Competition between alkenes in intramolecular ketene-alkene [2 + 2] cycloaddition: What does it take to win?

Article abstract of DOI:10.1021/jo0483466

(Chemical Equation Presented). In the course of developing a new synthetic methodology using ketenes in sequential cycloaddition steps, we were faced with a competition problem with molecules containing a ketene tethered to more than one reacting partner.

Full text of DOI:10.1021/jo0483466

Competition between Alkenes in Intramolecular Ketene-Alkene
[2 + 2] Cycloaddition: What Does It Take to Win?
Guillaume Be´langer,* Franc¸ois Le´vesque, Julie Paˆquet, and Guillaume Barbe
Laboratoire de synthe`se organique et de de´veloppement de strate´gies de synthe`se, De´partement de Chimie,
Universite´ de Sherbrooke, 2500 boulevard Universite´, Sherbrooke, Que´bec J1K 2R1, Canada
guillaume.belanger@usherbrooke.ca
Received September 17, 2004
In the course of developing a new synthetic methodology using ketenes in sequential cycloaddition
steps, we were faced with a competition problem with molecules containing a ketene tethered to
more than one reacting partner. To pinpoint the electronic and tethering requirements for a
chemoselective reaction, we undertook a series of ketene-alkene [2 + 2] cycloaddition competition
experiments. Those experiments were conducted on molecules containing either two identical alkenes
having different tether lengths or two alkenes having the same tether length but being electronically
different. We demonstrated that the reaction is much faster for forming five-membered rings than
six-membered rings and calculated the Hammett constant F for intramolecular ketene-alkene
[2 + 2] cycloadditions to be -1.39.
Introduction
two mechanisms may compete, depending on the nature
of the alkene reacting with the ketene.2
Since their first preparation in 1905,1 ketenes have
been widely studied due to their unique reactivity. Many
different ketene-alkene [2 + 2] cycloaddition mecha-
nisms have been proposed,2 and nowadays, two of them
are commonly accepted: a stepwise mechanism involving
sequential nucleophilic additions via a zwitterionic in-
termediate3 and a concerted cycloaddition. The latter is
an antarafacial process, thermally allowed according to
the frontier molecular orbital (FMO) theory,4 and could
be highly asynchronous.2,5 It is also suggested that these
As we were developing a new synthetic strategy using
ketenes in sequential cycloaddition steps, we were faced
with a competition issue with molecules containing a
ketene tethered to more than one reacting partner. In
fact, our strategy is to build tricyclic skeletons of natural
products in one step from linear precursors (Scheme 1).
Because the first [2 + 2] cycloaddition would need to be
chemoselective, we turned our attention to competition
studies to determine the electronic and tethering require-
ments for such a chemoselectivity.
Intramolecular ketene-alkene [2 + 2] cycloadditions6
were shown to form five-membered rings more easily
than six-membered rings.7 However, the only evidence
supporting this affirmation is based on shorter reaction
time and higher yields for the formation of five-membered
rings. No competition experiments were run to quanti-
(1) Staudinger, H. Chem. Ber. 1905, 38, 1735-1739.
(2) For a review on proposed [2 + 2] cycloaddition mechanisms of
ketenes with alkenes, see: Tidwell, T. T. Ketenes; Wiley: New York,
1995; pp 486-502, and references therein.
(3) (a) Corey, E. J.; Arnold, Z.; Hutton, J. Tetrahedron Lett. 1970,
307-310. (b) Wagner, H. U.; Gompper, R. Tetrahedron Lett. 1970,
2819-2822. (c) Gompper, R. Angew. Chem., Int. Ed. Engl. 1969, 8,
312-327. (d) Becker, D.; Brodsky, N. C. J. Chem. Soc., Chem. Commun.
1978, 237-238.
(4) (a) Fleming, I. Frontier Orbitals and Organic Chemical Reac-
tions; Wiley: New York, 1976; pp 110-148. (b) Woodward, R. B.;
Hoffmann, R. Angew. Chem., Int. Ed, Engl. 1969, 8, 781-853. (c)
Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry;
Verlag Chimie/Academic: New York, 1970.
