Efficient approach to 4-sulfonamidoquinolines via copper(I)-catalyzed cascade reaction of sulfonyl azides with alkynyl imines

Article abstract of DOI:10.1021/ol400219n

A novel and efficient approach to 4-sulfonamidoquinolines via copper-catalyzed cascade reaction of sulfonyl azides with alkynyl imines has been developed in which a 1,3-dipole cycloaddition/ketenimine formation/6π-electrocyclization/[1,3]-H shift cascade

Full text of DOI:10.1021/ol400219n

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1480–1483
Efficient Approach to
4‑Sulfonamidoquinolines via
Copper(I)-Catalyzed Cascade Reaction
of Sulfonyl Azides with Alkynyl Imines‡
Guolin Cheng and Xiuling Cui*
Engineering Research Center of Molecular Medicine, Ministry of Education, Key
Laboratory of Xiamen Marine and Gene Drugs, Institutes of Molecular Medicine and
School of Biomedical Sciences, Huaqiao University, Xiamen 361021, P. R. China
cuixl@hqu.edu.cn
Received January 25, 2013
ABSTRACT
A novel and efficient approach to 4-sulfonamidoquinolines via copper-catalyzed cascade reaction of sulfonyl azides with alkynyl imines has been
developed in which a 1,3-dipole cycloaddition/ketenimine formation/6π-electrocyclization/[1,3]-H shift cascade reaction was involved. Various
4-sulfonamidoquinolines were afforded in up to 84% yield for 19 examples. This synthetic strategy features with atom economy, concise steps,
easy operation, and mild reaction conditions.
The structural motif of 4-aminoquinolines exists widely
in both pharmaceutical molecules and natural products,
which are exemplified by chloroquine (A), used as as an
antimalaria agent,1 and compound B, a natural product
with antioxidant activity (Figure 1).2 Consequently, devel-
oping mild and efficient access to polyfunctional 4-amino-
quinolines is of great significance.
Conventionally, 4-aminoquinolines were synthesized by
SNAr reaction of 4-haloquinolines and primary amines.
Elevated reaction temperature and tedious purification
steps were often required in this procedure.3 Palladium-
Figure 1. Two examples illustrating the importance of com-
pounds with the 4-aminoquinoline moiety.
catalyzed BuchwaldÀHartwig amination reaction was
proved to be a convenient alternative approach to
4-aminoquinolines from 4-haloquinolines in the past decade.4
However, some 4-haloquinolines and their derivatives are
not commercially available.
(3) (a) Riegel, B.; Lappin, G. R. J. Am. Chem. Soc. 1946, 68, 1229.
(b) Madrid, P. B.; Wilson, N. T.; DeRisi, J. L.; Guy, R. K. J. Comb. Chem.
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Basilico, N.; Prosperi, D.; Monti, D. Eur. J. Org. Chem. 2007, 6118.
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Franceschini, S.; Savini, L.; Campiani, G.; Fattorusso, C.; Butini, S. Tetra-
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‡ Dedicated to Professor Irina Petrovna Beletskaya for her contribution to
metal-catalyzed reactions.
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V. R.; Lee, H. Eur. J. Pharmacol. 2009, 625, 220. (c) Patel, J. J.; Thacker, D.;
Tan, J. C.; Pleeter, P.; Checkley, L.; Gonzales, J. M.; Deng, B.; Roepe, P. D.;
Cooper, R. A.; Ferdig, M. T. Mol. Microbiol. 2010, 78, 770. (d) Krafts, K.;
Hempelmann, E.; Skorska-Stania, A. Parasitol. Res. 2012, 111, 1.
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r
10.1021/ol400219n
Published on Web 03/22/2013
2013 American Chemical Society

