Creating structural manifolds from a common precursor: Basicity gradient-driven isomerization of halopyridines

Article abstract of DOI:10.1002/1099-0690(200212)2002:24<4174::AID-EJOC4174>3.0.CO;2-6

5-Chloro-2,3-difluoropyridine, an intermediate in the manufacturing process of an industrial pesticide, can be hydrolyzed to 5-chloro-3-fluoro-2H-pyridinone and the latter converted into 2,5-dichloro-3-fluoropyridine (1a), 2-bromo-5-chloro-3-fluoropyridine (1b), 5-chloro-3-fluoro-2-iodopyridine (1c) and 3-chloro-5-fluoropyridine (1d). Consecutive treatment of these four substrates with lithium diisopropylamide and carbon dioxide or lithium diisopropylamide and iodine affords the corresponding 4-pyridinecarboxylic acids 2 and 4-iodopyridines 3, respectively. Amide-promoted deprotonation of such 4-iodopyridines 3 triggers an isomerization in which lithium and iodine change places. The resulting species can be trapped with carbon dioxide to give the acids 5a-c or neutralized to give the halopyridines 4a-c. The iodopyridines 4a and 4b can be converted into the acids 6a and 6b, the latter product leading also to the congeners 6c and 6d. The diiodopyridine 4c provides an entry to the halopyridine 4d, which at the same time may act as the precursor to the acid 5d, the acid 7 or the bisacid 8. Finally, the acid 9 is accessible from either one of the 5-chloro-3-fluoro-2-halopyridines 1b and 1c. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2002).

Full text of DOI:10.1002/1099-0690(200212)2002:24<4174::AID-EJOC4174>3.0.CO;2-6

FULL PAPER
Creating Structural Manifolds from a Common Precursor:
Basicity Gradient-Driven Isomerization of Halopyridines
Manfred Schlosser*[a,b] and Carla Bobbio[a]
Keywords: Molecular diversity / Carboxylation / Fluoropyridines / Halogen/metal permutation / Hydrogen/metal
permutation / Nucleophilic heteroaromatic substitution
5-Chloro-2,3-difluoropyridine, an intermediate in the manu-
facturing process of an industrial pesticide, can be hy-
drolyzed to 5-chloro-3-fluoro-2H-pyridinone and the latter
converted into 2,5-dichloro-3-fluoropyridine (1a), 2-bromo-5-
sulting species can be trapped with carbon dioxide to give
the acids 5a−c or neutralized to give the halopyridines 4a−c.
The iodopyridines 4a and 4b can be converted into the acids
6a and 6b, the latter product leading also to the congeners
chloro-3-fluoropyridine (1b), 5-chloro-3-fluoro-2-iodopyrid- 6c and 6d. The diiodopyridine 4c provides an entry to the
ine (1c) and 3-chloro-5-fluoropyridine (1d). Consecutive
treatment of these four substrates with lithium diisopropyl-
amide and carbon dioxide or lithium diisopropylamide and
iodine affords the corresponding 4-pyridinecarboxylic acids
2 and 4-iodopyridines 3, respectively. Amide-promoted de-
protonation of such 4-iodopyridines 3 triggers an isomeriz-
halopyridine 4d, which at the same time may act as the pre-
cursor to the acid 5d, the acid 7 or the bisacid 8. Finally, the
acid 9 is accessible from either one of the 5-chloro-3-fluoro-
2-halopyridines 1b and 1c.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ation in which lithium and iodine change places. The re- Germany, 2002)
The spontaneous isomerization of lithiated bromo- or to prepare 3,5-dichloro-2-fluoropyridine. The third sub-
iodoarenes and bromo- or iodopyridines to less basic spe-
cies is a powerful, though not widely known, tool for ra-
tional structural modification.[1] To demonstrate the prac-
tical utility of this method, we have recently reported the
site-controlled conversion of 2,3,5-trichloropyridine, 3,5-
dichloro-2-fluoropyridine and 5-chloro-2,3-difluoropyrid-
ine into each time three carboxylic acids, two of which were
isomeric and the third one was an iodinated derivative of
one of them.[2]
strate, 5-chloro-2,3-difluoropyridine, is the key intermediate
for the industrial manufacture of a herbicide. The availabil-
ity of this material incited us to extend the scope of our
investigations. To this end, 5-chloro-2,3-difluoropyridine
was hydrolyzed in an alkaline medium to the 5-chloro-3-
fluoro-2H-pyridinone (91%) which was then treated with
phosphoryl trichloride or phosphoryl tribromide to afford
2,5-dichloro-3-fluoropyridine (1a) or 2-bromo-5-chloro-3-
fluoropyridine (1b), respectively, in almost quantitative
yield (91 and 97%). In contrast, the reaction between the
pyridinone and iodine in the presence of red phosphorus
proceeded sluggishly and only small amounts (1Ϫ5%) of 5-
chloro-3-fluoro-2-iodopyridine (1c) could be isolated.
Therefore, this compound was prepared in a satisfactory
yield (59%) from the bromo analog 1b by halogen/metal
interconversion with isopropylmagnesium chloride and sub-
sequent addition of elemental iodine. Reductive removal of
the heaviest halogen in the halopyridine 1b with zinc gave
3-chloro-5-fluoropyridine (1d; 92%).
Treatment of the four substrates 1 with lithium diisoprop-
ylamide (LIDA) or another strong base (e.g. butyllithium
with starting materials 1a and 1d) followed by carb-
oxylation and neutralization gave the 4-pyridinecarboxylic
acids 2a (82%), 2b (74%), 2c (84%) and 2d (85%). The iodo
compounds 3a (80%), 3b (76%), 3c (86%) and 3d (89%)
were obtained when carbon dioxide was replaced by iodine
as the electrophile.
2,3,5-Trichloropyridine is a fairly inexpensive commercial
product and at the same time it can serve as the precursor
[a]
´
Institut de Chimie moleculaire et biologique, Ecole
´ ´
Polytechnique Federale, BCh
1015 Lausanne, Switzerland
[b]
´
´
Faculte des Sciences, Universite, BCh
1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
4174
 2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1224Ϫ4174 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 4174Ϫ4180

Basicity Gradient-Driven Isomerization of Halopyridines
FULL PAPER
to 6d (X ϭ H). Instead concomitant reductive deiodina-
tion[4] (I Ǟ Li) and 2-lithiation triggering a basicity gradi-
[3,5]
ent driven iodine migration
took place. Depending on
the choice of the trapping reagent, 3:2 mixtures of 3-chloro-
5-fluoropyridine (1d) and 5-chloro-3-fluoro-2-iodopyridine
(1c) or 3-chloro-5-fluoro-4-pyridinecarboxylic acid (2d) and
5-chloro-3-fluoro-2-iodo-4-pyridinecarboxylic acid (2c)
were produced.
