Synthesis of some new pyrazole and pyrazolopyrimidine derivatives [1]

Article abstract of DOI:10.1002/jhet.482

A series of pyrazolo [3,4-d] pyrimidine, pyrazolo [1,5-a] pyrimidine, and pyrazolyl triazoles have been prepared via reaction of ethyl 5-amino-3-phenylpyrazole-4-carboxylate with isothiocyanic esters, α,β-unsaturated nitriles, and some active methylene re

Full text of DOI:10.1002/jhet.482

November 2010
Synthesis of Some New Pyrazole and Pyrazolopyrimidine
Derivatives [1]
1379
Said A. S. Ghozlan,* Fathy M. Abdelrazek,* Mona H. Mohamed,
and Khaled E. Azmy
Chemistry Department, Faculty of Science, Cairo University, Giza, A. R. Egypt
*E-mail: s_ghozlan@yahoo.com or prof.fmrazek@gmail.com
Received December 20, 2009
DOI 10.1002/jhet.482
Published online 25 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
A series of pyrazolo [3,4-d] pyrimidine, pyrazolo [1,5-a] pyrimidine, and pyrazolyl triazoles have
been prepared via reaction of ethyl 5-amino-3-phenylpyrazole-4-carboxylate with isothiocyanic esters,
a,b-unsaturated nitriles, and some active methylene reagents.
J. Heterocyclic Chem., 47, 1379 (2010).
INTRODUCTION
sation of the hydrazide NH2 with the benzoyl-carbonyl
group with elimination of water. This cyclization was
expected to occur with elimination of ethanol; however,
all spectral evidence showed the presence of the ester
function.
In the past decade, we have been involved in a pro-
gram aiming at the synthesis of new heterocyclic com-
pounds that may possess biologically active properties
to be used as potential biodegradable agrochemicals [2–
5]. In continuation of our earlier interest in 3(5)-amino-
pyrazole, we report here an efficient synthesis of the
hitherto unreported ethyl 5-amino-3-phenyl-1H-pyraz-
ole-4-carboxylate 3 and its exploitation for the synthesis
of some new fused pyrazole derivatives.
Thus, IR spectrum of the product showed that absorp-
tion bands at tmax ¼ 1651, 3415, and 3365 cmꢀ1 attrib-
utable to carbonyl and amino groups. The 1H NMR
spectrum revealed a triplet at d ¼ 1.17–1.24 ppm (J ¼
10.6 Hz) and quartet at d ¼ 4.12–4.23 ppm (J ¼ 10.6
Hz) characteristic for ethyl ester group, a singlet (2H,
D2O exchangeable) at d ¼ 6.21 ppm for amino group, a
multiplet (5H) at d ¼ 7.42–7.66 ppm for aromatic pro-
tons, and a broad singlet (1H) at d ¼ 12.05 ppm for the
pyrazole NH. Moreover, the mass spectrum of the reac-
tion product showed a strong absorption at m/z ¼ 231
(48%), which is compatible with the molecular formula
C12H13N3O2 for compound 3.
RESULTS AND DISCUSSION
Thus, ethyl benzoylacetate 1 reacts with trichloroace-
tonitrile in ethanol catalyzed by sodium acetate to afford
1:1 adduct, which could be formulated as ethyl
3-amino-2-benzoyl-3-trichloromethyl acrylate derivative
2. Structure 2 was assigned to this adduct on the basis
of analytical and spectral data (cf. Experimental part).
The reaction of 2 with hydrazine hydrate in refluxing
pyridine afforded directly ethyl 5-amino-3-phenyl-1H-
pyrazole-4-carboxylate 3. The formation of 3 is assumed
to occur via nucleophilic attack of hydrazine NH2 on 2
with elimination of chloroform followed by the conden-
Aminopyrazoles are the most extensively utilized het-
erocyclic amines in heterocyclic synthesis due to their
ready availability as well as their stability, which makes
them useful precursors in dyes, pharmaceuticals, and
agrochemical industries [6–13].
In conjunction with our interest in exploring the
potential utility of functionally substituted pyrazoles
C
V
2010 HeteroCorporation

1380
S. A. S. Ghozlan, F. M. Abdelrazek, M. H. Mohamed, and K. E. Azmy
Vol 47
Scheme 1. Preparation of compounds 2, 3, 4, 6a,b, 7, 8, 9 and 10.
