The bicyclo[2.2.2]octyl carbene system as a probe for migratory aptitudes of hydrogen to carbenic centers

Article abstract of DOI:10.1021/ja002407+

A series of tosylhydrazone derivatives of exo-6-substituted bicylo[2.2.2]octan-2-ones have been prepared. Thermal decomposition of the sodium salts of these tosylhydrazones gives carbene-derived products from 1,3-migration of either the C6 hydrogen (perturbed) or the C7 hydrogen (unperturbed), along with smaller amounts of alkenes derived from 1,2-hydrogen migration. The exo-6-substituent strongly activates 1,3-hydrogen migration in the case of SiMe₃ and weakly activates it in the case of CH₃ substitution. Thiomethoxy and carbomethoxy are weakly deactivating, while cyano and methoxy groups are strongly deactivating. B3LYP/6-31G* calculations on these substituted carbenes and transition states are in qualitative agreement with the ease of 1,3-hydrogen migration of perturbed vs unperturbed hydrogen. These experimental results and computational studies suggest carbene stabilization due to the exo-6-silyl group. They also suggest a reactant-like transition state for 1,3-hydrogen migration in which the inductive effect influences ease of migration. In the case of the exo-6-methoxy group, the inductive effect overwhelms any potential resonance-stabilizing effects.

Full text of DOI:10.1021/ja002407+

J. Am. Chem. Soc. 2001, 123, 1569-1578
1569
The Bicyclo[2.2.2]octyl Carbene System as a Probe for Migratory
Aptitudes of Hydrogen to Carbenic Centers
Xavier Creary* and Mark A. Butchko
Contribution from the Department of Chemistry and Biochemistry, UniVersity of Notre Dame,
Notre Dame, Indiana 46556
ReceiVed July 3, 2000. ReVised Manuscript ReceiVed October 19, 2000
Abstract: A series of tosylhydrazone derivatives of exo-6-substituted bicylo[2.2.2]octan-2-ones have been
prepared. Thermal decomposition of the sodium salts of these tosylhydrazones gives carbene-derived products
from 1,3-migration of either the C6 hydrogen (perturbed) or the C7 hydrogen (unperturbed), along with smaller
amounts of alkenes derived from 1,2-hydrogen migration. The exo-6-substituent strongly activates 1,3-hydrogen
migration in the case of SiMe3 and weakly activates it in the case of CH3 substitution. Thiomethoxy and
carbomethoxy are weakly deactivating, while cyano and methoxy groups are strongly deactivating. B3LYP/
6-31G* calculations on these substituted carbenes and transition states are in qualitative agreement with the
ease of 1,3-hydrogen migration of perturbed vs unperturbed hydrogen. These experimental results and
computational studies suggest carbene stabilization due to the exo-6-silyl group. They also suggest a reactant-
like transition state for 1,3-hydrogen migration in which the inductive effect influences ease of migration. In
the case of the exo-6-methoxy group, the inductive effect overwhelms any potential resonance-stabilizing
effects.
Introduction
are the major products generated. However, SiMe3 is an efficient
migrator, and the tricyclic 2 (R ) SiMe3) is formed exclusively.
One of the fundamental processes that singlet carbenes
undergo is 1,2-migration of adjacent hydrogen to the carbenic
center to form olefinic products.1 The optimal stereochemical
alignment for this migration is one in which the C-H bond is
aligned with the vacant p-orbital of the carbene.2 The effect of
substituents on this 1,2-migration, which has been termed
“bystander assistance” by Nickon, has also been examined.3 In
addition to the 1,2-migration process, more remote hydrogen
can also migrate to the carbenic center.4 The intramolecular 1,3-
hydrogen migration process, often termed “1,3-insertion”, results
in cyclopropane formation and will be a focus of this study.
We have now turned our attention to the influence of
substituents on the 1,3-migratory aptitude of hydrogen to
proximate carbenic centers. The bicyclo[2.2.1]hept-2-yl system
4 is of limited value as a probe since the parent carbene 4 (R
) H) gives almost exclusive 1,3-migration, forming 99.5% of
nortricyclane, 5 (R ) H).9 Increases in migratory aptitude due
to exo-6-substitution are therefore difficult to detect. The
bicyclo[2.2.2]oct-2-yl carbene system has therefore been used
as a probe for relative migratory aptitudes of hydrogen. The
behavior of the parent carbene 7 has been described, and
intramolecular rearrangement of 7 leads to 70% of the tricyclic
alkane 8 along with 30% of the alkene 9.10 We report here our
experimental findings on the rearrangement pathways for
substituted carbenes of type 10, where migration of Ha competes
with migration of Hb. The chemistry of the related 5-methoxy
derivative 11 was also investigated. Also reported are compu-
tational studies on carbene 7, as well as substituted variations
10 and 11.
We5 and others6,7 have been interested in the chemistry of
carbenes that contain silicon in the proximity of the carbenic
center. This interest grows out of our finding that silicon has a
high propensity to migrate to carbenic centers. During the course
of these studies, we have used 6-substituted 2-norbornyl
carbenes 1 as a probe for 1,3-migratory aptitudes of various
groups R.8 Groups such as CH3, CH2SiMe3, Ph, and OCH3 are
loath to migrate to the carbenic center in 1, and the alkenes 3
(1) For leading references, see: (a) Schaefer, H. F. Acc. Chem. Res. 1979,
12, 288. (b) Kirmse, W. K. Carbene Chemistry; Academic Press: New
York, 1971. (c) Carbenes; Jones, M., Jr., Moss, R. A., Eds.; Wiley: New
York, 1973.
(2) (a) Press, L. S.; Shechter, H. J. Am. Chem. Soc. 1979, 101, 509. (b)
Nickon, A.; Bronfenbrenner, J. K. J. Am. Chem. Soc. 1982, 104, 2022.
(3) Nickon, A. Acc. Chem. Res. 1993, 26, 84.
(4) Friedman, L.; Shechter, H. J. Am. Chem. Soc. 1961, 83, 3159.
(5) (a) Creary, X.; Wang, Y.-X. Tetrahedron Lett. 1989, 19, 2493. (b)
Creary, X.; Wang, Y.-X. J. Org. Chem. 1994, 59, 1604. (c) Creary, X.;
Jiang, Z.; Butchko, M.; McLean, K. Tetrahedron Lett. 1995, 37, 579.
(6) Baird, M. S.; Dale, C. M.; Dulayymi, J. R. A. J. Chem. Soc., Perkin
Trans. 1 1993, 1373.
(9) (a) Friedman, L.; Shechter, H. J. Am. Chem. Soc. 1961, 83, 3159.
(b) Freeman, P. K.; George, D. E.; Rao, V. N. M. J. Org. Chem. 1964, 29,
1682.
(7) Kirmse, W.; Konrad, W.; Schnitzler, D. J. Org. Chem. 1994, 59,
3821.
(8) Creary, X.; Wang, Y.-X. Res. Chem. Intermed. 1994, 20, 201.
(10) Grob, C. A.; Hostynek, J. HelV. Chim. Acta 1963, 46, 1676.
10.1021/ja002407+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/02/2001

1570 J. Am. Chem. Soc., Vol. 123, No. 8, 2001
Creary and Butchko
Hydrolysis of 19 gave the known â-hydroxyketone 20,13 which
was converted in a straightforward manner to the mesylate.
Reaction of the mesylate with NaSCH3 in methanol gave the
exo-6-thiomethoxy ketone 21, which was readily converted to
the carbene precursor, tosylhydrazone 22. The exo-stereochem-
istry of the thiomethoxy group in 21 was confirmed by the
observation of W-coupling (1.8 Hz) of the endo-6-hydrogen
atom at δ 2.90 with the appropriate hydrogen atom on C7.
Results
Synthetic Aspects. The precursors to the desired carbenes
10 and 11 were tosylhydrazones derived from the corresponding
ketones. The preparation of ketone 14 used methodology similar
to that developed by the groups of Vogel and Salomon.11
Bicyclo[2.2.2]oct-5-en-2-one, 12, was reacted with PhSeBr
followed by oxidation, selenoxide elimination, and ketalization
to give the vinyl bromide 13. Lithium-halogen exchange
followed by methylation, diimide reduction, and hydrolysis gave
a mixture of the known ketone 14 and the endo-methyl
stereoisomer. Separation of the desired ketone 14 was ac-
complished by chromatography, and this ketone was converted
by the standard method to the tosylhydrazone 15. In similar
fashion, lithium-halogen exchange on 13 followed by silylation,
hydrolysis, and catalytic hydrogenation produced ketone 16,
which was separated by silica gel chromatography from the
epimeric ketone.12 The stereochemistry of 16 was confirmed
by the observation of W-coupling (1.8 Hz) of the endo-6-
hydrogen at δ 1.09 with the appropriately situated hydrogen
atom on C7. Conversion of 16 to the tosylhydrazone 17 was
straightforward.
