One-Pot Acid-Promoted Synthesis of 6-Aminopyrazolopyrimidines from 1 H-Pyrazol-5-yl- N, N-dimethylformamidines or 5-Amino-1 H-pyrazole-4-carbaldehydes with Cyanamide

Article abstract of DOI:10.1021/acs.joc.9b02653

A convenient and efficient one-pot acid-promoted synthesis of 6-aminopyrazolo[3,4-d]pyrimidine has been developed by treatment of 1H-pyrazol-5-yl-N,N-dimethylformamidines or 5-amino-1H-pyrazole-4-carbaldehydes with cyanamide (NH₂CN) in an acid-

Full text of DOI:10.1021/acs.joc.9b02653

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Article
One-Pot Acid-promoted Synthesis of 6-Aminopyrazolopyrimidines
from 1H-Pyrazol-5-yl-N,N-dimethylformamidines or 5-
Amino-1H-pyrazole-4-carbaldehydes with Cyanamide
Ching-Chun Tseng, Shuo-En Tsai, Sin-Min Li, and Fung Fuh Wong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02653 • Publication Date (Web): 18 Nov 2019
Downloaded from pubs.acs.org on November 19, 2019
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One-Pot Acid-promoted Synthesis of
6
-Aminopyrazolopyrimidines from
H-Pyrazol-5-yl-N,N-dimethylformamidines or
-Amino-1H-pyrazole-4-carbaldehydes with Cyanamide
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†,‡
†,‡
§
†,＊
Ching-Chun Tseng, Shuo-En Tsai, Sin-Min Li, Fung Fuh Wong
†School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung,
0402, Taiwan
‡Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, No.
1, Hsueh-Shih Rd., Taichung, 40402, Taiwan
4
9
§Master Program for Pharmaceutical Manufacture, China Medical University, No. 91,
Hsueh-Shih Rd., Taichung 40402, Taiwan
*Corresponding author. Tel.: +886 4 2205 3366 ext. 5603; Fax: +886 4 2207 8083.
E-mail address: wongfungfuh@yahoo.com.tw, ffwong@mail.cmu.edu.tw (F. F.
Wong).
Key words: 6-Aminopyrazolo[3,4-d]pyrimidines, Pyrazolopyrimidines, Cyanamide,
Formamidines, Heterocyclization, Microwave-assisted synthesis
ABSTRACT: A convenient and efficient one-pot acid-promoted synthesis of
6
1
-aminopyrazolo[3,4-d]pyrimidine has been developed by treatment of
H-pyrazol-5-yl-N,N-dimethylformamidines
or
5-amino-1H-pyrazole-4-carbaldehydes with cyanamide (NH
2
C≡N) in an
acid-mediated solution. This synthetic route involves four steps of deprotection,
imination, the key acid-promoted heterocyclization, and aromatization. Based on
optimized studies, methanesulfonyl chloride is considered to be the best solvent.
Furthermore, the microwave-assisted synthetic technique was also carried out to
improve the major product 6-aminopyrazolo[3,4-d]pyrimidines in this method.
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Moreover, our proposed mechanism was confirmed in this study, which demonstrates
that
N-[(5-amino-1,3-diaryl-1H-pyrazol-4-yl)methylene]cyanamide
is
the
intermediate.
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INTRODUCTION
Pyrazolo[3,4-d]pyrimidines are important bioactive heterocyclic molecules that
have attracted attention as potential drugs or molecular tools.1-10,14 In particular,
6
-aminopyrazolo[3,4-d]pyrimidine analogs exhibit pharmacological activities; for
11
example, inhibition of multiple-mitotic kinase (MMK), of human epidermal growth
factor receptor (EGFR) tyrosine kinase,12 phosphodiesterase,13 as well as
anti-inflammat,14
and
cytotoxic
activity.15
Moreover,
6
-aminopyrazolo[3,4-d]pyrimidines have demonstrated their antitumor activity by
targeting Aurora kinases involved in mitosis.11,16-18 Several methods are available for
the preparation of 6-aminopyrazolo[3,4-d]pyrimidines.18 Well-established synthetic
strategies involve the regioselective formylation of 5-bromo-2,4,-dichloropyrimidine
with morpholine-4-carbaldehyde, substitution and cyclization with hydrazine, as well
as hydrogenation and amination with ammonium formate in the presence of palladium
catalyst ((1) of Scheme 1). However, this synthetic pathway is complicated and
cannot provide satisfactory yields. Wainwright et al. have simultaneously developed a
more satisfactory procedure that uses 2-amino-4,6-dihydroxypyrimidine as starting
material, whereby the formylation and chlorination with Vilsmeier reagent
(
POCl /DMF) and cyclization with hydrazine provides a 78% yield in two steps ((2)
3
1
9
of Scheme 1). Based on this observation, we aimed to develop a convenient and
efficient acid-promoted method for synthesis of 6-aminopyrazolo[3,4-d]pyrimidines,
C≡N)20
by treating 1H-pyrazol-5-yl-N,N-dimethylformamidines with cyanamide (NH
2
in the presence of an acid-mediated solvent (Scheme 1). In comparison with the
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method described by Wainwright et al., our isolated yields and material costs are
similar. However, our procedure is simpler and more direct.
Scheme 1. Synthesis Routes of 6-Aminopyrazolo[3,4-d]pyrimidines
1
1
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Functional cyanamide (NH
group transformations, including the conversion of cyanamide to carbodiimide,21
dicyandiamide,22 guanidines,23 sulflimines,24 urea,25 thiourea,26
2
C N) can be used to produce different functional
and
27
selenazadiphospholaminediselenides, etc. Several modified cyanamides act as the
electrophilic cyanating agent towards carbon, nitrogen, oxygen, and sulfur
nucleophiles.28 They also serve as readily available intermediates or versatile
precursors for the synthesis of many natural and biologically active heterocyclic
2-aminoimidazoles,29
tetrazoles,30
compounds,
including
1-substituted
1
,3-diazepanes,31 3,4-dihydropyrimidin-2-ones,32 1,2,4-benzotriazine 1,4-dioxide,33
3
4
35
melamine, and N-alkyl or N-aryl imides etc. Therefore, we examined cyanamide
(
NH C≡N) as an alternative aminating reagent and its reaction towards
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1H-pyrazol-5-yl-N,N-dimethylformamidine under the acidic condition. Our results
indicated that methanesulfonyl chloride is the best acidic solution. We also found that
the microwave-assisted technique markedly promoted the formation of
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-aminopyrazolo[3,4-d]pyrimidines as major products (Scheme 1).
RESULTS AND DISCUSSION
Cyanamide has been widely used as an intermediate for preparation of many
heterocyclic compounds. Therefore, we evaluated a method for synthesis of
6
1
-aminopyrazolo[3,4-d]pyrimidines
by
reacting
H-pyrazol-5-yl-N,N-dimethylformamidine with cyanamide (NH
2
C≡N) as the
aminating agent under acidic conditions. Initially, we investigated the possibility of
the amination cyclization reaction of 1H-pyrazol-5-yl-N,N-dimethylformamidines 1
with NH
2
C≡N under different acid-mediated solvents, such as conc. HCl,
HCl(aq)/AcOH co-solvent, acetic acid (AcOH), trifluoroacetic acid (TFA),
3
6
methanesulfonic acid, methanesulfonylchloride, and p-toluenesulfonylchloride.
The initial solvent investigation used the typical amination cyclization to
synthesize 6-aminopyrazolo[3,4-d]pyrimidine, by reacting the model starting material
1
H-pyrazol-5-yl-N,N-dimethylformamidine 1a with 3.0 equivalent of cyanamide
(
NH C≡N) in the presence of an aqueous acid-mediated solvent solution including
2
aqueous conc. HCl and HCl(aq)/AcOH co-solvent (2.0 mL) at reflux for 3 h.
