Preparation of Trifluoromethylated (Arylaminomethylene)malononitriles Suitable for Synthesis of 4-Amino-2-(trifluoromethyl) quinoline Derivatives by Intramolecular Friedel-Crafts Reaction

Article abstract of DOI:10.1055/s-0037-1609433

An approach for the synthesis of 4-amino-2-(trifluoromethyl)quinolines via the intramolecular Friedel-Crafts reaction of 2-(1-(arylamino)-2,2,2-trifluoroethylidene)malononitrile derivatives is reported. This simple protocol provides a wide variety of 4-am

Full text of DOI:10.1055/s-0037-1609433

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 50, A–G
paper
A
en
F. Rahmani, A. Darehkordi
Paper
Synthesis
Preparation of Trifluoromethylated (Arylaminomethylene)malo-
nonitriles Suitable for Synthesis of 4-Amino-2-(trifluoromethyl)
quinoline Derivatives by Intramolecular Friedel–Crafts Reaction
R1
Fariba Rahmani
Ali Darehkordi*
CN
CN
NH2
NaH
MeCN
Et3N, Ph3P
CCl4
H
R1
N
CF3
CN
NC
NC
N
CF3
AlCl3
+
+
Department of Chemistry, Faculty of Science,
Vali-e-Asr University of Rafsanjan, Rafsanjan 77176, Iran
darehkordi@vru.ac.ir
CF3
r.t.
reflux
CF3COOH
N
Cl
R1
R1
NH2
adarehkordi@yahoo.com
R1 = 4-Cl, 4-Me, 2,4-Me2, 2-F, 4-Br, 4-F, 4-OMe, 2,5-F2
8 examples
up to 92%
6 examples
up to 83%
Received: 28.12.2017
Accepted after revision: 26.02.2018
Published online: 28.03.2018
alkyl group, especially trifluoromethyl moieties, into organ-
ic molecules is very important. The progress in the field of
fluorination of organic compounds has been summarized in
numerous review articles.7
DOI: 10.1055/s-0037-1609433; Art ID: ss-2017-z0840-op
Abstract An approach for the synthesis of 4-amino-2-(trifluorometh-
yl)quinolines via the intramolecular Friedel–Crafts reaction of 2-(1-
(arylamino)-2,2,2-trifluoroethylidene)malononitrile derivatives is re-
ported. This simple protocol provides a wide variety of 4-amino-2-(tri-
fluoromethyl)quinolines in good to excellent yields, without any purifi-
cation. Furthermore, the 2-(1-(arylamino)-2,2,2-trifluoroethylidene)
malononitrile derivatives used in this project have been synthesized by
the reaction of N-aryl-2,2,2-trifluoroacetimidoyl chlorides and malono-
nitrile at ambient temperature and under microwave irradiation in ex-
cellent yields, for the first time.
The most widely applicable routes for the direct intro-
duction of a trifluoromethyl group can be mainly divided
into two categories: one involves C–F bond formation via
substitution of a functional group by fluoride, such as the
Swarts reaction.8 The scope of the Swarts reaction is limited
to robust functional groups due to the harsh reaction con-
ditions. The second category involves C–C bond formation
using commercially available trifluoromethyl-substituted
compounds.9 This category can be further divided into
three classes, namely radical, electrophilic, and nucleophilic
trifluoromethylations, that have been summarized in many
review articles.6b,10 The synthesis of the required reagents
also involves the use of highly expensive iodide precursors.
Furthermore, nucleophilic trifluoromethylation reactions
still suffer from the limited availability of inexpensive and
low-molecular-weight trifluoromethyl sources.
Still, the development of efficient methods for the late-
stage trifluoromethylation of organic molecules is of high
interest for synthetic and large-scale industrial applica-
tions. For example, the use of trifluoroacetic acid and its an-
hydride (TFAA) in trifluoromethylation reactions was re-
cently reported.11 Also, in recent times, diverse methods for
the preparation of fluoroalkylated heterocycles, based on
exploration of fluorinated 1,3-dipoles such as nitrones,12a
nitrile imines,12b and nitrile oxides,12c have been reported.
