Proline potassium salt: A superior catalyst to synthesize 4-trifluoromethyl quinoline derivatives via Friedlander annulation

Article abstract of DOI:10.1016/j.tet.2013.06.017

Proline potassium salt was successfully firstly used to catalyze the Friedlander annulation toward the synthesis of 4-trifluoromethyl-substituted quinolines from the substituted 2-trifluoroacetyl anilines and variety carbonyl compounds under mild conditions in good to excellent yields. This catalyst provides several advantages, such as shorter reaction time, high regioselectivity, functional group tolerance, and broad substrate scope.

Full text of DOI:10.1016/j.tet.2013.06.017

Tetrahedron 69 (2013) 7481e7486
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Proline potassium salt: a superior catalyst to synthesize
4-trifluoromethyl quinoline derivatives via Friedlander annulationq
,
a,
Xiao Long Du a, Biao Jiang b , Yuan Chao Li
*
*
a Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Road Zu Chong Zhi, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China
b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Road Fengling, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 May 2013
Received in revised form 31 May 2013
Accepted 3 June 2013
Available online 11 June 2013
Proline potassium salt was successfully firstly used to catalyze the Friedlander annulation toward the
synthesis of 4-trifluoromethyl-substituted quinolines from the substituted 2-trifluoroacetyl anilines and
variety carbonyl compounds under mild conditions in good to excellent yields. This catalyst provides
several advantages, such as shorter reaction time, high regioselectivity, functional group tolerance, and
broad substrate scope.
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
Proline potassium salt
2-Trifluoroacetyl anilines
4-Trifluoromethyl quinoline
1. Introduction
Fluorine-containing quinoline derivatives, particularly tri-
fluoromethyl quinoline derivatives,1 have received a great deal
of interest in the medicinal, agricultural, and material sciences in
recent years because of their special physical, chemical, and bi-
ological properties.2 To synthesize the trifluoromethyl quinoline
derivatives, multiple steps synthesis3 or indirect synthetic pro-
tocol4 have been appealed due to the unavailability of starting
materials and poor regioselectivity when traditional methods
for the synthesis of quinoline compounds are employed.5 In
our previous works,6 two new methods for the synthesis of
4-trifluoromethyl quinoline derivatives with high regioselectivity
and yields were developed and the first proline-catalyzed synthesis
of 2-substituted 4-trifluoromethyl quinoline derivatives was re-
alized from the reaction of alkyl ketones and o-trifluoroacetyl
anilines. However, the method using proline as catalyst was too
much time consuming (>24 h) and many useful functionalized
ketones, such as ethyl pyruvate and ethyl acetylacetate could not
work in this condition, which greatly limited its popularity in
applications (Scheme 1).
Scheme 1. Our previous work and this work.
When exploring the reaction mechanism,6b we concluded that
proline-catalyzed Friedlander annulation presumably experienced
an aldol reaction followed by the acid-catalyzed cyclization se-
quence (Scheme 2) and the aldol reaction was the rate-determined
step. Then we suppose that the hydrogen-bonded effect between
the oxygen of trifluoroacetyl and the proton of carboxylic group
(Fig. 1) is presumably the key factor during the annulation,
according to the mechanism of the aldol reaction catalyzed by
proline as before.7 With this background, we tried to replace pro-
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
* Corresponding authors. Tel./fax: þ86 21 50807288 (Y.C.L.); tel.: þ86 21 54925201;
fax: þ86 21 64166128 (B.J.); e-mail addresses: jiangb@mail.sioc.ac.cn (B. Jiang),
ycli@mail.shcnc.ac.cn (Y.C. Li).
line with proline alkali salt as
a catalyst to synthesize 4-
trifluoromethyl quinoline derivatives via Friedlander annulation.
And we found that proline potassium salt was a superior catalyst to
0040-4020/$ e see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.017

7482
X.L. Du et al. / Tetrahedron 69 (2013) 7481e7486
Table 1
Catalysts studied in the Friedlander annulation with 2-pentanone and o-tri-
fluoroacetyl anilines as substratesa
Entry
Catalyst (mol %)
t
Yield (%)b
Lit.[6b]
1
2
3
4
5
6
7
Proline (30)c
12 h
98
98
86
89
90
92
95
96
98
93
92
34d
88
Proline potassium salt (25)
Proline lithium salt (25)
Proline sodium salt (25)
Proline potassium salt (5)
Proline potassium salt (10)
Proline potassium salt (50)
Proline potassium salt (100)
Proline (25)þKI (25)
35 min
90 min
35 min
4.5 h
2.5 h
30 min
23 min
12 h
10 h
30 min
17 h
Scheme 2. Proposed pathway for the synthesis of 4-trifluoromethyl quinolines.
8
9e
10
11e
12
Proline (25)
Tetrahydropyrrole (25)
Potassium acetate (25)
Proline cesium salt (25)
50 min
a
All reactions were performed on a 1.0 mmol scale in 2-pentanone (1.0 mL) and
DMSO (4.0 mL) at rt.
b
Isolated yield.
c
Performed on a 0.5 mmol scale at 50 ꢀC.
d
Conversion determined by 19F NMR.
The reaction was performed at 55 ꢀC.
e
Having established the optimized reaction conditions, we tested
the methodology with an array of substituent of o-trifluoroacetyl
anilines (Table 2). It was found that the electronic nature of the
substituents did not play a key role in this annulation reaction.
Substrates substituted with strong electron-withdrawing groups,
such as NO2 (3f) and donating groups, such as MeO (3e), were
well tolerated providing the desired quinoline derivatives in ex-
cellent yields. Notably, the tolerance of the nitro (3f), fluoro, chloro,
and bromo groups (3aec) offers the opportunity for further
functionalization.
Fig. 1. Proposed transition state in the aldol addition step with proline as catalyst.
synthesize 4-trifluoromethyl quinoline derivatives possessing
many advantages, such as the reaction time could be greatly re-
duced and many useful functionalized ketones (aromatic ketones,
ethyl pyruvate, ethyl acetylacetate, and so on) could also work
under this condition in good to excellent yields. Significantly, the
3-substituted quinolone derivatives could be obtained, when using
aldehydes as the reagents instead of ketones.
