Diels-Alder chemistry of siloles and their transformation into cyclohex-2-ene-1,4-cis-diols

Article abstract of DOI:10.1021/ol101453e

The synthesis of siloles with substitution patterns that are continuative toward natural product synthesis are described. Their reactivity in Diels-Alder chemistry was explored through thermal, Lewis acid, and high-pressure reactions. Furthermore, bicycli

Full text of DOI:10.1021/ol101453e

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3658-3661
Diels-Alder Chemistry of Siloles and
Their Transformation into
Cyclohex-2-ene-1,4-cis-diols
Andrew C. Stevens and Brian L. Pagenkopf*
The UniVersity of Western Ontario, Department of Chemistry,
London, Ontario N6A 5B7, Canada
bpagenko@uwo.ca
Received June 24, 2010
ABSTRACT
The synthesis of siloles with substitution patterns that are continuative toward natural product synthesis are described. Their reactivity in
Diels-Alder chemistry was explored through thermal, Lewis acid, and high-pressure reactions. Furthermore, bicyclic adducts were oxidatively
cleaved to reveal a highly functionalized cyclohexene core.
Acyclic organosilanes have been heavily investigated for
many years and have proven to be an invaluable tool in
synthetic organic chemistry.1 They have been applied in
diverse reactions such as allylations,2 annulations,3 crotyla-
tions,4 olefinations,5 and oxidations6 and as cross-coupling
partners.7 Recently, silacycles have drawn synthetic interest
as new reactivity patterns emerge. Kozmin has reported a
route to acyclic polyol compounds via an asymmetric
deprotonation of meso-silacyclopentenoxides8 and have ap-
plied their methodology in the enantioselective synthesis of
pinolidoxin.9 Steel has used silacyclohexenes in the Hosomi-
Sakurai reaction to yield 1,4-diols with the potential to install
up to four contiguous stereocenters.10 Leighton has intro-
duced a chiral oxazasilolidine reagent that can be used for
the asymmetric allylation of aldehydes11 or as a Lewis acid
in Diels-Alder chemistry.12 Despite advances in silacycles,
siloles remain a largely unexplored heterocycle in synthetic
organic chemistry, despite being extensively studied for their
intriguing electrochemical properties.13
(9) Liu, D.; Kozmin, S. A. Org. Lett. 2002, 4, 3005–3007.
(10) Sellars, J. D.; Steel, P. G.; Turner, M. J. Chem. Commun. 2006,
2385–2387.
(1) (a) Fleming, I.; Barbero, A.; Walter, D. Chem. ReV. 1997, 97, 2063–
2192. (b) Miura, K.; Hosomi, A. Main Group Metals in Organic Synthesis;
Yamamoto, H., Oshima, K., Eds.; Wiley-VCH: Wienheim, Germany, 2004;
Vol. 2, Silicon in Organic Synthesis, 409 pp.
(11) (a) Kinnaird, J. W.A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton,
J. L. J. Am. Chem. Soc. 2002, 124, 7920–7921. (b) Wang, X.; Meng, Q.;
Nation, A. J.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 10672–10673.
(c) Kubota, K.; Leighton, J. L. Angew. Chem., Int. Ed. 2003, 42, 946–948.
(12) Kubota, K.; Hamblett, C. L.; Wang, X.; Leighton, J. L. Tetrahedron
2006, 62, 11397–11401.
(2) (a) Hosomo, A. Acc. Chem. Res. 1988, 21, 200–206. (b) Kira, M.;
Sato, K.; Sakurai, H. J. Am. Chem. Soc. 1988, 110, 4599–4602.
(3) Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836–9837.
(4) Lipomi, D. J.; Panek, J. S. Org. Lett. 2005, 7, 4701–4704.
(5) Peterson, D. J. Org. Chem. 1968, 33, 780–784.
(13) (a) Yamaguchi, S.; Tamao, K. J. Chem. Soc., Dalton Trans. 1998, 3693–
3702. (b) Yamaguchi, S.; Goto, T.; Tamao, K. Angew. Chem., Int. Ed. 2000,
39, 1695–1696. (c) Boydston, A. J.; Pagenkopf, B. L. J. Am. Chem. Soc. 2004,
126, 3724–3725. (d) Boydston, A. J.; Pagenkopf, B. L. Angew. Chem., Int. Ed.
2004, 43, 6336–6338. (e) Boydston, A. J.; Yin, Y.; Pagenkopf, B. L. J. Am.
Chem. Soc. 2004, 126, 10350–10354. (f) Usta, H.; Lu, G.; Facchetti, A.; Marks,
T. J. J. Am. Chem. Soc. 2006, 128, 9034–9035. (g) Lee, S. H.; Jang, B.-B.;
Kafafi, Z. H. J. Am. Chem. Soc. 2005, 127, 9071–9078. (h) Booker, C.; Wang,
X.; Haroun, S.; Zhou, J.; Jennings, M.; Pagenkopf, B. L.; Ding, Z. Angew.
Chem., Int. Ed. 2008, 47, 7731–7735. (i) Zhan, X.; Barlow, S.; Marder, S. R.
Chem. Commun. 2009, 1948–1955.
(6) (a) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694–1696. (b) Tamao, K.; Kumada, M. Tetrahedron Lett. 1984,
25, 321–324. (c) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc. Chem.,
Chem. Commun. 1984, 29–31. (d) Fleming, I.; Henning, R.; Parker, D. C.;
Plaut, H. E.; Sanderson, P. E. J. Chem. Soc., Perkin Trans. 1995, 1, 317–
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10.1021/ol101453e  2010 American Chemical Society
Published on Web 07/29/2010