(5) For calculations of transition states for ketene-alkene [2 + 2]
cycloadditions, see: (a) Bernardi, F.; Bottoni, A.; Robb, M. A.; Ven-
turini, A. J. Am. Chem. Soc. 1990, 112, 2106-2114. (b) Wang, X.; Houk,
K. N. J. Am. Chem. Soc. 1990, 112, 1754-1756.
(6) For a review on intramolecular ketene-alkene [2 + 2] cycload-
ditions, see: Snider. B. B. Chem. Rev. 1988, 88, 793-811.
10.1021/jo0483466 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/20/2004
J. Org. Chem. 2005, 70, 291-296
291

Be´langer et al.
SCHEME 1
SCHEME 2
SCHEME 3
tatively assess the ring size effect on the relative cycload-
dition rates. Second, it is known that ketenes are electron
deficient and react preferentially with electron-rich al-
kenes, as was nicely demonstrated in ketene [2 + 2]
cycloadditions with various para-substituted styrenes.8
However, this is the only study of the influence of the
electronic character of alkenes in [2 + 2] cycloadditions
involving ketenes, and the interpretation of the results
was neither conclusive nor quantitative.9 Because this
information is crucial to us in order to develop our
synthetic methodology, we decided to run a series of
ketene-alkene [2 + 2] cycloaddition competition experi-
ments. The results presented herein are divided into two
main parts: the study of the influence of the tether length
and the study of the influence of the electronic character
of alkenes in intramolecular [2 + 2] cycloadditions with
ketenes.
SCHEME 4
Results and Discussion
Study of the Influence of the Tether Length
between a Ketene and an Alkene in Intramolecular
[2 + 2] Cycloadditions. We chose substrates containing
identical alkenes attached to the ketene with different
tether lengths. The synthesis of the first model compound
is described in Scheme 2. An alkylation of the dianion of
hept-6-enoic acid (1) with 6-iodohex-1-ene gave the
branched acid 2 (61% yield).10 The latter was then treated
with oxalyl chloride in refluxing toluene, and the result-
ing acyl chloride 3 was clean and was used without
purification for the generation of ketene 4 by deprotona-
tion with triethylamine in refluxing toluene. This was
followed by an in situ [2 + 2] cycloaddition. We were
1
pleased to obtain only one product (>95:5 by H NMR
analysis of the crude material) in excellent yield (82%).
At that point, spectral analysis could not tell us which
of the two possible adducts (5 or 6) was preferentially
formed.
To determine the identity of the cycloadduct, we
independently prepared both the [3.2.0] and the [4.2.0]
bicyclic adducts. On one hand, the synthesis of 8 was
accomplished in three steps, starting with the alkylation
of 1 with 1-iodohexane (60% yield, Scheme 3). The ketene
was prepared from the corresponding acyl chloride and
gave the bicyclo[3.2.0]heptanone 8 in 86% yield.
On the other hand, the bicyclo[4.2.0]octanone 11 was
prepared from ethyl heptanoic acid (9; Scheme 4) using
exactly the same reactions as described in Scheme 2. We
were delighted to observe that the methylene next to the
carbonyl of 11 had measurably different chemical shifts
and coupling constants for its protons compared to those
of compound 8 (Scheme 3).
(7) (a) Marko´, I.; Ronsmans, B.; Hesbian-Frisque, A.-M.; Dumas, S.;
Ghosez, L. J. Am. Chem. Soc. 1985, 107, 2192-2194. (b) Snider, B.
B.; Hui, R. A. H. F.; Kulkarni, Y. S. J. Am. Chem. Soc. 1985, 107, 2194-
2196. (c) Brady, W. T.; Giang, Y. F. J. Org. Chem. 1985, 50, 5177-
5179. (d) Intramolecular [2 + 2] cycloadditions using ketene iminiums
have been for different ring sizes: Brady, W. T.; Giang, Y. F.; Weng,
L.; Dad, M. M. J. Org. Chem. 1987, 52, 2216-2220.
(8) (a) Baldwin, J. E.; Kapecki, J. A. J. Am. Chem. Soc. 1970, 92,
4868-4873. (b) For the ketenes’ preference for electron-rich alkenes,
see also: Brady, W. T.; O’Neal, H. R. J. Org. Chem. 1967, 32, 2704-
2707.
