Eco-friendly synthesis and antioxidant activity of new trifluoromethyl-substituted N-(pyrimidin-2-yl)benzo[d]thiazol-2-amines and some N-derivatives

Article abstract of DOI:10.1007/s00706-016-1829-0

Abstract: A convenient and environmentally benign procedure for the synthesis of a new series of trifluoromethyl-substituted N-(pyrimidin-2-yl)benzo[d]thiazol-2-amines by the cyclocondensation reaction of (benzo[d]thiazolyl)guanidine with either 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones or 2,2,2-trifluoro-1-(2-methoxycyclohexen-1-en-1-yl)ethanone is described. The main reactions were performed in refluxing water as the solvent (8–24?h), without catalysts, and the corresponding new N-(pyrimidinyl)-1H-(benzo[d]thiazolyl)amines were obtained at a 60–88?% yield. Subsequently, some di(hetero)arylamines were derivatized to the respective tertiary amines via easy N-alkylation and N-alkenylation reactions at 55–82?% yields. Finally, the Lipinski parameters and the total antioxidant activity of the new series of secondary arylamines were also evaluated. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-016-1829-0

Monatsh Chem
DOI 10.1007/s00706-016-1829-0
ORIGINAL PAPER
Eco-friendly synthesis and antioxidant activity of new
trifluoromethyl-substituted N-(pyrimidin-2-yl)benzo[d]
thiazol-2-amines and some N-derivatives
Helio G. Bonacorso1 Tainara P. Calheiro1 Melissa B. Rodrigues1
•
•
•
Sılvio T. Stefanello Felix A. A. Soares Nilo Zanatta1 Marcos A. P. Martins1
2
2
•
•
•
´
´
Received: 25 May 2016 / Accepted: 26 July 2016
Ó Springer-Verlag Wien 2016
Abstract A convenient and environmentally benign pro-
cedure for the synthesis of a new series of trifluoromethyl-
substituted N-(pyrimidin-2-yl)benzo[d]thiazol-2-amines by
the cyclocondensation reaction of (benzo[d]thiazolyl)-
guanidine with either 4-alkoxy-4-alkyl(aryl/heteroaryl)-
Graphical abstract
1,1,1-trifluoroalk-3-en-2-ones
or
2,2,2-trifluoro-1-(2-
methoxycyclohexen-1-en-1-yl)ethanone is described. The
main reactions were performed in refluxing water as the
solvent (8–24 h), without catalysts, and the corresponding
new N-(pyrimidinyl)-1H-(benzo[d]thiazolyl)amines were
obtained at
a 60–88 % yield. Subsequently, some
di(hetero)arylamines were derivatized to the respective
tertiary amines via easy N-alkylation and N-alkenylation
reactions at 55–82 % yields. Finally, the Lipinski param-
eters and the total antioxidant activity of the new series of
secondary arylamines were also evaluated.
Keywords Benzothiazoles Á Pyrimidines Á Amines Á
Antioxidant activity Á N-Alkylation
Introduction
The synthesis of nitrogen-containing heterocycles in a
simple and efficient manner has been attracting consider-
able attention from both academia and industry [1].
The benzothiazole is a privileged bicyclic ring system
with multiple applications, and it is known to exhibit a
wide range of biological properties [2], mainly antimi-
crobial activity [3]. Benzothiazoles and their derivatives
have also shown pronounced antioxidant activity [4].
Antioxidants have the capacity to interact with free rad-
icals and to stop their chain reactions before essential
vital molecules that are damaged [5]. Particularly, they
have also recently been studied as drug candidates for
combatting various maladies, such as carcinogenesis,
inflammatory processes, atherogenesis, and aging in aer-
obic organisms [6, 7].
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-016-1829-0) contains supplementary
material, which is available to authorized users.
& Helio G. Bonacorso
helio.bonacorso@ufsm.br
1
´
´
Nucleo de Quımica de Heterociclos (NUQUIMHE),
Departamento de Quımica, Universidade Federal de Santa
´
Maria, Santa Maria, RS 97.105-900, Brazil
2
´
Departamento de Bioquımica e Biologia Molecular,
Universidade Federal de Santa Maria, Santa Maria,
RS 97.105-900, Brazil
123

H. G. Bonacorso et al.
Likewise, systems containing pyrimidine scaffolds as a
core unit are known to exhibit various pharmacological
activities. Furthermore, trifluoromethyl-substituted pyrim-
idines have been well-described in the literature as
compounds with potential inhibitory activity towards Try-
panosoma cruzi [8]. In addition, the presence of a
trifluoromethyl group in heterocycles can be used to reg-
ulate their chemical, physical, and biological properties. It
has been extensively documented that the trifluoromethyl
group present in organic compounds also has an important
role in physiological activities, mostly due to the increased
lipophilicity of the molecules, which causes greater cell
permeability and resistance to enzyme degradation [9]. One
of the most useful methodologies for the insertion of a
trifluoromethyl group into heterocycles can be accom-
plished by direct trifluoroacetylation of enol ethers or
acetals, which are very useful precursors that act as 1,3-
dielectrophiles in many cyclocondensation reactions
[10–15].
by the cyclocondensation reaction of (benzo[d]imida-
zolyl)guanidine with 4-alkoxy-1,1,1-trifluoroalk-3-en-2-
ones, which results in good yields [23]. Moreover, water
has gained tremendous attention from us as an effective
alternative reaction medium for this reaction type [24].
Besides being nontoxic, inexpensive, noninflammable, and
safe to use, it also has numerous other advantages.
Continuing the work already developed in our research
group [22, 23], and considering the importance of
pyrimidines, 1-(benzo[d]thiazolyl)guanidines, and trifluo-
romethyl-substituted heterocycles, as well as the possible
pharmacological and biological potential of these struc-
tures and the possibility of developing methodologies that
could be performed in an aqueous medium, the aim of this
paper is to present the results of the study of cyclocon-
densation reactions of (benzo[d]thiazolyl)guanidine (1) and
4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-
ones
2 to obtain a series of N-(pyrimidinyl)-1H-
(benzo[d]thiazolyl)amines 3 in an aqueous medium. Sub-
sequently, to find better solubility in organic solvents for
secondary amines 3, a synthetic application of some aryl-
amines is demonstrated through an easy alkylation and
alkenylation reaction which employs two different alkyl
halides and furnishes tertiary amines. Finally, evaluations
via Lipinski’s parameters and the results of the total
antioxidant activity through the phosphomolybdenum and
DPPH methods of the arylamines 3a–3j are also presented.
Considering the high reactivity and synthetic versatility
of guanidines and their derivatives, it is possible to perform
a large number of heterocyclization reactions involving
guanidines and various 1,3-dielectrophiles, thus enabling
the generation of a large number of azaheterocycles with
varying degrees of structural complexity [16]. More
specifically, guanidines can serve as excellent 1,3-dinu-
cleophilic precursor blocks for the synthesis of 2-amino-
substituted heterocycles. Many reactions of amidines and
guanidines with a,b-unsaturated carbonyl and 1,3-dicar-
bonyl compounds (and derivatives thereof), which lead to
pyrimidines and aminopyrimidines, respectively, have been
well documented in the literature [17, 18]. However, most
synthetic methods described in the literature for obtaining
specifically benzothiazolyl guanidine precursors employ
microwave radiation, metal catalysts, additives, and high-
temperature conditions, which affect the cost effectiveness
and eco-friendly nature of the reaction [19].
