Three chloro(trifluoromethyl)pyridines as model substrates for regioexhaustive functionalization

Article abstract of DOI:10.1002/ejoc.200400066

As a further test of the concept of regioexhaustive functionalization, 2-chloro-6-(trifluoromethyl)pyridine, 2-chloro-5-(trifluoromethyl)pyridine and 3-chloro-4-(trifluoromethyl)-pyridine were each converted into the three possible carboxylic acids 2, 4, 6, 8, 10, 12, 16, 17 and 20. This was achieved by employing several, but not all of the organometallic "tool-box methods": transformation of a more basic organometallic species into a less basic isomer by transmetalation-equilibration, site discriminating deprotonation with lithium N,N-diisopropylamide or lithium 2,2,6,6- tetramethylpiperidide, regio-divergent iodine migration and steric screening of acidic positions by a bulky trialkylsilyl group. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400066

FULL PAPER
Three Chloro(trifluoromethyl)pyridines as Model Substrates for
Regioexhaustive Functionalization
Fabrice Cottet[a] and Manfred Schlosser*[a,b]
Keywords: Carboxylation / Halogen-metal permutation / Metalation / Iodine migration / Pyridines
As a further test of the concept of regioexhaustive func-
species into a less basic isomer by transmetalation-equilibra-
tionalization, 2-chloro-6-(trifluoromethyl)pyridine, 2-chloro- tion, site discriminating deprotonation with lithium N,N-di-
5-(trifluoromethyl)pyridine and 3-chloro-4-(trifluoromethyl)-
pyridine were each converted into the three possible carb-
oxylic acids 2, 4, 6, 8, 10, 12, 16, 17 and 20. This was achieved
by employing several, but not all of the organometallic ‘‘tool-
box methods’’: transformation of a more basic organometallic
isopropylamide or lithium 2,2,6,6-tetramethylpiperidide, re-
gio-divergent iodine migration and steric screening of acidic
positions by a bulky trialkylsilyl group.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
whether the metalation, whatever the reagent, could be di-
rected at all in the vicinity of the trifluoromethyl group.
The three model substrates selected carry the CF3 sub-
stituent at a different ring position: 2-chloro-6-(trifluoro-
methyl)pyridine, 2-chloro-5-(trifluoromethyl)pyridine and
3-chloro-4-(trifluoromethyl)pyridine. All three are commer-
cial reagents, but only 2-chloro-5-(trifluoromethyl)pyridine
is inexpensive (about 100 EUR/mol). Thus, we prepared the
other two by applying the iodine/trifluoromethyl[19] dis-
placement method.
[1]
The concept of ‘‘regioexhaustive substitution’’
has
been devised to optimally exploit the derivatization poten-
tial of a given core structure. The practical realization relies
on a set of complementary organometallic methods (the
‘‘toolbox methods’’ [1]) which enables the site-specific intro-
duction of an alkali or alkaline earth metal in any vacant
position of the substrate. The choice of suitable electrophilic
trapping reagents is almost unlimited, and hence, a single
organometallic intermediate can be proliferated into hun-
dreds of new compounds.
The concept of regioexhaustive substitution and the tool-
box methods have so far been tested with 1,3-difluoroben-
zene,[2] 1,3-dichlorobenzene,[3] a series of di- and trifluoro-
phenols,[4] 6- and 7-fluoroquinolines,[5] 4-, 5-, 6- and 7-
fluoroindoles,[6] and 3-fluoropyridine.[1,7] The reason to ex-
tend such kind of investigations to chloro(trifluoromethyl)-
pyridines was twofold. In this way, a variety of halogenated
pyridinecarboxylic acids and other attractive building
blocks, all unknown prior to our preliminary work in this
field,[8] would become easily available. On the other hand,
success was by no means guaranteed. (Trifluoromethyl)ar-
enes tend to deviate the attack of a strong base from an
Carboxylic Acids Derived From 2-Chloro-6-(trifluoromethyl)-
pyridine
As reported,[20] 2-chloro-6-(trifluoromethyl)pyridine was
adjacent to a more remote position.[9,10] Apparently, the
[11Ϫ17]
bulkiness
of the substituent offsets its powerful in-
ductive electron-withdrawing effect. As a chlorine atom can
also act as a strong ortho-activator,[18] we were not sure deprotonated by lithium diisopropylamide (LIDA) con-
comitantly at the 3- and 4-positions. However, after the re-
action mixture had been stored for 4 h at Ϫ85 °C, the more
[a]
´
Institut de Chimie moleculaire et biologique,
basic 4-lithio species was found to have been completely
converted into the less basic 3-lithio isomer. Upon trapping
with iodine, only 2-chloro-3-iodo-6-(trifluoromethyl)pyrid-
ine (1; 69%) was obtained.[20]
´ ´
Ecole Polytechnique Federale, BCh,
1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
[b]
´
´
Faculte des Sciences, Universite, BCh,
1015 Lausanne, Switzerland
Eur. J. Org. Chem. 2004, 3793Ϫ3798
DOI: 10.1002/ejoc.200400066
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F. Cottet, M. Schlosser
FULL PAPER
(2; 79%). When the 2-chloro-6-(trifluoromethyl)pyrid-3-yl-
lithium was trapped with chlorotrimethylsilane rather than
with dry ice, 2-chloro-6-trifluoromethyl-3-(trimethyl-
silyl)pyridine (3) was isolated in 85% yield.[20] Its consecu-
tive treatment with lithium 2,2,6,6-tetramethylpiperidide
(LITMP), carbon dioxide and tetrabutylammonium fluor-
ide trihydrate gave the 6-chloro-2-(trifluoromethyl)pyridine-
3-carboxylic acid (4; 70%). The compound 2-chloro-3-iodo-
6-(trifluoromethyl)pyridine (1) was cleanly converted by
[11,20Ϫ22]
LIDA-promoted heavy halogen migration
into its
4-iodo isomer 5 (83%). Halogen/metal permutation, car-
boxylation and neutralization provided the 2-chloro-6-(tri-
fluoromethyl)pyridine-4-carboxylic acid (6; 74%).
