Diversion from bicyclo[4.2.0]octanol formation through the use of vinyl electrophiles

Article abstract of DOI:10.1055/s-2005-869993

Bicyclo[4.2.0]octanols can be obtained from the reaction of phenyl vinyl sulfoxide and the lithium enolate of cyclohexanone under controlled conditions. Diversion to alkylation or Michael-Michael-ring closure was observed when alternative vinyl electrophi

Full text of DOI:10.1055/s-2005-869993

2220
PAPER
Diversion from Bicyclo[4.2.0]octanol Formation Through the Use of Vinyl
Electrophiles
D
iversion from Bicyclo[
e
4. 2.0]octan
n
ol Formatio
d
y A. Loughlin,* Catherine C. Rowen, Peter C. Healy
School of Science, Eskitis Institute, Griffith University, Nathan, Brisbane, QLD, 4111, Australia
Fax +61(7)38757656; E-mail: w.loughlin@griffith.edu.au
Received 7 March 2005
O
O
P
Abstract: Bicyclo[4.2.0]octanols can be obtained from the reaction
of phenyl vinyl sulfoxide and the lithium enolate of cyclohexanone
Ph
Ph
S(O)nPh
OEt
under controlled conditions. Diversion to alkylation or Michael–
3 n = 0
4 n = 1
5 n = 2
6
7
Michael-ring closure was observed when alternative vinyl electro-
philes were used. Novel bicyclic disulfones and hydroxyhexahy-
dronaphthalenes were isolated. The use of a vinyl sulfoxide
electrophile is crucial to the formation of bicyclo[4.2.0]octanols
from simple ketones.
Figure 1 a,b-Unsaturated electrophiles used in this work
In this study, the lithium enolate of cyclohexanone was
generated from cyclohexanone or TMS cyclohexyl ether,
either method giving similar results with phenyl vinyl
sulfoxide (4) as previously described.2 To allow for com-
parison, the lithium enolate of cyclohexanone was treated
with electrophiles 3, 5–7 under conditions that had previ-
ously given moderate to good yields of bicyclo[4.2.0]oc-
tan-1-ols with 4 (–30 °C, 5 min or –10 °C, 10 min).1 A
range of results was obtained (Table 1).
Key words: alkylations, bicyclic compounds, ketones, Michael ad-
ditions, ring closure
Previously, the efficient assembly of bicyclo[n.2.0]alkan-
1-ols was achieved by reaction of the lithium enolate of
(simple) ketones and phenyl (or tolyl) vinyl sulfoxide (for
example 1, Scheme 1).1–4 Controlled reaction conditions
are required to favour bicyclo[n.2.0]alkanol formation
over alkylation products such as 2.1 Notably alternate
electrophiles have not been tested under the specific con-
ditions required for bicyclo[n.2.0]alkanol formation. Now
selected a,b-unsaturated electrophiles were considered in
order to explore whether other novel functionality could
be introduced to produce functionalized bicyclo[4.2.0]oc-
tan-1-ols in this process.
Reaction of the lithium enolate of cyclohexanone with
phenyl vinyl sulfide (3), yielded only unreacted 3 (entry 1,
Table 1). This result may not be unexpected. Although
phenyl vinyl sulfide (3) has been used as an electrophile
in reactions with nucleophiles such as alkyllithium bases5
and the t-BuOK catalysed addition of some ketones and
nitriles,6 conjugate addition of lithium enolates to a,b-un-
saturated sulfides is unreported.
OH
S(O)Ph
Reaction of the lithium enolate of cyclohexanone with
phenyl vinyl sulfone (5) under controlled conditions gave
a complex mixture of products, including unreacted cy-
clohexanone (entry 4, Table 1). Signals attributable to
phenyl vinyl sulfone (5) were not detected in the 1H NMR
(400 MHz) spectrum of the crude product mixture, indi-
cating that the electrophile had been completely con-
sumed in the reaction. Monoalkylated ketone 87,8 (2.5%)
and 2,4-bis(phenylsulfonyl)octahydronaphthalen-4a-ols
O
1. LDA, –10 °C
H
1
2. PhS(O)CH = CH2
O
–10 °C, 10 min
3. aq NH4Cl
S(O)Ph
2
Scheme 1
9–14 (46%) (Figure 2) were isolated in
33:22:7:14:13:11 ratio of 9:10:11:12:13:14.
a
Presently, the role of oxidation state and geometry at sul-
fur, and the polarity of the sulfur–oxygen bond in the elec-
In the course of this work, single crystals of bicyclic di-
sulfones 9, 10, 11 and 12, were obtained and the X-ray
crystal structures determined. The ORTEP-3 diagrams are
shown in Figure 3.9 The relative stereochemistry of 9, 10,
11 and 12, assigned using the X-ray crystal structures
were consistent with the stereochemistry assigned by
NMR spectroscopy.
trophile were probed, using cyclohexanone as
a
representative ketone. Phenyl vinyl sulfide (3), phenyl vi-
nyl sulfone (5), ethyl acrylate (6) and diphenylvinylphos-
phine oxide (7), were selected as electrophiles (Figure 1).
Acrylonitrile was not considered due to its propensity to
polymerise.
Crystal packing of structures 9–12 is stabilized by O–
H…O(s) and C–H…O(s) hydrogen bonding and by both face-
to-face p…p and edge-to-face C–H…p phenyl–phenyl in-
SYNTHESIS 2005, No. 13, pp 2220–2226
Advanced online publication: 13.07.2005
x
x.
x
x
.
