Ultrasound irradiation promotes the synthesis of new 1,2,4-triazolo[1,5-a] pyrimidine

Article abstract of DOI:10.1016/j.ultsonch.2013.12.007

Ultrasonic irradiation was used in the synthesis of a series of novel 1,2,4-triazolo[1,5-a]pyrimidines. The products were synthetized from the cyclocondensation reaction of 1,1,1-trifluoro-4-metoxy-3-alken-2-one [CF ₃C(O)CHC(R)OMe, where R = Ph, 4-F-C₆H₄, 4-Br-C₆H₄, 4-I-C₆H₄, 4-CH ₃-C₆H₄, 4-CH₃O-C₆H ₄, Thien-2-yl, Biphen-4-yl] or β-enaminones [RC(O)CHCHNMe ₂, where R = Ph, 4-F-C₆H_4, 4-Br-C ₆H_4, 4-I-C₆H_4, 4-CH ₃-C₆H₄, 4-CH₃O-C₆H ₄, 4-NO₂-C₆H₄, Thien-2-yl, Biphen-4-yl, Naphth-2-yl, Pyrrol-2-yl, CCl₃] with 5-amino-1,2,4-triazole in acetic acid at 99 C with 5-17 min of ultrasound irradiation. This methodology has shown several advantages, such as shorter reaction times, mild conditions, high regioselectivity, and excellent yields, when compared with conventional thermal heating (oil bath).

Full text of DOI:10.1016/j.ultsonch.2013.12.007

Ultrasonics Sonochemistry 21 (2014) 958–962
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultson
Ultrasound irradiation promotes the synthesis of new 1,2,4-triazolo
[1,5-a]pyrimidine
Clarissa P. Frizzo, Elisandra Scapin, Mara R.B. Marzari, Taiana S. München, Nilo Zanatta,
⇑
⇑
Helio G. Bonacorso, Lilian Buriol , Marcos A.P. Martins
Núcleo de Química de Heterociclos, Departamento de Química, Universidade Federal de 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:
Received 15 June 2013
Received in revised form 28 November 2013
Accepted 11 December 2013
Available online 21 December 2013
Ultrasonic irradiation was used in the synthesis of a series of novel 1,2,4-triazolo[1,5-a]pyrimidines. The
products were synthetized from the cyclocondensation reaction of 1,1,1-trifluoro-4-metoxy-3-alken-2-
one [CF3C(O)CH@C(R)OMe, where R = Ph, 4-F-C6H4, 4-Br-C6H4, 4-I-C6H4, 4-CH3-C6H4, 4-CH3O-C6H4,
Thien-2-yl, Biphen-4-yl] or b-enaminones [RC(O)CH@CHNMe2, where R = Ph, 4-F-C6H4, 4-Br-C6H4, 4-I-
C6H4, 4-CH3-C6H4, 4-CH3O-C6H4, 4-NO2-C6H4, Thien-2-yl, Biphen-4-yl, Naphth-2-yl, Pyrrol-2-yl, CCl3]
with 5-amino-1,2,4-triazole in acetic acid at 99 °C with 5–17 min of ultrasound irradiation. This method-
ology has shown several advantages, such as shorter reaction times, mild conditions, high regioselectiv-
ity, and excellent yields, when compared with conventional thermal heating (oil bath).
Ó 2013 Elsevier B.V. All rights reserved.
Keywords:
Ultrasound
1,2,4-Triazolo[1,5-a]pyrimidine
Enaminones
Trifluoromethyl enones
1. Introduction
hydrophobicity, acidity/basicity, reactivity, as well as the confor-
mation of compounds where fluorine atoms or the trifluoromethyl
Triazolo [1,5-a]pyrimidine derivatives have attracted a lot of
attention in the medical field due to their broad-spectrum biolog-
ical activities as cardiovascular vasodilators [1] and human A2a
adenosine and A3 receptor ligands [2]. Additionally, substituted
triazolopyrimidine-2-sulfonamides, such as flumetsulam [3], flo-
rasulam [4], and metosulam [5], have shown excellent herbicidal
and plant growth regulation [6]. Consequently, various derivatives
of 1,2,4-triazolo[1,5-a]pyrimidine have found applications in
pharmaceutics, agriculture, and other areas [7]. The synthesis of
triazolopyridines from the heterocyclization of aminotriazole and
1,3-dieletrophiles such as enaminones, chalcones, dicarbonyl and
substituted vinyl ketones is conventionally performed in the reflux
of acetic acid, acetonitrile, ethanol, or pyridine/HCl; however, sig-
nificant variations in yields and reaction times limit the choice of
substrates that can be utilized. The synthesis of trifluoromethylat-
ed triazolo[1,5-a]pyrimidine from trifluoromethylated substrates
is limited [8]. The incorporation of fluorine into a drug allows
simultaneous modulation of electronic, lipophilic and steric
parameters, all of which can critically influence both the pharma-
codynamic and pharmacokinetic properties of drugs. The small
size, very low polarizability, and the strong inductive effect are
responsible for biophysical and chemical properties such as
group is present [9].
