An Improved Access to 4-Trifluoromethyl-2(1H)-quinolinones: The "Watering Protocol"

Article abstract of DOI:10.1002/ejoc.200300531

Condensation of anilines with ethyl 4,4,4-trifluoroacetoacetate (7) to afford the corresponding 4,4,4-trifluoro-3-oxobutaneanilides (10), precursors to 4-(trifluoromethyl)-2-quinolinones (11), can be favored and the competing condensation to produce the e

Full text of DOI:10.1002/ejoc.200300531

FULL PAPER
An Improved Access to 4-Trifluoromethyl-2(1H)-quinolinones:
The ‘‘Watering Protocol’’
Marc Marull,[a] Olivier Lefebvre,[a] and Manfred Schlosser*[a,b]
Keywords: Halogens / Heterocycles / Hydrogen-metal permutation / Regioselectivity / Trifluoromethyl substituents
Condensation of anilines with ethyl 4,4,4-trifluoroacetoace- the anilides has to be accomplished under carefully controlled
tate (7) to afford the corresponding 4,4,4-trifluoro-3-oxobut- conditions. The resulting 4-(trifluoromethyl)-2-quinolinones
aneanilides (10), precursors to 4-(trifluoromethyl)-2-quinolin- (11) can be converted into 4-(trifluoromethyl)quinolines (13),
ones (11), can be favored and the competing condensation to 4-(trifluoromethyl)-2-quinolinecarboxylic acids (14), and 2-
produce the ethyl 4,4,4-trifluoro-3-(phenylimino)butanoate, bromo-4-(trifluoromethyl)quinolines (12), the last of which
the precursor to 2-(trifluoromethyl)-4-quinolinones, avoided may in turn be converted into 2-bromo-4-(trifluoromethyl)-3-
if water is occasionally added to the reaction mixture while quinolinecarboxylic acids (15) and eventually 4-trifluorome-
ethanol is continuously removed by distillation. The anilides thyl-3-quinolinecarboxylic acids (16).
10 also form selectively when 4,4,4-trifluoroacetoacetyl chlo- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ride (6) is allowed to react with anilines. The cyclization of Germany, 2004)
Introduction
Following literature precedents, we have recently pre-
pared a variety of 2-trifluoromethyl-4(1H)-quinolinones[1]
and 4-trifluoromethyl-2(1H)-quinolinones.[2] In the latter
series, however, yields were poor at best (21Ϫ36%). When-
ever the aniline carried an electron-withdrawing substitu-
ent, even if only a moderately powerful one, the isomeric 4-
quinolinone was obtained rather than the expected 2-quino-
linone. To gain insight, we embarked on a systematic study.
The 2-/4-quinolinone dichotomy was first recognized by
L. Knorr.[3Ϫ5] Leaving a mixture of aniline and ethyl ace-
toacetate (1) at ambient temperature for a few days was
found to give the anil 2 (or rather the tautomeric ethyl β-
anilinocrotonate).[3Ϫ5] In contrast, the acetoacetanilide 4 re-
sults when the two components are briefly heated to about
150 °C.[4,6] When treated with concentrated sulfuric acid at
85 °C (or 100 °C), the anilide 4 undergoes smooth cycliza-
tion to the 4-methyl-2(1H)-quinolinone (5), whereas the
cyclization to the isomeric 2-methyl-4(1H)-quinolinone (3)
is generally brought about by heating the crotonate to ap-
proximately 250 °C.[7,8] These reaction conditions suggest
an intramolecular FriedelϪCrafts-type process operating in
the former case and an electrocyclic ring-closure in the lat-
ter. Crotonates and anilides can be mutually interconverted
by heating them in the presence of water or in ethanol (the
latter in the presence of a drying agent), respectively.[5,8]
[a]
´
Institut de Chimie moleculaire et biologique, Ecole
´ ´
Polytechnique Federale, BCh,
1015 Lausanne, Switzerland
[b]
´
´
Faculte des Sciences, Universite, BCh,
Replacement of ethyl acetoacetate by ethyl 4,4,4-trifluo-
roacetoacetate (7), a bulk material made from 4,4,4-trifluo-
1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
54
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300531
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Improved Access to 4-Trifluoromethyl-2(1H)-quinolinones
FULL PAPER
roacetoacetyl chloride[1] (6), does not alter the funda- which is already sufficiently activated by the neighboring
mentals but requires adjustment of the experimental con- fluorine atoms. The protonated carboxamide function, be-
ditions. To prepare the crotonates 8, the reactants have to ing part of the newly formed hemiaminal, would now dock
be heated in the presence of polyphosphoric acid for 90 min at the ortho-position of the aromatic ring, whereas the other
at 150 °C.[9,10] The anilides 10 have been obtained, although one would remain electronically passive because the pro-
generally in poor yields, by heating the aniline and ethyl tonation of the carboxamide immobilizes the lone pair. De-
4,4,4-trifluoroacetoacetate (7) either to 235 °C for a few mi- hydration and elimination of the initial aniline would ter-
nutes[11] or to 155 °C for a prolonged period of time (typi- minate the reaction sequence.
cally 18 h).[12] The cyclization of the crotonates 8 can be
brought about thermally, at temperatures ranging from 170
°C to 250 °C,[9,10] and that of the anilides 10 by heating
with concentrated sulfuric acid at 90Ϫ95 °C.[11,12]
As demonstrated in a recent series of publications,[16Ϫ18]
the preparation of the anilides and their cyclization can be
contracted into a single operational step merely by heating
the condensation components aniline and ethyl 4,4,4-tri-
fluoroacetoacetate for several hours under reflux in ethanol
and in the presence of zinc chloride. From our own experi-
Results
A modified procedure[13] employs methanesulfonic acid
in the presence of phosphorus pentoxide for the cyclization
of 4,4,4-trifluoroacetoacetanilides (4,4,4-trifluoro-3-oxobu-
tananilides, 10). We applied this method to the parent com-
pound 4,4,4-trifluoroacetoacetanilide and the anilides de-
rived from 2- and 3-toluidine, 2-fluoroaniline, and 2- and
4-anisidine, but invariably isolated the 2-(trifluoromethyl)-
4(1H)quinolinones (9; 41Ϫ51%) rather than the expected 4-
(trifluoromethyl)-2(1H)quinolinones (11). This is remi-
niscent of the surprising outcome of the acid-catalyzed
cyclization of 4-anilino-1,1,1-trifluoro-3-buten-2-ones to 2-
rather than 4-(trifluoromethyl)quinolines.[14] The suggested
ence, however, this method suffers from an extremely nar-
row scope of applicability. It appears to work well only with
markedly electron-rich anilines such as 3-anisidine[19] and
1,3-diaminobenzene[20] and its congeners. Even 3-hydroxy-
aniline provides only small amounts of 7-hydroxy-4-tri-
fluoromethyl-2(1H)-quinolinone, along with a further by-
product and the main component, 7-amino-4-trifluorome-
thyl-2H-1-benzopyran-2-one, resulting from a Pechmann
reaction.[19] No quinolinone at all was formed when aniline,
4-toluidine, 2- or 3-fluoroaniline, and 4-trifluoromethoxy-
aniline were used as the starting materials.
The lesson thus learned was that none of the literature
mechanism[15] may also provide a clue as to how to explain procedures offers an expedient and universal entry to the
the present findings. Under strongly acidic conditions, pro- family of 4-trifluoromethyl-2-quinolinones. As the cycliza-
tonation of both carbonyl groups, the one residing in the tion proceeds reliably and with satisfactory yields when
ketone part and the other one belonging to the amide func- brought about with concentrated sulfuric acid, the problem
tion, may occur simultaneously. Free aniline, always present can be narrowed down to the preparation of the required
in minute amounts due to unavoidable hydrolysis, might 4,4,4-trifluoroacetoacetanilide intermediates 10. A possible
come by and add to the activated carbenium-oxonium ion. solution is to be found in the patent literature.[21] The acyl
Alternatively, aniline could add directly to the oxo group, carbonyl group of 4,4,4-trifluoroacetoacetyl chloride (6) be-
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55

M. Marull, O. Lefebvre, M. Schloser
FULL PAPER
ing far more electrophilic than any ester carbonyl group, (11d, 11i, 11j, 11k, and 11l) prepared for the first time were
nucleophiles Ϫ including anilines Ϫ directly attack the ter- converted into the 2-bromo-4-(trifluoromethyl)quinolines
minal functionality. In this way, we have been able to obtain 12 (Table 3), and these in turn into the 4-(trifluorome-
six different 4,4,4-trifluoroacetoanilides in yields ranging thyl)quinolines 13 (Table 3), the 4-(trifluoromethyl)quino-
from 71Ϫ81% (see Table 1).
line-2-carboxylic acids 14 (Table 3), the 2-bromo-4-(trifluor-
omethyl)quinoline-3-carboxylic acids 15 (Table 3), and the
4-(trifluoromethyl)quinoline-3-carboxylic acids 16 (Table 3)
by application of the same methods as described pre-
viously.[2]
Table 1. 4,4,4-Trifluoroacetoacetanilides 10 produced by conden-
sation between anilines and 4,4,4-trifluoroacetoacetyl chloride (6)
or ethyl 4,4,4-trifluoroacetoacetate (7): yields of isolated products
[a]
Compound
R
From 6
From 7[b]
a
b
c
d
e
f
g
h
i
H
p-H3C
p-F
p-F3CO
m-H3C
m-H3CO
m-F
o-H3C
o-F
81%
78%
Ϫ
74%
81%
76%
Ϫ
Ϫ
Ϫ
71%
Ϫ
Ϫ
91%
88%
82%
72%
92%
87%
93%
87%
56%
51%
44%
41%
j
k
l
o-Cl
o-Br
o-I
[a]
Substituent R as present in the aniline starting material and its
[b]
position (ortho, meta, or para) in the aromatic ring. Application
of the ‘‘watering protocol’’.
This approach, of course, depends totally on the avail-
ability of 4,4,4-trifluoroacetoacetyl chloride (6),[22,23] which
is difficult to make and unstable at ambient temperature.
We have therefore reinvestigated the condensation reaction
between aniline and ethyl 4,4,4-trifluoroacetoacetate (7).
The amino function should rapidly add to the extremely
electrophilic carbonyl group activated by the neighboring
trifluoromethyl entity without even requiring acid catalysis.
