HFIP-promoted synthesis of substituted tetrahydrofurans by reaction of epoxides with electron-rich alkenes

Article abstract of DOI:10.3390/molecules25153464

In the present work, the employment of fluorinated alcohols, specifically 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), as solvent and promoter of the catalyst-free synthesis of substituted tetrahydrofuranes through the addition of electron-rich alkenes to epoxydes is described. The unique properties of this fluorinated alcohol, which is very different from their non-fluorinated analogs, allows carrying out this new straightforward protocol under smooth reaction conditions affording the corresponding adducts in moderate yields in the majority of cases. Remarkably, this methodology has allowed the synthesis of new tetrahydrofuran-based spiro compounds as well as tetrahydrofurobenzofuran derivatives. The scope and limitations of the process are also discussed. Mechanistic studies were also performed pointing towards a purely ionic or a SN2-type process depending on the nucleophilicity of the alkene employed.

Full text of DOI:10.3390/molecules25153464

molecules
Article
HFIP-Promoted Synthesis of Substituted
Tetrahydrofurans by Reaction of Epoxides with
Electron-Rich Alkenes
Natalia Llopis and Alejandro Baeza *
Departamento de Química Orgánica and Instituto de Síntesis Orgánica (ISO), Facultad de Ciencias,
Universidad de Alicante. Apdo. 99, E-03080 Alicante, Spain; natalia.llopis@ua.es
* Correspondence: alex.baeza@ua.es; Tel.: +34-965-903-728
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Roman Dembinski
Received: 3 July 2020; Accepted: 28 July 2020; Published: 30 July 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: In the present work, the employment of fluorinated alcohols, specifically 1,1,1,3,3,3-
hexafluoroisopropanol (HFIP), as solvent and promoter of the catalyst-free synthesis of
substituted tetrahydrofuranes through the addition of electron-rich alkenes to epoxydes is
described. The unique properties of this fluorinated alcohol, which is very different from their
non-fluorinated analogs, allows carrying out this new straightforward protocol under smooth
reaction conditions affording the corresponding adducts in moderate yields in the majority of
cases. Remarkably, this methodology has allowed the synthesis of new tetrahydrofuran-based spiro
compounds as well as tetrahydrofurobenzofuran derivatives. The scope and limitations of the process
are also discussed. Mechanistic studies were also performed pointing towards a purely ionic or a
SN2-type process depending on the nucleophilicity of the alkene employed.
Keywords: tetrahydrofuranes; fluorinated alcohols; green chemistry
1. Introduction
The substituted tetrahydrofuran structure is present in a wide variety of bioactive natural
compounds and has gained considerable interest in pharmaceutical research. In general,
natural compounds containing tetrahydrofuran ring derivatives have been found in different classes of
terrestrial and marine organisms [
both isolated from the Caribbean marine sponge Calyx podatypa [
heartwood of the tree Thespesia populnea [ ]. Other examples are the lignans Fragransin C1 (among other
1–
3]. One of these representative examples are Caloxylanes A and B,
4,5], or Corsifuran A, isolated from the
6
compounds from the Fragransin family) [
1,
7] and Conocarpan [
1
,8], both having demonstrated to
exhibit biological activity (Figure 1).
OMe
O
O
Ph
Ph
O
Ph
Ph
MeO
Caloxylane A
Caloxylane B
Corsifuran A
OMe
HO
OH
O
O
MeO
OH
Me
Me
Fragransin C1
OMe
Me
Conocarpan
Figure 1. Natural products and bioactive molecules containing tetrahydrofuran moiety.
Molecules 2020, 25, 3464; doi:10.3390/molecules25153464 www.mdpi.com/journal/molecules

Molecules 2020, 25, 3464
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It is not surprising then that a considerable amount of strategies have been already described in
order to gain access to these interesting molecules. Among them, probably the most straightforward
method is based on the reaction between alkenes and epoxides, which are commercially available and
highly abundant in bulk. This perfect atom-economy route provides direct access to different substituted
tetrahydrofurans allowing a wide range of substitution patterns on the structure. However, to the best
of our knowledge, only a limited number of publications following this protocol have been reported,
being those mainly radical [9] or metal-catalyzed processes (Scheme 1) [10–13].
Scheme 1. Synthesis of substituted tetrahydrofurans by reaction between alkenes and epoxides.
In the last years, our research group has become interested in the use of fluorinated alcohols
as solvents and promoters of organic reactions [14,15]. The unique chemical and physical properties
that fluoroalkyl alcohols have in comparison with their non-fluorinated analogues, such as their high
hydrogen bond donor ability, high polarity and ionizing power, and low nucleophilicity values together
with the slightly acidic character, make them perfect candidates as promoters of reactions involving
ionic processes [16–22]. On the other hand, fluorinated alcohols have already proven to be efficient
promoters in the ring-opening reaction of epoxides with different nucleophiles [23–26].
With all these precedents in mind, we envisioned a new strategy based on the use of fluorinated
alcohols as solvents and reaction promoters in a metal and radical-free ring-opening reaction of
epoxides with different electron-rich alkenes as nucleophiles in order to obtain the corresponding
substituted tetrahydrofurans in an efficient, cost-effective, and environmentally friendly chemical
manner. The results of this investigation are herein described.
2. Results and Discussion
Firstly, the reaction between styrene oxide (1a) and α-methylstyrene (1b) was selected as a model
in order to obtain the optimal reaction conditions. Different solvents were selected to evaluate their
performance as promoters at 45 ◦C (Table 1, entries 1–4). When water and 2-propanol, which possesses
quite high polarity and hydrogen bond ability, were used, the reaction produced the diol 4 as major
product and failed (Table 1, entries 1 and 2). Next, 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and
2,2,2-trifluoroethanol (TFE), as readily available and inexpensive fluorinated alcohols, were tested.