Scheme 1. Synthetic Route to 4-Sulfonamidoquinolines
Cascade reactions, which allow multiple transforma-
tions in a one-pot process, were recognized as an envi-
ronmentally friendly and atom-economical strategy for
building molecular complexity.5 Several examples in con-
structing 4-aminoquinolines using this strategy have
emerged. For example, the research groups of Schmidt,6
Tverdomed,7 Strekowski,8 Luo,9 and Rossi10 have reported
pioneering work on synthesis of 4-aminoquinolines and
their derivatives from pyrazolium-3-carboxylates, 2-amino-
benzonitriles, 2-(trifluoromethyl)anilines, o-oxazoline-
substituted anilines, and β-(2-aminoaryl) R,β-ynones, re-
spectively. Despite these notable advances in this area,
some challenges still exist, such as the difficulty to access
substrate, harsh reaction conditions, and inferior tolerance
of functional groups. It continues to be an area of intense
interest to develop new protocols to build such a valuable
molecule from cheap and readily accessible starting mate-
rials by concise steps under milder reaction conditions.
A propargylÀallenyl isomerization/6π-electrocycliza-
tion cascade process has become an important synthetic
method to access 4-substituted quinolines from alkynyl imines
(Scheme 1, eq 1).11 On the other hand, a copper-catalyzed 1,3-
dipole cycloaddition/ringÀchain isomerization/ketenimine
formation cascade process was well developed by Chang,
Wang, and other groups (Scheme 1, eq 2).12 Considering
the advancement of alkynyl imine chemistry and keten-
imine chemistry, we envisioned that 4-sulfonamidoquino-
lines 3 could be synthesized via a cascade reaction of N-aryl
alkynyl imines 1 with sulfonyl azides 2. Moreover, the
sulfonamide skeleton is often used in the design of
pharmaceuticals.13 Over 30 drugs containing N-arylsulfon-
amides are in clinical use as antibacterials,14 non-nucleo-
tide reverse transcriptase inhibitors,15 antitumor agents,16
and HIV-1 protease inhibitors.17 Herein, we disclose a
highly practical procedure to build 4-sulfonamidoquino-
lines in one step, in which a novel copper-catalyzed
1,3-dipole cycloaddition/ketenimine formation/6π-
electrocyclization/[1,3]-H shift cascade reaction was
involved (Scheme 1, eq 3). The reaction features mild
reaction conditions and a general substrate scope.
(11) (a) Sangu, K.; Fuchibe, K.; Akiyama, T. Org. Lett. 2004, 6, 353.
(b) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 4592. (c)
Gao, G.-L.; Niu, Y.-N.; Yan, Z.-Y.; Wang, H.-L.; Wang, G.-W.;
Shaukat, A.; Liang, Y.-M. J. Org. Chem. 2010, 75, 1305. (d) Li, S.;
Yuan, Y.; Zhu, J.; Xie, H.; Chen, Z.; Wu, Y. Adv. Synth. Catal. 2010,
352, 1582. (e) Zhou, H.; Liu, L.; Xu, S. J. Org. Chem. 2012, 77, 9418.
(12) (a) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2008, 47, 2836.
(b) Yoo, E. J.; Chang, S. Org. Lett. 2008, 10, 1163. (c) Yoo, E. J.; Chang,
S. Curr. Org. Chem. 2009, 13, 1766. (d) Lu, P.; Wang, Y. G. Synlett 2010,
165. (e) Kim, S. H.; Park, S. H.; Choi, J. H.; Chang, S. Chem.;Asian J.
2011, 6, 2618.
(4) (a) Burton, G.; Cao, P.; Li, G.; Rivero, R. Org. Lett. 2003, 5, 4373.
(b) Wolf, C.; Lerebours, R. J. Org. Chem. 2003, 68, 7077. (c) Jonckers,
T. H.; Maes, B. U. W.; Lemiere, G. L. F.; Rombouts, G.; Pieters, L.;
Haemers, A.; Dommisse, R. A. Synlett 2003, 615. (d) Jaime-Figueroa, S.;
Liu, Y. Z.; Muchowski, J. M.; Putman, D. G. Tetrahedron Lett. 1998, 39,
1313. (e) Margolis, B. J.; Long, K. A.; Laird, D. L. T.; Ruble, J. C.;
Pulley, S. R. J. Org. Chem. 2007, 72, 2232. (f) Ronco, C.; Jean, L.;
Outaabout, H.; Renard, P.-Y. Eur. J. Org. Chem. 2011, 302.
(5) (a) Wasilke, J. C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem.
Rev. 2005, 105, 1001. (b) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev.
2009, 38, 2993. (c) Climent, M. J.; Corma, A.; Iborra, S. Chem. Rev.
2011, 111, 1072.
(13) (a) Casini, A.; Scozzafava, A.; Supuran, C. T. Expert Opin. Ther.
Pat. 2002, 12, 1307. (b) Scozzafava, A.; Owa, T.; Mastrolorenzo, A.;
Supuran, C. T. Curr. Med. Chem. 2003, 10, 925.
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Papai, I.; Schmidt, A. Eur. J. Org. Chem. 2010, 4296. (b) Schmidt, A.;
Muenster, N.; Dreger, A. Angew. Chem., Int. Ed. 2010, 49, 2790.
(7) Duda, B.; Tverdomed, S. N.; Ionin, B. I.; Roeschenthaler, G.-V.
Eur. J. Org. Chem. 2012, 3684.
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Tetrahedron 2004, 60, 11391.
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Johnson, P. D.; Skulnick, H. I.; Dolak, L. A.; Seest, E. P.; Tomich, P. K.;
Bohanan, M. J.; Horng, M. M.; Lynn, J. C.; Chong, K. T.; Hinshaw,
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J. Med. Chem. 1998, 41, 3467.
Org. Lett., Vol. 15, No. 7, 2013
1481

