Ultrasound assisted one-pot synthesis of 1,2-diaryl azaindoles via Pd/C-Cu catalysis: Identification of potential cytotoxic agents

Article abstract of DOI:10.1016/j.tetlet.2019.151326

Ultrasound assisted one-pot and direct access to 1,2-diaryl substituted azaindole derivatives has been achieved via the sequential N-arylation followed by coupling-cyclization under Pd/C-Cu catalysis. The methodology involved initial C[sbnd]N bond forming

Full text of DOI:10.1016/j.tetlet.2019.151326

Journal Pre-proofs
Ultrasound assisted one-pot synthesis of 1,2-diaryl azaindoles via Pd/C-Cu cat-
alysis: identification of potential cytotoxic agents
Rapolu Venkateshwarlu, Shambhu Nath Singh, Vidavalur Siddaiah, Hindupur
Ramamohan, Rambabu Dandela, Manojit Pal
PII:
S0040-4039(19)31113-X
https://doi.org/10.1016/j.tetlet.2019.151326
TETL 151326
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 September 2019
18 October 2019
24 October 2019
Please cite this article as: Venkateshwarlu, R., Nath Singh, S., Siddaiah, V., Ramamohan, H., Dandela, R., Pal, M.,
Ultrasound assisted one-pot synthesis of 1,2-diaryl azaindoles via Pd/C-Cu catalysis: identification of potential
cytotoxic agents, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151326
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will
undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing
this version to give early visibility of the article. Please note that, during the production process, errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier Ltd.

Graphical Abstract
Ultrasound assisted one-pot synthesis of 1,2-diaryl
azaindoles via Pd/C-Cu catalysis: identification of potential
cytotoxic agents
Leave this area blank for abstract info.
Rapolu Venkateshwarlu, Shambhu Nath Singh, Vidavalur Siddaiah, Hindupur Ramamohan, Rambabu
Dandela,* and Manojit Pal*
Ar1I
Pd/C-Cu cat
Br
Br
N
Ar2
C6H4OMe-p
C6H4Me-p
N
N
N
Ar2
N
N
Ar1
NH
Ar1
NH2
The first ultrasound assisted azaindole synthesis was achieved under Pd/C-Cu catalysis. Some of the azaindoles were
identified as promising cytotoxic agents.

Tetrahedron Letters
journal homepage: www.elsevier.com
Ultrasound assisted one-pot synthesis of 1,2-diaryl azaindoles via Pd/C-Cu catalysis:
identification of potential cytotoxic agents
Rapolu Venkateshwarlu,ab Shambhu Nath Singh,a Vidavalur Siddaiah,b Hindupur Ramamohan,a Rambabu
Dandela,c* and Manojit Pald,*
aCustom Pharmaceutical Services and Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, India.
bDepartment of Organic Chemistry & FDW, Andhra University, Visakhapatnam 530003, Andhra Pradesh, India.
cDepartment of Industrial and Engineering Chemistry, Institute of Chemical Technology, Indianoil Odisha Campus, Samantpuri, Bhubaneswar 751013, India.
dDr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Ultrasound assisted one-pot and direct access to 1,2-diaryl substituted azaindole derivatives has
been achieved via the sequential N-arylation followed by coupling-cyclization under Pd/C-Cu
catalysis. The methodology involved initial C-N bond forming reaction (step 1) between an
appropriate o-bromo substituted amino pyridine and iodoarene followed by C-C and C-N bond
formation (step 2) between the resulting N-aryl substituted intermediate and a terminal alkyne in
the same pot. A variety of azaindoles was prepared by using this method. These compounds
were assessed for their cytotoxic properties against two different metastatic breast cancer cell
lines. Compounds 4i, 4k and 4o showed promising growth inhibition of these cell lines and
SIRT1 inhibition in vitro.
Available online
Keywords:
Azaindole
Ultrasound
Pd/C
2009 Elsevier Ltd. All rights reserved.
Cytotoxicity
The azaindole framework, bioisostere of the indole scaffold, is
prevalent in many molecules or agents of pharmacological
interest. This is exemplified by inhibitors of several enzymes or
proteins including mitotic kinase monopolar spindle 1 (MPS1)
inhibitors,1 e.g. A (Fig. 1) cyclooxygenase inhibitors2 or cyclin-
dependent kinase (CDK) inhibitors.3,4 Indeed, variolins isolated
from Antartic sponge Kirkpatrickia varialosa showed activities
against P388 murine leukemia cells and Variolin B was the most
active among them.5,6 In our effort we have previously reported
2-substituted 7-azaindole derivatives B that showed sirtuin
inhibiting properties in yeast without showing significant cell
toxicities.7 Notably, sirtuins the class III NAD-dependent
deacetylases are shown to be up-regulated in various types of
cancer and hence are considered as promising targets for cancer
therapeutics.8,9 Indeed, inhibition of sirtuins allows re- expression
of silenced tumor suppressor genes, leading to reduced growth of
cancer cells. Nevertheless, in order to identify more effective
inhibitors of sirtuins we focused on various types of azaindoles C
(including 7-azaindoles) possessing aryl groups at both 1- and 2-
positions (Fig. 1). Our previous study indicated that the ‘‘N–7’’
of the azaindole moiety of B played a key role in the interaction
with sirtuin in silico via forming the H-bond with the Asn484
NMe
N
R
N
N
HN
N
N
N
Boc
SO2R'
Cl
B
C
Ar2
N
A1
NMe
N
A
Fig. 1. Known bioactive azaindoles (A and B) and targeted analogues (C)
of the current work
residue when docked into the active site of Sir2.7 We anticipated
that aryl group at position 1- (unlike the strong electron
withdrawing sulfonyl moiety at the same position in case of B)
would strengthened the H-bonding ability not only for ‘‘N–7’’
but also for this endocyclic nitrogen at other position like 4-, 5-
and 6- position. Moreover, the H-bonding abilities thereby the
potential sirtuin inhibitory properties could be (or expected to be)
modulated by the nature of aryl group introduced at 1- position.
Needless to say that the nature and type of aryl group at 2-
position is expected to play a key role too. Hence it was essential
to assess compounds derived from C possessing diverse set of
aryl groups both at 1- and 2- position. Indeed, a small library of
molecules could be generated for related SAR (Structure Activity
Relationship) study and therefore we were in need of a direct as
well as convenient access to target molecules based on the
azaindole framework C.
----------------
*Corresponding author: Tel.: +91 40 6657; fax: +91 40 6657 1581
E-mail address: r.dandela@iocb.ictmumbai.edu.in (R. Dandela);
manojitpal@rediffmail.com (M. Pal)
1