Pyrazolo[3,4-d]pyrimidine product 3a was revealed to be the major product in 48% to
6
2% yields without the expected 6-aminopyrazolo[3,4-d]pyrimidine product 2a
Table 1, entries 1–3). The screening of acetic acid (AcOH), trifluoroacetic acid (TFA),
methanesulfonic acid (MsOH), methanesulfonylchloride (MsCl), and
p-toluenesulfonylchloride (TsCl) organic acids, 6-aminopyrazolo[3,4-d]pyrimidine
(
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product 2a and pyrazolo[3,4-d]pyrimidine product 3a, were produced in 13–57% and
3
3–52% yields, respectively (Table 1, entries 4–8). Based on this result, the reactivity
tendency of acid-mediated solvents was revealed to be in the order of
methanesulfonylchloride (MsCl) methanesulfonic acid (MsOH)
1
1
1
1
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>
>
p-toluenesulfonylchloride (TsOH) > TFA > AcOH > aqueous acid solvents. In
particular, the optimal result with a 57% yield with 6-aminopyrazolo[3,4-d]pyrimidine
product 2a was achieved by using methanesulfonylchloride (MsCl) as the
acid-mediated solvent. In next attempt to optimization study, we used different
amounts of cyanamide (NH
resulting 6-aminopyrazolo[3,4-d]pyrimidine 2a was isolated in 19–57% yields,
especially for 3.0 equivalent of NH C≡N in the better yield (57%, Table 1, entries
–11). Based on the above experimental result and cost consideration, the 3.0
2
C≡N) including 1.0, 2.0, 3.0, and 4.0 equivalents. The
2
8
equivalent of NH C≡N is the most appropriate amount in the reaction condition.
2
Table 1. Optimization of Reaction Conditions for Synthesis of
6
-Aminopyrazolo[3,4-d]pyrimidine
Yields (%)b
Equiv. of
Entry
Solvent
Reaction condition
NH
2
C≡N
2a
3a
o
-a
1
2
35% HCl(aq)
3
at reflux (~101 C)/3 h
62
56
3
3
5% HCl(aq)/AcOH
o
-a
-a
3
3
at reflux (~105 C)/3 h
(2 : 8)
5% HCl(aq)/AcOH
o
3
at reflux (~107 C)/3 h
48
(1 : 9)
o
-a
4
5
AcOH
TFA
3
3
at reflux (~113 C)/3 h
13
16
o
at reflux (~69 C)/3 h
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o
-a
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33
39
48
33
27
12
8
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7
TsCl
MsOH
MsCl
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3
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4
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1
3
3
3
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3
3
3
at reflux (~131 C)/3 h
33
37
57
48
28
19
52
57
63
71
83
44
-a
o
~160 C/3 h
o
8
at reflux (~157 C)/3 h
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9
MsCl
at reflux (~157 C)/3 h
o
10
MsCl
at reflux (~157 C)/3 h
o
11
MsCl
at reflux (~157 C)/3 h
o
1
1
2
3
MsCl
85–95 C/6 h
o
MsCl
65–75 C/8 h
o
14
MsCl
50–60 C/10 h
o
1
1
1
5
6
7
MsCl
MW/65–75 C/50 min
15
6
o
MsCl
MW/50–60 C/2 h
o
MsCl/THF
MsCl/EtOH
MW/50–60 C/2 h
39
-a
o
18
MW/50–60 C/2 h
anot-detectable.
bAll of yields were obtained via chromatography purification.
We then examined the effect of the reaction conditions on the ratio of 2a/3a.
Compound 2a underwent a further deamination reaction to form compound 3a under
the above-mentioned reflux conditions. Consequently, we attempted to adjust the
reaction time and temperature from reflux to ~50, 70, and 90C, respectively (Table 1,
entries 12–14). Reducing the reaction temperature and prolonging the reaction time
impacted
positively
on
the
acid-promoted
heterocyclization,
with
6
-aminopyrazolo[3,4-d]pyrimidine product 2a yielding 52%, 57% and 63%, from
progressively higher to lower ranges in temperature, respectively (Table 1, entries
12–14). However, a moderate amount of starting material 1a was recovered under a
mild reaction condition.
Microwave irradiation was utilized to facilitate this developed reaction owing to
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it raises the temperature of the whole volume simultaneously (bulk heating) for
increasing efficiency in many organic reactions to accelerate chemical transformation
and increase higher yields in comparison with conventional heating.37 Thus, we
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designed
a
heterocyclization
reaction
planned
by
to
synthesize
reacting
6-aminopyrazolo[3,4-d]pyrimidines
1
H-pyrazol-5-yl-N,N-dimethylformamidine 1a with 3.0 equivalent of cyanamide
NH C≡N) in a methanesulfonylchloride solution under microwave irradiation. The
model
1H-pyrazol-5-yl-N,N-dimethylformamidine 1a with 3.0 equivalents of NH
(
2
procedure
involved
the
treatment
of
2
C≡N in
methanesulfonylchloride solution at ~55 C or ~70 C with 100W of microwave
energy within 50 min or 2 h, respectively. When the aminating cyclization reaction
was completed, the corresponding 6-aminopyrazolo[3,4-d]pyrimidine product 2a was
obtained in 71% and 83% yields, respectively (Table 1, entries 15–16). These results
demonstrated that the microwave-assisted synthetic technique efficiently optimizes
the yield of 6-aminopyrazolo[3,4-d]pyrimidine product 2a and positions
pyrazolo[3,4-d]pyrimidine 3a as the minor product. On the other hands, the co-solvent
systems containing MsCl/THF or MsCl/EtOH (ratio = 1/1) were tried to perform
under the same condition. However, they were unbeneficial for improvement of this
reaction (Table 1, entries 17–18).
After
H-pyrazol-5-yl-N,N-dimethylformamidines 1b–k bearing various N-1 substituents,
including o-, m-, p-Me-Ph, o-, m-, p-Cl-Ph, p-Br-Ph, p-OMe-Ph, m-NO -Ph,
and –CH Ph, the aminating cyclization proved feasible to produce corresponding
-aminopyrazolo[3,4-d]pyrimidines 2b–k in 63–86% yields (Scheme 2). Furthermore,
the substitution effect focused on the C-3 position of pyrazolic ring containing t-butyl,
applying
the
above
standard
procedure
to
1
2
2
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p-Cl-Ph, p-OMe-Ph, and p-Me-Ph groups of compounds 1l–o. The reactions
successfully resulted in corresponding 2l–o products in 64–74% yields (Scheme 2). In
comparison with compound 1a, we obtained lower isolated yields with grafting
t-butyl (1l), p-Cl-Ph (1m), p-OMe-Ph (1n), and p-Me-Ph (1o) groups on the C-3
position of the pyrazolic ring. The simple and co-plane phenyl group favored the
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performance
of
the
aminating
cyclization
reaction.
All
6
-aminopyrazolo[3,4-d]pyrimidines 2a–o were fully characterized by spectroscopic
methods. For example, compound 2a presented one singlet peaks at δ 9.06 ppm of
pyrimidinic ring in 1H NMR. In FT-IR spectrum, compound 2a exhibited
–1
characteristic broad absorption at 3454 cm . The structure of compound 2c was also
characterized by X-ray crystallographic analysis (as the single-crystal X-ray
diffraction study, ORTEP).
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Scheme
2.
Scope
of
Microwave-assisted
Synthesis
of
6
-Aminopyrazolo[3,4-d]pyrimidines
Based on our control experimental studies, as well as previously reported
results,20,38 we predicted a plausible mechanism as shown in Scheme 3, to account for
the formation of 6-aminopyrazolo[3,4-d]pyrimidines 2. At first, amidines 1a–o were
used to simultaneously perform the imination and acid promoted reactions by
cyanamide (NH
2
C≡N) and methanesulfonylchloride to convert to the activated
sulfonamide cation intermediate 4.38 Under microwave heating, deamination
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5
6
effectively
N-[(5-amino-1,3-diphenyl-1H-pyrazol-4-yl)methylene]cyanamide intermediate
Path A). Cyanamide (NH C≡N) was reacted towards intermediate 5 to produce an
provided
5
(
2
0
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0
intramolecular cyclization to generate compound 6. After the proton transformation,
the final products 6-aminopyrazolo[3,4-d]pyrimidines 2a–o were generated to
accomplish acid-promoted heterocyclization and aromatization.
