Palladium-Catalyzed Silylation of Aryl Bromides Leading to Functionalized Aryldimethylsilanols

Article abstract of DOI:10.1021/ol035288m

Equation presented. A mild and general palladium-catalyzed insertion of 1,2-diethoxy-1,1,2,2-tetramethyldisilane into a variety of aryl bromides affords the aryldimethylsilyl ethers in high yields. Hydrolysis of the ethers under pH-optimized conditions results in the exclusive formation of the desired aryldimethylsilanols.

Full text of DOI:10.1021/ol035288m

ORGANIC
LETTERS
2003
Vol. 5, No. 19
3483-3486
Palladium-Catalyzed Silylation of Aryl
Bromides Leading to Functionalized
Aryldimethylsilanols
Scott E. Denmark* and Jeffrey M. Kallemeyn
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
600 S. Mathews AVenue, Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received July 11, 2003
ABSTRACT
A mild and general palladium-catalyzed insertion of 1,2-diethoxy-1,1,2,2-tetramethyldisilane into a variety of aryl bromides affords the
aryldimethylsilyl ethers in high yields. Hydrolysis of the ethers under pH-optimized conditions results in the exclusive formation of the desired
aryldimethylsilanols.
Transition-metal-catalyzed cross-coupling has become a
powerful and general method for the selective construction
of carbon-carbon bonds due in large measure to the
pioneering work of Stille and Suzuki on organotin- and
organoboron-based reagents, respectively.1 To avoid the
toxicity and relatively low stability of the organotin and
boron reagents, organosilicon reagents have proved to be a
viable alternative in the cross-coupling reaction.2 Recent
reports from these laboratories have identified the specific
advantages of aryl- and alkenyldimethylsilanols as substrates
for palladium-catalyzed cross-coupling reactions.3,4 Whereas
hydrosilylation is often used to prepare alkenyldimethyl-
silanols, the preparation of aryl dimethylsilanols is limited
to lithium-halogen exchange followed by trapping with a
silicon electrophile.5 Several transition-metal-catalyzed
silylation reactions between aryl halides and triethoxysilane
or hexamethyldisilane give arylsilanes; however, a general
method for producing monooxygenated arylsilyl ethers or
silanols has not been described. In general, silylations with
triethoxysilane6 proceed well with electron-rich and -neutral
aryl iodides; however, electron-deficient aryl iodides suffer
from significant amounts of reduction.7 The scope of the
silylation can be extended to include electron-rich and
-neutral aryl bromides with the use of bulky phosphine
ligands.8 Recently, it has been shown that a limited number
of electron-deficient aryl bromides and iodides also react with
triethoxysilane in the presence of [Rh(cod)(MeCN)2]BF4.9
Alternatively, palladium-catalyzed silylation with hexam-
ethyldisilane gives a wide variety of both electron-rich and
-deficient aryltrimethylsilanes; however, activation of the
disilane by fluoride or hydroxide is required for efficient
transfer.10 It would be desirable to introduce dimethylsilanol
units onto aryl groups by a direct method that would tolerate
(1) Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: Weinheim, Germany, 1998.
(2) (a) Hiyama, T.; Shirakawa, E. Top. Curr. Chem. 2002, 219, 61. (b)
Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50, 1531.
(3) Denmark, S. E.; Ober, M. H. Org. Lett. 2003, 5, 1357.
(4) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835.
(5) (a) Hirabayashi, K.; Ando, J.; Kawashima, J.; Nishihara, Y.; Mori,
A.; Hiyama, T. Bull. Chem. Soc. Jpn. 2000, 73, 1409. (b) Lickiss, P. D.
AdV. Inorg. Chem. 1995, 42, 147.
(6) Triethoxysilane is highly toxic and may cause blindness.
(7) Murata, M.; Suzuki, K.; Watanabe, S.; Masuda, Y. J. Org. Chem.
1997, 62, 8569.
(8) Manoso, A. S.; DeShong, P. J. Org. Chem. 2001, 66, 7449.
(9) Murata, M.; Ishikura, M.; Nagata, M.; Watanabe, S.; Masuda, Y.
Org. Lett. 2002, 4, 1843.
10.1021/ol035288m CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/19/2003

