1-Phenylthio-3-vinyl-3-cyclohexenol, a new reagent for bis-annelation of silyl enol ethers

Article abstract of DOI:10.1016/j.tet.2005.11.060

1-Phenylthio-3-vinyl-cyclohex-1-en-3-ol (2) has been synthesized and investigated as a new bis-annelation reagent for silyl enol ethers. Reagent 2 can be synthesized by a Grignard reaction of vinyl magnesium bromide with 3-phenylthiocyclohexenone. The rea

Full text of DOI:10.1016/j.tet.2005.11.060

Tetrahedron 62 (2006) 1749–1755
1-Phenylthio-3-vinyl-3-cyclohexenol, a new reagent
for bis-annelation of silyl enol ethers
a
a,c
Olga Konstantinova,a,b Florence C. E. Saraber, Enrique Melguizo,
`
Ben J. M. Jansena and Aede de Groota,
*
aLaboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen, The Netherlands
bInstitute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich str. 5/2, 220141, Minsk, Belarus
cDepartamento de Quimica Organica, Facultad de Sciencias, Universidad de Granada, 18071, Granada, Spain
Received 31 May 2005; accepted 24 November 2005
Available online 20 December 2005
Abstract—1-Phenylthio-3-vinyl-cyclohex-1-en-3-ol (2) has been synthesized and investigated as a new bis-annelation reagent for silyl enol
ethers. Reagent 2 can be synthesized by a Grignard reaction of vinyl magnesium bromide with 3-phenylthiocyclohexenone. The reaction with
silyl enol ethers takes place under Lewis acid catalysis and generally proceeds in good yields. The resulting phenylthiodienes can be
hydrolyzed to enones, which have been cyclized in a homologous aldol reaction to polycyclic compounds.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
under mild Lewis acid conditions. A consecutive reaction
with a suitable silyl enol ether then should lead to
intermediates of type 4, which, after hydrolysis, should
give the unsaturated diketones 5. Vinylogous aldol
condensation of compounds like 5 to polycyclic compound
6 has been mentioned in the literature. It was estimated that
1-phenylthio-3-vinyl-cyclohex-1-en-3-ol 2 could meet the
requirements for a good starting material31 (see Scheme 1).
Bis-annelation usually refers to the attachment of two new
fused six-membered rings in one reaction sequence and it is
a valuable method for the synthesis of polycyclic natural
products. In principle, bis-annelation can be achieved using
two consecutive, but separate annelation reactions with
methyl vinyl ketone (MVK) or an equivalent thereof.1–16
A
more efficient one pot annelation of two six-membered rings
is possible using oct-7-ene-2,6-dione or its equivalents and
several of such reagents have been developed.6,10,17–19
Other possibilities are offered by precursors of oct-7-ene-2,
6-dione like 6-methyl-2-vinylpyridine,20–23 2,6-dimethyl-
4H-pyran-4-one24 or the already partly cyclised bis-
annelation reagent 3-vinylcyclohexenone. With these
reagents, an extended (1,6) Michael addition followed by
a vinylogous aldol condensation are the key reactions in the
annelation of the two rings.25–28
2. Results and discussion
Reagent 2 was obtained from 3-phenylthiocyclohexenone
132 by addition of vinyl magnesium bromide. Purification of
reagent 2 on silica gel led to decomposition, but after a
standard work up procedure, the compound could be used
directly in the addition reactions with silyl enol ethers.
Storage for some time was possible in a slightly basic
solution.
In previous publications we have shown that additions of
carbocations to silyl enol ethers can be a high yielding key
step in short syntheses of polycyclic compounds and
steroids.29,30 A similar strategy can be possible for bis-
annelations using a precursor for 3-vinylcyclohexenone
from which a carbocationic intermediate could be generated
To get information about the stability and reactivity of
reagent 2, its Lewis acid catalysed reaction with several silyl
enol ethers has been investigated (see Table 1). The latter
were selected to get an impression about the influence of
steric hindrance and electronic factors on the reaction and
about its stereoselectivity.
Keywords: 1-Phenylthio-3-vinyl-cyclohex-1-en-3-ol; Bis-annelation;
Addition; Silyl enol ethers.
A moderate excess of silyl enol ether over reagent 2 was
found to be favourable for the reaction yield. The Lewis acid
used had to be powerful enough to generate a carbocation
*
Corresponding author. Tel.: C31 317482370; fax: C31 317484914;
e-mail: aede.degroot@wur.nl
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.060

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O. Konstantinova et al. / Tetrahedron 62 (2006) 1749–1755
Scheme 1.
