Probing the formation of bicyclo[4.2.0]octan-1-ols

Article abstract of DOI:10.1021/jo049576n

Reaction of lithium enolates of simple ketones with (±)-phenyl vinyl sulfoxide has potential for the convergent construction of complex fused ring systems containing a bicyclo[n.2.0]alkan-1-ol. The formation of sulfinylbicyclo[4.2.0]octan-1-ols 1-3 from the lithium enolate of cyclohexanone with (±)-phenyl vinyl sulfoxide or (R)-(+)-p-tolyl vinyl sulfoxide 18 was used to probe the mode of this novel cyclization reaction. Using phenyl vinyl sulfoxide, variations in the reaction lighting and solvent were investigated, in conjunction with radical trapping (TEMPO) and isotope labeling (deuterium) experiments. Cyclization to form sulfinylbicyclooctanols 1-3 is likely to proceed via an intermediate that ring closes to the bicycloalkanol anion 11 and was presently favored by the use of solvents such as THF or DME.

Full text of DOI:10.1021/jo049576n

P r obin g th e F or m a tion of Bicyclo[4.2.0]octa n -1-ols
Wendy A. Loughlin,* Catherine C. Rowen, and Peter C. Healy
School of Science, Griffith University, Brisbane, QLD 4111, Australia
w.loughlin@griffith.edu.au
Received March 14, 2004
Reaction of lithium enolates of simple ketones with (()-phenyl vinyl sulfoxide has potential for the
convergent construction of complex fused ring systems containing a bicyclo[n.2.0]alkan-1-ol. The
formation of sulfinylbicyclo[4.2.0]octan-1-ols 1-3 from the lithium enolate of cyclohexanone with
(()-phenyl vinyl sulfoxide or (R)-(+)-p-tolyl vinyl sulfoxide 18 was used to probe the mode of this
novel cyclization reaction. Using phenyl vinyl sulfoxide, variations in the reaction lighting and
solvent were investigated, in conjunction with radical trapping (TEMPO) and isotope labeling
(deuterium) experiments. Cyclization to form sulfinylbicyclooctanols 1-3 is likely to proceed via
an intermediate that ring closes to the bicycloalkanol anion 11 and was presently favored by the
use of solvents such as THF or DME.
In tr od u ction
Recently we have shown that, using accurate control
of temperature, concentration, and reaction time, the
reaction of the enolate generated from cyclohexanone and
LDA at -78 °C in THF, in the dark, with (()-phenyl vinyl
sulfoxide gave novel sulfinylbicyclo[4.2.0]octan-1-ols 1-3
and monoalkylated cyclohexanone 4 in a 95:5 ratio
(Scheme 1).13 The relative stereochemistries of the sulfi-
nylbicyclooctanols 1-3 were established by X-ray struc-
tural determination.13
In a further study we demonstrated that a range of
simple ketones of varying ring sizes (five- to eight-
membered) can react likewise with phenyl vinyl sulfox-
ide. Upon oxidation with m-chloroperoxybenzoic acid
(MCPBA), sulfonylbicyclo[3.2.0]heptan-1-ols 5 and 6,
sulfonylbicyclo[5.2.0]nonan-1-ols 7 and 8, and sulfonylbi-
cyclo[6.2.0]decan-1-ols 9 and 10 were obtained in par-
tially optimized yields of 27.5-70% (Chart 1).14 In addi-
Bicyclo[n.2.0]alkan-1-ols are an integral part of the
framework of various natural product compounds and are
synthetic precursors to other natural products. Exam-
plary of the incorporation into natural products are
functionalized bicyclo[3.2.0]heptan-1-ols contained within
spatane-type diterpenes1,2 and bourbonene-derived com-
pounds;3 functionalized bicyclo[4.2.0]octan-1-ols con-
tained within terpenes,4 diterpenes,5 sesquiterpenes,6
sesquiterpenoids,7 diterpenoids,8 indole-isoprenoids,9 and
neolignans;10 functionalized bicyclo[5.2.0]nonan-1-ols con-
tained within sesquiterpenoids;11 and functionalized
bicyclo[6.2.0]decan-1-ols contained within neolignans10
and sesquiterpenes.7d,12 Given the synthetic challenge of
such natural product structures, the development of new
synthetic methodology toward viable synthetic precursors
of natural products is of constant interest.
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10.1021/jo049576n CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/27/2004
5690
J . Org. Chem. 2004, 69, 5690-5698

Formation of Bicyclo[4.2.0]octan-1-ols
SCHEME 1 a
CHART 2
as the counterion-oxygen bond has more ionic character
compared to lithium enolates.16 The lithium and potas-
sium enolates of cyclohexanone were treated with phenyl
vinyl sulfoxide in tert-butyl alcohol solvent using the
appropriate t-butoxide as base, at room temperature for
a longer reaction time (1.5 h). Monoalkylated ketone 4
(23%) and dialkylated ketone 13 (17%) were obtained
from the lithium enolate and dialkylated ketone 13 (57%)
from the potassium enolate. The identity of the dialky-
lated ketone 13 was confirmed upon oxidation with
MCPBA to the dialkylated sulfonyl ketone 14 (Chart 2).17
The sulfinylbicyclooctanols 1-3 were not detected in the
product mixture. As a result of the more ionic character
of the potassium-oxygen bonding, equilibration is pro-
moted and the dialkylated ketone 13 obtained. Further
exploration of the reaction conditions for the formation
of sulfinylbicyclooctanols 1-3 was carried out.
Rea ction Ligh tin g. Photochemical methods of cy-
clobutane formation are well-known18 but generally do
not involve an enolate as reactant. One exception is the
photochemical [2 + 2] cycloaddition between aluminum
enolates and phenyl vinyl sulfoxide.19 The lithium enolate
of cyclohexanone and phenyl vinyl sulfoxide were reacted
under normal laboratory lighting in THF (transmittance
range >220 nm), in the dark, and with irradiation20
(Table 1) from a quartz tungsten halogen lamp (150 W,
wavelength range 240-2700 nm), using a standard Pyrex
reaction vessel (transmittance range >280 nm). A further
experiment using irradiation from a quartz tungsten
halogen lamp and a quartz reaction vessel (transmittance
range >200 nm) was performed. All yields are based on
conversion of nonvolatile phenyl vinyl sulfoxide rather
than cyclohexanone, which was often lost during evapo-
rative workup. The reaction between the lithium enolate
of cyclohexanone and phenyl vinyl sulfoxide requires
cleavage of carbon-carbon double bonds. The bond
dissociation energy for carbon-carbon double bonds is
typically 427 kJ /mol, and under photochemical conditions
this would require a wavelength of 250 nm.21 Competing
photochemically initiated reaction of phenyl vinyl sul-
foxide with itself was considered unlikely. From the
results in Table 1, minor variations in the ratio of
a
Conditions: (i) LDA, THF, -78 °C; (ii) PhSOCHdCH2 (bolus
addition), -10 °C, 10 min, dark; (iii) aq NH4Cl.
CHART 1
tion, structuralaspects of selected sulfonylbicyclo[n.2.0]-
alkanols were reported.15 The previous work13-15 has
demonstrated that this novel cyclization methodology has
potential scope using the one methodology for the con-
vergent construction of complex fused ring systems
containing a bicyclo[n.2.0]alkan-1-ol with bridgehead
hydroxyl group. In the present work, we investigate the
formation of sulfinylbicyclo[4.2.0]octan-1-ols 1-3 from
the lithium enolate of cyclohexanone with (()-phenyl
vinyl sulfoxide, as the representative example. By inves-
tigating how bicyclo[4.2.0]octan-1-ols might form, further
synthetic applications toward important natural products
and other synthetic intermediates may be realized.
Resu lts a n d Discu ssion
Th er m od yn a m ic Con tr ol. In previous work we had
shown that, within a 24 h time course experiment,14 the
ratio of sulfinylbicyclooctanols 1-3 to the monoalkylated
ketone 4 decreased from 91:9 at 15 min reaction time,
with the monoalkylated ketone 4 being the only product
at 24 h. Likewise, increased reaction temperature pro-
moted the formation of the monoalkylated ketone 4.14
This suggested that the bicyclooctanol anion(s) 11, which
upon protonation gives sulfinylbicyclooctanols 1-3, is the
kinetic product and the monoalkylated anion 12, which
upon protonation gives the monoalkylated ketone 4, is
the thermodynamic product. Presently, we carried out
the reactions of the lithium and potassium enolates of
cyclohexanone with phenyl vinyl sulfoxide under condi-
tions of forcing thermodynamic control to confirm the
absence of sulfinylbicyclooctanols 1-3 derived from these
conditions. A potassium enolate was chosen in addition
(16) Ladd, M. F. C. Theor. Chim. Acta 1968, 12, 333.
