Straightforward synthesis of pyrrolo[3,4-b]quinolines through intramolecular Povarov reactions

Article abstract of DOI:10.1016/j.tetlet.2015.10.107

A series of novel pyrrolo[3,4-b]quinolines have been synthesized from N-alkynyl aldehydes and various substituted arylamines in good to excellent yields utilizing an intramolecular Povarov reaction catalyzed by boron trifluoride diethyl etherate as the key final step.

Full text of DOI:10.1016/j.tetlet.2015.10.107

Accepted Manuscript
Straightforward synthesis of pyrrolo[3,4-b]quinolines through intramolecular
Povarov reactions
Abdulrahman I. Almansour, Natarajan Arumugam, Raju Suresh Kumar, J.
Carlos Menéndez, Hazem A. Ghabbour, Hoong-Kun Fun, Raju Ranjith Kumar
PII:
S0040-4039(15)30304-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.107
TETL 46936
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 April 2015
23 July 2015
29 October 2015
Please cite this article as: Almansour, A.I., Arumugam, N., Kumar, R.S., Carlos Menéndez, J., Ghabbour, H.A.,
Fun, H-K., Kumar, R.R., Straightforward synthesis of pyrrolo[3,4-b]quinolines through intramolecular Povarov
reactions, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.10.107
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Graphical Abstract
Straightforward synthesis of pyrrolo[3,4-b]
quinolines through intramolecular Povarov
reactions
Leave this area blank for abstract info.
Abdulrahman I. Almansour, Natarajan Arumugam,* Raju Suresh Kumar, J. Carlos Menéndez, Hazem A.
Ghabbour, Hoong-Kun Fun, Raju Ranjith Kumar

1
Tetrahedron Letters
journal homepage: www.els evier.com
Straightforward synthesis of pyrrolo[3,4-b]quinolines through intramolecular Povarov
reactions
Abdulrahman I. Almansour,a Natarajan Arumugam,a,* Raju Suresh Kumar,a J. Carlos Menéndez,b Hazem
A. Ghabbour,c Hoong-Kun Fun,c,d Raju Ranjith Kumare
aDepartment of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
bDepartamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, Madrid 28040, Spain
cDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
dX-ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, Penang 11800, Malaysia
eDepartment of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of novel pyrrolo[3,4-b]quinolines have been synthesized from N-alkynyl aldehydes and
various substituted arylamines in good to excellent yields utilising an intramolecular Povarov
reaction catalyzed by boron trifluoride diethyl etherate as the key final step.
Received in revised form
Accepted
2013 Elsevier Ltd. All rights reserved
.
Available online
Keywords:
N-Propargylated aldehyde
[4+2] Cycloaddition reactions
Intramolecular Povarov reactions
Pyrrolo[3,4-b]quinolines
The quinoline nucleus is one of the most prevalent heterocyclic
scaffolds and is found in several bio-active natural products.1
Compounds with the quinoline sub-structure play a unique role in
drug discovery programs and have been found to exhibit a wide