(9) The Hammett constant F for [2 + 2] cycloadditions of diphen-
ylketene with para-substituted styrenes reported by Baldwin is
-0.73.8a This value is solely based on p-(trifluoromethyl)styrene and
p-methylstyrene. With only two points in the Hammett plot, the
linearity of the Hammett equation could not be verified,23 thus casting
doubt on the validity of the reported F value.
(10) Snider, B. B.; Vo, N. H.; Foxman, B. M. J. Org. Chem. 1993,
58, 7228-7237.
292 J. Org. Chem., Vol. 70, No. 1, 2005

Ketene-Alkene [2 + 2] Cycloaddition
TABLE 1. NMR Data of Possible Adducts 19
1H
13C
δ (ppm)
position
δ (ppm)
multiplicity
J (Hz)
1
2
3
3.04
s
48
61
36
3.16
t
3.5
FIGURE 1. Model for electronic study.
2.45 (eq)
2.45 (ax)
1.70 (eq)
1.90 (ax)
2.25 (eq)
2.45 (ax)
m
m
dqna
m
14.5, 8.5
19
40
SCHEME 5
4
5
ddd
m
13.0, 8.5, 4.0
6
7
8
72
219
29
1.12
1.28
1.22
1.45
1.85
1.95
5.90
6.20
td
td
m
13.0, 3.5
13.0, 4.5
9
23
35
m
10
m
septb
dt
d
7.0
16.0, 7.0
16.0
11
12
130
130
a Doublet of quintets. b Septuplet.
pot Knoevenagel condensation-hydroboration reaction.
This procedure constitutes an efficient way to synthesize
monoalkylated dicarbonyls.13 The resulting diester 13
was then transesterified and decarboxylated in ethanol
using microwaves at 170 °C. The stereochemical integrity
of the alkene was preserved.14 After a DIBALH reduction
of the ester 14 in 98% yield, the resulting alcohol 15 was
iodinated (89% yield) and then doubly alkylated on
Meldrum’s acid in 47% yield using cesium carbonate. A
microwave-assisted hydrolysis-decarboxylation of 16
cleanly generated the corresponding monoacid 17, which
was transformed into the desired cycloadduct 19 (or 18)
via the acyl chloride and ketene intermediates.
1
Finding suitable proton signals in the H NMR spec-
We then reduced the alkene of the crude material (5
or 6) obtained from the competition experiment (Scheme
2), and the product obtained gave an NMR spectrum that
matched perfectly that of compound 8. This result
confirmed that the adduct 5 was the only product
obtained from the competition experiment, thus showing
a strong dependence of the intramolecular ketene-alkene
[2 + 2] cycloaddition on the size of the ring that is formed.
Study of the Influence of Alkene Electronic
Character in Intramolecular [2+2] Cycloadditions
with Ketenes. This study was designed to pit a tethered
alkene substituted with either an electron-withdrawing
or an electron-donating substituent against a tethered,
unsubstituted alkene. Because we wanted to study only
the influence of the electronic character of the substituted
alkene in the cycloaddition, we had to make sure that
the steric hindrance of the substituent would not inter-
fere with the reaction rate. For this reason, we elected
to put the substituent on a remote position, separated
from the alkene by an aromatic ring (Figure 1).
trum to use in the determination of product ratios was
not easy, since the vinylic proton signals were overlap-
ping with unreacted starting material and/or with an
anhydride side product.15 The assignations of proton and
carbon signals in adduct 19 (or 18) were accomplished
using 1H, COSY, NOESY, TOCSY,16a HSQC,16b and
HMBC16c and are gathered in Table 1. From a portion of
(12) Trans-1,2-disubstituted alkenes react more quickly than cis-
1,2-disubstituted alkenes with ketenes in intramolecular [2 + 2]
cycloadditions, due to steric reasons. See: (a) Huisgen, R.; Mayr, H.
Tetrahedron Lett. 1975, 16, 2965-2968. (b) Snider, B. B. Walner, M.
B. Tetrahedron 1989, 45, 3171-3182. (c) Snider, B. B., Allentoff, A.
J., Walner, M. B. Tetrahedron 1990, 46, 8031-8042. Also, we wanted
to diminish the chance of side reactions, such as alkene isomerization,
in the cycloaddition step, which occurs at elevated temperature
(refluxing toluene).
