Recommendable routes to trifluoromethyl-substituted pyridine- and quinolinecarboxylic acids

Article abstract of DOI:10.1002/ejoc.200390215

As part of a case study, rational strategies for the preparation of all ten 2-, 3-, or 4-pyridinecarboxylic acids and all nine 2-, 3-, 4-, or 8-quinolinecarboxylic acids bearing trifluoromethyl substituents at the 2-, 3-, or 4-position were elaborated. The trifluoromethyl group, if not already present in the precursor, was introduced either by the deoxygenative fluorination of suitable carboxylic acids with sulfur tetrafluoride or by the displacement of ring-bound bromine or iodine by trifluoromethylcopper generated in situ. The carboxy function was produced by treatment of organolithium or organomagnesium intermediates, products of halogen/metal or hydrogen/ metal permutation, with carbon dioxide. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Full text of DOI:10.1002/ejoc.200390215

FULL PAPER
Recommendable Routes to Trifluoromethyl-Substituted Pyridine- and
Quinolinecarboxylic Acids
Fabrice Cottet,[a] Marc Marull,[a] Olivier Lefebvre[a] and Manfred Schlosser*[a,b]
Keywords: Building blocks / Carboxylation / Heterocycles / Organometallic intermediates / Sulfur tetrafluoride /
Trifluoromethylcopper
As part of a case study, rational strategies for the preparation
of all ten 2-, 3-, or 4-pyridinecarboxylic acids and all nine 2-,
3-, 4-, or 8-quinolinecarboxylic acids bearing trifluoromethyl
substituents at the 2-, 3-, or 4-position were elaborated. The
trifluoromethyl group, if not already present in the precursor,
was introduced either by the deoxygenative fluorination of
displacement of ring-bound bromine or iodine by trifluoro-
methylcopper generated in situ. The carboxy function was
produced by treatment of organolithium or organomagne-
sium intermediates, products of halogen/metal or hydrogen/
metal permutation, with carbon dioxide.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
suitable carboxylic acids with sulfur tetrafluoride or by the Germany, 2003)
Introduction
all ten trifluoromethyl-substituted 2-, 3-, and 4-pyridinecar-
boxylic acids and all nine 2-, 3-, 4-, and 8-quinolinecar-
boxylic acids bearing the trifluoromethyl group in the het-
erocyclic ring.
After nitrogen, fluorine occupies the position of second
favorite heteroelement in life science-oriented research.[1Ϫ5]
Over 10% of newly registered pharmaceutical drugs[6,7] and
some 40% of newly registered agrochemicals[8,9] contain one
or more fluorine atoms. The halogen is often incorporated
as a p-fluorophenyl group, but (trifluoromethyl)phenyl enti-
ties are also not infrequent. In contrast, fluorinated or, even
more so, trifluoromethyl-substituted heterocycles are rela-
tively rare. This is especially true if the simultaneous pres-
ence of a carboxy or similar functional group is required.
We have previously investigated[10] how (trifluoromethyl)-
pyridines and (trifluoromethyl)quinolines can be directly
converted into functional derivatives by application of a
simple metalation/carboxylation sequence. Thus, four pyri-
dinecarboxylic acids and five quinolinecarboxylic acids, all
bearing trifluoromethyl substituents, were made accessible
in a most straightforward manner. With this achieved, we
started to look for another set of methods that would allow
one to prepare, in a rational Ϫ even if more lengthy Ϫ way,
Obviously the crucial issue is at what stage and how to
introduce the trifluoromethyl substituent. The most advan-
tageous solution to this problem would of course be to
identify a suitable precursor already containing the CF3
group. Thus, 2-chloro-3-(trifluoromethyl)pyridine and 2-
chloro-5-(trifluoromethyl)pyridine are commercially avail-
able at a reasonable cost (400 and 100 EUR/mol, respec-
tively) whereas the prices of three other isomers, 2-chloro-
4-(trifluoromethyl)pyridine,2-chloro-6-(trifluoromethyl)pyr-
idine, and 3-chloro-5-(trifluoro-methyl)pyridine (at 14000,
70000, and 10000 EUR/mol, respectively) are prohibitive.
Three methods for the de novo creation of trifluoromethyl
[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
1559
Eur. J. Org. Chem. 2003, 1559Ϫ1568  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0408Ϫ1559 $ 20.00ϩ.50/0

F. Cottet, M. Marull, O. Lefebvre, M. Schlosser
FULL PAPER
substituents warrant consideration. Perchloration of pyri-
dine- or quinoline-attached methyl groups and subsequent
Lewis acid-catalyzed chlorine/fluorine displacement with
hydrogen fluoride is most attractive from an industrial
point of view,[11] while the fluorinative deoxygenation of
carboxylic acids with sulfur tetrafluoride[12] or, particularly,
the treatment of bromo or iodo derivatives of pyridines and
quinolines with trifluoromethylcopper generated in
situ[13Ϫ16] can be accomplished more conveniently on a lab-
oratory scale.
The most economical route to the carboxy function
would presumably be palladium-catalyzed halogen/cyano
exchange[17,18] and subsequent hydrolysis of the resulting ni-
trile, or the palladium- or nickel-catalyzed carbonylation[19]
of chloro or bromo derivatives of hetarenes. However, for
operational simplicity, we preferred to make the acids by
carboxylation of organolithium or organomagnesium inter-
mediates, which could easily be generated by hydrogen/me-
tal or halogen/metal permutation.
Many of the required halopyridines were obtained by si-
lane-mediated chlorine/bromine exchange.[20] A final key
step in several preparative sequences was the reductive re-
moval of bromine that had temporarily served as a protec-
tive group and deprotonation promoter.
Trifluoromethyl-Substituted Pyridinecarboxylic
Acids
The preparation of the four pyridinecarboxylic acids
5؊8, each bearing the trifluoromethyl group in the 3-posi-
tion, again relied heavily on halogen/metal permutation fol-
lowed by carboxylation. Thus, 2-bromo-3-(trifluoromethyl)-
pyridine, 3-bromo-5-(trifluoromethyl)pyridine, and 2-
2-Trifluoromethyl-3-pyridinecarboxylic acid (1; 61%
overall) was prepared from 3-bromo-2-iodopyridine (made
in four steps from 2-chloropyridine) by trifluoromethylating
displacement of iodine at the 2-position, followed by con-
secutive halogen/metal permutation and carboxylation. To
obtain 2-trifluoromethyl-4-pyridinecarboxylic acid (2; 45%
overall), 2-(trifluoromethyl)pyridine[16] was deprotonated
and iodinated at the 3-position before being subjected to a
base-mediated halogen migration[21,22] and subsequent hal-
ogen/metal permutation and carboxylation. When 2,5-di-
bromopyridine was treated with butyllithium in toluene,
halogen/metal permutation occurred regioselectively at the
2-position.[23] The 5-bromo-2-pyridinecarboxylic acid
(64%) obtained upon carboxylation was converted into 5-
bromo-2-(trifluoromethyl)pyridine (33%) by use of sulfur
tetrafluoride. The 6-trifluoromethyl-3-pyridinecarboxylic
acid (3; 85%) was again prepared by application of the hal-
ogen/metal permutation and carboxylation sequence to 5-
bromo-2-(trifluoromethyl)pyridine. The latter compound
was in turn made from 2,5-dibromopyridine, either through
the 5-bromo-2-pyridinecarboxylic acid (by selective bro-
mine/lithium exchange[23]), which was then treated with sul-
fur tetrafluoride (21% overall) or through 5-bromo-2-iodo-
pyridine, which was then subjected to a halogen/trifluoro-
methyl displacement (60% overall[16]). In the same way, 6-
trifluoromethyl-2-pyridinecarboxylic acid (4; 87%) was ob-
tained from 2-bromo-6-(trifluoromethyl)pyridine, which
was in turn derived from 2-bromo-6-iodopyridine by tri-
fluoromethylating displacement of iodine.[16]
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Eur. J. Org. Chem. 2003, 1559Ϫ1568

Trifluoromethyl-Substituted Pyridine- and Quinolinecarboxylic Acids
FULL PAPER
bromo-5-(trifluoromethyl)pyridine,
produced
either boxylation, to afford the 2-trifluoromethyl-8-quinolinecar-
through silane-mediated chlorine/bromine exchange[20] or boxylic acid (13) in 73% yield.
by copper-promoted iodine/trifluoromethyl displace-
ment,[16] were converted into 3-trifluoromethyl-2-pyridine-
carboxylic acid (5; 68%), 5-trifluoromethyl-3-pyridinecar-
boxylic acid (7; 33%), and 5-trifluoromethyl-2-pyridinecar-
boxylic acid (8; 67%), respectively. An alternative reaction
sequence consisted of the deprotonation and subsequent
carboxylation of commercially available 2-chloro-5-(trifluo-
romethyl)pyridine derivatives and subsequent reductive re-
moval of the heavier halogen. In this way, the 3-trifluoro-
methyl-4-pyridinecarboxylic acid (6; 70%) and, again, the
5-trifluoromethyl-3-pyridinecarboxylic acid (7; 57%) were
prepared.
The route to the 4-trifluoromethyl-substituted pyridine-
carboxylic acids 9 and 10 was once more based on the
methodical principles already outlined. 2-Bromo-4-(trifluo-
romethyl)pyridine (65%) was obtained by the reaction of 2-
chloro-4-(trifluoromethyl)pyridine[16] with bromotrimeth-
ylsilane.[20] Consecutive treatment with butyllithium, car-
bon dioxide and hydrochloric acid provided the 4-trifluoro-
methyl-2-carboxylic acid (9; 54%), whereas deprotonation
with lithium diisopropylamide followed by carboxylation,
neutralization, and dechlorinative hydrogenation produced
the isomeric 4-trifluoromethyl-3-pyridinecarboxylic acid
(10; overall 73%).
