High-rate accelerations in oxy-Cope rearrangements induced by sulfur substitution: Kinetic study involving electronically and geometrically differentiated 1-alkenyl-2-(Z-1-propenyl)-7,7-dimethyl-exo-norbornan-2-ols

Article abstract of DOI:10.1021/ja0025402

The rates of anionically promoted oxy-Cope rearrangement of five structurally related exonorbornanols have been determined. A critical difference in the substitution pattern of these substrates is the presence or absence of oxygen or sulfur functionality

Full text of DOI:10.1021/ja0025402

10788
J. Am. Chem. Soc. 2000, 122, 10788-10794
High-Rate Accelerations in Oxy-Cope Rearrangements Induced by
Sulfur Substitution: Kinetic Study Involving Electronically and
Geometrically Differentiated
1-Alkenyl-2-(Z-1-propenyl)-7,7-dimethyl-exo-norbornan-2-ols
Leo A. Paquette,*,† Y. Ravindra Reddy,† Grigoriy Vayner,‡ and K. N. Houk*,‡
Contribution from the EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio
43210-1185 and the Department of Chemistry and Biochemistry, UniVersity of California at Los Angeles,
Los Angeles, California 90095-1569
ReceiVed July 12, 2000
Abstract: The rates of anionically promoted oxy-Cope rearrangement of five structurally related exo-
norbornanols have been determined. A critical difference in the substitution pattern of these substrates is the
presence or absence of oxygen or sulfur functionality at the terminal carbon of the bridgehead vinyl group and
the geometric nature of the olefinic center. The results convincingly establish that although an OPMP substituent
exerts, at best, a very modest decelerative kinetic effect, the presence of the PhS substituent causes rearrangement
to occur approximately 103 times faster by lowering the activation energy to the extent of 3-4 kcal/mol. This
remarkable divergence in behavior is shown to correlate well with the highly dissociative nature of the transition
state that is predicted computationally.
The development of synthetic strategies that incorporate one
These advances have become overshadowed by the remark-
able finding that rate enhancements of 1010-1017 can be
achieved by conversion to the respective potassium alkoxides,9
most notably in the presence of an equivalent of 18-crown-6.
This tremendous kinetic acceleration, which is believed to
originate from alkoxide-induced weakening of the C3-C4 sigma
or more [3,3] sigmatropic rearrangements for achieving fully
stereocontrolled structural elaboration holds special value in
modern organic synthesis. While the Cope1 and Claisen rear-
rangements2 have been important mainstays for several decades
since their early discovery, variants thereof have more recently
outdistanced the parent reactions in their ability to serve with
increasingly encouraging success in utilitarian C-C bond
construction schemes. The oxy-Cope rearrangement, discovered
in 1964,3 is an outstanding case in point. The simple placement
of an OH group at C3 or C4 of a 1,5-diene results after thermal
isomerization in the stereoselective production of a dienol. The
subsequent tautomerism gives rise irreversibly in most cases4
to an enone that is amenable to further chemical manipulation.
A major shortcoming of this process is the concomitant
operation of a retro ene fragmentation whenever geometrically
possible.5 This complication can, however, be skirted by
preliminary O-alkylation6 or acylation7 or by making recourse
to N-methylpyrrolidinone as the reaction medium.8
bond,10 allows for the possibility of bringing about these
rearrangements at or below 0 °C.11 As a consequence, sensitive
functionality is well-tolerated, thereby enabling the oxyanionic
Cope rearrangement to serve broadly in the preparation of
structurally intricate ketonic products.12 A particularly advanta-
geous feature of this reaction is its adoption of highly ordered
cyclic transition states such that the new stereogenic centers
are formed stereospecifically and double bond geometry is
† The Ohio State University.
‡ University of California at Los Angeles.
(1) (a) Rhoads, S. J.; Raulins, N. R. Org. React. (N.Y.) 1975, 22, 1. (b)
Hill, R. K. In Asymmetric Synthesis, Morrison, J. D., Ed.: Academic
Press: New York; 1984; Vol. 3, p 503. (c) Gajewski, J. J. Hydrocarbon
Thermal Isomerizations, Academic Press: New York, 1981; pp 166-176.
(d) Hill, R. K. In ComprehensiVe Organic Synthesis; Trost, B. M.; Fleming,
I.; Paquette, L. A., Eds.: Pergamon Press: Oxford, 1991; Vol. 5, Chapter
7.1.
(2) (a) Bartlett, P. A. Tetraheron 1980, 36, 3. (b) Lutz, R. P. Chem.
ReV. 1984, 84, 205. (c) Ziegler, F. E. Chem. ReV. 1988, 88, 1423. (d) Wipf,
P. In ComprehensiVe Organic Synthesis, Trost, B. M.; Fleming, I.; Paquette,
L. A., Eds.: Pergamon Press: Oxford, 1991; Vol. 5, Chapter 7.2.
(3) Berson, J. A.; Jones, M., Jr. J. Am. Chem. Soc. 1964, 86, 5017.
(4) (a) Elmore, S. W.; Paquette, L. A. Tetrahedron Lett. 1991, 32, 319.
(b) Tsui, H.-C.; Paquette, L. A. J. Org. Chem. 1998, 63, 9968.
(5) For example: (a) Viola, A.; Iorio, E. J. J. Org. Chem. 1970, 35,
856. (b) Viola, A.; Iorio, E. J.; Chen, K. K.; Glover, G. M.; Nayak, U.;
Kocienski, P. J. J. Am. Chem. Soc. 1967, 89, 3462.
(7) Bader, A.; Weiss, F. French Patent 1 519 701 (Chem. Abstr. 1969,
70, 96 177).
(8) (a) Fujita, Y.; Onishi, T.; Nishida, T. J. Chem. Soc., Chem. Commun.