Table 2
Prolinepotassiumsalt-catalyzedFriedlanderannulationofsubstituted2-trifluoroacetyl
anilines and 2-pentanone for the synthesis of 4-trifluoromethyl quinoline derivatives
3aefa
2. Results and discussion
We initiated our investigation with the reaction between
4-chloro-2-trifluoroacetyl aniline 1a and 2-pentanone 2a (Table 1,
entry 1). Gratifyingly, the use of proline potassium salt (25 mol %) as
catalyst in DMSO at rt yielded 3a in 98% yield and the reaction
finished within 35 min, which was much shorter than that (48 h,
50 ꢀC) when proline was employed as catalyst. For comparison,
a range of catalyst loadings and other alkali salts were screened and
outlined in Table 1. The result showed that lithium and sodium
proline salts led to slightly lower yields (Table 1, Entries 2, 3). Re-
actions performed with lower catalyst loading gave lower yields
and required much longer reaction time (Table 1, Entry 4, 5). While
raising the catalyst loading did not result in any effect in yield or
reaction time (Table 1, Entry 6, 7). To verify that whether just
incorporation of potassium cation into reaction can produce such
a result, the mixture of proline and potassium iodide in equal molar
ratio served as the co-catalyst for this reaction (Table 1, entry 8).
As expected, the reaction was completed after 12 h, which was
similar to what the proline as the only catalyst did. The striking
difference of the catalyst activity between proline and proline po-
tassium salt is likely a result of difference in the substrateecatalyst
interaction model. In addition to the coordination effect with the
oxygen of the trifluoroacetyl group, the potassium cation may be an
additional effect with the nitrogen of the amino group, which
probably leads to a great energy decrease in the transition state.
[a] All reactions were performed on a 1.0 mmol scale. [b] Isolated yield.
Encouraged by the successful results in the annulation of sub-
stituent of o-trifluoroacetyl anilines, we turned our attention to
additional substrates bearing synthetically useful functionalized
carbonyl compounds. In most cases, not only aliphatic ketones but
also aromatic ketones exclusively led to give the desired products in
good to excellent yields, as shown in Table 3. It is noteworthy that

X.L. Du et al. / Tetrahedron 69 (2013) 7481e7486
7483
Table 3
bearing electron rich groups worked equally well to get the cor-
responding products in good yields with the requirement of higher
temperature or longer reaction time (4kem, 4p). Particularly
remarkable was the participation of aldehydes in this reaction,
providing the corresponding C3-substituted quinolines in good
yield (4q, 4r).
Proline potassium salt catalyzed Friedlander annulation of (4-chloro-2-trifluoroacetyl
aniline) and carbonyl compounds for the synthesis of 4-trifluoromethyl quinoline
derivatives 4aera
O
CF3
Prolinate potassium
25 mol %
Cl
O
Cl
R2
R1
CF3
R2
+
DMSO
R1
NH2
1a
N
3. Conclusion
2
4
CF3
N
CF3
CF3
In summary, we have developed a mild and efficient method for
the synthesis of 4-trifluoromethyl-substituted quinolines derivatives
utilizing proline potassium salt as a novel catalyst via Friedlander
annulation in good to excellent yields. This catalyst provides several
advantages, such as shorter reaction time, high regioselectivity,
functional group tolerance, and broad substrate scope. Most impor-
tantly, the 3-substituted quinoline derivatives could be obtained,
when using aldehydes as the reagents instead of ketones.
Cl
Cl
Cl
N
N
4a: 3min, 92%[b]
4b: 12h, 85%
4c: 18h, 97%
CF3
CF3
CF3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OMe
N
N
N
OMe
4d[c]: 20min, 91%
4. Experimental section
4f: 3h, 85%
4e: 12h, 88%
CF3
CF3
CF3
OH
COOEt
4.1. General methods and materials
N
COOEt
N
N
Mass spectra and high-resolution mass spectra were measured
on a Finnigan MAT-95 mass spectrometer. 1H and 13C NMR spectra
were determined on Bruker AM-300, Bruker AM-400, using tetra-
methylsilane as internal reference. Data are presented as follows:
chemical shift, multiplicity (s¼singlet, br s¼broad singlet,
d¼doublet, br d¼broad doublet, t¼triplet, m¼multiplet), J¼coupling
constant in hertz (Hz). Silica gel 60H (200e300 mesh) manufactured
by Qingdao Haiyang Chemical Group Co. (China) was used for gen-
eral chromatography. All the reagents were purchased from Aldrich
and used without further purification. Prolinate alki salt was syn-
thesized according to published procedures.
4i[d]: 12h, 75%
4h[d]: 9h, 70%
4g: 4.5H, 84%
CF3
CF3
CF3
Cl
O
N
N
N
NO2
OMe
Cl
4k[c]: 7h, 95%
4l: 48h, 95%
4j: 35min, 85%
CF3
CF3
CF3
Cl
Cl
Cl
S
N
N
N
N
S
N
4m: 40h, 91%
4n: 50min, 91%
4o: 25min, 90%
4.2. Preparation of the prolinate alki salt
CF3
CF3
CF3
The alki metal hydroxide (10 mmol) was added rapidly to the
Cl
Cl
solution of proline (L, or D, or DL) (1.15 g, 10 mmol) dissolving in
N
50 mL of methanol at 0 ꢀC with stirring. After 30 min, the system
was allowed stirring at rt for 2 h. Concentration of the solution
under reduced pressure provided white solid, which was dried in
vacuo for 10 h and used to catalyze the Friedlander annulation
reaction without further purification.
N
N
4r[d]: 35min, 73%
4q[d]: 30min, 97%
4p: 21h, 95%
[a] All reactions were performed on a 1.0 mmol scale; [b] Isolated yield. [c]
The reaction was performed at 55 oC; [d] 3 drops of acetic acid was added.
4.3. General procedures and characterizations
the reaction between 4-chloro-2-trifluoroacetyl aniline and ace-
tone was complete within 3 min even without stirring at rt in 92%
yield (4a). In contrast, aliphatic ketones with bulky substituents
were tolerated with good yields obtained, despite the requirement
of the longer reaction time (4b, 4c). For cyclic ketone substrates,
such as cyclopentanone, the desired Friedlander annulation pro-
ceeded smoothly as well (4d). In addition, enone substrate, such as
mesityl oxide, was readily converted to the corresponding product
in good yield (4e). It is interesting that two acetone derivatives
bearing different activated groups was transformed to the quino-
lines with opposite regioselectivity (4f, 4g). However, when other
carbonyl compounds, such as ethyl pyruvate and ethyl acetylace-
tate were treated under the optimized conditions, no desired
product was obtained. We speculated that self-condensation or
other side reaction might lead to the failure in releasing catalyst
following the aldol addition. Finally, we were pleased to find that
this reaction was successful by adding of three drops of acetic acid
into the mixture, which can probably help to stimulate the de-
composition of the imine intermediate, providing the corre-
sponding products in mild yield (4h, 4i). The aromatic ketones
To a solution of o-trifluoroacetyl aniline (1.0 mmol) and methyl
ketone (7.0 mmol) in DMSO (4.0 mL) was added potassium proli-
nate (38.2 mg, 0.25 mmol) in one portion (for 4h, 4i, 4q, 4r in
Table 3, three drops of acetic acid was added) and the resulted
mixture was stirred at the temperature indicated in Tables 2 and 3.
