Regioselective Synthesis of 5-(Trifluoromethyl)[1,2,4]triazolo[1,5- a ]pyrimidines from β-Enamino Diketones

Article abstract of DOI:10.1055/s-0037-1611765

The use of β-enamino diketones as an easy entry to the regioselective synthesis of [1,2,4]triazolo[1,5- a ]pyrimidines is reported. These ketones reacted with 3-amino-1 H -1,2,4-triazoles to furnish exclusively 6-substituted 5-(trifluoromethyl)[1,2,4]tria

Full text of DOI:10.1055/s-0037-1611765

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
paper
A
en
Synthesis
V. P. Andrade et al.
Paper
Regioselective Synthesis of 5-(Trifluoromethyl)[1,2,4]triazolo
1,5-a]pyrimidines from -Enamino Diketones
[
Valquiria P. Andrade
Mateus Mittersteiner
Helio G. Bonacorso
Clarissa P. Frizzo
R1
0
0
0
0-0
0
0
2-8
5
0
1-8
4
4
X
N
O
O
N
O
CF3
New starting material for
triazolopyrimidine synthesis
N
H2N
H
R
CF3
R
N
High yielding and easy
purification products
Marcos A. P. Martins
68–94% yields
Me2N
N
N
Nilo Zanatta*
0
0
0
0-0
0
0
2-0
9
5
9-
9
0
4
3
Access to a new pattern of
substituition on the pyrimidine ring
N
R1
R = aryl, heteroaryl
R1 = H, SMe, CO2H
Núcleo de Química de Heterociclos (NUQUIMHE), Universidade
Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
nilo.zanatta@ufsm.br
Received: 30.01.2019
Accepted after revision: 01.03.2019
Published online: 21.03.2019
group recently reported the preparation of 7-(trifluoro-
methyl)[1,2,4]triazolo[1,5-a]pyrimidines, from -alkoxyvi-
nyl trifluoromethyl ketones (enones) and the aforemen-
DOI: 10.1055/s-0037-1611765; Art ID: ss-2019-m0062-op
19
tioned aminoazoles, in very good yields (see Scheme 1). In
this previous study, it was shown that the reaction of 4-
substituted enones and 3-aminotriazoles furnished exclu-
sively 5-substituted 7-(trifluoromethyl)triazolopyrimi-
dines. In this present study, the same reaction using -
enamino diketones furnished only 6-substituted 5-(trifluo-
romethyl)triazolopyrimidines (Scheme 1).
Abstract The use of -enamino diketones as an easy entry to the regi-
oselective synthesis of [1,2,4]triazolo[1,5-a]pyrimidines is reported.
These ketones reacted with 3-amino-1H-1,2,4-triazoles to furnish exclu-
sively6-substituted5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidines
in yields of up to 95%. The regioselectivity of the reactions performed
was maintained regardless of the substituent in the starting ketone or
aminoazole.
Key words -enamino diketones, 1,3-diones, triazolopyrimidines,
aminotriazoles, fluorinated heterocycles
Previous work
R1
CF3
7
N
1
O
OR1
N
N 2
6
N
N
R1
Due to their extensive biological, pharmacological, and
agricultural applications, the triazolopyrimidine scaffold
and its derivatives are an important class of compounds.1
Despite the extensive results that have been reported re-
garding the synthesis of compounds containing these py-
rimidine–azole-fused heterocycles, there are few reports
regarding those bearing a trifluoromethyl group. Since it is
widely known that the insertion of fluorinated groups (e.g.,
H2N
H
F3C
R
R
5
N
3a
N
3
4
–4
R1
This work
N
O
O
N
O
CF3
N
5
H2N
6
R
CF3
H
R
N4
3a
N 3
7
Me2N
N
CF ) can affect the chemical, physical, and biochemical
3
1N
R = aryl, heteroaryl.
R1 = H, SMe, CO2H.
2
properties of a targeted molecule, the development of new
and efficient synthetic routes for these compounds is still a
challenge to be explored.5–9
R1
3
Scheme 1 Comparison of the previously reported and present studies
A common strategy for the synthesis of the triazolopy-
rimidine scaffold involves the cyclocondensation reaction
of 1,3-dielectrophilic compounds, such as ,-unsaturated
1
In turn, -enamino diketones (in which R = CO Et, see
2
10–13
14,15
ketones
and 1,3-dicarbonyl compounds,
with 3-
Scheme 2) have proven to be suitable starting materials to
20
21
22
amino-1H-1,2,4-triazoles. Although these starting materi-
als are suitable for the synthesis of the targeted products,
they usually furnish regioisomeric mixtures, with lengthy
purification steps and low-yielding products.16–18 In our
search for ways to overcome these drawbacks, our research
prepare pyrazoles, isoxazoles, pyrimidines, and other
aza-heterocycles.23 The synthetic versatility of these specif-
ic ketones can be attributed to their three electrophilic re-
active sites, which have very different reactivity in cyclo-
condensation reactions, which leads to highly regiocon-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

B
Synthesis
V. P. Andrade et al.
Paper
trolled products. In the case of reactions with
dinucleophiles, electrophilic centers 2 and 3 undergo the
cyclocondensation preferably over 1 (Scheme 2).
