Manipulating micellar environments for enhancing transition metal-catalyzed cross-couplings in water at room temperature

Article abstract of DOI:10.1021/jo200746y

The remarkable effects of added salts on the properties of aqueous micelles derived from the amphiphile PTS are described. Most notably, Heck reactions run in the presence of NaCl lead to couplings on aryl bromides in water at room temperature. Olefin cross- and ring-closing metathesis reactions run in the presence of small amounts of pH-lowering KHSO₄ are also accelerated, another phenomenon that does not apply to typical processes in organic media. These salt effects allow, in general, for synthetically valuable C-C bond-forming processes to be conducted under environmentally benign conditions. Recycling of the surfactant is also demonstrated.

Full text of DOI:10.1021/jo200746y

ARTICLE
pubs.acs.org/joc
Manipulating Micellar Environments for Enhancing Transition
Metal-Catalyzed Cross-Couplings in Water at Room Temperature
Bruce H. Lipshutz,* Subir Ghorai, Wendy Wen Yi Leong, and Benjamin R. Taft
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
Daniel V. Krogstad
Materials Department, University of California, Santa Barbara, California 93106, United States
S Supporting Information
b
ABSTRACT: The remarkable effects of added salts on the
properties of aqueous micelles derived from the amphiphile
PTS are described. Most notably, Heck reactions run in the
presence of NaCl lead to couplings on aryl bromides in water at
room temperature. Olefin cross- and ring-closing metathesis
reactions run in the presence of small amounts of pH-lowering
KHSO4 are also accelerated, another phenomenon that does
not apply to typical processes in organic media. These salt
effects allow, in general, for synthetically valuable CꢀC bond-
forming processes to be conducted under environmentally
benign conditions. Recycling of the surfactant is also demonstrated.
’ INTRODUCTION
’ RESULTS AND DISCUSSION
Salt Effects on Reactions in Aqueous PTS. Heck Reactions.6
The impetus for studying reactions in solutions of PTS/H2O of
varying ionicity followed from early trials using seawater as the
reaction medium, in place of standard HPLC-grade water.
Unexpectedly, significant rate accelerations were observed in
Heck couplings between an acrylate and either an aryl iodide or
bromide.7 As shown in Table 1, iodide 2 and t-butyl acrylate,
using (PtBu3)2Pd as catalyst, reacted in 5 wt % PTS/H2O (0.5 M
global concentration of aryl halide) at room temperature in the
presence of Et3N to afford 3 in 96% yield after four hours (entry
2).8 Of the many catalysts that were screened (Figure 1), only
(PtBu3)2Pd was effective. Catalysts originating at the Pd(II)
oxidation state (entries 1, 4ꢀ6) gave low levels of conversion,
or no reaction at all (entries 7ꢀ10) even in the presence of
excess zinc metal (entry 8). Surprisingly, switching from the
Pd(0) species 5 to the analogous Pd(0) catalyst 11, where only
one of three t-butyl groups on each phosphorus is replaced by a
p-dimethylaminophenyl residue, completely inhibits the cou-
pling. Reducing the amount of PTS from 5 to 2 wt % with the
same catalyst led to moderate product formation in the same
time frame (entry 3). In seawater, the yield reached 98% within
one hour (entry 11).
Micellar catalysis is a well-known phenomenon in organic
synthesis.1 Typically, an amphiphilic species of the anionic, cationic,
or nonionic variety spontaneously aggregates in water at low
concentrations forming “normal” (as opposed to “inverted”)
micellar arrays. Such particles can be organized into spheres, rods
or worms, vesicles, or combinations thereof, with their polar
portions outwardly interacting with the surrounding water, while
their nonpolar subsection(s) make up the interior. These lipophilic
cores function as hosts for organic compounds; in essence, as
solvent. Given the huge influence of solvent effects in organic
chemistry, variations in the nature of amphiphiles could well
determine the level of success realized in various synthetic trans-
formations. We have identified a first generation “designer” surfac-
tant in PTS (Polyoxyethanyl R-Tocopheryl Sebacate; 1)2 as a
generally useful nanoparticle-forming reagent that enables several
Pd- and Ru-catalyzed “name” reactions,3 as well as asymmetric
CuH-catalyzed 1,4-reductions,4 to be carried out in purely aqueous
media at room temperature. In this contribution we describe
further advances in PTS nanotechnology; advances applied to
especially useful cross-coupling chemistry resulting from either
control of nanoparticle size via adjustments in ionic strength,5 or
through the expediency of changes in pH, of the surrounding water.
The effect of adding NaCl (3 M) to HPLC grade water, rather
than using seawater, was even more pronounced with iodide 12,
where the cinnamate was obtained in 96% yield after three hours
at room temperature (Scheme 1). In the absence of salt, this
Received: April 12, 2011
Published: May 03, 2011
r
2011 American Chemical Society
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Table 1. Catalyst Screening for Heck Reactions
Scheme 1. Effect of NaCl on Heck Reactions in PTS/water
entry
catalyst
conversion (%)a
1
4
<5
96b
68b
50
2
3c
5
5
4
6
5
7
25
6
8
<5
7
8d
9
N R
N R
N R
N R
98b
9
9
10
11
5
10
11e
Table 2. Comparison of Amphiphiles for Heck Couplings in
Water
a Based on GC. b Yield of chromatographically pure materials. c Using 2
wt % PTS/H2O. d Zn dust (20 mol %) used. e Reaction run in seawater
for 1 h.
entry
surfactanta
PTS
yield (%)b
1
2
3
4
5
6
99
98
97
57
60
48
PTS in seawater
Solutol
Cremophor
TPGS
“on water”
a Five wt % used in all cases. b Chromatographically pure materials.
However, heating the reaction in PTS/H2O to 40 °C drove the
coupling to completion (entry 3). On the other hand, when the
aqueous phase contained PTS and NaCl (3 M), essentially
complete conversion was observed for both substrates, and high
yields of the desired products 17 and 19 were obtained at
ambient temperature (entries 4 and 10). Dropping the salt
concentration from 3 M in NaCl to either 1 or 2 M led to far
slower reactions (48% and 68% yields, respectively, after the
same 14 h). The salt effect on the corresponding reaction in
solutol was also minimal (entry 5), as expected (vide infra).
When run “on water,”12 again, limited conversion was noted
(entry 6). An identical Heck reaction on 16 run in toluene
afforded enoate 17 in only 40% yield, along with a significant
amount of the product of reduction of the aryl bromide, in
addition to small amounts of unreacted starting halide remain-
ing (entry 7).14
Several examples of related cinnamates prepared using NaCl-
containing PTS/HPLC water are illustrated in Table 4. The
nature of the ester in the acrylate partners appears to be of no
consequence. Both electron-rich and -poor aryl bromides react
equally well under these micellar conditions in 4ꢀ14 h (0.5 M
global concentration) at ambient temperatures. Lower levels of
PTS (e.g., 2 wt %) led to reactions that were equally rapid but not
as clean, judging from TLC analyses.
Figure 1. Palladium catalysts screened for Heck reactions.
reaction takes eight hours at 50 °C to realize the same yield at the
same concentration. A similar effect was also observed for
naphthyl iodide 13, where the reaction is done within three
hours when NaCl is present in solution; otherwise, 24 h are
required to reach completion.
Comparisons between PTS/water and PTS/seawater with
other surfactants were made in reactions with both aryl iodides
and bromides. The former educt type was studied using
iodobenzoate 14 along with t-butyl acrylate. As illustrated in
Table 2, BASF’s solutol9 as the nanoparticle-forming amphiphile
in water, as with PTS in pure water or seawater, led to high-
yielding reactions (entries 1ꢀ3). Other surfactants including
cremophor10 (entry 4) and TPGS11 (entry 5), however, were not
as effective. The corresponding reaction “on water”12 (entry 6)
gave the lowest level of conversion, which is consistent with
observations made in related micellar chemistry.13
More challenging aryl bromides 16 and 18 were expectedly
sluggish at ambient temperature (Table 3), with neither PTS
(entries 1 and 8) nor solutol (entries 2 and 9) affording
synthetically useful amounts of cinnamates after fourteen hours.
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Table 3. Comparison of Amphiphiles for Heck Couplings in
Water
Table 4. Heck Couplings of Aryl Bromides with Acrylates
added NaCl were only slightly faster (Table 6, entry 1 vs 2).
Trials that replaced water totally (HOAc, entry 7), or in large
measure (MeOH, entry 3; EtOH, entry 4; 95% EtOH; entries 6
and 10) gave inferior levels of conversion. On the other hand,
rather than adding NaCl, addition of small amounts of KHSO4
(0.02 M) had a much greater impact; e.g., in the case of MVK, the
resulting acidic conditions (pH 2)19 drove this reaction to almost
full conversion, with either the Grubbs-2 (entry 11) or Neolyst
M2 catalyst (entry 12). Replacing water with 95% EtOH led to
only trace amounts of product enone (entry 13). Figure 2
illustrates graphically the effect of added KHSO4 relative to both
aqueous PTS and CH2Cl2 alone.
Under these slightly acidic conditions, acetal 22 remained
intact (Scheme 2). Not only MVK but also ethyl vinyl ketone and
phenethyl vinyl ketone coupled with olefin 20 to give products
23 and 24 in 88% and 81% yields, respectively, under these
standard conditions (Scheme 3). Curiously, no product was
observed from the control reaction performed “on water” in the
presence of KHSO4 (0.02 M) with phenethyl vinyl ketone.
Although 20 reacted with MVK in a highly efficient manner
(Table 6, entry 11, and Table 7, entry 1), coupling with
acrylonitrile could only be achieved to the extent of 30%.
Nonetheless, under these room temperature conditions, reaction
in the typically used solvent20 CH2Cl2 gave product in only 4%
yield after the same four hours (Table 7, entry 2). Acrolein is
another difficult case in CH2Cl2 at ambient temperature
(9%),18a,21 and while aqueous PTS led to an improved 43%
yield after 8 h, the presence of KHSO4 raised the yield to 70%
under otherwise identical conditions (entry 3). Likewise, the
corresponding CM with a vinylphosphonate22 gave the best yield
(65%) under these pH-adjusted conditions.
a Conditions: tert-butyl acrylate (2 equiv), cat. 5 (2 mol %), Et3N (3
equiv) surfactant/H2O, 22 °C, 14 h. b Five wt % used in all cases.
c Chromatographically pure materials.