In Path B, the intramolecular cyclization of intermediate 4 was effectively
realized under a high temperature heating reaction. Subsequently, the decyanation
reaction took place by nucleophiles (e.g., water or excess cyanamide) to generate the
pyrazolo[3,4-d]pyrimidine product 3a. A similar result and mechanism has been
predicted and demonstrated by the LC-MS analysis technique.36
Scheme 3. Proposed Reaction Mechanism
According to the predicted mechanism, 5-amino-1H-pyrazole-4-carbaldehyde
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8a38 was considered to be the deprotected form of compound 1a. Theoretically,
compound 8a could be used to react with cyanamide (NH
methanesulfonylchloride solution at ~55 C with 100W of microwave energy within
0 min to give the same 6-aminopyrazolo[3,4-d]pyrimidines 2a. Remarkably, we
2
C≡N) in
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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2
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0
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2
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6
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8
9
0
5
obtained this result and isolated the product 2a in 87% yield (Scheme 4). On the other
hand, intermediate 5a was expected as the chemical synthetic equivalent of
intermediate 5 (Schemes 3 and 4). Fortunately, intermediate 5 was also successfully
isolated and fully characterized by spectroscopic methods. For example,
N-[(5-amino-1,3-diphenyl-1H-pyrazol-4-yl)methylene]cyanamide
5
presented
a
1
singlet peak at δ 8.86 ppm for –CH=N–C≡N in H NMR (Figure 1) and exhibited two
characteristic peaks at 118.10 ppm for N–C≡N and 171.74 ppm for –CH=N–C≡N,
1
3
which represented the C in NMR. The IR absorptions of 5 showed peaks at 2184
–
1
–1
cm for stretching of the –C≡N group and at 3288 and 3391 cm for stretching of
the –NH group.
2
Scheme 4. Demonstration Study of Mechanism
In further investigations, the timed programming of the acid promoted
heterocyclization reaction was conducted under microwave irradiation to demonstrate
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6
the mechanism and is shown in Figure 1. The reaction mixture was sampled every 20
1
min and analyzed by the H-NMR spectroscopic method. This result led us to consider
that starting material 8a was gradually converted to the imination intermediate 5a.
Subsequently, the acid-promoted heterocyclization reaction occured and most of the
starting material 8a and intermediate 5a was successfully transferred to the
corresponding 6-aminopyrazolo[3,4-d]pyrimidines product 2a in 87% yield.
Therefore, we speculated that the starting material 8a diminished and progressively
transformed into the intermediate compound 5a, which subsequently cyclized into 2a
under the acidic condition (Scheme 4 and Figure 1). The experimental results support
our proposed mechanism.
0
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9
0
1
Figure 1. (a) The reaction condition was started at ~55 C (∆: H NMR of the starting
1
material 8a). (b, c) Reaction conditions at ~55 C for 20 and 40 min ( H NMR of ○:
1
intermediate 5a). (d) The reaction condition at ~55C for 50 min (□: H NMR of
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6-aminopyrazolo[3,4-d]pyrimidines product 2a).
To
continue
our
exploratory
study,
a
series
of
5
-amino-1H-pyrazole-4-carbaldehydes 8a–i were prepared39,40 and probed as model
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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3
3
3
4
4
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4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
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5
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7
8
9
0
1
2
3
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5
6
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0
1
2
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2
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5
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8
9
0
1
2
3
4
5
6
7
8
9
0
substrates for acid-promoted heterocyclization under microwave irradiation. This
procedure was applied to 5-amino-1H-pyrazole-4-carbaldehydes 8b–i bearing various
substituents, including o-, m-, p-Me, o-, m-, p-Cl, p-Br, and p-OMe, and the one-pot
acid-promoted heterocyclization smoothly underwentat 50–60 C with 100W of
microwave energy within 50 min to generate the corresponding
6
-aminopyrazolo[3,4-d]pyrimidine products 2b–i in good yields (77–89%, Scheme 5).
All 6-aminopyrazolo[3,4-d]pyrimidines 2a–i were confirmed and fully characterized
using
the
1H-NMR
spectroscopic
method.
In
comparison
with
and
1
5
H-pyrazol-5-yl-N,N-dimethylformamidines
1
-amino-1H-pyrazole-4-carbaldehydes 8 as the starting reactants, we found that
compounds 8 can provide higher isolated yields (77–89% yields, Scheme 5). Based on
the manufacturing steps and commercial costs, we believed that
1
H-pyrazol-5-yl-N,N-dimethylformamidines 1 were easily prepared and adaptable for
generating the desired 6-aminopyrazolo[3,4-d]pyrimidines 2.
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9
0
Scheme
5.
Scope
of
Microwave-assisted
Synthesis
Methdology
CONCLUSIONS
We have developed a microwave-assisted acid-promoted synthesis of
6-aminopyrazolo[3,4-d]pyrimidines
by
treating
or
1
5
H-pyrazol-5-yl-N,N-dimethylformamidines
-amino-1H-pyrazole-4-carbaldehydes with cyanamide (NH
2
C≡N) under an
acid-mediated solution. A scanning optimization study determined that
methanesulfonylchloride was the most appropriate solvent to use in an acid-mediated
solution. Microwave irradiation produced a superior reaction condition compared with
the conventional heating condition. According to our results, greater isolated yields of
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6-aminopyrazolo[3,4-d]pyrimidines
are
synthesized
than
from
from
5
1
-amino-1H-pyrazole-4-carbaldehydes
8
H-pyrazol-5-yl-N,N-dimethylformamidines 1. In consideration of the route of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
4
4
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4
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4
4
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5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
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0
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2
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0
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2
3
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5
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9
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2
3
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5
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8
9
0
1
2
3
4
5
6
7
8
9
0
synthesis and commercial costs, 1H-pyrazol-5-yl-N,N-dimethylformamidines 1 were
favored as the starting materials to prepare 6-aminopyrazolo[3,4-d]pyrimidines.
EXPERIMENTAL SECTION
3
9
40
General Procedure: Starting substrates 1a–o and 8a–h are synthesized according
to our previously reported methods. 1H-Pyrazol-5-yl-N,N-dimethylformamidines,
a,39,40
1c,40
1d,41
1e–f,40
41
1h–j,40
1l–o,40
1
1g
,
and
and
5
-amino-1H-pyrazole-4-carbaldehyde 8a39 are all known compounds, and their
physical and spectral data were consistent with those previously reported. Other
reagents were commercially available and were used directly without further
purification. Analytical thin-layer chromatography was performed on 0.25 mm silica
1
gel 60-F254. Visualization was carried out with UV light. H NMR was recorded on a
Bruker instrument (400 or 500 MHz). Chemical shifts were quoted in parts per
million (ppm) referenced to 0.0 ppm for tetramethylsilane and referenced to residual
protium in the NMR solvent (CDCl = δ 7.24). The following abbreviations (or
3
combinations thereof) were used to explain multiplicities: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad. Coupling constants, J, were reported in
13
hertz (Hz). C NMR spectra were recorded on a Bruker instrument (100 or 125 MHz)
and were fully decoupled by broad band proton decoupling. Chemical shifts were
reported in ppm and referenced to the center line of a triplet at 77.0 ppm of
chloroform-d. Infrared (IR) spectra were recorded as neat solutions or solids; mass
spectra were recorded using electron impact or electrospray ionization techniques.
–1
The wavenumbers reported are referenced to the polystyrene 1601 cm absorption.
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6
High-resolution mass spectra (HRMS) were recorded on a JEOL JMS-HX110 mass
spectrometer with an electron ionization (EI) source.
Microwave Irradiation Experiments. All microwave irradiation experiments
described herein were performed with a single-mode Discover Labmate System from
CEM Corporation, using a 25 mL Pyrex round-bottomed flask for open-vessel heating
chemical reactions. Experiments were performed under a controlled temperature
mode, subjecting the open vessel to temperatures of between 50 C and 75 C for 50
min or 2 h. In all experiments, the internal reaction temperature was monitored by an
FO probe sensor. Conventional heating was performed with a standard hot
plate/magnetic stirrer for comparison experiments.
