A facile one-pot synthesis of 7-substituted pyrazolo[1,5-a]pyrimidines by base induced three-component reaction

Article abstract of DOI:10.1016/j.tetlet.2014.05.021

The preparation of steroid/nonsteroid fused 7-substituted pyrazolo[1,5-a]pyrimidines is described by a one-pot reaction of steroidal/nonsteroidal ketones, aromatic aldehydes and 3-amino-1H-pyrazoles/5- amino-1H-pyrazoles in the presence of potassium tert-butoxide in good yield under reflux condition in ethanol.

Full text of DOI:10.1016/j.tetlet.2014.05.021

Accepted Manuscript
A facile one-pot synthesis of 7-substituted pyrazolo[1,5-a]pyrimidines by base
induced three-component reaction
Pallabi Saikia, Partha Pratim Kaishap, Rashmi Prakash, Kommuri Shekarrao,
Sanjib Gogoi, Romesh C Boruah
PII:
S0040-4039(14)00799-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.021
TETL 44612
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 February 2014
9 May 2014
10 May 2014
Please cite this article as: Saikia, P., Kaishap, P.P., Prakash, R., Shekarrao, K., Gogoi, S., Boruah, R.C., A facile
one-pot synthesis of 7-substituted pyrazolo[1,5-a]pyrimidines by base induced three-component reaction,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.021
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A facile one-pot synthesis of 7-substituted pyrazolo[1,5-a]pyrimidines by base induced
three-component reaction
Pallabi Saikia, Partha Pratim Kaishap, Rashmi Prakash, Kommuri Shekarrao, Sanjib Gogoi,*
Romesh C Boruah*
*Corresponding author, Tel.: +91 3762372948; fax: +913762370011; Email:
skgogoi1@gmail.com, rc_boruah@yahoo.co.in
Medicinal Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat
785006, India
______________________________________________________________________________
Abstract: The preparation of steroid/nonsteroid fused 7-substituted pyrazolo[1,5-a]pyrimidines
is described by a one-pot reaction of steroidal/nonsteroidal ketones, aromatic aldehydes and 3-
amino-1H-pyrazoles/5-amino-1H-pyrazoles in the presence of potassium tert-butoxide in good
yield under reflux condition in ethanol.
Keywords: Pyrazolo[1,5-a]pyrimidine, steroid, potassium tert-butoxide, heterocycle, amino-1H-
pyrazole.
____________________________________________________________________________
Pyrazolo[1,5-a]pyrimidine derivatives are of great pharmaceutical importance because of
their wide range of biological activities. For example, they show antitrypanosomal and
antischistosomal activities,1 and many of them are used as COX-2 selective inhibitors, CRF1
antagonists, HMG-CoA reductase inhibitors, histamine-3 receptor ligands and antianxiety
agents.2 Among the pyrazolo[1,5-a]pyrimidine derivatives, recently, 7-substituted cycloalkane
ring fused pyrazolo[1,5-a]pyrimidine derivatives as well as 7-substituted pyrazolo[1,5-
a]pyrimidines turned out to be very promising molecules due to their interesting biological
activities. For example, 7-substituted cyclopentane ring fused pyrazolo[1,5-a]pyrimidine
derivative I (Figure 1) is found to have sub-nanomolar affinity (Ki < 1 nM) as 5-HT6 receptor
antagonist3. 7-Substituted pyrazolo[1,5-a]pyrimidine derivatives II and III are known drugs for
1

the treatment of sleep disorder4 and cyclopentane ring fused pyrazolo[1,5-a]pyrimidine
derivative IV has the highest affinity (Ki = 88 pM) to the 5-HT6 receptor5.
The incorporation of a heterocycle or fusion of a heterocycle in the skeleton of a steroidal
molecule changes the activity of the steroidal molecule. Taking advantage of this phenomenon
medicinal chemists have been trying to develop new active molecules in the last couple of
decades by annulating steroidal moiety with different heterocycles such as pyridine, pyrazole,
isoxazole, pyrrole, pyran and pyrimidine using various synthetic strategies.6 As a part of our
continuing research on development of new methodology for the synthesis of novel steroidal and
nonsteroidal heterocyclic compounds,7 herein we report a new one-pot three component
approach for the synthesis of steroid and nonsteroid fused 7-aryl substituted pyrazolo[1,5-
a]pyrimidine derivatives under thermal conditions.
There are few methods reported in the literature for the synthesis of substituted pyrazolo[1,5-
a]pyrimidines in the last few decades. Most of these synthetic methods used the reaction between
2

