Apparent Carbon Monoxide Insertion via Double Isocyanide Incorporation during Palladium-Catalyzed Construction of Indoloquinoline Ring in a Single Pot: Synthesis of New Cytotoxic Agents

Article abstract of DOI:10.1002/adsc.201600599

The formation of an amide bond via incorporation of two isocyanide units during a palladium-catalyzed construction of the indoloquinoline ring afforded N-substituted 6H-indolo[2,3-b]quinoline-11-carboxamides as new cytotoxic agents. The solvent and base play a key role in the selective and unprecedented synthesis of this class of amides. (Figure presented.).

Full text of DOI:10.1002/adsc.201600599

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DOI: 10.1002/adsc.201600599
Apparent Carbon Monoxide Insertion via Double Isocyanide
Incorporation during Palladium-Catalyzed Construction of
Indoloquinoline Ring in a Single Pot: Synthesis of New
Cytotoxic Agents
Suresh Babu Nallapati,a,b Bagineni Prasad,a B. Yogi Sreenivas,a Rajnikanth Sunke,a
Y. Poornachandra,c C. Ganesh Kumar,c B. Sridhar,d S. Shivashankar,a
K. Mukkanti,b and Manojit Pala,*
a
Dr. Reddyꢀs Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad – 500 046, India
E-mail: manojitpal@rediffmail.com
Institute of Science and Technology, JNT University Hyderabad, Hyderabad – 500085, India
Chemical Biology Laboratory, Med Chem and Pharmacology Division, CSIR-IICT, Tarnaka, Hyderabad – 500007, India
X-ray Crystallography Division, CSIR-IICT, Tarnaka, Hyderabad – 500007, India
b
c
d
Received: June 10, 2016; Revised: September 1, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600599.
Abstract: The formation of an amide bond via in-
corporation of two isocyanide units during a palladi-
um-catalyzed construction of the indoloquinoline
ring afforded N-substituted 6H-indolo[2,3-b]quino-
line-11-carboxamides as new cytotoxic agents. The
solvent and base play a key role in the selective and
unprecedented synthesis of this class of amides.
a potent and selective dopamine D3 receptor antago-
nist useful for the treatment of drug addiction.[2c] No-
tably, recent studies have indicated that dopamine re-
ceptor antagonists might be useful for the potential
treatment of cancer.[3a,b]
The 11-arylamino-substituted 6H-indolo[2,3-b]qui-
nolines (A, Figure 1) on the other hand showed prom-
ising cytotoxic properties against a number of cancer
cell lines (breast, lung and CNS).[3c] It was therefore
intriguing to know the potential medicinal value of
the newly designed framework B containing a cyclo-
hexyl amide moiety as well as the structural features
of A and SB-277,011A (Figure 1).
Keywords: amides; cytotoxic agents; indoloquino-
lines; isocyanides; palladium
The preparation of amides[4] based on B appeared
Due to the carbene-like reactivity of their divalent to be challenging. Moreover, a direct and straightfor-
carbon atom, isocyanides have emerged as remarka- ward strategy leading to B was desirable for the
bly useful building blocks in organic synthesis. Thus, quicker access to a library of target compounds. Re-
the development of new strategies based on isocya- cently we have reported the construction of the
nide insertion that allows the rapid build-up of molec- indolo[2,3-b]quinoline ring possessing an amine
ular complexities is of particular interest.[1]
moiety at C-11 (Scheme 1).[5]
Heteroaryl carboxamides are an attractive class of
small molecules because of their interesting pharma-
cological properties. For example, a series of cyclic
amines has been explored as modulators of 11bHSD1
for the potential treatment of diabetes, obesity and
other related diseases.[2a] Specifically, the cyclohexyl
amide derivatives have been explored as corticotropin
releasing factor (CRF-1) receptor antagonists for the
treatment or prevention of gastrointestinal disorders
including irritable bowel syndrome, inflammatory
bowel diseases, etc.[2b] Indeed, the usefulness of the
cyclohexyl amide moiety is best represented by the
Figure 1. Known drug SB-277,011A, the cytotoxic agent A
approved drug SB-277,011A (Figure 1) that acts as and the proposed new molecules B.