As observed in the table, whereas the reaction with HFIP afforded the desired product in high
conversion, TFE barely produced tetrahydrofuran 3aa (Table 1, entries 3 and 4, respectively). This sharp
contrast in the performance of both fluorinated alcohols in this transformation can be explained
by their different properties. Thus, HFIP has higher acidity (pKa(TFE) = 12.37, pKa(HFIP) = 9.30);
higher hydrogen bond ability (αTFE = 1.51, αHFIP = 1.96), which can facilitate the activation of epoxide
ring; and much lower nucleophilicity (NTFE
would explain the obtention of fluoroalkyl ether
contrary, the corresponding fluorinated ether , derived from HFIP (along with phenylacetaldehyde
=
−
2.78, NHFIP
=
−
4.23) [16–22]. This last parameter
5
as major product when TFE was essayed. On the
6
and acetophenone) was obtained only as by-product. The absence of any solvent was also checked
and, as was expected, the reaction did not take place (Table 1, entries 5). Then, efforts to improve the

Molecules 2020, 25, 3464
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conversion of 3aa by using a series of HFIP/CH2Cl2 [16
–
22] mixtures were implemented (Table 1,
entrie◦s 6–8), but turned out to be unsuccessful in all the cases. Lowering the reaction temperature
to 25 C also resulted in a drop in the conversion towards the desired product (Table 1, entry 9).
Other changes in reaction stoichiometry were also essayed but did not produce any amelioration.
After the search for the best conditions, those described in entry 3, involving the use of HFIP at 45 ◦C,
were selected as optimal, realizing that reaction was complete in less than 10 h.
Table 1. Optimization of the reaction parameters a.
Conv. (%) b
Entry
Solvent
Temp (◦C)
1
2
3
4
5
6
7
8
9
H2O
iPrOH
HFIP
TFE
None
45
45
45
45
45
45
45
45
25
13
0
72
3
2
HFIP/CH2Cl2 (9/1)
HFIP/CH2Cl2 (1/1)
HFIP/CH2Cl2 (1/9)
HFIP
50
15
23
30
a
All reactions were carried out using 0.15 mmol of 1a and 0.25 mmol of 2a in 150
Conversion towards formation of 3aa, determined by GC-MS.
µ
L of the solvent at 45 ◦C for 20 h.
b
With these conditions in hand, the scope of the reaction was next investigated. Different electron-
rich alkenes were employed as nucleophiles for the ring opening reaction of styrene oxide (Scheme 2).
It is important to mention that in the majority of cases, the ring-opening reaction was highly
regioselective, but when a mixture of diastereoisomers was obtained, low diastereoselective ratios were
observed. First, a selection of substituted styrenes was chosen. As mentioned above,
α-methylstyrene
(2a) produced the corresponding tetrahydrofuran 3aa in moderate isolated yield. Better results
were observed when a more electron-rich alkene, 2b, was employed; reaching up to 67% yield
for 3ab. The more sterically crowded 1,1-diphenylethylene (2c) gave the corresponding product
in only modest yield. In this case, some amount (25%) of the other regioisomer was also obtained,
probably due to the mentioned steric hindrance. Next, styrene was essayed obtaining the corresponding
caloxylane 3ad (as 65:35 mixture of diastereosiomers) in 39% yield. Similar results were obtained
when 4-chlorostyrene was employed. Surprisingly, the more electron-rich alkene, 4-methoxystyrene
(
2f), gave rise to the corresponding product in low yields. At this point, it is worth mentioning
that in the majority of the styrenes employed the presence of dimers or trimers of the styrene
were detected by GC-MS, thus lowering the yield of the process. Methylenecyclohexane 2g) was
(
next tested, obtaining spiro-compound 3ag in modest yield. Stilbenes were also submitted to the
reaction conditions but failed and only a low conversion was observed when the cis-isomer was
employed. Trisubstituted alkenes such as 1-phenylcyclohexene (2i) were also taken into account,
obtaining the interesting octahydrobenzofuran derivative 3ai in 34% yield. Finally, benzocondensed
alkenes were also essayed. Thus, whereas indene produced the corresponding product 3aj in modest
yield, the reaction with 1,2-dihydronaphthalene barely worked. Finally, when benzofuran (2l) was
employed as alkene, the corresponding tetrahydrofuro[3,2-b]benzofuran derivative 3al, arising from the

Molecules 2020, 25, 3464
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attack of benzofuran through its 2-position onto the epoxide, obtained with moderate yield and quite
good diastereoselectivity. It is important to remark that in all the cases ether along with the products
6
coming from the Meinwald rearrangement [27] of the epoxide (benzaldehyde and acetophenone, the
first one with higher proportion) were obtained as by-products.
OMe
O
O
O
Ph
Ph
Ph
Ph
R1 = Me, R2 = H
, 54%, 55 : 45
Ph
Ph
R1 = Ph, R2 = H
R1 = Me, R2 = OMe
d
d
b
3aa
3ab
3ac
, 38%
, 67%, 55 : 45
Cl
OMe
O
O
O
Ph
Ph
Ph
R1, R2 = H
Ph
R1 = H, R2 = Cl
R1 = H, R2 = OMe
d
d
c
3ad
3ae
3af
, 39%, 65 : 35
, 36%, 60 : 40
(15% conv.)
Ph
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
3ai, 34%, 55 : 45d
From
From
R1, R2 = H, X = Ph
3ah (13% conv.)c
3ag, 45%
Ph
O
O
O
Ph
Ph
O
R1, R2 = H
R1, R2 = H
R1, R2 = H
X = CH2, n = 0
X = CH2, n = 1
X = O2, n = 0
, 58%,b 80 : 20d
3al
d
c
3aj
3ak
, 40%, 60 : 40
(15% conv.)
a All reactions were carried out using 0.15 mmol of 1a and 0.25 mmol of 2a in 150 µL of the solvent. b Estimation
1
c
1
of the yield from H NMR data. Conversion towards formation of tetrahydrofuran, determined by H NMR
and/or GC-MS. d Diastereomeric ratio determined by 1H NMR and/or GC-MS of the crude compounds.
Scheme 2. Reaction between styrene oxide and electron-rich alkenes a.
