Bissilyl enal: A useful linchpin for synthesis of functionalized vinylsilane species by anion relay chemistry

Article abstract of DOI:10.1021/ol202942a

Bissilyl enal, prepared by a Mannich reaction of 3,3-bissilyl aldehyde with formaldehyde, has proven to be a useful linchpin in an efficient three-component coupling process. The reaction features a [1,4]-Brook rearrangement to generate the silylallyl ani

Full text of DOI:10.1021/ol202942a

ORGANIC
LETTERS
2012
Vol. 14, No. 1
158–161
Bissilyl Enal: A Useful Linchpin for
Synthesis of Functionalized Vinylsilane
Species by Anion Relay Chemistry
Lu Gao,† Xinglong Lin,† Jian Lei,† Zhenlei Song,*,†,‡,§ and Zhi Lin†
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal
Chemistry, West China School of Pharmacy, State Key Laboratory of Biotherapy,
West China Hospital, Sichuan University, Chengdu 610041, P. R. China, and State Key
Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
zhenleisong@scu.edu.cn
Received November 1, 2011
ABSTRACT
Bissilyl enal, prepared by a Mannich reaction of 3,3-bissilyl aldehyde with formaldehyde, has proven to be a useful linchpin in an efficient three-
component coupling process. The reaction features a [1,4]-Brook rearrangement to generate the silylallyl anion, which adopts a predominant
endo-orientation and can undergo addition to electrophiles in a regio- and stereoselective manner, giving various E-vinylsilane species in good
yields.
The multicomponent reaction1 is a powerful synthetic
strategy for the rapid and efficient construction of complex
molecules in a single operation. In the past decade, Smith
III et al. have developed a series of fascinating multi-
component coupling protocols by anion relay chemistry
(ARC) involving negative charge migration in a “through-
space” fashion.2 In these reactions, the key step is a Brook
rearrangement3 of organosilane species as a bifunctional
linchpin to generate a new carbanion, which allows subse-
quent addition to a wide range of electrophiles. Generally,
the newly formed carbanions either involve aryl,4,2d,2g,2h
† Key Laboratory of Drug-Targeting of Education Ministry and Depart-
ment of Medicinal Chemistry, West China School of Pharmacy, Sichuan
University.
(3) For reviews, see: (a) Brook, A. G. Acc. Chem. Res. 1974, 7, 77. (b)
Moser, W. H. Tetrahedron 2001, 57, 2065. For the latest advances, see:
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Wuest, W. M. Angew. Chem., Int. Ed. 2008, 47, 7082. (e) Akai, S.; Ikawa,
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Takeda, T. Org. Lett. 2001, 3, 3811. (b) Taguchi, H.; Takami, K.;
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‡ State Key Laboratory of Biotherapy, West China Hospital, Sichuan
University.
§ Lanzhou University.
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Ugi, I. I. Angew. Chem., Int. Ed. 2000, 39, 3168. (c) Domling, A. In
Multicomponent Reactions; Zhu, J., Eds.; Wiley-VCH: Weinheim, Ger-
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2008, 5883. For the latest advances in this group, see:(c) Smith, A. B.,
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Org. Lett. 2011, 13, 3328.
r
10.1021/ol202942a
Published on Web 11/30/2011
2011 American Chemical Society

