Selective and efficient structural elaboration of 2-(trifluoromethyl)quinolinones

Article abstract of DOI:10.1002/ejoc.200390217

The acid-catalyzed cyclization-condensation between anilines and ethyl 4,4,4-trifluoroacetoacetate affords 1,4-dihydro-2-trifluoromethyl-4H-4-quinolinones (1), which can easily be converted into 4-bromo-2-(trifluoromethyl)quinolines. These undergo halogen/metal exchange, generating 2-trifluoromethyl-4-quinolyllithiums, when treated with butyllithium, and hydrogen/metal exchange, generating 4-bromo-2-trifluoromethyl-3-quinolyllithiums, when treated with lithium diisopropylamide. Trapping of the latter intermediates provides 3-functionalized products that may be further elaborated by electrophilic substitution of the bromine atom. A few unexpected findings resulted from these investigations, the most noteworthy being an unprecedented buttressing effect and a counterintuitive halogen reactivity. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Full text of DOI:10.1002/ejoc.200390217

FULL PAPER
Selective and Efficient Structural Elaboration of
2-(Trifluoromethyl)quinolinones
Marc Marull[a] and Manfred Schlosser*[a,b]
Keywords: Bromine-lithium exchange / Ethyl 4,4,4-trifluoroacetoacetate / Heterocycles / Hydrogen-lithium exchange /
Regioselectivity
The acid-catalyzed cyclization-condensation between ani-
lines and ethyl 4,4,4-trifluoroacetoacetate affords 1,4-dihy-
lithium diisopropylamide. Trapping of the latter intermediates
provides 3-functionalized products that may be further
dro-2-trifluoromethyl-4H-4-quinolinones (1), which can eas- elaborated by electrophilic substitution of the bromine atom.
ily be converted into 4-bromo-2-(trifluoromethyl)quinolines.
These undergo halogen/metal exchange, generating 2-tri-
fluoromethyl-4-quinolyllithiums, when treated with butyl-
lithium, and hydrogen/metal exchange, generating 4-bromo-
2-trifluoromethyl-3-quinolyllithiums, when treated with
A few unexpected findings resulted from these investi-
gations, the most noteworthy being an unprecedented but-
tressing effect and a counterintuitive halogen reactivity.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Ethyl 4,4,4-trifluoroacetoacetate, technically manufac-
tured by addition of trifluoroacetyl chloride to ketene,[1] is a
most versatile component for condensation and cyclization
reactions. From this building block, considerable numbers
of 2-(trifluoromethyl)furans,[2] 2,5-dihydro-4-trifluorometh-
yl-2-furanones,[3] trifluoromethyl-substituted sugars[4,5] or
cyclohexenones[6] and 4-trifluoromethyl-2-benzopyranones
have been prepared. An even greater variety of five- and
six-membered nitrogen heterocycles has also been made
available in such a way: 3-(trifluoromethyl)pyrroles,[7,8] 5-
substituent such as trifluoromethyl is allowed to interfere
with a polar organometallic reaction. We shall substantiate
(trifluoromethyl)pyrazoles,[9,10]
rolinones,[11Ϫ15]
3-(trifluoromethyl)-5-pyr-
1,4-dihydro-2,6-bis(trifluoromethyl)pyri-
dines,[16] 2-hetero-substituted 4-trifluoromethyl-6-pyri-
dinones,[17Ϫ19] 2-amino-substituted 4-(trifluoromethyl)-
pyrimidines[20,21] or -pyrimidones[22Ϫ25] and (trifluoro-
methyl)quinolinones.[25Ϫ29]
The purpose of this report is to draw attention to the
synergies which can be exploited when an electronegative
[a]
´
Institut de Chimie moleculaire et biologique,
´ ´
Ecole Polytechnique Federale, BCh,
1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
[b]
´
´
Faculte des Sciences, Universite, BCh
1015 Lausanne, Switzerland
1576
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0408Ϫ1576 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 1576Ϫ1588

2-(Trifluoromethyl)quinolinones
FULL PAPER
the point by showing how easily 2-trifluoromethyl-4(1H)-
The cyclization with ethyl 4,4,4-trifluoroacetoacetate pro-
quinolones (1) can be converted into 4-bromo-2-(trifluoro- ceeded without any problem when ortho- or para-substi-
methyl)-quinolines (2) and, by use of the latter as kind of a tuted anilines were employed (Table 1). On the other hand,
turntable, into 2-(trifluoromethyl)quinolines (3) and various two regioisomeric 4-quinolinones 1 can result from meta
families of quinolinecarboxylic acids (4, 5, 6, and 7).
isomers of anilines, with the substituent emerging either at
the 5- or at the 7-position. Depending on the reaction con-
ditions, either a mixture (e.g. 1b ϩ 1g or 1c ϩ 1h) was ob-
tained or the latter isomer (e.g. 1g or 1h) was formed almost
exclusively (see formula scheme and Table 1).
The conversion of the 4-quinolones 1 into the corre-
sponding 4-bromo-2-(trifluoromethyl)quinolines 2 was ac-
complished with phosphorus oxytribromide as described
previously.[26] Despite considerable losses during workup,
yields of isolated products were generally high (Table 2).
Table 1. 2-Trifluoromethyl-4(1H)-quinolones (1) from anilines and
ethyl 4,4,4-trifluoroacetoacetate (yields of isolated and purified
products)
Table 2. 4-Bromo-2-(trifluoromethyl)quinolines (2) from 2-trifluo-
romethyl-4(1H)-quinolones (1) and phosphorus oxytribromide:
yields of isolated and purified products
R
Reaction cond.
Yield
[a]
[a]
[a]
[a]
[a]
[a]
[b]
[b]
[a]
[a]
[a]
Subst. R
React. cond.
Yield
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
51%
5-H3CO
5-F
6-H3C
6-F
6-F3CO
7-H3CO
7-F
8-F
8-Br
8-I
22%[c]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
14%[d] 2a
H
88%
55%[b]
52%
87%
84%
78%
70%
68%
81%
83%
49%[c]
62%
69%
63%
51%
55%
79%
64%
46%
2b
2c
2d
2e
2f
2g
2h
2i
5-H3CO
5-F
6-H3C
6-F
6-F3CO
7-H3CO
7-F
8-F
8-Br
8-I
1j
1k
2j
2k
[a]
The reaction components were heated for 2 h at 150 °C in the
[b]
presence of a large excess of polyphosphoric acid. The reaction
components were dissolved in diphenyl ether and heated under re-
flux, in the presence of a few drops of concentrated hydrochloric
acid, for 45 min. [c] Along with 32% of 1g. [d] Along with 36% of 1h.
[a]
The reaction components were heated, without solvent, for 2 h
at 150 °C. [b] Along with 14% of 4,8-dibromo-5-methoxy-2-(trifluo-
[c]
romethyl)quinoline as a by-product. Along with 22% of 2j.
Eur. J. Org. Chem. 2003, 1576Ϫ1588
1577

M. Marull, M. Schlosser
FULL PAPER
As already reported,[26] the bromine in the heterocyclic exchange, trace amounts of the dibromo compound 2j pre-
compounds can be exchanged for lithium by treatment with sumably acting as a turntable.
butyllithium, although the yields of trapping products were
When the halogen/metal permutation was carried out
only moderate. When the diethyl ether solvent was replaced with isopropylmagnesium chloride, the resulting 8-mag-
with tetrahydrofuran and the temperature was lowered from nesium species proved stable. Upon carboxylation, the
Ϫ35 °C to Ϫ75 °C, the 2-(trifluoromethyl)quinolines 3 were quinolinecarboxylic acid 8 was obtained in 84% yield. The
formed almost quantitatively upon quenching with meth- same compound was prepared independently from 8-
anol (Table 3).
bromo-2-trifluoromethyl-4(1H)-quinolinone (1j), in a six-
step sequence passing through 8-bromo-4-methoxy-2(tri-
Table 3. Removal of the heavy halogen from 4-bromo-2-(trifluoro-
methyl)quinolines (2) by consecutive treatment with butyllithium
and methanol: yields of isolated and purified 2-(trifluorometh-
yl)quinolines (3)
fluoromethyl)quinoline,
4-methoxy-2-trifluoromethyl-8-
quinolinecarboxylic acid, the corresponding methyl ester
and methyl 4-bromo-2-trifluoromethyl-8-quinolinecar-
boxylate as the key intermediates (see Exp. Sect.).
Subst. R
React. cond.[a]
Yield
[b]
[b]
[b]
[b]
[b]
3a
3d
3e
3g
3h
H
6-H3C
6-F
7-H3CO
7-F
81%
74%
89%
79%
80%
[a]
The bromine/lithium permutation requires only two or three
[b]
minutes if tert-butyllithium is employed instead of butyllithium.
Butyllithium in tetrahydrofuran at Ϫ75 °C for 15 min, then
quenching with methanol.
The organometallic intermediates emanating from the
halogen/metal interconversion can, of course, be intercepted
with other electrophiles. Thus, carboxylation followed by
neutralization afforded the acids 4 (Table 4).
Table 4. 2-Trifluoromethyl-4-quinolinecarboxylic acids (4) made
from 4-bromo-2-(trifluoromethyl)quinolines (2) with butyllithium
and carbon dioxide: yields of isolated and purified products
We were nevertheless able to obtain the 8-iodo-2-trifluoro-
methyl-4-quinolinecarboxylic acid (4k). The dibromoquino-
line 2j was subjected to a double halogen/metal permutation
with butyllithium, and the generated dilithio species
was intercepted with iodine to afford 4,8-diiodo-2-(trifluoro-
methyl)quinoline (9; 69%). A fresh halogen/metal in-
terconversion, this time carried out with isopropylmag-
nesium chloride, followed by carboxylation and neutrali-
zation gave the desired acid 4k (59%).
Subst. R
React. cond.
Yield
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
4a
4b
4c
4d
4e
4f
H
74%
89%
82%
77%
83%
74%
74%
84%
79%
57%[b,c]
5-H3CO
5-F
6-H3C
6-F
6-F3CO
7-H3CO
7-F
4g
4h
4i
8-F
8-Br
4j
[a] Butyllithium was added at Ϫ75 °C to the bromo compound 2 in
tetrahydrofuran, and after 45 min the mixture was poured onto an
[b]
excess of freshly crushed dry ice.
Not even a trace of the re-
gioisomer resulting from halogen/metal interconversion at the 8-
[c]
position was detected.
If the halogen/metal exchange is per-
formed with isopropylmagnesium chloride (in tetrahydrofuran at 0
°C for 2 h) instead with butyllithium, acid 4j can be isolated in
89% yield.
The same carboxylic acid 4j was obtained regardless of
whether the 4,8-dibromoquinoline 2j or the 4-bromo-8-
iodoquinoline 2k was used as the substrate. Obviously, the
latter had initially undergone a halogen/metal exchange at
As initially demonstrated with 3-bromofuran, halogen-
the 8-position. However, the generated intermediate was ated heterocycles undergo hydrogen/metal rather than hal-
subsequently isomerized to the 8-bromo-2-trifluoromethyl- ogen/metal permutation when the organolithium reagent is
4-quinolyllithium in another intermolecular halogen/metal replaced by a lithium dialkylamide.[30] In the same way, 4-
1578
Eur. J. Org. Chem. 2003, 1576Ϫ1588

2-(Trifluoromethyl)quinolinones
FULL PAPER
bromo-2-(trifluoromethyl)quinoline (2a) and its 6-, 7- or 8- two purposes simultaneously, protecting the 4-position
substituted congeners (2d Ϫ 2j) react smoothly with lithium against deprotonation and also facilitating the hydrogen/
diisopropylamide with deprotonation at the 3-position and metal exchange at the 3-position. Having fulfilled its task,
give the corresponding acids 5 upon carboxylation in al- it may be removed. The dehalogenation of the 4-bromo-2-
most quantitative yield (Table 5). In contrast, the 5-substi- trifluoromethyl-3-quinolinecarboxylic acids 5 can be ac-
tuted analogues proved to be totally inert under the same complished in two ways. Firstly, the acid 5 may be con-
conditions (Table 5). This once again suggests the operation verted into its methyl (11) or ethyl ester, and this can be
of a buttressing effect.[31Ϫ33]
treated with tributyltin hydride to provide the debrominated
congener (12), and finally hydrolyzed to the reduced acid 6
(Table 6, Method A).
Table 5. Production of 4-bromo-2-trifluoromethyl-3-quinolinecar-
boxylic acids (5) by consecutive treatment of 4-bromo-2-(trifluoro-
methyl)quinolines (2) with lithium diisopropylamide and carbon
dioxide: yields of isolated and purified products
Subst. R
React. cond.
Yield
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
[a]
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
88%
0%[b]
0%[b]
74%
81%
89%
86%
0%[c]
86%
62%
78%
5-H3CO
5-F
6-H3C
6-F
6-F3CO
7-H3CO
7-F
8-F
8-Br
8-I
5j
5k
Alternatively, the acid 5 may be treated at Ϫ75 °C or
Ϫ100 °C with two equivalents of butyllithium. The O,C-
[a] The substrate 2 was treated consecutively with LIDA (2 h at Ϫ75
°C) and with an excess of freshly crushed dry ice. [b] Starting materi-
als 2b and 4b were recovered almost quantitatively. For an expla- dilithio species thus generated can subsequently be pro-
[c]
nation, see text. Deprotonation and functionalization at the 8-
tonated to afford the debrominated acid 6 in high yield
(Table 6, Method B).
rather than the 3-position; 80% of product 9, see text and Exp. Sect.
Another surprise was the behavior of 4-bromo-7-fluoro-
2-(trifluoromethyl)quinoline (4h). Deprotonation did not,
as expected, occur at the 3-position to produce acid 5h after
carboxylation, but rather at the nitrogen-adjacent 8-posi-
tion, providing the corresponding carboxylic acid 10a in
80% yield and, after bromine/lithium exchange and sub-
Table 6. 2-Trifluoromethyl-3-quinolinecarboxylic acids (6) by re-
sequent neutralization, the acid 10b.
duction of 4-bromo-2-trifluoromethyl-3-quinolinecarboxylic acids
(5): yields of isolated and purified products
R
Method A[a]
Method B[b]
6a
6d
6f
6g
6i
H
71%
60%
59%
59%
64%
91%
83%
87%
86%
81%
6-H3C
6-F3CO
7-H3CO
8-F
[a]
Overall yields: esterification, reduction with tributyltin hydride,
[b]
and ester hydrolysis.
and methanol.
Consecutive treatment with butyllithium
The O,C-dilithio species can also, of course, be trapped
by electrophiles other than a proton source. Aldehydes 7
were obtained when N,N-dimethylformamide was used.
However, the yields were poor and the 4-unsubstituted ac-
ids 6 were inevitably formed as by-products (Table 7,
When the quinoline starting materials 2 are treated with Method C, M ϭ Li). Apparently the O,C-dilithio inter-
secondary lithium amides, the bromine substituent serves mediates, as soon as generated, cluster with unmodified
Eur. J. Org. Chem. 2003, 1576Ϫ1588
1579

