Exploring Structural Opportunities: The Regioflexible Substitution of 1,3-Difluorobenzene

Article abstract of DOI:10.1002/ejoc.200300354

To demonstrate the superiority of modern organometallic methods, the inexpensive starting material 1,3-difluorobenzene has been selectively converted into the three benzoic acids and all seven bromobenzoic acids containing the two fluorine atoms in homovicinal positions. The 2,6-difluorobenzoic acid (1) was prepared in a one-pot reaction consisting of direct metallation and carboxylation. The key step on the route to the bromobenzoic acid 4 was a deprotonation-triggered bromine migration from the 2- to the 4-position. All other products were attained through (2,6-difluorophenyl)triethylsilane (11). Consecutive deprotonation of the sites adjacent to the fluorine atoms, followed by appropriate electrophilic substitution, provided not only the acid 7 but also the dibromo and iodobromo derivatives 13 and 23. These in turn gave the isomers 14 and 24 upon base-mediated migration of the heaviest halogen, which made the acids 8 and 10 directly accessible. The regiocontrolled monodebromination of intermediate 14 afforded (4-bromo-2,6-difluoro)triethylsilane (15), which opened the route to the acids 3 and 5 (by carboxylation and protodesilylation) and to acid 9 (by carboxylation and bromodesilylation). Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300354

FULL PAPER
Exploring Structural Opportunities: The Regioflexible Substitution of
1,3-Difluorobenzene
Manfred Schlosser*[a,b] and Christophe Heiss[a]
Keywords: Basicity / Carboxylation / Halogens / Lithiation / Bromodesilylation
To demonstrate the superiority of modern organometallic
methods, the inexpensive starting material 1,3-difluoroben-
zene has been selectively converted into the three benzoic
acids and all seven bromobenzoic acids containing the two
fluorine atoms in homovicinal positions. The 2,6-difluoroben-
zoic acid (1) was prepared in a one-pot reaction consisting of
direct metallation and carboxylation. The key step on the
route to the bromobenzoic acid 4 was a deprotonation-trig-
gered bromine migration from the 2- to the 4-position. All
other products were attained through (2,6-difluorophenyl)tri-
trophilic substitution, provided not only the acid 7 but also
the dibromo and iodobromo derivatives 13 and 23. These in
turn gave the isomers 14 and 24 upon base-mediated migra-
tion of the heaviest halogen, which made the acids 8 and 10
directly accessible. The regiocontrolled monodebromination
of intermediate 14 afforded (4-bromo-2,6-difluoro)triethylsil-
ane (15), which opened the route to the acids 3 and 5 (by
carboxylation and protodesilylation) and to acid 9 (by carb-
oxylation and bromodesilylation).
ethylsilane (11). Consecutive deprotonation of the sites adja- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
cent to the fluorine atoms, followed by appropriate elec- Germany, 2003)
Introduction
In a recent publication[1] we have shown how 1,2,3-tri-
fluorobenzene can be converted into the two corresponding
trifluorobenzoic acids and the three corresponding bromo-
trifluorobenzoic acids. All reactions were straightforward
and expeditious. The precursors to the acids having in-
variably been lithium species, any functional entity besides
the carboxy group could have been introduced into the aro-
matic nucleus in the same way.
1,3-Difluorobenzene, a particularly inexpensive starting
material (approx. 30 Euro/mol retail price), can give rise to
a great variety of derivatives. This time, three benzoic acids
familiar direct hydrogen/metal and halogen/metal permu-
and seven bromobenzoic acids containing two fluorine
tations,[4] modern modifications were applied individually
or in any suitable combination:
· metallation of the next reactive site after blocking of the
most acidic position by the introduction of bromine,
· metallation of the next reactive site after protection of
the most acidic position with a trialkylsilyl group (to be
removed later by hydrolysis or halogenolysis),
· deprotonation-triggered and basicity gradient-driven
halogen migration,
atoms in homovicinal positions were targeted. The bromo
compounds may be used as components in Suzuki coup-
ling reactions.[1]
Starting from 1,3-difluorobenzene, we have made all
these ten compounds, most of them yet unknown. To secure
the required regioflexibility, we again relied on the same
toolbox of organometallic methods that had already proven
successful in previous model studies.[1Ϫ3] Besides the
· element-specific halogen/metal permutation, an iodo-
bromoarene being the substrate, and
· site-specific halogen/metal permutation, a dibromo-
arene being the substrate.
The chart below offers a survey of all the reactions car-
ried out in the course of this investigation. Details of prep-
aration are described thereafter.
[a]
´
Institut de Chimie moleculaire et biologique
´ ´
Ecole Polytechnique Federale, BCh
CH-1015 Lausanne, Switzerland
[b]
´
Faculte des Sciences
CH-1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300354
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The Regioflexible Substitution of 1,3-Difluorobenzene
FULL PAPER
2,6-Difluorobenzoic acid (1; 90% after crystallization) and neutralization in almost quantitative yield.[5] If the or-
was obtained after lithiation (with butyllithium in tetra- ganolithium intermediate was instead intercepted with chlo-
hydrofuran at Ϫ75 °C for 45 min), carboxylation (dry ice), rotriethylsilane, (2,6-difluorophenyl)triethylsilane (11; 89%)
was formed, again in high yield. Consecutive treatment of
this compound with sec-butyllithium and carbon dioxide
gave the acid 16 (89%), which was desilylated with potas-
sium hydroxide in ethanol to afford the 2,4-difluorobenzoic
acid (2; 98%). Alternatively, the silane 11 was subjected to
a sequence of lithiation and bromination and thus con-
verted into the bromo derivative 12 (92%). When this com-
pound was deprotonated with lithium diisopropylamide
(LIDA) and halogenated with 1,2-dibromotetrafluoroeth-
ane, the dibromo compound 13 (82%) was obtained first.
