Construction of a six-membered fused N-heterocyclic ring via a new 3-component reaction: Synthesis of (pyrazolo)pyrimidines/pyridines

Article abstract of DOI:10.1039/c1cc16418j

A conceptually new three-component reaction was developed to construct a six-membered fused N-heterocyclic ring affording (pyrazolo)pyrimidines/pyridines as potential inhibitors of PDE4. The reaction is catalyzed by triflic acid in acetic acid in the pres

Full text of DOI:10.1039/c1cc16418j

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COMMUNICATION
Construction of a six-membered fused N-heterocyclic ring via a new
3-component reaction: synthesis of (pyrazolo)pyrimidines/pyridinesw
P. Mahesh Kumar,ab K. Siva Kumar,a Pradeep Kumar Mohakhud,a K. Mukkanti,b
R. Kapavarapu,c Kishore V. L. Parsac and Manojit Pal*c
Received 15th October 2011, Accepted 21st October 2011
DOI: 10.1039/c1cc16418j
A conceptually new three-component reaction was developed to
construct a six-membered fused N-heterocyclic ring affording
(pyrazolo)pyrimidines/pyridines as potential inhibitors of PDE4.
The reaction is catalyzed by triflic acid in acetic acid in the
presence of aerial oxygen.
The development of convergent, atom-economic, expedient and
Fig. 1 Ibudilast and pyrazolo[1,5-a]pyrimidines as PDE4 inhibitors.
eco-friendly chemical methods is of utmost interest in modern
While numerous methods are known for the synthesis of
synthetic chemistry. In particular, single-step or cascade reactions,
pyrazolo[1,5-a]pyrimidines,7 including the use of the Suzuki
reaction or Pd-mediated coupling of an organometallic
reagent, e.g. ArZnI,8 most of these methods, however, are
useful for the preparation of specific compounds. One of the
major challenges and aims of the present work was therefore
to develop a suitable methodology leading to heterocyclic
structure C. We envisaged that the one-pot three-component
synthesis of pyrazolo[1,5-a]pyrimidines from an aromatic
aldehyde, terminal alkyne and a third reactant containing
–CQC(NH2)–NH– moiety could be handy in the present case.
In order to maintain the pyrazole ring of C the 5-amino-1
such as multi-component reactions (MCRs),1 often provide an
inherently more efficient approach to chemical synthesis than
conventional bimolecular reactions. Well known examples of
MCR include the Strecker, Passerini, Ugi, Pauson–Khand,
Biginelli and Mannich reactions. Since MCRs provide a powerful
tool for the discovery of new chemical entities (NCEs) required by
pharmaceutical and agrochemical industries,2 the development
and application of new MCRs have become a frontier area of
research, both in academic and industrial organizations.
Over the last twenty years, the pyrazolo[1,5-a]pyrimidine
framework has been a versatile scaffold for various pharmaco-
logical studies.3 On the other hand, during the last ten years, the
pharmaceutical industry has focused on developing novel anti-
inflammatory agents that inhibit phosphodiesterase 4 (PDE-4)
to treat chronic obstructive pulmonary disease (COPD) and
asthma.4 Recently, we have reported the usefulness of 7-(hetero)-
aryl-substituted pyrazolopyrimidine B (Fig. 1) derived from
Ibudilast A as a potential scaffold for the development of novel
PDE4 inhibitors.5 In further continuation of this research and
our long standing interest in PDE4/TNF-a inhibitors,4,6 we
planned to generate a library of compounds based on C (Fig. 1).
In this communication, we wish to present our preliminary
work on the identification of potential PDE4 inhibitors, the
synthesis of which was carried out using a conceptually
new MCR.
Table 1 The effect of reaction conditions on MCR using ethyl
5-amino-1H-pyrazole-4-carboxylate (1a) with benzaldehyde (2a) and
1-ethynyl-4-methylbenzenea (3a)
Entry Solvent
Catalyst
Time (h) %Yieldb
1
2
3
4
5
6
7
CH3CN
CF3CO2H-AcOH (1 : 1) 15
74c
20d
82
CH3CO2H CF3CO2H
CH3CO2H CF3SO3H
CH3CO2H No catalyst
CH3CN
CH3CN
CH3CO2H ZnBr2
15
2
36
15
15
15
56
CF3SO3H
I2
78c
70c
10d
a Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited,
Bollaram Road Miyapur, Hyderabad 500 049, India
b Chemistry Division, Institute of Science and Technology,
Jawaharlal Nehru Technological University, Hyderabad 500 049, India
c Institute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad 500 046, India.
a
All of the reactions were carried out using 5-amino-1H-pyrazole-4-
carboxylate 1a (1.0 mmol), benzaldehyde 2a (1.0 mmol), 1-ethynyl-4-
methylbenzene 3a (1.0 mmol) and a catalyst (0.10 mmol) in a solvent
b
c
E-mail: manojitpal@rediffmail.com; Tel: +91 40 6657 1500
w Electronic supplementary information (ESI) available: Experimental
procedures, spectral data for all new compounds, results of docking
study. See DOI: 10.1039/c1cc16418j
(5 mL) at 100–110 1C in the presence of air. Isolated yield. The reaction
was carried out at 80–85 1C. d A number of unknown side products
formed.
c
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Chem. Commun., 2012, 48, 431–433 431

