Microwave-assisted palladium mediated efficient synthesis of pyrazolo[3,4-b]pyridines, pyrazolo[3,4-b]quinolines, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]quinazolines

Article abstract of DOI:10.1039/c4ra02865a

An efficient method was developed for the synthesis of pyrazole fused heterocycles via the palladium-catalyzed solvent free reaction of β-halovinyl/aryl aldehydes and 3-aminopyrazoles/5-aminopyrazoles under microwave irradiation in good yields. This method is applicable for the efficient synthesis of a wide range of substituted pyrazolo[3,4-b]pyridines, pyrazolo[3,4-b]quinolines, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a] quinazolines. Four of the synthesized pyrazole fused compounds showed in vitro cytotoxic activities almost comparable to the drug doxorubicin against the cervical HeLa cancer cell line and prostate DU 205 cancer cell line. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c4ra02865a

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Microwave-assisted palladium mediated efficient
synthesis of pyrazolo[3,4-b]pyridines, pyrazolo-
[3,4-b]quinolines, pyrazolo[1,5-a]pyrimidines and
pyrazolo[1,5-a]quinazolines†
Cite this: RSC Adv., 2014, 4, 24001
Received 1st April 2014
Accepted 22nd May 2014
Kommuri Shekarrao,a Partha Pratim Kaishap,a Venkateshwarlu Saddanapu,b
DOI: 10.1039/c4ra02865a
b
a
a
*
*
Anthony Addlagatta, Sanjib Gogoi and Romesh C. Boruah
www.rsc.org/advances
An efficient method was developed for the synthesis of pyrazole fused pyrazolo[3,4-b]pyridines using indole-3-carboxaldehyde deriva-
heterocycles via the palladium-catalyzed solvent free reaction of tives and aminopyrazoles as the starting materials.1a Acid
b-halovinyl/aryl aldehydes and 3-aminopyrazoles/5-aminopyrazoles catalyzed syntheses of pyrazolo[3,4-b]pyridines, pyrazolo[3,4-b]-
under microwave irradiation in good yields. This method is applicable quinolines and pyrazolo[1,5-a]pyrimidines under microwave
for the efficient synthesis of a wide range of substituted pyrazolo[3,4- irradiation are also reported in the literature.1d,2f,3b Very recently,
b]pyridines, pyrazolo[3,4-b]quinolines, pyrazolo[1,5-a]pyrimidines and Batra S. and coworkers reported one Pd catalyzed synthesis of
pyrazolo[1,5-a]quinazolines. Four of the synthesized pyrazole fused similar type of pyrazolopyridines using potassium 2-amino-
compounds showed in vitro cytotoxic activities almost comparable to (hetero)benzoates and 2-haloarylaldehydes as the starting
the drug doxorubicin against the cervical HeLa cancer cell line and materials.1i In spite of the presence of these synthetic methods
prostate DU 205 cancer cell line.
for the synthesis of pyrazole fused compounds with different
substituted patterns, there is still lack of environmentally
benign general method for the synthesis of all of these impor-
tant fused heterocycles.
Introduction
Pyrazole fused heterocycles such as pyrazolo[3,4-b]pyridine,
pyrazolo[3,4-b]quinoline, pyrazolo[1,5-a]pyrimidine and pyr-
azolo[1,5-a]quinazoline are found as building blocks of
different pharmaceutically important heterocyclic compounds
and they possess a wide range of biological activities.1–4 Fig. 1
shows some of the biologically important pyrazole fused
heterocycles. Pyrazolo[3,4-b]pyridine derivative I (BAY 41-2272)
stimulates soluble guanylate cyclase (sGC) and induces vaso-
dilation,5 6-aryl pyrazolo[3,4-b]pyridine II is reported as potent
inhibitor of glycogen synthase kinase-3 (GSK-3),6 cyclo-
pentapyrazolo[1,5-a]pyrimidine (III) is a 5-HT6 receptor antag-
onist with Ki < 1 nM,7 compound IV (Zaleplon) is a known drug
for the treatment of sleep disorder8 and cyclopentane ring fused
pyrazolo[1,5-a]pyrimidine V has the highest affinity (Ki ¼ 88 pM)
to the 5-HT6 receptor.9 The importance of these pyrazole fused
heterocycles has led to the development of new procedures for
the synthesis of these targets.1–4 For example, recently, Park S. B.
