Selective synthesis of pyrazolo[3,4-d]pyrimidine, N-(1H-pyrazol-5-yl) formamide, or N-(1H-pyrazol-5-yl)formamidine derivatives from N-1-substituted-5-aminopyrazoles with new Vilsmeier-type reagents

Article abstract of DOI:10.1016/j.tet.2012.11.002

Various halomethyleniminium salts as novel Vilsmeier agents were synthesized from formamide or N-methylformamide with POCl₃. Treatment of N-1-substituted-aminopyrazoles including N-1-phenyl-5-aminopyrazoles, N-1-(2-pyridinyl)-5-aminopyrazoles,

Full text of DOI:10.1016/j.tet.2012.11.002

Tetrahedron 69 (2013) 1378e1386
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selective synthesis of pyrazolo[3,4-d]pyrimidine, N-(1H-pyrazol-5-yl)
formamide, or N-(1H-pyrazol-5-yl)formamidine derivatives from
N-1-substituted-5-aminopyrazoles with new Vilsmeier-type reagents
Chun-Hsi Chang a, Henry J. Tsai b, Yu-Ying Huang a, Hui-Yi Lin c, Li-Ya Wang d, Tian-Shung Wu c,
,
Fung Fuh Wong a
*
a Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
b Department of Health and Nutrition Biotechnology, Asia University, Taichung County 413, Taiwan, ROC
c School of Pharmacy, China Medical University, No. 91 Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
d The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2012
Received in revised form 24 October 2012
Accepted 2 November 2012
Available online 16 November 2012
Various halomethyleniminium salts as novel Vilsmeier agents were synthesized from formamide or
N-methylformamide with POCl3. Treatment of N-1-substituted-aminopyrazoles including N-1-phenyl-5-
aminopyrazoles, N-1-(2-pyridinyl)-5-aminopyrazoles, and N-1-(2-quinolinyl)-5-aminopyrazoles with
these agents gave the corresponding pyrazolo[3,4-d]pyrimidine, N-(1H-pyrazol-5-yl)formamide, or N-(1H-
pyrazol-5-yl)formamidine. The reaction was different from the traditional Vilsmeier-type reaction and the
plausible reactive pathways were proposed for the unexpected result.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Vilsmeier reaction
5-Aminopyrazoles
Pyrazolo[3,4-d]pyrimidine
Formamidine
Formamide
1. Introduction
we report the investigation of the modified halomethyleniminium
salts, which were prepared by means of formamide or N-methyl-
Vilsmeier-type reaction has evolved into a powerful synthetic
tool for building up many heterocyclic compounds.1e5 The classical
Vilsmeier reagent involves the electrophilic substitution of an
formamide in the presence of phosphorous oxychloride (POCl3). The
reactivity via the modified halomethyleniminium salts with various
N-1-substituted-aminopyrazoles,includingN-1-phenyl-5-aminopy-
razoles, N-1-(2-pyridinyl)-5-aminopyrazoles, and N-1-(2-quinolin-
yl)-5-aminopyrazoles were investigated. Three new Vilsmeier-type
reactions to synthesize pyrazolo[3,4-d]pyrimidine, N-(1H-pyrazol-
5-yl)formamide, and N-(1H-pyrazol-5-yl)formamidine derivatives
were eventually developed. The plausible reactive pathways were
also provided to explain our experimental result.
activated aromatic or heterocyclic compound with
a hal-
omethyleniminium salt, which results from the reaction between
an acid agent (e.g., POCl3, PBr3, (COCl)2 or SOCl2) and an amide
solvent, usually DMF.6 Thus, Vilsmeier reaction is usually called as
Vilsmeier formylation.6 Due to its wide application, many of
modified Vilsmeier reagents7 were enthusiastically developed to
explore the new skeleton, extend the construction, or improve the
yields.
Halomethyleniminium salt (Vilsmeier agent) was not only a for-
mylating agent,6 but also as an activating reagent for carboxylic acids
to give esters,8 amides,9 and acid chlorides,10 and for alcohols to give
alkyl chlorides,11 esters,12 alkyl aryl sulfides,13 and imides.14 Herein,
2. Result and discussion
Functionalized N-arylpyrazole moiety has been shown to ex-
hibit antihyperglycemic, analgesic, anti-inflammatory, sedative,
and hypnotic activities.15e17 More specifically, 5-alkyl/arylamino
substituted pyrazoles have been exploited in the design of phar-
maceuticals and agrochemical agents exhibiting a range of bi-
ological activities.16,18e20 In the previous published literature, the
electrophilic N-1-aryl-5-aminopyrazoles 1 were treated with clas-
sical Vilsmeier reagent (DMFþPOCl3) under the microwave-
* Corresponding author. Tel.: þ886 4 2205 3366x5603; fax: þ886 4 2207 8083;
e-mail addresses: wongfungfuh@yahoo.com.tw, ffwong@mail.cmu.edu.tw (F.F.
Wong).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.002

C.-H. Chang et al. / Tetrahedron 69 (2013) 1378e1386
1379
assisted21,22 or normal heating reaction.23,24 The Vilsmeier for-
mylated amidines 2 were formed as the major products (see
Scheme 1), which was introduced with a formyl group at the C-4
position on pyrazoyl ring with N-(1H-pyrazol-5-yl)formamidines 3
as the minor product.6c,21,25
d
8.48 ppm for eC1H]O in 1H NMR. In 13C NMR spectrum, com-
pound 6e possessed characterization absorptions at d 157.1 ppm for
carbonyl carbon e13CH]O. The IR absorptions of 6e showed peaks
at 1697 cmꢁ1 for stretching of the eNHCH]O amide group. The
ORTEP drawing of compound 6e was shown in Fig. 1. Following our
NMe2
O
N
H
H
NMe2, POCl3
X N
CHO
Classical Vilsmeier reagent
N
R
N
2
NHMe
H
O
NH2
H
NHMe, POCl3
X N
N
N
X = Ph
N
R = t-Bu, Ph, p-MePh, p-ClPh, or p-
R
R
O
OMePh
1a-1e. X = Ph
4a-4e. X= 2-pyridinyl
5a-5e. X= 2-quinolinyl
3a-3e
O
HN
H
H
NHMe, POCl3
N
X = 2-pyridinyl, 2-quinolinyl
N
N
R = t-Bu, Ph, p-MePh, p-ClPh, or p-
OMePh
R
6a-6e. X = 2-pyridinyl
7a-7e. X = 2-quinolinyl
Scheme 1.
By employing the newly developed Vilsmeier reagent, which was
synthesized by using N-methylformamide in the presence of phos-
phorous oxychloride POCl3, toward N-1-phenyl-5-aminopyrazoles
1aee at 50e60 ꢀC with 100 W of microwave energy within
20e30 min, the unexpected N-(1H-pyrazol-5-yl)formamidine prod-
ucts 3aee without forming a formyl group were produced in 76e97%
yields (see Scheme 1 and Table 1).
Table 2
Reactions N-1-(2-pyridinyl)-5-aminopyrazoles 4aee, and N-1-(2-quinolinyl)-5-
aminopyrazoles 5aee with N-methylformamide in the presence of POCl3
Pyrazoles (4aee and 5aee)
Products
N-(1H-Pyrazol-5-yl)formamides
(6aee and 7aee)
S.M.
N1-R1
C3-R2
No.
Yield (%)
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
2-Pyridinyl
2-Pyridinyl
2-Pyridinyl
2-Pyridinyl
2-Pyridinyl
2-Quinolinyl
2-Quinolinyl
2-Quinolinyl
2-Quinolinyl
2-Quinolinyl
t-Bu
Ph
p-MePh
p-ClPh
p-OMePh
t-Bu
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
84
86
82
88
81
82
92
87
91
84
Table 1
Reaction of the N-1-phenyl-5-aminopyrazoles with N-methylformamide in the
presence of POCl3
N-1-phenyl-5-
aminopyrazoles (1aee)
Products
Ph
N-(1H-Pyrazol-5-yl)
formamidines (3aee)
p-MePh
p-ClPh
p-OMePh
S.M.
C3-R
No.
Yield (%)
1a
1b
1c
1d
1e
t-Bu
Ph
p-MePh
p-ClPh
p-OMePh
3a
3b
3c
3d
3e
76
97
88
91
94
For further investigation of the substituent effect, we applied this
newly developed Vilsmeier reagent (N-methylformamideþPOCl3)
to N-1-(2-pyridinyl)-5-aminopyrazoles 4aee, and N-1-(2-quino-
linyl)-5-aminopyrazoles 5aee, which containing Me, tert-butyl, p-
MeePh, p-ClePh, or p-OMeePh groups at the C-3 position of the
pyrazolic ring. The unexpected N-(1H-pyrazol-5-yl)formamides
6aee and 7aee were produced in 81e88% and 82e92% yields, re-
spectively (see Scheme 1 and Table 2). All of the N-(1H-pyrazol-5-yl)
formamide products 6aee and 7ae7e were fully characterized by
spectroscopic methods including single-crystal X-ray diffraction
study (ORTEP). For example, compound 6e presented a peak at
Fig. 1. The ORTEP diagram of N-(1-(2-pyridinyl)-3-(4-methoxyphenyl)-1H-pyrazol-5-
yl)formamide 6e.

