Synthesis of highly substituted 2-perfluoroalkyl quinolines by electrophilic iodocyclization of perfluoroalkyl propargyl imines/amines

Article abstract of DOI:10.1039/b815398a

A series of highly substituted 2-perfluoroalkyl-3-iodoquinolines are prepared by two different methods in good to excellent yields under mild reaction conditions. The first method involves iodocyclization of perfluoroalkyl propargyl imines with I₂

Full text of DOI:10.1039/b815398a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of highly substituted 2-perfluoroalkyl quinolines by electrophilic
iodocyclization of perfluoroalkyl propargyl imines/amines†
Pravin R. Likhar,*a Madavu Salian Subhas,a Sarabindu Roy,a Mannepalli Lakshmi Kantam,a
Balasubramanian Sridhar,b Ratanesh Kumar Sethc and Sukla Biswasc
Received 9th September 2008, Accepted 15th October 2008
First published as an Advance Article on the web 10th November 2008
DOI: 10.1039/b815398a
A series of highly substituted 2-perfluoroalkyl-3-iodoquinolines are prepared by two different methods
in good to excellent yields under mild reaction conditions. The first method involves iodocyclization of
perfluoroalkyl propargyl imines with I2-CAN. The second method involves iodocyclization of
perfluoroalkyl propargyl amines using I2 and ICl. The perfluoroalkyl propargyl amines are prepared in
excellent yields via Sonogashira coupling of easily accessible imidoyl iodides with alkynes followed by
reduction with NaBH3CN. The scope of this methodology is extended by using the resulting
2-perfluoroalkyl-3-iodo quinolines in Suzuki, annulation, dehalogenation and carboxylation
reactions. Antimalarial activity of the 2-perfluoroalkyl-3-iodoquinolines is discussed.
protocol does not provide access to 3- or 4- substituted 2-
Introduction
perfluoroalkylquinolines. In 2001, Amii et al. reported one-pot
Recently, fluorinated compounds have attracted considerable
synthesis of highly substituted fluorinated quinolines by Rh(I)-
attention from the synthetic and medicinal chemists due to the
catalyzed cyclization of N-aryl trifluoroacetimidoyl chlorides
using alkynes.11 Unfortunately this procedure suffered from poor
regioselectivity when unsymmetrical internal alkynes were used.
Consequently, the development of an efficient and selective
synthesis of 2-perfluoroalkyl substituted quinolines using mild
reaction conditions remains an active research area.
The synthesis of carbocycles and heterocycles can be achieved
through cyclization of aryl-substituted alkynes via intramolec-
ular hydroarylation. Recently, the electrophilic cyclization of
functionalized alkenes and alkynes has received considerable
attention by organic chemists for synthesizing furans, quino-
lines, benzo[b]furans, benzothiophenes, indoles, isoquinolines
and furopyridines etc.12 Such work provides encouragement for
the synthesis of 2-perfluoroalkyl quinolines via an electrophilic
iodocyclization reaction.
unique physical and biological properties imparted by fluorine.
Substitution of an aromatic hydrogen atom by a perfluoroalkyl
group has a substantial effect on these characteristics.1 In par-
ticular, trifluoromethylated quinolines have been found to possess
special biological properties.2–5 For example, 2-trifluoromethylated
quinolines are of significant pharmacological interest for their use
as potent antimalarial agents (mefloquine),2 PDE4 inhibitors,3
DPP-IV inhibitors,4 and leishmanicidal agents.5
In view of the importance of fluorine-containing quinoline
compounds, considerable effort has been placed in developing an
efficient method for the synthesis of trifluoromethylated quinoline
derivatives. The usual synthetic methods for the introduction of
a CF3 group into aromatic systems have been fluorination of a
suitable functional group6 (i.e. halogen exchange of –CCl3, –CBr3),
fluorination of –CO2H7 upon treatment with a fluorinated Lewis
acid (SbF3, SbF5, SF4, etc.) or by Ullmann-type reaction of per-
fluoroalkyl iodides and aryl halides using copper powder.8 Many
other methods are known for the synthesis of 2-perfluoroalkyl-
subsituted quinolines but many such methodologies afford the
products in low yields.9
Results and discussion
It is assumed that 2-perfluoroalkyl quinolines can be synthesized
by electrophilic cyclization of 2-perfluoroalkynyl imines as shown
in Scheme 1. Accordingly, the 2-perfluoroalkynyl imine (3b) was
synthesized via Sonogashira coupling13,14 of imidoyl iodide (1b)15
and phenylacetylene (2b) (Scheme 2).