and coworkers reported an acid catalyzed synthetic method for
aMedicinal Chemistry Division, North-East Institute of Science and Technology, Jorhat,
Assam 785 006, India. E-mail: skgogoi1@gmail.com; rc_boruah@yahoo.co.in; Fax:
+91 3762370011; Tel: +91 3762372948
bCenter for chemical biology, CSIR-IICT, Tarnaka, Hyderabad, AP-500 607, India
† Electronic supplementary information (ESI) available: Copies of 1H NMR, 13C
NMR spectra of compounds 3a–p, 6a–l and MTT assay protocol. See DOI:
10.1039/c4ra02865a
Fig. 1 Examples of bioactive pyrazolo[3,4-b]pyridines and pyrazolo-
[1,5-a]pyrimidines.
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Microwave heating to perform a chemical reaction is the pyrazolo[3,4-b]pyridine ring proton. This 1H NMR spectrum
becoming popular nowadays due to the decreased reaction also showed a doublet signal at d 8.43 (J ¼ 7.6 Hz, 2H), two
time, high and cleaner yield of products and enhancement of triplet signals at d 7.52 (J ¼ 7.4 Hz, 2H) and 7.23 (J ¼ 5.1 Hz, 1H),
the chemo-, regio- and stereoselectivity of the reactions. Again, because of the phenyl group attached to nitrogen atom of pyr-
1
microwave heating has been used to perform several novel azolo[3,4-b]pyridine. Moreover, the H NMR of this compound
reactions using transition-metals as the catalysts.10
showed two doublet signals at d 8.38 (J ¼ 8.7 Hz, 1H), 6.75 (J ¼
In view of the occurrence of these pyrazolo[3,4-b]pyridine, 2.5 Hz, 1H) and one double doublet signal at d 6.93 (J ¼ 8.6 Hz &
pyrazolo[3,4-b]quinoline pyrazolo[1,5-a]pyrimidine and pyr- 2.6 Hz, 1H) for the protons of dihydronaphthalene ring. The 13
C
azolo[1,5-a]quinazoline moieties in biologically active mole- NMR spectrum of 3a showed twenty one signals. The EI mass
cules, as well as our interest in the synthesis of novel spectra of compound 3a exhibited molecular ion peaks at m/z
heterocycles11 we sought to develop an efficient method for the 341.2. Aer conrming the structure of 3a we tried the same
synthesis of all of these classes of compounds using readily reaction of 1a and 2a using 2.5 mol% of Pd(OAc)2 as the catalyst
available starting materials. Herein, we report an efficient Pd in DMF which provided slightly improved yield of compound 3a
catalyzed synthesis of these important pyrazole fused hetero- (22%, entry 2, Table 1). Use of solvent DMSO in place of DMF in
cycles using b-halovinyl/aryl aldehydes and 3-aminopyrazoles/5- this reaction diminished the yield of 3a (15%, entry 3, Table 1).
aminopyrazoles as the starting materials under microwave Then, we examined the inuence of microwave (MW) irradia-
irradiation in solvent-free condition.
tion (700 W, 120 ꢀC, 14 bar) on the reaction of 1a and 2a in
presence of 2.5 mol% Pd(OAc)2 catalyst in DMF.
