Molecular iodine-catalyzed one-pot synthesis of substituted quinolines from imines and aldehydes

Article abstract of DOI:10.1016/j.tetlet.2006.02.136

A mild, efficient, and general method for the synthesis of substituted quinolines via a molecular iodine-catalyzed one-pot domino reaction of imines with enolizable aldehydes has been described.

Full text of DOI:10.1016/j.tetlet.2006.02.136

Tetrahedron Letters 47 (2006) 3127–3130
Molecular iodine-catalyzed one-pot synthesis of substituted
quinolines from imines and aldehydes
Xu-Feng Lin, Sun-Liang Cui and Yan-Guang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
Received 16 January 2006; revised 23 February 2006; accepted 24 February 2006
Available online 10 March 2006
Abstract—A mild, efficient, and general method for the synthesis of substituted quinolines via a molecular iodine-catalyzed one-pot
domino reaction of imines with enolizable aldehydes has been described.
Ó 2006 Elsevier Ltd. All rights reserved.
Quinoline and their derivatives, which usually possess
diverse biological activities, play important roles as
R1
N
versatile building blocks for the synthesis of natural
products and as therapeutic agents.1 In particular,
2-arylquinolines are biologically active and occur in
structures of a number of antimalarial compounds and
antitumor agents.2 Therefore, the synthesis of quinolines
has attracted much attention in organic synthesis. The
classic methods for the synthesis of quinolines include
Skraup, Doebner–von Miller, Conrad–Limbach, Com-
bes, and Pfitzinger quinoline syntheses.3 A number of
general synthetic methods have also been reported.4
However, some of these methods suffer from several
disadvantages such as harsh reaction conditions, multi-
steps, a large amount of promoters, and/or long reaction
time. Therefore, the development of new synthetic
approaches using mild reaction conditions remains an
active research area.
R2
R3
1
+
I2 (1 mol%)
benzene
R1
N
O
reflux, 0.5 h
R2
R3
3
H
2
Scheme 1.
We have examined the conditions for the reaction of 1a
with 2a. Among the solvents tested, benzene gave the
best result (Table 1, entries 7 and 8). CH3CN,
ClCH2CH2Cl, MeOH, THF, or DMSO gave the pro-
duct 3a in lower yields (Table 1, entries 1–5). When the
Iodine has been used as a mild and efficient catalyst for
various organic transformations.5 In continuation of
our efforts to develop new synthetic routes of hetero-
cycles,6 herein we report a molecular iodine-catalyzed
one-pot synthesis of substituted quinolines from imines
and enolizable aldehydes (Scheme 1).
Table 1. Screening for the reaction conditionsa
Entry
Catalyst
(mol %)
Solvent
Temp
(°C)
Time
(h)
Yieldb
(%)
1
2
3
4
5
6
7
8
9
1
1
1
10
10
10
1
10
0
THF
Reflux
Reflux
Reflux
Reflux
80
0.5
0.5
0.5
12
2
12
0.5
0.1
12
60
65
72
15
45
Trace
79
80
0
CH3CN
ClCH2CH2Cl
MeOH
In a preliminary experiment, refluxing a solution of imine
1a, decyl aldehyde (2a), and iodine (10 mol %) in benzene
under an air atmosphere for 1 h afforded 2-phenyl-
3-octylquinoline (3a) in 80% isolated yield. The product
3a was fully characterized by spectroscopic analysis.
DMSO
Benzene
Benzene
Benzene
Benzene
rt
Reflux
Reflux
Reflux
a All reactions were performed using 1a (1.2 mmol), 2a (1.0 mmol), and
a solvent (5 mL) under an air atmosphere.
b Isolated yield.
*
Corresponding author. Tel./fax: +86 571 87951512; e-mail addresses:
orgwyg@zju.edu.edu.c; orgwyg@zju.edu.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.136

3128
X.-F. Lin et al. / Tetrahedron Letters 47 (2006) 3127–3130
reaction was performed at room temperature (Table 1,
entry 6) or in the absence of iodine (Table 1, entry 9),
no product was obtained. Furthermore, the reaction
time and the catalyst concentration can be reduced
to 0.5 h and 1 mol %, respectively (Table 1, entries 7
and 8).
Table 2. Iodine-catalyzed reaction of imines 1 with aldehydes 2a
Entry
Imine
Aldehyde
Product
Yield (%)b
79
1
n-C8H17CH2CHO 2a
3a
N
1a
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
n-C7H15CH2CHO 2b
n-C6H13CH2CHO 2c
n-C5H11CH2CHO 2d
n-C4H9CH2CHO 2e
i-C3H7CH2CHO 2f
PhCH2CHO 2g
3b
3c
3d
3e
3f
75
80
72
70
75
65
3g
8
2a
3h
86
N
Br
1b
MeO
EtO
Br
9
10
11
2a
2a
2a
3i
80
63
68
N
Br
Me
Me
1c
3j
N
1d
3k
N
Me
1e
EtO
12
13
2b
2c
3l
81
82
N
Cl 1f
1b
3m
Br
14
15
2c
2c
3n
3o
75
77
N
1g
EtO
N
1h
16
17
1f
2d
2f
3p
3q
75
82
Me
N
Br
1i
18
1b
2g
3r
69
a All reactions were performed using 1a (1.2 mmol), 2a (1.0 mmol), and I2 (0.01 mmol) in benzene (5 mL) under an air atmosphere and reflux for
0.5 h.
b Isolated yields.

