The structural proliferation of 2,6-difluoropyridine through organometallic intermediates

Article abstract of DOI:10.1002/ejoc.200300649

Contrary to a literature claim, 2,6-difluoropyridine-3-carboxaldehyde can be readily prepared by consecutive treatment of 2,6-difluoropyridine with lithium diisopropylamide and N,N-dimethylformamide. Regioselective displacements of fluorine from the aldehyde by nucleophiles were carried out. To demonstrate the versatility of the organometallic approach, some two dozens of further 2,6-difluoropyridine derivatives were prepared applying a combination of modern organometallic methods such as site selective hydrogen/metal and halogen/metal permutations and deprotonation-triggered heavy halogen migrations. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300649

FULL PAPER
The Structural Proliferation of 2,6-Difluoropyridine through Organometallic
Intermediates
Manfred Schlosser*[b] and Thierry Rausis[a]
Keywords: Metalations / Carboxylation / Formylation / Deprotonation / Halogens / Metal Permutation / Regioselectivity
Contrary to a literature claim, 2,6-difluoropyridine-3-carb- rivatives were prepared applying a combination of modern
oxaldehyde can be readily prepared by consecutive treat- organometallic methods such as site selective hydrogen/
ment of 2,6-difluoropyridine with lithium diisopropylamide
and N,N-dimethylformamide. Regioselective displacements
of fluorine from the aldehyde by nucleophiles were carried
out. To demonstrate the versatility of the organometallic ap-
proach, some two dozens of further 2,6-difluoropyridine de-
metal and halogen/metal permutations and deprotonation-
triggered heavy halogen migrations.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Although all 16 dichloropyridinecarboxylic acids are
known,[1,2] only a single difluoro analog has been reported
so far. After treating the commercially available 2,6-di-
fluoropyridine in tetrahydrofuran with lithium diiso-
propylamide (LIDA) in the same way as this had been pre-
viously been performed with 2-fluoropyridine[3,4] and trap-
ping the organometallic intermediate with N-methyl-N-
(pyridin-2-yl)formamide, G. M. Shutske et al.[5] isolated a
crude product mixture which contained the allegedly air-
sensitive
2,6-difluoropyridine-3-carboxaldehyde.
Sub-
sequent oxidation provided the 2,6-difluoropyridine-3-carb-
oxylic acid in poor yield. When the lithiated 2,6-difluoro-
pyridine was treated with N,N-dimethylformamide, the only
identified compounds were a 2:3 mixture (66%) of 2-di-
methylamino-6-fluoropyridine-3-carbaldehyde and 6-di-
methylamino-2-fluoropyridine-3-carbaldehyde. The prob-
lems encountered by the authors of that work raised our
curiosity and encouraged us to embark on the systematic
study described below.
Results
The first step was to convert 2,6-difluoropyridine
through the 3-lithiated species into a variety of 3-hetero-
and 3-carbosubstituted derivatives. Thus the reaction with
iodine afforded 2,6-difluoro-3-iodopyridine (1; 96%), with
1,2-dibromo-1,1,2,2-tetrafluoroethane
3-bromo-2,6-di-
fluoropyridine (2; 72%), with 1,1,2-trichloro-1,2,2-trifluoro-
ethane 3-chloro-2,6-difluoropyridine (3; 76%), with fluoro-
dimethoxyborane[6,7] and ensuing treatment with alkaline
hydrogen peroxide 2,6-difluoropyridin-3-ol (4; 80%), with
chlorotrimethylsilane (2,6-difluoropyridin-3-yl)trimethylsil-
ane (5; 95%), with acetone 2,6-difluoro-α,α-dimethyl-3-pyri-
[a]
´
Institut de Chimie moleculaire et biologique, Ecole
´ ´
Polytechnique Federale, BCh,
1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
Faculte des Sciences, Universite, BCh,
[b]
´
´
1015 Lausanne, Switzerland
1018
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300649
Eur. J. Org. Chem. 2004, 1018Ϫ1024

Structural Proliferation of 2,6-Difluoropyridine through Organometallic Intermediates
FULL PAPER
dinemethanol (6; 97%), with N,N-dimethylformamide 2,6-
difluoropyridine-3-carbaldehyde (7; 72%), with diethyl oxa-
late ethyl 2-(2,6-difluoropyridin-3-yl)-2-oxoacetate (8; 58%),
and with dry ice 2,6-difluoropyridine-3-carboxylic acid (9;
94%).
Another facile access to the acid 12 involved the LIDA-
mediated deprotonation of the chloro derivative 3. It oc-
curred with poor regioselectivity leading to a mixture of 3-
chloro-2,6-difluoro-4-iodopyridine (14; 77%) and 3-chloro-
2,6-difluoro-5-iodopyridine (15; 15%) after iodination. Ob-
viously the intrinsically higher acidity[10,11] of the pyridine
4-position and the stronger neighboring group assistance[12]
provided by a fluorine compared with a chlorine atom com-
pensate each other to quite some extent. The main compo-
nent 14 was again purified by crystallization. Carboxylation
of the magnesium species generated from it by halogen/me-
tal permutation afforded the 3-chloro-2,6-difluoropyridine-
4-carboxylic acid (16; 90%). Transfer hydrogenation gave
the 2,6-difluoropyridine-4-carboxylic acid (12; 94%).
To obtain the aldehyde 7 in high yield, the adduct formed
with N,N-dimethylformamide had to be neutralized at Ϫ75
°C. At higher temperatures, the lithium (α-dimethylami-
no)alkoxide intermediate (O-lithiated hemiaminal) was
found to dissociate reversibly to the aldehyde 7 and lithium
dimethylamide. These two components entered into a nucleo-
philic heteroaromatic substitution process giving eventually
rise to the regioisomeric mixture of (dimethylamino)fluoro-
pyridine-3-carbaldehydes 10a and 10b mentioned above in
a 1:10 ratio.
