Buttressing Effects Rerouting the Deprotonation and Functionalization of 1,3-Dichloro- and 1,3-Dibromobenzene

Article abstract of DOI:10.1002/ejoc.200300355

A systematic comparison between 1,3-difluorobenzene, 1,3-dichlorobenzene, and 1,3-dibromobenzene did not reveal major differences in their behavior towards strong bases such as lithium diisopropylamide or lithium 2,2,6,6-tetramethyl-piperidide. Thus, all 2,6-dihalobenzoic acids 1 are directly accessible by consecutive treatment with a suitable base and dry ice. In contrast, (2,6-dichlorophenyl)- and (2,6-bromo-phenyl)triethylsilane (2a and 2b) were found to undergo deprotonation at the 5-position (affording acids 3 and, after deprotection, 4), whereas the 1,3-difluoro analog is known to react at the 4-position. The 2,4-dihalobenzoic acids 7 were selectively prepared from either the silanes 2 (by bromination at the 4-position, metalation and carboxylation of the neighboring position, followed by desilylation and debromination) or the 1,3-dihalo-2-iodobenzenes 8 (by base-promoted migration of iodine to the 4-position followed by iodine/magnesium permutation and subsequent carboxylation). Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300355

FULL PAPER
Buttressing Effects Rerouting the Deprotonation and Functionalization of
1,3-Dichloro- and 1,3-Dibromobenzene
Christophe Heiss,[a] Elena Marzi,[a] and Manfred Schlosser*[a,b]
Keywords: Electrophilic substitution / Lithiation / Protecting groups / Carboxylation / Buttressing effects
A systematic comparison between 1,3-difluorobenzene, 1,3-
dichlorobenzene, and 1,3-dibromobenzene did not reveal
major differences in their behavior towards strong bases such
react at the 4-position. The 2,4-dihalobenzoic acids 7 were
selectively prepared from either the silanes 2 (by bromination
at the 4-position, metalation and carboxylation of the neigh-
as lithium diisopropylamide or lithium 2,2,6,6-tetramethyl- boring position, followed by desilylation and debromination)
piperidide. Thus, all 2,6-dihalobenzoic acids 1 are directly or the 1,3-dihalo-2-iodobenzenes 8 (by base-promoted mi-
accessible by consecutive treatment with a suitable base and
dry ice. In contrast, (2,6-dichlorophenyl)- and (2,6-bromo-
phenyl)triethylsilane (2a and 2b) were found to undergo de-
protonation at the 5-position (affording acids 3 and, after de-
protection, 4), whereas the 1,3-difluoro analog is known to
gration of iodine to the 4-position followed by iodine/mag-
nesium permutation and subsequent carboxylation).
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
We have previously shown how 1,3-difluorobenzene can
be elaborated to the three conceivable benzoic acids.[1] The
2,6-difluoro isomer was obtained in one step by the metal-
ation of the starting material with sec-butyllithium followed
by carboxylation. The preparation of the 2,4-difluoro iso-
mer was also straightforward. The most acidic 2-position
having been blocked with a trialkylsilyl group, the attack of
the organometallic base was deflected to the next reactive
4-position. All that remained to be done after carboxylation
was to remove the protective substituent. The route leading
to the 3,5-difluoro isomer passed through six isolable inter-
mediates. Despite its length, it was found to be economical
and expedient.
An extension of this study to 1,3-dichlorobenzene and
1,3-dibromobenzene did not promise much excitement. We
nevertheless embarked on this project, because it was not
clear at the outset how one could convert 1,3-dibromoben-
zene into 3,5-dibromobenzoic acid without triggering ‘‘hal-
ogen scrambling’’ processes.[2] The 3,5-dibromobenzoic acid
could, of course, be most conveniently prepared starting
from the commercial 1,3,5-tribromobenzene. One would
simply have to treat this compound consecutively with bu-
tyllithium and carbon dioxide. However, our ambition was
to derive all targeted acids from the same two substrates,
namely 1,3-dichlorobenzene and 1,3-dibromobenzene.
It caused no trouble at all to obtain the 2,6-dichloroben-
zoic acid (1a; 95%) and 2,6-dibromobenzoic acid (1b; 87%).
The substrates were just deprotonated with lithium 2,2,6,6-
tetramethylpiperidide (LITMP),[3] carboxylated with dry ice
and isolated after neutralization.