One of the straightforward method for the preparation of 1,2-
diaryl azaindoles appeared to be N-arylation of 2-aryl azaindoles.
While this strategy worked for 2-substituted azaindoles
(affording low yields of products)10-12 the N-arylation of 2-aryl
azaindoles was reported to be more challenging perhaps due to
the steric hindrance.12 Among the other methods for the synthesis
of azaindoles the Pd-catalyzed construction of a pyrrole ring on a
pyridine moiety is a common strategy.13-26 These include Pd-
catalyzed annulations of aryl halide with (i) terminal alkynes
under Sonogashira conditions14-24 or (ii) internal alkynes under
Larock conditions.25-26 While some of these methods afforded
1,2-disubstituted azaindoles only few of them were found to be
effective for the synthesis of 1,2-diaryl azaindoles. Thus it was
necessary to adopt an appropriate strategy for the synthesis of
compounds represented by C (Fig. 1). The use of ultrasound as
an alternative source of energy in organic reactions27 has gained
increasing interest particularly from the viewpoint of green
chemistry. Indeed, a wide application of ultrasound has been
found in many areas of organic chemistry such as heterocyclic
chemistry, organic synthesis (e.g. condensation / substitution /
addition reactions, protection / deprotection reactions, oxidation /
reduction), photochemical processes, polymerization etc.28 Its
application in transition metal mediated coupling reactions has
also been documented.29,30 Notably, the use of ultrasound for the
synthesis of azaindoles is not common in the literature. Herein
we report the first use of ultrasound irradiation in synthesizing
1,2-diaryl azaindoles (4) via Pd/C-Cu catalyzed sequential C-N
coupling followed by coupling-cyclization in a single pot
(Scheme 1). The methodology involved initial C-N bond forming
reaction (step 1) between an appropriate o-bromo substituted
amino pyridine (1) and aryl iodide (2) followed by C-C and C-N
bond formation (step 2) between the resulting N-aryl substituted
intermediate and a terminal alkyne (4).
without changing the other factors / conditions. To our
satisfaction the yield of 4a was increased significantly (entry 2,
Table 1) but not up to the desired level yet. Hence the reaction
time (first step) was increased further to 2.5 h when 4a was
isolated in 57% yield (entry 3, Table 1). Notably, further increase
of reaction time in the first step as well as in the second step did
not improve the product yield (entry 4 and 5, Table 1). We then
evaluated the need as well as role of each component of the
catalyst system used and hence reactions were performed under
varying conditions accordingly (entries 6-8, Table 1). It was
evident that the omission of any component of the catalyst
10%Pd/C-PPh3-CuI decreased the reaction efficiency drastically
thereby the product yield. The use of other Pd catalyst e.g.
Pd(OAc)2 (in combination with PPh3) (entry 9, Table 1) or
(PPh3)2PdCl2 (entry 10, Table 1) or (PPh3)4Pd (entry 11, Table 1)
was tested but the product yield was lower in these cases.
While the reaction proceeded in the absence of ultrasound
affording 4a in acceptable yield (entry 12, Table 1) however
longer duration was required for both steps. Thus ultrasound
