The formation of bicyclo[n.2.0]alkan-1-ols from the reaction of the lithium enolates of simple ketones and phenyl vinyl sulfoxide

Article abstract of DOI:10.1039/b208365e

The enolates generated from cyclopentanone, cycloheptanone or cyclooctanone and LDA at -78°C in THF react with (±)-phenyl vinyl sulfoxide under controlled conditions of temperature, reaction time, and concentration. Upon oxidation with MCPBA of the produc

Full text of DOI:10.1039/b208365e

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The formation of bicyclo[n.2.0]alkan-1-ols from the reaction of the
lithium enolates of simple ketones and phenyl vinyl sulfoxide†
Wendy A. Loughlin* and Michelle A. McCleary
School of Science, Griffith University, Brisbane, QLD, 4111, Australia.
E-mail: w.loughlin@sct.gu.edu.au
Received 28th August 2002, Accepted 20th February 2003
First published as an Advance Article on the web 18th March 2003
The enolates generated from cyclopentanone, cycloheptanone or cyclooctanone and LDA at Ϫ78 ЊC in THF react
with ( )-phenyl vinyl sulfoxide under controlled conditions of temperature, reaction time, and concentration. Upon
oxidationwithMCPBAoftheproductmixtures,thenovelsulfonylbicyclo[3.2.0]heptan-1-ols10–12,sulfonylbicyclo[5.2.0]-
nonan-1-ols 16–18, and sulfonylbicyclo[6.2.0]decan-1-ols 21 and 22 in conjunction with alkylated ketones 8, 9, 15, 19
and 20 were obtained from the respective ketones. The enolate generated from cyclobutanone and LDA at Ϫ78 ЊC in
THF reacts with ( )-phenyl vinyl sulfoxide and upon oxidation with MCPBA, the cyclohexanone 4 and monoalkyl-
ated cyclobutanone 5 were obtained. The ratio of bicyclo[n.2.0]alkan-1-ol to alkylated products varied with the
ketone enolate, conversion of phenyl vinyl sulfoxide, time, temperature and concentration of reaction and the
stability and steric strain of the final bicyclo[n.2.0]alkan-1-ol product.
photocycloaddition of bicyclo[3.3.1]nonanediones to allene,7
Introduction
photochemical cyclisation of aliphatic 4-oxoacetals,8 cyclo-
During the course of investigations towards the synthesis of
addition of a silylenol ether with propynoates,9 arynic conden-
fused-ring natural products we sought to access a fused six and
sation of ketone enolates,10 condensation of dehydro dihydro-
four member carbocyclic ring bearing a bridgehead hydroxyl
pyrans with ketone enolates,11 and Norrish type-II cyclization.12
group. Recently in concurrent studies we have shown that
Rearrangements are also observed and include rearrangement
provided accurate control of temperature, concentration, and
of tricyclo[3.1.1.03,6]heptyl and tricyclo[3.2.1.03,6]octyl sys-
reaction time was maintained, the reaction of the enolate
generated from cyclohexanone and LDA at Ϫ78 ЊC in THF
with ( )-phenyl vinyl sulfoxide gave novel sulfinylbicyclo[4.2.0]-
octan-1-ols and monoalkylated sulfinylcyclohexanone in a
tems,13 cationic rearrangement of α-aryl pentacyclooctanes,14
and solvolysis of substituted cyclopropyl carbinylic systems to
include ring enlargement to form substituted cyclobutanols.15
Other transformations include Clemmensen reduction of
95 : 5 ratio. These compounds were oxidised with MCPBA to
strained diketones,16 intramolecular reductive ring closure with
the sulfonylbicyclo[4.2.0]octan-1-ols 1 and 2 and the mono-
samarium iodide of alkene chloroketones,17 samarium diiodide-
alkylated sulfone 3 (Scheme 1).1 The relative stereochemistries
mediated pinacolization of diketones,18 and reduction of
of the bicyclooctanols 1–2 were established by X-ray structural
α-acetoxy ketones.19 Facile access to bicyclo[3.2.0]heptan-1-ols,
determination.2
bicyclo[5.2.0]nonan-1-ols and bicyclo[6.2.0]decan-1-ols bearing
a bridgehead hydroxyl in simple systems using the one method-
ology is unreported. Described herein are our investigations
into the reaction of the lithium enolates of simple ketones with
( )-phenyl vinyl sulfoxide and the controlled formation of
bicyclo[n.2.0]alkan-1-ols.
Results and discussion
Synthesis of the bicycloalkanols
The current investigation sought to explore the potential scope
of the cyclisation (Scheme 1) with respect to the ring size of the
Scheme 1
starting ketone and thus the formation of bicyclo[n.2.0]alkan-1-
In the current study we sought to explore the potential
ols. Four representative ketones were reacted with ( )-phenyl
scope of this cyclisation reaction, by exploring the ring size of
vinyl sulfoxide under the initial cyclisation conditions that had
the starting ketone. One previous example with the use of a
generated bicyclo[4.2.0]alkan-1-ols from cyclohexanone and
functionalised ketone has been reported.3 The construction
phenyl vinyl sulfoxide. The lithium enolate of cyclobutanone,
of bicyclo[3.2.0]heptan-1-ols, bicyclo[5.2.0]nonan-1-ols and
cyclopentanone, cycloheptanone or cyclooctanone was reacted
bicyclo[6.2.0]decan-1-ols bearing a bridgehead hydroxyl occurs
at 0.155 M with ( )-phenyl vinyl sulfoxide in THF under
typically within polycyclic compounds, although such un-
a nitrogen atmosphere for 45 minutes (Method A, Table 1).
functionalised bicyclo[n.2.0]alkan-1-ols have been observed
Direct oxidation of the crude sulfoxide mixture using MCPBA
in limited mechanism and solvolysis studies.4 Access to
was followed by analysis of the crude sulfone product mixture
1
bicyclo[n.2.0]alkan-1-ols includes addition processes such as
by H NMR (400 MHz) spectroscopy. The product ratios are
intramolecular [2ϩ2] photochemical cycloaddition,5 [2 ϩ 2]
reported in Table 1. All yields are calculated on conversion of
phenyl vinyl sulfoxide, as the starting ketones were generally
photoaddition of a cyclic enone with a silyl enol ether,6
volatile.
Cyclobutanone was reacted with phenyl vinyl sulfoxide using
† Electronic supplementary information (ESI) available: full experi-
mental details. See http://www.rsc.org/suppdata/ob/b2/b208365e/
method A and upon oxidation gave the cyclohexanone 420 and
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 4 7 – 1 3 5 3
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Table 1 Product yields for the reaction of cyclobutanone, cyclopentan-
one, cycloheptanone or cyclooctanone and phenyl vinyl sulfoxide from
methods A–D
Reaction methoda
A
B
C
D
Ketone
Product
(% yield)
Cyclobutanone
4
5.5
38.5
0
6
18
0.5
—
—
—
26.5
1
22
0
0.5
26.5
42
5
0
6
13.5
6
0
—
—
—
22.5
1
25.5
0
5
PVSb
10
11
Cyclopentanone
3
18.5
0.5
19.5
0.5
0.5
6
61.5
8.5
1
3
5
19
3.5
49.5
9
2.5
55.5
2.5
1.5
0
26
8
0
41
0
2
0
65
14.5
0
8
9
Scheme 3
12
1
PVSb
16
6.5
43.5
12
0
intermediate 14. This is perhaps promoted by conformational
effects arising from the presence of two alkyl side chains at
position two.
Cycloheptanone
Cyclooctanone
17
18
15
9
PVSb
21
12
23
6
47
7
22
19
44
2
21
20
PVSb
0
0.5
a Method A (0.155 M, 45 min, Ϫ30 ЊC to 0 ЊC, laboratory light);
Method B (0.155 M, 5 min, Ϫ30 ЊC, dark); Method C (0.01 M, 5 min,
Ϫ30 ЊC, dark); Method D (0.31 M, 5 min, Ϫ30 ЊC, dark). b Combined
recovery of phenyl vinyl sulfoxide and/or yield of phenyl vinyl sulfone.
