Efficient entry to trifluoromethyl substituted chromanes from oxidative aromatization of tetrahydro-2H-chromen-5(6H)-ones using iodine/alcohol with conventional and microwave methods

Article abstract of DOI:10.1016/j.jfluchem.2012.06.024

This paper describes the one-pot simple and efficient oxidative aromatization reaction employing an iodine/alcohol medium for the preparation of a series of 11 new 3-acyl-2-hydroxy-5-alkoxy-4-aryl-2-(trifluoromethyl) chromanes, where acyl = Ac, Bz, furan-

Full text of DOI:10.1016/j.jfluchem.2012.06.024

Journal of Fluorine Chemistry 142 (2012) 90–95
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Efficient entry to trifluoromethyl substituted chromanes from oxidative
aromatization of tetrahydro-2H-chromen-5(6H)-ones using iodine/alcohol
with conventional and microwave methods
*
Helio G. Bonacorso , Jussara Navarini, Carson W. Wiethan, Andrizia F. Junges, Susiane Cavinatto,
´
Rosalia Andrighetto, Marcos A.P. Martins, Nilo Zanatta
Nu´cleo de Quı´mica de Heterociclos (NUQUIMHE), Departamento de Quı´mica, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
A R T I C L E I N F O
A B S T R A C T
Article history:
This paper describes the one-pot simple and efficient oxidative aromatization reaction employing an
iodine/alcohol medium for the preparation of a series of 11 new 3-acyl-2-hydroxy-5-alkoxy-4-aryl-2-
(trifluoromethyl)chromanes, where acyl = Ac, Bz, furan-2-oyl; aryl = Ph, 4-NO2C6H4, 4-OCH3C6H4 and
alkoxy = OMe, O-Prn, EtO and OBn from the respective 3-acyl-4-aryl-2-(trifluoromethyl)-2-hydroxy-
3,4,7,8-tetrahydro-2H-chromen-5(6H)-ones. Yields in the range of 50–89% were obtained when the
oxidative reactions were performed using both conventional thermal heating (CTH) and microwave
(MW) procedures. In general, the MW method produced similar yields with shorter reaction times and
easier reaction workups. As an example, a representative X-ray diffraction ORTEP for 3-benzoyl-2-
hydroxy-5-methoxy-4-methoxyphenyl-2-(trifluoromethyl)chromane is also shown.
Received 4 May 2012
Received in revised form 18 June 2012
Accepted 27 June 2012
Available online 4 July 2012
Keywords:
Iodine
Chromanes
Aromatization
Benzopyrans
Microwave irradiation
ß 2012 Elsevier B.V. All rights reserved.
1. Introduction
On the other hand, the synthesis of fluoroorganic compounds is a
challenging topic of the modern organic chemistry. Especially, the
In recent years, the use of molecular iodine has received
considerable attention. Molecular iodine is the simplest, least
expensive, least toxic, most readily available oxidant for
aromatization of cyclohexenone derivatives and their heterocy-
clic analogs that may possess some biological activity or serve as
building blocks for the synthesis of derivatives with biological
applications [1].
Iodine in methanol has been used as a novel reagent for
the conversion of 2-cyclohexenones into the corresponding
anisole derivatives. This methodology was reported first in 1980
by Tamura and Yoshimoto [2], who subjected a series of
cyclohexenones to iodine in refluxing methanol to yield
variously substituted anisole derivatives. Iodine in methanol
was applied by Kotnis [3] to Hagemann’s esters to afford
substituted p-methoxybenzoates. Hedge et al. [4] have reported
the aromatization of 2-cyclohexenone-4-carboxylates with
iodine and sodium ethoxide. This methodology can also be
used for the aromatization of 1,4-dihydropyridines into
pyridines [5a] and tetrahydro-4-quinolines into 2-aryl-4-
methoxyquinolines [5b].
presence of trifluoromethyl moiety in the target molecule often
results in significant changes of its physical, chemical and biological
properties [6]. Design and synthesis of trifluoromethyl-containing
compounds has received recently significant attention due to their
application in various fields like pharmacy, medicine, agriculture
and material science [7–9]. The trifluoromethyl group is a bulky and
highly electron withdrawing group (electronegativity of 3.5 on the
Pauling scale) that strongly affects the reactivity of the adjacent
functional groups. The incorporation of a trifluoromethyl group into
organicmolecules generally increases their chemical stability owing
to the high bond strength that can induce increased resistance to
metabolic decomposition [10,6f].
Compounds in which a benzene ring and a pyran ring are fused
together with various levels of saturation and oxidation are very
common in nature. The 1-benzopyrans include structural
skeletons such as chromane, 4H-chromene and 2H-chromene
[11]. The class of compounds including the chromane (known as
3,4-dihydro-2H-1-benzopyran) is not itself found in nature, but the
chromane unit is present in many natural products. Vitamin E
(
a
-tocopherol) [12a,b], a substituted chromane, is found in plant
oils and in the leaves of green vegetables as well as the antibiotic
LLD253 [13] and the aromatase inhibitor pinostrobin [14].
a
Certain benzopyrans have also been highlighted because of their
photochromic and thermochromic properties [11].
* Corresponding author. Fax: +55 55 3220 8031.