a wide range of functional groups which are incompatible
with lithium reagents.
Table 2. Silylation of Aryl Halides with 5
To obtain the desired aryldimethylsilanols, a two-step
process was envisioned that comprised an initial silylation
of an aryl bromide to afford an aryldimethylsilyl ether, which
could then be hydrolyzed to the aryldimethylsilanol under
appropriate conditions. Herein we report a general, mild, one-
pot palladium-catalyzed silylation and hydrolysis procedure
that provides functionally diverse aryldimethylsilanols from
the corresponding aryl bromides.
entry
ArylX
temp, °C
time, h
3, %a
4, %a
6, %a
1
2
3
4
2a
2a
7a
7d
rt
48
2
10
6
66
54
94
93
17
4
3
16
41
1
60
60
60
Initially, silylation with ethoxydimethylsilane (1) was
investigated using 4-iodoanisole (2a). The predominant
competing pathway in the formation of the desired aryldi-
methylsilyl ether (3a) was reduction to afford anisole (4a).
After a brief optimization, the preferred reaction conditions
involved stirring PdCl2, 2-(di-tert-butylphosphino)biphenyl
(BPTBP), and i-Pr2EtN with 4-iodoanisole for 30 min to
allow a homogeneous solution to form prior to addition of
1. With this protocol, the reaction was complete in under 30
min at room temperature and only a small amount of anisole
was formed. (Table 1, entry 1). However, with 4-iodo-
acetophenone (2b) or 4-iodonitrobenzene (2c), reduction
became the predominant pathway (entries 2 and 3).
2
5
a Reported as area % by GC analysis.
catalytic species is a BPTBP-ligated palladium(0) species
that is formed during the course of the reaction.
Table 3. Effect of Palladium Source and Ligands on Silylation
Table 1. Silylation of Aryl Iodides with Dimethylethoxysilane
entry
catalyst
PdCl2
PdCl2
Pd(PPh3)2Cl2
Pd(dba)2
ligand
3d , %a
1
2
3
4
5
BPTBP
dppb
90
4
0
65
87
BPTBP
BPTPB
3, %a
4, %a
[allylPdCl]2
entry
aryl iodide
R
a Determined at 2 h by GC analysis using an internal standard.
1
2
3
2a
2b
2c
-OMe
-COMe
-NO2
93
35
5
7
64
90
a Reported as area % by GC analysis.
Decreasing the amount of the base from 3.0 to 1.1 equiv
resulted in reaction stalling before silylation was complete
(Table 4, entries 1 and 2). The use of a tertiary amine base
allowed the reaction to reach completion, but i-Pr2EtN was
To overcome competitive reduction of the aryl halide, 1,2-
diethoxy-1,1,2,2-tetramethyldisilane (5) was employed as the
silylation reagent. Reaction of 4-iodoanisole (2a) with 5a at
ambient temperature or at 60 °C gave, in addition to 3, large
amounts of the homocoupling product (6) (Table 2, entries
1 and 2). The formation of 6 could be substantially
suppressed by the use of 4-bromoanisole (7a) in place of 4a
(entry 3). Even an electron-deficient aryl bromide, ethyl
4-bromobenzoate (7d) (entry 4), gave almost exclusive
formation of the silyl ether.
Table 4. Effect of Base on Silylation
entry
base
equiv
3d , %a
The next stage in the optimization involved changing both
the ligand and the palladium source in the silylation of 7d.
In the ligand screen, only BPTBP yielded the desired product,
whereas dppb and PPh3 were ineffective (Table 3, entries
1-3). Changing the palladium source showed only a
moderate effect (entries 1, 4, and 5), suggesting that the active
1
2
3
4
5
6
7
i-Pr2EtN
i-Pr2EtN
Et3N
pyridine
2,6-lutidine
i-Pr2NH
KH2PO4
3.0
1.1
3.0
3.0
3.0
3.0
3.0
90
55
45
0.0
0.0
0.3
1 (31)b
a Determined at 2 h by GC analysis using an internal standard. b Amount
of 8d formed.
(10) (a) Shirakawa, E.; Kurahashi, T.; Yoshida, H.; Hiyama, T. Chem.
Commun. 2000, 1895. (b) Gooâen, L. J.; Ferwanah, A. S. Synlett 2000,
1801.
3484
Org. Lett., Vol. 5, No. 19, 2003

