Efficient synthesis and subsequent transformations of phenylsulfanylbicyclo[2.2.2]octenones and phenylselenylbicyclo[2.2.2]octenones

Article abstract of DOI:10.1021/jo802295p

Inverse-electron-demand Diels-Alder reactions of masked o-benzoquinones 2 with phenyl vinyl sulfide and phenyl vinyl selenide furnished highly functionalized bicyclo[2.2.2]octenone derivatives 3 and 4, respectively, in excellent regio- and stereoselectivities and yields up to 90%. The bicyclo[2.2.2]octenone derivatives 3 with the sulfur functionality were subjected to an oxidation-elimination process to furnish bicyclo[2.2.2] octadienone systems 7 in good yields. During the reduction process, the Diels-Alder adducts 3e and 4e led to 8, whereas the carbon-centered radicals generated from the other adducts 3a-d and 4a-d provided various rearranged products 9-13 depending on the substitution pattern and reagents utilized (Raney-Ni or n-Bu₃SnH). Surprisingly these radicals showed preference for the carbonyl functionality to the olefinic double bond, leading to interesting rearrangement reactions of mechanistic importance and possible synthetic utility. Interestingly the alcohols obtained from the reduction of Diels-Alder adducts 3a-d underwent desulfurization smoothly to give desulfurized products in high yields; thus a detoured method of "reduction- desulfurization-oxidation" provides an entry to desulfurized bicyclo[2.2.2]octenones without rearrangement.

Full text of DOI:10.1021/jo802295p

Efficient Synthesis and Subsequent Transformations of
Phenylsulfanylbicyclo[2.2.2]octenones and
Phenylselenylbicyclo[2.2.2]octenones
Shih-Yu Gao, Santhosh Kumar Chittimalla, Gary Jing Chuang, and Chun-Chen Liao*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 30013, Taiwan, and Department of
Chemistry, Chung Yuan Christian UniVersity, Chungli 32023, Taiwan
ccliao@mx.nthu.edu.tw
ReceiVed October 15, 2008
Inverse-electron-demand Diels-Alder reactions of masked o-benzoquinones 2 with phenyl vinyl sulfide
and phenyl vinyl selenide furnished highly functionalized bicyclo[2.2.2]octenone derivatives 3 and 4,
respectively, in excellent regio- and stereoselectivities and yields up to 90%. The bicyclo[2.2.2]octenone
derivatives 3 with the sulfur functionality were subjected to an oxidation-elimination process to furnish
bicyclo[2.2.2]octadienone systems 7 in good yields. During the reduction process, the Diels-Alder adducts
3e and 4e led to 8, whereas the carbon-centered radicals generated from the other adducts 3a-d and
4a-d provided various rearranged products 9-13 depending on the substitution pattern and reagents
utilized (Raney-Ni or n-Bu3SnH). Surprisingly these radicals showed preference for the carbonyl
functionality to the olefinic double bond, leading to interesting rearrangement reactions of mechanistic
importance and possible synthetic utility. Interestingly the alcohols obtained from the reduction of
Diels-Alder adducts 3a-d underwent desulfurization smoothly to give desulfurized products in high
yields; thus a detoured method of “reduction-desulfurization-oxidation” provides an entry to desulfurized
bicyclo[2.2.2]octenones without rearrangement.
Introduction
octenone derivatives and as a part of the effort to demonstrate
the versatility of the developed strategies, these processes were
utilized as key steps in the synthesis of cis-decalin natural
products such as (()-clerodane diterpenic acids,2a,b (()-
eremopetasidione,2c (()-3ꢀ-methacryloyloxyfuranoeremophil-
ane,2d (()-3ꢀ-angeloyloxyfuranoeremophilane,2d refuted (()-
bilosespenes A and B,2e triquinane-based natural products like
(()-magellanine3 and (()-capnellene,1h and other natural
products such as (()-reserpine,4a (()-forsythide aglucone
dimethyl ester,4b (()-annuionone, and (()-tanarifuranonol.4c
Another area of our interest is the photochemical rearrangements
of highly substituted heteroarene-fused barrelenes.5 Compared
to barrelenes and benzobarrelenes, heteroarene-fused barrelenes
may have complicated reaction mechanisms due to the additional
Designing effective and short routes for the stereoselective
construction of polycyclic molecules is one of the main
challenges in synthetic organic chemistry. Conceptually new
methods for the construction of highly functionalized systems
need to be developed. In this perspective, as a building block
for rapid and efficient synthesis of structurally complex frame-
works, bicyclo[2.2.2]octenone systems hold great promise for
eventual applications in the total syntheses of natural products.1
These bicyclic derivatives can be obtained via the Diels-Alder
reactions of suitably substituted masked o-benzoquinones
(MOBs) with appropriate dienophiles. Our laboratory has
succeeded in developing several strategies based on bicyclo[2.2.2]-
1632 J. Org. Chem. 2009, 74, 1632–1639
10.1021/jo802295p CCC: $40.75 2009 American Chemical Society
Published on Web 01/20/2009

Functionalized Bicyclo[2.2.2]octenone DeriVatiVes
n,π* states.5g,i In the context of studying the competitive aptitude
of several possible reaction pathways in these reactions, easy
access to bicyclo[2.2.2]octadienones were needed as suitable
precursors for further manipulations to deliver the necessary
heteroarene-fused barrelenes.5g,i
heteroarene-fused barrelenes for photochemical studies. A C-S
or C-Se bond can also be homolytically cleaved to generate a
radical. For many years, radical reactions have drawn the
attention of organic chemists from both mechanistic and
synthetic perspectives.9 Though radical species are known to
be reactive in both neucleophilic and electrophilic fashions,
radicals are not solvated like cations, and the rates of radical
reactions are thus less solvent-dependent. Addition of carbon-
centered radicals to alkenes and alkynes are usually exothermic
and irreversible, whereas the addition to carbon heteroatom
multiple bonds can be reversible.9e The addition of a radical to
a π-bond followed by fragmentation of a different bond
accomplishes a group transfer reaction. A radical generated on
these functionally rich bridged cycloadducts could in principle