[14–16], we report here a simple and efficient synthesis
of some new polyfunctionally substituted pyrazolopyri-
midines of expected biological interest starting with our
new pyrazole 3.
protons and three singlets at d ¼ 11.82, 12.99, and
13.88 ppm for NH-pyrazole and two NH-pyrimidine
protons. The formation of 6a from 4 seemed to proceed
via alcoholysis with loss of the benzoyl moiety and the
formation of the nonisolable intermediate 5, which
undergoes cyclization through ethanol elimination to
give 6a (Scheme 1). An authentic sample of 6a has
been obtained from the reaction of the pyrazole 3 with
thiourea by fusion in an oil bath at 120ꢁC (The same
melting point, mixed melting point, and same analytical
and spectral analyses). The loss of the benzoyl moiety
in similar reaction is reported in [16–18].
Thus, ethyl 5-amino-3-phenyl-1H-pyrazole-4-carboxy-
late 3 reacts with benzoyl isothiocyanate and phenyl
isothiocyanate to afford the 1:1 adducts 4 and 8, respec-
tively, via electrophilic attack at the amino group, which
was considered most likely for these adducts based on
their stability under the conditions reported to effect
decomposition of N-thiocarbamoyl pyrazoles [16–18].
Attempts to effect cyclization of both reaction products
4 and 8 by boiling in ethanolic sodium ethoxide has
resulted in the formation of pyrazolo[3,4-d]pyrimidines
6a and 9, respectively. Structures 6a and 9 are identified
on the basis of analytical and spectral data, where the
1H NMR spectrum of 6a revealed the presence of a
multiplet at d ¼ 7.45–8.15 ppm (5H) for aromatic
The thiourea derivatives 4 and 8 reacted with hydra-
zine hydrate and afforded products for which structures
7 and 10 were assigned on the basis of analytical and
spectral analyses, where the 1H NMR spectrum of 7
showed the presence of a triplet at d ¼ 1.13 ppm (J ¼
7.2 Hz), a quartet at d ¼ 4.15 ppm (J ¼ 7.2 Hz), a
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis of Some New Pyrazole and Pyrazolopyrimidine Derivatives
1381
Scheme 2. Preparation of compounds 13, 14, 16, 18, 20, 22, 24 and 26.
multiplet at d ¼ 7.45–8.15 ppm for 10 protons (aromatic
protons), a singlet at d ¼ 9.20 ppm for Pyrazole-NH,
and two singlets at d ¼ 11.90 and 13.05 ppm for both
exocyclic NH and triazole-NH protons.
Pyrazolo[1,5-a]pyrimidines are important due to their
ability to inhibit 30,50-cyclic phosphodiestrase and their
cardiotropic properties [19,20]. Moreover, the reported
activities of pyrazolo[1,5-a]pyrimidines as antipyretics,
anti-inflammatory, anticancer, and antischistosomal
agents [21–23] prompted us to prepare some of their
new derivatives via reacting our new 5-aminopyrazole
derivative 3 with some a,b-unsaturated nitriles and
active methylene reagents.
1
On the other hand, the H NMR of 10 revealed the
presence of a singlet at d ¼ 5.56 ppm for the amino
group protons, a multiplet at d ¼ 7.11–8.39 ppm inte-
grated for 10H (2-Ph protons), a singlet at d ¼ 9.47
ppm for pyrazole-NH, and a singlet at d ¼ 13.18 ppm
for hydrazine-NH. The 13C NMR spectrum of 10
revealed signals at 102.64 (C-4 pyrazolopyrimidine),
121.62, 123.60, 127.54, 128.18, and 128.62 (CH aro-
matic), 132.77 (C-9 pyrazolopyrimidine), 136.28,
138.25, and 147.12 (CH aromatic), 150.91 (C-3 pyrazo-
lopyrimidine), 153.76 (C-7 pyrazolopyrimidine), and
157.59 (C-6 pyrazolopyrimidine) (CO).
Thus, ethyl 5-amino-3-phenyl-1H-pyrazole-4-caboxy-
late 3 reacts with the cinnamonitrile derivative 11 in
refluxing ethanol with few drops of piperidine as a cata-
lyst to afford products for which structures 12 or 13
seemed possible (cf. Scheme 2).
