Efficient acid catalytic synthesis of pyrazolopyrimidines from 1H-pyrazol-5-yl-N,N-dimethylformamidines with cyanamide

Article abstract of DOI:10.1016/j.tet.2018.04.048

The efficient acid catalytic synthesis of pyrazolo [3,4-d]pyrimidine was developed by treating 1H-pyrazol-5-yl-N,N-dimethylformamidine with various aminating agents including N,O-bis(trimethylsilyl)hydroxylamine (NHSiMe₃(OSiMe₃)), cy

Full text of DOI:10.1016/j.tet.2018.04.048

Accepted Manuscript
Efficient acid catalytic synthesis of pyrazolopyrimidines from 1H-pyrazol-5-yl-N,N-
dimethylformamidines with cyanamide
Shuo-En Tsai, Wan-Ping Yen, Ching-Chun Tseng, Jia-Jun Xie, Min-Yu Liou, Yi-Ting
Li, Naoto Uramaru, Fung Fuh Wong
PII:
S0040-4020(18)30437-X
10.1016/j.tet.2018.04.048
TET 29463
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 February 2018
Revised Date: 13 April 2018
Accepted Date: 17 April 2018
Please cite this article as: Tsai S-E, Yen W-P, Tseng C-C, Xie J-J, Liou M-Y, Li Y-T, Uramaru
N, Wong FF, Efficient acid catalytic synthesis of pyrazolopyrimidines from 1H-pyrazol-5-yl-N,N-
dimethylformamidines with cyanamide, Tetrahedron (2018), doi: 10.1016/j.tet.2018.04.048.
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ACCEPTED MANUSCRIPT
Efficient Acid Catalytic Synthesis of Pyrazolopyrimidines from
1H-Pyrazol-5-yl-N,N-dimethylformamidines with Cyanamide
Shuo-En Tsai, Wan-Ping Yen, Ching-Chun Tseng, Jia-Jun, Xie, Min-Yu Liou,
Yi-Ting, Li, Naoto Uramaru, Fung Fuh Wong＊
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Efficient Acid Catalytic Synthesis of Pyrazolopyrimidines
from 1H-Pyrazol-5-yl-N,N-dimethylformamidines with
Cyanamide
Shuo-En Tsai,a,b Wan-Ping Yen,a,b,e Ching-Chun Tseng,a,b Jia-Jun, Xie,c Min-Yu Liou,c
Yi-Ting, Li,c Naoto Uramaru,d Fung Fuh Wong＊
,a,b
aSchool of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung,
40402, Taiwan
bPh.D. Program for Biotech Pharmaceutical Industry, China Medical University, No.
91, Hsueh-Shih Rd., Taichung, 40402, Taiwan
cMaster Program for Pharmaceutical Manufacture, China Medical University, No. 91,
Hsueh-Shih Rd., Taichung 40402, Taiwan
dDepartment of Environmental Science, Nihon Pharmaceutical University, 10281,
Komuro, Ina-machi, Kitaadachi-gun, Saitama, Japan
eThe contribution equal to first author.
*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: Pyrazolopyrimidines, Cyanamide, Formamidines, Heterocyclization
ABSTRACT: The efficient acid catalytic synthesis of pyrazolo[3,4-d]pyrimidine was
developed by treating 1H-pyrazol-5-yl-N,N-dimethylformamidine with various
aminating
agents
including
cyanamide
N,O-bis(trimethylsilyl)hydroxylamine
(NH2C≡N), hydroxylamine (NH2OH),
(NHSiMe3(OSiMe3)),
methoxyamine (NH2OMe), hydrazine (NH2NH2), and urea (NH2C(O)NH2) in acidic
solution at reflux. Based on the experimental result, cyanamide (NH2C≡N) and
methanesulfonic acid were indicated the best aminating agent and acid mediated
solvent. On the other hands, the reactivity tendency was involved the activity of
original leaving species grafting on the aminating agents, such
as –OH, –OMe, –OSiMe3, –NH2, –OSiMe3, –C(O)NH2, and –C≡N, in acid catalytic
heterocyclic reaction.
