The role ionic liquid [BMIM][PF6] in one-pot synthesis of tetrahydropyran rings through tandem barbier–prins reaction

Article abstract of DOI:10.3390/molecules24112084

Tetrahydropyran (THP) rings are common in several natural products, therefore, various strategies are being developed to synthesize these rings. The present work described the study of a one-pot synthesis of 2,4,6-trisubstituted tetrahydropyran compounds

Full text of DOI:10.3390/molecules24112084

molecules
Article
The Role Ionic Liquid [BMIM][PF6] in One-Pot
Synthesis of Tetrahydropyran Rings through Tandem
Barbier–Prins Reaction
Poliane K. Batista, João Marcos G. de O. Ferreira, Fabio P. L. Silva, Mario L. A. A Vasconcellos and
Juliana A. Vale *
Departamento de Química, Universidade Federal da Paraíba, Cidade Universitária, 58051-900 João Pessoa-PB,
Brazil; polianekarenine@gmail.com (P.K.B.); profjoaomarcos@hotmail.com (J.M.G.d.O.F.);
pedrosalinssilva@gmail.com (F.P.L.S.); mlaav00@gmail.com (M.L.A.A.V.)
* Correspondence: julianadqf@yahoo.com.br; Tel.: +558332167433
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Antonio Massa
Received: 29 March 2019; Accepted: 28 April 2019; Published: 31 May 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Tetrahydropyran (THP) rings are common in several natural products, therefore, various
strategies are being developed to synthesize these rings. The present work described the study of a
one-pot synthesis of 2,4,6-trisubstituted tetrahydropyran compounds promoted by the ionic liquid
1-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF6] through a Barbier–Prins reaction
between allyl bromide and aldehydes. The use of [BMIM][PF6] gave Prins products from several
aldehydes in good yields and reaction times. We also found that the anion, PF6-, accelerates the Barbier
reaction when used alone, and the excess SnBr2 from the reaction conditions of the Barbier reaction
leads to the formation of the THP rings, thus acting as a catalyst for Prins cyclization. Additionally,
we demonstrate that ionic liquid can be recovered and reused five times in the preparation of
4-bromo-tetrahydro-2,6-diphenyl-2H-pyran without significant yield loss.
Keywords: ionic liquids; tetrahydropyran; Barbier–Prins Reaction; catalysis; [BMIM][PF6]
1. Introduction
A significant number of biologically important natural products contain tetrahydropyran (THP)
rings, such as neurotoxin brevetoxin B [1] and the antibiotics monensin and 17-deoxyroflamycoin [2].
THP’s rings present interesting biological, pharmaceutical, antimicrobial [
antitumor [ ], antiviral [ ], analgesic [ ], anti-inflammatory [ ], and antidiabetic [
Thus, the THP skeleton has become an attractive object of study in the field of organic synthesis.
3
], antifungal [
4],
5
6
7
8
9
] properties.
As reactions of hetero-Diels–Alder [10], iodolactonization reaction [11], selenium etherification
of unsaturated alcohols [12], 6-endo cyclization of vinyl epoxides [13], reductive etherification [14],
ring closing metathesis [15], Takeda olefination [16], SmI2-mediated radical cyclization [17], Iterative
epoxide opening cyclization [18], and Prins cyclization reaction are some synthesis methodologies
developed aiming at the formation of tetrahydropyran rings.
The Prins cyclization is a synthetic methodology developed with the objective of forming THP
rings that commonly occur between homoallylic alcohols (or ethers) and aldehydes (or acetals),
primarily mediated by a Lewis acid (AlCl3 [19], SnCl4 [20], SnBr4 [21], InCl3 [22], among others)
(Scheme 1). A more viable alternative for forming THPs rings is a one-pot synthesis under traditional
Barbier reaction conditions [23], using a homoallylic alcohol as a reaction intermediate, followed by a
Prins cyclization [2,24].
Molecules 2019, 24, 2084; doi:10.3390/molecules24112084
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X
R4
O
R1
R2
R5
R3
R4
MX (Lewis acid)
R1
+
OH
R5
O
R2 R3
R1, R2, R3, R4, R5 = H, alkyl ou aryl
X = OH, Halogen
Scheme 1. Lewis acid mediated Prins cyclization reaction.