LIDA-promoted heavy halogen migration[3] produced the
vicinal dibromo isomer 14 (86%; though still contaminated
with small amounts of its precursor 13). Butyllithium selec-
tively attacked the doubly activated bromine flanked by the
other bromine and one of the fluorine atoms. Quenching of
the resulting organolithium species with methanol afforded
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M. Schlosser, C. Heiss
FULL PAPER
the 4-bromo-2,6-difluorosilane 15 (59%), which upon con-
secutive halogen/metal permutation and carboxylation gave
the silylated acid 17 (93%) and, after treatment of the latter
with potassium hydroxide, the 3,5-difluorobenzoic acid (3;
97%).
The route to the 3-bromo-2,4-difluorobenzoic acid (6;
84%) passed through the silylated acid 16 (see above). The
heavy halogen substituent was introduced by the powerful
and versatile method of bromodesilylation.
Another basicity gradient-driven halogen migration
made the first of the five bromodifluorobenzoic acids ac-
cessible. 2-Bromo-1,3-difluorobenzene (18; 94%), prepared
from 1,3-difluorobenzene by consecutive treatment with bu-
tyllithium and bromine, underwent a 1,3-bromine shift
when treated with LIDA. However, the oil collected upon
distillation after neutralization consisted of a 3:2 ratio of
the expected product 19 (35% crude) and starting material
18 (23%). The latter isomer was selectively destroyed by
treatment with the stoichiometrically required amount of
butyllithium, followed by carboxylation and distillation
(without prior neutralization). The pure 1-bromo-2,4-di-
fluorobenzene (19; 20% overall) was eventually converted
into the 3-bromo-2,6-difluorobenzoic acid (4) by depro-
Protodesilylation was the last step in a reaction sequence
providing the 5-bromo-2,4-difluorobenzoic acid (7; 95%).
The preceding silylated acid 21 (70%) was obtained by treat-
ment of the bromodifluorosilane 12 consecutively with
LIDA and carbon dioxide.
tonation
with lithium
2,2,6,6-tetramethylpiperidide
(LITMP), followed by carboxylation.
Analogously, the 2-bromo-4,6-difluorobenzoic acid (8;
94%) was produced from the silylated derivative 22 by pro-
todesilylation. The latter intermediate was prepared from
the vic-dibromodifluorosilane 14 by site-selective halogen/
metal permutation followed by carboxylation, in 98% yield.
Fluoride-mediated protodesilylation of silane 15 afforded
1-bromo-3,5-difluorobenzene (20; 93%), which opened an
alternative route to the 3,5-difluorobenzoic acid (3; 91%) by
consecutive reaction with butyllithium and dry ice. If
LITMP was employed as the base instead, the 4-bromo-2,6-
[6]
difluorobenzoic acid
boxylation.
(5; 96%) was formed upon car-
Bromodesilylation offered the most convenient access to
4-bromo-3,5-difluorobenzoic acid (9; 87%). The key inter-
mediate was the already described (see above) silylated di-
fluorobenzoic acid 17.
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The Regioflexible Substitution of 1,3-Difluorobenzene
FULL PAPER
NMR spectra were recorded at 400 and 101 MHz, respectively, of
samples dissolved in deuteriochloroform. Stationary phases in gas
chromatographic columns are coded as OV-17 (silicon rubber) and
FFAP or C-20M (both of the polyethylene glycol type).
1. Difluorobenzoic and Bromodifluorobenzoic Acids
2,6-Difluorobenzoic Acid (1): A solution of 1,3-difluorobenzene
(2.3 mL, 2.9 g, 25 mmol) and butyllithium (25 mmol) in hexanes
(16 mL) and tetrahydrofuran (35 mL) was kept at Ϫ75 °C for
45 min before being poured on an excess of freshly crushed dry
ice. The mixture was acidified with an ethereal solution (15 mL) of
hydrogen chloride (30 mmol). The volatile components were evapo-
rated, and the residue was extracted with boiling ethyl acetate (3 ϫ
15 mL). Upon filtration and concentration of the combined or-
The last bromodifluorobenzoic acid proved to be a chal-
lenge. Firstly, iodine had to be introduced into the 5-posi-
tion of silane 12, and the resulting intermediate 23 (86%)
then had to be isomerized to the silane 24 (57%) by LIDA-
triggered migration of the iodine (rather than the bromine)
atom. Next, the iodine had to be replaced by lithium under
carefully controlled conditions in order to prevent the com- ganic layers, the product crystallized as tiny, colorless needles; m.p.
