Microwave-assisted expeditious and efficient synthesis of cyclopentene ring-fused tetrahydroquinoline derivatives using three-component Povarov reaction

Article abstract of DOI:10.1016/j.tetlet.2013.09.107

We report here an efficient and expeditious microwave-assisted synthesis of cyclopentadiene ring-fused tetrahydroquinolines using the three-component Povarov reaction catalyzed by indium (III) chloride. This method has an advantage of shorter reaction tim

Full text of DOI:10.1016/j.tetlet.2013.09.107

Accepted Manuscript
Microwave-assisted Expeditious and Efficient Synthesis of Cyclopentene Ring-
fused Tetrahydroquinoline Derivatives Using Three-component Povarov Reac-
tion
Abhijit R. Kulkarni, Ganesh A. Thakur
PII:
S0040-4039(13)01672-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.09.107
TETL 43607
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
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19 September 2013
21 September 2013
Please cite this article as: Kulkarni, A.R., Thakur, G.A., Microwave-assisted Expeditious and Efficient Synthesis
of Cyclopentene Ring-fused Tetrahydroquinoline Derivatives Using Three-component Povarov Reaction,
Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.09.107
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Graphical Abstract
Microwave-assisted Expeditious and
Efficient Synthesis of Cyclopentene Ring-
fused Tetrahydroquinoline Derivatives Using
Three-component Povarov Reaction
Leave this area blank for abstract info.
Abhijit R. Kulkarnia and Ganesh A. Thakura,b,*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Microwave-assisted Expeditious and Efficient Synthesis of Cyclopentene Ring-
fused Tetrahydroquinoline Derivatives Using Three-component Povarov
Reaction
Abhijit R. Kulkarnia and Ganesh A. Thakura,b, 
a
Department of Pharmaceutical Sciences, Bouvé College of Pharmacy, Northeastern University, Boston, MA, 02115, USA
Center for Drug Discovery, Northeastern University, Boston, MA, 02115, USA
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We report here an efficient and expeditious microwave-assisted synthesis of cyclopentadiene
ring-fused tetrahydroquinolines using the three-component Povarov reaction catalyzed by
indium (III) chloride. This method has an advantage of shorter reaction time (10 – 15 min) with
high and reproducible yields (up to 90%) and is suitable for parallel library synthesis. The
optimization process is reported and the results from the microwave route are compared with
those of the conventional synthetic route. In almost all cases, the microwave acceleration
consistently provided improved yields favoring the cis-diastereomer.
Available online
Keywords:
Tetrahydroquinolines
Cyclopentene ring-fused tetrahydroquinolines
Microwave-assisted synthesis
Parallel synthesis
2009 Elsevier Ltd. All rights reserved.
Povarov reaction
1. Introduction
constructing such tetrahydroquinolines and among them the
three-component Povarov reaction has been most empowering
and versatile.12,11,1,13 This reaction which is also known as aza-
attracted
The
tetrahydroquinoline derivatives have
considerable attention because of their important biological
activities and occurrence in natural products.1 Those containing
fused cyclopentene ring have been found to exhibit a variety of
pharmacological activities like agonism at BKCa receptor (1),2
GPR30 estrogen receptor (2)3,4 and allosteric modulation at the
7 nicotinic acetylcholine receptors (nAChRs)5-7 as well as anti-
tubercular activity against M. tuberculosis (Figure 1).8 One such
representative tetrahydroquinoline derivative is TQS (3; 4-(1-
naphthyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-
sulfonamide), a potent type II positive allosteric modulator
(PAM) of 7 nAChRs.7,9,5,10 Such type II PAMs have been
preclinically shown to be useful in improving memory, cognition
Diels Alder reaction can be carried out in a one-pot fashion using
Scheme 1. Microwave acclerated synthesis of TQS.
an aniline, an aldehyde and an electron-rich dienophile in the
11,14
presence of various Brønsted as well as Lewis acids.
Although the original Povarov reaction was carried out with
cyclopentadiene as a dienophile, most of the later optimization
and scope expansion of this reaction was focused on shelf-stable
dienophiles such as pyran, furan etc.14,11 Synthesis of
cyclopentene ring-fused tetrahydroquinolines has been relatively
low yielding7,6,14,11 due to thermal instability of cyclopentadiene
leading to its spontaneous dimerization at room temperature and
gradual polymerization even at low temperature.15 Various
Brønsted and Lewis acids have been utilized to accelerate and
improve reaction times, but have led to only limited success.16-
Figure 1. Representative biologically-active cyclopentene ring-fused
tetrahydroquinolines.
and in treating neuropathic pain. Therefore, synthesis of new
tetrahydroquinolines still holds great interest.11,1 A variety of
synthetic methods have been developed for
21,2,22,23
Microwave-assisted organic synthesis has become an
important tool in organic synthesis for rate enhancement,
improving reaction yields, and reducing thermal degradation
byproducts.24 To the best of our knowledge use of microwave
———
G.A.T.: Department of Pharmaceutical Sciences and Center for Drug Discovery. Tel.: +1-617-373-8163; fax: +1-617-373-8886; e-mail:
g.thakur@neu.edu

2
Tetrahedron Letters
acceleration for the Povarov reaction has been limited to
thermally-stable N-vinylpyrrolidin-2-one25, pyran26, furan26, 2-
methoxyacrylate27 and acrylamides27 dienophiles.
