Ferric sulfate [Fe2(SO4)3·xH 2O]: An efficient heterogeneous catalyst for the synthesis of tetrahydroquinoline derivatives using Povarov reaction

Article abstract of DOI:10.1016/j.tetlet.2011.06.080

Fe₂(SO₄)₃·xH₂O can be used as an efficient and reusable catalyst for the synthesis of pyrano- and furanotetrahydroquinolines via one-pot three-component Povarov reaction involving aromatic aldehydes, aromatic am

Full text of DOI:10.1016/j.tetlet.2011.06.080

Tetrahedron Letters 52 (2011) 4539–4542
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Tetrahedron Letters
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Ferric sulfate [Fe2(SO4)3ÁxH2O]: an efficient heterogeneous catalyst for the
synthesis of tetrahydroquinoline derivatives using Povarov reaction
⇑
Abu T. Khan , Deb Kumar Das, Md. Musawwer Khan
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Fe2(SO4)3ÁxH2O can be used as an efficient and reusable catalyst for the synthesis of pyrano- and furano-
tetrahydroquinolines via one-pot three-component Povarov reaction involving aromatic aldehydes,
aromatic amines, and cyclic enol ethers. The catalyst is recyclable, economically viable, and environmen-
tally benign. This protocol provides good yields and diastereoselectivity as well as applicability on a wide
range of substrates.
Received 13 May 2011
Revised 17 June 2011
Accepted 19 June 2011
Available online 25 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ferric sulfate [Fe2(SO4)3ÁxH2O]
Heterogeneous catalyst
Tetrahydroquinoline derivatives
Povarov reaction
Multicomponent reactions
In recent years, ferric sulfate [Fe2(SO4)3ÁxH2O] has received
considerable attention as a mild, inexpensive, and reusable catal-
yst for various organic transformations, such as tetrahydropy-
ranylation of alcohols,1 preparation of acylals from aldehydes,2
2,3-unsaturated glycosides via Ferrier rearrangement,3 and per-
O-acetylation of sugars.4 Due its wide applicability as a catalyst,
we presume that it would be an efficient catalyst for the one-pot
three-component synthesis of the fused tetrahydroquinoline deriv-
atives by employing Povarov reaction.
acid,10b SmI2,10c NbCl5,10d TMSCl,10e lanthanide triflates,10f silica
chloride or amberlyst-15,10g GdCl3,10h I2,10i SbCl3,10j and Cu
(OTf)2.10k Some of these methods are associated with certain limi-
tations such as use of excess catalyst,10h,10i and some of them are
very expensive10f and non-reusable catalysts. Consequently, there
is further scope to find out a greener catalyst, which provides bet-
ter yields and selectivity. In this paper, we would like to report
Fe2(SO4)3ÁxH2O as a useful catalyst for synthesis of fused tetrahy-
droquinoline derivatives.
Tetrahydroquinoline derivatives exhibit interesting biological
activities. For example, 2-aryl-2,3-dihydro-4-quinolone (1) showed
antitumor activity5 and 2-aryl-1,2,3,4-tetrahydro-quinoline (2) is a
core structure of the compounds possessing 5-lipoxygenase inhib-
itor properties as well as potential therapeutic application in asth-
ma6 as shown in Figure 1. Due to its pharmaceutical importance
the development of new methods for the construction of a tetrahy-
droquinoline framework is in continuous interest to the synthetic
organic chemists.7
Recently, multicomponent reactions (MCRs) have received con-
siderable interest among synthetic chemists for construction of
complex molecules.8 Using this approach, fused tetrahydroquino-
line derivatives can be easily accessible by employing aromatic
aldehydes, aromatic amines, and 3,4-dihydropyran (DHP) or 2,3-
dihydrofuran in the presence of suitable catalysts.9 Over the years,
a number of reagents have been explored as catalysts to access
these compounds, such as proline triflate,10a 4-nitrophthalic
For the present study, the mixture of benzaldehyde (1 mmol),
aniline (1 mmol), and 3,4-dihydropyran (DHP) (1 mmol) was trea-
ted with 10 mol % of Fe2(SO4)3ÁxH2O in acetonitrile (4 mL) at room
temperature. Pyranoquinolines 3c and 4c were obtained in 54%
combined yield with good diastereoselectivity (30:70). The prod-
ucts were characterized from 1H NMR, 13C NMR spectra, and by
their elemental analysis.
For optimizing the amount of catalyst and choosing the suitable
solvent, various trial reactions were carried out with a combination
of 4-chlorobenzaldehyde, aniline, and 3,4-dihydropyran. The re-
sults and observations are summarized in Table S1 (Supplementary
data). It was noted that 10 mol % of the catalyst provides the best
result for the formation of product under reflux conditions. It has
also been observed that acetonitrile is conducive for the present
reaction as compared to other solvents, such as ethanol, dichloro-
methane, dimethylformamide, toluene,
and water.
After optimizing the reaction conditions, the mixture of benzal-
dehyde (1 mmol), aniline (1 mmol), and 3,4-dihydropyran
(1 mmol) in acetonitrile was treated with 10 mol % Fe2(SO4)3ÁxH2O
⇑
Corresponding author. Tel.: +91 361 2582305; fax: +91 361 2582349.
E-mail address: atk@iitg.ernet.in (A.T. Khan).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.080

