The direct metalation and subsequent functionalization of trifluoromethyl-substituted pyridines and quinolines

Article abstract of DOI:10.1002/ejoc.200390216

Depending on the choice of the reagent, 2-(trifluoromethyl)-pyridine can be selectively metalated and subsequently carboxylated of otherwise functionalized either at the 3- or at the 6-position. "Optional site selectivity" can also be achieved with 4-(trifluoromethyl)pyridine, which may be deprotonated either at the 2- or at the 3-position. In contrast, 3-(trifluoromethyl)pyridine undergoes nucleophilic addition and ensuing decomposition whatever the base. Depending on the reaction conditions, 2-(trifluoromethyl)quinoline displays reactivity toward lithium reagents at its 3-, 4-, or 8-positions, 3-(trifluoromethyl)quinolines at the 2- or 4-positions, and 4-(trifluoromethyl)quinoline at the 2- or 3-positions. It was therefore possible to prepare four trifluoromethyl-substituted pyridinecarboxylic acids (1, 4, 9, and 10) and six trifluoromethyl-substituted quinolinecarboxylic acids (11, 13, 14, 15, 17, and 18) regioisomerically uncontaminated and in a most straightforward way. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Full text of DOI:10.1002/ejoc.200390216

FULL PAPER
The Direct Metalation and Subsequent Functionalization of Trifluoromethyl-
Substituted Pyridines and Quinolines
Manfred Schlosser*[a,b] and Marc Marull[a]
`
Keywords: Carboxylation / Caubere’s base / Dialkylamides / Fluorinated building blocks / Heterocycles / Lithium /
Optional site selectivity / Regioisomers
Depending on the choice of the reagent, 2-(trifluoromethyl)-
pyridine can be selectively metalated and subsequently car-
boxylated or otherwise functionalized either at the 3- or at
the 6-position. ‘‘Optional site selectivity’’ can also be
achieved with 4-(trifluoromethyl)pyridine, which may be de-
protonated either at the 2- or at the 3-position. In contrast,
3-(trifluoromethyl)pyridine undergoes nucleophilic addition
and ensuing decomposition whatever the base. Depending
on the reaction conditions, 2-(trifluoromethyl)quinoline dis-
positions, 3-(trifluoromethyl)quinolines at the 2- or 4-posi-
tions, and 4-(trifluoromethyl)quinoline at the 2- or 3-posi-
tions. It was therefore possible to prepare four trifluoro-
methyl-substituted pyridinecarboxylic acids (1, 4, 9, and 10)
and six trifluoromethyl-substituted quinolinecarboxylic acids
(11, 13, 14, 15, 17, and 18) regioisomerically uncontaminated
and in a most straightforward way.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
plays reactivity toward lithium reagents at its 3-, 4-, or 8- Germany, 2003)
According to gas-phase studies of arenes, the trifluoro- sequent carboxylation thus afforded the acid 4 (71%) ex-
methyl group has a stronger acidifying effect than any other clusively. The amide base lithium 2,2,6,6-tetramethylpiperi-
halogen substituent, including chlorine, fluorine, and dide (LITMP) deprotonated the 5- and the 6-positions con-
trifluoromethoxy.[1Ϫ3] On the other hand, (trifluoromethyl)- comitantly, as evidenced by the formation of acids 3 and 4
benzene (α,α,α-trifluorotoluene, benzotrifluoride) reacts in a 4:3 ratio when the reaction was carried out in diethyl
with butyllithium[4] or sec-butyllithium in the presence of ether (DEE). When employed in tetrahydrofuran, though,
N,N,NЈ,NЈЈ,NЈЈ-pentamethyldiethylenetriamine (PMDTA)[2] the same base was found to abstract protons most rapidly
sluggishly and non-regioselectively, clean and expedient or- from the 4-position, thus producing predominantly the acid
tho-metalation only being achieved with the superbasic mix- 2 after early quenching (Յ 15 min). However, the acid 1
tures of butyllithium or methyllithium with potassium (73%) was isolated as the sole product, when the reaction
tert-butoxide.[2,5]
time was extended to 6 h.
We wondered whether similar deprotonation/electrophilic
trapping procedures could successfully be elaborated for tri-
fluoromethyl-substituted pyridines and quinolines. This
would open a very short route to functionalized derivatives,
potentially valuable building blocks for pharmaceutical re-
search. Carbon dioxide was once again selected as the
standard electrophile.
Depending on the reagent and the reaction conditions,
the first substrate investigated provided access to any of the
four possible derivatives and thus set an unprecedented ex-
ample of maximum optional site selectivity.[6,7] When the
metalation was performed with an excess of lithium 2-(di-
`
methylamino)ethoxide-activated butyllithium (‘‘Caubere’s
base’’),[8,9] metalation occurred at the 6-position, and sub-
[a]
´
Institut de Chimie moleculaire et biologique,
To explain this divergence in reaction outcomes, one has
to invoke the interplay of inductive, coordinative, and steric
effects. According to base-catalyzed hydrogen/deuterium ex-
change experiments,[10,11] proton mobility in the unsubsti-
´ ´
Ecole Polytechnique Federale, BCh
1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
[b]
´
´
Faculte des Sciences, Universite, BCh
1015 Lausanne, Switzerland
1569
Eur. J. Org. Chem. 2003, 1569Ϫ1575  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0408Ϫ1569 $ 20.00ϩ.50/0

M. Schlosser, M. Marull
FULL PAPER
tuted pyridine is highest at the 4-position and lowest at the ination and further nucleophilic addition of the
2-position. Although counterintuitive at first sight, this or- reagent.[18Ϫ20] The isolation of 2-butyl-5-(difluorometh-
der of kinetic acidities is corroborated by the sharply yl)pyridine as a by-product (14%) provided evidence in sup-
decreasing basicity[12] in the diazene series on going from port of the postulated addition/elimination mode.