1978, 972. (b) Fujita, Y.; Onishi, T.; Nishida, T. Synthesis 1978, 934. (c)
Onishi, T.; Fujita, Y.; Nishida, T. Synthesis 1980, 651. (d) Fujita, Y.; Amiya,
S.; Onishi, T.; Nishida, T. Bull. Chem. Soc. Jpn. 1979, 52, 1983.
(9) (a) Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765.
(b) Evans, D. A.; Nelson, J. V. J. Am. Chem. Soc. 1980, 102, 774.
(10) (a) Evans, D. A.; Baillargeon, D. J. Tetrahedron Lett. 1978, 3319.
(b) Ahlgren, G. Tetrahedron Lett. 1979, 915. (c) Steigerwald, M. L.;
Goddard, W. A., III; Evans, D. A. J. Am. Chem. Soc. 1979, 101, 1994. (d)
Rozeboom, M. D.; Kiplinger, J. P.; Bartmess, J. E. J. Am. Chem. Soc. 1984,
106, 1025. (e) Gajewski, J. J.; Gee, K. R. J. Am. Chem. Soc. 1991, 113,
967.
(11) Wilson, S. R. Org. React. (N.Y.) 1993, 43, 93.
(12) (a) Paquette, L. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609. (b)
Paquette, L. A. Synlett 1990, 67. (c) Paquette, L. A. Chem. Soc. ReV. 1995,
24, 9. (d) Paquette, L. A. Tetrahedron 1997, 53, 13971.
(6) Berson, J. A.; Walsh, E. J., Jr. J. Am. Chem. Soc. 1968, 90, 4729.
10.1021/ja0025402 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/11/2000

High-Rate Accelerations in Oxy-Cope Rearrangements
J. Am. Chem. Soc., Vol. 122, No. 44, 2000 10789
introduced with high fidelity. In short, the level of asymmetric
transmission is unparalleled.
These differing electronic influences hold potentially useful
applications. For example, proper selection of the group Y in
A can serve to modulate matters such that one proceeds
smoothly to conversion to B or induces the fragmentation of
A. Regioselective intramolecular competitions should also be
possible. Whatever the case, the quantification of these effects
would prove highly desirable. In this paper, we present a kinetic
and theoretical analysis of the response of the isomeric carbinol
pairs 10/12 and 11/13 as their potassium salts to anionic
Remarkably, these developments have not initiated an
intensive search for additional stereoelectronic effects on
oxyanionic sigmatropy. Amino-Cope rearrangements have been
accorded scant attention.13,14 A few examples of anionic oxy-
Cope rearrangement involving 1,5-diene-3-alkoxides carrying
either a 4-methoxy (1) or a 4-thiophenoxy group (3) have been
reported.15 Note was taken of the fact that 1 isomerized at a
sigmatropy.19 The purpose of the simpler vinyl derivative 9 is
to play a calibrative role. The large magnitude of the rate
enhancements exhibited by the sulfur derivatives 11 and 13 is
quite impressive.
much slower rate than 3. More recently, the discovery was made
that a PhS substituent at the C6 position of bicyclic divinyl
carbinol 7 significantly accelerated rearrangement, whereas an
alkoxy group at the same position (as in 5) caused deceleration.16
Results and Discussion
Synthetic Considerations. Enantiopure bicyclic ketone 14,
which is readily available from D-camphor-10-sulfonyl chlo-
ride,20 offers several advantages as a starting material for this
investigation: (1) it is amenable to conversion to keto aldehyde
15 by direct ozonolysis;21 (2) the latter can be chemoselectively
olefinated with the p-methoxy-phenoxy (OPMP) ylide 1622 and
its sulfur equivalent 1723 with generation of chromatographically
separable E/Z isomer pairs; (3) the presence of apical methyl
groups in 14 and its homologues serves to relegate entry of
(Z)-1-propenylmagnesium bromide24 (necessarily in the presence
of anhydrous cerium trichloride in order to deter enolization25)
exclusively to the endo surface; and (4) the structural features
of 9-13 were expected to lend themselves to [3,3] sigmatropic
rearrangement exclusively via an endo-chair transition state21
An early simple model of substituent effects predicted that
both donor and acceptor groups at saturated carbons C3 and
C4 in A should increase the rate.17 The application of density
functional theory to this problem has, however, revealed
otherwise.18 By means of this computational method, a SMe
group at C4 or C6 was found to cause acceleration, which is
likely because of adoption of a homolytic cleavage pathway in
order to take advantage of a strong stabilizing effect by divalent
sulfur. In contrast, an OCH3 substituent at either of the same
critical sites impedes heterolytic cleavage and slows the
concerted sigmatropic rearrangement.
(19) A preliminary communication has appeared: Paquette, L. A.; Reddy,
Y. R.; Haeffner, F.; Houk, K. N. J. Am. Chem. Soc. 2000, 122, 740.
(20) Fischer, N.; Opitz, G. Organic Syntheses: Wiley: New York, 1973;
Collect. Vol. V, p 877.
(21) Paquette, L. A.; Pegg, N. A.; Toops, D.; Maynard, G. D.; Rogers,
R. D. J. Am. Chem. Soc. 1990, 112, 277.
(22) Paquette, L. A.; Huber, S. K.; Thompson, R. C. J. Org. Chem. 1993,
58, 6874.
(23) Paquette, L. A.; Johnston, J. N.; Tsui, H.-C. J. Org. Chem. 1998,
63, 129.
(24) (a) Derguini-Boumechal, F.; Linstrumelle, G. Tetrahedron Lett.
1976, 3225. (b) Sviridov, A. F.; Ermolenko, M. S.; Yashunsky, D. V.;
Kochetkov, N. K. Tetrahedron Lett. 1983, 24, 4359.