1380
C.-H. Chang et al. / Tetrahedron 69 (2013) 1378e1386
experimental result, the yield of N-(1H-pyrazol-5-yl)formamide
products seemed related to N-1 substituted 2-pyridinyl and
2-quinolinyl groups (see Scheme 1).
two singlet peaks at
d 9.02 ppm and 9.31 ppm for pyrimidine ring
in 1H NMR. In 13C NMR spectrum, compound 12b possessed
characterization absorptions at
d
155.0 ppm for pyrimidine carbon
Furthermore, we proposed the plausible mechanism shown in
Scheme 2, to account for the generation of N-(1H-pyrazol-5-yl)form-
amides 6aee and 7aee. Firstly, N-methylformamide was fast reacted
with phosphorous oxychloride POCl3 to form the reactive hal-
omethyleniminium salts 8 (see Scheme 2).26 Further, pyrazoles 6 were
in situ reacted with the reactive iminium species 8 to generate the N-
(1H-pyrazol-5-yl)formamidine intermediate 9 (see Scheme 2). After
aqueous workup, nucleophile H2O attacked toward intermediate 9 to
form intermediate 10 and left methylamine. Finally, the active for-
mimidic acid 11 formed and tautomerized to generate 6 or 7.
N]13CHeN]C, at
d
34.4 ppm for e13C(CH3)3, and at 30.0 ppm
for eC(13CH3)3.
Furthermore, weextendedthis newconditiontoward 5-amino-1-
(2-pyridinyl)-3-substituted pyrazoles 4, 5-amino-1-(2-quinolinyl)-
3-substituted pyrazoles 5, and 1-methyl-1H-pyrazol-5-amine 6,
which contained the H, methyl, tert-butyl, Ph, p-MeePh, p-ClePh, p-
OMeePh groups at the C-3 position of pyrazolic ring. The corre-
sponding heterocyclization products 13aee, 14aee, and 15 were
obtained the in 87e96%, 87e96%, and 93% yields, respectively (see
Scheme 3 and Table 3). All of pyrazolo[3,4-d]pyrimidines 13aee,
O
O
HN
H
NH2
N
N
H
NHMe, POCl3
N
N
N
N
R
R
4 and 5
6 and 7. Y = N
Cl
Me
H
C N
H
8
Reactive specie
H
OH
H
H2O
H2O
NHMe
N
N
N
H
N
N
NHMe
N
N
N
N
N
N
N
R
R
R
NH2Me
9
10
11
Scheme 2.
Consequently, we explored another modified halomethyle-
niminium salts by means of formamide in the presence of phos-
phorous oxychloride POCl3 to various 5-amino-1-arylpyrazole
substrates 1aee bearing various C3-substituted substituents, in-
cluding Me, t-Bu, Ph, p-MeePh, p-ClePh, and p-OMeePh (see
Scheme 3). The experimental procedure involved the treatment of
5-amino-1-arylpyrazoles 1aee with 3.0 equiv of POCl3 in form-
amide solution at 80e90 ꢀC within 0.5e1 h. After work-up and
purification by column chromatography on silica gel, we isolated
the unexpected pyrazolo[3,4-d]pyrimidine products 12aee in
good to excellent yields (>91%, see Scheme 4 and Table 3). All of
pyrazolo[3,4-d]pyrimidines 12aee were fully characterized by
spectroscopic methods. For example, compound 12b presented
14aee, and 15 were also fully characterized by spectroscopic
methods and consistent with the published data.27
The plausible mechanism for the unexpected Vilsmeier heter-
ocyclization reaction is shown in Scheme 4 to account for the de-
sign of our approach. Formamide was reacted with POCl3 coupling
agent to form the Vilsmeier reactive specie 16.26 In the model study,
reaction of 5-aminopyrazole 1b with 16 through the amidination
reaction gave the azadiene 17 (see Scheme 4). In the presence of
excess Vilsmeier agent, azadiene compound 17 was simultaneously
reacted with secondary equivalent of oxonium specie 16 to carry
out the electrophilic heteroaromatic substitution and give the
corresponding imination intermediate 18. After the hydrolysis re-
action was completed and went through intermediate 19, the
O
NH2
N
N
H
NH2, POCl3
X N
X N
X = Me, Ph, 2-pyridinyl, 2-quinolinyl
N
N
R = H, t-Bu, Ph, p-MePh, p-ClPh,
R
R
or p-OMePh
1a-1e. X = Ph
12a-12e. X = Ph
4a-4e. X= 2-pyridinyl
13a-13e X = 2-pyridinyl
14a-14e. X = 2-quinolinyl
15. X = Me, R = H
5a-5e. X= 2-quinolinyl
6. X= Me, R = H
Scheme 3.

C.-H. Chang et al. / Tetrahedron 69 (2013) 1378e1386
1381
O
O
N
N
NH2
O
H
NR1R2, POCl3, MW
HN
H
N
H
NH2, POCl3
+
N
N
N
NR1R2 = NHMe, NH Bu
t
N
N
N
Ph
Ph
NH2
Cl
H
H
H
Ph
N
1b
12b
C
N
NH3
7b
N
N
16
NR1R2
H
O
Ph
Cl
H
NR1R2, POCl3, MW
N
5b
N
N
N
NR1R2 = NMe , NEt ,
H
N
2
2
H
N
N
Ph
N
NH2
20-22
NH2
N
N
N
Scheme 5.
N
Ph
Ph
19
17
H
were obtained as main products in 91e95% yield and very small
amount of N-(1H-pyrazol-5-yl)formamide 7b (3.0%) was observed
in DEF (see Table 4).
N
NH2
H
Cl
H
C
N
N
H
H
NH
15
N
H2O
Ph
Cl
18
3. Conclusion
Scheme 4.
Various Vilsmeier agents were synthesized by using formamide
or N-methylformamide in the presence of phosphorous oxy-
chloride POCl3. The N-1-substituted-aminopyrazoles, including N-
1-phenyl-5-aminopyrazoles, N-1-(2-pyridinyl)-5-aminopyrazoles,
and N-1-(2-quinolinyl)-5-aminopyrazoles, were reacted with the
newly developed Vilsmeier agents to give the corresponding
products such as pyrazolo[3,4-d]pyrimidine, N-(1H-pyrazol-5-yl)
formamide, or N-(1H-pyrazol-5-yl)formamidine derivations. Our
experimental result was different with the traditional Vilsmeier-
type reaction. Furthermore, the plausible reactive mechanisms
were proposed to describe the unexpected result.
Table 3
Reactions N-1-phenyl-5-aminopyrazoles 1aee, N-1-(2-pyridinyl)-5-aminopyrazoles
4aee, N-1-(2-quinolinyl)-5-aminopyrazoles 5aee, and 1-methyl-1H-pyrazol-5-
amine 6 with formamide in the presence of POCl3
Pyrazoles (1aee, 4aee, 5aee and 6)
Products
Pyrazolo[3,4-d]
pyrimidines (12aee,
13aee, 14aee and 15)
S.M.
N1-R1
C3-R2
No.
Yield (%)
1a
1b
1c
1d
1e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
6
Ph
Ph
Ph
Ph
t-Bu
Ph
o-MePh
p-ClPh
p-OMePh
t-Bu
12a
12b
12c
12d
12e
13a
13b
13c
13d
13e
14a
14b
14c
14d
14e
15
91
96
93
91
94
84
86
82
88
81
82
92
87
91
84
93
4. Experimental section
4.1. General procedure
Ph
2-Pyridinyl
2-Pyridinyl
2-Pyridinyl
2-Pyridinyl
2-Pyridinyl
2-Quinolinyl
2-Quinolinyl
2-Quinolinyl
2-Quinolinyl
2-Quinolinyl
Me
All chemicals were reagent grade and used as purchased. All re-
actions were carried out under nitrogen atmosphere and monitored
by TLC analysis. Flash column chromatography was carried out on
silica gel (230e400 mesh). Commercially available reagents were
used without further purification unless otherwise noted. Dichloro-
methane, ethyl acetate, ethanol, hexanes, and methanol were pur-
chased from Mallinckrodt Chemical Co. The following compounds
were purchased from Acoros Chemical Co: benzoylacetonitrile,
N,N-diethylformamide, formamide, N-methylformamide, pivaloyl-
acetonitrile. 2-Hydrazinopyridine was purchased from Aldrich
Chemical Co. N-tert-Butylformamide, 4-chlorobenzoylacetonitrile,
2-chloroquinoline, 4-methoxybenzoylacetonitrile, methanesulfonic
acid, and p-toluoylacetonitrile were purchased from Alfa Chemical
Co. Phosphorylchloride was purchased from FERAK Chemical Co.
Purification by gravity column chromatography was carried out by
use of Merck Reagents Silica Gel 60 (particle size 0.063e0.200 mm,
70e230 mesh ASTM). Infrared (IR) spectra were measured on
a Bomem Michelson Series FT-IR spectrometer. The wavenumbers
reported are referenced to the polystyrene 1601 cmꢁ1 absorption.
Absorption intensities are recordedby the following abbreviations: s,
strong; m, medium; w, weak. Proton NMR spectra were obtained on
a Bruker (200 or 500 MHz) spectrometer by use of CDCl3 as solvent.
Carbon-13 NMR spectra were obtained on a Bruker (50 or 100 MHz)
spectrometer by used of CDCl3 as solvent. Carbon-13 chemical shifts
Ph
o-MePh
p-ClPh
p-OMePh
t-Bu
Ph
o-MePh
p-ClPh
p-OMePh
H
intramolecular heterocyclization was accomplished to give the final
product 12b.
