Further metalations and functionalizations of chloro-, bromo- and iodo(trifluoromethyl)pyridines

Article abstract of DOI:10.1055/s-2004-829111

In accordance with the concept of regioexhaustive functionalization, both 3-chloro-2-(trifluoromethyl)pyridine and 2-bromo-6-(trifluoromethyl)pyridine were converted each time into the three possible carboxylic acids (1, 4 and 5 and 6, 9 and 12, respectively). 2-Bromo-4-(trifluoromethyl)pyridine, 2-bromo-5-(trifluoromethyl)pyridine, 2-iodo-4-(trifluoromethyl)pyridine and 4-iodo-2-(trifluoromethyl)pyridine were selectively deprotonated and subsequently carboxylated at the respective 3-positions thus affording the acids 13-16. Finally, the N-pivaloyl-protected 2-amino-3-chloro-5-(trifluoromethyl) pyridine was deprotonated at the 4-position and the intermediate trapped with iodine and benzaldehyde to provide, after amide cleavage, the aminopyridines 17 and 18.

Full text of DOI:10.1055/s-2004-829111

PAPER
1619
Further Metalations and Functionalizations of Chloro-, Bromo- and
Iodo(trifluoromethyl)pyridines
Site-Selective
aMetalation
b
and Functio
r
nalizatio
i
ns of
H
c
a
lo(trifluo
e
romethyl)pyridine
C
s
ottet,a Marc Marull,a Florence Mongin,b,c David Espinosa,b Manfred Schlosser*a,b
a
Institut de Chimie moléculaire et biologique, Ecole Polytechnique Fédérale, BCh, 1015 Lausanne, Switzerland
Fax +41(21)6939365; E-mail: manfred.schlosser@epfl.ch
b
c
Faculté des Sciences, Université, BCh, 1015 Lausanne, Switzerland
Present address: Lab. de Chimie org. fine et hétérocyclique, UPRESA 6014, IRCOF, BP 08, 76131 Mont Saint-Aignan, France
Received 10 February 2004
philically delivered substituent (El), in general a carboxy
group (Scheme 1, El = COOH).
Abstract: In accordance with the concept of regioexhaustive func-
tionalization, both 3-chloro-2-(trifluoromethyl)pyridine and 2-bro-
mo-6-(trifluoromethyl)pyridine were converted each time into the
three possible carboxylic acids (1, 4 and 5 and 6, 9 and 12, respec-
tively). 2-Bromo-4-(trifluoromethyl)pyridine, 2-bromo-5-(trifluo-
romethyl)pyridine, 2-iodo-4-(trifluoromethyl)pyridine and 4-iodo-
2-(trifluoromethyl)pyridine were selectively deprotonated and sub-
sequently carboxylated at the respective 3-positions thus affording
the acids 13–16. Finally, the N-pivaloyl-protected 2-amino-3-chlo-
ro-5-(trifluoromethyl)pyridine was deprotonated at the 4-position
and the intermediate trapped with iodine and benzaldehyde to pro-
vide, after amide cleavage, the aminopyridines 17 and 18.
The present article describes the extension of this study to
another chloro(trifluoromethyl)pyridine and to a bro-
mo(trifluoromethyl)pyridine. In addition, the direct meta-
lation of two further bromo(trifluoromethyl)pyridines,
two iodo(trifluoromethyl)pyridines and of one amino-
chloro(trifluoromethyl)pyridine are reported.
Three Regioisomeric Derivatives of 3-Chloro-2-(tri-
fluoromethyl)pyridine
Key words: halogen/metal permutation (‘exchange’), halogen mi-
gration, metalations, lithium diisopropylamide, pyridines, site se-
lectivity
Readily prepared from 3-chloro-2-iodopyridine3 and (tri-
fluoromethyl)trimethylsilane in 46% yield,4 3-chloro-2-
(trifluoromethyl)pyridine underwent selective deprotona-
tion when treated with lithium diisopropylamide (LIDA)
in tetrahydrofuran at –75 °C for two hours. Upon trapping
of the intermediate with carbon dioxide or molecular io-
dine, 3-chloro-2-(trifluoromethyl)pyridine-4-carboxylic
acid (1, 81%) or 3-chloro-4-iodo-2-(trifluoromethyl)pyri-
dine (2, 86%) were obtained, respectively. LIDA-trig-
gered heavy halogen migration followed by neutralization
In a preceding article it was demonstrated how the con-
cept of regioexhaustive functionalization1 can be applied
to 2-chloro-5-(trifluoromethyl)pyridine, 2-chloro-6-(tri-
fluoromethyl)pyridine and 3-chloro-4-(trifluorometh-
yl)pyridine.2 Taking advantage of the ‘toolbox methods’,1
any of the each time three vacant positions was lithiated
and the metal was subsequently replaced by an electro-
El
El
El
F3C
N
Cl F3C
F3C
N
N
N
Cl F3C
N
Cl
F3C
F3C
Cl
Cl
N
Cl
Cl
N
El
F3C
N
F3C
F3C
N
F3C
El F3C
F3C
Cl El
Cl El
Cl
N
Cl
N
Cl
El
N
El
El = COOH, etc
Scheme 1
SYNTHESIS 2004, No. 10, pp 1619–1624
x
x.
x
x
.