The precursor tosylhydrazones to the exo-6-carbomethoxy and
the exo-6-cyano carbenes were prepared by analogous proce-
dures. The exo-ester 23 was formed as the minor product in the
Diels-Alder reaction of methylacrylate with cyclohexadiene.14
This was separated from the major endo-isomer by a saponifica-
tion-iodolactonization-re-esterification procedure.15 The pure
exo-ester 29 was then subjected to hydroboration followed by
chromic acid oxidation. The 2- and 3-keto regioisomers were
then separated by chromatography, and the desired isomer 24
was converted by standard methods to the corresponding
tosylhydrazone 25. The exo-nitrile 26 was also available from
a Diels-Alder reaction (acrylonitrile and cyclohexadiene),
which gave a 50:50 mixture of exo- and endo-isomers.16 These
isomers were readily separated by chromatography on silica gel,
and the pure exo-isomer 26 was subjected to the same protocol,
which gave the tosylhydrazone 28.
The precursor to the exo-6-thiomethoxy carbene was also
prepared starting with bicyclo[2.2.2]oct-5-en-2-one, 12. Ketal-
ization followed by hydroboration/oxidation gave a mixture of
alcohols which was further oxidized (Swern) to a mixture of
ketone 18 and the 5-keto regioisomer. Reduction with NaBH4
gave a mixture of three alcohols from which the desired endo-
alcohol 19 was readily separated. This alcohol is strongly
intramolecularly hydrogen bonded, as indicated by the sharp
O-H stretch at 3522 cm-1 and the lack of a free O-H stretch,
even in dilute CCl4 solution. This intramolecular hydrogen
bonding results in facile chromatographic separation of 19,
which elutes more readily than the isomeric alcohol products.
This hydroboration/chromic acid oxidation sequence was also
used to form a mixture of the ketoethers 31 and 32, which were
separated by column chromatography. The starting methyl ether
30 used in this sequence was prepared by a standard methylation
procedure on the pure exo-alcohol 29,17 which was available
as the minor product formed in the hydride reduction of the
ketone 12.
(13) Almqvist, F.; Eklund, L.; Frejd, T. Synth. Commun. 1993, 1499.
(14) Brecknell, D. J.; Carman, R. M.; Day, P. J. Aust. J. Chem. 1984,
37, 2323.
(15) Ohwada, T.; Uchiyama, M.; Tsuji, M.; Okamoto, I.; Shudo, K.
Chem. Pharm. Bull. 1996, 44, 296.
(11) (a) Carrupt, P.-A.; Vogel, P. Tetrahedron Lett. 1982, 23, 2563. (b)
Lal, K.; Salomon, R. G. J. Org. Chem. 1989, 54, 2628.
(12) The stereochemistry of this epimeric ketone was verified by
conversion to the tosylhydrazone and an X-ray analysis.
(16) Alder, K.; Krieger, H.; Weiss, H. Chem. Ber. 1955, 88, 144.
(17) (a) Brown, H. C.; Muzzio, J. J. Am. Chem. Soc. 1966, 88, 2811.
(b) Brown, R. S.; Marcinko, R. W. J. Am. Chem. Soc. 1977, 99, 6500. (c)
Fraser, R. R.; O’Farrell, S. Tetrahedron Lett. 1962, 24, 1143.

Probe for Migratory Aptitudes of H to Carbenic Centers
J. Am. Chem. Soc., Vol. 123, No. 8, 2001 1571
Table 1. Products from Rearrangement of Carbenes 7, 10, and 11
Tosylhydrazone Salt Pyrolyses. The tosylhydrazones 15, 17,
22, 25, 28, 33, and 34 served as sources of the desired carbenes
10 and 11. Thus, treatment of these tosylhydrazones with sodium
methoxide led to the corresponding salts 35, and pyrolysis under
vacuum generated the carbenes 10, presumably via the in situ-
generated diazo compounds 36.18 The working assumption is
that these reactions all involve the carbenes 10 as discrete
intermediates and that loss of nitrogen and carbene rearrange-
ment are not concerted processes. Indeed, studies19,20 have
suggested that free carbenes can sometimes be bypassed in
reactions involving nitrogenous precursors. These concerns have
been summarized in a caveat presented by Nickon.3 However,
since our reactions are not excited-state photochemical reactions,
and the migrating hydrogens are not anti to the departing
nitrogen in the diazo compound, it is a reasonable assumption
that loss of nitrogen is not concerted with hydrogen migration.
a Data from ref 6. b Combined yield of exo (15%)- and endo (15%)-
isomers. See text. c Combined yield of exo (29%)- and endo (9%)-
isomers. See text.
ene were also formed. These minor endo-alkene products
presumably arise from epimerization of the exo-alkenes 39 under
the reaction conditions, where there is a slight excess of sodium
methoxide. Product mixtures were separated by preparative gas
chromatography, and structures were determined by NMR
spectroscopic methods and/or independent syntheses. Table 1
summarizes the products formed under these pyrolytic condi-
tions.
Immediately apparent is the contrasting behavior of the silyl-
substituted tosylhydrazone 17 (R ) SiMe3) relative to those of
the other substrates. This system gives exclusive migration of
the trimethylsilyl-activated hydrogen Ha, forming 37 (R )
SiMe3). Neither the potential tricyclic product 38 (R ) SiMe3)
from 1,3-migration of Hb, nor the alkene 38 (R ) SiMe3) from
1,2-hydrogen migration, is observed. Silicon appears to exert
an unusually strong activating effect such that Ha migration is
exclusive.
The tosylhydrazone 15 (R ) CH3) gives preferential 1,3-
insertion into the tertiary CH bond (Ha) relative to the secondary
CH bond (Hb). Hence, methyl activation of Ha migration appears
to be a small but measurable effect. By way of contrast, the
thiomethoxy group slightly deactiVates Ha migration, as indi-
cated by the formation of the tricyclic thioether 38 (R ) SCH3)
as the major product from 22 (R ) SCH3). In view of this
unexpected deactivation by SCH3, the OCH3 derivative 33 was
examined. In this case, Ha is completely deactiVated, and the
exclusive tricyclic ether formed is 38 (R ) OCH3). As in all
cases except 17, there is also some alkene 39 produced.
In a further search for deactivating substituents, the ester
derivative 25 (R ) CO2CH3) was examined. Indeed, Ha is
These tosylhydrazone salt pyrolyses gave the two possible
1,3-hydrogen migration products, 37 and 38, as major products,
along with minor amounts of alkene 39 formed from 1,2-
hydrogen migration. In the case of tosylhydrazones 25 and 28,
small amounts of the isomeric alkenes endo-6-carbomethoxy-
bicyclo[2.2.2]oct-2-ene and endo-6-cyanobicyclo[2.2.2]oct-2-
(18) For a discussion of the tosylhydrazone salt pyrolysis method of diazo
compound and carbene generation, see: (a) Bamford, W. R.; Stevens, T. S.
J. Chem. Soc. 1952, 4735. (b) Kaufman, G. M.; Smith, J. A.; Vander Stouw,
G. G.; Shechter, H. J. Am. Chem. Soc. 1965, 87, 935. (c) Creary, X. Org.
Synth. 1986, 64, 207.
(19) For a recent study and leading references, see: Thamattoor, D. M.;
Jones, M., Jr.; Pan, W.; Shevlin, P. B. Tetrahedron Lett. 1996, 37, 8333.
For a computational study related to concerted nitrogen loss/hydrogen
migration, see also: Keating, A. E.; Garcia-Garibay, M. A.; Houk, K. N. J.
Am. Chem. Soc. 1997, 119, 10805.
(20) (a) Huang, H.; Platz, M. S. Tetrahedron Lett. 1996, 37, 8337. (b)
Jackson, J. E.; Platz, M. S. In AdVances in Carbene Chemistry; Brinker, U.
H., Ed.; JAI Press Inc.: Greenwich, CT, 1994; Volume 1, p. 89-160.

1572 J. Am. Chem. Soc., Vol. 123, No. 8, 2001
Creary and Butchko
deactivated by this electron-withdrawing ester substituent, but
a small amount (9%) of Ha still migrates. However, CO2CH3
appears to be somewhat more deactivating than SCH3. The
potent electron-withdrawing cyano group in 28 (R ) CN) gives
complete deactivation of Ha such that the only tricyclic product
formed is 38 (R ) CN).