Table 1
Entry
Silyl enol ethers
Reaction
conditions
Coupling products
Yields (%)
O
1
2
a
a
54
TBDMSO
3a
O
O
O
5a
O
55
TBDMSO
3b
5b
3
b
65
O
TBDMSO
3c
5c
4
c
44
O
TBDMSO
O
3d
5d
5
d
28
O
TBDMSO
3e
O
5e
CN
6
e
No product
TBDMSO
3f
(a) Silyl enol ether (1.5 equiv), 1 equiv of ZnBr2, THF, K40 8C to room temperature. (b) Silyl enol ether (2 equiv), 1 equiv of ZnBr2, THF/CH2Cl2, K40 8C to
room temperature. (c) Silyl enol ether (1.5 equiv), 1 equiv of ZnBr2, THF/CH2Cl2, K40 8C to room temperature. (d) Silyl enol ether (1.7 equiv), 1 equiv of
ZnBr2, THF/CH2Cl2, K40 8C to room temperature. (e) Silyl enol ether (1.4 equiv), 1 equiv of ZnBr2, THF/CH2Cl2, K40 8C to room temperature.

O. Konstantinova et al. / Tetrahedron 62 (2006) 1749–1755
1751
from 2, but it should leave the silyl enol ether intact as long
as possible and ZnBr2 became our catalyst of choice.
Usually a stoichiometric amount of ZnBr2 was used, as
applying a large excess of Lewis acid appeared to cause
hydrolysis of the silyl enol ethers. Also the nature of the
solvent influenced the rate and as a consequence also the
yield of the reactions. Dichloromethane had given good
results in the carbocation reactions performed before, but in
this reaction the yields of coupled products were very low
due to the instability of reagent 2 in this solvent. For the
most reactive silyl enol ethers good results were obtained in
tetrahydrofuran as solvent (Table 1, entries 1 and 2). As
soon as the reactivity of the silyl enol ether was somewhat
lowered, a mixture of tetrahydrofuran and dichloromethane
gave the best results. The intermediate phenylthio dienes 4
are stable enough to allow isolation, but generally mixtures
of stereoisomers were obtained, which were hydrolyzed
immediately to the corresponding enones. Acidic conditions
and HgCl2 catalysis can be applied for unmasking these
intermediate phenylthio dienes to the enones 5. Mostly
compound 7 was isolated as a sideproduct in a yield of about
30%. Formation of this product can be explained by the
reaction sequence depicted in Scheme 2.
The reactions of reagent 2 with silyl enol ethers 3a–c
proceeded without problems and after hydrolysis of the
intermediate phenylthiodienes, the corresponding enones
5a–c were obtained in 54, 55 and 65% overall yields,
respectively. The introduction of a methyl group on C2 in
the silyl enol ether seemed to have a rate accelerating effect,
determined by following the reactions on TLC, although in
both cases reactions were left to stir overnight for complete
conversion.
The stereoselectivity of the reaction was tested with silyl
enol ether 3d, which can be obtained from carvone.33 The
overall yield of enone 5d was 44%, which is good for a two
step reaction, and also the stereoselectivity was good. The
reactions with the silyl enol ether 3e gave a lower yield but
here the stereoselectivity was complete when a mixture of
dichloromethane and tetrahydrofuran was used as solvent.
NOE measurements proved the enone 5e to be the trans-
coupled product. No reaction could be observed with silyl
enol ether 5f, which probably has to be attributed to the
lower nucleophilicity of the silyl enol ether due to the
negative inductive effect of the cyano group.34,35
Scheme 2.
Scheme 3.

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O. Konstantinova et al. / Tetrahedron 62 (2006) 1749–1755
Scheme 4.
Cyclisation was first attempted on the coupled thiophenol
intermediates 4a and 4b, adding a solution of HCl in water
to the reaction mixture in THF and omitting in this way the
HgCl2 deprotection step (see Scheme 3). For the cyclo-
hexanone derivative 4a, this gave a reasonable overall yield
over four steps of 29% of compound 6a, which means an
average yield of 73% per step, together with 14% of non-
cyclised compound 5a. For compound 4b the yield dropped
to 16% of 6b, which means an average of 63% per step,
together with 18% of compound 5b.
product 6b. The better yields, mentioned in the literature for
vinylogous aldol cyclisations of compounds of type 5,
mostly concern substrates with an extra carbonyl group in
the right upper ring. This second carbonyl group on the b
position will enhance the reactivity of the first one for
nucleophilic attack as is necessary for the vinylogous aldol
condensation. Besides there are two carbonyl groups
available for reaction in such compounds. No cyclisation
experiments have been carried out with compounds 5c and
5e or their precursors.
