Pt-Catalyzed Rearrangement of Oxaspirohexanes to 3-Methylenetetrahydrofurans: Scope and Mechanism

Article abstract of DOI:10.1021/acs.joc.5b00604

A novel Pt-catalyzed rearrangement of oxaspirohexanes to 3-methylenetetrahydrofurans is reported. Mechanistic studies by ¹³C-labeling experiments confirm oxidative addition of Pt(II) regioselectively to the least substituted carbon-carbon bond

Full text of DOI:10.1021/acs.joc.5b00604

Article
pubs.acs.org/joc
Pt-Catalyzed Rearrangement of Oxaspirohexanes to
3‑Methylenetetrahydrofurans: Scope and Mechanism
Christian A. Malapit, Sampada M. Chitale, Meena S. Thakur, Rosa Taboada, and Amy R. Howell*
Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269-3060, United States
S
* Supporting Information
ABSTRACT: A novel Pt-catalyzed rearrangement of oxaspir-
ohexanes to 3-methylenetetrahydrofurans is reported. Mech-
anistic studies by 13C-labeling experiments confirm oxidative
addition of Pt(II) regioselectively to the least substituted
carbon−carbon bond of the cyclopropane to form a
platinacyclobutane intermediate. To our knowledge, this is
the first alkoxy-substituted platinacyclobutane that has been
observed spectroscopically. The scope and a proposed mechanism of this new Pt-catalyzed transformation are described.
INTRODUCTION
■
In exploring the reactivity of unusual oxetanes, we have shown
that oxetane oxocarbenium ions 1, generated from either 2-
methyleneoxetanes1 or dioxaspirohexanes2 using electrophiles
or Lewis acids (Figure 1), can be converted to a variety of
Figure 2. Madsen’s Zeise’s dimer-catalyzed ring-opening of 1,2-
cyclopropanated sugars.4
Figure 3. Anticipated transformation of oxaspirohexanes 4 in the
presence of 3 to give novel psico-nucleosides 5.
Figure 1. Routes to oxetane intact products from methyleneoxetanes
or dioxaspirohexanes through oxocarbenium ions 1a or 1b.
Unexpectedly, under the Madsen conditions,4 oxaspirohex-
ane 4a (or 4b) gave mixtures of two products, 3-
methylenetetrahydrofuran 6a (or 6b) and allyl ether 7a (or
7b) (Table 1). Moreover, in the absence of MeOH, 4a was
converted to just 3-methylenetetrahydrofuran 6a, while allyl
ether 7a was the sole isolable product in the presence of excess
MeOH. Neither outcome could be rationalized by oxocarbe-
nium ions like 8 (Figure 3). Thus, these initial results
represented a novel pathway for reactions between oxygen-
substituted cyclopropanes and Zeise’s dimer.
With the unanticipated rearrangement to synthetically useful
3-methylenetetrahydrofurans,7 we decided to optimize the
reaction and explore the scope of this transformation.
Moreover, since it was apparent that oxidative addition of Pt
was not occurring in the cyclopropane adjacent to the C−O
oxetane intact species, including epi-oxetin2b and novel psico-
nucleosides (e.g., a psico-oxetanocin, Figure 1).1a We previously
reported the preparation of oxaspirohexanes from methyl-
eneoxetanes3 and were interested in exploring new reactivities
of this strained heterocycle. Our attention was captured by
reports from Madsen and co-workers that 1,2-cyclopropanated
sugars gave C2-substituted glycosides 2 when reacted with
alcohols in the presence of Zeise’s dimer, [Pt(C2H4)Cl2]2 (3)
(Figure 2).4 From these results and prior reports of the reaction
of Zeise’s dimer with silyloxycyclopropanes5 and alkoxycyclo-
propanes,6 a mechanism involving oxidative addition of
platinum into the cyclopropane next to the CO bond to give
an oxocarbenium ion4b was proposed (Figure 2). On the basis
of these Madsen results, we postulated that oxaspirohexanes 4
could be converted to psico-nucleosides 5 (Figure 3, for Nu =
nucleobase) with Zeise’s dimer insertion into the cyclopropane
providing an alternative access to oxetane oxocarbenium ions.
Received: March 17, 2015
© XXXX American Chemical Society
A
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literature precedent showing that the formation of platinacy-
clobutanes is achieved almost exclusively using Zeise’s dimer as
the Pt source.9,10
Table 1. Initial Findings on the Reaction of Oxaspirohexanes
with Zeise’s Dimer
a
It is well-known that electron-donating ligands stabilize
platinacycle complexes;9 so common nitrogen and phosphorus
ligands were examined. In general, phosphine ligands provided
improved reactivity and increased isolated yields (Table 3). The
b
MeOH (equiv)
2
substrate
ratio (6:7)
% yield 6
% yield 7
Table 3. Examination of the Effect of Ligands on the
Isomerization of Oxaspirohexanes with Zeise’s Dimer
4a
4b
4a
4a
1:1.5
1:2
excess
0
7a only
6a only
0
50
34
0
a
b
1
Reaction conditions: 0.5−1.0 mmol 4a/b. Ratios are based on H
NMR of the crude reaction mixture.
a
bond, mechanistic studies were undertaken. 13C-labeling
experiments provided clear evidence of an alternative insertion.
These results are described herein.
entry
substrate
ligand (mol %)
t
isolated yield (%)
1
2
4h
4c
4c
4h
4h
4h
4h
4c
4h
4h
4h
4h
4h
none
2.5 h
20 h
41
34
0
PPh3 (20)
b
3
P(C6F5)3 (20)
P(t-Bu)3 (20)
P(n-octyl)3 (20)
bipyridine (10)
DCPE (10)
PCy3 (20)
20 h
RESULTS AND DISCUSSION
4
5
6
7
8
9
2 h
60
66
61
70
64
69
70
68
72
73
■
4.5 h
2.25 h
30 min
45 min
40 min
6 h
Optimization and Scope. Initial variables examined to
optimize the rearrangement of oxaspirohexanes to 3-methyl-
enetetrahydrofurans included solvent, temperature, and con-
centration (Table 2). Evaluation of solvents for the reaction
showed that noncoordinating solvents, such as methylene
chloride, chloroform, and toluene, gave clean conversion of
oxaspirohexane 4a to 3-methylenetetrahydrofuran 6a at
concentrations from 0.2 to 1.0 M. Solvents such as diethyl
ether, tetrahydrofuran, and ethyl acetate gave poor reaction
outcomes. Furthermore, an increase in reaction temperature
decreased the time needed for complete conversion (entries 4−
7); however, isolated yields decreased slightly at higher
temperatures. Subsequent reactions were conducted at 45 °C
and with a concentration of 0.5 M in CH2Cl2.
PCy3 (20)
c
10
PCy3 (20)
11
P(OEt)3 (20)
P(OEt)3 (20)
P(OEt)3 (10)
15 min
4 h
c
12
cd
,
13
6 h
a
Reaction time based on complete consumption of starting material as
monitored by H NMR. After 20 h, no conversion was observed.
Reaction run at room temperature. Catalyst loading decreased to 5
b
1
c
d
mol %.
On the basis of the literature,4−6,8 it was initially reasoned
that the rearrangement was initiated by oxidative addition of
Pt(II); so a variety of Pt catalysts were examined (Table 2,
entries 8−13). Oxaspirohexane 4a did not react with the
common Pt catalysts shown. This is consistent with the
use of an electron-withdrawing phosphine (entry 3) blocked
conversion, even after 20 h of heating. On the other hand,
tricyclohexyl phosphine and triethyl phosphite decreased
reaction times to 1 h or less and provided increased isolated
yields (up to 70%). In addition, the reaction could be
Table 2. Optimization of Conditions for the Isomerization of Oxaspirohexanes
a
b
entry
solvent
Pt catalyst
temp
rt
conc (M)
time (h)
% conv. (yield)
1
2
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
CDCl3
tol-D8
3
3
3
3
3
3
3
0.2
0.5
1.0
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
20
20
20
1
65
rt
100
3
rt
100
4
45 °C
45 °C
55 °C
80 °C
45 °C
80 °C
45 °C
45 °C
45 °C
45 °C
100
5
1
100 (34%)
6
0.75
0.5
20
20
20
20
20
20
100 (30%)
7
100 (25%)
8
CD2Cl2
tol-D8
PtCl2
0
0
0
0
0
0
9
PtCl2
10
11
12
13
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
CODPtCl2
C2H4-Pt(PPh3)3
c
(dfmp)2PtMe2
d
(dfepe)2PtEt2
a
b
Time to complete consumption of the starting material or until a reaction time of 20 h. Conversions were monitored by 1H NMR (isolated yields
c
d
in parentheses). Dfmp = Me(C2F5)2P. Dfepe = (C2F5)2PCH2CH2P(C2F5)2.
B
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a
performed at room temperature with no diminution in yield
(entries 10, 12, and 13). Also, decreasing the catalyst loading to
5 mol % at room temperature still gave clean conversion with
73% yield (entry 13). Although triethyl phophite provided the
highest yield for 4h, tricyclohexylphosphine gave better results
for a broader range of substrates.
Table 5. Reaction of 4-Oxaspirohexanes with Zeise’s Dimer
A variety of oxaspirohexanes 4a−n were prepared (Table 4)
to explore the scope of the rearrangement. The oxaspirohex-
Table 4. . Preparation of 4-Oxaspiro[2.3]hexanes
a
Reaction conditions: 0.5−1.0 mmol scale, 10 mol % [Pt(C2H4)Cl2]2,
b
20 mol % PCy3, 0.5 M in CH2Cl2. No reaction was observed even
after 20 h. Reaction was conducted at room temperature. Reaction
was conducted using 5 mol % Pt(C2H4)Cl2]2, 10 mol % P(OEt)3 at
c
d
e
room temperature. There was a small amount of an inseparable,
unidentified impurity (see spectra in the Supporting Information).
presumably due to the interaction of the catalyst with the
nitrogen groups.
Unexpectedly, when 5,6-cis-substituted oxaspirohexane 4l
was reacted under the standard conditions, ring-opened allyl
chloride 11 was isolated as the major product (Scheme 1).
When 5,6-cis-substituted oxaspirohexane 4k was used, ring-
opened alcohol 12 was obtained in 42% yield. Analysis of the
1H NMR of the crude reaction mixture and the byproducts
isolated from column chromatography showed the formation of
additional, inseparable olefinic compounds, which could be the
Scheme 1. Reaction of cis-5,6-Oxaspirohexanes with Zeise’s
a
Dimer
anes were synthesized from the corresponding 2-methyleneox-
etanes 10a−n in moderate to high yields by a modified
Simmon−Smith cyclopropanation.3 The methyleneoxetanes
were obtained in good yields by methylenation of β-lactones
9a−n.11
Monosubstituted oxaspirohexanes rearranged to the corre-
sponding 3-methylenetetrahydrofurans 6c−e in good yields
(Table 5). Similarly, trans-3-methylenetetrahydrofurans 6h−j
were obtained in up to 80% yield. Also of note, the reaction
tolerated most aromatic groups, but for substrates with aryl
groups directly attached to the oxetane ring, such as 4a, poor
conversions and low yields were observed. With substrates
containing protected amine substituents at C-6 (4f and 4g), no
conversion was observed even with prolonged heating (20 h),
a
Reaction conditions: 0.5 mmol scale, 10 mol % 3, 20 mol % PCy3, 0.5
b
M in CH2Cl2. cis-3-Methylenetetrahydrofuran 6l was isolated in a
trace amount and characterized (see the Experimental Section). cis-3-
Methylenetetrahydrofuran 6k was isolated as a mixture with 14.
c
C
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source of the hydrogen needed to form the ring-opened,
reduced alcohol product 12. It is worth noting that
consumption of both 5,6-cis-substituted oxaspirohexanes took
longer than was required for the 5,6-trans-substituted
compounds. The reactions were also carried out without
tricyclohexyl phosphine, and the same products were observed,
although the reaction times were even longer. The rearranged
products, 3-methylenetetrahydrofurans 6l and 6k, were also
isolated, but in trace amounts. These alternative outcomes and
the longer reaction times will be discussed later.