E-mail address: heliogb@base.ufsm.br (H.G. Bonacorso).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.06.024

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 142 (2012) 90–95
91
In addition, chromenones are not only important biologically
active compounds and natural products but also valuable
substrates for the synthesis of related pharmacologically interest-
ing compounds. In this context, we decided to study the oxidative
aromatization of a series of trifluoromethyl-substituted chrome-
nones, which we had been previously synthesized in our
laboratory [15]. These heterocyclic compounds, besides having a
cyclohexenone ring, also include a 3,4,7,8-tetrahydro-2H-chro-
men-5(6H)-one. The 3,4,7,8-tetrahydro-2H-chromen-5(6H)-one
structure is the core of the complex structure with four main
attached substituents, viz., a hydroxyl and a trifluoromethyl group
at the C2-position and an acyl and an aryl substituent at the C3-
and C4-positions, respectively. Although the study of the oxidative
aromatization of some chromenones is described in the literature
[16,17], the specific oxidative aromatization reactions of tetra-
substituted chromenone 1, which contains functional groups
amenable to oxidative processes, have not been studied.
We are particularly interested in the transformation of
chromenones to chromanes as the product of aromatization
reactions that potentially provide an efficient and interesting
intermediate for synthesis of the other trifluoromethylated
derivative compounds in this class.
Considering the importance of the heterocyclic precursors 1
and product 2 and according to the previously published work
[16,17], the aim of this work is to report the synthesis of a new
series of high substituted chromane derivatives (2) from the
2-trifluoromethyl-2H-chromenones (1) employing iodine/alco-
hol as an efficient and selective oxidative medium with the
conventional thermal heating (CTH) and microwave (MW)
irradiation procedures.
author, 1 mmol of substrate and 2 mmol of iodine in methanol
(5 mL/mmol of 1a) were used under reflux for 2 h. However, under
these reaction conditions, it was not possible to obtain the
compound 2a, and only the starting material was recovered.
To investigate better reaction conditions, the reaction was
carried out under different conditions such as varying the reaction
time from 6 to 16 h and varying the volume of solvent from 5 to
20 mL because the amount of methanol used was very important
for dissolving the chromenone precursor 1a. The best results were
obtained when the reaction conditions were 16 h of reflux in 20 mL
of solvent. The product 2a was obtained as oil, with a yield of 89%.
The oil was identified by 1H NMR experiments and GC/MS.
With the optimal reaction conditions using CTH in hand, it was
extended to all. Thus, we carried out the synthesis of a series of
5-methoxy-chromanes (2a–i) from other chromenone derivatives
1 with yields of 68–89% (Scheme 1). Unfortunately, due to the low
solubility of 1f, the optimal conditions failed to obtain chromane 2f
(R = 2-furyl, R1 = Me and Ar = 4-NO2C6H4). Using a high dilution
(up to 50 mL/mol of 1f) and longer reaction times (up to 24 h)
did not change this unsatisfactory result.
The compounds 2 were obtained as solids or oils, and the
structures were fully confirmed by 1H NMR, 13C NMR, GC/MS,
and X-ray diffraction. The purity was confirmed by CHN
elemental analysis. The 1H NMR spectra showed an important
feature, the absence of methylene proton signals from the
cyclohexenone ring in the region
d
2.62–1.93 ppm and the
3.34 ppm.
presence of a singlet for the OMe group in the region
d
13C NMR also showed important features such as the absence of
the signal for the carbonyl carbon C-5, which showed NMR
signals in the range of
now appearing in the region of
of the CF3 group, the C-2 carbon presented a characteristic
d
194.9 ppm for the 1 series, with signals
d
157.6 ppm. Due to the presence
2. Results and discussion
2
quartet at
group showed
1JCF = 286 Hz. The new methoxy group of the anisole structure
showed an NMR signal in the region of 55.1 ppm.
d
93.9 ppm with JCF = 33 Hz. Additionally, the CF3
The 2-trifluoromethyl-2H-chromenones
1
were readily
a
typical quartet at 122.3 ppm with
d
prepared using a multicomponent reaction (MCR) methodology
from 4-methoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalken-3-
en-2-ones, aryl aldehydes and 1,3-cyclohexanedione in the
presence of a catalytic amount of triethylamine, as described
by us previously [15].
We first performed the oxidative aromatization reaction of the
3-acetyl-2-hydroxy-4-phenyl-2-trifluoromethyl-3,4,7,8-tetrahy-
dro-2H-chromen-5(6H)-one (1a) based on the methodology
described by Mphahlele and Moekwa [16]. According to this
d
The X-ray diffraction measurement was carried out for
compound 2h (Fig. 1) [18], proving that H3 and H4 are situated
trans to each other, as are the aryl and acyl substituents attached to
these carbons. The X-ray data clearly demonstrate the presence of
an anisole unit fused to the pyran ring at C4a–C8a, confirming that
the oxidative aromatization reaction on the chromen-5-one
precursor has occurred.
OMe
Ar
O
O
Ar
O
R
R
i or ii
OH
OH
68 - 89% (CTH)
50 - 86% (MW)
O
CF3
O
CF3
2a-i
1a-i
i = I2 (2 equiv.), MeOH (20 - 50mL), 16 h, reflux (CTH)
ii = I2 (2 equiv.), MeOH (3mL), 0.5 h, 100 ºC (MW)
1,2
a
b
c
d
e
f
g
h
i
Ar
R
Ph Ph
Ph
4-NO2Ph 4-NO2Ph 4-NO2Ph
CH3 Ph 2-Furyl
4-MeOPh
CH3
4-MeOPh
Ph
4-MeOPh
2-Furyl
CH3 Ph 2-Furyl
Scheme 1. Synthesis of 5-methoxychromane derivatives (2a–i).