In addition to the above-mentioned methods, commer-
cially available, trifluoromethyl-containing starting materi-
als can be used for the synthesis of trifluoromethylated
compounds. They should contain potential functional
groups usable for further reactions in order to achieve mo-
lecular modification. On this basis, trifluoroacetimidoyl
chlorides are unique reagents for the synthesis of trifluoro-
Key words 4-amino-2-(trifluoromethyl)quinolones,
Friedel–Crafts reaction, trifluoromethylated
intramolecular
(arylaminomethy-
lene)malononitriles, trifluoroacetimidoyl chlorides, trifluoromethylated
compounds
Quinolines are one of the most important classes of or-
ganic compounds for chemists, as well as biologists, be-
cause they are potent, broad-spectrum antibacterial agents
and have a favorable pharmacokinetic profile.1 Quinoline
derivatives have been found useful in diverse applications
including pharmaceuticals and are available as drugs today.
For example, they are used as antimalarial drugs (quinine, qui-
nidine, chloroquine, mefloquine, amodiaquine, primaquine).2,3
Ciprofloxacin, levofloxacin, gatifloxacin, and norfloxa-
cin are some known fluoroquinolone antibiotic drugs that
have been successfully synthesized and widely used in the
clinic. Due to its steric and electronic properties, fluorine
can alter the physical and chemical properties of molecules,
such as bioavailability, lipophilicity, and metabolic stability,
which play a crucial role in drugs, functional materials, and
reagents.4 In order to synthesize compounds with applica-
tions in agrochemistry, the pharmaceutical industry, and
materials science,5,6 the direct incorporation of a polyfluoro-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 50, A–G

B
F. Rahmani, A. Darehkordi
Paper
Synthesis
methylated compounds due to following advantages: easy
synthesis with high yields, relatively stable upon storage,
and containing highly potential functional groups.13 Tri-
fluoroacetimidoyl chlorides were described for the first
time in 1994 and were applied in the electrochemically
performed synthesis of 2-(trifluoromethyl)-3H-indole de-
rivatives.14
CN
CN
H
N
NC
NC
CF3
Cl
NaH, MeCN
r.t.
+
N
CF3
R1
R1
1a–h
2a–h
Scheme 2 Synthesis of 2-(1-(arylamino)-2,2,2-trifluoroethylidene)-
malononitrile derivatives 2a–h
In recent decades, research efforts on trifluoroacetimi-
doyl chlorides have led to the synthesis of different trifluo-
romethylated heterocycles.15–17 Earlier, we have reported
the synthesis of trifluoromethylated tetrazoles and pyrroles
by using trifluoroacetimidoyl chlorides. As an extension of
our results,18,19 we decided to investigate whether this
method could be employed for the synthesis of trifluoro-
methylated quinolines. Uneyama’s group in Japan have
shown the utility of trifluoroacetimidoyl chlorides in the
synthesis of 1-unsubstituted 2-trifluoromethylated quino-
lones.20 Also recently, the synthesis of fluorinated com-
pounds via the Friedel–Crafts reaction was reported.21
In this project, at first, we synthesized the 2-(1-(aryl-
amino)-2,2,2-trifluoroethylidene)malononitrile derivatives
2a–h by the reaction of trifluoroacetimidoyl chlorides 1
with malononitrile in the presence of sodium hydride (Ta-
ble 1). Then, compounds 2 were subjected to cyclization
with AlCl3 under solvent-free conditions to obtain 4-ami-
no-2-(trifluoromethyl)quinolines 3a–f (Table 2), in good to
excellent yields. This simple, two-step procedure shows the
use of anilines and trifluoroacetimidoyl chlorides as build-
ing blocks for the construction of trifluoromethylated het-
erocycles (Scheme 1).
In order to reduce reaction time and enhance the yields,
we also sought to carry out the reaction under microwave
irradiation. As shown in Table 1, it was found that this
method could reduce reaction times, and also gave higher
product yields and a more convenient operation. A wide
range of substrates, and both electron-withdrawing and
electron-releasing substituents, could be accommodated
without significant differences in reaction time or yield (Ta-
ble 1). The pure products can be obtained simply by wash-
ing with n-hexane, without use of the traditional purifica-
tions by chromatography or recrystallization. The structure
1
of products 2 was confirmed by IR, H NMR, and 13C NMR
spectroscopy, mass spectrometry, elemental analysis, and
X-ray crystal structure analysis. For some derivatives, the
1
NH proton was not observed in the H NMR spectrum due
to the tautomeric equilibrium of NH–C=C.
