One-step reaction leading to new pyrazolo[1,5-a]pyrimidines by condensation of 2-pyrone with 5(3)-amino-3(5)-arylpyrazoles

Article abstract of DOI:10.1016/j.tet.2011.01.070

Condensation of 5(3)-amino-3(5)-arylpyrazoles with 4-hydroxy-6-methylpyran- 2-one leads to 5,7-dimethyl-2-arylpyrazolo[1,5-a]pyrimidines, 5-alkoxycarbonylmethyl-7-methyl-2-arylpyrazolo[1,5-a]pyrimidines and their isomeric 7-alkoxycarbonylmethyl-5-methyl-2

Full text of DOI:10.1016/j.tet.2011.01.070

Tetrahedron 67 (2011) 2279e2286
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-step reaction leading to new pyrazolo[1,5-a]pyrimidines by condensation of
2-pyrone with 5(3)-amino-3(5)-arylpyrazoles
,
,
d
d
Ibtissam Bassoude a b, Sabine Berteina-Raboin a , Jean-Michel Leger , Christian Jarry ,
*
El Mokhtar Essassi b , Gerald Guillaumet
Institut de Chimie Organique et Analytique, Universite d’Orleans, UMR CNRS 6005, BP 6759, 45067 ORLEANS Cedex 2, France
Laboratoire de Chimie Organique Heterocyclique, Universite Mohammed V-Agdal, Faculte des Sciences, avenue Ibn-Batouta, RABAT, Morocco
INANOTECH (Institute of Nanomaterials and Nanotechnology), MAScIR, Av. Armee Royale, RABAT, Morocco
,
c
a
ꢀ
a
ꢀ
ꢀ
b
c
ꢀ ꢀ
ꢀ
ꢀ
ꢀ
d
ꢀ
ꢀ
ꢀ
EA4318-Pharmacochimie, UFR des Sciences Pharmaceutiques, Universite Victor Segalen Bordeaux 2, 146 rue Leo Saignat, 33 076 BORDEAUX Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 October 2010
Received in revised form 20 January 2011
Accepted 24 January 2011
Available online 28 January 2011
Condensation of 5(3)-amino-3(5)-arylpyrazoles with 4-hydroxy-6-methylpyran-2-one leads to 5,7-di-
methyl-2-arylpyrazolo[1,5-a]pyrimidines,
5-alkoxycarbonylmethyl-7-methyl-2-arylpyrazolo[1,5-a]py-
rimidines and their isomeric 7-alkoxycarbonylmethyl-5-methyl-2-arylpyrazolo[1,5-a]pyrimidines. These
compounds result from competitive reactions and from different cyclization pathways. Structure and
mechanism of formation of these new products are reported.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazolo[1,5-a] pyrimidines
5(3)-Amino-3(5)-arylpyrazoles
2-Pyrones
Heterocyclization
Microwave irradiation
1. Introduction
compounds. Pyrones are reported to be electrophilic and highly
reactive towards binucleophiles.12e20 Thus condensation of 4-hy-
Pyrazolo[1,5-a]pyrimidines have attracted considerable interest
because of their biological activity. For instance, this heterocyclic
system is found as purine analogues and has useful properties as
antimetabolites in purine biochemical reactions.1 Several com-
pounds of this class display interesting antitrypanosomal2 and
antischistosomal activities.3 They are used as HMG-CoA reductase
inhibitors,4 COX-2 selective inhibitors,5 30,50-cyclic-AMP phospho-
diesterase inhibitors,6 CRF1 antagonists,7aed selective peripheral
benzodiazepine receptor ligands,8aec potassium channel9and his-
tamine-3 receptor ligands10 and antianxiety agents.11 This led to the
developmentof newefficient general procedures for the synthesis of
pyrazolo[1,5-a]pyrimidines derivatives. As part of our interest in the
use of2-pyrone, as versatile synthonforobtaining new pyrazolo[1,5-
a]pyrimidine derivatives, we investigated the condensation of 4-
hydroxy-6-methylpyran-2-one with 5(3)-amino-3(5)-arylpyrazole
in various refluxing alcohols and under microwave irradiation.
Pyrone derivatives are versatile synthons often used in organic
synthesis, in particular to gain access in new types of heterocyclic
droxy-6-methylpyran-2-one with 3-amino-5-hydroxypyrazole is
reported to give a single 7-alkoxycarbonylmethyl-5-methyl-2-hy-
droxy-pyrazolo[1,5-a]pyrimidine,19 whereas, in our investigation,
we established that, the use of 5(3)-amino-3(5)-arylpyrazole in
place of 5-amino-3-hydroxypyrazole gave a mixture of two isomeric
pyrazolo[1,5-a]pyrimidines (i) 7-alkoxycarbonylmethyl-5-methyl-
2-arylpyrazolo[1,5-a]pyrimidines and (ii) 5-alkoxycarbonylmethyl-
7-methyl-2-arylpyrazolo-[1,5-a]pyrimidines. Hence, we found this
condensation was a simple method for preparing new pyrazolo[1,5-
a]pyrimidines with potential pharmacological activity.
2. Results and discussion
We first tested the reaction conditions already described in the
literature.19 Equimolar amounts of 4-hydroxy-6-methylpyran-2-
one 1 and 3-amino-5-phenylpyrazole 2 were reacted in refluxing
methanol for 48 h to give compounds 3a and 4a in modest 3% and
12% yields, respectively, with a significant amount of starting ma-
terial 2 being recovered (Table 1, entry 1). The reaction conditions
were modified to improve 5-methoxycarbonylmethyl-7-methyl-2-
phenylpyrazolo[1,5-a] pyrimidine 3a and 7-methoxycarbonyl-
methyl-5-methyl-2-phenylpyrazolo[1,5-a] pyrimidine 4a yields.
* Corresponding author. Tel.: þ33 238 494 856; fax: þ33 238 417 281; e-mail
address: sabine.berteina-raboin@univ-orleans.fr (S. Berteina-Raboin).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.070

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I. Bassoude et al. / Tetrahedron 67 (2011) 2279e2286
Table 1
Condensation of 2-pyrone 1 with 3-amino-5-phenylpyrazole 2 in refluxing methanol
O
O
N
OH
Ph
N
Ph
N
N
Ph
N
MeOH
Ph
N
HN
+
+
+
N
N
NH
N
N
reflux, 48 h
O
2
O
1
O
O
2
3a
4a
5
Entry
1a
2a
3ab
4ab
5b
Global yieldb
1
2
3
1
2
3
1
1
1
3
19
20
12
34
36
d
4
4
15
57
60
a
equivalent.
Yields in isolated products.
b
Compounds 3a, 4a and 5 were isolated in 19%, 34% and 4% yield,
respectively (Table 1, entry 2), but an excess of 1 was recovered.
Moreover, formation of 5 as a new compound was observed when
2 equiv of 1 were used. No significant effect on the yields was ob-
served by using 3 equiv of compound 1 (Table 1, entry 3).
The scope of this reaction under the optimized condition (Table 1,
entry 2) was next investigated starting with several alcohols. The
results (Table 2) showed that 5,7-dimethyl-2-phenylpyrazolo[1,5-a]
pyrimidines 5, 5-alkoxycarbonylmethyl-7-methyl-2-phenylpyrazolo
[1,5-a]pyrimidines 3(aed) and their isomeric 7-alkoxycarbonyl-
be achieved in only 1 h when the reaction mixture was heated at
120 ꢀC. Hence, compounds 3a, 4a and 5 were obtained in 28%, 68%
and 2% yield, respectively, indicating a 98% global yield (Table 3,
entry 3). By applying these reaction conditions, i.e. [4-hydroxy-6-
methylpyran-2-one
1 (2 equiv), 3-amino-5-phenylpyrazole 2
(1 equiv) in methanol at 120 ꢀC for 1 h under irradiation micro-
wave], we evaluated the scope and limitation of the method by
using other alcohols (Table 3, entries 4e8). Thus, under irradiation
microwave the condensation of 1 with starting material 2 in eth-
anol for 1 h at 120 ꢀC gave the desired products in 84% global yield
after total conversion (Table 3, entry 4). Increasing the temperature
of reaction to 125 ꢀC afforded the desired compounds in similar
yield (Table 3, entry 5). Replacement of ethanol with 1-propanol at
methyl-5-methyl-2-phenylpyrazolo
[1,5-a]pyrimidines
4(aed)
resulting from two competitive cyclizations were identified in mod-
erate yields in all the conducted experiments (Table 2, entries 1e4).