In view of the unexpected behavior of carbene 10f (R )
OCH3), the 5-methoxy isomer 11 was examined. Interestingly,
only one tricyclic product, 40, was observed in the product
mixture. It was important to distinguish between 40 and the
other potential product, the isomer 41, for which spectroscopic
differences should be quite subtle. The structure of 40 was based
on NMR spectroscopic evidence, which showed the hydrogen
labeled Hx as a multiplet at δ 3.206 (J ) 9.5, 3.7, 3.7, 1.3 Hz)
coupled to four different hydrogens. The 1.3-Hz W-coupling
of Hx with Hw is clearly visible, as are the 9.5 Hz cis coupling
with Ha, the 3.7-Hz trans coupling, and the 3.7-Hz coupling
with the adjacent bridgehead H. These couplings rule out the
potential isomer 41, in which Hx should have only three coupling
interactions and no large (≈10 Hz) coupling interaction.
of Nickon3 for OCH3 suggests that oxygen is quite activating.
The carbenic center in 42 inserts readily into the “oxygen-
activated” C-H bond of the methyl group.8 Carbenes 4322 and
4423 show increased propensity for migration of the “oxygen-
activated” hydrogens to the carbenic center. Certain carbenes
are also known to insert preferentially into the “ oxygen-
activated” R-C-H bond of ethers.24-26 This activation has been
rationalized in terms of a transition state 45 involving hydridic
character in the hydrogen that begins to migrate to the vacant
orbital of the carbene.22 The nonbonding electrons on oxygen
stabilize this transition state. Despite these observations and
rationalization, the effect of the methoxy group remains
complex. Carbenoid 46 (generated from the dibromocyclopro-
pane and methyllithium) inserts into the CH bonds remote from
the methoxy group, while 47 inserts preferentially into the CH
bond R to the methoxy group.27 Conformational and electronic
effects appear to be important in these insertions.
The lack of migration of Ha in carbene 10f suggests that the
transition state for Ha migration is not stabilized. The effect of
the methoxy group in carbene 10f is quite subtle. Conjugative
stabilization of a transition state such as 48 cannot be a major
factor. Therefore, the extent of charge development in transition
state 48 is suggested to be smaller than that in transition state
45. Hence, the conjugative electron-donating influence of the
methoxy group is overwhelmed by the inductive effect of the
methoxy group. The transition state for Hb migration, 49, is
not destabilized by the inductive effect of the methoxy group,
and hence Hb migrates. These results suggest that the methoxy
group can be either an activator or a deactivator of hydrogen
migration to carbenic centers. The amount of charge develop-
ment in the transition state will be critical in determining the
methoxy effect in carbenes.
Discussion
What is the origin of the activating effect of the trimethylsilyl
group on Ha in carbene 10a? Qualitatively, it is suggested that
the effect of the electropositive silicon atom is to increase the
hydridic nature of Ha. Since migrations to electrophilic carbene
centers presumably begin with an interaction with the vacant
carbene orbital, increasing the hydridic character of Ha should
increase the ease of hydrogen migration. The electron-donor
properties of the methyl group in carbene 10b (R ) CH3) also
account for the increased propensity for Ha migration relative
to Hb migration. By way of contrast, the electron-withdrawing
carbomethoxy and cyano groups exert the opposite effect; i.e.,
they increase the acidic character of Ha. Hence, the carbenes
10d and 10e show decreased propensity for Ha migration, with
Ha being completely deactivated by the strongly electron-
withdrawing cyano group. This deactivation of 1,3-hydrogen
migration by electron-withdrawing groups is analogous to the
deactivation of 1,2-hydrogen migration recently reported for the
CF3 group.21
In the regioisomeric carbene 11, Ha remains deactivated
relative to Hb migration. Although further removed from the
carbenic center, the inductive effect of the remotely oriented
methoxy group apparently remains strong enough to completely
deactivate Ha toward 1,3-migration. The deactivating effect of
(22) Kirmse, W.; Buschhoff, M. Chem. Ber. 1967, 100, 1491.
(23) Press, L. S.; Shechter, H. J. Am. Chem. Soc. 1979, 101, 509.
(24) Moore, W. R.; Ward, H. R.; Merritt, R. F. J. Am. Chem. Soc. 1961,
83, 2019.
(25) Doering, W. v. E.; Knox, L. H.; Jones, M., Jr. J. Org. Chem. 1959,
24, 136.
(26) For an example of a carbenoid insertion into ethyl ether, see: Fischer,
H.; Schmid, J.; Ma¨rkl, R. J. Chem. Soc., Chem. Commun. 1985, 9, 572.
(27) Paquette, L. A.; Zon, G.; Taylor, R. T. J. Org. Chem. 1974, 39,
2677.
The effect of the methoxy group on carbene 10f is of much
interest. The complete deactivation of Ha contrasts with previous
results, which indicate that oxygen can increase migratory
aptitudes of adjacent hydrogen. The bystander assistance factor
(21) Pezacki, J. P.; Couture, P.; Dunn, J. A.; Warkentin, J.; Wood, P.
D.; Lusztyk, J.; Ford, F.; Platz, M. S. J. Org. Chem. 1999, 64, 4456.

Probe for Migratory Aptitudes of H to Carbenic Centers
J. Am. Chem. Soc., Vol. 123, No. 8, 2001 1573
to 17.5 kcal/mol) of ∆Eq. The B3LYP method, which includes
electron correlation, gives a more “reasonable” value of 5.4 kcal/
mol for ∆Eq, while the MP2 value of 1.6 kcal/mol probably
underestimates the barrier to 1,3-hydrogen migration. The MP3
value (calculated using the B3LYP/6-31G* optimized geometry)
is comparable to the B3LYP value, but this calculation is more
time-consuming. Therefore, the B3LYP/6-31G* calculation was
the method of choice as a rapid, yet reasonable method for the
carbenes and transition states studied.33
Table 2. Barriers for 1,3-Hydrogen Migration in Carbene 7 at
Various Computational Levels
method
HF/STO-3G
HF/3-21G*
∆Eq (kcal/mol)
31.7
23.6
17.5
5.4
4.2
1.6
HF/6-31G*
B3LYP/6-31G*
B3LYP/6-31G**
MP2/6-31G*
MP3/6-31G*//B3LYP/6-31G*
5.9
The calculated geometry of carbene 10g (R ) SiH3) is of
interest. For computational ease, this analogue was evaluated
instead of the more time-consuming carbene 10a (R ) SiMe3).
sulfur on Ha in carbene 10c (R ) SCH3) can also be rationalized
in terms of inductive effects. Conjugative stabilization of the
transition state for Ha migration is minimal. However, because
of the smaller inductive effect of sulfur relative to oxygen, a
small amount of Ha (20%) still migrates.
Computational Studies. Ab initio molecular orbital calcula-
tions have now been used to shed further light on bicyclo[2.2.2]-
octy-2-yl carbenes and migration processes. Over the years,
numerous calculations on carbenes have been carried out. We
desired a reasonably fast, yet reliable method for evaluating
carbene and transition state energies and geometries. Recently,
high-level MP2 calculations28 as well as density functional
methods29 have been used in carbene studies. A previous
computational study has been carried out on bicyclic carbenes
at the BHandHLYP/DZP level.30 Some recent carbene compu-
tational studies have been carried out at the B3LYP/6-31G*
level.31 A B3LYP/6-31G* evaluation of substituent effects on
1,2-hydrogen and 1,2-phenyl migration to carbene centers has
also recently appeared.32 To evaluate the various computational
levels, preliminary studies were therefore carried out on the
parent bicyclo[2.2.2]octy-2-yl carbene 7 and the transition state
for 1,3-hydrogen migration at a variety of computational levels.
The carbene 7 is calculated to be an unsymmetrical species,
with the endo-hydrogen on C6 tilted slightly toward the carbenic
center. The degree of tilt depends on the computational level,
with Hartree-Fock methods showing only minimal deformation
from the symmetrical species. The B3LYP/6-31G* optimized
geometry of 7 is shown here.
The B3YLP/6-31G* optimized structure of 10g is twisted
such that the endo-6-hydrogen is significantly closer (2.127 Å)
to the carbenic center than the analogous 7-hydrogen (3.002
Å). This distortion is not believed to be steric in origin, since
calculations on 10b, 10c, 10e, and 10f do not show such
twisting. The distortion in 10g suggests a stabilizing interaction
of the carbene vacant orbital with the endo-C6-H orbital. In
order to evaluate this interaction energetically, the stability of
10g was compared to that of the unsubstituted carbene 7 using
the isodesmic reaction of carbene 10g with bicyclo[2.2.2]octane,
51. On the basis of this reaction, carbene 10g is stabilized by
2.3 kcal/mol relative to the unsubstituted carbene 7.
