Cascading radical cyclization of bis-vinyl ethers: Mechanistic investigation reveals a 5-exo/3-exo /retro-3-exo/5-exo pathway

Article abstract of DOI:10.1021/jo301565u

We recently described an iterative synthesis of oligo-vinyl ethers, followed by a radical cascade to provide a family of hexahydro-2H-furo[3,4-b] pyrans. Our results for the radical cascade were consistent with either a direct 6-endo-trig addition of a vinyl radical onto the first vinyl ether function or an initial 5-exo-trig addition, followed by rearrangement to the more stable anomeric radical intermediate. In this report, we describe our further mechanistic studies aimed at distinguishing between these two possibilities and conclude that the 5-exo/3-exo/retro-3-exo pathway is dominant.

Full text of DOI:10.1021/jo301565u

Article
pubs.acs.org/joc
Cascading Radical Cyclization of Bis-Vinyl Ethers: Mechanistic
Investigation Reveals a 5-exo/3-exo/retro-3-exo/5-exo Pathway
Natasha F. O’Rourke, Katherine A. Davies, and Jeremy E. Wulff*
Department of Chemistry, University of Victoria, Victoria, British Columbia, Canada V8W 3V6
S
* Supporting Information
ABSTRACT: We recently described an iterative synthesis of oligo-vinyl ethers, followed by a radical cascade to provide a family
of hexahydro-2H-furo[3,4-b]pyrans. Our results for the radical cascade were consistent with either a direct 6-endo-trig addition of
a vinyl radical onto the first vinyl ether function or an initial 5-exo-trig addition, followed by rearrangement to the more stable
anomeric radical intermediate. In this report, we describe our further mechanistic studies aimed at distinguishing between these
two possibilities and conclude that the 5-exo/3-exo/retro-3-exo pathway is dominant.
predominate. This reversal of regioselectivity in radical
cyclizations has been harnessed by several groups in the
synthesis of six-membered rings but is particularly notable in
the work of Pattenden and co-workers, who developed a series
of cascading 6-endo-trig cyclizations to access steroidlike carbon
skeletons (and related structural frameworks) from acyclic
precursors (e.g., E → F, Scheme 1).4
Interestingly, some apparent 6-endo-trig radical cyclizations
have been revealed upon further study to result from initial 5-
exo-trig cyclizations, followed by rearrangement of the
intermediate radical (i.e., C → D, Scheme 1).5 This type of
rearrangement can occur when the initially reacting radical
center (X in Scheme 1) can itself act as a transient radical
acceptor. In such cases, intermediate C can be converted to
intermediate D through a 3-exo/retro-3-exo pathway.6 Such
rearrangements are particularly common when X is part of an
aromatic ring, in which case the overall transformation is
referred to as a neophyl rearrangement.5a,d,e,g,h
INTRODUCTION
■
Reactive centers (anions, cations, or radicals) tethered three
atoms away from an alkene acceptor (e.g., an electrophilic
alkene to react with an anion, a nucleophilic alkene to react
with a cation, or an accessible π system to react with a radical)
can engage in either a 5-exo-trig or 6-endo-trig cyclization. Both
of these reaction trajectories are considered “favored” according
to Baldwin’s rules (originally intended to describe reactions
with anions but now loosely taken as a general guideline for
planning all types of cyclizations),1 although the 5-exo process
is typically the faster of the two.2
Particularly for intramolecular radical additions to alkenes,
pioneering work by Beckwith and others showed that the rates
of 5-exo-trig reactions (A → C, Scheme 1) are usually much
faster than the corresponding 6-endo-trig reactions (B → D),
except in cases where the 5-position is more sterically
encumbered.3 In these cases, the 6-endo-trig cyclization may
On the other hand, many 6-endo-trig cyclizations
particularly those in which the 5-position is fully substituted,
as in the Pattenden examples noted abovehave been found to
result from direct 6-endo cyclization and to not involve any
intermediate addition/rearrangement steps.4,5d,7 Clearly, careful
experimentation is required to differentiate between these two
mechanistic possibilities.
Scheme 1. Comparison of 5-exo-trig and 6-endo-trig Radical
Cyclizations
We recently described an iterative synthesis of oligo-vinyl
ethers (e.g., 2, Scheme 2) from simple alcohol building blocks
Received: July 30, 2012
Published: September 5, 2012
© 2012 American Chemical Society
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Scheme 2. Iterative Synthesis of Vinyl Ethers and Radical
Cascade Reaction
Scheme 4. Divergent Reactivity with Trifluoromethyl-
Substituted Vinyl Ethers
exposure of the bis-trifluoromethyl-substituted vinyl ether 4
to a source of tin radicals resulted not in the expected 6-endo/5-
exo cascade but in the generation of compound 5 as the sole
isolable product.
(e.g., 1) and proposed that chemo-orthogonal cascade reactions
across these structures could provide an efficient means to
access variously functionalized complex molecules.8 As a proof
of principle for this approach, we reported a cascading 6-endo/
5-exo radical cascade across a selection of bis-vinyl ethers, to
afford a series of hexahydro-2H-furo[3,4-b]pyrans (3). To the
best of our knowledge, this was the first report of a radical
cascade in a bis-vinyl ether system.
Compound 5 appeared to result from a 5-exo-trig cyclization,
followed by β-scission. In contrast, bis-vinyl ether 6, containing
a single trifluoromethyl substituent, cyclized to give the usual
bicyclic system in good yield. The first vinyl ether group to
participate in a radical cyclization reaction is the same for
compounds 4 and 6, and it seemed unlikely that a change in
substituents on the second vinyl ether could trigger a change in
regioselectivity of the initial radical cyclization. A far more likely
explanation for the divergent reactivity is that both 4 and 6
reacted through an initial 5-exo attack but that the presence of
the second trifluoromethyl substituent in compound 4 favored
a fast β-scission, essentially trapping intermediate H (Scheme
3) before it had a chance to rearrange to the apparent 6-endo
intermediate I.
In discussing the likely mechanism for the cascade reaction,8
we noted that we could not conclusively distinguish between a
direct 6-endo-trig cyclization (i.e., G → I, Scheme 3) and the
Scheme 3. Two Mechanistic Possibilities for Closure of the
Six-Membered Ring
This single experiment is compelling evidence in favor of a 5-
exo/3-exo/retro-3-exo process, but we recognized the possibility
that the reactivity displayed by trifluoromethyl-substituted
compounds 4 and 6 may not be representative of reactivity
in simpler alkyl-substituted vinyl ethers. We therefore sought to
install cyclopropane groups into our structures as probes12 for
the presence of radical character at both the 5- and 6-positions
(relative to the approaching radical) throughout the cyclization
of the six-membered ring.
In designing these reactivity probes, we recognized that
building the cyclopropane substituents into bis-vinyl ether
substrates was unnecessary, since our early optimization studies
had shown that even mono-vinyl ethers (e.g., 8, Scheme 5)
cyclized to give exclusively the six-membered-ring product (e.g.,
9), so long as the vinyl ether function contained an additional
substituent on the oxygen-bearing carbon and was not
conjugated to an electron-withdrawing function. Less-substi-
tuted vinyl ethers (e.g., 10), as well as those conjugated to
esters (e.g., 13) cyclized to give mixtures of five- and six-
membered-ring products. Combining these two structural
features, we found that less-substituted vinyl ethers that also
contained an electron-withdrawing group (e.g., 16) cyclized to
give exclusively the five-membered-ring product.
Therefore, to test the hypothesis that all of these vinyl ether
substrates (2, 4, 6, 8, 10, 13, and 16) cyclized through a
conserved initial 5-exo-trig addition, we targeted cyclopropanes
21 and 32 (Schemes 6−8) as mechanistic probes.
Compound 21, incorporating a cyclopropane substituent on
the oxygen-bearing carbon of the vinyl ether function, was
accessed by conjugate addition of butynol 1 to the known
corresponding 5-exo/3-exo/retro-3-exo pathway (i.e., G → H
→ J → I) to close the first ring9 and promised additional
mechanistic studies to resolve this question. In the present
report, we describe the results of these mechanistic studies,
which confirm the involvement of an initial 5-exo-trig addition
to the first vinyl ether moiety. Understanding the origins of the
regiochemical control in this unusual radical cascade will
ultimately permit other types of bicycles (and higher order
systems) to be accessed from iteratively synthesized precur-
sors.10
RESULTS AND DISCUSSION
■
Our first indication that the 5-exo/3-exo/retro-3-exo pathway
might be operative came with an attempt to extend our
cyclization methodology toward the preparation of trifluor-
omethyl-substituted bicycles.11 As shown in Scheme 4,
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Scheme 5. Cyclizations of Mono-Vinyl Ethers: Substitution
Dictates Regioselectivity
Scheme 8. Synthesis of Cyclopropane 32
unstable alcohol 20 and subject it to methylation conditions
before it was able to decompose.
Compound 32, incorporating a cyclopropane on the non-
oxygen-bearing carbon of the vinyl ether function, proved more
challenging to synthesize. Inspired by literature precedent
showing the selective cyclopropanation of dienyl ethers,14 we
initially hoped to access 32 through a carefully controlled
cyclopropanation of diene 25 (Scheme 7). This substrate was
prepared by conjugate addition and reduction to access the
known alcohol 23,8 followed by oxidation with IBX and
subsequent olefination.
Scheme 6. Synthesis of Cyclopropane 21
Unfortunately, we were unable to drive the cyclopropanation
of 25 to completion without causing extensive decomposition
of the substrate. Control experiments with dienyl ethers lacking
alkynes (not shown) were more successful, suggesting that the
problem lay in cross-reactivity of the cyclopropanating reagents
(several of which were tried in the hopes of exploiting 25) with
the terminal alkyne.
We therefore sought to protect the alkyne throughout the
cyclopropanation step. Silyl-protected alkynes 26a,b were
prepared following literature protocols15 and were subjected
to a conjugate addition/reduction sequence (Scheme 8) to
afford alcohols 28a,b in good yield, with no evident migration
of the silyl substituents onto the primary alcohol. Oxidation and
olefination proceeded in poor yield, but the diene substrates
(30a,b) could nonetheless be obtained in sufficient quantity to
permit evaluation of the cyclopropanation step.
Scheme 7. Synthesis of Diene 25
We were pleased to find that both 30a,b were much better
substrates for the cyclopropanation than was unprotected
alkyne 25. Treatment with an excess of freshly generated
diazomethane, in the presence of a palladium(II) acetylaceto-
nate catalyst,16 resulted in good conversion to the correspond-
ing cyclopropane, without inducing decomposition. Finally,
both silyl protecting groups could be removed by treatment
with a fluoride source, affording 32 (contaminated with a small
quantity of 25, owing to incomplete conversion in the
cyclopropanation step) for use in radical cyclization experi-
ments.
cyclopropane-containing propynoate 18,13 followed by reduc-
tion and methylation (Scheme 6). The unexpectedly low yield
for the addition step was attributed to the instability of both the
reactant (18) and the product (19). The reduction product
(20) proved even more unstable, such that we were unable to
access it under our usual DIBAL reduction conditions, which
require >2 h to proceed to completion. Switching to a more
reactive reducing agent (LiAlH4) allowed us to access the
As expected, cyclization of compound 21 yielded exclusively
the cyclopropane-opened pyran derivative 33 (Scheme 9),
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To probe the order of steps in radical cyclization processes
such as these, it is common to repeat the reaction under study
at various temperatures, with varying rates of addition of the tin
hydride/radical initiator mixture. Whichever product is favored
at lower temperatures and faster addition times is understood
to correspond to the earlier-formed intermediate in the
cyclization reaction. Unfortunately, these types of experiments
are not appropriate for the substrates described here, for two
important reasons. First, even for simple mono-vinyl ether/
alkyne conjugates (e.g., 8) the cyclization reaction is a multistep
process involving first the addition of a tin radical to the alkyne
and then cyclization; attempts to add the tin reagent more
quickly led mostly to the product of direct Sn−H addition
across the alkyne function. Second, for most of the reactions
described above, we observed only a single product; a brief
survey of alternative reaction conditions failed to yield any
other cyclization product that we could use as a basis for
comparison.
Scheme 9. Probing for the Location of Radical Character
during the Cyclization
To resolve these issues and permit the further study of the
radical cascade reaction, we targeted compounds 39a−c
(Scheme 10) as probes.17 We envisioned that these substrates
would allow us to generate the vinyl radical intermediate
(analogous to G in Scheme 3) directly from the vinyl bromide
Scheme 10. Synthesis of Vinyl Bromide Substrates
confirming that the radical character is maintained throughout
the cyclization and that the initial vinyl radical resulting from
tin addition to the alkyne (G, Scheme 3) does not participate in
any single-electron-oxidation or -reduction processes prior to
cyclization. Although intermediate anions or cations might lead
to similar cyclization products, these would not be expected to
trigger opening of the cyclopropane in this manner.
Gratifyingly, compound 32 cyclized to provide exclusively
the cyclopropane-opened furan derivative 34, lending consid-
erable support to the hypothesis that 5-exo-trig cyclization is the
initial step in the overall cyclization mechanism leading to
bicycle 3.
Somewhat surprisingly, even diene 25 cyclized to give only
the five-membered-ring products 35a,b in a 4/1 ratio, lending
additional support to this hypothesis. Isomers 35a,b were not
separable by column chromatography, but treatment with
PdCl2(MeCN)2 in refluxing benzene isomerized the terminal
olefin in 35b, affording a clean sample of 35a for character-
ization purposes.
The results in Scheme 9 are compelling, but we could not
ignore the possibility (however unlikely) that the apparent 5-
exo-trig/β-scission products 5, 34, and 35 could in fact arise
throught initial 6-endo-trig cyclization, followed by isomer-
ization to the apparent 5-exo intermediate and subsequent
fragmentationessentially the exact opposite of our proposed
mechanistic pathway!
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function, thereby removing (at least partially) the first problem
noted above. The use of an electron-withdrawing group
conjugated to the vinyl ether was expected to result in a
mixture of pyran and furan products (as previously noted in the
cyclization of 13; Scheme 5), thus resolving the second
problem and providing us with two detectable species, the
relative concentrations of which might vary in response to
applied cyclization conditions. At the same time, the presence
of electron-donating (X = OCH3), electron-neutral (X = H) or
electron-withdrawing (X = C(O)CH3) functional groups on
the aromatic ring might provide some useful information
regarding the energetic barrier associated with the 3-exo/retro-
3-exo isomerization process.