Baraznenok et al.10 have reported an elegant high yielding
synthesis of 2-perfluroalkyl substituted quinolines from anilines
and 4-dimethylamino-1,1,1-trifluoro-3-buten-2-one. However this
In an attempt to cyclize the imine product, 3b was treated with
I2 (2.0 equiv) and NaHCO3 (2.0 equiv) in acetonitrile at room
temperature. Only a trace amount of the product, 5b was obtained
(Table 1, entry 1). When a strong eletrophile, ICl was employed,
the product was isolated in 10% yield (entry 2).
After recent success in iodocyclization of the (2-methoxyaryl)-
system,16 the iodocyclization of 3b (0.5 mmol) was examined,
using I2 (2.0 mmol)-CAN (1.0 mmol) in 0.1 M CH3CN at room
temperature. Product 5b was obtained in 65% isolated yield
(entry 3). Subsequently, conditions for optimization of I2 and
CAN to afford maximum product yield were tested (Table 1). The
aInorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology, Uppal Road, Tarnaka, Hyderabad, 500670, India. E-mail:
plikhar@iict.res.in; Fax: +91-40-27160921
bX-Ray Crystallography Division, Indian Institute of Chemical Technology,
Uppal Road, Tarnaka, Hyderabad, 500670, India
cNational Institute of Malaria Research (ICMR), 22 Shamnath Marg,
Delhi, 110 054, India
† Electronic supplementary information (ESI) available: Characterization
of the compounds, spectral data and antimalarial study data. CCDC
reference numbers 696932 and 696933. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/b815398a
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Table 2 Iodocyclization of perfluoroalkyl propargyl iminesa
Entry
1
3
Time (h)
3
5
Isolated yields (%)
86
5a
2
3
4
5
6
3
5b
5c
5d
5e
5f
85
0
24
3
Scheme 1 Retrosynthetic approach for synthesis of 2-perfluoroalkyl-sub-
stituted quinolines.
82
83
86
4
Scheme 2 Synthesis of 2-perfluoroalkynyl imines using coupling of
imidoyl iodide and phenylacetylene.
Table 1 Optimization of I2, ICl, and I2/CAN in the iodocyclization of
3ba
2
7
3
5g
78
Entry
I+ (equiv)
CAN (equiv)
Time (h)
Yield (%)b
1
2
3
4
5
6
I2 (2.0)
ICl (2.0)
I2 (2.0)
I2 (2.0)
I2 (3.0)
I2 (1.0)
0
0
1.0
2.0
2.0
2.0
24
24
5
2
3
Trace c
10d
65
85
85
8
9
4
5h
5i
5j
75
81
86b
5
53
a Reaction condition: 0.5 mmol of 3b, I2 and CAN in 0.1M of CH3CN at
room temp. b Yield of isolated product, 5b. c 2 equiv of NaHCO3 was used.
d 2 equiv of NaHCO3 in 0.1M CH2Cl2 was used.
4
highest yield (85%) was obtained with 2 equiv of I2 and 2 equiv of
CAN in 0.1 M CH3CN at room temperature (entry 4).
10
12
To investigate the scope of the reaction, the effect of various
R1 groups on the aniline moiety were examined. The electron-
donating methyl group afforded corresponding quinoline in 86%
yield, while the strongly electron-withdrawing fluorine failed to
afford the product (Table 2, entries 1 and 3). The unsubstituted
aniline and naphthylamine provided good product yields (entries
4 and 5). The effect of various substitutents on the alkyne moiety
was then examined. The substituted aromatic alkynes underwent
smooth iodocyclization to afford the corresponding quinolines in
a Reaction conditions: 0.5 mmol of 3, I2 (2 equiv) and CAN (2 equiv) in
5 mL of CH3CN at room temp. b I2 (3 equiv) and CAN (2 equiv) were
employed.
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Table 3 Electrophilic ipso iodocyclization of para-methoxy-substituted
the activated triple bond results in the formation of perfluoroalkyl
quinolines 5 (Scheme 3).
perfluoroalkyl propargyl iminesa
R3
Time (h)
6
% Yieldb
Scheme 3 Plausible mechanism for the formation of compound 5
(Table 2).
Entry
3
1
2
3
4
3k
3l
3k
3l
H
p-MeO
H
0.5
0.5
24
6a
6b
6a
6b
92
90
In the case of para-methoxy substituted aniline, the formation
of the azaspiro compound can be explained similarly to above
where the iodonium intermediate A is generated in the first step.
The intermediate A can in turn undergo intramolecular ipso-
cyclization with the electron rich aromatic ring. The removal of the
methyl group via nucleophilic displacement results into formation
of compound 617(Scheme 4).
78c
80c
p-MeO
24
a Reaction conditions: 0.5 mmol of 3, 2 equiv of I2 and 2 equiv of CAN in
0.1 M CH3CN at room temp. b Isolated yields. c 2 equiv of I2 and 2 equiv
of NaHCO3 in 0.1 M CH3CN at room temp.
excellent yields (entries 6, 7 and 8). The olefin-substituted
alkyne gave the desired product with 81% yield (entry 9). A good
yield was observed when the perfluoroalkyl chain was changed
from CF3 to C4F9 (entry 10).