158Ϫ160 °C (from hexanes; ref.[11] m.p. 161Ϫ162 °C); yield: 3.55 g
petitive exchange of the doubly activated bromine atom
1
(90%). H NMR: δ ϭ 7.51 (ddd, J ϭ 8.1, 6.5, 2.2 Hz, 1 H), 7.03
next to the fluorine. The remaining steps were trivial. The
(t, J ϭ 8.5 Hz, 2 H) ppm.
organolithium species was carboxylated and the benzoic
acid 25 (91%) was isolated and subsequently protodesilyl-
ated to afford the 2-bromo-3,5-difluorobenzoic acid 10
(97%).
2,4-Difluorobenzoic Acid (2): 2,4-Difluoro-3-(triethylsilyl)benzoic
acid (16; 6.8 g, 25 mmol) in a 4:1 (v/v) mixture of ethanol and water
(25 mL) and potassium hydroxide (2.5 g) were heated under reflux
for 2 h. The solvents were evaporated and the residue acidified with
aqueous hydrochloric acid (1.0 , 10 mL). The acid was extracted
with diethyl ether (3 ϫ 20 mL). Crystallization from hexanes
(20 mL) gave colorless needles; m.p. 186Ϫ189 °C (ref.[12] m.p.
182Ϫ184 °C); yield: 3.84 g (98%). 1H NMR: δ ϭ 8.08 (td, J ϭ 8.5,
6.5 Hz, 1 H), 6.99 (symm. m, 1 H), 6.93 (ddd, J ϭ 11.1, 8.6, 2.5 Hz,
1 H) ppm.
3,5-Difluorobenzoic Acid (3): 3,5-Difluoro-4-(triethylsilyl)benzoic
acid (17; 3.4 g, 15 mmol) was treated in the same way as described
in the preceding paragraph; colorless needles; m.p. 120Ϫ122 °C
(from chloroform; ref.[13] m.p. 120Ϫ122 °C); yield: 2.30 g (97%). 1H
NMR: δ ϭ 7.63 (symm. m, 2 H), 7.09 (tt, J ϭ 8.5, 2.5 Hz, 1 H)
ppm. When 1-bromo-3,5-difluorobenzene was added at Ϫ75 °C to
a solution of butyllithium (15 mmol) in hexanes (10 mL) and di-
ethyl ether (20 mL), the mixture being quenched after 15 min by
carboxylation and worked up as described for acid 2, the acid 3
was obtained in a 91% yield.
3-Bromo-2,6-difluorobenzoic Acid (4): 2,2,6,6-Tetramethylpiperi-
dine (2.5 mL, 2.1 g, 15 mmol) and 1-bromo-2,4-difluorobenzene
(19; 2.9 g, 15 mmol) were added consecutively at Ϫ75 °C to a solu-
tion of butyllithium (15 mmol) in hexanes (9.5 mL) and tetrahydro-
furan (20 mL). After 2 h, freshly crushed dry ice was added. The
reaction mixture was worked up as described for the acid 1; color-
less needles; m.p. 137Ϫ139 °C (from hexanes; ref.[14,15] m.p.
140Ϫ141 °C); yield: 3.26 g (92%). 1H NMR: δ ϭ 7.70 (ddd, J ϭ
9.0, 7.4, 5.5 Hz, 1 H), 6.95 (td, J ϭ 9.0, 1.6 Hz, 1 H) ppm.
It may not be immediately obvious why we have preferred
to use the triethylsilyl rather than the more common tri-
methylsilyl substituent as a protective group. Although it is
difficult to predict when such side reactions will really oc-
cur, (trimethylsilyl)alkenes[7] and (trimethylsilyl)arenes[8] are
known to be readily metallated at the silicon-bound methyl
groups. Therefore, it was merely an act of precaution to
avoid such complications through the use of triethylsilyl
homologues.
4-Bromo-2,6-difluorobenzoic Acid (5): 2,2,6,6-Tetramethylpiperi-
dine (4.2 mL, 3.5 g, 25 mmol) and 1-bromo-3,5-difluorobenzene
(4.8 g, 25 mmol) were added to
a solution of butyllithium
(25 mmol) in hexanes (16 mL) and tetrahydrofuran (35 mL) kept at
Ϫ75 °C. After 2 h, freshly crushed dry ice was added and the reac-
tion mixture was worked up as described above; colorless needles;
m.p. 196Ϫ198 °C (from hexanes; ref.[6] m.p. 195Ϫ197 °C); yield:
1
5.67 g (96%). H NMR: δ ϭ 7.21 (d, J ϭ 8.3 Hz, 2 H) ppm.
