All-carbon-substituted vinylsilane stable to TBAF: Synthesis of allyldimethylvinylsilane and its Pd-catalyzed cross-coupling under mild conditions

Article abstract of DOI:10.1021/ol061288l

Allyldimethylvinylsilanes 3 are easily synthesized by the reaction of silylallylmetals, generated from 1 by n-BuLi/t-BuOK, with carbonyl compounds in the absence or presence of metal halides. They can tolerate 2 equiv of TBAF in THF at room temperature fo

Full text of DOI:10.1021/ol061288l

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3733-3736
All-Carbon-Substituted Vinylsilane
Stable to TBAF: Synthesis of
Allyldimethylvinylsilane and Its
Pd-Catalyzed Cross-Coupling under Mild
Conditions
Lianhai Li* and Neenah Navasero
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research,
P.O. Box 1005, Pointe-Claire-DorVal, Quebec, Canada H9R 4P8
lianhai_li@merck.com
Received May 26, 2006
ABSTRACT
Allyldimethylvinylsilanes 3 are easily synthesized by the reaction of silylallylmetals, generated from 1 by n-BuLi/t-BuOK, with carbonyl compounds
in the absence or presence of metal halides. They can tolerate 2 equiv of TBAF in THF at room temperature for at least 6 h but can be easily
activated in the presence of a palladium catalyst and TBAF to perform the cross-coupling reaction with aryl iodides at room temperature.
The Pd-catalyzed cross-coupling of vinylmetals1 with aryl
or vinyl halides/triflates is of great interest to synthetic
chemists. However, in practice, the application of most
vinylmetals as cross-coupling partners in complex synthesis
is limited by the reactivity of the carbon-metal bond. Often,
the vinylmetals are prepared in situ and used right away. In
contrast, the silicon-carbon bond of silafunctional vinylsi-
lane, which was recently demonstrated to undergo Pd-
catalyzed cross-coupling under very mild conditions,2 is
highly stable. This makes it possible to carry the vinylsilane
functionality through several steps in complex syntheses,
making synthetic design more flexible. Optimally, the other
substituents on the silicon atom of the vinylsilane should
also be stable. Unfortunately, it has been found that at least
one labile substituent is essential to carry out the coupling
reaction under mild conditions.2 One strategy that has proven
effective in overcoming this issue is to develop a vinylsilane
with an all-carbon-substituted silyl group, in which at least
one carbon substituent could be easily activated to meet the
requirement for a mild cross-coupling.3 Several carbon
substituents on the silicon of a vinylsilane, including
2-thiophenyl,3a 2-pyridyl,3b benzyl,3c and 1,3-propanediyl3d
have been developed for this purpose.
We previously reported a convenient three-component
synthesis of homoallylic alcohols (4) as shown in Scheme
1.4 We intended to incorporate the sequence into a compli-
cated multistep synthesis that requires the vinylsilane func-
(1) For a review, see: Diederich, F., Stang, P. J., Eds. Metal-Catalyzed,
Cross-coupling Reactions; Wiley-VCH: Weinheim, 1998.
(2) For reviews, see: (a) Denmark, S. E.; Sweis, R. F. Chem. Pharm.
Bull. 2002, 50, 1531. (b) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res.
2002, 35, 835. (c) Denmark, S. E.; Ober, M. E. Aldrichimica Acta 2003,
36, 75.
(3) (a) Hosoi, K.; Nozaki, K.; Hiyama, T. Chem. Lett. 2002, 138. (b)
Itami, K.; Nokami, T.; Yoshida, J.-I. J. Am. Chem. Soc. 2001, 123, 5600.
(c) Trost, B. M.; Machacek, M. R.; Ball, Z. T. Org. Lett. 2003, 5, 1895. (d)
Denmark, S. E.; Choi, J. Y. J. Am. Chem. Soc. 1999, 121, 5821.
(4) Li, L.; Navasero, N. Org. Lett. 2004, 6, 3091.
10.1021/ol061288l CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/21/2006

