Influence of Alkoxy Groups on Rates of Acetal Hydrolysis and Tosylate Solvolysis: Electrostatic Stabilization of Developing Oxocarbenium Ion Intermediates and Neighboring-Group Participation to Form Oxonium Ions

Article abstract of DOI:10.1021/acs.joc.5b00338

The hydrolysis of 4-alkoxy-substituted acetals was accelerated by about 20-fold compared to that of sterically comparable substrates that do not have an alkoxy group. Rate accelerations are largest when the two functional groups are linked by a flexible cyclic tether. When controlled for the inductive destabilization, an alkoxy group can accelerate acetal hydrolysis by up to 200-fold. The difference in rates of acetal hydrolysis between a substrate where the alkoxy group was tethered to the acetal group by a five-membered ring compared to one where it was tethered by an eight-membered ring was less than 100-fold, suggesting that fused-ring intermediates were not formed. By comparison, the difference in rates of solvolysis of structurally related tosylates were nearly 10⁶-fold between the five- and eight-membered ring series. This observation implicates neighboring-group participation in the solvolysis of tosylates but not in the hydrolysis of acetals. The acceleration of acetal hydrolysis by an alkoxy group is better explained by electrostatic stabilization of intermediates that accumulate positive charge at the acetal carbon atom. (Chemical Presented).

Full text of DOI:10.1021/acs.joc.5b00338

Article
pubs.acs.org/joc
Influence of Alkoxy Groups on Rates of Acetal Hydrolysis and
Tosylate Solvolysis: Electrostatic Stabilization of Developing
Oxocarbenium Ion Intermediates and Neighboring-Group
Participation To Form Oxonium Ions
Angie Garcia, Douglas A. L. Otte, Walter A. Salamant,† Jillian R. Sanzone, and K. A. Woerpel*
Department of Chemistry, New York University, 100 Washington Square East, New York, New York 10003, United States
S
* Supporting Information
ABSTRACT: The hydrolysis of 4-alkoxy-substituted acetals was
accelerated by about 20-fold compared to that of sterically comparable
substrates that do not have an alkoxy group. Rate accelerations are
largest when the two functional groups are linked by a flexible cyclic
tether. When controlled for the inductive destabilization, an alkoxy
group can accelerate acetal hydrolysis by up to 200-fold. The differ-
ence in rates of acetal hydrolysis between a substrate where the alkoxy
group was tethered to the acetal group by a five-membered ring
compared to one where it was tethered by an eight-membered ring was less than 100-fold, suggesting that fused-ring
intermediates were not formed. By comparison, the difference in rates of solvolysis of structurally related tosylates were nearly
106-fold between the five- and eight-membered ring series. This observation implicates neighboring-group participation in the
solvolysis of tosylates but not in the hydrolysis of acetals. The acceleration of acetal hydrolysis by an alkoxy group is better
explained by electrostatic stabilization of intermediates that accumulate positive charge at the acetal carbon atom.
have been interpreted as deriving from electrostatic stabilization
of the positive charge developing at C-1 of the oxocarbenium
ion intermediate by the partial negative charge of the alkoxy
group at C-4, as illustrated in oxocarbenium ion 3a (eq 1).8−10
An alternative explanation, involving reaction of oxonium ion
3b (which would be in equilibrium with the oxocarbenium ion
3a), is unlikely because alkoxy groups are generally considered
to be nonparticipating groups. Furthermore, such close
interaction would be disfavored because it would approximate
the formation of a 2,7-dioxabicyclo[2.2.1]heptane structure
(3b, eq 1), effectively destabilizing this onium ion by up to 15
kcal/mol.11
INTRODUCTION
■
The automated synthesis of oligosaccharides depends upon
the ability to control both the stereochemical outcome
of glycosylation reactions and the relative rates of activation
of various components of the reaction.1,2 The most reliable
method for controlling stereochemistry in glycosylation
reactions involves using participating groups, most prevalently
acyloxy groups, at the adjacent carbon atom to control the
stereoselectivity.3 The relative reactivity issue has been more
difficult to address. The relative rates of activation of substrates
such as thioglycosides,1,4 which parallel relative rates of
hydrolysis of acetals,5−7 depend upon the relative stability of
the cationic reactive intermediates, leading to differences in rate
depending upon the nature of substituents on the ring and the
relative stereochemical configurations of those substituents. For
example, the activation of glucose-derived thioacetal 1 is slower
than the galactose isomer 2, even though they differ only in the
relative stereochemistry at a stereocenter relatively far from the
reactive center (Figure 1).4 Similar rate differences have been
observed for hydrolysis.8 The relative rates of these reactions
In this Article, we provide evidence that alkoxy groups, which
are generally considered to be nonparticipating with respect to
stereochemistry,12−20 can accelerate the ionization of acetals.
Preliminary studies suggested that the influence of alkoxy
groups on the rates of ionization of acetals (up to 20-fold
acceleration compared to that for substrates without alkoxy
groups) occurs by electrostatic stabilization of an oxocarbenium
ion intermediate, not neighboring-group participation through
covalently bonded intermediates.21 Additional studies with
Figure 1. Relative rates of activation of carbohydrate-derived
thioacetals (Ar = 4-MeC6H4) by N-iodosuccinimide/triflic acid.4
Received: February 12, 2015
© XXXX American Chemical Society
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more acetals and also comparisons with the rates of reactions of
tosylates, which likely require formation of onium ion inter-
mediates when undergoing ionization, provide further support
for this analysis.
Chart 1. Substrates Evaluated for Rates of Hydrolysis
RESULTS AND DISCUSSION
■
To discover whether alkoxy groups can participate in the
reactions of acetals such as acid-catalyzed ionization, it was
necessary to design substrates that would place the alkoxy
group in a position where participation would be possible. In
carbohydrate systems, participation by alkoxy groups is highly
unlikely because it requires formation of strained rings. In the
case of 2-alkoxy systems, the energetic benefit conferred by
formation of the oxonium ion (about 15 kcal/mol)22 would be
outweighed by the ring strain of a three-membered ring (27
kcal/mol).23 Similarly, neighboring-group participation by
remote alkoxy groups would create strained bicyclic systems,
which are disfavored;24 such structures are also disfavored for
substrates with remote acyloxy groups.25 Because the strongest
evidence for neighboring-group participation of acyloxy groups
is found in systems involving fusion of a five-membered ring
dioxocarbenium ion to the ring undergoing substitution,26 we
designed substrates 4 that could form five-membered ring
oxonium ions. These substrates contain a benzyloxy group that
is positioned four carbon atoms away from the acetal carbon
(Figure 2). To make the entropic costs of participation in this
trans- and cis-9. Like substrates 5−8, these compounds position
a benzyloxy group four carbon atoms away from the acetal
carbon atom, but in this case, formation of the oxonium ion by
neighboring-group participation would require formation of a
bridged bicyclic system, which would develop significant ring
strain.33 Similarly, acetals trans- and cis-10 possess an alkoxy
group four atoms from the acetal, but they would also engender
ring strain if acceleration required the alkoxy group to approach
the acetal carbon atom. The hydrolysis of a completely flexible
acetal 11, related to a system that had shown deceleration in
acetal hydrolysis experiments under neutral conditions,32 was also
examined. Simple alkyl acetals 12 and 13 with branching similar
to that of the cyclic acetals were included as benchmarks to
determine whether the presence of an alkoxy group decelerated
ionization relative to compounds without an alkoxy group, as has
been established for carbohydrates8 and simple acetals.32
Figure 2. Dimethyl acetal substrate template.
