Halogen-metal exchange in 1,2-dibromobenzene and the possible intermediacy of 1,2-dilithiobenzene

Article abstract of DOI:10.1021/jo7013033

(Chemical Equation Presented) The one-step high-yield synthesis of 1,2-bis(trimethylsilyl)-benzene from 1,2-dibromobenzene using tert-butyllithium and trimethylsilyltriflate is reported. A mechanistic investigation shows that 1,2-dilithiobenzene is not an intermediate in this reaction; the coexistence of trimethylsilyltriflate and tert-butyllithium at very low temperatures allows a sequence of bromine-lithium exchange and subsequent derivatization reactions to operate.

Full text of DOI:10.1021/jo7013033

TABLE 1. Yields (in %, from GC/MS Analysis) of the Products
Obtained from Trapping the Reaction Mixture of
1,2-Dibromobenzene and t-BuLi in Et2O/THF (1:1) at -120 °C with
Various Electrophiles EX (See Experimental Section for Detailed
Reaction Conditions)
Halogen-Metal Exchange in 1,2-Dibromobenzene
and the Possible Intermediacy of
1,2-Dilithiobenzene
entry
EX
condition
7
9
5
5d
7d
Holger F. Bettinger* and Matthias Filthaus
1
2
3
4
5
6
7
8
9
TMSOTf
TMSCl
ICl
A
A
A
A
A
A
A
A
89
0
0
0
0
<1
0
0
5
6
40
0
0
0
<2
0
11
0
0
0
0
56
7
<3
28
<2
>90
77
0
<1
<1
<1
<1
<1
<1
5
4
0
0
Lehrstuhl fu¨r Organische Chemie 2, Ruhr-UniVersita¨t Bochum,
UniVersita¨tsstrasse 150, 44780 Bochum, Germany
0
91
92
68
92
0
I2
ICH2CH2I
MeOTf
SO2(OMe)2
MeI
DCl
EtOD
holger.bettinger@rub.de
ReceiVed June 19, 2007
0
Aa
Aa
Bb
Bb
92
90
0
10
11
12
6
0
0
0
0
0
TMSOTf
EtOH/HCl
14
0
<1
<1
0
a
Before addition of 1,2-dibromobenzene, the cooled reaction mixture
is treated with 0.1 mL (0.148 mmol) of t-BuLi in pentane. bVarious biphenyl
and terphenyl products are obtained in varying amounts from the aryne
route (see Supporting Information).
The one-step high-yield synthesis of 1,2-bis(trimethylsilyl)-
benzene from 1,2-dibromobenzene using tert-butyllithium
and trimethylsilyltriflate is reported. A mechanistic investiga-
tion shows that 1,2-dilithiobenzene is not an intermediate in
this reaction; the coexistence of trimethylsilyltriflate and tert-
butyllithium at very low temperatures allows a sequence of
bromine-lithium exchange and subsequent derivatization
reactions to operate.
Reaction of 1 in Et2O/THF (1:1) with 2 equiv of t-BuLi per
bromine13,14 at temperatures as low as -120 °C for a variable
amount of time gives a yellow reaction mixture. Trapping of
this mixture with an excess of trimethylsilyltriflate (TMSOTf),
and subsequent quenching with HCl/EtOH, results in the
formation of 1,2-bis(trimethylsilyl)benzene 7a in up to >89%
yield based on GC/MS. Under ideal conditions, we could easily
isolate a >92% yield of 7a in very high purity (see Supporting
Information). This procedure allows for a high-yield synthesis
of 7a, avoiding the environmentally critical HMPTA of the
standard protocol.15
Is the high yield of 7a due to the intermediacy of 6? It has
been recognized over the past 20 years that difunctionalized
products can arise from an alternating sequence of Li-Br
exchange and derivatization reactions if electrophiles can coexist
with lithium organyls at low temperatures to some extent.9,10,16,17
In particular, the claimed preparation of 1,2-dilithiotetrafluo-
robenzene from the corresponding dibromo compound using
n-butyl lithium (n-BuLi) at -78 °C by Tamborski and Soloski18
has received skepticism in a critical review by Maercker.17
To establish the mechanism of formation of 7a, via 6 or via
an alternating sequence of Li-Br exchange and derivatizations
involving 5, we have treated the reaction mixture with a number
of electrophiles under varying conditions (Table 1). With 6 as
intermediate, we should obtain high combined yields of 7 plus
9 (low electrophile reactivity might impede formation of 7 for
steric reasons in favor of 9) but essentially no 5 (Scheme 1).