3-Bromo-2,4-difluorobenzoic Acid (6): 2,4-Difluoro-3-(triethylsilyl)-
benzoic acid (16; 6.8 g, 25 mmol) in carbon tetrachloride (25 mL)
and bromine (2.6 mL, 8.0 g, 50 mmol) were heated under reflux for
12 h. Evaporation of the solvent and the bromine gave the acid 6;
colorless needles; m.p. 132Ϫ134 °C (from hexanes); yield: 4.98 g
Experimental Section
Generalities: See related publications from this laboratory[1,9Ϫ10] for
working routine and abbreviations. 1H and (1H-decoupled) 13C
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M. Schlosser, C. Heiss
FULL PAPER
1
(84%). H NMR: δ ϭ 8.05 (ddd, J ϭ 9.0, 7.9, 6.2 Hz, 1 H), 7.06
(3-Bromo-2,6-difluorophenyl)triethylsilane (12): A solution of sec-
butyllithium (0.15 mol) in cyclohexane (0.10 L) was added to the
(ddd, J ϭ 9.0, 7.2, 1.7 Hz, 1 H) ppm. 13C NMR: δ ϭ 163.0 (s),
162.4 (dd, J ϭ 255, 4 Hz), 159.7 (dd, J ϭ 263, 5 Hz), 132.7 (d, J ϭ silane 11 (26 mL, 26 g, 0.15 mol) in tetrahydrofuran (0.20 L). After
11 Hz), 116.7 (d, J ϭ 12 Hz), 112.3 (dd, J ϭ 21, 3 Hz), 99.0 (t, J ϭ 45 min, bromine (7.7 mL, 24 g, 0.15 mol) was added. After evapor-
25 Hz) ppm. C7H3BrF2O2 (237.00): calcd. C 35.48, H 1.28; found
C 35.49, H 1.31.
ation of the volatile components, direct distillation afforded a col-
orless oil; b.p. 71Ϫ73 °C/0.6 Torr; n2D0 ϭ 1.5018; d420 ϭ 1.243; yield:
1
42.4 g (92%). H NMR: δ ϭ 7.50 (ddd, J ϭ 8.7, 7.0, 6.0 Hz, 1 H),
3-Bromo-4,6-difluorobenzoic Acid (7): 3-Bromo-4,6-difluoro-5-(tri-
ethylsilyl)benzoic acid (21; 8.8 g, 25 mmol) in a mixture of ethanol
and water (4:1 v/v, 50 mL) and potassium hydroxide (2.8 g,
50 mmol) were heated at reflux for 2 h. The reaction mixture was
worked up as described for acid 2; colorless needles; m.p. 148Ϫ150
6.73 (ddd, J ϭ 9.9, 8.7, 7.0 Hz, 1 H), 1.0 (m, 15 H) ppm. 13C NMR:
δ ϭ 166.4 (dd, J ϭ 242, 12 Hz), 162.7 (dd, J ϭ 245, 17 Hz), 135.0
(dd, J ϭ 8, 2 Hz), 113.1 (t, J ϭ 39 Hz), 112.3 (dd, J ϭ 28, 4 Hz),
103.9 (dd, J ϭ 27, 5 Hz), 7.0 (s), 4.1 (s) ppm. C12H17BrF2Si
(307.25): calcd. C 46.91, H 5.58; found C 46.90, H 5.19.
1
°C; yield: 5.59 g (95%). H NMR: δ ϭ 8.31 (t, J ϭ 8.0 Hz, 1 H),
7.03 (dd, J ϭ 10.1, 8.1 Hz, 1 H) ppm. 13C NMR: δ ϭ 164.2 (s),
163.4 (dd, J ϭ 261, 11 Hz), 163.2 (dd, J ϭ 255, 12 Hz), 138.2 (s),
118.6 (dd, J ϭ 11, 3 Hz), 108.2 (t, J ϭ 28 Hz), 105.1 (dd, J ϭ 20,
4 Hz) ppm. C7H3BrF2O2 (237.00): calcd. C 35.48, H 1.28; found C
35.46, H 1.33.
(3,5-Dibromo-2,6-difluorophenyl)triethylsilane (13): Diisopropyl-
amine (14 mL, 10 g, 0.10 mol) and (3-bromo-2,6-difluorophen-
yl)triethylsilane (12; 24 mL, 30 g, 0.10 mol) were added consecu-
tively to a solution of butyllithium (0.10 mol) in hexanes (60 mL)
and tetrahydrofuran (0.14 L), cooled in a methanol/dry ice bath.
After 2 h, 1,2-dibromotetrafluoroethane (14 mL, 31 g, 0.12 mol)
was added. After 45 min at Ϫ75 °C, the reaction mixture was
washed with hydrochloric acid (10%, 50 mL) and extracted with
hexanes (3 ϫ 50 mL). Upon distillation a colorless oil was ob-
tained; b.p. 91Ϫ93 °C/0.15 Torr; n2D0 ϭ 1.5421; d420 ϭ 1.662; yield:
2-Bromo-4,6-difluorobenzoic Acid (8): 2-Bromo-4,6-difluoro-5-(tri-
ethylsilyl)benzoic acid (22; 8.8 g, 25 mmol) was protodesilylated in
the same way as described in the preceding paragraph; colorless
needles; m.p. 91Ϫ93 °C (from pentanes); yield: 5.56 g (94%). 1H
NMR: δ ϭ 7.24 (dm, J ϭ 7.9 Hz, 1 H), 6.91 (symm. m, J ϭ 8.5,
2.1 Hz) ppm. 13C NMR: δ ϭ 168.2 (s), 163.5 (dd, J ϭ 258, 12 Hz),
160.8 (dd, J ϭ 259, 13 Hz), 121.7 (dd, J ϭ 12, 3 Hz), 119.5 (dd,
J ϭ 18, 2 Hz), 117.2 (dd, J ϭ 25, 3 Hz), 104.2 (t, J ϭ 25 Hz) ppm.