give rise to several interesting transformations through usual
or unusual mechanisms. The sulfide or the selenide functionality
present in the phenylsulfanyl or selenylbicyclo[2.2.2]octenones
can be exploited for the generation of bicyclo[2.2.2]octenone
radicals. Thus, we proposed a systematic study on the fate of
the bicyclo[2.2.2]octenone radicals generated from phenylsul-
fanyl/selenyl bicyclo[2.2.2]octenones, which in turn were
obtained from the Diels-Alder reactions between MOBs and
phenyl vinyl sulfide/selenide. Recently Marko and co-workers
found that lactone-group-bearing compounds of the bicy-
clo[2.2.2] skeleton embedded with a sulfide/selenide underwent
radical rearrangement with reducing agents Raney nickel
(Raney-Ni) or n-Bu3SnH to give bicyclo[3.3.0]octane derivatives
in good yields.10 Herein we present a full account of our
investigations on the Diels-Alder reactions of MOBs with
phenyl vinyl sulfide12 and phenyl vinyl selenide. Interestingly,
the radical generated on these systems showed preferential
addition to carbonyl functionality (oxa-di-π-methane type) rather
than the olefinic double bond (di-π-methane type) in the
reaction. This unusual behavior was studied by selecting
differently substituted bicyclo[2.2.2]octenone systems with the
hope of finding a proper reason for their unique reaction pathway
in radical chemistry. These reactions at first sight look to have
a di-π-methane or oxa-di-π-methane rearrangement-type reac-
tion pathways. Though the fate of electronically excited triplets
cannot be compared with that of the radicals in the ground states,
we recently reported, during our study of photochemical
reactions on bicyclo[2.2.2]octadienones, the competition be-
tween di-π-methane and oxa-di-π-methane bridgings.5,11
Organosulfur compounds are used as versatile reagents in
organic synthesis and bio-organic and medicinal chemistry.6
They can be prepared with great ease and possess a large range
of applications, as the sulfur functionality can easily be removed
or subjected to a variety of reactions to achieve interconversions
of useful functional groups. Phenyl vinyl sulfide was extensively
used as an electron-rich alkene in [1 + 2],7a [2 + 2],7b-d [3 +
2],7e,f and [4 + 2]7g cycloaddition reactions. Organoselenium
and organosulfur chemistries are closely related, and yet each
one has its own advantages and disadvantages.8 Phenyl vinyl
sulfide or phenyl vinyl selenide are valuable dienophiles that
can both act as ethylene and acetylene equivalents. With the
extensive sulfide and selenide chemistry and highly reactive
MOB building blocks in hand, we have investigated the
Diels-Alder reactions of phenyl vinyl sulfide/selenide with
various MOBs and contemplated that their cycloadducts would
be potentially useful. Initially the bicyclo[2.2.2]octenones were
sought and subsequently converted to the bicyclo[2.2.2]-
octadienones, which can be further transformed to the desired
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W.-C.; Liao, C.-C. Synlett 1998, 912. (c) Hsu, D.-S.; Hsu, P.-Y.; Liao, C.-C.
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Org. Chem. 2008, 73, 2554. (e) Hsu, D.-S.; Liao, C.-C. Org. Lett. 2003, 5, 4741.
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H.-P.; Liao, C.-C. Org. Lett. 2008, 10, 449.
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1990, 545. (b) Liao, C.-C.; Lin, S.-Y.; Hsieh, H.-P.; Yang, P.-H. J. Chin. Chem.
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Photochemistry and Photobiology; Horspool, W. M., Soon, P. S., Eds.; CRC
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Liao, C.-C. Tetrahedron Lett. 2003, 44, 8761. (g) Liao, C.-C.; Peddinti, R. K.
CRC Handbook of Organic Photochemistry and Photobiology, 2nd ed.; CRC
Press: Boca Raton, FL, 2004,pp 32/1-32/17. (h) Chen, A.-C.; Chuang, G. J.;
Villarante, N. R.; Liao, C.-C. J. Org. Chem. 2007, 72, 9690. (i) Chen, A.-C.;
Lin, S.-Y.; Villarante, N. R.; Chuang, G. J.; Wu, T.-C.; Liao, C.-C. Tetrahedron
2008, 64, 8907.
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Wiley: New York, 1996; pp 1-262. (c) Oae, S.; Okuyama, T. Organosulfur
Chemistry: Biochemical Aspects; CRC Press: Boca Raton, FL, 1992; pp 1–260.
(d) Handbook of Chalcogen Chemistry: New PerspectiVes in Sulfur, Selenium
and Tellurium; Devillanova, F. A., Ed.; Royal Society of Chemistry: London,
2006.
Results and Discussion
Diels-Alder Reactions of MOBs 2a-g with Phenyl
Vinyl Sulfide and Phenyl Vinyl Selenide. At the outset, the
inverse-electron-demand Diels-Alder reactions of various
MOBs generated in situ from 2-methoxyphenols with phenyl
vinyl sulfide were studied. In most cases, the competition
between self-dimerization of MOB and the Diels-Alder reaction
with the added dienophile is often observed, though to a varying
degree. To avoid or suppress the undesired dimerization, several
(7) (a) Weber, A.; Sabbioni, G.; Galli, R.; Stampfli, U.; Neuenshwander, M.
HelV. Chim. Acta 1988, 71, 2026. (b) Bruckner, R.; Huisgen, R. Tetrahedron
Lett. 1990, 31, 2561. (c) Sugimura, H.; Osumi, K. Tetrahedron Lett. 1989, 30,
1571. (d) Pabon, R. A.; Bellville, D. J.; Bauld, N. L. J. Am. Chem. Soc. 1984,
106, 2730. (e) Singleton, D. A.; Church, K. M. J. Org. Chem. 1990, 55, 4780.
(f) Tsuge, O.; Kanemasa, S.; Sakamoto, K.; Takenaka, S. Bull. Chem. Soc. Jpn.
1988, 61, 2513. (g) Gupta, R. B.; Franck, R. W.; Onan, K. D.; Soll, C. E. J.
Org. Chem. 1989, 54, 1097, and references therein.
(9) (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon
Bonds; Pergamon Press: Oxford, 1986. (b) Curran, D. P. ComprehensiVe Organic
Synthesis; Pergamon Press: Oxford, 1991; Vol. 4, Chapters 4.1 and 4.2. (c)
Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. ReV. 1991, 91, 1237. (d)
Giese, B. Tetrahedron 1985, 41, 3887. (e) Giese, B. Angew. Chem., Int. Ed.
1983, 22, 753.
(10) Marko, I. E.; Warriner, S. L.; Augustyns, B. Org. Lett. 2000, 20, 3123.
(11) (a) Chang, S.-Y.; Huang, S.-L.; Villarante, N. R.; Liao, C.-C. Eur. J.
Org. Chem. 2006, 4648. (b) Yang, M.-S.; Lu, S.-S.; Rao, C. P.; Tsai, Y.-F.;
Liao, C.-C. J. Org. Chem. 2003, 68, 6543.