92
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 142 (2012) 90–95
AnanalysisoftheoxidationnumberofcarbonatomsC4a, C5,C8a,
C6, C7 and C8 shows that although the carbons C8a (+2 to +1) and C6
(+1 to À1) were reduced from the intermediate IV to the products 2,
the second oxidation process occurs in the intermediate IV due to
the elimination of two molecules of HI and the formation of two
doublebonds. Inthislaststep, thecarbonsC7andC8(À2toÀ1)were
oxidized while C5 did not change its oxidation number (+1).
Thus, when we analyzed the oxidation numbers for the carbons
of the cyclohexenone moiety in the precursors (1a–i) and in the
products 2a–i, we found for 1a–i: C4a(0), C5(+2), C6(À2), C7(À2),
C8(À2), C8a(+1) and for the products 2a-i: C4a(0), C5(+1), C6(À1),
C7(À1), C8(À1), C8a(+1). We can see that the oxidation number for
the carbons C4a and C8a did not change; C5 was reduced (+2 to +1),
but the carbons C6, C7 and C8 were oxidized (À2 to À1). Finally, the
average oxidation number of the carbons belonging to the
cyclohexenone ring changed from (À3) to (À1), resulting in an
oxidative aromatization process in the molecules 1a–i.
It is important to mention also that the reaction was highly
chemoselective because there are two carbonyls on the starting
material but only the endocyclic carbonyl reacted with the
alkoxyde anion and iodine underwent an oxidative aromatization.
Another important point is the fact that the geminal hydroxyl
group to the trifluoromethyl group could be eliminated under the
employed reaction conditions to give an
a,b-unsaturated ketone
with an exocyclic carbonyl, which could then have an analogous
reaction to the endocyclic carbonyl leading to the other products.
Because a long reaction time is required by the conventional
procedure, a large amount of solvent and a difficult workup by
column chromatography are necessary to obtain the compounds of
the series 2, an oxidative aromatization reaction of 2-trifluor-
omethyl-2H-chromenones 1 was also investigated using the
microwave (MW) irradiation methodology. The reactions were
performed in sealed vessels containing the substrates; 1: iodine
(1:2 molar ratio) in methanol (3 mL) and were submitted to
microwave irradiation (200 W) for 0.5 h at a temperature of 100 8C
and at 2.5 bar of pressure. After the reaction time, the mixture was
transferred to a flask where the solvent was evaporated under
reduced pressure and the residue was taken up into dichlor-
omethane. The organic solution was sequentially washed with
saturated aqueous sodium thiosulfate, sodium bicarbonate and
brine and then dried over Na2SO4. The mixture was filtered
and evaporated under reduced pressure. All the products 2
obtained were identified by 1H NMR experiments and GC/MS
and comparison with the conventional methodology (Table 1).
Fig. 1. ORTEP representation of the X-ray-determined molecular structure of 3-
benzoyl-2-hydroxy-5-methoxy-4-methoxyphenyl-2-(trifluoromethyl)chromane
(2h) with atoms labeled (CCDC 872165) [18]. Displacement ellipsoids are drawn in
at the 50% probability level.
The corresponding mechanism for the preparation of chro-
manes 2 could be proposed from the conversion of some
a,b-
unsaturated cyclohexanones into anisoles by iodine in alcohol or
with metal alkoxide, as reported previously [2–5]. We therefore
proposed a suitable mechanism for this reaction, as shown in
Scheme 2. The first step of the reaction mechanism would be an
initial 1,2-addition of the alcohol to carbonyl carbon C-5 at the
chromenones 1 with the formation of a hemiketal I. A subsequent
dehydration affords an enol ether intermediate II, which might be
present in equilibrium with the intermediate III also. It is thus
possible that the 1,4-addition of iodine occurs with the formation
of intermediate IV. Finally, a double dehydrohalogenation of IV
can furnish the desired 5-(alkoxy)chromanes 2.
OR1
Ar
O
O
O
Ar
O
O
Ar
O
HO
OR1
R
R
R1OH
R
CF3
OH
CF3
-H2O
CF3
O
OH
OH
II
1
I
OR1
Ar
O
O
OR1
Ar
O
OR1
Ar
O
I
R
R
R
I2
CF3
OH
CF3
OH
CF3
OH
-2HI
O
O
I
III
2
IV
Scheme 2. Plausible mechanism for the oxidative aromatization of the chromenones 1.

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 142 (2012) 90–95
93
O
Ph
O
OR1
Ph
O
CH3
CH3
i or ii
OH
OH
50 - 71%
O
CF3
O
CF3
3a (R1 = Et)
4a (R1 = Prn)
1a
i = I2 (2 equiv.), R1OH (20mL), 16 h, reflux (CTH)
ii = I2 (2 equiv.), R1OH (3mL), 0.5 h, 100 ºC (MW)
Scheme 3. Synthesis of 5-(alkoxy)chromane derivatives 3a and 4a.
Table 1
3. Conclusion
Synthesis of 5-(alkoxy)chromane derivatives (2–4) using conventional thermal
heating and microwave irradiation procedures.
In summary, we applied the well-known method of oxidative
aromatization using iodine/methanol for the selective synthesis of
new trifluoromethyl-substituted chromanes from the respective
tetrahydro-2H-chromen-5(6H)-ones. This synthesis was per-
formed using both conventional and microwave heating proce-
dures, where the microwave demonstrated advantages such as
shorter reaction times, simplicity of the reaction, a reduced
amount of solvent and good yields.