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A Pd-catalyzed isocyanide insertion followed by
a nucleophilic attack involving the indole C-3 and N-
desulfonylation were key steps in this reaction. We
wondered if any of these steps could be influenced to
alter the product formation. Indeed, we have ob-
served that changes of base and solvent afforded 3
(cf, B) instead of 4 as the result of a double incorpo-
ration of isocyanide units. This was remarkable as ap-
parently a “C=O” group was inserted into the C-11–N
bond of 4 without using CO gas or CO-containing
agents.[6] While cascade reactions involving double
isocyanide insertion[7,8] are known, a similar approach
that allows apparent insertion of a “C=O” group into
a C–N bond thereby creating an amide moiety is not
known. Herein we report an isocyanide insertion-
based, unprecedented strategy leading to 3 in a single
pot (Scheme 1) along with an in vitro pharmacological
evaluation of the compounds synthesized.
Our initial challenge was to establish the appropri-
ate reaction conditions for accessing 3 preferentially
over 4. In our previous study,[5] two reactions were
performed using isocyanocyclohexane (2a) when the
desired products belonging to type 4 were obtained
(in moderate yields) along with a side product. To
study this further, we performed the reaction of 1a[5]
Scheme 1. Pd-catalyzed isocyanide insertion based strategy
leading to 3 and 4.
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst/Ligand
Base
Solvent
Time [h]
Yield [%][b]
4a
3a
1
2
3
4
5
6
7
8
Pd(OAc)2/PPh3
Pd(OAc)2/Xantphos
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/X-Phos
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
PdCl2/PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DIPEA
K2CO3
K2CO3
DBU
DBU
DBU
DBU
DBU
DMF
DMF
DMSO
MeCN
DMF
5
5
5
4
6
5
5
34
30
38
20
–
26
18
24
14
40
52
15
–
–
–
–
–
DMF
–
DMSO[c]
DMSO[c]
DMSO[c]
DMF
40
78
58
62
52
54
62
56
50
35 min
2
45 min
4
4
3
9
10
11
12
13
14
15
THF
MeCN
DMSO[c]
DMSO[c]
DMSO[c]
DBU
DBU
DBU
–
–
–
Pd(PPh3)2Cl2/PPh3
Pd(OAc)2/PPh3
2
5[d]
[a]
Reaction conditions: 1a (1 mmol), 2a (3 mmol), catalyst (5 mol%) ligand (10 mol%) and base in a solvent (2.0 mL) at
808C.
Isolated yield.
5% aqueous DMSO was used.
The reaction was performed at room temperature.
[b]
[c]
[d]
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with 2a under various conditions (Table 1). The reac- solvent (entries 10–12, Table 1), Pd catalyst (entries 13
tion carried out in the presence of Pd(OAc)2-PPh3 or and 14, Table 1) or temperature (entry 15, Table 1).
Pd(OAc)2-Xantphos and Cs2CO3, at 808C in DMF af- The role of Pd catalyst and DBU was also examined
forded both products 3a and 4a in low yields (en- in the absence of which the reaction did not proceed.
tries 1 and 2, Table 1). The change of solvent (en- Indeed, replacing Pd(OAc)2 with Cu(OAc)2 failed to
tries 3 and 4, Table 1) or base (entries 5 and 6, produce any product indicating the need of a Pd cata-
Table 1) did not improve the yield or give better lyst for the reaction to proceed. The role of water was
product selectivity. Notably, the use of K2CO3 in 5% confirmed by performing the reaction in dry DMSO
aqueous DMSO afforded 3a as a major product albeit that afforded poor yields of 3a. Notably, an increase
in 40% yield (entry 7, Table 1). While 4a was obtained of the water content from 5% to 10% did not im-
in 15% yield in this case, its formation was suppressed prove the yield beyond the 78% of entry 8 (Table 1).
when K2CO3 was replaced by DBU (entry 8, Table 1). Overall, the combination of Pd(OAc)2-PPh3-DBU in
Indeed, the reaction was completed within 35 min and 5% aqueous DMSO at 808C (entry 8, Table 1) was
the yield of 3a was increased dramatically. We were found to be optimal for the synthesis of 3a.
delighted with this observation and continued our
The substrate scope and generality of the present
study to achieve further improvement in product Pd-catalyzed cascade reaction was assessed by synthe-
yield. While product selectivity was maintained when sizing a large number of N-substituted 6H-indolo[2,3-
DBU was used as a base the yield of 3a was de- b]quinoline-11-carboxamide derivatives (3) (Table 2).
creased with the change of ligand (entry 9, Table 1), To fulfil our goal, mostly N-cyclohexyl analogues
Table 2. Pd-catalyzed synthesis of N-substituted 6H-indolo[2,3-b]quinoline-11-carboxamide derivatives (3).[a] (see also Table
S-2 in the Supporting Information).
