Gold-catalyzed 5- and 6-exo-dig selective cyclizations of alkynyl silyl enol ethers: Efficient method for [3 + 2] and [4+2] annulations onto α,β-enones

Article abstract of DOI:10.1002/adsc.200700304

An efficient method for the annulation of five- and six-membered rings onto α,β-enones is described via gold-catalyzed 5- and 6-exo-dig selective cyclizations of alkynyl silyl enol ethers.

Full text of DOI:10.1002/adsc.200700304

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DOI: 10.1002/adsc.200700304
Gold-Catalyzed 5- and 6-exo-dig Selective Cyclizations of
Alkynyl Silyl Enol Ethers: Efficient Method for [3+2] and
[4+2]Annulations onto a,b-Enones
Kooyeon Leea and Phil Ho Leea,*
a
National Research Laboratory of Catalytic Organic Reaction, Department of Chemistry, Kangwon National University,
Chunchon 200-701, Republic of Korea
Fax : (+82)-33-253-7582; e-mail: phlee@kangwon.ac.kr
Received: June 23, 2007; Revised: July 10, 2007; Published online: September 11, 2007
This paper is dedicated to the memory of Professor Moon Hwan Cho.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An efficient method for the annulation of
five- and six-membered rings onto a,b-enones is de-
scribed via gold-catalyzed 5- and 6-exo-dig selective
cyclizations of alkynyl silyl enol ethers.
needed to overcome problems related to the availabil-
ity and ease of handling of the reagents, operational
simplicity and selectivity. Also, various tungsten-medi-
ated annulation methods are effective only for the
cyclization of compounds having C/C multiple bond
such as an alkynyl and allenyl group at the termi-
nus.[4,5] As part of a project aimed at finding new cy-
clopentene and cyclohexene annulations that would
be useful in organic synthesis, we report herein an ef-
ficient gold-catalyzed synthetic method for the annu-
lation of five- and six-membered rings onto alkenes as
Keywords:
ACHTREUNG[3+2]annulation; HCATRE[UGN 4+2]annulation; cat-
alysis; cyclization; gold
The development of novel methods for the annulation a result of 5- and 6-exo-dig carbocyclizations of 7-
of five- and six-membered rings onto alkenes is very siloxy-6-en-1-ynes and 8-siloxy-7-en-1-ynes, respec-
important in the field of synthetic organic chemistry tively (Scheme 1).[6]
because such methods enable a facile construction of
the carbon frameworks found in natural products.[1]
Although a variety of methods has been developed
for this purpose, it is not easy to effectively achieve
the annulation of a five- or six-membered ring onto
a,b-enones. Danheiser et al. found a useful method
for the [3+2]annulation of substituted trimethylsilyl-
allenes and a,b-enones in the presence of an excess
amount of TiCl4.[2] Addition reactions of silyl enol
Scheme 1. 5- or 6-exo-dig Selective cyclization catalyzed by
Au.
ethers to alkynes were mediated by EtAlCl2.[3] Re-
cently, Iwasawa et al. reported a novel W(CO)5(L)-
catalyzed cyclization of w-acetylenic silyl enol
ethers,[4] where 5-siloxy-5-en-1-ynes undergo 6-endo-
In the first place, various 7-siloxy-6-en-1-ynes or 8-
dig cyclization[4a,b] and 7-siloxy-6-en-1-ynes undergo siloxy-7-en-1-ynes were prepared from the 1,4-addi-
either 5-exo-dig or 6-endo-dig cyclization by the ap- tion of propargyl or homopropargyl malonate to a,b-
propriate choice of the reaction conditions.[4c] More- enones followed by in situ trapping of the intermedi-
over, Iwasawa and Lee et al. revealed that 6-siloxy-5- ate enolate using tert-butyldimethylsilyl triflate in
en-1-ynes
and
6-siloxy-1,2,5-trienes
undergo moderate to good yields (Scheme 2).
Next, the reaction conditions for the gold-catalyzed
W(CO)5(L)-catalyzed 5-endo-dig and 5-endo-trig cy-
clization to give b,g-enones and g,d-enones in good to cyclization were examined employing 7-siloxy-6-en-1-
excellent yields, respectively.[5] Despite this recent yne 1c as a substrate and the results are summarized
progress, a variety of efficient synthetic annulation in Table 1. 5 mol% AuCl gave the cyclopentene prod-
methods for a five- and six-membered ring is still uct 2c in 65% yield via 5-exo-dig cyclization followed
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Adv. Synth. Catal. 2007, 349, 2092 – 2096

Efficient Method for [3+2] and [4+2]Annulations onto a,b-Enones
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20% yield (entry 5). However, 5 mol% Ph3PAuCl
gave selectively the desired product 2c in 70% yield
(entry 6). No ketone compound was formed, indicat-
ing that the enol silyl ether is more easily desilylated
in AuCl and AuCl3 than in Ph3PAuCl and the ketone
might be produced by hydrolysis due to trace
amounts of water in the reaction mixture. 5 mol%
Ph3PAuCl and 5 mol% AgOTf in DCE at 808C for
9 h under a nitrogen atmosphere produced selectively
a,b-enone 2c in 91% yield via 5-exo-dig cylization fol-
lowed by isomerization (entry 7). The use of 5 and 15
mol% AgOTf gave 2c in 66% and 50% yield conta-
minated by ketone in 30% and 44% yields, respec-
tively (entries 8 and 9). DCE was the best solvent
among several reaction media (CH2Cl2, toluene, and
benzene) that were examined. Although 5 mol%
AuCl3 gave 2c in 82% yield at 258C for 5 min, 5
mol% Ph3PAuCl and 5 mol% AgOTf in DCE at
808C was chosen as optimum conditions because
ketone formation caused to hydrolysis of 1c is avoida-
ble.
Scheme 2. 1,4-Adition of active methylene componuds
having alkynyl group to a,b-enones.
Table 1. Optimization of the cyclization reactions of alkynyl
silyl enol ethers.[a]
To demonstrate the efficiency and scope of the
present method, a variety of 7-siloxy-6-en-1-ynes were
treated with 5 mol% Ph3PAuCl and 5 mol% AgOTf.
The results are summarized in Table 2. Under the op-
timum conditions, compound 1a and 1b were cyclized
smoothly to give the desired products having double
bond at b,g-position via 5-exo-dig cylization followed
by isomerization in 90% and 84% yields, respectively
(entries 1 and 2). In case of silyl enol ether 1d having
a propargyl malonitrile, the desired product 2d was
obtained in 82% yield (entry 4). In addition, the silyl
enol ether having a terminal alkynyl group obtained
from 2-methyl-2-cyclohexen-1-one gave 2e in 72%
yield (entry 5). The yield of cyclization in 1b and 1e
might be decreased due to steric hindrance of the
methyl group at the a-position (entry 1 vs. 2 and
entry 3 vs. 5). 7-Siloxy-6-en-1-yne (1f) derived from 2-
cyclohepten-1-one and propargyl malonate gave rise
[a]
5 mol% AuCl, 5 mol% AuCl3, 5 mol% Ph3PAuCl and
15 mol% AgOTf were used.
GC yield based on 2-methoxynaphthalene as an internal
standard.
1 mol% AuCl3 was used.
Molecular sieve (3 Š) was added as an additive.
Compound 1c was recovered in 48% yield on GC.
Hours.
[b]
[c]
[d]
[e]
[f]
to the bicycloACHTRE[UNG 5.3.0]decenone 2f in 84% yield
[g]
5 mol% AgOTf was used.
(entry 6). Exposure of the silyl enol ether derived
from 4-hexen-3-one and propargyl malonate to opti-
mum conditions furnished the cyclized product 2g in
by isomerization together with the ketone produced 80% yield (a,b-enone:b,g-enone=7:1) via 5-exo-dig
by hydrolysis of 1c in 28% yield (entry 1). In addi- cylization (entry 7).
tion, 1 mol% AuCl3 afforded 2c and ketone in 48%
Encouraged by these results, silyl enol ethers de-
and 44% yields, respectively (entry 3). Although the rived from dimethyl malonate having an internal al-
use of 5 mol% AuCl3 increased the yield of 2c kynyl group were treated with optimum conditions
(82%), hydrolysis of enol silyl ether before cycliza- and the results are summarized in Table 3. Reaction
tion is inevitable (entry 2). Examination of tempera- of 1h with 5 mol% Ph3PAuCl and 5 mol% AgOTf in
ture changes and a variety of solvents failed to sup- DCE gave 2h in 45% yield via 5-exo-dig cyclization
press the formation of ketone with catalytic AuCln followed by isomerization together with the ketone
(n=1 and 3). The use of molecular sieve as an addi- compound in 38% yield at 908C for 13 h (entry 1). 7-
tive did not improve the yield of 2c and suppress the Siloxy-6-en-1-yne 1i possessing a phenyl substituent at
formation of ketone (entry 4). Compound 2c was pro- the terminal alkynyl group produced the [3+2]annu-
duced in 72% yield using 5 mol% AuCl3 in the pres- lation product 2i and ketone in 56% and 35% yields,
ence of 15 mol% AgOTf together with the ketone in respectively (entry 3). However, 10 mol% Ph3PAuCl
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Kooyeon Lee and Phil Ho Lee
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Table 2. Gold-catalyzed 5-exo-dig cyclization of alkynyl silyl
Table 3. Gold-catalyzed 5-exo-dig cyclization of alkynyl silyl
enol ethers having a terminal alkynyl group.[a]
enol ethers having an internal alkynyl group.[a]
[a]
5 mol% Ph3PAuCl and 5 mol% AgOTf were used. E=
CO2Me.
[b]
Isolated yield. Numbers in parenthesis indicate the yield
of ketone compound obtained from hydrolysis of silyl
enol ether.
10 mol% Ph3PAuCl and 10 mol% AgOTf were used.
[c]
silyl enol ethers having an internal alkynyl group
were cyclized to give the desired product in good
yield. This is contrast to the specific cyclization of al-
kynyl silyl enol ethers having terminal alkynes with
catalytic amount of tungsten.
On the basis of above results, the [4+2]annulation
of w-alkynyl silyl enol ethers derived from 2-cycloalk-
en-1-one and homopropargyl malonate was examined
in detail (Table 4). Treatment of 1j with 10 mol%
Ph3PAuCl and 10 mol% AgOTf afforded the bicyclic
a,b-enone via 6-exo-dig cylization followed by isomer-
Table 4. Gold-catalyzed 6-exo-dig cyclization of alkynyl silyl
enol ethers having a terminal alkynyl group.[a]
[a]
5 mol% Ph3PAuCl and 5 mol% AgOTf were used. E=
CO2Me.
Isolated yield.
Ratio of a,b-enone and b,g-enone=7:1.
[b]
[c]
and 10 mol% AgOTf increased the yields (62% and
71%) of 2h and 2i, respectively (entries 2 and 4). The
cyclization of 1i is more efficient than that of 1h due
to the generation of a more stable partial positive
charge. Because cyclization of silyl enol ethers an
having internal alkynyl group needed a longer reac-
tion time than that for a terminal alkynyl group,
yields of ketone compounds via hydrolysis of enol
silyl ethers might be increased. It is noteworthy that
[a]
10 mol% Ph3PAuCl and 10 mol% AgOTf were used.
E=CO2Me.
Isolated yield. Numbers in parenthesis indicate the yield
of ketone compound obtained from hydrolysis of silyl
enol ether.
[b]
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Efficient Method for [3+2] and [4+2]Annulations onto a,b-Enones
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ization and ketone compound via hydrolysis of silyl exo-dig or 6-exo-dig carbocyclizations of 7-siloxy-6-
enol ether in 83% and 12% yields, respectively en-1-ynes or 8-siloxy-7-en-1-ynes, respectively. It is
(entry 1). Reaction of 1k with cat-gold under the opti- noteworthy that sily enol ethers having internal al-
mum conditions gave the bicycloACHTRE[UGN 4.4.0]decenone in kynes as well as terminal alkynes were smoothly cy-
80% yield (entry 2). 8-Siloxy-7-en-1-yne 1l obtained clized to give cyclopentene and cyclohexene annula-
from 2-cyclohepten-1-one and homopropargyl malo- tion products in good to excellent yields. The present
nate gave rise to the bicyclo
yield (entry 3).
ACHTREUNG
At present the reaction is assumed to proceed as of handling of reagents, operational simplicity, and
follows: treatment of the silyl enol ether 1c with 5 high selectivity. These results should immediately pro-
mol% Ph3PAuCl and 5 mol% AgOTf generates the vide more opportunities for the elucidation of effi-
h2-alkyne complexes A and/or the vinylidene complex cient new cyclopentene and cyclohexene annulation
D.[6] When this complex A is formed, the alkyne part strategies.
becomes electron deficient due to the [Au]+ and intra-
molecular attack of the silyl enol ether occurs to give
the vinyl metallic intermediate B, which is finally pro- Experimental Section
tonated and isomerized to give the cyclopentene 2c
(Scheme 3). Because [4+2]annulation product via E General Remarks
from 1c was not produced, the intermediate vinyli-
dene complex D was excluded in this mechanism. To
obtain information on the mechanism of this reaction,
Reactions were carried out in oven-dried glassware under a
nitrogen atmosphere. All commercial reagents were used
without purification, and all solvents were reaction grade.
we have carried out D2O experiments. After comple-
tion of cyclization of 1c (808C, 9 h), addition of D2O
(15 equivs.) to the reaction mixture produced a com-
pound[7] with deuterium incorporated in the methyl-
ene group at the a’-position instead of the compound
with deuterium incorporated in the methyl group at
the b-position, indicating that vinylgold B might ab-
stract acidic protons at the a- and/or a’-position of in-
termediate B. Treatment of 1c with cat-Ph3PAuCl/
AgOTf in the presence of D2O (15 equivs.) gave the
complicated results on TLC.
THF was freshly distilled from sodium/benzophenone under
a nitrogen. DCE was freshly distilled from calcium hydride
under a nitrogen. All reaction mixtures were stirred magnet-
ically and were monitored by thin-layer chromatography
using Merck silica gel 60 F254 precoated glass plates, which
were visualized with UV light, and then, developed by using
Fluka silica gel 60 (0.040–0.063 mm, 230–400 mesh). Com-
mercially available solvents were purified by standard proce-
dures.
Preparation ofDimethyl 3- tert-Butyldimethylsilyl-2-
cyclohexen-1-yl propargylmalonate (1c)
In conclusion, a novel gold-catalyzed synthetic
method for the annulation of a five- or six-membered
ring onto alkenes was developed as a result of the 5-
To a suspension of NaH (60%, 76.8 mg, 1.92 mmol) in THF
(5 mL) was added dimethyl propargylmalonate (219.5 mg,
Scheme 3. Proposed pathway for the cyclization of siloxy enynes.
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Kooyeon Lee and Phil Ho Lee
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1.29 mmol) at 08C under a nitrogen atmosphere. After
30 min, 2-cyclohexen-1-one (96.1 mg, 1.0 mmol) and
TBSOTf (301.4 mg, 1.14 mmol) were added at room temper-
ature. After 2 h, the reaction mixture was quenched with
buffer solution (pH 7, KH2PO4 +Na2HPO4). The aqueous
layer was extracted with EtOAc (3”20 mL). The combined
organics were washed with water and brine, dried with
MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatogra-
phy (n-hexane:EtOAc=20:1) to give the desired product;
yield: 304.0 mg (80%).
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To a suspension of Ph3PAuCl (11.1 mg, 0.0223 mmol) and
AgOTf (5.7 mg 0.0223 mmol) in DCE (1.3 mL) was added
7-siloxy-6-en-1-yne or 8-siloxy-6-en-1-yne (0.45 mmol) in
DCE (1 mL) at room temperature under a nitrogen atmos-
phere. After being stirred at 808C for 9 h, the reaction mix-
ture was cooled at room temperature. The reaction mixture
was diluted with CH2Cl2 (5 mL), filtered through Celite and
then the solvent was removed under reduced pressure. The
residue was purified by silica gel column chromatography
(n-hexane:EtOAc=3:1) to give the desired product.
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Supporting Information
Characterization data for the products are available in the
Supporting Information.
Acknowledgements
This work was supported by the Korea Science and Engineer-
ing Foundation (KOSEF) through the National Research
Lab. Program funded by the Ministry of Science and Tech-
nology (No. M10600000203–06J0000–20310), by the CMDS
at KAIST, and by the Korea Science and Engineering Foun-
dation (KOSEF, R01–2006–000–11283–0). The NMR and
mass data were obtained from the central instrumental facility
in Kangwon National University.
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2096
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 2092 – 2096