Efficient synthesis of alkynylsilyl ethers and silaketals via base-induced alkynylsilane alcoholysis

Article abstract of DOI:10.1021/jo048908l

The efficient silylation of alcohols with di- and trialkynylsilanes was achieved under base-catalyzed conditions to afford alkynyl silyl ethers and symmetrical alkynyl silaketals in good yield. A selective alcoholysis of dialkynyl silyl ethers to mixed si

Full text of DOI:10.1021/jo048908l

SCHEME 1. Silyl Ether- and Silaketal-Based
Ring-Closing Enyne Metathesis
Efficient Synthesis of Alkynylsilyl Ethers
and Silaketals via Base-Induced
Alkynylsilane Alcoholysis
Jonathan B. Grimm and Daesung Lee*
Department of Chemistry, University of
WisconsinsMadison, Madison, Wisconsin 53706
dlee@chem.wisc.edu
Received June 28, 2004
Abstract: The efficient silylation of alcohols with di- and
trialkynylsilanes was achieved under base-catalyzed condi-
tions to afford alkynyl silyl ethers and symmetrical alkynyl
silaketals in good yield. A selective alcoholysis of dialkynyl
silyl ethers to mixed silaketals was also demonstrated. These
products served as substrates for enyne ring-closing me-
tathesis and, consequently, as precursors to stereochemically
defined 1,3-dienes.
SCHEME 2. Catalytic Cycle of Alkynylsilane
Alcoholysis
The silyl ether is one of the most widely used protecting
groups1 and temporary tethers2,3 in modern synthetic
chemistry due to the ease of its formation and removal
in the presence of other common protecting groups. Many
silylating agents and reaction conditions have been
developed, yet the use of reagents of the form R3Si-X (X
) Cl, OTf) and appropriate amine bases is most general.1
In our study of silicon-tethered enyne metathesis of silyl
ether 1 and silaketal 3 to the corresponding siloxanes 2
and 4 (Scheme 1), an efficient preparation of 1 and 3 was
required. Although the typical silylation procedures serve
well for the purpose of protecting hydroxyl groups with
common silylating agents, the preparation of silyl ethers
and silaketals possessing more elaborate substituents (as
in 1 and 3) requires a different silylation protocol.4
Alternative silylation reactions such as transition-metal-
catalyzed alcoholysis of hydrosilanes5 and acid-catalyzed
alcoholysis of allylsilanes6 have been developed; however,
their reaction scope has often been limited to simple,
saturated alcohol substrates.
Conceptually, a new base-catalyzed silylation method
can be developed with a silylating agent R3Si-Y where Y
is a reasonably good leaving group that retains a mod-
erately high level of basicity. We deem alkynylsilanes 5
and 6 to possess these characteristics. As shown in the
catalytic cycle (Scheme 2), the alkoxide generated by a
base initiator would react with 5 (or 6) to form the
corresponding pentacoordinated silicate adduct, which
would produce the silyl ether product by the dissociation
of an alkynyl anion from the silicon center (or, alterna-
tively, by a direct protonation of the Csp-Si bond). A
(1) (a) Protective Groups in Organic Synthesis, 3rd ed.; Greene, T.
W., Wuts, P. G. M., Eds.; John Wiley & Sons: New York, 1999. (b)
Lalonde, M.; Chan, T. H. Synthesis 1985, 817. (c) Muzart, J. Synthesis
1993, 11.
(2) Recent examples of silicon tethers in metathesis: (a) Evans, P.