The trifluoromethyl group at the 3-position of the
quinolinecarboxylic acids 14؊16 was introduced by the re-
Trifluoromethyl-Substituted Quinolinecarboxylic
Acids
4-Bromo- and 4,8-dibromo-2-(trifluoromethyl)quinoline,
the key intermediates in the production of the 2-trifluoro-
methyl-substituted 3-, 4- and 8-quinolinecarboxylic acids,
emanated from the acid-catalyzed cyclocondensation of
ethyl 4,4,4-trifluoroacetoacetate with aniline and 2-bromo-
aniline, respectively.[24] 4-Bromo-2-(trifluoromethyl)quino-
line was transformed into the 2-trifluoromethyl-4-quino-
linecarboxylic acid (12; 88%) by butyllithium-promoted hal-
ogen/metal permutation followed by carboxylation and
neutralization, and also into the isomeric 2-trifluoromethyl-
3-quinolinecarboxylic acid (11; 80%) by consecutive depro-
tonation with LIDA, carboxylation and reductive hydro-
genation. The 4,8-dibromo-2-(trifluoromethyl)quinoline
was first selectively debrominated at the 4-position[24] before
being subjected to a halogen/metal permutation and car-
Eur. J. Org. Chem. 2003, 1559Ϫ1568
1561

F. Cottet, M. Marull, O. Lefebvre, M. Schlosser
FULL PAPER
action of a suitable chloro-3-iodoquinoline with trifluoro-
methylcopper generated in situ.[16] Subsequent chlorine/
bromine displacement[20] at the 2- and 4-positions gave in-
termediates which, when consecutively subjected to hal-
ogen/metal permutation and carboxylation, provided the
acids 14 and 15 in 54% and 59% overall yields, respectively.
The remaining isomer 16 was produced from 8-bromo-2-
chloro-3-iodoquinoline by a sequence comprising iodine/
trifluoromethyl substitution (64%), halogen/metal permu-
tation followed by carboxylation (68%), and dechlorinat-
ing hydrogenation (54%).
By means of a high-temperature protocol, the cyclo-
condensation between ethyl 4,4,4-trifluoroacetylacetate and
aniline can be reoriented towards the 4-trifluoromethyl-
2(1H)-quinolinone and, from 2-iodoaniline, towards the 8-
iodo-4-trifluoromethyl-2(1H)-quinolinone.[25] The corre-
sponding 2-bromoquinolines were obtained by the reaction
with phosphorus oxybromide. Upon consecutive treatment
with butyllithium and dry ice, they afforded the 4-trifluoro-
methyl-2-quinolinecarboxylic acid (17; 72%) and 2-bromo-
4-trifluoromethyl-3-quinolinecarboxylic acid (88%), respec-
tively. Debromination of the latter compound gave 4-(tri-
fluoromethyl)-8-quinolinecarboxylic acid (19; 79%). The 2-
bromo-4-trifluoromethyl-3-quinolinecarboxylic acid (88%)
was formed by deprotonation of 2-bromo-4-(trifluorometh-
yl)quinoline with LIDA and subsequent carboxylation.
Experimental Section
1H and 13C NMR spectra of samples dissolved in deuteriochloro-
form (or, if marked by an asterisk, in perdeuterioacetone) were re-
corded at 400 and 101 MHz, respectively, chemical shifts being
given relative to tetramethylsilane (δ ϭ 0.00 ppm). Working habits
and abbreviations have been explained in previous publications
from this laboratory.[26Ϫ28]
1. Bromochloro- and Bromoiodopyridines
3-Bromo-2-chloropyridine:
A solution of 2-chloro-3-(trimethyl-
silyl)pyridine[29,30] (56 g, 0.30 mol) and bromine (23 mL, 72 g, 0.45
mol) in tetrachloromethane (0.15 L) was heated under reflux for 3
days (75 h). Upon immediate distillation, a yellowish oil was col-
lected. This solidified; m.p. 54Ϫ56 °C (colorless needles from pen-
tanes) (ref.[31] m.p. 55 °C); b.p. 95Ϫ97 °C/10 Torr; yield: 53.1 g
(92%).
2,3-Dibromopyridine: A mixture of 3-bromo-2-chloropyridine (38 g,
0.20 mol) and bromotrimethylsilane (37 mL, 46 g, 0.30 mol) in pro-
pionitrile (0.10 L) was heated under reflux for 2 days (50 h) in a
flask connected to a reflux condenser, the cooling jacket of which
was kept at ϩ75 °C by a continuous flow of warm water. The chloro-
trimethylsilane formed was allowed to escape through the calcium
chloride tube attached at the condenser outlet. The propionitrile
and excess bromotrimethylsilane were evaporated off. The residue
was taken up in aqueous sodium hydroxide (2.0 , 0.10 L) and
extracted with diethyl ether (3 ϫ 0.10 L). The combined organic
layers were dried and the solvents were evaporated. Distillation of
Butyllithium-promoted debromination gave the 4-trifluoro- the residue afforded a colorless oil, which rapidly solidified; m.p.
58Ϫ59 °C (ref.[32] m.p. 58.5Ϫ59.5 °C); b.p. 117Ϫ119 °C /15 Torr;
yield: 42.2 g (89%).
methyl-3-quinolinecarboxylic acid (18; 64%).
3-Bromo-2-iodopyridine: A mixture of 2,3-dibromopyridine (47 g,
0.20 mol), chlorotrimethylsilane (25 mL, 22 g, 0.20 mol), sodium
iodide (90 g, 0.60 mol), and propionitrile (0.20 L) was heated under
reflux for 3 days (75 h). The product was isolated by distillation
as a light yellow oil, which later solidified; colorless needles (from
hexanes); m.p. 50Ϫ52 °C; b.p. 137Ϫ139 °C/13 Torr; yield: 42.0 g,
(74%). 1H NMR: δ ϭ 8.31 (dd, J ϭ 4.6, 1.7 Hz, 1 H), 7.82 (dd,
J ϭ 8.1, 1.9 Hz, 1 H), 7.16, (dd, J ϭ 8.1, 4.6 Hz, 1 H) ppm. 13C
NMR: δ ϭ 148.2, 139.7, 129.8, 124.0, 123.7. C5H3BrIN (283.89):
calcd. C 21.15, H 1.06; found C 21.33, H 1.02. If 2,3-dibromopyri-
dine was replaced by its precursor 3-bromo-2-chloropyridine, only
a 41% yield of 3-bromo-2-iodopyridine was obtained under other-
wise identical conditions.
5-Bromo-2-iodopyridine: This compound was prepared analogously,
from 2,5-dibromopyridine (47 g, 0.20 mol), except that the reflux
time was extended to 5 days (125 h); colorless platelets (from ace-
tone); m.p. 110Ϫ111 °C (ref.[33] m.p. 113 °C); yield: 49.4 g (87%).
2. Bromo-, Iodo- and Chloroiodo(trifluoromethyl)pyridines
3-Bromo-2-(trifluoromethyl)pyridine: Copper() iodide (21 g, 0.11
mol) and spray-dried anhydrous potassium fluoride (6.4 g, 0.11
mol) were heated with a Bunsen burner under reduced pressure
(1 Torr) while being gently shaken until a homogeneously greenish
powder was obtained. After the addition of 3-bromo-2-iodopyri-
In summary, the trifluoromethyl-substituted quino-
dine (28 g, 0.10 mol), (trifluoromethyl)trimethylsilane (15 mL, 14 g,
linecarboxylic acids 11؊19 and the corresponding pyridine-
0.10 mol), and N-methylpyrrolidinone (0.10 L), the suspension was
carboxylic acids 1؊10 can be prepared in a few uncompli-
vigorously stirred at ϩ25 °C, until after 3Ϫ6 h it had turned into
cated and generally high-yielding steps. This once more il-
a brown solution and all the fluorotrimethylsilane formed had es-
lustrates the versatility and operational advantages of or-
ganometallic methods in synthesis.
caped. The mixture was poured into aqueous ammonia (12%,
0.20 L) and extracted with diethyl ether (3 ϫ 50 mL). The com-
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Eur. J. Org. Chem. 2003, 1559Ϫ1568

Trifluoromethyl-Substituted Pyridine- and Quinolinecarboxylic Acids
FULL PAPER
bined organic layers were washed with aqueous ammonia (12%, 3
ϫ 50 mL) and brine (2 ϫ 50 mL) and dried, and the solvents were
evaporated. The residue was purified by distillation; m.p. 34Ϫ36
0.10 mol); colorless oil; m.p. Ϫ21 to Ϫ 20 °C; b.p. 161Ϫ162 °C;
1
yield: 14.8 g (65%). H NMR: δ ϭ 8.60 (d, J ϭ 5.8 Hz, 1 H), 7.75
(symm. m, 1 H), 7.51 (d, J ϭ 5.1 Hz, 1 H) ppm. 13C NMR: δ ϭ
151.3, 143.0, 140.6 (q, J ϭ 35 Hz), 124.3, 121.9 (q, J ϭ 274 Hz),
°C (colorless prisms from hexanes); b.p. 97Ϫ99 °C/35 Torr; yield:
1
23.0 g (74%). H NMR: δ ϭ 8.63 (dd, J ϭ 4.6, 1.0 Hz, 1 H), 8.08 118.5. C6H3BrF3N (225.99): calcd. C 31.89, H 1.34, N 6.20; found
(dm, J ϭ 8.1 Hz, 1 H), 7.39, (dd, J ϭ 8.1, 4.6 Hz, 1 H) ppm. 13C C 32.03, H 1.63, N 6.18.