Table 2
Condensation of 2-pyrone 1 with 3-amino-5-phenylpyrazole 2 in various refluxing alcohols
N
O
O
N
R
N
Ph
N
Ph
O
OH
N
N
Ph
N
Ph
NH
N
R-OH
+
+
2
N
+
HN
N
2
O
1
O
O
reflux, 48 h
R
5
4
(a-d)
3(a-d)
a : R= CH ; b: R= C H
3
2
5
c : R= C H ; d: R= C H
9
3
7
4
Entry
ReOH
Product yield [%]
Global yield (%)
3:5
4
1
2
3
4
CH3eOH
19a:3a
17b:6b
16b:6b
17a:7a
34a
32a
41a
21a
56
55
63
45
C2H5eOH
C3H7eOH
C4H9eOH
a
Yields in isolated products.
b
The ratio was determined by 1H NMR spectroscopy.
To improve the yields, we decided to optimize the reaction
130 ꢀC under same reaction conditions led to 3c, 4c and 5 in goods
yields (Table 3, entry 7).
conditions under microwave irradiation. We first irradiated the
reaction conditions already used in refluxing methanol under mi-
crowave at 100 ꢀC for 30 min. Compounds 3a, 4a and 5 were iso-
lated in 17%, 27% and 4% yield, respectively, with a significant
amount of starting material 2 being recovered (Table 3, entry 1). On
the other hand, the reaction between starting material 2 and
compound 1 at 100 ꢀC for 1 h leads to incomplete conversion and
3a, 4a and 5 were obtained in only 22%, 36% and 8% yield, re-
spectively, (Table 3, entry 2). However, complete conversion could
The use of 1-butanol as the solvent, permitting an irradiation
microwave at 138 ꢀC for 1 h afforded the desired compounds in 99%
global yield. These results enlightened the favourable influence of
microwave irradiation for the preparation of compounds 3(aed), 4
(aed) and 5. The reaction was completed and both electron-rich
(R1¼OMe) and electron-poor (R1¼F) substituents in the para-po-
sition of 3(5)-amino-5(3)-phenylpyrazoles 2 reacted to give 4(eel)
as major products (Table 4). Structures of 5e7 were determined by

I. Bassoude et al. / Tetrahedron 67 (2011) 2279e2286
2281
Table 3
Microwave assisted condensation of 2-pyrone 1 with 3-amino-5-phenylpyrazole 2 in various alcohols
N
O
O
N
R
N
Ph
N
Ph
O
OH
N
N
N
Ph
Ph
N
R-OH
+
+
NH
N
+
2
HN
O
1
O
N
O
Microwave
R
5
4
(a-d)
2
3(a-d)
a : R= CH ; b: R= C H
3
2
5
c : R= C H ; d: R= C H
9
3
7
4
Entry
R
t (h)
T ( ꢀC)
Yielda (%)
Global yield (%)
3
4
5
1
2
3
4
5
6
7
8
9
CH3
CH3
CH3
C2H5
C2H5
C3H7
C3H7
C4H9
C4H9
0.5
1
1
1
1
1
1
1
1
100
100
120
120
125
120
130
120
138
17
22
28
15
17
15
23
23
27
27
36
68
67
68
58
66
62
69
4
8
2
2
2
1
2
0
3
48
66
98
84
87
74
91
85
99
a
Yields in isolated products.
comparison of theirs physical and spectral characteristics with the
references.21,22 In compounds 3(ael) 1H NMR spectrum revealed
a singlet at 3.9 ppm corresponding to the methylene protons at the
microwave synthesis instrument and temperatures were measured
€
by an IR sensor. Melting points were determined with a Buchi SMP-
20 melting point apparatus and were uncorrected. 1H and 13C NMR
a
position of the carbonyl ester, while the signal shifts downfield to
were recorded on a Bruker Avance DPX400 spectrometer
4.2 ppm in 4(ael). 13C NMR spectrum of compounds 3(ael) and 4
(ael) revealed in particular the signal attributed to the carbonyl, at
170e168 ppm (see Experimental data). The structures of 3b and 4a
were confirmed using X-ray diffraction (Figs.1 and 2). The proposed
mechanism for explaining the synthesis of 3(ael), 4(ael) and 5e7
can be subdivided into two ways18 (Scheme 1). Initial competitive
attack (way a) of the amino group of 2 takes place on carbon C6 of 4-
hydroxy-6-methylpyran-2-one 1, giving the intermediate [A]. Af-
terwards [A] evolves according to decarboxylation and esterifica-
tion competitive reactions towards the intermediates [B] and [C].
Intramolecular cyclization of the aforementioned intermediates
leads, after the loss of a water molecule to 4(ael) and 5e7. Second
competitive attack (way b) of the (eNH) group of the 5(3)-amino-3
(5)-arylpyrazole 2 takes place on carbon C6 of 1 giving the in-
termediate [D]. [D] evolves according to decarboxylation and es-
terification competitive reactions towards the intermediates [E]
and [F]. Intramolecular cyclization of the aforementioned in-
termediates leads, after the loss of a water molecule, to 3(ael) and
5e7 (Scheme 1).
(400.13 MHz 1H, 100.62 MHz 13C) and a Bruker Avance DPX250
spectrometer (250.19 MHz 1H, 62.89 MHz 13C), using TMS as the
internal standard, multiplicities were determined by the DEPT 135
sequence. Chemical shifts (d) are reported in parts per million.
Coupling constants are reported in hertz. The following abbrevia-
tions are used in splitting patterns as s¼singlet, br¼broad single,
dd¼double doublet, d¼doublet, t¼triplet, dt¼double triplet,
m¼multiplet. HRMS was recorded with a TOF spectrometer (ESI
mode) or with a Finnigan MAT 95 XL (CI mode) at the Regional
Center of Physical Measurement University Blaise Pascal Clermont-
Ferrand. IR spectra (wave numbers in cmꢁ1) were recorded on
a NICOLET IS10 FT-IR spectrometer. All commercial solvents were
used without further purification. Column chromatography was
carried out with silica gel 60 N (spherical, neutral, 40e63 mm,
Merck).
4.2. General procedure for the synthesis of compounds 3
(aed), 4(aed) and 5 in various refluxing alcohols (Tables 1
and 2)
3. Conclusion
A solution of 4-hydroxy-6-methylpyran-2-one 1 (1.6 g,
12.6 mmol) and 5(3)-amino-3(5)-arylpyrazole 2 (1 g, 6.3 mmol) in
40 mL of alcohol, under an atmosphere of argon, was heated to
reflux for 48 h. After evaporation of solvent under reduced pres-
sure, the residue was purified on silica gel by column chromatog-
raphy using 90:10 (v/v) mixture of petroleum ether and ethyl
acetate as eluent to give compounds 3(aed), 4(aed) and 5.
We have confirmed the interest of 4-hydroxy-6-methylpyran-2-
one in the synthesis of new pyrazolo[1,5-a]pyrimidines substituted
at position 5 and 7, some of these molecules presented biological
interesting properties23 or can be used as precursors for other
heterocyclic systems.
4. Experimental section
4.3. General procedure for the synthesis of compounds 3
(ael), 4(ael) and 5e7 under microwave irradiation (Tables 3
and 4)
4.1. General remarks and methods
All reagents were purchased from SigmaeAldrich, Acros Or-
ganics or Alfa Aesar and were used without further purification.