Scheme 1
Table 1. Generation of an Allyl Anion and Addition to
Carbonyls
tional to be carried through several synthetic operations.
However, this was confounded by the unstable Si-O bond
in 6, which readily hydrolyzed on silica gel. We now describe
our efforts to identify a stable all-carbon replacement for
the isopropoxy group we used previously.
We evaluated some simple and low molecular weight
groups and found that an allyl group might serve our
purpose.5 First of all, an allyl group would be compatible
with our method in synthesizing the vinylsilane from a
silylallyl anion, which can be generated from the simple
diallyldimethylsilane as an equivalent to the allyldimethyl-
(2-propoxy)silane (Scheme 2). Furthermore, the widely
carbonyl
compd
product
(yield %)
entry
conditionsa
diallylsilane
1
2
3
4
5
6
7
8
9
A
B
C
C
C
D
D
C
E
C
F
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
2a
2a
2a
2b
2c
2b
2c
2d
2d
2d
2a
3a (49)
3a (45)
3a (67)
3b (5)
3c (30)
3b (54)
3c (52)
3d (34)b
3d (58)
3e (33)
3e (63)
10
11
a A: s-BuLi (0.9 equiv)/TMEDA (0.9 equiv)/-78 °C/THF/1 h. B:
n-BuLi (1.1 equiv)/t-BuOK (1.1 equiv)/-78 °C/THF/1 h. C: n-BuLi (0.9
equiv)/t-BuOK (0.9 equiv)/-78 °C/THF/1 h. D: Conditions C/ZnCl2/1
h/room temperature. E: Conditions C/CuCN/1 h/-78 °C. F: n-BuLi (0.9
equiv)/t-BuOK (0.9 equiv)/-78 °C to room temperature/Et2O/1 h b About
an equal molar amount of the R-adduct obtained.
Scheme 2
documented synthetic application as well as reactivity of
allylsilane can provide the necessary information to facilitate
the design in a complex synthesis.
being observed (entry 3, Table 1). However, when acetone
or cyclohexanone was employed as a representative aliphatic
ketone, the yield decreased to 5% and 30%, respectively
(entries 4 and 5, Table 1). We thought that this was due to
the presence of t-BuOK, a strong base which might cause
the enolization of the carbonyl compounds employed. To
avoid it, ZnCl2 was added to modify the reactivity of the
generated anion complex. By this modification,8 vinylsilanes
3b and 3c were obtained in 54% and 52% yields, respectively
(entries 6 and 7, Table 1). It is worth noting that in all cases
only the trans-substituted γ-adduct was observed. The direct
addition of the silylallyl anion generated by Schlosser’s base
to 3-phenylpropanal produced the desired product in 29%
yield (entry 8, Table 1). In this case, the low yield was caused
by the generation of an equal amount of R-adduct. The
modification by ZnCl2 and some other metal halides such
We first attempted to generate the silylallyl anion from
1a with a s-BuLi/TMEDA complex6 in THF. The addition
of the resulting anion to PhCHO only afforded 3a in 49%
yield (entry 1, Table 1). We then turned our attention to
Schlosser’s base7 and found that when a stirred solution of
1a with 1.1 equiv of t-BuOK in THF was treated with 1.1
equiv of n-BuLi at -78 °C for 1 h and then reacted with
benzaldehyde the desired product 3a was obtained in 45%
yield along with the formation of 10% of the divinylsilane,
which resulted from the addition of both metalated allyl
groups to benzaldehyde (entry 2, Table 1). To avoid this
byproduct, we decided to use 0.9 equiv of t-BuOK and 0.9
equiv of n-BuLi to perform the reaction; this improved the
reaction yield to 67% with no formation of the byproduct
(5) For a previous application of the allyldimethylsilyl group as a latent
stable silafunctional group that enables the Tamao oxidation, see: Tamao,
K.; Ishida, N. Tetrahedron Lett. 1984, 25, 4249.
(6) Tamao, K.; Nakajo, E.; Ito, Y. Synth. Commun. 1987, 17, 1637.
(7) Schlosser, M.; Franzini, L. Synthesis 1998, 707.
(8) For a previous application of ZnCl2 in modifying the reactivity of
silylallylmetal, see: Ehlinger, E.; Magnus, P. J. Am. Chem. Soc. 1980, 102,
5004.
3734
Org. Lett., Vol. 8, No. 17, 2006