Gratifyingly, under this condition substantial increase in
yield of 3a to 68% along with a signicant reduction in reaction
time from 24 hours to 15 minutes was observed (entry 4,
Table 1). Interestingly, when we performed the reaction in neat
condition, we observed further increase in yield of 3a to 81%
(entry 5, Table 1) under microwave irradiation. The enhance-
ment of reaction rate under solvent-free condition was quite
encouraging due to the different advantages of solvent-free
reactions.12 To explore the effect of catalyst loading, when the
quantity of the loaded catalyst was increased to 5 mol% under
solvent free condition, there was no improvement in the yield of
the product 3a (entry 6, Table 1). But when the catalyst loading
Results and discussion
We started our work by examining the reaction of b-bromovinyl
aldehyde 1a (1.0 mmol) with equimolar amount of 5-amino-
pyrazole 2a (1.2 mmol) in presence of Pd catalyst (Table 1). At
the beginning, we observed that a catalytic amount (2.5 mol%)
of PdCl2 along with triphenylphosphine (5 mol%) as a ligand
furnished compound 3a in 15% yield under thermal condition
in 24 hours using DMF as the solvent (entry 1, Table 1).
Compound 3a was fully characterized by 1H NMR, 13C NMR and
mass spectroscopy. The 1H NMR spectrum of compound 3a
exhibited a characteristic aromatic singlet signal at d 7.70 for
Table 1 Optimization of the reaction conditions for the synthesis of 3aa
%Yieldb
Entry
Pd source (mol%)
Solvent
Thermal/MW
Time
3a
4a
1
2
3
4
5
6
7
8
PdCl2 (2.5)
DMF
DMF
DMSO
DMF
Neat
Neat
Neat
Neat
Neat
Neat
Neat
120 ꢀ
120 ꢀ
120 ꢀ
MW (700 W)
MW (700 W)
MW (700 W)
MW (700 W)
MW (700 W)
MW (700 W)
MW (500 W)
MW (800 W)
C
C
C
24 h
24 h
24 h
15
22
15
68
81
80
64
45
0
72
65
64
18
7
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (5)
Pd(OAc)2 (1.5)
PdCl2(PPh3)2 (2.5)
—
15 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
8
14
38
83
24
4
9
10
11
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
52
77
a
All reactions were performed in presence of PPh3 (5 mol%) and K2CO3 (2.1 mmol). b Isolated yield.
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was decreased to 1.5 mol%, we observed the decreased yield of Using the optimized reaction condition (entry 5, Table 1), we
3a (64%) under solvent free condition (entry 7, Table 1). More- evaluated the scope of the reaction by using different b-hal-
over, the yield of desired product 3a decreased to 45% when ovinyl/aryl aldehydes 1a–i and 5-aminopyrazoles 2a–e (Table 2).
PdCl2(PPh3)2 was used as the catalyst (entry 8, Table 1). Our The reactions of different cyclic b-bromovinyl aldehydes and b-
attempt to perform the reaction without catalyst furnished only bromovinyl-b-phenyl aldehydes with a range of 1-substituted-5-
the imine derivative 4a under the solvent free condition (entry 9, aminopyrazoles under the optimized reaction condition affor-
Table 1). Then, we looked at the effect of microwave power on ded pyrazolo[3,4-b]pyridines 3b–h in 67–80% yields. Similarly,
the yield of compound 3a and we noticed that use of 500 Watt the reaction of steroidal b-bromovinyl aldehyde with different 1-
MW power decreased the yield of 3a to 52% (entry 10, Table 1). substituted-5-aminopyrazoles afforded an array of steroidal
The use of 800 Watt MW power also afforded slightly less yield pyrazolo[3,4-b]pyridines 3i–m in 68–75% yields. These steroids
(77%) of compound 3a (entry 11, Table 1). In all the above bearing heterocycles are very important compounds due to their
reaction conditions the reaction of b-bromovinyl aldehyde remarkable biological activities and in last few decades enor-
1a and 5-aminopyrazole 2a afforded the imine derivative 4a as mous efforts are being made to annelate steroidal moiety with
a byproduct with different yields which are shown in Table 1. different heterocycles.13 In addition to b-bromovinyl aldehydes,
we performed the reaction of 2-bromobenzaldehyde derivatives
having electron donating/withdrawing groups with 1-
substituted-5-aminopyrazoles under the optimized condition to
provide the pyrazolo[3,4-b]quinolines 3n–p in 68–76% yields.