We are of interest to realize the reactivity of the various modi-
fied Vilsmeier reagents. Therefore, 5-amino-1-(2-quinolinyl)-3-
phenylpyrazole (5a) was selected as the model case to react with
various Vilsmeier reagents, which were prepared by amides solvent
such as N-tert-butylformamide, N,N-dimethylformamide (DMF),
N,N-diethylformamide (DEF), N,N-diisopropylformamide, and pi-
peridine-1-carbaldehyde, in the presence of phosphorous oxy-
chloride POCl3 under the microwave-assisted condition (see
Scheme 5).
When 5-amino-1-(2-quinolinyl)-3-phenylpyrazole (5a) was
treated toward N-tert-butylformamide, we found only N-(1H-pyr-
azol-5-yl)formamide 7b product was obtained in 89% yield (see
Scheme 5 and Table 4). Furthermore, sterically hindered amides
including N,N-dimethylformamide (DMF), N,N-diethylformamide
(DEF), and 1-pyrrolidinecarboxaldehyde cyclic amide were used as
reaction solvents, the N-(1H-pyrazol-5-yl)formamidines 20e22
are referenced to the center of the CDCl3 triplet (d 77.0 ppm). Multi-
plicities are recorded by the following abbreviations: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; J, coupling constant (Hz).
Elemental analyses were carried out on a Heraeus CHN-O RAPID
element analyzer.

1382
C.-H. Chang et al. / Tetrahedron 69 (2013) 1378e1386
Table 4
The results of 5-amino-1-(2-quinolinyl)-3-phenylpyrazole 5b with various modified Vilsmeier reagents
NR1R2
H
O
NH2
N
HN
H
N
N
N
N
Amide solvents HC(¼O)
N
N
NR1R2
N
N
N
Ph
Ph
Ph
Formamide (7b)
Formamidines (20e22)
Substrates
R1
R2
Products
Yield (%)
Products
Yield (%)
5b
5b
5b
5b
5b
H
H
Me
Et
Me
t-Bu
Me
Et
7b
7b
7b
7b
7b
90
89
da
3
da
da
20
21
22
da
da
91
92
95
Pyrrolidinyl
da
a
Non-detectable.
4.2. Standard procedure for the preparation of N-(1H-pyr-
azol-5-yl)formamidines 3aee
137.4,150.9,152.1,152.3; IR (KBr) 3265 (m), 2333 (m),1616 (m, eC]
N), 1519 (m), 1489 (m), 1305 (m), 1267 (m), 1151 (m), 937 (m) cmꢁ1
;
EIMS m/z (relative intensity) 290 (100), 289 (Mþ, 5), 249 (28), 248
(20), 221 (5), 91 (10), 77 (10). Anal. Calcd for C18H18N4; C: 74.46; H:
6.25; N: 19.30. Found: C: 74.50; H: 6.27; N: 19.33.
The reliable procedure involved the treatment of N-1-phenyl-5-
aminopyrazoles (1aee, 1.0 equiv) with catalytic amount of POCl3
(w3 equiv) with N-methylformamide (2 mL) at 50e60 ꢀC with
100 W of microwave energy within 20e30 min. When the reaction
was completed, the reaction mixture was concentrated, added to
saturate sodium bicarbonate (15 mL), and extracted with
dichloromethane (15 mL). The organic extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residues were purified by column chromatography on silica gel to
give the corresponding N-(1H-pyrazol-5-yl)formamidines 3aee in
76e97% yield.
4.2.4. N0-(1-Phenyl-3-(4-chlorophenyl)-1H-pyrazol-5-yl)-N-methyl-
methanimidamide (3d). Mp (purified by column chromatography
on silica gel) 179e180 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 2.95e3.03
(m, 3H, CH3), 4.91 (s,1H, NH), 6.14 (s,1H, pyrazole-H), 7.20e7.44 (m,
6H, ArH), 7.73e7.93 (m, 4H, ArH), 7.70 (s, 1H, N]CeH); 13C NMR
(50 MHz, CDCl3)
d
27.9 (CH3), 88.8, 123.5 (2ꢂCH), 125.9, 126.8
(3ꢂCH), 128.4, 128.6 (3ꢂCH), 132.4, 133.3, 149.7, 152.1, 152.5; IR
(KBr) 3427 (m), 2355 (m), 1627 (m, eC]N), 1527 (m), 1492 (m),
1442 (m), 1340 (m), 1284 (m), 948 (m) cmꢁ1; EIMS m/z (relative
intensity) 312 (Mþ2, 33), 310 (100), 309 (Mþ, 5), 270 (12), 269 (28),
268 (19), 92 (5), 77 (16). Anal. Calcd for C17H15ClN4; C: 65.70; H:
4.86; N: 18.03. Found: C: 65.71; H: 4.88; N: 18.01.
4.2.1. N0-(1-Phenyl-3-tert-butyl-1H-pyrazol-5-yl)-N-methyl-meth-
animidamide (3a). Mp (purified by column chromatography on
silica gel) 159e160 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 1.32 (s, 9H,
CH3ꢂ3), 2.92 (s, 3H, CH3), 4.98 (s, 1H, NH), 5.71 (s, 1H, pyrazole-H),
7.15 (s, 1H, N]CeH), 7.35e7.38 (m, 2H, ArH), 7.82e7.84 (m, 3H,
4.2.5. N0-(1-Phenyl-3-(4-methoxylphenyl)-1H-pyrazol-5-yl)-N-methyl-
ArH); 13C NMR (50 MHz, CDCl3)
d
27.8 (CH3), 30.4 (CH3ꢂ3), 32.4
methanimidamide (3e). Mp (purified by column chromatography on
(CH3), 88.3, 123.4 (2ꢂCH), 125.2, 128.3 (2ꢂCH), 140.4, 151.2, 151.7,
161.8; IR (KBr) 3442 (m), 2900 (m),1631 (m, eC]N),1537 (m),1500
(m), 1443 (m), 1410 (m), 1371 (m), 908 (m) cmꢁ1; EIMS m/z (relative
intensity) 256 (95), 255 (Mþ, 15), 241 (100), 214 (40), 200 (37), 207
(9), 77 (15). Anal. Calcd for C15H20N4; C: 70.28; H: 7.86; N: 21.86.
Found: C: 70.31; H: 7.84; N: 21.85.
silica gel) 160e161 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 2.87e2.89 (m, 3H,
CH3), 3.82 (s, 3H, OCH3), 5.08 (s, 1H, NH), 6.04 (s, 1H, pyrazole-H),
6.90e6.91 (m, 2H, ArH), 7.22e7.25 (m, 1H, ArH), 7.35e7.43 (m,
2H, ArH), 7.75e7.80 (m, 4H, ArH), 7.89 (s, 1H, N]CeH); 13C NMR
(50 MHz, CDCl3)
d
27.7 (CH3), 55.3 (OCH3), 88.5, 113.9 (3ꢂCH), 123.4
(2ꢂCH), 125.6, 126.7 (3ꢂCH), 128.3 (2ꢂCH), 140.1, 150.7, 152.2, 159.3;
IR (KBr) 3423 (m), 2351 (m), 1627 (m, eC]N), 1506 (m), 1446 (m),
1400 (m), 1336 (m), 1244 (m), 960 (m) cmꢁ1; EIMS m/z (relative in-
tensity) 306 (100), 305 (Mþ), 250 (10), 132 (5), 92 (5), 91 (5), 77 (16).
Anal. Calcd for C18H18N4O; C: 70.57; H: 5.92; N: 18.29. Found: C:
70.59; H: 5.93; N: 18.27.
4.2.2. N0-(1,3-Diphenyl-1H-pyrazol-5-yl)-N-methyl-methanimidamide
(3b). Mp (purified by column chromatography on silica gel)
157e158 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 2.90e2.92 (m, 3H, CH3),
4.98 (s, 1H, NH), 6.14 (s, 1H, pyrazole-H), 7.19e7.43 (m, 6H, ArH),
7.83e7.94 (m, 4H, ArH), 7.87 (s, 1H, N]CeH); 13C NMR (50 MHz,
CDCl3)
d
27.7 (CH3), 88.9, 123.5 (2ꢂCH), 125.6 (2ꢂCH), 125.8, 127.7,
4.3. Standard procedure for the preparation of N-(1H-pyrazol-
5-yl)formamides 6aee and 7aee
128.4 (2ꢂCH), 128.5 (2ꢂCH), 133.9, 140.1, 150.9, 152.4, 152.6; IR (KBr)
3269 (m), 2360 (m), 1626 (m, eC]N), 1538 (m), 1501 (m), 1464 (m),
1423 (m), 1368 (m), 954 (m) cmꢁ1; EIMS m/z (relative intensity) 276
(100), 275 (Mþ, 5), 246 (12), 235 (28), 234 (27), 207 (9), 77 (19). Anal.
Calcd for C17H16N4; C: 73.89; H: 5.84; N: 20.27. Found: C: 73.93; H:
5.87; N: 20.23.
The reliable procedure involved the treatment of N-1-(2-
pyridinyl)-5-aminopyrazoles (4aee 1.0 equiv) or N-1-(2-
quinolinyl)-5-aminopyrazoles (5aee, 1.0 equiv) with catalytic
amount of POCl3 (w3 equiv) with N-methylformamide (2 mL) at
80e90 ꢀC within 0.5e1 h. When the reaction was completed, the
reaction mixture was concentrated, added to saturate sodium bi-
carbonate (15 mL), and extracted with dichloromethane (15 mL).