Carboxylic Acids Derived From 2-Chloro-5-(trifluoro-
methyl)pyridine
Carefully controlled conditions were required to prepare
2-chloro-4-iodo-5-(trifluoromethyl)pyridine (7; 67%) from
Equilibration of the organometallic intermediates at Ϫ85
°C followed by carboxylation and neutralization provided
the 2-chloro-6-(trifluoromethyl)pyridine-3-carboxylic acid
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Three Chloro(trifluoromethyl)pyridines as Model Substrates for Regioexhaustive Functionalization
FULL PAPER
2-chloro-5-(trifluoromethyl)pyridine by treatment with 60Ϫ70% yield. Obviously, the initially generated lithium 2-
LIDA in the presence of lithium N,N-diisopropylcarbamate chloro-5-(trifluoromethyl)pyridine-4-carboxylate rapidly
(LIDCB) and catalytic amounts of lithium bromide, and underwent a new ortho-lithiation,[27,28] thus paving the way
subsequent addition of molecular iodine. The iodo com- to the vic-diacid.
pound 7 became the turntable leading to the three car-
boxylic acids 8, 10 and 12. Immediate halogen/metal per-
mutation followed by carboxylation and neutralization pro-
duced the 2-chloro-5-(trifluoromethyl)pyridine-4-carboxylic
acid (8; 87%). Treatment with LIDA and subsequent neu-
tralization gave 6-chloro-2-iodo-3-(trifluoromethyl)pyridine
(9; 77%), the conversion of which into 6-chloro-3-(trifluoro-
methyl)pyridine-2-carboxylic acid (10; 87%) proved to be
straightforward. Finally, when lithium piperidide (LIPIP)
was used to promote the isomerization of the 4-iodo com-
pound 7, 2-chloro-3-iodo-6-(trifluoromethyl)pyridine (11;
46%) was obtained as a pure isomer. With this intermediate
at hand, 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic
acid (12; 65%) was prepared without problems.
Carboxylic Acids Derived From 3-Chloro-4-(trifluoro-
methyl)pyridine
The dichotomy in the outcome of the iodopyridine 7 iso-
merization, depending on whether mediated by LIDA or
LIPIP, can be rationalized on the basis of the different steric
hindrance experienced by these reagents and the differences
in their basicities, and hence, proton abstraction capaci-
ties.[25] Lithium N,N-diisopropylcarbamate appears to com-
bine with LIDA, and the resulting adduct discriminates 4:1
in favor of deprotonation of the 4- rather than of the 3-
position, whereas in its absence both sites are randomly at-
tacked. In contrast, the role of lithium bromide still remains
quite mysterious. The action of lithium bromide must be
catalytic as less than stoichiometric amounts of it are used.
For example, it may assist in the reorganization of the in-
volved aggregates or mixed aggregates.
The reactions involving the third substrate 3-chloro-4-(tri-
fluoro-methyl)pyridine proceeded as expected. Both LIDA
or LITMP abstracted a proton rapidly and exclusively from
the 2-position. In this way, it was possible to access the
silane 15 (74%) and 3-chloro-4-(trifluoromethyl)pyridine-2-
carboxylic acid (16; 57%) directly. LITMP-promoted metal-
ation of the silane 15 and the subsequent carboxylation oc-
curred at the 5-position, providing the 5-chloro-4-(trifluoro-
methyl)pyridine-3-carboxylic acid (17; 83%) after deprotec-
tion of its silylated precursor. Trapping of the lithiated sil-
ane 15 with molecular iodine gave 3-chloro-5-iodo-4-
As this example illustrates, clean metalation reactions of
pyridines bearing trifluoromethyl groups at the 3- (or 5-)
position can be brought about with difficulty, if at all. The
major obstacle is presumably their extraordinary tendency
towards nucleophilic addition of organometallic reagents
and intermediates.[26] Indeed, a considerable quantity (32%)
of the dimer 13 (M ϭ H, after neutralization) was formed
when only half of the standard amount of base was used
under otherwise optimized conditions.