Using electrophiles other than TMSOTf, however, does not give
7 in appreciable amounts. With trimethylsilylchloride the
Halogen-metal exchange in 1,2-dibromobenzenes 1 using
organolithium reagents results in ortho-benzyne 2 due to the
thermal instability of ortho-lithiobromobenzene 3, and this has
been exploited for the synthesis of biphenyls 4.1,2 However, 3
has a finite lifetime at temperatures below -90 °C as shown
by Chen et al.3 and can thus be trapped with suitable electro-
philes to give ortho-substituted bromobenzenes 5.
The question then arises whether a second lithiation step is
possible at very low temperatures to give 1,2-dilithiobenzene
6, provided a highly reactive organolithium reagent, like tert-
butyl lithium (t-BuLi), is used. While 6 is known since the
work of Wittig and his group dating back to the 1950s,4-6
its synthesis requires an organomercury precursor.7,8 It would
thus be desirable to establish a more convenient and nontoxic
access to this valuable reactive intermediate. We are not aware
of a systematic investigation of this interesting problem but note
that the other dilithiobenzene isomers9 and 1,3,5-trilithioben-
zene10,11 have been prepared and even hexalithiobenzene12 has
been claimed.
(1) Gilman, H.; Gaj, B. J. J. Org. Chem. 1957, 22, 447.
(2) Leroux, F.; Schlosser, M. Angew. Chem., Int. Ed. 2002, 41, 4272.
(3) Chen, L. S.; Chen, G. J.; Tamborski, C. J. Organomet. Chem. 1980,
193, 283.
(4) Wittig, G.; Bickelhaupt, F. Angew. Chem. 1957, 69, 93.
(5) Wittig, G.; Bickelhaupt, F. Chem. Ber. 1958, 91, 883.
(6) Winkler, H. J. S.; Wittig, G. J. Org. Chem. 1963, 28, 1733.
(7) Leroux, F.; Schlosser, M. Angew. Chem. 2002, 114, 4447; Angew.
Chem. Int. Ed. 2002, 41, 4272.
(8) Brown, D. S.; Massey, A. G.; Wickens, D. A. Inorg. Chim. Acta
1980, 44, L193.
(9) Fossatelli, M.; den Besten, R.; Verkrujisse, H. D.; Brandsma, L. Recl.
TraV. Chim. Pays-Bas 1994, 113, 527.
(10) Rot, N.; Bickelhaupt, F. Organometallics 1997, 16, 5027.
(11) Rot, N.; de Kanter, F. J. J.; Bickelhaupt, F.; Smeets, W. J. J.; Spek,
A. L. J. Organomet. Chem. 2000, 593-594, 369.
(12) Baran, J. R.; Hendrickson, C.; Laude, D. A.; Lagow, R. J. J. Org.
Chem. 1992, 57, 3759.
(13) Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94, 7210.
(14) Neumann, H.; Seebach, D. Chem. Ber. 1978, 111, 2785.
(15) Kitamura, T.; Todaka, M.; Fujiwara, Y. Org. Synth. 2000, 78, 104.
(16) Nwokogu, G. C.; Hart, H. Tetrahedron Lett. 1983, 24, 5725.
(17) Maercker, A., Ed. Houben-Weyl, Carbanionen; Springer-Verlag:
Heidelberg, 1987; Vol. E19d, p 486.
(18) Tamborski, C.; Soloski, E. J. J. Organomet. Chem. 1969, 20, 245.
10.1021/jo7013033 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/07/2007
9750
J. Org. Chem. 2007, 72, 9750-9752

SCHEME 1
combined yield of derivatization products is similar to that
obtained with TMSOTf, but the relative yields differ dramati-
cally: 7a cannot be detected at all, while the yield of 5d
increases from 0 to 56%. Also the production of 9a is
significantly increased. This qualitative change in product
composition with electrophile reactivity is incompatible with
the intermediacy of 6 and is best rationalized by a consecutive
mechanism. The different outcome may reflect the higher
reactivity of TMSOTf toward phenyllithium nucleophiles having
bulky ortho-substituents.19
Reaction products obtained from trapping with iodine con-
taining electrophiles (I2, ICl, 1,2-diiodoethane) are also incom-
patible with the intermediacy of 6. Formation of the major
product, 1-bromo-2-iodobenzene 5b, can be rationalized with
a consecutive halogen-lithium exchange reaction mechanism.