In view of
this, we report here microwave-assisted synthesis of
oxygen- and nitrogen- containing substrates and functional
groups.28,29 Additionally, it is
a
preferred catalyst in
multicomponent reactions providing better regio- and diastero-
a
selectivities.28
cyclopentene ring-fused tetrahydroquinolines using InCl3 as a
Lewis acid, which provides excellent results in terms of yield,
reaction time and diasteroselectivity.
We began our optimization by executing the TQS synthesis
(Scheme 1) under microwave irradiation at 100C and utilizing
20 mol% of InCl3 and 3 equivalents of cyclopentadiene in
acetonitrile as a solvent. The reaction was complete within 15
minutes, giving TQS in 60% yield (Table 1). The reaction was
very clean and no chromatographic purification was required as
the product was obtained in greater
2. Chemistry and Discussion:
As significant pharmacological work has been done around
the 7 nAChR allosteric modulator TQS (3), we selected it’s
synthesis as a model reaction. To date, it has been synthesized in
a maximum of 22% yield with a reaction time of 24 hrs at room
temperature and using 20 mol% InCl3 as the catalyst.6
Table 2: Effect of catalyst and cyclopentadiene loading
Entry
InCl3 (mol%)
Cyclopentadiene (equiv.)
Yield (%)
1
2
3
4
5
6
10
15
20
25
20
20
3
3
3
3
1
41
50
60
60
43
45
Table 1: Influence of reaction temperature and time
Entry
Temperature (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
100
75
15
15
15
5
60
60
35
49
60
55
50
2
75
1
than 99% purity (by HPLC and H-NMR). TQS has three chiral
centers with the cyclopentene and 1- naphthyl rings oriented cis-
to each other. We observed that these reaction conditions favored
the formation of the cis-diastereomer. The relative orientation of
cyclopentene ring and 1-naphthyl ring was cis as determined
from the coupling constants and NOE measurements (Figure 2).
In the 1H NMR spectra of compound 3, the two doublets at  5.45
and 4.25 were attributed to protons H-4 and H-9b respectively.
75
10
5
120
With an objective of improving this reaction yield and reducing
reaction time, we carried out optimization under microwave
irradiation by evaluating four different aspects of this reaction: a.
reaction temperature; b. reaction time (Table 1); c. catalyst
loading and d. cyclopentadiene loading (Table 2). We preferred
InCl3 as a Lewis acid for our optimization because compared to
the conventional Lewis acids, it has some advantages including
its compatibility with both organic and aqueous media,
recyclability, operational simplicity and a strong tolerance to
The coupling constants between protons H-3a and H-4 (J3a,4
=
3.5Hz) in 1H NMR confirmed the cis- relationship of these
protons.
Table 3: Comparison of microwave-assisted synthesis of tetrahydroquinoline under standard reaction conditions.
Compound
R1
R2
Microwave Heating
Conventional heating
Time
Yield (%)
Time
48 h
Yield (%)
22 (ref:7)
p-SO2NH2
10 min
60
3
p-SO2NH2
p-SO2NH2
15 min
15 min
66
90
24 h
24 h
2 (ref:7)
4
5
20 (ref:7)
p-SO2NH2
p-SO2NH2
p-SO2NH2
p-SO2NH2
10 min
15 min
15 min
15 min
61
67
66
67
48 h
24 h
12 h
--
19 (ref:7)
30 (ref:6)
13 (ref:7)
--
6
7
8
9

3
Compound
R1
R2
Microwave Heating
Conventional Heating
Time
15 min
Yield (%)
Time
--
Yield (%)
--
o-SO2NH2
10
55
p-COCH3
p-SO2NH2
p-OMe
2 h
--
98 (ref: 3)
11
12
13
15 min
15 min
10 min
74
40
58
--
--
--
p-Br
--
--
14
10 min
56
-H
p-SO2NH2
p-COOH
--
--
--
--
15
16
15 min
15 min
48
65
In summary, we have developed a microwave-assisted, rapid
and high yielding one-pot Povarov reaction for the synthesis of
cyclopentene ring-fused tetrahydroquinoline derivatives. In
general, the reactions for various substrates were rapid, clean and
in most cases no chromatographic purification was necessary,
produced superior yields with high diastereoselectivities and
could be scaled up to gram quantities.