M. Marull, M. Schlosser
FULL PAPER
After some insoluble material had been removed by filtration, the
clear solution was acidified with concentrated (32%) hydrochloric
acid. The solid obtained was collected and crystallized from
ethanol.
acids 6, thus promoting proton transfer within mixed
aggregates.[34Ϫ35] Such complications can be avoided if the
acids 5 are converted into tetrabutylammonium rather than
lithium carboxylates before subjection to halogen/metal ex-
change and subsequent electrophilic trapping. Under such
conditions, pure aldehyde-acids 7 were isolated (Table 7,
Method D, M ϭ N(C4H9)4].
2-(Trifluoromethyl)-4-quinolinone (1a): This compound was pre-
pared from aniline (23 mL, 23 g, 0.25 mol); short colorless needles;
m.p. 206Ϫ208 °C (repr.; ref.[26] 210.5Ϫ211.5 °C); yield: 21.0 g
(51%). 1H NMR*: δ ϭ 11.39 (br. s, 1 H), 8.32 (dd, J ϭ 8.3, 0.9 Hz,
1 H), 7.98 (d, J ϭ 8.4 Hz, 1 H), 7.84 (td, J ϭ 6.9, 1.4 Hz, 1 H),
7.61 (t, J ϭ 7.6 Hz, 1 H), 7.05 (s, 1 H) ppm. 13C NMR*: δ ϭ 168.3,
148.5, 147.7 (qr, J ϭ 34.4 Hz), 133.1, 128.6, 128.0, 124.7, 123.4 (qr,
J ϭ 274.8 Hz), 118.3, 103.3 ppm. 19F NMR*: δ ϭ Ϫ67.3 (s) ppm.
MS (c.i.): m/z (%) ϭ 214 (100) [Mϩ ϩ 1], 213 (89) [Mϩ], 185 (13),
165 (19), 144 (17). C10H6F3NO (213.16): calcd. C 56.35, H 2.84;
found C 56.19, H 3.00.
5-Methoxy-2-(trifluoromethyl)-4-quinolinone (1b): This compound
was prepared from m-anisidine (28 mL, 31 g, 0.25 mol). The crude
reaction mixture was adsorbed on silica gel and eluted with a 1:9
(v/v) mixture of ethyl acetate and hexanes to afford 1b and 1g in a
2:3 ratio; colorless needles; m.p. 130Ϫ132 °C (ref.[29] 131Ϫ132 °C);
yield: 13.3 g (22%). 1H NMR*: δ ϭ 10.52 (br. s, 1 H), 7.76 (dd,
J ϭ 8.4, 8.1 Hz, 1 H), 7.66 (d, J ϭ 8.5 Hz, 1 H), 7.20 (d, J ϭ
7.9 Hz, 1 H), 7.10 (s, 1 H), 4.22 (s, 3 H) ppm. 13C NMR*: δ ϭ
165.3, 157.3, 151.5, 150.0 (qr, J ϭ 33.1 Hz), 132.0, 123.5, 122.5 (qr,
J ϭ 274.4 Hz), 112.8, 107.0, 102.5, 57.2 ppm. 19F NMR*: δ ϭ
Ϫ67.5 (s) ppm. MS (c.i.): m/z (%) ϭ 244 (100) [Mϩ ϩ 1)], 243 (22)
[Mϩ], 228 (1), 200 (1).
Table 7. Conversion of 4-bromo-2-trifluoromethyl-3-quinolinecar-
boxylic acids (5) into 4-formyl-2-trifluoromethyl-3-quinolinecar-
boxylic acids (7) through their lithium or tetrabutylammonium car-
boxylates
[a,b,c]
R
H
Method C
Method D[d,e]
56%
7a
15% (ϩ 22% 6a)
5-Fluoro-2-(trifluoromethyl)-4-quinolinone (1c) and 7-Fluoro-2-(tri-
fluoromethyl)-4-quinolinone (1h): These compounds were obtained
from 3-fluoroaniline (24 mL, 28 g, 0.25 mol); 28.9 g (50%). At-
tempts to separate the two regioisomers by chromatography or by
fractional crystallization failed.
7f
7g
6-F3CO
7-H3CO
39% (ϩ 20% 6f)
Ϫ
83%
63%
[a] Treatment with 2.0 equiv. of butyllithium in diethyl ether at Ϫ100
°C. [b] Trapping with N,N-dimethylformamide, followed by hydroly-
sis. [c] Gas chromatographically determined yields. [d] Neutralization
of the acid 5 with tetrabutylammonium hydroxide, removal of
water, and consecutive treatment with 1.0 equiv. of butyllithium,
N,N-dimethylformamide, and water. [e] Yields of isolated and puri-
fied products 7.
6-Methyl-2-(trifluoromethyl)-4-quinolinone (1d): This compound
was prepared from p-toluidine (27 g, 0.25 mol); m.p. 251Ϫ253 °C
1
(repr.); yield: 43.0 g (62%). H NMR (D3CSOCD3): δ ϭ 8.02 (s, 1
H), 7.93 (br. s, 1 H), 7.66 (d, J ϭ 8.6 Hz, 1 H), 7.16 (br. s, 1 H),
2.53 (s, 3 H) ppm. 13C NMR (D3CSOCD3): δ ϭ 164.4, 148.6 (qr,
J ϭ 35.3 Hz), 138.2, 134.8, 130.3, 125.0, 123.4 (qr, J ϭ 273.1 Hz),
123.2, 118.1, 102.1, 22.4 ppm. 19F NMR (D3CSOCD3): δ ϭ Ϫ62.0
(s) ppm. MS (c.i.): m/z (%) ϭ 228 (100) [Mϩ ϩ 1], 227 (38), [Mϩ],
207 (2), 184 (1), 158 (2). C11H8F3NO (277.18): calcd. C 58.16, H
3.55; found C 57.89, H 3.80.
Experimental Section
Details concerning standard operations and abbreviations can be
found in previous publications from this laboratory.[36Ϫ38] 1H, 13C,
and 19F NMR spectra were recorded at 400, 101, and 376 MHz,
respectively, the samples having been dissolved in deuteriochloro-
form or, if marked by an asterisk (*), deuterioacetone, unless stated
otherwise. Mass spectra were obtained at 70 eV ionization poten-
tial, while a source temperature of 200 °C was maintained. When-
ever no molecular peak was observed under such standard con-
ditions, chemical ionization (‘‘c.i.’’) in an ammonia atmosphere at
100 °C source temperature was applied.
6-Fluoro-2-(trifluoromethyl)-4-quinolinone (1e): This compound was
prepared from 4-fluoroaniline (24 mL, 28 g, 0.25 mol). Short, col-
orless needles; m.p. 250Ϫ251 °C (repr.; ref.[27] 255Ϫ260 °C); yield:
1
39.8 g (69%). H NMR*: δ ϭ 8.09 (dd, J ϭ 9.2, 5.1 Hz, 1 H), 7.89
(dd, J ϭ 9.3, 2.9 Hz, 1 H), 7.69 (td, J ϭ 8.4, 2.9 Hz, 1 H), 7.15 (br.
s, 1 H) ppm. 13C NMR*: δ ϭ 164.1, 160.2 (d, J ϭ 251.5 Hz), 146.2
(qr, J ϭ 32.9 Hz), 144.5, 131.3 (d, J ϭ 9.6 Hz), 125.6, 121.4 (qr,
J ϭ 276.3 Hz), 121.5 (d, J ϭ 25.7 Hz), 106.2 (d, J ϭ 23.3 Hz),
100.9 ppm. 19F NMR*: δ ϭ Ϫ67.0 (s, 3 F), Ϫ111.3 (m, 1 F) ppm.
MS (c.i.): m/z (%) ϭ 232 (100) [Mϩ ϩ 1], 231 (699 [Mϩ], 212 (6),
183 (8), 162 (16), 134 (12), 107 (18).
2-Trifluoromethyl-4(1H)-quinolones (1)
An aniline (0.25 mmol) was added dropwise, over 15 min and with
mechanical stirring, to a mixture of ethyl 4,4,4-trifluoro-3-oxobut-
6-Trifluoromethoxy-2-(trifluoromethyl)-4-quinolinone (1f): This
compound was prepared from 4-(trifluoromethoxy)aniline (34 mL,
anoate (38 mL, 50 g, 0.25 mol) and polyphosphoric acid (0.20 kg), 44 g, 0.25 mol). Short, colorless needles; m.p. 229Ϫ230 °C (repr.);
heated at 100 °C. The temperature was then raised to 150 °C and
kept there for 2 h. When cold, the mixture was diluted with aque-
ous sodium hydroxide (5%, 0.80 L). The precipitate formed was
dissolved in a 10% aqueous solution (0.30 L) of sodium hydroxide.
yield: 46.8 g (63%). 1H NMR*: δ ϭ 8.14 (d, J ϭ 9.2 Hz, 1 H), 8.11
(d, J ϭ 1.4 Hz, 1 H), 7.76 (dd, J ϭ 9.3, 2.4 Hz, 1 H), 7.21 (br. s, 1
H) ppm. 13C NMR*: δ ϭ 166.9, 149.5, 148.5, 147.4 (qr, J ϭ
35.5 Hz), 132.3, 126.9, 124.5, 123.3 (qr, J ϭ 256.2 Hz), 122.4 (qr,
1580
Eur. J. Org. Chem. 2003, 1576Ϫ1588

