Investigation of quantitative structure-reactivity relationships in the aliphatic Claisen rearrangement of bis-vinyl ethers reveals a dipolar, dissociative mechanism

Article abstract of DOI:10.1039/c3ob42011f

Kinetic investigations of substituent effects in the thermal rearrangement of bis-vinyl ether substrates are reported. Findings indicate that the influence of the various substituent patterns on the rate of rearrangement in these compounds differs from that documented in the literature for the analogous [3,3]-sigmatropic rearrangement of allyl vinyl ethers. In addition, the thermochemical data collected suggests the existence of a dissociative transition state with significant dipolar character. These findings provide a unique contribution to the already extensive body of literature dedicated to mechanistic investigation of the Claisen rearrangement of aliphatic allyl vinyl ethers.

Full text of DOI:10.1039/c3ob42011f

Organic &
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PAPER
Investigation of quantitative structure–reactivity
relationships in the aliphatic Claisen
rearrangement of bis-vinyl ethers reveals a dipolar,
dissociative mechanism†
Cite this: Org. Biomol. Chem., 2014,
12, 1292
Natasha F. O’Rourke and Jeremy E. Wulff*
Kinetic investigations of substituent effects in the thermal rearrangement of bis-vinyl ether substrates are
reported. Findings indicate that the influence of the various substituent patterns on the rate of rearrange-
ment in these compounds differs from that documented in the literature for the analogous [3,3]-sigma-
tropic rearrangement of allyl vinyl ethers. In addition, the thermochemical data collected suggests the
existence of a dissociative transition state with significant dipolar character. These findings provide a
unique contribution to the already extensive body of literature dedicated to mechanistic investigation of
the Claisen rearrangement of aliphatic allyl vinyl ethers.
Received 6th October 2013,
Accepted 18th December 2013
DOI: 10.1039/c3ob42011f
www.rsc.org/obc
Introduction
The development of the Claisen rearrangement (and variants
thereof) over the past century has unambiguously demon-
strated the power and synthetic utility of this deceptively
simple transformation.1–6 While the regio- and stereoselective
formation of new carbon–carbon bonds in this manner has
been widely accepted to occur through a concerted, albeit
asynchronous,7–10 bond reorganization process via a six-
membered cyclic transition state,11,12 many details about the
reaction trajectory remain elusive (Fig. 1). Most notably,
substituent effects on the rate of Claisen rearrangement have
often afforded contradictory interpretations of what the tran-
sition-state structure may look like (be it diradical13–21 or
dipolar21–23 in nature) and theoretical predictions are not
always consistent with experimental results.15,17,24 For these
reasons, substituent17,18,22,25–41 and solvent effects27,42–44 have
been thoroughly investigated over the past three decades in
order to elucidate the mechanistic details of the rearrange-
ment and, more specifically, the nature and geometry of the
transition-state structure. Although the precise electronic
structure of the transition state presumably varies somewhat
with changing substitution patterns on the allyl vinyl ether
scaffold, there is general consensus as to the highly organized
Fig. 1 Mechanistic options for the aliphatic Claisen rearrangement, and
a summary of known substituent effects.
nature of the transition structure itself, consistent with a
significant negative ΔS‡ (vide infra).
For the past few years, our research group has been
interested in the iterative synthesis and synthetic exploitation
of oligo-vinyl ethers (Fig. 2).45–47 As part of this research
program, we have had ample opportunity to observe the
propensity – or lack thereof – for bis-vinyl ether substrates
to undergo Claisen rearrangement. Bis-vinyl ethers are
structurally related to the allyl vinyl ethers summarized in
Fig. 1 (differing only in the presence of an additional oxygen
atom at C-6) but the influence of substitution on their
Department of Chemistry, University of Victoria, Victoria, BC, Canada, V8W 3V6.
E-mail: wulff@uvic.ca
†Electronic supplementary information (ESI) available: 1H NMR and 13C NMR
spectra for all new compounds, as well as Eyring and Arrhenius plots used to
determine thermodynamic properties. See DOI: 10.1039/c3ob42011f
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Fig. 2 Iterative synthesis of oligo-vinyl ethers, and synthetic applications.
Fig. 3 Reactivity of bis-vinyl ethers toward Claisen rearrangement. A:
summary of Claisen rearrangement substituent effects observed from
our earlier bis-vinyl ether studies; B: two plausible mechanistic possibili-
ties for the rearrangement.
ability to undergo Claisen rearrangement has not been exten-
sively studied, notwithstanding some significant early contri-
butions by the Curran22,31,48–50 and Augé51,52 groups.
In our early studies in this area, we were surprised to find
that the substituent effects for our bis-vinyl ethers appeared to
differ from those described previously for the analogous allyl
vinyl ethers. For instance, in a series of compounds that we
prepared as mimics of insect juvenile hormones (Fig. 2), we
found that the presence of an electron-withdrawing ester func-
tion at the terminus of the bis-vinyl ether system enabled the
compounds to undergo a facile Claisen rearrangement at low
temperature.45 This, combined with the ability of the Claisen
products to undergo further decomposition (mostly through
elimination) to afford volatile byproducts, led us to propose
that such compounds might be useful as ecologically degrad-
able insect control agents.45
By contrast, compounds in which the electron-withdrawing
group was absent were relatively resistant to Claisen rearrange-
ment, such that they could be used as substrates for high-
temperature radical cascade reactions.46,47 The fact that the
addition of an electron-withdrawing substituent at C-1 (allyl
vinyl ether numbering) resulted in such a dramatic increase in
the rate of Claisen rearrangement was surprising, given that
previous studies for allyl vinyl ether systems27,30,32,33,38 had
shown that electron donating groups at C-1 increased the rate
of rearrangement, while electron withdrawing groups actually
stabilized the substrates.25,37
This early indication that bis-vinyl ethers might undergo
Claisen rearrangement through a fundamentally different
mechanism than most other allyl vinyl ethers was further sup-
ported by a careful study of the stabilities of our variously sub-
stituted juvenile hormone mimics (Fig. 3A). As we reported
previously,45 the rate of Claisen rearrangement was greatly
enhanced by the addition of an electron-withdrawing CF3
group at C-2 (to such an extent that most such products could
not be isolated), but this propensity to undergo rearrangement
could be completely mitigated by the installation of a second
CF3 function at C-6 (to the point where <20% Claisen
rearrangement was observed after 14 days of incubation at
37 °C). These data suggested that the rearrangement was pro-
moted by a “push–pull” mechanism (Fig. 3B) where the elec-
tron-rich half of the bis-vinyl ether system (C-4 to C-6) acted to
stabilize a (partial) positive charge, while the more electron-
poor half of the system (C-1 to O-3) acted to stabilize a
(partial) negative charge. This description of the reactivity of
bis-vinyl ethers is reminiscent of Curran’s earlier postulated
“vinylogous anomeric” effect to describe the role of the C-6
oxygen,31,50 but goes further in rationalizing substituent
effects at C-1 and C-2.53
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The implications of this “push–pull” hypothesis for bis- previous studies45,46 that aromatic groups were not well-tole-
vinyl ethers are significant. First, it suggests the possibility rated at RB (see Fig. 2 and 3 for labelling), we elected to install
that – if a full charge separation can be supported – bis-vinyl a series of substituted aromatic rings at RA. Similarly, we chose
ethers may rearrange through a fully dissociated dipolar mech- to focus most of our efforts on bis-vinyl ether systems that
anism, which is distinct from that observed for other allyl vinyl were terminated in an ester, since we knew these substrates to
ethers. Reasoning that such a distinct mechanism would have rearrange at accessible temperatures. For the alcohol that we
implications for the thermodynamic properties associated used to initiate the iterative synthesis (ROH in Fig. 2), we
with the rearrangement (particularly the ΔS‡), we undertook chose 2,2-dimethylpropanol, since the neopentyl group (Np)
to more extensively study the thermally induced Claisen has few signals to complicate the NMR spectra, yet contains
rearrangement of substituted bis-vinyl ethers by variable temp- sufficient mass to render the various synthetic intermediates
erature NMR methods.
non-volatile. Compounds 5a–5g (Table 1) therefore became our
primary target for synthesis.
Each of these compounds was accessed efficiently, using
the addition/reduction/addition sequence that we developed
previously. A broad selection of functional groups (X) on the
Results and discussion
In designing our substrates for this study, we looked to identify aryl ring was well-tolerated, allowing us to access substrates
incorporating functionality ranging from very electron-rich
a family of compounds where:
(1) we could systematically vary the electronic properties for (e.g. p-CH3O, entry 1) to very electron-poor (e.g. p-CF3, entry 8).
at least one of the vinyl ether motifs in the bis-vinyl ether For most substrates, a methyl group was placed in the RB posi-
tion, although we also prepared one compound (5c, entry 3)
lacking this substituent, for comparative purposes. We also
system, in the hopes that subsequent Hammett analysis would
shed further light on the mechanism of the reaction;
(2) the substrates would undergo Claisen rearrangement at synthesized a deuterated analogue (5b-d2, entry 4) with which
to carry out kinetic isotope experiments.
a temperature that was consistent with study by variable-temp-
erature NMR spectroscopy, in order to measure the ΔS‡ for the
rearrangement;
With all of the desired substrates in hand, we studied their
rate of Claisen rearrangement by variable-temperature NMR
spectroscopy. Each compound was allowed to rearrange at 4
different temperatures (see Table 2 for temperature ranges;
(3) few overlapping signals would be present in the 1H NMR
spectrum; and
(4) the substrates could be made using our existing iterative each substrate was measured at 130 °C to provide a direct
point of comparison, as well as at 3 other temperatures chosen
to provide an analytically feasible data set), in bromobenzene-
protocols, and would be stable enough to isolate and charac-
terize, prior to their use in NMR studies.
We recognized that an aromatic substituent at either C-2 or d5 containing hexamethylbenzene as an internal standard.
Significantly, each of the rearrangements produced a ∼1 : 1
C-6 would be ideal for the purpose of systematically varying
the electronic properties of the substrates. Since we knew from ratio of diastereomeric products. While we recognized the
Table 1 Synthesis of substrates for VT-NMR studiesa
Entry
X
RB
1st addition yield (E : Z)
Reduction yield (E : Z)
4a 97% (18 : 1)
4b 82% (20 : 1)
4b 82% (20 : 1)
4b-d2 75% (14 : 1)
4d 98% (>20 : 1)
2nd addition yield (E : Z)b
1
2
3
4c
5
6
7
8
CH3O
CH3
CH3
CH3
H
F
Cl
CH3
CH3
H
CH3
CH3
CH3
CH3
CH3
3a 94% (15 : 1)
3b 99% (17 : 1)
3b 99% (17 : 1)
3b 99% (17 : 1)
3dd 94% (>20 : 1)
3e 82% (13 : 1)
3f 89% (13 : 1)
3g 78% (>20 : 1)
5a
5b 100% (9 : 1)
5c 100% (9 : 1)
99% (9 : 1)
5b-d2 97% (8 : 1)
5d 98% (9 : 1)
4e
4f
4g
88% (14 : 1)
99% (15 : 1)
86% (>20 : 1)
5e
5f
5g
87% (7 : 1)
82% (8 : 1)
99% (11 : 1)
CF3
a Conditions: (i) CH2Cl2, 0 to 23 °C, 16 h. (ii) Et2O, −78 to −40 °C, 4 h. b For compounds with more than one vinyl ether, the E : Z ratio refers to
the ratio of all E-product to all other adducts. c Compound 5b was deuterated at the 4-position, by employing LiAlD4 in place of DIBAL-H in the
reduction step. d The methyl ester was used in place of the ethyl ester for this step.
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Table 2 Rate constants, relative rates, and activation parameters for
rearrangement of bis-vinyl ethers in bromobenzene-d5
k at 130 °Cb
ΔG‡c,d
Compound
X
T (°C)a
(×10−6 s−1
)
krel
(kcal mol−1
)
5a
5b
5d
5e
5f
CH3O
CH3
H
F
Cl
100–130
110–140
115–130
115–140
120–145
130–145
783
373
237
212
114
51.0
3.3
1.6
1.0
0.9
0.5
0.2
29.5
30.1
30.5
30.6
31.1
31.7
5g
CF3
a Temperature range of kinetic measurements ( 1 °C); a range of
25–30 °C was used, except in cases where this led to problematic
decomposition, or where the solvent could not accommodate such a
large range. b The rate of rearrangement for compounds 5b, 5c, 5b-d2
and 19 was measured multiple times at a fixed temperature (see
Table 6); in each case the standard deviation was less than 10%.