(8) (a) Comasseto, J. V. J. Organomet. Chem. 1983, 253, 131. (b) Paulmier,
C. Selenium Reagents and Intermediates in Organic Synthesis: Pergamon Press:
New York, 1986. (c) Reich, H. J. Acc. Chem. Res. 1979, 12, 22.
(12) Gao, S.-Y.; Lin, Y.-L.; Rao, P. D.; Liao, C.-C. Synlett 2000, 421.
J. Org. Chem. Vol. 74, No. 4, 2009 1633

Gao et al.
TABLE 1. Diels-Alder reactions of MOBs 2a-g with Phenyl
Vinyl Sulfide and Phenyl Vinyl Selenide
SCHEME 1. Domino Retro-Diels-Alder/Diels-Alder
Procedure To Generate 3g and 4e
but MOB 2f has shown similar results in our previous studies.13a
The importance of this method, which allows the one-pot
assembly of the highly substituted bicyclo[2.2.2]octenone
framework from readily available starting materials under mild
conditions in high yields, may be underscored. The encouraging
results obtained with phenyl vinyl sulfide and MOBs prompted
us to attempt to explore the effectiveness of phenyl vinyl
selenide in the inverse-electron-demand Diels-Alder reaction.
Phenyl vinyl selenide, prepared following the reported proce-
dure,15 though closely related to phenyl vinyl sulfide, was found
to be less reactive in the inverse-electron-demand Diels-Alder
reaction with MOBs. Nevertheless, the reactions worked
smoothly, and the corresponding products could be isolated in
excellent to moderate yields with high selectivities when 10
equiv of the dienophile was utilized (Table 1). Though MOBs
2a-c furnished good yields of expected Diels-Alder adducts
with phenyl vinyl selenide, MOBs 2d and 2e afforded the
corresponding adducts in much lower yields. Attempts at
improving the yield of 4e utilizing the detour method (domino
retro-Diels-Alder/Diels-Alder procedure)14 from the dimer of
MOB 2e with phenyl vinyl selenide proved to be partially
successful furnishing adduct 4e in 20% yield (Scheme 1).
It is noteworthy that in all cases studied the Diels-Alder
reactions of MOBs with both phenyl vinyl sulfide and phenyl
vinyl selenide had excellent regio- and stereoselectivity. Struc-
tures of all the adducts were unambiguously identified with 1H
NMR, 13C NMR, DEPT, and high- and low-resolution mass
spectroscopy. For most of the high-resolution mass spectra
recorded in electron impact mode (70 eV), the peaks corre-
sponding to the molecular ion (M+) could not be seen; instead
the peaks corresponding to [M - CO]+ were observed,
indicating that the extrusion of CO resulted from facile
fragmentation. All the cycloadducts exhibited IR absorptions
at 1732-1755 cm-1 due to the characteristic features of the
carbonyl functional group adjacent to R,R-dimethoxyl groups
in a functionalized bicyclo[2.2.2]octenone skeleton. Stereo- and
regioselectivities were ascertained by extensive decoupling
experiments and comparing the δ and J coupling constants with
that of similar reported compounds.13 As a result of the
deshielding effect by the methoxy group, Hf appeared at δ
2.51-2.64, whereas He appeared at δ 1.21-1.65, thus proving
the assigned regiochemistry (structure of compound 3/4 depicted
in Table 1). The coupling constants J(He-Hf) ) 9.0-9.6 Hz
and J(He-Hg) ) 4.8-6.0 Hz showing the cis and trans relation,
respectively, could confirm the assigned stereochemistry. The
regioselectivities observed in the present study have literature
precedents, due to the greater influence of the carbonyl
functionality than the two methoxy groups present on the MOB
moiety.13
dienophile/ methoda/ time,
adduct
entry phenol MOB
equiv
temp
h
(yield %b)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
X ) SPh/4
B/rt
A/rt
B/50 °C
B/50 °C
B/reflux
B/rt
B/rt
A/rt
A/rt
B/50 °C
A/rt
B/50 °C
A/rt
B/50 °C
A/rt
B/50 °C
B/50 °C
A/rt
1
0.5
1
1
1
3a (85)
3b (84)
3c (89)
3d (90)
3e (58)
3f (58)
3g (30)
4a (87)
4a (87)
4a (50)
4b (90)
4b (24)
4c (6)
X ) SPh/4
X ) SPh/4
X ) SPh/4
X ) SPh/4
X ) SPh/20
X ) SPh/10
X ) SePh/10
X ) SePh/4
X ) SePh/10
X ) SePh/4
X ) SePh/10
X ) SePh/10
X ) SePh/10
X ) SePh/10
X ) SePh/10
X ) SePh/10
X ) SePh/10
1
1
7
8
9
1g
1a
1a
1a
1b
1b
1c
1c
1d
1d
1d
1e
2g
2a
2a
2a
2b
2b
2c
2c
2d
2d
2d
2e
0.5
0.5
1
0.5
1
1
2
1
1
10
11
12
13
14
15
16
17
18
4c (70)
4d (7)
4d (16)
4d (30)
4e (7)
3
4.5
a See Experimental Section. b The yields are of isolated products.
procedures were developed to obtain the desired DA adducts
in good yields.13,14 Owing to the electron-rich nature of phenyl
vinyl sulfide, initially we envisioned that electron-deficient MOB
2a generated from methyl vanillate could be a potential starting
point. Consequently, the inverse-electron-demand Diels-Alder
reaction between phenyl vinyl sulfide with MOB 2a gave 85%
yield of the expected adduct 3a. As a result, the present reaction
was investigated with variously substituted MOBs. The reaction
conditions providing the optimal results in each case are listed
in Table 1. In general, 4 equiv of phenyl vinyl sulfide was used.
Except for 6,6-dimethoxycyclohexa-2,4-dienone (2g), which is
prone to self-dimerization to give 5g, other MOBs 2a-f
provided good to excellent yields of Diels-Alder adducts with
phenyl vinyl sulfide. In our recent studies on the inverse-
electron-demand Diels-Alder reactions, dienophiles benzyl
vinyl ether and dihydrofuran provided lower yields of cycload-
ducts with MOB 2g, along with substantial amounts of dimer.
A marginal improvement in the yield of bicyclo[2.2.2]octenone
3g was observed by utilizing a domino rDA/DA protocol
(Scheme 1) recently developed in our laboratory.14 The reactivity
of MOB 2e with an electron-donating methyl group toward
inverse-electron-demand Diels-Alder reaction was lower than
expected, and only 58% of the Diels-Alder adduct was
obtained. The reason for the low yield of adduct 3f is not clear,
(13) (a) Gao, S.-Y.; Ko, S.; Lin, Y.-L.; Peddinti, R. K; Liao, C.-C.