range of pharmaceutical activities such as antimalarial,2
The reaction has gained considerable recent attention as it allows
the construction of tetrahydroquinolines using multicomponent
reaction methodology in the presence of protic and Lewis acids.
2,4-Disubsititued quinolines have been synthesized by several
research groups using alkynes as dienophiles using the Povarov
reaction followed by either an aerobic oxidation or by using an
additional oxidant. The substrate imines are known to act as an
oxidant to produce quinolines from di- and tetra-hydroquinolines,
giving the corresponding amine as a byproduct.22 The synthesis
of quinolines via the Povarov reaction and a subsequent
hydrogen transfer reaction using triflic imide as an auto tandem
catalyst has been reported by Takasu and co-workers.23
antiprotozoal,3
antitubercular,4
anti-HIV,5
antibacterial,6
antifungal7 and anticancer.8 Quinoline derivatives also act as
fluorophores9 and have been studied as potential organic
semiconductors.10 Furthermore, its derivatives such as quinine
have been reported to exhibit antipyretic activity11 as well as
being found a large number of drugs such as the fluoroquinolone
antibacterials viz. Ciprofloxacin12 and levofloxacin.13
Owing to its importance in multidisciplinary fields, much effort
has been devoted to develop efficient and convenient strategies
for the synthesis of quinoline derivatives. Classical methods,
such as the Skraup,14 Combes,15 Friedlander,16 Pfitzinger17 and
Doebner-von Miller18 reactions have been frequently employed.
However, they typically do not allow the formation of quinolines
with wide diversity.
The anticancer alkaloids camptothecin and luotonin A and their
semi-synthetic analogs topotecan and irinotecan24,25 each contain
the pyrrolo[3,4-b]quinoline moiety (Figure 1). The
intramolecular Povarov reaction has been utilized by Stevenson
and co-workers for the synthesis of luotonin A26 and by Batey
and co-workers for the syntheses of the pyrrolo[3,4-b]quinoline
core of camptothecin and the total synthesis of luotonin A.27
Despite this precedent, the intramolecular Povarov reaction is
relatively unexploited in the literature. In recent years, our
research group has largely been involved in the synthesis of
hybrid bioactive heterocycles using inter/intramolecular
cycloaddition methodology.28-30 With this synthetic background,
and our aim for the synthesis of luotonin inspired heterocyclic
hybrids, herein we describe the first synthesis of 3-benzyl-2-
tosyl-2,3-dihydro-1H-pyrrolo[3,4-b] quinolone derivatives, a key
The Povarov reaction,19–21 is an inverse electron-demand aza-
Diels-Alder (IED-DA) reaction of N-aryl imines, derived from
aldehydes and anilines, with electron-rich olefins, which has
become one of the most efficient protocols for the synthesis of
quinolines. ______
*Corresponding author. Tel. +9664675907; Fax: +966 4675992
E-mail address: anatarajan@ksu.edu.sa; aruorgchem@gmail.com