Surprisingly, when para-substituted methoxy perfluoroalkyl
propargyl imine 3k was subjected to iodocyclization, only the
azaspiro compound 6a was obtained in 92% and in 0.5h instead of
the desired quinoline product, 5k (Table 3, entry 1).17 Similarly, 6b
was obtained in 90% yield from 3l (entry 2). As an alternative, it
was also found that I2/NaHCO3 was effective for the synthesis of
azaspiro compound, however the reaction was more sluggish than
the I2-CAN system (entries 3 and 4). The structure of the azaspiro
compound 6a was confirmed by 1H NMR, 13C NMR, HRMS and
by single-crystal X-ray diffraction study (Fig. 1).18
Scheme 4 Plausible mechanism for the formation of compound 6
(Table 3).
To potentially overcome the limitations of I2/CAN system
in the above iodocyclization process, the iodocyclization of
perfluoroalkyl propargyl amines, a reduction product of perflu-
oroalkyl propargyl imines was examined. Thus 2-trifluoromethyl-
substituted propargyl imine 3k was treated with NaBH3CN
in acetic acid at 0 ◦C to afford 2-trifluoromethyl-substituted
propargyl amine, 4k in quantitative yields (Scheme 5).
Scheme 5 Reduction of 2-trifluoromethyl-substituted propargyl imine,
3k to 2-trifluoromethyl-substituted propargyl amine 4k.
The potentially useful trifluoro propargyl amines were prepared
by the addition of acetylenes to trifluoro methyl iminium ions,
generated from the corresponding oxazolidines20 or aminal21 in
the presence of Lewis acid. Recently, another preparation has been
reported which describes addition of acetylides to trifluoromethyl
aldimines.22 However, to the best of the authors’ knowledge, the
synthesis of perfluoroalkyl propargyl amines by the reduction
of perfluoroalkyl propargyl imines prepared from Sonogashira
coupling reaction of easily accessible corresponding imidoyl
iodides and alkynes has not yet been reported.
Fig. 1 ORTEP diagram of compound 6a (see Table 3).
The observed results can be plausibly explained by electrophilic
attack of the iodine cation which is generated in situ by activating
with CAN, on the carbon-carbon triple bond of the propargylic
aniline to give the iodonium intermediate A. It is believed that
CAN acts as an efficient and convenient activator for I2 and
during the activation process, reduces Ce(IV) to Ce(III).19 The
intramolecular ortho cyclization of the aniline aromatic ring with
Next, 4k was treated with 3 equiv. of iodine in the presence of
2 equiv. of NaHCO3 in 0.1 M acetonitrile and 2-trifluromethyl-
substituted quinoline 5k obtained in 90% yield (Table 4, entry 9).
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Table 4 Iodocyclization of perfluoroalkyl propargyl aminesa
Table 4 (Contd.)
Entry
1
4
I+
I2
Time (h)
0.5
5
Yield (%)b
90
Entry
18
4
I+
I2
Time (h)
0.5
5
Yield (%)b
76
5a
5p
2
3
I2
ICl
24
0.5
5b
5b
54
82
19
20
I2
0.5
5q
5r
81
64
4
5
I2
ICl
24
0.5
5c
5c
43
74
I2
1
6
7
I2
ICl
1
1
5d
5d
0
38
21
22
I2
ICl
1
1
5s
5s
58
64
8
I2
0.5
5e
80
23
I2
0.5
5t
78
9
10
I2
ICl
0.5
0.5
5k
5k
90
92 (79) c
a Reaction conditions: 0.5 mmol of 3, 2 equiv of I2 and 2 equiv of NaHCO3
in 5 mL of CH3CN at room temp. b Isolated yields. c Room temperature.
d Yield of isolated product, 3,6-diiodo-substituted quinoline.
11
12
I2
ICl
0.5
0.5
5l
5l
57
84
It can be seen from these experiments that by changing the imine-
amine substrates, selective ipso or ortho cyclization may be realised.
The effect of different solvents and bases on the iodocyclization
of 4k to improve the yield was then examined. It was found that
the combination of 0.1 M of acetonitrile and 2 equiv. of NaHCO3
was favourable. (Table 4, entry 9). Encouraged by the results
obtained with iodine, the efficacy and generality of the current
protocol was studied by employing the stronger electrophile ICl
on the cyclization of compound 4k. It was observed that ICl
demonstrated improved results at 0 ◦C compared to the reaction
at room temperature (Table 4, entry 10).