In order to further expand the scope of the reaction, other epoxides were tested with those alkenes
that provided the best results. First, α-methylstyrene oxide (1b) was evaluated. Good yields were
achieved when 2a and 2b were the alkenes employed. However, modest yields were only achieved
when ethylenecyclohexane (2g) and benzofuran (2l) were used. Next, when 1-phenylcyclohexene oxide
(1c) was the substrate submitted to the reaction with the same alkenes, modest yields were obtained
for adducts 3ca and 3cb. Unfortunately, the reaction with 2g did not work. Although, in a modest 38%
yield, benzofuran (2l) rendered the interesting tetracyclic compound 3cl. Finally, commercial available
ethyl 3-methyl-3-phenylglycidate (1d) was also tested. It is remarkable that, contrary to the normal
trend observed concerning the low diastereoselectivity achieved in previous cases, moderate to
good diastereoselectivities were achieved when 1d was the substrate employed. Modest yield was
achieved when α-methylstyrene (2a) was employed, rendering the densely substituted 3da in 43%
yield. However, the more electron-rich alkene 2b did not produce satisfactory results, being the
dimerization and trimerization product of the alkene the major products observed by GC-MS. To our
surprise, alkene 2c gave rise to the corresponding tetrahydrofuran 3dc in 60% yield and a 90:10
diastereomeric ratio. Encouraged by this result, styrene was also employed obtaining 3dd in modest

Molecules 2020, 25, 3464
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yield. Unfortunately, the reaction with alkenes 2g and 2j turned out to be unsuccessful and low
conversions towards the desired products were obtained. Finally, benzofuran (2l) rendered the
corresponding tricyclic compound in a modest 44% yield. It is worth mentioning that other epoxides
such as cyclohexene oxide, 1-octene oxide, indene oxide, and cis- and trans-stilbene oxide were also
submitted to the reaction with the alkenes depicted in Table 2; however, to our regret the reaction failed.
Table 2. Reaction between styrene oxide and electron-rich alkenes a.
OMe
O
O
O
Ph
Ph
Ph
Ph
2g
From
3bg
R4 = Me, R5 = H
3ba, 62%, 50: 50d
R4 = Me, R5 = OMe
3bb, 58%, 55 : 45d
b
, 30%
OMe
O
O
O
Ph
Ph
Ph
Ph
O
R1, R2 = H
X = O2, n = 0
R4 = Me, R5 = H
R4 = Me, R5 = OMe
3cb
(32% conv.)
c,e
c
3ca
(40% conv.)
, 35%,b 55 : 45d
3bl
EtO2C
O
O
O
Ph
Ph
Ph
O
Ph
R1, R2 = H
2g
From
R4 = Me, R5 = H
3da
, 43%, 65 : 35
X = O2, n = 0
, 38%, 55 : 45
d
c
d
3cg
(5% conv.)
3cl
EtO2C
EtO2C
EtO2C
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
OMe
R4 = Me, R5 = OMe
R4 = Ph, R5 = H
3dc, 60%, 90 : 10d
R4, R5 = H
3dd, 47%, 90 : 10d
c
3db
(5% conv.)
EtO2C
O
CO2Et
O
Ph
Ph
O
R1, R2 = H
X = O2, n = 0
2g
From
c
3dg
d
(15% conv.)
3dl
, 44%, 70 : 30
a All reactions were carried out using 0.15 mmol of 1a and 0.25 mmol of 2a in 150
µ
L of the solvent. b Estimation of the
yield from 1H NMR data. c Conversion towards formation of tetrahydrofuran, determined by 1H NMR and/or GC-MS.
Diastereomeric ratio determined by 1H NMR and/or GC-MS of the crude compounds. Product decomposition
d
e
after purification was observed.
At this point, as epoxides are synthesized from alkenes, and fluorinated alcohols have proven to
be efficient mediators in the oxidation of alkenes using H2O2 [28], we decided to explore the possibility
of performing the HFIP-promoted alkene oxidation/ring opening of epoxides in a one-pot reaction
(Scheme 3). For such purpose, an excess of
α-methylstyrene (2a) was treated with 1 equivalent of H2O2
(30%) for 24 h. After this time among a myriad of products detected by GC-MS coming from the ring

Molecules 2020, 25, 3464
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opening of the epoxide with H2O or HFIP, 2-phenylpropanaldehyde from Meinwald rearrangement
and acetophenone from oxidative cleavage of the alkene, tetrahydrofuran 3aa was observed in 27%
conv. Although the product was obtained in low amount, it can be seen as a proof of concept that
substituted tetrahydrofurans can be easily obtained from readily available materials as styrenes.
Scheme 3. One-pot oxidation/ring opening reaction.
Concerning the reaction mechanism, three possible scenarios were taken into account (Scheme 4).
In route 1, direct nucleophilic attack of the alkene onto activated epoxide would occur rendering
intermediate A, which cyclizes to afford the corresponding tetrahydrofuran. In route 2, intermediate A
is obtained as consequence of a double nucleophilic attack, the first one carried out by the more
abundant HFIP followed by a nucleophilic substitution. In the route 3, carbocationic intermediate C is
formed, which could be stabilized by the formation of ionic pair or by other electrostatic interactions
with HFIP. Route 2 was soon discarded due to the fact that intermediate B has been observed in the
reaction and if this would have been the operating route, longer reaction times would render higher
conversions, which did not happen. Nevertheless, ether
by 8 h at room temperature, and after a quick purification, was allowed to react with
2a) for 24 h under the optimized conditions. After this time, no reaction was observed. In order to
find out whether route 1 or 3 was operating in the process, we decided to carry out the reaction
using enantiopure (R)-styrene oxide and -methylstyrene (2a) and styrene (2d) as alkenes (Scheme 5).
6
was synthesized by reacting 1a with HFIP
α
-methylstyrene
(
α
Thus, if route 1 is the one taking place, the configuration of the stereocenter will be somehow preserved.
As depicted in Scheme 4, corroborated by chiral HPLC analysis (see Supplementary Materials for
further details), when styrene (2d) was the nucleophile, the stereochemistry of the chiral center was lost
giving a racemic mixture in each diastereoisomer of caloxylane (3ad). However, the better nucleophile
α
-methylstyrene (2a) gave rise to a mixture of diastereoisomers both presenting a loss of enantiopurity
in the chiral centre (46% ee and 49% ee, respectively), which was determined by chiral HPLC analysis
(see Supplementary Materials for further details). Therefore, these experimental evidences point that
the mechanism of the reaction seemingly is highly dependent on the nucleophilicity of the alkene
employed. Thus, whereas styrene (2d) apparently follows a purely ionic route (SN1-type mechanism
(route 3, Scheme 4)) in the
Scheme 3) is operating.