The hemiacetal thus produced should give the crotonate
upon loss of water. Despite the enhanced thermodynamic
stability of the anilide, its formation is sluggish because it
has to be preceded by the energetically unattractive addition
of the aniline to the ethoxycarbonyl unit. The only chance
to reorient the course of the condensation-cyclization se-
quence towards the 4-(trifluoromethyl)quinolinones 11 is to
make all reaction steps reversible and to shift the equilib-
As already reported,[24] 2-bromo-8-iodo-4-(trifluorome-
rium from the crotonate 8 to the anilide intermediates 10 thyl)quinoline (12l) undergoes a selective iodine/lithium
by allowing the by-product ethanol to escape while retain- permutation to afford, upon carboxylation, the 2-bromo-4-
ing water, the by-product resulting from crotonate forma- (trifluoromethyl)quinoline-8-carboxylic acid (17) and, after
tion. As we have found, this can most conveniently be reductive debromination, the 4-(trifluoromethyl)quinoline-
achieved by keeping the mixture of the two reactants in an 8-carboxylic acid. To introduce lithium into the 2-position
open vessel at 130 °C and replenishing it portionwise with rather than the 8-position and thus to pave the way to the
water in 30 min intervals. In this way, we have been able to 8-iodo-4-(trifluoromethyl)quinoline-2-carboxylic acid (14l),
make a variety of 4,4,4-trifluoroacetoacetanilides (see one would first have to exchange[25] the bromine in quino-
Table 1), mostly in excellent yields (10aϪh: 72Ϫ92%), al- line 12l with another iodine atom. 2,8-Dibromo-4-(trifluo-
though only in moderate yields when o-haloanilines were romethyl)quinoline (12k) preferentially underwent the per-
employed as the starting materials (10iϪl: 44Ϫ56%).
mutational interconversion at the 2-position with alkyl-
The cyclization of the anilides 10 proceeded smoothly lithium reagents, although perfect regioselectivity was
when promoted by concentrated sulfuric acid at 95 °C, and achieved only under carefully optimized conditions (lithium
provided the 4-(trifluoromethyl)-2(1H)-quinolinones 11 in tributylmagnesiate[26Ϫ28] in toluene). In contrast, 8-bromo-
high yields (80Ϫ92%; see Table 2). Those quinolinones 2-iodo-4-(trifluoromethyl)quinoline (18), readily obtained
56
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Improved Access to 4-Trifluoromethyl-2(1H)-quinolinones
FULL PAPER
decoupled 13C, and 19F NMR spectra of samples dissolved in deut-
eriochloroform or, if marked by an asterisk, in hexadeuterioacetone
were recorded at 400, 101, and 376 MHz, respectively, chemical
shifts being given relative to tetramethylsilane and trichlorofluoro-
methane as the internal standards.
Table 2. Acid-promoted cyclization of the anilides 10 to the 4-tri-
fluoromethyl-2(1H)-quinolinones 11: yields of isolated products
[a]
[b]
R
H
Position
Product 11
a
b
c
d
e
f
g
h
i
Ϫ
6
6
90%
89%
92%
84%
87%
83%
91%
89%
57%
80%
22%
39%
4,4,4-Trifluoroacetoacetanilides (10): Ethyl 4,4,4-trifluoro-3-oxobu-
tanoate (7; 58 mL, 74 g, 0.40 mol) and the aniline (0.20 mol) were
heated at 130 °C. Water (4.0 mL) was added every 30 min over a
period of 6 h. At 0 °C, after spontaneous crystallization, the solid
mass was filtered and washed with hexanes (3 ϫ 0.20 L) before
being recrystallized from a 1:1 (v/v) mixture of ethyl acetate and
hexanes.
p-H3C
p-F
p-F3CO
m-H3C
m-H3CO
m-F
o-H3C
o-F
o-Cl
6
7[c]
7[c]
7[c]
8
8
8
8
8
Alternatively, 4,4,4-trifluoro-3-oxobutanoyl chloride[1] (6; 0.20 mol)
in dichloromethane (85 mL) was added dropwise, over the course
of 2 h, to a solution of aniline (0.20 mol) and triethylamine (28 mL,
20 g, 0.20 mol) in dichloromethane (50 mL), kept in an ice bath.
The volatiles were evaporated, and the residue was taken up in
diethyl ether (0.25 L) and washed with water (3 ϫ 0.25 L). The
product was again purified by crystallization.
j
k
l
o-Br
o-I
[a]
Substituent R as present in the aniline starting material and its
[b]
position (ortho, meta, or para) in the aromatic ring. Position of
the substituent R in the cyclization product (quinolinone 11).
No 5-isomer detected.
[c]
4,4,4-Trifluoro-3-oxo-N-phenylbutanamide (10a): This compound
was prepared from aniline (18 mL, 19 g, 0.20 mol) and ethyl 4,4,4-
trifluoroacetoacetate; colorless prisms; m.p. 94Ϫ95 °C; yield 42.1 g
(91%). 1H NMR: δ ϭ 7.50 (d, J ϭ 8.4 Hz, 2 H), 7.37 (t, J ϭ 8.6 Hz,
2 H), 7.19 (t, J ϭ 7.19 Hz, 1 H), 2.81 (s, 2 H) ppm. 13C NMR*:
δ ϭ 170.0, 138.6, 129.3, 125.2, 124.1 (q, J ϭ 286 Hz), 120.5, 93.5
(q, J ϭ 32 Hz), 39.0 ppm. MS (c.i.): m/z (%) ϭ 249 (5) [Mϩ ϩ 18],
232 (40) [Mϩ ϩ 1], 231 (42) [Mϩ], 93 (100). C10H8F3NO2 (231.16):
calcd. C 51.96, H 3.49; found C 51.44, H 3.44. When 4,4,4-trifluo-
roacetoacetyl chloride was used instead of the ester, amide 10a was
obtained in 81% yield (37.3 g).
Table 3. Conversion of the quinolinones 11 into 2-bromo-4-(trifluo-
romethyl)quinolines 12, 4-(trifluoromethyl)quinolines 13, 4-(tri-
fluoromethyl)quinoline-2-carboxylic acids 14, 2-bromo-4-(trifluo-
romethyl)quinoline-3-carboxylic acids 15, and 4-(trifluorome-
thyl)quinoline-3-carboxylic acids 16: yields of isolated products
R (in 11)
12
13
14
15
16
d
i
6-F3CO
8-F
8-Cl
8-Br
8-I
89%
55%
79%
59%
88%
75%
63%
86%
92%
82%
69%
73%
61%
58%
Ϫ
40%
83%
78%
81%
89%
81%
83%
89%
78%
83%
j
4,4,4-Trifluoro-N-(4-methylphenyl)-3-oxobutanamide (10b): This
compound was prepared from 4-methylaniline (p-toluidine; 21 g,
0.20 mol) and ethyl 4,4,4-trifluoroacetoacetate; colorless prisms;
m.p. 92Ϫ94 °C; yield 43.2 g (88%). 1H NMR: δ ϭ 7.37 (d, J ϭ
8.0 Hz, 2 H), 7.16 (d, J ϭ 8.0 Hz, 2 H), 2.79 (s, 2 H), 2.34 (s, 3 H)
ppm. 13C NMR*: δ ϭ 170.0, 136.4, 134.8, 130.1, 123.9 (q, J ϭ
286 Hz), 119.8, 94.0 (q, J ϭ 32 Hz), 39.1, 20.9 ppm. MS (c.i.): m/z
(%) ϭ 263 (45) [Mϩ ϩ 18], 246 (67) [Mϩ ϩ 1], 245 (13) [Mϩ], 198
(1), 176 (6), 107 (100). C11H10F3NO2 (245.20): calcd. C 53.88, H
4.11; found C 53.94, H 4.04. When 4,4,4-trifluoroacetoacetyl chlo-
ride was used instead of the ester, amide 10b was obtained in 78%
yield (38.3 g).
K
l
from the dibromo compound 12k by halogen/halogen dis-
placement,[25] was found to react exclusively at the 2-posi-
tion, where the heaviest halogen was located, thus opening
a convenient and clean entry to the 2-bromo-4-(trifluoro-
methyl)quinoline-2-carboxylic acid (14k).
4,4,4-Trifluoro-N-(4-fluorophenyl)-3-oxobutanamide (10c): This
compound was prepared from 4-fluoroaniline (19 mL, 22 g, 0.20
mol) and ethyl 4,4,4-trifluoroacetoacetate; colorless prisms; m.p.
1
102Ϫ104 °C; yield 40.9 g (82%). H NMR: δ ϭ 7.44 (dd, J ϭ 9.1,
4.6 Hz, 2 H), 7.05 (dd, J ϭ 8.9, 8.3 Hz, 2 H), 5.59 (s, 1 H) ppm.
13C NMR: δ ϭ 168.3, 160.2 (d, J ϭ 247 Hz), 159.3 (q, J ϭ 37 Hz),
132.0, 128.3 (q, J ϭ 9 Hz), 122.6, 119.3 (q, J ϭ 276 Hz), 117.0, (d,
J ϭ 21 Hz), 116.0 (d, J ϭ 23 Hz), 93.3 (d, J ϭ 23 Hz) ppm. MS
(c.i.): m/z (%) ϭ 267 (6) [Mϩ ϩ 18], 250 (37) [Mϩ ϩ 1], 249 (42)
[Mϩ], 180 (9), 111 (100), 83 (23). C10H7F4NO2 (249.16): calcd. C
48.21, H 2.83; found C 48.06, H 2.60.
4,4,4-Trifluoro-3-oxo-N-[4-(trifluoromethoxy)phenyl]butanamide
(10d): This compound was prepared from 4-(trifluoromethoxy)ani-
line (27 mL, 35 g, 0.20 mol) and ethyl 4,4,4-trifluoroacetoacetate;
colorless prisms; m.p. 63Ϫ65 °C; yield 45.4 g (72%). 1H NMR: δ ϭ
7.55 (d, J ϭ 9.0 Hz, 2 H), 7.22 (d, J ϭ 8.8 Hz, 2 H), 5.61 (s, 1 H)
ppm. 13C NMR*: δ ϭ 170.5, 146.1, 138.2, 123.9 (q, J ϭ 286 Hz),
122.6, 122.2, 120.4, 94.0 (q, J ϭ 33 Hz) ppm. MS (c.i..): m/z (%) ϭ
Experimental Section
Details regarding standard operations and abbreviations can be
found in previous publications from this laboratory.[29,30] 1H, 1H-
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57

M. Marull, O. Lefebvre, M. Schloser
333 (93) [Mϩ ϩ 18], 316 (43) [Mϩ ϩ 1], 315 (71) [Mϩ], 246 (4), [Mϩ], 134 (23), 111 (100). C10H7F4NO2 (249.16): calcd. C 48.21, H
FULL PAPER
177 (100), 108 (35). C11H7F6NO3 (315.16): calcd. C 41.92, H 2.24,
N 4.44; found C 42.06, H 2.17, N 4.53. When 4,4,4-trifluoroace-
toacetyl chloride was used instead of the ester, amide 10d was ob-
tained in 74% yield (46.6 g).