Additionally, the development in the last few years of synthetic
protocols employing ultrasound irradiation has led to an important
change in organic reactions and has permitted the activation of
poorly reactive substrates [10]. Notable features of the ultrasonic
irradiation method include enhanced reaction rates, the formation
of purer products at high yields, easier manipulation, and im-
proved energy conservation, when compared with the conven-
tional thermal heating method (oil bath) [11]. These
characteristics for using ultrasound irradiation are demonstrated
in the synthesis of various heterocycles described in the literature
[12]. Our research group has published about the synthesis of azol-
opyrimidines, both under ultrasound irradiation and with the con-
ventional method. The results showed that the use of ultrasound
furnishes shorter reaction times than the microwave method and
higher yields [13,14].
Over the past 20 years, our research group has been studying
the synthesis of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones and their
effectiveness in heterocyclic preparations [15]. During this time
we have supported the importance of these halogen-containing
building blocks in heterocyclic synthesis and more recently we
have been focusing our attention on minimizing waste generation,
reducing reaction time, and improving yields, by using ionic liquid
[16], solvent-free solutions [17], microwave [16d,e,18], and ultra-
sound irradiation [8a,13] to promote the reactions. Therefore, in
the continuation of our work, and considering the importance of
⇑
Corresponding authors. Tel.: +55 5532208756.
E-mail addresses: liburiol@yahoo.com.br (L. Buriol), 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.2013.12.007

C.P. Frizzo et al. / Ultrasonics Sonochemistry 21 (2014) 958–962
959
Table 2
triazolo[1,5-a]pyrimidine and the restrictions to its synthesis, we
Synthesis of compounds 3a-h.
will describe an efficient and mild approach to the synthesis of reg-
iospecific 1,2,4-triazolo[1,5-a]pyrimidines under ultrasonic irradi-
ation and compare the results with those from conventional
thermal heating.
N
R
N
N
NH2
NH
O
OMe
R
i or ii
N
+
N
F3C
N
CF3
2. Results and Discussion
1a-h
2
We started our investigation by examining the cyclocondensa-
tion reaction of 1,1,1-trifluoro-4-methoxy-4-phenyl-3-alken-2-
one (1a) with aminotriazole (2), under ultrasound irradiation.
The ultrasound amplitude was established based on the relation
between temperature reached by theses solvents during 5 min of
irradiation. Solvents such as AcOH, EtOH, and CH3CN reached the
highest temperature when an amplitude of 20% was tested to opti-
mize the reaction. According to Table 1, the reactions in AcOH lead
to products that have higher yields than for other solvents. Thus,
the best reaction condition for obtaining compound 3a was when
AcOH was used as the solvent at 99 °C for 5 min.
i: AcOH, reflux, 6 h
ii: US, AcoH, 5-15 min, 99ºC
Entry
R
Product
Yield (%)a
Oil Bath
Ultrasound
1
2
3
4
5
6
7
8
Ph
3a
3b
3c
3d
3e
3f
94
84
97
85
91
88
95
97
84
82
81
87
80
78
60
84
4-F-C6H4
4-Br-C6H4
4-I-C6H4
4-CH3-C6H4
4-CH3O-C6H4
Thien-2-yl
Biphen-4-yl
3g
3h
The optimization reaction was used as a model for the synthesis
of novel 1,2,4-triazolo[1,5-a]pyrimidines 3b–h and the products
were obtained at a yield of between 78% and 97%. The reactions
were also performed using the conventional method (oil bath),
based on the literature [14,19]. Thus, the mixture of 1,1,1-tri-
fluoro-4-methoxy-3-alken-2-ones 1a–h with aminotriazole 2 in
AcOH was refluxed for 6 h to obtain compounds 3a–h at yields
of between 70% and 97%. The results are shown in the Table 2.
