Stereospecific palladium-catalyzed cross-coupling of (E)- and (Z)-alkenylsilanolates with aryl chlorides

Article abstract of DOI:10.1021/ja065988x

The cross-coupling of geometrically defined (E)- and (Z)-alkenyl- and styrylsilanolates with a wide variety of aromatic and heteroaromatic chlorides has been achieved. Under catalysis by bulky, biphenyl-derived phosphines and allylpalladium chloride, the (preformed, stable) potassium salts of di-, tri- and tetrasubstituted alkenyldimethylsilanols undergo high yielding and highly stereospecific coupling to aryl chlorides in THF or dioxane. A variety of functional groups are compatible with these reaction conditions including nitro, ester, ketone, and nitrile. Both (E)- and (Z)-alkenylsilanolates coupled with nearly identical rate and efficiency. Copyright

Full text of DOI:10.1021/ja065988x

Published on Web 12/02/2006
Stereospecific Palladium-Catalyzed Cross-Coupling of (E)- and
(Z)-Alkenylsilanolates with Aryl Chlorides
Scott E. Denmark* and Jeffrey M. Kallemeyn
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
Received August 17, 2006; E-mail: denmark@scs.uiuc.edu
Table 1. Ligand Survey for the Cross-Coupling of (E)-1 with
2-Chloroanisole
The power and versatility of palladium-catalyzed cross-coupling
reactions of organoboranes,1a -stannanes,1b and -silanes1c is attribut-
able in large measure to the wide range of electrophilic coupling
partners that participate in the process. In recent years the ability
to engage ubiquitous and inexpensive organic chlorides has
contributed significantly to the reaction scope. Thanks to advances
in ligand design,2,3 cross-coupling reactions of aryl- and alkenyl-
stannanes,3a,4 aryl- and alkenylsilanes,5 and arylboronic acids,3c,e,6
with aryl chlorides have been reported. However, only limited
success has been obtained in the cross-coupling of alkenylboronic
acids with aryl chlorides. These substrates suffer from low reactivity
and, consequently, double bond isomerization during the cross-
coupling reaction.3e,7 Organosilanol-based cross coupling, developed
in these laboratories, has emerged as a useful method because of
the high reactivity, ease of preparation, and shelf-stability of the
silanols.8 Furthermore, the use of preformed silanolates precludes
addition of an external activator thereby increasing the functional
group tolerance and lowering the overall cost of the reaction.9
Ongoing mechanistic studies have shown that this reaction proceeds
through the intermediacy of an organoPd(II) silanolate complex,
formed by displacement of an organoPd(II) halide with an orga-
nosilanolate.10 Therefore, the extension of this cross-coupling
process to aryl chlorides not only needs to address the issue of
oxidative addition, but also the difficulties associated with displace-
ment of the strong Pd-Cl bond by the silanolate to form the
organoPd(II) silanolate.11 Herein, we describe the development of
a general, highly stereospecific, high-yielding, palladium-catalyzed
cross-coupling of (E)- and (Z)-alkenyldimethylsilanolates with a
wide variety of aryl chlorides.
entry
palladium source
ligand
conversion, %a
1
2
3
APC
Cy3P
9
0
1
(t-Bu3P)2Pd
(t-Bu3P)2Pd, APCb
4
5
6
7
8
9
10
6
6
7
4
82
8
39
60
10
APC
APC
APC
APC
APC
APC
Me(t-Bu)2P‚HBF4
4a
4b
5a
5b
5c
a Determined by GC analysis vs internal standard of tetradecane.
b (t-Bu3P)2Pd (2.5 mol %), APC (1.25 mol %).
Table 2. Counterion Effects in the Cross-Coupling of (E)-1 with
2-Chloroanisole
We began our investigation with the cross-coupling between
potassium heptenyldimethylsilanolate, (E)-1, and 2-chloroanisole,
2a, using allylpalladium chloride (APC) as the palladium source.12
A variety of ligands known to be active for cross-coupling of aryl
chlorides were screened (Table 1). Disappointingly, bulky trialkyl-
phosphines and an N-heterocyclic carbene palladium precatalyst
67b were not effective at promoting this cross-coupling reaction
(entries 1-4). However, biphenyl-based ligands, developed by
Buchwald,3e showed promise. In the presence of ligands 4a and
5b, the test reaction proceeded to 82% and 60% conversion after
1 h, respectively (entries 6 and 9). Further variation of the phosphine
substituent led to poorer results. Although the reaction using 4a
proceeded at room temperature, it stalled before the aryl chloride
was completely consumed.
Because of our concern that displacement on the organoPd(II)
chloride might be turnover limiting,10 the influence of the silanolate
counterion was studied. A marked difference was observed between
the rate of reaction of the sodium and potassium silanolates, but
only a negligible difference was observed between the potassium
and cesium silanolates (Table 2). Subsequent studies were perform-
ed with the potassium silanolate owing to the ease of preparation.