2-(Trifluoromethyl)quinolinones
FULL PAPER
J ϭ 274.7 Hz), 115.0, 103.7 ppm. 19F NMR*: δ ϭ Ϫ57.5 (s, 3 F),
Ϫ67.3 (s, 3 F) ppm. MS (c.i.): m/z (%) ϭ 298 (100) [Mϩ ϩ 1], 297
(2) [Mϩ], 278 (2), 228 (3), 200 (4). C11H5F6NO2 (297.15): calcd. C
44.46, H 1.70; found C 44.43, H 1.87.
needles; m.p. 157Ϫ158 °C; yield: 39.0 g (46%). 1H NMR*: δ ϭ
11.28 (br. s, 1 H), 8.51 (1dd, J ϭ 7.3, 1.2 Hz, 1 H), 8.37 (dd, J ϭ
7.4, 1.2 Hz, 1 H), 7.45 (t, J ϭ 7.6 Hz, 1 H), 7.32 (s, 1 H) ppm. 13C
NMR*: δ ϭ 165.5, 150.6 (qr, J ϭ 35.3 Hz), 149.3, 143.4, 129.8,
124.8, 123.7, 123.2 (qr, J ϭ 275.5 Hz), 104.3, 102.5 ppm. 19F
NMR*: δ ϭ Ϫ67.3 (s) ppm. MS (c.i.): m/z (%) ϭ 340 (100) [Mϩ
ϩ 1], 339 (35) [Mϩ], 311 (5), 268 (2), 214 (4). C10H5F3INO (339.05):
calcd. C 35.42, H 1.49; found C 35.36, H 1.63.
7-Methoxy-2-(trifluoromethyl)-4-quinolinone (1g): This compound
was prepared from m-anisidine (28 mL, 31 g, 0.25 mol); colorless
needles; m.p. 249Ϫ251 °C (repr.; ref.[29] 254Ϫ255 °C); yield: 19.4 g
(32%). 1H NMR*: δ ϭ 11.00 (br. s, 1 H), 8.19 (d, J ϭ 9.1 Hz, 1
H), 7.31 (s, 1 H), 7.23 (d, J ϭ 8.9 Hz, 1 H), 6.94 (br. s, 1 H), 3.99
(s, 3 H) ppm. 13C NMR*: δ ϭ 164.1, 161.9, 151.5, 149.0 (qr, J ϭ
35.4 Hz), 124.7, 122.7, (qr, J ϭ 275.6 Hz), 120.7, 117.1, 108.5,
100.0, 56.8. Ϫ19F NMR*: δ ϭ Ϫ67.3 (s) ppm. MS (c.i.): m/z (%) ϭ
244 (100) [Mϩ ϩ 1], 243 (50) [Mϩ], 200 (4), 144 (4).
4-Bromo-2-(trifluoromethyl)quinolines (2 and 9)
The 2-trifluoromethyl-4(1H)-quinolinone (0.15 mol) was slowly ad-
ded, with mechanical stirring, to phosphorus oxybromide (43 g,
0.15 mol) while the temperature was raised from 75 °C to 150 °C.
After 2 h at 150 °C, the mixture was poured into ice-water (0.40 L).
The insoluble material was collected and crystallized from meth-
anol.
Product 1g could be prepared regioisomerically pure by application
of a modified procedure. m-Anisidine (0.25 mol) and ethyl 4,4,4-
trifluoro-3-oxobutanoate (38 mL, 50 g, 0.25 mol) were dissolved in
warm diphenyl ether (0.25 L) containing 5 drops of concentrated
hydrochloric acid. The mixture was heated at reflux (ഠ 265 °C) for
45 min. After a few hours at 25 °C, a white solid deposited and
was collected, washed with pentanes, and crystallized from ethanol
as colorless needles; 1g: m.p. 249Ϫ251 °C (ref.[29] 254Ϫ255 °C);
yield: 29.5 g (51%).
4-Bromo-2-(trifluoromethyl)quinoline (2a): This compound was pre-
pared from quinolinone 1a (32 g, 0.15 mol); colorless needles; m.p.
37Ϫ38 °C (ref.[26] 38Ϫ39 °C); yield: 31.6 g (88%). 1H NMR: δ ϭ
8.17 (d, J ϭ 6.8 Hz, 1 H), 8.14 (dd, J ϭ 8.4, 1.0 Hz, 1 H), 7.97 (s,
1 H), 7.81 (td, J ϭ 7.0, 1.3 Hz, 1 H), 7.69 (td, J ϭ 6.9, 1.2 Hz, 1
H) ppm. 13C NMR: δ ϭ 147.4, 147.3 (qr, J ϭ 36.0 Hz), 135.7,
131.5, 130.5, 129.3, 128.7, 126.6, 120.9 (qr, J ϭ 274.9 Hz),
120.8 ppm. 19F NMR: δ ϭ Ϫ67.8 (s) ppm. MS (c.i.): m/z (%) ϭ
278 (24) [Mϩ ϩ 1], 277 (100) [Mϩ], 276 (239 [Mϩ ϩ 1], 275 (99)
[Mϩ], 258 (5), 213 (16), 149 (16).
7-Fluoro-2-(trifluoromethyl)-4-quinolinone (1h): This compound was
prepared from 3-fluoroaniline (24 mL, 28 g, 0.25 mol); colorless
needles; m.p. 248Ϫ250 °C (repr.); yield: 31.8 g (55%). 1H NMR
(D3CSOCD3): δ ϭ 8.36 (dd, J ϭ 9.2, 6.2 Hz, 1 H), 7.64 (dd, J ϭ
10.2, 2.5 Hz, 1 H), 7.48 (td, J ϭ 8.5, 2.5 Hz, 1 H), 7.06 (s, 1 H)
ppm. 13C NMR (D3CSOCD3): δ ϭ 164.8, 164.7 (d, J ϭ 251.5 Hz),
150.2 (qr, J ϭ 34.4 Hz), 132.5, 126.9, 122.4 (qr, J ϭ 277.0 Hz),
120.0, 118.0, 113.1, 101.5. Ϫ19F NMR (D3CSOCD3): δ ϭ Ϫ67.5
(s, 3 F), Ϫ107.5 (m, 1 F) ppm. MS (c.i.): m/z (%) ϭ 232 (100) [Mϩ
ϩ 1], 231 (72) [Mϩ], 203 (7), 183 (16), 162 (15), 107 (22).
C10H5F4NO (231.15): calcd. C 51.96, H 2.18, N 6.06; found C
51.92, H 2.08, N 6.09.
4-Bromo-5-methoxy-2-(trifluoromethyl)quinoline (2b): This com-
pound was prepared from quinolinone 1b (36 g, 0.15 mol), the
crude reaction mixture being adsorbed on silica and eluted with a
mixture 9:1 (v/v) of hexanes and dichloromethane to afford color-
1
less needles; m.p. 140Ϫ141 °C; yield: 21.9 g (55%). H NMR: δ ϭ
7.95 (s, 1 H), 7.80 (dd, J ϭ 8.5, 1.0 Hz, 1 H), 7.70 (dd, J ϭ 8.4,
8.0 Hz, 1 H), 7.03 (d, J ϭ 7.8 Hz, 1 H), 3.98 (s, 3 H) ppm. 13C
NMR: δ ϭ 155.6, 149.8, 147.1 (qr, J ϭ 35.0 Hz), 131.2, 130.8,
125.0, 123.0, 120.8 (qr, J ϭ 273.7 Hz), 120.5, 108.3, 55.8 ppm. 19F
The same procedure (45 min in refluxing diphenyl ether) that en-
abled the regioselective preparation of 1g gave also pure 1h; m.p.
248Ϫ250 °C; yield: 31.8 g (55%).
NMR: δ ϭ Ϫ68.3 (s) ppm. MS (c.i.): m/z (%) ϭ 308 (23) [Mϩ
ϩ
1], 307 (100) [Mϩ], 306 (99) [Mϩ ϩ 1], 305 (98) [Mϩ], 264 (20), 262
(19), 214 (3), 212 (3), 183 (17). C11H7BrF3NO (306.08): calcd. C
43.17, H 2.31; found C 43.22, H 2.18.
8-Fluoro-2-(trifluoromethyl)-4-quinolinone (1i): This compound was
prepared from 2-fluoroaniline (24 mL, 28 g, 0.25 mol); short color-
less needles; m.p. 150Ϫ151 °C (ref.[27] 144Ϫ145 °C); yield: 45.6 g
4,8-Dibromo-5-methoxy-2-(trifluoromethyl)quinoline, a by-product
of longer retention time, followed; colorless needles; m.p. 170Ϫ172
°C; yield: 7.0 g (14%). 1H NMR: δ ϭ 8.05 (d, J ϭ 8.6 Hz, 1 H),
8.03 (s, 1 H), 6.93 (d, J ϭ 8.5 Hz, 1 H), 3.99 (s, 3 H) ppm. 13C
NMR: δ ϭ 155.6, 149.8, 147.3 (qr, J ϭ 35.2 Hz), 131.3, 130.6,
125.0, 123.0, 120.8 (qr, J ϭ 274.0 Hz), 120.4, 108.3, 55.2 ppm. 19F
1
(79%). H NMR*: δ ϭ 11.21 (br. s, 1 H), 8.12 (dd, J ϭ 7.4 Hz, 1
H), 7.65 (m, 2 H), 7.29 (br. s, 1 H) ppm. 13C NMR*: δ ϭ 154.5,
158.5 (d, J ϭ 251.0 Hz), 149.1 (qr, J ϭ 35.3 Hz), 139.5, 128.0 (d,
J ϭ 6.6 Hz), 124.5, 122.6 (qr, J ϭ 274.8 Hz), 119.3, 116.5 (d, J ϭ
18.5 Hz), 102.8 ppm. 19F NMR*: δ ϭ Ϫ67.3 (s, 3 F), Ϫ123.5 (m,
1 F) ppm. MS (c.i.): m/z (%) ϭ 232 (100) [Mϩ ϩ 1], 231 (39) [Mϩ],
203 (5), 183 (10). C10H5F4NO (231.15): calcd. C 51.96, H 2.18, N
6.06; found C 52.37, H 2.09, N 6.26.
NMR: δ ϭ Ϫ68.1 (s) ppm. MS (c.i.): m/z (%) ϭ 388 (12) [Mϩ
ϩ
1], 387 (50) [Mϩ], 386 (57) [Mϩ ϩ1], 385 (100) [Mϩ], 384 (81) [Mϩ
ϩ1], 383 (52) [Mϩ], 342 (20), 305 (5). C11H6Br2F3NO (384.98):
calcd. C 34.32, H 1.77; found C 34.18, C 1.66.
8-Bromo-2-(trifluoromethyl)-4-quinolinone (1j): This compound was
prepared from 2-bromoaniline (43 g, 0.25 mol); colorless needles;
m.p. 137Ϫ139 °C; yield: 46.7 g (64%). 1H NMR*: δ ϭ 8.27 (dd,
J ϭ 8.4, 1.3 Hz, 1 H), 8.16 (dd, J ϭ 7.4, 1.1 Hz, 1 H), 7.53 (t, J ϭ
7.8 Hz, 1 H), 7.33 (s, 1 H) ppm. 13C NMR*: δ ϭ 164.8, 150.7 (qr,
J ϭ 35.2 Hz), 147.3, 136.5, 129.1, 126.3, 124.5, 123.8, 123.2 (qr,
J ϭ 274.0 Hz), 102.6 ppm. 19F NMR*: δ ϭ Ϫ67.3 (s) ppm. MS
(c.i.): m/z (%) ϭ 294 (97) [Mϩ ϩ 1], 293 (44) [Mϩ], 292 (100) [Mϩ
ϩ 1], 291 (24) [Mϩ], 214 (10), 134 (25). C10H5BrF3NO (292.05):
calcd. C 41.73, H 1.73; found C 40.92, H 1.96.
4-Bromo-5-fluoro-2-(trifluoromethyl)quinoline (2c): A mixture of 2c
and 2h was obtained in a 27:73 ratio (determined by GC 30 m, DB
1701, 130 °C; 30 m, DB 210, 120 °C) from the mixture of quinolin-
ones 1c and 1h (34 g, 0.15 mol). The quinolinone 2c was separated
by elution from silica gel (0.30 L) with hexanes; m.p. 62Ϫ64 °C;
1
yield: 7.3 g (19%). H NMR: δ ϭ 8.09 (d, J ϭ 8.6 Hz, 1 H), 8.04
(s, 1 H), 7.80 (td, J ϭ 8.4, 5.2 Hz, 1 H), 7.44 (ddd, J ϭ 11.4, 7.9,
1.0 Hz, 1 H) ppm. 13C NMR: δ ϭ 157.3 (d, J ϭ 264.1 Hz), 149.1,
148.0 (m), 131.0 (d, J ϭ 9.5 Hz), 129.3, 127.1 (d, J ϭ 4.5 Hz),
123.1, 120.7 (qr, J ϭ 273.0 Hz), 119.2, 114.5 (d, J ϭ 22.0 Hz) ppm.
19F NMR: δ ϭ Ϫ68.1 (s, 3 F), Ϫ111.0 (dd, J ϭ 11.5, 5.0 Hz, 1 F)
ppm. MS (c.i.): m/z (%) ϭ 296 (100) [Mϩ ϩ 1], 295 (78) [Mϩ], 294
8-Iodo-2-(trifluoromethyl)-4-quinolinone (1k): This compound was
prepared from 2-iodoaniline (55 g, 0.25 mol); short colorless
Eur. J. Org. Chem. 2003, 1576Ϫ1588
1581

M. Marull, M. Schlosser
FULL PAPER
(97) [Mϩ ϩ 1], 293 (66) [Mϩ], 250 (9), 216 (17). C10H4BrF4N NMR: δ ϭ 8.07 (s, 1 H), 8.02 (d, J ϭ 8.6 Hz, 1 H), 7.72 (ddd, J ϭ
(294.04): calcd. C 40.85, H 1.37, N 4.76; found C 41.14, H 1.35, 8.3, 8.1, 5.0 Hz, 1 H), 7.59 (ddd, J ϭ 9.5, 7.9, 1.1 Hz, 1 H) ppm.
N 4.87.
13C NMR: δ ϭ 157.9 (d, J ϭ 256.6 Hz), 147.5 (qr, J ϭ 35.5 Hz),
144.3, 138.1 (d, J ϭ 12.5 Hz), 135.8 (d, J ϭ 4.0 Hz), 129.8 (d, J ϭ
8.2 Hz), 122.6 (d, J ϭ 4.5 Hz), 122.0, 120.6 (qr, J ϭ 274.8 Hz),
115.5 (d, J ϭ 18.0 Hz) ppm. 19F NMR: δ ϭ Ϫ67.8 (s, 3 F), Ϫ121.3
(dd, J ϭ 10.0, 5.0 Hz, 1 F) ppm. MS (c.i.): m/z (%) ϭ 296 (89) [Mϩ
ϩ 1], 295 (47) [Mϩ], 294 (100) [Mϩ ϩ 1], 293 (26) [Mϩ], 250 (6), 216
(6). C10H4BrF4N (294.04): calcd. C 40.85, H 1.37, N 4.76; found C
40.56, H 1.18, N 4.76.
4-Bromo-6-methyl-2-(trifluoromethyl)quinoline (2d): This com-
pound was prepared from quinolinone 1d (41 g, 0.15 mol); m.p.
71Ϫ72 °C (ref.[26] 70Ϫ71 °C); yield: 32.8 g (87%). 1H NMR: δ ϭ
8.07 (d, J ϭ 8.6 Hz, 1 H), 7.96 (s, 2 H), 7.66 (dd, J ϭ 8.7, 1.7 Hz,
1 H), 2.61 (s, 3 H) ppm. 13C NMR: δ ϭ 146.5 (qr, J ϭ 35.3 Hz),
146.0, 140.6, 135.0, 134.0, 130.4, 126.5, 125.0, 121.0 (qr, J ϭ
274.8 Hz), 120.9, 22.0 ppm. 19F NMR: δ ϭ Ϫ67.8 (s) ppm. MS
(c.i.): m/z (%) ϭ 292 (90) [Mϩ ϩ 1], 291 (34) [Mϩ], 290 (100) [Mϩ 4,8-Dibromo-2-(trifluoromethyl)quinoline (2j): This compound was
ϩ 1], 289 (23) [Mϩ], 271 (1), 212 (24), 140 (5).
prepared from quinolinone 1j (44 g, 0.15 mol); colorless needles;
m.p. 86Ϫ87 °C; yield: 38.3 g (83%). 1H NMR: δ ϭ 8.25 (d, J ϭ
8.5 Hz, 1 H), 8.20 (d, J ϭ 7.5 Hz, 1 H), 8.08 (s, 1 H), 7.61 (t, J ϭ
8.3 Hz, 1 H) ppm. 13C NMR: δ ϭ 148.0 (qr, J ϭ 35.9 Hz), 144.7,
136.2, 135.3, 130.0, 129.6, 126.7, 126.2, 121.9, 120.7 (qr, J ϭ
276.4 Hz) ppm. 19F NMR: δ ϭ Ϫ68.0 (s) ppm. MS (c.i.): m/z (%) ϭ
358 (63) [Mϩ ϩ 1], 357 (22) [Mϩ], 356 (100) [Mϩ ϩ 1], 355 (19)
[Mϩ], 354 (70) [Mϩ ϩ 1], 353 (5) [Mϩ], 278 (5), 276 (5).
C10H4Br2F3N (354.95): calcd. C 33.84, H 1.14; found C 33.72, H
1.24.
4-Bromo-6-fluoro-2-(trifluoromethyl)quinoline (2e): This compound
was prepared from quinolinone 1e (34 g, 0.15 mol); colorless
needles; m.p. 90Ϫ91 °C (ref.[27] 93Ϫ95 °C); yield: 32.0 g (84%). H
1
NMR: δ ϭ 8.24 (dd, J ϭ 9.3, 5.3 Hz, 1 H), 8.04 (s, 1 H), 7.89 (dd,
J ϭ 9.3, 2.8 Hz, 1 H), 7.64 (ddd, J ϭ 8.6, 7.9, 2.8 Hz, 1 H) ppm.
13C NMR: δ ϭ 162.8 (d, J ϭ 251.5 Hz), 147.1 (qr, J ϭ 35.2 Hz),
144.7, 134.9 (d, J ϭ 6.4 Hz), 133.7 (d, J ϭ 9.6 Hz), 130.1, 122.3 (d,
J ϭ 26.4 Hz), 121.6, 120.8 (qr, J ϭ 275.6 Hz), 110.7 (d, J ϭ
24.8 Hz) ppm. 19F NMR: δ ϭ Ϫ67.8 (s, 3 F), Ϫ107.1 (m, 1 F)
ppm. MS (c.i.): m/z (%) ϭ 296 (100) [Mϩ ϩ 1], 295 (58) [Mϩ], 294 4-Bromo-8-iodo-2-(trifluoromethyl)quinoline (2k): This compound
(97) [Mϩ ϩ 1], 293 (51) [Mϩ], 276 (3), 274 (3), 216 (12), 145 (17).
was prepared from quinolinone 1k (51 g, 0.15 mol); colorless
needles; m.p. 112Ϫ113 °C; yield: 25.6 g (49%). 1H NMR: δ ϭ 8.48
(dd, J ϭ 7.4, 1.2 Hz, 1 H), 8.26 (dd, J ϭ 8.5, 1.2 Hz, 1 H), 8.06 (s,
1 H), 7.47 (dd, J ϭ 8.4, 7.5 Hz, 1 H) ppm. 13C NMR: δ ϭ 148.1
(qr, J ϭ 36.5 Hz), 146.5, 142.4, 136.3, 131.1 (qr, J ϭ 278.0 Hz),
130.8, 128.9, 127.6, 121.8, 104.3 ppm. 19F NMR: δ ϭ Ϫ67.9 (s)
ppm. MS (c.i.): m/z (%) ϭ 404 (91) [Mϩ ϩ 1], 403 (89) [Mϩ], 402
(100) [Mϩ ϩ 1], 401 (73) [Mϩ], 356 (16), 324 (23), 276 (9), 156 (11).
C10H4BrF3IN (401.95): calcd. C 29.88, H 1.00, N 3.48; found C
29.78, H 1.03, N 3.54.
4-Bromo-6-trifluoromethoxy-2-(trifluoromethyl)quinoline (2f): This
compound was prepared from quinolinone 1f (44 g, 0.15 mol); col-
orless needles; m.p. 70Ϫ71 °C; yield: 32.1 g (78%). H NMR: δ ϭ
8.44 (d, J ϭ 11.1 Hz, 1 H), 8.17 (m, 2 H), 7.76 (dd, J ϭ 11.0,
3.1 Hz, 1 H) ppm. 13C NMR: δ ϭ 149.8, 148.3 (qr, J ϭ 35.5 Hz),
145.8, 135.5, 133.5, 129.3, 125.8, 120.4 (qr, J ϭ 259.3 Hz), 120.3
(qr, J ϭ 264.1 Hz), 122.0, 116.8 ppm. 19F NMR: δ ϭ Ϫ58.3 (s, 3
F), Ϫ68.3 (s, 3 F) ppm. MS (c.i.): m/z (%) ϭ 362 (53) [Mϩ ϩ 1],
361 (80) [Mϩ], 360 (62) [Mϩ ϩ 1], 359 (100) [Mϩ], 342 (17), 282
1
(64), 281 (84). C11H4BrF6NO (360.05): calcd. C 36.70, H 1.12; 4,8-Diiodo-2-(trifluoromethyl)quinoline (9): 4,8-Dibromo-2-(trifluo-
found C 36.84, H 1.11.
romethyl)quinoline (28 g, 79 mmol) in tetrahydrofuran (0.10 L) and
butyllithium (0.16 mol) in hexanes (0.10 L) were mixed at Ϫ75 °C
and kept for 45 min. Iodine (41 g, 0.16 mol) in tetrahydrofuran
(50 mL) was added. The solvents were evaporated and the residue
was taken up in diethyl ether (0.10 L). The organic layer was
washed with aqueous sodium thiosulfate (1.0 , 2 ϫ 50 mL) and
dried, and the solvents were evaporated. The residue was crys-
tallized from methanol; colorless prisms; m.p. 157Ϫ159 °C; yield:
4-Bromo-7-methoxy-2-(trifluoromethyl)quinoline (2g): This com-
pound was prepared from quinolinone 1g (36 g, 0.15 mol); colorless
needles; m.p. 126Ϫ128 °C; yield: 28.3 g (71%). H NMR: δ ϭ 8.12
1
(d, J ϭ 9.3 Hz, 1 H), 7.87 (s, 1 H), 7.54 (d, J ϭ 2.5 Hz, 1 H), 7.34
(dd, J ϭ 9.3, 2.5 Hz, 1 H), 3.98 (s, 3 H) ppm. 13C NMR: δ ϭ 162.5,
149.6, 147.3 (qr, J ϭ 35.2 Hz), 135.6, 127.8, 123.9, 123.5, 121.0 (qr,
J ϭ 274.8 Hz), 118.8, 107.7, 56.1 ppm. 19F NMR: δ ϭ Ϫ68.1 (s, 3
F) ppm. MS (c.i.): m/z (%) ϭ 308 (90) [Mϩ ϩ 1], 307 (34) [Mϩ],
306 (100) [Mϩ ϩ 1], 305 (25) [Mϩ], 278 (3), 228 (57), 114 (7).
C11H7BrF3NO (306.08): calcd. C 43.17, H 2.31; found C 43.12,
H 2.04.
1
24.6 g (69%). H NMR: δ ϭ 8.45 (dd, J ϭ 7.5, 1.1 Hz, 1 H), 8.30
(s, 1 H), 8.07 (dd, J ϭ 8.3, 1.1 Hz, 1 H), 7.42 (dd, J ϭ 8.3, 7.5 Hz,
1 H) ppm. 13C NMR: δ ϭ 148.0 (qr, J ϭ 36.0 Hz), 145.3, 142.4,
135.3, 132.5, 131.0, 129.1, 120.2 (qr, J ϭ 276.0 Hz), 113.5,
104.5 ppm. 19F NMR: δ ϭ Ϫ67.8 (s) ppm. MS (c.i.): m/z (%) ϭ
450 (25) [Mϩ ϩ 1], 449 (100) [Mϩ], 448 (81), 403 (11), 322 (12).
C10H4F3I2N (448.94): calcd. C 26.75, H 0.90, N 3.12; found C
26.96, H 0.96, N 3.17.
4-Bromo-7-fluoro-2-(trifluoromethyl)quinoline (2h): This compound
was prepared from quinolinone 1h (34 g, 0.15 mol); colorless
needles; m.p. 64Ϫ65 °C; yield: 26.0 g (68%). 1H NMR: δ ϭ 8.27
(dd, J ϭ 9.3, 5.8 Hz, 1 H), 7.98 (s, 1 H), 7.84 (dd, J ϭ 9.4, 2.6 Hz,
1 H), 7.55 (ddd, J ϭ 9.3, 7.9, 2.6 Hz, 1 H) ppm. 13C NMR: δ ϭ
164.1, (d, J ϭ 254.6 Hz), 148.8 (d, J ϭ 12.9 Hz), 148.7 (qr, J ϭ
2-(Trifluoromethyl)quinolines (3)
The 4-bromo-2-(trifluoromethyl)quinoline (2; 25 mmol) was added
35.3 Hz), 138.3, 129.3 (d, J ϭ 9.8 Hz), 125.5, 120.7 (qr, J ϭ to a precooled solution of butyllithium (25 mmol) in tetrahydro-
275.5 Hz), 120.5 (2 C), 144.0 (d, J ϭ 21.0 Hz) ppm. 19F NMR: δ ϭ furan (15 mL) and hexanes (15 mL). After the mixture had been
Ϫ68.3 (s, 3 F), Ϫ106.3 (m, 1 F,) ppm. MS (c.i.): m/z (%) ϭ 296
kept for 15 min at Ϫ75 °C, methanol (2.0 mL, 50 mmol) was added
(91) [Mϩ ϩ 1], 295 (37) [Mϩ], 294 (100) [Mϩ ϩ 1], 293 (30) [Mϩ], by syringe and the product was isolated by crystallization from
278 (3), 276 (4), 216 (94), 145 (9). C10H4BrF4N (294.04): calcd. C pentanes.
40.85, H 1.37; found C 40.96, H 1.20.
2-(Trifluoromethyl)quinoline (3a): This compound was prepared
4-Bromo-8-fluoro-2-(trifluoromethyl)quinoline (2i): This compound
was prepared from quinolinone 1i (34 g, 0.15 mol); colorless
from 2a (4.1 g, 15 mmol); colorless needles; m.p. 57Ϫ58 °C (ref.[39]
57.0Ϫ57.5 °C); yield: 2.39 g (81%). 1H NMR: δ ϭ 8.37 (d, J ϭ
needles; m.p. 69Ϫ71 °C, (ref.[27] 68Ϫ69 °C); yield: 35.7 g (81%). 1H 8.5 Hz, 1 H), 8.24 (d, J ϭ 8.5 Hz, 1 H), 7.93 (d, J ϭ 8.3 Hz, 1 H),
1582
Eur. J. Org. Chem. 2003, 1576Ϫ1588