Entry
Compound (1): R1, R2, R3, Z, Y1, Y2
Compound (2): R4
Product (3)
Yield [%][b]
1
2
3
4
5
6
7
8
(1a): Me, allyl, H, p-tolyl, H, H
(1b): Br, allyl, H, p-tolyl, H, H
(1c): Cl, Me, H, Me, H, H
(1d): Me, Me, H, Me, H, H
(1e): F, allyl, H, Me, H, H
(1f): F, allyl, OMe, Me, H, H
(1g): Cl, allyl, H, Me, H, H
(1h): Me, allyl, OMe, p-tolyl, H, H
(1i): H, allyl, H, p-tolyl, H, H
(1j): Me, i-Pr, H, p-tolyl, H, H
(1k): Cl, allyl, F, p-tolyl, H, H
1a
(2a): cyclohexyl
2a
2a
2a
2a
2a
2a
2a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
78
72
69
75
70
67
64
65
68
64
69
80
74
72
76
66
64
70
62
70
60
64
65
72
78
67
9
2a
2a
2a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
(2b): n-pentyl
2b
2b
2b
2b
2b
2b
2b
2b
2b
2a
2a
1d
(1l): F, allyl, H, p-tolyl, H, H
(1m): F, allyl, OMe, p-tolyl, H, H
1i
(1n): Me, allyl, Cl, p-tolyl, H, H
(1o): Cl, allyl, Br, p-tolyl, H, H
(1p): Me, Me, H, p-tolyl, Me, H
(1q): F, Me, H, p-tolyl, H, Cl
(1r): Me, allyl, F, p-tolyl, Me, H
1p
3s
3t
3u
3v
3w
3x
3y
3z
1q
1a
(2c): i-propyl
2c
(2d): PhCH2
(1s): Me, Me, H, p-tolyl, H, H
(1t): Cl, Et, H, p-tolyl, H, H
[a]
All the reactions were carried out using 1 (1 mmol), 2 (3 mmol), Pd(OAc)2 (5 mol%), PPh3 (10 mol%) and DBU
(2.5 mmol) in 5% aqueous DMSO (2 mL) at 808C for 35–40 min under open air.
Isolated yield.
[b]
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were prepared by using 2a for in vitro assay (en-
tries 1–11, 22 and 23, Table 2). However, the use of
other isocyanides, for example, 2b and 2c was also
successful (entries 12–21, 24 and 25, Table 2). Notably,
the use of t-butyl isocyanide afforded the correspond-
ing analog of 4a instead of 3a. We also employed
1 having a variety of substituents, for example, Me, F,
Cl and Br on the benzene ring (entries 1–8, 10–15,
17–26, Table 2) and OMe, F, Cl and Br (entries 6, 8,
11, 15, 17, 18, 20, 21 and 23, Table 2) on the indole
ring. The indole nitrogen may be substituted with an
allyl (entries 1, 2, 5-9, 11, 12, 14-18, 21, and 24,
Table 2), or alkyl group (entries 3, 4, 10, 13, 19, 20, 22,
23, 25 and 26, Table 2). The position of the substituent
on the benzene or indole ring was also varied to
afford the desired products. Having examined
a number of alkyl isocyanides (2a–d) we then focused
on the use of other types of isocyanides such as PhNC
(2e), EtOCOCH2NC (2f) and TsCH2NC (2g)
(Scheme 2). While the isocyanide 2e afforded the de-
sired product 3aa the isocyanide 2f afforded the prod-
uct (5a, b) that seemed to be formed via following
a slightly different pathway.[9a] The isocyanide 2g did
not participate in the reaction as the product 6 was
formed via the known Pd-mediated intramolecular
cyclization of the reactant employed.[9b] Notably, all
these reactions (except using 2f) were performed
under open air as the methodology was insensitive to
aerial oxygen. All the compounds synthesized were
characterized by spectral (NMR, IR, MS and HPLC)
Figure 2. X-ray crystal structure of 3t (ORTEP diagram).