These results prove the efficiency of ultrasonic irradiation for this
reaction and the value of synthesizing 7-trifluoromethyltriazol-
o[1,5-a]pyrimidines. It is important to highlight that 1,2,4-triazol-
o[1,5-a]pyrimidines 3b–h are novel compounds – their synthesis
and spectral properties are described here for the first time. Only
compound 3a has been previously described using 2-ethoxyvinyl
trifluoromethyl ketones and 2,2-diethoxyvinyl trifluoromethyl ke-
tone with 3-amino-1,2,4-triazole and conventional thermal heat-
ing [8b].
Continuing with our work, we also evaluated the synthesis of
7-aryl-1,2,4-triazolo[1,5-a]pyrimidine from the cyclocondensation
reaction of b-enaminone 4a with aminotriazole 2 under ultrasound
irradiation. The solvents and conditions tested were the same as
those tested in the reaction with 1,1,1-trifluoro-4-metoxy-3-al-
ken-2-ones. According to Table 3, the best condition for total
conversion of the reactants into 7-aryl-1,2,4-triazolo[1,5-a]pyrim-
idine 5a was by heating AcOH at 99 °C for 17 min, using 20%
amplitude.
a
Yield of isolated product.
Table 3
Optimization reaction for compound 5a.
N
N
N
N
O
NH2
NH
i
Me
N
+
N
Me
N
4a
2
5a
i: US
Entry
Solvent
Time (min)
Temperature (°C)
yield (%)a
1
2
3
4
5
6
AcOH
AcOH
AcOH
AcOH
EtOH
EtOH
5
10
15
17
5
99
99
99
99
75
75
55
72
76
93
5
15
15
a
Yield of isolated product.
Table 4
Synthesis of compounds 5a-l.
N
O
N
N
NH2
NH
i or ii
Subsequently, we investigated the scope of this reaction by
extending the synthesis to other 1,2,4-triazolo[1,5-a]pyrimidines,
Me
N
+
N
R
N
Me
N
R
Table 1
Optimization reactions for obtaining compound 3a.
4a-l
2
5a-l
N
Ph
N
N
NH2
NH
i: AcOH, reflux, 16 h.
ii: AcOH, 99ºC, 17 min.
O
OMe
Ph
i
N
+
N
R
Product
Yield (%)a
F3C
N
Oil Bath
Ultrasound
CF3
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
94
89
89
85
91
90
82
89
96
90
85
83
93
76
83
90
96
96
82
91
94
76
74
79
1a
2
3a
4-F-C6H4
4-Br-C6H4
4-I-C6H4
i: US
4-CH3-C6H4
4-OCH3-C6H4
4-NO2-C6H4
Biphen-4-yl
Naphth-2-yl
Thien-2-yl
Pirrol-2-yl
CCl3
Entry
Solvent
Time (min)
Temperature (°C)
Yielda (%)
1
2
3
4
5
6
CH3CN
CH3CN
EtOH
AcOH
AcOH
AcOH
5
10
5
5
10
10
81
81
78
99
99
99
0
7
0
84
66
52
5j
5k
5l
a
a
Yield of isolated product.
Yield of isolated product.

960
C.P. Frizzo et al. / Ultrasonics Sonochemistry 21 (2014) 958–962
Table 5
using the condition aforementioned. The 7-aryl-1,2,4-triazolo[1,5-a]
pyrimidines 5b–l were obtained at yields of between 65% and 96%
(Table 4). To prove the effect of the ultrasound irradiation for this
reaction, they were also synthesized using the conventional meth-
od (oil bath) [14]. Thus, the mixture of b-enaminone (4a–l) and
aminotriazole 2 in AcOH was stirred under reflux for 16 h to
furnish the compounds 5a–l at yields of between 73% and 96%
(Table 4). It is worth noting that compounds 5e, 5i and 5j are
described here for the first time. Compounds 5a–d,f–h have
previously been described using salt vinyloqous iminium salts
[20], and compounds 5k,l have been described using N,N-dimeth-
ylformamide dimethyl acetal instead of enaminones [21].
Crystal data and structure refinement of 7-Phenyl-1,2,4-triazolo[1,5-a]pyrimidine
(5a).
CCDC No.
941736
C11H8N4
196.21
293(2)
0.71073
Orthorhombic, p212121
Formula
Mr
Temperature (K)
Wavelength (Å)
Crystal system, space group
Unit cell parameters
a (Å)
7.2004(4)
10.3021(6)
12.7074(7)
90
b (Å)
c (Å)
a
(°)
The ultrasonic cavitation process provokes higher energy by
formation, growth, and collapse of several million microscopic va-
por bubbles (voids) in the liquid [22]. This cavitationally induced
phenomenon is known to activate reactant molecules entering into
cavity and consequently converts them into reactive intermedi-
ates. In the reactions studied in this paper, the effects of ultrasonic
irradiation are probably physical. The higher temperature and the
formation of the stable colloidal particles enable it to shorten the
reaction time. The formation of chemical species that are able to
accelerate the reaction is possible; however, the formation of inter-
mediates was not monitored. Thus, it is not possible to affirm that
chemical effects are occurring [22].
