A two-step, single pot procedure for the synthesis of substituted dihydropyrazolo-pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2013.12.057

In this study, we report a two-step, one pot tandem microwave-assisted reaction of 3-formylchromones with aminopyrazoles followed by a tin-free radical addition. A library of alkyl substituted dihydropyrazolopyrimidines was prepared using this new process.

Full text of DOI:10.1016/j.tetlet.2013.12.057

Tetrahedron Letters 55 (2014) 936–940
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A two-step, single pot procedure for the synthesis of substituted
dihydropyrazolo-pyrimidines
a
a
a
a
Jake R. Zimmerman a, , Brian J. Myers , Samantha Bouhall , Allison McCarthy , Olivia Johntony ,
⇑
Madhuri Manpadi b
a Ohio Northern University, Department of Chemistry and Biochemistry, 525 South Main Street, Ada, OH, USA
b Drury University, Department of Chemistry, Springfield, MO, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, we report a two-step, one pot tandem microwave-assisted reaction of 3-formylchromones
with aminopyrazoles followed by a tin-free radical addition. A library of alkyl substituted dihydropyraz-
olopyrimidines was prepared using this new process.
Received 25 November 2013
Revised 9 December 2013
Accepted 14 December 2013
Available online 21 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Dihydropyrazolopyrimidine
Tin-free radical
3-Formyl chromone
Tandem reaction
Amino pyrazole
Many pyrazole containing fused heterocycles have shown
biological activities in both pesticide and medicinal applications.1
More specifically, pyrazolopyrimidine derivatives represent an
important class of heterocycles due to their synthetic utility,
significant biological activities, and pharmacological importance
as purine analogs.2 Other related compounds such as 4-hydroxypy-
razolopyrimidine (allopurine), which are used in the treatment of
hyperuricemia and gout, inhibit de novo purine synthesis and xan-
thine oxidase.3 Furthermore, several other analogs have shown
anti-tumor and anti-leukemic activities.4 Finally, it is also known
that alkyl substituted pyrazoles have shown anti-allergic, anti-
inflammatory, and anti-arthritic properties.5
Quiroga and coworkers reported the synthesis of a class of
pyrazolopyrimidines from a benzoyl substituted chromone and
several 5-amino pyrazoles via a microwave-assisted protocol.6
Similarly, the same group showed that refluxing in ethanol yields
the same class of molecules using 3-formyl chromones as sub-
strates.7 Based on this previous work, we surmised that using a
variety of commercially available 3-formyl chromones and substi-
tuted amino pyrazoles, we could rapidly prepare pyrazolopyrimi-
dines 3 using a microwave-assisted protocol. More importantly,
however, we wanted to investigate the ability to modify the pyraz-
olopyrimidine core. Our goal was to use a tin-free8,9 radical addi-
tion onto intermediate 3 in order to prepare a small library of
alkyl substituted dihydropyrazolopyrimidines. Even though there
are very few reports for this class of compounds in the literature,
they have been studied for their biological applications including
an extensive investigation by researchers at Bristol Myers Squib
as potential antiarrhythmic drugs.10 Due to the potential impor-
tance of this class of molecules, we focused on developing a two-
step, one-pot tandem reaction sequence (Scheme 1) starting with
a microwave-assisted step to form pyrazolopyrimidine 3 followed
by a tin-free radical addition to yield the substituted dihydropyraz-
olopyrimidine 4.
We initially studied the efficiency of the reaction of chromone
1a with aminopyrazole 2a under a variety of conditions (Table 1).
The previous report by Quiroga uses a solvent-free microwave-
assisted protocol. Although this is appealing, our protocol requires
solvent for the second step. Therefore we opted to begin our stud-
ies using green solvents such as water and ethanol. Using ethanol,
pyrazolopyrimidine 3a was isolated in 95% yield after stirring for
1 h at room temperature. Refluxing for 1 h gave 3a in 89% yield.
This process was repeated using a mixture of water and ethanol
(1:1). Stirring for 1 h at room temperature in this mixture of sol-
vents gave pyrazolopyrimidine 3a in 94% yield, while refluxing
for 1 h gave pyrazolopyrimidine 3a in 87% yield. Although these
yields were satisfactory, we were interested in decreasing the reac-
tion time to enable more rapid preparation of a library of pyrazol-
opyrimidines. Therefore, we began to study a microwave-assisted
protocol for synthesizing substituted pyrazolopyrimidines
(Table 2). Product 3a was formed in 70% yield when using water
⇑
Corresponding author. Tel.: +1 419 772 2342; fax: +1 419 772 2985.
E-mail address: j-zimmerman.3@onu.edu (J.R. Zimmerman).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.057