The reaction was monitored by TLC until the verification of the
disappearance of the reagent. Then the reaction mixture was di-
luted with ethyl acetate (50 mL) and ether (10 mL) and washed
with saturated brine three times (20 mL per times). The organic
phase was dried over anhydrous sodium sulfate and the solvent
was removed under the reduced pressure to give the crude product.
Purification of the crude product by flash chromatography on silica
gel afforded 4-trifluoromethyl quinoline derivatives.
4.3.1. 3a: 6-Chloro-2-propyl-4-(trifluoromethyl)quinoline.6b Follow-
ing general procedure, the indicated compound was purified by
flash column chromatography on silica as a white solid, yield 98%,
mp: 39.0e39.9 ꢀC. 1H NMR (300 MHz in d6-acetone):
d 1.02
(t, J¼7.4 Hz, 3H), 1.81e1.97 (m, 2H), 3.02 (t, J¼7.7 Hz, 2H), 7.76
(dd, J¼8.9, 1.9 Hz, 1H), 7.81 (s, 1H), 7.99 (t, J¼2.0 Hz, 1H), 8.06

7484
X.L. Du et al. / Tetrahedron 69 (2013) 7481e7486
(d, J¼9.2 Hz, 2H). 13C NMR (100 MHz in d6-acetone):
d
12.4, 22.6,
68.5e70.9 ꢀC. 1H NMR (300 MHz in d6-acetone):
d
0.89 (t, J¼7.3 Hz,
40.6, 119.8 (q, J¼5.2 Hz), 121.7, 122.4 (q, J¼2.0 Hz), 123.6 (q,
J¼274.7 Hz), 130.9, 132.0, 132.8 (q, J¼31.3 Hz), 133.2, 147.3, 163.2. IR
(cmꢁ1): 686.46, 778.98, 743.32, 832.45, 1176.40, 1258.98, 1295.56,
1496.30, 1559.42, 1614.2, 2925.64, 2972.51, 3035.24, 3058.01. 19F
3H), 1.73e1.87 (m, 2H), 3.00 (t, J¼7.6 Hz, 2H), 7.92 (s, 1H), 8.21 (d,
J¼9.3 Hz, 1H), 8.48 (dd, J¼9.0, 1.7 Hz, 1H), 8.80 (s, 1H). 13C NMR
(100 MHz in d6-acetone):
d
13.2, 21.8, 40.7, 119.8, 119.8 (q, J¼3.1 Hz),
120.9 (q, J¼5.0 Hz), 123.2 (q, J¼274.0 Hz), 123.4, 131.8, 134.9 (q,
J¼32.6 Hz), 145.8, 150.4, 166.9. IR (cmꢁ1): 654.80, 727.10, 743.81,
926.22, 1165.04, 1503.16, 1538.95, 1611.79, 2971.62, 2934.83,
NMR (282 MHz in d6-acetone):
MS(EI): calcd for C13H11ClF3N: 273.0532; found: 273.0533.
d
ꢁ62.60. EI-MS: 273 (Mþ). HR-
3054.40, 3110.62. 19F NMR (282 MHz in d6-acetone):
d
ꢁ62.30.
4.3.2. 3b: 8-Bromo-6-chloro-2-propyl-4-(trifluoromethyl)quinoline.
Following general procedure, the indicated compound was purified
by flash column chromatography on silica as light yellow oil, yield
EI-MS: 284 (Mþ). HR-MS(EI): calcd for C13H11F3N2O2: 284.0773;
found: 284.0775.
99%. 1H NMR (300 MHz in d6-acetone):
d
1.03 (t, J¼7.6 Hz, 3H),
4.3.7. 4a: 6-Chloro-2-methyl-4-(trifluoromethyl)quinoline.6b Follow-
ing general procedure, the indicated compound was purified by
flash column chromatography on silica as white oil, yield 92%, 1H
1.87e2.01 (m, 2H), 3.08 (t, J¼7.5 Hz, 2H), 7.93 (s, 1H), 7.97 (t, J¼1.2 Hz,
1H), 8.15 (d, J¼1.8 Hz, 1H). 13C NMR (100 MHz in d6-acetone):
d 13.2,
21.7, 40.3, 120.9 (q, J¼5.0 Hz), 122.2 (q, J¼2.0 Hz), 122.4, 123.3
(q, J¼274.9 Hz), 126.7, 132.7, 133.3 (q, J¼31.1 Hz), 133.9,144.1, 164.1. IR
(cmꢁ1): 683.1, 698.4, 773.8, 864.5, 907.9, 1097.8, 1135.9, 1263.6,
1369.9, 1465.5, 1551.7, 1599.2, 1615.5, 2874.0, 2932.3, 2963.4, 3100.1.
NMR (300 MHz in d6-acetone):
d
2.92 (s, 3H), 7.96 (d, J¼8.8 Hz, 1H),
8.01 (s, 1H), 8.10 (s, 1H), 8.32 (d, J¼9.3 Hz, 1H). 13C NMR (100 MHz in
d6-acetone):
d
19.5, 120.9 (q, J¼5.1 Hz), 121.7, 122.4 (q, J¼2.2 Hz),
123.2 (q, J¼273.4 Hz), 130.5, 131.5, 133.5, 133.6 (q, J¼31.5 Hz), 159.6,
170.9. IR (cmꢁ1): 716.83, 830.92, 1083.58, 1153.63, 1258.65, 1495.12,
1535.72, 1608.15, 2924.61, 3036.43, 3066.00, 3428.02. 19F NMR
19F NMR (282 MHz in d6-acetone):
HR-MS(EI): calcd for C13H10BrClF3N: 350.9637; found: 350.9642.
d
ꢁ62.24. EI-MS: 352 (Mþ1þ).
(282 MHz in d6-acetone):
d
ꢁ62.80. EI-MS: 245 (Mþ). HR-MS(EI):
4.3.3. 3c: 5,6-Difluoro-2-propyl-4-(trifluoromethyl)quinoline. Follow-
ing general procedure, the indicated compound was purified by flash
column chromatography on silica as a white solid, yield 92%, mp:
calcd for C11H7ClF3N: 245.0219; found: 245.0221.
4.3.8. 4b: 6-Chloro-2-isopropyl-4-(trifluoromethyl)quinoline. Follow-
ing general procedure, the indicated compound was purified by flash
column chromatography on silica as colorless oil, yield 85%. 1H NMR
42.0e43.3 ꢀC. 1H NMR (300 MHz in d6-acetone):
d
0.98 (t, J¼7.4 Hz,
3H), 1.79e1.93 (m, 2H), 3.02 (t, J¼7.5 Hz, 2H), 7.87 (q, J¼9.2 Hz, 1H),
7.95 (s, 1H), 8.00 (q, J¼4.6 Hz,1H). 13C NMR (100 MHz in d6-acetone):
(300 MHz in d6-acetone):
7.96 (d, J¼9.0 Hz, 1H), 8.06e8.13 (m, 2H), 8.48 (dd, J¼8.8, 1.1 Hz, 1H).
