Simple construction of bicyclo[4.3.0]nonane, bicyclo[3.3.0]octane, and related benzo derivatives by palladium-catalyzed cycloalkenylation

Article abstract of DOI:10.1021/ol020187u

(equation presented) Bicyclo[4.3.0]nonanes (hydrindanes) and bicyclo[3.3.0]octanes (octahydropentalenes) are easily synthesized by palladium-catalyzed cycloalkenylations. Additionally, benzo-fused bicyclo[3.3.0]octanes are prepared for the first time thro

Full text of DOI:10.1021/ol020187u

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4293-4296
Simple Construction of
Bicyclo[4.3.0]nonane,
Bicyclo[3.3.0]octane, and Related Benzo
Derivatives by Palladium-Catalyzed
Cycloalkenylation
Masahiro Toyota,* Andivelu Ilangovan, Rei Okamoto, Tomohito Masaki,
Makoto Arakawa, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
mihara@mail.pharm.tohoku.ac.jp.
Received September 18, 2002
ABSTRACT
Bicyclo[4.3.0]nonanes (hydrindanes) and bicyclo[3.3.0]octanes (octahydropentalenes) are easily synthesized by palladium-catalyzed cyclo-
alkenylations. Additionally, benzo-fused bicyclo[3.3.0]octanes are prepared for the first time through intramolecular coupling between silyl
enol ethers and aromatic rings in the presence of catalytic palladium acetate.
Since the mid-1970s, transition metal promoted carbon-
carbon bond-forming reactions have been widely applied in
the synthesis of bioactive complex natural products.1 Cur-
rently, it is difficult to find synthetic approaches to natural
products that do not involve transition metal chemistry.2 In
our own contributions to this field, we have stereoselectively
constructed several bioactive polycyclic natural products,
such as methyl atis-16-en-19-oate3 and C20 gibberellins,4
employing palladium-catalyzed cycloalkenylation.5 We sought
to extend the chemistry to the intramolecular cyclization
between silyl enol ethers and unactivated alkenes, allowing
the simple synthesis of bicyclo[3.3.0]octanes (octahydro-
pentalenes)6 and bicyclo[4.3.0]nonanes (hydrindanes).7 These
ring systems are partial structures of many bioactive natural
products (Scheme 1). We herein report the concise synthesis
(1) Tsuji, J. Palladium Reagents and Catalysts; Wiley: New York, 1995.
(2) de Meijere, A., Ed. Chem. ReV. 2000, 100, 2741-3282.
(3) Toyota, M.; Wada, T.; Ihara, M. J. Org. Chem. 2000, 65, 4565-
4570.
Scheme 1
(4) Toyota, M.; Odashima, T.; Ihara, M. J. Am. Chem. Soc. 2000, 122,
9036-9037.
(5) (a) Pioneers: Ito, Y.; Aoyama, H.; Hirao, T.; Mochizuki, A.; Saegusa,
T. J. Am. Chem. Soc. 1979, 101, 494-496. (b) Kende, A. S.; Roth, B.;
Sanfilippo, P. J.; Blacklock, T. J. J. Am. Chem. Soc. 1982, 104, 5808-
5810. (c) Shibasaki, M.; Mase, T.; Ikegami, S. J. Am. Chem. Soc. 1986,
108, 2090-2091. (d) Catalytic conditions: Toyota, M.; Wada, T.; Fukumoto
K.; Ihara, M. J. Am. Chem. Soc. 1998, 120, 4916-4925. (e) Stemodin
synthesis: Toyota, M.; Seishi, T.; Fukumoto, K. Tetrahedron Lett. 1993,
34, 5947-5950. (f) Recent review: Toyota, M.; Ihara, M. Synlett 2002,
1211-1222. (g) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002,
41, 1569-1572. (h) Albeniz, A. C.; Catalina, N. M.; Espinet, P.; Redon,
R. Organometallics 1999, 18, 5571-5576.
of octahydropentalenes, cis-hydrindanes, and benzo-fused
octahydropentalenes by palladium-catalyzed cycloalkenyl-
ation.
10.1021/ol020187u CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/07/2002

