Resourceful synthesis of pyrazolo[1,5-a]pyrimidines under ultrasound irradiation

Article abstract of DOI:10.1016/j.ultsonch.2013.02.006

Pyrazolo[1,5-a]pyrimidines were synthesized via the ultrasonic sonochemical method using the cyclocondensation reaction of 4-alkoxy-1,1,1-trifluoro-3- alken-2-ones [CF₃C(O)CH = C(R)(OMe) - where R = Me, Bu, i-Bu, Ph, 4-Me-C₆H₄, 4-F-C₆H₄, 4-Cl-C ₆H₄, 4-Br-C₆H₄, naphth-2-yl and biphen-4-yl] - with 3-amino-5-methyl-1H-pyrazole in the presence of EtOH for 5 min. This methodology has several advantages, for example, it is a simple procedure, it has an easy work-up, mild conditions, short reaction times (5 min) and produces satisfactory yields (61-98%).

Full text of DOI:10.1016/j.ultsonch.2013.02.006

Ultrasonics Sonochemistry 20 (2013) 1139–1143
Contents lists available at SciVerse ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultson
Short Communication
Resourceful synthesis of pyrazolo[1,5-a]pyrimidines under ultrasound irradiation
Lilian Buriol, Taiana S. München, Clarissa P. Frizzo, Mara R.B. Marzari, Nilo Zanatta, Helio G. Bonacorso,
⇑
Marcos A.P. Martins
Center for Heterocyclic Chemistry (NUQUIMHE), Federal University of Santa Maria, 97105-900 Santa Maria, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyrazolo[1,5-a]pyrimidines were synthesized via the ultrasonic sonochemical method using the cyclo-
Received 11 December 2012
Received in revised form 18 February 2013
Accepted 25 February 2013
Available online 6 March 2013
condensation reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF3C(O)CH = C(R)(OMe)
– where
R = Me, Bu, i-Bu, Ph, 4-Me–C6H4, 4-F–C6H4, 4-Cl–C6H4, 4-Br–C6H4, naphth-2-yl and biphen-4-yl] – with
3-amino-5-methyl-1H-pyrazole in the presence of EtOH for 5 min. This methodology has several advan-
tages, for example, it is a simple procedure, it has an easy work-up, mild conditions, short reaction times
(5 min) and produces satisfactory yields (61–98%).
Keywords:
Ultrasound
Ó 2013 Elsevier B.V. All rights reserved.
Pyrazolo[1,5-a]pyrimidines
Enones
Trifluoromethyl
1. Introduction
[20,21], microwave [18,20,21], and ultrasound irradiation [4,7,22]
to promote the reactions. Thus, in the continuation of our work,
Ultrasound irradiation has emerged as a powerful technique for
the promotion of organic reactions. The advantages of using cavita-
tion (the creation, growth, and collapse of micrometer-sized bub-
bles that are formed when an acoustic pressure wave propagates
through a liquid) as an energy source to promote organic reactions
include shorter reaction times and higher yields when compared
with conventional thermal heating methods (oil bath) [1–3]. Con-
sequently, ultrasound irradiation has been used to accelerate a
number of synthetically useful reactions, especially in heterocyclic
compounds such as pyrazoles [4], pyrazolo[3,4-b]pyridinones [5],
thiazolidinones [6], 1,2,4-oxadiazoles [7], and triazoles [8].
Pyrazolo[1,5-a]pyrimidines are of considerable chemical and
pharmacological importance, since they have shown COX-2 selec-
tive inhibition [9] and KDR kinase inhibition [10]. More recently,
pyrazolo[1,5-a]pyrimidine was described as the first class of allo-
steric agonists for the nicotinic acid receptor GPR109A [11,12].
Also, the number of patents for pyrazolo[1,5-a]pyrimidines with
pharmacological activity has increased drastically [13,14].
and considering the importance of pyrazolo[1,5-a]pyrimidine as
well as the limited cases of pyrazolo[1,5-a]pyrimidine trifluoro-
methyl [23–25] described in the literature, the aim of this study
was to present the synthesis of 7-trifluoromethylpyrazolo[1,5-
a]pyrimidines under ultrasonic irradiation and compare the results
with those from conventional thermal heating and the microwave
method.
