Cross-coupling reactions of arylsilanols with substituted aryl halides

Article abstract of DOI:10.1021/ol034328j

(Matrix presented) The palladium-catalyzed cross-coupling of arylsilanols with aryl iodides and aryl bromides (in the presence of cesium carbonate) furnished various biaryl products in high yield. An extensive series of optimizations led to the identifica

Full text of DOI:10.1021/ol034328j

ORGANIC
LETTERS
2
003
Vol. 5, No. 8
357-1360
Cross-Coupling Reactions of
Arylsilanols with Substituted Aryl
Halides
1
Scott E. Denmark* and Michael H. Ober
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
600 South Mathews AVenue, Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received February 25, 2003
ABSTRACT
The palladium-catalyzed cross-coupling of arylsilanols with aryl iodides and aryl bromides (in the presence of cesium carbonate) furnished
various biaryl products in high yield. An extensive series of optimizations led to the identification of key variables, including activator, solvent,
catalyst, and hydration level, that influence the rate and selectivity of the process. Manipulation of these features provided an effective coupling
method of wide scope and generality.
The transition metal-catalyzed cross-coupling of aryl halides
and aryl organometallic nucleophiles has gained considerable
attention as an effective method for the formation of the
use of organosilanes as aryl organometallic nucleophiles for
the formation of biaryls has been limited to a few cases.
6
7
Aryl(fluoro)silanes and aryl(chloro)silanes, activated by a
fluoride source, have been shown to undergo palladium-
catalyzed cross-coupling with aryl bromides, iodides, and
biaryl subunit.1,2 Organotin and organoboron reagents have
found wide use in synthetic organic chemistry as a viable
approach toward this structural motif, but due to the toxicity
and sensitivity of these reagents, the development of alterna-
tive methods is of great interest. Organosilanes are a stable
and nontoxic alternative to these methods, allowing for
3
4
6a
triflates to give unsymmetrical biaryl products. This method
7a
has also been applied to solid-phase synthesis. Under milder
8
9
conditions, aryl(trialkoxy)silanes and arylsilacyclobutanes
have also been reported as viable approaches to fluoride-
activated aryl-aryl cross-coupling.
5
similar or superior reactivity and scope in most cases. The
A recent report from these laboratories described the
(
1) (a) Hassan, J.; S e´ vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. ReV. 2002, 102, 1359. (b) Stanforth, S. P. Tetrahedron 1998, 54,
63. (c) Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem., Int. Ed.
Engl. 1990, 29, 977. (d) Sainsbury, M. Tetrahedron 1980, 36, 3327.
2) (a) Diederich, F., Stang, P. J., Eds. Metal-catalyzed, Cross-coupling
palladium-catalyzed cross-coupling of alkenylsilanols under
1
0
2
fluoride-free conditions. This modification highlights the
inherent reactivity of alkenyldimethylsilanols through activa-
(
Reactions; Wiley-VCH: Weinheim, Germany, 1998. (b) Heck, R. F.
Palladium Reagents in Organic Synthesis; Academic Press: New York,
(6) (a) Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1990, 31, 2719. (b)
Hatanaka, Y.; Fukushima, S.; Hiyama, T. Chem. Lett. 1989, 1711.
(7) (a) Homsi, F.; Hosoi, K.; Nozaki, K.; Hiyama, T. J. Organomet.
Chem. 2001, 624, 208. (b) Hagiwara, E.; Gouda, K.; Hatanaka, Y.; Hiyama,
T. Tetrahedron Lett. 1997, 38, 439. (c) Hatanaka, Y.; Goda, K.; Okahara,
Y.; Hiyama, T. Tetrahedron 1994, 50, 8301.
(8) (a) Mowery, M. E.; DeShong, P. Org. Lett. 1999, 2, 2137. (b) Lee,
H. M.; Nolan, S. P. Org. Lett. 2000, 2, 2053. (c) Mowery, M. E.; DeShong,
P. J. Org. Chem. 1999, 64, 1684. (d) Shibata, K.; Miyazawa, K.; Goto, Y.
Chem. Commun. 1997, 1309.