Another complication encountered with 2-chloro-5-(tri-
fluoromethyl)pyridine was the in situ transformation of a
primary reaction product. When carbon dioxide was added
slowly to a solution containing the substrate together with
three equivalents of LIDA and some sodium bromide, the
diacid 14 (M ϭ H after neutralization) was produced in a
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F. Cottet, M. Schlosser
FULL PAPER
poured onto an excess of freshly crushed dry ice before being
treated at ϩ25 °C with 2.0  hydrochloric acid (50 mL). The vol-
atiles were evaporated and the residue crystallized from a 6:1 (v/v)
mixture of hexanes and ethyl acetate as colorless needles. M.p.
106Ϫ108 °C; yield: 3.56 g (79%). 1H NMR*: δ ϭ 8.59 (dq, J ϭ
7.7, 0.7 Hz, 1 H), 8.03 (d, J ϭ 8.0 Hz, 1 H) ppm. 13C NMR*: δ ϭ
164.9, 150.3, 149.6 (q, J ϭ 35 Hz), 143.4, 131.9, 121.5 (q, J ϭ
274 Hz), 120.8 (q, J ϭ 3 Hz) ppm. C7H3ClF3NO2 (225.55): calcd.
C 37.28, H 1.34; found C 37.15, H 1.54.
trifluoromethyl-5-(trimethylsilyl)pyridine (18; 85%), which
was isomerized to the 6-iodo isomer 19 (62%) by treatment
with LITMP and subsequent neutralization. Compound 19
was converted into the 5-chloro-4-(trifluoromethyl)pyrid-
ine-2-carboxylic acid (20, 75%) by consecutive halogen/
metal permutation (using butyllithium), carboxylation and
protodesilylation.
6-Chloro-2-(trifluoromethyl)pyridine-3-carboxylic Acid (4): 2-
Experimental Section
Chloro-6-trifluoromethyl-3-(trimethylsilyl)pyridine[20]
(5.4 g,
25 mmol) was added to a solution prepared from butyllithium
(25 mmol) and 2,2,6,6-tetramethylpiperidine (4.2 mL, 3.5 g,
25 mmol) in tetrahydrofuran (50 mL) and hexane (16 mL) cooled
in a dry ice/methanol bath. After 45 min at Ϫ75 °C, the reaction
mixture was poured onto an excess of freshly crushed dry ice co-
vered with tetrahydrofuran (25 mL). The solvents were evaporated
and the residue partitioned between diethyl ether (75 mL) and 6.0
 hydrochloric acid (20 mL). The organic layer was dried and the
solvents evaporated. The residue was treated with tetrabutyl-
ammonium fluoride trihydrate (7.9 g, 25 mmol) in tetrahydrofuran
(50 mL) for 20 h at 25 °C. The solvents were evaporated, and the
residue taken back into diethyl ether (100 mL) and washed with
2.0  hydrochloric acid (2 ϫ 50 mL). The organic phase was dried,
evaporated and the residue crystallized from chloroform as color-
General Remarks: Working practices and abbreviations are speci-
fied in previous articles from this laboratory.[29Ϫ31] 1H and (1H-
decoupled) 13C NMR spectra were recorded at 400 and 101 MHz,
respectively, relative to the internal standard tetramethylsilane
(chemical shift δ ϭ 0.00 ppm). The samples were dissolved in deu-
teriochloroform or, if marked by an asterisk, in hexadeuterioace-
tone.
1. Starting Materials
The preparation of 2-chloro-6-(trifluoromethyl)pyridine has been
described recently.[19] 2-Chloro-5-(trifluoromethyl)pyridine was
purchased from Apollo (Whitefield Rd, Bredbury, Stockport,
Cheshire, SK6 2QR). 2-Chloro-3-iodopyridine (1),[20] 2-chloro-3-
(trimethylsilyl)pyridine (3),[20] 2-chloro-4-iodo-6-(trifluoromethyl)-
pyridine (5)[20] and 3-chloro-4-iodopyridine[32] were prepared fol-
lowing literature procedures.
1
less needles. M.p. 160Ϫ162 °C; 3.8 g (70%). H NMR*: δ ϭ 8.40
(d, J ϭ 8.0 Hz, 1 H), 7.93 (d, J ϭ 8.0 Hz, 1 H) ppm. 13C NMR*:
δ ϭ 165.7, 153.0, 145.7 (q, J ϭ 36 Hz), 142.9, 128.9, 128.5, 121.6
(q, J ϭ 275 Hz) ppm. C7H3ClF3NO2 (225.55): calcd. C 37.28, H
1.34; found C 37.09, H 1.08.