2. Experimental
2.1. Materials
Unless otherwise indicated, all common reagents and solvents
were used as obtained from commercial suppliers without further
purification. The reactions in US were carried out with a tapered
microtip probe (6.5 mm) connected to a 500 W Sonics Vibra-cell
ultrasonic processor equipped with an integrated probe tempera-
ture control. The device operates at 20 kHz of frequency and the
amplitude was set to 20% of the maximum power output. Reac-
tions in MW were performed using a CEM Discover (300 W) micro-
wave mono mode for synthesis with fiber optic temperature sensor
controlled by Synergis Version 3.5.9 software. The irradiation
power was established at a maximum level of 200 W, the internal
vessel pressure at a maximum level of 250 psi. 1H and 13C NMR
spectra were recorded on a Bruker DPX 400 (1H at 400.13 MHz
and 13C at 100.62 MHz) and Bruker DPX-200 (1H at 200.13 MHz
and 13C at 50.32 MHz) in CDCl3/TMS solutions at 298 K, with chem-
ical shifts (d) given in ppm. Mass spectra were registered in a HP
In the last 20 years, we have developed a general synthesis of 4-
alkoxy-1,1,1-trihalo-3-alken-2-ones and shown their usefulness in
heterocyclic preparations [15–17]. In these papers, we have sup-
ported the importance of these halogen-containing building blocks
in the heterocyclic synthesis. Additionally, we have devoted our
attention to improving yields, reducing reaction time, and mini-
mizing waste generation by using ionic liquid [18,19], solvent-free
⇑
Corresponding author. Fax: +55 55 2208031.
E-mail address: mmartins@base.ufsm.br (M.A.P. Martins).
1350-4177/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ultsonch.2013.02.006

1140
L. Buriol et al. / Ultrasonics Sonochemistry 20 (2013) 1139–1143
5973 MSD connected to a HP 6890 GC and interfaced by a Pentium
PC. The GC was equipped with a split–splitless injector, cross-
linked to a HP-5 capillary column (30 m, 0.32 mm i.d.), and helium
was used as the carrier gas. The melting points were measured
using a Microquímica MQAPF 301.
d = 13.6 (C12), 14.5 (CH3), 22.2 (C11), 30.6 (C10), 38.0 (C9), 96.5
(C3), 105.2 (q, 3J4, C6), 119.4 (q, 1J274, CF3), 132.7 (q, 2J37, C7),
150.0 (C3a), 156.2 (C2), 161.5 (C5). MS (EI, 70 eV): m/z % = 257
(M+, 18), 238 (4), 215 (100).
7-Trifluoromethyl-2-methyl-5-(1-methylpropil)pyrazolo[1,5-
a]pyrimidine (3c): m.p. 43–46 °C; 1H NMR (200 MHz, CDCl3):
d = 0.98 (d, 6H, H11, H110), 2.19 (sext, 1H, H10), 2.55 (s, 3H, H8),
2.72 (d, 2H, H9), 6.52 (s, 1H, H3), 6.92 (s, 1H, H6). 13C NMR
(100 MHz, CDCl3): d = 14.7 (CH3), 22.4 (C11, C110), 28.8 (C10),
47.5 (C9), 96.7 (C3), 105.8 (q, 3J4, C6), 119.6 (q, 1J273, CF3), 133.1
(q, 2J36, C7), 150.1 (C3a), 156.4 (C2), 160.9 (C5). MS (EI, 70 eV):
m/z % = 257 (M+, 19), 242 (42), 215 (100).
2.2. Synthesis of enones
Enones 1a–j were obtained from the acylation reaction of enol
ether or acetal with trifluoroacetic anhydride, in accordance with
the methodology developed in our laboratory [26–28].