2
0
0
5
DOI: 10.1055/s-2005-869993; Art ID: P03205SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Diversion from Bicyclo[4.2.0]octanol Formation
2221
Table 1 Reaction of Electrophiles 3–7 with Enolate Precursors
Entry
Enolate Precursor
cyclohexanone
Electrophile Temp (°C) Time (min) Product (Yield, %)
1
2
3
4
5
6
3
4
4
5
6
7
–30
–30
–10
–10
–30
–10
5
5
3 (95)
cyclohexanone
1 (42), 2 (3)
1 (74), 2 (4)
cyclohexanone
10
10
5
cyclohexanone
8 (2.5), 9 (15), 10 (10), 11 (3.5), 12 (6.5), 13 (6), 14 (5)
cyclohexanone
15 (14.5), 16 (6.5), 17 (36)
18 (89)
cyclohexenyloxy-TMS
10
O
the axial phenyl sulfonyl group at C2. The relative stereo-
chemistry was thus assigned as (2RS,4SR,4aSR,8aRS)-14.
The absent isomers (2RS,4RS,4aRS,8aSR and
2RR,4RR,4aRR,8aRR) both have conformations which ei-
ther have unfavourable 1,3-diaxial phenylsulfonyl inter-
actions or hydroxy, phenylsulfonyl gauche interactions.
Alkylation of enolates by phenyl vinyl sulfone,10 domino
Michael reactions leading to tricyclo[3.2.1.02,7]octan-6-
ones,11 bicyclo[2.2.2]octan-2,5-diones,12 decalones13 and
a hydrindanol14 have been observed. Here we report the
first example of a Michael–Michael-Ring Closure (MIM-
IRC) of phenyl vinyl sulfone to form a hydroxyhexahy-
dronaphthalene, with determination of the diastereomers
obtained.
SO2Ph
8
H
H
HO
HO
H
SO2Ph
SO2Ph
SO2Ph
SO2Ph
H
H
H
9
10
H
H
HO
HO
H
SO2Ph
SO2Ph
SO2Ph
SO2Ph
H
H
HO
H
H
11
12
Next, the lithium enolate of cyclohexanone was reacted
with ethyl acrylate under controlled conditions (entry 5,
Table 1). H NMR (400 MHz) spectroscopic analysis of
the crude mixture obtained indicated that unreacted cyclo-
hexanone was present, ethyl acrylate had been completely
consumed and other products were present. Three diesters
15–17 were isolated from the crude product mixture in a
H
H
OH
SO2Ph
1
SO2Ph
SO2Ph
SO2Ph
H
H
H
13
14
Figure 2 Products from the reaction of phenyl vinyl sulfone (5) combined unoptimised yield of 57%. Monoalkylation of
with the enolate of cyclohexanone
cyclohexanone was not observed. Assignment of the rela-
tive stereochemistry of diesters 15–17 was based on H
1
NMR spectra coupling constants for individual protons
teractions. In all four structures, the hexahydronaphtha-
and are shown in Figure 4.
lene rings lie in a fused chair-chair conformation.
Bicyclic esters 15–17 arose from a MIMIRC process, as
observed with the reaction of the phenyl vinyl sulfone (5).
However, the MIMIRC process was more selective when
ethyl acrylate (6) was used as the electrophile instead of
phenyl vinyl sulfone (5). The different distribution of iso-
mers was attributed to the relative reactivity of the electro-
phile and subsequent steric interactions in the resultant
Since crystals suitable for X-ray structure determination
could not be obtained for bicyclic disulfones 13 and 14,
the relative stereochemistry for these bicyclic disulfones
1
was assigned from the H NMR spectra coupling con-
stants (H2 as pseudo equatorial and H4 as axial) and the
construction of simple models.
For bicyclic disulfone 13, it was determined that H2 pseu-
do equatorial and H4 axial would be on opposite faces of
the molecule. With a trans ring junction, the hydroxyl
group must be on the same face as H2 and the relative ste-
reochemistry was thus assigned as (2RS,4SR,4aRS,8aRS)-
13. In bicyclic disulfone 14, H2 equatorial and H4 axial
would be on opposite faces of the molecule and with a cis
ring junction the hydroxyl group must occupy the same
face as H4. In the 1H NMR spectrum, the chemical shift of
H4 axial (d = 4.01) was consistent with deshielding of this
proton as a result of proximity to the hydroxyl group and
products. Sequential MIMIRC of vinyl esters in the for-
mation of polyfunctionalised cyclohexanols have been re-
ported.15 Here, we report the first ‘unfunctionalised’
example, with the formation of diesters 15–17.
In a final example, the lithium enolate of cyclohexanone
was reacted with diphenyl phosphine oxide (7),16 under
controlled conditions (entry 6, Table 1). The only product
observed was phosphine oxide 18 (89%).16 Phosphine ox-
ide 18 arose from simple alkylation, and has been de-
scribed previously as the product formed from the
Synthesis 2005, No. 13, 2220–2226 © Thieme Stuttgart · New York

2222
W. A. Loughlin et al.
PAPER
H
H
HO
H
HO
H
CO2Et
CO2Et
CO2Et
CO2Et
H
H
15
16
H
HO
H
CO2Et
CO2Et
H
17
Figure 4 Products from the reaction of ethyl acrylate (6) with the
enolate of cyclohexanone
pyrrolidine enamine of cyclohexanone and diphenylvi-
nylphosphine oxide.17
The results presented above highlight the critical role of
the sulfoxide functional group in the formation of bicy-
clo[4.2.0]octan-1-ols from the lithium enolate of cyclo-
hexanone and phenyl vinyl sulfoxide (4). The recovery of
phenyl vinyl sulfide (3) confirmed the requirement for the
electrophile to at least be reactive to nucleophilic attack
by a ketone enolate in conjugate addition.
Changing the oxidation state of sulfur from sulfoxide to
sulfone dramatically diverted the reaction from bicy-
clooctanol formation to MIMIRC and generated the novel
bicyclic disulfones 9–14. Replacing sulfur with carbon or
phosphorus also stopped bicyclo[4.2.0]octan-1-ol forma-
tion. In the reaction with the lithium enolate of
cyclohexanone, ethyl acrylate (6) gave novel hydroxy-
hexahydronaphthalenes 15–17 resulting from MIMIRC
whereas diphenylvinylphosphine oxide (7) gave a single
product of monoalkylation 18 (Figure 5). These results
imply that the different valence, hybridisation and geom-
etry of sulfur with carbon and phosphorus and the polarity
of the S–O bond must be important to the reaction inter-
mediate(s) required for bicyclo[4.2.0]octanol formation.