2.83; found C 48.07, H 2.76.
N-(2-Chlorophenyl)-4,4,4-trifluoro-3-oxobutanamide (10j): This
compound was prepared from 2-chloroaniline (21 mL, 26 g, 0.20
mol) and ethyl 4,4,4-trifluoroacetoacetate; colorless prisms; m.p.
1
4,4,4-Trifluoro-N-(3-methylphenyl)-3-oxobutanamide (10e): This
compound was prepared from 3-methylaniline (m-toluidine; 22 g,
0.20 mol) and ethyl 4,4,4-trifluoroacetoacetate; colorless prisms;
m.p. 78Ϫ80 °C; yield 45.1 g (92%). 1H NMR: δ ϭ 7.48 (s, 1 H),
7.34 (s, 1 H), 7.23 (m, 1 H), 7.00 (d, J ϭ 6.7 Hz, 1 H), 2.79 (s, 2
H), 2.35 (s, 3 H) ppm. 13C NMR: δ ϭ 168.7, 159.4 (q, J ϭ 37 Hz),
139.6, 136.4, 129.4, 126.8, 121.5, 118.7 (q, J ϭ 276 Hz), 118.1, 93.8,
21.4 ppm. MS (c.i.): m/z (%) ϭ 263 (2) [Mϩ ϩ 18], 246 (53) [Mϩ
ϩ 1], 245 (36) [Mϩ], 176 (5), 107 (100). C11H10F3NO2 (245.20):
calcd. C 53.88, H 4.11, N 5.71; found C 53.86, H 4.07, N 5.69.
When 4,4,4-trifluoroacetoacetyl chloride was used instead of the
ester, amide 10e was obtained in 81% yield (39.7 g).
79Ϫ81 °C; yield 27.1 g (51%). H NMR: δ ϭ 8.24 (d, J ϭ 8.2 Hz,
1 H), 7.89 (s, 1 H), 7.39 (d, J ϭ 8.1 Hz, 1 H), 7.29 (t, J ϭ 8.0 Hz,
1 H), 7.12 (t, J ϭ 7.6 Hz, 1 H), 2.89 (s, 2 H) ppm. 13C NMR: δ ϭ
168.6, 133.5, 129.5, 128.2, 128.1, 126.4, 122.8, 118.9 (q, J ϭ
275 Hz), 93.6 (q, J ϭ 33 Hz), 38.8 ppm. MS (c.i.): m/z (%) ϭ 285
(19) [Mϩ ϩ 18], 283 (45) [Mϩ ϩ 18], 268 (34) [Mϩ ϩ 1], 267 (27)
[Mϩ], 266 (76) [Mϩ ϩ 1], 265 (38) [Mϩ], 230 (60), 196 (9), 127
(100). C10H7ClF3NO2 (265.62): calcd. C 45.22, H 2.66, N 5.28;
found C 45.52, H 2.59, N 5.30. When 4,4,4-trifluoroacetoacetyl
chloride was used instead of the ester, amide 10j was obtained in
71% yield (37.7 g).
N-(2-Bromophenyl)-4,4,4-trifluoro-3-oxobutanamide (10k): This
compound was prepared from 2-bromoaniline (34 g, 0.20 mol) and
ethyl 4,4,4-trifluoroacetoacetate; colorless prisms; m.p. 84Ϫ86 °C;
4,4,4-Trifluoro-N-(3-methoxyphenyl)-3-oxobutanamide (10f): This
compound was prepared from 3-methoxyaniline (m-anisidine;
22 mL, 25 g, 0.20 mol) and ethyl 4,4,4-trifluoroacetoacetate; color-
1
yield 27.3 g (44%). H NMR: δ ϭ 8.20 (dd, J ϭ 8.2, 1.5 Hz, 1 H),
1
less prisms; m.p. 168Ϫ170 °C; yield 45.4 g (87%). H NMR*: δ ϭ
7.57 (dd, J ϭ 8.1, 1.4 Hz, 1 H), 7.33 (td, J ϭ 7.8, 1.3 Hz, 1 H),
7.06 (td, J ϭ 7.9, 1.5 Hz, 1 H), 2.91 (s, 3 H) ppm. 13C NMR: δ ϭ
168.4, 136.8, 132.5, 128.5, 123.0, 122.3 (q, J ϭ 286 Hz), 114.3, 93.0
7.58 (d, J ϭ 8.7 Hz, 1 H), 6.73 (dd, J ϭ 8.9, 2.5 Hz, 1 H), 6.63 (d,
J ϭ 2.5 Hz, 1 H), 5.89 (s, 1 H), 3.86 (s, 3 H), 2.98 (s, 2 H) ppm.
13C NMR*: δ ϭ 167.2, 162.4, 140.2, 129.4, 126.9 (q, J ϭ 286 Hz),
113.9, 109.0, 101.9, 72.9 (q, J ϭ 30 Hz), 55.8, 40.3 ppm. MS (c.i.):
m/z (%) ϭ 279 (0) [Mϩ ϩ 18], 262 (42) [Mϩ ϩ 1], 261 (38) [Mϩ],
243 (10), 192 (100), 174 (14). C11H10F3NO3 (261.20): calcd. C
50.58, H 3.86; found C 50.85, H 3.60. When 4,4,4-trifluoroace-
toacetyl chloride was used instead of the ester, amide 10f was ob-
tained in 76% yield (39.7 g).
(q, J ϭ 33 Hz), 38.8 ppm. MS (c.i.): m/z (%) ϭ 329 (96) [Mϩ
ϩ
18], 327 (100) [Mϩ ϩ 18], 312 (28) [Mϩ ϩ 1], 311 (11) [Mϩ], 310
(30) [Mϩ ϩ 1], 309 (9) [Mϩ], 230 (12), 173 (20), 171 (21).
C10H7BrF3NO2 (310.07): calcd. C 38.74, H 2.28; found C 38.01,
H 2.20.
4,4,4-Trifluoro-N-(2-iodophenyl)-3-oxobutanamide (10l): This com-
pound was prepared from 2-iodoaniline (44 g, 0.20 mol) and ethyl
4,4,4-trifluoroacetoacetate; colorless prisms; m.p. 102Ϫ104 °C;
4,4,4-Trifluoro-N-(3-fluorophenyl)-3-oxobutanamide (10g): This
compound was prepared from 3-fluoroaniline (19 mL, 22 g, 0.20
mol) and ethyl 4,4,4-trifluoroacetoacetate; colorless prisms; m.p.
1
yield 29.3 g, (41%). H NMR: δ ϭ 8.09 (dd, J ϭ 8.3, 1.3 Hz, 1 H),
7.82 (dd, J ϭ 8.0, 1.0 Hz, 1 H), 7.63 (s, 1 H), 7.38 (ddd, J ϭ 8.0,
7.4, 1.3 Hz, 1 H), 6.94 (ddd, J ϭ 8.0, 7.7, 1.3 Hz, 1 H), 2.88 (s, 2
H) ppm. 13C NMR: δ ϭ 168.5, 139.0, 137.4, 128.9, 127.3, 126.6,
122.5 (q, J ϭ 286 Hz), 93.5, 92.8 (q, J ϭ 32 Hz), 38.9 ppm. MS
(c.i.): m/z (%) ϭ 375 (100) [Mϩ ϩ 18], 358 (41) [Mϩ ϩ 1], 357 (7)
[Mϩ], 230 (11), 134 (3). C10H7F3INO (357.06): calcd. C 33.64, H
1.98; found C 33.54, H 2.39.
1
93Ϫ95 °C (dec.), yield 46.3 g (93%). H NMR: δ ϭ 7.46 (dm, J ϭ
10.9 Hz, 1 H), 7.29 (m, 2 H), 7.13 (dd, J ϭ 7.7, 1.0 Hz, 1 H), 6.88
(ddd, J ϭ 8.6, 8.3, 1.9 Hz, 1 H), 5.60 (s, 1 H) ppm. 13C NMR: δ ϭ
168.8, 163.0 (d, J ϭ 245 Hz), 159.5 (q, J ϭ 37 Hz), 130.5 (d, J ϭ
10 Hz), 118.6 (q, J ϭ 275 Hz), 116.0 (d, J ϭ 3 Hz), 112.4, (d, J ϭ
21 Hz), 108.4 (d, J ϭ 27 Hz), 93.5 (q, J ϭ 4 Hz), 38.6 ppm. MS
(c.i.): m/z (%) ϭ 267 (0) [Mϩ ϩ 18], 250 (8) [Mϩ ϩ 1], 249 (8)
[Mϩ], 180 (2), 111 (100). C10H7F4NO2 (249.16): calcd. C 48.21, H
2.83; found C 48.17, H 2.78.
4-(Trifluoromethyl)quinolin-2(1H)-ones (11): The anilide (10; 0.10
mol) was dissolved in sulfuric acid (96%, 0.10 L) and the mixture
was heated at 90 °C for 50 min before being poured into water
(0.25 L). The precipitate formed was filtered and crystallized from
ethanol.
4,4,4-Trifluoro-N-(2-methylphenyl)-3-oxobutanamide (10h): This
compound was prepared from 2-methylaniline (o-toluidine; 21 mL,
21 g, 0.20 mol) and ethyl 4,4,4-trifluoroacetoacetate; colorless
1
4-(Trifluoromethyl)quinolin-2(1H)-one (11a): This compound was
prepared from amide 10a (23 g, 0.10 mol); colorless needles; m.p.