1
985. (c) Tsuji, J. Palladium Reagents and Catalysis, InnoVations in Organic
Synthesis; Wiley: Chichester, UK, 1995.
3) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Farina,
V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1998, 50, 1.
4) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (b) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (c) Suzuki, A. Pure Appl. Chem.
994, 66, 213. (d) A. Suzuki, Pure Appl. Chem. 1985, 57, 1749.
5) (a) Hiyama, T.; Shirakawa, E. Top. Curr. Chem. 2002, 219, 61. (b)
(
(
1
(
Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 12, 1531. (c)
Hiyama, T.; Hatanaka, Y. Pure and Appl. Chem. 1994, 66, 1471. (d)
Hiyama, T. In Metal-catalyzed, Cross-coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998.
(9) Denmark, S. E.; Wu, Z. Org. Lett. 1999, 1, 1495.
(10) (a) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835.
(b) Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2001, 123, 6439.
1
0.1021/ol034328j CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/22/2003

tion with mild inorganic bases and demonstrates the compat-
ibility of this protocol with a wide scope of coupling partners.
The intrinsic advantage of organodimethylsilanols is also
manifested in the ease of synthesis and stability of the
coupling precursors.11 An important extension is to apply
this method to the less reactive arylsilanols for the formation
of unsymmetrical biaryl compounds. The use of silver salts
for the activation of aryl(dimethyl)silanols, arylsilanediols,
and arylsilanetriols toward coupling with aryl bromides and
iodides has been previously explored by Hiyama and co-
workers.12 Careful investigation of the palladium-catalyzed
cross-coupling of aryl(dimethyl)silanols in these labs has now
acceptable rates of conversion of the aryl iodide but afforded
the undesired cross-coupling product preferentially (entry 4).
All of the experiments described in Table 1 were hetero-
geneous; Cs CO was observed throughout the course of the
2
3
reaction.
To further accelerate the cross-coupling process and
suppress the homocoupling pathway, the use of additives in
the reaction of 1 with ethyl 4-iodobenzoate was explored
(Table 2). The addition of 20 mol % triphenylphosphine (2/1
Table 2. Effect of Additive on the Cross-Coupling of 1 with
Ethyl 4-Iodobenzoatea
revealed that cesium carbonate can also be employed as an
activator for this reaction.13
Initial investigation of the cross-coupling of (4-methoxy-
11b
phenyl)dimethylsilanol (1) with ethyl 4-iodobenzoate and
cesium carbonate under catalysis by allylpalladium chloride
dimer ([allylPdCl] ) at 90 °C did provide the desired cross-
2
coupling product (2a) but also provided the undesired
homocoupling product (3a).14 The low reactivity of 1 and
the formation of 3a in significant quantities focused the
optimization on improving the reaction rate and suppressing
the homocoupling pathway.
To increase the reaction rate, the nature of the basic
2 3
activator was surveyed. TBAF, TMSOK, and Rb CO were
competent activators for the reaction but were not selective
for the cross-coupling product. Next, a survey of reaction
solvents revealed that toluene (entry 1, Table 1) provided a
time conversion product ratio
entry
ligandb
(h)
(%)c
(2a /3a )d
1
2
3
4
5
6
7
8
9
Ph3P
12
24
24
12
3
12
3
3
100
67e
68e
99
99
100
99
99
99
99
68.3/31.7
84.4/15.6
54.4/45.6
63.0/37.0
79.3/20.7
91.6/8.4
11.9/88.1
73.1/26.9
85.9/14.1
73.0/27.0
(o-tol)3P
(C6F5)3P
(t-Bu)3P
(furyl)3P
AsPh3
2-biphenyl-(t-Bu)2P
DPPPf,g
DPPBf,h
DPPFf,i
3
12
Table 1. Solvent Optimization of the Cross-Coupling of 1 with
Ethyl 4-Iodobenzoatea
10
a
All reactions employed 1.2 equiv of silanol. b 20 mol % ligand.