[a]
´
Institut de Chimie Moleculaire et Biologique, Ecole
´ ´
Polytechnique Federale, BCh,
CH-1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
[b]
´
´
Faculte des Sciences, Universite, BCh,
CH-1015 Lausanne, Switzerland
Eur. J. Org. Chem. 2003, 4625Ϫ4629
DOI: 10.1002/ejoc.200300355
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4625

C. Heiss, E. Marzi, M. Schlosser
FULL PAPER
The silanes 2a (89%) and 2b (78%) were obtained anal-
ogously. Then (2,6-dichlorophenyl)triethylsilane (2a) was
deprotonated with LITMP before pouring the mixture onto
freshly crushed dry ice. To our great surprise, the reaction
product turned out to be 3,5-dichloro-4-(triethylsilyl)ben-
zoic acid (3a; 71%) rather than the expected 2,4,3-isomer.
The same compound was formed in 52% and 61% yields,
respectively, when LITMP was replaced by lithium diiso-
propylamide (LIDA) or sec-butyllithium. (2,6-Dichlorophe-
nyl)trimethylsilane, when treated consecutively with sec-bu-
tyllithium and dry ice, gave the 3,5-dichloro-4-(trimethyl-
silyl)benzoic acid (59%) again as the sole derivative. To
achieve the deprotonation of (2,6-dibromophenyl)triethylsi-
lane (2b) one had to employ the ‘‘Faigl mix’’[4] (LITMP in
the
presence
of
potassium
tert-butoxide
and
N,NЈ,NЈ,NЈЈ,NЈЈ-pentamethyldiethylenetriamine) as the
base. Carboxylation provided the isomerically uncontami-
nated 3,5-dibromo-4-(triethylsilyl)benzoic acid (3b; 42%).
Desilylation to the 3,5-dichlorobenzoic acid (4a; 91%) and
the 3,5-dibromobenzoic acid (4b; 90%) was accomplished
with potassium hydroxide.
again LITMP and 1,2-dibromo-1,1,2,2-tetrafluoroethane,
the (2,4,6-tribromophenyl)triethylsilane (5b; 47%) was ob-
tained. This silane, being totally inert towards bases,[6]
could not be subjected to the standard deprotonation/
carboxylation sequence to give acid 10. Therefore, silane 5b
was deprotected to give 1,3,5-tribromobenzene, a commer-
cial and expensive product. Subsequent deprotonation and
carboxylation afforded the 2,4,6-tribromobenzoic acid 11[6]
(88%). The selective removal of one ortho-bromo substitu-
ent was accomplished with lithium tributylmagnesiate,[7Ϫ9]
the acid 7b being isolated in a 92% yield.
The unforeseen site selectivity in favor of the halogen re-
mote position simplified the task of preparing the remain-
ing 2,4-dihalobenzoic acids 7a and 7b. The (4-bromo-2,6-
dichlorophenyl)triethylsilane (5a) was made by the consecu-
tive treatment of silane 2a with sec-butyllithium and bro-
mine. Deprotonation with LITMP and carboxylation af-
forded 6-bromo-2,4-dichloro-3-(triethylsilyl)benzoic acid
(6a; 93%) and, after base-promoted desilylation and sub-
sequent reductive debromination, respectively 2-bromo-4,6-
dichlorobenzoic acid (8; 98%) and 2,4-dichlorobenzoic acid
(7a; 98%). The acid 7a was also obtained via the intermedi-
ate 3c by simple inversion of the debromination and desilyl-
ation steps.
The 2,4-dibromobenzoic acid (7b) was prepared from the
[5]
readily accessible
2,4-dibromo-1-iodobenzene (9) by
iodine/metal permutation using isopropylmagnesium
chloride followed by carboxylation and neutralization in a
91% yield. The reaction was less clean when butyllithium
was employed as the base.
For reasons of thematic coherence, we also wanted to
make the acid 7b starting from 1,3-dibromobenzene. Upon
consecutive treatment with LITMP, chlorotriethylsilane,
4626
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4625Ϫ4629

Deprotonation and Functionalization of 1,3-Dichloro- and 1,3-Dibromobenzene
FULL PAPER
a methanol/dry ice bath. After 2 h at Ϫ75 °C, the mixture was
poured on an excess of freshly crushed solid carbon dioxide and
worked up as described in the preceding paragraph, giving colorless
needles (from hexanes); m.p. 144Ϫ146 °C (ref.[23] 146.5 °C); yield:
6.02 g (87%). 1H NMR: δ ϭ 7.59 (d, J ϭ 8.0 Hz, 2 H), 7.18 (t, J ϭ
8.0 Hz, 1 H) ppm.
The reaction sequences starting from 1,3-dichloroben-
zene and 1,3-dibromobenzene could not be extended to 1,3-
diiodobenzene. Lacking sufficient acidity, the latter sub-
strate was not amenable to deprotonation. The 2,6-diiodob-
enzoic acid (12) was found to be accessible by subjecting the
dibromo analogous compound 1b to a double magnesiate-
promoted halogen/metal permutation, followed by treat-
ment with elemental iodine.