X.-F. Lin et al. / Tetrahedron Letters 47 (2006) 3127–3130
3129
H
I2
Under the optimized reaction conditions, a variety of
H
n-C6H13
n-C6H13
2c'
imines 1a–i and enolizable aldehydes 2a–g were tested
(Table 2).7 Diphenylimine 1a reacted with aldehydes
2a–g to afford the corresponding 3-substituted 2-phenyl
quinolines 3a–g in moderate to good yields (Table 2,
entries 1–7). Substituted imines 1b–i bearing functional
groups such as Br, Me, or MeO, also reacted smoothly
with various aldehydes to afford the desired substituted
2-arylquiniolines 3h–r (Table 2, entries 8–18). It is note-
worthy that bromoquinolines may be subjected to
further transformation via a C–C bond coupling reac-
tion. However, when using enolizable acetophenone in-
stead of the aliphatic aldehydes, no quinoline product
was isolated.
O
OH
2c
I2
N
N
Ph
Ph
I2
1a
1a'
C6H13-n
OH
C6H13-n
O
Ph
2c'
Ph
I2
+
1a'
HN
HN
3c-1
3c-2
C6H13-n
To expand the preparative utility, a two-step, one-pot
synthesis of 2-arylquinolines from an arylamine, an aro-
matic aldehyde and an aliphatic aldehyde was examined
(Scheme 2). Using 1 mol % of iodine as catalyst, the
imine generated in situ from aniline and 4-bromobenz-
aldehyde (1 equiv) in benzene reacted with decanal (2a)
under reflux and an air atmosphere conditions to afford
the quinoline 3h in 70% yield. The addition of anhy-
C6H13-n
Ph
Ph
air (O2)
N
HN
-H2O
3c-3
3c
Scheme 4.
˚
drous MgSO4 or 4 A molecular sieve powder did not
help to improve the yield.
immediately reacts with the iodine-activated imine 1a0
to form intermediate 3c-1,11 followed by an intramole-
cular Friedel–Crafts cyclization to give 3c-2. The subse-
quent dehydration of 3c-2 results in dihydroquinoline
3c-3, which is further oxidized by air to give an aroma-
tized quinoline 3c. These reactions take place in a one-
flask domino manner.
We also examined the in situ generated alkylimines,
which are hygroscopic, unstable, and difficult to be puri-
fied by distillation, recrystallization, or column chroma-
tography. When p-tolylamine (1.0 equiv) was treated
with nonanal (2b) (2.3 equiv) in the presence of iodine
(1 mol %) in benzene under reflux and an air atmo-
sphere, the resulting alkylimine further reacted with
excess aldehyde 2b to give the corresponding 3,4-di-
alkyl-substituted quinoline 4 in 60% yield (Scheme 3).8
In summary, we have developed a new and general route
to substituted quinolines from imines and enolizable
aldehydes. A catalytic amount of molecular iodine
(1 mol %) effectively initiates the reaction in a one-pot
domino process to give the products. The procedure
offers several advantages including mild and metal-free
reaction conditions, operational simplicity, inexpensive
reagents, and short reaction time.
According to the literatures,5e,9 we think that iodine cata-
lyzes the reaction as a mild Lewis acid. The mechanism
was proposed as shown in Scheme 4. In the presence of
iodine, octanal (2c) is in equilibrium with the enol form
2c0, in the presence of iodine, which was confirmed by
1H NMR experiment.10 The in situ generated enol
Acknowledgments
1) I2 (1 mol%)
C8H17-n
This work was financially supported by the Specialized
Research Fund for Doctoral Program of Higher Educa-
tion, China (No. 20050335101), the Natural Science
Foundation of Zhejiang Province (No. R404109) as well
as the Teaching and Research Award Program for Out-
standing Young Teachers in Higher Education Institu-
tions of MOE, P.R.C.
NH2
benzene, reflux, 5 min
+
O
O
N
2)
C8H17-n
H
3h
H
Br
70%
air, reflux, 30 min
Br
Scheme 2.
References and notes
Me
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60%
I
2 (1 mol%)
NH2
benzene, air
reflux, 30 min
+
O
N
C7H15-n
H
4
(2.3 equiv)
Scheme 3.