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Table
2
TfOH-mediated synthesis of 5,7-diaryl substituted
Table 2 (continued )
Entry Aldehydes (2)
pyrazolo[1,5-a]pyrimidinesa
Alkynes
(3)
Yieldb
(%)
Products (4)
10
11
2d
3c
77
Alkynes
(3)
Yieldb
(%)
Entry Aldehydes (2)
Products (4)
2b
2c
3c
3c
80
PhCHO
2a
1
82
12
82c
m-BrC6H4CHO
2b
2
3a
3a
80
84
a
All of the reactions were carried out using 1a (1.0 mmol), aryl aldehyde
2 (1.0 mmol), terminal alkyne 3 (1.0 mmol) and TfOH (0.10 mmol) in
b
acetic acid (5 mL) at 100–110 1C for 2 h in the presence of air. Isolated
yield. Ethyl-3-amino-5-bromo-1H-pyrazole-4-carboxylate (1b) was used
in place of 1a.
c
p-CH3C6H4CHO
2c
3
H-pyrazole derivative appeared as an appropriate third
component that would eventually allow the construction of
the central pyrazolo[1,5-a]pyrimidine framework. To this end,
we have observed that treatment of ethyl-5-amino-1H-pyrazole-
4-carboxylate (1a) with benzaldehyde (2a) and 1-ethynyl-4-
methylbenzene (3a) in the presence of a catalyst and air in a
suitable solvent at an elevated temperature produced ethyl
5-phenyl-7-p-tolylpyrazolo[1,5-a]pyrimidine-3-carboxylate (4a)
as the only product (Table 1). Initially, the reaction was carried
out using 1 : 1 trifluoroacetic acid (TFA)–acetic acid (AcOH) as
the catalyst in acetonitrile for 15 h at 80–85 1C, when the desired
product 4a was isolated in 74% yield (entry 1, Table 1). The use
of AcOH as a solvent increased the formation of impurities with
a reduction in product yield (entry 2, Table 1). The use of
trifluoromethanesulfonic acid (TfOH) in AcOH, however,
significantly decreased the reaction time and increased the yield
of 4a (entry 3, Table 1). This reaction was carried out
at 100–110 1C. The product yield dropped considerably in the
absence of TfOH (entry 4, Table 1) indicating the key role
played by the catalyst in the present 3-component reaction.
Changing the solvent to acetonitrile did not affect the yield of 4a
(entry 5, Table 1). The use of other catalysts, e.g. iodine in
acetonitrile, was found to be effective (entry 6, Table 1), whereas
ZnBr2 in AcOH was less efficient (entry 7, Table 1). Thus a
combination of TfOH, AcOH and air was identified as the best
reaction conditions for the preparation of 4a.
4
2a
84
5
2c
3b
83
o-ClC6H4CHO
2d
6
3b
72
7
8
2a
85
76
With the optimized reaction conditions in hand, we then
examined the generality and scope of the present MCR. We
were pleased to find that the reaction proceeded well with a
variety of aromatic aldehydes and terminal alkynes to give a
range of 5,7-diaryl substituted derivatives (Table 2). The use of
ethyl-3-amino-5-bromo-1H-pyrazole-4-carboxylate (1b) in place of
1a provided the corresponding bromo compound (entry 12,
Table 2), which was amenable to further structural elaboration
via Suzuki, Heck or Sonogashira coupling.9 Notably, isomeric
pyrazolo[3,4-b]pyridine derivatives (5a–b) were obtained when
p-HOC6H4CHO
2e
3c
3c
9
2c
84
c
432 Chem. Commun., 2012, 48, 431–433
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Scheme 1 The synthesis of pyrazolo[3,4-b]pyridine derivatives.
Fig. 2 Docking of 4h at the active site of PDE4B.
In conclusion, a one-pot TfOH-mediated cascade reaction
has been developed to construct a fused pyrimidine ring in the
presence of aerial oxygen affording (pyrazolo) pyrimidines/
pyridines as potential inhibitors of PDE4.
P. M. K. thanks Dr Vilas Dahanukar and the analytical group
of DRL. M. P. and K. P. thank Prof. J. Iqbal for support.
Scheme 2 The proposed reaction mechanism.
1H-pyrazol-5-amine possessing no substitution at C-4 was
employed (Scheme 1). Compounds 5a–b were characterized
by the appearance of an NH signal in the region d 11.2–11.3 in
1H NMR and 3140–3145 cmÀ1 in the IR spectra, which was
absent in case of 4. In order to understand the mechanism of
the reaction, a number of experiments were carried out.
Accordingly, the reaction of 1a with 2a and 3a was examined
separately under the conditions presented previously (cf. entry
