Intermolecular Diels-Alder reactions of brominated masked o-benzoquinones with electron-deficient dienophiles. A detour method to synthesize bicyclo[2.2.2]octenones from 2-methoxyphenols

Article abstract of DOI:10.1021/jo020171h

Intermolecular Diels-Alder reactions of masked o-benzoquinones, i.e., 6,6-dimethoxy-2,4-cyclohexadienones 5-7 and 21-24 generated from 2-methoxyphenols 1-3 and 17-20, respectively, with electron-deficient dienophiles leading to highly functionalized bicyclo[2.2.2]octenones are described. The masked o-benzoquinones (MOBs) 5-7 underwent Diels-Alder cycloadditions with methyl acrylate, methyl methacrylate, and methyl vinyl ketone to provide bicyclo[2.2.2]octenones 13a-c to 15a-c (direct method) in low to moderate yields with the concomitant formation of considerable amounts of dimers 9-11. To retard dimerization and to improve the yields of the requisite bicyclo[2.2.2]octenones, a detour method comprised of sequential bromination of 2-methoxyphenols 1-4, oxidation and Diels-Alder reaction, and debromination has been developed. The oxidation of bromophenols 17-20 produced MOBs 21-24 which are stable enough to be isolated. The MOBs 21-24 underwent cycloaddition with electron-deficient dienophiles in a very efficient manner to afford the corresponding cycloadducts 25a-c to 28a-c in good to high yields without self-dimerization. When the cycloadducts 25a-c to 28a-c were treated with either Bu₃SnH/AIBN or tributylammonium formate-palladium reagent, the corresponding debrominated products 13a-c to 16a-c were obtained in high to excellent yields. In general, the cycloadducts 13a-c to 15a-c were obtained in 20-40% higher yields via the detour method than those via the direct method. In both routes, the Diels-Alder reactions proceeded in a highly regio- and stereoselective manner to furnish a single cycloadduct in each case.

Full text of DOI:10.1021/jo020171h

In ter m olecu la r Diels-Ald er Rea ction s of Br om in a ted Ma sk ed
o-Ben zoqu in on es w ith Electr on -Deficien t Dien op h iles. A Detou r
Meth od to Syn th esize Bicyclo[2.2.2]octen on es fr om
2-Meth oxyp h en ols
Chien-Hsun Lai, Yi-Ling Shen, Min-Nen Wang, N. S. Kameswara Rao, and Chun-Chen Liao*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 300
ccliao@mx.nthu.edu.tw
Received March 11, 2002
Intermolecular Diels-Alder reactions of masked o-benzoquinones, i.e., 6,6-dimethoxy-2,4-cyclo-
hexadienones 5-7 and 21-24 generated from 2-methoxyphenols 1-3 and 17-20, respectively,
with electron-deficient dienophiles leading to highly functionalized bicyclo[2.2.2]octenones are
described. The masked o-benzoquinones (MOBs) 5-7 underwent Diels-Alder cycloadditions with
methyl acrylate, methyl methacrylate, and methyl vinyl ketone to provide bicyclo[2.2.2]octenones
13a -c to 15a -c (direct method) in low to moderate yields with the concomitant formation of
considerable amounts of dimers 9-11. To retard dimerization and to improve the yields of the
requisite bicyclo[2.2.2]octenones, a detour method comprised of sequential bromination of 2-meth-
oxyphenols 1-4, oxidation and Diels-Alder reaction, and debromination has been developed. The
oxidation of bromophenols 17-20 produced MOBs 21-24 which are stable enough to be isolated.
The MOBs 21-24 underwent cycloaddition with electron-deficient dienophiles in a very efficient
manner to afford the corresponding cycloadducts 25a -c to 28a -c in good to high yields without
self-dimerization. When the cycloadducts 25a -c to 28a -c were treated with either Bu3SnH/AIBN
or tributylammonium formate-palladium reagent, the corresponding debrominated products 13a -c
to 16a -c were obtained in high to excellent yields. In general, the cycloadducts 13a -c to 15a -c
were obtained in 20-40% higher yields via the detour method than those via the direct method. In
both routes, the Diels-Alder reactions proceeded in a highly regio- and stereoselective manner to
furnish a single cycloadduct in each case.
In tr od u ction
[3.3.0.02,8]octanones,10 variously fused triquinanes,12 cis-
decalins,13 and bicyclo[4.2.2]decenones.13a Bicyclo[2.2.2]-
octenones can undergo interesting and useful photochem-
ical reactions, viz., oxa-di-π-methane rearrangement and
1,3-acyl migration.10,14 Further, they have a wide range
of applications in the synthesis of natural products.15
The Diels-Alder reactions are the most versatile and
synthetically useful reactions in which four new contigu-
ous stereogenic centers can be generated in a single
laboratory operation.1-3 The methodology allows the
introduction of a plethora of functionality in an expedi-
tious manner with regio- and stereoselectivity.4 A wide
variety of ring structures have been constructed by using
various dienes and dienophiles bearing an array of
functionalities in the Diels-Alder reactions.5 Bicyclo-
[2.2.2]octenones6,7 obtained via the Diels-Alder reactions
are useful synthons for polysubstituted cyclohexanes,8
bicyclo[3.2.1]octenones,9 bicyclo[4.2.0]octenones,10,11 tricyclo-
(6) (a) Alder, K.; Flock, F. H.; Lessenich, H. Chem. Ber. 1957, 90,
1709. (b) Metlesics, W.; Wessely, F.; Budzikiewicz, H. Monatsh. Chem.
1958, 89, 102. (c) Hirao, K.; Unno, S.; Miura, H.; Yonemutsu, O. Chem.
Pharm. Bull. 1977, 25, 3354. (d) Yates, P.; Stevens, K. E. Tetrahedron
1981, 37, 4401. (e) Schultz, A. G.; Dittami, J . P.; Lavieri, F. P.; Salowey,
C.; Sundararaman, P.; Szymula, M. J . Org. Chem. 1984, 49, 4429.
(7) For the preparation of bicyclo[2.2.2]octenones by other methods,
see for example: (a) Ranganathan, S.; Ranganathan, D.; Mehrothra,
A. K. Synthesis 1977, 289. (b) Uyehara, T.; Kabasawa, Y.; Kato, T.
Tetrahedron Lett. 1985, 26, 2343. (c) Yates, P.; Burnell, D. J .; Freer,
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C.-C. Tetrahedron Lett. 1991, 32, 4011. (e) Hung, S.-C.; Liao, C.-C. J .
Chem. Soc., Chem. Commun. 1993, 1457. (f) Hung, S.-C.; Liao, C.-C.
J . Chin. Chem. Soc. 1994, 41, 817.
(8) Chu, C.-S.; Liao, C.-C.; Rao, P. D. Chem. Commun. 1996, 1537.
(9) Uyehara, T.; Osanai, K.; Sugimoto, M.; Suzuki, I.; Yamamoto,
M. J . Am. Chem. Soc. 1989, 111, 7264.
(10) (a) Zimmerman, H. E.; Armesto, D. Chem. Rev. 1996, 96, 3065.
(b) Demuth, M. Org. Photochem. 1991, 11, 37.
(11) (a) Givens, R. S.; Oettle, W. F.; Coffin, R. L.; Carlson, R. G. J .
Am. Chem. Soc. 1971, 93, 3957. (b) Demuth, M.; Schaffner, K. Angew.
Chem., Int. Ed. Engl. 1982, 21, 820. (c) Singh, V.; Porinchu, M. J .
Chem. Soc., Chem. Commun. 1993, 134.
(1) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon: Oxford, UK, 1990.
(2) Advances in Cycloaddition; Curran, D. P., Ed.; J AI Press:
Greenwich, CT, 1990; Vols. 1-3.
(3) For a review of the intermolecular Diels-Alder reaction, see:
Oppolzer, W. Combining C-C π-bonds. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds; Pergamon
Press: Oxford, UK, 1991; Vol. 5, Chapter 4.1.
(4) Masamune, S.; Choy, W.; Petersen, J . S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
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Org. Lett. 2002, 4, 493.
10.1021/jo020171h CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/13/2002
J . Org. Chem. 2002, 67, 6493-6502
6493

Lai et al.
SCHEME 1
We have found that oxidation of simple and readily
available 2-methoxyphenols in methanol with diacetoxy-
iodobenzene (DAIB) or [bis(trifluoroacetoxy)]iodobenzene
(BTIB) produces unstable o-benzoquinone monodimethyl-
acetals which are generically called masked o-benzo-
quinones (MOBs).16 We have previously reported a
methodology based on intermolecular Diels-Alder reac-
tions of MOBs17,18 wherein we encountered some MOBs
that were not stable enough to be isolated and were found
to dimerize under reaction conditions. In most of these
MOBs, the competition between self-dimerization and the
Diels-Alder reaction with external dienophiles was often
observed, though to a varying degree. To avoid dimer-
ization, a large excess of the dienophiles is used and the
concentration of the MOB in the reaction mixture is kept
low throughout the course of the reaction by employing
a high dilution technique. In some cases (vide infra), even
high dilution could not overcome the high propensity of
MOBs toward dimerization, which still was the main
constraint for their use in organic synthesis.19 To prevent
dimerization and to improve the yields of requisite
bicyclo[2.2.2]octenones, a detour method comprised of
sequential bromination of 2-methoxyphenols 1-4, oxida-
tion, Diels-Alder reaction, and debromination has been
developed.20 We present herein a detailed account of our
investigations on the intermolecular Diels-Alder reac-
tions of unstable MOBs 5-7, their stable brominated
equivalents 21-23 and brominated MOB 24 with electron-
deficient dienophiles, methyl acrylate (MA), methyl
methacrylate (MMA), and methyl vinyl ketone (MVK) to
synthesize bicyclo[2.2.2]octenones.
at room temperature. In the absence of an external
dienophile, the reaction produced exclusively dimer 9,
which indicates the high unstable nature of MOB 5.
Therefore, high dilution technique and a large ratio of
the dienophile to MOB was maintained throughout the
course of the reaction to minimize dimerization and to
increase the yield of the Diels-Alder adduct. Thus, to a
mixture of DAIB and MA (25 equiv) in methanol was
added guaiacol (1) slowly at room temperature, using a
syringe pump, over a period of 10 h. The reaction was
continued for another hour at the same temperature.
Usual workup and chromatography still furnished mainly
the dimer 9 in 70% yield along with the Diels-Alder
adduct 13a in only 29% yield (Scheme 1, Table 1).
However, the yield of the cycloadduct 13a was marginally
improved to 40% and the yield of dimer was dropped to
60% when 1 was added to a mixture of DAIB and MA
(25 equiv) under reflux (Method A). When the MOB 5
was allowed to react with MMA, the yield of the cyclo-
adduct 13b was substantially dropped (9% at room
temperature and 28% under reflux), presumably due to
the steric hindrance caused by the additional methyl
group in the dienophile. We then utilized another electron-
deficient dienophile MVK in the Diels-Alder reaction
with MOB 5, which afforded the cycloadduct 13c (54%
yield when addition time of 1 to the reaction mixture was
5 h and 62% when the addition time was 10 h) at room
temperature.
Resu lts a n d Discu ssion
The oxidation of the parent 2-methoxyphenol, i.e.,
guaiacol (1), in methanol was first carried out with DAIB
(12) (a) Demuth, M.; Hinsken, W. Angew. Chem., Int. Ed. Engl.