The organic extracts were dried over MgSO4, filtered, and concen-
trated under reduced pressure. The residues were purified by col-
umn chromatography on silica gel to give the corresponding N-(1H-
pyrazol-5-yl)formamide products 6aee and 7aee were obtained in
81e88% yield and in 82e91% yield, respectively.
4.2.3. N0-(1-Phenyl-3-(4-methylphenyl)-1H-pyrazol-5-yl)-N-methyl-
methanimidamide (3c). Mp (purified by column chromatography
on silica gel) 182e183 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 2.21e2.36
(m, 3H, CH3), 2.82e2.95 (m, 3H, CH3), 4.93 (s, 1H, NH), 6.14 (s, 1H,
pyrazole-H), 6.97e7.40 (m, 5H, ArH), 7.43e7.77 (m, 4H, ArH),
7.91 (s, 1H, N]CeH); 13C NMR (50 MHz, CDCl3)
d
21.3 (CH3), 27.8
(CH3), 88.8, 123.5, 125.4 (3ꢂCH), 128.3 (3ꢂCH), 129.2 (3ꢂCH), 131.0,

C.-H. Chang et al. / Tetrahedron 69 (2013) 1378e1386
1383
4.3.1. N0-(1-(2-Pyridinyl)-3-tert-butyl-1H-pyrazol-5-yl)-formamide
(6a). Mp (purified by column chromatography on silica gel)
(s, 1H, pyrazole-H), 7.45e7.53 (m, 1H, ArH), 7.66e7.90 (m, 3H, ArH),
8.18e8.30 (m, 2H, ArH), 8.53 (s, 1H, CHO), 12.6 (s, 1H, NH); 13C NMR
210e212 ꢀC; 1H NMR (CDCl3, 500 MHz)
d
1.33 (s, 9H, CH3ꢂ3), 6.82 (s,
(50 MHz, CDCl3)
d
29.7, 30.0 (CH3ꢂ3), 32.7, 96.3, 113.8, 125.9, 127.2,
1H, pyrazole-H), 7.09e7.12 (m, 1H, ArH), 7.79e7.82 (m, 1H, ArH),
8.05e8.07 (m, 1H, ArH), 8.29e8.30 (m, 1H, ArH), 8.44 (s, 1H, CHO),
127.9, 130.5, 138.8, 139.3, 144.9, 153.8, 156.9, 163.9; IR (KBr) 3169
(m), 2960 (m), 1699 (s, C]O), 1537 (m), 1504 (m), 1433 (m), 1375
(m), 1246 (m), 977 (m) cmꢁ1; EIMS m/z (relative intensity) 294 (33),
293 (Mþ, 10), 267 (14), 266 (79), 265 (13), 251 (74), 101 (11). Anal.
Calcd for C17H18N4O; C: 69.37; H: 6.16; N: 19.03. Found: C: 69.35; H:
6.18; N: 19.05.
12.09(s,1H, NH);13C NMR (125 MHz, CDCl3)
d
30.0 (CH3ꢂ3), 30.4, 95.8,
114.1, 119.9, 138.4, 139.2, 146.0, 145.7, 156.9, 163.7; IR (KBr) 3217 (m),
2962 (m),1695 (s, C]O),1595 (m),1550 (m),1440 (m),1398 (m),1249
(m), 981 (m) cmꢁ1; EIMS m/z (relative intensity) 244, 243 (Mþ), 216
(90), 201 (100),174 (40), 94 (13), 79 (13). Anal. Calcd for C13H16N4O; C:
63.91; H: 6.60; N: 22.93. Found: C: 63.90; H: 6.62; N: 22.95.
4.3.7. N0-(1-(2-Quinolinyl)-3-phenyl-1H-pyrazol-5-yl)-formamide
(7b). Mp (purified by column chromatography on silica gel)
4.3.2. N0-(1-(2-Pyridinyl)-3-phenyl-1H-pyrazol-5-yl)-formamide
163e164 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 7.36e7.58 (m, 4H, ArH),
(6b). Mp (purified by column chromatography on silica gel)
7.35 (s, 1H, pyrazole-H), 7.70e7.93 (m, 5H, ArH), 8.27e8.43 (m, 2H,
117e118 ꢀC; 1H NMR (CDCl3, 200 MHz)
d
7.13e7.20 (m, 1H, ArH),
ArH), 8.60 (s, 1H, CHO), 12.06 (s, 1H, NH); 13C NMR (50 MHz, CDCl3)
7.29 (s, 1H, pyrazole-H), 7.34e7.47 (m, 3H, ArH), 7.81e7.94 (m, 3H,
ArH), 7.81e7.82 (m, 1H, ArH), 8.33e8.36 (m, 1H, ArH), 8.50 (s, 1H,
d
96.1, 114.2, 120.5, 126.0 (2ꢂCH), 128.6 (3ꢂCH), 132.5, 139.3, 139.4,
146.1, 152.5, 154.5, 157.1; IR (KBr) 3441 (m), 2063, 1645 (s, C]O),
CHO), 12.10 (s, 1H, NH); 13C NMR (50 MHz, CDCl3)
d
96.1, 114.2,
1627 (m), 1537 (m), 1371 (m), 1242 (m), 1035 (m), 912 (m) cmꢁ1
;
120.5, 126.0 (2ꢂCH), 128.6 (3ꢂCH), 132.5, 139.3, 139.4, 146.1, 152.5,
154.5, 157.1; IR (KBr) 2920 (m), 1695 (s, C]O), 1538 (m), 1448 (m),
1363 (m), 1244 (m), 1029 (m), 946 (m) cmꢁ1; EIMS m/z (relative
intensity) 264 (41), 263 (Mþ, 7), 236 (100), 235 (26), 196 (41), 102
(12), 79 (12). Anal. Calcd for C15H12N4O; C: 68.17; H: 4.58; N: 21.20.
Found: C: 68.19; H: 4.56; N: 21.22.
EIMS m/z (relative intensity) 314 (42), 313 (Mþ, 10), 286 (100), 246
(30), 143 (11), 128 (25), 102 (15). Anal. Calcd for C19H14N4O; C:
72.60; H: 4.49; N: 17.82. Found: C: 72.61; H: 4.51; N: 17.80.
4.3.8. N0-(1-(2-Quinolinyl)-3-(4-methylphenyl)-1H-pyrazol-5-yl)-
formamide (7c). Mp (purified by column chromatography on silica
gel) 123e124 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 2.39 (s, 3H, CH3),
4.3.3. N0-(1-(2-Pyridinyl)-3-(4-methylphenyl)-1H-pyrazol-5-yl)-
7.22e7.32 (m, 1H, ArH), 7.52 (s, 1H, pyrazole-H), 7.53e7.57 (m, 1H,
ArH), 7.74e7.95 (m, 6H, ArH), 8.26e8.42 (m, 2H, ArH), 8.60 (s, 1H,
formamide (6c). Mp (purified by column chromatography on silica
gel) 123e124 ꢀC; 1H NMR (CDCl3, 200 MHz)
d
2.37 (s, 3H, CH3),
CHO), 12.12 (s, 1H, NH); 13C NMR (50 MHz, CDCl3)
d 96.5, 110.0,
7.18e7.20 (m, 2H, ArH), 7.26 (s, 1H, pyrazole-H), 7.78e7.88 (m, 4H,
ArH), 8.15e7.20 (m, 1H, ArH), 8.33e8.35 (m, 1H, ArH), 8.49 (s, 1H,
113.8, 126.1, 126.3 (2ꢂCH), 127.3, 128.0, 128.7, 128.8, 130.8 (2ꢂCH),
132.5, 139.6, 139.7, 146.1, 152.5, 154.5, 157.0; IR (KBr) 2920 (m), 2360
(m), 1689 (s, C]O), 1548 (m), 1506 (m), 1463 (m), 1408 (m), 1367
(m), 825 (m) cmꢁ1. Anal. Calcd for C20H16N4O; C: 73.15; H: 4.91; N:
17.06. Found: C: 73.12; H: 4.93; N: 17.08.
CHO), 12.11 (s, 1H, NH); 13C NMR (50 MHz, CDCl3)
d 21.3 (CH3), 95.9,
114.1, 120.4, 125.9 (2ꢂCH), 129.3, 129.7, 138.5, 139.2, 139.4, 146.4,
152.6, 154.5, 157.1; IR (KBr) 3439 (m), 3064 (m), 1712 (s, C]O), 1552
(m), 1456 (m), 1303 (m), 1244 (m), 1091 (m), 995 (m) cmꢁ1. Anal.
Calcd for C16H14N4O; C: 69.05; H: 5.07; N: 20.13. Found: C: 69.04; H:
5.09; N: 20.14.