There are few examples in the literature that describe the formation of THP rings prepared via
one-pot reactions. Among them, we cite the work of Yi and collaborators [25], who accidentally
obtained a mixture of tetrahydropyran-4-ol and 4-bromotetrahydropyran compounds in the presence
of indium metal.
On the other hand, in the search for sustainability and technologies that do not harm the
environment, one of the routes being explored is the substitution of “traditional” organic solvents
with ionic liquids. Due to strong interactions between the ions, they are not volatile and can exercise
unexpected catalytic activity [26].
Recently, Zhao et al. [27] showed that ionic liquids containing halide anions promote the formation
of THPs rings in good yields via a one-pot Barbier–Prins sequence of reactions; however, the reaction
is sensitive to the presence of water in the tin (II) halide. In contrast, Tang et al. [28] subjected the
Barbier reaction to using [BMIM][BF4] as the ionic liquid, with the homoallylic alcohol as the only
product obtained with 88% yield for benzaldehyde (Scheme 2). Additionally, McCluskey [29] using
[BMIM][PF6], performed the allylation of an aldehyde from tetraallylstannane and obtained only the
homoallylic alcohol as the product in good yields. These observations drew our attention to further
study the Barbier–Prins reaction under different conditions using [BMIM][PF6] as the solvent aiming
at obtaining tetrahydropyrano rings.
X
OH
SnCl2.2H2O
[BMIM][BF4]
SnCl2
BPyCl
+ Br
PhCHO
Ph
O
Ph
Ph
78%
88%
X = Cl, Br
N Bz
BPy
N
N
Me
Bu
BMIM
Scheme 2. Different products obtained under Barbier reaction conditions in ionic liquids.
In the present study, we propose the one-pot synthesis of 2,4,6-trisubstituted tetrahydropyran
compounds promoted by ionic liquids [BMIM][PF6] and your role in the tandem Barbier–Prins reaction.
The ionic liquid [BMIM][PF6] was chosen because it has been routinely used based on the premise
that the imidazolium does not have halide contamination as a result of its preparation [30]. In addition,
it is a safe, environmentally friendly, immiscible with water, and especially for this reaction, there are
no experimental discussions about its participation in Barbier–Prins reactions.
2. Results and Discussion
We started our studies with the reaction between benzaldehyde, allyl bromide, and stannous
chloride dihydrate described in the Barbier protocol, using [BMIM][PF6] as a reaction medium under
different conditions. The reaction formed products 4a and 4b by the Prins cyclization and the
homoallylic alcohol 3 under certain conditions. The results are shown in Table 1.

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Table 1. Reaction between benzaldehyde (1) and allyl bromide (2) promoted by SnCl2
[BMIM][PF6].
·
2H2O in
X
OH
SnCl2.2H2O
+
PhCHO
1
+
Br
Ph
[BMIM][PF6], 8 h
O
Ph
Ph
2
3
4a, X= Cl
4b, X = Br
Entry a
1:2 Ratio
Conversion (%) b
Ratio b (3:4a:4b)%
1
2
3
4
1:1.5
1:3
1:4
12
51
92
92
0:92:8
0:84:16
0:73:27
0:69:31
1:6
a
Allyl bromide (1.32 mmol), Benzaldehyde (0.33 mmol), SnCl2
·
2H2O (0.5 mmol), [BMIM][PF6] (2.4 mmol), Reaction
b
time: 8 h, room temperature. Determined by GC/FID.
We observed that an increased quantity of allyl bromide during the reaction led to an increased
Prins product conversion (Entry 3). Interestingly, when the halogen atom of the allyl compound and
the tin halide are different, two 2,4,6-trisubstituted tetrahydropyran compounds were formed, wherein
THP chlorine is preferably formed in all tests performed in Table 1.
The methodology developed by Houllemare [31], in which addition of potassium iodide (KI)
accelerates the Barbier reaction to obtain homoallylic alcohols, was tested. Under these conditions,
the presence of KI resulted in the lack of Prins product formation consequently only the homoallylic
alcohol 3 was observed (Scheme 3).
OH
SnCl2.2H2O, KI
Ph
+
PhCHO
1
Br
,
[BMIM][PF6], 24 h
65%
3
2
Scheme 3. Reaction of (1) and (2) with KI in [BMIM][PF6].
