Oxy-cope rearrangements of bicyclo[3.2.0]heptenones. Synthesis of bicyclo[4.2.1]non-l(4)-en-6-ones and bicyclo[5.2.1]dec-1(10)-en-5-ones

Article abstract of DOI:10.1021/jo991765w

6-exo-Methylbicyclo[3.2.0]hepten-7-ones and their 2-alkylidene analogues are readily prepared from dialkyl squarates. These compounds undergo facial oxy-Cope ring expansions upon treatment with vinyllithium; the former leads to bicyclo[4.2.1]non-1(4)-en-6

Full text of DOI:10.1021/jo991765w

J . Org. Chem. 2000, 65, 3379-3386
3379
Oxy-Cop e Rea r r a n gem en ts of Bicyclo[3.2.0]h ep ten on es. Syn th esis
of Bicyclo[4.2.1]n on -1(4)-en -6-on es a n d
Bicyclo[5.2.1]d ec-1(10)-en -5-on es
Sharad K. Verma, Que H. Nguyen, J ames M. MacDougall, Everly B. Fleischer, and
Harold W. Moore*
Department of Chemistry, University of California, Irvine, California 92697-2025
Received November 12, 1999
6-exo-Methylbicyclo[3.2.0]hepten-7-ones and their 2-alkylidene analogues are readily prepared from
dialkyl squarates. These compounds undergo facial oxy-Cope ring expansions upon treatment with
vinyllithium; the former leads to bicyclo[4.2.1]non-1(4)-en-6-ones and the latter to the first examples
of bicyclo[5.2.1]dec-1(10)-en-5-ones, compounds having exceptionally strained bridgehead double
bonds. The transformations are controlled by the 6-exo-methyl group in the starting material along
with the substituent at position-1 (bridgehead) which force attack of the lithium reagent from the
concave face of the starting material, thus allowing the cyclopentenyl or alkylidene groups to
participate in the sigmatropic event.
Sch em e 1
In tr od u ction
1-Alkenylbicyclo[3.2.0]hepten-7-ones and their 2-alky-
lidene analogues of general structures 1 and 6 (Scheme
1) are readily available from squaric acid and have been
shown to be useful synthetic intermediates.1,2 Previously,
we reported syntheses of bicyclo[6.3.0]undecenones 4 and
9 from, respectively, 1 and 6 (R ) H) upon treatment of
alkenyllithium reagents.3,4 Such oxy-Cope transforma-
tions arise via convex face attack of the alkenyllithium
to give the corresponding adducts 2 and 7 and subsequent
participation of the 1-alkenyl group in the sigmatropic
reaction.5 In contrast, we now report that vinyllithium
attacks 1 and 6 from the concave face for those examples
bearing an exo-disposed methyl group at position-6 (R )
Me). This new reaction results in adducts 3 and 8, which
then proceed to, respectively, bicyclo[4.2.1]non-1(4)-en-
6-ones 5 and the previously unknown highly strained
bridgehead alkenes, bicyclo[5.2.1]dec-1(10)-en-5-ones 10,
via oxy-Cope reactions in which the cyclopentenyl or
alkylidenyl double bonds are participants.
Specific examples of the previously reported convex
face attack mode are represented by the tandem reaction
sequence outlined in Scheme 2. Here, bicyclo[3.2.0]-
heptenone 11 was observed to give the triquinane 13
(67%) via an initial oxy-Cope ring expansion to 12
followed by transannular ring closure upon hydrolytic
(1) For a recent review of the synthesis and reactions of cyclobuten-
ones, see: Moore, H. W.; Yerxa, B. R. Adv. Strain Org. Chem. 1995, 4,
81-162.
desilylation during the workup procedure.3a Analogously,
2-alkylidenebicyclo[3.2.0]heptanone 14 provided the
triquinane 16 (67%) via the intermediate 15. It is
noteworthy that the reaction can be terminated at the
bicyclo[6.3.0]undecenone stage when the starting materi-
als bear tert-butyldimethylsilyl (TBS) rather than trim-
ethylsilyl (TMS) protecting groups.
(2) Gayo, L. G.; Winters, M. P.; Moore, H. W. J . Org. Chem. 1992,
57, 6896.
(3) For examples see the following and references therein: (a)
Santora, V. S.; Moore, H. W. J . Org. Chem. 1996, 61, 7976. (b) Santora,
V. S.; Moore, H. W. J . Am. Chem. Soc. 1995, 117, 8486. (c) J ung, M.
E.; Rayle, H. L. J . Org. Chem. 1997, 62, 4601. (d) Enholm, E. J .; Zia,
Z. Z. J . J . Org. Chem. 1997, 62, 174.
(4) For reviews of the oxy-Cope rearrangement, see: (a) Paquette,
L. A. Tetrahedron 1997, 53, 13971-14020. (b) Paquette, L. A. Angew.
Chem., Int. Ed. Engl. 1990, 29, 609-626. (c) Lutz, R. P. Chem. Rev.
1984, 84, 6-243.
Resu lts a n d Discu ssion
(5) (a) MacDougall, J . M.; Turnbull, P. S.; Verma, S. K.; Moore, H.
W. J . Org. Chem. 1997, 62, 3792. (b) MacDougall, J . M.; Santora, V.
J .; Verma, S. K.; Turnbull, P.; Hernandez, C. R.; Moore, H. W. J . Org.
Chem. 1998, 63. 6905.
Reported herein are the results of a study of the oxy-
Cope ring expansions of bicyclo[3.2.0]heptenones induced
by 1,2-addition of vinyllithium to the carbonyl group from
10.1021/jo991765w CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/11/2000

3380 J . Org. Chem., Vol. 65, No. 11, 2000
Verma et al.
Sch em e 2
Sch em e 4
Sch em e 3
strained polycyclic bridgehead alkenes.7 Specifically, 21-
25 gave 26-30, respectively, in yields ranging from 56
to 65% (Scheme 4).
This rearrangement is of particular note since it
appears to be general, and the starting materials are
readily prepared in a variety of substitution patterns. In
this regard, the conversion of 25 to 30 is highlighted since
it shows the reaction to be applicable for examples
bearing groups other than the bulky 2-methylpropenyl
group at the bridgehead position. Also of mechanistic
interest is the observation that treatment of 31a ,b under
the reaction conditions gave, respectively, bicyclo[6.3.0]-
undecenones 32a (59%) and 32b (51%), both of which
must arise via the convex attack mode. Thus, as dis-
cussed above, the presence of a 6-exo-methyl group in the
starting material is a requisite to induce the reaction
sequence arising from concave attack of vinyllithium.
The structure assignments for 18 and 20 are based
upon characteristic spectral data. Their stereochemistry
the concave face of the molecule. This modification is
complrmentary to the tandem sequence described above
and appears to be generally applicable if the starting
materials bear an exo-methyl group at position-6.
For example, 17 gives the bicyclo[4.2.1]nonenone 18
as a single diastereomer in 57% isolated yield and 19
gives 20 in 56% yield (Scheme 3). This transformation is
of potential importance as a possible key step in the
synthesis of natural products such as secolongifolenone,
an antipode of a fungal metabolite of Helminthosporium
sativum.6
In a similar fashion, 6-exo-methyl-2-alkylidenebicyclo-
[3.2.0]heptanones gave bicyclo[5.2.1]dec-1(10)-en-5-ones,
members of the previously unknown class of highly
(7) For a review of strained bridgehead alkenes, see: Warner, P.
M. Chem. Rev. 1989, 89, 1067.
(6) Satyanarayana, N.; Nayak, U. K. Synth. Commun. 1985, 15, 331.