A maximum error of 10% is therefore assigned to all rates. c ΔG‡ at
130 °C, calculated using the Eyring equation from the observed rate of
rearrangement. d A maximum error of 10% in the rate of the reaction
corresponds to a maximum error of 0.1 kcal mol−1 in the ΔG‡.
possibility that the rearrangement products, 6, could be prone
to epimerization under the reaction conditions, this obser-
vation provided the first suggestion that a dissociative tran-
sition state might be involved in the rearrangement.
Fig. 4 Hammett plots for the rate of rearrangement of compounds 5,
plotted against different σ values (derived from either polar or radical
Analysis of the rate of reaction was complicated somewhat reactions) to probe mechanism.
by the fact that E,E-5 can undergo partial isomerization to
afford mixtures of E,E; E,Z; Z,E; and Z,Z isomers at these temp-
eratures (though not to an extent that would account for the polar transition state). We hoped to find a large difference
observed mixture of diastereomeric products54), as well as by between the quality of these fits, which would therefore
the fact that the Claisen product 6 can undergo further decompo- provide important information about the nature (and relative
sition. Nonetheless, when these factors were properly accounted spin density) of the transition state under study here.
for (refer to the Experimental section for details of the NMR ana-
To this end, log(kX/kH) was plotted against: (1) Arnold’s
lysis), the rates and energies of activation for the rearrangements σα• parameters based on EPR hyperfine coupling of benzyl rad-
•
could be accurately calculated (see Table 2 for values).
icals (Fig. 4A);55 (2) Creary’s σC parameters taken from the
As shown in Table 2, the presence of electron-donating rearrangement of methylenecyclopropane systems (Fig. 4B);56,57
•
groups on the aromatic ring enhanced the rate of rearrangement (3) Jiang and Ji’s σjj parameters measured from the cyclo-
(relative to phenyl-substituted compound 5d), while electron- dimerization of trifluorostyrenes (Fig. 4C);58,59 (4) Hammett’s
withdrawing groups impeded the reaction. Looking to further original σp parameters based on ionization of para-substituted
quantify the influence of electronics on the rearrangement, benzoic acids (Fig. 4D);60 and (5) Brown’s σp parameters
+
the rate data from Table 2 was plotted against a variety of based on solvolysis of substituted t-cumyl chlorides (Fig. 4E).61
Hammett parameters available from the literature. Our objec-
All of the radical-based Hammett parameters provided a
tive in this exercise was to identify which set of parameters pro- very poor correlation (R2 < 0.5) to the data obtained for the rate
vided the best fit to our experimental data. We were of rearrangement of bis-vinyl ethers 5 at 130 °C. By contrast,
particularly interested in comparing the fit for Hammett para- using either set of σ values derived from polar reactions (σp or
meters derived from radical reactions (which therefore report σp+) provided an excellent fit to the data (R2 = 0.97 in both
the substituents’ ability to stabilize a radical-type transition cases). Attempts to use dual correlations incorporating both
state) to those parameters derived from polar reactions (and radical- and polar-stabilizing effects, as described by Kim,62
which therefore report the substituents’ ability to stabilize a only worsened the degree of fit. Interestingly, the best fit
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(R2 = 0.99, Fig. 4F) came from plotting our rate data against the
sum of σp and σp . While precedented by the work of both Brown61
+
and Kim,62 we stress that the “blending” of σ parameters
employed here is strictly empirical, and that the fit in Fig. 4F
is not necessarily any more meaningful than that in 4D or 4E.
At the same time, this approach may be justified if one con-
siders that the original Hammett values over-emphasize induc-
tive effects at the expense of resonance contributions, while
the values calculated by Brown may be said to incorporate reso-
nance effects to a greater degree than might be reasonable in
this case.63 In any event, the data in Fig. 4 clearly argue against
the involvement of a diradical-type transition state, and
strongly support the existence of a highly polarized transition
state.
The measured ρ values are −1.4 for Fig. 4D, and −0.87 for
Fig. 4E. These values indicate that a substantial degree of posi-
tive charge is associated with the C-6 carbon atom in the tran-
sition state, but do not necessarily indicate whether or not the
reaction is fully dissociative.64 In order to more fully probe the
degree of organization in the transition state, we sought to
examine the change in ΔG‡ with temperature, as a probe
for ΔS‡.
Fig. 5 Change in ΔG‡ with temperature for bis-vinyl ethers 5 and 13.
Coloured data points correspond to measurements for compounds 5a–
5g (see legend in Fig. 4 for details). Black data points correspond to
measurements for compound 13. Inset plot shows the change in ΔG‡ (in
units of kcal mol−1) for all aryl-substituted compounds, relative to the
measured ΔG‡ at 130 °C.65
rearrange through a dissociated transition state prompted us
to consider the ΔS‡ for our system, with the hypothesis that a
more dissociative transition state would be revealed by the
presence of an atypically positive (i.e., less negative) ΔS‡.66
As shown in Fig. 5, for each of the bis-vinyl ether esters
examined, the ΔG‡ remains constant, within experimental
error. Since the slope of ΔG‡ vs. temperature must correspond
to −ΔS‡, this indicates that the entropy of activation must be
small. Indeed, each of the coloured lines in Fig. 5 (corres-
ponding to best fits through the raw data for compounds 5a–
5g) has a slope of less than 5 cal K−1 mol−1 – suggestive of a
less negative ΔS‡ than for any of the compounds indicated in
Table 3.
A survey of the literature for the aliphatic Claisen rearrange-
ment of simpler allyl vinyl ethers (e.g., 7–10, Table 3) demon-
strates that the rearrangement of most such compounds –
even those containing an oxygen atom at C-6, like compound
10 – proceeds with a significant negative entropy of activation,
indicative of a highly ordered, associative transition state. The
experimental indications that bis-vinyl ether esters 5 might
Table 3 Kinetic data and activation parameters for rearrangements of
oxygen-substituted allyl vinyl ethers
Canonical determination of ΔS‡ by Eyring analysis was
somewhat complicated by the fact that for some of our com-
pounds (5a, 5b, and 5f) overlap of characteristic NMR signals
used for kinetic analysis (see Experimental for details) pre-
vented accurate integration. This necessarily led to small
uncertainties in the rates, which in turn led to Eyring plots
with less than perfect fits (R2 = 0.98 or below; refer to the ESI†
for Eyring and Arrhenius plots). Because determination of ΔS‡
by this method requires that one extrapolate far outside of
one’s data points to obtain the intercept, this led to unsatisfac-
tory errors in the determination of the activation entropy. For
each of these three substrates, the calculated range for ΔS‡
encompassed 0 cal K−1 mol−1 (suggesting, at least, that the
actual value is small), but the calculated uncertainty (based on
the standard error of the intercept) associated with these
ka
ΔH‡
ΔS‡
Compound
(×10−6 s−1
)
krel
1.0
(kcal mol−1
)
(cal K−1 mol−1
)
0.649b,c
25.4c
–15.9c
62.1d
96
22.4d
–14.7d
0.0161d
6.12d
0.025 30.9d
–7.0d
measurements was larger than 5 cal K−1 mol−1
.
9.5
24.7d
–12.8d
Fortunately, for compounds 5d, 5e and 5g, good-quality
data sets could be collected at all temperatures used in the
study. For each of these compounds, high-quality Eyring plots
(R2 > 0.99) could be obtained, which limited the calculated
uncertainty in the measurement of ΔS‡. Data for these com-
pounds are shown in Table 4, and reveal that the rearrange-
ment of each compound is associated with a small positive
a Rate in benzene-d6 at 80 °C. b Study performed in di-n-butyl ether
rather than in benzene. c Values taken from ref. 25. d Values taken from
ref. 22.
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Table 4 Entropy of activation, determined by Eyring plot
ΔS‡ a
Compound
RA
Product dr
1 : 1
(cal K−1 mol−1
)
5d
+4.8 3.7
+2.8 4.6
+4.9 3.6
5e
5g
1 : 1
1 : 1
13
3 : 1
−13.5 3.2
Scheme 1 Synthesis of additional substrates for temperature studies.
a Calculated uncertainties are based on the standard error of the
intercept, as determined by the XLfit statistical analysis package.
substituents were conjugated. In order to evaluate the effect
that the aromatic function, itself, had on stabilizing the disso-
ciative transition state through the presence of additional con-
jugation, we repeated the temperature study with alkyl-
ΔS‡, in distinct contrast to the larger, negative values reported substituted bis-vinyl ether 13, prepared as indicated in
for the prototypical allyl vinyl ethers in Table 3.
Scheme 1.
The data for compounds 5d, 5e and 5g in Table 4 are com-
Compound 13 was similarly allowed to rearrange at 5 temp-
pelling, but necessarily neglect measurements associated with eratures in bromobenzene-d5, and the energy of activation was
more electron-rich aromatic rings. In order to include these calculated in an identical manner to the experiments
data in our determination of ΔS‡, we devised an alternative described above for substrates 5a–5g. The results (see Fig. 5 for
method: if one assumes that all of compounds 5a–5g have a comparison of ΔG‡ data from 5 and 13, and Table 4 for the
approximately the same entropy of activation (i.e., that the product ratio and ΔS‡) indicated that alkyl-substituted com-
differences in rates are entirely due to enthalpic factors associ- pound 13 behaves significantly differently than the aryl-substi-
ated with electron-withdrawing or -releasing groups), then one tuted analogues 5a–5g. Instead of producing a 1 : 1 mixture of
can normalize the ΔG‡ data in Fig. 5, by shifting the 130 °C diastereomers, 13 rearranged to afford a 3 : 1 ratio of pro-
data for each compound to the same, arbitrary, point on the ducts,67 with a calculated ΔS‡ of approximately −13 cal K−1
graph. ΔG‡ measurements at other temperatures can then be mol−1. This is significantly different than the ΔS‡ measured
plotted according to their distance above or below the for compounds 5 (i.e., the two best fit lines shown in black in
measured ΔG‡ at 130 °C. All of the data in the resulting plot – Fig. 5 reveal significantly different relationships), and is within
included as an inset to Fig. 5 – can then be used to fit a single experimental error of the value reported for compound 10 (see
line, the slope of which (multiplied by −1) corresponds to the Table 3). These data indicate that the transition state for the
consensus ΔS‡ for compounds 5. In the event, this method rearrangement of 13 is less dissociative than that for com-
provided an activation entropy of +2.3 cal K−1 mol−1. This is pounds 5.
consistent with the values in Table 4, and is arguably a better
Alkyl-substituted bis-vinyl ether 13 was found to rearrange
measure of the true consensus ΔS‡ for compounds 5, since it considerably faster than 5a–5g, necessitating the use of a lower
is drawn from a greater number of individual measurements.65 temperature range in order to obtain a good-quality data set.
To the best of our knowledge, this is the least negative ΔS‡ The ΔG‡ for 13 is approximately 90% that of phenyl-substi-
determined for the thermal aliphatic Claisen rearrangement of tuted bis-vinyl ether 5d, while the relative rate of rearrange-
any allyl vinyl ether substrate, and it provides strong evidence ment (corrected to 130 °C by extrapolating from the Eyring
in favour of a dissociative transition state.
equation) is approximately 28 times faster.