Next, cycloheptanone was reacted with phenyl vinyl sulfoxide
using method A and upon oxidation gave monoalkylated
cycloheptanone 1522 as the major product, in conjunction with
the bicyclo[5.2.0]nonan-1-ols 16 and 17 (Scheme 4). In the final
example, cyclooctanone was reacted with phenyl vinyl sulfoxide
using method A and upon oxidation gave monoalkylated
cyclooctanone 1922 as the major product in conjunction with
the dialkylated cyclooctanone 20 and bicyclo[6.2.0]decan-1-ol
21 (Scheme 5). Compared to the previous results for cyclo-
pentanone and cycloheptanone, in the cyclooctanone example
an increase in the dialkylated product 20 was observed. This
was attributed to a difference in reactivity of the cyclooctanone
enolate and a monoalkylated cyclooctanone enolate with
phenyl vinyl sulfoxide. The structural identity of the novel
bicyclo[n.2.0]alkan-1-ols was unambiguously determined prior
to further synthetic investigations.
Scheme 2
monoalkylated cyclobutanone 5 (Scheme 2). Apparent polymer-
isation of the phenyl vinyl sulfoxide to some extent was
evidenced by polymeric material in the workup. No bicyclo-
[2.2.0]hexan-1-ols in the crude product mixture were evident in
the 1H NMR spectrum or by HPLC analysis. However the pres-
ence of a bicyclohexanolide intermediate 6 in the formation of
the cyclohexanone 4 is plausible. Ring opening of the inter-
mediate 6 to break the strained bridgehead bond could give rise
to an anion 7 in equilibrium with enolate anions that upon
quenching and oxidation would give the cyclohexanone 4.
Next, cyclopentanone was reacted with phenyl vinyl sulfoxide
using method A and upon oxidation gave monoalkylated
cyclopentanone 8 as the major product, in conjunction with
minor amounts of dialkylated cyclopentanone 9, bicyclo-
[3.2.0]heptan-1-ols 10 and 11 and the unexpected bicyclo[3.2.0]-
heptan-1-ol 12 (Scheme 3). The predominance of monoalkyl-
ated cyclopentanone 8 was consistent with the longer reaction
time of 45 minutes, where a similar trend was observed with
cyclohexanone.1 Polyalkylations of non-symmetrical ketone
enolates in which only alkyl groups are present are generally not
regioselective and are dependent on the nature of the substrate,
the base, the cation and the solvent.21 Thus, equilibration of the
monoalkylated enolate must occur at two sites to give the sub-
stitution patterns observed in dialkylated cyclopentanone 9 and
substituted bicyclo[3.2.0]heptan-1-ol 12. The formation of the
corresponding sulfinylbicyclo[3.2.0]heptan-1-olide intermediate
13 presumably arises from cyclisation of the 2,2-dialkylated
Scheme 4
Structure of the bicycloalkanols
Analytical samples of the sulfone derivatives were obtained by
preparative HPLC for structural determination and character-
isation. From these studies eight novel sulfonylbicyclo[n.2.0]-
alkan-1-ols were obtained, bicyclo[3.2.0]heptan-1-ols 10–12,
bicyclo[5.2.0]nonan-1-ols 16–18, and bicyclo[6.2.0]decan-1-ols
21 and 22 (Schemes 3, 4 and 5). The characterisation data for
bicyclo[n.2.0]alkan-1-ols 10, 16 and 21 have been reported in
a recent separate structural study.2 The sulfonylbicyclo[n.2.0]-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 4 7 – 1 3 5 3
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1
Table 2 Key assignments and δ values (ppm) from the H and 13C NMR spectra of bicyclo[3.2.0]heptan-1-ols 10–12, bicyclo[5.2.0]nonan-1-ols
16–18 and bicyclo[6.2.0]decan-1-ols 21 and 22
δ (ppm)
Ca
Cb
Cc
Hb
Hc
Hc1
Hd
10
11
12
16
17
18
21
22
83.6
85.3
83.4
78.9
81.8
81.7
78.3
81.4
64.2
65.3
62.2
64.1
66.0
62.7
65.3
67.3
46.3
44.6
49.2
48.7
45.0
49.6
48.1
44.6
3.62 (ddd, 9.5, 5.5, < 1 Hz)
3.79 (ddd, 10, 10, 1 Hz)
3.5 (dd, 10, 7 Hz)
3.530 (ddd, 9.5, 5.5, 1 Hz)
3.600 (dd, 10, 9 Hz)
3.74 (dd, 10.5, 4 Hz)
3.44 (ddd, 10, 6, 1 Hz)
3.58 (dd, 10.5, 9 Hz)
2.62–2.72
2.04–2.22
2.20
2.48–2.66
1.90–2.07
2.47–2.62
2.61
1.46–1.60
1.68–1.95
1.60–1.74
1.54–1.80
1.65–1.78
1.27–1.46
1.39–1.60
1.62–1.77
2.62–2.72
2.45–2.54
2.48–2.66
2.17–2.30
2.47–2.62
2.30–2.39
1.96–2.05
1.86–1.95
NMR spectrum displayed characteristic couplings and shifts
for Hb, dependent on the epimer observed at Cb. These trends
were correlated by X-ray crystallography of selected examples
(bicyclo[n.2.0]alkan-1-ols 1, 2, 10, 16, 21). By analogy, the
relative stereochemistry of the bicyclo[n.2.0]alkan-1-ols 11, 17
and 22 was inferred from the shift (δ ppm) and the coupling
constants of Hb in the 1H NMR as the relative stereochemistry
was not established by 2D NMR spectroscopy methods.
An upfield δ value of Hb was indicative of a cis relationship
between the hydroxyl and sulfonyl groups. For bicyclo[n.2.0]-
alkan-1-ols 10, 16 and 21, couplings of 9.5–10 Hz and 5.5–6 Hz
to Hc and Hc1 and a long range coupling of 1 Hz, typical of
cyclobutyl ring systems,23 to Hd was observed for Hb. The long
range coupling between Hb and Hd was correlated with a trans
relationship of Hb and Hd in bicyclo[n.2.0]alkan-1-ols 10, 16
and 21. For bicyclo[n.2.0]alkan-1-ols 11, 17, and 22 couplings
of 9–10 Hz, and 10–10.5 Hz to Hc and Hc1 were observed for
Hb. The absence of the 1 Hz coupling between Hb and Hd was
correlated with a cis relationship of Hb and Hd and thus a trans
relationship between the hydroxyl and sulfonyl groups in
bicyclo[n.2.0]alkan-1-ols 11, 17 and 22. The additional 1 Hz
coupling observed for Hb of bicyclo[3.2.0]heptan-1-ol 11 was
assigned to a W-coupling between Hb and the hydrogen alpha
to Ca in the cyclopentyl ring. Thus, it was established that
bicyclo[3.2.0]heptan-1-ol 11 was the (1RS,5SR,7RS)-isomer,
bicyclo[5.2.0]nonan-1-ol 17 was the (1RS,7SR,9RS)-isomer
and bicyclo[6.2.0]decan-1-ol 22 was the (1RS,8SR,10RS)-iso-
mer as shown (Schemes 3–5).
Scheme 5
alkan-1-ols 10–12, 16–18, 21 and 22 were characterized by
interpretation of spectral data from 1H and 13C one-
dimensional and gCOSY, HMQC, HSQC and HMBC two-
dimensional NMR spectroscopy studies. Key assignments
and δ values are reported in Table 2. Using non-IUPAC labels
(Fig. 1) to aid comparison, the connectivity of the cyclobutyl
ring system typically was established as follows. The connectiv-
ity of the cyclobutyl ring was apparent from correlations
between the signals due to Hb (δ = 3.44–3.79 ppm) and Hc
(δ = 1.86–2.72 ppm) and Hc1 (δ = 1.27–1.95 ppm) in the gCOSY.
In the HSQC, CH signals were observed for Cb–Hb and
Cd–Hd with the carbon signals for Cb and Cd occurring typi-
cally at around δ 65 and δ 46 ppm respectively. The quaternary
carbon for Ca (about δ 80 ppm) was identified by its absence in
the HSQC. In the HMBC, 2J and 3J correlations were observed
between Ca and Hb, Hc/Hc1 and Hd.