series comparable to those costs for the acyloxy group in
glycoside systems,27 we included a second ring so that any
interaction between the alkoxy group at C-4 and the acetal
carbon atom C-1 would form a fused bicyclic system, just as for
the carbohydrate systems. The benzyloxy group was chosen
because it is a commonly used protecting group in carbohy-
drate chemistry and because loss of this group during ionization
would suggest participation through oxonium ions resembling
bicyclic ion 3b (eq 1).13,28,29
The rates of ionization of these acetals would be used to
provide evidence for or against the involvement of alkoxy
groups in ionization. Rates would be compared to constrained
model compounds that would exhibit similar through-bond
inductive effects30,31 but, because of their constrained geo-
metry, could not be stabilized efficiently because the alkoxy
group could not be brought close to the developing positive
charge. Rates of ionization of appropriate compounds without
alkoxy groups would also be examined to determine whether an
alkoxy group can accelerate hydrolysis, although previous
studies with acyclic acetals demonstrated that it cannot.32
Chart 1 shows the alkoxy-substituted acetals used for this
study. The two key functional groups were fused to rings of
different sizes (five- to eight-membered rings in the trans
series) and placed with different relative stereochemical con-
figurations (including cis and trans isomers in some cases) to
study how the flexibility of the fused ring and the relative
orientation of the benzyloxy group and acetal affected the rate
of ionization. The relative positions of the benzyloxy group
and the acetal moiety were also investigated with substrates
Substrate Synthesis. The substrates listed in Chart 1 were
prepared by various methods. Scheme 1 shows the route used
Scheme 1
to prepare acetal trans-5, involving an epoxide ring-opening
reaction followed by functionalization.21 Starting from the
appropriate epoxide, acetals trans-6, trans-7, and trans-8 with
larger rings were prepared by a similar pathway. The synthesis
of the five- and six-membered ring acetals cis-5 and cis-6
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followed the general synthetic route but proceeded through
alcohols cis-15 and cis-18, which were prepared by inversions of
the configurations of the hydroxyl groups on alcohols trans-15
and trans-18 (Scheme 2). The disubstituted cyclohexane acetals
spectroscopy, as illustrated in eq 2. Concentrations were
measured over one to six half-lives (depending upon the
substrate) by integrations of one-pulse experiments and
comparisons of integrations to those of an internal standard
(1,4-dimethoxybenzene) of known concentration. Each experi-
ment was repeated at least two additional times. In no case
were products other than the aldehyde 31 observed, indicating
that no debenzylation occurred (vide infra). The rates were
consistent with pseudo-first-order kinetics, with plots of
ln[acetal] versus time giving lines with R2 ≥ 0.96. Higher
concentrations of acid were required to obtain measurable rates
of some substrates, so rates are reported as observed rate
constants divided by the concentration of acid used. Table 1
reports these normalized rate constants to two significant
Scheme 2
Table 1. First-Order Rate Constants at 23 °C and Relative
Rates of Hydrolysis of Acetals in Acetone-d6/D2O
Normalized to the Same Concentration of DCl/D2O (1 M)
cis-9 and trans-9 were prepared from a common starting
material and separated as esters cis-23 and trans-23, which were
reduced and converted to the acetals separately (Scheme 3).21
Scheme 3
The tetrahydropyran acetals cis-10 and trans-10 were prepared
as a mixture of isomers from δ-decanolactone (25) as shown in
Scheme 4.21 Acetals 11−13 have been reported previously.34−36
Scheme 437
Rates of Acetal Hydrolysis. The rates of hydrolysis of the
acetals shown in Chart 1 were measured by 1H NMR
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figures for acetal hydrolysis reactions in order from slowest to
fastest. Acetal 12, which contained no alkoxy group, was used as
the reference point for establishing the relative rates. It is
anticipated that all of the β-branched acetals are sterically
similar to acetal 12 because the two-carbon chain of the cyclic
acetals would adopt a conformer minimizing double-gauche
interactions, as observed for isobutyl-substituted cyclohexanes38
and 1-butanol,39 resulting in the acetal group being placed near
a methylene group of the ring. It does not appear that steric
effects play a considerable role in these reactions,40 considering
that the β-branched and α-branched acetals 12 and 13,
respectively, ionize at similar rates.
The flexibility of the ring connecting the alkoxy group plays a
significant role in acetal hydrolysis, with larger rings undergoing
ionization more rapidly. While the cyclopentane-derived acetal
trans-5 ionized nearly four times slower than the sterically
equivalent alkyl acetal 12, the cyclooctane-derived acetal trans-8
ionized over 20 times faster than the alkyl acetal. The trend
of increasing rate as more carbon atoms are introduced to the
tethering ring is consistent with the idea that the more flexible
ring44,45 allows the alkoxy group to approach the acetal
undergoing substitution more closely, leading to accelerated
hydrolysis, as observed for galactosides compared to glucosides
(Figure 1). The nearly three-fold slower reaction of the cis-
substituted acetal cis-6 with a six-membered ring compared
to its trans-substituted analogue trans-6 may reflect minor
differences in the energies of transition states resembling fused
rings (trans-hydrindane being slightly less strained than the cis
isomer46,47). Too much flexibility did not lead to faster ion-
ization, however, as illustrated by the slower hydrolysis of
flexible benzyloxy-substituted acetal 11. In that case, any
enthalpic stabilization to the transition state conferred by
the benzyloxy group would be offset by entropic penalties27
incurred upon restricting conformational mobility.
The slow ionization of cyclopentane-derived acetal trans-5
compared to that of the other trans-substituted acetals and even
to the alkyl acetal 12 provides insight into how an alkoxy group
accelerates hydrolysis. According to the Hammond postulate,48
the transition state for hydrolysis should share structural and
energetic features with the high-energy cationic intermediate
formed upon ionization.49 The alkoxy group could stabilize the
positive charge on the acetal carbon atom9,10 without forming a
new covalent bond (as in oxocarbenium ion 37, Figure 5). This
The rate acceleration of hydrolysis conferred by a benzyloxy
group is significant based upon comparisons of the rates in Table 1.
Simply comparing the rate of hydrolysis of acetal trans-6 to that of
isovaleraldehyde acetal 12 shows that an alkoxy group can
accelerate hydrolysis compared to that of an acyclic acetal by nearly
one order of magnitude. Because acetal hydrolysis involves
reversible protonation followed by rate-limiting ionization,8,41 the
cationic intermediate formed from acetal trans-6 must be stabilized
by the alkoxy group four atoms away. It cannot be differentiated
whether this effect results from electrostatic stabilization by the
benzyloxy group, as suggested for hydrolysis of galactose (eq 1),9,10
or whether a new covalent bond is formed during ionization,
resulting in formation of an onium ion intermediate (Figure 3).
Figure 5. Two possible modes of interaction by an alkoxy group upon
ionization of acetal trans-5.
