A convenient iron-catalyzed method for the preparation of 1,2-bis(trimethylsilyl)benzenes

Article abstract of DOI:10.1055/s-0030-1258144

A convenient iron-catalyzed method for the preparation of 1,2-bis(trimethylsilyl)benzenes is presented. Compared to the current procedures, low temperatures and toxic solvents are avoided, allowing large-scale preparation. Additionally, a variety of subst

Full text of DOI:10.1055/s-0030-1258144

PAPER
2759
A Convenient Iron-Catalyzed Method for the Preparation of
1,2-Bis(trimethylsilyl)benzenes
I
ron-Catalyzed
a
Silylationmuel L. Bader, Simon N. Kessler, Hermann A. Wegner*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax +41(61)2670976; E-mail: hermann.wegner@unibas.ch
Received 4 March 2010; revised 28 April 2010
Br
M
Mg or LiAlk
Abstract: A convenient iron-catalyzed method for the preparation
of 1,2-bis(trimethylsilyl)benzenes is presented. Compared to the
current procedures, low temperatures and toxic solvents are avoid-
ed, allowing large-scale preparation. Additionally, a variety of sub-
Br
Br
1
2
3
stituents are tolerated.
Mg or
LiAlk
Key words: Grignard reaction, catalysis, iron, silicon, metalation
E
M
M
E+
Trialkylsilyl-substituted aryl compounds are useful pre-
E
cursors for transmetalation reactions.1 These molecules
5
4
can be prepared2 via radical substitution reactions,3 nu-
Scheme 1 Elimination of 1,2-dibromoaromatics under metalation
cleophilic substitution reactions with trialkylsilyl alkali-
metal compounds,4 palladium-catalyzed reactions,5 and
[2+2+2]- or [4+2]-cycloaddition reactions.6 One of the
most used methods is the reaction of Grignard7a or aryl-
lithium compounds with trialkylsilyl chlorides.7 Howev-
er, this transformation is problematic for the synthesis of
1,2-bis(trialkylsilyl)aryls. In this case, elimination to the
corresponding aryne is observed, which can undergo fur-
ther undesired reactions (Scheme 1).8
trimethylsilyl triflate has to be used. Furthermore, the re-
action is also performed at high dilutions of 80 mmol/L,
leading, together with the very low temperature, to prob-
lems in the preparation of larger quantities. Another pro-
cedure uses hexamethylphosphoramide (HMPA) as a
solvent to stabilize the organometalic intermediate to
overcome the elimination.10 However, HMPA is highly
toxic and should be avoided.
To prevent this elimination a number of different proce-
dures have been developed: Use of very low temperatures
(–120 °C) avoids the elimination pathway,9 but is incon-
venient in the laboratory. Moreover, trimethylsilyl chlo-
ride is not sufficiently electrophilic at low temperature.
Therefore, the more reactive, but much more expensive,
Therefore, we present a new, convenient procedure that
allows the preparation of 1,2-bis(trimethylsilyl)benzenes
without the need for low temperature conditions or toxic
solvents.
Table 1 Optimization of the Grignard Reaction with 1,2-Dibromobenzene
Mg, solvent, DIBAL-H
additives, temp, TMSCl
Br
TMS
Br
TMS
1a
6a
Entry
Solvent
THF
Additives (equiv)
Temp (°C)
reflux
reflux
reflux
reflux
reflux
–10
Yield (%)
1
2
3
4
5
6
7
LiCl (2.1)
27
–
dioxane
LiCl (2.1)
THF–Et2O
–
30
37
33
36
41
THF
THF
THF
THF
–
TMEDA (0.2)
TMEDA (1.2), FeCl3 (10 mol%)
TMEDA (1.2), FeCl3 (3 mol%)
–10
SYNTHESIS 2010, No. 16, pp 2759–2762
x
x.
x
x
.