The aromatic ring in substrates 5a–5g was added to allow
The lower temperature required for the rearrangement of 13
us to explore the electronic effects of various substituents on meant that it was a superior substrate for the measurement of
the properties of the vinyl ether moiety to which those solvent effects, since a greater range of solvents could be
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Table 5 Claisen rearrangements of non-aryl substrates, solvent effects
and effect of reduction at C-1
Table 6 Substituent effects at C-2 and C-4
Compound
ka (×10−6 s−1
)
krel
Notes
k at 70 °C
ΔG‡ c
T (°C)a
(×10−6 s−1
)
krel (kcal mol−1
)
b
5b
5c
5b-d2
19
373 8b
253 24c
251 10b
451 2c
1.00
Compound Solvent (ε)
0.68 0.08
0.67 0.04
1.21 0.03
kH/kD = 1.48 0.10
k19/k5c = 1.79 0.20
13
13
13
13
14
C6D6 (2.3)
C6D5Br (5.2)
(CD2Cl)2 (10.4) 70
CD3CN (37.5)
C6D5Br (5.2)
70
20.3
0.5 27.5
1.0 27.0
4.7 25.9
8.9 25.5
70–100 44.1
207
393
a Measured at 130 °C. b Standard deviation over 4 measurements.
c Standard deviation over 3 measurements.
70
110
d
d
d
—
—
—
a Temperature range of kinetic measurements ( 1 °C). b Relative to the
rate of compound 13 in C6D5Br. c ΔG‡ at 70 °C, calculated from the
observed rate of rearrangement. d Attempts to measure the rate of
rearrangement of 14 revealed an autocatalytic process that did not
display first order kinetics.
smoothly at 110 °C in bromobenzene-d5, to give
a
∼5 : 1 mixture of diastereomeric products. Unfortunately,
reproducible measurement of the rate of this reaction was not
possible under the conditions of our NMR experiment. The
attempted kinetic analysis of the rearrangement of 14 revealed
a substantial lack of linearity that was most consistent with an
employed. We therefore monitored the Claisen rearrange-
ment of 13 in both less polar (benzene-d6) and more polar, auto-catalytic process. We speculate that the rearrangement
aprotic (dichloroethane-d4, acetonitrile-d3) NMR solvents product from 14 undergoes decomposition under the con-
(see Table 5). The results showed a substantial increase in
ditions of the experiment, and that one of the resulting
reaction rate with increasing dielectric constant. Attempts decomposition products serves to promote the initial
to monitor the reaction in methanol-d4 or D2O were un- rearrangement.68
successful, in that both the rearrangement and subsequent
decomposition occurred too rapidly to follow by NMR spectro- beyond the scope of the current work, these data nonetheless
Although a full study of reduced bis-vinyl ethers like 14 is
scopy, even at 30 °C.
suggest that such compounds rearrange by a distinct mechan-
By contrast, the aliphatic Claisen rearrangement of less-sub-
ism to that of 5 or 13. Presumably, in the absence of an elec-
stituted allyl vinyl ethers is known to be relatively unaffected tron-withdrawing group at C-1, this class of compounds
by changes in solvent polarity; for example, compound 10 cannot stabilize the C-1–O-3 anion required for the dissociative
experiences only a 3.2-fold increase in the rate of rearrange-
transition state, and so instead proceeds through a higher-
ment at 80 °C, upon moving from benzene to acetonitrile energy associative transition state that is better described by
(compared to a 19.4-fold increase for 13).22 The fact that the Curran’s “vinylogous anomeric” model.
rearrangement of 13 is much more sensitive to solvent effects
Returning to the aromatic substrates (5), we next compared
than is 10, strongly suggests that 13 rearranges through a more the rate of rearrangement for 5b (bearing a methyl substituent
polarized transition state. This would be most consistent with at the C-2 position) to that for 5c (which lacks this substitu-
a greater degree of heterolytic cleavage of the O-3–C-4 bond,
ent). Compound 5c was found to rearrange at a lower rate than
prior to the formation of the new bond between C-1 and C-6. 5b in bromobenzene-d5 (Table 6). This is opposite to the result
Thus, while alkyl-substituted bis-vinyl ether 13 evidently for prepared films of our juvenile hormone analogues, in
rearranges through a more organized transition state than do
which the rate of rearrangement decreased moving from
aryl-substituted bis-vinyl ethers 5 (as evidenced by the more hydrogen, to methyl, to ethyl at the position labeled RB in
negative ΔS‡), its transition state nonetheless appears to be Fig. 2. The difference may be due to slight changes to the
more fragmented than that experienced by the simpler allyl
vinyl ether substrate 10.
mechanism of rearrangement for solvated vs. adsorbed
samples. In any event, the change in rate for 5c compared to
The lower temperature required for the rearrangement 5b is relatively small, and is probably more reflective of steric
of ester 13 (relative to 5) also provided an opportunity for
demands than of electronic effects.
us to investigate the reaction of the corresponding reduced
More informative was our study of the secondary deuterium
analogue, 14. We knew from our previous studies that bis-vinyl isotope effect at C-4. Although 5b and 5b-d2 have essentially
ether substrates not containing electron-withdrawing groups at
the same steric properties, the deuterated analogue rearranged
C-1 were relatively resistant to Claisen rearrangement (e.g., see considerably slower, resulting in a large secondary isotope
Fig. 2); as a result, the reduced forms of 5a–5g were not effect of 1.48. This is consistent with a large degree of bond-
expected to rearrange at accessible temperatures, and so were
breaking between O-3 and C-4 (and therefore a significant
not pursued. Since 13 rearranged more easily, however, we change in hybridization at C-4) early in the reaction pathway.
hoped that the corresponding methyl ether would provide a The large kH/kD ratio thus provides additional evidence favor-
ing a dissociative transition state.69
tractable target for study. We therefore prepared 14 as shown
in Scheme 1, and studied its rearrangement by NMR spec-
As an additional mechanistic probe, we were interested in
troscopy. Gratifyingly, the reaction – although slower than the the effect of placing a CF3 substituent at the C-4 position. We
corresponding transformation for 13 – was found to proceed
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reasoned that the presence of an electron-withdrawing group
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Scheme 2 Synthesis of a C-4 analogue.
at this position might reduce the rate of reaction, by destabiliz-
ing the carbocation present on the C-4–C-6 fragment in the
dissociative transition state.
We were unable to access the appropriate substrate through
a modification of our iterative synthetic protocol, and so
instead made use of a route reported by Bonacorso,70 to access
trifluoroketone 17 (Scheme 2). The ketone function was selec-
tively reduced, and the resulting alcohol was added to ethyl
propiolate to furnish substrate 19 in good overall yield. The
rearrangement of this substrate was monitored under the
usual conditions, and was found to proceed nearly twice as
fast as the closest analogue, 5c (see Table 6 for data). This is a
larger rate enhancement than for the analogous C4-trifluoro-
methylated allyl vinyl ether described by Gajewski (krel = 1.3
compared to allyl vinyl ether).18
Fig. 6 Rationale for transition state stabilization by the CF3 substituent.
A: Postulated resonance structures for the dissociative transition state.
B: Calculated electronic potential maps for the cationic fragments of
transition states leading from 5c and 19.
At this stage in our investigation, we had uncovered signifi-
Although unexpected, the faster rate of rearrangement for cant evidence supporting a largely dissociative transition state
19 relative to 5c is understandable if one considers that the (TS-I, Fig. 6) for bis-vinyl ethers like 5a–5g and 19 that contain
CF3 group has a significant destabilizing influence on only one both an electron-withdrawing C-1 function, as well as
of the three resonance structures in the proposed fully-disso- additional conjugation at C-6. In order to probe the extent of
ciative transition state (TS-Ic, Fig. 6A). For the other two poss- this dissociation, we conducted
a crossover experiment
ible resonance structures (both of which are likely to be more (Scheme 3), in which substrates 5d and 5e′ were allowed to
significant contributors to the overall electronic structure), the react in solution together, under a variety of conditions. Only
CF3 substituent may actually be stabilizing, since it allows for the products from individually reacting substrates (6d and 6e′)
additional substitution at the C-4–C-5 olefin. This analysis was were observed, in a ∼1 : 1 ratio. No crossover products were
further supported by DFT calculations,71 which confirmed that detected by MS analysis. This indicates that the two fragments
most of the positive charge for the cationic fragment postu- depicted in TS-I (Fig. 6) are tightly associated with one
lated to occur in TS-I is located at the carbon (C-6) bearing the another. Although they can presumably react with different
aromatic substituent (Fig. 6B). The CF3 substituent at C-4 trajectories (to form diastereomeric mixtures of products) they
therefore has little electronic influence, other than to provide are not free to diffuse through solution in either polar or non-
additional substitution.
polar solvents.
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principally focused on here) and TS-II (Curran’s “vinylogous
anomeric” model).
Bis-vinyl ethers like 5a–5g and 19, containing both an elec-
tron-withdrawing C-1 function and additional conjugation at
C-6, are best described as rearranging through TS-I. This
model explains the complete lack of diastereoselectivity for
these reactions, as well as the observed substituent effects,
near-zero entropy of activation, and large secondary isotope
effect. TS-I is essentially a heterolytic fragmentation pathway,
but crossover experiments confirm that the two fragments
remain tightly associated, and cannot diffuse through solu-
tion. The ΔS‡ measured for compounds 5 is particularly note-
worthy; at +2.3 cal K−1 mol−1, this is the most positive ΔS‡ ever
reported for a non-catalyzed aliphatic Claisen rearrangement.
We believe that this represents the first conclusive evidence of
a fully dissociative transition state in a Claisen rearrangement,
though earlier reports have suggested similar mechanistic
hypotheses for unusually fast rearrangements.22,72
Although compounds lacking electron-withdrawing groups
at C-1 (e.g., 10 and 14) are not the principal focus of this work
(since these compounds have already been ably studied by
others)22,40 it appears that the inability for these compounds
to stabilize an anion in the C-1–O-3 fragment of the allyl vinyl
ether system does not permit these substrates to rearrange
through a dissociative transition state; as a result, these com-
pounds must react through a more traditional associative
pathway as described earlier by Curran. This would explain the
improved diastereoselectivity observed for the rearrangement
of 14, although non-linear effects make it more challenging to
assess the thermodynamic properties for this rearrangement.
Substrate 13, which has the ester substituent at C-1 to
stabilize an anion in the transition state, but lacks the aro-
matic function to assist in additional resonance stabilization
for the carbocation fragment in TS-I, might be said to occupy
mechanistic space somewhere in the middle of this conti-
nuum. This compound rearranged with a substantial negative
entropy of activation, but nonetheless afforded a modest
diastereoselectivity and showed a large solvent effect – both
hallmarks of a more dissociative transition state than experi-
enced by those compounds lacking the C-1 ester function.
Scheme 3 Crossover experiment.
Conclusion
Several lines of evidence described herein support the mechan-
istic hypothesis illustrated in Scheme 4. In this hypothesis, we
view the aliphatic Claisen rearrangement of bis-vinyl ethers as
taking place on a continuum between two mechanistic
extremes: TS-I (the “push–pull” mechanism that we have
Experimental
General experimental procedures
All reactions were performed in oven- or flame-dried glassware,
under a positive pressure of argon, unless otherwise indicated.
Organic solutions were concentrated between 35–40 °C by
rotary evaporation under vacuum. Analytical thin-layer chrom-
atography (TLC) was performed using aluminum plates pre-
coated with silica gel (0.20 mm, 60 Å pore-size, 230–400 mesh,
Macherey-Nagel) impregnated with a fluorescent indicator
(254 nm). TLC plates were visualized by exposure to ultraviolet
light followed by staining with potassium permanganate.
Flash-column chromatography was performed over silica gel
60 (Caledon, 63–200 µM).
Scheme 4 Mechanistic proposal, accounting for differences in reactiv-
ity with different C-1 and C-6 substitution.
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All reagents were used as received from Sigma Aldrich, General procedure for acylation of aryl alkynes74
unless otherwise indicated. Commercial solvents were used as
n-BuLi (1.05 mmol, 2.5 M in hexanes) was added dropwise to a
stirred solution of ethynylarene (1.00 mmol) in 1 mL of dry
tetrahydrofuran at −78 °C. The mixture was reacted at −78 °C
received with the following exceptions. Anhydrous tetrahydro-
furan was distilled from sodium/benzophenone prior to use.
Dichloromethane was dried by passage through a column of
alumina in a commercial solvent purification system (SPS). Tri-
ethylamine was distilled over calcium hydride and degassed by
freeze–pump–thaw prior to use.
for 1.5
h followed by addition of ethyl chloroformate
(1.20 mmol) and subsequently warmed to ambient tempera-
ture overnight (19 h). The reaction was quenched with a satu-
rated solution of NH4Cl (aq.) and extracted twice with ethyl
acetate. The combined organic extracts were dried over anhy-
drous sodium sulfate, filtered, concentrated in vacuo and puri-
fied by flash column chromatography on silica gel to afford
known compounds 2a–g.
