Fluorine-flanked congested sites: Minimal, though perceptible buttressing effects on the proton mobility of arenes

Article abstract of DOI:10.1002/ejoc.200500552

(2,6-Difluorophenyl)trimethylsilane, -triethylsilane and -triisopropylsilane undergo sec-butyllithium-mediated metalation at the 3- and 4-position (ortho and meta relative to the halogen) in ratios of 99.6:0.4, 98:2 and 95:5, respectively. The steric pressure transmitted by the fluorine atoms can be increased if the trialkylsilyl group is locked up on the other side by a relatively voluminous substituent. Whereas (2,6-difluorophenyl)triethylsilane is attacked by lithium 2,2,6,6-tetramethylpiperidide under deprotonation of the 4- and 5-position in a ratio of 99.4:0.6, the proportion of "ortho"/ "meta" metalation changes to 84:16 when (2-bromo-6-fluorophenyl) triethylsilane acts as the substrate. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500552

FULL PAPER
DOI: 10.1002/ejoc.200500552
Fluorine-Flanked Congested Sites: Minimal, Though Perceptible Buttressing
Effects on the Proton Mobility of Arenes
Christophe Heiss,[a,b] Frédéric Leroux,[b] and Manfred Schlosser*[a]
Keywords: Arynes / Biphenyls / Buttressing effects / Fluoroarenes / Metalation / Regioselectivity
(2,6-Difluorophenyl)trimethylsilane, -triethylsilane and -tri-
isopropylsilane undergo sec-butyllithium-mediated metal-
ation at the 3- and 4-position (ortho and meta relative to the
halogen) in ratios of 99.6:0.4, 98:2 and 95:5, respectively. The
steric pressure transmitted by the fluorine atoms can be in-
creased if the trialkylsilyl group is locked up on the other
side by a relatively voluminous substituent. Whereas (2,6-di-
fluorophenyl)triethylsilane is attacked by lithium 2,2,6,6-tet-
ramethylpiperidide under deprotonation of the 4- and 5-posi-
tion in a ratio of 99.4:0.6, the proportion of “ortho”/“meta”
metalation changes to 84:16 when (2-bromo-6-fluorophenyl)-
triethylsilane acts as the substrate.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
pentamethylethylenediamine (PMDTA)[8] or, better,
LITMP alone,[9] at the 4-position and by tert-butyllithium[8]
in tetrahydropyran (rather than in the standard solvent
tetrahydrofuran) concomitantly at the 4-position and –
sic! – 5-position. Simultaneous proton abstraction from the
4- and 5-position was also observed with lithium 2-(3-tri-
fluoromethylphenyl)ethoxide[10] and from the 3- and 4-posi-
tion with 1,2-bis(trifluoromethyl)benzene.[9]
Introduction
Halobenzenes, anisoles and other electronegatively sub-
stituted arenes or heterocycles are known to react with al-
kyllithium reagents under permutational hydrogen/metal in-
terconversion at a position adjacent to the heteroatom or
hetero group.[1] The “directed ortho metalation” (a some-
what distorted translation of G. Wittig’s “gezielte ortho-Me-
tallierung”) has become a most popular and even irreplace-
able tool for synthetically oriented work in the field of aro-
matic chemistry.
Exceptions to the ortho rule have so far passed almost
unnoticed. Naphthalenes carrying strongly coordinating,
but poorly electron-withdrawing substituents such as li-
thiooxy,[2] dialkylamino[3,4] or dialkylaminomethyl[5] at the
α-position are deprotonated preferentially or even exclu-
sively at the peri- rather than the β-position. Depending on
the base employed, 3-fluorobenzotrifluoride[6] and 3-chlo-
robenzotrifluoride[7] are attacked either at the doubly acti-
vated 2-position or at the sterically uncongested 4-position
whereas 3-bromobenzotrifluoride[7] reacts solely at the lat-
ter site when treated with a lithium dialkylamide. 1,3-Bis-
(trifluoromethyl)benzene displays a unique acidity profile
as it is metalated by the superbasic mixture of butyllithium
and potassium tert-butoxide (LIC + KOR = LIC-KOR)[8]
or, better, lithium 2,2,6,6-tetramethylpiperidide (LITMP) in
the presence of potassium tert-butoxide[9] at the 2-position,
by sec-butyllithium in the presence of N,N,NЈ,NЈЈ,NЈЈ-
We came recently across a novel and totally unexpected
deviation from the ordinary regioselectivity of metalation.