2.3. Synthesis of pyrazolo[1,5-a]pyrimidines under ultrasonic
sonochemistry
7-Trifluoromethyl-2-methyl-5-phenylpyrazolo[1,5-a]pyrimi-
dine (3d): m.p. 123–124 °C; 1H NMR (200 MHz, CDCl3): d = 2.59 (s,
3H, H8), 6.65 (s, 1H, H3), 7.52 (s, 1H, H6), 7.52 (s, 3H, H Ar), 8.06–
8.08 (m, 2H, Ar). 13C NMR (100 MHz, CDCl3): d = 14.7 (CH3), 97.7
(C3), 102.6 (q, 3J4, C6), 127.1, 129.0, 130.8, 136.3 (C–Ar), 119.5
(q, 1J274, CF3), 133.5 (q, 2J37, C7), 150.3 (C3a), 154.9 (C2), 156.9
(C5). MS (EI, 70 eV): m/z % = 277 (M+, 100), 256 (35), 224 (15),
128 (13).
7-Trifluoromethyl-2-methyl-5-(4-methylphenyl)-pyrazolo[1,5-
a]pyrimidine (3e): m.p. 142–145 °C; 1H NMR (200 MHz, CDCl3):
d = 2.41 (s, 3H, 4-CH3–Ar), 2.57 (s, 3H, H8), 6.60 (s, 1H, H3), 7.29
(d, 2H, Ar), 7.46 (s, 1H, H6), 7.94 (d, 2H, Ar). 13C NMR (100 MHz,
CDCl3): d = 14.7 (CH3), 21.3 (CH3), 97.4 (C3), 102.4 (q, 3J4, C6),
127.0, 129.7, 133.5, 141.3 (C–Ar), 119.6 (q, 1J274, CF3), 133.4 (q,
2J37, C7), 150.3 (C3a), 154.9 (C2), 156.7 (C5). MS (EI, 70 eV): m/z
% = 291 (M+, 100), 276 (11), 256 (13).
7-Trifluoromethyl-5-(4-fluorophenyl)-2-methylpyrazolo[1,5-
a]pyrimidine (3f): m.p. 141–144 °C; 1H NMR (200 MHz, CDCl3):
d = 2.59 (s, 3H, H8), 6.63 (s, 1H, H3), 7.21 (dd, 2H, Ar), 7.47 (s,
1H, H6), 8.09 (dd, 2H, Ar). 13C NMR (100 MHz, CDCl3): d = 14.8
(CH3), 97.8 (C3), 102.3 (q, 3J4, C6), 116.2 (d, 2J21, Ar), 119.6 (q,
1J274, CF3), 129.3 (d, 3J8, Ar), 132.6 (d, 4J3, Ar), 133.4 (q, 2J36, C7),
150.3 (C3a), 153.9 (C2), 157.1 (C5), 164.6 (d, 1J251, Ar). MS (EI,
70 eV): m/z % = 295 (M+, 100), 274 (13), 242 (6).
5-(4-Chlorophenyl)-7-trifluoromethyl-2-methylpyrazolo[1,5-
a]pyrimidine (3g): m.p. 164–166 °C; 1H NMR (200 MHz, CDCl3):
d = 2.59 (s, 3H, H8), 6.64 (s, 1H, H3), 7.47 (s, 1H, H6), 7.50 (d, 2H,
Ar), 8.03 (d, 2H, Ar). 13C NMR (100 MHz, CDCl3): d = 14.8 (CH3),
97.9 (C3), 102.2 (q, 3J4, C6), 119.5 (q, 1J273, CF3), 128.4, 129.3,
134.7, 137.2 (CAr), 134.4 (q, 2J36, C7), 150.2 (C3a), 153.6 (C2),
157.2 (C5). MS (EI, 70 eV): m/z % = 311 (M+, 100), 290 (5), 162 (7).
5-(4-Bromophenyl)-7-trifluoromethyl-2-methylpyrazolo[1,5-
a]pyrimidine (3h): m.p. 171–173 °C; 1H NMR (200 MHz, CDCl3):
d = 2.60 (s, 3H, H8), 6.66 (s, 1H, H3), 7.49 (s, 1H, H6), 7.67 (d, 2H,
Ar), 7.98 (d, 2H Ar). 13C NMR (100 MHz, CDCl3): d = 14.8 (CH3),
97.9 (C3), 102.2 (q, 3J4, C6), 119.5 (q, 1J274, CF3), 125.7, 128.6,
132.3, 135.2 (C–Ar), 133.8 (q, 2J37, C7), 150.3 (C3a), 153.7 (C2),
157.2 (C5). MS (EI, 70 eV): m/z % = 355 (M+, 100), 336 (5), 255 (12).