Microwave assisted reactions were carried out in a Biotage Initiator
4-Hydroxy-6-methylpyran-2-one 1 (0.16 g, 1.26 mmol) was
added under argon to a solution of 5(3)-amino-3(5)-arylpyrazole 2
(0.1 g, 0.63 mmol) in 4 mL of alcohol in microwave tube. The

2282
I. Bassoude et al. / Tetrahedron 67 (2011) 2279e2286
Table 4
Microwave assisted condensation of 2-pyrone 1 with 5(3)-amino-3(5)-arylpyrazole 2 in various alcohols
N
O
O
N
R
N
Ar
N
Ar
O
OH
N
N
Ar
N
Ar
NH
2
N
R-OH
+
+
N
+
N
N
H
O
1
O
O
Microwave
R
2
4
(e-l)
6-7
3(e-l)
Entry
1
Ar
R
t (min) T (ꢀC)
Products; yields (%)a
Global yields (%)
CH3
60
70
120
120
120
120
130
130
69
(6; 1)
(7; 2)
(6; 1)
(4e; 48)
(4f; 25)
(4g; 48)
(4h; 28)
(3e; 20)
(3f; 14)
(3g; 15)
(3h; 11)
2
3
4
5
6
7
CH3
41
64
41
59
52
C2H5 60
C2H5 65
C3H7 60
C3H7 60
(7; 2)
(6; 2)
(7; 2)
(4i; 40)
(3i; 17)
(4j; 37)
(3j; 13)
C4H9 70
138
138
76
62
(6; 0)
(4k; 56)
(3k; 20)
8
C4H9 60
(7; 1)
(4l; 46)
(3l; 15)
a
Yields in isolated products.

I. Bassoude et al. / Tetrahedron 67 (2011) 2279e2286
2283
on silica gel by column chromatography using mixture of petro-
leum ether and ethyl acetate as eluent to give compounds 3(ael), 4
(ael) and 5e7.20,21
4.4. Experimental data
4.4.1. 5,7-Dimethyl-2-phenylpyrazolo[1,5-a]pyrimidine 5. Beige sol
id, mp 154e155 ꢀC21. 1H NMR (400 MHz, CDCl3): 8.01 (2H, 2HeAr, d,
J¼8.0 Hz), 7.46 (2H, 2HeAr, t, J¼7.5 Hz), 7.38 (1H, 1HeAr,
t, J¼7.3 Hz), 6.85 (1H, H3, s), 6.54 (1H, H6, s), 2.79 (3H, CH3eC7, s),
2.56(3H, CH3eC5, s). 13C NMR (100.62 MHz, CDCl3): 158.3 (C), 155.6
(C), 149.7 (C), 145.2 (C), 133.2 (C), 128.7 (CH), 128.7 (2ꢂCH), 126.5
(2ꢂCH), 108.3 (CH, C6), 92.6 (C3), 24.6(CH3eC5), 17.1(CH3eC7). IR:
Fig. 1. ORTEP diagram derived from the single-crystal X-ray analysis of compound 3b.
nCeN¼1030 cmꢁ1
,
n
C]C¼1549 cmꢁ1. HRMS: m/z [MþH]þ calcd for
C14H14N3: 224.1202; found: 224.1188.4.4.2.
4.4.2. 5,7-Dimethyl-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine
6. Yellow solid, mp 150e151 ꢀC. 1H NMR (250 MHz, CDCl3): 7.94
(2H, 2HeAr, d, J¼9 Hz), 6.99 (2H, 2HeAr, d, J¼9 Hz), 6.76 (1H, H3, s),
6.50 (1H, H6, d, J¼0.7 Hz), 3.86 (3H, CH3 s), 2.76(3H, CH3eC7, d,
J¼0.7 Hz), 2.55 (3H, CH3eC5, s). 13C NMR (62.89 MHz, CDCl3): 160.2
(C), 158.1 (C), 155.5 (C), 149.7 (C), 145.1 (C), 127.8 (2ꢂCH), 125.9 (C),
114.1 (2ꢂCH), 108.0 (CH, C6), 91.9 (CH, C3), 55.3(OeCH3), 24.6
(CH3eC5), 17.1 (CH3eC7). IR: nCeO¼1025 cmꢁ1
,
nCeN¼1172 cmꢁ1
,
n
C]C¼1520 cmꢁ1
.
HRMS: m/z [MþH]þ calcd for C15H16N3O:
254.1306; found: 254.1293.
4.4.3. 7,5-Dimethyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyrim-idine 7.
Yellow solid, mp 186e187 ꢀC.22 1H NMR (250 MHz, CDCl3): 7.98
4
(2H, 2HeAr, dd, JH,H¼8.8 Hz, JH,F¼5.5 Hz), 7.14 (2H, 2HeAr, t,
JHH¼3JH,F¼8.8 Hz), 6.79 (1H, H3, s), 6.54 (1H, H6, s), 2.77 (3H,
CH3eC7, s), 2.56 (3H, CH3eC5, s). 13C NMR (100.62 MHz, CDCl3):
163.2(C, d, JCF¼248.5 Hz), 158.4 (C), 154.6 (C), 149.7 (C), 145.2 (C),
129.5 (C, d, J¼3.02 Hz), 128.3 (2ꢂCH, d, 3JCF¼8.05 Hz), 115.6 (2ꢂCH,
Fig. 2. ORTEP diagram derived from the single-crystal X-ray analysis of compound 4a.
2
d, JCF¼22.1 Hz), 108.4 (CH, C6), 92.3 (CH, C3), 24.6 (CH3eC5), 17.0
(CH3eC7). IR: nCeN¼1159 cmꢁ1
,
nCeF¼1220 cmꢁ1
,
n
C]C¼1529 cmꢁ1
.
HRMS: m/z [MþH]þ calcd for C14H13N3F: 242.1086; found:
242.1094.
4.4.4. 5-Methoxycarbonylmethyl-7-methyl-2-phenylpyrazolo[1,5-a]
pyrimidine 3a. White solid, mp 96e97 ꢀC. 1H NMR (400 MHz,
CDCl3): 8.01 (2H, 2HeAr, d, J¼8.0 Hz), 7.47 (2H, 2HeAr, t, J¼7.4 Hz),
7.39 (1H, 1HeAr, t, J¼7.3 Hz), 6.93 (1H, H3, s), 6.70 (1H, H6, s), 3.86
(2H, CH2eCO, s), 3.76 (3H, CH3eO, s), 2. 82 (3H, CH3eC7, s). 13C NMR
(100.62 MHz, CDCl3): 170.1 (CO), 156.0 (C), 153.6 (C), 149.5 (C), 145.9
(C), 133.1 (C), 128.9 (CH), 128.7 (2ꢂCH), 126.6 (2ꢂCH), 108.0 (CH, C6),
93.4 (CH, C3), 52.4 (CH3eO), 43.8 (CH2eCO), 17.3 (CH3eC7). IR:
nCeN¼1150 cmꢁ1
,
n
C]C¼1552 cmꢁ1
,
n
C]O¼1721 cmꢁ1. HRMS: m/z
[MþNa]þ calcd for C16H15N3O2Na: 304.1072; found: 304.1062.
4.4.5. 7-Methoxycarbonylmethyl-5-methyl-2-phenylpyrazolo[1,5-a]
pyrimidine 4a. White solid, mp 118e119 ꢀC. 1H NMR (400 MHz,
CDCl3): 7.98 (2H, 2HeAr, d, J¼8.0 Hz), 7.45 (2H, 2HeAr, t, J¼7.4 Hz),
7.38 (1H, 1HeAr, t, J¼7.3 Hz), 6.87 (1H, H3, s), 6.69 (1H, H6, s), 4.20
(2H, CH2eCO, s), 3.78 (3H, CH3eO, s), 2, 60 (3H, CH3eC5, s). 13C NMR
(100.62 MHz, CDCl3): 168.4 (CO), 158.4 (C), 155.58 (C), 149.6 (C),
140.7 (C), 133.0 (C), 128.8 (CH), 128.7 (2ꢂCH), 126.5 (2ꢂCH), 109.0
(CH, C6), 92.9 (CH, C3), 52.6 (CH3eO), 36.0 (CH2eCO), 24.8 (CH3eC5).
IR: nCeN¼1203 cmꢁ1
,
n
C]C¼1556 cmꢁ1
,
n
C]O¼1731 cmꢁ1. HRMS:
m/z [MþH]þ calcd for C16H16N3O2: 282.1257; found: 282.1243.
Scheme 1. Proposed mechanism.