α-methylstyrene (2a) case, predominantly a SN2-type pathway (route 1,
Scheme 4. Possible operating reaction mechanisms.

Molecules 2020, 25, 3464
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Ph
Ph
O
O
O
2a
2d
Ph
Ph
Ph
HFIP, 45 ºC
12 h
HFIP, 45 ºC
12 h
Ph
Ph
3aa
(R)-1a
3ad
55 : 45 dr
46% ee : 49% ee
50 : 50 dr
rac. : rac.
Scheme 5. Mechanism elucidation tests.
3. Materials and Methods
All reagents and solvents were obtained commercially and used without further purification.
Substrates that were not commercially available were synthesized according to known literature
procedures. NMR spectra were performed on a Bruker AV-300 or Bruker AV-400 (Bruker Corporation,
Billerica, MA, USA) using CDCl3 as solvent and TMS as internal standard unless otherwise stated.
Conversions and low-resolution mass spectra (MS) of the tetrahydrofurans 3 were recorded in the
electron impact mode (EI, 70 eV, He as carrier phase) using an Agilent GC/MS 5973 Network Mass
Selective Detector spectrometer apparatus equipped with a HP-5MS column (30 m
×
0.25 mm)
(Agilent technologies, Bilbao, Spain) and giving fragment ions in m/z with relative intensities (%) in
parentheses. High-resolution mass spectra (HRMS) were obtained on an Agilent 7200 Quadrupole-Time
of Flight apparatus (Q-TOF) (Agilent Technologies), with the ionization employed being electron impact
(EI). Chiral HPLC analysis was performed in an Agilent 1100 Series HPLC equipped with a G1315B
diode array detector and a Quat Pump G1311A (Agilent Technologies) equipped with the corresponding
Daicel chiral column. Analytical TLC was performed on Merck silica gel plates and the spots visualized
with UV light at 254 nm (Merck millipore, Darmstadt, Germany). Flash chromatography employed
Merck silica gel 60 (0.040–0.063 mm). Silica gel 60 F254 containing gypsum was employed for preparative
layer chromatography (Merck millipore).
General Procedure for the HFIP-Promoted Synthesis of Substituted Tetrahydrofurans
In a capped tube, onto a mixture of the corresponding epoxide (0.15 mmol) and alkene (0.25 mmol),
HFIP (150 µ
L) was added in one portion. The reaction was then stirred at 45 ◦C for 6–15 h, until the
reaction was judged to be completed (no starting epoxide remaining) by GC-MS. After this time,
solvent was evaporated and the crude material was directly purified by flash chromatography or
preparative TLC.
2-Methyl-2,4-diphenyltetrahydrofuran (3aa) [11]: yellow oil; purification by flash chromatography
(hexane/EtOAc), 54% yield; (cis/trans) = 55:45; 1H NMR (300 MHz, CDCl3): cis isomer: δH = 7.52–7.45
(m, 4H), 7.43–7.28 (m, 10H), 7.27–7.16 (m, 6H), 4.42 (t, J = 7.6 Hz, 1H), 3.84 (dd, J = 10.0, 8.2 Hz, 1H),
3.70 (tt, J = 10.3, 7.7 Hz, 1H), 2.41–2.15 (m, 2H), 1.63 (s, 3H) ppm; further signals for the trans isomer:
δH = 4.35 (t, J = 8.4 Hz, 1H), 4.00 (t, J = 8.7 Hz, 1H), 3.31 (ddd, J = 15.9, 11.3, 8.6 Hz, 1H), 2.81–2.60
(m, 2H), 1.68 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3): cis isomer: δC = 148.9, 140.8, 128.5, 128.3,
127.4, 126.6, 126.5, 124.5, 74.4, 47.9, 45.8, 30.6, ppm; further signals for trans isomer: 147.6, 141.6,
128.5, 128.2, 127.3, 126.6, 126.4, 124.7, 73.9, 48.3, 44.6, 30.2 ppm; MS (EI): m/z 238 (M+, 0.31%), 224 (19),
223 (100), 193 (12), 117 (27), 115 (18), 105 (90), 91 (16), 77 (18). Chiral HPLC analysis: Chiralpak IA
column, Hexane/iPrOH 99:1, flow rate = 0.2 mL/min,
λ = 210 nm, retention times: = 25.5 and 26.5 min.
(major diastereosiomer) and 27.4 and 28.4 min. (minor diastereoisomer).
2-(4-Methoxyphenyl)-2-methyl-4-phenyl tetrahydrofuran (3ab): orange oil; purification by flash
chromatography (hexane/EtOAc), 67% yield; (cis/trans) = 55:45; 1H NMR (300 MHz, CDCl3): cis isomer:
δH = 7.43–7.37 (m, 3H), 7.33–7.28 (m, 3H), 7.27–7.16 (m, 6H), 6.95–6.93 (m, 2H), 6.92–6.90 (m, 2H),
4.40 (t, J = 7.9 Hz, 1H), 3.84 (s, 3H), 3.82 (dd, J = 3.5, 1.9 Hz, 1H), 3.76–3.64 (m, 1H), 2.63 (dd, J = 12.4,
8.0 Hz, 1H), 2.32 (dd, J = 12.3, 10.5 Hz, 1H), 2.24–2.17 (m, 1H), 1.61 (s, 3H) ppm; further signals for

Molecules 2020, 25, 3464
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the trans isomer: δH = 4.33 (t, J = 8.4 Hz, 1H), 3.98 (t, J = 8.6 Hz, 1H), 3.85 (s, 3H), 3.39–3.25 (m, 1H),
2.71 (dd, J = 12.1, 7.1 Hz, 1H), 2.32 (dd, J = 12.3, 10.5 Hz, 1H), 1.66 (s, 3H) ppm; 13C NMR (101 MHz,
CDCl3): mixture of isomers, δC = 158.3, 158.2, 141.7, 141.1, 141.0, 139.7, 128.5, 128.5, 127.4, 127.3, 126.6,
126.6, 125.8, 125.7, 113.6, 113.5, 85.2, 84.7, 74.4, 73.9, 55.3, 55.2, 48.3, 48.1, 45.8, 44.6, 30.6, 30.3 ppm; MS
(EI): m/z 268 (M+, 6%), 254 (17), 253 (93), 135 (100), 117 (14), 91 (11); HRMS (GC/MS-EI/Q-TOF): m/z
calcd. for C18H20O2 268.1463, found 268.1463.
