An efficient synthesis of 3-triazolyl-2(1H)-quinolones by CuTC-catalyzed azide-alkyne cycloaddition reaction

Article abstract of DOI:10.1002/aoc.2946

A facile and efficient Cu(I)-catalyzed azide-alkyne cycloaddition reaction for the synthesis of a series of 3-triazolyl-2(1H)-quinolones 3 have been developed using 3-azido-quinolin-2(1H)-one as the coupling partner. The optimized reaction conditions involve the use of eco- friendly ethanol as the solvent in the presence of copper(I) thiophene-2-carboxylate as the catalyst, to afford good to excellent yields of 3-triazolyl-2(1H)-quinolone derivatives of biological interest. Copyright

Full text of DOI:10.1002/aoc.2946

Full Paper
Received: 5 September 2012
Revised: 15 October 2012
Accepted: 17 October 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.2946
An efficient synthesis of 3-triazolyl-2(1H)-
quinolones by CuTC-catalyzed azide–alkyne
cycloaddition reaction
Samir Messaoudi*, Marie Gabillet, Jean-Daniel Brion and Mouâd Alami*
A facile and efficient Cu(I)-catalyzed azide–alkyne cycloaddition reaction for the synthesis of a series of 3-triazolyl-2(1H)-
quinolones 3 have been developed using 3-azido-quinolin-2(1H)-one as the coupling partner. The optimized reaction condi-
tions involve the use of eco- friendly ethanol as the solvent in the presence of copper(I) thiophene-2-carboxylate as the
catalyst, to afford good to excellent yields of 3-triazolyl-2(1H)-quinolone derivatives of biological interest. Copyright ©
2013 John Wiley & Sons, Ltd.
Keywords: triazole; quinolin-2(1H)-one; CuTC; hsp90 inhibitors
would have the great advantage of making these analogues
Introduction
suitable for combinatorial chemistry. To the best of our knowledge,
except for our previous result[15] there is no report describing the
In recent years, the copper-catalyzed [3+ 2] azide–alkyne cycload-
dition (CuAAC) reaction has attracted considerable attention.[1]
synthesis of targeted 3-triazolyl-2(1H)-quinolone derivatives of
type A (Fig. 1).
This reaction, discovered independently by Tornøe et al.[2] and
Rostovtsev et al.,[3] constitutes a substantial improvement of the
During our recent studies on the functionalization of hetero-
classical Huisgen thermal 1,3-dipolar cycloaddition.[4] The resulting
cycles via transition metal-catalyzed reactions,[16] we have
1,4-disubstituted 1,2,3-triazoles are obtained in high yields with
developed an in situ direct amination of (hetero)aryl halides
using sodium azide as the amino source.[15] The catalytic system
exclusive regioselectivity under mild conditions. The wide scope
of CuAAC is firmly demonstrated by its use in different areas,[5]
based on Cu-powder/pipecolinic acid/ascorbic acid proved to
including synthetic and medicinal chemistry,[6] surface and
be highly efficient and versatile for the preparation of various
polymer chemistry,[7] as well as bioconjugation applications.[8]
(hetero)aromatic amines, including 3-aminoquinolinones. In
In an ongoing medicinal chemistry program directed toward
addition, we have demonstrated through a preliminary result
hsp90,[9] an exciting target in cancer drug discovery, we identi-
that the use of CuI (10 mol%) together with pipecolinic acid
(30 mol%) and ascorbic acid (20 mol%) enabled cycloaddition of
3-azidoquinolin-2(1H)-one (1a) with 4-methoxyphenylacetylene
(2a) in a good 80% yield (Table 1, entry 1). Given the practical
fied 4TCNA[10] as a simplified denoviose analogue of novobiocin
(Nvb). Biological evaluation revealed that 4TCNA manifested
micromolar anti-proliferative activities and exhibited higher po-
tency than Nvb itself to induce client–protein degradation.[11]
importance of efficient 3-triazolylquinolones synthesis for the
Further structure–activity relationships (SAR) studies led us, very
purpose of our hsp90 medicinal chemistry program, attention was
consequently paid to improving our reported protocol,[15] and to
recently, to discover 6BrCaQ as a lead compound in which the
coumarin unit has been replaced by a 2-quinoleinone moiety
extend the scope of the Cu-catalyzed CuAAC reactions with
(Fig. 1). 6BrCaQ displayed the most potent antiproliferative
3-azidoquinolones. In this paper we wish to detail our progress in
activity against a panel of cancer cell lines, and manifested down-
regulation of several hsp90 client proteins. Moreover, 6BrCaQ in-
duced a high level of apoptosis in MCF-7 breast cancer cells by
activation of caspases, and the subsequent cleavage of PARP.[12]
Modifications to both the quinolin-2(1H)-one core and benza-
this reaction, which provides a wide range of 3-triazolylquinolones
A of biological interest.