Oxy-Cope Rearrangements of Bicyclo[3.2.0]heptenones
J . Org. Chem., Vol. 65, No. 11, 2000 3381
Ta ble 1. Obser ved a n d Ca lcu la ted Distor tion
P a r a m eter s for Br id geh ea d Alk en esa
compd
ÌE
ÌB
Ìm
τ
Φ1
Φ2
θ1
θ2
28 (obsd) 11.1 23.9 17.5 22.1 -15.7 -28.5 140.5 174.4
28 (calcd) 10.0 19.9 14.9 21.8 -16.9 -26.6 143.6 175.8
33 (obsd) 20.8 13.4 17.1 29.3 -25.6 -33.0 133.6 167.8
33 (calcd) 16.1 20.0 18.0 24.7 -22.7 -26.7 137.3 173.4
26 (calcd) 11.1 20.0 15.5 20.9 -16.4 -25.3 143.6 174.8
27 (calcd) 11.2 20.1 15.7 21.8 -17.3 -26.2 142.6 173.9
29 (calcd) 11.0 19.9 15.4 20.2 -15.7 -24.6 144.4 175.3
30 (calcd) 16.3 20.1 18.2 18.9 -16.9 -20.9 142.0 179.2
a
Calculations are based upon the cff91 Potential Set with
Insight-Discover 93.
appears to be common to nearly all of the bridgehead
alkenes described herein as evidenced by the force field
calculations presented in Table 1; i.e., the τ-values are
consistently of greater magnitude than the Ìm values.
An exception is compound 30, where the degree of
pyramidalization Ìm(30))18.2° is calculated to be nearly
equivalent to the torsional strain (τ30)18.9°).
It is noteworthy that even though the degree of
pyramidalization is nearly the same in both 28 and 33
(Ìm ) 17.5 cf 17.1°), there is an inverse correlation
between the individual olefinic carbon atoms. That is, the
bridgehead carbon atom in 33 shows less pyramidaliza-
tion (ÌB ) 13.4°) than that in 28 (ÌB ) 23.9°), while the
exocyclic double bond in 33 shows more (ÌE ) 20.8°) than
that in 28 (ÌE ) 11.1°). This apparent anomaly may be
due to a greater interaction of the bromine in 33 with
the C4-H (exo) of the pentamethylene bridge as compared
to the analogous interaction of the C13-(3-methylprope-
nyl) with the C4-H (exo) in 28. Thus, the former requires
greater pyramidalization at C11 than the latter at C13.
Finally, it is noted that the bridgehead CdC bond
length in 28, like that in 33 as well as in other bridgehead
olefins,9 does not suffer significant elongation despite the
high degree of distortion; i.e., the bond distance in 28 is
1.348(3) Å and that in 33 is 1.319(8) Å.
The requisite substituted bicycloheptenones used in
this study were prepared in analogy to previously re-
ported methods starting with dialkyl squarates.1,2,5,11 For
example, 17 and 19 stem from 3-ethenyl-4,4-dimethoxy-
2-methylcyclobutenone 34, which is easily prepared from
dimethylsquarate in a “one pot” sequence of reactions,
i.e., treatment of the squarate ester with vinyllithium in
THF at -78 °C followed by the sequential addition of
trifluroacetic anhydride and then methanol.3a Allylation
of 34 upon treatment with, respectively, the Grignard
reagents obtained from 3-chloro-2-methylpropene or al-
lylmagnesium bromide followed by acidic workup and
silylation using TBSOTf gave the cyclobutenones 35a
(68%) and 35b (63%) (Scheme 5).12 Thermolysis (toluene,
110 °C) of these induced their electrocyclic ring opening
to the corresponding vinylketenes, which give the respec-
tive bicyclo[3.2.0]heptenones upon intramolecular [2 +
2] cycloaddition.3 Treatment of the resulting products
with LDA followed by MeI then gave 17 and 19 in 63-
67% overall yield.
F igu r e 1. View along the bridgehead double bond of 28.
is assumed on the basis of mechanistic considerations.
The 13C NMR spectrum of 18 shows a carbonyl carbon
atom absorption at δ 216 and a tertiary alkoxy carbon
at δ 85. The presence of eight CH3, four CH2, and two
CH groups was established by DEPT analysis. In addi-
tion, the 13C NMR spectrum reveals the presence of two
quaternary carbon atoms and two tetrasubstituted ole-
1
finic carbon atoms. The H NMR spectra showed absorp-
tions for the vinyl protons at δ 6.27 (dd, J ) 17.9, 11.6
Hz), 5.31 (dd, J ) 17.9, 1.8 Hz), and 5.28 (dd, J ) 11.6,
1.8 Hz), together with a doublet for the methyl substi-
tuted methine group at δ 1.06 (J ) 7.5 Hz). Two singlets
at δ 1.76 and 1.22 account for the methyl groups attached
to quaternary carbon atoms. The infrared spectrum
shows carbonyl absorption at 1701 cm-1. Similar data
were observed for 20 (see the Experimental Section).
The structure of 28 was unambiguously established by
single-crystal X-ray crystallography. This provides the
foundation for the assigned structure and stereochemis-
try of 26, 27, 29, and 30, all of which show common
characteristic spectral features.
Analysis of the X-ray data for 28 reveals it to have one
of the most distorted double bonds experimentally de-
tected. Indeed, it compares to that reported for 11-bromo-
endo-9-chloro-7-ethoxybicyclo[5.3.1]undec-1(11)-ene (33,
Figure 1), a compound claimed to have the most distorted
double bond for which X-ray data exists.8,9 The trans-
cyclooctene double bonds in both 28 and 33 are in the
particularly unfavorable position being directed toward
the smallest one carbon bridge. Strain relief in both
compounds stems more from torsion (τ33 ) 29.3°, cf. τ28
) 22.1°) than from pyramidalization of the olefinic carbon
atoms (Ìm(33) ) 17.1°, cf. Ìm(28) ) 17.5°). This is unusual
since, per degree of deformation, torsion requires more
energy than pyramidalization,8,10 and thus, geometrically
less restricted alkenes respond preferentially by pyra-
midalization. The dominance of torsional strain release
Syntheses of 215a and 31a ,b are outlined in Scheme 6.
A preliminary account describing these compounds has
appeared.5a The known cyclobutenone 36 was prepared
(8) Wijsman, G. W.; de Wolf, W. H.; Bickelhaupt, F.; Kooijman, H.;
Spek, A. L. J . Am. Chem. Soc. 1992, 114, 9191.
(9) For a review concerning the X-ray data of bridged alkenes, see:
Lease, T. G.; Shea, K. J . Advances in Theoretically Interesting
Molecules; J AI Press Inc.: New York, 1992; Vol. 2, pp 79-112.
(10) Ermer, O.; Lifson, S. J . Am. Chem. Soc. 1973, 95, 4121.
(11) Liu, H.; Tomooka, C.; Moore, H. W Synth. Commun. 1997, 27,
2177.
(12) For the preparation of TBSOTf, see: Corey, E. J . et. al.
Tetrahedron Lett. 1981, 3465.

3382 J . Org. Chem., Vol. 65, No. 11, 2000
Verma et al.
Sch em e 5
Sch em e 7
Sch em e 6
Sch em e 8
of 38 with the corresponding diorganocuprates gave
cyclobutenones 41-43 (65-68%), which upon thermolysis
(p-xylene, 138 °C) gave the bicyclo[3.2.0]heptenones 22-
24 in yields ranging from 68 to 83% (Scheme 7).
Bicycloheptanone 25 was efficiently prepared using the
methods outlined above (Scheme 8). Specifically, the
cyclobutenone 44 was prepared from diisopropyl squarate
and then converted to 45 (80%), 46 (90%), and 47 (80%)
using standard procedures. Cyclobutenone 48 was then
obtained in 75% yield upon treatment with lithium di-
(2-propenyl)cuprate. Thermolysis (p-xylene, 138 °C) fol-
lowed by convex face methylation of the resulting bicyclo-
[3.2.0]heptenone gave 25 in 87% yield.
from diisopropyl squarate.5b O-Methylation of the free
hydroxyl group gave 375a (90%), which was converted to
38 (90%) and 39 (90%) upon treatment with, respectively,
vinyllithium or 4-lithio-1-butene. Cyclobutenone 38 is a
key starting material for the synthesis of a number of
substituted cyclobutenones since it readily undergoes 1,6-
addition of cuprates.13 For example, its treatment with
lithium di-(2-propenyl)cuprate gave 405a in 83% yield.
Thermolysis of 40 resulted in 31a (91%), which then gave
21 (60%) upon methylation. In analogy, 39 gave 31b upon
thermolysis (96%).