Results and discussion
Initially, the precursor 1-(1H-benzo[d]thiazol-2-yl)guani-
dine (1) was obtained from the reaction of cyanoguanidine
with 2-aminothiophenol, in accordance with the literature
[25].
The 4-ethoxy-1,1,1-trifluorobut-3-en-2-one (2a) and
4-alkoxy-3(4)-methyl-1,1,1-trifluoroalk-3-en-2-ones 2b, 2c
were obtained through a trifluoroacetylation reaction of
(commercially available) enol ethers [26–29]. The acetals
obtained from the reaction of the respective cyclohex-
anone, 4-substituted acetophenones, and 2-acetylthiophene,
with trimethyl ortoformate and p-toluenesulfonic acid in
methanol as solvent, underwent a trifluoroacetylation
reaction with trifluoroacetic anhydride in the presence of
pyridine, in accordance with procedures described in the
literature [30–33] for obtaining the 2,2,2-trifluoro-1-(2-
methoxycyclohex-1-en-1-yl)ethanone (2d) and 4-methoxy-
4-(aryl/heteroaryl)-1,1,1-trifluorobut-3-en-2-ones 2e–2j.
The cyclocondensation reactions of 1-(1H-benzo[d]-
thiazol-2-yl)guanidine (1) with 4-alkoxy-4-alkyl(aryl/het-
eroaryl)-1,1,1-trifluoroalk-3-en-2-ones 2 (Scheme 1) were
tested using water or ethanol as the solvent, because the
yields obtained when the reactions were performed in
The 2-arylaminopyrimidine derivatives, which are no
less important but are rare in the literature and could have
originated from arylguanidines, are generally synthesized
by direct nucleophilic substitution of pyrimidinyl halides
[20] and sulfone [21] with anilines, which often entails
prolonged heating at high temperatures or a large excess of
anilines.
Recently, we reported the syntheses of a series of N-
(pyridinyl-triazolyl)pyrimidin-2-amines by the cyclocon-
densation reaction of N-[5-(pyridinyl)-1H-1,2,4-triazol-3-
yl]guanidine with 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-
trifluoroalk-3-en-2-ones [22], in ethanol (a green solvent)
under reflux for 18 h, which resulted in yields of 40–68 %.
We also recently reported an environmentally benign and
mild procedure in ethanol or water for synthesizing a novel
series of N-(pyrimidinyl)-1H-(benzo[d]imidazolyl)amines
123

Eco-friendly synthesis and antioxidant activity of new trifluoromethyl-substituted…
Scheme 1
Table 1 Reaction data for the obtainment of N-[4-(trifluoromethyl)pyrimidin-2-yl]benzo[d]thiazol-2-amines 3a–3j
Compds.
R1
R2
Reaction time/h
Yield/%
3a
3b
3c
3d
3e
3f
H
H
24
24
24
24
24
24
16
8
65
75
88
60
80
70
60
80
70
60
CH3
H
H
CH3
–(CH2)4–
C6H5
H
H
H
H
H
H
4-CH3O-C6H4
4-CH3-C6H4
4-Br-C6H4
4-F-C6H4
2-Thienyl
3g
3h
3i
8
3j
8
Reaction conditions: guanidine (1, 5 mmol), ketones 2a–2j (10 mmol), 25 cm3 water, reflux 8–24 h (isolated yields)
1
ethanol were similar to the yields for the procedure using
water. Thus, to optimize the cyclocondensation reactions,
we performed the procedures in aqueous media, under
reflux, and with conventional heating. Reaction times were
optimized individually according to the precursors 2a–2j
used. The secondary amines generated 3a–3j were obtained
in optimal refluxing times of 8–24 h.
and confirmed by H NMR, 13C NMR, and mass spec-
trometry (GC/MS-EI, 70 eV), and their degree of purity
was confirmed by CHN elemental analysis.
It is important to mention that some di(heteroaryl)ami-
nes exhibiting antitumoral activity have been prepared at
ca. 50 % yield by palladium-catalyzed (C–N) Buchwald–
Hartwig coupling employing halogenated deactivated
heteroarylamines and aminoheterocycles in the presence of
Pd(OAc)2, xantphos as the ligand, Cs2CO3 as the base in
dry dioxane as a solvent at 120 °C for 2–5 h [34, 35].
During the execution of the procedures for the synthesis
and isolation of the secondary di(hetero)arylamines 3a–3j,
it could be clearly seen that better yields for this series of
compounds were obtained when the ketone precursor 2
displayed the R2 = Me at the carbonyl a-position (2c,
Thus, by optimizing this environmentally benign pro-
cedure, it was possible to synthesize ten new
trifluoromethylated
N-(pyrimidinyl)-1H-(benzo[d]thia-
zolyl)amines 3 at 60–88 % yields—see Table 1. After the
reaction time, the compounds 3a–3j were able to be iso-
lated at a high degree of purity through a simple filtration
process followed by washing with cold ethanol and drying
under reduced pressure. Their structures were characterized
123

H. G. Bonacorso et al.
88 %). Moreover, it appears that the electron-donating or
electron-withdrawing character of the R1 substituents in
2e–2j, as well as the carbocyclic moiety R1–R2 =
–(CH2)4–, did not have a significant influence on the yields
of the products of 3e–3j (60–80 %).
maximum of 10 H-bond acceptors (expressed as the total
sum of oxygens, nitrogens, sulfurs, and halogens) = the
values remaining within the 06–07 range of H-bond
acceptors for the all the compounds of 3. It has been
reported previously by Yamazaki et al. [37] that the tri-
fluoromethyl group can establish intermolecular H-bonds.
In 2013, Luzina et al. [38] considered the formation of just
one H-bond relative to the CF3 group for the Lipinski
calculations. Thus, due to both the aforementioned publi-
cations, we also considered the CF3 group in our
calculation.
The structures of the synthesized secondary amines 3a–
3j were identified via one- and two-dimensional NMR
experiments—their spectral signals were assigned through
comparison with other pyrimidines synthesized in our
laboratory [22, 23] and via data already described in the
literature for benzothiazoles [3].
Due to the synthesized compounds having low solubility
in polar solvents, such as CDCl3, CD3COCD3, D2O, and
According to the results obtained, it can be concluded
that the series for the compounds of 3 is in complete
agreement with three and partially in agreement with the
other of the four parameters set by Lipinski’s rule, and the
compounds can, therefore, be considered to be drug can-
didates, since they comply with most of the evaluated
parameters.
1
DMSO-d6, the obtainment of H and 13C NMR spectra
could be registered in DMSO-d6 solution, but at very low
concentration for all the amines; mainly for compounds 3c,
3d, 3f, and 3i.
Evaluation of the Lipinski parameters [36]
Antioxidant evaluation
According to the literature, Lipinski parameters have the
ability to estimate the activities of the compounds in the
organism by evaluating the hydrogen donor and receptor
interactions and estimated lipophilicity through the use of
partition coefficient calculations. The Lipinski parameters
were applied to the series 3a–3j (see Table 2) which gave
the following results for the evaluated compounds: (1) the
molecular weight must be less than 500
(g/mol) = 296.03 B MW B 449.98 for all of the amines
3; (2) the limited lipophilicity (expressed by Log
P \ 5) = 3.46 B ClogP B 5.0 for amines 3a–3d and
5.46 B ClogP B 6.43 for amines 3e–3j (calculated with
ChemDrawTM Ultra, version 12.0); (3) maximum 05
H-bond donors (expressed as the sum of OHs and
NHs) = 01 for all the compounds of 3; and (4) the
Considering the potential for antioxidant evaluation of
heterocycles in this study, the synthesized secondary ami-
nes 3 were evaluated for total antioxidant activity through
the phosphomolybdenum [39] and DPPH methods [40].