Here, excess t-BuLi preferentially abstracts iodine from 5 thus
excluding formation of 9b and 7b. The products obtained using
carbon electrophiles (MeOTf, dimethylsulfate, and methyliodide)
are also compatible with a sequential bromine-lithium exchange-
derivatization mechanism. With MeOTf high yields of 5c and
only trace amounts of o-xylene 7c and toluene 9c are obtained.
Compared with TMSOTf, the less sterically protected MeOTf
should have an increased reactivity toward t-BuLi. Dimethyl-
sulfate, on the other hand, does not react with o-bromolithioben-
zene 3 under our conditions, as bromobenzene 5d is observed
as the major reaction product. Trapping with iodomethane, on
the other hand, gives bromobenzene 5d as the major product
along with some 11% toluene 9c. This result is somewhat
unexpected but might indicate a decreased reactivity of MeI
compared to MeOTf toward o-bromolithiobenzene 3.
yield increases slightly. Likewise, trapping of the lithium organic
compounds with DCl or EtOD in Et2O yields ortho-deutero-
bromobenzene 5e in g90% yield but also 5-6% of 1,2-[D2]-
benzene 7e.
To establish that the observed formation of 1,2-[D2]-benzene
7e is due to the coexistence of DCl or EtOD with t-BuLi at
-120 °C, another set of experiments was performed at slightly
elevated temperatures. After the t-BuLi had reacted with 1 for
30 min, the cooling bath was removed, and the reaction mixture
was allowed to warm for 10 min. The color of the mixture
changed from yellow to orange before it was cooled down to
-120 °C and treated with the electrophile. Dilithiobenzene 6
should be stable thermally under these conditions as Wittig and
co-workers generate it in diethylether at room temperature.5,6
Only when thermally labile 3 is the major reactive intermediate,
biphenyl products should be formed Via the aryne route. Such
reaction products are indeed observed: after briefly warming
the reaction mixture and trapping the lithium organic species
with TMSOTf, no more 7a is found by GC/MS. The major
products are silylated biphenyls and terphenyls along with some
dibenzosilol derivatives.20 Similarly, biphenyl and terphenyl
derivatives in varying amounts were obtained from trapping of
the reaction mixture with HCl rather than TMSOTf after briefly
warming.20 Benzene is no longer observed, indicating that DCl
or EtOD and t-BuLi can coexist at very low temperatures.
In summary, we conclude that the high-yield one-step
synthesis of 1,2-bis(trimethylsilyl)benzene 7a from 1,2-dibro-
mobenzene 1, t-BuLi, and trimethylsilyltriflate proceeds through
a sequence of lithiation-derivatization steps and does not
involve 1,2-dilithiobenzene 6 as reactive intermediate in sig-
nificant amounts. Note that extension of the reaction time or
activation of the organolithium reagent by addition of TMEDA
or glyme does not give indication for the formation of 6 either.
The high yield of difunctionalized benzene 7a arises from the
fortuitous coexistence of TMSOTf and t-BuLi in our ethereal
solvent system at -120 °C: TMSOTf shows sufficient stability
toward t-BuLi but undergoes reactions with both 3 and the
In all experiments mentioned so far, trace amounts of benzene
7d can be detected in the product mixture by GC/MS, but these
are due to residual traces of water and can be eliminated by
treating the solvent with a small amount of t-BuLi before adding
the reactants. Only when electrophiles of low reactivity,
iodomethane and dimethylsulfate, are used does the benzene
(19) Very recently, Kawachi et al. showed that the related o-(fluorodim-
ethylsilyl)phenyllithium does not react with TMSCl at -78 °C. Kawachi,
A.; Tani, A.; Machida, K.; Yamamoto, Y. Organometallics 2007, 26, 4697.
(20) As the temperature increase cannot be controlled precisely under
our conditions, the yields of the individual species vary appreciably.