It was concluded that the sulfoxide functionality in a,b-
unsaturated electrophile was essential to the formation of
bicyclo[4.2.0]octan-1-ols from the lithium enolate of cy-
clohexanone. The crucial involvement of phenyl vinyl
sulfoxide has implications for further applications of the
cyclisation methodology for the formation of bicycloal-
kanols.
O
P(O)Ph2
18
Figure 5 Product from the reaction of diphenylvinylphosphine
oxide (7) with the enolate of cyclohexanone
Figure 3 ORTEP-3 diagrams for the molecular structure of the bi-
cyclic disulfones 9–12 shown with the assignment of the relative ste-
reochemistry in each case. Displacement ellipsoids for the non-
hydrogen atoms are drawn with 30% probability.
The general experimental conditions, reaction with phenyl vinyl
sulfoxide and instrumentation have been described elsewhere.1–3
Solvents and commercially available reagents were purified in the
standard manner. Diphenylvinylphosphine oxide 7 was prepared
according to literature procedure.16
Synthesis 2005, No. 13, 2220–2226 © Thieme Stuttgart · New York

PAPER
Diversion from Bicyclo[4.2.0]octanol Formation
2223
Data Collection, Structure Solution and Refinement
and the reaction mixture stirred for 10 min. The temperature was
maintained at –10 °C during this time. The reaction was quenched
and worked up as described above to give the crude mixture as an
X-ray diffraction data were collected at 295(2) K on a Rigaku
AFC7R diffractometer, MoKa radiation (l = 0.71069 Å), graphite
monochromator, using w/2q or w scans. Absorption corrections
were not applied. The structures were solved by direct methods and
refined using full-matrix least squares on F2. Non-hydrogen atoms
were refined anisotropically. The carbon protons were included at
calculated position and constrained as riding atoms with C–H 0.95
Å. The hydroxyl protons were located by difference methods and
constrained as a riding atoms with O–H 0.90 Å. Uiso(H) values were
set to 1.2 Ueq of the parent atom. Computation used the TeXsan18
and SHELX-9719 program systems, and ORTEP-320 software.
1
amber oil (2.136 g). The crude reaction mixture, analysed by H
NMR (400 MHz), spectroscopy included a complex mixture of 2,4-
bis(phenylsulfonyl)octahydronaphthalen-4a-ol (bicyclic disulfones
9–14), the monoalkylated ketone 8, and unreacted cyclohexanone.
The crude product mixture was fractionated by silica column chro-
matography using a solvent gradient starting with 100% hexane and
increasing to EtOAc–hexane (50:50). Five major fractions and other
minor fractions (298 mg) containing complex mixtures of products
were obtained. Fraction 1 contained a mixture of the monoalkylated
ketone 8 and bicyclic disulfone 14 (90 mg, 47:53). Fraction 2 con-
tained a mixture of monoalkylated ketone 8 and bicyclic disulfones
9, 10 and 14 (197 mg, 10:50:16:24). Fraction 3 contained a mixture
of bicyclic disulfones 9 and 10 (283 mg, 50:50). Fraction 4 con-
tained a mixture of bicyclic disulfones 9, 10, 11 and 12 (153 mg,
20:20:20:40). Fraction 5 contained a mixture of bicyclic disulfones
9, 11, 12 and 13 (280 mg, 15:15:25:45). The yields of the major
products contained in the major fractions were calculated (based on
phenyl vinyl sulfone) to be: 9 (15%), 10 (10%), 11 (3.5%), 12
(6.5%), 13 (6%), 14 (5%), and the monoalkylated ketone 8 (2.5%).
The bicyclic disulfones 9–14 were isolated and purified as follows.
Crystal Data
9
C22H26O5S2, M = 434.6. Triclinic, space group P–1, a = 13.360(3),
b = 14.369(6), c = 5.749(3) Å, a = 99.67(4), b = 102.41(3),
g = 96.69(2)°, V = 1049 Å3. Dc (Z = 2) = 1.376 g cm–3. Crystal size:
0.35 × 0.20 × 0.20 mm;. 2qmax = 55°; 5678 reflections collected,
4824 unique (Rint = 0.035). R = 0.040 [3428 reflections with
I>2s(I)], wR(F2) (all data) = 0.117. |Drmax| = 0.280 eÅ–3.
10
C22H26O5S2, M = 434.6. Monoclinic, space group P21/n,
a = 21.384(9), b = 9.560(4), c = 10.635(4) Å, b = 94.30(3),
Column fraction 1: Bicyclic disulfone 14 and monoalkylated ketone
8 were separated by semipreparative HPLC (EtOAc–hexane, 50:50,
3 mL/min).
V = 2168 Å3. Dc (Z = 4) = 1.325
g
cm–3. Crystal size:
0.40 × 0.30 × 0.30 mm;. 2qmax = 55°; 6041 reflections collected,
5007 unique (Rint = 0.064). R = 0.050 [2579 reflections with
I>2s(I)], wR(F2) (all data) = 0.154. |Drmax| = 0.401 eÅ–3.
(2RS,4SR,4aSR,8aRS)-2,4-Bis(phenylsulfonyl)octahydronaph-
thalen-4a-ol (14)
Compound 14 (22 mg) was isolated (tR 8.6 min) as an analytically
pure sample; white solid; mp 229–230 °C.
IR (KBr): 3434, 1302, 1146 cm–1.