Iodine being the least acidifying of all halogens, proton
abstraction from 2,6-difluoro-3-iodopyridine (1) occurred
initially, i.e. upon 5Ϫ15 min of exposure to LIDA, almost
exclusively at the 5- rather than the 4-position. Trapping
with dry ice or iodine provided the 2,6-difluoro-5-iodopyri-
dine-3-carboxylic acid (17; 72%) or the 2,6-difluoro-3,5-di-
iodopyridine (18; 81%) respectively. However, when the re-
action time with LIDA was prolonged to 30 h, reversible
return to the starting material 1 set the stage for a sporadic
deprotonation at the 4-position. This unleashed instan-
The iodo compound 1 was isomerized by LIDA-pro-
moted heavy halogen migration[8,9] to 2,6-difluoro-4-iodo-
pyridine (11; 81%) which was purified by crystallization
thus removing unaltered starting material (1; 16%). Product
11 was transformed to the 2,6-difluoropyridine-4-carboxylic
acid (12; 87%) by consecutive halogen/metal permutation
and carboxylation. To obtain the 2,6-difluoro-4-iodopy-
ridine-3-carboxylic acid (13; 91%), 2,6-difluro-4-iodopy-
ridine (11) was treated first with LIDA and subsequently
with dry ice.
Eur. J. Org. Chem. 2004, 1018Ϫ1024
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1019

M. Schlosser, T. Rausis
FULL PAPER
taneously a basicity gradient-driven heavy halogenmigr-
The bis(silane) 23 was also obtained in 92% yield when
ation[9] producing the isomeric 2,6-difluoro-3,4-diiodopyri- 2,6-difluoropyridine was exposed to the simultaneous ac-
dine (19; 80%) after iodination.
tion of LIDA and chlorotrimethylsilane, both in twofold
excess. This result does by no means imply the intermediacy
of 3,5-dilithiated species. When 2,6-difluoropyridine was
consecutively treated with each time two equivalents of
LIDA and molecular iodine, only the monoiodopyridine 1
and not even trace amounts of the diiodo compound 18
were formed. Chlorotrimethylsilane is known to react with
bulky reagents such as lithium diisopropylamide, lithium
2,2,6,6-tetramethylpiperidide and tert-butyllithium much
more slowly than with aryllithiums.[13Ϫ16] Consequently, or-
ganometallic intermediates such as 2,6-difluoropyridin-3-
yllithium and 2,6-difluoro-5-(trimethylsilyl)pyridine-3-
yllithium can be generated in situ, in other words in the
presence of the trapping reagent chlorotrimethylsilane.
The LIDA-promoted deprotonation of (2,6-difluoropyri-
din-3-yl)trimethylsilane (5) also took place at the 5-posi-
tion. The intermediate was trapped with dry ice or 1,1,2-
trichloro-1,2,2-trifluoroethane to give 2,6-difluoro-5-(tri-
methylsilyl)pyridine-3-carboxylic acid (20; 98%) or (5-
chloro-2,6-difluoropyridin-3-yl)trimethylsilane (21; 97%)
respectively. Using iodine chloride, the acid 20 was iodo-
desilylated to the 2,6-difluoro-5-iodopyridine-3-carboxylic
acid (17; 96%). Under the same conditions, the chlorosilane
21 gave 3-chloro-2,6-difluoro-5-iodopyridine (15; 93%). The
latter compound was converted into the 5-chloro-2,6-di-
fluoropyridine-3-carboxylic acid (22; 91%), by halogen/me-
tal permutation followed by carboxylation.
Condensation of the 5-lithiated (2,6-difluoropyridin-3-yl)
trimethylsilane (5) with chlorotrimethylsilane provided the
(2,6-difluoropyridin-3,5-diyl)bis(trimethylsilane) (23; 94%)
which reacted with iodine chloride smoothly under double
iododesilylation to afford the 2,6-difluoro-3,5-diiodopy-
ridine (18; 93%) whereas the bromodesilylation effected
with elemental bromine rigorously stopped after a unilat-
eral displacement producing (5-bromo-2,6-difluoropyridin-
3-yl)trimethylsilane (24; 95%). 3,5-Dibromo-2,6-difluoro-
pyridine (25; 90%) was found to be accessible only in-
Experimental Section
Details regarding standard operations and abbreviations were ex-
plained in previous publications from this laboratory.[11,17,18] 1H
and 13C NMR spectra were recorded of samples dissolved in
deuterochloroform or, if marked by an asterisk, in perdeuteroace-
tone. Chemical shifts are listed relative to tetramethylsilane as an
internal standard.
2,6-Difluoro-3-iodopyridine (1): Diisopropylamine (7.0 mL, 5.1 g,
directly by subjecting 3-bromo-2,6-difluoro-5-iodopyridylsi- 50 mmol) and 2,6-difluoropyridine (4.5 mL, 5.8 g, 50 mmol) were
added consecutively to a solution of butyllithium (50 mmol) in
tetrahydrofuran (0.10 L) and hexanes (30 mL), cooled in a meth-
anol/dry ice bath. After 45 min at Ϫ75 °C, the mixture was treated
with a solution of iodine (13 g, 50 mmol) in tetrahydrofuran
(50 mL) before being washed with a 10% aqueous solution (25 mL)
of sodium sulfite. The organic phase was dried and the volatiles
evaporated. Crystallization of the residue from hexanes afforded
lane (26) to element-specific halogen/metal permutation
and subsequent bromination. The latter precursor 26 was
readily prepared by iododesilylation of the bromopyridyl-
silane 24 in 91% yield.
1
colorless platelets; m.p. 40Ϫ42 °C; yield: 11.6 g (96%). H NMR:
δ ϭ 8.20 (td, J ϭ 8.1, 7.3 Hz, 1 H), 6.70 (dd, J ϭ 8.3, 3.0 Hz, 1 H)
ppm. 13C NMR: δ ϭ 161.9 (dd, J ϭ 248, 13 Hz), 160.1 (dd, J ϭ
242, 14 Hz), 153.5 (dd, J ϭ 7, 2 Hz), 108.2 (dd, J ϭ 35, 6 Hz), 69.1
(dd, J ϭ 41, 6 Hz) ppm. C5H2F2IN (240.98): calcd. C 24.92, H
0.84; found C 24.97, H 1.00. When lithium diisopropylamide was
replaced by butyllithium (25 mmol) under otherwise identical con-
ditions, 2,6-difluoro-4-iodopyridine (11; see below) was identified
by gas chromatography (30 m, DB-1, 100 °C; 30 m, DB-WAX, 100
°C; calibrated internal standard: tridecane) as a by-product (7%)
along with 2,6-difluoro-3-iodopyridine (1) as the main component
(86%).
