Catalytic Nucleophilic Allylation Driven by the Water-Gas Shift Reaction

Article abstract of DOI:10.1021/acs.joc.7b02658

The ruthenium-catalyzed allylation of aldehydes with allylic pro-nucleophiles has been demonstrated to be an efficient means to form carbon-carbon bonds under mild conditions. The evolution of this reaction from the initial serendipitous discovery to its general synthetic scope is detailed, highlighting the roles of water, CO, and amine in the generation of a more complete catalytic cycle. The use of unsymmetrical allylic pro-nucleophiles was shown to give preferential product formation through the modulation of reaction conditions. Both (E)-cinnamyl acetate and vinyl oxirane were efficiently used to form the anti-branched products (up to >20:1 anti/syn) and E-linear products (up to >20:1 E/Z) in high selectivity with aromatic, α,β-unsaturated, and aliphatic aldehydes, respectively. Attempts to render the reaction enantioselective are highlighted and include enantioenrichment of up to 75:25 for benzaldehyde.

Full text of DOI:10.1021/acs.joc.7b02658

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Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Catalytic Nucleophilic Allylation Driven by the Water−Gas Shift
Reaction
Scott E. Denmark,* Zachery D. Matesich, Son T. Nguyen,† and Selena Milicevic Sephton†
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States
S
* Supporting Information
ABSTRACT: The ruthenium-catalyzed allylation of aldehydes with allylic pro-
nucleophiles has been demonstrated to be an efficient means to form carbon−
carbon bonds under mild conditions. The evolution of this reaction from the
initial serendipitous discovery to its general synthetic scope is detailed,
highlighting the roles of water, CO, and amine in the generation of a more
complete catalytic cycle. The use of unsymmetrical allylic pro-nucleophiles was
shown to give preferential product formation through the modulation of reaction
conditions. Both (E)-cinnamyl acetate and vinyl oxirane were efficiently used to
form the anti-branched products (up to >20:1 anti/syn) and E-linear products (up
to >20:1 E/Z) in high selectivity with aromatic, α,β-unsaturated, and aliphatic aldehydes, respectively. Attempts to render the
reaction enantioselective are highlighted and include enantioenrichment of up to 75:25 for benzaldehyde.
process for producing hydrocarbons and the production of
methanol from synthesis gas are industrial applications of the
WGSR.15,16
INTRODUCTION
■
The quintessential transformation in organic synthesis is the
formation of a carbon−carbon bond. One of the more
commonly applied methods to generate this bond, which has
been extensively studied, is the allylation of carbonyl
compounds due to the impressive versatility and capacity to
generate two or more new stereogenic centers with high levels
of stereocontrol.1−4 The major drawback with many of the
current allylation methods is the requirement of a preformed
allylmetal species, and thus, the production of significant
amounts of metal waste and a lack of atom-economy. In
response to this shortcoming, a major focus of research in
recent years has been to develop reactions that are catalytic in
metal.5 One such method is the ruthenium-catalyzed
nucleophilic allylation, recently developed by these laboratories,
which uses carbon monoxide as the stoichiometric reductant
and only produces AcOH and CO2 as the stoichiometric
byproducts.6 The process by which this reaction uses CO as the
terminal reductant is known as the water−gas shift reaction
(WGSR), a transformation of long-standing industrial relevance
that converts a mixture of carbon monoxide and water into
hydrogen and carbon dioxide (eq 1).7−12
More interestingly from the perspective of organic synthesis
is the application of the WGSR to drive reductive processes.
For these reactions, the reduction potential of the WGSR is
employed to either reduce organic compounds or aid in the
turnover of a catalytic cycle. These reactions include hydro-
formylations, nitro reductions, reductive aminations, and
hydrogenation of carbonyls and alkenes.17 One of the chief
advantages of using the WGSR in organic synthesis is the
avoidance of other stoichiometric reducing agents as are
typically employed in these reductive processes. This objective
is in line with the first of the “Grand Challenges” identified by
the NRC report “Sustainability in the Chemical Industry” which
calls for the reduction of waste and the identification of
environmentally benign strategies (“it is better to prevent waste
than to clean it up after it is formed”).18 The ruthenium-catalyzed
allylation satisfies this criterion through the use of CO as the
terminal reductant in place of other stoichiometric reducing
agents and because of the negligible impact of the waste that it
produces.