Con clu sion
Further demonstration of the efficient 1,6-addition of
cuprates to 38 is outlined in Scheme 7. Here, treatment
In conclusion, we wish to note the following significant
points: (1) 6-exo-methylbicyclo[3.2.0]heptenones and their
2-alkylidene analogues are readily available from dialkyl
(13) For related 1.6-additions of cuprates, see: Liu, H.; Tomooka,
C.; Moore, H. W. J . Org. Chem. 1996, 61, 6009.

Oxy-Cope Rearrangements of Bicyclo[3.2.0]heptenones
J . Org. Chem., Vol. 65, No. 11, 2000 3383
was added n-BuLi (0.98 mL, 1.23 mmol). After being stirred
for 10 min, the reaction mixture was cooled to ca. -78 °C and
the above product (301 mg, 1.03 mmol) in THF (1 mL) was
added. The cold bath was immediately removed, and after 45
min, methyl iodide (0.083 mL, 1.33 mmol) was added. After
an additional 45 min, the reaction was quenched with H2O (5
mL). The aqueous layer was extracted with ether, and the
combined organic layer was washed with brine, dried (MgSO4),
filtered, and concentrated. Chromatography (95% hexanes/
EtOAc) gave 17 (220 mg, 70%) as a pale yellow oil: 1H NMR
δ 5.53 (d, J ) 17.6, 10.8 Hz, 1H), 5.28 (dd, J ) 17.6, 1.7 Hz,
1H), 5.22 (dd, J ) 10.8, 1.7 Hz, 1H), 3.22 (q, J ) 7.6 Hz, 1H),
2.50 (dd, J ) 16.0, 2.4 Hz, 1H), 2.39 (dd, J ) 16.0, 1.7 Hz,
1H), 1.48 (s, 3H), 1.04 (d, J ) 7.6 Hz, 3H), 0.98 (s, 3H), 0.94
(s, 9H), 0.15 (s, 6H); 13C NMR δ 212.6, 148.9, 132.6, 118.1,
114.3, 81.2, 60.0, 48.2, 39.3, 25.6 (3C), 18.1, 16.5, 9.8, 8.5, -3.9
(2C); IR (neat) 1768, 1670 cm-1; HRMS (EI) calcd for C18H30O2-
Si (M+) 306.2015, found 306.2014.
Sch em e 9
(()-1-t er t -B u t y ld im e t h y ls ilo x y -3-e t h e n y l-(en d o)2,
(en d o)4,5-tr im eth ylbicyclo[4.2.1]n on -1(4)-2-en -6-on e (18).
Vinyllithium (1.22 mL, 0.915 mmol) was added to a solution
of 17 (0.140 g, 0.458 mmol) in 10 mL of THF (-78 °C). After
being stirred for 10 min, the reaction mixture was allowed to
warm to ambient temperature. After 30 min, it was quenched
with H2O (5 mL). The aqueous layer was extracted with ether,
and the combined organic layers were washed with brine (1
× 10 mL), dried over MgSO4, filtered, and concentrated.
Chromatography (95% hexanes/EtOAc) gave 18 (87 mg, 57%)
as a colorless oil: 1H NMR δ 6.27 (dd, J ) 17.9, 11.6 Hz, 1H),
5.31 (dd, J ) 17.9, 1.8 Hz, 1H), 5.28 (dd, J ) 11.6, 1.8 Hz,
1H), 2.45 (q, J ) 7.5 Hz, 1H), 2.36 (ddd, J ) 6.1, 4.8, 2.0 Hz,
1H), 2.07-2.03 (m, 1H), 1.89 (dd, J ) 12.3, 2.2 Hz, 1H), 1.88-
1.83 (m, 1H), 1.80 (d, J ) 12.3 Hz, 1H), 1.76 (s, 3H), 1.75-
1.69 (m, 1H), 1.22 (s, 3H), 1.06 (d, J ) 7.5 Hz, 3H), 0.862 (s,
9H), 0.068 (s, 3H), 0.039 (s, 3H); 13C NMR δ 216.5, 142.5, 137.0,
132.2, 117.8, 85.4, 61.7, 55.2, 46.5, 35.8, 35.1, 26.4, 25.8 (3C),
squarates and are useful precursors to bicyclo[4.2.1]-
nonenones and bicyclo[5.2.1]decenones, respectively; (2)
the complexity of these structures and their relation to
a starting dialkyl squarate is generally outlined in
Scheme 9; e.g., bicyclo[5.2.1]decenone 49 and bicyclo-
[4.2.1]nonenone 52 translate respectively to 50 and 53
and these to dimethyl squarate 51; (3) finally, it is noted
that the rearrangements reported here add to a growing
list of polycyclic compounds (e.g., polyquinanes, bicyclo-
[6.3.0]undecenones, bicyclo[4.2.1]non-1(4)-en-6-ones, and
bicyclo[5.2.1]dec-1(10)-en-5-ones) that are now available
from the oxy-Cope ring expansions of the squarate-
derived cyclobutenones.
18.1, 14.8, 10.4, -2.1, -2.5; IR (neat) 1701, 1671, 1632 cm-1
,
HRMS (EI) calcd for C20H34O2Si (M+) 334.2328, found 334.2326.
(()-3-t er t -Bu t yld im e t h ylsiloxy-1-e t h e n yl-2,(en d o)6-
bicyclo[3.2.0]h ep t-2-en -7-on e (19). In the manner analogous
to the preparation of 17, the title compound was prepared by
refluxing a solution of 35b (3.20 g, 11.5 mmol) in toluene (250
mL), which gave (()-1-ethenyl-2-methyl-3[(trimethylsilyl)oxy]-
bicyclo[3.2.0]hept-2-en-7-one (3.05 g, 95%) as a pale yellow oil.
This product (0.145 g, 0.521 mmol) was treated directly with
LDA, prepared from diisopropylamine (0.090 mL, 0.677 mmol)
and n-BuLi (0.410 mL, 0.677 mmol), and methyl iodide (0.050
mL, 0.781 mmol). Workup and chromatography (90% hexanes/
EtOAc) gave 19 (0.100 g, 66%) as a pale yellow oil: 1H NMR
δ 5.85 (dd, J ) 17.5, 10.7 Hz, 1H), 5.22 (dd, J ) 17.5, 1.5 Hz,
1H), 5.12 (dd, J ) 10.7, 1.5 Hz, 1H), 2.96-2.91 (m, 1H), 2.88-
2.82 (m, 1H), 2.30-2.26 (m, 1H), 2.09 (dd, J ) 5.2, 2.1 Hz,
1H), 1.51 (t, J ) 2.1 Hz, 3H), 1.19 (d, J ) 7.6 Hz, 3H), 0.946
(s, 9H), 0.149 (s, 3H), 0.143 (s, 3H); 13C NMR δ 211.5, 148.9,
134.9, 115.6, 112.9, 79.5, 57.6, 47.1, 39.0, 25.6 (3C), 18.1, 14.0,
9.2, -4.0 (2C); IR (neat) 1772, 1672 cm-1; HRMS (CI) calcd
for C17H29O2Si (MH+) 293.1936, found 293.2183.
Exp er im en ta l Section
Gen er a l In for m a tion . All reactions were conducted under
a positive pressure of nitrogen or argon at ambient tempera-
ture using flame-dried glassware unless otherwise indicated.
Temperatures designated to be 0 or -78 °C are approximate
and refer to bath temperatures. Air- and moisture-sensitive
liquids were transferred via syringe at ambient temperature
or via cannula at -78 °C through rubber septa. Silica gel (230-
400 mesh) was used for column chromatography unless
otherwise specified. Tetrahydrofuran and diethyl ether were
purged with nitrogen and then passed through two 4 × 36 in.
columns of anhyd neutral A-2 alumina (8 × 14 mesh). Toluene,
p-xylene, and CH2Cl2 were distilled from CaH2 immediately
before use. Triethylamine and 2,6-lutidine were distilled from
CaH2 and stored over KOH pellets. n-Butyllithium and tert-
butyllithium were used as solutions in hydrocarbon solvents.
Methyllithium and vinyllithium14 were used as solutions in
ether and their molarities established by titration against
diphenyl acetic acid in THF. Methyl iodide was filtered
through a pipet of basic alumina under N2 before use. All other
solvents and reagents were used as received. 1H NMR and 13C
NMR spectra were recorded at 500 and 125 MHz, respectively,
in CDCl3, unless specified otherwise. Melting points are
uncorrected.
