Pd-mediated construction of a cyclopentane ring fused with indoles

Article abstract of DOI:10.1039/c3cc42309c

Unprecedented synthesis of functionalized indoles of potential pharmacological interest has been developed via a Pd-mediated cascade reaction involving an intramolecular Heck coupling followed by the construction of a fused cyclopentane ring in a single pot.

Full text of DOI:10.1039/c3cc42309c

Chemical Communications
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Volume 49 | Number 60 | 4 August 2013 | Pages 6691–6814
ISSN 1359-7345
COMMUNICATION
Manojit Pal et al.
Pd-mediated construction of a cyclopentane ring fused with indoles

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Pd-mediated construction of a cyclopentane ring fused
with indoles†
Cite this: Chem. Commun., 2013,
49, 6716
Bagineni Prasad,a B. Yogi Sreenivas,a G. Rama Krishna,b Ravikumar Kapavarapuc
and Manojit Pal*a
Received 29th March 2013,
Accepted 29th April 2013
DOI: 10.1039/c3cc42309c
www.rsc.org/chemcomm
Unprecedented synthesis of functionalized indoles of potential
pharmacological interest has been developed via a Pd-mediated
cascade reaction involving an intramolecular Heck coupling followed
by the construction of a fused cyclopentane ring in a single pot.
Rigid conformation via restriction of three dimensional relation-
ships of multiple functional groups present on a polycyclic–
heterocyclic system often renders specific and promising
pharmacological properties, highly desirable for medicinal
chemistry/drug discovery efforts. Cascade reactions1 involving
formation of several bonds and stereogenic centers in a single
synthetic operation on the other hand are considered as power-
ful tools for the construction of such polycyclic–heterocyclic
structures. Thus the development of cascade reactions especially
those catalyzed by transition metals is of remarkable interest.
Indoles are prevalent in Nature and considered as valuable
building blocks in organic synthesis2 as well as privileged pharmaco-
phores in drug discovery. For example, a fused indole i.e. 1,2,3,4-
tetrahydrocyclopenta[b]indole is an integral part of natural product
bruceollines3a and a known drug laropiprant.3b This prompted us to
explore cyclopenta[b]indole D as a new class of potential inhibitors of
phosphodiesterase 4 (PDE4). PDE4 inhibitors are proved to be
promising anti-inflammatory agents for the potential treatment of
chronic obstructive pulmonary disease (COPD) and asthma.4 Our
target molecules D derived from a known PDE4 inhibitor A via B5a
and incorporating some of the structural features of another known
inhibitor C5b (Fig. 1) were designed based on the in silico docking
studies of a representative compound E in the active site of PDE4B
(see 4b in the ESI†).5c
Fig. 1 Design of D as novel inhibitors of PDE4.
While elegant methods leading to cyclopenta[b]indoles via
Lewis acid catalyzed formal [3+2] addition of indolylmethyl cations
to alkenes6a,b or Pd-mediated approaches e.g. aerobic oxidative
annulations of indoles6c or domino N–H/C–H bond activation6d,e
are known none of them appeared to be handy for the quick access
to D. As part of our ongoing studies on newer synthesis of
functionalized heteroaromatics7 including fused indoles8 we
further investigated the reactivity of N-(1-allyl-1H-indol-2-yl)-
N-(2-iodoaryl)thiophene-2-sulfonamides towards Pd catalysts.
To our surprise the reaction followed an unusual path affording
novel cyclopenta[b]indoles i.e. N-(2-(7-substituted-1,2,3,4-tetra-
hydrocyclopenta[b]indol-3-yl)-aryl)thiophene-2-sulfonamides as
unexpected products (Scheme 1). We were delighted with this
timely observation as this appeared to have potential to become a
methodology for the direct access to a library of small molecules
based on D. Herein we report conceptually new synthesis of
functionalized cyclopenta[b]indoles via a Pd-mediated cascade
reaction involving an intramolecular Heck coupling followed by
the construction of a fused cyclopentane ring as a result of
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
c Doctoral Program in Experimental Biology and Biomedicine, Center for
Neuroscience and Cell Biology, University of Coimbra, Portugal
† Electronic supplementary information (ESI) available: Experimental proce-