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INTRODUCTION
Pyrazolo[3,4-d]pyrimidines have attracted attention as potential drugs or
molecular tools.1-10 Some recently reported synthetic methods for this class of
compounds
are
included
functionalized
barbituic
dithiones,12
acid,11
or
1-phenyl-5H,7H-pyrazolo[3,4-d]pyrimidine
pyrazolo[3,4-d]pyrimidin-4-ones,13 and intramolecular heterocyclization of
acid14
5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole
carboxylic
or
5-amino-4-cyano-pyrazoles.15 However, most of the methods are not straightforward
and troublesome for preparation of starting materials. Therefore, we have previously
also designed the convenient synthetic routes involved 5-aminopyrazoles with
Vilsmeier reagents to construct pyrazolo[3,4-d]pyrimidine core structures via the
directed intramolecular heterocyclization16 or the sequential intermolecular
heterocyclization with hexamethyldisilazane (NH(SiMe3)2) under neutralization/basic
reaction condition (Figure 1).17 Based on the above observations, we found most of
approach were dangerous exothermic reaction. As a result, we planned to develop a
efficient acid catalystic method for synthesis of pyrazolo[3,4-d]pyrimidines by
treating 1H-pyrazol-5-yl-N,N-dimethylformamidines with aminating agent under the
acidic solution (Figure 1).
At first, we estimated 1H-pyrazol-5-yl-N,N-dimethylformamidine with a series
of aminating equivalent agents including N,O-bis(trimethylsilyl)hydroxylamine
(NHSiMe3(OSiMe3)),
cyanamide
(NH2C≡N),
hydroxylamine
(NH2OH),
methoxyamine (NH2OMe), hydrazine (NH2NH2), and urea (NH2C(O)NH2) under the
different acid mediated solution. Fortunately, we successfully found cyanamide
(NH2C≡N) and methanesulfonic acid were respectively indicated the best aminating
agent
and
acid
mediated
solvent
for
synthesizing
the
desired
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pyrazolo[3,4-d]pyrimidine products.
Figure 1. The published one-pot cascade reaction and acid catalytic synthesis of
pyrazolo[3,4-d]pyrimidines.
RESULTS AND DISCUSSION
In view of our previous investigation experience of Vilsmeier-Haack reagent16,17
we estimated 1H-pyrazol-5-yl-N,N-dimethylformamidines18 were respectively
important starting materials for the new designed synthesis. On the other hands,
cyanamides (NH2C≡N) were available versatile aminating intermediates or precursors
for synthesis of widely heterocyclic compounds.19-25 Therefore, we initiated our study
to explore the possibility of the amination cyclization reaction between
1H-pyrazol-5-yl-N,N-dimethylformamidine 1a and cyanamides (NH2C≡N). Table 1
presents the typical amination cyclization study by reacting the model starting
material 1H-Pyrazol-5-yl-N,N-dimethylformamidine 1a with cyanamide (NH2C≡N,
3.0 equiv) in presence of a series of acidic mediate solutions (2.0 mL), such as
aqueous HCl solution (5%, 10%, and 35%), acetic acid (AcOH), trifluoroacetic acid
(TFA), methanesulfonic acid, and p-toluenesulfonic acid at reflux for 3.0–5.0 h. The
corresponding pyrazolo[3,4-d]pyrimidine product 2a were afforded from ~32% to
82% yields (Table 1, entries 1–7). Based on the control experimental result, the
promoted reactivity tendency of acid mediated solvents was methanesulfonic acid >
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35% HCl(aq) > TFA > p-toluenesulfonic acid > 10% HCl(aq) > 5% HCl(aq) > AcOH. The
result was also revealed the Brønsted-Lowry acid catalytic heterocyclization was
favorable carried out in strong acid reaction condition.