1985, 24, 973. (b) Hwang J .-T.; Liao, C.-C. Tetrahedron Lett. 1991,
32, 6583. (c) Mehta, G.; Subrahmanyam, D. J . Chem. Soc., Perkin
Trans. 1 1991, 395. (d) Singh V.; Thomas, B. J . J . Org. Chem. 1997,
62, 5310. (e) Hsu, D.-S.; Rao, P. D.; Liao, C.-C. Chem. Commun. 1998,
1798.
(13) (a) Lee, T.-H.; Liao, C.-C.; Liu, W.-C. Tetrahedron Lett. 1996,
37, 6819. (b) Hsu, P.-Y.; Lee, Y.-C.; Liao, C.-C. Tetrahedron Lett. 1998,
39, 659.
(14) Schuster, D. I. In Rearrangements in Ground and Excited
States; de Mayo, P., Ed.; Academic Press: New York, 1980; Vol. 3, p 167.
(15) (a) Desimoni, G.; Tacconi, G.; Barco, A.; Pollini, G. P. Natural
Products Synthesis Through Percyclic Reactions; ACS Monograph no.
180; American Chemical Society: Washington, DC, 1983. (b) Ho, T.-
L. In Carbocyclic Ring Construction in Terpene Synthesis; VCH:
Weinheim, Germany, 1988. (c) Deslongchamps, P.; Belanger, A.;
Berney, D. J . F.; Boreschberg, H.-J .; Brousseau, R.; Doutheau, A.;
Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C.-C.;
Maclachlan, F. N.; Maffrand, J .-P.; Marazza, F.; Martino, R.; Moreau,
C.; Ruest, L.; Saint-Laurent, L.; Saintonge, R.; Soucy, P. Can. J . Chem.
1990, 68, 115 and 127.
(16) Liao, C.-C. Synthetic Applications of Masked Benzoquinones.
In Modern Methodology in Organic Synthesis, Kyoto; Sheno, T., Ed.;
Kodansha: Tokyo, J apan, 1992; pp 409-424.
(17) (a) Chu, C.-S.; Lee, T.-H.; Liao, C.-C. Synlett 1994, 635. (b) Chen,
C.-H.; Rao, P. D.; Liao, C.-C. J . Am. Chem. Soc. 1998, 120, 13254.
(18) Liao, C.-C.; Chu, C.-S.; Lee, T.-H.; Rao, P. D.; Ko, S.; Song, L.-
D.; Shiao, H.-C. J . Org. Chem. 1999, 64, 4102.
(19) (a) In general, the existing methods provide 2,4-cyclohexadi-
enones in moderate yields, especially those that rely on Wessely
oxidation, which lacks selectivity and produces mixtures of products.
(b) Kende, A. S.; MacGregor, P. J . Am. Chem. Soc. 1961, 83, 4197. (c)
Vannerberg, N. G.; Brasen, S. Acta Chem. Scand. 1970, 24, 1894. (d)
Karrlsson, B.; Kierkegaard, P.; Pilotti, A.-M.; Wiehager, A.-C.; Lindgren,
B. O. Acta Chem. Scand. 1973, 27, 1428. (e) Karrlsson, B.; Pilotti, A.-
M.; Wiehager, A.-C.; Lindgren, B. O. Acta Chem. Scand. 1973, 27, 2945
and 2955.
Taking the electron-deficient nature of the diene
moiety in MOB 5 into account, we then considered the
MOBs 6 and 7 bearing an electron-releasing methyl
group at positions 2 and 3, respectively. Gratifyingly, the
formation of dimer 10 was supressed drastically and the
requisite bicyclic derivative 14a was obtained in good
yield. When these conditions (Table 1) were extended to
MMA and MVK, the cycloadducts 14b and 14c were
obtained in lower yields due to the formation of dimer
10 in considerable amounts. Similarly, the reactions of
MOB 7 generated from phenol 3 with MA, MMA, and
MVK produced substantial amounts of dimer 11 with
poor yields of the Diels-Alder adducts 15a -c. Though
the chemical yields are not encouraging, each of these
reactions provided a single isomer indicating the excel-
lent regio- and stereoselectivities.
(20) Lai, C.-H.; Shen, Y.-L.; Liao, C.-C. Synlett 1997, 1351.
6494 J . Org. Chem., Vol. 67, No. 18, 2002

Synthesis of Bicyclo[2.2.2]octenones from 2-Methoxyphenols
TABLE 1. In ter m olecu la r Diels-Ald er Rea ction s of Ma sk ed o-Ben zoqu in on es 5-8 w ith MA, MMA, a n d MVK (d ir ect
m eth od )a
reaction conditions
entry
phenol
MOB
dienophileb
addition timec/temp
after additiond
adduct/Y (%)
dimer/Y (%)
1
2
3
4
5
6
7
8
9
10
11
12
13e
14e
15e
1
5
MA
MA
10 h/rt
10 h/reflux
10 h/rt
48 h/reflux
5 h/rt
10 h/rt
rt/1 h
reflux/1 h
rt/1 h
reflux/1 h
rt/1 h
reflux/1 h
reflux/1 h
reflux/1 h
reflux/1 h
reflux/1 h
reflux/1 h
reflux/1 h
rt/60 h
13a /29
13a /40
13b/9
9/70
9/60
9/90
9/65
9/24
9/10
10/13
10/38
10/42
11/34
11/45
11/48
12/0
MMA
MMA
MVK
MVK
MA
MMA
MVK
MA
MMA
MVK
MA
MMA
MVK
13b/28
13c/54
13c/62
14a /86
14b/43
14c/22
15a /35
15b/19
15c/25
16a /86
16b/84
16c/88
2
3
4
6
7
8
8 h/reflux
8 h/reflux
8 h/reflux
8 h/reflux
8 h/reflux
8 h/reflux
rtf
rtf
rt/72 h
rt/20 h
12/0
12/0
rtf
a
b
Reactions in entries 1-12 were carried out following Method A. About 25 equiv of dienophiles was used in Method A. c Time during
d
which 2-methoxyphenol (1-3) was added to the reaction mixture. Temperature of the reaction and the time for which the reaction
mixture was stirred after the complete addition of 2-methoxyphenol (1-4). e Data taken from ref 15 for comparing the results.
f 2-Methoxyphenol (4) was added in one portion.
SCHEME 2
From the above results, it appears that the lower yields
of the desired Diels-Alder adducts obtained in one step
(direct method) are mainly due to the rapid dimerization
of these MOBs under reaction conditions. On the basis
of our earlier observations on MOB chemistry, it is
apparent that the presence of a bulky group on MOB
retards dimerization significantly. We have shown previ-
ously that a dioxolane in the 4-position also gives higher
yields of Diels-Alder product and no dimer.18 Thus, we
envisioned that a bromine atom introduced as an ad-
ditional removable substituent at the 4-position of MOBs
21-23 would retard the dimerization, consequently
increasing the yields of the Diels-Alder adducts.20
The required 4-bromophenols 17-19 were prepared
from phenols 1-3, respectively, by bromination with
NBS/AcOH, using a modified literature procedure.21 The
oxidation of 4-bromophenol 17 in methanol carried out
with DAIB at room temperature reached completion
within 10 min to afford MOB 21 in 94% yield with no
traces of the dimer of MOB 21 (Scheme 2). The oxidation
of 18 in a similar manner furnished a minor product 29
(5%) in addition to MOB 22 in 82% yield. The aromatized
product 29 was presumably derived from dimer 30 via
dehydrobromination, reduction, and loss of methanol.
Upon oxidation of 19 with DAIB in methanol, MOB 23
and its dimer 31 were obtained in 77% and 5% yields,
respectively (Chart 1). Obviously, the introduction of a
bromine atom at the 4-position increased the stability of
the corresponding brominated MOBs, thereby facilitating
their isolation in the pure form and in good yields. We
thus anticipated the increased yields of the Diels-Alder
adducts with these brominated MOBs 21-23.
As indicated in Scheme 2 and Table 2, we have
examined the Diels-Alder reactions of MOBs 21-23
obtained from bromophenols 17-19, respectively, with
MA, MMA, and MVK. The crude MOB 21 obtained from
17 was taken in CH2Cl2, MA was added, and the mixture
was stirred for 10 h at room temperature. The usual
workup followed by column chromatography furnished
CHART 1
the cycloadduct 25a in 72% yield. When the MOB 21 was
generated in situ and subjected to cycloaddition with MA
(10 h) (Method B), the adduct 25a was obtained in 70%
yield. Since the bicyclic derivative 25a was produced in
almost the same yields in these two conditions, it was
planned to generate MOB in situ for latter cycloadditions.
The dienophiles MMA and MVK reacted efficiently with
MOB 21 to provide the Diels-Alder adducts 25b and 25c,
respectively. The reactions of MOB 22 (Method C) with
MA, MMA, and MVK produced the adducts 26a -c in
good to excellent yields. We then carried out the reaction
(21) Mitchell R. H.; Lai, Y. H.; Williams R. V. J . Org. Chem. 1979,
44, 4733.
J . Org. Chem, Vol. 67, No. 18, 2002 6495

Lai et al.
TABLE 2. In ter m olecu la r Diels-Ald er Rea ction s of Ma sk ed 4-Br om o-o-ben zoqu in on es 21-24 w ith MA, MMA, a n d MVK
(d etou r m eth od )
Diels-Alder reaction
overall yields of 13-16a -c
debrominated
productc/Y (%)
entry
phenol
MOB
dienophilea
method/timeb
adduct/Y (%)
direct
detour
1
2
3
4
5
6
7
8
9
17
21
MA
B/10 h
B/48 h
B/5 h
C/17 h
C/22 h
C/17 h
C/36 h
C/60h
C/10 h
D/4 h
25a /70
25b/65
25c/85
26a /75
26b/72
26c/83
27a /72
27b/62
27c/90
28a /94
28b/95
28c/96
13a /95
13b/94
13c/90
14a /96
14b/93
14c/81
15a /85
15b/87
15c/77
16a /86
16b/88
16c/84
40
28
62
86
43
22
35
19
25
86
84
88
65
59
76
66
61
61
60
53
68
81
84
83
MMA
MVK
MA
MMA
MVK
MA
MMA
MVK
MA
MMA
MVK
18
19
20
22
23
24
10
11
12
D/10 h
D/3 h
a
b
1.1 equiv of dienophiles in Method B, 1.5 equiv in Method C, and 2 equiv in Method D were used. Time for which the reaction
mixtures were allowed to stir. c Debrominated products (13a -c to 15a -c (entries 1-9) were obtained from Method E and 16a -c (entries
10-12) were obtained from Method F.
SCHEME 3
SCHEME 4
of MOB 23 with MA, MMA, and MVK (Method C). The
MOB 23 generated in situ from 19 underwent the Diels-
Alder cycloaddition smoothly with MA, MMA, and MVK
to provide bromo-adducts 27a -c in good to high yields.
The 1H NMR (400 MHz) spectra of the crude reaction
mixtures did not show the peaks corresponding to the
minor isomer(s), indicating that the cycloaddition pro-
ceeded in a highly regio- and stereoselective manner.
In the DAIB-mediated oxidation of 19 in the presence
of MA and MMA (but not in the case of MVK) we have
also isolated the compound 33 in 6 and 13% yields,
respectively. The formation of 33 might be explained
through the tandem, one-step addition-elimination of
methanol to 32 as shown in Scheme 3.