pyridazine (pKa ϭ 2.6), through pyrimidine (pKa ϭ 1.3) to
pyrazine (pKa ϭ 0.7), the three azapyridines being isoelec-
tronic species with respect to the three pyridinides (pyridine
anions). The introduction of the strongly electron-with-
drawing trifluoromethyl group[2] next to the nitrogen in-
creases local acidities everywhere, but most markedly at the
neighboring 3-position, which thus becomes the most acidic
That competitive, though reversible, deprotonation at the
site. However, this inductive activation is counterbalanced
2-position nevertheless does occur was demonstrated by an
by the steric hindrance caused by the fairly bulky substitu-
in situ trapping experiment. When 3-(trifluoromethyl)pyri-
dine was simultaneously treated in THF at Ϫ100 °C with
chlorotrimethylsilane and a mixture (‘‘Faigl mix") of
ent. Therefore, lithiation initially occurs at the 4-position.
Despite its lower basicity, the 3-lithiated species prevails
only later, as a consequence of equilibration due to the
reversibility of deprotonation. A change of the medium
LITMP, potassium tert-butoxide, and N,N,NЈ,NЈЈ,NЈЈ-
pentamethyldiethylenetriamine (PMDTA), trimethyl-2-[(3-
from THF to DEE deprives the reagent of adequate
trifluoromethyl)pyridyl]silane was obtained in 30% yield.
solvation. Complexation of the metal to the heterocyclic
nitrogen now becomes crucial and directs the attack of the
base to the 6-position or, through aggregate-mediated, long-
range coordination, to the 5-position.
The successful metalation of 3-(trifluoromethyl)pyridine
at the 2-position with butyllithium in diethyl ether has al-
ready been reported by W. Dmowski et al.[13] However, de-
Clean and again optionally site-selective hydrogen/metal
spite numerous attempts undertaken independently by sev-
interconversion reactions could be performed with 4-(tri-
eral collaborators, we were unable to reproduce these find-
fluoromethyl)pyridine as the substrate. Whereas both lith-
ings. A variety of other bases was examined next, but these
ium diisopropylamide (LIDA) and lithium 2,2,6,6-tetra-
also failed to produce any practically useful result. The
methylpiperidide (LITMP) abstracted protons exclusively
crude reaction mixtures, analyzed by gas chromatography
from the 3-position, thus paving the way towards the acid
after esterification with diazomethane, contained trace
`
10, Caubere’s base once more proved perfectly specific in
amounts of acid 5 at best and no isomers 6, 7, or 8 at all.
The first compound was unequivocally identified by the
comparison of its retention times with those of an authentic
sample.[14]
favor of the nitrogen-adjacent 2-position, as evidenced by
the formation of acid 9. Both acids 9 and 10 were indepen-
dently prepared from 2- and 3-iodo-4-(trifluoromethyl)pyri-
dine, respectively, by halogen/metal permutation followed
by carboxylation.
Depending on the reagent and the reaction conditions, 2-
Nucleophilic addition of the reagent to the nitrogen-ad- (trifluoromethyl)quinoline can be converted into three dif-
jacent 2-position,[15Ϫ17] a menace anyhow, appears to out- ferent quinolinecarboxylic acids by metalation and sub-
perform the competing deprotonation mode completely sequent carboxylation. LIDA as the base in tetrahydrofuran
when it is assisted by the strongly electron-withdrawing tri- promoted deprotonation at the 3-position, thus giving the
fluoromethyl group attached to the antinodal 5-position ac- acid 11 as the final product. The bulkier LITMP in THF
ross the ring. The resulting dihydropyridylmetal intermedi- concomitantly attacked the 3-position and the sterically less
ate then is rapidly destroyed by consecutive fluoride elim- hindered 4-position to afford a 3:2 mixture of acids 11 and
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Eur. J. Org. Chem. 2003, 1569Ϫ1575

Trifluoromethyl-Substituted Pyridines and Quinolines
FULL PAPER
12. When diethyl ether was used as the solvent, however,
coordination of the reagent by the nitrogen lone pair be-
came a crucial factor and the metalation was rerouted to
the 8-position. After carboxylation, the acid 13 was isolated
without any regioisomeric contamination.
and 10 and the quinolinecarboxylic acids 11, 12, 13, 14, 15,
and 18. The fact that some of these products were isolated
only in moderate yield does not matter very much, as the
unconsumed starting material can be integrally recovered at
the end of the reaction.
To identify regioisomeric by-products or to rule out their
presence, authentic samples of the acids 2؊3, 5؊8, 16, and
19 were required. Their preparation is described in the pre-
ceding publication.[14]
3-(Trifluoromethyl)quinoline offered another noteworthy
and unprecedented case of optional site selectivity. LIDA
neatly deprotonated the 4-position (giving the acid 32%),
thus exploiting the presumably higher acidity of the latter
in comparison with the 2-position.[11,21,22] Conversely,
LITMP preferred to avoid the congestion caused by the
peri-hydrogen atom and exclusively attacked the 2-position
(to produce, after carboxylation, the same carboxylic
acid 14 that could also be obtained after treatment with
Experimental Section
1. Generalities
`
Caubere’s base, although in only 12% yield).
Starting materials, if commercially available, were purchased from
Aldrich-Fluka (9479 Buchs, Switzerland), Acros Organics (2440
Geel, Belgium) and Apollo (Stockport SK6 2QR, United King-
dom) and used as such, provided that adequate checks (melting
ranges, n2D0, gas chromatography) had confirmed the claimed purity.
