Synthesis of 2-aryl-3-trifluoromethylquinolines using (E)-trimethyl(3,3,3- trifluoroprop-1-enyl)silane

Article abstract of DOI:10.1021/jo400859s

The Hiyama cross-coupling reaction of (E)-trimethyl(3,3,3-trifluoroprop-1- enyl)silane (1) with 2-iodoaniline (2) proceeded without any protection of the amino group. The coordination of copper(II) fluoride to 2,2′-bipyridyl provided the fluoride source required to trigger this reaction, affording (E)-2-(3,3,3-trifluoroprop-1-enyl)aniline (3). In the presence of a stoichiometric amount of [Cu(OTf)]₂·C₆H ₆, the treatment of 3 with an aryl aldehyde at 200 C provided the 2-aryl-3-trifluoromethylquinoline (4) via the oxidative cyclization of an in situ-generated imine substructure.

Full text of DOI:10.1021/jo400859s

Article
pubs.acs.org/joc
Synthesis of 2‑Aryl-3-trifluoromethylquinolines Using
(E)‑Trimethyl(3,3,3-trifluoroprop-1-enyl)silane
Masaaki Omote, Miyuu Tanaka, Miki Tanaka, Akari Ikeda, Atsushi Tarui, Kazuyuki Sato, and Akira Ando*
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata 573-0101, Japan
S
* Supporting Information
ABSTRACT: The Hiyama cross-coupling reaction of (E)-
trimethyl(3,3,3-trifluoroprop-1-enyl)silane (1) with 2-iodoani-
line (2) proceeded without any protection of the amino group.
The coordination of copper(II) fluoride to 2,2′-bipyridyl
provided the fluoride source required to trigger this reaction,
affording (E)-2-(3,3,3-trifluoroprop-1-enyl)aniline (3). In the
presence of a stoichiometric amount of [Cu(OTf)]2·C6H6, the
treatment of 3 with an aryl aldehyde at 200 °C provided the 2-
aryl-3-trifluoromethylquinoline (4) via the oxidative cyclization of an in situ-generated imine substructure.
demonstrating that 1 was a useful 3,3,3-trifluoropropenylation
reagent for aryl iodides.8 During the course of that particular
study, the Hiyama cross-coupling reaction of 1 was found to be
applicable to 2-iodoaniline (2) when the reaction was
conducted in the presence of copper(II) fluoride coordinated
by 2,2′-bipyridine (bipy) as a source of fluoride anions. The
reaction afforded (E)-2-(3,3,3-trifluoroprop-1-enyl)anilines (3)
in quantitative yields without the need to protect the amino
group in 2 (Scheme 1). The structure of 3 was critical to the
INTRODUCTION
■
Trifluoromethylated quinolines have recently been the subject
of considerable levels of attention because of the important
roles they play in pharmaceutical, agrochemical, and high-
performance materials.1,2 A wide variety of different synthetic
methods have been reported for the construction of 2- and 4-
trifluoromethylquinolines, including the direct trifluoro-
methylation of 2- and 4-halogenoquinolines3 and the cyclo-
condensation of aniline derivatives with trifluoromethyl
ketones.4,5 In contrast, synthetic studies toward the develop-
ment of methods providing access to 3-trifluoromethyl-
quinolines remain scarce. The main difficulty associated with
the construction of the 3-trifluoromethylquinoline core is the
lack of a useful synthetic protocol that is compatible with the
use of common aniline derivatives. Direct trifluoromethylation
reactions have recently been established involving the cross-
coupling of 3-quinolineboronic acid, but the chemical yields of
the 3-trifluoromethylquinoline products were relatively low.6
Furthermore, the synthesis of 2-substituted 3-trifluoromethyl-
quinolines according to these methods becomes incredibly
difficult because of the steric hindrance provided by the
trifluoromethyl group, and only a few reports have been
published in this particular area.1d,7 The difficulties associated
with the construction of 3-trifluoromethylquinolines have
limited their use in the synthesis of several promising
therapeutic targets.1,2 With these issues in mind, we envisaged
that the development of an efficient synthetic protocol
involving the use of aniline derivatives would provide facile
access to a wide range of 3-trifluoromethylquinolines and
complement the existing library of trifluoromethylquinolines
already available for the synthesis of potential therapeutic
agents.
Scheme 1. Synthetic Approach for the Construction of 2-
Aryl-3-trifluoromethylquinolines
success of the subsequent oxidative cyclocondensation reaction
because the 3,3,3-trifluoroprop-1-enyl chain of 3 was perfectly
aligned to participate in the cyclocondensation reaction. The
oxidative cyclization reaction itself proceeded smoothly in the
presence of [Cu(OTf)]2·C6H6 to give a series of 2-aryl-3-
trifluoromethylquinolines (4). Herein, we wish to report the
synthesis of 4 via the Hiyama cross-coupling reaction of 1 with
2 followed by an oxidative cyclocondensation reaction.