Table 1. The amination study for synthesis of pyrazolopyrimidines in the different of
acid mediated solvents
Entry
1
Solvent
5% HCl(aq)
Aminating Agents Equiv.
Yields (%) of 2a
NH2C N
NH2C N
3
3
3
3
3
3
3
4
2
1
3
3
3
3
3
32
43
62
6
2
10% HCl(aq)
3
35% HCl(aq)
NH2C N
4
AcOH
NH2C N
5
TFA
NH2C N
52
46
83
81
61
27
26
75
37
6
p-Toluenesulfonic acid
Methanesulfonic acid
Methanesulfonic acid
Methanesulfonic acid
Methanesulfonic acid
Methanesulfonic acid
Methanesulfonic acid
Methanesulfonic acid
Methanesulfonic acid
Methanesulfonic acid
NH2C N
7
NH2C N
8
NH2C N
9
NH2C N
10
11
12
13
14
15
NH2C N
NH2OH
NH2OMe
NH2NH2
a
NH2(C=O)NH2
NHSiMe3(OSiMe3)
-
73
anot-detectable.
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For the further optimization, we tried to use the different equivalent of
cyanamide (NH2C≡N) including 1.0, 2.0, 3.0, and 4.0 equivalent amounts. The
corresponding isolated yields of pyrazolo[3,4-d]pyrimidine product 1a were obtained
in 27–83% yields, especially for 3.0 equivalents of NH2C≡N in 83% yield (Table 1,
entries 7–10). Based on the experimental result, we believed the 3.0 equivalent of
NH2C≡N is the suitable amount in our reaction condition.
Next, we investgated a range of aminating equivalent agents including
N,O-bis(trimethylsilyl)hydroxylamine (NHSiMe3(OSiMe3)), cyanamide (NH2C≡N),
hydroxylamine (NH2OH), methoxyamine (NH2OMe), hydrazine (NH2NH2), and urea
(NH2C(O)NH2) in the same reaction condition (Table 1, entries 7 and 11–15). Among
of aminting agents be able to afford the corresponding pyrazolo[3,4-d]pyrimidine
product 2a,25 except for urea. Note that cyanamide (NH2C≡N) can provide the best
result in 83% yield and the reactivity order was NH2C≡N > NHSiMe3(OSiMe3) >
NH2OMe > NH2NH2 > NH2OH >> NH2C(O)NH2 (Table 1, entries 7 and 11–15). As a
result, the reactivity tendency was involved the activity of original leaving species
grafting on the aminating agents in acid catalytic heterocyclization reaction. Several
control experiments were conducted that the best reliable procedure for synthesis of
pyrazolo[3,4-d]pyrimidines
was
involved
the
treatment
of
1H-pyrazol-5-yl-N,N-dimethylformamidine 1a with 3.0 equivalent of NH2C≡N in
methanesulfonic acid solution at reflux for 3.0–5.0 h. When the aminating cyclization
reaction was completed, the resulting mixture was worked-up and purified by
chromatography. The corresponding pyrazolo[3,4-d]pyrimidine product 2a was
obtained in 83% yield (Table 1).
Application
of
the
reliable
standard
procedure
to
1H-pyrazol-5-yl-N,N-dimethylformamidines 1b–j bearing various N-1 substituents,
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including o-, m-, p-Me-Ph, o-, m-, p-Cl-Ph, p-Br-Ph, p-OMe-Ph, and p-NO2-Ph, the
aminating cyclization proceeded smoothly to give the corresponding
pyrazolo[3,4-d]pyrimidines 2b–j in 63–83% yields (Table 2). All of
pyrazolo[3,4-d]pyrimidines 2a–j were characterized by spectroscopic methods, the
physical properties and spectroscopic characteristics were consistent with our
previously published data.16
Table 2. The results of synthesis of pyrazolopyrimidines from
1H-pyrazol-5-yl-N,N-dimethylformamidines with cyanamide (NH2C≡N)
S.M.