Figure 4. Possible platinacycle intermediates obtained from
oxaspirohexanes via the cyclopropane ring (path a) or the oxetane
ring (path b).
Completely different results were realized with 5,5,6,6-
tetrasubstituted-oxaspirohexanes 4m and 4n (Scheme 2).
Scheme 2. Reaction of 5,5-Substituted-Oxaspirohexanes with
Zeise’s Dimer
diiodomethane (Scheme 3). The labeled compound was
obtained in 71% yield as a pair of isotopic stereoisomers.
a
Scheme 3. Synthesis of 13C-Labeled 4-Oxaspirohexane 13C-
4h
13C-labeled 4h was treated with stoichiometric Zeise’s dimer
and PCy3 in CD2Cl2 at room temperature, and the reaction was
monitored by 13C NMR. Figure 5 provides a summary of the
13C-DEPT NMR analysis of the reaction. Two intermediates
with 13C-labeled carbon chemical shifts at 15.04/7.94 ppm
(region A) and at 49.52/113.70 ppm (regions B and B′) were
observed. These intermediates were present over the course of
the reaction (Figure 5b,c) and largely disappeared after
complete conversion of 13C-4h (Figure 5d). Specifically, they
were observed for a span of 3 h when the reaction was
monitored at room temperature or could persist for up to 15 h
at 0 °C.
a
Reaction conditions: 1.0 mmol scale, 10 mol % 3, 20 mol % PCy3, 0.5
b
1
M in CH2Cl2. Based on the H NMR analysis of the crude mixture.
When 5,5-diphenylsubstituted oxaspirohexane 4m was treated
with Zeise’s dimer, no 3-methylenetetrahydrofuran resulted;
instead, tetrasubstituted alkene 15 was isolated in 40% yield.
On the other hand, 5,5-dialkyldisubstituted oxaspirohexane 4n
gave β,γ-unsaturated ketone 16 in 50% yield as the only isolable
product. The different results with 4m and 4n and with the
oxaspirohexanes with cis-substituents on the oxetane ring again
led us to question the pathway of these Pt-promoted processes.
Mechanistic Study. It is known that cyclopropanes and the
C−O bond of β-lactones undergo oxidative addition to Pt(II)
to produce stable platinacyclobutane9,10 and platinalactone12
complexes, respectively. Likewise, formation of platinaoxetane
intermediates has been postulated in the Pt-mediated activation
of epoxides.13 While platinacyclobutanes are known to be stable
and isolable, with many being well-characterized, there have
been no reports of alkoxy-substituted platinacyclobutanes being
isolated or spectroscopically observed. This may be due to
favorable formation of oxocarbenium ions, resulting in
isomerizations to form ring-opened products.4−6
The peaks with 13C-labeled carbons at 15.04 and 7.94 ppm
(region A), correspond to the expected chemical shifts of
carbon bonded to Pt in platinacyclobutanes (Figure 6).9 These
13C-labeled carbons show large Pt-13C coupling constants of
556.6 and 622.4 Hz, respectively, which fall in the range of
usual 1JPt‑ C values in platinacyclobutanes9 or Pt−C σ-bonds in
13
general.15 This key intermediate was rationalized to be
platinacyclobutane 13C-18 (as a pair of 13C-labeled isotopic
stereoisomers).
The additional intermediate peaks observed in regions B and
B′ were rationalized to be from Pt-allyl complexes, which can
be obtained from the facile ring-puckering16 of the oxy-
platinacyclobutane 13C-18. The large differences in 13C
On the basis of the literature precedent related to Pt
reactions with strained rings, potential initial oxidative addition
of Pt that might be anticipated to occur included (a) into the
cyclopropane ring (Figure 4, path a) to produce either
intermediate I or II or (b) into the C−O bond of the oxetane
ring (path b) to give intermediate III or IV. As previously
mentioned, isomerization to the 3-methylenetetrahydrofurans
cannot be rationalized from oxocarbenium intermediate I.
Similarly, intermediate IV would not lead to the formation of
the observed products, and to date, there have been no reports
of oxidative addition of Pt(II) into simple oxetanes.14
13C
chemical shifts (49.5 and 113.70 ppm) and the JP‑ values
(19.1 and 2.5 Hz, respectively) suggest that the intermediate
observed is an η1 Pt-allyl complex15,17 as a pair of isotopomers.
Specifically, the Pt-η1-allyl intermediate observed in region B′
3
corresponds to 13C-19B′ as indicated by the small JPt‑ (22.7
13
C
Hz), while the intermediate at region B corresponds to the
other isotopomer, Pt-η1-allyl 13C-19B. Given that the observed
1
13
JPt‑ C in region B (30.6 Hz) is relatively small compared to that
of usual Pt−C σ-bonds,15 the Pt−13C bond must be rather
weak.17 The stability of η1 and η3 Pt-allyl complexes is highly
dependent on the counterion.16 It would seem that the Pt allyl
intermediate prefers a σ-coordination mode17 due to the
propensity of intramolecular coordination of the negatively
In order to determine which path was operational, 13C-
labeled 4-oxaspirohexane 13C-4h was synthesized by cyclo-
propanation of methyleneoxetane 10h using 13C-labeled
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Figure 5. 13C DEPT NMR monitoring of the reaction of 13C-4h (0.1 mmol) with a stoichiometric amount of Zeise’s dimer and PCy3 and with 0.2 M
13C-4h in CD2Cl2 at RT. (a) 13C DEPT NMR spectra of oxaspirohexanes 13C-4h. (b) 13C NMR spectrum after 1 h. (c) 13C DEPT after 2 h. (d) 13
DEPT NMR after 4 h. (e) 13C DEPT of methylenetetrahydrofuran products 13C-6h. (f) 13C DEPT of allyl chloride byproducts 13C-17.
C
charged oxygen atom to the positively charged Pt to form a six-
membered Pt-η1-allyl complex. Sakaki and co-workers reported
that a hydride coordinated Pt-η1-allyl complex is 8 kcal/mol
more stable that its corresponding η3-allyl complex.18 Likewise,
Pregosin and co-workers have demonstrated that methoxy-
modified MOP Pt allyl complexes prefer a σ-coordination
mode, albeit with a weak σ-bond.17 Although the Pt-allyl
intermediates observed here appear to be of an η1 character, the
occurrence of Pt-η3-allyl intermediates is not ruled out. In fact,
unresolved peaks were also seen at around 64 and 73 ppm,
which may correspond to Pt-η3-allyl intermediates15,17 as a pair
of isotopomers.
was not observed when a catalytic amount (5−10 mol %) of
Zeise’s dimer was used.
The evidence delineated above is suggestive of the
mechanistic interpretation shown in Figure 7. First, regiose-
lective oxidative addition of Pt(II) into the least substituted C−
C bond in the cyclopropane provides platinacyclobutane 20.
Due to the reactivity of oxygen-substituted platinacyclobutanes
and perhaps also to the ring strain associated with oxetanes,19
ring-opening to Pt-allyl complexes results. Cyclization gives 3-
methylenetetrahydrofurans 6. This mechanism is consistent
with the formation of allyl ethers/chlorides by intermolecular
reactions of the Pt-allyl complexes with methanol or chloride
ion when the reaction is conducted in the presence of methanol
or a stoichiometric amount of Zeise’s dimer. The observed
regioselective oxidative addition of Pt(II) into the cyclopropane
is remarkable because this has not been the case for all
examples of Pt-catalyzed transformations of oxygen-substituted
After purification, 13C-labeled 3-methylenetetrahydrofurans
13C-6h (with 13C peaks at 103.32 and 71.36 ppm, Figure 5e)
were isolated in 55% yield as an isotopomeric mixture (Scheme
4). In addition, isotopomeric byproducts 13C-17 (with 13C
peaks at 115.69 and 48.06 ppm, Figure 5f) were also observed
and isolated in 20% yield. The formation of the allyl chloride
E
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Figure 6. Regions in 13C DEPT NMR monitoring showing the 13C-labeled carbon peaks observed as intermediates from the reaction of 13C-4h with
Zeise’s dimer: (A) 13C peaks for platinacyclobutane intermediate 13C-18 (as a pair of 13C-labeled isotopic stereoisomers) and (B/B′) 13C peaks for
Pt-η1-allyl intermediate 13C-19 as a pair of 13C-labeled isotopic stereoisomers.
Scheme 4. Reaction of 13C-Labeled Oxaspirohexane 13C-4h with a Stoichiometric Amount of Zeise’s Dimer
Figure 7. Proposed mechanism for Zeise’s dimer-catalyzed rearrangement of oxaspirohexanes to 3-methylenetetrahydrofurans.
cyclopropanes, where C−C bond cleavage has always occurred
Attempts to isolate the observed platinacyclobutane by
adding ligands (e.g., pyridine, bipyridine) used previously in the
adjacent to the oxygen.4−6
F
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crystallization of platinacyclobutanes9a were not successful. In
most cases, rearrangement to the 3-methylenetetrahydrofuran
was still the outcome.
To understand the unexpected outcome of oxaspirohexanes
with cis-substituents on the oxetane, 13C-labeling experiments
were again conducted. 13C-labeled cis-oxaspirohexane 13C-4l
was obtained as a pair of isotopic stereoisomers from the
reaction outcome from 13C-4h, cis-oxaspirohexane 13C-4l gave
allyl chloride 13C-11 and 3-methylenetetrahydrofuran 13C-6l as
the major and minor products, respectively. As a reference,
unlabeled cis-oxaspirohexane 4l was also treated with a
stoichiometric amount of Ziese’s dimer. Allyl chloride 11 was
obtained as the major product in 52% yield, and 3-
methylenetetrahydrofuran 6l was obtained in 16% yield
(Scheme 6).
Scheme 5. Synthesis of 13C-Labeled 4-Oxaspirohexane 13C-4l
Scheme 6. Reaction of Oxaspirohexane 4l with a
Stoichiometric Amount of Zeise’s Dimer
cyclopropanation of cis-methyleneoxetane 10l (Scheme 5). The
13C-labeled cis-oxaspirohexane was treated with a stoichiometric
amount of Zeise’s dimer under the same conditions as those
used for the trans-isomer 13C-4h, and the reaction was
monitored by 13C DEPT NMR (see the Supporting
Information).
Results from the 13C-labeling studies with cis-isomer 13C-4l
demonstrate that the initial intermediates involved in the
reactions of cis-oxaspirohexanes with Zeise’s dimer are identical
to those observed with the trans-oxaspirohexanes, even though
the product distribution is different. Initial oxidative addition of
cyclopropane to Pt to form platinacyclobutanes is followed by
ring-opening to Pt-allyl intermediates (Figure 9). However,
rather than cyclization, the allyl intermediate reacts with a
chloride ion to form allyl chloride 11. For 4k, the Pt-allyl
intermediate undergoes reductive elimination to give homoallyl
alcohol 12 (Scheme 1). The contrasting outcome (reduction vs
substitution) between cis-oxaspirohexanes 4k and 4l requires
that the allyl intermediates undergo different reactions. For the
reaction of 4k, the isolation of a significant amount of dienone
13 (which must arise from 4k, rather than a Pt-allyl
intermediate) suggests a hydride source. Steric encumbrance
could prevent 4l from providing a hydride. We propose that the
low reactivity of the cis-isomers is due to steric effects that
Somewhat unexpectedly, intermediate peaks analogous to
those observed from 13C-4h were also witnessed for a span of 3
h. Specifically, peaks at 8.60 and 12.98 ppm (region A, Figure
8) correspond to platinacyclobutanes 13C-21 with Pt satellites
(1JPt‑ values of 622.4 and 556.3 Hz, respectively). Likewise,
13C
similar to results with 13C-4h, isotopomer peaks were observed
at 49.4 ppm (region B) with a 1JPt‑ C value of 30.9 (JP‑ C = 33.9
13
13
1
13
Hz) and at 113.6 ppm (region B′) with a JPt‑ value of 32.4.