R1
Et3N, Ph3P, CCl4
NH2
CF3COOH
+
reflux
NC
NC
NaH, MeCN
CF3
+
r.t.
N
Cl
R1
1a–h
Figure 1 X-ray crystal structure of 2a
CN
CN
CF3
CN
R1
N
H
N
AlCl3
In a continuation of this work, we investigated the intra-
molecular Friedel–Crafts cyclization reaction for the syn-
thesis of 4-amino-2-(trifluoromethyl)quinoline derivatives.
In a typical procedure, 2-{1-[(4-chlorophenyl)amino]-2,2,2-
trifluoroethylidene}malononitrile (2a) and AlCl3, under sol-
vent-free conditions, was heated at 140 °C for 2 hours;
then, the mixture was cooled and poured into ice–water.
The crude product was collected by filtration, washed with
water, and dried to give 3a in 95% yield (Scheme 3).
The substrate scope for the cyclization step was then in-
vestigated, and the results are summarized in Table 2. We
tested derivative 2b with an electron-donating methyl group
and also derivatives with electron-withdrawing groups such
CF3
R1
NH2
2a–h
3a–f
Scheme 1 Synthesis of 4-amino-2-(trifluoromethyl)quinoline derivatives
N-Aryl-2,2,2-trifluoroacetimidoyl chlorides 1a–h were
reacted with malononitrile in acetonitrile and in the pres-
ence of sodium hydride at ambient temperature, which
produced the corresponding 2-(1-(arylamino)-2,2,2-triflu-
oroethylidene)malononitrile derivatives 2a–h in high yields
(Scheme 2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 50, A–G

C
F. Rahmani, A. Darehkordi
Paper
Synthesis
Table 1 Synthesis of 2-(1-(Arylamino)-2,2,2-trifluoroethylidene)malononitrile Derivatives 2a–h
CF3
CF3
Cl
NaH
NC
NC
CN
CH2
+
R1
N
R1
N
MeCN
H
CN
R1
Product
At room temperature
Under microwave conditions
Melting point (°C)
Time (h)
Isolated yield Microwave irradiation time
Isolated yield
(%)
(%)
84
(min)
30
4-Cl
2a
16
95
190–192
CN
H
N
CN
CF3
Cl
4-Me
2,4-Me2
2-F
2b
2c
2d
16
16
16
78
76
78
30
30
30
92
90
95
144–145
115–116
135–136
CN
H
N
CN
CF3
Me
Me
Me
CN
H
N
CN
CF3
F
CN
H
N
CN
CF3
4-Br
2e
2f
16
16
16
16
69
68
71
75
30
30
30
30
94
97
96
93
177–180
CN
H
N
CN
CF3
Br
4-F
160–162
CN
H
N
CN
CF3
F
4-OMe
2,5-F2
2g
2h
143–146 (142–143)14
CN
H
N
CN
CF3
MeO
F
121–123
CN
H
N
CN
CF3
F
X-ray crystallographic analysis revealed the structure of compound 2a as depicted in Figure 1.22
as the chloro and fluoro group. The reaction of these sub-
strates afforded the final products in good to high yields.
N
CF3
CN
CF3
AlCl3
solvent-free, 140 °C
CN
The structure of compounds 3 was deduced from their
N
Cl
Cl
H
IR, 1H NMR, and 13C NMR spectra. For example, the 1H NMR
CN
NH2
spectrum of 3a showed a broad singlet signal for NH2 at
8.49 ppm, and two doublet signals at 8.68 and 7.99 ppm
and a multiplet signal at 7.95–7.92 ppm for aromatic pro-
tons. The decoupled 13C NMR spectrum of 3a showed 11
2a
3a
Scheme 3 Synthesis of 4-amino-6-chloro-2-(trifluoromethyl)quino-
line-3-carbonitrile (3a)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 50, A–G

D
F. Rahmani, A. Darehkordi
Paper
Synthesis
Table 2 Synthesis of 4-Amino-2-(trifluoromethyl)quinoline Deriva-
tives 3a–fa
distinct resonances, in agreement with the proposed struc-
ture. The IR spectrum of 3a displayed characteristic CN and
NH2 vibrations at 2218 and 3365 cm–1, respectively.