appeared to play a key role in accelerating the current one-pot
reaction leading to the desired azaindole 4a. Overall, the
conditions of entry 3 (Table 1) was chosen as the optimal
condition and was used not only for the synthesis of other
analoges of 4a but also to expand the scope and generality of
this ultrasound assisted methodology.
Table 1: The effect of reaction parameters.a
Br
Ph
1) PhI (2a)
Pd-cat, Cs2CO3
PEG-400
N
N
N
NH2
Ph
4a
1a
(3a)
Ph
2)
1
Br
2
Ar I ( )
Br
Ar2
Entry
Catalysts
Time (h)
Step 1
1
% Yieldb
N
N
N
Ar2
10% Pd/C, PPh3
CuI, Cs2CO3
PEG-400
N
Ar1
NH
Ar1
NH2
Step 2
3
( )
95-100 oC, 4h
4
1
1.
10%Pd/C-PPh3-CuI
10%Pd/C-PPh3-CuI
10%Pd/C-PPh3-CuI
10%Pd/C-PPh3-CuI
10%Pd/C-PPh3-CuI
10%Pd/C-CuI
4
4
4
4
6
4
4
4
4
4
4
24
21
45
57
55
58
9
95-100 oC, 2.5 h
2.
2
3.
2.5
3
Scheme 1. Ultrasound assisted one-pot synthesis of 1,2-diaryl
azaindoles under Pd/C-Cu catalysis
4.
5.
3
Initially, it was necessary to test the feasibility of our approach
involving sequential C-N, C-C and C-N bond formation in a
single pot. If successful then it was also essential to establish the
reaction conditions that would afford the optimum yield of
desired product 4. Accordingly, the ultrasound assisted reaction
sequence involving 2-amino-3-bromo pyridine (1a) and
iodobenzene (2a) initially and then phenyl acetylene (3a) was
studied under various conditions (Table 1). A laboratory
ultrasonic bath SONOREX SUPER RK 510H model producing
irradiation of 35 kHz was used for this purpose. The fact that
Cs2CO3 is a commonly used base in N-arylation reaction31
prompted us to use this particular base in our case too. Moreover,
our earlier success on the use of 10%Pd/C-PPh3-CuI as a
catalyst system during tandam C-C/C-N bond forming
reaction32 at 95-100 ºC encouraged us to use the same catalyst /
temperature in the current study. Thus, the coupling of 1a with
2a and subsequently with 3a in the same pot was performed in
the presence of 10%Pd/C-PPh3-CuI in PEG-400 under
ultrasound at 95-100 ºC. The reaction was performed for 1h for
the initial step and for 4h for the next step (after addition of 3a).
The desired product 4a was isolated in this case albeit in low
yield (entry 1, Table 1). The reason for low yield of 4a was found
to be due to the poor conversion in the first step i.e. coupling of
1a with 2a as indicated by TLC. To address this issue the
duration of the reaction (first step) was increased to double i.e. 2h
6.
2.5
2.5
2.5
2.5
2.5
2.5
12
7.
PPh3-CuI
0
8.
10%Pd/C-PPh3
0
9.
Pd(OAc)2-PPh3-CuI
(PPh3)2PdCl2-CuI
(PPh3)4Pd-CuI
38
33
32
52c
10.
11.
12.
10%Pd/C-PPh3-CuI
aAll the reactions were carried out using 1a (1.0 mmol), 2a
(1.0 mmol), Pd catalyst (0.010 mmol), CuI (0.010 mmol), PPh3
(0.022 mmol) and Cs2CO3 (3 mmol) in PEG-400 (3 mL) (step 1)
followed by addition of 3a (1.2 mmol) under nitrogen
atmosphere.
bIsolated yield.
cThe reaction was performed in the absence of ultrasound.
A range of 1,2-diaryl substituted azaindoles (4a-p) were
prepared using the established optimized conditions and results
are presented in Table 2. We have varied all three reactants e.g.
bromopyridine (1a-d), iodoarene (2a-c) and terminal alkyne (3a-
e).33,34 The iodoarenes containing groups like Me, Cl were
employed whereas terminal alkynes containing electron donating