The structures of compounds 3a–h and 5b–l were determined
using 1H and 13C NMR spectroscopy and mass spectrometry. The
compounds exhibited chemical shifts of protons (1H NMR spectra)
that are typical for these type of compounds. For example, we can
cite compound 3c – the chemical shift of H6 was 8.65 ppm and for
H2 it was 7.88 ppm. The same compound showed 13C NMR spectra
with chemical shifts at the C5 and C2 of 160.7 and 157.4 ppm,
respectively. Additionally, signals of the C6, C7, and CF3 groups ap-
peared at 105.1, 135.9 and 118.7 ppm as a quartet with 3J4, 2J39
and 1J274 Hz, respectively, due to a 13CA19F scalar coupling. An-
other example analyzed was the compound 5a which presented
chemical shifts at 7.25 ppm for the H6, a signal at 8.56 ppm for
the H2, and a signal at 8.88 ppm for the H5.
b (°)
90
90
942.63(9)
4
1.383
0.089
408
c
(°)
V (Å3)
Z
Density (calculated) (mg/m3)
Absorption coefficient (mm-1
F (000)
)
Crystal size (mm)
h Range for data collection (°)
Limiting indices
Reflections collected / unique
Completeness to h = 30.08 (%)
Absorption correction
Max. and min. transmission
Refinement method
0.35 x 0.21 x 0.19
2.55 to 27.92
-10 6 h 6 10, -15 6 k 6 15, -23 6 l 6 23
8529 / 2264 [R(int) = 0.0226]
98.8
Gaussian
0.9833 and 0.9695
Full-matrix least-square on F2
2264 / 0 / 136
Data / restraints / parameters
Goodness-of-fit on F2
1.031
Final R indices [I > 2d(I)]
R indices (all data)
R
R
1 = 0.0401, wR2 = 0.0983
1 = 0.0623, wR2 = 0.1124
Largest diff. peak and hole (e A-3
)
0.106 and -0.161
3. Experimental
3.1. Materials
The reagents and solvents used were obtained from commercial
suppliers without further purification. The reactions in ultrasound
were done with a tapered microtip probe (6 mm) connected to a
Sonics Vibra-Cell™ (500 W) ultrasonic processor equipped with
an integrated temperature control probe. The device operates at
20 kHz of frequency and the amplitude was set to 20% of the max-
imum power output. The equipment can operate at a maximum
temperature of 99 °C. 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. Chemical shifts (d) are given in
ppm. Mass spectra were registered in a HP 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 cap-
illary column (30 m, 0.32 mm i.d.), and helium was used as the car-
rier gas. The melting points were measured using a Microquímica
MQAPF 301.
This information corresponds with the proposed structure that
was confirmed by X-ray diffraction for compound 5a, as shown in
Fig. 1. The crystal data and details about data collection and struc-
tural refinement are given in Table 5 [23].
3.2. Synthesis of 1,1,1-trifluoro-4-methoxy-4-phenyl-3-alken-2-one
1,1,1-Trifluoro-4-methoxy-4-phenyl-3-alken-2-one 1a–h were
obtained from the acylation reaction of enol ether or acetal with
trifluoroacetic anhydride, in accordance with the methodology
developed in our laboratory [15b,c].
3.3. Synthesis of b-enaminones
b-Enaminones 4a–l were prepared from the reaction of N,N-
dimethylformamide dimethylacetal with methyl ketones, in accor-
dance with the methodology developed in our laboratory [15a].
Fig. 1. ORTEP of 7-Phenyl-1,2,4-triazolo[1,5-a]pyrimidine 5a.

C.P. Frizzo et al. / Ultrasonics Sonochemistry 21 (2014) 958–962
961
3.4. General procedure for the preparation of 1,2,4-triazolo[1,5-a]
pyrimidines 3a–h and 5a–l under ultrasonic irradiation
d = 3.91 (s, 3H, OCH3), 7.07 (d, 2H, H-Ar), 7.83 (s, 1H, H2), 8.22 (d,
2H, H-Ar), 8.58 (s, 1H, H6). 13C NMR (100 MHz, CDCl3): d = 55.5
(OCH3), 105.0 (q, 3J4, C6), 114.7 (C3a), 118.7 (q, 1J275, CF3), 127.4,
129.7, 156.2, 156.9 (C-Ar), 135.5 (q, 2J39, C7), 161.3 (C2), 163.3
(C5). MS (EI, 70 eV): m/z % = 294 (M+, 100), 251 (14), 224 (5).
