Transition metal mediated construction of pyrrole ring on 2,3-dihydroquinolin-4(1H)-one: Synthesis and pharmacological evaluation of novel tricyclic heteroarenes

Article abstract of 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

Full text of DOI:10.1039/c0ob00771d

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COMMUNICATION
Transition metal mediated construction of pyrrole ring on
2,3-dihydroquinolin-4(1H)-one: synthesis and pharmacological evaluation
of novel tricyclic heteroarenes†
Mohosin Layek,a,b Appi Reddy M.,a A. V. Dhanunjaya Rao,a Mallika Alvala,c M. K. Arunasree,c
Aminul Islam,a K. Mukkanti,b Javed Iqbal*c and Manojit Pal*c
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.
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,8 or (ii) the construction of a pyrrole ring onto
a 2,3-dihydroquinolin-4(1H)-one.9 Recently, derivative of C has
been isolated as a side product during Pt-mediated cyclization
of N-(2-alkynylphenyl)lactams.10 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 strategy11
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.
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 pharmacological properties.1–4
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-529311.5 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 disorder6 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 resveratrol7 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
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,12
was reacted with a number of terminal alkynes in the presence
of 10%Pd/C–CuI–PPh3 in EtOH using Et3N as a base (e.g.
Sonogashira coupling) to afford the desired products 3.13 The
results are summarized in Table 1.
Fig. 1 Design of new template C as potential pharmacophore.
aCustom Pharmaceutical Services, Dr Reddy’s Laboratories Limited, Bol-
laram Road Miyapur, Hyderabad, 500 049, India
bChemistry Division, Institute of Science and Technology, Jawaharlal Nehru
Technological University, Hyderabad 500085, Andhra Pradesh, India
cInstitute 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
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)a
Table 3 Synthesis of 5-subtituted 2,3-dihydro-1H-pyrrolo[3,2,1-
ij]quinolin-1-ones (4) under Pd-catalysisa
Entry
1; Z =
Alkyne; R =
Time (h)
Product (3)
% Yieldb
Entry Alkyne 3
Product (4)
Time (h) % Yieldb
1
2
3
4
5
6
7
8
1a; Me
1a
C6H5
4.0
2.0
6.0
10
12
12
3a
3b
3c
3d
3e
3f
88
70
60
90
90
55
85
76
1
3.0
88
C6H5Me-p
C6H4NO2-m
(CH2)3CN
(CH2)3Cl
CMe3
(CH2)2OH
C6H5
1a
1a
1a
1a
1a
4.0
8.0
3g
3h
1b; Cl
2
4.0
70
a All the reactions were carried out using 1 (1.0 mmol), terminal alkyne (1.5
mmol), 1 : 4 : 10 ratio of Pd/C-PPh3-CuI and Et3N (2.6 mmol) in EtOH at
80 ◦C. b Isolated yield.
Table 2 Transition metal-mediated intramolecular cyclization of 3aa
Entry Catalyst (mmol) Solvent
Time (h) T/◦C % Yieldb
3
4.0
60
1
2
3
4
5
6
7
8
9
AgNO3 (0.5)
AgSbF6 (0.5)
AgSbF6 (0.5)
AgSbF6 (0.5)
PdCl2 (0.5)
PdCl2 (0.05)
CuI (0.5)
DMF
DMF
Ethylene glycol 12
DMSO
MeCN
MeCN
DMF
12
10
80
80
80
80
80
80
100
100
100
75
80
70
70
85
88
75
75
11
15
3.0
3.0
12
12
12
CuI (1.0)
No cat.
DMF
MeCN
4
5
6
6.0
5.0
4.0
90
90
65
a All the reactions were carried out using 3a (1.0 mmol) and catalyst in a
solvent. b Isolated yield.
Scheme 2 Preparation of 8-iodo-2,3-dihydroquinolin-4(1H)-ones (1).
e.g. (a) AgNO3 in DMF at 80 ◦C (entry 1, Table 2) or (b) AgSbF6
in DMF at 80 ◦C (entries 2–4, Table 2) or (c) PdCl2 in acetonitrile
at 80 ◦C (entry 5 & 6, Table 2) or (d) CuI in DMF at 100 ◦C
(entries 7 & 8, Table 2). However, the best results were obtained
by using 0.05 equiv of PdCl2 in acetonitrile at 80 ◦C for 3 h when
the desired product 4a was isolated in 88% yield. The use of other
[e.g. Cu(OAc)2] 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 PdCl2 in CH3CN (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).
7
8
10
85
76
4.0
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
a All the reactions were carried out using 3 (0.6 mmol) and PdCl2 (0.028
mmol) in MeCN at 80 ◦C. b 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, Ag and Cu) to form the
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.
Fig. 3 Docking of 4f into the active site of SIRT1.
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.
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).
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SIRT1 activation by some of the 5-subtituted 2,3-dihy-
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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
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The Royal Society of Chemistry 2011
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