13C NMR (100 MHz in d6-acetone):
d
1.45 (d, J¼6.8 Hz, 6H), 3.50e3.73 (m, 1H),
d
13.1, 21.8, 40.2, 112.35 (d, J¼10.7 Hz), 120.2 (d, J¼21.4 Hz), 120.9 (q,
J¼6.6 Hz), 123.1 (q, J¼272.7 Hz), 127.2 (dd, J¼7.4, 4.4 Hz), 130.6 (qd,
J¼34.3, 6.5 Hz), 142.4 (dd, J¼257.5, 15.4 Hz), 145.8, 148.3 (dd, J¼247.7,
13.7 Hz), 162.8. IR (cmꢁ1): 645.93, 682.20, 739.72, 833.32, 1065.07,
1488.24, 1615.81, 1639.44, 2883.11, 2942.10, 2970.38, 3083.28. 19F
d
21.2 (2C), 35.8 (t, J¼19.7 Hz),
118.7 (q, J¼5.4 Hz), 121.9, 122.4 (q, J¼2.0 Hz), 123.4 (q, J¼274.4 Hz),
131.1, 131.2, 133.7 (q, J¼32.4 Hz),133.4,146.0,167.6. IR (cmꢁ1): 665.01,
692.69, 715.20, 838.65, 1090.43, 1123.07, 1254.52, 1496.43, 1560.61,
1619.14, 2963.50, 2989.57, 3072.20, 3411.63, 3470.55. 19F NMR
NMR (282 MHz in d6-acetone):
d
ꢁ62.60 (d, J¼39.5 Hz, 3F), ꢁ138.99
(m, 1F), ꢁ140.45 (m, 1F). EI-MS: 275 (Mþ). HR-MS(EI): C13H10F5N:
(282 MHz in d6-acetone):
calcd for C13H11ClF3N: 273.0532; found: 273.0527.
d
ꢁ62.69. EI-MS: 273 (Mþ). HR-MS(EI):
275.0733; found: 275.0735.
4.3.4. 3d: 2-Propyl-6-(trifluoromethoxy)-4-(trifluoromethyl)quinoli-
ne. Following general procedure, the indicated compound was
purified by flash column chromatography on silica as a white solid,
yield 94%, mp: 95.0e96.7 ꢀC. 1H NMR (300 MHz in d6-acetone):
4.3.9. 4c: 6-Chloro-2-cyclopropyl-4-(trifluoromethyl)quinoline.6b
Following general procedure, the indicated compound was purified
by flash column chromatography on silica as a white solid, yield 97%,
mp: 47.0e48.3 ꢀC. 1H NMR (300 MHz in d6-acetone):
d
1.11e1.30 (m,
4H), 2.31e2.42 (m, 1H), 7.70 (d, J¼9.0 Hz, 1H), 7.80 (s, 1H), 7.88e7.98
(m, 2H). 13C NMR (100 MHz in d6-acetone):
11.3 (2C), 17.65, 119.1 (q,
d
0.99 (t, J¼7.5 Hz, 3H), 1.85e1.96 (m, 2H), 1.98e2.02 (m, 2H),
7.93e8.03 (m, 2H), 8.20 (s, 1H), 8.69 (d, J¼8.6 Hz, 1H). 13C NMR
d
(100 MHz in d6-acetone):
d
13.0, 22.3, 29.1 (q, J¼19.5 Hz), 114.6,
J¼4.8 Hz), 121.6, 122.4 (q, J¼2.1 Hz), 123.6 (q, J¼273.8 Hz), 130.9, 131.5,
132.5 (q, J¼32.2 Hz), 132.5, 147.2, 164.2. IR (cmꢁ1): 663.85,
771.33, 838.19, 1050.32, 1257.20, 1444.88, 1496.26, 1557.73, 3011.18,
120.5 (q, J¼257.5 Hz), 121.3 (q, J¼5.2 Hz), 122.1, 123.0 (q,
J¼274.3 Hz), 125.6, 129.7, 136.1 (q, J¼32.5 Hz), 143.5, 148.1, 163.5. IR
(cmꢁ1): 637.73, 701.24, 883.14, 925.02, 1205.57, 1264.18, 1467.71,
1529.35, 1566.55, 1627.01, 1737.82, 2877.53, 2937.20, 3388.79. 19F
NMR (282 MHz in d6-acetone):
HR-MS(EI): calcd for C14H11F6NO: 323.0745; found: 323.0739.
3092.56, 3119.19. 19F NMR (282 MHz in d6-acetone):
d
ꢁ66.88. EI-MS:
271 (Mþ). HR-MS(EI): calcd for C13H9ClF3N: 271.0376; found: 271.0380.
d
ꢁ59.11, ꢁ62.96. EI-MS: 323 (Mþ).
4.3.10. 4d: 7-Chloro-9-(trifluoromethyl)-2,3-dihydro-1H-cyclopenta
[b]quinoline. Following general procedure, the indicated compound
was purified by flash column chromatography on silica as a white
solid, yield 90%, mp: 71.1e74.0 ꢀC. 1H NMR (300 MHz in d6-acetone):
4.3.5. 3e: 8-Methoxy-2-propyl-4-(trifluoromethyl)quinoline. Follow-
ing general procedure, the indicated compound was purified by flash
column chromatography on silica as a white solid, yield 90%, mp:
d
2.14e2.28 (m, 2H), 3.09 (t, J¼7.8 Hz, 2H), 3.23e3.36 (m, 2H), 7.65 (d,
86.4e88.5 ꢀC. 1H NMR (300 MHz in d6-acetone):
d
0.98 (t, J¼7.2 Hz,
J¼9.0 Hz, 1H), 7.86e7.98 (m, 2H). 13C NMR (100 MHz in d6-acetone):
3H), 1.97e1.93 (m, 2H), 3.02 (t, J¼7.5 Hz, 2H), 4.04 (s, 3H), 7.24 (dd,
d
22.6, 31.1 (q, J¼3.7 Hz), 34.0, 122.5, 122.6 (q, J¼3.1 Hz), 124.6 (q,
J¼6.2, 2.6 Hz,1H), 7.54e7.64 (m, 2H), 7.79 (s,1H).13C NMR (100MHz in
J¼276.0 Hz), 126.9 (q, J¼31.5 Hz), 129.6, 131.6, 132.6, 135.7, 146.7,
169.4. IR (cmꢁ1): 644.45, 681.94, 719.08, 738.65, 838.33, 1104.88,
1468.24, 1496.04, 1613.47, 2840.29, 2980.70, 3033.40, 3090.79. 19F
NMR (282 MHz in d6-acetone):
HR-MS(EI): calcd for C13H9ClF3N: 271.0376; found: 271.0377.
d6-acetone):
d
13.5, 22.8, 40.7, 55.7, 109.3, 114.9 (q, J¼5.4 Hz), 119.1 (q,
J¼3.1 Hz), 122.4, 124.4 (q, J¼274.9 Hz), 128.2, 133.5 (q, J¼30.6 Hz),
140.9, 156.2, 161.0. IR (cmꢁ1): 699.459, 714.34, 751.12, 835.10,1008.06,
1150.27, 1465.49, 1511.44, 1562.63, 1613.38, 2875.08, 2932.26,
d
ꢁ61.45. EI-MS: 271 (Mþ).