2-(Trifluoromethyl)quinolinones
FULL PAPER
7.84 (dd, J ϭ 8.5, 7.2 Hz, 1 H), 7.75 (d, J ϭ 8.5 Hz, 1 H), 7.69 (t, 2-Trifluoromethyl-4-quinolinecarboxylic Acid (4a): This compound
J ϭ 8.5 Hz, 1 H) ppm. 13C NMR: δ ϭ 147.8 (qr, J ϭ 34.4 Hz), was prepared from 2a (6.9 g, 25 mmol); colorless prisms; m.p.
1
147.0, 137.9, 130.7, 129.9, 128.8, 128.3, 127.5, 121.6 (qr, J ϭ
275.6 Hz), 116.5 ppm. 19F NMR: δ ϭ Ϫ68.0 (s) ppm. MS (c.i.):
m/z (%) ϭ 198 (10) [Mϩ ϩ 1], 197 (45) [Mϩ], 128 (28), 96 (30),
83 (100).
181Ϫ182 °C (ref.[26] 196Ϫ197 °C); yield: 4.46 g (74%). H NMR*:
δ ϭ 8.96 (dd, J ϭ 8.6, 0.8 Hz, 1 H), 8.35 (s, 1 H), 8.27 (d, J ϭ
8.4 Hz, 1 H), 8.01 (ddd, J ϭ 8.5, 6.8, 1.4 Hz, 1 H), 7.91 (ddd, J ϭ
8.5, 6.7, 1.3 Hz, 1 H) ppm. 13C NMR*: δ ϭ 167.5, 150.0, 148.8 (qr,
J ϭ 34.4 Hz), 139.7, 133.0, 132.0 (2 C), 127.8 (2 C), 123.4 (qr, J ϭ
274.0 Hz), 119.7 ppm. 19F NMR*: δ ϭ Ϫ67.1 (s) ppm. MS (c.i.):
m/z (%) ϭ 242 (27) [Mϩ ϩ 1], 241 (100) [Mϩ], 224 (7), 196 (6), 185
(1). C11H6F3NO2 (241.17): calcd. C 54.78, H 2.51; found C 54.78,
H 2.88.
6-Methyl-2-(trifluoromethyl)quinoline (3d): This compound was
prepared from 2d (4.4 g, 15 mmol); colorless prisms; m.p.
89.5Ϫ91.5 °C (ref.[39] 88Ϫ89 °C); yield: 2.34 g (74%). 1H NMR:
δ ϭ 8.26 (d, J ϭ 8.6 Hz, 1 H), 8.12 (d, J ϭ 9.4 Hz, 1 H), 7.70 (d,
J ϭ 8.6 Hz, 1 H), 7.65 (m, 2 H), 2.58 (s, 3 H) ppm. 13C NMR: δ ϭ
147.1 (qr, J ϭ 34.4 Hz), 145.9, 139.0, 137.4, 133.3, 129.7, 129.0,
126.5, 122.0 (qr, J ϭ 274.8 Hz), 116.8, 21.7 ppm. 19F NMR: δ ϭ
Ϫ67.9 (s) ppm. MS (c.i.): m/z (%) ϭ 212 (100) [Mϩ ϩ 1], 211 (37)
[Mϩ], 191 (4), 142 (2).
5-Methoxy-2-trifluoromethyl-4-quinolinecarboxylic Acid (4b): This
compound was prepared from 2b (7.6 g, 25 mmol); colorless
prisms; m.p. 249Ϫ250 °C (repr.); yield: 6.03 g (89%). 1H NMR*:
δ ϭ 7.91 (m, 1 H), 7.84 (s, 1 H), 7.81 (dd, J ϭ 8.6, 0.8 Hz, 1 H),
7.31 (d, J ϭ 8.0 Hz, 1 H), 4.03 (s, 3 H) ppm. 13C NMR*: δ ϭ
169.1, 155.6, 149.5, 148.3 (qr, J ϭ 35.0 Hz), 142.6, 132.9, 123.0,
122.5 (qr, J ϭ 274.0 Hz), 117.6, 114.8, 109.3, 56.8 ppm. 19F NMR*:
δ ϭ Ϫ67.3 (s) ppm. MS (c.i.): m/z (%) ϭ 272 (51) [Mϩ ϩ 1], 271
(100) [Mϩ], 270 (42), 253 (6), 239 (18), 224 (5). C12H8F3NO3
(271.19): calcd. C 53.15, H 2.97; found C 53.13, H 3.23.
6-Fluoro-2-(trifluoromethyl)quinoline (3e): This compound was pre-
pared from 2e (4.4 g, 15 mmol); colorless needles; m.p. 59Ϫ60 °C;
1
yield: 2.87 g (89%). H NMR: δ ϭ 8.30 (d, J ϭ 8.6 Hz, 1 H), 8.14
(dd, J ϭ 9.4, 5.4 Hz, 1 H), 7.75 (d, J ϭ 8.6 Hz, 1 H), 7.60 (ddd,
J ϭ 11.0, 9.2, 2.7 Hz, 1 H), 7.51 (dd, J ϭ 8.6, 2.7 Hz, 1 H) ppm.
13C NMR: δ ϭ 161.4 (d, J ϭ 251.7 Hz), 147.3 (qr, J ϭ 34.4 Hz),
144.1, 137.3 (d, J ϭ 5.6 Hz), 132.7 (d, J ϭ 9.6 Hz), 129.6 (d, J ϭ
10.4 Hz), 121.4 (qr, J ϭ 274.8 Hz), 121.3 (d, J ϭ 25.6 Hz), 117.5,
111.1 (d, J ϭ 21.6 Hz) ppm. 19F NMR: δ ϭ Ϫ68.0 (s), Ϫ110.0 (m,
1 F) ppm. MS (c.i.): m/z (%) ϭ 216 (100) [Mϩ ϩ 1], 215 (42) [Mϩ],
193 (2), 146 (4). C10H5F4N (215.15): calcd. C 55.83, H 2.34, N
6.51; found C 55.67, H 2.50, N 6.32.
5-Fluoro-2-trifluoromethyl-4-quinolinecarboxylic Acid (4c): This
compound was prepared from 2c (7.3 g, 25 mmol); colorless
prisms; m.p. 237Ϫ239 °C (repr.); yield: 5.31 g (82%). 1H NMR*:
δ ϭ 8.15 (d, J ϭ 8.5 Hz, 1 H), 8.10 (s, 1 H), 8.05 (ddd, J ϭ 8.4,
7.9, 5.7 Hz, 1 H), 7.68 (ddd, J ϭ 11.2, 7.9, 0.9 Hz, 1 H) ppm. 13C
NMR*: δ ϭ 169.0, 158.5 (d, J ϭ 257.8 Hz), 150.0 (qr, J ϭ 35.3 Hz,
2 C), 141.5, 133.5 (d, J ϭ 8.8 Hz), 128.3 (d, J ϭ 3.2 Hz), 123.1 (qr,
J ϭ 275.5 Hz), 117.0 (2 C), 116.0 (d, J ϭ 20.1 Hz) ppm. 19F NMR*:
δ ϭ Ϫ67.3 (s, 3 F), Ϫ111.9 (m, 1 F) ppm. MS (c.i.): m/z (%) ϭ
260 (100) [Mϩ ϩ 1], 259 (76) [Mϩ], 234 (36), 215 (9), 183 (12).
C11H5F4NO2 (259.16): calcd. C 50.98, H 1.94, N 5.40; found C
50.82, H 1.86, N 5.44.
7-Methoxy-2-(trifluoromethyl)quinoline (3g): This compound was
prepared from 2g (4.6 g, 15 mmol); colorless needles; m.p. 69Ϫ71
1
°C (ref.[39] 65Ϫ66 °C); yield: 2.69 g (79%). H NMR: δ ϭ 8.21 (d,
J ϭ 8.3 Hz, 1 H), 7.73 (d, J ϭ 9.1 Hz, 1 H), 7.58 (d, J ϭ 8.3 Hz,
1 H), 7.48 (d, J ϭ 2.4 Hz, 1 H), 7.28 (dd, J ϭ 8.9, 2.4 Hz, 1 H),
3.94 (s, 3 H) ppm. 13C NMR: δ ϭ 161.6, 149.3, 148.1 (qr, J ϭ
34.4 Hz), 137.7, 128.8, 124.4, 122.2, 121.7 (qr, J ϭ 275.5 Hz), 114.7,
107.5, 55.8 ppm. 19F NMR: δ ϭ Ϫ67.9 (s) ppm. MS (c.i.): m/z
(%) ϭ 228 (100) [Mϩ ϩ 1], 227 (61) [Mϩ], 216 (12), 197 (11), 128
(5).
6-Methyl-2-trifluoromethyl-4-quinolinecarboxylic Acid (4d): This
compound was prepared from 2d (7.2 g, 25 mmol); colorless
prisms; m.p. 212Ϫ213 °C (repr.; ref.[26] 215Ϫ216 °C); yield: 4.91 g
(77%). 1H NMR*: δ ϭ 8.71 (s, 1 H), 8.31 (s, 1 H), 8.11 (d, J ϭ
8.7 Hz, 1 H), 7.80 (dd, J ϭ 8.7, 1.9 Hz, 1 H), 2.62 (s, 3 H) ppm.
13C NMR*: δ ϭ 168.3, 148.7, 147.8 (qr, J ϭ 34.5 Hz), 142.4, 140.0,
135.0, 131.6, 127.7, 126.5, 123.4 (qr, J ϭ 273.9 Hz), 119.3,
23.0 ppm. 19F NMR*: δ ϭ Ϫ67.0 (s) ppm. MS (c.i.): m/z (%) ϭ
256 (100) [Mϩ ϩ 1], 255 (25) [Mϩ], 212 (13), 117 (1).
7-Fluoro-2-(trifluoromethyl)quinoline (3h): This compound was pre-
pared from 2h (4.4 g, 15 mmol); colorless prisms; m.p. 49Ϫ50 °C
(ref.[39] 52Ϫ53 °C); yield: 2.58 g (80%). 1H NMR: δ ϭ 8.35 (d, J ϭ
8.6 Hz, 1 H), 7.91 (dd, J ϭ 9.1, 5.9 Hz, 1 H), 7.83 (dd, J ϭ 9.7,
2.4 Hz, 1 H), 7.73 (d, J ϭ 8.6 Hz, 1 H), 7.46 (td, J ϭ 8.6, 2.7 Hz,
1 H) ppm. 13C NMR: δ ϭ 163.8 (d, J ϭ 252.5 Hz), 149.2 (qr, J ϭ
35.2 Hz), 148.3 (d, J ϭ 13.6 Hz), 138.1, 130.0 (d, J ϭ 9.6 Hz),
126.0, 121.5 (qr, J ϭ 274.8 Hz), 119.5 (d, J ϭ 25.6 Hz), 116.3, 113.7
(d, J ϭ 20.8 Hz) ppm. 19F NMR: δ ϭ Ϫ68.1 (s, 3 F), Ϫ107.3 (m,
1 F) ppm. MS (c.i.): m/z (%) ϭ 216 (100) [Mϩ ϩ 1], 215 (57) [Mϩ],
193 (7), 146 (11).
6-Fluoro-2-trifluoromethyl-4-quinolinecarboxylic Acid (4e): This
compound was prepared from 2e (7.3 g, 25 mmol); colorless
prisms; m.p. 194Ϫ196 °C (ref.[27] 207Ϫ09 °C); yield: 5.37 g (83%).
1H NMR*: δ ϭ 8.66 (dd, J ϭ 11.0, 2.9 Hz, 1 H), 8.40 (s, 1 H),
8.30 (dd, J ϭ 9.3, 5.7 Hz, 1 H), 7.83 (ddd, J ϭ 9.3, 8.0, 2.9 Hz, 1
H) ppm. 13C NMR*: δ ϭ 166.3, 163.8 (d, J ϭ 251.5 Hz), 162.5,
147.8 (qr, J ϭ 37.2 Hz), 146.5, 137.5 (d, J ϭ 6.4 Hz), 134.3 (d, J ϭ
10.0 Hz), 128.3 (d, J ϭ 11.8 Hz), 122.5 (d, J ϭ 26.7 Hz), 122.4 (qr,
J ϭ 274.6 Hz), 110.5 (d, J ϭ 25.7 Hz) ppm. 19F NMR*: δ ϭ Ϫ67.0
(s), Ϫ106.5 (m, 1 F) ppm. MS (c.i.): m/z (%) ϭ 260 (96) [Mϩ ϩ 1,
259 (100) [Mϩ], 242 (13), 214 (9), 194 (3).
2-(Trifluoromethyl)-4-quinolinecarboxylic Acids (4)
The 4-bromo-2-(trifluoromethyl)quinoline (2; 25 mmol) was added
at Ϫ75 °C to a solution of butyllithium (25 mmol) in tetrahydrofu-
ran (15 mL) and hexanes (15 mL). After 45 min at this temperature, 6-Trifluoromethoxy-2-trifluoromethyl-4-quinolinecarboxylic
the mixture was poured onto an excess of freshly crushed dry ice. (4f): This compound was prepared from 2f (9.0 g, 25 mmol); color-
Water (0.10 L) was added, and the aqueous phase was washed with less prisms; m.p. 201Ϫ202 °C (repr.); yield: 6.02 g (74%). H NMR*:
Acid
1
diethyl ether (3 ϫ 50 mL) before being acidified to pH 4 with con-
centrated hydrochloric acid. Extraction with ethyl acetate (3 ϫ
50 mL), drying of the combined organic layers, and evaporation
gave a residue, which was crystallized from a 2:1 (v/v) mixture of
chloroform and ethyl acetate.
δ ϭ 9.00 (d, J ϭ 1.3 Hz, 1 H), 8.48 (s, 1 H), 8.40 (d, J ϭ 9.3 Hz,
1 H), 7.95 (dd, J ϭ 9.3, 1.6 Hz, 1 H) ppm. 13C NMR*: δ ϭ 165.3,
149.5, 147.8 (qr, J ϭ 34.5 Hz), 146.5, 137.5, 133.0, 126.8, 125.0,
121.4 (qr, J ϭ 256.3 Hz), 120.8 (qr, J ϭ 275.5 Hz), 119.5,
116.0 ppm. 19F NMR*: δ ϭ Ϫ57.3 (s, 3 F), Ϫ67.3 (s, 3 F) ppm.
Eur. J. Org. Chem. 2003, 1576Ϫ1588
1583