7-Trifluoromethyl-5-(thien-2-yl)-1,2,4-triazolo[1,5-a]pyrim-
idine (3g): mp 133 °C–135 °C; 1H NMR (200 MHz, CDCl3): d = 7.21
(t, 3J4, 1H, thien-2-yl), 7.25 (d, 3J5, 1H, thien-2-yl), 7.72 (s, 1H, H2),
7.92 (d, 3J3, 1H, thien-2-yl), 8.57 (s, 1H, H6). 13C NMR (100 MHz,
CDCl3): d = 104.8 (q, 3J2, C6), 118.7 (q, 1J275, CF3), 128.9, 130.3,
134.2, 140.9 (C-thien-2-yl), 135.5 (q, 2J38, C7), 155.9 (C3a), 156.6
(C2), 157.1 (C5). MS (EI, 70 eV): m/z % = 270 (M+, 100), 167 (6),
91 (8).
5-(Biphen-4-yl)-7-trifluoromethyl-1,2,4-triazolo[1,5-a]pyrim-
idine (3h): mp: 185 °C–187 °C; 1H NMR (200 MHz, CDCl3):
d = 7.52–7.41 (m, 3H, H-Ar), 7.68–7.65 (m, 2H, H-Ar), 7.79 (d, 2H,
H-Ar), 7.93 (s, 1H, H2), 8.31 (d, 2H, H-Ar), 8.63 (s, 1H, H6). 13C
NMR (100 MHz, CDCl3): d = 106.6 (q, 3J2, C6), 118.8 (q, 1J275,
CF3), 126.6, 127, 128, 128.5, 128.7, 138.5, 143.3 (C-Ar), 133.9 (q,
2J38, C7), 155.5 (C3a), 156.3 (C2), 160.7 (C5). MS (EI, 70 eV): m/z
% = 340 (M+, 100), 263 (1), 69 (1).
A mixture of the 3-amino-1,2,4-triazole 2 (1.0 mmol) and the
precursor 1,3-dieletrophilic 1 or 4 (1.0 mmol) in AcOH (5 mL)
was placed in a 10 mL vessel. The reaction mixtures were then son-
icated by an ultrasonic probe of 6 mm and amplitude of 20%, at a
programmed temperature of between 75 °C and 99 °C, for
5–17 min. After the reaction time, the solvent was removed under
reduced pressure. Chloroform (10 mL) was added and the resulting
mixture was washed with distilled water (3 Â 10 mL), dried on so-
dium sulfate (Na2SO4), and the solvent was then removed under
reduced pressure. The products 3a–h and 5a–l were recrystallized
from hexane and obtained in their pure form.
3.5. General procedure for the preparation of 1,2,4-triazolo[1,
5-a]pyrimidines 3a–h and 5a–l using conventional thermal heating
method (oil bath)
A mixture of the 3-amino-1,2,4-triazole 2 (1.0 mmol) and the
precursor 1,3-dieletrophilic 1 or 4 (1.0 mmol) in AcOH (5 mL) were
placed in a round-bottomed flask and magnetically stirred for 16 h
under reflux. After the reaction time, the solvent was removed in a
rotary evaporator. Chloroform (10 mL) was added, and the result-
ing mixture was washed with distilled water (3 Â 10 mL), dried
on sodium sulfate (Na2SO4), and the solvent was then removed un-
der reduced pressure. The products 3a–h and 5a–l were recrystal-
lized from hexane and obtained in their pure form.
7-Phenyl-1,2,4-triazolo[1,5-a]pyrimidine (5a): mp 128 °C–
132 °C; 1H NMR (200 MHz, CDCl3): d = 7.25 (d, 3J4, 1H, H5), 7.61–
7.64 (m, 3H, H-Ar), 8.08–8.13 (m, 2H, H-Ar), 8.56 (s, 1H, H2),
8.88 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 109.0 (C6),
128.9, 129.2, 129.6, 131.9 (C-Ar), 148.3 (C7), 154.3 (C5), 155.8
(C3a), 156.3 (C2). MS (EI, 70 eV): m/z % = 196 (M+, 100), 77 (10),
140 (4), 168 (10).