246Ϫ247 °C (reprod.); yield 19.2 g (90%). 1H NMR (D3CSOCD3):
δ ϭ 7.71 (d, J ϭ 8.4 Hz, 1 H), 7.65 (td, J ϭ 7.6, 1.0 Hz, 1 H), 7.43
(d, J ϭ 8.5 Hz, 1 H), 7.32 (td, J ϭ 7.7, 1.0 Hz, 1 H), 6.98 (s, 1 H)
ppm. 13C NMR (D3CSOCD3): δ ϭ 160.0, 139.8, 136.6 (q, J ϭ
31 Hz), 131.7, 124.3, 122.8, 122.6 (q, J ϭ 277 Hz), 122.0 (q, J ϭ
5 Hz), 116.5, 113.1 ppm. MS (c.i.): m/z (%) ϭ 231 (27) [Mϩ ϩ 18],
214 (100) [Mϩ ϩ 1], 213 (34) [Mϩ], 185 (8), 166 (2). C10H6F3NO
(213.16): calcd. C 56.35, H 2.84; found C 56.19, H 3.00.
prisms; m.p. 91Ϫ92 °C; yield 42.7 g (87%). H NMR: δ ϭ 7.61 (d,
J ϭ 8.0 Hz, 1 H), 7.16Ϫ7.27 (m, 3 H), 2.83 (s, 2 H), 2.29 (s, 3 H)
ppm. 13C NMR*: δ ϭ 170.3, 136.2, 132.6, 131.2, 126.8, 126.7,
125.8, 124.1 (q, J ϭ 287 Hz), 94.0 (q, J ϭ 30 Hz), 38.8, 17.9 ppm.
MS (c.i.): m/z (%) ϭ 263 (0) [Mϩ ϩ 18], 246 (12) [Mϩ ϩ 1], 245
(9) [Mϩ], 107 (100). C11H10F3NO2 (245.20): calcd. C 53.88, H 4.11;
found C 53.74, H 3.92.
4,4,4-Trifluoro-N-(2-fluorophenyl)-3-oxobutanamide (10i): This
compound was prepared from 2-fluoroaniline (19 mL, 22 g, 0.20
mol) and ethyl 4,4,4-trifluoroacetoacetate; colorless prisms; m.p.
85Ϫ87 °C; yield 27.9 g (56%). 1H NMR: δ ϭ 8.20 (dd, J ϭ 8.5, 6-Methyl-4-(trifluoromethyl)quinolin-2(1H)-one (11b): This com-
7.4 Hz, 1 H), 7.40 (s, 1 H), 7.08 (m, 3 H), 5.66 (s, 1 H) ppm. 13C
pound was prepared from amide 10b (24 g, 0.10 mol); colorless
1
NMR: δ ϭ 168.5, 159.4 (q, J ϭ 36 Hz), 152.9 (d, J ϭ 245 Hz), needles; m.p. 257Ϫ260 °C (reprod.); yield 20.2 g (89%). H NMR
125.8 (d, J ϭ 7 Hz), 124.5 (q, J ϭ 2 Hz), 122.5, 118.4 (q, J ϭ (D3CSOCD3): δ ϭ 7.6 (m, 2 H), 7.47 (d, J ϭ 8.50 Hz, 1 H), 7.07
275 Hz), 115.3 (d, J ϭ 19 Hz), 93.5 (q, J ϭ 3 Hz), 38.5 ppm. MS
(s, 1 H), 2.54 (s, 3 H) ppm. 13C NMR (D3CSOCD3): δ ϭ 160.9,
138.9, 137.3 (q, J ϭ 33 Hz), 134.9, 133.3, 133.1, 123.7, 123.5 (q,
(c.i.): m/z (%) ϭ 267 (44) [Mϩ ϩ 18], 250 (77) [Mϩ ϩ 1], 249 (24)
58
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 54Ϫ63

Improved Access to 4-Trifluoromethyl-2(1H)-quinolinones
FULL PAPER
J ϭ 277 Hz), 117.4, 114.0, 21.7 ppm. MS (c.i.): m/z (%) ϭ 245 (2) less needles; mp. 248Ϫ251 °C (reprod.); yield 20.2 g (89%). 1H
[Mϩ ϩ 18], 228 (100) [Mϩ ϩ 1], 227 (61) [Mϩ], 198 (4).
NMR (D3CSOCD3): δ ϭ 7.68 (d, J ϭ 7.3 Hz, 1 H), 7.60 (d, J ϭ
C11H8F3NO (227.18): calcd. C 58.16, H 3.55, N 6.17; found C 7.0 Hz, 1 H), 7.34 (t, J ϭ 7.6 Hz, 1 H), 7.11 (s, 1 H), 2.61 (s, 3 H)
58.09, H 3.55, N 6.12.
ppm. 13C NMR (D3CSOCD3): δ ϭ 161.3, 139.0, 137.9 (q, J ϭ
31 Hz), 133.8, 125.9, 123.7 (q, J ϭ 272 Hz), 123.5, 123.0, 122.6,
114.1, 18.8 ppm. MS (c.i.): m/z (%) ϭ 245 (0) [Mϩ ϩ 18], 228 (100)
[Mϩ ϩ 1], 227 (35), 198 (2), 130 (1). C11H8F3NO (227.15): calcd.
C 58.16, H 3.55, N 6.17; found C 57.93, H 3.29, N 6.18.
6-Fluoro-4-(trifluoromethyl)quinolin-2(1H)-one (11c): This com-
pound was prepared from amide 10c (25 g, 0.10 mol); short color-
less needles; m.p. 252Ϫ253 °C (decomp.); yield 21.3 g (92%). 1H
NMR (D3CSOCD3): δ ϭ 7.59 (ddd, J ϭ 9.2, 8.4, 4.6 Hz, 1 H),
7.49 (dd, J ϭ 9.1, 4.9 Hz, 1 H), 7.41 (d, J ϭ 9.5 Hz, 1 H), 7.08 (s,
8-Fluoro-4-(trifluoromethyl)quinolin-2(1H)-one (11i): This com-
1 H) ppm. 13C NMR (D3CSOCD3): δ ϭ 159.6, 156.4 (d, J ϭ pound was prepared from amide 10i (25 g, 0.10 mol); colorless
1
238 Hz), 136.5, 135.7 (q, J ϭ 36 Hz), 123.1 (q, J ϭ 5 Hz), 121.9 (q,
J ϭ 275 Hz), 120.0 (d, J ϭ 25 Hz), 118.4 (d, J ϭ 18 Hz), 113.3 (d,
needles; m.p. 220Ϫ222 °C (reprod.); yield 13.2 g (57%). H NMR*:
δ ϭ 11.0 (s, 1 H), 7.61 (m, 1 H), 7.53 (ddd, J ϭ 10.8, 8.2, 1.3 Hz,
J ϭ 9 Hz), 109.3 (d, J ϭ 25 Hz) ppm. MS (c.i.): m/z (%) ϭ 249 (0) 1 H), 7.34 (td, J ϭ 8.2, 5.3 Hz, 1 H), 7.03 (s, 1 H) ppm. 13C NMR*:
[Mϩ ϩ 18], 232 (40) [Mϩ ϩ 1], 231 (100) [Mϩ], 203 (26), 184 (19). δ ϭ 161.3, 151.0 (d, J ϭ 246 Hz), 130.5 (d, J ϭ 15 Hz), 124.6 (q,
C10H5F4NO (231.15): calcd. C 51.96, H 2.18; found C 52.03, H
2.10.
J ϭ 5 Hz), 124.0 (d, J ϭ 7 Hz), 123.9 (q, J ϭ 274 Hz), 121.4, 118.0
(d, J ϭ 17 Hz), 116.8 ppm. MS (c.i.): m/z (%) ϭ 249 (2) [Mϩ
ϩ
18], 232 (100) [Mϩ ϩ 1], 231 (71) [Mϩ], 203 (9), 184 (7).
C10H5F4NO (231.15): calcd. C 51.96, H 2.18; found C 51.83, H
2.10.
4-Trifluoromethyl-6-(trifluoromethoxy)quinolin-2(1H)-one
(11d):
This compound was prepared from amide 10d (32 g, 0.10 mol);
colorless needles; m.p. 178Ϫ180 °C; 25.0 g (84%). 1H NMR
(D3CSOCD3): δ ϭ 7.71 (dd, J ϭ 8.8, 1.6 Hz, 1 H), 7.56 (d, J ϭ
8-Chloro-4-(trifluoromethyl)quinolin-2(1H)-one (11j): This com-
9.7 Hz, 1 H), 7.52 (s, 1 H), 7.11 (s, 1 H) ppm. 13C NMR pound was prepared from amide 10j (27 g, 0.10 mol); colorless
1
(D3CSOCD3): δ ϭ 161.0, 144.0, 139.7, 136.8 (q, J ϭ 32 Hz), 126.2, needles; m.p. 203Ϫ205 °C (reprod.); yield 19.8 g (80%). H NMR
124.6, 123.2 (q, J ϭ 257 Hz), 121.0 (q, J ϭ 276 Hz), 119.6, 117.2,
(D3CSOCD3): δ ϭ 7.83 (d, J ϭ 7.9 Hz, 1 H), 7.72 (d, J ϭ 8.2 Hz,
114.4 ppm. MS (c.i.): m/z (%) ϭ 315 (0) [Mϩ ϩ 18], 298 (27) [Mϩ 1 H), 7.36 (t, J ϭ 8.0 Hz, 1 H), 7.13 (s, 1 H) ppm. 13C NMR
ϩ 1], 297 (100) [Mϩ], 269 (3), 228 (10), 200 (10). C11H5F6NO2 (D3CSOCD3): δ ϭ 161.2, 137.4 (q, J ϭ 31 Hz), 133.0, 128.3, 128.2,
(297.15): calcd. C 44.46, H 1.70, N 4.71; found C 44.46, H 1.90,
N 4.68.
125.6, 125.4, 124.5, 123.0 (q, J ϭ 273 Hz), 112.4 ppm. MS (c.i.):
m/z (%) ϭ 267 (0) [Mϩ ϩ 18], 265 (0) [Mϩ ϩ 18], 250 (10) [Mϩ
ϩ
1], 249 (37) [Mϩ], 248 (36) [Mϩ ϩ 1], 247 (100) [Mϩ], 219 (20), 200
(13). C10H5ClF3NO (247.60): calcd. C 48.51, H 2.04, N 5.66; found
C 48.45, H 2.00, N 5.66.