(()-1-ter t-Bu t yld im et h ylsiloxy-2,(en d o)5-d im et h yl-3-
eth en ylbicyclo[4.2.1]n on -2-en -6-on e (20). Following the
general procedure as described for 18, the title compound was
prepared from 19 (95 mg, 0.358 mmol) and vinyllithium (0.358
mL, 0.358 mmol). Workup and chromatography (90% hexanes/
1
EtOAc) gave 20 (58 mg, 56%) as a pale yellow oil: H NMR δ
6.64 (dd, J ) 17.6, 11.1 Hz, 1H), 5.23 (d, J ) 17.6 Hz, 1H),
5.17 (d, J ) 11.1 Hz, 1H), 3.10 (t, J ) 7.0 Hz, 1H), 2.80 (quin,
J ) 7.0 Hz, 1H), 2.30 (dt, J ) 11.6, 5.1 Hz, 1H), 2.24-2.19 (m,
1H), 2.16-2.12 (m, 1H), 1.85-1.80 (m, 1H), 1.77-1.68 (m, 2H),
1.72 (s, 3H), 1.05 (d, J ) 7.3 Hz, 3H), 0.858 (s, 9H), 0.074 (s,
3H), 0.038 (s, 3H); 13C NMR δ 216.0, 144.1, 134.7, 131.9, 115.3,
87.7, 55.1, 47.2, 40.6, 36.2, 34.0, 29.7, 25.7 (3C), 17.4, 9.2, -2.1,
-2.5; IR (neat) 1701 cm-1; HRMS (EI) calcd for C19H32O2Si
(M+) 320.2171, found 320.2179.
(()-3-ter t-Bu t yld im et h ylsiloxy-1-et h en yl-2-en d o-5,6-
tr im eth ylbicyclo[3.2.0]h ep t-2-en e-7-on e (17). A solution of
35a (1.0 g, 3.42 mmol) in 40 mL of toluene was refluxed for 5
h. The solvent was removed in vacuo to give (()-3-tert-
butyldimethylsiloxy-1-ethenyl-2,5-dimethylbicyclo[3.2.0]hept-
2-en-7-one as a yellow oil that slowly solidified. To a 0 °C THF
(20 mL) solution of diisopropylamine (0.161 mL, 1.23 mmol)
(()-en d o-6,7-Dim et h yl-exo-2-m et h oxy-10-(2-m et h yl-1-
p r op en yl)bicyclo[5.2.1]d ec-1(10)-en -5-on e (26). Vinyllith-
ium (0.272 mL, 0.272 mmol) and 215a (55 mg, 0.248 mmol)
(14) For a preparation of vinyllithium, see: Seyfurth, D.; Wiener,
M. A. J . Am. Chem. Soc. 1961, 83, 3583.

3384 J . Org. Chem., Vol. 65, No. 11, 2000
Verma et al.
were used to prepare 26 in a manner analogous to the
procedure used for the preparation of 18. Chromatographic
purification of the crude product (80% hexanes/EtOAc) gave
1.80-1.72 (m, 1H), 1.74 (d, J ) 1.3 Hz, 3H), 1.60-1.58 (m,
2H), 1.51 (d, J ) 0.9 Hz, 3H), 1.49-1.45 (m, 3H), 1.28-1.25
(m, 2H), 13C NMR (100 MHz, CDCl3) δ 210.5, 143.8, 136.3,
121.6, 121.5, 76.5, 59.8, 56.4, 48.7, 37.9, 29.1, 26.2, 26.1, 21.4,
21.3, 20.7, 20.1; IR (neat) 1745, 1672 cm-1; HRMS (CI) calcd
for C17H24O2 (M+) 260.1776, found 260.1774.
1
26 (37 mg, 60%) as a white solid: mp 73-74 °C; H NMR δ
6.03 (s, 1H), 4.13 (dd J ) 7.0, 2.3 Hz, 1H), 3.32 (s, 3H), 2.51 (t,
J ) 12.6 Hz, 1H), 2.44 (q, J ) 7.4 Hz, 1H), 2.20-2.10 (m, 3H),
2.02-1.95 (m, 2H), 1.87 (s, 3H), 1.75 (s, 3H), 1.72-1.64 (m,
2H), 1.23 (d, J ) 7.5 Hz, 3H), 1.06 (s, 3H); 13C NMR δ 217.5,
144.1, 138.4, 136.8, 121.7, 80.9, 67.3, 57.3, 55.7, 35.6, 35.0, 34.7,
29.7, 26.6, 21.6, 19.9, 13.6; IR (neat) 1691, 1640 cm-1; HRMS
(EI) calcd for C17H26O2 (M+) 262.1933, found 262.1931.
(()-2-[2-(E)-(Meth oxy)m eth ylid en e]-1-(2-m eth yl-1-p r o-
pen yl)-6-en do-m eth ylbicyclo[3.2.0.]h eptan -7-on e (22). The
title compound was prepared by refluxing a solution of 41 (77
mg, 0.350 mmol) in p-xylene (15 mL) for 2 h. Concentration
and filtration through a plug of silica (10:1 hexanes/EtOAc)
gave 22 (54 mg, 72%) as a pale yellow oil: 1H NMR δ 5.87 (s,
1H), 5.38 (s, 1H), 3.58 (s, 3H), 2.84-2.77 (m, 2H), 2.46 (t, J )
6.0 Hz, 1H), 2.43-2.34 (m, 1H), 2.08-2.01 (m, 1H), 1.89
(overlapping d, J ) 8.1, 4.7 Hz, 1H), 1.71 (s, 3H), 1.56 (s, 3H),
1.18 (d, J ) 7.5 Hz, 3H), 13C NMR δ 212.8, 143.2, 135.8, 123.3,
121.2, 77.3, 59.9, 55.1, 48.8, 30.4, 26.2 (2C), 20.1, 13.7; IR (neat)
1770, 1675 cm-1; HRMS (EI) calcd for C14H20O2 (M+) 220.1463,
found 220.1468.
(()-exo-2-Met h oxy-14-(2-m et h yl-1-p r op en yl)t r icyclo-
[7.4.1.01,10]tetr a d ec-1(14)-en -5-on e (29). The title compound
was prepared from 24 (47 mg, 0.181 mmol) and vinyllithium
(0.400 mL, 0.400 mmol) in analogy to the procedure used for
the synthesis of 26. Chromatography (80% hexanes/EtOAc)
gave 29 (33 mg, 65%) as a white solid: mp 83-84 °C; 1H NMR
δ 6.27 (s, 1H), 4.13 (dd J ) 6.9, 2.5 Hz, 1H), 3.27 (s, 3H), 2.55
(dt, J ) 11.5, 1.5 Hz, 1H), 2.37 (dd, J ) 9.1, 4.2 Hz, 1H), 2.21-
2.14 (m, 1H), 2.11-2.06 (m, 2H), 2.01-1.91 (m, 1H), 1.90-
1.80 (m, 3H), 1.86 (s, 3H), 1.79-1.69 (m, 2H), 1.71 (s, 3H),
1.63-1.53 (m, 4H), 1.48-1.40 (m, 1H) 1.24-1.12 (m, 1H); 13
C
NMR δ 217.6, 145.5, 140.8, 135.2, 123.8, 80.9, 71.1, 57.3, 55.5,
36.4, 35.7, 35.1, 33.9, 28.8, 26.2 (2C), 24.6, 22.5, 19.5; IR (neat)
1684 cm-1; HRMS (EI) calcd for C19H28O2 (M+) 288.2089, found
288.2093.