C
These shifts correspond to Pt-η1-allyl intermediates 13C-22B
and 13C-22B′, respectively. As with the unresolved intermediate
peaks observed in the reaction of trans-oxaspirohexane 13C-4h,
peaks at around 66 and 68 ppm, which could correspond to Pt-
η3-allyl intermediates,15,17 were also observed. In contrast to the
Figure 8. Regions in 13C DEPT NMR monitoring showing the 13C-labeled carbon peaks observed as intermediates from the reaction of 13C-4l with
Zeise’s dimer: (A) 13C peaks for platinacyclobutane intermediate 13C-21 (as a pair of 13C-labeled isotopic stereoisomers) and (B/B′) 13C peaks for
Pt-η1-allyl intermediate 13C-22 as an isotopomeric mixture.
G
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Scheme 7. (a) Reaction of a 1,1-Disubstituted Cyclopropane
with Zeise’s Dimer.20 (b) Preparation of Cyclopropane-
Substituted Oxaspirohexane 4o. (c) Reaction of
a
Oxaspirohexane 4o with Zeise’s Dimer
Figure 9. Proposed explanation for alternative pathway for the Zeise’s
dimer-catalyzed rearrangement of cis-oxaspirohexanes.
disfavor the conformation required for the formation of 3-
methylenetetrahydrofurans, which leaves the door open for
alternative pathways.
a
Reaction conditions: 1.0 mmol scale, 10 mol % 3, 20 mol % PCy3, 0.5
1
M in CH2Cl2. Cis/trans ratio was based on H NMR analysis of the
crude mixture.
For the case of 5,5-disubstituted oxaspirohexanes, we
postulate a rearrangement where Pt-mediated bond breaking
of the C−O bond in the oxetane ring occurs before cleavage of
the cyclopropane (Figure 10). This is presumably due to the
was warranted. Nevertheless, it seemed worthwhile to examine
the effect of placing additional substitution on the cyclo-
propane. An oxaspirohexane bearing a substituent at the
cyclopropyl moiety was prepared by the cyclopropanation of
10o using diodoethane (Scheme 7b). This provided 4o in 78%
yield (isolated as a single enantiomeric pair, but with the
relative stereochemistries unknown). Other diasteromeric
products were also obtained as an inseparable mixture in
trace amounts. 1-Methyl-substituted oxaspirohexane 4o was
treated with Zeise’s dimer, and 3-methylenetetrahydrofuran,
isolated in 76% yield (4:1 cis/trans), resulted (Figure 7c). The
observed complete regioselectivity and formation of the cis-
isomer as the major product further supports the intermediacy
of a Pt-allyl intermediate that undergoes a 5-exo cyclization
mode via the more stable transoid Pt-allyl intermediate. Such
outcomes were observed in cyclizations of related Pd-allyl
systems with O-nucleophiles.21 These results demonstrate that
an additional alkyl substituent on the cyclopropane did not alter
the outcome of the reaction, confirming that the regioselectivity
cannot be entirely explained by steric effects.
Figure 10. Rationalization of the different outcomes of 5,5-
disubstituted oxaspirohexanes.
formation of a tertiary carbocation that ultimately leads to 15 or
16. The zwitterionic β-platinum(II) ketone intermediate 23 is
analogous to the intermediates proposed5 and the platinum
complex20 isolated by Ryu and Sonoda during their mechanistic
investigation of the Pt-catalyzed isomerization of silyloxycyclo-
propane to allyl silylethers.
It could be argued that the regioselective formation of a
platinacyclobutane between the methylenes of the cyclo-
propane is governed by steric effects. Indeed, most reports of
the reaction of Zeise’s dimer with 1,1-disubstituted cyclo-
propanes give products consistent with initial substitution into
this less-hindered C−C bond.9a However, earlier reports of the
reaction of Zeise’s dimer with silyloxycyclopropanes had
included 1,1-disubstituted compounds. For example, arylsilox-
ycyclopropanes were converted to aryl ketones in the presence
of Zeise’s dimer (Scheme 7a).20 Formation of the ketone
requires cleavage of the oxygen-substituted cyclopropane C−C
bond. Thus, our initial expectation of platinacyclobutane
formation through the C−C bond adjacent to the oxetane
CONCLUSION
■
A novel Zeise’s dimer-catalyzed rearrangement of oxygen-
substituted cyclopropanes that provides functionalized tetrahy-
drofurans has been discovered. This work highlights the first
detection of alkoxy-substituted platinacyclobutane intermedi-
ates. In contrast to previous reactions with oxygen-substituted
cyclopropanes, where oxidative addition to Pt occurred
adjacent to the C−O bond, regioselective platinacyclobutane
formation through the distal methylene carbons of the
cyclopropane ring resulted. The key platinacyclobutane and
Pt-allyl intermediates were observed by 13C NMR studies using
13C-labeled oxaspirohexanes. In particular, these studies
clarified that, although outcomes with cis-5,6-disubstituted
oxaspirohexanes were different than those with trans-5,6-
disubstituted (or 5- or 6-substituted) oxaspirohexanes, the
intermediates were identical. An oxaspirohexane bearing a
H
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Article
(d, J = 11.4 Hz, 1H), 4.45 (d, J = 11.4 Hz, 1H), 3.85 (d, J = 6.4 Hz,
1H), 3.63 (ddd, J = 4.8, 4.8, 4.8 Hz, 1H) 2.33 (d, J = 4.9 Hz, 1H), 1.70
(m, 2H), 1.63 (m, 4H), 1.51 (s, 9H), 1.30−1.03 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 203.4, 137.1, 128.6, 128.3, 128.2, 85.5, 76.6,
73.5, 47.6, 39.2, 29.8, 26.7, 26.5, 26.4, 26.1; HRMS (ESI) calcd for
C20H31O3S (M + H)+ m/z 351.1994, found 351.1998.
substituent on the cyclopropane ring was also efficiently
converted to a 3-methylenetetrahydrofuran with complete
regioselectivity.
EXPERIMENTAL SECTION
■
Preparation of β-Lactones. Known β-lactones 9a,22 b,11 c,23a
d,23b f,2b g,24 i,25 m,26 and n26 were prepared by literature procedures.
Spectral data are in accordance with the literature references.
trans-3-Benzyloxy-4-cyclohexyloxetan-2-one (9j). (2R*,3R*)-2-
Benzyloxy-S-tert-butyl-3-cyclohexyl-3-hydroxy-1-thiopropiolate (24)
(2.00 g, 5.71 mmol) was dissolved in dry CH3CN (200 mL) under
nitrogen at rt. Hg(OTFA)2 (2.74 g, 6.41 mmol) was added to this
solution at once. The resulting reaction mixture was quickly immersed
into a preheated oil bath (50 °C). After 5 min, the mixture was filtered
through a pad of Celite, which was washed with CH2Cl2 (3 × 5 mL).
The filtrate was then concentrated to give a pale brown oil. Purification
by flash chromatography on silica gel (petroleum ether/EtOAc, 92:8)
afforded 9j as a colorless oil (0.68 g, 46%): IR (neat) 3064, 3032,
4-Cyclohexyloxetan-2-one (9e).27 A solution of Ag(SbF6)3 (9.10 g,
26.6 mmol) in dry CH2Cl2 (60 mL) was added to a solution of AlCl3
(1.18 g, 8.88 mmol) and i-Pr2EtN (4.60 mL, 26.6 mmol) in CH2Cl2
(60 mL) at −25 °C under N2 to form a heterogeneous mixture. i-
Pr2EtN (7.70 mL, 44.4 mmol), acetyl chloride (4.70 mL, 66.5 mmol),
and a solution of cyclohexylcarboxaldehyde (5.00 g, 44.3 mmol) in
CH2Cl2 (13 mL) were added, and the resulting mixture was stirred at
−25 °C for 4 h. The reaction mixture was then filtered through a pad
of Celite, and the Celite was washed with CH2Cl2 (3 × 5 mL). The
filtrate was then concentrated to give a pale yellow oil. Purification by
flash chromatography on silica gel (petroleum ether/EtOAc, 90:10)
afforded 9e as a colorless oil (4.9 g, 72%):28 1H NMR (300 MHz,
CDCl3) δ 4.20 (m, 1H), 3.43 (dd, J = 16.3, 5.8 Hz, 1H), 3.11 (dd, J =
16.3, 4.4 Hz, 1H), 1.97−1.52 (m, 6H), 1.39−0.90 (m, 5H).
1
2928, 2854, 1833, 1451, 1146, 865, 698 cm−1; H NMR (400 MHz,
CDCl3) δ 7.40−7.32 (m, 5H), 4.81 (d, J = 11.6 Hz, 1H) 4.66 (d, J =
11.5 Hz, 1H), 4.64 (d, J = 3.6 Hz, 1H), 4.22 (dd, J = 8.5, 3.6 Hz, 1H),
1.87 (m, 1H) 1.79−1.50 (m, 5H), 1.28−1.13 (m, 3H), 1.08−0.96 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 168.4, 136.4, 128.7, 128.4,
128.1, 83.8, 83.6, 72.5, 40.1, 28.4, 27.1, 25.9, 25.3, 25.1; HRMS (ESI)
calcd for C16H21O3 (M + H)+ m/z 261.1491, found 261.1465.
cis-3-Methyl-4-(2-phenylethyl)oxetan-2-one (9k). 3-Methylene-4-
(2-phenylethyl)oxetan-2-one35 (1.88 g, 10 mmol) and 10% Pd on
carbon (0.30 mmol, 0.32 g) were mixed in dry THF (10 mL) under a
N2 atmosphere. The reaction vessel was purged with H2 for 10 min.
The reaction mixture was stirred at rt for 2 h under a balloon filled
with H2. The crude mixture was filtered through a pad of Celite. The
Celite was washed with CH2Cl2 (3 × 10 mL), and the filtrate was
trans-4-Benzyloxymethyl-3-methyloxetan-2-one (9h).29 Anhy-
drous ZnCl2 (5.45 g, 39.9 mmol) was freshly fused at ∼0.5 mmHg.