Compounds 39a,b were synthesized as shown in Scheme 10.
The appropriate aryl halide starting material (36a,b) was
coupled to unprotected alkyne 1 in a Sonogashira reaction. The
cross-coupled product (37) was then subjected to a hydroxy-
directed hydrozirconation,18 the product of which was reacted
with N-bromosuccinimide to afford the desired vinyl bromide
as a single regio- and stereoisomer (38). Conjugate addition
proceeded smoothly as expected, to provide the desired
cyclization substrates.
conducted under identical conditions. Compound 39c did not
react under these conditions, presumably because the electron-
withdrawing ketone conjugated to the vinyl halide function
made the bromide more difficult to abstract.
Changing to a faster addition rate (entries 4 and 5)19 resulted
in a significant increase in the amount of the five-membered-
ring product (41) relative to the six-membered-ring product
(42). This result unambiguously confirms the 5-exo-trig
addition as the first step in the cascade, thus establishing the
overall mechanism in the synthesis of bicycle 3 as 5-exo-trig/3-
exo-trig/retro-3-exo-trig/5-exo-trig.20
The fact that the methoxy-substituted vinyl bromide
substrate (39b) gave a very similar ratio of 5-exo and 6-endo
product to the unsubstituted substrate (39a) was somewhat
surprising; we had anticipated that the presence of the electron-
donating methoxy group would help to stabilize the product of
the 3-exo-trig cyclization (analogous to intermediate J in
Scheme 3), thereby reducing the overall barrier to isomer-
ization and favoring the six-membered-ring product 42. To
explain why this did not occur, we turned to DFT calculations21
to evaluate the relative heats of formation for the various
intermediate radical species.22 As shown in Chart 1, the
Efficient assembly of compound 39c required that the
carbonyl group be unmasked for the Sonogashira step (where
an electron-deficient aryl group was advantageous) but be
protected for the hydrozirconation step (where a nucleophilic
alkene was required for optimal reactivity). A protect/deprotect
sequence was therefore included in the synthesis of this
substrate.
Chart 1. DFT Calculations Investigating the Effect of
Substitution on the Aromatic Ring
Vinyl bromides 39a−c were subjected to our usual radical
cyclization conditions. Varying the temperature of the reaction
did not provide any useful information: lower temperatures led
to no reaction, while higher temperatures resulted only in
premature decomposition of the radical initiator. However,
varying the rate of addition of the Ph3SnH/AIBN mixture
proved much more informative.
Substrates 39a,b both cyclized to afford an approximately 1/
1 ratio of five-membered- and six-membered-ring products
(Table 1, entries 1 and 2) when the Ph3SnH and AIBN
reagents were added over a 6.25 h period. This result agrees
very well with the cyclization of 13 (Scheme 5), which was
presence of the methoxy group does not substantially change
the relative energies of the 3-exo product (J′). In fact, the
calculated energies for all three cyclic intermediates (relative to
that of the original vinyl radical) are essentially identical
between the two series. The calculated energies for the five- and
six-membered-ring radical intermediates (H′ and I′, respec-
tively) are also quite close together (within about 1 kcal/mol),
favoring the formation of a product mixture. This is consistent
with the experimental result reported in Table 1, in which
compounds 41 and 42 were observed in similar quantities when
the tin hydride source was added slowly.
Table 1. Change in Product Distribution with Addition
Rate
a
b
entry
substrate
X
addition time, h
40/41/42
Taken together, our results provide compelling evidence that
radical cyclization of each of the vinyl ether species discussed
here proceeds through an initial 5-exo attack. Viewed from this
perspective, however, the results in Scheme 5 were somewhat
puzzling. At first glance, the enhanced preference for six-
membered-ring products observed for the methyl-substituted
vinyl ethers 8 and 13, relative to that observed for the less-
substituted analogues 10 and 16, looks like a classic kinetically
controlled regioselectivity bias, where the incoming radical has
been directed away from the more-substituted end of the vinyl
ether function. But this cannot be the case if all of our
1
2
3
4
5
39a
39b
39c
39a
39b
H
6.25
6.25
6.25
2.50
2.50
0.5/1.0/1.0
0.8/1.2/1.0
c
OCH3
C(O)CH3
H
1.0/1.5/1.0
1.3/1.5/1.0
OCH3
a
Conditions: (i) Ph3SnH (1.5 equiv) and AIBN (0.1 equiv) was added
to a refluxing solution of 39 (8 mM) in benzene. Heating was
continued for 1.5 h prior to workup. Compound 42 was formed as a
1/1 mixture of geometric isomers. Only recovered starting material
b
c
was observed.
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cyclizations in fact proceed through initial 5-exo attack. Instead,
the regiochemical control must be due either to a change in the
rate of the five-membered-ring to six-membered-ring isomer-
ization or to a difference in the thermodynamic preference for
the six-membered-ring radical precursor (I, Scheme 3) relative
to the five-membered-ring radical precursor (H, Scheme 3).
To explore the means by which substitution on the vinyl
ether dictates the regiochemical outcome for the cyclization
reaction, we again turned to DFT calculations20 to evaluate the
relative heats of formation for the intermediate radical species
leading to compounds analogous to 9 versus those leading to
11 and 12. To avoid relativistic effect problems associated with
the tin atom, we replaced the triphenyl tin substituent with a
methyl group.
hydride source (Ph3SnH), an identical product would result to
those described above. However, such a mechanism would
undermine the potential utility of future radical cascade
reactions, in which these intermediate radical species are
required to persist long enough to engage in additional
cyclization steps.
To evaluate the likelihood of such unwanted reactions taking
place, we synthesized a series of deuterated analogues, by using
LiAlD4 in place of the usual reducing agent (either DIBAL or
LiAlH4) in the conjugate addition/reduction sequence. In
designing these experiments, we intentionally chose a substrate
(48) that we knew from our previous studies8 to provide both
monocyclic and bicyclic products (49 and 50) upon cyclization.
In this way, we anticipated being able to isolate and characterize
two distinct products deriving from each deuterated substrate,
thereby allowing us to more completely probe the stability of
the various intermediate radical species. We were particularly
interested in interrogating the monocyclic product 50, since we
reasoned that unwanted hydrogen (or deuterium) transfer to
the relatively long-lived anomeric radical species I was among
the more likely of several potential unwanted radical
scramblings. If no deuteration were detected at the anomeric
position of product 50 following the cyclization of a deuterated
substrate, this could be taken as promising evidence against the
likelihood of premature quenching through hydrogen atom
transfer.
As shown in Chart 2, the presence of the methyl group at the
R1 position, relative to a hydrogen atom, both destabilizes the 5-
Chart 2. DFT Calculations Investigating the Effect of
Substitution on the Vinyl Ether
As shown in Scheme 11, the complete series of deuterium-
substituted substrates (48a−d) was accessed efficiently.
Scheme 11. Synthesis of Deuterated Substrates
exo radical intermediate H″ (due to steric strain associated with
the introduction of an extra quaternary center) and stabilizes
the corresponding anomeric radical intermediate I″ (by
incorporating a greater degree of substitution at the radical
center). Together, these two effects work to nearly double the
degree to which the six-membered-ring radical intermediate is
favored (7.4 kcal/mol when R1 = CH3 vs 4.4 kcal/mol when R1
= H). While this analysis of course omits any discussion of the
rate at which these species may be quenched by the incoming
hydride donor, it nonetheless provides some explanation for the
extent to which substitution on the vinyl ether group can
control the regiochemical outcome of the reaction without
changing the site of initial radical attack.
The detailed understanding of mechanism developed thus far
for the conversion of 2 into 3 should be useful in the design of
future radical cascades leading to alternatively fused bicycles
and polycycles. However, this will only be true if the various
radical intermediates (G−K) are well-behaved and do not
participate in hydrogen atom transfers with other positions on
the substrate. In particular, we recognized that two carbon
centers on bis-vinyl ether 2 were positioned between alkenes
and oxygen atoms. As a result, the C−H bonds at these centers
should have relatively low bond strengths (i.e., the resulting
radicals would be highly stabilized). If hydrogen atom
abstraction from these positions should occur, such that the
transferred hydrogen atom quenches a late-stage radical
intermediate (H, I, or K) prior to quenching with the desired
Gratifyingly, cyclization of these compounds (Table 2, entries
1−4) led to no migration of the deuterium label(s) from the
starting locations, in either the fully cyclized (49; see Figure 1)
or partially cyclized (50; see Figure 2) products. No partial
deuteration of undeuterated positions could be detected by
NMR integration of the purified products, nor could any degree
of deuterium erosion be detected from initially deuterated
positions. These results were confirmed by MS analysis of the
products.
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a
Table 2. Cyclization of Deuterated Substrates
49
50
d
d
d
d
d
d
entry
substrate + hydride source
yield, %
X
Y
Z
yield, %
X
Y
Z
b
1
2
3
4
5
48a + Ph3Sn−H
48b + Ph3Sn−H
48c + Ph3Sn−H
48d + Ph3Sn−H
48a + Ph3Sn−D
55 (49a)
H (>90)
H (>90)
D (>90)
D (>90)
H (>90)
H (>90)
D (>90)
H (>90)
D (>90)
H (>90)
H (>90)
H (>90)
H (>90)
H (>90)
27 (50a)
39 (50b)
42 (50c)
50 (50d)
40 (50e)
H (>90)
H (>90)
D (>90)
D (>90)
H (>90)
H (>90)
D (>90)
H (>90)
D (>90)
H (>90)
H (>90)
H (>90)
H (>90)
H (>90)
D (>90)
44 (49b)
46 (49c)
35 (49d)
36 (49e)
c
D (>90)
a
Conditions: (i) Ph3SnZ (1.5 equiv) and AIBN (0.1 equiv) were added to a refluxing solution of 48 in benzene. Heating was continued for 1.5 h
b
prior to workup. The reaction shown in entry 1 was run at a lower concentration (1.6 mM) than for the reactions in entries 2−5 (8 mM). This has
the effect of increasing the yield of 49, relative to that of 50. For product 49e, two diastereotopic hydrogen atoms can be replaced by deuterium;
approximately 50% deuteration was observed at each position. The percent incorporation is given in parentheses.
c
d
Figure 2. 1H NMR data showing deuteration of monocycle 50.
Legend: (a) compound 50 was formed as a mixture of geometric
isomers at the tin-bearing alkene, and tin satellite peaks are also visible
in this region.
1
Figure 1. H NMR data showing deuteration of bicycle 49. Legend:
(a) compound 49 was formed as a mixture of geometric isomers at the
tin-bearing alkene, and tin satellite peaks are also visible in this region;
(b) upon deuteration of position X, signals for a proton from the
while a series of experiments with deuterium-substituted
minor isomer are revealed; (c) 50% deuteration at each of the two
positions labeled Z was achieved.
trig pathway for the radical cascade leading to the formation of
bicycle 3. This result is further supported by DFT calculations,
cyclization substrates confirmed that the radical intermediates
are positionally stable, implying that mechanistically related
radical cascades could be used to access an increased diversity
of ring structures.
To complete this series of experiments, we prepared Ph3Sn-
D23 and used this in a cyclization of the nondeuterated bis-vinyl
ether 48a (Table 2, entry 5). As anticipated, we observed
complete deuteration at the anomeric position of 50 (see
Figure 2), along with 50% deuteration at each of two
diastereotopic positions in bicycle 49 (see Figure 1).
EXPERIMENTAL SECTION
■
General Methods. 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 and 40 °C
by rotary evaporation under vacuum. Analytical thin-layer chromatog-
raphy (TLC) was performed using aluminum plates precoated 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 p-
CONCLUSION
■
Taken together, the experimental results described here
strongly support a 5-exo-trig/3-exo-trig/retro-3-exo-trig/5-exo-
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anisaldehyde. Flash column chromatography was performed over silica
gel 60 (Caledon, 63−200 μM).
silyl-protected alkynol 28, a competing side reaction led to an
inseparable mixture of compounds following IBX oxidation. The crude
product was therefore taken forward to the Wittig olefination step, at
which point diene 30 could be cleanly isolated.
All reagents were used as received, unless otherwise indicated.
Bis(cyclopentadienyl)zirconium(IV) chloride hydride was purchased
from Strem Chemicals, stored in a glovebox, and used without further
purification. Commercial solvents were used as received with the
following exceptions. Anhydrous tetrahydrofuran was distilled from
sodium/benzophenone prior to use. Acetonitrile, diethyl ether, and
dichloromethane were dried by passage through a column of alumina
in a commercial solvent purification system (SPS). Triethylamine was
distilled over calcium hydride and stored under an inert atmosphere of
argon. Benzene was distilled over calcium hydride and degassed by
freeze−pump−thaw prior to use.
General Procedure for the Wittig Olefination. n-Butyllithium
(2.0 M in hexanes, 1.10 mmol) was added dropwise to a stirred
solution of methyltriphenylphosphonium bromide (1.10 mmol) in
anhydrous tetrahydrofuran (6 mL) at −15 °C. The resulting clear,
orange solution was kept at −15 °C for 15 min. A solution of aldehyde
(24 or 29, 1.00 mmol) in anhydrous tetrahydrofuran (2 mL) was
added dropwise, via cannula, and the resultant slurry was gradually
warmed from −15 °C to room temperature over 2.5 h. The reaction
mixture was quenched with water and extracted twice with diethyl
ether. The combined organic extracts were dried over sodium sulfate,
filtered, concentrated in vacuo, and purified by flash column
chromatography using 1% triethylamine-treated silica gel to afford
dienes 25 and 30 as clear, colorless to pale yellow oils.
General Procedure for the Cyclopropanation Reaction.
Alkene 30a or 30b (0.58 mmol) was dissolved in anhydrous diethyl
ether (10 mL) and cooled to 0 °C. Palladium(II) acetylacetonate
(0.0021 g, 0.0069 mmol) was added to the reaction vessel, followed by
6 mL of diazomethane in ether (∼20 mg of diazomethane/mL of
ether). The resulting mixture was warmed to room temperature for 45
min and then cooled to 0 °C. The addition of palladium(II)
acetylacetonate followed by diazomethane was repeated a total of six
times while cycling through from 0 °C to room temperature after each
set of additions. After the sixth addition of reagents, the reaction vessel
was gradually warmed to room temperature and the reaction mixture
was stirred overnight (∼14 h). The reaction contents were filtered
through a plug of Celite, concentrated in vacuo, and then purified by
flash column chromatography (1% triethylamine-treated silica gel) to
afford cyclopropane 31a or 31b (with 8−14% of contaminant 30, after
purification).