2
0
0
4
Advanced online publication: 23.06.2004
DOI: 10.1055/s-2004-829111; Art ID: T01904SS
© Georg Thieme Verlag Stuttgart · New York

1620
F. Cottet et al.
PAPER
isomerized the latter compound to 3-chloro-5-iodo-2-(tri- into the three isomeric carboxylic acids (Scheme 3). The
fluoromethyl)pyridine (3, 69% after crystallization). treatment with LIDA followed by carboxylation and neu-
Halogen/metal permutation with isopropylmagnesium tralization afforded directly the 2-bromo-6-(trifluoro-
chloride in tetrahydrofuran at 0 °C, carboxylation and methyl)pyridine-3-carboxylic acid (6, 49%). When the
neutralization afforded the 5-chloro-6-(trifluorometh- organometallic intermediate was trapped with molecular
yl)pyridine-3-carboxylic acid (4, 77%). 5-Chloro-6-(tri- iodine instead, 2-bromo-3-iodo-6-(trifluoromethyl)pyri-
fluoromethyl)pyridine-2-carboxylic acid (5) was formed dine (7, 78%) was obtained. Its LIDA-promoted isomer-
after metalation with Caubère’s base,5,6 excess of butyl- ization by basicity gradient-driven heavy halogen
lithium and lithium 2-(dimethylamino)ethoxide (LID- migration gave 2-bromo-4-iodo-6-(trifluoromethyl)pyri-
MAE), although only in poor yield (26%) (Scheme 2).
dine (8, 82%) which, when subjected to a halogen/metal
permutation using isopropylmagnesium chloride, afford-
ed the 2-bromo-6-(trifluoromethyl)pyridine-4-carboxylic
acid (9, 88%). Consecutive exposure of 2-bromo-6-(tri-
fluoromethyl)pyridine to LIDA and chlorotrimethylsilane
produced the silane 10 (85%) which upon deprotonation
by lithium 2,2,6,6-tetramethylpiperidide (LITMP) fol-
lowed by carboxylation, neutralization and deprotection
of the silylated intermediate 11 provided 6-bromo-2-(tri-
fluoromethyl)pyridine-3-carboxylic acid (12) in satisfac-
tory overall yield (49%).
Cl
N
CF3
f
a
I
Li
N
Cl
Cl
Cl
c
N
CF3
Li
N
CF3
CF3
2
a
I
Li
Cl
N
CF3
SiR3
Br
I
F3C
N
N
Br
F3C
N
N
F3C
N
Li
N
Br
7
10
f,g
c
Li
N
a
h
d
I
Cl
Li
Li
SiR3
Br
Ι
CF3
F3C
Br
F3C
F3C
Br
b
d
e
b
I
Cl
I
Li
b
N
N
CF3
3
F3C
F3C
F3C
F3C
N
Br
e
I/ClMg
Cl
b
Ι
HOOC
F3C
SiR3
Br
CF3
N
Br
N
b
11
8
HOOC
f
HOOC
Cl
Cl
Cl
MgCl/Ι
N
CF3
HOOC
N
CF3
N
CF3
i
1
4
5
N
Br
Scheme 2 a) Lithium diisopropylamide (LIDA) in THF at –75 °C
for 2 h; b) (1.) Excess solid carbon dioxide, (2.) Ethereal hydrogen
chloride; c) Molecular iodine in THF; d) Methanol; e) Isopropyl-
magnesium chloride in THF at 0 °C; f) Butyllithium and lithium
2-(dimethylamino)ethoxide (LIDMAE) in hexanes at –75 °C for 45
min.
b
COOH
COOH
Br
HOOC
F3C
F3C
N
N
Br
N
Br
9
6
12
Scheme 3 a) LIDA in THF at –85 °C for 2 h; b) (1.) Excess solid
carbon dioxide, (2.) HCl; c) Molecular iodine in THF; d) LIDA in
THF at –75 °C for 15 min; e) HCl; f) Isopropylmagnesium chloride in
THF at 0 °C for 5 min; g) Chlorotrimethylsilane; h) Lithium 2,2,6,6-
tetramethylpiperidide (LITMP) in THF at –75 °C for 45 min; i) Tetra-
butylammonium fluoride trihydrate (TBAF) in refluxing THF for 1
min.
Three Regioisomeric Derivatives of 2-Bromo-6-(tri-
fluoromethyl)pyridine
As previously described for 2-chloro-6-(trifluorometh-
yl)pyridine,2 the 2-bromo analog was readily converted
Synthesis 2004, No. 10, 1619–1624 © Thieme Stuttgart · New York

PAPER
Site-Selective Metalations and Functionalizations of Halo(trifluoromethyl)pyridines
1621
pound 17 and of the alcohol 18 were obtained in 39% and
47% overall yield, respectively (Scheme 6).
Derivatization of 2-Bromo-4- and 5-Bromo-2-(tri-
fluoromethyl)pyridine
2-Bromo-4-(trifluoromethyl)pyridine7 and 5-bromo-2-
(trifluoromethyl)pyridine4 were cleanly deprotonated by
LIDA at the bromine-adjacent position. After carboxyl-
ation and neutralization, 2-bromo-4-(trifluoromethyl)py-
ridine-3-carboxylic acid (13) and 5-bromo-2-
(trifluoromethyl)pyridine-4-carboxylic acid (14) were
isolated in 54% and 67% yield, respectively (Scheme 4).