Compound
R
R1
Ar
Yield (%)
CTHa
MWb
2a
2b
2c
2d
2e
2f
CH3
CH3
Ph
89
80
71
85
54
71
86
70
75
72
60
78
60
50
Ph
CH3
Ph
2-Furyl
CH3
CH3
Ph
CH3
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
Ph
CH3
76
c
2-Furyl
CH3
CH3
2g
2h
2i
CH3
79
75
68
60
4. Experimental
Ph
CH3
2-Furyl
CH3
CH3
3a
4a
5a
CH2CH3
CH2CH2CH3
CH2Ph
4.1. Synthesis
CH3
Ph
71
c
63
c
CH3
Ph
Unless otherwise indicated, all common reagents and solvents
were used as obtained from commercial suppliers without further
purification. All melting points were determined on a Reichert
Thermovar apparatus. The 1H and 13C spectra were recorded at
298 K on a Bruker DPX 400 spectrometer (1H at 400.13 MHz, 13C at
100.63 MHz) with digital resolution of Æ0.01 ppm, in CDCl3 using
TMS as the internal reference. Mass spectra were recorded on an HP
5973 MSD connected to a HP 6890 GC and interfaced to a Pentium PC.
The GC was equipped with a split–splitless injector, autosampler,
cross-linked HP-5 capillary column (30 m, 0.32 mm internal
diameter), and helium was used as the carrier gas. Elemental
a
Conventional thermal heating (CTH).
Microwave irradiation (MW).
Recovery of reagents.
b
c
The reactions that yield the compound 2f do not occurred when
conventional procedures for oxidative aromatization are employed
and only the starting material 1f was recovered, to our surprise,
when the microwave irradiation methodology was used, this
compound was obtained in 72% yield without byproducts.
The beneficial effects of microwave irradiation are playing an
increasing role in chemical developments, specifically in this
synthetic process where the classical method (CTH) forced and
prolonged the times that resulted in unsuccessful reactions. The
oxidative aromatization under microwave irradiation offered
shorter reaction times, use of a smaller amount of solvent, easier
reaction workup, good yields and no by-products as the main
advantages for the synthesis of chromane 2f.
analyses were performed on
a
Perkin-Elmer 2400 CHN
elemental analyzer (Sa˜o Paulo University-Sa˜o Paulo, Brazil). The
diffraction measurements were carried out by graphite-monochro-
˚
matized Mo Ka radiation with l = 0.71073 A on a Bruker SMART CCD
diffractometer [19]. The structure of 2h was solved by direct
methods using the SHELXS-97 program [20] and refined on F2 using
the full-matrix least squares component of the SHELXL-97 package
[21]. The absorption correction was performed by Gaussian methods
[22]. Anisotropic displacement parameters for non-hydrogen atoms
were applied. The hydrogen atoms were placed at calculated
Finally, we investigated oxidative aromatization reactions
employing conventional procedures and microwave irradiation,
as well as different alcohols such as ethanol, n-propanol and
benzyl alcohol (Scheme 3). The reaction was performed for
˚
˚
positions with 0.96 A (methyl CH3), 0.97 A (methylene CH2),
˚
˚
˚
0.98 A (methyne CH), 0.93 A (aromatic CH) and 0.82 A (OH) using
a riding model. The hydrogen isotropic thermal parameters were
kept equal to Uiso(H) = xUeq (carrier C atom), with x = 1.5 for methyl
groups and x = 1.2 otherwise. The valence angles C–C–H and H–C–H
of methyl groups were set to 109.58, and the H atoms were allowed
to rotate around the C–C bond. A molecular graph was prepared
using ORTEP3 for Windows [23]. Microwave irradiation was
conducted in a multimode microwave ETHOS-1 (Milestone Inc.)
with a twin magnetron having maximum delivered power of
1300 W. The temperature was set to 100 8C, and the irradiation
was automatically stopped at this temperature. The temperature
and pressure were measured throughout with an ATC-400 CE and
APC-55 detector, respectively.
compound
3-acetyl-2-hydroxy-4-phenyl-2-trifluoromethyl-
3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (1a) in the presence
of iodine and the alcohols mentioned above, using both of the
heating methods described in this work. As a result, we found that
the reactions with ethanol and n-propanol were successful in
obtaining chromane products 3a and 4a. However, when the
reaction was performed in benzyl alcohol, the formation of the
product 5a was not observed using either method (CTH and MW).
From the proposed mechanism, we suggest that the repulsion
between the aromatic moiety of the benzyl alcohol and the
phenyl substituent at the C-4 could be responsible.

94
H.G. Bonacorso et al. / Journal of Fluorine Chemistry 142 (2012) 90–95
4.2. General procedure for the synthesis of 3-acyl-2-hydroxy-5-
H6), 6.45 (d, J = 8 Hz, 1H, H8), 6.33 (d,d, J = 2 Hz, 1H, Fur), 4.42 (d,
J = 11 Hz, 1H, H3), 4.00 (d, J = 11 Hz, 1H, H4), 3.33 (s, 3H, OCH3).
alkoxy-4-aryl-2-(trifluoromethyl)chromenes (2a–i) and (3a, 4a)
13C NMR (CDCl3):
d = 189.6 (C55O), 157.6 (C5), 151.9 (1C, Fur),
4.2.1. Conventional thermal heating procedure (CTH)
150.6 (C8a), 148.8 (1C, Fur), 142.9, 128.7, 128.1, 126.9 (6C, Ph),
126.4 (C7), 122.4 (q, J = 286, CF3), 120.9 (1C, Fur), 112.8 (C4a), 112.6
(1C, Fur), 110.4 (C8), 105.9 (C6), 94.4 (q, J = 33 Hz, C2), 53.3 (OCH3),
49.6 (C3), 42.1 (C4).