RESULTS AND DISCUSSION
To begin our study, we screened a variety of different reaction
conditions for the Hiyama cross-coupling reaction of 1 and 2
■
We recently reported the use of (E)-trimethyl(3,3,3-
trifluoroprop-1-enyl)silane (1) for the 3,3,3-trifluoro-
propenylation of aryl iodide according to the Hiyama cross-
coupling reaction to afford β-trifluoromethylstyrene derivatives,
Received: April 22, 2013
© XXXX American Chemical Society
A
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(Table 1). It is noteworthy that procedures for the protection
and deprotection of the amino group were omitted from the
in 2 as a consequence of their good affinity, eliminating the
detrimental effect of the chelation of the nitrogen atom with
palladium; and (3) the viable generation of the fluoride anions
necessary for C−Si bond dissociation through the chelation
process. These hypotheses have been partially supported by the
fact that the yield for the reaction was substantially reduced
when N-Boc-protected 2a was used (Table 1, entry 10) because
the chelation between the nitrogen atom of the aniline and the
copper would have been weakened by the Boc-substitution.
Another palladium source, allylpalladium(II) chloride dimer,
also participated in the reaction efficiently to give 3a in the
same yield. On the basis of these optimization experiments, we
effectively developed an efficient Hiyama cross-coupling
reaction of 1 with 2a to afford 3a without the need for any
tedious protection and deprotection steps of the aniline.
With an optimized procedure in hand for the Hiyama cross-
coupling reaction, we proceeded to investigate the oxidative
cyclocondensation of 3a to 4a. In 1988, Baine et al.9 reported
the convenient synthesis of 2-aryl-3-methoxycarbonylquinolines
via the thermal electrocyclic rearrangement of methyl 3-(2-
benzylideneamino)phenylacrylates. Although this reaction
required high-temperature conditions of 200 °C to facilitate
the electrocyclic rearrangement, it was simple and environ-
mentally friendly because it only produced a small amount of
waste. From a structural perspective, the N-benzylidene-2-
alkenylaniline substructure employed in the reaction would be
readily derived from 3a, suggesting that the reaction would
operate through 3a. At the beginning of the current study, 3a
was subjected to the same condition reported by Baine et al.,9
and a mixture of 3a and benzaldehyde in 1,2,4-trichlorobenzene
was heated to a temperature of 200 °C. The reaction proceeded
to give the desired product 4a, albeit in a low yield of 33%,
following an even longer reaction time than that reported by
Baine et al.9 (Table 2, entry 1). The low yield observed in this
particular case was attributed to the electron-deficient nature of
the 3,3,3-trifluoromethylpropenyl group, which could interfere
with the electrocyclic rearrangement. Changing the solvent to
triglyme did not provide any improvement in the yield of the
reaction (Table 2, entry 2). The addition of a stoichiometric
amount of copper(I) iodide also failed to provide any
Table 1. Optimization of Conditions for the Hiyama Cross-
Coupling Reaction of 1 with 2a
time
(h)
3a yield
a
entry
1
catalyst (mol %)
Pd2(dba)3(1.5)/
F anion (equiv)
CsF (2)
(%)
19
P(mesityl)3 (15)
Pd(dppe)2 (5)
Pd(dppe)2 (5)
Pd(dppe)2 (5)
2
3
4
TBAF (2)
KF (2)
15
19
24
ZnF2 (2)/2,2′-bipy
(2)
5
Pd(dppe)2 (5)
AgF (2)/2,2′-bipy
23
(2)
6
7
Pd(dppe)2 (5)
Pd(dppe)2 (5)
CuF2 (2)
20
20
CuF2 (2)/1,10-
phen (2)
13
61
8
9
Pd(dppe)2 (5)
Pd(dppe)2 (5)
Pd(dppe)2 (5)
[Pd(allyl)Cl]2 (5)
CuF2 (2)/2,2′-bipy
6
19
16
20
(2)
c
CuF2 (2)/2,2′-bipy
90 (81)
16
(2)
b
10
CuF2 (2)/2,2′-bipy
(2)
11
CuF2 (2)/2,2′-bipy
91
(2)
a
NMR yields, which were calculated by 19F NMR integration of
products 3a relative to the internal standard of ethyl 2,2,2-trifluoro-
b
c
acetate. The N-Boc substrate was used. The values in parentheses
indicate the isolated yields of 3a.
screening process to simplify the overall transformation. When
the reaction was carried out under the optimized conditions
developed in our previous report, which involved the use of
cesium fluoride and Pd2(dba)3 in DMF at a temperature of 80
°C (Table 1, entry 1), none of the desired product was
observed. The failure of this reaction was attributed to the
irreversible chelation of the nitrogen atom of the aniline to the
palladium. The evaluation of several other reagents as fluoride
sources under the same conditions also proved unsuccessful
(Table 1, entries 2−5). During our search for suitable
conditions, we discovered that copper(II) fluoride had a
tendency toward accelerating the reaction when used in
conjunction with an appropriate ligand. For example, although
the use of copper(II) fluoride alone did not provide any of the
desired product (Table 1, entry 6), the coordinative interaction
of 1,10-phenanthroline (1,10-phen) with copper(II) fluoride
began to initiate the reaction to afford a coupling product (3a)
in a 13% yield (Table 1, entry 7). Pleasingly, the use of bipy as a
ligand instead of 1,10-phen provided a significant enhancement
in the yield of the reaction to give 3a in a 61% yield over a
shorter reaction time (Table 1, entry 8). The extension of the
reaction time led to an increase in the yield of 3a to 90%, and
these conditions were determined to be optimal (Table 1, entry
9). Although it remains unclear why the combination of
copper(II) fluoride and bipy had such a significant impact on
the success of the reaction, we hypothesized that three
significant effects resulted from this combination: (1) an
increase in the solubility of copper(II) fluoride resulting from
its coordination with bipy; (2) the enhanced feasibility of
chelation between copper and the nitrogen atom of the aniline
Table 2. Screening Process To Identify the Optimal
Reaction Conditions for the Oxidative Cyclocondensation of
3a
a
entry
1
catalyst (mol %)
temp (°C) time (h) 4a yield (%)
200
200
200
180
150
180
200
200
48
48
22
1
33
b
2
24
3
4
5
6
7
8
CuI (1)
27
[Cu(OTf)]2·PhCH3 (1)
[Cu(OTf)]2·PhCH3 (1)
[Cu(OTf)]2·PhCH3(0.1)
49
30
9
9
18
·
[Cu(OTf)]2 PhCH3 (1)
2
81
c
·
[Cu(OTf)]2 C6H6(1)
2
82 (78)
a
NMR yields, which were calculated by 19F NMR integration of
products 3a relative to the internal standard of ethyl 2,2,2-
b
c
trifluoroacetate. Triglyme was used as a solvent. The values in
parentheses indicate the isolated yields of 3a.