A possible mechanism for this two-step reaction is pro-
posed in Scheme 4.
In conclusion, we have successfully designed and syn-
thesized a new series of quinoline derivatives which con-
tain a trifluoromethyl group at the 2-position in good to ex-
cellent yields via the intramolecular Friedel–Crafts reaction
N
CF3
CN
CF3
AlCl3
R1
CN
N
140 °C
R1
H
CN
NH2
R1
Product
Isolated
yield (%)
Melting point
(°C)
of
2-(1-(arylamino)-2,2,2-trifluoroethylidene)malononi-
4-Cl
3a
95
226–229
N
CF3
CN
trile derivatives. These intermediates were synthesized
from N-aryl-2,2,2-trifluoroacetimidoyl chlorides and malo-
nonitrile in excellent yields. This method constitutes a fac-
ile, easy workup, and inexpensive route to obtain 4-amino-
2-(trifluoromethyl)quinolines which are of great impor-
tance in medicinal chemistry.
Cl
NH2
N
4-Me
2-F
3b
3c
93
96
195–197
290
CF3
CN
Me
NH2
F
All chemicals and solvents were purchased from commercial sources
and used without further purification unless otherwise stated. Melt-
ing points were determined with a Barnstead electrothermal and are
uncorrected. IR spectra were obtained on a Mattson-1000 FT-IR spec-
trophotometer. Peaks are reported in wavenumbers (cm–1). NMR
spectra were recorded on a Bruker DRX-400 Avance (1H: 400 MHz,
13C: 100 MHz, 19F: 375 MHz) or a Varian (1H: 500 MHz, 13C: 125 MHz)
N
CF3
CN
NH2
4-Br
4-F
3d
3e
91
95
83
201–204
168–170
158–160
N
CF3
CN
NMR spectrometer. Chemical shifts for H and 13C NMR are reported
1
in parts per million from TMS as an internal standard and for 19F NMR
in parts per million from CFCl3 as an internal standard, in DMSO-d6 as
a solvent. GC-EIMS analyses were carried out by using a Hewlett-
Packard HP 6890N Network GC system/5975 Mass Selective Detector
equipped with an electron impact ionizer at 70 eV.
Br
NH2
N
CF3
F
CN
NH2
2-[1-(Arylamino)-2,2,2-trifluoroethylidene]malononitrile Deriva-
tives 2a–h; General Procedures
2,5-F2 3f
F
F
N
CF3
A: At Room Temperature
A mixture of a trifluoroacetimidoyl chloride 1 (1 mmol), malononi-
trile (1 mmol), NaH (1 mmol), and acetonitrile (5 mL) was stirred at
room temperature for 16 h; after completion of the reaction, as indi-
cated by TLC, the reaction mixture was filtered. After removal of the
CN
NH2
a The R1 substituent numbering refers to the starting material 2.
CN
R1
N
N
CF3
N
N
C
C
CN
C
C
R1
NaH, MeCN
r.t.
Cl
CH2
CH
CF3
N
–
R1
NH
CF3
NC
N
N
AlCl3
R1
R1
Cl3Al
R1
N
1,3-H
shift
HN
NC
H2N
N
H
N
NC
N
NC
CF3
CF3
CF3
Scheme 4 Possible mechanism for the synthesis of 4-amino-2-(trifluoromethyl)quinolines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 50, A–G

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F. Rahmani, A. Darehkordi
Paper
Synthesis
solvent under reduced pressure, if necessary the crude product was
purified by washing with n-hexane.
2-{2,2,2-Trifluoro-1-[(2-fluorophenyl)amino]ethylidene}malono-
nitrile (2d)
Prepared according to General Procedure A and B; yield: 242 mg
(95%); mp 135–136 °C.
B: Under Microwave Conditions
IR (KBr): 3216, 2230, 2227 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 7.51–7.44 (m, 2 H), 7.39 (t, J = 9 Hz,
1 H), 7.30 (t, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 157.32 (d, J = 252 Hz, C–F), 154.22
(q, J = 35 Hz, C–CF3), 131.72, 125.48, 125.45, 119.49 (q, J = 279 Hz,
CF3), 116.54, 113.86, 111.79.
.