Olefin Metathesis.15 Early in our studies on room temperature
olefin ring-closing and cross-metathesis reactions (RCM and
CM, respectively) in aqueous nanoparticles of PTS, we de-
scribed conditions that avoided both chlorinated solvents and
heat.16 Type 1 olefins17 studied focused mainly on terminal
alkenes, although E- or Z-disubstituted systems readily partici-
pated. Not included previously in our work were couplings
involving trisubstituted olefins of the isopropylidene variety.17
The impetus to examine Type 1 olefins of this sort derived not
only from an interest in extending the limits of metathesis in
micelles, but in anticipation that this naturally occurring array
might be amenable to analog formation. Table 5 lists several
examples of such educts and their derived products from cross-
metathesis in water at room temperature using the Grubbs-2
catalyst. Reaction efficiencies are high in all cases, although a
tetrazole (entry 5) and ethyl chrysanthemate (entry 7) did not
give full conversion under the standard conditions employed
(0.5 M, 12 h). While racemic citronellol TBS ether was
smoothly converted to the corresponding enoate over twelve
hours (84%; entry 8), the identical reaction run in 3 M aqueous
NaCl/PTS afforded essentially the same yield (86%) but in half
the time. The corresponding acetate derivative also led to good
yields in CM reactions with t-butyl and 2-ethylhexyl acrylates
(entry 9).
The effect of added NaCl was not significant, in general, for
cross metathesis reactions involving Type 1 alkenes other than
those containing an isopropylidene unit. Even in the case of
especially challenging couplings using Type 2 olefins such as
methyl vinyl ketone (MVK),18 reactions in PTS/water with
Ring-closing metathesis reactions, either in 3 M aqueous
NaCl/PTS solutions, or in the presence of KHSO4, were only
marginally improved relative to that achieved in PTS/H2O alone
(Table 8). The best result (92% yield; entry 3) was obtained
through the expediency of added KHSO4. The corresponding
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Table 5. Olefin CM Reactions in 2.5% aqueous PTSa
Table 6. Salt Effect on Olefin CM Reactions in 2.5% aq. PTS
entry
conditions
conversion (%)a
1
PTS/water
64
75
59
54
33
22
20
30
<5
28
95
94
<5
2
3 M NaCl, PTS/water
PTS/waterꢀmethanolb
PTS/waterꢀethanolc
2.5% solutol/water
95% ethanol
3
4
5
6
7
AcOH
8
CH2Cl2
9
CH2Cl2þPTSA (10 mol %)
PTS/95% ethanol
10
11
12
13
0.02 M KHSO4 PTS/water
0.02 M KHSO4 PTS/waterd
0.02 M KHSO4 PTS/95% ethanol
a Based on 1H NMR. b Water:methanol = 19:1. c Water:ethanol = 19:1.
d Neolyst M2 used instead of Grubbs-2.
Figure 2. Conversion versus time profile for CM reaction of olefin 20
and MVK with Grubbs-2 catalyst in CH2Cl2 (1), PTS/water (2), and
0.02 M KHSO4, PTS/water (3), as measured by 1H NMR spectroscopy.
Scheme 2. Olefin CM Reaction in the Presence of an Acetal
a Reaction were conducted at 0.5 M over 12 h at 22 °C using 3 mol %
c
Grubbs-2. b Chromatographically pure materials. Based on recovered
starting material. d Isolated. e Mixture of cis and trans isomers. f Reaction
run in 3 M aqueous NaCl/PTS for 6 h.
experiment in the absence of PTS (i.e., “on water”; entry 4), as in
all previous comparisons herein, was not competitive.
Catalysts other than those in the Grubbs-1, -2, and Grubbs-
Hoveyda-1 series, including those shown in Figure 3, have all
been tested for their compatibility with micellar conditions, and
ultimately, their effectiveness in olefin metathesis reactions.
Among the Umicore series of Neolyst catalysts,23 an RCM
example (Table 9) suggested that the internally chelated species
Neolyst M51 mediates a very efficient cyclization, while catalyst
Neolyst M2 is apparently preferred for cross-metathesis
(Table 10). Likewise, among the two ruthenium carbene Zhan
catalysts24 RC-303 and RC-304 tested in a challenging cross-
metathesis example with MVK, RC-303 was found to work well,
even in the absence of KHSO4, while being roughly comparable
to both the Grubbs-2 and Neolyst M2 analogs at lower pH
(Table 11). Not surprisingly, with no phosphine ligand present in
RC-303 and GH-2, the rate of their catalysis is unaffected by the
presence of acid in the aqueous medium.19a
Another option for improving olefin cross metathesis under
micellar conditions is inclusion of a copper salt in the medium.
Surprisingly, although CuCl is routinely used to assist with formation
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Scheme 3. Olefin CM Reactions with Vinyl Ketones
Table 7. More Difficult Olefin CM Reactions
yield (%)a,b
c
entry
R
time (h)
PTS
PTS/KHSO4
CH2Cl2
1
2
3
4
COMe
CN
4
4
8
4
74d
20
43
51
91
30
70
65
30
4
CHO
9
P(O)(OEt)2
39
a Chromatographically pure materials. b Two and a half wt % PTS used.
c KHSO4 (0.02 M) used. d Reaction run for 12 h.
Figure 3. Structures of Ru-based catalysts used for olefin metathesis.
Table 9. Olefin RCM Reactions Using Neolyst Catalysts
Table 8. RCM Under Aqueous Conditions
entry
conditions
PTS/water
yield (%)a
entry
catalyst
conversion (%)a
1
2
3
4
85
90
92
42
1
2
3
4
5
Neolyst M41
Neolyst M42
Neolyst M3
Neolyst M51
Neolyst M2
N.R.
N.R.
3 M NaCl, PTS/water
0.02 M KHSO4 PTS/water
0.02 M KHSO4/water
84
100 (99)b
a Chromatographically pure materials.
82
a Based on 1H NMR. b Yield of chromatographically pure materials.
of Grubbs-Hoveyda-1 or Grubbs-Hoveyda-2 ruthenium carbene
complexes,25 use of copper to accelerate metathesis reactions is
rare.26 Among several Cu(I) and Cu(II) species investigated, CuI
(3 mol %) has been found to enhance the extent of conversion to
product alkenes at room temperature.27 Thus, as illustrated in
Table 12, three cases were studied: entry 1 is particularly noteworthy,
as numerous attempts (by varying the nature and percentage of the
surfactant, reaction temperature, and the amount of catalyst) to drive
this coupling beyond the 55% reported previously had not been
successful.16a The examples in entries 2 and 3 reflect problems
normally encountered due to Type 1 olefin homocoupling, especially
involving styrenes.17,28 Standard conditions for each of these exam-
ples compare well with those typically employed (refluxing CH2Cl2
over ca. 12 h). Levels of carbene catalyst needed in organic media are
also rarely less than 5 mol %,29 whereas with nanomicelles in water,
2 mol % is sufficient. Attempts to apply the benefits of both added
KHSO4 and CuI did not lead to a cumulative effect.
close model system to that used by Rychnovsky and co-workers
in their synthesis of (þ)-epicalyxin F, which relied on olefin
metathesis (without complication due to the chalcone fragment)
as a crucial means of attaching the required carbon framework for
subsequent intramolecular conjugate addition.30 Under condi-
tions that employed an organic solvent (PhH), heat (60 °C),
time (24 h), and catalyst (20 mol %), enone 27 was obtained in
modest (47%) yield (60% brsm). The corresponding reaction
between model enone 25 and ethyl vinyl ketone could be effected
in water at room temperature in eight hours using 4 mol % of the
Grubbs-2 Ru carbene to give 26 in 75% yield.
Salt Effects. The positive impact on reaction rates observed
due to the salts present in seawater on Heck reactions suggested
that the nature of the PTS micellar nanoreactors was being
perturbed. A DLS experiment on PTS in seawater revealed that
the average particle size had increased from ca. 25 to 75 nm in
diameter. A study on particle size vs concentration of NaCl in
HPLC-grade water revealed a steady increase in the average
The potential for applications of this technology to synthesis is
demonstrated by the cross-coupling reaction between olefin 25
and ethyl vinyl ketone (Scheme 4). This combination serves as a
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Table 10. Olefin CM Reactions Using Neolyst Catalysts
Table 12. Effect of CuI on Olefin CM Reactions
entry
catalyst
conversion (%)a
1
2
3
4
5
Neolyst M41
Neolyst M42
Neolyst M3
Neolyst M51
Neolyst M2
N.R.
N.R.
27 (40)b
80
99 (93)c
a Based on 1H NMR. b Homocoupling product. c Yield of chromatogra-
phically pure materials.
Table 11. Effect of pH on Olefin CM Reactions Using
Metathesis Catalysts
a Chromatographically pure materials. b 3 mol % CuI.
Scheme 4. Comparison of Conditions with a Close Litera-
ture Example
conversion(%)a,b
entry
catalyst
PTS
PTS/KHSO4c
1
2
3
4
5
RC-304
RC-303
G-2
0
88
64
64
61
0
90
95
94
62
Neolyst M2
GH-2
a Based on 1H NMR. b Two and a half wt % PTS used. c KHSO4 (0.02
M) used.
diameter with increasing ionic strength; at 3 M NaCl, nanopar-
ticles averaging 110 nm are present (Figure 4). Other salts led to
highly variable changes in particle size, although given the
influence of factors such as viscosity on DLS measurements,31
no quantitative inferences as to relative particle size should be
made. What does follow literature precedent is the qualitative
sense of particle growth due to the “salting out” effect for NaCl,
as well as several other salts (e.g., Na2SO4, NaBr, KCl, LiCl, etc.),
a well-known phenomenon for nonionic surfactants.5 On the
other hand, weakly hydrated salts such as iodides and thiocya-
nates lead to a “salting in” effect, where water is directed in and
around the micellar array, thereby reducing particle size. Salts
such as NaCl, however, effectively compete for, and thus with-
draw, water (of hydration) from the PEGylated portions of PTS
micelles thereby increasing particle size. These effects of halides
are further manifested by additional Heck reactions on 16 run in
the presence of 3 M NaBr and 3 M NaI (Scheme 5). Thus, while
the corresponding couplings in 3 M NaCl led to product
cinnamate 17 in 95% yield, those run in smaller micelles gave
considerably slower reactions. Nonionic surfactants other than
PTS responded to an increase in ionic strength due to the
presence of NaCl in a similar albeit far less pronounced fashion.