In the literature, good yields of 80–90%, were mentioned for
the vinylogous aldol cyclisation of intermediates of type 5,
using para-toluenesulfonic acid (p-TsOH) in acetic acid
under reflux conditions.21–28,36 We therefore also investi-
gated the cyclisation of compound 5b using these conditions
with a catalytic, equimolar or excess quantity of p-TsOH,
which led to 40, 48 and 44% yield of 6b, respectively. The
use of equimolar amounts gave the best yield but, in our
hands, the yields were not as good as in the literature and
never exceeded those obtained with the HCl catalysed
cyclisation. Besides compound 6b, resulting from the
expected vinylogous aldol cyclisation reaction, a second
product was isolated in 19% yield as the result of a
competing Michael addition, which led to spiro compound 8
as a 2:1 mixture of two stereoisomers. Moreover, when
applying the p-TsOH–acetic acid conditions to the
cyclisation of compound 5c, the yield of the vinylogous
aldol cyclisation dropped dramatically, giving only 16% of
the cyclised product 6c, next to starting material (22%) and
a large amount (61%) of the spiro compound 9 again as a 2:1
mixture of two stereoisomers. The structure of spiro
compound 9 was confirmed by 2D NMR measurements.
3. Conclusions
The reactions of reagent 2 with silyl enol ethers 3 show that
enones 5 can be obtained in good yields in two steps. Steric
factors decrease the yield but improve the stereoselectivity
of the reaction, which is in agreement with the reactions of
silyl enol ethers with other carbocation precursors.30
Cyclisation of the enones 5 to polycyclic compound 6
could be accomplished in good to moderate yields, with a
spirocyclisation reaction as alternative.
4. Experimental
4.1. General procedure: see former paper
4.1.1. 3-Phenylthio-cyclohex-2-enone (1). 1,3-Cyclohex-
andione (5.0 g, 44 mmol) and thiophenol (5.5 ml, 53 mmol)
were dissolved in benzene (100 ml) and stirred at reflux
temperature for 6 h in a Dean–Stark apparatus. After
cooling, the solution was diluted with saturated NaHCO3
solution (50 ml), The layers were separated and the water
layer was extracted with EtOAc (3!25 ml). The organic
layers were combined, dried (MgSO4) and the solvent
was evaporated under reduced pressure. The crude product
was purified by column chromatography (PE/EtOAc
grad. 20:1–1:1) giving compound 1 in 71% yield (6.5 g).32
Mp 43–44 8C (hexane–ethyl acetate).
Also a solution of p-TsOH in benzene for the cyclisation of
5b and 5c did not improve the yield of the vinylogous aldol
cyclisation products 6b (44%) and 6c (16%). Under these
conditions the spiro cyclisation products 8 were obtained in
33% yield and compound 9 were obtained also in this case
as the main products in 63% yield.
1
IR (CCl4 sol.) cmK1: 2950, 1672, 1579, 1290; H NMR
The formation of spiro compounds 8 and 9 has, to our
knowledge, only been mentioned in literature twice for
similar compounds,28,37 but can easily be explained by
enolisation of the non-conjugated carbonyl followed by a
Michael reaction instead of the vinylogous aldol cyclisation
(see Scheme 4).
(CDCl3) d: 1.94–2.07 (m, 2H), 2.34 (t, JZ6.2 Hz, 2H), 2.49
(t, JZ6.1 Hz, 2H), 5.44 (s, 1H), 7.36–7.47 (m, 5H); 13C
NMR (CDCl3) d: 22.89 (t), 30.18 (t), 37.20 (t), 120.71 (d),
127.47 (s), 129.51 (2d), 130.15 (d), 135.46 (2d), 166.95 (s),
196.12 (s). HRMS: MC, found 204.0607. C12H12OS
requires 204.0609. MS m/e (%) 204 (MC, 100), 187 (12),
176 (74), 171 (23), 148 (45), 147 (39), 127 (35), 110 (20), 67
(81).