The total antioxidant activity was evaluated through the
reduction of molybdenum(VI) (Mo6?
) to molybde-
num(V) (Mo5?). In this study, we found that at all of the
concentrations tested, the compounds (3f, 3h, 3i) had a
lower antioxidant effect than that found for BHT 100 lg/
cm3. However, the highest concentration tested for 3e, 3g,
and 3j had a similar effect to that of the control. In addi-
tion, at concentrations above 10 lg/cm3, compounds 3b
and 3d showed a similar antioxidant effect to that of BHT
100 lg/cm3. Furthermore, the concentration of 100 lg/cm3
Table 2 Lipinski’s parameters for amines 3a–3j
Compounds
MW /g mol-1
ClogP
3.4643
H-bond donor
H-bond acceptor
Lipinski (score out of 4)
3a
296.03
310.05
310.05
350.08
372.07
402.08
386.08
449.98
390.06
378.02
\500
1
4
4
4
4
4
3
3
3
3
3
3
–
3b
3.9633
3.9633
5.0363
5.5623
5.6036
6.061
1
4
3c
1
4
3d
1
4
3e
1
4
3f
1
5
3g
1
4
3h
6.4264
5.7064
5.457
1
4
3i
1
4
3j
1
4
Lipinski’s Parameters
\5.0
1–5
1–10
123

Eco-friendly synthesis and antioxidant activity of new trifluoromethyl-substituted…
Table 3 Total antioxidant capacity (%) of the compounds determined via the phosphomolybdenum method, presented as mean SEM
Compds.
Concentration
1 lg/cm3
10 lg/cm3
100 lg/cm3
1000 lg/cm3
3a
3b
3c
57.48 2.0
65.58 2.4
59.20 2.3
63.81 0.7
65.60 3.3
51.26 2.3
64.74 1.0
57.35 1.9
54.89 2.1
57.84 3.1
50.98 4.8
87.27 2.1
79.46 4.2
70.46 10.4
90.60 1.7
73.08 2.0
56.51 3.6
66.29 6.5
53.50 1.6
49.60 5.1
59.50 0.9
62.06 5.1
137.35 3.6
91.68 8.8
166.57 19.7
115.63 8.6
101.82 2.9
75.27 24.0
109.06 4.7
81.73 5.7
61.98 4.0
85.76 9.4
99.99 1.4
278.72 15.3
162.49 19.5
495.59 12.2
142.4 10.3
547.74 12.8
431.03 18.4
388.92 22.6
441.40 23.0
434.38 3.5
384.71 24.3
133.79 3.4
3d
3e
3f
3g
3h
3i
3j
BHT
Scheme 2
of 3a and 3c resulted in a higher antioxidant effect when
compared with BHT 100 lg/cm3—see Table 3. The DPPH
evaluation for the secondary amines synthesized (3a–3j)
showed that the arylamines of 3 were unable to scavenge
free radicals from the DPPH.
amines, the amines 3c, 3e, and 3f were selected to perform
N-alkylation and N-alkenylation reactions with two struc-
turally different alkylating agents (methyl iodide and allyl
bromide). The reactions were done in an ice bath using
sodium hydride in anhydrous DMF as the solvent, followed
by the addition of the alkylating reagent (Scheme 2).
After purification, the series of compounds 4 and 5 were
isolated at a high degree of purity. Their structures were
Our results demonstrated that all the compounds had a
total antioxidant capacity (TAC %) that was dependent on
the concentration (Table 3). Compounds 3b, 3f, 3h, 3i, and
3j displayed significant antioxidant capacity when com-
pared with BHT (100 lg/cm3), but only at the highest
concentration tested (1000 lg/cm3). In addition, at con-
centrations above 10 lg/cm3, compounds 3a, 3c, 3d, 3e,
and 3g had higher antioxidant activity than that found for
the BHT (100 lg/cm3).
We subsequently performed N-alkylation and
N-alkenylation reactions to demonstrate the synthetic
application of some of the secondary amines 3, and also to
enable analysis of the physical and spectroscopic properties
of the new tertiary amines 5.
1
characterized and confirmed by H NMR, 13C NMR, and
mass spectrometry (GC/MS-EI, 70 eV), and their degree of
purity was confirmed by CHN elemental analysis.
Various factors are responsible for the differences
between melting points of secondary amines when com-
pared to the corresponding N-methyl-substituted tertiary
amines. For example, when N-methylaniline (m.p. -57 °C)
undergoes an N-methylation and is converted into N,N-
dimethylaniline (m.p. ?2 °C), there is an increase of 59 °C
in the melting point. On the other hand, when dipheny-
lamine (m.p. ?53 °C) is also N-methylated and converted
into N-methyldiphenylamine (m.p. -7.5 °C), there is a
decrease of ca. 60 °C in the melting point. Thus, it is
interesting to note in Table 4 that initially, the melting
For the N-derivatization reactions, we used an experi-
mental procedure that has already been described in the
literature [41]. With the aim of obtaining six tertiary
123

H. G. Bonacorso et al.
Table 4 Melting point values of the synthesized amines 3–5
R1
R2
Amines 3 M.p./°C
Methylamines 4 M.p./°C
Allylamines 5 M.p./°C
H
CH3
H
3c; 270–271
3e; 275–276
3f; 276–277
4c; 150–152
4e; 175–177
4f; 182–184
5c; 154–156
5e; 136–138
5f; 148–150
C6H5
4-CH3OC6H4
H
point of the secondary amines 3c, 3e, and 3f is slightly
sensitive to the changes in the substituents R1 and R2,
showing variations of up to 6 °C in their melting points.
The tertiary amine derivatives 4 and 5 show significant
changes in their melting points in relation to the 3 series.
Upon performing a comparison between the values of the
melting points of the precursor amines (3c, 3e, and 3f), it
appears that the melting point decreased by around 100 °C
in relation to the methyl-substituted tertiary amines 4c, 4e,
and 4f and by around 116–139 °C in relation to the allyl-
substituted tertiary amines 5c, 5e, and 5f. It can also be
seen that there is practically no change in the melting point
of the methyl- (4c) and allyl-substituted (5c) tertiary ami-
nes when R1 = H and R2 = Me. However, when R1 = H
and R2 = aryl, there is a decrease of ca. 40 °C, giving the
allyl-substituted tertiary amines 5e and 5f the lowest
melting points. Likewise, it can be seen experimentally that
the alkylation reactions of the nitrogen led to a better
solubility of the tertiary amines which, initially in the form
of secondary amines, were only slightly soluble in polar
solvents and practically insoluble in apolar solvents.
constant (2JCF) in the range of 34–35 Hz. Due to the low
solubility of compounds 3d, 3e, and 3g–3j, it was not
possible to accurately measure the respective 2JCF for C-4’.
The CF3 group displays for all compounds a typical quartet
in the range of 120.7–127.5 ppm due to 1JCF in the range of
240–287 Hz.
Even after the insertion of the N-methyl and N-allyl
substituents, there were no significant changes in the
1
chemical shift values of H NMR and 13C NMR for the
atoms belonging to the pyrimidine and benzothiazole rings.