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A. T. Khan et al. / Tetrahedron Letters 52 (2011) 4539–4542
in 3a indicating the cis relationship, whereas the coupling constant
O
value is 10.8 Hz in case of trans isomer 4a as shown in Figure 2,
which is in agreement with the reported literature value.10d
The reaction with various substituted aromatic aldehydes, such
as Me, OMe, Cl, Br, and NO2 with aniline and 3,4-dihydropyran
were carried out under the same reaction conditions. The reaction
time, percentage yield, and cis:trans ratio of the products 3 and 4
are shown in Table 1 (entries b–g). Likewise, various other alde-
hydes, such as 2-furaldehyde, 2-naphthaldehyde, and 3-methyl-
2-thiophenecarboxaldehyde were reacted with aniline and
dihydropyran under identical reaction conditions to provide the
desired imino-Diels–Alder products (Table 1, entries h–j).
Furthermore, reactions with several substituted anilines were
also studied with aromatic aldehydes and dihydropyran with the
same amount of catalyst under similar reaction conditions (Table 1,
entries k–o). The desired products 3k–o and 4k–o were obtained in
good yields with similar diastereoselectivity. In the case of 2-naph-
thylamine, we have isolated the trans products 4p and 4q
exclusively.
N
H
Ph
N
H
Ph
(1)
(2)
Figure 1. Biologically active tetrahydroquinoline derivatives.
J
4a,10b value = 2.0-2.9 Hz
J
4a,10b value = 2.3-2.8 Hz
O
H
10b
O
H
10b
4a
4a
R2
R2
H
H
5
5
N
H
N
H
H
H
R1
R1
Cis
trans
4a,5 value = 8.1-11.1 Hz
J
J
4a,5 value =4.6-5.6 Hz
The structure of compound 4q was determined through single
crystal XRD data as shown in Figure 3.12 Unfortunately, 4-hydroxy-
benzaldehyde did not provide the desired tetrahydroquinoline on
reaction with amine and DHP under identical conditions even after
prolonging the reaction for 12 h. Similarly, 4-nitroaniline also did
not undergo Povarov reaction with other aromatic aldehydes. The
scope of the presented protocol was verified with other enol ether,
for example, 2,3-dihydrofuran (Table 1, entries r–t).
In view of a greener chemistry, the efficient recovery of the cat-
alyst is highly desirable. In the present protocol, the catalyst Fe2
(SO4)3ÁxH2O can be recovered conveniently from the reaction mix-
ture at the end of the reaction. The reusability of the recovered
Figure 2. Coupling constant values used for determining stereochemistry.
under identical reaction conditions and the desired tetrahydro-
quinoline derivatives 3a and 4a were obtained in 87% combined
yield. The stereochemistry of the fused ring junctures and other
positions was established from their coupling constant values.
The coupling constant between H4a and H10b (J4a,10b) was found
to be 2.0–2.9 Hz for all the products indicating a cis ring junction
between the quinoline and pyran rings. Similarly, the coupling
constant value between H4a and H5 (J4a,5) was found to be 5.6 Hz
Table 1
Scope of various substituted pyrano/furanotetrahydroquinoline derivatives11
( )n
O
( )n
O
NH2
O
Fe2(SO4)3. xH2O
CH3CN, reflux
CHO
R1
( )n
n=1, 2
R1
R1
N
R2
N
R2
H
R2
H
1
4
2
3
Entry
R1
2
n
Time (h)
Yielda (%)
Ratiob (3:4)
a
b
c
d
e
f
g
h
i
Ph
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
2
2
2
2
2
2
2
2
2
1.5
1.0
1.5
1.5
1.0
1.5
1.5
1.5
1.5
87
91
87
89
88
84
86
82
86
22:78
20:80
19:81
22:78
19:81
23:77
18:82
21:79
21:79
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
3-NO2C6H4
4-NO2C6H4
2-furyl
2-naphthyl
Me
j
PhNH2
2
1.5
78
0:100
S
k
l
m
n
o
Ph
Ph
Ph
Ph
4-MeC6H4NH2
4-ClC6H4NH2
4-MeOC6H4NH2
4-BrC6H4NH2
4-ClC6H4NH2
NH2
2
2
2
2
2
1.0
1.5
1.0
1.5
1.0
92
89
91
87
91
20:80
14:86
21:79
17:83
20:80
4-ClC6H4
p
Ph
2
2.5
82
0:100
NH2
q
2-naphthyl
2
1.5
85
0:100
r
s
t
4-MeC6H4
2-furyl
Ph
PhNH2
PhNH2
4-ClC6H4NH2
1
1
1
1.5
1.5
1.5
87
82
85
23:77
22:78
21:79
a
Isolated yields.
b
The product ratio was determined from crude 1H NMR spectra.