CO + H2O ⇌ CO2 + H2 ΔGo = −6.8 kcal/mol
(1)
BACKGROUND
■
General Catalytic Allylation Reactions Avoiding the
Use of Superstoichiometric Amounts of Metals. An ideal
carbonyl allylation reaction uses allyl sources that do not
require the stoichiometric use of metal reagents. Substoichio-
metric amounts of metal catalysts or Lewis acids can perform
many of the same reactions as the allylmetals and generate less
metal waste. As some of these reactions do not employ metals
Industrially, this reaction is used to refine synthesis gas (CO
+ H2), as the ratio of CO to H2 can vary depending upon on
the method of production.13 As industrial processes require
specific percentages of each gas for high efficiency, the WGSR
can adjust this ratio to the optimal value or remove CO
altogether by converting it to CO2. One specific application for
the WGSR is that of the Haber−Bosch process for ammonia
synthesis,14 in which CO is removed from synthesis gas,
producing high purity H2 to avoid poisoning the Fe-based
ammonia synthesis catalyst. Furthermore, the Fischer−Tropsch
Received: October 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b02658
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as the reductant for the catalytic cycle, other means of allowing
for catalyst turnover must be employed.
alcohol is not formed. The formation of a ruthenium carbonyl
species is further confirmed by the fact that the reaction of an
independently synthesized ruthenium π-allyl complex with
benzaldehyde in a stoichiometric reaction gives the intended
homoallylic alcohol product in 66% yield by GC (Scheme 2).32
As the use of a CO atmosphere is not required in this
stoichiometric reaction, this suggests that CO is required only
to form the initial ruthenium metal complex or to serve to
stabilize the ruthenium carbonyl species in the catalytic
reaction.
For example, Krische and co-workers have developed a
highly efficient and selective catalytic allylation of aldehydes
that employs an iridium-based, transfer hydrogenation catalyst
to produce homoallylic alcohols in high yield and enantiose-
lectivity starting from allylic acetates, dienes, or allenes.19
Through the use of these iridium catalysts, the formation of
enantioenriched products containing quaternary stereocen-
ters,20 the hydroxylmethylation of allylic acetates by enantio-
topic π-facial discrimination,21 and asymmetric allylation of
glycidols while avoiding the common match-mismatch
concerns22 can be efficiently conducted. Also highlighted is
the precise chemoselectivity that this method entails as
demonstrated through the enantioselective allylation at the
site of a single alcohol in a polyol without the need for
protecting groups.23 Progress has also been made by employing
other metal catalysts in this method, specifically ruthenium,
while maintaining the reactivity profile of the iridium catalysts
in the allylation reactions of allenes and dienes with
aldehydes.24−27 In an impressive illustration of the utility of
the transfer hydrogenation methodology, Krische synthesized
the natural product swinholide A in only 15 steps (longest
linear sequence), as compared to previous syntheses which
required 27−35 steps.28 This accomplishment is possible
because of the greatly increased “redox-economy” that is
allowed through the use of transfer hydrogenation as many
traditional redox and C−C bond formations steps can be
combined into a single step.
Scheme 2
According to Kondo, the superstoichiometric amount of
Et3N is required as it is the stoichiometric reductant. To
provide evidence for this hypothesis, the authors employed
deuterium-labeled Et3N, benzaldehyde, and solvent in a
stoichiometric reaction with a π-allyl ruthenium complex to
determine the source of hydrogen in the reaction (Scheme 3).32
Deuterium is incorporated into the homoallylic alcohol product
only when deuterated Et3N is employed. This result therefore
identifies Et3N as the reductant for the catalytic reaction and
the source of the necessary hydrogen.
Scheme 3
Another method in which the formal allylation of carbonyl
compounds can be achieved, with high atom economy and
without a stoichiometric metal additive, is the carbonyl ene
reaction. This reaction has found success in the synthesis of
highly enantioenriched products via a six-electron pericyclic
process between an olefin bearing an allylic hydrogen and an
enophile, which is typically an electron-deficient multiple
bond.26,29 Alper and co-workers have shown that a rhodium-
catalyzed allylation reaction is also possible through the use of
an ionic diamine carbonyl rhodium complex and a stoichio-
metric amount of Cs2CO3.30
Catalytic Nucleophilic Allylation of Aldehydes Em-
ploying CO as the Reductant. An early report form
Watanabe and co-workers described the formation of
homoallylic alcohols under catalysis by ruthenium using a
trialkylamine as the reducing agent. This reaction employs 140
psi of CO in combination with a superstoichiometric amount of
aldehyde with respect to allyl acetate to produce homoallylic
alcohols in good to moderate yields (Scheme 1).31
On the basis of these experimental observations, Kondo
proposed a catalytic cycle (Scheme 4). After oxidative addition
of allyl acetate to the ruthenium(0) metal center i and the
formation of π-allyl complex ii, an insertion of an aldehyde into
this complex forms species iii. Coordination of Et3N to iii and
subsequent β-hydride elimination generates the
hydridoruthenium(II) complex iv which can then undergo
reductive elimination to release the homoallylic alcohol
product, regenerating the ruthenium(0) catalyst i. This catalytic
cycle thereby forms the homoallylic alcohol product with only
AcOH and an enamine as the stoichiometric byproducts.
The requirement for high temperatures may limit the types
of functional groups that can be used in this reaction.