A further two bicyclo[n.2.0]alkan-1-ols were isolated and
determined using gCOSY, HSQC and HMBC two-dimensional
NMR spectroscopy studies to be the substituted bicyclo[n.2.0]-
alkan-1-ols 12 and 18. The relative stereochemistry at C5 in 12
and C2 in 18 was not established by 2D NMR spectroscopy
methods. However upon comparison of shifts and coupling
1
constants, as discussed above, for key signals in the H NMR
spectra, it was inferred that bicyclo[3.2.0]heptan-1-ol 12 was the
(1RS,5RS,7SR)-isomer as shown (Scheme 3) and bicyclo-
[5.2.0]nonan-1-ol 18 was the (1RS,2RS,7SR,9SR)-isomer as
shown (Scheme 4).
The FTIR spectra of bicyclo[n.2.0]alkan-1-ols 10–12, 16–18,
21 and 22 displayed sharp absorption bands with maximums
in the range 3448–3536 cmϪ1 in combination with weak to
strong broad bands at about 3400 cmϪ1. The sharp hydroxyl
stretching bands at about 3500 cmϪ1 were attributed to the ‘free’
hydroxyl group of the alcohol and the broad absorption bands
at about 3400 cmϪ1 to intermolecular hydrogen bonding. The
appearance of both types of hydroxyl stretches is consistent
with intermolecular hydrogen bonding increasing as the
concentration of the KBr disc increases.
Fig. 1 Correlation of IUPAC numbering and generalised label for
bicyclo[n.2.0]alkan-1-ols.
The relative stereochemistries of the sulfonylbicyclo[n.2.0]-
alkan-1-ols 10–12, 16–18, 21 and 22 were established through a
combination of X-ray crystallography and NMR spectroscopy.
Using X-ray crystallography, the relative stereochemistry of
bicyclo[n.2.0]alkan-1-ols 10, 16 and 21 was established as
reported elsewhere.2 Thus it was determined that bicyclo-
[3.2.0]heptan-1-ol 10 was the (1RS,5SR,7SR)-isomer, bicyclo-
[5.2.0]nonan-1-ol 16 was the (1RS,7SR,9SR)-isomer and
bicyclo[6.2.0]decan-1-ol 21 was the (1RS,8SR,10SR)-isomer as
shown (Schemes 3–5). In previous work1,2 we noted that the 1H
Synthesis variations
With the structure of the novel bicyclo[n.2.0]alkan-1-ols estab-
lished, we now sought to improve the ratio of bicyclo[n.2.0]-
alkan-1-ols to alkylated products observed. Guided by our
concurrent studies on cyclohexanone we altered the reaction
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 4 7 – 1 3 5 3
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Table 3 Product ratios for the reaction of cyclopentanone, cyclo-
heptanone or cyclooctanone and phenyl vinyl sulfoxide from methods
B–D
nonan-1-ol 16 as the major product in significant preference to
the alkylated cycloheptanone 15 (Table 3). Interestingly, at the
intermediate concentration (0.155 M) the notably best ratio
of 96 : 4 for bicyclo[5.2.0]nonan-1-ols 16 and 17 to alkylated
cycloheptanone 15 was obtained. Cyclooctanone gave yet a dif-
ferent product ratio. For all concentrations, the monoalkylated
cyclooctanone 19 is obtained as the major product (Table 3).
The ratio changes to increase the preference towards bicyclo-
[6.2.0]decan-1-ols 21 and 22 as the concentration increases.
Thus, at the higher concentration (0.31 M) a ratio of 35 : 65 for
bicyclo[6.2.0]decan-1-ols 21 and 22 to alkylated cyclooctanones
19 and 20 was obtained. However, the apparent trends in
Table 3 of the changes in ratio of bicyclo[n.2.0]alkan-1-ol to
alkylated ketones as reaction concentration was varied from
0.01 M to 0.155 M to 0.31 M may be distorted by the reduction
of conversion of phenyl vinyl sulfoxide at 0.01 M.
Comparison of the yields of bicyclo[n.2.0]alkan-1-ols to
alkylated ketones for each ketone at a concentration of 0.01,
0.155 or 0.31 M displayed a distinct trend. Fig. 2 shows the
trend for the 0.31 M series and is illustrative of the trend
observed at the other concentrations of 0.01 M and 0.155 M.
For the ketones which gave bicyclo[n.2.0]alkan-1-ols as
products, the smallest ring ketone, cyclopentanone, gave the
lowest conversion of phenyl vinyl sulfoxide with combined
yields of bicyclo[n.2.0]alkan-1-ol and alkylated ketones of 39–
49% compared to cycloheptanone (53–73%) and cyclooctanone
(52–80%). The slightly improved conversions of cyclooctanone
were in favour of alkylation not bicyclo[6.2.0]decan-1-ol form-
ation as previously discussed. Cycloheptanone consistently
gave the highest yields of bicycloalkan-1-ols.
Reaction methoda
C
B
D
Ketone
Products
(product ratio)
Cyclopentanone
Cycloheptanone
Cyclooctanone
10 ϩ 11 : 8 ϩ 9
16 ϩ 17 : 15
21 ϩ 22 : 19 ϩ 20
56 : 44
89 : 11
12 : 88
49 : 51
96 : 4
28 : 72
48 : 52
86 : 14
35 : 65
a Method B (0.155 M, 5 min, Ϫ30 ЊC, dark); Method C (0.01 M, 5 min,
Ϫ30 ЊC, dark); Method D (0.31 M, 5 min, Ϫ30 ЊC, dark).
conditions. We carried out ensuing reactions in the dark, to
exclude potential competing pathways that may be promoted
by light.24 Phenyl vinyl sulfoxide was added rapidly to decrease
the time for potential equilibration of intermediates and the
reaction time was decreased to 5 minutes. Short reaction times
of less than 15 minutes had favoured bicyclo[4.2.0]octan-1-ol
formation over monoalkylation in the cyclohexanone case.1
The lithium enolate of cyclobutanone, cyclopentanone, cyclo-
heptanone or cycloctanone was reacted rapidly with phenyl
vinyl sulfoxide in THF under a nitrogen atmosphere at Ϫ30 ЊC
for 5 minutes in the dark (Method B, Table 1). Upon oxidation
of the crude sulfoxide mixtures with MCPBA, sulfone products
were identified. The yields are presented in Table 1.
For the cyclobutanone example, no bicyclo[2.2.0]hexan-1-ol
was observed, rather lower yields of the cyclohexanone 4 and
monoalkylated cyclobutanone 5 were observed in conjunction
with the decreased reaction time. For the cyclopentanone
example, an increase in the major bicyclo[3.2.0]heptan-1-ol 10
from 3% to 18.5% was observed with a concomitant decrease in
the yield of monoalkylated cyclopentanone 8 from 55.5% to
19.5%, and with a slight decrease (6% recovery) in the over-
all conversion of phenyl vinyl sulfoxide. This trend was also
observed for cycloheptanone and cyclooctanone with an
increase in yields of bicyclo[n.2.0]alkan-1-ol products 16 and 21
and a decrease in yields of monoalkylated ketones 15 and 19.
Compared to Method A, two further bicyclo[n.2.0]alkan-1-ols
18 and 22 were observed from the Method B results using the
ketones cycloheptanone and cyclooctanone respectively. The
substituted bicyclo[5.2.0]nonan-1-ol 18 was observed in 1%
yield from cycloheptanone (Method B). Its formation must
occur by a process similar to that for bicyclo[3.2.0]heptan-1-ol
12, the difference in regiochemistry a consequence of pKa and
conformational effects in the enolate intermediates.
Having obtained a generally improved product ratio of
bicyclo[n.2.0]alkan-1-ols to monoalkylated product for cyclo-
pentanone, cycloheptanone and cyclooctanone we sought to
explore the effects of total concentration of the reaction mix-
ture on the product outcome. A dilute set of reaction condi-
tions of 0.01 M (Method C, Table 1) and a more concentrated
set of reaction conditions of 0.31 M (Method D, Table 1)
were employed for cyclopentanone, cycloheptanone and cyclo-
octanone. Notably, there was decreased conversion for the
dilute conditions (Method C, Table 1) where 13.5–26.5% of
phenyl vinyl sulfoxide was unreacted. A comparison of the
results for the three concentrations (Methods C, B and D)
for cyclopentanone, cycloheptanone and cyclooctanone is
displayed in Table 3.