dures, spectral data for all new compounds, results of in vitro and docking study.
CCDC 918746. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3cc42309c
Scheme 1 Pd-mediated synthesis of novel cyclopenta[b]indoles.
c
6716 Chem. Commun., 2013, 49, 6716--6718
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Table 2 Synthesis of cyclopenta[b]indoles (4) (Scheme 1)a
Entry
Compound (3); R1, R2, X
Product (4); R1, R2
Yieldb (%)
1
2
3
4
5
6
7
8
H, Cl, I (3a)
H, H, I (3b)
F, H, I (3c)
CH3, H, I (3d)
Cl, H, I (3e)
H, Cl (4a)
H, H (4b)
F, H (4c)
CH3, H (4d)
Cl, H (4e)
80
81
71
76
78
68
83
72
70
81
80
68
62
78
70
71
66
68
68
59
62
73
69
-
Scheme 2 Iodine-mediated synthesis of sulfonamide 3.
CH3, Cl, I (3f)
Br, Br, I (3g)
H, Br, I (3h)
H, OMe, I (3i)
CH3, OMe, I (3j)
CH3, Br, I (3k)
Br, OMe, I (3l)
F, OMe, I (3m)
Br, H, I (3n)
Br, Cl, I (3o)
Cl, Cl, I (3p)
Cl, NO2, I (3q)
Cl, Br, I (3r)
CH3, Cl (4f)
Br, Br (4g)
H, Br (4h)
H, OMe (4i)
CH3, OMe (4j)
CH3, Br (4k)
Br, OMe (4l)
F, OMe (4m)
Br, H (4n)
Br, Cl (4o)
Cl, Cl (4p)
Cl, NO2 (4q)
Cl, Br (4r)
cleavage of two C–N bonds and formation of several C–C bonds
in a single pot.
9
The key starting material 3 required was prepared via C-2 amina-
tion of indoles (2) using N-sulfonyl arylamines (1) (Scheme 2).9 The
Pd-mediated cascade reaction of 3a was then performed under a
variety of conditions (Table 1) to establish the optimized reaction
conditions. Initially, 3a was treated with Pd2dba3 and Et3N in EtOH
at 80 1C for 15 h, when 4a was obtained as a major product (48%)
along with indolo[2,3-b]indole 5 (12%) and some unreacted 3a
(entry 1, in Table 1). Though the yield of 4a was increased when
the reaction was performed in PEG or DMF–H2O (entries 2 and 3,
Table 1) a significant improvement was observed when DMF alone
was used (entry 4, Table 1). The use of other bases e.g. DBU or
K2CO3 was not effective (entries 5 and 6, Table 1). 4a was also not
obtained when Pd(OAc)2 was used as a catalyst (entry 7, Table 1),
whereas the use of Pd(PPh3)2Cl2, Pd(PPh3)4 or Pd/C-PPh3 afforded
4a in poor yield (entries 8–10, Table 1). The combination of
Pd(OAc)2 with PPh3 or X-Phos (entries 11–13, Table 1) or the use
of Cu(OAc)2 as a co-catalyst (entries 14 and 15, Table 1) mainly
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
F, Cl, I (3s)
F, Cl (4s)
Cl, CN, I (3t)
F, NO2, I (3u)
CH3, NO2, I (3v)
Cl, OMe, I (3w)
CH3, OMe, Br (3x)
Cl, CN (4t)
F, NO2 (4u)
CH3, NO2 (4v)
Cl, OMe (4w)
No reaction
a
Reactions were performed using 3 (0.4 mmol), Pd2(dba)3 (5 mol%) and
b
Et3N (1.2 mmol) in DMF (2 mL) at 130 1C for 7 h under N2. Isolated yield.
provided 5 as a major or the only product. The use of LiCl
additive afforded a 1 : 1 mixture of 4a and 5 (entry 16, Table 1)
whereas Cu(OAc)2 in place of the Pd-catalyst was found to be
ineffective (entry 17, Table 1). Overall, Pd2(dba)3 and Et3N in
DMF (entry 4, Table 1) were found to be optimum for the
preparation of 4a.
Table 1 Optimization of reaction conditionsa
We then performed the Pd-mediated cascade reaction using
various indole derivatives 3 (Table 2). Substituents like F, Cl, Br,
and OMe or electron withdrawing NO2 and CN groups were well
tolerated and afforded 4 in good to acceptable yields. Notably,
unlike 3 its bromo analogue i.e. N-(1-allyl-5-methoxy-1H-indol-2-yl)-
N-(2-bromo-4-methylphenyl)thiophene-2-sulfonamide 3x failed to
participate in the present reaction (entry 24, Table 2). All the
compounds synthesized were well characterized by spectral (NMR,
IR and MS) data and the molecular structure of a representative
compound 4b was confirmed unambiguously by single crystal
Yieldb (%)
Entry Catalyst/additive
Base/solvent
Time (h) 4a
5
1c,d
2
3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Et3N/EtOH
Et3N/PEG
15
7
7
7
7
7
4
7
7
12
5
4
4
4
48
67
63
80
58
—
—
30
32
30
—
22
—
—
12
25
28
Et3N/DMF : H2O (8 : 2)
Et3N/DMF
DBU/DMF
K2CO3/DMF
Et3N/DMF
Et3N/DMF
Et3N/DMF
Et3N/DMF
Et3N/DMF
Et3N/DMF
Et3N/DMF
Et3N/DMF
4
5
Pd2(dba)3
Pd2(dba)3
16 X-ray diffraction study (Fig. 2).10
36
75
84
—
—
—
84
70
83
81
6
7
Pd2(dba)3
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd/C/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/X-Phos
Pd(OAc)2/X-Phos
Pd(PPh3)2Cl2/
Cu(OAc)2
8e
9e
10e
11
12
13 f
14
15
Pd2(dba)3/Cu(OAc)2 Et3N/DMF
4
7
8
—
47
—
83
48
—
16
Pd2(dba)3/LiCl
Cu(OAc)2
Et3N/DMF
Et3N/DMF
17g
a