2960.66. 19F NMR (282 MHz in d6-acetone):
d
ꢁ66.77. EI-MS: 269
(Mþ). HR-MS(EI): Ccalcd for C14H14F3NO: 269.1027; found: 269.1031.
4.3.11. 4e:
6-Chloro-2-(2-methylprop-1-enyl)-4-(trifluoromethyl)
quinoline. Following general procedure, the indicated compound
was purified by flash column chromatography on silica as a
white solid, yield 87%, mp: 40.8e42.7 ꢀC. 1H NMR (300 MHz in
4.3.6. 3f: 6-Nitro-2-propyl-4-(trifluoromethyl)quinoline. Following
general procedure, the indicated compound was purified by flash
column chromatography on silica as a white solid, yield 94%, mp:
d6-acetone): d 2.01 (s, 3H), 2.33 (s, 3H), 6.52 (s, 1H), 7.71 (s, 1H), 7.78

X.L. Du et al. / Tetrahedron 69 (2013) 7481e7486
7485
(d, J¼8.6 Hz, 1H), 7.94 (s, 1H), 8.05 (d, J¼8.4 Hz, 1H). 13C NMR
(d, J¼9.3 Hz, 2H), 8.49e8.58 (m, 3H). 13C NMR (100 MHz in
(100 MHz in d6-acetone):
d
19.8, 27.2, 120.8, 120.9 (q, J¼5.7 Hz),
d6-DMSO):
d
118.5 (d, J¼5.1 Hz), 122.5, 123.6 (q, J¼275.4 Hz), 124.5
122.2 (q, J¼2.1 Hz), 123.5, 123.5 (q, J¼274.5 Hz), 130.9, 131.9, 132.5
(q, J¼31.6 Hz), 132.8, 146.5, 147.1, 157.4. IR (cmꢁ1): 646.07, 672.85,
773.64, 936.59, 1085.34, 1257.51, 1493.73, 1548.82, 1611.78, 1649.27,
2934.36, 2967.26, 3064.49, 3096.99. 19F NMR (282 M Hz in d6-ac-
(2C), 129.4 (2C), 132.5, 133.2, 133.8 (d, J¼33.2 Hz), 134.7, 143.2, 147.1,
149.1, 154.8. IR (cmꢁ1): 669.03, 721.60, 839.89, 1055.53, 1269.77,
1490.34, 1541.44, 1607.18, 3083.45, 3440.84. 19F NMR (282 MHz in
d6-acetone):
C16H8ClF3N2O2: 352.0226; found: 352.0225.
d
ꢁ62.59. EI-MS: 352 (Mþ). HR-MS(EI): calcd for
etone):
d
ꢁ62.79. EI-MS: 285 (Mþ). HR-MS(EI): calcd for
C
14H11ClF3N: 285.0532; found: 285.0535.
4.3.17. 4k: 6-Chloro-2-(4-methoxyphenyl)-4-(trifluoromethyl)quino-
line. Following general procedure, the indicated compound was
purified by flash column chromatography on silica as a white
solid, yield 95%, mp: 156.0e157.3 ꢀC. 1H NMR (300 MHz in
4.3.12. 4f: 6-Chloro-2-(dimethoxymethyl)-4-(trifluoromethyl)quino-
line. Following general procedure, the indicated compound was
purified by flash column chromatography on silica as a white solid,
yield 85%, mp: 46.0e48.3 ꢀC. 1H NMR (300 MHz in d6-acetone):
d6-acetone):
d
3.78 (s, 3H), 7.00 (d, J¼8.5 Hz, 2H), 7.77 (dd, J¼9.0,
d
3.49 (s, 6H), 5.49 (s, 1H), 7.91 (dd, J¼9.0, 2.2 Hz, 1H), 8.01 (s, 1H),
2.2 Hz, 1H), 7.93 (d, J¼1.4 Hz, 1H), 8.09 (d, J¼9.2 Hz, 1H), 8.23 (d,
8.08 (t, J¼1.6 Hz, 1H), 8.21 (d, J¼9.1 Hz, 1H). 13C NMR (100 MHz in
J¼8.8 Hz, 2H), 8.31 (s, 1H). 13C NMR (100 MHz in d6-acetone):
d6-acetone):
d
53.9 (2C),104.7,116.9 (q, J¼4.9 Hz),122.4,122.9,123.4
d
55.9, 114.9 (2C), 117.40 (q, J¼5.2 Hz), 121.6, 122.4, 123.6 (q,
(q, J¼273.5 Hz), 131.3, 132.4, 133.5 (q, J¼31.6 Hz), 134.4, 146.5, 158.7.
IR (cmꢁ1): 634.71, 661.79, 698.79, 841.14, 1080.64, 1254.54, 1456.01,
1494.57, 1608.30, 2878.78, 2946.06, 3061.18, 3425.30. 19F NMR
J¼269.2 Hz), 129.7 (2C), 129.9, 132.0, 132.7, 133.1, 133.3 (q,
J¼31.1 Hz), 147.3, 156.5 (2C), 161.9. IR (cmꢁ1): 664.72, 702.61,
828.06, 1031.61, 1090.28, 1251.10, 1493.85, 1546.65, 1610.52,
2840.59, 2938.33, 3070.54, 3444.15. 19F NMR (282 MHz in d6-ac-
(282 MHz in d6-acetone):
d
ꢁ62.71. EI-MS: 306 (Mþ1þ). HR-MS(EI):
calcd for C13H11ClF3NO2: 305.0430; found: 305.0431.
etone):
d
ꢁ62.65. EI-MS: 337 (Mþ). HR-MS(EI): calcd for
C
17H11ClF3NO: 337.0481; found: 337.0486.