11
C22H26O5S2, M = 434.6. Monoclinic, space group P21/n,
a = 15.672(6), b = 10.462(4), c = 13.148(5) Å, b = 97.46(3),
V = 2137 Å3. Dc (Z = 4) = 1.350
g
cm–3. Crystal size:
1H NMR (400 MHz, CDCl3): d = 1.18–1.47 (m, 3 H, 1 × H8,
2 × H7), 1.47–1.80 (m, 5 H, H3eq, 1 × H5, 2 × H6, 1 × H8), 1.80–
2.07 (m, 3 H, 2 × H1, H8a), 2.36 (ddd, J3ax,2eq = 6 Hz, J3ax,4ax = 13.5
Hz, J3,3 = 14.5 Hz, 1 H, H3ax), 2.46–2.59 (m, 1 H, 1 × H5), 2.97 (d,
J = 1.5 Hz, 1 H, OH), 3.14 (dddd, J2eq,1eq = 2 Hz, J2eq,3eq = 2 Hz,
J2eq,1ax = 6Hz, J2eq,3ax = 6 Hz, 1 H, H2eq), 4.01 (dd, J4ax,3eq = 3.5 Hz,
J4ax,3ax = 13.5 Hz, 1 H, H4ax), 7.36–7.90 (m, 10 H, C6H5).
13C NMR (100 MHz, CDCl3): d = 21.4 (C6), 22.1 (C3), 25.0 (C1),
25.2 (C7 or C8), 28.2 (C7 or C8), 37.3 (C5), 40.0 (C8a), 58.4 (C2),
64.7 (C4), 72.1 (C4a), 128.1, 128.2 (o-C6H5), 129.2, 129.4 (m-
C6H5), 133.7, 133.8 (p-C6H5), 137.4, 139.3, (i-C6H5),
0.30 × 0.30 × 0.20 mm;. 2qmax = 55°; 5520 reflections collected,
4905 unique (Rint = 0.034). R = 0.046 [2762 reflections with
I>2s(I)], wR(F2) (all data) = 0.144. |Drmax| = 0.363 eÅ–3.
12
C22H26O5S2, M = 434.6. Monoclinic, space group Cc, a = 5.865(3),
b = 21.999(9), c = 15.908(5) Å, b = 93.05(3), V = 2049 Å3. Dc
(Z = 4) = 1.408 g cm–3. Crystal size: 0.30 × 0.15 × 0.10 mm;.
2qmax = 55°; 2770 reflections collected, 2361 unique (Rint = 0.028).
R = 0.036 [1762 reflections with I>2s(I)], wR(F2) (all
data) = 0.094. |Drmax| = 0.235 eÅ–3.
MS (ESMS +ve): m/z = 457 (MNa+).
Reaction of Enolate of Cyclohexanone with Phenyl Vinyl Sul-
fide (3)
Anal. Calcd for C22H26O5S2: C, 60.80; H, 6.03. Found: C, 60.78; H,
6.05.
The lithium enolate of cyclohexanone, generated from LDA (~2.0
M, 2.80 mL, 5.60 mmol) and cyclohexanone (0.50 g, 0.53 mL, 5.10
mmol) in THF (30 mL), was allowed to warm to –30 °C and to this
was added phenyl vinyl sulfide (3; 0.69 g, 0.67 mL, 5.10 mmol) in
one portion. The reaction mixture was stirred for 5 min and the tem-
perature was maintained at –30 °C during this time. The reaction
was quenched with aq sat. NH4Cl and extracted with EtOAc (3 × 50
mL). The combined organic layers were washed with brine (100
mL), dried (MgSO4), filtered and the solvent removed in vacuo to
give the crude mixture as an amber oil (674 mg). The mixture was
2-[2¢-(Phenylsulfonyl)ethyl]cyclohexanone (8)7,8
Compound 8 (17 mg) was isolated (tR 9.4 min) and recrystallised;
white solid; mp 72–73 °C (Et2O) [Lit.7 71–72 °C (petroleum
ether)].
1H NMR (400 MHz, CDCl3): d = 1.32 (dddd, J3ax,4eq = 4 Hz,
J3ax,4ax = 13 Hz, J3ax,2ax = 13 Hz, J3ax,3eq = 13 Hz, 1 H, H3ax), 1.50–
1.72 (m, 3 H, 1 × H1¢, 1 × H4, 1 × H5), 1.80–1.89 (m, 1 H, 1 × H4),
1.93–2.12 (m, 3 H, 1 × H1¢, H3eq, 1 × H5), 2.19–2.38 (m, 2 H,
2 × H6), 2.41–2.52 (m, 1 H,H2ax), 3.08 (ddd, J2¢,1¢ 6 Hz, J2¢,1¢ = 10
Hz, J2¢,2¢ = 14 Hz, 1 H, 1 × H2¢), 3.25 (ddd, J2¢,1¢ = 6 Hz, J2¢,1¢ = 10
Hz, J2¢,2¢ = 14 Hz, 1 H, 1 × H2¢), 7.51–7.59 (m, 2 H, m-C6H5), 7.60–
7.67 (m, 1 H, p-C6H5), 7.84–7.92 (m, 2 H, o-C6H5).
1
analysed by H NMR (200 MHz) spectroscopy and determined to
contain unreacted phenyl vinyl sulfide 3 (>95%).
Reaction of Enolate of Cyclohexanone with Phenyl Vinyl Sul-
fone (5)
The lithium enolate of cyclohexanone, generated from LDA (~2.0
M, 4.70 mL, 9.40 mmol) and cyclohexanone (0.92 g, 0.97 mL, 9.40
mmol) in THF (50 mL), was allowed to warm to –10 °C. Phenyl vi-
nyl sulfone (5; 1.58 g, 9.40 mmol) in THF (5 mL) was added rapidly
13C NMR (100 MHz, CDCl3): d = 23.1 (C1¢), 25.1 (C4), 27.9 (C5),
34.4 (C3), 42.1 (C6), 48.9 (C2), 54.0 (C2¢), 128.0 (o-C6H5), 129.2
(m-C6H5), 133.6 (p-C6H5), 139.1 (i-C6H5), 211.8 (C1).
Column fraction 3: Bicyclic disulfones 9 and 10 were separated by
semipreparative HPLC (EtOAc–hexane, 30:70, 3 mL/min).
Synthesis 2005, No. 13, 2220–2226 © Thieme Stuttgart · New York

2224
W. A. Loughlin et al.
PAPER
(2RS,4RS,4aSR,8aRS)-2,4-Bis(phenylsulfonyl)octahydronaph-
thalen-4a-ol (10)
Compound 10 was contained in the first fraction and obtained as an
analytically pure sample (tR 24.3 min); white solid; mp 234–235 °C.
