Electrophile-driven regioselective synthesis of functionalized quinolines

Article abstract of DOI:10.1021/ol2007154

Highly substituted 3-iodoquinolines bearing different alkyl and aryl moieties can be synthesized in moderate to excellent yields (up to 99%) by 6-endo-dig iodocyclization of 2-tosylaminophenylprop-1-yn-3-ols with molecular iodine (I₂) under mil

Full text of DOI:10.1021/ol2007154

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2598–2601
Electrophile-Driven Regioselective
Synthesis of Functionalized Quinolines
Shaukat Ali, Hai-Tao Zhu, Xiao-Feng Xia, Ke-Gong Ji, Yan-Fang Yang,
Xian-Rong Song, and Yong-Min Liang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, and State Key
Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese
Academy of Science, Lanzhou 730000, People’s Republic of China
liangym@lzu.edu.cn
Received March 16, 2011
ABSTRACT
Highly substituted 3-iodoquinolines bearing different alkyl and aryl moieties can be synthesized in moderate to excellent yields (up to 99%) by
6-endo-dig iodocyclization of 2-tosylaminophenylprop-1-yn-3-ols with molecular iodine (I2) under mild conditions. The cyclization is highly
regioselective and the resulting 3-iodoquinolines can be further functionalized by various coupling reactions.
Quinoline derivatives are a major class of heterocycles
which occur in various natural products, especially in alka-
loids. The quinoline skeleton is often used for the construction
of many synthetic compounds with diverse pharmacological
properties.1 In particular, halogen-containing quinolines are
of special interest because the halogen atom sometimes plays
an important role in the compound’s bioactivity, and such
compounds provide a further avenue for functionalization.2
As a result, a number of attempts have been made to prepare
and functionalize them since the late 1800s. The structural
core of quinoline can be synthesized by various conventional
methods.3À8 However, these classical syntheses often make
use of elevated temperatures and prolonged reaction times
and/or use of strong acids and bases, which cannot be applied
to sensitive substrates. There are also many new metal-
catalyzed protocols for preparing quinolines.9À12 Thus, a
metal free, mild, and environmentally benign protocol for
preparing quinolines from readily available and simple sub-
strates is still of high demand because of their extreme
significance. In recent years, the electrophilic cyclization of
heteroatom nucleophiles, such as oxygen, nitrogen, and
sulfur, with tethered alkynes has proven to be an effective
(9) For selected papers, see: (a) Berman, A. M.; Lewis, J. C.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 14926. (b) Horn, J.;
Marsden, S. P.; Nelson, A.; House, D.; Weingarten, G. G. Org. Lett. 2008,
10, 4117.
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Chem. 2006, 691, 5109. (b) Movassaghi, M.; Hill, M. D. J. Am. Chem.
Soc. 2006, 128, 4592.
(11) Liu, X.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2008, 47, 3805.
(12) For selected papers, see: (a) Zhang, Z.; Tan, J.; Wang, Z. Org.
Lett. 2008, 10, 173. (b) Sakai, N.; Annaka, K.; Fujita, A.; Sato, A.;
Konakahara, T. J. Org. Chem. 2008, 73, 4160. (c) Arcadi, A.; Aschi, M.;
Marinelli, F.; Verdecchia, M. Tetrahedron. 2008, 64, 5354. (d) Li, L.;
Jones, W. D. J. Am. Chem. Soc. 2007, 129, 10707. (e) Gabriele, B.;
Mancuso, R.; Salerno, G.; Ruffolo, G.; Plastina, P. J. Org. Chem. 2007,
72, 6873. (f) Sakai, N.; Annaka, K.; Konakahara, T. J. Org. Chem. 2006,
71, 3653. (g) Godet, T.; Belmont, P. Synlett 2008, 2513.
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S.-H.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2007, 9, 397. (b) Xie, Y.-X.;
Liu, X.-Y.; Wu, L.-Y.; Han, Y.; Zhao, L.-B.; Fan, M.-J.; Liang, Y.-M.
Eur. J. Org. Chem. 2008, 1013. (c) Wen, S.-G.; Liu, W.-M.; Liang, Y.-M.
J. Org. Chem. 2008, 73, 4342. (d) Xie, Y.-X.; Yan, Z.-Y.; Qian, B.; Deng,
W.-Y.; Wu, L.-Y.; Liu, X.-Y.; Liang, Y.-M. Chem. Commun. 2009, 5451.
(e) Xie, Y.-X.; Yan, Z.-Y.; Wang, D.-Z.; Wu, L.-Y.; Qian, B.; Liu, X.-Y.;
Liang, Y.-M. Eur. J. Org. Chem. 2009, 2283. (f) Ji, K.-G.; Zhu, H.-T.;
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r
10.1021/ol2007154
Published on Web 04/14/2011
2011 American Chemical Society