7-Methyl-4-(trifluoromethyl)quinolin-2(1H)-one (11e): This com-
pound was prepared from amide 10e (25 g, 0.10 mol); colorless
1
needles; m.p. 210Ϫ213 °C (reprod.); yield 19.8 g (87%). H NMR
(D3CSOCD3): δ ϭ 7.59 (d, J ϭ 8.6 Hz, 1 H), 7.22 (s, 1 H), 7.14
8-Bromo-4-(trifluoromethyl)quinolin-2(1H)-one (11k): This com-
pound was prepared from amide 10k (31 g, 0.10 mol); colorless
(d, J ϭ 8.2 Hz, 1 H), 6.89 (s, 1 H), 2.41 (s, 3 H) ppm. 13C NMR
(D3CSOCD3): δ ϭ 160.1, 142.0, 139.7, 136.2 (q, J ϭ 31 Hz), 124.2, needles; m.p. 178Ϫ180 °C; yield 6.43 g, (22%). 1H NMR
123.8, 122.5 (q, J ϭ 276 Hz), 120.5 (q, J ϭ 5 Hz), 116.0, 110.9, (D3CSOCD3): δ ϭ 8.00 (d, J ϭ 7.9 Hz, 1 H), 7.76 (d, J ϭ 8.0 Hz,
21.1 ppm. MS (c.i.): m/z (%) ϭ 245 (1) [Mϩ ϩ 18], 228 (100) [Mϩ 1 H), 7.30 (t, J ϭ 8.1 Hz, 1 H), 7.13 (s, 1 H) ppm. 13C NMR
ϩ 1], 227 (47) [Mϩ], 198 (7), 130 (3), 102 (1). C11H8F3NO (227.18): (D3CSOCD3): δ ϭ 160.3, 138.2 (q, J ϭ 32 Hz), 136.0, 129.7, 125.5
calcd. C 58.16, H 3.55, N 6.17; found C 58.06, H 3.64, N 6.31.
(q, J ϭ 3 Hz), 124.7, 124.0 (q, J ϭ 3 Hz), 123.5 (q, J ϭ 276 Hz),
116.2, 110.2 ppm. MS (c.i.): m/z (%) ϭ 311 (0) [Mϩ ϩ 18], 309 (0)
7-Methoxy-4-(trifluoromethyl)quinolin-2(1H)-one (11f): This com-
pound was prepared from amide 10f (26 g, 0.10 mol); short pale
yellow needles; m.p. 219Ϫ222 °C (reprod.); yield 20.2 g (83%). H
NMR (D3CSOCD3): δ ϭ 7.72 (dm, J ϭ 8.0 Hz, 1 H), 7.05 (dd,
J ϭ 9.5, 2.5 Hz, 1 H), 7.04 (s, 1 H), 6.89 (s, 1 H), 3.94 (s, 3 H)
[Mϩ ϩ 18], 294 (65) [Mϩ ϩ 1], 293 (100) [Mϩ], 292 (80) [Mϩ
ϩ
1], 291 (95) [Mϩ], 263 (16). C10H5BrF3NO (292.05): calcd. C 41.13,
H 1.73; found C 41.13, H 1.73.
1
8-Iodo-4-(trifluoromethyl)quinolin-2(1H)-one (11l): This compound
ppm. 13C NMR (D3CSOCD3): δ ϭ 162.9, 161.7, 143.0, 137.5 (q, was prepared from amide 10l (36 g, 0.10 mol); colorless needles;
J ϭ 21 Hz), 126.8, 123.8 (q, J ϭ 278 Hz), 119.4 (q, J ϭ 6 Hz), m.p. 199Ϫ201 °C (reprod.); yield 13.2 g, (39%). 1H NMR*: δ ϭ
113.3, 108.1, 100.2, 56.7 ppm. MS (c.i.): m/z (%) ϭ 261 (14) [Mϩ 8.22 (dd, J ϭ 8.0, 1.2 Hz, 1 H), 7.85 (d, J ϭ 8.1 Hz, 1 H), 7.19 (t,
ϩ 18], 244 (100) [Mϩ ϩ 1], 243 (24) [Mϩ]. C11H8F3NO2 (243.14): J ϭ 7.6 Hz, 1 H), 7.03 (s, 1 H) ppm. 13C NMR*: δ ϭ 161.2, 144.8,
calcd. C 54.34, H 3.32, N 5.76; found C 54.46, H 3.32, N 5.88.
143.1, 138.1 (q, J ϭ 31 Hz), 128.4, 125.8, 123.9 (q, J ϭ 275 Hz),
123.5, 112.4, 102.3 ppm. MS (c.i.): m/z (%) ؍ 357 (25) [Mϩ ϩ 18],
341 (29) [Mϩ ϩ2], 340 (100) [Mϩ ϩ 1], 339 (93) [Mϩ], 338 (40),
311 (7). C10H5F3INO (339.05): calcd. C 35.43, H 1.49; found C
35.72, H 1.88.
7-Fluoro-4-(trifluoromethyl)quinolin-2(1H)-one (11g): This com-
pound was prepared from amide 10g (25 g, 0.10 mol); short color-
less needles; m.p. 166Ϫ167 °C (decomp.); yield 21.2 g (91%). 1H
NMR (D3CSOCD3): δ ϭ 7.87 (tm, J ϭ 8.0 Hz, 1 H), 7.30 (m, 2
H), 7.05 (s, 1 H) ppm. 13C NMR (D3CSOCD3): δ ϭ 164.2 (d, J ϭ 2-Bromo-4-(trifluoromethyl)quinolines (12): The 4-(trifluorome-
247 Hz), 161.2, 142.6 (d, J ϭ 12 Hz), 137.4 (d, J ϭ 31 Hz), 128.0 thyl)quinolin-2(1H)-one (11; 50 mmol) was added whilst stirring to
(d, J ϭ 10 Hz), 123.2 (q, J ϭ 267 Hz), 121.5, 112.4 (d, J ϭ 23 Hz),
111.2, 103.1 (d, J ϭ 26 Hz) ppm. MS (c.i.): m/z (%) ϭ 249 (0)
phosphorus oxybromide (29 g, 0.10 mol) while the temperature was
raised from 75 °C to 150 °C. After 2 h at 150 °C, the mixture was
[Mϩ ϩ 18], 232 (100) [Mϩ ϩ 1], 231 (88) [Mϩ], 203 (19), 184 (8). poured into ice-water (0.40 L). The precipitate was collected and
C10H5F4NO (231.10): calcd. C 51.97, H 2.18, N 6.06; found C crystallized from methanol.
52.03, H 1.95, N 6.18.
2-Bromo-6-trifluoromethoxy-4-(trifluoromethyl)quinoline (12d): This
8-Methyl-4-(trifluoromethyl)quinolin-2(1H)-one (11h): This com-
pound was prepared from amide 10h (25 g, 0.10 mol); short color-
compound was prepared from quinolone 11d (14.9 g, 50 mmol);
colorless needles; m.p. 55Ϫ56 °C; yield 16.0 g (89%). 1H NMR:
Eur. J. Org. Chem. 2004, 54Ϫ63
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
59

M. Marull, O. Lefebvre, M. Schloser
FULL PAPER
δ ϭ 8.19 (d, J ϭ 9.3 Hz, 1 H), 7.91 (s, 1 H), 7.87 (s, 1 H), 7.70 (d,
hydrochloric acid in ethanol. After the mixture had been heated
J ϭ 9.3, 2.0 Hz, 1 H) ppm. 13C NMR: δ ϭ 148.4, 147.4, 141.1, under reflux for 2 h, the solvent was evaporated and water (10 mL)
136.4 (q, J ϭ 33 Hz), 131.9, 125.1, 124.3 (q, J ϭ 6 Hz), 122.4, 122.2
was added. Extraction with hexanes (2 ϫ 15 mL) and evaporation
(q, J ϭ 276 Hz), 120.4 (q, J ϭ 261 Hz), 115.0 ppm. MS (c.i.): m/z gave a residue, which was crystallized from pentanes.
(%) ϭ 379 (0) [Mϩ ϩ 18], 377 (0) [Mϩ ϩ 18], 362 (5) [Mϩ ϩ 1],
6-Trifluoromethoxy-4-(trifluoromethyl)quinoline (13d): This com-
361 (2) [Mϩ], 360 (6) [Mϩ ϩ 1], 359 (1) [Mϩ], 282 (7), 116 (46), 76
pound was prepared from the bromoquinoline 12d (3.60 g,
(100), 75 (63). C11H4BrF6NO (360.05): calcd. C 36.69, H 1.12;
10 mmol); b.p. 113Ϫ114 °C/4.5 Torr; n2D0 ϭ 1.4742; yield 2.11 g
found C 36.59, H 1.14.
(75%). 1H NMR: δ ϭ 9.07 (d, J ϭ 4.3 Hz, 1 H), 8.27 (d, J ϭ
9.2 Hz, 1 H), 7.95 (s, 1 H), 7.76 (d, J ϭ 4.4 Hz, 1 H), 7.70 (dd, J ϭ
9.4, 2.0 Hz, 1 H) ppm. 13C NMR: δ ϭ 149.9, 148.1, 146.9, 134.3
(q, J ϭ 33 Hz), 132.6, 124.0, 123.1, 122.9 (q, J ϭ 275 Hz), 120.3
(q, J ϭ 259 Hz), 118.7 (q, J ϭ 6 Hz), 114.6 ppm. MS (c.i.): m/z
(%) ϭ 299 (10) [Mϩ ϩ 18], 282 (12) [Mϩ ϩ 1], 281 (84) [Mϩ], 184
(100). C11H5F6NO (281.15): calcd. C 44.99, H 1.79; found C 46.66,
H 1.74.
2-Bromo-8-fluoro-4-(trifluoromethyl)quinoline (12i): This compound
was prepared from quinolone 11i (11.6 g, 50 mmol); colorless
needles; m.p. 80Ϫ81 °C; yield 8.09 g (55%). 1H NMR: δ ϭ 7.90
(m, 2 H), 7.68 (ddd, J ϭ 13.1, 8.0, 5.1 Hz, 1 H), 7.55 (ddd, J ϭ
9.6, 8.0, 1.3 Hz, 1 H) ppm. 13C NMR: δ ϭ 157.7 (d, J ϭ 260 Hz),
141.6, 139.9 (d, J ϭ 13 Hz), 136.7 (qd, J ϭ 33, 3 Hz), 129.3 (d, J ϭ
8 Hz), 124.8 (q, J ϭ 6 Hz), 123.8, 122.6 (q, J ϭ 275 Hz), 120.3
(sext, J ϭ 3 Hz), 116.1 (d, J ϭ 19 Hz) ppm. MS (c.i.): m/z (%) ϭ
313 (0) [Mϩ ϩ 18], 311 (0) [Mϩ ϩ 18], 296 (3) [Mϩ ϩ 1], 295
(41) [Mϩ], 294 (7) [Mϩ ϩ 1], 293 (35) [Mϩ], 214 (47), 194 (100).
C10H4BrF4N (294.04): calcd. C 40.85, H 1.37; found C 41.09, H
1.12.