4.4.6. 5-Ethoxycarbonylmethyl-7-methyl-2-phenylpyrazolo[1,5-a]
pyrimidine 3b. White solid, mp 92e93 ꢀC. 1H NMR (400 MHz,
CDCl3): 8.01(2H, 2HeAr, d, J¼8.0 Hz), 7.47 (2H, 2HeAr, t, J¼7.4 Hz),
7.39 (1H, 1HeAr, t, J¼7.3 Hz), 6.92 (1H, H3, s), 6.72 (1H, H6, s), 4.22
(2H, CH2eO, q, J¼7.1 Hz), 3.84 (2H, CH2eCO, s), 2.83 (3H, CH3eC7, s)
reaction vessel was sealed with a silicon septum and subjected to
microwave at T ( ꢀC) with stirring for (60e70) min. The reaction
vessel then was allowed to cool to room temperature. After evap-
oration of solvent under reduced pressure, the residue was purified

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I. Bassoude et al. / Tetrahedron 67 (2011) 2279e2286
1.29 (3H, CH3, t, J¼7.1 Hz). 13C NMR (100.62 MHz, CDCl3): 169.5 (CO),
155.7 (C), 153.6 (C), 149.3 (C), 145.7 (C), 132.9 (C), 128.7 (CH), 128.5
(2ꢂCH), 126.4 (2ꢂCH), 107.8 (CH, C6), 93.2 (CH, C3), 61.2 (CH2,
CH2eO), 43.8 (CH2, CH2eCO), 17.1 (CH3eC7), 14.0 (3H, CH3). IR:
(CH), 128.7 (2ꢂCH), 126.0 (2ꢂCH), 109.9(CH, C6), 92.2 (CH, C3), 64.4
(CH2eO), 36.1 (CH2eCO), 30.1 (CH2), 24.3 (CH3eC5), 18.4 (CH2),
13.4 (CH3). IR: nCeN¼1197 cmꢁ1
,
n
C]C¼1556 cmꢁ1
,
n
C]O¼1722 cmꢁ1. HRMS: m/z [MþH]þ calcd for C19H22N3O2:
nCeN¼1023 cmꢁ1
,
n
C]C¼1551 cmꢁ1
,
n
C]O¼1722 cmꢁ1. HRMS: m/z
324.1713; found: 324.1712.
[MþNa]þ calcd for C17H17N3O2Na: 318.1229; found: 318.1218.
4.4.12. 5-Methoxycarbonylmethyl-2-(4-methoxyphenyl)-7-methyl-
pyrazolo[1,5-a]pyrimidine 3e. White solid, mp 86e87 ꢀC. 1H NMR
(400 MHz, CDCl3): 7.94 (2H, 2HeAr, d, J¼8.4 Hz), 6.99 (2H, 2HeAr, d,
J¼8.4 Hz), 6.84 (1H, H3, s), 6.67 (1H, H6, s), 3.87 (3H, OCH3), 3.84(2H,
CH2eCO, s), 3.75 (3H, CH3eO, s), 2. 81(3H, CH3eC7, s). 13C NMR
(100.62 MHz, CDCl3): 170.2 (CO), 160.3 (C), 155.9 (C), 153.5 (C), 149.5
(C), 145.8 (C), 127.9 (2ꢂCH), 125.8 (C), 114.1 (2ꢂCH), 107.7 (CH, C6),
92.7 (CH, C3), 55.3(CH3eO), 52.4 (CH3eO), 43.8 (CH2eCO),17.3
4.4.7. 7-Ethoxycarbonylmethyl-5-methyl-2-phenylpyrazolo[1,5-a]
pyrimidine 4b. White solid, mp 116e117 ꢀC. 1H NMR (400 MHz,
CDCl3): 7.98 (2H, 2HeAr, d, J¼6.8 Hz), 7.45 (2H, 2HeAr, t, J¼7.4 Hz),
7.38 (1H, 1HeAr, t, J¼7.3 Hz), 6.87 (1H, H3, s), 6.69 (1H, H6, s), 4.24
(2H, CH2eO, t, J¼7.1 Hz), 4.18 (2H, CH2eCO, s), 2, 60 (3H, CH3eC5, s)
1.27 (3H, CH3 t, J¼7.1 Hz). 13C NMR (100.62 MHz, CDCl3): 167.9 (CO),
158.4 (C), 155.5 (C), 149.6 (C), 140.9 (C), 133.0 (C), 128.8 (CH), 128.7
(2ꢂCH), 126.5 (2ꢂCH), 109.0(CH, C6), 92.8 (CH, C3), 61.6(CH2eO),
(CH3eC7). IR: nCeO¼1031 cmꢁ1
,
nCeN¼1155 cmꢁ1
,
n
C]C¼1532 cmꢁ1
,
36.2 (CH2eCO), 24.8 (CH3eC5), 14.1 (CH3). IR: nCeN¼1027 cmꢁ1
,
n
C]O¼1729 cmꢁ1. HRMS: m/z [MþH]þ calcd for C17H18N3O3:
n
C]C¼1555 cmꢁ1
,
n
C]O¼1722 cmꢁ1. HRMS: m/z [MþNa]þ calcd for
312.1362; found: 312.1348.
C17H17N3O2Na: 318.1215; found: 318.1218.
4.4.13. 7-Methoxycarbonylmethyl-2-(4-methoxyphenyl)-5-methyl-
pyrazolo[1,5-a]pyrimidine 4e. White solid, mp 128e129 ꢀC. 1H NMR
(400 MHz, CDCl3): 7.91 (2H, 2HeAr, d, J¼8.8 Hz), 6.97 (2H, 2HeAr, d,
J¼8.8 Hz), 6.78 (1H, H3, s), 6.65 (1H, H6, s), 4.18 (2H, CH2eCO, s), 3.86
(3H, CH3eO, s), 3.77 (3H, CH3eO, s), 2.59 (3H, CH3eC5, s). 13C NMR
(100.62 MHz, CDCl3): 168.4 (CO), 160.2 (C), 158.3 (C), 155.5 (C), 149.6
(C), 140.6 (C), 127.8 (2ꢂCH), 125.7 (C), 114.1 (2ꢂCH), 108.7 (CH, C6),
92.2 (CH, C3), 55.3 (CH3eO), 52.6 (CH3eO), 36.0 (CH2eCO), 24.7
4.4.8. 7-Methyl-5-propoxycarbonylmethyl-2-phenylpyrazolo[1,5-a]
pyrimidine 3c. White solid, mp 79e80 ꢀC. 1H NMR (400 MHz,
DMSO): 8.06 (2H, 2HeAr, d, J¼6.8 Hz), 7.45 (2H, 2HeAr, t, J¼7.4 Hz),
7.43 (1H, 1HeAr, t, J¼7.3 Hz), 7.16 (1H, H3, s), 6.98 (1H, H6, s), 4. 05
(2H, CH2eO, t, J¼6.6 Hz), 3.91 (2H, CH2eCO, s), 2.77 (3H, CH3eC7, s),
1.64e1.56 (2H, CH2eCH2eCH3, m), 0.87 (3H, CH2eCH3 t, J¼7.4 Hz).
13C NMR (100.62 MHz, DMSO): 169.5(CO), 154.8(C), 154.6 (C), 148.9
(C), 145.6 (C), 132.6 (C), 128.9 (CH), 128.8 (2ꢂCH), 126.2 (2ꢂCH),
108.79 (CH, C6), 92.78(CH, C3), 66.02 (CH2eO), 43.11 (CH2eCO),
(CH3eC5). IR: nCeO¼1029 cmꢁ1
,
nCeN¼1179 cmꢁ1
,
n
C]C¼1533 cmꢁ1
,
n
C]O¼1731 cmꢁ1. HRMS: m/z [MþH]þ calcd for C17H18N3O3:
21.47 (CH2), 16.63 (CH3eC7), 10.18 (CH3). IR: nCeN¼1149 cmꢁ1
,
312.1364; found: 312.1348.
n
C]C¼1553 cmꢁ1
,
n
C]O¼1720 cmꢁ1. HRMS: m/z [MþNa]þ calcd for
C18H19N3O2Na: 332.1388; found: 332.1375.
