γ-silyl-substituted norbornyl carbocations and carbenes

Article abstract of DOI:10.1021/jo500007p

endo-2-Trimethylsilyl-anti-7-norbornyl triflate undergoes solvolysis reactions 1.8 × 10⁴ faster than 7-norbornyl triflate in CD ₃CO₂D and 1.3 × 10⁵ times faster in CF₃CH₂OH. The exclusive substitution products with retained stereochemistry point to a significantly stabilized γ-trimethylsilyl carbocation intermediate. The endo-2-trimethylsilyl-7- norbornyl carbene gives a major rearrangement product where the trimethylsilyl-activated hydrogen migrates to the carbenic center. This rearrangement product implies stabilization of the carbene by the γ-trimethylsilyl group. Isodesmic computational studies (M062X/6-311+G* *) indicate that the endo-2-trimethylsilyl-7- norbornyl cation is stabilized by 16.2 kcal/mol and that the endo-2-trimethylsilyl-7-norbornyl carbene is stabilized by a smaller factor of 1.8 kcal/mol. By way of contrast, anti-7-trimethylsilyl-endo-2-norbornyl mesylate undergoes solvolysis in CD₃CO₂D only 2.6 times faster than endo-2-norbornyl mesylate and 9.4 times faster in CF ₃CH₂OH. The substitution products have only partially retained stereochemistry, and significant rearrangements are observed. The anti-7-trimethylsilyl-2-norbornyl carbene gives a rearrangement product via 1,3-hydrogen migration of the C6 hydrogen, which is completely analogous to the behavior of the unsubstituted 2-norbornyl carbene. Isodesmic calculations show that the anti-7-trimethylsilyl-2-norbornyl cation is stabilized by only 3.2 kcal/mol relative to the 2-norbornyl cation, and the corresponding anti-7-trimethylsilyl-2-norbornyl carbene is stabilized by a negligible 0.9 kcal/mol.

Full text of DOI:10.1021/jo500007p

Article
pubs.acs.org/joc
γ‑Silyl-Substituted Norbornyl Carbocations and Carbenes
Xavier Creary* and Anna Heffron
Department of Chemistry and Biochemistry University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: endo-2-Trimethylsilyl-anti-7-norbornyl triflate undergoes solvolysis reactions 1.8 × 104 faster than 7-norbornyl
triflate in CD3CO2D and 1.3 × 105 times faster in CF3CH2OH. The exclusive substitution products with retained
stereochemistry point to a significantly stabilized γ-trimethylsilyl carbocation intermediate. The endo-2-trimethylsilyl-7-norbornyl
carbene gives a major rearrangement product where the trimethylsilyl-activated hydrogen migrates to the carbenic center. This
rearrangement product implies stabilization of the carbene by the γ-trimethylsilyl group. Isodesmic computational studies
(M062X/6-311+G**) indicate that the endo-2-trimethylsilyl-7-norbornyl cation is stabilized by 16.2 kcal/mol and that the endo-
2-trimethylsilyl-7-norbornyl carbene is stabilized by a smaller factor of 1.8 kcal/mol. By way of contrast, anti-7-trimethylsilyl-endo-
2-norbornyl mesylate undergoes solvolysis in CD3CO2D only 2.6 times faster than endo-2-norbornyl mesylate and 9.4 times
faster in CF3CH2OH. The substitution products have only partially retained stereochemistry, and significant rearrangements are
observed. The anti-7-trimethylsilyl-2-norbornyl carbene gives a rearrangement product via 1,3-hydrogen migration of the C6
hydrogen, which is completely analogous to the behavior of the unsubstituted 2-norbornyl carbene. Isodesmic calculations show
that the anti-7-trimethylsilyl-2-norbornyl cation is stabilized by only 3.2 kcal/mol relative to the 2-norbornyl cation, and the
corresponding anti-7-trimethylsilyl-2-norbornyl carbene is stabilized by a negligible 0.9 kcal/mol.
The γ-effect of silicon on carbocations and carbenes has been
less appreciated. Shiner7 observed this phenomenon in
solvolysis of brosylate 3, which reacted 452 times faster than
trans-4-t-butylcyclohexyl brosylate. This rate enhancement was
attributed to a γ-silyl effect, where the intermediate carbocation
was stabilized by an interaction involving the rear lobe of the
C−Si σ-bond in a “W” fashion. A subsequent study by Grob8
revealed a modest rate enhancement in solvolysis of the
adamantyl system 4, and this was also attributed to the γ-silyl
effect. 4-Trimethylsilyl-1-norbornyl triflate, 5, gave an even
larger rate enhancement of 1300 in trifluoroethanol solvent.9
More recently we have found remarkable rate-enhancing effects
in solvolysis reactions that lead to carbocations of type 6.10
Cation 6 (R = H) forms even faster than the 2-trimethylsilyl-
cyclobutyl cation in solvolysis reactions. Computational studies
also suggest that cation 6 (R = H) is more stable than the 2-
trimethylsilylcyclobutyl cation, i.e., the γ-silyl effect leading to
cation 6 (R = H) is even greater than the β-silyl effect. A recent
experimental and computational study of carbene 7 also reveals
a large stabilizing interaction due to the transannular
INTRODUCTION
■
We have been interested in the chemistry of carbenes and
carbocations that contain the trimethylsilyl group. We have
studied a variety of carbocations1 and carbenes2 that contain a
silyl group in the β-position. The so-called β-effect of a silyl
group on carbocations 1 is well understood3 and is attributed to
an interaction of the cation vacant orbital with the C−Si σ-
bond. This β-effect can lead to carbocation formation at rates
up to 1011 times faster than from unsilylated analogs.4
Computational studies5 support this mode of carbocation
stabilization and argue against potential silicon bridged
intermediates. An X-ray crystallographic study6 on an isolable
β-silyl vinyl carbocation confirms the preferred alignment of the
C−Si σ-bond. Our studies have shown that β-silyl carbenes 2
are stabilized by a similar mechanism.2 Moreover, these
carbenes are prone to rearrange by migration of the silyl
group to the carbenic center. In addition, the silyl group also
increases the propensity for adjacent hydrogen to migrate.