Results and Discussion
mide side chain has been pursued, resulting in the production
of preliminary SAR. However, modifications to the geometry of
the amide bond have not been realized. Thus we proposed the
synthesis of a series of 6BrCaQ analogues replacing the amide
bond with a triazole ring, which could facilitate SAR analysis for
At the outset, we were keen to determine the optimized reaction
conditions using 1a and 2a as model substrates. Thus a variety of
the aryl side chain. Triazoles have been shown to possess a
number of desirable features in the context of medicinal chemis-
try. For example, the 1,2,3-triazole ring may act as bioisoster
of the amide moiety[13] due to similarities in both electronic
and spatial characteristics. In addition, it is metabolically
stable to hydrolysis.[14] Finally, the substitution with a triazole ring
*
Correspondence to: S. Messaoudi, Laboratoire de Chimie Thérapeutique, Faculté
de Pharmacie, Université Paris-Sud, CNRS, BioCIS, UMR 8076, LabEx LERMIT, rue
J. B. Clément F-92296 Châtenay-Malabry, France. E-mail: samir.messaoudi@u-psud.fr
or: mouad.alami@u-psud.fr
Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, Université Paris-
Sud, Châtenay-Malabry, France
Appl. Organometal. Chem. 2013, 27, 155–158
Copyright © 2013 John Wiley & Sons, Ltd.

S. Messaoudi et al.
OH
OH
4
H
N
O
3
OTs
O
H
N
O
7
O
O
O
MeO
O
O
HO
O
O
OH
H2N
O
Novobiocin (Nvb)
IC50 = 220 µM (MDA-MB-231)
4TCNA
IC50 = 45 µM (MDA-MB-231)
OMe
N
N
R1
H
Br
N
N
R2
O
N
O
N
O
Chemical Diversity
6BrCaQ
IC50 = 2 µM (MDA-MB-231)
A
(3-triazolyl-2(1H)-quinolones)
Figure 1. Nvb, 4TCNA, 6BrCaQ and the targeted 3-triazolyl-quinolones of general structure A.
reaction conditions were screened. In contrast to our previously
reported conditions[15] (Table 1, entry 1), we found that the addi-
tion of a ligand or an additive was unnecessary since the reaction
of 1a with 2a (2 equiv.) in the presence of CuI (10 mol%) and
sodium ascorbate (entry 2) or pipecolinic acid (entry 3) in EtOH
at 40ꢀC led to the triazole 3a in comparable yields. Interestingly,
a similar result was observed when running the reaction in
the absence of both sodium ascorbate and pipecolinic acid, sug-
gesting that these reactants had no beneficial effect on
the formation of 3a (entry 4). Further optimization with respect
to the copper source (entries 4–13) showed that copper(I)
thiophene-2-carboxylate (CuTC)[17] was the best catalyst, provid-
ing 3a in 91% yield within only 3 h (entry 8). The developed
reaction conditions constitute a clear simplification and improve-
ment when compared to our previous report, particularly the
absence of additives and ligand.
Table 1. Optimization of the copper-catalyzed formation of triazole
3aa
With a viable CuAAC procedure in hand, we became interested
to explore the scope of the reaction with various commercially
available terminal alkynes (2) possessing different steric and elec-
tronic properties. As can be observed in Table 2, a variety of ter-
minal alkynes, including aromatic, heteroaromatic and aliphatic
derivatives, participated in the cycloaddition reaction, furnishing
the corresponding triazoles in moderate to excellent yields, and
high purity after simple filtration. Notably, electron-rich and
electron-deficient, meta- and para-substituted arylalkynes all
underwent efficiently the 1,3-dipolar cycloaddition in good yield
(entries 1–3 and 7–10). In addition, the sterically demanding
ortho substitution pattern was tolerated toward the CuAAC
reaction of 1a, leading to triazoles 3d–f in yields ranging from
35% to 88% (entries 4–6). Interestingly, this cycloaddition also
proceeded successfully in the case of heteroaromatic alkynes,
such as 3-quinoleinylylacetylene (2k) and 2-pyridylacetylene
(2l), leading to triazoles 3k and 3l in 60% and 70% yields, respec-
tively (entries 11 and 12). The scope of our protocol was next
examined with aliphatic terminal alkynes. Thus hept-1-yne (2m)
was more sluggish to react, with incomplete conversion, leading
to only 20% of triazole 3m (entry 13). Finally, challenging functiona-
lized substrates, such as tert-butyldimethyl(prop-2-ynyloxy)silane
(2n), trimethylsilyl-acetylene (2o) and methyl propiolate (2p),
were also investigated and found competent in this reaction,
producing corresponding triazoles in reasonable to good yields
(72%, 50%, and 80%, respectively).