Solutions of butyllithium, sec-butyllithium, and tert-butyllithium
in pentanes, hexanes, or cyclohexane were supplied by Chemetall
(60487 Frankfurt, Germany) and potassium tert-butoxide by
Callery (Pittsburgh, PA 15230, USA). When known compounds
had to be prepared by literature procedures, pertinent references
are given.
Air- and moisture-sensitive materials were stored in Schlenk tubes
or Schlenk burettes. They were protected by and handled under an
atmosphere of 99.995% pure nitrogen, using appropriate glassware
(Glasgerätebau Pfeifer, 98711 Frauenfeld, Germany).
Paraffinic or aromatic hydrocarbons (hexanes, toluene) were sub-
mitted to azeotropic distillation. Diethyl ether and tetrahydrofuran
were dried by distillation over sodium wire after the characteristic
blue color of sodium diphenyl ketyl (benzophenoneϪsodium ‘‘rad-
ical anion’’) generated in situ had been observed to persist.[33Ϫ34]
4-(Trifluoromethyl)quinoline was converted solely into
the acid 18 regardless of whether LIDA or LITMP was em-
`
ployed as the base. Caubere’s base, however, once again
took advantage of the neighboring group assistance pro-
vided by the ring-incorporated nitrogen atom and oriented
the hydrogen/metal interconversion and the subsequent car-
boxylation to the 2-position (providing acid 17).
Ethereal or other organic extracts were dried by washing with brine
and then by storage over sodium sulfate. Prior to distillation, a
spatula tip of hydroquinone or potassium carbonate was added to
compounds prone to radical polymerization or sensitive to acids.
If no reduced pressure is specified, boiling ranges (b.p.) refer to
ordinary atmospheric conditions (725 Ϯ 25 Torr).
(Trifluoromethyl)pyridines[23Ϫ25] and 2-, 3-, and 4-
(trifluoromethyl)quinolines[26Ϫ32] are readily accessible.
Thus, the metalation/functionalization sequence disclosed
above currently offers the most straightforward route to the
Melting ranges (m.p.) given were found to be reproducible after
resolidification, unless stated otherwise (‘‘decomp.’’), and were cor-
trifluoromethyl-substituted pyridinecarboxylic acids 1, 4, rected by use of a calibration curve established with authentic
Eur. J. Org. Chem. 2003, 1569Ϫ1575 1571

M. Schlosser, M. Marull
FULL PAPER
standards. If melting points are absent, this means all attempts
failed to crystallize the liquid at temperatures down to Ϫ75 °C. The
temperature of dry ice/methanol baths is consistently indicated as
Ϫ75 °C and ‘‘room temperature’’ (22Ϫ26 °C) as 25 °C.
In principle, 2-chloro-6-(trifluoromethyl)pyridine and 2-chloro-4-
(trifluoromethyl)pyridine could be reduced analogously to afford
2- and 4-(trifluoromethyl)pyridine, respectively. However, the prices
of the precursors (approx. 70000 and 15000 EUR/mol) are prohibi-
tive.
Silica gel (Merck Kieselgel 60) of 70Ϫ230 mesh (0.06Ϫ0.20 mm)
particle size was used for column chromatography. The solid sup-
port was suspended in hexanes and, when all air bubbles had es-
caped, was washed into the column. When the level of the liquid
was still 3Ϫ5 cm above the support layer, the dry powder obtained
by adsorption of the crude mixture onto some 25 mL of silica and
subsequent evaporation of the solvent was poured on top of the
column.
The 2- and 4-isomers of (trifluoromethyl)quinoline can readily be
obtained by the regiocontrolled condensation and cyclization of
aniline with ethyl 4,4,4-trifluoroacetylacetate, treatment of the re-
sulting 2- or 4-quinolinone with phosphorus oxybromide and final
debromination of the obtained 2- or 4-bromo-(trifluoromethyl)quin-
oline.[31,32] The isomer bearing the trifluoromethyl group at the 3-
position has to be prepared by means either of the reaction between
3-quinolinecarboxylic acid and sulfur tetrafluoride[26] or of that be-
tween 3-bromoquinoline and trifluoroiodomethane[27] or bromotri-
fluoromethane[28] in the presence of copper powder.
Whenever possible and appropriate, yields of products were deter-
mined, prior to isolation, by gas chromatographic comparison of
their peak areas with those of known amounts of reference sub-
stances (‘‘internal standards’’) and correction of the ratios obtained
by means of separately established calibration factors. The purity
of distilled compounds was checked on at least two columns loaded
with stationary phases of contrasting polarity. Chromosorb G-AW
of 80Ϫ100 and 60Ϫ80 mesh particle size was used as the support
for packed columns for the analytical and preparative scales (2 or
3 m long, 2 mm inner diameter and 3 or 6 m long, 1 cm inner
diameter, respectively). Packed columns were made of glass, while
quartz was the material selected for capillary columns (Ͼ 10 m
long). For programmed temperature increase, a constant rate of 10
°C per minute was applied. The stationary phases employed are
encoded as DB-1, OV-17, or SE-30 (of the silicone type), DEGS or
DBS (both of the polyester type), AP-L (Apiezon-L hydrocarbon),
and C-20M, DB-WAX, or DB-FFAP (all belonging to the poly-
ethylene glycol family).