Received: January 2, 2014
Published: February 18, 2014
© 2014 American Chemical Society
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trimethylsilyl group.11 This interaction leads to preferential
formation of 1-trimethylsilylbicyclobutane from 7. A labeling
study showed that the source of the bicyclobutane was 1,3-
hydrogen migration to the carbene center (and not
trimethylsilyl migration).
Scheme 1. Synthesis of Precursors to Cation 8 and Carbene
9
In view of the remarkable carbocation and carbene stabilizing
effect of the γ-silyl group on cations of type 6 and carbene 7, we
wanted to further examine the generality of this effect. The
norbornyl system was chosen in view of its rigid nature and the
ability to control stereochemistry of the trimethylsilyl group
relative to the cation/carbene center. We have now generated
carbocations 8 and 10 as well as carbenes 9 and 11 and now
report on the effect of the trimethylsilyl group on these reactive
intermediates.
Table 1. Solvolysis Rates for Substrates in CD3CO2D and
CF3CH2OH
RESULTS AND DISCUSSION
■
The synthesis of precursors to cation 8 and carbene 9 (Scheme
1) began with anti-7-norbornen-7-ol.12 Protection of the
alcohol as the TBS ether 13, followed by reaction with
phenylselenyl bromide and hydrogen peroxide oxidation, gave
the vinyl bromide 14. Introduction of the trimethylsilyl group
was accomplished by lithium-halogen exchange and reaction
with trimethylsilyl chloride. Catalytic hydrogenation and
subsequent removal of the TBS protection resulted in a
mixture of exo and endo-isomers 16 and 17 from which pure 16
could be separated by chromatography. Conversion of alcohol
16 to triflate 18 was straightforward.
completely retained. The large rate enhancement as well as the
product of complete retention point toward a significant
interaction of the trimethylsilyl group with the cationic
intermediate in the acetolysis of 18. The suggested intermediate
is the rear lobe stabilized γ-silyl cation 8, where capture at
carbon by acetic acid occurs from the rear of this delocalized
cation.
The triflate 18 reacted readily at room temperature in
CD3CO2D. This triflate is much more reactive (1.8 × 104
times) than the desilylated analog, 7-norbornyl triflate, 20
(Table 1). In trifluoroethanol, the rate enhancement relative to
7-norbornyl triflate is an even larger factor of 1.3 × 105. These
rate enhancements are substantially greater than in the less rigid
cyclohexyl system 3 and also greater than in the rigid systems 4
and 5. The sole product from acetolysis of 18 is the acetate 21
where the stereochemistry of this substitution product is
Computational studies13 at the M062X/6-311+G** level
strongly support the suggested involvement of cation 8 in the
solvolytic reaction of triflate 18. Figure 1 shows the M062X/6-
311+G** calculated structure of cation 8. The cation shows a
C7−C2 bond distance of only 1.714 Å as well as an elongated
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small amount of the silane 23 (3.5%). The structure of 28 was
determined by NMR spectroscopy. Specifically, the proton
coupled 13C NMR spectrum shows two cyclopropyl carbons
with one bond C−H coupling. The C7 cyclopropyl carbon
shows JCH = 181 Hz, which is characteristic of a highly strained
cyclopropyl carbon. The structure of the minor product 23 was
determined by NMR spectral comparison with an authentic
sample. The behavior of carbene 9 therefore contrasts with that
of the 7-norbornyl carbene 25, which was studied many years
ago by Moss and Whittle.15 Carbene 25 gives bicyclo[3.2.0]-
hept-1-ene as the major product (74%), along with norbornane
(14%), and only 12% of 32, the hydrocarbon analog of 28.
Computational studies provide insight into the contrasting
behaviors of carbenes 9 and 25. As can be seen in Figure 1, the
carbenic center in 9 tilts slightly toward the hydrogen on C2.
The isodesmic reaction in Scheme 3 also suggests that carbene
9 is slightly stabilized (1.8 kcal/mol) relative to the
unsubstituted 7-norbornyl carbene. While silyl stabilization of
carbene 9 does not approach that of the carbocation 8, it
appears to be a real, albeit small factor. The computational
study in Scheme 5 also reveals an increased propensity for
migration of the exo-2-hydrogen to the carbenic center. There
is a rather substantial barrier to migration (11.1 kcal/mol) of
the exo-2-hydrogen to the carbenic center in 25. However, the
trimethylsilyl group of 9 results in a substantial lowering of the
exo-2-hydrogen migration barrier to only 5.8 kcal/mol. This is
consistent with the observed major product in Scheme 4 and
the fact that 32 is only a minor product (12%) from the 7-
norbornyl carbene, 25.
Scheme 2. Solvolysis of Triflate 18 in CD3CO2D
C2−Si bond (2.005 Å vs 1.892 Å in the neutral silane 23).
These bond lengths are completely consistent with the
proposed carbocation stabilization by a rear lobe interaction
of the cationic center with the C2−Si bond. Also of interest is
the C1−C2 bond, which is unusually long at 1.651 Å. This
suggests another stabilizing interaction between the carbocation
vacant orbital and the C1−C2 σ-bond, as represented by 8a.
The magnitude of the stabilization of cation 8 can be
estimated using an isodesmic calculation, as shown in Scheme
3. Cation 8 is stabilized by 16.2 kcal/mol relative to the 7-
norbornyl cation, 24, which itself is a delocalized cation
involving σ-bond stabilization. While this stabilization is
substantial, it is somewhat less than in the rear-lobe stabilized
cation 6 (R = H), where the trimethylsilyl group stabilizes by
22.6 kcal/mol relative to the cyclobutyl cation.