4.3.13. 4g: 6-Chloro-2-methyl-4-(trifluoromethyl)quinolin-3-ol. Follow-
ing general procedure, the indicated compound was purified by flash
column chromatography on silica as a yellow solid, yield 84%, the
product was changed into black oil at 148 ꢀC. 1H NMR (300 MHz in d6-
4.3.18. 4l:
6-Chloro-2-(furan-2-yl)-4-(trifluoromethyl)quinoline.
Following general procedure, the indicated compound was purified
by flash column chromatography on silica as a gray-pink solid, yield
95%, mp: 121.5e122.8 ꢀC. 1H NMR (300 MHz in d6-acetone):
acetone):
d
2.59 (s, 3H), 7.63 (dd, J¼9.0, 2.2 Hz, 1H), 7.94e8.02 (m, 2H),
9.48 (br, 1H). 13C NMR (100 MHz in d6-acetone):
d
20.5, 112.2 (q,
d
6.74e6.77 (m, 1H), 7.49 (dd, J¼3.5, 0.6 Hz, 1H), 788e7.94 (m, 2H),
J¼29.6 Hz), 121.7 (q, J¼4.5 Hz),124.3,124.6 (q, J¼275.7 Hz),131.3,127.3,
133.0, 140.9, 148.1, 154.6. IR (cmꢁ1): 638.02, 696.54, 821.06, 1452.00,
1499.41, 1595.99, 2961.79, 3135.50. 19F NMR (282 MHz in d6-acetone):
8.03e8.07 (m, 1H), 8.18 (d, J¼9.0 Hz, 1H), 8.27 (s, 1H). 13C NMR
(100 MHz in DMSO):
d
113.5, 113.6, 116.6 (d, J¼5.3 Hz), 121.7, 122.6,
123.5 (q, J¼275.6 Hz), 132.3, 132.5, 133.4, 133.3 (q, J¼31.1 Hz), 146.8,
147.2, 148.7, 152.1. IR (cmꢁ1): 664.48, 692.39, 746.65, 1081.28,
1263.73, 1495.82, 1448.45, 1553.20, 1616.83, 3072.20, 3117.36,
d
ꢁ55.49. EI-MS: 261 (Mþ). HR-MS(EI): calcd for C11H7ClF3NO:
261.0168; found: 261.0172.
3158.18. 19F NMR (282 MHz in d6-acetone):
d
ꢁ62.66. EI-MS: 297
4.3.14. 4h: 6-Chloro-4-(trifluoromethyl)quinoline-2-carboxylate
ethyl. Following general procedure, the indicated compound was
purified by flash column chromatography on silica as light brown oil,
(Mþ). HR-MS(EI): calcd for C14H7ClF3NO: 297.0168; found: 297.0170.
4.3.19. 4m: 6-Chloro-2-(thiophen-2-yl)-4-(trifluoromethyl)quinoli-
ne. Following general procedure, the indicated compound was
purified by flash column chromatography on silica as a yellow solid,
yield 95%, mp: 152.5e155.0 ꢀC. 1H NMR (300 MHz in d6-acetone):
yield 70%. 1H NMR (300 MHz in d6-acetone):
d
1.49 (t, J¼7.1 Hz, 3H),
4.56(q, J¼7.3Hz, 2H), 8.07 (dd,J¼9.0, 2.2 Hz,1H), 8.20(t, J¼2.0 Hz,1H),
8.39 (d, J¼9.0 Hz,1H), 8.50 (s, 1H). 13C NMR (100 MHz in d6-acetone):
d
13.6, 62.0, 118.9 (q, J¼5.5 Hz), 122.6 (q, J¼2.3 Hz), 123.1 (q,
d
7.26e7.30 (m, 1H), 7.86 (d, J¼4.9 Hz, 1H), 7.94 (dd, J¼9.2, 1.8 Hz,
1H), 7.98 (t, J¼2.2 Hz, 1H), 8.16 (d, J¼8.9 Hz, 1H), 8.28 (d, J¼3.6 Hz,
1H), 8.54 (s, 1H). 13C NMR (100 MHz in DMSO):
J¼273.7 Hz),124.1,132.1,133.4,133.9 (q, J¼32.2 Hz),136.4,146.9,148.7,
163.71. IR (cmꢁ1): 664.6, 688.0, 790.2, 836.1, 1022.2, 1120.7, 1165.1,
1178.5, 1288.9, 1455.1, 1496.8, 1625.4, 1723.1, 2983.8, 3052.0, 3078.6,
d
117.1 (d, J¼4.9 Hz),
121.9, 122.6 (d, J¼3.3 Hz), 123.5 (q, J¼274.3 Hz), 129.4, 129.9, 131.9,
132.2, 132.3, 133.2, 133.3 (q, J¼31.7 Hz), 143.4, 147.0, 152.7. IR
(cmꢁ1): 843.59, 1154.20, 1263.22, 1276.48, 1354.89, 1378.20,
1422.03, 1493.90, 1551.75, 1611.62, 3106.91. 19F NMR (282 MHz in
3379.0.19F NMR (282 MHz in d6-acetone):
d
ꢁ62.73. EI-MS: 303 (Mþ).
HR-MS(EI): calcd for C13H9ClF3NO2: 303.0274, found: 303.0278.
4.3.15. 4i: 6-Chloro-2-methyl-4-(trifluoromethyl)quinoline-3-
carboxylate ethyl. Following general procedure, the indicated
compound was purified by flash column chromatography on silica
as white grain-like solid, yield 75%, mp: 78.9e81.2 ꢀC. 1H NMR
d6-acetone):
d
ꢁ62.25. EI-MS: 313 (Mþ). HR-MS(EI): calcd for
C14H7ClF3NS: 312.9940; found: 312.9945.
4.3.20. 4n:
6-Chloro-2-(thiazole-2-yl)-4-(trifluoromethyl)quinoli-
(300 MHz in d6-acetone):
(q, J¼7.1 Hz, 2H), 7.75 (dd, J¼9.0, 1.9 Hz, 1H), 8.04 (d, J¼9.3 Hz, 1H),
8.10 (s, 1H). 13C NMR (100 MHz in Cl3CD):
13.9, 23.2, 62.7, 121.5,
d
1.73 (t, J¼7.1 Hz, 3H), 2.74 (s, 3H), 4.51
ne. Following general procedure, the indicated compound was
purified by flash column chromatography on silica as a white sheet-
like crystal, yield 90%, mp: 158.6e160.3 ꢀC. 1H NMR (300 MHz in
d
122.9 (q, J¼276.8 Hz),123.6 (q, J¼4.2 Hz),126.7,129.7 (q, J¼32.2 Hz),
131.2, 131.8, 134.3, 146.5, 154.9, 166.8. IR (cmꢁ1): 630.42, 668.68,
717.43, 759.14, 1065.04, 1491.06, 1598.46, 1731.91, 2906.24, 2989.11,
3052.75, 3118.13, 3444.71. 19F NMR (282 MHz in d6-acetone):
d6-acetone):
d
8.02e8.08 (m, 2H), 8.10 (d, J¼3.4 Hz, 1H), 8.16 (d,
J¼3.1 Hz, 1H), 8.30 (d, J¼8.7 Hz, 1H), 8.60 (s, 1H). 13C NMR (100 MHz
in DMSO):
d
116.5 (q, J¼5.8 Hz), 122.8 (d, J¼5.3 Hz), 123.3 (q,
J¼274.9 Hz), 123.3, 125.5, 132.7, 132.6, 133.7 (q, J¼32.0 Hz), 134.8,
145.4, 146.9, 151.3, 166.9. IR (cmꢁ1): 663.73, 735.12, 856.08, 1063.65,
1254.79, 1492.63, 1557.03, 1607.86, 3035.56, 3063.89, 3084.81. 19F
NMR (282 MHz in d6-acetone):
HR-MS(EI): calcd for C13H6ClF3N2S: 313.9892; found: 313.9898.