7-Trifluoromethyl-2-methyl-5-(naphth-2-yl)-pyrazolo[1,5-
a]pyrimidine (3i): m.p. 152–154 °C; 1H NMR (200 MHz, CDCl3):
d = 2.60 (s, 3H, H8), 6.67 (s, 1H, H3), 7.53–8.50 (m, 7H, Ph), 7.65
(s, 1H, H6). 13C NMR (100 MHz, CDCl3): d = 14.8 (CH3), 97.8 (C3),
102.7 (q, 3J4, C6), 119.7 (q, 1J274, CF3), 123.8, 126.8, 127.4, 127.6,
127.7, 128.9, 129.0, 133.1, 133.6, 134.4 (C–Ar), 133.6 (q, 2J37, C7),
150.4 (C3a), 154.8 (C2), 157.0 (C5). MS (EI, 70 eV): m/z % = 327
(M+, 100), 305 (6), 258 (1), 163 (5).
Enone 1a–j (1 mmol), 3-amino-5-methyl-1H-pyrazole
2
(1.2 mmol), and EtOH (10 mL) were placed in a 25 mL beaker.
The reaction mixtures were then sonicated by a 6 mm ultrasonic
probe with amplitude of 20%, using a programmed temperature
of 75 °C. The reaction temperature was raised 68–72 °C during
5 min of sonication. After cooling to room temperature, the EtOH
was evaporated under reduced pressure. Chloroform (5 mL) was
then added and the reaction mixture was washed with water
(3 ꢀ 5 mL). The organic phases were dried over anhydrous Na2SO4
and the solvent was evaporated under reduced pressure to furnish
the products 3a–j.
2.4. Synthesis of pyrazolo[1,5-a]pyrimidines under microwave
irradiation
Enone 1a,c,d,f,i (1 mmol), 3-amino-5-methyl-1H-pyrazole 2
(1.2 mmol), and EtOH (5 mL) were placed in a vessel (10 mL)
equipped with a standard cap (the vessel was supplied by CEM
corporation). The reaction mixtures were irradiated at 75 °C for
5 min. The data were then plotted using Synergy software (ver-
sion 3.5.9), applying an irradiation level of 200 W and internal
vessel pressure of 250 psi. Subsequently, the EtOH was evaporated
under reduced pressure. Chloroform (5 mL) was then added, and
the reaction mixture was washed with water (3 ꢀ 5 mL). The or-
ganic phases were dried over anhydrous Na2SO4 and the solvent
was evaporated under reduced pressure to furnish the products
3a,c,d,f,i.
2.5. Synthesis of pyrazolo[1,5-a]pyrimidines using conventional
thermal heating method (oil bath)
Enone 1a,c,d,f,i (1 mmol), 3-amino-5-methyl-1H-pyrazole 2
(1.2 mmol), and EtOH (5 mL) were placed in a round-bottomed
flask. The reaction mixtures were kept under magnetic stirring at
75 °C for 2 h. Subsequently, the EtOH was evaporated under re-
duced pressure. Chloroform (5 mL) was then added and the reac-
tion mixture was washed with water (3 ꢀ 5 mL). The organic
phases were dried over anhydrous Na2SO4 and the solvent was
evaporated under reduced pressure to furnish the products
3a,c,d,f,i.
7-Trifluoromethyl-2,5-dimethylpyrazolo[1,5-a]pyrimidine (3a):
Oil; 1H NMR (200 MHz, CDCl3): d = 2.55 (s, 3H, H8), 2.64 (s, 3H, H9),
6.50 (s, 1H, H3), 6.96 (s, 1H, H6). 13C NMR (100 MHz, CDCl3):
d = 14.6 (CH3), 24.7 (C9), 96.5 (C3), 105.9 (q, 3J4, C6), 119.4 (q,
1J274, CF3), 133.1 (q, 2J37, C7), 150.0 (C3a), 156.3 (C2), 157.7
(C5). MS (EI, 70 eV): m/z % = 215 (M+, 100), 187 (15), 162 (39),
146 (17).