When the iodo compounds 3aϪ3c were incubated with a
solution of lithium 2,2,6,6-tetramethylpiperidide (LITMP)
in tetrahydrofuran, deprotonation obviously had to occur
at the 6-position. However, the species thus generated could
not be trapped as it isomerized instantaneously by iodine/
metal permutation presumably involving small amounts of
the corresponding diiodopyridine as a turntable.[3] After the
mixture had been quenched with water, the trihaloiodopyri-
dines 4a, 4b and 4c were found by gas chromatography to
be present in 51%, 66% and 30% yield. However, due to
their contamination by reduction products, they were isol-
ated in only 46%, 57% and 23% yield, respectively. Expo-
sure of compounds 4aϪ4c to LIDA followed by carb-
oxylation afforded the acids 5a (89%), 5b (88%) and 5c
(82%) whereas the acids 6a (80%) and 6b (79%) were
formed when the deprotonation step was replaced by a
halogen/metal permutation performed with isopropyl-
magnesium chloride.
All what remained to be done was to prepare the still
missing target compounds 4d, 5d, 6c and 6d. The regio-
chemical preference for deprotonation at the position next
to fluorine is readily explained by the superior ortho-dir-
ecting effect of this element when compared with chlorine.[6]
For this reason, 3-chloro-5-fluoro-2,6-diiodopyridine (4c)
underwent with butyllithium a halogen/metal permutation
almost exclusively at the 6- and only marginally at the 2-
position. Reaction of the 2-pyridyllithium intermediate with
dry ice provided the 5-chloro-3-fluoro-6-iodo-2-pyridine-
carboxylic acid (7; 35%), whereas hydrolysis gave the halo-
pyridine 4d (60%) which was submitted to consecutive de-
protonation and carboxylation to afford the acid 5d (85%).
Treatment of 3-chloro-5-fluoro-2,6-diiodopyridine (4c) with
2 equiv. of butyllithium generated a dilithio species as evi-
denced by the trapping product 3-chloro-5-fluoro-2,6-di-
carboxylic acid (8; 39%).
The reaction takes a different course when the halogen at
the 2-position is missing. The base then attacks the fluo-
rine-adjacent rather than the chlorine-adjacent position.
Thus, none of the intermediates is generated that could lead
to the compounds 4d and 5d and from there ultimately also
Both acids 6c (46%) and 6d (67%) could be selectively
prepared from 6-bromo-3-chloro-5-fluoro-2-pyridinecar-
boxylic acid (6b) by esterification and silyl-mediated bro-
Eur. J. Org. Chem. 2002, 4174Ϫ4180
4175

M. Schlosser, C. Bobbio
FULL PAPER
1. Starting Materials
5-Chloro-3-fluoro-2(1H)-pyridinone: 5-Chloro-2,3-difluoropyridine
(0.30 kg, 2.0 mol) in an aqueous solution (1.5 L) of sodium hydrox-
ide (0.30 kg) was heated to 75 °C for 20 h. At 25 °C, precipitated
salts were removed. The filtrate was diluted with water (3.0 L),
acidified with hydrochloric acid to pH ϭ 1 and heated under reflux
until the solution had become homogeneous. At 25 °C, the product
crystallized as colorless needles; m.p. 149Ϫ151 °C (from chloro-
form); 268 g (91%). 1H NMR (D3CCOCD3): δ ϭ 7.47 (dd, J ϭ
3.8, 1.4 Hz, 1 H), 7.42 (dd, J ϭ 10.1, 3.7 Hz, 1 H) ppm. 13C NMR
(D3CCOCD3): δ ϭ 155.6 (d, J ϭ 25 Hz), 152.5 (d, J ϭ 254 Hz),
130.2 (d, J ϭ 6 Hz), 123.9 (d, J ϭ 20 Hz), 111.1 (d, J ϭ 7 Hz)
ppm. C5H3ClFNO (147.54): calcd. C 40.70, H 2.05; found C 40.90,
H 2.20.
[7]
mine/iodine displacement followed by hydrolysis and by
reduction, respectively. The 3-chloro-5-fluoro-2-pyridine-
carboxylic acid 6d was also obtained from 3-chloro-5-
fluoro-2-iodopyridine (4d) by consecutive treatment with
butyllithium and dry ice in a 79% yield.
2,5-Dichloro-3-fluoropyridine
(1a):
N,N-Dimethylformamide
(4.0 mL, 3.6 g, 50 mmol), phosphoryl trichloride (47 mL, 77 g, 0.50
mol) and 5-chloro-3-fluoro-2(1H)-pyridinone (74 g, 0.50 mol) were
heated to 130 °C for 2 h, before being submitted to a steam distilla-
tion. Extraction of the condensate with diethyl ether (3 ϫ 50 mL),
drying with sodium sulfate, filtration, evaporation of the solvent
and crystallization from hexanes afforded colorless platelets; m.p.
1
34Ϫ35 °C; b.p. 55Ϫ56 °C/2 Torr; yield: 76 g (91%). H NMR: δ ϭ
8.22 (d, J ϭ 2.0 Hz, 1 H), 7.54 (ddd, J ϭ 7.5, 2.1, 0.5 Hz, 1 H)
ppm. 13C NMR: δ ϭ 154.2 (d, J ϭ 267 Hz), 143.6 (d, J ϭ 5 Hz),
137.4 (d, J ϭ 19 Hz), 131.1 (s), 124.9 (d, J ϭ 21 Hz) ppm.
C5H2Cl2FN (165.98): calcd. C 36.18, H 1.21; found C 36.18; H
1.21.
2-Bromo-5-chloro-3-fluoropyridine (1b): Analogously from 5-
chloro-3-fluoro-2(1H)-pyridinone (74 g, 0.50 mol) and phosphoryl
tribromide (0.14 kg, 0.50 mol); colorless platelets; m.p. 28Ϫ30 °C
(from hexanes); b.p. 77Ϫ78 °C/7 Torr; yield: 102 g (97%). 1H NMR:
δ ϭ 8.23 (d, J ϭ 2.2 Hz, 1 H), 7.48 (dd, J ϭ 7.0, 2.2 Hz, 1 H) ppm.