X
Products
Yields of 2a–j (%)
Ph
83
1a
2a
o-Me-Ph
m-Me-Ph
p-Me-Ph
o-Cl-Ph
63
73
79
70
68
81
71
78
68
1b
1c
1d
1e
1f
2b
2c
2d
2e
2f
m-Cl-Ph
p-Cl-Ph
1g
1h
1i
2g
2h
2i
p-Br-Ph
p-OMe-Ph
p-NO2-Ph
1j
2j
A plausible mechanism for synthesis of pyrazolo[3,4-d]pyrimidines was depicted
in Scheme 1. Preliminarily, 1H-pyrazol-5-yl-N,N-dimethylformamidines 1a–j was
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effectively initiated by Brønsted-Lowry methanesulfonic acid to form the activate
sulfonamide cation intermediate 3. Subsequently, the aminating agent cyanamide
(NH2C≡N) was added to happen the nucleophilic attacking towards intermediate 3
affording an active cyanimino species 4. Due to the strength driving force by the
excellent leaving-group ability in quaternary ammonium cation moiety, the
intramolecular cyclization was effectively occurred and the de-cyanating reaction took
place by nucleophile (ex. Water or excess cyanamide) to give the corresponding
pyrazolo[3,4-d]pyrimidine products 2a–j were obtained from 63% to 83% yields. On
the other hands, dicyanamide and cyanic acid could be formed as the side-products.26
Notably, dicyanamide and urea were able be identified in aqueous layer by LC-MS
analysis technique. Urea may come from the hydrolysis of excess cyanamide under
acidic mediate.19,27 Therefore, this result provided the specific proof for the proposed
mechanism.
Scheme 1. The plausible mechanism for the newly developed acid catalytic synthesis
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of pyrazolo[3,4-d]pyrimidines.
CONCLUSIONS
We have successfully developed new Brønsted-Lowry acid catalytic synthesis of
pyrazolo[3,4-d]pyrimidines, involving the subsequent imination, heterocyclization,
and aromation three steps. Based on the control experimental results, cyanamide
(NH2C≡N) was the best aminating agent. Furthermore, the key heterocyclic reaction
was catalyzed by methanesulfonic acid to yield the corresponding
pyrazolo[3,4-d]pyrimidine products in moderate yields.
EXPERIMENTAL SECTION
General Procedure: All chemicals were reagent grade and used as purchased. All
reactions were carried out under nitrogen atmosphere and monitored by TLC analysis.
Flash column chromatography purification of compounds was carried out by gradient
1
elution using hexanes in ethyl acetate (EA) unless otherwise stated. H NMR were
recorded at 400 or 500 MHz and 13C NMR recorded at 100 or 125 MHz, respectively,
in CDCl3, CD3OD, and DMSO-d6 as solvent. The standard abbreviations s, d, t, q, and
m refer to singlet, doublet, triplet, quartet, and multiplet, respectively. Coupling
constant (J), whenever discernible, have been reported in Hz. Infrared spectra (IR)
were recorded as neat solutions or solids; and mass spectra were recorded using
electron impact or electrospray ionization techniques. The wavenumbers reported are
referenced to the polystyrene 1601 cm–1 absorption. High-resolution mass spectra
were obtained by means of a JEOL JMS-HX110 mass spectrometer.
Standard Procedure for Synthesis of Pyrazolo[3,4-d]pyrimidines (2a–j). The
reliable
procedure
involved
the
treatment
of
1H-pyrazol-5-yl-N,N-dimethylformamidines (1a–j, 1.0 equiv) with 3.0 equivalent of
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various
aminating
agents
including
N,O-bis(trimethylsilyl)hydroxylamine
hydroxylamine (NH2OH2),
(NHSiMe3(OSiMe3)),
cyanamide
(NH2C≡N),
methoxyamine (NH2OMe), hydrazine (NH2NH2), or urea (NH2C(O)NH2) in
methanesulfonic acid solution (2 mL) at reflux for 3–5 h. When the reaction was
completed (monitored by TLC), the resulting mixture was added to water (15 mL) and
extracted with dichloromethane (15 mL × 2). The organic extracts were washed with
saturate sodium bicarbonate (15 mL × 2), dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue solution was purified by column
chromatography (EtOAc/n-hexane as eluent) on silica gel to give the corresponding
pyrazolo[3,4-d]pyrimidines products (2a–j) in 63–83% yields.