Entry
[Cu]
Ligand
Pipecolinic acid NaAscc
Additives Time (h) Yieldb (%)
1
CuI
CuI
CuI
CuI
6
6
9
9
6
6
9
3
3
3
3
3
3
80
79
77
76
70
19
65
91
77
25
31
10
8
2
—
Pipecolinic acid
—
NaAsc
—
3
4
—
5
Cu(SO4)2.5H2O
Cu
6
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
7
Cu2O
8
CuTcd,e
Cu(OAc)2
CuCN
9
10
11
12
13
CuNO3
CuBr.DMS
CuCl
aReaction conditions: 1a (1 mmol), 2a (2 mmol), [Cu] (10 mol%);
Additive (20 mol%) in EtOH (6 ml) was heated in a sealed Schlenk
tube at 40ꢀC.
bIsolated yield of 3a.
cNaAsc, sodium ascorbate.
dCuTC, copper(I) thiophene-2-carboxylate.
eFor control experiments, no conversion at all was observed in the
absence of CuTc.
Upon construction of the 3-triazolyl-2(1H)-quinolone deriva-
tives, the newly synthesized compounds were subjected to anti-
tumor evaluation against MCF-7 (estrogen-receptor positive
breast cancer cells) cell lines in vitro. Unfortunately, in comparison
to previously described quinolone-containing analogues,[12] our
wileyonlinelibrary.com/journal/aoc
Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 155–158

3-Triazolyl-2(1H)-quinolone synthesis by CuAAC reaction
Table 2. Click 1,3-cycloaddition toward the synthesis of 3-triazolyl-
2(1H)-quinolones 3a
Experimental
General Experimental Methods
All glassware was oven-dried at 140ꢀC and all reactions were con-
ducted under a nitrogen atmosphere. Solvents for chromatogra-
phy – cyclohexane, ethyl acetate (EtOAc) – were technical grade.
All compounds were identified by the usual physical methods,
i.e. 1H NMR, 13C NMR, IR and elemental analysis. 1H and 13C NMR
spectra were measured in CDCl3 or DMSO-d6 with a Bruker ARX
400 or Bruker Avance 300 and chemical shifts are reported
in ppm. The following abbreviation are used: m (multiplet), s
(singlet), br s (broad singlet), d (doublet), t (triplet), dd (doublet
of doublet), td (triplet of doublet), q (quadruplet). IR spectra were
measured on a Bruker Vector 22 spectrophotometer (neat, cmÀ1).
Elemental analyses were performed with a PerkinElmer 240
analyzer. Analytical thin-layer chromatography was performed
on Merck pre-coated silica gel 60F plates. Merck silica gel 60
(230–400 mesh) was used for column chromatography.
Entry
R1
Product 3 yield (%)b
1
2
3
4
5
p-MeO-Ph
p-Me2N-Ph
Ph 2c
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
91
75
68
45
88
o-MeO-Ph
Experimental Procedure for CuAAC Synthesis of 3-Triazolyl-2
(1H)-Quinolones
6
1-Np
2f
2g
2h
2i
3f
3g
3h
3i
35
64
60
74
65
60
7
2,3,4, MeO-Ph
p-F-Ph
8
A flame-dried resealable 2–5 mL Pyrex reaction vessel was charged
with the solid reactant(s): CuTc (10 mol%), 3-azidoquinolin-2(1H)-
one (1a) (1 mmol) and alkyne 2 (2 mmol) in EtOH (6 mL). The reac-
tion vessel was capped with a Teflon screw cap. The reaction vessel
was sealed and then heated at 40ꢀC. The resulting suspension was
cooled to room temperature and filtered, and the resulting solid
product was washed with H2O (30 ml) and c-hexane (200 ml).
9
m-F-Ph
10
11
m-Cl-Ph
2j
3j
2k
3k
12
13
14
15
16
2-Py
2l
2m
2n
2o
2p
3l
3m
3n
3o
3p
70
20
72
50
80
(CH2)4-CH3
CH2-OTBS
Me3Si
Acknowledgments
The authors thank the Centre National de Recherche Scientifique
(CNRS) for support of this research. Thanks to A. Solgadi for
performing mass spectra analysis (SAMM platform, Châtenay-
Malabry). Our laboratory BioCIS-UMR 8076 is a member of the
Laboratory of Excellence LERMIT, supported by a grant from
ANR (ANR-10-LABX-33).