3, Table 1). The reaction proceed in the first case (but not in
the second case) to give the corresponding imine. Based on
Notes and references
1 For excellent reviews, see: (a) B. B. Toure and D. G. Hall, Chem.
Rev., 2009, 109, 4439; (b) B. Ganem, Acc. Chem. Res., 2009, 42, 463.
2 For a review on the use of MCRs in drug discovery, see: C. Hulme
and V. Gore, Curr. Med. Chem., 2003, 10, 51.
3 A. Kodimuthali, T. C. Nishad, P. L. Prasunamba and M. Pal,
Tetrahedron Lett., 2009, 50, 354 and references cited therein.
4 A. Kodimuthali, S. Jabaris and M. Pal, J. Med. Chem., 2008,
51, 5471.
5 A. Kodimuthali, R. Gupta, K. V. L. Parsa, P. L. Prasunamba and
M. Pal, Lett. Drug Des. Discovery, 2010, 7, 402.
these observations,
a plausible mechanism is proposed
6 (a) G. R. Reddy, T. R. Reddy, S. C. Joseph, K. S. Reddy,
L. S. Reddy, P. M. Kumar, G. R. Krishna, C. M. Reddy,
D. Rambabu, R. Kapavarapu, C. Lakshmi, T. Meda,
K. K. Priya, K. V. L. Parsa and M. Pal, Chem. Commun., 2011,
47, 7779; (b) S. Pal, S. Durgadas, S. B. Nallapati, K. Mukkanti,
R. Kapavarapu, C. L. T. Meda, K. V. L. Parsa and M. Pal, Bioorg.
Med. Chem. Lett., 2011, 21, 6573; (c) 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. Shivakumar,
K. K. Priya, K. V. L. Parsa and M. Pal, Chem. Commun., 2011,
47, 5010; (d) K. S. Kumar, P. M. Kumar, M. A. Reddy,
Md. 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.
7 See, for example: (a) S. Bondock, R. Rabie, H. A. Etman and
A. A. Fadda, Eur. J. Med. Chem., 2008, 20, 1; (b) E. I. Al-Afaleg,
Synth. Commun., 2000, 30, 1985; (c) A. Thomas, M. Chakraborty and
H. H. Junjappa, Tetrahedron, 1990, 46, 577; (d) A. S. Kiselyov
and L. Smith, Tetrahedron Lett., 2006, 47, 2611; (e) M. H. Elnagdi
and A. W. Erian, Bull. Chem. Soc. Jpn., 1990, 63, 1854;
(f) M. M. Abdel-Khalik, S. M. Agamy and M. H. Elnagdi, Synthesis,
2001, 1861.
(Scheme 2). The reaction seems to proceed through four steps,
e.g. (i) in situ generation of imine via condensation of amine 1
and aldehyde 2, (ii) subsequent nucleophilic addition of alkyne
3 to imine leading to the key propargyl amine Z, (iii) cycloiso-
merization of Z via intramolecular nucleophilic attack of
pyrazole nitrogen (N-1) or carbon (C-4) in a 6-endo-dig
fashion depending on the nature of X present and, finally,
(iv) aerial oxidation of the resulting dihydropyrazolopyrimi-
dine intermediate affording the product 3 or 4. To gain further
evidence, the reaction of 1a, 2a and 3a (cf. entry 3, Table 1)
was carried out strictly under an argon atmosphere when the
corresponding dihydro derivative (e.g. ethyl-5-phenyl-7-p-tolyl-
4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate) was isolated
instead of 4a, confirming the role of air in the last step.
Some of the compounds synthesized were tested for their
PDE4B inhibitory potential in vitro using PDE4B enzyme10
and rolipram as a reference compound. Compounds 4h and 4k
showed 67 and 33% inhibition of PDE4B at 30 mM, respectively.
This was supported by the docking results (Fig. 2) of 4h with
PDE4B protein (binding energy À10.2 Kcal molÀ1), which
showed H-bonding interactions between the –OH group of 4h
and THR345 residue of PDE4B. Additionally, p–p stacking
interactions between the central pyrazolopyrimidine moiety of
4h with the PHE414, PHE446 and TYR223 residues of PDE4B
was also observed.
8 G. W. Shipps, K. E. Rosner, J. Popovic-Muller, Y. Deng, T. Wang
and P. J. Curran, U. S. Patent Application US, 2004/0038993 A1,
February 25, 2004.
9 For example, reaction of 4l with 3-carbamoylphenylboronic acid in
the presence of (PPh3)2PdCl2, PPh3 in DMF at 100–110 1C for 2 h
provided the corresponding Suzuki product (92%). Similarly, the
Sonogashira product (75%) was obtained when 4l was reacted with
1-ethynylcyclohexanol in the presence of (PPh3)2PdCl2, CuI in
DMF at 100–110 1C for 2 h (see ESIw).
10 P. Wang, J. G. Myers, P. Wu, B. Cheewatrakoolpong, R. W. Egan
and M. M. Billah, Biochem. Biophys. Res. Commun., 1997, 234, 320.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 431–433 433