NMR: δ ϭ 147.1, 146.0 (q, J ϭ 34 Hz), 143.0, 127.3, 121.0 (q, J ϭ
2-Iodo-5-(trifluoromethyl)pyridine: This compound was prepared
from 2-chloro-5-(trifluoromethyl)pyridine (36 g, 0.20 mol) and
chlorotrimethylsilane (24 mL, 22 g, 0.20 mol) in the presence of
sodium iodide (60 g, 0.40 mol) in propionitrile (0.10 L) as described
275 Hz), 118.1. C6H3BrF3N (225.99): calcd. C 31.89, H 1.34; found
C 32.02, H 1.33.
5-Bromo-2-(trifluoromethyl)pyridine:[16] This compound was pre-
pared analogously, from 5-bromo-2-iodopyridine (28 g, 0.10 mol);
purified by distillation; colorless needles (from hexanes); m.p.
37Ϫ39 °C; b.p. 76Ϫ78 °C/23 Torr; yield: 15.6 g (69%). 1H NMR:
δ ϭ 8.79 (d, J ϭ 1.9 Hz, 1 H), 8.02 (dd, J ϭ 8.3, 1.9 Hz, 1 H), 7.59
(d, J ϭ 8.3 Hz, 1 H) ppm. 13C NMR: δ ϭ 151.3, 146.6 (q, J ϭ
35 Hz), 140.0, 124.0, 121.7, 121.3 (q, J ϭ 274 Hz). C6H3BrF3N
(226.00): calcd. C 31.89, H 1.34, N 6.20; found C 31.75, H 1.40, N
6.24. When 2,5-dibromopyridine was used instead of 5-bromo-2-
iodopyridine, only a 1:1 mixture of starting material and 5-bromo-
2-(trifluoromethyl)pyridine was obtained even after 20 h of reac-
tion time, but the product was regioisomerically uncontaminated.
5-Bromo-2-(trifluoromethyl)pyridine was also made in 33% yield
by treatment of 5-bromo-2-pyridinecarboxylic acid (see following
paragraph; 35 g, 0.17 mol) with sulfur tetrafluoride (0.44 mol) and
hydrogen fluoride (1.7 mol) in an autoclave for 20 h at 125 °C.
above (see the preparation of 3-bromo-2-iodopyridine); colorless
needles (from hexanes); m.p. 82Ϫ83 °C (ref.[35] m.p. 77Ϫ80 °C);
yield: 44.6 g (82%). 1H NMR: δ ϭ 8.64 (s, 1 H), 7.91 (d, J ϭ 8.2 Hz,
1 H), 7.56 (d, J ϭ 8.2 Hz, 1 H) ppm. 13C NMR: δ ϭ 147.3 (q, J ϭ
4 Hz), 135.0, 134.2 (q, J ϭ 3 Hz), 126.2 (q, J ϭ 33 Hz), 123.3 (q,
J ϭ 272 Hz), 122.1. C6H3F3IN (272.99): calcd. C 26.40, H 1.11, N
5.13; found C 26.27, H 1.32, N 5.06.
3-Iodo-2-(trifluoromethyl)pyridine:
2,2,6,6-Tetramethylpiperidine
(8.5 mL, 7.1 g, 50 mmol) and 2-(trifluoromethyl)pyridine[16,36]
(5.8 mL, 7.4 g, 50 mmol) were added consecutively to a solution
of butyllithium (50 mmol) in tetrahydrofuran (50 mL) and hexanes
(30 mL), cooled in a dry ice/methanol bath. After 2 h at Ϫ75 °C,
the mixture was treated with iodine (0.10 mol) and then poured
into aqueous sodium thiosulfate (1.0 , 50 mL), which was then
extracted with diethyl ether (3 ϫ 50 mL). The product was purified
by steam distillation and subsequent crystallization from hexanes;
colorless needles; m.p. 42Ϫ43 °C; yield: 12.2 g (89%). 1H NMR:
δ ϭ 8.63 (dd, J ϭ 4.6, 1.2 Hz,1 H), 8.36 (d, J ϭ 8.0 Hz, 1 H), 7.20
(dd, J ϭ 8.0, 4.6 Hz, 1 H) ppm. 13C NMR: δ ϭ 149.8, 148.9 (q,
J ϭ 33 Hz), 147.4, 127.1, 121.0 (q, J ϭ 275 Hz), 88.8. C6H3F3IN
(272.99): calcd. C 26.40, H 1.11, N 5.13; found C 26.22, H 1.19,
N 5.15.
5-Bromo-2-pyridinecarboxylic Acid: 2,5-Dibromopyridine (71 g,
0.30 mol) was added to a solution of butyllithium (0.30 mol) in
toluene (0.42 L) and hexanes (0.18 L), kept in a methanol/dry ice
bath. After 2 h at Ϫ75 °C, the mixture was poured onto an excess
of freshly crushed dry ice. After evaporation of the volatiles, the
residue was dissolved in water (0.30 L). The product precipitated
upon neutralization with concentrated hydrochloric acid; colorless
prisms (from acetic acid); m.p. 173Ϫ174 °C (ref.[34] 175 °C); yield:
1
4-Iodo-2-(trifluoromethyl)pyridine: Diisopropylamine (1.4 mL,
1.0 g, 20 mmol) and 3-iodo-2-(trifluoromethyl)pyridine (5.5 g,
20 mmol) were added consecutively to a solution of butyllithium
(20 mmol) in tetrahydrofuran (20 mL) and hexanes (12 mL). After
2 h at Ϫ75 °C, the mixture was neutralized with methanol (1.0 mL,
0.8 g, 25 mmol), the solvents were evaporated, and the residue was
crystallized from hexanes; colorless needles; m.p. 24Ϫ26 °C; yield:
38.8 g (64%). H NMR: δ ؍ 8.81 (d, J ϭ 2.5 Hz, 1 H), 8.27 (dd,
J ϭ 8.4, 2.3 Hz, 1 H), 8.10 (dd, J ϭ 8.4, 1.0 Hz, 1 H) ppm. 13C
NMR: δ ϭ 166.1, 152.0, 148.3, 142.1, 127.8, 126.5.
2-Bromo-3-(trifluoromethyl)pyridine: A mixture of 2-chloro-3-(tri-
fluoromethyl)pyridine (18 g, 0.10 mol) and bromotrimethylsilane
(26 mL, 31 g, 0.20 mol) in propionitrile (0.10 L) was alternately
heated under reflux and cooled to ϩ50 °C in 1 h intervals for a
total period of 3 days. Upon distillation a colorless oil was col-
lected, and was crystallized from hexanes as prisms; m.p. 37Ϫ39
1
3.33 g (61%). H NMR: δ ϭ 8.40 (d, J ϭ 5.1 Hz, 1 H), 8.06 (s, 1
H), 7.90 (d, J ϭ 5.1 Hz, 1 H) ppm. 13C NMR: δ ϭ 150.0, 148.8 (q,
J ϭ 35 Hz), 135.7, 130.0, 120.6 (q, J ϭ 276 Hz), 106.1. C6H3F3IN
(272.99): calcd. C 26.40, H 1.11, N 5.13; found C 26.35, H 1.24,
N 5.17.
1
°C; b.p. 67Ϫ69 °C/9 Torr; yield: 18.5 g (82%). H NMR: δ ϭ 8.55
(d, J ϭ 4.8 Hz, 1 H), 7.99 (d, J ϭ 7.7 Hz, 1 H), 7.42 (dd, J ϭ 7.7,
4.8 Hz, 1 H) ppm. 13C NMR: δ ϭ 152.6, 139.6, 136.4 (q, J ϭ 5 Hz),
127.9 (q, J ϭ 35 Hz), 122.3 (q, J ϭ 273 Hz), 122.3. C6H3BrF3N
(225.99): calcd. C 31.89, H 1.34, N 6.20; found C 32.03, H 1.63,
N 6.18.
2-Chloro-4-iodo-5-(trifluoromethyl)pyridine:
Tetrahydrofuran
(0.15 L), diisopropylamine (14 mL, 10 g, 0.10 mol), lithium bro-
mide (0.87 g, 10 mmol), and lithium N,N-diisopropylcarbamate
(15 g, 0.10 mol; freshly prepared from molar equivalents of diiso-
propylamine and butyllithium and an excess of carbon dioxide gas
in tetrahydrofuran, isolated as a white powder after evaporation
of the volatiles and drying) were added consecutively, at 0 °C, to
butyllithium (0.10 mol) in hexanes (60 mL). The mixture was vigor-
ously stirred until it became homogeneous. It was then placed in a
dry ice/methanol bath and, after the addition of neat 2-chloro-5-
(trifluoromethyl)pyridine (18 g, 0.10 mol), was kept for 2 h at Ϫ75
°C, after which iodine (25 g, 0.10 mol) in tetrahydrofuran (0.15 L)
was rapidly added. After the mixture had been kept for 45 min at
Ϫ75 °C, the solvents were evaporated, and the residue was taken
up in diethyl ether (0.10 L), washed with saturated aqueous sodium
thiosulfate (50 mL), hydrochloric acid (2.0 , 2 ϫ 100 mL), satu-
2-Bromo-5-(trifluoromethyl)pyridine:[16] A solution of 2-chloro-5-
(trifluoromethyl)pyridine (18 g, 0.10 mol) and bromotrimethylsi-
lane (26 mL, 31 g, 0.20 mol) in propionitrile (0.10 L) was heated
under reflux for 20 h, after which the product was isolated by distil-
lation; colorless prisms (from hexanes); m.p. 43Ϫ44 °C; b.p. 98Ϫ99
1
°C/50 Torr; yield: 17.2 g (76%). H NMR: δ ϭ 8.66 (s, 1 H), 7.80
(dd, J ϭ 8.5, 2.5 Hz, 1 H), 7.66 (d, J ϭ 8.4 Hz, 1 H) ppm. 13C
NMR: δ ϭ 147.1 (q, J ϭ 4 Hz), 145.9, 135.3(q, J ϭ 3 Hz), 128.3,
126.0 (q, J ϭ 33 Hz), 123.1 (q, J ϭ 273 Hz). C6H3BrF3N
(225.99):calcd. C 31.89, H 1.34, N 6.20; found C 32.12, H 1.33,
N 6.30.