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, δ 2.05;
CD2Cl2, δ 5.32). Likewise, 13C chemical shifts are referenced to the
carbon resonances of the solvent (CDCl3, δ 77.22; CD3C(O)CD3, δ
29.85). Accurate masses were obtained using an Orbitrap MS. Infrared
spectra were collected using an FT-IR spectrometer.
General Procedure for Conjugate Addition. The alkyne (18,
22, 43, or ethyl propiolate, 1.00 mmol) was added dropwise to a
stirred solution of alcohol (1, 26, 38, or 45, 1.00 mmol) and
trimethylphosphine (1.0 M in THF, 0.10 mmol) in dry dichloro-
methane (5 mL). The reaction mixture was stirred at room
temperature for 18 h. The solvent was then removed under vacuum,
and the residue was resuspended in diethyl ether (∼10 mL). The
resulting suspension was filtered through a thin layer of basic alumina.
The filtrate was concentrated in vacuo and purified by flash column
chromatography using silica gel pretreated with 1% triethylamine, to
afford the conjugate addition product (13, 16, 19, 27, 39, 44, or 46) as
clear, colorless to orange oils. Alcohols 39a,b (1.00 mmol) were first
washed with saturated Na2S2O3(aq) prior to their use in the conjugate
addition reaction.
General Procedure for the TBAF Deprotection of Cyclo-
propanes 31. Tetrabutylammonium fluoride (1.10 mmol) was added
dropwise to a stirred solution of cyclopropane 31a or 31b (1.00
mmol) in anhydrous tetrahydrofuran (27 mL) at 0 °C. The progress of
the reaction was monitored by TLC. After complete conversion was
indicated by TLC, the reaction mixture was quenched with saturated
NH4Cl(aq) and extracted twice with diethyl ether. The organic
extracts were dried over anhydrous sodium sulfate, filtered,
concentrated in vacuo, and then purified by flash column
chromatography (1% triethylamine-treated silica gel) to afford 32a
or 32b as a clear, pale yellow oil.
General Procedure for the Sonogoshira Coupling. Bis-
(triphenylphosphine)palladium(II) dichloride (0.02 mmol), copper(I)
iodide (0.01 mmol), aryl halide (1.00 mmol) and 3-butyn-1-ol (1; 1.20
mmol) were dissolved in dry triethylamine (∼6 mL) and subsequently
heated to reflux. After 2.5 h, the reaction mixture was quenched with
an ethyl acetate/water mixture (1/1, 25 mL) and the aqueous and
organic phases were separated. The organic layer was washed with
water and then brine, dried over anhydrous sodium sulfate, filtered,
concentrated in vacuo, and purified by flash column chromatography
on silica gel to afford 37a−c as clear, orange oils.
General Procedure for the Hydrozirconation Reaction. A
solution of 37a, 37b, or 37d (1.00 mmol) in dry dichloromethane (2.5
mL) was added, via cannula, to a stirred suspension of bis-
(cyclopentadienyl)zirconium(IV) chloride hydride (3.00 mmol) in
dry dichloromethane (3.8 mL) at ambient temperature, followed by
rinsing with dichloromethane (2.5 mL). The mixture was stirred in the
absence of light for 3 h, forming a clear yellow to orange solution. N-
Bromosuccinimide (2.00 mmol) in anhydrous tetrahydrofuran (4 mL)
was added dropwise to the reaction mixture, which was stirred for an
additional 0.5 h. The reaction mixture was quenched by addition of a
mixed aqueous solution of saturated Na2S2O3 and saturated NaHCO3
(1/1, 20 mL) and diluted with diethyl ether, and the aqueous and
organic layers were separated. The aqueous layer was extracted twice
with diethyl ether, and the combined organic layers were dried over
anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified
General Procedure for LiAlH4 Reduction. Lithium aluminum
hydride (or lithium aluminum deuteride) (2.00 mmol) was added in
one portion to a stirred solution of the ester (13, 19, 27, 44, or 46,
1.00 mmol) in anhydrous diethyl ether (10 mL) maintained at 0 °C.
After 1.5 h the reaction mixture was diluted with diethyl ether and
subsequently quenched with 10% KOH(aq). The two phases were
separated, and the aqueous layer was extracted twice with diethyl
ether. The combined organic extracts were dried over anhydrous
sodium sulfate, filtered, concentrated in vacuo, and purified by flash
column chromatography using silica gel pretreated with 1% triethyl-
amine, to afford alcohols 20, 23, 28, 45, and 47 as clear, colorless to
pale yellow oils.
General Procedure for Methylation. Following our procedure
reported earlier,8 iodomethane (3.00 mmol) was added dropwise via
syringe to a stirred mixture of alcohol (20 or 47, 1.00 mmol) in dry
tetrahydrofuran at 0 °C. Sodium hydride (60% w/w in mineral oil,
2.00 mmol) was added in one portion to the reaction mixture, and the
resulting slurry was warmed to ambient temperature overnight (∼18
h). The reaction was quenched with saturated NH4Cl(aq) and 10%
KOH(aq) and extracted twice with diethyl ether. The combined
organic extracts were dried over anhydrous sodium sulfate, filtered,
concentrated in vacuo, and purified by flash column chromatography
(1% triethylamine-treated silica gel, hexanes/ethyl acetate, 40/1 to 1/2
gradient), to afford methyl ethers 21 and 48 as clear, colorless to pale
yellow oils.
General Procedure for IBX Oxidation. 2-Iodoxybenzoic acid
(1.20 mmol) was added in one portion to a stirred solution of alcohol
(23 or 28, 1.00 mmol) in dry acetonitrile (3.0 mL) at ambient
temperature. The progress of the reaction was monitored by TLC.
Upon consumption of the alcohol (∼3 h), the reaction was quenched
with brine and solids were removed by filtration through a fritted-glass
funnel. The two phases were separated, and the aqueous layer was
extracted twice with dichloromethane. The combined organic layers
were dried over sodium sulfate, filtered, concentrated in vacuo, and
purified by flash column chromatography using 1% triethylamine-
treated silica gel to afford the corresponding aldehyde. In the case of
8641
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by flash column chromatography to afford 38a, 38b, or 38c as a single
regio- and stereoisomer.
60.7 (CH2), 59.1 (CH), 34.9 (CH2), 19.3 (CH3), 14.5 (CH3); IR
(neat, cm−1) 3064 (m), 2978 (m), 1732 (s), 1609 (m), 1091 (s), 729
(s), 699 (s); HRMS (ESI) calcd for C28H30O3Sn + H+ 535.1290,
found 535.1301.
Procedure for the Acetal Protection of 37c. p-Toluenesulfonic
acid (20.8 mg, 0.0710 mmol), 37c (290.1 mg, 1.541 mmol), and
ethylene glycol (0.34 mL, 3.96 mmol) in 30 mL of benzene were
heated to reflux with a Dean−Stark apparatus for 25 h. The reaction
mixture was cooled to room temperature and washed once with
saturated NaHCO3(aq) and twice with brine. The organic layer was
dried over anhydrous sodium sulfate, filtered, concentrated in vacuo,
and purified by flash column chromatography on silica gel (hexanes/
ethyl acetate, 1/1) to afford 37d (220.3 mg, 0.9484 mmol) as a clear,
pale yellow oil.
Procedure for the Acetal Deprotection of 38c. Hydrochloric
acid (1.0 M, 0.45 mL) was added to a stirred solution of 38c (30.5 mg,
0.0974 mmol) in methanol (7.5 mL) at room temperature. After 1 h
the solution was diluted with water and methanol was removed by
concentration under reduced pressure. The aqueous mixture was
extracted twice with diethyl ether, and the organic extracts were
washed with brine, dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo to afford 38d (21.5 mg, 0.0799 mmol) as a
clear, yellow-orange oil which was used without further purification.
General Procedure for the Radical Cyclization Reaction. A
solution of triphenyltin hydride (1.50 mmol) and azobisisobutyroni-
trile (0.10 mmol) in deoxygenated benzene (10 mL) was added, via
syringe pump, to a refluxing solution of enyne (8, 10, 13, 16, 21, 25,
32, or 48) or vinyl bromide 39 (1.00 mmol) in deoxygenated benzene
(115 mL) over 6.25 h. The reaction mixture was maintained at reflux
for an additional 1.5 h, cooled to room temperature, concentrated in
vacuo, and then purified by flash-column chromatography to afford
products 9, 11, 12, 14, 15, 17, 33, 34, 35, 40, 41, 42, 49, and 50 as
clear, colorless to pale yellow oils.
Ethyl 2-(2-methyl-3-((triphenylstannyl)methylene)-
tetrahydrofuran-2-yl)acetate (15): clear, colorless oil (73.1 mg,
46% yield); Rf = 0.19 (hexanes/dichloromethane/ethyl ether, 10/4/
1); 1H NMR (300 MHz, CDCl3) δ 7.63−7.54 (m, 5H), 7.44−7.34 (m,
10H), 5.96 (t, J = 2.3 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.95−3.78 (m,
2H), 2.72 (d, J = 18.1 Hz, 1H), 2.68 (d, J = 18.1 Hz, 1H), 2.66−2.43
(m, 2H), 1.49 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.5 (C), 168.2 (C), 138.5 (C), 137.1 (CH), 129.3 (CH),
128.9 (CH), 113.1 (CH), 83.4 (C), 65.1 (CH2), 60.5 (CH2), 45.5
(CH2), 35.6 (CH2), 26.6 (CH3), 14.4 (CH3); IR (neat, cm−1) 3064
(m), 2978 (m), 1733 (s), 1622 (w), 1075 (m), 729 (s), 700 (s);
HRMS (ESI) calcd for C28H30O3Sn + Na+ 557.1109, found 557.1117.
Ethyl 3-(but-3-yn-1-yloxy)acrylate (16): clear, colorless oil (670.9
mg, 93% yield, 1.00/0.06 E/Z); Rf = 0.54 (hexanes/dichloromethane/
1
ethyl ether, 5/5/1); H NMR (300 MHz, (CD3)2CO) δ 7.59 (d, J =
12.6 Hz, 1H), 5.25 (d, J = 12.6 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 4.06
(t, J = 6.6 Hz, 2H), 2.62 (td, J = 6.5, 2.8 Hz, 2H), 2.46 (t, J = 2.8 Hz,
1H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, (CD3)2CO) δ
167.6 (C), 162.8 (CH), 97.7 (CH), 80.9 (C), 71.5 (CH), 70.1 (CH2),
60.0 (CH2), 19.7 (CH2), 14.7 (CH3); IR (neat, cm−1) 3296 (s), 3093
(m), 2982 (s), 2951 (s), 2896 (s), 2124 (w), 1708 (s), 1628 (s), 1468
(s), 1045 (s), 970 (s), 825 (s), 646 (s); HRMS (ESI) calcd for
C9H12O3 + Na+ 191.0679, found 191.0679.
Ethyl 2-(3-((triphenylstannyl)methylene)tetrahydrofuran-2-yl)-
acetate (17): clear, colorless oil (149.0 mg, 83% yield); Rf = 0.54
1
(hexanes/dichloromethane/ethyl ether, 5/5/1); H NMR (500 MHz,
CDCl3) δ 7.59−7.54 (m, 5H), 7.44−7.34 (m, 10H), 6.02 (app q, J =
2.1 Hz, 1H), 4.82−4.74 (m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.94 (ddd, J
= 8.5, 7.6, 5.3 Hz, 1H), 3.75 (app dt, J = 8.3, 7.7 Hz, 1H); 2.75 (dd, J =
15.5, 4.0 Hz, 1H), 2.63 (dd, J = 15.5, 8.7 Hz, 1H), 2.54−2.38 (m, 2H),
1.27 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.2 (C),
163.9 (C), 138.3 (C), 137.0 (CH), 129.3 (CH), 128.9 (CH), 113.8
(CH), 79.0 (CH), 67.2 (CH2), 60.8 (CH2), 40.7 (CH2), 35.4 (CH2),
14.3 (CH3); IR (neat, cm−1) 3064 (s), 3047 (s), 2980 (s), 2863 (s),
1735 (s), 1625 (m), 1480 (m), 1429 (s), 1163 (s), 1075 (s), 729 (s),
699 (s); HRMS (ESI) calcd for C27H28O3Sn + Na+ 543.0953, found
543.0955.
Triphenyl((2-(trifluoromethyl)-2-vinyldihydrofuran-3(2H)-
ylidene)methyl)stannane (5): clear, pale yellow oil (43.9 mg, 80%
1
yield); Rf = 0.78 (hexanes/ethyl acetate, 2:1); H NMR (500 MHz,
CDCl3) δ 7.60−7.54 (m, 6H), 7.43−7.37 (m, 9H), 6.43 (br s, 1H),
6.08 (dd, J = 16.9, 10.6 Hz, 1H), 5.65 (d, J = 17.2 Hz, 1H), 5.40 (d, J =
10.6 Hz, 1H), 4.06 (td, J = 8.1, 5.9 Hz, 1H), 3.91 (app q, J = 7.7 Hz,
1H), 2.62 (dtd, J = 15.6, 7.7, 2.4 Hz, 1H), 2.49 (dddd, J = 15.9, 7.7,
5.6, 2.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 158.1 (C), 137.8
(C), 137.1 (CH), 132.8 (CH), 129.5 (CH), 129.0 (CH), 124.7 (q, J =
287.0 Hz, CF3), 121.6 (CH), 117.8 (CH2), 85.3 (q, J = 28.4 Hz, C),
67.8 (CH2), 35.6 (CH2); IR (neat, cm−1) 3047 (m), 2915 (s), 1146
(m), 1071 (m), 727 (s), 693 (s); HRMS (ESI) calcd for C26H23OF3Sn
+ Na+ 551.0626, found 551.0635.
Ethyl 3-(but-3-yn-1-yloxy)-3-cyclopropylacrylate (19): clear, color-
less oil (261.7 mg, 45% yield); Rf = 0.69 (hexanes/ethyl acetate, 4/1);
1H NMR (500 MHz, (CD3)2CO) δ 5.06 (s, 1H), 4.09 (q, J = 7.1 Hz,
2H), 3.88 (t, J = 6.3 Hz, 2H), 3.25 (tt, J = 8.4, 5.0 Hz, 1H), 2.57 (td, J
= 6.3, 2.4 Hz, 2H), 2.43 (t, J = 2.7 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H),
0.97 (ddd, J = 6.3, 5.2, 3.4 Hz, 2H), 0.77 (ddd, J = 8.5, 6.4, 3.4 Hz,
2H); 13C NMR (125 MHz, (CD3)2CO) δ 174.5 (C), 168.3 (C), 91.7
(CH), 81.2 (C), 71.1 (CH), 66.7 (CH2), 59.5 (CH2), 19.3 (CH2),
14.8 (CH3), 12.0 (CH), 7.4 (CH2); IR (neat, cm−1) 3300 (s), 3091
(m), 2954 (s), 2123 (w), 1702 (s), 1606 (s), 1146 (s), 1051 (s);
HRMS (ESI) calcd for C12H16O3 + H+ 209.1178, found 209.1177.