3-Chloro-4-(trifluoromethyl)pyridine: After thorough mixing, spray
dried potassium fluoride (6.4 g, 0.11 mol) and cuprous iodide (21 g,
0.11 mol) were heated with the flame of a Bunsen burner under
vacuum (1 Torr) with gentle shaking for about 10 min until a
homogeneous greenish color was obtained. N-Methylpyrrolidinone
(0.10 L) and trimethyl(trifluoromethyl)silane (16 mL, 15.6 g, 0.11
mol) were added, and the slurry was slowly heated to 50 °C under
vigorous stirring. After 30 min, when evolution of gas had ceased,
3-chloro-4-iodopyridine[32] (25 g, 0.11 mol) was added, and the
mixture was kept for 20 h at 50 °C, before being cooled to 25 °C,
poured into a 12% aqueous ammonia solution (0.20 L) and ex-
tracted with diethyl ether (3 ϫ 0.15 L). The combined organic
phases were consecutively washed with 12% aqueous ammonia
solution (3 ϫ 0.10 L), 2.0  hydrochloric acid (0.10 L), a saturated
aqueous solution of sodium hydrogencarbonate (0.10 L) and brine
(0.10 L) and dried. Upon distillation, a colorless oil was collected.
2-Chloro-4-iodo-6-(trifluoromethyl)pyridine (5): 2-Chloro-3-iodo-6-
(trifluoromethyl)pyridine[20] (1; 6.1 g, 20 mmol) was added to a
solution prepared from butyllithium (20 mmol) and diisopropyl-
amine (2.8 mL, 2.0 g, 20 mmol) in tetrahydrofuran (40 mL) and
hexanes (13 mL) cooled in a dry ice/methanol bath. After 45 min
at Ϫ75 °C, the reaction mixture was partitioned between 2.0 
hydrochloric acid (20 mL) and diethyl ether (40 mL). The organic
layers were washed with a saturated aqueous solution (20 mL) of
sodium hydrogencarbonate and brine (20 mL), dried and the sol-
vents evaporated. Crystallization of the residue from ethanol af-
forded colorless prisms. M.p. 94Ϫ95 °C (ref. 20: m.p. 93Ϫ95 °C);
yield: 5.10 g (83%).
2-Chloro-6-(trifluoromethyl)pyridine-4-carboxylic Acid (6): Butyl-
magnesium chloride (3.3 mmol), tetrahydrofuran (15 mL) and 2-
chloro-4-iodo-6-(trifluoromethyl)pyridine[20] (5; 3.1 g, 10 mmol)
were added at 10 min intervals to a solution of butyllithium
(6.7 mmol) in hexanes (4 mL) at 0 °C. After 5 min, the reaction
mixture was poured onto an excess of freshly crushed dry ice, eva-
porated and partitioned between diethyl ether (50 mL) and 2.0 
hydrochloric acid (50 mL). The organic layer was dried and the
solvents were evaporated. The residue crystallized from hexanes as
pale yellow needles. M.p. 116Ϫ118 °C; yield: 1.68 g (74%). 1H
NMR: δ ϭ 8.23 (s, 1 H), 8.18 (s, 1 H) ppm. 13C NMR: δ ϭ 167.3,
153.3, 149.6 (q, J ϭ 37 Hz), 141.0, 127.8, 120.3 (q, J ϭ 275 Hz),
118.9 (q, J ϭ 3 Hz) ppm. C7H3ClF3NO2 (225.55): calcd. C 37.28,
H 1.34; found C 37.15, H 1.39.
20
B.p. 142Ϫ144 °C; m.p. Ϫ23 to Ϫ20 °C; yield: 13.8 g (69%). nD
1.4559; d420 1.407. 1H NMR: δ ϭ 8.78 (s, 1 H), 8.67 (d, J ϭ 4.8 Hz,
1 H), 7.58 (d, J ϭ 4.8 Hz, 1 H) ppm. 13C NMR: δ ϭ 151.6, 148.5,
135.8 (q, J ϭ 33 Hz), 129.2 (q, J ϭ 2 Hz), 121.7 (q, J ϭ 274 Hz),
120.9 (q, J ϭ 5 Hz) ppm. C6H3ClF3N (181.54): calcd. C 39.78, H
1.74; found C 39.70, H 1.67.
2. Derivatives of 2-Chloro-6-(trifluoromethyl)pyridine
The preparation of 2-chloro-3-iodo-6-trifluoromethylpyridine (1)
and 2-chloro-6-trifluoromethyl-3-(trimethylsilyl)pyridine (3) has al-
ready been described in a previous publication.[20]
2-Chloro-6-(trifluoromethyl)pyridine-3-carboxylic Acid (2): At Ϫ85
°C, diisopropylamine (2.8 mL, 2.0 g, 20 mmol) and 2-chloro-6-(tri-
3. Derivatives of 2-Chloro-5-(trifluoromethyl)pyridine
fluoromethyl)pyridine[19] (3.6 g, 20 mmol) were added consecutively The preparation of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (7),
to a solution of butyllithium (10 mmol) in tetrahydrofuran (50 mL) 2-chloro-5-(trifluoromethyl)pyridine-4-carboxylic acid (8), 2-
and hexanes (6 mL). After 4 h at Ϫ85 °C, the reaction mixture was
chloro-3-iodo-5-(trifluoromethyl)pyridine (11) and 2-chloro-5-(tri-
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Three Chloro(trifluoromethyl)pyridines as Model Substrates for Regioexhaustive Functionalization
FULL PAPER
fluoromethyl)-pyridine-3-carboxylic acid (12) have been described bromide (3.1 g, 30 mmol) and kept in a dry ice/methanol bath.