I
F3C
Cl
d
N
17
NH2
b,
Li
N
F3C
Cl
NHCOC(CH3)3
F3C
Cl
N
a
N
C
C(CH3)3
LiO
C6H5
F3C
F3C
F3C
c,
CHOH
Cl
Li
COOH
Br
d
F3C
a
a
b
N
Li
Br
N
N
Br
N
NH2
13
18
COOH
Scheme 6 a) LIDA (2 equiv) in THF at –75 °C for 2 h; b) Molecular
iodine; c) Benzaldehyde; d) Kept in refluxing 20% H2SO4 for 15 h.
Br
Br
Br
b
N
CF3
N
CF3
N
CF3
14
Working practices and abbreviations are specified in previous arti-
cles from this laboratory.10–12 1H and (1H-decoupled) 13C NMR
spectra were recorded at 400 and 101 MHz, respectively, relative to
the internal standard tetramethylsilane (chemical shift d = 0.00
ppm). The samples were dissolved in CDCl3 or, if marked by an as-
terisk, in acetone-d6.
Scheme 4 a) LIDA in THF at –75 °C for 45 min; b) (1.) Excess so-
lid carbon dioxide, (2.) Hydrochloric acid.
Derivatization of 2-Iodo-4-(trifluoromethyl)pyridine
and 4-Iodo-2-(trifluoromethyl)pyridine
3-Chloro-2-(trifluoromethyl)pyridine
After thorough mixing, spray-dried KF (4.6 g, 80 mmol) and CuI
(15 g, 80 mmol) were heated with the flame of a Bunsen burner un-
der gentle shaking and at reduced pressure (1 Torr) for some 10 min
until a homogeneous greenish color appeared. Anhydrous N-meth-
ylpyrrolidinone (75 mL), 3-chloro-2-iodopyridine3 (18 g, 75 mmol)
and trimethyl(trifluoromethyl)silane (11 mL, 11 g, 75 mmol) were
added. Being vigorously stirred for 6 h at 50 °C, the slurry gradually
changed to a brownish solution which was eventually poured into
12% aq NH3 (0.20 L). The product was extracted with Et2O (3 ×
0.10 L). The combined organic layers were washed with 12% aq
NH3 (3 × 50 mL), 1.0 M HCl (0.10 L), a sat. solution of NaHCO3
(0.10 L), and brine (0.10 L) and dried. Upon distillation, a colorless
oil was collected which solidified.
Even 2-iodo-4-(trifluoromethyl)pyridine8 and 4-iodo-2-
(trifluoromethyl)pyridine7 were cleanly deprotonated by
LIDA in tetrahydrofuran at –75 °C. Trapping of the orga-
nometallic intermediates with dry ice followed by neutral-
ization gave the 2-iodo-4-(trifluoromethyl)pyridine-3-
carboxylic acid (15, 51%) and the 4-iodo-2-(trifluoro-
methyl)pyridine-3-carboxylic acid (16, 31%) (Scheme 5).
F3C
F3C
F3C
Li
COOH
a
b
15
N
I
N
I
N
I
Colorless prisms (from hexanes); mp 40–42 °C; bp 172–174 °C;
yield: 6.4 g (46%).
I
I
I
Li
COOH
CF3
1H NMR: d = 8.55 (dd, 1 H, J = 4.7, 1.1 Hz), 7.87 (d, 1 H, J = 8.1
Hz), 7.46 (dd, 1 H, J = 8.0, 4.7 Hz).
13C NMR: d = 146.7, 144.7 (q, J = 34 Hz), 139.6, 130.5, 127.3,
121.0 (q, J = 274 Hz).
a
b
16
N
CF3
N
N
CF3
Scheme 5 a) LIDA in THF at –75 °C for 2 h; b) (1.) Excess solid
carbon dioxide, (2.) Hydrochloric acid.
Anal. Calcd for C6H3ClF3N (181.54): C, 39.70; H, 1.67. Found: C,
39.71; H, 1.69.
N-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2,2-dimethylpro-
panamide
Derivatization of 2-Amino-3-chloro-5-(trifluoro-
methyl)pyridine
The solution of 2-amino-3-chloro-5-(trifluoromethyl)pyridine (4.9
g, 25 mmol), pivaloyl chloride (3.4 mL, 3.4 g, 28 mmol) and pyri-
dine (2.2 mL, 2.2 g, 28 mmol) in CH2Cl2 (50 mL) was heated under
reflux for 5 d. The organic phase was washed with a 2.0 M aq solu-
tion Na2CO3 (50 mL), dried and evaporated. Crystallization from
hexanes gave colorless needles.
2-Amino-3-chloro-5-(trifluoromethyl)pyridine is readily
accessible from the industrially inexpensive 2,3-dichloro-
5-(trifluoromethyl)pyridine by simple nucleophilic sub-
stitution with ammonia.9 The N-pivaloyl-protected sub-
strate was treated with two equivalents of LIDA in
tetrahydrofuran at –75 °C for two hours before the orga-
nometallic intermediate was trapped with iodine and
benzaldehyde. The deprotected forms of the iodo com-
Mp 106–109 °C; yield: 3.0 g (43%).
1H NMR: d = 8.78 (q, 1 H, J = 1.1 Hz), 8.41 (s, 1 H), 8.07 (d, 1 H,
J = 4.0 Hz), 1.40 (s, 9 H).