Tetrahedron 2001, 57, 297. (b) Liao, C.-C.; Chu, C.-S.; Lee, T.-H.; Rao, P. D.;
Ko, S.; Song, L.-D.; Hsiao, H.-C. J. Org. Chem. 1999, 64, 4102. (c) Lai, C.-H.;
Shen, Y.-L.; Wang, M.-N.; Rao, N. S. K.; Liao, C.-C. J. Org. Chem. 2002, 67,
6493.
(14) (a) Chittimalla, S. K.; Liao, C.-C. Synlett 2002, 565. (b) Chittimalla,
S. K.; Shiao, H.-Y.; Liao, C.-C. Org. Biomol. Chem. 2006, 6, 2267.
Synthesis of Bicyclo[2.2.2]octadienones 7a-d,f from
Bicyclo[2.2.2]octenones 3a-d,f. With the installation of sulfur
(15) (a) Hagiwara, H.; Sakai, H.; Kirita, M.; Suzuki, T.; Ando, M.
Tetrahedron 2000, 56, 1445. (b) Keefer, L. K.; Lunn, G. Chem. ReV. 1989, 89,
459.
1634 J. Org. Chem. Vol. 74, No. 4, 2009

Functionalized Bicyclo[2.2.2]octenone DeriVatiVes
SCHEME 2. Versatile Synthesis of
Bicyclo[2.2.2]octadienones 7 from Bicyclo[2.2.2]octenones 3
without affecting the chemical yield of 9a. Thus, to improve
the yield of compound 8a, the reaction was carried out in the
presence of pyrrolidine to reduce the reactivity of Raney-Ni,
which could potentially increase the selectivity of the reduction
of the sulfides.18 Interestingly, this procedure increased selectiv-
ity for the formation of rearranged product 9a to 30%. Formation
of the bicyclo[3.2.1]octane skeleton from the bicyclo[2.2.2]octane
system is a very useful method in organic synthesis,16a-c as
these moieties are found as a subunit in many bioactive sesqui-
and diterpenes.17 Though the yield of 9a is synthetically not
acceptable, we obtained an interesting and unique sequence to
obtain bicyclo[3.2.1]octene skeleton from the corresponding
bicyclo[2.2.2]octene. Similarly, the reaction of acetovanillin-
derived cycloadduct 3b with Raney-Ni furnished 8b in 42%
yield along with 16% of 9b. However, after considerable
experiments, the yield of bicyclo[3.2.1]octenone 9b could be
successfully improved to 50% by performing the reaction in
the presence of pyrrolidine. We were able to obtain 8c and 11c
in better quantities from 3c based on the reaction conditions.
When the position of electron-withdrawing substitution was
changed as in cycloadduct 3d, treatment with Raney-Ni provided
desulfurization product 8d in 39% yield; however, the
bicyclo[3.2.1]octenone 9d was formed in poor yield. Conse-
quently, a change in product distribution could be found with
the variation of the reaction conditions. The extent to which
the products are formed reflects the competition between the
hydrogen abstraction and radical isomerization. Regardless of
the position of the substitution in the starting compounds, in
all cases studied, the reactions showed the same types of
products formed from competing mechanistic pathways. Inter-
estingly, no rearrangement was observed for the reduction of
creosol-derived adduct 3e, from which the clean reaction gave
8e in 90% yield. Hence, the position and nature of substitution
in the starting compound plays a role in this rearrangement
reaction.
Reduction of Diels-Alder Adducts 3a-g with n-Bu3SnH.
We then examined the reactions of 3 with tri-n-butyltin hydride
(n-Bu3SnH) in the presence of radical initiator azobisisobuty-
ronitrile (AIBN). Thus treatment of 3a with n-Bu3SnH and
AIBN in refluxing toluene for 15 min yielded 17% of
bicyclo[3.2.1]octenone 9a and 60% of bicyclo[3.2.1]octadienol
12a together with 7% of 11a. Interestingly, no 8a was observed.
At first view, the reaction looks to have taken a complicated
pathway, but at closer observation it is clear that compounds
9a and 11a are different only at the double bond position and
could have been derived from a common intermediate as in the
case of Raney-Ni. Compound 12a should have been formed
via a completely different mechanism. Even when the reaction
was carried out in benzene for 5.5 h, compounds 9a and 12a
were isolated in similar quantities; however, 11a was not
observed. The reaction of 3b provided 9b exclusively, albeit in
moderate yield. The cycloadduct 3c, upon treatment with
n-Bu3SnH and AIBN, afforded 58% of 12c and 18% of a
separable 5:1 epimeric mixture of 11c. Interestingly, the reaction
of 3d in toluene provided 9d in 52% together with 30% of
bicyclo[3.2.1]octenone 13d. In a similar observation as in the
case of Raney-Ni reduction, the adduct 3e bearing methyl
and selenide functionalities in the bicyclic systems, a selected
set of adducts 3a-d and 3f were subjected to the oxidation-
elimination reaction sequence. The oxidation of the sulfide
moiety to the corresponding sulfoxides 5 was accomplished by
standard mCPBA reaction condition, and the obtained crude
reaction mixtures were refluxed in mesitylene; much to our
satisfaction, the bicyclo[2.2.2]octadienones 7 were obtained in
good yields (Scheme 2) in all the cases studied irrespective of
the nature and the position of the substitution. The appearance
of two newly formed olefinic protons at 6.41-6.53 ppm and
the proton shift changes of the bridge-head hydrogens (Scheme
2, Ha changed from 2.98-3.67 to 4.51-4.72 and Hd changed
from 3.25-3.83 to 4.13-4.14) confirmed the formation of the
bicyclo[2.2.2]octadienone systems. Similar to their parent
compounds, these bicyclo[2.2.2]octadienones have also shown
the [M - CO]+ peak instead of the molecular ion (M+) in the
high-resolution mass spectra recorded. Thus, this reaction
sequence provides an expedient route to highly functionalized
bicyclo[2.2.2]octadienone systems. These structural frameworks
are highly promising as the key starting points for the synthesis
of heteroarene-fused barrelenes of photochemistry interest.5h To
explore the possibility of reducing a synthetic step, phenyl vinyl
sulfoxide was subjected for the Diels-Alder reaction with MOB
2a, but only exclusive formation of dimer 5a and no trace of
expected adduct 6a was observed. We then expected the
formation of the bicyclo[2.2.2]octadienone system 7a from
domino retro-Diels-Alder/Diels-Alder procedure from the
dimer 5a and phenyl vinyl sulfoxide as shown in Scheme 1.
