Trifluoromethyl-substituted phenylsilanes: The regiochemical course of their metalation dictated by buttressing effects

Article abstract of DOI:10.1002/ejoc.200500729

Triethyl[(2-trifluoromethyl)phenyl]silane reacts with the superbasic LIC-KOR mixture of butyllithium and potassium tert-butoxide exclusively at the 4-position ("meta-metalation") and not at all at the 3-position ("ortho-metalation"). Two further substrates which simultaneously contain two trifluoromethyl groups, triethyl[2,4- and 2,5-bis(trifluoromethyl) phenyl]silane, undergo deprotonation at the 5- and 4-position, respectively. Thus, a buttressing effect blocks the attack of metalating agents on the ortho position of any trifluoromethyl group which is neighbored, on the other side, by a trialkyl substituent. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500729

FULL PAPER
DOI: 10.1002/ejoc.200500729
Trifluoromethyl-Substituted Phenylsilanes: The Regiochemical Course of Their
Metalation Dictated by Buttressing Effects
Manfred Schlosser,*[a] Christophe Heiss,[a,b] and Frédéric Leroux[b]
Keywords: Buttressing / Metalation / Regioselectivity / Silanes / Steric hindrance / Trifluoromethyl groups
Triethyl[(2-trifluoromethyl)phenyl]silane reacts with the su-
perbasic LIC-KOR mixture of butyllithium and potassium
tert-butoxide exclusively at the 4-position (“meta-metal-
ation”) and not at all at the 3-position (“ortho-metalation”).
Two further substrates which simultaneously contain two tri-
fluoromethyl groups, triethyl[2,4- and 2,5-bis(trifluoro-
methyl)phenyl]silane, undergo deprotonation at the 5- and
4-position, respectively. Thus, a buttressing effect blocks the
attack of metalating agents on the ortho position of any tri-
fluoromethyl group which is neighbored, on the other side,
by a trialkyl substituent.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
strated by gas chromatographic analysis. To this end, the
reaction mixture was first protodesilylated before being
treated with an excess of ethereal diazomethane in order
to convert the resulting 3-(trifluoromethyl)benzoic acid (2b)
into its more volatile methyl ester.
As previously reported,[1–3] chlorine and bromine atoms
are potent transmitters of the steric pressure emanating
from an adjacent trialkylsilyl substituent. As we expected
trifluoromethyl groups to behave similarly, we have selected
three archetypical model compounds belonging to the ben-
zotrifluoride family to verify this hypothesis. The course of
the metalation reaction was indeed found to be dominated
by buttressing effects in each case.
Results and Discussion
Whereas the superbasic LIC-KOR mixture composed of
stoichiometric amounts of butyllithium and potassium tert-
butoxide metalates benzotrifluoride exclusively at the ortho
position,[4,5] simple butyllithium in refluxing diethyl ether
produces ortho, meta, and para derivatives in a 83:16:1 ra-
tio.[6,7] The proneness to meta attack should manifest itself
more pronouncedly if a buttressing interaction[1,8,9] dis-
criminates against ortho-metalation. In fact, triethyl[(2-tri-
fluoromethyl)phenyl]silane (1) was found to undergo hydro-
gen/metal permutation (“metalation”) exclusively at the
CF3-remote 4-position and not at all at the CF3-adjacent
3-position. After trapping with dry ice, the presence of 4-