In the 1H NMR spectra of the N-methyl-substituted
tertiary amines 4, the appearance of a signal in the form of
a singlet related to the methyl substituent could be
assignment at ca. 4.18 ppm.
For the respective N-allyl-substituted amines 5, the
appearance of multiplets could be assignment: in the range
of 6.20–6.05 ppm in relation to the H-2’’, in the region of
5.50–5.36 ppm in relation to the H-1’’, and at
5.21–5.18 ppm in relation to the H-3’’.
In the 13C NMR spectra of the N-methylated amines 4,
the emergence of a signal was registered at approximately
35.6 ppm, which was related to the methyl carbon, whereas
for the N-allylic carbons of amines 5, the appearance of
signals could be observed in average at approximately
132.5 ppm (C-2’’), 117.5 ppm (C-3’’), and 49.6 ppm (C-
1’’).
1
The H NMR analysis for the synthesized heterocycles
3a–3j presented the characteristic and chemical shifts as
per the description of them in the literature [4, 22]. The
presence of a signal related to the proton of the 5-position
of the pyrimidine ring (H-5’) in the region of
d = 7.3–8.0 ppm was another spectral feature observed. It
is worth noting that the amines 3c, 4c, and 5c do not dis-
play this characteristic signal, since the 5-position of the
pyrimidine ring is occupied by a methyl substituent.
The 13C NMR chemical shifts found for the synthesized
heterocycles 3a–3j were also very characteristic, as per the
description of them in the literature [4, 22]. For the hete-
rocycles 3a–3c and 3f, the C-4’ directly attached to the CF3
Conclusions
In summary, we have developed an eco-friendly, mild, and
efficient method (without oxidants or metal catalysts) for
the synthesis of a new series of ten trifluoromethyl-sub-
stituted
N-(pyrimidinyl)-1H-(benzo[d]thiazolyl)amines
displays
a
characteristic quartet in the range of
[di(hetero)arylamines] 3, which according to Lipinski’s
rule, can be considered to be drug candidates. When
d = 151.9–156.1 ppm with a carbon–fluorine coupling
123

Eco-friendly synthesis and antioxidant activity of new trifluoromethyl-substituted…
compared with the standard BHT (100 lM), the amines 3b
and 3d had the best results as promising antioxidants at
concentrations above 10 lM. The N-alkylation and
N-alkenylation reactions were useful for obtaining six new
tertiary amines 4, 5 with a significant decrease in the
melting points in relation to the precursor amines, and they
also permitted an increase in the functionalization of these
Fig. 1 Structure and numbering of compounds 3
amines and a significant improvement in their solubility in
organic solvents in relation to the respective secondary
amines.
7.53 (d, J = 5 Hz, 1H, H-5’), 7.43 (dt, J = 1 Hz, 7 Hz,
1H, H-5), 7.28 (dt, J = 1 Hz, 7 Hz, 1H, H-6) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 162.3 (C-2), 159.4 (Ar),
Experiment
2
158.1 (C-2’), 154.9 (q, JCF = 35 Hz, C-4’), 149.6 (C-6’),
132.4 (Ar), 126.5 (Ar), 123.4 (Ar), 121.8 (Ar), 121.4 (q,
3
Unless otherwise indicated, all common reagents and sol-
vents were used as obtained from commercial suppliers,
without further purification. Cyanoguanidine, 2-aminoth-
iophenol, allyl bromide, and iodomethane were
commercially obtained from Aldrich (ACS grade). All
melting points were determined on a Reichert Thermovar
1JCF = 275 Hz, CF3), 120.4 (Ar), 110.3 (q, JCF = 2 Hz,
ꢀ
C-5’) ppm; IR (KBr): m = 3060, 2922, 1623,1124,
755 cm-1; GC–MS (EI, 70 eV): m/z (%) = 296 (M?,
100), 277 (4), 227 (33), 175 (8), 135 (3), 69 (5).
N-[6-Methyl-4-(trifluoromethyl)pyrimidin-2-
or Electrothermal Mel-Temp 3.0 apparatus. The 1H and 13
C
yl]benzo[d]thiazol-2-amine (3b, C13H9F3N4S)
spectra were recorded at 298 K on a Bruker DPX 400
spectrometer (1H at 400.13 MHz and 13C at 100.63 MHz)
for one-dimensional experiments, and on a Bruker Avance
III 600 MHz, with digital resolution of 0.01 ppm, in
DMSO-d6 or CDCl3, using TMS as the internal reference.
Mass spectra were registered in an HP 5973 MSD con-
nected to an HP 6890 GC. The GC was equipped with a
split-splitless injector, auto-sampler, cross-linked HP-5
capillary column (30 m and 0.32 mm internal diameter),
and helium was used as the carrier gas. The infrared spectra
of the samples were obtained using KBr pastilles on a
Bruker Tensor-27 spectrophotometer. Elemental analyses
were performed on a Perkin-Elmer 2400 CHN elemental
analyzer (Sa˜o Paulo University, Sa˜o Paulo, Brazil).
Reaction time 24 h; white solid; yield 1.162 g (75 %); m.p.:
285–286 °C; 1H NMR (400 MHz, DMSO-d6): d = 12.32 (s,
1H, NH), 7.98 (d, J = 8 Hz, 1H, H-7), 7.71 (d, J = 8 Hz, 1H,
H-4), 7.49 (s, 1H, H-5’), 7.42 (t, J = 8 Hz, 1H, H-5), 7.27 (t,
J = 8 Hz, 1H, H-6), 2.63 (s, 3H, CH3) ppm; 13C NMR
(150 MHz, DMSO-d6): d = 172.7 (C-2), 159.5 (C-2’), 155.8
(Ar), 154.6 (q, 2JCF = 35 Hz, C-4’), 149.7 (C-6’), 132.6 (Ar),
126.4 (Ar), 123.3 (Ar), 121.7 (Ar), 121.1 (q, 1JCF = 275 Hz,
CF3), 120.4 (Ar), 110.1 (C-5’), 24.4 (CH3) ppm; IR (KBr):
mꢀ = 3188, 2898, 1618, 1120, 757 cm-1; GC–MS (EI, 70 eV):
m/z (%) = 310 (M?, 100), 295 (6), 241 (19), 175 (8), 69 (6).
N-[5-Methyl-4-(trifluoromethyl)pyrimidin-2-
yl]benzo[d]thiazol-2-amine (3c, C13H9F3N4S)
Reaction time 24 h; white solid; yield 1.364 g (88 %);
m.p.: 270–271 °C; 1H NMR (400 MHz, DMSO-d6):
d = 12.10 (s, 1H, NH), 8.84 (s, 1H, H-6’), 7.94 (dt,
J = 1 Hz, 8 Hz, 1H, H-7), 7.67 (d, J = 8 Hz, 1H, H-4),
7.40 (dt, J = 1 Hz, 8 Hz, 1H, H-5), 7.24 (dt, J = 1 Hz,
General procedure for the synthesis of N-[4-(trifluo-
romethyl)pyrimidin-2-yl]-1H-benzo[d]thiazol-2-amines
3a–3j
A solution of 0.960 g 1-(1H-benzo[d]thiazol-2-yl)guani-
dine (1, 5 mmol) and the respective 4-alkoxy-4-alkyl(aryl/
heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones (2, 10 mmol) in
25 cm3 water was heated under reflux for 8–24 h. After
cooling, the amines 3 were filtered, washed with cold
ethanol, and dried under reduced pressure. The reaction
times ranged according to the precursor used (2), as
described by spectroscopic data and in Table 1 (Fig. 1).