d
ꢁ57.38. EI-MS: 317 (Mþ). HR-MS(EI): calcd for C14H11ClF3NO2:
317.0430; found: 317.0422.
d
ꢁ62.99. EI-MS: 314 (Mþ).
4.3.16. 4j:
6-Chloro-2-(4-nitrophenyl)-4-(trifluoromethyl)quinoli-
ne. Following general procedure, the indicated compound was
purified by flash column chromatography on silica as yellow solid,
yield 85%, mp: 206.2e207.5 ꢀC. 1H NMR (300 MHz in d6-acetone):
4.3.21. 4o: 6-Chloro-2-(pyridin-4-yl)-4-(trifluoromethyl)quinoline.
Following general procedure, the indicated compound was purified
by flash column chromatography on silica as white powder, yield
d
7.85 (dd, J¼9.1, 2.1 Hz, 1H), 8.00 (s, 1H), 8.21 (d, J¼9.0 Hz, 1H), 8.31

7486
X.L. Du et al. / Tetrahedron 69 (2013) 7481e7486
90%, mp: 135.3e136.0 ꢀC. 1H NMR (300 MHz in d6-acetone):
d
7.90
128.9, 130.7, 132.4, 134.3, 135.0 (q, J¼1.6 Hz), 137.3, 146.5, 153.3.
IR (cmꢁ1): 653.45, 769.34, 831.75, 1091.74, 1444.58, 1493.84,
1608.32, 3027.63, 3064.49, 3087.63, 3415.45. 19F NMR (282 MHz in
(dd, J¼8.2, 2.1 Hz, 1H), 8.03e8.08 (m, 1H), 8.20e8.27 (m, 3H), 8.51
(s, 1H), 8.78 (d, J¼6.2 Hz, 1H). 13C NMR (100 MHz in d6-acetone):
d
116.9 (d, J¼5.5 Hz), 121.2 (2C), 122.4 (d, J¼2.5 Hz), 122.8, 123.4 (q,
d6-acetone):
d
ꢁ53.44. EI-MS: 307 (Mþ). HR-MS(EI): calcd for
J¼274.3 Hz), 131.7, 132.7, 134.1 (d, J¼32.2 Hz), 134.7, 144.2, 147.3,
150.7 (2C), 154.5. IR (cmꢁ1): 669.28, 713.63, 789.23, 828.34,
1085.33, 1266.84, 1491.76, 1593.11, 1611.17, 3041.92. 19F NMR
(282 MHz in d6-acetone):
calcd for C15H8ClF3N2: 308.0328; found: 308.0320.
C16H9ClF3N: 307.0376; found: 307.0381.
References and notes
d
ꢁ62.50. EI-MS: 308 (Mþ). HR-MS(EI):
1. (a) Zhao, S.; Shen, Y. X.; Van, O. A.; Marschke, K. B.; Zhi, L. Bioorg. Med. Chem. Lett.
2008, 18, 3431e3435; (b) Long, Y. O.; Higuchi, R. I.; Caferro, T. R.; Lau, T. L. S.; Wu,
M.; Cummings, M. L.; Martinborough, E. A.; Marschke, K. B.; Chang, W. Y.; Lopez,
F. J.; Karanewsky, D. S.; Zhi, L. Bioorg. Med. Chem. Lett. 2008, 18, 2967e2971; (c)
Zhu, L. J.; Miao, Z. Y.; Sheng, C. Q.; Guo, W.; Yao, J. Z.; Liu, W. F.; Che, X. Y.; Wang,
W. Y.; Cheng, P. F.; Zhang, W. N. Eur. J. Med. Chem. 2010, 45, 2726e2732; (d)
Chambers, R. D. In Organofluorine Chemistry Techniques and Synthons; Chambers,
R. D., Ed.; Topics in Current Chemistry; Springer: Berlin, Heidelberg, Germany,
1997; Vol. 193, p 3; (e) Organofluorine Compounds: Chemistry and Applications;
Hiyama, T., Ed.; Springer: Berlin, Germany, 2000; p 137; (f) Dade, J.; Provot, O.;
Moskowitz, H.; Mayrargue, J.; Prina, E. Chem. Pharm. Bull. 2001, 49, 480e483; (g)
Michel, B. W.; Steffens, L. D.; Sigman, M. S. J. Am. Chem. Soc. 2011,133, 8317e8325; (h)
Pillai, S.; Kozlov, M.; Marras, S. A. E.; Mustaev, A.; Krasnoperov, L. N. J. Fluoresc. 2012, 22,
1021e1032; (i) Jia, C. S.; Zhang, Z.; Tu, S. J.; Wang, G. W. Org. Biomol. Chem. 2006, 4,
104e110; (j) Wang, G. W.; Jia, C. S.; Dong, Y. W. Tetrahedron Lett. 2006, 47,1059e1063;
(k) Jia, C. S.; Zhang, Z.; Tu, S. J.; Wang, G. W. Tetrahedron 2007, 63, 892e897; (l) Han, J.;
Cao, L.; Bian, L. L., et al. Adv. Synth. Catal. 2013, 355, 1345e1350.
4.3.22. 4p: 6-Chloro-2-(naphthalen-2-yl)-4-(trifluoromethyl)quino-
line. Following general procedure, the indicated compound was
purified by flash column chromatography on silica as a white solid,
yield 95%, mp: 119.1e120.4 ꢀC. 1H NMR (400 MHz in d6-acetone):
d
7.52e7.63 (m, 2H), 7.69 (t, J¼7.7 Hz,1H), 7.87 (d, J¼7.0 Hz,1H), 7.98
(dd, J¼9.2, 2.5 Hz, 1H), 8.05 (d, J¼7.7 Hz, 1H), 8.11 (d, J¼8.4 Hz, 1H),
8.19 (s, 1H), 8.24 (s, 1H), 8.27 (d, J¼8.7 Hz,1H), 8.30 (d, J¼9.0 Hz,1H).