1H chemical shifts are reported in parts per million (ppm,
δ scale) downfield from tetramethylsilane, and are referenced to
residual protium in the NMR solvent (CDCl3: δ 7.26; CD3C(O)-
CD3: 2.05; C6D6: 7.16). Likewise, 13C chemical shifts are refer-
enced to the carbon resonances of the solvent (CDCl3: δ 77.22;
CD3C(O)CD3: 29.85; C6D6: 128.06). Accurate masses were
obtained using an orbitrap MS. Infrared spectra were collected
using an FT-IR spectrometer.
General procedure for conjugate addition
The alkyne (2a–g, ethyl propiolate or ethyl-2-butynoate,
1.00 mmol) was added dropwise to a stirred solution of
alcohol (1, 4a–g, 12 or 18, 1.00 mmol) and trimethylphosphine
(1.0 M in THF, 0.10 mmol) in dry dichloromethane (10 mL) at
0 °C and then warmed to room temperature overnight (18 h).
The solvent was removed under vacuum, and the residue was
re-suspended in diethyl ether (∼5 mL). The resulting suspen-
sion was filtered through a thin layer of basic alumina, the fil-
trate was concentrated in vacuo and purified by flash column
chromatography using silica gel pretreated with 1% triethyl-
amine to afford the conjugate addition product 3a–g, 5a–g, 11,
13 or 19 as clear colourless to yellow oils.
Synthesis of aryl-alkynoates (2a–g)
Aryl alkynoates were accessed from commercially available
para-substituted aryl iodides following the general procedures
described below for the Sonogashira coupling to trimethylsilyl-
acetylene, followed by TBAF deprotection to the aryl acetylide
and final acylation in the presence of ethyl or methyl
chloroformate.
General procedure for the Sonogashira coupling73
General procedure for DIBAL-H reduction
To a two-neck round bottom flask containing bis-(triphenyl-
phosphine)palladium(II) dichloride (0.02 mmol), copper(I)
iodide (0.04 mmol) and 1.8 mL of dry, degassed triethylamine,
kept under an atmosphere of argon, was added the appropriate
aryl iodide (1.00 mmol) followed by trimethylsilylacetylene
(1.20 mmol). The reaction mixture was stirred at 60 °C for 5 h
before being partitioned between ethyl acetate and water (1 : 1,
25 mL). The aqueous and organic phases were separated and
the aqueous layer extracted twice with ethyl acetate. The com-
bined organic extracts were washed with a saturated solution
of NaCl (aq.), dried over anhydrous magnesium sulfate, fil-
tered, concentrated in vacuo, and purified by flash column
chromatography on silica gel to afford the corresponding,
known alkynylsilanes, with spectral data that were in good
agreement with the literature.
Diisobutylaluminum hydride (1.0 M in hexanes, 2.20 mmol)
was added dropwise to a stirred solution of ester (3a–g, 11 or
13, 1.00 mmol) in diethyl ether75 (15 mL) at −78 °C. After 1 h
the reaction flask was moved to a −40 °C bath for an
additional 2 h. The reaction mixture was poured into a vigor-
ously stirred mixture of Rochelle’s salt (0.5 M, 100 mL), diethyl
ether (100 mL) and glycerol (0.2 mL mmol−1 DIBAL-H). Vigor-
ous stirring was maintained until the phases became clear, at
which point the aqueous and organic layers were separated.
The aqueous layer was extracted with diethyl ether (2 × 30 mL)
and the combined organic layers were dried over anhydrous
sodium sulfate, filtered, concentrated in vacuo and purified by
flash column chromatography using silica gel pretreated with
1% triethylamine to afford alcohols 4a–g, 12 and 13′ as clear
colourless to yellow oils.
General procedure for the TBAF deprotection of alkynylsilanes
Procedure for methylation of 13′
Tetrabutylammonium fluoride (1.10 mmol) was added drop- Following our procedure reported earlier,46 iodomethane
wise to a solution of trimethyl(arylethynyl)silane (1.00 mmol) (3.00 mmol) was added dropwise via syringe to a stirred
in anhydrous tetrahydrofuran (2.4 mL) at 0 °C. After 20 min mixture of alcohol 13′ (1.00 mmol) in dry tetrahydrofuran
the reaction was quenched with a saturated solution of NH4Cl (3.5 mL) at 0 °C. Sodium hydride (60% w/w in mineral oil,
(aq.) and extracted three times with diethyl ether. The organic 3.00 mmol) was added in one portion to the reaction mixture
extracts were dried over anhydrous sodium sulfate, filtered, and the resulting slurry was warmed to ambient temperature
concentrated in vacuo, and then purified by flash column overnight (∼18 h). The reaction was quenched with saturated
chromatography to afford the volatile phenyl acetylene deriva- NH4Cl (aq.) and 10% KOH (aq.) and extracted twice with
tives used in the subsequent acylation step with ethyl or diethyl ether. The combined organic extracts were dried over
methyl chloroformate.
anhydrous sodium sulfate, filtered, concentrated in vacuo and
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purified by flash column chromatography using silica gel pre-
Ethyl 3-(4-methoxyphenyl)propiolate (2a).78 Clear, colorless
treated with 1% triethylamine to afford methyl ether 14 as a oil (943 mg, 91% yield); Rf = 0.53 (hexanes–ethyl acetate, 4 : 1);
clear, colourless oil.
1H NMR (300 MHz, CDCl3) δ 7.54 (d, J = 9.1 Hz, 2H), 6.88 (d,
J = 9.1 Hz, 2H), 4.29 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 1.35 (t, J =
7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 161.7 (C), 154.6 (C),
135.1 (CH), 114.5 (CH), 111.6 (C), 87.1 (C), 80.4 (C), 62.1 (CH2),
Procedure for preparation of 1,1,1-trifluoro-4-methoxy-4-(4-
methylphenyl)-3-buten-2-one (17)70
To a stirred solution of 4-methylacetophenone dimethylacetal 55.6 (CH3), 14.3 (CH3).
1676 (1.00 mmol) and pyridine (2.00 mmol) in chloroform Ethyl 3-(4-methylphenyl)propiolate (2b).78 Clear, yellow oil
(1.0 mL) at °C was added trifluoroacetic anhydride (2.30 g, 95% yield); Rf = 0.57 (hexanes–ethyl acetate, 4 : 1);
0
(2.00 mmol) dropwise. The resulting reaction mixture was 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J = 8.2 Hz, 2H), 7.17 (d,
warmed to ambient temperature and then heated at 45 °C over- J = 7.9 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H), 1.35 (t, J =
night (16 h). The reaction mixture was cooled and then 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 154.4 (C), 141.5 (C),
quenched by addition of 0.1 M HCl (∼2 mL). The aqueous and 133.2 (CH), 129.5 (CH), 116.7 (C), 86.8 (C), 80.6 (C), 62.2 (CH2),
organic phases were separated. The organic layer was washed 21.9 (CH3), 14.3 (CH3).
with 0.1 M HCl (2 × 2.5 mL), then water (5 mL), dried over
Ethyl 3-(4-fluorophenyl)propiolate (2e).78 Orange solid
anhydrous sodium sulfate, filtered and concentrated in vacuo. (1.42 g, 96% yield); Rf = 0.52 (hexanes); 1H NMR (300 MHz,
Purification was achieved by filtration through a plug of basic CDCl3) δ 7.59 (dd, J = 9.1, 5.3 Hz, 2H), 7.07 (t, J = 8.6 Hz, 2H),
alumina to afford 17 as a bright yellow solid.
4.30 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 164.1 (d, JC–F = 254.0 Hz, CF), 154.2 (C),
135.4 (d, JC–F = 8.8 Hz, CH), 116.3 (d, JC–F = 22.2 Hz, CH), 116.0
(d, JC–F = 3.3 Hz, C), 85.2 (C), 80.8 (C), 62.4 (CH2), 14.3 (CH3).
Ethyl 3-(4-chlorophenyl)propiolate (2f).78 Orange solid
Synthesis of 1,1,1-trifluoro-4-methoxy-4-(4-methylphenyl)-3-
buten-2-ol (18)
Lithium aluminum hydride (1.50 mmol) was added in one
portion to a stirred solution of 17 (1.00 mmol) in dry diethyl (1.74 g, 80% yield); Rf = 0.59 (hexanes); 1H NMR (300 MHz,
ether (20 mL) at 0 °C. After 20 min the reaction was quenched CDCl3) δ 7.51 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 4.31
with 10% KOH (aq.) and then extracted with diethyl ether (2 × (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz,
15 mL). The combined organic extracts were washed with a CDCl3) δ 153.9 (C), 137.1 (C), 134.2 (CH), 129.1 (CH), 118.2 (C),
saturated solution of NaCl (aq.), dried over anhydrous sodium 84.7 (C), 81.6 (C), 62.3 (CH2), 14.2 (CH3).
sulfate, filtered, concentrated in vacuo and purified by flash
Ethyl 3-(4-(trifluoromethyl)phenyl)propiolate (2g).79 Brown-
column chromatography using silica gel pretreated with 1% orange oil (295 mg, 84% yield); Rf = 0.61 (10 : 4 : 1 hexanes–
triethylamine to afford 18 as a clear, colourless oil.
dichloromethane–diethyl ether); 1H NMR (300 MHz, CDCl3)
δ 7.70 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 4.32 (q, J =
7.1 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
General procedure for kinetic measurements
A solution of bis-vinyl ether (0.01 mmol) in the specified δ 153.8 (C), 133.3 (CH), 132.6 (C), 125.7 (q, JC–F = 3.7 Hz, CH),
solvent (0.5 mL) spiked with an internal standard (0.005 M 123.7 (C), 123.4 (q, JC–F = 272.7 Hz, CF3), 84.0 (C), 82.5 (C), 62.6
hexamethylbenzene or 0.010 M 1,4-dioxane for RA = aryl or (CH2), 14.3 (CH3).
alkyl, respectively) was added to a 5 mm NMR tube and the
Ethyl 3-(4-methoxyphenyl)-3-(neopentyloxy)acrylate (3a). Clear,
progress of the reaction monitored by 1H NMR spectroscopy pale yellow oil (465 mg, 94% yield, 15 : 1 E : Z); Rf = 0.52
over time at 500 MHz in an instrument pre-equilibrated to the (hexanes–ethyl acetate, 4 : 1); 1H NMR (300 MHz, (CD3)2CO)
temperature indicated ( 1 °C). Plots of [A]t/[A]o vs. t were δ 7.58 (d, J = 9.1 Hz, 2H, major), 7.45 (d, J = 9.1 Hz, 2H,
obtained for 5 or 13, where [A]t is the integral for the observed minor), 7.00 (d, J = 8.8 Hz, 2H, major), 6.92 (d, J = 9.1 Hz, 2H,
protons in the starting bis-vinyl ether (the average of the minor), 5.44 (s, 1H, major), 5.19 (s, 1H, minor), 4.12 (q, J =
∑(vinyl ether olefins)) normalized to the internal standard, 7.1 Hz, 2H, major), 3.98 (q, J = 7.1 Hz, 2H, minor), 3.86 (s, 3H,
and [A]o is the sum of the normalized integrals for the starting major), 3.84 (s, 3H, minor), 3.69 (s, 2H, major), 3.65 (s, 2H,
bis-vinyl ether and rearrangement product (using the ∑(alpha- minor), 1.25 (t, J = 7.0 Hz, 3H, major), 1.13 (t, J = 7.0 Hz, 3H,
protons) for both diastereomers produced). By-products pro- minor), 1.03 (s, 9H); 13C NMR (75 MHz, (CD3)2CO) δ 168.6 (C),
duced in the reaction (i.e. elimination products) were also 165.4 (C), 162.4 (C), 129.8 (CH), 128.7 (C), 114.8 (CH), 98.5
accounted for in the calculation of [A]o, based on normalized (CH), 83.2 (CH2), 59.8 (CH2), 55.8 (CH3), 33.3 (C), 26.8 (CH3),
signals for the terminal olefin. First-order rate constants, k, 14.8 (CH3); IR (neat, cm−1) 2957 (m), 2904 (w), 2870 (w), 2839 (w),
were obtained by fitting the data to equation [A]t = [A]oe−kt + B 1716 (s), 1606 (s), 1512 (s), 1253 (s), 1156 (s), 1098 (s), 1032 (m),
using linear least squares analysis.77 The activation energy was 836 (m), 666 (w); HRMS (ESI) calcd for C17H24O4 + Na+
calculated directly from k using the Eyring equation, ΔG‡
RT[ln(kB/h) − ln(k/T)]. Eyring and Arrhenius parameters were also
=
315.1567, found 315.1564.