Unfortunately, this method led only to untractable reaction
mixtures.
Reduction of Diels-Alder Adducts 3a-g with Raney
Nickel. Raney-Ni is a versatile reducing reagent, capable of
many interesting transformations conveniently with unique
selectivity among various functional groups, including hydro-
genolysis of the C-S bond. Intrigued by the possibility that
the phenylthio moiety present in 3 could be hydrogenolyzed to
generate bicyclo[2.2.2]octenone 8, a cycloadduct formally
derived from ethylene and a masked o-benzoquinone, we carried
out the reactions of 3 with Raney-Ni. Thus, treatment of 3a
with Raney-Ni in ethanol for 15 min provided 36% of
desulfurization product 8a along with 10% of rearranged
bicyclo[3.2.1]octenone 9a and the over-reduced compound
bicyclo[2.2.2]octanone 10a in 25% yield. The reduction of
conjugated double bonds in the presence of Raney-Ni is a well-
known phenomenon,15b and thus the formation of compound
10a was not surprising. At shorter exposures to Raney-Ni or at
a higher concentration of 3a, 8a was produced in higher yields
(16) (a) Hariprakash, H. K.; Subba Rao, G. S. R. Tetrahedron Lett. 1997,
38, 5343. (b) Kim, D.; Hong, S. W.; Park, C. W. J. Chem. Soc., Chem. Commun.
1997, 2263. (c) Bickel, A. F.; Knotnerus, J.; Kooyman, E. C.; Vegter, G. C.
Tetrahedron 1960, 9, 230.
(17) Filippini, M.-H.; Rodriguez, J. Chem. ReV. 1999, 99, 27.
(18) Humber, D. C.; Pinder, A. R.; Williams, R. A. J. Org. Chem. 1967, 32,
2335.
J. Org. Chem. Vol. 74, No. 4, 2009 1635

Gao et al.
TABLE 2. Reductions of Adducts 3 with Raney Nickel
yield (%)a)
entry
cycloadduct
concn (M)
pyrrolidine
rxn time
8
9 (11c)
10
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3b
3b
3b
3b
3c
3c
3d
3d
3e
0.02
0.02
0.04
0.04
0.02
0.04
0.04
0.04
0.04
0.04
0.04
0.04
0.04
15 min
6 min
10 min
3 h
36
58
57
34
28
42
10
24
49
17
39
10
90
10
12
10
30
21
16
42
50
32b
49b
7
25
7
<1
1 mL/14 g Raney-Ni
7 min
28
16
1 mL/9 g Raney-Ni
1 mL/14 g Raney-Ni
4 h
5 h
10 min
2.5 h
11 min
3 h
9
10
11
12
13
1 mL/14 g Raney-Ni
1 mL/14 g Raney-Ni
27
22
8 min
a Yields are of isolated products. b Yield of 11c.
TABLE 3. Reductions of Adducts 3 with Tributyltin Hydride in
the Presence of AIBN
experiment, saturation of Hc gave rise to increased signal
intensity of Hb (4.5%), while saturation of Hb brought about
significant NOE effect in Hc (7.2%), proving the assigned
stereochemistry (Figure 1).
FIGURE 1. NOE experiment of 11c.
A reasonable mechanism for the conversion using Raney-Ni
of 3 into bicyclo[2.2.2]octane derivatives 8 and 10 and
bicyclo[3.2.1]octenones 9 and 11 is shown in Scheme 3. The
radical I-1 generated from 3 may undergo hydrogen abstraction
to form 8, which may subsequently give 10 upon hydrogen-
atom transfer. On the other hand, I-1 may proceed through an
oxa-di-π-methane type of mechanism, in which the ꢀ-scission
of the C-C bond and following C-C bond cleavage led to the
formation of bicyclo[3.2.1]octenones 9 and/or 11. The generated
radical can in principle undergo intramolecular addition to either
the carbonyl group or the vinyl group.19 In the present study,
the bridging toward the ketone or the olefinic moiety are equally
possible, leading to a cyclopropane intermediate with high strain.
While it is a well-known phenomena that radicals readily add
to alkenes and addition to carbonyls is usually less common
because the CdO π-bond is much stronger than the CdC
π-bond;20 there are also examples of intramolecular cyclization
yield (%)a
cyclo- concn
entry adduct (M)
rxn
time
solvent
8
9
11
12 13
1
2
3
4
5
6
7
8
3a
3a
3b
3c
3c
3d
3d
3e
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
toluene 15 min
benzene 5.5 h
toluene 15 min
toluene 15 min
benzene 2 h
toluene 15 min
benzene 2 h
benzene 3 h
17
17
23
7
60
65
15 + 3b 65
14 + 5b 58
52
48
30
32
88
a Yields are of isolated products. b Yields of major and minor
epimers.
substitution again furnished the desulfurized product 8e exclu-
sively in 88% yield.
Structural Effects on the Rearrangements of Radicals
Generated. All structures of the rearranged products were
thoroughly characterized by standard analytical data including
NOE experiments for compound 11c and CH-COSY and HH-
COSY in the case of compound 12a. For 11c in the NOE
(19) (a) Tsang, R.; Dickson, J. K., Jr.; Walton, R.; Fraser-Reid, B. J. Am.
Chem. Soc. 1987, 109, 3484. (b) Beckwith, A. L. J.; Hay, B. P. J. Am. Chem.
Soc. 1989, 111, 230.
(20) (a) Cottrell, T. L. The Strengths of Chemical Bonds, 2nd ed.; Butter-
worths: London, 1958; A-21 to A-34. (b) Benson, S. W. J. Chem. Educ. 1965,
42, 502.
1636 J. Org. Chem. Vol. 74, No. 4, 2009

Functionalized Bicyclo[2.2.2]octenone DeriVatiVes
SCHEME 3. A Plausible Mechanism for the Formation of Compounds 9, 10, 11, and 13
SCHEME 4. A Plausible Mechanism for the Formation of
Compounds 12
SCHEME 5. Desulfurization of the Reduced Compound 15
process where the carbon radical in sterically congested
substrates showed preference of carbonyl group over olefin.19a
A possible explanation could be that the intramolecular addition
of the carbon-centered radical onto a olefinic double bond might
be highly prone to reversible reaction to regenerate the original
radical, and hence di-π-methane bridging products 13 are not
observed from the reaction of 3 with Raney-Ni. Though the
olefinic moiety does not take place in the reaction, it might be
playing a major role in dictating the reaction pathway depending
on the substitution present on it. The electron-poor olefin due
to an electron-withdrawing substitution (regardless of the
position of the substitution) in compounds 3a-d may provide
a stabilizing factor to the rearranged radical centers, whereas
the lacking of such an effect in 3e leads to a high yield of 8e
from the Raney-Ni or Bu3SnH reduction of 3e.