Figure 3. Interaction of alkoxy group with ionizing acetal in the
transition state for hydrolysis of acetal trans-6.
interaction has been proposed to explain the faster hydrolysis of
galactose compared to that of glucose.9,10 A similar electrostatic
stabilization has also been invoked to explain the small
acceleration observed in the hydrolysis of carbohydrate
derivatives bearing acyloxy groups at C-2.50 Alternatively, a
new covalent bond could form between the alkoxy group and
the acetal carbon atom during hydrolysis. The resulting inter-
mediate oxonium ion 38, however, would develop a significant
fraction of the ring strain inherent in the trans-bicyclo[3.3.0]-
octane system (>15 kcal/mol).46,47 If this pathway were
followed, then it would be anticipated that the rate of
ionization of the trans-substituted acetal trans-5 would be
much slower than that for cis-5, which would form a cis-
bicyclo[3.3.0]octane system, which possesses less ring strain
than the trans isomer (by about 6 kcal/mol).46,47 The rate
difference between the isomers, however, is only about six-fold
(Table 1). Consequently, the small difference in reactivity
between the two isomers cis-5 and trans-5 is better
accommodated by considering a looser structure resembling
oxocarbenium ion 37 rather than an onium ion such as 38,
where the carbon−oxygen bond lengths would need to be
shorter.51
The observation that acetal hydrolysis can be accelerated by
an alkoxy group would not be anticipated on the basis of
previous studies. In carbohydrates, the presence of an alkoxy
group at C-4, regardless of its orientation, decelerates
hydrolysis. In simple ketone-derived acetals, the presence of
an alkoxy group or an alkylthio group decelerated acetal
hydrolysis (Figure 4).32 We observed similar reduced reactivity
Figure 4. Relative rates of hydrolysis (1:1 dioxane/water) for acetals
34−36.32
of the acyclic aldehyde-derived acetal 11: the presence of the
remote alkoxy group decelerated hydrolysis by about 25%
compared to the hydrolysis of alkyl acetal 12 (Table 1). In
some cases, the presence of a neighboring group can accelerate
acetal hydrolysis, but this effect has been observed only with
carboxylates as neighboring groups under conditions that favor
deprotonation of a nearby carboxylic acid group.42,43
The above rate accelerations of hydrolysis of up to 21-fold
by an alkoxy group do not account for the inherent
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electron-withdrawing nature of the benzyloxy group. This rate
difference compares acetals that are not electronically similar.
An electronegative group such as an alkoxy group should
destabilize positively charged intermediates and transition
states, leading to attenuation of reaction rates.8,50 The more
appropriate comparison point would be an acetal that possessed
the alkoxy group the same number of atoms away from the
acetal carbon atom but with that alkoxy group fixed so that it
could not approach the acetal carbon by rotation about the
intervening bonds.
To demonstrate whether distal alkoxy groups inductively
destabilize reactive intermediates, the rates of hydrolysis for two
different types of constrained acetals were examined. It is
unlikely that during the hydrolysis of acetals cis- and trans-9 and
cis- and trans-10 that the remote alkoxy groups can approach
the acetal carbon atom because they are held in fixed
orientations relative to each other. Acetal trans-9 positions
both critical substituents on opposite faces of the ring, so they
can never be particularly close (trans-39, Figure 6). Similarly,
participate in acetal hydrolysis. Instead, in carbohydrate-derived
systems, it does not engage in participation because to do so
would impart ring strain. The powerful mitigating force of
strain is illustrated by the results with the cyclopentane-derived
acetal trans-5, which ionizes about 30 times slower than its
cyclohexane-derived analogue trans-6.
Computational Studies. Computational analyses of the
cations formed upon hydrolysis were performed to help
understand the observed differences in rates between the acetal
substrates. While a more thorough analysis would require
investigation of the structures, energies, and conformational
distributions of starting materials, products, and transition states
for hydrolysis,53 as well as application of solvent corrections to the
calculations,54 comparisons of the energies of related inter-
mediates were nevertheless informative. Computational analysis
involved a search for low-energy conformers of the oxocarbenium
ion intermediates for each substrate using semiempirical
methods55 and optimization using density functional methods
(B3LYP/6-31G*).56 Once the lowest energy conformer for each
substrate was determined, the proximity of the oxygen atom of
the benzyloxy group to the oxocarbenium ion carbon atom was
measured. These results are summarized in Table 2.
Table 2. Calculated Distances between C1 and O5 of the
Lowest Energy Conformer of Cationic Intermediates 41
Derived from Acetals and Comparison to Relative Rates of
Hydrolysis (B3LYP/6-31G*)57
Figure 6. Protonated acetals that would be involved during acetal
hydrolysis.
for the acetal and alkoxy groups to approach each other in cis-9,
both would need to be oriented axially (cis-39, Figure 6),
yielding a bicyclic oxonium ion with significant steric and ring
strain (approximately 12.1 kcal/mol).33 Consequently, only
through-bond inductive effects were expected to influence the
transition state for ionization of these acetals. This prediction
was consistent with the observation that hydrolyses of the
constrained acetals 9 were slowed by two- to four-fold
compared to the ionization of the acetal of isovaleraldehyde
(12). A similar analysis would pertain to acetals cis- and trans-
10: to bring the ring’s oxygen atom near to the acetal carbon
atom, sterically disfavored axial conformations resembling 40
with a significant number of gauche-butane interactions52
would need to be formed. As a result, these hydrolyses are four
to eight times slower than the reactions of the alkyl acetal 12.
The measurement of the inductive deceleration of acetal
hydrolysis by an alkoxy group permits an estimate of how much
an alkoxy group can accelerate acetal hydrolysis in uncon-
strained systems. Comparisons of the rate of hydrolysis of the
eight-membered ring acetal trans-8, the most flexible cyclic
system, to the rates of hydrolysis of constrained acetals reveals
a 40- to 200-fold acceleration of hydrolysis that can be attributed
to bringing the alkoxy group near the acetal carbon atom. The
accelerations in the six-membered ring substrate trans-6 are only
slightly lower (10- to 70-fold, depending upon the comparison
made). Whatever substrate is chosen and whichever comparison is
made, it is evident that the influence of an alkoxy group on acetal
hydrolysis is larger than the effect determined for acyloxy groups
in similar systems, which exert a seven- to thirteen-fold rate
acceleration after compensation for inductive destabilization.50
The hydrolysis rates reported here indicate that it is not
appropriate to make the generalization that an alkoxy group (or
likely a hydroxyl group, which is electronically similar) cannot
For related series of compounds, the faster the acetals
underwent ionization, the closer the ether oxygen atom (O5)
approached the cationic carbon atom (C1) in the calculated
structure of the oxocarbenium ion. The correlation between
rate of ionization and C1−O5 distance is consistent with the
observation that the benzyloxy group stabilizes the oxocarbe-
nium ion intermediate. The longest distance between the atoms
was observed for the cyclopentane-derived acetal trans-5.
Because bringing O5 close to the cationic carbon atom C1
would form a ring resembling a trans-fused [3.3.0]-bicyclic
system, the benzyloxy group was held further away from the
carbocationic carbon atom (2.44 Å), thereby diminishing the
stabilization of the transition state for hydrolysis. When the two
substituents are positioned cis on the cyclopentane ring, as for
acetal cis-5, the distance between C1 and O5 is closer (1.64 Å),
which is reflected in a rate of ionization that is seven times
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faster than trans-5. Although detailed studies comparing the
relative energies of the starting materials and transition states
of ionization are required to draw firm conclusions, the data
presented here convey a correlation between the proximity of
the benzyloxy group and the oxocarbenium ion carbon atom
and the rate of ionization.