In an effort to ascertain whether the bromo-substitu-
tion at the 3-position of MOB 24 has influenced the
cycloaddition, we have synthesized MOB 24 and studied
its Diels-Alder reactivity. The bromination of vanillin
acetate (34) with bromine/water followed by hydrolysis22
and p-TSA-catalyzed ketalization of the resulting alde-
hyde 35 provided the requisite bromophenol 20 in near
quantitative yield (Scheme 4). The oxidation of phenol
20 with DAIB at 0 °C in methanol in the presence of
KHCO3 proceeded efficiently to produce MOB 24 in 92%
yield. The yield of 28a , the adduct of MOB 24 with MA,
was better when 24 was used after isolation and purifica-
tion than that when 24 was generated in situ. The
reactions of MOB 24 with MMA and MVK were also quite
efficient to give the corresponding adducts 28b,c in
excellent yields (Table 2).
ucts 13a -c to 16a -c in high to excellent yields. Thus,
we have achieved the desired cycloadducts via the detour
method in overall yields, in general, 20-40% higher than
those obtained via the direct method in one step (see
Table 2 for comparison of yields). In addition, only 1
molar equiv or a slight excess of dienophile is enough for
the brominated MOBs 21-24 to undergo the Diels-Alder
reactions, whereas a large excess of dienophiles is neces-
sary for MOBs 5-8.
The structures of all the new compounds were estab-
lished by IR, 1H and 13C NMR, DEPT, and low- and high-
resolution mass spectral analyses. For the majority of the
cycloadducts, satisfactory elemental analyses were ob-
tained. For most of the adducts in both low-resolution
and high-resolution mass spectra recorded in electron
impact mode (70 eV), the peaks corresponding to the
molecular ion could not be seen; instead, the peaks
corresponding to M+ - 28 were observed, indicating the
facile extrusion of CO from the molecular ions. The IR
specta of all the cycloadducts showed a strong absorption
at 1733-1741 cm-1, characteristic of the carbonyl group
Then the cycloadducts 25a -c to 28a -c were subjected
to debromination by using either Bu3SnH/AIBN23 or
tributylammonium formate-palladium reagent [Bu3N,
HCO2H/Pd(PPh3)2Cl2]24 to afford the corresponding prod-
(22) Wriede, U.; Fernandez, M.; West, K. F.; Harcourt, D.; Moore,
H. W. J . Org. Chem. 1987, 52, 4485.
(23) Abeywickrema, A. N.; Beckwith, A. L. J .; Gerba, S. J . Org.
Chem. 1987, 52, 4072.
(24) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 42,
4821.
6496 J . Org. Chem., Vol. 67, No. 18, 2002

Synthesis of Bicyclo[2.2.2]octenones from 2-Methoxyphenols
CHART 2
Exp er im en ta l Section
Gen er a l Meth od s. For general experimental details and
instrumentation, see our earlier publication.18
Gen er a l P r oced u r es for Diels-Ald er R ea ct ion s of
MOBs: Meth od A. To a suspension of DAIB (1.8 mM, 1.2
equiv) and a dienophile (25 equiv) in methanol (2 mL) was
added a solution of phenol (1-3, 1.5 mM, 1 equiv) in methanol
(6 mL) over a period of time at either room temperature (only
for the reaction of 1 with MVK) or under reflux in nitrogen
atmosphere. Stirring was continued for an additional hour
under reflux (see Table 1). After the reaction was complete,
the reaction mixture was cooled to room temperature and
concentrated under reduced pressure, and the residue was
purified by silica gel column chromatography with EtOAc/
hexanes as eluent to furnish the pure cycloadduct (13a -c to
15a -c).
Meth od B. To a suspension of DAIB (1.1 mM, 1.1 equiv)
and a dienophile (2 equiv) in methanol (5 mL) was added in
one portion a solution of phenol 17 (1 mM, 1 equiv) in methanol
(5 mL) at room temperature under nitrogen atmosphere.
Stirring was continued for a further period of time (see Table
2). Then the reaction mixture was worked up and the residue
was purified as described in Method A to afford the adduct
(25a -c).
Meth od C. To a suspension of DAIB (1 mM, 1.1 equiv) and
KHCO3 (2.5 mM, 2.5 equiv) in methanol (5 mL) was added in
one portion a solution of phenol (18 or 19, 1 mM, 1 equiv) in
methanol (5 mL) at 0 °C under nitrogen atmosphere. After
the mixture was stirred for 5 min, dienophile (1.5 mM, 1.5
equiv) was added in one portion and the reaction mixture was
allowed to warm to room temperature. After the solution was
stirred for a period of time (Table 2), the volatiles were
removed under reduced pressure. The residue was dissolved
in CH2Cl2 (10 mL), washed with water followed by brine, and
dried over anhydrous MgSO4. Removal of the solvent followed
by silica gel column chromatography yielded the pure cyclo-
adduct (26a -c and 27a -c).
Meth od D. To MOB 24 (1 mM, 1 equiv) in CH2Cl2 (1 mL)
was added a dienophile (1.1 mM, 1.1 equiv) in one portion at
room temperature under nitrogen atmosphere. After the
mixture was stirred for a period of time (see Table 2), the
volatiles were removed under reduced pressure and the residue
was recrystallized to give the pure product (28a -c).
Gen er a l P r oced u r e for th e Debr om in a tion of Cyclo-
a d d u cts: Meth od E.23 A mixture of bromo compound (25a -c
to 27a -c, 0.5 mM), AIBN (0.02 mM), and Bu3SnH (0.74 mM)
in dry benzene (5 mL) was heated under reflux for 3 h under
nitrogen atmosphere. Then additional amounts of AIBN (0.014
mM) and Bu3SnH (0.37 mM) were added and the heating was
continued for another 3 h at the same temperature. The
reaction contents were cooled to room temperature, silica gel
(1 g, 70-230 mesh) was added, and stirring was continued
for an additional 2 h at the same temperature. The reaction
mixture was then filtered and the filtrate was concentrated
under reduced pressure. The residue was subjected to silica
gel column chromatography (EtOAc/hexanes) to furnish the
pure product (13a -c to 15a -c).
adjacent to the R,R-dimethoxyl groups in the function-
alized bicyclo[2.2.2]octenone skeletons.18,25
The regio- and stereochemistries of the adducts 13a -c
to 16a -c which are in line with the literature prece-
dents6e,18,25,26 were thoroughly determined by 1H-1H
decoupling experiments. The coupling patterns of Ha-
Hg (J ) 1.4-2.0 Hz) and Hd-He or Hd-Hf (J ) 2.4-3.6
Hz) are in agreement with the assigned regiochemistry
(see Chart 2). The chemical shifts of the bridgehead
protons Ha and Hd were observed between δ 3.21-3.75
and δ 3.01-3.44, respectively. The methylenic protons
He and Hf were observed at δ 2.14-2.92 and δ 1.50-1.94,
respectively. The observed long-range W-type coupling
between Hb and Hg and/or Hc and He supports the endo
stereochemistry. The coupling constants between He-Hg
(J ) 9.6-10.3 Hz) and Hf-Hg (J ) 5.7-6.8 Hz) clearly
show the cis relationship of protons He and Hg, which
further confirm the assigned stereochemistry.
The structural assignments of 25a -c to 28a -c were
based on the spectroscopic methods and the chemical
transformation into the corresponding debrominated
products 13a -c to 16a -c. The chemical shifts and the
coupling patterns in the 1H NMR spectra of 25a -c to
28a -c are analogous to those observed in case of 13a -c
to 16a -c respectively. The ortho regiochemistry and endo
stereochemistry of the cycloadduct 26b were further
confirmed from the single-crystal X-ray diffraction
method.27
Con clu sion
In summary, we have developed a new and useful
strategy to synthesize the hitherto unknown derivatives
of bicyclo[2.2.2]octenones. The MOBs 5-7 and 21-24
generated from 2-methoxyphenols 1-3 and 17-20, re-
spectively, underwent highly regio- and stereoselective
intermolecular Diels-Alder reactions with electron-
deficient dienophiles to furnish exclusively ortho,endo
adducts 13a -c to 15a -c and 25a -c to 28a -c. The
introduction of a bromine atom at the 4-position of the
2-methoxyphenols allowed us to isolate and characterize
the resultant MOBs. Furthermore, the reduced propen-
sity of these bromo-substituted MOBs to dimerize made
it possible to use stoichiometric amounts or a slight
excess of dienophiles. These vinly bromides 25a -c to
28a -c may be considered to act as valuable handles for
the olefin synthesis by organometallic coupling reactions.
Standard debromination of cycloadducts 25a -c to 27a -c
afforded bicyclo[2.2.2]octenones 13a -c to 15a -c in over-
all 20-40% higher yields via the detour method than
those obtained via the direct method. The present
protocol has already been utilized as a key step in the
total synthesis of a cis-clerodane diterpenic acid.28
Meth od F .24 To the bromo compound (28a -c, 0.65 mM)
were added successively Bu3N (1.95 mM), HCO2H (1.3 mM),
and Pd(PPh3)2Cl2 (0.02 mM) in dry DMF (0.6 mL) under
nitrogen atmosphere and the contents were heated at 60-80
°C for 8 h. The reaction mixture was cooled to room temper-
ature and diluted with EtOAc and worked up as usual. The
residue was subjected to silica gel column chromatography
(EtOAc/hexanes) to afford pure product (16a -c).
2-Meth oxy-6-m eth ylp h en ol (2).29 A mixture of 2-hydroxy-
3-methoxybenzaldehyde (o-vanillin, 22.88 g, 150.42 mM) and
10% Pd/C (2 g) in EtOAc (225 mL) was taken in a 500-mL
(25) Gao, S.-Y.; Ko, S.; Lin, Y.-L.; Peddinti, R. K.; Liao, C.-C.
Tetrahedron 2001, 57, 297.
(26) Katayama, S.; Hiramatsu, S.; Aoe, K.; Yamauchi, M. J . Chem.
Soc., Perkin Trans. 1 1997, 561.
(27) CCDC No. 168593.
(28) Liu, W.-C.; Liao, C.-C. Synlett 1998, 912.
(29) Hwu, R. H.; Wong, F. F.; Huang, J .-J .; Tsay, S.-C. J . Org. Chem.
1997, 62, 4097.
J . Org. Chem, Vol. 67, No. 18, 2002 6497

Lai et al.
flask and subjected to hydrogenation at 40 psi at room
temperature. After 5 h, the reaction mixture was filtered
through Celite and the filtrate was evaporated. The residue
was distilled under vacuum (50 °C, 0.05 mm) to give 2 (19.72
g, 95% yield) as a light yellow solid. Mp 41-42 °C (from
and the residue was purified by column chromatography
(EtOAc/hexanes) to afford dimer 11 as a colorless solid (see
Table 1 for yields). Mp 211-214 °C (from EtOAc-hexanes);
1
IR (neat) 1735, 1695, 1637 cm-1; H NMR (400 MHz, CDCl3)
δ 1.65 (d, J ) 1.6 Hz, 3H), 1.97 (d, J ) 1.6 Hz, 3H), 3.01 (dd,
J ) 6.8, 1.6 Hz, 1H), 3.05 (s, 3H), 3.15-3.23 (m, 3H), 3.24 (s,
3H), 3.39 (s, 3H), 3.44 (s, 3H), 5.83 (ddq, J ) 6.8, 1.6, 1.6 Hz,
1H), 5.92 (dq, J ) 1.6, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 21.4, 22.1, 38.6, 39.7, 43.2, 48.8, 49.4, 50.0, 50.6, 57.7, 94.8,
98.6, 124.7, 126.4, 137.4, 155.9, 193.0, 202.3; MS (EI, 70 eV)
m/z (rel intensity) 308 (M+ - CO, 93), 261 (20), 248 (39), 201
(82), 159 (53), 115 (41), 105 (100), 91 (60), 75 (49), 59 (71);
HRMS (EI) calcd for C17H24O5 (M+ - CO) 308.1624, found
308.1620. Anal. Calcd for C18H24O6: C, 64.27; H, 7.19. Found:
C, 64.14; H, 7.23.
hexanes, lit.29 mp 40-41 °C); IR (film) 3426, 2949, 1271 cm-1
;
1H NMR (400 MHz, CDCl3) δ 2.26 (s, 3H), 3.88 (s, 3H), 5.68
(br s, 1H), 6.70-6.78 (m, 3H); 13C NMR (100 MHz, CDCl3)
δ 15.3, 55.9, 108.2, 119.1, 123.12, 123.9, 143.7, 146.2; MS
(EI, 70 eV) m/z (rel intensity) 138 (M+, 78), 123 (100), 95
(29), 77 (61), 67 (51), 65 (47), 63 (14), 55 (41), 53 (30), 51 (61);
HRMS (EI) calcd for C8H10O2 (M+) 138.0680, found 138.0689.