1,3-Diphenyl-1H-pyrazolo[3,4-d]pyrimidine
(2a).16
A
solution
of
1H-pyrazol-5-yl-N,N-dimethylformamidine 1a (159mg, 0.50 mmol, 1.0 equiv), and
cyanamide (63.1 mg 1.5 mmol, 3.0 equiv) was stirred in methanesulfonic acid (2.0mL)
at reflux for 3–5 h. The reaction mixture was then worked-up, and the residue was
purified by chromatography on silica gel to give pure 2a in 83% yield (111 mg).
Light-yellow solid; mp 157–158°C (hexane–EtOAc) ;1H NMR (CDCl3, 500 MHz): δ
7.37–7.40 (1H, m, ArH), 7.49–7.52(1H, m, ArH), 7.55–7.58(4H, m, ArH), 8.05 (2H,
13
d, J = 7.5 Hz, ArH), 8.27–8.29 (2H, m, ArH), 9.15 (1H, s), 9.58 (1H, s); C NMR
(125 MHz, CDCl3): δ 114.0, 121.5 (2 × C), 127.2, 127.4 (2 × C), 129.3 (4 × C), 129.9,
131.0, 138.2, 145.6, 151.6, 153.0, 154.1; IR (KBr): 1577, 1558, 1501, 1418, 1364,
1219, 1090 cm–1. EIMS m/z: 272 (M+, 100), 273 (19), 271 (32), 142 (12), 77 (30), 51
(10).
1-(2-Methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2b).16 A solution of
1H-pyrazol-5-yl-N,N-dimethylformamidine 1b (116 mg, 0.50 mmol, 1.0 equiv), and
cyanamide (63.1 mg 1.5 mmol, 3.0 equiv) was stirred in methanesulfonic acid (2.0mL)
at reflux for 3–5 h. The reaction mixture was then worked-up, and the residue was
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purified by chromatography on silica gel to give pure 2b in 63% yield (90.2 mg).
1
Light-yellow solid; mp 140–141°C (hexane–EtOAc); H NMR (CDCl3, 400 MHz): δ
2.49 (3H, s, CH3), 7.42–7.51(1H, m, ArH), 7.48–7.46(1H, m, ArH), 7.55–7.58 (3H, m,
ArH), 8.06–8.11 (4H, m, ArH), 9.13 (1H, s), 9.51 (1H, s); 13C NMR (100 MHz,
CDCl3): δ 21.63, 114.19, 118.77, 122.18, 127.42 (2 × C), 127.78, 129.24 (2 × C),
129.62, 131.56, 138.39, 139.33, 144.92, 152.80, 153.33, 155.61. IR (KBr): 1634,
1609, 1585, 1557, 1493, 1364, 1229, 1098, 1085 cm–1. EIMS m/z: 286 (M+ , 100),
287 (20), 285 (25), 272 (17), 271 (10), 156 (10),91 (12), 77 (30), 65 (12).
1-(3-Methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2c).16 A solution of
1H-pyrazol-5-yl-N,N-dimethylformamidine 1c (116 mg, 0.50 mmol, 1.0 equiv), and
cyanamide (63.1 mg 1.5 mmol, 3.0 equiv) was stirred in methanesulfonic acid (2.0mL)
at reflux for 3–5 h. The reaction mixture was then worked-up, and the residue was
purified by chromatography on silica gel to give pure 2c in 73% yield (104 mg).