In the n-Bu3SnH reduction reactions, formation of the
observed bicyclo[3.2.1]octadienol products 12 could be rational-
ized by the attack of n-Bu3Sn on the carbonyl oxygen to generate
radical I-6 followed by cyclopropane ring formation and release
of phenylthio radical (Scheme 4). In the absence of such a
preference to oxygen atom, in the case of Raney-Ni, no 12 could
be obtained. Compound 13d might have arisen from the radical
intermediate I-1 (R1 ) R3 ) H, R2 ) CO2Me) via di-π-methane
bridging (Scheme 3). Here in the n-Bu3SnH reduction reaction
of adduct 3d, the oxa-di-π-methane and di-π-methane bridging
seems to be competing and in favor of the former. For the radical
intermediate I-1, the competing processes of hydrogen abstrac-
tion to form 8 or bridging process toward I-2 should be
controlled by reaction kinetics. Hence the rate of the bridging
process is faster in a substrate having an electron-withdrawing
group, yielding mainly the rearrangement products 9-13.
To confirm the suggested mechanism that the radical prefers
the carbonyl functionality rather than the olefinic double bond
and interference of carbonyl function is the reason for the
rearranged products, the carbonyl functionality in compound
3a was reduced with NaBH4 to provide separable isomers 14
(63%) and 15 (30%) in excellent combined yield (Scheme 5).
The stereochemistry in the compound 14 was confirmed by NOE
experiments. Irradiating Ha brought about significant NOE on
the signal intensities of Hb (12%) and when Hb was saturated,
enhancement in the signal intensity of Ha (9%) and Hc (7%)
could be observed. Thus the stereochemistry in compound 15
could be assigned as shown. The hydroxyl compound 15
provided a single nonrearranged reaction product 16 in both
the sulfide reduction conditions in high yield (Scheme 5).
Neither oxa-di-π-methane nor di-π-methane-like rearrangement
products were observed.
We then applied the detoured strategy to 3a-d (Scheme 6);
in all cases, the sulfide groups were removed by Raney-Ni
smoothly and the resulting alcohols were oxidized to ketones
using pyridinium dichromate (PDC). The desire products 8a-d
were obtained in good yield via a three-step procedure.
Effect of C-S and C-Se Bond Strengh on the Reduction.
The C-S bond energy is 264 KJ mol-1, whereas the C-Se
J. Org. Chem. Vol. 74, No. 4, 2009 1637

Gao et al.
TABLE 4. Reductions of Adducts 4 with n-Bu3SnH in the
Presence of AIBN
SCHEME 6. Detoured Desulfurization Method
7d
bond energy is around 222 KJ mol-1
.
Therefore, processes
involving cleavage of the latter type of bond is expected to occur
at a greater rate than the former. Thus, in the case of
organosulfur substrate, the slower cleavage of the C-S bond
as compared with the C-Se bond by the n-Bu3Sn radical could
potentially result in competition from other reactions, such as
direct addition of the n-Bu3Sn radical to the carbonyl group.21
The formation of intermediate I-1 (Scheme 2) should be more
favorable than that of intermediate I-6 (Scheme 2) for selenide
adducts. Consequently, the Diels-Alder adducts 4 were sub-
jected to similar reduction conditions described previously. The
deselenation reaction of compound 4a with Raney-Ni provided
the same products as for desulfurization with almost similar
yields. The interesting part of the result is when n-Bu3SnH was
utilized, no 12a was observed. This result suggests that
intermediate I-6 is not favored during n-Bu3SnH reduction of
selenide compounds 4. The expected selectivity in the rear-
rangement reaction was also observed with the other set of
selenium-containing compounds as shown in Table 3. Com-
pound 9b could be obtained in improved yield of 40% from
selenium reduction in 4b compared to sulfur reduction in 3b.
Compound 4c provided 2.2:1 ratio of 11c to 11c′ which is
different from the 5:1 ratio obtained with 3c. It is also important
to note that no 12c was observed, and the combined yield of
11c and 11c′ was improved. Interestingly, compound 4e
furnished deselenized product 8e in 90% yield, which is in
accord with the high yield of 8e from the reductions of 3e. These
results were presumably due to the lack of stabilizing factor
caused by the electron-withdrawing group in other cases.
yield (%)a
cyclo- concn
entry adduct (M)
rxn
time
solvent
8
9
11
12 13
1
2
3
4
4b
4c
4d
4e
0.02 toluene 15 min
0.02 toluene 15 min
0.02 toluene 15 min
0.02 benzene 3 h
40
45 + 20b
42
21
90
a Yields are of isolated products. b yields of major and minor epimers.
This study reveals unknown skeletal rearrangements of
bicyclo[2.2.2]octenones derived from MOBs. It is also demon-
strated, while changing the sulfide to a selenide function, that
the diversed reaction pathway leading to bicyclo[3.2.1]octenones
could be avoided. The radical reaction condition with n-Bu3SnH,
on a reactant bearing both selenide and carbonyl function, effects
the cleavage of selenide faster due to the weaker C-Se bond.
However, clean desulfurizations could be applied to the sulfide
groups on bicyclo[2.2.2]octenols derived from a simple reduc-
tion of the Diels-Alder adducts. Thus the desired bicyclo[2.2.2]-
octenones could also be accomplished by the detoured route of
“reduction of ketone-Raney-Ni reduction-PDC oxidation”
procedure. It is pertinent to mention that the transformation of
bicyclo[2.2.2]octenones bearing no bridghead methoxy group
into bicyclo[3.2.1]octenones have been successfully achieved
as compared to reported examples in which the bridgehead
methoxy group is a crucial factor to transform bicyclo[2.2.2]-
octenones into bicyclo[3.2.1]octenones.22
Conclusion
In conclusion, highly regio- and stereoselective inverse-
electron-demand Diels-Alder reactions of MOBs with phenyl
vinyl sulfide and phenyl vinyl selenide as dienophilic partners
were studied in detail. The Diels-Alder adducts thus obtained
from the above reaction sequence have proven to be important
synthetic intermediates. We could successfully prepare highly
substituted bicyclo[2.2.2]octadienones, which can be potential
starting materials for synthesis of heteroarene-fused barrelenes.