Unlike (2,6-difluorophenyl)trimethylsilane, which was
smoothly metalated at the 3-position,[11] the chloro and
bromo analogs were mainly or exclusively substituted at the
halogen-remote 4-position.[12]
[a] Institute of Chemical Sciences and Engineering, Ecole Polytech-
nique Fédérale, BCh,
1015 Lausanne, Switzerland
Fax: +41-21-6939365
E-mail: manfred.schlosser@epfl.ch
[b] Laboratoire de stéréochimie (CNRS-UMR7008), Université –
ECPM,
At the moment we suspect a special “buttressing ef-
fect”[13,14] to operate. Hypotheses about its origin, nature
67087 Strasbourg, France
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Fluorine-Flanked Congested Sites
FULL PAPER
and implications are still tentative.[15,16] To gain more in-
sight, one first has to explore the scope of the phenomenon.
As previously reported,[11] the consecutive treatment of
(2,6-difluorophenyl)trimethylsilane with sec-butyllithium
and standard electrophiles afforded 3-substituted products
in approximate yields of 90%. The deprotonation of the
fluorine-adjacent position (“ortho metalation”) caused no
surprise as the smallest halogen should be inefficient as a
transmitter of steric pressure. We nevertheless decided to
revisit this reaction and extend our investigations in two
directions. We wanted to vary the emitter of the buttressing
effect by including also (2,6-difluorophenyl)triethylsilane
and (2,6-difluorophenyl)triisopropylsilane into our study
and to use high-performance gas chromatography to search
for 4-substituted products (emanating from “meta metal-
ation”) possibly formed in minor or even just trace
amounts.
Results
In view of the thermal lability of ortho-lithiated (2,6-
dichlorophenyl)trimethylsilane,[17] we first tested the tem-
perature sensitivity of lithiated (2,6-difluorophenyl)trimeth-
ylsilane (1a), (2,6-difluorophenyl)triethylsilane (1b) and
(2,6-difluorophenyl)triisopropylsilane (1c). All three proved
to be perfectly stable at –75 °C, whereas slow decomposi-
tion started at –50 °C and became fast above –25 °C. On
one hand, the organometallic intermediate abstracted pro-
tons from the solvent and, on the other hand, it eliminated
lithium fluoride. The aryne thus set free was immediately
intercepted by the lithiated species which had served as its
precursor. In this way, silane 1a gave, after metalation with
sec-butyllithium at –75 °C and temperature raise to –50 °C
followed by neutralization, a 4:96 mixture of two regioisom-
eric adducts which were converted into 2,3Ј,4- and 2,4,4Ј-
trifluorobiphenyl (2 and 3; isolated in a combined yield of
50%) by protodesilylation. The structure assignment is
based on a comparison of retention times and spectroscopic
data with authentic samples independently and unambigu-
ously prepared by Suzuki–Miyaura coupling (see the Exp.
Sect.).
Next we made authentic samples of the acids 4 and 5
carrying the functional group at a fluorine-adjacent or flu-
orine-remote position. The “ortho isomers” 4 were simply
isolated by crystallization after direct metalation of the si-
lanes 1 and subsequent carboxylation. The “meta isomers”
5 were independently prepared starting from 1-bromo-3,5-
difluorobenzene which was selectively[18] lithiated and con-
verted into the silanes 6 before being subjected to a heavy
halogen/metal permutation and carboxylation.
Thus, the stage was set for systematically probing the re-
gioselectivity of the deprotonation of silanes 1. A variety of
bases were examined (see Table 1). The acids, which formed
in high yields (typically 85–95%), were converted into the
more volatile methyl esters by treatment with diazomethane
before the 4/5 (“ortho”/“meta”) ratios were assessed gas
chromatographically. As the juxtaposition (see Table 1) re-
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C. Heiss, F. Leroux, M. Schlosser
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veals, very little (1–2%) attack occurred at the halogen-re- butyllithium or mesityllithium. Alternatively, one could in-
mote 5-position when sec-butyllithium or lithium 2,2,6,6- directly increase the size of the silyl group by replacing one
tetramethylpiperidide (LITMP) was employed to ac- of the fluorine atoms with a more voluminous (but less
complish the deprotonation of the (2,6-difluorophenyl)tri- acidifying) substituent and in this way lock up the silyl en-
methylsilane (1a) or the triethyl analog 1b. The proportions tity. We have explored the latter possibility. When (2-bromo-
of the acid 5 in the product mixture increased noticeably 6-fluorophenyl)triethylsilane (7) was consecutively lithiated
when the triisopropylsilane 1c acted as the substrate but (using LITMP), carboxylated and protodesilylated, 4-
remained nevertheless small (approx. 5%). Other reagents bromo-2-fluorobenzoic acid (8) and 3-bromo-5-fluoroben-
produced rather minor variations of the 4/5 ratios. This zoic acid (9) were obtained in an 84:16 ratio and a 90%
holds true even for potassium-containing reagents such as combined yield.
the LIC-KOR superbase (butyllithium in the presence of
potassium tert-butoxide) which had exhibited a marked
preference for proton abstraction from the halogen-remote
Conclusions
position in the trialkyl(2,6-dichlorophenyl)silane series.[17]
As the present study has revealed, buttressing effects
manifest themselves only marginally, although perceptively,
when fluorine operates as the transmitter of steric pressure.