superior to Et3N (entry 3). Changing the base to pyridine,
2,6-lutidine, or i-Pr2NH inhibited the reaction, and no
conversion to the silyl ether was observed (entries 4-6).
Interestingly, when KH2PO4 was used, silylation proceeded
to 32% conversion with predominant in situ conversion to
the silanol before the reaction stalled (entry 7).
the pH 5-7 range, with increased amounts of 9d formed
either above or below this pH range (entries 1-7). The
phosphate buffers gave disappointingly slow hydrolysis
except at pH > 9, where the ratio of 8:9 is unacceptably
high (entries 8-12). These trends become clear when
conversions are plotted against reaction pH (Figure 1). The
results are in agreement with earlier studies that show that
mildly acidic conditions (near pH 4) maximize hydrolysis
of the silyl ether and minimize dimerization.13 The simplest
buffer system that falls into the ideal pH 5-7 range is a 1.0
M acetic acid/ammonium acetate buffer at pH 5.6. Using
this protocol, the hydrolysis of the silyl ether is complete
within 2 h and the amount of 9d formed is kept below 1%.
With optimized conditions in hand for the synthesis of
the silyl ether, its hydrolysis to the silanol was investigated
next. A well-known complication in the hydrolysis of silyl
ethers (under either acidic or basic conditions) to the silanols
8 is the competitive dimerization of 8 to the disiloxanes 9.11
Although the pH dependence of hydrolysis of alkyltrieth-
oxysilyl ethers12a and the dimerization of alkylsilanols12b have
been studied, no reports describe the relative amounts of 8
and 9 formed during the hydrolysis of silyl ethers. Thus, a
study on the effect of pH on the hydrolysis and dimerization
was undertaken. The optimization of the hydrolysis was
performed with unpurified silylation product mixtures with
the consequence that the reaction medium is intrinsically
basic because of the residual i-Pr2EtN from the silylation
reaction. Addition of either acidic or basic buffers to this
mixture resulted in a variety of in situ-formed ammonium
buffers of different pH. To create a homogeneous solution,
acetonitrile was added along with either an acetate or
phosphate buffer. GC analysis allowed for monitoring the
conversion of 3d to both 8d and 9d. Analysis of the reactions
with acetate buffers showed that the conversion to 8d is high
when the pH is held below 7 (Table 5, entries 1-6).
Increasing the pH above 7 resulted in a slower hydrolysis
reaction (entry 7). The ratio of 8d:9d appears to be ideal in
Figure 1. pH Dependence of formation of 8d and 9d.
Table 5. pH Dependence on the Hydrolysis and Dimerization
of 3d
A variety of aryl bromides were then subjected to the one-
pot silylation/hydrolysis procedure (Table 6). Good yields
were obtained with a range of substrates within a reasonable
reaction time. Increasing the amount of disilane 5 from 1.1
to 1.5 equiv effected a substantial increase in yield for a
number of substrates (entries 1-3 and 6-7), although not
for 8d (entry 4). The excess of 5 appears to increase the
rate of the silylation compared to reduction or homocoupling.
In the purification of the crude silanol products, a portion
of the palladium leached through the silica gel column,
affording colored products. Several palladium scavengers
were screened and evaluated by visual inspection of the
products and ease of removal. It was found that 2-(dimethyl-
amimo)ethanethiol hydrochloride was the simplest and most
cost-effective palladium scavenger.14 This solid is added
directly to the hydrolysis reaction mixture and is removed
with the palladium in the aqueous extraction.
concn,
M
pH of pH of 8d , ratio of
a
entry
buffer
buffer reaction
%
8d :9d
1
2
3
4
5
6
7
8
9
10.0 HOAc
2.0 HOAc
1.0 HOAc
1.07
2.02
2.23
2.89
3.79
4.92
5.98
4.20
5.16
5.63
6.17
6.31
6.97
8.98
6.98
7.25
8.62
9.06
9.00
75 97.1:2.9
83 99.2:0.8
77 98.9:1.1
80 99.4:0.6
82 98.8:1.2
80 99.2:0.8
62 86.5:13.5
25 98.7:1.3
17 98.0:2.0
18 95.4:4.6
63 85.5:14.5
63 83.1:16.9
1.0 HOAc/NaOAc
1.0 HOAc/NaOAc
1.0 HOAc/NaOAc
1.0 HOAc/NaOAc
1.0 KH2PO4/K2HPO4 4.46
1.0 KH2PO4/K2HPO 5.44
1.0 KH2PO4/K2HPO4 6.70
1.0 KH2PO4/K2HPO4 7.96
1.0 KH2PO4/K2HPO4 8.72
(11) (a) Akerman, E. Acta Chem. Scand. 1956, 10, 298. (b) Rutz, W.;
Lange, D.; Popowski, E.; Kelling, H. Z. Anorg. Allg. Chem. 1986, 536,
197. (c) Shirai, N.; Moriya, K.; Kawazoe, Y. Tetrahedron 1986, 42, 2211.
(12) Pohl, E. R.; Osterholtz, F. D. Polym. Sci. Technol. 1985, 27, 157.
(b) Pohl, E. R.; Osterholtz, F. D. In Silanes, Surfaces and Interfaces; Leyden,
D. E., Ed.; Gordon and Breach: New York, 1986; Vol. 1, pp 481-500.
(13) Osterholtz, F. D.; Pohl, E. R. J. Adhes. Sci. Technol. 1992, 6, 127.
(14) Both trisodium thiocyanuracic acid (see: Rosso, V. W.; Lust, D.
A.; Bernot, P. J.; Grosso, J. A.; Modi, S. P.; Rusowicz, A.; Sedergran, T.
C.; Simpson, J. H.; Srivastava, S. K.; Humora, M. J.; Anderson, N. G. Org.
Process Res. DeV. 1997, 1, 311) and mercapto-functionalized silica gel
(Silicycle, Quebec City) were also investigated with lesser success.
10
11
12
a Determined by GC analysis vs internal standard.
Org. Lett., Vol. 5, No. 19, 2003
3485