When comparing the concentrations of 0.01, 0.155 and
0.310 M for each ring size of the starting ketone, there was a
notable change in trends for product distribution. For the three
concentrations, cyclopentanone gave an approximate 50 : 50
ratio of bicyclo[3.2.0]heptan-1-ols 10 and 11 to alkylated cyclo-
pentanones 8 and 9 (Table 3) with the bicyclo[3.2.0]heptan-1-ol
10 being the major bicyclo[n.2.0]alkan-1-ol isomer. For the
three concentrations, cycloheptanone gave the bicyclo[5.2.0]-
Fig. 2 Ketone ring size vs. % composition of product in total reaction
products using Method D (0.31 M) for the products, monoalkylated
ketone (᭿), dialkylated ketone (ᮀ), bicyclo[n.2.0]alkan-1-ols (᭹), and
substituted bicyclo[n.2.0]alkan-1-ol (X).
Here, we account for the product preference in terms of the
stability and steric interactions observed in the final bicyclo-
[n.2.0]alkan-1-ol compound. Elsewhere, we have reported the
X-ray structures for bicyclo[n.2.0]alkan-1-ols 10, 16 and 21.2
Notably, it was seen that in the solid state structures, the torsion
angles at the ring junction varied between the bicyclo[n.2.0]-
alkan-1-ols 10, 16 and 21 and the overall steric strain is of the
order bicyclo[5.2.0]nonan-1-ol 16 < bicyclo[3.2.0]heptan-1-ol
10 ≅ bicyclo[6.2.0]decan-1-ol 21. Correspondingly, the yields of
bicyclo[n.2.0]alkan-1-ol products observed were in the order
bicyclo[3.2.0]heptan-1-ol 10 ≅ bicyclo[6.2.0]decan-1-ol 21 <
bicyclo[5.2.0]nonan-1-ol 16 for the higher concentrations (0.155
M and 0.31 M) employed and bicyclo[6.2.0]decan-1-ol 21 <
bicyclo[3.2.0]heptan-1-ol 10 < bicyclo[5.2.0]nonan-1-ol 16 at
the lower concentration (0.01 M) (Table 1). Generally, as the
strain of the bicyclo[n.2.0]alkan-1-ol product decreases, an
increase in product distribution towards the bicyclo[n.2.0]-
alkan-1-ol in conjunction with increased yield of bicyclo-
[n.2.0]alkan-1-ol is observed. This also was thought to account
for the preference of bicyclo[3.2.0]heptan-1-ol 10 over 11,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 4 7 – 1 3 5 3
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bicyclo[5.2.0]nonan-1-ol 16 over 17 and bicyclo[6.2.0]decan-1-
ol 21 over 22 for cyclopentanone, cycloheptanone and cyclo-
octanone respectively, where the trans relationship of the
hydroxyl group and sulfonyl group must alter the ring strain
and hydrogen bonding in the bicyclo[n.2.0]alkan-1-ols 11, 17
and 22. In addition, as changes in the reaction concentration
affect the bicyclo[n.2.0]alkan-1-ol to alkylated product ratio
obtained from an individual ketone, this may be linked to stabil-
ization of the transition states or intermediates leading to the
final bicyclo[n.2.0]alkan-1-ol products by the reaction solvent
(THF) and the basicity of the carbonyl group of cyclo-
pentanone (pKa Ϫ7.5),25 cycloheptanone (pKa Ϫ6.6)25 and
cyclooctanone (pKa Ϫ6.2)25 and thus preference for formation
of the final bicyclo[n.2.0]alkan-1-ol product.
Taking into consideration conversion of phenyl vinyl sulf-
oxide and overall yield of bicyclo[n.2.0]alkan-1-ol, in this study,
the optimal reaction concentration for formation of bicyclo-
[n.2.0]alkan-1-ols from cyclopentanone was 0.01 M, from
cycloheptanone was 0.155 M and from cyclooctanone was 0.31
M, the latter giving a slightly better result (about 5%) than
method B at 0.155 M. However, these results and the variances
observed at each reaction concentration also suggest that the
prediction of whether increasing or decreasing the reaction
concentration will favour formation of bicyclo[n.2.0]alkanols
from a ketone enolate is not singularly reflective of the product
outcome.
In conclusion, this study has demonstrated that a range of
simple ketones of varying ring sizes (five to eight members) can
react with phenyl vinyl sulfoxide to give bicyclo[3.2.0]heptan-1-
ols 10 and 11, bicyclo[5.2.0]nonan-1-ols 16 and 17 and bicyclo-
[6.2.0]decan-1-ols 21 and 22 under controlled conditions of
time, temperature and concentration of reaction in partially
optimised yields of 27.5–70%. It is noteworthy that the bicyclo-
[n.2.0]alkan-1-ol (n = 3, 5, 6) ring system is generated in a con-
vergent approach from readily available synthons, a cyclic
ketone and phenyl vinyl sulfoxide, and that the ring junction is
generated with apparent selectivity. Bicyclo[2.2.0]hexan-1-ols
could not be obtained under the current variations of reaction
conditions. The ratio of bicyclo[n.2.0]alkan-1-ols to alkylated
ketones was reflective of the balance of the variables of enolate
reactivity, conversion of phenyl vinyl sulfoxide, time, temper-
ature and concentration of reaction, and stability and steric
strain observed in the final bicyclo[n.2.0.]alkan-1-ol product.
This study, in conjunction with our previous work,1,2 has
demonstrated that this novel cyclisation methodology has
potential scope for the construction of complex fused ring sys-
tems. From both a preparative and mechanistic viewpoint the
reaction is important and further investigations are in progress.
yields greater than theoretical 100% were found to include
water and this was included in the calculations.
General procedures for synthesis of bicyclo[n.2.0]alkan-1-ol
sulfoxides
Method A: 45 min, laboratory light, 0.155 M. Lithium diiso-
propylamide (1 equivalent, 1.4–1.95 M) was added to THF
(19.5–39.5 ml) under an atmosphere of nitrogen at Ϫ10 ЊC and
the solution cooled to Ϫ75–78 ЊC. The ketone (1 equivalent)
was added over 5 minutes and the temperature maintained
between Ϫ70–78 ЊC. The system was allowed to warm to
Ϫ30 ЊC and phenyl vinyl sulfoxide (1 equivalent) was added
over 5 minutes. The reaction mixture was warmed to 0 ЊC,
stirred for 45 minutes and quenched with aqueous ammonium
chloride (40 ml). The mixture was extracted with ethyl acetate
(3 × 40 ml) and the combined organic layers were washed with
water (2 × 50 ml), brine (50 ml) and dried (MgSO4, anhydrous).
The solvent was removed under reduced pressure to afford the
crude sulfoxide mixture.
Method B: 5 min, dark, 0.155 M. The lithium enolate of the
ketone was generated according to method A using lithium
diisopropylamide (1 equivalent, 1.27–1.95 M), THF (12.5–
39.5 ml) and ketone (1 equivalent). The system was shielded
from light and allowed to warm to Ϫ30 ЊC. Phenyl vinyl
sulfoxide (1 equivalent) was added rapidly as a neat solution.
The reaction mixture was maintained at Ϫ30 ЊC, stirred for
5 minutes and quenched with ammonium chloride (40 ml). The
mixture was worked up according to method A.
Method C: 5 min, dark, 0.01 M. The lithium enolate of the
ketone was generated according to method B using lithium
diisopropylamide (1 equivalent, 1.70 M), THF (76–113 ml),
ketone (1 equivalent) and phenyl vinyl sulfoxide (1 equivalent).
The reaction was quenched with ammonium chloride (40 ml)
and worked up according to method A.
Method D: 5 min, dark, 0.31 M. The lithium enolate of the
ketone was generated according to method B using lithium
diisopropylamide (1 equivalent, 1.95 M), THF (7.3–14.2 ml),
ketone (1 equivalent) and phenyl vinyl sulfoxide (1 equivalent).