Table 1. Palladium-Catalyzed Cycloalkenylation of Silyl Enol Ethersa
a All reactions were carried out at 45 °C in DMSO in the presence of 10 mol % of palladium acetate under 1 atm of oxygen.
The requisite silyl enol ethers 1 were easily prepared from
the corresponding enones by the Kuwajima protocol8 and
purified by silica gel column chromatography.9 The pal-
ladium-catalyzed cycloalkenylations of the silyl enol ethers
were investigated at 45 °C in DMSO using 10 mol % of
palladium acetate under 1 atm of oxygen.10 Results of the
cyclization are summarized in Table 1. Initially, the formation
of the bicyclo[3.3.0]octane ring system was examined.
Although silyl enol ether 3a provided enone 8 as the major
product, the desired bicyclic compound 5a was also isolated
in 11% yield. When the reaction was performed on 3b, the
combined yield of cyclized products rose to 65%, and exo-
olefin 4b, endo-olefin 5b, and enone 6b were obtained in a
39:25:19 ratio. The separation of 4b, 5b, and 6b was
achieved by HPLC. The effect of the R1 substituent was also
evaluated. When 3c was subjected to the catalytic reaction,
exo-olefin 4c (kinetic product) was produced as the major
product. Thus, bicyclo[3.3.0]octanes (4, 5, and 6), potential
synthons for the construction of linear and angular poly-
quinanes, were easily synthesized in moderate to good yield
by the two-step catalytic reaction.
(6) A review: Singh, V.; Thomas, B. Tetrahedron 1998, 54, 3647-
3692.
(7) A review: Jankowski, P.; Marczak, S.; Wicha, J. Tetrahedron 1998,
54, 12071-12150.
(8) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. Tetra-
hedron Lett. 1986, 27, 4025-4028.
(9) Representative Procedure: To a stirred solution of homoallylmag-
nesium bromide13 (5.7 mmol) in anhydrous THF (7.8 mL) were added CuBr‚
SMe2 (95 mg, 0.46 mmol) and HMPA (1.3 mL, 7.5 mmol) at -78 °C.
After 0.5 h of stirring at -78 °C, an anhydrous THF solution (3.1 mL) of
2,3-dimethylcyclopentenone (0.30 mL, 3.0 mmol) and TMSCl (1.1 mL,
8.7 mmol) was added dropwise at -78 °C. The mixture was stirred at -78
°C for 1 h, and then Et3N (0.9 mL, 6.5 mmol) was added at -78 °C in one
portion. The reaction mixture was warmed to room temperature over 2 h
and stirred overnight. After dilution with pentane, the organic layer was
washed three times with water, saturated NaHCO3 solution, and brine and
dried over MgSO4. After removal of the solvent, the residue was chro-
matographed on silica gel with hexane to provide silyl enol ether 3c (672
mg, 94%) as a colorless oil. 1H NMR (400 MHz) (C6D6) δ 5.80-5.77 (1H,
m), 5.05 (1H, br d, J ) 16.0 Hz), 4.97 (1H, br d, J ) 12.0 Hz), 1.53 (3H,
br s), 0.97 (3H, s), and 0.15 (9H, s).
(10) Procedure for Palladium-Catalyzed Cycloalkenylation: To a stirred
solution of silyl enol ether 3c (154 mg, 0.68 mmol) in DMSO (7.7 mL)
was added palladium acetate (15.2 mg, 0.068 mmol) at room temperature.
The mixture was stirred at 45 °C for 20 h under 1 atm of oxygen. After
being cooled to room temperature, the mixture was diluted with water. The
resulting mixture was extracted three times with Et2O, and the combined
ethereal layers were washed with brine, dried over MgSO4, and evaporated
to yield an oil, which was chromatographed. Elution with hexanes-EtOAc
(9:1) afforded exo-olefin 4c (46.4 mg, 41%), endo-olefin 5c (7.9 mg, 8%),
and ketone 7c (0.55 mg, 1%). All the products were obtained as a colorless
1
oil. 4c: IR (neat) 1738 cm-1. H NMR (400 MHz) (CDCl3) δ 4.96-4.95
(2H, br s), 1.02 (3H, s), and 1.01 (3H, s). 5c: IR (neat) 1738 cm-1 1H
.
NMR (400 MHz) (CDCl3) δ 5.33 (1H, br s), 1.55 (3H, br s), 1.08 (3H, s),
and 0.98 (3H, s).
4294
Org. Lett., Vol. 4, No. 24, 2002

Table 2. Palladium-Catalyzed Cycloalkenylation of Benzyl-Substituted Silyl Enol Ethersa
a All reactions were carried out 45 °C in DMSO in the presence of 10 mol % of palladium acetate under 1 atm of oxygen. b Stoichiometric amount of
Pd(OAc)2 was used.
Encouraged by these results, we explored the preparation
of cis-hydrindane systems. Silyl enol ether 9a afforded cis-
hydrindanes (10a and 11a) in only 11% yield; however, when
the reaction was conducted on 9b, exo-olefin 10b was
obtained in 24% yield.
there is little precedent for such transition metal mediated
cyclizations.
To study the substituent effects for this reaction, we
designed two silyl enol ethers 20a and 20c. When 20a,
having no quaternary center, was treated with 10 mol % of
Pd(OAc)2, enone 24 was obtained as the major product.
However, contiguously disubstituted 20c gave exo-olefin 23c
as the single product. Although compounds 20a and 20c did
not yield the desired cyclization products, these observations
suggest possible reaction mechanisms for these reactions.
Since exo-olefin 23c was obtained as single product in
the case of 20c, the reaction mechanism is speculated to occur
as described in Scheme 2. Based on our previous observa-
An alternative approach for the formation of cis-hydrin-
dane systems by cyclization of siloxycyclohexenes (14) was
examined. Although 14a gave only 5% of the desired product
16a, cyclization of 14b increased the yield of cyclized
products to 45%. The additional R1 substituent in 14c also
proved to be effective in increasing the yield, providing a
mixture of hydrindanes (15c, 16c) in 56% yield. Noteworthy
is that the palladium-catalyzed cycloalkenylation sequence
produces a doubly functionalized cis-hydrindane, a substitu-
tion pattern found in many bioactive natural products. These
observations indicate that generation of cis-hydrindanes from
siloxycyclohexenes is more efficient than that from siloxy-
cyclopentenes.
Scheme 2. A Plausible Pathway for the Formation of
Benzo-Fused Bicyclo[3.3.0]octane
Since little is known about coupling aromatic rings and
silyl enol ethers,11 we investigated intramolecular coupling
of silyl enol ethers 20, bearing a benzyl substitution, in the
presence of a catalytic amount of palladium acetate. Surpris-
ingly, when 20b was subjected to the palladium-catalyzed
cycloalkenylation, benzo-fused bicyclo[3.3.0]octane deriva-
tive 21b12 was isolated in 40% yield (Table 2).
To improve the cyclization yield, the same reaction can
be performed using 1 equiv of palladium acetate to give 62%
of 21b. An electron-donating group on the aromatic ring in
20d and 20e had little effect on the yield. To our knowledge,
tions5e,f and reports by others,5a,b we anticipate that the
reaction takes place via an insertion pathway. Namely,
initially formed alkyl palladium complex A inserts into the
(11) There is an interesting example of C-C bond formation between
aromatic rings and multiple bonds utilizing strong acid and Pd(II). Jia, C.;
Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science, 2000
287, 1992-1995.
Org. Lett., Vol. 4, No. 24, 2002
4295

double bond of the aromatic ring, giving rise to an interme-
diate B, from which Pd(0) is eliminated to yield tricyclic
compound 21b. However, the other possible reaction mech-
anism cannot be ruled out.5g,h
In conclusion, cis-fused bicyclo[4.3.0]nonanes, bicyclo-
[3.3.0]octanes, and related benzo derivatives, potential syn-
thons for the synthesis of natural products, are easily
synthesized by palladium-catalyzed cycloalkenylations. In
addition, the coupling reaction between silyl enol ethers and
the aromatic ring was achieved for the first time in the
presence of palladium acetate. It is notable that reaction
between sp2 carbons of silyl enol ether and an aromatic ring
was observed under neutral reaction conditions. Further
studies to address the scope of this reaction are underway.
(12) Recently, benzo-fused bicyclo[3.3.0]octane derivatives have gener-
ated interest among organic chemists because of their biological activity14
or structural analogy to natural products.15 We envision that palladium-
catalyzed cycloalkenylation can serve as an alternative procedure for the
formation of the benzo-fused bicyclo[3.3.0]ocatane ring system. The
compound 21b was also isolated as a minor product in the samarium-
promoted intramolecular cyclization of 3-(1-oxo-indan-2-yl)propionitrile.16
(13) Benson, R. E.; McKusick, B. C. Organic Synthses; Wiley: New
York, 1963; Collect Vol. IV, pp 746-752.
(14) Ratilainen, J.; Huhtala, P.; Karjalainen, A.; Haapalinna, A.; Virtanen,
R.; Lehtimaki, J. U.S. Patent 6362211 B2, 2002.
(15) Bruce, I.; Cooke, N. G.; Diorazio, L. J.; Hall, R. G.; Irving, E.
Tetrahedron Lett. 1999, 40, 4279-4282.
(16) Kakiuchi, K.; Fujioka, Y.; Yamamura, H.; Tsutsumi, K.; Morimoto,
T.; Kurosawa, H. Tetrahedron Lett. 2001, 42, 7595-7598.
Acknowledgment. This work is supported by a Grant-
in-Aid (No. 14571994) from the Ministry of Education,
Science, Sports and Culture, Japan.
Supporting Information Available: Spectral data for 4b,
4c, 5a, 5b, 5c, 6b, 10a, 10b, 11a, 15c, 16a, 16b, 16c, 21a,
21b, 21c, and 23c. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL020187U
4296
Org. Lett., Vol. 4, No. 24, 2002