The spectral data of the reaction products suggested
structure 13 to be assigned to this product rather than 12
(cf. Experimental section). Compound 13 was trans-
formed into the fully aromatic pyrazolo[1,5-a]pyrimidine
derivative 14 on reflux in pyridine. When the reaction
of 3 with 11 was carried out in refluxing pyridine com-
pound 14 was also obtained. The identity of the two
The pyrazolo[3,4-d]pyrimidine-4,6-dione analogue 6b
has been obtained via reaction of the 5-aminopyrazole 3
with urea on fusion in oil bath at 120ꢁC. Structure 6b
was assigned on the basis of elemental analysis and
spectral data (cf. Experimental section).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1382
S. A. S. Ghozlan, F. M. Abdelrazek, M. H. Mohamed, and K. E. Azmy
Vol 47
Figure 1. Single crystal X-ray structure of compound 14 [24–26].
products was inferred from melting points and spectral
data. Structure 14 was assigned on the basis of the 13C
26 have been established, respectively, on the basis
of analytical and spectral analyses. The IR spectrum
of compound 22 revealed an absorption band at
mmax ¼1712 cmꢀ1 for carbonyl ester and another band
at mmax ¼1662 cmꢀ1 for amide carbonyl group.
1
NMR and H NMR spectra which revealed the disap-
pearance of the pyrimidine-4-H signal and presence of a
singlet at d ¼ 6.83 ppm integrated for two protons (NH2
protons) in addition to the other expected signals for ar-
omatic and ethyl ester protons (cf. Experimental). The
formation of 14 from 13 apparently takes place via
auto-oxidation under the reaction conditions. Similar
reactions have been reported [22,23].Structure 14 was
unambiguously confirmed on the basis of the single
crystal X-ray analysis [24–26] (cf. Fig. 1).
1
The H NMR spectrum of 24 showed two singlets at
d ¼ 2.70 and 2.80 ppm for the two methyl groups and a
singlet at d ¼ 6.75 ppm for pyrimidine-CH proton,
beside the other expected signals for aromatic and ethyl
ester protons. The formation of 26 apparently proceeds
in a manner similar to the addition of the cinnamonitrile
11 shown above (cf. Scheme 2, Fig. 1, Experimental).
The aminopyrazole 3 reacted with ethoxy-methylene
malononitrile 15 and afforded a product for which struc-
ture 16 is established based on analytical and spectral
analyses.
EXPERIMENTAL
The melting points were determined on a Stuart melting
point apparatus and are uncorrected. The IR spectra were
recorded as KBr pellets using a FTIR unit Bruker-Vector 22
spectrophotometer. The 1H and 13C NMR spectra were
recorded in DMSO-d6 as solvent at 300 MHz and 75 MHz,
respectively, on Varian Gemini NMR spectrometer using TMS
as internal standard. Chemical shifts are reported in d units
(ppm). Mass spectra were measured on a Shimadzu GCMS -
QP-1000 EX mass spectrometer at 70 eV. The elemental anal-
yses were performed at the Micro analytical Center, Cairo
University. The single crystal structure [24–26] was deter-
mined by X-ray unit at the National Research Center, Dokki,
Giza, A. R. Egypt.
On the other hand, when the 5-aminopyrazole 3 was
condensed with both the enaminonitrile 17 and the
enaminone 19, it yielded the pyrazolo[1,5-a]pyrimidine
derivatives 18 and 20, respectively.
Structure 18 could be established on the basis of spec-
1
tral analysis where the H NMR spectrum revealed the
amino group as a singlet at d ¼ 9.94 ppm and the
appearance of two doublets at d ¼ 6.56 ppm (J ¼ 7.2
Hz) and d ¼ 8.26 ppm (J ¼ 7.2 Hz) which may be
attributed to H-5 and H-6.
5-Aminopyrazole-4-carboxylate 3 was also condensed
with ethyl acetoacetate 21, acetylacetone 23, and
benzoylacetonitrile 25 by fusion on oil bath at 100–
120ꢁC to yield products for which structures 22, 24, and
3-Amino-2-benzoyl-4,4,4-trichloro-butyric acid ethyl ester
(2). To a solution of ethyl benzoylacetate 1 (1.92 g, 10 mmol)
in absolute ethanol (50 mL) containing sodium acetate,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis of Some New Pyrazole and Pyrazolopyrimidine Derivatives
1383
trichloroacetonitrile (1.44 g, 10 mmol) was added. Stirring
lasted overnight at room temperature then the reaction mixture
was poured into cold water. The resulting product obtained
was filtered off, dried, and recrystallized from ethanol. White
crystal (yield 80%), m.p. 107ꢁC. mmax cmꢀ1 ¼ 3375, 3240
(NH2), 1674, 1645 (CO). MS: m/z 336 (Mþ). Anal. Calcd. for
C13H12Cl3NO3 (336.05): C, 46.38; H, 3.59; N, 4.16; Cl,
31.59%. Found: C, 46.31; H, 3.52; N, 4.11; Cl, 31.53%.