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Standard
Procedure
for
the
Synthesis
solution
of
1
H-Pyrazol-5-yl-N,N-dimethylformamidines
(1a–o).39,40
A
of
pyrazol-5-amine derivatives (4.00 mmol, 1.0 equiv) and POCl (4.80 mmol, 1.2 equiv)
3
in DMF solution (12 mL) at 30–40 C was treated with 100 W of microwave energy
within 10–20 min. When the reaction was completed, the reaction mixture was
concentrated, added to water (10 mL) and extracted with CH
2
Cl
2
(4 × 20 mL). The
, filtered,
organic extracts were washed with saturated NaHCO , dried over MgSO
3
4
and concentrated under reduced pressure. The residue solution was purified by
column chromatography on silica gel using hexane/ethyl acetate as eluent to give the
corresponding 1H-pyrazol-5-yl-N,N-dimethylformamidines products (1a–o) in
81–96% yields.
N'-(4-Formyl-1,3-diphenyl-1H-pyrazol-5-yl)-N,N-dimethyl-methanimidamide (1a) It
1
was obtained in 93% yield as a yellow solid (1.18 g); mp 126–127 °C; H NMR
(
CDCl , 500 MHz): δ 3.03 (s, 3H), 3.14 (s, 3H), 7.26–7.30 (m, 1H), 7.39–7.47 (m,
3
5H), 7.68 (dd, J = 9.90, 1.49 Hz, 2H), 7.68 (dd, J = 12.5, 1.09 Hz, 2H), 8.71 (s, 1H),
.69 (s, 1H).39,40
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N'-[4-Formyl-1-(2-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methanim
idamide (1b) A solution of 1-(2-methylphenyl)-3-phenyl-1H-pyrazol-5-amine (1.00 g,
4
.0 mmol) and POCl (0.44 mL, 4.8 mmol) in DMF solution (12 mL) at 30–40 C was
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
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4
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5
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5
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5
5
5
5
5
6
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1
2
3
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0
treated with 100 W of microwave energy within 10–20 min. When the reaction was
completed, the reaction mixture was concentrated, added to water (10 mL) and
extracted with CH
2
Cl
2
(4 × 20 mL). The organic extracts were washed with saturated
, filtered, and concentrated under reduced pressure. The
NaHCO , dried over MgSO
3
4
residue solution was purified by column chromatography on silica gel (hexane/EtOAc
1
= 7:3) to give pure 1b; 83% yields (1.10 g), yellow solid; mp 102–105 C. H NMR
(CDCl
3
, 500 MHz): δ 2.20 (s, 3H), 2.81 (s, 3H), 3.07 (s, 3H), 7.22–7.29 (m, 3H), 7.32
(d, J = 7.45 Hz, 1H), 7.39–7.45 (m, 3H), 7.68 (dd, J = 8.10, 1.37 Hz, 2H), 8.83 (s, 1H),
1
3
1
9
.73 (s, 1H). C{ H} NMR (125 MHz, CDCl ): δ 18.22, 34.0, 40.6, 107.5 126.1,
3
128.0, 128.4 (2 × C), 128.65, 128.69, 129.4 (2 × C), 130.5, 132.5, 135.7, 138.1, 154.7,
–
1
1
55.8, 158.8, 185.2. IR (KBr): 2922, 1662, 1625, 1478, 1389, 1114, 1092 cm . EIMS
+
m/z: 333 (24), 332 (M , 100), 331 (10), 317 (41), 289 (16), 288 (43), 277 (15), 260
+
(
20), 90 (11). HRMS (EI) m/z: [M] Calcd for C20
H
20
4
N O: 332.1637; Found
332.1636.
N'-[4-Formyl-1-(3-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methanim
idamide (1c) It was obtained in 84% yield as a brown solid (1.12 g); mp 119–121 °C;
1H NMR (CDCl
, 500 MHz): δ 2.38 (s, 3H), 3.03 (s, 3H), 3.14 (s, 3H), 7.10 (d, J =
3
7.50 Hz, 1H), 7.29 (d, J = 7.79 Hz, 1H), 7.41–7.46 (m, 3H), 7.66–7.67 (m, 4H), 8.70
s, 1H), 9.69 (s, 1H).40
(
N'-[4-Formyl-1-(4-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methanim
idamide (1d) It was obtained in 96% yield as a light yellow solid (1.28 g); mp
1
154–156 °C; H NMR (CDCl
3
, 500 MHz): δ 2.37 (s, 3H), 3.02 (s, 3H), 3.14 (s, 3H),
7
.21 (d, J = 8.33 Hz, 2H), 7.40–7.46 (m, 3H), 7.67 (d, J = 7.29 Hz, 2H), 7.73 (d, J =
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2
2
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5
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5
5
5
6
8.31 Hz, 2H), 8.70 (s, 1H), 9.68 (s, 1H).41
N'-[1-(2-Chlorophenyl)-4-formyl-3-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methanimi
damide (1e): It was obtained in 81% yield as a brown solid (1.14 g); mp 134–135 °C;
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
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4
5
6
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1
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1H NMR (CDCl
, 500 MHz):δ 2.83 (s, 3H), 3.01 (s, 3H), 7.30–7.36 (m, 2H),
3
7.40–7.45 (m, 3H), 7.47–7.49 (m, 2H), 7.68 (d, J = 7.94 Hz, 2H), 8.93 (s, 1H), 9.73 (s,
H).40
1
N'-[1-(3-Chlorophenyl)-4-formyl-3-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methanimi
damide (1f): It was obtained in 88% yield as a light yellow solid (1.24 g); mp
1
1
45–146 °C; H NMR (CDCl
3
, 500 MHz): δ 3.07 (s, 3H), 3.17 (s, 3H), 7.24–7.26
(m, 1H), 7.34 (t, J = 8.08 Hz, 1H), 7.42–7.47 (m, 3H), 7.66 (dd, J = 7.85, 1.31 Hz,
2
1
H), 7.84 (dd, J = 8.25, 0.79 Hz, 1H), 8.05 (t, J = 1.90 Hz, 1H), 8.77 (s, 1H), 9.68 (s,
H).40
N'-[1-(4-Chlorophenyl)-4-formyl-3-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methanimi
damide (1g): It was obtained in 86% yield as a light yellow (1.21 g); mp 159–161 °C;
1H NMR (CDCl
H), 7.42–7.47 (m, 3H), 7.66 (dd, J = 7.95, 1.49 Hz, 2H), 7.86 (dd, J = 6.84, 2.01 Hz,
, 500 MHz):δ 3.04 (s, 3H), 3.16 (s, 3H), 7.38 (dd, J = 6.83, 2.03 Hz,
3
2
2H), 8.75 (s, 1H), 9.68 (s, 1H).41
N'-[1-(4-Bromophenyl)-4-formyl-3-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methanimi
1
damide (1h): It was obtained in 86% yield as a yellow (1.37 g); mp 171–173 °C; H
NMR (CDCl , 500 MHz):δ 3.04 (s, 3H), 3.16 (s, 3H), 7.42–7.47 (m, 3H), 7.53 (dd,
3
J = 6.90, 1.94 Hz, 2H), 7.65 (dd, J = 7.95, 1.40 Hz, 2H), 7.81 (dd, J = 6.94, 1.89 Hz,
H), 8.75 (s, 1H), 9.67 (s, 1H).40
2
N'-[4-Formyl-1-(4-methoxyphenyl)-3-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methani
midamide (1i): It was obtained in 93% yield as a light yellow (1.30 g); mp 146–149
1
°C; H NMR (CDCl
3
, 500 MHz):δ 3.01 (s, 3H), 3.14 (s, 3H), 3.82 (s, 3H), 6.93 (dd,
J = 6.89, 1.87 Hz, 2H), 7.40–7.46 (m, 3H), 7.67 (dd, J = 8.10, 1.44 Hz, 2H), 7.74 (dd,
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J = 6.88, 2.18 Hz, 2H), 8.72 (s, 1H), 9.68 (s, 1H).40
N'-[4-Formyl-1-(3-nitrophenyl)-3-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methanimid