4.3.9. N0-(1-(2-Quinolinyl)-3-(4-chlorophenyl)-1H-pyrazol-5-yl)-
formamide (7d). Mp (purified by column chromatography on silica
gel) 152e153 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 7.32 (s, 1H, pyrazole-
4.3.4. N0-(1-(2-Pyridinyl)-3-(4-chlorophenyl)-1H-pyrazol-5-yl)-form-
H), 7.37e7.43 (m, 2H, ArH), 7.51e7.58 (m, 2H, ArH), 7.71e7.85 (m,
5H, ArH), 8.27e8.39 (m, 1H, ArH), 8.59 (s, 1H, CHO), 12.70 (s, 1H,
amide (6d). Mp (purified by column chromatography on silica gel)
158e159 ꢀC; 1H NMR (CDCl3, 200 MHz)
d
7.13e7.19 (m, 1H, ArH),
NH); 13C NMR (50 MHz, CDCl3)
d 96.3,110.0,113.7,126.2,126.4,127.3
7.30e7.37 (m, 1H, ArH), 7.38 (s, 1H, pyrazole-H), 7.72e7.88 (m, 4H,
ArH), 8.11e8.15 (m, 1H, ArH), 8.31e8.33 (m, 1H, ArH), 8.48 (s, 1H,
(2ꢂCH), 128.0, 130.8 (2ꢂCH), 131.0, 134.6, 139.7, 139.8, 144.8, 151.6,
153.5, 157.1; IR (KBr) 2920 (m), 1695 (s, C]O), 1602 (m), 1502 (m),
1429 (m), 1367 (m), 1242 (m), 947 (m) cmꢁ1; EIMS m/z (relative
intensity) 312 (Mþ2, 14), 348 (41), 347 (Mþ, 28), 320 (100), 282,10
280 (29), 144 (12), 143 (11). Anal. Calcd for C19H13ClN4O; C: 65.43;
H: 3.76; N: 16.06. Found: C: 65.44; H: 3.73; N: 16.03.
CHO), 12.12 (s, 1H, NH); 13C NMR (50 MHz, CDCl3)
d 95.9, 113.7, 119.7,
127.2 (2ꢂCH), 128.8 (2ꢂCH), 131.0, 134.4, 139.4, 139.5, 146.5, 151.3,
154.4, 157.1; IR (KBr) 3199 (m), 2924 (m), 1695 (s, C]O), 1591 (m),
1448 (m), 1361 (m), 1244 (m), 1128 (m), 948 (m) cmꢁ1. Anal. Calcd
for C15H11ClN4O; C: 60.31; H: 3.71; N: 18.76. Found: C: 60.32; H:
3.73; N: 18.74.
4.3.10. N0-(1-(2-Quinolinyl)-3-(4-methoxylphenyl)-1H-pyrazol-5-
yl)-formamide (7e). Mp (purified by column chromatography on
4.3.5. N0-(1-(2-Pyridinyl)-3-(4-methoxylphenyl)-1H-pyrazol-5-yl)-
silica gel) 144e145 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 3.84 (s, 3H,
formamide (6e). Mp (purified by column chromatography on silica
OCH3), 6.94e6.96 (m, 2H, ArH), 7.29 (s, 1H, pyrazole-H), 7.42e7.56
(m, 1H, ArH), 7.65e8.05 (m, 6H, ArH), 8.13e8.41 (m, 2H, ArH), 8.59
gel) 144e145 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 3.84 (s, 3H, OCH3),
6.94e6.96 (m, 2H, ArH), 7.15e7.17 (m, 1H, ArH), 7.23e7.25 (m, 1H,
ArH), 7.85e7.87 (m, 3H, ArH), 8.17 (s, 1H, pyrazole-H), 8.33e8.35
(m,1H, ArH), 8.50 (s,1H, CHO),12.18 (s,1H, NH); 13C NMR (125 MHz,
(s, 1H, CHO), 12.18 (s, 1H, NH); 13C NMR (125 MHz, CDCl3)
d 55.3
(OCH3), 96.1, 113.7, 114.1 (2ꢂCH), 125.1, 126.2, 127.3, 127.4 (2ꢂCH),
127.9, 130.7, 139.5, 139.6, 144.9, 146.1, 152.4, 154.4, 157.0, 160.1; IR
(KBr) 2920 (m), 1695 (s, C]O), 1606 (m), 1531 (m), 1431 (m), 1369
(m), 1247 (m), 948 (m) cmꢁ1; EIMS m/z (relative intensity) 344
(100), 343 (Mþ, 13), 316 (94), 301 (5), 276 (39), 129 (25), 128 (34).
Anal. Calcd for C20H16N4O2; C: 69.76; H: 4.68; N: 16.27. Found: C:
69.77; H: 4.64; N: 16.25.
CDCl3)
d
55.3 (OCH3), 95.7, 114.0 (2ꢂCH), 149.1, 120.3, 125.3, 127.3
(2ꢂCH), 139.2, 139.4, 146.1, 152.4, 154.4, 157.0, 160.1; IR (KBr) 3209
(m, NH), 2922 (m), 1697 (s, C]O), 1531 (m), 1471 (m), 1246 (m),
1174 (m), 1028 (m), 948 (m) cmꢁ1; EIMS m/z (relative intensity) 294
(57), 293 (Mþ, 5), 266 (100), 251 (12), 226 (37), 133 (19), 79 (11).
Anal. Calcd for C16H14N4O2; C: 65.30; H: 4.79; N: 19.04. Found: C:
65.29; H: 4.80; N: 19.05.
4.4. Standard procedure for the preparation of pyrazolo[3,4-
d]pyrimidine products 12aee, 13aee, and 14aee
4.3.6. N0-(1-(2-Quinolinyl)-3-tert-butyl-1H-pyrazol-5-yl)-formam-
ide (7a). Mp (purified by column chromatography on silica gel)
The reliable procedure involved the treatment of N-1-phenyl-5-
aminopyrazoles, N-1-phenyl-5-aminopyrazoles (1a-e, 1.0 equiv),
125e126 ꢀC; 1H NMR (CDCl3, 200 MHz)
d
1.46 (s, 9H, CH3ꢂ3), 6.89

1384
C.-H. Chang et al. / Tetrahedron 69 (2013) 1378e1386
N-1-(2-pyridinyl)-5-aminopyrazoles (4aee 1.0 equiv), or N-1-(2-
quinolinyl)-5-aminopyrazoles (5aee, 1.0 equiv) with catalytic
amount of POCl3 (w3 equiv) with formamide (2 mL) in CH2Cl2
solution at 80e90 ꢀC within 0.5e1 h. When the reaction was
completed, the reaction mixture was concentrated, added to satu-
rate sodium bicarbonate (15 mL), and extracted with dichloro-
methane (15 mL). The organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. The residues
were purified by column chromatography on silica gel to give the
corresponding pyrazolo[3,4-d]pyrimidine products 12aee, 13aee
or 14aee were obtained in 91e96%, 81e88%, or 82e91% yield,
respectively.
C17H11ClN4; C: 66.56; H: 3.61; N: 18.26. Found: C: 66.53; H: 3.62; N:
18.29.
4.4.5. 3-(4-Methoxylphenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimi-
dine (12e). Mp (purified by column chromatography on silica gel)
175e176 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 3.87 (s, 3H, CH3),
7.08e7.84 (m, 2H, ArH), 7.32e7.36 (m, 1H, ArH), 7.50e7.56 (m, 2H,
ArH), 7.95e8.01 (m, 2H, ArH), 8.28e8.32 (m, 2H, ArH), 9.10 (s, 1H),
9.45 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 55.4 (CH3), 114.2, 114.6
(2ꢂCH), 121.3 (2ꢂCH), 124.1, 126.7, 128.7 (2ꢂCH), 129.2 (2ꢂCH),
138.6, 144.8, 152.8, 153.2, 155.5, 160.8; IR (KBr) 3047 (w), 2924 (w),
1612 (m), 1582 (m), 1503 (m), 1431 (m), 1356 (m), 1254 (m), 1219
(m), 1092 (m), 962 (m), 835 (m), 758 (m) cmꢁ1; EIMS m/z (relative
intensity) 302 (100), 301 (Mþ, 6), 287 (25)6c, 265 (4), 259 (8), 233
(3), 195 (2), 151 (4), 91 (5), 77 (12); HRMS (ESI) calcd for C18H141N4O
(MþHþ) 303.1168, found 303.1169. Anal. Calcd for C18H141N4O; C:
71.51; H: 4.67; N: 18.53. Found: C: 75.48; H: 4.68; N: 18.50.
4.4.1. 3-tert-Butyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (12a). Mp
(purified by column chromatography on silica gel) 48e49 ꢀC; 1H
NMR (CDCl3, 500 MHz)
7.44e7.52 (m, 2H, ArH), 8.19e8.12 (m, 2H, ArH), 9.02 (s, 1H), 9.31 (s,
1H); 13C NMR (125 MHz, CDCl3)
d
1.55 (s, 9H, 3ꢂCH3), 7.23e7.29 (m,1H, ArH),
d
30.3 (3ꢂCH), 34.4, 114.0, 121.0
(2ꢂCH),126.2,129.0 (2ꢂCH),138.6,152.8,153.1,154.8,155.0; IR (KBr)
4.4.6. 3-tert-Butyl-1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine
3049 (w), 2968 (w), 2666 (w), 1599 (m), 1578 (m), 1555 (m), 1508
(13a). 1H NMR (CDCl3, 500 MHz)
d 1.50 (s, 9H, CH3), 7.15e7.19 (m,
(m), 1427 (m), 1366 (m), 1261 (m), 1098 (m), 961 (m), 756 (m) cmꢁ1
;
1H, ArH), 7.77e7.81 (m, 1H, ArH), 8.05e8.07 (m, 1H, ArH),
EIMS m/z (relative intensity) 253 (100), 252 (Mþ, 34), 244 (5), 218
(5),195 (6),169 (4),142 (12),115 (4), 91 (2), 77 (14); HRMS (ESI) calcd
for C15H16N4 (MþHþ) 253.1375, found 253.1377. Anal. Calcd for
8.60e8.62 (m, 1H, ArH), 9.07 (s, 1H), 9.28 (s, 1H); 13C NMR
(125 MHz, CDCl3)
d 29.7, 34.4, 114.2, 116.1, 121.5, 138.2, 148.8, 151.1,
152.8, 153.6, 155.7, 155.7; IR (KBr) 2970 (w), 2227 (w), 1595 (m),
1556 (m), 1498 (m), 1450 (m), 1369 (m), 1192 (m), 1112 (m), 9100
(m), 779 (m) cmꢁ1; EIMS m/z (relative intensity) 253,23 252 (Mþ, 2),
238 (100), 198 (12), 171 (2), 105 (3), 78 (31), 57 (5), 51 (7). Anal.