MS (ESMS +ve): m/z = 457 (MNa+).
Anal. Calcd for C22H26O5S2: C, 60.80; H, 6.03. Found: C, 61.02; H,
6.05.
IR (KBr): 3434, 1305, 1146 cm–1.
(2RS,4SR,4aSR,8aSR)-2,4-Bis(phenylsulfonyl)octahydronaph-
thalen-4a-ol (11)
Compound 11 was isolated from the second fraction as an analyti-
cally pure sample (tR 36 min); white solid; mp 199–201 °C.
1H NMR (400 MHz, CDCl3): d = 1.10–1.36 (m, 2 H, 1 × H6,
1 × H8), 1.39–1.76 (m, 7 H, H1eq, H3eq, 1 × H5, 1 × H6, 2 × H7,
1 × H8), 1.76–1.90 (m, 1 H, H8a), 2.11 (ddd, J3ax,2ax = 13 Hz,
J3ax,4ax 13, J3,3 13, 1 H, H3ax), 2.25 (ddd, J1ax,8aeq = 5 Hz, J1ax,2ax = 13
Hz, J1,1 = 13 Hz, 1 H, H1ax), 2.66–2.76 (m, 1 H, 1 × H5), 2.97
(dddd, J2ax,1eq = 4 Hz, J2ax,3eq = 4 Hz, J2ax,1ax = 13 Hz, J2ax,3ax = 13 Hz,
1 H, H2ax), 3.44 (dd, J4ax,3eq = 3.5 Hz, J4ax,3ax = 13.5 Hz, 1 H, H4ax),
7.44–7.84 (m, 10 H, C6H5), (OH not observed).
13C NMR (100 MHz, CDCl3): d = 23.1 (C7), 23.7 (C3), 25.0 (C1),
25.5 (C6), 28.1 (C8), 38.4 (C5), 44.0 (C8a), 58.3 (C2), 60.8 (C4),
72.4 (C4a), 128.5, 129.0 (o-C6H5), 129.2, 129.4 (m-C6H5), 133.9,
134.2 (p-C6H5), 136.3, 138.3 (i-C6H5).
IR (KBr): 3453, 1304, 1144 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.27–1.85 (m, 10 H, 2 × H1,
1 × H3, 1 × H5, 2 × H6, 2 × H7, 2 × H8), 2.20 (dddd, J8aax,1eq = 4
Hz, J8aax,8eq = 4 Hz, J8aax,1ax 12 Hz, J8aax,8ax = 12 Hz, 1 H, H8aax),
2.26–2.41 (m, 2 H, 1 × H3, 1 × H5), 3.14 (dd, J4eq,3eq = 2 Hz,
J4eq,3ax = 5.5 Hz, 1 H, H4eq), 3.77 (dddd, J2ax,1eq = 3.5 Hz, J2ax,3eq =
3.5 Hz, J2ax,1ax = 13 Hz, J2ax,3ax = 13 Hz, 1 H, H2ax), 7.34–7.84 (m,
10 H, C6H5), (OH not observed).
13C NMR (100 MHz, CDCl3): d = 21.4 (C6), 22.8 (C3), 25.1 (C7),
26.3 (C1), 28.7 (C8), 37.6 (C5), 38.4 (C8a), 57.2 (C2), 68.2 (C4),
72.2 (C4a), 127.8, 128.9 (o-C6H5), 129.2, 129.3 (m-C6H5), 133.7,
133.8 (p-C6H5),138.7, 137.1, (i-C6H5).
MS (ESMS +ve): m/z = 457 (MNa+).
Anal. Calcd for C22H26O5S2: C, 60.80; H, 6.03. Found: C, 60.78; H,
6.10.
MS (ESMS +ve): m/z = 457 (MNa+).
(2RS,4RS,4aSR,8aSR)-2,4-Bis(phenylsulfonyl)octahydronaph-
thalen-4a-ol (9)
Compound 9 was contained in the second fraction and obtained as
an analytically pure sample (tR 24.7 min); white solid; mp 238–
239 °C.
Anal. Calcd for C22H26O5S2: C, 60.80; H, 6.03. Found: C, 60.57; H,
6.13.
Column fraction 5: Semipreparative HPLC (EtOAc–hexane, 30:70)
of a mixture of 9, 11, 12 and 13 gave bicyclic disulfone 13 (64 mg)
(tR 45 min).
IR (KBr): 3452, 1306, 1146 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.06–1.44 (m, 4 H, 1 × H5,
1 × H7, 1 × H8, H8a), 1.44–1.84 (m, 7 H, 2 × H1, H3eq, 2 × H6,
(2RS,4SR,4aRS,8aRS)-2,4-Bis(phenylsulfonyl)octahydronaph-
thalen-4a-ol (13)
1 × H7, 1 × H8), 2.10 (ddd, J3ax,2ax = 13 Hz, J3ax,4ax = 13 Hz, J3,3
=
Purification by semipreparative HPLC (EtOAc–hexane, 50:50)
gave an analytically pure sample of (tR 13 min); white solid; mp
178–179 °C.
IR (KBr): 3454, 1305, 1143 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.14–1.39 (m, 2 H, 1 × H7,
1 × H8), 1.39–1.79 (m, 7 H, 1 × H1, 1 × H3, 2 × H6, 1 × H7,
1 × H8, H8a), 1.79–1.95 (m, 2 H, 1 × H1, 1 × H3), 2.12 (ddd, 1 H,
J5ax,6eq = 4 Hz, J5ax,6ax = 13.5 Hz, J5,5 = 13.5 Hz, H5ax), 2.25–2.36
(m, 1 H, H5eq), 3.26 (dd, J4ax,3eq = 6 Hz, J4ax,3ax = 12.5 Hz, 1 H,
13 Hz, 1 H, H3ax), 2.46–2.58 (m, 1 H, 1 × H5), 2.85 (dddd,
J2ax,1eq = 4 Hz, J2ax,3eq = 4 Hz, J2ax,1ax = 13 Hz, J2ax,3ax = 13 Hz, 1 H,
H2ax), 2.91 (dd, J4ax,3eq = 3 Hz, J4ax,3ax = 13 Hz, 1 H, H4ax), 3.11 (d,
J = 1.5 Hz, 1 H, OH), 7.42–7.83 (m, 10 H, 2 × C6H5).