(13) Hrubowchak, D. M.; Smith, F. X. Tetrahedron Lett. 1983, 24,
4951-4954.
(14) For cis alkenes, used in other sequences of reactions that are
not mentioned in this paper, this step gave partial isomerization.
(15) Even with careful manipulations, traces of water could generate
an anhydride from two molecules of acyl chloride. The formation of
anhydride occurs during the ketene formation step, when the acyl
chloride is heated in the presence of triethylamine. The acyl chloride
formation itself is clean and usually quantitative. The amount of
anhydride observed is greater when the alkenes are deactivated toward
the [2 + 2] cycloaddition with the ketene.
Because no intramolecular ketene-styrene cycloaddi-
tion has been reported in the literature,11 we first decided
to prepare the bicyclo[3.1.1]heptane 19 (Scheme 5). The
alkene on the cycloaddition precursor needed to be
stereochemically pure (trans preferably);12 therefore, we
started from trans-cinnamaldehyde (12) and did a one-
(16) (a) TOCSY stands for total correlation spectroscopy and gives
long-range 1H-1H coupling, typically over three to four bonds. (b)
HSQC stands for heteronuclear single quantum correlation and gives
1H-13C coupling over one bond. (c) HMBC stands for heteronuclear
multiple bond correlation and gives long-range 1H-13C coupling,
typically over two to three bonds.
(11) Only the intermolecular version has been reported.8
J. Org. Chem, Vol. 70, No. 1, 2005 293

Be´langer et al.
SCHEME 6
SCHEME 7
1
FIGURE 2. Crude cycloadduct H NMR spectra.
TABLE 2. Ratios of Cycloadducts 24a-e and 25a-e
X
24:25a
σp value19
OMe (a)
Me (b)
Cl (c)
CF3 (d)
NO2 (e)
3.2:1.0
2.4:1.0
1.0:1.3
1.0:4.1b
1.0:9.0c
-0.27
-0.17
0.23
0.54
0.78
a Ratios determined from the average of the integration of H1
singlets and integration of H2 triplets. b The H1 singlets of 24d
and 25d are overlapping.20 c The H1 and H2 signals of 24e, as
well as the H2 triplet of 25e, are all in the same multiplet
(3.19-3.13 ppm).21
the HMBC spectrum, three pieces of evidence allowed
us to unambiguously assign the structure as being 19.17
Moreover, from the 1H NMR spectrum of 19, we
identified two characteristic signals of the cycloadduct:
the 3.16 ppm triplet and the 3.04 ppm singlet, corre-
sponding to H2 and H1, respectively. These peaks are
clearly identifiable in the crude mixture of the reaction.
This information proved crucial for ratio determination
in the following competition experiments.
With the structure of the cycloaddition product 19
secured, we then undertook the construction of a series
of substrates, depicted in Figure 1. We selected five aryl
substituents (X ) methoxy, methyl, chloro, trifluoro-
methyl, and nitro) that would enable us to generate a
standard Hammett plot and determine the F constant of
the reaction. The syntheses of the substrates are depicted
in Schemes 6 and 7. The alcohol 15 was oxidized using
Swern’s conditions, and then the monobranched Mel-
drum’s acid 20 was prepared using the usual Knoevena-
gel-hydroboration procedure (Scheme 6).
resulting para-substituted styrenes 22a-e were iodi-
nated in good yields and alkylated on 20. The Meldrum’s
acid moiety was then hydrolyzed and decarboxylated to
the corresponding carboxylic acids 23a-e. The latter
were transformed into the acyl chlorides followed by a
triethylamine treatment to generate the ketenes in situ,
which underwent the [2 + 2] cycloaddition. Mixtures of
24a-e and 25a-e were obtained, depending on the
nature of the X substituent on the aryl.
1
It is reasonable to think that the H NMR chemical
shifts for the H1 singlet and H2 triplet of 25 should be
nearly the same on going from X ) OMe (25a) to X )
NO2 (25e), as these groups are far from the bicyclic core.
This is exactly what we observed (Figure 2).