J. Org. Chem, Vol. 72, No. 25, 2007 9751

was allowed to warm for 10 min before it was cooled down to
-120 °C and treated with the electrophile as described above.
Preparation of 1,2-Bis(trimethylsilyl)benzene (7a). Compound
7a was prepared according to the general procedure (reaction
conditions A) by adding t-BuLi in pentane (36 mL, 53.28 mmol,
4.15 equiv) to 1,2-dibromobenzene 1 (1.5 mL, 12.44 mmol) in 160
mL THF/Et2O (1:1). The reaction mixture was quenched by
TMSOTf (12.5 mL, 69.06 mmol) in 15 mL Et2O, then treated with
EtOH/concd HCl (8:2) (5 mL). Then 100 mL of Et2O and 50 mL
of water were added. The organic layer was separated and washed
with a half-concd aqueous solution of NaCl, NaHCO3, and water
(30 mL) and dried. The solvent was evaporated, and the colorless
residue was dried in vacuo to remove trimethylsilyl benzene 9a.
The product 7a was obtained in >92% yield (2.56 g, 11.51 mmol)
with a purity of >99% based on GC analysis.
sterically more demanding 8. Other electrophiles investigated
here do not show this property and are thus not suited for
twofold derivatization under the conditions described here. In
view of our results, the reported synthesis of hexalithiobenzene
from hexachlorobenzene and an excess of t-BuLi in 1,4-dioxane/
pentane at very low temperatures is very remarkable.12
Experimental Section
General Procedure (Reaction Conditions A). A solution of
1,2-dibromobenzene 1 (0.1 mL, 0.829 mmol) in 60 mL of Et2O/
THF (1:1) was cooled to -120 °C with a nitrogen/ethanol cooling
bath, and a cold (-78 °C) pentane solution of t-BuLi (2.3 mL, 3.4
mmol, 4.15 equiv) was added very rapidly. The yellow reaction
mixture was stirred for 30 min at -120 °C, and the reaction was
treated with an excess (10 equiv) of a cold solution (-78 °C) of
the electrophile EX in 15 mL of Et2O and stirred for 30 min at
-120 to -110 °C. The solution was cooled down again to -120 °C
and quenched by addition of 3 mL of cold (-78 °C) EtOH/concd
HCl (8:2), stirred for 30 min, and warmed slowly to room
temperature. Then hexamethylbenzene (0.134 g, 0.829 mmol) in
100 mL of Et2O and 50 mL of water (or a half-concd solution of
Na2SO3 in the case of iodine containing electrophiles) were added
and stirred for 15 min. The organic layer was separated and washed
with a half-concd aqueous solution of NaCl, NaHCO3, and water
(25 mL) and dried over MgSO4. The products and their yields were
identified by GC/MS.
1H NMR (CDCl3) δ 0.36 (s, 6 H), 7.29-7.32 (dd, 2 H), 7.65-
7.67 (dd, 2 H); 13C NMR (CDCl3) δ 1.9, 127.7, 135.2, 146.0; MS
(EI): m/z (%): 222 (12) [M+•], 207 (100), 191 (98), 175 (39), 135
(6), 119 (13), 88 (8), 73 (91), 60 (21), 45 (57). Anal. Calcd for
C12H22Si2: C, 64.78, H, 9.97. Found: C, 64.63, H, 9.92. HRMS
calcd: 222.12654. Found: 222.12659.
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie and by the Deutsche Forschungsge-
meinschaft. We thank Prof. Dr. Wolfram Sander for his support
and Dr. Go¨tz Bucher for helpful discussions.
Supporting Information Available: Analytical data for 1,2-
bis(trimethylsilyl)benzene and GC/MS analyses of the reaction
products obtained under reaction conditions B. This material is
available free of charge via the Internet at http://pubs.acs.org.
Modification to Reaction Conditions A. In case of deutero-
electrophiles the solvent was treated with a small amount of t-BuLi
(0.1 mL, 0.148 mmol) before adding the reactants.
Reaction Conditions B. After the t-BuLi has reacted with 1 for
30 min, the cooling bath was removed and the reaction mixture
JO7013033
9752 J. Org. Chem., Vol. 72, No. 25, 2007