13C NMR (100 MHz, CDCl3): d = 21.2 (C6), 23.6 (C3), 25.4 (C7 or
C8), 26.3 (C1), 28.0 (C7 or C8), 37.1 (C5), 44.5 (C8a), 61.7 (C2),
69.0 (C4), 71.4 (C4a), 128.3, 128.9 (o-C6H5), 129.2, 129.4 (m-
C6H5), 133.8, 134.1 (p-C6H5), 136.5, 138.3 (i-C6H5).
MS (ESMS +ve): m/z = 457 (MNa+).
H4ax), 3.41 (dddd, J2eq,1eq/3eq = 4 Hz, J2eq,1eq/3eq = 7 Hz, J2eq,1ax/3ax =
8.5 Hz, J2eq,1ax/3ax = 13 Hz, 1 H, H2eq), 7.41–7.84 (m, 10 H, 2 ×
C6H5), (OH not observed).
13C NMR (100 MHz, CDCl3): d = 21.2 (C6), 22.9 (C3), 24.9 (C1),
25.1 (C7 or C8), 28.8 (C7 or C8), 35.4 (C5), 37.4 (C8a), 57.0 (C2),
69.2 (C4), 73.4 (C4a), 128.3, 128.8 (o-C6H5), 129.2, 129.3 (m-
C6H5), 133.8, 133.9 (p-C6H5), 136.7, 138.8 (i-C6H5).
Anal. Calcd for C22H26O5S2: C, 60.80; H, 6.03. Found: C, 61.03; H,
6.13.
Column fraction 4: Bicyclic disulfones 11 and 12 were isolated
from a mixture of 9, 10, 11, and 12 by semipreparative HPLC
(EtOAc–hexane, 30:70, 3 mL/min).
(2RS,4SR,4aRS,8aSR)-2,4-Bis(phenylsulfonyl)octahydronaph-
thalen-4a-ol (12)
Compound 12 was isolated from the first fraction as an analytically
pure sample (tR 32 minutes); white solid; mp 205–206 °C.
MS (ESMS +ve): m/z = 457 (MNa+).
Anal. Calcd for C22H26O5S2: C, 60.80; H, 6.03. Found: C, 60.84; H,
6.16.
IR (KBr): 3450, 1304, 1144 cm–1.
Reaction of Enolate of Cylohexanone with Ethyl Acrylate (6)
The lithium enolate of cyclohexanone, generated from LDA (~1.6
M, 3.50 mL, 5.60 mmol) and cyclohexanone (0.50 g, 0.53 mL, 5.10
mmol) in THF (30 mL), was allowed to warm to –30 °C. Ethyl acry-
late (6; 0.51 g, 5.10 mmol) was added rapidly and the mixture was
stirred for 5 min. The temperature was maintained at –30 °C during
this time. The reaction was quenched and worked up as described
above to give the crude product mixture (725 mg) as an amber oil.
Purification by silica gel column chromatography (EtOAc–hexane,
5:95) gave three major fractions and recovered cyclohexanone (130
mg, 26%). Fraction 1 contained the diester 15 (102 mg, 13%). Puri-
fication by silica column chromatography (EtOAc–hexane, 10:90)
gave 15 as a white solid; mp 32.5–34 °C.
1H NMR (400 MHz, CDCl3): d = 1.26–1.54 (m, 5 H, 1 × H5,
1 × H6, 2 × H7, 1 × H8), 1.68–1.83 (m, 1 H, 1 × H6), 1.83–2.13 (m,
5 H, 2 × H1, 1 × H3, 1 × H5, 1 × H8), 2.17–2.30 (m, 1 H, 1 × H3),
2.37–2.49 (m, 1 H, H8a), 3.27 (dd, J4eq,3eq = 3 Hz, J4eq,3ax = 5 Hz, 1
H, H4eq), 3.49 (d, JOH,5 = 1.5 Hz, 1 H, OH), 3.84 (dddd, J2ax,3eq/1eq
4 Hz, J2ax,3eq/1eq = 5 Hz, J2ax,3ax = 12 Hz, J2ax,1ax = 12 Hz, 1 H, H2ax),
7.39–7.90 (m, 10 H, 2 × C6H5).
13C NMR (100 MHz, CDCl3): d = 19.6 (C7), 21.0 (C6), 24.0 (C3),
26.0 (C1), 26.4 (C8), 33.3 (C5), 37.9 (C8a), 57.5 (C2), 68.2 (C4a),
73.7 (C4), 127.8, 128.7 (o-C6H5), 129.3 (m-C6H5), 133.8, 133.9 (p-
C6H5), 137.3, 140.0, (i-C6H5).
=
Synthesis 2005, No. 13, 2220–2226 © Thieme Stuttgart · New York

PAPER
Diversion from Bicyclo[4.2.0]octanol Formation
2225
(1RS,3SR,4aSR,8aSR)-8a-Hydroxydecahydronaphthalene-1,3-
dicarboxylic Acid Diethyl Ester (15)
Reaction of Enolate of Cyclohexanone with Diphenylvinylphos-
phine Oxide (7)
IR (KBr): 3500, 2933, 1727, 1705 cm–1.