7-Trifluoromethyl-2-methyl-5-(biphen-4-yl)pyrazolo[1,5-
a]pyrimidine (3j): m.p. 192–195 °C; 1H NMR (200 MHz, CDCl3):
d = 2.59 (s, 3H, CH3), 6.65 (s, 1H, H3), 7.39–8.18 (m, 9H, HAr),
7.55 (s, 1H, H6). 13C NMR (100 MHz, CDCl3): d = 14.8 (CH3), 97.7
(C3), 102.5 (q, 3J4, C6), 119.6 (q, 1J274, CF3), 127.1, 127.5, 127.6,
128.0, 128.9, 135.1, 139.9, 143.6 (C–Ar), 133.6 (q, 2J37, C7), 150.4
(C3a), 154.5 (C2), 157.0 (C5). MS (EI, 70 eV): m/z % = 353 (M+,
100), 332 (4), 276 (2), 176 (6).
5-Butyl-7-trifluoromethyl-2-methylpyrazolo[1,5-a]pyrimidine
(3b): Oil; 1H NMR (200 MHz, CDCl3): d = 0.97 (t, 3H, H12), 1.44
(sext, 2H, H11), 1.78 (qui, 2H, H10), 2.56 (s, 3H, H8), 2.87 (t, 2H,
H9), 6.53 (s, 1H, H3), 6.96 (s, 1H, H6). 13C NMR (100 MHz, CDCl3):

L. Buriol et al. / Ultrasonics Sonochemistry 20 (2013) 1139–1143
1141
In order to evaluate the scope and limitations of this reaction,
we extended it to other enones 1b–j. All the reactions were per-
formed in EtOH using reactants 1 with 2 at a molar ratio of 1:1.2
and employing ultrasound irradiation for 5 min at 75 °C. The pyr-
azolo[1,5-a]pyrimidines 3a–j were obtained at 61–98% yields
(Scheme 2). Products 3a–e,g,j were isolated in a pure form without
needing further purification. Product 3i was purified by recrystalli-
zation in EtOH and CHCl3 at a ratio of 1.5:1.0, respectively; and
products 3f,g were recrystallized in EtOH and DMSO at a ratio of
1.5:1.0, respectively. All products were fully characterized with
1H and 13C NMR and GC–MS and showed spectral data typical for
these compounds. For example, compound 3h presented 1H NMR
spectra with chemical shifts at 6.67 ppm that were assigned to
the pyrazole H3, a signal at 7.65 ppm that was assigned to the
pyrimidine H6, a signal at 2.60 ppm that was assigned to the CH3
and a signal at 7.53–8.50 ppm assigned to the aromatic ring. The
same compound showed 13C NMR spectra with chemical shifts at
the C3, C3a and C5 at 97.8, 150.4 and 157.0, respectively. The 13C
NMR signal of C6, C7 and CF3 group appeared at 102.7, 119.7 and
3. Results and discussion
The study of reaction conditions to furnish the pyrazolo[1,5-
a]pyrimidine 3a using ultrasound irradiation is shown in Scheme 1.
All the reactions were performed with enone 1a and 3-amino-5-
methyl-1H-pyrazole 2 at a molar ratio of 1:1.2. We had previously
developed a conventional thermal heating method using AcOH for
a similar reaction [25]. Thus, we initially performed the reaction in
AcOH as the solvent at 75 °C for 10 min under ultrasound irradia-
tion and we observed the formation of product 3a at a 62% yield
which was considered unsatisfactory. From this negative result,
we decided to use ethanol as the solvent. Generally, cycloconden-
sation reactions performed in the presence of ethanol are good and
ethanol is an environmentally friendly solvent [4]. The progression
of the reactions was monitored by CG–MS to obtain a conversion of
100% and a yield of isolated product of 82% after analysis by 1H
NMR. The reaction in ethanol resulted in the product with an excel-
lent yield. Thus, it can clearly be seen that the best condition was
achieved when using ethanol as the solvent at 75 °C for 5 min.