5-Amino-3-phenyl-1H-pyrazole-4-carboxylic acid ethyl
ester (3). To a suspension of 2 (3.36 g, 10 mmol) in ethanol
was added the equivalent amount of hydrazine hydrate (0.50
mL, 10 mmol) and triethylamine as catalyst. The reaction mix-
ture was refluxed for 5 h and then concentrated in vacuo. The
solid product obtained upon cooling was isolated by filtration
and recrystallized from a mixture of ethanol/dioxane. White
crystal (yield 50%). m.p. 172ꢁC. mmax cmꢀ1 ¼ 3415, 3365
(NH2), 3245, 1651 (CO). MS: m/z 231 (Mþ). dH ¼ 1.17 (t,
3H, J ¼ 10.6 Hz, CH3), 4.12 (q, 2H, J ¼ 10.6 Hz, CH2), 6.21
(s, 2H, NH2), 7.42–7.66 (m, 5H, Ar-H), 12.04 (s, 1H, NH-pyr-
azole). Anal. Calcd. for C12H13N3O2 (231.26): C, 62.32; H,
5.66; N, 18.17%. Found: C, 62.25; H, 5.60; N, 18.08%.
5-(3-Benzoyl-thioureido)-3-phenyl-1H-pyrazole-4-carbo-
xylic acid ethyl ester (4). A solution of 3 (2.31 g, 10 mmol)
and benzoyl isothiocyanate (1.63 g, 10 mmol) in dry acetone
(50 mL) were refluxed for 5 h. The reaction mixture was
evaporated under vacuo. The resulting solid was collected by
filtration and crystallized from ethanol. White crystal (yield
50%), m.p. 158ꢁC. tmax cmꢀ1 ¼ 3425, 3193 (NH), 1720, 1681
(CO). MS: m/z 394 (Mþ). Anal. Calcd. for C20H18N4O3S
(394.45): C, 60.89; H, 4.59; N, 14.20; S, 8.12%. Found: C,
60.81; H, 4.53; N, 14.13; S, 8.08%.
Synthesis of (6a). Method 1. Compound 4 (10 mmol) was
treated with ethanolic sodium ethoxide (0.23 g sodium in 50
mL ethanol), the reaction mixture was refluxed for 3 h and
allowed to cool then poured into cold water and neutralized
with dil. HCl. The resulting product was collected by filtration
and crystallized from ethanol to afford 6a in 72% yield.
Synthesis of (6a, b). Compound 3 (2.31 g, 10 mmol) was
treated with thiourea (0.76 g, 10 mmol) or urea (0.60 g,
10 mmol) and the reaction mixture was heated in oil bath at
100–120ꢁC for 2 h. The mixture was allowed to cool at room
temperature. The formed solid product was crystallized from
ethanol/dioxane to afford 6a and 6b, respectively.
3-Phenyl-6-thioxo-1,5,6,7-tetrahydro-pyrazolo [3,4-d] pyri-
midin-4-one (6a). Pale brown crystal (yield 65%), m.p >
300ꢁC. tmax cmꢀ1 ¼ 3215, 3120 (NH), 1593 (CO). MS: m/z
244 (Mþ). dH ¼ 7.50–8.15 (m, 5H, Ar-H), 11.82 (s, 1H,
NH-pyrazole), 12.99 (s, 1H, NH-pyrimidine), 13.88 (s, 1H,
NH-pyrimidine). Anal. Calcd. for C11H8N4OS (244.27): C,
54.09; H, 3.30; N, 22.93; S, 13.34%. Found: C, 54.02; H,
3.27; N, 22.85; S, 13.29%.
and were refluxed for 3 h and then allowed to cool at room
temperature. The reaction mixture was poured into ice cold
water and neutralized with dil. HCl. The resulting solid was
collected by filtration and crystallized from ethanol. The prod-
uct is identified as 8. Pale yellow crystal (yield 50%), m.p.
218ꢁC. tmax cmꢀ1 ¼ 3355, 3210 (NH), 1654 (CO). MS: m/z
366 (Mþ). Anal. Calcd. for C19H18N4O2S (366.49): C, 62.26;
H, 4.95; N, 15.28; S, 8.74%. Found: C, 62.21; H, 4.89; N,
15.23; S, 8.68%.
3,5-Diphenyl-6-thioxo-1,5,6,7-tetrahydro-pyrazolo [3,4-d]
pyrimidin-4-one (9). Compound 8 (10 mmol) was treated
with ethanolic sodium ethoxide solution (0.23 g sodium in 50
mL absolute ethanol). The reaction mixture was heated under
reflux for 3 h, allowed to cool, then poured onto ice cold water
and neutralized with dil. HCl. The resulting solid product is
collected by filtration and crystallized from ethanol and identi-
fied as 9. White crystal (yield 55%), m.p. > 300ꢁC. tmax cmꢀ1
¼ 3153, 3056 (NH), 1696 (CO). MS: m/z 320 (Mþ). Anal.