B
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discernible improvement in the yield of the reaction, although
the reaction profile became much cleaner with the generation
of byproducts being significantly suppressed.
isolated in relatively lower yields (Table 3, entries 5−8).
Pleasingly, the optimal conditions were tolerant of polycyclic
and heteroaromatic aldehydes, with naphthaldehyde and 2-
furylaldehyde proceeding smoothly through the reaction (Table
3, entries 9 and 10). Unfortunately, aliphatic aldehydes were
found to be unsuitable for this reaction (Table 3, entries 11 and
12). In the case of aliphatic aldehydes, the reactions became
messy and many byproducts were observed probably due to the
concomitant aldol-type reaction.
With the optimized conditions in hand for the sequential
synthesis of several different classes of 2-aryl-3-trifluoromethyl-
quinolines, we proceeded to expand upon the utility of this
reaction to deliver other 2-aryl-3-trifluoromethylquinolines
functionalized at a benzene ring. To date, direct functionaliza-
tion of quinolines was attained regioselectively at the 5- or 8-
position; however, it becomes quite difficult to functionalize
quinolines at the 6- or 7-position regioselectively.10,11 In this
view, we proceeded to apply our reaction to the synthesis of a
series of 6- and 7-chloro-3-trifluoromethylquinolines (Scheme
2). These compounds were particularly interesting because they
These results suggested that a copper(I) salt could be used as
a competent catalyst for the reaction. The use of [Cu-
(OTf)]2·PhCH3, which had superior solubility in the solvent,
had a significant impact on the reaction, with 4a being isolated
in a 49% yield when the mixture was heated for 1 h at 180 °C
(Table 2, entry 4). An attempt to conduct the reaction under
the same conditions, but at a lower temperature of 150 °C or
·
using [Cu(OTf)]2 PhCH3 as a catalyst, led to a reduction in the
yields of 4a to 9 and 18%, respectively. The optimal conditions
for the transformation were determined according to the
experiments shown in Table 2, entries 7 and 8. Interestingly, no
discernible difference was observed between the use of the
toluene and benzene complexes of copper(I) triflate. Although
the precise role of the copper(I) salt remained unclear from a
mechanistic perspective, the salt clearly provided a significant
level of activation to the reaction, even under a heavily
deoxygenated atmosphere. With this in mind, we hypothesized
that the copper(I) salt may be actively involved in promoting
both the cyclization of the benzylidene aniline intermediate and
the subsequent dehydrogenation reaction.
Scheme 2. Construction of 2-Aryl-3-trifluoromethyl-
a,b
quinolines via a Sequential Hiyama Cross-Coupling and
b,c
With the optimal conditions in hand, we proceeded to
explore the scope of the reaction toward the aldehyde
component. A series of different aldehydes were subjected to
the optimal reaction conditions (Table 3). The use of aryl
Oxidative Cyclocondensation Reaction Process To Give
the Corresponding 6- and 7-Chloro-3-
trifluoromethylquinolines
Table 3. Investigation of the Scope of the Oxidative
Cyclocondensation of 3a with a Variety of Different
Aldehydes
a
b,c
entry
R
time (h)
4
yield (%)
1
2
3
4
5
6
7
8
9
4-Me−C6H4
2-Me−C6H4
4-MeO−C6H4
2-MeO−C6H4
4-Cl−C6H4
3-Cl−C6H4
2-Cl−C6H4
4-Br−C6H4
2-naphthyl
2-furyl
1.0
3.0
2.0
3.5
2.0
1.5
2.0
2.5
2.0
1.5
2.0
2.0
4b
4c
4d
4e
4f
76 (74)
74 (68)
88 (65)
82 (78)
69 (63)
56 (44)
67 (47)
64 (52)
69 (50)
44 (37)
a
Reaction was performed in the condition according to entry 9 in
b
c
Table 1. Isolated yield. Reaction was conducted with 3 (0.2 mmol)
and [Cu(OTf)]2 C6H6 (0.2 mmol).
4g
4h
4i
·
4j
could be further derivatized through the functionalization of the
chlorine atom. The first Hiyama cross-coupling reactions with
2l and 2m were performed according to the conditions used in
Table 1, entry 9. Both of the reactions proceeded efficiently to
give 3l and 3m in good yields. These compounds were
subsequently cyclized according to the optimized condition
with benzaldehyde and 4-methoxybenzaldehyde to give the
desired products 4l−o in good yields.