C7H3BrF2O2 (237.00): calcd. C 35.48, H 1.28; found C 35.66, H
1.07.
1
31.6 g (82%). H NMR: δ ϭ 7.76 (t, J ϭ 7.4 Hz, 1 H), 1.0 (m, 15
H) ppm. 13C NMR: δ ϭ 162.1 (dd, J ϭ 248, 16 Hz), 137.6 (s),
114.6 (t, J ϭ 39 Hz), 105.1 (m), 7.6 (s), 4.4 (s) ppm. C12H16Br2F2Si
(386.15): calcd. C 37.33, H 4.18; found C 37.52, H 3.98.
(3,4-Dibromo-2,6-difluorophenyl)triethylsilane (14): Diisopropyl-
amine (11 mL, 7.6 g, 75 mmol) and the silane 13 (28.9 g, 75 mmol)
were added consecutively to a solution of butyllithium (75 mmol)
in hexanes (50 mL) and tetrahydrofuran (0.10 L). After 2 h at Ϫ75
°C, the reaction mixture was treated with methanol (3.2 mL, 2.9 g,
90 mmol), washed with hydrochloric acid (10%, 50 mL), and ex-
tracted with hexanes (3 ϫ 50 mL). Upon distillation a colorless
oil was collected; b.p. 92Ϫ94 °C/0.2 Torr; yield: 37.2 g (86%). The
colorless oil was a 5:1 mixture of isomer 14 and its precursor 13,
as shown by gas chromatography (2 m, 2% FFAP, 180 °C; 2 m, 2%
OV-17, 220 °C; internal standard: tridecane). The main component
was purified by preparative gas chromatography (2 m, 10% C-20M,
4-Bromo-3,5-difluorobenzoic Acid (9): 3,5-Difluoro-4-(triethylsilyl)-
benzoic acid (17; 4.1 g, 15 mmol) was treated with elemental bro-
mine (3.1 mL, 9.6 g, 60 mmol) in carbon tetrachloride (15 mL) at
reflux for 12 h. Upon evaporation, the acid 9 was left behind; color-
less needles; m.p. 177Ϫ178 °C (from hexanes); yield: 2.50 g (87%).
1H NMR: δ ϭ 7.70 (d, J ϭ 6.4 Hz, 2 H) ppm. 13C NMR: δ ϭ
165.7 (s), 161.3 (d, J ϭ 247 Hz), 134.2 (t, J ϭ 9 Hz), 114.6 (d, J ϭ
34 Hz), 104.4 (t, J ϭ 27 Hz) ppm. C7H3BrF2O2 (237.00): calcd. C
35.48, H 1.28; found C 35.59, H 1.21.
2-Bromo-3,5-difluorobenzoic Acid (10): 2-Bromo-3,5-difluoro-4-(tri-
ethylsilyl)benzoic acid (25; 5.3 g, 15 mmol) was protodesilylated by
a method analogous to that described above (see the acid 2); color-
less needles; m.p. 140Ϫ142 °C (from hexanes); yield: 3.43 (97%).
1H NMR: δ ϭ 7.55 (dm, J ϭ 8.2 Hz, 1 H), 7.11 (td, J ϭ 8.1,
3.0 Hz) ppm. 13C NMR: δ ϭ 166.4 (s), 163.5 (dd, J ϭ 250, 11 Hz),
161.1 (dd, J ϭ 249, 12 Hz), 137.8 (d, J ϭ 9 Hz), 115.5 (dd, J ϭ 25,
3 Hz), 109.1 (t, J ϭ 26 Hz), 105.2 (dd, J ϭ 22, 3 Hz) ppm.
C7H3BrF2O2 (237.00): calcd. C 35.48, H 1.28; found C 35.63, H
1.40.
1
230 °C); n2D0 ϭ 1.5411; d240 ϭ 1.663. H NMR: δ ϭ 7.16 (dd, J ϭ
7.9, 1.7 Hz, 1 H), 1.0 (m, 9 H), 0.9 (m, 6 H) ppm. 13C NMR: δ ϭ
165.7 (dd, J ϭ 252, 18 Hz), 163.3 (dd, J ϭ 249, 18 Hz), 127.3 (d,
J ϭ 12 Hz), 116.5 (dd, J ϭ 32, 3 Hz), 111.9 (t, J ϭ 38 Hz), 108.5
(dd, J ϭ 32, 3 Hz), 7.2 (s), 4.1 (s) ppm. C12H16Br2F2Si (386.15):
calcd. C 37.33, H 4.18; found C 37.55, H 4.00.