Depending on the specific trialkyl(2,6-difluorophenyl)silane
employed as the substrate and on the bulkiness of the meta-
lating agent the fluorine-adjacent (“ortho”) and fluorine-re-
mote (“meta”) position are attacked in ratios ranging from
99.5:0.5 to 95:5.
If the trialkylsilyl group is locked up on one side by a
relatively large substituent, its buttressing potential is en-
hanced. Due to such a relay amplification of steric pressure,
(2-bromo-6-fluorophenyl)triethylsilane undergoes LITMP-
promoted lithiation at the 5- and 4-position (“ortho” vs.
“meta” with respect to fluorine) in a 5:1 ratio, whereas the
2,6-difluoro analog shows a 60:1 ratio.
Buttressing effects on chemical reactivity may not be re-
stricted to rates of deprotonation, the mode of reaction that
has led to their discovery. It may be rewarding to look out
for such effects also in different areas. For example, no ra-
tionale is yet available to explain why 4-trifluoromethyl-3-
(1-phenylethyl)-3H-quinazolin-2-ones react smoothly with
cyclopropylethynylmagnesium bromide when the 5-position
is vacant (as in 10a) and not at all when it is occupied by a
fluorine substituent (as in 10b).[19]
Table 1. Consecutive reaction of trialkyl(2,6-difluorophenyl)silanes
1a–1c with various bases and dry ice: Ratio of benzoic acids 4/5
resulting from the attack on a halogen-adjacent or halogen-remote
position.
Base
a: R = CH3 b: R = C2H5 c: R = iC3H7
LiC4H9
LiCH(CH3)C2H5
LiC(CH3)3
–
98.6:1.4
98.0:2.0
95.6:4.4
96.1:3.9
98.4:1.6
97.7:2.3
97.9:2.1
–
99.6:0.4
95.1:4.9
–
–
–
–
LIC-KOR
LITMP
99.7:0.3
96.3:3.7
LITMP + PMDTA[a]
Faigl mix[b]
–
–
–
–
[a] LITMP + PMDTA = lithium 2,2,6,6-tetramethylpiperidide and
N,N,NЈ,NЈЈ,NЈЈ-pentamethyldiethylenetriamine. [b] Faigl mix
LITMP + PMDTA + KOR (potassium tert-butoxide).
=
Two options exist to further foster the chances of “meta
metalation”. One could subject the most congested silane
1c to the action of a particularly bulky reagent such as tert-
Experimental Section
1. Generalities: Starting materials, if commercial, were purchased
from Aldrich-Fluka (9479 Buchs, Switzerland), Acros Organics
(2440 Geel, Belgium) and Apollo (Whaley Bridge, SK23 7LY, UK).
They were used as such provided that adequate checks (melting
ranges, n2D0, gas chromatography) had confirmed the claimed purity.
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Eur. J. Org. Chem. 2005, 5242–5247

Fluorine-Flanked Congested Sites
FULL PAPER
Solutions of butyllithium, sec-butyllithium and tert-butyllithium in
pentanes, hexanes or cyclohexane were supplied by Chemetall
(60487 Frankfurt, Germany) and potassium tert-butoxide by Cal-
lery (Pittsburgh, PA 15230, USA). When known compounds hadto
be prepared according to literature procedures, pertinent references
are given. Air- and moisture-sensitive materials were stored
inSchlenk tubes or Schlenk burettes. They were protected by and
handled under 99.995% pure nitrogen, using appropriate glassware
(Glasgerätebau Pfeifer, 98711 Frauenfeld, Germany). Paraffinic or
aromatic hydrocarbons (hexanes, toluene) were subjected to azeo-
tropic distillation. Diethyl ether and tetrahydrofuran were dried by
distillation from sodium wire after the characteristic blue color of
in situ generated sodium diphenylketyl (benzophenone/sodium
“radical anion”) had been found to persist.[20,21] Ethereal or other
organic extracts were dried by washing with brine and subsequent
storage over sodium sulfate. Prior to distillation, a spatula tip of
hydroquinone or potassium carbonate was added to compounds
prone to radical polymerization or sensitive to acids. If no reduced
pressure is specified, boiling ranges (b.p.) refer to ordinary atmo-
spheric conditions (725 25 Torr). Melting ranges (m.p.) given were
found to be reproducible after resolidification, unless stated other-
wise (“decomp.”), and were corrected using a calibration curve es-
tablished with authentic standards. If melting points are missing,
it means that all attempts had failed to crystallize the liquid at
temperatures down to –75 °C. The temperature of dry ice/methanol
baths is consistently indicated as –75 °C and “room temperature”
(22–26 °C) as 25 °C. Silica gel (Merck Kieselgel 60) of 70–230 mesh
(0.06–0.20 mm) particle size was used for column chromatography.