10
11
12
4k
2-phenylethyl
benzyl
a
Reaction was conducted with 3a (0.2 mmol) and [Cu(OTf)]2·C6H6
b
(0.2 mmol). NMR yields, which were calculated by 19F NMR
integration of products 4 relative to the internal standard of ethyl
2,2,2-trifluoroacetate. The values in parentheses indicate the isolated
yields of 4.
c
CONCLUSION
aldehydes bearing electron-donating groups at their para-
position appeared to accelerate the reaction (Table 3, entries 1
and 3). In contrast, the use of aryl aldehydes bearing ortho-
substituents had an adverse impact on the reaction because of
the steric hindrance provided by the substituents, and extended
reaction times were required to provide 4 in good yield (Table
3, entries 2 and 4). When aryl aldehydes bearing electron-
withdrawing groups at the ortho-, meta-, or para-positions were
subjected to the optimal conditions, the products 4 were
■
In conclusion, we have successfully synthesized a series of 2-
aryl-3-trifluoromethylquinolines according to a sequential
Hiyama cross-coupling and oxidative cyclocondensation
reaction process. This process provides facile access to the 2-
aryl-3-trifluoromethylquinoline core, which would otherwise be
difficult to access according to existing techniques. We hope
this synthetic process will provide chemists with the
opportunity to synthesize a new library of 3-trifluoromethyl-
C
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Typical Procedure for Oxidative Cyclocondensation of 3 to
4. In a glovebox purged with argon gas, the copper(I) triflate benzene
complex (0.2 mmol) was placed in a flask. To the flask were added 3
(0.2 mmol), aryl aldehyde (0.2 mmol), and 1,2,4-trichlorobenzene (2.0
mL), and the mixture was stirred at 200 °C. After the flask was stirred
for the appropriate time listed in Table 3, the reaction mixture was
poured into ice water. If precipitate emerged, it was removed through a
pad of Celite. The whole mixture was extracted with Et2O, and the
organic layer was dried over anhydrous MgSO4. After filtration, the
filtrate was concentrated in vacuo, and the residue was purified by
silica gel column chromatography to give 4.
2-Phenyl-3-(trifluoromethyl)quinoline (4a). The title product (4a)
was purified by column chromatography (AcOEt/hexane = 1:9) and
was obtained in 78% yield (42.6 mg). A colorless solid: mp = 82−83
°C (recrystallized from dichloromethane and hexane); 1H NMR
(CDCl3) δ 7.45−7.52 (3H, m), 7.54−7.61 (2H, m), 7.63−7.71 (1H,
m), 7.84−7.90 (1H, m), 7.97 (1H, d, J = 7.9 Hz), 8.21 (1H, d, J = 8.5
Hz), 8.61 (1H, s); 13C NMR (100 MHz, CDCl3) δ 122.8 (q, J = 31.7
Hz), 123.6 (q, J = 272.7 Hz), 125.3, 127.7, 127.9, 128.2, 128.7 (q, J =
1.6 Hz), 128.7, 129.5, 132.0, 135.8 (q, J = 5.0 Hz), 139.6, 148.3, 157.2;
19F NMR (90 MHz, CDCl3) δ 18.11 (3F, s); MS m/z 273 (M+);
quinolines, which may make an important contribution to
future drug discovery projects.
EXPERIMENTAL SECTION
■
General Information. All experiments were carried out under an
argon atmosphere in flame-dried glassware using standard inert
techniques for introducing reagents and solvents, unless otherwise
noted. N,N-Dimethylformamide (DMF) was distilled over calcium
hydride and stored in a bottle with activated molecular sieves (4 Å).
All commercially available materials were used as received without
1
further purification. H and 13C NMR spectra were recorded at room
temperature on a commercial measurement device at 400 and 600
MHz. An 19F NMR spectrum was recorded at room temperature on a
commercial measurement device at 90 and 600 MHz. Chemical shifts
1
of H NMR and 13C NMR are reported in parts per million from
tetramethylsilane (TMS), used as an internal standard. Chemical shifts
of 19F NMR are reported in parts per million from ethyl 2,2,2-
trifluoroacetate, used as an internal standard. All data are reported as
follows: chemical shifts, relative integration value, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, sep = septet, br = broad,
brd = broad-doublet, m = multiplet), and coupling constants (Hz).
High-resolution mass spectroscopy (HRMS) experiments were
performed with a double-focusing mass spectrometer with EI. Melting
points are not corrected.
Typical Procedure for Hiyama Cross-Coupling Reaction. In a
glovebox purged with argon gas, bis[1,2-bis(diphenylphosphino)-
ethane]palladium(0) (0.010 mmol), CuF2 (0.4 mmol), and 2,2′-
bipyridyl (0.4 mmol) were placed in a flask. To the flask were added
anhydrous DMF (1.2 mL), 2-iodoaniline 2a (0.2 mmol), and 1 (0.4
mmol), and the mixture was stirred at 80 °C. After the reaction
mixture was stirred for about 20 h, it was poured into ice water. The
mixture was extracted with Et2O, and the organic layer was dried over
anhydrous MgSO4. After the solid was filtered, the solvent was
removed in vacuo, and the residue was purified by silica gel column
chromatography to give 3.