Synthesis 2004, No. 10, 1619–1624 © Thieme Stuttgart · New York

1622
F. Cottet et al.
PAPER
13C NMR: d = 175.6, 150.6, 144.0 (q, J = 4.0 Hz), 134.9 (q, J = 3.2),
123.6 (q, J = 22.3 Hz), 122.7 (q, J = 271.5), 121.4, 40.5, 27.4 (3 C).
mmol) in THF (6 mL) at 0 °C. After 2 h, CO2 was bubbled into the
solution for 20 min. The mixture was partitioned between Et2O (20
mL) and 6.0 M HCl (10 mL). After another extraction of the aque-
ous layer with Et2O (10 mL), the combined organic layers were
dried and evaporated to yield 0.63 g (94%) of a yellowish solid
which crystallized from a 6:1 (v/v) mixture of hexanes and EtOAc
as colorless needles.
Derivatives of 3-Chloro-2-(trifluoromethyl)pyridine
3-Chloro-2-(trifluoromethyl)pyridine-4-carboxylic Acid (1)
Diisopropylamine (2.8 mL, 2.0 g, 20 mmol) and 3-chloro-2-(trifluo-
romethyl)pyridine (3.6 g, 20 mmol) were consecutively added to a
solution of BuLi (20 mmol) in THF (30 mL) and hexanes (10 mL)
and cooled in a dry ice/MeOH bath. After 2 h at –75 °C, the mixture
was poured onto an excess of freshly crushed dry ice. After evapo-
ration of the volatiles, the residue was crystallized from a 9:1 (v/v)
mixture of 2.0 M HCl–EtOH as colorless needles.
Mp 112–114 °C; yield: 0.52 g (77%).
1H NMR: d = 9.23 (d, 1 H, J = 1.6 Hz), 8.54 (d, 1 H, J = 1.6 Hz).
13C NMR: d = 168.0, 148.4 (q, J = 35 Hz), 147.9, 141.3, 131.3,
128.9, 120.5 (q, J = 276 Hz).
Anal. Calcd for C7H3ClF3NO2 (225.55): C, 37.27; H, 1.34. Found:
C, 37.04; H, 1.24.
Mp 184–186 °C; yield: 3.66 g (81%).
1H NMR*: d = 8.82 (d, 1 H, J = 4.7 Hz), 8.05 (d, 1 H, J = 4.8 Hz).
13C NMR*: d = 164.4, 148.0, 145.6 (q, J = 34 Hz), 142.7, 127.6,
127.6, 121.6 (q, J = 275 Hz).
5-Chloro-6-(trifluoromethyl)pyridine-2-carboxylic Acid (5)
N,N-Dimethylaminoethanol (0.60 mL, 0.53 g, 6.0 mmol) in hexanes
(8 mL) was added dropwise over 15 min to BuLi (12 mmol) in hex-
anes (7.5 mL) and kept at 0 °C. At –75 °C, 3-chloro-2-(trifluorom-
ethyl)pyridine (0.36 g, 2.0 mmol) in hexanes (3.0 mL) was added
and the temperature was maintained for 45 min before the reaction
mixture was poured onto an excess of freshly crushed dry ice cov-
ered with Et2O (50 mL). At 25 °C, the reaction mixture was extract-
ed with a 2.0 M aq solution of NaOH (3 × 25 mL). The combined
aqueous layers were washed with Et2O (2 × 25 mL), acidified to pH
1 with 20% HCl, extracted with Et2O (3 × 25 mL), dried and evap-
orated. Most of the valeric acid was eliminated by co-evaporating
the oily residue 4 times with toluene (40 mL). Crystallization from
cyclohexane gave 0.17 g of yellowish needles. After sublimation, a
colorless solid was obtained.
Anal. Calcd for C7H3ClF3NO2 (225.55): C, 37.28; H, 1.34. Found:
C, 37.46; H, 1.41.
3-Chloro-4-iodo-2-(trifluoromethyl)pyridine (2)
Iodine (5.1 g, 20 mmol) in THF (20 mL) was poured all at once into
an analogously prepared reaction mixture. After evaporation of the
solvents, the residue was dissolved in Et2O (40 mL) and washed
with a 2.0 M aq solution of Na2S2O3 (20 mL), 2.0 M HCl (20 mL),
and a sat. aq solution of NaHCO3 (20 mL), dried and evaporated.
The residue crystallized from hexanes as yellowish needles.
Mp 81–82 °C; yield: 5.27 g (86%).
1H NMR: d = 8.17 (d, 1 H, J = 4.8 Hz), 8.04 (d, 1 H, J = 4.8 Hz).
13C NMR: d = 146.1, 144.9 (q, J = 34 Hz), 138.1, 135.1, 120.4 (q,
J = 273 Hz).
Mp 106–108 °C; yield: 0.12 g (26%).
1H NMR: d = 8.38 (d, 1 H, J = 8.3 Hz), 8.16 (d, 1 H, J = 8.3 Hz).
13C NMR: d = 163.1, 144.1 (q, J = 36 Hz), 143.7, 142.1, 135.4,
127.8, 120.1 (q, J = 276 Hz).
Anal. Calcd for C6H2ClF3IN (307.44): C, 23.44; H, 0.65. Found: C,
23.40; H, 0.71.
Anal. Calcd for C7H3ClF3NO2 (225.55): C, 37.27; H, 1.34. Found:
C, 37.63; H, 1.50.