Calcd. for C17H12N4OS (320.37): C, 63.73; H, 3.77; N, 17.48;
S, 10.00%. Found: C, 63.64; H, 3.69; N, 17.40; S, 9.92%.
General method for preparation of (7) and (10). Compound
4 or 8 (10 mmol) reacted with hydrazine hydrate (0.50 mL,
10 mmol) in pyridine (25 mL) and heated under reflux for 3 h,
then allowed to cool at room temperature. The reaction mix-
tures were poured onto ice cold water and neutralized with
dilute HCl. The resulting solids were collected by filtration
and crystallized from ethanol.
3-Phenyl-5-(5-phenyl-4H-[1,2,4]triazol-3-ylamino)-1H-pyrazole-
4-carboxylic acid ethyl ester (7). Pale brown crystal (yield
70%), m.p. > 300ꢁC. tmax cmꢀ1 ¼ 3325, 3175, 3150 (NH),
1676 (CO). MS: m/z 374 (Mþ). dH ¼ 1.13(t, 3H, J ¼ 7.2 Hz,
CH3), 4.15 (q, 2H, J ¼ 7.2 Hz, CH2), 7.45–8.15 (m, 10H,
3Ar-H), 9.20 (s, 1H, NH-pyrazole). 11.90 (s, 1H, NH), 13.05 (s,
1H, NH-triazole). Anal. Calcd. for C20H18N6O2 (374.41): C,
64.42; H, 4.84; N, 22.44%. Found: C, 64.38; H, 4.80; N, 22.37%.
6-Hydrazide-3,5-diphenyl-1,5-dihydro-pyrazolo [3,4-d] pyri-
midin-4-one (10). White crystal (yield 50%), m.p. 295ꢁC. tmax
cmꢀ1 ¼ 3350, 3235 (NH2), 3150 (NH). MS: m/z 318 (Mþ). dH
¼ 5.56 (s, 2H, NH2), 7.11–8.39 (m, 10H, 2Ar-H), 9.47 (s, 1H,
NH-pyrazole), 13.18 (s, 1H, NH-hydrazide). dC ¼ 102.64 (C-4
pyrazolopyrimidine), 121.62, 123.60, 127.54, 128.18, and
128.62 (CH aromatic), 132.77 (C-9 pyrazolopyrimidine),
136.28, 138.25, and 147.12 (CH aromatic), 150.91 (C-3 pyra-
zolopyrimidine), 153.76 (C-7 pyrazolopyrimidine), 157.59 (C-
5 pyrazolopyrimidine) (CO). Anal. Calcd. for C17H14N6O
(318.34): C, 64.14; H, 4.43; N, 26.39%. Found: C, 64.09; H,
4.38; N, 26.31%.
7-Amino-6-cyano-2,5-diphenyl-4,7-dihydro-pyrazolo[1,5-a]
pyrimidine-3-carboxylic acid ethyl ester (13). Compounds 11
(1.54 g, 10 mmol) were refluxed for 3 h with compound 3
(2.31 g, 10 mmol) in ethanol (50 mL) and few drops of piperi-
dine as catalyst. The reaction mixture was then poured into
ice-cold water and neutralized with dilute HCl. The resulting
solid product was collected by filtration and crystallized from
3-Phenyl-1,7-dihydro-pyrazolo [3,4-d] pyrimidine-4,6-dione
(6b). Pale yellow crystal (yield 60%), m.p > 300ꢁC. tmax
cmꢀ1 ¼ 3430, 3223 (NH), 1730, 1640 (CO). MS: m/z 228
(Mþ). dH ¼ 7.43–8.14 (m, 5H, Ar-H), 10.65 (s, 1H, NH-pyraz-
ole), 11.35 (s, 1H, NH-pyrimidine), 13.55 (s, 1H, NH-pyrimi-
dine). Anal. Calcd. for C11H8N4O2 (228.21): C, 57.89; H,
3.53; N, 24.55%. Found: C, 57.81; H, 3.48; N, 24.49%.