Table 2 Palladium catalyzed synthesis of pyrazolo[3,4-b]pyridines
(3a–m) and pyrazolo[3,4-b]quinolines (3n–p)a
Table 3 Palladium catalyzed synthesis of pyrazolo[1,5-a]pyrimidines
(6a–h) and pyrazolo[1,5-a]quinazolines (6i–k)a
a
A grinded mixture of b-halo aldehyde (1.0 mmol), 3-aminopyrazole/5-
a
A grinded mixture of b-halo aldehyde (1.0 mmol), 5-aminopyrazole (1.2 aminopyrazole (1.0 mmol), Pd(OAc)2 (2.5 mol%), PPh3 (5 mol%) and
mmol), Pd(OAc)2 (2.5 mol%), PPh3 (5 mol%) and K2CO3 (2.1 mmol) was K2CO3 (2.1 mmol) was irradiated in a closed vessel in a Synthos 3000
irradiated in a closed vessel in a Synthos 3000 microwave reactor at 700 microwave reactor at 700 Watt (120 ꢀC and 14 bar) for 15 minutes.
b
c
Watt (120 ꢀC and 14 bar) for 15 minutes.
H2 (ballon pressure), Pd/C, EtOH, rt, 2 h. Ref. 14b.
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Table 4 IC50 values of compounds 3a–p and 6a–l determined by MTT
assay
heteroatoms are usually challenging owing to their tendency to
form metal–heteroatom complexes, all the above reactions were
very effective to provide pyrazole derivatives.15 The starting
b-bromovinyl aldehydes (1a–e, 1i–l) were synthesized easily by
following known procedure.16 The nitro group in compound 6h
was hydrogenated easily to provide the pyrazolo[1,5-a]pyrimi-
dine 6l.14b Our attempt to scale up the compound 6h in four
gram scale also afforded 77% yield of 6h from its corresponding
starting b-bromovinyl aldehyde 1l under the optimized
condition.
Compound
IC50 at 10 mM (HeLa)
IC50 at 10 mM (DU-145)
3a–g, 3i–o
>100
>100
3h
3p
6a
6d
12.60 ꢁ 0.2021
11.34 ꢁ 0.1098
13.34 ꢁ 0.0604
10.41 ꢁ 0.2175
>100
10.37 ꢁ 0.219
10.09 ꢁ 0.277
9.75 ꢁ 0.156
10.77 ꢁ 0.124
>100
6b–c, 6e–l
Doxorubicin
9.76 ꢁ 0.1141
9.00 ꢁ 0.721
All the synthesized compounds (3a–p, 6a–l) were screened in
vitro for cytotoxic activities against cervical HeLa cancer cell line
and prostate DU 205 cancer cell line using MTT-micro cultured
tetrazolium assay17 and drug doxorubicin as a positive control.
Compounds 3h, 3p, 6a and 6d showed in vitro cytotoxic activi-
ties almost comparable to the drug doxorubicin against cervical
(Table 4).
The formation of the pyrazolo[3,4-b]pyridine 3 is envisaged
to occur via a mechanism which is shown in Scheme 2. Previ-
ously we found that in absence of Pd catalyst the reaction of
b-bromoaryl aldehyde 1a with 5-aminopyrazole 2a afforded only
the imine derivative 4a as shown in Table 1. In presence of Pd
catalyst, the Buchwald–Hartwig cross coupling reaction,18 and
The formation of isomer 3 was proved by comparison of new
spectral and physical data with those reported in the literature
for compound 3e.14c
Next, we shied our focus on the synthesis of pyrazolo[1,5-a]-
pyrimidines. It was interesting to nd that the reaction of
b-halovinyl aldehyde 1a and 3-aminopyrazole (5a) under the
above optimized condition was very regioselective and it affor-
ded 80% yield of pyrazolo[1,5-a]pyrimidine 6a (Table 3).