13
14
I2
ICl
2
0.5
5m
5m
0, 25 d
0
15
16
I2
ICl
2
0.5
5n
5n
72
74
In an effort to understand the scope of the reaction, the
effect of various substituents on the aniline ring was scrutinized.
As expected, the electron-rich-substituted anilines promote the
reaction and cyclize to give the corresponding quinolines in high
yields (Table 4, entry 1). The 4-bromo and 4-fluoro-substituted
anilines, in the presence of iodine, afforded moderate yields of the
corresponding quinolines with incomplete conversion (entries 2
and 3). Yields were dramatically enhanced when the cyclization
was carried out with ICl (entries 3 and 5). Unsubstituted aniline
(4d) in the presence of iodine yielded iodo-substituted propargyl
17
I2
0.5
5o
80
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amine rather than the quinoline 5d (entry 6). Replacing the iodine
with ICl afforded 5d in 38% isolated yield. The napthylamine 4h
also provided the corresponding iodoquinoline 5e in high yield
(entry 8). When 3-methoxy-substituted aniline 4m was treated
with iodine, only 25% of the 3,6-diiodo-substituted quinoline was
obtained along with uncyclized aromatic iodinated side products
(entry 13). No desired quinoline product was observed in this case
when ICl was used (entry 14). The iodocyclization of 2-methoxy-
substituted aniline, 4n afforded the corresponding quinoline in
good yield when both I2 and ICl electrophiles were used. (entries
15 and 16).
Attention was then focused on investigating the scope of this
cyclization protocol in terms of the perfluoroalkyl chain Rf. It
was observed that both the C2F5 and C4F9-substituted propargyl
amines gave high yields of the corresponding quinolines (Table 4,
entries 17 and 18). Further, the aryl substitution on the alkyne
moiety of the 2-perfluoroalkyl propargyl amines was varied. The
iodocyclization of 4-methoxyphenyl-substituted propargyl amines
4l gave moderate yield (57%) of the quinoline 5l in the presence of
I2. Yield was further increased to 84% when I2 was replaced with
ICl (Table 4, entry 12). The structure of the 2-trifluoromethylated
quinoline 5l was confirmed by 1H NMR, 13C NMR, HRMS and
by single crystal X-ray diffraction study (Fig. 2).18
Scheme 6 Plausible mechanism for the iodocyclization of perfluoroalkyl
propargyl amine and subsequent dehydrogenation to quinoline.
B. Subsequent oxidation of B by I2 produces the corresponding
quinoline 5.23
The presence of the iodide functional group at the 3-position of
the quinoline ring provides an opportunity to explore the scope
of the chemistry. Using 3-iodoquinoline 5k, some complex 2-
perfluoroalkyl-substituted heterocycles have been synthesized in
good yields.
Iodoquinoline 5k underwent facile Suzuki24 coupling with para-
tolylboronic acid to afford the highly substituted 6-methoxy-4-
phenyl-3-p-tolyl-2-trifluoromethylquinoline 8 in good yield (75%).
Next, 5k was further subjected to the palladium-catalyzed
annulation reaction25 with the diphenyl acetylene. This yielded
trifluoromethyl-substituted benzophenanthridine 10 in 70% yield.
In the metal-halogen exchange reaction,26 the treatment of n-
BuLi with 5k gave the 2-trifluoromethyl-substituted quinoline
27
11 in 95% yield, and subsequent treatment with CO2 afforded
highly substituted 2-trifluoromethyl quinoline-3-carboxylic acid
12 in 62% yield.
Fig. 2 ORTEP diagram of compound 5l.
Changing the substitution at the terminal position of the
C–C triple bond to alkyl chain afforded a satisfactory yield of
the corresponding quinolines (entries 19–23) in the presence of
iodine. When ICl was employed in place of iodine in the cyclization
of propargyl alcohol 4s, only a marginal increase in the yield
was observed (entry 22). The substrate with vinylic substitution
on the terminal alkyne 4t afforded the desired 2-trifluoromethyl-
substituted quinoline 5t in 78% yield (entry 23).
The plausible mechanism for iodocyclization of perfluoroalkyl
propargyl amine 4 presented herein is outlined in Scheme 6.
Initially, I2 coordinates to the alkyne moiety to form the iodonium
intermediate A. This is followed by intramolecular nucleophilic
attack of the aromatic ring of aniline on the activated alkyne
moiety leading to formation of intermediate 1,2-dihydroquinoline
Antimalarial activity of perfluoroalkyl quinolines
The antimalarial activity of some the compounds (5a, 5c, 5e,
5k, 5o, 5p, 5r, 8 and 10) against a Plasmodium falciparum strain
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(FDL-B) was examined at different doses, starting from 250 mg/ml
with 5-fold serial dilutions up to 0.016 mg/ml.28 The doses
were kept constant for all compounds in order to maintain the
comparative profile of their activities. The compounds, 5a and
5o showed substantial in vitro activity for total parasite growth
inhibition.