Particle size increases for solutol, TPGS, and Triton X-100, all
initially in the 10ꢀ13 nm range in pure water, do not exceed, on
average, 42 nm in diameter. Brij 30, which forms 110 nm micelles
in aqueous solution at room temperature, forms turbid mixtures
of particles of roughly twice their size in the presence of 3 M
NaCl. None of these alternative media, with or without added
salts, led to consistently competitive results in cross couplings
relative to those in PTS.
Data on PTS in water acquired from DLS measurements
provide insight as to the average particle size in solution but no
information as to particle shape(s) or individual micelle sizes. An
alternative technique, cryo-TEM,32 serves well in this capacity,
giving a good indication of the nature of the micelles present. For
PTS alone, cryo-TEM showed that both spherical micelles of ca.
10 nm are plentiful, along with a mix of worm- and rod-shaped
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Scheme 6. Recycling of PTS
Figure 4. Effect of different salt concentrations on the diameter of PTS
micelles.
Scheme 5. Impact of Halides on a Heck Coupling in PTS/
Water at rt
Recycling. Although PTS is used catalytically, the option to
recycle this surfactant was examined using three olefin metathesis
reactions: RCM; eq 1; CM; eqs 2 and 3 (Scheme 6). Reaction
handling involved the addition of EtOAc once the reaction
reached completion, stirring, and in-flask removal of solvent
leaving the aqueous layer behind. Reintroduction of fresh educt-
(s) and catalyst allowed for subsequent metathesis under other-
wise identical conditions. In the case of an azadiene, RCM took
place smoothly as previously noted (eq 1). Using an acrylate as
partner with olefin 20, the extent of conversion in 3 M aqueous
NaCl remained high and essentially unchanged after eight
recycles (eq 2). Likewise, with MVK, in this case using the pH-
lowering effect of KHSO4, 10 recycles did not alter the observed
level of conversion to the anticipated enone (eq 3).
Figure 5. Cryo-TEM image of (A) aqueous PTS (50 nm scale) and (B)
aqueous PTS in presence of 3 M NaCl (100 nm scale).
particles of considerably longer lengths (Figure 5A). Measure-
ments on PTS in 3 M NaCl, in stark contrast, clearly revealed a
fully interconnected, extended network (Figure 5B). In addition,
smaller, irregularly shaped closed loops can also be discerned
(white arrow). Thus, the enhanced cross-coupling chemistry
(vide supra) resulting from an increase in ionic strength of the
aqueous medium may be attributable to a dramatic change in the
nature of the nanoreactors in which these Pd- and Ru-catalyzed
couplings take place. While an explanation as to why such an
array might correlate with better catalysis, as opposed to that seen
with mainly spherical micelles formed by most other commonly
used surfactants, remains to be clarified, there are lessons that can
be learned from studies on both ionic and Gemini micelles.33
Rate enhancements are greater in the latter (e.g., for selec-
ted hydrolysis reactions), an observation that has been attributed
to greater binding constants (Kb) for both substrates and
catalysts.34
’ CONCLUSIONS
As viewed within the context of transition metal-mediated
CꢀC bond forming reactions, the observations provided herein
foreshadow the potential that spontaneously formed nanomi-
celles in water hold as alternative media to organic solvents. The
dynamic nature of these particles, along with their surrounding
aqueous environment through which educts and catalysts must
traverse, offer rare opportunities to leverage the influence of both
aqueous and nonaqueous solutions on cross-coupling reactions.
Additives such as simple salts can significantly realign surfactant
monomers, thereby perturbing particle size. These subtle
changes can be used to great synthetic advantage in synthesis,
impacting reaction rates, in particular with respect to Heck
couplings. Changes in pH have also been shown to increase
rates of olefin metathesis reactions in water as the only medium,
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especially when notoriously difficult Type 2 olefins are involved.
Several cases demonstrating surfactant recyclability, where work-
up procedures involve no increase in aqueous waste streams, also
support the inexpensive and environmentally friendly nature of
this chemistry.
CDCl3): δ 7.54 (d, J = 16.0 Hz, 1H), 7.14 (s, 2H), 7.01 (s, 1H), 6.35 (d, J
= 16.0 Hz, 1H), 2.33 (s, 6H), 1.54 (s, 9H); 13C NMR (100 MHz,
CDCl3): δ 166.6, 144.0, 138.5, 134.7, 131.9, 126.0, 119.9, 80.5, 28.4,
21.4; EI-MS m/z (%): 232 (Mþ, 26), 176 (100), 161 (75); HRMS (EI)
calcd for C15H20O2 [M]þ = 232.1463, found 232.1464.
(E)-t-Butyl 3-(3-methoxyphenyl)acrylate (19). Following the
general procedure using 3-methoxy bromobenzene (64 μL, 0.50 mmol)
and t-butyl acrylate (145 μL, 1.00 mmol), the reaction was stirred for 14
h at rt. Column chromatography on silica gel (eluting with 3% EtOAc/
hexanes) afforded the product as a colorless oil (115 mg, 98%). 1H NMR
(400 MHz, CDCl3): δ 7.54 (d, J = 16.0 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H),
7.09 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.90 (dd, J = 8.0, 2.4 Hz, 1H), 6.34
(d, J = 16.0 Hz, 1H), 3.81 (s, 3H), 1.52 (s, 9H).36
(E)-t-Butyl 3-(4-propylphenyl)acrylate. Following the general
procedure using 4-propyl bromobenzene (77 μL, 0.50 mmol) and t-
butyl acrylate (145 μL, 1.00 mmol), the reaction was stirred for 8 h at rt.
Column chromatography on silica gel (eluting with 2% EtOAc/hexanes)
afforded the product as a colorless oil (106 mg, 86%). IR (neat): 2968,
2872, 1713, 1633, 1609, 1568, 1512, 1456, 1418, 1391, 1367, 1323, 1256,
1210, 1149, 983 cmꢀ1; 1H NMR (400 MHz, CDCl3): δ 7.59 (d, J = 16.0
Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.35 (d, J =
16.0 Hz, 1H), 2.60 (t, J = 7.6 Hz, 2H), 1.65 (sextet, J = 7.6 Hz, 2H), 1.55
(s, 9H), 0.95 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 166.7,
145.2, 143.8, 132.5, 129.1, 128.1, 119.4, 80.5, 38.1, 28.4, 24.5, 13.9; EI-
MS m/z (%): 246 (Mþ, 12), 190 (88), 173 (24), 161 (100); HRMS(EI)
calcd for C16H22O2 [M]þ = 246.1619, found 246.1616.
(E)-t-Butyl 3-(3,4,5-trimethoxyphenyl)acrylate. Following
the general procedure using 5-bromo-1,2,3-trimethoxybenzene (124
mg, 0.50 mmol) and t-butyl acrylate (145 μL, 1.00 mmol), the reaction
was stirred for 4 h at rt. Column chromatography on silica gel (eluting
with 12% EtOAc/hexanes) afforded the product as a white solid (132
mg, 90%). 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 16.0 Hz, 1H),
6.74 (s, 2H), 6.28 (d, J = 16.0 Hz, 1H), 3.89 (s, 9H), 1.54 (s, 9H).37
(E)-Ethyl 3-(4-chloro-2-nitrophenyl)acrylate. Following the
general procedure using 1-bromo-4-chloro-2-nitrobenzene (118 mg,
0.50 mmol) and ethyl acrylate (109 μL, 1.00 mmol), the reaction was
stirred for 14 h at rt. Column chromatography on silica gel (eluting with
5% EtOAc/hexanes) afforded the product as a pale yellow solid (107 mg,
84%). 1H NMR (400 MHz, CDCl3): δ 8.07ꢀ8.03 (m, 2H), 7.65ꢀ7.59
(m, 2H), 6.37 (d, J = 15.6 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 1.36 (t, J =
7.2 Hz, 2H).38
’ EXPERIMENTAL SECTION
Typical Procedure for Heck Couplings. Catalyst (PtBu3)2Pd
(5.1 mg, 0.01 mmol) and aryl iodide/bromide (0.50 mmol) were added
under argon into a 5.0 mL microwave vial equipped with a large stir bar
and Teflon lined septum. An aliquot of 3 M NaCl in PTS/(degas-
sed)H2O (1.0 mL; 5.0% PTS by weight) solution, triethylamine (208
μL, 1.50 mmol), and acrylate/styrene (1.0 mmol) were added by
syringe, and the resulting solution was allowed to stir at rt until complete.
The homogeneous reaction mixture was then diluted with EtOAc
(2 mL), filtered through a bed of silica gel, and the bed further washed
(3 ꢁ 5 mL) with EtOAc to collect all of the coupled material. The
volatiles were removed in vacuo to afford the crude product which was
subsequently purified by flash chromatography on silica gel.