ed 3,5-diamino[1,2,4]triazoles, using acetic acid and reflux
for 24 hours. However, using these conditions for our model
reaction, we observed the elimination of COCF from 1a, be-
3
fore attack of the aminoazole 2a (Scheme 3). Thus, the -
enamino diketones underwent the reaction with 2a to fur-
nish 4, a compound that has already been reported. To ob-
O
19
R
N
tain the desired products and to maintain the CF group in
3
EtO2C
N
O
Ph
the molecule (e.g., to provide either the 1,5-regioisomer
and/or the 1,7-regioisomer; see Scheme 3), other reaction
conditions (see Table 1) had to be developed.
O
CF3
O
O
guanidine
R
N
R
R1
hydroxylamine
CO Et
2
R
1
3
N
NH2
Me2N
R = alkyl, aryl.
R1 = CO2Et, CF3.
2
N
Table 1 Optimization of the Reaction Conditions for the Synthesis of 3aa
O
O
Entry
Solvent
Temp (°C)
Time (h)
Yield (%)b
R1
R
1
2
3
4
5
6
AcOH
MeCN
MeCN
MeCN
MeCN
acetone
EtOH
118
25
82
82
82
56
79
24
24
8
–c
N
N
32
35
70
88
–d
Ph
Scheme 2 Uses of -enamino diketones20–23
16
24
24
24
Most of these heterocycles are prepared using -enami-
no diketones (in which R = CO Et), and the use of deriva-
tives containing the R = CF3 moiety has been little ex-
plored. In previous studies with such substrates, a mixture
of regioisomers and low-yielding products were usually ob-
1
2
1
–d
7
a
Reaction conditions: 1a (1 mmol), 2a (1.5 mmol), solvent (5 mL).
Isolated yield after recrystallization.
b
c
Compound 4 was obtained in 65% yield.
Starting material was recovered.
24–26
tained.
However, in this present study, we explored the
d
synthetic versatility of trifluoromethyl -enamino dike-
tones in the cyclocondensation reaction with 3-amino-1H-
1
,2,4-triazoles, in order to prepare a series of new 6-substi-
Due to compound 1a suffering elimination of COCF (in
3
29
tuted 5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidines,
which furnished both high yields and excellent regioselec-
tivity.
Initially, a series of -enamino diketones was synthe-
sized by the C-acylation reaction of -enaminones with tri-
fluoroacetic anhydride in the presence of pyridine, in accor-
dance with the method developed previously. The reac-
tion conditions first employed were in accordance with
those of Chernyshev and co-workers who prepared triflu-
oromethyl derivatives containing the triazolopyrimidine
scaffold from the reaction of -keto esters with 1-substitut-
the form of trifluoroacetic acid) when the literature con-
ditions were employed,28 we used solvents other than ace-
tic acid to optimize the reactions conditions. The choice of
solvents shown in Table 1 was based on the ability to solu-
bilize 2a. The reactions were followed by TLC analyses, in
which the disappearance of 1a was examined. The best re-
action conditions found were when MeCN was used as the
solvent under reflux conditions, since it is already known
that heat favors cyclocondensation reactions (Table 1). The
optimized time was 24 hours, which is in agreement with
27
28
O
CF3
5
N 4
O
CF3
7
O
O
1
N
6
6
N
Ph
Ph
N
N
Ph
Me2N
CF3
+
2
7
N
H2N
5
N
H
N
N 3
2
N
3
4
N
1
1
,7-regioisomer
1a
2a
3a
(
not observed)
1
,5-regioisomer
(obtained)
AcOH,
18 °C
–COCF3
1
Ph
N
N
N
N
4
Scheme 3 Possible regioisomers formed from the cyclocondensation reaction of 1a with 2a, and product from elimination of the COCF group
3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

C
Synthesis
V. P. Andrade et al.
Paper
O
CF3
O
O
N
MeCN
N
R
N
+
R
CF3
N
8
2 °C, 24 h
H2N
H
N
N
Me2N
O
1
a–g
3a–g
N
2a
CF3
O
CF3
N
O
CF3
N
N
N
N
N
MeO
N
N
N
N
N
N
3a - 88%
3b - 91%
3c - 94%
O
CF3
O
CF3
O
CF3
N
N
N
S
Br
N
F
N
N
N
N
N
e - 81% N
N
N
3
3f - 68%
3d - 95%
O
CF3
N
Cl
N
N
N
3g - 85%
Scheme 4 Scope of [1,2,4]triazolo[1,5-a]pyrimidines when varying the starting -enamino diketone
the literature for similar reactions.28,30 The product was pu-
rified by recrystallization from hexane/chloroform (1:1).
