Simple and practical synthesis of pyrano- and furano[3,2-c]-quinoline derivatives under non-Lewis acid catalysis

Article abstract of DOI:10.1016/j.cclet.2012.06.035

One-pot synthesis of substituted pyrano- and furano[3,2-c]quinoline derivatives from appropriately substituted anilines, substituted benzaldehydes and dienophiles via Povarov reaction catalyzed by HCl-ethanol were reported. Good to excellent yields with h

Full text of DOI:10.1016/j.cclet.2012.06.035

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1027–1030
www.elsevier.com/locate/cclet
Simple and practical synthesis of pyrano- and
furano[3,2-c]-quinoline derivatives under
non-Lewis acid catalysis
Rui Huan Liu a, Xin Yu b, Liang Hu a, Nie Fang Yu a,
*
a School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
b School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 51006, China
Received 10 May 2012
Available online 18 July 2012
Abstract
One-pot synthesis of substituted pyrano- and furano[3,2-c]quinoline derivatives from appropriately substituted anilines,
substituted benzaldehydes and dienophiles via Povarov reaction catalyzed by HCl–ethanol were reported. Good to excellent
yields with high diastereoselectivity were obtained in all entries tested.
# 2012 Nie Fang Yu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Non-Lewis acid; Catalysis; HCl–ethanol; Diastereoselectivity; Povarov reaction
The 1,2,3,4-tetrahydroquinoline skeleton is presented as an important subunit in many biological active alkaloids
including those that target NMDA receptor [1], CETP [2], G-protein coupled receptor [3] and HIV-1 RT [4]. Thus, the
construction of this skeleton has attracted a great deal of attentions. Diverse methods for the synthesis of
tetrahydroquinoline derivatives have been developed so far [5,6]. Among them, the aza-Diels–Alder reaction between
N-aryl imines and nucleophilic olefins was frequently applied for this synthesis purpose in the presence of suitable
catalyst. To date, a number of Lewis acids have been explored as catalysts for the preparation of these compounds,
including BF3ÁOEt2 [7], Yb(OTf)3 [8], VCl3 [9], and others [10–16]. However, the efficiency and/or readily
accessibility of the catalysts remain occasionally concerned issues in this aza-Diels–Alder reaction.
Herein, we describe a practical procedure for synthesis of substituted pyrano- and furano[3,2-c]quinolines via
Povarov reaction in the presence of HCl–ethanol, an inexpensive and readily accessible reagent compared with most of
Lewis acids. This synthetic procedure involves treating a mixture of 3,4-dihydro-2H-pyran and benzaldehyde with an
acetonitrile solution of aniline and HCl–ethanol (Scheme 1), to give the corresponding tetrahydroquinolines 3a and 4a
in 90% yield.
In the initial attempt, HCl–ethanol with different concentrations were prepared and applied in the model reaction of
aniline (0.93 g, 10 mmol), benzaldehyde (1.07 g, 10 mmol) with 3,4-dihydro-2H-pyran (0.84 g, 10 mmol) in
acetonitrile (25 mL) at ambient temperature (Scheme 1). As a result, the reaction rate appeared more reasonable in the
* Corresponding author.
E-mail address: niefang_yu@126.com (N.F. Yu).
1001-8417/$ – see front matter # 2012 Nie Fang Yu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.06.035

1028
R.H. Liu et al. / Chinese Chemical Letters 23 (2012) 1027–1030
Scheme 1.
Table 1
Effect of solvents and concentrations of HCl (in ethanol) on the reaction.
Round
Solvent
Concentrationa,b (wt%)
Volume of solvents (mL)
Time (h)
Conversion ratec (%)
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3OH
CH3CH2OH
CH2Cl2
0
5
25
25
25
25
25
25
25
25
2
0
32
95
93
92
89
85
47
2
10
15
20
10
10
10
1.5
2
2
2
2
2
a
Concentration of HCl in ethanol.
b
c
HCl–ethanol solutions with different concentrations were prepared by diluting 22.7% HCl–ethanol (fresh prepared) with ethanol.
The conversion rates were determined by LC/MS.
presence of 10% (wt) HCl–ethanol, while no significant changes were found when higher concentrated HCl–ethanol
were applied instead. Based on these findings, the effect of solvents on the reaction catalyzed by 10% (wt) HCl–
ethanol was studied, and acetonitrile was proved to be the better solvent than other solvents examined (Table 1).
We also assayed the ability of other seven common acids functioning as catalysts for the cycloaddition in this
reaction (Scheme 1). Our results indicated that HCl–ethanol was a more suitable catalyst, offering acceptable yield and
high diastereoselectivity. And the efficiency of HCl–ethanol could be also observed from the comparison between our
results and literature data of some other reported catalysts (Table 2).
To explore the scope of this protocol, the reactions of various substituted anilines and substituted benzaldehydes
with 3,4-dihydro-2H-pyran or 2,3-dihydrofuran were carried out under the optimized conditions [17], and the results
were summarized in Table 3. In all cases, the reactions went smoothly to give the corresponding products in moderate
Table 2
The catalytic efficiency of HCl–ethanol and some other catalysts.
Round
Catalyst
Amount
Reaction time (h)
Yielda (%)
Ratiob (3a:4a)
1
2
HCOOHc
AcOHc
1 mL
1 mL
12
12
24
24
2
48
25
10
5
68:32
55:45
3
HNO3 (35%)c
1 mL
85:15
c
4
H2SO4
1 mL
83:17
5
HCl (36%)c
HBr (40%)c
HI (45%)c
HCl–ethanol (10%)
Proline triflate
GdCl3
1 mL
9
55:45
6
1 mL
2
60
55
90
85
86
80
84
80:20
7
1 mL
2
78:22
8
1 mL
1.5
5
90:10 [17]
75:25 [10]
67:33 [11]
41:59 [13]
77:23 [16]
9
5 mol%
20 mol%
20 mol%
30 mol%
10
11
12
0.5
0.5
3
InCl3
I2
a
Isolated yields of 3a and 4a.
The product ratios were determined by LC/MS.
Similar reaction conditions as entry 8.
b
c