3130
X.-F. Lin et al. / Tetrahedron Letters 47 (2006) 3127–3130
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Compound 3a: Liquid; IR (neat): 2953, 2924, 2854, 1486,
1456, 1418, 767, 700 cmꢀ1. 1H NMR (400 MHz, CDCl3): d
8.16 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.83 (d, J = 8.0 Hz,
1H), 7.70–7.72 (m, 1H), 7.45–7.57 (m, 6H), 2.78 (t,
J = 8.0 Hz, 2H), 1.52–1.56 (m, 2H), 1.20–1.27 (m, 10H),
0.88 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d
160.71, 146.29, 140.89, 135.66, 134.08, 129.21, 128.73,
128.70, 128.22, 127.99, 127.60, 126.85, 126.30, 32.79,
31.74, 30.53, 29.22, 29.16, 29.05, 22.58, 14.06. MS (ESI):
m/z = 318 ([M+H]+). Anal. Calcd for C23H27N: C, 87.02;
H, 8.57; N, 4.41. Found: C, 87.00; H, 8.61; N, 4.35.
Compound 3c: Liquid; IR (neat): 2954, 2924, 2853, 1486,
1457, 1419, 767, 700 cmꢀ1. 1H NMR (400 MHz, CDCl3): d
8.15 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.82 (d, J = 8.0 Hz,
1H), 7.65–7.69 (m, 1H), 7.44–7.57 (m, 6H), 2.77 (t,
J = 8.0 Hz, 2H), 1.52–1.56 (m, 2H), 1.17–1.27 (m, 6H),
0.85 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): d
160.70, 146.29, 140.89, 135.63, 134.06, 129.21, 128.71,
128.67, 128.21, 127.97, 127.57, 126.84, 126.28, 32.77,
31.39, 30.48, 29.65, 22.40, 13.98. MS (ESI): m/z = 290
([M+H]+). Anal. Calcd for C21H23N: C, 87.15; H, 8.01; N,
4.84. Found: C, 87.08; H, 8.10; N, 4.77.
Compound 3k: White solid, mp 104–106 °C; IR (neat):
1
2954, 2919, 2853, 1467, 1454 cmꢀ1. H NMR (400 MHz,
CDCl3): d 7.98 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 2.0 Hz,
1H), 7.90 (s, 1H), 7.70 (dd, J = 2.4, 2.0 Hz, 1H), 7.31 (s,
1H), 7.23–7.24 (m, 2H), 2.77 (t, J = 8.0 Hz, 2H), 2.33 (s,
6H), 1.50–1.57 (m, 2H), 1.19–1.26 (m, 10H), 0.87 (t,
J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 161.34,
144.85, 138.03, 136.62, 136.53, 135.25, 134.38, 131.98,
130.97, 129.81, 129.35, 128.82, 128.59, 125.93,119.87,
32.74, 31.76, 30.42, 29.66, 29.16, 29.06, 22.59, 19.84,
19.10, 14.06. MS (ESI): m/z = 424 ([M+H]+). Anal. Calcd
for C25H30NBr: C, 70.75; H, 7.12; N, 3.30. Found: C,
70.71; H, 7.21; N, 3.23.
8. Spectral data of compound 4: Liquid; IR (neat): 2954,
2924, 2854, 1490, 1465, 824 cmꢀ1 1H NMR (400 MHz,
.
CDCl3): d 7.90 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.46 (s,
1H), 7.42 (d, J = 8.4 Hz, 1H), 2.94 (t, J = 8.0 Hz, 2H),
2.75 (t, J = 7.6 Hz, 2H), 2.49 (s, 3H), 1.72–1.80 (m, 2H),
1.61–1.70 (m, 2H), 1.25–1.45 (m, 18H), 0.85–0.91 (m, 6H).
13C NMR (100 MHz, CDCl3): d 161.30, 145.02, 135.11,
134.20, 134.02, 130.49, 128.07, 127.19, 125.70, 35.88,
32.37, 31.86, 31.78, 30.56, 29.95, 29.85, 29.67, 29.53,
29.50, 29.25, 29.16, 22.63, 21.48, 14.05, 14.07. MS (ESI):
m/z = 354 ([M+H]+). Anal. Calcd for C25H39N: C, 84.92;
H, 11.12; N, 3.96. Found: C, 84.86; H, 11.19; N, 3.87.
9. Ke, B. W.; Qin, Y.; He, Q. F.; Huang, Z. Y.; Wang, F. P.
Tetrahedron Lett. 2005, 46, 1751–1753.
10. To a NMR tube containing a solution of octanal
(0.1 mmol) in benzene-d6 (0.5 mL) was added iodine
(1.0 mg) and subject to a 1H NMR spectroscopy. When
the temperature was increased to 40 °C, new signals
corresponding to the enol 2c0 appeared. The chemical
shifts of the two protons of CH@CH and the proton of
OH in 2c0 were d 6.01, 4.81, and 3.75, respectively. The
ratio of enol form (13%) was determined by the integra-
7. General procedure for the synthesis of quinolines 3. The
appropriate imines 1 (1.2 mmol), enolizable aldehydes 2
(1.0 mmol), and iodine (0.01 mmol, 2.5 mg) were mixed in
5 mL of benzene. The mixture was vigorously stirred in an
open flask under reflux for 30 min and the reaction was
1
tion of the H NMR chemical shifts.
11. Xia, M.; Lu, Y. D. Synlett 2005, 2357–2361.