ChemInform Abstract: Transition Metal Mediated Construction of Pyrrole Ring on 2,3-Dihydroquinolin-4(1H)-one: Synthesis and Pharmacological Evaluation of Novel Tricyclic Heteroarenes.

Article (PDF Available)inOrganic & Biomolecular Chemistry 9(4):1004-7 · February 2011with44 Reads
DOI: 10.1039/c0ob00771d · Source: PubMed
A facile two-step method for the construction of fused pyrrole ring leading to 5-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-1-ones via C-C followed by intramolecular C-N bond forming reaction is described. In vitro pharmacological evaluation and molecular modelling studies of some of the compounds synthesized are presented.


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Org. Biomol. Chem.
, 2011, 9, 1004
Transition metal mediated construction of pyrrole ring on
2,3-dihydroquinolin-4(1H)-one: synthesis and pharmacological evaluation
of novel tricyclic heteroarenes†
Mohosin Layek,
Appi Reddy M.,
A. V. Dhanunjaya Rao,
Mallika Alvala,
M. K. Arunasree,
Aminul Islam,
K. Mukkanti,
Javed Iqbal*
and Manojit Pal*
Received 23rd September 2010, Accepted 3rd December 2010
DOI: 10.1039/c0ob00771d
A facile two-step method for the construction of fused pyrrole
ring leading to 5-substituted 2,3-dihydro-1H-pyrrolo[3,2,1-
ij]quinolin-1-ones via C–C followed by intramolecular C–N
bond forming reaction is described. In vitro pharmacological
evaluation and molecular modelling studies of some of the
compounds synthesized are presented.
The 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline framework (A,
Fig. 1) has attracted particular attention in the area of new drug
discovery because of their various phar macological properties.
The 6-oxopyrroloquinoline ring B (Fig. 1) on the other hand
though uncommon in nature has been an integral part of a
promising antiviral agent PHA-529311.
A combination of both
in a single molecule therefore would provide a new template
C for the design and identification of compounds of potential
pharmacological interest. Prompted by this idea and due to our
long standing interest in the area of metabolic disorder
we became
interested in the synthesis and pharmacological evaluation of a
library of compounds containing the heterocyclic structure C.
Our objective was to identify novel small molecules as activators of
SIRT1 that are structurally unrelated to resveratrol
which belongs
to the trans-stilbene class. Synthetic 2,3-dihydro-1H-pyrrolo[3,2,1-
ij]quinolin-1-ones have been reported in the literature preparation
Fig. 1 Design of new template C as potential pharmacophore.
Custom Pharmaceutical Services, Dr Reddy’s Laboratories Limited, Bol-
laram Road Miyapur, Hyderabad, 500 049, India
Chemistry Division, Institute of Science and Technology, Jawaharlal Nehru
Technological University, Hyderabad 500085, Andhra Pradesh, India
Institute of Life Sciences, University of Hyderabad Campus, Gachibowli,
Hyderabad 500 046, Andhra Pradesh, India
Electronic supplementary information (ESI) available: Experimental
procedures, spectral data for all new compounds, results of docking study.
See DOI: 10.1039/c0ob00771d
of which mainly involve two general strategies, for example, (i)
the construction of a new six membered ring between N1 and
C7 of an indole,
or (ii) the construction of a pyrrole ring onto
a 2,3-dihydroquinolin-4(1H)-one.
Recently, derivative of C has
been isolated as a side product during Pt-mediated cyclization
of N-(2-alkynylphenyl)lactams.
Nevertheless, a general method
for the synthesis of 5-subtituted 2,3-dihydro-1H-pyrrolo[3,2,1-
ij]quinolin-1-one following the second strategy is not common
in the literature. Due to our continuing interest in this strategy
we now report a new and two-step synthesis of 5-subtituted
2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-1-ones under transition
metal catalysis (Scheme 1) along with their pharmacological eval-
uation as potential SIRT1 activators. The present communication
addresses several challenging issues e.g. (i) the preparation and use
of iodoarene 1 as starting material (ii) the reactivity of alkyne 3
towards transition metal-mediated intramolecular cyclization, (iii)
the optimal catalyst system and (iv) SIRT1 activating potential of
tricyclic compound 4.