HRMS calcd for C16H10F3N 273.077 (M+), found 273.076.
2-(p-Tolyl)-3-(trifluoromethyl)quinoline (4b). The title product
(4b) was purified by column chromatography (hexane 100%) and was
obtained in 74% yield (42.5 mg). A colorless oil;: 1H NMR (CDCl3) δ
2.44 (3H, s), 7.29 (2H, d, J = 8.0 Hz), 7.48 (2H, d, J = 7.9 Hz), 7.63−
7.68 (1H, m), 7.83−7.89 (1H, m), 7.96 (1H, d, J = 8.0 Hz), 8.20 (1H,
d, J = 8.5 Hz), 8.59 (1H, s); 13C NMR (100 MHz, CDCl3) δ 21.4,
122.8 (q, J = 30.8 Hz), 123.6 (q, J = 272.7 Hz), 125.2, 127.6, 128.2,
128.6 (q, J = 1.7 Hz), 128.6, 129.5, 131.9, 135.8 (q, J = 5.8 Hz), 136.8,
138.6, 148.4, 157.6; 19F NMR (90 MHz, CDCl3) δ 18.09 (3F, s); MS
m/z 287 (M+); HRMS calcd for C17H12F3N 287.092 (M+), found
287.092.
2-(o-Tolyl)-3-(trifluoromethyl)quinoline (4c). The title product
(4c) was purified by column chromatography (AcOEt/hexane = 5:95)
and was obtained in 84% yield (186 mg). A colorless solid: mp = 90−
1
(E)-2-(3,3,3-Trifluoroprop-1-en-1-yl)aniline (3a).12 The title prod-
uct (3a) was purified by column chromatography (AcOEt/hexane =
1:9) and was obtained in 81% yield (30.3 mg). A colorless solid: mp
48−49 °C (recrystallized from dichloromethane and hexane); 1H
NMR (CDCl3) δ 3.81 (2H, br), 6.14 (1H, qd, J = 6.4, 15.9 Hz), 6.72
(1H, dd, J = 1.3, 7.9 Hz), 6.80 (1H, dt, J = 1.2, 7.3 Hz), 7.18 (1H, dt, J
= 1.5, 7.6 Hz), 7.25 (1H, qd, J = 2.1, 15.8 Hz), 7.29 (1H, dd, J = 1.5,
7.9 Hz); 13C NMR (100 MHz, CDCl3) δ 116.2 (q, J = 33.4 Hz),
116.7, 119.2, 119.4, 123.5 (q, J = 268.5 Hz), 127.9, 130.8, 133.3 (q, J =
6.7 Hz), 144.7; 19F NMR (90 MHz, CDCl3) δ 12.13 (3F, d, J = 4.7
Hz); MS m/z 187 (M+); HRMS calcd for C9H8F3N 187.061 (M+),
found 187.061.
(E)-4-chloro-2-(3,3,3-trifluoroprop-1-en-1-yl)aniline (3l). The title
product (3l) was purified by column chromatography (AcOEt/hexane
= 1:9) and was obtained in 54% yield (23.9 mg). A colorless solid: mp
43−44 °C (recrystallized from dichloromethane and hexane); 1H
NMR (CDCl3) δ 3.88 (2H, br), 6.11 (1H, qd, J = 6.4, 15.9 Hz), 6.72
(1H, d, J = 1.8 Hz), 6.76 (1H, dd, J = 1.5, 8.6 Hz), 7.16 (1H, qd, J =
1.9, 15.9 Hz), 7.20 (1H, d, J = 8.3 Hz); 13C NMR (100 MHz, CDCl3)
δ 116.3, 117.0 (q, J = 33.3 Hz), 117.7, 119.3, 123.3 (q, J = 267.7 Hz),
129.0, 132.3 (q, J = 7.5 Hz), 136.4, 145.6; 19F NMR (90 MHz, CDCl3)
δ 12.03 (3F, d, J = 6.2 Hz); MS m/z 221 (M+); HRMS calcd for
C9H7ClF3N 221.022 (M+), found 221.022.
(E)-5-chloro-2-(3,3,3-trifluoroprop-1-en-1-yl)aniline (3m). The
title product (3m) was purified by column chromatography
(AcOEt/hexane = 1:9) and was obtained in 62% yield (27.4 mg). A
colorless solid: mp = 48−50 °C (recrystallized from dichloromethane
and hexane); 1H NMR (CDCl3) δ 3.81 (2H, br), 6.14 (1H, qd, J = 6.4,
15.8 Hz), 6.66 (1H, d, J = 8.5 Hz), 7.13 (1H, dd, J = 2.4, 8.9 Hz), 7.17
(1H, dd, J = 2.2, 16.5 Hz), 7.26 (1H, s); 13C NMR (100 MHz, CDCl3)
δ 117.8 (q, J = 34.2 Hz), 117.9, 120.6, 123.2 (q, J = 268.5 Hz), 123.9,
127.3, 130.6, 132.1 (q, J = 6.6 Hz), 143.2; 19F NMR (90 MHz, CDCl3)
δ 11.89 (3F, d, J = 6.2 Hz); MS m/z 221 (M+); HRMS calcd for
C9H7ClF3N 221.022 (M+), found 221.023.