2,6-Diiodobenzoic Acid (12): 2,6-Dibromobenzoic acid (1b; 4.2 g,
15 mmol) in tetrahydrofuran (15 mL) was added to a solution of
butyllithium (15 mmol) and butylmagnesium chloride (10 mmol) in
tetrahydrofuran (70 mL) and hexanes (16 mL) at 0 °C. After 45 min
at 0 °C, iodine (7.6 g, 30 mmol) in tetrahydrofuran (25 mL) was
added. The reaction mixture was acidified with 2.0  hydrochloric
acid (10 mL) and washed with a saturated aqueous sodium sulfite
solution (30 mL). The product was extracted with hexanes (3 ϫ
50 mL). Crystallization from chloroform (30 mL) afforded tiny
needles; m.p. 182Ϫ184 °C; (ref.[24] 184Ϫ187 °C); yield: 5.05 g
(90%). 1H NMR: δ ϭ 7.87 (d, J ϭ 8.0 Hz, 2 H), 6.81 (t, J ϭ 7.9 Hz,
1 H) ppm.
The metalation of the 2,6-dichloro- and 2,6-dibromosil-
anes (2a and 2b) at a position not adjacent to, but remote
from, an ‘‘ortho-directing’’ group is without precedent. The
related case of 1,3-bis(trifluoromethyl)benzene has already
received much attention. Whereas the superbasic mixture of
butyllithium and potassium tert-butoxide abstracts a proton
exclusively from the most activated 2-position[10] and
LITMP cleanly from the 4-position,[11] tert-butyllithium
produces a 1:1 mixture of 4- and 5-lithiated species.[11] This
result, a singular exception, can be confidently attributed to
a steric bias against the proximity between a bulky substitu-
ent and a bulky reagent. The behavior of the (2,6-dichloro-
phenyl)triethylsilane (2a) and (2,6-dibromophenyl)triethyl-
silane falls into another category. If once again a ‘‘but-
tressing effect’’ manifests itself, it cannot be one of the fami-
liar kind.[12Ϫ18] At the moment we have to content ourselves
to draw attention to the phenomenon rather than to fathom
its origins.
3,5-Dichlorobenzoic Acid (4a): 3,5-Dichloro-4-(triethylsilyl)benzoic
acid (3a; 7.6 g, 25 mmol) and potassium hydroxide (5.5 g, 0.10 mol)
were heated under reflux in a 4:1 (v/v) mixture of methanol and
water (50 mL). After 2 h, the solvents were evaporated and the resi-
due was acidified with an aqueous 2.0  hydrochloric acid (5 mL)
solution. The acid was extracted with diethyl ether (3 ϫ 20 mL).
Crystallization from hexanes (50 mL) gave colorless needles; m.p.
1
183Ϫ185 °C (ref.[25] m.p. 182.5Ϫ183.0 °C); yield: 4.34 g (91%). H
NMR: δ ϭ 7.96 (d, J ϭ 1.9 Hz, 2 H), 7.59 (d, J ϭ 2.0 Hz, 1 H)
ppm.
3,5-Dibromobenzoic Acid (4b): 3,5-Dibromo-4-(triethylsilyl)benzoic
acid (3b, 3.9 g, 10 mmol) was analogously protodesilylated as the
acid 4a; colorless needles; m.p. 218Ϫ220 °C (ref.[26] m.p. 213Ϫ214
1
°C); yield: 2.52 g (90%). H NMR: δ ϭ 8.18 (d, J ϭ 1.8 Hz, 2 H),
7.92 (t, J ϭ 1.8 Hz, 1 H) ppm.
2,4-Dichlorobenzoic Acid (7a): 2-Bromo-3,5-dichlorobenzoic acid
(8a; 2.7 g, 10 mmol) and zinc dust (2.6 g, 40 mmol) in a 10% aque-
ous sodium hydroxide solution (5 mL) were stirred at 25 °C. After
2 h, a 2.0  aqueous hydrochloric acid solution (5 mL) was added
and the acid was extracted with diethyl ether (3 ϫ 30 mL). Upon
crystallization from hexanes (10 mL), colorless needles were ob-
tained; m.p. 158Ϫ160 °C (ref.[25] 159Ϫ160 °C); yield: 1.86 g (98%).