(E)-t-Butyl 3-(4-methoxyphenyl)acrylate (3). Following the
general procedure using 4-methoxyiodobenzene (117 mg, 0.50 mmol)
and t-butyl acrylate (145 μL, 1.00 mmol), the reaction was stirred for 4 h
at rt. Column chromatography on silica gel (eluting with 3% EtOAc/
hexanes) afforded the product as a colorless oil (112 mg, 96%). 1H NMR
(400 MHz, CDCl3): δ 7.55 (d, J = 16.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H),
6.90 (d, J = 8.8 Hz, 2H), 6.25 (d, J = 16.0 Hz, 1H), 3.84 (s, 3H), 1.54 (s,
9H).35
(E)-2-Ethylhexyl 3-(4-(3,7,11-trimethyldodecyloxy)phenyl)-
acrylate. Following the general procedure using 1-iodo-4-(3,7,11-tri-
methyldodecyloxy)benzene (215 mg, 0.50 mmol) and 2-ethylhexyl acrylate
(208 μL, 1.0 mmol), the reaction was stirred for 3 h at rt. Column
chromatography on silica gel (eluting with 4% EtOAc/hexanes) afforded
the product as a colorless oil (233 mg, 96%). 1H NMR (400 MHz, CDCl3):
δ 7.64 (d, J = 16.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz,
2H), 6.32 (d, J = 16.0 Hz, 1H), 4.14ꢀ4.08 (m, 2H), 4.06ꢀ3.98 (m, 2H),
1.86ꢀ1.80 (m, 1H), 1.70ꢀ1.03 (m, 25H), 0.96ꢀ0.85 (m, 18H).8
(E)-1-(2,4-Dimethylstyryl)-2-methoxynaphthalene. Follow-
ing the general procedure using 1-iodo-2-methoxynaphthalene (142 mg,
0.5 mmol) and 2,4-dimethylstyrene (147 μL, 1.0 mmol), the reaction
was stirred for 3 h at rt. Column chromatography on silica gel (eluting
with 5% EtOAc/hexanes) afforded the product as a semisolid (131 mg,
91%). 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 8.7 Hz, 1H), 7.81 (t, J
= 7.8 Hz, 2H), 7.68 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H),
7.40ꢀ7.30 (m, 4H), 7.10 (d, J = 8.2 Hz, 1H), 7.05 (s, 1H), 3.98 (s, 3H),
2.40 (s, 3H), 2.37 (s, 3H).8
(E)-t-Butyl 3-(2-(3,5-dichlorobenzamido)phenyl)acrylate.
Following the general procedure using N-(2-bromophenyl)-3,5-dichlor-
obenzamide (173 mg, 0.50 mmol) and t-butyl acrylate (145 μL, 1.00
mmol), the reaction was stirred for 14 h at rt. Column chromatography
on silica gel (eluting with 10% EtOAc/hexanes) afforded the product as
white solid (149 mg, 76%). IR (neat): 3243, 3065, 2979, 2932, 1705,
1682, 1660, 1635, 1587, 1529, 1483, 1455, 1368, 1322, 1253, 1152, 1104,
1050, 981, 911, 869, 760, 734 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ
8.18 (br s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 16.0 Hz, 1H), 7.74
(d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.43 (t, J = 8.0
Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 6.32 (d, J =
16.0 Hz, 1H), 1.51 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 166.0,
164.1, 138.0, 135.4, 133.3, 131.9, 130.7, 130.3, 128.0, 127.4, 126.6, 125.2,
123.4, 94.6, 81.1, 28.4. ESIꢀMS m/z: 414 (M þ Na). HRESIꢀMS calcd
for C20H19NO3Cl2Na [M þ Na]þ = 414.0640, found 414.0647.
(E)-t-Butyl 3-(2-methoxynaphthalen-1-yl)acrylate. Follow-
ing the general procedure using 1-bromo-2-methoxynaphthalene (119
mg, 0.50 mmol) and t-butyl acrylate (145 μL, 1.00 mmol), the reaction
was stirred for 14 h at rt. Column chromatography on silica gel (eluting
with 3% EtOAc/hexanes) afforded the product as a colorless oil (116
mg, 82%). IR (neat): 3059, 2977, 2935, 2842, 1704, 1622, 1591, 1568,
(E)-t-Butyl 3-(4-carboethoxylphenyl)acrylate (15). Follow-
ing the general procedure using ethyl 4-iodobenzoate (84 μL, 0.50
mmol) and t-butyl acrylate (145 μL, 1.00 mmol), the reaction was stirred
for 75 min at rt. Column chromatography on silica gel (eluting with 4%
EtOAc/hexanes) afforded the product as a colorless oil (137 mg, 99%).
1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 8.4 Hz, 2H), 7.60 (d, J =
16.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 6.46 (d, J = 16.0 Hz, 1H), 4.39 (q,
J = 7.2 Hz, 2H), 1.55 (s, 9H), 1.41 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 166.1, 165.9, 142.3, 138.9, 131.6, 130.1, 127.9, 122.6,
80.9, 61.3, 28.3, 14.4; ESI-MS m/z: 299 (M þ Na); HRESIMS calcd for
C16H20O4Na [M þ Na]þ = 299.1259, found 299.1262.
(E)-t-Butyl 3-(3,5-dimethylphenyl)acrylate (17). Following
the general procedure using 3,5-dimethyl bromobenzene (68 μL, 0.50
mmol) and t-butyl acrylate (145 μL, 1.00 mmol), the reaction was stirred
for 14 h at rt. Column chromatography on silica gel (eluting with 2%
EtOAc/hexanes) afforded the product as a colorless oil (110 mg, 95%).
IR (neat): 3006, 2978, 2922, 2870, 1707, 1637, 1603, 1455, 1391, 1366,
1
1513, 1469, 1391, 1367, 1270, 1146, 1102, 1045, 982, 850 cmꢀ1. H
1
1330, 1288, 1255, 1151, 1039, 982, 844 cmꢀ1; H NMR (400 MHz,
NMR (400 MHz, CDCl3): δ 8.30 (d, J = 16.0 Hz, 1H), 8.22 (d, J = 8.8
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ARTICLE
Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.53 (t, J = 8.4
Hz, 1H), 7.38 (t, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.70 (d, J =
16.0 Hz, 1H), 4.00 (s, 3H), 1.61 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 167.4, 156.6, 136.8, 132.9, 131.4, 129.1, 128.7, 127.4, 125.4, 124.0,
123.5, 117.0, 112.9, 80.4, 56.3, 28.5. EI-MS m/z (%): 284 (Mþ, 28), 228
was followed using 5-((11-methyldodec-10-en-1-yl)thio)-1-phenyl-1H-
tetrazole (179 mg, 0.50 mmol), t-butyl acrylate (128 mg, 1.00 mmol)
and Grubbs-2 catalyst (12.8 mg, 0.015 mmol). Column chromatography
on silica gel (eluting with 3% EtOAc/hexanes) afforded the product as a
colorless oil (118 mg, 55%). IR (neat): 3053, 2977, 2928, 2855, 1713,
1652, 1598, 1500, 1460, 1389, 1367, 1292, 1246, 1156, 1088, 1074, 1053,
(67), 211 (23), 183 (100). HRMS(EI) calcd for C18H20O3 [M]þ
284.1412, found 284.1415.
=
1014, 981, 914, 851, 762 cmꢀ1 1H NMR (400 MHz, CDCl3): δ
.
7.60ꢀ7.52 (m, 5H), 6.85 (dt, J = 15.6, 6.8 Hz, 1H), 5.73 (dt, J = 15.6, 0.8
Hz, 1H), 3.39 (t, J = 7.2 Hz, 2H), 2.15 (qd, J = 6.8, 0.8 Hz, 2H), 1.82
(quint, J = 7.2 Hz, 2H), 1.50ꢀ1.43 (m, 4H), 1.48 (s, 9H), 1.32ꢀ1.28 (m,
8H). 13C NMR (100 MHz, CDCl3): δ 166.4, 148.4, 133.9, 130.3, 130.0,
124.0, 123.1, 80.2, 33.5, 32.2, 29.5, 29.3, 29.24, 29.18, 28.8, 28.3, 28.2. EI-
MS m/z (%): 430 (Mþ, 8), 357 (19), 329 (14), 118 (76), 57 (100).
HRMS(EI) calcd for C23H34O2N4S [M]þ = 430.2402, found 430.2390.
(E)-2-Ethylhexyl 4-phenyl-2-butenoate (Table 5, entry 6).
The representative procedure was followed using (3-methylbut-2-en-1-
yl)benzene (73 mg, 0.50 mmol), 2-ethylhexyl acrylate (184 mg, 1.00
mmol), and Grubbs second-generation catalyst (23.4 mg, 0.0275
mmol). Column chromatography on silica gel (eluting with 5%
EtOAc/hexanes) afforded the product as a colorless oil (121 mg,
Typical Procedure for Cross Metathesis. Alkene (0.50 mmol),
acrylate (1.00 mmol)/ketone (1.50 mmol) and Grubbs-2 catalyst
(0.01ꢀ0.02 mmol) were sequentially added into a Teflon-coated-stir-
bar-containing Biotage 2ꢀ5 mL microwave reactor vial at rt, and then
sealed with a septum. An aliquot of 0.02 M of KHSO4 in PTS/H2O or
PTS/H2O (1.0 mL; 2.5% PTS by weight; all cross-coupling reactions
were conducted at 0.5 M unless stated otherwise) was added, via syringe,
and the resulting solution was allowed to stir at rt for 4ꢀ12 h. The
homogeneous reaction mixture was then diluted with EtOAc (2 mL),
filtered through a bed of silica gel, and the bed further washed (3 ꢁ
5 mL) with EtOAc to collect all of the cross-coupled material. The
volatiles were removed in vacuo to afford the crude product that was
subsequently purified by flash chromatography on silica gel.