Ethyl 3-(neopentyloxy)-3-p-tolylacrylate (3b). Clear, yellow oil
generated from the resulting k values, and associated error in (915 mg, 99% yield, 17 : 1 E : Z); Rf = 0.63 (hexanes–ethyl
thermodynamic properties determined on the basis of error acetate, 4 : 1); 1H NMR (300 MHz, (CD3)2CO) δ 7.51 (d, J =
associated with the slope and intercept for the data set were 8.2 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 5.45 (s, 1H), 4.13 (q, J =
obtained using the XLfit statistical analysis package.
7.1 Hz, 2H), 3.67 (s, 2H), 2.37 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H),
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1.02 (s, 9H); 13C NMR (75 MHz, (CD3)2CO) δ 168.7 (C), (hexanes–ethyl acetate, 4 : 1); 1H NMR (300 MHz, (CD3)2CO)
165.3 (C), 141.3 (C), 133.7 (C), 130.1 (CH), 128.2 (CH), 99.4 δ 7.41 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.38 (t, J =
(CH), 83.1 (CH2), 59.8 (CH2), 33.3 (C), 26.8 (CH3), 21.3 (CH3), 6.7 Hz, 1H), 4.33 (dd, J = 6.6, 5.7 Hz, 2H), 3.81 (s, 3H), 3.52 (t,
14.8 (CH3); IR (neat, cm−1) 3030 (w), 2957 (s), 2870 (s), J = 5.6 Hz, 1H), 3.28 (s, 2H), 1.01 (s, 9H); 13C NMR (75 MHz,
1713 (s), 1621 (s), 1273 (s), 1154 (s), 1097 (s), 1040 (s), 820 (s), (CD3)2CO) δ 160.7 (C), 155.2 (C), 129.3 (C), 128.3 (CH), 114.6
727 (w); HRMS (ESI) calcd for C17H24O3 + Na+ 299.1618, found (CH), 113.6 (CH), 81.6 (CH2), 57.3 (CH2), 55.6 (CH3), 33.0 (C),
299.1615.
26.9 (CH3); IR (neat, cm−1) 3367 (br, m), 2955 (s), 2901 (m),
Methyl 3-(neopentyloxy)-3-phenylacrylate (3d). Clear, pale 2868 (m), 2825 (w), 1655 (w), 1608 (s), 1510 (s), 1249 (s), 1173 (s),
yellow oil (437 mg, 94% yield, >20 : 1 E : Z); Rf = 0.42 (hexanes– 1033 (s), 967 (w), 837 (m); HRMS (ESI) calcd for C15H22O3 + Na+
1
ethyl acetate, 9 : 1); H NMR (300 MHz, (CD3)2CO) δ 7.64–7.59 273.1461, found 273.1462.
(m, 2H), 7.49–7.44 (m, 3H), 5.50 (s, 1H), 3.67 (s, 2H), 3.66 (s,
3-(Neopentyloxy)-3-p-tolylprop-2-en-1-ol (4b). Clear, colour-
3H), 1.02 (s, 9H); 13C NMR (75 MHz, (CD3)2CO) δ 168.7 (C), less oil (389 mg, 82% yield, 20 : 1 E : Z); Rf = 0.33 (hexanes–
165.6 (C), 136.4 (C), 131.1 (CH), 129.5 (CH), 128.2 (CH), 99.7 ethyl acetate, 4 : 1); 1H NMR (300 MHz, (CD3)2CO) δ 7.37 (d, J =
(CH), 83.1 (CH2), 51.0 (CH3), 33.3 (C), 26.7 (CH3); IR (neat, 8.2 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 5.44 (t, J = 6.6 Hz, 1H),
cm−1) 3056 (w), 2955 (s), 2870 (m), 1722 (s), 1622 (s), 1275 (s), 4.34 (d, J = 6.7 Hz, 2H), 3.56 (br s, 1H), 3.28 (s, 2H), 2.33 (s,
1156 (s), 1099 (s), 1015 (m), 777 (m), 699 (m); HRMS (ESI) 3H), 1.01 (s, 9H); 13C NMR (75 MHz, (CD3)2CO) δ 155.4 (C),
calcd for C15H20O3 + Na+ 271.1305, found 271.1305.
138.7 (C), 134.2 (C), 129.9 (CH), 126.9 (CH), 114.6 (CH), 81.6
Ethyl 3-(4-fluorophenyl)-3-(neopentyloxy)acrylate (3e). Clear, (CH2), 57.3 (CH2), 33.0 (C), 26.9 (CH3), 21.2 (CH3); IR (neat,
orange oil (1.71 g, 82% yield, 13 : 1 E : Z); Rf = 0.72 (hexanes– cm−1) 3325 (br, s), 3027 (w), 2955 (s), 2868 (s), 1652 (s), 1511 (s),
1
ethyl acetate, 4 : 1); H NMR (300 MHz, (CD3)2CO) δ 7.69 (dd, 1057 (s), 1019 (s), 968 (s), 825 (s), 803 (w), 770 (w), 722 (w);
J = 9.1, 5.3 Hz, 2H), 7.22 (t, J = 8.9 Hz, 2H), 5.49 (s, 1H), 4.13 HRMS (ESI) calcd for C15H22O2 + Na+ 257.1512, found
(q, J = 7.1 Hz, 2H), 3.68 (s, 2H), 1.25 (t, J = 7.2 Hz, 3H), 1.02 257.1513.
(s, 9H); 13C NMR (75 MHz, (CD3)2CO) δ 167.2 (C), 165.2 (C),
3-(Neopentyloxy)-3-p-tolylprop-2-en-1,1-dideuterio-1-ol (4b-
164.7 (d, JC–F = 248.6 Hz, CF), 132.9 (d, JC–F = 3.3 Hz, C), d2). Clear, pale yellow oil (116 mg, 75% yield, 14 : 1 E : Z);
1
130.5 (d, JC–F = 8.3 Hz, CH), 116.4 (d, JC–F = 22.1 Hz, CH), Rf = 0.30 (hexanes–dichloromethane–diethyl ether, 5 : 5 : 1); H
100.0 (CH), 83.3 (CH2), 60.0 (CH2), 33.3 (C), 26.8 (CH3), NMR (300 MHz, (CD3)2CO) δ 7.37 (d, J = 8.2 Hz, 2H), 7.18 (d,
14.8 (CH3); IR (neat, cm−1) 2958 (s), 2871 (m), 1716 (s), J = 7.9 Hz, 2H), 5.43 (s, 1H), 3.51 (br s, 1H), 3.28 (s, 2H), 2.33
1621 (s), 1508 (s), 1261 (m), 1157 (s), 1097 (m), 1040 (w), 842 (m); (s, 3H), 1.01 (s, 9H); 13C NMR (75 MHz, (CD3)2CO) δ 155.6 (C),
HRMS (ESI) calcd for C16H21FO3 + Na+ 303.1367, found 138.7 (C), 134.2 (C), 129.9 (CH), 126.9 (CH), 114.4 (CH), 81.6
303.1366.
(CH2), 33.0 (C), 27.0 (CH3), 21.2 (CH3); IR (neat, cm−1) 3344
Ethyl 3-(4-chlorophenyl)-3-(neopentyloxy)acrylate (3f). Clear, (br, s), 3027 (w), 2955 (s), 2918 (m), 2968 (m), 1651 (m), 1510
orange oil (936 mg, 89% yield, 13 : 1 E : Z); Rf = 0.65 (hexanes– (m), 1316 (m), 1062 (m), 1019 (w), 823 (m); HRMS (ESI) calcd
ethyl acetate, 4 : 1); 1H NMR (300 MHz, (CD3)2CO) δ 7.66 (d, J = for C15H20D2O2 + Na+ 259.1637, found 259.1636.
8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 5.54 (s, 1H), 4.14 (q, J =
3-(Neopentyloxy)-3-phenylprop-2-en-1-ol (4d). Clear, color-
7.1 Hz, 2H), 3.69 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.26 (s, 9H); less oil (334 mg, 98% yield, >20 : 1 E : Z); Rf = 0.60 (hexanes–
1
13C NMR (75 MHz, (CD3)2CO) δ 166.8 (C), 165.1 (C), 136.5 (C), ethyl acetate, 2 : 1); H NMR (300 MHz, (CD3)2CO) δ 7.51–7.46
135.3 (C), 129.8 (CH), 129.7 (CH), 100.5 (CH), 83.4 (CH2), 60.1 (m, 2H), 7.41–7.31 (m, 3H), 5.50 (t, J = 6.7 Hz, 1H), 4.36 (dd, J =
(CH2), 33.3 (C), 26.8 (CH3), 14.7 (CH3); IR (neat, cm−1) 2957 (s), 6.7, 5.6 Hz, 2H), 3.60 (t, J = 5.6 Hz, 1H), 3.29 (s, 2H), 1.02 (s,
2870 (m), 1716 (s), 1621 (s), 1489 (s), 1260 (s), 1161 (s), 1092 (s), 9H); 13C NMR (75 MHz, (CD3)2CO) δ 155.3 (C), 137.0 (C), 129.3
836 (s); HRMS (ESI) calcd for C16H21ClO3 + Na+ 319.1071, (CH), 129.0 (CH), 126.9 (CH), 115.4 (CH), 81.6 (CH2), 57.3
found 319.1070.
Ethyl 3-(4-(trifluoromethyl)phenyl)-3-(neopentyloxy)acrylate (w), 2956 (s), 2899 (s), 2868 (s), 1652 (m), 1363 (m), 1057 (s),
(CH2), 33.0 (C), 26.9 (CH3); IR (neat, cm−1) 3338 (m, br), 3059
(3g). Clear, orange oil (658 mg, 78% yield, >20 : 1 E : Z); Rf = 1028 (s), 755 (m), 698 (m); HRMS (ESI) calcd for C14H20O2
0.50 (hexanes–diethyl ether, 4 : 1); 1H NMR (300 MHz, Na+ 243.1355, found 243.1355.
+
(CD3)2CO) δ 7.88 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H),
3-(4-Fluorophenyl)-3-(neopentyloxy)prop-2-en-1-ol (4e). Clear,
5.65 (s, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.71 (s, 2H), 1.27 (t, J = orange-yellow oil (319 mg, 88% yield, 14 : 1 E : Z); Rf = 0.21
7.0 Hz, 3H), 1.03 (s, 9H); 13C NMR (75 MHz, (CD3)2CO) δ 166.1 (hexanes–ethyl acetate, 4 : 1); 1H NMR (300 MHz, (CD3)2CO)
(C), 165.1 (C), 140.5 (C), 132.0 (q, JC–F = 32.4 Hz, C), 128.9 δ 7.52 (dd, J = 8.8, 5.6 Hz, 2H), 7.14 (t, J = 8.9 Hz, 2H), 5.48 (t,
(CH), 126.4 (q, JC–F = 3.7 Hz, CH), 125.1 (q, JC–F = 271.1 Hz, J = 6.6 Hz, 1H), 4.35 (dd, J = 6.4, 5.6 Hz, 2H), 3.63 (t, J = 5.6 Hz,
CF3), 101.8 (CH), 83.5 (CH2), 60.2 (CH2), 33.3 (C), 26.7 (CH3), 1H), 3.29 (s, 2H), 1.01 (s, 9H); 13C NMR (75 MHz, (CD3)2CO)
14.7 (CH3); IR (neat, cm−1) 2960 (m), 2904 (w), 2872 (w), δ 163.5 (d, JC–F = 245.4 Hz, CF), 154.3 (C), 133.4 (d, JC–F = 3.3
1717 (s), 1616 (s), 1324 (s), 1169 (s), 1130 (s), 1067 (s), 848 (w), Hz, C), 128.9 (d, JC–F = 8.5 Hz, CH), 116.1 (d, JC–F = 21.4 Hz,
666 (w); HRMS (ESI) calcd for C17H21F3O3 + Na+ 353.1335, CH), 115.4 (CH), 81.7 (CH2), 57.3 (CH2), 33.0 (C), 26.9 (CH3); IR
found 353.1336.
