Regioselective synthesis and characterization of new 3-aryl-7- trifluoromethyl-[1,2,4]triazolo[4,3-a]pyrimidines

Article abstract of DOI:10.1002/jhet.608

The regioselective synthesis and characterization of a new series of 3-aryl-7-trifluoromethyl[1,2,4]triazolo[4,3-a]pyrimidines from the oxidative heterocyclization of 2-(N′-benzylidenehydrazino)-4- trifluoromethylpyrimidines with copper dichloride is described.

Full text of DOI:10.1002/jhet.608

September 2011
Regioselective Synthesis and Characterization of New 3-Aryl-7-
trifluoromethyl-[1,2,4]triazolo[4,3–a]pyrimidines
1085
Nilo Zanatta,* Simone S. Amaral, Josiane M. dos Santos,
Liana da S. Fernandes, Helio G. Bonacorso, and Marcos A. P. Martins
´
´
´
Nucleo de Quımica de Heterociclos (NUQUIMHE), Departamento de Quımica, Universidade
Federal de Santa Maria, 97.105-900, Santa Maria, RS, Brazil
*E-mail: zanatta@base.ufsm.br
Received April 12, 2010
DOI 10.1002/jhet.608
Published online 19 May 2011 in Wiley Online Library (wileyonlinelibrary.com).
The regioselective synthesis and characterization of a new series of 3-aryl-7-trifluoromethyl[1,2,4]tria-
zolo[4,3–a]pyrimidines from the oxidative heterocyclization of 2-(N0-benzylidenehydrazino)-4-trifluoro-
methylpyrimidines with copper dichloride is described.
J. Heterocyclic Chem., 48, 1085 (2011).
INTRODUCTION
[8a–b,9a,11], carbon disulfide [4a,10a–b,11a,11c,12],
and isothiocyanates [8a,13], among others [14].
The synthesis of heterocyclic compounds has been
extensively explored in the last few years due to their
important pharmacological proprieties [1]. Furthermore,
the presence of trihalogenated groups in such com-
pounds is frequently associated with the enhancement of
their biological activities [2].
Alternative methods from hydrazides and hydrazones
have been reported, but were unsuccessful in appli-
cations to a variety of systems and used toxic reagents
such as lead tetraacetate [11a,15], bromine [12,16], or
phosphorus oxychloride [10a]. To overcome these diffi-
culties, some authors suggested the substitution of the
toxic oxidation reagents by ferric chloride [9a,10a,17],
methyl iodide [18], and iodobenzene diacetate [19]. Later,
From a pharmacological point of view, triazoles are
among the most versatile existing heterocycles. These
compounds have been associated with analgesic, anti-
inflammatory, antimicrobial, and antiallergic activities,
among others [3]. In particular, 1,2,4-triazoles fused to het-
erocyclic rings are biologically active and have been
reported as herbicidal, antifungic, antibacterial [4], anxio-
lytic [5], anticonvulsivant [6], and antidepressant [7]
agents. This has brought about a clear demand for the syn-
thesis of novel representatives of this class of compounds.
Thus, in the continued search undertaken by our labora-
tory towards the preparation of potentially active hetero-
cycles, herein, we present the synthesis and characterization
of a series of new 3-aryl-7-trifluoro methyl[1,2,4]tria-
zolo[4,3–a]pyrimidines from the oxidative heterocycliza-
tion of 2-(N0-benzylidene-hydrazino)-4-trifluoromethyl-
pyrimidines from copper dichloride.
¨
Doring et al. demonstrated that substituted heterocyclic
imines were easily oxidized with copper dichloride, a
nonhazardous, less toxic and inexpensive reagent [20].
We have recently described the convergent synthesis
and cruzain inhibitory activity of some novel 2-(N0-ben-
zylidenehydrazino)-4-trifluoromethylpyrimidines [21].
These results prompted us to conduct the oxidative heter-
ocyclization of the structurally interesting and readily
available hydrazones with copper dichloride dihydrate to
afford a series of 3-aryl-7-trifluoro methyl[1,2,4]tri-
azolo[4,3–a]pyrimidines (3a–f, 4a–f) and 3-aryl-5-tri-
fluoromethyl[1,2,4]triazolo[4,3–a]pyrimidines (5a–f, 6a–
f) (Scheme 1). Although this method has been described
previously [20], the 2-(N0-benzylidene-hydrazino)-4-tri-
fluoromethylpyrimidines (1a–f, 2a–f) have not been used
as precursors in this type of reaction. Thus, we are inter-
ested to study how the presence of a trifluoromethyl group
in the pyrimidine moiety can affect the regiochemistry of
The most used methods to afford 1,2,4-triazoles fused
to heterocyclic rings involve the cyclization of heterocy-
clic hydrazines with aliphatic carboxylic acids [8], anhy-
drides [8d,9] and chlorides [8c–e,9a,10], orthoesters
C
V
2011 HeteroCorporation

1086
N. Zanatta, S. S. Amaral, J. M. dos Santos, L. da S. Fernandes, H. G. Bonacorso,
and M. A. P. Martins
Vol 48
Scheme 1
chloric acid was used, ring closure was achieved; however,
after stirring the reagents under reflux for 16 h, the reaction
remained incomplete allowing the recovery of 50% of the
starting material. Increasing the quantities of the acid also
failed to improve the reaction conversion.