A stirred mixture of chromenes 1 (1 mmol) and iodine (2 mmol)
in 20 mL of alcohol (2a, 2d, 3a, 4a) or 50 mL of alcohol (2b–c, 2e–i)
was boiled under reflux for 16–24 h. The solvent was evaporated
under pressure, and the residue was taken up into dichloromethane.
The organic solution was sequentially washed with saturated
aqueous sodium thiosulfate, sodium bicarbonate and brine and then
dried over Na2SO4. The mixture was filtered and evaporated under
reduced pressure, and the residue was purified by column
chromatography(hexane/ethylacetate1:1)anddried ina desiccator
over P2O5 under reduced pressure. The results were chromanes 2 in
high purity (as determined by elemental analysis data).
GC–MS (EI, 70 eV) m/z (%): 418 (M+, 5), 305 (68), 211 (91), 95
(100).
Anal. calcd. for C22H17F3O5 (418.10): C, 63.16; H, 4.10%. Found:
C, 63.30; H, 4.29%.
4.2.6. 3-Acetyl-2-hydroxy-5-methoxy-4-(4-nitrophenyl)-2-
(trifluoromethyl)chromane (2d): yellow oil, mp 68–70 8C
1H NMR (CDCl3):
d = 8.15 (d, J = 8 Hz, 2H, Ph), 7.30–7.32
(m, 3H, Ph, H7), 6.72 (d, J = 8 Hz, 1H, H6), 6.47 (d, J = 8 Hz, 1H,
H8), 4.42 (d, J = 11 Hz, 1H, H3), 3.43 (d, J = 11 Hz, 1H, H4), 3.33
(s, 3H, OCH3), 1.87 (s, 3H, CH3).
4.2.2. Microwave irradiation procedure (MW)
A solution of chromenes 1 (0.25 mmol) and iodine (0.50 mmol)
diluted in 3 mL of alcohol was irradiated in an ETHOS-1 microwave
at 200 W, 2.5 bar of pressure for 0.5 h, enough time to complete the
reaction. The temperature was set to 100 8C, and the irradiation
was automatically stopped at this temperature. The reaction
mixture was subsequently cooled to room temperature. The
solvent was evaporated under pressure, and the residue was taken
up in dichloromethane. The organic solution was sequentially
washed with saturated aqueous sodium thiosulfate, sodium
bicarbonate and brine and then dried over Na2SO4. The mixture
was filtered, and the solvent was evaporated under reduced
pressure. The chromanes 2 were obtained as solids and later dried
under vacuum in a desiccator containing P2O5. The products 2
showed a high degree of purity and were not recrystallized.
13C NMR (CDCl3):
d = 210.7 (C55O), 157.0 (C5), 150.9 (C8a),
150.4, 146.8, 129.6, (4C, Ph), 128.2 (C7), 123.9 (2C, Ph), 122.1
(q, J = 286, CF3), 110.8 (C4a), 110.4 (C8), 105.5 (C6), 93.5
(q, J = 33 Hz, C2), 55.1 (OCH3), 54.0 (C3), 41.4 (CH3), 33.1 (C4).
GC–MS (EI, 70 eV) m/z (%): 411 (M+, 14), 369 (100), 258 (87),
136 (68), 106 (51).
Anal. calcd. for C19H16F3NO6 (411.09): C, 55.48; H, 3.92; N,
3.41%. Found: C, 55.20; H, 4.30; N, 3.13%.
4.2.7. 3-Benzoyl-2-hydroxy-5-methoxy-4-(4-nitrophenyl)-2-
(trifluoromethyl)chromane (2e): white solid, mp 166–168 8C
1H NMR (400 MHz, CDCl3):
d = 7.96 (d, J = 8 Hz, 2H, Ph),
7.50–7.47 (m, 2H, Ph), 7.31–7.26 (m, 4H, Ph), 7.18–7.14 (m, 2H,
Ph, H7), 6.78 (d, J = 8 Hz, 1H, H6), 6.50 (d, J = 8 Hz, 1H, H8), 4.59
(d, J = 11 Hz, 1H, H3), 4.27 (d, J = 11 Hz, 1H, H4), 3.35 (s, 3H, OCH3).
4.2.3. 3-Acetyl-2-hydroxy-5-methoxy-4-phenyl-2-
(trifluoromethyl)chromane (2a): yellow oil
13C NMR (CDCl3):
d = 202.6 (C55O), 157.0 (C5), 150.7 (C8a),
1H NMR (CDCl3):
d
= 7.25–7.19 (m, 4H, Ph), 7.09–7.07 (m, 2H,
146.5, 135.8, 134.9, 128.5, 128.7 (6C, Ph), 128.2 (C7), 127.8, 123.6
(4C, Ph), 122.1 (q, J = 286, CF3), 111.1 (C4a), 110.6 (C8), 105.5 (C6),
94.1 (q, J = 33 Hz, C2), 55.1 (OCH3), 47.7 (C3), 42.5 (C4).
GC–MS (EI, 70 eV) m/z (%): 455 (18), 358 (45), 333 (100), 282
(22), 207 (83), 105 (81), 77 (45).
Ph), 6.70 (d, J = 8 Hz, 1H, H6), 6.47 (d, J = 8 Hz, 1H, H8), 4.25 (d,
J = 11 Hz, 1H, H3), 3.48 (d, J = 11 Hz, 1H, H4), 3.32 (s, 3H, OCH3),
1.82 (s, 3H, CH3).
