Conformationally restricted functionalized heteroaromatics: A direct access to novel indoloindoles via Pd-mediated reaction

Article abstract of DOI:10.1039/c2cc38342j

A new, versatile and direct Pd-mediated method involving intramolecular cyclization of N-(2-iodoaryl)-N-(1-alkyl-1H-indol-2-yl)alkane/arene/heteroarene sulfonamide has been developed leading to a diverse and unique class of indolo[2,3-b]indoles for the potential inhibition of sirtuins.

Full text of DOI:10.1039/c2cc38342j

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Conformationally restricted functionalized
heteroaromatics: a direct access to novel
indoloindoles via Pd-mediated reaction†
Bagineni Prasad,a B. Yogi Sreenivas,a D. Rambabu,a G. Rama Krishna,b
C. Malla Reddy,b K. Lalith Kumara and Manojit Pal*a
Cite this: Chem. Commun., 2013,
49, 3970
Received 20th November 2012,
Accepted 3rd January 2013
DOI: 10.1039/c2cc38342j
www.rsc.org/chemcomm
A new, versatile and direct Pd-mediated method involving intra-
molecular cyclization of N-(2-iodoaryl)-N-(1-alkyl-1H-indol-2-yl)alkane/
arene/heteroarene sulfonamide has been developed leading to a
diverse and unique class of indolo[2,3-b]indoles for the potential
inhibition of sirtuins.
The development of straightforward, versatile and new chemical
approaches leading to densely functionalized heteroaromatics is of
enormous importance as it allows the exploration of a diverse region
of chemical space useful for pharmaceutical/medicinal chemistry
efforts. Conformational restriction of heteroaromatics on the other
hand has provided valuable insight into the early stage of drug
discovery on several occasions.1 This2 and the importance of indoles
as privileged structural motifs in medicinal chemistry/drug discovery
prompted us to explore a new route to indolo[2,3-b]indoles (B, Fig. 1)
as potential inhibitors of sirtuins. The sirtuins (class III NAD-
dependent deacetylases) shown to be up-regulated in various types
of cancer are considered promising targets for cancer therapeutics.3
Inhibition of sirtuins allows re-expression of silenced tumor
Fig. 2 Binding mode of A in yeast Sir2 (PDBID: 1Q1A).
suppressor genes, leading to reduced growth of cancer cells. Our
target molecules derived from a known inhibitor,3b EX-537, were
designed based on the in silico binding studies of the represen-
tative compound A (Fig. 1) in the catalytic pocket of yeast Sir2
(Fig. 2). The study showed binding of A deep into the active site
(docking score À5.8) along with an H-bond interaction of sulfonyl
oxygen with the side chain amino group of ASN 35 (see ESI†).
In recent years, the intramolecular direct arylation leading to
fused heteroaromatics, via a radical pathway4 or transition metal-
catalyzed single5 or double C–H bond activation,6 has attracted
particular attention. These methodologies offer a quick access to
diverse and complex molecular structures via C–C bond forming
reactions. We envisioned that transition metal mediated C-3 aryla-
tion of indole in an intramolecular fashion could lead to our target
compounds A/B. Herein we report our preliminary results on
Pd-mediated intramolecular cyclization of N-(2-iodoaryl)-N-(1-alkyl-
1H-indol-2-yl)alkane/arene/heteroarene sulfonamide 3 leading to
indolo[2,3-b]indoles 4 (or B, Scheme 1). To the best of our
Fig. 1 Design of A/B as novel inhibitors of sirtuins.
a Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad 500 046, India. E-mail: manojitpal@rediffmail.com;
Tel: +91 40 6657 1500
b Department of Chemical Sciences, Indian Institute of Science Education and Research,
Kolkata, West Bengal 741252, India
† Electronic supplementary information (ESI) available: Experimental proce-
dures, spectral data for all new compounds, results of in vitro and docking study.
CCDC 903580. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c2cc38342j
Scheme 1 Pd-mediated synthesis of novel indolo[2,3-b]indoles.
c
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Table 1 Iodine-mediated synthesis of sulfonamide 3a
Table 2 Effect of conditions on intramolecular cyclization of 3aa
Entry Catalyst
Base
Solvent
Time (h) Yieldb (%)
Anilides (1)
Entry X, R1
Indole (2) Tb/ Product (3)
Yieldc
(%)
R2, R3, Y
Me, C6H4Me-p Me, H, CH
h
R2, R3, R1, X, Y
1
2
3
4
5
6
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
K2CO3 MeCN 10
K2CO3 1,4-Dioxane 10
K2CO3 Toluene
K2CO3 DMF
Et3N
Et3N
25c
40d
40e
75
85
50f
80
82
81
0
1
4
Me, H, C6H4Me-p,
Me, CH
75
10
5
5
5
4
4
4
10
10
12
1a
F, CH3
1b
Cl, CH3
1c
Me, CH3
1d
F, C6H4Me-p 2a
2a
2a
3a
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
2
3
4
5
6
7
6
6
4
5
Me, H, CH3, F, CH
3b
Me, H, CH3, Cl, CH
3c
Me, H, Me, CH3, CH
3d
Me, H, C6H4Me-p, F, CH 72
60
62
70
7
8
Pd(OAc)2, X-Phos Et3N
Pd(OAc)2, P(o-tol)3 Et3N
2a
2a
9
Pd(OAc)2, PPh3
Cu(OAc)2
CuI
Et3N
Et3N
Et3N
Et3N
10
11
12
0
Pd2(dba)3
38g
1e
3e
a
H, C6H4Me-p 2a
1f
Cl, C6H4Me-p 2a
4.5 Me, H, C6H4Me-p, H, CH 74
Reaction conditions: 3a (1.0 mmol), catalyst (5.0 mol%) and base
b
c
3f
(2.5 mmol) in solvent (2.0 mL) at 130 1C. Isolated yield. The reaction
was performed at 80 1C. The reaction was performed at 100 1C. The
d
e
4.5 Me, H, C6H4Me-p, Cl,
63
f
CH
3g
reaction was performed at 110 1C. 2.5 mol% catalyst was used.