1020
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1018Ϫ1024

Structural Proliferation of 2,6-Difluoropyridine through Organometallic Intermediates
FULL PAPER
3-Bromo-2,6-difluoropyridine (2): Analogously as described in the
as a colorless liquid; m.p. 19Ϫ20 °C; b.p. 64Ϫ66 °C/15 Torr; n2D0
ϭ
preceding paragraph with 1,2-dibromo-1,1,2,2-tetrafluoroethane 1.4918; d420 ϭ 1.378; yield: 10.3 g (72%). H NMR: δ ϭ 10.27 (s, 1
1
(13.0 g, 50 mmol) instead of iodine. Upon distillation, the product
was collected as a colorless liquid; b.p. 48Ϫ50 °C/12 Torr (ref.[19]
169.5 °C); n2D0 ϭ 1.5137 (ref.[19] n2D5 ϭ 1.5047); yield: 6.98 g (72%).
1H NMR: δ ϭ 8.04 (td, J ϭ 8.3, 6.9 Hz, 1 H), 6.79 (dd, J ϭ 8.3,
3.2 Hz, 1 H) ppm.
H), 8.47 (ddd, J ϭ 9.0, 8.3, 7.7 Hz, 1 H), 7.05 (dd, J ϭ 8.3, 2.6 Hz,
1 H) ppm. 13C NMR: δ ϭ 184.4 (s), 164.2 (dd, J ϭ 256, 15 Hz),
162.7 (dd, J ϭ 257, 16 Hz), 144.2 (dd, J ϭ 10, 3 Hz), 116.1 (dd,
J ϭ 20, 5 Hz), 107.8 (dd, J ϭ 35, 6 Hz) ppm. C6H3F2NO (143.09):
calcd. C 50.36, H 2.11; found C 50.38, H 2.07. The aldehyde 7
was left in the open air for several days without undergoing any
noticeable oxidation.
3-Chloro-2,6-difluoropyridine (3): Analogously as described for the
preparation of product 1 using 1,1,2-trichloro-1,2,2-trifluoroethane
(6.0 mL, 9.4 g, 50 mmol); colorless liquid; m.p. Ϫ8 to Ϫ10 °C; b.p.
Ethyl 2-(2,6-Difluoropyridin-3-yl)-2-oxoacetate (8): Analogously as
described for the preparation of product 1, using a solution of di-
ethyl oxalate (6.8 mL, 7.3 g, 50 mmol) in tetrahydrofuran (50 mL).
43Ϫ45 °C/20 Torr (ref.[20] 151 °C); n2D0 ϭ 1.4744 (ref.[19] n2D4
ϭ
1.4739); yield: 5.68 g (76%). 1H NMR: δ ϭ 7.90 (td, J ϭ 8.6,
6.7 Hz, 1 H), 6.85 (dd, J ϭ 8.3, 3.0 Hz, 1 H) ppm. 13C NMR: δ ϭ
Distillation gave a colorless liquid; b.p. 78Ϫ80 °C/10 Torr; n2D0
ϭ
1
159.3 (dd, J ϭ 248, 13 Hz), 156.4 (dd, J ϭ 246, 15 Hz), 144.5 (d, 1.4791; d420 ϭ 1.316; yield: 6.24 g (58%). H NMR: δ ϭ 8.52 (ddd,
J ϭ 8 Hz), 113.0 (dd, J ϭ 31, 7 Hz), 107.3 (dd, J ϭ 37, 7 Hz) ppm.
J ϭ 8.9, 8.3, 7.5 Hz, 1 H), 7.04 (dd, J ϭ 8.3, 2.7 Hz, 1 H), 4.46 (q,
J ϭ 7.2 Hz, 2 H), 1.42 (t, J ϭ 7.2 Hz, 3 H) ppm. 13C NMR: δ ϭ
181.4 (d, J ϭ 6 Hz), 164.4 (dd, J ϭ 257, 15 Hz), 162.7(s), 160.8
(dd, J ϭ 255, 16 Hz), 146.7 (d, J ϭ 10 Hz), 114.0 (dd, J ϭ 23,
6 Hz), 107.9 (dd, J ϭ 35, 6 Hz), 63.0 (s), 13.7 (s) ppm. C9H7F2NO3
(215.15): calcd. C 50.24, H 3.28; found C 50.20, H 3.20.
2,6-Difluoropyridin-3-ol (4): The mixture obtained by the reaction
of butyllithium with diisopropylamine and 2,6-difluoropyridine
was treated with fluorodimethoxyborane-diethyl ether complex[6,7]
(9.4 mL, 8.2 g, 50 mmol). After evaporation of the volatiles and
following the addition of a 30% aqueous hydrogen peroxide
(5.2 mL, 5.7 g, 50 mmol) and a 3.0  aqueous solution (50 mL) of
sodium hydroxide (0.15 mol), the mixture was stirred for 45 min
2,6-Difluoropyridine-3-carboxylic Acid (9): The mixture obtained by
the reaction of butyllithium, diisopropylamine, and 2,6-difluoro-
before being acidified with concentrated hydrochloric acid to pH 2 pyridine (see above) was poured on an excess of freshly crushed
and extracted with diethyl ether (3 ϫ 50 mL). The combined or- dry ice. At 25 °C, 2.0  ethereal hydrogen chloride (75 mmol) was
ganic layers were dried and the solvents evaporated. Crystallization added. Evaporation of the volatiles, extraction with hot ethyl acet-
of the residue from ethyl acetate afforded colorless platelets; m.p.
ate, filtration, concentration, and crystallization afforded the prod-
124Ϫ126 °C; yield: 5.24 g (80%). 1H NMR: δ ϭ 7.44 (ddd, J ϭ
uct as colorless needles; m.p. 165Ϫ167 °C (ref.[5] 164Ϫ165 °C);
9.9, 8.3, 6.7 Hz, 1 H), 6.67 (dd, J ϭ 8.3, 3.0 Hz, 1 H) ppm. 13C yield: 7.48 g (94%). H NMR: δ ϭ 8.54 (dt, J ϭ 9.1, 8.1 Hz, 1 H),
NMR: δ ϭ 152.9 (dd, J ϭ 239, 11 Hz), 149.4 (dd, J ϭ 241, 14 Hz), 6.94 (dd, J ϭ 8.3, 3.0 Hz, 1 H) ppm.