in a previous publication.[8]
After 2 h at Ϫ75 °C, an excess of solid carbon dioxide was added
to the reaction mixture. Diethyl ether (40 mL) was added, and the
product was extracted with 1.0  sodium hydroxide aqueous solu-
tion (3 ϫ 20 mL). The combined aqueous layers were washed with
diethyl ether (2 ϫ 20 mL), acidified to pH 1 and extracted with
diethyl ether (3 ϫ 30 mL). The combined organic layers were dried
and the solvents evaporated. According to gas chromatographic
analysis of a sample after treatment with diazomethane (30 m, DB-
1, 175 °C; DB-WAX, 30 m, 175 °C, methyl benzoate as internal
standard), an aliquot of the reaction product was obtained after
esterification with diazomethane methyl 2-chloro-5-(trifluorome-
thyl)pyridine-4-carboxylate (15%), methyl 2-chloro-5-(trifluorome-
thyl)pyridine-3-carboxylate (16%) and methyl 2-chloro-5-(trifluoro-
methyl)pyridine-3,4-dicarboxylate (64%). Crystallization of the
mixture of acids from a 1:1 (v/v) mixture of toluene and ethanol
afforded colorless needles. M.p. 180Ϫ182 °C; yield: 1.36 g (37%).
1H NMR: δ ϭ 8.74 (s) ppm. 13C NMR: δ ϭ 165.3, 165.1, 152.1,
147.7 (q, J ϭ 6 Hz), 142.1, 129.0, 122.4 (q, J ϭ 274 Hz), 121.9 (q,
J ϭ 33 Hz) ppm. C8H3ClF3NO4 (363.08): calcd. C 35.65, H 1.12;
found C 35.95, H 0.87.
6-Chloro-2-iodo-3-(trifluoromethyl)pyridine (9): In a dry ice/meth-
anol bath, 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (31 g, 0.10
mol) was added to a solution prepared from diisopropylamine
(14 mL, 10 g, 0.10 mmol) and butyllithium (0.10 mol) in tetra-
hydrofuran (0.15 L) and hexane (60 mL) containing also a spatula
tip of iodine. After 2 h at Ϫ75 °C, 2.0  hydrochloric acid (0.10 L)
was added. The organic layer was decanted and the aqueous phase
extracted with diethyl ether (0.10 L). The combined organic phases
were evaporated and the residue subjected to steam distillation.
The slightly yellow oil obtained was distilled. M.p. Ϫ5 to Ϫ4 °C;
b.p. 65Ϫ66 °C/1.5 Torr; yield: 23.8 g (77%). nD 1.557. H NMR:
δ ϭ 7.78 (d, J ϭ 8.2 Hz, 1 H), 7.42 (d, J ϭ 8.2 Hz, 1 H) ppm. 13C
NMR: δ ϭ 153.0, 137.0 (q, J ϭ 5 Hz), 130.9 (q, J ϭ 33 Hz), 122.9,
122.2 (q, J ϭ 273 Hz), 113.0 ppm. C6H2ClF3IN (307.44): calcd. C
23.44, H 0.66; found C 23.38, H 0.77.
20
1
6-Chloro-3-(trifluoromethyl)pyridine-2-carboxylic Acid (10): Isopro-
pylmagnesium chloride (25 mmol) was added to a solution of 6-
chloro-2-iodo-3-(trifluoromethyl)pyridine (7.7 g, 25 mmol) in tetra-
hydrofuran (50 mL) cooled in a dry ice/methanol bath. After
15 min at Ϫ75 °C, the suspension was poured onto an excess of
freshly crushed dry ice. It was treated with 2.0  ethereal hydro-
chloric acid (50 mL) and the solvents were evaporated. The residue
was crystallized from a 1:1 (v/v) mixture of ethyl acetate and hexanes
4. Derivatives of 3-Chloro-4-(trifluoromethyl)pyridine
3-Chloro-4-trifluoromethyl-2-(trimethylsilyl)pyridine (15): Lithium
diisopropylamide prepared from diisopropylamine (4.2 mL, 3.0 g,
as tiny colorless needles. M.p. 109Ϫ110 °C (reprod.); yield: 4.56 g 30 mmol) and butyllithium (30 mmol) in tetrahydrofuran (30 mL)
(81%). 1H NMR: δ ϭ 8.05 (d, J ϭ 8.4 Hz, 1 H), 7.60 (d, J ϭ and hexanes (18 mL) was added dropwise, over 1 h, to a solution of
8.4 Hz, 1 H) ppm. 13C NMR: δ ϭ 165.6, 154.0, 150.5, 137.7 (q, 3-chloro-4-(trifluoromethyl)pyridine (3.9 mL, 5.4 g, 30 mmol) and
J ϭ 4 Hz), 125.7, 123.2 (q, J ϭ 34 Hz), 122.5 (q, J ϭ 273 Hz) ppm. chlorotrimethylsilane (3.8 mL, 3.3 g, 30 mmol) in tetrahydrofuran
C7H3ClF3NO2 (225.55): calcd. C 37.27, H 1.34; found C 37.47,
H 1.72.