2,2,4-Triphenyltetrahydrofuran (3ac): yellow oil; purification by flash chromatography
(hexane/EtOAc), 38% estimated yield (not purely isolated); 1H NMR (300 MHz, CDCl3): δH = 7.54–7.49
(m, 4H), 7.37–7.34 (m, 4H), 7.34–7.30 (m, 4H), 7.27–7.24 (m, J = 1.6 Hz, 2H), 7.24–7.22 (m, 1H), 4.48
(
t, J = 8.4 Hz, 1H), 4.07 (t, J = 8.7 Hz, 1H), 3.61–3.43 (m, J = 16.0, 11.0, 5.2 Hz, 1H), 3.23 (dd, J = 12.3,
7.1 Hz, 1H) ppm; MS (EI): m/z 300 (M+, 55%), 270 (15), 224 (71), 223 (100), 192 (21), 191 (13), 179 (13),
178 (15), 165 (21), 118 (34), 117 (42), 115 (12), 105 (96), 91 (14), 77 (27); HRMS (GC/MS-EI/Q-TOF): m/z
calcd. for C22H20O 300.1514, found 300.1509.
2,4-Diphenyltetrahydrofuran (Caloxylane A and B) (3ad) [11]: yellow oil; purification by flash
chromatography (hexane/EtOAc), 39% yield; (cis/trans) = 65:35; 1H NMR (300 MHz, CDCl3): cis isomer:
δH = 7.49–7.29 (m, 20H), 5.11 (dd, J = 10.2, 5.7 Hz, 1H), 4.39 (t, J = 8.2 Hz, 1H), 4.05 (t, J = 8.5 Hz,
1H), 3.74–3.63 (m, 1H), 2.85–2.72 (m, 1H), 2.05 (q, J = 10.5, 1.9 Hz, 1H) ppm; further signals for the
trans isomer: δH = 5.26 (dd, J = 7.7, 5.8 Hz, 1H), 4.50 (t, J = 8.5, 7.4 Hz, 1H), 3.98 (t, J = 8.2 Hz, 1H),
3.63–3.51 (m, 1H), 2.57–2.45 (m, 1H), 2.36 (q, J = 12.5, 8.3, 5.8 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3):
cis isomer: δC = 142.6, 141.7, 128.6, 128.4, 127.4, 127.2, 125.7, 81.8, 75.1, 46.0, 43.7, pm; further signals for
the trans isomer: δC = 143.6, 142.0, 128.6, 128.3, 127.3, 127.1, 125.5, 80.6, 75.1, 44.4, 42.7 ppm; MS (EI):
m/z 224 (M+, 34%), 195 (14), 194 (93), 193 (100), 179 (58), 178 (89), 165 (13), 146 (27), 133 (34), 120 (27), 117
(90), 115 (57), 105 (45), 91 (48), 77 (30). Chiral HPLC analysis: Chiralcel OD-H column, Hexane/iPrOH
99:1, flow rate = 0.7 mL/min,
λ = 210 nm, retention times: = 23.1 and 23.2 min. (major diastereosiomer)
and 28.0 and 35.4 min. (minor diastereoisomer).
2-(4-Chlorophenyl)-4-phenyltetrahydrofuran (3ae) [11]: yellow oil; purification by flash
1
chromatography (hexane/EtOAc), 36% yield; (cis/trans) = 60:40; H NMR (400 MHz, CDCl3): cis
isomer: δH = 7.40–7.30 (m, 9H), 5.07 (dd, J = 10.1, 5.8 Hz, 1H), 4.38 (t, J = 8.2 Hz, 1H), 4.03 (t, J = 8.5 Hz,
1H), 3.78–3.61 (m, 1H), 2.86–2.72 (m, 1H), 1.98 (dd, J = 12.4, 10.4 Hz, 1H) ppm; further signals for the
trans isomer: δH = 5.22 (dd, J = 7.7, 5.9 Hz, 1H), 4.47 (dd, J = 8.4, 7.5 Hz, 1H), 3.97 (t, J = 8.2 Hz, 1H),
3.54 (t, J = 7.6 Hz, 1H), 2.50 (dt, J = 12.6, 7.7 Hz, 1H), 2.35–2.24 (m, 1H) ppm; 13C NMR (101 MHz,
CDCl3): cis isomer: δC = 141.5, 141.2, 133.0, 129.9, 128.8, 128.6, 128.3, 128.2, 127.3, 127.1, 126.7, 81.1,
75.1, 45.9, 43.8 ppm; further signals for the trans isomer: δC = 142.1, 142.7, 132.8, 129.8, 128.7, 128.5,
128.3, 128.1, 127.2, 126.9, 126.7, 126.4, 79.9, 72.7, 44.3, 42.7 ppm; MS (EI): m/z 258 (M+, 18%), 228 (25),
193 (100), 180 (15), 178 (22), 167 (22), 154 (16), 139 (27), 117 (64), 115 (54), 104 (17), 91 (27), 77 (13).
3-Phenyl-1-oxaspiro[4.5]decane (3ag): yellow solid, purification by flash chromatography
(hexane/EtOAc), 45% yield; 1H NMR (400 MHz, CDCl3): δH = 7.36–7.31 (m, 3H), 7.27–7.23 (m, 2H), 4.23
(t, J = 8.0 Hz, 1H), 3.80 (t, J = 17.6 Hz, 1H), 3.51 (tt, J = 17.6, 8.8 Hz, 1H), 2.30 (dd, J = 12.4, 8.2 Hz, 1H),
1.78 (dd, J = 12.4, 10.5 Hz, 1H), 1.74–1.48 (m, 10H) ppm; 13C NMR (126 MHz, CDCl3): δC = 141.9, 128.6,
128.5, 128.1, 127.3, 126.5, 83.3, 72.9, 45.0, 38.3, 37.3, 25.61, 23.8, 23.8 ppm; MS (EI): m/z 216 (M+, 55%),
174 (25), 173 (100), 160 (40), 118 (18), 117 (28), 104 (41), 91 (26), 55 (73); HRMS (GC/MS-EI/Q-TOF): m/z
calcd. for C15H20O 216.1514, found 216.1514.