3-(But-3-yn-1-yloxy)-3-cyclopropylprop-2-en-1-ol (20): clear, light
yellow oil (323.7 mg, 64% yield); Rf = 0.09 (hexanes/ethyl acetate, 4/
1); 1H NMR (500 MHz, (CD3)2CO) δ 4.71 (t, J = 7.5 Hz, 1H), 4.19
(dd, J = 7.5, 5.5 Hz, 2H), 3.70 (t, J = 6.5 Hz, 2H), 3.31 (t, J = 5.4 Hz,
1H), 2.48 (td, J = 6.5, 2.7 Hz, 2H), 2.38 (t, J = 2.7 Hz, 1H), 1.81 (tt, J
= 8.3, 5.0 Hz, 1H), 0.77 (ddd, J = 6.3, 5.0, 3.6 Hz, 2H), 0.56 (ddd, J =
8.4, 6.3, 3.6 Hz, 2H); 13C NMR (125 MHz, (CD3)2CO) δ 157.4 (C),
98.7 (CH), 81.7 (C), 70.7 (CH), 65.3 (CH2), 58.1 (CH2), 19.4
(CH2), 10.7 (CH), 4.9 (CH2); IR (neat, cm−1) 3368 (br, s), 3300 (s),
3094 (m), 2928 (s), 2120 (w), 1651 (s), 1102 (s), 1052 (s); HRMS
(ESI) calcd for C10H140O2 + Na+ 189.0891, found 189.0888.
((7-(2-methoxyethyl)-7a-(trifluoromethyl)tetrahydro-2H-furo[3,4-
b]pyran-4(3H)-ylidene)methyl)triphenylstannane (7): clear, light
yellow oil (23.8 mg, 64% yield, 1.00/0.15/0.06/0.06 dr); Rf = 0.64
1
(hexanes/ethyl acetate, 2 × 4/1); H NMR (CDCl3, 500 MHz) δ
7.58−7.46 (m, 6H), 7.38−7.34 (m, 9H), 6.01 (s, 1H), 4.12 (t, J = 8.6
Hz, 1H), 4.00 (d, J = 11.1 Hz, 1H), 3.87−3.83 (m, 1H), 3.76 (t, J = 9.4
Hz, 2H), 3.51−3.46 (m, 2H), 3.33 (s, 3H), 3.31 (t, J = 9.4 Hz, 1H),
2.48 (tdd, J = 13.1, 5.6, 1.1 Hz, 1H), 2.18 (dt, J = 14.7, 3.0 Hz, 1H),
2.07−2.00 (m, 1H), 1.90−1.80 (m, 1H); 13C NMR (CDCl3, 125
MHz) δ 150.1 (C), 138.5 (C), 137.0 (CH), 129.4 (CH), 128.9 (CH),
124.6 (CH), 86.2 (CH), 84.3 (q, J = 27.3 Hz, C), 79.3 (q, J = 285.93
Hz, CF3), 70.7 (CH2), 69.8 (CH2), 65.6 (CH2), 58.9 (CH3), 49.3
(CH), 33.1 (CH2), 29.9 (CH2); IR (neat, cm−1) 3058 (m), 2913 (s),
1605 (m), 1255 (m), 1071 (s), 727 (s), 697 (s); HRMS (ESI) calcd
for C30H31O3F3Sn + Na+ 635.1140, found 635.1125.
Ethyl 2-methyl-4-((triphenylstannyl)methylene)tetrahydro-2H-
pyran-3-carboxylate (14): clear, colorless oil (78.9 mg, 49% yield);
1
Rf = 0.23 (hexanes/dichloromethane/ethyl ether, 10/4/1); H NMR
(300 MHz, CDCl3) δ 7.62−7.52 (m, 5H), 7.44−7.32 (m, 10H), 6.02
(d, J = 1.5 Hz, 1H), 4.27 (dq, J = 10.8, 7.1 Hz, 1H), 4.17 (dq, J = 10.8,
7.1 Hz, 1H), 4.01 (ddd, J = 10.8, 6.1, 1.2 Hz, 1H), 3.68 (qd, J = 6.5, 3.4
Hz, 1H), 3.37 (d, J = 3.2 Hz, 1H), 3.31 (ddd, J = 12.5, 10.8, 2.4 Hz,
1H), 3.03 (dddd, J = 13.9, 12.4, 6.0, 1.4 Hz, 1H), 2.12 (ddt, J = 14.0,
2.3, 1.2 Hz, 1H), 1.32 (d, J = 6.4 Hz, 3H), 1.32 (t, J = 7.0 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 170.6 (C), 154.4 (C), 138.8 (C), 137.0
(CH), 129.3 (CH), 128.8 (CH), 122.4 (CH), 75.8 (CH), 68.8 (CH2),
(1-(But-3-yn-1-yloxy)-3-methoxyprop-1-en-1-yl)cyclopropane
(21): clear, light yellow oil (84.8 mg, 85% yield, 1.00/0.13 E/Z); Rf =
0.57 (hexanes/ethyl acetate, 4/1); 1H NMR (500 MHz, (CD3)2CO) δ
4.64 (t, J = 7.7 Hz, 1H, major), 4.61 (t, J = 7.7 Hz, 1H, minor), 4.03
(d, J = 7.3 Hz, 2H, major), 4.02 (d, J = 7.3 Hz, 2H, minor), 3.73 (t, J =
6.4 Hz, 2H), 3.24 (s, 3H, major), 3.23 (s, 3H, minor), 2.49 (td, J = 6.5,
2.8 Hz, 2H), 2.37 (t, J = 2.6 Hz, 1H), 1.82 (tt, J = 8.3, 5.0 Hz, 1H),
8642
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0.79 (ddd, J = 6.3, 5.0, 3.6 Hz, 2H), 0.59 (ddd, J = 8.3, 6.1, 3.7 Hz,
2H); 13C NMR (125 MHz, (CD3)2CO) δ 159.5 (C, minor), 159.2 (C,
major), 94.9 (CH, major), 94.3 (CH, minor), 81.7 (C), 70.8 (CH),
68.4 (CH2, minor), 68.2 (CH2, major), 65.5 (CH2), 56.9 (CH3,
major), 56.9 (CH3, minor), 19.5 (CH2), 10.9 (CH, major), 10.8 (CH,
minor), 5.0 (CH2, major), 4.9 (CH2, minor); IR (neat, cm−1) 3308
(s), 3093 (w), 2924 (s), 2122 (w), 1653 (s), 1104 (s), 1083 (s);
HRMS (ESI) calcd for C11H16O2 + Na+ 203.1048, found 203.1049.
3-(But-3-yn-1-yloxy)but-2-enal (24): clear, light yellow oil (766.0
(C), 65.5 (CH2), 58.8 (CH2), 21.0 (CH2), 16.3 (CH3), 0.2 (CH3); IR
(neat, cm−1) 3331 (br, s), 2959 (s), 2980 (m), 2180 (s), 1665 (s),
1250 (s), 842 (s); HRMS (ESI) calcd for C11H20O2Si + Na+ 235.1125,
found 235.1125.
3-((4-(tert-Butyldimethylsilyl)but-3-yn-1-yl)oxy)but-2-en-1-ol
(28b): clear, colorless oil (500.8 mg, 71% yield); 1H NMR (300 MHz,
(CD3)2CO) δ 4.68 (t, J = 7.4 Hz, 1H), 4.05 (dd, J = 7.3, 5.5 Hz, 2H),
3.76 (t, J = 6.7 Hz, 2H), 3.26 (t, J = 5.5 Hz, 1H), 2.60 (t, J = 6.7 Hz,
2H), 1.79 (s, 3H), 0.93 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz,
(CD3)2CO) δ 155.8 (C), 105.5 (C), 99.1 (CH), 84.0 (C), 65.6 (CH2),
58.9 (CH2), 26.4 (CH3), 21.0 (CH2), 17.0 (C), 16.3 (CH3), −4.3
(CH3); IR (neat, cm−1) 3332 (s), 2954 (s), 2929 (s), 2857 (s), 2179
(s), 1667 (s), 1472 (m), 1249 (s), 1079 (s), 838 (s); HRMS (ESI)
calcd for C14H26O2Si + Na+ 277.1594, found 277.1594.
1
mg, 76% yield); Rf = 0.25 (hexanes/ethyl ether, 1/2); H NMR (300
MHz, (CD3)2CO) δ 9.80 (d, J = 7.4 Hz, 1H), 5.36 (d, J = 7.4 Hz, 1H),
3.99 (t, J = 6.6 Hz, 2H), 2.65 (td, J = 6.5, 2.7 Hz, 2H), 2.46 (t, J = 2.7
Hz, 1H), 2.27 (s, 3H); 13C NMR (75 MHz, (CD3)2CO) δ 190.4
(CH), 176.0 (C), 105.7 (CH), 81.1 (C), 71.4 (CH), 67.5 (CH2), 19.4
(CH2), 17.7 (CH3); IR (neat, cm−1) 3304 (m), 3057 (m), 2958 (m),
2124 (w), 1703 (s), 1138 (m), 1060 (m); HRMS (ESI) calcd for
C8H10O2 + H+ 139.0759, found 139.0759.
3-((4-(tert-Butyldimethylsilyl)but-3-yn-1-yl)oxy)but-2-enal (29b):
clear, pale yellow oil (98.7 mg, 26% yield); Rf = 0.61 (hexanes-ethyl
1
ether, 1:3); H NMR (300 MHz, (CD3)2CO) δ 9.81 (d, J = 7.6 Hz,
4-(But-3-yn-1-yloxy)penta-1,3-diene (25): clear, colorless oil
(309.7 mg, 70% yield); 1H NMR (300 MHz, (CD3)2CO) δ 6.44
(dt, J = 16.7, 10.4 Hz, 1H), 5.36 (d, J = 10.7 Hz, 1H), 4.96 (dd, J =
16.7, 2.1 Hz, 1H), 4.76 (dd, J = 10.2, 2.1 Hz, 1H), 3.83 (t, J = 6.7 Hz,
2H), 2.56 (td, J = 6.7, 2.7 Hz, 2H), 2.40 (t, J = 2.7 Hz, 1H), 1.89 (s,
3H); 13C NMR (75 MHz, (CD3)2CO) δ 156.6 (C), 134.0 (CH),
111.4 (CH2), 102.2 (CH), 81.6 (C), 71.0 (CH), 65.9 (CH2), 19.7
(CH2), 16.7 (CH3); IR (neat, cm−1) 3304 (s), 3086 (w), 3053 (m),
2977 (s), 2123 (w), 1644 (s), 1113 (s), 1073 (s); HRMS (ESI) calcd
for C9H12O + H+ 137.0966, found 137.0963.
1H), 5.35 (d, J = 7.4 Hz, 1H), 4.00 (t, J = 6.5 Hz, 2H), 2.72 (t, J = 6.5
Hz, 2H), 2.27 (s, 3H), 0.93 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz,
(CD3)2CO) δ 190.2 (CH), 175.8 (C), 105.7 (CH), 104.6 (C), 84.6
(C), 67.5 (CH2), 26.4 (CH3), 20.8 (CH2), 17.6 (CH3), 17.0 (C), −4.4
(CH3); IR (neat, cm−1) 3453 (w), 2954 (s), 2929 (s), 2857 (s), 1667
(s), 1619 (s), 1226 (s), 1060 (m), 839 (s); HRMS (ESI) calcd for
C14H24O2Si + H+ 253.1619, found 253.1619.
Trimethyl(4-(penta-2,4-dien-2-yloxy)but-1-yn-1-yl)silane (30a):
clear, colorless oil (532.0 mg, 36% yield); Rf = 0.74 (hexanes/ethyl
1
acetate, 9:1); H NMR (300 MHz, (CD3)2CO) δ 6.44 (dt, J = 16.7,
4-(Trimethylsilyl)but-3-yn-1-ol (26a): clear, colorless oil (5.4068 g,
10.4 Hz, 1H), 5.36 (d, J = 10.5 Hz, 1H), 4.96 (dd, J = 16.7, 2.2 Hz,
1H), 4.75 (dd, J = 10.2, 2.1 Hz, 1H), 3.82 (t, J = 6.9 Hz, 2H), 2.60 (t, J
= 6.9 Hz, 2H), 1.88 (s, 3H), 0.12 (s, 9H); 13C NMR (75 MHz,
(CD3)2CO) δ 156.6 (C), 134.0 (CH), 111.4 (CH2), 104.6 (C), 102.3
(CH), 65.9 (CH2), 21.1 (CH2), 16.7 (CH3), 0.2 (CH3); IR (neat,
cm−1) 3086 (w), 2960 (s), 2925 (s), 2181 (s), 1651 (s), 1250 (s),
1073 (s), 844 (s), 760 (s); HRMS (ESI) calcd for C12H20OSi + H+
209.1356, found 209.1352.
1
82% yield); Rf = 0.39 (hexanes/ethyl acetate, 4/1); H NMR (300
MHz, CDCl3) δ 3.70 (q, J = 6.1 Hz, 2H), 2.49 (t, J = 6.3 Hz, 2H), 1.94
(t, J = 6.3 Hz, 1H), 0.15 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 103.5
(C), 87.2 (C), 61.1 (CH2), 24.4 (CH2), 0.3 (CH3); IR (neat, cm−1)
3350 (br, s), 2960 (s), 2900 (s), 2178 (s), 1410 (m), 1250 (s), 1055
(s), 1030 (s), 894 (s), 840 (s), 760 (s), 699 (s), 639 (s); HRMS (ESI)
calcd for C7H14OSi + Na+ 165.0706, found 165.0707.