The product ratios (24:25) were derived from these
crude 1H NMR spectra (Figure 2). The integration of the
H1 singlets on both 24 and 25 gave a ratio that matched
perfectly that obtained from the integration of the H2
triplets of 24 and 25. The average ratio from the
integrated singlets and triplets as well as the reported
σp values19 for every X substituent are given in Table 2.
Extracting kinetic data for competition experiments
usually involves determining ratios at different times
during the advancement of the reaction, since the con-
centration of the more reactive partner goes down as the
reaction proceeds. This is true for intermolecular reac-
The para-substituted aryls were introduced by a Su-
zuki coupling between the vinylic boronate 2118 and the
appropriate aryl iodide followed by a hydrochloric acid
cleavage of the silyl ether in the workup (Scheme 7). The
(17) The spectral evidence that allowed us to assign the structure
as being 19 is discussed in detail in the Supporting Information, section
V.
(18) Muir, J. C.; Pattenden, G.; Ye, T. J. Chem. Soc., Perkin Trans.
1 2002, 2243-2250.
(19) Hansch, C.; Leo, A.; Taft, W. Chem. Rev. 1991, 91, 165-195
and references therein.
294 J. Org. Chem., Vol. 70, No. 1, 2005

Ketene-Alkene [2 + 2] Cycloaddition
in toluene, from competition experiments between phen-
yl-substituted alkenes and alkenes bearing a para-
substituted aryl. Having a negative sign of the F value
means that the reaction is accelerated by electron-
donating groups, which is in accordance with reported
data.8 The absolute F value of 1.39 is the first clear and
quantified indication of a modest charge development at
the transition state, stabilized by electron-donating
groups on the styrene, for [2 + 2] cycloadditions with a
tethered ketene. The Hammett plot also serves as an
extremely useful prediction tool that will be crucial for
the development of our synthetic strategy using cascades
of ketene cycloadditions, as well as for any reacting
partner of known σ value.
FIGURE 3. Hammett plot for [2 + 2] cycloaddition.
Experimental Section
tions. In our case, for the intramolecular cycloaddition,
we ran the reaction at 0.055 M until complete consump-
tion of the starting material and determined the ratio of
(5′E)-1-(Hex-5′-enyl)bicyclo[3.2.0]heptan-7-one (5). A
solution of carboxylic acid 2 (400 mg, 1.9 mmol) in toluene (2.0
mL) was placed in a tube under argon. Oxalyl chloride (830
µL, 9.5 mmol) was added at room temperature, and the tube
was sealed, heated to 120 °C for 2 h in an oil bath, and then
cooled to room temperature and opened. The solution was
concentrated under mechanical pump vacuum. The crude acyl
chloride 3 was dissolved in toluene (33 mL), and Et3N (1.6 mL,
11.4 mmol) was added at room temperature. The tube was
sealed, heated to 120 °C overnight, cooled to room temperature,
and opened. Saturated aqueous NH4Cl was added, and the
biphasic mixture was extracted with EtOAc. The combined
organic layers were dried over anhydrous MgSO4, filtered, and
concentrated. The crude material was purified by flash chro-
matography (19:1 hexanes-EtOAc) to give 300 mg (82%) of
pure 5 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.69
(ddt, J ) 17.0, 10.0, 6.5 Hz, 1H), 4.90 (dd, J ) 17.5, 1.5 Hz,
1H), 4.84 (d, J ) 11.5 Hz, 1H), 3.01 (dd, J ) 18.0, 9.5 Hz, 1H),
2.49-2.44 (m, 1H), 2.33 (dd, J ) 18.0, 4.5 Hz, 1H), 1.99-1.87
(m, 4H), 1.78-1.15 (m, 10H); 13C NMR (75 MHz, CDCl3) δ
217.8, 138.6, 114.3, 75.8, 49.1, 35.3, 33.8, 33.5, 32.9, 32.6, 29.3,
1
the cycloadducts directly from the crude material by H
NMR. We think this is rigorous for three reasons: (1)
the ketene, being attached to the two alkenes in competi-
tion, is always in the presence of exactly 1 equiv of each
alkene throughout all of the reaction, (2) the cycloaddition
is irreversible, and (3) any intermolecular cycloaddition
is essentially negligible.22
From these ratios, we constructed a graph of the
reported σp values19 for each X group we used against
the log (k/k0) value, which is the ratio of 24 to 25 (Figure
3).23 The correlation coefficient r is 0.998, a value that
exceeds the required 0.95 for significant linear Hammett
correlation.24 This suggests that these [2 + 2] cycload-
ditions are following the same reaction path and mech-
anism for every X substituent.25 The slope of -1.39 is
the Hammett F value for this reaction.