5-aminopyrazoles and 1,3-bis-electrophilic compounds, such as β-dicarbonyl, alkoxymethylene-
β-dicarbonyl and β-enaminone compounds.8 Bennani et al. reported the synthesis of 7-aryl
substituted cycloalkane ring fused pyrazolo[1,5-a]pyrimidines by multi-step reactions where they
used 2-oxo-cycloalkylcarboxylic acid methyl ester and 2H-pyrazol-3-ylamine as the starting
meterials.3 Moreover, acid catalyzed reactions of 2-acetylcycloalkanones with aminopyrazoles
have been reported in the literature for the synthesis of 7-methyl substituted cycloalkane ring
fused pyrazolo[1,5-a]pyrimidines.5,9
The diversity-oriented synthesis is the facile preparation of clusters of structurally complex
and diverse compounds from simple starting materials.10 Although 7-aryl substituted cycloalkane
fused pyrazolo[1,5-a]pyrimidines possess interesting biological activity, to the best of our
knowledge a diversity-oriented synthesis using multi-component reaction of very common
starting materials has remained unexplored so far for these compounds.
Initially, we selected ketone 1a, benzaldehyde (2a) and 3-amino-1H-pyrazole (3a) as the
model substrates for the multi-component synthesis of compound 4a (Table 1). Refluxing a
mixture of ketone 1a and benzaldehyde (2a) in anhydrous DMF in the presence of base NaOMe
(two equivalent) for one hour followed by addition of 3-amino-1H-pyrazole (3a) and refluxing
the reaction mixture for another two hours furnished pyrazolo[1,5-a]pyrimidine 4a in 26% yield
(entry 1, Table 1). We observed that increase of duration of the reaction also could not increase
the yield of product 4a (entry 2, Table 1). After having the product 4a in hand it was identified
1
13
1
from H NMR, C NMR and mass spectral data. The H NMR of compound 4a exhibited two
characteristic aromatic doublet signals at δ 6.68 (J = 2.2 Hz, 1H) and at δ 8.01 (J = 2.2 Hz, 1H)
3

Table 1. Optimization of reaction conditions for the synthesis of pyrazolo[1,5-a]pyrimidine 4a
Entry
Basea
NaOMe
NaOMe
KOMe
KOH
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
EtOH
EtOH
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
3
12
3
3
3
3
3
3
3
26
27
29
19
32
57
59
50
79
76
NaH
NaOtBu
KOtBu
KOtBu
KOtBu
KOtBu
10
12
a Two equivalent of the base was used. Yield of the isolated product.
b
for the pyrazole ring protons. The 1H NMR also showed multiplet signal at δ 7.52-7.63 (5H) for
the protons of phenyl ring substituted in pyrazolo[1,5-a]pyrimidine moiety. The 13C NMR
spectrum of 4a showed signals for eighteen aromatic carbons. Finally, the structure of the
compound 4a and regioselectivity of the reaction was unambiguously established by X-ray
crystallography of compound 4a (Figure 2).11 To determine the ideal base and solvent for this
multi-component reaction we investigated this model reaction with some other bases and
solvents as shown in Table 1. We tried some other bases such as KOMe, KOH and NaH for the
above reaction which also could not increase the yield of the compound 4a to substantial
amounts (entry 3-5, Table 1). When we used NaOtBu and KOtBu in the above reaction, we
noticed that yield of desired product 4a increased to 57% and 59%, respectively in DMF (entry
6-7, Table 1). Further investigation on the solvent, it was found that ethanol was the most
effective among the tested solvents and the yield of 4a was increased to 79% (entry 9, Table 1),
while there was sharp decrease in yield of 4a to 50% (entry 8, Table 1) when dimethylsulfoxide
4