7-Trifluoromethyl-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine
(3a): mp 144 °C–146 °C; 1H NMR (200 MHz, CDCl3): d = 7.60–7.59
(m, 3H, H-Ar), 7.92 (s, 1H, H2), 8.26–8.21 (m, 2H, H-Ar), 8.63 (s,
1H, H6). 13C NMR (100 MHz, CDCl3): d = 108.7 (q, 3J2, C6), 120.0
(q, 1J275, CF3), 127.5, 128.8, 132.3, 134.0 (C-Ar), 156.6 (q, 2J35,
C7), 161.9 (C3a), 168.3 (C5). MS (EI, 70 eV): m/z % = 264 (M+,
100), 195 (8), 77 (10).
7-Trifluoromethyl-5-(4-fluorophenyl)-1,2,4-triazolo[1,5-a]pyrim
idine (3b): mp 135 °C–139 °C; 1H NMR (200 MHz, CDCl3): d = 7.27
(dd, 2H, 3J8, 3J9, H-Ar), 7.87 (s, 1H, H2), 8.27 (dd, 2H, 3J8, 3J9, H-Ar),
8.63 (s, 1H, H6). 13C NMR (100 MHz, CDCl3): d = 105.2 (q, 3J4, C6),
116.5 (d, 2J22, C-Ar), 118.7 (q, 1J275, CF3), 130.2 (d, 3J9, C-Ar),
131.2 (d, 4J3, Ar), 135.7 (q, 2J39, C7), 156.1 (C3a), 157.3 (C2),
160.6 (C5), 165.4 (d, 1J255, Ar). MS (EI, 70 eV): m/z % = 282 (M+,
100), 263 (6), 213 (7), 133 (6).
7-(4-Fluorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine (5b): mp
233 °C–236 °C; 1H NMR (200 MHz, CDCl3): d = 7.23 (d, 3J4, 1H,
H6), 7.27–7.36 (m, 2H, H-Ar), 8.17 (dd, 3J9, 3J5, 2H, H-Ar), 8.57 (s,
1H, H2), 8.89 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3):
d = 108.8 (q, 3J3, C6), 116.3 (d, 2J22, C-Ar), 118.8 (q, 1J275, CF3),
130.2 (d, 3J9, C-Ar),131.2 (d, 3J3, C-Ar), 135.7 (q, 2J39, C7), 156.1
(C5), 157.3 (C3a), 160.6 (C2), 165.4 (d, 1J254, C-Ar). MS (EI,
70 eV): m/z % = 214 (M+, 100), 95 (5), 120 (4), 186 (5).
7-(4-Bromophenyl)-1,2,4-triazolo[1,5-a]pyrimidine (5c): mp
217 °C–220 °C; 1H NMR (200 MHz, CDCl3): d = 7.27 (d, 3J3, 1H,
H6), 7.76 (d, 2H, H-Ar), 8.03 (d, 2H, H-Ar), 8.57 (s, 1H, H2), 8.89
(d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 108.8 (C6), 126.8,
128.4, 130.7, 132.3 (C-Ar), 147.2 (C7), 154.3 (C5), 155.9 (C3a),
156.3 (C2). MS (EI, 70 eV): m/z % = 276 (M+2, 98), 274 (M+, 100),
195 (20).
5-(4-Bromophenyl)-7-trifluoromethyl-1,2,4-triazolo[1,5-a]pyrim
idine (3c): mp 173 °C–175 °C; 1H NMR (200 MHz, CDCl3): d = 8.65
(s, 1H, H6), 8.13 (d, 2H, H-Ar), 7.88 (s, 1H, H2), 7.73 (d, 2H, H-
Ar). 13C NMR (100 MHz, CDCl3): d = 105.1 (q, 3J4, C6), 118.7 (q,
1J274, CF3), 127.5, 129.3, 132.6. 133.8 (C-Ar), 135.9 (q, 2J39, C7),
156.1 (C3a), 157.4 (C2), 160.7 (C5). MS (EI, 70 eV): m/z % = 344
(M+2, 98), 342 (M+, 100), 263 (14), 193 (3).
7-(4-Iodophenyl)-1,2,4-triazolo[1,5-a]pyrimidine (5d): mp
210 °C–215 °C; 1H NMR (200 MHz, CDCl3): d = 7.23 (d, 3J4, 1H,
H6), 7.86 (d, 3J8, 2H, H-Ar), 7.96 (d, 3J8, 2H, H-Ar), 8.55 (s, 1H,
H2), 8.87 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 99.1 (C-
Ar), 108.7 (C6), 129.0, 130.6, 138.2 (C-Ar), 147.3 (C7), 154.3 (C5),
155.9 (C3a), 156.2(C2). MS (EI, 70 eV): m/z % = 322 (M+, 100), 195
(12), 113 (6).