We performed the same reaction with two other ionic liquids, using 1-Butyl-3-methylimidazolium
(BMIM) as the cation and replaced the anion with [CF3CO2−] and [CF3SO3−]. The results of this study
show the Barbier–Prins reaction in the five different ionic liquids with SnCl2.2H2O (Table 2).
Table 2. Reaction of benzaldehyde (1) with allyl bromide (2) in different ionic liquids.
X
OH
SnCl2.2H2O
[IL], 8 h
+
PhCHO +
Br
Ph
O
Ph
4a
Ph
1
2
3
, X=Cl
4b, X= Br
Entry
Ionic Liquid
Isolated Yield (%)
Ratio (3:4a:4b) %
1 a
2
[BMIM][BF4]
[BPy][Br]27
[BMIM][PF6]
[BMIM][CF3CO2]
[BMIM][CF3SO3]
88
77
75
48
85
100:0:0
0:76:24
0:73:27
100:0:0
100:0:0
3 a
4 a
5 a
a
Allyl bromide (1,32 mmol), Benzaldehyde (0,33 mmol), SnCl2.2H2O (0.5 mmol), IL (2.4 mmol), room temperature, 8 h.

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As seen in Table 2, the tetrahydropyran compounds were obtained using the PF6 anion
combined with the cation (BMIM) (Entry 3), presenting similar results to the work of Wang et al [27
(Table 2, Entry 2).
]
Li and coworkers [28] obtained the homoallylic alcohol (3) using the liquid [BMIM][BF4] (Table 2,
entry 1). We also performed this same reaction under the conditions of entry 3 (Table 2). The results
showed similar behavior to that found by the authors with only the homoallylic alcohol obtained.
Of the ionic liquids applied in Table 2, [BMIM][PF6] is the only one that is immiscible with
water besides the only one provides formation of the THP product mixture, even when using the
hydrated salt (SnCl2.2H2O). Apart from our results, Wang and coworkers [27], when using the ionic
liquid BPyCl under the same conditions, only the homoallylic alcohol was obtained in a 93% yield
on the other hand, THPs were only observed when using anhydrous SnCl2. In view of these results,
we indicate that the use of an immiscible ionic liquids with water influenced the products formed from
the Barbier–Prins reaction.
-
-
The ionic liquids from [CF3CO2 ] and [CF3SO3 ], as well as the [BF4−] anions (Entry 1, 4, and 5),
did not generate the Prins product, as observed for the PF6 anion. The ionic liquids [BMIM][CF3CO2]
and [BMIM][CF3SO3] behaved similar to [BMIM][BF4] [28] and led to the exclusive formation of
homoallylic alcohol with yields of 48% and 82%, respectively.
We investigated the Barbier–Prins reaction in [BMIM][PF6] using other metallic sources, such as
Zn and Sn, which are also used in the Barbier reaction [23] (Table 3).
Table 3. Reaction of benzaldehyde (1) with allyl bromide (2) in [BMIM][PF6], varying the metallic sources.
X
OH
metallic sources
[BMIM][PF6], 8 h
+
+
PhCHO
Br
Ph
O
Ph
Ph
1
2
3
4a, X= Cl
4b, X = Br
Entry a
Metallic Sources
Conversion (%) c
Ratio 3:4a:4b
1
2
3
SnCl2·2H2O
92
0
0
0:73:27
0:0:0
0:0:0
Zn
Sn
4
SnCl2·2H2O/SnCl4
SnCl2·2H2O/AlCl3
SnBr2
85
86
90
0:82:18
0:83:17
0:0:100
5 b
6
Allyl bromide (1.32 mmol), Benzaldehyde (0.33 mmol), [BMIM][PF6] (2.4 mmol), ambient temperature, 8 h. a Metallic
sources (0.5 mmol), b SnCl4 (0.16 mmol) or AlCl3 (0.16 mmol), c Determined by GC/FID.
The reactions with metallic Zn and metallic Sn did not lead to the formation of any of the products
3
,
4a and 4b (entries 2 and 3). Using SnCl4 and AlCl3 as a Lewis acid, when introduced to the reaction
to activate the carbonyl group and accelerate the reaction, did not influence the conversion or the
reaction time (entries 4 and 5). Substituting SnCl2.2H2O for SnBr2 led to the exclusive formation of the
Prins product 4b with excellent conversion (entry 6).