25.0, 24.9; IR (film) ν 3077, 2935, 2865, 1774, 1068, 964 cm-1
;
MS (EI) m/z 192 (15) [M+], 150 (100), 135 (70), 121 (91), 108
(71); HRMS (EI) m/z calcd for C13H20O 192.1514, found
192.1519.
Conclusion
We demonstrated that the rate of intramolecular
ketene-alkene [2 + 2] cycloadditions is strongly depend-
ent on the size of the ring that is being formed during
the reaction: a five-membered ring is the only one
observed when competing with a six-membered ring. We
also determined that the F value for this reaction is -1.39
(E)-2,2-Dimethyl-5-(3′-phenylallyl)-1,3-dioxane-4,6-di-
one (13). Meldrum’s acid (9.51 g, 66.0 mmol) was added to a
solution of BH3‚HNMe2 complex (3.88 g, 65.9 mmol) in MeOH
(60 mL) at room temperature in a water bath. trans-Cinna-
maldehyde (12; 8.32 mL, 66.0 mmol) was then added dropwise
(exothermic). After 3 h at room temperature, H2O (160 mL)
was added (a white precipitate was formed) followed by 3 N
HCl (240 mL). The suspension was stirred overnight and then
was filtered and dried under vacuum over P2O5 to afford 12.1
g (71%) of pure 13 as a white solid: 1H NMR (300 MHz, CDCl3)
δ 7.36-7.19 (m, 5H), 6.61 (d, J ) 15.5 Hz, 1H), 6.26 (dt, J )
15.5, 7.5 Hz, 1H), 3.66 (t, J ) 5.0 Hz, 1H), 3.06-3.01 (m, 2H),
1.79 (s, 3H), 1.75 (s, 3H); HRMS (CI) calcd for C15H20NO4
(MNH4+) 278.1392, found 278.1386.26
(4E)-Ethyl 5-Phenylpent-4-enoate (14). A solution of 13
(2.70 g, 10.4 mmol) in EtOH (22 mL) was placed in a sealed
tube and heated to 170 °C for 1.5 h in a microwave oven. The
tube was then cooled to room temperature and opened, and
the solution was transferred to a round-bottom flask. Silica
gel was added, and the slush was concentrated under reduced
pressure. The resulting crude material adsorbed on silica gel
was loaded directly on a column and was purified by flash
chromatography (19:1 hexanes-EtOAc) to give 1.9 g (90%) of
pure 14 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.36-
7.17 (m, 5H), 6.43 (d, J ) 16.0 Hz, 1H), 6.21 (dt, J ) 16.0, 6.5
(20) The 1H NMR spectrum of 24d with Ph ) CF3C6H4 (i.e. with
two p-CF3-styrene branches) prepared independently showed an H1
singlet at 3.11 ppm and an H2 triplet at 3.18 ppm.
(21) See the 1H NMR spectra of isolated and purified 24e and 25e
in the Supporting Information.
(22) As an indication of the difference in reaction rates between an
intramolecular and an intermolecular reaction, 4-bromobutyl-1-amine
cyclizes in a five-membered ring 104 times faster than the dimerization
rate in a 1 M solution (Streitwieser, A., Jr Solvotic Displacement
Reactions; McGraw-Hill: New York, 1962; p 105), or 200 000 times
faster in a 0.055 M solution. Although the folding of the molecule for
this 5-exo-tet cyclization is not the same as for the [2 + 2] cycloaddition,
it is nonetheless an indication that the intermolecular reaction should
be negligible.
(23) See the Supporting Information for the details of the log (k/k0)
calculation. See also: Logan, S. Introduction a` la cine´tique chimique;
Dunod: Paris, 1998; pp 47-50. Schaal, R. Chemical Kinetics of
Homogeneous Systems, D. Riedel: Dordrecht, The Netherlands, 1974;
pp 30-32.