as CeCl3 resulted in no change to the reaction results.
Fortunately, we found that the problem could be solved by
the use of CuCN;9 the desired product was obtained in 58%
yield without the detection of an R-adduct (entry 9, Table
1). The addition of the anion generated from diallylsilane
1b by using Schlosser’s base in THF at -78 °C to
benzaldehyde was found to afford the desired vinylsilane in
33% yield (entry 10, Table 1), but the yield was improved
to 63% when the anion was generated in ether (entry 11,
Table 1).
conditions the desired coupling product 4a was obtained in
74% yield (entry 1, Table 3). The yield was relatively lower
Table 3. Optimization of Cross-Coupling
entry
1
conditions
yield % 4a
We then used 3a to investigate the activation of the allyl
group by TBAF in THF and found that when 3a was treated
with 2 equiv of TBAF in THF for 6 h at room temperature
95% of 3a was recovered (entry 1, Table 2). The presence
PhI/TBAF (2 equiv)/EtOH (6 equiv)
Pd2(dba)3 (5%)/THF/rt/4 h
1. TBAF (2 equiv)/EtOH (6 equiv)
Pd2(dba)3 (5%)/THF/rt/0.5 h
2. PhI/4 h
74
2
91
Table 2. Allyl Group Activation
than the coupling of the 2-propoxy-substituted vinylsilane
in a previous study.4 We suspected the lower yield in this
case was caused by the coupling of the allyl group with
iodobenzene. We found that the yield was improved to 91%
by running the activation for 30 min as described above
(entry 3, Table 2) and then adding iodobenzene to accomplish
the cross-coupling.
Being satisfied with the results obtained in entry 2 of Table
3, we moved on to test the variation of aryl iodide in this
Pd-catalyzed cross-coupling by using 3a and 3e as repre-
sentative vinylsilanes under these conditions. When para-
substituted aryl iodides were employed, the coupling reaction
consistently afforded the coupling product in good yields
(70-91%, entries 1-4 and 6-9, Table 4). The reaction was
entry
1
conditions
time (h)
6
results
TBAF (2 equiv)/THF/rt
95% 3a
recovereda
96% 3a
2
3
4
TBAF (2 equiv)/THF/rt
EtOH (6 equiv)
TBAF (2 equiv)/EtOH (6 equiv)
Pd2(dba)3 (5%)/THF/rt
EtOH (6 equiv)
6
recovereda
100% 3a
consumedb
98% 3a
0.5
6
Pd2(dba)3 (5%)/THF/rt
recovereda
a Isolated by flash chromatography. b TLC and crude H NMR.
1
Table 4. Variation of ArI in the Pd-Catalyzed Cross-Coupling
of 6 equiv of ethanol in the above reaction resulted in no
change of the reaction result; 96% of 3a could be recovered
after 6 h of reaction (entry 2, Table 2). However, when 2
equiv of TBAF, 6 equiv of EtOH, and 5% of Pd2(dba)3 were
employed together, TLC showed that 3a was consumed in
isolated
yield (%)
1
entry
ArIa
vinylsilane
product (Ar, R)
Ph
4-EtO2CC6H4, H
4-AcC6H4, H
4-MeOC6H4, H
2-MeOC6H4, H
Ph, Me
less than 30 min. After workup, H NMR characterization
of the crude product indicated that the distinctive signals
associated with the allyl group had completely disappeared
whereas those of the vinyl functionality were intact (entry
3, Table 2). As a comparison, we only recovered the starting
3a from the reaction run with Pd2(dba)3 and 6 equiv of EtOH
(entry 4, Table 2). These results suggest that the TBAF and
the Pd catalyst worked together to activate the allyl group.
A plausible explanation for this is that the interactions of
the Pd species with the double bonds (either with allyl or
with the vinyl or even with both) enhance the affinity of the
fluoride anion with silicon, thus accelerating the reaction.
Having demonstrated that the allyl group could serve as a
preactivation group under the coupling conditions, we
proceeded to test the Pd-catalyzed cross-coupling of 3a with
iodobenzene. We first performed the coupling reaction
without preactivation of the allyl group, under which
1
2
3
4
5
6
7
8
9
PhI
3a
3a
3a
3a
3a
3e
3e
3e
3e
3e
4a (91)
4b (85)
4c (84)
4d (78)
4e (63)
4f (74)
4-EtO2CC6H4I
4-AcC6H4I
4-MeOC6H4I
2-MeOC6H4Ib
PhI
4-EtO2CC6H4I
4-AcC6H4I
4-MeOC6H4I
2-MeOC6H4Ib
4-EtO2CC6H4, Me 4g (82)
4-AcC6H4, Me
4-MeOC6H4, Me
2-MeOC6H4, Me
4h (83)
4i (70)
4j (11)
10
a Catalyst: Pd2(dba)3/4 h. b Catalyst: (allylPdCl)2/24 h.
compatible with functional groups such as ketone and ester.
When 2-iodoanisole was employed and the coupling was
done by using (allylPdCl)2 as the catalyst, we found that 3a
acted as an efficient coupling partner (entry 5, Table 4), but
3e did not (entry 10, Table 4). The difference might be due
to the increased steric hindrance from the methyl group in
3e.
(9) For a previous application of CuCN in modifying the reactivity of
silylallylmetal, see: Corriu, R. J. P.; Guerin, C.; M’Boula, J. Tetrahedron
Lett. 1981, 22, 2985.
Org. Lett., Vol. 8, No. 17, 2006
3735