The solid support was suspended in hexanes and, when all air
bubbles had escaped, was washed into the column. When the level
of the liquid was still 3–5 cm above the support layer, the dry pow-
der, obtained by adsorption of the crude mixture to some 25–
50 mL of silica and the subsequent evaporation of the solvent, was
poured on top of the column. Whenever possible and appropriate,
yields of products were determined, prior to isolation, by gas chro-
matographic comparison of their peak areas with that of a known
amount of a reference substance (“internal standard”) and correc-
tion of the ratios thus obtained by means of separately established
calibration factors. The purity of distilled compounds was checked
on at least two columns loaded with stationary phases of contrast-
ing polarity. Chromosorb G-AW of 80–100 and 60–80 mesh par-
ticle size was used as the support for packed columns for the ana-
lytical and preparative scale (2 or 3 m long, 2 mm inner diameter
and 3 or 6 m long, 1 cm inner diameter, respectively). Packed col-
umns were made of glass, while quartz was the material selected
for capillary columns (Ͼ10 m long). In case of programmed tem-
perature increase, a constant rate of 10 °C/min was applied. The
stationary phases employed are encoded as HP-5, DB-1, OV-17 or
SE-30 (of the silicone type), DEGS or DBS (both of the polyester
type), AP-L (Apiezon-L hydrocarbon), C-20M, DB-WAX or DB-
FFAP (all belonging to the polyethylene glycol family) and PFO-
XR75 (perfluoropolyethylene type). 1H and 13C NMR spectra were
recorded of samples, dissolved in deuteriochloroform, at 400 and
101 MHz, respectively. Chemical shifts δ refer to the signal of tet-
ramethylsilane (δ = 0.00 ppm). Coupling constants J are given in
Hz and coupling patterns are, for example, abbreviated as q (qua-
druplet), quint (quintuplet), sext (sextuplet), sept (septuplet), oct
(octuplet), non (nonuplet), td (triplet of doublets) and m (mul-
tiplet). Elementary analyses were executed by the laboratory of I.
Beetz (96301 Kronach, Germany) or by Solvias Analytik (4058 Ba-
sel, Switzerland). The expected percentages were calculated using
the atomic weight numbers listed in the 1999 IUPAC recommenda-
tions.
1. Starting Materials and Compounds for Comparison
a) Silanes
(2,6-Difluorophenyl)trimethylsilane (1a) and (2,6-difluorophenyl)-
triethylsilane (1b) have been reported previously.[11]
(2,6-Difluorophenyl)triisopropylsilane (1c): 1,3-Difluorobenzene
(9.0 mL, 11 g, 0.10 mol) was added to a solution of sec-butyllith-
ium (0.10 mol) in cyclohexane (60 mL) and tetrahydrofuran
(0.14 L) cooled in a methanol/dry ice bath. After 45 min at –75 °C,
chlorotriisopropylsilane (21 mL, 19 g, 0.10 mol) was added to the
reaction mixture. Direct distillation afforded a colorless oil; b.p. 80–
82 °C/3 Torr; n2D0 = 1.5832; d420 = 0.998; yield: 23.3 g (86%). 1H
NMR: δ = 7.3 (m, 1 H), 6.83 (t, J = 8.0 Hz, 2 H), 1.54 (sept, J =
8.0 Hz, 3 H), 1.08 (d, J = 8.0 Hz, 18 H) ppm. 13C NMR: δ = 167.6
(dd, J = 245, 18 Hz), 132.0 (t, J = 12 Hz), 111.1 (symm. m), 109.5
(t, J = 36 Hz), 18.8 (s, 6 C), 12.3 (t, J = 3 Hz, 3 C) ppm. C15H24F2Si
(270.44): calcd. C 66.62, H 8.95; found C 66.31, H 8.72.
(4-Bromo-2,6-difluorophenyl)trimethylsilane (6a): Diisopropylamine
(7.1 mL, 5.1 g, 50 mmol) and 1-bromo-3,5-difluorobenzene (9.6 g,
50 mmol) were added consecutively to a solution of butyllithium
(50 mmol) in hexanes (30 mL) and tetrahydrofuran (70 mL) kept in
a dry ice/methanol bath. After 2 h at –75 °C, the mixture was
treated with chlorotrimethylsilane (6.4 mL, 5.4 g, 50 mmol). Imme-
diate distillation gave a colorless oil; b.p. 57–58 °C/2 Torr; n2D0
=
1.4975; d420 = 1.413; yield: 12.3 g (93%). H NMR: δ = 6.99 (d, J
= 6.8 Hz, 2 H), 0.35 (t, J = 1.5 Hz, 9 H) ppm. 13C NMR: δ = 167.0
(dd, J = 248, 18 Hz), 123.9 (t, J = 13 Hz), 120.1 (dd, J = 31, 3 Hz),
112.9 (t, J = 35 Hz), 0.1 (t, J = 3 Hz, 3 C) ppm. C9H11BrF2Si
(265.17): calcd. C 40.77, H 4.18; found C 41.25, H 4.05.