Scheme 1 Synthesis of 5-subtituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]qui-
nolin-1-ones (4).
To this end we focused on establishing an optimized condition
to obtain compound 4 via intramolecular C–N bond formation.
The starting alkynes 3 (Z = Me & Cl) were prepared by using a
Pd/C-mediated coupling reaction in ethanol. Thus, 6-substituted
8-iodo-2,3-dihydroquinolin-4(1H)-one (1), prepared according to
a modified procedure (Scheme 2) based on a reported method,
was reacted with a number of terminal alkynes in the presence
of 10%Pd/C–CuI–PPh
in EtOH using Et
Sonogashira coupling) to afford the desired products 3.
results are summarized in Table 1.
The intramolecular cyclization of alkyne 3a was examined using
a number of catalysts under various reaction conditions (Table 2),
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Table 1 Pd/C-mediated synthesis of 8-alkynyl-2,3-dihydroquinolin-
4(1H)-one (3)
Entry 1;Z= Alkyne; R = Time (h) Product (3)%Yield
1 1a;Me C
4.0 3a 88
2 1a C
Me-p 2.0 3b 70
3 1a C
-m 6.0 3c 60
4 1a (CH
CN 10 3d 90
5 1a (CH
Cl 12 3e 90
6 1a CMe
12 3f 55
7 1a (CH
OH 4.0 3g 85
8 1b;Cl C
8.0 3h 76
All the reactions were carried out using 1 (1.0 mmol), terminal alkyne (1.5
mmol), 1 : 4 : 10 ratio of Pd/C-PPh
-CuI and Et
N (2.6 mmol) in EtOH at
Isolated yield.
Table 2 Transition metal-mediated intramolecular cyclization of 3a
Entry Catalyst (mmol) Solvent Time (h) T/
1 AgNO
(0.5) DMF 12 80 75
2 AgSbF
(0.5) DMF 10 80 80
3 AgSbF
(0.5) Ethylene glycol 12 80 70
4 AgSbF
(0.5) DMSO 15 80 70
5 PdCl
(0.5) MeCN 3.0 80 85
6 PdCl
(0.05) MeCN 3.0 80 88
7 CuI (0.5) DMF 12 100 75
8 CuI (1.0) DMF 12 100 75
9 No cat. MeCN 12 100 11
All the reactions were carried out using 3a (1.0 mmol) and catalyst in a
Isolated yield.
Scheme 2 Preparation of 8-iodo-2,3-dihydroquinolin-4(1H)-ones (1).
e.g. (a) AgNO
in DMF at 80
C (entry 1, Table 2) or (b) AgSbF
in DMF at 80
C (entries 2–4, Table 2) or (c) PdCl
in acetonitrile
at 80
C (entry 5 & 6, Table 2) or (d) CuI in DMF at 100
(entries 7 & 8, Table 2). However, the best results were obtained
by using 0.05 equiv of PdCl
in acetonitrile at 80
the desired product 4a was isolated in 88% yield. The use of other
[e.g. Cu(OAc)
] or no catalyst (entry 9, Table 1) was also examined
but afforded lower yield of product. To assess the generality of
Pd-mediated intramolecular C–N bond forming reaction we then
treated other alkynes, i.e. 3b–h with PdCl
in CH
CN (Table 3).
All the 8-arylethynyl-2,3-dihydroquinolin-4(1H)-one (3a–c & 3h)
provided the desired products (4a–c & 4h) in moderate to good
yields (entries 1–3 & 8, Table 3) whereas the 8-alkylethynyl
derivatives (3d–g) afforded the corresponding products (4d–g)in
good yields (entries 4-7, Table 3).