Calcd for C14H15N5; C: 66.38; H: 5.97; N: 27.65. Found: C: 66.40; H:
5.99; N: 27.63.
C
15H16N4; C: 71.40; H: 6.39; N: 22.21. Found: C: 71.43; H: 6.35; N:
22.17.
4.4.2. 1,3-Diphenyl-1H-pyrazolo[3,4-d]pyrimidine (12b). Mp (puri-
fied by column chromatography on silica gel) 157e158 ꢀC (hex-
aneeEtOAc). 1H NMR (CDCl3, 500 MHz):
d
7.29e7.36 (1H, m),
7.41−7.48 (1H, m), 7.48e7.56 4H, m), 7.97e8.07 (2H, m), 8.25e8.35
(2H, m), 9.09 (1H, s), 9.45 (1H, s). 13C NMR (125 MHz, CDCl3):
114.1,
4.4.7. 3-Phenyl-1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine
d
(13b). Mp (purified by column chromatography on silica gel)
121.2 (2 ꢂ C), 126.7, 127.2 (2 ꢂ C), 129.0 (2 ꢂ C), 129.1 (2 ꢂ C), 129.5,
131.4, 138.5, 144.8, 152.7, 153.2, 155.5. IR (KBr): 2364, 2331, 1589,
1498, 1417, 1369, 1219, 1093 cmꢁ1. EIMS m/z (rel int): 272 (100, Mþ).
Anal. Calcd for C17H12N4: C, 74.98; H, 4.44; N, 20.58. Found: C, 74.96;
H, 4.45; N, 20.61.
206e207 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 7.22e7.30 (m, 1H, ArH),
7.41e7.55 (m, 3H, ArH), 7.83e7.91 (m, 1H, ArH), 7.99e8.05 (m, 2H,
ArH), 8.20e8.26 (m, 1H, ArH), 8.66e8.70 (m, 1H, ArH), 9.19 (s, 1H),
9.47 (s, 1H); 13C NMR (125 MHz, CDCl3)
d
114, 116, 122, 128 (2ꢂCH),
129 (2ꢂCH), 130, 131, 139, 146, 149, 151, 153, 154, 156; IR (KBr) 3049
(w), 2920 (w), 2851 (w), 2380 (w), 2349 (w), 1593 (m), 1481 (m),
1452 (m), 1368 (m), 1265 (m), 1219 (m), 1080 (m), 957 (m), 736 (m),
592 (m) cmꢁ1; EIMS m/z (relative intensity) 273 (100), 272 (Mþ, 17),
230 (16), 196 (10), 170 (22), 143 (27), 91 (20), 78(35), 51 (17). Anal.
Calcd for C16H11N5; C: 70.32; H: 4.06; N: 25.63. Found: C: 70.28; H:
4.09; N: 25.66.
4.4.3. 3-(4-Methylphenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine
(12c). Mp (purified by column chromatography on silica gel)
139e140 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 2.43 (s, 3H, CH3),
7.32e7.42 (m, 3H, ArH), 7.51e7.61 (m, 2H, ArH), 7.86e8.02 (m,
2H, ArH), 8.24e8.38 (m, 2H, ArH), 9.11 (s, 1H), 9.47 (s, 1H); 13C
NMR (125 MHz, CDCl3)
d
21.4 (CH3), 114.2, 121.3 (2ꢂCH), 126.7,
127.2 (2ꢂCH), 128.7, 129.2 (2ꢂCH), 129.9 (2ꢂCH), 138.5, 139.8,
145.0, 152.8, 153.3, 155.5; IR (KBr) 3030 (w), 2920 (w), 2374 (w),
2349 (w), 2313 (w), 1584 (m), 1503 (m), 1430 (m), 1368 (m),
1220 (m), 953 (m), 785 (m), 756 (m) cmꢁ1; EIMS m/z (relative
intensity) 286 (100), 285 (Mþ, 34), 244 (5), 218 (5), 195 (6), 169
(4), 142 (12), 115 (4), 91 (2), 77 (11). HRMS (ESI) calcd for
4.4.8. 3-(4-Methylphenyl)-1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]py-
rimidine (13c). Mp (purified by column chromatography on silica
gel) 127e128 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 2.42 (s, 1H, CH3),
7.28e7.34 (m, 3H, ArH), 7.89e7.95 (m, 3H, ArH), 8.26e8.28 (m, 1H,
ArH), 8.71e8.72 (m, 1H, ArH), 9.21 (s, 1H), 9.49 (s, 1H); 13C NMR
(125 MHz, CDCl3)
d
21.4, 114.7, 116.4, 122.0, 127.5 (2ꢂCH), 128.2,
C
C
18H14N4 (MþHþ) 287.1218, found 287.1216. Anal. Calcd for
129.8 (2ꢂCH), 138.5, 140.1, 146.2, 149.0, 151.1, 152.9, 153.9, 156.2; IR
(KBr) 2922 (W), 2853 (W), 1591 (m), 1481 (m), 1445 (m), 1366 (m),
1317 (m), 1221 (m), 1080 (m), 957 (m), 793 (m) cmꢁ1; EIMS m/z
(relative intensity) 287 (100), 286 (Mþ, 22), 259 (7), 196 (6), 170
(18), 154 (9), 143 (21), 91 (9), 78 (32), 65 (7), 51 (10). Anal. Calcd for
18H14N4; C: 75.50; H: 4.93; N: 19.57. Found: C: 75.49; H: 4.91;
N: 19.55.
4.4.4. 3-(4-Chlorophenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine
(12d). Mp (purified by column chromatography on silica gel)
C17H13N5; C: 71.06; H: 4.56; N: 24.37. Found: C: 71.08; H: 4.54; N:
24.39.
196e197 ꢀC; 1H NMR (CDCl3, 500 MHz)
d
7.34e7.38 (m, 1H, ArH),
7.48e7.58 (m, 4H, ArH), 7.96e8.02 (m, 2H, ArH), 8.24e8.30 (m, 2H,
ArH), 9.12 (s, 1H), 9.46 (s, 1H); 13C NMR (125 MHz, CDCl3)
114.0,
d
4.4.9. 3-(4-Chlorophenyl)-1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]py-
121.5 (2ꢂCH), 127.0, 128.5 (2ꢂCH), 129.3 (2ꢂCH), 129.5 (2ꢂCH),
130.0,135.7,138.4,143.8,152.6,153.3,155.7; IR (KBr) 3043 (w), 2926
(w), 2848 (w), 1585 (m), 1555 (m), 1503 (m), 1368 (m), 1219 (m),
1093 (m), 954 (m), 831 (m), 789 (m), 745 (m) cmꢁ1; EIMS m/z
(relative intensity) 306,5 305 (Mþ, 1), 302 (100), 287 (24), 259 (8),
233 (3), 195 (7), 151 (2), 91 (5), 77 (12); HRMS (ESI) calcd for
rimidine (13d). Mp (purified by column chromatography on silica
gel) 164e165 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 7.28e7.34 (m, 1H,
ArH), 7.48e7.52 (m, 2H, ArH), 7.88e8.02 (m, 3H, ArH), 8.25e8.29
(m, 1H, ArH), 8.70e8.74 (m, 1H, ArH), 9.22 (s, 1H), 9.48 (s, 1H); 13C
NMR (125 MHz, CDCl3)
d
114.5, 116.5, 122.3, 128.5 (2ꢂCH), 128.8,
129.5 (2ꢂCH), 136.0, 138.7, 145.0, 150.9, 152.7, 153.9, 156.4; IR (KBr)
C
17H11ClN4 (MþHþ) 307.0672, found 307.0671. Anal. Calcd for
2920 (w), 2851 (w), 1587 (m), 1481 (m), 1217 (m), 1094 (m), 957

C.-H. Chang et al. / Tetrahedron 69 (2013) 1378e1386
1385
(m), 833 (m), 770 (m) cmꢁ1; EIMS m/z (relative intensity) 309
(Mþ2, 30), 307 (100), 306 (Mþ, 13), 279 (5), 196 (9),174 (8), 170 (27),
143 (30), 111 (6), 78 (39), 75 (6), 51 (13). Anal. Calcd for C16H10ClN5;
C: 62.45; H: 3.28; N: 22.76. Found: C: 62.43; H: 3.30; N: 22.75.
(m), 1554 (m), 1477 (m), 1431 (m), 1219 (m), 1089 (m) cmꢁ1; EIMS
m/z (relative intensity) 359 (Mþ2, 34), 357 (100), 356 (Mþ, 17), 246
(13), 220 (26), 193 (36), 128 (42), 101 (15), 77 (7). Anal. Calcd for
C20H12ClN5; C: 67.14; H: 3.38; N: 19.57. Found: C: 67.12; H: 3.41; N:
19.57.