The lithium enolate of cyclohexanone generated as outlined
previously2 using MeLi in Et2O (~1.4 M, 0.46 mL, 0.64 mmol) and
cyclohex-1-enyloxytrimethylsilane (130 mg, 0.15 mL, 0.76 mmol)
in anhyd THF (7 mL). The solution was warmed to –10 °C and
diphenylvinylphosphine oxide (7;16 145 mg, 0.64 mmol) in THF
(1.5 mL) was added dropwise over 20 seconds and the reaction mix-
ture was stirred for 10 min. The temperature was maintained at
–10 °C during this time. The reaction was quenched and worked up
as described above to give the crude product mixture as an amber
oil (235 mg). The oil, analysed by 1H NMR (400 MHz) was deter-
mined to contain the alkylated ketone 269 (89%) with the remainder
attributable to EtOAc, unreacted cyclohexanone and polymeric ma-
terial. Recrystallisation gave 2-[2¢-(diphenylphosphoryl)ethyl]cy-
clohexanone (18)17 as a white solid; mp 110–112 °C (Et2O) [Lit.17
109–110 °C (EtOAc)].
1H NMR (400 MHz, CDCl3): d = 1.10–1.30 (m, 10 H, 2 × CH3,
H4aax, 1 × H5, 1 × H7, 1 × H8), 1.32–1.48 (m, 2 H, 1 × H5,
1 × H6), 1.48–1.56 (m, 1 H, 1 × H8), 1.58–1.70 (m, 3 H, H4eq,
1 × H6, 1 × H7), 1.77 (ddd, J4ax,3eq = 5.5 Hz, J4ax,4aax = 12 Hz, J4,4
13.5 Hz, 1 H, H4ax), 1.98–2.12 (m, 2 H, 2 × H2), 2.53 (dd, J1ax,2eq
=
=
5 Hz, J1ax,2ax = 12 HZ, 1 H, H1ax), 2.69 (dddd, J3eq,2eq = ~2.5 Hz,
J3eq,4eq = ~2.5 Hz, J3eq,2ax = ~5 Hz, J3eq,4ax = ~5, 1 H, H3eq), 3.10 (s,
1 H, OH), 4.20–4.05 (m, 4 H, 2 × OCH2).
13C NMR (100 MHz, CDCl3): d = 14.2 (2 × CH3), 21.4 (C6), 26.0
(C7), 26.2 (C2), 27.9 (C5), 28.7 (C4), 37.2 (C8), 38.3 (C3), 40.1
(C4a), 48.5 (C1), 60.3, 60.5 (2 × OCH2), 69.7 (C8a),174.8 (C3-
C=O), 176.4 (C1-C=O).
MS (ESMS +ve): m/z = 305 (MLi+).
1H NMR (400 MHz, CDCl3): d = 1.28–1.42 (m, 1 H, 1 × H3),1.51–
1.71 (m, 3 H, 1 × H1¢, 1 × H4, 1 × H5), 1.73–2.10 (m, 4 H, 1 × H1¢,
1 × H3, 1 × H4, 1 × H5), 2.10–2.27 (m, 2 H,1 × H2¢, 1 × H6), 2.27–
2.35 (m, 1 H,1 × H6), 2.35–2.54 (m, 2 H, 1 × H2¢, H2), 7.38–7.52
(m, 6 H, m- and p-C6H5), 7.66–7.74 (m, 2 H, o-C6H5), 7.75–7.82 (m,
2 H, o-C6H5).
13C NMR (50 MHz, CDCl3): d = 22.17 (d, JC,P = 3.5 Hz, C1¢), 25.03
(C4), 27.33 (d, JC,P = 72 Hz, C2¢), 28.06 (C5), 34.36 (C3), 42.24
(C6), 51.05 (d, JC,P = 12.5 Hz, C2), 128.57, 128.62 (d, JC,P = 11.5
Hz, o-C6H5), 130.62, 130.89, (d, JC,P = 9 Hz, m-C6H5), 131.58,
131.66, (d, JC,P = 2.5 Hz, p-C6H5), 132.53, 133.50 (d, JC,P = 87.5 Hz,
i-C6H5), 212.9 (C1).
Anal. Calcd for C16H26O5: C, 64.40; H, 8.78. Found: C, C, 64.33; H,
9.06.
Fraction 2 contained a mixture of the diesters 15 and 16 (62 mg,
8%). Purification by silica gel column chromatography (EtOAc–
hexane, 10:90) gave a 20:80 mixture of the diester 15 and 16 as a
colourless oil, which was inseparable by HPLC,
15 and (1RS,3RS,4aSR,8aSR)-8a-Hydroxydecahydronaphtha-
lene-1,3-dicarboxylic Acid Diethyl Ester (16) (20:80)
IR (Nujol): 3510, 2933, 1731 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.12–1.86 (m, 17 H, 2 × CH3,
2 × H4, H4aax, 2 × H5, 2 × H6, 2 × H7, 2 × H8), 1.93 (dddd,
J2eq,4 = 2 Hz, J2eq,1ax = 4 Hz, J2eq,3ax = 4 Hz, J2,2 = 13 Hz, 1 H, H2eq),
2.09 (ddd, J2ax,1ax = 13 Hz, J2ax,3ax = 13 Hz, J2,2 = 13 Hz, 1 H, H2ax),
2.26 (dd, J1ax,2eq = 4 Hz, J1ax,2ax = 13 Hz, 1 H, H1ax), 2.38 (dddd,
J3ax,2eq = 4 Hz, J3ax,4eq = 4 Hz, J3ax,2ax = 12 Hz, J3ax,4ax = 12 Hz, 1 H,
H3ax), 4.05–4.20 (m, 4 H, 2 × OCH2), (OH not observed).
31P NMR MHz, CDCl3): d = 33.48 (P=O).
MS (ESMS +ve): m/z = 333 (MLi+).
Acknowledgment
13C NMR (100 MHz, CDCl3): d = 14.2 (2 × CH3), 21.4 (C5 or C6 or
C7), 26.0 (C5 or C6 or C7), 27.6 (C2), 27.9 (C5 or C6 or C7), 30.4
(C4), 37.1 (C8), 42.3 (C3), 43.7 (C4a), 51.6 (C1), 60.4, 60.7 (2 ×
OCH2), 69.3 (C8a), 174.5 (C3-C=O), 175.7 (C1-C=O).