General procedure for the electrophilic cyclization of N-Aryl
perfluoroalkyl propargyl imines by I2–CAN
N-aryl perfluoroalkyl acetylenic imines 3 were prepared by
Sonogashira coupling of imidoyl iodide and alkyne according to
the literature procedure.15 To a solution of N-aryl perfluoroalkyl
propargyl imine, 3 (0.5 mmol) in CH3CN (5 mL), was added finely
grounded I2 (2 equiv) and CAN (2 equiv) successively and the
mixture was stirred at room temperature. After completion of
the reaction as monitored by TLC, the mixture was diluted with
30 mL of EtOAc, and washed with saturated aqueous solution
of Na2S2O3 (25 mL). The organic layer was separated and the
aqueous layer was extracted with fresh EtOAc (30 mL). The
combined organic layers were dried over anhydrous Na2SO4. The
solvent was evaporated under reduced pressure and the crude
product was purified by column chromatography on silica gel
using 10:1 hexane/EtOAc as eluent unless otherwise stated to get
pure 5.
3-Iodo-6-methyl-4-phenyl-2-(trifluoromethyl)quinoline (5a)
Pale yellow solid: mp 112–113 ◦C; 1H NMR (300 MHz, CDCl3):
d 8.09 (d, J = 8.7 Hz, 1H), 7.62-7.52 (m, 4H), 7.22-7.17 (m, 2H),
7.11-7.09 (m, 1H), 2.44 (s, 3H). 13C NMR (75.5 MHz, CDCl3): d
156.2, 146.5 (q, J = 32.9 Hz), 143.7, 141.4, 140.0, 133.1, 129.6,
128.93, 128.88, 128.70, 125.6, 121.4 (q, J = 276.6 Hz), 89.7, 21.9,
(one sp2 carbon missing due to overlap). 19F NMR (376.3 MHz,
CDCl3) d -65.20 (s, 3F). MS (ESI): m/z = 414 [M + H]+.
HRMS: m/z calcd for C17H12NF3I [M + H]+ 413.9966, found
413.9952.
Conclusions
In conclusion, efficient and simple new methodologies for the
synthesis of highly substituted perfluoroalkyl quinolines have been
developed. These methodologies offer various substitutions at
aniline ring or at the terminal alkyne using various perfluoroalkyl
groups to allow a diverse range of quinolines to be synthe-
sized. Therefore, such reactions may be distinctly important for
pharmacological applications. The iodocyclization processes using
I2/CAN, I2 and ICl showed considerable synthetic advantages in
terms of product diversity, mild reaction conditions, the simplicity
of the reaction process and good-to-excellent yields. A new route
for the synthesis of 2-perfluoroalkylpropargyl amines, which are
the building blocks of perfluoroalkyl heterocycles, have also been
demonstrated. Further work is in progress for the synthesis of
more complex molecular structures.
3-Iodo-4-phenyl-2-trifluoromethyl-1-azaspiro[4.5]deca-1,3,6,9-
tetraen-8-one (6a)
◦
1
White solid: mp 162–163 C; H NMR (200 MHz, CDCl3): d
7.44-7.24 (m, 5H), 6.48 (d, 2H, J = 10.3 Hz), 6.17 (d, 2H, J =
10.3 Hz). 13C NMR (75.5 MHz, CDCl3): d 184.2, 173.0, 167.7
(q, J = 37.3 Hz), 139.6, 132.6, 131.5, 130.2, 128.8, 127.3, 118.5
(q, J = 276.6 Hz), 83.7, 83.2. 19F NMR (376.3 MHz, CDCl3) d
-67.80 (s, 3F). MS (ESI): m/z = 438 [M + Na]+. HRMS: m/z
calcd for C16H9F3INO [M + Na]+ 437.9579, found 437.9581.
3-Iodo-4-(4-methoxyphenyl)-2-trifluoromethyl-1-azaspiro[4.5]
deca-1,3,6,9-tetraen-8-one (6b)
Experimental
White solid: mp 161–162◦C; 1H NMR (300 MHz, CDCl3): d 7.35
(d, 2H, J = 9.1 Hz), 6.87 (d, 2H, J = 9.1 Hz), 6.49 (d, 2H, J =
10.0 Hz), 6.17 (d, 2H, J = 10.0 Hz), 3.82 (s, 3H). 13C NMR
(75.5 MHz, CDCl3): d 184.4, 172.0, 167.8 (q, J = 37.3 Hz), 161.0,
140.3, 132.4, 129.0, 123.6, 118.6(q, J = 276.1 Hz), 114.2, 82.7,
81.9, 55.3. 19F NMR (376.3 MHz, CDCl3) d -67.76 (s, 3F). MS
(ESI): m/z = 445 [M + Na]+. HRMS: m/z calcd for C17H11F3INO2
[M + Na]+ 467.9684, found 467.9688.