2-Bromo-4-(trifluoromethyl)pyridine: This compound was prepared
analogously, from 2-chloro-4-(trifluoromethyl)pyridine[16] (18 g, rated aqueous sodium hydrogen carbonate (50 mL), and brine (2
Eur. J. Org. Chem. 2003, 1559Ϫ1568
1563

F. Cottet, M. Marull, O. Lefebvre, M. Schlosser
FULL PAPER
ϫ 50 mL), and dried, and the solvents were again evaporated. Crys-
(0.10 L) was kept for 2 h at 0 °C, before being poured onto an
tallization from ethanol gave colorless platelets; m.p. 126Ϫ127 °C; excess of freshly crushed dry ice. The solvent was evaporated and
yield: 20.6 g (67%). 1H NMR: δ ϭ 8.55 (s, 1 H), 8.04 (s, 1 H) ppm.
13C NMR: δ ϭ 154.9, 147.1 (q, J ϭ 6 Hz), 136.4, 129.1 (q, J ϭ
32 Hz), 122.2 (q, J ϭ 274 Hz), 104.6. C6H2ClF3IN (307.44): calcd.
C 23.44, H 0.66; found 23.46, H 0.81.
the residue was partitioned between diethyl ether (50 mL) and
aqueous sodium hydroxide (2.0 , 50 mL). The aqueous layer was
washed with diethyl ether (2 ϫ 10 mL), acidified to pH 2, and
extracted with diethyl ether (3 ϫ 10 mL). The combined organic
layers were dried, the solvents were evaporated, and the residue was
crystallized from ethyl acetate; colorless needles; m.p. 175Ϫ176 °C
(ref.[10] m.p. 175Ϫ176 °C; mixture m.p. without depression); yield:
2-Chloro-3-iodo-5-(trifluoromethyl)pyridine: Piperidine (4.9 mL,
4.2 g, 50 mmol) and 2-chloro-4-iodo-5-(trifluoromethyl)pyridine
(15 g, 50 mmol) were consecutively added to a solution of butyllith-
ium (50 mmol) in tetrahydrofuran (0.20 L) and hexanes (35 mL),
cooled in a dry ice/methanol bath. After 20 h at Ϫ75 °C, the mix-
ture was neutralized with hydrochloric acid (2.0 , 50 mL). Steam
distillation, followed by distillation under reduced pressure, af-
forded a colorless, slowly solidifying oil; prisms (from acetone);
m.p. 37Ϫ39 °C; b.p. 85Ϫ86 °C/8 Torr; yield: 7.07 g (46%). 1H
NMR: δ ϭ 8.63 (s, 1 H), 8.36 (s, 1 H) ppm. 13C NMR: δ ϭ 158.4,
145.7, 145.7, 126.3 (q, J ϭ 34 Hz), 122.0 (q, J ϭ 273 Hz), 94.8.
C6H2ClF3IN (307.44): calcd. C 23.44, H 0.66; found C 23.38, H
0.65.
1
3.21 g (84%). H NMR*: δ ϭ 8.87 (dd, J ϭ 4.7, 0.8 Hz, 1 H), 8.32
(dd, J ϭ 7.9, 0.8 Hz, 1 H), 7.86 (dd, J ϭ 7.9, 0.8 Hz, 1 H) ppm.
13C NMR*: δ ϭ 166.6, 151.6, 145.1 (q, J ϭ 35 Hz), 139.1, 129.5,
127.5, 122.4 (q, J ϭ 274 Hz). C7H4F3NO2 (191.11): calcd. C 43.99,
H 2.11; found C 44.13, H 2.23.
2-Trifluoromethyl-4-pyridinecarboxylic Acid (2): This compound
was prepared analogously, from 4-iodo-2-(trifluoromethyl)pyridine
(see Section 2; 2.7 g, 10 mmol) and butyllithium (10 mmol) in tetra-
hydrofuran (15 mL) and hexanes (5 mL) for 5 min at Ϫ75 °C; col-
orless prisms (from chloroform); m.p. 215Ϫ216 °C (reprod.); yield:
1
1.59 g (83%). H NMR: δ ϭ 9.00 (d, J ϭ 4.9 Hz, 1 H), 8.26 (s, 1
H), 8.21 (d, J ϭ 4.9 Hz, 1 H) ppm. 13C NMR*: δ ϭ 165.3, 152.5,
149.3 (q, J ϭ 35 Hz), 141.0, 127.4, 122.5 (q, J ϭ 276 Hz), 120.8.
C7H4F3NO2 (191.11): calcd. C 43.99, H 2.11; found C 44.01, H
2.24.
3. Chloro(trifluoromethyl)pyridinecarboxylic Acids
2-Chloro-5-trifluoromethyl-4-pyridinecarboxylic Acid: 2-Chloro-4-
iodo-5-(trifluoromethyl)pyridine (7.7 g, 25 mmol) was added as a
solid, at Ϫ75 °C, to butyllithium (50 mmol) in hexanes (30 mL) and
tetrahydrofuran (0.10 L). After 15 min at Ϫ75 °C, the suspension
formed was poured onto an excess of freshly crushed dry ice before
being treated, at ϩ25 °C, with ethereal hydrochloric acid (2.0 ,
50 mL). All volatiles were evaporated and the residue was crys-
tallized from a 1:1 mixture of ethyl acetate and hexanes; tiny color-
less needles; m.p. 185Ϫ186 °C (decomp.); yield: 4.9 g (87%). 1H
NMR: δ ϭ 8.76 (s, 1 H), 7.72 (s, 1 H) ppm. 13C NMR: δ ϭ 165.4,
155.7, 148.0 (q, J ϭ 6 Hz), 142.7, 124.4, 122.6 (q, J ϭ 274 Hz),122.5
(q, J ϭ 35 Hz). C7H3ClF3NO2 (225.55): calcd. C 37.27, H 1.34;
found C 36.94, H 1.76.
6-Trifluoromethyl-3-pyridinecarboxylic Acid (3): This compound
was prepared as described above (see the preparation of the acid
1), from 5-bromo-2-(trifluoromethyl)pyridine (see above; 11 g,
50 mmol) and isopropylmagnesium chloride (50 mmol) in tetra-
hydrofuran; colorless prisms (from a 1:1 mixture of methanol and
1
chloroform); m.p. 188Ϫ189 °C; yield: 8.50 g (89%). H NMR: δ ϭ
9.28 (s, 1 H), 8.63 (d, J ϭ 8.2 Hz, 1 H), 8.03 (d, J ϭ 8.2 Hz, 1 H)
ppm. 13C NMR*: δ ϭ 165.3, 151.8, 151.2 (q, J ϭ 35 Hz), 140.1,
130.1, 122.4 (q, J ϭ 274 Hz), 121.4. C7H4F3NO2 (191.11): calcd. C
43.99, H 2.11; found C 43.94, H 2.23.
6-Trifluoromethyl-2-pyridinecarboxylic Acid (4): This compound
was prepared by treatment of 2-bromo-6-(trifluoromethyl)pyri-
dine[16] (4.5 g, 20 mmol) with butyllithium (20 mmol, added drop-
wise) in diethyl ether (0.10 L) and hexanes (15 mL) for 15 min at
Ϫ75 °C; colorless prisms (from a 3:1 mixture of ethyl acetate and
hexanes); m.p. 156Ϫ157 °C (ref.[35] m.p. 156Ϫ157 °C; mixture m.p.
2-Chloro-5-trifluoromethyl-3-pyridinecarboxylic Acid: This com-
pound was prepared analogously, from 2-chloro-3-iodo-5-(trifluo-
romethyl)pyridine (7.7 g, 25 mmol); tiny colorless needles (from
ethyl acetate/hexanes); m.p. 167Ϫ168 °C (decomp.); yield: 3.67 g
(65%). 1H NMR: δ ϭ 8.75 (dq, J ϭ 2.5, 0.8 Hz, 1 H), 8.47 (dq,
J ϭ 2.5, 0.6 Hz, 1 H) ppm. 13C NMR: δ ϭ 164.9, 153.6, 148.1 (q,
J ϭ 4 Hz), 137.8 (q, J ϭ 3 Hz), 127.9, 125.6 (q, J ϭ 34 Hz), 122.7
(q, J ϭ 273 Hz). C7H3ClF3NO2 (225.55): calcd. C 37.27, H 1.34;
found C 37.31, H 0.95.
1
without depression); yield: 3.33 g (87%). H NMR: δ ϭ 8.41Ϫ8.32
(m, 2 H), 8.13 (dd, J ϭ 7.6, 1.2 Hz, 1 H) ppm. 13C NMR*: δ ϭ
166.0, 150.4, 149.0 (q, J ϭ 35 Hz), 141.8, 129.3, 125.8, 122.8 (q,
J ϭ 275 Hz). C7H4F3NO2 (191.11): calcd. C 43.99, H 2.11; found
C 44.07, H 2.23.