lithium alkoxide 3 provides a new route to the silylallyl
anion 4.13 Subsequent capture by electrophiles could then
lead to potentially interesting regio- and stereoselective
issues. First, the reaction could undergo either R-addition
to give allylsilane 6 or γ-addition to give vinylsilane 5.
Second, in the case of γ-addition, the double bond could
assume either the Z- or E-configuration. Here we report
detailed studies of this reaction.
Scheme 1. Anion Relay Chemistry of Bissilyl Enals
The necessaryenals were quicklypreparedbya Mannich
reaction of 3,3-bissilyl aldehydes 1 with formaldehyde.14
A
combination of pyrrolidine and C2H5CO2H appeared to
be the most effective catalyst togivea range of bissilyl enals
2 in good yields (Scheme 2). It is noteworthy that these
reactions can be reproducibly performed on a scale greater
than 10 g. Moreover, all of the bissilyl enals produced
could be purified simply by silica gel chromatography and
stored in the refrigerator for several weeks while maintain-
ing good quality.
vinyl,5,2e and allyl anions6 or are stabilized by dithiane,7
nitrile,6,8phenyl,2f and dihalide9 groups. Although the sta-
bilization of R-carbanions by silicon through the pꢀd
π-bonding interaction is well-known,10 little attention has
been paid to the silyl group as a stabilizing element in such
ARC reactions.11
Table 1. Screening of Reaction Conditions
Scheme 2. Preparation of Bissilyl Enals
a Reaction conditions: 3,3-bissilyl aldehyde (1.0 equiv), aqueous
HCHO (1.0 equiv), pyrrolidine (0.1 equiv), C2H5CO2H (0.1 equiv) in
i-PrOH at 45 °C. bIsolated yields after purification by silica gel column
chromatography.
Recently, we reported a facile retro-[1,4]-Brook rearran-
gementof3-silyl allyloxysilanestogeneratea variety of 3,3-
bissilyl carbonyl compounds efficiently.12 These new syn-
thons afford the opportunity to test the feasibility of ARC
using the corresponding bissilyl enal 2 as a linchpin. In the
proposed process (Scheme 1), [1,4]-Brook rearrangement of
a Reaction conditions: bissilyl enal (1.0 equiv), n-BuLi (1.1 equiv) in
THF at ꢀ78 °C; then TMEDA (1.1 equiv), warm to ꢀ15 °C; then benzyl
bromide (3.0 equiv) and HMPA (4.0 equiv); crude products were treated
with p-TsOH (0.2 equiv) in MeOH. b Selectivity was determined by 1H
NMR spectroscopy and configuration by NOE experiments on 5a.
c Isolated yields after purification by silica gel column chromatography.
(6) Smith, A. B., III; Duffey, M. O. Synlett 2004, 1363.
(7) (a) Tietze, L. F.; Geissler, H.; Gewert, J. A.; Jakobi, U. Synlett
1994, 511. (b) Smith, A. B., III; Boldi, A. M. J. Am. Chem. Soc. 1997, 119,
69.
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1 1979, 26. (b) Smith, A. B., III; Kim, D. S.; Xian, M. Org. Lett. 2007, 9,
3307.
(9) Shinokubo, H.; Miura, K.; Oshima, K.; Utimoto, K. Tetrahedron
1996, 52, 503.
(10) Brinkman, E. A.; Berger, S.; Brauman, J. I. J. Am. Chem. Soc.
Using bistriethylsilyl enal 2a as the model linchpin, we
then examined ARC involving n-BuLi as the nucleophile
and BnBr as the electrophile. The reaction was initially
performed in THF and promoted by 4.0 equiv of HMPA.
After selective desilylation of the silyl ether moiety with
p-TsOH in MeOH, the three products 5a-[γ/E], 5a-[γ/Z],
1994, 116, 8304.
(11) (a) Takeda, K.; Fujisawa, M.; Makino, T.; Yoshii, E. J. Am.
Chem. Soc. 1993, 115, 9351. (b) Fischer, M.-R.; Kirschning, A.; Michel,
T.; Schaumann, E. Angew. Chem., Int. Ed. 1994, 33, 217. (d) Takaku, K.;
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(12) Song, Z. L.; Lei, Z.; Gao, L.; Wu, X.; Li, L. J. Org. Lett. 2010, 12,
5298.
(13) Generally, R-silylallyl anions are obtained by metalation of
allylsilanes or alkyl-substituted vinylsilanes. For a review, see: Chan,
T. H.; Wang, D. Chem. Rev. 1995, 95, 1279.
€
(14) Erkkila, A.; Pihko, P. M. J. Org. Chem. 2006, 71, 2538.
Org. Lett., Vol. 14, No. 1, 2012
159