Anal. Calcd for C8H10O2: C, 69.55; H, 7.30. Found: C, 69.54;
H, 7.32.
2-Meth oxy-5-m eth ylp h en ol (3).30 Following the above
procedure with 3-hydroxy-4-methoxybenzaldehyde (isovanillin,
20.42 g, 134.22 mM), the crude product was recrystallized to
provide 3 (16.67 g, 90% yield) as a colorless solid. Mp 33-34
Meth yl (1S*,2S*,4S*)-8,8-Dim eth oxy-7-oxobicyclo[2.2.2]-
oct-5-en e-2-ca r boxyla te (13a ). Following the general pro-
cedure (Method A), MOB 5 generated in situ from phenol 1
was reacted with MA and the crude residue was subjected to
column chromatography (EtOAc/hexanes 1:3) to give 13a (40%
1
°C (from hexanes); IR (film) 3507, 2937, 1275 cm-1; H NMR
(400 MHz, CDCl3) δ 2.26 (s, 3H), 3.86 (s, 3H), 5.55 (br, 1H),
6.63-6.75 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 20.7, 56.0,
110.6, 115.4, 120.2, 131.1, 144.5, 145.4; MS (EI, 70 eV) m/z
(rel intensity) 138 (M+, 85), 123 (100), 95 (27), 77 (16), 55 (15);
HRMS (EI) calcd for C8H10O2 (M+) 138.0680, found 138.0689.
Anal. Calcd for C8H10O2: C, 69.55; H, 7.30. Found: C, 69.45;
H, 7.32.
yield) as a colorless liquid. IR (film) 1739, 1635, 1200 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.75 (ddd, J ) 13.2, 5.7, 3.2 Hz,
1H), 2.24 (ddd, J ) 13.2, 10.2, 2.8 Hz, 1H), 3.01 (ddd, J ) 10.2,
5.7, 1.8 Hz, 1H), 3.11-3.15 (m, 1H), 3.30 (s, 3H), 3.31 (s, 3H),
3.49 (ddd, J ) 6.5, 1.8, 1.6 Hz, 1H), 3.65 (s, 3H), 6.10 (ddd, J
) 7.9, 6.5, 1.0 Hz, 1H), 6.44 (ddd, J ) 7.9, 6.8, 1.4 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 24.3, 38.4, 38.7, 49.8, 49.9, 50.2,
52.2, 93.8, 125.7, 135.3, 173.3, 200.9; MS (EI, 70 eV) m/z (rel
intensity) 212 (100, M+ - CO), 181 (74), 165 (41), 153 (62),
151 (23), 105 (19), 79 (37), 77 (49); HRMS (EI) calcd for
(1R *,2R *,7R *,8S *)-3,3,10,10-Te t r a m e t h oxyt r icyclo-
[6.2.2.02,7]d od eca -5,11-d ien e-4,9-d ion e (9).31 Following the
general procedure (Method A), MOB 5 was generated in situ
from phenol 1 to react with MA, MMA, or MVK and the
residue was purified by column chromatography (EtOAc/
hexanes) to furnish dimer 9 as a colorless solid (see Table 1
for yields). Mp 187-190 °C (from EtOAc-hexanes); IR (film)
C
12H16O5 (M+) 240.0998, found 240.0963.
Meth yl (1S*,2S*,4S*)-2-Meth yl-8,8-d im eth oxy-7-oxobi-
cyclo[2.2.2]oct-5-en e-2-ca r boxyla te (13b). Following the
general procedure (Method A), MOB 5 generated in situ from
phenol 1 was reacted with MMA and the residue was purified
by column chromatography (EtOAc/hexanes 1:2) to provide
13b (28% yield) as a colorless solid. Mp 112.5-113.2 °C (from
1
1735, 1690, 1621 cm-1; H NMR (400 MHz, CDCl3) δ 3.06 (s,
3H), 3.12 (ddd, J ) 6.6, 1.6, 1.6 Hz, 1H), 3.21 (m, 1H), 3.22 (s,
3H), 3.29 (dd, J ) 8.0, 1.6 Hz, 1H), 3.37 (m, 1H), 3.39 (s, 3H),
3.43 (s, 3H), 5.90 (ddd, J ) 8.0, 6.6, 1.6 Hz, 1H), 6.03 (dd, J )
10.1, 1.8 Hz, 1H), 6.25 (ddd, J ) 8.0, 6.6, 1.4 Hz, 1H), 6.41
(dd, J ) 10.1, 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 38.8,
39.1, 40.1, 48.7, 49.6, 49.9, 50.4, 52.5, 94.7, 98.4, 128.5, 128.8,
132.1, 146.3, 193.6, 202.0; MS (EI, 70 eV) m/z (rel intensity)
280 (M+ - CO, 100), 205 (71), 189 (54), 173 (38), 115 (40), 111
(46), 77 (51), 75 (33), 59 (70); HRMS (EI) calcd for C16H20O6
(M+) 308.1260, found 308.1265.
EtOAc-hexanes); IR (film) 1737, 1637 cm-1 1H NMR (400
;
MHz, CDCl3) δ 1.25 (s, 3H), 1.77 (dd, J ) 14.0, 2.4 Hz, 1H),
2.24 (dd, J ) 14.0, 3.6 Hz, 1H), 3.01-3.05 (m, 1H), 3.25 (s,
3H), 3.29 (s, 3H), 3.28-3.31 (m, 1H), 3.61 (s, 3H), 6.10 (ddd, J
) 7.9, 6.4, 1.6 Hz, 1H), 6.33 (ddd, J ) 7.9, 6.6, 1.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 25.5, 31.7, 38.5, 46.4, 49.5, 50.2,
52.4, 56.4, 94.1, 127.9, 134.6, 176.2, 202.3; MS (EI, 70 eV) m/z
(rel intensity) 226 (M+ - CO, 100), 195 (15), 179 (31), 167 (51),
151 (38), 135 (49), 107 (20), 93 (45), 77 (43); HRMS (EI) calcd
for C13H18O5 (M+) 254.1154, found 254.1148. Anal. Calcd for
(1R*,2R*,7R*,8S*)-5,8-Dim et h yl-3,3,10,10-t et r a m et h -
oxytr icyclo[6.2.2.02,7]d od eca -5,11-d ien e-4,9-d ion e (10).31
Following the general procedure (Method A), MOB 6 generated
in situ from phenol 2 was reacted with MA, MMA, or MVK.
The residue was purified by column chromatography (EtOAc/
hexanes) and dimer 10 was isolated as a colorless solid. Mp
155-156 °C (from EtOAc-hexanes, lit.31 mp 152-155 °C); IR
C
13H18O5: C, 61.41; H, 7.14. Found: C, 61.52; H, 7.51.
(1S*,4S*,7S*)-7-Acetyl-3,3-d im eth oxybicyclo[2.2.2]oct-
5-en e-2-on e (13c). Following the general procedure (Method
A), MOB 5 generated in situ from phenol 1 was reacted with
MVK and the residue was subjected to column chromatogra-
phy (EtOAc/hexanes 1:10) to furnish 13c (62% yield) as a
colorless liquid. IR (film) 1741, 1711, 1616 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.68 (ddd, J ) 12.8, 6.4, 2.8 Hz, 1H), 2.14 (s,
3H), 2.17 (m, 1H), 3.05 (ddd, J ) 9.6, 6.4, 1.4 Hz, 1H), 3.13-
3.16 (m, 1H), 3.30 (s, 3H), 3.32 (s, 3H), 3.44 (ddd, J ) 6.4, 1.4,
1.2 Hz, 1H), 6.07 (ddd, J ) 7.3, 6.4, 0.8 Hz, 1H), 6.38 (ddd, J
) 7.4, 7.3, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 23.2,
28.2, 38.4, 46.6, 49.4, 49.7, 50.2, 93.9, 125.5, 134.7, 201.1, 205.7;
MS (EI, 70 eV) m/z (rel intensity) 196 (M+ - CO, 94), 165 (24),
153 (88), 151 (20), 121 (60), 79 (54), 77 (68), 75 (49), 43 (100);
HRMS (EI) calcd for C12H16O4 (M+) 224.1049, found 224.1050.
Meth yl (1S*,2S*,4S*)-8,8-Dim eth oxy-1-m eth yl-7-oxobi-
cyclo[2.2.2]oct-5-en e-2-ca r boxyla te (14a ). Following the
general procedure (Method A), MOB 6 generated in situ from
phenol 2 was reacted with MA and the residue was purified
by column chromatography (EtOAc/hexanes 2:7) to afford 14a
(86% yield) as a colorless liquid. IR (film) 1738, 1715 cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.24 (s, 3H), 1.67 (ddd, J ) 12.8,
6.4, 2.8 Hz, 1H), 2.33 (ddd, J ) 12.8, 9.8, 3.0 Hz, 1H), 2.76
(ddd, J ) 9.4, 6.4, 1.1 Hz, 1H), 3.14-3.18 (m, 1H), 3.33 (s, 3H),
(film) 1733, 1694, 1626 cm-1 1H NMR (400 MHz, CDCl3) δ
;
1.33 (s, 3H), 1.85 (s, 3H), 2.91 (ddd, J ) 8, 4.2, 1.6 Hz, 1H),
3.04 (s, 3H), 3.09 (ddd, J ) 6.8, 1.6, 1.2 Hz, 1H,), 3.22 (s, 3H),
3.27 (dd, J ) 8.0, 1.3 Hz, 1H), 3.39 (s, 3H), 3.46 (s, 3H), 5.54
(dd, J ) 8.0, 1.2 Hz, 1H), 6.20 (dd, J ) 8, 6.8 Hz, 1H), 6.27
(dd, J ) 4.2, 1.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 15.6,
16.1, 39.4, 39.9, 43.1, 48.8, 49.5, 50.3, 50.4, 52.2, 94.7, 98.7,
131.4, 133.9, 137.12, 139.0, 195.1, 204.1; MS (EI, 70 eV) m/z
(rel intensity) 308 (M+ - CO, 100), 293 (11), 261 (24), 233 (22),
201 (19), 171 (25), 159 (20), 105 (73), 91 (16), 59 (12); HRMS
(EI) calcd for C17H24O5 (M+ - CO) 308.1624, found 308.1626.
Anal. Calcd for C18H24O6: C, 64.27; H, 7.19. Found: C, 64.29;
H, 7.28.
(1S*,2R*,7S*,8R*)-6,12-Dim et h yl-3,3,10,10-t et r a m et h -
oxytr icyclo[6.2.2.02,7]dodeca-5,11-dien e-4,9-dion e (11). Fol-
lowing the general procedure (Method A), MOB 7 generated
in situ from phenol 3 was reacted with MA, MMA, or MVK
(30) Bunnett, J . F.; J envey, J . J . Org. Chem. 1996, 61, 8069.