As shown in Scheme 1, two regioisomers can be
obtained from the proposed methodology: 3-aryl-7-trifluoro-
methyl[1,2,4]triazolo[4,3–a]pyrimidines 3a–f, 4a–f, and
3-aryl-5-trifluoromethyl[1,2,4]triazolo[4,3–a]pyrimidines
5a–f, 6a–f. NMR and GC-MS data of the isolated products
indicated that most reactions were highly regioselective and
allowed the identification of only one isomer (Table 1). The
synthesis of some 1,2,4-triazolopyrimidines (entries nꢀ 1–5
and 8, Table 1) allowed the identification of two products.
These products presented the same number of signals in the
1H-NMR spectra and GC-MS data indicating that they pos-
sess the same molecular mass but different elution times.
The isolation of the major products was achieved after a sin-
gle recrystallization from ethanol.
the triazole cyclization, since this aspect was not
addressed previously [20].
RESULTS AND DISCUSSION
Scheme 1 outlines the synthesis of 3-aryl-7-trifluoro-
methyl[1,2,4]triazolo[4,3–a]pyrimidines (3a–f, 4a–f) and
3-aryl-5-trifluoromethyl[1,2,4]triazolo[4,3–a]pyrimidines
(5a–f, 6a–f) from the oxidative heterocyclization of 2-
(N0-benzylidenehydrazino)-4-trifluoromethylpyrimidines
with copper dichloride dihydrate in DMF.
All reactions were conducted in N,N0-dimethyl form-
amide within a period of 1.5 h. Table 1 shows that the
presence of different groups attached to the benzylidene
portion of the precursors 1a–f, 2a–f does not have much
influence on the reaction yields and reaction times,
although the 5-methylpyrimidine substituent did seem to
have a small effect on the regiochemistry, by providing
only angular isomers, except for entry 8.
STRUCTURAL STUDIES
To correctly assign the structure of 1,2,4-triazolo[4,3–
1
a]pyrimidines H and 13C-NMR data were investigated.
We observed that the H–5 of product 3a is more
deshielded than the corresponding H–6 of the precursor
1a and H–7 of the minor product 5a (Table 2). In addi-
tion, the C–5 of product 3a is more shielded than the cor-
responding C–6 of the precursor 1a and C–7 of the minor
product 5a. The constant presence of H–5 in lower fields
and C–5 in higher fields in comparison to the correspond-
ing hydrogens and carbons of the starting hydrazones 1a–f
and 2a–f, and minor products 5a–e and 6b, prompted us
to believe that the chemical shift trend of these hydro-
gens and carbons are consistent with steric effect. As a
consequence, the major regioisomers isolated are 3-aryl-
Other catalysts were also tested for the synthesis of tri-
azolopyrimidines 3–6 from 2-(N0-benzylidenehydrazino)-
4-trifluoromethylpyrimidines 1 and 2 and these included:
hydrochloric acid, sulfuric acid, trifluoroacetic acid, ferric
chloride, aluminum trichloride, and zinc chloride, all in
equivalent amounts. In our hands, these reagents failed to
afford the targeted compounds allowing the hydrazones to
be recovered after quenching the reaction. When hydro-
Table 1
Yield and regioisomeric ratio for the synthesis of [1,2,4]triazolo[4,3–a]pyrimidines (3a–f, 4a–f, 5a–f, and 6a–f).
Entry
R
Ar
Product
Regioiso-meric ratioa
Yield (%)b
1
2
3
H
H
H
Ph
2-Me-Ph
4-Me
3a þ 5a
3b þ 5b
3c þ 5c
3d þ 5d
3e þ 5e
3f
90:10
96:4
75:25
85:15
95:5
44
53
46
33
47
33
64
59
60
47
70
46
4
5
H
H
4-OMe
4-NO2
4-Cl
6
H
100:0
100:0
90:10
100:0
100:0
100:0
100:0
7
8
Me
Me
Me
Me
Me
Me
Ph
2-Me-Ph
4-Me
4-OMe
4-NO2
4-Cl
4a
4b þ 6b
9
4c
4d
10
11
12
4e
4f
a Obtained by GC-MS peak area of the total ion chromatograms.
b Yields of isolated products.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Regioselective Synthesis and Characterization of New
3-Aryl-7-trifluoromethyl-[1,2,4]triazolo[4,3–a]pyrimidines
1087
Table 2
pyrimidines 3a–6a had their energies minimized and
data showed that compound 3a is slightly more stable
than compound 5a by 6.49 kcal molꢁ1 and compound
4a is slightly more stable than compound 6a by 7.16
kcal molꢁ1. The calculations suggestted that the cycliza-
tion through the attack of N1 or N3 would be sterically
controlled to favor the formation of structures 3a and
4a, which are free of important steric interactions, rather
than the regioisomers 5a and 6a.
Chemical shifts of selected hydrogens and carbons of
compounds 1, 3, and 5.
In conclusion, a series of 3-aryl-7-trifluoromethyl
[1,2,4]triazolo[4,3–a]pyrimidines were synthesized from
2-(N0-benzylidenehydrazino)-4-trifluoromethylpyrimidines
in good yields via copper-mediated oxidative hetero-
cyclization. This method is extremely simple and allows
the construction of a great scope of 1,2,4-triazolo[4,3–
a]pyrimidines since there are a large number of com-
mercially available aldehydes for the synthesis of the
starting benzylidenehydrazinopyrimidines. Additionally,
the hydrazones of aromatic aldehydes with both electron-
withdrawing and electron-donating substituents were suc-
cessfully oxidized to give the corresponding 1,2,4-tria-
zolo[4,3–a]pyrimidines. Most fused heterocycles were
isolated as a single regioisomer. Some 1,2,4-triazolopyrim-
idines, however, presented a small quantity of a second iso-
mer after isolation. The major isomers were easily separated
from the mixture after a single recrystallization from etha-
nol. After analyzing the 1H- and 13C-NMR data, the 3-aryl-
7-trifluoromethyl[1,2,4]triazolo[4,3–a]pyrimidines have
been characterized as preferred regioisomers of these reac-
tions due to the steric compression effect observed from
the NMR spectra, in the form of deshielding of H–5 and
shielding of C–5, which are close in space. In addition, the
observation of a three-bond cross-peak between the H–5
and the C–3 further confirmed the structure of the obtained
compounds. These trends were considered to be the key in-
formation to assign the correct structure of the title com-
pounds. Furthermore, energy minimization obtained by
semiempirical molecular orbital (AM1) corroborate with
the sturcture of 3-aryl-7-trifluoromethyl[1,2,4]triazolo[4,3–
a]pyrimidines as the most stable isomers.
Compd.
dH-n ppma
dC-n ppma
Calculated dC-n ppmb
1a
3a
5a
1b
3b
5b
8.83 (H–6)
9.78 (H–5)
9.11 (H–7)
8.72 (H–6)
9.78 (H–5)
9.13 (H–7)
161.9 (C–6)
140.1 (C–5)
– (C–7)c
156.5 (C–6)
135.5 (C–5)
157.4(C–7)
156.5 (C–6)
135.5 (C–5)
157.4 (C–7)
161.9 (C–6)
139.9 (C–5)
– C–7c
a Spectra registered in DMSO-d6/TMS.
b Calculated value from Chemdraw.
c Signal not obtained due to the low signal to noise of the minor
isomer.
7-trifluoromethyl[1,2,4]triazolo[4,3–a]pyrimidines 3a–f,
4a–f and the minor regioisomers are 3-aryl-5-trifluoro-
methyl[1,2,4]triazolo[4,3–a]pyrimidines 5a–e, 6b.
To confirm our expectations, a HMBC experiment of
compound 4e was carried out. In the HMBC spectra a
three-bond cross-peak between H–5 and C–3 was observed,
which confirmed its structure. In addition, both electronic
and steric factors are essential for the regioselective
heterocyclization of 2-(N0-benzylidenehydrazino)pyrimi-
dines [17]. Electronic factors depend on the nucleophilicity
of the nitrogens present in the pyrimidine ring because the
preferred isomer is formed from the intramolecular nucle-
ophilic attack of the pyrimidine nitrogen to the imino car-
bon of the exocyclic portion of the ring. As extensively
demonstrated, the N1 of trifluoromethylpyrimidines is
more nucleophilic than the N3, probably due to electron-
withdrawing effect of the trifluoromethyl group [22]. The
attack of the N1 of the pyrimidine ring to the benzyli-
minic portion of hydrazones furnishes 1,2,4-triazolo[4,3–
a]pyrimidines 3a–f and 4a–f. The steric factor also favors
the attack of the N1 to the benzyliminic portion of hydra-
zones because N3 has a higher steric hindrance due to the
proximity of this atom to the trifluoromethyl group.
NOESY experiment was carried out with compound 4e
but it did not give the expected result.
EXPERIMENTAL
Unless otherwise indicated all common reagents and sol-
vents were used as obtained from commercial suppliers with-
out further purification. The synthesis of compounds 1a–f and
2a–f are reported in the literature [21]. All melting points were
determined on a MQAPF-301 apparatus and are uncorrected.
The CHN microanalyses were performed on a Perkin-Elmer
2400 elemental analyzer. High resolution mass spectra were
recorded in ESI-mode on a LC-MS-Bruker Daltonics Micro-
TOF mass analyzer. Both EA and HRMS were registered at
the Chemistry Department of the Universidade de Sa˜o Paulo
(USP), Sa˜o Paulo, SP, Brazil. Mass spectra were registered in
a HP 5973 MSD connected to a HP 6890 GC. The GC was
To confirm the influence of steric factors in the regio-
chemistry of the reactions, we were motivated to deter-
mine the most stable structures through semiempirical
molecular orbital (AM1) calculations [23]. The triazolo-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1088
N. Zanatta, S. S. Amaral, J. M. dos Santos, L. da S. Fernandes, H. G. Bonacorso,
and M. A. P. Martins
Vol 48
2
equipped with a split-splitless injector, auto-sampler, cross-
linked HP-5 capillary column (30 m, 0.32 mm of internal
DMSO-d6): d 166.6 (C-3), 158.2 (q, JC-F ¼ 34.4 Hz, C-7),
154.5 (C-8a), 141.2 (C-5), 140.0, 129.7, 127.1, 126.8 (Ar),
1
1
diameter), and helium was used as the carrier gas. H- and 13C-
120.0 (q, JC-F ¼ 278.0 Hz, CF3), 106.7 (C-6), 21.1 (Me); GC-
NMR spectra were acquired on a Bruker DPX 200 or DPX 400
spectrometers, 5 mm sample tubes, 298 K, digital resolution
60.01 ppm, in CDCl3 or DMSO-d6 using TMS as internal ref-
erence. The geometry of compounds were optimized using
semiempirical SCF, AM1 method implemented in the Hyper-
Chem 7.52 package (2002) [23]. The structures were fully opti-
mized without fixing any parameter, thus bringing all geometric
variables to their equilibrium values. The energy minimization
protocol used the Polak-Ribiere conjugated gradient algorithm.
Convergence to a local minimum was achieved when the energy
gradient was = 0.01 kcal mol–1. The RHF method was used in
the spin pairing for the two semiempirical tools.
General procedure for the synthesis of 3-aryl-7-trifluoro-
methyl [1,2,4]triazolo[4,3–a]pyrimidines (3a–f, 4a–f). A so-
lution of compound 1a–f, 2a–f (1.0 mmol) and dihydrate
copper II chloride (0.34 g, 2.0 mmols) in N,N-dimethylforma-
mide (5.0 mL) was stirred at 50ꢀC for 0.5 h. Subsequently, the
temperature was raised to 90ꢀC and the reaction was stirred for
1 h. After cooling to room temperature, the solvent was distilled
under reduced pressure and ethyl acetate (30.0 mL) was added
to the residue. Then, the organic layer was extracted with
NH4OH (30.0 mL) to remove the copper ions. The insoluble
product was filtered and dried under vacuum in desiccator.
The soluble portion of the product was washed with distilled
water until reaching neutral pH. The organic phase was dried
with anhydrous sodium carbonate and filtered and the solvent
was evaporated under reduced pressure. The insoluble and
soluble product fractions were taken together and were recrys-
tallized from ethanol to afford the pure major isomer.
MS (EI, 70 eV): m/z (%) ¼ 278 Mþ (100), 259 (5), 209 (2),
147 (4), 131 (25), 104 (3), 90 (24),77 (3). HRMS (ESI): m/z
calcd for C14H10F3N4 [MHþ]: 279.0857; found: 279.0779.
3-(4-Methoxy-phenyl)-7-trifluoromethyl[1,2,4]triazolo[4,3–a]-
pyrimidine (3d). This compound was obtained as a colorless
crystal in 33% yield, mp: 255–258ꢀC (ethanol); 1H-NMR (200
MHz, DMSO-d6): d 9.72 (d, 1H, J ¼ 6.8 Hz, H-5), 8.21 (d, 2H,
J ¼ 8.8 Hz, Ar), 7.81 (d, 1H, J ¼ 6.8 Hz, H-6), 7.15 (d, 2H, J
¼ 8.8 Hz, Ar), 3.86 (s, 3H, OMe); 13C-NMR (100 MHz,
DMSO-d6): d 166.6 (C-3), 161.7 (Ar), 154.4 (C-8a), 149.8 (q,
2JC-F ¼ 35.1 Hz, C-7), 139.6 (C-5), 128.6, 121.9 (Ar), 120.3 (q,
1JC-F ¼ 273.7 Hz, CF3), 114.4 (Ar), 106.3 (C-6), 55.3 (OMe);
GC-MS (EI, 70 eV): m/z (%) ¼ 294 Mþ (100), 275 (4), 251
(41), 147 (15), 90 (5). Anal. Calcd for C13H9F3N4O (294.24): C,
53.07; H, 3.08; N, 19.04. Found: C, 53.10; H, 2.87; N, 18.82.
3-(4-Nitro-phenyl)-7-trifluoromethyl[1,2,4]triazolo[4,3–a]-
pyrimidine (3e). This compound was obtained as a colorless
crystal in 47% yield, mp: 252–253ꢀC (ethanol);1H-NMR (200
MHz, DMSO-d6): d 9.84 (d, 1H, J ¼ 6.8 Hz, H-5), 8.51 (d,
2H, J ¼ 8.8 Hz, Ar), 8.44 (d, 2H, J ¼ 8.8 Hz, Ar), 7.92 (d,
1H, J ¼ 6.8 Hz, H-6); 13C-NMR (100 MHz, DMSO-d6): d
2
164.4 (C-3), 154.5 (C-8a), 150.8 (q, JC-F ¼ 36.1 Hz, C-7),
148.9 (Ar), 140.6 (C-5), 135.4, 128.2, 124.4 (Ar), 120.2 (q,
1JC-F ¼ 275.1 Hz, CF3), 107.5 (C-6); GC-MS (EI, 70 eV): m/z
(%) ¼ 309 Mþ (100), 279 (29), 264 (28), 251 (27), 147 (30).
Anal. Calcd for C12H6F3N5O2 (309.20): C, 46.61; H, 1.96; N,
22.65. Found: C, 47.13; H, 1.93; N, 22.41.
3-(4-Chloro-phenyl)-7-trifluoromethyl[1,2,4]triazolo[4,3–a]-
pyrimidine (3f). This compound was obtained as a colorless
crystal in 33% yield, mp: 272–273ꢀC (ethanol); 1H-NMR (200
MHz, DMSO-d6): d 9.78 (d, 1H, J ¼ 7.0 Hz, H-5), 8.27 (d, 2H,
J ¼ 8.4 Hz, Ar), 7.87 (d, 1H, J ¼ 7.0 Hz, H-6), 7.67 (d, 2H, J
¼ 8.4 Hz, Ar); 13C-NMR (100 MHz, DMSO-d6): d 165.4 (C-3),
3-Phenyl-7-trifluoromethyl[1,2,4]triazolo[4,3–a]pyrimidine
(3a). This compound was obtained as a colorless crystal in
44% yield, mp: 252–254ꢀC (ethanol); 1H-NMR (200 MHz,
DMSO-d6): d 9.72 (d, 1H, J ¼ 7.0 Hz, H-5), 8.30–8.25 (m, 2H,
Ar), 7.86 (d, 1H, J ¼ 7.0 Hz, H-6), 7.61–7.58 (m, 3H, Ar);
13C-NMR (100 MHz, DMSO-d6): d ¼ 166.6 (C-3), 154.5 (C-
2
154.2 (C-8a), 150.3 (q, JC-F ¼ 33.0 Hz, C-7), 139.8 (C-5),
1
135.7, 128.9, 128.5, 128.2 (Ar), 120.1 (q, JC-F ¼ 270.1 Hz,
2
CF3), 106.6 (C-6); GC-MS (EI, 70 eV): m/z (%) ¼ 298 Mþ
(100), 263 (5), 229 (9), 149 (9), 137 (8), 102 (11). HRMS (ESI):
m/z calcd for C12H7ClF3N4 [MHþ]: 299.0311; found: 299.0312.
8a), 150.3 (q, JC-F ¼ 34.5 Hz, C-7), 140.1 (C-5), 131.3, 129.1,
1
127.1 (Ar), 120.4 (q, JC-F ¼ 274.4 Hz, CF3), 119.9 (Ar), 106.9
(C-6); GC-MS (EI, 70 eV): m/z (%) ¼ 264 Mþ (100), 245 (7),
195 (19), 148 (7), 103 (16), 77 (27). HRMS (ESI): m/z calcd
for C12H8F3N4 [MHþ]: 265.0701; found: 265.0706.
3-Phenyl-7-trifluoromethyl-6-methyl[1,2,4]triazolo[4,3–a]-
pyrimidine (4a). This compound was obtained as a colorless
crystal in 64% yield, mp: 275–278ꢀC (ethanol); 1H-NMR (200
MHz, DMSO-d6): d 9.61 (s, 1H, H-5), 8.25–8.24 (m, 2H, Ar),
7.58–7.54 (m, 3H, Ar), 2.51 (s, 6H, Me); 13C-NMR (100 MHz,
DMSO-d6): d 166.1 (C-3), 152.9 (C-8a), 148.8 (q, 2JC-F ¼ 32.9 Hz,
3-(2-Methyl-phenyl)-7-trifluoromethyl[1,2,4]triazolo[4,3–a]-
pyrimidine (3b). This compound was obtained as a colorless
1
crystal in 53% yield, mp: 147–150ꢀC (ethanol); H-NMR (200
MHz, DMSO-d6): d 9.79 (d, 1H, J ¼ 7.0, H-5), 8.13 (d, 1H, J
¼ 7.6 Hz, Ar), 7.86 (d, 1H, J ¼ 7.0 Hz, H-6), 7.47–7.41 (m,
3H, Ar), 2.72 (s, 3H, Me); 13C-NMR (100 MHz, DMSO-d6): d
1
C-7), 138.9 (C-5), 130.8, 129.6, 128.7, 126.7 (Ar), 120.6 (q, JC-F
¼ 273.6 Hz, CF3), 117.6 (C-6); GC-MS (EI, 70 eV): m/z (%) ¼
278 Mþ (100), 259 (3), 209 (12), 143 (6), 103 (6), 77 (3). HRMS
(ESI) m/z calcd. for C13H10F3N4 [MHþ] 279.0857, found 279.0855.
2
167.6 (C-3), 153.6 (C-8a), 150.1 (q, JC-F ¼ 35.7 Hz, C-7),
139.1 (C-5), 137.52, 131.47, 130.3, 129.9, 128.6, 126.0 (Ar),
1
120.3 (q, JC-F ¼ 274.6 Hz, CF3), 106.6 (C-6), 21.4 (Me); GC-
3-(2-Methyl-phenyl)-7-trifluoromethyl-6-methyl[1,2,4]tri-
azolo[4,3–a]pyrimidine (4b). This compound was obtained as
a colorless crystal in 59% yield, mp: 180–183ꢀC (ethanol); H-
NMR (200 MHz, DMSO-d6): d 9.68 (s, 1H, H-5), 8.10 (d, 1H,
J ¼ 8.0 Hz, Ar), 7.45–7.36 (m, 3H, H-6), 2.70 (s, 3H, Me),
2.51 (s, 4H, Me); 13C-NMR (100 MHz, DMSO-d6): d 167.2
MS (EI, 70 eV): m/z (%) ¼ 278 Mþ (100), 259 (4), 209 (3),
148 (6), 131 (55), 104 (11), 89 (12),77 (4). HRMS (ESI): m/z
calcd for C13H10F3N4 [MHþ]: 279.0857; found: 279.0846.
1
3-(4-Methyl-phenyl)-7-trifluoromethyl[1,2,4]triazolo[4,3–a]-
pyrimidine (3c). This compound was obtained as a colorless
1
2
crystal in 46% yield, mp: 261–266ꢀC (ethanol); H-NMR (200
(C-3), 152.2 (C-8a), 148.9 (q, JC-F ¼ 34.2 Hz, C-7), 138.9
MHz, DMSO-d6): d 9.74 (d, 1H, J ¼ 6.8 Hz, H-5), 8.16 (d,
2H, J ¼ 8.0 Hz, Ar), 7.83 (d, 1H, J ¼ 6.8 Hz, H-6), 7.41 (d,
2H, J ¼ 8.0 Hz, Ar), 2.41 (s, 3H, Me); 13C-NMR (100 MHz,
(C-5), 137.4, 131.5, 130.2, 129.8, 128.8, 126.0 (Ar), 120.8 (q,
1JC-F ¼ 276.6 Hz, CF3), 117.5 (C-6), 21.3 (Me), 13.9 (Me);
GC-MS (EI, 70 eV): m/z (%) ¼ 292 Mþ (100), 273 (3), 223
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011
Regioselective Synthesis and Characterization of New
3-Aryl-7-trifluoromethyl-[1,2,4]triazolo[4,3–a]pyrimidines
1089
´
Almansa, C.; Garcıa-Rafanell, J. J Med Chem 1997, 40, 547; (c) McA-
tee, J. J.; Schinazi, R. F.; Liotta, D. C. J Org Chem 1998, 63, 2161;
(d) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635.
(2), 162 (7), 131 (54), 116 (9), 89 (13). HRMS (ESI): m/z
calcd for C14H12F3N4 [MHþ]: 293.1014; found: 293.1009.
3-(4-Methyl-phenyl)-7-trifluoromethyl-6-methyl[1,2,4]tri-
azolo[4,3–a]pyrimidine (4c). This compound was obtained as
[3] (a) Ram, V. J.; Srivastava, P.; Sing, S. K.; Kandpal, M.; Tek-
wani, B. L. Bioorg Med Chem Lett 1997, 7, 1087; (b) Wadsworth, H. J.;
Jenkins, S. M.; Orlek, B. S.; Cassidy, F.; Clark, M. S. G.; Brown, F.; Riley,
G. J.; Graves, D.; Hawlins, J.; Naylor, C. B. J Med Chem 1992, 35, 1280;
(c) Naito, Y.; Akahoshi, F.; Takeda, S.; Okada, T.; Kajii, M.; Nishimura,
H.; Sugiura, M.; Fukaya, C.; Kagitani, Y. J Med Chem 1996, 39, 3019.
[4] (a) Saleh, M. A.; Hafez, Y. A.; Abdel-hay, F. E.; Gad, W.
I. J Heterocycl Chem 2003, 40, 973 and references therein; (b) Pra-
kash, O.; Sadana, A. K.; Mirza, Y.; Aneja, K. R. Eur J Med Chem
2003, 38, 533; (c) Yang, G.-F.; Chen, Q.; Zhu, X.-L.; Jiang, L.-L.;
Liu, Z.-M. Eur J Med Chem 2008, 43, 595.
1
a colorless crystal in 60% yield, mp: 272–275ꢀC (ethanol); H-
NMR (200 MHz, DMSO-d6): d 9.57 (s, 1H, H-5), 8.14 (d, 2H,
J ¼ 8.2 Hz, Ar), 7.39 (d, 2H, J ¼ 8.2 Hz, Ar), 2.52 (s, 3H,
Mepir.), 2.41 (s, 3H, Me); 13C-NMR (100 MHz, DMSO-d6): d
2
¼ 166.7 (C-3), 158.2 (q, JC-F ¼ 34.4 Hz, C-7), 153.0 (C-8a),
1
141.2 (C-5), 140.0, 129.7, 127.1, 126.8 (Ar), 120.0 (q, JC-F
¼
278.0 Hz, CF3) 117.8 (C-6), 21.1 (Me), 14.0 (Me); GC-MS
(EI, 70 eV): m/z (%) ¼ 292 Mþ (100), 273 (3), 223 (1), 131
(19), 116 (8), 90 (13), 77 (2). HRMS (ESI): m/z calcd for
C14H12F3N4 [MHþ]: 293.1014; found 293.1009.
[5] Tarzia, G.; Ocelli, E.; Toja, E.; Barone, D.; Corsico, N.;
Gallico, L.; Luzzani, F. J Med Chem 1988, 31, 1115.
3-(4-Methoxy-phenyl)-7-trifluoromethyl-6-methyl[1,2,4]tri-
azolo[4,3–a]pyrimidine (4d). This compound was obtained as
a colorless crystal in 47% yield, mp: 240–244ꢀC (ethanol);
1H-NMR (200 MHz, DMSO-d6): d 9.53 (s, 1H, H-5), 8.18 (d,
2H, J ¼ 8.8 Hz, Ar), 7.12 (d, 2H, J ¼ 8.8Hz, Ar), 3.86 (s, 3H,
OMe), 2.50 (s, 3H, Me); 13C-NMR (100 MHz, DMSO-d6): d ¼
166.2 (C-3), 161.5 (Ar), 152.9 (C-8a), 148.5 (q, 2JC-F ¼ 34.9 Hz,
C-7), 138.6 (C-5), 128.5, 122.1 (Ar), 120.7 (q, 1JC-F ¼ 275.3 Hz,
CF3), 117.2 (C-6), 114.4 (Ar), 55.2 (OMe), 13.8 (Me); GC-MS
(EI, 70 eV): m/z (%) ¼ 308 Mþ (100), 293 (19), 265 (30), 161
(7), 90 (5). Anal. Calcd for C14H11F3N4O (308.26): C, 54.55; H,
3.60; N, 18.18. Found: C, 54.40; H, 3.85; N, 17.98.