Table 2. Scope of Nucleophiles and Electrophiles
a Reaction conditions: bissilyl enal (1.0 equiv), nucleophile (1.1 equiv) in THF at ꢀ78 °C; then TMEDA (1.1 equiv), warm to ꢀ15 °C; then
electrophile (3.0 equiv) and HMPA (4.0 equiv); crude products were treated with p-TsOH (0.2 equiv) in MeOH. b Stereoselectivity was determined by 1H
NMR spectroscopy. c Isolated yields after purification by silica gel column chromatography.
and 6a-[r] were obtained in an overall yield of 67% in the
ratio 73:8:19 (Table 1, entry 1). While addition of 1.1 equiv
of TMEDA apparently improved the yield and regio- and
stereoselectivity (entry 2), using more TMEDA reduced
the yield without changing the product ratio (entry 3).
Replacing the lithium ion with other counterions such as
Cu(I)15 or Kþ,16 or changing the solvent to the more bulky
Et2O17 or nonpolar toluene, decreased both the yield and
selectivity (entries 4ꢀ7). Interestingly, enal 2b with a (t-
BuMe2Si)2CH- group and enal 2c with a (PhMe2Si)2CH-
group showed higher E/Z selectivity for γ-addition, but
significantly lower regioselectivity (entries 8 and 9).
are summarized in Table 2. Reactions of benzyl and allyl
bromide derivatives with n-BuLi as the nucleophile pro-
vided quite good E/Z-selectivity and moderate γ/R-selec-
tivity (entries 1 and 2). Phenyl disulfide also proved to be a
suitable electrophile, which led to complete γ-addition but
only moderate E/Z-selectivity (entry 3). When aldehydes
and ketones were used as electrophiles, the reactions
showed excellent regio- and E/Z-selectivity (entries
4ꢀ9).18 However, only moderate yields of 5i and 5k were
obtained (entries 6 and 8). This may be due to deprotona-
tion of the R-position of carbonyl compounds by the
silylallyl anion. The reaction is also suitable for various
organolithium species such as vinyllithium, lithium acet-
ylide, and aryllithiums (entries 10ꢀ14). It is noteworthy
Having established the optimal reaction conditions, we
further examined the scope of this approach. The results
(15) Tamao, K.; Nakajo, E.; Ito, Y. Tetrahedron 1988, 44, 3997.
(16) Koumaglo, K.; Chan, T. H. Tetrahedron Lett. 1984, 25, 717.
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160
Org. Lett., Vol. 14, No. 1, 2012

that complete γ-addition was obtained in entry 13. This
result is in sharp contrast to the moderate regioselec-
tivity observed in other alkylation reactions shown in
Table 2. Probably, the nitrogen atom in the pyridine
might coordinate favorably with the lithium ion at-
tached to the γ-position of the silylallyl anion. Detailed
studies of this interesting regioselectivity are ongoing.
Additionally, only organolithium is applied for this
reaction, as a Grignard reagent cannot trigger the silyl
migration.
Scheme 4. Anion Relay Chemistry of Bissilyl Enone
The application of the E-vinylsilane22 products to the
synthesis of useful building blocks was investigated. As
shown in Scheme 5, treatment of 5a with NIS gave the
vinyliodide 9 in 83% yield with retention of the E-config-
uration. Subsequent Sonogashira coupling23 using term-
inal alkynes with different functional groups afforded
various enynes 10 in high yield.
Scheme 3. Model Analysis for the γ/E-Selectivity
Scheme 5. Transformation of Vinylsilanes to Enynes
A rationalization of the observed regio- and stereose-
lectivityisdescribedinScheme 3. Although simplesilylallyl
lithium is widely recognized as having an exo-orienta-
tion,19 the configuration of the acyclic species substituted
at the 2-position is poorly understood. Only one example
containing a 2-methyl group has been investigated, and it
seems to retain the exo-orientation.20 The observed high E/
Z selectivity in our studies suggests that the formed
silylallyl anion adopts the 4-endo structure predominantly,
which has an A1,3 strain21 between the silyl group and γ-H.
However, this is still more favorable than the 4-exo arrange-
ment, which encounters severe A1,2 strain between the silyl
group and the 2-substituent. The γ-regioselectivity can be
explained by the difference in accessibility between the
R- andγ-positions: the γ-position appears to be more accessi-
ble, since the R-position is attached to a bulky silyl group.
This explanation is further supported by the observed
complete γ/E selectivity when the bissilyl enone 7 is used as
a linchpin (Scheme 4). In this reaction, the formed silylallyl
lithium contains a larger 2-tertiary alkoxy group, which
increases the steric congestion at both the R- and γ-positions,
completely blocking the former.
We have described a facile, three-component coupling
process using the bissilyl enal as a linchpin. The route
provides a practical method for synthesizing various
E-vinylsilanes regio- and stereoselectively. Wehave demon-
strated the synthetic value of this approach by efficiently
preparing diverse enyne species. Further applications of
this method are underway.
Acknowledgment. This research was supported by
the National Natural Science Foundation of China
(20802044, 21021001), the National Basic Research
Program of China (973 Program, 2010CB833200), and
the RFDP (200806101091).
Supporting Information Available. Experimental proce-
dures and spectra data for products. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
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