Encouraged by this result, we tried to extend this reaction to
some other b-bromovinyl aldehydes with different 3-amino-
pyrazoles/5-aminopyrazole having free N–H group to furnish
pyrazolo[1,5-a]pyrimidines 6b–h in 71–79% yield. The forma-
1
tion of pyrazolo[1,5-a]pyrimidine was proved by H NMR, 13C
NMR and mass spectra. Although there was also the possibility
of the formation of regio isomer 8 as shown in Scheme 1, via
coupling reaction of the vinylic amino group of 5 with the vinyl
bromide group of 1, followed by elimination of a water mole-
cule, it is worth noting that only isomer 6 was formed under this
microwave condition. The formation of isomer 6 was proved by
comparison of new spectral and physical data with those
reported in the literature for compounds 6c and 6h.14a,b To see
the feasibility of the reaction for the synthesis of pyrazolo[1,5-a]-
quinazoline derivatives, b-bromoaryl aldehydes (1f–g) were
treated with 3-aminopyrazoles 5a–b under similar reaction
conditions which afforded the desired pyrazolo[1,5-a]quinazo-
lines 6i–k in 69–76% yields. In all the reactions good functional
group compatibility was demonstrated with b-bromovinyl
aldehydes substituted with methoxy/methyl/nitro phenyl rings.
Although metal catalyzed reactions in presence of multiple
Scheme 2 Proposed mechanism for the formation of 3.
Scheme 1 Synthesis of pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]quinazolines.
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imine formation reaction of the b-bromovinyl/aryl aldehyde 1
with 5-aminopyrazole 2 generates probably enaminoimine 9a,
which on rearrangement gives azadiene intermediate 9b
(Scheme 2). Then a six-electron cyclization of 9b affords nal
compound 3 with the loss of one molecule of 5-aminopyrazole 2
via intermediate 9c. Our attempt to perform the reaction
between 2a and 4a also afforded compound 3a, which also
supported our proposed mechanism. Although, there are few
references for the direct C-3 and C-4 alkylations of pyrazole
moiety by metal catalyst,19,1i to the best of our knowledge this is
the rst example of C-4 alkylation of pyrazole via cascade imi-
nation/coupling/cycloaddition which leads to the formation
pyrazolo[3,4-b]pyridine. On the other hand, the formation of the
product 6 is envisaged to occur via imine formation between
aldehyde group of 1 with free amine group of pyrazole 5, fol-
lowed by N–H tautomerization (in case of 3-aminopyrazoles, 5a–
c) and Buckwald–Hartwig cross coupling reaction.
C. R. Rodrigues and C. A. M. Fraga, J. Med. Chem., 2003,
46, 1144–1152; (f) F. Manetti, S. Schenone, F. Bondavalli,
C. Brullo, O. Bruno, A. Ranise, L. Mosti, G. Menozzi,
P. Fossa, M. L. Trincavelli, C. Martini, A. Martinelli,
C. Tintori and M. Botta, J. Med. Chem., 2005, 48, 7172–
7185; (g) J. N. Hamblin, T. D. R. Angell, S. P. Ballantine,
C. M. Cook, A. W. J. Cooper, J. Dawson, C. J. Delves,
P. S. Jones, M. Lindvall, F. S. Lucas, C. J. Mitchell,
M. Y. Neu, L. E. Ranshaw, Y. E. Solanke, D. O. Somers and
J. O. Wiseman, Bioorg. Med. Chem. Lett., 2008, 18, 4237–
4241; (h) J. Witherington, V. Bordas, A. Gaiba, N. S. Garton,
A. Naylor, A. D. Rawlings, B. P. Slingsby, D. G. Smith,
A. K. Takle and R. W. Ward, Bioorg. Med. Chem. Lett., 2003,
13, 3055–3057; (i) G. Pandey, S. Bhowmik and S. Batra, Org.