In the next phase of this study, we applied reaction conditions better established for other
aldehydes. The reaction was studied with SnCl2 2H2O and SnBr2, and the results are shown in Table 4.
·

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Table 4. Synthesis of several Tetrahydropyrans (THPs) varying tin halides promoted by [BMIM][PF6].
X
SnX2.nH2O
+
RCHO
Br
[BMIM][PF6], 8 h
O
R
R
2
5-9a X=Cl or
5-9b X=Br
Entry
1 a
Aldehyde
Tin Halide
SnCl2.2H2O
SnBr2
Yield Isolated (%)
Ratio
4a:4b (73:27)
4b
O
75
73
O
2 a
O
3 a
4 a
5 a
6 a
7 a
8 a
9 b
10 b
SnCl2.2H2O
SnBr2
71
70
71
72
60
62
40
45
5a:5b (63:37)
F
O
5b
6a:6b (62:38)
6b
F
O
SnCl2.2H2O
SnBr2
Cl
O
Cl
O
SnCl2.2H2O
SnBr2
7a:7b (65:35)
7b
H3C
O
H3C
O2N
SnCl2.2H2O
SnBr2
8a:8b (65:35)
8b
O
O2N
O
11 a
12 a
SnCl2.2H2O
SnBr2
61
60
9a:9b(60:40)
O
O
9b
Allyl bromide (1.32 mmol), Benzaldehyde (0.33 mmol), SnCl2
temperature, b Temperature 40 ◦C.
·
2H2O (0.5 mmol), [BMIM][PF6] (2.4 mmol), 8 h, a room
In general, reactions with aromatic aldehydes with electron withdrawing groups (entries 3–6) and
electron donating group (entries 7, 8) at the 4-position presented good yields, similar to the reaction
with the aromatic aldehyde without any substitution. However, the reaction with 4-NO2-benzaldehyde
(entries 9, 10), under the performed conditions, does not lead to formation of the homoallylic alcohol or
Prins product, even after 48 h of reaction time. These reactions were performed with a slight warming
of 40 degrees, obtaining the Prins product in a 40% yield, both when it was used with SnCl2 or SnBr2.
The results from the work of Slaton [32] show that the performance of the homoallylic alcohol formed
from the 4-NO2-benzaldehyde is lower compared with other substituents. Therefore, the reaction yield
is decreased, possibly because the homoallylic alcohol formed in the reaction is in a small quantity.
The reaction of the aliphatic aldehyde (entries 11, 12) has a similar behavior to aromatic aldehydes
(entries 1–8).
For all 2,4,6-trisubstituted tetrahydropyran compounds, the cis compound was obtained.
The structures of the compounds were confirmed by comparison with the literature data, where the
tetrahydropyrans obtained followed the same standards for the chemical shift data and the NMR
coupling constants [33].
In regard to [BMIM][PF6] being completely immiscible with water, it is easy to separate it from the
reaction medium and recycle it. The Figure 1 shows the yields of the one-pot Barbier–Prins cyclization
combined reaction, using benzaldehyde under the conditions of entry 6 in Table 3.

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Figure 1. Reuse of ionic liquid [BMIM][PF6] in the synthesis of 4b at room temperature.
As shown in Figure 1, the ionic liquid [BMIM][PF6] was reused consecutively, up to five times,
with little decrease in tetrahydropyran yield, ranging from 66% to 53%.
-
Later, we replaced the ionic liquids with water, using the salt KPF6 to test the influence of PF6 in
the reaction. It was found that the product conversion ratio is increased when the amount of water
decreased (Table 5, entries 2 and 3). However, upon removing the solvent (water), the reaction did not
proceed, suggesting that the water is part of the reaction (Table 5, entry 1). Water should provide the
-
energy required to cause the dissociation of KPF6. Without water, the dissociation of PF6 cannot occur.
Table 5. Reaction of benzaldehyde (1) with allyl bromide (2) promoted by KPF6.
Br
SnBr2/KPF6
+
PhCHO
Br
Solvent, 8 h
O
Ph
Ph
4b
1
2
Entry
Solvent
Yield Isolated (%)
1
2
3
4
5
6
7
-
0
H2O/0.5 mL
H2O/10 µL
Toluene/0.5 mL
Ethanol/0.5 mL
Acetonitrile/0.5 mL
CH2Cl2/0.5 mL
43
63
0
31
34
37
Conditions: Allyl bromide (1.32 mmol), Benzaldehyde (0.33 mmol), SnBr2. (0.5 mmol), 24 h, room temperature.