13C NMR: δ ϭ 155.6 (d, J ϭ 265 Hz), 144.3 (d, J ϭ 5 Hz), 131.6
(s), 127.7 (d, J ϭ 23 Hz), 124.3 (d, J ϭ 22 Hz) ppm. C5H2BrClFN
(210.44): calcd. C 28.54, H 0.96; found C 28.52, H 0.95.
Finally, the 5-chloro-3-fluoro-2-pyridinecarboxylic acid
(9) was prepared in a straight-forward manner by halogen/
metal permutation and carboxylation. Depending on the
starting material, 2-bromo-5-chloro-3-fluoropyridine or 5-
chloro-3-fluoro-2-iodopyridine, the yield attained was 71%
and 94%, respectively.
5-Chloro-3-fluoro-2-iodopyridine (1c): 2-Bromo-5-chloro-3-fluoro-
pyridine (1b; 21 g, 0.10 mol) in tetrahydrofuran (50 mL) was added
in the course of 15 min to a 2.0  solution of isopropylmagnesium
chloride (0.10 mol) in tetrahydrofuran (50 mL), kept in an ice bath.
After 2 h at 0 °C, the mixture was poured into a precooled solution
of iodine (25 g, 0.10 mol) in tetrahydrofuran (0.10 L) and kept at
Ϫ75 °C for 1 h with continuous stirring, before being partitioned
between brine (0.10 L) and diethyl ether (70 mL). The organic
phase was washed with a saturated aqueous solution of sodium
thiosulfate (50 mL), dried with sodium sulfate, filtered and the
solvents evaporated. Upon distillation under reduced pressure a
yellowish liquid was collected that slowly crystallized; colorless
needles; m.p. 39Ϫ40 °C (from methanol); b.p. 91Ϫ92 °C/6 Torr;
yield: 15 g (59%). 1H NMR: δ ϭ 8.26 (d, J ϭ 2.1 Hz, 1 H), 7.36
(dd, J ϭ 6.8, 2.2 Hz, 1 H) ppm. 13C NMR: δ ϭ 158.6 (d, J ϭ
263 Hz), 145.5 (d, J ϭ 4 Hz), 132.2 (d, J ϭ 2 Hz), 122.8 (d, J ϭ
23 Hz), 103.6 (d, J ϭ 29 Hz) ppm. C5H2ClFIN (257.43): calcd. C
23.33, H 0.78; found C 23.30, H 0.83.
3-Chloro-5-fluoropyridine (1d): 2-Bromo-5-chloro-3-fluoropyridine
(1b; 63 g, 0.30 mol) was stirred in an aqueous solution of sodium
hydroxide (0.24 L, 0.60 mol) in the presence of zinc powder (29 g,
0.45 mol) for 6 h at 25 °C. The mixture was diluted with water and
Experimental Section
Generalities: For the working practice and abbreviations, consult
previous articles from this laboratory .[2,8,9] 1H and 13C NMR spec-
tra were recorded at 400 and 101 MHz, respectively, for samples steam-distilled. Drying with sodium sulfate and distillation under
dissolved in deuteriochloroform unless stated otherwise, chemical
shifts being given relative to the signal of tetramethylsilane used as
an internal standard.
reduced pressure afforded a colorless liquid that crystallized spon-
taneously; m.p. 26Ϫ27 °C; b.p. 132Ϫ134 °C; yield: 36.3 g (92%).
1H NMR: δ ϭ 8.43 (s, broad, 1 H), 8.40 (d, J ϭ 2.5 Hz, 1 H), 7.47
4176
Eur. J. Org. Chem. 2002, 4174Ϫ4180

Basicity Gradient-Driven Isomerization of Halopyridines
FULL PAPER
(dt, J ϭ 8.1, 2.4 Hz, 1 H) ppm. 13C NMR: δ ϭ 158.6 (d, J ϭ
262 Hz), 144.6 (d, J ϭ 4 Hz), 136.0 (d, J ϭ 23 Hz), 131.8 (d, J ϭ
4 Hz), 123.1 (d, J ϭ 21 Hz) ppm. C5H3ClFN (131.54): calcd. C
45.65, H 2.30; found C 45.69, H 2.22.
25 mmol) in tetrahydrofuran (20 mL) was added. After 1 h at Ϫ75
°C, the mixture was warmed up to 25 °C and water (30 mL) and
diethyl ether (10 mL) were added. The organic phase was decanted,
washed with a saturated aqueous solution (20 mL) of sodium thio-
sulfate, dried and the solvents evaporated; colorless cubes; m.p.
1
2. Di- and Trihalo-4-pyridinecarboxylic Acids
114Ϫ116 °C (from chloroform); yield: 5.8 g (80%). H NMR: δ ϭ
8.18 (s) ppm. 13C NMR: δ ϭ 155.4 (d, J ϭ 262 Hz), 142.5 (s), 136.8
(s), 136.0 (d, J ϭ 23 Hz), 99.5 (d, J ϭ 26 Hz) ppm. C5HCl2FIN
(291.87): calcd. C 20.58, H 0.35; found C 20.61, H 0.29.
2,5-Dichloro-3-fluoro-4-pyridinecarboxylic Acid (2a): Diisopropyl-
amine (3.5 mL, 2.5 g, 25 mmol) and 2,5-dichloro-3-fluoropyridine
(1a; 4.1 g, 25 mmol) were consecutively added to a solution of bu-
tyllithium (25 mmol) in tetrahydrofuran (35 mL) and hexanes
(15 mL) kept in a dry ice/methanol bath. After 2 h at Ϫ75 °C, the
mixture was poured on an excess of freshly crushed solid carbon
dioxide. After evaporation of the volatiles, the residue was taken
up in water (50 mL), washed with diethyl ether (2 ϫ 15 mL), acidi-
fied to pH ϭ 1 and extracted with diethyl ether (3 ϫ 25 mL). After
evaporation of the solvent, the product was purified by crystalliza-
tion; m.p. 151Ϫ152 °C (from chloroform); yield: 4.3 g (82%). 1H
NMR (D3CCOCD3): δ ϭ 8.45 (s) ppm. 13C NMR (D3CCOCD3):
δ ϭ 161.5 (s), 151.5 (d, J ϭ 266 Hz), 145.6 (d, J ϭ 6 Hz), 138.3 (d,
J ϭ 19 Hz), 132.1 (d, J ϭ 19 Hz), 128.4 (s) ppm. C6H2Cl2FNO2
(209.99): calcd. C 34.32, H 0.96; found C 34.24, H 0.98.