7-Trifluoromethyl-5-(4-iodophenyl)-1,2,4-triazolo[1,5-a]pyrimi-
dine (3d): mp 178 °C–179 °C; 1H NMR (200 MHz, CDCl3): d = 7.86
(s, 1H, H2), 7.95 (m, 4H, H-Ar), 8.63 (s, 1H, H6). 13C NMR
(100 MHz, CDCl3): d = 105.0 (q, 3J4, C6), 118.7 (q, 1J273, CF3),
128.7, 129.1, 134.3, 138.6 (C-Ar), 135.7 (q, 2J38, C7), 156.0 (C3a),
157.4 (C2), 160.8 (C5). MS (EI, 70 eV): m/z % = 389.9 (M+, 100),
263 (17).
7-(4-Methylphenyl)-1,2,4-triazolo[1,5-a]pyrimidine (5e): mp
183 °C–186 °C; 1H NMR (200 MHz, CDCl3): d = 2.49 (s, 1H, CH3),
7.23 (d, 3J4, 1H, H6), 7.42 (d, 3J8, 2H, Ar), 8.05 (d, J8, 2H, Ar), 8.58
(s, 1H, H2), 8.86 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3):
d = 21.4 (CH3), 108.5 (C6), 126.8, 129.2, 129.5, 142.6 (C-Ar), 148.4
(C7), 154.1 (C5), 155.7 (C3a), 156.3 (C2). MS (EI, 70 eV): m/z
% = 210 (M+, 100), 186 (16), 115(14).
7-Trifluoromethyl-5-(4-methylphenyl)-1,2,4-triazolo[1,5-a]pyrim-
idine (3e): mp 157 °C–158 °C; 1H NMR (200 MHz, CDCl3): d = 2.47
(s, 3H, CH3), 7.38 (d, 2H, H-Ar), 7.88 (s, 1H, H2), 8.15 (d, 2H, H-H-
Ar), 8.61 (s, 1H, H6). 13C NMR (100 MHz, CDCl3): d = 21.4 (CH3),
105.2 (q, 3J4, C6), 118.9 (q, 1J275, CF3), 127.8, 130.0, 132.3, 143.3
(C-Ar), 135.5 (q, 2J38, C7), 156.2 (C3a), 157,1 (C2), 161.8 (C5). MS
(EI, 70 eV): m/z % = 278 (M+, 100), 250 (14), 167 (15), 91 (13).
7-Trifluoromethyl-5-(4-metoxyphenyl)-1,2,4-triazolo[1,
7-(4-Methoxyphenyl)-1,2,4-triazolo[1,5-a]pyrimidine (5f): mp
183 °C–186 °C; 1H NMR (200 MHz, CDCl3): d = 3.89 (s, 1H, CH3),
7.07 (d, 3J9, 2H, H-Ar), 7.9 (d, 3J4, 1H, H6), 8.13 (d, 3J9, 2H, H-Ar),
8.54 (s, 1H, H2), 8.81 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3):
d = 55.5 (CH3), 107.9 (C6), 114.3, 121.6, 131.1, 147.9 (C-Ar), 154.0
(C7), 155.5 (C5), 156.3 (C3a), 162.5 (C2). MS (EI, 70 eV): m/z
% = 226 (M+, 100), 195 (6).
7-(4-Nitrophenyl)-1,2,4-triazolo[1,5-a]pyrimidine (5g): mp
5-a]pyrimidine (3f): mp 159 °C–161 °C; 1H NMR (200 MHz, CDCl3):
241 °C–246 °C; 1H NMR (200 MHz, CDCl3): d = 7.70 (d, 3J4, 1H,

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C.P. Frizzo et al. / Ultrasonics Sonochemistry 21 (2014) 958–962
H6), 8.44 (s, 4H, H-Ar), 8.72 (s, 1H, H2), 9.00 (d, 3J4, 1H, H5). 13C
NMR (100 MHz, CDCl3): d = 110.4 (C6), 123.4, 130.6, 130.8, 135.3
(C-Ar), 144.9 (C7), 148.7 (C5), 155.0 (C3a), 155.4 (C2). MS (EI,
70 eV): m/z % = 241 (M+, 100), 195 (25), 113(26).