In the five-membered ring compound 5c the Michael
reaction is the predominant one, leading to spiro compound
9. In the six-membered ring compound 5b the steric
hindrance in the Michael adduct 8 is probably increased
and the equilibrium of the cyclisation reaction is shifted
more towards the side of the vinylogous aldol cyclisation
4.1.2. 3-Phenylthio-1-vinyl-cyclohex-2-enol (2) (general
procedure A). To a solution of ketone 1 (1.0 mmol) in
tetrahydrofuran (4 ml) was added vinyl magnesium bromide

O. Konstantinova et al. / Tetrahedron 62 (2006) 1749–1755
1753
(1.5 mmol, 1 M solution in tetrahydrofuran) at 0 8C. After
10 min the cooling bath was removed and the reaction
mixture was stirred at room temperature for 1.5 h. Then it
was poured into a cold saturated solution of ammonium
chloride and extracted with tert-butyl methyl ether. The
combined organic fractions were dried over sodium sulfate
and evaporated in vacuum to give alcohol 2, which was used
for reactions with the silyl enol ethers 3 without further
purification. An NMR sample of alcohol 2 was prepared by
flash column chromatography on silica gel.
4.1.4.2. 3-[2-(2-Oxo-cyclohexyl)-ethyl]-cyclohex-2-
enone (5a). Obtained as a clear yellow oil, according to
the general procedures A–C in 54% yield (245 mg) from
ketone 1 (420 mg). Procedure B included the use of
1.5 equiv of silyl enol ether 3b, 1 equiv of ZnBr2 and
tetrahydrofuran as solvent.
1
IR (CCl4 sol.) cmK1: 2938, 2866, 1713, 1674, 1627; H
NMR (C6D6) d: 1.02–2.28 (m, 19H), 6.02 (s, 1H); 13C NMR
(C6D6) d: 22.7 (t), 24.9 (t), 26.9 (t), 27.8 (t), 29.2 (t), 33.9 (t),
35.4 (t), 37.4 (t), 41.8 (t), 49.7 (d), 125.7 (d), 164.4 (s), 197.5
(s), 210.1 (s). HRMS: MC, found 220.1463. C14H20O2
requires 220.1463. MS m/e (%) 220 (MC, 15), 123 (100),
110 (30), 98 (21), 55 (11).
1H NMR (C6D6) d: 1.34–1.68 (m, 4H), 2.01–2.11 (m, 2H),
4.97 (dd, J1Z1.5 Hz, J2Z10.6 Hz, 1H), 5.23 (dd, J1Z
1.5 Hz, J2Z17.4 Hz, 1H), 5.76 (s, 1H), 5.83 (dd, J1Z
10.5 Hz, J2Z17.3 Hz, 1H), 6.95–7.10 (m, 3H), 7.41–7.47
(m, 2H); 13C NMR (C6D6) d: 19.87 (t), 29.80 (t), 35.81 (t),
71.64 (s), 112.61 (t), 127.45 (d), 129.14 (2d), 131.24 (d),
132.50 (2d), 133.42 (s), 137.01 (s), 144.15 (d).
4.1.4.3. 3-[2-(1-Methyl-2-oxo-cyclohexyl)-ethyl]-
cyclohex-2-enone (5b). Obtained as a clear yellow oil,
according to the general procedures A–C in 55% yield
(253 mg) from ketone 1 (400 mg). Procedure B included the
use of 1.5 equiv of silyl ether 3b, 1 equiv of ZnBr2 and
tetrahydrofuran as solvent.
4.1.3. Coupling reaction of reagent 2 and silyl enol ethers
3 (general procedure B). A solution of silyl enol ether 3
(1.5–2 mmol) in tetrahydrofuran or dichloromethane (1 ml,
choice used mentioned in procedure) was added to a
suspension of ZnBr2 (1 mmol) in tetrahydrofuran or
dichloromethane (1 ml, as above, choice used mentioned
in procedure) at K40 8C. Then to this mixture a solution of
reagent 2 (obtained from 1 mmol of ketone 1) in
tetrahydrofuran (1.5 ml) was added dropwise. During the
next 3–4 h the reaction mixture was warmed gradually to
room temperature and left stirring overnight. Then the
reaction mixture was mixed with cold brine and extracted
with tert-butyl methyl ether. The combined organic
fractions were dried over sodium sulfate and evaporated
in vacuum to give phenylthiodiene 4 as a crude oil.
IR (CHCl3 sol.) cmK1: 2939, 2869, 2356, 2252, 1702, 1664,
1623, 1455; 1H NMR (C6D6) d: 0.93 (s, 3H), 1.25–2.21 (m,
18H), 5.99 (s, 1H); 13C NMR (C6D6) d: 20.8 (t), 22.4 (q),
22.7 (t), 27.2 (t), 29.4 (t), 32.1 (t), 34.8 (t), 37.4 (t), 38.4 (t),
38.8 (t), 47.7 (s), 125.6 (d), 164.1 (s), 197.3 (s), 212.5 (s).