N
CH3
NH2
O
CH3
OCH3
i or ii
H3C
+
N
N
N
H3C
F3C
N
H
CF3
1a
i = US, AcOH, 10
= US, EtOH, 5 min (82 %)
2
3a
min (62 %)
ii
Scheme 1.
N
R
NH2
O
OCH3
R
i
H3C
+
N
N
N
H3C
F3C
N
H
CF3
3a-j
1a-j
2
i = US, EtOH, 5 min
Entry
R
Product Yield (%)a
1
2
Me
Bu
3a
3b
3c
3d
3e
3f
82
61
77
82
98
96
79
76
89
92
3
i-Bu
Ph
4
5
4-Me-C6H4
4-F-C6H4
7
8
4-Cl-C6H4
4-Br-C6H4
Naphth-2-yl
Biphen-4-yl
3g
3h
3i
9
10
11
3j
aYield of isolated product.
Scheme 2.

1142
L. Buriol et al. / Ultrasonics Sonochemistry 20 (2013) 1139–1143
Table 1
Table 2
Comparative study for synthesis of pyrazolo[1,5-a]pyrimidines 3a,c,d,f,i.
Crystal data and structural refinement for 7-trifluoromethyl-2-methyl-5-(naphth-2-
yl)-pyrazolo[1,5-a]pyrimidine (3i).
Entry
R
Product
Ultrasounda
Yield (%)d
Oil Bathb
Yield (%)d
Microwavec
Yield (%)d
CCDC No.
Formula
914143
18H12F3N3
C
1
2
3
4
5
Me
i-Bu
Ph
4-F–C6H4
Naphth-2-yl
3a
3c
3d
3f
82
77
82
96
89
87
83
52
51
73
87
84
80
81
93
Mr
327.31
296 (2)
0.71073
Monoclinic, P21/n
Temperature (K)
Wavelength (Å)
Crystal system, space group
3i
Unit cell parameters
a
b
c
a (Å)
b (Å)
c (Å)
7.8462 (5)
11.2089 (9)
16.8641 (12)
90
Conditions: ultrasound, EtOH, 5 min.
Conditions: EtOH, 75 °C, 2 h.
Conditions: MW, EtOH, 5 min.
Yield of isolated product.
d
a
(°)
b (°)
92.389 (5)
c
(°)
90
V (Å3)
1481.86 (18)
Z
4
Density (calculated) (mg/m3)
Absorption coefficient (mmꢁ1
F(000)
1.467
0.115
672
)
Crystal size (mm)
h Range for data collection (°)
0.42 ꢀ 0.08 ꢀ 0.08
2.18–30.08
Limiting indices
ꢁ10 6 h 6 10, ꢁ15 6 k 6 15,
ꢁ23 6 l 6 23
Reflections collected/unique
Completeness to h = 30.08 (%)
Absorption correction
23,457/4299 [R(int) = 0.0735]
98.8
Gaussian
Max. and min. transmission
Refinement method
0.9908 and 0.9531
Full-matrix least-square on F2
4299/0/217
Data/restraints/parameters
Goodness-of-fit on F2
0.954
Final R indices [I > 2d(I)]
R indices (all data)
R1 = 0.0535, wR2 = 0.1099
R1 = 0.1910, wR2 = 0.1521
None
0.200 and ꢁ0.161
Extinction coefficient
Largest diff. peak and hole (e Aꢁ3
)
Fig. 1. Structure [34] of 7-trifluoromethyl-2-methyl-5-(naphth-2-yl)-pyrazolo[1,5-
a]pyrimidine (3i).
The ultrasound effect in this reaction probably is physics
[30,31], in other words, the ultrasonic cavitation process, which
is formation, growth, and collapse of microscale bubbles in a liquid
solution increase the local temperatures and pressures inside the
cavities (‘hot spots’) [30,31]. In the process, ultrasonic irradiation
accelerates the formation of the stable colloidal particles, thus it
can shorten the reaction time. The formation of any chemical spe-
cie able to accelerate the reaction during ultrasound irradiation
was not monitored in this reaction. Thus, is not possible affirm that
chemical effects is occurring [30,31].