Chart 2. Tosylates Evaluated for Rates of Solvolysis
These computational studies could be interpreted as sup-
porting formation of a new covalent bond to the carbon atom
of the oxocarbenium ion (that is, neighboring-group partic-
ipation58) as the mechanism for ionization of acetals (42,
Figure 7), but that interpretation is not without problems.
group,62−67 so the magnitude of the influence of neighboring-
group participation could be measured as a function of ring size.
Chart 2 displays the tosylates used in the study. Only the trans-
fused five-, six-, and eight-membered ring substrates were
synthesized (Chart 2) because these substrates span the range
of rates of acetal hydrolysis. The synthesis of the tosylates
employed intermediates that were used to prepare the acetal
substrates; an example of the synthesis is shown in eq 3.
Figure 7. Possible modes of ionization of alkoxy-substituted acetals.
The C−O bond distances of approximately 1.6 Å for the
cations related to acetals cis-5, trans-7, and trans-8 suggest
formation of a covalent bond. Although C−O bonds are
typically 1.43 Å,51,59,60 C−O bonds in oxonium ions can be as
long as 1.658 Å,60 lending support to this argument. This inter-
action between carbon and oxygen atoms could result from
neighboring-group participation, in which the departing MeOH
fragment is ejected by the benzyloxy group to form an oxonium
ion intermediate (Figure 7).61 The considerably longer C−O
bond length observed in the oxocarbenium ions stemming from
the cyclohexane-derived acetal trans-6, which ionized eight
times faster than an acetal without an alkoxy group, however,
cannot be readily interpreted as deriving from neighboring-
group participation.60 These distances are, however, consistent
with electrostatic stabilization of an oxocarbenium ion, which is
even observed in cases where the C−O distance is around
3.3 Å.24 If the accelerated ionization of trans-substituted acetals
trans-7 and trans-8 involved neighboring-group participation
and the accelerated ionization of trans-6 did not, then the
difference between the efficiency of these mechanisms is small
(leading to rate differences less than three-fold), much smaller
than normally observed in cases of neighboring-group
participation (rate accelerations of several orders of magnitude
are more common).62−64 Furthermore, in an absolute sense,
the bond distance in the carbocation is not a good predictor of
the rate of ionization. Taken together, the computational
studies do not provide strong support for formation of a new
covalent bond in the transition state as being responsible for
the rate acceleration observed in the ionization of alkoxy-
substituted acetals.
Determination of the ionization rates of tosylates involved
dissolving them in acetic acid-d41 and measuring the
disappearance of starting material by H NMR spectroscopy.
The reactions exhibited first-order kinetics, as determined by
plots of ln(c0/c) versus time. As with acetal hydrolysis
experiments (eq 2), these experiments were repeated in
triplicate to ensure that the results were meaningful. The
products of the reaction were also analyzed to provide
additional insight into the mechanism of solvolysis. Scheme 5
Scheme 5. Products Expected upon Solvolysis of Tosylates
in Acetic Acid-d4
lists the products that were expected to be formed upon
hydrolysis if neighboring-group participation by the benzyloxy
group occurred.28,29
The relative rates of ionization of the tosylates exhibit a
profoundly larger dependence upon ring size than did the rates
of ionization of the corresponding acetals (Table 3). The
differences in solvolysis rates of the tosylates were so large that
measuring the relative rates proved to be difficult. Tosylate 47
was so reactive in acetic acid-d4 that it underwent solvolysis to a
significant extent (50%) in the 4 min between preparing the
sample and acquiring the first NMR spectrum. By contrast, a
sample of tosylate 45 at room temperature in acetic acid-d4
could be stored at room temperature for several weeks without
undergoing any reaction. Heating samples of tosylate 45 to
temperatures above 100 °C allowed for a more rapid deter-
mination of the rate, and application of the Arrhenius equation
allowed for comparison to the solvolysis rate of tosylate 45 at
room temperature.68
Solvolysis Studies. To determine the magnitude that
neighboring-group participation could influence ionization
rates, we examined the rates of solvolysis of structurally related
primary alkyl tosylates (Figure 8). The ionization of primary
tosylates likely requires participation of the neighboring alkoxy
Figure 8. Tosylate substrates 44 designed to be similar to acetals 4.
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magnitude difference in rate between the cyclooctane- and the
cyclopentane-derived substrates (47 and 45, respectively)
reflects the difference in ring strain between the bicyclic rings
resulting from neighboring-group participation.69 The larger
the second ring, the better it can be accommodated into the
fused ring onium ion 58, so the faster the ionization. The nearly
one million-fold difference in rates of solvolysis of tosylates
establishes a standard for what differences in rate should be
observed during neighboring-group participation by an alkoxy
group62−64,70 compared to ones that do not.
Table 3. Solvolysis Rate Constants, Relative Rates, and
Calculated Half-Lives of Solvolysis of Tosylates in Acetic
Acid-d4 at 23 °C
The dramatic differences in rates of reaction versus ring size
between the tosylate and acetal substrates suggest a difference
in how the alkoxy group facilitates ionization in both series.
The cyclooctane-derived tosylate 47 was found to ionize
670,000 times faster than cyclopentane-derived tosylate 45, an
approximately 10,000-fold larger difference in rate than was
observed for the hydrolysis of acetals of the same ring size
(Figure 10). Whereas the ionizations of the tosylates involve
a
Obtained by determining the rate at 100, 110, and 125 °C and
applying the Arrhenius equation to estimate the rate at 23 °C, as
discussed in the Supporting Information.
Product analysis studies of the solvolysis of tosylates
provided evidence that neighboring-group participation had
occurred. NMR spectroscopic analysis indicated that cyclic
ethers resembling 52 (Scheme 5) were obtained in all cases.
The cyclic products likely resulted from formation of cyclic
oxonium ion 58 (Figure 9), which then underwent ring
Figure 9. Oxonium ion that would be formed by neighboring-group
participation and bonds that were cleaved upon hydrolysis.
opening or debenzylation28,29 by nucleophiles present in
solution. Benzyl acetate-d3 and benzyl tosylate were also
observed. Preparative solvolysis reactions of tosylates 45−47 in
acetic acid allowed for full characterization of all major products
formed (eqs 4−6). It is worth noting that there was no
debenzylation in any acetal hydrolysis reactions (eq 2 and
Table 1), providing evidence against the formation of oxonium
ions in those reactions.
Figure 10. Graphical representation of hydrolysis of acetals versus
solvolysis of tosylates, plotting log (relative rates) vs ring size.
significant participation by the alkoxy group, the neighboring
benzyloxy group plays only a small role in the case of acetal
hydrolysis. This smaller role likely occurs because the cationic
intermediate can be stabilized primarily as the oxocarbenium
ion, diminishing the need for the cationic carbon atom to
gain stabilization by interaction with a neighboring group.
Related cases in which other modes of stabilization override
neighboring-group participation have been reported for
reactions involving cationic intermediates.71,72
The relative rate data and product analysis studies suggest
that reactions of acetals substituted by alkoxy groups are
influenced mostly by electrostatic effects, not by neighboring-
group participation. It is not necessary for an alkoxy group to
form a covalent bond to the acetal carbon atom upon ion-
ization. Instead, conformational changes can occur that bring
the electronegative oxygen atom close to the carbon atom
undergoing ionization, stabilizing the developing oxocarbenium
ion by electrostatic effects.