triethylsilyl-3-(trifluoromethyl)benzoic acid (2a; 86%) and
the absence of even trace amounts of the isomeric 3-trieth-
ylsilyl-2-(trifluoromethyl)benzoic acid (3a) was demon-
1,3-Bis(trifluoromethyl)benzene represents a model case
of optional site selectivity. It reacts with tert-butyllithium in
tetrahydropyran with equal probability at the 4- and the 5-
position, with lithium 2,2,6,6-tetramethylpiperidide
(LITMP) in tetrahydrofuran solely at the 4-position and
with mixed-metal reagents such as LITMP or butyllithium
or methyllithium in the presence of potassium tert-butoxide
solely at the 2-position.[4,5] The latter reaction mode got
entirely lost when a triethylsilyl group was introduced next
to one of the two trifluoromethyl substituents. Whatever
reagent and conditions applied, triethyl[2,4-bis(trifluoro-
methyl)phenyl]silane (4) underwent metalation only at the
unbuttressed 5-position to afford, upon silylation and car-
boxylation, 4,6-bis(trifluoromethyl)-1,3-phenylenebis(trie-
thylsilane) (5a; 89%) and 5-(triethylsilyl)-2,4-bis(trifluoro-
methyl)benzoic acid (5b; 91%), respectively. The spectra are
[a] Institute of Chemical Sciences and Engineering, Ecole Polytech-
nique Fédérale, BCh
1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
Fax: +41-21-6939365
[b] Laboratoire de Stéréochimie (CNRS UMR 7509), Université
Pasteur (ECPM),
25 rue Becquerel, 67087 Strasbourg, France
Eur. J. Org. Chem. 2006, 735–737
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
735

M. Schlosser, C. Heiss, F. Leroux
FULL PAPER
in perfect agreement with the assignment of structure 5a,
characterized by a mirror plane along the C(2),C(5) axis of
the bis(silane), and rules out the less symmetrical re-
gioisomer 6a.
Experimental Section
Generalities: For working routine and abbreviations, see related
publications from this laboratory.[9–11] Unless specified otherwise,
1
the H and 13C NMR spectra were recorded at 300 and 75 MHz,
respectively, of samples dissolved in deuteriochloroform.
1. Triethyl[(2-trifluoromethyl)phenyl]silane as the Substrate
Triethyl[(2-trifluoromethyl)phenyl]silane (1): 1-Bromo-2-(trifluoro-
methyl)benzene (23 g, 0.10 mol) was added to a solution of butyl-
lithium (0.10 mol) in hexane (60 mL) and tetrahydrofuran (0.14 L)
cooled in a dry ice/ethanol bath. After 45 min at –75 °C, chlorotri-
ethylsilane (17 mL, 15 g, 0.10 mol) was added to the reaction mix-
ture. Immediate distillation afforded a colorless oil; b.p. 50–52 °C/
0.8 Torr; n2D0 = 1.4751; d240 = 1.336; yield: 23.4 g (90%). H NMR:
1
δ = 7.7 (m, 2 H), 7.51 (symm. m, 2 H), 1.0 (m, 15 H) ppm. 13C
NMR: δ = 136.8 (s), 135.4 (q, J = 2 Hz), 135.3 (q, J = 31 Hz),
130.4 (d, J = 1 Hz), 128.8 (s), 126.2 (q, J = 15 Hz), 125.1 (q, J =
273 Hz), 7.4 (s), 3.9 (q, J = 2 Hz) ppm. C13H19F3Si (260.33): calcd.
C 59.97, H 7.36; found C 60.09, H 7.18.
3-Trifluoromethylbenzoic Acid (2b): Potassium tert-butoxide (1.7 g,
15 mmol) and the silane 1 (3.9 g, 15 mmol) were consecutively
added to a solution of butyllithium (15 mmol) in hexanes (10 mL)
and tetrahydrofuran (20 mL) cooled in a dry ice/ethanol bath. After
45 min at –75 °C, the reaction mixture was poured onto freshly
crushed dry ice. It was acidified with 2.0 m aqueous hydrochloric
acid (10 mL) before being extracted with diethyl ether (3×20 mL).