A. T. Khan et al. / Tetrahedron Letters 52 (2011) 4539–4542
4541
Figure 3. Single crystal X-ray structure of 4q (CCDC No. 793766).
Table 2
Results of the study on the recovery and reusability of Fe2(SO4)3ÁxH2Oa
CHO
NH2
O
O
O
Fe2(SO4)3.xH2O
CH3CN
N
H
N
H
4c
Cl
Cl
Cl
1c
2c
3c
Round
Catalyst recovered/mg
Reaction time (h)
Ratiob 3c:4c
Yieldc (%)
1
2
3
415
410
405
1.5
1.5
1.6
19:81
21:79
20:80
87
86
84
a
b
c
Reaction was carried out with 10 mmol scale.
The product ratio was determined from 1H NMR spectra.
Isolated yields.
catalyst was examined and the results are summarized in Table 2.
It clearly indicates that the catalyst can be reused for three succes-
sive times without losing activity.
as compared to FeCl3 method. Considering all these parameters, we
believe that Fe2(SO4)3ÁxH2O is a better catalyst for Povarov reaction.
In conclusion, we have demonstrated Fe2(SO4)3ÁxH2O can be
used for one-pot Povarov reaction for the synthesis of pyrano-
and furano[3,2-c]quinoline derivatives. In comparison to other
Lewis acids catalyst, it has been found to be effective, mild, and less
expensive. In addition, it requires shorter reaction times, providing
good yields and diastereoselectivity. Moreover, due to its
recyclability, the present method may open up an environmentally
benign pathway for the synthesis of fused pyrano- and
furanotetrahydroquinolines.
The efficiency and generality of the present protocol can be real-
ized at a glance by comparing our results with those of some re-
ported procedures as shown in Table 3. The results have been
compared with respect to the mole percent of the catalyst used,
yields, and diastereoselectivity. The similar Povarov reaction was
reported by Laszlo and co-workers using FeCl3 in combination of
other co-catalyst.13 It is worthy to mention that the present proto-
col provides better diastereoselectivity and avoidance of co-catalyst
Table 3
Comparison of our result with other results using different catalysts
CHO
NH2
O
O
O
Catalyst
N
H
N
H
Cl
1c
Cl
Time (h)
Cl
2c
3c
4c
Entry
Catalyst
Amount
Condition
Ratioa (3a:4a)
Yieldb,c
1
2
3
4
5
FeCl3
Proline triflate
4-Nitrophthalic acid
I2
Fe2(SO4)3ÁxH2O
10 mol %
5 mol %
25 mol %
30 mol %
10 mol %
rt
rt
50 °C
rt
reflux
6
5
3.5
3
1.5
50:50
25:75
39:61
23:77
19:81
8213
8510a
9010b
8410i
87d
a
b
c
The product ratio was determined from 1H NMR spectra.
Isolated yields.
Reported method with other catalysts.
The present protocol.
d

