Sequential cross-coupling of 1,4-bissilylbutadienes: Synthesis of unsymmetrical 1,4-disubstituted 1,3-butadienes

Article abstract of DOI:10.1021/ja0518373

A mild and general and stereospecific cross-coupling reaction of unsymmetrical 1,4-bissilyl-1,3-butadienes has been accomplished. By the use of either a benzyldimethylsilyl or 2-thienyldimethylsilyl unit at one end of the dienylsilanol, a selective cross-

Full text of DOI:10.1021/ja0518373

Published on Web 05/14/2005
Sequential Cross-Coupling of 1,4-Bissilylbutadienes: Synthesis of
Unsymmetrical 1,4-Disubstituted 1,3-Butadienes
Scott E. Denmark* and Steven A. Tymonko
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
Received March 22, 2005; E-mail: denmark@scs.uiuc.edu
Table 1. TMSOK-Promoted Cross-Coupling of 1 with Aryl Iodidesa
Highly conjugated systems, such as polyenes and aryl polyenes,
are a common structural motif in natural products1 and are also
featured prominently in nonlinear optical materials.2 Traditionally,
the synthesis of polyenes relies heavily on stepwise construction
of carbon-carbon double bonds independently.3 However, this
approach is tedious and often suffers from poor stereocontrol in
setting the alkene geometry. More recently, cross-coupling methods
have been employed for the synthesis of a number of polyene
natural products in which the key carbon-carbon bond forming
step creates the C-C single bond.4 Highly conjugated systems can
be rapidly accessed through double coupling of symmetrical
bisstannanes5 and bisboranes6 to form symmetrical products.
Unsymmetrical products can be prepared through stepwise cross-
coupling of 1,2-bis(tributylstannyl)ethylene7 or reagents bearing two
different metals.8
entry
R1
product
time (h)
yield (%)b
1
2
3
4
5
6
7
4-Me
4-CN
4-OMe
4-COMe
4-NO2
c
2a
2b
2c
2d
2e
2f
1
0.5
1
18
0.5
4
85
93
88
76
96
91
96
2-Me
2g
6
Recent reports from these laboratories9 have demonstrated that
many structurally diverse organosilanols are viable precursors in
cross-coupling reactions and that these silanols can couple by two
mechanistically distinct processes.10 One pathway is operative under
basic conditions and requires only that the silanolate be formed,
no additional activation is needed. The second pathway involves
the use of fluoride sources that can form the active fluorosiliconate
in situ from the silanol or from other precursors. In addition to
heteroatom functionalized precursors, a number of phantom or
“safety catch” silanes have been developed recently that bear a
fluoride cleavable carbon-based residue such as silacylcobutyl,9f
phenyldimethyl-,11 2-pyridyldimethyl-,12 benzyldimethyl-,13 and
2-thienyldimethylsilanes.14
a All reactions employed 1.0 equiv of halide. b Yields of analytically pure
material. c 1-Iodonaphthalene was used.
2-iodotoluene (entries 6, 7) required respectively 4 and 6 h to reach
completion. Surprisingly, 4-iodoacetophenone reacted extremely
slowly (18 h) under the reaction conditions (entry 4). This sluggish
coupling has been previously observed9d and could be attributed
to the presence of moderately acidic protons on the aryl iodide.
The successful and selective cross-coupling of the silanol moiety
in 1 allowed for the fluoride-based activation of the benzyldi-
methylsilyl unit for the second cross-coupling event. In the presence
of TBAF (2.0 equiv), the benzylsilane reacted cleanly with a wide
range of aryl iodides in excellent yield (Table 2). The reaction
The availability of these masked silanols presents the intriguing
possibility of devising a bissilyl reagent bearing one silyl substituent
which readily couples under basic activation while the other silyl
substituent is inert. Subsequent fluoride-promoted coupling of the
second silyl substituent would allow for sequential coupling in
unsymmetrical substrates with an otherwise symmetrical backbone.
In this manner, the different mechanistic pathways of base- and
fluoride-activated cross-coupling can be used to distinguish between
silicon substituents. We describe herein the preparation and sequen-
tial cross-coupling of two such differentiable 1,4-bissilylbutadienes.
The viability of this approach was first tested with the bissilyl
reagent (E,E)-[(4-benzyldimethylsilyl)-1,3-butadienyl]dimethylsi-
lanol (1).15 Under activation by KOTMS, bissilyldiene 1 displayed
reactivity comparable to that of simple vinyl silanols and reacted
uniquely at the silanol moiety, leaving the benzyldimethyl unit
intact.9d To explore the scope of the KOTMS-promoted reaction,
the coupling of 1 was performed with a variety of aryl iodides with
Pd(dba)2 as the catalyst (Table 1). The reaction was found to display
little dependence upon the electronic nature of the iodide as electron-
poor aryl iodides required 0.5 h to reach completion (entries 2 and
5) while electron-rich iodides required only 1 h (entries 1 and 3).
The introduction of ortho substituents was found to have a
significant rate-retarding effect. Thus, 1-iodonaphthylene and
Table 2. Fluoride-Promoted Cross-Coupling of 2 with Aryl
Iodidesa
entry
R1
substrate
R2
product
time (h)
yield (%)b
1
2
4-OMe
4-OMe
4-OMe
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
2c
2c
2c
2a
2a
2a
2a
2a
2a
2a
2a
2a
4-CO2Et
4-Me
3a
3b
3c
3d
3e
3b
3f
3g
3h
3i
15 min
15 min
15 min
1 h
88
86
91
85
90
91
90
74
92
72
90
89
3
4-OMe
4-CO2Et
4-COCH3
4-OMe
3-CO2Et
2-CO2Me
c
4
5
1 h
6
1 h
7
1 h
8
1 h
9
1 h
10
11
12
d
4 h
2-Me
3j
3k
1 h
2-CH2OH
12 h
a All reactions employed 1.0 equiv of halide. b Yields of analytically pure
material. c 1-Iodonaphthalene was used. d Ethyl (E)-3-iodoacrylate was used.
9
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J. AM. CHEM. SOC. 2005, 127, 8004-8005
10.1021/ja0518373 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
displays little dependence upon the electronic and steric nature of
the aryl iodide. Electron-poor and electron-rich substrates (entries
4 and 6) as well as ortho-, meta-, and para-substituted iodides
(entries 8, 7, and 4) all reacted completely in under 1 h. Notably,
(unprotected) 2-iodobenzyl alcohol was a viable substrate for the
cross-coupling, affording an 89% yield after 12 h (entry 12). Vinyl
iodides could also be engaged in the fluoride-promoted coupling
to prepare conjugated trienes. Reaction of 2a with ethyl (E)-3-
iodoacrylate, albeit slower than that of aryl substrates, provided
triene 3i in 72% yield after 4 h (entry 10). The overall yield of the
two-step coupling process could be improved by subjecting the
crude products obtained from the KOTMS-activated coupling to
the TBAF-promoted coupling conditions. In this manner, 1,4-diaryl-
1,3-butadienes 3b and 3d were prepared in enhanced yield relative
to the two-step procedure (86 vs 77% and 84 vs 72%, respectively)
without any loss in reaction rate or selectivity.
the 2-thienyl group was dispatched without incident, and the
fluoride-promoted cross-coupling of 5 with ethyl 4-iodobenzoate
provided the 1,4-diaryl-1,3-butadiene 6a bearing two electron-
withdrawing substituents.
In conclusion, we have demonstrated the ability to differentiate
the termini of a 1,4-bissilyl-1,3-diene by taking advantage of the
mechanistic duality in silicon-based cross-coupling reactions.
Through the use of substrates bearing two distinct silyl subunits
and complementary reaction promoters KOTMS and TBAF, this
approach allows for the construction of unsymmetrical disubstituted
1,4-butadienes. Extension of this method to the preparation of
substituted butadienes, geometric isomers of the butadienes, and
tetraenes is in progress.
Acknowledgment. We are grateful to the National Institutes
of Health for generous financial support. (GM 63167).
Whereas the electronic character of the iodide coupling partner
did not influence the reaction rate, the electronic nature of the
benzylsilanes has a significant effect on the fluoride-promoted
coupling. Cross-coupling with electron-rich substrate 2c (derived
from an initial coupling with 4-iodoanisole) was significantly faster
than the corresponding reactions with silane 2a (derived from an
initial coupling with 4-iodotoluene) (entries 1 and 4). Although the
increased reactivity of 2c is consistent with a turnover limiting
transmetalation to an electrophilic arylpalladium(II) intermediate,10a
the distance over which the electronic perturbation influences the
reaction is surprising. Unfortunately, this electronic influence
extends to benzylsilanes bearing electron-withdrawing substituents,
making then poor substrates for the fluoride-promoted coupling.
Under fluoride activation, migration of the benzyl group to the
diene, as recently demonstrated by Trost,16 is competitive with
cross-coupling. Attempts to unmask the latent silanol under acidic
conditions resulted in desilylation of the diene.
To overcome the problematic benzyl migration, bissilane 4, in
which a 2-thienyl group replaces the benzyl group, was prepared.15
It was expected that the 2-thienylsilane would survive the initial
cross-coupling and provide the desired silanol upon treatment with
fluoride without migration.12 Gratifyingly, KOTMS cleanly and
efficiently promoted the cross-coupling of 4 with 4-iodoacetonitrile
to afford 5 in 83% yield (Scheme 1). Most importantly, though,
Supporting Information Available: Preparation of 1 and 4,
detailed experimental procedures, 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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