2
Tetrahedron
intermediate for the synthesis of D-ring modified luotonin
inspired heterocyclic hybrids using the intramolecular Povarov
reactions.
yield,34 while the same reaction in acetonitrile gave only 68%
yield. Thus, BF3.OEt2 in dry CH2Cl2 was selected as the optimal
catalyst-solvent combination. Subsequent reactions aimed at
expansion of the reaction scope were carried out using the
optimized conditions, affording products 9a-h in excellent yields
(92-97%, Table 1).
Figure1. Promising anti-cancer leads related to the alkaloids camptothecin
and luotonin A
Scheme 2: Synthesis of pyrrolo[3,4-b]quinolines
The intramolecular Povarov reaction requires a strategically
positioned aldehyde functional group tethered to an alkynyl
component. Hence, for the construction of pyrrolo[3,4-b]
quinolines, an alkynyl-tethered aldehyde is necessary.
Consequently, our synthetic work began with the inexpensive,
readily available chiral pool precursor (S)-phenylalanine 1, which
was subjected to the sequence of transformations outlined in
Scheme 1. Thus, (S)-phenylalanine 1 was converted into its ethyl
ester hydrochloride 2 by treatment with an excess of thionyl
chloride in dry ethanol.31 The hydrochloride salt of the
phenylalanine ester was protected as the N-sulfonylester 3 in
good yield,32 which was then subjected to N-alkylation using
propargyl bromide to obtain N-propargyl ester 4 in excellent
yields (Scheme 1). The structure of N-propargyl ester 4 was
confirmed from NMR spectroscopic data.33 A two-step sequence
involving reduction of the ester to an alcohol and the subsequent
oxidation was adopted to obtain aldehyde 6. Thus, reduction
using 2 equiv. of sodium borohydride in ethanol afforded alcohol
5 in 95% yield, which was converted into cyclisation precursor 6
in quantitative yield using iodoxybenzoic acid (IBX) (Scheme 1).
The structures of alcohol 5 and aldehyde 6 were confirmed
through spectroscopic analysis.
Table 1. Synthesis of pyrrolo[3, 4-b]quinolines (9a-h)
Yield
(%)a,b
Entry Product
R
mp (oC)
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
H
164-166
188-190
176-178
189-191
187-189
200-202
198-200
180-191
92
93
95
97
95
96
94
92
2-Br
3-Br
4-Br
2-Cl
4-Cl
9g
9h
4-CH3
4-MeO
aIsolated yield after purification by column chromatography. bConditions:
BF3.OEt2, 20 mol%, 12 h, ambient temperature
The structures of compounds 9a-h were confirmed by 1H and
13C NMR spectral analysis. Furthermore, the structures of 9e and
9f were unambiguously corroborated by single crystal X-ray
diffraction analysis35 and ORTEP diagrams with all atom labels
are shown in Figure 1. X-ray analysis yielded a monoclinic,
crystal lattice with P21/c and C2/c space groups, respectively.
The pyrrolo[3,4-b]quinoline ring was almost planar, however the
two aryl rings attached to pyrrolo[3,4-b]quinoline moiety were
tilted. The dihedral angles between the aryl ring (C13-C18) and
the pyrrolo[3,4-b]quinoline (C1-C9/N2/C10-C11) were found to
be 51.13° and 67.38° in compounds 9e and 9f, respectively. The
methyl-aryl ring (C19-C24) showed a dihedral angle of 88.81°
and 88.70° for the pyrrolo[3,4-b]quinoline (C1-C9/N2/C10-C11)
in the compounds 9e and 9f, respectively. The crystal structure in
compound 9e was found to be stabilized by intra/intermolecular
hydrogen bonding C12—H12B•••O2, C20—H20A•••O1, C24—
H24A•••O2 and C23—H23A•••O1, whereas the crystal structure
of compound 9f was stabilized by C12—H12B•••O2, C24—
H24A•••O2 and C25—H25C•••O2 hydrogen bonding.
Scheme 1. Synthesis of N-alkynyl aldehyde 6
Having synthesized aldehyde
6
in good yield, an
intermolecular Povarov reaction was performed for the synthesis
of a series of hybrid heterocycles 9a-h (Scheme 2). For
optimization studies, this reaction was initially investigated by
the reaction of an equimolar mixture of aldehyde 6 and p-
toluidine 7g in the presence of Lewis acid catalysts such as InCl3,
InBr3, CAN and Yb(OTf)3 in acetonitrile at 70 oC for 12 hours. In
all these reactions, less than 5% of product 9g was obtained along
with a mixture of inseparable by-products. Extending the reaction
time to 48 hours resulted in a small increase in yield (22%) using
Yb(OTf)3, whilst there was no appreciable increase in yield using
InCl3, InBr3 and CAN. The reaction was then attempted using
boron trifluoride diethyl etherate (BF3.OEt2, 20 mol%) in dry
CH2Cl2 containing molecular sieves at ambient temperature for
12 h. Under these conditions, the reaction afforded 9g in 94%
A plausible mechanism for the formation of compounds 9 is
depicted in Scheme 3. The N-tethered propargyl aldehyde 6
reacts with the arylamine 7 to form arylimine 8, which then
undergoes
dihydroquinoline intermediate, which undergoes oxidative
a
formal [4+2] cycloaddition to form
a
aromatisation in air to afford the pyrrolo[3,4-b]quinolone 9.