1H NMR: δ ϭ 8.00 (d, J ϭ 8.5 Hz, 1 H); 7.52 (d, J ϭ 2.0 Hz, 1 H);
7.36 (dd, J ϭ 8.5, 2.0 Hz, 1 H) ppm. The acid 7a was independently
obtained in 92% yield by protodesilylation of 2,4-dichloro-3-
(triethylsilyl)benzoic acid (3c, 1.53 g, 5.0 mmol) according to the
standard protocol (see the preparation of acid 4a).
Experimental Section
Working practices and abbreviations are specified in previous
articles from this laboratory.[19Ϫ21] 1H and 1H-decoupled 13C NMR
spectra were recorded of samples dissolved in deuteriochloroform
at 400 and 101 MHz, respectively, relative to the internal standard
tetramethylsilane (chemical shift δ ϭ 0.00 ppm).
1. Halobenzoic Acids
2,6-Dichlorobenzoic Acid (1a): 1,3-Dichlorobenzene (3.0 mL, 3.7 g,
25 mmol) was added to a solution of butyllithium (25 mmol) in
hexanes (15.8 mL) and tetrahydrofuran (30 mL) kept in a dry-ice
bath for 45 min before being poured on an excess of freshly crushed
dry ice. The mixture was briefly stirred before an ethereal solution
(15 mL) of 2.0  hydrogen chloride (30 mmol) was added under
shaking. The volatiles were evaporated and the residue was ex-
tracted with boiling ethyl acetate (3 ϫ 15 mL). Upon filtration and
concentration of the combined organic layers, the product crys-
tallized as tiny colorless needles (from hexanes); m.p. 142Ϫ144 °C
(ref.[22] m.p. 147 °C); yield: 4.54 g (95%). 1H NMR: δ ϭ 7.3 (m)
ppm.
2,4-Dibromobenzoic Acid (7b): 2,4,6-Tribromobenzoic acid (10;
5.4 g, 15 mmol) in tetrahydrofuran (15 mL) was added to a solution
of butyllithium (20 mmol) and butylmagnesium chloride (10 mmol)
in tetrahydrofuran (9 mL), hexanes (13 mL) and toluene (40 mL) at
0 °C. After 45 min at 0 °C, methanol (0.7 mL, 0.6 g, 18 mmol) was
added. The reaction mixture was worked up as described for acid
1. Crystallization from dichloromethane (10 mL) gave the acid 7b
as colorless needles; m.p. 168Ϫ170 °C (ref.[27] m.p. 166.5 °C); yield:
3.85 g (92%). 1H NMR: δ ϭ 7.91 (d, J ϭ 8.4 Hz, 1 H), 7.90 (d,
J ϭ 2.0 Hz, 1 H), 7.57 (dd, J ϭ 8.4, 2.0 Hz, 1 H) ppm. The acid 7b
was also formed in a 91% yield when 2,4-dibromo-1-iodobenzene [5]
(9, 9.0 g, 25 mmol) was added to a solution of butyllithium in
hexanes (13 mL) and diethyl ether (60 mL) at Ϫ100 °C before
15 min later the mixture was treated with freshly crushed dry ice
2,6-Dibromobenzoic Acid (1b): 2,2,6,6-Tetramethylpiperidine
(4.1 mL, 3.5 g, 25 mmol) and 1,3-dibromobenzene (3.1 mL, 5.9 g,
25 mmol) were added consecutively to a solution of butyllithium
(25 mmol) in hexanes (16 mL) and tetrahydrofuran (40 mL) kept in and was worked up (as described for acid 1).
Eur. J. Org. Chem. 2003, 4625Ϫ4629
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4627

C. Heiss, E. Marzi, M. Schlosser
FULL PAPER
3,5-Dichloro-4-(triethylsilyl)benzoic Acid (3a): (2,6-Dichlorophen- as described for the acid 1; colorless needles (from hexanes); m.p.
1
yl)triethylsilane (2a, see Section 2; 11 mL, 13 g, 50 mmol) was ad- 119Ϫ122 °C; yield: 35.7 g (93%). H NMR: δ ϭ 7.55 (s, 1 H), 1.1
ded to a solution of sec-butyllithium (50 mmol) in cyclohexane (m, 6 H), 1.0 (m, 9 H) ppm. 13C NMR: δ ϭ 169.9, 143.3, 138.3,
(36 mL) and tetrahydrofuran (0.10 L) kept in a dry-ice bath. After 135.7, 134.8, 132.1, 120.0, 7.7, 6.0 ppm. C13H17BrCl2O2Si (384.17):
45 min at Ϫ75 °C, the reaction mixture was treated with an excess
of freshly crushed dry ice and worked up as described for the acid
1; colorless needles (from hexanes); m.p. 133Ϫ135 °C; yield: 10.8 g
(71%). 1H NMR: δ ϭ 7.93 (s, 2 H), 1.1 (m, 6 H), 1.0 (m, 9 H)
ppm. 13C NMR: δ ϭ 170.0, 142.7, 142.4, 131.5, 129.8, 7.5, 6.1 ppm.