8 Hz, 1H, H-6), 2.38 (q, 5JH-F = 2 Hz, 3H, CH3) ppm; 13
C
NMR (150 MHz, DMSO-d6): d = 163.9 (C-2), 156.6 (C-
2’), 156.0 (Ar), 151.9 (q, JCF = 34 Hz, C-4’), 149.7 (C-
2
6’), 132.4 (Ar), 126.4 (Ar), 123.2 (Ar), 122.7 (Ar), 121.8
1
(q, JCF = 277 Hz, CF3), 121.7 (Ar), 120.2 (C-5’), 14.1
(CH3) ppm; IR (KBr): mꢀ = 3172, 2940, 1622, 1133,
756 cm-1; GC–MS (EI, 70 eV): m/z (%) = 310 (M?,
100), 281 (4), 241 (3), 175 (17), 134 (6), 69 (4).
N-[4-(Trifluoromethyl)pyrimidin-2-yl]benzo[d]thiazol-2-
amine (3a, C12H7F3N4S)
N-[4-(Trifluoromethyl)-5,6,7,8-tetrahydroquinazolin-2-
yl]benzo[d]thiazol-2-amine (3d, C16H13F3N4S)
Reaction time 24 h; yellow solid; yield 0.965 g (65 %);
m.p.: 267–268 °C; 1H NMR (400 MHz, DMSO-d6):
d = 12.35 (s, 1H, NH), 9.03 (d, J = 5 Hz, 1H, H-6’),
7.98 (d, J = 8 Hz, 1H, H-7), 7.73 (d, J = 8 Hz, 1H, H-4),
Reaction time 24 h; white solid; yield 1.050 g (60 %);
m.p.: 279–280 °C; 1H NMR (400 MHz, DMSO-d6):
d = 12.00 (s, 1H, NH), 7.93 (d, J = 8 Hz, 1H, H-7),
123

H. G. Bonacorso et al.
7.68 (d, J = 8 Hz, 1H, H-4), 7.41 (t, J = 7 Hz, 1H, H-5),
7.26 (t, J = 7 Hz, 1H, H-6), 2.97–2.95 (m, 2H, CH2),
124.2 (Ar), 123.4 (Ar), 121.9 (Ar), 121.5 (q,
1JCF = 275 Hz, CF3), 105.9 (C-5’), 21.6 (CH3) ppm; IR
2.83–2.82 (m, 2H, CH2), 1.87–1.86 (m, 4H, CH2) ppm; 13
C
(KBr): m = 3185, 1609, 1135, 751 cm-1; GC–MS (EI,
ꢀ
NMR (100 MHz, DMSO-d6): d = 170.9 (C-8a’), 158.7 (C-
2), 153.8 (C-2’), 125.3 (Ar), 125.1 (q, JCF = 249 Hz,
70 eV): m/z (%) = 386 (M?, 100), 367 (2), 317 (5), 176
1
(13), 69 (2).
CF3), 122.1 (Ar), 120.6 (Ar), 119.7 (Ar), 119.2 (C-4’), 31.7
(C-8’), 22.2 (C-5’), 20.8 (C-6’), 20.4 (C-7’) ppm; IR (KBr):
N-[6-(4-Bromophenyl)-4-(trifluoromethyl)pyrimidin-2-
yl]benzo[d]thiazol-2-amine (3h, C18H10BrF3N4S)
m = 3161, 2938, 1607, 1128, 757 cm-1; GC–MS (EI,
ꢀ
Reaction time 8 h; yellow solid; yield 1.796 g (80 %);
m.p.: 275–276 °C; 1H NMR (400 MHz, DMSO-d6):
d = 12.34 (s, 1H, NH), 8.36 (d, J = 9 Hz, 2H, Ar), 8.06
(s, 1H, H-5’), 7.98 (d, J = 8 Hz, 1H, H-7), 7.84 (d,
J = 9 Hz, 2H, Ar), 7.72 (d, J = 8 Hz, 1H, H-4), 7.42 (dt,
J = 1 Hz, 8 Hz, 1H, H-5), 7.28 (dt, J = 1 Hz, 7 Hz, 1H,
H-6) ppm; 13C NMR (150 MHz, DMSO-d6): d = 167.0
(C-2), 159.3 (Ar), 158.1 (C-2’), 157.5 (C-4’), 136.9 (Ar),
134.7 (Ar), 132.7 (Ar), 131.3 (Ar), 130.5 (Ar), 129.8 (Ar),
127.8 (Ar), 126.6 (Ar), 123.0 (Ar), 121.5 (q,
1JCF = 275 Hz, CF3), 120.5 (Ar), 106.3 (C-5’) ppm; IR
70 eV): m/z (%) = 350 (M?, 100), 331 (3), 281 (10), 175
(8), 135 (2), 108 (3), 69 (2).
N-[6-Phenyl-4-(trifluoromethyl)pyrimidin-2-
yl]benzo[d]thiazol-2-amine (3e, C18H11F3N4S)
Reaction time 24 h; green solid; yield 1.488 g (80 %);
m.p.: 275–276 °C; 1H NMR (400 MHz, DMSO-d6):
d = 12.49 (s, 1H, NH), 8.48–8.45 (m, 2H, Ar), 8.11 (s,
1H, H-5’), 8.02 (d, J = 8 Hz, 1H, H-7), 7.74 (d, J = 8 Hz,
1H, H-4), 7.72-7.67 (m, 3H, Ar), 7.44 (dt, J = 1 Hz, 8 Hz,
1H, H-5), 7.30 (dt, J = 1, 8 Hz, 1H, H-6) ppm; 13C NMR
(150 MHz, DMSO-d6): d = 168.2 (C-2), 159.4 (C-2’),
158.3 (C-4’), 149.7 (C-6’), 135.6 (Ar), 132.8 (Ar), 132.4
(Ar), 129.6 (Ar), 128.5 (Ar), 126.5 (Ar), 123.4 (Ar), 122.1
(KBr): m = 3185, 2892, 1610, 1133, 756 cm-1; GC–MS
ꢀ
(EI, 70 eV): m/z (%) = 452 (M?, 100), 431 (4), 383 (6),
176 (27), 69 (9).
1
(Ar), 121.8 (Ar), 121.2 (q, JCF = 280 Hz, CF3), 120.4
ꢀ
N-[6-(4-Fluorophenyl)-4-(trifluoromethyl)pyrimidin-2-
yl]benzo[d]thiazol-2-amine (3i, C18H10F4N4S)
(Ar), 106.3 (C-5’) ppm; IR (KBr): m = 3184, 2893, 1609,
1120, 757 cm-1; GC–MS (EI, 70 eV): m/z (%) = 372
(M?, 100), 353 (3), 303 (8), 176 (13), 148 (2).