(neat, cm−1) 3335 (br, s), 3048 (w), 2956 (s), 2904 (s), 2869 (s),
3-(4-Methoxyphenyl)-3-(neopentyloxy)prop-2-en-1-ol (4a). Clear, 1652 (s), 1604 (s), 1507 (s), 1055 (s), 842 (s); HRMS (ESI) calcd
colourless oil (339 mg, 97% yield, 18 : 1 E : Z); Rf = 0.22 for C14H19FO2 + Na+ 261.1261, found 261.1260.
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3-(4-Chlorophenyl)-3-(neopentyloxy)prop-2-en-1-ol (4f). Clear, (CH), 127.4 (CH), 107.1 (CH), 92.1 (CH), 81.6 (CH2), 59.5 (CH2),
yellow oil (409 mg, 99% yield, 15 : 1 E : Z); Rf = 0.31 (hexanes– 33.1 (C), 26.9 (CH3), 21.2 (CH3), 19.2 (CH3), 14.8 (CH3);
ethyl acetate, 4 : 1); 1H NMR (300 MHz, (CD3)2CO) δ 7.51 (d, J = IR (neat, cm−1) 2956 (m), 2869 (m), 1712 (s), 1621 (s), 1279 (m),
8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 5.56 (t, J = 6.7 Hz, 1H), 1144 (s), 1069 (s), 824 (m); HRMS (ESI) calcd for 2(C21H28D2O4)
4.35 (dd, J = 6.4, 5.6 Hz, 2H), 3.65 (t, J = 5.6 Hz, 1H), 3.30 (s, + Na+ 719.4431, found 719.4432.
2H), 1.02 (s, 9H); 13C NMR (75 MHz, (CD3)2CO) δ 154.1 (C),
Ethyl 3-(3-(neopentyloxy)-3-p-tolylallyloxy)acrylate (5c). Clear,
135.8 (C), 134.2 (C), 129.4 (CH), 128.4 (CH), 116.2 (CH), 81.8 pale yellow oil (60.2 mg, 100% yield, 9 : 1 E : Z); 1H NMR
(CH2), 57.2 (CH2), 33.0 (C), 26.9 (CH3); IR (neat, cm−1) 3325 (300 MHz, (CD3)2CO) δ 7.65 (d, J = 12.6 Hz, 1H), 7.40 (d, J =
(br, m), 2956 (s), 2868 (m), 1652 (m), 1488 (s), 1092 (s), 1054 (s), 8.2 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 5.43 (t, J = 7.3 Hz, 1H),
1014 (s), 966 (m), 836 (m), 789 (w); HRMS (ESI) calcd for 5.31 (d, J = 12.6 Hz, 1H), 4.72 (d, J = 7.3 Hz, 2H), 4.10 (q, J = 7.1
C14H19ClO2 + Na+ 277.0966, found 277.0965.
Hz, 2H), 3.34 (s, 2H), 2.35 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H), 1.03
3-(Neopentyloxy)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-ol (s, 9H); 13C NMR (75 MHz, (CD3)2CO) δ 167.7 (C), 163.0 (CH),
(4g). Clear, pale yellow oil (214 mg, 86% yield, >20 : 1 E : Z); 159.8 (C), 139.7 (C), 133.1 (C), 130.1 (CH), 127.5 (CH), 106.9
Rf = 0.24 (hexanes–ethyl acetate, 4 : 1); 1H NMR (300 MHz, (CH), 97.5 (CH), 81.7 (CH2), 66.4 (CH2), 59.9 (CH2), 33.0 (C),
(CD3)2CO) δ 7.72 (s, 4H), 5.71 (t, J = 6.6 Hz, 1H), 4.39 (dd, J = 26.9 (CH3), 21.2 (CH3), 14.7 (CH3); IR (neat, cm−1) 2957 (m),
6.4, 5.6 Hz, 2H), 3.73 (t, J = 5.7 Hz, 1H), 3.32 (s, 2H), 1.03 (s, 2869 (m), 1712 (s), 1639 (m), 1623 (s), 1130 (s), 1056 (s), 827 (m),
9H); 13C NMR (75 MHz, (CD3)2CO) δ 153.7 (C), 140.9 (C), 130.2 666 (m); HRMS (ESI) calcd for C20H28O4 + Na+ 355.1880, found
(q, JC–F = 32.4 Hz, C), 127.3 (CH), 126.2 (q, JC–F = 4.1 Hz, CH), 355.1880.
125.3 (q, JC–F = 271.2 Hz, CF3), 118.1 (CH), 82.0 (CH2), 57.3
Ethyl 3-(3-(neopentyloxy)-3-phenylallyloxy)but-2-enoate (5d).
(CH2), 33.0 (C), 26.9 (CH3); IR (neat, cm−1) 3325 (br, m), 2959 (m), Clear, colorless oil (40.2 mg, 98% yield, 9 : 1 E : Z); 1H NMR
2906 (m), 2871 (m), 1651 (w), 1618 (w), 1327 (s), 1128 (s), (300 MHz, (CD3)2CO) δ 7.54–7.49 (m, 2H), 7.46–7.37 (m, 3H),
1069 (s), 967 (w), 852 (m); LRMS (ESI) calcd for 2(C15H19F3O2) + 5.48 (t, J = 7.0 Hz, 1H), 5.21 (s, 1H), 4.68 (d, J = 7.0 Hz, 2H),
K+ 615.23, found 615.33.
4.07 (q, J = 7.1 Hz, 2H), 3.36 (s, 2H), 2.27 (s, 3H), 1.22 (t, J = 7.0
Ethyl 3-(3-(4-methoxyphenyl)-3-(neopentyloxy)allyloxy)but-2- Hz, 3H), 1.03 (s, 9H); 13C NMR (75 MHz, (CD3)2CO) δ 172.3 (C),
enoate (5a). Clear, colourless oil (73.0 mg, 99% yield, 9 : 1 168.1 (C), 158.9 (C), 136.1 (C), 129.7 (CH), 129.4 (CH), 127.4
1
E : Z); H NMR (300 MHz, (CD3)2CO) δ 7.44 (d, J = 8.8 Hz, 2H), (CH), 108.1 (CH), 92.1 (CH), 81.7 (CH2), 63.8 (CH2), 59.5 (CH2),
6.96 (d, J = 8.8 Hz, 2H), 5.36 (t, J = 7.0 Hz, 1H), 5.20 (s, 1H), 33.1 (C), 26.9 (CH3), 19.1 (CH3), 14.8 (CH3); IR (neat, cm−1
)
4.64 (d, J = 7.0 Hz, 2H), 4.07 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 2957 (s), 2905 (m), 2869 (m), 1712 (s), 1621 (s), 1273 (s), 1141 (s),
3.34 (s, 2H), 2.27 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H), 1.03 (s, 9H); 1056 (s), 818 (m), 767 (m), 699 (m); HRMS (ESI) calcd for
13C NMR (75 MHz, (CD3)2CO) δ 172.4 (C), 168.1 (C), 161.2 (C), C20H28O4 + Na+ 355.1880, found 355.1878.
158.9 (C), 128.8 (CH), 128.4 (C), 114.8 (CH), 106.3 (CH), 92.0
Ethyl
3-(3-(4-fluorophenyl)-3-(neopentyloxy)allyloxy)but-2-
(CH), 81.6 (CH2), 63.8 (CH2), 59.5 (CH2), 55.6 (CH3), 33.0 (C), enoate (5e). Clear, pale yellow oil (65.5 mg, 87% yield, 7 : 1
1
26.9 (CH3), 19.2 (CH3), 14.8 (CH3); IR (neat, cm−1) 2956 (s), E : Z); H NMR (300 MHz, (CD3)2CO) δ 7.56 (dd, J = 8.9, 5.4 Hz,
2901 (m), 2869 (w), 2838 (w), 1711 (s), 1621 (s), 1511 (s), 1250 (s), 2H), 7.18 (t, J = 8.8 Hz, 2H), 5.47 (t, J = 7.0 Hz, 1H), 5.20 (s,
1141 (s), 1055 (s), 838 (m), 818 (m); HRMS (ESI) calcd for 1H), 4.66 (d, J = 6.7 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.35 (s,
C21H30O5 + Na+ 385.1985, found 385.1984.
2H), 2.27 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H), 1.03 (s, 9H); 13C NMR
Ethyl 3-(3-(neopentyloxy)-3-p-tolylallyloxy)but-2-enoate (75 MHz, (CD3)2CO) δ 172.9 (C), 168.1 (C), 163.9 (d, JC–F
=
(5b). Clear, colourless oil (56.8 mg, 100% yield, 9 : 1 E : Z); 245.4 Hz, CF), 157.9 (C), 132.5 (d, JC–F = 3.2 Hz, C), 129.5 (d,
1H NMR (300 MHz, (CD3)2CO) δ 7.40 (d, J = 8.2 Hz, 2H), 7.22 JC–F = 8.6 Hz, CH), 116.3 (d, JC–F = 22.1 Hz, CH), 108.2 (CH),
(d, J = 7.9 Hz, 2H), 5.41 (t, J = 6.9 Hz, 1H), 5.20 (s, 1H), 4.66 (d, 92.2 (CH), 81.8 (CH2), 63.7 (CH2), 59.5 (CH2), 33.1 (C), 26.9
J = 7.0 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.34 (s, 2H), 2.35 (s, (CH3), 19.1 (CH3), 14.8 (CH3); IR (neat, cm−1) 2958 (m), 2905 (w),
3H), 2.27 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H), 1.03 (s, 9H); 13C NMR 2871 (w), 1711 (s), 1622 (s), 1507 (m), 1271 (m), 1229 (m),
(75 MHz, (CD3)2CO) δ 172.3 (C), 168.1 (C), 159.0 (C), 139.6 (C), 1141 (s), 1053 (s), 953 (w), 843 (m), 818 (m); HRMS (ESI) calcd
133.3 (C), 130.0 (CH), 127.4 (CH), 107.2 (CH), 92.1 (CH), 81.6 for C20H27FO4 + Na+ 373.1786, found 373.1783.
(CH2), 63.8 (CH2), 59.5 (CH2), 33.1 (C), 26.9 (CH3), 21.2 (CH3),
Ethyl 3-(3-(4-fluorophenyl)-3-(neopentyloxy)allyloxy)pent-2-
19.2 (CH3), 14.8 (CH3); IR (neat, cm−1) 2956 (m), 2898 (m), enoate (5e′). Clear, yellow oil (55.4 mg, 88% yield, 6 : 1 E : Z);
2869 (m), 1712 (s), 1621 (s), 1274 (m), 1142 (s), 1056 (s), 825 (m); 1H NMR (300 MHz, (CD3)2CO) δ 7.57 (dd, J = 8.9, 5.4 Hz, 2H),
HRMS (ESI) calcd for C21H30O4 + Na+ 369.2036, found 7.19 (t, J = 8.9 Hz, 2H), 5.49 (t, J = 6.9 Hz, 1H), 5.14 (s, 1H),
369.2034.