J. R. Zimmerman et al. / Tetrahedron Letters 55 (2014) 936–940
937
single pot reaction
NH
N
R3
OH
O
R2
OH
O
O
O
R3-I, Et3B
N
NH2
N
2
N
RT
N
R1
H
R1
R1
R2
R2
EtOH, MW
5-15 min.
N
H
N
O
1
4
3
Scheme 1. One-pot synthesis of substituted dihydropyrazolo-pyrimidines.
Table 1
Synthesis of 3a under differing reaction conditions
OH
O
O
O
O
NH
CH3
N
conditions
N
N
H
+
CH3
N
NH2
1a
2a
3a
3a
Entry
Solvent
Conditions
Yielda (%)
1
2
3
4
5
6
7
EtOH
EtOH
EtOH/H2O (1:1)
EtOH/H2O (1:1)
H2O
1 h, rt
1 h, reflux
1 h, rt
1 h, reflux
40 s, MW
40 s, MW
40 s, MW
95
89
94
87
70
89
93
EtOH/H2O (1:1)
EtOH
a
Isolated yields.
Table 2
Synthesis of substituted pyrazolopyrimidines
OH
O
O
O
O
NH
EtOH
N
N
N
H
+
R2
R1
R1
R2
MW 40 s
NH2
N
1
2
3a-l
Entry
Product
R1
R2
Yielda (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
6-H
6-H
6-H
6-H
6-H
6-F
6-Cl
6-Br
6-ethyl
6,8-Cl
6,8-Br
5-CH3
5-H
5-Ph
4-CN
4-Br-5-CH3
5-CH3
5-CH3
5-CH3
5-CH3
5-CH3
5-CH3
93
92
91
70
84
89
87
84
87
92
81
9
10
11
3j
3k
a
Isolated yields.
as a solvent, and further attempts to increase this yield were
unsuccessful. However, using a mixture of water (1:1) and ethanol
greatly increased the yield of 3a to 89%. In the end, absolute etha-
nol proved to provide excellent yields of a variety of substituted
pyrazolopyrimidine (entries 3–12). These reactions were com-
pleted after only 40 s of microwave irradiation and were purified

938
J. R. Zimmerman et al. / Tetrahedron Letters 55 (2014) 936–940
Table 3
Radical and pyrazole scope of substituted dihydropyrazolo-pyrimidine formation
NH
1.
N
R2
OH
O
R1
O
O
O
NH2
EtOH
N
N
MW 40 s
H
R2
2. R1-I, Et3B,
RT, 5-15 min.
N
H
4a-j
1a
4g
Entry
Product
R1
R2
Yielda (%)
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
4g
4h
4i
iso-propyl
tert-butyl
c-hexyl
c-pentyl
ethyl
iso-propyl
iso-propyl
iso-propyl
iso-propyl
iso-propyl
5-CH3
5-CH3
5-CH3
5-CH3
5-CH3
5-H
5-Ph
4-CN
4-CO2Et
4-Br-5-CH3
85
93
80
70
72
78
82
85
70
73
4j
a
Isolated yields.
by simple filtration after cooling to room temperature. In order to
confirm the correct structural assignment for this class of com-
pounds, a crystal structure was obtained for compound 3a.
Next we studied the two-step one-pot tandem reaction by first
forming the pyrazolopyrimidine via the microwave-assisted proto-
col discussed above. Once the initial transformation was complete,
alkyliodide and triethylborane were added to the reaction mixture.
The radical reaction was generally complete after 15 min at room
temperature. It should be noted that intermolecular radical addi-
tions onto aromatic or heteroaromatic systems to yield the dihydro
product are quite rare.11 We tested the radical scope of this two-
step process using a variety of alkyliodide radical precursors,
which resulted in excellent yields for primary, secondary, and
tertiary radicals (Table 3, entries 1–5). Ethyl radical additions often
needed longer reaction times of 20–30 min for completion.
We then studied the pyrazole scope of the tandem reaction be-
tween 3-formylchromone and five different substituted aminopy-
razoles followed by isopropyl radical addition (Table 3, entries
6–10). This tandem transformation is tolerant of pyrazole substitu-
tion at the 4 and 5 positions since all of the reactions resulted in
modest to good yields of the substituted dihydropyrazolopyrimi-
dines 4f–j. In general, we found that the formation of the 5-methyl
aminopyrazole substrate (4a, b) along with secondary and tertiary
radicals gave the best yields. In addition, the formation of more
highly substituted aminopyrazoles such as 4i and 4j gave lower
yields of the desired compounds. A crystal structure of compound
4g clearly shows the radical adds to yield the dihydropyrazolopyr-
imidine scaffold (see Supporting information for three additional
crystal structures).
to high. Products formed using isopropyl radical such as 4a, 4k,
and 4t tended to behave very favorably while products made with
ethyl radical such as 4y, 4bb, and 4ee often needed longer reaction
times and gave lower yields. In general, monohalogenated 3-form-
ylchromones, with the exception of monofluorinated chromones,
worked very well for this reaction (entries 4–12) while dihalogen-
ated 3-formylchromones tended to give lower yields, particularly
when reacted with ethyl radical (entries 19–24).
A proposed mechanism for this tandem reaction sequence is
shown in Scheme 2.7 Based on work with other amines and 3-for-
myl chromones, we believe that the amino pyrazole and the chro-
mone initially condense to form an imine (5). Next, the
pyrazolopyrimidine ring is formed via an addition/elimination se-
quence followed by a proton transfer to ultimately give product
3b. The radical addition begins with the generation of an ethyl rad-
ical via the reaction of O2 with triethylborane.12 Atom abstraction
from the excess alkyl iodide reagent produces the desired alkyl
radical. Next, addition to the pyrazolopyrimidine acceptor gives
resonance-stabilized radical 7, which undergoes a reaction with
triethylborane to yield intermediate 8. Finally, boron enolate 8 is
protonated upon quenching followed by a tautomerization to give
the final dihydropyrazolopyrimidine product (4f).
Altogether we created a library of forty-five substituted pyraz-
olo- and dihydropyrazolopyrimidines using this two-step, one-
pot tandem reaction. This process worked for a number of different
substitutions on the 3-formylchromone and aminopyrazole, and
the free radical transformation worked with a number of different
radical precursors. This transformation is a unique intermolecular
radical addition onto a hetero-aromatic system wherein the prod-
uct retains a newly formed stereocenter and does not rearomatize
into an achiral molecule. Studies on the asymmetric version of this
reaction are currently underway. We have also begun looking at
Finally we studied the effects of varied substitutions on the
chromone with the methylaminopyrazole followed by iso-propyl,
tert-butyl, or ethyl radical (Table 4). Yields ranged from moderate