Having established the best conditions for the synthesis
of 3a, we prepared a series of [1,2,4]triazolo[1,5-a]pyrimi-
dines by reacting different -enamino diketones 1a–g with
aminoazole 2a. The products were obtained in moderate
With the optimized conditions for obtaining compound
3a in hand (Table 1, entry 5), different aminotriazoles were
used to enhance the reaction scope (Scheme 5). When ami-
notriazole 2b was used, the corresponding triazolopyrimi-
dine 5a was furnished in 80% yield. However, when the
aminotriazolecarboxylic acid 2c was used, we observed
elimination of the carboxyl group, which may have oc-
curred due to the high temperature used in the reaction.
The corresponding product 3a was obtained in 77% yield.
The decarboxylation reaction of aminotriazoles under heat-
(68%) to high (95%) yields; the isolated yields and structures
are shown in Scheme 4.
The regiochemistry of the products in Scheme 4 was
confirmed by single crystal X-ray analysis of compound 3e
31
30
(
Figure 1), where the trifluoromethyl group is observed at
ing has already been reported.
the 5-position of the pyrimidine ring.
O
CF3
R = SMe (2b)
Ph
N
N
N
N
R
SMe
O
O
N
5a (80%)
N
Ph
Me2N
CF3
+
N
H2N
H
O
CF3
1a
2b-c
Ph
N
R = CO2H (2c)
CO2H
N
N
–
N
3a (77%)
Figure 1 ORTEP diagram of compound 3e.31 Ellipsoids are drawn at the
Scheme 5 Reaction of 1a with different starting aminotriazoles 2b,c
50% probability level.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

D
Synthesis
V. P. Andrade et al.
Paper
Despite the low yield when the reaction of 1a with 2a
was carried out at room temperature (Table 1, entry 2), we
subsequently attempted to perform the reaction with 2c at
room temperature to avoid the decarboxylation process.
Consequently, without the heating, the solubility of this
specific aminotriazole was too low in all of the tested sol-
vents, and only the starting materials were recovered. Giv-
en this result, we enhanced the reaction scope of the
tained for compound 3a, for which the NMR data can be
used to characterize all compounds from series 3 and 5.
O
CF3
48.4
1
N
1
40.3
153.9
H
N
N
10.00
N
159.3
[
1,2,4]triazolo[1,5-a]pyrimidines by reacting different -
H 9.00
enamino diketones 1a–d with aminotriazole 2b. The choice
of the -enamino diketones used in this part of the study
was based on the best isolated yields obtained for the com-
pounds in Scheme 4. The isolated yields for compounds 5a–d
Figure 2 1H (in blue), 13C (in red), and 19F (in green) NMR chemical
shifts obtained for compound 3a
(
Table 2) obtained when using 2b were very similar to
In agreement with the crystalline structure of the start-
ing -enamino diketones,27 a plausible mechanism for the
reaction is presented. Single crystals of -enamino diketone
1b were obtained by slow evaporation of a chloroform solu-
when 2a was used, which indicates good tolerance regard-
ing structural aspects of the starting materials.
Products 3a–g and 5a–d were unambiguously charac-
1
13
19
31
terized by GC-MS and H, C, and F NMR spectroscopy.
tion. Its ORTEP diagram (Scheme 6) shows that the car-
Figure 2 shows the H, 13C, and 19F NMR chemical shifts ob-
1
bonyl attached to the CF group is in the plane of the car-
3
bon–carbon double bond and the dimethylamino group is
in an E-configuration to this group, making possible the
conjugation of these two groups. On the other hand, the
carbonyl group attached to the aryl group is outside the
molecular plane, not allowing the conjugation of that car-
bonyl with the rest of the molecule. Thus, the nitrogen of
the triazole ring attacks the -position of the diketone
Table 2 Reaction Scope of [1,2,4]Triazolo[1,5-a]pyrimidines 5a–da
SMe
O
CF3
O
O
N
MeCN
R
N
N
+
R
CF3
N
82 °C, 24 h
H2N
H
N
N
(Scheme 6), followed by the delocalization of charge and
Me2N
N
1a–d
2b
5a–d
SMe
elimination of a dimethylamine molecule (intermediate I).
In the next step, the amino group attacks the carbonyl car-
Entry
R
-Enamino diketone Product
Yield (%)b
bon next to the CF (intermediate II), resulting in the clo-
3
sure of the pyrimidine ring (intermediate III), which, by de-
localization of charges, eliminates a water molecule, there-
by providing products 3a–g and 5a–d.
In summary, we have presented a successful application
of trifluoromethyl -enamino diketones for the regioselec-
tive synthesis of a series of new 6-substituted 5-(trifluoro-
1
2
3
C
6
H
5
1a
1b
1c
1d
5a
5b
5c
5d
80
88
84
75
6 4
4-MeC H
4-MeOC
6 4
H
4
2-thienyl
a
Reaction conditions: 1a–d (1 mmol), 2b (1.5 mmol), MeCN (5 mL).