3. Trifluoromethyl-Substituted Pyridinecarboxylic Acids
2-Trifluoromethyl-3-pyridinecarboxylic Acid (1): 2,2,6,6-Tetrameth-
ylpiperidine (2.5 mL, 2.1 g, 15 mmol) and 2-(trifluoromethyl)pyri-
dine (1.7 mL, 2.2 g, 15 mmol) were consecutively added to a solution
of butyllithium (15 mmol) in tetrahydrofuran (15 mL) and hexanes
(10 mL), kept in a dry ice/methanol bath. After 6 h at Ϫ75 °C, the
mixture was poured onto an excess of freshly crushed lumps of
solid carbon dioxide. The volatiles were evaporated and the residue
was dissolved in water (50 mL). The aqueous phase was washed
with diethyl ether (2 ϫ 25 mL), acidified to pH 1 with 3.0  hydro-
chloric acid, and extracted with ethyl acetate (3 ϫ 25 mL). The
combined organic layers were dried, and the solvents were evapo-
rated to afford colorless prisms; m.p. 175Ϫ176 °C (from a mixture
1
of chloroform and methanol); yield: 2.09 g (73%). 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, 4.8 Hz, 1 H) ppm. 13C NMR*: δ ϭ 166.6, 151.6,
145.1 (qr, J ϭ 34.5 Hz), 139.1, 129.5, 127.5, 122.4 (qr, J ϭ
273.5 Hz) ppm. 19F NMR*: δ ϭ Ϫ63.7 (s) ppm. MS (c.i): m/z
(%) ϭ 192 (100) [Mϩ ϩ 1], 191 (41.7) [Mϩ], 174 (56.9), 146 (53.5),
127 (60.7), 78 (47.3), 77 (8.8). C7H4F3NO2 (191.11): calcd. C 43.99,
H 2.11; found C 44.13, H 2.23.
1H, 13C, and 19F nuclear resonance (NMR) spectra were recorded
at 400, 101, and 376 MHz, respectively, of samples dissolved in
deuteriochloroform or, if marked by an asterisk (*), in perdeu-
terioacetone. Chemical shifts δ refer to the signal of tetramethylsil-
ane (δ ϭ 0.00 ppm) and coupling constants J are given in Hz.
Coupling patterns are abbreviated as, for example, s (singlet), d
(doublet), t (triplet), qr (quartet), qn (quintet), hx (hextet), hp
(heptet), oct (octet), non (nonet), td (triplet of doublets) and m
(multiplet).
2-Trifluoromethyl-4-pyridinecarboxylic Acid (2): An analogous re-
action was performed, the only difference being that it was stopped
by carboxylation after only 15 min. After alkaline extraction and
acidification to pH 1, the products were treated with an ethereal
solution of diazomethane until persistence of the yellow color.
After addition of a know amount of nonane as internal standard,
the mixture was analyzed by gas chromatography (30 m, DB-1701,
120 °C; 30 m, DB-FFAP, 100 °C). Retention time comparison with
authentic samples[14] revealed the presence of 27% of methyl 2-tri-
fluoromethyl-3-pyridinecarboxylate and 41% of methyl 2-trifluoro-
methyl-4-pyridinecarboxylate.
A few of the mass spectra could be obtained by electron impact
fragmentation at 70 eV ionization potential and 200 °C source tem-
perature. In general, however, no molecular peak was observed un-
der such standard conditions, so chemical ionization (‘‘c.i.’’) in an
ammonia atmosphere at a potential of 95 eV and a source tempera-
ture of 100 °C was routinely applied.
Elementary analyses were performed by the laboratory of I. Beetz
(96301 Kronach, Germany). The expected percentages were calcu-
lated by use of the atomic weight numbers listed in the 1999
IUPAC recommendations.
6-Trifluoromethyl-3-pyridinecarboxylic Acid (3): An analogous re-
action was performed on a fivefold smaller scale (3.0 mmol), the
only other difference being that the solvent mixture of tetrahydro-
furan and hexanes was replaced by diethyl ether (3.0 mL) and hex-
anes (2.0 mL). After alkaline extraction and acidification to pH 1,
2. Starting Materials
All three (trifluoromethyl)pyridines have been made by fluorinative
deoxygenation of the respective pyridinecarboxylic acids with sul- the products were treated with an ethereal solution of diazometh-
fur tetrafluoride[23] and by halogen displacement with trifluorometh- ane until persistence of the yellow color. After addition of a known
ylcopper generated in situ.[25,27,28] The latter method has the advan-
tage of not requiring special pressure equipment and gives high
yields, at least in the case of the 2-isomer. 3-(Trifluoromethyl)pyri-
dine is commercially available, though expensive (approx. 2200 EUR/
mol). It can be advantageously prepared by catalytic hydrogenolysis
of 2-chloro-5-(trifluoromethyl)pyridine[14] (approx. 100 EUR/mol).
amount of nonane as an internal standard, the mixture was ana-
lyzed by gas chromatography (30 m, DB-1701, 120 °C; 30 m, DB-
FFAP, 100 °C). Retention time comparison with authentic
samples[14] showed the presence of 18% of methyl 6-trifluoro-
methyl-3-pyridinecarboxylate and 23% of methyl 6-trifluoromethyl-
2-pyridinecarboxylate.
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Eur. J. Org. Chem. 2003, 1569Ϫ1575

Trifluoromethyl-Substituted Pyridines and Quinolines
FULL PAPER
6-Trifluoromethyl-2-pyridinecarboxylic Acid (4): 2-(Dimethyl-
amino)ethanol (6.5 mL, 5.4 g, 60 mmol) and 2-(trifluoro- a few days even if stored in the dark. H NMR: δ ϭ 8.65 (s, 1 H),
to afford a colorless liquid, which became yellow and brown after
1
methyl)pyridine (1.7 mL, 2.2 g, 15 mmol) were added consecutively
to a solution of butyllithium (120 mmol) in diethyl ether (50 mL)
and hexanes (75 mL), kept in a dry ice/methanol bath. After 2 h at
Ϫ75 °C, the mixture was poured onto an excess of freshly crushed
lumps of solid carbon dioxide and worked up as described above
(see acid 1). The product was collected as colorless needles; m.p.