4-(tert-Butyldimethylsilyl)but-3-yn-1-ol (26b): clear, yellow oil
tert-Butyldimethyl(4-(penta-2,4-dien-2-yloxy)but-1-yn-1-yl)silane
1
(1.0938 g, 15% yield); H NMR (300 MHz, CDCl3) δ 3.71 (t, J =
(30b): clear, pale yellow oil (66.0 mg, 67% yield); Rf = 0.69 (hexanes/
6.3 Hz, 2H), 2.51 (t, J = 6.3 Hz, 2H), 1.88 (br s, 1H), 0.92 (s, 9H),
0.09 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 104.0 (C), 85.4 (C), 61.2
(CH2), 26.3 (CH3), 24.5 (CH2), 16.7 (C), −4.3 (CH3); IR (neat,
cm−1) 3338 (br, m), 2954 (s), 2930 (s), 2858 (s), 2176 (s), 1472 (m),
1250 (s), 1053 (m), 1030 (s), 838 (s), 776 (s), 682 (m); HRMS (ESI)
calcd for C10H20OSi + Na+ 207.1176, found 207.1176.
Ethyl 3-((4-(trimethylsilyl)but-3-yn-1-yl)oxy)but-2-enoate (27a):
clear, colorless oil (8.63 g, 96% yield); 1H NMR (300 MHz,
(CD3)2CO) δ 5.05 (s, 1H), 4.07 (q, J = 7.1 Hz, 2H), 3.93 (t, J = 6.6
Hz, 2H), 2.66 (t, J = 6.7 Hz, 2H), 2.25 (s, 3H), 1.21 (t, J = 7.0 Hz,
3H), 0.12 (s, 9H); 13C NMR (75 MHz, (CD3)2CO) δ 172.1 (C),
167.8 (C), 103.9 (C), 92.4 (CH), 86.4 (C), 67.0 (CH2), 59.5 (CH2),
20.8 (CH2), 18.8 (CH3), 14.8 (CH3), 0.1 (CH3); IR (neat, cm−1)
2960 (s), 2901 (s), 2181 (s), 1716 (s), 1634 (s), 1271 (s), 1141 (s),
1053 (s), 843 (s), 761 (s), 700 (m); HRMS (ESI) calcd for
C13H22O3Si + H+ 255.1411, found 255.1411.
1
ethyl acetate, 9/1); H NMR (300 MHz, (CD3)2CO) δ 6.44 (dt, J =
16.7, 10.4 Hz, 1H), 5.35 (d, J = 10.6 Hz, 1H), 4.95 (dd, J = 16.7, 2.2
Hz, 1H), 4.75 (dd, J = 10.3, 2.2 Hz, 1H), 3.84 (t, J = 6.7 Hz, 2H), 2.62
(t, J = 6.7 Hz, 2H), 1.88 (s, 3H), 0.93 (s, 9H), 0.07 (s, 6H); 13C NMR
(75 MHz, (CD3)2CO) δ 156.6 (C), 134.0 (CH), 111.3 (CH2), 105.2
(C), 102.2 (CH), 84.1 (C), 65.9 (CH2), 26.4 (CH3), 21.1 (CH2), 17.0
(C), 16.7 (CH3), −4.3 (CH3); IR (neat, cm−1) 2954 (s), 2929 (s),
2857 (s), 2179 (s), 1648 (s), 1472 (m), 1218 (s), 838 (s), 776 (s);
HRMS (ESI) calcd for C15H26OSi + H+ 251.1826, found 251.1828.
(4-((1-Cyclopropylprop-1-en-2-yl)oxy)but-1-yn-1-yl)-
trimethylsilane (31a): clear, colorless oil (107.0 mg, 87% yield; 1.00/
0.14 31a/30a); Rf = 0.80 (hexanes/ethyl acetate, 9:1); 1H NMR (300
MHz, CD2Cl2) δ 3.97 (d, J = 7.8 Hz, 1H), 3.64 (t, J = 7.1 Hz, 2H),
2.54 (t, J = 7.1 Hz, 2H), 1.86 (s, 3H), 1.36−1.21 (m, 1H), 0.64 (ddd, J
= 8.2, 6.0, 4.0 Hz, 2H), 0.21 (ddd, J = 6.0, 4.8, 4.0 Hz, 2H), 0.13 (s,
9H); 13C NMR (75 MHz, (CD3)2CO) δ 153.1 (C), 104.7 (C), 102.6
(CH), 85.6 (C), 65.5 (CH2), 21.1 (CH2), 16.8 (CH3), 9.4 (CH), 7.1
(CH2), 0.2 (CH3); IR (neat, cm−1) 3079 (m), 2958 (s), 2925 (s),
2872 (m), 2180 (s), 1664 (s), 1250 (s), 1151 (s), 843 (s); HRMS
(ESI) calcd for C13H22OSi + H+ 223.1513, found 223.1507.
Ethyl 3-((4-(tert-butyldimethylsilyl)but-3-yn-1-yl)oxy)but-2-
enoate (27b): clear, pale yellow oil (1.0558 g, 100% yield, 1.00/0.04
1
E/Z); H NMR (300 MHz, (CD3)2CO) δ 5.05 (s, 1H), 4.06 (q, J =
7.0 Hz, 2H), 3.95 (t, J = 6.6 Hz, 2H), 2.68 (t, J = 6.6 Hz, 2H), 2.25 (s,
3H), 1.21 (t, J = 7.2 Hz, 3H), 0.93 (s, 9H), 0.08 (s, 6H); 13C NMR
(75 MHz, (CD3)2CO) δ 172.2 (C), 167.9 (C), 104.8 (C), 92.4 (CH),
84.5 (C), 67.2 (CH2), 59.6 (CH2), 26.4 (CH3), 20.8 (CH2), 18.9
(CH3), 17.0 (C), 14.8 (CH3), −4.4 (CH3); IR (neat, cm−1) 2954 (s),
2930(s), 2858 (s), 2180 (s), 1714 (s), 1627 (s), 1275 (s), 1251 (s),
1142 (s), 1053 (s), 839 (s), 776 (s), 681 (m); HRMS (ESI) calcd for
C16H28O3Si + H+ 297.1881, found 297.1880.
tert-Butyl(4-((1-cyclopropylprop-1-en-2-yl)oxy)but-1-yn-1-yl)-
dimethylsilane (31b): clear, colorless oil (44.1 mg, 76% yield; 1.00/
1
0.09 31b/30b); H NMR (300 MHz, (CD3)2CO) δ 4.02 (d, J = 7.8
Hz, 1H), 3.65 (t, J = 6.8 Hz, 2H), 2.56 (t, J = 6.8 Hz, 2H), 1.84 (s,
3H), 1.34−1.26 (m, 1H), 0.93 (s, 9H), 0.63 (ddd, J = 8.2, 6.1, 3.8 Hz,
2H), 0.23−0.18 (m, 2H), 0.07 (s, 6H); 13C NMR (75 MHz,
(CD3)2CO) δ 153.2 (C), 105.5 (C), 102.6 (CH), 83.8 (C), 65.5
(CH2), 26.6 (CH3), 21.2 (CH2), 17.0 (C), 16.8 (CH3), 9.4 (CH), 7.1
(CH2), −4.3 (CH3); IR (neat, cm−1) 3079 (w), 2954 (s), 2928 (s),
2857 (s), 2179 (m), 1665 (m), 1250 (m), 1152 (m), 1079 (m), 838
(s), 825 (s); HRMS (ESI) calcd for C16H28OSi + H+ 265.1982, found
265.1980.
3-((4-(Trimethylsilyl)but-3-yn-1-yl)oxy)but-2-en-1-ol (28a): clear,
colorless oil (463.5 mg, 70% yield); Rf = 0.29 (hexanes/ethyl acetate,
1
2/1); H NMR (300 MHz, (CD3)2CO) δ 4.68 (t, J = 7.4 Hz, 1H),
4.04 (dd, J = 7.4, 5.5 Hz, 2H), 3.74 (t, J = 6.8 Hz, 2H), 3.28 (t, J = 5.5
Hz, 1H), 2.58 (t, J = 6.9 Hz, 2H), 1.79 (s, 3H), 0.12 (s, 9H); 13C
NMR (75 MHz, (CD3)2CO) δ 155.8 (C), 104.6 (C), 99.2 (CH), 85.9
8643
dx.doi.org/10.1021/jo301565u | J. Org. Chem. 2012, 77, 8634−8647

The Journal of Organic Chemistry
Article
(2-(But-3-yn-1-yloxy)prop-1-en-1-yl)cyclopropane (32): clear, pale
yellow oil (23.1 mg, 100% yield, 1.00/0.09 32/25); Rf = 0.55
(hexanes/ethyl ether, 20/1); 1H NMR (300 MHz, (CD3)2CO) δ 4.03
(d, J = 7.9 Hz, 1H), 3.65 (t, J = 6.7 Hz, 2H), 2.49 (td, J = 6.8, 2.8 Hz,
2H), 2.38 (t, J = 2.6 Hz, 1H), 1.84 (s, 3H), 1.35−1.30 (m, 1H), 0.64
(ddd, J = 8.1, 6.1, 4.0 Hz, 2H), 0.20 (ddd, J = 6.1, 4.7, 4.1 Hz, 2H); 13C
NMR (75 MHz, (CD3)2CO) δ 153.2 (C), 102.6 (CH), 81.9 (C), 70.8
(CH), 65.5 (CH2), 19.7 (CH2), 16.8 (CH3), 9.4 (CH), 7.1 (CH2); IR
(neat, cm−1) 3313 (m), 3079 (m), 3002 (s), 2925 (s), 2856 (m), 1663
(m), 1219 (s), 1151 (s), 1079 (s), 837 (s); HRMS (ESI) calcd for
C10H14O + Na+ 173.0937, found 173.0946.
((3-(Methoxymethyl)-2-propylidenedihydro-2H-pyran-4(3H)-
ylidene)methyl)triphenylstannane (33): clear, light yellow oil (115.6
mg, 58% yield); Rf = 0.59 (hexanes/ethyl acetate, 2 × 9/1); 1H NMR
(500 MHz, CDCl3) δ 7.62−7.50 (m, 6H), 7.37−7.35 (m, 9H), 5.94
(d, J = 0.7 Hz, 1H), 4.63 (t, J = 7.2 Hz, 1H), 4.02 (ddd, J = 10.3, 5.5,
2.9 Hz, 1H), 3.59 (d, J = 7.3 Hz, 2H), 3.43 (ddd, J = 11.4, 10.6, 2.9 Hz,
1H), 3.39 (s, 3H), 3.28 (t, J = 7.5 Hz, 1H), 2.59 (dddd, J = 14.4, 11.5,
5.5, 1.5 Hz, 1H), 2.19 (dtd, J = 14.3, 2.9, 0.7 Hz, 1H), 2.11 (dq, J =
15.5, 7.6 Hz, 1H), 2.05 (dq, J = 15.2, 7.5 Hz, 1H), 0.95 (t, J = 7.5 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 156.1 (C), 150.8 (C), 139.1
(C), 137.0 (CH), 129.2 (CH), 128.8 (CH), 119.8 (CH), 112.3 (CH),
74.8 (CH2), 69.4 (CH2), 59.0 (CH3), 54.0 (CH), 34.7 (CH2), 18.1
(CH2), 14.9 (CH3); IR (neat, cm−1) 3049 (m), 2974 (m), 1111 (s),
731 (s), 699 (s); HRMS (ESI) calcd for C29H32O2Sn + Na+ 555.1328,
found 555.1330.
((2-(But-1-en-1-yl)-2-methyldihydrofuran-3(2H)-ylidene)methyl)-
triphenylstannane (34): clear, colorless oil (76.7 mg, 46% yield, 1.00/
0.10 34/35); Rf = 0.39 (hexanes/dichloromethane/ethyl ether, 20/4/
1); 1H NMR (300 MHz, CDCl3) δ 7.63−7.56 (m, 5H), 7.43−7.35 (m,
10H), 5.95 (t, J = 2.3 Hz, 1H), 5.75 (dt, J = 15.5, 6.3 Hz, 1H), 5.51
(dt, J = 15.5, 1.5 Hz, 1H), 3.88- 3.71 (m, 2H), 2.55- 2.46 (m, 2H), 2.10
(qdd, J = 7.6, 6.1, 1.4 Hz, 2H), 1.46 (s, 3H), 1.03 (t, J = 7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 167.6 (C), 138.7 (C), 137.1 (CH),
132.8 (CH), 131.1 (CH), 129.2 (CH), 128.8 (CH), 113.4 (CH), 85.3
(C), 64.4 (CH2), 35.7 (CH2), 26.4 (CH3), 25.4 (CH2), 13.9 (CH3);
IR (neat, cm−1) 3063 (m), 2970 (m), 2870 (m), 1616 (w), 1480 (w),
1429 (s), 1075 (s), 1059 (m), 971 (m), 728 (s), 699 (s); HRMS (ESI)
calcd for C28H30O3Sn + Na+ 525.1211, found 525.1214.
(s), 2889 (s), 1506 (m), 1374 (s), 1248 (s), 1199 (s), 1039 (s), 839
(s); HRMS (ESI) calcd for C14H16O3 + H+ 233.1172, found 233.1172.
3-Bromo-4-phenylbut-3-en-1-ol (38a): clear, colorless oil (53.7
mg, 77% yield); Rf = 0.52 (hexanes/ethyl acetate, 2/1); 1H NMR (300
MHz, CDCl3) δ 7.30−7.17 (m, 5H), 7.08 (s, 1H), 3.85 (t, J = 6.1 Hz,
2H), 2.82 (td, J = 6.1, 0.6 Hz, 2H), 1.62 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 136.2 (C), 135.4 (CH), 128.7 (CH), 128.5 (CH), 127.7
(CH), 126.2 (C), 60.9 (CH2), 39.3 (CH2); IR (neat, cm−1) 3350 (br,
s), 3057 (m), 3025 (m), 2954 (m), 2884 (m), 1633 (m), 1494 (m),
1446 (m), 1211 (w), 1047 (s), 753 (s), 701 (s).
3-Bromo-4-(4-methoxyphenyl)but-3-en-1-ol (38b): clear, pale
yellow oil (278.7 mg, 79% yield); Rf = 0.20 (hexanes/ethyl acetate,
4/1); 1H NMR (300 MHz, CDCl3) δ 7.26 (d, J = 8.5 Hz, 2H), 7.10 (s,
1H), 6.87 (d, J = 8.8 Hz, 2H), 3.94 (q, J = 6.0 Hz, 2H), 3.81 (s, 3H),
2.91 (td, J = 6.1, 0.6 Hz, 2H), 1.55 (t, J = 5.9 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 159.2 (C), 135.0 (CH), 129.8 (CH), 128.8 (C), 124.7
(C), 114.1 (CH), 61.0 (CH2), 55.5 (CH3), 39.3 (CH2); IR (neat,
cm−1) 3413 (br, s), 2955 (w), 2828 (w), 1606 (m), 1511 (s), 1250 (s),
1035 (m), 822 (w); HRMS (ESI) calcd for C11H13BrO2 + Na+
278.9991, found 278.9981.