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A. T. Khan et al. / Tetrahedron Letters 52 (2011) 4539–4542
10 min at room temperature. Then, both enol ether (1 mmol) and the catalyst
Acknowledgments
ferric sulfate (0.042 g, 10 mol %) were added successively into the above
reaction mixture. Finally, the reaction flask is fitted with a reflux condenser
and kept for refluxing in an oil-bath. The progress of the reaction was
monitored by TLC. After completion of the reaction, the catalyst was separated
by filtration and usual work-up procedure was followed to obtain the crude
products. The products 3 and 4 were eluted in ethyl acetate/hexane (05:95) in
78–92 yield after column chromatographic separation. Spectral data of some
selected compounds: Compound 3d: White solid (0.067 g, 20%); mp 124 °C; Rf
(5% ethyl acetate/hexane) 0.34; IR (KBr): 3445, 3379, 2932, 2851, 1605,
D.K.D. is thankful to IIT Guwahati for his research fellowship.
M.M.K. acknowledges UGC for his research fellowship. We are
thankful to D.S.T. for providing XRD facility under the FIST
programme.
1482 cmÀ1 1H NMR (400 MHz, CDCl3): d = 7.50 (2H, dd, J = 6.4, 2.4 Hz), 7.42
.
Supplementary data
(1H, d, J = 7.6 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.10 (1H t, J = 7.6 Hz), 6.81 (1H, t,
J = 7.6 Hz), 6.60 (1H, d, J = 8.0 Hz), 5.31 (1H, d, J = 5.6 Hz), 4.65 (1H, d,
J = 2.0 Hz), 3.82 (1H, br s), 3.61–3.57 (1H, m), 3.42 (1H, td, J = 11.6, 2.0 Hz),
2.12–2.11 (1H, m), 1.57–1.42 (3H, m), 1.30–1.25 (1H, m). 13C NMR (100 MHz,
CDCl3): d = 145.1, 140.4, 131.7, 128.7, 128.4, 127.8, 121.4, 120.2, 118.8, 114.8,
72.8, 60.8, 59.1, 39.1, 25.6, 18.2. Anal. Calcd for C18H18BrNO (344.25): C, 62.80;
H, 5.27; N, 4.07. Found: C, 62.98; H, 5.19; N, 4.01. Compound 4d: White solid
(0.239 g, 69%); mp 133 °C; Rf (5% ethyl acetate/hexane) 0.23; IR (KBr): 3312,
Supplementary data (optimization table, X-ray crystallographic
data (CIF file) of 4q, spectral data of all compounds) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.06.080.
2937, 2838, 1613, 1487 cmÀ1 1H NMR (400 MHz, CDCl3): d = 7.50 (2H, d,
.
References and notes
J = 8.4 Hz), 7.30 (2H, d, J = 7.6 Hz), 7.22 (1H, d, J = 7.6 Hz), 7.10 (1H, t, J = 7.6 Hz),
6.72 (1H, t, J = 7.6 Hz), 6.53 (1H, d, J = 8.4 Hz), 4.69 (1H, d, J = 10.8 Hz), 4.38 (1H,
d, J = 2.4 Hz), 4.11–4.08 (1H, m), 4.03 (1H, br s), 3.72 (1H, td, J = 11.2, 2.0 Hz),
2.05–2.02 (1H, m), 1.83–1.75 (1H, m), 1.71–1.61 (1H, m), 1.47–1.42 (1H, m),
1.37–1.33 (1H, m). 13C NMR (100 MHz, CDCl3): d = 144.6, 141.5, 131.9, 131.0,
129.6, 129.5, 121.7, 120.8, 117.8, 114.4, 74.5, 68.7, 54.4, 39.0, 24.2, 22.1. Anal.
Calcd for C18H18BrNO (344.25): C, 62.80; H, 5.27; N, 4.07. Found: C, 62.61; H,
5.19; N, 4.22. Compound 4q: White solid (0.310 g, 85%); mp 214 °C; Rf (5%
ethyl acetate/hexane) 0.19; IR (KBr): 3391, 3055, 2931, 2900, 2839, 1620,
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J = 8.0 Hz), 7.56 (2H, t, J = 8.4 Hz), 7.50–7.42 (3H, m), 7.20 (1H, t, J = 7.6 Hz),
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11. General procedure for the synthesis of tetrahydroquinoline derivatives: Into a
25 mL round bottomed flask, a mixture of anilines (1 mmol) and aromatic
aldehydes (1 mmol) in acetonitrile (2 mL) was taken and left for stirring for
12. Crystallographic data. The X-ray crystal structures were determined with a
Siemens P-4 diffractometer. Complete crystallographic data of 4q have been
deposited with the Cambridge Crystallographic Data Centre, CCDC No. 793766.
Copies of this information may be obtained free of charge from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK, (fax: +44 1223 336033, e-mail: deposit@ccdc.cam.ac.uk or via:
www.ccdc.cam.ac.uk).
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