The combined organic layers were dried with sodium sulfate. After
evaporation of the volatiles, a colorless oil was left behind; yield:
3.92 g (86% with respect to C14H19F3O2Si). The oil (3.9 g) was
treated with tetrabutylammonium fluoride hydrate (19 g, 60 mmol)
in refluxing N,N-dimethylformamide (30 mL) for 60 h. The mixture
was poured into water (25 mL) and extracted with diethyl ether
(3×20 mL). Evaporation of the volatiles gave colorless needles;
m.p. 102–103 °C (ref.[6] 103.0–104.5 °C; ref.[12] 106 °C); yield: 1.02 g
(36%). According to gas chromatography (30 m, HP-5 methyl sil-
oxane, 150 °C) of the methyl ester obtained after exhaustive expo-
sure of the acid 2b to ethereal diazomethane, the raw material was
uncontaminated by any isomer or other by-product. 1H NMR
(400 MHz): δ = 8.1 (m, 2 H), 7.75 (s, broad, 1 H), 7.43 (s, broad,
1 H) ppm.
1,4-Bis(trifluoromethyl)benzene has four equivalent vac-
ant positions and hence reacts with standard bases (such as
LITMP) smoothly and virtually quantitatively (up to 93%
of isolated carboxylation product).[5] The introduction of a
triethylsilyl group changed this situation profoundly. The
metalation of the silane 7, accomplished with sec-butyllith-
ium, occurred exclusively at the 4-position, the 6-position
being sterically inaccessible and the 3-position disabled by
a buttressing effect. Depending on the trapping reagent em-
ployed, 2,5-bis(trifluoromethyl)-1,4-phenylenebis(triethylsil-
ane) (8a; 89%) and 4-triethylsilyl-2,5-bis(trifluoromethyl)-
benzoic acid (8b; 91%) were obtained.
2. Triethyl[2,4-bis(trifluoromethyl)phenyl]silane as the Substrate
Triethyl[2,4-bis(trifluoromethyl)phenyl]silane (4): 2,2,6,6-Tetrameth-
ylpiperidine and 1,3-bis(trifluoromethyl)benzene (15 mL, 21 g, 0.10
mol) were consecutively added to a solution of butyllithium (0.10
mol) in hexanes (60 mL) and tetrahydrofuran (0.14 L), cooled in a
dry ice/methanol bath. After 2 h at –75 °C, the mixture was treated
with chlorotriethylsilane (17 mL, 15 g, 0.10 mol) stored at +25 °C
for 12 h before being distilled under reduced pressure to afford a
colorless oil; b.p. 58–60 °C/0.8 Torr; n2D0 = 1.4426; d240 = 1.206; yield:
29.5 g (90%). 1H NMR (400 MHz): δ = 7.93 (s, 1 H), 7.82 (s, 1 H),
7.74 (s, 1 H), 0.92 (s, 15 H) ppm. 13C NMR (101 MHz): δ = 141.1
(s), 137.7 (s), 136.6 (q, J = 32 Hz), 131.6 (q, J = 32 Hz), 127.0 (d,
J = 3 Hz), 124.8 (q, J = 274 Hz), 123.1 (m, 2 C), 7.2 (s, 3 C) 3.8
(q, J = 3 Hz, 3 C) ppm. C14H18F6Si (328.37): calcd. C 51.21, H
5.53; found C 51.27, H 5.60.
Conclusions
The ordinary kinetic acidity gradient of benzotrifluorides
privileging the ortho position is suppressed by a vicinal tri-
alkylsilyl substituent. As a consequence, the metalating
agent is rerouted to the more remote meta position. Al-
though ignored until recently, buttressing effects on depro-
tonation rates are widespread and need to be taken into
account if one wishes to predict the outcome of metalation
experiments applied to phenylsilanes carrying halogenated
substituents at silyl-adjacent aromatic positions.