(24) As a criterion of linearity, the correlation coefficient r is required
to be at least 0.95 and preferably above 0.98. See: Connors, K. A.
Chemical Kinetics; VCH: New York, 1990; pp 315-320.
(25) For reactions that do not follow the same mechanism depending
on the nature (electron withdrawing or electron donating) of the
substrate (alkene in this case), a change of slope is usually observed
in the σ vs log (k/k0) graph.
(26) The characterization is identical with that reported for the same
compound, but prepared through another route. See: Prat, M.; Moreno-
Man˜as, M.; Ribas, J. Tetrahedron 1988, 44, 7205-7212.
J. Org. Chem, Vol. 70, No. 1, 2005 295

Be´langer et al.
Hz, 1H), 4.15 (q, J ) 7.0 Hz, 2H), 2.60-2.34 (m, 4H), 1.24 (t,
J ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 172.3, 137.1,
130.7, 128.1, 126.8, 125.8, 59.9, 33.6, 28.0, 13.9; MS (EI) m/z
204 (29) [M+], 130 (100), 117 (63), 91 (26); HRMS (EI) m/z calcd
for C13H16O2 204.1150, found 204.1142.27
was extracted with EtOAc, dried over anhydrous MgSO4,
filtered, and concentrated. The crude material was purified
by flash chromatography (9:1 hexanes-EtOAc) to give 300 mg
(74%) of pure 17 as a white solid: mp 88-92 °C; 1H NMR (300
MHz, CDCl3) δ 7.35-7.16 (m, 10H), 6.38 (d, J ) 16.0 Hz, 1H),
6.18 (dt, J ) 16.0, 7.0 Hz, 1H), 2.48-2.39 (m, 1H), 2.22 (q,
J ) 7.0 Hz, 4H), 1.75-1.46 (m, 8H); 13C NMR (75 MHz, CDCl3)
δ 182.6, 137.7, 130.2, 128.5, 126.9, 125.9, 45.2, 32.8, 31.6, 27.0;
IR (film) ν 3434 (br), 3024, 2931, 2856, 1699, 1452, 1238, 964
cm-1; MS (EI) m/z 348 (65) [M+], 143 (100), 117 (97), 91 (95);
HRMS (EI) m/z calcd for C24H28O2 348.2089, found 348.2083.
(4′E)-7-Phenyl-1-(5′-phenylpent-4′-enyl)bicyclo[3.1.1]-
heptan-6-one (19). Following the procedure used to form 5,
17 (100 mg, 0.29 mmol) was treated with oxalyl chloride (125
µL, 1.4 mmol) in toluene (2.0 mL) and then with Et3N (240
µL, 1.7 mmol) in toluene (5.0 mL) to give, after purification
by flash chromatography (9:1 hexanes-EtOAc), 53 mg (56%)
of pure 19 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
7.28-7.13 (m, 10H), 6.20 (d, J ) 16.0 Hz, 1H), 5.90 (dt, J )
16.0, 7.0 Hz, 1H), 3.16 (s, 1H), 3.04 (t, J ) 3.5 Hz, 1H), 2.52-
2.43 (m, 3H), 2.25 (ddd, J ) 13.0, 8.5, 4.0 Hz, 1H), 1.97-1.84
(m, 2H), 1.95 (sept, J ) 7.0 Hz, 1H), 1.70 (dqn, J ) 14.5, 8.5
Hz, 1H), 1.45-1.41 (m, 1H), 1.28 (td, J ) 13.0, 4.5 Hz, 1H),
1.28-1.20 (m, 1H), 1.12 (td, J ) 13.0, 3.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 216.0, 140.1, 137.7, 130.2, 130.0, 128.5,
128.3, 127.5, 126.7, 126.0, 70.7, 60.4, 48.0, 40.1, 34.6, 33.1, 28.9,
(4′E)-2,2-Dimethyl-5,5-bis(5′-phenylpent-4′-enyl)[1,3]-
dioxane-4,6-dione (16). I2 (1.95 g, 7.7 mmol) was added to a
solution of 15 (1.25 g, 7.7 mmol), PPh3 (1.99 g, 7.6 mmol), and
imidazole (630 mg, 9.2 mmol) in CH2Cl2 (20 mL) at 0 °C. The
solution was stirred overnight at room temperature and then
silica gel was added and the slush was concentrated under