was used. Increase of reaction time did not provide increase in yield of product 4a (entry 10,
Table 1). Under the optimized reaction conditions (entry 9, Table 1) the reaction of ketone 1a
with aromatic aldehyde 2b and 3-amino-1H-pyrazole (3a) afforded pyrazolo[1,5-a]pyrimidine
4b in 74% yield (entry 2, Table 2). Similarly, the reaction of ketone 1b and 1c with aromatic
aldehyde 2b and 3-amino-1H-pyrazoles (3a) under the above reaction condition afforded
nonsteroidal pyrazolo[1,5-a]pyrimidines 4c-d in 65-67% yield.
Figure 2. X-ray crystal structure of 4a.
To study the scope of this one pot reaction we then performed the reaction of steroidal ketone 1d
with aromatic aldehydes 2b-c and different 3-amino-1H-pyrazoles/5-amino-1H-pyrazoles (3a-f)
under the above optimized reaction condition which afforded pyrazolo[1,5-a]pyrimidine fused
heterosteroids 4e-k in A-ring of steroid in good yields (72-76%). The base catalyzed
condensation of aldehyde in the A-ring of steroidal ketone is known to afford 2-alkylidene
steroidal 3-ones.12 Moreover, due to the regioselective nature of the 3-amino-1H-pyrazole/5-
amino-1H-pyrazole addition reaction as determined by the above X-ray crystallographic
analysis, the reaction of steroidal ketone 1d, aldehydes 2b-c and pyrazoles (3a-f) afforded
steroidal pyrazolo[1,5-a]pyrimidine compounds 4e-k fused at 2,3-positions of steroids (entries 5-
11, Table 2). In addition, when this base induced reaction of steroidal ketone 1e was performed
with aldehydes 2d-e and 3-amino-1H-pyrazole (3a) we obtained good yield (70-75%) of D-ring
fused steroidal pyrazolo[1,5-a]pyrimidines 4l-m. It was noteworthy that in all the reactions of
5

steroidal/nonsteroidal ketones with aldehydes and aminopyrazoles under the above reaction
conditions afforded only one regioisomer of the pyrazolo[1,5-a]pyrimidine derivatives as shown
in Table 2. Moreover, it was observed that both electron-releasing groups and electron-
withdrawing groups on the aromatic aldehydes as well as substituents in the 3-amino-1H-
pyrazole and 5-amino-1H-pyrazole rings have no effect on the yield of pyrazolo[1,5-
a]pyrimidines in this one pot reaction.
Table 2. Synthesis of steroidal/nonsteroidal pyrazolo[1,5-a]pyrimidines
Entry
Ketone
Alde-
hyde
Pyrazole
Product
Yield
(%)a
79
1
74
3a
1a
2
2b
3a
67
3
2b
3a
65
4
6

5
3a
76
75
6
1d
3a
1d
75
7
2b
72
8
1d
2b
1d
74
9
2b
72
1d
10
2b
7

73
1d
11
12
13
2b
3a
3a
70
1e
75
aYield of the isolated product.
A probable mechanism for the formation of compound 4e is shown in Scheme 1. First,
condensation of ketone 1d with aldehyde 2b in presence of base affords 2-benzylidene ketone
5a. Then 5a reacts with 3-amino-1H-pyrazole (3a) to afford its corresponding imine which on
deprotonation in presence of potassium tert-butoxide generates the pyrazolide anion 5b.
Intramolecular aza-Michael addition of pyrazolide anion 5c (tautomer of 5b) followed by
aromatization furnishes compound 4e.
8

In conclusion, a new one-pot reaction for the synthesis of biologically important steroidal
A-, D- ring fused pyrazolo[1,5-a]pyrimidines and nonsteroidal pyrazolo[1,5-a]pyrimidines was
developed using KOtBu as the base under reflux conditions in ethanol. A wide variety of
steroidal/nonsteroidal cyclic ketones, aromatic aldehydes and 3-amino-1H-pyrazoles/5-amino-
1H-pyrazoles undergo this highly regioselective reaction to give good yields of pyrazolo[1,5-
a]pyrimidines derivatives.
Acknowledgements
P. S. thanks UGC, New Delhi for the award of junior research fellowship (UGC-JRF). We are
grateful to Director, CSIR-NEIST for his keen interest. This work was financially supported by
CSIR-OSDD (HCP-0001), CSIR-ACT (CSC0301) and CSIR-ORIGIN (CSC0108) projects. We
thank Dr. R. K. Baruah (Analytical division, CSIR-NEIST) for the help with the X-ray analysis.
Supplementary Material
Supporting Information (general experimental procedure, characterization data, 1H NMR and 13C
NMR spectra) for this article is available online at http://www.......
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