Conversion based on the loss of iodide determined by GC analysis.
c
d
f
e
Determined by GC analysis. Mass balance is unreacted starting material.
1
0 mol % ligand. g 1,3-Bis(diphenylphosphinopropane). h 1,4-Bis(diphenyl-
i
phosphinobutane). 1,1′-Bis(diphenylphosphinoferrocene).
ligand/palladium) along with 1, ethyl 4-iodobenzoate, 5 mol
%
2 2 3
[allylPdCl] , and 2 equiv of Cs CO (entry 1) did increase
conversion
product ratio
(%)b
(2a /3a )c
the rate of iodide consumption. However, the 2a/3a selectiv-
ity was significantly diminished compared to the additive-
free reaction (Table 1, entry 1) suggesting that the additive
did not effect the cross-coupling reaction but did enhance
the homocoupling pathway. The addition of substituted
triarylphosphines (entries 2 and 3) showed an attenuation of
entry
solvent
1
2
3
4
toluene
dioxane
DME
78
88
98
91.3/8.7
81.1/18.9
60.0/40.0
16.9/83.1
DMF
100
a
b
Reaction employed 1.2 equiv of silanol. Conversion based on the loss
9
c
the overall reaction rate. Tri-tert-butylphosphine (entry 4)
of iodide determined by GC analysis. Determined by GC analysis.
1
5
and tri-2-furylphosphine (entry 5), which are known to
moderate reaction rate and high selectivity for the cross-
coupling product (2a) over the homocoupling product (3a).
The use of ether-based solvents, dioxane (entry 2) and
dimethoxyethane (DME) (entry 3), led to an increase in the
conversion of the iodide to products but was less selective
for the cross-coupling process. Other solvents provided
(12) (a) Hirabayashi, K.; Mori, A.; Kawashima, J.; Suguro, M.; Nishihara,
Y.; Hiyama, T. J. Org. Chem. 2000, 65, 5342. (b) Hirabayashi, K.;
Kawashima, J.; Nishihara, Y.; Mori, A.; Hiyama, T. Org. Lett. 1999, 1,
299. For coupling of alkynylsilanols, see: (c) Chang, S.; Yang, S. H.; Lee,
P. H. Tetrahedron Lett. 2001, 42, 4833.
(13) For recent examples of palladium-catalyzed coupling reactions with
Cs2CO3, see: (a) Hennings, D. D.; Iwama, T.; Rawal, V. H. Org. Lett.
1999, 1, 1205. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999,
38, 2411. (c) Haddach, M.; McCarthy, J. R. Tetrahedron Lett. 1999, 40,
3109.
(
11) (a) Lickiss, P. D. AdV. Inorg. Chem. 1995, 42, 147. (b) Hirabayashi,
K. Takahisa, E.; Nishihara, Y.; Mori, A.; Hiyama, T. Bull. Chem. Soc. Jpn.
998, 71, 2409.
(14) Ikegashira, K.; Nishihara, Y.; Hirabayashi, K.; Mori, A.; Hiyama,
T. Chem. Commun. 1997, 1039.
(15) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
1
1358
Org. Lett., Vol. 5, No. 8, 2003

accelerate the cross-coupling of arylsilacyclobutanes and
organostannanes, gave essentially full conversion of the aryl
iodide in 12 and 3 h respectively, but unfortunately these
additives also accelerated the rate of the homocoupling to
provide a less favorable product distribution. Triphenylarsine
Table 3. Effects of Hydration on the Cross-Coupling of 1 with
Ethyl 4-Iodobenzoatea
(
entry 6), which has also been shown to provide rate
1
5
acceleration in the cross-coupling of organostannanes,
provided full conversion of the aryl iodide in 12 h while
also suppressing the homocoupling pathway, thus affording
a better product distribution than the additive-free reaction.