Yellow solid; mp 81–82°C (hexane–EtOAc); 1H NMR (CDCl3, 400 MHz): δ 2.47 (3H,
s, CH3), 7.15 (1H, d, J = 6.8 Hz, ArH), 7.39–7.48 (2H, m, ArH), 7.51–7.55 (2H, m,
ArH), 8.02–8.09 (4H, m, ArH), 9.10 (1H, s) , 9.46 (1H, s); 13C NMR (100 MHz,
CDCl3): δ 21.56, 114.07, 118.57, 121.96, 127.29 (2 × C), 127.62, 128.95, 129.11 (2 ×
C), 129.49, 131.44, 138.31, 139.19, 144.73, 152.67, 153.18, 155.46; IR (KBr): 1662,
1611, 1584, 1558, 1493, 1477, 1364, 1315, 1229, 1194, 1096 cm–1. EIMS m/z: 286
(M+, 100), 287 (20), 285 (24), 77 (16).
1-(4-Methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2d).16 A solution of
1H-pyrazol-5-yl-N,N-dimethylformamidine 1d (116 mg, 0.50 mmol, 1.0 equiv), and
cyanamide (63.1 mg 1.5 mmol, 3.0 equiv) was stirred in methanesulfonic acid (2.0mL)
at reflux for 3–5 h. The reaction mixture was then worked-up, and the residue was
purified by chromatography on silica gel to give pure 2d in 79% yield (113mg).
1
Yellow solid; mp 133–135°C (hexane–EtOAc); H NMR (CDCl3, 400 MHz): δ 2.41
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(3H, s, CH3), 7.34 (2H, d, J = 8.4 Hz, ArH), 7.46 –7.50 (3H, m, ArH), 8.04 (2H, d, J =
8.4 Hz, ArH), 8.13 (2H, d, J = 8.4 Hz, ArH), 9.09 (1H, s), 9.46 (1H, s); 13C NMR
(100 MHz, CDCl3): δ 21.11, 114.09, 121.51 (2 × C), 127.38 (2 × C), 129.21 (2 × C),
129.56, 129.80 (2 × C), 131.60, 136.05, 136.83, 144.74, 152.76, 153.15, 155.53; IR
(KBr): 1589, 1557, 1513, 1474, 1364, 1265, 1221, 1088 cm–1. EIMS m/z: 286 (M+,
100), 287 (21), 285 (28), 77 (14).
1-(2-Chlorophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2e).16 A solution of
1H-pyrazol-5-yl-N,N-dimethylformamidine 1e (176 mg, 0.50 mmol, 1.0 equiv), and
cyanamide (63.1 mg 1.5 mmol, 3.0 equiv) was stirred in methanesulfonic acid (2.0mL)
at reflux for 3–5 h. The reaction mixture was then worked-up, and the residue was
purified by chromatography on silica gel to give pure 2e in 70% yield (107 mg).
1
Yellow solid; mp 136–138°C (hexane–EtOAc); H NMR (CDCl3, 400 MHz): δ
7.44–7.49 (3H, m, ArH), 7.52–7.55 (2H, m, ArH), 7.60–7.63 (2H, m, ArH), 8.03–8.05
(2H, m, ArH), 9.07 (1H, s), 9.53 (1H, s); 13C NMR (125 MHz, CDCl3): δ 112.9, 127.3
(2 × C), 127.6, 129.1 (2 × C), 129.6 (2 × C), 131.0 (2 × C), 131.3, 132.1, 134.6, 145.6,
152.8, 154.4, 155.8; IR (KBr): 1582, 1557, 1495, 1362, 1223, 1161, 1086 cm–1. EIMS
m/z: 306 (M+, 74), 308 (M+ + 2, 25), 307 (16), 272 (20), 271 (100), 195 (19), 194 (12),
111 (17), 90 (14), 77 (79), 75 (21), 63 (12), 51 (26).
1-(3-Chlorophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2f).16 A solution of
1H-pyrazol-5-yl-N,N-dimethylformamidine 1f (176 mg, 0.50 mmol, 1.0 equiv), and
cyanamide (63.1 mg 1.5 mmol, 3.0 equiv) was stirred in methanesulfonic acid (2.0mL)
at reflux for 3–5 h. The reaction mixture was then worked-up, and the residue was
purified by chromatography on silica gel to give pure 2f in 68% yield (104 mg).