1
(4-Bromo-2,6-difluorophenyl)triisopropylsilane (6c): Prepared analo-
gously but using chlorotriisopropylsilane (11 mL, 9.6 g, 50 mmol)
as the reagent. Upon direct distillation, a colorless oil was ob-
tained; b.p. 96–99 °C/0.4 Torr; n2D0 = 1.4745; d420 = 1.302; yield:
1
15.0 g (86%). H NMR: δ = 7.03 (d, J = 7.0 Hz, 2 H), 1.52 (sept,
J = 7.2 Hz, 3 H), 1.08 (d, J = 7.8 Hz, 18 H) ppm. 13C NMR: δ =
167.4 (dd, J = 247, 18 Hz), 123.9 (t, J = 15 Hz), 115.2 (dd, J = 33,
4 Hz), 109.0 (t, J = 56 Hz), 18.6 (s, 6 C), 12.1 (t, J = 3 Hz, 3 C)
ppm. C15H23BrF2Si (349.33): calcd. C 51.57, 6.64; found C 51.51,
H 6.34.
(2-Bromo-6-fluorophenyl)triethylsilane
(7):
Diisopropylamine
(7.1 mL, 5.1 g, 50 mmol) and 1-bromo-3-fluorobenzene (5.1 mL,
8.7 g, 50 mmol) were added consecutively to a solution of butyllith-
ium (50 mmol) in hexanes (30 mL) and tetrahydrofuran (70 mL)
cooled in a methanol dry ice-bath. After 2 h at –75 °C, the reaction
mixture was treated with chlorotriethylsilane (8.5 mL, 7.5 g,
50 mmol) before, after 45 min at –75 °C, being evaporated and dis-
tilled under reduced pressure; b.p. 80–82 °C/1 Torr; n2D0 = 1.5282;
1
d420 = 1.413; yield: 13.0 g (90%). H NMR (CDCl3, 300 MHz): δ =
7.35 (dd, J = 7.8, 1.1 Hz, 1 H), 7.16 (td, J = 8.1, 2,1 Hz, 1 H), 6.93
(td, J = 9.4, 1.1 Hz, 1 H), 1.0 (m, 15 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 168.0 (d, J = 246 Hz), 131.7 (d, J = 13 Hz), 130.6
(d, J = 3 Hz), 129.6 (s), 125.2 (d, J = 34 Hz), 114.3 (d, J = 29 Hz),
7.5 (s), 4.5 (s) ppm. C12H18BrFSi (289.24): calcd. C 49.83, H 6.27;
found C 49.76, H 6.22.
b) Biphenyls
2,3Ј,4-Trifluorobiphenyl (2): 3-Fluorophenylboronic acid (1.4 g,
10 mmol), 2,4-difluoro-1-iodobenzene (1.3 mL, 2.4 g, 10 mmol),
tetrakis(triphenylphosphane)palladium(0) (0.34 g, 0.30 mmol),
benzene (10 mL) and a 2.0  aqueous solution of sodium carbon-
ate (10 mL, 20 mmol) were stirred vigorously at +25 °C for 12 h.
Then a 33% aqueous solution of hydrogen peroxide (10 mL) was
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C. Heiss, F. Leroux, M. Schlosser
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added, and stirring continued at +25 °C for further 45 min. The
organic layer was decanted and the aqueous phase extracted with
diethyl ether (3×10 mL). The combined organic layers were dried
and the solvents evaporated. Crystallization from hexanes gave
small colorless needles; m.p. 37–39 °C (ref.[22] 40 °C); yield: 1.95 g
(94%). 1H NMR: δ = 7.4 (m, 3 H), 7.2 (m, 2 H), 7.07 (tm, J =
8.6 Hz, 1 H), 6.9 (m, 1 H) ppm.
added to a solution of butyllithium (25 mmol) in hexanes (16 mL)
and diethyl ether (35 mL) kept in a dry ice/methanol bath. After
15 min at –75 °C, the reaction mixture was poured onto freshly
crushed dry ice before being acidified with an ethereal solution
(15 mL) of hydrogen chloride. The volatiles were evaporated and
the residue was extracted with boiling ethyl acetate (3×15 mL).