Acknowledgements
This work supported by grant from National Institute on Drug
Abuse (DA027113 to GAT).
Figure 2. Characteristic NOEs of TQS (3)
References
Although the above experiment gave the desired product in
good yield, in order to find optimal reaction conditions, we
executed this reaction under conditions varying in temperature
and time (Table 1). We got similar yields (i.e. 60%) for a shorter
period of time (10 min) and at a lower temperature (75 C).
Temperatures and reaction times higher or lower than this did not
improve reaction yields. In subsequent experiments, the amounts
of InCl3 and cyclopentadiene were varied only to confirm that
any reduction in these quantities led to reduced yields (entries 1,
2, 5 and 6; Table 2). Also increasing the quantities of InCl3 and
cyclopentadiene did not improve reaction yields. Thus, in our
hands, 3 equivalents of cyclopentadiene with 20 mol% of InCl3 at
75°C for 10 minutes in a Biotage Microwave Synthesizer was the
most efficient procedure for the synthesis of TQS.30 We then
extended the scope of this reaction to various substituted
aldehydes and anilines and compared their yields with those
reported under standard conditions (Table 3). As seen,
microwave-assisted reaction conditions provided significantly
improved reaction yields for almost all analogs synthesized
compared to those obtained under standard conditions. In all
cases, except for compound 8, we observed formation of only the
cis-diastereomer under our reaction conditions. Compound 8 was
obtained as a 72:28 mixture of cis: trans diastereomers.
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4
Tetrahedron Letters
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14.5 Hz, 9.0 Hz, 2.0 Hz, 1H), 1.66 (ddd, J = 15.5 Hz, 9.0
Hz, 1.5 Hz, 1H); m/z = 377.84 [M+H]+. Compound 12: 1H
NMR (500 MHz, DMSO-d6)  7.69 (brs, 1H), 7.66 (dd as
t, J = 1.5 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.32 (dd, J =
8.5 Hz, 2.0 Hz, 1H), 6.95 (s, 2H), 6.77 (d, J = 8.5 Hz, 1H),
6.59 (d, J = 1.5 Hz, 1H), 6.20 (s, 1H), 5.88 – 5.82 (m,1H),
5.67 – 5.63 (m, 1H), 4.51 (d, J = 2.0 Hz, 1H), 4.04 (d, J =
9.0 Hz, 1H), 2.99 (dq, J = 8.5 Hz, 3.5 Hz, 1H), 2.38 (ddd, J
= 16.5 Hz, 9.5 Hz, 2.5 Hz, 1H), 1.98 (dd, J = 16 Hz, 9 Hz,
1H); m/z = 317.64 [M+H]+ . Compound 13: 1H NMR (500
MHz, CDCl3)  8.12 (d, J = 8.5 Hz, 1H), 7.90 (dd, J = 7.0
Hz, 2.0 Hz, 1H), 7.82 (d, J = 7.0 Hz, 1H), 7.80 (d, J = 9.0
Hz, 1H), 7.57 – 7.46 (m, 3H), 6.72 (s, 1H), 6.64 (d, J = 1.5
Hz, 2H), 5.86 – 5.79 (m, 1H), 5.68 – 5.60 (m, 1H), 5.35 (d,
J = 3.0 Hz, 1H), 4.25 – 4.18 (m, 1H), 3.78 (s, 3H), 3.54 (s,
1H), 3.30 (dq, J = 9.0 Hz, 2.5 Hz, 1H), 2.66 (qdd, J = 17.0
Hz, 9.0 Hz, 2.5 Hz, 1H), 1.64 (tdd, J = 16.5 Hz, 9.0 Hz, 2.0
12.
Smith, C. D.; Gavrilyuk, J. I.; Lough, A. J.; Batey, R. A. J.