(e.g. OMe) or withdrawing (e.g. CN, SO2Me) were used. The
reaction proceeded in all these cases affording the desired
products in acceptable to good yield.
appeared near 142.3 and 141.8 ppm respectively, whereas the
carbon bearing -OMe group appeared near 159.7 ppm.
102.1 ppm

6.7
55.4 ppm
All the azaindole derivatives synthesized were characterized
by spectral (NMR, MS) data. While the C-3 proton could not be
detected for all the compounds (due to the overlapping of the

8.8
143.6 ppm
H
H
N

3.7
OMe
1
corresponding signal with other signals) in their HNMR spectra
N
a singlet in the range  7.0-6.5 (depending on the position of
endocyclic nitrogen atom in the bicyclic ring) could be assigned
to this proton. The corresponding C-3 carbon appeared near 100
ppm in the 13CNMR spectra. The partial 1H and 13C NMR data of
a representative compound i.e. 4n is shown in Fig 2. The -OMe
159.7 ppm
142.3 ppm
141.8 ppm
Cl
1
group appeared near  3.7 and 55.4 ppm in the H and 13C NMR
Fig. 2. Partial representation of 1H and 13C NMR spectral data of
azaindole derivative 4n
spectra, respectively. Similarly, the proton and carbon at 4-
1
position appeared near  8.8 and 143.6 ppm in the H and 13C
NMR spectra, respectively. Moreover, the 13C NMR spectra
showed that the carbon at 6-position and that attached to N-1
Table 2. Ultrasound assisted one-pot synthesis of azaindoles under Pd/C-Cu catalysis.a
Ar1I (2)
Br
Ar2
N
N
Ar2
10% Pd/C, PPh3
CuI, Cs2CO3
PEG-400
95-100 oC, 2.5 h
N
Ar1
NH2
(3)
95-100 oC, 4h
4
1
step 2
step 1
Entry
1.
Bromopyridine (1)
2; Ar1 =
3; Ar2 =
Product (4)
%Yieldc
57
Br
Ph
2a;
Ph
3a;
Ph
N
N
N
NH2
Ph
4a
1a
1a
2.
3.
Ph
2b;
C6H4Me-p
3a;
Ph
N
61
69
N
C6H4Me-p
4b
Br
Ph
2c;
Ph
3a;
Ph
N
N
N
NH2
Ph
1b
1b
4c
4.
Ph
C6H4Me-p
2b;
C6H4Me-p
3a;
Ph
N
N
60
4d
Br
5.
6.
N
N
Ph
2a;
Ph
3a;
Ph
N
67
68
NH2
Ph
1c
1c
4e
N
Ph
2b;
C6H4Me-p
3a;
Ph
N
C6H4Me-p
4f
N
Br
7.
N
2a;
3a;
Ph
Ph
Ph
53
N
NH2
1d
Ph
4g
3

N
8.
9.
1d
2b;
C6H4Me-p
3a;
Ph
55
Ph
N
C6H4Me-p
4h
N
C6H4OMe-p
2b;
3b;
N
1c
1c
C6H4Me-p
C6H4OMe-p
64
50
C6H4Me-p
4i
10.
11.
12.
13.
N
C6H4CN-p
2b;
C6H4Me-p
3c;
C6H4CN-p
N
C6H4Me-p
4j
N
C6H4OMe-p
1c
1c
1c
2a;
Ph
3b;
C6H4OMe-p
68
69
N
Ph
4k
N
Ph
2c;
C6H4Cl-p
3a;
Ph
N
C6H4Cl-p
4l
N
C6H4CN-p
2c;
C6H4Cl-p
3c;
C6H4CN-p
N
50
72
62
C6H4Cl-p
4m
14.
15.
N
C6H4OMe-p
1c
1c
2c;
C6H4Cl-p
3b;
C6H4OMe-p
N
C6H4Cl-p
4n
OMe
OMe
2c;
C6H4Cl-p
3d;
N
C6H3(OMe)2-m,m
N
C6H4Cl-p
4o
16.
N
C6H4SO2Me-p
2a;
Ph
3e;
N
1c
C6H4SO2Me-p
58
Ph
4p
aAll reactions were carried out using 1 (1.0 mmol), 2 (1.0 mmol), 10%Pd/C (0.010 mmol), CuI (0.010 mmol), PPh3 (0.022 mmol)
and Cs2CO3 (3 mmol) in PEG-400 (3 mL) for 2.5h (step 1) followed by addition of 3 (1.2 mmol) for 4h (step 2) under a nitrogen
atmosphere.
bIsolated yield.