136.9 (dd, J ϭ 25, 6 Hz), 131.2 (t, J ϭ 6 Hz), 106.0 (dd, J ϭ 37,
6 Hz) ppm. C5H3F2NO (131.08): calcd. C 45.81, H 2.31; found C
45.74, H 2.18.
1
2-Fluoro-6-dimethylamino-3-carbaldehyde (10b): When the same
protocol as applied to the preparation of aldehyde 7 was repeated
but ethereal hydrogen chloride was replaced by water (25 mL), 6-
(2,6-Difluoropyridin-3-yl)trimethylsilane (5): Analogously as de-
scribed for the preparation of product 1, this compound was ob-
tained from 2,6-difluoropyridine except that 1,2-dibromo-1,1,2,2-
tetrafluoroethane was replaced by using chlorotrimethylsilane
(6.3 mL, 5.4 g, 50 mmol); colorless liquid; m.p. 25Ϫ27 °C; b.p.
fluoro-2-dimethylamino-3-carboxaldehyde (10a), and 2-fluoro-6-
dimethylamino-3-carboxaldehyde (10b) were formed in a ratio of
1:10 (by gas chromatography: 30 m, DB-1, 150 °C; 30 m, DB-
WAX, 150 °C). The organic phase was dried and the solvents eva-
porated; crude yield: 7.31 g (87%). The main component was iso-
75Ϫ77 °C/20 Torr; yield: 8.89 g (95%). 1H NMR: δ ϭ 7.91 (q, J ϭ lated by crystallization from ethyl acetate; colorless needles; m.p.
8.1 Hz, 1 H), 6.81 (ddd, J ϭ 7.8, 2.4, 1.9 Hz, 1 H), 0.33 (d, J ϭ
101Ϫ103 °C (ref.[5] 98Ϫ100 °C). 1H NMR: δ ϭ 7.99 (t, J ϭ 9.1 Hz,
1.1 Hz, 9 H) ppm. 13C NMR: δ ϭ 165.2 (dd, J ϭ 243, 13 Hz), 1 H), 6.39 (dd, J ϭ 8.9, 2.2 Hz, 1 H), 3.19 (s, 6 H) ppm. 13C NMR:
163.0 (dd, J ϭ 247, 13 Hz), 150.6 (dd, J ϭ 10, 7 Hz), 116.6 (dd,
J ϭ 42, 5 Hz), 105.7 (dd, J ϭ 32, 5 Hz), Ϫ1.57 (s, 3 C) ppm.
δ ϭ 184.8 (s), 164.7 (d, J ϭ 247 Hz), 160.8 (d, J ϭ 19 Hz), 139.2
(d, J ϭ 3 Hz), 106.3 (d, J ϭ 22 Hz), 103.2 (d, J ϭ 3 Hz), 38.3 (s, 2
C8H11F2NSi (187.26): calcd. C 51.31, H 5.92; found C 51.25, H C) ppm. The mother liquor was absorbed on silica and eluted with
6.02.
a 3:7 mixture of ethyl acetate and hexanes. The minor component
had the shorter retention time.
2,6-Difluoro-α,α-dimethyl-3-pyridinemethanol (6): Analogously as
described for the preparation of product 1, using acetone (3.7 mL,
2.9 g, 50 mmol). After 45 min, 5.0  hydrochloric acid (25 mL)
were added. The organic phase was dried and upon distillation, the
product was collected as a colorless liquid; b.p. 102Ϫ104 °C/
6-Fluoro-2-dimethylamino-3-carbaldehyde (10a): M.p. 61Ϫ62 °C
1
(ref.[5] 61Ϫ63 °C). H NMR: δ ϭ 8.05 (t, J ϭ 8.3 Hz, 1 H), 6.31
(dd, J ϭ 8.3, 3.2 Hz, 1 H), 3.15 (s, 6 H) ppm.
2,6-Difluoro-4-iodopyridine (11): Diisopropylamine (7.0 mL, 5.1 g,
50 mmol) and 2,6-difluoro-3-iodopyridine (1; 12 g, 50 mmol) were
added consecutively to a solution of butyllithium (50 mmol) in
tetrahydrofuran (0.10 L) and hexanes (30 mL) kept in a methanol/
dry ice bath. After 30 h at Ϫ75 °C, the mixture was treated with
water (25 mL). Gas chromatography (30 m, DB-1, 50 °C [5 min] Ǟ
100 °C [15 min]; heating rate 30 °C/min; 30 m, DB-WAX, identical
temperature program; internal standard: tridecane) revealed the
presence of 2,6-difluoropyridine (3%), 2,6-difluoro-3-iodopyridine
(1; 16%), and 2,6-difluoro-4-iodopyridine (11; 81%). The organic
phase was dried and the solvents evaporated. Crystallization from
20 Torr; n2D0 ϭ 1.4770; d420 ϭ 1.236; yield: 8.40 g (97%). H NMR:
1
δ ϭ 8.18 (dt, J ϭ 9.9, 8.1 Hz, 1 H), 6.82 (dd, J ϭ 8.3, 3.0 Hz, 1
H), 2.40 (s, 1 H), 1.64 (d, J ϭ 1.1 Hz, 6 H) ppm. 13C NMR: δ ϭ
160.0 (dd, J ϭ 246, 14 Hz), 157.2 (dd, J ϭ 246, 14 Hz), 142.4 (t,
J ϭ 6 Hz), 127.2 (dd, J ϭ 25, 6 Hz), 105.7 (dd, J ϭ 34, 5 Hz), 70.5
(d, J ϭ 6 Hz), 29.8 (d, J ϭ 3 Hz, 2 C) ppm. C8H9F2NO (173.16):
calcd. C 55.49, H 5.24; found C 55.23, H 5.28.
2,6-Difluoropyridine-3-carbaldehyde (7): Analogously as described
for the preparation of product 1, using N,N-dimethylformamide
(7.7 mL, 7.3 g, 0.10 mol). After 45 min, 2.0  ethereal hydrogen
chloride (75 mL, 0.15 mol) were added still at Ϫ75 °C. All volatiles hexanes afforded the main product as colorless prisms; m.p. 80Ϫ82
were evaporated and upon distillation, the product was collected
°C; yield: 9.16 g (76%). 1H NMR: δ ϭ 7.24 (t, J ϭ 1.2 Hz, 2 H)
Eur. J. Org. Chem. 2004, 1018Ϫ1024
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1021

M. Schlosser, T. Rausis
FULL PAPER
ppm. 13C NMR: δ ϭ 161.1 (dd, J ϭ 252, 16 Hz, 2 C), 115.6 (symm.
