Geminal bis(silyl) enal: A versatile scaffold for stereoselective synthesizing C3,O1-disilylated allylic alcohols based upon anion relay chemistry

Article abstract of DOI:10.1021/ol400145z

Geminal bis(silyl) enal 2a is shown to be a useful scaffold for anion relay chemistry (ARC) aimed at the stereoselective synthesis of C³,O ¹-disilylated allylic alcohols. The ARC reaction is initiated by the addition of an alkyllithium to the aldehyde and features a CuCN-promoted C ^sp2-to-O 1,4-silyl migration to generate a vinylcuprate that reacts with activated electrophiles.

Full text of DOI:10.1021/ol400145z

ORGANIC
LETTERS
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Vol. XX, No. XX
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Geminal Bis(silyl) Enal: A Versatile
Scaffold for Stereoselective Synthesizing
C3,O1‑Disilylated Allylic Alcohols Based
upon Anion Relay Chemistry
Linjie Yan,† Xianwei Sun,† Hongze, Li,† Zhenlei Song,*,†,‡ and Zengjin, Liu†
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
zhenleisong@scu.edu.cn
Received January 17, 2013
ABSTRACT
Geminal bis(silyl) enal 2a is shown to be a useful scaffold for anion relay chemistry (ARC) aimed at the stereoselective synthesis of
C3,O1-disilylated allylic alcohols. The ARC reaction is initiated by the addition of an alkyllithium to the aldehyde and features a CuCN-promoted
Csp2-to-O 1,4-silyl migration to generate a vinylcuprate that reacts with activated electrophiles.
Geminal bis(silanes) 1 are a special type of organosilane
in which two silyl groups are attached to one carbon
center.1 Although these molecules show potential as syn-
thons in various contexts, so far they have been used primarily
because of their bulkiness to prepare sterically demanding
ligands for transition metal complexes.2 To explore potential
new reactivities and applications of this valuable species,
we recently launched a series of investigations on geminal
bis(silanes).3 Our results so far show that these compounds
exhibit attractive bifunctional reactivity, suggesting that
they can contribute to a much broader range of reactions
than previously thought.
Scheme 1. General Structure of Geminal Bis(silane) (left);
CuCN-Promoted Anion Relay Chemistry of Geminal Bis(silyl)
Enal (right)
† Key Laboratory of Drug-Targeting of Education Ministry and Depart-
ment of Medicinal Chemistry.
‡ State Key Laboratory of Biotherapy.
(1) For selected studies on geminal bis(silanes), see: (a) Fleming, I.;
Floyd, C. D. J. Chem. Soc., Perkin Trans. 1 1981, 969. (b) Brook, A. G.;
Chrusciel, J. J. Organometallics 1984, 3, 1317. (c) Klumpp, G. W.;
Mierop, A. J. C.; Vrielink, J. J.; Brugman, A.; Schakel, M. J. Am. Chem.
Soc. 1985, 107, 6740. (d) Bellasoued, M.; Majidi, A. J. Org. Chem. 1993,
58, 2517. (e) Lautens, M.; Delanghe, P. H. M.; Goh, J. B.; Zhang, C. H.
J. Org. Chem. 1995, 60, 4213. (f) Princet, B.; Gariglio, H. G.; Pornet, J.
J. Organomet. Chem. 2000, 604, 186. (g) Hodgson, D. M.; Barker, S. F.;
Mace, L. H.; Moran, J. R. Chem. Commun. 2001, 153. (h) Inoue, A.;
Kondo, J.; Shinokubo, H.; Oshima, K. Chem.;Eur. J. 2002, 8, 1370. (i)
Brook rearrangement,4 which is the intramolecular mi-
gration of a silyl group from a carbon to an oxygen atom,
ꢀ
Williams, D. R.; Morales-Ramos, A. I.; Williams, C. M. Org. Lett. 2006,
8, 4393.