4,6-Bis(trifluoromethyl)-1,3-phenylenebis(triethylsilane)
(5a):
2,2,6,6-Tetramethylpiperidine (4.2 mL, 3.5 g, 25 mmol), potassium
tert-butoxide (2.8 g, 25 mmol) and the silane 4 (6.8 mL, 8.2 g,
25 mmol) were consecutively added to a solution of butyllithium
(25 mmol) in hexanes (15 mL) and tetrahydrofuran (35 mL), cooled
in a dry ice/methanol bath. After 2 h at –75 °C, the reaction mix-
736
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 735–737

The Regiochemical Course of Metalation Dictated by Buttressing Effects
FULL PAPER
ture was treated with chlorotriethylsilane (4.2 mL, 3.8 g, 25 mmol) from acetone as colorless needles; m.p. 45–47 °C; yield: 9.85 g
and distilled immediately; colorless oil; b.p. 148–150 °C/3 Torr;
(89%). 1H NMR: δ = 7.95 (s, broad, 2 H), 0.94 (s, 30 H) ppm. 13C
NMR: δ = 137.2 (s, 2 C), 137.1 (q, J = 31 Hz, 2 C), 134.0 (q, J =
1
n2D0 = 1.4710; d240 = 1.366; yield: 9.85 g (89%). H NMR: δ = 8.04
(s, broad, 1 H), 8.00 (s, broad, 1 H), 0.96 (s, broad, 15 H) ppm. 5 Hz, 2 C), 124.7 (q, J = 274 Hz, 2 C), 7.2 (s, broad, 6 C), 3.7 (s,
13C NMR: δ = 145.6 (s), 138.0 (s), 136.2 (q, J = 32 Hz), 124.4 (q,
J = 274 Hz), 123.4 (sept, J = 6 Hz), 7.3 (s, 6 C), 3.7 (d, J = 2 Hz,
6 C) ppm. C20H32F6Si2 (442.64): calcd. C 54.27, H 7.29; found C
54.22, H 6.89.
broad, 6 C) ppm. C20H32F6Si2 (442.64): calcd. C 54.27, H 7.29;
found C 54.34, H 6.99.
2,5-Bis(trifluoromethyl)-4-(triethylsilyl)benzoic Acid (8b): The silane
7 (6.8 mL, 8.2 g, 25 mmol) was added to a solution of sec-butyllith-
ium (25 mmol) in cyclohexane (19 mL) and tetrahydrofuran
(30 mL) cooled in a dry ice/ethanol bath. After 45 min at –75 °C,
the reaction mixture was poured onto freshly crushed dry ice before
being acidified with 2.0 m hydrochloric acid (10 mL) and extracted
with diethyl ether (3×25 mL). After drying and evaporation, a yel-
5-Triethylsilyl-2,4-bis(trifluoromethyl)benzoic Acid (5b): 2,2,6,6-Tet-
ramethylpiperidine (4.2 mL, 3.5 g, 25 mmol), potassium tert-butox-
ide (25 mmol) and the silane 4 (6.8 mL, 8.2 g, 25 mmol) were added
consecutively to a solution of butyllithium (25 mmol) in hexanes
(15 mL) and tetrahydrofuran (35 mL) cooled in a dry ice/methanol
bath. After 2 h at –75 °C, the reaction mixture was poured onto
freshly crushed dry ice, neutralized with 2.0 m hydrochloric acid
and extracted with ethyl acetate (3×25 mL). One tenth of the or-
ganic phase was treated with diazomethane until the yellow color
persisted. According to gas chromatography (30 m, DB-1, 180 °C,
30 m, DB-WAX, 180 °C; internal calibrated standard: tridecane)
the crude product mixture contained 91% of the acid 5b. The bulk
organic phase was concentrated and the residue crystallized from
1
lowish oil was obtained; yield: 8.47 g (91%). H NMR: δ = 8.29 (s,
broad, 1 H), 8.10 (s, broad, 1 H), 0.96 (s, 15 H) ppm. 13C NMR:
δ = 170.9 (s), 142.9 (s), 139.1 (q, J = 32 Hz), 135.1 (q, J = 6 Hz),
130.6 (q, J = 33 Hz), 130.3 (s), 128.7 (q, J = 5 Hz), 123.7 (q, J =
275 Hz), 122.8 (q, J = 275 Hz), 7.2 (s, 3 C), 3.7 (d, J = 2 Hz, 3 C)
ppm. C15H18F6O2Si (372.38): calcd. C 48.38, H 4.87; found C
48.33, H 4.73.