92 °C (recrystallized from dichloromethane and hexane); H NMR
(CDCl3) δ 2.09 (3H, s), 7.26−7.40 (4H, m), 7.66−7.91 (1H, m),
7.85−7.91 (1H, m), 7.99 (1H, d, J = 7.7 Hz), 8.21 (1H, d, J = 8.6 Hz),
8.62 (1H, s); 13C NMR (100 MHz, CDCl3) δ 19.7, 123.2 (q, J = 30.9
Hz), 123.4 (q, J = 272.6 Hz), 125.0, 125.3, 127.8, 128.3, 128.6 (q, J =
1.6 Hz), 128.7, 129.5, 130.0, 131.9, 135.5 (q, J = 5.0 Hz), 136.1, 138.4,
148.4, 157.4; 19F NMR (90 MHz, CDCl3) δ 15.71 (3F, s); MS m/z
287 (M+); HRMS calcd for C17H12F3N 287.092 (M+), found 287.092.
2-(4-Methoxyphenyl)-3-(trifluoromethyl)quinoline (4d). The title
product (4d) was purified by column chromatography (AcOEt/
hexane = 1:9) and was obtained in 65% yield (39.4 mg). A colorless
solid: mp = 103−104 °C (recrystallized from dichloromethane and
1
hexane); H NMR (CDCl3) δ 3.88 (3H, s), 7.02 (2H, d, J = 8.9 Hz),
7.55 (2H, d, J = 8.8 Hz), 7.63−7.68 (1H, m), 7.84−7.89 (1H, m), 7.96
(1H, d, J = 7.9 Hz), 8.20 (1H, d, J = 8.2 Hz), 8.59 (1H, s); 13C NMR
(100 MHz, CDCl3) δ 55.4, 113.5, 122.8 (q, J = 31.7 Hz), 123.8 (q, J =
271.9 Hz), 125.2, 127.5, 128.2, 129.5, 130.1 (q, J = 1.7 Hz), 131.9,
132.2, 135.9 (q, J = 5.8 Hz), 148.4, 156.9, 160.1; 19F NMR (90 MHz,
CDCl3) δ 18.13 (3F, s); MS m/z 303 (M+); HRMS calcd for
C17H12F3NO 303.087 (M+), found 303.088.
2-(2-Methoxyphenyl)-3-(trifluoromethyl)quinoline (4e). The title
product (4e) was purified by column chromatography (AcOEt/hexane
= 1:9) and was obtained in 78% yield (47.3 mg). A colorless solid: mp
1
= 115−118 °C (recrystallized from dichloromethane and hexane); H
NMR (CDCl3) δ 3.86 (3H, s), 7.00−7.19 (3H, m), 7.39 (1H, t, J = 7.9
Hz), 7.67 (1H, t, J = 7.4 Hz), 7.87 (1H, t, J = 7.6 Hz), 7.97 (1H, d, J =
8.0 Hz), 8.22 (1H, d, J = 8.6 Hz), 8.60 (1H, s); 13C NMR (100 MHz,
CDCl3) δ 55.4, 114.3, 114.8, 121.2, 122.8 (q, J = 30.9 Hz), 123.5 (q, J
= 272.7 Hz), 125.3, 127.7, 128.2, 129.0, 129.6, 132.0, 135.8 (q, J = 5.0
Hz), 140.8, 148.3, 156.9, 159.1; 19F NMR (90 MHz, CDCl3) δ 15.18
(3F, s); MS m/z 303 (M+); HRMS calcd for C17H12F3NO 303.087
(M+), found 303.087.
2-(4-Chlorophenyl)-3-(trifluoromethyl)quinoline (4f). The title
product (4f) was purified by column chromatography (AcOEt/hexane
D
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The Journal of Organic Chemistry
Article
= 1:9) and was obtained in 63% yield (38.7 mg). A colorless solid: mp
= 118−120 °C (recrystallized from dichloromethane and hexane); H
NMR (CDCl3) δ 7.44−7.63 (5H, m), 7.80 (1H, dd, J = 2.4, 8.9 Hz),
8.96 (1H, d, J = 2.2 Hz), 8.15 (1H, d, J = 8.9 Hz), 8.52 (1H, s); 13C
NMR (100 MHz, CDCl3) δ 123.4 (q, J = 272.7 Hz), 123.7 (q, J = 32.5
Hz), 125.9, 126.8, 128.0, 128.6, 128.9, 131.1, 133.0, 133.6, 134.9 (q, J
= 5.9 Hz), 139.1, 146.7, 157.4; 19F NMR (90 MHz, CDCl3) δ 17.91
(3F, s); MS m/z 307 (M+); HRMS calcd for C16H9ClF3N 307.038
(M+), found 307.038.
1
NMR (CDCl3) δ 7.47 (2H, d, J = 8.5 Hz), 7.53 (2H, d, J = 8.6 Hz),
7.68 (1H, t, J = 7.7 Hz), 7.88 (1H, t, J = 8.3 Hz), 7.97 (1H, d, J = 8.2
Hz), 8.20 (1H, d, J = 8.5 Hz), 8.61 (1H, s); 13C NMR (100 MHz,
CDCl3) δ 122.7 (q, J = 31.7 Hz), 123.6 (q, J = 271.9 Hz), 125.3, 128.0,
128.2, 129.5, 130.1, 132.2, 135.0, 136.0 (q, J = 5.0 Hz), 138.0, 148.4,
155.9; 19F NMR (90 MHz, CDCl3) δ 1818 (3F, s); MS m/z 307
(M+); HRMS calcd for C16H9ClF3N 307.038 (M+), found 307.037.