Shown also is the geometry of the transition state 50 for 1,3-
hydrogen migration of the C6 hydrogen. Table 2 gives values
of ∆Eq (E50 - E7) for this migration at various computational
levels. Immediately apparent from Table 2 is the fact that
Hartree-Fock methods give unrealistically large values (31.7
B3LYP/6-31G* optimized transition states were calculated
for Ha migration (53) and for Hb migration (54) for a number
of carbenes. This allows calculation of ∆Eq for these 1,3-
hydrogen migrations. Results are summarized in Table 3. In
the case of carbene 10g (R ) SiH3), Ha (which is already tilted
(33) The B3LYP/6-31G* value of ∆Eq for 1,2-hydrogen migration in
carbene 7, via transition state i, is 7.5 kcal/mol and is consistent with the
experimental observation that this process is less facile than 1,3-hydrogen
migration.
(28) Ford, F.; Yazawa, T.; Platz, M. S.; Matzinger, S.; Fu¨lscher, M. J.
Am. Chem. Soc. 1998, 120, 4430.
(29) (a) Wong, M. W.; Wentrup, C. J. Org. Chem. 1996, 61, 7022. (b)
Xie, Y.; Schreiner, P. R.; Schleyer, P. v. R.; Schaefer, H. F., III. J. Am.
Chem. Soc. 1997, 119, 1370.
(30) Sulzbach, H. M.; Platz, M. S.; Schaefer, H. F., III; Hadad, C. M. J.
Am. Chem. Soc. 1997, 119, 5682.
(31) (a) Zhu, Z.; Bally, T.; Stracener, L. L.; McMahon, R. J. J. Am.
Chem. Soc. 1999, 121, 2863. (b) Geise, C. M.; Hadad, C. M. J. Am. Chem
Soc. 2000, 122, 5861.
(32) Keating, A. E.; Garcia-Garibay, M. A.; Houk, K. N. J. Phys. Chem.
A 1998, 102, 8467.

1574 J. Am. Chem. Soc., Vol. 123, No. 8, 2001
Creary and Butchko
Table 3. C2-Ha Distances and B3LYP/6-31G* Barriers for
1,3-Hydrogen Migration in Carbenes 7, 10, and 11
q
∆Eaq
(kcal/mol),
Ha migration
∆Eb
C2-Ha
distance
(Å)
(kcal/mol),
Hb migration
carbene
7
5.4
2.6
3.6
3.9
6.8
7.4
7.8
2.511
2.127
2.281
2.871
2.869
2.956
2.978
10g (R ) SiH3)
10b (R ) CH3)
10c (R ) SCH3)
10e (R ) CN)
10f (R ) OCH3)
11 (5-OCH3)
7.3
5.3
4.7
5.4
5.0
4.9
toward the carbenic center) migrates with the extremely low
activation energy of 2.6 kcal/mol. On the other hand, migration
of the further removed Hb is significantly more difficult (7.3
kcal/mol). This study supports the notion that a stabilizing
interaction between the carbene vacant orbital and the silicon-
induced hydridic C-H bond results in a facile 1,3-migration
process of Ha. These computational results are in line with the
experimental observation that carbene 10a (R ) SiMe3)
rearranges exclusively by migration of Ha.
seen in other calculated structures of the carbenes in Table 3.
The distance between the carbene center C2 in 10 and Ha mirrors
the ease of migration of Ha. Indeed, there is a good correlation
(r ) 0.99; omit 10c (SCH3)) in a plot of ∆Eq vs the C2-Ha
distance. This phenomenon is interpreted as a stabilizing
interaction between the carbene center and Ha which decreases
as Ha becomes less hydridic with respect to the carbenic center.
In other words, a tilt of Ha toward the carbene center is indicative
of a stabilizing interaction which makes Ha more prone to
migrate.
Experimentally, the methyl group in carbene 10b (R ) CH3)
activates Ha slightly, and this is in qualitative agreement with
the calculated barriers in Table 3. Of note is the fact that the
calculated barrier to Ha migration in 10b (3.6 kcal/mol) is not
as low as in the case of SiH3 substitution. Also in qualitative
agreement with the experimental data are the computational
results for carbene 10f (R ) CN). The cyano group is calculated
to be deactivating (∆Eq ) 6.8 kcal/mol), and this is indeed what
is observed experimentally. These results parallel those recently
calculated for the effect of methyl and cyano groups on 1,2-
hydrogen shifts in carbenes of type CH3-C-CH2R.28
The calculated effects of OCH3 substitution on carbenes 10e
(R ) OCH3) and 11 shed further light on the methoxy effect.
Computationally, the methoxy group in carbene 10e significantly
deactivates Ha migration (∆Eq ) 7.4 kcal/mol). As previously
suggested on the basis of the experimental behavior of 10e, this
is a manifestation of the large inductive effect of the methoxy
group in transition state 53 (R ) OCH3), where the resonance
effect of methoxy is small. Interestingly, the deactivation of Ha
in carbene 11 by the more remote â-OCH3 group is even larger
than the deactivation by the R-OCH3 in carbene 10e. Methoxy
deactivation of Ha in carbene 11 (∆Eq ) 7.8 kcal/mol) represents
an inductive effect which remains large in transition state 55.
The fact that the barrier to Ha migration in carbene 10e (R )
OCH3) is only 7.4 kcal/mol suggests that there is some offsetting
resonance stabilization of transition state 53 (R ) OCH3).
Hence, these calculations support the suggestion that the
inductive effect of methoxy can be the dominant feature
controlling 1,3-hydrogen migrations in carbenes, but there can
also be a variable offsetting resonance effect.
The agreement between the B3LYP/6-31G* calculated bar-
riers to hydrogen migration and the products formed from
carbenes 10 and 11 is quite good in all cases except for carbene
10c (R ) SCH3). In this case, the computational study predicts
that Ha migration (∆Eq ) 3.9 kcal/mol) should be slightly more
facile than Hb migration (∆Eq ) 4.7 kcal/mol). This is not the
case; i.e., experimentally SCH3 slightly deactiVates Ha migration.
Thus, while the B3LYP/6-31G* computational method appears
to be quite good at predicting large activating and deactivating
trends, this method may not be as useful in sorting out inductive
and resonance effects in certain transition states, where there is
a delicate balance between the two.
Conclusions
exo-6-Substituted bicyclo[2.2.2]oct-2-yl carbenes, 10, are a
useful probe for the effect of substituents on the migratory
aptitude of hydrogen to the carbene center. Electron-donating
substituents activate the perturbed hydrogen (Ha) toward 1,3-
migration, whereas electron-withdrawing substituents decrease
migratory aptitudes of Ha. Of the substituents studied, SiMe3
was highly activating, CH3 was slightly activating, SCH3 was
slightly deactivating, CO2CH3 was strongly deactivating, and
OCH3 and CN were completely deactivating. A â-OCH3
substituent also completely deactivated Ha in carbene 11. These
observations are consistent with a reactant-like transition state
in which the inductive effect of both R- and â-OCH3 groups
overwhelms any potential resonance-stabilizing effects. The
effect of the methoxy group on Ha is therefore quite different
from the methoxy effect in 1,2-hydrogen migrations.
More careful examination of the calculated structure of
carbenes 10g (R ) SiH3) and 10f (R ) OCH3) reveals
distortions which depend on the substituent. In the case of 10f
(R ) OCH3), Ha (which does not migrate) is significantly more
removed (2.956 Å) from the carbene center than in 10g (R )
SiHe3) (2.127 Å), where migration of Ha is facile. This trend is

Probe for Migratory Aptitudes of H to Carbenic Centers
J. Am. Chem. Soc., Vol. 123, No. 8, 2001 1575
33.3, 24.3, 22.3, -2.3. HRMS (EI): calcd for C11H18OSi 194.1128,
found 194.1123.
Molecular orbital calculations at the B3LYP/6-31G* level
give insight into the geometry of exo-6-substituted bicyclo[2.2.2]-
oct-2-yl carbenes, as well as barriers to 1,3-hydrogen migration.
The SiH3-substituted carbene 10g is stabilized by a favorable
interaction of the carbene vacant orbital with the endo-6-C-H
bond, resulting in a very small barrier to migration (2.6 kcal/
mol). With the exception of the SCH3 system, B3LYP/6-31G*
calculations are in qualitative agreement with experimentally
determined migratory aptitudes of perturbed hydrogens (Ha).
The 5-OCH3 substituent in carbene 11 is calculated to be even
more deactivating toward Ha migration than the 6-OCH3
substituent in carbene 10e. This is consistent with minor
conjugative stabilization in the transition state for Ha migration
to the carbene center in 10e.
A solution of 291 mg of 6-trimethylsilylbicyclo[2.2.2]oct-5-en-2-
one in 12 mL of ether containing 33 mg of 10% Pd-on-carbon was
hydrogenated at 50 psi for 2.5 h using a Parr hydrogenation apparatus.