CO2Me
aReaction conditions: 1a (1.0 equiv.), aryl alkyne (2.0 equiv.), CuTc
(10 mol%), in EtOH (6 ml) were heated in a sealed Schlenk tube
at 40ꢀC (time: see experimental section).
bIsolated yields of 3.
References
newly synthesized triazole derivatives exhibited lower cytotoxi-
city against the tested tumor cell line (IC50 >100 mM). These
compounds were not sufficiently active to be selected for the next
valuation concerning their ability to induce degradation of Hsp90-
dependent client proteins.
[1] a) F. Amblard, J. H. Cho, R. F. Schinazi, Chem. Rev. 2009, 109, 4207; b)
A. J. Dirks, J. L. M. Cornelissen, R. J. M. Nolte, Bioconjugate Chem.
2009, 20, 1129; c) P. Cintas, A. Barge, S. Tagliapietra, L. Boffa,
G. Cravotto, Nat. Protoc. 2010, 5, 607; d) S. V. Orski, A. A. Poloukhtine,
S. Arumugam, L. Mao, V. V. Popik, J. Locklin, J. Am. Chem. Soc. 2010,
132, 11024; e) U. Jakobsen, S. A. Shelke, S. Vogel, S. T. Sigurdsson,
J. Am. Chem. Soc. 2010, 132, 10424.
[2] C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057.
[3] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem.
Int. Ed. 2002, 41, 2596.
Conclusion
[4] a) R. Huisgen, G. Szeimies, L. Moebius, Chem. Ber. 1965, 98, 4014;
b) R. Huisgen, Pure Appl. Chem. 1989, 61, 6138.
In summary, we reported a CuAAC reaction of 3-azidoquinolones
with alkynes using CuTC as the catalyst without the need for
exogenous ligand and/or additives. The disclosed method offers
a quick and reliable route for the synthesis of various unknown
3-triazolyl-2(1H)-quinolone derivatives (3). The procedure works
well with a wide variety of alkynes including aromatic, heteroaro-
matic and aliphatic, as well as challenging functionalized sub-
strates. All the products were rapidly isolated by simple filtration
from the reaction mixture with no further purification. Studies are
currently under way for the synthesis of a library of substituted
3-triazolyl-2(1H)-quinolones related to 6BrCaQ and will be
reported in due course.
[5] a) M. Meldal, W. T. Tornøe, Chem. Rev. 2008, 108, 2952; b) S. Debola,
S. A. Nepogodiev, R. A. Field, Org. Biomol. Chem. 2007, 5, 1006;
c) F. Amblard, J. H. Cho, R. F. Schinazi, Chem. Rev. 2009, 109, 4207;
d) D. S. Pedersen, A. Abell, Eur. J. Org. Chem. 2011, 13, 2399.
[6] a) H. C. Kolb, K. B. Sharpless, Drug Discov. Today 2003, 8, 1128; b) B. L.
Wilkinson, L. F. Bornaghi, T. A. Houston, S.-A. Poulsen In Drug Design
Research Perspectives (Ed.: S. P. Kaplan), Nova Science Publishers,
Hauppauge, NY, 2007, 57.
[7] a) C. J. Hawker, V. V. Fokin, M. G. Finn, K. B. Sharpless, Aust. J. Chem.
2007, 60, 381; b) R. A. Evans, Aust. J. Chem. 2007, 60, 384.
[8] a) J.-F. Lutz, Z. Zarafshani, Adv. Drug Delivery Rev. 2008, 60, 958;
b) W. L. Dong, W. G. Zhao, Y. X. Li, Z. X. Liu, Z. M. Li, Chin. J. Org. Chem.
2006, 26, 2717; c) S. S. Gupta, J. Kuzelka, P. Singh, W. G. Lewis,
Appl. Organometal. Chem. 2013, 27, 155–158
Copyright © 2013 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

S. Messaoudi et al.
M. Manchester, M. G. Finn, Bioconjugate Chem. 2005, 16, 1572;
d) A. J. Dirks, S. S. Van Berkel, N. S. Hatzakis, J. A. Opsteen, F. L. van
Delft, J. J. L. M. Cornelissen, A. E. Rowan, J. C. M. van Hest, F. P. J. T.