M. Marull, M. Schlosser
MS (c.i.): m/z (%) ϭ 326 (100) [Mϩ ϩ 1], 325 (81) [Mϩ], 308 (10), 15 min at Ϫ75 °C), dry ice, and acid; m.p. 220Ϫ222 °C; yield
FULL PAPER
281 (14). C12H5F6NO3 (325.16): calcd. C 44.33, H 1.55; found C
44.09, H 1.75.
6.9 g (86%).
8-Iodo-2-trifluoromethyl-4-quinolinecarboxylic Acid (4k): 4,8-Iodo-
2-(trifluoromethyl)quinoline (9; 11.2 g, 25 mmol) was added to an
ice-cold solution of isopropylmagnesium chloride (25 mmol) in
tetrahydrofuran (25 mL). The mixture was kept 45 min at 0 °C be-
fore being poured onto an excess of freshly crushed dry ice. After
evaporation of the solvent, the residue was taken up in water
(0.10 L). The aqueous phase was washed with diethyl ether (3 ϫ
50 mL), acidified to pH 4 with concentrated hydrochloric acid, and
extracted with ethyl acetate (3 ϫ 50 mL). The combined organic
layers were washed with brine (50 mL), dried, and concentrated.
The product was collected after crystallization from a 1:1 (v/v) mix-
ture of chloroform and ethyl acetate; colorless prisms; m.p. 273
7-Methoxy-2-trifluoromethyl-4-quinolinecarboxylic Acid (4g): This
compound was prepared from 2g (7.6 g, 25 mmol); colorless
prisms; m.p. 235Ϫ236 °C (repr.); yield: 5.02 g (74%). 1H NMR*:
δ ϭ 8.85 (d, J ϭ 9.5 Hz, 1 H), 8.18 (s, 1 H), 7.58 (d, J ϭ 2.7 Hz,
1 H), 7.49 (dd, J ϭ 9.5, 2.7 Hz, 1 H), 4.06 (s, 3 H) ppm. 13C NMR*:
δ ϭ 166.8, 162.7, 151.5, 148.1 (qr, J ϭ 34.4 Hz), 138.3, 127.8, 124.4,
122.6 (qr, J ϭ 274.8 Hz), 122.3, 116.4, 108.8, 56.3 ppm. 19F NMR*:
δ ϭ Ϫ67.1 (s) ppm. MS (c.i.): m/z (%) ϭ 272 (32) [Mϩ ϩ 1], 271
(100) [Mϩ], 254 (1), 223 (3), 185 (2). C12H8F3NO3 (271.19): calcd.
C 53.15, H 2.97; found C 53.09, H 2.92.
1
7-Fluoro-2-trifluoromethyl-4-quinolinecarboxylic Acid (4h): This
compound was prepared from 2h (7.3 g, 25 mmol); colorless
prisms; m.p. 215Ϫ217 °C (repr.): yield: 5.44 g (84%). 1H NMR*:
δ ϭ 9.05 (dd, J ϭ 9.6, 6.1 Hz, 1 H), 8.33 (s, 1 H), 7.91 (dd, J ϭ
9.6, 2.7 Hz, 1 H), 7.76 (ddd, J ϭ 9.5, 8.3, 2.7 Hz, 1 H) ppm. 13C
NMR*: δ ϭ 167.2, 165.3 (d, J ϭ 253.0 Hz), 151.3 (d, J ϭ 12.9 Hz),
150.0 (qr, J ϭ 35.3 Hz), 139.9, 131.1 (dd, J ϭ 12.1, 9.6 Hz), 125.0,
123.0 (qr, J ϭ 274.7 Hz), 122.4 (d, J ϭ 25.7 Hz), 119.3, 115.3 (d,
J ϭ 20.9 Hz) ppm. 19F NMR*: δ ϭ Ϫ67.4 (s, 3 F), Ϫ107.0 (m, 1
F) ppm. MS (c.i.): m/z (%) ϭ 260 (100) [Mϩ ϩ 1], 259 (21) [Mϩ],
216 (50), 130 (15). C11H5F4NO2 (259.16): calcd. C 50.98, H 1.94;
found C 50.65, H 2.15.
Ϫ275 °C (dec.); yield 4.13 g (45%). H NMR*: δ ϭ 8.97 (dd, J ϭ
8.7, 1.1 Hz, 1 H), 8.65 (dd, J ϭ 7.4, 1.1 Hz, 1 H), 8.41 (s, 1 H),
7.65 (dd, J ϭ 8.7, 7.4 Hz, 1 H) ppm. 13C NMR*: δ ϭ 167.0, 149.0
(qr, J ϭ 35.2 Hz), 148.8, 144.0, 137.0, 133.3, 128.3, 127.6, 122.9
(qr, J ϭ 274.8 Hz), 120.5, 105.4 ppm. 19F NMR*: δ ϭ Ϫ66.9 (s)
ppm. MS (c.i.): m/z (%) ϭ 368 (100) [Mϩ ϩ 1], 367 (15) [Mϩ], 323
(8), 242 (7). C11H5F3INO2 (367.06): calcd. C 35.99, H 1.37, N 3.82;
found C 36.19, H 1.39, N 3.88.
The yield of isolated acid 4k dropped to 45% when the halogen/
metal exchange was performed with butyllithium in tetrahydrofu-
ran at Ϫ75 °C. Deiodination of the acid 4k (10 mmol) with zinc
(20 mmol) suspended in a 10% aqueous solution of sodium hydrox-
ide (50 mL) at 0 °C and with vigorous stirring for 2 h afforded the
acid 4a almost quantitatively; m.p. and mix-m.p. 181Ϫ183 °C.
8-Fluoro-2-trifluoromethyl-4-quinolinecarboxylic Acid (4i): This
compound was prepared from 2i (7.3 g, 25 mmol); colorless prisms;
m.p. 214Ϫ216 °C (repr.; ref.[27] 218Ϫ220 °C); yield: 5.12 g (79%).
1H NMR*: δ ϭ 8.74 (d, J ؍ 8.8 Hz, 1 H), 8.44 (s, 1 H), 7.89 (m,
1 H), 7.74 (ddd, J ϭ 10.5, 7.8, 1.0 Hz, 1 H) ppm. 13C NMR*: δ ϭ
165.2, 157.9 (d, J ϭ 261.6 Hz), 147.3 (qr, J ϭ 35.4 Hz), 138.5 (d,
J ϭ 12.5 Hz), 138.0, 130.4 (d, J ϭ 8.0 Hz), 127.4, 121.8, 121.3 (qr,
J ϭ 274.0 Hz), 119.0, 115.1 (d, J ϭ 18.5 Hz) ppm. 19F NMR*: δ ϭ
Ϫ67.0 (s, 3 F), Ϫ122.0 (m, 1 F) ppm. MS (c.i.): m/z (%) ϭ 260
(100) [Mϩ ϩ 1], 259 (22) [Mϩ], 242 (3), 203 (2). C11H5F4NO2
(259.16): calcd. C 50.98, H 1.94, N 5.40; found C 51.05, H 1.95,
N 5.72.
4-Bromo-2-trifluoromethyl-8-quinolinecarboxylic Acid (8): Quino-
line 2k (10.0 g, 25 mmol) was added at 0 °C to a 0.5  ethereal
solution of isopropylmagnesium chloride (25 mmol). After 45 min
at 0 °C, the mixture was poured onto dry ice and neutralized with
a saturated aqueous solution (50 mL) of ammonium chloride. The
organic phase was decanted and the aqueous one was extracted
with ethyl acetate (2 ϫ 25 mL). The combined organic layers were
dried and the solvents were evaporated. The residue was crys-
tallized from ethyl acetate; colorless needles; m.p. 128Ϫ130 °C
(from chloroform/ethyl acetate); yield: 6.72 g (84%).
8-Bromo-2-trifluoromethyl-4-quinolinecarboxylic Acid (4j): This
compound was prepared from 2j (8.9 g, 25 mmol); colorless prisms;
m.p. 220Ϫ222 °C (repr.); yield: 4.56 g (57%). H NMR*: δ ϭ 8.97
Methyl Ester: This was prepared from acid 8 (10 mmol) and diazo-
methane; colorless needles; m.p. 75Ϫ76 °C; yield: 3.11 g (93%). 1H
NMR: δ ϭ 8.39 (dd, J ϭ 8.5, 1.1 Hz, 1 H), 8.14 (dd, J ϭ 7.1,
1.2 Hz, 1 H), 8.07 (s, 1 H), 7.80 (dd, J ϭ 8.5, 7.2 Hz, 1 H), 4.05 (s,
3 H) ppm. 13C NMR: δ ϭ 167.4, 148.1 (qr, J ϭ 35.2 Hz), 144.8,
136.0, 133.6, 132.0, 129.6, 129.1, 128.6, 121.5, 120.6 (qr, J ϭ
275.6 Hz), 52.8 ppm. 19F NMR: δ ϭ Ϫ68.3 (s) ppm. MS (c.i.):
m/z (%) ϭ 336 (94) [Mϩ ϩ 1], 335 (41) [Mϩ], 334 (100) [Mϩ ϩ 1],
333 (3) [Mϩ], 277 (4), 275 (4), 256 (13). C12H7BrF3NO2 (334.09):
calcd. C 43.14, H 2.11; found C 43.21, H 2.21.
1
(dd, J ϭ 8.7, 1.2 Hz, 1 H), 8.45 (s, 1 H), 8.37 (dd, J ϭ 7.5, 1.2 Hz,
1 H), 7.82 (dd, J ϭ 8.7, 7.5 Hz, 1 H) ppm. 13C NMR*: δ ϭ 167.1,
149.5 (qr, J ϭ 36.1 Hz), 146.8, 144.0, 140.8, 136.8, 135.8, 132.5,
129.3, 122.8 (qr, J ϭ 274.7 Hz), 120.6 ppm. 19F NMR*: δ ϭ Ϫ67.0
(s) ppm. MS (c.i.): m/z (%) ϭ 322 (32) [Mϩ ϩ 1], 321 (100) [Mϩ],
320 (40) [Mϩ ϩ 1], 319 (95) [Mϩ], 303 (6), 276 (8), 184 (4).
C11H5BrF3NO2 (320.06): calcd. C 41.28, H 1.57; found C 41.10,
H 1.53.
The same acid (8) was prepared (93%) by hydrolysis (with formic
acid and catalytic amounts of boron trifluoride, 15 h 25 °C) of
methyl 4-bromo-2-trifluoromethyl-8-quinolinecarboxylate (m.p.
75Ϫ76 °C), obtained from methyl 4-methoxy-2-trifluoromethyl-8-
quinolinecarboxylate (m.p. 123Ϫ125 °C) in 11% yield by treatment
with phosphorus tribromide (2 h, 75 °C). The latter compound was
made by esterification of 4-methoxy-2-trifluoromethyl-8-quino-
linecarboxylic acid (m.p. 210Ϫ211 °C) with methyl iodide in the
presence of potassium carbonate in 83% yield. This compound
(74%) was obtained by consecutive treatment with butyllithium,
carbon dioxide, and acid of 8-bromo-4-methoxy-2-(trifluorometh-
yl)quinoline (m.p. 174Ϫ175 °C), which in turn was almost quanti-
tatively formed by the O-alkylation of quinoline 1j with dimethyl
Methyl Ester: This was prepared from acid 4j (10 mmol) and diazo-
methane; colorless needles; m.p. 131Ϫ132 °C; yield: 3.21 g (96%).
1H NMR: δ ϭ 8.85 (d, J ϭ 8.7 Hz, 1 H), 8.29 (s, 1 H), 8.21 (d,
J ϭ 7.5 Hz, 1 H), 7.63 (dd, J ϭ 8.2, 7.9 Hz, 1 H), 4.12 (s, 3 H)
ppm. 13C NMR: δ ϭ 165.1, 148.1 (qr, J ϭ 35.9 Hz), 145.5, 135.0,
131.2, 130.5, 127.4, 126.4, 125.5, 121.1 (qr, J ϭ 275.6 Hz), 119.1,
53.3 ppm. 19F NMR: δ ϭ Ϫ67.9 (s, 3 F) ppm. MS (c.i.): m/z (%) ϭ
336 (86) [Mϩ ϩ 1], 335 (43) [Mϩ], 334 (100) [Mϩ ϩ 1], 333 (16)
[Mϩ], 304 (4), 302 (4), 271 (11), 256 (3). C12H7BrF3NO2 (334.09):
calcd. C 43.14, H 2.11; found C 43.56, H 1.99.
The same acid 4j was isolated after consecutive treatment of quino-
line 2k (10.0 g, 25 mmol) with butyllithium (in tetrahydrofuran,
1584
Eur. J. Org. Chem. 2003, 1576Ϫ1588