4.66 (d, J = 7.0 Hz, 2H), 4.08 (q, J = 7.0 Hz, 2H), 3.36 (s, 2H),
Ethyl 3-(1,1-dideuterio-3-(neopentyloxy)-3-p-tolylallyloxy)but- 2.75 (q, J = 7.4 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H), 1.09 (t, J = 7.5
2-enoate (5b-d2). Clear, pale yellow oil (36.9 mg, 97% yield, Hz, 3H), 1.03 (s, 9H); 13C NMR (75 MHz, (CD3)2CO) δ 177.1 (C),
1
8 : 1 E : Z); H NMR (500 MHz, (CD3)2CO) δ 7.39 (d, J = 8.5 Hz, 167.8 (C), 163.9 (d, JC–F = 246.5 Hz, CF), 158.0 (C), 132.6 (d,
2H), 7.22 (d, J = 7.9 Hz, 2H), 5.41 (s, 1H), 5.20 (s, 1H), 4.07 (q, JC–F = 3.3 Hz, C), 129.5 (d, JC–F = 8.0 Hz, CH), 116.3 (d, JC–F
=
J = 7.1 Hz, 2H), 3.35 (s, 2H), 2.35 (s, 3H), 2.26 (s, 3H), 1.22 (t, 22.0 Hz, CH), 108.2 (CH), 91.3 (CH), 81.9 (CH2), 63.7 (CH2),
J = 7.0 Hz, 3H), 1.03 (s, 9H); 13C NMR (125 MHz, (CD3)2CO) 59.6 (CH2), 33.1 (C), 26.9 (CH3), 26.1 (CH2), 14.8 (CH3), 12.3
δ 172.4 (C), 168.1 (C), 159.1 (C), 139.6 (C), 133.3 (C), 130.1 (CH3); IR (neat, cm−1) 2971 (m), 2958 (m), 2904 (w), 2870 (w),
1304 | Org. Biomol. Chem., 2014, 12, 1292–1308
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1712 (s), 1620 (s), 1508 (s), 1377 (m), 1228 (m), 1141 (s), 1053 (s), 2904 (m), 2870 (m), 1712 (s), 1664 (m), 1619 (s), 1390 (m),
843 (m), 822 (m); HRMS (ESI) calcd for 2(C21H29FO4) + Na+ 1272 (m), 1212 (m), 1132 (s), 1035 (s), 939 (w), 815 (w); HRMS
751.3992, found 751.3991.
Ethyl 3-(3-(4-chlorophenyl)-3-(neopentyloxy)allyloxy)but-2-
(ESI) calcd for C15H26O4 + Na+ 293.1723, found 293.1719.
3-(3-(Neopentyloxy)but-2-enyloxy)but-2-en-1-ol (13′). Clear,
enoate (5f). Clear, pale yellow oil (120 mg, 82% yield, 8 : 1 yellow oil (146 mg, 80% yield, >20 : 1 E : Z); Rf = 0.36 (hexanes–
1
1
E : Z); H NMR (300 MHz, (CD3)2CO) δ 7.53 (d, J = 8.8 Hz, 2H), ethyl acetate, 2 : 1); H NMR (300 MHz, (CD3)2CO) δ 4.71 (t, J =
7.44 (d, J = 8.8 Hz, 2H), 5.54 (t, J = 7.0 Hz, 1H), 5.20 (s, 1H), 7.8 Hz, 1H), 4.66 (t, J = 7.2 Hz, 1H), 4.18 (d, J = 7.6 Hz, 2H),
4.67 (d, J = 7.0 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.36 (s, 2H), 4.05 (dd, J = 7.5, 5.4 Hz, 2H), 3.34 (s, 2H), 3.19 (t, J =
2.27 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H), 1.03 (s, 9H); 13C NMR 5.6 Hz, 1H), 1.83 (s, 3H), 1.77 (s, 3H), 0.96 (s, 9H); 13C NMR
(75 MHz, (CD3)2CO) δ 172.2 (C), 168.0 (C), 157.6 (C), 135.0 (C), (75 MHz, (CD3)2CO) δ 158.5 (C), 156.2 (C), 98.6 (CH), 93.6
134.9 (C), 129.6 (CH), 128.9 (CH), 109.0 (CH), 92.2 (CH), 81.9 (CH), 77.3 (CH2), 64.2 (CH2), 59.0 (CH2), 32.0 (C), 26.9 (CH3),
(CH2), 63.6 (CH2), 59.5 (CH2), 33.0 (C), 26.8 (CH3), 19.1 (CH3), 16.6 (CH3); IR (neat, cm−1) 3419 (br, m), 2956 (s), 2869 (s),
14.8 (CH3); IR (neat, cm−1) 2957 (m), 2869 (w), 1711 (s), 1621 (s), 1661 (s), 1479 (m), 1204 (s), 1079 (s), 936 (m), 900 (m), 783 (w);
1272 (m), 1142 (s), 1054 (s), 839 (w), 818 (w); HRMS (ESI) calcd HRMS (ESI) calcd for C13H24O3 + Na+ 251.1618, found
for C20H27ClO4 + Na+ 389.1490, found 389.1486.
Ethyl 3-(3-(neopentyloxy)-3-(4-(trifluoromethyl)phenyl)-
251.1618.
1-Methoxy-3-(3-(neopentyloxy)but-2-enyloxy)but-2-ene (14).
allyloxy)but-2-enoate (5g). Clear, colourless oil (86.9 mg, 99% Clear, colourless oil (64.9 mg, 70% yield, >20 : 1 E : Z); Rf = 0.54
1
yield, 11 : 1 E : Z); H NMR (500 MHz, (CD3)2CO) δ 7.76 (s, 4H), (hexanes–ethyl acetate, 4 : 1); 1H NMR (300 MHz, (CD3)2CO)
5.69 (t, J = 6.8 Hz, 1H), 5.21 (s, 1H), 4.71 (d, J = 7.2 Hz, 2H), δ 4.67 (t, J = 7.2 Hz, 1H), 4.62 (t, J = 7.2 Hz, 1H), 4.21 (d, J =
4.08 (q, J = 7.2 Hz, 2H), 3.39 (s, 2H), 2.28 (s, 3H), 1.22 (t, J = 7.3 Hz, 2H), 3.88 (d, J = 7.3 Hz, 2H), 3.34 (s, 2H), 3.21 (s, 3H),
7.2 Hz, 3H), 1.05 (s, 9H); 13C NMR (125 MHz, (CD3)2CO) 1.83 (s, 3H), 1.78 (s, 3H), 0.96 (s, 9H); 13C NMR (75 MHz,
δ 172.2 (C), 168.0 (C), 157.2 (C), 140.1 (C), 130.9 (q, JC–F
=
(CD3)2CO) δ 158.6 (C), 157.8 (C), 94.9 (CH), 93.5 (CH), 77.3
32.4 Hz, C), 127.9 (CH), 126.4 (q, JC–F = 3.8 Hz, CH), 125.2 (q, (CH2), 69.2 (CH2), 64.4 (CH2), 56.9 (CH3), 32.0 (C), 26.9 (CH3),
JC–F = 271.3 Hz, CF3), 110.8 (CH), 92.3 (CH), 82.0 (CH2), 63.6 16.8 (CH3), 16.6 (CH3); IR (neat, cm−1) 2956 (s), 2923 (s),
(CH2), 59.6 (CH2), 33.1 (C), 26.8 (CH3), 19.1 (CH3), 14.8 (CH3); 2892 (s), 2869 (s), 2813 (w), 1661 (s), 1479 (m), 1389 (s),
IR (neat, cm−1) 2959 (s), 2866 (m), 1713 (s), 1622 (s), 1326 (s), 1207 (s), 1070 (s), 1048 (s), 946 (w), 901 (w), 782 (w); HRMS
1273 (m), 1141 (s), 1068 (s), 1017 (m), 852 (w), 819 (w); HRMS (ESI) calcd for C14H26O3 + Na+ 265.1774, found 265.1774.
(ESI) calcd for C20H25F3O4 + Na+ 409.1597, found 409.1600.
1,1,1-Trifluoro-4-methoxy-4-(4-methylphenyl)-3-buten-2-one
Ethyl 3-(neopentyloxy)but-2-enoate (11). Clear, colorless oil (17).80 Yellow solid (500 mg, 71% yield, 9 : 1 E : Z); 1H NMR
(1.88 g, 92% yield, >20 : 1 E : Z); Rf = 0.56 (hexanes–ethyl ether, (300 MHz, (CD3)2CO) δ 7.68 (d, J = 8.2 Hz, 2H, minor), 7.43 (d,
1
9 : 1); H NMR (300 MHz, (CD3)2CO) δ 5.02 (s, 1H), 4.06 (q, J = J = 8.2 Hz, 2H, major), 7.34 (d, J = 7.9 Hz, 2H, minor), 7.24 (d,
7.0 Hz, 2H), 3.48 (s, 2H), 2.27 (s, 3H), 1.20 (t, J = 7.0 Hz, 3H), J = 8.2 Hz, 2H, major), 6.20 (s, 1H, minor), 5.97 (s, 1H, major),
0.99 (s, 9H); 13C NMR (75 MHz, (CD3)2CO) δ 172.8 (C), 168.1 (C), 4.09 (s, 3H, minor), 4.04 (s, 3H, major), 2.41 (s, 3H, minor),
91.8 (CH), 78.5 (CH2), 59.5 (CH2), 31.9 (C), 26.7 (CH3), 18.9 2.38 (s, 3H, major); 13C NMR (75 MHz, (CD3)2CO) δ 179.6 (C),
(CH3), 14.8 (CH3); IR (neat, cm−1) 2959 (m), 2871 (w), 1713 (s), 177.6 (q, JC–F = 32.8 Hz, C), 144.0 (C), 132.2 (C), 130.4
1623 (s), 1281 (m), 1139 (s), 1056 (s), 817 (w); HRMS (ESI) calcd (CH, minor), 130.0 (CH, major), 129.4 (CH, major), 129.3
for C11H20O3 + H+ 201.1485, found 201.1486.
(CH, minor), 117.9 (q, JC–F = 292.6 Hz, CF3), 95.7 (CH, minor),
3-(Neopentyloxy)but-2-en-1-ol (12). Clear, colorless oil 92.3 (CH, major), 63.3 (CH3, minor), 58.3 (CH3, major),
(257 mg, 79% yield, >20 : 1 E : Z); Rf = 0.32 (hexanes–ethyl 21.5 (CH3).
1
ether, 1 : 1); H NMR (300 MHz, (CD3)2CO) δ 4.65 (t, J = 7.3 Hz,
1,1,1-Trifluoro-4-methoxy-4-p-tolylbut-3-en-2-ol (18). Clear,
1H), 4.04 (dd, J = 7.3, 5.6 Hz, 2H), 3.29 (s, 2H), 3.19 (t, J = colourless oil (130 mg, 93% yield, 14 : 1 E : Z); Rf = 0.15
5.6 Hz, 1H), 1.80 (s, 3H), 0.95 (s, 9H); 13C NMR (75 MHz, (hexanes–dichloromethane–diethyl ether, 10 : 4 : 1); 1H NMR
(CD3)2CO) δ 156.5 (C), 98.5 (CH), 77.1 (CH2), 59.0 (CH2), 31.9 (C), (300 MHz, (CD3)2CO) δ 7.40 (d, J = 8.2 Hz, 2H, minor), 7.34 (d,
26.9 (CH3), 16.3 (CH3); IR (neat, cm−1) 3330 (br, s), 2956 (s), J = 8.2 Hz, 2H, major), 7.24 (d, J = 7.9 Hz, 2H, major), 7.11 (d,
2902 (s), 2870 (s), 1661 (s), 1245 (s), 1080 (s), 986 (s), 841 (w), J = 7.9 Hz, 2H, minor), 5.12 (d, J = 6.2 Hz, 1H), 4.88 (d, J =
792 (m); HRMS (ESI) calcd for C9H18O2 + Na+ 181.1199, found 10.2 Hz, 1H), 4.51–4.38 (m, 1H), 3.72 (s, 3H, major), 3.54 (s,
181.1201.