8-Fluoro-4-(trifluoromethyl)quinoline (13i): This compound was
prepared from the bromoquinoline 12i (2.94 g, 10 mmol); colorless
1
needles; m.p. 37Ϫ39 °C; yield 1.35 g (63%). H NMR: δ ϭ 9.12 (d,
J ϭ 4.5 Hz, 1 H), 7.95 (dm, J ϭ 8.6 Hz, 1 H), 7.79 (d, J ϭ 4.5 Hz,
1 H), 7.66 (ddd, J ϭ 8.6, 7.7, 5.2 Hz, 1 H), 7.54 (ddd, J ϭ 9.9, 7.7,
1.3 Hz, 1 H) ppm. 13C NMR: δ ϭ 158.2 (d, J ϭ 258 Hz), 149.9 (d,
J ϭ 2 Hz), 139.4 (d, J ϭ 12 Hz), 134.3 (qd, J ϭ 33, 4 Hz), 128.6
(d, J ϭ 8 Hz), 124.5, 123.1 (q, J ϭ 274 Hz), 120.0 (sext, J ϭ 3 Hz),
119.0 (q, J ϭ 5 Hz), 114.7 (d, J ϭ 19 Hz) ppm. MS (c.i.): m/z (%) ϭ
233 (0) [Mϩ ϩ 18], 216 (28) [Mϩ ϩ 1], 215 (100) [Mϩ], 165 (5), 84
(9). C10H5F4N (215.15): calcd. C 55.83, H 2.34; found C 55.74,
H 2.23.
2-Bromo-8-chloro-4-(trifluoromethyl)quinoline (12j): This com-
pound was prepared from quinolone 11j (12.4 g, 50 mmol); color-
less needles; m.p. 66Ϫ68 °C; yield 12.3 g (79%). 1H NMR: δ ϭ 8.02
(d, J ϭ 8.8 Hz, 1 H), 7.94 (d, J ϭ 7.4 Hz, 1 H), 7.89 (s, 1 H), 7.63
(t, J ϭ 8.1 Hz, 1 H) ppm. 13C NMR: δ ϭ 145.7, 141.6, 136.7 (q,
J ϭ 33 Hz), 133.9, 131.5, 128.6, 124.4 (q, J ϭ 6 Hz), 123.4, 123.1
(q, J ϭ 3 Hz), 122.2 (q, J ϭ 277 Hz) ppm. MS (c.i.): m/z (%) ϭ
331(0) [Mϩ ϩ 18], 329 (4) [Mϩ ϩ 18], 327 (3) [Mϩ ϩ 18], 314 (25)
[Mϩ ϩ 1], 313 (19) [Mϩ], 312 (100) [Mϩ ϩ 1], 311 (23) [Mϩ], 310
(81) [Mϩ ϩ 1], 309 (8) [Mϩ], 291 (8), 247 (14). C10H4BrClF3N
(310.50): calcd. C 38.68, H 1.30; found C 38.63, H 1.46.
8-Chloro-4-(trifluoromethyl)quinoline (13j): This compound was
prepared from the bromoquinoline 12j (3.11 g, 10 mmol); colorless
1
needles; m.p. 35Ϫ37 °C; yield 2.0 g (86%). H NMR: δ ϭ 9.13 (d,
J ϭ 4.4 Hz, 1 H), 8.10 (dm, J ϭ 8.6 Hz, 1 H), 7.97 (d, J ϭ 7.7 Hz,
1 H), 7.80 (d, J ϭ 4.3 Hz, 1 H), 7.63 (dd, J ϭ 7.8, 7.4 Hz, 1 H)
ppm. 13C NMR: δ ϭ 150.0, 145.1, 134.7 (q, J ϭ 32 Hz), 134.6,
130.6, 128.3, 124.5, 123.1, 123.0 (q, J ϭ 3 Hz), 118.9 (q, J ϭ 5 Hz)
ppm. MS (c.i.): m/z (%) ϭ 251 (0) [Mϩ ϩ 18], 249 (0) [Mϩ ϩ 18],
234 (34) [Mϩ ϩ 1], 233 (53) [Mϩ], 232 (100) [Mϩ ϩ 1], 231 (80)
[Mϩ], 162 (25), 127 (10). C10H5ClF3N (231.60): calcd. C 51.86, H
2.18; found C 51.86, H 1.90.
2,8-Dibromo-4-(trifluoromethyl)quinoline (12k): This compound
was prepared from quinolone 11k (14.6 g, 50 mmol); colorless
1
needles; m.p. 70Ϫ72 °C; yield 10.5 g (59%). H NMR: δ ϭ 8.15 (d,
J ϭ 8.0 Hz, 1 H), 8.07 (dd, J ϭ 8.7, 1.2 Hz, 1 H), 7.88 (s, 1 H),
7.55 (dd, J ϭ 8.0, 7.6 Hz, 1 H) ppm. 13C NMR: δ ϭ 146.6, 141.8,
136.8 (q, J ϭ 33 Hz), 135.2, 129.0, 124.9, 124.4 (q, J ϭ 6 Hz),
123.9, 122.8, 122.0 (q, J ϭ 276 Hz) ppm. MS (c.i.): m/z (%) ϭ 375
(0) [Mϩ ϩ 18], 373 (0) [Mϩ ϩ 18], 371 (0) [Mϩ ϩ 18], 358 (18) 8-Bromo-4-(trifluoromethyl)quinoline (13k): This compound was
[Mϩ ϩ 1], 357 (50) [Mϩ], 356 (33) [Mϩ ϩ 1], 355 (100) [Mϩ], 354
(34) [Mϩ ϩ 1], 353 (55) [Mϩ], 274 (40), 254 (29). C10H4Br2F3N needles; m.p. 82Ϫ84 °C; yield 2.54 g (92%). 1H NMR: δ ϭ 9.18 (d,
prepared from the bromoquinoline 12k (3.55 g, 10 mmol); colorless
(354.95): calcd. C 33.84, H 1.14; found C 33.83, H 1.09.
J ϭ 4.4 Hz, 1 H), 8.18 (d, J ϭ 7.5 Hz, 1 H), 8.14 (d, J ϭ 9.0 Hz,
1 H), 7.79 (d, J ϭ 4.3 Hz, 1 H), 7.56 (dd, J ϭ 8.6, 7.5 Hz, 1 H)
ppm. 13C NMR: δ ϭ 150.3, 145.9, 134.9 (q, J ϭ 33 Hz), 134.0,
128.8, 125.9, 124.4, 123.8, 123.2 (q, J ϭ 276 Hz), 118.9 (q, J ϭ
4 Hz) ppm. MS (c.i.): m/z (%) ϭ 295 (0) [Mϩ ϩ 18], 293 (0) [Mϩ
ϩ 18], 278 (24) [Mϩ ϩ 1], 277 (100) [Mϩ], 276 (26) [Mϩ ϩ 1], 275
(94) [Mϩ], 256 (4), 196 (31), 176 (14). C10H5BrF3N (276.05): calcd.
C 43.51, H 1.83; found C 43.37, H 1.73.
2-Bromo-8-iodo-4-(trifluoromethyl)quinoline (12l): This compound
was prepared from quinolone 11l (17.0 g, 50 mmol); colorless
1
needles; m.p. 102Ϫ104 °C; yield 17.7 g, (88%). H NMR: δ ϭ 8.45
(d, J ϭ 7.4 Hz, 1 H), 8.10 (d, J ϭ 8.1 Hz, 1 H), 7.87 (s, 1 H), 7.41
(dd, J ϭ 8.2, 7.3 Hz, 1 H) ppm. 13C NMR: δ ϭ 148.4, 142.0, 141.7,
136.9 (q, J ϭ 32 Hz), 129.5, 124.6, 124.3 (q, J ϭ 6 Hz), 122.5, 122.0
(q, J ϭ 276 Hz), 102.6 ppm. MS (c.i.): m/z (%) ϭ 421 (0) [Mϩ
ϩ
18], 419 (0) [Mϩ ϩ 18], 404 (70) [Mϩ ϩ 1], 403 (100) [Mϩ], 402
(99) [Mϩ ϩ 1], 401 (84) [Mϩ], 355 (16), 356 (15). C10H4BrIF3N
(401.95): calcd. C 29.88, H 1.00; found C 29.90, H 1.11.
8-Iodo-4-(trifluoromethyl)quinoline (13l): This compound was pre-
pared from the bromoquinoline 12l (4.02 g, 10 mmol); colorless
needles; m.p. 95Ϫ96 °C; yield 2.65 g, (82%). 1H NMR: δ ϭ 9.14
(d, J ϭ 4.5 Hz, 1 H), 8.48 (d, J ϭ 7.5 Hz, 1 H), 8.17 (d, J ϭ 4.5 Hz,
1 H), 7.79 (d, J ϭ 4.4 Hz, 1 H), 7.42 (dd, J ϭ 8.2, 7.9 Hz, 1 H)
ppm. 13C NMR: δ ϭ 150.6, 147.8, 141.2, 135.0 (q, J ϭ 32 Hz),
129.3, 124.8 (q, J ϭ 3 Hz), 123.8, 123.1 (q, J ϭ 275 Hz), 119.1 (q,
J ϭ 5 Hz), 104.4 ppm. MS (c.i.): m/z (%) ϭ 341 (0) [Mϩ ϩ 18], 324
(49) [Mϩ ϩ 1], 323 (100) [Mϩ], 196 (33), 176 (19), 127 (5).
C10H5F3IN (323.05): calcd. C 37.18, H 1.56; found C 37.41, H 1.46.
4-(Trifluoromethyl)quinolines (13): The 2-bromo-4-(trifluorome-
thyl)quinoline (12d, 12i, or 12j; 10 mmol) was added to a precooled
solution of butyllithium (10 mmol) in toluene (40 mL) and hexanes
(6.25 mL). After the mixture had been kept for 15 min at Ϫ75 °C,
methanol (2.00 mL, 1.60 g, 50 mmol) was injected. The volatiles
were evaporated and the residue was crystallized from pentanes.