13C NMR (100 MHz in d6-acetone):
d 121.3, 121.4, 121.9, 123.1 (q,
J¼275.5 Hz), 125.0, 125.4, 126.2, 127.1, 128.4, 128.6, 129.8, 130.3,
131.6, 132.5 (q, J¼32.3 Hz), 132.5, 133.4, 133.5, 136.2, 146.6, 158.9. IR
(cmꢁ1): 636.19, 669.52, 781.07, 825.63, 1274.11, 1492.64, 1552.21,
1591.47, 1608.81, 3000.16, 3043.47, 3085.70, 3106.91. 19F NMR
2. (a) Dade, J.; Provot, O.; Moskowitz, H.; Mayrargue, J.; Prina, E. Chem. Pharm. Bull.
2001, 49, 480e483; (b) Schlosser, M.; Cottet, F.; Heiss, C.; Lefebvre, O.; Marull,
M.; Masson, E.; Scopelliti, R. Eur. J. Org. Chem. 2006, 729e734.
(282 MHz in d6-acetone):
calcd for C20H11ClF3N: 357.0532; found: 357.0532.
d
ꢁ64.94. EI-MS: 357 (Mþ). HR-MS(EI):
3. (a) Golubev, A. S.; Bogomolov, V. O.; Shidlovskii, A. F.; Dezhenkova, L. G.; Per-
egudov, A. S.; Shtil, A. A.; Chkanikov, N. D. Russ. Chem. Bull., Int. Ed. 2010, 59,
209e218; (b) Hosokawa, T.; Matsumura, A.; Katagiri, T.; Uneyama, K. J. Org. Chem.
2008, 73, 1468e1474; (c) Bonacorso, H. G.; De Moraes, T. S.; Zanatta, N.; Pinto
Martins, M. A. Synth. Commun. 2009, 39, 3677e3686; (d) Bonacorso, H. G.; An-
drighetto, R.; Zanatta, N.; Martins, M. A. P. Tetrahedron Lett. 2010, 51, 3752e3755;
(e) Bonacorso, H. G.; Andrighetto, R.; Krueger, N.; Martins, M. A. P.; Zanatta, N. J.
Braz. Chem. Soc. 2011, 22, 1426e1438.
4. (a) Lefebvre, O.; Marull, M.; Schlosser, M. Eur. J. Org. Chem. 2003, 2115e2121; (b)
Micotto, T. L.; Brown, A. S.; Wilson, J. N. Chem. Commun. 2009, 7548e7550; (c)
Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem., Int. Ed.
2011, 50, 3793e3798; (d) Shidlovskii, A. F.; Golubev, A. S.; Gusev, D. V.; Supo-
nitsky, K. Y.; Peregudov, A. S.; Chkanikov, N. D. J. Fluorine Chem. 2012, 143,
272e280.
5. (a) Linderman, R. J.; Kirollos, K. S. Tetrahedron Lett. 1990, 31, 2689e2692; (b)
Sloop, J. C.; Bumgardner, C. L.; Loehle, W. D. J. Fluorine Chem. 2002, 118, 135e147 For
other methods to synthesize 4-trifluoromethyl quinoline derivatives, see: (c) Okada,
E.; Tsukushi, N.; Huang, T.; Tone, H.; Gotoh, N.; Takeuchi, H.; Hojo, M. Heterocycles
1998, 48, 95e102; (d) Strekowski, L.; Lin, S. Y.; Lee, H.; Zhang, Z. Q.; Mason, J. C.
Tetrahedron 1998, 54, 7947e7954.
4.3.23. 4q: 6-Chloro-3-ethyl-4-(trifluoromethyl)quinoline. Follow-
ing general procedure, the indicated compound was purified by
flash column chromatography on silica as light brown oil, yield 97%.
1H NMR (300 MHz in d6-acetone):
d
1.32 (t, J¼7.6 Hz, 3H), 3.10 (qq,
J¼7.5, 2.3 Hz, 2H), 7.81 (dd, J¼8.9, 2.2 Hz, 1H), 8.10 (t, J¼2.1 Hz, 1H),
8.14 (d, J¼8.8 Hz, 1H), 8.97 (s, 1H). 13C NMR (100 MHz in d6-ace-
tone):
d
15.6, 25.4 (q, J¼4.1 Hz), 122.9 (q, J¼5.4 Hz), 123.8, 124.8 (q,
J¼276.4 Hz), 128.4, 129.8, 132.2, 133.8, 137.0 (q, J¼2.4 Hz), 145.9,
154.6. IR (cmꢁ1): 644.6, 656.9, 722.3, 833.5, 931.3, 1054.8, 1096.8,
1126.2, 1296.3, 1495.7, 1609.9, 2882.4, 2939.5, 2980.9. 19F NMR
(282 MHz in d6-acetone):
calcd for C12H9ClF3N: 259.0376; found: 259.0376.
d
ꢁ55.13. EI-MS: 259 (Mþ). HR-MS(EI):
4.3.24. 4r: 6-Chloro-3-phenyl-4-(trifluoromethyl)quinoline. Follow-
ing general procedure, the indicated compound was purified by
flash column chromatography on silica as a white solid, yield 73%,
6. (a) Jiang, B.; Si, Y. G. J. Org. Chem. 2002, 67, 9449e9451; (b) Jiang, B.; Dong, J. J.;
Jin, Y.; Du, X. L.; Xu, M. Eur. J. Org. Chem. 2008, 2693e2696.
7. (a) List, B. Synlett 2001, 1675e1686; (b) Pidathala, C.; Hoang, L.; Vignola, N.; List,
B. Angew. Chem., Int. Ed. 2003, 42, 2785e2788; (c) Heine, A.; DeSantis, G.; Luz, J.
G.; Mitchell, M.; Wong, C. H.; Wilsoon, I. A. Science 2001, 294, 369e374; (d)
Rankin, K. N.; Gauld, J. W.; Boyd, R. J. J. Phys. Chem. A 2002, 106, 5155e5159; (e)
Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125,
2475e2479.
mp: 81.5e83.6 ꢀC. 1H NMR (300 MHz in d6-acetone):
d 7.44e7.56
(m, 5H), 7.92 (dd, J¼9.0, 2.1 Hz, 1H), 8.19 (t, J¼2.1 Hz, 1H), 8.24 (d,
J¼8.6 Hz, 1H), 8.89 (s, 1H). 13C NMR (100 MHz in d6-acetone):
d
123.4 (q, J¼4.1 Hz), 123.5, 123.9 (q, J¼276.1 Hz), 128.3, 128.5, 128.8,