3H, minor), 2.36 (s, 3H, major, minor); 13C NMR (75 MHz,
Ethyl 3-(3-(neopentyloxy)but-2-enyloxy)but-2-enoate (13). Clear, (CD3)2CO) δ 163.7 (C), 140.0 (C), 133.2 (C), 129.7 (CH), 129.4
colourless oil (82.0 mg, 96% yield containing 10% Claisen (CH), 126.6 (q, JC–F = 281.2 Hz, CF3), 94.1 (q, JC–F = 2.2 Hz, CH),
rearrangement product, >20 : 1 E : Z); 1H NMR (300 MHz, 69.2 (q, JC–F = 31.6 Hz, CH), 55.8 (CH3), 21.3 (CH3); IR (neat,
(CD3)2CO) δ 5.08 (s, 1H), 4.72 (t, J = 7.6 Hz, 1H), 4.40 (d, J = cm−1) 3391 (br, s), 3009 (w), 2942 (m), 2839 (w), 1652 (s), 1355 (s),
7.6 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.38 (s, 2H), 2.25 (s, 3H), 1270 (s), 1171 (s), 1128 (s), 1106 (s), 1038 (s), 977 (w), 857 (m),
1.88 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H), 0.99 (s, 9H); 13C NMR 827 (m), 743 (m), 695 (s), 668 (w); LRMS (ESI) calcd for
(75 MHz, (CD3)2CO) δ 172.6 (C), 168.1 (C), 160.0 (C), 92.3 (CH), C12H13F3O2 + H+ 247.09, found 247.07.
91.9 (CH), 77.5 (CH2), 66.2 (CH2), 59.4 (CH2), 32.0 (C), 26.9
Ethyl 3-(1,1,1-trifluoro-4-methoxy-4-p-tolylbut-3-en-3-yloxy)-
(CH3), 19.2 (CH3), 16.6 (CH3), 14.8 (CH3); IR (neat, cm−1) 2957 (s), acrylate (19). Clear, pale yellow oil (69.7 mg, 100% yield, 4 : 1
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E : Z); Rf
=
0.35 (hexanes–dichloromethane–ethyl ether,
Notes and references
1
10 : 4 : 1); H NMR (300 MHz, (CD3)2CO) δ 7.38 (d, J = 12.0 Hz,
1H), 7.34–7.35 (m, 4H), 5.16 (d, J = 12.3 Hz, 1H), 5.02 (dq, J =
10.2, 6.0 Hz, 1H), 4.98 (d, J = 10.2 Hz, 1H), 4.08 (qd, J = 7.1, 0.7
Hz, 2H), 3.81 (s, 3H), 2.39 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H);
13C NMR (75 MHz, (CD3)2CO) δ 167.3 (C), 167.0 (C), 160.2
(CH), 140.7 (C), 132.4 (C), 130.2 (CH), 129.5 (CH), 124.9 (q,
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JC–F = 279.0 Hz, CF3), 100.8 (CH), 89.9 (CH), 78.6 (q, JC–F
=
32.4 Hz, CH), 60.2 (CH2), 56.5 (CH3), 21.3 (CH3), 14.6 (CH3);
IR (neat, cm−1) 3031 (w), 2982 (m), 2941 (m), 2841 (w), 1714
(s), 1645 (s), 1370 (m), 1322 (m), 1274 (s), 1179 (s), 1128 (s),
1043 (m), 1022 (m), 947 (m), 887 (w), 827 (m), 696 (m);
HRMS (ESI) calcd for C17H19F3O4 + Na+ 367.1128, found
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Representative Claisen product from 13
Clear, colourless oil (1.00 : 1.74 dr81); Rf = 0.35 (hexanes-
dichloromethane-ethyl ether, 10 : 4 : 1); 1H NMR (300 MHz,
C6D6) δ 6.13 (dd, J = 17.6, 10.8 Hz, 1H, major), 5.91 (dd, J =
17.9, 10.8 Hz, 1H, minor), 5.15 (dd, J = 17.6, 1.5 Hz, 1H,
major), 5.15 (dd, J = 17.9, 1.3 Hz, 1H, minor), 5.11 (dd, J =
10.1, 1.3 Hz, 1H, major), 5.09 (dd, J = 10.8, 1.2 Hz, 1H, minor),
3.91 (m, 2H major, 2H minor), 3.82 (s, 1H, minor), 3.77 (s, 1H,
major), 2.89 (d, J = 10.2 Hz, 1H, major), 2.86 (d, J = 10.8 Hz,
1H, major), 2.86 (d, J = 10.8 Hz, 1H, minor), 2.83 (d, J = 11.1
Hz, 1H, minor), 2.17 (s, 3H, minor), 2.11 (s, 3H, major), 1.56
(s, 3H, minor), 1.47 (s, 3H, major), 0.92 (t, J = 7.1 Hz, 3H,
major), 0.92 (t, J = 7.1 Hz, 3H, minor), 0.89 (s, 9H, major), 0.86
(s, 9H, minor); 13C NMR (75 MHz, C6D6) δ 201.3 (C, minor),
200.6 (C, major), 167.5 (C, major), 167.4 (C, minor), 140.9 (CH,
minor), 140.5 (CH, major), 117.0 (CH2, minor), 116.6 (CH2,
major), 78.4 (C, minor), 77.9 (C, major), 72.0 (CH2, minor),
71.9 (CH2, major), 68.7 (CH, major), 68.1 (CH, minor), 60.8
(CH2, major), 60.7 (CH2, minor), 32.4 (CH3, minor), 31.9
(C, major), 31.7 (C, minor), 31.5 (CH3, major), 27.0 (CH3), 19.9
(CH3, major), 18.2 (CH3, minor), 14.1 (CH3); IR (neat, cm−1
2975 (m), 2955 (s), 2903 (m), 2869 (m), 1733 (s), 1716 (s), 1143 (s),
1071 (s), 927 (w); LRMS (ESI) calcd for C15H26O4 + Na+ 293.17,
found 292.87.
)
24 C. J. Burrows and B. K. Carpenter, J. Am. Chem. Soc., 1981,
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25 C. J. Burrows and B. K. Carpenter, J. Am. Chem. Soc., 1981,
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Acknowledgements
We thank the Natural Sciences and Engineering Research
Council (NSERC) of Canada for operating funds, and for a 26 W. N. White and W. K. Fife, J. Am. Chem. Soc., 1961, 83,
fellowship to N.F.O. We are also grateful to the Canada 3846.
Research Chairs program (CRC) and the Michael Smith Foun- 27 H. M. Frey and D. C. Montague, Trans. Faraday Soc., 1968,
dation for Health Research (MSFHR) for salary support to J.W., 64, 2369.
and to the University of Victoria for additional operating 28 S. E. Denmark and M. A. Harmata, J. Am. Chem. Soc., 1982,
funds. Finally, we thank Dr Ori Granot and the UVic Genome 104, 4972.
BC Proteomics Centre for mass spectrometry support and 29 S. E. Denmark and M. A. Harmata, Tetrahedron Lett., 1984,
Dr Christopher Barr for assistance with NMR experiments.
25, 1543.
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Paper
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localized to a single benzylic center, ρ values of −1.7 to
−6.7 have been reported (see ref. 63). For the rearrange-
ment of compounds 5, several factors would be expected
to reduce this value, although the magnitude of this
reduction is difficult to predict. These factors include:
(1) substantial delocalization of the positive charge onto
both the neighboring oxygen atom and C-4 (as illustrated
in Fig. 6A); (2) structural constraints in the transition state,
leading to a disruption of coplanarity of the aryl system
with the developing carbocation; and (3) the existence of a
closely associated counterion, as evidenced from the cross-
over experiments (vide infra).
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to lie between approximately 0 and 5 cal K−1 mol−1
.
66 The presence of gem-dialkyl substituents at position 4 can
also lead to a reduced ΔS‡, by providing a higher degree of
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67 We are hesitant to ascribe too much meaning to the dia-
stereomeric ratio observed in the rearrangement product,
given that 6 and related structures could presumably
undergo epimerization or diastereoselective decomposi-
tion under the reaction conditions. Nonetheless, for the
substrates studied here, the diastereoselectivity of the
product (when measured directly in the reaction mixture)
appears to track with other measures of transition-state
organization.
52 A. Lubineau, J. Augé, N. Bellanger and S. Caillebourdin, 68 The diastereoselectivity of the rearrangement of 14 also
Tetrahedron Lett., 1990, 31, 4147.
appears to change over time, which lends additional
support to the hypothesis that more than one mechanism
is operative for this substrate.
53 Curran invoked a possible zwitterionic ion pair to rationalize
the unusually fast Claisen rearrangement of α-ethoxyallyl
enol ethers with nitrile substitution at C-1, but this was not 69 An increase in sp2 character at C-4 in the transition state
investigated further; see ref. 22.
(relative to the ground state) would be expected to contrib-
ute to a large secondary kinetic isotope effect, of the same
sign and approximate size as that observed here. However,
estimation of the maximum extent of this effect is difficult
to predict, since the precise electronic role of the C-6
alkoxy substituent is not perfectly understood. It is possible
that hyperconjugative effects owing to the presence of
the C-6 alkoxy group lead to an inflated kinetic isotope
effect.
54 For example, the normalized integration for Z-containing
isomers of 5g is maintained throughout the course of the
reaction, but still provides a 1 : 1 mixture of diastereomers
as products. This precludes any contribution that bond iso-
merization may have with respect to product distribution,
as only E,E-5g undergoes rearrangement at any appreciable
rate.
55 J. M. Dust and D. R. Arnold, J. Am. Chem. Soc., 1983, 105,
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56 X. Creary, M. E. Mehrsheikh-Mohammadi and S. McDonald,
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58 X.-K. Jiang and G.-Z. Ji, J. Org. Chem., 1992, 57, 6051.
71 DFT calculations were carried out at the B3LYP/6-31G* level
of theory.
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72 R. M. Coates and S. J. Hobbs, J. Org. Chem., 1984, 49, 140.
73 H.-K. Chang, Y.-C. Liao and R.-S. Liu, J. Org. Chem., 2007,
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compound 5g, for instance, we determined the following
rates: 130 °C: k = 5.10 × 10−5 s−1; 135 °C: k = 8.59 × 10−5 s−1
;
140 °C: k = 1.35 × 10−4 s−1; 145 °C: k = 2.45 × 10−4 s−1. If B
is not included in the fitting algorithm, the following
values are obtained: 130 °C: k = 5.66 × 10−5 s−1; 135 °C:
k = 1.03 × 10−4 s−1; 140 °C: k = 1.49 × 10−4 s−1; 145 °C: k =
2.52 × 10−4 s−1. In other words, the rates when B is fixed to
zero are higher in each case by an average of 11%. This is a
minor difference in comparison to the overall 5-fold differ-
ence in rate observed in the 145 °C experiment relative to
the 130 °C experiment. Even more significantly for the con-
clusions drawn here, the slope of k vs. temperature is the
same to three significant figures whether or not B is
included in the fit.
74 H. Gao and J. Zhang, Chem.–Eur. J., 2012, 18, 2777.
75 Rigorously dried diethyl ether caused the DIBAL-H
reduction to repeatedly fail, indicating that small amounts
of water are required for successful conversion. Use of
commercially available bulk-quantity diethyl ether, drawn
straight from the bottle, affords the most consistent results.
76 Compound 16 was accessed from 4′-methylacetophenone
(15) following the procedure outlined by Neier: D. Thevenet
and R. Neier, Helv. Chim. Acta, 2011, 94, 331.
77 For a first-order reaction, B should be equal to zero.
However, it is customary in studies such as this one (see
for example: ref. 39) to allow B to float as a way to account 78 C. Pan, F. Luo, W. Wang, Z. Ye and J. Cheng, Tetrahedron
for small experimental errors. These include: (a) the fact Lett., 2009, 50, 5044.
that geometric isomers other than the major E,E species 79 S. T. Gadge and B. M. Bhanage, Synlett, 2013, 24, 981.
will have a different reaction rate, or may not rearrange at 80 G. M. Siqueira, A. F. C. Flores, G. Clar, N. Zanatta and
all; (b) the fact that the substrate may constitute slightly
M. A. P. Martins, Quím. Nova, 1994, 17, 24.
less than 100% of the sample mixture at the nominal 81 Claisen rearrangement was induced at 40 °C in MeOH for a
“start-time” of the reaction; (c) the fact that the sample will
not necessarily be at a single homogenous temperature at
the start of the reaction; and (d) other minor experimental
departures from ideality. Although allowing for a non-zero
value of B provides a better fit to the data, its presence
does not greatly change the observed rate data. For
representative sample of the Claisen adduct from
compound 13. Flash chromatography on silica gel, pre-
treated with 1% triethylamine, afforded a mixture of two
diastereomers (1.00 : 1.74). The dr is not representative of
the product ratio of the crude reaction mixture prior to
purification.
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