2
0
1
0
Advanced online publication: 01.07.2010
DOI: 10.1055/s-0030-1258144; Art ID: T04910SS
© Georg Thieme Verlag Stuttgart · New York

2760
S. L. Bader et al.
PAPER
When 1,2-dibromobenzene (1a) is treated in tetrahydrofu-
ran with magnesium powder (activated with 0.2 mol%
DIBAL-H11) and trimethylsilyl chloride at reflux, the de-
sired 1,2-bis(trimethylsilyl)benzene (6a) can be isolated
in 33%. Although the yield is only moderate, the reaction
can be performed on a 50 mmol scale without decrease in
yield. The main drawback was that only a few substituents
on the aryl portion were tolerated. Therefore, further opti-
mization studies were conducted (Table 1). Different sol-
vents (Et2O or dioxane) did not improve the reaction.
Different additives were screened such as lithium chloride
or N,N,N¢,N¢-tetramethylethylendiamine (TMEDA), how-
ever, in our system, no positive influence on the yield
could be observed.
Table 2 Iron(III) Chloride Catalyzed Grignard Reactions with Sub-
stituted 1,2-Dibromides
Br
Br
TMS
TMS
method A or B
R
R
1a–g
6a–g
Entry
1
Starting material
Methoda
Yield (%)
Br
A
B
37
41
Br
1a
Br
A
B
0
19
2
3
4
5
Br
It has also been shown that iron complexes can catalyze
the formation of Grignard species.12 Jacobi von Wangelin
and co-workers recently investigated the influence of
iron(III) chloride on the Grignard transformation in more
detail.13 Initial results using 10 mol% iron(III) chloride
did not improve the yield, but did allow the reaction to be
performed below 0 °C. Lowering the iron concentration to
3 mol% increased the yield to 41% (Table 1, entries 6 and
7).
1b
Br
A
B
0
14
t-Bu
1c
Br
Br
Br
MeO
A
B
12
36b
MeO
1d
The most important improvement was the tolerance of a
range of substituents (Me, t-Bu or F). Even 1,2,4,5-tet-
rakis(trimethylsilyl)benzene could be prepared in satis-
factory yield (Table 2).
Br
O
A
B
28
81
O
Br
1e
Interestingly, when method B was used for substrate 1e,
81% of the desired bis-TMS compound could be isolated
(Table 2, entry 5). Substrate 1d, however, gave the bis-
TMS product only in 1.4% yield at –10 °C. Since the low
yield might be explained by complexation of the
dimethoxy moiety with the iron, the reaction was then
conducted in the presence of lithium chloride (2.1 equiv).
Under these conditions the desired bis-silylated com-
pound could be isolated in 36%, together with 28% of the
mono-silylated derivative (Table 2, entry 4). Performing
the reaction with a stoichiometric amount of iron(III)
chloride gave a very similar result. GC-MS analysis of the
crude reaction mixture showed the formation of mainly
side products resulting from only one bromine exchange
and mono-silylation. Only in a few cases was starting ma-
terial observed with no biaryl or other side products. How-
ever, the formation of larger oligomers or polymers
cannot be ruled out.
F
F
F
F
Br
A
B
0
49
6
7
Br
1f
Br
Br
B
38
Br
Br
1g
a Reaction conditions: Method A: Mg (2.5 equiv), TMSCl
(2.5 equiv), THF, reflux, 45 min. Method B: Mg (3 equiv), TMSCl
(3 equiv), TMEDA (1.2 equiv), FeCl3 (3 mol%), THF, –10 °C, 18 h.
b LiCl (2.1 equiv) was added; the product was isolated together with
28% of 3,4-dimethoxy(trimethylsilyl)benzene.