method for the synthesis of heterocyclic compounds.13À31
We13 and others have reported that electrophilic cyclization14
of alkynes can be a very powerful tool for the preparation of a
wide variety of important heterocyclic compounds due to the
mild, efficient, and clean reactions. Many important hetero-
cycles, such as benzo[b]thiophenes,15 benzofurans,16 2,3-dihy-
dropyrroles and pyrroles,17 furans,13b,18 dihydropyrans,13f,19
indoles,20 isochromenes,21 isocoumarins and R-pyrones,22
isoquinolines and quinolines,23 isoxazoles24 and oxazoles,25
furanones,26 furopyridines,27 spiro[4,5]trienones,28 coume-
stans and coumestrols,29 naphthols,30 and naphthalenes,31
have been reported based on this strategy. Also very recently,
Wai’s group reported the synthesis of N-tosylated indoles
using 2-tosylaminophenylprop-1-yn-3-ols as starting materi-
als in the prescence of gold catalyst.32 We envisioned that the
treatment of 2-tosylaminophenylprop-1-yn-3-ol (1a) with
molecular iodine (I2) would lead to iodocyclization in a
5-exo-dig manner resulting in an indole derivative. To test
the viability of the above hypothesis we treated 1a with I2, but
unexpectedly the 1H and 13C NMR data revealed quinoline
derivative 2a (Scheme 1). Herein, we report a general and
highly regioselective protocol for the synthesis of substituted
quinolines by 6- endo-dig iodocyclization of 2-tosylamino-
phenylprop-1-yn-3-ols. In 2005, although Flynn developed
the synthesis of 3-iodoquinolinium salts by a related
process,33 the lengthy preparation of their starting materials,
the low substrate scope, and the separation of quinolinium
salts make it less attractive synthetically. We were extremely
pleased to see that our 2-tosylaminophenylprop-1-yn-3-ols
reacted smoothly to gave 3-iodoquinolines in a single step
with no quinolinium salts.
Scheme 1. Design of an Electrophile-Driven Cascade Cycliza-
tion
delight, the quinoline derivative 2a was obtained in 38%
yield after 2 h. Increasing the amountof iodine to 2.0 equiv,
the yield slightily increased to 41%. Further increasing the
amount of iodine resulted in a decrease of yield. The
influence of different acids and increase of reaction tem-
perature in nitromethane was studied but no useful results
were obtained. We then discovered that the best result can
be obtained by carrying out the reaction in methanol at 60
°C. Thus, changing the solvent from polar aprotic to polar
protic the yield dramatically increased to 93%. The protic
nature of the solvent is most probably involved in the easy
removal of hydroxyl group to give intermediate D (see the
mechanism, Scheme 2). Solvents such as dichloromethane,
acetonitrile, and tetrahydrofuran were found to be less
effective, whereas dimethylformamide and 1,4-dioxane were
found to be ineffective (see the Supporting Information).
To investigate the scope of the cascade iodocyclization a
variety of differently aliphatic and aromatic substituted
2-tosylaminophenylprop-1-yn-3-ols were subjected to the
To explore suitable reaction conditions for this useful
transformation, we started by using 0.2 mmol of 1a and 1.5
equiv of I2 in nitrommethane at room temperature; to our
Table 1. Cascade 6-Endo-Dig Iodocyclization of 2-Tosylaminophenylprop-1-yn-3-ols (eq 1)a
alcohol
entry
no.
R1
R2
R3
time (h)
quinoline
isolated yield (%)
1
2
1a
1b
1c
1d
1e
1f
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
6
6
2a
2b
2c
2d
2e
2f
93
94
96
88
81
77
84
66
71
60
88
76
62
74
99
54
40
H
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
m-MeC6H4
m-MeOC6H4
o-MeC6H4
o-ClC6H4
o,p-Cl2C6H3
Ph
3
H
6
4
H
6
5
H
6
6
H
6
7
1g
1h
1i
H
6
2g
2h
2i
8
H
12
12
12
12
12
12
6
9
H
10
11
12
13
14
15
16
17
1j
H
2j
1k
1l
5-Cl
5-Br
H
2k
2l
Ph
1m
1n
1o
1p
1q
n-propyl
Ph
2m
2n
2o
2p
2q
H
p-MeC6H4
p-BrC6H4
Me
H
Ph
6
H
Ph
12
12
H
Et
Ph
a All reactions were run with 0.2 mmol of the alcohol, 2 equiv of I2 in 2.0 mL of CH3OH at 60 °C, followed by addition of 8.0 mL of saturated aqueous
Na2S2O3 to remove the excess I2.
Org. Lett., Vol. 13, No. 10, 2011
2599