A mixture of trifluoroacetimidoyl chloride (1 mmol), malononitrile (1
mmol), NaH (1 mmol), and acetonitrile (3 mL) was irradiated in a mi-
crowave oven at 400 W for 30 min; after completion of the reaction,
as indicated by TLC, the reaction mixture was filtered. After removal
of the solvent under reduced pressure, if necessary the crude product
was purified by washing with n-hexane.
Anal. Calcd for C11H5F4N3: C, 51.78; H, 1.98; N, 16.47. Found: C, 51.67;
H, 1.92; N, 16.34.
2-{1-[(4-Chlorophenyl)amino]-2,2,2-trifluoroethylidene}malono-
nitrile (2a)
Prepared according to General Procedure A and B; yield: 257 mg
(95%); mp 190–192 °C.
2-{1-[(4-Bromophenyl)amino]-2,2,2-trifluoroethylidene}malono-
nitrile (2e)
IR (KBr): 3225, 2231, 2225 cm–1
.
Prepared according to General Procedure A and B; yield: 297 mg
(94%); mp 177–180 °C.
1H NMR (400 MHz, DMSO-d6): δ = 11.25 (s, 1 H, NH), 7.51 (d, J = 6.0
Hz, 2 H), 7.43 (d, J = 6.0 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 153.91 (q, J = 32 Hz, C–CF3),
134.74, 133.51, 129.38, 128.47, 119.46 (q, J = 278 Hz, CF3).
19F NMR (375 MHz, DMSO-d6): δ = –65.63.
GC-EIMS: m/z (%) = 273 (34), 272 (15), 271 (100) [M+], 175 (16), 11
IR (KBr): 3228, 2229, 2216 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 7.65 (d, J = 10 Hz, 2 H), 7.37 (d,
J = 10 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 153.7 (q, J = 36 Hz, C–CF3), 135.64,
132.86, 132.39, 128.64, 121.82, 119.59 (q, J = 278 Hz, CF3).
(24).
Anal. Calcd for C11H5BrF3N3: C, 41.80; H, 1.59; N, 13.29. Found: C,
41.75; H, 1.56; N, 13.16.
Anal. Calcd for C11H5ClF3N3: C, 48.64; H, 1.86; N, 15.47. Found: C,
48.54; H, 1.73; N, 15.55.
2-{2,2,2-Trifluoro-1-[(4-fluorophenyl)amino]ethylidene}malono-
nitrile (2f)
2-[2,2,2-Trifluoro-1-(p-tolylamino)ethylidene]malononitrile (2b)
Prepared according to General Procedure A and B; yield: 230 mg
(92%); mp 144–145 °C.
Prepared according to General Procedure A and B; yield: 247 mg
(97%); mp 160–162 °C.
IR (KBr): 3233, 2222, 2216 cm–1
.
IR (KBr): 3225, 2231, 2216 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.31 (s, 1 H, NH), 7.26–7.21 (m, 4
H), 2.31 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 138.07, 129.77, 125.87, 116.02,
114.83, 21.12.
1H NMR (500 MHz, DMSO-d6): δ = 7.34 (dd, J = 5, 8 Hz, 2 H), 7.24 (t,
J = 9 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 161.66 (d, J = 242 Hz, C–F), 153.92
(q, J = 32 Hz, C–CF3), 134.71 (d, J = 88 Hz), 128.01, 119.80 (q, J = 278
Hz, CF3), 116.13 (d, J = 22 Hz), 114.90, 114.59.
19F NMR (375 MHz, DMSO-d6): δ = –66.28.
GC-EIMS: m/z (%) = 252 (15), 251 (100) [M+], 232 (11), 231 (57), 230
(11), 155 (17).
Anal. Calcd for C11H5F4N3: C, 51.78; H, 1.98; N, 16.47. Found: C, 51.68;
H, 1.93; N, 16.42.
Anal. Calcd for C12H8F3N3: C, 57.37; H, 3.21; N, 16.73. Found: C, 57.24;
H, 3.32; N, 16.54.
2-{2,2,2-Trifluoro-1-[(4-methoxyphenyl)amino]ethylidene}malo-
nonitrile (2g)
2-{1-[(2,4-Dimethylphenyl)amino]-2,2,2-trifluoroe-
thylidene}malononitrile (2c)
Prepared according to General Procedure A and B; yield: 256 mg
(96%); mp 143–146 °C (Lit.14 142–143 °C).