Reaction time 8 h; yellow solid; yield 1.365 g (70 %);
m.p.: 269–270 °C; 1H NMR (400 MHz, DMSO-d6):
d = 12.33 (s, 1H, NH), 8.53–8.49 (m, 2H, Ar), 8.05 (s,
1H, H-5’), 7.98 (d, J = 8 Hz, 1H, H-7), 7.74 (d, J = 8 Hz,
1H, H-4), 7.48–7.41 (m, 3H, H-5, Ar), 7.28 (dt, J = 1 Hz,
7 Hz, 1H, H-6) ppm; 13C NMR (150 MHz, DMSO-d6):
d = 166.9 (C-2), 166.0 (Ar), 164.4 (Ar), 159.3 (C-2’),
158.1 (C-4’), 149.8 (C-6’), 132.3 (Ar), 131.3 (Ar), 131.2
(Ar), 126.6 (Ar), 123.5 (Ar), 121.9 (Ar), 121.1 (q,
1JCF = 275 Hz, CF3), 120.6 (Ar), 116.8 (Ar), 106.2 (C-
N-[6-(4-Methoxyphenyl)-4-(trifluoromethyl)pyrimidin-2-
yl]benzo[d]thiazol-2-amine (3f, C19H13F3N4OS)
Reaction time 24 h; white solid; yield 1.407 g (70 %);
m.p.: 276–277 °C; 1H NMR (400 MHz, DMSO-d6):
d = 12.21 (s, 1H, NH), 8.43 (d, J = 9 Hz, 2H, Ar), 7.98
(d, J = 8 Hz, 1H, H-7), 7.97 (s, 1H, H-5’), 7.72 (d,
J = 8 Hz, 1H, H-4), 7.42 (dt, J = 1 Hz, 8 Hz, 1H, H-5),
7.28 (dt, J = 1 Hz, 8 Hz, 1H, H-6), 7.18 (d, J = 9 Hz, 2H,
Ar), 3.90 (s, 3H, OCH3) ppm; 13C NMR (150 MHz,
DMSO-d6): d = 167.6 (C-2), 163.4 (Ar), 159.4 (C-2’),
ꢀ
5’) ppm; IR (KBr): m = 3104, 2895, 1594, 1130,
754 cm-1; GC–MS (EI, 70 eV): m/z (%) = 390 (M?,
2
158.1 (Ar), 156.1 (q, JCF = 35 Hz, C-4’), 149.3 (C-6’),
100), 371 (4), 321 (8), 176 (16), 69 (4).
132.3 (Ar), 130.5 (Ar), 127.8 (Ar), 126.5 (Ar), 123.4 (Ar),
1
121.8 (Ar), 121.2 (q, JCF = 275 Hz, CF3), 120.4 (Ar),
N-[6-(Thien-2-yl)-4-(trifluoromethyl)pyrimidin-2-
yl]benzo[d]thiazol-2-amine (3j, C16H9F3N4S2)
Reaction time 8 h; green solid; yield 1.083 g (60 %); m.p.:
115.1 (Ar), 105.5 (C-5’), 56.1 (OCH3) ppm; IR (KBr):
m = 3185, 1593, 1137, 755 cm-1; GC–MS (EI, 70 eV): m/
ꢀ
z (%) = 402 (M?, 100), 383 (2), 333 (4), 149 (2), 69 (4).
1
289–290 °C; H NMR (400 MHz, DMSO-d6): d = 12.43
(s, 1H, NH), 8.40 (d, J = 4 Hz, 1H, thienyl), 8.03–8.02 (m,
2H, H-7, H-5’), 7.74 (d, J = 8 Hz, 1H, H-4), 7.44 (t,
J = 8 Hz, 1H, H-5), 7.35 (t, J = 5 Hz, 1H, thienyl), 7.30
(t, J = 7 Hz, 1H, H-6) ppm; 13C NMR (150 MHz, DMSO-
d6): d = 162.5 (C-2), 159.3 (C-2’), 157.9 (C-4’), 141.1 (C-
6’), 134.0 (Ar), 132.3 (Ar), 129.7 (Ar), 126.6 (Ar), 123.4
(Ar), 122.1 (q, 1JCF = 275 Hz, CF3), 121.7 (Ar), 104.8 (C-
N-[6-(p-Tolyl)-4-(trifluoromethyl)pyrimidin-2-
yl]benzo[d]thiazol-2-amine (3g, C19H13F3N4S)
Reaction time 16 h; white solid; yield 1.158 g (60 %);
m.p.: 273–274 °C; 1H NMR (400 MHz, DMSO-d6):
d = 12.26 (s, 1H, NH), 8.34 (d, J = 8 Hz, 2H, Ar),
7.99–7.97 (m, 2H, Ar), 7.72 (d, J = 8 Hz, 1H, H-4), 7.46–
7.44 (m, 2H, H-5, H-5’), 7.28 (t, J = 8 Hz, 1H, H-6), 2.44
(s, 3H, CH3) ppm; 13C NMR (150 MHz, DMSO-d6):
d = 167.9 (C-2), 159.4 (C-2’), 158.1 (C-4’), 143.2 (C-6’),
132.7 (Ar), 132.4 (Ar), 130.3 (Ar), 128.5 (Ar), 126.5 (Ar),
5’) ppm; IR (KBr): m = 3100, 1692, 1126, 759 cm-1; GC–
ꢀ
MS (EI, 70 eV): m/z (%) = 378 (M?, 100), 359 (3), 309
(3), 176 (23), 149 (3), 69 (5).
123

Eco-friendly synthesis and antioxidant activity of new trifluoromethyl-substituted…
7.88 (d, J = 8 Hz, 1H, H-7), 7.83 (d, J = 8 Hz, 1H, H-4),
7.56 (s, 1H, H-5’), 7.43 (t, J = 7 Hz, 1H, H-5), 7.29 (t,
J = 8 Hz, 1H, H-6), 7.10 (d, J = 9 Hz, 2H, Ar), 4.19 (s,
3H, CH3), 3.94 (s, 3H, OCH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 167.2 (C-2), 163.1 (C-2’), 161.9 (Ar), 158.5
2
(Ar), 156.1 (q, JCF = 36 Hz, C-4’), 148.8 (C-6’), 133.5
(Ar), 129.6 (Ar), 128.0 (Ar), 125.8 (Ar), 123.2 (Ar), 120.8
1
(Ar), 120.7 (q, JCF = 275 Hz, CF3), 120.6 (Ar), 114.6
Fig. 2 Structure and numbering of compounds 4 and 5
(Ar), 104.4 (C-5’), 55.5 (OCH3), 35.7 (CH3) ppm; GC–MS
(EI, 70 eV): m/z (%) = 416 (M?, 100), 385 (6), 163 (14),
136 (10), 77 (6).
General procedure for the synthesis of synthesis of N-
alkyl(allyl)-N-[4-(trifluoromethyl)pyrimidin-2-yl]-1H-
benzo[d]thiazol-2-amines 4, 5
N-Allyl-N-[5-methyl-4-(trifluoromethyl)pyrimidin-2-
To amagneticallystirred solution of 10 cm3 anhydrous DMF
and 0.012 g NaH (0.5 mmol)at 0 °C, previously synthesized
aryl amines 3 (2 mmol) were added. The reaction system
remained at 0 °C for 1 h. After this time, the respective pure
alkylating reagent (2 mmol) was added, and the reaction
mixture was then kept at room temperature for 16 h. After
the end of the reaction, 10 cm3 distilled water was added and
the precipitated product was filtered. All the products 4, 5
were easy recrystallized from ethanol (Fig. 2).