(E)-t-Butyl 12-(t-butyldimethylsilyloxy)dodec-2-enoate
(Table 5, entry 1). The representative procedure above was followed
using t-butyldimethyl(11-methyldodec-10-en-1-yloxy)silane (156 mg,
0.50 mmol), t-butyl acrylate (128 mg, 1.00 mmol) and Grubbs-2 catalyst
(12.8 mg, 0.015 mmol). Column chromatography on silica gel (eluting
with 3% EtOAc/hexanes) afforded the product as a colorless oil (177
mg, 92%). 1H NMR (400 MHz, CDCl3): δ 6.87 (dt, J = 15.6, 7.2 Hz,
1H), 5.74 (dt, J = 15.6, 1.6 Hz, 1H), 3.60 (t, J = 6.8 Hz, 2H), 2.16 (qd, J =
6.8, 1.6 Hz, 2H), 1.55ꢀ1.50 (m, 2H), 1.49 (s, 9H), 1.46ꢀ1.40 (m, 2H),
1.33ꢀ1.28 (m, 10H), 0.90 (s, 9H), 0.05 (s, 6H).39
1
88%). H NMR (400 MHz, CDCl3): δ 7.33 (t, J = 7.2 Hz, 2H), 7.25
(tt, J = 7.2, 1.2 Hz, 1H), 7.19 (dd, J = 7.2, 1.2 Hz, 2H), 7.10 (dt, J = 15.6,
6.8 Hz, 1H), 5.84 (dt, J = 15.6, 1.6 Hz, 1H), 4.06 (dd, J = 14.4, 6.0 Hz,
1H), 4.03 (dd, J = 14.4, 6.0 Hz, 1H), 3.54 (dd, J = 6.8, 1.6 Hz, 2H), 1.60
(septet, J = 6.4 Hz, 1H), 1.42ꢀ1.26 (m, 8H), 0.90 (t, J = 7.2 Hz, 6H).16a
(E)-Ethyl 3-(3-(t-Butoxy)-3-oxoprop-1-en-1-yl)-2,2-dimethyl-
cyclopropanecarboxylate (Table 5, entry 7). The representative
procedure above was followed using ethyl chrysamthemate (135 mg, 0.50
mmol, mixture of cis and trans isomers), t-butyl acrylate (128 mg, 1.00
mmol) and Grubbs-2 catalyst (12.8 mg, 0.015 mmol). Column chroma-
tography on silica gel (eluting with 2% EtOAc/hexanes) afforded the
mixture of cis and trans isomers as a colorless oil (143 mg, 84%). For cis
isomer: IR (neat): 2979, 1727, 1713, 1643, 1455, 1415, 1391, 1368, 1309,
1270, 1189, 1157, 1135, 1086, 985 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ
7.24ꢀ7.15 (m, 1H), 5.90 (d, J = 15.2 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 1.87
(d, J = 5.2 Hz, 1H), 1.86 (d, J = 5.2 Hz, 1H), 1.48 (s, 9H), 1.35 (s, 3H), 1.27
(t, J = 7.2 Hz, 3H), 1.23 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 170.5,
165.7, 143.5, 124.5, 80.2, 60.5, 35.3, 34.0, 28.9, 28.8, 28.4, 15.2, 14.5. ESI-MS
m/z: 307 (M þ K), 291 (M þ Na). HRESIꢀMS calcd for C15H24O4Na
[Mþ Na]þ = 291.1572, found 291.1559. For trans isomer: IR (neat): 2979,
2933, 1728, 1714, 1645, 1457, 1427, 1392, 1381, 1367, 1313, 1281, 1232,
1197, 1155, 1137, 1114, 982 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 6.57
(dd, J = 15.2, 10.0 Hz, 1H), 5.91 (d, J = 15.2 Hz, 1H), 4.19ꢀ4.07 (m, 2H),
2.14 (dd, J = 10.0, 5.2 Hz, 1H), 1.76 (d, J = 5.2 Hz, 1H), 1.47 (s, 9H), 1.28
(s, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.24 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 171.3, 165.9, 145.3, 124.4, 80.4, 60.8, 35.7, 35.5, 30.4, 28.3, 22.4,
20.5, 14.5; ESI-MS m/z: 291 (M þ Na). HRESIꢀMS calcd for
C15H24O4Na [M þ Na]þ = 291.1572, found 291.1558.
(R,E)-t-Butyl 12-(2-(Benzyloxycarbonylamino)-3-phenyl-
propanoyloxy)dodec-2-enoate (Table 5, entry 2). The repre-
sentative procedure above was followed using (R)-11-methyldodec-10-
en-1-yl 2-(benzyloxycarbonylamino)-3-phenylpropanoate (240 mg,
0.50 mmol), t-butyl acrylate (128 mg, 1.00 mmol) and Grubbs-2 catalyst
(12.8 mg, 0.015 mmol). Column chromatography on silica gel (eluting
with 3% EtOAc/hexanes) afforded the product as a colorless oil (267
mg, 97%). 1H NMR (400 MHz, CDCl3): δ 7.38ꢀ7.32 (m, 4H),
7.31ꢀ7.24 (m, 4H), 7.11 (dd, J = 7.2, 1.2 Hz, 2H), 6.87 (dt, J = 15.6,
6.8 Hz, 1H), 5.74 (dt, J = 15.6, 1.2 Hz, 1H), 5.24 (d, J = 8.4 Hz, 1H), 5.12
(d, J = 12.4 Hz, 1H), 5.08 (d, J = 12.4 Hz, 1H), 4.66 (dt, J = 8.4, 5.6 Hz,
1H), 4.12 (dd, J = 10.8, 6.8 Hz, 1H), 4.06 (dd, J = 10.8, 6.8 Hz, 1H), 3.14
(dd, J = 13.6, 5.6 Hz, 1H), 3.09 (dd, J = 13.6, 5.6 Hz, 1H), 2.17 (qd, J =
7.2, 1.6 Hz, 2H), 1.60ꢀ1.55 (m, 2H), 1.49 (s, 9H), 1.46ꢀ1.41 (m, 2H),
1.32ꢀ1.28 (m, 10H).16a
(E)-4-Phenylbut-2-en-1-yl Acetate (Table 5, entry 3). The
representative procedure above was followed using (3-methylbut-2-en-
1-yl)benzene (73 mg, 0.50 mmol), (Z)-but-2-ene-1,4-diyl diacetate (172
mg, 1.00 mmol) and Grubbs-2 catalyst (12.8 mg, 0.015 mmol). Column
chromatography on silica gel (eluting with 3% EtOAc/hexanes) afforded
(E)-t-Butyl 8-(tert-Butyldimethylsilyloxy)-6-methyloct-2-
t
enoate (Table 5, entry 8, R = Bu). The representative procedure
1
the product as a colorless oil (80 mg, 84%). H NMR (400 MHz,
above was followed using t-butyl(3,7-dimethyloct-6-en-1-yloxy)dimethy-
lsilane42 (135 mg, 0.50 mmol), t-butyl acrylate (128 mg, 1.00 mmol) and
Grubbs-2 catalyst (12.8 mg, 0.015 mmol). Column chromatography on
silica gel (eluting with 2% EtOAc/hexanes) afforded the product as a
colorless oil (143 mg, 84%). IR (neat): 2956, 2929, 2858, 1717, 1654, 1472,
1462, 1390, 1366, 1289, 1255, 1156, 1096, 983, 897, 836, 775 cmꢀ1. 1H
NMR (400 MHz, CDCl3): δ 6.86 (dt, J = 15.6 Hz, 1H), 5.74 (dt, J = 15.6,
1.6 Hz, 1H), 3.69ꢀ3.59 (m, 2H), 2.26ꢀ2.10 (m, 2H), 1.65ꢀ1.41 (m, 3H),
1.48 (s, 9H), 1.38ꢀ1.23 (m, 2H), 0.89 (s, 9H), 0.892 (d, J = 6.4 Hz, 3H),
0.05 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 166.4, 148.4, 123.0, 80.2,
61.4, 39.9, 35.5, 29.8, 29.2, 28.4, 26.2, 19.6, 18.5, ꢀ5.1. MS (CI) m/z
(%): 343 (M þ H, 100), 287 (89), 269 (83), 229 (65), 109 (29), 59
(76). HRMS (CI) calcd for C19H39O3Si [M þ H]þ = 343.2668, found
343.2669.
CDCl3): δ 7.33ꢀ7.18 (m, 5H), 5.97ꢀ5.90 (m, 1H), 5.68ꢀ5.61 (m,
1H), 4.55 (d, J = 6.4 Hz, 2H), 3.41 (d, J = 6.4 Hz, 2H), 2.07 (s, 3H).40
(E)-t-Butyl 4-phenyl-2-butenoate (Table 5, entry 4). The
representative procedure above was followed using (3-methylbut-2-en-
1-yl)benzene (73 mg, 0.50 mmol), t-butyl acrylate (128 mg, 1.00 mmol),
and Grubbs second-generation catalyst (12.8 mg, 0.015 mmol). Column
chromatography on silica gel (eluting with 4% EtOAc/hexanes) afforded
1
the product as a colorless oil (96 mg, 88%). H NMR (400 MHz,
CDCl3): δ 7.33 (td, J = 8.4, 1.2 Hz, 2H), 7.25 (t, J = 8.4 Hz, 1H), 7.19 (d,
J = 8.4 Hz, 2H), 7.00 (dt, J = 15.6, 6.8 Hz, 1H), 5.74 (dt, J = 15.6, 1.6 Hz,
1H), 3.51 (d, J = 6.8 Hz, 2H), 1.48 (s, 9H).41
(E)-t-Butyl 12-((1-Phenyl-1H-tetrazol-5-yl)thio)dodec-2-
enoate (Table 5, entry 5). The representative procedure above
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ARTICLE
(E)-Ethyl 8-(t-Butyldimethylsilyloxy)-6-methyloct-2-eno-
ate (Table 5, entry 8, R = Et). The representative procedure above
was followed using t-butyl(3,7-dimethyloct-6-en-1-yloxy)dimethylsi-
lane42 (135 mg, 0.50 mmol), ethyl acrylate (0.11 mL, 1.00 mmol) and
Grubbs-2 catalyst (12.8 mg, 0.015 mmol). Column chromatography on
silica gel (eluting with 50% CH2Cl2/hexanes) afforded the product as a
colorless oil (129 mg, 82%). IR (neat): 2957, 2856, 1725, 1656, 1464,
1388, 1367, 1308, 1257, 1198, 1171, 1094, 1048, 984, 939, 897, 836,
776 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 6.96 (dt, J = 15.6, 1H), 5.82
(dt, J = 15.6, 1.6 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.69ꢀ3.58 (m, 2H),
2.29ꢀ2.13 (m, 2H), 1.66ꢀ1.43 (m, 3H), 1.38ꢀ1.24 (m, 2H), 1.28 (t, J =
7.2 Hz, 3H), 0.895 (s, 9H), 0.894 (d, J = 6.4 Hz, 3H), 0.45 (s, 6H). 13C
NMR (100 MHz, CDCl3): δ 167.0, 149.7, 121.4, 61.4, 60.3, 39.9, 35.4,
29.9, 29.2, 26.2, 19.6, 18.5, 14.5, ꢀ5.1. EI-MS m/z (%): 299 (M ꢀ CH3,
3), 257 (M ꢀ C4H9, 100), 211 (16). HRMS (EI) calcd for C13H25O3Si
[M ꢀ C4H9]þ = 257.1573, found 257.1580.
afforded the product as a colorless oil (134 mg, 88%). IR (neat): 3063, 3035,
2956, 2897, 2857, 1697, 1682, 1632, 1599, 1583, 1495, 1454, 1451, 1361,
1258, 1201, 1123, 1107, 1043, 982, 934, 838, 781, 756, 704, 663 cmꢀ1. 1H
NMR (400 MHz, CDCl3): δ7.14 (td, J = 7.6, 1.6 Hz, 1H), 7.10 (dd, J = 7.2,
1.6 Hz, 1H), 6.98 (dt, J = 16.0, 6.8 Hz, 1H), 6.91 (td, J = 7.2, 1.2 Hz, 1H),
6.83 (d, J = 7.6 Hz, 1H), 6.05 (dt, J = 16.0, 1.6 Hz, 1H), 3.53 (dd, J = 6.8, 1.6
Hz, 2H), 2.56 (q, J = 7.6 Hz, 2H), 1.09 (t, J = 7.6 Hz, 3H), 1.01 (s, 9H), 0.25
(s, 6H). 13C NMR (100 MHz, CDCl3): δ 201.2, 153.7, 145.3, 130.9, 130.7,
128.6, 128.0, 121.4, 118.6, 33.6, 33.2, 26.0, 18.4, 8.3, ꢀ3.9. ESIꢀMS m/z:
327 (M þ Na), 305(Mþ H). HRESIꢀMS calcd for C18H28O2SiNa [M þ
Na]þ = 327.1756, found 327.1758.