1
amide (1j): It was obtained in 84% yield as a yellow (1.22 g); mp 218–220 °C; H
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (CDCl , 500 MHz):δ 3.13 (s, 3H), 3.21 (s, 3H), 7.45–7.49 (m, 3H), 7.58 (t, J
3
= 8.21 Hz, 1H), 7.68 (dd, J = 7.85, 1.48 Hz, 2H), 8.11 (dd, J = 8.22, 1.40 Hz, 1H),
.36 (dd, J = 8.16, 1.11 Hz, 1H), 8.90 (s, 1H), 9.19 (t, J = 2.10 Hz, 1H), 9.68 (s, 1H).40
8
N'-(1-Benzyl-4-formyl-3-phenyl-1H-pyrazol-5-yl)-N,N-dimethyl-methanimidamide (1k)
A solution of 1-benzyl-3-phenyl-1H-pyrazol-5-amine (1.00 g, 4.0 mmol) and POCl
3
(0.44 mL, 4.8 mmol) in DMF solution (12 mL) at 30–40 C was treated with 100 W
of microwave energy within 10–20 min. When the reaction was completed, the
reaction mixture was concentrated, added to water (10 mL) and extracted with CH
4 × 20 mL). The organic extracts were washed with saturated NaHCO , dried over
MgSO , filtered, and concentrated under reduced pressure. The residue solution was
2
Cl
2
(
3
4
purified by column chromatography on silica gel (hexane/EtOAc = 8:2) to give pure
1
1
k; 89% yields (1.18 g), yellow solid; mp 101–102 C. H NMR (CDCl
3
, 500 MHz): δ
3
.07 (s, 3H), 3.13 (s, 3H), 5.34 (s, 2H), 7.22–7.24 (m, 1H), 7.27–7.33 (m, 4H),
1
3
1
7.37–7.43 (m, 3H), 7.58 (d, J = 6.78 Hz, 2H), 8.99 (s, 1H), 9.62 (s, 1H). C{ H}
NMR (125 MHz, CDCl ): δ 34.1, 40.7, 51.0, 107.7, 127.4, 127.9 (2 × C), 128.38 (2 ×
C),128.41 (2 × C), 128.50, 129.4 (2 × C), 132.6, 137.2, 153.4, 155.4, 160.0, 185.9. IR
3
–
1
+
(KBr): 2924, 1662, 1622, 1479, 1383, 1113, 701 cm . EIMS m/z: 333 (12), 332 (M ,
+
57), 255 (20), 245 (13), 91 (100), 83 (79). HRMS (EI) m/z: [M] Calcd for C20
H
20
4
N O:
3
32.1637; Found 332.1632.
N'-[4-Formyl-3-t-butyl-1-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methanimidamide
1
(1l) : It was obtained in 83% yield as a brown (0.99 g); mp 117–120 °C; H NMR
(CDCl
3
, 500 MHz):δ 1.44 (s, 9H), 3.02 (s, 3H), 3.07 (s, 3H), 7.21–7.24 (m, 1H),
7
.37 (t, J = 7.91 Hz, 2H), 7.81 (d, J = 7.59, 2H), 7.96 (s, 1H), 9.77 (s, 1H).40
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
N'-[3-(4-Chlorophenyl)-4-formyl-1-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methanimi
1
damide (1m) : It was obtained in 92% yield as a brown (1.30 g); mp 133–135 °C; H
NMR (CDCl , 500 MHz):δ 3.03 (s, 3H), 3.14 (s, 3H), 7.29 (t, J = 7.43 Hz, 1H),
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
.40–7.43 (m, 4H), 7.65 (d, J = 8.49, 2H), 7.84 (d, J = 7.58, 2H), 8.62 (s, 1H), 9.65 (s,
1H).40
N'-[4-Formyl-3-(4-methoxylphenyl)-1-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methani
midamide (1n) : It was obtained in 94% yield as a light yellow (1.31 g); mp 136–138
1
°
C; H NMR (CDCl
3
, 500 MHz):δ 3.02 (s, 3H), 3.14 (s, 3H), 3.84 (s, 3H), 6.98 (d, J
= 8.68, 2H), 7.27 (t, J = 7.42, 1H), 7.41 (t, J = 7.89, 2H), 7.62 (d, J = 2.89, 2H), 7.86
d, J = 8.18, 2H), 8.67 (s, 1H), 9.67 (s, 1H).40
(
N'-[4-formyl-3-(4-methylphenyl)-1-phenyl-1H-pyrazol-5-yl]-N,N-dimethyl-methanimi
1
damide (1o) : It was obtained in 96% yield as a brown (1.28 g); mp 124–125 °C; H
NMR (CDCl
3
, 500 MHz):δ 2.39 (s, 3H), 3.03 (s, 3H), 3.14 (s, 3H), 7.24–7.29 (m,
3
1
H), 7.41 (t, J = 7.91 Hz, 2H), 7.57 (d, J = 7.85, 2H), 7.86 (d, J = 7.77, 2H), 8.70 (s,
H), 9.68 (s, 1H).40
Method A: Standard Procedure of Scanning Acid-mediated Solvents for
Synthesis of 6-Aminopyrazolo[3,4-d]pyrimidine 2a and
pyrazolo[3,4-d]pyrimidine 3a. The procedure involved the treatment of
H-pyrazol-5-yl-N,N-dimethylformamidines (1a, 1.0 equiv) with 3.0 equivalent of
cyanamide (NH C≡N) in aqueous conc. HCl, HCl(aq)/AcOH co-solvent, acetic acid
AcOH), trifluoroacetic
methanesulfonylchloride/THF,
1
2
(
acid
(TFA),
methanesulfonic
acid,
methanesulfonylchloride/EtOH
co-solvent,
methanesulfonylchloride, or p-toluenesulfonylchloride solution (2.0 mL) at reflux,
5
0–60 C, 65–75 C, or 85–95 C, for 3, 6, 8, or 10 h. When the reaction was
completed (monitored by TLC), the resulting mixture was added to water (15 mL) and
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extracted with dichloromethane (2 × 15 mL). The organic extracts were washed with
saturated sodium bicarbonate (2 × 15 mL), dried over MgSO
concentrated under reduced pressure. The residue solution was purified by column
chromatography on silica gel using CH Cl /ethyl acetate as eluent to give the
corresponding 6-aminopyrazolo[3,4-d]pyrimidine 2a or/and
pyrazolo[3,4-d]pyrimidine 3a product.
-Amino-1,3-diphenyl-1H-pyrazolo[3,4-d]pyrimidine (2a). H NMR (CDCl
MHz): δ 5.38(br, 2H), 7.29 (t, J = 7.38 Hz, 1H), 7.43–7.53(m, 5H), 7.98 (d, J = 7.16
4
, filtered, and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
1
6
3
, 400
1
3
1
Hz, 2H), 8.23 (d, J = 7.80 Hz, 2H), 9.06 (s, 1H). C{ H} NMR (100 MHz, CDCl
3
): δ
08.6, 121.2 (2 × C), 126.2, 127.3 (2 × C), 129.0 (2 × C), 129.1 (2 × C), 129.3, 132.0,
38.9, 145.5, 154.3, 155.9, 161.5.
,3-Diphenyl-1H-pyrazolo[3,4-d]pyrimidine (3a). H NMR (CDCl
1
1
1
1
3
, 400 MHz): δ
7.35 (t, J = 7.42 Hz, 1H), 7.45–7.49 (m, 1H), 7.54 (t, J = 15.49 Hz, 4H), 8.04 (d, J =
13
1
7
.11 Hz, 2H), 8.29 (d, J = 7.63 Hz, 2H), 9.11 (s, 1H), 9.48 (s, 1H). C{ H} NMR
100 MHz, CDCl ): δ 114.2, 121.4 (2 × C), 126.8, 127.3 (2 × C), 129.2 (4 × C), 129.6,
31.4, 138.5, 144.9, 152.8, 153.3, 155.5. Physical and spectral data were consistent
(
3
1
with those previously reported.42
Method B: Standard
-Aminopyrazolo[3,4-d]pyrimidines (2a–o). The reliable procedure involved the
treatment of 1H-pyrazol-5-yl-N,N-dimethylformamidines (1a–o, 1.0 equiv) with 3.0
equivalent of cyanamide (NH C≡N) in methanesulfonylchloride solution (5.0 mL) at
0–60 C with 100 W of microwave energy for 2 h. When the reaction was completed,
Procedure
for
Synthesis
of
6
2
5
the resulting mixture was added to saturated sodium bicarbonate (15 mL) and
extracted with dichloromethane (2 × 15 mL). The organic extracts were dried over
MgSO
4
, filtered, and concentrated under reduced pressure. The residue solution was
Cl /ethyl acetate as the
purified by column chromatography on silica gel using CH
2
2
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
eluent to give the corresponding 6-aminopyrazolo[3,4-d]pyrimidine products (2a–n)
in 63–86% yields.