3,7a-Diphenyloctahydrobenzofuran (3ai): orange oil; purification by flash chromatography
(hexane/EtOAc); 34% yield; diastereomeric ratio = 55:45; 1H NMR (300 MHz, CDCl3): major isomer: δH
= 7.58 (dd, J = 8.5, 1.1 Hz, 2H), 7.54–7.48 (m, 2H), 7.44–7.35 (m, 6H), 7.34–7.28 (m, 4H), 7.23 (m, 6H),
7.16–7.08 (m, 2H), 4.40 (m, 2H), 4.00–3.91 (m, 1H), 3.59 (m, 1H), 2.67 (dd, J = 12.0, 5.5 Hz, 1H), 2.13–1.85
(m, 4H), 1.83–1.52 (m, 12H) ppm; furher signals for the minor isomer: δH = 4.27 (t, J = 8.6 Hz, 1H), 3.42
(td, J = 9.6, 5.5 Hz, 1H), 2.57 (dt, J = 11.4, 5.7 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): major isomer:
δC = 148.6, 141.2, 128.6, 128.2, 128.1, 126.9, 126.4, 125.9, 84.8, 72.6, 51.2, 46.6, 35.8, 24.2, 21.9, 20.0 ppm;
further signals for minor isomer: δC = 146.5, 138.2, 128.3, 128.1, 127.9, 126.7, 126.2, 124.5, 86.8, 67.3, 49.4,

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46.4, 38.3, 24.6, 22.1, 20.0 ppm; MS (EI): m/z 278 (M+, 85%), 236 (19), 235 (100), 221 (18), 115 (14), 105
(67), 91 (25), 77 (18); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C20H22O 278.1671, found 278.1667.
3-Phenyl-3, 3a, 4, 8b-tetrahydro-2H-indeno [1,2-b]furan (3aj) [11]: yellow oil; purification by flash
chromatography (hexane/EtOAc), 40% yield; (cis/trans) = 60:40; 1H NMR (300 MHz, CDCl3): cis isomer:
δH = 7.53–7.47 (m, 2H), 7.39–7.29 (m, 8H), 5.73 (d, J = 7.2 Hz, 1H), 4.13 (dd, J = 8.6, 6.7 Hz, 1H), 3.92
(dd, J = 8.6, 7.7 Hz, 1H), 3.26–3.16 (m, 2H), 3.12–3.03 (m, 1H), 3.01–2.91 (m, 1H) ppm; further signals for
the trans isomer: δH = 7.51–7.46 (m, 1H), 7.36–7.24 (m, 6H), 7.14–7.09 (m, 2H), 5.69 (d, J = 6.8 Hz, 1H),
4.27–4.21 (m, 1H), 3.82–3.73 (m, 2H), 3.59–3.47 (m, 1H), 2.83 (dd, J = 17.4, 9.3 Hz, 1H), 2.60 (dd, J = 17.4,
4.8 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): mixture of isomers, δC = 142.5, 141.9, 141.7, 141.6, 128.8,
128.7, 128.4, 128.4, 127.5, 127.2, 127.0, 126.7, 126.5, 125.6, 125.2, 124.4, 87.9, 87.8, 74.6, 68.2, 53.3, 50.1, 48.5,
45.5, 38.7, 36.6 ppm; MS (EI): m/z 236 (M+, 34%), 207 (17), 206 (100), 205 (27), 128 (20), 115 (27), 91 (86).
3-Phenyl-2,3,3a,8b-tetrahydrofuro[3,2-b]benzofuran (3al): yellow oil; purification by flash
chromatography (hexane/EtOAc), 40% estimated yield, mixture of isomers (not purely isolated);
1H NMR (400 MHz, CDCl3): δH = 7.50–7.46 (m, 1H), 7.40–7.38 (m, 3H), 7.35–7.30 (m, 3H), 6.99
(
td, J = 7.4, 0.9 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 5.81 (d, J = 6.0 Hz, 1H), 5.19 (dd, J = 6.0, 1.2 Hz, 1H),
4.08 (dd, J = 9.1, 2.3 Hz, 1H), 3.96 (dd, J = 9.1, 5.5 Hz, 1H), 3.67 (d, J = 5.5 Hz, 1H) ppm; MS (EI): m/z 238
(M+, 34%), 220 (66), 219 (43), 208 (45), 207 (100), 191 (15), 189 (17), 178 (19), 165 (13), 131 (24), 117 (12);
HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C16H14O 238.0994, found 238.0990.
2,4–Dimethyl–2,4–diphenyltetrahydrofuran (3ba) [29]: yellow solid; purification by flash
chromatography (hexane/EtOAc), 62% yield; (cis/trans) = 50:50; the cis isomer is highlighted in
1
bold; H NMR (300 MHz, CDCl3): δH = 7.54–7.49 (m, 2H), 7.45–7.39 (m, 2H), 7.39–7.30 (m, 8H),
7.26–7.21 (m, 4H), 7.20–7.10 (m, 4H), 4.30 (d, J = 8.6 Hz, 1H), 4.10 (dd, J = 8.4, 1.0 Hz, 1H), 4.06
(
d, J = 8.5 Hz, 1H), 3.96 (dd, J = 8.4, 0.6 Hz, 1H), 2.72 (d, J = 12.6 Hz, 1H), 2.58 (s, 2H), 2.47 (dd, J = 12.6,
1.1 Hz, 1H), 1.70 (s, 3H), 1.59 (s, 6H), 1.50 (s, 3H) ppm; MS (EI): m/z 252(M+, 0.08%), 237 (100), 207 (12),
129 (13), 117 (29), 105 (97), 91 (14), 77 (15).