IR (KBr): 3225, 2226, 2217 cm–1
1H NMR (500 MHz, DMSO-d6): δ = 11.33 (br s, 1 H, NH), 7.34 (d, J = 9
Hz, 2 H), 7.00 (d, J = 9 Hz, 2 H), 3.79 (s, 3 H, OMe).
.
Prepared according to General Procedure A and B; yield: 238 mg
(90%); mp 115–116 °C.
IR (KBr): 3438, 2210, 2198 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 6.79 (s, 1 H), 6.76 (d, J = 7.8 Hz, 1
H), 6.42 (d, J = 7.7 Hz, 1 H), 2.16 (s, 3 H, Me), 1.92 (s, 3 H, Me).
13C NMR (125 MHz, DMSO-d6): δ = 160.02, 154.34 (q, J = 32 Hz, C–
CF3), 128.41, 128.13, 123.14, 119.60 (q, J = 278 Hz, CF3), 114.62, 55.89.
13C NMR (100 MHz, DMSO-d6): δ = 131.02, 130.29, 127.34, 126.41,
120.68, 119.59, 20.91, 17.57.
Anal. Calcd for C12H8F3N3O: C, 53.94; H, 3.02; N, 15.73. Found: C,
53.87; H, 2.95; N, 15.75.
19F NMR (375 MHz, DMSO-d6): δ = –68.08.
2-{1-[(2,5-Difluorophenyl)amino]-2,2,2-trifluoroe-
thylidene}malononitrile (2h)
GC-EIMS: m/z (%) = 266 (16), 265 (100) [M+], 264 (14), 200 (39), 196
(31), 131 (18).
Prepared according to General Procedure A and B; yield: 253 mg
(93%); mp 121–123 °C.
Anal. Calcd for C13H10F3N3: C, 58.87; H, 3.80; N, 15.84. Found: C, 58.67;
H, 3.85; N, 15.78.
IR (KBr): 3227, 2207, 2203 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 50, A–G

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F. Rahmani, A. Darehkordi
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Synthesis
1H NMR (500 MHz, DMSO-d6): δ = 8.80 (br s, 1 H, NH), 7.11–7.06 (m, 1
H), 6.81–6.77 (m, 1 H), 6.52–6.47 (m, 1 H).
1H NMR (500 MHz, DMSO-d6): δ = 8.79 (d, J = 4 Hz, 1 H), 8.28 (br s, 2
H, NH2), 7.99 (dd, J = 4, 8 Hz, 1 H), 7.85 (d, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 168.73, 158.69 (d, J = 237 Hz, C–F),
149.32 (d, J = 233 Hz, C–F), 144.46 (q, J = 35 Hz, C–CF3), 140.94,
131.94, 129.26, 116.79 (q, J = 273 Hz, CF3), 109.99, 106.52.
13C NMR (125 MHz, DMSO-d6): δ = 157.74, 155.57, 148.66, 143.64,
136.48, 132.57, 126.02, 121.58, 118.63, 115.35, 80.96 (CN).
Anal. Calcd for C11H5BrF3N3: C, 41.80; H, 1.59; N, 13.29. Found: C,
41.68; H, 1.95; N, 13.52.
Anal. Calcd for C11H4F5N3: C, 48.37; H, 1.48; N, 15.38. Found: C: 48.16,
H: 1.39, N: 15.45%.
4-Amino-6-fluoro-2-(trifluoromethyl)quinoline-3-carbonitrile
(3e)
4-Amino-2-(trifluoromethyl)quinoline Derivatives 3a–f; General
Procedure
Yield: 242 mg (95%); mp 168–170 °C.
A mixture of a 2-[1-(arylamino)-2,2,2-trifluoroethylidene]malononi-
trile 2 (1 mmol) and AlCl3 (4 mmol) was heated at 140 °C for 2 h, then
cooled and poured into ice–water. The crude product was collected by
filtration, washed with water, and dried under vacuum at room tem-
perature to yield the pure product.
IR (KBr): 3362, 3257, 2221 cm–1
1H NMR (500 MHz, DMSO-d6): δ = 8.34–8.30 (m, 1 H), 8.20 (br s, 2 H,
.