(E)-6-(2-(t-Butyldimethylsilyloxy)phenyl)-1-phenylhex-4-
en-3-one (24). The representative procedure above was followed
using t-butyl(2-allylphenoxy)dimethylsilane44 (20) (124 mg, 0.50
mmol), 5-phenylpent-1-en-3-one (240 mg, 1.50 mmol) and Grubbs-2
catalyst (8.5 mg, 0.01 mmol). Column chromatography on silica gel
(eluting with 3% EtOAc/hexanes) afforded the product as a colorless oil
(154 mg, 81%). IR (neat): 3062, 3028, 2955, 2929, 2896, 2858, 1697,
1674, 1628, 1600, 1582, 1492, 1453, 1362, 1256, 1105, 981, 928, 839,
(E)-t-Butyl 8-acetoxy-6-methyloct-2-enoate (Table 5, en-
try 9, R = tBu). The representative procedure above was followed using
3,7-dimethyloct-6-en-1-yl acetate43 (99 mg, 0.50 mmol), t-butyl acrylate
(128 mg, 1.00 mmol) and Grubbs-2 catalyst (12.8 mg, 0.015 mmol).
Column chromatography on silica gel (eluting with 6% EtOAc/hexanes)
afforded the product as a colorless oil (108 mg, 80%). IR (neat): 2973,
2931, 2874, 1740, 1715, 1653, 1458, 1391, 1367, 1290, 1236, 1157, 1125,
1049, 984, 851 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 6.82 (dt, J = 15.6,
6.8 Hz, 1H), 5.72 (dt, J = 15.9, 1.6 Hz, 1H), 4.13ꢀ4.02 (m, 2H),
2.25ꢀ2.08 (m, 2H), 2.02 (s, 3H), 1.69ꢀ1.38 (m, 3H), 1.45 (s, 9H),
1.36ꢀ1.23 (m, 2H), 0.90 (d, J = 6.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 171.3, 166.2, 147.9, 123.2, 80.2, 62.8, 35.4, 35.2, 29.6, 29.5,
28.3, 21.2, 19.3. ESIꢀMS m/z: 293 (M þ Na). HRESIꢀMS calcd for
C15H26O4Na [M þ Na]þ = 293.1723, found 293.1730.
1
781, 756, 699 cmꢀ1. H NMR (400 MHz, CDCl3): δ 7.30ꢀ7.26 (m,
2H), 7.20ꢀ7.18 (m, 3H), 7.14 (td, J = 7.2, 1.2 Hz, 1H), 7.08 (dd, J = 7.2,
1.2 Hz, 1H), 6.98 (dt, J = 16.0, 6.4 Hz, 1H), 6.91 (t, J = 7.2 Hz, 1H), 6.83
(d, J = 8.0 Hz, 1H), 6.05 (d, J = 16.0 Hz, 1H), 3.52 (d, J = 6.4 Hz, 2H),
2.96ꢀ2.92 (m, 2H), 2.88ꢀ2.84 (m, 2H), 1.00 (s, 9H), 0.25 (s, 6H). 13C
NMR (100 MHz, CDCl3): δ 199.7, 153.7, 146.0, 141.5, 131.1, 130.7,
128.7, 128.54, 128.49, 128.1, 126.2, 121.5, 118.7, 41.7, 33.6, 30.2, 26.0,
18.4, ꢀ3.9. ESIꢀMS m/z: 403 (M þ Na), 381 (M þ H); HRESIꢀMS
calcd for C24H32O2SiNa [M þ Na]þ = 403.2069, found 403.2078.
(E)-5-(2-(t-Butyldimethylsilyloxy)phenyl)pent-3-en-2-one
(Table 7, entry 1). The representative procedure above was followed
using t-butyl(2-allylphenoxy)dimethylsilane44 (20) (124 mg, 0.50
mmol), methyl vinyl ketone (106 mg, 1.50 mmol) and Grubbs-2 catalyst
(8.5 mg, 0.01 mmol). Column chromatography on silica gel (eluting
with 3% EtOAc/hexanes) afforded the product as a colorless oil (132
mg, 91%). IR (neat): 3062, 3034, 2932, 2894, 2859, 1699, 1676, 1626,
1599, 1582, 1492, 1472, 1452, 1422, 1390, 1361, 1254, 1182, 1108, 1043,
982, 929 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.15 (td, J = 7.6, 1.6 Hz,
1H), 7.11 (dd, J = 7.6, 1.6 Hz, 1H), 6.95(dt, J = 16.0, 6.4 Hz, 1H), 6.92
(td, J = 7.6, 1.2 Hz, 1H), 6.84 (dd, J = 7.6, 1.2 Hz, 1H), 6.03 (dt, J = 16.0,
1.6 Hz, 1H), 3.54 (dd, J = 6.4, 1.6 Hz, 2H), 2.24 (s, 3H), 1.01 (s, 9H),
0.26 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 198.8, 153.7, 146.8,
132.0, 130.7, 128.4, 128.1, 121.4, 118.6, 33.7, 26.9, 25.9, 18.4, ꢀ4.0. EI-
MS m/z (%): 275 (M ꢀ CH3þ, 2), 233 (M ꢀ C4H9þ, 100), 215 (20),
(E)-2-Ethylhexyl 8-Acetoxy-6-methyloct-2-enoate (Table 5,
entry 9, R = 2-Ethylhexyl). The representative procedure above was
followed using 3,7-dimethyloct-6-en-1-yl acetate43 (99 mg, 0.50 mmol),
2-ethylhexyl acrylate (0.21 mL, 1.00 mmol) and Grubbs-2 catalyst (12.8 mg,
0.015 mmol). Column chromatography on silica gel (eluting with 6%
EtOAc/hexanes) afforded the product as a colorless oil (127 mg, 78%). IR
(neat): 2959, 2930, 2873, 2861, 1741, 1721, 1655, 1462, 1382, 1366, 1309,
1239, 1171, 1125, 1047, 985 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 6.92
(dt, J = 15.6, 6.8 Hz, 1H), 5.81 (dt, J = 15.9, 1.6 Hz, 1H), 4.13ꢀ4.04 (m,
2H), 4.03ꢀ3.98 (m, 2H), 2.27ꢀ2.12 (m, 2H), 2.02 (s, 3H), 1.70ꢀ1.27 (m,
14H), 0.92ꢀ0.86 (m, 9H). 13C NMR (100 MHz, CDCl3): δ 171.3, 167.0,
149.1, 121.6, 66.8, 62.8, 38.9, 35.4, 35.2, 30.6, 29.7, 29.5, 29.1, 24.0, 23.1,
21.2, 19.3, 14.2, 11.2. ESIꢀMS m/z: 349 (M þ Na), 327 (M þ H).
HRESIꢀMS calcd for C19H34O4Na [M þ Na]þ = 349.2349, found
349.2354.
151 (8), 75 (42). HRMS(EI) calcd for C13H17O2Si [M ꢀ C4H9]þ
=
233.0998, found 233.1006.
(E)-12-(1,3-Dioxolan-2-yl)dodec-3-en-2-one. The represen-
tative procedure above was followed using 2-(dec-9-en-1-yl)-1,3-dioxo-
lane (22) (106 mg, 0.50 mmol), methyl vinyl ketone (106 mg, 1.50
mmol) and Grubbs-2 catalyst (8.5 mg, 0.01 mmol). Column chroma-
tography on silica gel (eluting with 3% EtOAc/hexanes) afforded the
product as a colorless oil (114 mg, 90%). IR (neat): 2926, 2855, 1697,
1675, 1626, 1465, 1434, 1361, 1253, 1139, 1036, 980 cmꢀ1. 1H NMR
(400 MHz, CDCl3): δ 6.78 (dt, J = 16.0, 7.2 Hz, 1H), 6.04 (dt, J = 16.0,
1.2 Hz, 1H), 4.81 (t, J = 4.8 Hz, 1H), 3.98ꢀ3.90 (m, 2H), 3.87ꢀ3.78 (m,
2H), 2.22 (s, 3H), 2.19 (qd, J = 7.2, 1.2 Hz, 2H), 1.63 (td, J = 7.2, 4.8 Hz,
2H), 1.46ꢀ1.28 (m, 12H). 13C NMR (100 MHz, CDCl3): δ 198.8,
148.7, 131.4, 104.8, 65.0, 34.0, 32.6, 29.6, 29.5, 29.4, 29.3, 28.2, 27.0,
24.2. ESIꢀMS m/z: 393 (M þ K), 277 (M þ Na). HRESIꢀMS calcd
for C15H26O3Na [M þ Na]þ = 277.1780, found 277.1774.