Having prepared a number of 5-subtituted 2,3-dihydro-1H-
pyrrolo[3,2,1-ij]quinolin-1-ones (4) we explored further structural
elaboration of some of the compounds synthesized. Accordingly,
compound 4a was converted to a chloro dialdehyde 8 under
Table 3 Synthesis of 5-subtituted 2,3-dihydro-1H-pyrrolo[3,2,1-
ij ]quinolin-1-ones (4) under Pd-catalysis
Entry Alkyne 3 Product (4) Time (h) % Yield
1 3.0 88
4.0 70
4.0 60
6.0 90
5.0 90
4.0 65
10 85
4.0 76
All the reactions were carried out using 3 (0.6 mmol) and PdCl
mmol) in MeCN at 80
Isolated yield.
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Vilsmeier-Haack conditions and a simple oxime 9 in good yields
(Scheme 3).
Scheme 3 Structural elaboration of compound 4a.
Mechanistically, the intramolecular cyclization of 3 seemed
to proceed via initial activation of the triple bond of 3 via
coordination to the M-salt (M = Pd,AgandCu)toformthe
s-complex X (Scheme 4, see ESI†). Nucleophilic attack of the
tetrahydroquinoline moiety to the M-coordinated triple bond
through its nitrogen in an endo dig fashion provides the M-vinyl
species Y. This on subsequent protonation in situ regenerates the
catalyst producing the expected product 4.
The in vitro activity of some of the compounds synthesized on
SIRT1 was determined by using SIRT1 fluorescence activity assay
kit. Compounds 4a, 4b, 4e, 4f, 4h and 4c along with suramin,
a known inhibitor of SIRT1 were tested in this assay (Fig. 2).
At the concentration of 10 mM compound 4f showed significant
activation whereas 4a and 4b showed moderate to low activation
of SIRT1 in compared to the inhibitory effect of suramin. A
molecular docking simulation study to understand the interaction
of 4f with the protein i.e. homology model of hSIRT1 (144–217
amino acid residues) indicated that eight amino acid residues
played key roles with the binding energy of -6.09 Kcal/mol
(Fig. 3, see ESI†). Since activation of SIRT1 could serve as a novel
approach to treat type II diabetes and other metabolic disorders
hence compounds 4a,4b and 4f may have pharmaceutical value.
Fig. 2 SIRT1 activation by some of the 5-subtituted 2,3-dihy-
dro-1H-pyrrolo[3,2,1-ij]quinolin-1-ones in vitro.
In summary, we have developed a simple method to give
5-subtituted 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-1-ones that
Fig. 3 Docking of 4f intotheactivesiteofSIRT1.
were not easily accessible via earlier methods. This general method
proceeds via Pd-mediated C–C bond forming reaction followed
by C–N bond to afford an array of compounds of potential
pharmacological significance.
The authors thank Dr Vilas Dahanukar, Dr Dipak Kalita and
the analytical group of DRL. M.P. thanks DST, new Delhi, India
for financial support (Grant NO. SR/S1/OC-53/2009).
Notes and references
1 D. Paris, M. Cottin, P. Demonchaux, G. Augert, P. Dupassieux, P.
Lenoir, M. J. Peck and D. Jasserand, J. Med. Chem., 1995, 38, 669.
2 M. Isaac, A. Slassi, A. O’Brien, L. Edwards, N. MacLean, D.
Bueschkens, D. K. H. Lee, K. McCallum, L. D. Lannoy, I. Demchyshyn
and R. Kamboj, Bioorg. Med. Chem. Lett., 2000, 10, 919.
3 R. S. Al-awar, J. E. Ray, K. A. Hecker, J. Huang, P. P. Waid, C. Shih,
H. B. Brooks, C. D. Spencer, S. A. Watkins, B. R. Patel, N. B. Stamm,
C. A. Ogg, R. M. Schultz, E. L. Considine, M. M. Faul, K. A. Sullivan,
S. P. Kolis, J. L. Grutsch and S. Joseph, Bioorg. Med. Chem. Lett., 2004,
14, 3217.