2-(3-Chlorophenyl)-3-(trifluoromethyl)quinoline (4g). The title
product (4g) was purified by column chromatography (AcOEt/
hexane = 5:95) and was obtained in 44% yield (27.0 mg). A colorless
solid: mp = 82−83 °C (recrystallized from dichloromethane and
7-Chloro-2-phenyl-3-(trifluoromethyl)quinoline (4m). The title
product (4m) was purified by column chromatography (AcOEt/
hexane = 1:9) and was obtained in 62% yield (38.1 mg). A colorless
solid: mp = 87−88 °C (recrystallized from dichloromethane and
1
hexane); H NMR (CDCl3) δ 7.47−7.59 (5H, m), 7.63 (1H, dd, J =
2.2, 8.9 Hz), 7.91 (1H, d, J = 8.5 Hz), 8.22 (1H, d, J = 1.8 Hz), 8.58
(1H, s); 13C NMR (100 MHz, CDCl3) δ 123.0 (q, J = 31.7 Hz), 123.4
(q, J = 272.6 Hz), 123.6, 128.0, 128.6, 128.6, 128.9, 128.9, 129.4, 135.7
(q, J = 5.0 Hz), 138.2, 139.1, 148.6, 158.3; 19F NMR (90 MHz,
CDCl3) δ 18.04 (3F, s); MS m/z 307 (M+); HRMS calcd for
C16H9ClF3N 307.038 (M+), found 307.038.
1
hexane); H NMR (CDCl3) δ 7.38−7.51 (3H, m), 7.59 (1H, s), 7.70
(1H, t, J = 8.0 Hz), 7.90 (1H, t, J = 8.2, Hz), 7.99 (1H, d, J = 8.0 Hz),
8.21 (1H, d, J = 8.3 Hz), 8.63 (1H, s); 13C NMR (100 MHz, CDCl3) δ
122.6 (q, J = 31.7 Hz), 123.4 (q, J = 272.6 Hz), 125.4, 126.9 (q, J = 1.7
Hz), 128.1, 128.3, 128.9, 129.0 (q, J = 1.7 Hz), 129.2, 129.5, 132.3,
134.0, 136.0 (q, J = 5.0 Hz), 141.1, 148.3, 155.5; 19F NMR (90 MHz,
CDCl3) δ 18.15 (3F, s); MS m/z 307 (M+); HRMS calcd for
C16H9ClF3N 307.038 (M+), found 307.038.
6-Chloro-2-(4-methoxyphenyl)-3-(trifluoromethyl)quinoline (4n).
The title product (4n) was purified by column chromatography
(AcOEt/hexane = 1:9) and was obtained in 80% yield (53.9 mg). A
colorless solid: mp = 127−129 °C (recrystallized from dichloro-
methane and hexane); 1H NMR (CDCl3) δ 3.88 (3H, s), 7.02 (2H, d,
J = 8.8 Hz), 7.54 (2H, d, J = 8.8 Hz), 7.79 (1H, dd, J = 2.4, 9.2 Hz),
7.94 (1H, d, J = 2.2 Hz), 8.13 (1H, d, J = 8.8 Hz), 8.50 (1H, s); 13C
NMR (100 MHz, CDCl3) δ 55.4, 113.6, 123.5 (q, J = 272.7 Hz), 123.7
(q, J = 31.7 Hz), 125.7, 126.7, 130.1, 131.0, 131.7, 132.9, 133.4, 135.0
(q, J = 5.0 Hz), 146.8, 157.1, 160.2; 19F NMR (90 MHz, CDCl3) δ
17.94 (3F, s); MS m/z 337 (M+); HRMS calcd for C17H11ClF3NO
337.048 (M+), found 337.047.
7-Chloro-2-(4-methoxyphenyl)-3-(trifluoromethyl)quinoline (4o).
The title product (4o) was purified by column chromatography
(AcOEt/hexane = 1:9) and was obtained in 76% yield (51.2 mg). A
colorless solid: mp = 113−114 °C (recrystallized from dichloro-
methane and hexane); 1H NMR (CDCl3) δ 3.88 (3H, s), 7.02 (2H, d
= 8.9 Hz), 7.54 (2H, d, J = 8.5 Hz), 7.57−7.62 (1H, m), 7.88 (1H, d, J
= 8.5 Hz), 8.19 (1H, s), 8.56 (1H, s); 13C NMR (100 MHz, CDCl3) δ
55.4, 113.6, 123.0 (q, J = 31.7 Hz), 123.5, 123.6 (q, J = 271.8 Hz),
128.5, 128.7, 129.3, 130.1 (q, d = 1.7 Hz), 131.8, 135.7 (q, J = 5.8 Hz),
138.1, 148.8, 158.0, 160.3; 19F NMR (90 MHz, CDCl3) δ 18.09 (3F,
s); MS m/z 337 (M+); HRMS calcd for C17H11ClF3NO 337.048 (M+),
found 337.047.