Upon filtration and concentration of the combined organic layers,
the acid 5a was crystallized from hexanes (10 mL); colorless need-
2,4,4Ј-Trifluorobiphenyl (3): As described in the preceding para-
graph, but starting from 4-fluorophenylboronic acid (1.4 g,
10 mmol) and 2,4-difluoro-1-iodobenzene (2.4 g, 10 mmol); color-
less needles; m.p. 81–83 °C (from methanol; ref.[23–25] 83 °C); yield:
1.83 g (88%). 1H NMR: δ = 7.5 (m, 2 H), 7.35 (dd, J = 8.9, 2.3 Hz,
1 H), 7.12 (tm, J = 8.5 Hz, 2 H), 6.9 (m, 2 H) ppm.
1
les; m.p. 138–140 °C; yield: 5.35 g (94%). H NMR: δ = 7.51 (d, J
= 7.7 Hz, 2 H), 0.40 (t, J = 1.5 Hz, 9 H) ppm. 13C NMR: δ = 168.4
(dd, J = 243, 15 Hz), 166.4 (t, J = 10 Hz), 137.0 (t, J = 10 Hz),
120.4 (t, J = 30 Hz), 113.5 (symm. m), 0.89 (t, J = 3 Hz, 3 C) ppm.
C10H12F2O2Si (230.28): calcd. C 52.16, H 5.25; found C 51.86, H
5.19.
c) Carboxylic Acids
3,5-Difluoro-4-(triisopropylsilyl)benzoic Acid (5c): Prepared analo-
gously from (4-bromo-2,6-difluorophenyl)triisopropylsilane (6c;
6.7 mL, 8.7 g, 25 mmol); colorless needles; m.p. 169–171 °C (from
hexanes); yield: 7.38 g (94%). 1H NMR: δ = 7.53 (d, J = 8.3 Hz, 2
H), 1.56 (sept, J = 7.3 Hz, 3 H), 1.09 (d, J = 7.4 Hz, 18 H) ppm.
13C NMR: δ = 169.0 (dd, J = 244, 16 Hz), 166.0 (t, J = 3 Hz),
166.5 (t, J = 36 Hz), 137.2 (t, J = 10 Hz), 113.9 (dd, J = 31, 3 Hz),
19.8 (s, 6 C), 13.7 (t, J = 3 Hz, 3 C) ppm. C16H24F2O2Si (314.44):
calcd. C 61.11, H 7.69; found C 61.04, H 7.44.
2,4-Difluoro-3-(triethylsilyl)benzoic acid (4b) and 3,5-difluoro-4-
(triethylsilyl)benzoic acid (5b) have been described previously.[11]
All benzoic acids were converted into the more volatile methyl es-
ters for gas chromatographic analysis by treatment with an excess
of ethereal diazomethane.
2,4-Difluoro-3-(trimethylsilyl)benzoic Acid (4a): At dry ice tempera-
ture, (2,6-difluoro-phenyl)trimethylsilane (1a; 4.5 mL, 4.6 g,
25 mmol) was added to a solution of sec-butyllithium (25 mmol) in
cyclohexane (20 mL) and tetrahydrofuran (30 mL). After 45 min
at –75 °C, the reaction mixture was poured onto an excess of freshly
crushed dry ice before being acidified with 2.0  hydrochloric acid
(20 mL) and extracted with ethyl acetate (3×25 mL). One tenth
of the organic solution was treated with an ethereal solution of
diazomethane. According to gas chromatographic analysis (30 m,
DB-WAX, 200 °C; 30 m, DB-1, 200 °C; internal calibrated stan-
dard: tridecane), the raw material contained the acids 4a and 5a in
the ratio of 99.4: 0.6. The rest of the organic solution was concen-
trated and the solid residue thus obtained was crystallized from
hexanes (10 mL); colorless needles; m.p. 124–126 °C; yield: 5.29 g
(92%). 1H NMR: δ = 8.04 (ddd, J = 8.6, 6.7, 1.9 Hz, 1 H), 6.89 (t,
J = 8.6 Hz, 1 H), 0.40 (t, J = 1.6 Hz, 9 H) ppm. 13C NMR: δ =
171.0 (dd, J = 249, 16 Hz), 168.0 (dd, J = 256, 17 Hz), 166.1 (d, J
= 4 Hz), 137.3 (dd, J = 11, 3 Hz), 117.1 (dd, J = 14, 4 Hz), 116.2
(t, J = 35 Hz), 113.1 (dd, 27, 4 Hz), 1.10 (t, J = 3 Hz, 3 C) ppm.
C10H12F2O2Si (230.28): calcd. C 52.16, H 5.25; found C 51.87, H
5.20. When lithium 2,2,6,6-tetramethylpiperidide was used as the
base under the same reaction conditions, the acids 4a and 5a were
obtained in the ratio 99.7:0.3. Upon crystallization from hexanes
(10 mL), the acid 4a was obtained in a yield of 5.06 g (88%).