5-Iodo-3-chloro-2-(trifluoromethyl)pyridine (3)
BuLi (15 mmol) in hexanes (9.1 mL) and 3-chloro-4-iodo-2-(tri-
fluoromethyl)pyridine (4.6 g, 15 mmol) were consecutively added
to diisopropylamine (2.1 mL, 1.5 g, 15 mmol) in THF (60 mL) and
kept in a dry ice/MeOH bath. After 2 h at –75 °C, the mixture was
treated with MeOH (2.0 mL) and the solvents were evaporated. The
residue was taken up in Et2O (30 mL) and washed with 2.0 M HCl
(20 mL) and a sat. aq solution of NaHCO3 (20 mL). The organic
phase was dried and evaporated to yield 4.38 g of an orange oil con-
taining 5-iodo-3-chloro-2-(trifluoromethyl)pyridine (78%), 3-chlo-
ro-4-iodo-2-(trifluoromethyl)pyridine (9%) and 3-chloro-2-
(trifluoromethyl)pyridine (9%) as determined by gas chromatogra-
phy (DB-WAX, 30 m, 150 °C; DB-1, 30 m, 150 °C; tridecane as an
internal standard). The products were eluted from silica gel (0.10 L)
with a 9:1 (v/v) mixture of hexanes and EtOAc. After evaporation
of the solvents, 5-iodo-3-chloro-2-(trifluoromethyl)pyridine crys-
tallized slowly as colorless needles.
Derivatives of 2-Bromo-6-(trifluoromethyl)pyridine
2-Bromo-6-(trifluoromethyl)pyridine-3-carboxylic Acid (6)
2-Bromo-6-(trifluoromethyl)pyridine4 (2.3 g, 10 mmol) in THF (25
mL) was added over 10 min to a solution prepared from BuLi (10
mmol) and diisopropylamine (1.4 mL, 1.0 g, 10 mmol) in THF (15
mL) and hexanes (6.5 mL) at –85 °C. After 2 h at –85 °C, the reac-
tion mixture was poured onto an excess of freshly crushed dry ice
covered with THF (25 mL). The solvents were evaporated and the
residue partitioned between Et2O (20 mL) and 6.0 M HCl (15 mL).
The aqueous phase was extracted with Et2O (20 mL). The combined
organic phases were dried and evaporated and the residue crystal-
lized from a 5:1 (v/v) mixture of heptane and EtOAc to give the
product as colorless needles.
Mp 116–119 °C; yield: 1.32 g (49%).
Mp 42–44 °C; yield: 3.20 g (69%).
1H NMR: d = 8.78 (d, 1 H, J = 1.6 Hz), 8.24 (dq, 1 H, J = 1.6, 0.6
Hz).
13C NMR: d = 152.9, 147.2, 143.8 (q, J = 35 Hz), 131.0, 121.0 (q,
J = 275 Hz), 96.6.
1H NMR: d = 8.46 (d, 1 H, J = 8.0 Hz), 7.81 (d, 1 H, J = 8.0 Hz).
13C NMR: d = 168.9, 150.8 (q, J = 35 Hz), 142.0, 141.7, 130.8,
120.0 (q, J = 275 Hz), 119.2 (q, J = 3 Hz).
Anal. Calcd for C7H3BrF3NO2 (270.00): C, 31.14; H, 1.12. Found:
C, 31.08; H, 1.21.
Anal. Calcd for C6H2ClF3IN (307.44): C, 23.44; H, 0.65. Found: C,
23.57; H, 0.65.
2-Bromo-3-iodo-6-(trifluoromethyl)pyridine (7)
Analogously, 2-bromo-6-(trifluoromethyl)pyridine (9.0 g, 40
mmol) was treated with a solution of lithium diisopropylamide (40
mmol) in THF (60 mL) and hexanes (25 mL) for 2 h at –85 °C be-
fore iodine (11 g, 40 mmol) in THF (50 mL) was added. The sol-
5-Chloro-6-(trifluoromethyl)pyridine-3-carboxylic Acid (4)
Isopropylmagnesium chloride (3.0 mmol) in THF (1.4 mL) was
added to 3-chloro-5-iodo-2-(trifluoromethyl)pyridine (0.92 g, 3.0
Synthesis 2004, No. 10, 1619–1624 © Thieme Stuttgart · New York

PAPER
Site-Selective Metalations and Functionalizations of Halo(trifluoromethyl)pyridines
1623
vents were evaporated. The residue was taken up in Et2O (0.10 L)
and washed with a 2.0 M aq solution of Na2S2O3 (20 mL), 2.0 M
HCl (2 × 50 mL), a sat. solution of NaHCO3 (50 mL) and brine (50
mL), dried and evaporated. The residue was distilled to afford
slightly yellowish needles.
Anal. Calcd for C9H11BrF3NSi (298.18): C, 36.25; H, 3.72. Found:
C, 36.64; H, 3.53.
6-Bromo-2-(trifluoromethyl)pyridine-3-carboxylic Acid (12)
2-Bromo-6-trifluoromethyl-3-(trimethylsilyl)pyridine (5.3 mL, 7.5
g, 25 mmol) was added to the solution prepared from BuLi (25
mmol) and 2,2,6,6-tetramethylpiperidine (4.2 mL, 3.5 g, 25 mmol)
in THF (50 mL) and hexanes (16 mL) and kept in a dry ice/MeOH
bath. After 45 min at –75 °C, the reaction mixture was poured onto
an excess of freshly crushed dry ice covered with THF (25 mL). The
solvents were evaporated and the residue partitioned between Et2O
(0.10 L) and 6.0 M HCl (50 mL). The organic phase was then evap-
orated and the residue dissolved in THF (50 mL) containing tetrabu-
tylammonium fluoride trihydrate (5.6 g, 18 mmol). The mixture
was refluxed for 5 min, before being evaporated. The residue was
partitioned between Et2O (100 mL) and 6.0 M HCl (25 mL). The or-
ganic phase was evaporated and the residue crystallized from a 2:1
(v/v) mixture of heptane and EtOAc.