Lett., 2013, 15, 5044–5047.
2 For pyrazolo[3,4-b]quinoline see: (a) K. Karnakar,
S. N. Murthy, K. Ramesh, G. Satish, J. B.Nanubolu and
Y. V. D. Nageswar, Tetrahedron Lett., 2012, 53, 2897–2903;
(b) R. G. Stein, J. H. Beil and T. Singh, J. Med. Chem., 1970,
13, 153–155; (c) S. T. Selvi, V. Nadaraj, S. Mohan, R. Sasi
and M. Hema, Bioorg. Med. Chem., 2006, 14, 3896–3903; (d)
P. Smirnoff and R. R. Crenshaw, Antimicrob. Agents
Chemother., 1977, 11, 571–573; (e) J. R. Mali, U. R. Pratap,
D. V. Jawale and R. A. Mane, Tetrahedron Lett., 2010, 51,
3980–3982; (f) S. Paul, M. Gupta, R. Gupta and A. Loupy,
Tetrahedron Lett., 2001, 42, 3827–3829.
3 For pyrazolo[1,5-a]pyrimidine see: (a) I. Bassoude,
S. Berteina-Raboin, J.-M. Leger, C. Jarry, E. M. Essassi and
G. Guillaumet, Tetrahedron, 2011, 67, 2279–2286; (b)
R. Daniels, K. Kim, E. Lebois, H. Muchalski, M. Hughes
and C. Lindsley, Tetrahedron Lett., 2008, 49, 305–310; (c)
J. Quiroga, J. Portilla, R. Abonia, B. Insuasty, M. Nogueras
and J. Cobo, Tetrahedron Lett., 2008, 49, 6254–6256; (d)
J. Quiroga, J. Portilla, R. Abonia, B. Insuasty, M. Nogueras
and J. Cobo, Tetrahedron Lett., 2007, 48, 6352–6355; (e)
A. S. Kiselyov and L. Smith, Tetrahedron Lett., 2006, 47,
2611–2614; (f) C. Simon, T. Constantieux and J. Rodriguez,
Eur. J. Org. Chem., 2004, 4957–4980; (g) C. A. Almansa,
F. Alberto, F. L. Cavalcanti, L. A. Gomez, A. Miralles,
M. Merlos, J. Garcia-Rafanell and J. Forn, J. Med. Chem.,
2001, 44, 350–361; (h) M. Suzuki, H. Iwasaki, Y. Fujikawa,
M. Sakashita, M. Kitahara and R. Sakoda, Bioorg. Med.
Chem. Lett., 2001, 11, 1285–1288; (i) C. Chen,
K. M. Wilcoxen, C. Q. Huang, Y.-F. Xie, J. R. McCarthy,
T. R. Webb, Y.-F. Zhu, J. Saunders, X.-J. Liu, T.-K. Chen,
H. Bozigian and D. E. Grigoriadis, J. Med. Chem., 2004, 47,
4787–4798.
Conclusions
In conclusion, we have developed an environmentally friendly
general procedure for the efficient and fast synthesis of bio-
logically important pyrazole fused heterocycles pyrazolo[3,4-b]-
pyridines, pyrazolo[3,4-b]quinolines, pyrazolo[1,5-a]pyrimi-
dines and pyrazolo[1,5-a]quinazolines. A wide range of b-hal-
ovinyl/aryl aldehydes undergo this reaction with N-substituted
5-aminopyrazoles and N–H free 3-aminopyrazoles/5-amino-
pyrazoles in presence of palladium catalyst (2.5 mol%) under
microwave irradiation. The general applicability for the
synthesis of all four important heterocycles, simplicity in
operation, solvent-free synthesis, energy efficiency (shorter
reaction time under microwave irradiation), very less catalyst
loading and good yields of products make this procedure
greener and more cost-effective. Preliminary in vitro cytotoxic
studies showed that compounds 3h, 3p, 6a and 6d have cyto-
toxic activities almost comparable to the drug doxorubicin
against cervical HeLa cancer cell line and prostate DU 205
cancer cell line.