The reaction was quenched with ammonium chloride (40 ml)
and worked up according to method A.
Oxidation of bicyclo[n.2.0]alkan-1-ol sulfoxide mixtures
The crude sulfoxide mixture (1 mole, based on crude yield
inclusive of ethyl acetate in some instances and assumed con-
version to monoalkylated product) dissolved in chloroform
(10–20 ml) was added to a vigorously stirred solution of
MCPBA (1.0–1.1 mole, 57–77%) and chloroform (10–30 ml) at
0 ЊC, over 20 minutes. The mixture was stirred at room temper-
ature for 16 hours and the solvent was removed under reduced
pressure. The residue was dissolved in ethyl acetate (50 ml),
washed with aqueous sodium hydrogen carbonate (3 × 40 ml),
brine (40 ml) and dried (MgSO4, anhydrous). The solvent was
removed under reduced pressure and dried under high vacuum
Experimental
The general experimental conditions and instrumentation have
been described elswhere.1 Solvents and commercially available
reagents were purified in the standard manner. A full descrip-
tion of all experiments is given in the Electronic Supplementary
Information.†
1
to afford the crude sulfone mixture, the H NMR spectrum of
1H-NMR product analysis and determination of percentage
composition
which displayed no signals due to sulfoxide products (bicyclo-
[n.2.0]alkan-1-ols or alkylated products).
The crude product mixtures from oxidation were dried under
high vacuum, and the mass of the crude product determined.
The H-NMR (400 MHz) spectra were obtained using CDCl3
as solvent. Integration of the baseline resolved key peaks
(to 1%) in the region δ 2.80–3.80 ppm, for bicyclo[n.2.0]alkan-
1-ol and monoalkylated and dialkylated products, and in the
region δ 5.80–6.80 ppm, for unreacted phenyl vinyl sulfoxide as
phenyl vinyl sulfoxide and/or phenyl vinyl sulfone, was used to
calculate the percentage composition of these components if
present from the integral of the total crude mixture. Crude
Reaction of cyclobutanone
1
From Method A using cyclobutanone (0.53 ml, 7.134 mmole)
the crude sulfoxide mixture (1.408 g, 6.334 mmole) was oxidised
according to the general procedure to give the crude sulfone
mixture (0.877 g). Column chromatography (hexane–ethyl
acetate, 60 : 40) and semi preparative HPLC (hexane–ethyl
acetate; 4, 70 : 30; 5, 50 : 50) were performed.
2-(Phenylsulfonyl)cyclohexanone 4 was isolated as a white
solid, mp 65.7–66.6 ЊC (ethyl acetate–hexane) (lit.20 87 ЊC from
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 4 7 – 1 3 5 3
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CCl4) (Rt 13.0 min, 3 ml minϪ1) (Found: C, 60.53; H, 6.11. Calc.
for C12H14SO3: C, 60.48; H, 5.92%); νmax(KBr)/cmϪ1 1710, (CO),
1309, (SO2), 1149, (SO2); δH (400 MHz, CDCl3) 7.85–7.90 (2 H,
m, o-C6H5), 7.61–7.67 (1 H, m, p-C6H5), 7.51–7.57 (2 H, m,
m-C6H5), 3.82 (1 H, ddd, J2,3 5.5, J2,3 5.5, J2,4 or 6 1.5, 2-H), 2.80
(1 H, ddd, J6,6 15, J6,5 9.5, J6,5 5, 6-H), 2.47–2.60 (1 H, m, 3-H),
2.37–2.45 (1 H, m, 6-H), 2.13–2.28 (2 H, m, 3-H, 4-H), 1.93–
2.05 (1 H, m, 5-H), 1.67–1.87 (2 H, m, 4-H, 5-H); δC (50 MHz,
CDCl3) 202.3 C-1; 138.4 i-C6H5; 134.2 p-C6H5; 129.3 m-C6H5;
129.1 o-C6H5; 72.9 C-2; 41.9 C-6; 27.8 C-3; 26.7 C-5; 22.3 C-4;
(ESMSϩ) 245 (MLiϩ, 24%), 261 (MNaϩ, 100%).
2-[2Ј-(Phenylsulfonyl)ethyl]cyclobutanone 5 was isolated as a
white solid, mp 40.5–41.8 ЊC (ethyl acetate–hexane) (Rt 9.4
min, 3 ml minϪ1) (Found: C, 60.31; H, 6.05; S, 13.30. Calc. for
C12H14SO3: C, 60.48; H, 5.92; S, 13.45%); νmax(KBr)/cmϪ1 1776,
(CO), 1294, (SO2), 1144, (SO2); δH (400 MHz, CDCl3) 7.86–7.91
(2 H, m, o-C6H5), 7.63–7.69 (1 H, m, p-C6H5), 7.51–7.60 (2 H,
m, m-C6H5), 3.36 (1 H, dddddd, J2,3 10.5, J2,3 7.5, J2,1Ј 7.5, J2,1Ј
7.5, J2,4 2.5, J2,4 2.5, 2-H), 3.26 (1 H, ddd, J2Ј,2Ј 14, J2Ј,1Ј 10, J2Ј,1Ј 6,
2Ј-H), 3.12 (1 H, ddd, J2Ј,2Ј 14, J2Ј,1Ј 10, J2Ј,1Ј 6, 2Ј-H), 3.05 (1 H,
dddd, J4,4 18.5, J4,3 10, J4,3 7.5, J4,2 2.5, 4-H), 2.90 (1 H, dddd,
J4,4 18, J4,3 9.5, J4,3 5, J4,2 3, 4-H), 2.22 (1 H, dddd, J3,3 10.5, J3,4
10.5, J3,2 10.5, J3,4 5, 3-H), 1.90–2.08 (2 H, m, 2 × 1Ј-H), 1.62
(1 H, dddd, J3,3 11, J3,4 9.5, J3,4 8, J3,2 8, 3-H); δC (50 MHz,
CDCl3) 209.3 C-1; 139.9 i-C6H5; 133.8 p-C6H5; 129.3 m-C6H5;
128.0 o-C6H5; 57.9 C-2; 53.7 C-2Ј; 44.8 C-4; 22.8 C-1Ј; 16.9 C-3;
(ESMSϩ) 245 (MLiϩ, 40%), 261 (MNaϩ, 100%).
δH (400 MHz, CDCl3) 7.82–7.92 (2 H, m, o-C6H5), 7.58–7.68
(1 H, m, p-C6H5), 7.48–7.58 (2 H, m, m-C6H5), 3.79 (1 H, ddd,
J7,6 10, J7,6 10, J7,4 1, 7-H), 2.90 (1 H, ddd, J2,2 14, J2,3 7, J2,3 4,
2-H), 2.45–2.54 (1 H, m, 5-H), 2.04–2.22 (2 H, m, 3-H, 6-H),
1.68–1.95 (3 H, m, 3-H, 4-H, 6-H), 1.53–1.68 (2 H, m, 2-H,
4-H), OH not observed; δC (50 MHz, CDCl3) 140.2 i-C6H5;
133.4 p-C6H5; 129.2 m-C6H5; 127.6 o-C6H5; 85.3 C-1; 65.3 C-7;
44.6 C-5; 36.8 C-2; 31.3 C-4; 25.6 C-3; 20.8 C-6; (ESMSϩ) 275
(MNaϩ, 100%).