We repeated the reaction using KPF6 with other solvents (Table 5, entry 4–7) for example when
toluene was used (entry 4) no product is formed. However the use of polar solvents as ethanol
(entry 5), acetonitrile (entry 6) and dichloromethane (entry 7) enabled yields were very similar at
approximately 30%.
From the experiments in Table 5, we verify that the KPF6 salt is an important reactant in the
Barbier–Prins reaction in aqueous medium, with the best result obtained when only 10 µL of water
was used as the reaction solvent (Entry 3). However, it would still be necessary to investigate this
working step, in which the KPF6 salt was acting as a catalyst in the Barbier reaction or the Prins reaction.
For this, we conducted another experiment (Table 6) to investigate the performance of KPF6 and SnBr2
for the Prins cyclization reaction between the homoallylic alcohol and benzaldehyde.

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Table 6. Reaction of benzaldehyde (1) with homoallylic alcohol (3) promoted by SnBr2.
Br
OH
conditions
H2O, 8 h
PhCHO +
Ph
O
Ph
Ph
1
3
4b
Entry
Condition
Yield Isolated (%)
1
2
SnBr22H2O/KPF6
78
77
SnBr2.2H2O
Conditions: 1-phenylbut-3-en-1-ol (0.33 mmol), Benzaldehyde (0.33 mmol), SnBr2 (0.5 mmol), KPF6 (0.16 mmol),
H2O (10 µL), room temperature, 8 h.
The product 4b was obtained in good yield in only an 8 h reaction by Prins cyclization from allylic
alcohol (Table 6, entries 1 and 2) moreover it can be observed that without KPF6 the same reaction
showed similar yields. In fact, we concluded with the Barbier reaction is very slow without KPF6,
therefore this salt acts as a catalyst in the Barbier reaction and has no influence on the Prins cyclization.
On the other hand, SnBr2 in slight excess acts as Lewis acid in the Prins cyclization (Scheme 4).
Br
-
OH
SnBr2
SnBr /
PF6
2
PhCHO
+
Br
Ph
PhCHO
O
Ph
Ph
4b
Scheme 4. The role of ionic liquid [BMIM][PF6] and SnBr2 in the THP-4b synthesis.
3. Experimental
3.1. Synthesis of 2,4,6-Trisubstituted Tetrahydropyran Compounds (General Procedure)
A mixture of aldehyde (0.33 mmol), allyl bromide (1.32 mmol), SnBr2·2H2O (0.5 mmol) and
[BMIM][PF6] (0.5 mL) was agitated at room temperature for 8 h. The reaction mixture was extracted
in diethyl ether (three times) and then an aqueous solution of HCl was added in the combined ether
phases. The organic phase was separated and dried with anhydrous Na2SO4.– The solvent was
removed under vacuum, and the THPs product was purified by silica gel column chromatography,
using a mixture of ethyl acetate and petroleum ether (1:50) as an eluent; a colorless solid was obtained.
An aliquot the crude product was analyzed with gas chromatography for obtained the conversion of
reaction and ratio between chlorinated and brominated compounds. The NMR spectra (1H and 13C)
for compounds 4b–9b is shown in the Supplementary Materials.
3.2. Characterization Data [32a]
1
4-Bromo-tetrahydro-2,6-diphenyl-2H-pyran (4b): H NMR (200 MHz, CDCl3)
δ = 7.35 (m, 10H, ArH),
4.57 (d, J = 12 Hz, 2H, H2ax e H6ax), 4.44 (m, 1H, H4ax), 2.56 (m, 2H, H3ax e H5ax), 2.11 (m, 2H, H3eq
e
H5eq). 13C NMR (50 MHz, CDCl3) δ = 145.13, 132.34, 131.68, 129.70, 83.66, 50,08, 49.03. Yield 73%.