Siloles have been shown to engage in Diels-Alder
chemistry,14 but the scope and potential usefulness of the
resulting adducts has yet to be thoroughly investigated. At
the onset of this work we speculated that that the bicyclic
adduct of a silole Diels-Alder reaction could undergo
silicon-carbon bond oxidation to form a highly function-
alized cyclohex-2-ene-1,4-diol (Scheme 1). The structural
deliver the silole, and thus a stepwise reaction sequence was
developed. Dihydroxylation and mesylation of 2 afforded
the bis-mesylate 4, but it failed to undergo double elimination
with a variety of bases. Next, through a sequence similar to
that employed by Kozmin,8 the allylic alcohol 5 was obtained
by epoxidation of 2 followed by elimination with lithium
diisopropylamide. Unfortunately, derivatives of compund 5
were highly susceptible to silicon-carbon bond cleavage to
give silanol 6, even when relatively stable leaving groups
(sulfonates) were introduced, as well as with the milder
elimination protocols of Burgess17 or Grieco.18
Scheme 1
.
Cyclohex-2-ene-1,4-diols from Siloles and Potential
Applications
Faced with the difficulties encountered in forming 3, we
turned our attention to the more stable C-substituted siloles
(i.e., 8, Scheme 3).19 Additionally, because tertiary alcohols
Scheme 3. Preparation of an Alkyl Silole Dimer
features contained in 1 can potentially facilitate rapid access
to a diverse range of compounds, which could lead to the
synthesis of natural products such as the eudesmanolides.
In this communication we describe the Diels-Alder reaction
of several siloles with a variety of dienophiles, as well as a
subsequent Tamao-Fleming oxidation to deliver highly
functionalized cyclohex-2-ene-1,4-diols.
The initial goal of this study was to examine the reactivity
of a C-unsubstituted silole.15 We had envisioned preparing
the desired siloles by either direct oxidation or through an
oxidation-elimination sequence of the readily accessible
dihydrosilole 2 (Scheme 2). Synthetic efforts began with
are more readily eliminated from dihydrosiloles than are
secondary alcohols, milder reaction conditions should be
compatible.19 The same three-step protocol was used to
prepare tertiary alcohol 7 from isoprene and dichlorodiphe-
nylsilane. Elimination of the tertiary alcohol in 7 was
achieved through formation of a carbamate, followed by
thermolysis; however, only the dimerization product 9 was
obtained, and the monomeric silole was not observed.
Introducing a reactive dienophile after carbamate formation
but prior to thermolysis was successful at trapping the
monomeric silole, and the Diels-Alder product 10 was
obtained in 79% yield over two steps. Unfortunately, this
interception strategy could not be extended to other dieno-
philes. Attempts to crack the dimer and trap it with maleic
anhydride under prolonged high-temperature conditions
(refluxing xylenes) resulted only in slow decomposition of
the dimer. Room-temperature eliminations were investigated
with the corresponding sulfonates, but again dimerization
proved more facile than the desired Diels-Alder cycload-
dition.
Scheme 2. Problematic Routes toward an Unsubstituted Silole
formation of the dihydrosilole 2 through reductive cyclization
of commercially available dichlorodiphenylsilane with buta-
diene and Rieke magnesium (Mg*).16 Unfortunately, direct
oxidation of 2 with DDQ, MnO2, Pd/C, or SeO2 failed to
(14) Balasubramanian, R.; George, M. V. Tetrahedron 1973, 29, 2395–
2404.
(17) Burgess, E. W.; Penton, H. R.; Taylor, E. A. J. Am. Chem. Soc.
1970, 92, 5224–5226.
(15) Kako, M.; Obs, S.; Nakadaira, Y. J. Organomet. Chem. 1993, 461,
173–175.
(18) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485–1486.
(16) Rieke, R. D.; Xiong, H. J. Org. Chem. 1991, 56, 3109–3118.
Alternatively, allylation and ring-closing metathesis may be used: Schmidt,
B.; Pohler, M.; Costisella, B. J. Org. Chem. 2003, 69, 1421–1424.
(19) Dubac, J.; Laporterie, A.; Iloughmane, H. J. Organomet. Chem.
1985, 293, 295–311.
Org. Lett., Vol. 12, No. 16, 2010
3659

A stable monomeric silole was secured by installation of
an additional methyl group about the silole ring (Scheme
4). Employment of the same three-step protocol afforded
Table 1. Thermal Diels-Alder Reaction of Siloles
Scheme 4. Synthesis of Silole 12
tertiary alcohol 11. Formation of a carbamate followed by
thermolysis succeeded in delivering silole 12 in 82% yield
over two steps.
Having secured a reliable route to a monomeric silole, the
breadth of the Diels-Alder cycloaddition was investigated
(Table 1). Reactions with highly reactive dienophiles such
as maleic anhydride or maleimide (entries a and b) were
complete after 16 h at room temperature, whereas less
reactive dienophiles, such as fumarates and quinones (entries
c-e), required elevated temperatures to undergo cyclization.
Because of the sluggish nature of these silole Diels-Alder
reactions, Lewis acidic conditions and high-pressure experi-
ments, both of which are known to facilitate Diels-Alder
reactions, were explored (Table 1).20 After screening several
Lewis acids, it was found that diethylaluminum chloride
catalyzed the reaction of dienophiles bearing a single
activating group (e.g., acrylates, methylvinyl ketone, entries
f-i), and the desired adducts could be obtained at ambient
temperature in substantially reduced reaction times (from 16
to 2 h). High-pressure conditions also faciliated access to
the desired products in yields comprable to those observed
with diethylaluminium chloride. Furthermore, acrolein, which
polymerized under both thermal and Lewis acidic conditions,
was found to be an ammicable dienophile when subjected
to high pressure (entry j).
Having successfully discovered complementary reaction
conditions for the Diels-Alder reaction with siloles, more
interesting silole substrates with greater potential utility in
natural product synthesis were prepared. The cyclohexyl
fused silole 14 (Table 2) was prepared from 1,2-dimethyl-
enecyclohexane and Rieke magnesium using the same
sequence of reactions described in Scheme 4, and the
C-unsubstituted silole 15 was synthesized according to
literature procedures.15 The cyclohexyl-fused silole 14 was
found to undergo the cycloaddition with maleic anhydride,
methyl fumarate, methylacrolein, and methylvinyl ketone
(entries a-d) in yields comparable to those found with silole
12. Likewise, C-unsubstitued silole 15 formed the desired
cycloadducts with methacrolein, methylvinyl ketone, and
a Xylenes, reflux, 16 h. b Et2AlCl, PhMe, 2 h. c High pressure, 160 000
psi, CH2Cl2,16 h. d PhMe, 22 °C, 16 h. e PhMe, reflux, 16 h
benzoquinone (entires a-g); however, there was a noticeable
increase in reaction times, likely due to the butressing affects
of the mesityl groups.21
The relative stereochemistry of the Diels-Alder adducts
was determined by observing NOE interactions between the
methine proton R to the electron-withdrawing group and one
of the protons of the phenyl ring attached to the silicon
atom.22 Furthermore, the typically diagnostic chemical shift
difference between the axial and equatorial positions of all-
carbon [2.2.1] bicyclic systems suggests that the exo products
(20) (a) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1990. (b) Oppolzer, W. ComprehensiVe Organic
Synthesis; Trost, M. B., Fleming, I., Paquette, L. A., Eds.; Pergamon: New
York, 1991; Vol. 5, 315 pp. (c) Pindur, U.; Lutz, G.; Otto, C. Chem. ReV.
1993, 93, 741–761. (d) Isaacs, N. S. High Pressure Techniques in Chemistry
and Physics; Holzapfel, W. W., Isaacs, N. S., Eds.; Oxford University Press:
New York, 1997; Chapter 7.
(21) Siloles 12 and 14 required 2 h for the Lewis acid Diels-Alder
reaction (cf., Table 1 entry f, Table 2, entry c), whereas silole 15 required
24 h for the reaction to complete in one instance (Table 2, entry e).
(22) See Supporting Information for NOE specta.
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Org. Lett., Vol. 12, No. 16, 2010

Table 2. Additional Substituted Silole Substrates
Scheme 5. Tamao-Fleming Oxidation of the Diels-Alder
Adducts
adducts 13f, 13i, and 16c diastereoselectively to their
respective cis-diols, in 44-50% isolated yield (which cor-
relates to a 65-70% yield per oxidation).24
In summary, we have explored the reactivity of siloles in
Diels-Alder chemistry. Various promoters, including el-
evated temperatures, Lewis acids, and ultrahigh pressures,
were necessary to expand the reaction scope with less active
dienophiles, and in all cases complete endo selectivity was
observed. Furthermore, we have successfully cleaved the
resulting bicyclic adducts to reveal a highly substituted
cyclohex-2-ene-1,4-diol. We are currently investigating the
single-step oxidation of dihydrosiloles to siloles and these
results will be reported in due course.
a PhMe, 22 °C, 16 h. b PhMe, Et2AlCl, 2 h. c PhMe, Et2AlCl, 24 h.
d CH2Cl2, 160 000 psi.
Acknowledgment. We thank the National Sciences and
Engineering Research Council of Canada for financial
support. We thank Prof. Michael A. Kerr (The University
of Western Ontario) for the use of his high pressure reactor.
were never formed in quantity sufficient to be detected by
NMR spectroscopy.23
Supporting Information Available: General experimental
procedures and characterization of all new compounds and
copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
The 7-silabicyclo[2.2.1]hept-2-ene framework displays
several functional groups that evoke opportunities for
synthetic manipulation. To illustrate this point, oxidation of
the carbon-silicon bond by the Tamao-Fleming reaction6
successfully converted representative silole Diels-Alder
OL101453E
(23) Davis, J. C., Jr.; Auken, T. V. V. J. Am. Chem. Soc. 1965, 87,
3900–3905.
(24) Thus far only aryl-substitued silanes have been investigated because
of precedence in the Tamao-Fleming oxidation; see ref 6.
Org. Lett., Vol. 12, No. 16, 2010
3661