(1RS,5RS,7SR)-7-(Phenylsulfonyl)-5-[2-(phenylsulfonyl)-
ethyl]bicyclo[3.2.0]heptan-1-ol 12 was isolated after extensive
drying as a hygroscopic gum. (Rt 16.2 min, 4 ml minϪ1) (Found:
C, 58.84; H, 5.67. Calc. for C21H24S2O5ؒ½H2O: C, 58.72; H,
5.87%). νmax(KBr)/cmϪ1 3451, (OH), 1305, (SO2), 1147, (SO2);
δH (400 MHz, CDCl3) 7.84–7.96 (4 H, m, o-C6H5), 7.50–7.70
(6 H, m, p-C6H5, m-C6H5), 4.27 (1 H, br s, Wh/2 1.5, OH), 3.01–
3.15 (2 H, m, 2 × 2Ј-H), 3.50 (1 H, dd, J7,6 10, J7,6 7, 7-H), 2.20
(1 H, dd, J6,6 14, J6,7 7, 6-H), 2.11 (1 H, ddd, J1Ј,1Ј 13.5, J1Ј,2Ј 11,
J1Ј,2Ј 6, 1Ј-H), 1.88 (1 H, ddd, J1Ј,1Ј 13.5, J1Ј,2Ј 11, J1Ј,2Ј 5.5, 1Ј-H),
1.75–1.82 (1 H, m, 3-H), 1.60–1.74 (2 H, m, 2-H, 6-H), 1.36–
1.59 (4 H, m, 2-H, 3-H, 2 × 4-H); δC (100 MHz, CDCl3) 139.7,
138.7 i-C6H5; 133.9, 133.8 p-C6H5; 129.4, 129.3 m-C6H5; 128.2,
127.9 o-C6H5; 83.4, C-1; 62.2, C-7; 52.3, C-2Ј; 49.2 C-5; 40.1
C-2; 35.9 C-4; 26.7 C-1Ј; 26.6 C-6; 21.8 C-3; (ESMSϩ) 427
(MLiϩ, 100%), 443 (MNaϩ, 100%).
Reaction of cycloheptanone
From Method A using cycloheptanone (0.5 ml, 4.239 mmole),
the crude sulfoxide mixture (1.074 g, 4.063 mmole) was oxidised
according to the general procedure to give the crude sulfone
mixture (0.890 g). Column chromatography (hexane–ethyl
acetate, 60 : 40) and semi preparative HPLC (hexane–ethyl
acetate; 16, 70 : 30; 15, 17, 50 : 50) were performed.
Reaction of cyclopentanone
From Method A using cyclopentanone (0.55 ml, 6.220 mmole),
the crude sulfoxide mixture (1.365 g, 5.775 mmole) was oxidised
according to the general procedure to give the crude sulfone
mixture (1.139 g). Column chromatography (hexane–ethyl
acetate, 60 : 40) and semi preparative HPLC (hexane–ethyl
acetate; 11, 70 : 30; 8, 9, 10, 12, 50 : 50) were performed.
2-[2Ј-(Phenylsulfonyl)ethyl]cyclopentanone 8 was isolated as
a white solid, mp 75.2–76.0 ЊC (ethyl acetate–hexane) (Rt 10.7
min, 4 ml minϪ1) (Found: C, 61.98; H, 6.43. Calc. for C13H16-
SO3: C, 61.87; H, 6.39%); νmax(KBr)/cmϪ1 1733, (CO), 1299,
(SO2), 1143, (SO2); δH (400 MHz, CDCl3) 7.85–7.93 (2 H, m,
o-C6H5), 7.60–7.68 (1 H, m, p-C6H5), 7.50–7.60 (2 H, m,
m-C6H5), 3.31 (1 H, ddd, J2Ј,2Ј 7, J2Ј,1Ј 5.5, J2Ј,1Ј 3, 2Ј-H), 3.16
(1 H, ddd, J2Ј,2Ј 7, J2Ј,1Ј 5.5, J2Ј,1Ј 3, 2Ј-H), 2.00–2.15 (4 H, m, 2-H,
3-H, 2 × 5-H), 1.93–2.00 (2 H, m, 4-H, 1Ј-H), 1.67–1.83 (2 H,
m, 4-H, 1Ј-H), 1.42–1.52 (1 H, m, 3-H); δC (50 MHz, CDCl3)
219.7 C-1; 139.3 i-C6H5; 133.7 p-C6H5; 129.7 m-C6H5; 128.3
o-C6H5; 54.0 C-2Ј; 47.5 C-2; 37.4 C-5; 29.3 C-3; 22.8 C-1Ј; 20.5
C-4; (ESMSϩ) 259 (MLiϩ, 94%), 275 (MNaϩ, 100%). HRMS
(Found: 253.08884. C13H17SO3 requires 253.0898).
2-[2Ј-(Phenylsulfonyl)ethyl]cycloheptanone 1522 was isolated
as an oil (Rt 10.0 min, 3 ml minϪ1); νmax (KBr)/cmϪ1: 1702,
(CO), 1306, (SO2), 1148, (SO2); δH (200 MHz, CDCl3) 7.80–7.92
(2 H, m, o-C6H5), 7.47–7.70 (3 H, m, m-C6H5, p-C6H5), 2.95–
3.23 (2 H, m, 2 × 2Ј-H), 2.62–2.80 (1 H, m, 2-H), 2.30–
2.55 (2 H, m, 2 × 7-H), 1.07–2.10 (10 H, m, 2 × 3-H, 2 × 4-H, 2
× 5-H, 2 × 6-H, 2 × 1Ј-H); δC (50 MHz, CDCl3) 214.3 C-1;
139.1 i-C6H5; 133.6 p-C6H5; 129.2 m-C6H5; 127.9 o-C6H5; 54.0
C-2Ј; 49.8 C-2; 43.2 C-7; 31.8, 29.1, 28.8, 25.0, 23.8 C-3,
C-4, C-5, C-6, C-1Ј; (ESMSϩ) 287 (MLiϩ, 44%), 303 (MNaϩ,
100%).
(1RS,7SR,9SR)-9-(Phenylsulfonyl)bicyclo[5.2.0]nonan-1-ol
162 was isolated as a white solid, mp 99.3–101.1 ЊC (ethyl
acetate–hexane) (Rt 8.8 min, 3 ml minϪ1).
(1RS,7SR,9RS)-9-(Phenylsulfonyl)bicyclo[5.2.0]nonan-1-ol
17 was isolated as a tacky solid (Rt 11.4 min, 3 ml minϪ1
)
2,5-Bis[2Ј-(Phenylsulfonyl)ethyl]cyclopentanone 9 was iso-
lated as a tacky solid. (Rt 15.7 min, 4 ml minϪ1) (Found: C,
59.67; H, 5.96. Calc. for C21H24S2O5: C, 59.96; H, 5.75%).
νmax(KBr)/cmϪ1 1738, (CO), 1305, (SO2), 1150, (SO2); δH (400
MHz, CDCl3) 7.80–7.94 (4 H, m, o-C6H5), 7.63–7.73 (2 H,
m, p-C6H5), 7.53–7.63 (4 H, m, m-C6H5), 2.80–3.12 (4 H, m,
2 × 2Ј-H, 2 × 2Љ-H), 2.17–2.30 (2 H, m, 2-H, 5-H), 1.67–2.00 (8
H, m, 2 × 3-H, 2 × 4-H, 2 × 1Ј-H, 2 × 1Љ-H); δC (50 MHz,
CDCl3) 219.3 C-1; 138.8 i-C6H5; 134.0 p-C6H5; 129.5 m-C6H5;
128.0 o-C6H5; 51.1 C-2Ј, C-2Љ; 37.5 C-2, C5; 25.7 C-1Ј, C-1Љ;
18.4 C-3, C-4; (ESMSϩ) 427 (MLiϩ, 100%), 443 (MNaϩ,
100%); (ESMSϪ) 419 (M Ϫ H 54%).
(Found: C, 64.29; H, 7.22; S, 11.55. Calc. for C15H20SO3: C,
64.25; H, 7.19; S, 11.43%); νmax(KBr)/cmϪ1 3452, (OH), 1300,
(SO2), 1143, (SO2); δH (400 MHz, CDCl3) 7.78–7.85 (2 H, m,
o-C6H5), 7.56–7.62 (1 H, m, p-C6H5), 7.45–7.56 (2 H, m,
m-C6H5), 3.60 (1 H, dd, J9,8 10, J9,8 9, 9-H), 2.31–2.41 (1 H, m,
2-H), 2.17–2.30 (2 H, m, 2-H, 7-H), 1.90–2.07 (2 H, m, 6-H,
8-H), 1.78–1.86 (1 H, m, 4-H), 1.65–1.78 (4 H, m, 2 × 3-H, 5-H,
8-H), 1.11–1.36 (3 H, m, 4-H, 5-H, 6-H), OH not observed;
δC (50 MHz, CDCl3) 140.2 i-C6H5; 133.3 p-C6H5; 129.1 m-C6H5;
127.6 o-C6H5; 81.8 C-1; 66.0 C-9; 45.0 C-7; 34.3 C-6; 32.1 C-2;
31.8 C-4; 26.7 C-5; 23.7, 23.4 C-3, C-8; (ESMSϩ) 287 (MLiϩ,
8%), 303 (MNaϩ, 100%).