The use of 2-(di-tert-butylphosphino)biphenyl16 (entry 7)
surprisingly provided a switch in the reaction selectivity,
favoring the formation of 3a over 2a. The bidentate additives
conversion
(%)c
product ratio
(2a /3a )d
entry
nb
1
2
3
4
5
6
0
1
2
3
4
5
50
73
87
88
87
80
100/0
(entries 7-9) gave enhanced reactivity for conversion of the
94.0/6.0
94.0/6.0
94.4/5.6
93.6/6.4
91.8/8.2
aryl iodide but did not afford any improvement in the product
distribution of the reaction. Thus, the additives did provide
an increase in the reaction rate (entries 1, 4, 5, and 7-9)
but did not improve the selectivity of the reaction. Only
triphenylarsine (entry 6) was found to enhance both the rate
and selectiVity of the reaction.
a
Reactions employed 1.2 equiv of silanol. b Equiv of H2O relative to
Cs2CO3. Conversion based on loss of iodide determined by GC analysis.
c
d
Determined by GC analysis.
With the optimized reaction conditions in hand, the scope
and generality of the reaction was investigated. However,
during the course of this survey, a reaction rate dependence
on the source of Cs CO was discovered. Bottles of Cs CO
2 3 2 3
from different suppliers and of different vintages gave
different results! We suspected that varying levels of
Now with a reproducible procedure, the scope of the
reaction could be investigated with 1 and a series of
4-substituted aryl iodides (Table 4). In all cases, the reaction
showed high compatibility as well as acceptable yield for
all of the coupling products. 4-Substituted aryl iodides
containing electron-withdrawing substituents (entries 1, 3,
and 5-7) exhibited reactivity similar to that of iodobenzene
(entry 4) and those with electron-donating substituents (entry
2). All substrates showed good levels of selectivity for the
cross-coupling product.
hydration was the origin of the problem. Analysis of Cs
2 3
CO
samples from commercial sources revealed that each con-
17
tained different amounts of H
of Cs CO employed in the foregoing optimization studies
3
contained the most water (ca. 1.9 equiv of H O per Cs CO )
2
O. Interestingly, the sample
2
3
2
2
and was found to be the most active in the cross-coupling
reaction.
2 3
Clearly, “anhydrous” Cs CO is not the ideal activator for
Table 4. Cross-Coupling of 1 with 4-Substituted Aryl Iodidesa
this process, nor are commercial samples uniform in their
level of hydration. Thus, to determine the optimal hydration
level, anhydrous cesium carbonate (purchased from Aldrich
18
Chemical Co. ) was suspended in toluene and varying
amounts of H O were added to form the hydrated species in
2
situ. The cross-coupling reaction of 1 with ethyl 4-iodo-
benzoate under otherwise optimized reaction conditions was
carried out, and the results are collected in Table 3. With
time
(h)
yield
(%)b
product ratio
2 3
the anhydrous sample of Cs CO (Table 3, entry 1), the rate
entry
R
product
(2/3)c
of consumption of ethyl 4-iodobenzoate was significantly
attenuated compared to reactions that employed the hydrated
salt (Table 3, entries 2-6). The optimal hydration level was
1
2
3
4
5
6
7
CO C H
2
2
5
8
6
3
8
6
3
6
2a
2b
2c
2d
2e
2f
87
90
91
91
85
87
88
95.7/4.3
94.2/5.8
100/0
93.7/6.3
93.3/6.7
95.4/4.6
94.0/6.0
CH3
COCH3
H
2 2 3
found to be 2-4 equiv of H O per Cs CO ; addition of more
than 3 equiv of H
2
O had a slight adverse effect on the
CN
reaction rate.1
9,20
CF3
NO2
2g
(
16) (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38,
413. (b) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550.
17) Hydration level determined by thermal gravimetric analysis (TGA)
in the University of Illinois Microanalytical Service Laboratory.
18) TGA analysis of this sample showed 0.2 equiv of H2O per
Cs2CO3.
a
Reactions employed 1.2 equiv of silanol. b Yield of chromatographed,
2
recrystallized products. c Determined by GC analysis.
(
(
The reaction of aryl bromides with 1 under the conditions
determined for 4-substituted aryl iodides was found to be
problematic, giving little or no desired product in most cases.