With a reliable cross-coupling method in hand, a variety of aryl
chlorides was surveyed to investigate the scope of the reaction.
a Determined by GC analysis vs internal standard of tetradecane.
The survey was performed at 60 °C with 1.3 equiv of (E)-1 and
these conditions were tolerant of aryl chlorides bearing nitrile, ester,
nitro, and ketone substituents (Table 3, entries 1-4). Furthermore,
2 and 3-chloropyridine reacted smoothly (entries 6-7). Mono- and
diortho substituted aryl chlorides reacted smoothly thus revealing
the limited influence of the increased steric bulk on the aryl chloride
(entries 9-11). In general, electron rich aryl chlorides were less
reactive as illustrated in the cross-coupling of 2-chloro and
4-chloroanisole (entries 12-13). For these unactivated substrates,
additional silanolate (1.5 equiv) and a slightly higher temperatures
(66 °C) were required for the aryl chloride to be consumed. Of
particular note is the compatibility of the TBS-protected benzyl
alcohol (entry 14), which showed that the silanolate-based cross-
coupling is compatible with synthetically useful silicon protecting
groups. In all cases the coupling was highly stereospecific, but a
more compelling test was the extension to the (Z)-alkenyl silanolates
that are more prone to isomerization. Gratifyingly, the cross-
coupling of (Z)-heptenylsilanolate, (Z)-1, also proceeded with high
9
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J. AM. CHEM. SOC. 2006, 128, 15958-15959
10.1021/ja065988x CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Cross-Coupling of (E)- and (Z)-1 with Aryl Chlorides
Table 5. Cross-Coupling of Tri- and Tetrasubstituted Silanols with
2-Chloroanisole
entry
silanol
R3
time, h
product
yield, %a
E/Zb
1
2
(E)-1
(E)-1
(E)-1
(E)-1
(E)-1
(E)-1
(E)-1
(E)-1
(E)-1
(E)-1
(E)-1
(E)-1
(E)-1
(E)-1
(Z)-1
(Z)-1
(Z)-1
(Z)-1
(Z)-1
(Z)-1
4-CN
2
(E)-3b
(E)-3c
(E)-3d
(E)-3e
(E)-3f
(E)-3g
(E)-3h
(E)-3i
(E)-3j
(E)-3k
(E)-3l
(E)-3m
(E)-3a
(E)-3n
(Z)-3d
(Z)-3h
(Z)-3i
(Z)-3l
91
87
97
98
91
87
85
93
95
95
95
89
95
92
97
91
92
87
96
98
99.2:0.8
99.2:0.8
99.6:0.4
99.5:0.5
99.7:0.3
99.6:0.4
99.8:0.2
99.4:0.6
99.6:0.4
99.8:0.2
99.7:0.3
99.6:0.4
99.5:0.5
98.8:1.2
1.2:98.8
0.7:99.3
1.4:98.6
0.2:99.8
0.5:99.5
0.4:99.6
4-NO2
0.33
0.5
0.5
1
3
4-CO2t-Bu
4-COPh
4-CF3
2-pyridyl
3-pyridyl
H
4-Me
2-Me
2,6-Me2
4-OMe
2-OMe
4-CH2OTBS
4-CO2t-Bu
3-pyridine
H
2,6-Me2
2-OMe
4-CH2OTBS
4
entry
silanol
time, h
product
yield, %a
E/Zb
5
6
3
1
2
3
4
(E)-9c
(Z)-9d
(E)-10
(Z)-11
0.5
0.5
1.0
(E)-12
(Z)-12
(E)-13
(Z)-14
97
89
98
95
98.8:1.2
1.4:98.6
>99:1
7
1.5
1.5
2
8
9
0.75
<1:99
10
11
12c
13c
14
15
16
17
18
19c
20
2
2
3.5
3
1.5
0.33
1.5
1.5
2
3
1.5
a Yield of isolated, analytically pure product. b Determined by GC
analysis. c (E)-9/(Z)-9, 98.9:1.1. d (E)-9/(Z)-9, 1.5:98.5.
In conclusion, we have demonstrated a stereospecific and high
yielding cross-coupling of di-, tri- and tetrasubstituted alkenyl-
dimethylsilanolates with aryl chlorides. This method overcomes the
limitations associated with the cross-coupling of alkenylboronic
acids with aryl chlorides and thus affords a general synthesis of
aryl-substituted alkenes.
(Z)-3a
(Z)-3n
a Yield of isolated, analytically pure product. b Determined by GC
analysis. c Used 1.5 equiv of (E)-1 or (Z)-1 at 66 °C.
Acknowledgment. We are grateful to the National Institutes
of Health for generous financial support. (Grant R01 GM63167).
J.M.K. thanks Pfizer, Inc. and Johnson and Johnson PRI for
Graduate Fellowships. This paper is dedicated to the memory of
Prof. Nelson J. Leonard.
stereospecificity, functional group compatibility, and yield to afford
the (Z)-alkenyl products (entries 15-20). The characteristics of the
reaction of (Z)-1 in terms of the rate, specificity, and yield were
nearly identical to those of (E)-1.
Because of the problems associated with the coupling of
alkenylboronic acids with chlorides, we chose to test the coupling
of (E)- and (Z)-styrylsilanolates ((E)-7 and (Z)-7) which are much
more prone to isomerization. Although the reactions proceeded in
DME or toluene at 90 °C, they stalled and reduction products were
also detected. Remarkably, switching the solvent to dioxane (at 90
°C) led to complete conversion and very clean products. Even at
90 °C, the reaction proceeded with complete retention of the double-
bond geometry. Here again, the TBS-protected benzyl alcohol was
compatible under these reaction conditions (Table 4).
Supporting Information Available: Detailed experimental pro-
cedures and full characterization of all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
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(E)-7
(E)-7
(E)-7
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(Z)-7
4-CO2t-Bu
2,6-Me2
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