2-Bromo-5-chloro-3-fluoro-4-iodopyridine (3b): Analogously from 2-
bromo-5-chloro-3-fluoropyridine (1b; 5.3 g, 25 mmol); colorless
prisms; m.p. 111Ϫ114 °C (from ethyl acetate); yield: 6.4 g (76%).
1H NMR: δ ϭ 8.20 (s) ppm. 13C NMR: δ ϭ 156.6 (d, J ϭ 261 Hz),
143.3 (d, J ϭ 6 Hz), 137.4 (s), 126.2 (d, J ϭ 27 Hz), 99.0 (d, J ϭ
26 Hz) ppm. C5HBrClFIN (336.33): calcd. C 17.86, H 0.30; found
C 17.93, H 0.50.
5-Chloro-3-fluoro-2,4-diiodopyridine (3c): Analogously from 5-
chloro-3-fluoro-2-iodopyridine (1c; 6.4 g, 25 mmol); colorless
1
needles; m.p. 120Ϫ121 °C (from methanol); yield: 8.2 g (86%). H
NMR: δ ϭ 8.18 (s) ppm. 13C NMR: δ ϭ 159.1 (d, J ϭ 258 Hz),
144.5 (d, J ϭ 5 Hz), 137.8 (s), 101.6 (d, J ϭ 33 Hz), 97.3 (d, J ϭ
28 Hz) ppm. C5HClFI2N (383.33): calcd. C 15.67, H 0.26; found
2-Bromo-5-chloro-3-fluoro-4-pyridinecarboxylic Acid (2b): Analog-
ously from 2-bromo-5-chloro-3-fluoropyridine (1b; 5.3 g, C 15.78, H 0.38.
25 mmol); colorless prisms; m.p. 192Ϫ194 °C (from ethyl acetate);
1
yield: 4.7 g (74%). H NMR (D3CCOCD3): δ ϭ 8.48 (s) ppm. 13C
NMR (D3CCOCD3): δ ϭ 161.4 (s), 152.8 (d, J ϭ 265 Hz), 146.3
(d, J ϭ 6 Hz), 131.4 (d, J ϭ 21 Hz), 128.8 (d, J ϭ 24 Hz), 128.7
(s) ppm. C6H2BrClFNO2 (254.45): calcd. C 28.32, H 0.79; found
C 28.38, H 0.86.
3-Chloro-5-fluoro-4-iodopyridine (3d): As described for compound
2d starting from 3-chloro-5-fluoropyridine (1d; 3.3 g, 25 mmol) but
adding, after 2 h at Ϫ75 °C, a solution of iodine (6.3 g, 25 mmol)
in tetrahydrofuran (20 mL). At 25 °C, water (30 mL) and diethyl
ether (10 mL) were added. The organic phase was decanted,
washed with a saturated aqueous solution (20 mL) of sodium thio-
sulfate, dried with sodium sulfate, filtered and the solvents evapo-
rated; colorless needles; m.p. 113Ϫ115 °C (from methanol); yield:
5.7 g (89%). 1H NMR: δ ϭ 8.37 (s, 1 H), 8.19 (s, broad, 1 H) ppm.
5-Chloro-3-fluoro-2-iodo-4-pyridinecarboxylic Acid (2c): Analog-
ously from 5-chloro-3-fluoro-2-iodopyridine (1c; 6.4 g, 25 mmol);
colorless prisms; m.p. 217 °C (decomp.; from methanol); yield:
6.3 g (84%). 1H NMR (D3CCOCD3): δ ϭ 8.49 (s) ppm. 13C NMR 13C NMR: δ ϭ 159.9 (d, J ϭ 259 Hz), 144.3 (d, J ϭ 4 Hz), 137.7
(D3CCOCD3): δ ϭ 161.4 (s), 155.6 (d, J ϭ 262 Hz), 147.4 (d, J ϭ
(s), 134.8 (d, J ϭ 27 Hz), 98.6 (d, J ϭ 24 Hz) ppm. C5H2ClFIN
5 Hz), 129.7 (d, J ϭ 21 Hz), 129.0 (s), 105.2 (d, J ϭ 29 Hz) ppm. (257.43): calcd. C 23.33, H 0.78; found C 23.26, H 0.77.
C6H2ClFINO2 (301.44): calcd. C 23.91, H 0.67; found C 23.85,
4. 6-Iodo-Substituted Di- and Trihalopyridines
H 0.65.
2,5-Dichloro-3-fluoro-6-iodopyridine (4a): At Ϫ100 °C, 2,2,6,6-
tetramethylpiperidine (8.5 mL, 7.1 g, 50 mmol) and 2,5-dichloro-3-
fluoro-4-iodopyridine (3a; 7.3 g, 25 mmol) were consecutively ad-
ded to a solution of butyllithium (50 mmol) in neat tetrahydrofuran
(50 mL). After 15 min at Ϫ75 °C, the mixture was treated with
methanol before being poured into water (30 mL) and diethyl ether
(10 mL). The organic phases were washed with brine (3 ϫ 50 mL).
According to gas chromatography (30 m, DB-WAX, 120 °C; 30 m,
DB-23, 120 °C; ‘‘internal standard’’: nonadecane), it contained
22% of 2,5-dichloro-3-fluoropyridine (1a) and 51% of the iodo
compound 4a. The latter was isolated upon distillation as an oily
liquid which rapidly solidified; colorless needles; m.p. 52Ϫ54 °C
(from ethanol); b.p. 91Ϫ92 °C/4 Torr; yield: 3.4 g (46%). 1H NMR:
δ ϭ 7.54 (d, J ϭ 7.3 Hz) ppm. 13C NMR: δ ϭ 154.2 (d, J ϭ
267 Hz), 137.8 (s), 136.2 (d, J ϭ 20 Hz), 124.9 (d, J ϭ 22 Hz), 111.6
(d, J ϭ 3 Hz) ppm. C5HCl2FIN (291.87): calcd.C 20.58, H 0.35;
found C 20.59, H 0.70.
3-Chloro-5-fluoro-4-pyridinecarboxylic Acid (2d): A solution of 3-
chloro-5-fluoropyridine (1d; 3.3 g, 25 mmol) and butyllithium
(25 mmol) in tetrahydrofuran (35 mL) and hexanes (15 mL) was
kept in a dry ice/methanol bath. After 2 h at Ϫ75 °C, the mixture
was poured on an excess of freshly crushed solid carbon dioxide.