1H NMR: δ ϭ 8.23 (dd, J ϭ 8.3, 7.0 Hz, 1 H) ppm. 13C NMR:
m, 2 C), 110.0 (t, J ϭ 7 Hz) ppm. C5H2F2IN (240.98): calcd. C δ ϭ 158.3 (dd, J ϭ 243, 12 Hz), 156.9 (dd, J ϭ 248, 13 Hz), 152.3
24.92, H 0.84; found C 24.88, H 0.84.
(dd, J ϭ 3, 2 Hz), 114.2 (dd, J ϭ 32, 7 Hz), 69.7 (dd, J ϭ 43, 6 Hz)
ppm. C5HClF2IN (275.42): calcd. C 21.80, H 0.37; found C 21.94,
H 0.30.
2,6-Difluoropyridine-4-carboxylic Acid (12): The solutions of butyl-
magnesium chloride (8.0 mmol) in tetrahydrofuran (4 mL) and of
butyllithium (17 mmol) in hexanes (11 mL), were mixed in an ice
bath. After 15 min at 0 °C, a solution of 2,6-difluoro-4-iodopy-
ridine (11; 6.0 g, 25 mmol) in toluene (50 mL) was added. After
45 min at 0 °C, the mixture was poured on an excess of freshly
crushed dry ice and neutralized with 5.0  hydrochloric acid
(25 mL). The aqueous phase was extracted with diethyl ether (3 ϫ
25 mL) and the combined organic layers were dried. Evaporation
of the volatiles and crystallization of the residue from ethyl acetate
afforded colorless platelets; m.p. 147Ϫ149 °C; yield: 3.47 g (87%).
1H NMR*: δ ϭ 7.48 (s, 2 H) ppm. 13C NMR*: δ ϭ 164.7 (s), 163.6
(dd, J ϭ 245, 15 Hz, 2 C), 150.1 (t, J ϭ 7 Hz), 108.2 (symm. m, 2
C) ppm. C6H3F2NO2 (159.09): calcd. C 45.30, H 1.90; found C
45.35, H 1.81. The same acid 12 was obtained when 10% palladium
on charcoal (2.5 g, 2.4 mmol) was suspended in a solution of 3-
chloro-2,6-difluoropyridine-4-carboxylic acid (16; see below; 4.9 g,
25 mmol) and ammonium formate (7.9 g, 0.13 mmol) in methanol
(25 mL) and the slurry was stirred for 6 h at 25 °C; yield: 3.74 g
(94%).
3-Chloro-2,6-difluoropyridine-4-carboxylic Acid (16): The solutions
of butylmagnesium chloride (8.0 mmol) in tetrahydrofuran (4 mL)
and of butyllithium (17 mmol) in hexanes (11 mL) were mixed in an
ice bath. After 15 min at 0 °C, a solution of 3-chloro-2,6-difluoro-4-
iodopyridine (14; 6.9 g, 25 mmol) in toluene (50 mL) was added.
After 45 min at 0 °C, the mixture was poured on an excess of
freshly crushed dry ice and neutralized with 5.0  hydrochloric acid
(25 mL). The aqueous phase was extracted with diethyl ether (3 ϫ
25 mL) and the combined organic layers were dried. Evaporation
of the volatiles and crystallization of the residue from chloroform
afforded colorless needles; m.p. 106Ϫ108 °C; yield: 4.35 g (90%).
1H NMR: δ ϭ 7.38 (d, J ϭ 3.0 Hz, 1 H) ppm. 13C NMR: δ ϭ
167.3 (t, J ϭ 3 Hz), 159.1 (dd, J ϭ 249, 13 Hz), 157.8 (dd, J ϭ 247,
15 Hz), 143.6 (d, J ϭ 7 Hz), 113.7 (dd, J ϭ 33, 8 Hz), 108.6 (dd,
J ϭ 38, 6 Hz) ppm. C6H2ClF2NO2 (193.54): calcd. C 37.24, H 1.04;
found C 37.13, H 1.08.
2,6-Difluoro-5-iodopyridine-3-carboxylic Acid (17): At Ϫ75 °C, di-
isopropylamine (7.0 mL, 5.1 g, 50 mmol) and a solution of 2,6-di-
fluoro-3-iodopyridine (1; 12.1 g, 50 mmol) in tetrahydrofuran
(50 mL) were consecutively added to butyllithium (50 mmol) in
tetrahydrofuran (60 mL) and hexanes (35 mL). After 15 min at Ϫ75
°C, the mixture was poured on an excess of freshly crushed dry ice.
The volatiles were evaporated and the residue was dissolved in a
2.0  aqueous solution (50 mL) of sodium hydroxide. The aqueous
phase was washed with diethyl ether (2 ϫ 25 mL), acidified with
hydrochloric acid to pH 2 and extracted with diethyl ether (3 ϫ
50 mL). The combined organic layers were dried and the solvents
evaporated. According to gas chromatography (30 m, DB-1, 100
°C [15 min] Ǟ 175 °C [15 min]; heating rate 30 °C/min; 30 m, DB-
WAX, same temperature program; internal standard: tridecane),
the organic solution contained 2,6-difluoro-3-iodopyridine (1; 9%),
2,6-difluoro-3,5-diiodopyridine (18; 8%), and methyl 2,6-difluoro-
5-iodopyridine-3-carboxylate (72%). Crystallization from ethyl
acetate afforded the product as colorless platelets; m.p. 166Ϫ168
°C (decomp.); yield: 9.52 g (67%). 1H NMR*: δ ϭ 8.90 (t, J ϭ
8.3 Hz, 1 H) ppm. 13C NMR*: δ ϭ 162.7 (dd, J ϭ 244, 14 Hz),
162.1 (d, J ϭ 7 Hz), 161.4 (dd, J ϭ 258, 14 Hz), 157.3 (dd, J ϭ 5,
2 Hz), 114.0 (dd, J ϭ 23, 6 Hz), 70.5 (dd, J ϭ 42, 6 Hz) ppm.
C6H2F2INO2 (284.99): calcd. C 25.29, H 0.71; found C 25.45, H
1.18.