(17) Hickmott, P. W.; Rae, B.; Pienaar, D. H. S. Afr. J . Chem. 1988,
41, 85.
(14) Loughlin, W. A.; McCleary, M. A. Org. Biomol. Chem. 2003, 1,
1347.
(15) (a) Healy, P. C.; Loughlin, W. A.; McCleary, M. A.; Pierens, G.
K.; Rowen, C. C. J . Phys. Org. Chem. 2002, 15, 733. (b) Loughlin, W.
A.; McCleary, M. A.; Healy, P. C. Acta Crystallogr., Sect. E 2003, E59,
o789. (c) Loughlin, W. A.; Rowen, C. C.; van den Berg, Z. D.; Healy, P.
C. Acta Crystallogr., Sect. E 2002, E58, o303.
(18) Crimmins, M. T. In Comprehensive Organic Synthesis; Trost,
B., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 123.
(19) Bienayme´, H.; Guicher, N. Tetrahedron Lett. 1997, 38, 5511.
(20) Calvert, J . G., Pitt, J . N. Photochemistry; Wiley: New York,
1966.
(21) Smith, M. B. Organic Synthesis; McGraw-Hill: New York, 1994;
p 1192.
J . Org. Chem, Vol. 69, No. 17, 2004 5691

Loughlin et al.
TABLE 1. Va r ia tion in Ligh tin g Con d ition s for Rea ction betw een th e Lith iu m En ola te of Cycloh exa n on e a n d P h en yl
Vin yl Su lfoxid e u n d er Sta n d a r d Con d ition sa
yield (%)
entry
conditions
1
2
3
4
yield (%) 1-4
PVS(O)b (%)
product ratios 1:2:3
1
darkc/Pyrexd
labe/Pyrexd
hνg/Pyrexd
hνg/quartzh
21.5 ( 1.5
13.5 ( 1.5
14.3 ( 1.3
12.5 ( 1.5
38 ( 6
23.5 ( 3.5
26.5 ( 4.5
22 ( 6
5 ( 3
3.5 ( 1.5
3 ( 1
10.5 ( 6.5
24.0 ( 4
20.5 ( 5.5
19.5 ( 1.5
75 ( 3.5
64 ( 5
64 ( 1
59 ( 7
3 ( 2
2.5 ( 4.5
6 ( 1
31-37:59:4-11
2f
3
31-34:55-61:5-11
31-35:59-61:5-8
31-32:47-62:7-21
4
5 ( 2
6.4 ( 4.7
a
Standard reaction conditions: lithium enolate of cyclohexanone (0.085 M) generated from LDA, dropwise addition of phenyl vinyl
sulfoxide over 20 s at -10 °C, 10 min reaction time, in THF. Results are from duplicate runs (entries 1, 3, 4) and triplicate runs (entry
b
2) with average values ( variation indicated. PVS(O) ) recovered phenyl vinyl sulfoxide. c Light excluded from reaction for total reaction
d
time. Pyrex reaction vessel. e Laboratory lighting on reaction for total reaction time. f Runs were carried out with 1.0 or 1.1 equiv of
g
LDA or 1.0 equiv of diisopropylamine/butyllithium. Irradiation of reaction by quartz tungsten halogen lamp (150 W) for total reaction
h
time. Quartz reaction vessel.
TABLE 2. Va r ia tion in Solven t for Rea ction betw een th e Lith iu m En ola te of Cycloh exa n on e a n d P h en yl Vin yl
Su lfoxid e u n d er Sta n d a r d Con d ition sa
yield (%)
entry
solvent
DME
EΤ(30)
1
2
3
4
yield (%) 1-4 PVS(O)b (%) product ratios 1-3:4
1
38.2
37.4
34.6
30.9
17
29
5
11
24 ( 4
62
64 ( 5
59.5 ( 4.5
61
10
82:18
60:40 ( 2:2
51:49 ( 2:2
26:74
2c
3d
4
THF
13.5 ( 1.5 23.5 ( 3.5 3.5 ( 1.5
2.5 ( 4.5
diethyl ether
hexane
14.5 ( 0.5
15 ( 4
10
10
0.5 ( 0.5 29.5 ( 7.5
4 ( 4
6
11
0
0
45
31
7
0
5
HMPAe THF
52
40:60
a
Standard reaction conditions: lithium enolate of cyclohexanone (0.085 M) generated from LDA, dropwise addition of phenyl vinyl
sulfoxide over 20 s at -10 °C, 10 min reaction time. PVS(O) ) recovered phenyl vinyl sulfoxide. c Triplicate runs, entry 2, Table 1.
b
Duplicate runs. e 4.0 equiv.
d
sulfinylbicyclooctanols 1:2:3 (Table 1, entries 1-4) and
product yields were observed. A slight enhancement of
the yields of sulfinylbicyclooctanols 1 and 2 and the
overall product yield was observed under dark reaction
conditions (entry 1, Table 1). The overall conversion of
phenyl vinyl sulfoxide within experimental variations
(entries 1-4, Table 1) did not significantly change. The
use of alternative light sources and the addition of
sensitizers were not explored. The remaining studies
were carried out using normal laboratory lighting as a
result of technical ease.
Solven t. The lithium enolate of cyclohexanone and
phenyl vinyl sulfoxide were reacted in solvents of varying
polarity (ET(30)22), namely, DME, THF, diethyl ether, and
hexane, under standard conditions (entries1-4, Table 2).
The formation of sulfinylbicyclooctanols 1-3 was favored
in reactions carried out in relatively polar solvents (THF,
DME). In addition, sulfinylbicyclooctanol 3 was detected
only in these reactions (Table 2, entries 1 and 2). As
solvent polarity decreased, the ratio of the sulfinylbicy-
clooctanols 1-3 to the monoalkylated ketone 4 changed
from 82:18 in DME to 26:74 in hexane. In a final
variation, the lithium enolate of cyclohexanone was
generated with LDA in THF containing the chelating
agent HMPA23 (4 equiv because of the low the reaction
temperature of -10 °C) and reacted with phenyl vinyl
sulfoxide (entry 5, Table 2). Sulfinylbicyclooctanol 3 was
not detected in the product mixture. Partial chelation of
lithium of the enolate of cyclohexanone by HMPA favored
alkylation and thus formation of monoalkylated ketone
4, as compared to when THF alone was used (entry 2,
Table 2).
En ola te Gen er a tion . During the course of our stud-
ies, competing anionic polymerization of phenyl vinyl
sulfoxide24 was seen to occur in random reactions. These
results are not included here. The polymerization was
attributed to a catalytic excess of LDA. LDA has been
used as an initiator for the anionic polymerization of, for
example, methacrylates.25 Although LDA was titrated
with dimethoxybenzyl alcohol26 or benzyl chloride27 to
accurately determine its concentration, the recovery of
phenyl vinyl sulfoxide from most reactions (Tables 1 and
2) indicates a degree of quenching (possibly by water in
the reactants) of the 1.1 equiv of LDA used and thus
incomplete generation of the lithium enolate of cyclo-
hexanone. In effect, 0.94-0.98 equiv of LDA was em-
ployed in these reactions. Notably when 1.0 equiv of LDA
was used to generate the lithium enolate of cyclohex-
anone with predried reagents, the product yields and
ratios were comparable to the previous results (entry 2,
Table 1). Alternatively, the generation of the lithium
enolate of cyclohexanone using methyllithium and excess
1-cyclohexenyloxytrimethylsilane28 and reaction with
phenyl vinyl sulfoxide gave an overall product yield (49%)
lower than what had been achieved with LDA (64-75%),
but the distribution of sulfinylbicyclooctanols 1-3 and
the ratio of 1-3:4 (90:10) was comparable to what had
been obtained previously using LDA. The variance of
(24) (a) Ederle, Y.; Reibel, D.; Mathias, C. Synth. Metals 1996, 77,
139. (b) Leung, L. M.; Tam, K. H. Polymer 1994, 35, 1556. (c) Kanga,
R. S.; Hogen-Esch, T. E.; Randrianalimanana, E.; Soum, A.; Fontanille,
M. Macromolecules 1990, 23, 4235.
(25) Antoun, S.; Teyssie, Ph.; J erome, R. Macromolecules 1997, 30,
1556.