(30 mL) cooled in a dry ice/methanol bath. After 1 h at Ϫ75 °C,
the mixture was filtered through basic alumina (50 mL), eluted with
diethyl ether (2 ϫ 50 mL), dried and distilled to obtain a colorless
2,6Ј-Dichloro-3,5Ј-bis(trifluoromethyl)-2,5-dihydro-2,4Ј-bipyridine
(13): Lithium N,N-diisopropylcarbamate (3.8 g, 25 mmol) was
freshly prepared from molar equivalents of diisopropylamine and
butyllithium and an excess of carbon dioxide gas in tetrahydrofu-
ran. It was isolated after evaporation of the volatiles and dried as
a white powder. It was added at 0 °C to the solution prepared
from diisopropylamine (3.5 mL, 2.5 g, 25 mmol), lithium bromide
20
oil. B.p. 75Ϫ76 °C/12 Torr; m.p. 4Ϫ6 °C; yield: 5.61 g (74%). nD
20
1
1.4675; d4 1.210. H NMR: δ ϭ 8.81 (d, J ϭ 4.8 Hz, 1 H), 7.49
(d, J ϭ 4.8 Hz, 1 H), 0.46 (s, 9 H) ppm. 13C NMR: δ ϭ 169.5,
148.1, 135.5 (q, J ϭ 2 Hz), 134.3 (q, J ϭ 32 Hz), 122.1 (q, J ϭ
274 Hz), 120.0 (q, J ϭ 5 Hz), Ϫ1.0 ppm. C9H11ClF3NSi (253.72):
calcd. C 42.60, H 4.37; found C 42.49, H 4.16.
(0.17 g, 2.0 mmol) and butyllithium (25 mmol) in tetrahydrofuran 3-Chloro-4-(trifluoromethyl)pyridine-2-carboxylic Acid (16): At
(35 mL) and hexanes (15 mL). The mixture was vigorously stirred Ϫ100 °C, 3-chloro-4-(trifluoromethyl)pyridine (1.3 mL, 1.8 g,
until it became homogeneous. It was placed in a dry ice/methanol 10 mmol) was added to a solution prepared from butyllithium
bath and, after solid 2-chloro-5-(trifluoromethyl)pyridine (9.1 g,
50 mmol) was dissolved in it, kept for 2 h at Ϫ75 °C before it was
treated with 2.0  hydrochloric acid (10 mL). The solvents were
evaporated, the residue taken up in diethyl ether (0.10 L), washed
(20 mmol) and 2,2,6,6-tetramethylpiperidine (3.4 mL, 2.8 g,
20 mmol) in diethyl ether (50 mL) and hexanes (12 mL). After 2 h
at Ϫ75 °C, the mixture was poured onto an excess of freshly
crushed dry ice covered with diethyl ether (25 mL). At 25 °C, the
with 2.0  hydrochloric acid (2 ϫ 50 mL), a saturated aqueous mixture was extracted with 2.0  aqueous sodium hydroxide solu-
solution (50 mL) of sodium hydrogencarbonate and brine (2 ϫ
50 mL), dried. The solvents were evaporated. Crystallization from
chloroform gave colorless needles. M.p. 208Ϫ210 °C (reprod.);
yield: 2.92 g (32%). 1H NMR: δ ϭ 8.70 (s, 1 H), 7.53 (s, 1 H), 7.17
(dq, J ϭ 5.4, 1.6 Hz, 1 H), 4.32 (d, J ϭ 9.0 Hz, 1 H), 3.16 (dd, J ϭ
tion (3 ϫ 25 mL). The combined aqueous phases were washed with
diethyl ether (2 ϫ 20 mL), acidified to pH 1 and extracted with
diethyl ether (3 ϫ 20 mL). The organic solvent was evaporated and
the residue crystallized from a 2:1 (v/v) mixture of heptane and
ethyl acetate as colorless needles. M.p. 106Ϫ108 °C (decomp.);
17.2, 9.1 Hz, 1 H), 2.66 (d, J ϭ 17.1 Hz, 1 H) ppm. 13C NMR: δ ϭ yield: 1.29 g (57%). 1H NMR*: δ ϭ 8.85 (d, J ϭ 4.8 Hz, 1 H), 8.00
167.3, 156.9, 163.9, 149.1 (q, J ϭ 6 Hz), 134.5 (q, J ϭ 6 Hz), 125.4 (d, J ϭ 4.8 Hz, 1 H) ppm. 13C NMR*: δ ϭ 165.2, 152.8, 149.6 (q,
(q, J ϭ 269 Hz), 124.6 (q, J ϭ 273.4 Hz), 123.9, 123.3 (q, J ϭ J ϭ 1 Hz), 149.6, 137.6 (q, J ϭ 33 Hz), 124.0 (q, J ϭ 5 Hz), 122.7
31 Hz), 104.8 (q, J ϭ 32 Hz), 37.5, 33.0 ppm. C12H6Cl2F6N2
(q, J ϭ 274 Hz) ppm. C7H3ClF3NO2 (225.55): calcd. C 37.28, H
(363.08): calcd. C 39.69, H 1.66; found C 36.63, H 2.04.