3-Phenyl-5-(3-phenyl-thioureido)-1H-pyrazole-4-carboxylic
acid ethyl ester (8). Phenyliso-thiocyanate (1.35 g, 10 mmol)
was added to a solution of 3 (2.31 g, 10 mmol) in pyridine
ethanol. White crystal (yield 65%), m.p. 220ꢁC. tmax cmꢀ1
¼
3446, 3400 (NH2), 3315 (NH), 2190 (CN), 1686 (CO). MS: m/
z 385 (Mþ). dH (CDCl3) ¼ 1.18 (t, 3H, J ¼ 7.2 Hz, CH3),
4.17 (q, 2H, J ¼ 7.2 Hz, CH2), 5.48 (s, 3H, NH2, CH-pyrimi-
dine), 6.72 (s, 1H, NH-pyrimidine), 7.39–7.70 (m, 10H, 2Ar-
H). Anal. Calcd. for C22H19N5O2 (385.43): C, 68.55; H, 4.96;
N, 18.17%. Found: C, 68.50; H, 4.92; N, 18.08%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1384
S. A. S. Ghozlan, F. M. Abdelrazek, M. H. Mohamed, and K. E. Azmy
Vol 47
Hz, thiophene-H-1), 8.57 (d, 1H, J ¼ 7.2 Hz, pyrazolopyrimi-
dine-H-6), 8.80 (d, 1H, J ¼ 7.2 Hz, pyrazolopyrimidine-H-5).
Anal. Calcd. for C19H15N3O2S (349.41): C, 65.31; H, 4.33; N,
12.03; S, 9.18%. Found: C, 65.22; H, 4.38; N, 11.92; S,
9.05%.
General procedure for preparation of compounds (22),
(24), and (26). Compound 3 (2.31 g, 10 mmol) and 10 mmol
of either ethyl acetoacetate 21, acetylacetone 23, or benzoyla-
cetonitrile 25 were reacted under thermal conditions in oil bath
at 100–120ꢁC for 2 h. The formed solid products were washed
well with ethanol and crystallized from ethanol/dioxane to
afford 22, 24, and 26, respectively.
7-Methyl-5-oxo-2-phenyl-4,5-dihydro-pyrazolo[1,5-a]pyrimi-
dine-3-carboxylic acid ethyl ester (22). White crystal (yield
70%), m.p 185ꢁC. tmax cmꢀ1 ¼ 3200 (NH), 1712, 1662 (CO).
MS: m/z 299 (Mþþ2). dH ¼ 1.17(t, 3H, J ¼ 7.2 Hz, CH3),
3.30 (s, 3H, CH3), 4.22 (q, 2H, J ¼ 7.2 Hz, CH2), 5.87 (s, 1H,
pyrimidine-H), 7.43–7.71 (m, 5H, Ar-H), 11.54 (s, 1H, NH-
pyrimidine). Anal. Calcd. for C16H15N3O3 (297.32): C, 64.63;
H, 5.08; N, 14.13%. Found: C, 64.56; H, 4.98; N, 14.02%.
5,7-Dimethy-2-phenyl-pyrazolo[1,5-a] pyrimidine-3-carbox-
ylic acid ethyl ester (24). Yellow crystal (yield 50%), m.p.
124ꢁC. tmax cmꢀ1 ¼ 3060 (CH-Aromatic), 1678 (CO). MS: m/
z 295 (Mþ). dH ¼ 1.25 (t, 3H, J ¼ 6.9 Hz, CH3), 2.70 (s, 3H,
CH3), 2.80 (s, 3H, CH3), 4.31 (q, 2H, J ¼ 6.9 Hz, CH2), 6.75
(s, 1H, pyrimidine-H) 7.44–7.77 (m, 5H, Ar-H). Anal. Calcd.
for C17H17N3O2 (295.34): C, 69.13; H, 5.80; N, 14.22%.
Found: C, 69.05; H, 5.75; N, 14.17%.
7-Amino-6-cyanio-2,5-diphenyl-pyrazolo[1,5-a]pyrimidine-
3-carboxylic acid ethyl ester (14). Compound 13 (3.85 g,
10 mmol) was dissolved in 25 mL pyridine (or 25 mL DMF)
and heated under reflux for 3 h, then evaporated in vacuo and
diluted with cold water (50 mL) then treated with few drops
of dil. HCl. The resulting solid product is filtered off, washed
well with cold water, and crystallized from ethanol/dioxane
mixture. The solid product is identified as 14. Brown crystal
(yield 55%), m.p. 208ꢁC. tmax cmꢀ1 ¼ 3415, 3365 (NH2),
2219 (CN), 1685 (CO). MS: m/z 382 (Mþ-1). dH ¼ 1.31
(t, 3H, J ¼ 7.2 Hz, CH3), 4.34 (q, 2H, J ¼ 7.2 Hz, CH2), 6.83
(s, 2H, NH2) 7.48–8.07 (m, 10H, 2Ar-H). dC ¼ 14.11 (CH3
ester), 60.55 (CH2 ester), 75.27 (C-7 pyrazolopyrimidine),
106.23 (C-8 pyrazolopyrimidine), 115.41 (CN), 127.95,
128.59, 128.93, 129.59, 129.64, 131.07, 131.83, and 136.54
(CH aromatic), 148.69 (C-6 pyrazolopyrimidine), 150.55 (C-2
pyrazolopyrimidine), 159.99 (C-4 pyrazolopyrimidine), 160.79
(C-3 pyrazolopyrimidine), 162.69 (CO). Anal. Calcd. for
C22H17N5O2 (383.41): C, 68.91; H, 4.46; N, 18.26%. Found:
C, 68.87; H, 4.37; N, 18.19%.