After cooling to ambient temperature, CH2Cl2 (140 mL) was added,
and the ZnCl2 was broken up into small pieces with a spatula. 2-
Benzyloxyacetaldehyde30 (4.00 g, 26.6 mmol) dissolved in dry CH2Cl2
(20 mL) was then added, resulting in a cloudy solution. After 15 min
of stirring, TBS-thiopyridylketene acetal29 (8.25 g, 29.3 mmol) in dry
CH2Cl2 (20 mL) was added, and the reaction mixture was stirred for
45 h at rt. After completion of the reaction, freshly made phosphate
buffer (pH = 7, 25 mL) was added, and the resulting mixture was
stirred vigorously for 15 min. It was then filtered through Celite, and
the Celite was washed with CH2Cl2 (3 × 10 mL). The aqueous and
organic layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 15 mL). The combined organic extracts were dried
(MgSO4), and CuBr2 (8.50 g, 38.1 mmol) was added. The reaction
mixture was stirred for 1.5 h at rt. It was then filtered through a pad of
Celite, and the Celite was washed with CH2Cl2 (3 × 10 mL). The
filtrate was washed with saturated aqueous K2CO3 (15 mL) and then
brine (15 mL). The organic layer was dried (MgSO4) and
concentrated to give a sticky oil. Purification by flash chromatography
on silica gel (petroleum ether/EtOAc, 90:10) yielded 9h as a colorless
oil (3.85 g, 70%): IR (neat) 3064, 3031, 2975, 1936, 2875, 1822, 1454,
1
concentrated to give a pale yellow oil. H NMR analysis of the crude
product showed a diastereomer ratio of 10:1 (cis:trans). Purification by
flash chromatography on silica gel (petroleum ether/EtOAc, 92:8)
afforded 9k as a pale yellow oil (1.67 g, 88%):34 1H NMR (300 MHz,
CDCl3) δ 7.38−7.24 (m, 5H), 4.57 (ddd, J = 4.5, 4.5, 4.5 Hz, 1H),
3.74 (dq, J = 14.6, 7.4 Hz, 1H), 2.90 (ddd, J = 14.2, 5.3, 5.3 Hz, 1H),
2.73 (m, 1H), 2.06 (m, 2H), 1.28 (d, J = 7.7 Hz, 3H).
cis-4-Benzhydryl-3-methyloxetan-2-one (9l). 4-Benzhydryl-3-
methyleneoxetan-2-one33 (4.0 mmol, 1.0 g) and 10% Pd on carbon
(0.12 mmol, 0.12 g) were mixed in dry THF (4 mL) under a N2
atmosphere. The reaction vessel was purged with H2 for 10 min. The
reaction mixture was stirred at rt for 2 h under a balloon filled with H2.
The crude mixture was filtered through a pad of Celite. The Celite was
washed with CH2Cl2 (3 × 10 mL), and the filtrate was concentrated to
give a pale yellow oil. 1H NMR analysis of the crude product showed a
diastereomer ratio of 20:1.7 (cis:trans). Purification by flash
chromatography on silica gel (petroleum ether/EtOAc, 92:8) afforded
9l as a pale yellow oil (0.91g, 88%): IR (neat) 3054, 3035, 2950, 1820,
1
1120, 839 cm−1; H NMR (400 MHz, CDCl3) δ 7.38−7.26 (m, 5H),
4.61 (d, J = 12.6 Hz, 1H), 4.58 (d, J = 12.6 Hz, 1H), 4.31 (ddd, J = 4.0,
4.0, 4.0 Hz, 1H), 3.79 (dd, J = 11.8, 3.7 Hz, 1H), 3.72 (d, J = 11.1, 4.7
Hz, 1H), 3.58 (dq, J = 7.7, 4.4 Hz, 1H), 1.39 (d, J = 7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 171.6, 137.6, 128.7, 128.1, 127.9, 77.5,
73.9, 69.3, 47.6, 12.4; HRMS (ESI) calcd for C12H15O3 (M + H)+ m/z
207.1021, found 207.1011.
1
1450, 1144 cm−1; H NMR (400 MHz, CDCl3) δ 7.37−7.21 (m,
10H), 5.28 (dd, J = 11.2, 6.1, 1H), 4.28 (d, J = 11.2, 1H), 3.86 (m,
1H), 1.12 (d, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.2,
140.8, 139.6, 129.2, 128.8, 128.4, 128.0 127.5, 127.3, 76.9, 51.5, 48.0,
9.1; HRMS (ESI) calcd for C17H17O2 (M + H)+ m/z 253.1229, found
253.1233.
(2R*,3R*)-2-Benzyloxy-3-cyclohexyl-3-hydroxy-1-S-tert-butyl-
thiopropiolate (24).31 2-Benzyloxy-S-tert-butyl-1-thioacetate32 (4.25 g,
17.8 mmol) was dissolved in dry CH2Cl2 (60 mL) under nitrogen and
cooled to −78 °C. A solution of TiCl4 (1 M in CH2Cl2, 17.8 mL, 17.8
mmol) was added to the flask dropwise over 10 min. After 5 min, Et3N
(5.00 mL, 35.7 mmol) was added. The solution was stirred at −78 °C
for 30 min, and then a solution of cyclohexylcarboxylaldehyde (2.00 g,
17.8 mmol) in CH2Cl2 (18 mL) was added dropwise. The reaction
was stirred at −78 °C for 4 h. The reaction was quenched by the
addition of saturated aqueous NaHCO3 (30 mL), and the resulting
slurry was filtered through Celite. The Celite was washed with CH2Cl2
(3 × 5 mL). The organic and aqueous layers were then separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 25 mL). The
combined organic extracts were dried (MgSO4) and concentrated
under reduced pressure. Purification by flash chromatography on silica
gel (petroleum ether/EtOAc, 85:15) afforded 24 as a colorless oil
(3.18 g, 51%): IR (neat) 3031, 2912, 2853, 1826, 1728, 1452, 1115,
General Procedure for the Preparation of 2-Methyleneox-
etanes. A solution of dimethyltitanocene11 (0.5 M in toluene, 1.5−2.5
equiv) and β-lactone (1 equiv) was stirred in the dark at 80 °C under
N2. The progress of the reaction was monitored over a period of 2−4 h
by TLC until the disappearance of the starting material. The cooled
reaction mixture was added to petroleum ether (10 volumes) and
stirred overnight. The resulting mixture was filtered through a pad of
Celite, washing with petroleum ether until the filtrate was colorless.
The filtrate was concentrated to about one-third of the original volume
of toluene, and the residue was purified by flash column
chromatography on silica gel (deactivated by 4% Et3N in petroleum
ether).
Spectral data for known methyleneoxetanes 10a,1b b,1b e,35 f,2b g,2b
i,1b and m3 are in accordance with the literature references.
4-tert-Butyldiphenylsilyloxymethyl-2-methyleneoxetane (10d). 4-
tert-Butyl-diphenylsilyloxymethyl-2-methyleneoxetane (10d) was pre-
1
892 cm−1; H NMR (400 MHz, CDCl3) δ 7.38−7.30 (m, 5H), 4.81
I
DOI: 10.1021/acs.joc.5b00604
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The Journal of Organic Chemistry
Article
pared from 9d (1.2 g, 3.6 mmol) using 2.0 equiv of dimethyl-
titanocene. Purification by flash column chromatography on silica gel
(petroleum ether/Et3N 98:2) gave 10d as a yellow oil (0.6 g, 49%): IR
(m, 2H), 1.64−1.52 (m, 8H), 1.22 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 173.1, 90.1, 75.2, 46.4, 33.0, 25.3, 22.7, 22.1; HRMS (ESI)
calcd for C11H19O (M + H)+ m/z 167.1436, found 167.1424.
3General Procedure for the Preparation of 4-Oxaspiro[2.3]-
hexanes. A flame-dried three-neck reaction flask with a stir bar was
charged with dry Et2O (3/4 total volume) under N2. After the solvent
was cooled to −15 °C, neat Et2Zn (2.0 equiv) was added dropwise.
The cloudy solution was stirred until clear (approximately 5 min), and
CH2I2 (4.0 equiv) was then added while maintaining the internal
temperature below −15 °C. After the addition was complete, the
reaction was allowed to warm to −5 °C (over 10 min). The solution
was cooled to −15 °C again, and a solution of 2-methyleneoxetane (1
equiv, 1.0 to 1.5 M) in dry Et2O (1/4 total volume) was then added.
The solution was stirred at −15 °C for 5 min and was then transferred
to an ice bath (0 °C). The reaction was stirred at 0 °C until complete
consumption of 2-methyleneoxetane was observed by TLC (3−4 h).
The reaction was quenched with saturated aqueous NH4Cl (5 mL) by
dropwise addition at 0 °C with stirring for 5 min. The aqueous and
organic layers were then separated, and the aqueous layer was
extracted with Et2O (3 × 10 mL). The combined organic extracts were
washed with brine, dried (MgSO4), and concentrated in vacuo. Spectral
data for known 4-oxaspiro[2.3]hexanes 4a, 4b, and 4m are in
accordance with the literature.3
1
(neat) 3047, 2935, 2858, 1471, 802, 743 cm−1; H NMR (400 MHz,
CDCl3) δ 7.72 (m, 4H), 7.44 (m, 6H), 4.84 (m, 1H), 4.18 (m, 1H),
3.90 (dd, J = 11.8, 3.5 Hz, 1H), 3.85 (dd, J = 11.8, 4.4 Hz, 1H), 3.78
(m, 1H), 3.15 (m, 2H), 1.10 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
162.8, 135.9, 135.8, 133.4, 130.0, 127.9, 127.9, 79.9, 78.7, 65.6, 30.5,
27.0, 19.5; HRMS (ESI) m/z calcd for C21H26O2Si (M + Na)+
361.1594, found 361.1597.
trans-4-Benzyloxymethyl-3-methyl-2-methyleneoxetane (10h).
trans-4-Benzyloxymethyl-3-methyl-2-methyleneoxetane (10h) was pre-
pared from 9h (0.50 g, 2.4 mmol) using 2.5 equiv of dimethyl-
titanocene. Purification by flash chromatography on silica gel
(petroleum ether/EtOAc/Et3N, 95.5:4:0.5) afforded 10h as a pale
yellow oil (0.38 g, 75%): IR (neat) 3031, 2934, 2878, 1715, 1496,
1
1454, 1359, 1275, 1114, 740 cm−1; H NMR (300 MHz, CDCl3) δ
7.37−7.28 (m, 5H), 4.62 (m, 2H), 4.57 (ddd, J = 4.7, 4.7, 4.7 Hz, 1H),
4.13 (dd, J = 3.6, 2.3 Hz, 1H), 3.79 (dd, J = 3.6, 1.7 Hz, 1H), 3.75−
3.65 (m, 2H), 3.30 (m, 1H), 1.30 (d, J = 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 168.4, 138.1, 128.5, 127.8, 112.1, 85.5, 78.4, 73.7,
71.4, 38.6, 16.5; HRMS (ESI) calcd for C13H17O2 (M + H)+ m/z
205.1229, found: 205.1220.
trans-3-Benzyloxy-4-cyclohexyl-2-methyleneoxetane (10j). trans-
4-Benzyloxy-3-cyclohexyl-2-methyleneoxetane (10j) was prepared
from 9j (0.42 g, 1.6 mmol) using 1.5 equiv of dimethyltitanocene.
Purification by flash chromatography on silica gel (petroleum ether/
Et2O/Et3N, 95.5:4:0.5) afforded 10j as a clear oil (0.23 g, 57%): IR
(neat) 2927, 2853, 1726, 1451, 1119, 739 cm−1; 1H NMR (400 MHz,
CDCl3) δ7.35 (4H), 7.32−7.25 (m, 1H), 4.61 (s, 2H), 4.57 (dd, J =
1.7, 1.7 Hz, 1H), 4.42 (dd, J = 8.2, 3.8 Hz, 1H), 4.25 (dd, J = 3.3, 1.6
Hz, 1H), 4.01 (dd, J = 3.5, 1.0 Hz, 1H), 1.86 (m, 1H), 1.78−1.74 (m,
2H), 1.70−1.63 (m, 2H), 1.60−1.53 (m, 1H), 1.25−1.12 (m, 3H),
1.03−0.92 (m, 2H); 13C NMR (100 MHz, CDCl3) δ164.2, 137.7,
128.7, 128.2, 128.0, 91.2, 81.7, 77.7, 71.1, 41.1, 28.1, 26.9, 26.4, 25.7,
25.4; HRMS (ESI) calcd for C17H23O2 (M + H)+ m/z 259.1698, found
259.1674.
cis-3-Methyl-2-methylene-4-(2-phenylethyl)oxetane (10k). cis-3-
Methyl-2-methylene-4-(2-phenylethyl)oxetane (10k) was prepared
from 9k (0.5 g, 2.7 mmol) using 2 equiv of dimethyltitanocene.