Attention was next turned to the carbene 9. The ketone 19,
available from oxidation of alcohol 16, was converted to the
tosylhydrazone, which was deprotonated with sodium meth-
oxide to give the salt 26 (Scheme 4). Vacuum pyrolysis of the
dry sodium salt 26 generated the carbene 9 via a transient
diazocompound 27 that loses nitrogen under the pyrolytic
conditions (Bamford−Stevens reaction).14 Examination of the
pyrosylate revealed a major product 28 (96.5%), where
hydrogen had migrated to the carbenic center, along with a
Attention was next turned to reactive intermediates 10 and
11, where the electron-deficient carbon is at the 2-position. The
ketone 33 served as the starting material for generation of these
intermediates (Scheme 6). This ketone was previously
prepared16 by the Nef reaction of 2-nitro-anti-7-
trimethylsilylbicyclo[2.2.1]heptane, where it was proposed
that a γ-silyl effect was responsible for the relatively high
yield of 33. While lithium aluminum hydride reduction of 33
gave endo-alcohol 34 contaminated with 15% of the exo-isomer,
lithium tri-sec-butylborohydride reduction of 33 gave pure 34.
Figure 1. M062X/6-311+G** calculated structures of cation 8 and carbene 9.
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Scheme 3. Isodesmic Reactions of Cation 8 and Carbene 9
Scheme 4. Generation and Rearrangement of Carbene 9
Scheme 6. Synthesis of Precursors to Cation 10 and Carbene
11
Scheme 7. Solvolyses of Mesylate 35 in CD3CO2D and
CF3CH2OH
Scheme 5. Calculated Barriers to Rearrangement of
Carbenes 9 and 25
Conversion of 34 to the mesylate 35 was straightforward. The
ketone 33 could also be readily converted to the
tosylhydrazone 36. Deprotonation of 36 with sodium
methoxide gave the tosylhydrazone salt 37, which served as
the precursor to carbene 11.
By way of contrast with triflate 18, the behavior of mesylate
35 under solvolytic conditions is quite complex. Five products
are formed (Scheme 7) when 35 reacts in CD3CO2D, including
38 and 42 with unrearranged carbon skeleton and structurally
rearranged products 39, 40, and 41. Mesylate 35 is only 2.6
times more reactive than the desilylated analog, endo-2-
norbornyl mesylate, 45 (Table 1) in CD3CO2D. In
CF3CH2OH, a more highly ionizing solvent that favors kΔ
processes, the endo-trifluoroethyl ether 44 is the major
solvolysis product (53%) derived from 35. Also formed are
smaller amounts of rearranged products 39, 40, and 43. The
rate enhancement in CF3CH2OH is a modest factor of 9.4 and
is slightly larger than one would expect from a purely inductive
effect.
On the basis of the negligible rate enhancement in
CD3CO2D as well as the rearranged products 39-41, it is
suggested that the major reaction pathway is ionization without
participation of the silyl group (Path A of Scheme 8).
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cation 10 is involved. Computationally, with a proper starting
geometry, we have been able to locate such a delocalized cation
(Figure 2). However, if one starts the calculation with a
geometry similar to that expected for a classical cation 46, then
the structure optimizes to give the rearranged β-silyl cation
47,18 which lies 6.9 kcal/mol lower energy than 10. The long
C7−Si bond (1.990 Å) and the long C1−C7 bond (1.668 Å)
suggest that cation 10 derives stabilization from an interaction
with the C−Si rear lobe as well as an interaction with the C1−
C7 σ-bond, as represented by 10a.
Scheme 8. Mechanistic Pathways for Solvolyses of Mesylate
34
The lack of a significant rate enhancement in acetolysis of 35
as well as the large amounts of rearranged products indicate
that γ-silyl stabilization of cation 10 is not as large as in cations
6 or 8. Computational studies concur with this assessment and
the isodesmic calculation shown in Scheme 9 indicates that 10
is only stabilized by 3.2 kcal/mol relative to the 2-norbornyl
cation, 49. This trimethylsilyl stabilization in 10 does not
approach the 22.6 kcal/mol and the 16.2 kcal/mol seen in
cations 6 and 8, where the demand for stabilization in these
intrinsically more strained and destabilized cations is much
greater.
The generation of carbene 11 from ketone 33 was
straightforward using the Bamford−Stevens reaction. The sole
product derived from this carbene was the tricyclic product 51,
formed via 1,3-migration of the endo C6 hydrogen to the
carbenic center (Scheme 10). The structure of this product is
based partially on the proton coupled 13C NMR spectrum that
shows three cyclopropyl carbons with single bond JCH values of
173−174 Hz. This product 51 is quite analogous to that
formed from the 2-norbornyl carbene, 50, where nortricyclane
is the predominant product.19 Figure 2 shows the calculated
structure of carbene 11, and no unusual bonding interactions
are apparent in this structure. The isodesmic reaction shown in
Scheme 8 shows negligible stabilization of this carbene by the
7-trimethylsilyl group relative to the unsubstituted 2-norbornyl
carbene, 50. The product 51 also argues against any large
interaction of the carbenic center in 11 with the silyl group. A
calculation of migration barriers readily explains the observed
product. Scheme 10 shows that migration of the endo-C6
hydrogen in 11 is an extremely facile process (ΔE⧧ = 1.9 kcal/
Ionization of 35 proceeds via the “classical” ion pair 46, where
solvent capture leads to the small amount (6%) of the exo-
acetate 38. Cation 46 undergoes rapid rearrangement to give
the β-silyl cation 47, which is the source of rearranged products
39−41, via proton elimination (22%), trimethylsilyl elimination
(17%), or solvent capture (37%).