6
-Amino-1,3-diphenyl-1H-pyrazolo[3,4-d]pyrimidine (2a). The standard procedure
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
involved
the
treatment
of
N'-(4-formyl-1,3-diphenyl-1H-pyrazol-5-yl)-N,N-dimethyl-methanimidamide
(1a,
9
8.7 mg, 0.31 mmol, 1.0 equiv) with cyanamide (39.1 mg, 0.93 mmol, 3.0 equiv)
methanesulfonylchloride solution (5.0 mL) at 50–60 C with 100 W of microwave
energy for 1–2 h. When the reaction was completed, the resulting mixture was added
to saturated sodium bicarbonate (15 mL) and extracted with dichloromethane (2 × 15
mL). The organic extracts were dried over MgSO
4
, filtered, and concentrated under
reduced pressure, then the residue was purified by chromatography on silica gel
(
CH
2
Cl
2
/EtOAc = 9:1) to give pure 2a; 83% yields (73.9 mg), yellow solid; mp
1
167–168 C (Hexane–EtOAc). H NMR (CDCl
3
, 400 MHz): δ 5.36 (br, 2H), 7.29 (t, J
=
7.40 Hz, 1H), 7.45–7.54 (m, 5H), 7.98 (d, J = 7.24 Hz, 2H), 8.24 (d, J = 7.88 Hz,
13
1
2
1
H), 9.06 (s, 1H). C{ H} NMR (100 MHz, CDCl
3
): δ 108.6, 121.2 (2 × C), 126.1,
27.2 (2 × C), 129.01 (2 × C), 129.03 (2 × C), 129.3, 132.0, 138.9, 145.5, 154.3,
–
1
155.9, 161.4. IR (KBr): 3474, 3416, 2058, 1643, 1632, 1557 cm . EIMS m/z: 288
+
(
20), 287 (M , 100), 286 (50), 272 (33), 271 (13), 77 (26). HRMS (EI) m/z: [M]+
Calcd for C17
H
13
5
N : 287.1171; Found 287.1163.
6
-Amino-1-(2-methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine
(2b).
treatment
The
of
standard
procedure
involved
the
N'-[4-formyl-1-(2-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]-N,N-di-methyl-methani
midamide (1b, 103 mg, 0.31 mmol, 1.0 equiv) with cyanamide (39.1 mg, 0.93 mmol,
3
.0 equiv) methanesulfonylchloride solution (5.0 mL) at 50–60 C with 100 W of
microwave energy for 1–2 h.When the reaction was completed, the resulting mixture
was added to saturated sodium bicarbonate (15 mL) and extracted with
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dichloromethane (2 × 15 mL). The organic extracts were dried over MgSO , filtered,
4
and concentrated under reduced pressure, then the residue was purified by
chromatography on silica gel (CH
2
Cl
2
/EtOAc = 19:1) to give pure 2b; 81% yields
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
(
75.7 mg), white solid; mp 207–208 C (Hexane–EtOAc). H NMR (CDCl
3
, 400
MHz): δ 2.22 (s, 3H), 5.43 (br, 2H), 7.33–7.40 (m, 3H), 7.42–7.46 (m, 2H), 7.50 (t, J
1
3
1
=
7.36 Hz, 2H), 7.96 (d, J = 7.08 Hz, 2H), 9.08 (s, 1H). C{ H} NMR (100 MHz,
CDCl ): δ 18.3, 107.2, 126.7, 127.2 (2 × C), 127.8, 129.1 (2 × C), 129.2, 129.3, 131.3,
32.0, 135.8, 136.3, 145.6, 153.6, 156.5, 161.2. IR (KBr): 3416, 3400, 2039, 2014,
3
1
–1
1694, 1614, 1597, 1557, 1514, 1470, 1410, 1275, 1165 cm . EIMS m/z: 302 (19),
+
+
3
01 (M , 100), 300 (42), 224 (6), 221 (9). 147 (6). HRMS (EI) m/z: [M] Calcd for
: 301.1327; Found 301.1331.
-Amino-1-(3-methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine
standard procedure involved the treatment
C
18
H
15
N
5
6
(2c).
The
of
N'-[4-formyl-1-(3-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]-N,N-di-methyl-methani
midamide (1c, 96.4 mg, 0.29 mmol, 1.0 equiv) with cyanamide (36.6 mg, 0.87 mmol,
3
.0 equiv) methanesulfonylchloride solution (5.0 mL) at 50–60 C with 100 W of
microwave energy for 1–2 h. When the reaction was completed, the resulting mixture
was added to saturated sodium bicarbonate (15 mL) and extracted with
dichloromethane (2 × 15 mL). The organic extracts were dried over MgSO
4
, filtered,
and concentrated under reduced pressure, then the residue was purified by
chromatography on silica gel (CH
2
Cl
2
/EtOAc = 19:1) to give pure 2c; 76% yields
1
(
66.4 mg), white solid; mp 161–162 C (hexane–EtOAc). H NMR (CDCl
3
, 400
MHz): δ 2.44 (s, 3H), 5.45 (br, 2H), 7.11 (d, J = 7.48 Hz, 1H), 7.37 (t, J = 7.83 Hz,
H), 7.44 (t, J = 7.32 Hz, 1H), 7.51 (t, J = 7.42 Hz, 2H), 7.97 (d, J = 0.48 Hz, 1H),
1
1
3
1
7.98 (s, 2H), 8.01 (d , J = 8.12 Hz, 1H), 9.04 (s, 1H). C{ H} NMR (100 MHz,
CDCl ): δ 21.6, 108.5, 118.6, 121.9, 127.1, 127.2 (2 × C), 128.8, 129.0 (2 × C), 129.2,
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
132.1, 138.7, 139.0, 145.4, 154.2, 155.8, 161.5. IR (KBr): 3439, 3418, 2070, 2064,
–
1
+
1
651, 1643, 1634 cm . EIMS m/z: 302 (22), 301 (M , 100), 300 (38). HRMS (EI)
+
m/z: [M] Calcd for C18
H
15
5
N : 301.1327; Found 301.1321.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
-Amino-1-(4-methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine
(2d).
The
of
standard
procedure
involved
the
treatment
N'-[4-formyl-1-(4-methylphenyl)-3-phenyl-1H-pyrazol-5-yl]-N,N-di-methyl-methani
midamide (1d, 99.7 mg, 0.30 mmol, 1.0 equiv) with cyanamide (37.8 mg, 0.90 mmol,
3
.0 equiv) methanesulfonylchloride solution (5.0 mL) at 50–60 C with 100 W of
microwave energy for 1–2 h. When the reaction was completed, the resulting mixture
was added to saturated sodium bicarbonate (15 mL) and extracted with
dichloromethane (2 × 15 mL). The organic extracts were dried over MgSO
4
, filtered,
and concentrated under reduced pressure, then the residue was purified by
chromatography on silica gel (CH
2
Cl
2
/EtOAc = 19:1) to give pure 2d; 74% yields
1
(
66.9mg), white solid; mp 125–126 C (Hexane–EtOAc). H NMR (CDCl
3
, 400
MHz): δ 2.39 (s, 3H), 5.33 (br, 2H), 7.29 (d, J = 8.40 Hz, 2H), 7.44–7.46 (m, 1H),
.51 (dd, J = 14.80, 7.60 Hz, 2H), 7.98 (d, J = 7.60, 2H), 8.06 (d, J = 8.40, 2H), 9.04
7
1
3
1
(s, 1H). C{ H} NMR (100 MHz, CDCl
3
): δ 21.1, 108.5, 121.3 (2 × C), 127.2 (2 × C),
1
29.0 (2 × C), 129.2, 129.5 (2 × C), 133.1, 136.0, 136.4, 145.2, 154.2, 155.7, 161.4.