1.34; found C 37.30, H 1.27.
2-Chloro-5-(trifluoromethyl)pyridine-3,4-dicarboxylic Acid (14): 2-
5-Chloro-4-(trifluoromethyl)pyridine-3-carboxylic Acid (17): 3-
Chloro-5-(trifluoromethyl)pyridine (1.8 g, 10 mmol) was added as Chloro-4-trifluoromethyl-2-(trimethylsilyl)pyridine (2.1 mL, 2.5 g,
a solid to a solution prepared from butyllithium (30 mmol) and 10 mmol) was added to a solution prepared from 2,2,6,6-tetrameth-
diisopropylamine (4.2 mL, 3.0 g, 30 mmol) in tetrahydrofuran ylpiperidine (1.7 mL, 1.4 g, 10 mmol) and butyllithium (10 mmol)
(30 mL) and hexanes (16 mL) containing finely powdered sodium in tetrahydrofuran (50 mL) and hexanes (6 mL) kept in a dry ice/
Eur. J. Org. Chem. 2004, 3793Ϫ3798
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3797

F. Cottet, M. Schlosser
methanol bath. After 2 h at Ϫ75 °C, the mixture was poured onto 9.00 (s, 1 H), 8.39 (s, 1 H) ppm. 13C NMR*: δ ϭ 164.6, 152.2,
FULL PAPER
an excess of freshly crushed dry ice covered with tetrahydrofuran
(25 mL). The solvents were then evaporated, and the residue re-
fluxed for 1 min in 5% aqueous sodium hydroxide solution
(50 mL). After cooling, the mixture was washed with diethyl ether
(2 ϫ 20 mL), acidified to pH 1 and extracted with diethyl ether (3
ϫ 20 mL). The organic solvent was evaporated, and the residue
crystallized from a 3:1 (v/v) mixture of heptanes and ethyl acetate
as colorless platelets. M.p. 157Ϫ159 °C; yield: 1.87 g (83%). 1H
NMR*: δ ϭ 8.98 (s, 1 H), 8.86 (s, 1 H) ppm. 13C NMR*: δ ϭ
166.4, 153.8, 148.4, 132.4 (q, J ϭ 33 Hz), 130.3 (q, J ϭ 2 Hz), 130.0
(q, J ϭ 2 Hz), 122.6 (q, J ϭ 275 Hz) ppm. C7H3ClF3NO2 (225.55):
calcd. C 37.28, H 1.34; found C 37.49, H 1.29.
148.6, 136.9 (q, J ϭ 33 Hz), 132.9 (q, J ϭ 2 Hz), 123.0 (q, J ϭ
5 Hz), 122.6 (q, J ϭ 274 Hz) ppm. C7H3ClF3NO2 (225.55): calcd.
C 37.28, H 1.34; found C 37.15, H 1.20.
Acknowledgments
This work was financially supported by the Schweizerische Natio-
nalfonds zur Förderung der wissenschaftlichen Forschung, Bern
(grant 20Ϫ100Ј336Ϫ02). The authors also wish to express their
gratitude to the Ishihara Sangyo Kaisha (ISK) Company, Tokyo,
for a generous gift of polyhalogenated pyridines.
[1]
M. Schlosser, review article in press (Angew. Chem.).
3-Chloro-5-iodo-4-trifluoromethyl-2-(trimethylsilyl)pyridine
(18):
[2]
M. Schlosser, C. Heiss, Eur. J. Org. Chem. 2003, 4618Ϫ4624.
[3]
Compound 18 was made analogously from 3-chloro-4-trifluoro-
methyl-2-(trimethylsilyl)pyridine (13 mL, 15 g, 60 mmol), but the
organometallic intermediate was trapped with iodine (15 g,
60 mmol) in tetrahydrofuran (60 mL). After 15 min at Ϫ75 °C, a
2.0  solution (50 mL) of sodium thiosulfate was added, and the
mixture was then allowed to reach 25 °C. The phases were sepa-
rated, and the aqueous phase extracted with diethyl ether (50 mL).
The combined organic phases were washed with brine (0.10 L),
dried, evaporated and distilled to obtained a yellowish oil. B.p.
C. Heiss, E. Marzi, M. Schlosser, Eur. J. Org. Chem. 2003,
4625Ϫ4629.