The relative rates of solvolysis of 45−47 define a range of
reactivity that would be expected for these fused systems should
neighboring-group participation occur. The nearly six orders of
G
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Article
78.3 (CH), 44.5 (CH), 34.1 (CH2), 32.7 (CH2), 29.8 (CH2), 22.2
(CH2); IR (ATR) 3073, 1713, 1641, 1270, 1069 cm−1; HRMS (TOF
MS ES+) m/z calcd for C15H18NaO2 (M + Na)+, 253.1199; found,
253.1198. Anal. Calcd for C15H18O2: C, 78.23; H, 7.88. Found: C,
77.96; H, 8.07.
CONCLUSIONS
■
Our results demonstrate that alkoxy groups can exert strong
influences on the formation of oxocarbenium ions, not just in
the stereochemistry of their reactions.73 When an alkoxy group
can participate without engendering ring strain, it can exert
influences on ionization rates at least as powerfully as acyloxy
groups do in carbohydrate systems. The acceleration in the
rate of ionization exerted by the acyloxy group of acetal 59
(Figure 11) through neighboring-group participation was
(1R*,2R*)-2-Allylcyclopentanol (cis-15). Ester cis-19 (2.58 g,
11.2 mmol) in Et2O (112 mL) was added by cannula to a cooled
(0 °C) solution of LiAlH4 (0.890 g, 22.4 mmol) in Et2O (112 mL).
After 30 min, H2O (11.5 mL) was added, followed by NaOH (23 mL,
1.0 M in H2O) and H2O (35 mL) again. The layers were separated,
and the organic layer was washed with brine (200 mL), dried over
MgSO4, filtered, and concentrated in vacuo. Purification by flash
chromatography (10:90 EtOAc/hexanes) afforded alcohol cis-15 as a
1
yellow oil (1.18 g, 83%): H NMR (600 MHz, CDCl3) δ 5.91−5.84
(m, 1H), 5.08 (dq, J = 17.1, 1.7, 1H), 4.99 (ddt, J = 10.1, 2.1, 1.2, 1H),
4.18−4.16 (m, 1H), 2.30−2.25 (m, 1H), 2.20−2.14 (m, 1H), 1.88−
1.72 (m, 4H), 1.69−1.63 (m, 1H), 1.60−1.53 (m, 2H), 1.45−1.38 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 138.3 (CH), 115.2 (CH2), 74.7
(CH), 45.4 (CH), 34.8 (CH2), 33.9 (CH2), 28.9 (CH2), 22.0 (CH2);
IR (ATR) 3372, 1640, 989 cm−1; HRMS (TOF MS ES+) m/z calcd
for C8H18NO (M + NH4)+, 144.1383; found, 144.1392.
Figure 11. Related acetals.
determined to be 13-fold after correction for inductive effects.50
In the related acetal trans-6, which positions an oxygen atom at
the same distance (Figure 11), the alkoxy group accelerated the
rate of ionization by 33- to 67-fold after correction for inductive
effects. These results suggest that appropriate caveats should
be taken when it is assumed that an alkoxy group cannot
participate in the reactions of acetals.
((((1R*,2R*)-2-Allylcyclopentyl)oxy)methyl)benzene (cis-16).
NaH (1.12 g, 60% dispersion in mineral oil, 28.0 mmol) and BnBr
(1.3 mL, 11.0 mmol) were added to a solution of alcohol cis-15
(1.18 g, 9.34 mmol) in THF (19 mL), and the reaction mixture was
heated at 60 °C. After 14 h, saturated aqueous NH4Cl (20 mL) and
Et2O (40 mL) were added, the layers were separated, and the aqueous
layer was extracted with Et2O (2 × 40 mL). The combined Et2O layers
were washed with brine (120 mL), dried over MgSO4, filtered, and
concentrated in vacuo. Purification by flash chromatography (1:99
EtOAc/hexanes) afforded benzyl ether cis-16 as a colorless oil (2.05 g,
95%): 1H NMR (400 MHz, CDCl3) δ 7.36−7.30 (m, 4H), 7.29−7.25
(m, 1H), 5.83 (ddt, J = 17.2, 10.1, 7.2 1H), 5.03 (ddt, J = 17.1, 2.3, 1.5,
1H), 4.93 (ddt, J = 10.1, 2.2, 1.1, 1H), 4.55 (d, J = 12.1, 1H), 4.39 (d,
J = 12.1, 1H), 3.84 (td, J = 4.8, 2.6, 1H), 2.43−2.36 (m, 1H), 2.17−
2.09 (m, 1H), 1.90−1.81 (m, 2H), 1.79−1.65 (m, 3H), 1.60−1.42 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 139.5 (C), 138.9 (CH), 128.4
(CH), 127.5 (CH), 127.4 (CH), 114.8 (CH2), 81.7 (CH), 70.8
(CH2), 44.8 (CH), 33.7 (CH2), 30.6 (CH2), 29.2 (CH2), 21.8 (CH2);
IR (ATR) 1640, 1205, 1065 cm−1; HRMS (TOF MS ES+) m/z calcd
for C15H21O (M + H)+, 217.1587; found, 217.1592. Anal. Calcd for
C15H20O: C, 83.28; H, 9.32. Found: C, 83.04; H, 9.35.
((((1R*,2R*)-2-(2,2-Dimethoxyethyl)cyclopentyl)oxy)-
methyl)benzene (cis-5). Ozone was bubbled into a cooled (−78 °C)
solution of benzyl ether cis-16 (0.509 g, 2.35 mmol) in CH2Cl2
(12 mL) for 15 min. After stirring for 1 h at −78 °C, PPh3 (1.85 g,
7.06 mmol) was added, and the reaction mixture was brought to room
temperature. After 14 h, the reaction mixture was concentrated in
vacuo. Purification by flash chromatography (5:95 EtOAc/hexanes)
afforded an aldehyde as a colorless oil (0.309 g, 60%): 1H NMR
(600 MHz, CDCl3) δ 9.80 (t, J = 1.7, 1H), 7.34−7.32 (m, 2H), 7.30−
7.25 (m, 3H), 4.53 (d, J = 11.9, 1H), 4.32 (d, J = 11.9, 1H), 3.95−3.93
(m, 1H), 2.81 (ddd, J = 17.3, 7.5, 1.6, 1H), 2.49 (ddd, J = 17.3, 6.7, 1.7,
1H), 2.37−2.31 (m, 1H), 1.89−1.71 (m, 4H), 1.62−1.53 (m, 1H),
1.51−1.40 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 203.0 (CH),
139.0 (C), 128.4 (CH), 127.60 (CH), 127.56 (CH), 81.2 (CH), 70.8
(CH2), 44.1 (CH2), 38.8 (CH), 30.6 (CH2), 29.7 (CH2), 22.1 (CH2);
IR (ATR) 2953, 2869, 1720, 1205, 1064 cm−1; HRMS (TOF MS
ES+) m/z calcd for C14H18NaO2 (M + Na)+, 241.1199; found,
241.1194.