A.; Murthy, V. S. J. Org. Chem. 1998, 63, 6768. (b) Hoye, T. R.; Promo,
M. A. Tetrahedron Lett. 1999, 40, 1429. (c) Zhu, S. S.; Cefalo, D. R.;
La, D. S.; Jamieson, J. Y.; Davis, W. M.; Hoveyda, A. H.; Schrock, R.
R. J. Am. Chem. Soc. 1999, 121, 8251. (d) Barrett, A. G. M.; Beall, J.
C.; Braddock, D. C.; Flack, K.; Gibson, V. C.; Salter, M. M. J. Org.
Chem. 2000, 65, 6508. (e) Yao, Q. Org. Lett. 2001, 3, 2069. (f) Harrison,
B. A.; Verdine, G. L. Org. Lett. 2001, 3, 2157. (g) Aeilts, S. L.; Cefalo,
D. R.; Bonitatebus, P. J.; Houser, J. H.; Hoveyda, A. H.; Schrock, R.
R. Angew. Chem., Int. Ed. 2001, 40, 1452. (h) Se´meril, D.; Cle´ran, M.;
Bruneau, C.; Dixneuf, P. H. Adv. Synth. Catal. 2001, 343, 184. (i)
Se´meril, D.; Cle´ran, M.; Perez, A. J.; Bruneau, C.; Dixneuf, P. H. J.
Mol. Catal. A-Chem. 2002, 190, 9. (j) Kiely, A. F.; Jernelius, J. A.;
Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 2868. (k)
Van de Weghe, P.; Aoun, D.; Boiteau, J.-G.; Eustache, J. Org. Lett.
2002, 4, 4105. (l) Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2002,
124, 15196. (m) Evan, P. A.; Ciu, J.; Buffone, G. P. Angew. Chem., Int.
Ed. 2003, 42, 1734. (n) Evans, P. A.; Ciu, J.; Gharpure, S. J.;
Polosukhin, A.; Zhang, H.-R. J. Am. Chem. Soc. 2003, 125, 14702.
(3) For reviews of silicon tethers, see: (a) Bols, M.; Skrydstrup, T.
Chem. Rev. 1995, 95, 1253. (b) Fensterbank, L.; Malacria, M.; Sieburth,
S. McN. Synthesis 1997, 813. (c) Gauthier, D. R., Jr.; Zandi, K. S.; Shea,
K. J. Tetrahedron 1998, 54, 2290. Examples of silicon tethers in other
reactions: (d) Stork, G.; Chan, T. Y.; Breault, G. A. J. Am. Chem. Soc.
1992, 114, 7578. (e) Righi, P.; Marotta, E.; Landuzzi, A.; Rosini, G. J.
Am. Chem. Soc. 1996, 118, 9446. (f) Ishikawa, T.; Kudo, T.; Shigemori,
K.; Saito, S. J. Am. Chem. Soc. 2000, 122, 7633. (g) Friestad, G. K.;
Massari, S. E. Org. Lett. 2000, 2, 4237. (h) Mayasundari, A.; Young,
D. G. J. Tetrahedron Lett. 2001, 42, 203. (i) Pearson, A. J.; Kim, J. B.
Org. Lett. 2002, 4, 2837.
(4) Other protocols for the preparation of alkynylsilyl ethers: (a)
Stork, G.; Keitz, P. F. Tetrahedron Lett. 1989, 30, 6981. (b) Petit, M.;
Chouraqui, G.; Aubert, C.; Malacria, M. Org. Lett. 2003, 5, 2037.
(5) Recent examples: (a) Luo, X.-L.; Crabtree, R. H. J. Am. Chem.
Soc. 1989, 111, 2527. (b) Doyle, M. P.; High, K. G.; Bagheri, V.; Pieters,
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Lorenz, C.; Schubert, U. Chem. Ber. 1995, 128, 1267. (d) Maifeld, S.
V.; Miller, R. L.; Lee, D. Tetrahedron Lett. 2002, 43, 6363. (e) Field, L.
D.; Messerle, B. A.; Rehr, M.; Soler, L. P.; Hambley, T. W. Organo-
metallics, 2003, 22, 2387. (f) Schmidt, D. R.; O’Malley, S. J.; Leighton,
J. L. J. Am. Chem. Soc. 2003, 125, 1190. (g) Miller, R. L.; Maifeld, S.
V.; Lee, D. Org. Lett. 2004, 6, 2773. Reviews: (h) Lukevics, E.;
Dzintara, M. J. Organomet. Chem. 1985, 295, 265. (i) Corey, J. Y. Adv.
Silicon Chem. 1991, 1, 327.
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21, 835. (b) Morita, T.; Okamoto, Y.; Sakurai, H. Synthesis 1981, 745.
(c) Hosomi, A.; Sakurai, H. Chem. Lett. 1981, 85. (d) Olah, G. A.;
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10.1021/jo048908l CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/06/2004
J. Org. Chem. 2004, 69, 8967-8970
8967