[4]
E. Marzi, J. Gorecka, M. Schlosser, Synthesis 2004,
1609Ϫ1618.
M. Marull, M. Schlosser, Eur. J. Org. Chem. 2004, 1008Ϫ1013.
M. Schlosser, A. Ginanneschi, manuscript in preparation.
[5]
[6]
[7]
E. Marzi, C. Bobbio, F. Cottet, M. Schlosser, manuscript sub-
mitted.
[8]
F. Cottet, M. Marull, O. Lefebvre, M. Schlosser, Eur. J. Org.
Chem. 2003, 1559Ϫ1568.
20
20
82Ϫ83 °C/4 Torr; yield: 19.4 g (85%). nD 1.5405; d4 1.648. 1H
NMR: δ ϭ 9.18 (s, 1 H), 0.42 (s, 9 H) ppm. 13C NMR: δ ϭ 168.6,
156.6, 137.0 (q, J ϭ 1 Hz), 135.8 (q, J ϭ 31 Hz), 120.8 (q, J ϭ
278 Hz), 89.3 (q, J ϭ 2 Hz), Ϫ1.1 ppm. C9H11ClF3INSi (379.62):
calcd. C 28.47, H 2.66; found C 28.66, H 2.66.
[9]
M. Schlosser, G. Katsoulos, S. Takagishi, Synlett 1990,
747Ϫ748.
[10]
S. Takagishi, G. Katsoulos, M. Schlosser, Synlett 1991,
360Ϫ362.
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37, 2767Ϫ2770.
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M. Schlosser, F. Mongin, J. Porwisiak, W. Dmowski, H. H.
3-Chloro-6-iodo-4-trifluoromethyl-2-(trimethylsilyl)pyridine (19): 3-
Chloro-5-iodo-4-trifluoromethyl-2-(trimethylsilyl)pyridine (5.7 mL,
9.5 g, 25 mmol) was added to a solution prepared from 2,2,6,6-
tetramethylpiperidine (8.4 mL, 7.1 g, 50 mmol) and butyllithium
(50 mmol) in diethyl ether (0.13 L) and hexanes (30 mL) cooled in
a dry ice/methanol bath. After 1 h at Ϫ75 °C, 1.0  hydrochloric
acid (50 mL) was added. The ethereal layer was collected and dried
and the solvents were evaporated. Distillation afforded a colorless
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S. H. Unger, C. Hansch, Progr. Phys. Org. Chem. 1976, 12,
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R. Gallo, Progr. Phys. Org. Chem. 1983, 14, 115Ϫ163.
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M. Hudlicky), Am. Chem. Soc., Washington, 1995, p. 25.
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W. E. Della, J. Am. Chem. Soc. 1967, 89, 5221Ϫ5224.
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102, 5618Ϫ5626.
20
oil. B.p. 76Ϫ78 °C/2 Torr; m.p. 9Ϫ11 °C; yield: 5.90 g (62%). nD
[18]
20
1
M. Iwao, J. Org. Chem. 1990, 55, 3622Ϫ3627.
1.5244; d4 1.569. H NMR: δ ϭ 7.84 (s, 1 H), 0.42 (s, 9 H) ppm.
13C NMR: δ ϭ 172.5, 135.7 (q, J ϭ 2 Hz), 135.4 (q, J ϭ 32 Hz),
130.9 (q, J ϭ 5 Hz), 120.8 (q, J ϭ 275 Hz), 115.6, Ϫ1.3 ppm.
C9H11ClF3INSi (379.62): calcd. C 28.47, H 2.66; found C 28.75,
H 2.53.
[19]
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Lett. 1998, 39, 1749Ϫ1752.
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5-Chloro-4-(trifluoromethyl)pyridine-2-carboxylic Acid (20): 3-
Chloro-6-iodo-4-trifluoromethyl-2-(trimethylsilyl)pyridine (2.4 mL,
3.8 g, 10 mmol) was added to a solution of butyllithium (10 mmol)
in toluene (40 mL) and hexanes (6.1 mL) cooled in a dry ice/meth-
anol bath. After 15 min at Ϫ75 °C, the mixture was poured onto
an excess of freshly crushed dry ice covered with tetrahydrofuran
(25 mL). At 25 °C, the mixture was washed with 6.0  hydrochloric
acid (20 mL) and the solvents were evaporated. The residue was dis-
solved in tetrahydrofuran (25 mL) containing tetrabutylammonium
fluoride trihydrate (3.5 g, 10 mmol) and heated under reflux for
1 min. After evaporation of the solvents, the residue was par-
titioned between diethyl ether (75 mL) and 2.0  hydrochloric acid
(50 mL). The solvent was evaporated, and the residue crystallized
from a 4:1 (v/v) mixture of heptanes and ethyl acetate; colorless
needles. M.p. 146Ϫ144 °C; yield: 1.68 g (75%). 1H NMR*: δ ϭ
2001, 42, 4841Ϫ4844.
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Received January 30, 2004
3798
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3793Ϫ3798