The product that is more difficult to rationalize is the 18%
endo-acetate 42, where substitution has occurred with net
retention. This type of product (endo-substitution) is not
formed in solvolysis reactions of endo-2-norbornyl derivatives,
where only exo-substitution products are observed.17 The
unrearranged endo-substitution product 44 becomes the major
product (53%) in CF3CH2OH. A mechanism that would
account for the endo-substitution products 42 and 44 involves
the competing Path B in Scheme 8, where the γ-silyl-stabilized
Figure 2. M062X/6-311+G** calculated structures of cation 10 and carbene 11.
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Scheme 9. Isodesmic Reactions of Cation 10 and Carbene 11
(3.14 mmol), 12,12 and 520 mg of t-butyldimethylsilyl chloride (3.46
mmol) in 5 mL of dry THF was stirred as 391 mg of imidazole (5.75
mmol) was added. The mixture was refluxed for 3 h and then taken up
into 20 mL of pentane and 15 mL of water. The pentane extract was
washed with 2 additional portions of water, saturated NaCl solution,
and dried over a mixture of Na2SO4 and MgSO4. After filtration, the
solvent was removed using a rotary evaporator. The residue was
distilled to give 669 mg of liquid 13 (95% yield), bp 88−91 °C (15
mm). 1H NMR of 13 (CDCl3) δ 5.94 (t, J = 2.2 Hz, 2 H), 3.43 (br s, 1
H), 2.42 (m, 2 H), 1.80 (m, 2 H), 0.91 (m, 2 H), 0.87 (s, 9 H), 0.02
(s, 6 H). 13C NMR of 13 (CDCl3) δ 134.2, 82.8, 46.3, 25.8, 21.8, 17.9,
−4.8. Exact mass (EI) calcd for C13H24OSi: 224.1596. Found:
224.1592.
Scheme 10. Generation and Rearrangement Pathways of
Carbene 11
Preparation of anti-7-t-Butyldimethylsiloxy-2-bromobicyclo-
[2.2.1]hept-2-ene, 14. A solution of 667 mg of the TBS ether 13
(2.98 mmol) in 9 mL of CH2Cl2 was stirred as 705 mg of PhSeBr
(2.99 mmol) was added in small portions over 30 min. The color
faded gradually after each addition. On completion of the addition, the
mixture was stirred for 1.5 h at room temperature. The CH2Cl2 was
then removed via rotary, the residue was immediately dissolved in 10
mL of dry THF, and the solution was cooled in an ice bath. The
solution was stirred as 1.95 g of 30% H2O2 was added dropwise,
followed by 30 mg of acetic acid. The mixture was then warmed to
room temperature for 3 h and then transferred to a separatory funnel
using pentane. The mixture was washed with two portions of water
and then with Na2CO3 solution. The pentane extract was dried over
Na2SO4 and filtered, and the solvent was then removed using a rotary
evaporator. The residue was chromatographed on 12 g of silica gel,
and the column was eluted with pentane. The product rapidly eluted,
and the pentane was removed using a rotary evaporator. The residue
was distilled to give 403 mg of liquid 14 (45% yield), bp 90−93 °C (1
mm). 1H NMR (CDCl3) δ 6.02 (d of d, J = 3.7, 1.2 Hz, 1 H), 3.60 (br
s, 1 H), 2.55 (m, 1 H), 2.50 (m, 1 H), 1.83 (m, 2 H), 1.10 (m, 2 H),
0.86 (s, 9 H), 0.03 (br s, 6 H). 13C NMR of 14 (CDCl3) δ 133.5,
122.7, 81.5, 54.7, 48.7, 25.7, 23.1, 21.7, 17.9, −4.83, −4.87. Exact mass
(EI) calcd for C13H23BrOSi: 302.0702. Found: 302.0743.
P r ep ar at io n o f an t i- 7- t -B u tyl di m e th y l si lo x y - 2 -
trimethylsilylbicyclo[2.2.1]hept-2-ene, 15. A solution of 374 mg of
the vinyl bromide 14 (1.23 mmol) in 6 mL of THF was cooled to −78
°C, and 820 μL of 1.6 M n-BuLi in hexanes (1.31 mmol) was added.
The mixture was stirred at −78 °C for 45 min, and then 225 mg of
ClSiMe3 (2.07 mmol) was added. The mixture was warmed and kept
at room temperature for 1.5 h and then recooled in an ice bath.
Triethylamine (75 mg) was then added followed by water, and the
mixture was then transferred to a separatory funnel using pentane. The
pentane phase was washed with 3 portions of water, saturated NaCl
solution, and dried over Na2SO4. The solvent was removed using a
rotary evaporator, and the residue was distilled to give 336 mg (92%
yield) of liquid 15, bp 72−75 °C (0.3 mm). 1H NMR of 15 (CDCl3) δ
6.22 (d of d, J = 3.3, 0.9 Hz, 1 H), 3.36, (br s, 1 H), 2.48 (m, 1 H),
2.42 (m, 1 H), 1.78 (m, 2 H), 0.88 (m, 1 H), 0.86 (s, 9 H), 0.77 (m, 1
H), 0.03 (s, 9 H), 0.011 (s, 3 H), 0.005 (s, 3 H). 13C NMR of 15
(CDCl3) δ 148.4, 143.4, 82.9, 48.9, 47.8, 25.8, 21.84, 21.82, 17.9, −1.8,
mol). The trimethylsilyl-perturbed hydrogen on C7 shows little
propensity to migrate, as revealed by the 13.7 kcal/mol
migration barrier.
CONCLUSIONS
■
Experimental and computational studies reveal a significant γ-
silyl stabilization of the endo-2-trimethylsilyl-7-norbornyl cation
as well as the endo-2-trimethylsilyl-7-norbornyl carbene. By way
of contrast, computational and experimental studies suggest
only minimal γ-silyl stabilization of the anti-7-trimethylsilyl-2-
norbornyl cation and no stabilization of the anti-7-trimethyl-
silyl-2-norbornyl carbene. Therefore γ-silyl stabilization can
best be described as “enormous” in the 3-trimethylsilylcyclo-
butyl carbocation and carbene, “quite significant” in 2-
trimethylsilyl-7-norbornyl carbocation and carbene, and “min-
imal to non-existent” in the 7-trimethylsilyl-2-norbornyl
carbocation and carbene.