HRMS: MC, found 234.1615. C15H22O2 requires 234.1620.
MS m/e (%) 234 (MC, 5), 123 (81), 112 (100), 110 (13), 97
(21), 55 (13).
4.1.4.4. 3-[2-(1-Methyl-2-oxo-cyclopentyl)-ethyl]-
cyclohex-2-enone (5c). Obtained as a colourless oil,
according to the general procedures A–C in 65% yield
(211 mg) from ketone 1 (300 mg). Procedure B included the
use of 2 equiv of silyl enol ether 7–40, 1 equiv of ZnBr2 and
dichloromethane as solvent.
4.1.4. Hydrolysis of phenylthiodienes 4 to diketones 5
(general procedure C). To a solution of unpurified product
4 in ethanol (2 ml) was added dropwise a solution of
mercury (II) chloride (2 mmol, calculated on the amount of
used ketone 1) in water (0.5 ml) and 37% hydrochloric acid
(0.5 ml). The obtained mixture was stirred for 3 h at room
temperature. The precipitate was filtered and washed with
ethanol. The filtrate was mixed with pyridine (0.5 ml) and
concentrated in vacuum. The residue was mixed with brine
and extracted with dichloromethane. The combined organic
fractions were washed with a saturated NaHCO3 solution
and a saturated NH4Cl solution, dried (Na2SO4) and the
solvent was evaporated under reduced pressure. The
obtained oil was purified by column chromatography (PE/
EtOAc grad. 15:101:1) to give compound 5, and usually
some amount of compound 7.
1
IR (CCl4 sol.) cmK1: 2960, 1738, 1674, 1628; H NMR
(C6D6) d: 0.81 (s, 3H), 1.21–1.62 (m, 8H), 1.62–2.11 (m,
6H), 2.11–2.24 (m, 2H), 5.94 (s, 1H); 13C NMR (C6D6) d:
18.5 (t), 21.5 (q), 22.6 (t), 29.2 (t), 32.5 (t), 33.7 (t), 35.2 (t),
37.1 (t), 37.3 (t), 47.3 (s), 125.7 (d), 164.1 (s), 197.4 (s),
220.1 (s). HRMS: MC, found 220.1463. C14H20O2 requires
220.1463. MS m/e (%) 220 (MC, 7), 123 (100), 110 (7), 98
(48), 83 (6), 67 (4), 55 (14).
4.1.4.5. 3-[2-(4-Isopropenyl-1,2-dimethyl-6-oxo-cyclo-
hexyl)-ethyl]-cyclohex-2-enone (5d). Obtained as a
slightly yellow oil, according to the general procedures
A–C in 44% yield (91 mg) from ketone 1 (146 mg).
Procedure B included the use of 1.5 equiv of silyl enol
ether 3d, 1 equiv of ZnBr2 and dichloromethane as solvent.
4.1.4.1. 3-(2-Phenylsulfanyl-ethyl)-cyclohex-2-enone
(7). IR (CCl4 sol.) cmK1: 2930, 1678, 1628; 1H NMR
(CDCl3) d: 1.84–2.05 (m, 2H), 2.17–2.40 (m, 4H), 2.49 (t,
JZ7.4 Hz, 2H), 3.03 (t, JZ7.5 Hz, 2H), 5.86 (s, 1H), 7.12–
7.40 (m, 5H); 13C NMR (CDCl3) d: 22.5 (t), 29.4 (t), 31.1
(t), 37.2 (t), 37.4 (t), 126.5 (d), 126.7 (d), 129.0 (2d), 129.8
(2d), 135.4 (s), 163.4 (s), 199.5 (s). HRMS: MC, found
232.0923. C14H20O2 requires 232.0922. MS m/e (%) 232
(MC, 63), 204 (4), 176 (4), 123 (100), 110 (6), 109 (5), 77
(10), 45 (16).