Thermal ellipsoids are drawn at 50% probability level.
data and this was supported by the molecular struc- played a key role, a probable reaction mechanism is
ture of 3t being confirmed by X-ray analysis presented in Scheme 3. While a cleavage of the N–
(Figure 2).[10]
SO2Z bond of E-1 by Cs2CO3 could afford the prod-
Based on the fact that (i) the weaker base DBU uct[5] 4 this bond cleavage perhaps was not favoured
favoured the formation of 3 over 4 and (ii) water in the initial stage in the presence of DBU. Thus once
formed, E-1 undergoes an intramolecular attack by C-
3 of indole[11a] on Pd to give E-2, which on reductive
elimination of Pd regenerates Pd(0) and E-3. Aroma-
tization of E-3 affords E-4 the imine moiety of which
on further nucleophilic attack by 2 generates E-5.[11b]
The release of amine from E-5 affords E-6 which on
reaction with the water molecule provides E-7. Hy-
drolysis of E-7 during work-up affords the desired
compound 3. Notably, the formation of E-7 was indi-
cated by the M+ signal in the corresponding mass
spectra. In the case of 2f, the corresponding inter-
mediate E-4 reacted with the carbanion[11c] generated
from 2f in situ and followed a somewhat different
pathway (see Scheme S-1 in the Supporting Informa-
tion) presumably involving elimination of ethyl 2-ami-
noacetate initially and then p-tosyl group with the
conversion of the isocyanide moiety to a TsNH group
affording the product 5a, b.[11d]
The cytotoxicity of these compounds was deter-
mined on the basis of measurement of in vitro growth
inhibition of four cancer cell lines, for example, HeLa
(cervical), DU145 (prostate), MCF7 (breast) and
Scheme 2. Pd-catalyzed reaction of 1 with isocyanides 2e–g;
conditions: (a) 808C for 35–40 min; (b) 1108C in a sealed
tube for 3–4 h.
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Scheme 3. The probable reaction mechanism.
A549 (lung) using an MTT assay with doxorubicin as compounds, 3c, 3d, 3e, and 3i were found to be prom-
a reference compound. The IC50 values of most active ising (IC50 <8 mM) against lung cancer cells, 3e was
compounds are presented in Table 3. Among these active against cervical and prostate cancer cells
Table 3. In vitro growth inhibition of cancer cell lines by compounds 3.
Compound
IC50 values[a] (mM)
HeLa
DU145
MCF7
A549
HUVEC
3b
3c
3d
3e
3i
14.2Æ0.2
10.3Æ0.2
12.1Æ0.3
9.9Æ0.2
10.6Æ0.2
14.7Æ0.4
14.3Æ0.2
11.1Æ0.2
11.6Æ0.2
23.6Æ0.3
20.7Æ0.1
12.5Æ0.3
9.4Æ0.1
39.8Æ0.2
15.7Æ0.3
11.3Æ0.2
17.5Æ0.2
13.6Æ0.3
16.7Æ0.4
9.7Æ0.4
10.6Æ0.2
11.9Æ0.4
22.6Æ0.5
9.7Æ0.1
12.8Æ0.3
11.4Æ0.4
12.5Æ0.1
8.7Æ0.2
7.2Æ0.4
6.9Æ0.3
7.7Æ0.2
7.9Æ0.3
18.4Æ0.3
8.5Æ0.3
12.3Æ0.3
12.9Æ0.3
98.6Æ0.2
101.2Æ0.4
88.5Æ0.4
132.5Æ0.2
91.0Æ0.3
89.9Æ0.3
99.4Æ0.5
92.5Æ0.4
88.2Æ0.5
3j
3n
3q
3u
[a]
All the experiments were performed in triplicate and the IC50 values are expressed in meanÆSD.
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whereas 3c and 3j were active against breast cancer Acknowledgements
cells. Notably, none of these compounds showed a sig-
The authors thank the management of DRILS and CSIR
[Grant 02(0127)/13/EMR-II] for support.
nificant effect (IC50 >88 mM) on non-cancerous
HUVEC cells indicating their selectivity (>10-fold)
towards cancer cells. To understand the mechanism of
action, 3c and 3e were tested for their inhibitory po-
tential against sirtuins (class III NAD-dependent de- References
acetylases) that are shown to be up-regulated in vari-
ous types of cancer[12] and their inhibition allows re-
expression of silenced tumour suppressor genes lead-
ing to reduced growth of cancer cells. In the Sirt1
fluorescence activity assay[13a] 3c, 3e and the reference
drug suramin showed 71, 67 and 78% inhibition [and
no inhibition by doxorubicin (negative control)] at
10 mM (see Figure S-1 in the Supporting Information)
indicating that the anticancer properties of 3c and 3e
are possibly due to their sirtuin inhibiting proper-
ties.[13b] Based on encouraging cytotoxicity, selectivity
and sirtuin inhibitory properties, the compounds 3c
and 3e appeared to be of further interest. Overall,
our study confirmed that modification of A via incor-
porating the structural features of SB-277,011A
(Figure 1) afforded compounds based on B that main-
tained the cytotoxic properties of A.