2-Chloro-4-trifluoromethyl-3-pyridinecarboxylic Acid: Diisopro-
pylamine (7.0 mL, 5.1 g, 50 mmol) and 2-chloro-4-(trifluorometh-
yl)pyridine[16] (6.4 mL, 9.1 g, 50 mmol) were added consecutively
to a solution of butyllithium (50 mmol) in tetrahydrofuran (70 mL)
and hexanes (25 mL). After 2 h at Ϫ75 °C, the mixture was poured
onto an excess of freshly crushed dry ice before being treated, at
ϩ25 °C, with hydrochloric acid (2.0 , 50 mL). All volatiles were
evaporated, and the residue was crystallized from ethyl acetate to
provide colorless prisms; m.p. 150Ϫ151 °C; 9.3 g (82%). 1H NMR:
δ ϭ 8.62 (d, J ϭ 5.2 Hz, 1 H), 7.54 (d, J ϭ 5.2 Hz, 1 H) ppm. 13C
NMR: δ ϭ 165.4, 150.5, 148.9, 137.4 (q, J ϭ 35 Hz), 124.4, 121.7
(q, J ϭ 275 Hz), 118.8 (q, J ϭ 4 Hz). C6H3ClF3NO2 (225.55):calcd.
C 37.28, H 1.34, N 6.21; found C 37.21, H 1.32, N 6.26.
3-Trifluoromethyl-2-pyridinecarboxylic Acid (5): Butyllithium
(50 mmol) in hexanes (30 mL) was added at Ϫ100 °C to 2-bromo-
3-(trifluoromethyl)pyridine (see Section 2; 11 g, 50 mmol) in azeo-
tropically dried toluene (0.10 L). After 2 h at Ϫ75 °C, the mixture
was carboxylated and worked up as described above; tiny colorless
platelets (from equal volumes of ethyl acetate and hexanes); m.p.
1
116Ϫ117 °C (decomp.); yield: 6.5 g (68%). H NMR: δ ϭ 8.91 (s,
1 H), 8.22 (d, J ϭ 8.0 Hz, 1 H), 7.42 (dd, J ϭ 7.8, 4.9 Hz, 1 H)
ppm. 13C NMR: δ ϭ 164.1, 151.0, 147.3, 136.4 (q, J ϭ 5 Hz), 126.3
(q, J ϭ 35 Hz), 126.2, 122.5 (q, J ϭ 274 Hz). C7H4F3NO2 (191.11):
calcd. C 43.99, H 2.11, N 7.33; found C 43.91, H 2.17, N 7.21.
3-Trifluoromethyl-4-pyridinecarboxylic Acid (6): Palladium (10% on
charcoal, 1.5 g) was added with stirring, at ϩ25 °C, to a solution of
2-chloro-5-trifluoromethyl-4-pyridinecarboxylic acid (see Section 3;
4. (Trifluoromethyl)pyridinecarboxylic Acids
2-Trifluoromethyl-3-pyridinecarboxylic Acid (1): A solution of 3-
bromo-2-(trifluoromethyl)pyridine (see above; 4.5 g, 20 mmol) and 5.6 g, 25 mmol) and ammonium formate (5.0 g, 42 mmol) in meth-
isopropylmagnesium chloride (20 mmol) in tetrahydrofuran
1564
anol (25 mL). The evolution of a gas started almost immediately
Eur. J. Org. Chem. 2003, 1559Ϫ1568

Trifluoromethyl-Substituted Pyridine- and Quinolinecarboxylic Acids
FULL PAPER
and ceased completely some 15 min later. The reaction mixture was
filtered under suction and the filter cake was washed with methanol
(50 mL). The solution was evaporated and the residue was crys-
tallized from equal volumes of ethyl acetate and hexanes; colorless
prisms; m.p. 205Ϫ207 °C (decomp.); yield: 3.87 g (81%). 1H NMR:
δ ϭ 9.00 (s, 1 H), 8.90 (d, J ϭ 5.0 Hz, 1 H), 7.70 (d, J ϭ 4.9 Hz,
1 H) ppm. 13C NMR: δ ϭ166.6, 153.4, 147.5 (q, J ϭ 6 Hz) 140.0,
123.2 (q, J ϭ 32 Hz), 123.0, 122.8 (q, J ϭ 274 Hz). C7H4F3NO2
(191.11): calcd. C 43.99, H 2.11, N 7.33; found C 43.90, H 1.99,
N 7.33.
5. Bromoquinolinones and Haloquinolines
8-Bromo-2(1H)-quinolinone: A mixture of cinnamoyl chloride (84 g,
0.50 mol), 2-bromoaniline (86 g, 0.50 mol), and potassium carbo-
nate (0.10 kg, 0.75 mol) in water (0.25 L) and acetone (0.20 L) was
kept for 2 h at 0 °C before being poured into ice-water (0.50 L).
The precipitate formed was collected and crystallized from hexanes
to afford 2-bromocinnamanilide; colorless prisms; m.p. 152Ϫ154 °C;
1
yield: 139 g (92%). H NMR: δ ϭ 8.51 (d, J ϭ 8.2 Hz, 1 H), 7.81
(s, 1 H), 7.77 (d, J ϭ 15.9 Hz, 1 H), 7.59Ϫ7.38 (m, 6 H), 7.34 (t,
J ϭ 7.9 Hz, 1 H), 6.99 (t, J ϭ 7.9 Hz, 1 H), 6.60 (d, J ϭ 15.9 Hz,
1 H) ppm. 13C NMR: δ ϭ 163.9, 143.8, 135.8, 134.3, 132.2, 130.0,
128.8, 128.4, 128.0, 125.2, 122.3, 120.6. C15H12BrNO (302.17):
calcd. C 59.62, H 4.00; found C 59.65, H 4.01. A solution of 2-
bromocinnamanilide (0.12 kg, 0.40 mol) and aluminium chloride
(0.32 kg, 2.4 mol) in chlorobenzene (0.40 L) was heated to 125 °C
for 2 h. At 50 °C, it was then poured onto ice, and the resulting
precipitate was filtered and crystallized from ethanol; colorless
5-Trifluoromethyl-3-pyridinecarboxylic Acid (7): This compound
was prepared analogously, from 2-chloro-5-trifluoromethyl-3-pyri-
dinecarboxylic acid (see Section 3; 5.6 g, 25 mmol); colorless plate-
lets (from a 1:1 mixture of ethyl acetate and hexanes); m.p.
180Ϫ182 °C (decomp.); yield: 4.16 g (87%). 1H NMR: δ ϭ 9.43 (d,
J ϭ 1.7 Hz, 1 H), 9.06 (d, J ϭ 1.4 Hz, 1 H), 8.59 (symm. m, 1 H)
ppm. 13C NMR: δ ϭ 165.5, 153.7, 149.3 (q, J ϭ 4 Hz), 134.5 (q,
J ϭ 4 Hz), 127.1, 126.6 (q, J ϭ 34 Hz), 122.9 (q, J ϭ 272 Hz).
C7H4F3NO2 (191.11): calcd. C 43.99, H 2.11, N 7.33; found C
43.92, H 2.02, N 7.24. Acid 7 was also obtained from 3-bromo-5-
(trifluoromethyl)pyridine[16] (6.8 g, 30 mmol), although in at most
33% yield. The best reaction conditions identified were treatment
with lithium tributylmagnesiate[37Ϫ39] [obtained by mixing 20 mmol
of butyllithium in 12 mL of hexanes and 10 mmol of butylmag-
nesium chloride in 6.0 mL of tetrahydrofuran] in toluene (40 mL)
for 15 min at Ϫ75 °C before carboxylation.
1
needles; m.p. 196Ϫ198 °C; yield: 50.2 g (56%). H NMR: δ ϭ 8.11
(s, 1 H), 7.71 (d, J ϭ 9.4 Hz, 1 H), 7.53 (dd, J ϭ 7.8, 1.1 Hz, 1 H),
7.80 (t, J ϭ 7.8 Hz, 1 H), 6.68 (d, J ϭ 9.4 Hz, 1 H) ppm. 13C NMR:
δ ϭ 161.8, 140.1, 135.3, 133.2, 127.2, 122.9, 122.4, 120.6, 115.8.
C9H6BrNO (224.06): calcd. C 48.25, H 2.70; found C 48.54, H 2.69.
8-Bromo-2-chloroquinoline: Phosphorus oxychloride (37 mL, 61 g,
0.40 mol) and 8-bromo-2(1H)-quinolinone (45 g, 0.20 mol) were
heated to 125 °C for 2 h before being poured onto ice. The resulting
precipitate was filtered and crystallized from methanol; colorless
1
prisms; m.p. 113Ϫ114 °C; yield: 40.3 g (83%). H NMR: δ ϭ 8.10
5-Trifluoromethyl-2-pyridinecarboxylic Acid (8): This compound
was prepared by consecutive treatment of 2-bromo-5-(trifluoro-
methyl)pyridine (see Section 2; 22 g, 50 mmol) with butyllithium
(50 mmol) in toluene (50 mL) for 2 h at Ϫ75 °C and carbon dioxide
as described above (see the preparation of the acid 5); colorless tiny
needles (from a 1:1 mixture of ethyl acetate and hexanes); m.p.
(d, J ϭ 8.3 Hz, 1 H), 8.05 (d, J ϭ 7.8 Hz, 1 H), 7.78 (d, J ϭ 7.8 Hz,
1 H), 7.49Ϫ7.39 (m, 2 H) ppm. 13C NMR: δ ϭ 151.8, 145.0, 139.3,
134.1, 131.2, 128.0, 127.4, 123.4, 122.5. C9H5BrClN (242.50): calcd.
C 44.58, H 2.08; found C 44.78, H 2.09.
8-Bromo-2-chloro-3-iodoquinoline: Diisopropylamine (21 mL, 15 g,
0.15 mol) and 8-bromo-2-chloroquinoline (36 g, 0.15 mol) were ad-
ded consecutively to butyllithium (0.15 mol) in tetrahydrofuran
(0.20 L) and hexanes (90 mL), cooled in a methanol/dry ice bath.