(3) (a) Song, Z. L.; Lei, Z.; Gao, L.; Wu, X.; Li, L. J. Org. Lett. 2010,
12, 5298. (b) Gao, L.; Lin, X. L.; Lei, J.; Song, Z. L.; Lin, Z. Org. Lett.
2012, 14, 158. (c) Sun, X. W.; Lei, J.; Sun, C. Z.; Song, Z. L.; Yan, L. J.
Org. Lett. 2012, 14, 1094. (d) Gan, Z. B.; Wu, Y.; Gao, L.; Sun, X. W.;
Lei, J.; Song, Z. L.; Li, L. J. Tetrahedron 2012, 68, 6928. (e) Lu, J.; Song,
Z. L.; Zhang, Y. B.; Gan, Z. B.; Li, H. Z. Angew. Chem., Int. Ed. 2012, 51,
5367. (f) Gao, L.; Zhang, Y. B.; Song, Z. L. Synlett 2013, 24, 139–144.
(2) For the most recent examples, see: (a) Althaus, H.; Breunig, H. J.;
€
Rosler, R.; Lork, E. Organometallics 1999, 18, 328. (b) Saito, M.;
Tokitoh, N.; Okazaki, R. J. Am. Chem. Soc. 2004, 126, 15572. (c) Agou,
T.; Sugiyama, Y.; Sasamori, T.; Sakai, H.; Furukawa, Y.; Takagi, N.;
Guo, J. D.; Nagase, S.; Hashizume, D.; Tokitoh, N. J. Am. Chem. Soc.
2012, 134, 4120.
r
10.1021/ol400145z
XXXX American Chemical Society

could potentially offer a very powerful method for the
functionalization of organosilanes, if initiated by a nearby
lithium alkoxide, which generated an organolithium or
cuprate, to set up a subsequent trapping with an electro-
phile. Recent work with this reaction has led to many
significant achievements in both areas of synthetic meth-
odology and natural product synthesis.5 For example, the
group of Smith has developed a series of elegant reactions
involving anion relay chemistry (ARC) over the past
decade. In this approach, diverse organosilanes serve as
linchpins in rapid multicomponent couplings that give
complex molecules in a single step.6 Herein we describe
geminal bis(silyl) enal 2a as a new type of scaffold that can
undergo ARC via CuCN-promoted Csp2-to-O 1,4-silyl
migration7 (Scheme 1). This approach provides an efficient
starting point for the stereoselective synthesis of trisubsti-
tuted vinylsilanes, which can be further transformed into 1,1-
disubstituted (E)-crotylsilanes. Crotylsilanes, in turn, can
serve as useful synthons in the Sakurai reaction with acetals.
The required geminal bis(silyl) enals were synthesized by
two different methods, routes A and B (Scheme 2). In route
A, 3,3-bis(triethylsilyl) benzyl enol ether 43a,d underwent
deprotonation and regioselective thiolation to give 5,8
which was transformed via m-CPBA oxidation9 into gem-
inal bis(triethylsilyl) enal 2a in 54% overall yield. In route
B, the known 3-iodide-substituted 3-trimethylsilyl allylox-
ysilane 6 first underwent a retro-Brook rearrangement to
generate geminal bis(trimethylsilyl) allylic alcohol 7,10
which was then oxidized by IBX to provide enal 2b in
75% overall yield.
Table 1. Screening of Reaction Conditions
Scheme 2. Synthesis of Geminal Bis(silyl) Enals 2a and 2b
a Reaction conditions: 2a (0.14 mmol) and n-BuLi (0.28 mmol) in
THF (0.6 mL) at À78 °C for 30 min, followed by CuCN (0.28 mmol) in
DMF (1.8 mL) at 0 °C for 30 min, and finally allyl chloride (0.42 mmol)
at rt for 2 h. b The E-configuration was assigned based on NOE
experiments on the corresponding allylic alcohol of 3c. c Isolated yields
after purification by silica gel column chromatography.
