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P. P. Kaishap et al. / Tetrahedron Letters 55 (2014) 3117–3121
R1
N
N
R1
R
H2N
N
O
N
HO
HO
R
N
H
3
4
R
N
+
Or
N
R1
R1
NH2
HO
R
N
1a
N
N
H
2
Scheme 1. Base induced synthesis of steroidal pyrazolo[1,5-a]pyrimidines.
pyrazolo[1,5-a]pyrimidines, heterocycle fused steroids, and in
continuation of our research on the development of new method-
ologies for the synthesis of heterocyclic compounds,9 herein, we
describe a new approach for the synthesis of steroid/nonsteroid
fused 5-methyl-pyrazolo[1,5-a]pyrimidine derivatives (Scheme 1).
We started the synthesis of steroidal pyrazolo[1,5-a]pyrimidine
19% in toluene (entry 3, Table 1). Further investigation into the
base, we noticed that yield of compound 3a was increased to
76% and 82% when NaOtBu and KOtBu were used, respectively, as
the base in the above cyclization reaction (entries 4 and 5, Table 1).
We also noticed that increase of duration of the KOtBu induced
reflux reaction could not significantly change the yield of 3a in
24 h (83%, not shown in Table). Moreover, in the absence of base,
the reaction of 1a and 2a could not provide the desired compound
3a (entry 6, Table 1).
3a by the reaction of a,b-unsaturated ketone 1a (1.0 mmol), 3-ami-
no-1H-pyrazole (2a, 1.0 mmol), and NaOMe (3.0 mmol) in ethanol.
After refluxing for 6 h, the reaction mixture afforded the pyrazol-
o[1,5-a]pyrimidine 3a in 23% yield (entry 1, Table 1). We observed
that increase of duration of the reflux reaction also could not in-
crease the yield of product 3a (entry 2, Table 1). This compound
3a was fully characterized by 1H NMR, 13C NMR, and mass
spectroscopy. The 1H NMR of compound 3a exhibited two charac-
teristic aromatic doublet signals at d 6.57 (J = 1.0 Hz, 1H) and d 8.06
(J = 1.0 Hz, 1H) for the pyrazolo[1,5-a]pyrimidine ring protons. The
1H NMR also showed a singlet signal at d 2.61 (3H) for the 5-substi-
tuted methyl protons of the pyrazolo[1,5-a]pyrimidine moiety.
Moreover, 1H NMR exhibited a multiplet for the olefin proton at
d 5.37–5.42 (1H), a multiplet for the proton attached to hydroxyl
group at d 3.53–3.57 (1H), a singlet for two angular methyl groups
at d 1.11 (6H), and the characteristic multiplets at d 0.80–3.40
(18H) for the remaining protons of steroid moiety. The 13C NMR
spectrum of 3a showed signals for eight aromatic carbons at d
95.3, 120.7, 130.7, 141.3, 144.8, 147.9, 148.9, and 155.1. The EI
mass spectra of compound 3a exhibited molecular ion peak at m/
z = 377. After confirming the structure of compound 3a, in order
to determine the ideal base and solvent for the above reaction
we investigated some other bases and solvents. When NaH was
used as a base, the yield of desired product 3a decreased to only
With the optimized reaction condition in hand (entry 5, Table 1),
we studied the reactions of steroidal ketone 1a with different
3-amino-1H-pyrazoles/5-amino-1H-pyrazoles 2a–e, 2g–j to afford
new 5-methyl-pyrazolo[1,5-a]pyrimidine fused steroidal deriva-
tives 3b–e, 3g–j in 75–82% yields (entries 2–5,7–10, Table 2). It
was observed that the substituents present in 3-amino-1H-pyra-
zole and 5-amino-1H-pyrazole rings such as methyl, tert-butyl,
p-fluoro-phenyl, p-methoxy-phenyl and thiophene moieties have
no effect on the yield of pyrazolo[1,5-a]pyrimidines in this
reaction. Surprisingly, the reaction of steroidal ketone 1a and
3-amino-1H-pyrazole-4-carbonitrile 2f afforded only 64% yield of
pyrazolo[1,5-a]pyrimidine derivative 3f (entry 6, Table 2). To see
the scope of this cyclization reaction, we then performed the reac-
tion of nonsteroidal ketone 1b with 5-amino-1H-pyrazoles 2h and
2g under the above optimized reaction condition which afforded
nonsteroidal 5-methyl-pyrazolo[1,5-a]pyrimidine fused com-
pounds 3k–l in 80–82% yields (entries 11–12, Table 2). In addition,
when this base induced reaction of nonsteroidal ketone 1c was
performed with 5-amino-1H-pyrazole 2g and 3-amino-1H-pyra-
zole 2e we obtained good yield (76–80%) of nonsteroidal
5-methyl-pyrazolo[1,5-a]pyrimidine compounds 3m–n. It is worth
noting that all the above reactions afforded only one regioisomer of
the product (3), although there was a possibility of formation of the
other regioisomer (4) in the reaction, as shown in Scheme 1. The
formation of the regioisomer 3 was confirmed by comparing the
spectral data of compound 3n with the reported spectral data4.
A probable mechanism for the formation of compound 3a is
shown in Scheme 2. First, 1a reacts with 3-amino-1H-pyrazole
(2a) to afford imine derivative which on potassium tert-butoxide
induced deprotonation generates the pyrazolide anion 5a.
Intramolecular aza-Michael addition of 5b, which is a different
resonance form of the anion 5a, followed by aromatization of the
obtained intermediate 5c furnishes compound 3a.
Table 1
Optimization of reaction conditions for the synthesis of steroidal 5-methyl-pyrazol-
o[1,5-a]pyrimidine 3a
N
O
+
Base,
solvent,
reflux
H2
N
N
N
N
N
H
HO
HO
2a
3a
1a
Entry
Basea
Solvent
Time (h)
Yieldb (%)
In conclusion, a new reaction for the synthesis of biologically
important steroidal 5-methyl-pyrazolo[1,5-a]pyrimidines and
nonsteroidal 5-methyl-pyrazolo[1,5-a]pyrimidines was developed
using KOtBu as the base under reflux condition in ethanol. A wide
1
2
3
4
5
6
NaOMe
NaOMe
NaH
EtOH
EtOH
Toluene
EtOH
EtOH
EtOH
6
24
12
6
6
6
23
27
19
76
82
0
NaOtBu
KOtBu
—
variety of steroidal/nonsteroidal
a,b-unsaturated ketones and
3-amino-1H-pyrazoles/5-amino-1H-pyrazoles undergo this regio-
selective reaction to afford good yields of steroidal/nonsteroidal
5-methylpyrazolo[1,5-a]pyrimidine derivatives.
a
Three equivalents of the base were used.
Yield of the isolated product.
b
Kaishap, Partha Pratim