The solution was filtered to remove the catalyst, and the ether was
removed using a rotary evaporator. Gas chromatographic analysis
showed a mixture of endo-6-trimethylsilylbicyclo[2.2.2]octan-2-one and
exo-6-trimethylsilylbicyclo[2.2.2]octan-2-one, 16, in a 1:1 ratio. This
product mixture was chromatographed on 20 g of silica gel and eluted
with increasing amounts of ether (2-5%) in hexanes. The endo-6-
trimethylsilylbicyclo[2.2.2]octan-2-one eluted first, followed by the exo-
6-trimethylsilylbicyclo[2.2.2]octan-2-one, 16. 1H NMR of endo-6-
trimethylsilylbicyclo[2.2.2]octan-2-one (CDCl3): δ 2.31-2.04 (m, 4 H),
1.93-1.56 (m, 5 H), 1.45 (m, 1 H), 1.14 (d of d of d, J ) 11.6, 8.2,
1.6 Hz, 1 H), -0.053 (s, 9 H). 13C NMR of endo-6-trimethylsilylbicyclo-
[2.2.2]octan-2-one (CDCl3): δ 217.8, 44.9, 43.5, 27.9, 27.4, 26.6, 23.8,
1
23.7, -3.4. H NMR of 16 (CDCl3): δ 2.38 (m, 1 H), 2.70-2.16 (m,
Experimental Section
3 H), 1.96-1.45 (m, 6 H), 1.090 (d of d of t, J ) 11.6, 8.0, 1.8 Hz, 1
H), 0.064 (s, 9 H). 13C NMR of 16 (CDCl3): δ 216.8, 43.5, 42.7, 28.5,
26.2, 25.4, 21.0 (d), 21.0 (t), -2.3. HRMS (EI): calcd for C11H20OSi
196.1283, found 196.1279.
Preparation of Ketal 13. A solution of 5.837 g of PhSeBr (24.7
mmol) in 15 mL of THF was added dropwise to a solution of 2.967 g
of bicyclo[2.2.2]oct-5-ene-2-one 1234 (24.3 mmol) in 15 mL of
tetrahydrofuran (THF) at 0 °C. The reaction mixture was stirred at room
temperature for 6 h and then cooled to -30 °C. An additional 15 mL
of THF was added followed by 1.798 g of acetic acid (29.9 mmol).
Aqueous hydrogen peroxide (5.701 g of 30%; 50.3 mmol) was then
added dropwise at -30 °C. The mixture was then stirred at room
temperature for 6 h. The mixture was then taken up into 200 mL of
ether, and the ether extract was washed with Na2CO3 solution and
saturated NaCl solution and dried over a mixture of Na2SO4 and MgSO4.
After filtration, the solvent was removed using a rotary evaporator.
The crude product was then chromatographed on 25 g of silica gel and
eluted with increasing amounts of ether in hexanes. The chromato-
graphed product was then fractionally distilled to give 3.479 g (58%
yield) of 6-bromobicyclo[2.2.2]oct-5-en-2-one, bp 56-60 °C (0.05
Preparation of Methyl Ketone 14. A solution of 1.557 g (6.3 mmol)
of bromoketal 13 in 20 mL of THF was cooled to -78 °C, and 8.6 mL
of 1.7 M t-BuLi in pentane (14.6 mmol) was added dropwise. After
the mixture was stirred at -78 °C for 45 min, a solution of 2.61 g of
methyl iodide (18.4 mmol) in 2 mL of THF was added. The reaction
mixture was then warmed to room temperature and stirred for 2.5 h.
The mixture was then quenched with water and extracted with ether.
The ether extract was washed with water and saturated NaCl solution
and dried over a mixture of Na2SO4 and MgSO4. After filtration, the
ether was removed using a rotary evaporator, and the crude product
was distilled to give 1.040 g (91% yield) of 2,2-dimethoxy-6-
1
methylbicyclo[2.2.2]oct-5-ene, bp 68-70 °C (2.0 mmHg). H NMR
(CDCl3): δ 5.85 (d of m, J ) 1.6 Hz, 1 H), 3.20 (s, 3 H), 3.14 (s, 3 H),
2.61 (m, 1 H), 2.53 (m, 1 H), 1.83 (d, J ) 1.6 Hz, 3 H), 1.75 (m, 1 H),
1.56-1.42 (m, 3 H), 1.26 (m, 1 H), 1.10 (m, 1 H).
1
mmHg). H NMR of 13 (CDCl3): δ 6.63 (d of d, J ) 2.1, 6.9 Hz, 1
H), 3.35 (d of t, J ) 2.7, 4.8 Hz, 1 H), 3.08 (m, 1 H), 2.12-1.54 (m,
6 H). 13C NMR of 13 (CDCl3): δ 209.3, 136.0, 117.6, 58.0, 39.8, 34.4,
24.3, 23.2.
A solution of 2.829 g of glacial acetic acid (47.1 mmol) in 10 mL
of methanol was added dropwise over 1 h to a suspension of 4.540 g
of freshly prepared35 potassium azodicarboxylate (23.2 mmol) and 509
mg of 2,2-dimethoxy-6-methylbicyclo[2.2.2]oct-5-ene (2.79 mmol) in
10 mL of methanol at room temperature under nitrogen. The reaction
mixture was stirred at room temperature for 6 h. At this point, the yellow
color of the azodicarboxylate was no longer present. An additional 4.511
g of potassium azodicarboxylate (23.2 mmol) was added to the reaction
mixture, followed by the dropwise addition of 2.922 g of glacial acetic
acid in 5 mL of methanol. The mixture was then stirred at room
temperature for an additional 17 h, and 10 mL of water was then added.
Most of the methanol solvent was then removed using a rotary
evaporator, and the remaining residue was extracted into ether. The
ether extract was washed with 1 M Na2CO3 solution and saturated NaCl
solution and dried over a mixture of Na2SO4 and MgSO4. After
filtration, the ether was removed using a rotary evaporator to give 311
mg of crude products.
A mixture of 3.475 g of 6-bromobicyclo[2.2.2]oct-5-ene-2-one (17.3
mmol), 2.254 g of trimethylorthoformate (21.2 mmol), and 65 mg of
p-toluenesulfonic acid (0.37 mmol) in 25 mL of methanol was stirred
at room temperature for 19 h, and 0.4 mL of 1.0 M NaOCH3 in
methanol was then added to neutralize the acid catalyst. The solvent
was removed using a rotary evaporator, and the crude product was
distilled to give 4.150 g of ketal 13 (97% yield), bp 58-62 °C (0.05
1
mmHg). H NMR of 13 (CDCl3): δ 6.40 (d of d, J ) 2.1, 7.2 Hz, 1
H), 3.21 (s, 3 H), 3.20 (s, 3 H), 3.04 (d of t, J ) 3.0, 5.1 Hz, 1 H),
2.72 (m, 1 H), 1.84 (m, 1 H), 1.60-1.30 (m., 5 H). 13C NMR of 13
(CDCl3): δ 133.4, 121.3, 105.8, 49.0, 48.5, 47.6, 38.1, 33.9, 24.2, 20.6.
HRMS (EI): calcd for C10H15BrO2 246.0255, found 246.0251.
Preparation of exo-6-Trimethylsilylbicyclo[2.2.2]octan-2-one, 16.
A solution of 1.590 g (6.44 mmol) of bromoketal 13 in 22 mL of THF
was cooled to -78 °C, and 8.9 mL of 1.7 M tert-butyllithium in pentane
(15.1 mmol) was added dropwise. After 45 min at -78 °C, 1.72 g of
ClSiMe3 was added. The mixture was slowly warmed to room
temperature, and after 2.5 h, the mixture was quenched with water and
vigorously stirred for 5 min. The mixture was taken up into ether, and
the ether extract was washed with water and saturated NaCl solution
and dried over a mixture of Na2SO4 and MgSO4. After filtration, the
solvents were removed using a rotary evaporator. The residue was
distilled, and, after a small forerun, 1.076 g (86% yield) of
6-trimethylsilylbicyclo[2.2.2]oct-5-en-2-one was collected, bp 85-87
°C (1.5 mmHg). 1H NMR of 6-trimethylsilylbicyclo[2.2.2]oct-5-en-2-
one (CDCl3): δ 6.71 (d of d, J ) 6.0, 0.8 Hz, 1 H), 3.196 (m, 1 H),
2.97 (heptet, J ) 2.9 Hz, 1 H), 1.98 (m, 2 H), 1.87 (m, 1 H), 1.77 (m,
1 H), 1.53-1.32 (m, 2 H), 0.056 (s, 9 H). 13C NMR of 6-trimethylsilyl-
bicyclo[2.2.2]oct-5-en-2-one (CDCl3): δ 213.6, 145.3, 142.8, 50.9, 40.5,
The crude products obtained above were dissolved in 3 mL of THF,
and 3 mL of 1% aqueous H2SO4 was added. After being stirred at room
temperature for 5 h, the mixture was neutralized with Na2CO3 and
extracted with ether. The ether extract was dried in the usual manner,
and solvent was removed using a rotary evaporator to give 224 mg of
a mixture containing approximately 36% 6-methylbicyclo[2.2.2]oct-
5-en-2-one, 23% endo-6-methylbicyclo[2.2.2]octan-2-one,36 and 41%
exo-6-methylbicyclo[2.2.2]octan-2-one, 14.36a A pure sample of 14 was
isolated by preparative gas chromatography using an 8-ft 5% SE30 on
1
Chromosorb G column at 120 °C. H NMR of 14 (CDCl3): δ 2.24-
1.50 (m, 10 H), 1.15 (m, 1 H), 1.08 (d, J ) 6.6 Hz, 3 H). 13C NMR of
14 (CDCl3): δ 218.0 (quat), 48.6 (CH), 43.4 (CH2), 34.0 (CH2), 28.4
(CH), 27.1 (CH), 25.4 (CH2), 19.4 (CH3), 17.2 (CH2).