(25) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392.
(13) Sprules, T. J.; Galpin, J. D.; Macdonald, D. Tetrahedron Lett. 1993,
34, 247.
(14) Yoo, H. Y.; Houk, K. N.; Lee, K. J.; Scialdone, M. A.; Meyers, A.
I. J. Am. Chem. Soc. 1998, 120, 205.
(15) Evans, D. A.; Baillargeon, D. J.; Nelson, J. V. J. Am. Chem. Soc.
1978, 100, 2242.
(16) Paquette, L. A.; Wang, H.-L.; Zeng, Q.; Shih, T.-L. J. Org. Chem.
1998, 63, 6432.
(17) (a) Carpenter, B. K. Tetrahedron 1978, 34, 1877. (b) Wilcox, C.
F., Jr.; Carpenter, B. K. J. Am. Chem. Soc. 1979, 101, 3897.
(18) Haeffner, F.; Houk, K. N.; Reddy, Y. R.; Paquette, L. A. J. Am.
Chem. Soc. 1999, 121, 11880.

10790 J. Am. Chem. Soc., Vol. 122, No. 44, 2000
Paquette et al.
Table 1. Rate Profiles for the Charge-Accelerated Oxy-Cope
Rearrangements of 9-13
reactant
k, s-1 (t)
relative rate
9
- K+
2.25 ((0.18) × 10-5 (-30 °C)
3.20 ((0.25) × 10-5 (-30 °C)
1.13 ((0.25) × 10-4 (-10 °C)
7.66 ((0.42) × 10-4 (+10 °C)
1.16 × 10-7 (-78 °C)a,b
1
1.4
10- K+
0.52a
0.075
12- K+
1.68 ((0.41) × 10-6 (-30 °C)
3.58 ((0.42) × 10-6 (-10 °C)
2.15 ((0.16) × 10-5 (+10 °C)
1.66 × 10-8 (-78 °C)a,c
0.075a
3450
1175
11- K+
13- K+
7.68 ((0.24) × 10-4 (-78 °C)
2.61 ((0.42) × 10-4 (-78 °C)
a Extrapolated values. b An Eyring plot gives ∆Hq ) 10.2 kcal/mol
and ∆Sq ) -36 cal/(mol K). c An Eyring plot gives ∆Hq ) 8.1 kcal/
mol and ∆Sq ) -51 cal/(mol K).
Figure 1. Least-squares plot of rate data for 9 at -30 °C.
The rate constants determined for all five potassium alkoxides
are compiled in Table 1. The rate difference that was observed
between the ionized forms of 9 and 10 is very small, thus
indicating that a trans aryloxy substituent has little observable
impact on the overall reaction velocity. When the same OPMP
group is fixed cis at C6, as in 12, rearrangement occurs at a
relative rate of 0.07, as compared to 9. The deceleration
conforms to previous observations recorded for 5.16
In contrast, the rate data for the rearrangement of the
potassium alkoxides of the sulfur-containing systems 11 and
13 proved to be so accelerated as to require measurements at
-78 °C. Although the trans-S/cis-S rate difference (k11/k13
)
2.9 at -78 °C) reasonably closely parallels that seen for the
oxygen series (k10/k12 ) 20 at -30 °C), the speed of reaction is
markedly enhanced for both 11 and 13. A direct comparison of
the k values experimentally determined for the sulfides versus
the extrapolated rate constants for the OPMP derivatives is
especially telling: k11/k10 ) 6620 and k13/k12 ) 15 700. These
findings support the concept of a more dissociative transition
state when the C6 substituent is constituted of a divalent sulfur
atom. The increased stability of these transition states could arise
by substantial contribution on the part of sulfur to delocalization,
thereby causing a lowering in activation enthalpy. An alternative
explanation is that complete sigma-bond homolysis occurs in
the direction of a less energy-demanding nonconcerted reaction
trajectory. The most recent calculations available favor the latter
option.18 The consequences are clearly very dramatic.
Figure 2. Least-squares plot of rate data for 12 at -30 °C.
because no exception to the adoption of this reaction trajectory
by related compounds is currently known.26
Determination of Rearrangement Rates. The thermody-
namic driving force underlying the oxy-Cope rearrangements
of 9-13 is sufficiently elevated that no need existed to introduce
18-crown-6 in order to sequester the potassium ions. At the
experimental level, 5% solutions of each carbinol in rigorously
dried and deoxygenated THF were thermostated at the appropri-
ate temperature and treated via a precooled syringe or an
insulated cannula with comparably cooled solutions of potassium
hexamethyldisilazide in toluene (0.5 M). Three equivalents of
this base served to achieve conditions that were first-order in
potassium alkoxide.
Product Characterization. A compelling feature of the [3,3]
sigmatropic behavior of exo-2-norbornanols related to 9-13 is
the wholesale extent to which the so-called “endo-chair”
topography (as in C) is adopted by these substances. The
particular spatial orientation of both the bridgehead double bond
and its counterpart at C2 eventuates in stereospecific transfer
of chirality during the conversion to enolate anion D, which is
formed in strikingly regiocontrolled fashion as well. Finally,
proton transfer to D delivers E, whose olefinic geometry and
combination of stereogenic centers are uniformly generated with
high fidelity.26
In each of the five examples selected for kinetic analysis,
only a single product was formed. Two options were exercised
for preparative-scale purposes. In the first, the accumulated
aliquots from the rate studies were combined, dissolved in THF,
and resubjected to the action of potassium hexamethyldisilazide
until such time that no carbinol remained (TLC analysis).