2,6-Difluoro-4-iodopyridine-3-carboxylic Acid (13): Diisopropyl-
amine (3.5 mL, 2.5 g, 25 mmol) and 2,6-difluoro-4-iodopyridine
(11; 6.1 g, 25 mmol) were added consecutively to a solution of bu-
tyllithium (25 mmol) in tetrahydrofuran (50 mL) and hexanes
(15 mL) cooled in a methanol/dry ice bath. After 45 min at Ϫ75 °C,
the mixture was poured onto an excess of carbon dioxide and
worked up as described for the preparation of acid 9; colorless
platelets (from chloroform); m.p. 126Ϫ128 °C; yield: 6.48 g (91%).
1H NMR*: δ ϭ 7.74 (d, J ϭ 2.6 Hz, 1 H) ppm. 13C NMR*: δ ϭ
164.5 (d, J ϭ 5 Hz), 161.6 (dd, J ϭ 251, 15 Hz), 157.7 (dd, J ϭ
249, 16 Hz), 121.5 (dd, J ϭ 32, 6 Hz), 118.7 (dd, J ϭ 37, 6 Hz),
111.7 (dd, J ϭ 8, 2 Hz) ppm. C6H2F2INO2 (284.99): calcd. C 25.29,
H 0.71; found C 25.30, H 0.77.
3-Chloro-2,6-difluoro-4-iodopyridine
(14):
Diisopropylamine
(7.0 mL, 5.1 g, 50 mmol) and 3-chloro-2,6-difluoropyridine (3;
7.5 g, 50 mmol) were added consecutively to a solution of butyllith-
ium (50 mmol) in tetrahydrofuran (0.10 L) and hexanes (30 mL),
cooled in a methanol/dry ice bath. After 45 min at Ϫ75 °C, the
mixture was treated with a solution of iodine (13 g, 50 mmol) in
tetrahydrofuran (50 mL) before being washed with a 10% aqueous
solution (25 mL) of sodium sulfite. According to gas chromatogra-
phy (30 m, DB-1, 100 °C; 30 m, DB-WAX, 100 °C; internal stand-
ard: tridecane), it contained 3-chloro-2,6-difluoro-4-iodopyridine
(14; 77%) and 3-chloro-2,6-difluoro-5-iodopyridine (15; 15%; see
below). After evaporation of the volatiles, the residue was crys-
tallized from hexanes; colorless prisms; m.p. 90.5Ϫ92.5 °C; yield:
2,6-Difluoro-3,5-diiodopyridine (18): When the mixture resulting
from the reaction between butyllithium, diisopropylamine and 2,6-
difluoro-3-iodopyridine (1; see the preceding paragraph) was
treated with a solution of iodine in tetrahydrofuran at Ϫ75 °C
(rather than poured on dry ice), the residue contained, according
to gas chromatography (30 m, DB-1, 100 °C [15 min] Ǟ 175 °C
[15 min]; heating rate 30 °C/min; 30 m, DB-WAX, same tempera-
ture program; internal standard: tridecane), 2,6-difluoro-3-iodo-
pyridine (1; 2%), 2,6-difluoro-3,4-diiodopyridine (19; 17%; see be-
low), and 2,6-difluoro-3,5-diiodopyridine (18; 81%). Washing with
an aqueous solution (50 mL) of sodium sulfite, evaporation and
1
9.78 g (71%). H NMR: δ ϭ 7.37 (d, J ϭ 3.2 Hz, 1 H) ppm. 13C
NMR: δ ϭ 158.9 (dd, J ϭ 251, 14 Hz), 155.3 (dd, J ϭ 249, 16 Hz),
119.2 (dd, J ϭ 32, 7 Hz), 117.7 (dd, J ϭ 38, 6 Hz), 115.5 (d, J ϭ
8 Hz) ppm. C5HClF2IN (275.42): calcd. C 21.80, H 0.37; found C
21.69, H 0.50.
3-Chloro-2,6-difluoro-5-iodopyridine (15): A solution of (5-chloro-
2,6-difluoropyridin-3-yl)trimethylsilane (21; see below; 22 g, 0.10 crystallization from hexanes gave colorless needles; m.p. 108Ϫ110
1
mol) and iodine monochloride (32 g, 0.20 mol) in tetrachloro-
°C; yield: 13.8 g (75%). H NMR: δ ϭ 8.52 (t, J ϭ 7.5 Hz, 1 H)
methane (0.10 L) were heated under reflux for 20 h. The mixture ppm. 13C NMR: δ ϭ 160.6 (dd, J ϭ 244, 14 Hz, 2 C), 160.5 (s),
was washed with a saturated aqueous solution (75 mL) of sodium
sulfite, dried and the solvents evaporated. Crystallization from
hexanes gave colorless needles; m.p. 58Ϫ60 °C; yield: 25.6 g (93%).
70.8 (symm. m, 2 C) ppm. C5HF2I2N (366.87): calcd. C 16.37, H
0.27; found C 16.22, H 0.31. The same compound 18 was isolated
in 93% yield (8.53 g) after a solution of (2,6-difluoropyridin-3,5-
1022
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1018Ϫ1024

Structural Proliferation of 2,6-Difluoropyridine through Organometallic Intermediates
FULL PAPER
diyl)bis(trimethylsilane) (23; see below; 6.5 g, 25 mmol) and iodine
monochloride (16 g, 0.10 mol) in tetrachloromethane (0.10 L) had
been heated for 20 h under reflux.
NMR: δ ϭ 166.9 (dd, J ϭ 244, 14 Hz, 2 C), 156.2 (t, J ϭ 10 Hz),
116.1 (symm. m, 2 C), Ϫ1.4 (s, 6 C) ppm. C11H19F2NSi2 (259.44):
calcd. C 50.92, H 7.38; found C 50.74, H 7.41. The same bissilane
23 was isolated by distillation in 92% yield (5.97 g) 2 h after 2,6-
difluoropyridine (2.3 mL, 2.9 g, 25 mmol) had been added at Ϫ75
°C to a solution containing chlorotrimethylsilane (6.3 mL, 5.4 g,
50 mmol) and lithium diisopropylamide, generated from each time
50 mmol of diisopropylamine and butyllithium in tetrahydrofuran
(70 mL) and hexanes (30 mL).
2,6-Difluoro-3,4-diiodopyridine (19): A second reaction was under-
taken exactly as described in the preceding paragraph, except that
the reaction time at Ϫ75 °C was extended from 15 min to 30 h.