Fortunately, replacement of the triphenylarsine with the
(
19) For a recent review on the accelerating effect of water in organic
transformations, see: Ribe, S.; Wipf, P. Chem. Commun. 2001, 299.
(
effected by the hydration level of the cesium carbonate.
20) It is interesting to note that the selectivity of the reaction is not
Org. Lett., Vol. 5, No. 8, 2003
1359

21
bidentate additive (DPPB) led to satisfactory rates of cross-
coupling for these substrates (Table 5). In general, the
reactions were slower than those with the aryl iodides (entries
Table 6. Cross-Coupling of 1 with 2-Substituted Aryl Iodidesa
1-3), but no homocoupling product was observed in any of
the cases.
Table 5. Cross-Coupling of 1 with 4-Substituted Aryl
Bromidesa
entry
R
product
yield (%)
1
2
3
4
5
6
CH3
CF3
OCH3
NO2
CO2CH3
1-naphthyl
4a
4b
4c
4d
4e
4f
85c
82b,d
84b,d
83c
88c
86c
a
Reactions employed 1.2 equiv of silanol. b Yield of chromatographed,
time
(h)
yield
(%)b
product ratio
c
recrystallized products. Yield of chromatographed, distilled products.
Yield of analytically pure material.
entry
R
product
(2/3)c
d
1
2
3
4
5
CO2C2H5
CH3
H
OCH3
c-hexyl
24
18
12
18
18
2a
2b
2d
2h
2i
90
90
85
92
79e
100/0
100/0
100/0
d
and electron-donating substituents (entries 1, 3 and 6)
exhibited similar reactivity and yield.
In summary, Cs CO was found to be an efficient activator
2 3
f
for the formation of unsymmetrical biaryls in the palladium-
catalyzed cross-coupling reaction of arylsilanols. The im-
portance of water in ensuring reasonable reaction rates has
been demonstrated. The reaction solvent and added ligands
have also been identified as crucial experimental variables
that effect the rate and the selectivity of the coupling process.
The success of the reaction with various aryl iodides and
aryl bromides was dependent on manipulation of these key
features to provide optimal results. This study provides the
guidelines for a logical adjustment of reaction parameters
to provide efficient, high rates, yields, and selectivities for a
wide range of substrates. The expansion of the scope of
silanol coupling partners is currently under investigation.
a
b
Reactions employed 1.2 equiv of silanol. Yield of chromatographed,
c
d
recrystallized products. Determined by GC analysis. Not applicable.
Yield of analytically pure material. Not determined
e
f
The final class of electrophilic substrates, 2-substituted aryl
iodides, also coupled slowly with 1 under the conditions
previously developed for 4-substituted aryl iodides. Changing
the reaction solvent to dioxane did facilitate the cross-
coupling and had no detrimental effect on the selectivity of
the reaction. Reinvestigation of the effect of hydration in
2 3
dioxane identified the (in-situ-formed) dihydrate of Cs CO
as the optimal activator for this system. Even under these
optimized conditions, the reaction rates were still attenuated
compared to those obtained with 4-substituted aryl iodides
in the cross-coupling of 1 (Table 6). Nevertheless, the yields
of coupling products from a variety of 2-substituted aryl
iodides were still high and no homocoupling products were
observed in any of the cases.22 2-Substituted aryl iodides
containing both electron-withdrawing (entries 2, 4, and 5)
Acknowledgment. We are grateful to the National
Institutes of Health for generous financial support (R01 GM
GM63167-01A1). M.H.O. acknowledges the University of
Illinois for a Graduate Fellowship.
Supporting Information Available: Detailed procedures
for all coupling reactions and full characterization of 2a-i
and 4a-f. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
21) Other bidentate ligands (DPPE, DPPP, and DPPF) also facilitated
the cross-coupling of 1 with arylbromides.
22) Determined by GC analysis of the crude reaction mixture.
(
OL034328J
1360
Org. Lett., Vol. 5, No. 8, 2003