Purification by flash chromatography on silica gel (petroleum ether/
Et2O/Et3N, 97.5:2:0.5) afforded 10k as a pale yellow oil (0.36 g, 72%):
IR (neat) 3026, 2924, 2854, 1706, 1603, 1496, 1454, 1180, 1082, 1030
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.33−7.26 (m, 2H), 7.22−7.18
(m, 3H), 4.80 (ddd, J = 9.6, 7.0, 3.9 Hz, 1H), 4.09 (dd, J = 3.4, 2.4 Hz,
1H), 3.73 (dd, J = 3.4, 1.7 Hz, 1H), 3.55 (m, 1H), 2.81 (ddd, J = 14.1,
9.9, 5.1 Hz, 1H), 2.60 (m, 1H), 2.16 (dddd, J = 19.1, 14.4, 9.5, 5.2 Hz,
1H), 1.88 (dddd, J = 20.8, 10.8, 6.9, 4.0 Hz, 1H), 1.18 (d, J = 7.3 Hz,
3H); 13C NMR (75 Hz, CDCl3) δ 169.8, 141.5, 128.7, 126.3, 82.4,
78.0, 38.3, 32.8, 31.5, 12.4; HRMS (ESI) calcd for C13H17O (M+) m/z
189.1279, found 189.1268.
5-Benzyloxymethyl-4-oxaspiro[2.3]hexane (4c). 5-Benzyloxymeth-
yl-4-oxaspiro[2.3]hexane (4c) was prepared using 10c (0.14 g, 0.75
mmol). Purification by flash chromatography on silica gel (petroleum
ether/Et2O, 94:6) afforded 4c as a colorless oil (0.12 g, 78%): IR
1
(neat) 2922, 1558, 1457, 1103 cm−1; H NMR (400 MHz, CDCl3) δ
7.34 (m, 5H), 4.94 (m, 1H), 4.68 (d, J = 12.1 Hz, 1H), 4.65 (d, J =
12.1 Hz, 1H), 3.80 (dd, J = 10.9, 5.8 Hz, 1H), 3.71 (dd, J = 10.9, 3.8
Hz, 1H), 2.88 (dd, J = 10.8, 7.9 Hz, 1H), 2.70 (dd, J = 10.8, 6.2 Hz,
1H), 0.84 (m, 2H), 0.54 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
138.5, 128.6, 127.9, 127.8, 75.8, 73.7, 73.6, 66.2, 31.3, 10.6, 10.5;
HRMS (ESI) calcd for C13H16O2 (M + Na)+ m/z 227.1043, found
227.1066.
5-tert-Butyldiphenylsilyloxymethyl-4-oxaspiro[2.3]hexane (4d).
5-tert-Butyldiphenylsilyloxymethyl-4-oxaspiro[2.3]hexane (4d) was
prepared using 10d (0.32 g, 0.95 mmol). Purification by flash
chromatography on silica gel (petroleum ether/EtOAc 98:2) afforded
4d as a colorless oil (0.23 g, 68%): IR (neat) 3072, 2958, 1428, 1113,
824, 741 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.74 (m, 4H), 7.42 (m,
6H), 4.83 (m, 1H), 3.87 (d, J = 4.2 Hz, 2H), 2.84 (dd, J = 10.5, 7.7 Hz,
1H), 2.76 (dd, J = 10.7, 6.0 Hz, 1H), 0.95 (s, 9H), 0.83 (m, 2H), 0.54
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 135.9, 135.9, 133.8, 133.7,
129.8, 127.9, 76.9, 67.0, 66.0, 30.5, 27.0, 19.5, 10.8, 10.6; HRMS (ESI)
calcd for C22H28O2SiNa (M + Na)+ m/z 375.1751, found 375.1740.
5-Cyclohexyl-4-oxaspiro[2.3]hexane (4e). 5-Cyclohexyl-4-
oxaspiro[2.3]hexane (4e) was prepared using 10e (0.27 g, 1.8
mmol). Purification by flash chromatography on silica gel (petroleum
ether/Et2O, 99:1) afforded 4e as a pale yellow oil (0.12 g, 40%): IR
1
(neat) 1966, 1925, 1738, 1570, 1076 cm−1; H NMR (400 MHz,
cis-4-Benzhydryl-3-methyl-2-methyleneoxetane (10l). cis-4-Benz-
hydryl-3-methyl-2-methyleneoxetane (10l) was prepared from 9l (0.15
g, 0.60 mmol) using 2 equiv of dimethyltitanocene. Purification by
flash chromatography on silica gel (petroleum ether/Et2O/Et3N,
CDCl3) δ 4.42 (ddd, J = 7.2, 7.2, 7.2 Hz, 1H), 2.75 (dd, J = 10.7, 7.6
Hz, 1H), 2.54 (dd, J = 11.2, 6.4 Hz, 1H), 1.90 (m, 1H), 1.78−1.74 (m,
2H), 1.70−1.61 (m, 4H), 1.32−1.14 (m, 2H), 0.98 (m, 2H), 0.83−
0.70 (m, 2H), 0.53 (ddd, J = 11.8, 5.9, 5.9 Hz, 1H), 0.43 (ddd, J =
10.4, 5.4, 5.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ81.2, 65.2, 44.3,
32.6, 27.9, 26.7, 26.6, 25.9, 25.7, 10.7, 10.6.; HRMS (ESI) calcd for
C11H19O (M + H)+ m/z 167.1436, found 167.1417.
(S)-6-tert-Butoxycarbonylamino-4-oxaspiro[2.3]hexane (4f). (S)-
6-tert-Butoxycarbonylamino-4-oxaspiro[2.3]hexane (4f) was prepared
using 10f (0.22 g, 1.2 mmol). Purification by flash chromatography on
silica gel (petroleum ether/EtOAc 90:10) afforded 4f as a white solid
(0.12 g, 51%): mp 97−99 °C; [α]2D5 22.3 (c 0.52, CH2Cl2); IR (KBr)
3339, 2970, 1687, 1538, 1368, 1255, 1165 cm−1; 1H NMR (100 MHz,
CDCl3) δ 4.96 (m, 2H), 4.82 (dd, J = 6.6, 6.6 Hz, 1H), 4.33 (dd, J =
6.0, 6.0 Hz, 1H), 1.39 (s, 9H), 0.92 (m, 1H), 0.64 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 155.0, 80.2, 75.1, 74.6, 50.5, 28.5, 10.2, 6.7;
HRMS (FAB) calcd for C10H17NO3Na (M + Na)+ m/z 222.1101,
found 222.1123.
1
97.5:2:0.5) afforded 10l as a pale yellow oil (0.12 g, 78%). H NMR
(500 MHz, CDCl3) δ 7.05−6.99 (m, 6H), 6.96−6.89 (m, 4H), 5.27
(dd, J = 11.2, 6.8 Hz, 1H), 4.14 (d, J = 11.2 Hz, 1H), 3.86 (dd, J = 3.6,
2.2 Hz, 1H), 3.50 (dd, J = 3.6, 1.7 Hz, 1H), 3.37 (m, 1H), 0.78 (d, J =
7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 168.8, 141.6, 140.7,
129.0, 128.8, 128.5, 128.2, 127.0, 127.0, 83.9, 78.4, 51.9, 39.0, 13.4;
HRMS (ESI) calcd for C18H18O (M + H)+ m/z 251.1435, found
251.1422.
3,3-Dimethyl-2-methylene-1-oxaspiro[3.5]nonane (10n). 3,3-Di-
methyl-2-methylene-1-oxaspiro[3.5]nonane (10n) was prepared from
9n (1.5 g, 8.9 mmol) using 2 equiv of dimethyltitanocene. Purification
by flash chromatography on silica gel (petroleum ether/Et3N,
99.5:0.5) afforded 10n as a pale yellow oil (1.1 g, 70%): IR (neat)
2925, 2859, 1693, 1469, 1368, 1123 cm−1; 1H NMR (300 MHz,
CDCl3) δ 3.93 (d, J = 3.3 Hz, 1H), 3.62 (d, J = 3.3 Hz, 1H), 1.97−1.92
J
DOI: 10.1021/acs.joc.5b00604
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The Journal of Organic Chemistry
Article
(S)-6-Tritylamino-4-oxaspiro[2.3]hexane (4g). (S)-6-Tritylamino-
4-oxaspiro[2.3]hexane (4g) was prepared using 10g (0.18 g, 0.59
mmol). Purification by flash chromatography on silica gel (petroleum
ether/EtOAc 95:5) afforded 4g as a white solid (0.09 g, 45%): mp
177−179 °C; [α]2D5 13.0 (c 0.26, CH2Cl2); IR (KBr) 3055, 2885, 1490,
1450, 1191, 946, 741, 712 cm−1; 1H NMR (100 MHz, CDCl3) δ 7.45
(m, 6H), 7.32−7.21 (m, 9H), 4.22 (ddd, J = 12.6, 6.7, 6,7 Hz, 1H),
3.99 (dd, J = 6.5, 6.5 Hz, 1H), 3.66 (dd, J = 6.3, 6.3 Hz, 1H), 2.34 (d, J
= 11.6 Hz, 1H), 0.96 (ddd, J = 12.8, 6.8, 6.8 Hz, 1H), 0.82 (ddd, J =
11.7, 7.0, 7.0 Hz, 1H), 0.66 (ddd, J = 13.0, 6.9, 6.9 Hz, 1H), 0.40 (ddd,
J = 11.4, 7.0, 7.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 146.5,
128.5, 128.3, 126.8, 78.9, 75.4, 70.2, 53.5, 9.0, 6.4; HRMS (ESI) calcd
for C24H23NONa (M + Na)+ m/z 364.1672, found 364.1695.
(400 MHz, CDCl3) δ 7.33−7.13 (m, 10H), 5.63 (dd, J = 11.0, 7.4 Hz,
1H), 4.47 (d, J = 11.0 Hz, 1H), 3.20 (dq, J = 7.2, 7.2 Hz, 1H), 0.96 (d,
J = 7.2 Hz, 3H), 0.92−0.87 (m, 1H), 0.67−0.62 (m, 1H) 0.60−0.50
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 142.1, 141.5, 128.9, 128.7,
128.5, 128.3, 126.8, 126.7, 81.8, 70.9, 52.7, 37.0, 12.0, 10.0, 6.4; HRMS
(ESI) calcd for C19H21O (M + H)+ m/z, 265.1592, found 265.1599.