Pd/C
L
1
2
Ar I ( )
Pd
Br
trans
organometallation
Pd(0)-PPh3
complex in
solution
N
NH
Ar1
CuBr
Ar2
E-5
oxidative
addition
(L = PPh3)
oxidative
addition
CuI
3
I
Pd Ar1
Cu
L
Br
L
Ar2
2nd cycle
E-1
Pd
1st cycle
Pd(0)L
+
N
N
NH
Ar1
1
reductive
elimination
NH
Ar1
E-4
E-6
Br
Ar1
L
Pd
Ar2
Ar1
Br
N
Pd(0)L
N
+
NH2
reductive
elimination
Pd
I
X
Cu
NH
L
E-2
N
Cs2CO3
CuX
PEG-400
Ar2
E-3
Cu
CsI
NH
Ar1
E-7
CuX
-X
N
4
Cu-coordination
N
Ar2
NH
Ar1
N
Ar1
E-8
Scheme 2. The proposed reaction mechanism for the formation of azaindole derivatives (4)
Form the viewpoint of reaction mechanism (Scheme 2) the
Pd/C-CuI-PPh3 catalysed one-pot synthesis of azaindole 4
involved two catalytic cycles, e.g. (i) N-arylation via the C-N
bond forming reaction35,36 followed by (ii) coupling-cyclization
via C-C and C-N bond formation.7 While both the catalytic cycle
was mainly catalyzed by the Pd-catalyst, the CuI played the role
of a co-catalyst in the second catalytic cycle. Indeed, the
cyclization step of the second catalytic cycle was aided by Cu-
catalyst where the Pd-catalyst (being the Pd(0) species) appeared
to have no role. Nevertheless, an active Pd(0) species37 was
generated in situ from the Pd/C as a result of the leaching process
in the presence of PPh3 (Scheme 3).38 The reaction then followed
the usual N-arylation steps35,36 e.g. (i) oxidative addition of Pd(0)
to the iodoarene 2 to generate E-1, (ii) interaction of amine 1
with E-1 followed by deprotonation afforded the Pd-amide
species E-3 (via E-2) and (iii) reductive elimination of Pd(0)
from E-3 to complete the first catalytic cycle affording the N-
arylated intermediate E-4. In the second catalytic cycle the
reaction followed the usual Sonogashira steps39 e.g. (i) oxidative
addition of Pd(0) to E-4 to generate E-5, (ii) trans-
organometallation of E-5 with Cu-acetylide generated in situ
from 3 to give E-6 and (iii) reductive elimination of Pd(0) from
E-6 to complete the cycle. The alkyne moiety of E-6 was then
activated via coordination with the Cu(I)-species that facilitated
intramolecular cyclization followed by protodemetalation (aided
by PEG-400) to give the desired azaindole derivative 4 (with the
regeneration of Cu(I)-species). Though it is not clear if all steps
or any particular step of this coupling-cyclization process was
accelerated by ultrasound but the overall process appeared to be
influenced by the ultrasound. Indeed, the higher efficiency of the
reaction (entry 3 vs 12, Table 1) can be explained by faster Pd
leaching process assisted by ultrasound thereby facilitating the
subsequent steps.
these compounds at a concentration of 10 µM. Suramin was used
as a reference standard in this assay. Notably suramin is not only
known to inhibit the cell proliferation in ovarian and cervical
cancer41 but also an inhibitor of human sirtuin 1 (SIRT1).
Nevertheless, the assay results are presented in Table 3. The
compound 4f, 4i, 4k and 4o showed comparable anti proliferative
properties to suramin. Indeed the compound 4i was found to be
better than suramin. Among the rest of azaindole derivatives
some compounds showed moderate to weak cytotoxic properties.
Though presenting a precise Structure-Activity-Relationship
(SAR) within this series of azaindole derivatives was not
straightforward the position of endocyclic “N” atom and the
nature as well as type of aryl substituents at 1- and 2- position
appeared to play a key role in activities (Fig. 3). In general 5-
azaindole framework was found to be the most effective among
all azaindoles tested. Among the substitutents of aryl rings
present at 1- and 2- position the groups that are electron donating
in nature were preferred over the electron withdrawing groups.
Particularly compounds containing a methoxy group (e.g. 4f, 4i
and 4o) showed superior activities over those (e.g. 4j, 4m and
4p) containing CN or SO2Me substituents. Notably, “OMe” at m-
position decreased the activity (e.g. 4o). The 1-aryl ring
containing a “Me” substituent at p- position was favored over the
“Cl” substituent at the same place (e.g. 4i vs 4n). Nevertheless,
having screened in the MTT assay we focused on assessing
SIRT1 inhibitory properties of these molecules. Accordingly, all
these compounds were tested at 10 μM using the Fluor-de-Lys
peptide as
a substrate following a reported biochemical
enzymatic assay method.42 Notably, over expression of SIRT1
has been observed in several types of cancer and inhibition of
SIRT1 by small molecules demonstrated inhibition of cancer cell
proliferation. The compounds that were found to be active in this
assay (>50% inhibition, Table 3) include 4i, 4k and 4o. The
compound 4i and 4k appeared to possess SIRT1 inhibitory
properties comparable to suramin. This was further supported by
the concentration dependent study of compound 4i and suramin
against SIRT1 enzyme. Indeed, 4i was found to be a potent
inhibitor of SIRT1 with an IC50 of 3.13±0.27 µM compared to the
IC50 of suramin as 2.25±0.16 µM. Thus the current series of 5-
azaindole derivatives are of further medicinal interest.
The current ultrasound assisted one-pot method afforded a
series of 1,2-diaryl substituted azaindole derivatives. These
compounds were initially assessed for their cytotoxic properties
against two different metastatic breast cancer cell lines e.g.
MDA-MB-231 and MCF-7. An MTT [(4,5-dimethylthiazol-2-
yl)-2,5-diphenyltetrazolium bromide] assay40 was used to test
5