All reactions were conducted in flame dried glass apparatus.
Reactions were followed by TLC analysis using silica plates
1
visualized with a UV lamp. H, 13C, and 19F NMR spectra were
recorded in Fourier transform mode. Chemical shifts are given
in ppm, the internal standard reference is Trimethylsilane for
1H and 13C, and CFCl3 for 19F spectra. Multiplicities in the
1H NMR spectra are described as: s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, br = broad; coupling
constants are reported in Hz. For low (MS) and high (HRMS)
resolution mass spectra ion mass/charge (m/z) ratios are reported
as values in atomic mass units. Melting points were recorded on a
Toshniwal melting point apparatus. CAN was activated at 100◦C
under vacuum for 1h. All commercially available reagents were
purchased and used as supplied. DCM was freshly distilled from
P2O5.
General procedure for the synthesis of N-Aryl perfluoroalkyl
propargyl amines (4)
To a solution of N–aryl perfluoroalkyl acetylenic imine 3 (1 mmol)
in glacial acetic acid (4 mL) under nitrogen atmosphere at 0 ◦C was
added NaBH3CN (3 equiv.) in portions. The mixture was stirred
at room temperature for 30 min. The reaction mixture was diluted
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with EtOAc (50 mL) and washed with saturated aqueous solution
of NaHCO3 until effervescence ceased, followed by saturated
aqueous solution of NaCl. The organic layer was dried over
anhydrous Na2SO4. The solvent was evaporated under reduced
pressure and the product was purified by column chromatography
on silica gel using 10:1 hexane/EtOAc as eluent.
reduced pressure and the crude product was purified by column
chromatography on silica gel using 10:1 hexane/EtOAc as eluent
unless otherwise stated to get pure 5.
General procedure for the electrophilic cyclization of N-Aryl
perfluoroalkylated propargyl amines by ICl
0.5 mmol of the N-aryl perfluoroalkyl propargyl amine 4, 2 equiv
(3-Phenyl-1-trifluoromethyl-prop-2-ynyl)-p-tolylamine (4a)
of NaHCO3 and 4 mL of dry CH2Cl2 were placed in a 25 mL round
bottom flask at 0 C under the nitrogen atmosphere. 2 Equiv of
The indicated compound was obtained in 98% yield as pale yellow
oil. 1H NMR (300 MHz, CDCl3): d 7.44-7.37 (m, 2H), 7.34-7.23
(m, 3H), 7.0 (d, 2H, J = 8.2 Hz), 6.65 (d, 2H, J = 8.2 Hz),
4.85-4.74 (m, 1H), 3.80 (d, 1H, J = 9.6 Hz), 2.26 (s, 3H). 13C
NMR (75.5 MHz, CDCl3): d 142.7, 132.0, 129.9, 129.1, 128.3,
123.8 (q, J = 281.0 Hz), 121.4, 114.9, 86.1, 80.7, 51.1 (q, J =
35.1 Hz), 20.4, (one sp2 carbon missing due to overlap). 19F NMR
(376.3 MHz, CDCl3) d -76.05 (d, 3F, J = 6.1 Hz).MS (ESI):
m/z = 290 [M + H]+. HRMS: m/z calcd for C17H15F3N [M + H]+
290.1156, found 290.1163.
◦
ICl in 1 mL of dry CH2Cl2 were added dropwise to the flask. The
mixture was stirred at room temperature for the required time and
was then diluted with 30 mL of EtOAc, and washed with 25 mL
of saturated aqueous solution of Na2S2O3. The organic layer was
separated and the aqueous layer was extracted with fresh EtOAc
(30 mL). The combined organic layers were dried over anhydrous
Na2SO4. The solvent was evaporated under reduced pressure and
the product was purified by column chromatography on silica gel
using 10:1 hexane/EtOAc as eluent unless otherwise stated to get
pure 5.
Synthesis of 5,5,5-Trifluoro-4-(4-methoxyphenylamino)-
pent-2-yn-1-ol (4s)
3-Iodo-6-fluoro-4-phenyl-2-(trifluoromethyl)quinoline (5c)
To 3s (1 mmol) (prepared by Sonagashira coupling of N-(4-
methoxyphenyl)-2,2,2-triflyroacetimidoyl iodide and THP pro-
tected propargyl alcohol)◦ in glacial acetic acid (4 mL) under
nitrogen atmosphere at 0 C was added NaBH3CN (3 equiv.) in
portions. The mixture was stirred at room temperature for 30 min.