(()-en d o-5,6-Dim et h yl-(E)-2-m et h oxym et h ylid en e-1-
m eth ylbicyclo[3.2.0]h ep ta n -7-on e (25). A solution of cy-
clobutenone 48 (410 mg, 2.28 mmol) in 100 mL of p-xylene
was refluxed for 1 h. Removal of the solvent provided 396 mg
(96%) of a pale yellow oil that was used without further
purification. Methylation of this according to the procedure
used in the preparation of 17 followed by chromatographic
purification (90% hexanes/EtOAc) gave 25 (0.352 g, 91%) as a
yellow oil: 1H NMR δ 5.92-5.91 (m, 1H), 3.59 (s, 3H), 3.06 (q,
J ) 7.4 Hz, 1H), 2.69 (ddd, J ) 17.2, 8.9, 1.2 Hz, 1H), 2.46-
2.42 (m, 1H), 1.92 (overlapping d, J ) 8.2 Hz, 1H), 1.65-1.61
(m, 1H), 1.04 (s, 3H), 1.02 (s, 3H), 0.991 (d, J ) 7.4 Hz, 3H);
13C NMR δ 212.2, 142.8, 122.3, 70.2, 59.8, 57.0, 45.4, 37.7, 25.5,
15.5, 14.3, 8.0; IR (neat) 1766, 1688, 1674 cm-1; HRMS (EI)
calcd for C12H17O2 (M - 1) 193.1229, found 193.1223.
(()-exo-2-Met h oxy-en d o-6-m et h yl-10-(2-m et h yl-1-p r o-
p en yl)bicyclo[5.2.1]d ec-1(10)-en -5-on e (27). The title com-
pound was prepared from 22 (35 mg, 0.182 mmol) and
vinyllithium (0.200 mL, 0.200 mmol) according to the general
procedure used for the synthesis of 26. Workup and chroma-
tography (80% hexanes/EtOAc) gave 27 (24 mg, 61%) as a pale
yellow oil: 1H NMR δ 6.32 (s, 1H), 4.31 (dd J ) 6.9, 2.5 Hz,
1H), 3.32 (s, 3H), 2.85 (d, J ) 6.3 Hz, 1H), 2.66-2.59 (m, 2H),
2.24-2.15 (m, 3H), 1.99-1.82 (m, 3H), 1.87 (s, 3H), 1.80 (s,
3H), 1.68 (dd, J ) 12.4, 6.0 Hz, 1H), 1.30 (d, J ) 7.5 Hz, 3H);
13C NMR δ 218.3, 141.8, 138.5, 135.4, 122.1, 80.2, 62.8, 57.1,
55.6, 35.1, 34.3, 30.5, 27.0, 26.1, 20.3, 16.5; IR (neat) 1693 cm-1
;
HRMS (EI) calcd for C16H24O2 (M+) 248.1776, found 248.1769.
(()-2-[2-(E)-(Meth oxy)m eth ylid en e]-1-(2-m eth yl-1-p r o-
pen yl)-1H-cyclobu ta[1,2:1,4]dicyclopen ten -4-on e (23). The
title compound was prepared by refluxing a solution of 42 (205
mg, 0.830 mmol) in p-xylene (30 mL) for 3 h. Concentration
and filtration through a plug of silica (10:1 hexanes/EtOAc)
gave 23 (170 mg, 83%) as a white solid: mp 70-71 °C; 1H NMR
δ 5.80-5.79 (m, 1H), 5.28-5.27 (m, 1H), 3.55 (s, 3H), 3.09 (d,
J ) 8.9 Hz, 1H), 2.80 (dd, J ) 16.5, 8.4 Hz, 1H), 2.38-2.30
(m, 1H), 2.05-1.97 (m, 2H), 1.92-1.88 (m, 1H), 1.78-1.70 (m,
2H), 1.73 (d, J ) 1.3 Hz, 3H), 1.60-1.52 (m, 2H), 1.48 (s, 3H),
1.37-1.30 (m, 1H), 13C NMR δ 216.0, 143.2, 137.2, 120.8, 119.5,
75.5, 65.0, 59.8, 58.2, 35.5, 32.4, 29.6, 26.9, 26.6 26.1, 20.7; IR
(neat) 1765, 1677 cm-1; HRMS (EI) calcd for C16H22O2 (M+)
246.1619, found 246.1612.
(()-en do-6,7-Dim eth yl-exo-2-m eth oxy-10-m eth yl-bicyclo-
[5.2.1]d ec-1(10)-en -5-on e (30). The title compound was
prepared from 25 (53 mg, 0.273 mmol) and vinyllithium (0.875
mL, 0.656 mmol) in analogy to the procedure used for the
synthesis of 26. Workup and chromatography (80% hexanes/
EtOAc) gave 30 (36 mg, 60%) as an oil: 1H NMR δ 4.30 (dd, J
) 6.7 Hz, 1H), 3.28 (s, 3H), 2.46-2.40 (m, 2H), 2.25-2.20 (m,
1H), 2.09-2.06 (m, 1H), 2.04-1.99 (m, 2H), 2.02 (s, 3H), 1.97-
1.95 (m, 1H), 1.70 (ddd, J ) 12.4, 6.4, 1.4 Hz, 1H), 1.27-1.24
(m, 1H), 1.17 (d, J ) 7.5 Hz, 3H), 1.14 (s, 3H); 13C NMR δ
216.8, 142.4, 136.6, 79.6, 67.5, 56.9, 55.9, 35.2, 34.8, 34.3, 29.4,
20.1, 15.7, 13.8; IR (neat) 1691 cm-1; HRMS (EI) calcd for
C
14H22O2 (M+) 222.1620, found 222.1620.
(()-2-[2-(E)-(Meth oxy)m eth ylid en e]-5-exo-m eth yl-1-(2-
m eth yl-1-p r op en yl)bicyclo[3.2.0]h ep ta n -7-on e (31a ). The
title compound was prepared by refluxing a solution of 405a
(550 mg, 2.50 mmol) in p-xylene (100 mL). Concentration and
filtration through a plug of silica (10:1 hexanes/EtOAc) gave
31a (500 mg, 91%) of 31a as a clear oil: 1H NMR δ 5.83 (s,
1H), 5.24 (s, 1H), 3.57 (s, 3H), 2.89 (d, J ) 18.0 Hz, 1H), 2.79
(dd, J ) 16.8, 8.4 Hz, 1H), 2.64 (d, J ) 18.0 Hz, 1H), 2.33-
2.41 (m, 1H), 1.92 (dd, J ) 12.8, 7.9 Hz, 1H), 1.77 (dd, J )
12.2, 8.5 Hz, 1H), 1.76 (s, 3H), 1.54 (s, 3H), 1.21 (s, 3H); 13C
NMR δ 210.4, 143.3, 137.4, 121.0, 120.2, 77.1, 59.9, 54.7, 45.2,
38.7, 26.3, 25.8, 22.0, 21.0; IR (neat) 1771, 1675, cm-1; HRMS
(EI) calcd for C14H20O2 (M+) 220.1463, found 220.1469.
(()-1-F or m yl-3a â,8,8-tr im eth yl-cyclop en ta cycloocten -
1-en -5-on e (32a ). The title compound was prepared from 31a
(70 mg, 0.300 mmol) and vinyllithium (0.490 mL, 0.490 mmol)
in analogy to the procedure used for the synthesis of 26.
Workup and chromatography (90% hexanes/EtOAc) gave 32a
(44 mg, 59%) as a white solid: mp 88-89 °C; 1H NMR δ 9.93
(s, 1H), 2.78 (d, J ) 11.6 Hz, 1H), 2.68-2.63 (m, 2H), 2.52-
2.39 (m, 3H), 2.27 (ddd J ) 7.4, 4.6, 2.4 Hz, 1H), 1.95 (d, J )
14.1 Hz, 1H), 1.89-1.82 (m, 2H), 1.75-1.68 (m, 1H), 1.52 (dd,
J ) 8.1, 7.0 Hz, 1H), 1.14 (s, 3H), 1.08 (s, 3H), 1.02 (s, 3H);
13C NMR δ 212.3, 190.1, 165.4, 139.7, 49.5, 41.5, 37.5, 35.8,
35.5, 35.2, 29.7, 29.5, 28.9, 26.9, 25.6; IR (neat) 1697, 1664,
(()-exo-2-Met h oxy-13-(2-m et h yl-1-p r op en yl)t r icyclo-
[7.3.1.01,10]t r id ec-1(13)-en -5-on e (28). The title compound
was prepared from 23 (57 mg, 0.231 mmol) and vinyllithium
(0.580 mL, 0.580 mmol) in analogy to the procedure used for
the synthesis of 26. Chromatography (80% hexanes/EtOAc)
furnished 28 (38 mg, 60%) as a white solid: mp 73-74 °C; 1H
NMR δ 5.87 (s, 1H), 4.15 (t, J ) 7.5 Hz, 1H), 3.31 (s, 3H), 2.74
(dd, J ) 12.0, 7.5 Hz, 1H), 2.48 (dt, J ) 12.0, 1.6 Hz, 1H),
2.26-2.19 (m, 3H), 2.11-2.04 (m, 1H), 2.01-1.94 (m, 1H),
1.92-1.85 (m, 4H), 1.84 (s, 3H), 1.82-1.75 (m, 3H), 1.73 (s,
3H), 1.68-1.61 (m, 1H); 13C NMR δ 217.2, 144.9, 139.3, 136.6,
121.8, 80.9, 72.3, 66.5, 57.2, 35.7, 34.7, 33.5, 31.6, 30.1, 28.5,
26.5, 24.5, 19.8; IR (CHCl3) 1680, 1638 cm-1; HRMS (EI) calcd
for C18H26O2 (M+) 274.1932, found 274.1931.