1
4-Bromo-2,6-bis(4-fluorophenyl)-tetrahydro-2H-pyran (5b): H NMR (500 MHz, CDCl3)
δ
= 7.38 (m, 4H,
ArH), 7.06 (m, 4H, ArH), 4.55 (m, J = 10.0 Hz, 2H, H2ax e H6ax), 4.41 (m, 1H, H4ax), 2.55 (m, 2H, H3ax
e
H5ax), 2.09 (m, 2H, H3eq e H5eq); 13C NMR (125 MHz, CDCl3)
127.39, 115.50, 115.08, 79,08, 45,48, 44.92. Yield 71%.
δ = 164.69, 159.90, 136.85, 136.78, 127.55,

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1
4-Bromo-2,6-bis(4-chlorophenyl)-tetrahydro-2H-pyran (6b): H NMR (500 MHz, CDCl3)
δ
= 7.34 (m, 8H,
ArH), 4.54 (dd, J = 10.0, 2H, 8.0, H2ax e H6ax), 4.42 (m, 1H, H4ax), 2.54 (m, 1H, H3ax e H5ax), 2.06 (m,
1H, H3eq e H5eq); 13C NMR (125 MHz, CDCl3)
Yield 73%.
δ = 139.47, 133.59, 128.66, 127.14, 79.06, 45.27, 44.81.
4-Bromo-tetrahydro-2,6-dip-tolyl-2H-pyran (7b): 1H NMR (500 MHz, CDCl3)
δ = 7.31 (m, 8H, ArH),
4.54 (dd, J = 10.0 Hz, 2H, H2ax e H6ax), 4.45 (m, 1H, H4ax), 2.55 (m, 1H, H3ax e H5ax), 2,36 (s, 6H), 2.12
(m, 3H, H3eq e H5eq); 13C NMR (125 MHz, CDCl3)
16,25. Yield 60%.
δ
= 133.48, 132.51, 124.16, 120.99, 74.73, 41.55, 40.23,
1
4-Bromo-tetrahydro-2,6-bis(4-nitrophenyl)-2H-pyran (8b): H NMR (500 MHz, CDCl3)
δ
= 8.28 (m, 4H,
ArH), 7.63 (m, 4H, ArH), 4.75 (dd, J = 10.0, 2H, H2ax e H6ax), 4.49 (m, 1H, H4ax), 2.66 (m, 2H, H3ax
e
H5ax), 2.12 (m, 2H, H3eq e H5eq); 13C NMR (125 MHz, CDCl3)
43.87. Yield 40%.
δ = 147.55, 126.39, 123.84, 78.69, 44.32,
1
4-Bromo-tetrahidro-2,6-dihexyltetrahidropyrano (9b): H NMR (500 MHz, CDCl3):
δ = 4.12 (m, H4ax),
3.21 (m, H2ax e H6ax), 2.17 (dd, J = 10.0 Hz, H3eq e H5eq), 1.61 (m, H3ax e H5ax), 1.24 (m, 24H, (CH2)6),
0.83 (t, 6H, CH3). 13C NMR (125 MHz, CDCl3):
13.94. Yield 60%.
δ = 77.52, 47.33, 43.43, 35.74, 31.65, 29.03, 25.34, 22.45,
4. Conclusions
In this study, we showed tandem reactions combining Barbier and Prins for produces
stetrahydropyrans compounds from an allylbromide, tin halide, and aldehyde, promoted by the
ionic liquid [BMIM][PF6] with moderate to good yields in just an 8 h reaction. With other parallel
-
experiments, we can see how the reagents work in two reactions. In addition, the PF6 anion presents
in ionic liquid besides contributing the ionic medium to the reaction mechanism acts to accelerate the
reaction and only ionic medium influence on the Prins cyclization. Slight excess of SnBr2 under the
reaction conditions of the Barbier reaction leads to the formation of the product of THPs, thus acting as
a catalyst for Prins cyclization.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/24/11/2084/s1.
Author Contributions: The authors P.K.B., J.M.G.d.O.F. and F.P.L.S. were responsible for Investigation,
methodology, validation, formal analysis and Writing-Original Draft Preparation. The author M.L.A.A V. was
responsible for Investigation, Writing-Original Draft Preparation and Funding Acquisition. The corresponding
author J.A.V. was responsible for Conceptualization, Resources, Writing-Original Draft Preparation, Writing-Review
& Editing and Supervision.
Funding: This research received no external funding.
Acknowledgments: This research was supported by grants from the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes).
Conflicts of Interest: The authors declare no conflict of interest.
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