(26) Winkle, M. R.; Lansinger, J . M.; Ronald, R. C. J . Chem. Soc.,
Chem. Commun. 1980, 87.
(22) (a) Dimroth, K.; Reichardt, C.; Siepmann, T., Bohlmann, F. Ann.
1963, 661, 1-37. (b) Dimroth, K.; Reichardt, C. J ustus Liebigs Ann.
Chem. 1969, 727, 93-105.
(27) (a) Carvalho, I.; Constantino, M. G.; J ose da Silva, G. V. Quim.
Nova 1989, 12, 177. (b) Satoh, T.; Takano, K. Tetrahedron 1996, 52,
2349.
(23) Ager, D. J .; East, M. B. J . Org. Chem. 1986, 51, 3983.
(28) Seebach, D.; Teschner, M. Tetrahedron Lett. 1973, 51, 5113.
5692 J . Org. Chem., Vol. 69, No. 17, 2004

Formation of Bicyclo[4.2.0]octan-1-ols
CHART 3
diastereomers (see Supporting Information) was carried
out using 2D NMR spectra (gCOSY, gHSQC, gHMBC).
Key evidence for the position of the deuterium atom was
the appearance in the 13C NMR (100 MHz) spectrum of
a set of signals for C2′ that were present as 1:1:1 triplets
due to coupling to deuterium. The signals for all other
carbon atoms in the deuterated monoalkylated ketone 15
were singlets, confirming that the deuterated species was
not the alternative structure 16 and that only one
deuterium atom had been incorporated. The deuterated
monoalkylated ketone 15 was the only compound with a
deuterium atom observed in the crude product mixture,
as determined by 13C NMR spectroscopy.
yield was attributed partly to the presence of diethyl
ether (7%) as methyllithium was added as a solution in
diethyl ether (see solvent study, Table 2). Competing
phenyl vinyl sulfoxide polymerization was not observed
as the base was not used in excess. The stability of phenyl
vinyl sulfoxide toward the excess 1-cyclohexenyloxytri-
methylsilane in the absence of base was confirmed
independently. Phenyl vinyl sulfoxide and 1-cyclohex-
enyloxytrimethylsilane (1:1) were stirred in THF at room
temperature for 10 min under normal laboratory lighting
(Pyrex reaction vessel) and with irradiation from a quartz
tungsten halogen lamp (150 W) (quartz reaction vessel),
and no reaction occurred in either case. Thus in some
experiments the methyllithium method was used, oth-
erwise all reproducible results using LDA are reported.
Deu ter iu m Qu en ch . The lithium enolate of cyclohex-
anone was generated using methyllithium and 1-cyclo-
hexenyloxytrimethylsilane and reacted with phenyl vinyl
sulfoxide at -10 °C for 10 min. The reaction was
quenched with deuterated ammonium chloride (20 equiv)
in deuterium oxide. Upon workup and purification,
sulfinylbicyclooctanols 1 (16%) and 2 (13%) in conjunction
with the deuterated monoalkylated ketone 15 (29%) were
isolated. Neither the sulfinylbicyclooctanol 3 nor the
deuterated monoalkylated ketone 16 was observed (Chart
3). The 1H NMR (400 MHz) spectra of the sulfinyl
bicyclooctanols 1 and 2 isolated from the deuterium
labeling experiment were identical to those of authentic
samples. No changes in the multiplicity of signals in the
NMR spectra were observed. Notably, the 1H NMR
spectra of isolated 1 and 2 showed signals for hydroxyl
protons. This confirmed the presence of the protonated
(OH) rather than a deuterated (OD) species such as 17
(Chart 3). It was assumed that the deuterated species
17 formed when the reaction was quenched, but as a
result of the high lability of the deuterium label on the
oxygen atom, deuterium must have exchanged for hy-
drogen during workup and chromatography. The slight
decrease in formation of bicyclooctanol adducts was
attributed to quenching of the reaction with deuterated
ammonium chloride in deuterium oxide. The extent of
the solvent interactions with the intermediates would be
different in the deuterated solvent (D2O in THF).29 This
would result in a changed energy level for the intermedi-
ates and hence changed activation energy of the proto-
nation/deuteration step30 and apparently slightly promote
ring opening of sulfinylbicycloalkanol anion 11 upon
quenching.
Ra d ica l Tr a p p in g Agen t. Attempted trapping of
potential radical intermediates by TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy free radical),31 a radical
scavenger, was carried out. TEMPO reacts directly with
nonhindered carbon-centered radicals.32 First, a 1:1
mixture of phenyl vinyl sulfoxide and TEMPO was stirred
at room temperature for 20 min, and no reaction oc-
curred. Next, following enolate generation from methyl-
lithium and excess 1-cyclohexenyloxytrimethylsilane, a
solution of TEMPO dissolved in phenyl vinyl sulfoxide
1
(1.8:1) was added. Upon workup, analysis by H NMR
spectroscopy of the crude mixture indicated the presence
of phenyl vinyl sulfoxide, 1-cyclohexenyloxytrimethylsi-
lane, some cyclohexanone, sulfinylbicyclooctanols 1-3,
and monoalkylated ketone 4 in high mass recovery (92%,
see Supporting Information). No peaks attributable to
radical trapped products or radical recombination prod-
ucts33 were present, most of which would be unlikely to
decompose under the mild workup conditions. Purifica-
tion by column chromatography gave recovered TEMPO
(52%) (the rest lost to aqueous workup), phenyl vinyl
sulfoxide (32%), monoalkylated ketone 4 (10%), and
sulfinylbicyclooctanols 1 (24%), 2 (14%), and 3 (3%). No
products arising from radical trapping by TEMPO were
detected in the column fractions.
(+)-Tolyl Vin yl Su lfoxid e. In Scheme 1, the forma-
tion of the sulfinylbicyclooctanols 1-3 with different
relative stereochemistry at sulfur may have resulted from
the use of racemic phenyl vinyl sulfoxide. Instead reaction
with an optically active electrophile, such as (R)-(+)-p-
tolyl vinyl sulfoxide 18 was considered. (1R,2S,5R)-(-)-
Menthyl-(S)-p-toluenesulfinate was treated with vinyl-
magnesium bromide using a modified literature pro-
cedure,34 and upon separation from menthol by column
chromatography, (R)-(+)-p-tolyl vinyl sulfoxide 18 was
obtained (57%) in high optical purity. Reaction of the
lithium enolate of cyclohexanone (generated from cyclo-
hexanone and LDA) with (R)-(+)-p-tolyl vinyl sulfoxide
18 under conditions used for phenyl vinyl sulfoxide as
(31) Sobek, J .; Martschke, R.; Fischer, H. J . Am. Chem. Soc. 2001,
123, 2849.
(32) (a) Font-Sanchis, E.; Aliaga, C.; Bejan, E. V.; Cornejo, R.;
Scaiano, J . C. J . Org. Chem. 2003, 68, 3199. (b) Bowry, V. W.; Ingold,
K. U. J . Am. Chem. Soc. 1992, 114, 4992. (c) Sakata, T.; Takahashi,
S.; Terazima, M.; Azumi, T. J . Phys. Chem. 1991, 95, 8671. (d)
Chateauneuf, J .; Lusztyk, J .; Ingold, K. U. J . Org. Chem. 1988, 53,
1629.
(33) Comparison of spectra of possible recombination products was
carried out, for example, for [1,1′-bicyclohexyl]-2,2′-dione (Frazer, R.
H., J r.; Harlow, R. L. J . Org. Chem. 1980, 45, 5408) and 1,4-bis-
(phenylsulfonyl)butane (Bu, W. H.; Weng, W.; Du, M., Chen, W.; Li,
J .-R.; Zhang, R.-H.; Zhao, L.-J . Inorg. Chem. 2002, 41, 1007).
(34) Mase, N.; Swake, Y.; Toru, T. Tetrahedron Lett. 1998, 39, 5553.
Unambiguous determination of the structure of the
deuterated monoalkylated ketone 15 as a mixture of four
(29) Kresge, A. J .; More O’Ferrall R. A.; Powell, M. F. Isot. Org.
Chem. 1987, 7, 177.
(30) Swain C. G.; Bader, R. F. W. Tetrahedron 1960, 10, 182.
J . Org. Chem, Vol. 69, No. 17, 2004 5693

Loughlin et al.