(()-2-[2-(E)-(Meth oxy)m eth ylid en e]-1-(2-m eth yl-1-p r o-
pen yl)-1H-cyclopen ta[1,4]cyclobu ta[1,2]ben zen -4-on e (24).
The title compound was prepared by refluxing a solution of
43 (132 mg, 0.508 mmol) in p-xylene (15 mL) for 3 h.
Concentration and filtration through a plug of silica (10:1
hexanes/EtOAc) gave 24 (90 mg, 68%) as a white solid: mp
1
90-92 °C; H NMR (400 MHz, CDCl3) δ 5.85 (t, J ) 2.4 Hz,
1H), 5.42 (t, J ) 1.3 Hz, 1H), 3.56 (s, 3H), 2.99 (dd, J ) 8.1,
3.5 Hz, 1H), 2.80 (ddd, J ) 16.1, 9.0, 1.6 Hz, 1H), 2.57-2.47
(m, 1H), 2.10 (dd, J ) 12.8, 8.2 Hz, 1H), 1.96-1.90 (m, 1H),

Oxy-Cope Rearrangements of Bicyclo[3.2.0]heptenones
J . Org. Chem., Vol. 65, No. 11, 2000 3385
1614 cm-1; HRMS (CI) calcd for C15H23O2 (MH+) 235.1698,
found 235.1696.
and NaHCO3, dried over MgSO4, filtered, and concentrated.
Chromatography (30:1 hexanes/EtOAc) gave 35a (1.08 g, 69%)
as a pale yellow green oil: 1H NMR δ 6.15 (dd, J ) 17.6, 11.1
Hz, 1H), 5.95 (dd, J ) 17.6, 1.9 Hz, 1H), 5.46 (dd, J ) 11.1,
1.9 Hz, 1H), 4.80 (m, 1H), 4.74 (m, 1H), 2.51(dd, J ) 7.7 Hz,
2H), 2.15 (s, 3H), 1.71 (s, 3H), 0.85 (s, 9H), 0.10 (s, 3H), -0.05
(s, 3H); 13C NMR δ 193.4, 176.6, 145.3, 141.3, 123.3, 123.0,
115.0, 95.2, 43.7, 25.6 (3C), 23.5, 18.1, 11.5, -3.7, -3.8; IR
(neat) 1761, 1654, cm-1; HRMS (EI) calcd for C17H28O2Si (M+)
292.1859, found 292.1865.
2-Eth en yl-3-m eth yl-4-(2-p r op en yl)-4-ter t-bu tyld im eth -
ylsiloxy-2-cyclobu ten -1-on e (35b). In a manner analogous
to that used for the synthesis of 35a , 34 (355 mg, 2.11 mmol)
gave 35b (2.50 g, 91%) as a pale yellow oil: 1H NMR δ 6.13
(dd, J ) 17.6, 11.1 Hz, 1H), 5.95 (d, J ) 17.6, 1.9 Hz, 1H),
5.70 (m, 1H), 5.46 (dd, J ) 11.1, 1.9 Hz, 1H), 5.02 (m, 2H),
2.49 (dd, J ) 7.7 Hz, 2H), 2.14 (s, 3H), 0.85 (s, 9H), 0.11 (s,
3H), -0.01 (s, 3H); 13C NMR δ 193.7, 177.1, 145.2, 133.0, 123.3,
123.0, 117.9, 94.9, 39.8, 25.6 (3C), 18.1, 11.8, -3.7 (2C); IR
(neat) 1760, 1656, 1644 cm-1; HRMS (EI) calcd for C16H27O2-
Si (MH+) 279.1702, found 279.1780.
(()-2-[2-(E)-(Meth oxy)m eth ylid en e]-1-(2-m eth yl-1-p r o-
p en yl)bicyclo[3.2.0.]h ep ta n -7-on e (31b). The title com-
pound was obtained by refluxing a p-xylene solution (30 mL)
of 39 (166 mg, 0.806 mmol). Concentration and filtration
through a plug of Florisil (10:1 hexanes/EtOAc) gave the
product as a colorless oil (160 mg (96%), which consisted of a
4:1 mixture of E/ Z diastereomers (separable by chromatog-
raphy, 20:1 hexanes/EtOAc). Irradiation of the enolic vinyl
proton (δ, 5.85) of the major isomer resulted in a slight
enhancement of the absorbance of the proton at the bridghead
position (δ, 5.33), whereas an analogous study with the minor
isomer produced no effect. On the basis of these data, the major
isomer is assigned the E-configuration. Characteristic spectral
data for this compound follow: 1H NMR δ 5.85 (s, 1H), 5.33
(s, 1H), 3.59 (s, 3H), 3.13 (d, J ) 9.2 Hz, 1H), 2.91 (dd, J ) 9.1
Hz, 6.0 Hz, 1H), 2.78 (dd, J ) 16.6 Hz, 8.6 Hz, 1H), 2.61 (dd,
J ) 5.6 Hz, 1H), 2.34 (m, 1H), 2.01 (m, 1H), 1.83 (dd, J ) 13.2
Hz, 7.9 Hz, 1H), 1.73 (s, 3H), 1.58 (s, 3H); 13C NMR δ 210.9,
142.8, 136.5, 122.7, 120.8, 76.9, 59.9, 48.4, 39.5, 30.8, 26.1, 25.6,
20.1; [Z]-δ 5.72 (s, 1H), 5.40 (s, 1H), 3.54 (s, 3H), 3.13 (d, J )
9.2 Hz, 1H), 2.46-2.51 (m, 1H), 2.35-2.42 (m, 1H), 2.17-2.27
(m, 3H), 1.97-2.05 (m, 1H), 1.75 (s, 3H), 1.61 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 209.8, 141.9, 136.1, 121.0, 119.0, 70.2,
59.7, 55.1, 31.5, 29.5, 25.6, 20.3, 17.2; IR (neat) 1773, 1702,
1683; HRMS (EI) calcd for C13H18O2 (M+) 206.1307, found
206.1308.
3-Eth en yl-4-m eth oxy-2-(2-m eth yl-1-p r op en yl)-2-cyclo-
bu ten -1-on e (38). Vinyllithium (3.93 mL, 3.93 mmol) was
added to a THF (35 mL) solution of 375a (750 mg, 3.57 mmol)
at -78 °C. After the green-yellow solution was stirred for 15
min, 5 M HCl (2 mL) was added, and the cold bath was
removed. After 30 min, the reaction mixture was neutralized
with saturated NaHCO3 (10 mL). The aqueous layer was
extracted with ether and the combined organic layer washed
with brine, dried over MgSO4, filtered, and concentrated.