1
hexanes; colorless needles; m.p. 84–86 °C; yield: 7.63 g (82%). H
Acknowledgments
NMR (400 MHz): δ = 8.24 (s, 1 H), 8.08 (s, 1 H), 1.0 (m, 15 H)
13
ppm.
C NMR (101 MHz): δ = 171.4 (s), 142.3 (s), 139.4 (s),
This work was financially supported by the Swiss National Science
Foundation, Bern (grant 20-100Ј336-02) and the Federal Office for
Education and Science, Bern (grant C02.0060 linked to the COST-
D24 project WG0006-02).
139.2 (q, J = 33 Hz), 130.8 (s), 130.1 (q, J = 33 Hz), 124.7 (hept, J
= 5 Hz), 123.9 (s), 121.2 (s), 7.3 (s, 3 C), 3.6 (q, J = 2 Hz, 3 C) ppm.
C15H18F6O2Si (372.38): calcd. C 48.38, H 4.87; found C 48.26, H
4.66.
3. Triethyl[2,5-bis(trifluoromethyl)phenyl]silane as the Substrate
[1] C. Heiss, E. Marzi, M. Schlosser, Eur. J. Org. Chem. 2003,
4625–4629.
Triethyl[2,5-bis(trifluoromethyl)phenyl]silane (7): 1,4-Bis(trifluoro-
methyl)benzene (21 g, 0.10 mol) was added to a solution of sec-
butyllithium (0.10 mol) in cyclohexane (70 mL) and tetra-
hydrofuran (0.13 L) cooled in an dry ice/ethanol bath. After 45 min
at –75 °C, the reaction mixture was treated with chlorotriethylsilane
(17 mL, 15 g, 0.10 mol) and immediately distilled; colorless oil; b.p.
60–61 °C/0.8 Torr; n2D0 = 1.4425; d240 = 1.211; yield: 30.2 g (90%)
1H NMR: δ = 7.94 (s, broad, 1 H), 7.84 (d, J = 8.1 Hz, 1 H), 7.74
(d, J = 8.0 Hz, 1 H), 0.95 (s, 15 H) ppm. 13C NMR: δ = 138.7 (q,
J = 31 Hz), 137.6 (d, J = 2 Hz), 133.3 (q, J = 4 Hz), 132.4 (q, J =
34 Hz), 126.7 (q, J = 6 Hz), 125.8 (q, J = 4 Hz), 124.3 (q, J =
275 Hz), 123.7 (q, J = 273 Hz), 7.2 (s, 3 C), 3.7 (q, J = 3 Hz) ppm.
C14H18F6Si (328.37): calcd. C 51.21, H 5.53; found C 51.33, H 5.51.
[2] C. Heiss, F. Cottet, M. Schlosser, Eur. J. Org. Chem. 2005,
5236–5241.
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Masson, R. Scopelliti, Eur. J. Org. Chem. 2006, 729–734, pre-
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2,5-Bis(trifluoromethyl)-1,4-phenylenebis(triethylsilane) (8a):
A
solution containing the silane 7 (6.8 mL, 8.2 g, 25 mmol) and sec-
butyllithium (25 mmol) in cyclohexane (20 mL) and tetra-
hydrofuran (30 mL) was kept at –75 °C for 45 min before chlorotri-
ethylsilane (3.1 mL, 2.7 g, 25 mmol) was added. Upon addition of
water (20 mL), extraction with diethyl ether (3×25 mL) and evapo-
ration of the volatiles, a residue was collected which crystallized
Received: September 27, 2005
Published Online: November 30, 2005
Eur. J. Org. Chem. 2006, 735–737
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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