According to gas chromatography, the mixture contained 2,6-di-
fluoro-3-iodopyridine (1; 4%), 2,6-difluoro-3,5-diiodopyridine (18;
16%) and 2,6-difluoro-3,4-diiodopyridine (19; 80%) this time. The
main component was purified by crystallization from hexanes; col-
orless platelets; m.p. 91Ϫ93 °C; yield: 13.6 g (74%). 1H NMR: δ ϭ
7.41 (d, J ϭ 3.2 Hz, 1 H) ppm. 13C NMR: δ ϭ 161.7 (dd, J ϭ 251,
14 Hz), 159.9 (dd, J ϭ 244, 15 Hz), 125.9 (d, J ϭ 7 Hz), 117.4 (dd,
J ϭ 37, 6 Hz), 86.1 (dd, J ϭ 41, 6 Hz) ppm. C5HF2I2N (366.87):
calcd. C 16.37, H 0.27; found C 16.38, H 0.29.
(5-Bromo-2,6-difluoropyridin-3-yl)trimethylsilane (24): A solution of
(2,6-difluoropyridin-3,5-diyl)bis(trimethylsilane) (23; 13 g, 50 mmol)
and bromine (5.2 mL, 16.0 g, 0.10 mol) in tetrachloromethane
(50 mL) was heated for 20 h under reflux before it was washed with
a saturated aqueous solution (50 mL) of sodium sulfite, dried, and
the solvents evaporated. Distillation gave a colorless liquid; m.p.
0Ϫ2 °C; b.p. 84Ϫ86 °C/12 Torr; n2D0 ϭ 1.4975; d420 ϭ 1.399; yield:
2,6-Difluoro-5-(trimethylsilyl)pyridine-3-carboxylic Acid (20): Di-
isopropylamine (14 mL, 10 g, 0.10 mol) and (2,6-difluoropyridin-
3-yl)trimethylsilane (5; 19 g, 0.10 mol) were added consecutively to
a solution of butyllithium (0.10 mol) in tetrahydrofuran (0.20 L)
and hexanes (60 mL) cooled in a methanol/dry ice bath. After
45 min at Ϫ75 °C, the mixture was poured on an excess of freshly
crushed dry ice. At 25 °C, 2.0  ethereal hydrogen chloride (0.15
mol) was added. Evaporation of the volatiles, extraction with hot
chloroform, filtration, concentration, and crystallization afforded
the product; colorless needles; m.p. 171Ϫ173 °C; yield: 22.7 g
(98%). 1H NMR: δ ϭ 8.56 (dd, J ϭ 9.9, 7.7 Hz, 1 H), 0.38 (s, 9 H)
ppm. 13C NMR: δ ϭ 168.0 (d, J ϭ 7 Hz), 167.6 (dd, J ϭ 251,
14 Hz), 162.5 (dd, J ϭ 261, 17 Hz), 154.1 (d, J ϭ 13 Hz), 118.5
(dd, J ϭ 44, 7 Hz), 109.5 (dd, J ϭ 20, 5 Hz), Ϫ1.7 (s, 3 C) ppm.
C9H11F2NO2Si (231.27): calcd. C 46.74, H 4.79; found C 46.65,
H 4.80.
1
12.7 g (95%). H NMR: δ ϭ 7.98 (dd, J ϭ 9.4, 7.0 Hz, 1 H), 0.34
(s, 9 H) ppm. 13C NMR: δ ϭ 163.9 (dd, J ϭ 244, 12 Hz), 158.7
(dd, J ϭ 244, 15 Hz), 152.8 (d, J ϭ 10 Hz), 119.9 (dd, J ϭ 45,
6 Hz), 100.0 (dd, J ϭ 34, 6 Hz), Ϫ1.6 (s, 3 C) ppm. C8H10BrF2NSi
(266.16): calcd. C 36.10, H 3.79; found C 36.04, H 3.67.
3,5-Dibromo-2,6-difluoropyridine (25): At 0 °C, 3-bromo-2,6-di-
fluoro-5-iodopyridine (26; see below; 8.0 g, 25 mmol) was added to
a solution of isobutylmagnesium chloride (25 mmol) in tetrahydro-
furan (50 mL). The mixture was kept in an ice bath for 2 h, before
being treated with bromine (1.3 mL, 4.0 g, 25 mmol) and, 15 min
later, a 10% aqueous solution (25 mL) of sodium sulfite. Evapo-
ration of the volatiles and crystallization of the residue from hex-
anes afforded colorless platelets; m.p. 80Ϫ82 °C; yield: 6.14 g
1
(90%). H NMR: δ ϭ 8.21 (t, J ϭ 7.5 Hz, 1 H) ppm. 13C NMR:
δ ϭ 156.5 (dd, J ϭ 245, 13 Hz, 2 C), 149.4 (s), 100.6 (symm. m, 2
C) ppm. C5HBr2F2N (272.87): calcd. C 22.01, H 0.37; found C
21.92, H 0.34.
(5-Chloro-2,6-difluoropyridin-3-yl)trimethylsilane (21): Analogously
as described in the preceding paragraph using 1,1,2-trichloro-1,2,2-
trifluoroethane (11.9 mL, 18.7 g, 0.10 mol) instead of carbon diox-
ide. The product was collected upon distillation as a colorless
liquid; m.p. Ϫ8 to Ϫ6 °C; b.p. 87Ϫ89 °C/15 Torr; n2D0 ϭ 1.4779; d
3-Bromo-2,6-difluoro-5-iodopyridine (26): A solution of (2,6-di-
fluoropyridin-3,5-diyl)bis(trimethylsilane) (23; 13 g, 50 mmol) and
bromine (5.2 mL, 16 g, 0.10 mol) in tetrachloromethane (50 mL)
was heated under reflux for 20 h. After the addition of iodine mon-
ochloride (16 g, 0.10 mol), the heating under reflux was continued
for further 20 h. The mixture was washed with a saturated aqueous
solution (50 mL) of sodium sulfite, dried, and the solvents evapo-
rated. Crystallization from hexanes afforded colorless needles; m.p.
85Ϫ87 °C; yield: 14.6 g (91%). 1H NMR: δ ϭ 8.36 (dd, J ϭ 7.8,
7.3 Hz, 1 H) ppm. 13C NMR: δ ϭ 159.2 (dd, J ϭ 244, 13 Hz),
157.9 (dd, J ϭ 246, 14 Hz), 155.0 (s), 100.9 (dd, J ϭ 36, 6 Hz), 70.3
(dd, J ϭ 43, 6 Hz) ppm. C5HBrF2IN (319.87): calcd. C 18.77, H
0.32; found C 18.97, H 0.49.