An interesting extension of our methodology would be the
use of 1,2-dichlorobenzenes as starting materials. Under
the standard Grignard conditions (Method A), no silyla-
tion could be observed. In contrast to this, we were able to
perform the iron-catalyzed silylation reaction with 1,2-
dichlorobenzene although, due to the lower reactivity of
the chlorine, higher temperatures were required for reac-
tion. Interestingly, the two steps of the reaction could be
separated by controlling the reaction temperature. The
second silylation typically requires a temperature 20–
40 °C above that needed for the first step. Conducting the
reaction at 40 °C (Method B with higher temperature)
Mg, THF
DIBAL-H, TMEDA
Cl
Cl
TMS
Cl
FeCl3, –10 °C, TMSCl
52%
7
8
Mg, THF
DIBAL-H, TMEDA
FeCl3, 40 °C, TMSCl
TMS
TMS
5%
1a
Scheme 2 Silylation of 1,2-dichlorobenzene
Synthesis 2010, No. 16, 2759–2762 © Thieme Stuttgart · New York

PAPER
Iron-Catalyzed Silylation
2761
into a mixture of sat. aq NaHCO3 (25 mL) and ice (12 mL). Et2O (25
mL) was added and the solids were filtered off. The aqueous phase
was extracted with Et2O (25 mL, 20 mL, then 12 mL) and the com-
bined extract was dried over Na2SO4 and evaporated under reduced
pressure. The crude product was purified by column chromatogra-
phy over silica (hexane containing 1% Et3N) to yield a clear liquid
(1.21 g). Volatile impurities were removed under high vacuum to
give 6a (0.909 g, 41%) as clear oil.
leads to the isolation of 1-chloro-2-trimethylsilylbenzene
(8) in a yield of 52%. Increasing the temperature to reflux
gave the bis-silylated product 9 in 5% yield (Scheme 2).
The harsher conditions required for the second silylation
leads to other side reactions and also to decomposition of
the 1-chloro-2-trimethylsilylbenzene.
In summary, a convenient iron-catalyzed method for the
preparation of 1,2-bis(trimethylsilyl)benzenes has been
developed. Compared to the current procedures, low tem-
peratures and toxic solvents are avoided, allowing large-
scale preparation. Additionally, a range of different sub-
stituents are tolerated. The exact role of the iron catalyst
is currently under investigation.
4-tert-Butyl-1,2-bis(trimethylsilyl)benzene (1c)
Colorless oil; bp 67 °C/0.06 mbar.
IR: 2951 (w), 1262 (w), 1247 (m), 1099 (w), 874 (w), 851 (m), 825
(s), 751 (m), 726 (w), 690 (w), 676 (w), 636 (w), 622 (w), 596 (w),
502 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 0.40 (s, 9 H, H-TMS), 0.42 (s, 9 H,
H-TMS), 1.37 (s, 9 H, H-tBu), 7.40 (dd, J = 7.9, 2.1 Hz, 1 H, H-5),
7.67 (d, J = 7.9 Hz, 1 H, H-6), 7.78 (d, J = 2.1 Hz, 1 H, H-3).
All chemicals were used as received from Acros, Alfa Aesar, Fluka,
Fluorochem, or Sigma–Aldrich without any prior purification. An-
hydrous solvents for the reactions were purchased from Fluka or
Biosolve LTD. THF was continuously heated at reflux and freshly
distilled from sodium benzophenone ketyl under nitrogen. Techni-
cal grade solvents for extractions and chromatography were dis-
tilled once before use. All reactions were set up with dry glassware,
which was heated to 200 °C and dried in several evacuation–flush
cycles or just flushed by nitrogen. IR spectra were recorded with a
Shimadzu FTIR-8400S instrument; the compounds were analyzed
by using a Specac Golden Gate ATR sampling system. A Bruker
DPX NMR (400 MHz) instrument was used to measure the NMR
spectra. Chemical shifts (d) are reported in parts per million (ppm)
relative to residual solvent peaks or TMS. For GC-MS analysis, a
Hewlett–Packard 5890 Series II gas chromatography system, fitted
with a Macherey–Nagel OPTIMA 1 Me2Si column (25 m × 0.2
mm × 0.35 m), at 1 mL/min He flow rate (split = 20:1) with a
Hewlett–Packard 5971 Series mass-selective detector (EI 70 eV)
was used. The analytical data for 1a,9 1b,14 and 1g15 correspond to
those reported in the literature.