Chromatography (9:1 hexanes/EtOAc) furnished 566 mg (90%)
(()-3a â-8,8-Dim eth yl-1-for m ylcyclop en ta cycloocten -1-
en -5-on e (32b). The title compound was prepared from 31b
(75 mg, 0.364 mmol) and vinyllithium (0.400 mL, 400 mmol)
according to the general procedure used for the synthesis of
26. Workup and chromatography (90% hexanes/EtOAc) gave
32b (41 mg, 51%) as a colorless oil: 1H NMR δ 9.94 (s, 1H),
2.73 (t, J ) 11.6 Hz, 1H), 2.70-2.66 (m, 1H), 2.61-2.53 (m,
2H), 2.46-2.33 (m, 3H), 2.23-2.18 (m, 2H), 2.05 (d, J ) 14.2
Hz, 1H), 1.96-1.90 (m, 1H), 1.60-1.56 (m, 1H), 1.50-1.44 (m,
1H), 1.06 (s, 3H), 1.04 (s, 3H); 13C NMR δ 213.8, 189.6, 161.7,
141.6, 52.3, 44.4, 41.6, 37.4, 35.8, 35.4, 29.9, 29.5, 28.8, 28.6;
IR (neat) 2720, 1697, 1660, 1619 cm-1; HRMS (EI) calcd for
1
of 38 as a yellow oil: H NMR δ 6.83 (dd, J ) 17.3, 10.6 Hz,
1H), 5.92 (d, J ) 17.6 Hz, 1H), 5.76 (d, J ) 10.6 Hz, 1H), 5.71
(s, 1H), 5.11 (s, 1H), 3.40 (s, 3H), 2.07 (s, 3H), 1.87 (s, 3H); 13
C
NMR δ 190.5, 163.4, 146.9, 146.6, 126.9, 126.5, 112.3, 89.8,
55.1, 26.7, 21.7; IR (neat) 2977, 2920, 2826, 1746, 1647, 1613,
cm-1; HRMS (EI) calcd for C11H14O2 (M+) 178.0993, found
178.0994.
3-(3-Bu ten yl)-4-m eth oxy-2-(2-m eth yl-1-p r op en yl)-2-cy-
clobu ten -1-on e (39). 4-Lithio-1-butene in 125 mL of THF,
prepared from tert-butyllithium (13.3 mL, 22.6 mmol) and
4-bromo-1-butene (1.15 mL, 11.3 mmol, was added to a THF
(50 mL) solution of 375a (950 mg, 4.52 mmol) at - 78 °C. The
reaction mixture was then removed from the cold bath, treated
with 5 M HCl (3 mL), and allowed to warm to ambient
temperature. It was quenched with NaHCO3 (40 mL), and the
aqueous layer was extracted with ether. The combined organic
layer was washed with brine, dried over MgSO4, filtered, and
concentrated. Chromatography (9:1 hexanes/EtOAc) provided
832 mg (90%) of 39 as a colorless oil: 1H NMR δ 5.87-5.79
(m, 1H), 5.58 (s, 1H), 5.08 (d, J ) 17.0 Hz, 1H), 5.03 (d, J )
9.8 Hz, 1H), 4.81 (s, 1H), 3.46 (s, 3H), 2.74-2.69 (m, 1H), 2.67-
C
14H20O2 (MH+) 220.1463, found 220.1463.
2-Eth en yl-3-m eth yl-4-(2-m eth yl-2-p r op en yl)-4-ter t-bu -
tyld im eth ylsiloxy-2-cyclobu ten -1-on e (35a ). The Grignard
reagent was formed by the dropwise addition of an ether (260
mL) solution of 3-chloro-2-methylpropene (25.9 mL, 262 mmol)
to lightly sanded and cut magnesium ribbon (5.5 g, 227 mmol)
over 25 min. This was then added over 20 min at -78 °C to a
THF (300 mL) solution of 3-ethenyl-2-methyl-4,4-dimethoxy-
cyclobuutenone (34) (1.62 g, 9.63 mmol) until the green-yellow
color of the cyclobutenone had dissipated. This required 150
mL of the Grignard solution. Water (100 mL) was added and
the cooling bath was removed. The mixture was extracted with
ether, washed with brine, dried (Na2SO4), filtered, and con-
centrated. The resulting crude cyclobutenedione monoketal
intermediate was dissolved in THF (100 mL), cooled to 0 °C
and treated with 0.5 mL of 1 M HCl. After 40 min, 50 mL of
saturated NaHCO3 was added, and the mixture was extracted
with EtOAc, washed with brine, dried (Na2SO4), filtered, and
concentrated. Chromatography (2:1 hexanes/EtOAc) gave 2-ethe-
nyl-4-hydroxy-3-methyl-4-(2-methyl-2-propenyl)-2-cyclobuten-
1-one (1.57 g, 92%) as a white crystalline solid: mp 46-47
2.60 (m, 1H), 2.44-2.34 (m, 2H), 2.02 (s, 3H), 1.84 (s, 3H); 13
C
NMR δ 189.1, 173.3, 148.9, 145.0, 136.9, 115.8, 112.1, 91.0,
56.8, 30.2, 27.1, 26.4, 21.4; IR (neat) 1663, 1639 cm-1; HRMS
(EI) calcd for C13H18O2 (M+) 206.1307, found 206.1308.
4-Meth oxy-3-[(E)-3-p en ten yl]-2-(2-m eth yl-1-p r op en yl)-
2-cyclobu ten -1-on e (41). Following the general procedure as
described for 48, the title compound was prepared from 38 (100
mg, 0.562 mmol) and the lithium reagent prepared from trans-
1-bromopropene (0.174 mL, 2.02 mmol) and tert-butyllithium
(2.38 mL, 4.04),and CuBr‚SMe2 (208 mg, 1.01 mmol). Workup
and chromatography (20:1 hexanes/EtOAc) furnished 80 mg
(65%) 41 as a pale yellow oil: 1H NMR δ 5.58 (s, 1H), 5.54-
5.46 (m, 1H), 5.44-5.42 (m, 1H), 4.81 (s, 1H), 3.46 (s, 3H),
2.70-2.56 (m, 2H), 2.37-2.27 (m, 2H), 2.02 (s, 3H), 1.85 (s,
3H), 1.65 (d, J ) 6.2 Hz, 3H); 13C NMR δ 189.1, 173.8, 148.7,
144.7, 129.4, 126.4, 112.2, 91.0, 56.7, 29.1, 27.8, 26.7, 21.4, 17.8;
IR (neat) 1752, 1657, cm-1; HRMS (CI) calcd for C14H21O2
(MH+) 221.1541, found 221.1544.
1
°C; H NMR δ 6.18 (dd, J ) 17.6, 11.1 Hz, 1H), 5.98 (d, J )
17.6 Hz, 1H), 5.49 (d, J ) 11.1 Hz, 1H), 4.93 (s, 1H), 4.85 (s,
1H), 3.09 (bs, 1H), 2.59 (d, J ) 13.8 Hz, 1H), 2.46 (d, J ) 13.8
Hz, 1H), 2.17 (s, 3H), 1.79 (s, 3H); 13C NMR δ 193.2, 175.1,
146.1, 140.8, 123.8, 122.9, 115.9, 92.3, 42.1, 23.1, 11.0; IR (film,
cm-1) 3410, 3076, 1760, 1748, 1651, 1612, 1582; HRMS (EI)
calcd for C11H14O2 (M+) 178.0994, found 178.0992.
A CH2Cl2 (10 mL, 0 °C) solution of the above alcohol (0.950
g, 5.33 mmol) was treated with 2,6-lutidine (1.60 mL, 13.3
mmol) followed by TBSOTf (2.08 mL, 9.06 mmol).12 After 30
min, 0.5 mL of concentrated HCl was added, and the reaction
mixture was allowed to stand for 10 min. After neutralization
with aqueous NaHCO3, the aqueous layer was extracted with
ether, and the combined organic layer was washed with brine
4-Meth oxy-3-[2-(1-cyclop en ten yl)eth yl)]-2-(2-m eth yl-1-
p r op en yl)-2-cyclobu ten -1-on e (42). In analogy to the pro-
cedure used for the synthesis of 48, the title compound was
prepared from 38 (218 mg, 1.22 mmol), 1-iodocyclopentene
(0.65 mL, 5.86 mmol), tert-butyllithium (6.88 mL, 11.7 mmol),

3386 J . Org. Chem., Vol. 65, No. 11, 2000
Verma et al.
and CuBr‚SMe2 (602 mg, 2.93 mmol). Workup and chroma-
tography (20:1 hexanes/EtOAc) furnished 205 mg (68%) 42 as
a pale yellow oil: 1H NMR δ 5.57 (s, 1H), 5.37 (t, J ) 1.7 Hz,
1H), 4.79 (s, 1H), 3.44 (s, 3H), 2.80-2.74 (m, 1H), 2.70-2.64
(m, 1H), 2.40-2.36 (m, 2H), 2.30-2.24 (m, 4H), 2.00 (s, 3H),
1.88-1.82 (m, 2H), 1.83 (s, 3H); 13C NMR δ 189.1, 174.0, 148.6,
144.7, 142.9, 124.4, 112.1, 90.9, 56.7, 35.0, 32.4, 27.5, 26.4, 26.2,
23.4, 21.3; IR (neat) 1754, 1660 cm-1; HRMS (EI) calcd for
3-Eth en yl-4-m eth oxy-2-m eth yl-2-cyclobu ten -1-on e (47).