SCHEME 2 a
a
(i) LDA, THF, -78 °C; (ii) (R)-(+)-TolS(O)CHdCH2 18, -10
°C, 10 min; (iii) NH4Cl; (iv) MCPBA, CHCl3.
electrophile (dropwise addition of sulfoxide, -10 °C, 10
min, dark, THF, ∼0.08 M) gave, upon purification by
chromatography, the tolylsulfinylbicyclooctanols 19 (25%),
20 (6%), 21 (14%), and tolyl monoalkylated ketone 22
(12%) as a 1:1 mixture of diastereomers, epimeric at C2,
and in a combined yield of 57% (Scheme 2). The optical
rotations obtained for compounds 19-22 ([R]D ) 50-150)
indicated that total racemization had not occurred and
implied that some if not all of the stereochemistry at
sulfur had been retained and was R at sulfur as indicated
in Scheme 2. The ee’s of 19-22 could not be determined
by chiral HPLC.35 The ratio obtained of tolylsulfinylbi-
cyclooctanols 21:19:20 was 31:56:13 and tolylsulfinylbi-
cyclooctanols 19-21:tolyl monoalkylated ketone 22 was
79:21. The product distribution of tolylsulfinylbicyclo-
octanols 19-20 was consistent of that obtained when
phenyl vinyl sulfoxide was used under similar conditions
(Table 1, entry 2). Tolyl monoalkylated ketone 22 and
tolylsulfinylbicyclooctanol 21 were characterized as the
sulfones 23 and 24, respectively, upon oxidation with
MCPBA (Scheme 2).
F IGURE 1. ORTEP-3 diagram of the molecular structure of
tolylsulfinylbicyclooctanols 19/19′ and 20. Displacement el-
lipsoids are drawn with 30% probability.
conformation fused to the puckered four-membered ring.
For the tolylsulfinylbicyclooctanol 19, there are two
discrete molecules in the asymmetric unit of the unit cell
(19 and 19′). Disorder in the cyclohexyl ring at C4 is
evident in the structure of tolylsulfinylbicyclooctanol 20
(Figure 1). The bond lengths and angles for 19 and 20
are comparable to those recorded previously for the
sulfinylbicyclooctanols 2 and 3.13 The torsion angles about
the C1-C6 ring junction in the tolylsulfinylbicyclo-
octanols 19, 19′, and 20 were -17(1)° (19), -19(1)° (19′),
and -16.6(6)° (20) for C7-C6-C1-C8 and -34(2)° (19),
-34(2)° (19′), and -26(1)° (20) for C2-C1-C6-C5. Short
intermolecular O‚‚‚O distances are reflective of hydrogen
bonding interactions in 19 with O1‚‚‚O1′ (i), 2.78(1) Å and
O1‚‚‚O2′ (i), 2.69(1) Å ((i) symmetry code 2 - x, 1/2 + y,
1 - z) and in 20 with O1‚‚‚O2 (ii) 2.738(7) Å; (ii)
symmetry code 1/2 - x, 1 - y, 1/2 + z).
The tolylsulfinylbicyclooctanols 19-21 and tolylsul-
fonylbicyclooctanol 24 also were characterized by inter-
1
pretation of spectral data from H and 13C 1D NMR and
gCOSY, gHSQC, and gHMBC 2D NMR, FT-IR spectros-
copy, and mass spectrometry. The connectivity patterns
in the NMR spectra were similar to those observed for
the corresponding phenylbicyclooctanols 1-3.13 An im-
portant outcome of use of the optically active electrophile
was to establish the complete relative configuration of
the bicyclooctanol products. X-ray structural determina-
tion unambiguously indicated the relative configurations
(not the absolute configuration) of tolylsulfinylbicyclo-
octanols 19 and 20 and tolylsufonylbicyclooctanol 2415a
(Figure 1).
Discu ssion
The sulfinylbicyclooctanols 1-3 form on protonation
of the sulfinylbicycloalkanol anion 11 as the major
product(s) at short reaction time and lower temperature,
whereas with a much longer reaction time the sulfinyl-
bicycloalkanol anion 11 ring opens to the monoalkylated
anion 12 and gives the monoalkylated ketone 4 as the
only product. Similiarly, conditions of protonated solvent
and increased temperature promote of the formation of
monoalkylated cyclohexanone 4. Evidence for the anion
12 was obtained by isolation of the deuterated ketone 15
as the only deuterated compound when a deuterium
quench of the reaction was used. The absence of the
deuterated monoalkylated ketone 16 indicated that under
the reaction conditions employed equilibration of the
anion 12 did not occur. The percentage contribution
arising from ring opening of the bicyclo[4.2.0]octan-1-ol
In Figure 1, these diagrams each clearly show the cis
ring junction with the six-membered ring in a chair
(35) Chiral HPLC was carried out using a Chiralcel OD-H column,
Agilent 1100 series HPLC equipped with a Quat pump and diode array
detector. Racemic 2 was used as an appropriate standard for 19-22.
Racemic 2 could not be sufficiently resolved, and the optical purity
(ee) of 19-22 could not be determined.
5694 J . Org. Chem., Vol. 69, No. 17, 2004

Formation of Bicyclo[4.2.0]octan-1-ols
CHART 4
anion 11 versus the direct alkylation of the enolate of
cyclohexanone by phenyl vinyl sulfoxide (see 28 below)
could not be determined. The monoalkylated anion 12
must be considered the thermodynamic product of the
sulfinylbicycloalkanol anion 11 and can thus not be an
intermediate toward the formation of the bicycloalkanol
anion 11 via an ionic mechanism.
Sulfinylbicyclooctanols 1-3 formation could potentially
occur via a concerted pathway. Concerted [2 + 2] cyclo-
addition pathway in cyclobutane formation has been
described for a photochemical process18 and a thermal
process involving linear molecules such as ketenes and
allenes.36 In a synchronous or nonsynchronous concerted
mechanism for the formation of bicyclooctanols the
stereochemistry at sulfur should be preserved in the
products. When optically active (R)-(+)-p-tolyl vinyl sul-
foxide 18 was used, total racemization at sulfur did not
occur and the formation of epimers at C8 was observed.
The generation of a cis ring junction in all sulfinylbi-
cyclooctanols 1-3 and 19-21 was noteworthy. However,
the short length of the carbon chain in the phenyl/tolyl
vinyl sulfoxide electrophile may preclude attack from the
opposite face in a nonsynchronous process and formation
of a trans ring junction.
Single electron transfer also could provide a route to
the sulfinylbicycloalkanolide anion 11, via either a
photochemical or thermal process. Diagnostic criteria for
the detection of electron-transfer mechanisms are varied.
Spectroscopic methods for the detection of radicals in-
clude ESR spectroscopy37 and CIDNP38 using NMR
spectroscopy. Other criteria include the stereochemical
outcomes of the reaction, the formation of radical-derived
secondary products, kinetic studies, isotope effects, and
the failure of a reaction to conform to a simple linear free
energy relationship.39 Because formation of sulfinylbi-
cyclooctanols 1-3 in the reaction between the lithium
enolate of cyclohexanone and phenyl vinyl sulfoxide
occurs under anhydrous conditions and at low tempera-
ture, synthetic methods were chosen to explore for
evidence of any free radical intermediates.
The results reported in Table 1 indicate that no
consistent trend between reaction lighting conditions and
reaction outcome was observed. No significant effects
occurred in the distribution and yields of the products
when the lighting conditions were altered to promote a
photochemical process (entries 3 and 4, Table 1) or when
all light sources that would activate a photochemical
process were eliminated (entry 1, Table 1). The formation
of the sulfinylbicyclooctanols 1-3 in the dark excludes
any photochemical pathways to the sulfinylbicycloalkanol
anion 11. A thermal electron transfer may be occurring.
Electron transfer between the enolate and phenyl vinyl
sulfoxide could give rise to the radical/radical anion pair
25, which could combine in a number of ways. However,
the cyclohexanone radical is more likely to be carbon-
centered as the enolate of cyclohexanone has been shown
to react in a SET to give 2-phenylcyclohexanone.40 The
rate of radical-radical coupling should occur faster than
an ionic process.41 Thus combination of the radical/radical
anion ion pair 25a /25b is likely to form monoalkylated
anion 12 rather than bicycloalkanol anion 11 in a
concerted process. Alternatively, electron transfer of the
monoalkylated anion 12 could give rise to the species 26
(Chart 4). However, as both of these possible pathways
proceed via the monoalkylated anion 12 prior to forma-
tion of the sulfinylbicycloalkanol anion 11, they could be
considered unlikely because of the thermodynamic con-
sideration outlined above.