After evaporation of the volatiles, the residue was taken up in water
(50 mL) and washed with diethyl ether (2 ϫ 15 mL). When the
aqueous phase was acidified to pH ϭ 1, a precipitate formed which
was collected by filtration; colorless needles; m.p. 207Ϫ208 °C
(dec.; from methanol); yield: 3.7 g (85%). 1H NMR (D3CCOCD3):
δ ϭ 8.65 (s, 1 H), 8.62 (s, broad, 1 H) ppm. 13C NMR
(D3CCOCD3): δ ϭ 162.2 (s), 155.9 (d, J ϭ 263 Hz), 146.7 (d, J ϭ
5 Hz), 138.0 (d, J ϭ 23 Hz), 130.4 (d, J ϭ 19 Hz), 128.7 (s) ppm.
C6H3ClFNO2 (175.55): calcd. C 41.05, H 1.72; found C 41.23, H
1.87.
3. 4-Iodo-Substituted Di- and Trihalopyridines
2,5-Dichloro-3-fluoro-4-iodopyridine
(3.5 mL, 2.5 g, 25 mmol) and 2,5-dichloro-3-fluoropyridine (1a;
4.1 g, 25 mmol) were consecutively added to a solution of butyl-
(3a):
Diisopropylamine
2-Bromo-5-chloro-3-fluoro-6-iodopyridine (4b): Analogously from 2-
bromo-5-chloro-3-fluoro-4-iodopyridine (3b; 8.4 g, 25 mmol). Ac-
cording to gas chromatography (30 m, DB-WAX, 100 °C Ǟ 200
lithium (25 mmol) in tetrahydrofuran (35 mL) and hexanes (15 mL) °C; 30 m, DB-23, 100 °C Ǟ 200 °C; heating rate 25 °C/min; ‘‘in-
kept in a dry ice/methanol bath. After 2 h at Ϫ75 °C, iodine (6.3 g,
ternal standard": nonadecane), the crude product contained 18%
Eur. J. Org. Chem. 2002, 4174Ϫ4180
4177

M. Schlosser, C. Bobbio
FULL PAPER
of 2-bromo-5-chloro-3-fluoropyridine (1b) and 66% of the iodo de-
rivative 4b. Upon distillation a viscous liquid was collected that
slowly crystallized; colorless needles; m.p. 60Ϫ62 °C (from eth-
anol); b.p. 110Ϫ112 °C/2 Torr; yield: 4.8 g (57%). 1H NMR: δ ϭ
3-Chloro-5-fluoro-2,6-diiodo-4-pyridinecarboxylic Acid (5c): Ana-
logously from 3-chloro-5-fluoro-2,6-diiodopyridine (4c; 5.7 g,
15 mmol); colorless prisms; m.p. 238 °C (dec.; from ethyl acetate
and hexanes); yield: 3.1 g (49%), which improved to 5.3 g (82%)
7.47 (d, J ϭ 6.7 Hz) ppm. 13C NMR: δ ϭ 155.7 (d, J ϭ 266 Hz), when the reaction time was extended from 2 h to 6 h. 13C NMR
138.3 (s), 126.5 (d, J ϭ 24 Hz), 124.3 (d, J ϭ 23 Hz), 112.2 (d, J ϭ (D3CCOCD3): δ ϭ 161.0 (s), 155.9 (d, J ϭ 262 Hz), 134.9 (s), 130.0
4 Hz) ppm. C5HBrClFIN (336.33): calcd. C 17.86, H 0.30; found
C 18.04, H 0.33.
(d, J ϭ 23 Hz), 115.7 (s), 104.3 (d, J ϭ 30 Hz) ppm. C6HClFI2NO2
(427.34): calcd. C 16.86, H 0.24; found C 16.93, H 0.32.
3-Chloro-5-fluoro-2,6-diiodopyridine (4c): Analogously from 5-
chloro-3-fluoro-2,4-diiodopyridine (3c; 9.6 g, 25 mmol). According
to gas chromatography (30 m, DB-WAX, 140 °C Ǟ 200 °C; 30 m,
DB-23, 140 °C Ǟ 200 °C; heating rate 25 °C/min; ‘‘internal stand-
ard’’: nonadecane), the crude product contained 39% of 5-chloro-
3-fluoro-2-iodopyridine (1c) and 30% of iodo derivative 4c. The
latter compound was isolated by trituration of the crude product
with hexanes; colorless prisms; m.p. 105Ϫ106 °C (from hexanes);
3-Chloro-5-fluoro-2-iodo-4-pyridinecarboxylic Acid (5d): Diisoprop-
ylamine (1.4 mL, 1.0 g, 10 mmol) and 3-chloro-5-fluoro-2-iodopyr-
idine (4d; 2.6 g, 10 mmol) were consecutively added to a solution
of butyllithium (10 mmol) in tetrahydrofuran (13 mL) and hexanes
(7 mL) kept in a dry ice/methanol bath. After 2 h at Ϫ75 °C, the
mixture was poured on an excess of freshly crushed solid carbon
dioxide. After evaporation of the volatiles, the residue was taken
up in water (50 mL), washed with diethyl ether (3 ϫ 10 mL), acidi-
yield: 2.2 g (23%). 1H NMR: δ ϭ 7.34 (d, J ϭ 6.3 Hz) ppm. 13C fied to pH ϭ 1 and extracted with ethyl acetate (3 ϫ 15 mL). The
NMR: δ ϭ 158.8 (d, J ϭ 264 Hz), 138.7 (d, J ϭ 3 Hz), 122.8 (d, combined organic layers were dried and the solvents evaporated.
J ϭ 24 Hz), 113.4 (d, J ϭ 3 Hz), 102.2 (d, J ϭ 29 Hz) ppm.
C5HClFI2N (383.33): calcd. C 15.67, H 0.26; found C 16.04, H
0.38.
The product was purified by crystallization from ethyl acetate; col-
orless needles; m.p. 225Ϫ228 °C (dec.); yield: 2.6 g (85%). 1H NMR
(D3CCOCD3): δ ϭ 8.54 (s) ppm. 13C NMR (D3CCOCD3): δ ϭ
161.8 (s), 155.8 (d, J ϭ 264 Hz), 138.5 (d, J ϭ 24 Hz), 134.5 (s),
131.4 (d, J ϭ 19 Hz), 116.3 (d, J ϭ 3 Hz) ppm. C6H2ClFINO2
(301.44): calcd. C 23.91, H 0.67; found C 24.04, H 0.62.