X-ray crystallographic data using SIR92 [25] program to
solve structure: Yellow crystals, C22H17N5O2 (Mr ¼ 383.411
gmolꢀ1), orthorhombic prismatic, space group Pna-2(1), a ¼
ꢁ
˚
˚
˚
8.8207(2) A, b ¼ 16.6408(4) A, c ¼ 25.7103(9) A, a[ ] ¼
3
ꢁ
ꢁ
˚
90.00, b[ ] ¼ 90.00, c[ ] ¼ 90.00; V[A ] ¼ 3773.8(2). Z ¼ 8,
Dx ¼ 1.350 Mgmꢀ3, l(Mo Ka) ¼ 0.09 mmꢀ1; Fine-focus
sealed tube. Data were collected using KappaCCD. T[K] ¼
298, with graphite monochromator with Mo Ka radiation (k ¼
ꢁ
˚
7-Amino-2,5-diphenyl-pyrazolo[1,5-a] pyrimidine-3-carbox-
ylic acid ethyl ester (26). Yellow crystal (yield 55%), m.p. >
300ꢁC. tmax cmꢀ1 ¼ 3305, 3170 (NH2), 1654 (CO). MS: m/z
358 (Mþ). Anal. Calcd. for C21H18N4O2 (358.40): C, 70.37; H,
5.06; N, 15.63%. Found: C, 70.29; H, 4.97; N, 15.55%.
0.71073 A), y ¼ 2.910–25.028 . Measured reflections 6613,
Total independent reflections are 3780 were counted with
observed reflections 1830. Rint ¼ 0.031. R(all) ¼ 0.112, R(gt)
¼ 0.042, wR(ref) ¼ 0.078, and wR(all) ¼ 0.097.
General procedure for preparation of compounds (16),
(18), and (20). Compound 3 (2.31 g, 10 mmol) was added to
a solution of 15, 17, or 19 (10 mmol) in pyridine (25 mL) and
refluxed for 3 h. The reaction mixtures were evaporated under
vacuo then poured onto ice cold water, and neutralized with
diluted HCl. The resulting solids were collected by filtration
and crystallized from dioxane/ethanol and identified as 16, 18,
and 20, respectively.
REFERENCES AND NOTES
[1] This work is abstracted in part from the Ph.D. thesis of Mr.
Khaled E. Azmy.
[2] Abdelrazek, F. M.; Ghozlan, S. A.; Michael, F. A. J Hetero-
cycl Chem 2007, 44, 63.
[3] Ghozlan, S. A. S.; Hafez, E. A. A.; El-Bannany, A. A.
Arch Pharm 1987, 320, 850.
7-Amino-6-cyano-2-phenyl-pyrazolo [1,5-a]pyrimidine-3-car-
boxylic acid ethyl ester (16). Brown crystal (yield 60%), m.p.
282ꢁC. tmax cmꢀ1 ¼ 3406, 3220 (NH2), 2221(CN), 1697,
(CO). MS: m/z 307 (Mþ). Anal. Calcd. for C16H13N5O2
(307.31): C, 62.53; H, 4.26; N, 22.79%. Found: C, 62.45; H,
4.19; N, 22.69%.
7-Amino-2-phenyl-pyrazolo [1,5-a] pyrimidine-3-carboxylic
acid ethyl ester (18). White crystal (yield 70%), m.p. 204ꢁC.
tmax cmꢀ1 ¼ 3427, 3372 (NH2), 1671 (CO). MS: m/z 282
(Mþ). dH ¼ 1.21 (t, 3H, J ¼ 7.2 Hz, CH3), 4.28 (q, 2H, J ¼
7.2 Hz, CH2), 6.56 (d, 1H, J ¼ 7.2 Hz, pyrazolopyrimidine-H-
5), 7.50–7.81 (m, 5H, Ar-H), 8.26 (d, 1H, J ¼ 7.2 Hz, pyrazo-
lopyrimidine-H-6), 9.94 (s, 1H, NH2). Anal. Calcd. for
C15H14N4O2 (282.31): C, 63.81; H, 4.99; N, 19.84%. Found:
C, 63.72; H, 4.91; N, 19.79%.