EXPERIMENTAL SECTION
The synthesis and characterization of compounds trans-5, trans-6,
trans-7, trans-8, 9, 10, trans-15−18, 45, 46, 48, 55, and 56 have been
reported previously.21
■
4-Benzyloxybutyraldehyde Dimethyl Acetal (11). To a
solution of 4-benzyloxy-1-butane (0.507 g, 2.81 mmol) in CH2Cl2
(14 mL) were added 3 Å molecular sieves (1.41 g), silica (1.33 g), and
pyridinium chlorochromate (1.22 g, 5.66 mmol). After stirring
overnight at room temperature, the reaction mixture was filtered
through diatomaceous earth and silica gel with Et2O (300 mL).
Concentration in vacuo yielded a clear oil (0.390 g). To this oil were
added anhydrous methanol (5 mL), 3 Å molecular sieves (1.09 g), and
concentrated H2SO4 (3 drops). After stirring overnight at room tem-
perature, the solids were removed by filtration. The resulting filtrate
was diluted with CH2Cl2 (125 mL), washed with saturated aqueous
NaHCO3 (2 × 100 mL) and brine (1 × 100 mL), dried over Na2SO4,
and concentrated in vacuo. Purification by silica gel thin-layer
chromatography (10:90 EtOAc/hexanes) afforded dimethyl acetal 11
1
as a clear oil (0.262 g, 40% over two steps): H NMR (400 MHz,
CDCl3) δ 7.37−7.29 (m, 5H), 4.53 (s, 2H), 4.40 (t, J = 5.4, 1H), 3.51
(t, J = 6.1, 2H), 3.33 (s, 6H), 1.74−1.69 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 138.7 (C), 128.5 (CH), 127.7 (CH), 127.6 (CH),
104.5 (CH), 73.0 (CH2), 70.1 (CH2), 52.9 (CH3), 29.4 (CH2), 25.0
(CH2); IR (ATR) 2940, 2856, 1102 cm−1; HRMS (TOF MS ES+)
m/z calcd for C13H20NaO3 (M + Na)+, 247.1310; found, 247.1311.
(1R*,2R*)-2-Allylcyclopentyl Benzoate (cis-19). To a cooled
(−40 °C) solution of PPh3 (0.736 g, 2.81 mmol) and PhCO2H (0.343
g, 2.81 mmol) in PhMe (8.5 mL) was added alcohol trans-15 (0.295 g,
2.34 mmol) in PhMe (1.7 mL). Diethyl azodicarboxylate (DEAD,
0.44 mL, 2.81 mmol) in PhMe (3 mL) was added dropwise over
5 min. After stirring for 1.5 h at −40 °C, the reaction mixture was
brought to room temperature. After 4 h, saturated aqueous NaHCO3
(15 mL) was added, the layers were separated, and the organic layer
was concentrated in vacuo. Purification by flash chromatography (2:98
EtOAc/hexanes) afforded ester cis-19 as a colorless oil (0.441 g, 82%):
1H NMR (600 MHz, CDCl3) δ 8.04−8.02 (m, 2H), 7.56−7.54 (m,
1H), 7.46−7.42 (m, 2H), 5.81 (ddt, J = 17.0, 10.1, 7.0, 1H), 5.41 (td,
J = 4.9, 1.4, 1H), 4.99 (ddt, J = 17.0, 2.0, 1.5, 1H), 4.94 (ddt, J = 10.1,
2.1, 1.1, 1H), 2.34 (quint of t, J = 7.0, 1.3, 1H), 2.19−2.14 (m, 1H),
2.07−2.00 (m, 2H), 1.94−1.82 (m, 3H), 1.69−1.62 (m, 1H), 1.61−
1.54 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 166.2 (C), 137.6
(CH), 132.9 (CH), 131.0 (C), 129.6 (CH), 128.5 (CH), 115.5 (CH2),
To the aldehyde (0.282 g, 1.29 mmol) in MeOH (6 mL) were
added HC(OMe)3 (1.4 mL, 13 mmol) and H2SO4 (1 drop). After 4 h,
saturated aqueous NaHCO3 (6 mL) and CH2Cl2 (15 mL) were added,
and the layers were separated. The organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. Purification by flash
chromatography (1:5:94 Et3N/EtOAc/hexanes) afforded dimethyl
acetal cis-5 as a yellow oil (0.271 g, 80%): 1H NMR (500 MHz,
CDCl3) δ 7.34−7.31 (m, 4H), 7.28−7.24 (m, 1H), 4.57 (d, J = 12.1,
1H), 4.36 (t, J = 6.0, 1H and d, J = 12.2, 1H), 3.82 (td, J = 4.7, 2.1,
1H), 3.30 (s, 3H), 3.29 (s, 3H), 1.95 (ddd, J = 13.7, 6.9, 6.0, 1H),
H
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1.89−1.83 (m, 2H), 1.82−1.63 (m, 4H), 1.60−1.53 (m, 1H), 1.50−
1.44 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 139.3 (C), 128.4
(CH), 127.6 (CH), 127.4 (CH), 104.2 (CH), 81.6 (CH), 70.5 (CH2),
52.9 (CH3), 52.7 (CH3), 40.8 (CH), 31.9 (CH2), 30.5 (CH2), 29.6
(CH2), 22.0 (CH2); IR (ATR) 2828, 1193, 1123, 1059 cm−1; HRMS
(TOF MS ES+) m/z calcd for C16H24NaO3 (M + Na)+, 287.1618;
found, 287.1625. Anal. Calcd for C16H24O3: C, 72.69; H, 9.15. Found:
C, 72.93; H, 9.06.
((((1R*,2R*)-2-(2,2-Dimethoxyethyl)cyclohexyl)oxy)methyl)-
benzene (cis-6). Ozone was bubbled into a cooled (−78 °C) solution
of benzyl ether cis-21 (0.561 g, 2.43 mmol) in CH2Cl2 (12 mL) for
15 min. After stirring for 1 h at −78 °C, PPh3 (1.90 g, 7.29 mmol) was
added, and the reaction mixture was brought to room temperature.
After 14 h, the reaction mixture was concentrated in vacuo.
Purification by flash chromatography (5:95 EtOAc/hexanes) afforded
1
an aldehyde as a colorless oil (0.217 g, 38%): H NMR (400 MHz,
CDCl3) δ 9.74 (t, J = 1.9, 1H), 7.36−7.31 (m, 4H), 7.29−7.26 (m,
1H), 4.58 (d, J = 11.9, 1H), 4.35 (d, J = 11.9, 1H), 3.56−3.52 (m, 1H),
2.63 (ddd, J = 16.9, 6.4, 1.7, 1H), 2.37 (ddd, J = 16.8, 6.8, 2.2, 1H),
2.28−2.20 (m, 1H), 1.94−1.86 (m, 1H), 1.66−1.54 (m, 3H), 1.49−
1.30 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 203.0 (CH), 139.1
(C), 128.4 (CH), 127.7 (CH), 127.6 (CH), 76.4 (CH), 70.3 (CH2),
46.1 (CH2), 35.7 (CH), 28.3 (CH2), 27.8 (CH2), 24.5 (CH2), 21.2
(CH2); IR (ATR) 2928, 2856, 1720, 1206, 1059 cm−1; HRMS (TOF
MS ES+) m/z calcd for C15H20NaO2 (M + Na)+, 255.1361; found,
255.1356.