2-Bromo-4-(trifluoromethyl)quinoline (12kϪl; 10 mmol) and tin
tetrachloride (1.90 g, 10 mmol) were added to a 5.0  solution of
4-(Trifluoromethyl)quinoline-2-carboxylic Acids (14): At Ϫ75 °C, 2-
bromo-4-(trifluoromethyl)quinoline (12; 10 mmol) was added to a
60
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 54Ϫ63

Improved Access to 4-Trifluoromethyl-2(1H)-quinolinones
FULL PAPER
solution of butyllithium (10 mmol) in tetrahydrofuran (20 mL) and
excess of freshly crushed dry ice before being worked up as specified
hexanes (6.25 mL). After 45 min, the mixture was poured onto an for the acids 14.
excess of freshly crushed dry ice. Water (0.10 L) was added and the
2-Bromo-6-trifluoromethoxy-4-(trifluoromethyl)quinoline-3-carb-
aqueous phase was washed with diethyl ether (3 ϫ 10 mL) before
being acidified with concentrated hydrochloric acid to pH 4. Ex-
traction with ethyl acetate (3 ϫ 10 mL), drying of the combined
organic layers, and evaporation gave a residue, which was crys-
tallized.
oxylic Acid (15d): This compound was prepared from the bromo-
quinoline 12d (3.60 g, 10 mmol); colorless prisms; m.p. 176Ϫ178
1
°C (from ethyl acetate); yield 1.62 g, (40%). H NMR*: δ ϭ 8.43
(d, J ϭ 9.5 Hz, 1 H), 8.28 (s, 1 H), 8.04 (d, J ϭ 9.2, 2.7 Hz) ppm.
13C NMR*: δ ϭ 165.6, 151.2, 145.5, 144.4 (q, J ϭ 35 Hz), 134.6,
133.9, 130.3, 129.8, 127.2, 121.7 (q, J ϭ 277 Hz), 121.5 (q, J ϭ
260 Hz), 118.4;) ppm. MS (c.i.): m/z (%) ϭ 423 (0) [Mϩ ϩ 18], 421
6-Trifluoromethoxy-4-(trifluoromethyl)quinoline-2-carboxylic Acid
(14d): This compound was prepared from the bromoquinoline 12d
(3.60 g, 10 mmol); colorless prisms; m.p. 163Ϫ165 °C (from chloro-
(0) [Mϩ ϩ 18], 406 (33) [Mϩ ϩ 1], 405 (98) [Mϩ], 404 (31) [Mϩ
ϩ
1
form/ethyl acetate), yield 2.24 g (69%). H NMR*: δ ϭ 8.55 (s, 1 1], 403 (100) [Mϩ], 359 (59), 336 (12), 260 (7). C12H4BrF6NO3
H), 8.51 (d, J ϭ 9.1 Hz, 1 H), 8.07 (s, 1 H), 8.04 (d, J ϭ 9.4 Hz, 1 (404.06): calcd. C 35.67, H 1.00; found C 36.03, H 0.93.
H) ppm. 13C NMR*: δ ϭ 169.1, 154.6, 153.5, 151.3, 140.3 (q, J ϭ
2-Bromo-8-fluoro-4-(trifluoromethyl)quinoline-3-carboxylic
Acid
33 Hz), 139.2, 130.4, 129.1, 128.2 (q, J ϭ 275 Hz), 125.5 (q, J ϭ
258 Hz), 123.9 (q, J ϭ 4 Hz), 119.4 ppm. MS (c.i.): m/z (%) ϭ 343
(0) [Mϩ ϩ 18], 326 (4) [Mϩ ϩ 1], 325 (0) [Mϩ], 116 (6), 76 (100).
C12H5F6NO3 (325.16): calcd. C 44.33, H 1.55; found C 44.35, H
1.52.
(15i): This compound was prepared from the bromoquinoline 12i
(2.94 g, 10 mmol); colorless prisms; m.p. 211Ϫ213 °C (decomp.;
from methanol); yield 2.81 g (83%). 1H NMR*: δ ϭ 8.07 (dm, J ϭ
9.0 Hz, 1 H), 7.95 (ddd, J ϭ 13.1, 8.0, 5.1 Hz, 1 H), 7.82 (ddd, J ϭ
9.9, 8.0, 1.3 Hz, 1 H) ppm. 13C NMR*: δ ϭ 166.8, 158.7 (d, J ϭ
259 Hz), 147.8, 140.1 (d, J ϭ 13 Hz), 139.3 (d, J ϭ 1 Hz), 133.0
(qd, J ϭ 32, 3 Hz), 131.9 (d, J ϭ 8 Hz), 124.5, 124.0 (q, J ϭ
276 Hz), 122.3 (sext, J ϭ 4 Hz), 118.2 (d, J ϭ 18 Hz) ppm. MS
(c.i.): m/z (%) ϭ 357 (1) [Mϩ ϩ 18], 355 (1) [Mϩ ϩ 18], 340 (19)
[Mϩ ϩ 1], 339 (77) [Mϩ], 338 (18) [Mϩ ϩ 1], 337 (75) [Mϩ], 293
8-Fluoro-4-(trifluoromethyl)quinoline-2-carboxylic Acid (14i): This
compound was prepared from the bromoquinoline 12i (2.94 g,
10 mmol); colorless prisms; m.p. 188Ϫ190 °C (decomp.; from
chloroform); yield 1.89 g (73%). 1H NMR*: δ ϭ 8.56 (s, 1 H), 8.08
(m, 1 H), 8.00 (ddd, J ϭ 12.8, 7.7, 5.1 Hz, 1 H), 7.81 (ddd, J ϭ
10.2, 7.7, 1.3 Hz, 1 H) ppm. 13C NMR*: δ ϭ 166.0, 160.3 (d, J ϭ (79), 194 (100), 101 (92). C11H4BrF4NO2 (338.05): calcd. C 39.08,
260 Hz), 148.9 (d, J ϭ 2 Hz), 140.1 (d, J ϭ 13 Hz), 136.9 (qd, J ϭ H 1.19; found C 39.32, H 1.10.
33, 3 Hz), 133.3 (d, J ϭ 8 Hz), 127.0, 125.0 (q, J ϭ 274 Hz), 121.5
(sext, J ϭ 3 Hz), 120.5 (q, J ϭ 6 Hz), 117.4 (d, J ϭ 19 Hz) ppm.
MS (c.i.): m/z (%) ϭ 277 (0) [Mϩ ϩ 18], 260 (10) [Mϩ ϩ 1], 259 (8)
[Mϩ], 215 (100), 194 (32), 146 (13). C11H5F4NO2 (259.16): calcd. C
50.98, H 1.94; found C 50.87, H 1.87.
2-Bromo-8-chloro-4-(trifluoromethyl)quinoline-3-carboxylic
Acid
(15j): This compound was prepared from the bromoquinoline 12j
(3.10 g, 10 mmol); colorless prisms; m.p. 167Ϫ169 °C (from ethyl
acetate); yield 2.69 g, (78%). 1H NMR*: δ ϭ 8.19 (dm, J ϭ 8.8 Hz,
1 H), 8.15 (dd, J ϭ 7.7, 1.0 Hz, 1 H), 7.89 (dd, J ϭ 8.5, 7.6 Hz, 1
H) ppm. 13C NMR*: δ ϭ 165.7, 145.2, 138.8, 134.0, 133.0, 132.5
(q, J ϭ 32 Hz), 130.8, 125.5, 124.5 (q, J ϭ 4 Hz), 123.9, 123.0 (q,
J ϭ 278 Hz) ppm. MS (c.i.): m/z (%) ϭ 375 (0) [Mϩ ϩ 18], 373 (0)
8-Chloro-4-(trifluoromethyl)quinoline-2-carboxylic Acid (14j): This
compound was prepared from the bromoquinoline 12j (3.11 g,
10 mmol); colorless prisms; m.p. 167Ϫ169 °C (from ethyl acetate);
yield 1.68 g (61%). 1H NMR*: δ ϭ 8.56 (s, 1 H), 8.42 (dd, J ϭ 7.7, [Mϩ ϩ 18], 371 (0) [Mϩ ϩ 18], 358 (4) [Mϩ ϩ 1], 357 (17) [Mϩ],
1.3 Hz, 1 H), 8.29 (dq, J ϭ 8.6, 1.2 Hz, 1 H), 7.89 (dd, J ϭ 8.6, 356 (32) [Mϩ ϩ 1], 355 (100) [Mϩ], 354 (22) [Mϩ ϩ 1], 353 (84)
7.5 Hz, 1 H) ppm. 13C NMR*: δ ϭ 164.9, 149.3, 145.7, 136.6 (q, [Mϩ], 338 (59), 311 (29), 210 (71). C11H4BrClF3NO2 (354.51):
J ϭ 32 Hz), 136.0, 132.2, 127.3, 126.1, 124.5 (q, J ϭ 3 Hz), 124.1
(q, J ϭ 275 Hz), 119.6 (q, J ϭ 6 Hz) ppm. MS (c.i.): m/z (%) ϭ
295 (0) [Mϩ ϩ 18], 293 (0) [Mϩ ϩ 18], 278 (0) [Mϩ ϩ 1], 277 (2)
[Mϩ], 276 (3) [Mϩ ϩ 1], 275 (9) [Mϩ], 231 (100), 210 (29), 196 (19).
C11H5ClF3NO2 (275.61): calcd. C 47.94, H 1.83; found C 48.18,
H 1.81.
calcd. C 37.27, H 1.14; found C 36.96, H 1.18.
2,8-Dibromo-4-(trifluoromethyl)quinoline-3-carboxylic Acid (15k):
This compound was prepared from the bromo quinoline 12k
(3.55 g, 10 mmol); colorless prisms; m.p. 196Ϫ198 °C (decomp.;
from chloroform/ethyl acetate); yield 3.23 g, (81%). 1H NMR*: δ ϭ
8.42 (d, J ϭ 8.4 Hz, 1 H), 8.28 (d, J ϭ 7.5 Hz, 1 H), 7.87 (dd, J ϭ
8.4, 7.3 Hz, 1 H) ppm. 13C NMR*: δ ϭ 160.6, 147.1, 139.9, 137.6,
133.6 (qr. J ϭ 32 Hz), 132.1, 132.0 (q, J ϭ 3 Hz), 126.2 (q, J ϭ
8-Bromo-4-(trifluoromethyl)quinoline-2-carboxylic Acid (14k): This
compound was prepared from the iodoquinoline 18 (4.02 g,
10 mmol); colorless prisms; m.p. 199Ϫ201 °C (reprod.; from 4 Hz), 126.0, 124.8, 124.0 (q, J ϭ 277 Hz) ppm. MS (c.i.): m/z
chloroform/ethyl acetate); yield 1.86 g, (58%). 1H NMR*: δ ϭ 8.58
(s, 1 H), 8.25 (dd, J ϭ 8.6, 1.2 Hz, 1 H), 8.19 (dd, J ϭ 7.4, 1.2 Hz,
(%) ϭ 419 (0) [Mϩ ϩ 18], 417 (0) [Mϩ ϩ 18], 415 (0) [Mϩ ϩ 18],
402 (23) [Mϩ ϩ 1], 401 (36) [Mϩ], 400 (54) [Mϩ ϩ 1], 399 (61)
1 H), 7.78 (ddd, J ϭ 8.7, 7.5, 1.2 Hz, 1 H) ppm. 13C NMR*: δ ϭ [Mϩ]; 398 (32) [Mϩ ϩ 1], 397 (31) [Mϩ], 123 (71), 99 (100).