9,9-Dimethyl-3-oxadispiro[2.2.5.0]undecane (4n). 9,9-Dimethyl-
3-oxadispiro[2.2.5.0]undecane (4n) was prepared using 10n (0.70 g,
4.2 mmol). Flash chromatography on silica gel (petroleum ether/Et2O,
1
99.5:0.5) afforded 4n as a colorless oil (0.56 g, 75%): H NMR (400
MHz, CDCl3) δ 2.00 (m, 2H), 1.59−1.50 (br m, 8H), 1.05 (s, 6H),
0.58 (m, 2H), 0.44 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 86.9,
72.9, 41.3, 33.8, 25.6, 22.7, 20.7, 7.0; HRMS (ESI) calcd for C12H21O
(M + H)+ m/z 181.1592, found 181.1587.
trans-5-Benzyloxymethyl-6-methyl-4-oxaspiro[2.3]hexane (4h).
trans-5-Benzyloxymethyl-6-methyl-4-oxaspiro[2.3]hexane (4h) was
prepared using 10h (0.57 g, 2.8 mmol). Purification by flash
chromatography on slica gel (petroleum ether/EtOAc 95:5) afforded
4h as a colorless oil (0.49 g, 78%): IR (neat) 3065, 3031, 2961, 2926,
1-Methyl-6-(2-phenylethyl)-4-oxaspiro[2.3]hexane (4o). 1-Meth-
yl-6-(2-phenylethyl)-4-oxaspiro[2.3]hexane (4o) was prepared using
2-methylene-4-(2-phenylethyl)oxetane11 (10o) (0.17 g, 1.0 mmol)
and diiodoethane (3 equiv). Purification by flash chromatography on
silica gel (petroleum ether/Et2O, 99:1) afforded 4o as colorless oil
(0.15 g, 78%): IR (neat) 3061, 3025, 2926, 2867, 1453, 1440, 1279,
1
2871, 1722, 1455, 1116 cm−1; H NMR (400 MHz, CDCl3) δ7.34−
7.28 (m, 4H), 7.25−7.20 (m, 1H), 4.61 (d, J = 12.4 Hz, 1H), 4.57 (d, J
= 12.2 Hz, 1H), 4.46 (ddd, J = 5.7, 5.7, 3.9 Hz, 1H), 3.72 (dd, J = 10.9,
5.7 Hz, 1H), 3.64 (dd, J = 10.9, 3.8 Hz, 1H), 2.90 (dq, J = 6.7, 6.7 Hz,
1H), 1.10 (d, J = 6.9 Hz, 3H), 0.81 (m, 1H), 0.58 (m, 2H), 0.40 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 138.5, 128.4, 127.7, 127.7, 83.8,
73.5, 72.9, 71.3, 36.4, 15.6, 9.9, 6.5; HRMS (ESI) calcd for C14H19O2
(M + H)+ m/z 219.1385, found 219.1388.
1
1016 cm−1; H NMR (400 MHz, CDCl3) δ 7.31−7.17 (m, 5H), 4.74
(dddd, J = 6.4, 6.4, 6.4, 6.4 Hz, 1H), 2.81−2.63 (m, 2H), 2.68 (dd, J =
9.7, 6.3 Hz, 1H), 2.47 (dd, J = 10.6, 6.3 Hz, 1H), 2.21 (dddd, J = 13.4,
10.3, 6.1, 6.1 Hz, 1H), 2.06 (dddd, J = 12.4, 10.1, 6.1, 6.1 Hz, 1H),
1.11 (d, J = 6.2 Hz, 3H), 0.76−0.71 (m, 1H), 0.60 (dd, J = 9.8, 6.6 Hz,
1H), 0.32 (dd, J = 6.6, 6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
141.9, 128.6, 128.6, 126.1, 77.3, 68.4, 39.5, 35.0, 30.9, 17.4, 15.6, 12.6;
HRMS (ESI) calcd for C14H19O (M + H)+ m/z 203.1436, found
203.1441.
trans-6-Methyl-5-(2-phenylethyl)-4-oxaspiro[2.3]hexane (4i).
trans-6-Methyl-5-(2-phenylethyl)-4-oxaspiro[2.3]hexane (4i) was pre-
pared using 10i (0.34 g, 1.8 mmol). Flash chromatography on silica gel
(petroleum ether/Et2O, 97:3) afforded 4i as a colorless oil (0.28 g,
13C-Labeled trans-5-Benzyloxymethyl-6-methyl-4-oxaspiro[2.3]-
hexane (13C-4h). Compound 13C-4h was prepared using 10h (0.1 g,
0.5 mmol) and 13CH2I2 (1.1 equiv). Purification by column
chromatography on silica gel (petroleum ether/EtOAc 95:5) afforded
13C-labeled trans-5-benzyloxymethyl-6-methyl-4-oxaspiro[2.3]hexane
1
78%): IR (neat) 3027, 2927, 1604, 1454, 1194, 699 cm−1; H NMR
(400 MHz, CDCl3) δ 7.32−7.17 (m, 5H), 4.35 (ddd, J = 7.2, 5.8, 5.8
Hz, 1H), 2.80−2.72 (m, 2H), 2.69−2.61 (m, 1H), 2.23−2.13 (m, 1H),
2.11−2.01 (m, 1H), 1.10 (d, J = 6.9 Hz, 3H), 0.84 (ddd, J = 11.8, 7.5,
6.5 Hz, 1H), 0.66−0.56 (m, 2H), 0.44 (ddd, J = 10.6, 7.7, 6.5 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 141.8, 128.6, 126.0, 84.9, 70.4, 39.8,
38.6, 30.9, 15.7, 10.0, 6.5; HRMS (ESI) calcd for C14H19O (M + H)+
m/z 203.1436, found 203.1419.
(13C-4h) as a pair of 13C-labeled isotopic stereoisomers (colorless
1
oil) (0.08 g, 71%): H NMR (400 MHz, CDCl3) δ 7.42−7.25 (m,
5H), 4.65 (d, J = 12.2 Hz, 1H), 4.62 (d, J = 12.2 Hz, 1H), 4.50 (ddd, J
= 5.7, 5.7, 3.8 Hz, 1H), 3.76 (dd, J = 11.0, 5.8 Hz, 1H), 3.76 (dd, J =
11.0, 3.8 Hz, 1H), 2.94 (m, 1H), 1.14 (d, J = 6.9 Hz, 3H), 1.10−0.14
(m,36a 4H); 13C NMR (100 MHz, CDCl3) δ 138.5, 128.6, 127.8,
127.8, 83.9, 73.7, 73.0, 71.5 (71.3 for the other isotopic stereoisomer),
36.5, 15.7, 10.0 (13C-labeled), 6.6 (13C-labeled); HRMS (ESI) calcd
for C1313CH17O2 (M + H)+ m/z 220.1385, found 220.1375.
trans-6-Benzyloxy-5-cyclohexyl-4-oxaspiro[2.3]hexane (4j). trans-
6-Benzyloxy-5-cyclohexyl-4-oxaspiro[2.3]hexane (4j) using 10j (0.19
g, 0.75 mmol). Purification by flash chromatography on silica gel
(petroleum ether/Et2O, 99:1) afforded 4j as pale yellow oil (0.12 g,
60%): IR (neat) 3067, 3034, 2865, 1729, 1451, 1274, 1112, 1026
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.36−7.27 (m, 5H), 4.51 (d, J =
11.8 Hz, 1H), 4.39 (d, J = 2.9 Hz, 1H), 4.36 (dd, J = 3.8, 3.8 Hz, 1H),
4.33 (d, J = 4.6 Hz, 1H), 1.87 (m, 1H), 1.80−1.67 (m, 4H), 1.65−1.58
(m, 1H), 1.31−1.13 (m, 3H), 1.03 (dd, J = 11.8, 3.6 Hz, 1H), 0.97
(dd, J = 11.8, 3.4 Hz, 1H), 0.87 (m, 2H), 0.74 (m, 1H), 0.50−0.43 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 138.1, 128.6, 128.0, 127.8, 89.9,
79.8, 71.5, 70.6, 42.0, 28.3, 27.2, 26.5, 25.9, 25.7, 9.8, 6.9; HRMS (ESI)
calcd for C18H23O2 (M − H)+ m/z 271.1698, found 271.1694.
cis-6-Methyl-5-(2-phenylethyl)-4-oxaspiro[2.3]hexane (4k). cis-6-
Methyl-5-(2-phenylethyl)-4-oxaspiro[2.3]hexane (4k) was prepared
using 10k (0.50 g, 2.6 mmol). Purification by flash chromatography on
silica gel (petroleum ether/Et2O, 97:3) afforded 4k as a colorless oil
(0.41 g, 76%): IR (neat) 3078, 3063, 2933, 2238, 1641, 1497, 1173,
13C-Labeled cis-5-Benzhydryl-6-methyl-4-oxaspiro[2.3]hexane
(13C-4l). Compound 13C-4l was prepared using 10l (120 mg, 0.48
mmol) and 13CH2I2 (1.1 equiv). Purification by column chromatog-
raphy on silica gel (petroleum ether/EtOAc 95:5) afforded 13C-labeled
cis-5-benzhydryl-6-methyl-4-oxaspiro[2.3]hexane (13C-4l) as a pair of
13C-labeled isotopic stereoisomers (colorless oil) (69 mg, 55%): IR
1
(neat) 3082, 2925, 1495, 1451, 970, 695 cm−1; H NMR (400 MHz,
CDCl3) δ 7.32−7.11 (m, 10 H), 5.62 (dd, J = 11.1, 7.3 Hz, 1H), 4.46
(d, J = 11.1 Hz, 1H), 3.20 (m, 1H), 0.95 (d, J = 7.2 Hz, 3H), 1.26−
0.53 (m,36a 4H); 13C NMR (125 MHz, CDCl3) δ 142.1, 141.5, 128.9,
128.7, 128.6, 128.3, 126.8, 126.7, 81.8, 71.0 (70.8 for the other isotopic
stereoisomer), 52.7, 37.0, 10.0 (13C-labeled carbon), 6.4 (13C-labeled
carbon); HRMS (ESI) calcd for C1813CH21O (M + H)+ m/z 266.1592,
found 266.1605.
1
798 cm−1; H NMR (400 MHz, CDCl3) δ 7.35−7.21 (m, 5H), 4.83
(ddd, J = 9.7, 8.3, 4.5 Hz, 1H), 3.17 (dq, J = 7.1, 7.1 Hz, 1H), 2.78
(ddd, J = 13.9, 10.0, 5.1 Hz, 1H), 2.58 (ddd, J = 13.9, 9.7, 6.6 Hz, 1H),
2.18 (dddd, J = 14.2, 9.9, 9.9, 5.4 Hz, 1H), 1.89 (dddd, J = 10.6, 10.6,
6.6, 4.2 Hz, 1H) 1.04 (d, J = 7.0 Hz, 3H), 0.89−0.83 (m, 1H), 0.63−
0.58 (m, 1H), 0.56−0.51 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
141.9, 128.6, 128.5, 126.0, 80.1, 71.2, 36.1, 33.7, 31.4, 11.1, 9.7, 6.7;
HRMS (ESI) calcd for C14H19O (M + H)+ m/z 203.1436, found
203.1418.
General Procedure for the Pt-Catalyzed Rearrangement of
Oxaspirohexanes (4a−n). Dry CH2Cl2 (0.5 mL) was added to a
nitrogen purged flask containing Zeise’s dimer (0.1 mmol). PCy3 (0.2
mmol) was added to the solution all at once at rt. 4-Oxaspiro[2.3]-
hexane (1 mmol) dissolved in dry CH2Cl2 (1.5 mL) was then added,
and the reaction was heated at 45 °C. The reaction was monitored by
1H NMR/TLC for the disappearance of the 4-oxaspiro[2.3]hexane.
Products were isolated by column chromatography on neutral alumina
or silica gel.
3-Methylene-4-phenyltetrahydrofuran (6a). The general proce-
dure was followed using 4a (0.10 g, 0.63 mmol). The reaction was
stirred for 3.5 h. Purification by flash chromatography on neutral
alumina (petroleum ether/EtOAc, 96:4) afforded 6a as a colorless oil
cis-5-Benzhydryl-6-methyl-4-oxaspiro[2.3]hexane (4l). cis-5-Benz-
hydryl-6-methyl-4-oxaspiro[2.3]hexane (4l) was prepared using 10l
(0.12 g, 0.48 mmol). Purification by flash chromatography on silica gel
(petroleum ether/Et2O, 96:4) afforded 4l as a colorless oil (0.11 g,
1
86%): IR (neat) 3082, 2925, 1495, 1451, 970, 695 cm−1; H NMR
K
DOI: 10.1021/acs.joc.5b00604
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(34 mg, 34%). 1H NMR (400 MHz, CDCl3) δ 7.32 (m, 2H), 7.24 (m,
3H), 5.05 (m, 1H), 4.77 (dd, J = 4.6, 2.2 Hz, 1H), 4.51 (m, 2H), 4.29
(dd, J = 6.2, 6.2 Hz, 1H), 3.85 (m, 1H), 3.81 (d, J = 7.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 152.6, 141.3, 128.8, 128.5, 127.0, 106.2,
76.2, 72.3, 50.8. HRMS (ESI) calcd for C11H11O (M - H)+ m/z
159.0810, found 159.0795.