After 2 h at Ϫ75 °C, iodine (76 g, 0.30 mol) in precooled tetra-
hydrofuran (75 mL) was added. The mixture was washed with
aqueous sodium thiosulfate (1.0 , 0.20 L). The organic phase was
dried over anhydrous sodium sulfate and the solvents were evapo-
rated. Crystallization from methanol gave colorless prisms; m.p.
184Ϫ186 °C; yield: 43.7 g (79%). 1H NMR: δ ϭ 8.67 (s, 1 H), 8.06
(dd, J ϭ 7.5, 1.3 Hz, 1 H), 7.69 (dd, J ϭ 8.3, 1.3 Hz, 1 H), 7.43
(dd, J ϭ 8.1, 7.5 Hz, 1 H) ppm. 13C NMR: δ ϭ 153.5, 149.0, 144.2,
135.5, 129.0, 128.0, 126.1, 123.4, 92.5. C9H4BrClIN (368.39): calcd.
C 29.34, H 1.09; found C 29.43, H 1.09.
1
134Ϫ135 °C; yield: 6.4 g (67%). H NMR: δ ϭ 9.17 (s,1 H), 8.45
(d, J ϭ 8.1 Hz, 1 H), 8.27 (d, J ϭ 8.1 Hz, 1 H) ppm. 13C NMR:
δ ϭ 164.1, 150.0, 145.6, 136.0, 130.4 (q, J ϭ 34 Hz), 124.8, 122.7
(q, J ϭ 273 Hz). C7H4F3NO2 (191.11): calcd. C 43.99, H 2.11, N
7.33; found C 44.13, H 2.21, N 7.29. The yield dropped to 47%
when the same product 8 was prepared from 2-iodo-5-(trifluoro-
methyl)pyridine as the starting material.
4-Trifluoromethyl-2-pyridinecarboxylic Acid (9): This compound
was prepared analogously, from 2-bromo-4-(trifluoromethyl)pyri-
dine (see Section 2; 5.6 g, 25 mmol); colorless needles (from equal
volumes of ethyl acetate and hexanes); m.p. 156Ϫ157 °C (ref.[10]
m.p. 156Ϫ158 °C; no depression upon mixing); yield: 2.6 g
(54%).1H NMR: δ ϭ 9.82 (s, 1 H), 9.05 (d, J ϭ 5.0 Hz, 1 H), 8.51
(s, 1 H), 7.89 (d, J ϭ 5.0 Hz, 1 H) ppm. 13C NMR: δ ϭ 165.0,
150.4, 149.5, 139.7 (q, J ϭ 35 Hz), 122.4 (q, J ϭ 3 Hz), 122.2 (q,
J ϭ 273 Hz), 121.0 (q, J ϭ 3 Hz). C7H4F3NO2 (191.11): calcd. C
43.99, H 2.11; found C 43.71, H 1.99.
6. Bromo- and Chloro(trifluoromethyl)quinolines
The preparation of 4-bromo-2-(trifluoromethyl)quinoline,[25] 8-
bromo-2-(trifluoromethyl)quinoline,[25] 4,8-dibromo-2-(trifluoro-
methyl)quinoline,[25] 2-bromo-4-(trifluoromethyl)quinoline,[25,40] 8-
bromo-4-(trifluoromethyl)quinoline,[25,40] and 2-bromo-8-iodo-4-
(trifluoromethyl)quinoline[25,40] is reported in detail in forth-
coming publications.
4-Trifluoromethyl-3-pyridinecarboxylic Acid (10): This compound
was prepared by transfer hydrogenolysis of 2-chloro-4-trifluoro-
methyl-4-pyridinecarboxylic acid (see Section 3; 11 g, 50 mmol) as
described above (see the preparation of the acid 6); colorless plate-
lets (from equal volumes of ethyl acetate and hexanes); m.p.
146Ϫ147 °C (ref.[10] m.p. 146Ϫ147 °C; no depression upon mixing);
yield: 8.5 g (89%). 1H NMR: δ ϭ 9.17 (s, 1 H), 9.04 (d, J ϭ 5.2 Hz,
1 H), 7.88 (d, J ϭ 5.2 Hz, 1 H) ppm. 13C NMR*: δ ϭ 165.9, 154.1,
152.0, 136.9 (q, J ϭ 35 Hz), 126.8, 128.4 (q, J ϭ 275 Hz), 121.3 (q,
J ϭ 5 Hz). C7H4F3NO2 (191.11): calcd. C 43.99, H 2.11; found C
44.12, H 2.30.
2-Chloro-3-(trifluoromethyl)quinoline: 2-Chloro-3-iodoquinoline[41]
(38 g, 0.13 mol) was treated and worked up as described for the
preparation of 3-bromo-2-(trifluoromethyl)pyridine (Section 2), ex-
cept that the reaction time was extended to 20 h and the reaction
temperature was increased to 50 °C; colorless needles (from hex-
anes); m.p. 98Ϫ100 °C (ref.[42] m.p. 98Ϫ100 °C); yield: 24.1 g (80%).
4-Chloro-3-(trifluoromethyl)quinoline: This compound was pre-
pared analogously, from 4-chloro-3-iodoquinoline[43] (43 g, 0.15
Eur. J. Org. Chem. 2003, 1559Ϫ1568
1565

F. Cottet, M. Marull, O. Lefebvre, M. Schlosser
FULL PAPER
mol); colorless needles (from hexanes); m.p. 79Ϫ81 °C; yield: 27.4 g
collected and dissolved in methanol (0.25 L). The suspension ob-
(79%). 1H NMR: δ ϭ 9.01 (s, 1 H), 8.37 (d, J ϭ 8.6 Hz, 1 H), 8.12 tained upon addition of charcoal (3.0 g) was vigorously stirred for
(d, J ϭ 8.6 Hz, 1 H), 7.89 (ddd, J ϭ 8.6, 7.0, 1.3 Hz, 1 H), 7.74
(ddd, J ϭ 8.6, 7.0, 1.1 Hz, 1 H) ppm. 13C NMR: δ ϭ 150.1, 146.1 solvent was removed by evaporation and the residue was crys-
(q, J ϭ 6 Hz), 142.8, 132.5, 130.0, 128.9, 125.8, 124.9, 122.8 (q, tallized from methanol; colorless needles; m.p. 102Ϫ104 °C (after
J ϭ 274 Hz), 121.4 (q, J ϭ 32 Hz). C10H5ClF3N (231.60): calcd. C sublimation); yield: 17.7 g (88%). 1H NMR: δ ϭ 8.45 (d, J ϭ
1 h before being filtered through a pad of diatomaceous earth. The
51.86, H 2.18; found C 51.56, H 2.15.
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. C10H4BrF3IN (401.95): calcd. C 29.88, H 1.00;
found C 29.90, H 1.11.
2-Bromo-3-(trifluoromethyl)quinoline: 2-Chloro-3-(trifluorometh-
yl)quinoline (6.9 g, 30 mmol) was treated with bromotrimethylsil-
ane (5.9 mL, 6.9 g, 45 mmol) as described for the preparation of
2,3-dibromopyridine (Section 2). The residue was crystallized from
hexanes; colorless needles; m.p. 93Ϫ95 °C; yield: 6.9 g (83%). 1H
NMR: δ ϭ 8.45 (s, 1 H), 8.08 (d, J ϭ 8.3 Hz, 1 H), 7.90 (d, J ϭ
8.0 Hz, 1 H), 7.87 (ddd, J ϭ 8.6, 7.0, 1.3 Hz, 1 H), 7.68 (ddd, J ϭ
8.0, 7.0, 1.1 Hz, 1 H) ppm. 13C NMR: δ ϭ 149.0, 137.4 (q, J ϭ
5 Hz), 136.6, 132.9, 129.7, 128.6, 128.5, 125.2, 124.3 (q, J ϭ 33 Hz),
122.4 (q, J ϭ 272 Hz). C10H5BrF3N (276.06): calcd. C 43.51, H
1.83; found C 43.75, H 1.85.
7. (Trifluoromethyl)quinolinecarboxylic Acids
Details of the preparation and characterization of 4-bromo-2-tri-
fluoromethyl-3-quinolinecarboxylic acid,[24] 2-bromo-4-trifluoro-
methyl-3-quinolinecarboxylic acid,[25,40] 2-trifluoromethyl-3-quino-
linecarboxylic acid[24] (11), 2-trifluoromethyl-4-quinolinecarboxylic
acid[24] (12), 4-trifluoromethyl-2-quinolinecarboxylic acid[25,40] (17),
and 4-trifluoromethyl-3-quinolinecarboxylic acid[25,40] (18) are pre-
sented in forthcoming publications.
4-Bromo-3-(trifluoromethyl)quinoline: This compound was pre-
pared analogously, from 4-chloro-3-(trifluoromethyl)quinoline
(12 g, 50 mmol), but with extension of the reflux time to 20 h; col-
orless needles from hexanes; m.p. 79Ϫ80 °C; yield: 12.8 g (93%).
1H NMR: δ ϭ 9.04 (s, 1 H), 8.43 (dd, J ϭ 8.6, 1.3 Hz, 1 H), 8.18
(d, J ϭ 8.3 Hz, 1 H), 7.90 (ddd, J ϭ 8.3, 7.0, 1.1 Hz, 1 H), 7.76
(ddd, J ϭ 8.6, 7.0, 1.3 Hz, 1 H) ppm. 13C NMR: δ ϭ 149.8, 146.1
(q, J ϭ 6 Hz), 134.6, 132.4, 130.1, 129.1, 127.9, 127.4, 124.0 (q,
J ϭ 31 Hz), 123.0 (q, J ϭ 274 Hz). C10H5BrF3N (276.06): calcd. C
43.51, H 1.83; found C 43.66, H 1.91.