4.4.14. 5-Ethoxycarbonylmethyl-2-(4-methoxyphenyl)-7-methyl-
pyrazolo[1,5-a]pyrimidine 3g. White solid, mp 101e102 ꢀC. 1H NMR
(250 MHz, CDCl3): 7.94 (2H, 2HeAr, d, J¼8.9 Hz), 6.99 (2H, 2HeAr, d,
J¼8.9 Hz), 6.84 (1H, H3, s), 6.68 (1H, H6, d, J¼0.8 Hz), 4.22 (2H,
CH2eO, q, J¼7.0 Hz), 3.87 (3H, CH3eO, s), 3.83(2H, CH2eCO, s), 2.81
(3H, CH3eC7, d, J¼0.6 Hz), 1.28 (3H, CH2eCH3, t, J¼7.0 Hz). 13C NMR
(62.89 MHz, CDCl3): 169.8 (CO), 160.3 (C), 153.7 (C), 149.5 (C), 145.7
(C), 127.9 (2ꢂCH), 125.8 (C), 114.1 (2ꢂCH), 107.7 (CH, C6), 92.7 (CH,
C3), 61.3 (CH2eO), 55.3 (CH3eO), 44.0 (CH2eCO), 17.3 (CH3eC7), 14.2
4.4.9. 5-Methyl-7-propoxycarbonylmethyl-2-phenylpyrazolo[1,5-a]
pyrimidine 4c. White solid, mp 102e104 ꢀC. 1H NMR (400 MHz,
DMSO): 7.99 (2H, 2HeAr, d, J¼7.2 Hz), 7.48 (2H, 2HeAr, t, J¼7.4 Hz),
7.41 (1H, 1HeAr, t, J¼7.3 Hz), 7.09 (1H, H3, s), 6.98 (1H, H6, s), 4.27
(2H, CH2eCO, s), 4.05 (2H, CH2eO, t, J¼6.6 Hz), 2.54 (3H, CH3eC5, s),
1.59e1.50 (2H, CH2eCH2eCH3, m), 0.75 (3H, CH2eCH3, t, J¼7.4 Hz).
13C NMR (100.62 MHz, DMSO): 167.9 (CO), 158.7 (C), 154.2 (C), 149.1
(C), 141.2 (C), 132.6 (C), 128.9(CH), 128.8 (2ꢂCH), 126.0 (2ꢂCH),
109.9 (CH, C6), 92.3 (CH, C3), 66.2 (CH2eO), 36.0 (CH2eCO), 24.3
(CH3). IR: nCeO¼1022 cmꢁ1
,
nCeN¼1174 cmꢁ1
,
n
C]C¼1526 cmꢁ1
,
n
C]O¼1726 cmꢁ1. HRMS: m/z [MþH]þ calcd for C18H20N3O3:
(CH3eC5), 21.4 (CH2), 10.0 (CH3). IR: nCeN¼1181 cmꢁ1
,
326.1515; found: 326.1505.
n
C]C¼1555 cmꢁ1
,
n
C]O¼1729 cmꢁ1. HRMS: m/z [MþH]þ calcd for
C18H20N3O2: 310.1561; found: 310.1556.
4.4.15. 7-Ethoxycarbonylmethyl-2-(4-methoxyphenyl)-5-methyl-
pyrazolo[1,5-a]pyrimidine 4g. White solid, mp 109e110 ꢀC. 1H NMR
(400 MHz, CDCl3): 7.91 (2H, 2HeAr, d, J¼8.4 Hz), 6.97 (2H, 2HeAr, d,
J¼8.4 Hz), 6.78 (1H, H3, s), 6.65 (1H, H6, s), 4.24 (2H, CH2eO, q, J¼7.
2 Hz), 4.16 (2H, CH2eCO, s), 3.85(3H, OCH3, s), 2.58 (3H, CH3eC5, s),
1.26 (3H, CH3, t, J¼7.2 Hz). 13C NMR (100.62 MHz, CDCl3): 167.9 (CO),
160. 2 (C), 158.2 (C), 155.3 (C), 149.6 (C), 140.8 (C), 127.7 (2ꢂCH),
125.7 (C), 114.0 (2ꢂCH), 108.6 (CH, C6), 92.1 (CH, C3), 61.6 (CH2eO),
55.3 (CH3eO), 36.2 (CH2eCO), 24.7 (CH3eC5), 14.1 (CH3). IR:
4.4.10. 5-Butoxycarbonylmethyl-7-methyl-2-phenylpyrazolo[1,5-a]py-
rimidine 3d. White solid, mp 75e76 ꢀC. 1H NMR (400 MHz, DMSO):
8.06 (2H, 2HeAr, d, J¼7.2 Hz), 7.50 (2H, 2HeAr, t, J¼7.4 Hz), 7.42 (1H,
1HeAr, t, J¼7.3 Hz), 7.15 (1H, H3, s), 6.97 (1H, H6, d, J¼0.8 Hz), 4.09
(2H, CH2eO, t, J¼6.6 Hz), 3.90 (2H, CH2eCO, s), 2.77 (3H, CH3eC7, s)
1.60e1.53 (2H, CH2, m), 1.34e1.27 (2H, CH2, m), 0.87 (3H, CH2eCH3, t,
J¼7.4 Hz). 13C NMR (100.62 MHz, DMSO): 169.5 (CO), 154.7 (C), 154.6
(C), 148.9 (C), 145.6 (C), 132.6 (C), 128.9 (CH), 128.8 (2ꢂCH), 126.2
(2ꢂCH), 108.8 (CH, C6), 92.8 (CH, C3), 64.3 (CH2eO), 40.1 (CH2eCO),
nCeO¼1028
cmꢁ1
,
nCeN¼1174
cmꢁ1
,
n
C]C¼1531
cmꢁ1
,
n
C]O¼1730 cmꢁ1, HRMS: m/z [MþH]þ calcd for C18H20N3O3:
30.1 (CH2), 18.5 (CH2), 16.6 (CH3eC7), 13.5 (CH3). IR: nCeN¼1209 cmꢁ1
,
326.1504; found: 326.1505.
n
C]C¼1555 cmꢁ1
,
n
C]O¼1717 cmꢁ1. HRMS: m/z [MþH]þ calcd for
C19H22N3O2: 324.1713; found: 324.1712.
4.4.16. 2-(4-Methoxyphenyl)-7-methyl-5-propoxycarbonylmethylpyr-
azolo[1,5-a]pyrimidine 3i. White solid, mp 68e69 ꢀC. 1H NMR
(400 MHz, DMSO): 7.98 (2H, 2HeAr, d, J¼8.8 Hz), 7.06 (1H, H3, s), 7.05
(2H, 2HeAr, d, J¼8.8 Hz), 6.93 (1H, H6, d, J¼0.8 Hz), 4.05 (2H, CH2eO,
t, J¼6.6 Hz), 3.89 (2H, CH2eCO, s), 3.82(3H, OCH3), 2.76 (3H, CH3eC7,
4.4.11. 7-Butoxycarbonylmethyl-5-methyl-2-phenylpyrazolo[1,5-a]
pyrimidine 4d. White solid, mp 98e99 ꢀC. 1H NMR (400 MHz,
DMSO): 8.00 (2H, 2HeAr, d, J¼7.2 Hz), 7.48 (2H, 2HeAr, t,
J¼7.3 Hz), 7.41 (1H, 1HeAr, t, J¼7.3 Hz), 7.09 (1H, H3, s), 6.98 (1H,
H6, s), 4.26 (2H, CH2eCO, s), 4.09 (2H, CH2eO, t, J¼6.4 Hz), 2.54
(3H, CH3eC5, s), 1.53e1.46 (2H, CH2, m), 1.22e1.13 (2H, CH2, m),
0.74 (3H, CH2eCH3, t, J¼7.4 Hz). 13C NMR (100.62 MHz, DMSO):
167.9 (CO), 158.7 (C), 154.2 (C), 149.1 (C), 141.2 (C), 132.6 (C), 128.9
d, J¼0.4 Hz), 1.64e1.55 (2H, CH2, m), 0.87 (3H, CH3, t, J¼7.4 Hz). 13
C
NMR (100.62 MHz, DMSO): 169.6 (CO), 159.9 (C), 154.5 (C), 149.0 (C),
145.4 (C), 127.6 (2ꢂCH), 125.1 (C), 114.2 (2ꢂCH), 108.4 (CH, C6), 92.0
(CH, C3), 66.0 (CH2eO), 55.2 (CH3eO), 40.1 (CH2eCO), 21.5 (CH2),16.6
(CH3eC7), 10.2 (CH3). IR: nCeO¼1031 cmꢁ1
,
nCeN¼1174 cmꢁ1
,

I. Bassoude et al. / Tetrahedron 67 (2011) 2279e2286
2285
n
C]C¼1533 cmꢁ1
,
n
C]O¼1729 cmꢁ1. HRMS: m/z [MþH]þ calcd for
(CH2eCO), 24.8 (CH3eC5). IR: nCeN¼1156 cmꢁ1
,
nCeF¼1201 cmꢁ1
,
C19H22N3O3: 340.1660; found: 340.1661.
n
C]C¼1526 cmꢁ1
,
n
C]O¼1731 cmꢁ1. HRMS: m/z [MþH]þ calcd for
C16H15N3O2F: 300.1150; found: 300.1148.