3-Bromo-4-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)but-3-en-1-ol
(38c): clear, orange oil (63.2 mg, 44% yield); Rf = 0.50 (hexanes/ethyl
acetate, 1/1); 1H NMR (300 MHz, CDCl3) δ 7.43 (d, J = 8.2 Hz, 2H),
7.26 (d, J = 7.9 Hz, 2H), 7.11 (s, 1H), 4.04−3.98 (m, 2H), 3.91 (q, J =
6.0 Hz, 2H), 3.78−3.72 (m, 2H), 2.88 (td, J = 6.1, 0.6 Hz, 2H), 1.83
(t, J = 6.2 Hz, 1H), 1.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 142.9
(C), 135.8 (C), 135.1 (CH), 128.4 (CH), 126.3 (C), 125.7 (CH),
108.9 (C), 64.7 (CH2), 61.0 (CH2), 39.4 (CH2), 27.7 (CH3); IR
(neat, cm−1) 3433 (m), 2977 (m), 2916 (m), 2885 (m), 1251 (m),
1198 (m), 1039 (s), 871 (m); HRMS (ESI) calcd for C14H17BrO3 +
Na+ 335.0253, found 335.0253.
1-(4-(2-Bromo-4-hydroxybut-1-en-1-yl)phenyl)ethanone (38d):
clear, orange-yellow oil (21.5 mg, 82% yield); Rf = 0.50 (hexanes/
ethyl acetate, 1/1); 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J = 8.5 Hz,
2H), 7.43 (d, J = 8.5 Hz, 2H), 7.17 (br s, 1H), 3.96 (t, J = 6.2 Hz, 2H),
2.89 (td, J = 6.1, 0.6 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 197.8 (C), 140.9 (C), 136.1 (C), 134.4 (CH), 128.8 (CH),
128.8 (CH), 128.5 (C), 60.7 (CH2), 39.5 (CH2), 26.8 (CH3); IR
(neat, cm−1) 3426 (br, m), 2960 (m), 2917 (m), 2881 (m), 1680 (s),
1602 (s), 1407 (m), 1359 (m), 1268 (s), 1049 (m), 874 (m); HRMS
(ESI) calcd for C12H13BrO2 + Na+ 290.9991, found 290.9992.
Ethyl 3-((3-bromo-4-phenylbut-3-en-1-yl)oxy)but-2-enoate
(39a): colorless solid (135.4 mg, 99% yield); Rf = 0.38 (hexanes/
ethyl acetate, 9/1); 1H NMR (300 MHz, (CD3)2CO) δ 7.44−7.29 (m,
5H), 7.20 (s, 1H), 5.12 (s, 1H), 4.14 (t, J = 6.1 Hz, 2H), 4.08 (q, J =
7.1 Hz, 2H), 3.07 (td, J = 6.2, 0.9 Hz, 2H), 2.25 (s, 3H), 1.22 (t, J =
7.2 Hz, 3H); 13C NMR (75 MHz, (CD3)2CO) δ 172.2 (C), 167.8 (C),
136.9 (C), 135.9 (CH), 129.4 (CH), 129.2 (CH), 128.5 (CH), 126.0
(C), 92.5 (CH), 66.5 (CH2), 59.6 (CH2), 36.3 (CH2), 18.9 (CH3),
14.8 (CH3); IR (thin film, cm−1) 3058 (w), 3026 (w), 2979 (m), 2935
(m), 1711 (s), 1627 (s), 1274 (m), 1142 (s), 1055 (s), 817 (m), 755
(m), 705 (m); HRMS (ESI) calcd for C16H19BrO3 + Na+ 361.0410,
found 361.0410.
((2-Methyl-2-(prop-1-en-1-yl)dihydrofuran-3(2H)-ylidene)-
methyl)triphenylstannane (35a): clear, colorless oil (187.0 mg, 61%
yield, 1.00/0.10 35a/35b); Rf = 0.52 (hexanes/dichloromethane/ethyl
1
ether, 20/4/1); H NMR (500 MHz, CDCl3) δ 7.61−7.55 (m, 5H),
7.42−7.36 (m, 10H), 5.92 (t, J = 2.4 Hz, 1H), 5.69 (dq, J = 15.3, 6.4
Hz, 1H), 5.52 (dq, J = 15.5, 1.6 Hz, 1H), 3.81 (ddd, J = 8.3, 7.9, 5.6
Hz, 1H), 3.74 (dt, J = 8.3, 7.5 Hz, 1H), 2.56−2.40 (m, 2H), 1.72 (dd, J
= 6.4, 1.6 Hz, 3H), 1.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.6
(C), 138.7 (C), 137.1 (CH), 135.0 (CH), 129.2 (CH), 128.8 (CH),
124.2 (CH), 113.4 (CH), 85.2 (C), 64.5 (CH2), 35.7 (CH2), 26.4
(CH3), 17.9 (CH3); IR (neat, cm−1) 3063 (m), 2974 (m), 2926 (w),
2858 (w), 1620 (w), 1429 (s), 1075 (s), 1057 (m), 728 (s), 699 (s);
HRMS (ESI) calcd for C27H28OSn + Na+ 511.1054, found 511.1058.
1-(4-(4-Hydroxybut-1-yn-1-yl)phenyl)ethanone (37c): orange-yel-
low solid (479.3 mg, 92% yield); Rf = 0.28 (hexanes/ethyl acetate, 1/
1); 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 8.5 Hz, 2H), 7.49 (d, J
= 8.5 Hz, 2H), 3.84 (q, J = 6.2 Hz, 2H), 2.73 (t, J = 6.2 Hz, 2H), 2.60
(s, 3H), 1.76 (t, J = 6.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 197.6
(C), 136.1 (C), 132.0 (CH), 128.6 (C), 128.4 (CH), 90.5 (C), 81.9
(C), 61.2 (CH2), 26.8 (CH3), 24.1 (CH2); IR (KBr, cm−1) 3220 (m),
2952 (w), 2917 (w), 2885 (w), 1680 (s), 1602 (m), 1270 (m), 1045
(m), 834 (s), 594 (m); HRMS (ESI) calcd for C12H12O2 + H+
189.0910, found 189.0910.
Ethyl 3-((3-bromo-4-(4-methoxyphenyl)but-3-en-1-yl)oxy)but-2-
enoate (39b): clear, pale yellow oil (380.7 mg, 99% yield); Rf =
0.29 (hexanes/ethyl acetate, 9/1); 1H NMR (300 MHz, (CD3)2CO) δ
7.35 (d, J = 8.2 Hz, 2H), 7.11 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 5.12
(s, 1H), 4.13 (t, J = 6.1 Hz, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.81 (s,
3H), 3.07 (td, J = 6.1, 0.6 Hz, 2H), 2.25 (s, 3H), 1.22 (t, J = 7.0 Hz,
3H); 13C NMR (75 MHz, (CD3)2CO) δ 172.2 (C), 167.8 (C), 160.2
(C), 135.5 (CH), 130.5 (CH), 129.2 (C), 124.3 (C), 114.8 (CH),
92.5 (CH), 66.6 (CH2), 59.6 (CH2), 55.6 (CH3), 36.4 (CH2), 18.9
(CH3), 14.8 (CH3); IR (neat, cm−1) 2977 (w), 2952 (w), 2836 (w),
1710 (s), 1625 (s), 1511 (s), 1251 (s), 1141 (s), 1055 (s), 819 (m);
HRMS (ESI) calcd for C17H21BrO4 + H+ 369.0696, found 369.0696.
Ethyl 3-((4-(4-acetylphenyl)-3-bromobut-3-en-1-yl)oxy)but-2-
enoate (39c): clear, colorless oil (24.1 mg, 79% yield); Rf = 0.11
(hexanes/ethyl acetate, 9/1); 1H NMR (300 MHz, (CD3)2CO) δ 8.01
(d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.26 (s, 1H), 5.12 (s,
1H), 4.16 (t, J = 5.9 Hz, 2H), 4.07 (q, J = 7.1 Hz, 2H), 3.10 (td, J =
4-(4-(2-Methyl-1,3-dioxolan-2-yl)phenyl)but-3-yn-1-ol (37d):
clear, pale yellow oil (220.3 mg, 62% yield); Rf = 0.54 (hexanes/
1
ethyl acetate, 1/1); H NMR (300 MHz, CDCl3) δ 7.43−7.36 (m,
4H), 4.08−3.97 (m, 2H), 3.81 (q, J = 6.2 Hz, 2H), 3.83−3.69 (m,
2H), 2.69 (t, J = 6.3 Hz, 2H), 1.88 (t, J = 6.3 Hz, 1H), 1.63 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 143.3 (C), 131.7 (CH), 125.5 (CH),
123.0 (C), 108.8 (C), 86.7 (C), 82.5 (C), 64.7 (CH2), 61.4 (CH2),
27.6 (CH3), 24.0 (CH2); IR (neat, cm−1) 3413 (br, s), 2987 (s), 2958
8644
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Article
5.9, 0.6 Hz, 2H), 2.59 (s, 3H), 2.25 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H);
13C NMR (75 MHz, (CD3)2CO) δ 197.4 (C), 172.1 (C), 167.8 (C),
141.3 (C), 137.2 (C), 135.2 (CH), 129.4 (CH), 129.4 (CH), 128.0
(C), 92.6 (CH), 66.4 (CH2), 59.6 (CH2), 36.5 (CH2), 26.7 (CH3),
18.9 (CH3), 14.8 (CH3); IR (neat, cm−1) 2979 (w), 2936 (w), 2895
(w), 1710 (s), 1685 (s), 1626 (s), 1268 (s), 1143 (s), 1055 (s), 818
(m), 665 (m); HRMS (ESI) calcd for C18H21BrO4 + Na+ 403.0515,
found 403.0515.
Hz, 1H), 2.66 (dt, J = 14.3, 1.2 Hz, 1H), 2.14 (dt, J = 13.6, 1.2 Hz,
1H), 1.34 (t, J = 7.2 Hz, 3H), 1.31 (d, J = 6.4 Hz, 3H), 1.30 (t, J = 7.2
Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
171.2 (C), 171.0 (C), 136.9 (C), 136.6 (C), 135.6 (CH), 135.4 (CH),
129.2 (CH), 128.9 (CH), 128.5 (CH), 128.4 (CH), 127.5 (CH),
127.2 (CH), 127.0 (CH), 126.9 (CH), 75.4 (CH), 75.0 (CH), 69.5
(CH2), 68.3 (CH2), 60.7 (CH2), 60.5 (CH2), 56.0 (CH), 50.1 (CH),
33.9 (CH2), 27.3 (CH2), 19.4 (CH3), 14.5 (CH3), 14.5 (CH3); IR
(neat, cm−1) 2978 (m), 2849 (m), 1735 (s), 1447 (m), 1262 (m),
1150 (s), 1092 (s), 1059 (m), 749 (m), 700 (s); HRMS (ESI) calcd
for C16H20O3 + H+ 261.1485, found 261.1484.
Ethyl 3-((4-phenylbut-3-en-1-yl)oxy)but-2-enoate (40a): clear,
colorless oil (5.4 mg, 20% yield); Rf = 0.47 (hexanes/dichloro-
1
methane/ethyl ether, 10/4/1); H NMR (300 MHz, (CD3)2CO) δ
7.45−7.19 (m, 5H), 6.56 (dt, J = 15.8, 1.5 Hz, 1H), 6.34 (dt, J = 15.9,
6.8 Hz, 1H), 5.08 (s, 1H), 4.07 (q, J = 7.1 Hz, 2H), 3.97 (t, J = 6.6 Hz,
2H), 2.64 (qd, J = 6.6, 1.5 Hz, 2H), 2.26 (s, 3H), 1.21 (t, J = 7.0 Hz,
3H); 13C NMR (75 MHz, (CD3)2CO) δ 172.6 (C), 168.0 (C), 138.4
(C), 133.0 (CH), 129.4 (CH), 128.1 (CH), 126.9 (CH), 126.8 (CH),
92.1 (CH), 68.4 (CH2), 59.5 (CH2), 33.0 (CH2), 19.0 (CH3), 14.8
(CH3); IR (neat, cm−1) 3060 (w), 3028 (w), 2979 (m), 2933 (m),
1710 (s), 1624 (s), 1275 (m), 1141 (s), 1053 (s), 965 (m), 818 (m),
730 (m), 694 (m); HRMS (ESI) calcd for C16H20O3 + Na+ 283.1305,
found 283.1305.