J. R. Zimmerman et al. / Tetrahedron Letters 55 (2014) 936–940
939
Table 4
Chromone and radical variations for substituted dihydropyrazolo-pyrimidine formation
NH
1.
CH3
N
OH
O
R2
O
O
O
NH2
EtOH
N
N
MW 40 s
R1
CH3
H
R1
2. R2-I, Et3B,
RT, 5-15 min.
N
H
1
4a-hh
Entry
Product
R1
R2
Yielda (%)
1
2
3
4
5
6
7
8
4a
4b
4e
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
4y
6-H
6-H
6-H
6-Cl
6-Cl
6-Cl
6-Br
6-Br
6-Br
6-F
6-F
6-F
6-CH3
6-CH3
6-CH3
6-i-Pr
6-i-Pr
6-i-Pr
6,8-Cl
6,8-Cl
6,8-Cl
6,8-Br
6,8-Br
6,8-Br
6-Cl-7-CH3
6-Cl-7-CH3
6-Cl-7-CH3
iso-propyl
tert-butyl
ethyl
iso-propyl
tert-butyl
ethyl
iso-propyl
tert-butyl
ethyl
iso-propyl
tert-butyl
ethyl
iso-propyl
tert-butyl
ethyl
iso-propyl
tert-butyl
ethyl
iso-propyl
tert-butyl
ethyl
iso-propyl
tert-butyl
ethyl
85
93
72
91
79
86
93
40
76
45
52
57
96
86
80
88
91
51
70
80
31
81
96
25
92
57
66
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
4z
4aa
4bb
4cc
4dd
4ee
4ff
4gg
4hh
iso-propyl
tert-butyl
ethyl
a
Isolated yields.
H
N
O
O
O
N
N
N
O
N
1a + 2b
O
N
N
H
N
N
5
H
H
O
O
O
O
OH
O
proton
N
N
N
N
transfer
O
N
N
N
3b
N
N
H
H
end of step 1
I
I
R
Et3B/O2
R
Et
O
Et
O
Et
N
B
H
OH
O
R
OH
O
R
N
R
N
N
Et3B
N
quench
N
N
N
tautomerization
4f
N
H
7
8
Et
Scheme 2. Proposed mechanism for tandem reaction.
some biological applications for these new dihydropyrazolopyrim-
idines in a cytotoxic assay suggesting that this new class of alkyl-
substituted dihydropyrimidines do contain cytotoxic properties. A
full evaluation on the biological properties of these compounds
will be reported in the future.
Acknowledgments
Acknowledgment is made to the Donors of the American Chem-
ical Society Petroleum Research Fund for support of this research
(ACS PRF 53237-UR1). The authors thank the University of Toledo’s

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J. R. Zimmerman et al. / Tetrahedron Letters 55 (2014) 936–940
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Supplementary data
Supplementary data (experimental procedures; 1H and 13C NMR
Spectra of all the compounds; and X-ray data for 3a, 4f, 4g, 4p, and
4y) associated with this article can be found, in the online version,
at http://dx.doi.org/10.1016/j.tetlet.2013.12.057.
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