168.1, 151.6, 140.9, 135.8 (q, J ϭ 33 Hz), 134.5, 131.1, 130.5, 126.9,
C11H4Br2F3NO2 (398.96): calcd. C 33.12, H 1.01; found C 33.44,
123.4, 119.3, 117.6 (q, J ϭ 274 Hz) ppm. MS (c.i.): m/z (%) ϭ 339 H 0.85.
(0) [Mϩ ϩ 18], 337 (0) [Mϩ ϩ 18], 322 (52) [Mϩ ϩ 1], 321 (100)
[Mϩ], 320 (67) [Mϩ ϩ 1], 319 (84) [Mϩ], 184 (8), 98 (13).
C11H5BrF3NO2 (320.06): calcd. C 41.28, H 1.57; found C 41.55,
H 1.40.
2-Bromo-8-iodo-4-(trifluoromethyl)quinoline-3-carboxylic
Acid
(15l): This compound was prepared from the bromo quinoline 12l
(4.02 g, 10 mmol); colorless prisms; m.p. 193Ϫ194 °C (decomp.;
1
from ethyl acetate); yield 3.93 g, (89%). H NMR*: δ ϭ 8.66 (dd,
2-Bromo-4-(trifluoromethyl)quinoline-3-carboxylic Acids (15): At
Ϫ75 °C, diisopropylamine (1.42 mL, 1.01 g, 10 mmol) and bromo-
quinoline (12; 10 mmol) were added consecutively to a solution of
butyllithium (10 mmol) in tetrahydrofuran (20 mL) and hexanes
(6.25 mL). After 2 h at Ϫ75 °C, the mixture was poured onto an
J ϭ 7.5, 1.4 Hz, 1 H), 8.27 (dm, J ϭ 8.7 Hz, 1 h), 7.69 (dd, J ϭ
8.6, 7.2 Hz, 1 H) ppm. 13C NMR*: δ ϭ 165.8, 148.4, 143.8, 138.9,
133.1 (q, J ϭ 32 Hz), 131.8, 126.2 (q, J ϭ 3 Hz), 123.2, 122.9 (q,
J ϭ 276 Hz), 102.9 ppm. MS (c.i.): m/z (%) ϭ 465 (0) [Mϩ ϩ 18],
463 (0) [Mϩ ϩ 18], 448 (1) [Mϩ ϩ 1], 447 (2) [Mϩ], 446 (1) [Mϩ
Eur. J. Org. Chem. 2004, 54Ϫ63
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
61

M. Marull, O. Lefebvre, M. Schloser
ϩ 1], 445 (1) [Mϩ], 403 (94), 402 (100), 322 (19). C11H4BrF3INO2 385 (0) [Mϩ ϩ 18], 368 (100) [Mϩ ϩ 1], 367 (86) [Mϩ], 322 (8),
FULL PAPER
(445.96): calcd. C 29.63, H 0.90; found C 29.94, H 1.02.
100 (22). C11H5F3INO2 (367.06): calcd. C 35.99, H 1.37; found C
36.25, H 1.61.
4-(Trifluoromethyl)quinoline-3-carboxylic Acids (16): These com-
pounds were prepared as described above (see the preparation of
quinolines 12 k-l) from the 2-bromo-4-(trifluoromethyl)quinoline-
3-carboxylic acids (15; 10 mmol) and tin chloride (1.90 g,
10 mmol).
8-Bromo-2-iodo-4-(trifluoromethyl)quinoline (18): A mixture of 2,8-
dibromo-4-(trifluoromethyl)quinoline (12k; 5.32 g, 15 mmol), so-
dium iodide (6.75 g, 45 mmol), and propionitrile (15 mL) was
heated under reflux for 2 h. After distillation of the solvent, the
residue was crystallized in pentanes, affording colorless needles;
m.p. 97Ϫ99 °C; yield 5.37 g, (89%). 1H NMR: δ ϭ 8.15 (d, J ϭ
7.6 Hz, 1 H), 8.07 (s, 1 H), 8.05 (d, J ϭ 9.1 Hz, 1 H), 7.55 (dd, J ϭ
8.6, 7.5 Hz, 1 H) ppm. 13C NMR: δ ϭ 147.1, 134.9 (q, J ϭ 33 Hz),
134.7, 130.0 (q, J ϭ 6 Hz), 129.1, 125.2, 123.9, 123.3, 121.8 (q, J ϭ
276 Hz), 117.2 ppm. MS (c.i.): m/z (%) ϭ 421 (0) [Mϩ ϩ 18], 419
(0) [Mϩ ϩ 18], 404 (99) [Mϩ ϩ 1], 403 (83) [Mϩ], 402 (100) [Mϩ
ϩ 1], 401 (33) [Mϩ], 293 (9), 291 (9). C10H4BrF3IN (401.95): calcd.
C 29.88, H 1.00; found C 30.18, H 1.00.
6-(Trifluoromethoxy)-4-(trifluoromethyl)quinoline-3-carboxylic Acid
(16d): This compound was prepared from bromo acid 15d (4.04 g,
10 mmol); colorless needles; m.p. 188Ϫ189 °C (decomp.; from hex-
1
anes/ethyl acetate); yield 2.63 g, (81%). H NMR*: δ ϭ 9.24 (s, 1
H), 8.44 (d, J ϭ 9.2 Hz, 1 H), 8.10 (s, 1 H), 8.01 (d, J ϭ 9.3 Hz, 1
H) ppm. 13C NMR*: δ ϭ 167.3, 149.6, 148.0, 133.9, 130.2 (q, J ϭ
34 Hz), 128.5, 126.2, 123.9 (q, J ϭ 276 Hz), 123.3, 121.5 (q, J ϭ
259 Hz), 116.2 ppm. MS (c.i.): m/z (%) ϭ 343 (0) [Mϩ ϩ 18], 326
(40) [Mϩ ϩ 1], 325 (100) [Mϩ], 281 (40), 104 (43). C12H5F6NO3
(325.17): calcd. C 44.33, H 1.55; found C 44.55, H 1.37.
8-Fluoro-4-(trifluoromethyl)quinoline-3-carboxylic Acid (16i): This
compound was prepared from bromo acid 15i (3.38 g, 10 mmol);
colorless prisms; m.p. 217Ϫ219 °C (reprod.; from chloroform/ethyl
acetate); yield 2.15 g, (83%). 1H NMR*: δ ϭ 9.19 (s, 1 H), 8.09 (m,
1 H), 7.91 (ddd, J ϭ 8.6, 7.9, 5.3 Hz, 1 H), 7.77 (ddd, J ϭ 10.2,
8.0, 1.3 Hz, 1 H) ppm. 13C NMR*: δ ϭ 168.3, 159.7 (d, J ϭ
257 Hz), 149.8 (d, J ϭ 2 Hz), 140.8 (d, J ϭ 13 Hz), 131.5 (d, J ϭ
8 Hz), 131.2 (qd, J ϭ 32, 3 Hz), 129.0 (d, J ϭ 3 Hz), 125.3, 124.9
(q, J ϭ 276 Hz), 122.3 (m), 117.0 (d, J ϭ 19 Hz) ppm. MS (c.i.):
m/z (%) ϭ 277 (0) [Mϩ ϩ 18], 260 (100) [Mϩ ϩ 1], 259 (99) [Mϩ],
194 (15). C11H5F4NO2 (259.16): calcd. C 50.98, H 1.94; found C
50.88, H 1.82.
Acknowledgments
This work was financially supported by the Schweizerische Nation-
alfonds zur Förderung der wissenschaftlichen Forschung, Bern
(grant 20Ϫ55Ј303Ϫ98), the Bundesamt für Bildung und Wissensch-
aft, Bern (grant 97,0083 linked to the TMR project FMRXCT-
970129), and F. HoffmannϪLa Roche, Basel. The authors are also
indebted to Drs. D. Michel and J.-P. Roduit of Lonza, Visp,
for a generous gift of ethyl 4,4,4-trifluoro-3-oxobutanoate and
4,4,4-trifluoro-3-oxobutanoyl chloride.
8-Chloro-4-(trifluoromethyl)quinoline-3-carboxylic Acid (16j): This
compound was prepared from bromo acid 15j (3.55 g, 10 mmol);
colorless prisms; m.p. 210Ϫ212 °C (reprod.; from hexanes/ethyl
acetate); yield 2.45 g, (89%);1H NMR*: δ ϭ 9.24 (s, 1 H), 8.25 (dm,
J ϭ 8.7 Hz, 1 H), 8.17 (dd, J ϭ 7.7, 1.4 Hz, 1 H), 7.88 (dd, J ϭ
9.0, 7.8 Hz, 1 H) ppm. 13C NMR*: δ ϭ 167.4, 149.4, 145.9, 135.5,
132.3, 130.9 (q, J ϭ 32 Hz), 130.5, 128.2 (q, J ϭ 3 Hz), 124.7 (q,
J ϭ 4 Hz), 124.5 (q, J ϭ 276 Hz) ppm. MS (c.i.): m/z (%) ϭ 295
(0) [Mϩ ϩ 18], 293 (0) [Mϩ ϩ 18], 278 (26) [Mϩ ϩ 1], 277 (50)
[Mϩ], 276 (86) [Mϩ ϩ 1], 275 (100) [Mϩ], 258 (52), 99 (26).
C11H5ClF3NO2 (275.61): calcd. C 47.94, H 1.83; found C 47.97,
H 1.54.
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compound was prepared from bromo acid 15k (3.39 g, 10 mmol);
colorless prisms; m.p. 191Ϫ192 °C (from hexanes/ethyl acetate);
yield 2.87 g, (78%). 1H NMR*: δ ϭ 9.24 (s, 1 H), 8.39 (dd, J ϭ
7.6, 1.0 Hz, 1 H), 8.30 (d, J ϭ 8.6 Hz, 1 H), 7.83 (dd, J ϭ 8.7,
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