EXPERIMENTAL SECTION
■
General. NMR spectra were recorded on a 600 MHz spectrometer.
HRMS measurements were carried out using either an electrospray
ionization source with time-of-flight mass analyzer or a GC-mass
spectrometer with an electron impact ionization source. NMR analyses
were carried out on an instrument operating at 600 MHz for 1H NMR.
Preparation of anti-7-t-Butyldimethylsiloxybicyclo[2.2.1]hept-2-
ene, 13. A solution of 345 mg of anti-bicyclo[2.2.1]hept-2-en-7-ol
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−4.78, −4.85. Exact mass (EI) calcd for C16H32OSi2: 296.1992.
Found: 296.1995.
(m, 1 H), 1.12−1.04 (m, 2 H), 0.004 (s, 9 H). 13C NMR (CDCl3) δ
171.3, 83.5, 40.8, 38.7, 28.0, 27.7, 24.6, 24.5, 21.3, −1.7. Exact mass
(EI) calcd for C12H22O2Si: 226.1389. Found: 226.1373. Except for the
singlet at δ 2.03, the H NMR spectrum of 21-H3 in CD3CO2D was
identical to that of the product formed on solvolysis of 18 in
CD3CO2D.
Preparation of anti-7-Hydroxy-endo-2-trimethylsilylbicyclo-
[2.2.1]heptane, 16. The vinyl silane 15 (375 mg; 1.27 mmol) was
dissolved in 15 mL of dry ether, and 57 mg of 10% Pd/C was added.
The flask was flushed with H2, and the mixture was stirred under H2 at
1 atm pressure for 8 h. The mixture was then filtered through a small
amount of MgSO4 to remove the Pd/C, and the solvent was removed
using a rotary evaporator. The 1H NMR spectrum of the crude residue
showed 84% of endo-2-trimethylsilyl-anti-7-(t-butyldimethylsiloxy)-
bicyclo[2.2.1]heptane and 16% of exo-2-trimethylsilyl-anti-7-(t-
butyldimethylsiloxy)bicyclo[2.2.1]heptane. This crude residue was
used directly in the hydrolysis step.
The mixture obtained above was dissolved in 12 mL of THF, and
12 mL of 1.0 M HCl in water was added with stirring. After 22 h at
room temperature NMR analysis of a small portion of the reaction
mixture showed about 50% reaction. The mixture was then heated
with stirring at 50 °C for 24 h to complete the hydrolysis. The mixture
was then transferred to a separatory funnel with pentane, and the
aqueous phase was separated. The pentane extract was washed with
two portions of water and dried over MgSO4. After filtration, the
solvent was removed using a rotary evaporator. The NMR spectrum
showed a mixture containing 84% endo-2-trimethylsilylbicyclo[2.2.1]-
heptan-anti-7-ol, 16, and 16% exo-2-trimethylsilylbicyclo[2.2.1]heptan-
anti-7-ol, 17. The crude products were chromatographed on 15 g of
silica gel and eluted with increasing amounts of ether in pentane.
Mixtures of the alcohols 16 and 17 (205 mg, 88% yield) eluted with
13−16% ether in pentane. The early fractions were enriched in alcohol
17, while the latter fractions were enriched in alcohol 16, mp 66−68
°C. NMR of 16 (CDCl3) δ 4.03 (br, 1 H), 2.00 (m, 2 H), 1.88−1.72
(m, 3 H), 1.49 (m, 1 H), 1.41 (d, J = 3.5 Hz, 1 H), 1.18 (m, 1 H), 1.07
(d of d, J = 12, 7 Hz, 1 H), 1.00 (m, 1 H), 0.00 (s, 9 H). 13C NMR of
16 (CDCl3) δ 82.1, 43.0, 40.8, 28.6, 27.1, 25.3, 24.1, −1.6. Exact mass
(EI) calcd for C10H20OSi: 184.1283. Found: 184.1304.
Preparation of endo-2-Trimethylsilyl-anti-bicyclo[2.2.1]hept-7-yl
Triflate, 18. The alcohol 16 (23.3 mg; 0.127 mmol) was dissolved in
0.5 mL of CH2Cl2, and 23 mg of 2,6-lutidine (0.215 mmol) was added.
The mixture was cooled to −10 °C, and 49 mg of triflic anhydride
(0.174 mmol) in a small amount of CH2Cl2 was added in one portion.
The mixture was warmed to room temperature and then transferred to
a separatory funnel using a small amount of CH2Cl2. Five mL of
pentane was then added and a rapid aqueous workup followed. The
organic phase was washed successively with cold water, cold dilute
HCl solution, cold water, NaHCO3 solution, and saturated NaCl
solution. The solution was dried over MgSO4 and filtered, and the
solvent was removed using a rotary evaporator to give 38.8 mg of
liquid triflate 18 (97% yield). The unstable 18 was stored in pentane
solution at −20 °C. 1H NMR of 19 (CDCl3) δ 4.99 (br s, 1 H), 2.42,
(m, 2 H), 1.89 (m, 1 H), 1.82 (m, 2 H), 1.62 (m, 1 H), 1.32 (m, 1 H),
1.18 (d of d, J = 12.5, 7.2 Hz, 1 H), 1.04 (m, 1 H), 0.035 (s, 9 H). 13C
NMR of 18 (CDCl3) δ 118.7 (q, J = 319 Hz), 96.2, 42.1, 39.9, 27.03,
26.96, 23.9, 23.5, −1.8.