All the reactions were performed using 3a (0.4 mmol), catalyst (5.0 mol%)
b
c
and base (1.2 mmol) in a solvent (2.0 mL) at 130 1C. Isolated yield. The
reaction was performed at 80 1C. The starting material was not consumed
completely. Formation of an additional unidentified product was
observed. The reaction was performed at room temperature. 1.0 mmol
of catalyst was used.
d
e
f
g
Fig. 2 ORTEP representation of 4b. Thermal ellipsoids are drawn at the 50%
probability level.
c
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Some of the compounds synthesized were tested against
PDE4B in vitro12 when 4b, 4e, 4g, 4i, 4j, 4k, 4h, 4n and 4q
showed 43, 41, 40, 74, 49, 40, 42, 45 and 58% inhibition,
respectively, at 30 mM and 4i (IC50 > 5 mM vs. rolipram’s
IC50 B 1 mM) being the best among them.
In conclusion, novel cyclopenta[b]indoles have been synthesized
as potential inhibitors of PDE4 via a Pd-mediated new cascade
reaction involving an intramolecular Heck coupling followed by the
construction of a fused cyclopentane ring in a single pot.
BP thanks CSIR for a research fellowship. The authors thank
Prof. J. Iqbal and CSIR for support, Dr K. Parsa and Swetha
Chintala for in vitro assay and Dr C. Malla Reddy, IISER,
Kolkata, for X-ray studies.
Scheme 3 The proposed reaction mechanism.
Notes and references
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Fig. 3 The Heck product 6 isolated from the reaction of 3b and the side product
7 isolated from 3a.
Mechanistically, the reaction seemed to proceed via genera-
tion of E-1 in situ as a result of an intramolecular Heck reaction
which then undergoes a C–N bond cleavage near the indole
nitrogen to give E-2 (Scheme 3). A subsequent intramolecular
attack of the indole ring via its C-3 position on –CQC– provides
E-3. Activation of –CQN– of E-3 in the presence of Pd(0) aided
by the proximate sulfonamide moiety facilitated a further
intramolecular attack on the olefinic bond leading to E-4. The
six-membered Pd-containing ring of E-4 then undergoes C–N
bond cleavage to give E-5 which after following a few more steps
including the reductive elimination of Pd(0) to complete the
catalytic cycle afforded product 4. It is evident that the sulfon-
amide moiety played a key role in the present cascade reaction,
the electron releasing property of which towards Pd was greatly
facilitated by the electron rich thienyl moiety. This perhaps
provides some explanations to the observation that replacing
the thienyl moiety of 3 by a p-tolyl ring did not provide 4 as a
major product.8a Nevertheless, it is evident from Table 1 that
the formation of 4 was also dependent on the nature of catalyst/
solvent used.
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8 For our earlier study on the synthesis of functionalized indoles, see:
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The initial Heck type coupling was supported by the fact that
the corresponding Heck product 6 (cf. E-1, Fig. 3) was isolated
from the reaction of 3b (see ESI† for spectral data).11 While all
our attempts to isolate any other intermediates E-2-5 were not
successful we, however, were able to isolate a side product 7
9 Y. X. Li, H. X. Wang, S. Ali, X. F. Xia and Y. M. Liang, Chem.
Commun., 2012, 48, 2343.
10 CCDC 918746†.
(analogous to E-4) (Fig. 3) along with 4a from the conversion of 11 (a) Further, the reaction of a deiodinated analogue of 3ai.e.N-(1-allyl-
5-chloro-1H-indol-2-yl)-N-phenylthiophene-2-sulfonamide did not
proceed under the condition of entry 4 of Table 1; (b) While the
possibility of an initial Pd-mediated Claisen-type rearrangement
3a under the condition of entry 4 of Table 1 in the presence of
catalytic acetic acid. Compound 7 seemed to have formed via a
nucleophilic attack on the iminium nitrogen of the intermedi-
ate obtained from E-3 by the acetate ion (instead of Pd,
cf. Scheme 3). This suggests that the present cascade reaction
arguably proceeds via E-4.
followed by Heck reaction leading to E-3 (we thank one of the
reviewers for pointing out this) cannot be ruled out the isolation of 6
perhaps points towards the path shown in Scheme 3.
12 P. Wang, J. G. Myers, P. Wu, B. Cheewatrakoolpong, R. W. Egan and
M. M. Billah, Biochem. Biophys. Res. Commun., 1997, 234, 320.
c
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