Rutjes, R. J. M. Nolte, Chem. Commun. 2005, 4172; e) A. J. Link,
D. A. Tirrell, J. Am. Chem. Soc. 2003, 125, 11164; f) A. E. Speers, B. F.
Cravatt, Chem. Biol. 2004, 11, 535; g) K. E. Beatty, F. Xie, Q. Wang,
D. Tirrell, J. Am. Chem. Soc. 2005, 127, 14150; h) S. A. Sieber,
S. Niessen, H. S. Hoover, B. F. Cravatt, Nat. Chem. Biol. 2006, 2, 274.
[9] a) S. Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Alami, Expert Opin. Ther.
Pat. 2011, 21, 1501; b) S. Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Alami,
Anti-Cancer Agents Med. Chem. 2008, 8, 761; c) Y. L. Janin, Drug
Discov. Today, 2010, 15, 342.
[10] a) G. Le Bras, C. Radanyi, J.-F. Peyrat, J.-D. Brion, M. Alami, V. Marsaud,
B. Stella, J.-M. Renoir, J. Med. Chem., 2007, 50, 6189; b) C. Radanyi,
G. Le Bras, S. Messaoudi, C. Bouclier, J.-F. Peyrat, J.-D. Brion,
V. Marsaud, J.-M. Renoir, M. Alami, Bioorg. Med. Chem. Lett. 2008,
18, 2495; c) D. Audisio, S. Messaoudi, I. Ijjaali, E. Dubus, F. Petitet,
J.-F. Peyrat, J.-D. Brion, M. Alami, Eur. J. Med. Chem. 2010, 45, 2000.
[11] a) C. Radanyi, G. Le Bras, V. Marsaud, J.-F. Peyrat, S. Messaoudi, M. G.
Catelli, J.-D. Brion, M. Alami, J.-M. Renoir, Cancer Lett. 2009, 274, 88;
b) C. Radanyi, G. Le Bras, C. Bouclier, S. Messaoudi, J.-F. Peyrat,
J.-D. Brion, M. Alami, J.-M. Renoir, Biochem. Biophys. Res. Commun.
2009, 379, 514.
[12] D. Audisio, S. Messaoudi, L. Ceigeikowski, J.-F. Peyrat, J.-D. Brion,
D. Methy-Gonnot, C. Radanyi, J.-M. Renoir, M. Alami, ChemMedChem
2011, 6, 804.
[13] a) J. M. Holub, K. Kirshenbaum, Chem. Soc. Rev. 2010, 39, 1325;
b) Y. L. Angell, K. Burgess, Chem. Soc. Rev. 2007, 36, 1674.
[14] a) H. C. Kolb, K. B. Sharpless. Drug Discov. Today 2003, 8, 1128;
b) G. C. Tron, T. Pirali, R. A. Billington, P. L. Canonico, G. Sorba, A. A.
Genazzani, Med. Res. Rev. 2008, 28, 278.
[15] S. Messaoudi, J.-D. Brion, M. Alami, Adv. Synth. Catal. 2010, 352, 1677.
[16] a) D. Audisio, S. Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Alami, Tetrahedron
Lett. 2007, 48, 6928; b) S. Messaoudi, D. Audisio, J.-D. Brion, M. Alami,
Tetrahedron 2007, 63, 10202; c) D. Audisio, S. Messaoudi, J.-F. Peyrat,
J.-D. Brion, M. Alami, J. Org. Chem. 2011, 76, 4995; d) D. Audisio,
S. Messaoudi, J.-D. Brion, M. Alami, Eur. J. Org. Chem. 2010, 1046; e)
M. A. Soussi, D. Audisio, S. Messaoudi, O. Provot, J.-B. Brion, M. Alami,
Eur. J. Org. Chem. 2011, 5077; f) S. Sahnoun, S. Messaoudi, J.-F. Peyrat,
J. D. Brion, M. Alami, Tetrahedron Lett. 2008, 49, 7279; g) S. Sahnoun,
S. Messaoudi, J. D. Brion, M. Alami, Org. Biomol. Chem. 2009, 7,
4271; h) S. Sahnoun, S. Messaoudi, J. D. Brion, M. Alami, Eur. J. Org. Chem.
2010, 6097; i) S. Sahnoun, S. Messaoudi, J. D. Brion, M. Alami, ChemCatChem.
2011, 3, 893; j) S. Messaoudi, J.-D. Brion, M. Alami, Eur. J. Org. Chem.
2010, 6495.
[17] G. D. Allred, L. S. Liebeskind, J. Am. Chem. Soc. 1996, 118, 2748.
wileyonlinelibrary.com/journal/aoc
Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 155–158