1H), 4.23 (m, 1H), 3.32 (ddd, J = 8.8, 8.8, 3.1 Hz, 1H), 2.82 (ddd, J =
13.9, 10.8, 5.1 Hz, 1H), 2.62 (ddd, J = 13.8, 10.3, 6.4 Hz, 1H), 2.2 (m,
1H), 1.88 (m, 1H), 1.77 (m, 1H), 1.0 (d, J = 6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 154.0, 142.5, 128.6, 128.6, 126.0, 102.9, 85.8,
70.9, 43.7, 36.0, 32.7, 14.9; HRMS (ESI): calcd for C14H17O (M −
H)+ m/z 201.1279, found: 201.1278.
3-Methoxymethyl-2-phenylbut-3-en-1-ol (7a). The general pro-
cedure was followed using 4a (60 mg, 0.37 mmol) in the presence of
MeOH (20 equiv). The reaction was stirred for 2 h. Purification by
flash chromatography on neutral alumina (petroleum ether/EtOAc,
95:5) afforded 7a as a yellow oil (44 mg, 50%): IR (neat) 3060, 2924,
trans-3-Benzyloxy-2-cyclohexyl-4-methylenetetrahydrofuran
(6j). The general procedure was followed using 4j (60 mg, 0.22
mmol). The reaction mixture was stirred for 2 h. Purification by flash
chromatography on neutral alumina (petroleum ether/Et2O, 95:5)
afforded 6j as a colorless oil (45 mg, 75%): IR (neat) 2925, 2853,
1
1731, 1573, 1451, 1260, 1065 cm−1; H NMR (500 MHz, CDCl3) δ
1
2853, 1715, 1453, 1111 cm−1; H NMR (400 MHz, CDCl3) δ7.34−
7.35−7.34 (m, 4H), 7.30−7.27 (m, 1H), 5.24 (m, 1H), 5.19 (m, 1H),
4.66 (d, J = 11.7 Hz, 1H), 4.51 (d, J = 11.7 Hz, 1H), 4.46−4.43 (m,
1H), 4.32−4.27 (m, 1H), 4.09 (m, 1H), 3.76 (dd, J = 7.4, 3.0 Hz, 1H),
1.82 (m, 1H), 1.74−1.72 (m, 2H), 1.65−1.61 (m, 2H), 1.39−1.32 (m,
1H), 1.25−1.13 (m, 3H), 1.10−0.97 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 147.8, 138.4, 128.6, 128.0, 127.8, 109.8, 88.6, 81.9, 70.2,
70.0, 40.6, 29.6, 28.8, 26.6, 26.3, 26.1; HRMS (ESI): calcd for
C18H25O2 (M + H)+ m/z 273.1855, found 273.1837.
7.22 (m, 5H), 5.30 (s, 1H), 5.15 (s, 1H), 4.02 (dd, J = 18.1, 10.7 Hz,
1H), 3.91 (dd, J = 17.6, 6.8 Hz, 1H), 3.77 (d, J = 12.8 Hz, 1H), 3.75
(d, J = 12.6 Hz, 1H), 3.61 (dd, J = 7.0, 7.0 Hz, 1H), 3.27 (s, 3H), 2.01
(br s, 1H); 13C NMR (100 MHz, CDCl3) δ 145.7, 140.2, 128.8, 128.4,
127.2, 114.2, 75.2, 65.2, 58.2, 51.3; HRMS (FAB) calcd for C12H17O2
(M + H)+ m/z 193.1229, found 193.1236.
2-Benzyloxymethyl-4-methylenetetrahydrofuran (6c). The gen-
eral procedure was followed using 4c (39 mg, 0.19 mmol). The
reaction mixture was stirred for 40 min. Purification by flash
chromatography on neutral alumina (petroleum ether/EtOAc 96:4)
afforded 6c as a colorless oil (25 mg, 65%):37 IR (neat) 2919, 2857,
Reaction of cis-6-Methyl-5-(2-phenylethyl)-4-oxaspiro[2.3]-
hexane (4k). The general procedure was followed using 4k (110
mg, 0.54 mmol). The reaction mixture was stirred for 16 h.
Purification by flash chromatography on neutral alumina (petroleum
ether/EtOAc 99.5:0.5 to 95:5) afforded 12, 13, and 6k. (3R*,4R*)-
4,5-Dimethyl-1-phenylhex-5-en-3-ol (12) was obtained as the major
1
1497, 1101, 698 cm−1; H NMR (400 MHz, CDCl3) δ7.30 (m, 5H),
4.96 (ddd, J = 4.4, 2.2, 2.2 Hz, 1H), 4.90 (ddd, J = 4.3, 2.1, 2.1 Hz,
1H), 4.59 (d, J = 12.1 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H), 4.39 (m,
1H), 4.26 (m, 1H), 4.19 (m, 1H), 3.15 (m, 2H), 2.58 (m, 1H), 2.37
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 147.5, 138.2, 128.4, 127.7,
127.6, 104.4, 78.5, 73.4, 72.0, 71.2, 35.2; HRMS (ESI) calcd for
C13H15O2 (M − H)+ m/z 203.1072, found 203.1046.
1
product in the above reaction as a clear oil (46 mg, 42%): H NMR
(400 MHz, CDCl3) δ 7.30−7.26 (m, 2H), 7.22−7.16 (m, 3H), 4.85 (s,
1H), 4.78 (s, 1H), 3.59 (m, 1H), 2.85 (ddd, J = 14.0, 9.3, 6.0 Hz, 1H),
2.66 (ddd, J = 16.4, 9.0, 7.0 Hz, 1H), 2.20 (dq, J = 6.8, 6.8 Hz, 1H),
1.76 (m, 2H), 1.69 (s, 3H), 1.06 (d, J = 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 148.2, 142.4, 128.6, 128.6, 126.0, 111.7, 72.0, 46.6,
36.7, 32.8, 21.4, 13.6; HRMS (ESI) calcd for C14H21O (M + H)+ m/z
205.1592, found 205.1583. (E)-4-Methyl-7-phenylhepta-1,4-diene-3-
one (13) was obtained as the minor product from the above reaction
as a colorless oil (21 mg, 20%): 1H NMR (400 MHz, CDCl3) δ 7.31−
7.28 (m, 2H), 7.22−7.18 (m, 3H), 6.87 (dd, J = 17.0, 10.6 Hz, 1H),
6.65 (m, 1H), 6.19 (dd, J = 17.0, 1.8 Hz, 1H), 5.68 (dd, J = 10.6, 1.8
Hz, 1H), 2.79 (dd, J = 7.4, 7.4 Hz, 1H), 2.59 (ddd, J = 7.4, 7.4, 7.4 Hz,
1H), 1.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.7, 142.7,
141.2, 138.3, 132.1, 128.7, 128.5, 128.1, 126.4, 34.9, 31.1, 11.8; HRMS
(ESI): calcd for C14H17O (M + H+) m/z 201.1279, found 201.1249.
cis-3-Methyl-4-methylene-2-(2-phenylethyl)tetrahydrofuran (6k)
was also observed and obtained as a colorless oil in a trace amount
with an unknown impurity: 1H NMR (400 MHz, CDCl3) δ 7.22−7.16
(m, 5H), 4.89 (m, 1H), 4.84 (m, 1H), 4.41 (d, J = 13.3 Hz, 1H), 4.30
(d, J = 14.0 Hz, 1H), 3.95 (ddd, J = 8.9, 6.0, 4.6 Hz, 1H), 2.85 (m,
2H), 2.69 (m, 2H), 1.01 (d, J = 7.1 Hz, 3H).
2-tert-Butyldiphenylsilyloxymethyl-4-methylenetetrahydrofuran
(6d). The general procedure was followed using 4d (0.20 g, 0.57
mmol). The reaction was stirred for 2 h. Purification by flash
chromatography on neutral alumina (petroleum ether/EtOAc 98:2)
afforded 6d as a colorless oil (128 mg, 64%): IR (neat) 2929, 2856,
1
1113, 824, 701 cm−1; H NMR (400 MHz, CDCl3) δ 7.71 (m, 4H),
7.42 (m, 6H), 5.01 (s, 1H), 4.93 (s, 1H), 4.41 (d, J = 12.4 Hz, 1H),
4.31 (d, J = 13.0 Hz, 1H), 4.19 (ddd, J = 11.7, 6.2, 6.2 Hz, 1H), 3.73
(m, 2H), 2.65 (dd, J = 16.0, 6.6 Hz, 1H), 2.53 (dd, J = 15.3, 5.3 Hz,
1H), 1.09 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 148.2, 135.8,
133.8, 129.8, 127.9, 104.4, 80.1, 71.5, 66.2, 35.1, 27.0, 19.5; HRMS
(ESI) m/z calcd for C22H28NaO2Si (M + Na)+ 375.1751, found
375.1777.
2-Cyclohexyl-4-methylenetetrahydrofuran (6e). The general
procedure was followed using 4e (35 mg, 0.21 mmol). The reaction
was stirred for 1.5 h. Purification by flash chromatography on neutral
alumina (petroleum ether/Et2O, 99:1) afforded 6e as a colorless oil
(21 mg, 62%):23a 1H NMR (400 MHz, CDCl3) δ 4.95 (dd, J = 2.2, 2.2
Hz, 1H), 4.87 (dd, J = 2.2, 2.2 Hz, 1H), 4.36 (m, 1H), 4.21 (m, 1H),
3.60 (m, 1H), 2.56 (m, 1H), 2.25 (m, 1H), 1.96 (m, 2H), 1.80−1.59
(m, 4H), 1.44−1.14 (m, 3H), 0.99 (m, 2H).