2–(4–Methoxyphenyl)–2,4–dimethyl-4-phenyl tetrahydrofuran (3bb): white solid; purification
by flash chromatography (hexane/EtOAc), 58% yield; (cis/trans) = 45:55; the cis isomer is highlighted
1
in bold; H NMR (300 MHz, CDCl3): δH = 7.36–7.30 (m, 3H), 7.27–7.22 (m, 2H), 7.16–7.09 (m, 2H),
6.87–6.82 (m, 2H), 4.28 (d, J = 8.6 Hz, 1H), 4.07 (d, J = 9.1 Hz, 1H), 4.03 (s, 1H), 3.95 (d, J = 8.4 Hz, 1H),
3.84 (s, 3H), 3.80 (s, 3H), 2.70 (d, J = 12.6 Hz, 1H), 2.55 (d, J = 2.2 Hz, 1H), 2.42 (d, J = 12.5 Hz, 1H), 1.67
(s, 3H), 1.58 (s, 3H), 1.48 (s, 3H), 1.23 (s, 3H) ppm; Only major isomer is given, 13C NMR (101 MHz,
CDCl3): δH = 157.9, 147.7, 141.6, 128.3, 126.0, 125.9, 125.6, 113.5, 84.6, 77.8, 55.3, 53.9, 48.9, 32.8, 29.9
ppm; MS (EI): m/z 282(M+, 9%), 268 (16), 267 (83), 135 (100), 117 (13); HRMS (GC/MS-EI/Q-TOF): m/z
calcd. for C19H22O2 282.1620, found 282.1620.
3-Methyl-3-phenyl-1-oxaspiro[4,5]decane (3bg): colourless oil; purification by flash chromatography
(hexane/EtOAc), 30% estimated yield (not purely isolated); 1H NMR (300 MHz, CDCl3): δH = 7.36–7.30
(m, 4H), 7.26–7.23 (m, 1H), 4.05 (d, J = 8.7 Hz, 1H), 3.94 (d, J = 8.5 Hz, 1H), 2.12 (d, J = 12.6 Hz, 1H),
1.98 (dd, J = 12.6, 0.7 Hz, 1H), 1.79–1.7 (m, 5H), 1.61 (d, J = 2.7 Hz, 2H) 1.51 (d, J = 6.0 Hz, 3H), 1.46
(s, 3H) ppm; MS (EI): m/z 230(M+, 43%), 216 (16), 215 (100), 187 (59), 118 (19), 117 (25), 91 (14), 55 (30);
HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C16H22O 230.1671, found 230.1672.
3-Methyl-3-phenyl-2,3,3a,8b-tetrahydrofuro [3,2-b] benzofuran (3bl): Inseparable mixture of
regioisomers. The major isomer data is highlighted in bold. Yellow solid; purification by flash
1
chromatography (hexane/EtOAc), 35% estimated yield (not purely isolated); H NMR (400 MHz,
CDCl3): δH = 7.60–7.49 (m, 3H), 7.48–7.38 (m, 3H), 7.38–7.30 (m, 8H), 7.27–7.21 (m, 2H), 7.00–6.88
(m,2H), 5.60 (d, J = 6.0 Hz, 1H), 5.15 (d, J = 6.0 Hz, 1H), 4.31 (d, J = 9.3 Hz, 1H), 4.19 (d, J = 12.4 Hz, 1H),
3.91 (d, J = 5.7 Hz, 1H), 3.82 (d, J = 12.2 Hz, 1H), 3.64 (d, J = 9.3 Hz, 1H), 3.60 (d, J = 12.4 Hz, 1H), 1.61
(s, 3H), 1.52 (s, 3H), ppm; MS (EI): m/z 252 (M+, 71%), 237 (14), 221 (15), 207 (100), 194 (20), 178 (15), 145
(23), 131 (41), 129 (11), 118 (36), 115 (16), 105 (14), 91 (20), 89(15), 77 (14); HRMS (GC/MS-EI/Q-TOF): m/z
calcd. for C17H16O2 252.1150, found 252.1149.

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4a-Phenyl-1,2,3,4,4a,4b,9b,10a-octahydrobenzofuro[3,2-b]benzofuran (3cl): white solid; purification
by flash chromatography (hexane/EtOAc), 38% yield; diastereomeric ratio = 55:45; 1H NMR (400 MHz,
CDCl3): δH = 7.53–7.47 (m, 3H), 7.45–7.34 (m, 3H), 7.34–7.30 (m, 1H), 7.02–6.90 (m, 2H), 5.54
(d, J = 7.8 Hz, 1H), 5.15 (d, J = 7.9 Hz, 1H), 4.43 (t, J = 2.5 Hz, 1H), 2.17–2.03 (m, 1H), 2.00–1.85 (m, 1H),
1.51–1.39 (m, 3H), 1.05–0.82(m, 3H) ppm; 13C NMR (400 MHz, CDCl3): δC =130.7, 130.4, 128.5, 128.2,
128.0, 127.0, 126.4, 126.3, 126.2, 126.0, 120.9, 120.7, 110.0, 109.7, 96.8, 93.9, 80.7, 80.5, 78.9, 77.2, 75.3, 32.2,
29.7, 28.7, 26.5, 25.1, 21.1, 20.4, 20.2 ppm; MS (EI): m/z 292 (M+, 17%), 274 (20), 208 (17), 207 (100), 194
(25), 91 (11); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C20H20O2 292.1463, found 292.1460.
Ethyl 3,5-dimethyl-3,5-diphenyltetrahydrofuran-2-carboxylate (3da): yellow solid; purification by
flash chromatography (hexane/EtOAc), 43% yield; diastereomeric ratio = 65:35; 1H NMR (300 MHz,
CDCl3): δH = 7.68–7.62 (m, 2H), 7.54–7.49 (m, 2H), 7.42–7.34 (m, 6H), 7.26 (d, J = 2.0 Hz, 1H), 5.08
(s, 1H), 4.21 (qd, J = 7.1, 1.5 Hz, 2H), 2.75 (d, J = 12.9 Hz, 1H), 2.65 (d, J = 12.8 Hz, 1H), 1.61 (s, 3H), 1.23
(t, J = 7.1 Hz, 3H) 1.22 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3): only major isomer is given,
δC = 170.6, 148.7, 145.4, 128.3, 128.1, 126.4, 126.3, 126.3, 124.6, 84.7, 84.3, 60.7, 56.6, 31.8, 29.7, 23.5, 14.2
ppm; MS (EI): m/z 324 (M+, 0.13%), 309 (86), 251 (48), 233 (18), 207 (27), 173 (14), 133 (17), 129 (16), 105
(100), 91 (15), 77 (15); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C21H24O3 324.1725, found 324.1715.