2-Phenyl-7-thiophen-2-yl-pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid ethyl ester (20). Pale yellow crystal (yield 65%), m.p.
159ꢁC. tmax cmꢀ1 ¼ 3062 (CH-Aromatic), 1697(CO). MS:
m/z 349 (Mþ). dH ¼ 1.21(t, 3H, J ¼ 6.9 Hz, CH3), 4.27(q, 2H,
J ¼ 6.9 Hz, CH2), 7.39–7.90 (m, 6H, Ar-H, thiophene-H-2),
7.95 (d, 1H, J ¼ 3.9 Hz, thiophene-H-3), 8.14 (d, 1H, J ¼ 3.9
[4] Ghozlan, S. A. S.; Hassanien, A. Z. A. Tetrahedron 2002,
58, 9423.
[5] Abdelrazek, F. M.; Metwally, N. H.; Kassab, N. A.; Sobhy,
N. A. J Heterocycl Chem 2009, 46, 1380.
[6] Blass, B. E.; Srivastava, A.; Coburn, K. R.; Fanlkner, A. L.;
Seibel, W. L. Tetrahedron Lett 2003, 44, 3009.
[7] Domagala, J. M.; Peterson, P. J Heterocycl Chem 1989, 26,
1147.
[8] Gilman, A. G.; Goodman, L. S. The Pharmaceutical Basis
of Therapeutics; Macmillan: New York, 1985; p 1109.
[9] Fanger, F.; Nicklen, S.; Coulson, A. R. Proc Natl Acad Sci
USA 1977, 74, 5463.
[10] Wellinga, K.; Grosscurt, A. C.; Van Hes, R. J Agric Food
Chem 1977, 25, 987.
[11] Grosscurt, C.; Van Hes, R.; Wellinga, K. J Agric Food
Chem 1979, 27, 406.
[12] Elbannany, A.; Ghozlan, S. A. S. Egypt J Chem 1988, 31, 587.
[13] Rzepecki, P.; Wehner, M.; Molto, O.; Zadmard, R.; Harms,
K.; Schrader, T. Synthesis 2003, 1815.
[14] Abdallah, T. A.; Metwally, N. H.; Abdelrazek, F. M. Afini-
dad 2008, 65, 393.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Synthesis of Some New Pyrazole and Pyrazolopyrimidine Derivatives
1385
[15] Abdelrazek, F. M.; Michael, F. A.; Mohamed, A. E. Arch
Pharm Chem Life Sci (Weinheim) 2006, 339, 305.
[16] Zayed, E. M.; Ghozlan, S. A. S.; Ibrahim, A. A. H. Mon-
atsh Chem 1984, 115, 431.
[23] Senga, K.; Norenson, T.; Wilson, H. R.; Robrns, R. K. J
Med Chem 1981, 24, 610.
[24] Crystallographic data (excluding structure factors) for the
structure 8a reported in this article have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication no.
CCDC-755428. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax.:
(internat.) þ44 1223/336-033; e-mail: deposit@ccdc.cam.ac.uk].
[25] Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi,
A.; Burla, M. C.; Polidori, G.; Camalli, M. J Appl Crystallogr 1994,
27, 435.
[17] Sigma, K.; Kobe, J.; Robins, R. K.; O’Brien, D. L. J Heter-
ocycl Chem 1973, 12, 893.
[18] Vogel, A.; Troxler, F. Helv Chim Acta 1975, 58, 761.
[19] Makino, K.; Kim, H. S.; Kurasawa, Y. J Heterocycl Chem
1998, 35, 489.
[20] Bogza, S. D.; Ivanov, A. V.; Dulenko, V. I.; Kobrakov, K.
I. Chem Heterocycl Compd 1997, 33, 69.
[21] Komykhov, S. A.; Ostras, K. S.; Kostanyn, A. R.; Desenko,
S. M.; Orlov, V. D.; Meier, H. J Heterocycl Chem 2005, 42, 1111.
[22] Singa, K.; Brien, D. E.; Scholten, M. B.; Novenson, T.;
Miller, J. P.; Robins, R. K. J Med Chem 1982, 25, 243.
[26] Mackay, S.; Gilmore, C. J.; Edwards, C.; Stewart, N.;
Shankland, K. MaXus Computer Program for the Solution and Refine-
ment of Crystal Structures; Bruker Nonius: The Netherlands; MacS-
cience: Japan; University of Glasgow: Glasgow, 1999.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet