Convergent procedure for the synthesis of trifluoromethyl-containing N-(pyridinyl-triazolyl)pyrimidin-2-amines

Article abstract of DOI:10.1016/j.jfluchem.2010.08.002

This study describes a simple and efficient procedure to synthesize a novel series of fourteen 4-substituted N-(5-pyridinyl-1H-1,2,4-triazol-3-yl)-6- (trifluoromethyl)pyrimidin-2-amines, where the 4-substituents are H, CH ₃, C₆H

Full text of DOI:10.1016/j.jfluchem.2010.08.002

Journal of Fluorine Chemistry 131 (2010) 1297–1301
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Convergent procedure for the synthesis of trifluoromethyl-containing
N-(pyridinyl-triazolyl)pyrimidin-2-amines
*
Helio G. Bonacorso , Guilherme P. Bortolotto, Jussara Navarini, Liliane M.F. Porte, Carson W. Wiethan,
Nilo Zanatta, Marcos A.P. Martins, Alex F.C. Flores
Nu´cleo de Quı´mica de Heterociclos (NUQUIMHE), Departamento de Quı´mica, 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:
This study describes a simple and efficient procedure to synthesize a novel series of fourteen 4-
substituted N-(5-pyridinyl-1H-1,2,4-triazol-3-yl)-6-(trifluoromethyl)pyrimidin-2-amines, where the 4-
substituents are H, CH3, C6H5, 4-FC6H4, 4-CH3C6H4, 4-CH3OC6H4 and 2-Furyl; from the cyclocondensa-
tion reaction of N-[5-(pyridinyl)-1H-1,2,4-triazol-3-yl]guanidines with 4-alkoxy-4-alkyl(aryl/hetero-
aryl)-1,1,1-trifluoroalk-3-en-2-ones. The reactions were carried out in ethanol under reflux for 18 h and
led to 40–68% yields. N-(Pyridyl-triazolyl)guanidine precursors were further obtained from reactions of
cyanoguanidine with nicotinic or isonicotinic acid hydrazides and the halogenated enones from
trifluoroacetylation of enolethers or acetals.
Received 1 July 2010
Received in revised form 2 August 2010
Accepted 14 August 2010
Available online 20 August 2010
Keywords:
Pyrimidines
Pyrimidinamines
Triazoles
ß 2010 Elsevier B.V. All rights reserved.
Pyridines
Enones
1. Introduction
materials for the regioselective synthesis of numerous heterocyclic
compounds [6d].
Fluorine-containing compounds have attracted much interest
because of their unique chemical, physical and biological activities
[1,2]. Also, it is well documented that the influence of the
trifluoromethyl substituent on physiological activity is due mainly
to the increased lipophilicity of the molecules, causing greater cell
permeability [3]. In particular, fluorine-containing heterocycles
are now widely recognized as important organic molecules
showing interesting biological activities with potential for
applications in the fields of medicine and agriculture [4,5].
Among many useful reactions, the introduction of a trifluor-
omethyl group in organic molecules has received great attention in
the literature [6a,6b], where methyl fluorosulphonyl difluoroace-
tate (MFSDA), as convenient-to-handle liquid reagent, has allowed
the obtainment of a variety of CF3-containing compounds from
aryl, heteroaryl, vinyl, benzyl and allyl halides in good yields and
under mild conditions [6c]. However, one of the best methods to
introduce a trifluoromethyl group into heterocycles is based on the
trifluoromethylated building block approach. This building block
relies on the trifluoroacetylation of enolethers or acetals to give, in
one-step and good yields, 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-
trifluoroalk-3-en-2-ones which have proven to be useful starting
Among the many well-known heterocycles, the literature has
highlighted single pyridines [7], 1,2,4-triazoles [8–10], pyrimi-
dines [11–16] and, less commonly, their linked and fused
derivatives [13].On the other hand, when pyridines, triazoles
and pyrimidines are linked by single bonds at the specific ring
positions of bi- or tri-heterocyclic containing new molecules,
interesting physiological proprieties are observed. For example, we
can highlight the N-(1,2,4-triazolyl)pyrimidinamines. Recently, in
order to expeditiously test his hypothesis, Ahmad et al. [17]
designed an approach that introduced a variety of heterocycles
bonded to a poly-substituted pyrimidin-2-amino skeleton. This
effort, coupled with extensive in vitro and in vivo safety
characterization, resulted in the identification of 7-(4-(4-fluor-
ophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazol-5-
yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid (BMS-
644950) as a novel, potent and efficacious HMGR inhibitor
(treatment of hypercholesterolemia) with a potentially superior
safety profile that was advanced into clinical development.
However, it is not an easily synthetic process to achieve N-
(1,2,4-triazol-3-yl)pyrimidin-2-amino compounds that contain
substitution on the triazole and pyrimidine rings.The triazolylpyr-
idine systems, which also deserve much attention, are not found
free in nature, but its derivatives have many biological proprieties,
mostly as insecticides and antibacterial agents [18] and, more
recently, as carriers of anti-proliferative activity [19] against
* Corresponding author. Fax: +55 55 3220 8031.
E-mail address: heliogb@base.ufsm.br (H.G. Bonacorso).
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.08.002

1298
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 131 (2010) 1297–1301
several tumor cell lines. For example, the synthesis of a 1,2,4-
triazolylpyridine system, which causes cell cycle arrest in A431
cancer cell with EC50 values in the single digit nanomolar range,
from the reaction of dimethoxyaniline with ethyl-2-chloronicoti-
nate needed four-steps to promotes the 1,2,4-triazole ring closure
[19].
In the present study we employ N-[5-(pyridinyl)-1H-1,2,4-triazol-
3-yl]guanidines (4,5) as new precursors, which have been easily
synthesized by
a two-step procedure to prepare now the
interesting tricyclic amino systems (6,7) by
a convergent
methodology.
Thus,
4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalk-3-
Considering the importance of trifluoromethylated hetero-
cycles, pyridines, 1,2,4-triazoles, pyridimidines, and the new and
little studied triazolylpyridine and triazolylpyrimidinamine sys-
tems, the aim of this study is to report the results of
cyclocondensation reactions of 4-alkoxy-4-alkyl(aryl/hetero-
aryl)-1,1,1-trifluoroalk-3-en-2-ones (1a–g) with N-[3-(pyridi-
nyl)-1H-1,2,4-triazol-5-yl]guanidines (4,5) to obtain new 4-
alkyl(aryl/heteroaryl)-N-(5-pyridinyl-1H-1,2,4-triazol-3-yl)-6-
(trifluoromethyl)pyrimidin-2-amines (6,7), as three-component
aromatic heterocycles (Scheme 3). The method is convenient for
the synthesis of a series of ligands in which the substituents at
positions 3 and 5 of the triazole ring, as well as alkyl, aryl and
en-2-ones (1a–g) are readily available as 1,3-dielectrophile
synthetic blocks and were prepared from trifluoroacetylation
reactions of commercially available enol ethers (for 1a–b) or
generated in situ from the respective aryl- (for 1c–f) or heteroaryl-
(for 1g) methyl ketone acetals with trifluoroacetic anhydride,
respectively, in the presence of pyridine (Scheme 1), as described
in the literature [23].
In parallel, N-[5-(pyridinyl)-1H-1,2,4-triazol-3-yl]guanidines
(4,5) were obtained by an intramolecular cyclization of N-
(iso)nicotinamidobiguanides (2,3) by heating at 80 8C in a 2.5 M
sodium hydroxide solution for 6 h (Scheme 2). Previously,
commercially available hydrazides derived from nicotinic or
isonicotinic acids and cyanoguanidine reacted to each other, under
reflux for 8 h in an acidic (HCl) ethanol solution (37%) as solvent,
furnishing biguanides 2 and 3 in good yields (ꢀ80%) [24].
heteroaryl substituents attached to the position
trifluoromethylpyrimidine can also be varied.
4 of the
A review of the literature showed that the methodologies that
have been used until now [17,18,20], though efficient for the
synthesis of triazolylpyridines and triazolylpyrimidinamines,
require drastic conditions and a long reaction time, and also
involve many reactions steps with low yields. Therefore, we have
sought to develop a simple method, to obtain new 4-alkyl(aryl/
heteroaryl)-N-(5-pyridinyl-1H-1,2,4-triazol-3-yl)-6-(trifluoro-
methyl)pyrimidin-2-amines in a reaction with few steps where the
trifluoromethyl group was introduced into an electrophilic
Converging, we found that alkyl-, aryl- and heteroaryl-
substituted trifluoromethylated ketones 1a–g, when treated
directly with N-[5-(pyridinyl)-1H-1,2,4-triazol-3-yl]guanidines
(4,5) at a molar ratio of 1:1, in anhydrous ethanol as solvent
and under reflux for 18 h, produced fourteen new 2,4,6-trisubsti-
tuted-pyrimidines, as 4-alkyl(aryl/heteroaryl)-N-(5-pyridinyl-1H-
1,2,4-triazol-3-yl)-6-(trifluomethyl)pyrimidin-2-amines
(6,7)
(Scheme 3), which were easily isolated as stable white powders
with melting points in the range of 274–328 8C, in an analytically
pure form (elemental analysis) and in moderate yields (40–68%). It
should be also mentioned that due to the weakly solubility of
compounds 6 and 7 in various solvents, it was possible to perform
NMR structural analysis only in DMSO-d6.
precursor before the cyclocondensation reaction, through
conventional and efficient procedure.
a
2. Results and discussion
The structures of 4-alkyl(aryl/heteroaryl)-N-(5-pyridinyl-1H-
1,2,4-triazol-3-yl)-6-(trifluoromethyl)pyrimidin-2-amines (6a–g,
7a–g) were deduced from NMR experiments and by comparison
with NMR data of other pyrimidines [25] and pyridines [26]
formerly synthesized in our laboratory and of 1,2,4-triazoles from
literature data [27].
Recently, we reported the synthesis of a series of 4-(trihalo-
methyl)dipyrimidin-2-ylamines from the cyclocondensation reac-
tion of 4-(trichloromethyl)-2-guanidinopyrimidine with 4-alkoxy-
4-alkyl(aryl)-1,1,1-trifluoro(chloro)alk-3-en-2-ones [21]. The
reactions were carried out in acetonitrile under reflux for 16 h,
leading to the dipyrimidin-2-ylamines in 65–90% yields. However,
the 4-(trichloromethyl)-2-guanidinopyrimidine precursor was
prepared from 4-(trichloromethyl)pyrimidin-2(1H)-one by treat-
ment with POCl3 followed by nucleophilic substitution of the 2-
chloropyrimidine derivative by guanidine hydrochloride in the
The trifluoromethylated heterocycles 6 and 7 present the
typical 1H chemicals shifts of pyrimidine ring (A) proton H-5 in the
range of
1H chemical shifts in the narrow range of
proton of the pyrimidin-2-amino group showed 1H chemical shifts
d
7.36–8.01 ppm. The NH of the triazole ring (B) showed
d
13.17–13.62 ppm. The
[(chme_1)TD$FIG]
pS resence of potassium tert-butoxide, according to reference [22].
Scheme 1. Synthesis of 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones (1a–g).
[(Schme_2)TD$FIG]
Scheme 2. Synthesis of N-[5-(pyridinyl)-1H-1,2,4-triazol-3-yl]guanidines (4,5).

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H.G. Bonacorso et al. / Journal of Fluorine Chemistry 131 (2010) 1297–1301
1299
Scheme 3. Convergent synthesis of 4-alkyl(aryl/heteroaryl)-N-(5-pyridinyl-1H-1,2,4-triazol-3-yl)-6-(trifluoromethyl)pyrimidin-2-amines (6a–g, 7a-g).
also in a narrow range of
d
11.33–11.79 ppm. The 3-pyridinyl and
resolution of ꢁ0.01 ppm, in DMSO-d6 and using TMS as internal
the 4-pyridinyl rings (C) showed characteristic 1H NMR chemical
shifts according to the literature [26].
reference. 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
The typical 13C NMR chemical shifts for the trifluoromethylated
heterocycles 6 and 7 presented the pyrimidine ring carbons in the
with a split–splitless injector, auto-sampler, cross-linked HP-5
capillary column (30 m, 0.32 mm of internal diameter), and helium
was used as the carrier. Elemental analyses were performed on a
PerkinElmer 2400 CHN elemental analyzer (Sa˜o Paulo University-Sa˜o
Paulo, Brazil).
range of
effect of the substituents at position 4 of the pyrimidine ring and at
154.3–156.2 ppm (C-6, 2J = 35 Hz),
119.7–120.5 ppm (CF3,
1J = 275 Hz),
147.8–150.3 ppm (C-4) and 102.6–109.1 ppm (C-
5). The 1,2,4-triazolyl moiety showed signals in the range of
d 158.3–172.9 ppm (C-2), mainly due to the electronic
d
d
d
d
d
4.2. Preparation of 4-substituted N-(5-pyridinyl-1H-1,2,4-triazol-3-
153.7–158.9 ppm for C-30 and at
pyridinyl and the 4-pyridinyl rings again showed characteristic 13
NMR chemical shifts according to the literature [26].
d
153.7–156.5 ppm for C-50. The 3-
yl)-6-(trifluoromethyl)pyrimidin-2-amines (6,7)
C
4.2.1. General procedure
Although, the compounds 1–5 exhibited signals for all carbons
of the molecules, surprisingly, due to the weakly solubility in
DMSO-d6, we did not observe a signal relative to quaternary C-4
(pyrimidine ring A) for compounds 6c, 6e, 6g and 7d nor for
quaternary C-5 (triazole ring B) for 6c–f, 7c–d and 7f. This
phenomenon has been observed previously for other similar
trifluoromethylated pyrimidines [28].
A stirred solution of N-(5-pyridinyl-1,2,4-triazol-3-yl)guani-
dines (4,5) (0.5 g, 2.5 mmol) and 4-alkoxy-4-alkyl(aryl/hetero-
aryl)-1,1,1-trifluoroalk-3-en-2-ones (1) (2.5 mmol) in ethanol
(12 mL) was heated under reflux for 18 h. After cooling, the
products were filtered, washed with cold ethanol and dried under
reduced pressure.
4.2.1.1. N-(5-(pyridin-3-yl)-1H-1,2,4-triazol-3-yl)-6-(trifluoro-
3. Conclusion
methyl)pyrimidin-2-amine (6a). White solid, yield 63%, mp 290–
292 8C. 1H NMR (400 MHz, DMSO-d6):
d = 13.55 (s, H-1B), 11.79 (s,
In conclusion, we consider this multi-step convergent reaction
reported here to be a useful, simple, and convenient method, which
employs commercially available reagents and mild conventional
conditions to obtain novel interesting alkyl-, aryl- and heteroaryl-
substituted trifluoromethylated pyrimidines bearing at position 2
a N-moiety, viz. a pyridinyl-triazolyl system derived from nicotinic
and isonicotinic acids.
NH), 9.18 (s, H-4A), 8.94 (s, H-2C), 8.64 (s, H-6C), 8.31 (d, J = 8 Hz,
H-4C), 7.49–7.53 (m, H-5C and H-5A).
13C NMR (100 MHz, DMSO-d6):
d = 161.3 (C-2A), 158.2 (C-3B),
155.9 (C-5B), 154.8 (C-6A, 2J = 35 Hz), 150.1 (C-4A), 149.4 (C-2C),
146.3 (C-6C), 132.5 (C-4C), 123.3 (C-5C), 119.9 (CF3, 1J = 275 Hz),
108.8 (C-5A).
GC–MS (EI, 70 eV): m/z (%) = 307 (M+, 100), 238 (5), 148 (48), 79
(14).
4. Experimental
Anal. Calcd. for C12H8F3N7 (307.23): C, 46.91; H, 2.62; N, 31.91%.
Found: C, 46.89; H, 2.61; N, 31.91%.
4.1. Synthesis
4.2.1.2. 4-Methyl-N-(5-(pyridin-3-yl)-1H-1,2,4-triazol-3-yl)-6-(tri-
Unless otherwise indicated all common reagents and solvents
were used as obtained from commercial suppliers without further
purification. Cyanoguanidine, nicotinic acid hydrazide, isonicotinic
acid hydrazide were obtained commercially from Aldrich (ACS
fluoromethyl) pyrimidin-2-amine (6b). White solid, yield 68%, mp
276–277 8C. 1H NMR (400 MHz, DMSO-d6):
d = 13.22 (s, H-1B),
11.46 (s, NH), 9.17 (s, H-2C), 8.61 (d, J = 4 Hz, H-6C), 8.29 (d,
J = 8 Hz, H-4C), 7.50 (H-5C), 7.36 (s, H-5A), 2.64 (s, Me).
grade). All melting points were determined on
a
Reichert
13C NMR (100 MHz, DMSO-d6):
d = 172.9 (C-2A), 158.1 (C-3B),
Thermovar or Electrothermal Mel-Temp 3.0 apparatus. The 1H
and 13C spectra were recorded at 298 K on a Bruker DPX 400
spectrometer (1H at 400.13 MHz, 13C at 100.63 MHz) with digital
156.2 (C-5B), 154.7 (C-6A, 2J = 35 Hz), 150.3 (C-4A), 149.7 (C-2C),
146.6 (C-6C), 132.8 (C-4C), 127.1 (C-3C), 123.8 (C-5C), 120.5 (CF3,
1J = 275 Hz), 109.1 (C-5A), 23.8 (Me).

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H.G. Bonacorso et al. / Journal of Fluorine Chemistry 131 (2010) 1297–1301
GC–MS (EI, 70 eV): m/z (%) = 321 (M+, 95), 302 (10), 252 (5), 162
11.75 (s, NH), 9.18 (s, H-2C), 8.63 (s, H-6C), 8.31 (d, J = 8 Hz, H-4C),
(67), 78 (10).
8.12 (s, 1H, furyl), 7.87 (s, H-5A), 7.72 (s, 1H, furyl), 7.53 (s, H-5C),
6.84 (s, 1H, furyl).
Anal. Calcd. for C13H10F3N7 (321.26): C, 48.60; H, 3.14; N,
30.52%. Found: C, 48.72; H, 3.12; N, 30.57%.
13C NMR (100 MHz, DMSO-d6):
d = 158.3 (C-2A), 157.5 (C-3B),
156.0 (C-5B), 155.2 (C-6A, 2J = 35 Hz), 149.1 (C-2C), 146.8 (furyl),
146.1 (C-6C), 132.2 (C-4C), 123.1 (C-5C), 119.7 (CF3, 1J = 275 Hz),
115.5 (furyl), 112.5 (furyl), 102.6 (C-5A).
4.2.1.3. 4-Phenyl-N-(5-(pyridin-3-yl)-1H-1,2,4-triazol-3-yl)-6-(tri-
fluoromethyl)pyrimidin-2-amine (6c). White solid, yield 57%, mp 308–
310 8C. 1H NMR (400 MHz, DMSO-d6):
d
= 13.26 (s, H-1B), 11.37 (s,
GC–MS (EI, 70 eV): m/z (%) = 373 (M+, 100), 214 (76), 77 (29).
Anal. Calcd. for C16H10F3N7O (373.29): C, 51.48; H, 2.70; N,
26.27%. Found: C, 50.93; H, 2.69; N, 26.30%.
NH), 9.19 (s, H-2C), 8.63 (d, J = 4 Hz, H-6C), 8.29–8.31 (m, 2H, Ph and
H-4C), 7.95 (s, H-5A), 7.58–7.60 (m, 3H, Ph), 7.51 (t, J = 5 Hz, H-5C).
13C NMR (100 MHz, DMSO-d6):
d = 167.3 (C-2A), 158.9 (C-3B),
155.7 (C-6A, 2J = 35 Hz), 149.4 (C-2C), 146.3 (C-6C), 134.7 (Ph),
132.4 (C-4C), 131.5 (Ph), 128.4 (Ph), 127.3 (C-3C), 123.3 (C-5C),
120.1 (CF3, 1J = 275 Hz), 104.7 (C-5A).
4.2.1.8. N-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)-6-(trifluoro-
methyl)pyrimidin-2-amine (7a). White solid, yield 56%, mp 296–
297 8C. 1H NMR (400 MHz, DMSO-d6):
d = 13.62 (s, H-1B), 11.77 (s,
GC–MS (EI, 70 eV): m/z (%) = 383 (M+, 90), 364 (5), 224 (81), 77
(62).
Anal. Calcd. for C18H12F3N7 (383.33): C, 56.40; H, 3.16; N,
25.58%. Found: C, 56.41; H, 3.15; N, 25.59%.
NH), 8.93 (d, J = 4 Hz, H-4A), 8.68 (d, J = 5 Hz, H-2C and H-6C), 7.90
(d, J = 5 Hz, H-3C and H-5C), 7.48 (d, J = 4 Hz, H-5A).
13C NMR (100 MHz, DMSO-d6):
d = 161.5 (C-2A), 158.3 (C-3B),
156.5 (C-5B), 155.0 (C-6A, 2J = 35 Hz), 150.2 (C-4A), 150.0 (C-2C
and C-6C), 138.1 (C-4C), 120.0 (CF3, 1J = 275 Hz), 119.6 (C-3C and C-
5C), 109.1 (C-5A).
4.2.1.4. 4-(4-Fluorophenyl)-N-(5-(pyridin-3-yl)-1H-1,2,4-triazol-3-
yl)-6-(trifluoromethyl)pyrimidin-2-amine (6d). White solid, yield
48%, mp 308–310 8C. 1H NMR (400 MHz, DMSO-d6):
GC–MS (EI, 70 eV): m/z (%) = 307 (M+, 100), 288 (5), 238 (5), 148
(62), 79 (10).
d = 13.22 (s,
H-1B), 11.41 (s, NH), 9.18 (s, H-2C), 8.62 (s, H-6C), 8.36–8.40 (m,
2H, Ph), 8.30 (d, J = 8 Hz, H-4C), 7.96 (s, H-5A), 7.56 (s, H-5C), 7.38–
7.42 (m, 2H, Ph).
Anal. Calcd. for C12H8F3N7 (307.23): C, 46.91; H, 2.62; N, 31.91%.
Found: C, 46.82; H, 2.70; N, 31.93%.
13C NMR (100 MHz, DMSO-d6):
d
= 166.4 (C-2A), 164.5 (Ph,
4.2.1.9. 4-Methyl-N-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)-6-(tri-
1J = 250 Hz), 158.9 (C-3B), 156.0 (C-6A, 2J = 35 Hz), 150.0 (C-2C),
149.3 (C-4A), 146.3 (C-6C), 134.3 (C-4C), 131.3 (Ph), 130.2 (Ph,
3J = 9 Hz), 127.2 (C-3C), 124.4 (C-5C), 120.2 (CF3, 1J = 275 Hz), 115.6
(Ph, 2J = 22 Hz), 105.2 (C-5A).
fluoromethyl)pyrimidin-2-amine (7b). White solid, yield 65%, mp
305–306 8C. 1H NMR (400 MHz, DMSO-d6):
d = 13.33 (s, H-1B),
11.47 (s, NH), 8.67 (d, J = 5 Hz, H-2C and H-6C), 7.89 (d, J = 5 Hz, H-
3C and H-6C), 7.36 (s, H-5A), 2.64 (s, Me).
GC–MS (EI, 70 eV): m/z (%) = 333 (100), 247 (5), 77 (67).
Anal. Calcd. for C18H11F4N7 (401.32): C, 53.87; H, 2.76; N,
24.43%. Found: C, 53.61; H, 2.71; N, 24.35%.
13C NMR (100 MHz, DMSO-d6):
d = 172.2 (C-2A), 157.7 (C-3B),
156.0 (C-5B), 154.3 (C-6A, 2J = 35 Hz), 150.0 (C-4A), 149.6 (C-2C
and C-6C), 137.9 (C-4C), 119.9 (CF3, 1J = 275 Hz), 119.2 (C-3C and C-
5C), 108.7 (C-5A), 23.2 (Me).
4.2.1.5. 4-(4-Methylphenyl)-N-(5-(pyridin-3-yl)-1H-1,2,4-triazol-3-
GC–MS (EI, 70 eV): m/z (%) = 321 (M+, 100), 302 (5), 251 (2), 162
(81), 78 (6).
Anal. Calcd. for C13H10F3N7 (321.26): C, 48.60; H, 3.14; N,
30.52%. Found: C, 48.57; H, 3.09; N, 30.48%.
yl)-6-(trifluoromethyl)pyrimidin-2-amine (6e). White solid, yield 52%,
mp 325–328 8C. 1H NMR (400 MHz, DMSO-d6):
d
= 13.34 (s, H-1B),
11.56 (s, NH), 9.19 (s, H-2C), 8.64 (s, H-6C), 8.32 (d, J = 8 Hz, H-4C),
8.24 (s, 2H, Ph), 8.00 (s, H-5A), 7.54 (s, H-5C), 7.41 (s, 2H, Ph), 2.42
(s, Me).
4.2.1.10. 4-Phenyl-N-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)-6-(tri-
13C NMR (100 MHz, DMSO-d6):
d
= 167.3 (C-2A), 158.3 (C-3B),
fluoromethyl)pyrimidin-2-amine (7c). White solid, yield 58%, mp 274–
275 8C. 1H NMR (400 MHz, DMSO-d6):
d = 13.54 (s, H-1B), 11.58 (s,
NH), 8.71 (d, J = 5 Hz; H-2C and H-6C), 8.34 (d, J = 8 Hz; 2H, Ph),
8.00 (s, H-5A), 7.93 (d, J = 5 Hz, H-3C and H-5C), 7.60–7.63 (m, 3H,
Ph).
155.7 (C-6A, 2J = 35 Hz), 149.5 (C-2C), 146.4 (C-6C), 142.7 (Ph),
132.4 (C-4C), 131.8 (Ph), 128.4 (Ph), 127.5 (C-3C), 123.3 (C-5C),
120.1 (CF3, 1J = 275 Hz), 105.6 (C-5A), 24.9 (Me).
GC–MS (EI, 70 eV): m/z (%) = 397 (M+, 100), 238 (43), 77 (5).
Anal. Calcd. for C19H14F3N7 (397.36): C, 57.43; H, 3.55; N,
24.67%. Found: C, 57.40; H, 3.47; N, 24.63%.
13C NMR (100 MHz, DMSO-d6):
d = 167.2 (C-2A), 158.7 (C-3B),
155.6 (C-6A, 2J = 35 Hz), 149.7 (C-2C and C-6C), 149.4 (C-4A), 137.6
(C-4C), 134.5 (Ph), 131.6 (Ph), 128.4 (Ph), 127.3 (Ph), 120.0 (CF3,
1J = 275 Hz), 119.2 (C-3C and C-5C), 104.8 (C-5A).
4.2.1.6. 4-(4-Methoxyphenyl)-N-(5-(pyridin-3-yl)-1H-1,2,4-triazol-
3-yl)-6-(trifluoromethyl)pyrimidin-2-amine (6f). White solid, yield
GC–MS (EI, 70 eV): m/z (%) = 383 (M+, 88), 224 (100), 78 (56).
Anal. Calcd. for C18H12F3N7 (383.33): C, 56.40; H, 3.16; N,
25.58%. Found: C, 56.42; H, 3.10; N, 25.63%.
55%, mp 311–313 8C. 1H NMR (400 MHz, DMSO-d6):
d = 13.17 (s, H-
1B), 11.33 (s, NH), 9.18 (s, H-2C), 8.62 (d, J = 4 Hz, H-6C), 8.32 (s, H-
4C), 8.28 (d, J = 8 Hz, 2H, Ph), 7.89 (s, H-5A), 7.51 (s, H-5C), 7.12 (d,
J = 8 Hz, 2H, Ph), 3.87 (s, Me).
4.2.1.11. 4-(4-Fluorophenyl)-N-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-
13C NMR (100 MHz, DMSO-d6):
d
= 166.9 (C-2A), 162.4 (Ph),
yl)-6-(trifluoromethyl)pyrimidin-2-amine (7d). White solid, yield
40%, mp 280–282 8C. 1H NMR (400 MHz,DMSO-d6):
d = 13.54 (s,
158.8 (C-3B), 155.5 (C-6A, 2J = 35 Hz), 150.1 (C-4A), 149.7 (C-2C),
146.9 (C-6C), 133.0 (C-4C), 130.0 (Ph), 127.6 (C-3C), 127.0 (Ph),
124.7 (C-5C), 120.1 (CF3, 1J = 275 Hz), 114.1 (Ph), 104.3 (C-5A), 55.2
(OMe).
H-1B), 11.64 (s, NH), 8.70 (d, J = 5 Hz, H-2C and H-6C), 8.39–8.46
(m, 2H, Ph), 8.01 (s, H-5A), 7.93 (d, J = 5 Hz, H-3C and H-5C), 7.40–
7.49 (m, 2H, Ph).
GC–MS (EI, 70 eV): m/z (%) = 413 (M+, 100), 254 (52), 77 (10).
Anal. Calcd. for C19H14F3N7O (413.36): C, 55.21; H, 3.41; N,
23.72%. Found: C, 55.17; H, 3.41; N, 23.68%.
13C NMR (100 MHz, DMSO-d6):
d = 166.4 (C-2A), 164.4 (Ph,
1J = 250 Hz), 158.9 (C-3B), 156.0 (C-6A, 2J = 35 Hz), 150.0 (C-2C and
C-6C), 138.2 (C-4C), 131.3 (Ph), 130.2 (Ph, 3J = 9 Hz), 120.1 (CF3,
1J = 275 Hz), 119.5 (C-3C and C-5C), 115.6 (Ph, 2J = 22 Hz), 105.0 (C-
5A).
4.2.1.7. 4-(2-Furyl)-N-(5-(pyridin-3-yl)-1H-1,2,4-triazol-3-yl)-6-
(trifluoromethyl) pyrimidin-2-amine (6g). White solid, yield 45%, mp
GC–MS (EI, 70 eV): m/z (%) = 401 (M+, 100), 382 (5), 242 (62), 78
(10).
281–283 8C. 1H NMR (400 MHz, DMSO-d6):
d = 13.17 (s, H-1B),

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 131 (2010) 1297–1301
1301
(b) R. Filler, Y. Kobayashi, L.M. Yagupolskii, Organofluorine Compounds in Medi-
cal Chemistry and Biomedical Application, Elsevier, Amsterdam, 1993.
[4] R. Filler, R.E. Banks, Organofluorine and Their Industrial Applications, Ellis Hor-
wood, Chichester, UK, 1979.
Anal. Calcd. for C18H11F4N7 (401.32): C, 53.87; H, 2.76; N,
24.43%. Found: C, 53.85; H, 2.69; N, 24.10%.
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4.2.1.12. 4-(4-Methylphenyl)-N-(5-(pyridin-4-yl)-1H-1,2,4-triazol-
3-yl)-6-(trifluoromethyl)pyrimidin-2-amine (7e). White solid, yield
59%, mp 312–314 8C. 1H NMR (400 MHz, DMSO-d6):
d = 13.48 (s, H-
(b) F. Leroux, O. Lefebvre, M. Schlosser, Eur. J. Org. Chem. (2006) 3147;
(c) J.T. Welch, Tetrahedron 43 (1987) 3123;
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(2005) 3288.
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(b) M.A. McClinton, D.A. McClinton, Tetrahedron 48 (32) (1992) 6555;
(c) W.K.J. Hagmann, J. Med. Chem. 51 (2008) 4359;
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1B), 11.57 (s, NH), 8.70 (d, J = 5 Hz, H-2C and H-6C), 8.24 (d,
J = 8 Hz, 2H, Ph), 8.00 (s, H-5A), 7.92 (d, J = 5 Hz, H-3C and H-5C),
7.40 (d, J = 8 Hz, 2H, Ph), 2.41 (s, Me).
13C NMR (100 MHz, DMSO-d6 + TFA):
d = 162.9 (C-6A,
2J = 40 Hz), 158.4 (C-2A), 154.7 (C-3B), 153.7 (C-5B), 151.5 (C-
4C), 147.8 (C-4), 146.3 (C-2C and C-6C), 134.5 (Ph), 131.6 (Ph),
128.2 (Ph), 119.0 (CF3, 1J = 285 Hz), 112.4 (C-5A), 23.8 (Me).
GC–MS (EI, 70 eV): m/z (%) = 397 (M+, 100), 238 (86), 77 (14).
Anal. Calcd. for C19H14F3N7 (397.36): C, 57.43; H, 3.55; N,
24.67%. Found: C, 57.51; H, 3.61; N, 24.69%.
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Pergamon Press, 1979, pp. 85–141.
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p. 849.
[13] A.R. Katritzky, C.W. Rees, E.F.V. Scriven, 1st ed., Comprehensive Heterocyclic
Chemistry II, vols. 2–8, Pergamon Press, Oxford, 1996.
[14] R.M. Acheson, An Introduction to the Chemistry of Heterocyclic Compounds, 3rd
ed., John Wiley & Sons, 1976, pp. 392–407.
4.2.1.13. 4-(4-Methoxyphenyl)-N-(5-(pyridin-4-yl)-1H-1,2,4-tria-
zol-3-yl)-6-(trifluoromethyl)pyrimidin-2-amine (7f). White solid,
yield 51%, mp 289–290 8C. 1H NMR (400 MHz, DMSO-d6):
[15] D.L. Ladd, J. Heterocycl. Chem. 19 (1982) 917.
d
= 13.48 (s, H-1B), 11.50 (s, NH), 8.71 (d, J = 5 Hz, H-2C and H-
[16] D.J. Brown, in: A. Weissberger (Ed.), The Chemistry of Heterocyclic Compounds,
vol. 16, Wiley Interscience Publishers, New York, 1962, Chapter IX, 306.
[17] S. Ahmad, C.S. Madsen, P.D. Stein, E. Janovitz, C. Huang, K. Ngu, S. Bisaha, L.J.
Kennedy, B.C. Chen, R. Zhao, D. Sitkoff, H. Monshizadegan, X. Yin, C.S. Ryan, R.
Zhang, M. Giancarli, E. Bird, M. Chang, X. Chen, R. Setters, D. Search, S. Zhuang, V.
Nguyen-Tran, C.A. Cuff, T. Harrity, C.J. Darienzo, T. Li, R.A. Reeves, M.A. Blanar, J.C.
Barrich, R. Zahler, J.A. Robl, J. Med. Chem. 51 (2008) 2722.
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Antibiot. 54 (2001) 460.
[19] X. Ouyang, X. Chen, E.L. Piatnitski, A.S. Kiselyov, H.Y. He, Y. Mao, V. Pattaropong, Y.
Yu, K.H. Kim, J. Kincaid, L. Smith, W.C. Wong, S.P. Lee, D.L. Milligan, A. Malikzay, J.
Fleming, J. Gerlak, D. Deevi, J.F. Doody, H.H. Chiang, S.N. Patel, Y. Wang, R.L. Rolser,
P. Kussie, M. Labelle, M.C. Tuma, Bioorg. Med. Chem. Lett. 15 (2005) 5154.
[20] C.W. Thornber, J.M. Farell, D.S. Clarke, Synthesis (1983) 222.
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Chem. 39 (2002) 943.