[6] Tarzia, G.; Ocelli, E.; Barone, D. Il Farmaco 1989, 44, 3.
[7] Sarges, S.; Howard, H. R.; Browne, R. G.; Lebel, L. A.;
Seymour, P. A.; Koe, B. K. J Med Chem 1990, 33, 2240.
[8] (a) Allen, C. F. H.; Beilfuss, H. R.; Burness, D. M.; Reyn-
olds, G. A.; Tinker, J. F.; Vanallan, J. A. J Org Chem 1959, 24, 787;
(b) Allen, C. F. H.; Beilfuss, H. R.; Burness, D. M.; Reynolds, G. A.;
Tinker, J. F.; Vanallan, J. A. J Org Chem 1959, 24, 793; (c) Kottke,
K.;Ku¨hmstedt Pharmazie 1985, 40, 55; (d) Clark, J. Varvounis, G.;
Bakavoli, M. J Chem Soc Perkin Trans I 1986, 711; (e) Alagarsamy,
V.; Giridhar, R.; Yadav, M. R. Bioorg Med Chem Lett 2005, 15,
1877; (f) Alargasamy, V.; Solomon, V. R.; Murugan, M. Bioorg Med
Chem 2007, 15, 4009.
3-(4-Nitro-phenyl)-7-trifluoromethyl-6-methyl[1,2,4]tri-
azolo[4,3–a]pyrimidine (4e). This compound was obtained as a
colorless crystal in 70% yield, mp: 275–278ꢀC (ethanol); 1H-NMR
(200 MHz, DMSO-d6): d 9.66 (s, 1H, H-5), 8.49 (d, 2H, J ¼ 8.9
Hz, Ar), 8.41 (d, 2H, J ¼ 8.9 Hz, Ar), 2.54 (s, 3H, Me); 13C-NMR
(100 MHz, DMSO-d6): d ¼ 164.0 (C-3), 152.9 (C-8a), 149.5 (q,
2JC-F ¼ 33.2 Hz, C-7), 149.8 (Ar), 139.2 (C-5), 135.5, 127.9, 123.9
[9] (a) Tully, W. R.; Murdoch, R.; Westwood, R. J Heterocycl
´
´ ´
¨
Chem 1986, 23, 833; (b) Szilagyi, L.; Illyes, T.; Gyorgydeak, Z.;
´
Szabo, G.; Karacsony, A. ARKIVOV 2004, 243.
[10] (a) Al-Ashmawy, M. I.; Abd El-Samii, Z. K.; El Feky, S.
A.; Osman, N. A. Boll Chim Farmaceutico 1998, 4, 110; (b) El-Sher-
ief, H. A.; Abdel-Rahman, A. E.; El-Naggar, G. M.; Mahmoud, A. M.
Bull Chem Soc Jpn 1983, 56, 1227.
1
(Ar), 120.5 (q, JC-F ¼ 272.1 Hz, CF3), 118.3 (C-6), 13.8 (Me);
GC-MS (EI, 70 eV): m/z (%) ¼ 323 Mþ (100), 293 (41), 277 (31),
265 (26), 161 (14), 90 (5). HRMS (ESI): m/z calcd for
C13H9F3N5O2 [MHþ]: 324.0708; found: 324.0704.
[11] (a) Williams, L. A.; Allen, C. F. H.; Reynolds, G. A.; Tin-
ker, J. F. J Org Chem 1960, 25, 361; (b) Taylor, P. J.; Thomson, D.
A.; Bowie, R.; Edwards, P. N.; Nicholson, S. J Chem Soc Perkin I
1979, 1708; (c) El-Dean, A. M. K. Monatsh Chem 1998, 129, 523;
(d) Oganisyan, A. Sh.; Noravyan, A. S.; Karapetyan, A. A.; Aleksan-
yan, M. S.; Struchkov, Yu. T. Chem Heterocycl Compd 2001, 5, 628.
[12] Gineinah, M. M.; El-Sherbeny, M. A.; Nasr, M. N.; Maar-
ouf, A. R. Arch Pharm Med Chem 2002, 11, 556.
3-(4-Chloro-phenyl)-7-trifluoromethyl-6-methyl[1,2,4]tri-
azolo[4,3–a]pyrimidine (4f). This compound was obtained as
a colorless crystal in 46% yield, mp: decomposition at 260ꢀC;
1H-NMR (200 MHz, DMSO-d6): d 9.70 (s, 1H, H-5), 8.25 (d,
2H, J ¼ 8.3 Hz, Ar), 7.67 (d, 2H, J ¼ 8.3 Hz, Ar), 2.51 (s,
3H, Me); 13C-NMR (100 MHz, DMSO-d6): d ¼ 165.3 (C-3),
[13] El-Tombary, A. A.; Ismail, K. A.; Aboulwafa, O. M.;
Omar, A.-M. M. E.; El-Azzouni, M. Z.; El-Mansoury, S. T. Il Farmaco
1999, 54, 486 and references therein.