In the course of developing approaches to bicyclo[2.2.2]octanone
derivatives by desulfurization/deselenation, a number of possible
reaction pathways have been discovered, ranging from simple
hydrogenolysis of a C-X (X ) S or Se) bond to rearrangement
reactions, including di-π-methane and oxa-di-π-methane-like
rearrangements. The scope and limitation of these novel
rearrangement reactions is presented with a set of selected
examples.
Experimental Section
General Procedure for Raney-Ni Mediated Transformations.
A solution of cycloadduct 3 or 4 (0.5 mmol) in EtOH (7 mL) was
added to Raney-Ni (3.58 g, washed 4 times with EtOH) in EtOH
(8 mL) and the contents were stirred for appropriate time. Then
the suspension was filtered and the residue was washed with ether.
The filtrate was evaporated and subjected to column chromatog-
raphy to afford compounds 8, 9, and 10.
General Procedure for n-Bu3SnH Mediated Transformations.
To a solution of cycloadduct 3 or 4 (0.5 mmol) in toluene (20 mL)
was added a toluene (20 mL) solution of n-Bu3SnH (1.0 mmol)
and AIBN (35 mg) during a time interval of 15 min at reflux
temperature. The reaction was stopped after the TLC analysis
indicated the diappearance of starting material. After the removal
(22) (a) Singh, V.; Jagadish, B. Tetrahedron 1996, 52, 3693. (b) Uyehara,
T.; Murayama, T.; Sakai, K.; Ueno, M.; Sato, T. Tetrahedron Lett. 1996, 37,
7295. (c) Uyehara, T.; Osanai, K.; Sugimoto, M.; Suzuki, I.; Yamamoto, Y.
J. Am. Chem. Soc. 1989, 111, 7264. (d) Hua, D. H.; Gung, W.-Y.; Ostrander,
R. A.; Takusagawa, F. J. Org. Chem. 1987, 52, 2509. (e) Monti, S. A.; Dean,
T. R. J. Org. Chem. 1982, 47, 2679.
(21) (a) Sugawara, T.; Otter, B. A.; Ueda, T. Tetrahedron Lett. 1988, 29,
75. (b) Enholm, E. J.; Prasad, G. Tetrahedron Lett. 1989, 30, 4939. (c) Pereyre,
M.; Quintard, J.; Rahm, A. Tin in Organic Synthesis; Butterworths: London,
1987; p69.
1638 J. Org. Chem. Vol. 74, No. 4, 2009

Functionalized Bicyclo[2.2.2]octenone DeriVatiVes
of solvent the crude reaction mixture was chromatographed to afford
compounds 9, 11, 12, and 13.
intensity) 168 ([M - CO]+, 100), 153 (30), 137 (39), 121 (17),
105 (11), 94 (11), 93 (87), 79 (24), 75 (16), 59 (12); HRMS (EI)
calcd for C11H16O3 (M+) 196.1099, found 196.1098.
Methyl (1R*,4S*)-6,6-Dimethoxy-5-oxobicyclo[2.2.2]oct-2-ene-
2-carboxylate (8a). IR (film) 3064, 1745, 1716, 1626, 1438, 1263,
1226, 1082, 1054 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.35 (dddd,
J ) 3.1, 4.1, 12.0, 12.2 Hz, 1H), 1.61 (dddd, J ) 3.2, 3.3, 12.2,
12.3 Hz, 1H), 1.95-2.08 (m, 2H), 3.27 (s, 3H), 3.27-3.29 (m,
1H), 3.73 (dd, J ) 3.2, 6.8 Hz, 1H), 7.13 (dd, J ) 1.8, 6.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 19.3, 22.4, 38.4, 48.7, 49.9,
50.2, 51.9, 93.8, 137.3, 137.7, 164.5, 202.2; MS (70 eV) m/z
(relative intensity) 212 ([M - CO]+, 76), 181 (18), 165 (100), 153
(21), 137 (17), 121 (15), 93 (13), 79 (22), 77 (37), 59 (23); HRMS
(EI) calcd for C11H16O4 [M - CO]+ 212.1207, found 212.0998.
(1S*,4R*)-5-Acetyl-3,3-dimethoxybicyclo[2.2.2]oct-2-en-2-one (8b).
IR (film) 3064, 1745, 1668, 1615, 1462, 1380, 1260, 1100, 1055
Methyl (1R*,5R*)-7,7-Dimethoxy-6-oxobicyclo[3.2.1]oct-2-ene-
2-carboxylate (9a). IR (film) 3046, 1752, 1700, 1630, 1280, 1240,
1
1128, 1066, 1052 cm-1; H NMR (400 MHz, CDCl3) δ 1.67 (dd,
J ) 0.8, 11.5 Hz, 1H), 2.34 (dddd, J ) 0.8, 4.3, 5.2, 11.5 Hz, 1H),
2.43 (ddd, J ) 0.8, 2.0, 4.0 Hz, 1H), 2.55 (dd, J ) 3.0, 5.5 Hz,
1H), 2.60 (dd, J ) 3.0, 5.5 Hz, 1H), 2.65 (ddd, J ) 2.2, 5.0, 7.4
Hz, 1H), 3.26 (s, 3H), 3.33 (s, 3H), 3.55 (ddd, J ) 1.8, 2.4, 4.4
Hz, 1H), 3.73 (s, 3H), 6.84 (dd, J ) 3.0, 3.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 28.1, 33.6, 38.8, 42.3, 50.6, 51.2, 51.9, 105.2,
133.0, 137.6, 166.1, 212.1; MS (70 eV) m/z (relative intensity) 212
([M - CO]+, 100), 209 (42), 197 (21), 165 (53), 137 (53), 121
(21), 105 (30), 88 (34), 77 (49); HRMS (EI) calcd for C11H16O4
[M - CO]+ 212.1207, found 212.1050.
cm-1 1H NMR (400 MHz, CDCl3) δ 1.20-1.29 (m, 1H),
;
1.61-1.70 (m, 1H), 1.98-2.08 (m, 2H), 2.33 (s, 3H), 3.22 (s, 3H),
3.30 (ddd, J ) 2.0, 3.0, 6.6 Hz, 1H), 3.34 (s, 3H), 3.89 (ddd, J )
2.4, 4.8, 6.8 Hz, 1H), 7.06 (dd, J ) 2.0, 2.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 19.2, 22.5, 24.7, 36.4, 48.7, 50.0, 50.2, 93.8,
137.2, 146.4, 194.5, 202.3; MS (70 eV) m/z (relative intensity) 196
([M - CO]+, 100), 165 (33), 153 (14), 149 (84), 121 (20), 107
(11), 91 (16), 79 (20), 33 (77), 43 (62); HRMS (EI) calcd for
C11H16O3 [M - CO]+ 196.1099, found 196.1096.