The reaction mixture was again cooled to 0 ◦C and was added p-
TsOH (0.01mmol). The reaction mixture was then stirred at room
temperature for the required time. After completion of the reaction
as monitored by TLC, the reaction mixture was then diluted with
EtOAc (50 mL), and washed with saturated aqueous solution
of NaHCO3 until effervescence ceased, followed by saturated
aqueous solution of NaCl. The organic layer was dried over
Na2SO4 and filtered. The solvent was evaporated under reduced
pressure and the product was purified by column chromatography
on silica gel using 10:2 hexane/EtOAc as eluent to afford the
analytically pure product (4s) in 236 mg (91%).
White solid: mp 115–116 ◦C; 1H NMR (200 MHz, CDCl3): d 8.25
(dd, 1H, J = 9.5, 5.8 Hz), 7.67-7.51 (m, 4H), 7.26-7.19 (m, 2H), 7.01
(dd, 1H, J = 9.5, 2.9 Hz). 13C NMR (75.5 MHz, CDCl3): d 162.1
(d, J = 252.5 Hz), 156.5 (d, J = 6.6 Hz), 147.0 (q, J = 32.9 Hz),
142.3, 140.9, 132.8 (d, J = 11 Hz), 129.85 (d, J = 11 Hz), 129.11,
129.0, 128.8, 121.2 (q, J = 276.6 Hz), 121.3 (d, J = 26.3 Hz),
110.5 (d, J = 24.1 Hz), 90.8. 19F NMR (376.3 MHz, CDCl3) d
-65.43 (s, 3F), -107.60–107.68 (m, 1F). MS (ESI): m/z = 418
[M + H]+. HRMS: m/z calcd for C16H9F4IN (M + H)+ 417.9715,
found 417.9732.
Synthesis of 6-methoxy-4-phenyl-3-p-tolyl-2-(trifluoromethyl)
quinoline (8)
A 10 mL round bottom flask was charged with iodoquinoline
5k (107 mg, 0.25 mmol), p-tolylboronic acid (54 mg, 0.4 mmol),
Pd(PPh3)2Cl2 (7 mg, 0.01 mmol) and K2CO3 (69 mg, 0.5 mmol)
in 5 mL of DMF/H2O (v/v = 4/1). The reaction mixture was
stirred under N2 at 100 ◦C for 6h. The mixture was cooled to
room temperature and diluted with 25 mL of EtOAc, washed with
25 mL of H2O and 25 mL of saturated aqueous solution of NaCl.
The organic layer was dried over Na2SO4 and filtered. The solvent
was evaporated under reduced pressure to get the crude product.
The crude product was chromatographed on a silica gel column
using 10:1 hexane/EtOAc as eluent to afford the analytically pure
product (8) in 74 mg (75%).
1
Pale brown oil. H NMR (200 MHz, CDCl3): d 6.82-6.76 (m,
2H), 6.73-6.67 (m, 2H), 4.60-4.50 (m, 1H), 4.27 (d, 2H, J = 2.3 Hz),
3.77 (s, 3H). 13C NMR (75.5 MHz, CDCl3): d 154.0 138.6, 123.6
(q, J = 281.5 Hz), 116.7, 114.8, 84.6, 77.4, 55.6, 51.3 (q, J =
33.9 Hz), 50.5.19F NMR (376.3 MHz, CDCl3) d -76.05 (d, 3F, J =
7.4 Hz). MS (ESI): m/z = 260 [M + H]+. HRMS: m/z calcd for
C12H13F3NO2 [M + H]+ 260.0898, found 260.0888.
General procedure for the electrophilic cyclization of N-Aryl
perfluoroalkylated propargyl amines by molecular iodine
◦
1
To a mixture of N-aryl perfluoroalkylated propargylamine 4
(0.5 mmol), NaHCO3 (2 equiv.) and CH3CN (5 mL) in a 25 mL
round-bottomed flask, 3 equiv. of finely grounded iodine was
added and the mixture was stirred at room temperature for the
required time. After completion of the reaction as monitored
by TLC, the mixture was diluted with 30 mL of EtOAc, and
washed with saturated aqueous solution of Na2S2O3 (25 mL). The
organic layer was separated and the aqueous layer was extracted
with fresh EtOAc (30 mL). The combined organic layers were
dried over anhydrous Na2SO4. The solvent was evaporated under
White solid: mp 239–240 C; H NMR (300 MHz, CDCl3):
d 8.16 (d, 1H, J = 9.1 Hz), 7.39 (dd, 1H, J = 9.1, 3.0 Hz),
7.28-7.21 (m, 3H), 7.06-7.00 (m, 2H), 6.97-6.89 (m, 4H), 6.66 (d,
1H, J = 3.0 Hz), 3.69 (s, 3H), 2.28 (s, 3H). 13C NMR (75.5 MHz,
CDCl3): d 159.4, 148.9, 143.7 (q, J = 32.9 Hz), 141.9, 136.8, 136.1,
132.4, 132.1, 131.7, 130.3, 129.8, 129.6, 127.9, 127.5, 122.1 (q, J =
276.3 Hz), 122.9, 104.2, 55.4, 21.2, (one sp2 carbon missing due
to overlap).19F NMR (376.3 MHz, CDCl3) d -61.63 (s, 3F). MS
(ESI): m/z = 394 [M + H]+. HRMS: m/z calcd for C24H19F3NO
[M + H]+ 394.1418, found 394.1432.