and subsequently against SIRT1 enzyme. Compounds 4i, 4k and
4o showed promising growth inhibition of these cell lines and
SIRT1 inhibition in vitro. Indeed, 4i was found to be a potent
inhibitor of SIRT1. Overall, the current research demonstrated
the utility of ultrasound in combination with Pd/C-Cu catalysis
for the direct synthesis of 1,2-diaryl substituted azaindoles some
of which showed promising anticancer properties.
Table 3: In vitro cytotoxicity of 1,2-diaryl substituted
azaindole derivatives 4.
Compounds
% inhibition @ 10 µMa
Cell based assay
Enzymatic assay
MDA-MB-231
MCF-7
SIRT1
Control
Suramin
4a
0.39
38.0
25.3
29.3
19.8
35.1
34.7
38.3
23.6
0.45
45.0
31.2
22.6
27.5
38.5
41.3
46.7
20.4
0
Acknowledgement
80.3
43.1
39.4
35.1
48.3
47.0
48.9
21.8
The authors thank the management of Dr. Reddy’s Lab Ltd,
Hyderabad, India, for continuous support and encouragement.
4b
4c
Supplementary data
4d
4e
Supplementary data associated with this article can be found,
in the on line version, at xxxxxxxxx
4f
4g
4h
4i
24.3
53.5
39.6
59.3
32.5
78.5
References and notes
1.
Naud, S., Westwood, I.M., Faisal, A., Sheldrake, P., Bavetsias, V.,
Atrash, B., Cheung, K.M.J., Liu, M., Hayes, A., Schmitt, J.,
Wood, A., Choi, V., Boxall, K., Mak, G., Gurden, M., Valenti, M.,
de Haven Brandon, A., Henley, A., Baker, R., McAndrew, C.,
Matijssen, B., Burke, R., Hoelder, S., Eccles, S. A., Raynaud, F. I.,
Linardopoulos, S., van Montfort, R. L., Blagg, J. J. Med. Chem.
2013, 56, 10045–10065.
4j
35.4
45.5
38.9
36.0
23.7
47.0
19.8
46.5
42.1
32.6
34.1
20.1
34.1
10.9
44.3
76.8
39.9
38.4
19.8
68.4
16.8
4k
4l
4m
4n
4o
4p
2.
3.
Beswick, P., Gleave, R., Swarbrick, M., 7-Azaindole derivatives
as COX2 inhibitors. World patent application number WO
2005/016924 A1, 24 Feb 2005.
Echalier, A., Bettayeb, K., Ferandin, Y., Lozach, O., Clément, M.,
Valette, A., Liger, F., Marquet, B., Morris, J. C., Endicott, J. A.,
Joseph, B., Meijer, L., J. Med. Chem. 2008, 51, 737−751.
Walker, S. R., Carter, E. J., Huff, B. C., Morris, J. C., Chem. Rev.
2009, 109, 3080−3098.
Perry, N. B., Ettouatti, L., Litaudon, M., Blunt, J. W., Munro, M.
H. G., Parkin, S., Hope, H., Tetrahedron 1994, 50, 3987-3992.
Trimurtulu, G., Faulkner, D. J., Perry, N. B., Ettouatti, L.,
Litaudon, M., Blunt, J. W., Munro, M. H. G., Jameson, G. B.,
Tetrahedron 1994, 50, 3993-4000.
4.
5.
6.
aData represent the mean values of three independent
determinations.
"OMe" at m-position
decreased the activity
7.
Layek, M., Kumar, Y. S., Islam, A., Karavarapu, R., Sengupta, A.,
Halder, D., Mukkanti, K., Pal, M., Med. Chem. Commun. 2011, 2,
478-485.
8.
9.
Michan, S., Sinclair, D., Biochem. J., 2007, 404, 1-13.
Bedalov, A., Gatbonton, T., Irvine, W.P., Gottschling, D.E.,
Simon, J.A., Proc. Natl. Acad. Sci. U. S. A., 2001, 98, 15113-