1
Preparation of endo-2-Trimethylsilylbicyclo[2.2.1]heptan-7-one,
19. A solution of 88 mg of alcohol 16 (0.478 mmol) in 4 mL of
CH2Cl2 was stirred as 128 mg of pyridinium chlorochromate (0.594
mmol) was added in one portion. The mixture was stirred at room
temperature for 17 h, and then 8 mL of pentane was added. The
mixture was filtered through a small amount of silica gel, and the
solvent was removed using a rotary evaporator. The residue was
chromatographed on 4.5 g of silica gel, and the column was eluted with
increasing amounts of ether in pentane. The liquid ketone 19 (27.8
1
mg; 32% yield) eluted with 5% ether in pentane. H NMR of 19
(CDCl3) δ 2.06 (m, 1 H), 1.95−1.87 (m, 3 H), 1.83 (m, 1 H), 1.76
(m, 1 H), 1.47 (m, 1 H), 1.39 (d of d, J = 12, 8 Hz), 1.26 (m, 1 H),
0.09 (s, 9 H). 13C NMR of 19 (CDCl3) δ 217.2, 40.2, 38.4, 25.4, 24.9,
22.1, 21.2, −1.6. Exact mass (EI) calcd for C10H18OSi: 182.1127.
Found: 182.1133.
Preparation and Pyrolysis of Tosylhydrazone Salt 26. A
solution of 26.8 mg of ketone 19 (0.147 mmol) in 150 μL of CH3OH
was added to a suspension of 30.3 mg of tosylhydrazine (0.163 mmol)
in 350 μL of methanol. The mixture was stirred for 3 h at room
temperature, and then 380 μL of freshly prepared 0.478 M NaOCH3
in methanol (0.182 mmol) was added to the tosylhydrazone solution.
The solvent was then removed using a rotary evaporator, and the
residue was evacuated at 15 mm for 5 h, during which time the salt 26
gradually solidified.
The solid tosylhydrazone salt 26 was broken up with a spatula, and
a short path distillation head with a 5 mL receiver flask was attached.
The pressure was lowered to <0.1 mm, and the flask was gradually
heated (oil bath) to 90 °C. The receiver flask was cooled in a dry ice/
acetone bath, and the temperature of the oil bath was slowly raised to
135 °C. At around 120 °C the pressure rose slightly and remained
slightly elevated until about 130 °C. On completion of the pyrolysis,
the products 28 and 23 (96.5:3.5 ratio) were identified by 1H and 13
C
NMR spectroscopy. The structure of 23 was based on NMR spectral
comparison with an authentic sample.20 1H NMR of 28 (CDCl3) δ
2.39 (m, 1 H), 2.10 (d of t, J = 4.7, 2.7 Hz, 1 H), 2.02−1.95 (m, 2 H),
1.91 (m, 1 H), 1.63 (m, 1 H), 1.45 (d of d of t, J = 12, 7, 1.3 Hz, 1 H),
1.39 (t, J = 4.8 Hz, 1 H), 0.88 (d of d of d, J = 10, 2.7, 1.1 Hz, 1 H),
−0.10 (s, 9 H). 13C NMR of 28 (CDCl3) δ 37.8 (d, J = 145 Hz), 35.6
(t, J = 128 Hz), 29.3 (d, J = 181 Hz), 26.5 (d, J = 161 Hz), 24.9 (t, J =
134 Hz), 22.8 (t, J = 130 Hz), 14.1 (s), −2.9 (q, J = 118 Hz). Exact
mass (EI) calcd for C10H18Si: 166.1178. Found: 166.1164.
Preparation of anti-7-Trimethylsilyl-endo-bicyclo[2.2.1]heptan-2-
ol, 34. A solution of 29.0 mg of ketone 3316 (0.159 mmol) in 2 mL of
dry THF was cooled to −78 °C, and 250 μL of 1.0 M L-selectride in
THF (0.250 mmol) was added via syringe to the stirred solution. The
mixture was allowed to warm to room temperature and then recooled
to 0 °C, and a solution of 100 mg of NaOH in 1 mL of water was
added dropwise. After a few minutes, 300 μL of 30% hydrogen
peroxide was added, and the mixture was warmed to room
temperature. After 30 min the mixture was taken up into ether and
water. The ether extract was washed with water and dried over MgSO4.
After filtration, the solvent was removed using a rotary evaporator. The
residue was taken up into pentane and redried with Na2SO4, and the
pentane was removed using a rotary evaporator to give 26.8 mg (91%
yield) of alcohol 34. 1H NMR of 34 (CDCl3) δ 4.17 (m, 1 H), 2.28 (t,
J = 4.2 Hz, 1 H), 2.25 (t, J = 4.2 Hz, 1 H), 1.98 (m, 1 H), 1.88 (m, 1
H), 1.58 (m, 1 H), 1.42 (br, 1 H), 1.39 (m, 1 H), 1.29 (m, 1 H), 0.85
(d of d, J = 12.6, 3 Hz, 1 H), 0.76 (m, 1 H), 0.01 (s, 9 H). 13C NMR of
34 (CDCl3) δ 74.6, 44.8, 42.3, 39.8, 39.3, 29.7, 19.6, −0.8. Exact mass
(ESI) (M + Na+) calcd for C10H20NaOSi 207.1176. Found 207.1163.
Preparation of anti-7-Trimethylsilyl-endo-bicyclo[2.2.1]hept-2-yl
Mesylate, 35. A solution of 13.5 mg of alcohol 34 (0.0734 mmol) in
0.7 mL of CH2Cl2 was cooled to −60 °C, and 13.5 mg of CH3SO2Cl
(0.118 mmol) in a small amount of CH2Cl2 was added. A solution of
Solvolysis of Triflate 18 in CD3CO2D. A solution of 4.0 mg of
triflate 18 and 3.1 mg of 2,6-lutidine in 350 mg of CD3CO2D was
placed in a sealed 3 mm NMR tube at 25 °C for 72 h. The tube was
then analyzed by 1H NMR spectroscopy that showed acetate 21 as the
sole product. Acetate 21 was identified by 1H NMR spectral
comparison with an authentic sample of 21-H3 in CD3CO2D prepared
as described below.