C13H18Cl2O2Si (305.11): calcd. C 51.17, H 5.90; found C 51.28,
H 5.85.
calcd. C 40.69, H 4.46; found C 40.47, H 4.21.
2-Bromo-4,6-dichlorobenzoic Acid (8): 6-Bromo-2,4-dichloro-3-(tri-
ethylsilyl)benzoic acid (6a, 7.7 g, 20 mmol) was protodesilylated
analogously as the acid 4a; colorless needles (from hexanes); m.p.
159Ϫ161 °C; yield: 4.89 g (90%). 1H NMR: δ ϭ 7.58 (d, J ϭ
1.9 Hz, 1 H), 7.43 (d, J ϭ 1.9 Hz, 1 H) ppm. 13C NMR: δ ϭ 168.5,
136.5, 132.8, 132.0, 130.6, 128.1, 119.8 ppm. C7H3BrCl2O2
(269.86): calcd. C 31.15, H 1.11; found C 31.37, H 1.17.
3,5-Dichloro-4-(trimethylsilyl)benzoic Acid: Analogously from (2,6-
dichlorophenyl)trimethylsilane (6, 5.5 g, 25 mmol); colorless plate-
lets after recrystallization from toluene; m.p. 148Ϫ149 °C; yield:
2,4,6-Tribromobenzoic Acid (11): Diisopropylamine (7.4 mL, 5.1 g,
50 mmol) and 1,3,5-tribromobenzene (16 g, 50 mmol) were con-
secutively added to a solution of butyllithium (50 mmol) in hexanes
(22 mL) and tetrahydrofuran (80 mL). After 2 h, freshly crushed
dry ice was added. The reaction was worked up in the same manner
as described for the acid 1; colorless needles (from chloroform);
m.p. 188Ϫ190 °C (ref.[28] m.p. 189Ϫ190 °C); yield: 15.9 g (88%). 1H
NMR: δ ϭ 7.89 (s) ppm.
1
3.91 g (59%). H NMR: δ ϭ 7.93 (s, 2 H), 0.53 (s, 9 H) ppm. 13C
NMR:
δ ϭ 169.9, 143.8, 142.1, 131.5, 129.7, 2.6 ppm.
C10H12Cl2O2Si (263.20): calcd. C 45.64, H 4.60; found C 45.58,
H 4.66.
3,5-Dibromo-4-(triethylsilyl)benzoic Acid (3b): 2,2,6,6-Tetrameth-
ylpiperidine (4.3 mL, 3.5 g, 25 mmol), potassium tert-butoxide
(2.8 g, 25 mmol), N,NЈ,NЈ,NЈЈ,NЈЈ-(pentamethyl)diethylenetriamine
(4.3 g, 25 mmol) and (2,6-dibromophenyl)triethylsilane (2b,
6.2 mL, 8.8 g, 25 mmol) were consecutively added to a solution of
butyllithium (25 mmol) in hexanes (11 mL) and tetrahydrofuran
(40 mL) at Ϫ100 °C. After 2 h, freshly crushed dry ice was added
and the reaction mixture was worked up as described for the acid
1; colorless needles (from hexanes); m.p. 157Ϫ159 °C; yield: 5.1 g
(52%). 1H NMR: δ ϭ 8.20 (s, 2 H), 1.13 (q, J ϭ 7.8 Hz, 6 H), 1.01
(t, J ϭ 7.8 Hz, 9 H) ppm. 13C NMR: δ ϭ 170.4, 170.3, 147.0, 134.5,
131.8, 8.2, 6.8 ppm. C13H18Br2O2Si (394.18): calcd. C 39.61, H
4.60; found C 39.96, H 4.48.