Reaction of cis-5-Benzhydryl-6-methyl-4-oxaspiro[2.3]hexane
(4l). The general procedure was followed using 4l (27 mg, 0.1
mmol). The reaction mixture was stirred for 21 h. The reaction was
monitored by NMR/TLC for disappearance of cis-5-benzhydryl-6-
methyl-4-oxaspiro[2.3]hexane. The crude product was purified by flash
chromatography on neutral alumina (petroleum ether/EtOAc 99:1 to
95:5). (2S*,3R*)-4-Chloromethyl-3-methyl-1,1-diphenylpent-4-
trans-2-Benzyloxymethyl-3-methyl-4-methylenetetrahydrofuran
(6h). The general procedure was followed using 4h (50 mg, 0.23
mmol). The reaction mixture was stirred for 45 min. Purification by
flash chromatography on neutral alumina (petroleum ether/EtOAc,
96:4) afforded 6h as a colorless oil (34 mg, 69%): IR (neat) 3064,
1
ene-2-ol (11) was obtained as a clear oil (13 mg, 39%): H NMR
1
2964, 2931, 2872, 1766, 1723, 1453, 1379, 1091, 913 cm−1; H NMR
(400 MHz, CDCl3) δ 7.42−7.19 (m, 10H), 5.30 (s, 1H), 5.12 (s, 1H),
4.53 (ddd, J = 9.4, 3.1, 3.1 Hz, 1H), 4.14 (d, J = 3.1 Hz, 1H), 4.04 (d, J
= 11.8 Hz, 1H), 4.04 (d, J = 9.5 Hz, 1H), 2.51 (m, 3H), 1.56 (d, J =
3.1 Hz, 1H), 1.13 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
148.4, 142.1, 141.9, 129.1, 128.8, 128.4, 127.1 127.0, 116.2, 74.5, 56.1,
47.9, 38.8, 12.0; HRMS (ESI) calcd for C19H25NClO (M + NH4)+ m/
z 318.1625, found 318.1632. cis-2-Benzhydryl-3-methyl-4-methylene-
tetrahydrofuran (6l) was obtained from the reaction of cis-5-
benzhydryl-6-methyl-4-oxaspiro[2.3]hexane (4l) in a trace amount as
(400 MHz, CDCl3) δ 7.35−7.25 (m, 5H), 4.92 (m, 1H), 4.88 (ddd, J
= 2.5, 2.5, 2.5 Hz, 1H), 4.60 (s, 2H), 4.52−4.48 (m, 1H), 4.35−4.30
(m, 1H), 3.67−3.54 (m, 3H), 2.46 (m, 1H), 1.09 (d, J = 6.7 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 153.3, 138.4, 128.6, 127.9, 127.8,
103.3, 85.4, 73.7, 71.3, 40.1, 15.1; HRMS (ESI) calcd for C14H17O2 (M
+ H)+ m/z 217.1229, found 217.1198.
trans-3-Methyl-4-methylene-2-(2-phenylethyl)tetrahydrofuran
(6i). The general procedure was followed using 4i (50 mg, 0.25 mmol).
The reaction mixture was stirred for 45 min. Purification by flash
chromatography on neutral alumina (petroleum ether/Et2O, 98:2)
afforded 6i as a colorless oil (40 mg, 80%): IR (neat) 3027, 2917,
1
a colorless oil: H NMR (400 MHz, CDCl3) δ 7.81−7.14 (m, 10H),
4.91 (m, 1H), 4.84 (m, 1H), 4.68 (dd, J = 10.9, 4.7 Hz, 1H), 4.48 (m,
1H), 4.23 (m, 1H), 4.03 (d, J = 10.9 Hz, 1H), 2.66 (m, 1H), 0.98 (d, J
= 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 154.7, 143.4, 142.3,
128.9, 128.7, 128.3, 128.1, 126.8, 126.6, 103.7, 84.3, 70.7, 52.6, 41.5,
1
2853, 1765, 1496, 1455, 1377, 1030, 909 cm−1; H NMR (400 MHz,
CDCl3) δ 7.23−7.10 (m, 5H), 4.84 (m, 1H), 4.79 (m, 1H), 4.42 (m,
L
DOI: 10.1021/acs.joc.5b00604
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The Journal of Organic Chemistry
Article
15.5; HRMS (ESI) calcd for C19H21O (M + H)+ m/z 263.1436, found
263.1439.
1.70 (m, 1H), 1.28 (d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
of major isomer (cis) δ 153.5, 142.2, 128.6, 128.6, 126.0, 104.1, 76.5,
75.9, 39.1, 37.2, 32.5, 20.6; for the minor isomer (trans-6o) δ 153.4,
142.2, 128.6, 128.6, 126.0, 104.6, 76.5, 75.9, 38.9, 37.1, 32.5, 21.1.
HRMS (ESI): calcd for C14H19O (M + H)+ m/z 203.1436, found
203.1444.
1,1-Diphenyl-2-methylpropene (15). The general procedure for
the reaction of 4-oxaspirohexane with Zeise’s dimer was followed using
4m (20 mg, 0.075 mmol). The reaction was stirred for 20 h.
Purification by flash chromatography on neutral alumina (petroleum
ether/EtOAc, 99:1) afforded 15 (6 mg, 40%):38 1H NMR (400 MHz,
CDCl3) δ 7.30 (t, J = 7.4 Hz, 4H), 7.21 (t, J = 7.3 Hz, 2H), 7.17 (d, J =
7.3 Hz, 4H), 1.83 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 143.3,
138.8, 130.9, 129.7, 127.8, 125.9, 22.4.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
13C-labeling studies and H and 13C NMR spectra for all new
2-(1-Cyclohexenyl)-2-methylpentan-3-one (16). The general
procedure for the reaction of 4-oxaspirohexane with Zeise’s dimer
was followed using 4n (20 mg, 0.11 mmol). Purification by flash
chromatography on neutral alumina (petroleum ether/EtOAc, 99:1)
afforded 16 as clear oil (10 mg, 50%): 1H NMR (400 MHz, CDCl3) δ
5.62 (m, 1H), 2.35 (q, J = 7.3 Hz, 2H), 2.05 (m, 2H), 1.75 (m, 2H),
1.54 (m, 4H), 1.15 (s, 6H), 0.99 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 215.6, 140.4, 122.1, 53.6, 29.7, 26.1, 25.7, 23.3, 23.3,
22.4, 8.7; HRMS (ESI) calcd for (M + H)+ C12H21O m/z 181.1592,
found 181.1562.
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.joc.5b00604.
AUTHOR INFORMATION
Corresponding Author
*E-mail: amy.howell@uconn.edu (A.R.H.).
■
Notes
13C-Labeled trans-5-Benzyloxymethyl-4-methyl-3-methylene-
tetrahydrofuran (13C-6h). The general procedure was followed
using 13C-4h (22 mg, 0.1 mmol). The reaction mixture was
concentrated in vacuo. Purification by column chromatography using
petroleum ether/Et2O (95:5) afforded an isotopomeric mixture of
13C-labeled trans-5-benzyloxymethyl-4-methyl-3-methylenetetrahydro-
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is based upon work partially supported by the
National Science Foundation (NSF) under Grant Nos. CHE-
0111522 and CHE-1048717. We thank John Hoberg, Jose
Gascon, and Stewart Richardson for helpful discussions. NMR
support from Martha Morton, Carlos Pacheco, and Nicholas
Eddy is acknowledged.
1
furan (13C-6h) as a colorless oil (12 mg, 55%): H NMR (400 MHz,
CDCl3) for isotopomer A: δ 7.35−7.25 (m, 5H), 4.96 (dm,36b
J
=
1
13
C‑H
156.9 Hz, 1H), 4.91 (dm,36b 1J
= 157.7 Hz, 1H), 4.63 (s, 2H),
13C‑H
4.53−4.49 (m, 1H), 4.39−4.31 (m, 1H), 3.70−3.57 (m, 3H), 2.49 (m,
1H), 1.12 (d, J = 6.7 Hz, 3H); for isotopomer B: δ 7.35−7.25 (m, 5H),
4.96 (m, 1H), 4.91 (m, 1H), 4.63 (s, 2H), 4.53−4.49 (dm,36b
J
=
C‑H
1
13
REFERENCES
146.4 Hz, 1H), 4.35−4.30 (dm,36b
J
C‑H = 143.0 Hz, 1H), 3.70−3.57
1
■
13
(m, 3H), 2.49 (m, 1H), 1.12 (d, J = 6.7 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 153.3, 138.4, 128.6, 127.9, 127.8, 103.3 (13C-labeled
carbon in isotopomer A), 85.4, 73.7, 71.3, (13C-labeled carbon in
isotopomer B), 70.8, 40.0, 15.1 (match with compound 6h); HRMS
(ESI) calcd for C1313CH19O2 (M + H)+ m/z 220.1385, found
220.1379; (M + NH4)+, calc. 237.1651, found 237.1629, (M − OH)+,
202.1279, found 202.1298 and (M − H)+, 218.1229, found 218.1224.
13C-Labeled (2R*, 3S*)-1-Benzyloxy-4-chloromethyl-3-methyl-
pent-4-ene-2-ol (13C-17). The title compound was obtained as the
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Angew. Chem., Int. Ed. 2013, 52, 4466. (b) Trost, B. M.; Bringley, D.
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minor product (colorless oil, 5 mg, 20%): 1H NMR (400 MHz,
1
13C‑H
CDCl3) for isotopomer A: δ 7.38−7.30 (m, 5H), 5.31 (d, J
=
1
13
157.8 Hz, 1H), 5.11 (d, J C‑H = 156.8 Hz, 1H), 4.59 (d, J = 11.2 Hz),
3
13
4.54 (d, J = 11.9 Hz), 4.14 {dd, J = 5.9 Hz ( J C‑H), 5.9 Hz, 2H}, 3.79
(m, 1H), 3.59 (dd, J = 9.6, 3.1 Hz, 1H), 3.43 (dd, J = 9.6, 7.2 Hz, 1H),
2.54 (m, 1H), 2.35 (d, J = 3.7 Hz, 1H), 1.09 (d, J = 7.1 Hz, 3H); for
3
13C‑H
isotopomer B: δ 7.38−7.30 (m, 5H), 5.31 (d, J
= 8.0 Hz, 1H),
3
13
5.11 (d, J C‑H = 13.6 Hz, 1H), 4.59 (d, J = 11.2 Hz), 4.54 (d, J = 11.9
1
13
Hz), 4.14 {dd, J = 151.0 Hz ( J C‑H), 7.0 Hz, 2H}, 3.79 (m, 1H), 3.59
(dd, J = 9.6, 3.1 Hz, 1H), 3.43 (dd, J = 9.6, 7.2 Hz, 1H), 2.54 (m, 1H),
2.35 (d, J = 3.7 Hz, 1H), 1.09 (d, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 147.4 138.1, 128.7, 128.1, 128.0, 115.9 (13C-labeled
carbon in isotopomer A), 77.4, 73.7, 72.6, 53.6, 48.3 (13C-labeled
carbon in isotopomer B), 16.9; HRMS (ESI) calcd for C1313CH20ClO2
(M + H)+ m/z 256.1152, found 256.1168.
2-Methyl-3-methylene-5-(2-phenylethyl)tetrahydrofuran (Cis/
Trans Mixture) (6o). The general procedure was followed using 4o
(0.1 g, 0.5 mmol). The reaction mixture was stirred for 45 min.
Purification by flash chromatography on silica gel (petroleum ether/
Et2O, 98:2) afforded 6o (4:1 cis/trans mixture) as a colorless oil (76
mg, 76%): IR (neat) 3026, 2973, 2928, 2857, 1665, 1603, 1495, 1453,
1
1052, 1030, 882 cm−1; H NMR (400 MHz, CDCl3) of major isomer
(cis-6o) δ 7.30−7.16 (m, 5H), 4.92 (dd, J = 4.3, 2.2 Hz, 1H), 4.80 (dd,
J = 4.6, 2.1 Hz, 1H), 4.33 (m, 1H), 3.85 (dq, J = 9.4, 5.9 Hz, 1H), 2.76
(m, 2H), 2.68 (m, 2H), 1.99 (m, 1H), 1.85 (m, 1H), 1.33 (d, J = 6.3
Hz, 3H); for the minor isomer (trans-6o) δ 7.30−7.16 (m, 5H), 4.96
(dd, J = 4.2, 2.1 Hz, 1H), 4.83 (dd, J = 4.2, 2.1 Hz, 1H), 4.54 (m, 1H),
4.07 (m, 1H), 2.29 (m, 2H), 2.24 (m, 2H), 1.97−1.88 (m, 1H), 1.78−
M
DOI: 10.1021/acs.joc.5b00604
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1
13
(36) (a) Complex multiplets were observed as a result of J C‑H and
2
13
J
C‑H coupling (see spectra). (b) Doublet of multiplet (dm), where the
1
13
large coupling constant ( J C‑H) is shown.
N
DOI: 10.1021/acs.joc.5b00604
J. Org. Chem. XXXX, XXX, XXX−XXX