Table 1. Screening Reaction Parameters for the Cascade
Reaction of C,N-Diphenyl Alkynyl Imine and Tosyl Azide
Catalyzed by Copper(I)
Scheme 2. Copper(I)-Catalyzed Cascade Synthesis of
4-Sulfonamidoquinolines from Alkynyl Imines and Sufonyl
Azides
entry
Cu(I)
solvent
base
yielda (%)
1
CuI (0.05)
CuI (0.05)
CuI (0.05)
CuI (0.05)
CuI (0.05)
CuI (0.05)
CuI (0.05)
CuI (0.05)
CuI (0.05)
CuI (0.05)
CuI (0.05)
CuI (0.05)
CuI (0.05)
CuI (0.05)
CuI (0.01)
CuBr (0.05)
CuCl (0.05)
1,4-dioxane
THF
Et3N
30
25
29
35
38
<5
<5
<5
78
75
49
15
77
78
67
66
65
2
Et3N
3
toluene
chloroform
DCM
Et3N
4
Et3N
5
Et3N
6
DMF
Et3N
7
MeCN
DCM
Et3N
8
pyridine
K2CO3
KHCO3
Na2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
DCM
10
11
12
13b
14c
15
16
17
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
a Isolated yield based on C,N-diphenyl alkynyl imine 1a. b At 40 °C.
c 1.5 equiv of 2a was used. THF = tetrahydrofuran.
To the best of our knowledge, this is the first report
regarding the successful synthesis of 4-substituted quino-
lines bearing a sulfonamide group in one step at room
temperature.
The reaction of C,N-diphenyl alkynyl imine 1a
(0.5 mmol) with tosyl azide 2a was initially chosen as
a model reaction in the presence of CuI (5 mol %) and
1.5 equiv of Et3N in 1,4-dioxane (2 mL) under N2 atmo-
sphere at room temperature. The reaction was monitored
by TLC. The starting material 1a was consumed within
15 min, and a pale product 3a immediately precipitated
and was isolated in 30% yield (Table 1, entry 1). The
structure of 3a was identified to be 4-methyl-N-(2-phenyl-
4-quinolinyl)benzenesulfonamide by NMR spectra. In-
spired by this result, the various reaction parameters were
valued, including solvents, bases, temperature, and copper-
(I) salts. The results are listed in Table 1. The solvents were
tested first (entries 1À5). Dichloromethane (DCM) gave the
highest yield (38%, entry 5). Polar solvents, such as N,N-
dimethylformamide (DMF) (entry 6) and MeCN (entry 7),
made the reaction more complicated, and only a trace
amount of product was detected. Pyridine instead of Et3N
as base led to a trace amount of product (entry 8). Interest-
ingly, the yields increased obviously when inorganic bases,
such as K2CO3, KHCO3, and Na2CO3, except Cs2CO3,
were used instead of Et3N (entries 9À12). K2CO3 could
give 78% yield (entry 9). The reaction was not obviously
improved by elevating the reaction temperature (entry 13
vsentry 9) and the loading of 2a(entry 14vsentry 9). When
the catalyst loading was reduced to 1 mol % (entry 15)
or the other copper salts, such as CuBr and CuCl, were
used as a catalyst (entries 16 and 17), the yield decreased in
some extent. Finally, the optimized reaction conditions
were eventually identified as 1a (0.5 mmol), 1.1 equiv of 2a,
5 mol % of CuI, and 1.5 equiv of K2CO3 in 2 mL of DCM
under N2 atmosphere at room temperature.
With the optimized reaction conditions in hand, the
generality and scope of the substrates were examined as
shown in Scheme 2. First, we investigated the various
sulfonyl azides 2aÀd. Electron-rich sulfonyl azides favored
this transformation. Tosyl azide 2a gave the best result,
78% yield. Then the effect of different substitutes on the
N-aromatic moiety was studied. The evident electronic and
steric effects were observed. Electron-donating groups in
the para positions on the N-aryl ring gave higher yields
thanthose of electron-withdrawing groups (3eÀg vs3h, 3j).
The m-methyl substrate 1g gave 20:1 regioisomeric prod-
ucts in 65% yield. The major product was proved to be
4-methyl-N-(2-phenyl-5-methyl-4-quinolinyl)benzenesulfon-
amide 3j by NMR spectra. Only a trace amount of the
corresponding products (3k,l) were detected, probably due
to the substituents at the 8-position of the naphthyl ring,
1482
Org. Lett., Vol. 15, No. 7, 2013