4.4.17. 2-(4-Methoxyphenyl)-5-methyl-7-propoxycarbonylmethyl-
pyrazolo[1,5-a]pyrimidine 4i. White solid, mp 98e99 ꢀC. 1H NMR
(400 MHz, DMSO): 7.92 (2H, 2HeAr, d, J¼8.8 Hz), 7.03 (2H, 2HeAr,
d, J¼8.8 Hz), 6.99 (1H, H3, s), 6.93 (1H, H6, s), 4.25 (2H, CH2eCO, s),
4.04 (2H, CH2eO, t, J¼6.4 Hz), 3.82(3H, OCH3), 2.53 (3H, CH3eC5, s),
1.59e1.50 (2H, CH2, m), 0.76 (3H, CH3, t, J¼7.4 Hz). 13C NMR
(100.62 MHz, DMSO): 167.9 (CO),159.9 (C),158.4 (C),154.2 (C), 149.1
(C), 141.1 (C), 127.4 (2ꢂCH), 125.1 (C), 114.2 (2ꢂCH), 109.5 (CH, C6),
91.5 (CH, C3), 66.2 (CH2eO), 55.2 (CH3eO), 36.0 (CH2eCO), 24.3
4.4.22. 5-Ethoxycarbonylmethyl-2-(4-fluorophenyl)-7-methylpyrazolo
[1,5-a]pyrimidine 3h. White solid, mp 107e108 ꢀC. 1H NMR (400 MHz,
4
CDCl3): 7.98 (2H, 2HeAr, dd, JH,H¼8.8 Hz, JH,F¼5.2 Hz), 7.15 (2H,
2HeAr, t, JHH¼3JH,F¼8.8 Hz), 6.86 (1H, H3, s), 6.72 (1H, H6, d, J¼0.4 Hz),
4.22 (2H, CH2eO, q, J¼7.1 Hz), 3.84 (2H, CH2eCO, s), 2. 81(3H, CH3eC7,
s),1.29 (3H, CH3 t, J¼7.1 Hz). 13C NMR (100.62 MHz, CDCl3): 169.7 (CO),
1
163.3 (C, d, JCF¼248.5 Hz), 155.0(C), 154.0 (C), 149.5 (C), 145.9 (C),
129.3 (C, d, 4JCF¼3.02 Hz), 128.4 (2ꢂCH, d, 3JCF¼8.05 Hz), 115.7 (2ꢂCH,
2
(CH3eC5), 21.4 (CH2), 10.06 (CH3). IR: nCeO¼1036 cmꢁ1
,
d, JCF¼22.1 Hz), 108.1(CH, C6), 93.1 (CH, C3), 61.4 (CH2eO), 44.0
nCeN¼1185 cmꢁ1
,
n
C]C¼1531 cmꢁ1
,
n
C]O¼1730 cmꢁ1. HRMS: m/z
(CH2eCO), 17.2 (CH3eC7), 14.2 (CH3). IR: nCeN¼1155 cmꢁ1
,
[MþH]þ calcd for C19H22N3O3: 340.1677; found: 340.1661.
nCeF¼1201 cmꢁ1
,
n
C]C¼1534 cmꢁ1
,
n
C]O¼1720 cmꢁ1. HRMS: m/z
[MþH]þ calcd for C17H17N3O2F: 314.1309; found: 314.1305.
4.4.18. 5-Butoxycarbonylmethyl-2-(4-methoxyphenyl)-7-methylpyr-
azolo[1,5-a]pyrimidine 3k. White solid, mp 77e78 ꢀC. 1H NMR
(400 MHz, DMSO): 7.98 (2H, 2HeAr, d, J¼8.8 Hz), 7.05 (1H, H3, s),
7.06 (2H, 2HeAr, d, J¼8.8 Hz), 6.93 (1H, H6, d, J¼0.8 Hz), 4.09 (2H,
CH2eO, t, J¼6.6 Hz), 3.88 (2H, CH2eCO, s), 3.82 (3H, OCH3), 2.75(3H,
CH3eC7, d, J¼0.8 Hz), 1.60e1.53 (2H, CH2, m), 1.31 (2H, CH2, dq,
J¼14.6, 7.4 Hz), 0.87 (3H, CH3, t, J¼7.4 Hz). 13C NMR (100.62 MHz,
DMSO): 169.5 (CO), 159.9 (C), 154.5 (C), 149.0 (C), 145.4 (C), 127.6
(2ꢂCH), 125.1 (C), 114.2 (2ꢂCH), 108.4 (CH, C6), 92.0 (CH, C3), 64.2
(CH2eO), 55.2 (CH3eO), 39.7 (CH2eCO), 30.1 (CH2), 18.5 (CH2), 16.6
4.4.23. 7-Ethoxycarbonylmethyl-2-(4-fluorophenyl)-5-methylpyra-
zolo[1,5-a]pyrimidine 4h. White solid, mp 130e131 ꢀC. 1H NMR
4
(400 MHz, CDCl3): 7.95 (2H, 2HeAr, dd, JH,H¼8.6 Hz, JH,F¼5.4 Hz),
7.13 (2H, 2HeAr, t, JHH¼3JH,F¼8.6 Hz), 6.81 (1H, H3, s), 6.69 (1H, H6,
s), 4.24 (2H, CH2eO, q, J¼7. 1 Hz), 4.17 (2H, CH2eCO, s), 2.60 (3H,
CH3eC5, s),1.27 (3H, CH3, t, J¼7.1 Hz). 13C NMR (100.62 MHz, CDCl3):
167.9 (CO), 163.2(C, d, 1JCF¼248.5 Hz), 158.6 (C), 154.5 (C), 149.6 (C),
3
140.9 (C), 129.2 (C), 128.2 (2ꢂCH, d, JCF¼8.05 Hz), 115.6 (2ꢂCH, d,
2JCF¼22.1 Hz), 109.1 (CH, C6), 92.5 (CH, C3), 61.6 (CH2eO), 36.2
(CH3eC7), 13.5 (CH3). IR: nCeO¼1030 cmꢁ1
,
nCeN¼1163 cmꢁ1
,
(CH2eCO), 24.8 (CH3eC5), 14.1 (CH3). IR: nCeN¼1156 cmꢁ1
,
n
C]C¼1534 cmꢁ1
,
nCO¼1735 cmꢁ1. HRMS: m/z [MþH]þ calcd for
nCeF¼1196 cmꢁ1
,
n
C]C¼1529 cmꢁ1
,
n
C]O¼1724 cmꢁ1. HRMS: m/z
C20H24N3O3: 354.1833; found: 354.1818.
[MþH]þ calcd for C17H17N3O2F: 314.1300; found: 314.1305.
