Ruthenium-catalyzed silyl ether formation and enyne metathesis sequence: Synthesis of siloxacycles from terminal alkenyl alcohols and alkynylsilanes

Article abstract of DOI:10.1021/ol049019n

Two consecutive ruthenium-catalyzed reactions have been achieved for the synthesis of siloxacycles from terminal alkenyl carbenols and alkynylsilanes. The metal-catalyzed dehydrogenative condensation between alcohols and silanes, generating molecular hydr

Full text of DOI:10.1021/ol049019n

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2773-2776
Ruthenium-Catalyzed Silyl Ether
Formation and Enyne Metathesis
Sequence: Synthesis of Siloxacycles
from Terminal Alkenyl Alcohols and
Alkynylsilanes
Reagan L. Miller, Sarah V. Maifeld, and Daesung Lee*
Department of Chemistry, UniVersity of Wisconsin-Madison,
Madison, Wisconsin 53706
dlee@chem.wisc.edu
Received May 27, 2004
ABSTRACT
Two consecutive ruthenium-catalyzed reactions have been achieved for the synthesis of siloxacycles from terminal alkenyl carbenols and
alkynylsilanes. The metal-catalyzed dehydrogenative condensation between alcohols and silanes, generating molecular hydrogen as the only
byproduct, allows for the subsequent enyne metathesis without isolating the intermediate silyl ethers. This system provides a streamlined
synthesis of synthetically useful building blocks.
Enyne metathesis is a powerful carbon-carbon bond-forming
process.1 Unlike diene2 and diyne3 metathesis, which only
regenerate functionality of their own kind, enyne metathesis
generates a conjugated 1,3-diene from an alkene and an
alkyne. Despite this significant advantage, enyne metathesis
has been underdeveloped and far less used in natural product
synthesis.4 Efforts to expand the scope of this useful synthetic
method have successfully embraced various heteroatom (B,
N, O, P)-substituted alkynes5 to generate those functionalized
1,3-dienes (eq 1) yet, to the best of our knowledge, the
corresponding Si-substituted alkynes have not been engaged
previously (eq 2), despite the versatility of the resultant
(4) Examples of completed total synthesis of natural products with enyne
metathesis as a key step, see: (a) Kinoshita, A.; Mori, M. J. Org. Chem.
1996, 61, 8356. (b) Hoye, T. R.; Donaldson, S. M.; Vos, T. J. Org. Lett.
1999, 1, 277. (c) Mori, M.; Tonogaki, K.; Nishiguchi, N. J. Org. Chem.
2002, 67, 224. (d) Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am.
Chem. Soc. 2002, 124, 773. (e) Fukumoto, H.; Esumi, T.; Ishihara, J.;
Hatakeyama, S. Tetrahedron Lett. 2003, 44, 8047. (f) Brennema, J. B.;
Martin, S. F. Org. Lett. 2004, 6, 1329. (g) Aggarwal, V. K.; Astle, C. J.;
Rogers-Evans, M. Org. Lett. 2004, 6, 1469. (h) Mori, M.; Tomita, T.; Kita,
Y.; Kitamura, T. Tetrahedron Lett. 2004, 45, 4397.
(5) Other heteroatom-containing enyne RCM, see the following. With
boron: (a) Micalizio, G.; Schreiber, S. L. Angew. Chem., Int. Ed. 2002,
41, 3272. (b) Renaud, J.; Graf, C.-D.; Oberer, L. Angew. Chem., Int. Ed.
2000, 39, 3101. With nitrogen: (c) Huang, J.; Xiong, H.; Hsung, R. P.;
Rameshkumar, C.; Mulder, J. A.; Grebe, T. P. Org. Lett. 2002, 4, 2417. (d)
Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, 803. With oxygen: (e)
Clark, J. S.; Trevitt, G. P.; Boyall, D.; Stammen, B. Chem. Commun. 1998,
2629. (f) Clark, J. S.; Elustondo, F.; Trevitt, G. P.; Boyall, D.; Robertson,
J.; Blake, A. J.; Wilson, C.; Stammen, B. Tetrahedron 2002, 58, 1973. (g)
Schramm, M. P.; Reddy, D. S.; Kozmin, S. A. Angew. Chem., Int. Ed. 2001,
40, 4274. (h) Reddy, D. S.; Kozmin, S. A. J. Org. Chem. published online
June 12, http://dx.doi.org/10.1021/jo049431g. With phosphorous: Schramm,
M. P.; Reddy, D. S.; Kozmin, S. Angew. Chem., Int. Ed. 2002, 40, 4274.
With phosphorus: (i) Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.; van
der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 2001, 42, 8231.