2-(2-Chlorophenyl)-3-(trifluoroethyl)quinoline (4h). The title
product (4h) was purified by column chromatography (hexane
100%) and was obtained in 47% yield (28.9 mg). A colorless solid:
mp = 87−89 °C (recrystallized from dichloromethane and hexane);
1H NMR (CDCl3) δ 7.33−7.46 (3H, m), 7.51 (1H, d, J = 7.3 Hz),
7.70 (1H, m), 7.89 (1H, m), 8.00 (1H, d, J = 8.2 Hz), 8.23 (1H, d, J =
8.6 Hz), 8.62 (1H, s); 13C NMR (100 MHz, CDCl3) δ 123.1 (q, J =
31.6 Hz), 123.2 (q, J = 271.8 Hz), 125.6, 126.2, 128.1, 128.3, 129.4,
129.6, 130.0, 130.2, 132.1, 133.2, 135.6 (q, J = 5.0 Hz), 137.7, 148.3,
154.6; 19F NMR (90 MHz, CDCl3) δ 15.64 (3F, s); MS m/z 307
(M+); HRMS calcd for C16H9ClF3N 307.038 (M+), found 307.037.
2-(4-Bromophenyl)-3-(trifluoromethyl)quinoline (4i). The title
product (4i) was purified by column chromatography (AcOEt/hexane
= 1:9) and was obtained in 52% yield (36.6 mg). A colorless solid: mp
1
= 113−115 °C (recrystallized from dichloromethane and hexane); H
NMR (CDCl3) δ 7.47 (2H, d, J = 8.3 Hz), 7.63 (2H, d, J = 8.5 Hz),
7.67−7.72 (1H, m), 7.86−7.92 (1H, m), 7.98 (1H, d, J = 8.3 Hz),
3275.9 (1H, J = 8.6 Hz), 8.62 (1H, s); 13C NMR (100 MHz, CDCl3) δ
122.6 (q, J = 31.7 Hz), 123.3, 123.6 (q, J = 272.7 Hz), 125.3, 128.0,
128.3, 129.5, 130.4 (q, J = 1.7 Hz), 131.2, 132.2, 136.0 (q, J = 5.8 Hz),
138.4, 148.3, 155.9; 19F NMR (90 MHz, CDCl3) δ 18.20 (3F, s); MS
m/z 352 (M+); HRMS calcd for C16H9BrF3N 350.987 (M+), found
350.988.
ASSOCIATED CONTENT
■
2-(Naphthalen-2-yl)-3-(trifluoromethyl)quinoline (4j). The title
product (4j) was purified by column chromatography (AcOEt/hexane
= 1:9) and was obtained in 50% yield (32.3 mg). A colorless solid: mp
S
* Supporting Information
1
Copies of H and 13C spectra for the new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
= 94−97 °C (recrystallized from dichloromethane and hexane); H
NMR (CDCl3) δ 7.50−7.58 (2H, m), 7.64−7.74 (2H, m), 7.84−8.03
(5H, m), 8.07 (1H, s), 8.24 (1H, d, J = 9.2 Hz), 8.65 (1H, s); 13C
NMR (100 MHz, CDCl3) δ 123.0 (q, J = 31.7 Hz), 123.7 (q, J = 272.6
Hz), 125.3, 126.3, 126.6, 127.7, 127.8, 128.2, 128.3, 128.5, 129.6,
132.0, 132.8, 133.3, 135.9 (q, J = 5.8 Hz), 137.0, 148.4, 157.1; 19F
NMR (90 MHz, CDCl3) δ 18.24 (3F, s); MS m/z 323 (M+); HRMS
calcd for C20H12F3N 323.092 (M+), found 323.092.
AUTHOR INFORMATION
Corresponding Author
*E-mail: aando@pharm.setsunan.ac.jp. Tel: +81-72-866-3140.
Fax: +81-72-850-7020.
■
Notes
2-(Furan-2-yl)-3-(trifluoromethyl)quinoline (4k). The title product
The authors declare no competing financial interest.
(4k) was purified by column chromatography (AcOEt/hexane = 1:9)
1
and was obtained in 37% yield (19.5 mg). A colorless oil; H NMR
ACKNOWLEDGMENTS
We are grateful to Central Glass Co., Ltd. and Tosoh F-Tech,
Inc. for providing trifluoroacetaldehyde ethyl hemiacetal.
(CDCl3) δ 6.61 (1H, dd, J = 1.8, 3.4 Hz), 7.25 (1H, d, J = 3.3 Hz),
7.62 (1H, t, J = 7.7 Hz), 7.70 (1H, d, J = 1.2 Hz), 7.82−7.88 (1H, m),
7.91 (1H, d, J = 8.2 Hz), 8.19 (1H, d, J = 8.5 Hz), 8.59 (1H, s); 13C
NMR (100 MHz, CDCl3) δ 111.9, 113.4 (q, J = 2.5 Hz), 120.5 (q, J =
32.5 Hz), 123.5 (q, J = 271.8 Hz), 125.0, 127.7, 128.2, 129.3, 132.1,
136.5, (q, J = 6.7 Hz), 144.6, 145.5, 148.4, 151.0; 19F NMR (90 MHz,
CDCl3) δ 15.45 (3F, s); MS m/z 263 (M+); HRMS calcd for
C14H8F3NO 263.056 (M+), found 263.056.
■
REFERENCES
■
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1
= 82−83 °C (recrystallized from dichloromethane and hexane); H
E
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Article
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