6C), 8.33 (d, J = 8 Hz; 2H, Ph), 7.97 (s, H-5A), 7.93 (d, J = 5 Hz, H-3C
and H-5C), 7.14 (d, J = 8 Hz, 2H, Ph), 3.87 (s, Me).
13C NMR (100 MHz, DMSO-d6):
d = 166.8 (C-2A), 162.4 (Ph),
158.8 (C-3B), 155.5 (C-6A, 2J = 35 Hz), 150.1 (C-2C and C-6C), 149.7
(C-4A), 137.9 (C-4C), 129.5 (Ph), 127.0 (Ph), 120.4 (CF3,
1J = 275 Hz), 119.5 (C-3C and C-5C), 114.1 (Ph), 104.3 (C-5A),
55.2 (OMe).
GC–MS (EI, 70 eV): m/z (%) = 413 (M+, 100), 344 (6), 254 (65), 77
(15).
Anal. Calcd. for C19H14F3N7O (413.36): C, 55.21; H, 3.41; N,
23.72%. Found: C, 54.81; H, 3.45; N, 23.71%.
[22] N. Zanatta, I.L. Pacholski, D. Faoro, H.G. Bonacorso, M.A.P. Martins, Synth. Com-
mun. 31 (2001) 2855.
4.2.1.14. 4-(2-Furyl)-N-(5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl)-6-
(trifluoromethyl) pyrimidin-2-amine (7g). White solid, yield 47%, mp
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(b) F. Effenberger, K.H. Schonwalder, Chem. Ber. 117 (1984) 3270;
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(1986) 340;
305–307 8C. 1H NMR (400 MHz, DMSO-d6):
d = 13.29 (s, H-1B),
11.76 (s, NH), 8.70 (d, J = 5 Hz; H-2C and H-6C), 8.12 (s, 1H, furyl),
7.92 (d, J = 5 Hz, H-3C and H-5C), 7.87 (s, H-5A), 7.71 (s, 1H, furyl),
6.84 (s, 1H, furyl).
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2766;
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(1994) 24;
(i) H.G. Bonacorso, S.R.T. Bittencourt, M.A.P. Martins, R.V. Lourega, N. Zanatta,
A.F.C. Flores, J. Fluorine Chem. 99 (1999) 177;
(j) A.F.C. Flores, S. Brondani, N. Zanatta, A. Rosa, M.A.P. Martins, Tetrahedron Lett.
43 (2002) 8701.
13C NMR (100 MHz, DMSO-d6):
d = 158.6 (C-2A), 157.9 (C-5B),
156.4 (C-5B), 155.6 (C-6, 2J = 35 Hz), 150.0 (C-2C and C-6C), 149.5
(C-4A), 147.4 (furyl), 138.0 (C-4C), 120.1 (CF3, 1J = 275 Hz), 119.5
(C-3C and C-5C), 116.1 (furyl), 113.0 (furyl), 103.1 (C-5A).
GC–MS (EI, 70 eV): m/z (%) = 373 (M+, 75), 354 (6), 214 (100), 78
(31).
Anal. Calcd. for C16H10F3N7O (373.29): C, 51.48; H, 2.70; N,
26.27%. Found: C, 51.62; H, 2.68; N, 26.29%.
[24] (a) P. Mamalis, J. Green, D. McHale, J. Chem. Soc. (1960) 229;
(b) W. Ogemann, D. Artini, L. Canavesi, G. Tosolini, Chem. Ber. 96 (1963) 2909;
(c) A.V. Dolzhenko, B.J. Tan, A.V. Dolzhenko, G.N.C. Chiu, W.K. Chui, J. Fluorine
Chem. 129 (2008) 429.
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Fluorine Chem. 120 (2003) 29;
Acknowledgements
The authors thank the financial support from Conselho Nacional
(b) N. Zanatta, L. Fantinel, R.V. Lourega, H.G. Bonacorso, M.A.P. Martins, Synthesis
(2008) 358;
(c) N. Zanatta, S.S. Amaral, J.M. dos Santos, D.L. de Mello, L. da S. Fernandes, H.G.
Bonacorso, M.A.P. Martins, A.D. Andricopulo, D.M. Borchhardt, Bioorg. Med.
Chem. 16 (2008) 10236;
´
´
de Desenvolvimento Cientıfico e Tecnologico – CNPq (Proc.
303.296/2008-9). Fellowships from Coordenac¸a˜o de Aper-
´
feic¸oamento de Pessoal de Nıvel Superior – CAPES are also
(d) N. Zanatta, D. Faoro, L. da S. Fernandes, P.B. Brondani, D.C. Flores, A.F.C. Flores,
H.G. Bonacorso, M.A.P. Martins, Eur. J. Org. Chem. (2008) 5835.
[26] (a) H.G. Bonacorso, G.R. Paim, C.Z. Guerra, R.C. Sehnem, C.A. Cechinel, L.M.F. Porte,
M.A.P. Martins, N. Zanatta, J. Braz. Chem. Soc. 20 (2009) 509;
(b) H.G. Bonacorso, R.V. Lourega, E.D. Deon, N. Zanatta, M.A.P. Martins, Tetrahe-
dron Lett. 48 (2007) 4835;
acknowledged.
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