15118.
R1
N
N
"N" atom at 5-position
was most effective
A "OMe" at p-position
was favorable whereas
"CN" or "SO2Me" was
less effective
10. Mérour, J.-Y., Routier, S., Suzenet, F., Joseph, B., Tetrahedron
2013, 69, 4767−4834.
11. Cullen, M. H. S., Geng, B., Foley, M., Bastos, C. M., Munoz, B.,
Haeberlein, M. Proteasome activity enhancing compounds. World
patent application number WO 2015/073528, 21 May 2015.
12. (a) Qian, G., Hong, X., Liu, B., Mao, H., Xu, B., Org. Lett. 2014,
16, 5294−5297; (b) Purificacao, S. I.; Pires, M. J. D.; Rippel, R.;
Santos, A. S.; Marques, M. B. Org. Lett. 2017, 19, 5118-5121.
13. (a) Song, J. J., Reeves, J. T., Gallou, F., Tan, Z., Yeea, N. K.,
Senanayake, C. H. Chem. Soc. Rev. 2007, 36, 1120-1132; (b) For
the synthesis of 2-unsubstituted azaindoles, see: Xu, Z.; Hu, W.;
Zhang, F.; Li, Q.; Lu, Z.; Zhang, L.; Jia, Y. Synthesis 2008, 3981-
3987.
R2
A "Me" at p-position
was more favorable
than "Cl"
Fig. 3. Summary of SAR for cytotoxic activities of azaindole 4
In conclusion we have reported the first ultrasound assisted
one-pot and direct access to 1,2-diaryl substituted azaindole
derivatives via the sequential N-arylation followed by coupling-
cyclization under Pd/C-Cu catalysis. The methodology involved
initial C-N bond forming reaction (step 1) between an
appropriate o-bromo substituted amino pyridine and iodoarene
followed by C-C and C-N bond formation (step 2) between the
resulting N-aryl substituted intermediate and a terminal alkyne in
the same pot. The advantages associated with the use of Pd/C
include that it is an inexpensive, stable and widely used catalyst.
Moreover, the solvent used here i.e. PEG-400 is known to be an
environmentally friendly solvent. A variety of azaindoles was
prepared by using this methodology. These compounds were
assessed for their cytotoxic properties against two different
metastatic breast cancer cell lines e.g. MDAMB-231 and MCF-7
14. Koradin, C., Dohle, W., Rodriguez, A. L., Schmid, B., Knochel, P.
Tetrahedron 2003, 59, 1571-1587.
15. Rodriguez, A. L., Koradin, C., Dohle, W., Knochel, P., Angew.
Chem. Int. Ed. 2000, 39, 2488-2490.
16. Harcken, C., Ward, Y., Thomson, D., Riether, D. Synlett 2005,
3121-3125.
17. Sun, L.-P., Huang, X.-H., Wang, J.-X. J. Chinese Chem. Soc.
2007, 54, 569-573.
18. Majumdar, K. C., Mondal, S. Tetrahedron Lett. 2007, 48, 6951-
6953.
19. Majumdar, K. C., Samanta, S., Chattopadhyay, B., Tetrahedron
Lett. 2008, 49, 7213-7216.
20. Kumar, V., Dority, J. A., Bacon, E. R., Singh, B., Lesher, G. Y., J.
Org. Chem. 1992, 57, 6995-6998.
21. de Mattos, M. C., Alatorre-Santamaría, S., Gotor-Fernández, V.,
Gotor, V., Synthesis 2007, 2149-2152.
22. Sakai, N., Annaka, K., Fujita, A., Sato, A., Konakahara, T., J.
Org. Chem. 2008, 73, 4160-4165.