–1
+
IR (KBr): 3439, 3424, 2197, 2154, 1636, 1559 cm . EIMS m/z: 302 (22), 301 (M ,
+
9
7), 300 (35), 224 (33). 198 (90), 197 (100). HRMS (EI) m/z: [M] Calcd for
C
18
H
15
N
5
: 301.1327; Found 301.1333.
-Amino-1-(2-chlorophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine
standard procedure involved the treatment
6
(2e).
The
of
N'-[1-(2-chlorophenyl)-4-formyl-3-phenyl-1H-pyrazol-5-yl]-N,N-di-methyl-methanim
idamide (1e, 116 mg, 0.33 mmol, 1.0 equiv) with cyanamide (41.6 mg, 0.99 mmol,
3
.0 equiv) methanesulfonylchloride solution (5.0 mL) at 50–60 C with 100 W of
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microwave energy for 1–2 h. When the reaction was completed, the resulting mixture
was added to saturated sodium bicarbonate (15 mL) and extracted with
dichloromethane (2 × 15 mL). The organic extracts were dried over MgSO
4
, filtered,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and concentrated under reduced pressure, then the residue was purified by
chromatography on silica gel (CH
2
Cl
2
/EtOAc = 9:1) to give pure 2e; 64% yields (68.0
1
mg), brown solid; mp 61–62 C (Hexane–EtOAc). H NMR (CDCl
3
, 400 MHz): δ
7
2
.48–7.51 (m, 3H), 7.55 (t, J = 7.40 Hz, 2H), 7.60–7.65 (m, 2H), 8.05 (d, J = 7.56 Hz,
1
3
1
H), 9.08 (s, 1H). C{ H} NMR (100 MHz, CDCl ): δ 113.1, 127.4 (2 × C), 127.7,
3
128.4, 129.3 (2 × C), 129.68, 129.71, 130.8, 131.4, 132.2, 134.8, 145.8, 152.9, 154.6,
–1
1
55.9. IR (KBr): 3439, 3418, 2089, 1643, 1634, 1520, 1497, 1373, 1049 cm . EIMS
+
m/z: 321 (M , 12), 308 (35), 307 (21), 306 (100), 297 (15), 272 (19), 271 (92), 195
+
(
13), 168 (10), 77 (26). HRMS (EI) m/z: [M] Calcd for C17
H
12ClN : 321.0781;
5
Found 321.0788.
-Amino-1-(3-chlorophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine
standard procedure involved the treatment
6
(2f).
The
of
N'-[1-(3-chlorophenyl)-4-formyl-3-phenyl-1H-pyrazol-5-yl]-N,N-di-methyl-methanim
idamide (1f, 123 mg, 0.33 mmol, 1.0 equiv) with cyanamide (44 mg, 1.05 mmol, 3.0
equiv) methanesulfonylchloride solution (5.0 mL) at 50–60 C with 100 W of
microwave energy for 1–2 h. When the reaction was completed, the resulting mixture
was added to saturated sodium bicarbonate (15 mL) and extracted with
dichloromethane (2 × 15 mL). The organic extracts were dried over MgSO
4
, filtered,
and concentrated under reduced pressure, then the residue was purified by
chromatography on silica gel (CH
2
Cl
2
/EtOAc = 8:2) to give pure 2f; 86% yields (96.8
1
mg), light-yellow solid; mp 204–205 C (hexane–EtOAc). H NMR (CDCl
3
, 400
MHz): δ 5.36 (br, 2H), 7.23–7.26 (m, 1H), 7.41 (t, J = 8.13 Hz, 1H), 7.44–7.48 (m,
H), 7.50–7.54 (m, 2H), 7.97 (dt, J = 6.48, 1.52 Hz, 2H), 8.24 (dq, J = 8.24, 0.98 Hz,
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
1H), 8.37 (t, J = 2.02 Hz, 1H), 9.04 (s, 1H). C{ H} NMR (100 MHz, CDCl
3
): δ
08.8, 118.7, 120.8, 125.9, 127.29 (2 × C), 129.1 (2 × C), 129.5, 130.0, 131.8, 134.7,
40.0, 145.9, 154.4, 156.2, 161.5. IR (KBr): 3455, 3441, 3416, 2066, 1643, 1634,
1
1
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–1
+
+
506 cm . EIMS m/z: 323 (M + 2, 34), 321 (M , 100), 322 (31), 320 (34). HRMS
+
(EI) m/z: [M] Calcd for C17
H
12ClN : 321.0781; Found 321.0784.
5
6
-Amino-1-(4-chlorophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine
(2g).
The
of
standard procedure involved the treatment
N'-[1-(4-chlorophenyl)-4-formyl-3-phenyl-1H-pyrazol-5-yl]-N,N-di-methyl-methanim
idamide (1g, 113 mg, 0.32 mmol, 1.0 equiv) with cyanamide (40.4 mg, 0.96 mmol,
3
.0 equiv) methanesulfonylchloride solution (5.0 mL) at 50–60 C with 100 W of
microwave energy for 1–2 h. When the reaction was completed, the resulting mixture
was added to saturated sodium bicarbonate (15 mL) and extracted with
dichloromethane (2 × 15 mL). The organic extracts were dried over MgSO
4
, filtered,
and concentrated under reduced pressure, then the residue was purified by
chromatography on silica gel (CH
2
Cl
2
/EtOAc = 2:8) to give pure 2g; 63% yields (64.8
1
mg), light-yellow solid; mp 169–170 C (Hexane–EtOAc). H NMR (CDCl
3
, 400
MHz): δ 5.36 (br, 2H), 7.46 (t, J = 7.48 Hz, 3H), 7.52 (t, J = 7.40 Hz, 2H), 7.96 (d, J
1
3
1
=
7.20 Hz, 2H), 8.25 (d, J = 8.84 Hz, 2H), 9.04 (s, 1H). C{ H} NMR (100 MHz,
CDCl ): δ 108.7, 122.0 (2 × C), 127.2 (2 × C), 129.1 (4 × C), 129.4, 131.3, 131.8,
37.5, 145.8, 154.3, 155.9, 161.4. IR (KBr): 3287, 3154, 3113, 2916, 2849, 1634,
3
1
–
1
+
+
1591, 1489, 1402, 1192 cm . EIMS m/z: 323 (M + 2, 35), 322 (35), 321 (M , 100),
3
20 (40), 135 (16), 128 (11), 121 (11), 119 (10), 111 (86), 95 (20), 83 (14), 77 (26), 71
+
(
16), 69 (27), 57 (32), 55 (14). HRMS (EI) m/z: [M] Calcd for C17
H
12ClN : 321.0781;
5
Found 321.0777.
6-Amino-1-(4-bromophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine
(2h).