TABLE 1. Base-Induced Silylation with Dialkynylsilane
TABLE 2. Base-Induced Silylation with
Trialkynylsilane
TABLE 3. Symmetrical Silaketals from Trialkynylsilane
subsequent proton abstraction by the alkynyl anion from
another molecule of the substrate alcohol would regener-
ate the alkoxide, thereby establishing a smooth catalytic
cycle and constituting an efficient method for the syn-
thesis of mono- and dialkynyl silyl ethers. Although the
base-induced alcoholysis of alkynylsilanes is a standard
synthetic operation for the purpose of removing silyl
groups from silylalkynes,1a,7 this bond-making and bond-
breaking process has never been exploited as an effective
method of silyl ether synthesis. Herein we report the
development of an efficient silylation protocol using di-
and trialkynylsilanes as stable and reactive silylating
agents and its successful implementation in the synthesis
of alkynyl silyl ethers and silaketals.
In choosing specific alkynylsilanes for the development
of this methodology, moderate reactivity and stability of
the silanessas well as high volatility of the alkyne
byproductswere considered important attributes. Di-
phenyl dialkynylsilane 5 (R ) Ph, R′ ) CH2OMe) and
cyclopentyl trialkynylsilane 6 (R ) cyclopentyl, R′ ) CH2-
OMe) were found to possess these characteristics. A
series of silylation reactions were then performed with
silane 5 and a variety of alcohols to generate silyl ethers
7a-o (Table 1). The optimal conditions involved the use
of a catalytic amount of NaH (10 mol %) in hexanes.8 For
the primary and secondary alcohols, the reaction was
generally complete in a few minutes at room tempera-
ture, affording 7a-k in good to excellent yields after
chromatography (without an aqueous workup). The low
steric hindrance of these alcohol substrates necessitated
the use of an excess amount of 5 (1.5-2.0 equivalents)
to minimize the formation of symmetrical silaketals. In
the case of the tertiary alcohols, the silylation could be
performed with equimolar amounts of silane and alcohol
but often required an elevated reaction temperature (50
°C) for 2-3 h. One particularly hindered alcohol under-
went only partial conversion (47%) to the desired silyl
ether 7o.
In a similar fashion, trialkynylsilane 6 was treated
with substrate alcohols in the presence of a catalytic
amount of base (10 mol % NaH) to accrue silyl ethers
8a-h in moderate to good yields (Table 2). Once again,
the efficient formation of silyl ethers 8a-e from second-
ary alcohols demanded the use of excess silane (2.0-2.5
equiv). The slightly lower efficiency of 6 in this reaction
(relative to that of 5) was due to increased formation of
silaketals and trialkoxy adducts resulting from the
apparently higher reactivity of the trialkynylsilane. More
sterically hindered alcohols (such as the tertiary alcohol
precursors to 8f-h) required only a single equivalent of
silane and proceeded in high yield at 50 °C without the
formation of the aforementioned byproducts.
We then examined the feasibility of generating sym-
metrical alkynyl silaketals of the form 3 (R2 ) R3) from
trialkynylsilane 6 through a double displacement of
alkynyl groups. Pleasingly, the same reaction conditions
optimized for silyl ether formation gave 9a-g in moder-
ate to good yields by using 2 equiv of the alcohol
substrates (Table 3). Although the trialkoxysilane was a
(7) (a) Ben-Efraim, D. A. In The Chemistry of the Carbon-Carbon
Triple Bond; Patai, S., Ed.; John Wiley & Sons: Chichester, 1978; Vol.
2, Chapter 18. (b) Eaborn, C.; Walton, D. R. M. J. Organomet. Chem.
1965, 4, 217.
(8) Zacuto, M. J.; O’Malley, S. J.; Leighton, J. L. J. Am. Chem. Soc.
2002, 124, 7890.
8968 J. Org. Chem., Vol. 69, No. 25, 2004