No direct evidence was obtained for any radical inter-
mediates. Attempts to trap any radical intermediates
with TEMPO were unsuccessful, and radical trapped
products or radical recombination products were not
detected. However, radical reactions can be very rapid
and radical intermediates may indeed be present. The
solvent usually has little effect on free radical reactions,42
although there are cases where the rate of reaction for
trapping a radical is promoted by a more polar solvent.43
Notably a change in solvent polarity gave significant
changes in product distribution (entries 1-4, Table 2).
However, addition of the chelating agent HMPA (entry
5, Table 2) diverted the reaction away from the formation
of the sulfinylbicycloalkanols 1-3. These results are
generally indicative of an ionic process. Sulfinyl-stabilized
carbanions, derived from base removal of a proton R to a
sulfoxide, are generally assumed to be pyramidal and sp3-
hybridized, where lithium cation-oxygen chelation may
control the conformation in THF and retain the stere-
ochemisty at sulfur.44 Instead a free anion is predominant
in the presence of a chelating agent. However, R-lithio-
sulfoxides anions with increased sp2-hydridization and
with a stronger S-O‚‚‚Li chelation have been reported.45
The results presented herein can be accounted for by
a variety of mechanisms. Two more likely possible
mechanisms are presented in Scheme 3. Radical combi-
nation of the radical/radical ion pair 29 (tautomeric to
the radical/radical anion pair 25) or addition of the
enolate to phenyl vinyl sulfoxide via the complex 27
(arising from coordination of the lithium enolate with
phenyl vinyl sulfoxide) might provide the intermediate
(40) Scamehorn, R. G.; Hardacre, J . M.; Lukanich, J . M.; Sharpe,
L. R. J . Org. Chem. 1984, 49, 4881.
(41) For example: (a) Bailey, W. F.; Patricia, J . J .; DelGobbo, V. C.;
J arret, R. M.; Okarma, P. J . J . Org. Chem. 1993, 58, 6476. (b) Garst,
J . F.; Hines, J . B., J r. J . Am. Chem. Soc. 1984, 106, 6443.
(42) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry;
VCH: New York, 1988; pp 110-123.
(36) Wender P. A. In Photochemistry in Organic Synthesis; Coyle J .
D., Ed.; The Royal Society of Chemistry: London, 1986.
(37) (a) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 193. (b)
For example: Russell, G. A.; Pecoraro, J . M. J . Am. Chem. Soc. 1979,
101, 3331.
(43) Tronche, C.; Martinez, F. N.; Horner, J . H.; Newcomb, M.; Senn,
M.; Giese, B. Tetrahedron Lett. 1996, 33, 5845.
(38) (a) Closs, G. L.; Miller, R. J .; Redwine, O. D. Acc. Chem. Res.
1985, 18, 196. (b) Adrian, F. J . Rev. Chem. Intermed. 1986, 7, 173.
(39) Chanon, M.; Tobe, M. L. Angew. Chem., Int. Ed. Engl. 1982,
21, 1.
(44) Ogura, K. In Comprehensive Organic Synthesis; Trost, B.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991.
(45) Chassaing, G.; Lett, R.; Marquet, A. Tetrahedron Lett. 1978,
471 and references therein.
J . Org. Chem, Vol. 69, No. 17, 2004 5695

Loughlin et al.
7,15a 8,14 9,15a 10,14 24,15a and monoalkylated ketone 413,46 have
been characterized previously.
SCHEME 3
1H NMR Cr u d e P r od u ct An a lysis a n d Deter m in a tion
of P er cen ta ge Com p osition . The crude product mixtures
were dried under high vacuum and freeze-dried, and the mass
of the crude product was determined. The 1H NMR spectra
were obtained using CDCl3 as solvent. A D2O exchange was
performed on all samples, and the 1H NMR (400 MHz)
spectrum was obtained. Integration of the baseline resolved
peaks at δ 3.29, 3.14, 3.05, 2.95, and 6.18, for sulfinylbicy-
clooctanols 1, 2, 3, monoalkylated ketone 4 and unreacted
phenyl vinyl sulfoxide, respectively, was used to calculate the
percentage composition of these components from the integral
of the total crude mixture. The percentages reported are
calculated yields based on starting moles of phenyl vinyl
sulfoxide.
Lith iu m En ola te of Cycloh exa n on e a n d P h en yl Vin yl
Su lfoxid e in ter t-Bu tyl Alcoh ol. Cyclohexanone (0.50 g, 0.53
mL, 5.10 mmol) was added to a solution of butyllithium (1.4
M, 0.4 mL, 0.52 mmol) in tert-butyl alcohol (5 mL). Phenyl
vinyl sulfoxide (0.85 g, 0.75 mL, 5.60 mmol) was added, and
the mixture was stirred at room temperature for 1.5 h. The
reaction mixture was neutralized by dropwise addition of
glacial acetic acid and extracted with ethyl acetate (3 × 25
mL). The combined organic layers were washed with brine (50
mL), dried (MgSO4), and filtered, and the solvent was removed
in vacuo to give the crude product mixture as a yellow oil (1.17
g). The crude product mixture was separated by silica column
chromatography (ethanol/DCM 3:97). Fraction 1 contained the
monoalkylated ketone 4 (292 mg, 23%). Fraction 2 contained
a diastereomeric mixture of 2,2-bis[2′-(phenylsulfinyl)ethyl]-
cyclohexanone 13 (340 mg, 17%) isolated as an almost colorless
oil: FTIR (neat) 2932, 1701, 1044 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.44-2.74 (m, 16H, aliphatic), 7.35-7.60 (m, 10H,
C6H5); 13C NMR (CDCl3, 100 MHz,) δ 20.18, 25.39, 25.84, 26.03,
26.37, 26.50, 26.57, 26.62, 35.73, 35.91, 36.12, 38.53, 38.59,
38.65, 49.96, 50.13, 50.17, 50.27, 50.74, 50.77, 123.73, 123.82,
129.06, 130.86, 142.82, 143.07, 213.02; MS (ESI+ve) 425
(MNa+, 100%). Oxidation of the dialkylated ketone 13 (155
mg, 0.39 mmol) with 3-chloroperoxybenzoic acid (57%, 236 mg,
0.78 mmol) in CHCl3 (7 mL) gave the crude product as an
almost colorless oil (202 mg). The oil was analyzed by 1H NMR
(400 MHz) spectroscopy and was determined to contain the
dialkylated sulfonyl ketone 14 (80%) with the remainder
attributable to 3-chlorobenzoic acid and ethyl acetate. Purifica-
tion by silica column chromatography (ethyl acetate 100%)
gave 2,2-bis[2′-(phenylsulfonyl)ethyl]cyclohexanone 14 as a
white solid: mp 123-124 °C (ethyl acetate); FTIR (neat) 2931,
28. In both 27 and 29 the lithium cation is predisposed
to be associated with the sulfoxide oxygen and provide
the intermediate 28 by which racemization at carbon (C8
in the bicycloocatanol) and retention at sulfur can occur.
The species 28 is a thermodynamically distinct species
from the anion 12 as the result of solvation and ion-
pairing effects. Ring closure of 28 to the bicyclooctanol
anion 11 could be facilitated as the lithium cation is
available to make the carbonyl oxygen part of the
chelation cage. Ring opening (a slow process) of the
bicyclooctanol anion 11 to the monoalkylated anion 12
then occurs to produce a racemic anion, a consequence
of the intermediate 28, which upon quenching with
deuterium gives racemic deuterated ketone 15. The
lithium cation now has a stronger C‚‚‚Li interaction in
the sulfoxide anion 12 and is diverted away from chela-
tion with the carbonyl group and from ring closure as a
result. Clearly the addition of HMPA alters the reactivity
of the enolate and chelation effects of the reaction
intermediates as does the solvent used.
Con clu sion s
Although there is more than one possible pathway to
11, whether 11 arises from more than one pathway could
not be determined. Likewise no compelling evidence
allowed us to unambiguously determine a pathway for
formation of 11. However, the combination of results
obtained, such as sensitivity of bicyclooctanol formation
to solvent used and presence of a chelation agent (HMPA)
and epimerization at C8, suggests an intermediate (for
example 28) is present prior to formation of bicycloal-
kanol anion 11. Bicycloalkanol anion 11 then slowly ring
opens to the sp3-hybridized monoalkylated anion 12. With
some understanding in place, further synthetic applica-
tions of the cyclization reaction toward the construction
of more complex systems and manipulation of the sul-
foxide functional group can now proceed.