Alternatively, the analogous experiment originated with pure
carbinols. The charge-accelerated rearrangement of 9 gives 18,
a ketone that adopts a conformation particularly well-suited to
NOE analysis. Thus, the syn-apical methyl group is in suf-
The progress of each reaction was followed by the removal
of aliquots after specific periods of elapsed time with immediate
quenching in cold NH4Cl solution. Following ether extraction,
drying, and solvent evaporation, the individual samples were
analyzed by 1H NMR at 300 MHz. In each case, only a single
product was formed (see below). The extent to which the
carbinol was consumed and its oxy-Cope-derived ketone formed
was convenient to monitor because at least one proton signal
from each appeared in an isolated region of the spectrum.
Processing of the data by means of a weighted least-squares
analysis showed that good first-order behavior was being
observed. Exemplary plots for 9 and 12 at -30 °C are given in
Figures 1 and 2.
(26) For example: (a) Paquette, L. A. In Organic Chemistry: Its
Language and its State of the Art, Kisakurek, M. V., Ed. HelV. Chim. Acta
and VCH Publishers: 1993, 103-115. (b) Paquette, L. A. In Taxane
Anticancer Agents. Basic Science and Current Status, ACS Symposium
Series No. 583, American Chemical Society, Washington, D. C. 1995,
Chapter 23. (c) Paquette, L. A.; Zhao, M.; Montgomery, F.; Zeng, Q.; Wang,
T. Z.; Elmore, S.; Combrink, K.; Wang, H.-L.; Bailey, S.; Su, Z. Pure Appl.
Chem. 1998, 70, 1449.

High-Rate Accelerations in Oxy-Cope Rearrangements
J. Am. Chem. Soc., Vol. 122, No. 44, 2000 10791
B3LYP/6-31+G* for the core and PM3 for the peripheral
sections of the molecule. For computational simplicity, the
OPMP and SPh substituents of 10-13 were replaced with OMe
and SMe substituents. Solvation calculations were performed
on gas-phase optimized geometries. All transition structures were
proved by frequency calculations. All calculations were per-
formed using GAUSSIAN 98.28
ficiently close spatial proximity to the vinylic proton and to
the secondary methyl to elicit the significant interactions that
are noted on the formula.
When the heteroatomic substituent eventuates as the â isomer
(see 19 and 21), some flattening of the medium ring is
encountered because of the driving force underlying their
adoption of quasi-equatorial status. In these examples, the
stereochemistry of the double bond is again easily deduced. The
cis relationship of the vicinal X and CH3 substituents was made
possible by the unique chemical shifts of the associated methine
protons for which an interaction level of 7.6% was measured.
That the OPMP and SPh substituents are R-oriented in 20 and
22 was confirmed in comparable fashion. Particular attention
is called to the triple relay that proved feasible in this pair of
examples.
Results and Discussion. Acyclic molecules of the generic
type A are recognized to rearrange in one step through a
concerted highly asynchronous transition state. The ring strain
for compound 9, however, alters the mechanism. Now, cleavage
to an allyl anion and enone occurs (Figure 3). The combined
effects of the oxido substituent14 and ring strain weaken the
breaking bond so that even in the ground state (GS1), its length
is 1.69 Å. The activation energy for bond cleavage drops from
8.3 kcal/mol in 3-oxido-1,5-hexadiene to 2.5 kcal/mol in 9 (see
Table 2). The intermediate is slightly below the reactant in
energy. Solvation energies change the picture. Solvation in-
creases the energy of both transition states and the intermediate
relative to reactant. This raises the barrier of the reaction from
2.5 to 6.6 kcal/mol and moves the intermediate above the
transition states. The mechanism now resembles that of the gas-
phase rearrangement of the parent system.
The substituent influence was studied utilizing ONIOM and
B3LYP//ONIOM methods. The geometries obtained by the
ONIOM method for 9 are nearly the same as for the full B3LYP
calculation, but the ONIOM energies are not consistent with
experimental trends. The major geometrical deviation is a
slightly earlier transition state (TS1) from ONIOM geometries.
The breaking CC bond is 2.03 and 2.10 Å in ONIOM- and
B3LYP-calculated TS1 of 9, respectively.
Intermediates are formed in the gas phase for methoxy- and
thiomethoxy-substituted derivatives of 9. Solvation increases
the energies of the intermediates and, in the case of methoxy
derivatives, the intermediates become the highest-energy struc-
tures (see Table 3). For the thiomethoxy derivative, the
rearrangement is predicted to proceed without a barrier through
cleavage to an allyl anion that is stabilized by the thioalkyl
group, even in solution.
In conclusion, heteroatomic and structural effects on the rate
and mechanism of electronic reorganization operate with
(28) (b) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. J. A.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. M.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Laishenko, A.; Piskorz,
P.; Komaromi, I.; Gomperts, R.; Martim, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.;
Head-Gordon, M.; Replogle, E. S.; Pople, J. A. ReVision A; 7, Gaussian,
Inc.: Pittsburgh, PA, 1998.
Theoretical Methods. The rearrangement of 9 was studied
with B3LYP/6-31+G* calculations and the PCM solvation
model. The parent, 9, and alkoxy- and thioalkoxy-substituted
cases were investigated with the ONIOM method,27 using
(27) (a) Dapprich, S.; Komaromi, I.; Byun, K. S.; Morokuma, D.; Frisch,
M. J. Theochem - J. Mol. Struct. 1999, 462, 1-21. (b) Svensson, M.;
Jumbel, S.; Froese, R. D. J.; Matsubara, T.; Sieber, S.; Morokuma, K. J.
Phys. Chem. 1996, 100, 19357. (c) Humbel, S.; Sieber, S.; Morokuma, K.
J. Chem. Phys. 1996, 105, 1959.

10792 J. Am. Chem. Soc., Vol. 122, No. 44, 2000
Paquette et al.
Figure 3. B3LYP/6-31+G* energies and structures for the Cope rearrangement of 9.