Mp 28–31 °C; bp 93–95 °C/5 Torr; yield: 11.0 g (78%).
1H NMR: d = 8.31 (d, 1 H, J = 8.0 Hz), 7.37 (d, 1 H, J = 8.0 Hz).
13C NMR: d = 150.1, 149.1, 148.0 (q, J = 36 Hz), 121.0 (q, J = 274
Hz), 120.3 (q, J = 3 Hz), 104.3.
Anal. Calcd for C6H2BrF3IN (351.89): C, 20.48; H, 0.57. Found: C,
20.48; H, 0.63.
2-Bromo-4-iodo-6-(trifluoromethyl)pyridine (8)
Diisopropylamine (3.5 mL, 2.5 g, 25 mmol) and 2-bromo-3-iodo-6-
(trifluoromethyl)pyridine (8.8 g, 25 mmol) in THF (10 mL) were
consecutively added in 10 min interval to a solution of BuLi (25
mmol) in hexanes (16 mL) and THF (30 mL) and kept in a dry ice/
MeOH bath. After 15 min at –75 °C, the reaction mixture was par-
titioned between 2.0 M HCl (30 mL) and Et2O (50 mL). The organic
phase was filtered through a pad of basic alumina (100 mL) and
eluted with Et2O (150 mL). After evaporation of the volatiles, the
residue crystallized from hexanes as colorless needles.
Mp 175–177 °C; yield: 3.34 g (49%).
1H NMR*: d = 8.28 (d, 1 H, J = 8.0 Hz), 8.08 (d, 1 H, J = 8.0 Hz).
13C NMR*: d = 165.8, 145.9 (q, J = 36 Hz), 143.4, 142.2, 132.8,
128.8 (q, J = 1 Hz), 121.5 (q, J = 275 Hz).
Anal. Calcd for C7H3BrF3NO2 (270.01): C, 31.14; H, 1.12. Found:
C, 31.45; H, 0.89.
Mp 115–116 °C (after sublimation); yield: 7.20 g (82%).
1H NMR: d = 8.10 (s, 1 H), 7.98 (s, 1 H).
13C NMR: d = 148.8 (q, J = 36 Hz), 142.5, 139.6, 128.8 (q, J = 3
2-Bromo-4-(trifluoromethyl)pyridine-3-carboxylic Acid (13)
Diisopropylamine (1.4 mL, 1.0 g, 10 mmol) and 2-bromo-4-(tri-
fluoromethyl)pyridine7 (2.3 g, 10 mmol) were consecutively added
to a solution of BuLi (10 mmol) in THF (20 mL) and hexanes (6.3
mL) and kept in a dry ice/MeOH bath. After 45 min at –75 °C, the
reaction mixture was poured onto an excess of freshly crushed dry
ice covered with THF (25 mL). The residue obtained after evapora-
tion of the volatiles crystallized from a 2:1 (v/v) mixture of 2.0 M
HCl and EtOH as colorless prisms.
Hz), 119.7 (q, J = 275 Hz), 107.2.
Anal. Calcd for C6H2BrF3IN (351.89): C, 20.48; H, 0.57. Found: C,
20.28; H, 0.80.
2-Bromo-6-(trifluoromethyl)pyridine-4-carboxylic Acid (9)
Isopropylmagnesium chloride (10 mmol) in THF (4.9 mL) was add-
ed to 2-bromo-4-iodo-6-(trifluoromethyl)pyridine (3.5 g, 10 mmol)
in THF (15 mL) at 0 °C. After 5 min, CO2 was bubbled into the re-
action mixture for 20 min. The solvents were evaporated and the
residue was partitioned between Et2O (20 mL) and 6.0 M HCl (20
mL). The aqueous phase was extracted again with Et2O (20 mL).
The combined organic layers were dried and evaporated. The resi-
due was crystallized from heptane to give the product as colorless
needles.
Mp 159–161 °C; yield: 1.46 g (54%).
1H NMR: d = 8.61 (d, 1 H, J = 5.1 Hz), 7.57 (d, 1 H, J = 5.1 Hz).
13C NMR: d = 166.0, 150.7, 139.8, 136.8 (q, J = 34 Hz), 131.1,
121.4 (q, J = 275 Hz), 119.0 (q, J = 4 Hz).
Anal. Calcd for C7H3BrF3NO2 (270.01): C, 31.14; H, 1.12. Found:
C, 31.09; H, 1.12.
Mp 125–127 °C; yield: 2.37 g (88%).
1H NMR: d = 8.33 (s, 1 H), 8.26 (s, 1 H).
13C NMR: d = 168.1, 149.9 (q, J = 36 Hz), 143.5, 140.1, 131.5,
120.2 (q, J = 275 Hz), 119.2 (q, J = 3 Hz).
5-Bromo-2-(trifluoromethyl)pyridine-4-carboxylic Acid (14)
An analogous reaction performed with 5-bromo-2-(trifluorometh-
yl)pyridine (2.3 g, 10 mmol) afforded colorless pallets.
Mp 215–218 °C; yield: 1.81 g (67%).