13C NMR (CDCl3):
d = 212.4 (C55O), 157.6 (C5), 150.6 (C8a),
143.0 (Ph), 128.7 (C7), 128.6, 127.0, 126.8 (5C, Ph), 122.4 (q, J = 286,
CF3), 112.5 (C4a), 110.3 (C8), 105.9 (C6), 93.8 (q, J = 33 Hz, C2), 55.2
(OCH3), 54.3 (C3), 41.9 (CH3), 33.0 (C4).
Anal. calcd. for C24H18F3NO6 (473.10): C, 60.97; H, 3.83; N,
2.96%. Found: C, 60.50; H, 3.70; N, 3.15%.
GC–MS (EI, 70 eV) m/z (%): 366 (M+, 5), 305 (100), 211(25),
91 (27).
4.2.8. 3-(Furan-2-oyl)-2-hydroxy-5-methoxy-4-(4-nitrophenyl)-2-
(trifluoromethyl)chromane (2f): yellow solid, mp 101–103 8C
Anal. calcd. for C19H17F3O4 (366.10): C, 62.29; H, 4.68%. Found:
C, 62.14; H, 4.78%.
1H NMR (CDCl3):
d = 7.87 (d, J = 8 Hz, 1H, Ph), 7.42 (s, 1H, Fur),
7.27 (m, 2H, Fur, H7), 7.19 (d, d, J = 8 Hz, 1H, Ph), 6.77 (d, J = 2 Hz,
1H, H6), 6.49 (d, J = 2 Hz, 1H, H8), 6.40 (d,d, J = 1 Hz, 1H, Fur),
4.59 (d, J = 11 Hz, 1H, H3), 4.03 (d, J = 11 Hz, 1H, H4), 3.35
(s, 3H, OCH3).
4.2.4. 3-Benzoyl-2-hydroxy-5-methoxy-4-phenyl-2-
(trifluoromethyl)chromane (2b): white solid, mp 124–126 8C
1H NMR (CDCl3):
d
= 7.46–7.39 (m, 3H, Ph), 7.27–7.19
13C NMR (CDCl3):
d = 188.7 (C55O), 157.2 (OCH3), 151.9 (C8a),
(m, 4H, Ph), 7.03–6.98 (4H, Ph, H7), 6.75 (d, J = 8 Hz, 1H, H6),
6.49 (d, J = 8 Hz, 1H, H8), 4.45 (d, J = 11 Hz, 1H, H3), 4.30
(d, J = 11 Hz, 1H, H4), 3.33 (s, 3H, OCH3).
150.8 (Fur), 150.7 (Fur), 149.0 (Ph), 146.7 (Ph), 129.5 (C7), 127.8
(Ph), 123.8 (q, J = 286, CF3), 123.4 (Ph), 120.6, 113.3 (Fur), 111.1
(C4a), 110.6 (C8), 105.6 (C6), 94.4 (q, J = 33 Hz, C2), 55.1 (OCH3),
48.8 (C3), 41.85 (C4).
13C NMR (CDCl3):
d = 204.0 (C55O), 157.6 (C5), 150.7 (C8a),
142.9, 136.3, 134.2, 128.7, 128.4, 128.3 (Ph), 126.5 (C7), 122.3 (q,
J = 286, CF3), 112.9 (C4a), 110.5 (C8), 105.9 (C6), 94.4 (q, J = 33 Hz,
C2), 55.2 (OCH3), 48.8 (C3), 42.8 (C4).
GC–MS (EI, 70 eV) m/z (%): 428 (M+, 5), 305 (45), 211 (45),
105 (100), 77 (55).
GC–MS (EI, 70 eV) m/z (%): 433 (5), 334 (11), 207 (16), 95 (100).
Anal. calcd. for C22H16F3NO7 (463,09) C, 57.03; H, 3.48; N,
3.02%; C, 57.01; H, 3.52; N, 2.99%.
4.2.9. 3-Acetyl-2-hydroxy-5-methoxy-4-(4-methoxylphenyl)-2-
Anal. calcd. for C24H19F3O4 (428.12): C, 67.29; H, 4.47%. Found:
C, 67.55; H, 4.96%.
(trifluoromethyl)chromane (2g): yellow oil
1H NMR (CDCl3):
d = 7.15 (t, J = 8 Hz, 1H, H7), 6.98 (d, J = 8 Hz,
2H, Ph), 6.79 (d, J = 8 Hz, 2H, Ph), 6.68 (d, J = 8 Hz, 1H, H6), 6.44
(d, J = 8 Hz, H8), 4.20 (d, J = 11 Hz, 1H, H3), 3.47 (d, J = 11 Hz, 1H,
H4), 3.47 (s, 3H, p-OCH3), 3.3 3 (s, 3H, OCH3), 1.84 (s, 3H, CH3).
4.2.5. 3-(Furan-2-oyl)-2-hydroxy-5-methoxy-4-phenyl-2-
(trifluoromethyl)chromane (2c): yellow solid, mp 47–49 8C
1H NMR (CDCl3):
d
= 7.44 (dd, J = 1 Hz, 1H, Fur), 7.20 (s, 1H, Fur),
13C NMR (CDCl3):
d
= 212.8 (C55O), 158.3 (C5), 157.7 (Ph), 150.4
7.11–7.03 (m, 5H, Ph), 6.99–6.98 (m, 1H, H7), 6.74 (d, J = 8 Hz, 1H,
(C8a), 134.8 128.7 (3C, Ph), 128.0 (C7), 122.3 (q, J = 286, CF3), 114.0

H.G. Bonacorso et al. / Journal of Fluorine Chemistry 142 (2012) 90–95
95
(2C, Ph), 112.7 (C4a), 110.3 (C8), 105.9 (C6), 93.7 (q, J = 33 Hz, C2),
55.3, 55.1 (2C, OCH3), 54.2 (C3), 41.1 (CH3), 33.2 (C4).