(31) Andersson, G.; Berntsson, P. Acta Chem. Scand. B 1975, 29,
948.
6498 J . Org. Chem., Vol. 67, No. 18, 2002

Synthesis of Bicyclo[2.2.2]octenones from 2-Methoxyphenols
3.34 (s, 3H), 3.67 (s, 3H), 5.80 (ddd, J ) 8.0, 1.2, 1.1 Hz, 1H),
6.48 (dd, J ) 8.0, 7.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
15.2, 28.0, 38.3, 43.6, 49.9, 50.1, 50.7, 51.7, 93.7, 130.8, 134.1,
173.9, 201.1; MS (EI, 70 eV) m/z (rel intensity) 226 (M+ - CO,
100), 211 (25), 195 (26), 179 (26), 167 (35), 151 (25), 135 (35),
(1R*,4S*,7S*)-7-Acetyl-3,3-d im eth oxy-6-m eth ylbicyclo-
[2.2.2]oct-5-en e-2-on e (15c). Following the general procedure
(Method A), MOB 7 generated in situ from phenol 3 was
reacted with MVK and the residue was subjected to column
chromatography (EtOAc/hexanes 1:3) to give 15c (25% yield)
as a colorless liquid. IR (film) 1736, 1715 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.61 (ddd, J ) 12.7, 10.3, 3.0 Hz, 1H), 1.86 (d,
J ) 1.6 Hz, 3H), 2.17 (s, 3H), 2.25 (ddd, J ) 12.7, 10.3, 3.0 Hz,
1H), 3.05 (ddd, J ) 6.7, 3.0, 3.0 Hz, 1H), 3.09 (ddd, J ) 10.3,
6.7, 1.7 Hz, 1H), 3.11 (d, J ) 1.6 Hz, 1H), 3.33 (s, 3H), 3.34 (s,
3H), 6.01 (ddq, J ) 6.7, 1.7, 1.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.8, 24.5, 28.2, 38.0, 46.4, 50.0, 50.0, 54.6, 94.2,
127.1, 135.4, 100.9, 206.1; MS (EI, 70 eV) m/z (rel intensity)
210 (M+ - CO, 52), 163 (72), 135 (75), 119 (25), 91 (65), 75
(82), 43 (100); HRMS (EI) calcd for C12H18O3 (M+ - CO)
210.1256, found 210.1248.
91 (39), 77 (19), 59 (27); HRMS (EI) calcd for C12H18O4 (M+
CO) 226.1205, found 226.1199.
-
Met h yl (1S*,2S*,4S*)-8,8-Dim et h oxy-1,2-d im et h yl-7-
oxobicyclo[2.2.2]oct-5-en e-2-ca r boxyla te (14b). Following
the general procedure (Method A), MOB 6 generated in situ
from phenol 2 was reacted with MMA and the residue was
purified by column chromatography (EtOAc/hexanes 2:7) to
give 14b (43% yield) as a colorless liquid. IR (film) 1738, 1721
cm-1; 1H NMR (400 MHz, CDCl3) δ 1.91 (s, 6H), 1.93 (dd, J )
13.4, 2.7 Hz, 1H), 2.18 (dd, J ) 13.4, 3.3 Hz, 1H), 3.10
(apparent m, dddd, J ) 6.8, 3.3, 2.7, 1.7 Hz, 1H), 3.32 (s, 3H),
3.36 (s, 3H), 3.66 (s, 3H), 5.83 (dd, J ) 8.1, 1.7 Hz, 1H), 6.48
(dd, J ) 8.1, 1.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.4,
21.7, 36.0, 38.4, 48.0, 49.6, 49.9, 51.9, 55.5, 94.0, 133.0, 133.5,
175.6, 202.4; MS (EI, 70 eV) m/z (rel intensity) 240 (M+ - CO,
100), 225 (22), 193 (26), 181 (58), 165 (37), 149 (39), 107 (16),
4-Br om o-2-m eth oxy-6-m eth ylp h en ol (18).32 To 2-meth-
oxy-6-methylphenol (2.77 g, 20.0 mM) in acetic acid (40 mL)
was added N-bromosuccinamide (3.56 g, 20.0 mM) in acetic
acid (93 mL) slowly and the reaction mixture was stirred at
room temperature for 4 h. Solvent was removed under vacuum
and the residue was treated with water (140 mL) and NaHCO3
(140 g) and extracted with CH2Cl2 (3 × 150 mL). The combined
organic layer was dried over MgSO4 and concentrated. The
residue was chromatographed (EtOAc/hexanes 1:3) to provide
18 (3.94 g, 91% yield) as a colorless liquid. IR (film) 3496, 1275,
1089 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.20 (s, 3H), 3.85 (s,
3H), 5.58 (br, 1H), 6.81 (d, J ) 1.8 Hz, 1H), 6.87 (d, J ) 1.8
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 15.2, 56.2, 110.7, 111.6,
125.5, 125.7, 142.8, 146.7; MS (70 eV) m/z (rel intensity) 218
(M+ + 2, 99), 216 (M+, 100), 203 (35), 201 (36), 94 (39), 77
(11), 66 (27); HRMS (EI) calcd for C8H9O2Br 215.9785, found
215.9785.
91 (20), 75 (14), 59 (8); HRMS (EI) calcd for C13H20O4 (M+
CO) 240.1362, found 240.1367.
-
(1S*,4S*,7S*)-7-Acetyl-3,3-d im eth oxy-1-m eth ylbicyclo-
[2.2.2]oct-5-en e-2-on e (14c). Following the general procedure
(Method A), MOB 6 generated in situ from phenol 2 was
reacted with MVK and the residue was subjected to column
chromatography (EtOAc/hexanes 1:3) to provide 14c (22%
yield) as a colorless solid. Mp 99-100 °C (from EtOAc-
hexanes); IR (film) 1738, 1713 cm-1
;
1H NMR (400 MHz,
CDCl3) δ 1.26 (s, 3H), 1.50 (ddd, J ) 12.8, 6.9, 2.8 Hz, 1H),
2.14 (s, 3H), 2.34 (ddd, J ) 12.8, 9.8, 3.0 Hz, 1H), 2.90 (dd, J
) 9.8, 6.9 Hz, 1H), 3.10 (apparent m, dddd, J ) 6.8, 3.0, 2.8,
1.3 Hz, 1H), 3.33 (s, 3H), 3.35 (s, 3H), 5.86 (dd, J ) 8.0, 1.3
Hz, 1H), 6.43 (dd, J ) 8.0, 6.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 15.1, 27.7, 38.4, 49.9, 50.1, 50.5, 50.7, 93.8, 131.3,
133.3, 201.3, 207.7; MS (EI, 70 eV) m/z (rel intensity) 210 (M+
- CO, 47), 167 (100), 135 (24), 121 (11), 91 (37), 75 (66), 65
(12), 43 (90); HRMS (EI) calcd for C12H18O3 (M+ - CO)
210.1256, found 210.1260. Anal. Calcd for C13H18O4: C, 65.51;
H, 7.62. Found: C, 65.48; H, 7.60.
Meth yl (1R*,2S*,4S*)-8,8-Dim eth oxy-6-m eth yl-7-oxobi-
cyclo[2.2.2]oct-5-en e-2-ca r boxyla te (15a ). Following the
general procedure (Method A), MOB 7 generated in situ from
phenol 3 was reacted with MA and the residue was purified
by column chromatography (EtOAc/hexanes 1:4) to afford 15a
(35% yield) as a colorless liquid. IR (film) 1738, 1716 cm-1; 1H
NMR (400 MHz, CDCl3) δ 1.72 (ddd, J ) 13.0, 5.9, 2.9 Hz,
1H), 1.85 (d, J ) 1.6 Hz, 3H), 2.28 (ddd, J ) 13.0, 10.1, 2.9
Hz, 1H), 3.02-3.06 (m, 2H), 3.32-3.33 (m, 7H), 3.69 (s, 3H),
6.07 (ddq, J ) 6.7, 1.7, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 20.7, 25.3, 37.9, 38.4, 49.86, 50.0, 52.0, 55.1, 94.0, 127.5,
135.4, 173.5, 200.6; MS (EI, 70 eV) m/z (rel intensity) 226 (M+
- CO, 100), 195 (16), 179 (90), 151 (18), 135 (23), 107 (14), 91
(31), 77 (15), 59 (14); HRMS (EI) calcd for C12H18O4 (M+ - CO)
226.1205, found 226.1197.
Met h yl (1S*,2S*,4S*)-8,8-Dim et h oxy-2,6-d im et h yl-7-
oxobicyclo[2.2.2]oct-5-en e-2-ca r boxyla te (15b). Following
the general procedure (Method A), MOB 7 generated in situ
from phenol 3 was reacted with MMA and the residue was
purified by column chromatography (EtOAc/hexanes 1:3) to
furnish 15b (19% yield) as a colorless liquid. IR (film) 1733,
1722 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.32 (s, 3H), 1.80 (d,
J ) 1.6 Hz, 3H), 1.85 (dd, J ) 13.7, 2.5 Hz, 1H), 2.92 (dd, J )
13.7, 3.6 Hz, 1H), 2.99 (ddd, J ) 6.6, 3.6. 2.5 Hz, 1H), 3.21 (d,
J ) 1.6 Hz, 1H), 3.15 (s, 3H), 3.34 (s, 3H), 3.68 (s, 3H), 6.00
(ddq, J ) 6.6, 1.6, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
20.4, 25.5, 32.4, 38.3, 46.0, 49.6, 49.9, 52.2, 61.9, 94.3, 127.3,
137.2, 176.3, 201.9; MS (EI, 70 eV) m/z (rel intensity) 240
(M+ - CO, 79), 193 (100), 165 (41), 149 (37), 133 (24), 121 (28),
105 (43), 91 (56), 59 (39), 43 (39); HRMS (EI) calcd for C13H20O4
(M+ - CO) 240.1362, found 240.1368.
4-Br om o-2-m eth oxy-5-m eth ylp h en ol (19).33 Following
the above procedure (for 18), 2-methoxy-5-methylphenol (2.283
g, 20.0 mM) was reacted with NBS (3.56 g, 20.0 mM) and the
crude product was purified by column chromatography (EtOAc/
hexanes 1:3) to afford 19 (4.35 g, 98% yield) as colorless
needles. Mp 70-71 °C (from hexanes, lit.33 mp 70 °C); IR (film)
1
3394, 1253, 1029 cm-1; H NMR (400 MHz, CDCl3) δ 2.27 (s,
3H), 3.83 (s, 3H), 5.49 (br, 1H), 6.79 (s, 1H), 6.97 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 22.1, 56.1, 113.4, 114.6, 116.5, 130.4,
144.7, 145.1; MS (70 eV) m/z (rel intensity) 218 (M+ + 2, 44),
216 (M+, 43), 203 (12), 201 (11), 137 (8), 94 (29), 89 (100), 61
(28); HRMS (EI) calcd for C8H9O279Br (M+) 215.9785, found
215.9794. Calcd for C8H9O281Br 217.9766, found 217.9766.
5-Br om o-4-(1,3-d ioxola n -2-yl)-2-m et h oxyp h en ol (20).