4-Bromo-2-fluorobenzoic Acid (8): A solution of butyllithium
(10 mmol) in hexanes (6.0 mL) and a solution of 1,4-dibromo-5-
fluorobenzene (3.8 g, 15 mmol) in tetrahydrofuran (5.0 mL) were
added consecutively to a solution of butylmagnesium chloride
(5.0 mmol) in tetrahydrofuran (25 mL) cooled in a dry ice/ethanol
bath. After 45 min at 0 °C, the reaction mixture was poured onto
freshly crushed dry ice. It was acidified with 2.0  hydrochloric acid
(10 mL) and extracted with diethyl ether (3×15 mL). After drying
with sodium sulfate and concentration of the combined organic
layers, the acid 2 crystallized as small colorless needles; m.p. 209–
210 °C; yield: 2.95 g (90%). 1H NMR (CDCl3, 300 MHz): δ = 7.91
(t, J = 8.5 Hz, 1 H), 7.4 (m, 2 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 163.7 (d, J = 4 Hz), 162.1 (d, J = 263 Hz), 133.6 (d,
J = 1 Hz), 127.6 (d, J = 4 Hz), 127.2 (d, J = 10 Hz), 120.4 (d, J =
26 Hz), 118.2 (d, J = 8 Hz) ppm. C7H4BrFO2 (219.01): calcd. C
38.39, H 1.84; found C 38.19, H 1.81.
3-Bromo-5-fluorobenzoic Acid (9): Prepared analogously from 1,3-
dibromo-5-fluorobenzene (3.8 g, 15 mmol); colorless needles; m.p.
141–143 °C (from hexanes); yield: 2.92 g (89%). 1H NMR (CDCl3,
300 MHz): δ = 8.06 (s, 1 H), 7.73 (ddd, J = 8.5, 2.3, 1.3 Hz, 1 H),
7.51 (td, J = 7.7, 1.9 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 164.5 (d, J = 3 Hz), 161.8 (d, J = 250.9 Hz), 134.3 (d, J =
7 Hz), 128.5 (d, J = 3 Hz), 123.6 (d, J = 25 Hz), 122.3 (d, J =
10 Hz), 115.1 (d, J = 23 Hz) ppm. C7H4BrFO2 (219.01): calcd. C
38.39, H 1.84; found C 38.25, H 1.90.
2,4-Difluoro-3-(triisopropylsilyl)benzoic Acid (4c): Prepared analo-
gously from (2,6-difluorophenyl)triisopropylsilane (1c; 6.8 mL,
6.8 g, 25 mmol). As revealed by gas chromatography (30 m, DB-
WAX, 220 °C; 30 m, DB-1, standard: tridecane), the reaction mix-
ture contained the acids 4c and 5c in the ratio of 95.1:4.9. Crystalli-
zation from hexanes (10 mL) afforded colorless needles; m.p. 161–
163 °C; yield: 6.91 g (88%). 1H NMR: δ = 8.10 (dd, J = 8.9, 2.2 Hz,
1 H), 6.95 (t, J = 8.5 Hz, 1 H), 1.59 (sept, J = 7.5 Hz, 3 H), 1.12
(d J = 7.5 Hz, 18 H) ppm. 13C NMR: δ = 170.9 (dd, J = 252,
18 Hz), 169.3 (d, J = 2 Hz), 167.8 (dd, J = 261, 18 Hz),135.9 (dd,
J = 29, 2 Hz), 113.9 (dd, J = 19, 3 Hz), 111.4 (d, J = 12 Hz), 18.7
(s, 6 C), 12.2 (t, J = 3 Hz, 3 C) ppm. C16H24F2O2Si (314.44): calcd.
C 61.11, H 7.69; found C 61.05, H 7.47. When lithium 2,2,6,6-
tetramethylpiperidide was used as the base under the same reaction
conditions, the acids 2c and 3c were obtained in the ratio of
96.3:3.7. Crystallization from hexanes (10 mL) gave the acid 2c in
a yield of 6.52 g (83%).