yl]benzo[d]thiazol-2-amine (5c, C16H13F3N4S)
1
White solid; yield 0.518 g (74 %); m.p.: 154–156 °C; H
NMR (400 MHz, CDCl3): d = 8.60 (s, 1H, H-6’), 7.81 (d,
J = 8 Hz, 1H, H-7), 7.78 (d, J = 8 Hz, 1H, H-4), 7.39 (dt,
J = 1 Hz, 8 Hz, 1H, H-5), 7.24 (dt, J = 1 Hz, 8 Hz, 1H,
H-6), 6.11–6.15 (m, 1H, H-2’’), 5.36 (d, J = 5 Hz, 2H,
H-1’’), 5.18 (dd, J = 1 Hz, 1 Hz, 1H, H-3’’), 2.40 (s, 3H,
CH3) ppm; 13C NMR (100 MHz, CDCl3): d = 161.6 (C-
2
2), 160.2 (C-2’), 155.9 (C-3a), 153.2 (q, JCF = 34 Hz,
C-4’), 149.2 (C-6’), 133.8 (C-7a), 132.5 (C-2’’), 125.7 (C-
1
5), 123.0 (C-6), 121.5 (q, JCF = 277 Hz, CF3), 120.9 (C-
N-Methyl-N-[5-methyl-4-(trifluoromethyl)pyrimidin-2-
yl]benzo[d]thiazol-2-amine (4c, C14H11F3N4S)
1
7), 120.5 (C-4), 117.5 (C-3’’), 111.1 (C-5’), 49.6 (C-1’’),
14.0 (CH3) ppm; GC–MS (EI, 70 eV): m/z (%) = 350
(M?, 100), 335 (1), 173 (4), 135 (13), 69 (6).
White solid; yield 0.388 g (60 %); m.p.: 150–152 °C; H
NMR (400 MHz, CDCl3): d = 8.64 (s, 1H, H-6’), 7.85 (d,
J = 8 Hz, 1H, H-7), 7.80 (d, J = 8 Hz, 1H, H-4), 7.42 (t,
J = 8 Hz, 1H, H-5), 7.28 (t, J = 8 Hz, 1H, H-6), 4.11 (s,
3H, CH3), 2.45 (s, 3H, CH3) ppm; 13C NMR (100 MHz,
CDCl3): d = 161.6 (C-2), 161.1 (C-2’), 153.8 (q,
2JCF = 37 Hz, C-4’), 149.1 (C-6’), 133.8 (Ar), 125.7
N-Allyl-N-[6-phenyl-4-(trifluoromethyl)pyrimidin-2-
yl]benzo[d]thiazol-2-amine (5e, C21H15F3N4S)
1
White solid; yield 0.449 g (54 %); m.p.: 136–138 °C; H
NMR (400 MHz, CDCl3): d = 8.25–8.21 (m, 2H, Ar),
7.85–7.82 (m, 2H, Ar), 7.64–7.59 (m, 4H, Ar), 7.47 (s, 1H,
H-5’), 7.43–7.40 (m, 2H, Ar), 6.20–6.11 (m, 1H, H-2’’),
5.37-5.30 (m, 2H, H-1’’), 5.26-5.21 (m, 2H, H-3’’) ppm;
13C NMR (100 MHz, CDCl3): d = 167.8 (C-2), 158.0 (C-
1
(Ar), 125.3 (q, JCF = 287 Hz, CF3), 120.8 (Ar), 120.5
(Ar), 119.9 (Ar), 109.4 (C-5’), 35.3 (CH3), 13.9 (CH3)
ppm; GC–MS (EI, 70 eV): m/z (%) = 324 (M?, 100), 296
(3), 163 (38), 78 (2), 69 (6).
2
2’), 156.4 (q, JCF = 36 Hz, C-4’), 149.0 (C-6’), 135.6
N-Methyl-N-[6-phenyl-4-(trifluoromethyl)pyrimidin-2-
yl]benzo[d]thiazol-2-amine (4e, C19H13F3N4S)
(Ar), 133.7 (Ar), 132.4 (C-2’’), 132.1 (Ar), 129.2 (Ar),
1
127.9 (Ar), 125.8 (Ar), 123.5 (q, JCF = 240 Hz, CF3),
Yellow solid; yield 0.6176 g (80 %); m.p.: 175–177 °C; 1H
NMR(400 MHz,CDCl3):d = 8.24–8.20(m, 2H, Ar),7.82(t,
J = 7 Hz, 2H, Ar), 7.60–7.58 (m, 4H-Ar), 7.42 (t, J = 7 Hz,
1H, H-6), 7.26 (t, J = 8 Hz, 1H, H-5), 4.17 (s, 3H, CH3) ppm;
13C NMR (100 MHz, CDCl3): d = 167.6 (C-2), 160.8 (C-2’),
156.0(q, 2JCF = 36 Hz, C-4’),148.9(C-6’), 135.5(Ar), 133.6
(Ar), 129.1 (Ar), 127.8 (Ar), 126.0 (q, 1JCF = 241 Hz, CF3),
123.1 (Ar), 120.6 (Ar), 117.9 (Ar), 110.7 (Ar), 104.9 (C-5’),
35.6 (CH3) ppm; GC–MS (EI, 70 eV): m/z (%) = 386 (M?,
100), 317 (3), 252 (18), 163 (26), 136 (15).
123.2 (Ar), 120.7 (Ar), 117.8 (C-3’’), 105.2 (C-5’), 49.9 (C-
1’’) ppm; GC–MS (EI, 70 eV): m/z (%) = 412 (M?, 100),
397 (79), 173 (71), 77 (9).
N-Allyl-N-[6-(4-methoxyphenyl)-4-(trifluoromethyl)pyrim-
idin-2-yl]benzo[d]-thiazol-2-amine (5f, C22H17F3N4OS)
1
Yellow solid; yield 0.486 g (55 %); m.p.: 148–150 °C; H
NMR(400 MHz, DMSO-d6): d = 8.41 (d, J = 8 Hz, 2H,
Ar), 8.06 (s, 1H, H-5’), 7.98 (d, J = 8 Hz, 2H, H-7), 7.79
(d, J = 8 Hz, 2H, H-4), 7.44 (t, J = 7 Hz, 2H, H-5), 7.31
(t, J = 7 Hz, 2H, H-6), 7.18 (d, J = 9 Hz, 2H, Ar), 6.17-
6.10 (m, 1H, H-2’’), 5.38 (d, J = 5 Hz, 2H, H-1’’), 5.29
(dd, J = 1 Hz, 17 Hz, 1H, H-3’’), 5.21 (dd, J = 1 Hz,
10 Hz, 1H, H-3’’), 3.90 (s, 3H, OCH3) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 167.7 (C-2), 163.4 (C-2’),
N-[6-(4-Methoxyphenyl)-4-(trifluoromethyl)pyrimidin-2-
yl]-N-methylbenzo[d]thiazol-2-amine
(4f, C20H15F3N4OS)
1
White solid; yield 0.6822 g (82 %); m.p.: 182–184 °C; H
NMR (400 MHz, CDCl3): d = 8.24 (d, J = 9 Hz, 2H, Ar),
123

H. G. Bonacorso et al.
2
160.1 (Ar), 157.8 (Ar), 155.9 (q, JCF = 35 Hz, C-4’),
10. Nenajdenko VG, Balenkova ES (2011) Arkivoc i:246
11. Bonacorso HG, Cavinatto S, Moraes MC, Pittaluga EP, Peroza
LR, Venturini T, Alves SH, Stefanello ST, Soares FAA, Martins
MAP, Zanatta N, Frizzo CP (2015) J Braz Chem Soc 26:2346
12. Bonacorso HG, Rodrigues MB, Rosa WC, Silva LB, Frizzo CP,
Zanatta N, Martins MAP (2015) J Fluor Chem 178:296
13. Bonacorso HG, Paim GR, Porte LMF, Pittaluga EP, Cavinatto S,
Meyer AR, Martins MAP, Zanatta N (2014) J Heterocycl Chem
41:1171
149.0 (C-6’), 137.5 (Ar), 133.4 (Ar), 133.2 (Ar), 131.9 (C-
1
2’’), 130.5 (Ar), 127.8 (Ar), 127.5 (q, JCF = 286 Hz,
CF3), 126.4 (Ar), 123.8 (Ar), 121.5 (Ar), 121.0 (Ar), 117.4
(C-3’’), 115.2 (Ar), 112.3 (Ar), 105.8 (C-5’), 56.0 (OCH3),
49.9 (C-1’’) ppm; GC–MS (EI, 70 eV): m/z (%) = 442
(M?, 100), 427 (69), 415 (3), 402 (5),173 (73), 77 (5).