2-Trifluoromethyl-3-quinolinecarboxylic Acid (11): Butyllithium
(30 mmol) in hexanes (18 mL) was added to a precooled solution
of 4-bromo-2-trifluoromethyl-3-quinolinecarboxylic acid[24] (4.8 g,
15 mmol) in diethyl ether and the resulting suspension was stirred
at Ϫ75 °C for 6 h before being treated with methanol (5.0 mL,
4.0 g, 12 mmol) and water (50 mL) and extracted with diethyl ether
(3 ϫ 50 mL). The combined organic layers were dried and the sol-
vents were evaporated. The residue was crystallized from methanol;
colorless prisms; m.p. 207Ϫ209 °C (reprod.); 3.29 g (91%). 1H
NMR*: δ ϭ 9.01 (s, 1 H), 8.1Ϫ8.3 (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 (q, J ϭ 35 Hz), 142.2, 134.5, 131.5 (2 C), 130.5, 128.5, 126.0,
123.2 (q, J ϭ 275 Hz). C11H6F3NO2 (241.17): calcd. C 54.78, H
2.51; found C 54.78, H 2.99.
8-Bromo-2-(trifluoromethyl)quinoline:
4,8-Dibromo-2-(trifluoro-
methyl)quinoline[24] (7.1 g, 20 mmol) was added to a precooled
solution of butyllithium (25 mmol) in tetrahydrofuran (15 mL) and
hexanes (15 mL). After the mixture had been kept for 15 min at
Ϫ75 °C, methanol (2.0 mL, 50 mmol) was injected and the product
was isolated by crystallization from pentanes; colorless needles;
m.p. 62Ϫ63 °C (ref.[44,45]: m.p. 63.5Ϫ64.0 °C); yield: 4.20 g (76%).
1H NMR: δ ϭ 8.39 (d, J ϭ 8.6 Hz, 1 H), 8.16 (dd, J ϭ 7.5, 1.1 Hz,
1 H), 7.89 (dd, J ϭ 8.3, 1.1 Hz, 1 H), 7.80 (d, J ϭ 8.6 Hz, 1 H),
7.54 (dd, J ϭ 8.1, 7.8 Hz, 1 H) ppm. 13C NMR: δ ϭ 148.5 (q, J ϭ
35 Hz), 144.3, 138.8, 134.5, 130.0, 129.0, 127.5, 125.5, 121.2 (q, J ϭ
276 Hz), 117.8.
2-Trifluoromethyl-4-quinolinecarboxylic Acid (12): 4-Bromo-2-(tri-
fluoromethyl)quinoline[24] (6.9 g, 25 mmol) was added to a solution
of butyllithium (25 mmol) in tetrahydrofuran (15 mL) and hexanes
(15 mL), cooled to Ϫ75 °C. After 45 min at this temperature, the
mixture was poured onto an excess of freshly crushed dry ice. Water
(0.10 mL) was added, and the aqueous phase was washed with di-
ethyl ether (3 ϫ 50 mL) before being acidified to pH 1 with concen-
trated hydrochloric acid. Extraction with ethyl acetate (3 ϫ 50 mL),
drying of the combined organic layers, and evaporation gave a resi-
due, which was crystallized from a 2:1 (v/v) mixture of chloroform
and ethyl acetate; colorless prisms; m.p. 181Ϫ182 °C, 4.46 g (74%).
1H NMR*: δ ϭ 8.96 (d, J ϭ 8.4 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
(q, J ϭ 34 Hz), 139.7, 133.0, 132.0 (2 C), 127.8 (2 C), 123.4 (q, J ϭ
274 Hz), 119.7. C11H6F3NO2 (241.17): calcd. C 54.78, H 2.26;
found C 54.78, H 2.88.
8-Bromo-2-chloro-3-(trifluoromethyl)quinoline: 8-Bromo-2-chloro-
3-iodoquinoline (37 g, 0.10 mol) and (trifluoromethyl)trimethylsil-
ane (22 mL, 21 g, 0.15 mol) in 1-methyl-2-pyrrolidone (0.15 L) were
added to a mixture of copper iodide (29 g, 0.15 mol) and potassium
fluoride (8.7 g, 0.15 mol), pretreated as described.[16] Having been
heated at 50 °C for 20 h, the mixture was poured into aqueous
ammonium hydroxide (12%, 0.10 L). The resulting deep blue solu-
tion was extracted with diethyl ether (3 ϫ 0.10 L). The combined
organic layers were dried and the solvents were evaporated. The
residue was crystallized from hexanes; colorless needles; m.p.
107Ϫ109 °C; yield: 19.9 g (64%). 1H NMR: δ ϭ 8.53 (s, 1 H), 8.19
(dd, J ϭ 7.6, 1.2 Hz, 1 H), 7.90 (dd, J ϭ 8.2, 1.2 Hz, 1 H), 7.53 (t,
J ϭ 7.9 Hz, 1 H) ppm. 13C NMR: δ ϭ 147.0, 145.7, 138.5 (q, J ϭ
5 Hz), 136.5, 128.8, 128.2, 126.5, 123.4, 123.2 (q, J ϭ 34 Hz), 122.1
(q, J ϭ 272 Hz). C10H4BrClF3N (310.50): calcd. C 38.68, H 1.30;
found C 38.67, H 1.24.
2-Trifluoromethyl-8-quinolinecarboxylic Acid (13): This compound
was prepared analogously, from 8-bromo-2-(trifluoromethyl)quino-
line (see Section 6; 4.1 g, 15 mmol); colorless needles (from chloro-
1
form); m.p. 177Ϫ178 °C; yield: 2.64 g (73%). H NMR: δ ϭ 8.94
(dd, J ϭ 7.3, 1.4 Hz, 1 H), 8.69 (d, J ϭ 8.6 Hz, 1 H), 8.25 (dd, J ϭ
8.2, 1.4 Hz, 1 H), 7.96 (d, J ϭ 8.6 Hz, 1 H), 7.93 (t, J ϭ 7.5 Hz, 1
2-Bromo-8-iodo-4-(trifluoromethyl)quinoline:
8-Iodo-4-trifluoro-
methyl-2(1H)-quinolinone[40] (17 g, 50 mmol) was cautiously added H) ppm. 13C NMR*: δ ϭ 165.8, 147.0 (q, J ϭ 36 Hz), 144.1, 141.1,
at 60 °C to phosphorus oxybromide (29 g, 0.10 mol). After the
mixture had been heated at 120 °C for 2 h, it was poured onto
crushed ice (0.25 kg). The brown mass that had precipitated was
137.3, 133.1, 129.4 (2 C), 125.5, 119.5 (q, J ϭ 276 Hz), 117.8.
C11H6F3NO2 (241.17): calcd. C 54.78, H 2.51; found C 55.16, H
2.18.
1566
Eur. J. Org. Chem. 2003, 1559Ϫ1568

Trifluoromethyl-Substituted Pyridine- and Quinolinecarboxylic Acids
FULL PAPER
3-Trifluoromethyl-2-quinolinecarboxylic Acid (14): 2-Bromo-3-(tri-
122.3 (q, J ϭ 33 Hz). C11H5ClF3NO2 (275.61): calcd. C 47.94, H
fluoromethyl)quinoline (see Section 5; 6.9 g, 25 mmol) in toluene 1.83; found C 48.26, H 1.68.
(50 mL) was added dropwise, over 15 min, to a solution of butyl-
4-Trifluoromethyl-2-quinolinecarboxylic Acid (17): 2-Bromo-4-(tri-
lithium (25 mmol) in toluene (50 mL) and hexanes (15 mL), cooled
in a dry ice/methanol bath. After 45 min at Ϫ75 °C, the mixture
was poured onto an excess of freshly crushed solid carbon dioxide
covered with tetrahydrofuran (0.10 L). At ϩ25 °C, it was treated
with ethereal hydrogen chloride (2.0 , 15 mL), after which all vol-
atiles were evaporated. The residue was extracted with a hot 1:3 (v/
v) mixture of ethyl acetate and hexanes and, after concentration,
crystallized from this medium; colorless platelets; m.p. 125Ϫ126 °C
(ref.[10] m.p. 125Ϫ127 °C; no depression upon mixing); yield: 4.94 g
(82%). 1H NMR: δ ϭ 8.77 (s, 1 H), 8.26 (d, J ϭ 8.6 Hz, 1 H), 8.07
(d, J ϭ 8.3 Hz, 1 H), 8.01 (ddd, J ϭ 8.4, 7.0, 1.4 Hz, 1 H), 7.86
(ddd, J ϭ 8.1, 7.0, 1.1 Hz) ppm. 13C NMR: δ ϭ 161.8, 146.1, 143.6,
138.5 (q, J ϭ 6 Hz), 133.5, 130.6, 129.3, 128.5, 128.0, 122.8 (q, J ϭ
35 Hz), 122.6 (q, J ϭ 272 Hz). C11H6F3NO2 (241.17): calcd. C
54.78, H 2.51, N 5.81; found C 54.63, H 2.41, N 5.77.
fluoromethyl)quinoline[25] (4.1 g, 15 mmol) was added to a solution
of butyllithium (15 mmol) in tetrahydrofuran (20 mL) and hexanes
(10 mL), cooled in dry ice/methanol bath. After 45 min at Ϫ75 °C,
the mixture was poured onto an excess of freshly crushed solid
carbon dioxide covered with tetrahydrofuran (0.10 L). At ϩ25 °C,
it was treated with ethereal hydrogen chloride (2.0 , 15 mL), after
which all volatiles were evaporated. The residue was extracted with
ethyl acetate (3 ϫ 15 mL) and, after concentration, crystallized
from a 1:3 (v/v) mixture of chloroform and pentanes; colorless
1
prisms; m.p. 142Ϫ143 °C; yield: 4.3 g (72%). H NMR*: δ ϭ 8.47
(s, 1 H), 8.37 (dd, J ϭ 8.4, 1.4 Hz, 1 H), 8.27 (d, J ϭ 8.5 Hz, 1 H),
8.06 (td, J ϭ 6.9, 1.4 Hz, 1 H), 7.99 (td, J ϭ 7.0, 1.5 Hz, 1 H) ppm.