Table 6. Silylation and Hydrolysis of 4-Substituted Aryl
Table 7. Silylation and Hydrolysis of 2-Substituted Aryl
Bromides
Bromides
entry
R
product temp, °C equiv of 5 time, h yield, %a
1.1 equiv of 5
1.5 equiv of 5
1
2
3
4
CN
CN
CO2Et
OCH3
8h
8h
8i
60
60
80
80
1.1
1.5
1.5
2.0
24
12
24
18
57
82
56
47b
entry
R
product time, h yield, %a time, h yield, %a
1
2
3
4
5
6
7
OCH3
COCH3
NO2
CO2Et
CN
8a
8b
8c
8d
8e
8f
24
4
4
4
4
55
64
54
79
79
18
4
4
4
4
76
70
72
81
80
69
71
8j
a Yield of isolated, chromatographically pure material. b Starting material
was recovered (10%).
CH2OTHP
CH3
4
8g
18
60
12
In summary, we have developed a general procedure for
the formation of aryldimethylsilanols from aryl bromides by
a one-pot silylation/hydrolysis procedure. The hydrolysis
conditions are sufficiently mild that formation of the disi-
loxane is minimized. Investigations are underway to utilize
these silanols in cross-coupling reactions and to further
expand this silylation method to include alkenyl halides.
a Yield of isolated, chromatographically pure material.
To probe the scope of this reaction, several 2-substituted
aryl bromides were investigated. Silylation of 2-bromo-
benzonitrile occurred under the general reaction conditions
(Table 7, entries 1 and 2); however, both ethyl 2-bromo-
benzoate and 2-bromoanisole showed no conversion to the
product under these conditions. It is believed that the low
reactivity of these substrates is not entirely a steric effect
but that the Pd(II)-aryl species is coordinately stabilized by
the neighboring substituent. To circumvent this problem, the
silylation of ethyl 2-bromobenzoate and 2-bromoanisole were
carried out at 80 °C. This minor modification proved to be
effective for these substrates, although the yields were lower
than for the corresponding 4-substituted aryl bromides
(entries 3-4).
Acknowledgment. We are grateful to the National
Institutes of Health (RO1 GM63167) for generous financial
support. J.M.K. thanks the University of Illinois for a
graduate fellowship.
Supporting Information Available: Detailed procedures
for the synthesis of 5, all silylation reactions, and full
characterization of 8a-j. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL035288M
3486
Org. Lett., Vol. 5, No. 19, 2003