2. Miscellaneous
(2,6-Dichlorophenyl)triethylsilane
(2a):
1,3-Dichlorobenzene
(23 mL, 29 g, 0.20 mol) was added to a solution of sec-butyllithium
(0.20 mol) in cyclohexane (0.12 L) and tetrahydrofuran (0.18 L) at
Ϫ75 °C. After 45 min at Ϫ75 °C, chlorotriethylsilane (34 mL, 30 g,
0.20 mol) was added to the mixture. After 45 min at Ϫ75 °C, the
reaction mixture was distilled without prior workup to afford a
colorless oil; b.p. 143Ϫ145 °C/8 Torr; n2D0 ϭ 1.4781; d420ϭ 1.195;
1
yield: 46.5 g (89%). H NMR: δ ϭ 7.3 (m, 2 H), 7.1 (m, 1 H), 1.1
(m, 6 H), 1.0 (m, 9 ppm. 13C NMR: δ ϭ 142.3, 135.1, 130.0, 128.6,
7.9, 6.1 ppm. C12H18Cl2Si (261.11): calcd. C 55.19, H 6.89; found
C 55.26, H 6.91.
2,4-Dichloro-3-(triethylsilyl)benzoic Acid (3c): 6-Bromo-2,4-di-
chloro-3-(triethylsilyl)benzoic acid (see following paragraph; 6a,
23 g, 60 mmol) was treated (0.12 L) with potassium carbonate
(12 g, 15 mmol) and iodomethane (85 g, 40 mL, 60 mmol) at 60 °C
during 12 h. Upon filtration of the salts and evaporation of the
solvents, the methyl ester was obtained. Tributyltin hydride (11 mL,
12 g, 40 mmol) was added dropwise over a 15 min period to the
methyl ester (16 g, 40 mmol) in benzene (40 mL). Then, α,αЈ-azo-
bis(isobutyronitrile) (0.70 g, 4.0 mmol) was added in several por-
tions over 10 min. After 3 h at 60 °C, toluene (30 mL) was added
and the organic layer was washed with brine (2 ϫ 25 mL) before
(2,6-Dichlorophenyl)trimethylsilane: Analogously from 1,3-di-
chlorobenzene (5.7 mL, 7.4 g, 50 mmol) using chlorotrimethylsil-
ane (6.3 mL, 5.4 g, 50 mmol); colorless liquid after distillation of
the reaction mixture; b.p. 79Ϫ81 °C/4 Torr (ref.[29]: b.p. 52 °C/
0.3 Torr); n2D0 ϭ 1.5432 (ref. [29]: n2D0 ϭ 1.5427); yield: 4.69 g (79%).
1H NMR: δ ϭ 7.22 (d, J ϭ 7.9 Hz, 2 H), 7.13 (t, J ϭ 7.9 Hz, 1 H),
0.51 (s, 9 H) ppm. 13C NMR (CDCl3): δ ϭ 142.6, 137.2, 131.5,
129.6, 3.8 ppm.
being dried and evaporated. Distillation afforded a colorless oil; (2,6-Dibromophenyl)triethylsilane (2b): 2,2,6,6-Tetramethylpiperi-
b.p. 114Ϫ115 °C/0.8 Torr; yield: 9.5 g (74%). The methyl ester dine (16 mL, 14 g, 0.10 mol) and 1,3-dibromobenzene (12 mL, 23 g,
(3.2 g, 10 mmol) was treated with potassium hydroxide (1.6 g, 0.10 mol) were consecutively added to a solution of butyllithium
20 mmol) in a 4:1 (v/v) mixture of ethanol and water (10 mL). After
2 h at 25 °C, the solvent was evaporated. A 2.0  aqueous hydro- in a methanol/dry ice bath. After 2 h at Ϫ75 °C, chlorotriethylsilane
chloric acid solution (5.0 mL) was added and the acid was ex-
(17 mL, 15 g, 0.10 mol) was added. Then, a 2.0  aqueous hydro-
(0.10 mol) in hexanes (16 mL) and tetrahydrofuran (35 mL) kept
tracted with diethyl ether (3 ϫ 20 mL). After evaporation of the chloric acid solution (50 mL) was added and the product was ex-
volatiles, a crystallization from hexanes (10 mL) gave colorless tracted with hexanes (3 ϫ 0.10 L). The product was distilled after
needles; m.p. 87Ϫ89 °C; yield: 2.78 g (91%). 1H NMR: δ ϭ 7.71 it was dried and the solvents evaporated, affording a colorless oil;
(d, J ϭ 8.6 Hz, 1 H), 7.33 (d, J ϭ 8.6 Hz, 1 H), 1.09 (q, J ϭ 7.8 Hz, b.p. 97Ϫ99 °C/0.6 Torr; nD20 ϭ 1.5090; d420 ϭ 1.420; yield: 27.3 g
6 H), 0.99 (t, J ϭ 7.8 Hz, 9 H) ppm. 13C NMR: δ ϭ 171.6, 146.3, (78%). 1H NMR: δ ϭ 7.51 (d, J ϭ 8.0 Hz, 2 H), 7.27 (t, J ϭ 8.0 Hz,
141.3, 138.0, 132.3, 129.1, 128.5, 8.0, 6.5 ppm. C13H18Cl2O2Si 1 H), 1.13 (q, J ϭ 8.0 Hz, 6 H), 1.00 (t, J ϭ 8.0 Hz, 9 H) ppm. 13
C
(305.10): calcd. C 51.17, H 5.90; found C 51.33, H 5.97.