1702, 1306, 1147 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.55-
.
1.63 (m, 2H, 2 × H3), 1.63-1.76 (m, 4H, 2 × H4, 2 × H5),
1.81 (ddd, 2H, J 1′,1′ ) 14, J 1′,2′ ) 12, J 1′,2′ ) 5 Hz, 2 × H1′), 1.93
(ddd, 2H, J 1′,1′ ) 14, J 1′,2′ ) 12, J 1′,2′ ) 4 Hz, 2 × H1′), 2.23 (t,
2H, J ) 6.5 Hz, 2 × H6), 2.77 (ddd, 2H, J 2′,2′ ) 14, J 2′,1′ ) 12,
J 2′,1′ ) 4 Hz, 2 × H2′), 2.93 (ddd, 2H, J 2′,2′ ) 14, J 2′,1′ ) 12, J 2′,1′
) 5 Hz, 2 × H2′), 7.48-7.58 (m, 4H, m-C6H5), 7.58-7.67 (m,
2H, p-C6H5), 7.80-7.88 (m, 4H, o-C6H5); 13C NMR (CDCl3, 100
MHz,) δ 20.2 (C4), 26.5 (C1′, C5), 35.8 (C3), 38.6 (C6), 49.6
(C2), 50.8 (C2′), 127.8 (o-C6H5), 129.3 (m-C6H5), 133.9 (p-C6H5),
138.6 (i-C6H5), 212.4 (C1); MS (ESI+ve) 441 (MLi+, 100%);
HRMS calcd for C22H26O5S2 434.12217, found 434.12217. Anal.
Calcd for C22H26O5S2: C, 60.80; H, 6.03. Found: C, 61.06; H,
6.16.
Exa m p le of P r oced u r e of Va r ia tion in Ligh tin g: With
Ligh tin g fr om a Tu n gsten Ha logen La m p (150 W) in a
Qu a r tz Rea ction Vessel. The lithium enolate of cyclohex-
anone, generated from LDA (titrated against benzyl chloride)
(2.25 M, 1.25 mL, 2.80 mmol) and cyclohexanone (0.25 g, 0.26
mL, 2.55 mmol) in THF (30 mL), was allowed to warm to -10
°C, and phenyl vinyl sulfoxide (0.39 g, 0.34 mL, 2.55 mmol)
was added dropwise over 20 s, while light from a tungsten
Exp er im en ta l Section
The general experimental instrumentation and procedures
and procedure for oxidation of sulfoxides have been described
elsewhere.13 Optical rotations were measured on a J asco
P-1020 Polarimeter. Bicyclo[n.2.0]octan-1-ols 1-3,13 5,15a 6,14
(46) Montgomery, J .; Overman, L. J . Org. Chem. 1993, 58, 6476.
5696 J . Org. Chem., Vol. 69, No. 17, 2004

Formation of Bicyclo[4.2.0]octan-1-ols
halogen lamp (150 W) was applied at 10 cm from the reaction
vessel. The reaction mixture was stirred for 10 min under this
lighting, and the temperature was maintained at -10 °C
during this time. The reaction was quenched (aqueous NH4-
Cl, saturated) and extracted with ethyl acetate (3 × 50 mL).
The combined organic layers were washed with brine (100 mL),
dried (MgSO4), and filtered, and the solvent was removed in
vacuo. The crude product mixture was obtained as an amber
oil ((a) 570 mg; (b) 449 mg). The percentage composition of
the major products, as determined by analysis of the crude
product mixture by 1H NMR (400 MHz) spectroscopy, was
monoalkylated ketone 4 ((a) 21%; (b) 18%), sulfinylbicyclo-
octanol 1 ((a) 14%; (b) 11%), sulfinylbicyclooctanol 2 ((a) 28%;
(b) 16%), sulfinylbicyclooctanol 3 ((a) 3%; (b) 7%), and phenyl
vinyl sulfoxide ((a) 11%; (b) 1.7%).
bicyclooctanol 2 (73 mg, 13%). Fraction 3 contained sulfinyl-
bicyclooctanol 1 (88 mg, 16%). Incorporation of deuterium for
nonexchangeable protons was not evident by analysis by 1H
NMR (400 MHz) and 13C NMR (100 MHz) spectroscopy of the
sulfinylbicyclooctanols 1 and 2.
In t h e P r esen ce of 2,2,6,6-Tet r a m et h yl-1-p ip er id in -
yloxy F r ee Ra d ica l (TEMP O). Under an atmosphere of
nitrogen, methyllithium (1.4 M, 0.80 mL, 1.12 mmol) in ether
was added dropwise to a solution of 1-cyclohexeneyloxytri-
methylsilane (0.26 g, 0.30 mL, 1.54 mmol) in anhydrous THF
(10 mL). The temperature was maintained between -40 and
-30 °C during this time. The colorless solution was stirred
for 20 min and warmed -10 °C. 2,2,6,6-Tetramethyl-1-pip-
eridinyloxy free radical (TEMPO) (0.17 g, 1.9 mmol) dissolved
in phenyl vinyl sulfoxide (0.16 g, 0.14 mL, 1.05 mmol) and THF
(0.5 mL) was added dropwise over 20 s. The reaction was
stirred for 10 min, and the temperature was maintained at
-10 °C during this time. The translucent red solution was
quenched and worked up as described above. The crude
product mixture was obtained as a dark amber oil (397 mg)
and contained 1-cyclohexenyloxytrimethylsilane, which was
removed by further evaporation under reduced pressure. The
crude product mixture was separated by silica column chro-
matography (ether 100% followed by ethyl acetate 100%), and
two major fractions were obtained. Fraction 1 contained
recovered TEMPO (89 mg, 52% recovery based on moles of
starting TEMPO). Fraction 2 (209 mg), as determined by
analysis by 1H NMR (400 MHz) spectroscopy, contained phenyl
vinyl sulfoxide (32%), the monoalkylated ketone 4 (10%),
sulfinylbicyclooctanol 1 (24%), sulfinylbicyclooctanol 2 (14%),
and sulfinylbicyclooctanol 3 (3%).
Exa m p le of P r oced u r e of Va r ia tion in Solven t: In
Dim eth oxyeth a n e. The lithium enolate of cyclohexanone was
generated from LDA (titrated against benzyl chloride) (2.25
M, 1.25 mL, 2.80 mmol) and cyclohexanone (0.25 g, 0.26 mL,
2.55 mmol) in anhydrous DME (30 mL). The solution was
allowed to warm to -10 °C, and phenyl vinyl sulfoxide (0.39
g, 0.34 mL, 2.55 mmol) was added dropwise over 20 s. The
reaction mixture was stirred for 10 min, and the temperature
was maintained at -10 °C during this time. The reaction was
quenched and worked up as described above. The crude
product mixture was obtained as an amber oil (519 mg). The
percentage composition of the major products, as determined
1
by H NMR (400 MHz) analysis of the crude product mixture,
was monoalkylated ketone 4 (11%), sulfinylbicyclooctanol 1
(17%), sulfinylbicyclooctanol 2 (29%), sulfinylbicyclooctanol 3
(5%), and phenyl vinyl sulfoxide (10%).
Qu en ch w ith Deu ter a ted Am m on iu m Ch lor id e in
Deu ter iu m Oxid e. The lithium enolate of cyclohexanone was
generated as outlined above using methyllithium (1.4 M, 1.60
mL, 2.24 mmol) and 1-cyclohexeneyoxytrimethylsilane (0.46
g, 0.52 mL, 2.70 mmol) in THF (10 mL). The solution was
allowed to warm to -10 °C, and phenyl vinyl sulfoxide (0.34
g, 0.30 mL, 2.24 mmol) added dropwise over 20 s. The reaction
was stirred for 10 min, and the temperature was maintained
at -10 °C during this time. The pale yellow solution was
quenched with deuterated ammonium chloride (2.79 g, 48.50
mmol) in deuterium oxide (10 mL) and extracted with ethyl
acetate (3 × 50 mL). The combined organic layers were dried
(MgSO4) and filtered, and the solvent was removed in vacuo
to give the crude product mixture as an amber oil (466 mg).