NH2), 8.01–7.97 (m, 1 H), 7.79–7.74 (m, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 161.34 (q, J = 67 Hz), 161.13 (d, J =
245 Hz, C–F), 157.31, 146.45 (q, J = 32 Hz, C–CF3), 143.38, 133.30 (d,
J = 8 Hz), 121.18 (q, J = 275 Hz, CF3), 118.73, 114.62, 108.27 (d, J = 25
Hz), 80.67 (CN).
4-Amino-6-chloro-2-(trifluoromethyl)quinoline-3-carbonitrile
(3a)
Anal. Calcd for C11H5F4N3: C, 51.78; H, 1.98; N, 16.47. Found: C, 51.69;
H, 1.95; N, 16.52.
Yield: 257 mg (95%); mp 226–229 °C.
IR (KBr): 3365, 3255, 2218 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.68 (d, 4J = 2.4 Hz, 1 H), 8.49 (br s,
2 H, NH2), 7.99 (d, J = 8 Hz, 1 H), 7.95–7.92 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 156.93, 147.21 (q, J = 43 Hz, C–
CF3), 144.80, 133.67, 133.07, 132.25, 122.92, 121.10 (q, J = 274 Hz,
CF3), 118.63, 114.52, 81.12 (CN).
4-Amino-5,8-difluoro-2-(trifluoromethyl)quinoline-3-carboni-
trile (3f)
Yield: 226 mg (83%); mp 158–160 °C.
IR (KBr): 3443, 3331, 2208 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 7.00–6.96 (m, 1 H), 6.56 (dd,
J = 11.2, 7.5 Hz, 1 H), 5.35 (br s, 2 H, NH2).
13C NMR (125 MHz, DMSO-d6): δ = 161.43, 156.10 (d, J = 240 Hz, C–F),
147.01 (d, J = 232 Hz, C–F), 137.75 (q, J = 35 Hz, C–CF3), 121.15 (q, J =
270 Hz, CF3), 117.11, 116.94, 109.06, 102.66, 102.47, 83.55 (CN).
Anal. Calcd for C11H5ClF3N3: C, 48.64; H, 1.86; N, 15.47. Found: C,
48.53; H, 1.78; N, 15.45.
4-Amino-6-methyl-2-(trifluoromethyl)quinoline-3-carbonitrile
(3b)
Anal. Calcd for C11H4F5N3: C, 48.37; H, 1.48; N, 15.38. Found: C, 48.25;
H, 1.38; N, 15.29.
Yield: 233 mg (93%); mp 195–197 °C.
IR (KBr): 3474, 3372, 2209 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.33 (s, 1 H), 8.14 (br s, 2 H, NH2),
7.88–7.72 (m, 2 H), 2.5 (s, 3 H, overlap with DMSO).
Funding Information
13C NMR (100 MHz, DMSO-d6): δ = 158.06, 157.20, 154.25, 146.00 (q,
J = 32 Hz, C–CF3), 142.95, 138.39, 135.15, 130.21, 122.56, 116.24 (q,
J = 243 Hz, CF3), 79.98 (CN), 21.71 (Me).
We gratefully acknowledge the Vali-e-Asr University of Rafsanjan Fac-
ulty Research Grant for financial support.
)(
Anal. Calcd for C12H8F3N3: C, 57.37; H, 3.21; N, 16.73. Found: C, 57.25;
H, 3.19; N, 16.67.
Supporting Information
4-Amino-8-fluoro-2-(trifluoromethyl)quinoline-3-carbonitrile
(3c)
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609433.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Yield: 244 mg (96%); mp 290 °C.
IR (KBr): 3444, 3370, 2222 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 8.55 (br s, 2 H, NH2), 8.33 (d, J = 8
.
References
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13C NMR (100 MHz, DMSO-d6): δ = 158.01 (d, J = 253 Hz, C–F), 157.47,
147.18 (q, J = 43 Hz, C–CF3), 136.24, 128.64, 121.10 (q, J = 275 Hz, CF3),
119.54, 119.50, 118.17, 114.58, 81.31 (CN).
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H, 1.94; N, 16.23.
4-Amino-6-bromo-2-(trifluoromethyl)quinoline-3-carbonitrile
(3d)
Yield: 287 mg (91%); mp 201–204 °C.
IR (KBr): 3370, 3243, 2217 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 50, A–G

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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 50, A–G