156Ϫ157 °C (from a mixture of chloroform and hexanes); yield:
7.75 (dm, J ϭ 8.3 Hz, 1 H), 7.25 (d, J ϭ 8.1 Hz, 1 H), 6.69 (t, J ϭ
55.9 Hz, 1 H), 2.85 (dd, J ϭ 7.8, 7.5 Hz, 2 H), 1.7 (m, 2 H), 1.40
(hx, J ϭ 7.5 Hz, 2 H), 0.95 (t, J ϭ 7.5 Hz, 3 H) ppm. 13C NMR:
δ ϭ 165.3, 146.5, 133.5, 127.4 (t, J ϭ 24 Hz), 122.6, 113.6 (t, J ϭ
239 Hz), 38.0, 31.9, 22.5, 14.0 ppm. 19F NMR: Ϫ111.9 (d, J ϭ
56 Hz) ppm. MS (c.i.): m/z (%) ϭ 203 (2) [Mϩ ϩ NH4], 186 (72)
[Mϩ ϩ 1], 185 (7) [Mϩ], 161 (24), 143 (100), 124 (47). C10H13F2N
2.03 g (71%). 1H NMR*: δ ϭ 8.36 (m, 2 H), 8.13 (dd, J ϭ 7.6, (185.22): calcd. C 64.85, H 7.07; found C 64.05, H 7.22.
1.2 Hz, 1 H) ppm. 13C NMR*: δ ϭ 166.0, 150.4, 149.0 (qr, J ϭ
4-Trifluoromethyl-2-pyridinecarboxylic Acid (9): 4-(Trifluorometh-
35 Hz), 141.8, 129.3, 125.8, 122.8 (qr, J ϭ 275 Hz) ppm. 19F NMR*
yl)pyridine (1.7 mL, 2.2 g, 15 mmol) was treated with butyllithium
: δ ϭ Ϫ67.1 (s) ppm. MS (c.i.): m/z (%) ϭ 192 (100) [Mϩ ϩ 1], 191
(60 mmol) in the presence of lithium 2-(dimethylamino)ethoxide
(4) [Mϩ], 174 (33.2), 146 (8), 127 (6). C7H4F3NO2 (191.11): calcd.
(60 mmol) as described above (see acid 3). The product was isolated
C 43.99, H 2.11; found C 44.07, H 2.23.
in the same way; colorless prisms (from chloroform); m.p. 156Ϫ158
°C; yield: 1.18 g (41%). 1H NMR: δ ϭ 9.82 (br. s, 1 H), 9.05 (d,
2-Trimethylsilyl-3-(trifluoromethyl)pyridine:
2,2,6,6-Tetrameth-
J ϭ 5.0 Hz, 1 H), 8.51 (s, 1 H), 7.89 (d, J ϭ 5.0 Hz, 1 H) ppm. 13
C
ylpiperidine (2.8 g, 3.4 mL, 20 mmol), potassium tert-butoxide
(2.2 g, 20 mmol) and N,N,NЈ,NЈЈ,NЈЈ-pentamethyldiethylenetri-
amine (4.2 mL, 3.5 g, 20 mmol), chlorotrimethylsilane (2.5 mL, 2.1 g,
20 mmol), and (trifluoromethyl)pyridine (2.2 mL, 2.9 g, 20 mmol)
were added consecutively at Ϫ100 °C to butyllithium (20 mmol) in
tetrahydrofuran (20 mL) and hexanes (13 mL). After the mixture
had been kept for 6 h at Ϫ100 °C, methanol (2.0 mL, 1.6 g,
50 mmol) was injected. Trimethyl-2-[3-(trifluoromethyl)pyridyl]si-
lane (30%) was detected and quantified by gas chromatographic
analysis (30 m, DB-1701, 30 °C [5 min] Ǟ 110 °C; 30 m, DB-FFAP,
50 °C [5 min] Ǟ 100 °C; nonane as an internal standard). The bulk
of the solution was evaporated and concentrated, and the crude
residue was purified by preparative gas chromatography (5 m, 2%
NMR: δ ϭ 165.0, 150.4, 149.5, 139.7 (qr, J ϭ 35 Hz), 122.4 (qr,
J ϭ 3 Hz), 122.2 (qr, J ϭ 273 Hz), 121.0 (qr, J ϭ 3 Hz) ppm. 19F
NMR: Ϫ65.3 (s) ppm. MS (c.i.): m/z (%) ϭ 192 (73) [Mϩ ϩ 1],
191 (12) [Mϩ], 174 (37), 147 (100), 127 (19). C7H4F3NO2 (191.11):
calcd. C 43.99, H 2.11; found C 43.71, H 1.99.
4-Trifluoromethyl-2-pyridinecarboxylic acid (9) was also prepared
by addition, at Ϫ75 °C, of 2-iodo-4-(trifluoromethyl)pyridine
(1.2 mL, 2.7 g, 10 mmol; see below) to butyllithium (10 mmol) in
tetrahydrofuran (14 mL) and hexanes (6.0 mL), pouring the mix-
ture onto freshly crushed dry ice after 2 min and working it up as
described (see the preparation of acid 1); m.p. 156Ϫ158 °C; yield:
1.47 g (77%).