(35) Groves, J. T.; Ma, K. W. J. Am. Chem. Soc. 1977, 99, 4076.
(36) (a) Brown, J. M.; Hall, S. A. Tetrahedron 1985, 41, 4639. (b)
Morrill, K.; Linder, R. E.; Bruckmann, E. M.; Barth, G.; Bunnenberg, E.;
Djerassi, C.; Seamans, L.; Moscowitz, A. Tetrahedron 1977, 33, 907.
(34) Freeman, P. K.; Balls, D. M.; Brown, D. J. Org. Chem. 1968, 33,
2211.

1576 J. Am. Chem. Soc., Vol. 123, No. 8, 2001
Creary and Butchko
Preparation of 2,2-Dimethoxy-endo-6-hydroxybicyclo[2.2.2]-
octane, 19. A mixture of 4.66 g of bicyclo[2.2.2]oct-5-en-2-one, 12,
6.10 g of trimethylorthoformate, and 39 mg of p-toluenesulfonic acid
in 30 mL of methanol was stirred at room temperature for 21 h, and
0.38 mL of 1.0 M NaOCH3 in methanol was then added. The solvent
was removed using a rotary evaporator, and the crude product was
distilled to give 6.20 g (97% yield) of 2,2-dimethoxybicyclo[2.2.2]oct-
2-one was washed with a small amount of hexanes and dried under
vacuum at 15 mm. The yield of mesylate was 443 mg (69% based on
1
19). H NMR (CDCl3): δ 5.171 (m, 1 H), 3.015 (s, 3 H), 2.72 (m, 1
H), 2.40-2.24 (m, 3 H), 2.00-1.51 (m, 6 H). 13C NMR (CDCl3): δ
211.6, 78.3, 47.7, 44.3, 39.4, 34.2, 27.6, 23.3, 20.0. HRMS (EI): calcd
for C9H14O4S 218.0613, found 218.0604.
A solution of 160 mg of NaSCH3 and 141 mg of the mesylate
prepared above in 3.5 mL of methanol under nitrogen was refluxed
for 2.5 h. The mixture was then transferred to a separatory funnel with
water and ether, and a standard aqueous workup followed. The ether
extract was washed with water and saturated NaCl solution and dried
over a mixture of Na2SO4 and MgSO4. The ether solvent was removed
using a rotary evaporator, and the residue was chromatographed on 2
g of silica gel. The thioether 21 (78 mg; 71% yield) eluted with 10%
ether in hexanes. 1H NMR of 21 (CDCl3): δ 3.10 (m, 1 H), 2.44-2.31
(m, 2 H), 2.29-2.24 (m, 2 H), 2.23-2.10 (m, 2 H), 2.051 (m, 3 H),
1.80-1.50 (m, 3 H), 1.38 (m, 1 H). 13C NMR of 21 (CDCl3): δ 215.7,
45.9, 43.7, 40.6, 33.3, 28.1, 24.8, 17.5, 14.8. HRMS (EI): calcd for
C9H14OS 170.0765, found 170.0761.
1
5-ene, bp 60-61 °C (2 mmHg). H NMR of 2,2-dimethoxybicyclo-
[2.2.2]oct-5-ene (CDCl3): δ 6.28 (m, 1 H), 6.21 (m, 1 H), 3.20 (s, 3
H), 3.13 (s, 3 H), 2.82 (m, 1 H), 2.64 (m, 1 H), 1.80 (m, 1 H), 1.62-
1.47 (m, 3 H), 1.26 (m, 1 H), 1.12 (m, 1 H). 13C NMR of
2,2-dimethoxybicyclo[2.2.2]oct-5-ene (CDCl3): δ 134.4, 131.3, 105.9,
48.8, 47.7, 38.8, 36.6, 30.8, 24.0, 20.2.
A solution of 5.53 g of 2,2-dimethoxybicyclo[2.2.2]oct-5-ene,
prepared above, in 60 mL of THF was cooled to 0 °C, and 16.5 mL of
1.0 M BH3 in THF was added. The mixture was then stirred for 7 h at
room temperature, and a solution of 4.8 g of NaOH in 35 mL of water
was carefully added dropwise. Aqueous 30% H2O2 (11.7 g) was then
added dropwise, and the mixture was stirred for 10 h at room
temperature. Solid NaCl was then added to saturate the aqueous phase,
and the organic phase was separated and dried over a mixture of Na2SO4
and MgSO4. The solvent was removed using a rotary evaporator, and
the residue was distilled to give 5.33 g (87%) of a mixture of of 2,2-
dimethoxy-exo-5-hydroxybicyclo[2.2.2]octane and 2,2-dimethoxy-exo-
6-hydroxybicyclo[2.2.2]octane, bp 85-90 °C (0.1 mmHg), in a 57:43
ratio as determined by NMR.
A solution of 6.45 g of dimethyl sulfoxide in 65 mL of CH2Cl2 was
cooled to -78 °C, and 8.88 g of trifluoroacetic anhydride in 8 mL of
CH2Cl2 was added dropwise. The mixture was stirred for 10 min at
-78 °C, and a solution of 5.50 g of the alcohol mixture prepared above
in 5 mL of CH2Cl2 and 1 mL of DMSO was added slowly dropwise
with stirring. After the addition was complete, 11.6 g of triethylamine
was added dropwise at -78 °C, and the mixture was allowed to warm
to room temperature. Water was added, and the CH2Cl2 phase was
separated, washed with another portion of water, and dried over a
mixture of Na2SO4 and MgSO4. The solvent was removed using a rotary
evaporator, and the residue was distilled to give 5.37 g (97%) of a
mixture of 2,2-dimethoxybicyclo[2.2.2]octan-5-one and 2,2-dimeth-
oxybicyclo[2.2.2]octan-6-one, bp 70-75 °C (0.05 mmHg).
Preparation of exo-6-Carbomethoxybicyclo[2.2.2]octan-2-one, 24.
A solution of 741 mg of exo-ester 2315 (4.46 mmol) in 5 mL of THF
was cooled to 0 °C, and 3.6 mL of 1.0 M BH3 in THF (3.6 mmol) was
added dropwise. The mixture was stirred at 0 °C for 30 min and then
at room temperature for an additional 30 min. The reaction mixture
was then recooled to 0 °C, and 5 mL of water was added. A solution
of chromic acid, prepared by dissolving 1.59 g of Na2Cr2O7 dihydrate
(5.34 mmol) in 10 mL of 15% aqueous H2SO4, was then added dropwise
to the reaction mixture at 0 °C. After being stirred for 4 h at room
temperature, the mixture was diluted with 10 mL of water and extracted
with ether. The ether extract was washed with water and saturated NaCl
solution and dried over a mixture of Na2SO4 and MgSO4. The ether
was removed using a rotary evaporator to give a mixture containing
59% of exo-6-carbomethoxybicyclo[2.2.2]octan-2-one, 24,37 and 41%
of exo-5-carbomethoxybicyclo[2.2.2]octan-2-one.37 Chromatography
(30% ether in hexanes) on 50 g of silica gel gave 387 mg of 24 (48%
yield) as the first eluent, mp 38-39 °C, and 264 mg of exo-5-
carbomethoxybicyclo[2.2.2]octan-2-one (33% yield) as the second
1
eluent, mp 58-62 °C. H NMR of 24 (CDCl3): δ 3.73 (s, 3 H), 2.88
(m, 1 H), 2.61 (q, J ) 3.0 Hz, 1 H), 2.28-2.24 (m, 3 H), 2.19 (m, 1
H), 1.95-1.70 (m, 4 H), 1.58 (m, 1 H). 13C NMR of 24 (CDCl3): δ
214.74 (quat), 174.09 (quat), 52.11 (q, J ) 146 Hz), 44.43 (d, J ) 144
Hz), 43.72 (t, J ) 128 Hz), 38.15 (d, J ) 132 Hz), 27.55 (d, J ) 138
Hz), 27.33 (t, J ) 133 Hz), 24.17 (t, J ) 127 Hz), 19.14 (t, J ) 128
Hz).