Acknowledgements
Kommuri Shekarrao thanks CSIR, New Delhi for the award of
Senior Research Fellowship (CSIR-SRF). We are grateful to
Director, CSIR-NEIST for his keen interests. We gratefully
acknowledge nancial support from CSIR-ORIGIN (CSC0108),
CSIR-ACT (CSC0301) and CSIR-INSPIRE (CSC0107) projects.
4 For pyrazolo[1,5-a]quinazolines see: (a) S. Taliani,
I. Pugliesi, E. Barresi, S. Salerno, C. Marchand,
K. Agama, F. Simorini, C. La Motta, A. M. Marini,
F. S. Di Leva, L. Marinelli, S. Cosconati, E. Novellino,
Y. Pommier, R. Di Santo and F. Da Settimo, J. Med.
Chem., 2013, 56, 7458–7462; (b) A. Nazeer, N. Perveen,
M. Ain Khan, M. Naeem Khan, M. A. Munawar and
W.-O. Lin, Asian J. Chem., 2013, 25, 7705–7709; (c)
B. K. Ghotekar, M. N. Jachak and R. B. Toche,
J. Heterocycl. Chem., 2009, 46, 708–713.
References
1 For pyrazolo[3,4-b]pyridine see: (a) S. Lee and S. B. Park, Org.
Lett., 2009, 11, 5214–5217; (b) G. L. Beutner, J. T. Kuethe,
M. M. Kim and N. Yasuda, J. Org. Chem., 2009, 74, 789–
794; (c) J. Haeufel and B. Eberhard, Angew. Chem., Int. Ed.
Engl., 1974, 13, 604; (d) S.-L. Wang, Y.-P. Liu, B.-H. Xu,
X.-H. Wang, B. Jiang and S.-J. Tu, Tetrahedron, 2011, 67,
9417–9425; (e) E. J. Barreiro, C. A. Camara, H. Verli,
L. Brazil-Mas, N. G. Castro, W. M. Cintra, Y. Aracava,
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 24001–24006 | 24005

View Article Online
RSC Advances
Communication
5 J. P. Stasch, E. M. Becker, C. Alonso-Alija, H. Apeler,
K. Dembowsky, A. Feurer, R. Gerzer, T. Minuth, E. Perzborn,
U. Pleiss, H. Schroder, W. Schroeder, E. Stahl, W. Steinke,
A. Straub and M. Schramm, Nature, 2001, 410, 212–215.
6 J. Witherington, V. Bordas, A. Gaiba, N. S. Garton, A. Naylor,
A. D. Rawlings, B. P. Slingsby, D. G. Smith, A. K. Takle and
R. W. Ward, Bioorg. Med. Chem. Lett., 2003, 13, 3055–3057.
7 Y. L. Bennani, J. T. Anderson, J. Wang and M. G. Campbell,
Patent, US 2006/0009451 (A1), 2006.
D. S. Fischer, G. M. Allan, C. Bubert, N. Vicker, A. Smith,
H. J. Tutill, A. Purohit, L. Wood, G. Packham,
M. F. Mahon, M. J. Reed and B. V. L. Potter, J. Med. Chem.,
2005, 48, 5749–5770; (c) M. M. Abdelhalim, E. M. Kamel,
S. T. Rabie and N. R. Mohamed, Steroids, 2011, 76, 78–84;
(d) A. E. Amr and M. M. Abdalla, Bioorg. Med. Chem., 2006,
14, 4341–4352; (e) R. Hirschmann, P. Buchschacher,
N. G. Steinberg, J. H. Fried, R. Ellis, G. J. Kent, et al., J. Am.
Chem. Soc., 1964, 86, 1520–1527.
