Versatile Route to centro-Substituted Triquinacene Derivatives: Synthesis of 10-Phenyltriquinacene

Article abstract of DOI:10.1021/ol035546f

(Equation Presented) A versatile route to prepare centro-substituted triquinacene derivatives (1, R = various substituents), as exemplified by the preparation of 10-phenyltriquinacene (1, R = Ph), is reported. The quaternary, centro substituent (C-10) was installed by a trimethylsilyl chloride-promoted conjugate addition reaction of an organocuprate, derived from phenylmagnesium bromide, and the protected bicyclic enone (11). The resultant trimethylsilyl enol ether was then converted regioselectively to the C-2-allylated conjugate addition products (13, R = Ph). The allyl moiety, following oxidative cleavage of the carbon-carbon double bond, was used to elaborate the tricyclic ring system by an intramolecular aldol/ acetal deprotection reaction. The product of this reaction was then converted to the target compound using a standard series of functional group transformation reactions.

Full text of DOI:10.1021/ol035546f

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3983-3986
Versatile Route to centro-Substituted
Triquinacene Derivatives: Synthesis of
10-Phenyltriquinacene
Jay A. Cadieux, Donovan J. Buller, and Peter D. Wilson*
Department of Chemistry, Simon Fraser UniVersity, 8888 UniVersity DriVe,
Burnaby, British Columbia V5A 1S6, Canada
pwilson@sfu.ca
Received August 15, 2003
ABSTRACT
A versatile route to prepare centro-substituted triquinacene derivatives (1, R ) various substituents), as exemplified by the preparation of
10-phenyltriquinacene (1, R ) Ph), is reported. The quaternary, centro substituent (C-10) was installed by a trimethylsilyl chloride-promoted
conjugate addition reaction of an organocuprate, derived from phenylmagnesium bromide, and the protected bicyclic enone (11). The resultant
trimethylsilyl enol ether was then converted regioselectively to the C-2-allylated conjugate addition products (13, R ) Ph). The allyl moiety,
following oxidative cleavage of the carbon−carbon double bond, was used to elaborate the tricyclic ring system by an intramolecular aldol/
acetal deprotection reaction. The product of this reaction was then converted to the target compound using a standard series of functional
group transformation reactions.
Triquinacene (1, R ) H, C10H10-tricyclo[5.2.1.04,10]deca-
2,5,8-triene), a highly condensed tricyclic hydrocarbon, was
first synthesized by Woodward and co-workers in 1964
(Figure 1).1 The synthesis and study of the physical and
triquinacene (1, R ) H), which was first proposed by
Woodward nearly forty years ago, as a means to prepare
dodecahedrane (C20H20). This transformation has not been
achieved under photochemical or thermal reaction conditions
or by transition metal catalysis.2,3 The most notable efforts
to resolve this long-standing objective have involved the
incorporation of covalent tethers between the two triquinacene
moieties.4 In addition, the preparation of transition metal
complexes to correctly position the triquinacene moieties for
the dimerization reaction has been considered.5
In this Letter, we describe an efficient and versatile
synthesis of 10-phenyltriquinacene (1, R ) Ph) that will
Figure 1. Triquinacene (1, R ) H) and centro-(C-10)-substituted
triquinacenes (1, R ) Ph, OH, Br, CO2H).
(1) Woodward, R. B.; Fukunaga, T.; Kelly, R. C. J. Am. Chem. Soc.
1964, 86, 3612.
(2) Hopf, H. Classics in Hydrocarbon Chemistry; Wiley-VCH: Wein-
heim, 2000.
(3) For a review on the chemistry of dodecahedrane and related
molecules, see: Paquette, L. A. Chem. ReV. 1989, 89, 1051.
(4) (a) Deslongchamps, P.; Soucy, P. Tetrahedron 1981, 37, 4385. (b)
Roberts, W. P.; Shoham, G. Tetrahedron Lett. 1981, 22, 4895.
chemical properties of this novel hydrocarbon, and related
derivatives, have been the subject of continued scientific
investigation ever since.2 Particular interest has been directed
toward the photochemical [6π + 6π] dimerization of
10.1021/ol035546f CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/23/2003

allow for a series of related centro-substituted triquinacene
derivatives to be prepared and studied (Figure 1). For
example, the hitherto unknown 10-hydroxy- and 10-bromo-
triquinacene (1, R ) OH, Br) should serve as precursors for
the generation and study of the corresponding nonplanar tris-
homoallylic carbocation, anion, and radical.
The synthesis of triquinacene-10-carboxylic acid (1, R )
CO2H) is of particular interest to us in connection with a
novel solution to the triquinacene dimerization problem
(Figure 2). It is hoped that the photochemical dimerization
expected reaction product that was isolated from a palladium-
catalyzed substitution reaction of a triquinanedione system.9
However, the yield of this novel process was relatively low.
de Meijere has shown that 10-methyltriquinacene (1, R )
CH3) and 10-(trimethylsilyl)triquinacene (1, R ) SiMe3) can
be prepared efficiently by thermal rearrangement of the
corresponding diadamane derivatives 2, but again these
compounds are only available in low overall yield.6,10 10-
Triquinacyl-triquinacene 3 has been isolated as a byproduct
and in low yield from the radical dechlorination of perchlo-
rotriquinacene.11 The related disubstituted derivatives, 1,10-
dimethyltriquinacene 4 and 1,10-cyclohexanotriquinacene 5,
have been prepared by modification of Cook’s original
synthetic route to triquinacene (1, R ) H) from symmetrical
precursors.8g More recently, a series of studies concerning
the synthesis and properties of 10-azatriquinacene 6 have
been reported.7
Our synthetic approach to centro-substituted triquinacene
derivatives began with the Weiss-Cook condensation reac-
tion of glyoxal 7 and dimethyl â-ketoglutarate 8 (Scheme
1). We have modified this procedure from that reported in
that the bis-sodium salt, which is precipitated in the Weiss-
Cook reaction, was directly subjected to the hydrolysis/
decarboxylation reaction in acetic acid/aqueous hydrochloric
acid in order to negate a neutralization and solvent extraction
step.12 This afforded the known bicyclic dione 9. Reaction
of dione 9 with 1 equiv of neopentyl glycol and a catalytic
amount of para-toluenesulfonic acid provided an essentially
statistical mixture of the desired monoacetal 10 (52%), the
corresponding bis-acetal (21%), and the dione starting
material 9 (22%). The latter two compounds could be re-
equilibrated under similar reaction conditions to provide
further quantities of the monoacetal 10.13
Figure 2. Proposed dimerization of triquinacene-10-carboxylic acid
(1, R ) CO2H).
reaction could be carried out in the solid state following
crystallization or cocrystallization of this compound. Here,
the correct orientation of the triquinacene moieties could be
achieved through directional noncovalent bonding inter-
actions between the C-10 carboxylic acid substituents.6,7
A
subsequent double-decarboxylation reaction would then
afford dodecahedrane.
A number of centro-substituted triquinacene derivatives
have been prepared (Figure 3). Although numerous synthetic
The enone 11, which could serve as a key intermediate
for the synthesis of a variety of centro-substituted triquinacene
derivatives, was then prepared in high yield on oxidation of
the corresponding trimethylsilyl enol ether of the monoacetal
10 with palladium(II) acetate.14 Unfortunately, the yield of
(6) A related photochemical dimerization of diadamane-1-carboxylic acid,
as a means to prepare dodecahedrane-1,16-dicarboxylic acid in the solid
state, has been proposed; see: Bengtson, B. Ph.D. Dissertation, Universita¨t
Hamburg, Hamburg, 1986.
(7) Recently, the potential dimerization of 10-azatriquinacene has been
discussed; see: (a) Hext, N. M.; Hansen, J.; Blake, A. J.; Hibbs, D. E.;
Hursthouse, M. B.; Shishkin, O. V.; Mascal, M. J. Org. Chem. 1998, 63,
6016. (b) Mascal, M.; Lera, M.; Blake, A. J. J. Org. Chem. 2000, 65, 7253.
(c) Mascal, M.; Lera, M.; Blake, A. J.; Czaja, M.; Kozak, A.; Makowski,
M.; Chmurzynski, L. Angew. Chem., Int. Ed. 2001, 40, 3696. (d) Lera, M.;
Blake, A. J.; Wilson, C.; Mascal, M. J. Chem. Soc., Perkin Trans. 1 2001,
3145.
(8) (a) Jacobson, I. T. Acta Chem. Scand. 1967, 21, 2235. (b) de Meijere,
A.; Kaufmann, D.; Schallner, O. Angew Chem. Int. Ed. 1971, 10, 417. (c)
Mercier, C.; Soucy, P.; Rosen, W.; Deslongchamps, P. Synth. Commun.
1973, 3, 161. (d) de Meijere, A. Tetrahedron Lett. 1974, 1845. (e) Wyvratt,
M. J.; Paquette, L. A. Tetrahedron Lett. 1974, 2433. (f) Carceller, E.; Garcia,
M. L.; Moyano, A.; Serratosa, F. J. Chem. Soc., Chem. Commun. 1984,
825. (g) Gupta, A. K.; Lannoye, G. S.; Kubiak, G.; Schkeryantz, J.; Wehrli,
S.; Cook, J. M. J. Am. Chem. Soc. 1989, 111, 2169.
(9) Zuber, R.; Carlens, G.; Haag, R.; de Meijere, A. Synlett 1996, 542.
(10) de Meijere, A. In Cage Hydrocarbons; Olah, G., Ed.; Wiley: New
York, 1990; Chapter 4.
(11) Jacobson, I. T. Chem. Scripta 1974, 5, 227.
(12) Bertz, S.; Cook, J. M.; Gawish, A.; Weiss, U. Org. Synth. 1985,
64, 27.
Figure 3. Known and related centro-substituted triquinacenes.
routes to prepare triquinacene (1, R ) H) have been reported,
no practical or versatile preparations of centro-substituted
derivatives have been developed.1,8 For example, 10-phen-
yltriquinacene (1, R ) Ph) was elaborated from an un-
(5) Codding, P. W.; Kerr, K. A.; Oudeman, A.; Sorensen, T. S. J.
Organomet. Chem. 1982, 232, 193.
(13) Piers, E.; Karunaratne, V. Can. J. Chem. 1989, 67, 160.
(14) Dragojlovic, V. Molecules 2000, 5, 674.
3984
Org. Lett., Vol. 5, No. 21, 2003

addition product was also isolated in 15% yield, and no
diallylation reaction products were observed. The minor C-2-
allylated adducts (13, R ) Ph) were formed as a ∼1:1
mixture of diastereomers.19 Conjugate addition reactions of
enone 11 and a variety of organocuprates can also be
achieved in the absence of trimethylsilyl chloride. However,
the resultant intermediate copper enolates in these reactions
have proved to be unreactive toward a number of alkylating
agents.20 The major O-allylated adduct 12 could be cleanly
converted to the desired C-2-allylated adducts (13, R ) Ph),
by means of a Claisen rearrangement, on heating at reflux
in toluene (96% yield). In this case, the reaction product was
isolated as a ∼3:2 mixture of diastereomers. These two
combined processes have allowed for the regioselective
installation of the allyl moiety at C-2 of this bicyclic system
for subsequent elaboration of the third ring of the target
compound. Interestingly, no significant stereochemical pref-
erence was observed for the delivery of the allyl moiety to
the convex or concave face of this cis-bicyclo[3.3.0]octane
ring system. This can be attributed to the additional steric
hindrance provided by the phenyl substituent that is posi-
tioned over the convex face of this highly congested ring
system.
Scheme 1. Synthesis of the C-2-Allylated Conjugate Addition
Products (13, R ) Ph)a
a Reagents and conditions: (a) (i) NaOH, MeOH, H2O, rt, 16 h;
(ii) HCl (aq), AcOH, reflux, 3 h, 59%. (b) neopentyl glycol, p-TsOH
(cat.), PhH, reflux, Dean-Stark apparatus, 4 h, 52%. (c) (i) LDA,
THF, -78 °C, 30 min, then TMSCl, THF, -78 °C to room
temperature, 2 h; (ii) Pd(OAc)2, MeCN, 0 °C to room temperature,
14 h, 91%. (d) (i) PhMgBr, CuI, TMSCl, THF, 0 °C, 3 h, then
Et3N (excess, quench); (ii) MeLi, THF, 0 °C, 30 min, then allyl
bromide, HMPA, 0 °C to room temperature, 16 h, 65% (12 + 13,
R ) Ph, 5.5:1). (e) PhMe, reflux, 3 days, 96%.
The formation of the tricyclic ring system of the target
compound was achieved by first carrying out a dihydroxy-
lation/oxidative cleavage reaction of alkenes (13, R ) Ph)
that afforded the corresponding aldehydes 14 (Scheme 2).8g,21
The synthesis of the parent triquinacene ring system by
Deslongchamps and co-workers involved a tandem acetal
deprotection/intramolecular aldol reaction that was performed
in THF solution with dilute hydrochloric acid.8c Unfortu-
nately, these reaction conditions failed to effect either the
deprotection or the cyclization reaction of compound 14.
this process on employment of a substoichiometric amount
of palladium(II) acetate with benzoquinone or dichlorodi-
cyanoquinone as a co-oxidant proved to be less than
satisfactory.15 However, we have developed an alternative
dehydrogenation protocol that is somewhat lower yielding
but does not involve the stoichiometric use of palladium(II)
acetate. It was found that the monoacetal 10 could be
converted to the corresponding R-phenylselenide that in turn
could be oxidized with hydrogen peroxide to afford enone
11 in 57% overall yield.16,17
The trimethylsilyl chloride-promoted conjugate addition
reaction of enone 11 and an organocuprate, prepared from
phenylmagnesium bromide and copper(I) iodide, smoothly
afforded the conjugate addition product as the corresponding
trimethylsilyl enol ether.18 This intermediate was then treated
with methyllithium to generate the corresponding lithium
enolate, which was reacted with allyl bromide in the presence
of hexamethylphosphoramide. This two-step procedure af-
forded a chromatographically separable ∼5.5:1 mixture of
the O- and C-2-allylated adducts (12 and 13, respectively,
R ) Ph) in 65% combined yield. A nonallylated conjugate
A series of studies were then undertaken to identify
suitable reaction conditions for the tandem acetal deprotec-
tion/intramolecular aldol reaction. Treatment of compound
14 with a catalytic amount of para-toluenesulfonic acid in
aqueous acetone cleanly effected the desired acetal depro-
tection reaction but did not effect the desired aldol reaction.
Substitution of reagent-grade acetone for aqueous acetone
in the above reaction led to slow cyclization of compound
14 without deprotection of acetal moiety and cleanly afforded
the tricyclic acetal 15. Subsequent addition of water to the
reaction mixture finally effected the deprotection of the acetal
and afforded the required tricyclic diketo alcohol 16 as a
∼7:3 mixture of diastereomers in good yield (79%). The
tricyclic acetal 15 was also isolated from this reaction in
14% yield as a ∼5:1 mixture of diastereomers. This acetal
could be recycled and converted to the required aldol product
16 in 92% yield. The excellent overall yield of this process
indicates that the two diastereomers of the starting material
are efficiently interconverted under the reaction conditions.
(15) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(16) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Org. Chem. 1974, 39,
2133.
(17) Dehydrogenation of the monoacetal 10 or oxidation of the corre-
sponding trimethylsilyl enol ether with ortho-iodoxybenzoic acid (IBX)
under a variety of experimental conditions afforded only trace quantities
of the required product; see: (a) Nicolaou, K. C.; Montagnon, T.; Baran,
P. S. Angew. Chem., Int. Ed. 2002, 41, 993. (b) Nicolaou, K. C.; Gray, D.
L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem., Int. Ed. 2002, 41,
996.
(19) For an example of a conjugate addition reaction of a related bicyclic
enone that was not reacted with an alkylating agent, see: Paquette, L. A.;
Lau, C. J. Synth. Commun. 1984, 14, 1081.
(20) (a) Coates, R. M.; Sowerby, R. L. J. Am. Chem. Soc. 1971, 93,
1027. (b) Coates, R. M.; Sandefur, L. O. J. Org. Chem. 1974, 39, 275.