The mixture of ketones prepared above (5.365 g) was dissolved in
50 mL of methanol containing 1.0 g of NaOH, and 2.33 g of NaBH4
was added to the solution at 10 °C. The mixture was slowly warmed
to 50 °C and kept at that temperature for 1.5 h. The mixture was cooled
to room temperature, and a solution of 3.0 g of NaOH in 3 mL of
water was added. Most of the methanol was then removed using a rotary
evaporator, and 15 mL of water was added. The residue was extracted
with about 200 mL of ether, and the ether was dried over a mixture of
Na2SO4 and MgSO4. The solvent was removed using a rotary
evaporator, and the entire residue was chromatographed on 75 g of
silica gel. The column was eluted with increasing amounts of ether in
hexanes. The pure alcohol 19, bp 58-59 °C (0.1 mmHg) (1.586 g;
30%), eluted with 25% ether in hexanes. The other two alcohol products,
2,2-dimethoxy-exo-5-hydroxybicyclo[2.2.2]octane and 2,2-dimethoxy-
endo-5-hydroxybicyclo[2.2.2]octane, eluted with 35-60% ether in
Preparation of exo-6-Cyanobicyclo[2.2.2]octan-2-one, 27. A solu-
tion of 1.141 g of exo-nitrile 2638 in 10 mL of THF was cooled to 0
°C, and 5.0 mL of 1.0 M BH3 in THF was added dropwise. The mixture
was then stirred at room temperature for 1.5 h and recooled to 0 °C,
and 1 mL of water was added. A solution of chromic acid, prepared
by dissolving 3.4 g of Na2Cr2O7 dihydrate in 20 mL of water and adding
3.6 mL of H2SO4, was then added dropwise to the reaction mixture at
0 °C. After being stirred for 12 h at room temperature, the mixture
was diluted with water and extracted with ether. The ether extract was
washed with water and saturated NaCl solution and dried over a mixture
of Na2SO4 and MgSO4. Solvent was removed using a rotary evaporator,
and the residue was chromatographed on 20 g of silica gel. A small
amount of unreacted nitrile 26 eluted with 10% ether in hexanes. Pure
cyanoketone 27 (346 mg; 27%) eluted with 40-45% ether in hexanes,
and this was followed by fractions containing mixtures of 27 and the
1
hexanes. H NMR of 19 (CDCl3): δ 3.35 (br s, 1 H), 3.236 (s, 3 H),
3.196 (s, 3 H), 2.16-1.24 (m, 10 H). 13C NMR of 19 (CDCl3): δ 103.3,
68.3, 48.6, 47.0, 38.5, 38.4, 36.2, 25.9, 22.9, 19.4. HRMS (EI): calcd
for C10H18O3 186.1257, found 186.1260.
Preparation of exo-6-Thiomethoxybicyclo[2.2.2]octan-2-one, 21.
A solution of 495 mg of 2,2-dimethoxy-endo-6-hydroxybicyclo[2.2.2]-
octane, 19, in 8 mL of CH2Cl2 was stirred as 226 mg of 5% aqueous
HCl was added. After 45 min, 25 mg of NaHCO3 was added, and the
CH2Cl2 solution of endo-6-hydroxybicyclo[2.2.2]octan-2-one, 20,13 was
dried over a mixture of Na2SO4 and MgSO4. After filtration, 510 mg
of CH3SO2Cl was added to the solution, and the mixture was cooled
to -10 °C. A solution of 595 mg of Et3N in 3 mL of CH2Cl2 was
added to the stirred solution, which was then warmed to 0 °C. An
aqueous workup followed with ether extraction. The ether extract was
washed with dilute HCl solution and dried over a mixture of Na2SO4
and MgSO4. The solvent was removed using a rotary evaporator, and
the crude mesylate derivative of endo-6-hydroxybicyclo[2.2.2]octan-
1
isomeric product exo-5-cyanobicyclo[2.2.2]octan-2-one. H NMR of
27 (CDCl3): δ 3.054 (m, 1 H), 2.517 (q, J ) 2.8 Hz, 1 H), 2.40-2.20
(m, 3 H), 2.17-1.81 (m, 5 H), 1.71 (m, 1 H). 13C NMR of 27 (CDCl3):
δ 212.0, 120.8, 43.8, 43.6, 29.9, 27.2, 24.7, 23.8, 19.4. HRMS (EI):
calcd for C9H11NO 149.0841, found 149.0844.
Preparation of exo-6-Methoxybicyclo[2.2.2]oct-2-ene, 30. Sodium
hydride (720 mg of a 60% dispersion in mineral oil) was freed from
(37) Mehta, G.; Khan, F. A. J. Chem. Soc., Perkin Trans. 1 1993, 15,
1727.
(38) The pure exo-nitrile 32 was isolated by silica gel chromatography
(2.5% ether in hexanes) of the Diels-Alder adducts from acrylonitrile and
cyclohexadiene.16

Probe for Migratory Aptitudes of H to Carbenic Centers
J. Am. Chem. Soc., Vol. 123, No. 8, 2001 1577
oil by rinsing with hexanes (2 × 5 mL), and 5 mL of THF was then
added under nitrogen. A solution of 587 mg of exo-alcohol 2939 in 10
mL of THF was then added dropwise to the suspension. The mixture
was heated at reflux under nitrogen for 23 h, and 5.4 g of methyl iodide
was then added to the mixture. Reflux was continued for an additional
24 h. After being cooled, the mixture was quenched with water and
extracted with ether. The ether extract was washed with water, saturated
NaCl solution, and dried over a mixture of Na2SO4 and MgSO4. After
filtration, the ether was removed using a rotary evaporator, and the
crude product was distilled to give 598 mg of exo-ether 30,40 bp 71-
evaporator for several hours to give 254 mg of tosylhydrazone 22 (96%
yield), mp 186-190 °C. H NMR of 22 (CDCl3): δ 7.84 (d, J ) 8.2,
1
2 H), 7.56 (bs, 1 H), 7.32 (d, J ) 8.2 Hz, 2 H), 2.90 (d of d of d of d,
J ) 1.0, 5.7, 5.7, 10.4 Hz, 1 H), 2.46 (q, J ) 2.9 Hz, 1 H), 2.44 (s, 3
H), 2.25 (m, 1 H), 2.12-2.10 (br, 2 H), 2.07-1.94 (m, 2 H), 2.02 (s,
3 H), 1.61 (t, J ) 11.0 Hz, 1 H), 1.44-1.33 (m, 2 H), 1.26 (d of m, J
) 14.1 Hz, 1 H). 13C NMR of 22 (CDCl3): δ 163.81 (quat), 144.06
(quat), 135.51 (quat), 129.60 (d, J ) 161 Hz), 127.93 (d, J ) 166 Hz),
41.95 (d, J ) 142 Hz), 37.60 (d, J ) 140 Hz), 33.53 (t, J ) 131 Hz),
31.82 (t, J ) 128 Hz), 26.51 (d, J ) 136 Hz), 24.75 (t, J ) 129 Hz),
21.66 (q, J ) 127 Hz), 18.42 (t, J ) 133 Hz), 14.79 (q, J ) 138 Hz).
Anal. Calcd for C16H22N2O2S2: C, 56.77; H, 6.55. Found: C, 56.80;
H, 6.50.
1
73 °C (20 mmHg). H NMR of 30 (CDCl3): δ 6.29 (t, J ) 7.1 Hz, 1
H), 6.15 (t, J ) 7.5 Hz, 1 H), 3.34-3.27 (m, 1 H), 3.30 (s, 3 H), 2.76
(m, 1 H), 2.49 (m, 1 H), 1.92 (m, 1 H), 1.75 (m, 1 H), 1.61 (m, 1 H),
1.30-1.00 (m, 3 H). 13C NMR of 30 (CDCl3): δ 36.21 (d, J ) 163
Hz), 131.62 (d, J ) 165 Hz), 78.56 (d, J ) 145 Hz), 56.17 (q, J ) 140
Hz), 33.50 (t, J ) 131 Hz), 33.19 (d, J ) 137 Hz), 29.79 (d, J ) 137
Hz), 25.82 (t, J ) 130 Hz), 17.55 (t, J ) 132 Hz).