NMR: δ ϭ 139.3, 133.0, 131.8, 130.8, 8.3, 6.8 ppm. C12H18Br2Si
(350.17): calcd. C 41.16, H 5.18; found C 41.50, H 5.01.
6-Bromo-2,4-dichloro-3-(triethylsilyl)benzoic Acid (6a): 2,2,6,6-
Tetramethylpiperidine (17 mL, 14 g, 0.10 mol) and 4-bromo-2,6- (4-Bromo-2,6-dichlorophenyl)triethylsilane (5a): (2,6-Dichloro-
(dichlorophenyl)triethylsilane (5a, 26 mL, 34 g, 0.10 mol) were con- phenyl)triethylsilane (2a, 22 mL, 26 g, 0.10 mol) was added to a
secutively added to a solution of butyllithium (0.10 mol) in hexanes solution of sec-butyllithium (0.10 mol) in cyclohexane (70 mL) and
(53 mL) and tetrahydrofuran (0.15 L) at Ϫ75 °C. After 2 h, freshly tetrahydrofuran (0.20 L) at Ϫ75 °C. After 45 min at Ϫ75 °C, bro-
crushed dry ice was added. The reaction mixture was worked up mine (5.1 mL, 16 g, 0.10 mol) was added. The reaction mixture was
4628
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4625Ϫ4629

Deprotonation and Functionalization of 1,3-Dichloro- and 1,3-Dibromobenzene
FULL PAPER
[3]
E. Marzi, F. Mongin, C. Curti, F. Leroux, M. Schlosser, un-
published results (1999).
F. Faigl, E. Marzi, M. Schlosser, Chem. Eur. J. 2000, 6,
771Ϫ777.
S. M. Loh, E. E. Turner, J. Chem. Soc. 1955, 1274Ϫ1277.
F. Mongin, M. Schlosser, Tetrahedron Lett. 1997, 38,
1559Ϫ1562.
T. Iida, T. Wada, K. Tomimoto, T. Mase, Tetrahedron Lett.
2001, 42, 4841Ϫ4844.
A. Inoue, K. Kitagawa, H. Shinokubo, K. Oshima, J. Org.
Chem. 2001, 66, 4333Ϫ4339.
J. Kondo, A. Inoue, H. Shinokubo, K. Oshima, Angew. Chem.
2001, 113, 2146Ϫ2148; Angew. Chem. Int. Ed. 2001, 40,
2085Ϫ2087.
M. Schlosser, G. Katsoulos, S. Takagishi, Synlett 1990,
747Ϫ748.
M. Schlosser, F. Mongin, J. Porwisiak, W. Dmowski, H. H.
Büker, N. M. M. Nibbering, Chem. Eur. J. 1998, 4, 1281Ϫ1286.
R. Adams, H. C. Yuan, Chem. Rev. 1933, 12, 261Ϫ338.
S. L. Chien, R. Adams, J. Am. Chem. Soc. 1934, 56,
1787Ϫ1792.
G. B. Kistiakowsky, W. R. Smith, J. Am. Chem. Soc. 1936,
58, 1043Ϫ1045.
M. Rieger, F. H. Westheimer, J. Am. Chem. Soc. 1950, 72,
19Ϫ32.
F. H. Westheimer, Steric Effects in Organic Chemistry, (Ed.: M.
S. Newman), John Wiley & Sons, New York, 1956, pp.
523Ϫ555, spec. 552Ϫ554.
W. Theilacker, R. Hopp, Chem. Ber. 1959, 92, 2293Ϫ2301.
L. A. Paquette, J. M. Gardlik, J. Am. Chem. Soc. 1980, 102,
5033Ϫ5035.
washed with a saturated aqueous solution of sodium hydrogen sulf-
ite (50 mL). Upon extraction with hexanes (3 ϫ 50 mL), distillation
[4]
afforded a colorless oil; b.p. 122Ϫ123 °C/1 Torr; n2D0ϭ 1.5353; d420
ϭ
1
1.314; yield: 21.4 g (63%). H NMR: δ ϭ 7.41 (s, 2 H), 1.1 (m, 6
H), 1.0 (m, 9 H) ppm. 13C NMR: δ ϭ 143.0, 134.5, 131.5, 123.8,
8.3, 6.5 ppm. C12H18BrCl2Si (340.01): calcd. C 42.38, H 5.00; found
C 42.24, H 5.08.