The crude product mixture was separated by silica column
chromatography (2-propanol/DCM 4:96). Fraction 1 contained
2-[2′-2H-2′-(phenylsulfinyl)ethyl]cyclohexanone 15 as a mixture
of four diastereomers (a-d) and as a white solid (161 mg,
29%): mp 79-80 °C (ether); FTIR (KBr) 2931, 1700, 1040
Rea ction w ith (R)-(+)-p-Tolyl Vin yl Su lfoxid e 18. The
lithium enolate of cyclohexanone generated from LDA (∼2.18
M, 1.30 mL, 2.83 mmol) and cyclohexanone (0.25 g, 0.26 mL,
2.55 mmol) in THF (30 mL) at -78 °C was allowed to warm
to -10 °C and was placed in the dark. (R)-(+)-p-Tolyl vinyl
sulfoxide 18 (0.42 g, 2.55 mmol) was added dropwise over 20
s, and the reaction mixture 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. The
crude product mixture was obtained as an amber oil (454 mg).
Purification by silica column chromatography (2-propanol/
DCM 4:96) gave three fractions. Fraction 1 contained the
monoalkylated tolyl sulfoxide 22 and bicyclooctanol tolyl
sulfoxide 20 (135 mg). Further purification of fraction 1 by
silica column chromatography (ether 100%) and gave bicy-
clooctanol tolyl sulfoxide 20 (41 mg, 6%) and 2-{2′-[(4-
methylphenyl)sulfinyl]ethyl}cyclohexanone 22 as a 1:1 mixture
of diastereomers, (82 mg, 12%). Fraction 2 contained bicy-
clooctanol tolyl sulfoxide 19 (167 mg, 25%). Fraction 3 con-
tained bicyclooctanol tolyl sulfoxide 21 (94 mg, 14%).
cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.23-1.43 (m, 4H, 1 ×
H3a-d). 1.47-1.70 (m, 12H, 1 × H1′a-d, 1 × H4a-d, 1 ×
H5a-d), 1.70-1.93 (m, 6H, 1 × H1′b, 1 × H1′c, 1 × H4a-d),
1.93-2.12 (m, 10H, 1 × H1′a, 1 × H1′d, 1 × H3a-d, 1 × H5a-
d), 2.13-2.39 (m, 10H, H2b, H2c, 2 × H6a-d), 2.39-2.51 (m,
2H, H2a, H2d), 2.62-2.69 (m, 1H, H2′d), 2.77-2.86 (m, 2H,
H2′b, H2′c), 2.86-2.94 (m, 1H, H2′a), 7.40-7.49 (m, 12H, m-
and p-C6H5a-d), 7.53-7.59 (m, 8H, o-C6H5a-d); 13C NMR
(CDCl3, 100 MHz) δ 21.9 (C1′b, C1′c), 22.9 (C1′a, C1′d), 24.9,
25.0 (C4a-d), 27.8, 27.9 (C5a-d), 34.3, 34.4 (C3a-d), 42.0
(C6a-d), 49.2 (C2a, C2d), 49.7 (C2b, C2c), 53.9 (t, J C,D 21, C2′b,
C2′c), 54.7 (t, J C,D 21, C2′a), 54.8 (t, J C,D 21, C2′d), 123.9, 124.0
(o-C6H5a-d), 129.07, 129.10 (m-C6H5a-d), 130.77, 130.84 (p-
C6H5a-d), 143.3 (i-C6H5b, i-C6H5c), 143.9 (i-C6H5a, i-C6H5d),
212.0 (C1b, C1c), 212.1 (C1a, C1d); MS (ESI+ve) 274 (MNa+,
100%); HRMS calcd47 for C14H17O2DSH+ requires 252.11675,
found 252.11579. Anal. Calcd for C14H17DO2S: C, 66.90; H,
7.62. Found: C, 66.92; H, 7.47. Fraction 2 contained sulfinyl-
(1RSC,6SRC,8SRC,RSS)-8-(4-Methylphenyl)sulfinylbicyclo-
[4.2.0]octan-1-ol 20, purified by semipreparative HPLC (metha-
nol/DCM 3:97), was a white solid: mp 141-143 °C (ether);
[R]24 +153.9 (c 0.063, MeOH); FTIR (KBr) 3297, 2925, 1019
D
cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.20-1.37 (m, 3H, 1 × H5,
1 × H3, 1 × H4), 1.37-1.70 (m, 5H, 1 × H2, 1 × H3, 1 × H4,
1 × H5, 1 × H7), 1.88-1.98 (m, 1H, 1 × H2), 2.23 (ddd, 1H,
J 7,8R 4, J 7,6â 10, J 7,7 13, 1 × H7), 2.37 (s, 3H, CH3), 2.57-2.68
(m, 1H, H6â), 3.02 (ddd, 1H, J 8R,6â 1, J 8R,7 4, J 8R,7 8, H8R), 3.35
(s, 1H, OH), 7.25-7.30 (m, 2H, m-C6H4), 7.39-7.45 (m, 2H,
o-C6H4); 13C NMR (CDCl3, 100 MHz) δ 17.6 (C7), 20.8 (C3, C4),
21.4 (CH3), 24.7 (C5), 35.6 (C2), 43.4 (C6), 67.1 (C8), 74.7 (C1),
124.2 (o-C6H4), 129.7 (m-C6H4), 138.1 (p-C6H4), 140.9 (i-C6H4);
MS (ESI+ve) 287 (MNa+, 100%). Anal. Calcd for C15H20O2S:
C, 68.14; H, 7.63. Found: C, C, 68.23; H, 7.73.
2-{2′-[(4-Methylphenyl)sulfinyl]ethyl}cyclohexanone 22 as
a 50:50 mixture of diastereomers, was an off-white wax (82
mg, 12%): [R]24.1 +52.8 (c 0.075, MeOH); FTIR (Nujol) 1713,
D
(47) As the 1H and 13C NMR spectra of 11 indicated incorporation
1046 cm-1
;
1H NMR (CDCl3, 400 MHz, / denotes second
of one deuterium atom, it was assumed that the protonated species
14H17O2DSH+ had been generated during the ionization process of
diastereomer) δ 1.27-1.44 (m, 2H) 1.52-1.72 (m, 5H) 1.78-
C
HRMS.
1.98 (m, 5H) 1.98-2.14 (m, 4H) 2.17-2.38 (m, 6H) (4 × H2, 4
J . Org. Chem, Vol. 69, No. 17, 2004 5697

Loughlin et al.
× H3, 4 × H4, 4 × H5, 4 × H6, 2 × H1′), 2.38 (s, 6H, 2 ×
CH3), 2.43-2.56 (m, 1H, 1 × H2′), 2.70 (ddd, 1H, J 2′,1′ 5, J 2′,1′
10, J 2′,2′ 13, H2′*), 2.77-2.98 (m, 2H, 1 × H2′*, 1 × H2′), 7.26-
7.32 (m, 4H, m-C6H4), 7.44-7.52 (m, 4H, o-C6H4); 13C NMR
(CDCl3, 100 MHz) δ 21.3 (CH3), 22.0, 23.1 (C1′), 25.0 (C4), 27.9
(C5), 34.3, 34.4 (C3), 42.1 (C6), 49.3, 49.8 (C2), 54.4, 55.2 (C2′),
124.0 (o-C6H4), 129.7 (m-C6H4), 140.2 (p-C6H4), 141.1 (i-C6H4),
211.9 (C1); MS (ESI+ve) 287 (MNa+, 100%). Sulfinylmono-
alkylated ketone 22 was characterized as the sulfonyl-
monoalkyated ketone 23.