R.H. Liu et al. / Chinese Chemical Letters 23 (2012) 1027–1030
1029
Ref
Table 3
Synthesis of pyrano- and furano[3,2-c]quinoline derivatives under HCl–ethanol catalysis.
Entry
R1
R2
R3
R4
n
Time [h]
Yielda [%]
Ratiob (3:4)
a
b
c
d
e
f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
H
H
Br
H
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
1.5
2.5
2.5
1.5
2.5
1.0
2.5
1.5
2.5
1.5
1.5
2.5
3.5
2.0
2.5
1.0
2.5
1.5
77 (3a)
65 (3b)
70 (3c)
55 (3d)
63 (3e)
78 (3f)
65 (3g)
73 (3h)
70 (3i)
75 (4j)
58 (4k)
70 (4l)
58 (4m)
68 (4n)
67 (4o)
80 (4p)
62 (4q)
83 (4r)
90:10
72:18
95:5
[18]
[18]
[18]
[19]
CH3
Cl
H
H
OCH3
H
H
85:15
80:20
95:5
OH
NO2
CH3
H
H
[18]
[20]
[10]
[19]
[18]
g
h
i
H
86:14
85:15
87:13
9:91
H
H
OCH3
H
j
H
k
l
CH3
Cl
H
35:65
5:95
H
[18]
[11]
m
n
o
p
q
r
CH3
OCH3
H
OH
H
20:80
25:75
25:75
0:100
30:70
30:70
OH
NO2
CH3
H
H
[18]
[18]
H
H
a
Isolated yields.
b
The product ratios were determined by LC/MS.
Scheme 2.
1
to good yields. The major products were isolated and characterized by H NMR, 13C NMR and HRMS, and the
stereochemistry of the isolated products was assessed on the basis of the coupling constant values between H-C4a and
H-C5 (J4a,5) and comparison with literature data. The data acquired in this investigation suggested a close correlation
between the product diastereoselectivities and the dienophile used. Dihydropyran provided a great opportunity for the
generation of trans diastereosimers, while cis diastereoisomers were favored in cases of dihydrofuran. Adducts 3a–i,
exhibited higher coupling constants J4a,5 (8.1–11.1 Hz), typical for a trans conformation in which the pyran ring and
phenyl ring are on opposite sides of the quinoline ring. In adducts 4j–r, smaller coupling constants J4a,5 (4.6–5.6 Hz)
were observed indicating a cis conformation that the furan ring and phenyl group are on the same side (Scheme 2).
In conclusion, we have demonstrated that HCl, a readily available non-Lewis acid, can be used as catalyst for
construction of pyrano- and furano[3,2-c]quinolines. In comparison with the other acids examined (e.g., AcOH) and
some other reported catalysts (e.g., GdCl3), HCl–ethanol is more effective and affords better yields with high
diastereoselectivity according to our experimental results. Furthermore, our novel procedure possesses some other
advantages including chemistry more accessible and cleaner reaction mixture. These features make our procedure a
useful approach for the synthesis of fused-ring quinolines of biological importance.
Acknowledgments
The authors thank the National Natural Science Foundation of China for financial support (Nos. 30873137,
30772645 and 81172927).

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R.H. Liu et al. / Chinese Chemical Letters 23 (2012) 1027–1030
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(0.93 g, 10.0 mmol) in acetonitrile (10 mL) and left to stand for 10 min at ambient temperature. A solution of benzaldehyde (1.07 g,
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