(4-Bromo-2,6-difluorophenyl)triethylsilane (15): The 5:1 mixture of
the two dibromodifluorophenylsilanes 13 and 14 (19 g, 50 mmol)
was added to a solution of butyllithium (45 mmol) in hexanes
(35 mL) and diethyl ether (0.17 L) kept at Ϫ100 °C. After 15 min,
the reaction mixture was treated with methanol (2.1 mL, 1.9 g,
60 mmol) and the solvents were evaporated. The residue was dis-
2. (Difluorophenyl)-, (Bromodifluorophenyl)-, and (Dibromodifluoro-
phenyl)silanes
tilled to afford a colorless oil; b.p. 72Ϫ74 °C/0.8 Torr; n20
ϭ
(2,6-Difluorophenyl)triethylsilane (11): Butyllithium (0.20 mol) in
hexanes (0.12 L) was added at Ϫ75 °C to 1,3-difluorobenzene
(20 mL, 23 g, 0.20 mol) in tetrahydrofuran (0.40 L). After the mix-
ture had been kept for 45 min at Ϫ75 °C, chlorotriethylsilane
(34 mL, 30 g, 0.20 mol) was added. After a further 45 min, the
reaction solvents were evaporated and the residue was distilled to
D
1.4789; d240 ϭ 1.386; yield: 9.1 g (59%). H NMR: δ ϭ 7.00 (d, J ϭ
6.9 Hz, 2 H), 1.0 (m, 15 H) ppm. 13C NMR: δ ϭ 167.5 (dd, J ϭ
260, 17 Hz), 124.0 (t, J ϭ 12 Hz), 114.9 (m), 110.5 (t, J ϭ 35 Hz),
7.2 (s), 4.0 (s) ppm. C12H17BrF2Si (307.25): calcd. C 46.91, H 5.58;
found C 46.82, H 5.50.
1
afford a colorless oil; b.p. 53Ϫ55 °C/5 Torr; n2D0 ϭ 1.4844; d420
0.983; yield: 40.6 g (89%). 1H NMR: δ ϭ 7.3 (m, 1 H), 6.83 (t, J ϭ
ϭ
3. (Bromodifluoroiodophenyl)triethylsilanes
7.8 Hz, 2 H), 1.00 (m, 15 H) ppm. 13C NMR: δ ϭ 167.5 (dd, J ϭ (3-Bromo-2,6-difluoro-5-iodophenyl)triethylsilane (23): Diisopro-
228, 15 Hz), 132.0 (t, J ϭ 10 Hz), 111.5 (m), 111.0 (d, J ϭ 30 Hz), pylamine (14 mL, 10 g, 0.10 mol) and the silane 12 (25 mL, 31 g,
7.6 (s), 4.5 (s) ppm. C12H18F2Si (228.36): calcd. C 63.12, H 7.95; 0.10 mol) were added consecutively to a solution of butyllithium
found C 63.01, H 8.12. (0.10 mol) in hexanes (60 mL) and tetrahydrofuran (0.14 L), cooled
4622
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 4618Ϫ4624

The Regioflexible Substitution of 1,3-Difluorobenzene
FULL PAPER
in a methanol/dry ice bath. After the mixture had been kept at Ϫ75
°C for 2 h, iodine (25 g, 0.10 mol) in tetrahydrofuran (0.10 L) was
1-Bromo-2,6-difluorobenzene (18): Solutions of butyllithium (0.10
mol) in hexanes (65 mL) and 1,3-difluorobenzene (10 mL, 11 g,
added. The reaction mixture was washed with hydrochloric acid 0.10 mmol) in tetrahydrofuran (0.14 L) were mixed at Ϫ75 °C.
(10%, 50 mL) and extracted with hexanes (3 ϫ 0.10 L). Upon distil-
After the mixture had been kept for 45 min at this temperature,
bromine (5.1 mL, 16 g, 0.10 mol) was added. Immediate distillation
lation a colorless oil was obtained; b.p. 102Ϫ104 °C/0.6 Torr; nD20
ϭ
1.5672; d240 ϭ 1.780; yield: 37.2 g (86%). 1H NMR: δ ϭ 7.92 (t, J ϭ afforded a colorless oil; b.p. 135Ϫ137 °C/760 Torr; nD20 ϭ 1.5100;
8.0 Hz, 1 H), 1.0 (m, 15 H) ppm. 13C NMR: δ ϭ 165.0 (dd, J ϭ d240 ϭ 1.769; yield: 18.1 g (94%). H NMR: δ ϭ 7.3 (m, 1 H), 0.95
1
244, 15 Hz), 162.5 (dd, J ϭ 248, 15 Hz), 142.9 (s), 113.6 (t, J ϭ (dd, J ϭ 8.4, 2.1 Hz, 2 H) ppm.
38 Hz), 104.8 (dd, J ϭ 30, 4 Hz), 75.6 (dd, J ϭ 32, 4 Hz), 7.0 (s),
1-Bromo-2,4-difluorobenzene (19): Diisopropylamine (7.1 mL,
5.1 g, 50 mmol) and 1-bromo-2,6-difluorobenzene (18; 9.6 g,
50 mmol) were added consecutively at Ϫ75 °C to a solution of bu-
3.8 (s) ppm. C12H16BrF2ISi (433.15): calcd. C 33.28, H 3.72; found
C 33.78, H 3.87.