2-(Trifluoromethyl)quinolinones
FULL PAPER
sulfate in the presence of potassium carbonate in acetone. Elemen-
tal analyses, 1H, 13C, and 19F NMR spectra, and mass spectra were
in agreement with the assigned structure of all intermediates men-
tioned in this paragraph.
4-Bromo-6-fluoro-2-trifluoromethyl-3-quinolinecarboxylic Acid (5e):
This compound was prepared from quinoline 2e (7.3 g, 25 mmol);
1
colorless prisms; m.p. 181Ϫ183 °C; yield: 6.85 g (81%). H NMR*:
δ ϭ 8.35 (dd, J ϭ 9.3, 5.4 Hz, 1 H), 8.06 (dd, J ϭ 9.6, 2.8 Hz, 1
H), 7.93 (ddd, J ϭ 10.1, 8.2, 2.8 Hz, 1 H) ppm. 13C NMR*: δ ϭ
167.5, 164.1 (d, J ϭ 252.0 Hz), 143.5, 143.4 (qr, J ϭ 36.0 Hz), 134.8
(d, J ϭ 9.9 Hz), 133.7, 132.9 (d, J ϭ 5.8 Hz), 130.4 (d, J ϭ
10.8 Hz), 123.5 (d, J ϭ 26.1 Hz), 126.9 (qr, J ϭ 276.4 Hz), 111.8
(d, J ϭ 25.1 Hz) ppm. 19F NMR*: δ ϭ Ϫ62.8 (s, 3 F), Ϫ105.5 (dd,
4-Bromo-2-trifluoromethyl-3-quinolinecarboxylic Acids (5)
Diisopropylamine (3.5 mL, 2.5 g, 25 mmol) and the bromoquino-
line 2 (25 mmol) were added consecutively, at Ϫ75 °C, to a solution
of butyllithium (25 mmol) in tetrahydrofuran (30 mL) and hexanes
(15 mL). After 2 h at Ϫ75 °C, the mixture was poured onto an
excess of freshly crushed dry ice before being worked up as specified
for the acids 3.
J ϭ 11.0, 6.8 Hz, 1 F) ppm. MS (c.i.): m/z (%) ϭ 340 (40) [Mϩ
ϩ
1], 339 (90) [Mϩ], 338 (54) [Mϩ ϩ 1], 337 (89) [Mϩ], 322 (45), 320
(48), 295 (87), 293 (100), 270 (10), 268 (8), 194 (23). C11H4BrF4NO2
(338.05): calcd. C 39.08, H 1.19; found C 39.10, H 1.52.
A few of these 4-bromo-2-trifluoromethyl-3-quinolinecarboxylic
acids (each time 20 mmol) were converted into the methyl esters
by addition of methyl iodide (2.0 mL, 4.6 g, 32 mmol), potassium
carbonate (4.1 g, 30 mmol), and acetone (0.10 L) to the acid 5 and
stirring of the suspension at 25 °C for 6 h. The volatiles were evapo-
rated and the residue was extracted with diethyl ether (5 ϫ 50 mL)
after water had been added. The combined organic layers were
dried and concentrated. The ester was crystallized from hexanes.
4-Bromo-6-trifluoromethoxy-2-trifluoromethyl-3-quinolinecar-
boxylic Acid (5f): This compound was prepared from quinoline 2f
(9.0 g, 25 mmol); colorless prisms; m.p. 170Ϫ171 °C; yield: 8.99 g
(89%). 1H NMR*: δ ϭ 8.43 (d, J ϭ 9.2 Hz, 1 H), 8.27 (s, 1 H),
8.03 (dd, J ϭ 9.2, 2.6 Hz, 1 H) ppm. 13C NMR*: δ ϭ 165.8, 151.0,
145.4, 144.3 (qr, J ϭ 35.3 Hz), 134.5, 133.8, 130.3, 129.8, 127.3,
121.4 (q, J ϭ 258.1 Hz), 121.6 (qr, J ϭ 275.1 Hz), 118.3 ppm. 19F
NMR*: δ ϭ Ϫ57.3 (s, 3 F), Ϫ63.9 (s, 1 F) ppm. MS (c.i.): m/z
(%) ϭ 406 (49) [Mϩ ϩ 1], 405 (100) [Mϩ], 404 (60) [Mϩ ϩ 1], 403
(99) [Mϩ], 361 (44), 360 (26), 359 (50), 358 (18), 297 (18), 260 (9).
C12H4BrF6NO3 (404.06): calcd. C 35.67, H 1.00; found C 35.54,
H 1.22.
Methyl Ester 11f: This was prepared from the bromoacid 5a; color-
less needles; m.p. 77Ϫ78 °C; yield: 7.19 g (86%). 1H NMR: δ ϭ
8.31 (d, J ϭ 8.1 Hz, 1 H), 8.14 (s, 1 H), 7.76 (dd, J ϭ 8.2, 2.5 Hz,
1 H), 4.07 (s, 3 H) ppm. 13C NMR: δ ϭ 164.8, 150.3, 144.6, 144.0
(qr, J ϭ 36.0 Hz), 133.8, 133.4, 128.3, 128.8, 126.3, 120.4 (qr, J ϭ
276.4 Hz), 120.3 (q, J ϭ 260.4 Hz), 117.3, 53.6 ppm. 19F NMR:
δ ϭ Ϫ57.3 (s), Ϫ65.5 (s, 3 F) ppm. MS (c.i.): m/z (%) ϭ 420 (100)
[Mϩ ϩ 1], 419 (68) [Mϩ], 418 (74) [Mϩ ϩ 1], 417 (25) [Mϩ], 388
(24), 386 (26), 312 (24).
4-Bromo-2-trifluoromethyl-3-quinolinecarboxylic Acid (5a): This
compound was prepared from quinoline 2a (6.9 g, 25 mmol); color-
less prisms; m.p. 207Ϫ208 °C (dec.); yield: 7.04 g (88%). 1H NMR*:
δ ϭ 8.42 (dd, J ϭ 8.4, 0.9 Hz, 1 H), 8.27 (d, J ϭ 8.5 Hz, 1 H), 8.08
(ddd, J ϭ 9.8, 6.9, 1.4 Hz, 1 H), 8.01 (ddd, J ϭ 9.7, 7.0, 1.3 Hz, 1
H) ppm. 13C NMR*: δ ϭ 165.8, 147.0, 143.8 (m), 134.0, 133.5,
132.3, 130.7, 129.0, 128.0, 127.5, 121.7 (qr, J ϭ 275.8 Hz) ppm. 19
NMR*: δ ϭ Ϫ63.3 (s) ppm. MS (c.i.): m/z (%) ϭ 322 (27) [Mϩ
F
ϩ
1], 321 (100) [Mϩ], 320 (27) [Mϩ ϩ 1], 319 (95) [Mϩ], 305 (7), 304
(59), 303 (8), 302 (68), 277 (59), 276 (26), 275 (61), 274 (18), 176
(31). C11H5BrF3NO2 (320.06): calcd. C 41.28, H 1.57; found C
41.27, H 1.78.
Methyl Ester 11a: Colorless needles; m.p. 90Ϫ92 °C; yield: 6.35 g
(95%). 1H NMR: δ ϭ 8.30 (d, J ϭ 8.4 Hz, 1 H), 8.21 (d, J ϭ
8.5 Hz, 1 H), 7.91 (td, J ϭ 7.2, 1.1 Hz, 1 H), 7.81 (td, J ϭ 7.2,
1.1 Hz, 1 H), 4.06 (s, 3 H). Ϫ13C NMR: δ ϭ 165.4, 146.4, 143.4
(qr, J ϭ 35.3 Hz), 134.2, 132.3, 130.7 (2 C), 127.6, 127.1 (2 C),
120.5 (qr, J ϭ 276.3 Hz), 53.6. Ϫ19F NMR: δ ϭ Ϫ65.3 (s) ppm.
MS (c.i.): m/z (%) ϭ 336 (96) [Mϩ ϩ 1], 335 (40) [Mϩ], 334 (100)
[Mϩ ϩ 1], 333 (12) [Mϩ], 304 (12), 302 (12), 271 (10), 256 (15).
C12H7BrF3NO2 (334.09): calcd. C 43.14, H 2.11; found C 43.30,
H 2.25.
4-Bromo-7-methoxy-2-trifluoromethyl-3-quinolinecarboxylic
Acid
(5g): This compound was prepared from quinoline 2g (7.6 g,
25 mmol); colorless needles; m.p. 211 Ϫ212 °C (dec.); yield: 7.53 g
1
(86%). H NMR*: δ ϭ 8.26 (m, 1 H), 7.55 (m, 2 H), 4.09 (s, 3 H)
ppm. 13C NMR*: δ ϭ 170.5, 168.2, 153.5, 148.3 (qr, J ϭ 36.1 Hz),
137.6, 133.5, 131.4, 129.5, 128.0, 126.0 (qr, J ϭ 277.1 Hz), 113.0,
60.9 ppm. 19F NMR*: δ ϭ Ϫ64.0 (s) ppm. MS (c.i.): m/z (%) ϭ
352 (24) [Mϩ ϩ 1], 351 (87) [Mϩ], 350 (100) [Mϩ ϩ 1], 349 (9)
[Mϩ], 334 (28), 333 (27%), 332 (30), 331 (26), 231 (34).
C12H7BrF3NO3 (350.09): calcd. C 41.17, H 2.02; found C 41.16,
H 2.09.
4-Bromo-6-methyl-2-trifluoromethyl-3-quinolinecarboxylic
Acid
(5d): This compound was prepared from quinoline 2d (7.2 g,
25 mmol); colorless platelets; m.p. 224Ϫ225 °C (dec.); yield: 6.16 g
(74%). 1H NMR*: δ ϭ 8.12 (s, 1 H), 8.09 (d, J ϭ 8.6 Hz, 1 H),
7.86 (dd, J ϭ 8.6, 1.8 Hz, 1 H), 2.66 (s, 3 H) ppm. 13C NMR*: δ ϭ
167.0, 146.5, 144.1, 143.5 (qr, J ϭ 35.3 Hz), 136.6, 133.8, 131.9,
130.3, 129.5, 127.5, 122.7 (qr, J ϭ 275.5 Hz), 23.0 ppm. 19F NMR*:
δ ϭ Ϫ63.6 (s) ppm. MS: 336 (99) [Mϩ ϩ 1], 335 (53) [Mϩ], 334
(100) [Mϩ ϩ 1], 333 (20) [Mϩ], 318 (3), 316 (3), 292 (8), 290 (9),
256 (9). C12H7BrF3NO2 (334.09): calcd. C 43.14, H 2.11; found C
43.30, H 2.48.
Methyl Ester 11g: This was prepared from the bromoacid 5g; color-
less prisms; m.p. 138Ϫ139 °C (from hexanes); yield: 6.34 g (87%).
1H NMR: δ ϭ 8.17 (d, J ϭ 9.1 Hz, 1 H), 7.50 (d, J ϭ 2.4 Hz, 1
H), 7.13 (dd, J ϭ 9.1, 2.4 Hz, 1 H), 4.03 (s, 3 H), 3.98 (s, 3 H)
ppm. 13C NMR: δ ϭ 165.5, 162.9, 148.5 (qr, J ϭ 34.4 Hz), 133.5,
128.3, 125.1, 124.3, 123.0, 120.4 (qr, J ϭ 277.2 Hz), 107.8, 56.0,
53.5 ppm. 19F NMR: δ ϭ Ϫ65.4 (s) ppm. MS (c.i.): m/z (%) ϭ 366
(43) [Mϩ ϩ 1], 365 (98) [Mϩ], 364 (84) [Mϩ ϩ 1], 363 (100)
[Mϩ],334 (89), 332 (90), 306 (17), 304 (18).
Methyl Ester 11d: Colorless needles; m.p. 104Ϫ106 °C; yield: 6.20 g
4-Bromo-7-fluoro-2-trifluoromethyl-8-quinolinecarboxylic
Acid
(89%). 1H NMR: δ ϭ 8.11 (d, J ϭ 8.6 Hz, 1 H), 7.06 (s, 1 H), 7.73 (10a): This compound was prepared from quinoline 2h (7.3 g,
(dd, J ϭ 8.6, 1.3 Hz, 1 H), 4.05 (s, 3 H), 2.64 (s, 3 H) ppm. 13C
NMR: δ ϭ 165.4, 145.0, 142.5 (qr, J ϭ 35.0 Hz), 141.7, 134.6, 1H NMR*: δ ϭ 8.46 (dd, J ϭ 9.4, 5.7 Hz, 1 H), 8.32 (s, 1 H), 7.87
133.1, 130.0, 127.8, 127.3, 125.9, 120.6 (qr, J ϭ 276.3 Hz), 53.5,
(t, J ϭ 9.1 Hz, 1 H) ppm. 13C NMR*: δ ϭ 164.5, 162.5 (d, J ϭ
25 mmol); colorless prisms; m.p. 160Ϫ161 °C; yield: 6.76 g (80%).
22.1 ppm. 19F NMR: δ ϭ Ϫ65.3 (s) ppm. MS (c.i.): m/z (%) ϭ 350 258.6 Hz), 149.8 (qr, J ϭ 36.1 Hz), 146.8 (d, J ϭ 8.8 Hz), 138.2,
(100) [Mϩ ϩ 1], 349 (71) [Mϩ], 348 (72) [Mϩ ϩ 1], 347 (32) [Mϩ],
132.3 (d, J ϭ 11.2 Hz), 127.4, 123.0, 122.7 (d, J ϭ 26.5 Hz), 122.4
318 (28), 316 (29), 270 (7).
(qr, J ϭ 274.7 Hz), 121.5 (d, J ϭ 16.9 Hz) ppm. 19F NMR*: δ ϭ
Eur. J. Org. Chem. 2003, 1576Ϫ1588
1585