Ethyl 3-methyl-3,5,5-triphenyltetrahydrofuran-2-carboxylate (3dc): yellow oil; purification by
flash chromatography (hexane/EtOAc), 60% yield; diastereomeric ratio = 90:10; 1H NMR (300 MHz,
CDCl3): δH = 7.70–7.64 (m, 3H), 7.52–7.48 (m, 3H), 7.39–7.30 (m, 6H), 7.24–7.18 (m, 3H), 4.96 (s, 1H),
4.14 (q, J = 7.1 Hz, 2H), 3.33 (d, J = 13.1 Hz, 1H), 3.01 (d, J = 13.0 Hz, 1H), 1.34 (s, 3H), 1.20 (s, 3H)
ppm; 13C NMR (101 MHz, CDCl3): δC = 170.3, 147.2, 147.0, 145.1, 128.5, 128.3, 128.2, 128.1, 127.8, 126.8,
126.6, 126.5, 126.4, 126.3, 125.7, 125.5, 125.1, 87.6, 85.1, 60.7, 56.0, 51.2, 23.9, 14.2 ppm; MS (EI): m/z 386
(M+, 0.75%), 314 (15), 313 (59), 309 (45), 295 (24), 269 (26), 206 (12), 196 (75), 191 (30), 181 (12), 178 (16),
167 (86), 165 (30), 133 (24), 105 (100), 91 (1), 77 (19); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C26H26O3
386.1882, found 386.1884.
Ethyl-3-methyl-3,5-diphenyltetrahydrofuran-2-carboxylate (3dd): orange solid; purification by
flash chromatograhpy (hexane/EtOAc), 47% yield; diastereomeric ratio = 90:10; signals for the major
1
isomer: H NMR (400 MHz, CDCl3): δH = 7.66–7.60 (m, 1H), 7.55 (dd, J = 8.4, 1.1 Hz, 1H), 7.48–7.29
(m, 8H), 5.05 (d, J = 5.6 Hz, 1H), 5.01 (s, 1H), 4.36–4.25 (m, 2H), 2.71 (dd, J = 12.8, 5.6 Hz, 1H), 2.28
(dd, J = 12.8, 10.5 Hz, 1H), 1.46 (s, 3H), 1.35 (td, J = 7.1, 4.4 Hz, 3H) ppm; signals for the minor isomer:
1H NMR (300 MHz, CDCl3):
δH = 7.54–7.48 (m, 2H), 7.44–7.32 (m, 8H), 5.48 (dd, J =10.4, 5.5 Hz, 1H),
5.06 (s, 1H), 4.28 (q, J = 7.2 Hz, 2H), 2.57 (dd, J = 12.4, 5.6 Hz, 1H), 2.49–2.39 (m, 1H), 1.77 (s, 3H), 1.44
(s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δC = 172.2, 145.9, 141.5, 128.7, 128.4, 128.3, 128.0, 127.6, 126.7,
126.7, 126.5, 126.1, 125.8, 86.0, 81.3, 60.8, 51.2, 48.3, 24.7, 14.3 ppm; MS (EI): m/z 310 (M+, 0.59%), 237
(14), 191 (100), 147 (12), 145 (26), 120 (18), 115 (23), 105 (45), 91 (27), 77 (12); HRMS (GC/MS-EI/Q-TOF):
m/z calcd. for C20H22O3 310.1569, found 310.1565.
Ethyl 3-methyl-3-phenyl-2,3,3a,8b-tetrahydrofuro[3,2-b]benzofuran-2-carboxylate (3dl): yellow
oil; purification by flash chromatography (hexane/EtOAc), 44% yield; diastereomeric ratio = 70:30;
1H NMR (300 MHz, CDCl3): δH = 7.62–7.29 (m, 7H), 7.06–6.80 (m, 2H), 5.70 (d, J = 6.2 Hz, 1H), 5.17
(d, J = 6.2 Hz, 1H), 4.94 (s, 1H), 4.05 (qd, J = 7.1, 1.4 Hz, 2H), 1.56 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H) ppm;
13C NMR (101 MHz, CDCl3): δC = 169.2, 160.3, 139.0, 131.0, 127.9, 127.9, 126.9, 126.5, 125.0, 121.4, 109.9,
93.5, 81.8, 79.9, 61.1, 54.5, 20.8, 14.0 ppm; MS (EI): m/z 234 (M+, 40%), 251 (30), 221 (23), 208 (16), 207
(100), 178 (13), 145 (16), 133 (43), 118 (23), 105 (92); HRMS (GC/MS-EI/Q-TOF): m/z calcd. for C20H20O4
324.1362, found 324.1361.
4. Conclusions
In conclusion, we have described a new methodology for the straightforward synthesis of
substituted tetrahydrofurans based on the reaction of electron-rich alkenes with epoxides mediated by
fluorinated alcohol 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). Although the yields achieved are moderate
in most of the cases, the procedure can be envisioned as environmentally benign as it has a perfect atom

Molecules 2020, 25, 3464
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economy and the reactants are readily available from raw materials such as alkenes with minimum
manipulation. Using this methodology, not only densely substituted furans, but also spiro- and
polycyclic compounds containing furan moiety were obtained. Additionally, preliminary mechanistic
studies point towards a purely ionic pathway (SN1-type) or SN2-like mechanism depending on the
nucleophilicity of the alkene employed.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/25/15/3464/s1,
Experimental procedures, mechanism elucidation tests, compound characterization data, and copies of NMR
spectra for all new compounds.
Author Contributions: N.L. and A.B. conceived of and designed the experiments. N.L. performed the experiments.
A.B. supervised the experiments. N.L. and A.B. wrote the paper. Both authors have read and agreed to the
published version of the manuscript.
Funding: This research was funded by the Spanish Ministerio de Econom
í
a, Industria y Competitividad
(CTQ2015-66624-P and CTQ2017-88171-P) and Spanish Ministerio de Ciencia, Innovaci
ó
n y Universidades
(PGC2018-096616-B-I00) and the University of Alicante (UADIF17-27, VIGROB-285, VIGROB-316/19, UADIF19-106)
and we would like to thank them for the financial support.
Conflicts of Interest: The authors declare no conflicts of interest.
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Sample Availability: Samples of the compounds are available from the authors.
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