Isolated yield after recrystallization.
b
H
O
O
O
O
NH2
R
CF3
R
CF3
NH2
–
HNMe2
H
N
N
Me2N
Me2N
N
N
R1
N
N
R1
I
H
N
O
R
O
O
O
CF3
N
F3C
O
CF3
R
N
H
N
R
N
– H2O
N
N
N
NH2
N
N
N
R1
R1
R1
3a–g
ad
5
II
III
Scheme 6 ORTEP diagram of -enamino diketone 1b31 (ellipsoids are drawn at the 50% probability level) and proposed mechanism for the synthesis of
a–g and 5a–d.
3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

E
Synthesis
V. P. Andrade et al.
Paper
1
methyl)[1,2,4]triazolo[1,5-a]pyrimidines. Compounds 3a–g
and 5a–d were obtained in moderate to high yields,
through the cyclocondensation reaction of -enamino dike-
tones with 3-amino-1H-1,2,4-triazoles. These new synthe-
sized compounds are excellent models for studies on bio-
logical and pharmacological activity.
H NMR (400 MHz, CDCl ):  = 9.05 (s, 1 H, H-7), 8.76 (s, 1 H, H-2),
.75 (d, J = 7.5 Hz, 2 H, Ar), 7.36 (d, J = 7.5 Hz, 2 H, Ar), 2.49 (s, 3 H,
3
7
Me).
13
C NMR (100 MHz, DMSO-d ):  = 189.4 (C=O), 159.2 (C-2), 153.7 (C-
6
2
3
1
a), 148.4 (q, J = 36.4 Hz, C-5), 146.2 (C-7), 140.0 (Ar), 134.1 (Ar),
31.0 (Ar), 129.9 (Ar), 121.2 (C-6), 120.6 (q, J = 276.5 Hz, CF ), 21.7
C–F
1
C–F
3
(Me).
19
F NMR (565 MHz, DMSO-d ):  = –63.90 (CF ).
6
3
+
GC-MS (EI, 70 eV): m/z (%) = 306 (43, M ), 215 (6), 119 (100), 91 (37).
Anal. Calcd for C14 O: C, 54.91; H, 2.96; N, 18.29 Found: C,
54.91; H, 3.08; N, 18.12.
All reagents were acquired from commercial suppliers and used with-
1
13
out further purification. H and C NMR spectra were recorded on a
Bruker Avance III spectrometer operating at 400 MHz and at 100
MHz, respectively, on solutions in DMSO-d or CDCl . Chemical shifts
H F N
9 3 4
6
3
are reported in parts per million (ppm) relative to the internal stan-
dard TMS (0 ppm). Peak patterns are indicated using standard abbre-
viations and coupling constants, J, are reported in hertz (Hz). C NMR
(
4-Methoxyphenyl)(5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]py-
rimidin-6-yl)methanone (3c)
13
Yellow solid; yield: 303 mg (94%); mp 157–160 °C.
spectra were referenced to the internal solvent signals (central peak
1H NMR (400 MHz, CDCl
.83 (d, J = 8.9 Hz, 2 H, Ar), 7.02 (d, J = 8.9 Hz, 2 H, Ar), 3.93 (s, 3 H,
OMe).
):  = 9.06 (s, 1 H, H-7), 8.75 (s, 1 H, H-2),
3
19
3
9.5 ppm in DMSO-d6 or 77.0 ppm in CDCl3). F NMR spectra were
7
recorded on a Bruker Avance III 600 spectrometer (operating at 565
MHz), on solutions in DMSO-d and using fluorobenzene as external
6
1
3
reference with chemical shifts reported relative to the CFCl standard.
C NMR (100 MHz, DMSO-d
6
):  = 188.0 (C=O), 165.1 (Ar), 159.1 (C-
3
2
Mass spectra (GC-MS) were recorded on an Agilent 5975B GC-MSD
spectrometer in EI mode. The GC was equipped with a split–splitless
injector, autosampler, and crosslinked HP-5 capillary column (30 m,
2), 153.7 (C-3a), 148.4 (q, JC–F = 36.1 Hz, C-5), 139.9 (C-7), 133.5 (Ar),
129.5 (Ar), 121.4 (C-6), 120.6 (q, JC–F = 275.7 Hz, CF
(OMe).
1
), 114.8 (Ar), 56.2
3
0
.32 mm internal diameter), and helium was used as the carrier gas.
+
GC-MS (EI, 70 eV): m/z (%) = 322 (55, M ), 135 (100), 107 (8), 77 (15).
CHN microanalyses were performed on an elemental analyzer at the
Chemistry Institute of São Paulo University, Brazil.
Anal. Calcd for C14H F N O : C, 52.18; H, 2.82; N, 17.39. Found: C,
9
3
4
2
52.31; H, 2.98; N, 17.17.
5
-(Trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidines 3 and 5;
Thien-2-yl(5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-6-
yl)methanone (3d)
General Procedure
Into a flask were added the -enamino diketone 1 (1 mmol) along
with triazole 2a (0.126 g, 1.5 mmol) or 2b (0.196 g, 1.5 mmol) and
MeCN (5 mL). The mixture was refluxed for 24 h. After the reaction
time was complete, the mixture was allowed to cool to room tem-
perature and the solvent was evaporated under reduced pressure. The
Brown crystals; yield: 283 mg (95%); mp 205–207 °C.