4.4.19. 7-Butoxycarbonylmethyl-2-(4-methoxyphenyl)-5-methylpyr-
azolo[1,5-a]pyrimidine 4k. White solid, mp 77e78 ꢀC. 1H NMR
(400 MHz, DMSO): 7.92 (2H, 2HeAr, d, J¼8.8), 7.03 (2H, 2HeAr, d,
J¼8.8 Hz), 6.99 (1H, H3, s), 6.93 (1H, H6, s), 4.24 (2H, CH2eCO, s),
4.08 (2H, CH2eO, t, J¼6.4 Hz), 3.81(3H, OCH3), 2.53 (3H, CH3eC5, s),
1.52e1.46 (2H, CH2, m), 1.17 (2H, CH2, dq, J¼14.6, 7.4 Hz), 0.74 (3H,
CH3, t, J¼7.4 Hz). 13C NMR (100.62 MHz, DMSO): 167.9 (CO), 159.9
(C), 158.4 (C), 154.2 (C), 149.1 (C), 141.1 (C), 127.4 (2ꢂCH), 125.1 (CH),
114.1 (2ꢂCH), 109.5 (CH, C6), 91.5 (CH, C3), 64.3 (CH2eO), 55.2
(CH3eO), 36.1 (CH2eCO), 30.1 (CH2), 24.3 (CH3eC5), 18.4 (CH2), 13.4
4.4.24. 2-(4-Fluorophenyl)-7-methyl-5-propoxycarbonylmethylpyra-
zolo[1,5-a]pyrimidine 3j. Beige solid, mp 98e99 ꢀC. 1H NMR
(250 MHz, DMSO): 8.10 (2H, 2HeAr, dd, JH,H¼8.9 Hz, 4JH,F¼5.6 Hz),
7.33 (2H, 2HeAr, t, JHH¼3JH,F¼8.9 Hz), 7.16 (1H, H3, s), 6.98 (1H, H6,
s), 4. 05 (2H, CH2eO, t, J¼6.6 Hz), 3.91 (2H, CH2eCO, s), 2.77(3H,
CH3eC7, s), 1.67e1.53 (2H, CH2, m), 0.87 (3H, CH3, t, J¼7.4 Hz). 13
C
NMR (100.62 MHz, CDCl3): 169.8 (CO), 163.3 (C, d, 1JCF¼247.5 Hz),
155.0(C), 154.0 (C),149.5 (C), 145.8 (C), 129.3 (C, d, 4J¼3.02 Hz),128.3
3
2
(2ꢂCH, d, JCF¼9.05 Hz), 115.7 (2ꢂCH, d, JCF¼22.1 Hz), 108.1 (CH,
C6), 93.1 (CH, C3), 66.9 (CH2eO), 44.0 (CH2eCO), 21.9 (CH2), 17.2
(CH3). IR: nCeO¼1025 cmꢁ1
,
nCeN¼1182 cmꢁ1
,
n
C]C¼1534 cmꢁ1
,
(CH3eC7), 10.3 (CH3). IR: nCeN¼1163 cmꢁ1
,
nCeF¼1204 cmꢁ1
,
nCO¼1726 cmꢁ1
.
HRMS: m/z [MþH]þ calcd for C20H24N3O3:
n
C]C¼1526 cmꢁ1
,
n
C]O¼1726 cmꢁ1. HRMS: m/z [MþH]þ calcd for
354.1805; found: 354.1818.
C18H19N3O2F: 328.1477; found: 328.1461.
4.4.20. 2-(4-Fluorophenyl)-5-methoxycarbonylmethyl-7-methyl-
4.4.25. 2-(4-Fluorophenyl)-5-methyl-7-propoxycarbonylmethylpyra-
zolo[1,5-a]pyrimidine 4j. White solid, mp 112e113 ꢀC. 1H NMR
(250 MHz, DMSO): 8.03 (2H, 2HeAr, dd, JH,H¼8.7 Hz, 4JH,F¼5.6 Hz),
7.32 (2H, 2HeAr, t, JHH¼3JH,F¼8.7 Hz), 7.09 (1H, H3, s), 6.99 (1H, H6,
s), 4.27 (2H, CH2eCO, s), 4.04 (2H, CH2eO, t, J¼6.4 Hz), 2.54 (3H,
pyrazolo[1,5-a]pyrimidine 3f. White solid, mp 153e154 ꢀC. 1H NMR
4
(250 MHz, CDCl3): 7.99 (2H, 2HeAr, dd, JH,H¼8.8 Hz, JH,F¼5.4 Hz),
7.15 (2H, 2HeAr, t, JHH¼3JH,F¼8.8 Hz), 6.87 (1H, H3, s), 6.71 (1H, H6, d,
J¼0.7 Hz), 3.86 (2H, CH2eCO, s), 3.76 (3H, CH3eO, s), 2.82(3H,
CH3eC7, d, J¼0.7 Hz). 13C NMR (100.62 MHz, CDCl3): 170.1 (CO),
163.3 (C, d, 1JCF¼248.5 Hz), 155.0 (C), 153.8 (C), 149.5 (C), 145.9 (C),
CH3eC5, s), 1.60e1.46 (2H, CH2, m), 0.74 (3H, CH3, t, J¼7.4 Hz). 13
C
NMR (100.62 MHz, CDCl3): 167.9 (CO), 163.3 (C, d, JCF¼247.5 Hz),
158.6 (C), 154.6 (C), 149.6 (C), 140.9 (C), 129.2 (C), 128.2 (2ꢂCH, d,
3JCF¼8.0 Hz), 115.6 (2ꢂCH, d, 2JCF¼21.1 Hz), 109.1 (CH, C6), 92.6 (CH,
C3), 67.2 (CH2eO), 36.3 (CH2eCO), 24.8 (CH3eC5), 21.9 (CH2), 10.2
3
129.3 (C), 128.4 (2ꢂCH, d, JCF¼8.05 Hz), 115.7 (2ꢂCH, d,
2JCF¼21.1 Hz), 108.1 (CH, C6), 93.2 (CH, C3), 52.4 (CH3eO), 43.8
(CH2eCO), 17.2 (CH3eC7). IR: nCeN¼1158 cmꢁ1
,
nCeF¼1205 cmꢁ1
,
n
C]C¼1523 cmꢁ1
,
n
C]O¼1730 cmꢁ1. HRMS: m/z [MþH]þ calcd for
(CH3). IR: nCeN¼1155 cmꢁ1
,
nCeF¼1195 cmꢁ1
,
n
C]C¼1524 cmꢁ1
,
C16H15N3O2F: 300.1157; found: 300.1148.
n
C]O¼1725 cmꢁ1. HRMS: m/z [MþH]þ calcd for C18H19N3O2F:
328.1468; found: 328.1461.
4.4.21. 2-(4-Fluorophenyl)-7-methoxycarbonylmethyl-5-methylpyra-
zolo[1,5-a]pyrimidine 4f. White solid, mp 115e116 ꢀC. 1H NMR
(400 MHz, CDCl3): 7.95 (2H, 2HeAr, dd, JH,H¼8.8 Hz,
4JH,F¼5.6 Hz),7.13 (2H, 2HeAr, t, JHH¼3JH,F¼8.8 Hz), 6.81 (1H, H3, s),
6.69 (1H, H6, s), 4.18 (2H, CH2eCO, s), 3.77 (3H, CH3eO, s), 2.60 (3H,
CH3eC5, s). 13C NMR (100.62 MHz, CDCl3): 168.3 (CO), 163.3 (C, d,
1JCF¼247.5 Hz), 158.6 (C), 154.6 (C), 149.6 (C), 140.7 (C), 129.2 (C, d,
4.4.26. 5-Butoxycarbonylmethyl-2-(4-fluorophenyl)-7-methylpyra-
zolo[1,5-a]pyrimidine 3l. White solid, mp 135e136 ꢀC. 1H NMR
4
(250 MHz, DMSO): 8.10 (2H, 2HeAr, dd, JH,H¼8.8 Hz, JH,F¼5.7 Hz),
7.33 (2H, 2HeAr, t, JHH¼3JH,F¼8.8 Hz), 7.16 (1H, H3, s), 6.98 (1H, H6, s),
4.09 (2H, CH2eO, t, J¼6.5 Hz), 3.90 (2H, CH2eCO, s), 2.77(3H, CH3eC7,
s), 1.62e1.47 (2H, CH2, m), 1.31 (2H, CH2, dq, J¼14.5, 7.3 Hz), 0.87
(3H,CH3, t, J¼7.3 Hz). 13C NMR (100.62 MHz, CDCl3): 169.8 (CO),163.3
(C, d, 1JCF¼248.5 Hz),155.0 (C),154.0 (C),149.5 (C),145.8 (C), 129.3 (C),
3
4JCF¼4.02 Hz), 128.2 (2ꢂCH, d, JCF¼8.05 Hz), 115.6 (2ꢂCH, d,
2JCF¼22.1 Hz), 109.1 (CH, C6), 92.6 (CH, C3), 52.6 (CH3eO), 35.9