g
1g
N-(2-Bromo-4-methylphenyl)-4-methyl-N-(1-methyl-1H-indol-2-yl)benzene-
8
9
Br, C6H4Me-p 2a
4.5 Me, H, C6H4Me-p, Br,
62
sulfonamide was used in place of 3a.
CH
1h
3h
improved when DMF was used (entries 4 and 5, Table 2) along with
Et3N (entry 5, Table 2). The use of lower quantity of catalyst
decreased the product yield (entry 6, Table 2). The use of other
Pd-catalyst e.g. Pd(OAc)2 along with a ligand also afforded 4 in good
yield (entries 7–9, Table 2) whereas the use of Cu-catalysts was found
to be ineffective (entries 10 and 11, Table 2). The use of the 2-bromo
derivative instead of 3a was less effective (entry 12, Table 2). Overall,
we preferred Pd2(dba)3 to avoid the use of additional ligands.
We then investigated the substrate scope and generality of this
method (Table 3). Substituents like Me, allyl, and benzyl on the
indole nitrogen and Me, F, Cl and Br on the N-aryl ring of 3 were well
tolerated. Additionally, compound 3 containing N-alkyl, aryl and
heteroaryl sulfonyl groups participated well in the present reaction.
The Cl and Br present in 3 were also well tolerated and the reaction
was successful with azaindole 3t. The generality of this methodology
was demonstrated further by synthesizing 8-methoxy-1,3,5-trimethyl-
2-(thiophen-2-ylsulfonyl)-1,2-dihydroindolo[2,3-b]indole (4u) and
5-fluoro-1-methyl-8-nitro-2-(thiophen-2-ylsulfonyl)-1,2-dihydro-
indolo[2,3-b]indole (4v) in 74 and 68% yield, respectively (see
ESI†). All the compounds synthesized were well characterized
by spectral (NMR, IR and MS) data and the molecular structure
of 4p was confirmed unambiguously by single crystal X-ray
diffraction study (Fig. 3).8
CH3, 2-thienyl 2a
5
Me, H, 2-thienyl, CH3, 75
CH
3i
1i
10
11
12
13
14
15
F, 2-thienyl
1j
H, 2-thienyl
1k
1d
2a
2a
5
5
Me, H, 2-thienyl, F, CH 75
3j
Me, H, 2-thienyl, H, CH 76
3k
Allyl, H, CH3, CH3, CH 62
3l
Allyl, H, CH3, F, CH
3m
Allyl, H, CH3, Cl, CH
3n
Allyl, H, C6H4Me-p, CH3, 61
CH
Allyl, H, CH 5
2b
2b
2b
2b
1b
1c
1a
6
6
6
61
65
3o
16
17
18
19
1e
1g
1h
1e
1e
2b
2b
2b
5
5
6
6
6
Allyl, H, C6H4Me-p, F,
CH
3p
Allyl, H, C6H4Me-p, Cl, 58
CH
3q
Allyl, H, C6H4Me-p, Br, 61
CH
3r
Benzyl, H, C6H4Me-p, F, 58
CH
3s
64
Benzyl, H,
CH
2c
Me, Cl, N
2d
20
Me, Cl, C6H4Me-p, F, N 66
3t
a
Mechanistically (Scheme 2), the reaction proceeds via formation
of Pd(II) species E-1 [generated via oxidative addition of 3 to Pd(0)]
which may undergo intramolecular cyclization following the path a
or b. The path b i.e. Heck coupling seems less likely as the syn-
All the reactions were carried out using 1 (1.0 mmol), 2 (1.2 mmol), I2
(1.0 mmol) and Cs2CO3 (1.5 mmol) in acetonitrile (5.0 mL) at room
temperature under nitrogen. After adding indole 2. Isolated yield.
b
c
knowledge use of this strategy leading to 4 is unprecedented. The carbopalladation of the indole double bond would lead to the trans-
key starting material 3 required was prepared via C-2 amination fused intermediate E-3 possessing unfavorable ring-strain.