(1) For recent reviews of enyne metathesis, see: (a) Mori, M. Top.
Organomet. Chem. 1998, 1, 133. (b) Poulsen, C. S.; Madsen, R. Synthesis
2003, 1. (c) Mori, M. In Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-
VCH: Weinheim, Germany, 2003; Vol. 2, pp 176-204. (d) Giessert, A.
J.; Diver, S. T. Chem. ReV. 2004, 104, 1317.
(2) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b)
Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (c) Fu¨rstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3013. (d) Connon, S. J.; Blechert, S.
Angew. Chem., Int. Ed. 2003, 42, 1900. (e) Schrock, R. R.; Hoveyda, A.
H. Angew. Chem., Int. Ed. 2003, 42, 4592.
(3) (a) Katz, T. J.; McGinnis, J. J. Am. Chem. Soc. 1975, 97, 1592. (b)
Wengrovius, J. H.; Sancho, J. J. Am. Chem. Soc. 1981, 103, 3932. (c)
Schrock, R. R.; Clark, D. N.; Sancho, J.; Wengrovius, J. H.; Rocklage, S.
M.; Pedersen, S. F. Organometallics 1982, 1, 1645. (d) Fu¨rstner, A.; Seidel,
G. Angew. Chem., Int. Ed. 1998, 37, 1734. (e) Fu¨rstner, A.; Guth, O.;
Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.
10.1021/ol049019n CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/02/2004

isolation. To improve the overall synthetic efficiency by
eliminating the problematic isolation step, we decided to
sequentially carry out silyl ether formation and the RCM
reaction without isolation of the silyl ether. Toward this end,
we were intrigued by the possibility of employing the
transition metal-catalyzed dehydrogenative condensation
reaction of alcohols with silanes to generate silyl ethers.15
Because molecular hydrogen is the only byproduct in this
reaction, the isolation of the unstable silyl ether 1 might not
be necessary for the subsequent RCM reaction. However,
hydrogenation and hydrosilylation of the unsaturated func-
tionality was of concern for most of the known catalytic
systems.
Scheme 1
We examined various transition metal complexes to
identify a catalyst that would effectively promote the
dehydrogenative condensation but would not catalyze hy-
drogenation or hydrosilylation. Most of the metal complexes
screened ([Rh(COD)Cl]2, RhCl(PPh3)3, Rh(acac)(CO)2, RuCl2-
(PPh)3, [RuCl2(p-cymene)]2, RuCl2(binap), Co2(CO)8, Pd-
(OCOCF3)2, PtCl2, Cu(OTf)2, Ag(OTf)) were effective for
silyl ether formation from alcohols and silanes (Me2PhSiH,
MePh2SiH, Ph2SiH2, Ph3SiH, (PhCC)Me2SiH, Et3SiH, and
t-BuMe2SiH), yet hydrogenation of alkenes and hydrosily-
lation of alkynes were also observed. Only the reactions
performed with [RuCl2(p-cymene)]2 left alkene and alkyne
functionalities intact. On the basis of these observations,
[RuCl2(p-cymene)]2 was further examined for its generality
in the reactions of various alcohols containing unsaturated
functionalities and assorted silanes under solvent-free condi-
tions (Table 1).16 Alcohols with disubstituted (entries 1, 2,
and 7), trisubstituted (entries 3 and 5), and terminal (entry
6) alkenes or alkynes (entries 4, 8, 9, and 10) were reacted
vinylsilane in organic synthesis. This disparity could be due
to the observed detrimental effect of the bulky silyl group,
lowering the reactivity of the silyl-substituted alkyne toward
enyne metathesis.5e,f,6
In our continuing efforts to develop efficient enyne RCM
substrate platforms,7 as well as to broaden the scope of the
enyne metathesis reaction, we became interested in the RCM
reaction of alkynyl silyloxy-tethered enyne 1 (Scheme 1).8,9
We envisioned that the temporary connection of alkenyl
alcohols and alkynylsilanes followed by metathesis would
allow for prompt access to a variety of stereochemically
defined 1,3-dienylvinylsilanes 2, which can be further
manipulated, for example, via a silicon-based cross-coupling
reaction extensively studied by Denmark and co-workers.10
As such, the enyne metathesis converting 1 to 2 constitutes
a powerful synthetic method,11,12 whereby a less regio- and
stereoselective cross-metathesis between alkenes and alkynes
can be performed in a more selective intramolecular fash-
ion.13 Herein we report our development of an efficient
procedure for the consecutive ruthenium-catalyzed synthesis
of alkynylsilyl ethers (1) and their enyne RCM reactions to
generate siloxacycles (2).14
(11) Examples of silyloxy-tethered diene RCM reactions, see: (a) Chang,
S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757. (b) Evans, P. A.;
Murthy, S. J. Org. Chem. 1998, 63, 6768. (c) Hoye, T. R.; Promo, M. A.
Tetrahedron Lett. 1999, 40, 1429. (d) Shu, 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. (e) Taylor, R. E.; Engelhardt, F. C.; Schmitt,
M. J.; Yuan, H. J. Am. Chem. Soc. 2001, 123, 2964. (f) Kiely, A. F.;
Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002,
124, 2868. (g) Van de Weghe, P.; Aoun, D.; Boiteau, J.-G.; Eustache, J.
Org. Lett. 2002, 4, 4105. (h) Evans, P. A.; Cui, J.; Buffone, G. P. Angew.
Chem., Int. Ed. 2003, 42, 1734. (i) Evans, P. A.; Cui, J.; Gharpure, S. J.;
Polosukhin, A.; Zhang, H.-R. J. Am. Chem. Soc. 2003, 125, 14702.
(12) Examples of silyloxy-tethered enyne RCM, see: (a) Semeril, D.;
Cleran, M.; Bruneau, C.; Dixneuf, P. H. AdV. Synth. Catal. 2001, 343, 184.
(b) Yao, Q. Org. Lett. 2001, 3, 2069. (c) Semeril, D.; Cleran, M.; Perez, A.
J.; Bruneau, C.; Dixneuf, P. H. J. Mol. Catal. A. 2002, 190, 9.
(13) For general reviews on silicon tether, 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.
In the initial attempt for the preparation of alkynylsilyl
ether 1, we recognized its instability toward workup and
(6) Kim, S.-H.; Zeurcher, W. J.; Bowden, N.; Grubbs, R. H. J. Org.
Chem. 1996, 61, 1073.
(7) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2003, 125, 9582.
(8) For an alternative method of making alkynylsilyl ethers see: Stork,
G.; Keitz, P. F. Tetrahedron Lett. 1989, 30, 6981.
(9) For the use of alkynylsilyloxy-tethered ene-ynes in other reactions,
see: (a) Petit, M.; Chouraqui, G.; Aubert, C.; Malacria, M. Org. Lett. 2003,
5, 2037. (b) Chouraqui, G.; Petit, M.; Aubert, C.; Malacria, M. Org. Lett.
2004, 6, 1519.
(14) Synthesis of related siloxacycles by ruthenium-catalyzed intramo-
lecular hydrosilylation, see: Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc.
2003, 125, 30.
(15) (a) Ojima, I.; Kogure, T.; Nihonyangi, M.; Kono, H.; Inaba, S. Chem.
Lett. 1973, 501. (b) Luo, X.-L.; Crabtree, R. H. J. Am. Chem. Soc. 1989,
111, 2527. (c) Yamamoto, K.; Takemae, M. Bull. Chem. Soc. Jpn. 1989,
62, 2111. (d) Doyle, M. P.; High, K. G.; Bagheri, V.; Pieters, R. J.; Lewis,
P. J.; Pearson, M. M. J. Org. Chem. 1990, 55, 6082. (e) Maifeld, S. V.;
Miller, R. L.; Lee, D. Tetrahedron Lett. 2002, 43, 6363.
(10) Reviews, see: (a) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res.
2002, 35, 835. (b) Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002,
50, 1531. (c) Denmark, S. E.; Ober, M. H. Aldrichim. Acta 2003, 36, 75.
For mechanistic studies, see: (d) Denmark, S. E.; Sweis, R. F.; Wehrli, D.
J. Am. Chem. Soc. 2004, 126, 4865. (e) Denmark, S. E.; Sweis, R. F. J.
Am. Chem. Soc. 2004, 126, 4876.
(16) The ratio of O- to C-silylation is highly dependent on solvents,
see: (a) Zhang, C.; Laine, R. M. J. Am. Chem. Soc. 2000, 122, 6979. (b)
In CH2Cl2, 3-butyn-1-ol (entry 10 in Table 1) undergoes preferential
C-silylation, see: Na, Y.; Chang, S. Org. Lett. 2000, 2, 1887. For a review
of solvent free reactions, see: (c) Tanaka, K.; Toda, F. Chem. ReV. 2000,
100, 1025.
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Org. Lett., Vol. 6, No. 16, 2004

Table 1. Silyl Ether Synthesis under Optimized Conditionsa
Table 2. Consecutive Ruthenium Catalysis for the Synthesis of
Siloxacycle
a All reactions are carried out with 0.2-1.0 mmol of the alcohol, 1.0
equiv of silane and 0.1-0.5 mol % of catalyst. b Conversion of the starting
alcohol and silane to silyl ether determined by 1H NMR of the crude reaction
mixture. c The silane was prepared from 1-ethynylcyclohexene and diphe-
nylsilane with Rh(binap)Cl. d The relatively low yield is due to the instability
of the silyl ether. e 0.5 mol % of catalyst employed. f 5% triple bond
hydrosilylation. g 0.9 equiv of silane employed. h Isolated yields.
a 0.5 mol % of [RuCl2(p-cym)]2 was used to form the silyl ether. b All
reactions are carried out in refluxing CH2Cl2, with substrate concentrations
of 0.003 M and a catalyst loading of 7.5 mol %. c Chemical shift in ppm
of the endocyclic vinyl signal, relative to the internal standard TMS. d 10-
15% hydrogenation of the alkyne occurred during silyl ether formation.
e Two-step combined isolated yields for the reactions having filtration after
the first step. f The yields in parentheses are the two-step combined yield
for the one-pot reaction.
with alkyl, aryl, vinyl, and alkynylsilanes without loss of
unsaturation. An alcohol having a cis double bond and
existing silyl ether functionality cleanly yielded the expected
bis-silyl ether (entry 2). Most trialkylsilanes required elevated
temperature (ca. 50 °C) to generate the corresponding tert-
butyldimethylsilyl or triethylsilyl ethers (entries 1, 3, and
5). The formation of silyl ethers with both terminal and
internal alkynyl alcohols with vinyl or allyl silanes (entries
6-10) was also realized uneventfully. In general, most
reactions are so efficient that 1H NMR of the crude reaction
mixtures showed no byproducts present; filtration through a
silica plug to remove catalyst (if necessary) was the only
refinement needed to give pure silyl ethers. Also, these
reactions are readily scalable such that multigram quantities
of silyl ethers could be prepared with comparable ef-
ficiency.17
then either filtered on a pad of silica gel or directly subjected
to enyne metathesis conditions with Grubbs’ second genera-
tion catalyst (4, (H2Imes)(PCy3)(Cl)2RudCHPh; 7.5 mol %,
0.003 M in CH2Cl2, reflux). Clean RCM products 2a-h were
isolated in moderate to good yields within short (60-90 min)
reaction times (Table 2). For the one-pot silyl ether formation
and enyne RCM reaction sequence, after the complete
consumption of the starting alcohols and alkynylsilyl ethers,
the reaction mixture was diluted with CH2Cl2 to an appropri-
ate concentration and treated with 4 under reflux. The
efficiency of the RCM reaction is generally higher if the
catalyst in the first step is removed by filtration through a
silica plug. Both the terminal (1e and 1g) and internal alkynes
are appropriate yne counterparts for this RCM reaction. The
oxygen substituent at the propargylic carbon had a beneficial
effect, slowing down the hydrogenation of the triple bond,
but did not affect the efficiency of the RCM reaction (e.g.,
Securing the highly efficient synthesis of a variety of
structurally diverse silyl ethers using as low as 0.1 mol %
of [RuCl2(p-cymene)]2 as the catalyst loading, we next
prepared alkynylsilyl ethers 1a-h from terminal alkenyl
primary alcohols and alkynylsilanes. These silyl ethers were
(17) When entry 5 in Table 1 was repeated with 5.0 g (32.8 mmol) of
myrtenol, 8.16 g (93% yield) of the corresponding silyl ether was obtained.