14. Bonacorso HG, Moraes MC, Wiethan CW, Luz FM, Meyer AR,
Zanatta N, Martins MAP (2013) J Fluor Chem 156:112
15. Bonacorso HG, Navarini J, Wiethan CW, Bortolotto GP, Paim GR,
Cavinatto S, Martins MAP, Zanatta N (2011) J FluorChem 132:160
16. Shikhaliev KhS, Falaleev AV, Kryl’skii DV (2003) Izbrannye
metody sinteza i modifikatsii geterotsiklov (Selected Methods of
Synthesis and Modification of Heterocycles), vol 1. Moscow,
IBS, p 450
17. Katritzky A, Yousaf TI (1986) Can J Chem 64:2087
18. Chen H, Bai J, Jiao L, Guo Z, Yin Q, Li X (2009) Bioorg Med
Chem 17:3980
19. Zhang HQ, Xia Z, Vasudevan A, Djuric SW (2006) Tetrahedron
Lett 47:4881
DPPH: radical scavenging assay
The radical scavenging activities of the compounds 3 were
determined as previously described [40]. Each compound
together with butylated hydroxytoluene (BHT) was tested
at 10, 50, 100, 500, and 1000 lg/cm3. 2,2-Diphenyl-1-
picryl-hydrazil (DPPH) radical was added to the final
concentration of 0.3 mM and allowed to react at room
temperature for 30 min in dark conditions. The absorbance
was measured at 518 nm, using the Spectra Max Plate
ReaderÒ M2 (Molecular Devices, Sunnyvale, CA, USA).
20. Tavares FX, Boucheron JA, Dickerson SH, Griffin RJ, Preugschat
F, Thomson SA, Wang TY, Zhou H-Q (2004) J Med Chem
47:4716
21. Byth KF, Culshaw JD, Green S, Oakes SE, Thomas AP (2004)
Bioorg Med Chem Lett 14:2245
Total antioxidant capacity assay
22. Bonacorso HG, Bortolotto GP, Navarini J, Porte LMF, Wiethan
CW, Zanatta N, Martins MAP, Flores AFC (2010) J Fluor Chem
131:1297
23. Bonacorso HG, Calheiro TP, Zanatta N, Martins MAP (2015)
Monatsh Chem 146:1851
24. Bala M, Verma PK, Sharma D, Kumar N, Singh B (2015) Mol
Divers 19:263
25. Mohit D, Verma SM, Meena RP (2012) PDA J Pharm Sci
Technol 4:873
The total antioxidant potential of the compounds was
evaluated by the phosphomolybdenum method [39]. The
compounds 3 and BHT (positive control) were tested at 10,
50, 100, 500, and 1000 lg/cm3. The vials were capped and
incubated in a water bath at 95 °C for 90 min. After
cooling the mixture to room temperature, the absorbance
was measured at 695 nm using Spectra Max Plate ReaderÒ
M2 (Molecular Devices, Sunnyvale, California, USA).
26. Hojo M, Masuda R, Kokuryo Y, Shioda H, Matsuo S (1976)
Chem Lett 5:499
27. Masaru H, Ryo¯ichi M, Syu¯hei S, Makoto T (1986) Synthesis
1016
28. Colla A, Martins MAP, Clar G, Krimmer S, Fischer P (1991)
Synthesis 483
29. Martins MAP, Guarda EA, Frizzo CP, Moreira DN, Marzari
MRB, Zanatta N, Bonacorso HG (2009) Catal Lett 130:93
30. Flores AFC, Siqueira GM, Freitag R, Zanatta N, Martins MAP
(1994) Quim Nova 17:298
Acknowledgments The authors thank the Coordination for
Improvement of Higher Education Personnel (CAPES) for the fel-
lowships, as well as the National Council for Scientific and
Technological Development (CNPq) for financial support (Process
numbers 306.883/2015-5 and 471.269/2013-1-CNPq/Universal).
31. Kamitori Y, Hojo M, Masuda R, Fujitani T, Kobuchi T, Nishigaki
T (1986) Synthesis 340
References
32. Hojo M, Masuda R, Kamitori Y (1976) Tetrahedron Lett 1009
33. Siqueira GM, Flores AFC, Clar G, Zanatta N, Martins MAP
(1994) Quim Nova 17:24
34. Queiroz MJRP, Calhelha RC, Vale-Silva LA, Pinto E, Nasci-
mento MSJ (2010) Eur J Med Chem 45:5732
ˆ
1. Ali A, Correa A, Alves D, Schpector JZ, Westermann B, Ferreira
MAB, Paixa˜o MW (2014) Chem Commun 50:11926
2. Sahu PK, Sahu PK, Lal J, Thavaselvam D, Agarwal DD (2012)
Med Chem Res 21:3826
3. Ali R, Siddiqui N (2013) J Chem 2013:1
35. Queiroz MJRP, Peixoto D, Calhelha RC, Soares P, Santos T,
Lima RT, Campos JF, Abreu RMV, Ferreira ICFR, Vasconcelos
MH (2013) Eur J Med Chem 69:855
36. Lipinski CA, Lombardo F, Dominy BW, Freeney PJ (1997) Adv
Drug Deliv Rev 23:3
37. Yamazaki T, Taguchi T, Ojima I (2009) Fluorine in medicinal
chemistry and chemical biology. Wiley, Chichester, p 3
38. Luzina EL, Popov AV (2013) J Fluor Chem 148:41
39. Prieto P, Pineda M, Aguilar M (1999) Anal Biochem 269:337
40. Brand-Williams W, Cuvelier ME, Berset C (1995) LWT Food Sci
Technol 28:25
4. Reddy DRS, Kumar KH (2013) World J Pharm Pharm Sci 3:778
5. Ames BN, Shigenaga MK, Hagen TM (1993) Proc Natl Acad Sci
90:7915
6. Tyagi YK, Kumar A, Raj HG, Vohra P, Gupta G, Kumari R,
Kumar P, Gupta RK (2005) Eur J Med Chem 40:413
7. Karegoudar P, Karthikeyan MS, Prasad DJ, Mahalinga M, Holla
BS, Kumari NS (2008) Eur J Med Chem 43:261
8. Zanatta N, Amaral SS, Santos JM, Mello DL, Fernandes LF,
Bonacorso HG, Martins MAP, Andricopulo AD, Borchardt DM
(2008) Bioorg Med Chem 16:10236
9. Alonso C, Marigorta EM, Rubiales G, Palacios F (2015) Chem
Rev 115:1847
41. Zhou ZZ, Yanh GF (2006) Bioorg Med Chem 14:8666
123