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(500 MHz, CDCl3)  8.10 (d, J = 8.0 Hz, 1H), 7.90 (dd, J =
8.0 Hz, 2.0 Hz, 1H) 7.81 (d, J = 8.0 Hz, 1H), 7.77 (d, J =
6.5 Hz, 1H), 7.58 – 7.48 (m, 3H), 7.23 (dd, J = 2.5 Hz, 1.0
Hz, 1H), 7.10 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 5.82 – 5.79 (m,
1H), 5.68 – 5.62 (m, 1H), 5.40 (d, J = 3.0 Hz, 1H), 4.20 (d,
J = 9.0 Hz, 1H), 3.75 (s, 1H), 3.30 (dq, J = 8.5 Hz, 3.0 Hz,
1H), 2.62 (qdd, J = 17.0 Hz, 9.5 Hz, 2.5 Hz, 1H), 1.64
(qdd, J = 16.0 Hz, 8.5 Hz, 1.5 Hz, 1H); m/z = 377.16
[M+H]+. Compound 15: H NMR (500 MHz, DMSO-d6)
1
7.51 (d, J = 1.5 Hz, 1H), 7.32 (dd, J = 8.5 Hz, 2.0 Hz,
1H), 6.91 (s, 2H), 6.61 (d, J = 8.5 Hz, 1H), 6.31 (d, J = 1.5
Hz, 1H), 5.82 - 5.76 (m, 1H), 5.74 - 5.68 (m, 1H), 3.82 (s,
1H), 3.12 - 3.02 (m, 1H), 2.70 - 2.54 (m, 3H), 2.09 (dd, J =
9.0 Hz, 2.0 Hz, 1H); m/z = 250.99 [M+H]+. Compound 16:
1H NMR (500 MHz, DMSO-d6)  12.21 (s, 1H), 7.66 (s,
1H), 7.65 (d, J = 10.0 Hz, 1H), 7.52 (dt, J = 8.0 Hz, 2.0
Hz, 2H), 6.75 (d, J = 8.5 Hz, 2.0 Hz, 1H), 6.39 (s, 1H),
5.98 - 5.90 (m, 1H), 5.64 - 5.56 (m, 1H), 4.89 (d, J = 2.5
Hz, 1H), 4.08 (d, J = 8.5 Hz, 1H), 3.06 (ddq, J = 8.5 Hz,
3.5 Hz, 1.5 Hz, 1H), 2.36 (ddd, J = 15.5 Hz, 10.0 Hz, 2.0
Hz, 1H), 1.61 (dd, J = 15.0 Hz, 9.0 Hz, 1H); m/z = 361.23
[M+H]+.
26.
27.
28.
29.
30.
Auge, J.; Lubin-Germain, N.; Uziel, J. Synthesis 2007,
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Experimental procedure for the synthesis of TQS (3) : In a
microwave vial, cyclopentadiene (254 mg, 3.84 mmol, 3
equiv.) was added to a suspension of 1–naphthaldehyde
(200 mg, 1.28 mmol), 4-aminosulfonamide (220 mg, 1.28
mmol) and indium (III) chloride (55.6 mg, 0.256 mmol,
0.2 equiv.) in acetonitrile (5 mL). The reaction vial was
placed in a Biotage Initiator microwave synthesizer and
heated to 100°C for 15 min. The contents were added to
10% aqueous Na2CO3 solution (0.1 M; 10 mL) and
extracted with chloroform (3×20 mL). The combined
organic layer was washed with brine (15 mL), dried
(Na2SO4) and concentrated under reduced pressure. The
residue was treated with hexane/dichloromethane to
precipitate out compound 3 as an off white solid (290 mg;
yield 60%).7 Compounds 7, 8, 10, 11, 13, and 14 were
purified by column chromatography (EtOAc/Hexane =
10/90  50/50) to yield the desired product. The rest were
crystallized from dichloromethane/hexane. All compounds
were >95% pure by HPLC and 1H NMR.
Compound 9: 1H NMR (500 MHz, DMSO-d6) 7.34 (d, J
= 2.0 Hz, 1H), 7.26 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 6.89 (s,
2H), 6.80 (d, J = 9.0 Hz, 1H), 5.87 – 5.81 (m, 1H), 5.70 –
5.65 (m, 1H), 5.62 (s, 1H), 3.89 (d, J = 9.0 Hz, 1H), 3.02
(dd, J = 8.5 Hz, 2.0 Hz, 1H), 2.33 – 2.23 (m, 1H), 2.22 –
2,14 (m,2H), 1.88 – 1.60 (m, 4H), 1.34 – 1.10 (m , 4H),
1.16 – 0.88 (m, 2H); m/z = 333.79 [M+H]+. Compound
10: 1H NMR (500 MHz, CDCl3)  d J = 8.0 Hz, 1H),
7.90 (dd, J = 7.5 Hz, 1.5 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H),
7.74 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.57 –
7.44 (m, 3H), 7.27 (d, J = 7.5 Hz, 1H), 6.78 (t, J = 7.5 Hz,
1H), 5.99 (s, 1H), 5.84 – 5.79 (m, 1H), 5.65 – 5.59 (m,
1H), 5.52 (d, J = 3.0 Hz, 1H), 4.90 (s, 2H), 4.28 (d, J = 9.0
Hz, 1H), 3.33 (dq, J = 9.0 Hz, 2.0 Hz, 1H), 2.56 (ddd, J =