standard reaction conditions. The corresponding quinoline
products were obtained in moderate to excellent yields as
shown in Table 1. The structure of product 2b was also
confirmed by X-ray crystal structure analysis (Figure 1). As
evident, R2 and R3 can be alkyl or aryl. In the case of R2 and
R3 as phenyl groups, the reaction can tolerate both electron-
donating and electron-withdrawing groups at different
positions. The reaction is particularly good in the case of
a group with an unshared pair of electrons on the
Scheme 3. Palladium-Catalyzed Reactions of 3-Iodo-2,4-di-
phenylquinoline (2a)
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Figure 1. X-ray structure of 2b.
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para position of R2 (Table 1, entry 15). This result indicates
that electron donation is needed to stabilize the cyclic
intermediate D (see the mechanism in Scheme 2). The same
fact is also supported by the results that moderate yields are
obtained in the case of R2 as alkyl group (Table 1, entries
16 and 17).
The mechanism of this iodocyclization involves anti
attack of the electrophile and the nitrogen of the tosylated
amino group on the alkyne moiety of 1 to produce an
intermediate B, which undergoes a proton removal by the
iodide present in the reaction mixture to give compound C.
The intermediate compound Ccanbeisolatedifthereaction
is carried out in an aprotic solvent such as nitromethane.
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Scheme 2. Mechanistic Considerations
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2600
Org. Lett., Vol. 13, No. 10, 2011

cation D. Finally, D gains full aromaticity by eliminating a
tosyl group to form quinoline derivative 2 (Scheme 2).
Inconclusion, we have discovered anefficient and highly
regioselective protocol for preparing quinolines from read-
ily available and simple starting materials. The reaction is
metal-free and can produce substituted 3-iodoquinolines
in a single step in moderate to excellent yields. The result-
ing 3-iodoquinolines can befurther functionalized by using
known organopalladium chemistry, such as Sonogashira34
and Suzuki35 cross-couplings and the Heck reaction36
(Scheme 3). Further exploration of the reaction scope
and mechanism is underway.
Acknowledgment. We thank the National Science Fou-
ndation (NSF-21072080) for financial support. We also
acknowledge the National Basic Research Program of
China (973 Program), 2010CB833203.
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Supporting Information Available. Detailed experimen-
tal procedures, copies of 1H NMR and 13C NMR spectra
of all compounds, and X-ray data of 2b in CIF format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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