Preparation of anti-7-Acetoxy-endo-2-trimethylsilylbicyclo-
[2.2.1]heptane, 21-H3. A solution of 5.9 mg of alcohol 16 (0.0321
mmol) and 8 mg of acetic anhydride (0.0784 mmol) in 0.7 mL of
CH2Cl2 was stirred as 1.5 mg of dimethylaminopyridine was added.
After 3 h at room temperature, about 10 mg of CH3OH was added
followed by 3 mL of pentane. The mixture was extracted with water,
dilute HCl solution, water, saturated NaCl solution, and then dried
over MgSO4. After filtration, the solvent was removed using a rotary
evaporator to give 7.0 mg (96% yield) of liquid acetate product 21-H3.
1H NMR (CDCl3) δ 4.71 (br s, 1 H), 2.25, (m, 1 H), 2.19, (m, 1 H),
2.03 (s, 3 H), 1.84−1.73 (m, 2 H), 1.67 (m, 1 H), 1.48 (m, 1 H), 1.19
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15 mg of Et3N (0.149 mmol) in a small amount of CH2Cl2 was then
added dropwise. The mixture was allowed to warm to room
temperature and then taken up into ether, washed with cold water,
dilute HCl solution, water, NaHCO3 solution, saturated NaCl
solution, and then dried over a mixture of Na2SO4 and MgSO4.
After filtration, the solvent was removed using a rotary evaporator to
give 18.1 mg of mesylate 35 (94% yield). The crude product was
slurried with pentane, and the mixture was cooled to about −40 °C.
The pentane was decanted, and the residual solvent was removed
using a rotary evaporator to give mesylate 35, mp 57−58 °C. 1H NMR
of 35 (CDCl3) δ 4.92 (m, 1 H), 2.99 (s, 3 H), 2.61 (t, J = 4.2 Hz, 1
H), 2.33 (t, J = 4.2 Hz, 1 H), 2.07 (m, 1 H), 1.87 (m, 1 H), 1.62 (m, 1
H), 1.49 (m, 1 H), 1.33 (m, 1 H), 1.24 (d of d, J = 13.2, 3.6 Hz, 1 H),
0.76 (m, 1 H), 0.03 (s, 9 H). 13C NMR of 35 (CDCl3) δ 83.6, 43.7,
39.4, 38.9, 38.7, 38.3, 29.2, 20.4, −0.9.
Solvolysis of Mesylate 35 in CD3CO2D. A solution of 3.5 mg of
mesylate 35 and 2.5 mg of 2,6-lutidine in 460 mg of CD3CO2D was
sealed in a 3 mm NMR tube, and the tube was placed in a water bath
at 60.0 °C for 52.5 h. The tube was then analyzed by 1H NMR
spectroscopy that showed 38, 39, 40, 41, and 42 in a 6:22:17:37:18
ratio (see Supporting Information). These products were all identified
by 1H NMR spectral comparison with authentic samples in
CD3CO2D. Authentic samples of acetates 41-H3 and 42-H3 were
prepared as described below.
Preparation of exo-2-Acetoxy-endo-3-trimethylsilylbicyclo[2.2.1]-
heptane, 41-H3. A solution of 150 mg of endo-2-hydroxy-endo-3-
trimethylsilylbicyclo[2.2.1]heptane4b (0.815 mmol) and 131 mg of
2,6-lutidine (1.223 mmol) in 5 mL of ether was cooled to −10 °C, and
255 mg of trifluoroacetic anhydride (1.214 mmol) in 0.5 mL of ether
was added dropwise. The mixture was warmed to room temperature,
and after 10 min the mixture was taken up into pentane. The solution
was consecutively washed with cold water, cold dilute HCl solution,
water, NaHCO3 solution, and then dried over MgSO4. After filtration,
the solvent was removed using a rotary evaporator to give 226 mg
(99% yield) of endo-2-trifluoroacetoxy-endo-3-trimethylsilylbicyclo-
[2.2.1]heptane.
A solution of 220 mg of the trifuoroacetate (0.786 mmol) prepared
above, and 110 mg of 2,6-lutidine (1.027 mmol) in 8 mL of
CH3CO2H was heated in a sealed tube at 100 °C for 18 h. The
mixture was taken up into 15 mL of ether and 15 mL of pentane, and
the solution was washed with two portions of water, followed by dilute
Na2CO3 solution. The organic extract was dried over MgSO4 and
filtered, and the solvents were then removed using a rotary evaporator.
The residue was chromatographed on 3 g of silica gel, and the column
was eluted with increasing amounts of ether in pentane. The liquid
acetate 41-H3 (69 mg; 39% yield) eluted with 3% ether in pentane.
NMR spectra of 41-H3 showed 6% of an unidentified isomeric acetate.
1H NMR of 41-H3 (CDCl3) δ 4.61 (d, J = 4 Hz, 1 H), 2.35 (m, 1 H),
was added to a suspension of 92 mg of tosylhydrazine (0.494 mmol) in
500 μL of methanol. The stirred mixture was allowed to stand at room
temperature for 4 h, and then 1.15 mL of 0.478 M NaOCH3 in
methanol (0.550 mmol) was added. After 10 min, the methanol was
removed using a rotary evaporator, and the residue was evacuated at
15 mm for 5 h. The tosylhydrazone salt 37 gradually solidified. The
solid salt 37 was then broken up with a spatula.