13C NMR (100 MHz, CDCl3): d = 150.3, 146.0, 142.8, 135.7, 132.8,
125.1, 35.1, 31.6, 2.4.
GC-MS: m/z (%) = 278 (24) [M]+, 247 (100), 175 (14), 73 (48), 57
(23).
Anal. Calcd for C16H30Si2: C, 68.98; H, 10.85. Found: C, 69.29; H,
10.90.
4,5-Dimethoxy-1,2-bis(trimethylsilyl)benzene (1d)
Colorless oil.
IR: 2951 (w), 1556 (w), 1463 (w), 1299 (w), 1276 (w), 1244 (m),
1199 (w), 1130 (w), 1043 (m), 927 (w), 856 (w), 827 (s), 750 (m),
689 (w), 682 (w), 632 (w), 613 (w), 500 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 0.37 (s, 18 H, H-TMS), 3.90 (s,
6 H, H-OMe), 7.21 (s, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 2.5, 56.0, 119.2, 138.7, 148.6.
GC-MS: m/z (%) = 283 (25), 282 (93) [M]+, 268 (13), 267 (50), 253
(19), 252 (60), 251 (100), 238 (12), 237 (54), 179 (11), 89 (13), 73
(49), 59 (14), 45 (18).
Grignard Reaction; General Procedure (Method A)
Anal. Calcd for C14H26O2Si2: C, 59.52; H, 9.28. Found: C, 60.17; H,
9.25.
Pulverized Mg (3.04 g, 125 mmol, 2.50 equiv) was dried under vac-
uum at ~300 °C for 30 min. After cooling and flushing with N2,
THF (50 mL) and DIBAL-H (1 M in THF, 1.0 mL, 2 mol%) were
added and the mixture was heated at reflux for 5 min. After the ad-
dition of TMSCl (13.9 g, 16.3 mL, 125 mmol, 2.50 equiv), 1,2-di-
bromobenzene (1a; 11.8 g, 6.03 mL, 50.0 mmol, 1.00 equiv) was
added dropwise within 45 min whilst maintaining the mixture at re-
flux. The mixture was stirred for an additional 35 min then poured
into a mixture of sat. aq NaHCO3 (125 mL) and ice (60 mL). Et2O
(125 mL) was added and the solids were filtered off. The aqueous
phase was extracted with Et2O (125 mL, 100 mL, then 60 mL) and
the combined extract was dried over Na2SO4 and evaporated under
reduced pressure. The crude product was purified by distillation
over a Vigreux column (72–81 °C/1.1 mbar) to give 6a (4.08 g,
37%) as a clear oil.
4,5-Methylenedioxy-1,2-bis(trimethylsilyl)benzene (1e)
Colorless oil.
IR: 2954 (w), 2892 (w), 1608 (m), 1474 (m), 1417 (m), 1231 (m),
1040 (w), 939 (w), 875 (w), 859 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 0.35 (s, 18 H, H-TMS), 5.93 (s,
2 H, OCH2O), 7.20 (s, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 2.6, 100.8, 115.9, 140.3, 147.7.
GC-MS: m/z (%) = 267 (17), 266 (69) [M]+, 252 (13), 251 (56), 236
(23), 235 (100), 221 (25), 193 (20), 163 (11), 73 (42), 45 (18), 43
(12).
Anal. Calcd for C13H22O2Si2: C, 58.59; H, 8.32. Found: C, 58.56; H,
8.40.