Org. Lett., Vol. 6, No. 16, 2004
2775

1c vs 1d). The ring size-dependent characteristic chemical
shifts of the vinyl protons (â to the silicon atom) of the
cyclization products are noteworthy and facilitate the un-
ambiguous assignment of the ring size of each siloxacycle.
The facile enyne RCM reactions to form not only small-
to medium-sized siloxacycles ranging from 5 to 9 (entries
1-7) but also the 13-membered macrocycle 2h (entry 8)
underscore the highly activating nature of the alkynylsilyloxy
tether for the enyne RCM reaction. Contrary to the facile
RCM reaction of enynes 1a-h, the corresponding all carbon-
tethered enyne substrates 5-7 did not undergo ring closure
under the same reaction conditions. This difference may be
the consequence of the two additional aryl substituents on
the silicon tether, thereby manifesting the well-known
Thorpe-Ingold effect.18
Scheme 2. Rationale for the Formation of exo-Product 2
In summary, we have developed an efficient ruthenium-
catalyzed silyl ether formation and subsequent ring closing
enyne metathesis to form siloxacycles from terminal alkenyl
alcohols and alkynylsilanes. The excellent reactivity profile
of alkynylsilyloxy-tethered enynes toward the RCM reaction
allows for the formation of a variety of ring structures having
synthetically useful 1,3-dienyl-vinylsilanes ranging from
small-membered rings to macrocycles. Further study to
broaden the scope of alkynylsilyloxy-tethered enyne me-
tathesis with chiral secondary alcohols and silaketals is in
progress.
Furthermore, silyl ethers 1a-h underwent enyne RCM to
provide only exo products, showing no transition from the
exo to endo mode of ring closure,7 even with a ring size
favoring the endo mode ring closure (entry 8 in Table 2).
We believe that the metathesis process starts from the
terminal alkene moiety, thereby generating 8 as an initial
intermediate (Scheme 2). The endo mode RCM of this
alkylidene 8 would be disfavored due to the formation of
the sterically hindered silicon-substituted alkylidene 10
possessing the bulky ruthenium complex at the same carbon
bearing the silicon atom. Favorable formation of the other
intermediate alkylidene 9 would relieve steric congestion
around the metal center and would deliver the observed
product 2a-h.
Acknowledgment. We thank the Wisconsin Alumni
Research Foundation and the Dreyfus Foundation for finan-
cial support as well as NSF (CHE-9208463) and NIH (1 S10
RR0 8389-01) for NMR and mass spectrometry instrumenta-
tion. The generous support from a CBI Training Grant
(GM08505) for R.L.M. is greatly acknowledged.
Supporting Information Available: General procedures
for the synthesis of silanes, silyl ethers, and siloxacycles, as
well as characterization of represented compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) (a) Beesely, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915,
107, 1080. (b) Lightstone, F. C.; Bruice, T. C. J. Am. Chem. Soc. 1994,
116, 10789 and references therein.
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