We then chose three aryl iodides, which were iodobenzene,
4-iodo-acetophenone, and 2-iodoanisole to test the coupling
reaction with vinylsilanes 3b-d. We found that the coupling
of these vinylsilanes with iodobenzene or 4-iodo-acetophe-
none proceeded smoothly to afford the coupling products in
high yields (83-97%, entries 1, 2, 4, 5, 7, and 8, Table 5).
However, their coupling with 2-iodoanisole in the presence
of (allylPdCl)2 as the catalyst was less efficient with the
coupled products obtained in moderate yields (63-65%,
entries 3, 6, and 9, Table 5).
To conclude, we have found that silylallylmetals can be
generated upon treatment of diallyldimethylsilanes 1 with
n-BuLi/t-BuOK. These silylallylmetals react readily with
benzaldehyde to generate the desired vinylsilanes 3. They
also react smoothly with other carbonyl compounds to form
3 by using metal halides to modify their reactivity. Vinyl-
silanes 3 can tolerate 2 equiv of TBAF in THF at room
temperature for at least 6 h but can be easily activated if a
palladium catalyst and TBAF are both present. Being
activated, they can perform the cross-coupling reaction with
aryl iodides to give substituted homoallylic alcohols at room
temperature. Such reactivity makes this type of vinylsilanes
a unique member in the all-carbon-substituted vinylsilane
family.
Table 5. Variation of ArI and Silane in the Pd-Catalyzed
Cross-Coupling
vinyl-
silane
product 4
Ar; R1, R2
isolated
yield (%)
entry
ArIa
1
2
3
4
5
6
7
8
9
PhI
4-AcC6H4I
2-MeOC6H4Ib 3b 2-MeOC6H4; Me, Me
3b Ph; Me, Me
3b 4-AcC6H4; Me, Me
4k (85)
4l (87)
4m (65)
4n (83)
4o (83)
4p (60)
4q (97)
4r (85)
Acknowledgment. We would like to extend our great
thanks to Dr. Zhaoyin Wang for proofreading the manuscript.
PhI
3c Ph; -(CH2)5-
4-AcC6H4I
2-MeOC6H4Ib
PhI
3c 4-AcC6H4; -(CH2)5-
3c 2-MeOC6H4; -(CH2)5-
3d Ph; Ph(CH2)2, H
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
4-AcC6H4I
3d 4-AcC6H4; Ph(CH2)2, H
2-MeOC6H4Ib 3d 2-MeOC6H4; Ph(CH2)2, H 4s (63)
a Catalyst: Pd2(dba)3/4 h. b Catalyst: (allylPdCl)2/24 h.
OL061288L
3736
Org. Lett., Vol. 8, No. 17, 2006