4 G. Zhu, S. E. Conner, X. Zhou, H.–k Chan, C. Shih, T. A. Engler, R. S.
Al-awar, H. B. Brooks, S. A. Watkins, C. D. Spencer, R. M. Schultz,
J. A. Dempsey, E. L. Considine, B. R. Patel, C. A. Ogg, V. Vasudevan
andM.L.Lytle,Bioorg. Med. Chem. Lett., 2004, 14, 3057.
5 R. L. Dorow, P. M. Herrinton, R. A. Hohler, M. T. Maloney, M. A.
Mauragis, W. E. McGhee, J. A. Moeslein, J. W. Strohbach and M. F.
Veley, Org. Process Res. Dev., 2006, 10, 493.
6(a)M.Pal,Drug Discovery Today, 2009, 14, 784; (b)M.Pal,Curr.
Med. Chem., 2009, 16, 3858; (c)S.H.HavaleandM.Pal,Bioorg. Med.
Chem., 2009, 17, 1783.
7(a) SIRT1 is an NAD
-dependent protein deacetylase that appears
to produce beneficial effects on metabolic parameters such as glucose
and insulin homeostasis. Activation of SIRT1 by resveratrol has been
shown to modulate insulin resistance, increase mitochondrial content
and prolong survival in lower organisms and in mice on a high fat diet.
Sirt 1 activators are therefore reported to be beneficial for the potential
treatment of type 2 diabetes via anti-aging effect; for a review, see:
M. Shaday and D. Sinclair, Biochem. J., 2007, 404,1;(b) Resveratrol, a
naturally occurring activator of SIRT1, has been reported to extend life
span in yeast, drosophila and rodents. When administered to rodents,
resveratrol has been demonstrated to improve metabolism and glucose
tolerance, as well as overall physical performance in various stress tests,
see: M. Lagouge, C. Argmann, Z. Gerhart-Hines, H. Meziane, C. Lerin,
F. Daussin, N. Messadeq, J. Milne, P. Lambert, P. Elliott, B. Geny, M.
Laakso, P. Puigserver and J. Auwerx, Cell, 2006, 127, 1109.
8(a) K. Nishijima, T. Shinkawa, M. Ito, H. Nishida, L. Yamamoto, Y.
Onuki, H. Inaba and S. Miyano, Eur. J. Med. Chem., 1998, 33, 763;
1006 | Org. Biomol. Chem., 2011, 9, 1004–1007 This journal is
The Royal Society of Chemistry 2011
Downloaded by ST JOHNS UNIVERSITY on 21 January 2013
Published on 06 December 2010 on | doi:10.1039/C0OB00771D
View Article Online
(b) R. Neidlein and U. Rietdorf, Arch. Pharm., 1982, 315, 901; (c)S.
Mayer, J.-Y. M
erour, B. Joseph and G. Guillaumet, Eur. J. Org. Chem.,
2002, 1646.
9 J. Reisch and R. A. Salehi-Artimani, Pharmazie, 1990, 45, 831.
10 G. Li, X. Huang and L. Zhang, Angew. Chem., Int. Ed., 2008, 47, 346.
11 (a) M. Layek, A. V. D. Rao, V. Gajare, D. Kalita, D. K. Barange, A.
Islam, K. Mukkanti and M. Pal, Tetrahedron Lett., 2009, 50, 4878;
(b) M. Layek, V. Gajare, D. Kalita, A. Islam, K. Mukkanti and M. Pal,
Tetrahedron Lett., 2009, 50, 3867.
12 G. Bradley and J. Clark, J. Chem. Soc., Perkin Trans. 1, 1972, 2019An
attempt to prepare compound 1 from the corresponding o-iodoaniline
derivative was unsuccessful due to the failure of cyclization step using
polyphosphoric acid.
13 M. Pal, Synlett, 2009, 2896.
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