(1RS,5SR,7SR)-7-(Phenylsulfonyl)bicyclo[3.2.0]heptan-1-ol
102 was isolated as a white solid, mp 89.1–92.6 ЊC (ethyl
acetate–hexane) (Rt 8.9 min, 3 ml minϪ1).
(1RS,5SR,7RS)-7-(Phenylsulfonyl)bicyclo[3.2.0]heptan-1-
ol 11 was isolated as a white solid, mp 94.9–95.8 ЊC (ethyl
acetate–hexane) (Rt 28.7 min, 3 ml minϪ1) (Found: C, 61.84; H,
6.45; S, 12.35. Calc. for C13H16SO3: C, 61.87; H, 6.39; S,
12.72%); νmax(KBr)/cmϪ1 3457, (OH), 1295, (SO2), 1147, (SO2);
From Method B using cycloheptanone (0.530 ml, 4.458
mmole), the crude sulfoxide mixture (1.063 g, 4.021 mmole) was
oxidised according to the general procedure to give the crude
sulfone mixture (1.043 g). Column chromatography (hexane–
ethyl acetate, 60 : 40) and semi preparative HPLC (hexane–ethyl
acetate; 18, 70 : 30) were performed.
(1RS,2RS,7SR,9SR)-9-(Phenylsulfonyl)-2-[2-(phenyl-
sulfonyl)ethyl]bicyclo[5.2.0]nonan-1-ol 18 was isolated as a
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 4 7 – 1 3 5 3
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cream solid, mp 123.3–126.1 ЊC (ethyl acetate–hexane). Minor
inseparable impurities (< 5%) were present. (Rt 20.4 min, 3 ml
minϪ1); νmax(KBr)/cmϪ1 3536, (OH), 1302, (SO2), 1149, (SO2);
δH (400 MHz, CDCl3) 7.80–7.86 (4 H, m, o-C6H5), 7.60–7.63
(2 H, m, p-C6H5), 7.44–7.60 (4 H, m, m-C6H5), 3.74 (1 H, dd,
J9,8 10.5, J9,8 4, 9-H), 3.09 (1 H, ddd, J2Ј,2Ј 14, J2Ј,1 8, J2Ј,1Ј 6,
2Ј-H), 2.97 (1 H, ddd, J2Ј,2Ј 14.5, J2Ј,1Ј 8, J2Ј,1Ј 7, 2Ј-H), 2.47–2.62
(2 H, m, 7-H, 8-H), 1.46–1.91 (6 H, m, 2-H, 3-H, 4-H, 5-H, 6-H,
1Ј-H), 1.27–1.46 (2 H, m, 8-H, 1Ј-H), 1.06–1.27 (4 H, m, 3-H,
4-H, 5-H, 6-H), OH not observed; δC (50 MHz, CDCl3) 138.9
i-C6H5; 133.7, 133.5 p-C6H5; 129.2 m-C6H5; 128.2, 127.8
o-C6H5; 81.7 C-1; 62.7 C-9; 54.3 C-2Ј; 49.6 C-7; 43.6 C-2; 33.8
C-6; 30.4 C-3; 28.3 C-4; 27.0 C-5; 23.7 C-1Ј; 22.0 C-8;
(ESMSϩ) 455 (MLiϩ, 100%), 471 (MNaϩ, 100%). HRMS
(Found: 449.14396. C23H28S2O5 requires 449.14564).
1.45–1.58 (2 H, m, 3-H, 6-H), 1.28–1.40 (2 H, m, 2 × 5-H),
1.07–1.18 (1 H, m, 4-H); δC (50 MHz, CDCl3) 139.9,
i-C6H5; 133.4, p-C6H5; 129.2, m-C6H5; 127.7, o-C6H5; 81.4, C-1;
67.3, C-10; 44.6, C-8; 29.7, C-2; 28.5, C-6; 27.1, C-5; 24.7, C-4;
24.4, C-7; 24.2, C-3; 22.6, C-9; (ESMSϩ) 301 (MLiϩ 100%), 317
(MNaϩ 100%).
Acknowledgements
We gratefully acknowledge support for this work from the
Australian Research Council and Griffith University.
References
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Perkin Trans. 2, 2002, 296–302.
2 P. C. Healy, W. A. Loughlin, M. A. McCleary, G. K. Pierens and
C. C. Rowen, J. Phys. Org. Chem., 2002, 15, 733–741.
Reaction of cyclooctanone
3 R. K. Haynes, W. A. Loughlin and T. W. Hambley, J. Org. Chem.,
1991, 56, 5785–5790.
From Method A using cyclooctanone (0.5 ml, 3.796 mmole), the
crude sulfoxide mixture (1.128 g, 4.051 mmole) was oxidised
according to the general procedure to give the crude sulfone
mixture (1.021 g). Column chromatography (hexane–ethyl
acetate, 60 : 40) and semi preparative HPLC (hexane–ethyl
acetate; 20, 70 : 30; 21, 19 50 : 50) were performed.
4 S. Wilsey, P. Dowd and K. N. Houk, J. Org. Chem., 1999, 64, 8801–
8811; A. C. Razus, M. D. Gheorghiu and E. Bartha, Rev. Roum.
Chim., 1989, 34, 2075–2086; K. B. Wilberg, J. E. Hiatt and K. Hseih,
J. Am. Chem. Soc., 1970, 92, 544–553; P. G. Gassman, E. A.
Williams and F. J. Williams, J. Am. Chem. Soc., 1971, 93, 5199–5208;
M. Hanack, H. Schneider-Bernloehr, H. J. Schneider, R. Huettinger
and G. Wentrup, Justus Liebigs Ann. Chem., 1968, 717, 41–53.
5 L. U. Roman, N. Rebeca Morales, J. D. Hernandez, C. M. Cerda-
Garcia-Rojas, L. Gerardo Zepeda, C. A. Flores-Sandoval and
P. Joseph-Nathan, Tetrahedron, 2001, 57, 7269–7275; M. C. Carre,
M. L. Viriot-Villaume and P. Caubere, J. Chem. Soc., Perkin Trans.
1, 1979, 2542–2549.
6 H. Suginome and Y. Nakayama, Tetrahedron, 1994, 50, 7771–7782.
7 M. Benchick-le-Hocine, D. Do Khac, M. Fetizon, I. Hanna and
R. Zeghdoudi, Synth. Commun., 1987, 17, 913–920.
8 C. Manfrotto, M. Mella, M. Freccero, M. Fagnoni and A. Albini,
J. Org. Chem., 1999, 64, 5024–5028.
2-[2Ј-(Phenylsulfonyl)ethyl]cyclooctanone 1922 was isolated
as an oil. (Rt 9.5 min, 3 ml minϪ1); νmax(KBr)/cmϪ1 1698, (CO),
1306, (SO2), 1151, (SO2); δH (400 MHz, CDCl3) 7.80–7.91 (2 H,
m, o-C6H5), 7.57–7.80 (1 H, m, p-C6H5), 7.48–7.57 (2 H, m,
m-C6H5), 2.93–3.09 (2 H, m, 2 × 2Ј-H), 2.72–2.81 (1 H, m,
2-H), 2.23–2.42 (2 H, m, 2 × 8-H), 0.90–2.06 (10 H, m, 2 × 4-H,
2 × 5-H, 2 × 6-H, 2 × 7-H, 2 × 1Ј-H), 1.82–1.86 (1 H, m, 3-H),
1.42–1.64 (1 H, m, 3-H); δC (50 MHz, CDCl3) 218.4 C-1; 139.0
i-C6H5; 133.6 p-C6H5; 129.2 m-C6H5; 127.9 o-C6H5; 54.1 C-2Ј;
48.2 C-2; 42.5 C-8; 33.0 C-3; 27.4, 25.0, 24.8, 24.6 C-4, C-5, C-6,
C-7, C-1Ј; (ESMSϩ) 301 (MLiϩ, 27%), 317 (MNaϩ, 100%).