3-Chloro-5-fluoro-2-iodopyridine (4d): Butyllithium (17 mmol) in
hexanes (10 mL) was added to a solution of 3-chloro-5-fluoro-2,6-
diiodopyridine (4c; 5.7 g, 15 mmol) in toluene (20 mL) cooled in a
dry ice/methanol bath. After 15 min at Ϫ75 °C, the mixture was
treated with methanol before being poured into water (20 mL). The
organic layer was washed with water (15 mL), dried and the sol-
vents were evaporated. The product was purified by crystallization
from hexanes; colorless prisms; m.p. 82Ϫ84 °C; yield: 2.3 g (60%).
1H NMR: δ ϭ 8.24 (dd, J ϭ 2.7, 0.5 Hz, 1 H), 7.49 (dd, J ϭ 7.9,
2.7 Hz, 1 H) ppm. 13C NMR: δ ϭ 158.7 (d, J ϭ 264 Hz), 138.5 (d,
J ϭ 3 Hz), 136.7 (d, J ϭ 23 Hz), 124.1 (d, J ϭ 21 Hz), 114.3 (s)
ppm. C5H2ClFIN (257.43): calcd. C 23.33, H 0.78; found C 23.30,
H 0.76.
6. Di- and Trihalo-Substituted 2-Pyridinecarboxylic Acids
3,6-Dichloro-5-fluoro-2-pyridinecarboxylic Acid (6a): Isopropylmag-
nesium chloride (15 mmol) in tetrahydrofuran (7.5 mL) was added
to 2,5-dichloro-3-fluoro-6-iodopyridine (4a; 4.4 g, 15 mmol) in
tetrahydrofuran (10 mL) cooled in a dry ice/methanol bath. After
1 h at Ϫ75 °C, the mixture was poured on an excess of freshly
crushed solid carbon dioxide and worked up as described above
(see acid 5a) to give colorless prisms; m.p. 146Ϫ149 °C (from ethyl
acetate and hexanes); yield 2.5 g (80%). 1H NMR (D3CCOCD3):
δ ϭ 8.18 (d, J ϭ 7.8 Hz) ppm. 13C NMR (D3CCOCD3): δ ϭ 163.6
(s), 156.0 (d, J ϭ 268 Hz), 144.1 (d, J ϭ 6 Hz), 136.9 (d, J ϭ 20 Hz),
131.3 (d, J ϭ 3 Hz), 122.8 (d, J ϭ 22 Hz) ppm. C6H2Cl2FNO2
(209.99): calcd. C 34.32, H 0.96; found C 34.24, H 0.98.
5. Di- and Trihalo-6-iodo-4-pyridinecarboxylic Acids
2,5-Dichloro-3-fluoro-6-iodo-4-pyridinecarboxylic Acid (5a): Diiso-
propylamine (2.1 mL, 1.5 g, 15 mmol) and 2,5-dichloro-3-fluoro-6-
iodopyridine (4a; 4.4 g, 15 mmol) were consecutively added to a
6-Bromo-3-chloro-5-fluoro-2-pyridinecarboxylic Acid (6b): Analog-
solution of butyllithium (15 mmol) in tetrahydrofuran (20 mL) and ously from 2-bromo-5-chloro-3-fluoro-6-iodopyridine (4b; 5.0 g,
hexanes (10 mL) kept in a dry ice/methanol bath. After 2 h at Ϫ75
°C, the mixture was poured on an excess of freshly crushed solid
carbon dioxide. After evaporation of the volatiles, the residue was
15 mmol); colorless prisms; m.p. 156Ϫ158 °C (from ethyl acetate
1
and hexanes); yield 3.0 g (79%). H NMR (D3CCOCD3): δ ϭ 8.11
(d, J ϭ 7.4 Hz) ppm. 13C NMR (D3CCOCD3): δ ϭ 163.5 (s), 157.5
taken up in water (75 mL), washed with diethyl ether (3 ϫ 15 mL), (d, J ϭ 267 Hz), 144.8 (d, J ϭ 5 Hz), 131.8 (d, J ϭ 4 Hz), 128.1
acidified with hydrochloric acid to pH ϭ 1 and extracted with ethyl
acetate (3 ϫ 25 mL). The combined organic layers were dried and
the solvents evaporated. The product was purified by crystallization
from ethyl acetate and hexanes; colorless prisms; m.p. 224Ϫ226 °C
(decomp.); yield: 4.5 g (89%). 13C NMR (D3CCOCD3): δ ϭ 160.2
(s), 150.6 (d, J ϭ 266 Hz), 136.1 (d, J ϭ 20 Hz), 133.6 (s), 131.3
(d, J ϭ 20 Hz), 113.1 (d, J ϭ 4 Hz) ppm. C6HCl2FINO2 (335.89):
calcd. C 21.45, H 0.30; found C 21.31, H 0.36.
(d, J ϭ 23 Hz), 127.4 (d, J ϭ 24 Hz) ppm. C6H2BrClFNO2
(254.45): calcd. C 28.32, H 0.79; found C 28.43, H 0.80.
3-Chloro-5-fluoro-6-iodo-2-pyridinecarboxylic Acid (6c): 6-Bromo-
3-chloro-5-fluoro-2-pyridinecarboxylic acid (6b; 13 g, 50 mmol)
was dissolved in methanol (50 mL) in the presence of sulfuric acid
96% (0.14 mL, 2.5 mmol) and heated under reflux for 15 h. After
addition of a saturated aqueous solution of sodium bicarbonate
(70 mL) and diethyl ether (0.10 L), the organic layer was separated
and the solvents were evaporated. Crystallization from a 1:1 (v/v)
2-Bromo-5-chloro-3-fluoro-6-iodo-4-pyridinecarboxylic Acid (5b):
Analogously from 2-bromo-5-chloro-3-fluoro-6-iodopyridine (4b; mixture of diethyl ether and hexanes afforded methyl 6-bromo-3-
5.0 g, 15 mmol); colorless needles; m.p. 233Ϫ236 °C (decomp.;
from ethyl acetate and hexanes.); yield: 5.0 g (88%). 13C NMR
(D3CCOCD3): δ ϭ 161.0 (s), 152.9 (d, J ϭ 265 Hz), 134.9 (s), 131.6
chloro-5-fluoro-2-pyridinecarboxylate as colorless needles; m.p.