Table 2. Relative Energies (kcal/mol) of TS and Intermediates for
Rearrangement of 9 to 18
was stirred at 20 °C with dry THF (200 mL) for 4 h, and the resulting
slurry was cooled to -78 °C and titrated with tert-butyllithium until
an orange color developed. A solution of cis-1-propenylmagnesium
bromide (14.6 mmol) in dry THF (50 mL) was slowly introduced and
stirred at this temperature for 1 h in advance of the addition of 1420
(1.6 g, 9.8 mmol) in the same solvent (50 mL) via syringe. The reaction
mixture was stirred at -78 °C for 2.5 h, quenched with saturated NH4-
Cl solution, and extracted with ether. The combined organic phases
were washed with water and brine, dried, and concentrated. The residue
was purified by chromatography on silica gel (elution with 5% ethyl
acetate in petroleum ether) to furnish 1.12 g (56%) of 9 as a colorless
oil; IR (neat, cm-1) 3495, 1634, 1489, 1455; 1H NMR (300 MHz,
CDCl3) δ 6.18 (dd, J ) 17.7, 11.0 Hz, 1H), 5.78 (dd, J ) 11.3, 1.7
Hz, 1H), 5.56-5.45 (m, 1H), 5.28 (dd, J ) 11.0, 2.1 Hz, 1H), 5.11
(dd, J ) 17.7, 2.1 Hz, 1H), 2.39-2.32 (m, 1H), 1.84-1.47 (m, 9H),
1.23 (s, 3H), 0.80 (s, 3H) (OH not observed); 13C NMR (75 MHz,
CDCl3) δ 136.5, 136.4, 127.4, 117.1, 81.9, 59.4, 49.4, 47.8, 46.3, 26.6,
25.9, 21.6, 21.1, 15.2; HRMS (EI) m/z (M+) calcd 206.1671, obsd
206.1679; [R]2D2 -79.4 (c 5.3, CHCl3). Anal. Calcd for C14H22O: C,
81.50; H, 10.75. Found: C, 81.57; H, 10.66.
9
TS1 intermediate TS2
18
gas (B3LYP/6-31+G*)
THF (B3LYP/6-31+G*) 0.00 6.6
gas (ONIOM) 0.00 1.7
0.00 2.5
-0.9
5.0
-10.0
0.4 -13.8
3.5 -14.8
-3.2 -14.8
Table 3. B3LYP//ONIOM Relative Energies (kcal/mol) of TS and
Intermediates for Rearrangements of 9 and Its Methoxy and
Thiomethoxy Derivatives in THF Utilizing the PCM Solvation
Model
reactant
GS1
TS1
intermediate
TS2
9
0.00
0.00
0.00
0.00
4.4
4.1
4.8
7.3
8.2
7.6
-1.6
1.3
2.5
cis-methoxy
trans-methoxy
trans-thiomethoxy
-2.5
-3.1
-5.6
impressive consequences. On the basis of the present findings,
it is highly likely that the consequences of heteroatoms other
than O and S on the course of anionically accelerated sigmat-
ropic processes will be uncovered and additionally enrich these
reaction manifolds.
(1S,2S,4R)-1-[(E)-2-(p-Methoxyphenoxy)vinyl]-7,7-dimethyl-2-
[(Z)-1-propenyl]bicyclo[2.2.1]heptan-2-ol (10). Reaction of dry cerium
trichloride (634 mg, 1.7 mmol) and cis-1-propenylmagnesium bromide
(1.7 mmol) in anhydrous THF (45 mL) with (1S,4R)-1-[(E)-2-(p-
methoxyphenoxy)vinyl]-7,7-dimethyl-2-norbornanone22 (326 mg, 1.1
mmol) in the predescribed manner afforded 117 mg (31%) of 10 after
chromatographic purification (silica gel, elution with 4% ethyl acetate
Experimental Section
General Considerations. Melting points are uncorrected. The
column chromatographic separations were performed using Woelm
silica gel (230-400 mesh). Solvents were reagent grade and, in most
cases, dried prior to use. The purity of all compounds was shown to
be >95% by TLC and high-field 1H NMR. The high-resolution electron-
impact mass spectra were recorded at The Ohio State University
Campus Chemical Instrumentation Center. Elemental analyses were
performed at Atlantic Microlab, Inc., Norcross, GA.
in petroleum ether); white solid, mp 64-66 °C; IR (CH2Cl2, cm-1
)
1
3528, 1662, 1504, 1463, 1226; H NMR (300 MHz, CDCl3) δ 6.95-
6.83 (m, 4H), 6.31 (d, J ) 12.5 Hz, 1H), 5.75 (dd, J ) 12.9, 1.6 Hz,
1H), 5.60-5.52 (m, 2H), 3.77 (s, 3H), 2.38-2.32 (m, 1H), 1.84-1.49
(m, 9H), 1.23 (s, 3H), 0.86 (s, 3H) (OH not observed); 13C NMR (75
MHz, CDCl3) δ 155.2, 151.3, 144.7, 136.3, 127.6, 117.6, 114.6, 109.5,
(29) Paquette, L. A. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley and Sons: Chichester, 1995; Vol. 2, p
1031.