GC–MS (EI, 70 eV) m/z (%): 396 (M+, 12), 353 (15) 243 (45), 121
(100).
112.9 (C4a), 109.5 (C8), 105.9 (C6), 93.5 (q, J = 33 Hz, C2), 69.5
(OCH2), 58.7 (C3), 39.1 (CH3), 29.6 (C4), 21.4 (CH2), 10.0 (CH3).
GC–MS (EI, 70 eV) m/z (%): 394 (M+, 19), 333 (100), 291 (62),
207 (69), 91 (50), 69 (38).
Anal. calcd. for C20H19F3O5 (396.35): C, 60.61; H, 4.83%. Found:
C, 60.80; H, 4.98%.
Anal. calcd. for C21H21F3O4 (394.13): C, 63.95; H, 5.37%. Found:
C, 64.03%; H, 5.41%.
Acknowledgments
4.2.10. 3-Benzoyl-2-hydroxy-5-methoxy-4-(4-methoxyphenyl)-2-
(trifluoromethyl)chromane (2h): white solid, mp 158–160 8C
1H NMR (CDCl3):
d = 7.49–7.43 (M, 4H, Ph), 7.30 7.27
The authors are grateful for the financial support from Conselho
´
´
Nacional de Desenvolvimento Cientıfico e Tecnologico – CNPq
(Proj. #s 470.788/2010-0 Universal and 303.013/2011-7). Fellow-
ships from CAPES and CNPq are also acknowledged.
(m, 2H, Ph), 7.23–7.17 (m, 1H, H7), 6.89 (d, J = 8 Hz, 2H, Ph),
6.74 (d, J = 8 Hz, 1H, H6), 6.60 (d, J = 8 Hz, 2H, Ph), 6.50 (d, J = 8 Hz,
1H, H8), 4.42 (d, J = 11 Hz, 1H, H3), 4.30 (d, J = 11 Hz, 1H, H4), 3.67,
3.37 (s, 6H, OCH3).
13C NMR (CDCl3):
d = 204.1 (C55O), 158.1 (C5), 157.6 (Ph), 150.7
References
(C8a), 136.2, 134.9, 134.2 128.6, 128.5, 128.4 (Ph), 128.0 (C7), 122.3
(q, J = 286, CF3), 113.7 (2C, Ph), 113.3 (C4a), 110.4 (C8), 105.9 (C6),
94.4 (q, J = 33 Hz, C2), 55.3, 55.1 (2C, OCH3), 48.9 (C3), 42.01 (C4).
GC–MS (EI, 70 eV) m/z (%): 458 (M+, 5), 353 (9), 105 (100),
77 (32).
[1] (a) M.J. Mphahlele, Molecules 14 (2009) 5308;
(b) H. Togo, S. Iida, Synlett 14 (2006) 2159;
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Anal. calcd. for C25H21F3O5 (458.13): C, 65.50; H, 4.62%. Found:
C, 65.78; H, 4.94%.
[4] S.G. Hegde, A.M. Kassim, A.I. Kennedy, Tetrahedron 57 (2001) 1689.
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Journal of Chemical Research (1999) 706;
4.2.11. 3-(Furan-2-oyl)-2-hydroxy-5-methoxy-4-(4-
methoxyphenyl)-phenyl-2-(trifluoromethyl)chromane (2i): white
solid, mp 144–146 8C
(c) J.M. Kim, K.Y. Lee, J.N. Kim, Bulletin of the Korean Chemical Society 24
(2003) 1057;
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Transactions 2 (1996) 1455;
(e) P.T. Parvatkar, P.S. Parameswaran, S.G. Tilve, Chemistry- A European Journal
18 (2012) 5460.
1H NMR (CDCl3):
d = 7.65 (d,d, J = 1 Hz, 1H, Fur), 7.19 (t, J = 8 Hz,
1H, H7), 7.07 (d,d, J = 1 Hz, 1H, Fur), 6.92–6.88 (m, 3H, Fur, Ph), 6.74
(d, J = 8 Hz, 1H, H6), 6.61 (d J = 8 Hz, 2H, Ph), 6.49 (d, J = 8 Hz, 1H,
H8), 4.40 (d, J = 11 Hz, 1H, H3), 4.02 (d, J = 11 Hz, 1H, H4), 3.68, 3.37
(s, 6H, OCH3).
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2004;
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Wiley, Hoboken, NJ, 2008;
(d) P. Maienfish, R.G. Hall, Chimia 58 (2004) 93;
13C NMR (CDCl3):
d = 189.8 (C55O), 158.0 (C5), 157.6 (Ph), 151.9
(Fur), 150.6 (C8a), 148.9 (Fur), 134.9, 128.8 (3C, Ph), 127.9 (C7),
122.3 (q, J = 286, CF3), 121.0 (fur), 113.6 (Fur), 113.0 (2C, Ph), 112.9
(C4a), 110.4 (C8), 105.9 (C6), 94.2 (q, J = 33 Hz, C2), 55.4, 55.1 (2C,
OCH3), 49.8 (C3), 41.3 (C4).
(e) Z.-P. Liu, Current Organic Chemistry 14 (2010) 888;
(f) K. Mikami, Y. Itoh, M. Yamanaka, Chemical Reviews 1 (2004) 104.