Vinyllithium (5.10 mL, 4.37 mmol) was added to a THF (40
mL) solution of 46 (675 mg, 3.97 mmol) at -78 °C. After the
green-yellow solution was stirred for 15 min, HCl (5M, 2 mL)
was added, and the cold bath was removed. After 30 min the
reaction mixture was neutralized with saturated NaHCO3 (10
mL). The aqueous layer was extracted with and combined
organic layer was washed with brine, dried over MgSO4,
filtered, and concentrated. Chromatography (75% hexanes/
EtOAc) gave 47 (0.440 g, 80%) as a pale yellow oil: 1H NMR
δ 6.76 (dd, J ) 17.3, 10.6 Hz, 1H), 5.90 (d, J ) 17.3 Hz, 1H),
5.76 (d, J ) 10.6 Hz, 1H), 5.08 (s, 1H), 3.38 (s, 3H), 1.78 (s,
3H); 13C NMR δ 193.4, 168.8, 147.8, 127.0, 126.4, 90.7, 55.5,
C
16H22O2 (M+) 246.1619, found 246.1625.
4-Meth oxy-3-[2-(1-cycloh exen yl)eth yl)]-2-(2-m eth yl-1-
p r op en yl)-2-cyclobu ten -1-on e (43). In analogy to the pro-
cedure used for the synthesis of 48, the title compound was
prepared from 38 (140 mg, 0.787 mmol), 1-iodocyclohexene
(393 mg, 1.89 mmol), tert-butyllithium (2.22 mL, 3.78) and
CuBr‚SMe2 (194 mg, 0.944 mmol). Workup and chromatogra-
phy (20:1 hexanes/EtOAc) furnished 138 mg (68%) 43 as a pale
yellow oil: 1H NMR δ 5.56 (s, 1H), 5.44-5.43 (m, 1H), 4.80 (s,
1H), 3.45 (s, 3H), 2.75-2.69 (m, 1H), 2.65-2.59 (m, 1H), 2.29-
2.20 (m, 2H), 2.01 (s, 3H), 1.98-1.95 (m, 4H), 1.83 (s, 3H),
1.65-1.60 (m, 2H), 1.55-1.51 (m, 2H); 13C NMR δ 189.2, 174.3,
148.6, 144.6, 136.1, 122.1, 112.2, 91.0, 56.7, 34.1, 28.1, 26.4,
26.1, 25.2, 22.8, 22.3, 21.4; IR (neat) 1753, 1661 cm-1; HRMS
(EI) calcd for C17H24O2 (M+) 260.1776, found 260.1770.
4-H yd r oxy-3-isop r op oxy-2-m e t h yl-2-cyclob u t e n e -1-
on e (45). Lithium tri-tert-butoxyaluminohydride (2.12 g, 8.34
mmol) was slowly added to a THF (100 mL) solution of
4-methyl-3-isopropoxycyclobutene-1,2-dione (44) (1.0 g, 6.95
mmol) at 0 °C. After being stirred for 15 min, the colorless,
cloudy reaction mixture was quenched with 10% HCl (20 mL).
After 10 min, the aqueous phase was extracted with ether and
the combined organic layer washed with brine, dried over
MgSO4, filtered, and concentrated. Chromatography (50%
hexanes/EtOAc) gave 45 (0.810 g, 80%) as a colorless oil: 1H
NMR δ 5.46 (d, J ) 5.9 Hz, 1H), 5.08 (dd, J ) 5.9, 1.7 Hz,
1H), 4.82 (sept, J ) 6.2 Hz, 1H), 1.53 (s, 3H), 1.35 (d, 6.2 Hz,
3H), 1.30 (d, J ) 6.2 Hz, 3H); 13C NMR δ 192.1, 182.0, 122.1,
81.3, 77.1, 22.8, 22.3, 6.0; IR (neat) 3359, 1754, 1609; HRMS
(EI) calcd for C8H13O3 (MH+) 157.0864, found 157.0862.
3-Isop r op oxy-4-m e t h oxy-2-m e t h yl-2-cyclob u t e n -1-
on e (46). To a slurry containing 45 (0.720 g, 4.62 mmol), K2-
CO3 (6.38 g, 46.2 mmol) and Ag2O (2.14 g, 9.24 mmol) in
acetonitrile (50 mL) was added CH3I (2.88 mL, 46.2 mmol).
After stirring for 12 h at room temperature, the contents were
filtered through Celite (1/2"), and concentrated. Chromatog-
raphy (70% hexanes/EtOAc) gave 46 (0.708 g, 90%) as a pale
7.8; IR (neat), 1752, 1638, 1628 cm-1
.
3-(2-Met h yl-1-b u t en yl)-2-m et h yl-4-m et h oxy-2-cyclo-
bu ten -1-on e (48). To a THF (20 mL) solution of 2-bromopro-
pene (0.658 mL, 7.40 mmol) at -78 °C was added tert-
butyllithium (8.70 mL, 14.8 mmol). After 5 min, CuBr‚SMe2
(0.760 g, 3.70 mmol) was added in a single portion resulting
in an immediate color change from colorless to orange. After
5 min, the reaction mixture was warmed to 0 °C, at which
point it became homogeneous. A THF (5 mL) solution of 47
(0.425 g, 3.08 mmol) was added to the cuprate solution at -78
°C. The resulting bright red-orange reaction mixture was
stirred for 30 min while it was allowed to warm to ambient
temperature. The contents were quenched with saturated NH4-
Cl (5 mL) and diluted with H2O (10 mL). The aqueous layer
was extracted with ether and the combined organic layer
washed with aqueous NH4Cl, dried over MgSO4, filtered, and
concentrated. Chromatography (80% hexanes/EtOAc) gave 48
(0.413 g, 75%) as a volatile pale yellow oil: 1H NMR (400 MHz,
CDCl3) δ 4.77-4.75 (m, 2H), 4.69 (s, 1H), 3.42 (s, 3H), 2.77-
2.69 (m, 1H), 2.67-2.59 (m, 1H), 2.38-2.25 (m, 2H), 1.74 (s,
3H),1.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.3, 177.7,
148.9, 143.9, 110.7, 91.7, 56.9, 33.6, 25.8, 22.2, 7.6; IR (neat)
1762, 1637 cm-1; HRMS (CI) calcd for C11H17O2 (MH+)
181.1228, found 181.1233
Ack n ow led gm en t. The authors thank the National
Institutes of Health (GM-36312) for financial support
of this work and SmithKline Beecham for a generous
gift of squaric acid.
Su p p or t in g In for m a t ion Ava ila b le: X-ray crystallo-
graphic data for (()-exo-2-methoxy-13-(2-methyl-1-propenyl)-
tricyclo[7.3.1.01,10]tridec-1(13)-en-5-one (28). This material is
available free of charge via the Internet at http://pubs.acs.org.
1
yellow oil: H NMR δ 4.74-4.73 (m, 1H,), 4.63 (sept., J ) 6.2
Hz, 1H), 3.34 (s, 3H), 1.56 (s, 3H), 1.30 (d, J ) 6.2 Hz, 6H);
13C NMR δ 188.8, 179.3, 123.2, 88.8, 76.7, 55.8, 22.6, 22.3, 6.2;
IR (neat) 1623 cm-1; HRMS (EI) calcd for C9H14O3 (M+)
170.0943, found 170.0944.
J O991765W