Sulfuric acid promoted condensation cyclization of 2-(2-(trimethylsilyl) ethynyl)anilines with arylaldehydes in alcoholic solvents: an efficient one-pot synthesis of 4-alkoxy-2-arylquinolines

Article abstract of DOI:10.1016/j.tetlet.2009.02.206

An efficient method for the synthesis of 4-alkoxy-2-arylquinolines has been developed. The reaction proceeds smoothly by heating a mixture of easily accessible 2-(2-(trimethylsilyl) ethynyl)anilines and arylaldehydes in alcoholic solvents in the presence of sulfuric acid.

Full text of DOI:10.1016/j.tetlet.2009.02.206

Tetrahedron Letters 50 (2009) 2261–2265
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Tetrahedron Letters
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Sulfuric acid promoted condensation cyclization of 2-(2-(trimethylsilyl)
ethynyl)anilines with arylaldehydes in alcoholic solvents: an efficient
one-pot synthesis of 4-alkoxy-2-arylquinolines
*
Yong Wang, Changlan Peng, Lanying Liu, Jiaji Zhao, Li Su, Qiang Zhu
Institute of Chemical Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the synthesis of 4-alkoxy-2-arylquinolines has been developed. The reaction pro-
ceeds smoothly by heating a mixture of easily accessible 2-(2-(trimethylsilyl) ethynyl)anilines and aryl-
aldehydes in alcoholic solvents in the presence of sulfuric acid.
Received 18 December 2008
Revised 24 January 2009
Accepted 27 February 2009
Available online 4 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Quinoline derivatives are found to possess a broad spectrum of
biological activities such as antimalarial,1 antibacterial,2 anti-
fungal,3 and anticancer.4 Consequently, many classical methods
such as Skraup, Doebner–von Miller, Friedländer, and Combes syn-
theses have been developed for the preparation of quinoline deriv-
atives.5 However, many of these methods suffer from the need of
high temperatures, prolonged reaction times, and drastic reaction
conditions and also the unsatisfied yields. To overcome the afore-
mentioned drawbacks, more efficient methods such as modified
Friedlander strategies,6 hetero-Diels–Alder reaction of imines,7
and transition-metal catalyzed reactions8 have been developed.
Owing to the fascinating biological properties of quinolines, new
catalytic systems are being continuously explored to improve effi-
ciencies and cost effectiveness.9
In the course of studying a 3-component Passerini reaction
using o-(trimethylsilylethynyl) isocyanobenzene 4, benzaldehyde
2a, and acetic acid in methanol,13 no reaction product was
Table 1
Acid catalyzed cyclization of 2-(2-(trimethylsilyl)ethynyl)aniline 1a with benzalde-
hyde 2a in methanol under various conditionsa
TMS
OMe
acid, MeOH, reflux
CHO
+
NH2
1a
N
2a
3a
4-Alkoxy-2-arylquinoline derivatives have important biological
activities,10 such as antiplatelet.11 But only a limited number of
methods are available in the literature and most of them involve
multiple steps or toxic reagents.12 Herein we report an efficient
method for the synthesis of 4-alkoxy-2-arylquinolines from easily
accessible 2-(2-(trimethylsilyl)ethynyl)anilines 1 and arylalde-
hydes 2 in alcohols promoted by sulfuric acid (Scheme 1).
Entry
Acid (equiv)
Ratio (1a/2a)
Time (h)
3a Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
TMSCl (1.0)
TMSCl (1.5)
TFA (1.0)
3
3
3
3
3
3
3
3
3
1
2
3
4
5
3
3
3
3
3
3
17
17
17
17
17
17
17
17
17
17
17
17
17
17
17
4
42
50
24
40
46
34
56
Trace
24
36
41
65
60
59
70
38
40
69
67
52
PTSA (1.0)
BF3ÁOEt (1.5)
Concd HCl (1.0)
CF3SO3H (1.0)
Concd H2SO4 (0.1)
Concd H2SO4 (0.3)
Concd H2SO4 (0.5)
Concd H2SO4 (0.5)
Concd H2SO4 (0.5)
Concd H2SO4 (0.5)
Concd H2SO4 (0.5)
Concd H2SO4 (0.75)
Concd H2SO4 (0.75)
Concd H2SO4 (0.75)
Concd H2SO4 (1.0)
Concd H2SO4 (1.5)
Concd H2SO4 (2.0)
H2SO4 (0.75 equiv.),
R2OH, reflux, 17 hr
TMS
OR2
N
+
R1
R1
ArCHO
NH2
Ar
7
2
1
3
17
17
17
Scheme 1. 4-Alkoxy-2-arylquinolines from 2-(2-(trimethylsilyl)ethynyl)anilines 1
and arylaldehydes 2.
a
Reaction conditions: 2-(2-(trimethylsilyl)ethynyl)aniline (0.5 mmol) 1a, benz-
aldehyde 2a, and acid in 10 mL of dry methanol, reflux.
* Corresponding author. Tel.: +86 020 32290511; fax: +86 020 32290606.
E-mail address: zhu_qiang@gibh.ac.cn (Q. Zhu).
b
Yield of isolated product.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.206