Ethyl 3-((4-(4-methoxyphenyl)but-3-en-1-yl)oxy)but-2-enoate
(40b): clear, colorless oil (7.4 mg, 25% yield); Rf = 0.63 (hexanes/
dichloromethane/ethyl ether, 5/5/1); 1H NMR (300 MHz,
(CD3)2CO) δ 7.34 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H),
6.49 (dt, J = 15.8, 1.5 Hz, 1H), 6.17 (dt, J = 15.8, 6.9 Hz, 1H), 5.07 (s,
1H), 4.07 (q, J = 7.1 Hz, 2H), 3.94 (t, J = 6.6 Hz, 2H), 3.78 (s, 3H),
2.60 (qd, J = 6.7, 1.5 Hz, 2H), 2.25 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H);
13C NMR (75 MHz, (CD3)2CO) δ 172.6 (C), 168.0 (C), 160.1 (C),
Ethyl 4-(4-methoxybenzylidene)-2-methyltetrahydro-2H-pyran-
3-carboxylate (42b): clear, colorless oil (4.7 mg, 16% yield, 1.00/
0.62 dr); Rf = 0.44 (hexanes/dichloromethane/ethyl ether, 5/5/1); 1H
NMR (500 MHz, CDCl3) δ 7.21 (d, J = 8.7 Hz, 2H, major), 7.16 (d, J
= 8.7 Hz, 2H, minor), 6.88 (d, J = 8.7 Hz, 2H, major), 6.86 (d, J = 8.7
Hz, 2H, minor), 6.42 (d, J = 1.2 Hz, 1H, major), 6.39 (d, J = 1.2 Hz,
1H, minor), 4.26 (q, J = 7.2 Hz, 2H, major), 4.23 (q, J = 7.2 Hz, 2H,
minor), 4.20−4.12 (m, 1H, major), 4.09 (dd, J = 10.9, 5.8 Hz, 1H,
minor), 3.82 (s, 3H, major), 3.81 (s, 3H, minor), 3.69 (qd, J = 6.4, 3.4
Hz, 1H, minor), 3.58−3.52 (m, 2H, major), 3.49 (qd, J = 6.4, 3.4 Hz,
1H, major), 3.37 (ddd, J = 12.7, 11.1, 2.8 Hz, 1H, minor), 3.17−3.08
(m, 1H, major), 3.14 (d, J = 3.2 Hz, 1H, minor), 2.90 (dddd, J = 14.3,
12.3, 6.0, 2.0 Hz, 1H, minor), 2.64 (d, J = 14.3 Hz, 1H, minor), 2.11
(d, J = 13.9 Hz, 1H, major), 1.34 (t, J = 7.2 Hz, 3H, major), 1.30 (d, J
= 6.8 Hz, 3H, minor), 1.29 (t, J = 7.2 Hz, 3H, minor), 1.23 (d, J = 6.8
Hz, 3H, major); 13C NMR (125 MHz, CDCl3) δ 171.4 (C, minor),
171.2 (C, major), 158.7 (C, major), 158.6 (C, minor), 134.1 (C,
minor), 133.9 (C, major), 130.4 (CH, minor), 130.2 (CH, major),
129.4 (C, minor), 129.1 (C, major), 127.1 (CH, minor), 126.8 (CH,
major), 114.0 (CH, major), 113.8 (CH, minor), 75.4 (CH, minor),
74.9 (CH, major), 69.5 (CH2, major), 68.3 (CH2, minor), 60.8 (CH2,
major), 60.6 (CH2, minor), 56.0 (CH3, minor), 55.5 (CH3, major),
50.1 (CH), 33.9 (CH2, major), 27.3 (CH2, minor), 19.5 (CH3, minor),
19.5 (CH3, major), 14.6 (CH3, major), 14.6 (CH3, minor); IR (neat,
cm−1) 2975 (m), 2957 (m), 2917 (m), 2849 (m), 1732 (s), 1607 (s),
1511(s), 1296 (m), 1249 (s), 1177 (s), 1149 (s), 1091 (s), 1031 (s),
832 (m), 666 (m); HRMS (ESI) calcd for C17H22O4 + H+ 291.1591,
found 291.1590.
((7-(2-Methoxyethyl)-7,7a-dimethyltetrahydro-2H-furo[3,4-b]-
pyran-4(3H)-ylidene)methyl)triphenylstannane (49a): clear, light
yellow oil (34.9 mg, 55% yield, 1.00:0.20 dr); Rf = 0.12 (hexanes/
ethyl acetate, 2 × 9/1); 1H NMR (CDCl3, 300 MHz) δ 7.59−7.48 (m,
6H), 7.38−7.34 (m, 9H), 5.92 (s, 1H), 3.94 (t, J = 9.2 Hz, 1H), 3.87
(t, J = 8.8 Hz, 1H), 3.77 (dd, J = 11.6, 5.0 Hz, 1H), 3.58−3.53 (m,
2H), 3.48 (td, J = 12.2, 2.5 Hz, 1H), 3.35 (s, 3H), 3.15 (t, J = 9.5 Hz,
1H), 2.54 (td, J = 12.8, 6.3 Hz, 1H), 2.03 (d, J = 14.1 Hz, 1H), 1.76−
1.70 (m, 1H), 1.66−1.62 (m, 1H), 1.21 (s, 3H), 1.16 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 154.4 (C), 138.9 (C), 137.1 (CH), 129.2
(CH), 128.9 (CH), 122.7 (CH), 87.7 (C), 84.3 (C), 69.3 (CH2), 68.4
(CH2), 62.4 (CH2), 58.9 (CH3), 56.2 (CH), 36.4 (CH2), 33.4 (CH2),
17.8 (CH3), 14.8 (CH3); IR (neat, cm−1) 3063 (m), 2931 (s), 1605
(m), 1115 (s), 1041 (s), 728 (s), 699 (s); HRMS (ESI) calcd for
C31H36O3Sn + H+ 573.1760, found 573.1754.
132.5 (CH), 131.1 (C), 128.1 (CH), 124.3 (CH), 114.8 (CH), 92.1
(CH), 68.6 (CH2), 59.5 (CH2), 55.5 (CH3), 33.0 (CH2), 19.0 (CH3),
14.8 (CH3); IR (neat, cm−1) 2980 (w), 2952 (m), 2934 (m), 2835
(w), 1709 (s), 1622 (s), 1512 (s), 1276 (s), 1249 (s), 1141 (s), 1052
(s), 967 (m), 821 (m); HRMS (ESI) calcd for C17H22O4 + H+
291.1591, found 291.1592.
Ethyl 2-(3-benzylidene-2-methyltetrahydrofuran-2-yl)acetate
(41a): clear, colorless oil (9.5 mg, 35% yield); Rf = 0.17 (hexanes/
1
dichloromethane/ethyl ether, 10/4/1); H NMR (500 MHz, CDCl3)
δ 7.37−7.30 (m, 4H), 7.25−7.20 (m, 1H), 6.23 (t, J = 2.4 Hz, 1H),
4.13 (q, J = 7.2 Hz, 2H), 4.06 (ddd, J = 8.3, 7.6, 6.0 Hz, 1H), 3.96
(ddd, J = 8.7, 7.5, 6.8 Hz, 1H), 3.01−2.86 (m, 2H), 2.70 (d, J = 19.1
Hz, 1H), 2.68 (d, J = 19.5 Hz, 1H), 1.51 (s, 3H), 1.24 (t, J = 7.2 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 170.4 (C), 147.4 (C), 137.7
(C), 128.6 (CH), 128.4 (CH), 126.9 (CH), 120.7 (CH), 83.2 (C),
65.8 (CH2), 60.5 (CH2), 45.6 (CH2), 31.8 (CH2), 26.4 (CH3), 14.5
(CH3); IR (neat, cm−1) 2979 (m), 2921 (m), 2860 (w), 1733 (s),
1448 (w), 1180 (m), 1034 (m), 695 (s); HRMS (ESI) calcd for
C16H20O3 + Na+ 283.1305, found 283.1303.
Ethyl 2-(3-(4-methoxybenzylidene)-2-methyltetrahydrofuran-2-
yl)acetate (41b): clear, colorless oil (10 mg, 33% yield); Rf = 0.33
(hexanes/dichloromethane/ether, 5/5/1); 1H NMR (500 MHz,
CDCl3) δ 7.23 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.15
(t, J = 2.4 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 4.03 (ddd, J = 8.7, 7.9, 6.0
Hz, 1H), 3.97−3.91 (m, 1H), 3.79 (s, 3H), 2.95−2.81 (m, 2H), 2.66
(d, J = 20.3 Hz, 1H), 2.64 (d, J = 20.3 Hz, 1H), 1.48 (s, 3H), 1.21 (t, J
= 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.5 (C), 158.6 (C),
145.0 (C), 130.5 (C), 129.6 (CH), 120.1 (CH), 114.0 (CH), 83.2
(C), 65.8 (CH2), 60.5 (CH2), 55.5 (CH3), 45.7 (CH2), 31.7 (CH2),
26.3 (CH3), 14.5 (CH3); IR (neat, cm−1) 2799 (m), 2917 (m), 1735
(s), 1608 (m), 1512 (s), 1250 (s), 1177 (m), 1033 (m), 826 (w);
HRMS (ESI) calcd for C17H22O4 + H+ 291.1591, found 291.1590.
Ethyl 4-benzylidene-2-methyltetrahydro-2H-pyran-3-carboxylate
(42a): clear, colorless oil (9.1 mg, 34% yield, 1.00/1.00 dr); Rf = 0.22
(hexanes/dichloromethane/ethyl ether, 10/4/1); 1H NMR (500
MHz, CDCl3) δ 7.37−7.30 (m, 4H), 7.27−7.20 (m, 6H), 6.49 (d, J
= 1.2 Hz, 1H), 6.46 (d, J = 1.2 Hz, 1H), 4.27 (q, J = 7.0 Hz, 2H);
4.25−4.13 (m, 3H), 4.10 (dd, J = 11.1, 6.0 Hz, 1H), 3.70 (qd, J = 6.5,
3.6 Hz, 1H), 3.59−3.52 (m, 1H), 3.54 (d, J = 3.2 Hz, 1H), 3.50 (qd, J
= 6.4, 3.4 Hz, 1H), 3.38 (ddd, J = 12.3, 11.1, 2.8 Hz, 1H), 3.24−3.12
(m, 1H), 3.17 (d, J = 3.2 Hz, 1H), 2.91 (dddd, J = 14.3, 12.3, 6.3, 2.0
((3-(((4-Methoxybut-2-en-2-yl)oxy)methyl)-2-methyldihydro-2H-
pyran-4(3H)-ylidene)methyl)triphenylstannane (50a): clear, light
yellow oil (17.4 mg, 27% yield, 1.00/0.25 dr); Rf = 0.56 (hexanes/
ethyl acetate, 2 × 4/1); 1H NMR (CDCl3, 300 MHz) δ 7.61−7.49 (m,
6H), 7.37−7.33 (m, 9H), 5.88 (s, 1H), 4.66 (t, J = 7.5 Hz, 1H), 3.99
(dd, J = 9.6, 6.5 Hz, 1H), 3.92 (dd, J = 7.5, 1.1 Hz, 2H), 3.85 (dd, J =
9.8, 7.7 Hz, 2H), 3.73 (qd, J = 6.7, 2.7 Hz, 1H), 3.31 (s, 3H), 3.31−
3.27 (m, 1H), 2.78 (td, J = 7.3, 2.4 Hz, 1H), 2.35 (tdd, J = 12.9, 5.6,
1.0 Hz, 1H), 2.04 (dt, J = 13.7, 2.6 Hz, 1H), 1.84 (s, 3H), 1.21 (d, J =
6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 158.4 (C), 158.0 (C),
139.3 (C), 137.0 (CH), 129.2 (CH), 128.8 (CH), 119.0 (CH), 93.9
(CH), 76.3 (CH), 69.1 (CH2), 68.6 (CH2), 64.2 (CH2), 57.6 (CH3),
52.8 (CH), 35.0 (CH2), 18.4 (CH3), 16.8 (CH3); IR (neat, cm−1)
3063 (s), 2932 (s), 1662 (m), 1074 (s), 1042 (s), 728 (s), 699 (s);
HRMS (ESI) calcd for C31H36O3Sn + Na+ 595.1580, found 595.1573.
8645
dx.doi.org/10.1021/jo301565u | J. Org. Chem. 2012, 77, 8634−8647

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Article
((7-(2,2-Dideuterio-2-methoxyethyl)-7,7a-dimethyltetrahydro-
2H-furo[3,4-b]pyran-4(3H)-ylidene)methyl)triphenylstannane
(49b): clear, light yellow oil (35.3 mg, 44% yield, 1.00:0.24 dr); Rf =
0.47 (hexanes/ethyl acetate, 2 × 4/1); 1H NMR (CDCl3, 300 MHz) δ
7.64−7.44 (m, 6H), 7.38−7.33 (m, 9H), 5.92 (s, 1H), 3.94 (t, J = 9.2
Hz, 1H), 3.87 (t, J = 8.8 Hz, 1H), 3.77 (dd, J = 11.5, 5.0 Hz, 1H), 3.48
(td, J = 12.2, 2.4 Hz, 1H), 3.34 (s, 3H), 3.15 (t, J = 9.2 Hz, 1H), 2.54
(tdd, J = 12.8, 6.2, 1.0 Hz, 1H), 2.02 (dt, J = 13.1, 1.0 Hz, 1H), 1.70 (s,
1H), 1.64 (s, 1H), 1.21 (s, 3H), 1.15 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ 154.5 (C), 138.97 (C), 137.0 (CH), 129.3 (CH), 128.9
(CH), 122.7 (CH), 87.7 (C), 84.3 (C), 68.4 (CH2), 62.4 (CH2), 58.9
(CH3), 56.2 (CH), 36.2 (CH2), 33.4 (CH2), 17.8 (CH3), 14.8 (CH3);
IR (neat, cm−1) 3058 (m), 2916 (s), 1602 (m), 1093 (m), 1074 (s),
728 (s), 698 (s); HRMS (ESI) calcd for C31H34O3D2Sn + H+
575.1886, found 575.1893.
14.8 (CH3); IR (neat, cm−1) 3063 (m), 2930 (s), 1605 (m), 1095 (s),
1074 (s), 730 (s), 699 (s); HRMS (ESI) calcd for C31H32O3D4Sn +
H+ 577.2011, found 577.2003.
((3-(Dideutereo((4,4-dideuterio-4-methoxybut-2-en-2-yl)oxy)-
methyl)-2-methyldihydro-2H-pyran-4(3H)-ylidene)methyl)-
triphenylstannane (50d): clear, light yellow oil (45.2 mg, 50% yield,
1
1.00/0.20 dr); Rf = 0.50 (hexanes/ethyl acetate, 2 × 4/1); H NMR
(CDCl3, 300 MHz) δ 7.66−7.46 (m, 6H), 7.37−7.33 (m, 9H), 5.88 (s,
1H), 4.66 (s, 1H), 3.85 (ddd, J = 10.9, 5.6, 2.0 Hz, 1H), 3.73 (qd, J =
6.6, 2.6 Hz, 1H), 3.31 (s, 3H), 3.30−3.28 (m, 1H), 2.78 (s, 1H), 2.35
(tdd, J = 12.7, 5.7, 0.9 Hz, 1H), 2.04 (dt, J = 14.0, 2.7 Hz, 1H), 1.85 (s,
3H), 1.21 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 158.4
(C), 158.1 (C), 139.3 (C), 137.0 (CH), 129.2 (CH), 128.8 (CH),
119.0 (CH), 93.7 (CH), 76.3 (CH), 68.6 (CH2), 57.5 (CH3), 52.6
(CH), 35.0 (CH2), 18.4 (CH3), 16.8 (CH3); IR (neat, cm−1) 3058 (s),
2913 (s), 1657 (m), 1095 (s), 1071 (m), 728 (s), 698 (s); HRMS
(ESI) calcd for C31H32O3D4Sn + H+ 577.2011, found 577.2023.