1
White solid; mp 180–182°C (hexane–EtOAc); H NMR (CDCl3, 400 MHz): δ 7.31
(1H, d, J = 8.0 Hz, ArH), 7.45–7.58 (4H, m, ArH), 8.04 (2H, d, J = 7.6 Hz, ArH),
13
8.32–8.43 (2H, m, ArH), 9.14 (1H, s), 9.50 (1H, s); C NMR (100 MHz, CDCl3): δ
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114.46, 118.82, 121.10, 126.63, 127.42 (2 × C), 129.26 (2 × C), 129.86, 130.22,
134.96, 139.59, 145.39, 152.90, 153.60, 155.75; IR (KBr): 1585, 1489, 1404, 1368,
1213, 1132, 1092 cm–1. EIMS m/z: 306 (M+, 100), 308 (M+ + 2, 34), 307 (28), 305
(25), 77 (26).
1-(4-Chlorophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2g).16 A solution of
1H-pyrazol-5-yl-N,N-dimethylformamidine 1g (176 mg, 0.50 mmol, 1.0 equiv), and
cyanamide (63.1 mg 1.5 mmol, 3.0 equiv) was stirred in methanesulfonic acid (2.0mL)
at reflux for 3–5 h. The reaction mixture was then worked-up, and the residue was
purified by chromatography on silica gel to give pure 2g in 81% yield (124 mg).
1
Yellow solid; mp 149–151°C (hexane–EtOAc); H NMR (CDCl3, 500 MHz): δ
7.48–7.51 (3H, m, ArH), 7.54–7.57 (2H, m, ArH), 8.03 (2H, d, J = 8.0 Hz, ArH), 8.32
13
(2H, d, J = 9.0 Hz, ArH), 9.12 (1H, s), 9.49 (1H, s); C NMR (125 MHz, CDCl3):
δ114.3, 122.2 (2 × C), 127.4 (2 × C), 129.2 (2 × C), 129.3 (2 × C), 129.8, 131.2, 132.1,
137.1, 145.2, 152.9, 153.3, 155.6; IR (KBr): 1587, 1555, 1499, 1406, 1265, 1219,
1084 cm–1. EIMS m/z: 306 (M+, 100), 308 (M+ + 2, 31), 307 (24), 305 (20), 296 (14),
294 (31), 159 (11), 91 (28), 77 (26).
1-(4-Bromophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2h).16 A solution of
1H-pyrazol-5-yl-N,N-dimethylformamidine 1h (199 mg, 0.50 mmol, 1.0 equiv), and
cyanamide (63.1 mg 1.5 mmol, 3.0 equiv) was stirred in methanesulfonic acid (2.0mL)
at reflux for 3–5 h. The reaction mixture was then worked-up, and the residue was
purified by chromatography on silica gel to give pure 2h in 71% yield (125 mg).
1
White solid; mp 177–178°C (hexane–EtOAc); H NMR (CDCl3, 500 MHz): δ
7.49–7.2 (1H, m, ArH), 7.55–7.58 (2H, m, ArH), 7.65–7.67 (2H, dd, J = 1.5, 1.5
Hz,ArH), 8.04–8.05 (2H, dd, J = 1, 1 Hz , ArH), 8.27–8.29 (2H, dd, J = 1, 1 Hz, ArH),
9.13 (1H, s), 9.49 (1H, s); 13C NMR (125 MHz, CDCl3): δ 114.4, 120.0, 122.5 (2 × C),
127.4 (2 × C), 129.3 (2 × C), 129.8, 131.2, 132.3 (2 × C), 137.7, 145.3, 152.9, 153.4,
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155.7; IR (KBr): 3030, 2920, 1572, 1551, 1488, 1403, 1216, 1072 cm–1. EIMS m/z:
350 (M+, 5), 352 (M+ + 2, 5), 319 (22), 318 (100), 317 (36), 303 (17), 275 (15), 274
(20), 262 (11), 248 (10), 246 (10), 186 (18), 143 (10), 116 (10), 104 (10), 84 (12), 83
(15), 77 (60), 51 (13).