(1S,2S,4R)-7,7-Dimethyl-2-[(Z)-1-propenyl]-1-vinylbicyclo[2.2.1]-
heptan-2-ol (9). Anhydrous cerium trichloride29 (5.44 g, 14.6 mmol)

High-Rate Accelerations in Oxy-Cope Rearrangements
J. Am. Chem. Soc., Vol. 122, No. 44, 2000 10793
81.6, 56.6, 55.6, 49.6, 47.6, 45.7, 26.8, 26.7, 21.5, 21.1, 15.2; HRMS
(EI) m/z (M+) calcd 328.2038, obsd 328.2030; [R]2D2 -62.1 (c 0.73,
CHCl3). Anal. Calcd for C21H28O3: C, 76.79; H, 8.59. Found: C, 76.89;
H, 8.62.
ride (558 mg, 1.5 mmol) and cis-1-propenylmagnesium bromide (1.5
mmol) in anhydrous THF (40 mL) with (1S,4R)-7,7-dimethyl-1-[(Z)-
2-(phenylthio)vinyl]-2-norbornanone (272 mg, 1.0 mmol) dissolved in
dry THF (10 mL) in the manner described above gave, following
chromatographic purification on silica gel (elution with 2% ethyl acetate
in petroleum ether), 112 mg (32%) of 12 as a colorless oil; IR (neat,
cm-1) 3553, 1584, 1479, 1457; 1H NMR (300 MHz, CDCl3) δ 7.39-
7.21 (m, 5H), 6.47 (d, J ) 10.9 Hz, 1H), 6.16 (dd, J ) 1.5, 11.3 Hz,
1H), 5.90 (d, J ) 10.8 Hz, 1H), 5.60-5.54 (m, 1H), 2.40-2.36 (m,
1H), 2.18-2.10 (m, 2H), 1.87-1.64 (m, 7H), 1.27 (s, 3H), 1.14-1.11
(m, 1H), 0.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 137.3, 137.2,
129.6, 129.1, 128.9, 128.0, 126.8, 126.3, 83.2, 60.2, 50.9, 48.0, 45.3,
27.4, 27.2, 21.6, 21.5, 15.1; HRMS (EI) m/z (M+) calcd 314.1704, obsd
314.1696; [R]2D2 -58.7 (c 1.13, CHCl3). Anal. Calcd for C20H26OS: C,
76.38; H, 8.33. Found: C, 76.00; H, 8.38.
(1S,2S,4R)-1-[(Z)-2-(p-Methoxyphenoxy)vinyl]-7,7-dimethyl-2-
[(Z)-1-propenyl]bicyclo[2.2.1]heptan-2-ol (12). Reaction of dry cerium
trichloride (303 mg, 0.81 mmol) and cis-1-propenylmagnesium bromide
(0.74 mmol) in anhydrous THF (40 mL) with (1S,4R)-1-[(Z)-2-(p-
methoxyphenoxy)vinyl]-7,7-dimethyl-2-norbornanone22 (156 mg, 0.54
mmol) dissolved in THF (20 mL) in the manner described above led
to the isolation (SiO2, elution with 3% ethyl acetate in petroleum ether)
of pure 12 (52 mg, 29%) as a colorless oil; IR (neat, cm-1) 3553, 1584,
1478, 1455, 1438; 1H NMR (300 MHz, CDCl3) δ 7.23-6.75 (m, 4H),
6.43 (d, J ) 10.6 Hz, 1H), 6.12 (dd, J ) 14.7, 1.6 Hz, 1H), 5.54-5.45
(m, 1H), 4.70 (d, J ) 10.6 Hz, 1H), 3.75 (s, 3H), 2.38-2.31 (m, 1H),
2.03-1.59 (m, 9H), 1.21 (s, 3), 0.89 (s, 3H) (OH not observed); 13C
NMR (75 MHz, CDCl3) δ 155.1, 151.4, 143.3, 137.3, 127.3, 117.3,
114.6, 108.3, 82.3, 57.1, 55.6, 49.9, 47.4, 45.2, 28.2, 27.1, 21.6, 21.5,
15.1; HRMS (EI) m/z (M+) calcd 328.2038, obsd 328.2036; [R]2D2
-105.8 (c 1.23, CHCl3). Anal. Calcd for C21H28O3: C, 76.79; H, 8.59.
Found: C, 77.00; H, 8.64.
(1R,5S,7E)-5,11,11-Trimethylbicyclo[6.2.1]undec-7-en-3-one (18).
A solution of 9 (412 mg, 2.0 mmol) in dry THF (10 mL) containing
18-crown-6 (1.58 g, 6.0 mmol) was cooled to 0 °C, deoxygenated with
N2 for 30 min, treated with potassium hexamethyldisilazide (11.9 mL
of 0.5 M in toluene, 6.0 mmol), stirred at 0 °C for 25 min, and warmed
to room temperature. After another 30 min, saturated NH4Cl solution
was introduced, and the product was extracted into ether. The combined
organic layers were washed with water and brine, dried, and concen-
trated. Chromatography of the residue on silica gel (elution with 10%
ethyl acetate in petroleum ether) afforded 290 mg (70%) of 18 as a
(E and Z)-(1S,4R)-7,7-Dimethyl-1-[2-(phenylthio)vinyl]-2-nor-
bornanone. Commercial [(phenylthio)methyl]triphenylphosphonium
chloride (4.2 g, 10 mmol) was dissolved in dry THF (50 mL) under
N2, cooled to 0 °C, and treated dropwise with a solution of potassium
hexamethyldisilazide in toluene (23 mL of 0.5 M, 10 mmol). After the
reaction mixture had been stirred at this temperature for 45 min, a
solution of keto aldehyde 1522 (1.5 g, 9.0 mmol) in dry THF (25 mL)
was introduced, the cooling bath was removed, and stirring was
continued for 2 h. Following a quench with saturated NH4Cl solution,
the products were extracted into ether, washed with brine, dried, and
freed of solvent. Chromatography of the residue on silica gel (elution
with 7% ethyl acetate in petroleum ether) gave 1.29 g (54%) of a 65:
35 mixture of the Z and E isomers (GC analysis). Separation was
effected by MPLC (SiO2, elution with 5% ethyl acetate in hexanes).