2286
I. Bassoude et al. / Tetrahedron 67 (2011) 2279e2286
128.3 (2ꢂCH, d, 3JCF¼8.0 Hz),115.7 (2ꢂCH, d, 2JCF¼22.1 Hz),108.1 (CH,
C6), 93.1 (CH, C3), 65.3 (CH2eO), 44.0 (CH2eCO), 30.5 (CH2), 19.1
6. Novinson, T.; Hanson, R.; Dimmitt, M. K.; Simmon, L. N.; Robins, R. K.; O’Brien,
D. E. J. Med. Chem. 1974, 17, 645.
7. (a) Chen, C.; Wilcoxen, K. M.; Huang, C. Q.; Xie, Y.-F.; McCarthy, J. R.; Webb, T. R.;
Zhu, Y.-F.; Saunders, J.; Liu, X.-J.; Chen, T.-K.; Bozigian, H.; Grigoriadis, D. E.
J. Med. Chem. 2004, 47, 4787; (b) Huang, C. Q.; Wilcoxen, K. M.; Grigoriadis, D.
E.; McCarthy, J. R.; Chen, C. Bioorg. Med. Chem. Lett. 2004, 14, 3943; (c) Chen, C.;
Wilcoxen, K. M.; Huang, C. Q.; McCarthy, J. R.; Chen, T.; Grigoriadis, D. E. Bioorg.
Med. Chem. Lett. 2004, 14, 3669; (d) Wustrow, D. J.; Capiris, T.; Rubin, R.; Kno-
belsdorf, A.; Akunne, H.; Davis, M. D.; MacKenzie, R.; Pugsley, T. A.; Zoski, K. T.;
Heffner, T. G.; Wise, L. D. Bioorg. Med. Chem. Lett. 1998, 8, 2067.
8. (a) Selleri, S.; Gratteri, P.; Costagli, C.; Bonaccini, C.; Costanzo, A.; Melani, F.;
Guerrini, G.; Ciciani, G.; Costa, B.; Spinetti, F.; Martini, C.; Bruni, F. Bioorg. Med.
Chem. 2005, 13, 4821; (b) Selleri, S.; Bruni, F.; Costagli, C.; Costanzo, A.; Guerrini,
G.; Ciciani, G.; Costa, B.; Martini, C. Bioorg. Med. Chem. 2001, 9, 2661; (c) Selleri,
S.; Bruni, F.; Costagli, C.; Costanzo, A.; Guerrini, G.; Ciciani, G.; Costa, B.; Martini,
C. Bioorg. Med. Chem. 1999, 7, 2705.
9. Drizin, I.; Holladay, M. W.; Yi, L.; Zhang, H. Q.; Gopalakrishnan, S.; Gopa-
lakrishnan, M.; Whiteaker, K. L.; Buckner, S. A.; Sullivan, J. P.; Carroll, W. A.
Bioorg. Med. Chem. Lett. 2002, 12, 1481.
10. Altenbach, R.J.; Black, L.A.; Chang, S.; Cowart, M.D.; Faghih, R.; Gfesser, G.A.; Ku,
Y.; Liu, H.; Lukin, K.A.; Nersesian, D.L.; Pu, Y.; Curtis, M.P. Tri- and Bi-Cyclic
Heteroaryl Histamine-3-Receptor Ligands. U.S. Patent Appl. 256,309, 2005.
Chem. Abstr. 2005, 144, 36332.
(CH2), 17.2 (CH3eC7), 13.6 (CH3). IR: nCeN¼1164 cmꢁ1
,
nCeF¼1206 cmꢁ1
,
n
C]C¼1535 cmꢁ1
,
n
C]O¼1727 cmꢁ1. HRMS: m/z
[MþH]þ calcd for C19H21N3O2F: 342.1617; found: 342.1618.
4.4.27. 7-Butoxycarbonylmethyl-2-(4-fluorophenyl) -5-methylpyra-
zolo[1,5-a]pyrimidine 4l. White solid, mp 105e106 ꢀC. 1H NMR
(250 MHz, DMSO): 8.03 (2H, 2HeAr, dd, JH,H¼8.8 Hz, 4JH,F¼5.5 Hz),
7.32 (2H, 2HeAr, t, JHH¼3JH,F¼8.8 Hz), 7.09 (1H, H3, s), 6.98 (1H, H6, s),
4.26(2H, CH2eCO, s), 4.08(2H, CH2eO, t, J¼6.4 Hz), 2.54 (3H, CH3eC7,
s), 1.54e1.42 (2H,CH2, m), 1.20e1.08 (2H, CH2, m), 0.73 (3H, CH3, t,
J¼7.3 Hz). 13C NMR (100.62 MHz, CDCl3): 167.9 (CO), 163.3 (C, d,
1JCF¼248.5 Hz), 158.6 (C), 154.6 (C), 149.6 (C), 140.9 (C), 129.2 (C, d,
3
4J¼3.0 Hz), 128.2 (2ꢂCH, d, JCF¼8.0 Hz), 115.6 (2ꢂCH, d,
2JCF¼21.1 Hz), 109.1 (CH, C6), 92.5 (CH, C3), 65.5 (CH2eO), 36.3
(CH2eCO), 30.5 (CH2), 24.8 (CH3eC5), 19.0 (CH2), 13.6 (CH3). IR:
nCeN¼1159
cmꢁ1
,
nCeF¼1210
cmꢁ1
,
n
C]C¼1531
cmꢁ1
,
11. Kirkpatrick, W. E.; Okabe, T.; Hillyard, I. W.; Robin, R. K.; Dren, A. T. J. Med. Chem.
1977, 20, 386.
n
C]O¼1722 cmꢁ1. HRMS: m/z [MþH]þ calcd for C19H21N3O2F:
12. El Abbassi, M.; Essassi, E. M.; Fifani, J. Tetrahedron Lett. 1987, 28, 1389.
13. Djerrari, B.; El Abbassi, M.; Essassi, E. M.; Fifani, J. Tetrahedron Lett. 1989, 30,
1389.
342.1608; found: 342.1618.
Acknowledgements
ꢁ
14. Hamdi, M.; Grech, O.; Sakellariou, R.; Speziale, V. J. Heterocycl. Chem.1994, 31, 509.
15. El Abbassi, M.; Essassi, E. M.; Fifani, J. Bull. Soc. Chim. Belg. 1997, 106, 205.
16. El Kihel, A.; Benchidmi, M.; Essassi, E. M.; Danion-Bougot, R. Synth. Commun.
1999, 29, 2435.
17. Fadel, S.; Hajbi, Y.; Rakib, E. M.; Khouili, M.; Pujol, M. D.; Guillaumet, G. Synth.
Commun. 2004, 34, 1295.
This work was supported by Programme Hubert Curien
Volubilis.
18. Elotmani, B.; El Mahi, M.; Essassi, E. C. R. Chem. 2002, 5, 517.
19. Elotmani, B.; El Hakmoui, A.; Essassi, E.; Fifani, J.; Gueiffier, A. C. R. Acad. Sci.
Paris, Chem. 2001, 4, 285.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.01.070.
20. (a) Quiroga, J.; Portilla, J.; Abonía, R.; Insuasty, B.; Nogueras, M.; Cobo, J. Tet-
rahedron Lett. 2008, 49, 6254; (b) Quiroga, J.; Mejía, D.; Insuasty, B.; Abonía, R.;
ꢀ
Nogueras, M.; Sanchez, A.; Cobo, J.; Low, J. N. J. Heterocycl. Chem. 2002, 39, 51.
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References and notes
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