2262
Y. Wang et al. / Tetrahedron Letters 50 (2009) 2261–2265
O
O
N
TMS
OMe
TMSCl, MeOH, reflux
40%
CHO
O
+
+
NC
OH
N
OH
NOT 5
4
2a
3a
Scheme 2. Unexpected 4-methoxy-2-phenylquinoline 3a from an isocyano based multi-component reaction.
Table 2
Sulfuric acid catalyzed cyclization of 2-(2-(trimethylsilyl)ethynyl)anilines 1 with aldehydes 2 in alcoholsa
H2SO4 (0.75 equiv.),
R2OH, reflux, 17 hr
TMS
OR2
N
+
R1
R1
ArCHO
NH2
Ar
2
1
3
Entry
R1
R2
Ar
Product
Yieldb (%)
OMe
1
H
Me
4-MeC6H4
65
N
3b
1a
2b
OMe
N
2
3
4
5
6
4-MeOC6H4
68
81
68
31
78
OMe
3c
2c
OMe
N
4-HOC6H4
OH
OH
3d
2d
OMe
N
3-HOC6H4
3e
2e
OMe
2-HOC6H5
N
HO
3f
2f
OMe
N
4-ClC6H4
Cl
3g
2g

Y. Wang et al. / Tetrahedron Letters 50 (2009) 2261–2265
2263
Table 2 (continued)
Entry
R1
R2
Ar
Product
Yieldb (%)
OMe
N
7
3-ClC6H4
75
Cl
3h
2h
OMe
N
Cl
8
9
2-ClC6H4
10
61
49
3i
2i
OMe
N
4-BrC6H4
Br
3j
2j
OMe
N
10
4-MeO2CC6H4
CO2Me
3k
2k
OMe
N
11
12
13
4-NCC6H4
16
20
0
CN
3l
2l
OMe
N
4-(HO)2BC6H4
B(OH)2
3m
2m
OMe
N
4-NO2C6H4
NO2
3n
2n
OMe
N
14
15
2-Furanyl
49
53
O
S
3o
3p
2o
OMe
N
2-Thiophenyl
2p
(continued on next page)

2264
Y. Wang et al. / Tetrahedron Letters 50 (2009) 2261–2265
Table 2 (continued)
Entry
R1
R2
Ar
Product
Yieldb (%)
OMe
N
16
4-Me
2a
57
3q
1b
OMe
Cl
17
18
4-Cl
67
65
N
3r
1c
O
N
1a
Et
3s
3t
O
N
19
i-Pr
58
a
Reaction conditions: 2-(2-(trimethylsilyl)ethynyl)anilines 1 (0.5 mmol), aldehydes 2 (1.5 mmol), and sulfuric acid (37 mg, 0.375 mmol) in 10 mL of dry alcohol, reflux for
17 h.
observed even under reflux overnight (Scheme 2). A new and clean
or halogens gave moderate to good yields (Table 2, entries 1–9),
while electron-deficient aldehydes provided much lower yields
(Table 2, entries 10–13). No desired products were observed when
strong electron-deficient 4-nitrobenzaldehyde 2n and 2-pyridine-
carboxaldehyde (result not shown) were used as substrates. The
major by-products in these cases were corresponding methoxyace-
tals. Stereo-hindered substrates were also unfavorable to the reac-
tion (Table 2, entries 5 and 8). Electron-rich heteroaromatic
aldehydes were suitable substrates for this reaction (Table 2, en-
tries 14 and 15). There was no significant influence on yields when
substituted 2-(2-(trimethylsilyl)ethynyl)anilines 1b and 1c were
applied (Table 2, entries 16 and 17). Ethanol and 2-propanol were
also suitable solvents for this reaction and the corresponding
4-ethoxy and 4-isopropoxy quinoline derivatives were formed in
moderate yields (Table 2, entries 18 and 19). Aliphatic aldehyde
such as isobutyraldehyde failed even as much as 10 equiv of it
was used. We tried to extend this method for the synthesis of
3-substituted 4-alkoxy-2- arylquinolines by replacing the TMS
group in 1a with alkyl or phenyl substituents. Unfortunately, these
substrates failed to give the desired products.14
spot appeared when 1.0 equiv of TMSCl was added to the reaction
mixture and stirred for another 12 h under reflux. The product was
isolated in 40% yield and identified as 4-methoxy-2-phenylquino-
line 3a not 5 as we originally designed. It was obvious that the ter-
minal carbon of isocyanide was not present in the product, nor was
acetic acid. We proposed that the isocyanide was hydrolyzed to
formamide and further to amine first, and then imine was formed
with benzaldehyde. Instead of isocyanide 4, o-(trimethylsilylethy-
nyl)aniline 1a was used and the same product 3a was obtained in
similar yield.
The reaction conditions were optimized and the results are
summarized in Table 1. We first tested the effectiveness of differ-
ent acids with 3 equiv of benzaldehyde 2a in refluxing methanol
overnight. Among the acids screened, sulfuric acid was found to
be the most effective (Table 1, entries 1–7, 12) and 3a was obtained
in 65% yield. The amount of acid used was also crucial. By increas-
ing the equivalent of H2SO4 gradually from 0.1 to 2.0, the yield
reached its maximum of 70% at 0.75 equiv and then declined (Ta-
ble 1, entries 8, 9, 12, 15, 18–20). Altering the equivalent of benz-
aldehyde 2a and reaction time cannot push the yield further (Table
1, entries 10–14, 16, 17). So, the best conditions we optimized were
heating a mixture of 1a and 3 equiv of 2a in dry methanol in the
presence of 0.75 equiv of H2SO4 under reflux for 17 h.
It is reasonable to propose the reaction mechanism through
intermediate 2’-aminoacetophenone 6, since hydration of phenyl-
acetylene with electron-donating groups to phenylketone is well
documented.15 2’-Aminoacetophenone 6 was isolated in 83% yield
under the same reaction conditions without aldehyde (Scheme 3).
But the yield of 3a was much lower (49%) when using 6 instead of
The scope of the reaction was examined under the optimized
conditions (Table 2). Arylaldehydes with electron-donating groups
3.0 equiv. benzaldehyde,
H2SO4 (0.75 equiv.),
MeOH, reflux, 15 hr
TMS
OMe
O
H2SO4 (0.75 equiv.),
MeOH, reflux, 2 hr
NH2
N
83%
NH2
49%
1a
3a
6
Scheme 3. Stepwise synthesis of 4-methoxy-2-phenylquinoline 3a.

Y. Wang et al. / Tetrahedron Letters 50 (2009) 2261–2265
2265
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Scheme 4. Proposed mechanism for the acid promoted cyclization of
2-(2-(trimethylsilyl)ethynyl)aniline 1a with arylaldehydes 2 in methanol.
1a as substrate. This result suggests that the mechanism in Scheme
4 is more reasonable, which involves: (1) imine formation under
acid catalysis; (2) intramolecular attack of the alkyne to iminium
A; (3) the resulting vinyl cation B quenched by methanol; and fi-
nally (4) desilylation and air oxidation of 1,2-dihydroquinoline C
to give the final product.
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In summary, we have demonstrated a convenient method for
the construction of 4-alkoxy-2-arylquinolines from 2-(2-(trimeth-
ylsilyl)ethynyl)anilines 1 and arylaldehydes 2 in alcoholic solvents
catalyzed by sulfuric acid. This novel three-component, one-pot
reaction provides an efficient way for the synthesis of diversified
4-alkoxy-2-arylquinolines.
Acknowledgment
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Bioorg. Med. Chem. Lett. 2001, 11, 279–282.
This work was financially supported by Start-up Foundation for
New Investigators from Guangzhou Institutes of Biomedicine and
Health (GIBH).
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14. General procedure: To
a
solution of 2-(2-(trimethylsilyl)ethynyl)anilines
1
(0.5 mmol) and aldehydes
2
(1.5 mmol) in 10 mL of dry alcohols was
added sulfuric acid (37 mg, 0.375 mmol). The reaction mixture was stirred
at 65 °C for 17 h under air. After removal of most solvent under vacuum,
50 mL of EtOAc was added. The solution was washed successively with
saturated NaHCO3 twice and brine and then dried over Na2SO4.
The residue was purified by column chromatography on silica gel after
evaporation
of
solvent.
Compound
3c
4-methoxy-2-(4-methoxy-
phenyl)quinoline: 1H NMR (400 MHz, CDCl3) d: 8.17 (d, J = 8.4 Hz, 1H),
8.09 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.46
(t, J = 8.0 Hz, 1H), 7.14 (s, 1H), 7.04 (d, J = 8.8 Hz, 2H), 4.11 (s, 3H), 3.89 (s,
3H). 13C NMR (100 MHz, CDCl3) 162.7, 160.8, 158.4, 149.2, 132.9, 129.9,
129.0, 128.9, 125.1, 121.6, 120.2, 114.1, 97.5, 55.6, 55.4. MS (EI) 266
[M+H]+. HRMS calcd for C17H15O2N: 265.1103, found: 265.1097.
15. Hintermann, L.; Labonne, A. Synthesis 2007, 1121–1150.
4. (a) Dassonneville, L.; Lansiaux, A.; Wattelet, A.; Wattez, N.; Mahieu, C.; Van
Miert, S.; Pieters, L.; Bailly, C. Eur. J. Pharmacol. 2000, 409, 9; (b) Dassonneville,