1
colorless oil; IR (neat, cm-1) 1730, 1687, 1452, 1383; H NMR (300
MHz, CDCl3) δ 5.25 (dd, J ) 14.2, 2.2 Hz, 1H), 2.55-2.28 (m, 4H),
2.14-1.77 (series of m, 7H), 1.66 (dd, J ) 12.7, 4.4 Hz, 1H), 1.24 (s,
3H), 1.07 (s, 3H), 1.02 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 212.1,
147.4, 120.7, 51.7, 49.4, 45.12, 45.09, 31.8, 30.4, 24.9, 23.9, 22.9, 22.1,
21.8; HRMS (EI) m/z (M+) calcd 206.1671, obsd 206.1674; [R]2D2
-69.3 (c 2.3, CHCl3). Anal. Calcd for C14H22O: C, 81.49; H, 10.74.
Found: C, 81.44; H, 10.65.
Oxyanionic Rearrangements of 10-13. These experiments were
performed as described above but without added 18-crown-6 at the
highest temperature given in Table 1. In several examples, the
concentrated aliquots from the kinetic runs were combined and used
to deliver the product ketones.
For the Z-isomer: white crystals, mp 71-72 °C; IR (CH2Cl2, cm-1
)
1
1738, 1570, 1472, 1413, 1260; H NMR (300 MHz, CDCl3) δ 7.38-
7.20 (m, 5H), 6.55 (d, J ) 10.6 Hz, 1H), 5.61 (d, J ) 10.6 Hz, 1H),
2.50-2.31 (m, 2H), 2.16-1.92 (m, 3H), 1.51-1.42 (m, 2H), 1.05 (s,
3H), 0.97 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 214.9, 136.7, 129.5,
129.2, 128.9, 126.4, 124.6, 63.8, 49.4, 45.1, 43.4, 42.5, 27.4, 26.4, 20.3,
19.9; HRMS (EI) m/z (M+) calcd 272.1235, obsd 272.1241; [R]2D2
-80.2 (c 1.0, CHCl3). Anal. Calcd for C17H20OS: C, 74.95; H, 7.40.
Found: C, 74.71; H, 7.43. For the E-isomer: colorless oil; IR (neat,
(1R,5R,6R,7E)-6-(p-Methoxyphenoxy)-5,11,11-trimethylbicyclo-
[6.2.1] undec-7-en-3-one (19): white crystals, mp 77-79 °C; IR (CH2-
1
Cl2, cm-1) 1730, 1686, 1506, 1421; H NMR (300 MHz, CDCl3) δ
6.85-6.77 (m, 4H), 5.34 (d, J ) 1.8 Hz, 1H), 4.94 (dd, J ) 10.7, 7.5
Hz, 1H), 3.75 (s, 3H), 3.03-2.96 (m, 1H), 2.63-1.87 (series of m,
9H), 1.29 (s, 3H), 1.13 (s, 3H), 1.09 (d, J ) 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 211.5, 171.9, 155.2, 137.3, 135.3, 129.0, 128.9,
127.1, 116.2, 116.1, 115.3, 66.9, 66.2, 56.9, 38.3, 32.6, 28.1, 26.9, 24.9;
HRMS (EI) m/z (M+) calcd 328.2038, obsd 328.2056; [R]2D2 -82.6 (c
0.78, CHCl3). Anal. Calcd for C21H28O3: C, 76.79; H, 8.59. Found:
C, 76.38; H, 8.93.
1
cm-1) 1741, 1582, 1479, 1452, 1439; H NMR (300 MHz, CDCl3) δ
7.37-7.21 (m, 5H), 6.39 (d, J ) 15.5 Hz, 1H), 5.84 (d, J ) 15.5 Hz,
1H), 2.49-2.40 (m, 1H), 2.15-1.87 (m, 4H), 1.69-1.42 (m, 2H), 0.97
(s, 3H), 0.93 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 216.1, 135.6, 129.0,
128.9, 128.1, 126.6, 126.3, 63.9, 49.0, 43.5, 43.0, 27.2, 27.0, 20.1, 19.4;
HRMS (EI) m/z (M+) calcd 272.1235, obsd 272.1234; [R]2D2 -59.2 (c
0.5, CHCl3). Anal. Calcd for C17H20OS: C, 74.95; H, 7.40. Found: C,
74.93; H, 7.50.
(1S,2S,4R)-7,7-Dimethyl-1-[(E)-2-(phenylthio)vinyl]-2-[(Z)-1-pro-
penyl] bicyclo[2.2.1]heptan-2-ol (11). Reaction of dry cerium trichlo-
ride (279 mg, 0.75 mmol) and cis-1-propenylmagnesium bromide (0.75
mmol) in anhydrous THF (40 mL) with (1S,4R)-7,7-dimethyl-1-[(E)-
2-(phenylthio)vinyl]-2-norbornanone (136 mg, 0.50 mmol) dissolved
in THF (20 mL) in the manner described above gave, following
chromatographic purification on silica gel (elution with 3% ethyl acetate
in petroleum ether), 48 mg (32%) of 11 as a colorless oil; IR (neat,
cm-1) 3518, 1584, 1478, 1437; 1H NMR (300 MHz, CDCl3) δ 7.35-
7.19 (m, 5H), 6.35 (d, J ) 15.5 Hz, 1H), 6.21 (d, J ) 15.5 Hz, 1H),
5.74 (dd, J ) 11.0, 1.7 Hz, 1H), 5.54-5.50 (m, 1H), 2.37-2.30 (m,
1H), 1.81-1.55 (m, 9H), 1.28 (s, 3H), 0.90 (s, 3H) (OH not observed);
13C NMR (75 MHz, CDCl3) δ 136.5, 136.4, 134.1, 128.9, 128.6, 127.8,
126.1, 123.8, 82.2, 60.1, 50.2, 48.2, 46.2, 26.7, 26.5, 21.6, 21.2, 15.2;
HRMS (EI) m/z (M+) calcd 314.1704, obsd 314.1693; [R]2D2 -62.2 (c
1.22, CHCl3). Anal. Calcd for C20H26OS: C, 76.38; H, 8.33. Found:
C, 76.22; H, 8.43.