1H NMR*: d = 9.07 (s, 1 H), 8.19 (s, 1 H).
Anal. Calcd for C7H3BrF3NO2 (270.00): C, 31.14; H, 1.12. Found:
C, 31.23; H, 0.84.
13C NMR*: d = 164.8, 155.1, 147.6 (q, J = 35 Hz), 142.8, 122.9,
2-Bromo-6-trifluoromethyl-3-(trimethylsilyl)pyridine (10)
At –85 °C, 2-bromo-6-(trifluoromethyl)pyridine (9.0 g, 40 mmol)
in THF (0.12 L) was added in the course of 20 min to the solution
prepared from BuLi (40 mmol) and diisopropylamine (5.6 mL, 4.0
g, 40 mmol) in THF (50 mL) and hexanes (25 mL). After 45 min at
–85 °C, the mixture was treated with chlorotrimethylsilane (5.1 mL,
4.4 g, 40 mmol), filtered through a pad of basic alumina (50 mL)
and eluted with Et2O (50 mL). Upon distillation, a colorless oil was
collected.
122.3 (q, J = 3 Hz), 122.3 (q, J = 273 Hz).
Anal. Calcd for C7H3BrF3NO2 (270.00): C, 31.14; H, 1.12. Found:
C, 31.07; H, 1.14.
2-Iodo-4-(trifluoromethyl)pyridine-3-carboxylic Acid (15)
2-Iodo-4-(trifluoromethyl)pyridine (2.7 g, 10 mmol) in THF (5.0
mL) was added to a solution prepared from BuLi (10 mmol) and di-
isopropylamine (1.4 mL, 1.0 g, 10 mmol) in hexanes (5.6 mL) and
THF (10 mL), kept in a dry ice/MeOH bath. After 2 h at –75 °C, the
reaction mixture was poured onto an excess of freshly crushed dry
ice covered with THF (25 mL). At 25 °C, H2O (50 mL) was added.
The aqueous layer was washed with Et2O (3 × 50 mL), acidified to
pH 1 with 4.0 M HCl and extracted with Et2O (3 × 50 mL). The
combined organic phases were dried and evaporated. Crystalliza-
tion of the residue from a 1:1 mixture of CHCl3 and MeOH afforded
colorless prisms.
Bp 108–110 °C/11 Torr; yield: 10.1 g (85%).
1H NMR: d = 7.90 (d, 1 H, J = 7.7 Hz), 7.61 (d, 1 H, J = 7.7 Hz),
0.46 (s, 9 H).
13C NMR: d = 149.0 (q, J = 36 Hz), 148.9, 146.3, 143.6, 120.9 (q,
J = 274 Hz), 118.9 (q, J = 3 Hz).
Synthesis 2004, No. 10, 1619–1624 © Thieme Stuttgart · New York

1624
F. Cottet et al.
PAPER
Mp 182–184 °C (dec.); yield: 1.62 g (51%).
1H NMR*: d = 8.70 (d, 1 H, J = 5.2 Hz), 7.85 (d, 1 H, J = 5.2 Hz).
13C NMR*: d = 162.6, 153.0, 152.5, 135.3 (q, J = 34 Hz), 122.5 (q,
J = 275 Hz), 120.3 (q, J = 4 Hz), 117.3.
H2SO4 (0.15 L). The solution was heated for 15 h under reflux be-
fore it was poured into a mixture of ice (0.15 kg) and concentrated
NH3 (0.10 L). The product was extracted with EtOAc (3 × 25 mL),
purified by column chromatography (see above) and obtained as
colorless needles.
Anal. Calcd for C7H3F3INO2 (317.00): C, 26.52; H, 0.95. Found: C,
26.29; H, 1.04.
Mp 125–127 °C; yield: 2.66 g (55%).
1H NMR: d = 8.08 (s, 1 H), 5.68 (s, 2 H).
4-Iodo-2-(trifluoromethyl)pyridine-3-carboxylic Acid (16)
The same protocol was applied to 4-iodo-2-(trifluoromethyl)pyri-
dine (2.7 g, 10 mmol) and the product was obtained as colorless
prisms from a 1:1 (v/v) mixture of CHCl3and MeOH.
13C NMR: d = 156.2, 144.3 (q, J = 7.2 Hz), 122.6 (q, J = 273.1 Hz),
121.8, 121.5, 108.2.
Anal. Calcd for C6H3ClF3IN2 (322.45): C, 22.35; H, 0.94. Found: C,
22.21; H, 0.91.
Mp 217–219 °C (dec.); yield: 0.98 g (31%).
[2-Amino-3-chloro-5-(trifluoromethyl)pyridin-4-yl](phe-
nyl)methanol (18)
N-[3-Chloro-4-(a-hydroxybenzyl)-5-(trifluoromethyl)pyridin-2-
yl]-2,2-dimethylpropanamide (5.8 g, 15 mmol) was hydrolyzed and
isolated as described in the preceding paragraph to afford the prod-
uct as colorless needles.
1H NMR*: d = 8.45 (d, 1 H, J = 5.2 Hz), 8.32 (d, 1 H, J = 5.2 Hz).
13C NMR*: d = 167.9, 151.5, 144.8 (q, J = 35 Hz), 139.8, 137.5,
122.6 (q, J = 276 Hz), 107.5.
Anal. Calcd for C7H3F3INO2 (317.00): C, 26.52; H, 0.95. Found: C,
26.57; H, 1.08.
Mp 126–129 °C; yield: 3.09 g (68%).
