Efficient method for the synthesis of 2-(3-arylbenzo[f]quinolin-2-yl) ethanol derivatives through an unusual ring-opening of THF-involved reaction

Article abstract of DOI:10.1016/j.tetlet.2010.11.152

An efficient synthesis of 2-(3-arylbenzo[f]quinolin-2-yl)ethanol derivatives by an unusual THF-involved reaction of aromatic aldehyde and naphthalen-2-amine promoted by iodine has been demonstrated with good yields. The ring-opening of THF reaction is pro

Full text of DOI:10.1016/j.tetlet.2010.11.152

Tetrahedron Letters 52 (2011) 612–614
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Tetrahedron Letters
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Efficient method for the synthesis of 2-(3-arylbenzo[f]quinolin-2-yl)ethanol
derivatives through an unusual ring-opening of THF-involved reaction
⇑
Xiang-Shan Wang , Jie Zhou, Ke Yang, Yu-Ling Li
School of Chemistry and Chemical Engineering, Xuzhou Normal University, The Key Laboratory of Biotechnology on Medical Plant, Xuzhou Jiangsu 221116, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 2-(3-arylbenzo[f]quinolin-2-yl)ethanol derivatives by an unusual THF-involved
reaction of aromatic aldehyde and naphthalen-2-amine promoted by iodine has been demonstrated with
good yields. The ring-opening of THF reaction is proposed in the possible mechanism.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 4 September 2010
Revised 22 November 2010
Accepted 30 November 2010
Available online 4 December 2010
Keywords:
Benzoquinoline
THF
Iodine
Ring-opening
Quinoline and its derivatives represent an important class of
nitrogen-containing heterocycles as they are useful dyes and
intermediates in organic synthesis,1 and they also possess a broad
spectrum of biological activities, such as antiasthmatic, anti-
inflammatory, and antimalarial activity.2 In addition, quinoline
derivatives have been evaluated as anticancer and anthelmintic
agents.3 Therefore, a number of synthetic strategies have been
developed for the preparation of substituted quinolines,4 except
for the classic methods, for example, Skraup, Doebner–Von Miller,
Conrad–Limbach, Combes, Pfitzinger, and Povarov quinoline syn-
theses.5 Among these name reactions, the Povarov reaction
between N-aryl imines (Schiff bases) with electron-rich dieno-
philes is one of the most convenient methods of quinoline prepara-
tion. This reaction is usually catalyzed by various Lewis acids,
which is well documented as a review by Kouznetsov in 2009.6
In recent years, the use of molecular iodine in organic synthesis
has received considerable attention as an inexpensive, non-toxic,
and readily available mild Lewis acid catalyst for organic transfor-
mations, such as dehydration of tertiary alcohols to alkenes,7 syn-
thesis of benzyl alkyl ethers,8 synthesis of mixed ethers under
hydrogen pressure,9 bis-indoles,10 deprotection of acetals,11 ester-
ification,12 transesterification,13 and Michael addition.14
our previous research on this iodine-catalyzed reaction, we would
like to report an efficient synthesis of 2-(3-arylbenzo[f]quinolin-
2-yl)ethanol derivatives by an unusual THF-involved reaction
between aromatic aldehyde and naphthalen-2-amine in THF cata-
lyzed by iodine.
In our initial study, we tested the reaction of 4-bromobenzalde-
hyde 1a with naphthalen-2-amine 2 in THF at room temperature to
gain Schiff base 3 (Scheme 1). A small amount of iodine (5 mol %)
was added to enhance the rate of conversion. The product 3a
was obtained in high yield after the completion of reaction by
monitoring the reactant of 2. Simultaneously, a little unknown
byproduct 4 was observed by thin layer chromatogram, which
was not isolated for its poor yield.
In order to confirm the structure of byproduct 4, the above reac-
tion was repeated in twice equivalency of reactants (4 mmol). The
byproduct 4 was isolated successfully in the low yield (about 5%)
by silica column chromatography. We are surprised to find that
the byproduct is 2-(3-(4-bromophenyl)benzo[f]quinolin-2-yl)
ethanol 4a, which is confirmed by X-ray diffraction analysis and
its crystal structure is shown in Figure 1. This raises an interesting
In our previous studies, we have synthesized a series of
benzo[f]quinoline derivatives through Povarov reaction using
iodine as catalyst.15 It was found that naphthalen-2-amine
involved-reactions always gave the desired products in high yields
and good stereo-selectivity for its high activity. In connection with
CHO
Br
NH2
N
I2
+
Byproduct
THF
+
Br
1a
2
3
4
⇑
Corresponding author.
E-mail address: xswang1974@yahoo.com (X.-S. Wang).
Scheme 1. Reaction of 1a and 2 in THF.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.152