C-20M, 150 °C); colorless liquid; b.p. 54Ϫ55 °C/11 Torr; n2D0
ϭ
1.6385. 1H NMR: δ ϭ 8.99 (d, J ϭ 4.6 Hz, 1 H), 7.49 (d, J ϭ
8.1 Hz, 1 H), 7.31 (dd, J ϭ 8.1, 4.8 Hz, 1 H), 0.38 (s, 9 H) ppm.
13C NMR: δ ϭ 167.5, 151.5, 131.8 (m, 2 C), 124.5 (qr, J ϭ 273 Hz),
121.7, 0.4 (3 C) ppm. 19F NMR: Ϫ59.1 (s) ppm. MS (c.i.): m/z
(%) ϭ 220 (24) [Mϩ ϩ 1], 219 (42) [Mϩ], 168 (81), 104 (53), 77
(100). C9H12F3NSi (219.28): calcd. C 49.30, H 5.52; found C 49.20,
H 5.44.
2-Iodo-4-(trifluoromethyl)pyridine: Diisopropylamine (4.3 mL,
3.0 g, 30 mmol) and 3-iodo-4-(trifluoromethyl)pyridine (3.7 mL,
8.2 g, 30 mmol; see below) were added consecutively to a solution
of butyllithium (30 mmol) in tetrahydrofuran (40 mL) and hexanes
(20 mL), kept in a methanol/dry ice bath. After 2 h at Ϫ75 °C, the
mixture was neutralized with hydrochloric acid (2.0 , 30 mL).
Steam distillation followed by distillation under reduced pressure
afforded a colorless liquid; m.p. Ϫ10 to Ϫ8 °C; b.p. 35Ϫ37 °C/
6 Torr; n2D0 ϭ 1.5325; yield: 2.5 g (44%). 1H NMR: δ ϭ 8.57 (d, J ϭ
5.1 Hz, 1 H), 7.96 (s, 1 H), 7.61 (d, J ϭ 5.1 Hz, 1 H) ppm. 13C
NMR: δ ϭ 151.6, 139.5 (qr, J ϭ 34 Hz), 130.7 (qr, J ϭ 3 Hz), 121.6
(qr, J ϭ 273 Hz), 118.5 (qr, J ϭ 3 Hz), 118.0 ppm. 19F NMR: Ϫ65.5
(s) ppm. MS (c.i.): m/z (%) ϭ 291 (100) [Mϩ ϩ NH4], 274 (44) [Mϩ
ϩ 1], 273 (6) [Mϩ], 247 (7), 116 (53), 99 (60), 75 (100). C6H3F3IN
(272.99): calcd. C 26.40, H 1.11, N 5.13; found C 26.32, H 1.10,
N 5.12.
3-Trifluoromethyl-2-pyridinecarboxylic Acid (5): Diisopropylamine
(0.42 mL, 0.30 g, 3.0 mmol) and 3-(trifluoromethyl)pyridine
(0.34 mL, 0.44 g, 3.0 mmol) were added consecutively to a solution
of butyllithium (3.0 mmol) in tetrahydrofuran (13 mL) and hexanes
(2.0 mL), kept in a methanol/dry ice bath. After 2 h at Ϫ75 °C, the
mixture was poured onto an excess of freshly crushed lumps of
solid carbon dioxide. The product was extracted and esterified as
described above (see acid 3). The presence of 1.5% of methyl 3-
trifluoro-2-pyridinecarboxylate was detected by gas chromato-
graphic analysis (30 m, DB-1701, 30 °C [5 min] Ǟ 110 °C; 30 m,
DB-FFAP, 50 °C [5 min] Ǟ 100 °C) in comparison with authentic
samples[14] of the methyl esters of all possible acids 5؊8 and
nonane as an internal standard for quantification.
3-Iodo-4-(trifluoromethyl)pyridine:
2,2,6,6-Tetramethylpiperidine
(8.5 mL, 7.1 g, 50 mmol) and 4-(trifluoromethyl)pyridine (5.7 mL,
7.4 g, 50 mmol) were added consecutively to butyllithium
(50 mmol) in tetrahydrofuran (70 mL) and hexanes (30 mL), cooled
in a methanol/dry ice bath. After the mixture had been kept at Ϫ75
°C for 2 h, iodine (25 g, 0.10 mol) was added with vigorous stirring.
2-Butyl-5-(difluoromethyl)pyridine:
3-(Trifluoromethyl)pyridine
(2.9 g, 2.2 mL, 20 mmol) was added to a solution of butyllithium The solvents were evaporated and the residue, in the presence of
(40 mmol) in diethyl ether (50 mL) and hexanes (26 mL), kept in a
methanol dry ice bath. After 2 h at Ϫ75 °C, the mixture was poured
onto an excess of freshly crushed lumps of solid carbon dioxide.
The mixture was neutralized with hydrochloric acid (2.0 , 20 mL)
and the product was extracted with diethyl ether (3 ϫ 20 mL). The
presence of 14% of 2-butyl-5-(difluoromethyl)pyridine was detected
sodium thiosulfate (10 g, 63 mmol), was subjected to steam distil-
lation followed by distillation under reduced pressure to give a col-
orless liquid; m.p. Ϫ5 to Ϫ3 °C; b.p. 41Ϫ43 °C/5 Torr; n2D0
ϭ
1
1.5415; yield: 10.8 g (79%). H NMR: δ ϭ 9.14 (s, 1 H), 8.69 (d,
J ϭ 5.1 Hz, 1 H), 7.55 (d, J ϭ 5.1 Hz, 1 H) ppm. 13C NMR: δ ϭ
160.0, 149.4, 140.4 (qr, J ϭ 33 Hz), 121.5 (qr, J ϭ 6 Hz), 121.4 (qr,
by gas chromatographic analysis (30 m, DB-1701, 30 °C [5 min] Ǟ J ϭ 275 Hz), 89.8 ppm. 19F NMR: Ϫ65.8 (s) ppm. MS (c.i.): m/z
110 °C; 30 m, DB-FFAP, 50 °C [5 min] Ǟ 100 °C). The remaining (%) ϭ 291 (100) [Mϩ ϩ NH4], 274 (11) [Mϩ ϩ 1], 273 (2) [Mϩ],
ethereal solution was evaporated, and the crude material was puri-
fied by preparative gas chromatography (5 m, 5% SE-30, 140 °C)
225 (9), 116 (14). C6H3F3IN (272.99): calcd. C 26.40, H 1.11, N
5.13; found C 26.31, H 1.07, N 5.12.