M. Marull, M. Schlosser
FULL PAPER
Ϫ67.0 (s, 3 F), Ϫ106.8 (m, 1 F) ppm. MS (c.i.): m/z (%) ϭ 340 (96) kept under nitrogen at 75 °C for 20 h. The solvent was evaporated
[Mϩ ϩ 1], 339 (23) [Mϩ], 338 (100) [Mϩ ϩ 1], 337 (13) [Mϩ], 296
(9), 295 (19), 294 (10), 293 (21), 194 (3), 117 (4). C11H4BrF4NO2
(338.05): calcd. C 39.08, H 1.19; found C 39.13, H 1.10.
and the residue was recrystallized from hexanes.
Methyl 2-Trifluoromethyl-3-quinolinecarboxylate (12a): This com-
pound was prepared from bromo compound 11a; colorless plate-
1
4-Bromo-8-fluoro-2-trifluoromethyl-3-quinolinecarboxylic Acid (5i):
lets; m.p. 51Ϫ52 °C; yield: 3.45 g (90%). H NMR: δ ϭ 8.70 (s, 1
This compound was prepared from quinoline 2i (7.3 g, 25 mmol);
H), 8.26 (d, J ϭ 8.6 Hz, 1 H), 7.98 (d, J ϭ 8.2 Hz, 1 H), 7.92 (td,
J ϭ 7.7, 1.4 Hz, 1 H), 7.75 (td, J ϭ 7.6, 1.0 Hz, 1 H), 4.01 (s, 3 H)
ppm. 13C NMR: δ ϭ 166.0, 147.0, 144.9 (qr, J ϭ 35.3 Hz), 140.4,
132.6, 130.0, 129.6, 128.3, 127.5, 123.6, 121.2 (qr, J ϭ 274.7 Hz),
53.3 ppm. 19F NMR: δ ϭ Ϫ64.5 (s) ppm. MS (c.i.): m/z (%) ϭ 256
(100) [Mϩ ϩ 1], 255 (43) [Mϩ], 236 (3), 224 (33), 196 (3).
C12H8F3NO2 (255.19): calcd. C 56.48, H 3.16; found C 56.56, H
3.25.
1
colorless prisms; m.p. 182Ϫ183 °C; yield: 7.27 g (86%). H NMR*:
δ ϭ 8.22 (d, J ϭ 8.6 Hz, 1 H), 8.01 (ddd, J ϭ 8.3, 8.2, 5.1 Hz, 1
H), 7.85 (ddd, J ϭ 10.0, 7.9, 1.1 Hz) ppm. 13C NMR*: δ ϭ 166.5,
159.6 (d, J ϭ 260.2 Hz), 144.5 (qr, J ϭ 36.1 Hz), 138.2 (d, J ϭ
13.6 Hz), 136.4, 134.9 (d, J ϭ 3.2 Hz), 133.3 (d, J ϭ 8.0 Hz), 131.1
(d, J ϭ 5.6 Hz), 124.9, 122.4 (qr, J ϭ 275.5 Hz), 118.1 (d, J ϭ
18.5 Hz) ppm. 19F NMR*: δ ϭ Ϫ64.0 (s, 3 F), Ϫ121.7 (m, 1 F)
ppm. MS (c.i.): m/z (%) ϭ 340 (90) [Mϩ ϩ 1], 339 (75) [Mϩ], 338
(100) [Mϩ ϩ 1], 337 (50) [Mϩ], 296 (3), 295 (7), 294 (7), 293 (7),
194 (2). C11H4BrF4NO2 (338.05): calcd. C 39.08, H 1.19, N 4.14;
found C 38.97, H 1.23, N 4.19.
Methyl Ester 11i: Colorless needles; m.p. 128Ϫ130 °C; yield: 6.45 g
(92%). 1H NMR: δ ϭ 8.10 (dt, J ϭ 8.8, 1.1 Hz, 1 H), 7.78 (td, J ϭ
8.1, 4.8 Hz, 1 H), 7.61 (ddd, J ϭ 9.2, 7.8, 1.2 Hz, 1 H), 4.06 (s, 3
H) ppm. 13C NMR: δ ϭ 165.0, 157.9 (d, J ϭ 262.6 Hz), 143.5 (qr,
J ϭ 36.0 Hz), 136.1 (d, J ϭ 12.5 Hz), 134.1 (d, J ϭ 4.0 Hz), 131.0
(d, J ϭ 8.0 Hz), 129.3, 128.4, 123.0 (d, J ϭ 4.5 Hz), 120.3 (qr, J ϭ
276.3 Hz), 116.5 (d, J ϭ 18.5 Hz), 53.3 ppm. 19F NMR: δ ϭ Ϫ65.1
(s, 3 F), Ϫ121.0 (m, 1 F) ppm. MS (c.i.): m/z (%) ϭ 354 (100) [Mϩ
ϩ 1], 353 (42) [Mϩ], 352 (77) [Mϩ ϩ 1], 351 (15) [Mϩ], 322 (15),
320 (13), 289 (2).
Methyl 6-Methyl-2-trifluoromethyl-3-quinolinecarboxylate (12d):
This compound was prepared from bromo compound 11f; colorless
platelets; m.p. 101Ϫ103 °C; yield: 3.11 g (77%). 1H NMR: δ ϭ 8.60
(s, 1 H), 8.14 (d, J ϭ 8.6 Hz, 1 H), 7.74 (dd, J ϭ 8.6, 1.7 Hz, 1 H),
7.71 (s, 1 H), 4.01 (s, 3 H), 2.60 (s, 3 H) ppm. 13C NMR: δ ϭ 166.0,
145.6, 143.8 (qr, J ϭ 35.9 Hz), 140.2, 139.3, 135.0, 129.7, 127.5,
126.9, 123.5, 121.5 (qr, J ϭ 277.1 Hz), 53.1, 21.8 ppm. 19F NMR:
δ ϭ Ϫ64.5 (s) ppm. MS (c.i.): m/z (%) ϭ 270 (100) [Mϩ ϩ 1], 269
(26) [Mϩ], 238 (20), 217 (4).
Methyl
6-Trifluoromethoxy-2-trifluoromethyl-3-quinolinecarbox-
ylate (12f): This compound was prepared from bromo com-
pound 11d; colorless prisms; m.p. 103Ϫ105 °C; yield: 4.17 g (82%).
1H NMR: δ ϭ 8.70 (s, 1 H), 8.36 (d, J ϭ 9.0 Hz, 1 H), 7.79 (s, 1
H), 7.75 (d, J ϭ 9.1 Hz, 1 H), 4.03 (s, 3 H) ppm. 13C NMR: δ ϭ
165.4, 159.2, 145.3 (qr, J ϭ 36.0 Hz), 145.0, 140.0, 132.5, 127.9,
126.3, 124.7, 120.4 (qr, J ϭ 276.3 Hz), 120.9 (qr, J ϭ 259.4 Hz),
117.4, 53.3 ppm. 19F NMR: δ ϭ Ϫ58.3 (s), Ϫ64.8 (s) ppm. MS
(c.i.): m/z (%) ϭ 340 (100) [Mϩ ϩ 1], 339 (20) [Mϩ], 308 (22),
274 (10).
4,8-Dibromo-2-trifluoromethyl-3-quinolinecarboxylic Acid (5j): This
compound was prepared from quinoline 2j (8.9 g, 25 mmol); color-
1
less needles; m.p. 192Ϫ194 °C; yield: 6.18 g (62%). H NMR: δ ϭ
8.36 (dd, J ϭ 8.4, 1.0 Hz, 1 H), 8.26 (dd, J ϭ 7.5, 1.1 Hz, 1 H),
7.69 (dd, J ϭ 8.3, 7.4 Hz, 1 H) ppm. 13C NMR: δ ϭ 167.5, 143.9
(qr, J ϭ 36.9 Hz), 143.6, 136.1, 134.3, 131.0, 129.3, 128.0, 127.3,
126.3, 120.2 (qr, J ϭ 277.1 Hz) ppm. 19F NMR: δ ϭ Ϫ64.9 (s)
ppm. MS (c.i.): m/z (%) ϭ 402 (48) [Mϩ ϩ 1], 401 (50) [Mϩ], 400
(100) [Mϩ ϩ 1], 399 (75) [Mϩ], 398 (59) [Mϩ ϩ 1], 397 (34) [Mϩ],
320 (27), 242 (3). C11H4Br2F3NO2 (398.96): calcd. C 33.12, H 1.01;
found C 33.00, H 1.22.
Methyl Ester 11j: colorless needles; m.p. 101Ϫ103 °C; yield: 7.76 g
(94%). 1H NMR: δ ϭ 8.29 (dd, J ϭ 8.5, 1.1 Hz, 1 H), 8.22 (dd,
J ϭ 7.5, 1.1 Hz, 1 H), 7.66 (dd, J ϭ 8.3, 7.8 Hz, 1 H), 4.06 (s, 3 H)
ppm. 19F NMR: δ ϭ Ϫ65.4 (s) ppm. MS (c.i.): m/z (%) ϭ 415 (54)
[Mϩ ϩ 1], 414 (64) [Mϩ], 413 (100) [Mϩ ϩ 1], 412 (72) [Mϩ], 382
(21), 354 (15), 319 (5), 317 (5). C12H6Br2F3NO2 (412.98): calcd. C
34.90, H 1.46, N 3.39; found C 35.22, H 1.46, N 3.48.
Methyl 7-Methoxy-2-trifluoromethyl-3-quinolinecarboxylate (12g):
This compound was prepared from the bromo compound 11g; col-
orless needles; m.p. 128Ϫ129 °C (from hexanes); yield: 3.46 g
(81%). 1H NMR: δ ϭ 8.63 (s, 1 H), 7.83 (d, J ϭ 9.1 Hz, 1 H), 7.86
(d, J ϭ 2.4 Hz, 1 H), 7.36 (dd, J ϭ 9.1, 2.4 Hz, 1 H), 3.98 (s, 3 H),
4.01 (s, 3 H) ppm. 13C NMR: δ ϭ 165.8, 163.1, 149.0, 145.0 (qr,
J ϭ 35.2 Hz), 139.8, 129.1, 123.3, 122.5, 121.1 (qr, J ϭ 275.6 Hz),
121.0, 107.5, 55.9, 52.9 ppm. 19F NMR: δ ϭ Ϫ64.6 (s) ppm. MS
(c.i.): m/z (%) ϭ 286 (40) [Mϩ ϩ 1], 285 (100) [Mϩ], 254 (95), 226
(82), 183 (8), 116 (7).
Methyl 8-Fluoro-2-trifluoromethyl-3-quinolinecarboxylate (12i):
This compound was prepared from bromo compound 11i; colorless
needles; m.p. 96Ϫ98 °C; yield: 3.24 g (79%). 1H NMR: δ ϭ 8.75
(s, 1 H), 7.78 (d, J ϭ 8.0 Hz, 1 H), 7.71 (td, J ϭ 7.8, 4.6 Hz, 1 H),
7.60 (dd, J ϭ 9.2, 8.0 Hz, 1 H), 4.02 (s, 3 H) ppm. 13C NMR: δ ϭ
165.3, 157.8 (d, J ϭ 261.8 Hz), 144.6 (qr, J ϭ 35.4 Hz), 139.8, 137.0
(d, J ϭ 12.0 Hz), 130.0 (d, J ϭ 9.6 Hz), 128.8, 124.5, 123.8 (d, J ϭ
4.6 Hz), 120.9 (qr, J ϭ 275.5 Hz), 116.6 (d, J ϭ 18.5 Hz), 53.3 ppm.
19F NMR*: δ ϭ Ϫ64.6 (s, 3 F), Ϫ122.4 (m, 1 F) ppm. MS (c.i.):
m/z (%) ϭ 274 (100) [Mϩ ϩ 1], 273 (30) [Mϩ], 242 (29), 220 (14).
4-Bromo-8-iodo-2-trifluoromethyl-3-quinolinecarboxylic Acid (5k):
This compound was prepared from quinoline 2k (10.0 g, 25 mmol);
1
colorless needles; m.p. 207Ϫ208 °C (dec.); yield: 8.70 g (78%). H
NMR*: δ ϭ 8.69 (dd, J ϭ 7.4, 1.1 Hz, 1 H), 8.45 (dd, J ϭ 8.5,
1.1 Hz, 1 H), 7.74 (dd, J ϭ 8.4, 7.5 Hz, 1 H) ppm. 13C NMR*: δ ϭ
166.5, 146.9, 145.0, 144.8 (qr, J ϭ 36.1 Hz), 135.5, 133.9, 130.8,
130.0, 129.8, 122.3 (qr, J ϭ 275.5 Hz), 105.3 ppm. 19F NMR*: δ ϭ
Ϫ63.8 (s) ppm. MS (c.i.): m/z (%) ϭ 447 (90) [Mϩ ϩ 1], 446 (100)
[Mϩ], 445 (99) [Mϩ ϩ 1], 444 (55) [Mϩ], 402 (22), 400 (23), 322
(6), 320 (7), 194 (10). C11H4BrF3INO2 (445.96): calcd. C 29.63, H
0.90, N 3.14; found C 29.72, H 0.97, N 3.20.
By Consecutive Treatment of the Lithium Carboxylate with Butyl-
lithium and Methanol: Butyllithium (30 mmol) in hexanes (20 mL)
was added to a precooled solution of bromoacid 5 (15 mmol), and
the resulting suspension was stirred for 6 h at Ϫ75 °C before being
2-Trifluoromethyl-3-quinolinecarboxylic Acids (6)
By Reduction of the Ester with Tributyltin Hydride: A solution of
the methyl 4-bromo-2-(trifluoromethyl)quinoline-3-carboxylate treated with methanol (5 mL) and water (50 mL). The products
(15 mmol), tributyltin hydride (8.1 mL, 8.7 g, 30 mmol), and azo-
isobutyronitrile (0.24 g, 1.5 mmol) in tetrahydrofuran (30 mL) was
were identical in every respect with the carboxylic acids obtained
by saponification of the methyl esters described in the preceding
1586
Eur. J. Org. Chem. 2003, 1576Ϫ1588