1H NMR (400 MHz, DMSO-d
):  = 10.13 (s, 1 H, H-7), 9.03 (s, 1 H, H-
6
2), 8.29 (dd, J = 1.2, 4.9 Hz, 1 H, Ar), 7.95 (dd, J =1.2, 3.9 Hz, 1 H, Ar),
7.32 (dd, J = 3.9, 4.9 Hz, 1 H, Ar).
residue was washed with water (20 mL), extracted with CHCl (3 × 20
13
3
C NMR (100 MHz, DMSO-d ):  = 181.8 (C=O), 159.3 (C-2), 153.7 (C-
6
mL), and the organic phase separated and dried with anhydrous sodi-
um sulfate. Then, the solvent was evaporated under reduced pressure.
The resulting solid was recrystallized from hexane/CHCl3 (1:1, 20
mL). Single crystals of compound 3e were obtained by slow evapora-
tion of the aforementioned mixture of solvents.
2
3a), 148.2 (q, J = 36.2 Hz, C-5), 143.4 (Ar), 140.4 (C-7), 139.8 (Ar),
C–F
1
139.0 (Ar), 129.7 (Ar), 120.6 (C-6), 120.5 (q, J = 275.8 Hz, CF3).
C–F
+
GC-MS (EI, 70 eV): m/z (%) = 298 (55, M ), 215 (6), 111 (100), 83 (5).
Anal. Calcd for C11H F N OS: C, 44.30; H, 1.69; N, 18.79. Found: C,
5
3
4
44.53; H, 1.72; N, 18.88.
Phenyl(5-(trifluoyromethyl)[1,2,4]triazolo[1,5-a]pyrimidin-6-
yl)methanone (3a)
(
4-Bromophenyl)-(5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]py-
rimidin-6-yl)methanone (3e)
White solid; yield: 257 mg (88%); mp 171–173 °C.
Yellow crystals; yield: 300 mg (81%); mp 142–145 °C.
1
1
H NMR (400 MHz, DMSO-d ):  = 10.00 (s, 1 H, H-7), 9.00 (s, 1 H, H-
6
H NMR (400 MHz, DMSO-d ):  = 10.04 (s, 1 H, H-7), 9.03 (s, 1 H, H-
2), 8.04 (d, J = 7.9 Hz, 2 H, Ar), 7.78 (t, J = 7.6 Hz, 1 H, Ar), 7.61 (t, J = 7.7
6
2
1
), 7.98 (d, J = 8.4 Hz, 2 H, Ar), 7.83 (d, J = 8.5 Hz, 2 H, Ar).
Hz, 2 H, Ar).
3
1
3
C NMR (100 MHz, DMSO-d ):  =189.2 (C=O), 159.3 (C-2), 153.8 (C-
C NMR (100 MHz, DMSO-d ):  = 189.9 (C=O), 159.3 (C-2), 153.9 (C-
6
6
2
2
3a), 148.4 (q, J = 36.1 Hz, C-5), 140.5 (C-7), 135.6 (Ar), 132.6 (Ar),
132.7 (Ar), 129.8 (Ar), 120.6 (C-6), 120.5 (q, J
3
1
a), 148.4 (q, J = 36.1 Hz, C-5), 140.3 (C-7), 136.5 (Ar), 135.2 (Ar),
31.0 (Ar), 129.4 (Ar), 121.1 (C-6), 120.6 (q, JC–F = 271.8 Hz, CF3).
C–F
C–F
1
1
C–F
= 276.9 Hz, CF3).
1
9
19
F NMR (565 MHz, DMSO-d ):  = –63.60 (CF ).
6 3
F NMR (565 MHz, DMSO-d ):  = –66.04 (CF ).
6
3
GC-MS (EI, 70 eV): m/z (%) = 372 (55, M+, 81Br), 370 (56, M+, 79Br), 215
28), 185 (98), 183 (100), 157 (25), 155 (25).
+
GC-MS (EI, 70 eV): m/z (%) = 292 (47, M ), 215 (15), 105 (100), 77 (40).
(
Anal. Calcd for C13H F N O: C, 53.43; H, 2.82; N, 19.17. Found: C,
7
3
4
Anal. Calcd for C13H BrF N O: C, 42.07; H, 1.63; N, 15.10. Found: C,
53.19; H, 2.41; N, 19.13.
6
3
4
42.29; H, 1.67; N, 15.22.
(
4-Methylphenyl)(5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrim-
(
4-Fluorophenyl)(5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrim-
idin-6-yl)methanone (3b)
idin-6-yl)methanone (3f)
Yellow solid; yield: 279 mg (91%); mp 188–190 °C.
White solid; yield: 211 mg (68%); mp 172–176 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

F
Synthesis
V. P. Andrade et al.
Paper
1
1
H NMR (400 MHz, DMSO-d ):  = 10.04 (s, 1 H, H-7), 9.04 (s, 1 H, H-
H NMR (400 MHz, DMSO-d ):  = 9.81 (s, 1 H, H-7), 7.98 (d, J = 7.1 Hz,
6
6
2), 8.14 (dd, J = 9.0, 5.4 Hz, 2 H, Ar), 7.44 (t, J = 9.0 Hz, 2 H, Ar).