4-(2-(t-Butyldimethylsilyloxy)phenyl)but-2-enenitrile
(Table 7, entry 2). The representative procedure above was followed
using t-butyl(2-allylphenoxy)dimethylsilane44 (20) (124 mg, 0.50
mmol), acrylonitrile (80 mg, 1.50 mmol) and Grubbs-2 catalyst (8.5
mg, 0.01 mmol). Column chromatography on silica gel (eluting with 3%
EtOAc/hexanes) afforded the product as a colorless oil (41 mg, 30%). IR
(neat): 3067, 3035, 2956, 2931, 2896, 2859, 2222, 1683, 1620, 1599,
1583, 1492, 1472, 1454, 1390, 1362, 1258, 1184, 1109, 1045, 1108, 928,
838 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.17ꢀ7.14 (m, 2H), 6.93 (t,
J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.65 (dt, J = 11.2, 7.2 Hz, 1H),
5.38 (d, J = 11.2 Hz, 1H), 3.74 (d, J = 7.2 Hz, 2H), 1.03 (s, 9H), 0.27 (s,
6H). 13C NMR (100 MHz, CDCl3): δ 153.3, 130.8, 130.4, 128.6, 128.4,
121.6, 118.7, 116.3, 99.7, 34.4, 33.2, 26.0, ꢀ3.9. FI-MS m/z: 273 (M),
216 (M ꢀ C4H9). HRFI-MS calcd for C16H23NOSi [M]þ = 273.1549,
found 273.1557.
(E)-6-(2-(t-Butyldimethylsilyloxy)phenyl)hex-4-en-3-one
(23). The representative procedure above was followed using t-butyl
(2-allylphenoxy)dimethylsilane44 (20) (124 mg, 0.50 mmol), ethyl vinyl
ketone (126 mg, 1.50 mmol) and Grubbs-2 catalyst (8.5 mg, 0.01 mmol).
Column chromatography on silica gel (eluting with 3% EtOAc/hexanes)
(E)-4-(2-(t-Butyldimethylsilyloxy)phenyl)but-2-enal (Table 7,
entry 3). The representative procedure above was followed using t-butyl
(2-allylphenoxy)dimethylsilane44 (20) (124 mg, 0.50 mmol), acrolein (84
mg, 1.50 mmol) and Grubbs-2 catalyst (8.5 mg, 0.01 mmol). Column
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The Journal of Organic Chemistry
ARTICLE
chromatography on silica gel (eluting with 3% EtOAc/hexanes) afforded the
product as a colorless oil (97 mg, 70%). IR (neat): 3365, 3064, 3035, 2932,
2895, 2859, 2810, 2739, 1686, 1635, 1599, 1582, 1491, 1471, 1452, 1413,
1390, 1361, 1254, 1183, 1128, 1095, 1043, 1008, 978, 927, 838, 782, 757, 734,
704 cmꢀ1.1H NMR (400 MHz, CDCl3):δ9.53(d,J=7.6Hz,1H),7.16(td,
J = 7.6, 1.6 Hz, 1H), 7.11 (dd, J = 7.6, 1.6 Hz, 1H), 6.99 (dt, J = 15.6, 6.4 Hz,
1H), 6.93 (td, J = 7.6, 1.6 Hz, 1H), 6.84 (dd, J = 7.6, 1.6 Hz, 1H), 6.07 (ddt,
J = 15.6, 7.6, 1.6 Hz, 1H), 3.64 (dd, J = 6.4, 1.6 Hz, 2H), 1.00 (s, 9H), 0.26 (s,
6H). 13C NMR (100 MHz, CDCl3): δ 194.1, 157.1, 153.7, 133.5, 130.7,
128.4, 127.9, 121.6, 118.7, 34.0, 26.0, 18.4, ꢀ3.9. ESIꢀMS m/z: 315 (M þ
J = 7.6, 4.8 Hz, 1H), 2.97ꢀ2.89 (m, 1H), 2.83ꢀ2.76 (m, 1H), 2.54 (q,
J = 7.2 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H).21a
t-Butyldimethyl(11-methyldodec-10-en-1-yloxy)silane.
TBSCl (0.29 g, 1.92 mmol) and imidazole (0.17 g, 2.50 mmol) were
dissolved in dry CH2Cl2 (6 mL) in a round-bottom flask. 11-methyldo-
dec-10-en-1-ol46 (0.25 g, 1.26 mmol) was then added dropwise and the
resulting solution was allowed to warm to rt and left to stir for another
12 h, after which it was quenched with water. The aqueous layer was
extracted with CH2Cl2 and the organic extracts were washed with water
and dried over Na2SO4. The volatiles were removed in vacuo to afford
the crude product which was subsequently purified by column chroma-
tography on silica gel (eluting with 5% EtOAc/hexanes) to yield the
product (0.38 g, 96%) as a colorless oil. IR (neat): 2851, 1464, 1386,
1361, 1253, 1100, 1007, 984, 938, 840, 775 cmꢀ1. 1H NMR (400 MHz,
CDCl3): δ 5.12 (t, J = 7.2 Hz, 1H), 3.60 (t, J = 6.8 Hz, 2H), 1.96 (q, J =
6.8 Hz, 2H), 1.69 (s, 3H), 1.61 (s, 3H), 1.51 (quint, J = 6.8 Hz, 2H), 1.28
(br s, 12H), 0.91 (s, 9H), 0.06 (s, 6H). 13C NMR (100 MHz, CDCl3): δ
131.3, 125.2, 63.6, 33.1, 30.1, 29.9, 29.8, 29.7, 29.6, 29.6, 28.3, 26.2, 26.0,
18.6, 17.9, ꢀ5.0. EI-MS m/z (%): 255 (M ꢀ C4H9, 70), 75 (100).
HRMS (EI) calcd for C15H31OSi [M ꢀ C4H9]þ = 255.2144, found
255.2146.
(R)-11-Methyldodec-10-en-1-yl 2-(benzyloxycarbonyla-
mino)-3-phenylpropanoate. To a 50 mL round-bottomed-flask
containing a stir bar, was added CH2Cl2 (12 mL) which was cooled to
0 °C. N-carbobenzyloxy-L-phenylalanine (0.45 g, 1.51 mmol), 11-
methyldodec-10-en-1-ol46 (0.25 g, 1.26 mmol), 1-(3-dimethylaminop-
ropyl)-3-ethylcarbodiimide hydrochloride (0.33 g, 2.14 mmol), and
4-dimethylaminopyridine (0.015 g, 0.13 mmol) were then added. The
resulting solution was allowed to warm to rt over a 20 h period, after
which it was quenched by the addition of H2O. The reaction mixture was
extracted with CH2Cl2, and the organic layer washed with aqueous
NaHCO3, water and dried over anhydrous Na2SO4. Removal of the
volatiles in vacuo afforded the crude residue, which was purified by
column chromatography on silica gel (eluting with 10% EtOAc/
hexanes) to yield the product (0.58 g, 96%) as a colorless liquid. IR
(neat): 3348, 3087, 3063, 3031, 2925, 2854, 1720, 1604, 1499, 1455,
1395, 1376, 1346, 1254, 1208, 1081, 1057, 1029 cmꢀ1. 1H NMR (400
MHz, CDCl3): δ 7.39ꢀ7.22 (m, 8H), 7.11 (dd, J = 7.6, 1.6 Hz, 2H), 5.25
(d, J = 8.4 Hz, 1H), 5.14ꢀ5.07 (m, 3H), 4.66 (dt, J = 8.4, 5.6 Hz, 1H),
4.15ꢀ4.05 (m, 2H), 3.14 (dd, J = 13.6, 5.6 Hz, 1H), 3.10 (dd, J = 13.6,
5.6 Hz, 1H), 1.99ꢀ1.95 (m, 2H), 1.70 (s, 3H), 1.61 (s, 3H), 1.60ꢀ1.58
(m, 2H), 1.28 (br s, 12H). 13C NMR (100 MHz, CDCl3): δ 171.6,
155.7, 136.4, 135.9, 131.2, 129.4, 128.61, 128.58, 128.2, 128.1, 127.1,
125.0, 67.0, 65.8, 55.0, 38.5, 30.1, 29.68, 29.65, 29.5, 29.4, 28.6, 28.2,
26.0, 25.9, 17.9. ESIꢀMS m/z: 502 (M þ Na). HRESIꢀMS calcd for
C30H41NO4Na [M þ Na]þ = 502.2933, found 502.2909.
K), 299 (M þ Na). HRESIꢀMS calcd for C16H24O2SiNa [M þ Na]þ
=
299.1443, found 299.1445.
(E)-Diethyl (3-(2-(t-Butyldimethylsilyloxy)phenyl)prop-1-
en-1-yl)phosphonate (Table 7, entry 4). The representative
procedure above was followed using t-butyl(2-allylphenoxy)dimethy-
lsilane44 (20) (124 mg, 0.50 mmol), diethyl vinylphosphonate (164 mg,
1.00 mmol) and Grubbs-2 catalyst (17 mg, 0.02 mmol). Column chroma-
tography on silica gel (eluting with 25% EtOAc/hexanes) afforded the
product as a colorless oil (125 mg, 65%). IR (neat): 3063, 2931, 2900, 2859,
1631, 1599, 1583, 1493, 1472, 1453, 1391, 1362, 1250, 1164, 1104, 1023,
964 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.12 (td, J = 7.6, 1.6 Hz, 1H),
7.08 (dd, J = 7.6, 1.6 Hz, 1H), 6.94 (dt, J = 17.2, 6.0 Hz, 1H), 6.92ꢀ6.85 (m,
1H), 6.80 (d, J = 8.0 Hz, 1H), 5.59ꢀ5.49 (m, 1H), 4.08ꢀ3.99 (m, 4H),
3.53ꢀ3.51 (m, 2H), 1.29 (t, J = 7.2 Hz, 6H), 0.99 (s, 9H), 0.22 (s, 6H). 13C
NMR (100 MHz, CDCl3): δ 153.7, 151.83, 151.78, 130.8, 128.2, 128.0,
121.4, 118.6, 116.7, 61.73, 61.67, 35.1, 34.9, 25.9, 18.4, 16.54, 16.47, ꢀ4.0.
ESIꢀMS m/z: 407 (M þ Na), 385 (M þ H). HRESIꢀMS calcd for
C19H33O4SiPNa [M þ Na]þ = 407.1783, found 407.1783.