(21) Pappo, R.; Allen, D. S. Jr.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
(18) Bertz, S. H.; Miao, G.; Rossiter, B. E.; Snyder, J. P. J. Am. Chem.
Soc. 1995, 117, 11023 and references therein.
Org. Lett., Vol. 5, No. 21, 2003
3985

activated neutral alumina in dichloromethane.22 This afforded
10-phenyltriquinacene (1, R ) Ph) in 44% yield from the
triols 17. The spectral data and physical properties of this
material were identical to those reported previously.9
In conclusion, a practical and potentially versatile synthetic
route to centro-substituted triquinacene derivatives has been
developed as exemplified by the preparation of 10-phenyl-
triquinacene (1, R ) Ph). This synthesis was achieved in 12
steps from glyoxal 7 and dimethyl â-ketoglutarate 8 in ∼5%
overall yield. The quaternary, centro substituent (C-10) was
installed in this highly condensed ring system by means of
a conjugate addition reaction. The extension of this synthetic
route to prepare other centro-substituted triquinacene deriva-
tives, particularly those capable of engaging in noncovalent
bonding interactions, is underway and will be reported in
due course. Current studies involve the conjugate addition
reactions of protected hydroxymethyl anion equivalents
(MCH2OP) to enone 11 in order to prepare triquinacene-10-
carboxylic acid (1, R ) CO2H).23 Subsequent elaboration
of the latter compound will allow for the preparation of the
remaining target centro-substituted triquinacene derivatives,
10-hydroxy- and 10-bromotriquinacene (1, R ) OH, Br),
for the study of their physical and chemical properties.
Scheme 2. Synthesis of 10-Phenyltriquinacene (1, R ) Ph)a
Acknowledgment. We are grateful to the Natural Sci-
ences and Engineering Research Council of Canada (NSERC)
and Simon Fraser University for financial support. J.A.C.
thanks NSERC for a PGS B predoctoral scholarship. Profes-
sor A. de Meijere is thanked for kindly providing a copy of
Dr. Bengtson’s thesis that concerns the synthesis of diada-
mane derivatives.
a Reagents and conditions: (a) OsO4 (cat.), NaIO4, p-dioxane,
H2O, rt, 6 h, 85%; (b) p-TsOH (cat.), acetone, rt, 5 days, then H2O,
2 days, 14% (15) and 79% (16); (c) p-TsOH (cat.), acetone/H2O
(2/1), rt, 2 days, 92%; (d) BH3‚THF, THF, 0 °C to room
temperature, 16 h, 77%; (e) MsCl, Et3N, CH2Cl2, 0 °C to room
temperature, 2 h; (f) activated neutral Al2O3, CH2Cl2, rt, 3 days,
44% (over two steps).
Supporting Information Available: Detailed experi-
mental procedures and product characterization data for all
of the compounds synthesized, as well as 1H and 13C NMR
spectra for compounds 12, 13 (R ) Ph), 14-16, and 1 (R
) Ph). This material is available free of charge via the
Internet at http://pubs.acs.org.
The synthesis of 10-phenyltriquinacene (1, R ) Ph) was
completed by modification of the protocol developed by
Cook and co-workers for the preparation of the parent
hydrocarbon, triquinacene (1, R ) H).8g Reduction of the
diketo alcohols 16 with borane-tetrahydrofuran complex
afforded the triols 17 as a complex mixture of stereoisomers
in 77% yield. Activation of this mixture of triols by
conversion to the corresponding trimesylates 18 was then
readily achieved under standard reaction conditions. Finally,
elimination of the three mesylate moieties was accomplished
on stirring the crude mesylates 18 with a slurry of highly
OL035546F
(22) Posner, G. H.; Gurria, G. M.; Babiak, K. A. J. Org. Chem. 1977,
42, 3173.
(23) (a) Knochel, P.; Chou, T.-S.; Jubert, C.; Rajagopal, D. J. Org. Chem.
1993, 58, 588. (b) Avolio, S.; Malan, C.; Marek, I.; Knochel, P. Synlett
1999, 1820. (c) Ferna´ndez-Meg´ıa, E.; Ley, S. V. Synlett 2000, 455 and
references therein.
3986
Org. Lett., Vol. 5, No. 21, 2003