[a]D25 K30.4 (c 2.70 in CHCl3); IR (CHCl3 sol.) cmK1
:
3088, 2938, 2889, 2252, 1699, 1666, 1626, 1456, 1428,
1
1257; H NMR (C6D6) d: 0.69 (d, JZ7.0 Hz, 3H), 0.88 (s,
3H), 1.55 (s, 3H), 2.16 (t, JZ6.3 Hz, 2H), 2.37 (s, 2H), 4.77
(s, 1H), 4.82 (s, 1H), 6.00 (s, 1H); 13C NMR (C6D6) d: 15.5
(q), 18.8 (q), 20.9 (q), 22.7 (t), 29.3 (t), 32.2 (t), 32.3 (t), 33.9
(t), 35.0 (d), 37.3 (t), 40.3 (d), 42.4 (t), 51.1 (s), 110.8 (t),
125.7 (d), 147.3 (s), 163.9 (s), 197.3 (s), 212.6 (s). HRMS:
MC, found 288.2086. C19H28O2 requires 288.2089. MS m/e

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O. Konstantinova et al. / Tetrahedron 62 (2006) 1749–1755
(%) 288 (MC, 4), 166 (18), 151 (8), 123 (100), 110 (15), 97
(9), 69 (11), 67 (9), 41 (17).
extracted with CH2Cl2 (3!50 ml) and the organic fractions
were combined and dried (Na2SO4). The solvent was
evaporated under reduced pressure and the resulting crude
oil was purified by column chromatography (PE/EtOAc
grad. 20:1–2:1), yielding compound 6b in 40, 48 and 44%,
respectively, as a thick slightly yellow oil, next to some
amount of compound 8 (19%) as a mixture of two isomers
(1:1).
4.1.4.6. 3-[2-(1-Methyl-2-oxo-5-vinyl-cyclopentyl)-
ethyl]-cyclohex-2-enone (5e). Mixture of cis–trans (1/3),
obtained according to the general procedures A–C in 16%
yield (24 mg) from ketone 1 (126 mg). Procedure B
included the use of 1.7 equiv of silyl enol ether 3e,30
2.2 equiv of ZnBr2 and tetrahydrofuran as solvent. Data of
the cis–trans mixture: 1H NMR (C6D6) d: 0.66 and 0.93 (s, s,
3H), 0.85–2.37 (m, 15H), 4.85–5.10 (m, 2H), 5.41–5.65 (m,
1H), 5.96 and 6.01 (s, s, 1H); 13C NMR-cis isomer (C6D6) d:
19.8 (q), 22.6 (t), 23.7 (t), 28.5 (t), 29.5 (t), 31.6 (t), 35.4 (t),
37.3 (t), 50.4 (s), 52.0 (d), 116.3 (t), 125.4 (d), 136.8 (d),
164.0 (s), 197.5 (s), 218.7 (s).
4.1.6. Cyclisation of 5b using p-TsOH in benzene.
Compound 5b (115 mg, 0.49 mmol) was dissolved in
benzene (15 ml) and p-TsOH (190 mg, 0.49 mmol) was
added. The reaction mixture was stirred under N2 during 5 h
at 60 8C, then cooled and neutralised with a saturated
NaHCO3 solution (50 ml). The mixture was extracted with
CH2Cl2 (3!50 ml) and the organic fractions were
combined and dried (Na2SO4). The solvent was evaporated
under reduced pressure and the resulting crude oil was
purified by column chromatography (PE/EtOAc grad.
20:1–2:1), yielding compound 6b (47 mg, 44%) as a thick
slightly yellow oil, next to some amount of compound 8
(33%) as a mixture of two isomers (2:1).
Trans-isomer, obtained as a slightly yellow oil, according to
the general procedures A–C in 28% yield (62 mg) from
ketone 1 (182 mg). Procedure B included the use of
1.7 equiv of silyl enol ether 3e, 1 equiv of ZnBr2 and
dichloromethane as solvent.
1
IR (CCl4 sol.) cmK1: 2964, 1740, 1674, 1628; H NMR
(C6D6) d: 0.65 (s, 3H), 0.81–2.31 (m, 15H), 4.92 (d, JZ
17.1 Hz, 1H), 5.00 (d, JZ10.3 Hz, 1H), 5.46 (ddd, J1Z
7.8 Hz, J2Z10.3, 17.1 Hz, 1H), 6.00 (s, 1H); 13C NMR
(C6D6) d: 17.5 (q), 22.6 (t), 24.2 (t), 29.1 (t), 32.5 (t), 32.7
(t), 36.5 (t), 37.3 (t), 47.4 (d), 50.7 (s), 116.3 (t), 125.9 (d),
137.2 (d), 163.8 (s), 197.3 (s), 219.3 (s). HRMS: MC, found
246.1618. C16H22O2 requires 246.1620. MS m/e (%) 246
(MC, 3.5), 124 (80), 123 (100), 110 (7), 109 (12, 95 (6),
81 (7).