((7-(1-Deuterio-2-methoxyethyl)-7,7a-dimethyltetrahydro-2H-
furo[3,4-b]pyran-4(3H)-ylidene)methyl)triphenylstannane (49e):
clear, light yellow oil (32.1 mg, 36% yield, 1.00/0.30 dr); Rf = 0.28
((3-(((4,4-Dideuterio-4-methoxybut-2-en-2-yl)oxy)methyl)-2-
methyldihydro-2H-pyran-4(3H)-ylidene)methyl)triphenylstannane
(50b): clear, light yellow oil (29.9 mg, 39% yield, 1.00/0.05 dr); Rf =
1
0.51 (hexanes/ethyl acetate, 2 × 4/1); H NMR ((CD3)2CO, 300
MHz) δ 7.71−7.52 (m, 6H), 7.44−7.37 (m, 9H), 5.95 (s, 1H), 4.69 (s,
1H), 4.06 (dd, J = 10.0, 6.5 Hz, 1H), 3.88 (dd, J = 10.0, 8.0 Hz, 1H),
3.84 (td, J = 5.7, 2.1 Hz, 1H), 3.73 (qd, J = 6.6, 2.7 Hz, 1H), 3.30 (td, J
= 11.5, 2.8 Hz, 1H), 3.21 (s, 3H), 2.87 (td, J = 8.0, 2.5 Hz, 1H), 2.41
(tdd, J = 11.7, 5.7, 1.0 Hz, 1H), 2.14 (tdd, J = 12.6, 5.7, 1.0 Hz, 1H),
1.82 (d, J = 0.8 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H); 13C NMR
((CD3)2CO, 75 MHz) δ 160.0 (C), 157.7 (C), 139.9 (C), 137.5
(CH), 129.9 (CH), 129.5 (CH), 118.7 (CH), 95.0 (CH), 76.9 (CH),
68.8 (CH2), 64.8 (CH2), 56.8 (CH3), 53.4 (CH), 35.8 (CH2), 18.6
(CH3), 16.7 (CH3); IR (neat, cm−1) 3058 (s), 2918 (s), 1653 (m),
1093 (s), 1071 (s), 728 (s), 698 (s); HRMS (ESI) calcd for
C31H34O3D2Sn + Na+ 597.1705, found 597.1696.
1
(hexanes/ethyl acetate, 2 × 4/1); H NMR (CDCl3, 300 MHz) δ
7.58−7.55 (m, 6H, minor), 7.54−7.48 (m, 6H, major), 7.38−7.34 (m,
9H, major/minor), 5.98 (s, 1H, minor), 5.92 (s, 1H, major), 3.93 (t, J
= 9.2 Hz, 1H, major/minor), 3.87 (t, J = 8.8 Hz, 1H, major/minor),
3.77 (dd, J = 11.4, 6.0 Hz, 1H), 3.55 (d, J = 7.8 Hz, 2H), 3.47 (td, J =
12.0, 2.6 Hz, 1H, major/minor), 3.34 (s, 3H, major), 3.26 (s, 3H,
minor), 3.14 (t, J = 9.2 Hz, 1H, major), 3.09 (t, J = 9.2 Hz, 1H,
minor), 2.74 (tdd, J = 13.5, 6.0, 1.7 Hz, 1H, minor), 2.74 (tdd, J =
13.5, 6.3, 1.0 Hz, 1H, major), 2.22 (d, J = 13.7 Hz, 1H, minor), 2.02
(d, J = 14.1 Hz, 1H, major), 1.70 (t, J = 7.2 Hz, 0.5H, major/minor),
1.61 (t, J = 7.8 Hz, 0.5H, major/minor), 1.24 (s, 3H, minor), 1.20 (s,
3H, minor), 1.15 (s, 3H, major), 1.09 (s, 3H, minor); 1D NMR
(CHCl3) δ 1.67 (s, br); 13C NMR (CDCl3, 75 MHz) δ 155.1 (C,
minor), 154.5 (C, major), 139.0 (C, major), 138.9 (C, minor), 137.1
(CH, minor), 137.0 (CH, major), 129.4 (CH, minor), 129.3 (CH,
major), 128.9 (CH, minor), 128.9 (CH, major), 122.7 (CH, major),
122.4 (CH, minor), 87.6 (C), 84.3 (C), 69.3 (CH2, major), 69.0 (CH2,
minor), 68.4 (CH2, major), 67.5 (CH2, minor), 62.7 (CH2, minor),
62.4 (CH2, major), 59.0 (CH3, major), 58.8 (CH3, minor), 56.2 (CH,
major), 53.2 (CH, minor), 33.4 (CHD), 29.9 (CH2), 17.8 (CH3,
major), 17.6 (CH3, minor), 14.8 (CH3, major), 14.4 (CH3, minor); IR
(neat, cm−1) 3051 (s), 2934 (s), 1606 (s), 1074 (s), 1041 (s), 732 (s),
699 (s); HRMS (ESI) calcd for C31H35O3DSn + Na+ 596.1624, found
596.1625.
((5,5-Dideuterio-7-(2-methoxyethyl)-7,7a-dimethyltetrahydro-
2H-furo[3,4-b]pyran-4(3H)-ylidene)methyl)triphenylstannane (49c):
clear, light yellow oil (44.0 mg, 46% yield, 1.00/0.27 dr); Rf = 0.44
1
(hexanes/ethyl acetate, 2 × 4/1); H NMR (CDCl3, 300 MHz) δ
7.64−7.44 (m, 6H), 7.38−7.34 (m, 9H), 5.92 (s, 1H), 3.77 (dd, J =
11.5, 5.1 Hz, 1H), 3.56 (t, J = 7.1 Hz, 2H), 3.48 (td, J = 12.3, 2.3 Hz,
1H), 3.35 (s, 3H), 3.13 (s, 1H), 2.52 (tdd, J = 13.1, 6.3, 1.2 Hz, 1H),
2.02 (dt, J = 14.1, 1.2 Hz, 1H), 1.77−1.68 (m, 2H), 1.21 (s, 3H), 1.15
(s, 3H); 13C NMR (CDCl3, 75 MHz) δ 154.5 (C), 139.0 (C), 137.0
(CH), 129.3 (CH), 128.8 (CH), 122.7 (CH), 87.6 (C), 84.4 (C), 69.4
(CH2), 62.4 (CH2), 58.9 (CH3), 56.0 (CH), 36.5 (CH2), 33.4 (CH2),
17.8 (CH3), 14.8 (CH3); IR (neat, cm−1) 3063 (m), 2930 (s), 1605
(m), 1095 (s), 1074 (s), 730 (s), 699 (s); HRMS (ESI) calcd for
C31H34O3D2Sn + H+ 575.1886, found 575.1887.
((3-(Dideuterio((4-methoxybut-2-en-2-yl)oxy)methyl)-2-methyldi-
hydro-2H-pyran-4(3H)-ylidene)methyl)triphenylstannane (50c):
clear, light yellow oil (40.7 mg, 42% yield, 1.00/0.11 dr); Rf = 0.53
((2-Deuterio-3-(((4-methoxybut-2-en-2-yl)oxy)methyl)-2-methyl-
dihydro-2H-pyran-4(3H)-ylidene)methyl)triphenylstannane (50e):
clear, light yellow oil (28.5 mg, 40% yield, 1.00/0.17 dr); Rf = 0.53
1
(hexanes/ethyl acetate, 2 × 4/1); H NMR (CDCl3, 300 MHz) δ
1
(hexanes/ethyl acetate, 2 × 4/1); H NMR (CDCl3, 300 MHz) δ
7.66−7.46 (m, 6H), 7.38−7.32 (m, 9H), 5.88 (s, 1H), 4.67 (t, J = 7.5
Hz, 1H), 3.93 (d, J = 7.6 Hz, 2H), 3.86 (ddd, J = 10.9, 5.6, 2.1 Hz,
1H), 3.74 (qd, J = 6.4, 2.7 Hz, 1H), 3.31 (s, 3H), 3.30−3.28 (m, 1H),
2.77 (s, 1H), 2.35 (tdd, J = 12.7, 5.7, 1.0 Hz, 1H), 2.04 (dt, J = 12.7,
3.0 Hz, 1H), 1.85 (s, 3H), 1.21 (d, J = 6.7 Hz, 3H); 13C NMR (CDCl3,
75 MHz) δ 158.4 (C), 158.0 (C), 139.3 (C), 137.0 (CH), 129.1
(CH), 128.8 (CH), 119.0 (CH), 93.9 (CH), 76.3 (CH), 69.1 (CH2),
68.6 (CH2), 57.6 (CH3), 52.6 (CH), 35.0 (CH2), 18.6 (CH3), 16.7
(CH3); IR (neat, cm−1) 3052 (s), 2984 (s), 1661 (m), 1082 (s), 1075
(s), 733 (s), 703 (s); HRMS (ESI) calcd for C31H34O3D2Sn + H+
575.1886, found 575.1883.
7.66−7.46 (m, 6H), 7.37−7.33 (m, 9H), 5.88 (s, 1H), 4.67 (t, J = 7.6
Hz, 1H), 4.00 (dd, J = 9.7, 6.5 Hz, 1H), 3.93 (d, J = 7.6 Hz, 2H), 3.85
(dd, J = 9.9, 7.6 Hz, 2H), 3.33−3.27 (m, 1H), 3.32 (s, 3H), 2.78 (t, J =
7.2 Hz, 1H), 2.36 (tdd, J = 12.8, 6.0, 1.0 Hz, 1H), 2.05 (dt, J = 12.8,
2.4 Hz, 1H), 1.85 (s, 3H), 1.21 (s, 3H); 1D NMR (CHCl3) δ 3.72 (s,
br); 13C NMR (CDCl3, 75 MHz) δ 158.4 (C), 158.0 (C), 139.3 (C),
137.0 (CH), 129.2 (CH), 128.8 (CH), 119.0 (CH), 93.9 (CH), 75.8
(t, J = 20.7 Hz, CD), 69.1 (CH2), 68.5 (CH2), 64.2 (CH2), 57.6
(CH3), 52.7 (CH), 35.1 (CH2), 18.3 (CH3), 16.7 (CH3); IR (neat,
cm−1) 3051 (s), 2933 (s), 1662 (m), 1074 (s), 1041 (s), 735 (s), 700
(s); HRMS (ESI) calcd for C31H35O3DSn + Na+ 596.1624, found
596.1625.
((5,5-Dideuterio-7-(2,2-dideuterio-2-methoxyethyl)-7,7a-dime-
thyltetrahydro-2H-furo[3,4-b]pyran-4(3H)-ylidene)methyl)-
triphenylstannane (49d): clear, light yellow oil (31.7 mg, 35% yield,
1
1.00/0.24 dr); Rf = 0.44 (hexanes/ethyl acetate, 2 × 4:1); H NMR
ASSOCIATED CONTENT
(CDCl3, 300 MHz) δ 7.63−7.44 (m, 6H), 7.38−7.34 (m, 9H), 5.92 (s,
1H), 3.77 (dd, J = 11.5, 5.1 Hz, 1H), 3.47 (td, J = 12.2, 2.3 Hz, 1H),
3.34 (s, 3H), 3.13 (s, 1H), 2.54 (tdd, J = 13.3, 6.2, 1.0 Hz, 1H), 2.03
(dt, J = 14.1, 1.0 Hz, 1H), 1.69 (s, 1H), 1.63 (s, 1H), 1.20 (s, 3H), 1.15
(s, 3H); 13C NMR (CDCl3, 75 MHz) δ 154.5 (C), 139.0 (C), 137.0
(CH), 129.3 (CH), 128.8 (CH), 122.7 (CH), 87.6 (C), 84.4 (C), 62.4
(CH2), 58.9 (CH3), 56.0 (CH), 36.2 (CH2), 33.4 (CH2), 17.8 (CH3),
■
S
* Supporting Information
Figures and tables giving 1H NMR and 13C NMR spectra for all
new compounds and absolute energies and Cartesian
coordinates for calculated radical intermediates. This material
is available free of charge via the Internet at http://pubs.acs.org.
8646
dx.doi.org/10.1021/jo301565u | J. Org. Chem. 2012, 77, 8634−8647

The Journal of Organic Chemistry
Article
(c) Gom
́ ́
ez, A. M.; Company, M. D.; Uriel, C.; Valverde, S.; Lopez, J.
AUTHOR INFORMATION
■
C. Tetrahedron Lett. 2002, 43, 4997−5000.
Corresponding Author
*E-mail: wulff@uvic.ca.
(8) Davies, K. A.; Wulff, J. E. Org. Lett. 2011, 13, 5552−5555.
(9) E → Z isomerism of vinyl radical intermediate G is expected to
be a very fast process. See ref 5f and references therein. Our own
molecular modeling calculations suggest that the ground-state
structure for the vinyl radical looks approximately like the drawing
of G in Scheme 3, but with somewhat distorted bond angles. However,
this is not far in energy from the corresponding geometric isomer,
which presumably cyclizes more quickly to generate the observed
products.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council (NSERC) of Canada for operating funds and for a
fellowship to N.F.O. We are also grateful to the Canada
Research Chairs program (CRC) and the Michael Smith
Foundation for Health Research (MSFHR) for salary support
to J.E.W. and to the University of Victoria for additional
operating funds. Finally, we thank Dr. Ori Granot and the UVic
Genome BC Proteomics Centre for mass spectrometry support,
Dr. Christopher Barr for assistance with NMR experiments, and
Prof. Glenn Sammis (University of British Columbia) for
helpful discussions.
(10) For an application of uncyclized bis-vinyl ethers, see: Davies, K.
A.; Kou, K. G. M.; Wulff, J. E. Tetrahedron Lett. 2011, 52, 2302−2305.
(11) Compounds 4 and 6 were synthesized from ethyl 4,4,4-
trifluorobutynoate. For the preparation of this reagent, see: Hamper, B.
C. Org. Synth. 1992, 70, 246−255.
(12) For a discussion of the use of cyclopropanes as radical clocks,
see: (a) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317−323.
(b) Beckwith, A. L. J.; Bowry, V. W. J. Am. Chem. Soc. 1994, 116,
2710−2716.
(13) Bengtson, G.; Keyaniyan, S.; de Meijere, A. Chem. Ber 1986,
119, 3607−3630.
(14) (a) Tomilov, Y. V.; Kostitsyn, A. B.; Shulishov, E. V.; Nefedov,
O. M. Synthesis 1990, 246−248. (b) Hahn, N. D.; Nieger, M.; Dotz, K.
̈
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