Using geminal bis(triethylsilyl) enal 2a as a scaffold, we
examined an ARC reaction involving 2.0 equiv of n-BuLi
as the nucleophile and allyl chloride as the electrophile
(Table 1). While 4.0 equiv of HMPA promoted silyl
migration of the initially formed lithium alkoxide of 9a,
no further allylation occurred in the absence of any Cu(I)
or in the presence of 1.0 equiv of CuI. Only protonated
product 8a was formed in ∼40% yield (entries 1 and 2).
Replacing CuI with CuCN led to the desired allylated
product 3a, but the yield was only 34% and 8a was
generated in parallel in 17% yield (entry 3). Interestingly,
using a large excess of HMPA appeared to suppress silyl
migration to a certain extent, giving 9a in 28% yield (entry 4).
Incorporating DMF as a cosolvent remarkably improved
both the selectivity and yield of the reaction (entry 5).
(4) For reviews, see: (a) Brook, A. G. Acc. Chem. Res. 1974, 7, 77. (b)
Moser, W. H. Tetrahedron 2001, 57, 2065.
(5) For the selected advances, see: (a) Boyce, G. R.; Johnson, J. S.
Angew. Chem., Int. Ed. 2010, 49, 8930. (b) Song, Z. L; Kui, L. Z; Sun,
X. W.; Li, L. J. Org. Lett. 2011, 13, 1440. (c) Hayashi, M.; Nakamura, S.
Angew. Chem., Int. Ed. 2011, 50, 2249. (d) Li, H.; Liu, L. T.; Wang, Z. T;
Zhao, F.; Zhang, S. G; Zhang, W. X; Xi, Z. F. Chem.;Eur. J. 2011, 17,
7399. (e) Sasaki, M.; Kondo, Y.; Kawahata, M.; Yamaguchi, K.;
Takeda, K. Angew. Chem., Int. Ed. 2011, 50, 6375. (f) Martin,
D. B. C.; Vanderwal, C. D. Chem. Sci. 2011, 2, 649. (g) Matsuya, Y.;
Koiwai, A.; Minato, D.; Sugimoto, K.; Toyooka, N. Tetrahedron Lett.
2012, 53, 5955. (h) He, Y. P.; Hu, H. T.; Xie, X. G.; She, X. G.
Tetrahedron Lett. 2013, 69, 559.
(6) For reviews, see: (a) Smith, A. B., III.; Adams, C. M. Acc. Chem.
Res. 2004, 37, 365. (b) Smith, A. B., III.; Wuest, W. M. Chem. Commun.
2008, 5883. For the latest advances from this research group, see: (c)
Smith, A. B., III.; Kim, W. S.; Tong, R. B. Org. Lett. 2010, 12, 588. (d)
Smith, A. B., III.; Tong, R. B. Org. Lett. 2010, 12, 1260. (e) Smith, A. B.,
III.; Kim, W. S. Proc. Nat. Acad. Sci. 2011, 108, 6787. (f) Smith, A. B.,
III.; Tong, R. B.; Kim, W. S.; Maio, W. A. Angew. Chem., Int. Ed. 2011,
50, 8904. (g) Smith, A. B., III.; Han, H.; Kim, W. S. Org. Lett. 2011, 13,
3328. (i) Smith, A. B., III.; Hoye, A. T.; Martinez-Solorio, D.; Kim,
W.-S.; Tong, R. B. J. Am. Chem. Soc. 2012, 134, 4533. (j) Sokolsky, A.;
Smith, A. B., III. Org. Lett. 2012, 14, 4470. (k) Sanchez, L.; Smith, A. B.,
III. Org. Lett. 2012, 14, 6314.
(9) Mandai, T.; Hara, K.; Nakajima, T.; Kawada, M.; Otera, J.
Tetrahedron Lett. 1983, 24, 4993.
(10) Kim, K. D.; Wagtiotis, P. A. Tetrahedron Lett. 1990, 131, 6137.