To bromo compound 36 (1.52 g, 10 mM) and p-toluenesulfonic
acid (19 mg, 0.1 mM) in benzene (15 mL) was added ethylene
glycol (1.24 g, 20 mM) and the reaction mixture was heated
under reflux for 10 h in a Dean-Stark apparatus. The contents
were cooled to room temperature and concentrated and the
residue was chromatographed (EtOAc/hexanes 1:2) to furnish
20 (1.91 g, 97% yield) as a colorless solid. Mp 97-98 °C
1
(EtOAc-hexanes); IR (film) 3345, 1662, 1510, 1085 cm-1; H
NMR (300 MHz, CDCl3) δ 3.91 (s, 3H), 4.05-4.20 (m, 4H), 5.71
(s, 1H), 5.98 (s, 1H), 7.11 (s, 1H), 7.12 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 56.0, 65.2, 102.6, 109.7, 113.8, 118.6, 127.5,
146.0, 147.0; MS (70 eV) m/z (rel intensity) 276 (M+ + 2, 50),
274 (M+, 50), 231 (80), 229 (75), 215 (25), 202 (25), 189 (20),
135 (30), 73 (100); HRMS (EI) calcd for C10H11O479Br (M+)
273.9840, found 273.9857; HRMS (EI) calcd for C10H11O481Br
275.9834, found 275.9820.
4-Br om o-6,6-d im eth oxy-2,4-cycloh exa d ien -1-on e (21).
To a solution of DAIB (384.9 mg, 1.10 mM) in methanol (5
mL) was added a solution of phenol 17 (206.2 mg, 1.02 mmol)
in methanol (5 mL) at room temperature under nitrogen
(32) (a) Daukshas, V. K.; Martinkus, R. S.; Kuleshyus, V. A.;
Shtel’bene, V. P. J . Org. Chem. USSR (Engl. Transl.) 1983, 19, 458.
(b) Daukshas, V. K.; Martinkus, R. S.; Kuleshyus, V. A.; Shtel’bene,
V. P. Zh. Org. Khim. 1983, 19, 522.
(33) Chan, H. T. J .; Elix, J . A. Aust. J . Chem. 1973, 26, 1069.
J . Org. Chem, Vol. 67, No. 18, 2002 6499

Lai et al.
atmosphere and the reaction mixture was stirred for 10 min.
The solvent was then removed and the residue was purified
(EtOAc/hexanes 1:5) to give MOB 21 (223.3 mg, 94% yield) as
a greenish yellow oil. IR (film) 1690, 1628, 1257 cm-1; 1H NMR
(400 MHz, CDCl3) δ 3.35 (s, 6H), 5.94 (dd, J ) 10.2, 0.8 Hz,
1H), 6.65 (dd, J ) 2.4, 0.8 Hz, 1H), 6.85 (dd, J ) 10.2, 2.4 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 50.2, 92.9, 119.4, 126.6,
135.3, 143.1, 192.8; MS (EI, 70 eV) m/z (rel intensity) 234 (M+
+ 2, 22), 232 (M+, 36), 162 (67), 160 (62), 153 (28), 120 (60),
119 (73), 118 (100), 117 (91), 116 (69), 115 (61), 114 (55); HRMS
(EI) calcd for C8H9O379Br (M+) 231.9735, found 231.9728;
HRMS (EI) calcd for C8H9O381Br 233.9715, found 233.9727.
4-Br om o-6,6-d im eth oxy-2-m eth yl-2,4-cycloh exa d ien -1-
on e (22). To a suspension of DAIB (709.2 mg, 2.2 mM) and
KHCO3 (512.5 mg, 5.12 mM) in methanol (10 mL) was added
slowly a solution of phenol 18 (436.5 mg, 2.0 mM) in methanol
(5 mL) in one portion at 0 °C under nitrogen atmosphere. After
5 min stirring, the reaction mixture was quenched with brine
(10 mL). Then water (10 mL) was added and extracted with
CH2Cl2. The organic layer was dried over anhydrous MgSO4
and concentrated. The residue was purified by column chro-
matography (EtOAc/hexanes 1:4) to furnish MOB 22 (405.5
purified by column chromatography (EtOAc/hexanes 1:10) to
give 25a (70% yield) as a colorless solid. Mp 83.3-83.6 °C (from
CH2Cl2-hexanes); IR (film) 1763, 1710, 1610, 1222, 1056 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.93 (ddd, J ) 13.4, 6.0, 2.8 Hz,
1H), 2.26 (ddd, J ) 13.1, 10.1, 3.1 Hz, 1H), 2.96 (ddd, J ) 10.1,
6.0, 2.0 Hz, 1H), 3.25-3.28 (m, 1H), 3.27 (s, 3H), 3.32 (s, 3H),
3.47 (dd, J ) 6.8, 2.0 Hz, 1H), 3.63 (s, 3H), 6.22 (dd, J ) 6.8,
2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 24.9, 38.7, 49.0,
50.0, 50.7, 51.9, 52.3, 93.6, 124.8, 125.0, 172.5, 198.7; MS (EI,
70 eV) m/z (rel intensity) 292 (63), 290 (M+ - CO, 64), 233
(25), 231 (28), 211 (38), 151 (19), 77 (32), 59 (100); HRMS (EI)
calcd for C11H15O479Br (M+ - CO) 290.0154, found 290.0141.
Anal. Calcd for C12H15O5Br: C, 45.16; H, 4.74. Found: C, 45.07;
H, 4.74.
Meth yl (1S*,2S*,4R*)-5-Br om o-8,8-d im eth oxy-2-m eth -
yl-7-oxobicyclo[2.2.2]oct-5-en e-2-ca r boxyla te (25b). Fol-
lowing the general procedure (Method B), MOB 21 generated
in situ from phenol 17 was reacted with MMA and the crude
product was purified by column chromatography (EtOAc/
hexanes 1:10) to give 25b (65% yield) as a colorless liquid. IR
(film) 1737, 1706, 1606, 1290, 1051 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.24 (s, 3H), 1.84 (dd, J ) 14.0, 2.4 Hz, 1H), 2.45
(dd, J ) 14.0, 3.6 Hz, 1H), 3.20 (ddd, J ) 3.6, 2.8, 2.4 Hz, 1H),
3.30 (s, 3H), 3.32 (d, J ) 6.8 Hz, 1H), 3.33 (s, 3H), 3.64 (s,
3H), 6.25 (dd, J ) 6.8, 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 25.1, 32.0, 46.4, 49.2, 49.7, 50.7, 52.6, 58.3, 93.8, 124.9, 126.9,
175.6, 200.0; MS (EI, 70 eV) m/z (rel intensity) 306 (85), 304
(M+ - CO, 87), 275 (11), 273 (11), 247 (40), 245 (43), 225 (43),
91 (70), 59 (100); HRMS (EI) calcd for C12H17O479Br (M+ - CO)
304.0310, found 304.0297.
mg, 82% yield) as a yellow oil. IR (film) 1685, 1634, 1244 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.89 (d, J ) 1.6 Hz, 3H), 3.34
(s, 6H), 6.54 (d, J ) 1.6 Hz, 1H), 6.66 (td, J ) 1.6, 1.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 14.7, 50.3, 93.2, 119.9, 132.8,
134.9, 139.1, 193.4; MS (70 eV) m/z (rel intensity) 248 (M+
+
2, 6), 246 (M+ , 6), 218 (69), 216 (70), 203 (53), 201 (49), 94
(53), 89 (97), 65 (44), 61 (100); HRMS (EI) calcd for C9H11O379Br
(M+)245.9891, found 245.9885;HRMS (EI)calcd for C9H11O381Br
247.9871, found 247.9861.
(1S*,4R*,7S*)-7-Acetyl-5-br om o-3,3-d im eth oxybicyclo-
[2.2.2]oct-5-en e-2-on e (25c). Following the general procedure
(Method B), MOB 21 generated in situ from phenol 17 was
reacted with MVK and the crude product was purified by
column chromatography (EtOAc/hexanes 1:4) to provide 25c
(85% yield) as a colorless liquid. IR (neat) 1752, 1708, 1610,
4-Br om o-6,6-d im eth oxy-3-m eth yl-2,4-cycloh exa d ien -1-
on e (23). To a suspension of DAIB (354.5 mg, 1.1 mM) and
KHCO3 (245.6 mg, 2.45 mM) in methanol (5 mL) was added
slowly a solution of phenol 19 (216.0 mg, 1.0 mM) in methanol
(5 mL) in one portion at 0 °C under nitrogen atmosphere. After
5 min of stirring, the reaction mixture was quenched with
brine (10 mL). Then water (10 mL) was added and extracted
with CH2Cl2. The organic layer was dried over anhydrous
MgSO4 and concentrated. The residue was purified by column
chromatography (EtOAc/hexanes 1:3) to furnish MOB 23
(189.5 mg, 77% yield) as a greenish yellow oil. IR (film) 1681,
1
1061 cm-1; H NMR (400 MHz, CDCl3) δ 1.85 (ddd, J ) 13.1,
6.6, 2.8 Hz, 1H), 2.13 (s, 3H), 2.25 (ddd, J ) 13.1, 10.0, 2.8
Hz, 1H), 3.01 (ddd, J ) 10.0, 6.6, 1.6 Hz, 1H), 3.29 (dt, J )
2.8, 2.5 Hz, 1H), 3.31 (s, 3H), 3.34 (s, 3H), 3.43 (dd, J ) 1.6,
6.7, 1.6 Hz, 1H), 6.21 (dd, J ) 6.7, 2.5 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 24.0, 28.2, 46.8, 49.1, 50.1, 50.8, 51.4, 93.9,
124.0, 125.1, 199.1, 204.9; MS (EI, 70 eV) m/z (rel intensity)
276 (63), 274 (M+ - CO, 63), 233 (78), 231 (79), 78 (28), 77
(40), 75 (25), 43 (100); HRMS (EI) calcd for C11H15O379Br (M+
- CO) 274.0205, found 274.0208; HRMS (EI) calcd for
1
1631, 1037 cm-1; H NMR (400 MHz, CDCl3) δ 2.15 (d, J )
1.6 Hz, 3H), 3.35 (s, 6H), 5.96 (q, J ) 1.6 Hz, 1H), 6.73 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 24.0, 50.2, 92.6, 124.2,
124.5, 135.7, 150.5, 192.9; MS (70 eV) m/z (rel intensity) 248
(M+ + 2, 21), 246 (M+, 22), 217 (98), 215 (100), 167 (40), 139
(100), 108 (24), 93 (32), 65 (12); HRMS (EI) calcd for C9H11O379Br
(M+)245.9891, found 245.9899;HRMS (EI)calcd for C9H11O381Br
247.9871, found 247.9885.
C
11H15O381Br 276.0185, found 276.0180.
Meth yl (1S*,2S*,4R*)-5-Br om o-8,8-d im eth oxy-1-m eth -
yl-7-oxobicyclo[2.2.2]oct-5-en e-2-ca r boxyla te (26a ). Fol-
lowing the general procedure (Method C), MOB 22 generated
in situ from phenol 18 was reacted with MA and the crude
product was purified by column chromatography (EtOAc/
hexanes 2:7) to furnish 26a (75% yield) as a colorless solid.