A short path distillation head with a 5 mL receiver flask was
attached, and the pressure was lowered to <0.1 mm. The flask was
gradually heated (oil bath) under vacuum and at 100 °C, and the
receiver flask was cooled in a dry ice/acetone bath. The temperature
was slowly raised to 155 °C. At around 130 °C the pressure rose
slightly and remained slightly elevated until about 150 °C. On
completion of the pyrolysis, the yield of the liquid product 51 in the
receiver flask was 69 mg (86% yield). 1H NMR of 51 (CDCl3) δ 1.95
(m, 1 H), 1.26 (m, 1 H), 1.19 (m, 1 H), 1.12 (m, 1 H), 1.10−1.05 (m,
2 H), 1.03−0.99 (m, 2 H), 0.62 (m, 1 H), −0.01 (s, 9 H). 13C NMR of
51 (CDCl3) δ 36.4 (t, J = 132 Hz), 33.1 (d, J = 118 Hz), 32.2 (d, J =
146 Hz), 31.5 (t, J = 132 Hz), 12.8 (d, J = 173 Hz), 10.5 (d, J = 174
Hz), 10.0 (d, J = 174 Hz), −1.4 (q, J = 119 Hz). Exact mass (EI) calcd
for C10H18Si: 166.1178. Found: 166.1182.
Solvolyses of Triflates and Mesylates. Kinetics Procedures.
Rate constants reported in Table 1 were all determined using 600
MHz 1H NMR spectroscopy. Kinetic studies in CD3CO2D were
carried out by dissolving ∼4 mg of the appropriate substrate in 350 mg
of CD3CO2D containing ∼1.5 equiv of 2,6-lutidine. The sample was
then sealed in a 3 mm NMR tube, and the tube was placed in a
constant temperature bath at the appropriate temperature. At
appropriate time intervals, the tube was quenched in a water bath at
1
15 °C and rapidly analyzed by H NMR at ambient temperature to
determine relative amounts of starting triflate or mesylate. For triflate
18, readings were carried out with the NMR probe temperature at 25.0
°C, and the sample was placed in a constant temperature bath at 25.0
°C between readings. All kinetic studies in trifluoroethanol (0.05 M in
2,6-lutidine) were carried out using our previously described method21
where the chemical shift of the added 2,6-lutidine was monitored as a
function of time.
For triflate 18 in CD3CO2D, the rate of disappearance of the TMS
singlet at δ 0.054 was monitored relative to the product signal at δ
0.024. For 7-norbornyl triflate, 20,22 the peak at δ 5.06 was monitored
using the 2,6-lutidine signal at δ 7.60 as an internal standard. For
mesylate 35, the area of the mesylate signal at δ 3.025 was monitored
using the 2,6-lutidine signal at δ 2.74 as an internal standard. For 2-
norbornyl mesylate, 45,23 the rate of disappearance of the signal at δ
3.026 was monitored relative to the product mesylate anion
developing at δ 2.857. First-order rate constants for disappearance of
substrates were calculated by standard least-squares procedures.
Correlation coefficients were all greater than 0.9998. Typical data
are given as Supporting Information.
Computational Studies. Ab initio molecular orbital calculations
were performed using the Gaussian 09 series of programs.13 Structures
were characterized as energy minima via frequency calculations that
showed no negative frequencies or as transition states that showed one
negative frequency.
2.30 (d, J = 5 Hz, 1 H), 1.98 (s, 3 H), 1.55−1.46 (m, 2 H), 1.33 (m, 1
H), 1.27−1.19 (m, 2 H), 1.06 (m, 1 H), 0.90 (m, 1 H), 0.04 (s, 9 H).
13C NMR of 41-H3 (CDCl3) δ 170.7, 79.2, 42.8, 38.7, 38.20, 38.17,
26.0, 24.4, 21.5, −1.4. Exact mass (ESI)(M + Na+) calcd for
C12H22O2SiNa: 249.1281. Found: 249.1284.
Preparation of anti-7-Trimethylsilyl-endo-2-acetoxybicyclo-
[2.2.1]heptane, 42-H3. A solution of 9.8 mg of alcohol 34 (0.0533
mmol) and 12 mg of acetic anhydride (0.118 mmol) in 1.0 mL of
CH2Cl2 was stirred as 3.3 mg of dimethylaminopyridine was added.
After 8 h at room temperature 15 mg of CH3OH was added followed
by 5 mL of pentane. The mixture was extracted with water, dilute HCl
solution, water, saturated NaCl solution, and then dried over MgSO4.
After filtration, the solvent was removed using a rotary evaporator to
give 11.5 mg (96% yield) of liquid acetate 42-H3. 1H NMR (CDCl3) δ
4.87 (m, 1 H), 2.54 (t, J = 4.2 Hz, 1 H), 2.29 (t, J = 4.4 Hz, 1 H), 2.04
(s, 3 H), 2.00 (m, 1 H), 1.72 (m, 1 H), 1.58 (m, 1 H), 1.38 (m, 1 H),
1.27 (m, 1 H), 1.02 (d of d, J = 13, 3.6 Hz, 1 H), 0.78 (br, 1 H), 0.015
(s, 9 H). 13C NMR (CDCl3) δ 171.4, 77.0, 42.5, 39.4, 39.1, 38.8, 29.3,
21.3, 20.7, −0.8. Exact mass (ESI)(M + Na+) calcd for C12H22O2SiNa:
249.1281. Found: 249.1281.
ASSOCIATED CONTENT
* Supporting Information
■
S
Complete ref 13, the M062X/6-311+G* calculated structures,
energies, and Cartesian coordinates of 8−11, 22−25, 30, 31,
47−50, 52, and 53, 1H and 13C NMR spectra of 13−16, 18, 19,
1
21-H3, 23, 28, 34, 35, 41-H3, 42-H3, 43, 44, and 51, the H
NMR spectrum of the acetolysis products from mesylate 35 as
well as kinetics studies on 18 and 35. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: creary.1@nd.edu
■
Preparation and Pyrolysis of Tosylhydrazone Salt 37. A
solution of 88 mg of ketone 33 (0.484 mmol) in 500 μL of CH3OH
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Notes
The authors declare no competing financial interest.
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