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J. P. Mogensen, A. R. Larsen, J. P. Kilburn, World
Patent Appl. WO2004089470 A2, 2004; b) D. Beattie,
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Hadley, A. J. Hunter, C. N. Johnson, D. J. Nash, K. M.
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2004, 12, 6539.
In conclusion, the change of solvent and base af-
forded a new, straightforward and inexpensive yet in-
novative method to synthesize N-substituted 6H-
indolo[2,3-b]quinoline-11-carboxamides. An apparent
CO insertion whereby an amide bond formation via
double isocyanide incorporation during Pd-catalyzed
construction of indoloquinoline ring in a single pot is
the key feature of this method that was facilitated by
the use of DBU in aqueous DMSO. This operational-
ly simple methodology that afforded a new class of
promising cytotoxic agents is unprecedented and may
find applications in organic/medicinal chemistry.
[4] For an excellent review, see: V. R. Pattabiraman, J. W.
Bode, Nature 2011, 480, 471.
[5] B. Prasad, S. B. Nallapati, S. K. Kolli, A. K. Sharma, S.
Yellanki, R. Medisetti, P. Kulkarni, S. Sripelly, K. Muk-
kanti, M. Pal, RSC Adv. 2015, 5, 62966.
[6] a) H. Liu, G. Laurenczy, N. Yan, P. J. Dyson, Chem
Commun. 2014, 50, 341; b) for a review, see: C. L.
Allen, J. M. J. Williams, Chem. Soc. Rev. 2011, 40, 3405.
[7] a) Q. Gao, P. Zhou, F. Liu, W.-J. Hao, C. Yao, B. Jiang,
S.-J. Tu, Chem. Commun. 2015, 51, 9519; b) Y.-Y. Pan,
Y.-N. Wu, Z.-Z. Chen, W.-J. Hao, G. Li, S.-J. Tu, B.
Jiang, J. Org. Chem. 2015, 80, 5764; c) G. C. Senadi,
W.-P. Hu, S. S. K. Boominathan, J.-J. Wang, Chem. Eur.
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Angew. Chem. Int. Ed. 2007, 46, 3043.
[8] a) D. Tejedor, F. Garcia-Tellado, Chem. Soc. Rev. 2007,
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[9] a) The reaction was performed in a sealed tube at
1108C. The reaction did not proceed well when per-
formed at 808C in a round-bottom flask; b) B. Prasad,
B. Y. Sreenivas, D. Rambabu, G. R. Krishna, C. M.
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[10] Crystal data for 3t: C22H21N3OFCl (M=397.87): mono-
clinic, space group P21/n (no. 14), a=15.627(3) ꢄ, b=
7.9992(13) ꢄ, c=16.280(3) ꢄ, b=103.130(2)8, V=
Experimental Section
General Procedure for the Preparation of Indolo[2,3-
b]quinolin-11-carboxamides (3)
To a mixture of N-(4-substituted-2-iodophenyl)-N-(1-alkyl-
1H-indol-2-yl)methanesulfonamide (1) (1 mmol), Pd(OAc)2
(5 mol%), PPh3 (10 mol%) and DBU (2.5 mmol) in 5%
aqueous DMSO (2 mL) was added isocyanide (3 mmol)
slowly and then the mixture was stirred at 808C for 35-.40
min. The progress of the reaction was monitored by TLC.
Upon completion of the reaction, the mixture was cooled to
room temperature, and filtered to remove the solid materi-
als. The filtrate was extracted with ethyl acetate (3ꢂ15 mL).
The organic layers were collected, combined, dried over an-
hydrous Na2SO4, filtered and concentrated under a reduced
pressure. The residue was purified by column chromatogra-
phy over silica gel using 5–10% ethyl acetate-hexane to give
the desired product 3.
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1981.8(6) ꢄ3,
Z=4,
T=294.15K,
m(MoKa)=
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0.219 mmÀ1, Dcalc =1.333 g/mm3, 15813 reflections mea-
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COMMUNICATIONS
8 Apparent Carbon Monoxide Insertion via Double
Isocyanide Incorporation during Palladium-Catalyzed
Construction of Indoloquinoline Ring in a Single Pot:
Synthesis of New Cytotoxic Agents
Adv. Synth. Catal. 2016, 358, 1 – 8
Suresh Babu Nallapati, Bagineni Prasad, B. Yogi Sreenivas,
Rajnikanth Sunke, Y. Poornachandra, C. Ganesh Kumar,
B. Sridhar, S. Shivashankar, K. Mukkanti, Manojit Pal*
Adv. Synth. Catal. 0000, 000, 0 – 0
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ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!