To the aldehyde (0.157 g, 0.677 mmol) in MeOH (7 mL) were
added HC(OMe)3 (0.74 mL, 6.80 mmol) and H2SO4 (1 drop), and
the reaction mixture was stirred for 4 h. Saturated aqueous NaHCO3
(7 mL) and CH2Cl2 (15 mL) were added, and the layers were
separated. The organic layer was dried over MgSO4 and concentrated
in vacuo. Purification by flash chromatography (1:10:89 Et3N/EtOAc/
hexanes) afforded dimethyl acetal cis-6 as a yellow oil (0.154 g, 82%):
1H NMR (600 MHz, CDCl3) δ 7.37−7.31 (m, 4H), 7.27−7.24 (m,
1H), 4.59 (d, J = 11.9, 1H), 4.38 (d, J = 12.0, 1H and t, J = 6.0, 1H),
3.51 (dt, J = 5.1, 2.6, 1H), 3.279 (s, 3H), 3.275 (s, 3H), 1.97−1.94 (m,
1H), 1.80 (dt, J = 14.0, 6.2, 1H), 1.71−1.66 (m, 1H), 1.64−1.50 (m,
4H), 1.44−1.26 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 139.5 (C),
128.4 (CH), 127.7 (CH), 127.4 (CH), 103.3 (CH), 76.6 (CH), 70.1
(CH2), 52.8 (CH3), 52.5 (CH3), 36.9 (CH), 34.2 (CH2), 28.4 (CH2),
27.8 (CH2), 25.0 (CH2), 21.2 (CH2); IR (ATR) 2855, 1193,
1027 cm−1; HRMS (TOF MS ES+) m/z calcd for C17H26NaO3 (M +
Na)+, 301.1775; found, 301.1780. Anal. Calcd for C17H26O3: C, 73.34;
H, 9.41. Found: C, 73.28; H, 9.51.
2-((1R*,2S*)-2-(Benzyloxy)cyclooctyl)ethanol (49). An alde-
hyde was prepared from alkene 48 using methods previously
reported.21 NaBH4 (0.144 g, 3.81 mmol) was added in portions to
the aldehyde (0.331 g, 1.27 mmol) in anhydrous MeOH (12.7 mL) at
0 °C. The reaction mixture stirred for 24 h at room temperature
(23 °C). H2O (13 mL) and Et2O (26 mL) were added, and the layers
were separated. The organic layer was washed with H2O (2 × 26 mL),
dried over MgSO4, filtered, and concentrated in vacuo. The product
was purified by flash chromatography (10:90 EtOAc/hexanes) to
afford the alcohol as a yellow oil (0.208 g, 63%, over two steps from
alkene 48): 1H NMR (400 MHz, CDCl3) δ 7.36−7.34 (m, 4H), 7.33−
7.27 (m, 1H), 4.61 (d, J = 11.2, 1H), 4.35 (d, J = 11.2, 1H), 3.71−3.57
(m, 2H), 3.32−3.28 (m, 1H), 2.22 (br s, 1H), 1.93−1.74 (m, 5H),
1.73−1.62 (m, 4H), 1.60−1.51 (m, 1H), 1.47−1.34 (m, 4H), 1.31−
1.22 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 138.4 (C), 128.6
(CH), 128.3 (CH), 127.8 (CH), 84.4 (CH), 70.8 (CH2), 61.6 (CH2),
39.8 (CH), 37.8 (CH2), 28.9 (CH2), 28.6 (CH2), 26.6 (CH2), 26.3
(CH2), 26.1 (CH2), 25.9 (CH2); IR (ATR) 3382, 1357, 1089, 1062 cm−1;
HRMS (TOF MS ES+) m/z calcd for C17H26NaO2 (M + Na)+, 285.1830;
found, 285.1825. Anal. Calcd for C17H26O2: C, 77.82; H, 9.99. Found: C,
77.66; H, 10.18.
(1R*,2R*)-2-Allylcyclohexyl Benzoate (cis-20). Following a
procedure by Hon and co-workers,74 a solution of alcohol trans-18
(2.74 g, 19.6 mmol) in PhMe (14 mL) was added to a cooled
(−40 °C) solution of PPh3 (6.15 g, 23.5 mmol) and PhCO2H (2.87 g,
23.5 mmol) in PhMe (80 mL). DEAD (3.70 mL, 23.5 mmol) in PhMe
(25 mL) was then added dropwise over 20 min. After stirring for 1.5 h
at −40 °C, the reaction mixture was brought to room temperature.
After 13.5 h, saturated aqueous NaHCO3 (100 mL) was added, and
the layers were separated. The organic layer was washed with
NaHCO3 (100 mL) and H2O (100 mL), dried over MgSO4, filtered,
and concentrated in vacuo. The unpurified compound was passed
through a plug of silica gel (3:97 EtOAc/hexanes) and used without
further purification to afford compound cis-20 as a colorless oil (2.20 g,
46% unpurified yield): 1H NMR (400 MHz, CDCl3) δ 8.09−8.06 (m,
2H), 7.59−7.54 (m, 1H), 7.49−7.44 (m, 2H), 5.78 (ddt, J = 17.3, 10.2,
7.1, 1H), 5.29−5.25 (m, 1H), 4.99−4.92 (m, 2H), 2.16 (quint of t, J =
6.9, 1.0, 1H), 2.09−1.98 (m, 2H), 1.81−1.75 (m, 1H), 1.72−1.63 (m,
2H), 1.61−1.52 (m, 4H), 1.41−1.30 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 166.0 (C), 136.8 (CH), 132.9 (CH), 131.1 (C), 129.7
(CH), 128.5 (CH), 116.3 (CH2), 72.7 (CH), 40.6 (CH), 37.1 (CH2),
30.4 (CH2), 27.6 (CH2), 25.3 (CH2), 21.2 (CH2); HRMS (TOF MS
ES+) m/z calcd for C16H20NaO2 (M + Na)+, 267.1361; found,
267.1356.
(1R*,2R*)-2-Allylcyclohexanol (cis-18). To a cooled (0 °C)
solution of LiAlH4 (0.700 g, 17.4 mmol) in Et2O (87 mL) was added
ester cis-20 (2.13 g, 8.72 mmol) in Et2O (87 mL) by cannula. After
40 min, H2O (10 mL) was added, followed by NaOH (20 mL, 1.0 M
in H2O) and then H2O (30 mL). The layers were separated, and the
organic layer was washed with brine (180 mL), dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash chromatog-
raphy (10:90 EtOAc/hexanes) afforded alcohol cis-18 as a colorless oil
1
(0.910 g, 75%): H NMR (600 MHz, CDCl3) δ 5.81 (ddt, J = 17.2,
10.1, 7.1, 1H), 5.05 (ddt, J = 17.0, 2.2, 1.5, 1H), 5.00 (ddt, J = 10.1,
2.2, 1.0, 1H), 3.91−3.87 (m, 1H), 2.16 (quint of t, J = 7.1, 1.2, 1H),
2.02 (quint of t, J = 7.3, 1.2, 1H), 1.80−1.76 (m, 1H), 1.68−1.63 (m,
1H), 1.59−1.54 (m, 1H), 1.53−1.47 (m, 1H), 1.46−1.41 (m, 2H),
1.40−1.34 (m, 1H), 1.33−1.30 (m, 1H), 1.28−1.21 (m, 1H); 13C
NMR (150 MHz, CDCl3) δ 137.6 (CH), 115.9 (CH2), 69.2 (CH),
41.4 (CH), 36.8 (CH2), 33.2 (CH2), 26.5 (CH2), 25.3 (CH2), 20.6
(CH2); HRMS (TOF MS ES+) m/z calcd for C9H17O (M + H)+,
141.1279; found, 141.1274.