(3-Bromo-2,6-difluoro-4-iodophenyl)triethylsilane (24): Diisopro-
pylamine (7.1 mL, 5.1 g, 50 mmol) and the silane 23 (12 mL, 22 g,
50 mmol) were added consecutively to a solution of butyllithium
(50 mmol) in hexanes (30 mL) and tetrahydrofuran (70 mL) cooled
in a methanol/dry ice bath. After 2 h at Ϫ75 °C, the reaction mix-
ture was treated with methanol (2.1 mL, 1.9 g, 60 mmol), washed
with hydrochloric acid (10%, 20 mL), and extracted with hexanes
(3 ϫ 50 mL). The combined organic phases were concentrated,
dried with sodium sulfate, and distilled. A colorless oil was ob-
tained; yield: 17.8 g (82%). The colorless oil was composed of prod-
uct 24 and its isomeric precursor 23 in a 3:2 ratio as shown by gas
chromatography (2 m, 2% FFAP, 200 °C; 2 m, 2% OV-17, 250 °C;
internal standard: pentadecane). Most of the material (17.3 g,
40 mmol) was added to a solution of butyllithium (14 mmol) in
hexanes (26 mL) and diethyl ether (20 mL) cooled to Ϫ100 °C.
After 15 min at this temperature, an excess of powdered dry ice was
poured into the reaction mixture, which afterwards was immedi-
tyllithium (50 mmol) in hexanes (35 mL) and tetrahydrofuran
(70 mL). After 2 h at Ϫ75 °C, the mixture was treated with meth-
anol (2.0 mL, 1.9 g, 60 mmol) and the solvents were evaporated.
Immediate distillation afforded a colorless oil; b.p. 130Ϫ134 °C/
760 Torr; yield: 5.57 g (58%). According to gas chromatography (2
m, 2% FFAP, 100 °C; 2 m, 2% OV-17, 120 °C; internal standard:
undecane) it was composed of the product 19 and its isomeric pre-
cursor 18 in a 3:2 ratio. Most of the material (4.8 g, 25 mmol) was
added to a solution of butyllithium (10 mmol) in hexanes (6.5 mL)
and diethyl ether (40 mL) cooled to Ϫ75 °C. After 15 min, freshly
crushed dry ice was poured into the reaction mixture. Immediate
distillation afforded a colorless oil; b.p. 145Ϫ147 °C (ref.[16] b.p. 147
°C); n2D0 ϭ 1.5061 (ref.[16] n2D0 ϭ 1.5059); yield: 2.71 g (57%).
Bromo-3,5-difluorobenzene (20): A biphasic mixture containing the
silane 15 (15 g, 50 mmol), potassium fluoride (12 g, 0.20 mol),
tetrahydrofuran (40 mL), and water (10 mL) was heated under re-
flux for 2 h. Evaporation, followed by distillation, afforded a color-
ately distilled to give a colorless oil; b.p. 110Ϫ112 °C/0.1 Torr; nD20
ϭ
less oil; b.p. 58Ϫ60 °C/30 Torr (ref.[3] b.p. 140 °C/760 Torr); n2D0
ϭ
1.4977; d240 ϭ 1.772; yield: 9.8 g (57%). 1H NMR: δ ϭ 7.37 (dd,
J ϭ 7.6, 1.7 Hz, 1 H), 0.9 (m, 15 H) ppm. 13C NMR: δ ϭ 165.8
(dd, J ϭ 250, 18 Hz), 162.0 (dd, J ϭ 249, 18 Hz), 122.8 (dd, J ϭ
32, 3 Hz), 113.0 (dd, J ϭ 29, 4 Hz), 112.9 (t, J ϭ 38 Hz), 103.0 (d,
J ϭ 10 Hz), 7.2 (s), 4.0 (s) ppm. C12H16BrF2ISi (433.15): calcd. C
33.28, H 3.72; found C 33.55, H 3.83.
1.4988 (ref.[3] nD20 ϭ 1.4989); yield: 8.96 g (93%). 1H NMR: δ ϭ
7.06 (symm. m, 2 H), 6.78 (symm. m, 1 H) ppm.
3-Bromo-4,6-difluoro-5-(triethylsilyl)benzoic Acid (21): Diisopro-
pylamine (7.1 mL, 5.1 g, 50 mmol) and (3-bromo-2,6-difluorophe-
nyl)triethylsilane (12; 12 mL, 15 g, 50 mmol) were added consecu-
tively to a solution of butyllithium (50 mmol) in hexanes (30 mL)
and tetrahydrofuran (70 mL), cooled in a methanol/dry ice bath.
After the mixture had been kept for 2 h at Ϫ75 °C, an excess of
freshly powdered dry ice was added. The reaction mixture was
worked up as described for acid 1; colorless needles; m.p. 67Ϫ69
4. Difluoro(triethylsilyl)benzoic Acids and Bromodifluoro(triethylsi-
lyl)benzoic Acids
2,4-Difluoro-3-(triethylsilyl)benzoic Acid (16): (2,6-Difluorophen-
yl)triethylsilane (11; 12 mL, 11 g, 50 mmol) was added to a pre-
cooled solution of sec-butyllithium (50 mmol) in cyclohexane
(40 mL) and tetrahydrofuran (60 mL). After 45 min, an excess of
freshly powdered dry ice was poured into the reaction mixture.
Workup was as described for acid 1; colorless needles; m.p. 45Ϫ47
°C (from hexanes); yield: 12.1 g (89%). 1H NMR: δ ϭ 8.07 (dt, J ϭ
7.8, 6.5 Hz, 1 H), 6.93 (t, J ϭ 6.5 Hz, 1 H), 1.0 (m, 15 H) ppm.