4.1.6.1. 8a-Methyl-4,5,6,7,8,8a,9,10-octahydro-3H-
phenanthren-2-one (6b). IR (CCl4 sol.) cmK1: 2932,
1669, 1606, 1448, 1381, 1340, 1271, 1219; 1H NMR
(C6D6) d: 0.89 (s, 3H), 0.92–2.45 (m, 16H), 5.86 (s, 1H); 13
C
NMR (C6D6) d: 22.2 (t), 23.4 (d), 25.7 (t), 26.3 (t), 27.7 (t),
28.1 (t), 36.6 (s), 37.6 (t), 38.6 (t), 42.3 (t), 123.0 (d), 124.5
(s), 148.8 (s), 155.5 (s), 197.5 (s). HRMS: MC, found
216.1516. C15H20O requires 216.1514. MS m/e (%) 216
(MC, 67), 201 (100), 187 (7), 173 (9), 160 (11), 159 (15),
148 (10), 131 (11), 117 (10), 91 (11). Data are in accordance
with literature data.38
4.1.4.7. 4,5,6,7,8,8a,9,10-Octahydro-3H-phenanthren-
2-one (6a). After having performed procedures A and B
starting from 0.86 mmol 1, the crude reaction mixture was
cooled on ice to 5 8C and 1 ml of concentrated HCl (37%)
was added drop wise. The colour of the reaction mixture
immediately turned red. The temperature was kept at 5 8C
for 30 min, after which the mixture was allowed to warm to
room temperature and 5 ml of water, followed again by 1 ml
of concentrated HCl (37%), was added. The mixture was
left to stir overnight, diluted with a saturated Na2CO3
solution and extracted with tert-butyl methyl ether (3!
15 ml). The combined organic layers were dried (Na2SO4)
and the solvent was removed under reduced pressure. The
crude product was purified by column chromatography (PE/
EtOAc grad. 20:1–1:1) yielding 29% of compound 6a
(50 mg) as a colourless oil, next to 14% of compound 5a
(26 mg, for data see above).
Compound 8. IR (CCl4 sol.) cmK1: 2937, 1716, 1455, 1381,
1313, 1231; 1H NMR (CDCl3) d: 0.92 (s, 3H), 1.43–2.34 (m,
21H); 13C NMR (CDCl3) d: 21.2 (M) and 21.3 (m) (t), 21.8
(M) and 21.9 (m) (t), 24.6 (q), 29.8 (m) and 30.2 (M) (t), 31.2
(M) and 31.5 (m) (t), 34.0 (m) and 35.3 (M) (t), 37.4 (M) and
37.7 (m) (t), 41.2 (M) and 41.3 (m) (t), 43.1 (M) and 43.2 (m)
(t), 46.3 (s), 47.9 (s), 51.5 (M) and 52.3 (m) (t), 56.5 (m) and
57.6 (M) (d), 210.6 (M) and 211.0 (m) (s), 219.4 (M) and
219.8 (m) (s). HRMS: MC, found 234.1622. C15H20O
requires 234.1620. MS m/e (%) 234 (MC, 33), 123 (100),
112 (30), 111 (53), 95 (7), 93 (7), 79 (7), 67 (9), 55 (15),
41 (11).
4.1.7. Cyclisation of 5c using p-TsOH in AcOH.
4.1.7.1. 3a-Methyl-1,2,3,3a,4,5,8,9-octahydro-cyclo-
penta[a]naphthalen-7-one (6c). The method and scale as
described for the cyclisation of 5b was used. Compound 6c
was obtained in 16% yield as a slightly yellow oil.
1H NMR (CDCl3) d: 1.10–2.85 (m, 17H), 5.66 (s, 1H); 13
C
NMR (CDCl3) d: 25.4 (t), 26.1 (t), 27.6 (t), 29.3 (t), 30.3
(2t), 35.4 (t), 37.2 (t), 39.5 (d), 122.1 (d), 124.3 (s), 147.2 (s),
158.1 (s), 200.1 (s). Data are in accordance with literature
data.20
IR (CCl4 sol.) cmK1: 2931, 1742, 1667, 1634, 1582, 1440,
1261, 1233, 1024; 1H NMR (CDCl3) d: 0.97 (s, 3H), 0.92–
2.77 (m, 14H), 5.66 (s, 1H); 13C NMR (CDCl3) d: 21.7 (t),
23.1 (q), 25.5 (t), 29.4 (t), 30.1 (t), 35.9 (t), 37.1 (t), 42.0 (t),
43.3 (s), 121.9 (d), 123.2 (s), 156.5 (s), 158.0 (s), 200.1 (s).