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Synthesis of 2-methoxy-7,8-diphenyl-6-
(trifluoromethyl)benzo[k]phenanthridine (10)
was acidified with hydrochloric acid to pH 2 and extracted with
ethyl acetate (3 ¥ 25 mL). The combined organic layers were dried
over Na2SO4. The solvent was evaporated under reduced pressure
to get the crude product, which was crystallized from mixture of
chloroform and hexane 1:2 (v/v) to afford the analytically pure
A 10 mL round-bottomed flask was charged with iodoquinoline
5k (107 mg, 0.25 mmol), diphenylacetylene (89 mg, 0.5 mmol),
Pd(OAc)2 (2.8 mg, 0.012 mmol), NaOAc (41 mg, 0.5 mmol) and
LiCl (11 mg, 0.25 mmol) in 5 mL of DMF The reaction mixture
was stirred at 100 ◦C under the atmosphere of nitrogen for 20h. The
mixture was cooled to room temperature and diluted with 25 ml of
EtOAc, washed with H2O (25 mL) and saturated aqueous solution
of NaCl (25 mL). The organic layer was dried over Na2SO4.
The solvent was evaporated under reduced pressure. The reaction
mixture was chromatographed on a silica gel column using 10:1
hexane/EtOAc as eluent to afford the analytically pure product
(10) in 84 mg (70%).
◦
1
product (12) in 54 mg (62%). White solid; mp 196–197 C; H
NMR (200 MHz, CDCl3): d 8.13 (d, 1H, J = 9.4 Hz), 7.57-7.43
(m, 4H), 7.42-7.33 (m, 2H), 6.82 (d, 1H, J = 3.1 Hz), 3.72 (s,
3H). 13C NMR (75.5 MHz, CD3OD + CH3OH): d 169.4, 161.6,
147.8, 143.8, 141.5 (q, J = 35.1 Hz), 136.0, 132.4, 130.6, 130.4,
130.1, 129.6, 127.2, 125.5, 123.0 (q, J = 274.4 Hz), 105.0, 56.0. 19
F
NMR (376.3 MHz, CDCl3) d -58.62 (s, 3F). MS (ESI): m/z 348
[M + H]+. HRMS: m/z calcd for C18H13F3NO3 [M + H]+ 348.0847.
The structure of 12 was further confirmed by preparing the methyl
ester derivative (13) of corresponding acid using CH2N2. White
◦
1
White solid: mp 214–215 C; H NMR (300 MHz, CDCl3): d
9.03 (d, 1H, J = 8.3 Hz), 8.30 (d, 1H, J = 2.3 Hz), 8.23 (d, 1H, J =
9.1 Hz), 7.75-7.56 (m, 3H), 7.49 (dd, 1H, J = 9.1, 3.0 Hz), 7.29-
7.21 (m, 3H), 7.12-7.00 (m, 5H), 6.98-6.92 (m, 2H), 4.03 (s, 3H).
13C NMR (75.5 MHz, CDCl3): d 159.8, 144.1 (q, J = 32.9 Hz),
139.6, 139.4, 138.6, 138.3, 135.1, 134.8, 133.7, 132.6, 131.2, 130.8,
128.5, 127.83, 127.75, 127.70, 126.91, 126.85, 126.6, 125.3, 121.4,
121.2 (q, J = 276.6 Hz), 119.5, 108.0, 55.8, (two sp2 carbon missing
due to overlap). 19F NMR (376.3 MHz, CDCl3) d -59.34 (s, 3F).
MS (ESI): m/z 480 [M + H]+. HRMS: m/z calcd for C31H21F3NO
[M + H]+ 480.1575, found 480.1597.
◦
1
solid; mp 75–76 C; H NMR (200 MHz, CDCl3): d 8.15 (d,
1H, J = 8.5 Hz), 7.62-7.28 (m, 6H), 6.78 (d, 1H, J = 3.1 Hz), 3.73
(s, 3H), 3.58 (s, 3H).
Acknowledgements
M. S. S. and S. R. thank CSIR for providing a research fellowship.
We are thankful to NMR, MS, and Analytical Division, IICT for
providing spectral data. We also thank R. L. Wilson of RMIT
University, Australia, for proof-reading the final manuscript.
Synthesis of 6-methoxy-4-phenyl-2-(trifluoromethyl)quinoline (11)
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©