X.-S. Wang et al. / Tetrahedron Letters 52 (2011) 612–614
613
R
O
I2
I2
Air
HOCH2CH2CH2CHO
H
HO
I
NH2
N
Ar
+
ArCHO
HO
R
OH
I2
H
R
Povarov
reaction
N
I2
Ar
N
Ar
II
R
R
-H2O
Air(O2)
Figure 1. The crystal structure of product 4a.
N
Ar
N
Ar
question: where do the four carbon atoms come from in the two-
component reaction of 4-bromobenzaldehyde and naphthalen-
2-amine?
R = CH2CH2OH
III
Scheme 3. The possible reaction mechanism to explain the formation of product 4.
Total of four carbon atoms in the solvent of THF was suspicious
of the carbon source firstly, so the same reaction (2 mmol) was
treated in the THF at room temperature to reflux in the presence
of iodine. The Schiff base of (E)-N-(4-bromophenylidene)naphtha-
len-2-amine formed as yellow precipitate immediately (monitored
by TLC). Subsequently, the generated precipitate disappeared
gradually when the reaction time increases. At last the designed
reaction completed to give 2-(3-(4-bromophenyl)benzo[f]quino-
lin-2-yl) ethanol in good yield (72%) for 42 h.
In our continued study, using the conversion of 4-bromobenzal-
dehyde 1a and naphthalen-2-amine as a model reaction, different
parameters, such as the amounts of catalyst iodine (5, 10 and
20 mol %) and various reaction temperatures (room temperature,
50 °C, and reflux) were analyzed to optimize the conditions. An
optimized yield of 82% was obtained in the presence of 10 mol %
iodine in THF at reflux for 36 h. Subsequently, these optimized con-
ditions were applied for the conversion of various aromatic alde-
hydes 1 (Scheme 2) into the corresponding benzo[f]quinoline
analogs 4b–j (Table 1). However, we failed to get the expected
products when other amines were used, such as naphthalen-
1-amine or p-toluidine. A possible reason is that the activity of
p-toluidine or naphthalen-1-amine is less than that of naphtha-
lene-2-amine.
In our previous studies,17 we have demonstrated that aliphatic
aldehyde, such as propionaldehyde and n-butyl aldehyde, was able
to react with 1 and 2 catalyzed by iodine, giving 2-substituted-
3-arylbenzo[f]quinolines as the final products, whose structures
are very similar to those of products 4. In addition, it was also
reported that the THF could be oxidized directly to 4-hydroxybu-
tylaldehyde by various kinds of oxidants in the literature,18 there-
fore, 4-hydroxybutylaldehyde may be formed from THF in this
iodine-catalyzed reaction. According to the Povarov reaction,5f
the formation of 4 can be explained by the possible mechanism
presented in Scheme 3. The Schiff base may be formed by the reac-
tion of aromatic aldehyde and naphthalen-2-amine firstly, losing a
molecule of water. The THF-ring is oxidized by air to 4-hydroxybu-
tylaldehyde in the presence of iodine, which is in equilibrium with
the enol form I. Subsequently, the Povarov reaction between the
enol and iodine-activated Schiff base immediately takes place to
form intermediate II, then II results in dihydroquinoline III by
dehydration, which is further oxidized by air to give an aromatized
2-benzo[f]quinolin-2-yl) ethanol 4.
NH2
O
+
I2
OH
+
ArCHO
THF
N
Ar
4
1
2
In order to get more insight into the above mechanism,
aldehyde acetal of 2-ethoxytetrahydrofuran was selected as a
reactant to react with 4-bromobenzaldehyde and 2 in a mixture
of acetonitrile and water at reflux (Scheme 4). It was found that
compound 4a was obtained in 43% yield, another product of
exo-benzo[f]furo[3,2-c]quinoline 5 was also separated by silica
column chromatography in 28% yield.
Scheme 2. The reaction of 1,2, and THF catalyzed by iodine.
Table 1
Synthetic results of 4 catalyzed by iodine in THFa,16
Entry
Ar
Products
Time (h)
Isolated yields (%)
1
2
3
4
5
6
7
8
9
4-BrC6H4
2,3-Cl2C6H3
2-BrC6H4
2-FC6H4
2-ClC6H4
4-NO2C6H4
4-CH3C6H4
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
36
30
40
32
32
30
42
40
32
32
84
86
82
80
78
86
86
80
82
88
Br
O
O
I2
2
4a
+
+
+
OEt
CH3CN-H2O
N
H
2,4-Cl2C6H3
4-ClC6H4
CHO
10
4j
Br
1a
5
a
Reagents and conditions:
0.051 g), THF (10 mL).
1 (2 mmol), 2 (0.286 g, 2 mmol), I2 (0.2 mmol,
Scheme 4. The reaction of 1a, 2, and 2-ethoxytetrahydrofuran.