2
153.0 (C-8a), 150.3 (q, JC-F ¼ 33.0 Hz, C-7), 139.1 (C-5),
2
135.8, 128.9, 128.5, 128.2 (Ar), 12.0 (q, JC-F ¼ 270.1 Hz,
[14] (a) Hassaneen, H. M.; Abdelhadi, H. A.; Abdallah, T. A. Tet-
rahedron 2001, 57, 10133; (b) Yachenko, V. A.; Gur’eva, A. N.; Khairu-
lin, A. R.; Demchenko, A. M. Chem Heterocycl Compd 2002, 9, 1138;
(c) Dandia, A.; Sarawgi, P.; Arya, K.; Khaturia, S. ARKIVOC 2006, 83;
(d) Vas’kevich, R. I.; Savitskii, P. V.; Zborovskii, Y. L.; Staninets, V. I.;
Turov, A. V.; Chernega, A. N. Russ J Org Chem 2006, 42, 1396;
(e) Vas’kevich, R. I.; Savitskii, P. V.; Zborovskii, Y. L.; Staninets, V. I.;
Turov, A. V.; Chernega, A. N. Russ J Org Chem 2006, 42, 1403.
[15] (a) Bower, J. D.; Doyle, F. P. J Chem Soc 1957, 727;
(b) Svete, J.; Groselj, U.; Bevk, D.; Jakse, R.; Meden, A.; Stanovnik,
B. Tetrahedron Asymmetry 2005, 16, 2927; (c) Tsujikawa, T.; Tat-
suda, M. Chem Pharm Bull 1977, 12, 3137.
CF3) 118.1 (C-6), 13.9 (Me); GC-MS (EI, 70 eV): m/z (%) ¼
312 Mþ (100), 293 (2), 243 (9), 177 (6). HRMS (ESI): m/z
calcd for C13H8ClF3N4 [MHþ]: 313.0468; found: 313.0470.
Acknowledgment. The authors thank the financial support from
´
´
the Conselho Nacional de Desenvolvimento Cientıfico e Tecnolo-
gico (Universal Grant Nꢀ 473512/2009-2) and fellowships
(S.S.A., L.S.F., and J.M.S.).
REFERENCES AND NOTES
[1] Eicher, T.; Hauptmann, S. The Chemistry of Hetero-
cycles—Structure, Reactions, Synthesis, and Applications, 2nd ed.;
Willey-VHC Verlag GmbH and Co. KGaA, 2003.
[16] (a) Harper, R. W.; Jackson, W. T.; Froelich, L. L.; Boyd,
R. J.; Aldridge, T. E.; Herron, D. K. J Med Chem 1994, 37, 2411;
(b) Gibson, M. S. Tetrahedron 1963, 19, 1587; (c) Shaban, M. A. E.;
Taha, M. A. M.; Nasr, A. Z.; Morgaan, A. E. A. Pharmazie 1995, 50,
784; (d) Svete, J.; Groselj, U.; Recnik, S.; Meden, A.; Stanovnik, B.
Tetrahedron: Assymetry 2002, 13, 821.
´
´
[2] (a) De Arriba, A. F.; Gomez-Carajus, L. A.; Cavalcanti, F.;
´
Almansa, C.; Garcıa-Rafanell, J.; Forn, J. Eur J Pharmacol 1996, 318,
´
´
341; (b) De Arriba, A. F.; Gomez-Carajus, L. A.; Cavalcanti, F.;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1090
N. Zanatta, S. S. Amaral, J. M. dos Santos, L. da S. Fernandes, H. G. Bonacorso,
and M. A. P. Martins
Vol 48
¨
[20] Doring, M.; Ciesielski, M.; Pufky, D. Tetrahedron 2005, 61,
[17] Awad, M. K.; Saleh, M. A. J Mol Struct (Theochem) 2004,
678, 129.
[18] (a) Vas’kevich, R. I.; Savitskii, P. V.; Zborovskii, Y. L.;
5942.
[21] Zanatta, N.; Amaral, S. S.; dos Santos, J. M.; de Mello, D.
L.; Fernandes L. da, S.; Bonacorso, H. G.; Martins, M. A. P.; Andrico-
pulo, A. D.; Borchhardt, D. M. Bioorg Med Chem 2008, 16, 10236.
Staninets, V. I.; Turov, A. V.; Chernega, A. N. Russ J Org Chem
2006, 42, 1396; (b) Vas’kevich, R. I.; Savitskii, P. V.; Zborovskii, Y.
L.; Staninets, V. I.; Turov, A. V.; Chernega, A. N. Russ J Org Chem
2006, 42, 1403.
[22] (a) Zanatta, N.; Flores, D. C.; Amaral, S. S.; Flores, A. F. C.;
Bonacorso, H. G.; Martins, M. A. P. Synlett 2005, 3079; (b) Zanatta, N.;
Faoro, D.; Fernandes, L. da S.; Brondani, P. B.; Flores, D. C.; Flores, A.
F. C.; Bonacorso, H. G.; Martins, M. A. P. Eur J Org Chem 2008, 5832.
[19] (a) Varma, R. S.; Rao, V.; Kumar, D.; Sekhar, K. V. G. C.;
Dhillon, H. Green Chem 2004, 6, 156; (b) Prakash, O.; Gujral, H. K.;
Rani, N.; Singh, S. P. Synth Commun 2000, 3, 417; (c) Song, Y.; Joe, B.
S.; Son, H. Y. Heterocycles 2008, 75, 3091; (d) Prakash, O.; Bhardwaj,
V.; Kumar, R.; Tyagi, P.; Aneja, K. R. Eur J Med Chem 2004, 39, 1073.
[23] Hypercube, Inc. HYPERCHEMTM Professional 7.52, Hyper-
cube, Inc., Gainesville, FL, 2002.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet