Cyclopentannulation of enones with organocuprate reagents containing an acetal or an orthoester function

Article abstract of DOI:10.1016/S0040-4020(01)01248-0

1,1-Dimethyl-3-(phenylthio)-propane 4 was deprotonated with t-BuLi, then converted to the corresponding organocuprate reagent which, in the presence of HMPA and TMSCI, was added to a variety of enones to give the corresponding silylenol ethers 7. These were cyclised without purification upon acidic conditions to give the cyclopentannulation products 9. A similar result was obtained with the corresponding orthoester reagent 6. This cyclopentannulation sequence is applicable to a wide variety of enones except for those bearing substituents near the reacting centre.

Full text of DOI:10.1016/S0040-4020(01)01248-0

TETRAHEDRON
Pergamon
Tetrahedron 58 &2002) 1565±1571
Cyclopentannulation of enones with organocuprate reagents
containing an acetal or an orthoester function
a
Pingyu Ding and Leon Ghosez
a,b,p
Â
a
Á Â
Laboratoire de Chimie Organique de Synthese, Universite catholique de Louvain, Place Louis Pasteur 1,
B-1348 Louvain-la-Neuve, Belgium
Institut Europeen de Chimie et Biologie 'IECB), c/o ENSCPB 16, Avenue Pey Berland, F-33607 Pessac, France
b
Â
Received 6 October 2001; revised 16 November 2001; accepted 13 December 2001
AbstractÐ1,1-Dimethyl-3-&phenylthio)-propane 4 was deprotonated with t-BuLi, then converted to the corresponding organocuprate
reagent which, in the presence of HMPA and TMSCl, was added to a variety of enones to give the corresponding silylenol ethers 7.
These were cyclised without puri®cation upon acidic conditions to give the cyclopentannulation products 9. A similar result was obtained
with the corresponding orthoester reagent 6. This cyclopentannulation sequence is applicable to a wide variety of enones except for those
bearing substituents near the reacting centre. q 2002 Published by Elsevier Science Ltd.
1. Introduction
In our continuing search for new cyclopentannulation
reagents, we have examined organometallic derivatives of
compound 4. A potential advantage of these complexes over
the previously studied reagents 1±3 results fromthe possi-
bility of introducing a chiral ligand on the metal. An elegant
example of this type of approach has recently been reported
by Feringa's group.1n,s
The power of cycloaddition and cyclocondensation reac-
tions for the construction of a new ring results fromtheir
convergent character and often high regio- and stereo-selec-
tivities. Among these, asymmetric addition or condensation
reactions of C3 reagents to ole®ns have received much
attention.1 Our own group has been involved in the study
of the 1,3-dipole equivalents 1 which have been success-
fully used as annulation reagents of aldehydes, ketones and
cyclic enones &Scheme 1).2 Enantioselective versions of
these reactions using the readily available reagents 2 and
3 have recently been reported.3,4
2. Results and discussion
2.1. Synthesis of the C3 reagents
Both acetal 4 and orthoester 5 were readily prepared by a
conventional sequence of reactions &Scheme 2).
The more stable bicyclic orthoester 6 was obtained in
excellent yields according to Scheme 3.
Scheme 2. Reagents and conditions: &a) HC&OMe)3, montmorillonite k-10,
rt, 12 h; &b) HClg in CH2Cl2, EtOH &1.5 equiv.); &c) HOCH2CH2OH
&2 equiv.), CH2Cl2, 1 day at rt then re¯ux, 12 h.
Scheme 1.
Keywords: cyclopentannulation; conjugate addition; Mukaiyama aldol reaction; cuprate reagents; enones; acetal; orthoester.
Corresponding author. Tel.: 132-10-472741; fax: 111-32-10-474168; e-mail: ghosez@chim.ucl.ac.be; leon.ghosez@iecb-polytechnique.u-bordeaux.fr
p
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020&01)01248-0

1566
P. Ding, L. Ghosez / Tetrahedron 58 '2002) 1565±1571
Scheme 3. Reagents and conditions: &a) 1,10-carbonyldiimidazole &1.1 equiv.), 3-methyl-3-oxetanemethanol &1.1 equiv.); &b) BF3´OEt2.
2.2. Cyclopentannulation reactions
Compound 4 was readily deprotonated at 2788C with
t-BuLi in THF containing 2.5 equiv. of HMPA &Scheme
4).5 The resulting organolithiumcompound was poured
into a suspension of CuBr´SMe2 in THF. After 30 min at
2408C, a mixture of cyclohexenone, TMSCl and triethyl-
amine was added to the organocuprate reagent and kept for
1 h at 2408C. An aqueous work-up to remove HMPA was
found necessary for a successful cyclisation of the inter-
mediately formed silylenol ether 7 which was obtained in
nearly pure formafter removal of the solvent &Scheme 4;
Table 1, Entry a). The cyclisation was successfully
performed with TiCl4 or, alternatively, with SnCl4±
ZnCl2.6 Quenching crude 7 with aqueous tetrabutylammo-
nium¯uoride yielded ketal 8 which also cyclised upon
treatment with HCl. Both cyclisations gave a 3:2 mixture
of epimers 9 which were separated by column chromo-
tography.
Scheme 4. Reagents and conditions: &a) 4, t-BuLi &1.2 equiv.) in THF,
HMPA &2.5 equiv.), 2788C, 2 h then CuBr´SMe2 &1.2 equiv.), 30 min,
2788C to 2408C; &b) enone &1.1 equiv.), TMSCl &2.5 equiv.), Et3N
&2.5 equiv.), 1 h, 2408C; &c) TiCl4 &1 equiv.), 4 A MS, CH2Cl2, 1 h at
Ê
2788C or SnCl4±ZnCl2 &0.1 equiv.), 4 A MS, CH2Cl2, 1 h at 2788C;
Ê
&d) 1.0 M TBAF &1.2 equiv.) in THF, 08C, 30 min; &e) 36.5% HCl1THF
&25 vol), 3 h, rt.
The same experimental procedure was applied to the
Table 1. Cyclopentannulation of enones
Entry
Enone
Adduct 8
Yield &%)a
Annulation product 9
Yield &%)a
a
87
81
b
c
85
82
40
77
d
e
88
75
93
91
f
Recovery of starting
materials or
decomposition products
a
Pure products.

P. Ding, L. Ghosez / Tetrahedron 58 '2002) 1565±1571
1567
cyclopentannulation of various enones. The reaction was
3. Conclusions
not sensitive to ring size &Table 1, entries a±c) and could
be applied to acyclic enones &entries d, e). However, the
sequence was extremely sensitive to substituents at C3, C4
and C5 of cyclohexenone or cyclopentenone &Entry f). For
these more crowded systems, enolisation probably com-
peted favorably with 1,4 addition.
We have described a facile albeit not general method for the
cyclopentannulation of enones. The products are densely
functionalised. In particular, they contain a phenylthioether
function which could be used for the introduction of a
double bond by b-elimination via the corresponding sulf-
oxide or for the formation of an organolithium compound
by reductive lithiation. The present work also showed that
an organocuprate bearing an a-thioether group could be
generated by transmetallation from the corresponding
organolithiumderivative. Synthetic applications of these
cyclopentannulation are being currently explored in our
group.
The functional density of cyclopentannulation product 9
should make them useful building blocks for synthesis.
The lack of stereoselectivity of the 1,4 addition of 4 to the
enone is of no importance since the thiophenyl substituent
would be eliminated at a later stage. The addition
products 8 are also useful synthetic intermediates as
shown in Scheme 5.
4. Experimental
4.1. General
All reaction requiring anhydrous or inert conditions were
carried out under an atmosphere of dried argon in ¯ame-
dried glassware. All solvents were dried by standard pro-
cedures and freshly distilled. Infrared spectra were recorded
on a Perkin±Elmer 681 spectrophotometer. 1H NMR spectra
were recorded in CDCl3 on a Varian XL-300 or a Varian
XL-200 spectrometer. 13C spectra &50 MHz) were recorded
on a Varian XL-200 or a VXR-200 spectrometer. Chemical
shifts &d) are expressed in ppmrelative to TMS as internal
standard. Mass spectra were recorded on Varian MAT-44 or
Finnigan MAT-TSQ70 spectrometers &electronic impact
70 eV or chemical ionisation with N2O±CH4 as ionising
gas). Thin-layer chromatography &TLC) was run on
precoated silica gel plates &Merck 60F254). Flash chroma-
tography was carried out using ¯ash silica gel 60 Merck
&40±63 mm) as the stationary phase.
Scheme 5. Reagents and conditions: &a) HOAc±THF±H2O &3:1:1) 2 h at
608C; &b) mCPBA &1 equiv.), 30 min at 08C; &c) 1 h in toluene, 708C.
We also tried to performthe cyclopentannulation of cyclo-
hexenone using the orthoester reagent 5. This invariably led
to decomposition products &Scheme 6). It is conceivable that
the sensitive orthoester function of 5 was not compatible
with the conditions to generate the organocuprate reagent.
This interpretation was supported by the observation that
the cyclopentannulation sequence could be successfully
performed with the more stable orthoester reagent 6
&Scheme 7). In this case, the cyclisation was effected with
the powerful silylating agent TMSNTf2 acting as a Lewis
acid catalyst.7 The resulting cyclopentannulation products
are highly functionalised and similar bicyclic compounds
have been shown to be easily converted into bicyclic cyclo-
pentenone 12.
4.1.1. [)3,3-Dimethoxypropyl)thio]-benzene )4). This
product had been prepared earlier.8 We found the following
procedure more practical:9 The k-10/trimethyl orthoformate
reagent is readily prepared by stirring k-10 montmorillonite
Scheme 6.
Scheme 7. Reagents and conditions: &a) t-BuLi &1.2 equiv.), in THF1HMPA &1.2 equiv.), 2788C to 2108C, 2.5 h, then CuBr´SMe2 &1.2 equiv.), 20 min
at 2788C then 40 min at 2408C; &b) cyclohexenone or cycloheptenone &0.67 equiv.), TMSCl &2.33 equiv.), Et3N &2.67 equiv.), 2788C to 2408C, 2 h;
&c) TMSNTf2 &0.1 equiv.), 1 h at 2788C.

1568
P. Ding, L. Ghosez / Tetrahedron 58 '2002) 1565±1571
clay &60 g) with trimethyl orthoformate &90 ml), followed
by ®ltration. 2-&Phenylthio)propyl aldehyde &29.5 g, 177.4
mmol) was stirred with the resulting wet cake in 150 ml dry
n-hexane until TLC showed complete conversion &about
3 h). The product was isolated after ®ltration, washing the
®ltrate with sodiumbicarbonate solution followed by water,
drying and evaporation of the solvent. The product was
distilled as a colorless oil at 94±958C/4.4£1022 mmHg in
95% yield. 1H NMR &200 MHz): 7.39±7.11 &m, 5H), 4.51 &t,
Jˆ5.4 Hz, 1H), 3.32 &s, 6H), 2.96 &t, Jˆ7.5 Hz, 2H), 1.94
&dt, Jˆ5.4, 7.5 Hz, 2H); 13C NMR &50 MHz): 136.97,
129.95, 129.68, 126.68, 103.97, 53.88, 33.07, 29.52.
until all the starting material was consumed &TLC analysis).
The reaction was then quenched by the addition of triethyl-
amine &22.96 ml, 65.1 mmol), diluted with ether and ®ltered
to remove the amine±BF3 complex. The ®ltrate was concen-
trated and puri®ed by column chromatography on silica gel
with cyclohexane/ethyl acetate 4:1. The column was washed
with 10% Et3N in cyclohexane/ethyl acetate 4:1 before the
chromatography. The product 6 was obtained as a white
solid in 80% yield &17.6 g). FT-IR &cm21): 2959, 2880,
1
2360, 1441, 1288, 1046; H NMR &300 MHz): 7.33±7.12
&m, 5H), 3.88 &s, 6H), 3.02 &t, Jˆ8.4 Hz, 2H), 2.01 &t, Jˆ
8.4 Hz, 2H), 0.79 &s, 3H); 13C NMR &50 MHz): 137.15,
129.59, 129.52, 126.38, 108.97, 73.33, 37.56, 30.98,
27.95, 15.18; EI-MS: m/z &%)ˆ266&M1z, 100), 236&7),
181&7), 163&13), 144&15), 123&13), 109&16), 55&8); HRMS:
calculated for C14H18O3S: 266.0976; found: 266.0975.
4.1.2. )3-Phenylthio)-dioxolane ethyl orthopropionate
)5). Ethanol &6 ml, 103 mmol) was added to a solution of
3-phenylthiopropionitrile &12 g, 73.51 mmol)10 in 250 ml
CH2Cl2. The reaction mixture was saturated with HCl gas
at 2558C, then kept at 258C overnight. After warming to
room temperature, the solvent was evaporated, and 60 ml
CCl4 were added. This process was repeated three times
to remove residual HCl gas. The resulting white solid was
dissolved in 100 ml CH2Cl2, then ethylene glycol &4.099 ml,
73.51 mmol) was added and the reaction mixture was stirred
at roomtemperature for 24 h, then re¯uxed overnight. After
cooling, the solvent was evaporated. The residue was
puri®ed by column chromatography on silica gel with cyclo-
hexane/ethyl acetate 3:1. The column must be washed with
10% Et3N in cyclohexane/ethyl acetate 3:1 prior to the
chromatography. The product 5 &11.22 g, 60%) was
4.2. General procedure for the preparation of compound
8
tert-BuLi 1.7 M &3.768 ml, 5.652 mmol) was added to a
solution of compound 4 &1 g, 4.71 mmol) and hexamethyl-
phosphoramide &2.048 ml, 11.77 mmol) in THF &8 ml) at
2788C. After stirring at 2788C for 2 h, the reaction mixture
was added by the double-ended cannula to another three-
necked ¯ask containing a suspension of copper&I) bromide±
dimethyl sul®de complex &1.271 g, 6.123 mmol) in 4 ml
THF. After 20 min at 2788C and 45 min at 2408C, the
solution became orange and clear. Then enone &5.181
mmol), chlorotrimethylsilane &2.092 ml, 16.48 mmol)
and triethylamine &2.291 ml, 16.48 mmol) were added at
2788C. After 30 min, the reaction mixture was brought to
2408C &1.5 h), then warmed to room temperature. It was
quenched by 1 M solution of tetrabutylammonium ¯uoride
in THF &6.123 ml, 6.123 mmol). After total disappearance
of the intermediate silyl enol ether &^15 min), the mixture
was diluted with water, ®ltered through a pad of Celite,
extracted with diethyl ether, and washed with cold water
four times to remove HMPA completely. Chromatography
on silica gel with cyclohexane/ethyl acetate &3:1) gave the
product 8.
1
obtained as a colorless oil. H NMR &300 MHz): 7.35±
7.15 &m, 5H), 4.13±3.97 &m, 4H), 3.53 &q, Jˆ7.1 Hz, 2H),
3.05 &t, Jˆ8.4 Hz, 2H), 2.14 &t, Jˆ8.4 Hz, 2H), 1.18 &t, Jˆ
7.1 Hz, 3H). HRMS: calculated for C13H18O3S: 254.0976;
found: 254.0973.
4.1.3. 3-)Phenylthio)propionate ester of 3-methyl-3-
hydroxy-methyloxetane. A solution of 3-&phenylthio)pro-
panoic acid11 &5 g, 27.43 mmol) in 10 ml CH2Cl2 was added
to a solution of 1,10-carbonyldiimidazole &4.893 g, 30.18
mmol) in 20 ml CH2Cl2. After stirring the reaction mixture
at room temperature for 30 min, 3-methyl-3-oxetanemetha-
nol &3 ml, 30.18 mmol) was added through a syringe. The
reaction mixture was stirred for another 34 h until TLC
showed the conversion was complete. After removal of
the solvent, the residue was puri®ed by column chroma-
tography on silica gel with cyclohexane/ethyl acetate 3:1.
The column was washed with 10% Et3N in cyclohexane/
ethyl acetate 3:1 before the chromatography. The product
4.2.1. 3,3-Dimethoxy-1-)3-oxocyclohexyl)-1-phenylthio-
propane )8a): mixture of isomers. Yellow oil, 87%
yield. H NMR &300 MHz): 7.45±7.18 &m, 5H), 4.68 &dd,
1
Jˆ3.5, 7.6 Hz, 1H), 3.32, 3.31, 3.26, 3.22 &each s, 6H),
3.25±3.15 &m, 1H), 2.55±2.18 &m, 5H), 2.15±1.52 &m,
6H); EI-MS: m/z &%)ˆ308&M1z, 88), 245&15), 167&50),
135&47), 109&43), 84&99), 75&100), 47&83); HRMS: calcu-
lated for C17H24O3S: 308.1446, found: 308.1439.
1
&6.37 g, 87%) was obtained as a colorless oil. H NMR
&300 MHz): 7.38±7.21 &m, 5H), 4.50 &d, Jˆ6 Hz, 2H),
4.37 &d, Jˆ6 Hz, 2H), 4.18 &s, 2H), 3.18 &t, Jˆ6.9 Hz,
2H), 2.68 &t, Jˆ6.9 Hz, 2H), 1.21 &s, 3H); 13C NMR
&50 MHz): 172.47, 135.74, 130.91, 129.74, 127.36, 80.16,
69.57, 39.69, 34.95, 29.78, 21.81; EI-MS: m/z &%)ˆ
266&M1z, 100), 236&11), 182&30), 165&12), 163&8),
137&14), 123&23), 109&24).
4.2.2. 3,3-Dimethoxy-1-)3-oxocyclopentyl)-1-phenylthio-
propane )8b): mixture of isomers. Yellow oil, 85% yield.
1H NMR &300 MHz): 7.46±7.15 &m, 5H), 4.77 &dd, Jˆ3.6,
7.7 Hz, 1H), 3.35, 3.33, 3.28, 3.26 &each s, 6H), 3.30±3.20
&m, 1H), 2.54±2.04 &m, 5H), 2.04±1.63 &m, 4H); EI-MS:
m/z &%)ˆ294&M1z, 100), 231&16), 153&100), 109&48);
HRMS: calculated for C16H22O3S: 294.1289; found:
294.1294.
4.1.4. 1-)2-Phenylthioethyl)-4-methyl-2,6,7-trioxabicyclo-
[2,2,2]-octane )6). Boron tri¯uoride diethyl etherate
&2.598 ml, 20.64 mmol) was added dropwise at 08C to a
solution of 3-phenylthiopropionate ester of 3-methyl-3-
hydroxy-methyloxetane &22 g, 82.59 mmol) in 80 ml
CH2Cl2, then the reaction mixture was stirred for 2.5 h
4.2.3. 3,3-Dimethoxy-1-)3-oxocycloheptyl)-1-phenylthio-
propane )8c): mixture of isomers. Yellow oil, 82% yield.
1H NMR &300 MHz): 7.45±7.19 &m, 5H), 4.66 &dd, Jˆ3.3,

P. Ding, L. Ghosez / Tetrahedron 58 '2002) 1565±1571
1569
8.2 Hz, 1H), 3.314, 3.310, 3.26, 3.25 &each s, 6H), 3.28±
3.23 &m, 1H), 2.65±2.62 &m, 1H), 2.52±2.32 &m, 2H), 2.06±
1.80 &m, 6H), 1.80±1.22 &m, 4H); EI-MS: m/z &%)ˆ
322&M1z, 17), 291&16), 259&15), 181&81), 154&50), 136&43),
84&33), 49&100); HRMS: calculated for C18H26O3S:
322.0816; found: 322.0844.
2.21 &m, 1H), 2.10±1.91 &m, 2H), 1.83±1.69 &m, 2H); 13C
NMR &50 MHz): 199.34, 143.23, 136.78, 132.43, 130.67,
129.59, 126.94, 51.27, 50.00, 40.97, 40.60, 27.18, 24.21.
4.3.2. One isomer of compound 9b. FT-IR &cm21): 3430
&bs), 2939, 2360, 1741, 1480, 1438; H NMR &300 MHz):
1
7.44±7.26 &m, 5H), 3.89±3.83 &m, 1H), 3.52±3.42 &m, 1H),
2.59±2.10 &m, 5H), 1.65 &dd, Jˆ3.3, 12.5 Hz, 2H), 1.32±
1.23 &m, 2H); 13C NMR &50 MHz): 218.97, 134.51, 133.32,
129.79, 128.22, 71.49, 52.98, 48.43, 40.81, 36.87, 36.40,
34.72; EI-MS: m/z &%)ˆ248&M1, 100), 153&9), 149&10),
136&8), 121&11), 110&26), 93&15); HRMS: calculated for
C14H16O2S: 248.0871; found: 248.0870.
4.2.4. 7,7-Dimethoxy-5-)phenylthio)heptan-2-one )8d).
Yellow oil, 88% yield. FT-IR &cm21): 2935, 2831, 1716
&CvO), 1125, 1056; H NMR &200 MHz): 7.40±7.15 &m,
1
5H), 4.67 &t, Jˆ5.7 Hz, 1H), 3.29 &s, 3H), 3.27 &s, 3H),
3.26±3.10 &m, 1H), 2.67 &t, Jˆ7.3 Hz, 2H), 2.08 &s, 3H),
2.05±1.60 &m, 4H); 13C NMR &50 MHz): 208.28, 135.21,
132.72, 129.47, 127.58, 103.31, 53.98, 53.52, 45.27, 41.07,
38.99, 29.47; EI-MS: m/z &%)ˆ282&M1z, 24), 192&13),
141&100), 115&11), 109&14), 75&27), 43&35); HRMS: calcu-
lated for C15H22O3S: 282.1289; found: 282.1284.
4.3.3. Compound 9c. 3:5 &cis/trans) Isomers ratio was
measured according to the H NMR of the crude product.
1
The two isomers could be isolated by chromatography on
silica gel with cyclohexane/ethyl acetate &7:1) as eluent.
4.2.5. 8,8-Dimethoxy-6-)phenylthio)octan-3-one )8e).
Yellow oil, 75% yield. FT-IR &cm21): 2937, 1712 &CvO),
1125, 1056, 747, 693; H NMR &200 MHz): 7.41±7.20 &m,
cis isomer: FT-IR &cm21): 2922, 1679, 1608, 1438, 1320,
1175; H NMR &300 MHz): 7.38±7.24 &m, 5H), 6.69 &dd,
1
1
5H), 4.67 &t, Jˆ5.7 Hz, 1H), 3.30 &s, 3H), 3.28 &s, 3H),
3.23±3.14 &m, 1H), 2.65 &t, Jˆ7.4 Hz, 2H), 2.46±2.27 &m,
2H), 2.04±1.71 &m, 4H), 1.02 &t, Jˆ7.4 Hz, 3H); 13C NMR
&50 MHz): 211.50, 135.12, 132.80, 129.57, 127.69, 103.21,
54.05, 53.58, 39.77, 38.94, 36.62, 29.52, 8.45; EI-MS: m/z
&%)ˆ296&M1z, 23), 192&17), 155&100), 110&9), 75&24),
57&18); HRMS: calculated for C16H24O3S: 296.1446;
found: 296.1447.
Jˆ2.7, 4.4 Hz, 1H), 3.45 &dt, Jˆ6.2, 8.3 Hz, 1H), 2.97 &ddt,
Jˆ2.5, 2.7, 8.3 Hz, 1H), 2.87±2.78 &m, 1H), 2.61±2.42 &m,
3H), 2.15±1.93 &m, 3H), 1.58±1.27 &m, 3H); 13C NMR
&50 MHz): 200.38, 147.31, 139.91, 136.14, 131.68,
129.63, 127.42, 52.92, 52.76, 45.45, 40.65, 37.02, 31.02,
25.84; EI-MS: m/z &%)ˆ259[&M11)1, 8], 149&100),
131&30), 121&68), 105&38), 93&51), 79&19); HRMS: calcu-
lated for C16H18OS: 258.1078; found: 258.1077.
trans isomer: 1H NMR &300 MHz): 7.35±7.26 &m, 5H), 6.74
&dd, Jˆ1.0, 3.2 Hz, 1H), 4.04 &dt, Jˆ8.0, 9.6 Hz, 1H), 3.08±
3.01 &m, 1H), 2.82 &ddd, Jˆ3.2, 8.0, 18.5 Hz, 1H), 2.62±
2.42 &m, 3H), 2.31±2.25 &m, 1H), 2.12±1.91 &m, 2H), 1.55±
1.27 &m, 3H); 13C NMR &50 MHz): 201.05, 149.31, 139.36,
127.01, 129.98, 129.58, 126.74, 50.65, 48.29, 45.10, 38.99,
32.17, 31.07, 25.49.
4.3. General procedure for the preparation of cyclised
compound 9
0.45 ml of 36.5% HCl aq. was added to a solution of
compound 8 &2.269 mmol) in 30 ml THF. The reaction
mixture was stirred at room temperature for 4 h. The solvent
was then removed and the residue was dissolved in CH2Cl2,
washed with sat. NaHCO3 solution and water, dried over
MgSO4. Chromatography on silica gel using cyclohexane/
ethyl acetate &7:1) as eluent gave the isomer mixture, which
could be further separated.
4.3.4. 1-[3-)Phenylthio)cyclopent-1-enyl]ethan-1-one )9d).
Yellow oil, 93% yield from 8d. FT-IR &cm21): 3058, 2943,
1667 &CvO), 1374, 740, 691; H NMR &200 MHz): 7.35±
1
7.18 &m, 5H), 6.64 &bs, 1H), 4.03±3.90 &m, 1H), 3.16±2.80
&m, 4H), 2.30 &s, 3H); 13C NMR &50 MHz): 196.41, 144.84,
141.94, 136.27, 131.01, 129.50, 127.10, 43.54, 41.99, 38.99,
27.00; EI-MS: m/z &%)ˆ218&M1z, 100), 175&13), 109&84),
93&7), 65&12), 43&75); HRMS: calculated for C13H14OS:
218.0765; found: 218.0766.
4.3.1. 1-Phenylthio-1,2,5,6,7,7a-hexahydro-4H-inden-4-
one )9a). 9a 2:3 &cis/trans) Isomers ratio was measured
according to the H NMR of the crude product, The two
isomers could be separated by chromatography on silica gel
with cyclohexane/ethyl acetate &10:1) as eluent.
1
cis isomer: FT-IR &cm21): 3056, 2938, 1683, 1615, 1479,
1232, 1089; 1H NMR &300 MHz): 7.43±7.25 &m, 5H), 6.57
&dd, Jˆ3.3, 5.8 Hz, 1H), 3.55 &dt, Jˆ8.3, 9.6 Hz, 1H), 2.93±
2.80 &m, 2H), 2.55±2.44 &m, 2H), 2.25±2.11 &m, 2H), 2.05±
1.95 &m, 1H), 1.79±1.63 &m, 1H), 1.29 &ddd, Jˆ3.3, 12.7,
15.9 Hz, 1H); 13C NMR &50 MHz): 198.88, 144.29, 137.07,
135.75, 132.37, 129.66, 127.71, 54.31, 52.40, 40.83, 40.63,
30.80, 24.04; EI-MS: m/z &%)ˆ[&M11)1, 100], 227&24),
180&14), 135&98), 117&17), 107&12), 92&10), 79&11);
HRMS: calculated for C15H16OS: 244.0921; found:
244.0926.
4.3.5. 1-[3-)Phenylthio)cyclopent-1-enyl]propan-1-one
)9e). Yellow oil, 91% yield from 8e. FT-IR &cm21): 2975,
1667 &CvO), 740, 691; H NMR &200 MHz): 7.35±7.14
&m, 5H), 6.63 &bs, 1H), 4.00±3.92 &m, 1H), 3.12±2.98 &m,
2H), 2.71±2.60 &m, 4H), 1.08 &t, Jˆ7.4 Hz, 3H); 13C NMR
&50 MHz): 199.48, 144.01, 140.65, 136.25, 130.82, 129.50,
127.00, 43.21, 41.90, 39.06, 32.45, 8.82; EI-MS: m/z &%)ˆ
232&M1z, 100), 175&9), 109&84), 149&9), 123&30), 110&30),
93&14), 65&15), 57&32); HRMS: calculated for C14H16OS:
232.0921; found: 232.0926.
1
4.4. General procedure for the preparation of
a,b-unsaturated ketoaldehydes 10
trans isomer: 1H NMR &300 MHz): 7.42±7.26 &m, 5H), 6.66
&dd, Jˆ3, 5.6 Hz, 1H), 4.25 &dt, Jˆ1.2, 6.9 Hz, 1H), 3.32±
3.24 &m, 1H), 2.97±2.86 &m, 1H), 2.62±2.47 &m, 2H), 2.32±
A solution of compound 8 &1.82 mmol) in 10 ml of acetic

1570
P. Ding, L. Ghosez / Tetrahedron 58 '2002) 1565±1571
acid±water±tetrahydrofuran &v/v/vˆ3:1:1) was kept at
658C for 2.5 h until TLC showed complete hydrolysis.
The solvents were evaporated and the residue was dissolved
in diethyl ether and washed with sat. Na2CO3 solution and
water. It was then dried over MgSO4, ®ltered, and concen-
trated. The resulting aldehyde was dissolved in 6 ml
CH2Cl2, and a solution of 3-chloroperoxybenzoic acid
&438.4 mg, 1.829 mmol) in 5 ml CH2Cl2 was added drop-
wise at 08C. The reaction mixture was stirred at 08C for 1 h,
then diluted with 20 ml CH2Cl2 and washed with sat.
NaHCO3 solution and brine. After drying over MgSO4,
®ltration, and concentration, the residue was dissolved in
13 ml toluene and the mixture was re¯uxed for 4 h. Puri®-
cation by column chromatography on silica gel using cyclo-
hexane/ethyl acetate &3:2) as eluent gave the product 10.
30 min, the mixture was kept at 2408C for another 1.5 h.
The reaction was quenched by water, diluted with diethyl
ether, ®ltered through a pad of Celite. The organic phase
was separated, the water phases were extracted with diethyl
ether, the combined organic phase was washed with cold
water four times to remove the HMPA completely, dried
over MgSO4, ®ltered and concentrated to afford the crude
silyl enol ether.
The crude silyl enol ether was dissolved in 18 ml CH2Cl2,
the mixture was cooled to 2788C, TMSNTf2 &79 ml,
0.325 mmol) was added. After stirring at 2788C for 1 h,
the reaction was quenched with water, diluted with 20 ml
CH2Cl2, washed with sat. NaHCO3 and brine, dried over
MgSO4, ®ltered, concentrated. Chromatography on silica
gel with cyclohexane/ethyl acetate &1:2) afforded the
product.
4.4.1.
trans-3-)3-Oxocyclohexyl)-2-propenal
)10a).
Yellow oil, 72% yield from 8a. FT-IR &cm21): 2938,
1709, 1685, 1653; 1H NMR &200 MHz): 9.54 &d, Jˆ
7.6 Hz, 1H), 6.80 &dd, Jˆ6.2, 15.8 Hz, 1H), 6.11 &ddd, Jˆ
1.4, 7.6, 15.8 Hz, 1H), 2.94±1.58 &m, 9H); 13C NMR
&50 MHz): 209.64, 194.29, 159.48, 132.07, 46.13, 41.70,
41.51, 30.45, 25.99; EI-MS: m/z &%)ˆ152&M1z, 100),
134&77), 123&72), 106&75), 94&96), 91&10); HRMS: calcu-
lated for C9H12O2: 152.0837; found: 152.0842.
4.4.4.1. Preparation of 11a. White powder solid, 55%
yield. FT-IR &cm21): 3446 &OH), 3034, 2945, 2864, 1705
&CvO), 1152, 1047; H NMR &300 MHz): 7.40±7.21 &5H,
1
m), 3.76±3.57 &m, 3H), 3.43 &d, Jˆ11.3 Hz, 2H), 2.76 &d,
Jˆ7.1 Hz, 1H), 2.67 &dd, Jˆ7.6, 12.8 Hz, 2H), 2.54±2.33
&m, 3H), 2.03 &dd, Jˆ12.0, 12.4 Hz, 2H), 1.95±1.86 &m, 1H),
1.61±1.42 &m, 2H), 0.70 &s, 3H); 13C NMR &50 MHz):
209.88, 126.18, 131.10, 129.68, 127.28, 109.19, 69.05,
67.99, 65.17, 63.66, 48.69, 44.68, 41.96, 38.50, 35.18,
24.13, 22.65, 17.66; EI-MS: m/z &%)ˆ362&M1z, 5), 266&19),
253&100), 144&11), 109&10), 84&13); HRMS: calculated for
C20H26O4S: 362.1551; found: 362.1547.
4.4.2. trans-3-)3-Oxocyclopentyl)-2-propenal )10b).
Yellow oil, 77% yield from 8b. FT-IR &cm21): 2964,
1734, 1684, 1653; 1H NMR &200 MHz): 9.56 &d, Jˆ
7.7 Hz, 1H), 6.90 &dd, Jˆ7.0, 15.6 Hz, 1H), 6.14 &ddd,
Jˆ1.2, 7.7, 15.6 Hz, 1H), 3.20±3.11 &m, 1H), 2.60±1.78
&m, 6H); 13C NMR &50 MHz): 216.62, 193.90, 158.67,
132.71, 44.04, 40.18, 38.37, 29.31; EI-MS: m/z &%)ˆ
139[&M11)1, 100], 121&42), 109&28), 92&80), 77&98),
67&50), 65&36), 55&25); HRMS: calculated for C8H10O2:
138.0680; found: 138.0677.
4.4.4.2. Preparation of 11b. White powder solid, 58%
yield. FT-IR &cm21): 3469 &OH), 3056, 2928, 2857, 1702
&CvO), 1150, 1047; H NMR &300 MHz): 7.38±7.17 &m,
1
5H), 3.85±3.53 &m, 5H), 3.41 &d, Jˆ11.7 Hz, 1H), 3.33 &d,
Jˆ11.7 Hz, 1H), 3.02 &d, Jˆ13.1 Hz, 1H), 2.76±2.41 &m,
4H), 2.18±1.88 &m, 5H), 1.59±1.21 &m, 3H), 0.66 &s, 3H);
13C NMR &50 MHz): 211.35, 126.34, 131.43, 129.42,
127.02, 108.92, 68.91, 67.13, 65.50, 63.91, 50.52, 45.47,
44.45, 39.86, 35.08, 32.01, 30.34, 25.32, 17.62; EI-MS:
m/z &%)ˆ&M1z, 5), 268&15), 267&100), 165&5), 137&5),
109&6), 57 &7); HRMS: calculated for C21H28O4S:
376.1708; found: 376.1712.
4.4.3. trans-3-)3-Oxocycloheptyl)-2-propenal )10c).
Yellow oil, 75% yield from 8c. FT-IR &cm21): 2937,
1716, 1684, 1653; 1H NMR &200 MHz): 9.51 &d,
Jˆ7.7 Hz, 1H), 6.78 &dd, Jˆ6.5, 15.7 Hz, 1H), 6.11 &ddd,
Jˆ1.1, 7.7, 15.7 Hz, 1H), 2.69±2.52 &m, 5H), 2.50±2.19 &m,
4H), 1.78±1.48 &m, 2H); 13C NMR &50 MHz): 212.41,
194.38, 161.01, 131.69, 48.30, 44.55, 39.54, 36.24, 28.79,
24.44; EI-MS: m/z &%)ˆ166&M1, 67), 152&100), 139&95),
107&44), 93&43), 79&47); HRMS: calculated for C10H14O2:
166.0993; found: 166.0997.
Acknowledgements
Á
This work was generously supported by the `Ministere de
l'Education et de la Recherche, Communaute francËaise de
Â
4.4.4. Cyclopentannulation reactions with reagent 6. tert-
BuLi 1.7 M &3.9 ml, 5.856 mmol) was added by syringe to a
solution of 1-&2-thiophenylethyl)-4-methyl-2,6,7-trioxa-
bicyclo[2,2,2]-octane &1.3 g, 4.88 mmol) and hexamethyl-
phosphoramide &2.264 ml, 13.01 mmol) in 10 ml THF at
2788C. After stirring for 2 h at 2788C, kept at 2108C for
30 min, and then cooled to 2788C again. The resulting
reaction mixture was added by the double-ended cannula
to a suspension of copper&I) bromide±dimethyl sul®de
complex &1.216 g, 5.856 mmol) in 4 ml THF. After stirring
for 20 min at 2788C and another 40 min at 2408C, the
reaction solution became orange and clear. The mixture
was cooled to 2788C again. Enone &3.253 mmol), chloro-
trimethylsilane &1.445 ml, 11.38 mmol) and triethylamine
&1.809 ml, 13.01 mmol) were added, after stirring for
Â
Â
Belgique' &action concertee 96/01-197) and the `Universite
catholique de Louvain'. We thank Professor E. de Hoffmann
for the mass spectra.
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