4.4.10. 3-(4-Methoxyphenyl)-1-(pyridin-2-yl)-1H-pyrazolo[3,4-d]
pyrimidine (13e). Mp (purified by column chromatography on silica
4.4.15. 3-(4-Methoxyphenyl)-1-(quinolin-2-yl)-1H-pyrazolo[3,4-d]
gel) 167e168 ꢀC; 1H NMR (CDCl3, 500 MHz)
d
3.84 (s, 1H, CH3),
pyrimidine (14e). Mp (purified by column chromatography on silica
6.99e7.05 (m, 2H, ArH), 7.22e7.28 (m, 1H, ArH), 7.87e7.99 (m, 3H,
ArH), 8.22e8.26 (m, 1H, ArH), 8.66e8.70 (m, 1H, ArH), 9.18 (s, 1H),
gel) 153e154 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 3.86 (s, 3H, CH3),
7.05e7.07 (m, 2H, ArH), 7.53e7.55 (m, 1H, ArH), 7.72e7.76 (m, 1H,
ArH), 7.83e7.85 (m,1H, ArH), 8.02e8.04 (m, 2H, ArH), 8.23e8.25 (m,
1H, ArH), 8.32e8.34 (m, 1H, ArH), 8.45e8.47 (m, 1H, ArH), 9.21 (s,
9.44 (s, 1H); 13C NMR (125 MHz, CDCl3)
d
55.4, 114.0 (2ꢂCH), 114.6,
116.3, 122.0, 123.6, 129.0 (2ꢂCH), 138.5, 146.0, 149.0, 151.1, 152.9,
153.8, 156.2, 161.0; IR (KBr) 3460 (w), 3057 (w), 2960 (w), 2924 (w),
2850 (w), 1614 (m), 1529 (m), 1367 (m), 1253 (m), 1219 (m), 1178
(m), 1080 (m) cmꢁ1. Anal. Calcd for C17H13N5O; C: 67.32; H: 4.32; N:
23.09. Found: C: 67.35; H: 4.30; N: 23.11.
1H), 9.49 (s, 1H); 13C NMR (125 MHz, CDCl3)
d
55.5, 114.7 (2ꢂCH),
114.9, 115.5, 123.7, 126.7, 127.1, 127.5, 129.1 (2ꢂCH), 129.4, 130.4,
139.0,146.4,147.0, 149.8, 153.0,156.3,161.1,167.8; IR (KBr) 2955 (w),
2924 (w), 2851 (w),1612 (m),1583 (m),1530 (m),1503 (m),1481 (m),
1433 (m), 1251 (m), 1219 (m), 1177 (m), 1090 (m), 1030 (m) cmꢁ1
;
4.4.11. 3-tert-Butyl-1-(quinolin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine
EIMS m/z (relative intensity) 353 (100), 352 (Mþ, 12), 338 (13), 128
(35), 102 (3), 101 (8), 77 (4), 75 (2). Anal. Calcd for C21H15N5O; C:
71.38; H: 4.28; N: 19.82. Found: C: 71.39; H: 4.25; N: 19.81.
(14a). Mp (purified by column chromatography on silica gel)
144e145 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 1.58 (s, 3H, CH3),
7.49e7.53 (m, 1H, ArH), 7.70e7.72 (m, 1H, ArH), 7.80e7.82 (m, 1H,
ArH), 8.18e8.20 (m, 1H, ArH), 8.29e8.31 (m, 1H, ArH), 9.18 (s, 1H),
4.4.16. 1-Methyl-1H-pyrazolo[3,4-d]pyrimidine (15). Mp (purified
by column chromatography on silica gel) 105e106 ꢀC; 1H NMR
9.38 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 29.8, 34.6, 114.6, 115.5,
126.5, 126.9, 127.4, 129.3, 130.1, 138.8, 146.9, 150.0, 152.9, 154.3,
154.7, 156.2; IR (KBr) 2964 (w), 2922 (w), 2851 (w), 1622 (m), 1600
(m), 1583 (m), 1502 (m), 1433 (m), 1367 (m), 1190 (m), 1047
(m) cmꢁ1. Anal. Calcd for C18H17N5; C: 71.27; H: 5.65; N: 23.09.
Found: C: 71.29; H: 5.62; N: 23.11.
(CDCl3, 500 MHz)
d 4.12 (s, 3H, CH3), 8.11 (s, 1H), 9.00 (s, 1H), 9.15 (s,
1H); 13C NMR (125 MHz, CDCl3)
d
33.8, 114.4132.3 (2ꢂCH), 152.2,
155.1; IR (KBr) 3093 (w), 2924 (w), 2353 (w), 1735 (m), 1689 (m),
1558 (m), 1504 (m), 1411 (m), 1357 (m), 1249 (m), 1195 (m), 1141
(m), 1095 (m), 987 (m) cmꢁ1. Anal. Calcd for C6H6N4; C: 53.72; H:
4.51; N: 41.77. Found: C: 53.71; H: 4.48; N: 41.76.
4.4.12. 3-Phenyl-1-(quinolin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine
(14b). Mp (purified by column chromatography on silica gel)
4.5. Standard procedure for the preparation of meth-
animidamide products 20e22
194e195 ꢀC; 1H NMR (CDCl3, 500 MHz)
d
7.49e7.59 (m, 4H, ArH),
7.75e7.79 (m, 1H, ArH), 7.87e7.89 (m, 1H, ArH), 8.11e8.13 (m, 2H,
ArH), 8.37e8.39 (m, 1H, ArH), 8.47e8.49 (m, 1H, ArH), 9.26 (s, 1H),
The reliable procedure involved the treatment of N-1-phenyl-5-
aminopyrazoles, N-1-(2-quinolinyl)-5-aminopyrazoles (5b, 1.0 equiv)
with catalytic amount of POCl3 (w3 equiv) with N,N-dimethylforma-
mide (DMF), N,N-diethylformamide (DEF), or 1-pyrrolidine-
carboxaldehyde (2 mL) in CH2Cl2 solution at 80e90 ꢀC within
0.5e1 h. When the reaction was completed, the reaction mixture was
concentrated, added to saturate sodium bicarbonate (15 mL), and
extracted with dichloromethane (15 mL). The organic extracts were
dried over MgSO4, filtered, and concentrated under reduced pressure.
The residues were purified by column chromatography on silica gel to
give the corresponding methanimidamide products 19e21 were ob-
tained in 91e95% yield.
9.55 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 114.9, 115.6, 126.8, 127.2,
127.5, 127.8 (2ꢂCH), 129.2 (2ꢂCH), 129.5, 130.4, 131.2, 139.0, 146.6,
147.0, 149.8, 153.0, 154.4, 156.4; IR (KBr) 3055 (w), 2376 (w), 2347
(w), 1582 (m), 1557 (m), 1502 (m), 1477 (m), 1409 (m), 1368 (m),
1325 (m), 1219 (m), 1090 (m), 962 (m), 825 (m), 761 (m), 694
(m) cmꢁ1; EIMS m/z (relative intensity) 323 (100), 295 (Mþ, 21)
246,17 220 (29), 193 (39), 140 (12), 128 (46), 101 (18), 77 (21). Anal.
Calcd for C20H13N5; C: 74.29; H: 4.05; N: 21.66. Found: C: 74.31; H:
4.07; N: 21.69.
4.4.13. 3-(4-Methylphenyl)-1-(quinolin-2-yl)-1H-pyrazolo[3,4-d]py-
rimidine (14c). Mp (purified by column chromatography on silica
gel) 163e164 ꢀC; 1H NMR (CDCl3, 500 MHz)
d
2.42 (s, 3H, CH3),
4.5.1. N0-(1-(2-quinolinyl)-3-diphenyl-1H-pyrazol-5-yl)-N,N-dime-
7.32e7.36 (m, 2H, ArH), 7.50e7.58 (m, 1H, ArH), 7.70e7.86 (m, 2H,
ArH), 7.96e8.00 (m, 2H, ArH), 8.22e8.48 (m, 3H, ArH), 9.23 (s, 1H),
thylmethanimidamide (20). Mp (purified by column chromatogra-
phy on silica gel) 166e167 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 2.96 (s,
9.51 (s, 1H); 13C NMR (125 MHz, CDCl3)
d
21.4, 114.8, 115.4, 126.7,
6H, CH3ꢂ2), 6.19 (s, 1H, pyrazole-H), 7.28e7.49 (m, 4H, ArH),
7.62e7.69 (m, 1H, ArH), 7.74e7.80 (m, 2H, ArH), 7.91e7.95 (m, 2H,
ArH), 8.09e8.16 (m, 2H, ArH), 8.13 (s, 1H, N]CeH); 13C NMR
127.0, 127.4, 127.5 (2ꢂCH), 128.3, 129.4, 129.8 (2ꢂCH), 130.3, 138.8,
140.1, 146.5,146.9,149.7, 152.9, 154.3,156.3; IR (KBr) 3473 (m), 3048
(w), 2924 (w), 2855 (w), 1557 (m), 1504 (m), 1477 (m), 1431 (m),
1367 (m), 1325 (m), 1217 (m), 1089 (m), 1022 (m) cmꢁ1; EIMS m/z
(relative intensity) 337 (100), 336 (21), 316 (5), 220 (17), 193 (22)
128 (31), 101,9 77.5 Anal. Calcd for C21H15N5; C: 74.46; H: 4.48; N:
20.76. Found: C: 74.48; H: 4.50; N: 20.73.
(50 MHz, CDCl3)
d
34.5 (CH3), 40.3 (CH3), 89.5 (2ꢂCH),117.9 (2ꢂCH),
126.0 (4ꢂCH), 127.3 (2ꢂCH), 127.9 (3ꢂCH), 128.4 (2ꢂCH), 129.3
(2ꢂCH), 129.6 (2ꢂCH), 137.3 (2ꢂCH), 154.8 (2ꢂCH); IR (KBr) 3045
(m), 2924 (m), 1693 (m, eC]N), 1556 (m), 1514 (m), 1317 (m), 1265
(m), 1107 (m), 948 (m) cmꢁ1; EIMS m/z (relative intensity) 341 (61),
340 (Mþ, 3), 326 (50), 297 (36), 237 (13), 168 (17), 128 (100). Anal.
