50 (m, 5H), 7.43 (dd, J=9.3 Hz, J=1.5 Hz, 1H),
7.21 (d, J=1.5 Hz, 1H), 4.55 (q, J=7.0 Hz, 2H), 3.80 (s, 3H), 1.47
(t, J=7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.5, 159.4,
147.9, 145.3, 144.2, 137.8, 132.6, 129.2, 129.1, 128.7, 128.6,
122.7, 121.7, 103.1, 62.0, 55.4, 14.3. MS (EI, m/z) 307 [M]þ;
HRMS (EI) calcd for C19H17NO3 [M]þ 307.1208, found
307.1214.
The reaction was then stirred at ambient temperature for 24 h.
The crude reaction mixture was concentrated and purified by
flash column chromatography (petroleum ether/ethyl acetate)
to yield the expected product. The data obtained are as men-
tioned above.
Acknowledgment. We gratefully acknowledge financial
support from the National Natural Science Foundation
of China (Grants 20721003 and 20872153), International
Collaboration Projects (Grants 2007DFB30370 and
20720102040), and the 863 Hi-Tech Program of China
(Grants 2006AA020602).
General Procedure for the Synthesis of 7a through a Three-
Component Reaction. A mixture of ethyl glyoxylate (372 μL,
50% solution in toluene), aniline (170 mg), and phenylacety-
lene (100 μL) was dissolved in CH2Cl2 (2.0 mL). Subse-
quently, 0.2 equiv of Cu(OTf)2 was added to this mixture.
Supporting Information Available: Detailed experimental
procedures and compound characterization data for all pro-
ducts. This material is available free of charge via the Internet at
http://pubs.acs.org.
5480 J. Org. Chem. Vol. 74, No. 15, 2009