We gratefully acknowledge support for this work from the Austra-
lian Research Council (Small Scheme), Griffith University, and the
award of an APAWS to C.C. Rowen.
MS (ESMS +ve): m/z = 305 (MLi+).
References
HRMS: m/z calcd for C16H26O5: 298.17802; found: 298.17863
(1) Loughlin, W. A.; Rowen, C. C.; Healy, P. C. J. Chem. Soc.,
Perkin Trans. 2 2002, 296.
(2) Loughlin, W. A.; Rowen, C. C.; Healy, P. C. J. Org. Chem.
2004, 69, 5690.
Fraction 3 contained the diester 17 (274 mg, 36%). Purification by
silica column chromatography (EtOAc–hexane, 10:90) gave diester
17 as a colourless oil,
(3) Loughlin, W. A.; McCleary, M. A. Org. Biomol. Chem.
2003, 1, 1347.
(1RS,3RS,4aRS,8aSR)-8a-Hydroxydecahydronaphthalene-1,3-
dicarboxylic Acid Diethyl Ester (17)
(4) Loughlin, W. A.; McCleary, M. A. Synthesis 2005, 761.
(5) Cabiddu, M. G.; Cabiddu, S.; Cadoni, E.; Cannas, R.;
Fattuoni, C.; Melis, S. Tetrahedron 1998, 54, 14095.
(6) Bunlaksananusorn, T.; Rodriguez, A. L.; Knochel, P. Chem.
Commun. 2001, 745.
(7) Risaliti, A.; Fatutta, S.; Forchiassin, M. Tetrahedron 1967,
23, 1451.
(8) Fatutta, S.; Risaliti, A. J. Chem. Soc., Perkin Trans. 1 1974,
2387.
(9) Atom coordinates, bond lengths, angles and thermal
parameters have been deposited at the Cambridge
Crystallographic Data Centre for structures 9–12 (CCDC
reference numbers 265361–265364, respectively). Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax:+ 44
(1223)336033; email:deposit@ccdc.cam.ac.uk).
(10) (a) Pearson, A. J.; Mortezaei, R. Tetrahedron Lett. 1989, 30,
5049. (b) Auvray, P.; Knochel, P.; Normant, J. F.
Tetrahedron 1988, 44, 6095.
IR (Nujol): 3519, 1738, 1716 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.20–1.78 (m, 16 H, 2 × CH3,
H4eq, H4aeq, 2 × H5, 2 × H6, 2 × H7, 2 × H8), 1.88–1.98 (m, 1
H,H2eq), 2.12 (ddd, J2ax,1ax = 13 Hz, J2ax,3ax = 13 Hz, J2,2 = 13 Hz, 1
H,H2ax), 2.25 (ddd, J4ax,4aeq = 5 Hz, J4ax,3ax = 13 Hz, J4,4 = 13 Hz, 1
H, H4ax), 2.51 (dddd, J3ax,2eq = 4 Hz, J3ax,4eq = 4 Hz, J3ax,2ax = 13 Hz,
J3ax,4ax = 13 Hz, 1 H, H3ax), 2.88 (dd, J1ax,2eq = 4 Hz, J1ax,2ax = 13 Hz,
1 H, H1ax), 4.10 (q, J = 7 Hz, 2 H, OCH2), 4.16 (q, J = 7 Hz, 2 H,
OCH2), (OH not observed).
13C NMR (50 MHz, CDCl3): d = 14.0 (2 × CH3), 23.5 (C5 or C6 or
C7), 25.8 (C5 or C6 or C7), 27.4 (C2), 28.0 (C5 or C6 or C7), 29.2
(C4), 36.9 (C3), 38.6 (C8), 41.4 (C4a), 42.5 (C1), 60.2, 60.6
(2 × OCH2), 70.3 (C8a), 174.8 (C3-C=O), 175.6 (C1-C=O).
MS (ESMS +ve): m/z = 305 (MLi+).
Anal. Calcd for C16H26O5: C, 64.40; H, 8.78. Found: C, 64.39; H,
8.98.
Synthesis 2005, No. 13, 2220–2226 © Thieme Stuttgart · New York

2226
W. A. Loughlin et al.
PAPER
(16) Collins, D. J.; Rowley, L. E.; Swan, J. M. Aust. J. Chem.
(11) (a) Cory, R. M.; Renneboog, R. M. J. Org. Chem. 1984, 49,
3898. (b) Cory, R. M.; Renneboog, R. M. J. Chem. Soc.,
Chem. Commun. 1980, 1081.
(12) Hagiwara, H.; Endou, S.; Fukushima, M.; Hoshi, T.; Suzuki,
T. Org. Lett. 2004, 6, 1115.
(13) Hagiwara, H.; Akama, T.; Okano, A.; Uda, H. J. Chem. Soc.,
Perkin Trans. 1 1993, 2173.
(14) Haynes, R. K.; Loughlin, W. A.; Hambley, T. W. J. Org.
Chem. 1991, 56, 5785.
1974, 27, 841.
(17) Wallace, P.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1992,
3169.
(18) TeXsan for Windows Version 1.06, 2001; Molecular
Structure Corporation: The Woodlands, TX, 2001.
(19) Sheldrick, G. M. SHELX-97 Program for Crystal Structure
Determination; University of Göttingen: Göttingen, 1997.
(20) Farrugia, L. J. J. Appl. Cryst. 1997, 30, 565.
(15) (a) Ye, B.; Qiao, L.-X.; Zhang, Y.-B.; Wu, Y.-L.
Tetrahedron 1994, 50, 9061. (b) Posner, G. H.; Lu, S.-B.;
Asirvatham, E.; Silversmith, E. F.; Shulman, E. M. J. Am.
Chem. Soc. 1986, 108, 511. (c) Posner, G. H.; Asirvatham,
E. Tetrahedron Lett. 1986, 27, 663. (d) Dionne, G.; Engel,
C. R. Can. J. Chem. 1978, 56, 419.
Synthesis 2005, No. 13, 2220–2226 © Thieme Stuttgart · New York