2-(Trifluoromethyl)quinolinones
paragraphs (sodium hydroxide in aqueous methanol, 50 °C for 6 h; 15 min; colorless platelets; m.p. 204Ϫ206 °C (reprod.; from meth-
FULL PAPER
1
overall yields are given in Table 6).
anol); yield: 2.25 g (58%). H NMR*: δ ϭ 8.90 (d, J ϭ 8.5 Hz, 1
H), 8.42 (dd, J ϭ 9.2, 5.7 Hz, 1 H), 8.07 (d, J ϭ 8.5 Hz, 1 H), 7.80
(t, J ϭ 9.5 Hz, 1 H) ppm. 13C NMR*: δ ϭ 165.5, 162.0 (d, J ϭ
256.4 Hz), 150.0 (qr, J ϭ 35.0 Hz), 146.3 (d, J ϭ 8.5 Hz), 141.5,
133.6 (d, J ϭ 11.0 Hz), 132.0, 127.8, 123.1 (qr, J ϭ 275.6 Hz), 121.9
(d, J ϭ 26.4 Hz), 118.6 ppm. 19F NMR*: δ ϭ Ϫ67.0 (s, 3 F),
Ϫ107.8 (m, 1 F) ppm. MS (c.i.): m/z (%) ϭ 260 (100) [Mϩ ϩ 1],
259 (4), 242 (13), 215 (19). C11H5F4NO2 (259.16): calcd. C 50.98,
H 1.94, N 5.40; found C 50.96, H 2.08, N 5.42.
2-Trifluoromethyl-3-quinolinecarboxylic Acid (6a): This compound
was prepared from 4-bromo-3-quinolinecarboxylic acid 5a (4.8 g,
15 mmol); colorless prisms; m.p. 207Ϫ209 °C (repr.); yield: 2.42 g
1
(67%). H NMR*: δ ϭ 9.01 (s, 1 H), 8.25 (m, 2 H), 8.05 (t, J ϭ
7.8 Hz, 1 H), 7.89 (t, J ϭ 7.6 Hz, 1 H) ppm. 13C NMR*: δ ϭ 167.4,
148.4, 145.9 (qr, J ϭ 35.0 Hz), 142.2, 134.5, 131.5 (2 C), 130.5,
128.5, 126.0, 123.2 (qr, J ϭ 274.9 Hz) ppm. 19F NMR*: δ ϭ Ϫ63.5
(s) ppm. MS (c.i.): m/z (%) ϭ 242 (35) [Mϩ ϩ 1], 241 (100) [Mϩ],
224 (46), 197 (48), 101 (33). C11H6F3NO2 (241.17): calcd. C 54.78,
H 2.51; found C 54.78, H 2.99.
4-Formyl-2-trifluoromethyl-3-quinolinecarboxylic Acids 7
The bromoquinolinecarboxylic acid 5 (10 mmol) was dissolved in
a 1.0  methanolic solution (10 mL) of tetrabutylammonium hy-
droxide (10 mmol). The solvent was replaced by toluene (0.10 L)
and the mixture was heated at reflux in a DeanϪStark trap until
all water had been removed. The toluene was evaporated and the
residue was taken up in tetrahydrofuran (50 mL), to which butyl-
lithium (10 mmol) in hexane (10 mL) was added at Ϫ75 °C. After
15 min, N,N-dimethylformamide (0.77 mL, 0.73 g, 10 mmol) was
added. After a further 1 h at Ϫ75 °C, the mixture was poured into
water (50 mL), washed with diethyl ether (2 ϫ 15 mL), acidified to
pH 1 with concentrated hydrochloric acid, and extracted with ethyl
acetate (3 ϫ 25 mL). The combined organic layers were dried, and
the solvents were evaporated. The residue was crystallized from a
mixture of chloroform and methanol.
6-Methyl-2-trifluoromethyl-3-quinolinecarboxylic Acid (6d): This
compound was prepared from 4-bromo-3-quinolinecarboxylic acid
5d (5.0 g, 15 mmol), colorless platelets; m.p. 211Ϫ213 °C (dec.);
yield: 2.60 g (68%). 1H NMR*: δ ϭ 8.86 (s, 1 H), 8.10 (d, J ϭ
8.7 Hz, 1 H), 7.98 (s, 1 H), 7.86 (dd, J ϭ 8.7, 1.9 Hz, 1 H), 2.63 (s,
3 H) ppm. 13C NMR*: δ ϭ 167.5, 147.1 (qr, J ϭ 34.6 Hz), 142.1,
141.3, 136.5 (2 C), 131.0, 129.5, 128.9, 126.0, 123.1 (qr, J ϭ
274.8 Hz), 22.5 ppm. 19F NMR*: δ ϭ Ϫ63.4 (s) ppm. MS (c.i.):
m/z (%) ϭ 256 (100) [Mϩ ϩ 1], 255 (22) [Mϩ], 238 (6), 211 (8), 186
(17). C12H8F3NO2 (255.19): calcd. C 56.48, H 3.16; found C 56.22,
H 3.19.
6-Trifluoromethoxy-2-trifluoromethyl-3-quinolinecarboxylic
Acid
(6f): This compound was prepared from 4-bromo-3-quinolinecar-
boxylic acid 5f (6.0 g, 15 mmol); colorless platelets; m.p. 191Ϫ193
4-Formyl-2-trifluoromethyl-3-quinolinecarboxylic Acid (7a): This
compound was prepared from 4-bromo-2-trifluoromethyl-3-quino-
linecarboxylic acid (5a; 5.6 g, 10 mmol); colorless platelets; m.p.
258Ϫ260 °C (dec.); yield: 1.51 g (56%). 1H NMR*: δ ϭ 8.47 (d,
J ϭ 8.3 Hz, 1 H), 8.40 (d, J ϭ 8.5 Hz, 1 H), 8.19 (ddd, J ϭ 8.5,
7.0, 1.5 Hz, 1 H), 8.04 (ddd, J ϭ 8.2, 7.0, 1.2 Hz, 1 H), 7.63 (br. s,
1 H), 7.30 (s, 1 H) ppm. 13C NMR*: δ ϭ 164.5, 159.4, 148.9, 143.2
(m), 135.0, 131.6 (2 C), 126.0, 124.3, 121.5 (qr, J ϭ 274.4 Hz),
118.2, 97.4 ppm. 19F NMR*: δ ϭ Ϫ67.9 (s) ppm. MS (c.i.): m/z
(%) ϭ 287 (100) [Mϩ ϩ NH4ϩ], 270 (91) [Mϩ ϩ 1], 269 (11) [Mϩ],
192 (24), 134 (45). C12H6F3NO3 (269.18): calcd. C 53.55, H 2.25,
N 5.20; found C 53.92, H 2.36, N 5.28.
1
°C; yield: 2.78 g (57%). H NMR*: δ ϭ 9.12 (s, 1 H), 8.38 (d, J ϭ
9.2 Hz, 1 H), 8.26 (s, 1 H), 7.98 (dd, J ϭ 9.5, 2.5 Hz, 1 H) ppm.
13C NMR*: δ ϭ 167.0, 150.4, 146.8, 146.1 (m), 142.3, 134.1, 130.0,
128.1, 126.8, 122.9 (qr, J ϭ 274.7 Hz), 121.2 (qr, J ϭ 257.0 Hz),
120.3 ppm. 19F NMR*: δ ϭ Ϫ57.4 (s), Ϫ63.3 (s) ppm. MS (c.i.):
m/z (%) ϭ 326 (100) [Mϩ ϩ 1], 325 (23) [Mϩ], 308 (23), 281 (36).
C12H5F6NO3 (325.16): calcd. C 44.33, H 1.55, N 4.31; found C
44.37, H 1.61, N 4.47.
7-Methoxy-2-trifluoromethyl-3-quinolinecarboxylic Acid (6g): This
compound was prepared from the bromoquinolinecarboxylic acid
5g (5.3 g, 15 mmol); colorless prisms; m.p. 211Ϫ212 °C (from meth-
anol); yield 3.42 g (84%). 1H NMR: δ ϭ 8.90 (s, 1 H), 8.12 (d, J ϭ
9.0 Hz, 1 H), 7.55 (d, J ϭ 2.6 Hz, 1 H), 7.46 (dd, J ϭ 9.0, 2.6 Hz,
1 H), 4.08 (s, 3 H) ppm. 13C NMR: δ ϭ 167.4, 165.0, 150.8, 146.5
(qr, J ϭ 33.7 Hz), 141.9 (2 C), 131.5, 124.8, 123.5, 123.3 (qr, J ϭ
275.4 Hz), 109.1, 57.3 ppm. 19F NMR: δ ϭ Ϫ63.1 (s) ppm. MS
(c.i.): m/z (%) ϭ 272 (52) [Mϩ ϩ 1], 271 (100) [Mϩ], 254 (28), 226
(9). C12H8F3NO3 (271.19): calcd. C 53.15, H 2.97, N 5.16; found
C 53.46, H 2.97, N 5.30.
4-Formyl-6-trifluoromethoxy-2-trifluoromethyl-3-quinolinecar-
boxylic Acid (7f): This compound was prepared from 4-bromo-6-
trifluoromethoxy-2-trifluoromethyl-3-quinolinecarboxylic acid (5f;
4.0 g, 10 mmol); colorless prisms, m.p. 175Ϫ177 °C (dec.); yield:
1
2.93 g (83%). H NMR*: δ ϭ 8.56 (d, J ϭ 9.3 Hz, 1 H), 8.34 (d,
J ϭ 1.5 Hz, 1 H), 8.14 (dd, J ϭ 9.2, 2.6 Hz, 1 H), 7.79 (br. s, 1 H),
7.36 (s, 1 H) ppm. 13C NMR*: δ ϭ 164.3, 159.8, 150.4, 147.1, 144.0
(qr, J ϭ 37.2 Hz), 134.5, 133.5 128.5, 127.3, 123.7 (qr, J ϭ
247.4 Hz), 121.5 (qr, J ϭ 274.7 Hz), 116.0, 97.5 ppm. 19F NMR*:
δ ϭ Ϫ57.6 (s, 3 F), Ϫ65.6 (s, 3 F) ppm. MS (c.i.): m/z (%) ϭ 371
(100) [Mϩ ϩ NH4], 354 (48) [Mϩ ϩ 1], 353 (3) [Mϩ], 308 (11), 116
(2), 76 (3). C13H5F6NO4 (353.17): calcd. C 44.21, H 1.43, N 3.97;
found C 44.43, H 1.56, N 4.15.
8-Fluoro-2-trifluoromethyl-3-quinolinecarboxylic Acid (6i): This
compound was prepared from 4-bromo-3-quinolinecarboxylic acid
5i (5.1 g, 15 mmol); colorless prisms; m.p. 233Ϫ235 °C (dec.); yield:
1
2.25 g (58%). H NMR*: δ ϭ 9.07 (s, 1 H), 8.10 (d, J ϭ 8.2 Hz),
7.89 (ddd, J ϭ 8.2, 7.9, 4.9 Hz, 1 H), 7.79 (ddd, J ϭ 10.6, 7.8,
1.2 Hz) ppm. 13C NMR*: δ ϭ 167.2, 159.5 (d, J ϭ 259.4 Hz), 146.1
(qr, J ϭ 36.9 Hz), 142.0 (d, J ϭ 16.9 Hz), 131.9 (d, J ϭ 7.2 Hz),
131.0, 127.7, 126.3 (2 C), 123.4 (qr, J ϭ 275.5 Hz), 118.3 (d, J ϭ
18.5 Hz) ppm. 19F NMR*: δ ϭ Ϫ63.4 (s, 3 F), Ϫ123.5 (m, 1 F)
ppm. MS (c.i.): m/z (%) ϭ 260 (100) [Mϩ ϩ 1], 259 (18) [Mϩ], 242
(18), 206 (17). C11H5F4NO2 (259.16): calcd. C 50.98, H 1.94, N
5.40; found C 50.88, H 2.10, N 5.44.
4-Formyl-7-methoxy-2-trifluoromethyl-3-quinolinecarboxylic Acid
(7g): This compound was prepared from 4-bromo-7-methoxy-2-tri-
fluoromethyl-3-quinolinecarboxylic acid (5g; 3.5 g, 10 mmol); col-
orless platelets; m.p. 232Ϫ235 °C (dec.); yield: 1.88 g (63%). 1H
NMR*: δ ϭ 8.34 (d, J ϭ 9.20 Hz, 1 H), 7.55 (s, 1 H), 7.74 (d, J ϭ
2.6 Hz, 1 H), 7.63 (dd, J ϭ 9.2, 2.6 Hz, 1 H), 7.21 (s, 1 H), 4.62 (s,
3 H) ppm. 13C NMR*: δ ϭ 166.3, 159.8, 152.4, 145.1 (qr, J ϭ
35.1 Hz), 128.0, 127.5, 125.5, 122.6 (qr, J ϭ 274.8 Hz), 120.0, 116.8,
7-Fluoro-2-trifluoromethyl-8-quinolinecarboxylic Acid: The bromo
acid 10a (5.1 g, 15 mmol) was treated at Ϫ100 °C with butyllithium 110.8, 98.0, 57.6 ppm. 19F NMR*: δ ϭ Ϫ65.3 (s,) ppm. MS (c.i.):
(30 mmol) in diethyl ether (40 mL) and hexanes (20 mL) for
m/z (%) ϭ 300 (100) [Mϩ ϩ 1], 299 (34) [Mϩ], 284 (17), 254 (6).
Eur. J. Org. Chem. 2003, 1576Ϫ1588
1587

M. Marull, M. Schlosser
FULL PAPER
C13H8F3NO4 (299.20): calcd. C 52.19, H 2.69, N 4.68; found C
52.46, H 2.81, N 4.69.
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Acknowledgments
This work was financially supported by the Schweizerische Natio-
nalfonds zur Förderung der wissenschaftlichen Forschung, Bern
(grant 20Ϫ55Ј303Ϫ98), the Bundesamt für Bildung und Wissen-
schaft, Bern (grant 97.0083 linked to the TMR project FMRXCT-
970129) and Hoffmann-LaRoche, Basel. The authors are also in-
debted to Lonza AG (Drs. W. Brieden and D. Michel), Visp, for a
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Received October 7, 2002
[O02553]
1588
Eur. J. Org. Chem. 2003, 1576Ϫ1588