1H NMR: d = 8.35 (s, 1 H), 7.3 (m, 5 H), 6.30 (s, 1 H), 5.40 (s, 2 H),
3.36 (s, 1 H).
13C NMR: d = 158.3, 147.6, 144.6 (q, J = 6.4 Hz), 140.2, 128.4,
127.5, 125.4, 123.9 (q, J = 273.0 Hz), 116.4 (q, J = 30.6), 114.6,
70.8.
N-[3-Chloro-4-iodo-5-(trifluoromethyl)pyridin-2-yl]-2,2-di-
methylpropanamide
Diisopropylamine (3.5 mL, 2.5 g, 25 mmol) and N-[3-chloro-5-(tri-
fluoromethyl)pyridin-2-yl]-2,2-dimethylpropanamide (7.0 g, 25
mmol) were added consecutively to BuLi (50 mmol) in THF (65
mL) and hexanes (35 mL), cooled in a dry ice/MeOH bath. After
having been kept for 2 h at –75 °C, the mixture was treated with io-
dine (6.3 g, 25 mmol), absorbed on silica gel (20 mL) and eluted
from a column filled with more silica (0.10 L) using solvent mix-
tures which were gradually changed from neat Et2O to neat CH2Cl2.
The product was collected as colorless needles.
Anal. Calcd for C13H10ClF3N2O (302.68): C, 51.59; H, 3.33. Found:
C, 51.27; H, 3.25.
Acknowledgment
Mp 152–154 °C; yield: 8.74 g (86%).
1H NMR: d = 8.51 (s, 1 H), 8.33 (s, 1 H), 1.37 (s, 9 H).
13C NMR: d = 175.7, 149.9, 144.2 (q, J = 7.2 Hz), 128.1, 127.7 (q,
J = 31.3), 121.9 (q, J = 273.8 Hz), 109.4, 40.7, 27.4 (3 C).
This work was financially supported by the Schweizerische Natio-
nalfonds zur Förderung der wissenschaftlichen Forschung, Bern
(grant 20-100’336-02). The authors are further indebted to the staff
of Ishihara Syngyo Kaisha Ltd., Tokyo, for a generous gift of star-
ting materials.
Anal. Calcd for C11H11ClF3IN2O (406.57): C, 32.50; H, 2.73.
Found: C, 32.53; H, 2.90.
References
N-[3-Chloro-4-(a-hydroxybenzyl)-5-(trifluoromethyl)pyridin-
2-yl]-2,2-dimethylpropanamide
(1) Schlosser, M. Angew. Chem. 2004, review article in press.
(2) Cottet, F.; Schlosser, M. Eur. J. Org. Chem. 2004, in press.
(3) Schlosser, M.; Cottet, F. Eur. J. Org. Chem. 2002, 4181.
(4) Cottet, F.; Schlosser, M. Eur. J. Org. Chem. 2002, 327.
(5) Gros, P.; Fort, Y.; Quéguiner, G.; Caubère, P. Tetrahedron
Lett. 1995, 36, 4791.
(6) Gros, P.; Fort, Y.; Caubère, P. J. Chem. Soc., Perkin Trans.
1 1998, 1685.
(7) Cottet, F.; Marull, M.; Lefebvre, O.; Schlosser, M. Eur. J.
Org. Chem. 2003, 1559.
Prepared analogously by replacing iodine with benzaldehyde (2.5
mL, 2.7 g, 25 mmol). The reaction mixture was treated with 2.0 M
ethereal hydrogen chloride (30 mL, 60 mmol). The product was iso-
lated by column chromatography (as specified in the preceding
paragraph) as colorless needles.
Mp 168–170 °C; yield: 5.61 g (58%).
1H NMR: d = 8.90 (s, 1 H), 8.49 (s, 1 H), 7.4 (m, 5 H), 6.51 (d, 1 H,
J = 8.3 Hz), 3.43 (d, 1 H, J = 8.5 Hz), 1.33 (s, 9 H).
(8) Marull, M.; Schlosser, M. Eur. J. Org. Chem. 2003, 1569.
(9) Haga, T.; Fujikawa, K.-i.; Koyanagi, T.; Nakajima, T.;
Hayashi, K. Heterocycles 1984, 22, 117.
(10) Wang, Q.; Wei, H.-x.; Schlosser, M. Eur. J. Org. Chem.
1999, 3263.
13C NMR: d = 175.7, 152.0, 149.0, 144.4 (q, J = 7.2 Hz), 139.7,
128.4, 127.6, 125.6, 125.4, 123.2 (q, J = 273.9 Hz), 1221.9 (q,
J = 29.7 Hz), 121.3, 70.5, 40.6, 27.3 (3 C).
Anal. Calcd for C18H18ClF3N2O2 (386.80): C, 55.89; H, 4.69.
Found: C, 55.73; H, 4.82.
(11) Bobbio, C.; Schlosser, M. Eur. J. Org. Chem. 2001, 4533.
(12) Heiss, C.; Schlosser, M. Eur. J. Org. Chem. 2003, 447.
3-Chloro-4-iodo-5-(trifluoromethyl)pyridin-2-amine (17)
N-[3-Chloro-4-iodo-5-(trifluoromethyl)pyridin-2-yl]-2,2-dimethyl-
propanamide (6.1 g, 15 mmol) was added to an 20% aq solution of
Synthesis 2004, No. 10, 1619–1624 © Thieme Stuttgart · New York