A novel reaction for annulation onto α,β-unsaturated ketones: W(CO)5·L promoted exo-and endo-selective cyclizations of ω-acetylenic silyl enol ethers prepared by 1,4-addition of propargyl malonate to enones

Article abstract of DOI:10.1021/ol016718g

equation presented A highly useful method for five-and six-membered ring annulation onto α,β-unsaturated ketones is described. 1,4-Addition of propargylmalonate to α,β-unsaturated ketones in the presence of silyl triflate gives 7-siloxy-6-en-1-yne derivatives in good yield. W(CO)₅·L-catalyzed cyclization of these substrates can be induced to give preferentially either exo-or endo-cyclized products in good yield simply by changing the reaction solvent.

Full text of DOI:10.1021/ol016718g

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3871-3873
A Novel Reaction for Annulation onto
r,â-Unsaturated Ketones: W(CO)5‚L
Promoted Exo- and Endo-Selective
Cyclizations of ω-Acetylenic Silyl Enol
Ethers Prepared by 1,4-Addition of
Propargyl Malonate to Enones
,†
Nobuharu Iwasawa,* Katsuya Maeyama,§ and Hiroyuki Kusama†
Department of Chemistry, Tokyo Institute of Technology, 2-12-1, O-okayama,
Meguro-ku, Tokyo 152-8551, Japan, and Department of Chemistry, Graduate School of
Science, the UniVersity of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
niwasawa@chem.titech.ac.jp
Received September 7, 2001
ABSTRACT
A highly useful method for five- and six-membered ring annulation onto r,â-unsaturated ketones is described. 1,4-Addition of propargylmalonate
to r,â-unsaturated ketones in the presence of silyl triflate gives 7-siloxy-6-en-1-yne derivatives in good yield. W(CO)5‚L-catalyzed cyclization
of these substrates can be induced to give preferentially either exo- or endo-cyclized products in good yield simply by changing the reaction
solvent.
The development of useful methods for annulating a five-
or six-membered ring onto alkenes continues to be of great
importance for the preparation of cyclic carbon frameworks.
Especially desirable are methods allowing selective prepara-
tion of either five- or six-membered carbocycles from the
same starting materials by slight adjustment of the reaction
conditions.1 We have recently reported a novel method for
the endo-selective cyclization of ω-acetylenic silyl enol ethers
using a catalytic amount of W(CO)5‚THF, and when a
7-siloxy-6-en-1-yne derivative was employed as substrate
under these conditions, either the exo- or endo-cyclized
product could be obtained via the alkyne-W(CO)5 π-com-
plex and/or the corresponding vinylidene complex by chang-
ing the reaction solvent.2,3 In this Letter is described a highly
useful method for five- and six-membered ring annulation
(2) Maeyama, K.; Iwasawa, N. J. Am. Chem. Soc. 1998, 120, 1928. See
also: (a) Maeyama, K.; Iwasawa, N. J. Org. Chem. 1999, 64, 1344. (b)
Iwasawa, N.; Shido, M.; Maeyama, K.; Kusama, H. J. Am. Chem. Soc.
2000, 122, 10226. (c) Iwasawa, N.; Shido, M.; Kusama, H. J. Am. Chem.
Soc. 2001, 123, 5814.
(3) There are only a few methods for the endo-selective intramolecular
nucleophilic addition of carbon nucleophiles to alkynes. For examples,
see: (a) McDonald, F. E.; Olson, T. C. Tetrahedron Lett. 1997, 38, 7691.
(b) Imamura, K.; Yoshikawa, E.; Gevorgyan, V.; Yamamoto, Y. J. Am.
Chem. Soc. 1998, 120, 5339. (c) Imamura, K.; Yoshikawa, E.; Gevorgyan,
V.; Yamamoto, Y. Tetrahedron Lett. 1999, 40, 4081. See also: McDonald,
F. E. Chem. Eur. J. 1999, 5, 3103.
† Department of Chemistry, Tokyo Institute of Technology.
§ Department of Chemistry, Graduate School of Science, the University
of Tokyo. Present address: Department of Organic and Polymer Materials
Chemistry, Tokyo University of Agriculture and Technology, Koganei,
Tokyo 184-8588, Japan.
(1) Only a few papers on such reactions have been reported. See for
examples: (a) Negishi, E.; Tour, J. M. Tetrahedron Lett. 1986, 27, 4869.
(b) Snider, B. B.; Merritt, J. E.; Dombroski, M. A.; Buckman, B. O. J.
Org. Chem. 1991, 56, 5544. (c) Lemaire-Audoire, S.; Savignac, M.; Dupuis,
C.; Geneˆt, J.-P. Tetrahedron Lett. 1996, 37, 2003. (d) Kim, K.; Okamoto,
S.; Sato, F. Org. Lett. 2001, 3, 67.
10.1021/ol016718g CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/31/2001

onto R,â-unsaturated ketones based on the following strat-
egy: 1,4-addition of propargylmalonate to R,â-unsaturated
ketones in the presence of silyl triflate, followed by either
an exo- or an endo-selective cyclization, both catalyzed by
W(CO)5‚L.
Table 1. Influenece of the Reaction Solvent and the Silyl
Group on the Exo vs Endo Selectivity Using 1a and 1b (n ) 1,
R ) H) as Substrate
In the first place, the 1,4-addition of propargylmalonate
to cyclohexenone followed by in situ trapping of the
intermediate enolate as a silyl enol ether was examined.
Although no reaction occurred when the Na salt of pro-
pargylmalonate was treated with cyclohexenone in THF at
0 °C, addition of TBSOTf to the reaction mixture induced
instantaneous formation of the desired substrate 1a, a
7-siloxy-6-en-1-yne, in good yield.4 Several cycloalkenones
were converted to the corresponding products according to
this procedure in moderate to good yields as shown in
Scheme 1.
entry
SiR′3
solvent
THFa
CH2Cl2
benzeneb
tolueneb
yield/%
exo:endo
1
2
3
4
5
6
SiMe2t-Bu (1a )
SiMe2t-Bu
SiMe2t-Bu
SiMe2t-Bu
Sii-Pr3 (1b)
Sii-Pr3
97
62
89
73
79
81
>95:5
42:58
17:83
15:85
9:91
b
Scheme 1
b
CH2Cl2
tolueneb
3:97
a Conditions A: 10 mol % of W(CO)5‚THF, ∼3 molar amounts of H2O,
rt. b Conditions B: 110-150 mol % of W(CO)6, ∼3 molar amounts of H2O,
hν.
2a ) 97:3).5,7,8 In this reaction, both exo- and endo-cyclized
products were obtained as single diastereomers, whose
stereochemistries were assigned as cis in both cases using
NOE experiments.
Since the optimal conditions for the selective preparation
of both exo- and endo-cyclized products have been estab-
lished, reactions of several other cyclic substrates 1c to 1f
were examined under these conditions. As summarized in
Table 2, all the exo-cyclizations proceeded smoothly to give
Since an efficient method for preparation of the requisite
substrates had been established, the reaction conditions for
the W(CO)5‚L catalyzed cyclization were next examined
employing 1a (n ) 1, R ) H, R′3Si ) t-BuMe2Si) as a
substrate. For exo-cyclization, the reaction proceeded cleanly
through an alkyne-W(CO)5 π-complex on carrying out the
reaction at room temperature in THF with a 10 mol %
amount of preformed W(CO)5‚THF in the presence of H2O
(conditions A), to give bicyclo[4.3.0]nonanone 2a (n ) 1,
R ) H) in high yield5 (Table 1, entry 1). On the other hand,
the most favorable conditions for the endo-cyclization
reported earlier (W(CO)6, H2O, CH2Cl2, direct irradiation)2
gave only about a 1:1 mixture of endo- and exo-cyclized
products (Table 1, entry 2). We went on to examine how to
improve this selectivity, the results being summarized in
Table 1. As is clear from this table, the bulkiness of the silyl
group has a significant influence on the endo vs exo
selectivity, with a bulky silyl group6 favoring formation of
the endo-cyclized product. Of the several solvents examined,
toluene gave the best result. Thus, by directly irradiating a
mixture of W(CO)6 and a substrate containing the TIPS group
1b (n ) 1, R ) H, R′3Si ) i-Pr3Si) in toluene in the presence
of H2O (conditions B), the cyclized product was obtained in
81% yield with high endo vs exo selectivity (endo 3a:exo
Table 2. Construction of Bicyclo[m.3.0] and Bicyclo[m.4.0]
Systems Using W(CO)5‚L Catalyzed Cyclization (m ) n + 3)
conditions Aa
conditions Bb
n
R
yield/%
exo:endo
yield/%
exo:endo
0
1
1
2
3
H (1c)
H (1b)
Me (1d )
H (1e)
H (1f)
quant.
quant.
quant.
quant.
95
>95:5
>95:5
>95:5
>95:5
91:9
86
81
80
44
77c
13:87
3:97
30:70
25:75
17:83
a Conditions A: 10 mol % of W(CO)5‚THF in THF, ∼3 molar amounts
of H2O, rt. b Conditions B: 110-150 mol % of W(CO)6 in toluene, ∼3
molar amounts of H2O, hν. c MeOH was used as a proton source.
the corresponding bicyclic methylenecyclopentane deriva-
tives 25,9 in high yields by the use of a 10 mol % amount of
W(CO)5‚THF (conditions A). For the endo-selective cycliza-
tion, a modest to good level of selectivity for formation of
cyclohexene derivatives 3 was realized in most cases by
directly irradiating a mixture of W(CO)6 and substrate in
(4) It should be noted that TBSOTf does not silylate Na propargyl-
malonate but works as an effective activator of cyclohexenone.
(5) It is necessary to carry out column chromatography using silica gel
deactivated with 10% H2O, as otherwise, partial isomerization of the double
bond occurs to give R,â-unsaturated ketones.
(6) Ru¨cker, C. Chem. ReV. 1995, 95, 1009.
3872
Org. Lett., Vol. 3, No. 24, 2001

toluene in the presence of H2O (conditions B).5,7,10 Thus, we
can prepare synthetically useful bicyclo[m.3.0] and bicyclo-
[m.4.0] systems from the same starting materials via the same
intermediates simply by changing the reaction conditions in
the final step.
We next applied this annulation reaction to acyclic
systems.11 On carrying out the reaction in THF with a 10
mol % amount of W(CO)5‚THF, exo-selective cyclization
proceeded again without any problem and the corresponding
methylenecyclopentanes 5 were obtained in high yields
(Table 3). In every case examined only one diastereomer
the complex prepared by irradiating W(CO)6 in toluene in
the presence of MeOH (conditions C).13 Again, only one
diastereomer (trans) was obtained.11 These diastereoselec-
tivities are readily understood by considering the conforma-
tion of the molecules when the silyl enol ether attacks the
π-complex or the vinylidene complex as depicted in A and
B.
Table 3. Exo- and Endo-Selective Cyclization of Acyclic
Systems
Finally, this reaction was applied to the formation of a
spirocyclic skeleton. Although the selectivity for formation
of the endo-cyclized product 9 was not necessarily high, both
exo- and endo-cyclized spirocyclic compounds could be
obtained as a single diastereomer by changing the reaction
solvent. The stereochemistry of the exo-cyclized product 8
was determined to be as shown in Scheme 2 by X-ray
analysis.
conditions Aa
conditions Cb
R1
R2
yield/%
exo:endo
yield/%
exo:endo
Scheme 2
Ph
Ph
Ph
Et
Ph(major)
Ph(minor)
Me
99
88
quant.
96
>95:5
>95:5
>95:5
>95:5
71
70
70
68
23:77
23:77
16:84
30:70
Me
a Conditions A: 10 mol % of W(CO)5‚THF in THF, ∼3 molar amounts
of H2O, rt. b Conditions C: 100-130 mol % of W(CO)5‚MeOH in toluene,
∼4 molar amounts of MeOH, rt.
was obtained, whose relative stereochemistry was confirmed
by NMR analysis to be trans regardless of the geometry of
the starting material double bond.12 The corresponding endo-
cyclized products 6 were obtained in moderate to good
selectivity on carrying out the reaction in toluene, employing
In conclusion, we have developed a useful method for five-
and six-membered ring annulation onto R,â-unsaturated
ketones. By this novel protocol, we can prepare two types
of synthetically useful compounds from the same starting
materials via the same intermediates simply by changing the
reaction conditions. Due to its simple reaction procedure and
wide generality, this reaction should find wide use in the
synthesis of such cyclic molecules.
(7) It is necessary to control the irradiation time when the reaction is
run under conditions B. Longer irradiation results in a decrease in yield of
the endo-cyclized product.
(8) Use of a catalytic amount of W(CO)6 in toluene slightly lowered the
endo selectivity, while the reaction with a stoichiometric amount of W(CO)5‚
THF in THF gave the exo-cyclized product selectively. Thus, the amount
of W(CO)6 employed is not the cause for this difference of the exo vs endo
selectivity.
(9) Under conditions A, exo-cyclized products 2a-2e were obtained as
a single isomer, whose stereochemistry (ring junction) was confirmed to
be cis by NOE experiments. 2f was obtained as a 10:1 isomeric mixture of
two exo-cyclized products, accompanied by a small amount of endo-cyclized
product 3f.
(10) Under conditions B, all endo-cyclized products 3a-3f were obtained
as a single isomer. The stereochemistry (ring junction) of 3a-3d was
confirmed to be cis by NOE experiments. That of 3e and 3f was tentatively
assigned as trans, because we could not observe NOE between protons on
the ring junction. We are currently trying to confirm the stereochemistry
of these two products.
(11) When acyclic R,â-unsaturated ketones were employed as Michael
acceptors, in some cases 1,4-addition of propargylmalonate did not proceed
smoothly in THF. In such cases, the Na propargylmalonate was prepared
in Et2O, the solvent was removed in vacuo, and then the 1,4-addition reaction
was carried out in the presence of TIPS triflate in CH2Cl2. By this modified
procedure, the desired substrates 4 were obtained in good yields.
(12) See the Supporting Information for the details of the method for
the determination of the stereochemistry of the starting materials and the
products.
Acknowledgment. This research was partly supported by
the Toray Science Foundation and a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science,
Sports and Culture of Japan. We would like to thank Ms.
Sachiyo Kubo for performing X-ray analysis.
Supporting Information Available: Preparative methods
and spectral and analytical data of compounds 1-9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL016718G
(13) Use of W(CO)5‚MeOH complex prepared by irradiation of W(CO)6
in toluene in the presence of MeOH (conditions C) gave slightly better
results than the direct irradiation method (conditions B).
Org. Lett., Vol. 3, No. 24, 2001
3873