((((1R*,2R*)-2-Allylcyclohexyl)oxy)methyl)benzene (cis-21).
NaH (0.780 g, 60% dispersion in mineral oil, 19.5 mmol) and BnBr
(0.930 mL, 7.89 mmol) were added to a solution of alcohol cis-18
(0.910 g, 6.49 mmol) in THF (13 mL). The reaction mixture was
heated at 60 °C for 14 h. Saturated aqueous NH4Cl (15 mL) and Et2O
(30 mL) were added to the reaction mixture, and the layers were
separated. The aqueous layer was extracted with Et2O (2 × 30 mL),
and the combined organic layers were washed with brine (90 mL),
dried over MgSO4, and concentrated in vacuo. Purification by flash
chromatography (1:99 EtOAc/hexanes) afforded benzyl ether cis-21 as
2-((1R*,2S*)-2-(Benzyloxy)cyclooctyl)ethyl 4-methylbenze-
nesulfonate (47). p-TsCl (0.729 g, 3.83 mmol) was added to
alcohol 49 (0.502 g, 1.91 mmol) in pyridine (3.3 mL) at 0 °C, and the
reaction mixture was stirred until the solids dissolved. The reaction
mixture was then stored in the freezer (−22 °C) for 2 days. The
resulting needles were filtered off. The filtrate solution was poured into
ice water, and Et2O (6 mL) was added to the solution. The layers were
separated, and the aqueous phase was extracted with Et2O (2 × 6 mL).
The combined organic layers were washed with H2O (18 mL), dried
over MgSO4, filtered, and concentrated in vacuo. The unpurified
mixture of tosylate 47 contained cyclic ether 57, benzyl tosylate,
and unreacted p-TsCl. The tosylate was not stable to chromato-
graphy and was used unpurified for future experiments (0.498 g, 62%
1
a colorless oil (1.41 g, 95%): H NMR (400 MHz, CDCl3) δ 7.38−
7.32 (m, 4H), 7.29−7.24 (m, 1H), 5.78 (ddt, J = 17.1, 10.1, 7.1, 1H),
5.04−5.01 (m, 1H), 4.99−4.95 (m, 1H), 4.59 (d, J = 11.9, 1H), 4.39
(d, J = 11.9, 1H), 3.58−3.54 (m, 1H), 2.30−2.23 (m, 1H), 2.09−2.02
(m, 1H), 2.00−1.94 (m, 1H), 1.68−1.47 (m, 4H), 1.44−1.22 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 139.7 (C), 138.2 (CH), 128.4 (CH),
127.6 (CH), 127.3 (CH), 115.5 (CH2), 76.4 (CH), 70.3 (CH2), 41.3
(CH), 36.2 (CH2), 28.7 (CH2), 27.3 (CH2), 25.1 (CH2), 21.2 (CH2);
HRMS (TOF MS ES+) m/z calcd for C16H22NaO (M + Na)+,
253.1568; found, 253.1563. Anal. Calcd for C16H22O: C, 83.43; H,
9.63. Found: C, 83.52; H, 9.57.
I
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1
unpurified yield): H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 8.3,
ASSOCIATED CONTENT
■
2H), 7.35−7.31 (m, 2H), 7.29−7.26 (m, 5H), 4.54 (d, J = 11.4, 1H),
4.25 (d, J = 11.4, 1H), 4.10−4.06 (m, 2H), 3.19−3.16 (m, 1H), 2.42
(s, 3H), 2.06−2.00 (m, 1H), 1.84−1.80 (m, 2H), 1.79−1.74 (m, 1H),
1.66−1.50 (m, 7H), 1.42−1.35 (m, 2H), 1.34−1.22 (m, 4H).
Experimental integration values below δ 2.0 ppm for tosylate 47 are
slightly higher than expected due to overlapping peaks from cyclic
ether 57, which was present in an 88:12 ratio with tosylate 47, as the
minor product: 13C NMR (150 MHz, CDCl3) δ 144.6 (C), 138.7 (C),
133.4 (C), 129.9 (CH), 128.5 (CH), 127.99 (CH), 127.97 (CH),
127.6 (CH), 83.6 (CH), 70.8 (CH2), 70.2 (CH2), 39.5 (CH), 33.2
(CH2), 28.6 (CH2), 27.6 (CH2), 26.4 (CH2), 26.3 (CH2), 25.9 (CH2),
25.2 (CH2), 22.0 (CH3); IR (ATR) 1595, 1358, 1172 cm−1; HRMS
(TOF MS ES+) m/z calcd for C24H32NaO4S (M + Na)+, 439.1919;
found, 439.1914.
S
* Supporting Information
General experimental procedures, NMR spectroscopic data for
all new compounds, and kinetic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kwoerpel@nyu.edu.
Present Address
†(W.A.S.) Bridgestone Americas Center for Research and
Technology, 1659 South Main Street, Akron, Ohio 44301,
United States.
Characterization of Solvolysis Products. General procedures
for the isolation of solvolysis products and characterization of the
products from solvolysis of tosylate 46 (eq 5) have previously been
reported (see the Supporting Information).21
Notes
The authors declare no competing financial interest.
1
Products from Equation 4. H NMR spectroscopic analysis of
ACKNOWLEDGMENTS
the unpurified reaction mixture showed a 1:0.80:0.61 ratio of 53 to
tosylate starting material 45 to cyclic ether 54. The listed spectroscopic
data for the cyclic ether 54 was obtained using the unpurified reaction
mixture, which also contained benzyl acetate and benzyl tosylate.
Experimental integration values for 54 are higher than expected due
to overlapping peaks of acetate 53, tosylate starting material (45),
and possible impurities from the reaction mixture. The following
was obtained by referencing the integration of acetate 53 to 1:
(3aR*,6aS*)-Hexahydro-2H-cyclopenta[b]furan (54): 1H NMR
(400 MHz, CDCl3) δ 4.15−4.02 (m, 5.4H), 1.98−1.78 (m, 10.9H),
1.75−1.48 (m, 12.7H), 1.26−1.06 (m, 3.6H); 13C NMR (125 MHz,
CDCl3) δ 81.2 (CH), 66.0 (CH2), 42.4 (CH), 32.7 (CH2), 32.4
(CH2), 31.8 (CH2), 31.7 (CH2); HRMS (TOF MS ES+) m/z calcd
for C7H13O (M + H)+, 113.0966; found, 113.0961. 2-((1R*,2S*)-2-
(Benzyloxy)cyclopentyl)ethyl acetate (53): The spectral data (1H
NMR and 13C NMR) are consistent with the data reported for the
authentic acetate 53 shown below. The spectral data for benzyl acetate
and benzyl tosylate are consistent with the reported data (1H NMR
and 13C NMR).75,76
■
This research was supported by the National Institutes of
Health, National Institute of General Medical Sciences (GM-
61066). D.A.L.O acknowledges the Margaret Strauss Kramer
Fellowship. We thank Lisa Barker for intellectual contributions
made during the initial phases of this work and Dr. Chin Lin
(NYU) for assistance with NMR spectroscopy and mass
spectrometric data. We also thank the NYU High Performance
Computing Service for access to its computational resources.
REFERENCES
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DOI: 10.1021/acs.joc.5b00338
J. Org. Chem. XXXX, XXX, XXX−XXX