Mp 70-71 °C (from hexanes); IR (film) 1739, 1714, 1613, 1264,
1051 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.22 (s, 3H), 1.87 (ddd,
J ) 13.1, 6.5, 3.0 Hz, 1H), 2.35 (ddd, J ) 13.1, 9.6, 3.6 Hz,
1H), 2.71 (dd, J ) 9.6, 6.5 Hz, 1H), 3.32 (m, 4H), 3.37 (s, 3H),
3.67 (s, 3H), 5.95 (d, J ) 2.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 15.3, 28.3, 43.9, 48.8, 50.2, 50.7, 52.0, 53.5, 93.8,
123.3, 129.9, 173.2, 199.2; MS (70 eV) m/z (rel intensity) 306
(27), 304 (M+ - CO, 29), 259 (22), 257 (21), 247 (18), 245
(21), 225 (100), 91 (35); HRMS (EI) calcd for C12H17O479Br
(M+ - CO) 304.0310, found 304.0305; HRMS (EI) calcd for
3-Br om o-6,6-d im eth oxy-4-(1,3-d ioxola n -2-yl)-2,4-cyclo-
h exa d ien -1-on e (24). To a suspension of DAIB (1.75 g, 5.44
mM) and KHCO3 (1.3 g, 12.98 mM) in methanol (10 mL) was
added slowly a solution of phenol 20 (1.42 g, 5.18 mM) in
methanol (10 mL) in one portion at 0 °C under nitrogen
atmosphere. After 5 min of stirring, the reaction mixture was
quenched with brine (10 mL) and extracted with ethyl acetate.
The organic layer was dried over anhydrous MgSO4 and
concentrated. The residue was purified by column chromatog-
raphy (EtOAc/hexanes 1:3 with 1% Et3N) to furnish MOB 24
(1.45 g, 92% yield) as a yellow oil. IR (film) 1680, 1640, 1450,
1
1070 cm-1; H NMR (300 MHz, CDCl3) δ 3.34 (s, 6H), 3.98-
4.05 (m, 4H), 5.73 (s, 1H), 6.52 (s, 1H), 6.58 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 50.2, 65.2, 91.5, 101.0, 129.5, 132.4, 133.6,
139.2, 191.4; MS (70 eV) m/z (rel intensity) 306 (M+ + 2, 20),
304 (M+, 20), 292 (80), 290 (80), 276 (50), 274 (50), 264 (20),
262 (20), 246 (25), 244 (25), 196 (30), 168 (40), 105 (100), 75
(60).
C
C
12H17O481Br 306.0290, found 306.0309. Anal. Calcd for
13H17O5Br: C, 46.86; H, 5.14. Found: C, 46.81; H, 5.14.
Met h yl (1S*,2S*,4R*)-5-Br om o-8,8-d im et h oxy-1,2-d i-
m eth yl-7-oxobicyclo[2.2.2]oct-5-en e-2-ca r boxyla te (26b).
Following the general procedure (Method C), MOB 22 gener-
ated in situ from phenol 18 was reacted with MMA and the
crude product was purified by column chromatography (EtOAc/
hexanes 2:11) to afford 26b (72% yield) as a colorless solid.
Mp 82-82.5 °C (from hexanes); IR (film) 1734, 1713, 1619,
Meth yl (1S*,2S*,4R*)-5-Br om o-8,8-d im eth oxy-7-oxobi-
cyclo[2.2.2]oct-5-en e-2-ca r boxyla te (25a ). Following the
general procedure (Method B), MOB 21 generated in situ from
phenol 17 was reacted with MA and the crude product was
6500 J . Org. Chem., Vol. 67, No. 18, 2002

Synthesis of Bicyclo[2.2.2]octenones from 2-Methoxyphenols
1
1231, 1048 cm-1; H NMR (400 MHz, CDCl3) δ 1.18 (s, 3H),
(s, 3H), 2.14 (s, 3H), 2.33 (ddd, J ) 12.8, 10.2, 3.2 Hz, 1H),
3.04 (ddd, J ) 10.2, 6.8, 1.6 Hz, 1H), 3.28 (dd, J ) 3.2, 3.2 Hz,
1H), 3.30 (s, 3H), 3.36 (s, 3H), 3.38 (d, J ) 1.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 20.1, 25.2, 28.1, 46.7, 48.9, 50.2,
50.5, 56.1, 94.2, 118.0, 132.8, 198.8, 205.4; MS (70 eV) m/z (rel
intensity) 290 (63), 288 (M+ - CO, 68), 287 (15), 285 (12), 259
(18), 257 (19), 247 (53), 245 (56), 177 (33), 91 (15), 75 (100);
HRMS (EI) calcd for C13H17O479Br 316.0310, found 316.0305;
HRMS (EI) calcd for C13H17O481Br 318.0290, found 318.0438.
Anal. Calcd for C13H17O4Br: C, 49.23; H, 5.40; Found: C, 49.12;
H, 5.41.
1.19 (s, 3H), 1.94 (dd, J ) 13.5, 2.8 Hz, 1H), 2.36 (dd, J )
13.5, 3.2 Hz, 1H), 3.25 (ddd, J ) 3.2, 2.8, 2.8 Hz, 1H), 3.34 (s,
3H), 3.38 (s, 3H), 3.66 (s, 3H), 5.96 (d, J ) 2.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 13.4, 21.2, 36.0, 48.2, 48.8, 49.7,
50.5, 52.1, 58.0, 93.8, 122.6, 132.2, 174.9, 200.2; MS (70 eV)
m/z (rel intensity) 320 (98), 318 (M+ - CO, 100), 303 (7), 289
(19), 287 (21), 261 (52), 259 (60), 239 (59), 105 (43), 75 (42);
HRMS (EI) calcd for C13H19O479Br (M+ - CO) 318.0467, found
318.0431; HRMS (EI) calcd for C13H19O481Br 320.0447, found
320.0446. Anal. Calcd for C14H19O5Br: C, 48.43; H, 5.52.
Found: C, 48.42; H, 5.47.
(1S*,4R*,7S*)-7-Acetyl-5-br om o-3,3-d im eth oxy-1-m eth -
ylbicyclo[2.2.2]oct-5-en e-2-on e (26c). Following the general
procedure (Method C), MOB 22 generated in situ from phenol
18 was reacted with MVK and the crude product was purified
by column chromatography (EtOAc/hexanes 4:7) to give 26c
(83% yield) as a colorless solid. Mp 104-104.5 °C (from
hexanes); IR (film) 1725, 1712, 1613, 1223, 1053 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.23 (s, 3H), 1.69 (ddd, J ) 12.8, 6.8, 2.7
Hz, 1H), 2.13 (s, 3H), 2.37 (ddd, J ) 12.8, 9.7, 3.4 Hz, 1H),
2.85 (dd, J ) 9.7, 6.8 Hz, 1H), 3.33 (m, 4H), 3.37 (s, 3H), 6.01
(d, J ) 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 15.1, 27.8,
30.8, 48.8, 50.1, 50.6, 50.7, 53.4, 93.8, 122.2, 130.5, 199.4, 206.7;
MS (EI, 70 eV) m/z (rel intensity) 290 (33), 288 (M+ - CO,
35), 259 (13), 257 (13), 247 (100), 245 (82), 209 (13), 165 (16),
91 (36), 75 (33), 65 (15); HRMS (EI) calcd for C13H17O479Br (M+)
316.0310, found 316.0334; HRMS (EI) calcd for C13H17O481Br
318.0290, found 318.0293. Anal. Calcd for C13H17O4Br: C,
49.23; H, 5.40. Found: C, 49.05; H, 5.43.
Meth yl (1R*,2S*,4S*)-6-Br om o-8,8-d im eth oxy-5-(1,3-d i-
oxola n -2-yl)-7-oxob icyclo[2.2.2]oct -5-en e-2-ca r b oxyla t e
(28a ). Following the general procedure (Method D), MOB 24
generated in situ from phenol 20 was reacted with MA and
the crude product was crystallized from EtOAc-hexanes to
give pure 28a (94% yield) as a colorless solid. Mp 106-108 °C
(from EtOAc-hexanes); IR (film) 1735, 1714, 1642, 1450, 1202,
1
1060 cm-1; H NMR (300 MHz, CDCl3) δ 1.83 (ddd, J ) 13.2,
6.1, 2.9 Hz, 1H), 2.33 (ddd, J ) 13.2, 9.9, 2.0 Hz, 1H), 3.11
(ddd, J ) 2.0, 6.1, 9.9 Hz, 1H), 3.33 (s, 3H), 3.34 (s, 3H), 3.44
(dd, J ) 2.9, 2.9 Hz, 1H), 3.72 (s, 3H), 3.75 (d, J ) 2.0 Hz,
1H), 3.90-4.20 (m, 4H), 5.60 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 25.6, 39.4, 39.8, 49.8, 50.1, 52.3, 60.0, 65.1, 65.3, 93.2,
100.7, 116.1, 140.9, 172.1, 197.6; MS (70 eV) m/z (rel intensity)
392 (M+ + 2, 2), 390 (M+, 2), 364 (10), 362 (10), 332 (30), 299
(8), 287 (10), 251 (52), 229 (12), 199 (10), 179 (8), 149 (8), 103
(100), 73 (32), 59 (10); HRMS (EI) calcd for C15H19O779Br (M+)
390.0314, found 390.0318; HRMS (EI) calcd for C15H19O781Br
392.0294, found 392.0294. Anal. Calcd for C15H19O7Br: C,
46.05; H, 4.90. Found: C, 45.95; H, 4.90.
Meth yl (1R*,2S*,4R*)-5-Br om o-8,8-d im eth oxy-6-m eth -
yl-7-oxobicyclo[2.2.2]oct-5-en e-2-ca r boxyla te (27a ). Fol-
lowing the general procedure (Method C), MOB 23 generated
in situ from phenol 19 was reacted with MA and the residue
was subjected to column chromatography (EtOAc/hexanes 1:3)
to give 27a (72% yield) as a colorless liquid. IR (film) 1740,
Meth yl (1R*,2S*,4S*)-6-Br om o-8,8-d im eth oxy-5-(1,3-d i-
oxola n -2-yl)-2-m eth yl-7-oxobicyclo[2.2.2]oct-5-en e-2-ca r -
boxyla te (28b). Following the general procedure (Method D),
MOB 24 generated in situ from phenol 20 was reacted with
MMA and the crude product was crystallized from EtOAc-
hexanes to furnish pure 28b (95% yield) as a colorless solid.
Mp 140-142 °C (from EtOAc-hexanes); IR (film) 1741, 1730,
1713, 1646, 1266, 1059 cm-1 1H NMR (400 MHz, CDCl3) δ
;
1.87 (s, 3H), 1.92 (ddd, J ) 13.2, 6.0, 3.0 Hz, 1H), 2.32 (ddd, J
) 13.2, 10.0, 3.0 Hz, 1H), 3.11 (ddd, J ) 10.0, 6.0, 1.6 Hz, 1H),
3.27 (dd, J ) 3.0, 3.0 Hz, 1H), 3.30 (s, 3H), 3.36 (s, 3H), 3.45
(d, J ) 1.6 Hz, 1H), 3.68 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 19.9, 25.8, 38.7, 48.9, 50.1, 50.4, 52.2, 56.7, 94.0, 118.7, 132.5,
172.8, 198.4; MS (70 eV) m/z (rel intensity) 306 (87), 304
(M+ - CO, 100), 275 (21), 273 (25), 259 (20), 257 (22), 75 (41);
1648, 1461, 1282, 1055 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.32 (s, 3H), 1.87 (dd, J ) 13.7, 2.4 Hz, 1H), 2.40 (dd, J )
13.7, 3.5 Hz, 1H), 3.34 (s, 3H), 3.36 (s, 3H), 3.59 (s, 1H), 3.72
(s, 3H), 3.91 (dd, J ) 3.5, 2.4 Hz, 1H), 3.90-4.15 (m, 4H), 5.6
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 24.7, 32.4, 39.9, 47.5, 49.8,
49.9, 52.5, 65.2, 65.4, 66.4, 93.4, 100.8, 117.5, 140.8, 174.9,
198.8; MS (70 eV) m/z (rel intensity) 378 (10), 376 (M+ - CO,
10), 347 (10), 345 (10), 303 (8), 301 (8), 66 (40), 103 (100), 75
HRMS (EI) calcd for
C
13H17O579Br (M+) 332.0259, found
332.0367; HRMS (EI) calcd for C13H17O581Br 334.0239, found
334.0248.