of indoles (2) using N-sulfonyl arylamines (1) (Table 1).7
All the compounds synthesized were tested at 50 mM initially
Initially we examined the intramolecular cyclization of for their ability to inhibit the yeast sirtuin family NAD-dependent
N-(2-iodoaryl)indole derivative 3a in the presence of Pd2(dba)3 and histone deacetylase (HDAC) Sir2 protein. A known inhibitor
K2CO3 in MeCN, 1,4-dioxane and toluene when the desired product Splitomicin was used as a reference compound in this yeast cell
4a was isolated in low yield (entries 1–3, Table 2). The yield was based reporter silencing assay. The compounds (4) were tested
c
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Table 3 Pd-mediated synthesis of indolo[2,3-b]indoles (Scheme 1)a
Product (4)
Entry
1
Indole (3)
R2, R3, R1, X, Y
Yieldb (%)
85
3a
Me, H, C6H4Me-p, Me, CH
4a
2
3b
3c
3d
3e
3f
Me, H, CH3, F, CH
4b
Me, H, CH3, Cl, CH
4c
Me, H, Me, CH3, CH
4d
Me, H, C6H4Me-p, F, CH
4e
Me, H, C6H4Me-p, H, CH
4f
Me, H, C6H4Me-p, Cl, CH
4g
Me, H, C6H4Me-p, Br, CH
4h
Me, H, 2-thienyl, CH3, CH
4i
Me, H, 2-thienyl, F, CH
4j
Me, H, 2-thienyl, H, CH
4k
Allyl, H, CH3, CH3, CH
4l
Allyl, H, CH3, F, CH
4m
Allyl, H, CH3, Cl, CH
4n
Allyl, H, C6H4Me-p, CH3, CH
4o
Allyl, H, C6H4Me-p, F, CH
4p
Allyl, H, C6H4Me-p, Cl, CH
4q
78
76
80
85
83
81
68
87
84
80
74
70
78
78
76
70
69
75
70
3
4
5
Scheme 2 The proposed reaction mechanism.
6
7
3g
3h
3i
presence of 5-FOA. A parallel screening was performed in the
absence of 5-FOA to check the cytotoxicity of the compounds.
Among all the compounds tested 4a, 4b (or A, Fig. 1) and 4e
showed significant inhibition10 (>40%) in the presence of 5-FOA
and no significant toxic effect in the absence of 5-FOA.
In conclusion, functionalized indolo[2,3-b]indoles have been
synthesized for the first time as a novel and unique class of
heteroaromatics via a new and versatile Pd-mediated method
for the potential inhibition of yeast sirtuins.
8
9
10
11
12
13
14
15
16
17
18
19
20
3j
3k
3l
3m
3n
3o
3p
3q
3r
BP thanks CSIR for a research fellowship. The authors thank
Prof. J. Iqbal and DST (Grant SR/S1/OC-53/2009) for support
and Dr D. Haldar for in vitro assay.
Notes and references
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2 For our earlier effort on the synthesis of functionalized heteroaromatics,
see: (a) K. S. Kumar, P. M. Kumar, K. A. Kumar, M. Sreenivasulu, A. A.
Jafar, D. Rambabu, G. R. Krishna, C. M. Reddy, R. Kapavarapu, K. S.
Kumar, K. K. Priya, K. V. L. Parsa and M. Pal, Chem. Commun., 2011,
47, 5010; (b) K. S. Kumar, P. M. Kumar, M. A. Reddy, M. Ferozuddin,
M. Sreenivasulu, A. A. Jafar, G. R. Krishna, C. M. Reddy, D. Rambabu,
K. S. Kumar, S. Pal and M. Pal, Chem. Commun., 2011, 47, 10263; (c) P. M.
Kumar, K. S. Kumar, P. K. Mohakhud, K. Mukkanti, R. Kapavarapu,
K. V. L. Parsa and M. Pal, Chem. Commun., 2012, 48, 431; (d) R. Adepu,
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Allyl, H, C6H4Me-p, Br, CH
4r
Benzyl, H, C6H4Me-p, F, CH
4s
3s
3t
Me, Cl, C6H4Me-p, F, N
4t
a
Reaction conditions: 3 (1.0 mmol), Pd2(dba)3 (5 mol%) and Et3N
(2.5 mmol) in DMF (5 mL) at 130 1C for 5 h under N2. Isolated yield.
b
4 (a) Y. Antonio, E. M. DeLaCruz, E. Galeazzi, A. Guzman, B. L. Bray,
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Fig. 3 ORTEP representation of the compound 4p. Thermal ellipsoids are drawn
at 50% probability level.
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8 CCDC 903580 (4p).
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for their ability to inhibit Sir2 protein by estimating inhibition of
growth of the yeast strain containing the Ura3 gene at the
telomeric locus, in the presence of 5-fluoroorotic acid (5-FOA)
(see ESI†).9 A compound having the sirtuin inhibitory effect
would inhibit the Sir2 protein, and thus the URA3 gene would
be de-repressed resulting in the death of the yeast cell in the
10 4b showed superior inhibition than 4a which corroborated with the
results of docking studies (see ESI†).
c
3972 Chem. Commun., 2013, 49, 3970--3972
This journal is The Royal Society of Chemistry 2013