1-Tosyl-2,3,4,7-tetrahydro-1H-azepine (Table 8). The repre-
sentative procedure above was followed using N-allyl-4-methyl-N-(pent-
4-en-1-yl)benzenesulfonamide45 (56 mg, 0.20 mmol) and Grubbs-2
catalyst (3.4 mg, 0.004 mmol). Column chromatography on silica gel
(eluting with 4% EtOAc/hexanes) afforded the product as a colorless oil
(46 mg, 92%). 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.0 Hz, 2H),
7.28 (d, J = 8.0 Hz, 2H), 5.79ꢀ5.74 (m, 1H), 5.67ꢀ5.62 (m, 1H),
3.83ꢀ3.82 (m, 2H), 3.38 (t, J = 6.0 Hz, 2H), 2.42 (s, 3H), 2.20ꢀ2.15 (m,
2H), 1.82ꢀ1.76 (m, 2H).45
(E)-t-Butyl 6-(1-Phenyl-1H-tetrazol-5-ylthio)-2-hexenoate
(Table 12, entry 1). The representative procedure above was followed
using 5-(pent-4-en-1-ylthio)-1-phenyl-1H-tetrazole16a (123 mg, 0.50
mmol), t-butyl acrylate (217 μL, 1.50 mmol), CuI (7.2 mg, 0.038
mmol) and Grubbs-2 catalyst (21.2 mg, 0.025 mmol). Column chro-
matography on silica gel (eluting with 10% EtOAc/hexanes) afforded
the product as colorless oil (138 mg, 80%). 1H NMR (400 MHz,
CDCl3): δ 7.59ꢀ7.55 (m, 5H), 6.82 (dt, J = 15.6, 7.2 Hz, 1H), 5.79 (dt, J
= 15.6, 1.6 Hz, 1H), 3.41 (t, J = 7.2 Hz, 2H), 2.36 (qd, J = 7.2, 1.6 Hz,
2H), 2.03 (quintet, J = 7.2 Hz, 2H), 1.48 (s, 9H).16a
5-((11-Methyldodec-10-en-1-yl)thio)-1-phenyl-1H-tetra-
zole. A solution of DCAD (0.51 g, 1.39 mmol) in CH2Cl2 (10 mL) was
slowly added at rt via cannula to a solution of PPh3 (0.37 g, 1.39 mmol),
1-phenyl-1H-tetrazole-5-thiol (0.25 g, 1.39 mmol) and the 11-methyl-
dodec-10-en-1-ol46 (0.25 g, 1.26 mmol) in CH2Cl2 (5 mL). The
resulting cloudy solution was stirred at rt for 12 h. Filtration of the
reaction mixture was then carried out to afford reduced DCAD as a white
powder. The filtrate was removed in vacuo to afford the crude product,
which was purified by column chromatography on silica gel (eluting with
10% EtOAc/hexanes) to yield the product (0.23 g, 51%) as a colorless
liquid. IR (neat): 2925, 2853, 1598, 1499, 1462, 1411, 1386, 1278, 1243,
1087, 1074, 1053, 1014, 979, 912, 761, 694 cmꢀ1; 1H NMR (400 MHz,
CDCl3): 7.60ꢀ7.52 (m, 5H), 5.13-5.09 (m, 1H), 3.39 (t, J = 7.2 Hz,
2H), 1.97-1.92 (m, 2H), 1.81 (quint, J = 7.2 Hz, 2H), 1.68 (s, 3H), 1.59
(s, 3H), 1.44 (quint, J = 7.2 Hz, 2H), 1.31ꢀ1.27 (m, 10H); 13C NMR
(100 MHz, CDCl3): 154.7, 133.9, 131.3, 130.2, 129.9, 125.0, 124.0,
33.5, 30.0, 29.62, 29.59, 29.4, 29.22, 29.19, 28.8, 28.2, 25.9, 17.8; ESI-MS
(E)-t-Butyl 3-(2,4-Dimethylphenyl)-2-propenoate (Table 12,
entry 3). The representative procedure above was followed using 2,4-
dimethylstyrene (74 μL, 0.50 mmol), t-butyl acrylate (145 μL, 1.00 mmol),
CuI (2.9 mg, 0.015 mmol) and Grubbs second-generation catalyst (8.5 mg,
0.010 mmol). Column chromatography on silica gel (eluting with 2%
EtOAc/hexanes) afforded the product as colorless oil (94 mg, 81%). 1H
NMR (400 MHz, CDCl3): δ 7.88 (d, J = 15.6 Hz, 1H), 7.46 (d, J = 8.4 Hz,
1H), 7.02ꢀ7.00 (m, 2H), 6.28 (d, J = 15.6 Hz, 1H), 2.40 (s, 3H), 2.33 (s,
3H), 1.55 (s, 9H).16a
(E)-7-(4-Nitrophenoxy)-7-phenylhept-4-en-3-one (26). The
representative procedure above was followed using 1-nitro-4-(1-phenyl-
but-3-en-1-yloxy)benzene (25)21a (135 mg, 0.50 mmol), ethyl vinyl ketone
(126 mg, 1.50 mmol) and Grubbs-2 catalyst (8.5 mg, 0.01 mmol). Column
chromatography on silica gel (eluting with 15% EtOAc/hexanes) afforded
the product as a pale yellow liquid (122 mg, 75%). 1H NMR (400 MHz,
CDCl3): δ 8.07 (d, J = 9.2 Hz, 2H), 7.38ꢀ7.27 (m, 5H), 6.89 (d, J = 9.2 Hz,
2H), 6.83 (dt, J = 16.0, 7.2 Hz, 1H), 6.17 (d, J = 16.0 Hz, 1H), 5.34 (dd,
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The Journal of Organic Chemistry
ARTICLE
m/z: 381 (M þ Na), 359 (M þ H); HRESIMS calcd for C20H30N4SNa
[M þ Na]þ = 381.2089, found 381.2072.
’ REFERENCES
(1) (a) Dwars, T.; Paetzold, E.; Oehme, G. Angew. Chem., Int. Ed.
2005, 44, 7174–7199.(b) Khan, M. N. Micellar Catalysis; CRC Press:
Boca Raton, FL, 2006.
2-(Dec-9-en-1-yl)-1,3-dioxolane (22). A round-bottom flask,
equipped with a stirrer bar and a DeanꢀStark apparatus, was charged
with Undec-10-enal (1.34 g, 8.00 mmol), ethylene glycol (2.7 mL, 48.00
mmol), pTSA.H2O (0.06 g, 0.32 mmol), and benzene (15 mL) and the
reaction mixture heated at reflux for 8 h. After usual workup the pure
acetal (1.52 g, 90%) was obtained by distillation in vacuo as a colorless oil.
IR (neat): 3076, 2976, 2926, 2855, 1640, 1465, 1438, 1411, 1361, 1212,
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1142, 1037, 993, 944, 910 cmꢀ1 1H NMR (400 MHz, CDCl3):
.
δ 5.87ꢀ5.76 (m, 1H), 5.02ꢀ4.92 (m, 2H), 4.85 (t, J = 4.8 Hz, 1H),
4.01ꢀ3.93 (m, 2H), 3.90ꢀ3.81 (m, 2H), 2.04 (q, J = 7.2 Hz, 2H),
1.68ꢀ1.63 (m, 2H), 1.45ꢀ1.29 (m, 12H). 13C NMR (100 MHz,
CDCl3): δ 139.3, 114.2, 104.8, 65.0, 34.1, 34.0, 29.8, 29.7, 29.6, 29.3,
29.1, 24.3. EI-MS m/z (%): 211 (M ꢀ H, 2), 73 (100). HRMS (EI) calcd
for C13H23O2 [M ꢀ H]þ = 211.1698, found 211.1693.
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mg, 0.10 mmol) and Grubbs-2 catalyst (1.7 mg, 0.002 mmol) were both
added into a Teflon-coated-stir-bar-containing Biotage 5 mL microwave
reactor vial at rt, and sealed with a septum. An aliquot of PTS/H2O
(1.0 mL; 2.5% PTS by weight) was added, via syringe, and the resulting
solution was allowed to stir at rt for 2 h. Et2O (3 mL) was then added to
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allowed to separate and the upper (Et2O) layer was removed by pipet.
The aqueous layer was successively washed with Et2O (3 ꢁ 3 mL). The
combined Et2O extracts layers were evaporated in vacuo to afford the
crude product, which was examined by 400 MHz 1H NMR spectroscopy
to reveal complete conversion of diene and clean formation of the
corresponding cyclized product. 1H NMR (400 MHz, CDCl3): δ 7.72
(d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 5.65 (t, J = 4.4 Hz, 2H), 4.11
(t, J = 4.4 Hz, 2H), 2.42 (s, 3H).47 For the second run, the diene (25 mg,
0.10 mmol) and Grubbs-2 catalyst (1.7 mg, 0.002 mmol) were both
added again to the same reaction vessel and stirred at rt for another 2 h.
The workup was conducted in exactly the same way as described for the
first cycle. This reaction was repeated eight more times, each using the
above diene (25 mg, 0.10 mmol) and Grubbs-2 catalyst (1.7 mg, 0.002
mmol).
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’ ASSOCIATED CONTENT
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S
Supporting Information. Synthesis of starting materials
b
and copies of 1H and 13C NMR spectra of all new compounds
and copies of H NMR spectra of all known compounds. This
material is available free of charge via the Internet at http://pubs.
1
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: lipshutz@chem.ucsb.edu.
’ ACKNOWLEDGMENT
Financial support provided by the NIH (GM 86485) is
warmly acknowledged. We also thank Dr. Thomas J. Colacot
(Johnson Matthey), Dr. Richard Pederson (Materia) and Dr.
Oliver Briel (Umicore) for supplying the palladium, Grubbs, and
Neolyst catalysts, respectively, and to Zannan Pharma Ltd. for
catalysts RC-303 and RC-304, used in this study. We are also
grateful to the Materials Research Lab Central Facilities at UCSB,
supported by the MRSEC Program of the National Science
Foundation (DMR05-20415), for cryo-TEM experiments.
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The Journal of Organic Chemistry
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