8 (a) R. E. Petroski, J. E. Pomeroy, R. Das, H. Bowman, 14 (a) A. Thomas, M. Chakraborty, H. Ila and H. Junjappa,
W. Yang, A. P. Chen and A. C. Foster, J. Pharmacol. Exp.
Ther., 2006, 317, 369–377; (b) C. F. P. George, Lancet, 2001,
358, 1623–1626; (c) T. Padmanathan, Patent, US5714607 A,
1998; (d) J. D. Albright, J. P. Dusza and A. S. Tomcufcik,
Patent, US4626538 A, 1986.
Tetrahedron, 1990, 46, 577–586; (b) A. C. Shaikh and
C. Chen, J. Labelled Compd. Radiopharm., 2008, 51, 72–76;
(c) A. Zheng, W. Zhang and J. Pan, Synth. Commun., 2006,
36, 1549–1556.
15 J. F. Hartwig, Organotransition Metal Chemistry, from Bonding
to Catalysis, University Science Books, New York, 2010.
9 A. V. Ivachtchenko, D. E. Dmitriev, E. S. Golovina,
M. G. Kadieva, A. G. Koryakova, V. M. Kysil, O. D. Mitkin, 16 (a) T. Thiemann, M. Watanabe and S. Mataka, New J. Chem.,
I. M. Okun, S. E. Tkachenko and A. A. Vorobiev, J. Med.
Chem., 2010, 53, 5186–5196.
10 (a) A. Maiti and D. Maiti, Green Chem., 2012, 14, 2314–2320;
2001, 25, 1104–1107; (b) S. Gogoi, K. Shekarrao, A. Duarah,
T. C. Bora, S. Gogoi and R. C. Boruah, Steroids, 2012, 77,
1438–1445.
(b) C. O. Kappe, Angew. Chem., Int. Ed., 2004, 43, 6250–6284; 17 (a) S. Myadaraboina, M. Alla, V. Saddanapu, V. R. Bommena
(c) M. Irfan, M. Fuchs, T. N. Glasnov and C. O. Kappe, Chem.–
Eur. J., 2009, 15, 11608–11618.
and A. Addlagatta, Eur. J. Med. Chem., 2010, 45, 5208–5216;
(b) For MTT assay protocol see ESI†
11 (a) P. P. Kaishap, K. Shekarrao, P. Saikia, S. Gogoi and 18 K. W. Anderson, R. E. Tundel, T. Ikawa, R. A. Altman and
R. C. Boruah, Tetrahedron Lett., 2014, 55, 1927–1930; (b)
S. L. Buchwald, Angew. Chem., Int. Ed., 2006, 45, 6523–
K. Shekarrao, P. P. Kaishap, S. Gogoi and R. C. Boruah,
6527.
RSC Adv., 2014, 4, 14013–14023; (c) U. Bora, A. Saikia and 19 (a) S. Kumar, H. Ila and H. Junjappa, J. Org. Chem., 2009, 74,
R. C. Boruah, Org. Lett., 2003, 5, 435–438.
7046–7051; (b) Y. Fall, H. Doucet and M. Santelli, Synthesis,
2010, 127–135; (c) M. Ye, A. J. F. Edmunds, J. A. Morris,
D. Sale, Y. Zhang and J.-Q. Yu, Chem. Sci., 2013, 4, 2374–
2379.
12 K. Tanaka and F. Toda, Chem. Rev., 2000, 100, 1025–1074.
13 (a) L.-H. Huang, Y.-F. Zheng, Y.-Z. Lu, C.-J. Song, C.-G. Wang,
B. Yu and H.-M. Liu, Steroids, 2012, 77, 710–715; (b)
24006 | RSC Adv., 2014, 4, 24001–24006
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