The
of
standard procedure involved the treatment
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2
3
4
5
6
7
8
9
N'-[1-(4-bromophenyl)-4-formyl-3-phenyl-1H-pyrazol-5-yl]-N,N-di-methyl-methani
midamide (1h, 107 mg, 0.27 mmol, 1.0 equiv) with cyanamide (34.1 mg, 0.81 mmol,
3
.0 equiv) methanesulfonylchloride solution (5.0 mL) at 50–60 C with 100 W of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
microwave energy for 1–2 h. When the reaction was completed, the resulting mixture
was added to saturated sodium bicarbonate (15 mL) and extracted with
dichloromethane (2 × 15 mL). The organic extracts were dried over MgSO
4
, filtered,
and concentrated under reduced pressure, then the residue was purified by
chromatography on silica gel (CH
2
Cl
2
/EtOAc = 8:2) to give pure 2h; 73% yields
1
(72.2 mg), light-yellow solid; mp 161–162 C (Hexane–EtOAc). H NMR (CDCl
3
,
4
00 MHz): δ 5.32 (br, 2H), 7.47 (d, J = 7.22 Hz, 1H), 7.52 (t, J = 7.29 Hz, 2H), 7.60
d, J = 8.83 Hz, 2H), 7.97 (d, J = 6.93 Hz, 2H), 8.20 (dd, J = 6.97, 1.93 Hz, 2H), 9.05
(
(
1
3
1
s, 1H). C{ H} NMR (100 MHz, CDCl ): δ 108.7, 119.1, 122.3 (2 × C), 127.2 (2 ×
3
C), 129.1 (2 × C), 129.4, 131.8, 132.0 (2 × C), 138.0, 145.8, 154.4, 156.0, 161.4. IR
(KBr): 3285, 3156, 3107, 2957, 2926, 2855, 1634, 1586, 1487, 1398, 1273, 1123,
–1
+
+
1
1
072 cm . EIMS m/z: 368 (21), 367 (M + 2, 100), 366 (42), 365 (M
,
99), 364 (22),
+
49 (11), 77 (13). HRMS (EI) m/z: [M] Calcd for C17
H12BrN
5
: 365.0276; Found
365.0280.
-Amino-1-(4-methoxylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2i). The
standard procedure involved the treatment of
6
N'-[4-formyl-1-(4-methoxylphenyl)-3-phenyl-1H-pyrazol-5-yl]-N,N-di-methyl-metha
nimidamide (1i, 132 mg, 0.38 mmol, 1.0 equiv) with cyanamide (47.9 mg, 1.14 mmol,
3
.0 equiv) methanesulfonylchloride solution (5.0 mL) at 50–60 C with 100 W of
microwave energy for 1–2 h. When the reaction was completed, the resulting mixture
was added to saturated sodium bicarbonate (15 mL) and extracted with
dichloromethane (2 × 15 mL). The organic extracts were dried over MgSO
4
, filtered,
and concentrated under reduced pressure and the residue was purified by
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
chromatography on silica gel (CH
2
Cl
2
/EtOAc = 17:3) to give pure 2i; 71% yields
1
(85.6 mg), light-yellow solid; mp 206–207 C (Hexane–EtOAc). H NMR (CDCl
3
,
4
7
00 MHz): δ 3.85 (s, 3H), 5.29 (br, 2H), 7.02 (dd, J = 6.98, 2.11 Hz, 2H), 7.45 (d, J =
.61 Hz, 1H), 7.51 (t, J = 7.45 Hz, 2H), 7.97 (d, J = 7.10 Hz, 2H), 8.05 (dd, J = 6.92,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
2.18 Hz, 2H), 9.04 (s, 1H). C{ H} NMR (100MHz, CDCl
3
): δ 55.5, 108.3, 114.2 (2
×
C), 123.1 (2 × C), 127.2 (2 × C), 129.0 (2 × C), 129.1, 132.0, 132.1, 145.1, 154.2,
–1
1
55.4, 158.0, 161.4. IR (KBr): 3439, 3424, 2255, 1634, 1520, 1470, 1410 cm . EIMS
+
+
m/z: 318 (22), 317 (M , 100), 316 (15), 302 (15). HRMS (EI) m/z: [M] calcd for
O: 317.1277; Found 317.1273.
-Amino-1-(3-nitrophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2j). The standard
procedure involved the treatment of
C
18
H
15
N
5
6
N'-[4-formyl-1-(3-nitrophenyl)-3-phenyl-1H-pyrazol-5-yl]-N,N-di-methyl-methanimi
damide (1j, 98.1 mg, 0.27 mmol, 1.0 equiv) with cyanamide (34.1 mg, 0.87 mmol, 3.0
equiv) methanesulfonylchloride solution (5.0 mL) at 50–60 C with 100 W of
microwave energy for 1–2 h. When the reaction was completed, the resulting mixture
was added to saturated sodium bicarbonate (15 mL) and extracted with
dichloromethane (2 × 15 mL). The organic extracts were dried over MgSO
4
, filtered,
and concentrated under reduced pressure, then the residue was purified by
chromatography on silica gel (CH
2
Cl
2
/EtOAc = 9:1) to give pure 2j; 70% yields (62.8
1
mg), yellow solid; mp 134–135 C (Hexane–EtOAc). H NMR (CDCl
3
, 400 MHz): δ
5.41 (br, 2H), 7.49–7.56 (m, 3H), 7.64–7.68 (m, 1H), 7.99 (d, J = 8.00 Hz, 2H), 8.11
1
3
1
(
d, J = 8.00 Hz, 1H), 8.73 (d, J = 8.00 Hz, 1H), 9.08 (s, 1H), 9.33 (s, 1H). C{ H}
NMR (100 MHz, CDCl ): δ 108.9, 115.3, 120.1, 125.8, 127.4 (2 × C), 129.2 (2 × C),
29.75, 129.83, 131.5, 140.1, 146.5, 148.7, 154.6, 156.6, 161.6. IR (KBr): 3418, 3402,
3
1
–
1
+
1643, 1634, 1584, 1408, 1348, 1169 cm . EIMS m/z: 333 (21), 332 (M , 100), 331
13), 321 (10), 308 (11), 306 (29), 286 (11), 271 (30), 77 (31). HRMS (EI) m/z: [M]+
(
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2
3
4
5
6
7
8
9
calcd for C17
H
12
N
6
O
2
: 332.1022; Found 332.1016.
6
-Amino-1-benzyl-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2k). The standard
procedure involved the treatment of
N'-(1-benzyl-4-formyl-3-phenyl-1H-pyrazol-5-yl)-N,N-di-methyl-methanimidamide
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(1k, 103 mg, 0.31 mmol, 1.0 equiv) with cyanamide (39.2 mg, 0.93 mmol, 3.0 equiv)
methanesulfonylchloride solution (5.0 mL) at 50–60 C with 100 W of microwave
energy for 1–2 h. When the reaction was completed, the resulting mixture was added
to saturated sodium bicarbonate (15 mL) and extracted with dichloromethane (2 × 15
mL). The organic extracts were dried over MgSO
4
, filtered, and concentrated under
reduced pressure, then the residue was purified by chromatography on silica gel
(
CH
2
Cl
2
/EtOAc = 19:1) to give pure 2k; 73% yields (68.2 mg), light yellow solid; mp
1
1
77–179 C (Hexane–EtOAc). H NMR (CDCl
3
, 400 MHz): δ 5.36 (br, 2H), 5.50 (s,
2H), 7.22–7.34 (m, 5H), 7.37–7.41 (m, 1H), 7.46 (t, J = 7.44 Hz, 2H), 7.88–7.90 (m,
1
3
1
2
1
1
H), 8.98 (s, 1H). C{ H} NMR (100 MHz, CDCl
3
): δ 50.0, 107.2, 127.0 (2 × C),
27.67, 127.74 (2 × C), 128.6 (2 × C), 128.98, 128.93 (2 × C), 132.4, 136.7, 144.6,
–
1
54.0, 156.0, 161.3. IR (KBr): 3471, 3308, 3186, 1634, 1599, 1466, 1417, 1260 cm .
+
EIMS m/z: 302 (17), 301 (M , 100), 300 (56), 224 (29), 140 (29), 91 (81). HRMS (EI)
+
m/z: [M] calcd for C18
H
15
5
N : 301.1327; Found 301.1330.
6
-Amino-3-tert-butyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2l). The standard
procedure involved the treatment of
N'-[4-formyl-3-t-butyl-1-phenyl-1H-pyrazol-5-yl]-N,N-di-methyl-methanimidamide
1l, 98.5 mg, 0.33 mmol, 1.0 equiv) with cyanamide (41.6 mg, 0.99 mmol, 3.0 equiv)
(
methanesulfonylchloride solution (5.0 mL) at 50–60 C with 100 W of microwave
energy for 1–2 h. When the reaction was completed, the resulting mixture was added
to saturated sodium bicarbonate (15 mL) and extracted with dichloromethane (2 × 15
mL). The organic extracts were dried over MgSO , filtered, and concentrated under
4
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