Calcd for C21H19N5; C: 73.88; H: 5.61; N: 20.51. Found: C: 73.89; H:
5.63; N: 20.50.
4.4.14. 3-(4-Chlorophenyl)-1-(quinolin-2-yl)-1H-pyrazolo[3,4-d]py-
rimidine (14d). Mp (purified by column chromatography on silica
gel) 127e128 ꢀC; 1H NMR (CDCl3, 500 MHz)
d
7.50e7.60 (m, 4H,
ArH), 7.69e7.89 (m, 3H, ArH), 8.01e8.07 (m, 2H, ArH), 8.22e8.26
(m, 1H, ArH), 8.33e8.49 (m, 2H, ArH), 9.24 (s, 1H), 9.50 (s, 1H); 13
NMR (125 MHz, CDCl3) 114.6, 115.5, 126.9, 127.2, 127.6, 128.9
4.5.2. N0-(1-(2-Quinolinyl)-3-diphenyl-1H-pyrazol-5-yl)-N,N-dieth-
C
ylmethanimidamide (21). Mp (purified by column chromatography
d
on silica gel) 142e143 ꢀC; 1H NMR (CDCl3, 500 MHz)
d 1.08e1.11 (m,
(3ꢂCH), 129.5 (3ꢂCH), 130.5, 136.1, 139.1, 145.3, 147.0, 149.5, 152.8,
3H, CH3), 1.08e1.11 (m, 3H, CH3), 3.21e3.25 (m, 2H, CH2), 3.44e3.48
(m, 2H, CH2), 6.20 (s, 1H, pyrazole-H), 7.27e7.38 (m, 1 H, ArH),
154.4, 156.4; IR (KBr) 3455 (m), 3051 (w), 2922 (w), 1602 (m), 1581

1386
C.-H. Chang et al. / Tetrahedron 69 (2013) 1378e1386
Commun. 2001, 31, 2199e2202; (g) Amaresh, R. R.; Perumal, P. T. Synth. Com-
mun. 2000, 30, 2269e2274; (h) Selvi, S.; Perumal, P. T. Synth. Commun. 2000, 30,
3925e3928; (i) Selvi, S.; Perumal, P. T. Indian J. Chem., Sect. B 2000, 39B,
163e165; (j) Amaresh, R. R.; Perumal, P. T. Tetrahedron 1999, 55, 8083e8094;
(k) Perumal, P. T.; Majo, V. J.; Anand, R. V. Indian J. Chem., Sect. B 1999, 38,
763e765; (l) Amaresh, R. R.; Perumal, P. T. Tetrahedron 1998, 54, 14327e14340;
(m) Amaresh, R. R.; Perumal, P. T. Tetrahedron Lett. 1998, 39, 3837e3840; (n)
Majo, V. J.; Perumal, P. T. J. Org. Chem. 1998, 63, 7136e7142; (o) Selvi, S.;
Perumal, P. T. Tetrahedron Lett. 1997, 38, 6263e6266; (p) Majo, V. J.; Perumal, P.
T. Tetrahedron Lett. 1997, 38, 6889e6892; (q) Majo, V. J.; Perumal, P. T. Tetra-
hedron Lett. 1996, 37, 5015e5018; (r) Balasundaram, B.; Venugopal, M.;
Perumal, P. T. Tetrahedron Lett. 1993, 34, 4249e4252.
4. (a) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605e618; (b) Akila, S.; Selvi, S.;
Balasubramanian, K. Tetrahedron 2001, 57, 3465e3469.
5. Balasubramanian, M.; Keay, J. G. In Comprehensive Heterocyclic Chemistry II;
Kartritzky, A. R., Ress, C. W., Scriven, E. F. V., Eds.; Pergamor: Oxford, 1996; Vol.
5; Chapter 5.06, p 245.
7.39e7.45 (m, 2H, ArH), 7.47e7.48 (m, 1H, ArH), 7.64e7.67 (m, 1H,
ArH), 7.77e8.11 (m, 7H, ArH), 7.53 (s, 1H, N]CeH); 13C NMR
(125 MHz, CDCl3)
d 12.5 (CH3), 12.7 (CH3), 40.0 (CH2), 41.7 (CH2),
89.5, 117.8, 125.8, 125.9, 126.7, 127.2 (2ꢂCH), 127.8, 128.3, 129.3,
129.4, 133.7, 137.1, 147.0, 151.3, 152.3, 153.6, 154.1, 162.1; IR (KBr)
2924 (m), 2852 (m), 1701 (m, eC]N), 1602 (m), 1539 (m), 1504 (m),
1435 (m), 1265 (m), 740 (m) cmꢁ1. Anal. Calcd for C23H23N5; C:
74.77; H: 6.27; N: 18.96. Found: C: 74.79; H: 6.27; N: 18.98.
4.5.3. N0-(1-(2-Quinolinyl)-3-diphenyl-1H-pyrazol-5-yl)-N-pyrroli-
dinmethanimidamide (22). Mp (purified by column chromatogra-
phy on silica gel) 168e169 ꢀC; 1H NMR (CDCl3, 200 MHz)
d 1.23
(m, 4H), 3.40 (m, 4H), 6.17 (s, 1H, pyrazole-H), 7.23e7.46 (m, 4H,
ArH), 7.59e7.74 (m, 2H, ArH), 7.91e7.97 (m, 1H, ArH), 8.07 (s, 1H,
6. (a) Campaigne, E.; Archer, W. L. J. Am. Chem. Soc. 1953, 75, 989e996; (b) Treihs,
W.; Neupert, H. J.; Hiebsch, J. Chem. Ber. 1959, 92, 141e145; (c) Damodiran, M.;
Panneer, N.; Paramasivan, S.; Perumal, T. Tetrahedron Lett. 2009, 50, 5474e5478.
N]CeH), 7.12e8.19 (m, 2H, ArH); 13C NMR (50 MHz, CDCl3)
d 24.5
(CH), 25.2 (CH), 45.6 (CH), 48.8 (CH), 89.4, 117.9, 126.0, 126.7, 127.3
(2ꢂCH), 127.9, 128.3, 128.7 (2ꢂCH), 129.3, 129.5, 133.7, 137.2, 147.1,
151.3,151.7,152.3,154.2; IR (KBr) 3849 (m), 3645 (m),1693 (m, eC]
€
7. (a) Haufel, V. J.; Breitmaier, E. Angew. Chem. 1974, 86, 671e672; (b) Mason, H. J.;
Wu, X.; Schmitt, R.; Macor, J. E.; Yu, G. Tetrahedron Lett. 2001, 42, 8931e8934.
8. (a) Procopiou, P. A.; Brodie, A. C.; Deal, M. J.; Hayman, D. F. Tetrahedron Lett.
1993, 34, 7483e7486; (b) Procopiou, P. A.; Brodie, A. C.; Deal, M. J.; Hayman, D.
F. J. Chem. Soc., Perkin Trans. 1 1996, 2249e2253.
N), 1556 (m), 1587 (m), 1116 (m), 1082 (m), 948 (m), 827 (m) cmꢁ1
;
EIMS m/z (relative intensity) 367 (100), 366 (Mþ, 26), 310 (23), 297
(34), 264 (11), 129 (26), 128 (70). Anal. Calcd for C23H21N5; C: 75.18;
H: 5.76; N: 19.06. Found: C: 75.12; H: 5.72; N: 19.02.
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Acknowledgements
We are grateful to the Tsuzuki Institute for Traditional Medicine,
the China Medical University (CMU100-ASIA-17, CMU100-TS-13,
and CMU101-S-23), and the National Science Council of Republic of
China (NSC-99-2320-B-039-014-MY3) for financial support. This
study is also supported in part by Taiwan Department of Health
Clinical Trial and Research Center of Excellence (DOH100-TD-B-
111-004).
17. Huang, Y. R.; Katzenellenbogen, J. A. Org. Lett. 2000, 2, 2833e2836 and refer-
ences therein.
Supplementary data
18. Nishigaki, N. Bioorg. Med. Chem. Lett. 2003, 13, 2985e2988; (b) Braibante, M. E.
F.; Braibante, H. T. S.; da Roza, J. K.; Henriques, D. M. Synthesis 2003, 1160e1162;
(c) Schenone, S.; Bruno, O.; Ranise, A.; Bondavalli, F.; D’Amico, M.; Filippelli, W.;
Falcone, G.; De Novellis, V. Il Farmaco 1995, 50, 179e182; (d) Cooper, C. B.; Helal,
C. J.; Sanner, M. A.; Wagner, T. T. PCT WO 18346 A1, 2002.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.11.002.
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