(11) In both reactions of entries 5 and 6, excess n-BuLi should competi-
tively consume a certain amount of CuCN to form n-Bu(CuCN)Li.
Therefore, compared to 1.0 equiv of CuCN, 2.0 equiv would lead to the
desired transformation of ROLi into ROCu more completely, which would
further result in a higher yield of 3c.
(7) (a) Taguchi, H.; Ghoroku, K.; Tadaki, M.; Tsubouchi, A.;
Takeda, T. Org. Lett. 2001, 3, 3811. (b) Tsubouchi, A.; Enatsu, S.;
Kanno, R.; Takeda, T. Angew. Chem., Int. Ed. 2010, 49, 7089.
(8) Pelter, A.; Al-Bayati, R. I. H.; Ayoub, M. T.; Lewis, W.;
Pardasani, P.; Hansel, R. J. Chem. Soc., Perkin Trans. 1 1987, 717.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Scope of Nucleophilesa
Table 3. Scope of Electrophilesa
a Reaction conditions: 2a (0.14 mmol) and NuLi (0.28 mmol) in THF
(0.6 mL) at À78 °C for 30 min, followed by CuCN (0.28 mmol) in DMF
(1.8 mL) at 0 °C for 30 min, and finally allyl chloride (0.42 mmol) at rt for
2 h. b Isolated yields after purification by silica gel column chromatography.
a Reaction conditions: 2a (0.14 mmol) and n-BuLi (0.28 mmol) in THF
(0.6 mL) at À78 °C for 30 min, followed by CuCN (0.28 mmol) in DMF
(1.8 mL) at 0 °C for 30 min, and finally allyl chloride (0.42 mmol) at rt for
2 h. b Isolated yields after purification by silica gel column chromatography.
byproducts 8a and 9a detected (entry 6).11 Decreasing the
loading of n-BuLi to 1.2 equiv still gave complete addition
Moreover, increasing the loading of CuCN from 1.0 to
2.0 equiv led to 3a in an even higher yield of 85%, with no
Org. Lett., Vol. XX, No. XX, XXXX
C

but only partial subsequent silyl migration (entry 7).12 In
addition, the silyl group in enal 2 dramatically affected
the reaction efficiency: using trimethylsilyl-substituted 2b
gave 3b in only 36% yield (entry 8).
In order to demonstrate the bifunctionality of geminal
bis(silane), the resulting vinylsilane 3c was further trans-
formed by selective desilylation on the oxygen and sub-
sequent JohnsonÀClaisen rearrangement (Scheme 3). The
resulting 1,1-disubstituted (E)-crotylsilane 1016 was pro-
duced in 80% overall yield. Crotylsilane 10 is a valuable
synthon in Sakurai reactions17 involving diverse acetals.
The reaction gave rise to a range of highly functionalized
homoallylic methyl ethers 11 in good yield and with high
E-syn-selectivity.18
The scope of this ARC approach was further evaluated
using 2a and allyl chloride (Table 2). The reaction could be
applied to a wide variety of organolithiums, including ones
that were alkyl (entries 1 and 2), vinyl (entries 3À5), aryl and
heterocyclic (entries 6À9), and alkynyl (entries 10 and 11).
Interestingly, the reaction generating 3d in 70% yield (entry 2)
showed selectivity for 1,4-triethylsilyl migration over 1,3-
trimethylsilyl migration. This selectivity is surprising given
that 1,3-silyl migration is thought to be much faster than the
corresponding 1,4-migration,13 and the SiMe3 group mi-
grates more easily than does the SiEt3 group.14 A possible
explanation for the observed selectivity is that 1,4-triethylsilyl
migration generates a silicon-stabilized15 vinyl carbon anion,
which has greater anionic stability than the primary anion
generated in the competing 1,3-trimethylsilyl migration.