(10); HRMS (EI) calcd for
C
16H21O779Br 404.0470, found
404.0478. Anal. Calcd for C16H21O7Br: C, 47.42; H, 5.22.
Found: C, 47.24; H, 5.18.
Met h yl (1R*,2S*,4R*)-5-Br om o-8,8-d im et h oxy-2,6-d i-
m eth yl-7-oxobicyclo[2.2.2]oct-5-en e-2-ca r boxyla te (27b).
Following the general procedure (Method C), MOB 23 gener-
ated in situ from phenol 19 was reacted with MA and the
residue was purified by column chromatography (EtOAc/
hexanes 1:4) to furnish 27b (62% yield) as a colorless liquid.
(1R*,4S*,7S*)-7-Acet yl-6-b r om o-3,3-d im et h oxy-5-(1,3-
d ioxola n -2-yl)bicyclo[2.2.2]oct-5-en e-2-on e (28c). Follow-
ing the general procedure (Method D), MOB 24 generated in
situ from phenol 20 was reacted with MVK and the crude
product was crystallized from EtOAc-hexanes to give 28c
(96% yield) as a colorless solid. Mp 116-117 °C (from EtOAc-
hexanes); IR (film) 1740, 1708, 1640, 1205, 1050 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.76 (ddd, J ) 12.4, 6.4, 3.2 Hz, 1H), 2.22
(s, 3H), 2.28 (ddd, J ) 12.4, 9.0, 3.2 Hz, 1H), 3.14 (ddd, J )
9.0, 6.4, 2.0 Hz, 1H), 3.38 (s, 3H), 3.35 (s, 3H), 3.47 (dd, J )
3.2, 3.2 Hz, 1H), 3.72 (d, J ) 2.0 Hz, 1H), 3.90-4.10 (m, 4H),
5.57 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 24.7, 28.1, 39.4,
47.9, 49.8, 50.1, 59.4, 65.1, 65.3, 93.3, 100.7, 116.2, 140.5, 198.0,
204.4; MS (70 eV) m/z (rel intensity) 348, 346 (M+ - CO, 12),
314 (15), 303 (10), 271 (15), 223 (80), 199 (13), 192 (10), 151
(16), 119 (8), 103 (50), 89 (40), 73 (100), 59 (16); HRMS (EI)
calcd for C15H19O679Br (M+) 374.0365, found 374.0360; HRMS
(EI) calcd for C15H19O681Br 376.0345, found 376.0345. Anal.
Calcd for C15H19O6Br: C, 48.02; H, 5.10. Found: C, 47.95; H,
5.06.
IR (film) 1737, 1715, 1648, 1290, 1117 cm-1 1H NMR (400
;
MHz, CDCl3) δ 1.27 (s, 3H), 1.82 (s, 3H), 1.87 (dd, J ) 13.8,
3.0 Hz, 1H), 2.47 (dd, J ) 13.8, 3.0 Hz, 1H), 3.21 (dd, J ) 3.0,
3.0 Hz, 1H), 3.32 (s, 1H), 3.33 (s, 3H), 3.36 (s, 3H), 3.67 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 19.7, 25.2, 32.7, 46.3, 49.2,
49.9, 50.5, 52.4, 63.5, 94.1, 119.3, 134.0, 175.7, 199.7; MS (70
eV) m/ z (rel intensity) 320 (94), 318 (M+ - CO, 100), 289 (15),
287 (16), 273 (22), 271 (22), 261 (19), 259 (19), 239 (26), 229
(18), 227 (18), 105 (29), 75 (59); HRMS (EI) calcd for
C
14H19O579Br (M+) 346.0416, found 346.0407; HRMS (EI)
calcd for C14H19O581Br 348.0396, found 348.0373.
(1R*,4R*,7S*)-7-Acetyl-5-br om o-3,3-d im eth oxy-6-m eth -
ylbicyclo[2.2.2]oct-5-en -2-on e (27c). Following the general
procedure (Method C), MOB 23 generated in situ from phenol
19 was reacted with 3 with MVK and the residue was
subjected to column chromatography (EtOAc/hexanes 2:7) to
afford 27c (90% yield) as a colorless solid. Mp 126-127 °C
(from hexanes); IR (film) 1739, 1714, 1261, 1057 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.78 (ddd, J ) 12.8, 6.8, 3.2 Hz, 1H), 1.89
(1R*,8S*)-11-Br om o-4,8-d im et h yl-5-h yd r oxy-6,10,10-
t r im et h oxyt r icyclo[6.2.2.02,7]d od eca -2,4,6,11-t et r a en -9-
on e (29). A byproduct formed in the preparation of MOB 22
J . Org. Chem, Vol. 67, No. 18, 2002 6501

Lai et al.
from phenol 18 in 5% yield as a colorless solid. Mp 178-179
°C (from EtOAc-hexanes); IR (film) 1736, 1602, 1206, 1060
245.9898; HRMS (EI) calcd for C9H11O381Br 247.9871, found
247.9880. Anal. Calcd for C9H11O3Br: C, 43.75; H, 4.49.
Found: C, 43.5; H, 4.46.
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.61 (s, 3H), 2.23 (s, 3H),
3.24 (s, 3H), 3.48 (s, 3H), 3.91 (s, 3H), 4.59 (d, J ) 2.4 Hz,
1H), 5.61 (s, 1H), 6.31 (d, J ) 2.4 Hz, 1H), 6.75 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 13.0, 15.9, 50.4, 51.1, 51.4, 57.4,
63.1, 92.2, 120.3, 123.9, 124.9, 128.0, 129.4, 135.2, 142.9, 146.3,
195.9; MS (70 eV) m/z (rel intensity) 384 (M+ + 2, 2), 382 (M+,
2), 356 (15), 354 (16), 325 (21), 323 (20), 303 (23), 282 (100),
280 (100), 275 (49), 267 (94), 265 (95), 75 (92); HRMS (EI) calcd
for C17H19O579Br (M+) 382.0415, found 382.0414; HRMS (EI)
calcd for C17H19O581Br 384.0396, found 384.0381. Anal. Calcd
for C17H19O5Br: C, 53.28; H, 5.00. Found: C, 53.27; H, 5.02.
(1R*,2S*,7S*,8S*)-7,12-Dibr om o-6,11-d im eth yl-3,3,9,9-
tetr a m eth oxytr icyclo[6.2.2.02,7]d od eca -5,11-d ien e-4,10-d i-
on e (31). A byproduct formed in the preparation of MOB 23
from phenol 19 in 5% yield as a colorless solid. Mp 164-166
°C (from hexanes); IR (film) 1742, 1705, 1646, 1622, 1216, 1063
5-Br om o-4-for m yl-2-m eth oxyp h en ol (35).34 To the sus-
pension of aldehyde 35 (3.23 g, 16.7 mM) in KBr (6.67 g) and
distilled water (80 mL) was added bromine (2.94 g, 18.4 mmol)
dropwise. The reaction mixture was stirred for 10 h at room
temperature and then subjected to filtration. The precipitate
was suspended in 6 N HCl (80 mL) at 90 °C for 10 h. The
reation mixture was then cooled and filtered and the resulting
solid was dissolved in EtOAc and washed with saturated
NaHCO3 solution. The organic layer was dried over MgSO4
and concentrated. The residue was recrystallized from EtOAc-
hexanes to give 35 (3.58 g, 93% yield) as a colorless solid. Mp
174-75 °C (from hexanes, lit.34 mp 174-175 °C); IR (film)
3210, 2910, 1680, 1201, 1040 cm-1; 1H NMR (300 MHz, CDCl3)
δ 3.95 (s, 3H), 6.18 (s, 1H), 7.18 (s, 1H), 7.43 (s, 1H), 10.18 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 56.4, 110.4, 119.2, 120.8,
126.4, 146.5, 151.9, 190.8; MS (70 eV) m/z (rel intensity) 232
(M+ + 2, 99), 230 (M+, 100), 215 (10), 203 (16), 187 (13), 173
(12), 159 (30), 142 (11), 133 (10), 122 (10), 107 (9); HRMS (EI)
calcd for C8H7O379Br 229.9578, found 229.9564; HRMS (EI)
calcd for C8H7O381Br 231.955, found 231.954.
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.67 (s, 3H), 2.12 (d, J )
1.4 Hz, 3H), 3.15 (s, 3H), 3.32 (d, J ) 2.2 Hz, 1H), 3.35 (s,
3H), 3.39 (s, 3H), 3.48 (s, 3H), 3.59 (s, 1H), 4.02 (d, J ) 2.2
Hz, 1H), 6.01 (q, J ) 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 19.9, 21.7, 49.0, 50.0, 50.2, 50.4, 51.1, 51.4, 61.2, 67.7, 94.1,
97.3, 118.7, 126.5, 135.5, 153.7, 190.7, 196.4; MS (70 eV) m/z
(rel intensity) 468 (3), 466 (6), 464 (M+ - CO, 3), 387 (99), 385
(100), 355 (28), 353 (29), 281 (39), 279 (40), 253 (25), 251 (28),
129 (26), 128 (22), 115 (21), 59 (39); HRMS (EI) calcd for
Ack n ow led gm en t. We gratefully acknowledge the
financial support from the National Science Council
(NSC) of the Republic of China. One of us (N.S.K.R.)
thanks the Ministry of Education for a postdoctoral
fellowship under the Program for Promoting Academic
Excellence of Universities, 89-B-FA-04-1-4. We thank
Dr. R. K. Peddinti for helpful discussions.
C
18H22O679Br79Br (M+) 491.9783, found 491.9770; HRMS (EI)
calcd for C18H22O679Br81Br 493.9763, found 493.9744; HRMS
(EI) calcd for C18H22O681Br81Br 495.9743, found 495.9740. Anal.
Calcd for C18H22O6Br2: C, 43.75; H, 4.49. Found: C, 43.54; H,
4.47.
4-Br om o-2-m eth oxy-5-(m eth oxy)m eth ylp h en ol (33). A
byproduct formed in the Diels-Alder reactions of MOB 23
(derived from phenol 19) with MA and MMA in 6 and 13%
yields, respectively, as a colorless solid. Mp 85-86 °C (from
hexanes); IR (film) 3396, 2932, 1614, 1278, 1029 cm-1; 1H NMR
(400 MHz, CDCl3) δ 3.39 (s, 3H), 3.86 (s, 3H), 4.41 (s, 2H),
5.51 (s, 1H), 6.99 (s, 1H), 7.00 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 56.2, 58.3, 73.5, 112.0, 114.8, 115.4, 130.3, 145.0,
146.5; MS (70 eV) m/z (rel intensity) 248 (74), 246 (M+ - CO,
100), 217 (52), 215 (52), 167 (38), 165 (5), 137 (5), 65 (3);
HRMS (EI) calcd for C9H11O379Br (M+ - CO) 245.9891, found
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
and DEPT spectra for compounds 13a -c to 15a -c and 25a -c
to 28a -c, tables of selected 1H NMR chemical shifts and
coupling constants for compounds 13a -c to 15a -c and 25a -c
to 28a -c, and an ORTEP plot of the crystal structure of Diels-
Alder adduct 26b. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O020171H
(34) Martin, P. Helv. Chim. Acta 1989, 72, 1554.
6502 J . Org. Chem., Vol. 67, No. 18, 2002