Eur. J. Org. Chem. 2003, 1569Ϫ1575
1573

M. Schlosser, M. Marull
FULL PAPER
4-Trifluoromethyl-3-pyridinecarboxylic Acid (10): When lithium
2,2,6,6-tetramethylpiperidide (15 mmol) was employed in tetra-
(qr, J ϭ 276 Hz), 117.8 ppm. 19F NMR: Ϫ68.0 (s) ppm. MS (c.i.):
m/z (%) ϭ 214 (100) [Mϩ ϩ 1], 213 (89) [Mϩ], 185 (13), 165 (19),
hydrofuran (15 mL) and hexanes (10 mL) as described above (see 144 (17). C11H6F3NO2 (241.17): calcd. C 54.78, H 2.51; found C
acid 1), 4-(trifluoromethyl)pyridine (1.7 mL, 2.2 g, 15 mmol) gave
an isomeric product; m.p. 146Ϫ147 °C (from chloroform and meth-
anol); yield: 2.41 g (84%). 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 (qr, J ϭ 35 Hz), 126.8, 128.4 (qr, J ϭ
275 Hz), 121.3 (qr, J ϭ 5 Hz) ppm. 19F NMR*: δ ϭ Ϫ61.2 (s) ppm.
MS (c.i.): m/z (%) ϭ 192 (100) [Mϩ ϩ 1], 191 (43.6) [Mϩ], 174
(49.5), 146 (79.4), 127 (28), 99 (20.7). C7H4F3NO2 (191.11): calcd.
C 43.99, H 2.11; found C 44.12, H 2.30. The yield was decreased
slightly (to 80%) when lithium 2,2,6,6-tetramethylpiperidide was re-
placed by lithium diisopropylamide in tetrahydrofuran. The acid
10 was independently prepared by addition, at Ϫ75 °C, of 3-iodo-
4-(trifluoromethyl)pyridine (1.2 mL, 2.7 g, 10 mmol; see above) to
butyllithium (10 mmol) in tetrahydrofuran (14 mL) and hexanes
(6.0 mL), the mixture being poured onto freshly crushed dry ice
after 2 min and worked up as described (see acid 1); m.p. 146Ϫ147
°C; yield: 1.55 g (81%).
55.16, H 2.18.
3-Trifluoromethyl-2-quinolinecarboxylic Acid (14): 2,2,6,6-Tetra-
methylpiperidine (2.5 mL, 2.1 g, 15 mmol) and 3-(trifluorometh-
yl)quinoline (3.0 g, 15 mmol) were added consecutively to a solu-
tion of butyllithium (15 mmol) in tetrahydrofuran (15 mL) and hex-
anes (10 mL), kept in a dry ice/methanol bath. After the mixture
had been kept at Ϫ75 °C for 2 h, the usual carboxylation and
workup procedure (see Section 2, acid 1) gave the product as color-
less prisms; m.p. 125Ϫ127 °C (from chloroform); yield: 1.48 g
(41%). 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 (qr, J ϭ 6 Hz), 133.5, 130.6, 129.3, 128.5, 128.0, 122.8 (qr,
J ϭ 35 Hz), 122.6 (qr, J ϭ 272 Hz) ppm. 19F NMR: Ϫ60.4 (s) ppm.
MS (c.i.): m/z (%) ϭ 242 (31) [Mϩ ϩ 1], 241 (3) [Mϩ], 197 (100),
176 (14), 147 (3). C11H6F3NO2 (241.17): calcd. C 54.78, H 2.51, N
5.81; found C 54.63, H 2.41, N 5.77.
4. Trifluoromethyl-Substituted Quinolinecarboxylic Acids
3-Trifluoromethyl-4-quinolinecarboxylic Acid (15): When exactly the
same reaction as described in the preceding paragraph was conduc-
ted with lithium diisopropylamide (15 mmol), a different re-
gioisomer was obtained; colorless prisms; m.p. 259Ϫ261 °C (dec.;
from chloroform); yield: 1.16 g (32%). 1H NMR*: δ ϭ 9.24 (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,
130.6, 127.6, 125.4 (qr, J ϭ 273 Hz), 123.8, 119.1 (qr, J ϭ 32 Hz)
ppm. 19F NMR*: δ ϭ Ϫ58.3 (s) ppm. MS (c.i.): m/z (%) ϭ 242
(94) [Mϩ ϩ 1], 241 (100) [Mϩ], 224 (10), 197 (57), 185 (16).
C11H6F3NO2 (241.17): calcd. C 54.78, H 2.51, N 5.81; found C
54.73, H 2.48, N 5.92.
2-Trifluoromethyl-3-quinolinecarboxylic Acid (11): Diisopropyl-
amine (2.1 mL, 1.5 g, 15 mmol) and 2-(trifluoromethyl)quinoline
(3.0 g, 15 mmol) were consecutively added to a solution of butyl-
lithium (15 mmol) in tetrahydrofuran (65 mL) and hexanes
(10 mL), kept in a dry ice/methanol bath. After 2 h at Ϫ75 °C, the
mixture was poured onto an excess of freshly crushed lumps of
solid carbon dioxide and extracted as described above (see acid 1).