2 catalyzed by copper gave the triazole intermediate a,
which isomerized to form the ketenimne intermediate b.12
The intramolecular 6π-electrocyclization occurred and
provided the intermediate c. The following [1,3]-H shift
process gave the final product 4-sulfonamidequinoline 3.
In summary, we have developed an efficient approach to
a variety of 4-sulfonamidoquinolines in one step, which
features a novel copper-catalyzed cascade reaction under
mild reaction conditions. N-Phenyl alkynyl imines suc-
cessfully underwent 1,3-dipole cycloaddition/ketenimine
formation/6π-electrocyclization/[1,3]-Hshift cascadereac-
tions with sulfonyl azides catalyzed by cheap copper salt at
room temperature. The desired products were provided in
moderate to good yields.
Scheme 3. Proposed Mechanistic Pathway
Acknowledgment. ThisworkwassupportedbytheNSF
of China (21202048), Program for Minjiang Scholar pro-
gram (10BS216), Science Research Item of Science and
Technology of Xiamen City (3502z201014), and Funda-
mental Research Funds of Huaqiao University.
which blocked the 6π-electrocyclization process. It is
worth noting that N-(1-naphthyl)alkynyl imine 1j could
proceed well and gave the desired product 3m in 82% yield
under the optimal conditions. In addition, the substituted
scope on imine carbon was also examined. Electron-rich
substituents on the imine carbon led to higher yields than
that of an electron-deficient substituents (3nÀq vs 3r). The
thienyl-substituted substrate 1p also could give the corre-
sponding product 3s in moderate yield (56%).
Supporting Information Available. Synthesis proce-
dure, characterization, and 1H NMR and 13C NMR
spectra of products 1aÀp and 3aÀj,mÀs. This material
is available free of charge via the Internet at http://pubs.
acs.org.
A possible reaction mechanism was proposed according
to the literature and the results obtained (Scheme 3).
First, the reaction of alkynyl imine 1 with sulfonyl azide
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
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