20
1
ϭ 1.179; yield: 21.5 g (97%). H NMR: δ ϭ 7.85 (dd, J ϭ 9.6,
4
7.0 Hz, 1 H), 0.34 (s, 9 H) ppm. 13C NMR: δ ϭ 162.7 (dd, J ϭ
243, 12 Hz), 157.5 (dd, J ϭ 246, 16 Hz), 149.7 (dd, J ϭ 11, 2 Hz),
119.3 (dd, J ϭ 45, 7 Hz), 112.9 (dd, J ϭ 29, 7 Hz), Ϫ1.8 (s, 3 C)
ppm. C8H10ClF2NSi (221.71): calcd. C 43.34, H 4.55; found C
43.57, H 4.44.
5-Chloro-2,6-difluoropyridine-3-carboxylic Acid (22): From 3-
chloro-2,6-difluoro-5-iodopyridine (15; 6.9 g, 25 mmol) analogous
as described for the preparation of compound 16; colorless platelets
(from ethyl acetate); m.p. 136Ϫ138 °C; yield: 4.40 g (91%). 1H
NMR*: δ ϭ 8.66 (t, J ϭ 8.3 Hz, 1 H) ppm. 13C NMR*: δ ϭ 162.3
(d, J ϭ 8 Hz), 159.1 (dd, J ϭ 257, 14 Hz), 158.8 (dd, J ϭ 248,
15 Hz), 148.3 (t, J ϭ 3 Hz), 114.0 (dd, J ϭ 25, 6 Hz), 113.7 (dd,
J ϭ 17, 6 Hz) ppm. C6H2ClF2NO2 (193.54): calcd. C 37.24, H 1.04;
found C 37.44, H 1.02.
Acknowledgments
This work was financially supported by the Schweizerische National-
fonds zur Förderung der wissenschaftlichen Forschung, Bern (grant
20-55Ј303-98), the Bundesamt für Bildung und Wissenschaft, Bern
(grant 97.0083 linked to the TMR project FMRXCT-970129) and
Hoffmann-LaRoche, Basel.
(2,6-Difluoropyridin-3,5-diyl)bis(trimethylsilane) (23): Diisopro-
pylamine (28.3 mL, 20.2 g, 0.20 mol) and (2,6-difluoropyridin-3-
yl)trimethylsilane (5; 37.5 g, 0.20 mol) were added consecutively to
a solution of butyllithium (0.20 mol) in tetrahydrofuran (0.35 L)
and hexanes (0.12 L) cooled in a methanol/dry ice bath. After
45 min at Ϫ75 °C, the mixture was treated with chlorotrimethylsil-
ane (25 mL, 22 g, 0.20 mol) and, again 45 min later, with water
(0.10 L). Upon distillation, the product was collected as a colorless
liquid; m.p. 23Ϫ25 °C; b.p. 60Ϫ62 °C/0.6 Torr; yield: 49.0 g (94%).
1H NMR: δ ϭ 7.89 (t, J ϭ 9.1 Hz, 1 H), 0.33 (s, 18 H) ppm. 13C
[1]
M. Schlosser, Organometallics in Synthesis: A Manual (Ed.: M.
Schlosser), 2nd edition, Wiley, Chichester, 2002, pp. 1Ϫ352,
spec. 247.
[2]
E. Marzi, A. Bigi, M. Schlosser, Eur. J. Org. Chem. 2001,
1371Ϫ1376.
G. W. Gribble, M. G. Saulnier, Tetrahedron Lett. 1980, 21,
4137Ϫ4140.
[3]
Eur. J. Org. Chem. 2004, 1018Ϫ1024
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1023

M. Schlosser, T. Rausis
FULL PAPER
[4]
[12]
[13]
[14]
[15]
[16]
´
L. Estel, F. Marsais, G. Queguiner, J. Org. Chem. 1988, 53,
F. Mongin, M. Schlosser, Tetrahedron Lett. 1996, 37,
6551Ϫ6554.
H. O. House, L. J. Czuba, M. Gall, H. D. Olmstead, J. Org.
Chem. 1969, 34, 2324Ϫ2336.
T. D. Krizan, J. C. Martin, J. Am. Chem. Soc. 1983, 105,
6155Ϫ6157.
B. H. Lipshutz, M. R. Wood, C. W. Lindsley, Tetrahedron Lett.
1995, 36, 4385Ϫ4388.
M. Schlosser, L. Guio, F. Leroux, J. Am. Chem. Soc. 2001,
123, 3822Ϫ3823.
C. Bobbio, M. Schlosser, Eur. J. Org. Chem. 2001, 4533Ϫ4536.
C. Heiss, M. Schlosser, Eur. J. Org. Chem. 2003, 447Ϫ451.
M. M. Boudakian, J. Fluorine Chem. 1981, 18, 497Ϫ506.
F. Mutterer, C. D. Weis, Helv. Chim. Acta 1976, 59, 229Ϫ235.
Received October 13, 2003
2740Ϫ2744.
[5]
[6]
[7]
[8]
G. M. Shutske, J. E. Roehr, J. Heterocycl. Chem. 1997, 34,
789Ϫ795.
G. Rauchschwalbe, M. Schlosser, Helv. Chim. Acta 1975, 58,
1094Ϫ1099.
M. Schlosser, L. Franzini, Synthesis 1998, 707Ϫ709, spec. foot-
note (14).
F. Mongin, O. Desponds, M. Schlosser, Tetrahedron Lett. 1996,
37, 2767Ϫ2770.
T. Rausis, M. Schlosser, Eur. J. Org. Chem. 2002, 3351Ϫ3358.
I. F. Tupitsyn, N. N. Zatsepina, A. V. Kirova, Y. L. Kaminskii,
A. G. Ivanenko, Reakts. Sposobnost Org. Soedin. 1973, 10,
143Ϫ162; Chem. Abstr. 1973, 79, 114928v.
M. Schlosser, M. Marull, Eur. J. Org. Chem. 2003, in press.
[9]
[17]
[18]
[19]
[20]
[10]
[11]
1024
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1018Ϫ1024