The mechanism proposed for the formation of the compounds
of 3 was described in previous work [25,32]. It initially involves
a C–N bond formation from the attack of the nitrogen atom of
the NH2 group on the b-carbon of enone 1, with subsequent sub-
stitution of the alkoxy group to furnish the enamino ketone
intermediates. Subsequently, there was an intramolecular nucle-
ophilic addition of the pyrazole ring nitrogen atom to the car-
bonyl carbon of enone 1, with subsequent elimination of one
molecule of water. The X-ray structure of compound 3i (Fig. 1)
confirms the structure proposed. The crystal data and details
concerning data collection and structural refinement are given
in Table 2 [33].
133.6 ppm as a quartet with J = 4, 274 and 37 Hz respectively, be-
cause of a 13C–19F scalar coupling.
The synthesis of pyrazolo[1,5-a]pyrimidines shown here is very
important, because the synthesis and spectral data of these com-
pounds are not well represented in the literature. Only the synthe-
sis of compounds 3d,e,h has been described [29].
Additionally, to highlight even more the importance of ultra-
sound for promoting pyrazolo[1,5-a]pyrimidine synthesis, the
reaction of enones 1a,c,d,f,i (1.0 equivalent) with 3-amine-5-
methyl-1H-pyrazole 2 (1.2 equivalent) was performed under con-
ventional thermal heating (oil bath) in EtOH at 75 °C for 2 h. The
products were obtained at 51–87% yields (Table 1). These yields
are similar to or lower than those obtained under ultrasonic irradi-
ation. For the enones 1d,f,i, which have Ph, 4-F–C6H4 and naphth-
2-yl attached, the yields were higher when using ultrasound
irradiation. Moreover, the reaction time using ultrasound irradia-
tion was shorter and yields were better than for conventional ther-
mal heating (oil bath).
The reaction of enones 1a,c,d,f,i (1.0 equivalent) with 3-amine-
5-methyl-1H-pyrazole 2 (1.2 equivalent) was also performed un-
der microwave irradiation, using EtOH as the solvent at 75 °C for
5 min, resulting in the products at 80–93% yield (Table 1). The
yields are similar to those obtained under ultrasonic irradiation.
From these results it can be seen that there was no appreciable in-
crease in yield; the effect of microwaves on the synthesis of pyraz-
olo[1,5-a]pyrimidines is as efficient as ultrasound, and both are
better than the conventional thermal heating (oil bath). Thus, the
ultrasonic irradiation method offers advantages including
faster reaction rates and satisfactory yields for obtaining pyrazol-
o[1,5-a]pyrimidines. Accordingly, these results demonstrate that
alternative energies are favorable for the synthesis of these triflu-
oromethylated compounds.
4. Conclusion
In summary, we have developed an effective methodology for
the synthesis of pyrazolo[1,5-a]pyrimidines under ultrasound irra-
diation. The methodology has several advantages which make it
highly attractive, for example, it is a simple procedure, it has an
easy work-up, mild conditions, short reaction times (5 min) and
produces excellent yields (61–98%). Furthermore, this series may
provide new classes of biologically active compounds.

L. Buriol et al. / Ultrasonics Sonochemistry 20 (2013) 1139–1143
1143
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Acknowledgements
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The authors are grateful for the financial support of the National
Council for Scientific and Technological Development (CNPq/Uni-
versal Process No. 578426/2008-0 and 471519/2009-0); the Foun-
dation for Research Support of the State of Rio Grande do Sul
(FAPERGS/CNPq-PRONEX Edital No. 008/2009 and Process No. 10/
0037-8); and the Coordination for Improvement of Higher Educa-
tion Personnel (CAPES/PROEX). The fellowships from CNPq
(M.A.P.M., T.S.M., M.R.B.M., N.Z., H.G.B.) and CAPES (C.P.F., L.B.)
are also acknowledged.
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