Pyrolysis of Tosylhydrazone Salts. General Procedure.18 The solid
tosylhydrazone (1.00 equiv) was placed in a flask, and 1.06 equiv of
NaOCH3 (1.0 M in methanol) was added with stirring. After the
tosylhydrazone disssolved, the methanol solvent was removed using a
rotary evaporator. The solid salt was further dried by evacuation at 15
mmHg and at 0.05 mmHg. The flask containing the dry salt was then
fitted with a short path distillation head and a receiver flask and placed
in an oil bath. The temperature of the oil bath was gradually raised to
80 °C, and then the receiver flask was cooled in a dry ice-acetone
bath. The temperature of the oil was then raised gradually to 180 °C
while the system was maintained under vacuum. During this time, the
pressure rose to approximately 2 mmHg and then decreased back to
0.05 mmHg. The products of these pyrolyses collected in the cold
Hydroboration-Oxidation of exo-6-Methoxybicyclo[2.2.2]oct-2-
ene. Preparation of Ketones 31 and 32. A solution containing 536
mg of exo-6-methoxybicyclo[2.2.2]oct-2-ene, 30, in 6 mL of THF was
cooled to 0 °C, and then 3.4 mL of 1.0 M of BH3 in THF was added
dropwise. The mixture was stirred at 0 °C for 30 min and then at room
temperature for an additional 30 min. The reaction mixture was then
recooled to 0 °C and quenched by slow addition of 5 mL of water. A
solution of chromic acid was prepared by dissolving 1.38 g of sodium
dichromate dihydrate in 10 mL of 15% aqueous H2SO4. This chromic
acid solution was then added dropwise to the reaction mixture at 0 °C.
After being warmed to room temperature and stirred for 4 h, the mixture
was diluted with 10 mL of water and extracted with ether. The ether
extract was washed with water and saturated NaCl solution and dried
over a mixture of Na2SO4 and MgSO4. After filtration, the ether was
removed using a rotary evaporator to give a mixture containing 61%
ketone 31 and 39% ketone 32. This mixture was chromatographed on
73 g of silica gel. Ketone 31 (279 mg; 47% yield) eluted first with
30% ether in hexanes, and ketone 32 (168 mg; 28% yield) eluted
1
receiver flask. Product ratios were determined by H NMR spectros-
copy. Pure samples of products were isolated by preparative gas
chromatography. Results of these pyrolyses are given in Table 1. The
alkenes 39 were identified by NMR spectral comparison with authentic
samples. NMR spectral data for tricyclic products 37 and 38 are given
in the Supporting Information. The following procedure is representa-
tive.
Tosylhydrazone 34 (exo-5-OCH3) (288 mg; 0.890 mmol) was
dissolved in 0.95 mL of 1.0 M NaOCH3 (0.95 mmol) in methanol.
The mixture was stirred at room temperature for 10 min, and the
methanol was then removed using a rotary evaporator. The salt was
dried on a rotary evaporator for 1 h and further dried using a vacuum
pump (0.05 mmHg) for 3 h. Vacuum pyrolysis, as described above, of
the dry sodium salt gave 71.2 mg of a mixture containing 81% of
tricyclic compound 40 and 19% of olefin 30. The olefin 30 was
identified by NMR spectral comparison with an authentic sample
prepared as described above. 1H NMR of 40 (CDCl3): δ 3.23 (s, 3 H),
3.19 (d of d of d of d, J ) 1.3, 3.7, 3.7, 9.5 Hz, 1 H), 2.17 (d of d of
d, J ) 3.1, 9.5, 14.8 Hz, 1 H), 2.09 (d of d of d, J ) 3.3, 5.8, 5.8 Hz,
1 H), 1.91 (d, J ) 12 Hz, 1 H), 1.72 (d of d of d, J ) 2.2, 6.4, 12.3 Hz,
1 H), 1.67 (d of d of d, J ) 2.6, 4.0, 14.8 Hz, 1 H), 1.44 (d, 12 Hz, 2
H), 1.21 (d of d, J ) 1.3, 7.7 Hz, 2 H), 0.68 (d of d of d of d, J ) 2.6,
2.6, 7.7, 7.7, 1 H). 13C NMR of 40 (CDCl3): δ 78.35 (d, J ) 131 Hz),
55.40 (q, J ) 140 Hz), 33.74 (d, J ) 138 Hz), 29.63 (t, J ) 132 Hz),
25.67 (t, J ) 127 Hz), 23.44 (t, J ) 129 Hz), 15.67 (d, J ) 170 Hz),
15.20 (d, J ) 169 Hz), 10.96 (d, J ) 161 Hz). HRMS (EI): calcd for
C9H140 138.1045, found 138.1043.
1
second. H NMR of 31 (major product) (CDCl3): δ 3.64 (d of d of d
of d, J ) 1.3, 3.3, 3.3, 9.7 Hz, 1 H), 3.28 (s, 3 H), 2.65 (q, J ) 3.1 Hz,
1 H), 2.26-1.52 (m, 10 H). 13C NMR of 31 (CDCl3): δ 215.89 (quat),
74.60 (d, J ) 145 Hz), 56.25 (q, J ) 141 Hz), 46.92 (d, J ) 141 Hz),
43.91 (t, J ) 130 Hz), 34.66 (t, J ) 132 Hz), 27.43 (d, J ) 139 Hz),
24.30 (t, J ) 130 Hz), 15.86 (t, J ) 132 Hz). HRMS (EI): calcd for
1
C9H14O2 154.0994, found 154.0966. H NMR of 32 (minor product)
(CDCl3): δ 3.55 (d of d of d of d, J ) 1.3, 3.7, 3.7, 8.5 Hz, 1 H), 3.33
(s, 3 H), 2.37 (sextet, J ) 3.0 Hz, 1 H), 2.25 (m, 1 H), 2.20-1.60 (m,
7 H), 1.44 (m, 1 H). 13C NMR of 32 (CDCl3): δ 216.38 (quat), 76.75
(d, J ) 140 Hz), 56.30 (q, J ) 140 Hz), 42.35 (d, J ) 140 Hz), 41.37
(t, J ) 132 Hz), 31.47 (t, J ) 131 Hz), 31.21 (d, J ) 133 Hz), 23.01
(t, J ) 130 Hz), 17.65 (t, J ) 128 Hz). HRMS (EI): calcd for C9H14O2
154.0994, found 154.0996.
Preparation of Tosylhydrazones. General Procedure. Tosyl-
hydrazine (1.03 equiv) was suspended in a small amount of absolute
methanol, and the appropriate ketone (1.00 equiv) in a small amount
of methanol was added in one portion with stirring until the mixture
became homogeneous. After a period of time, the tosylhydrazones
crystallized. The mixture was then cooled in a freezer, and the methanol
was decanted using a pipet. The last traces of solvent were removed
under vacuum. The following procedure is representative.
A suspension of 151 mg of tosylhydrazine (0.809 mmol) in 0.5 mL
of methanol was stirred as 133 mg of ketone 21 (exo-6-SCH3) (0.781
mmol) in 1.5 mL of methanol was added. Upon addition of the ketone,
the mixture became homogeneous. A precipitate formed after 5 min,
and the mixture was kept at room temperature for 1 h. The mixture
was placed in a freezer for 12 h, and the methanol was then decanted
from the cold mixture. The remaining solid was dried using a rotary
Computational Studies. Ab initio molecular orbital calculations
were performed using the Gaussian 94 and Gaussian 98 series of
programs.41 Structures of carbenes were characterized as minima via
frequency calculations which showed no negative frequencies.
(41) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; 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.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Gomperts, R.; Martin, 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.;
Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian
98, Revision A.7; Gaussian, Inc.: Pittsburgh, PA, 1998.
(39) The pure exo-alcohol 35 was isolated by silica gel chromatography
of the mixture of exo- and endo-isomers. See: (a) Brown, H. C.; Muzzio,
J. J. Am. Chem. Soc. 1966, 88, 2811. (b) Brown, R. S.; Marcinko, R. W. J.
Am. Chem. Soc. 1977, 99, 6500. (c) Fraser, R. R.; O’Farrell, S. Tetrahedron
Lett. 1962, 24, 1143.
(40) Coxon, J. M.; Steel, P. J.; Whittington, B. I. J. Org. Chem. 1989,
54, 3702.

1578 J. Am. Chem. Soc., Vol. 123, No. 8, 2001
Creary and Butchko
Acknowledgment is made to the National Science Founda-
tion for support of this research.
for carbene rearrangements, and NMR spectral data for com-
pounds 37, 38, and 39c (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
Supporting Information Available: Structures and energies
of carbenes 7, 10b, 10c, 10e, 10f, 10g, and 11, transition states
JA002407+