1
87Ϫ88 °C; yield: 9.9 g (74%). H NMR: δ ϭ 7.59 (d, J ϭ 6.8 Hz,
1 H), 4.00 (s, 3 H) ppm. 13C NMR: δ ϭ 162.8 (s), 156.6 (d, J ϭ
(d, J ϭ 21 Hz), 127.5 (d, J ϭ 24 Hz), 114.7 (d, J ϭ 3 Hz) ppm. 270 Hz), 143.1 (d, J ϭ 5 Hz), 131.7 (d, J ϭ 3 Hz), 127.4 (d, J ϭ
C6HBrClFINO2 (380.34): calcd. C 18.95, H 0.26; found C 19.10,
H 0.18.
24 Hz), 126.5 (d, J ϭ 22 Hz), 53.3 (s) ppm. C7H4BrClFNO2
(268.47): calcd. C 31.32, H 1.50; found C 31.52, H 1.62. Under
4178
Eur. J. Org. Chem. 2002, 4174Ϫ4180

Basicity Gradient-Driven Isomerization of Halopyridines
FULL PAPER
nitrogen, sodium iodide (7.5 g, 50 mmol) and chlorotrimethylsilane
analyzed by gas chromatography (30 m, DB-23, 170 °C; 30 m, DB-
(5.4 g, 6.5 mL, 50 mmol) were consecutively added to a solution of WAX, 180 °C). By comparison of the peak retention times with
this 6-bromo ester (6.7 g, 25 mmol) in acetonitrile (25 mL). After
6 h at reflux, water (30 mL) and diethyl ether (25 mL) were added
and the organic phase was decanted, washed with a saturated aque-
ous solution of sodium thiosulfate (20 mL), dried with sodium sul-
those of authentic samples and the peak areas relative to that of
the reference compound after response correction by means of cal-
ibration factors derived from authentic mixtures, the crude product
contained 65% of compound 7, 7% of 3-chloro-5-fluoro-2,6-dicarb-
fate and filtered. Concentration to dryness and crystallization from oxylic acid (8; see below) and 5% of compound 6c. The remainder
1:1 (v/v) mixture of diethyl ether and hexanes gave methyl 3-chloro- of the dried organic solution was concentrated. By trituration of
5-fluoro-6-iodo-2-pyridinecarboxylate as colorless needles; m.p. the solid obtained with chloroform (2 ϫ 10 mL) and recrystalliza-
1
70Ϫ71 °C; yield: 5.4 g (69%). H NMR: δ ϭ 7.45 (d, J ϭ 7.2 Hz,
1 H), 3.99 (s, 3 H) ppm. 13C NMR: δ ϭ 162.9 (s), 159.0 (d, J ϭ
268 Hz), 144.5 (d, J ϭ 5 Hz), 132.0 (d, J ϭ 4 Hz), 124.7 (d, J ϭ
tion from ethyl acetate, acid 7 was obtained as colorless prisms;
m.p. 171Ϫ172 °C (decomp.); yield: 1.6 g (35%). 1H NMR
(D3CCOCD3): δ ϭ 8.09 (d, J ϭ 9.5 Hz) ppm. 13C NMR
24 Hz), 103.3 (d, J ϭ 30 Hz), 53.3 (s) ppm. C7H4ClFINO2 (315.47): (D3CCOCD3): δ ϭ 162.0 (d, J ϭ 6 Hz), 159.7 (d, J ϭ 275 Hz),
calcd. C 26.65, H 1.28; found C 26.81, H 1.34. This 6-iodo ester 142.9 (d, J ϭ 5 Hz), 136.7 (d, J ϭ 10 Hz), 127.6 (d, J ϭ 24 Hz),
(3.1 g, 10 mmol) and lithium hydroxide monohydrate (0.84 g, 114.0 (d, J ϭ 3 Hz) ppm. C6H2ClFINO2 (301.44): calcd. C 23.91,
20 mmol) were dissolved in 10 mL of a 3:1 (v/v) mixture of tetrahy-
drofuran and water. After 1 h at 25 °C, the mixture was diluted
with water (10 mL) and acidified to pH ϭ 1. Extraction with di-
ethyl ether (3 ϫ 15 mL), drying with sodium sulfate, filtration,
evaporation of the solvents and crystallization from chloroform af-
forded compound 6c as colorless needles; m.p. 127Ϫ129 °C; yield:
2.7 g (91%). 1H NMR (D3CCOCD3): δ ϭ 7.97 (d, J ϭ 7.0 Hz, 1
H) ppm. 13C NMR (D3CCOCD3): δ ϭ 163.6 (s), 160.5 (d, J ϭ
265 Hz), 145.8 (d, J ϭ 4 Hz), 132.1 (d, J ϭ 4 Hz), 126.1 (d, J ϭ
25 Hz), 103.8 (d, J ϭ 30 Hz) ppm. C6H2ClFINO2 (301.44): calcd.
C 23.91, H 0.67; found C 24.16, H 0.76.
H 0.67; found C 23.80, H 0.69.
3-Chloro-5-fluoro-2,6-pyridinedicarboxylic Acid (8): Butyllithium
(20 mmol) in hexanes (13 mL) was added to a solution of 3-chloro-
5-fluoro-2,6-diiodopyridine (4c; 3.8 g, 10 mmol) in toluene (13 mL)
kept in a dry ice/methanol bath. After 15 min at Ϫ75 °C, the mix-
ture was poured on an excess of freshly crushed solid carbon diox-
ide. After addition of water (50 mL), acidification to pH ϭ 1, ex-
traction with ethyl acetate (3 ϫ 10 mL), drying with sodium sulfate
and evaporation of the solvent, the product was crystallized from
a 5:1 (v/v) mixture of chloroform and ethyl acetate; colorless
prisms; m.p. 128Ϫ129 °C (dec.); yield: 0.85 g (39%). 1H NMR
(D3CCOCD3): δ ϭ 8.11 (d, J ϭ 9.5 Hz) ppm. 13C NMR
(D3CCOCD3): δ ϭ 163.6 (s), 162.1 (d, J ϭ 6 Hz), 160.2 (d, J ϭ
278 Hz), 143.7 (d, J ϭ 5 Hz), 137.7 (d, J ϭ 6 Hz), 135.2 (d, J ϭ
10 Hz), 129.9 (d, J ϭ 23 Hz) ppm. C6H2ClFINO2 (219.55): calcd.
C 38.29, H 1.38; found C 38.01, H 1.32.