(1R,5R,6S,7E)-6-(p-Methoxyphenoxy)-5,11,11-trimethylbicyclo-
[6.2.1] undec-7-en-3-one (20): colorless oil; IR (neat, cm-1) 1728,
1686, 1505, 1465; 1H NMR (300 MHz, CDCl3) δ 6.81-6.78 (m, 4H),
5.39 (d, J ) 4.8 Hz, 1H), 4.35 (dd, J ) 4.9, 4.9 Hz, 1H), 3.74 (s, 3H),
2.89-2.86 (m, 1H), 2.66-2.59 (m, 2H), 2.48-2.47 (m, 1H), 2.12-
1.94 (m, 6H), 1.26 (d, J ) 7.2 Hz, 3H), 1.25 (s, 3H), 1.01 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 212.8, 184.5, 153.5, 152.3, 150.0, 121.1,
116.2, 114.2, 81.2, 55.6, 49.7, 45.6, 45.1, 41.8, 25.6, 25.2, 23.6, 22.1,
21.9; HRMS (EI) m/z (M+) calcd 328.2038, obsd 328.2047; [R]2D2
-121.9 (c 0.52, CHCl3). Anal. Calcd for C21H28O3: C, 76.79; H, 8.59.
Found: C, 77.08; H, 8.74.
(1R,5R,6R,7E)-5,11,11-Trimethyl-6-(phenylthio)bicyclo[6.2.1]undec-
1
7-en-3-one (21): IR (neat, cm-1) 1728, 1687, 1582, 1498; H NMR
(300 MHz, CDCl3) δ 7.60-7.38 (m, 3H), 7.25-7.15 (m, 2H), 5.24 (d,
J ) 12.0 Hz, 1H), 4.12 (dd, J ) 11.9, 12.0 Hz, 1H), 2.82-2.76 (m,
1H), 2.58-2.45 (m, 2H), 2.26-2.07 (m, 2H), 1.94-1.80 (m, 5H), 1.28
(s, 3H), 1.20 (d, J ) 7.0 Hz, 3H), 1.08 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 210.9, 149.5, 151.1, 130.8, 128.6, 126.3, 121.1, 51.8, 50.6,
48.2, 45.7, 45.4, 35.2, 28.9, 24.9, 24.8, 22.9, 21.8; HRMS (EI) m/z
(M+) calcd 314.1704, obsd 314.1701; [R]D22 -248.9 (c 0.19, CHCl3).
Anal. Calcd for C20H26OS: C, 76.38; H, 8.33. Found: C, 76.00; H,
8.73.
(1S,2S,4R)-7,7-Dimethyl-1-[(Z)-2-(phenylthio)vinyl]-2-[(Z)-1-pro-
penyl] bicyclo[2.2.1]heptan-2-ol (13). Reaction of dry cerium trichlo-

10794 J. Am. Chem. Soc., Vol. 122, No. 44, 2000
Paquette et al.
(1R,5R,6S,7E)-5,11,11-Trimethyl-6-(phenylthio)bicyclo[6.2.1]undec-
7-en-3-one (22): colorless oil; IR (neat, cm-1) 1731, 1686, 1468, 1264;
1H NMR (300 MHz, CDCl3) δ 7.35-7.31 (m, 2H), 7.27-7.18 (m,
3H), 5.73 (d, J ) 10.1 Hz, 1H), 3.34-3.32 (m, 1H), 2.68-2.59 (m,
3H), 2.33-2.24 (m, 2H), 1.98-1.85 (m, 5H), 1.24 (s, 3H), 1.22 (d, J
) 6.5 Hz, 3H), 1.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 213.1,
151.3, 138.0, 129.8, 128.6, 125.9, 123.0, 51.3, 51.1, 50.8, 45.4, 44.1,
41.5, 26.8, 25.1, 23.5, 22.5, 22.4; HRMS (EI) m/z (M+) calcd 314.1704,
obsd 314.1694 [R]D22 -215.1 (c 1.27, CHCl3). Anal. Calcd for C20H26-
OS: C, 76.38; H, 8.33. Found: C, 76.09; H, 8.36.
temperature equilibration, the base solution was transferred via a
precooled syringe or insulated cannula into the reaction mixture. A
first aliquot was immediately removed at time zero. Following this,
additional aliquots were removed at 15-60 min intervals, quenched
with cold (0 °C) saturated NH4Cl solution, and extracted with ether.
The combined organic layers were washed with water and brine prior
to drying and solvent evaporation. 1H NMR analysis at 300 MHz
followed, and the percent conversion versus time (s) data were subjected
to least-squares analysis. All experiments were performed in triplicate.
Good first-order behavior was observed in all cases.
Kinetic Experiments. All flasks were base-washed (20% ethanolic
KOH) and flame-dried under argon immediately prior to use. A 5%
THF solution of the carbinol (ca 30 mg) was introduced, deoxygenated
with bubbling N2 for 15 min, and cooled to the desired temperature in
a thermostated cooling bath. In another flask was placed a THF solution
of potassium hexamethyldisilazide (0.5 M in toluene, 3.0 molar equiv),
and this vessel was cooled to the same temperature. After 15 min of
Acknowledgment. We thank Prof. Jose´ Cabral for his
assistance with processing of the kinetic data and Dr. Kurt
Loening for providing appropriate nomenclature. Financial
support was provided by the Paquette Research Fund.
JA0025402