[5]
[6]
[7]
[8]
[9]
(2,4,6-Tribromophenyl)triethylsilane (5b): 2,2,6,6-Tetramethylpip-
eridine (17 mL, 14 g, 0.10 mol), potassium tert-butoxide (11 g, 0.10
mol), N,NЈ,NЈ,NЈЈ,NЈЈ-(pentamethyl)diethylenetriamine (21 mL,
17 g, 0.10 mol) and (2,6-dibromophenyl)triethylsilane (2b, 25 mL,
35 g, 0.10 mol) were consecutively added to a solution of butyllith-
ium (0.10 mol) in hexanes (65 mL) and tetrahydrofuran (0.14 L) at
Ϫ100 °C. After 2 h, 1,2-dibromotetrafluoroethane (31 g, 0.12 mol)
was added. The reaction mixture was washed with an aqueous 2.0
 hydrochloric acid solution (0.10 L). After extraction with hex-
anes (3 ϫ 0.10 L), a distillation afforded a colorless oil; b.p.
130Ϫ132 °C/0.4 Torr; nD20 ϭ 1.5665; d240 ϭ 1.843; yield: 19.7 g
(46%). 1H NMR: δ ϭ 7.70 (s, 2 H), 1.1 (m, 6 H), 1.0 (m, 9 H)
ppm. 13C NMR: δ ϭ 134.7, 131.9, 129.5, 120.2, 4.6, 3.3 ppm.
C12H17Br3Si (429.07): calcd. C 33.59, H 3.99; found C 34.00, H
4.39.
[10]
[11]
[12]
[13]
[14]
[15]
[16]
1,3,5-Tribromobenzene: The product 5b (9.3 mL, 17 g, 40 mmol)
and potassium fluoride (9.3 g, 0.16 mol) in a 4:1 (v/v) of tetrahydro-
furan and water (40 mL) were heated under reflux during 12 h.
Upon extraction with hexanes (3 ϫ 50 mL), the product was crys-
tallized to give colorless needles (from pentanes); m.p. 118Ϫ120 °C
(ref.[30] m.p. 118.5 °C); yield: 11.5 g (91%). 1H NMR: δ ϭ 7.80
(s) ppm.
[17]
[18]
[19]
Q. Wang, H.-x. Wei, M. Schlosser, Eur. J. Org. Chem. 1999,
3263Ϫ3268.
[20]
[21]
[22]
[23]
[24]
C. Bobbio, M. Schlosser, Eur. J. Org. Chem. 2001, 4533Ϫ4536.
M. Schlosser, M. Marull, Eur. J. Org. Chem. 2003, 1569Ϫ1575.
C. Cohen, G. Dakin, J. Chem. Soc. 1901, 79, 1111Ϫ1134.
V. M e y e r, Ber. Dtsch. Chem. Ges. 1895, 28, 1254Ϫ1270.
J. Kulhanek, O. Pytela, Collect. Czech. Chem. Commun. 1997,
62, 913Ϫ924.
E. Lellmann, C. Koltz, Justus, Liebigs Ann. Chem. 1885, 231,
308Ϫ326.
H. Hübner, F. Hasemann, L. Koehler, Justus Liebigs Ann.
Chem. 1884, 222, 166Ϫ203.
A. Claus, A. Weil, Justus Liebigs Ann. Chem. 1892, 269,
216Ϫ224.
C. Sudborough, Ber. Dtsch. Chem. Ges. 1894, 27, 510Ϫ514.
I. Haiduc, H. Gilman, J. Organomet. Chem. 1968, 13, P4 Ϫ P6.
O. Stüber, Ber. Dtsch. Chem. Ges. 1871, 4, 961Ϫ962.
Received June 6, 2003
Acknowledgments
[25]
[26]
[27]
This work was financially supported by the Schweizerische Natio-
nalfonds zur Förderung der wissenschaftlichen Forschung, Bern
(Grant 20Ϫ55Ј303Ϫ98) and the Bundesamt für Bildung und Wis-
senschaft, Bern (Grant 97.0083 linked to the TMR Project
FMRXCT-970129).
[28]
[29]
[30]
[1]
M. Schlosser, C. Heiss, Eur. J. Org. Chem., preceding manu-
script.
[2]
F. Mongin, E. Marzi, M. Schlosser, Eur. J. Org. Chem. 2001,
2771Ϫ2777.
Eur. J. Org. Chem. 2003, 4625Ϫ4629
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4629