614
X.-S. Wang et al. / Tetrahedron Letters 52 (2011) 612–614
J. Org. Chem. 1999, 937–941; (c) Ali, M. M.; Tasneem, K. C.; Rajanna, P. K.;
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Oyarzabal, J. Tetrahedron 1999, 55, 5947–5964; (e) Charpentier, P.; Lobregat, V.;
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4-hydroxybutylaldehyde, which can be converted into 4-hydrox-
ybutylaldehyde by hydrolysis in the mixture of I2–CH3CN–H2O,
the latter reacted with 1a and 2 to give 4a. This result indicates
that 4-hydroxybutylaldehyde may be the intermediate in the for-
mation of product 4a. It was reported19 that the 2-ethoxytetrahy-
drofuran was also easy to eliminate a molecule of EtOH to form
2,3-dihydrofuran. The subsequent imino-Diels–Alder reaction
(Povarov reaction) between Schiff base and 2,3-dihydrofuran takes
place to give 5, this result is in agreement to that of our previous
reported work.15c
In conclusion, we found an unusual THF-involved reaction of
aromatic aldehyde and naphthalen-2-amine catalyzed by iodine.
This three-component reaction provides a novel method to con-
struct 2-(3-arylbenzo[f]quinolin-2-yl)ethanol derivatives in good
yields. The features of this procedure are mild reaction conditions,
good yields, and operational simplicity.
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Acknowledgments
13. Chavan, S. P.; Kale, R. R.; Shivasankar, K.; Chandake, S. I.; Benjamin, S. B.
Synthesis 2003, 2695–2698.
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We are grateful to the National Natural Science Foundation of
China (20802061) and the Natural Science Foundation
(08KJD150019) and Qing Lan Project (08QLT001) of Jiangsu Educa-
tion Committee for financial support.
16. General procedure for the syntheses of 2-(3-Arylbenzo[f]quinolin-2-yl)ethanol
Supplementary data
derivatives 4a–j:
A dry 50 mL flask was charged with aromatic aldehyde
(2.0 mmol), naphthalen-2-amine (0.286 g, 2.0 mmol), I2 (0.051 g, 0.2 mmol),
and THF (10 mL). The reaction mixture was stirred at reflux for 30–42 h. After
completion of the reaction as indicated by TLC, another portion of THF was
added to the mixture until all the yellow solid was dissolved. The final products
4 were obtained as pale yellow crystals, when the mixture was cooled to room
Crystallographic data for the structure of 4a reported in this
paper has been deposited at the Cambridge Crystallographic Data
Centre as supplementary publication with No. CCDC-798451,
Copies of available material can be obtained, free of charge, on
application to the Director, CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, (fax: +44 (0) 1223-336033 or e-mail: deposit@ccdc.cam.a-
c.uk). Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.11.152.
temperature.
Selected
data:
2-(3-(4-Bromophenyl)benzo[f]quinolin-2-
yl)ethanol 4a: mp: 184–185 °C. IR (KBr): 3243, 3063, 2962, 2932, 2877,
1606, 1592, 1478, 1449, 1408, 1386, 1367, 1276, 1232, 1175, 1073, 1059, 1025,
1010, 870, 833, 749, 722 cmÀ1 1H NMR (DMSO-d6, 400 MHz): dH 3.05 (t,
.
J = 6.8 Hz, 2H, CH2), 3.69–3.70 (m, 2H, CH2), 4.78 (s, 1H, OH), 7.62 (d, J = 8.4 Hz,
2H, ArH), 7.71–7.80 (m, 4H, ArH), 7.90 (d, J = 8.8 Hz, 1H, ArH), 8.06–8.10 (m,
2H, ArH), 8.92 (d, J = 8.0 Hz, 1H, ArH), 9.20 (s, 1H, ArH). HRMS (ESI, m/z): calcd
for
C
21H17BrNO
(M+H+)
378.0494,
found
378.0484.
2-(3-p-
References and notes
Tolylbenzo[f]quinolin-2-yl)ethanol 4g: mp: 213–215 °C. IR (KBr): 3251, 3062,
3027, 2958, 2921, 2876, 1606, 1479, 1448, 1408, 1367, 1275, 1232, 1182, 1146,
1060, 1018, 873, 832, 751, 710, 689 cmÀ1 1H NMR (DMSO-d6, 400 MHz): dH
.
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J = 5.2 Hz, 1H, OH), 7.33 (d, J = 8.0 Hz, 2H, ArH), 7.53 (d, J = 8.0 Hz, 2H, ArH),
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