2 H, Ar), 7.10 (d, J = 7.2 Hz, 2 H, Ar), 3.90 (s, 3 H, OMe), 2.73 (s, 3 H,
1
3
SMe).
C NMR (100 MHz, DMSO-d ):  = 188.7 (C=O), 159.3 (C-2), 153.7 (C-
6
2
13
3
1
a), 148.6 (q, J = 36.1 Hz, C-5), 140.5 (C-7), 134.2 (Ar), 134.1 (Ar),
20.6 (q, J = 277.9 Hz, CF ), 120.0 (C-6), 116.7 (Ar), 116.5 (Ar).
C NMR (100 MHz, DMSO-d ):  = 188.2 (C=O), 171.9 (C-2), 165.0
C–F
6
1
2
(Ar), 154.4 (C-3a), 147.4 (q, J = 36 Hz, C-5), 138.3 (C-7), 133.5 (Ar),
129.4 (Ar), 120.7 (q, JC–F = 276.6 Hz, CF
C–F
3
C–F
1
+
3
), 120.6 (C-6), 114.8 (Ar), 56.3
GC-MS (EI, 70 eV): m/z (%) = 310 (54, M ), 207 (51), 123 (100), 95 (63).
(OMe), 13.8 (SMe).
Anal. Calcd for C13H F N O: C, 50.33; H, 1.95; N, 18.06. Found: C,
5
6
4
4
19
F NMR (565 MHz, DMSO-d ):  = –63.90 (CF ).
0.13; H, 1.83; N, 18.90.
6
3
+
GC-MS (EI, 70 eV): m/z (%) = 368 (92, M ), 215 (6), 135 (100), 107 (11),
2 (16), 77 (21).
9
(4-Chlorophenyl)(5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrim-
idin-6-yl)methanone (3g)
Anal. Calcd for C15H11F N O S: C, 48.91; H, 3.01; N, 15.21. Found: C,
3
4
2
White solid; yield: 278 mg (85%); mp 195–198 °C.
48.33; H, 3.03; N, 14.91.
1
H NMR (400 MHz, DMSO-d ):  = 10.04 (s, 1 H, H-7), 9.04 (s, 1 H, H-
6
(
2-(Methylthio)-5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimi-
2
), 8.07 (d, J = 8.6 Hz, 2 H, Ar), 7.68 (d, J = 8.6 Hz, 2 H, Ar).
din-6-yl)(thien-2-yl)methanone (5d)
13
C NMR (100 MHz, DMSO-d ):  = 188.9 (C=O), 159.3 (C-2), 153.8 (C-
6
2
White solid; yield: 258 mg (75%); mp 120–123 °C.
1
3a), 148.4 (q, J = 36.3 Hz, C-5), 140.5 (C-7), 135.2 (Ar), 132.7 (Ar),
C–F
1
129.6 (Ar), 120.6 (q, J = 276.3 Hz, CF ), 120.1 (C-6).
H NMR (400 MHz, DMSO-d ):  = 9.96 (s, 1 H, H-7), 8.27 (d, J = 3.8 Hz,
C–F
3
6
GC-MS (EI, 70 eV): m/z (%) = 328 (15, M+, 37Cl), 326 (44, M+, 35Cl), 215
16), 141 (32), 139 (100), 113 (10), 111 (32), 75 (14).
1 H, Ar), 7.91 (d, J = 2.6 Hz, 1 H, Ar), 7.32–7.29 (m, 1 H, Ar), 2.73 (s, 3 H,
SMe).
(
1
3
C NMR (100 MHz, DMSO-d ):  = 181.8 (C=O), 172.1 (C-2), 154.4 (C-
Anal. Calcd for C13H ClF N O: C, 47.80; H, 1.85; N, 17.15. Found: C,
6
6
3
4
2
3
1
a), 147.3 (q, J = 36.3 Hz, C-5), 143.3 (C-7), 139.7 (Ar), 139.1 (Ar),
38.7 (Ar), 129.7 (Ar), 120.6 (q, J = 272.4 Hz, CF ), 119.8 (C-6), 13.8
47.75; H, 1.91; N, 17.12.
C–F
1
C–F
3
(
SMe).
GC-MS (EI, 70 eV): m/z (%) = 345 (16), 344 (100, M ), 343 (3), 249 (13),
11 (63), 83 (7).
Anal. Calcd for C12
2.01; H, 2.08; N, 16.46.
(
2-(Methylthio)-5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimi-
+
din-6-yl)(phenyl)methanone (5a)
1
White solid; yield: 271 mg (80%); mp 150–153 °C.