The ARC reaction also proved suitable for coupling a
wide range of 2- or 3-substituted allyl electrophiles in good
to excellent yields (Table 3, entries 1À7). Moreover, the
leaving group was not limited to halides. Sulfonated
electrophiles, which are easier to synthesize and isolate
than halides, gave similarly good results. Using propargyl
electrophiles altered the regioselectivity of the reaction
(entries 8 and 9). While the reaction involving SiEt3-
substituted propargyl tosylate led to normal R-propargy-
lation to produce 3u in 94% yield (entry 8), using phenyl-
substituted propargyl tosylate led to a reaction in which
γ-allenylation dominated, affording 3v in 72% yield (entry 9).
In addition, phenyl disulfide also proved to be a good
coupling partner, generating 3w in 40% yield (entry 10).
Scheme 3. Transformation of 3c to 1,1-Disubstituted
(E)-Crotylsilane 10, followed by Sakurai-Type Allylation
of 10 with Acetals
In summary, we have demostrated that geminal bis(silyl)
enal 2ais a new and useful scaffold for ARC that allows the
stereoselective synthesis of trisubstituted vinylsilanes. The
reaction features a CuCN-promoted Csp2-to-O 1,4-silyl
migration and can be implemented with a wide range of
nucleophiles and electrophiles. The resulting vinylsilanes
can be converted into 1,1-disubstituted (E)-crotylsilanes,
which are valuable synthons for the Sakurai reaction with
diverse acetals. More extensive studies on other applica-
tions of this reaction are underway.
(12) Detailed studies are underway to explore the mechanism by
which excess n-BuLi promotes silyl migration.
(13) (a) Eisch, J. J.; Tsai, M.-R. J. Organomet. Chem. 1982, 225, 5. (b)
Lautens, M.; Delanghe, P. H. M.; Goh, J. B.; Zhang, C. H. J. Org. Chem.
1992, 57, 3270.
(14) Evans, D. A.; Takacs, J. M.; Hurst, K. M. J. Am. Chem. Soc.
1979, 101, 371.
(15) (a) Brinkman, E. A.; Berger, S.; Brauman, J. I. J. Am. Chem. Soc.
1994, 116, 8304. (b) Chan, T. H.; Wang, D. Chem. Rev. 1995, 95, 1279.
(16) (a) Zhang, Y.; Panek, J. S. Org. Lett. 2007, 9, 3141. (b)
Kacprzynski, M. A.; May, T. L.; Kazane, S. A.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2007, 46, 4554.
(17) For a selected review, see: Fleming, I. Allylsilanes, allylstan-
nanes and related systems. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 6, pp 563À593.
(18) The E-configuration was assigned based on NOE experiments
on 11a. See Supporting Information for details. The syn-stereochemistry
was assigned based on Panek’s elegant studies on the Sakurai reaction of
various 1-mono- or 1,1-disubstituted crotylsilanes with acetals. In those
reactions similar to ours, reliable syn-stereochemical control is generally
predominant. For selected references, see: (a) Panek, J. S.; Masse, C. E.
Chem. Rev. 1995, 95, 1293. (b) Panek, J. S.; Zhu, B. J. Am. Chem. Soc.
1997, 119, 12022. (c) Hu, T.; Panek, J. S. J. Am. Chem. Soc. 1997, 119,
12022. (d) Huang, H. B.; Panek, J. S. Org. Lett. 2004, 6, 4383. (e)
Kesavan, S.; Panek, J. S.; Porco, J. A., Jr. Org. Lett. 2007, 9, 5203. (f)
Qin, H. L.; Panek, J. S. Org. Lett. 2008, 10, 2477. (g) Wu, J.; Chen, Y.;
Panek, J. S. Org. Lett. 2010, 12, 2112. (h) Wu, J.; Panek, J. S. J. Org.
Chem. 2011, 76, 9900.
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(21172150, 21021001, 21290180), the National Basic Re-
search Program of China (973 Program, 2010CB833200),
and the 985 Project of Sichuan University.
Supporting Information Available. Experimental pro-
cedures and spectra data for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
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