7-(Biphen-4-yl)-1,2,4-triazolo[1,5-a]pyrimidine (5h): mp 193 °C
–195 °C; 1H NMR (200 MHz, CDCl3): d = 7.30 (d, 3J4, 1H, H6), 7.50
(m, 3H, H-Ar), 7.70 (d, 3J7, 2H, H-Ar), 7.85 (d, 3J8, 2H, H-Ar), 8.23
(d, 3J8, 2H, H-Ar), 8.60 (s, 1H, H2), 8.91(d, 3J4, 1H, H5). 13C NMR
(100 MHz, CDCl3): d = 108.8 (C6), 127.1, 127.2, 128.1, 128.9,
129.7 (C-Ar), 139.5 (C7), 144.7, 147.9 (C-Ar), 154.3 (C2), 155.7
(C3a), 156.0 (C5). MS (EI, 70 eV): m/z % = 272 (M+, 100), 245 (7),
152 (7).
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7-(Naphth-2-yl)-1,2,4-triazolo[1,5-a]pyrimidine (5i): mp 145 °C
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7.69 (m, 2H, H-Ar), 7.92–8.10 (m, 4H, H-Ar), 8.61 (s, 1H, H2), 8.74
(s, 1H, H-Ar), 8.91 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3):
d = 109.0 (C6), 124.9, 126.7, 127.0, 127.6, 128.3, 128.5, 129.0,
130.5, 132.6, 134.5 (C-Ar), 148.0 (C7), 154.1 (C5), 155.7 (C3a),
156.3 (C2). MS (EI, 70 eV): m/z % = 246 (M+, 100), 127 (5).
7-(Thien-2-yl)-1,2,4-triazolo[1,5-a]pyrimidine (5j): mp 172 °C–
174 °C; 1H NMR (200 MHz, CDCl3): d = 7.33 (m, 1H, H-Ar), 7.47 (d,
3J4, 1H, H6), 7.82 (d, 3J5, 1H, H-Ar), 8.46 (d, 3J3, 1H, H-Ar), 8.63 (s,
1H, H2), 8.81 (d, 3J4, 1H, H5). 13C NMR (100 MHz, CDCl3): d = 105.6
(C6), 128.4, 130.4 (C-Ar), 132.8 (C7), 133.5 (C-Ar), 141.7 (C5), 153.6
(C3a), 155.5 (C-Ar), 156 (C2). MS (EI, 70 eV): m/z % = 202 (M+, 100),
146 (7), 121 (6), 69 (4).
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7-(Pyrrol-2-yl)-1,2,4-triazolo[1,5-a]pyrimidine (5k): mp 196 °C
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7.35 (s, 1H, H2), 7.63 (d, 3J4, H6), 7.72 (d, 3J1, 1H, H-Ar), 8.68 (d,
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7-Trichloromethyl-1,2,4-triazolo[1,5-a]pyrimidine (5l): mp
105 °C–107 °C; 1H NMR (200 MHz, CDCl3): d = 7.80 (d, 3J4, 1H,
H6), 8.72 (s, 1H, H2), 9.04 (d, 3J4, 1H, H5). 13C NMR (100 MHz,
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(M+, 100), 201 (M + 2, 67), 166 (10), 110 (9).
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4. Conclusion
We have developed a fast, new, practical and simple method for
the preparation of 1,2,4-triazolo[1,5-a]pyrimidine. New trifluo-
romethylated 1,2,4-triazolo[1,5-a]pyrimidines were synthesized
with high regioselectivity in short reaction times and at excellent
yields. These compounds, especially those having the trifluoro-
methyl group in their structure, are excellent models for studies
on the biological activities.
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Acknowledgments
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The authors are grateful for the financial support from the Na-
tional Council for Scientific and Technological Development (CNPq
– Universal Proc. No. 578426/2008-0; 471519/2009-0), the Rio
Grande do Sul Research Support Foundation (FAPERGS/CNPq-PRO-
NEX Edital No. 008/2009, Proc. No. 10/0037-8), and the Coordina-
tion for Improvement of Higher Education 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 (L.B.) are also acknowledged.
(b) H. Zang, Y. Zhang, Y. Zang, B.W. Cheng, Ultrason. Sonochem. 17 (2010) 495;
(c) M.R.P. Heravi, Ultrason. Sonochem. 16 (2009) 361;
(d) B.S. Singh, H.R. Lobo, D.V. Pinjari, K.J. Jarag, A.B. Pandit, G.S. Shankarling,
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[23] The crystallographic data for structure reported in this paper have been
deposited with the Cambridge Crystallographic Data Center (CCDC 941736).
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (Fax: 01223-336033) or via
www.cam.ac.uk/datarequest/cif.