13C NMR: δ ϭ 171.2 (dd, J ϭ 252, 15 Hz), 169.5 (s), 168.0 (dd,
J ϭ 260, 18 Hz), 136.0 (d, J ϭ 12 Hz), 113.9 (d, J ϭ 15 Hz), 113.4
(t, J ϭ 38 Hz), 112.0 (d, J ϭ 31 Hz), 7.6 (s), 4.5 (s) ppm.
C13H18F2O2Si (272.37): calcd. C 57.33, H 6.66; found C 57.25, H
6.52.
1
°C (from hexanes); yield: 12.3 g (70%). H NMR: δ ϭ 8.26 (m, 1
H), 1.0 (m, 15 H) ppm. 13C NMR: δ ϭ 168.7 (s), 166.3 (dd, J ϭ
261, 16 Hz), 166.0 (dd, J ϭ 256, 17 Hz), 138.3 (s), 115.1 (m), 114.8
(m), 104.4 (d, J ϭ 26 Hz), 7.2 (s), 4.0 (s) ppm. C13H17BrF2O2Si
(351.26): calcd. C 44.85, H 4.88; found C 44.46, H 4.85.
2-Bromo-4,6-difluoro-5-(triethylsilyl)benzoic Acid (22): A mixture of
the two dibromodifluorosilanes 13 and 14 (5:1, 9.7 g, 25 mmol) was
added at Ϫ100 °C to a solution of butyllithium (20 mmol) in hex-
anes (15 mL) and diethyl ether (90 mL). After 15 min at this tem-
perature, the mixture was treated with an excess of powdered dry
ice. The reaction mixture was worked up as described for acid 1,
3,5-Difluoro-4-(triethylsilyl)benzoic Acid (17): (4-Bromo-2,6-di-
fluorophenyl)triethylsilane (15; 15.3 g, 50 mmol) was added to a
solution of butyllithium (45 mmol) in hexanes (25 mL) and diethyl
ether (80 mL), cooled in a methanol/dry ice bath. After the mixture
had been kept at Ϫ75 °C for 15 min , freshly crushed dry ice was
added and the reaction mixture was worked up as described for
acid 1; colorless needles; m.p. 101Ϫ103 °C (from hexanes); yield:
1
yielding 8.60 g (98%) of a viscous oil. H NMR: δ ϭ 7.21 (d, J ϭ
8.1 Hz, 1 H), 1.0 (m, 15 H) ppm. 13C NMR: δ ϭ 169.8 (s), 167.8
(dd, J ϭ 252, 18 Hz), 164.5 (dd, J ϭ 253, 18 Hz), 122.3 (dd, J ϭ
6, 5 Hz), 119.5 (dd, J ϭ 23, 3 Hz), 116.5 (dd, J ϭ 32, 3 Hz), 111.7
(t, J ϭ 38 Hz), 7.1 (s), 4.0 (s) ppm.
2-Bromo-3,5-difluoro-4-(triethylsilyl)benzoic Acid (25): The silane
24 (8.7 g, 20 mmol) in diethyl ether (10 mL) was added at Ϫ100 °C
to a solution of butyllithium (20 mmol) in hexanes (15 mL) and
1
12.6 g (93%). H NMR: δ ϭ 7.52 (d, J ϭ 7.1 Hz, 2 H), 1.0 (m, 15
H) ppm. 13C NMR: δ ϭ 170.4 (s), 167.3 (dd, J ϭ 245, 18 Hz),
133.1 (t, J ϭ 12 Hz), 118.5 (t, J ϭ 36 Hz), 112.6 (m), 7.1 (s), 4.0 diethyl ether (30 mL). After 15 min, powdered dry ice was added
(s) ppm. C13H18F2O2Si (272.37): calcd. C 57.33, H 6.66; found C and the reaction mixture was worked up as described for acid 1;
57.29, H 6.72.
colorless needles; m.p. 52Ϫ54 °C (from hexanes); yield: 6.40 g
Eur. J. Org. Chem. 2003, 4618Ϫ4624
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4623

M. Schlosser, C. Heiss
FULL PAPER
(91%). H NMR: δ ϭ 7.43 (dd, J ϭ 8.4, 1.5 Hz, 1 H), 1.0 (m, 15
H) ppm. 13C NMR: δ ϭ 170.4 (s), 165.7 (dd, J ϭ 246, 18 Hz),
163.4 (dd, J ϭ 245, 18 Hz), 134.9 (d, J ϭ 10 Hz), 117.6 (t, J ϭ
38 Hz), 114.2 (d, J ϭ 32 Hz), 104.7 (dd, J ϭ 30, 4 Hz), 7.2 (s), 4.1
(s) ppm. C13H17BrF2O2Si (351.26): calcd. C 44.85, H 4.88; found
C 44.40, H 4.64.
1
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Acknowledgments
[10]
[11]
This work was financially supported by the Schweizerische
Nationalfonds zur Förderung der wissenschaftlichen Forschung,
Bern (grant 20Ϫ55/303Ϫ98) and the Bundesamt für Bildung und
Wissenschaft, Bern (grant 97.0083 linked to the TMR project
FMRXCT-970129).
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[4]
Received June 6, 2003
4624
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Eur. J. Org. Chem. 2003, 4618Ϫ4624