methylphenyl)sulfonylbicyclo[4.2.0]octan-1-ol 24 as a white
solid, mp 139-141 °C (ether), the spectral data of which were
identical to those of the tolylsulfonylbicyclooctanol 24, de-
scribed previously.15a
Cr yst a l St r u ct u r e Det er m in a t ion of 8-Tolylsu lfin yl-
bicyclo[4.2.0]octa n ols 19 a n d 20. Da ta Collection , Str u c-
tu r e Solu tion , a n d Refin em en t. Unique data sets were
measured at 295 K within 2θmax ) 50° (19), 55° (20) using a
Rigaku AFC7R four circle diffractometer (ω-2θ scan mode,
monochromated Mo KR radiation, λ ) 0.71069 Å) yielding N
independent reflections, No with I > 2σ(I) being considered
“observed”. The structures were solved by direct methods and
refined by full matrix least squares refinement on |F|. Aniso-
tropic thermal parameters were refined for non-hydrogen
(1SRC,6RSC,8RSC,RSS)-8-(4-Methylphenyl)sulfinylbicyclo-
[4.2.0]octan-1-ol 19 recrystallized as a white solid: mp 121-
122 °C (ether); [R]23.7 +129.8 (c 0.172, MeOH); FTIR (KBr)
D
1
3373, 2923, 1053 cm-1; H NMR (CDCl3, 400 MHz) δ 1.26-
atoms; (x, y, z, Uiso
)
were included and constrained at
H
1.40 (m, 2H, 1 × H4, 1 × H5), 1.40-1.52 (m, 3H, 1 × H4, 2 ×
H3), 1.54-1.63 (m, 1H, 1 × H2), 1.67-1.82 (m, 3H, 1 × H2, 1
× H5, 1 × H7), 1.98 (ddd, 1H, J 7,8R 4, J 7,6â 10, J 7,7 13, 1 × H7),
2.38 (s, 3H, CH3), 2.71-2.81 (m, 1H, H6â), 3.13 (ddd, 1H, J 8R,6â
1, J 8R,7 4, J 8R,7 8, H8R), 4.12 (s, 1H, OH), 7.26-7.31 (m, 2H,
m-C6H4), 7.52-7.58 (m, 2H, o-C6H4); 13C NMR (CDCl3, 100
MHz) δ 20.8 (C3), 21.1 (C4), 21.4 (C7), 21.6 (CH3), 25.0 (C5),
36.8 (C2), 41.5 (C6), 66.1 (C8), 76.6 (C1), 125.1 (o-C6H4), 129.8
(m-C6H4), 139.6 (p-C6H4), 141.5 (i-C6H4); MS (ESI+ve) 271
(MLi+, 100%). Anal. Calcd for C15H20O2S: C, 68.14; H, 7.63;
S, 12.13. Found: C, 68.03; H, 7.87; S, 11.92.
estimated values with the exception of the hydroxyl protons,
which were not located from difference Fourier maps. Weights
derivative of w ) 1/[σ2(F)] were employed. Conventional
residuals R, Rw on |F| at convergence are quoted; statistical
weights were employed. Neutral atom complex scattering
factors were employed, computation used the teXsan crystal-
lographic software package for Windows version 1.06 (Molec-
ular Structure Corporation),49 ORTEP-3,50 and PLATON.51
Crystallographic data for the structural analyses have been
deposited with the Cambridge Crystallographic Data Centre
CCDC nos. 242235 - 242236.
(1RSC,6SRC,8SRC,RSS)-8-(4-Methylphenyl)sulfinylbicyclo-
Cr ysta l Da ta . (1RSC,6SRC,8SRC,SRS)-8-(4-Methylphenyl)-
sulfinylbicyclo-[4.2.0]octan-1-ol 19 recrystallized from ether:
[4.2.0]octan-1-ol 2148 recrystallized as a white solid: mp 168-
170 °C (ether); [R]23.3 +80.6 (c 0.172, MeOH); FTIR 3386,
D
C
15H20O2S1, M ) 264.4, monoclinic, space group P21, a )
2932, 1028 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.22-1.54 (m,
5H) 1.54-1.68 (m, 3H) 2.03-2.32 (m, 3H) (2 × H2, 2 × H3, 2
× H4, 2 × H5, H6â, 2 × H7), 2.38 (s, 3H, CH3), 3.25 (dd, 1H,
J 8â,7 8, J 8â,7 10, H8â), 3.73 (s, 1H, OH), 7.25-7.30 (m, 2H,
m-C6H4), 7.45-7.51 (m, 2H, o-C6H4); 13C NMR (CDCl3, 100
MHz) δ 18.8, 20.1, 21.3, 21.4, 23.3 (C3, C4, C5, C7, CH3), 31.7
(C2), 38.5 (C6), 69.4 (C8), 74.5 (C1), 124.2 (o-C6H4), 129.9 (m-
C6H4), 139.1 (p-C6H4), 141.5 (i-C6H4); MS (ESI+ve) 271 (MLi+,
100%). Anal. Calcd for C15H20O2S: C, 68.14; H, 7.63; S, 12.13.
Found: C, 68.18; H, 7.87; S, 12.38.
9.99(1), b ) 11.47(1), c ) 13.073(5) Å, â ) 108.77(4)o, U )
1417(2) Å3, Z ) 2, Dc ) 1.24 g cm-3, µ ) 2.21 cm-1. Crystal
size: 0.40 × 0.30 × 0.25 mm3, N ) 2643, No ) 1104; R ) 0.058,
Rw ) 0.051.
(1RSC,6SRC,8SRC,RSS)-8-(4-Methylphenyl)sulfinylbicyclo-
[4.2.0]octan-1-ol 20 recrystallized from ether. C15H20O2S1, M
) 264.4, orthorhombic, space group P212121, a ) 9.237(2), b )
25.003(6), c ) 6.240(2) Å, U ) 1441.2(6) Å3, Z ) 4, Dc ) 1.22
g cm-3, µ ) 2.17 cm-1. Crystal size: 0.30 × 0.30 × 0.25 mm3,
N ) 2151, No ) 931; R ) 0.056, Rw ) 0.054.
Crude monoalkylated tolyl sulfone 23 was obtained from
tolyl monoalkylated ketone 22 (56 mg, 0.21 mmol) as a white
solid (45 mg, 76%). Recrystallization gave 2-{2′-[(4-methyl-
phenyl)sulfonyl]ethyl}cyclohexanone 23 as a white solid: mp
96-98 °C (ether); FTIR (KBr) 1713, 1302, 1147 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.32 (dddd, 1H, J 3ax,4eq 3.5, J 3ax,2ax 13,
J 3ax,4ax 13, J 3ax,3eq 13, H3ax), 1.50-1.72 (m, 3H, 1 × H1′, 1 ×
H4, 1 × H5), 1.80-1.88 (m, 1H, 1 × H4), 1.92-2.12 (m, 3H, 1
× H1′, H3eq, 1 × H5), 2.19-2.37 (m, 2H, 2 × H6), 2.42 (s, 3H,
CH3), 2.42-2.52 (m, 1H, H2ax), 3.08 (ddd, 1H, J 2′,1′ 6, J 2′,1′ 10,
J 2′,2′ 14, 1 × H2′), 3.24 (ddd, 1H, J 2′,1′ 6, J 2′,1′ 10, J 2′,2′ 14, 1 ×
H2′), 7.30-7.36 (m, 2H, m-C6H4), 7.72-7.79 (m, 2H, o-C6H4);
13C NMR (CDCl3, 100 MHz) δ 21.6 (CH3), 23.2 (C1′), 25.1 (C4),
27.9 (C5), 34.3 (C3), 42.1 (C6), 48.9 (C2), 54.0 (C2′), 127.9 (o-
C6H4), 129.8 (m-C6H4), 136.1 (p-C6H4), 144.5 (i-C6H4), 211.6
(C1); MS (ESI+ve) 303 (MNa+, 100%). Anal. Calcd for
Ack n ow led gm en t. We gratefully acknowledge per-
tinent comments from a referee regarding the possible
mechanism and identification of the kinetic product. We
thank Natural Product Discovery, Griffith University
for access to chiral HPLC. Financial support for this
work was provided by the Australian Research Council
(ARC small scheme) and Griffith University and the
award of an APAWS to C.C.R.
Su p p or tin g In for m a tion Ava ila ble: Standardization of
LDA; full description of experiments; discussion of assignment
of the NMR spectra of deuterated ketone 15; listing of purity
data for known compounds 1-4, 16, and 24; and crystal-
lographic data in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
C
15H20O3S: C, 64.25; H, 7.19; S, 11.43. Found: C, 64.22; H,
7.28; S, 11.36.
J O049576N
Crude tolylsulfonylbicyclooctanol 24 was obtained from
tolylsulfinylbicyclooctanol 21 (71 mg, 0.27 mmol) as a white
solid (60 mg, 79%). Purification by silica column chromatog-
raphy (ethyl acetate/hexane 50:50) gave (1RS,6SR,8RS)-8-(4-
(49) TeXsan for Windows, Single-Crystal Structure Analysis Soft-
ware, Version 1.06; Molecular Structure Corporation: The Woodlands,
2001.
(50) Farrugia, L. J . J . Appl. Cryst. 1977, 30, 365.
(51) Spek, A. L. PLATON for Windows, version 121201; Univeristy
of Utrecht: Utrecht.
(48) The stereochemistry at sulfur was assigned by correlation of
spectra with the corresponding phenyl sulfinylbicyclooctanols 1-3.
5698 J . Org. Chem., Vol. 69, No. 17, 2004