23. Amjad, M., Knight, D. W., Tetrahedron Lett. 2004, 45, 539-541.
24. Xu, L., Lewis, I. R., Steven, K. D., Summers, J. B., Tetrahedron
Lett. 1998, 39, 5159-5162.
25. Park, S. S., Choi, J.-K., Yum, E. K., Tetrahedron Lett. 1998, 39,
627-630.
42. Milne, J., Lambert, P.D., Schenk, S., Carney, D.P., Smith, J.J.,
Gagne, D.J., Jin, L., Boss, O., Perni, R.B., Vu, C. B., Bemis, J.E.,
Xie, R., Disch, J.S., Ng, P. Y., Nunes, J.J., Lynch, A.V., Yang, H.,
Galonek, H., Israelian, K., Choy, W., Iffland, A., Lavu, S.,
Medvedik, O., Sinclair, D.A., Olefsky, J.M., Jirousek, M.R.,
Elliott, P.J., Westphal, C. H. Nature 2007, 450, 712-716.
26. Ujjainwalla, F., Walsh, T. F., Tetrahedron Lett. 2001, 42, 6441-
6445.
27. Mason, T. J., Chem. Soc. Rev. 1997, 26, 443-451. DOI:
10.1039/CS9972600443
28. Puri, S., Kaur, B., Parmar, A., Kumar, H., Curr. Org. Chem. 2013,
17, 1790-1828
Ultrasound assisted one-pot synthesis of 1,2-diaryl
azaindoles via Pd/C-Cu catalysis: identification of potential
cytotoxic agents
Leave this area blank for abstract info.
Rapolu Venkateshwarlu, Shambhu Nath Singh, Vidavalur Siddaiah, Hindupur Ramamohan, Rambabu
Dandela,* and Manojit Pal*
Ar1I
Pd/C-Cu cat
Br
Br
N
Ar2
C6H4OMe-p
C6H4Me-p
N
N
N
Ar2
N
N
Ar1
NH
Ar1
NH2
The first ultrasound assisted azaindole synthesis was achieved under Pd/C-Cu catalysis. Some of the azaindoles were
identified as promising cytotoxic agents.
29. Ghotbinejad, M., Khosropour, A. R., Mohammadpoor-Baltork, I.,
Declaration of interests
Moghadam, M., Tangestaninejad, S., Mirkhani, V., RSC Adv.,
2014, 4, 8590-8596.
30. Palimkar, S. S., More, V. S., Srinivasan, K. V., Ultrason.
☒ The authors declare that they have no known
Sonochem., 2008, 15, 853-862.
31. Riedmüller, S., Nachtsheim, B. J., Beilstein J. Org. Chem. 2013, 9,
competing financial interests or personal
relationships that could have appeared to influence
1202–1209.
32. Prasad, B., Kumar, K. S., Babu, P. V., Anusha, K., Rambabu, D.
Kandale, A., Vanaja, G. R., Kalle, A. M., Pal, M., Tetrahedron
Lett. 2012, 53, 6059–6066.
the work reported in this paper.
33. Burroughs, L., Ritchie, J., Ngwenya, M., Khan, D., Lewis, W.,
Woodward, S., Beilstein J. Org. Chem. 2015, 11, 273-279.
34. Dell’Acqua, M., Ronda, L., Piano, R., Pellegrino, S., Clerici, F.,
Rossi, E., Mozzarelli, A., Gelmi, M. L., Abbiati, G., J. Org. Chem.
2015, 50, 10939-10954.
35. Driver, M.S., Hartwig, J.F., J. Am. Chem. Soc., 1997, 119, 8232–
8245.
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
36. Widenhoefer, R.A., Buchwald, S.L., Organometallics 1996, 15,
2755–2763.
37. Chen, J.-S., Vasiliev, A.N., Panarello, A.P., Khinast, J.G., Appl.
Catal. A: Gen. 2007, 325, 76-86.
38. Kohler, K., Heidenreich, R.G., Krauter, J.G., Pietsch, J., Chem. A
Eur. J. 2002, 8, 622-631.
39. Sonogashira, K., Tohda, Y., Hagihara, N., Tetrahedron Lett.,
1975, 16, 4467–4470.
40. Plumb, J. A., Methods Mol. Med., 2004, 88, 165-169.
41. Li, H. P., Li, H. L., Qu, H. J., Zhao, M. Z., Yuan, B., Cao, M. H.,
Cui, J. Q., Cancer Cell Int. 2015, 15, 52. doi: 10.1186/s12935-
015-0196-y
Graphical Abstract
Highlights
 Reported the first ultrasound assisted one-
pot and direct synthesis of 1,2-diaryl
7

azaindoles.
 Synthesis involved sequential N-arylation
/ coupling-cyclization under Pd/C-Cu
catalysis
 Three azaindoles showed cytotoxicities
against MDAMB-231 / MCF-7 cell lines
 One of them was identified as a potent
inhibitor of SIRT1.