Method B
A mixture of pulverized Mg (0.729 g, 30.0 mmol, 3.00 equiv) and
anhydrous FeCl3 (48.7 mg, 0.300 mmol, 3 mol%) were dried for 30
min under vacuum and heated to ~300 °C for 5 min. After cooling
down and flushing with N2, THF (10 mL), TMEDA (1.39 g, 1.81
mL, 12.0 mmol, 1.20 equiv) and DIBAL-H (1 M in THF, 2 mol%,
0.2 mL) were added and the mixture was stirred for 5 min. Then,
TMSCl (3.26 g, 3.83 mL, 30.0 mmol, 3.00 equiv) was added and the
mixture was cooled to –10 °C. 1,2-Dibromobenzene (1a; 2.36 g,
1.21 mL, 10.0 mmol, 1.00 equiv) was added dropwise over 6 h,
whilst maintaining the temperature between –10 and 0 °C. The mix-
ture was stirred for an additional 18 h at –10 to 0 °C, then poured
3,4,5,6-Tetrafluoro-1,2-bis(trimethylsilyl)benzene (1f)
Colorless oil.
IR: 1603 (w), 1474 (w), 1390 (m), 1370 (w), 1285 (w), 1270 (w),
1251 (m), 1089 (m), 1038 (w), 1020 (m), 835 (s), 818 (m), 766 (m),
699 (w), 686 (w), 630 (w), 621 (w), 502 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 0.41 (m, H-TMS).
13C NMR (100 MHz, CDCl3): d = 3.0, 128.3, 128.4, 128.5, 128.6,
131.2, 133.3, 139.0, 139.1, 140.7, 141.7, 141.8, 151.4, 153.7, 164.8.
Synthesis 2010, No. 16, 2759–2762 © Thieme Stuttgart · New York

2762
S. L. Bader et al.
PAPER
19F NMR (376 MHz, CDCl3): d = –167.60 (m, AA¢XX¢-system),
–164.09 (s), –155.20 (m), –133.10 (d), –125.75 (d), –123.23 (d),
–120.42 (m), –118.31 (m), –94.71 (s), –87.45 (m).
GC-MS: m/z (%) = 294 (6) [M]+, 280 (11), 179 (47), 155 (17), 101
(13), 91 (20), 87 (18), 81 (67), 77 (100), 75 (18), 74 (10), 73 (80),
63 (15), 51 (15), 49 (24), 47 (26), 45 (22), 43 (11).
(3) For an example, see: Sakurai, H.; Hosomi, A.; Kumada, M.
Tetrahedron Lett. 1969, 10, 1755.
(4) For an examples, see: Shippey, M. A.; Dervan, P. B. J. Org.
Chem. 1977, 42, 2654.
(5) For examples, see: Matsumoto, H.; Nagashima, S.;
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5027. (b) Hilt, G.; Janikowski, J.; Hess, W. Angew. Chem.
Int. Ed. 2006, 45, 5204.
Anal. Calcd for C12H18F4Si2: C, 48.95; H, 6.16. Found: C, 49.54; H,
6.46.
(7) For examples, see: (a) Tuulmets, A.; Ploom, A.; Panov, D.;
Järv, J. Synthesis 2010, 291. (b) Effenberger, F. Liebigs
Ann. Chem. 1979, 842.
Acknowledgment
(8) (a) Gilman, H.; Gaj, B. J. J. Org. Chem. 1957, 22, 447.
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We thank the Swiss National Science foundation (SNSF) for finan-
cial support. H.A.W. is indebted to the Fonds der Chemischen Indu-
strie for a Liebig fellowship.
(9) Bettinger, H. F.; Filthaus, M. J. Org. Chem. 2007, 72, 9750.
(10) Kitamura, T.; Todaka, M.; Fujiwara, Y. Org. Synth., Coll.
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(15) Mach, K.; Turecek, F.; Antropiusová, H.; Hanus, V.
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Synthesis 2010, No. 16, 2759–2762 © Thieme Stuttgart · New York