13C NMR*: δ ϭ 165.0, 158.5 (2 C), 139.0, 136.0 (q, J ϭ 35 Hz),
132.5, 131.8 (2 C), 124.7, 124.4 (q,
J ϭ 274 Hz), 118.3.
C11H6F3NO2 (241.17): calcd. C 54.78, H 2.51; found C 54.52, H
2.48.
3-Trifluoromethyl-4-quinolinecarboxylic Acid (15): 4-Bromo-3-(tri-
fluoromethyl)quinoline (see Section 5; 2.8 g, 10 mmol) in tetra-
hydrofuran (20 mL) was added dropwise at Ϫ100 °C, over 15 min,
to butyllithium (10 mmol) in tetrahydrofuran (20 mL) and hexanes.
Immediately afterwards the mixture was poured onto an excess of
freshly crushed dry ice. The product was isolated as described in
the preceding paragraph; colorless tiny needles (from ethyl acetate);
m.p. 259Ϫ260 °C (decomp.; ref.[10] m.p. 259Ϫ262 °C; m.p. of mix-
4-Trifluoromethyl-3-quinolinecarboxylic Acid (18): 2-Bromo-4-tri-
fluoromethyl-3-quinolinecarboxylic acid[25] (1.5 g, 5.0 mmol) in di-
ethyl ether (15 mL) was added dropwise, over the course of 15 min,
to a vigorously stirred solution of butyllithium in diethyl ether
(15 mL) and hexanes (6.0 mL), cooled to Ϫ100 °C. After 2 h at this
temperature, the mixture was treated with methanol (1.0 mL,
0.80 g, 25 mmol). After evaporation of the volatiles, the residue was
crystallized from acetic acid; colorless prisms; m.p. 182Ϫ184 °C
1
ture without depression); yield: 1.95 g (81%). H NMR*: δ ϭ 9.24
1
(decomp.); yield: 0.76 g (64%). H NMR*: δ ϭ 9.14 (s, 1 H), 8.27
(s, 1 H), 8.24 (d, J ϭ 8.5 Hz, 1 H), 8.10 (d, J ϭ 8.4 Hz, 1 H), 8.04
(ddd, J ϭ 8.4, 6.9, 1.4 Hz, 1 H), 7.88 (ddd, J ϭ 8.3, 7.0, 1.3 Hz, 1
H) ppm. 13C NMR*: δ ϭ 168.0, 151.0, 147.5, 142.3, 134.0, 131.5,
127.6, 125.4 (q, J ϭ 273 Hz), 123.8, 119.1 (q, J ϭ 32 Hz).
C11H6F3NO2 (241.17): calcd. C 54.78, H 2.51, N 5.81; found C
54.73, H 2.48, N 5.92.
(d, J ϭ 8.1 Hz, 1 H), 8.26 (d, J ϭ 8.7 Hz, 1 H), 8.00 (ddd, J ϭ 8.2,
7.0, 1.2 Hz, 1 H), 7.90 (ddd, J ϭ 8.9, 7.0, 1.6 Hz, 1 H) ppm. 13C
NMR*: δ ϭ 167.9, 150.0, 148.8, 132.3, 131.3, 130.4, 127.3, 125.4
(q, J ϭ 3 Hz), 124.6 (q, J ϭ 276 Hz), 122.7. C11H6F3NO2 (241.17):
calcd. C 54.78, H 2.51, N 5.80; found C 54.81, H 2.45, N 5.76.
2-Bromo-4-trifluoromethyl-8-quinolinecarboxylic Acid: 2-Bromo-8-
iodo-4-(trifluoromethyl)quinoline (see Section 6; 8.0 g, 20 mmol)
was added to butyllithium (20 mmol) in toluene (90 mL) and hex-
anes (10 mL), kept in a methanol/dry ice bath. After 15 min at Ϫ75
°C, the mixture was poured onto an excess of freshly crushed solid
carbon dioxide. After treatment with ethereal hydrogen chloride
(2.0 , 15 mL), the volatiles were evaporated and the residue crys-
tallized from ethyl acetate; colorless needles; m.p. 169Ϫ171 °C;
yield: 5.19 g (81%). 1H NMR: δ ϭ 8.81 (dd, J ϭ 9.0, 1.4 Hz, 1 H),
8.50 (dm, J ϭ 8.8 Hz, 1 H), 8.35 (s, 1 H), 8.12 (dd, J ϭ 8.8, 7.2 Hz,
1 H) ppm. 13C NMR*: δ ϭ 165.4, 147.4, 141.9, 138.2 (q, J ϭ
33 Hz), 137.0, 130.4, 129.8, 126.9, 125.4 (q, J ϭ 6 Hz), 123.4 (q,
J ϭ 276 Hz), 123.1. C11H5BrF3NO2 (320.07): calcd. C 41.28, H
1.57; found C 41.75, H 1.58.
3-Trifluoromethyl-8-quinolinecarboxylic Acid (16): Palladium (10%
on charcoal, 2.0 g) was added to a solution of 2-chloro-3-trifluoro-
methyl-8-quinolinecarboxylic acid (see following paragraph; 4.1 g,
15 mmol) and ammonium formate (1.9 g, 30 mmol) in methanol
(30 mL). The suspension was stirred for 45 min at ϩ25 °C before
being filtered. The volatiles were evaporated and the residue was
crystallized from ethanol; colorless prisms; m.p. 182Ϫ185 °C (de-
1
comp.); yield: 1.95 g (54%). H NMR: δ ϭ 9.45 (d, J ϭ 2.0 Hz, 1
H), 9.22 (q, J ϭ 1.0 Hz, 1 H), 8.88 (dd, J ϭ 7.2, 1.6 Hz, 1 H), 8.59
(dd, J ϭ 8.2, 1.6 Hz, 1 H), 8.06 (dd, J ϭ 8.2, 7.2 Hz, 1 H) ppm.
13C NMR: δ ϭ 167.0, 157.9, 147.0, 139.2, 138.7, 136.2, 130.3,
128.6, 127.4, 125.5 (q, J ϭ 32 Hz), 125.3 (q, J ϭ 272 Hz).
C11H6F3NO2 (241.17): calcd. C 54.78, H 2.51; found C 54.43, H
2.50.
4-Trifluoromethyl-8-quinolinecarboxylic Acid (19): 2-Bromo-4-tri-
2-Chloro-3-trifluoromethyl-8-quinolinecarboxylic Acid: Precooled
fluoromethyl-8-quinolinecarboxylic acid (see the preceding para-
solutions of 8-bromo-2-chloro-3-(trifluoromethyl)quinoline (see graph; 1.6 g, 10 mmol) and zinc (1.3 g, 20 mmol) were added to
above; 7.8 g, 25 mmol) in toluene (30 mL) and butyllithium
aqueous sodium hydroxide (15%, 10 mL, 42 mmol),[46] and the
(25 mmol) in hexanes (15 mL) were mixed and kept for 15 min at slurry was vigorously stirred at 25 °C. After 2 h, the mixture was
Ϫ75 °C before being poured onto an excess of freshly crushed dry
ice. At ϩ25 °C, water was added (50 mL). The aqueous layer was
filtered, acidified to pH 2 with hydrochloric acid, and extracted
with ethyl acetate (3 ϫ 15 mL). The combined organic layers were
washed with diethyl ether (3 ϫ 25 mL), acidified to pH 1 with evaporated and the residue was crystallized from a 1:3 mixture of
hydrochloric acid, and extracted with ethyl acetate (3 ϫ 25 mL).
The combined organic layers were dried and the solvents were
ethyl acetate and hexanes; colorless prisms; m.p. 186Ϫ189 °C; yield:
1.91 g (79%). H NMR: δ ϭ 9.39 (d, J ϭ 4.6 Hz, 1 H), 8.86 (dd,
1
evaporated; colorless prisms (from ethanol); m.p. 212Ϫ215 °C (de-
J ϭ 7.4, 1.4 Hz, 1 H), 8.51 (dm, J ϭ 8.7 Hz, 1 H), 8.26 (d, J ϭ
1
comp.); yield: 4.68 g (68%). H NMR: δ ϭ 9.30 (s, 1 H), 8.85 (dd, 4.7 Hz, 1 H), 8.10 (dd, J ϭ 8.6, 7.4 Hz, 1 H) ppm. 13C NMR*: δ ϭ
J ϭ 7.6, 1.3 Hz, 1 H), 8.61 (dd, J ϭ 8.2, 1.3 Hz, 1 H), 8.06 (dd, 166.2, 150.3, 146.7, 136.8 (q, J ϭ 33 Hz), 136.5, 130.2, 129.8, 127.8,
J ϭ 8.2, 7.6 Hz, 1 H) ppm. 13C NMR: δ ϭ 168.4, 145.8, 145.6, 124.1 (q, J ϭ 276 Hz), 123.9, 120.6 (q, J ϭ 6 Hz). C11H6F3NO2
141.9 (m), 134.8, 133.5, 132.1, 129.5, 126.5, 123.4 (q, J ϭ 272 Hz), (241.17): calcd. C 54.78, H 2.51; found C 54.70, H 2.30.
Eur. J. Org. Chem. 2003, 1559Ϫ1568
1567

F. Cottet, M. Marull, O. Lefebvre, M. Schlosser
FULL PAPER
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Acknowledgments
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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 also feel
indebted to Mr. Roger Ith and Mr. Renato Bregonzi, who demon-
strated outstanding technical skills and perseverance in the manu-
facture of a specifically designed autoclave for reactions with
sulfur tetrafluoride.
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