3
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In conclusion, N-alkynylaldehyde 6 was obtained in five steps
in good yield from readily available (S)-phenylalanine. The
BF3.OEt2 catalyzed intramolecular Povarov reaction of 6 with
various substituted arylamines afforded a series of pyrrolo[3,4-
b]quinolines in excellent yields. To the best of our knowledge,
this is the first report for the preparation of 3-benzyl-2-tosyl-2,3-
dihydro-1H-pyrrolo[3,4-b]
intermediates for the synthesis of D-ring modified luotonin
inspired heterocyclic hybrids.
quinolines,
which are
key
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Acknowledgments
This Project was funded by the National Plan for Science,
Technology and Innovation (MAARIFAH), King Abdulaziz City
for Science and Technology, Kingdom of Saudi Arabia, Award
Number (12MED2503-02).
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Supplementary Material
Supplementary data associated with this article can be found in
the online version, at http://
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4
Tetrahedron
Suresh Kumar, R.; Periyasami, G.; Ghabbour, H. A.; Fun, H.-K.
Molecules 2015, 20, 780.
concentrated under reduced pressure. The crude product was
subjected to flash column chromatography eluting with hexane–
ethyl acetate mixture (9:1) to obtain pure. (S)-ethyl 2-(4-methyl-N-
(prop-2-yn-1-yl)phenylsulfonamido)-3-phenylpropanoate, 4 5.05
g, 91%, white solid, mp: 112-114 oC; 1H NMR (400 MHz,
CDCl3): δH 1.06 (t, J = 6.96 Hz, 3H), 2.18 (s, 1H), 2.40 (s, 3H),
3.05 (dd, J = 13.92, 7.32 Hz, 1H), 3.30 (dd, J = 13.96, 8.8 Hz,
1H), 3.94-4.02 (m, 2H), 4.25-4.26 (m, 2H), 4.75 (t, J = 8.08 Hz,
1H), 7.19-7.65 (m, Ar-H, 9H) ppm; 13C NMR (100 MHz, CDCl3):
δC 14.3, 22.0, 34.6, 37.2, 61.4, 61.8, 73.4, 79.6, 127.3, 128.2,
129.0, 129.7, 129.8, 137.0, 137.2, 143.0, 170.7 ppm. LC/MS
(ESI): 386 (M+); Anal.Calcd for C21H23NO4S: C, 65.43; H, 6.01;
N, 3.63%. Found: C, 65.54; H, 6.11; N, 3.73%.
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34. General procedure for synthesis of pyrrol[3,4-b]quinolines, 9a-h
To (S)-4-methyl-N-(1-oxo-3-phenylpropan-2-yl)-N-(prop-2-yn-1-
yl)benzenesulfonamide (6) (100 mg, 0.29 mmol) in dry CH2Cl2
was added p-toluidine 7g (27 mg, 0.29 mmol) followed by added
BF3.OEt2 (20 mol%). The reaction mixture was stirred for 12 h at
ambient temperature. Upon completion of the reaction as evident
by TLC analysis, the solvent was removed under reduced
pressure. The crude product was purified by column
chromatography eluting with hexane:ethyl acetate mixture
(8.5:1.5) to obtain 3-benzyl-2-tosyl-2,3-dihydro-1H-pyrrolo[3,4-
b]quinoline in good yield. Characterization data for representative
31. Poornachandran, M.; Raghunathan, R. Tetrahedron: Asymmetry
2008, 19, 2177.
32. (a) Dauban, P.; Dodd, R. H. Tetrahedron Lett. 1998, 39, 5739; (b)
Kostyanovsky, R. G.; Shustov, G. V.; Zaichenko, N. L.
Tetrahedron 1982, 38, 949.
33. Preparation
of
(S)-ethyl
2-(4-methyl-N-(prop-2-yn-1-
yl)phenylsulfonamido)-3-phenyl-propanoate, 4 To a solution of
(S)-ethyl 2-(4-methylphenylsulfonamido)-3-phenylpropanoate (5
g, 0.144 mol) in dry acetone (40 mL) under nitrogen atmosphere
was added K2CO3 (6.95 g, 0.054 mole). To this stirred solution,
propargyl bromide (2.57 g, 0.215mol) in dry acetone (10 mL) was
added and the stirring was continued for 8–10 h. After completion
of the reaction, the solid was filtered and the residue was washed
with acetone (3 ×15 mL) and before the filtrate was concentrated
in vacuo and extracted with CH2Cl2 (30 mL) and water (30 mL).
The organic extract was washed with a brine solution (50 mL × 2)
and
compounds
3-benzyl-7-methyl-2-tosyl-2,3-dihydro-1H-
pyrrolo[3,4-b]quinoline, 9g: (118 mg, 94%); Colorless crystals.1H
NMR (400 MHz, CDCl3): δH 2.30 (s, 3H), 2.48 (s, 3H), 3.49 (dd, J
= 13.20, 2.92 Hz, 1H), 3.60 (dd, J = 13.20, 5.12 Hz, 1H), 4.05 (d,
J = 14.68 Hz, 1H), 4.50 (d, J =14.64 Hz, 1H), 5.28-5.29 (m, 1H),
6.90-7.97 (m, Ar-H, 13H) ppm; 13C NMR (100 MHz, CDCl3): δC
21.42, 21.48, 41.36, 51.64, 65.95, 126.18, 126.62, 127.21, 127.67,
128.42, 128.54, 128.72, 129.86, 130.11, 130.57, 131.88, 134.77,
135.95, 136.56, 143.69, 146.62, 160.06 ppm. LC/MS (ESI): 429
(M+1); Anal.Calcd for C26H24N2O2S: C, 72.87; H, 5.64; N, 6.54%.
Found: C, 72.96; H, 5.55; N, 6.66%.
35. Crystallographic data (including structure factors) for the
compounds 9e and 9f have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 1046773-1046776. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].