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Elsevier, Amsterdam, 1982;
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Medicinal Chemistry and Biomedical Applications, Elsevier, Amsterdam, 1993.
[8] R.E. Filler, Organic Chemistry in Medicinal Chemistry and Applications, Plenum
and Elsevier, Amsterdam, 1993.
GC–MS (EI, 70 eV) m/z (%): 448 (M+, 5), 241 (9), 121 (23), 95
(100).
Anal. calcd. for C23H19F3O6 (448.11): C, 61.61; H, 4.27%. Found:
C, 62.05; H, 4.40%.
[9] R. Ling, M. Yoshida, P.S. Mariano, Journal of Organic Chemistry 61 (1996) 4439.
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(b) P. Lin, J. Jiang, Tetrahedron 56 (2000) 3635.
4.2.12. 3-Acetyl-5-ethoxy-2-hydroxy-4-phenyl-2(-
trifluoromethyl)chromane (3a): yellow oil
[11] E.E. Schweizer, D. Meeder-Nycz, Heterocyclic Compounds: Chromenes, Ellis G.P.,
New York, 1977, pp. 11–139.
[12] (a) T. Harada, T. Hayashiya, I. Wada, N. Iwa-ake, A. Oku, Journal of the American
Chemical Society 109 (1987) 527;
(b) S. Inoue, H. Ikeda, S. Sato, K. Horie, T. Ota, O. Miyamoto, K. Sato, Journal of
Organic Chemistry 52 (1987) 5495.
[13] I.M. Chandler, C.R. McIntyre, T.J. Simpson, Journal of the Chemical Society, Perkin
Transactions 1 (1992) 2271.
1H NMR (CDCl3):
d = 7.25–7.20 (m, 4H, Ph), 7.11–7.05
(m, 2H, Ph, H7), 6.66 (d, J = 8 Hz, 1H, H6), 6.42 (d, J = 8 Hz, 1H,
H8), 4.25 (d, J = 11 Hz, 1H, H3), 3.84–3.69 m (m, 1H, CH2), 3.47
(d, J = 11 Hz, 1H, H4), 3.40–3.36 (m, 1H, CH2), 1.80 (s, 3H, CH3), 0.73
(t, J = 7 Hz, 3H, CH3).
13C NMR (CDCl3):
d = 212.9 (C55O), 156.8 (C5), 150.5 (C8a),
[14] (a) H. Haberlein, K.-P. Tschiersch, Biochemical Systematics and Ecology 26
(1998) 97;
143.0 128.8, 128.6 127.1 (6C, Ph), 126.6 (C7), 122.3 (q, J = 286, CF3),
111.7 (C4a), 109.9 (C8), 105.9 (C6), 93.5 (q, J = 33 Hz, C2), 63.5
(CH2), 54.0 (C3), 42.0 (C4), 33.0, 13.8 (CH3).
GC–MS (EI, 70 eV) m/z (%): 380 (M+, 14), 319 (100), 291 (20),
105 (14).
(b) H. Poerwono, S. Sasaki, Y. Hattori, K. Higashiyama, Bioorganic and Medicinal
Chemistry Letters 20 (2010) 2086.
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M.A.P. Martins, N. Zanatta, M.S.B. Caro, Journal of Fluorine Chemistry 132
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[18] Crystallographic data for the structure of 2h, reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre and allocated the
deposition number CCDC 872165. Copies of the data can be obtained free of
charge, on application to CCDC 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44
1223 336033 or e-mail: deposit@ccdc.com.ac.uk).
[19] Bruker, APEX2 (Version 2.1), COSMO (Version 1.56), BIS (Version 2.0.1.9), SAINT
(Version 7.3A) and SADABS (Version 2004/1) and XPREP9 (Version 2005/4),
Bruker AXS Inc., Madison, WI, USA, 2006.
Anal. calcd. for C20H19F3O4 (380.35): C, 63.15; H, 5.03%. Found:
C, 63.14; H, 5.09%.
4.2.13. 3-Acetyl-2-hydroxy-4-phenyl-5-propoxy-2-
(trifluoromethyl)chromane (4a): yellow oil
1H NMR (CDCl3):
d = 7.27–7.20 (m, 3H, Ph), 7.15 (t, J = 8 Hz, 1H,
H7), 7.08–7.06 (m, 2H, Ph), 6.67 (J = 8 Hz, 1H, H8), 6.43 (d, J = 8 Hz,
1H, H6), 4.26 (d, J = 11 Hz, 1H, H3), 3.65–3.60 (m, 1H, CH2), 3.46
(d, J = 11 Hz, 1H, H4), 3.40–3.35 (m, 1H, CH2), 1.79 (s, 3H, CH3), 1.13
(sex, J = 7 Hz, 2H, CH2), 0.60 (t, J = 7 Hz, 3H, CH3).
[20] G.M. Sheldrick, SHELXS-97, Program for Crystal Structure Solution, University of
Go¨ttingen, Germany, 1997.
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of Go¨ttingen, Germany, 1997.
[22] P. Coppens, L. Leiserowitz, D. Rabinovich, Acta Crystallographica 18 (1965) 1035.
[23] L.J. Farrugia, Journal of Applied Crystallography 30 (1997) 565.
13C NMR (CDCl3):
143.1, 128.4, 128.0, 127.0 (Ph), 126.1 (C7), 122.3 (q, J = 286, CF3),
d = 204.2 (C55O), 156.85 (C5), 150.5 (C8a),