reduced pressure. The resulting crude material adsorbed on
silica gel was loaded directly on a column and was purified by
flash chromatography (19:1 hexanes-Et2O) to give 1.86 g
(89%) of pure iodide as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 7.41-7.23 (m, 5H), 6.49 (d, J ) 15.5 Hz, 1H), 6.18
(dt, J ) 15.5, 7.0 Hz, 1H), 3.26 (t, J ) 7.0 Hz, 2H), 2.36 (q,
J ) 7.0 Hz, 2H), 2.05 (qn, J ) 7.0 Hz, 2H); HRMS (EI) m/z
calcd for C11H13I 272.0062, found 272.0069.28 Cs2CO3 (3.40 g,
10.5 mmol) was added to a solution of Meldrum’s acid (430
mg, 2.99 mmol) and the previously prepared iodide (1.86 g,
6.8 mmol) in acetonitrile (10 mL) at room temperature. The
reaction mixture was stirred for 3 days at room temperature
and then silica gel was added and the slush was concentrated
under reduced pressure. The resulting crude material adsorbed
on silica gel was loaded directly on a column and was purified
by flash chromatography (9:1 hexanes-EtOAc) to give 0.60 g
(47%) of pure 16 as a colorless oil: 1H NMR (300 MHz, CDCl3)
δ 7.34-7.17 (m, 10H), 6.37 (d, J ) 16.0 Hz, 2H), 6.31 (dt, J )
16.0, 7.0 Hz, 2H), 2.11 (q, J ) 7.0 Hz, 4H), 2.09-2.03 (m, 4H),
1.73 (s, 6H), 1.53-1.42 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
169.4, 137.4, 130.9, 129.0, 128.4, 127.0, 126.0, 105.5, 54.6, 53.8,
38.8, 32.7, 29.8, 25.3; IR (film) ν 3001, 2933, 2859, 2366, 1743,
22.8, 18.3; IR (film) ν 3028, 2940, 2865, 1765, 1491, 1447 cm-1
;
MS (EI) m/z 330 (14) [M+], 200 (36), 185 (22), 169 (52), 141
(21), 130 (100), 118 (80), 91 (78); HRMS (EI) m/z calcd for
C24H26O 330.1984, found 330.1990.
Acknowledgment. We thank EÄ tienne Dauphin for
his input on this project, Luc Tremblay for the 2D-NMR
experiments, and Gaston Boulay for mass spectrometric
analyses. We also acknowledge the FQRNT, CFI, and
NSERC for financial support.
1280, 1206 cm-1; MS (CI) m/z 450 (100) [MNH4+], 348 (48),
+
130 (89); HRMS (CI) m/z calcd for C28H30NO4 (MNH4
450.2644, found 450.2651.
)
(4′E,6E)-7-Phenyl-2-(5′-phenylpent-4′-enyl)hept-6-eno-
ic Acid (17). A solution of 16 (500 mg, 1.16 mmol) in THF
(3.8 mL) and H2O (1.8 mL) was placed in a sealed tube and
heated to 165 °C for 4 h in a microwave oven. The tube was
then cooled to room temperature and opened, and the solution
Supporting Information Available: Text giving experi-
mental procedures for compounds 2, 7, 8, 10, 11, 15, 20, and
22-25, figures giving 1H and 13C NMR spectra for compounds
2, 5, 7, 8, 10, 11, 13-17, 19, 20, and 22-25, and figures giving
COSY, NOESY, TOCSY, HSQC, and HMBC spectra for 19.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(27) The characterization is identical with that reported for the same
compound, but prepared through another route. See: Arnold, R. T.;
Kulenovic, S. T. J. Org. Chem. 1980, 45, 891-894.
(28) See: Ren, X. F.; Turos, E.; Lake, C. H.; Churchill, M. R. J. Org.
Chem. 1995, 60, 6468-6483.
JO0483466
296 J. Org. Chem., Vol. 70, No. 1, 2005