1-(4-Methoxylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2i).16 A solution of
1H-pyrazol-5-yl-N,N-dimethylformamidine 1i (174 mg, 0.50 mmol, 1.0 equiv), and
cyanamide (63.1 mg 1.5 mmol, 3.0 equiv) was stirred in methanesulfonic acid (2.0mL)
at reflux for 3–5 h. The reaction mixture was then worked-up, and the residue was
purified by chromatography on silica gel to give pure 2i in 78% yield (118 mg).
1
Brown solid; mp 167–168°C (hexane–EtOAc); H NMR (CDCl3, 400 MHz): δ 3.87
(1H, s, OCH3), 7.05 (2H, d, J = 8.0 Hz, ArH), 7.34 (1H, t, J = 7.5 Hz, ArH), 7.54 (2H,
t, J = 8.0, ArH), 7.98 (2H, d, J = 8.0, ArH), 8.28 (2H, d, J = 8.0, ArH), 9.09 (1H, s),
13
9.44 (1H, s); C NMR (125 MHz, CDCl3): δ 55.35, 114.57 (2 × C), 121.26 (2 × C),
123.99, 126.61, 126.78, 128.61 (2 × C), 129.14 (2 × C), 129.39, 138.49, 144.74,
152.66, 155.42, 160.71. IR (KBr): 1643, 1587, 1555, 1497, 1402, 1368, 1215, 1130,
1074. EIMS m/z: 302 (M+ , 100), 303 (21), 301 (17), 287 (18), 258 (11), 77 (47), 51
(12).
1-(4-Nitrophenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (2j). A solution of
1H-pyrazol-5-yl-N,N-dimethylformamidine 1i (182 mg, 0.50 mmol, 1.0 equiv), and
cyanamide (63.1 mg 1.5 mmol, 3.0 equiv) was stirred in methanesulfonic acid (2.0mL)
at reflux for 3–5 h. The reaction mixture was then worked-up, and the residue was
purified by chromatography on silica gel to give pure 2i in 68% yield (108 mg).
1
Brown solid; mp 182–184°C (hexane–EtOAc); H NMR (CDCl3, 400 MHz): δ
7.55–7.61 (3H, m, ArH), 8.06 (2H, d, ArH, J = 7.2 Hz, ArH), 8.41 (2H, d, J = 8.4 Hz,
13
ArH), 8.74 (2H, dd, J = 8.4 Hz, J = 2 Hz ArH), 9.19 (1H, s), 9.54 (1H, s); C NMR
(100 MHz, CDCl3): δ 115.06, 120.42 (2 × C), 124.99 (2 × C), 127.53 (2 × C), 129.38
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(2 × C), 130.31, 130.71, 143.58, 145.26, 146.59, 153.08, 154.39, 156.00; IR (KBr):
1596, 1561, 1516, 1503, 1408, 1335, 1213, 1110, 1081 cm–1. EIMS m/z: 317 (M+,
100), 318 (20), 287 (10), 168 (10), 77 (24); HRMS Calcd. for C17H11N5O2: 317.0913;
Found: 317.0909.
ACKNOWLEDGMENTS
We are grateful to Tsuzuki Institute for Traditional Medicine and Siuguan
Pharmaceutical Industry for financial support.
Supporting Information
Copies of 1H NMR and 13C NMR spectra for products 2a–j. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Efficient Acid Catalytic Synthesis of Pyrazolopyrimidines from
1H-Pyrazol-5-yl-N,N-dimethylformamidines with Cyanamide
Shuo-En Tsai, Wan-Ping Yen, Ching-Chun Tseng, Jia-Jun, Xie, Min-Yu Liou,
Yi-Ting, Li, Naoto Uramaru, Fung Fuh Wong＊
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