1
H F N OS : C, 41.86; H, 2.05; N, 16.27. Found: C,
7 3 4 2
H NMR (400 MHz, DMSO-d ):  = 9.86 (s, 1 H, H-7), 8.02 (d, J = 8.0 Hz,
6
4
2
3
H, Ar), 7.78 (t, J = 8.0 Hz, 1 H, Ar), 7.60 (t, J = 8.0 Hz, 2 H, Ar), 2.73 (s,
H, SMe).
1
3
C NMR (100 MHz, DMSO-d ):  = 189.9 (C=O), 172.2 (C-2), 154.4 (C-
6
Funding Information
3
1
a), 147.6 (q, 2JC–F = 34 Hz, C-5), 138.5 (C-7), 136.4 (Ar), 135.3 (Ar),
30.8 (Ar), 129.4 (Ar), 120.6 (q, J = 282.0 Hz, CF ), 120.3 (C-6), 13.8
1
C–F
3
The authors are grateful for financial support from the Fundação de
Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS/CNPq –
PRONEX – Grant No. 16/2551-0000477-3) and Conselho Nacional de
(
SMe).
GC-MS (EI, 70 eV): m/z (%) = 338 (100, M ), 293 (13), 215 (11), 105
47), 77 (43).
Anal. Calcd for C14H F N OS: C, 49.70; H, 2.68; N, 16.56. Found: C,
+
(
Desenvolvimento Científico
e
Tecnológico (CNPq, Grant No.
407898/2018-2), and for fellowships from CNPq (V.P.A.) and CAPES
9
3
4
(M.M.).
F
u
n
d
a
ç
ã
o
d
e
A
m
p
aro
à
P
esq
u
i
sa
d
o
Esta
d
o
d
o
R
i
o
Gra
n
d
e
d
o
S
u
l(16/2
5
5
1-0
0
0
0
4
7
7-3)C
o
nse
l
h
o
N
a
c
i
o
n
a
ld
e
D
ese
n
v
o
l
v
i
m
e
nto
C
i
e
ntífi
c
o
e
T
e
c
n
o
l
ó
g
i
c
o
(4
0
7
8
9
8/2
0
1
8-2)
4
9.81; H, 2.85; N, 16.32.
4
-(Methylphenyl)(2-(methylthio)-5-(trifluoromethyl)[1,2,4]tri-
Supporting Information
azolo[1,5-a]pyrimidin-6-yl)methanone (5b)
White solid; yield: 310 mg (88%); mp 195–198 °C.
Supporting information for this article is available online at
1
https://doi.org/10.1055/s-0037-1611765.
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
H NMR (400 MHz, DMSO-d ):  = 9.82 (s, 1 H, H-7), 7.90 (d, J = 8.2 Hz,
6
2
H, Ar), 7.40 (d, J = 8.3 Hz, 2 H, Ar), 2.73 (s, 3 H, SMe), 2.44 (s, 3 H,
Me).
References
13
C NMR (100 MHz, DMSO-d ):  = 189.4 (C=O), 171.9 (C-2), 154.4 (C-
6
2
3a), 147.4 (q, J = 36.1 Hz, C-5), 146.2 (Ar), 138.5 (C-7), 134.0 (Ar),
C–F
(1) Emelina, E. E.; Petrov, A. A. Russ. J. Org. Chem. 2009, 45, 417.
(2) Okamura, T.; Kurogi, Y.; Hashimoto, K.; Nishikawa, H.; Nagao, Y.
Bioorg. Med. Chem. Lett. 2004, 14, 2443.
(3) Novinson, T.; Springer, R. H.; O’Brien, D. E.; Scholten, M. B.;
Miller, J. P.; Robins, R. K. J. Med. Chem. 1982, 25, 420.
1
131.1 (Ar), 130.0 (Ar), 120.6 (q, J = 275.8 Hz, CF ), 120.4 (C-6), 21.8
C–F
3
(
Me), 13.8 (SMe).
GC-MS (EI, 70 eV): m/z (%) = 352 (100, M ), 307 (8), 207 (31), 119 (62),
1 (45).
+
9
(
4) Kleschick, W. A.; Gerwick, B. C.; Carson, C. M.; Monte, W. T.;
Snider, S. W. J. Agric. Food Chem. 1992, 40, 1083.
Anal. Calcd for C15H11F N OS: C, 51.13; H, 3.15; N, 15.90. Found: C,
3
4
51.04; H, 3.31; N, 15.60.
(5) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111,
4
55.
(
4-Methoxyphenyl)(2-(methylthio)-5-(trifluoromethyl)[1,2,4]tri-
(
(
(
6) Rulev, A. Y.; Romanov, A. R. RSC Adv. 2016, 6, 1984.
7) Tsai, S. W. J. Mol. Catal. B: Enzym. 2016, 127, 98.
8) Zhu, W.; Wang, J.; Wang, S.; Gu, Z.; Aceña, J. L.; Izawa, K.; Liu, H.;
Soloshonok, V. A. J. Fluorine Chem. 2014, 167, 37.
azolo[1,5-a]pyrimidin-6-yl)methanone (5c)
White solid; yield: 310 mg (84%); mp 181–183 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

G
Synthesis
V. P. Andrade et al.
Paper
(
9) Ruzziconi, R.; Buonerba, F. J. Fluorine Chem. 2013, 152, 12.