TABLE 4. Unsymmetrical Silaketals from
Trialkynylsilane
SCHEME 3. Enyne Metathesis of Siloxane
Products
amounts of the symmetrical silaketals. A number of
secondary and tertiary silyl ethers were similarly reacted
with secondary and primary alcohols, respectively, to
generate silaketals 10b-f in moderate yield (Table 4,
entries 2-6). In all cases, the reactions were performed
with equimolar amounts of silyl ether and alcohol,
providing the silaketals in less than 60 min at room
temperature. Small amounts of the symmetrical silaket-
als were seen in a few of these examples (10b and 10d),
but the desired product was easily separated from these
minor components by chromatography. Silaketals 10b-d
possessed the added complexity of existing as diastere-
omeric mixtures. For each of these compounds, however,
the corresponding NMR signals of the various diastere-
omers were often not distinguishable.
To demonstrate the utility of these silyl ethers and
silaketals in synthetic transformations such as enyne
ring-closing metathesis,9 7d and 9f were treated with a
catalytic amount of second-generation Grubbs catalyst
11 in CH2Cl2,10 providing enyne RCM product 12 (70%)
and tandem enyne-diene RCM11 product 14 (83%),
respectively (Scheme 3). Removal of the temporary silicon
minor product in most of these reactions, sterically
unhindered alcohols provided significant amounts of this
byproduct (9a and 9f), which could be minimized through
the use of less alcohol (1.5 equiv). The employment of
racemic secondary alcohols to form 9d, 9e, and 9g led to
the generation of each product as the expected mixture
of three diastereomers. The 1H and 13C NMR of 9d show
three sets of complex signals, with evident differences
in chemical shifts among the three diastereomers (the
two meso compounds RS and SR and the enantiomeric
pair RR/SS). Interestingly, the spectra of 9e and 9g were
much simpler, with substantially less (if any) distinction
between the diastereomeric resonances. Only a single set
of signals was seen in the NMR spectra of 9f, as it was
derived from a homochiral sample of the secondary
alcohol.
Encouraged by the efficient formation of alkynylsilyl
ethers and symmetrical silaketals, we also pursued the
synthesis of unsymmetrical silaketals of type 3 (R2 * R3)
by the second alcoholysis of dialkynyl silyl ethers among
8a-i. Although these silyl ethers possess two alkynyl
leaving groups on silicon, the alkoxide moiety could also
serve as a potential leaving group. Such an alkoxide-
exchange process would greatly complicate the reaction
by generating a mixture of the symmetrical and unsym-
metrical silaketals. Hence, it was with some trepidation
that the second alkynyl displacement reaction was at-
tempted with silyl ether 8a and 1,8-nonadien-5-ol (Table
4, entry 1) under the same conditions optimized for
symmetrical silaketals. The desired unsymmetrical si-
laketal 10a was obtained in 77% yield with only trace
(9) Recent reviews on enyne metathesis: (a) Poulsen, C. S.; Madsen,
R. Synthesis 2003, 1. (b) Mori, M. In Handbook of Metathesis; Grubbs,
R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vol. 2, pp 176-
204. (c) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317.
(10) (a) Scholl, S.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 6543.
(11) For selected examples of tandem enyne RCM, see: (a) Kim, S.-
H.; Bowden, N.; Grubbs, R. H. J. Am. Chem. Soc. 1994, 116, 10801.
(b) Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H. J. Org.
Chem. 1996, 61, 1073. (c) Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.;
van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 2001, 42, 8231.
(d) Boyer, F.-D.; Hanna, I. Tetrahedron Lett. 2002, 43, 7469. (e) Huang,
J.; Xiong, H.; Hsung, R. P.; Rameshkumar, C.; Mulder, J. A.; Grebe,
T. P. Org. Lett. 2002, 4, 2417. (f) Fukumoto, H.; Esumi, T.; Ishihara,
J.; Hatakeyama, S. Tetrahedron Lett. 2003, 44, 8047. (g) Garcia-
Fandin˜o, R.; Codesido, E. M.; Sobarzo-Sa´nchez, E.; Castedo, L.; Granja,
J. R. Org. Lett. 2004, 6, 193. (h) Honda, T.; Namiki, H.; Kaneda, K.;
Mizutani, H. Org. Lett. 2004, 6, 87.
J. Org. Chem, Vol. 69, No. 25, 2004 8969

tether from these siloxanes with TBAF12 proceeded
smoothly with retention of double-bond configuration to
afford the corresponding homoallylic alcohol 13 and
homoallylic diol 15 as single stereoisomers.
In summary, we have developed an efficient silylation
protocol by taking advantage of the basicity and leaving
group ability of alkynyl anions. Under these base-induced
silylation conditions, a variety of mono- and dialkynyl
silyl ethers as well as symmetrical and unsymmetrical
alkynyl silaketals have been prepared. The utility of
these compounds has also been demonstrated via ring-
closing metathesis and subsequent protodesilylation to
form stereochemically defined 1,3-dienes. Further explo-
ration of the ring-closing metathesis of alkynylsilyl ethers
and alkynyl silaketals to form more complex siloxacycles
is in progress.
Acknowledgment. D.L. gratefully acknowledges
the Wisconsin Alumni Research Foundation (WARF),
the NSF, and the Camille and Henry Dreyfus Founda-
tion for their generous financial support. J.B.G. thanks
NSF for a predoctoral fellowship. Support for NMR and
mass spectrometry instrumentation from the NSF and
NIH are greatly acknowledged.
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) O’Malley, S. J.; Leighton, J. L. Angew. Chem., Int. Ed. 2001,
40, 2915.
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