3-Chloro-5-fluoro-2-pyridinecarboxylic Acid (6d): 3-Chloro-5-
fluoro-2-iodopyridine (4d; 1.3 g, 5.0 mmol) was added to a solution
of butyllithium (5 mmol) in toluene (7 mL) and hexanes (3 mL)
kept in a dry ice/methanol bath. After 1 h at Ϫ75 °C, the reaction
mixture was poured on an excess of freshly crushed solid carbon
dioxide. After evaporation of the volatiles, the residue was taken
up in water (50 mL), washed with diethyl ether (2 ϫ 10 mL), acidi-
fied to pH ϭ 1 and extracted with diethyl ether (3 ϫ 15 mL). Dry-
ing with sodium sulfate, filtration, evaporation of the solvent and
crystallization from chloroform gave colorless needles; m.p.
142Ϫ144 °C (dec.); yield: 0.69 g (79%). 1H NMR (D3CCOCD3):
δ ϭ 8.59 (d, J ϭ 2.5 Hz, 1 H), 8.02 (dd, J ϭ 8.4, 2.5 Hz, 1 H) ppm.
13C NMR (D3CCOCD3): δ ϭ 164.4 (s), 160.5 (d, J ϭ 264 Hz),
144.8 (s), 136.7 (d, J ϭ 24 Hz), 132.0 (d, J ϭ 5 Hz), 127.0 (d, J ϭ
22 Hz) ppm. C6H3ClFNO2 (175.55): calcd. C 41.05, H 1.72; found
C 41.11, H 1.83. Compound 6d has also been obtained from 6-
bromo-3-chloro-5-fluoro-2-pyridinecarboxylic acid (6b; 6.4 g,
25 mmol) with zinc powder (2.4 g, 37 mmol) in an aqueous solution
of sodium hydroxide (2.0 g, 20 mL, 50 mmol) stirring at 25 °C for
6 h. After filtration and washing with water (75 mL), the filtrate
was acidified to pH ϭ 1 with hydrochloric acid. Extraction with
diethyl ether (6 ϫ 20 mL), evaporation of the solvent and crystal-
lization from chloroform afforded 2.9 g (67%) of colorless needles.
5-Chloro-3-fluoro-2-pyridinecarboxylic Acid (9): 5-Chloro-3-fluoro-
2-iodopyridine (1c; 3.9 g, 15 mmol) was added to a solution of bu-
tyllithium (15 mmol) in toluene (20 mL) and hexanes (10 mL) kept
in a dry ice/methanol bath. After 1 h at Ϫ75 °C, the reaction mix-
ture was poured on an excess of freshly crushed solid carbon diox-
ide. After evaporation of the volatiles, the residue was taken up in
water (50 mL), washed with diethyl ether (2 ϫ 15 mL) and acidified
to pH ϭ 1. The precipitate formed was collected, dried and recrys-
tallized from ethanol; colorless prisms; m.p. 172Ϫ174 °C; yield
2.5 g (94%). 1H NMR (D3CCOCD3): δ ϭ 8.57 (dd, J ϭ 1.9, 0.9 Hz,
1
H), 8.05 (dd, J ϭ 9.9, 1.9 Hz, 1
H) ppm. 13C NMR
(D3CCOCD3): δ ϭ 162.8 (d, J ϭ 6 Hz), 159.7 (d, J ϭ 275 Hz),
144.8 (d, J ϭ 5 Hz), 136.5 (d, J ϭ 4 Hz), 136.0 (d, J ϭ 9 Hz), 127.0
(d, J ϭ 23 Hz) ppm. C6H3ClFNO2 (175.55): calcd. C 41.05, H 1.72;
found C 40.91, H 2.08. As described above but starting from 2-
bromo-5-chloro-3-fluoropyridine (1b; 3.1 g, 15 mmol) compound 9
has been obtained in 71% yield.
5-Chloro-3-fluoro-6-iodo-2-pyridinecarboxylic Acid (7): Butyl-
lithium (15 mmol) in hexanes (10 mL) was added to a solution of 3-
chloro-5-fluoro-2,6-diiodopyridine (4c; 5.7 g, 15 mmol) in toluene
(20 mL) cooled in a dry ice/methanol bath. After 15 min at Ϫ75
°C, the mixture was poured on an excess of freshly crushed solid
carbon dioxide. After evaporation of the volatiles, the residue was
taken up in water (50 mL) washed with diethyl ether (3 ϫ 15 mL),
acidified with hydrochloric acid to pH ϭ 1 and extracted with ethyl
acetate (3 ϫ 20 mL). One twentieth of the solution was withdrawn
and, after addition of a known amount (approx. 10 mg) of 2-bi-
phenylcarboxylic acid as an internal reference compound, treated
with ethereal diazomethane until the yellow color persisted, and
Acknowledgments
This work was financially supported by the Schweizerische Na-
tionalfonds zur Förderung der wissenschaftlichen Forschung, Bern
(grant 20-55Ј303-98) and the Bundesamt für Bildung und Wissen-
schaft, Bern (grant 97.0083 linked to the TMR project
FMRXCT-970129).
[1]
M. Schlosser, in Organometallics in Synthesis: A Manual (Ed.:
M. Schlosser), 2nd ed., Wiley, Chichester, 2002, p. 1Ϫ352, spe-
cially p. 262Ϫ265.
Eur. J. Org. Chem. 2002, 4174Ϫ4180
4179

M. Schlosser, C. Bobbio
FULL PAPER
[2]
[7]
[8]
[9]
C. Bobbio, M. Schlosser, Eur. J. Org. Chem. 2001, 4533Ϫ4536.
F. Mongin, A. Tognini, F. Cottet, M. Schlosser, Tetrahedron
M. Schlosser, F. Cottet, Eur. J. Org. Chem. 2002, 4181Ϫ4184,
[3]
following paper.
Lett. 1998, 39, 1749Ϫ1752.
M. Schlosser, J. Porwisiak, F. Mongin, Tetrahedron 1998, 54,
[4]
F. Mongin, E. Marzi, M. Schlosser, Eur. J. Org. Chem. 2001,
895Ϫ900.
2771Ϫ2777.
Q. Wang, H. Wei, M. Schlosser, Eur. J. Org. Chem. 1999,
[5]
M. Schlosser, Eur. J. Org. Chem. 2001, 3975Ϫ3984.
3263Ϫ3268.
[6]
F. Mongin, M. Schlosser, Tetrahedron Lett. 1996, 37,
Received July 16, 2002
[O02393]
6551Ϫ6554.
4180
Eur. J. Org. Chem. 2002, 4174Ϫ4180