(20) Da Silva, M. J. V.; Poletto, J.; Jacomini, A. P.; Pianoski, K. E.;
Gonçalves, D. S.; Ribeiro, G. M.; Melo, S. M. D. S.; Back, D. F.;
Moura, S.; Rosa, F. A. J. Org. Chem. 2017, 82, 12590.
(21) Silva, R. G. M.; Da Silva, M. J. V.; Jacomini, A. P.; Moura, S.; Back,
D. F.; Basso, E. A.; Rosa, F. A. RSC Adv. 2018, 8, 4773.
(22) Rosa, F. A.; Machado, P.; Fiss, G. F.; Vargas, P. S.; Fernandes, T. S.;
Bonacorso, H. G.; Zanatta, N.; Martins, M. A. P. Synthesis 2008,
3639.
(
(
(
10) Kolosov, M. A.; Kulyk, O. G.; Starchenko, O. I.; Orlov, V. D. Chem.
Heterocycl. Compd. 2013, 49, 1166.
11) Lipson, V. V.; Desenko, S. M.; Ignatenko, I. V.; Shishkin, O. V.;
Shishkina, S. V. Russ. Chem. Bull. 2006, 55, 345.
12) Lipson, V. V.; Desenko, S. M.; Orlov, V. D.; Shishkin, O. V.;
Shirobokova, M. G.; Chernenko, V. N.; Zinov’eva, L. I. Chem. Het-
erocycl. Compd. 2000, 36, 1329.
(
13) Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G. Tetrahedron
(23) Souza, T. F.; Silva, M. J. V.; Silva, R. G. M.; Gonçalves, D. S.; Simon,
P. A.; Jacomini, A. P.; Basso, E. A.; Moura, S.; Martins, M. A. P.;
Back, D. F.; Rosa, F. A. Asian J. Org. Chem. 2017, 6, 627.
(24) Berber, H.; Soufyane, M.; Santillana-Hayat, M.; Mirand, C. Tetra-
hedron Lett. 2002, 43, 9233.
2007, 63, 7753.
(
14) Kuznetsova, O. A.; Filyakova, V. I.; Pashkevich, K. I.; Ulomskii, E.
N.; Plekhanov, P. V.; Rusinov, G. L.; Kodess, M. I.; Rusinov, V. L.
Russ. Chem. Bull. 2003, 52, 1190.
(
15) Boechat, N.; Pinheiro, L. C. S.; Silva, T. S.; Aguiar, A. C. C.;
Carvalho, A. S.; Bastos, M. M.; Costa, C. C. P.; Pinheiro, S.; Pinto,
A. C.; Mendonça, J. S.; Dutra, K. D. B.; Valverde, A. L.; Santos-
Filho, O. A.; Ceravolo, I. P.; Krettli, A. U. Molecules 2012, 17,
(25) Touzot, A.; Soufyane, M.; Berber, H.; Toupet, L.; Mirand, C. J. Flu-
orine Chem. 2004, 125, 1299.
(26) Mirand, C.; Soufyane, M.; van den Broek, S.; Khamliche, L. Het-
erocycles 1999, 51, 2445.
8
285.
(27) Rosa, F. A.; Machado, P.; Rossatto, M.; Vargas, P. S.; Bonacorso, H.
G.; Zanatta, N.; Martins, M. A. P. Synlett 2007, 3165.
(28) Chernyshev, V. M.; Astakhov, A. V.; Starikova, Z. A. Tetrahedron
2010, 66, 3301.
(29) Wang, L.-H.; Zhao, J. Eur. J. Org. Chem. 2018, 4345.
(30) Souza, L.; Santos, J.; Mittersteiner, M.; Andrade, V.; Lobo, M.;
Santos, F.; Bortoluzzi, A.; Bonacorso, H.; Martins, M.; Zanatta, N.
Synthesis 2018, 50, 3686.
(
(
(
16) Liu, Y. C.; Qu, R. Y.; Chen, Q.; Yang, J. F.; Cong-Wei, N.; Zhen, X.;
Yang, G. F. J. Agric. Food Chem. 2016, 64, 4845.
17) Krasovsky, A. L.; Moiseev, A. M.; Nenajdenko, V. G.; Balenkova, E.
S. Synthesis 2002, 901.
18) Zanatta, N.; Amaral, S. S.; dos Santos, J. M.; Fernandes, L. da. S.;
Bonacorso, H. G.; Martins, M. A. P. J. Heterocycl. Chem. 2011, 48,
1085.
(
19) Frizzo, C. P.; Scapin, E.; Marzari, M. R. B.; München, T. S.;
Zanatta, N.; Bonacorso, H. G.; Buriol, L.; Martins, M. A. P. Ultra-
son. Sonochem. 2014, 21, 958.
(31) CCDC 1488187 (3e) and CCDC 1865842 (1b) contain the supple-
mentary crystallographic data for this paper. The data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/getstructures.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G