HRMS: MC, found 202.1358. C14H18O requires 202.1358.
MS m/e (%) 202 (MC, 45), 187 (100), 174 (10), 160 (12),
159 (10), 145 (11), 131 (11), 117 (12), 91 (15).
4.1.5. Cyclisation of 5b using p-TsOH in AcOH.
Compound 5b (200 mg, 0.86 mmol) was dissolved in acetic
acid (AcOH, 6 ml) and p-TsOH was added in catalytic,
equimolar and excess amounts. The reaction mixture was
stirred during 1 h at reflux, then cooled and neutralised with
a saturated NaHCO3 solution (50 ml). The mixture was

O. Konstantinova et al. / Tetrahedron 62 (2006) 1749–1755
1755
11. Stork, G.; Jung, M. E. J. Am. Chem. Soc. 1974, 96, 3682.
12. Stork, G.; Jung, M. E.; Colvin, E.; Noel, Y. J. Am. Chem. Soc.
1974, 96, 3684.
Compound 9 was obtained in 61% yield as a slightly yellow
oily mixture of two isomers, ratio 2:1.
IR (CCl4 sol.) cmK1: 2939, 2875, 1747, 1716, 1452, 1319,
13. Stotter, P.; Hill, K. A. J. Am. Chem. Soc. 1974, 96, 6524.
14. Boeckman, R., Jr.,; Blum, D. M.; Ganem, B.; Halvey, N. Org.
Synth. 1978, 58, 152.
1
1230; H NMR (CDCl3) d: 0.91 (s, 3H), 0.90–2.27 (m,
19H); 13C NMR (CDCl3) d: 18.2 (m) and 18.6 (M) (t), 19.1
(q), 21.8 (M) and 21.9 (m) (t), 27.7 (M) and 29.5 (m) (t), 29.9
(M) and 30.0 (m) (t), 32.2 (m) and 35.8 (M) (t), 38.7 (m) and
38.9 (M) (t), 41.3 (M) and 41.4 (m) (t), 45.7 (s), 49.2 (M) and
52.2 (m) (t), 49.7 (s), 53.2 (m) and 55.8 (M) (d), 210.8 (M)
and 210.9 (m) (s), 219.2 (M) and 219.4 (m) (s). HRMS: MC,
found 220.1467. C14H22O2 requires 220.1463. MS m/e (%)
220 (MC, 60), 192 (7), 123 (100), 110 (10), 97 (65), 55 (12).
15. Boeckman, R., Jr. Tetrahedron 1983, 39, 925.
16. Duhamel, P.; Dujardin, G.; Hennequin, L.; Poirier, J. M.
J. Chem. Soc., Perkin Trans. 1 1992, 387.
17. Ireland, R. E.; Hengartner, U. J. Am. Chem. Soc. 1972, 94,
3652.
18. Stork, G.; McMurry, J. E. J. Am. Chem. Soc. 1967, 89, 5463.
19. Stork, G.; McMurry, J. E. J. Am. Chem. Soc. 1967, 89, 5464.
20. Danishefsky, S.; Cavanaugh, R. J. Am. Chem. Soc. 1968, 90,
520.
4.1.8. Cyclisation of 5c using p-TsOH in benzene.
4.1.8.1. 3a-Methyl-1,2,3,3a,4,5,8,9-octahydro-cyclo-
penta[a]naphthalen-7-one (6c). The method and scale as
described for the cyclisation of 5b was used. Compound 6c
was obtained in 16% yield as a slightly yellow oil.
Compound 9 was obtained in 63% yield as a slightly
yellow oil and as a mixture of two stereoisomers, ratio 2:1.
21. Danishefsky, S.; Nagel, A. J. Chem. Soc., Chem. Commun.
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22. Danishefsky, S.; Peterson, D. J. Chem. Soc., Chem. Commun.
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24. Yamamoto, M.; Iwasa, S.; Takatsuki, K.; Yamada, K. J. Org.
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Acknowledgements
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The authors gratefully acknowledge financial support from
Organon International. The authors thank B. van Lagen for
NMR and IR spectroscopic data, and M.A. Posthumus for
mass spectroscopic measurements.
26. Panouse, J. J.; Sannie, C. Bull. Soc. Chim. Fr. 1956, 1429.
27. Panouse, J. J.; Sannie, C. Bull. Soc. Chim. Fr. 1956, 1435.
28. Sakai, K.; Amemiya, S. Chem. Pharm. Bull. 1970, 18, 641.
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31. Grieco et al. have shown that phenylthio enol stabilized
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