2,8-Bis[2Ј-(phenylsulfonyl)ethyl]cyclooctanone 20 was iso-
lated as a white solid, mp 122.8–124.1 ЊC (ethyl acetate–hexane)
(Rt 25.8 min, 3 ml minϪ1) (Found: C, 62.44; H, 6.59; S, 13.72.
Calc. for C24H30S2O5: C, 62.31; H, 6.54; S, 13.86%); νmax(KBr)/
cmϪ1 1690, (CO), 1305, (SO2), 1144, (SO2); δH (400 MHz,
CDCl3) 7.80–7.89 (4 H, m, o-C6H5), 7.45–7.70 (6 H, m, m-C6H5,
p-C6H5), 3.05 (2 H, ddd, J2Ј/2Љ,2Ј/2Љ 14, J2Ј/2Љ,1Ј/1Љ 9, J2Ј/2Љ,1Ј/1Љ 6.5, 2Ј-H,
2Љ-H), 2.91 (2 H, ddd, J2Ј/2Љ,2Ј/2Љ 14, J2Ј/2Љ,1Ј/1Љ 9.5, J2Ј/2Љ,1Ј/1Љ 6.5, 2Ј-H,
2Љ-H), 2.53–2.66 (2 H, m, 2-H, 8-H), 1.72–1.95 (4 H, m, 2 ×
1Ј-H, 2 × 1Љ-H), 1.43–1.72 (6 H, m, 2 × 3-H, 2 × 4-H or 2 × 6-H,
2 × 7-H), 1.10–1.43 (4 H, m, 2 × 5-H, 2 × 4-H or 2 × 6-H);
δC (50 MHz, CDCl3) 218.9 C-1; 138.8 i-C6H5; 133.8 p-C6H5;
129.4 m-C6H5; 128.0 o-C6H5; 53.8 C-2Ј, C-2Љ; 48.4 C-2, C-8;
32.5 C-3, C-7; 26.1 C-4, C-6; 25.7 C-1Ј, C-1Љ; 24.5 C-5;
(ESMSϩ) 469 (MLiϩ, 100%), 485 (MNaϩ, 100%).
9 M. Franck-Neumann, M. Miesch, A. Cotte, L. Gross and B. Metz,
Tetrahedron: Asymmetry, 1993, 4, 2475–2482.
10 For example: P. Geoffroy, A. Mouaddib, M. C. Carre and
P. Caubere, Tetrahedron Lett., 1988, 29, 1385–1388; M. A. Zouaoui,
A. Mouaddib, B. Jamart-Gregoire, S. Ianelli, M. Nardelli and
P. Caubere, J. Org. Chem., 1991, 56, 4078–4081; B. Gregoire,
M. C. Carre and P. Caubere, J. Org. Chem., 1986, 51, 1419–1427;
B. Jamart-Gregoire, C. Leger and P. Caubere, Tetrahedron Lett.,
1990, 31, 7599–7602; M. L. Viriot, J. Chem. Res., Synop., 1979, 324;
G. Adam, J. Andrieux and M. Plat, Tetrahedron, 1985, 41, 399–407.
11 B. Jamart-Gregoire, V. Grand, S. Lanelli, M. Nardelli and
P. Caubere, Tetrahedron Lett., 1990, 31, 7603–7606.
12 G. Olovsson, J. R. Scheffer, J. Trotter and C.-H. Wu, Tetrahedron
Lett., 1997, 38, 6549–6552; A. Osuka, H. Shimizu, H. Suzuki and
K. Maruyama, Chem. Lett., 1987, 1061–1064.
13 E. W. Della, W. K. Janowski and P. E. Pigou, Aust. J. Chem., 1992,
45, 1205–1211.
14 T. Hasegawa, Y. Kimura, Y. Kuwatani, H. Higuchi, M. Hatanaka
and I. Ueda, Bull. Chem. Soc. Jpn., 1994, 67, 462–472.
15 A. C. Razus, M. D. Gheorghiu, Z. G. Arvay, A. I. Iancu and
E. Bartha, Rev. Roum. Chim., 1989, 34, 1397–1403.
16 F. J. C. Martins, L. Fourie, H. J. Venter and P. L. Wessels,
Tetrahedron, 1990, 46, 623–632.
17 S. C. Suri and K. I. Hardcastle, J. Org. Chem., 1992, 57, 6357–6360.
18 O. Nowitzki, I. Muennich, H. Stucke and H. M. R. Hoffmann,
Tetrahedron, 1996, 52, 11799–11810.
19 M. A. Zouaoui, M. C. Carre, B. Jamart-Gregoire, P. Geoffroy and
P. Caubere, Tetrahedron, 1989, 45, 5485–5496.
20 M. C. Mussatto, D. Savoia, C. Trombini and A. Umani-Ronchi,
J. Chem. Soc., Perkin Trans. 1, 1980, 260–263.
21 For example: E. S. Binkley and C. H. Heathcock, J. Org. Chem.,
1975, 40, 2156–2160; G. Stork, P. Rosen and N. L. Goldman,
J. Am. Chem. Soc., 1961, 83, 2965–2966.
22 P. W. Hickmott, K. K. Jutle and D. H. Pienar, J. Chem. Soc.,
Perkin Trans. 1, 1990, 2399–2402.
23 P. E. Butler and K. Griesbaum, J. Org. Chem., 1968, 33, 1956–1958.
24 R. G. Scamehorn and J. F. Bunnett, J. Org. Chem., 1977, 42, 1449–
1457; R. G. Scamehorn, J. M. Hardacre, J. M. Lukanich and L. R.
Sharpe, J. Org. Chem., 1984, 49, 4881–4883; M. F. Semmelhack and
T. Bargar, J. Am. Chem. Soc., 1980, 102, 7765–7774.
25 The Chemistry Of The Carbonyl Group, ed. S. Patai, Interscience
Publishers, London, 1966, vol. 1, p. 431.
(1RS,8SR,10SR)-10-(Phenylsulfonyl)bicyclo[6.2.0]decan-1-
ol 212 was isolated as a white solid, mp 98.1–100.2 ЊC (ethyl
acetate–hexane) (Rt 7.70 min, 3 ml minϪ1).
From Method B using cyclooctanone (0.5 ml, 3.796 mmole),
the crude sulfoxide mixture (1.033 g, 3.710 mmole) was oxidised
according to the general procedure to give the crude sulfone
mixture (0.933 g). Column chromatography (hexane–ethyl
acetate, 60 : 40) and semi preparative HPLC (hexane–ethyl
acetate; 22, 75 : 25) were performed.
(1RS,8SR,10RS)-10-(Phenylsulfonyl)bicyclo[6.2.0]decan-1-
ol 22 was isolated as a white solid, mp 132.6–134.5 ЊC (ethyl
acetate–hexane (Rt 19.7 min, 3 ml minϪ1) (Found: C, 65.12; H,
7.54; S, 10.60. Calc. for C16H22SO3: C, 65.26; H, 7.53; S,
10.90%); νmax(KBr)/cmϪ1: 3448, (OH), 1284, (SO2), 1143, (SO2);
δH (400 MHz, CDCl3) 7.77–7.84 (2 H, m, o-C6H5), 7.57–7.64
(1 H, m, p-C6H5), 7.49–7.55 (2 H, m, m-C6H5), 3.58 (1 H, dd,
J10,9 10.5, J10,9 9, 10-H), 2.45 (1 H, br s, Wh/2 = 2.5 Hz, OH), 2.40
(1 H, ddd, J2,2 15.5, J2,3 4.5, J2,3 3.5, 2-H), 2.24 (1 H, ddd,
J2,2 15.5, J2,3 13, J2,3 3, 2-H) 1.96–2.05 (1 H, m, 8-H), 1.86–1.95
(1 H, m, 9-H), 1.62–1.77 (6 H, m, 3-H, 4-H, 6-H, 2 × 7-H, 9-H),
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 3 4 7 – 1 3 5 3
1353