2. Thermal Decomposition of 3-Lithiated (2,6-Difluorophenyl)tri-
methylsilane
(2,6-Difluorophenyl)trimethylsilane (1a, 9.0 mL, 9.3 g, 50 mmol)
was added to a solution of sec-butyllithium (50 mmol) in cyclohex-
ane (40 mL) and tetrahydrofuran (60 mL) cooled in a dry ice/meth-
anol bath. After 45 min at –75 °C, the reaction mixture was kept
at –50 °C for 12 h before methanol (2.1 mL, 1.9 g, 60 mmol) was
added. According to gas chromatographic analysis (30 m, DB-1,
50 °C; 1 m, SE-30, 5%, 50 °C; nonane as the internal calibrated
standard), the crude reaction mixture contained 46% of (2,6-di-
fluorophenyl)trimethylsilane (1a). The solvents were evaporated
and the residue was extracted with hexanes (3×50 mL). After evap-
3,5-Difluoro-4-(trimethylsilyl)benzoic Acid (5a): (4-Bromo-2,6-di- oration of the solvents, a yellowish oil was collected (9.23 g). Distil-
fluorophenyl)trimethylsilane (6a; 4.7 mL, 6.6 g, 25 mmol) was lation under reduced pressure gave 3.44 g (37%) of (2,6-difluo-
5246
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2005, 5242–5247

Fluorine-Flanked Congested Sites
FULL PAPER
rophenyl)trimethylsilane (1a) as a colorless liquid; b.p. 35–37 °C/
6 Torr (ref.[26] 75 °C/30 Torr) and as a second fraction, a slightly
yellowish oil (4.75 g). According to gas chromatography (1 m,
PFO-XR75, 130 °C; 1 m, C-20M, 180 °C; 2,2Ј,6,6Ј-tetrabromobi-
phenyl as the internal calibrated standard), the latter was composed
of two products in a 4:96 ratio (4.40 g). A major part of the second
fraction (2.6 g, 7.5 mmol) was heated with an excess of tetrabu-
tylammonium fluoride trihydrate (4.7 g, 15 mmol) in dimethyl-
formamide (50 mL) at +100 °C for 24 h. Water (20 mL) was added
and the reaction mixture was extracted with hexanes (3×50 mL).
The two products obtained in a 4:96 ratio were identified as 2,3Ј,4-
trifluorobiphenyl (5) and 2,4,4Ј-trifluorobiphenyl (6) (2 m, PFO-
XR75, 130 °C; 2 m, C-20M, 150 °C, standard: 2,2Ј,6,6Ј-tetra-
bromobiphenyl). Distillation under reduced pressure afforded
1.56 g (30%) of the biphenyls 5 and 6, again in the ratio of 4:96;
b.p. 94–97 °C/0.8 Torr.
Acknowledgments
This work was supported by the Schweizerische Nationalfonds zur
Förderung der Wissenschaftlichen Forschung, Bern (grant 20-
100Ј332-02) and by the Bundesamt für Bildung und Wissenschaft,
Bern (grant C02.0060 linked to the COST-D24 project WG0006-
02). The authors are further indebted to Prof. Reinhard Neier,
Neuchâtel, for excellent comments and hints.
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Trialkyl(2,6-difluorophenyl)silane (25 mmol) was added to a solu-
tion containing sec-butyllithium (25 mmol) or lithium 2,2,6,6-tet-
ramethylpiperidide (prepared from butyllithium and 2,2,6,6-tet-
ramethylpiperidine, each 25 mmol) in a paraffinic hydrocarbon
(20 mL) and tetrahydrofuran (30 mL) cooled in a dry ice/methanol
bath. After 45 min at –75 °C, the reaction mixture was poured onto
an excess of freshly crushed dry ice and the residue, after evapora-
tion of the volatiles, acidified with a 2.0  hydrochloric acid
(10 mL) before being extracted with ethyl acetate (3×25 mL). An
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b) (2-Bromo-6-fluorophenyl)triethylsilane (7) as the Substrate
2,2,6,6-Tetramethylpiperidine (2.5 mL, 2.1 g, 15 mmol) and the si-
lane 7 (3.0 mL, 4.3 g, 15 mmol) were added consecutively to a solu-
tion of butyllithium (15 mmol) in hexanes (10 mL) and tetra-
hydrofuran (20 mL) cooled in a dry ice/methanol bath. After 2 h
at –75 °C, the reaction mixture was poured onto freshly crushed
dry ice, concentrated, acidified with 2.0  hydrochloric acid
(10 mL) and extracted with ethyl acetate (3×15 mL). The yellowish
oil obtained after the concentration of the combined organic layers
(4.8 g) was treated with tetrabutylammonium fluoride hydrate
(19 g, 60 mmol) in refluxing N,N-dimethylformamide (20 mL) for
12 h. The reaction mixture was diluted with 2.0  hydrochloric acid
(20 mL) and extracted with diethyl ether (3×20 mL). Evaporation
of the volatiles gave a colorless solid; yield: 3.03 g (90%). Accord-
ing to gas chromatography (30 m, HP-5 methylsiloxane, 150 °C; tri-
decane as the internal calibrated standard), the raw material con-
tained the acids 2 (76%) and 3 (14%). When the same reaction
was conducted in the presence of potassium tert-butoxide (1.7 g,
15 mmol), the acids 2 (80%) and 3 (6.4%) were obtained in slightly
different ratios.
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Received: July 21, 2005
Published Online: October 20, 2005
Eur. J. Org. Chem. 2005, 5242–5247
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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