Methyl (1R*,4S*)-4,6,6-Trimethoxy-5-oxobicyclo[2.2.2]oct-2-ene-
2-carboxylate (8c). IR (film) 3070, 1757, 1717, 1629, 1439, 1264,
1139, 1057, 1023 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.42-1.49
(m, 1H), 1.71-1.79 (m, 1H), 1.99-2.11 (m,. 2H), 3.27 (s, 3H),
3.36 (s, 3H), 3.67 (dd, J ) 3.0, 5.0 Hz, 1H), 3.79 (s, 3H), 7.17 (d,
J ) 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 19.7, 26.9, 37.7,
49.9, 50.4, 52.1, 53.7, 84.7, 93.9, 136.3, 138.4, 164.0, 200.1; MS
(70 eV) m/z (relative intensity) 242 ([M - CO]+, 61), 227 (100),
211 (26), 195 (34), 168 (17), 167 (17), 135 (12), 123 (23), 109
(17), 108 (15); HRMS (EI) calcd for C12H18O5 [M - CO]+
242.1154, found 242.1153.
(1R*,5R*)-2-Acetyl-7,7-dimethoxybicyclo[3.2.1]oct-2-en-6-one (9b).
IR (film) 3067, 1754, 1670, 1627, 1378, 1438, 1280, 1232, 1129,
1
1072, 1054 cm-1; H NMR (400 MHz, CDCl3) δ 1.59 (dd, J )
1.2, 11.4 Hz, 1H), 2.29 (s, 3H), 2.34 (ddd, J ) 3.9, 3.9, 11.4 Hz,
1H), 2.44∼2.52 (m, 1H), 2.62 (dd, J ) 2.8, 5.2 Hz, 1H), 2.65∼2.69
(m, 1H), 3.24 (s, 3H), 3.25 (s, 3H), 3.72∼3.74 (m, 1H), 6.71∼6.73
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 25.5, 27.9, 34.0, 37.0,
42.3, 50.7, 51.3, 105.1, 138.2, 142.3, 196.8, 212.2; MS (70 eV)
m/z (relative intensity) 196 ([M - CO]+, 100), 193 (25), 153 (59),
149 (66), 121 (35), 107 (26), 91 (20), 88 (34), 79 (26), 77 (30);
HRMS (EI) calcd for C11H16O3 [M - CO]+ 196.1099, found
196.1103.
Methyl (1R*,5S*)-7,7-Dimethoxy-6-oxobicyclo[3.2.1]oct-2-ene-
3-carboxylate (9d). IR (film) 1763, 1700, 1717, 1653, 1250, 1128,
1
1131, 1089, 1056 cm-1; H NMR (400 MHz, CDCl3) δ 1.73 (dd,
J ) 1.4, 11.5 Hz, 1H), 2.28 (ddd, J ) 3.8, 4.9, 11.5 Hz, 1H), 2.54
(dd, J ) 2.5, 17.8 Hz, 1H), 2.62 (ddd, J ) 1.9, 5.2, 17.8 Hz, 1H),
2.73 (ddd, J ) 2.5, 4.9, 5.2 Hz, 1H), 3.01 (dd, J ) 2.6, 7.0 Hz,
1H), 3.26 (s, 3H), 3.35 (s, 3H), 3.70 (s, 3H), 7.04 (ddd, J ) 1.4,
1.9, 7.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 27.5, 32.6, 40.0,
42.4, 50.5, 51.1, 51.8, 105.3, 129.8, 139.2, 166.4, 211.4; MS (70
eV) m/z (relative intensity) 240 (M+, 1), 212 ([M - CO]+,100),
197 (14), 165 (18), 153 (33), 137 (20), 121 (14), 88 (20), 77 (19),
58 (13); HRMS (EI) calcd for C12H16O5 (M+) 240.0998, found
240.1010.
Methyl (1S*,4R*)-5,5-Dimethoxy-6-oxobicyclo[2.2.2]oct-2-ene-
2-carboxylate (8d). IR (film) 3073, 1741, 1716, 1718, 1628, 1438,
1
1266, 1110, 1085, 1055 cm-1; H NMR (400 MHz, CDCl3) δ
1.27-1.37 (m, 1H), 1.58-1.67 (m, 1H), 1.93-2.04 (m, 2H), 3.27
(s, 3H), 3.29-3.31 (m, 1H), 3.33 (s, 3H), 3.71-3.73 (m, 1H), 3.75
(s, 3H), 7.37 (dd, J ) 1.8, 4.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 18.8, 22.5, 39.7, 46.8, 50.2, 51.9, 93.9, 131.7, 143.8,
164.2, 202.1; MS (70 eV) m/z (relative intensity) 212 ([M - CO]+,
100), 181 (48), 165 (83), 153 (29), 149 (10), 137 (38), 121 (19),
107 (10), 93 (15), 77 (25); HRMS (EI) calcd for C12H16O5 (M+)
240.0998, found 240.0980.
Acknowledgment. We gratefully acknowledge financial
support from the National Science Council of Taiwan (NSCT).
S.K.C. and G.J.C. thank NSCT for postdoctoral fellowships.
We thank Dr. R. K. Peddinti for helpful discussion.
(1S*,4R*)-3,3-Dimethoxy-5-methylbicyclo[2.2.2]oct-5-en-2-one
(8e). IR (film) 3051, 1735, 1582, 1439, 1131, 1190, 1052 cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.30 (ddt, J ) 3.3, 9.0, 14.8 Hz, 1H),
1.52∼1.64 (m, 1H), 1.81 (d, J ) 1.2 Hz, 1H), 1.83∼1.97 (m, 2H),
2.90 (ddd, J ) 1.7, 1.9, 3.5 Hz, 1H), 2.97 (ddd, J ) 2.1, 2.9, 7.2
Hz, 1H), 3.30 (s, 3H), 3.31 (s, 3H), 5.96 (dddd, J ) 1.2, 1.9, 3.2,
7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.1, 20.4, 21.7, 38.3,
49.8, 50.1, 53.2, 94.7, 126.9, 137.0, 203.4; MS (70 eV) m/z (relative
Supporting Information Available: General procedures,
characterization data, and copies of 1H NMR for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO802295P
J. Org. Chem. Vol. 74, No. 4, 2009 1639