The product was collected as colorless prisms; m.p. 207Ϫ209 °C
(reprod.; from chloroform); yield: 1.12 g (31%). 1H 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 Hz), 142.2, 134.5, 131.5 (2 C), 130.5, 128.5, 126.0, 123.2 (qr, J ϭ
275 Hz) ppm. 19F NMR*: Ϫ63.5 (s) ppm. MS (c.i.): m/z (%) ϭ
214 (100) [Mϩ ϩ 1], 213 (89) [Mϩ], 185 (13), 165 (19), 144 (17).
C11H6F3NO2 (241.17): calcd. C 54.78, H 2.51; found C 54.78, H
2.99.
4-Trifluoromethyl-2-quinolinecarboxylic Acid (17): 4-(Trifluoro-
methyl)quinoline (3.0 g, 15 mmol) was treated with butyllithium
(60 mmol) in the presence of lithium 2-(dimethylamino)ethoxide
(60 mmol) as described in the preceding Section (see acid 3). After
carboxylation, the product was isolated by extraction, neutrali-
zation, and crystallization; colorless prisms; m.p. 142Ϫ143 °C (from
chloroform and methanol); yield: 1.30 g (36%). 1H NMR*: δ ϭ
8.47 (s, 1 H), 8.37 (ddd, J ϭ 8.4, 1.4, 0.7 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
(qr, J ϭ 35 Hz), 132.5, 131.8 (2 C), 124.7, 124.5 (qr, J ϭ 274 Hz),
118.3 ppm. 19F NMR*: δ ϭ Ϫ69.0 (s) ppm. MS (c.i.): m/z (%) ϭ
242 (23) [Mϩ ϩ 1], 241 (22) [Mϩ], 197 (100), 176 (16) 147 (4), 128
(12). C11H6F3NO2 (241.17): calcd. C 54.78, H 2.51, found C 54.52,
H 2.48.
2-Trifluoromethyl-4-quinolinecarboxylic Acid (12): When lithium di-
isopropylamide was replaced by lithium 2,2,6,6-tetramethylpiperi-
dide (from 2,2,6,6-tetramethylpiperidine, 2.5 mL, 2.1 g, 15 mmol)
under otherwise identical conditions, a mixture of products was
obtained. After alkaline extraction, acidification, and exhaustive
esterification with diazomethane, methyl 2-trifluoromethyl-3-
quinolinecarboxylate (ester of 11; 54%) and methyl 2-trifluoro-
methyl-4-quinolinecarboxylate (ester of 12; 5%) were identified by
gas chromatography (30 m, DB-1701, 180 °C; 30 m, DB-FFAP,
200 °C) with the use of authentic samples[14] for retention time
comparison and an internal standard for quantification.
4-Trifluoromethyl-3-quinolinecarboxylic Acid (18): When 4-(trifluo-
romethyl)quinoline (3.0 g, 15 mmol) was treated with lithium
2,2,6,6-tetramethylpiperidide (15 mmol) in tetrahydrofuran
(15 mL) and hexanes (10 mL) for 2 h at Ϫ75 °C and then with
carbon dioxide, a regioisomerically pure product was isolated in the
The same reaction carried out at 0.50  concentration (20 mL rather
than 65 mL of tetrahydrofuran, still 10 mL of hexanes) afforded the
esters derived from 11 and 12 in 43% and 27% yield, respectively.
2-Trifluoromethyl-8-quinolinecarboxylic Acid (13): When 2-(trifluo-
romethyl)quinoline (3.0 g, 15 mmol) was treated at Ϫ75 °C with usual way (see Section 2, acid 1); colorless prisms; m.p. 210Ϫ212 °C
two equivalents of lithium 2,2,6,6-tetramethylpiperidide (30 mmol)
in diethyl ether (55 mL) and hexanes (20 mL) for 6 h, subsequent
carboxylation afforded a regioisomerically pure product as tiny col-
orless needles; m.p. 177Ϫ178 °C (from chloroform); yield: 0.72 g
(reprod.; from chloroform); yield: 2.75 g (76%). 1H NMR*: δ ϭ
9.14 (s, 1 H), 8.27 (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 (2 C),
(20%). 1H NMR: δ ϭ 8.94 (dd, J ϭ 7.3, 1.4 Hz, 1 H), 8.69 (d, J ϭ 130.4, 127.3, 125.4 (qr, J ϭ 3 Hz), 124.6 (qr, J ϭ 276 Hz),
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, 122.7 ppm. 19F NMR*: δ ϭ Ϫ57.0 (s) ppm. MS (c.i.): m/z (%) ϭ
1 H), 7.93 (t, J ϭ 7.5 Hz, 1 H) ppm. 13C NMR: δ ϭ 165.8, 147.0 242 (100) [Mϩ ϩ 1], 241 (17) [Mϩ], 224 (9). C11H6F3NO2 (241.17):
(qr, J ϭ 36 Hz), 144.1, 141.1, 137.3, 133.1, 129.4 (2 C), 125.5, 119.5
calcd. C 54.78, H 2.51, N 5.81; found C 54.81, H 2.45, N 5.76.
1574
Eur. J. Org. Chem. 2003, 1569Ϫ1575

Trifluoromethyl-Substituted Pyridines and Quinolines
FULL PAPER
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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-
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[O02552]
Eur. J. Org. Chem. 2003, 1569Ϫ1575
1575