Furthermore, the superstoichiometric use of aldehyde (which
is often the precious synthetic material) is undesirable. Despite
these deficiencies, this reaction was believed to be a good
starting point because, at the onset of this project, very few
reports mentioned the nucleophilic activity of π-allyl ruthenium
complexes.33 Considering the uniqueness of this reactivity and
the potential for applications in carbonyl allylation, this process
Scheme 1
In the case of RuCl3, a ruthenium carbonyl species is
proposed to be the active catalyst. When RuCl3 is employed in
the reaction under a CO atmosphere, FT-IR absorptions
indicative of a carbonyl species are observed. Alternatively,
when RuCl3 is employed under an Ar atmosphere, the same
FT-IR absorptions are not observed and the homoallylic
B
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Scheme 4
was chosen for investigation. Furthermore, at the time it was
one of only a few carbonyl allylation reactions that were truly
catalytic in metal.
introduced to the reaction upon opening the vessel to air,
leading to a significant increase in conversion.
To identify the origin of this effect, a battery of experiments
was performed in which controlled amounts of oxygen and/or
water were blended into the reaction mixtures (Table 2).
Dioxane was chosen as the reaction solvent and for practical
purposes; from here on, benzaldehyde was used as the limiting
reagent and allyl acetate was used in slight excess (1.1−1.2
equiv). Without water or oxygen, product yield was low, and
very little of 2 was consumed (entry 1). As soon as water was
introduced into the reaction, the yield of 3a sharply increased
(entries 2 and 3), but as soon as the CO pressure was lowered
to 120 psi, a small negative impact was observed with respect to
yield (entry 4). The inclusion of oxygen into the reaction gave a
corresponding increased 3a yield but also resulted in a
significant propene formation (a product of unproductive
consumption of 2) (entries 5 and 6). The best conditions
seemed to be 120/20 psi of P(CO)/P(oxygen) and 0.3 equiv of
water and were used in the next experiments.
RESULTS
■
Development of the Ruthenium-Catalyzed Nucleo-
philic Allylation Reaction. Initial Reaction Discovery. To
orient the efforts in seeking a more efficient ruthenium-
catalyzed allylation, reactions at lower temperature, lower
catalyst loading, and in various solvents were executed (Table
1). Because of the high pressure of CO required, a six-well
autoclave was employed to perform the optimization. In each of
these experiments, a low product yield was observed.
Table 1. Initial Survey of Solvents
Next, the stoichiometry of Et3N was systematically varied
(Table 3). Interestingly, the conversions were the same when
the stoichiometry of Et3N was varied between 10 and 150 mol
a
entry
solvent
3a yield (%)
1
2
3
4
5
6
cyclohexane
toluene
8
10
21
22
12
31
dioxane
THF
Table 2. Effects of Water and Oxygen
acetonitrile
DMSO
a
1
Determined by H NMR analysis using hexamethylbenzene as the
internal standard.
a
a
a
CO
entry (psi)
O2
(psi)
H2O
(equiv)
1a recovery 2 recovery
3a yield
(%)
To answer the question whether the conversion was low
because of slow catalyst turnover or because the catalyst was
rendered inactive after a certain period, reaction progress was
monitored over time. Interestingly, it was discovered that in
some cases the reaction proceeded faster after the reaction
vessel was cooled and opened in air for sampling (Figure 1). As
demonstrated for dioxane, after first opening the autoclave
around 24 h, the conversion of 1a was roughly 20% but after
the vessel was resealed and reheated, the conversion at 36 h was
nearly 100%. It appeared as though some variable was
(%)
(%)
1
2
3
4
5
6
140
140
140
120
120
120
0
0
0.0
0.3
1.5
0.3
0.3
0.6
83
66
62
75
43
33
78
71
64
79
44
6
17
32
37
23
54
49
0
0
b
b
20
20
a
1
Determined by H NMR analysis using hexamethylbenzene as the
internal standard. In these reactions, propene was also observed.
b
C
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Figure 1. Reaction conversion over time.
% (entries 2−5). However, in the absence of an amine, no
reaction occurred (entry 1).
likely due to faster unproductive consumption of 2 as
significant amounts of propene were observed (entry 5).
These results marked a critical departure from the original
conditions in which Et3N was believed to be the stoichiometric
reducing reagent. In this new system, CO must be the
stoichiometric reducing reagent which in combination with
water provides the necessary hydrogen atoms and allows for
turnover of the catalyst (WGSR).
Table 3. Effects of Et3N Stoichiometry
a
a
Table 4. Dual Effects of Water and Et3N
entry
Et3N (mol %)
2 recovery (%)
3a yield (%)
1
2
3
4
5
0
10
110
64
66
67
0
42
43
44
44
50
100
150
67
a
1
H2O
(equiv)
Determined by H NMR analysis using hexamethylbenzene as the
a
a
entry CO (psi) O2 (psi)
2 recovery (%) 3a yield (%)
internal standard.
1
2
3
4
5
120
120
120
140
140
20
20
20
0
0.6
1.5
44
24
30
0
70
79
75
95
53
It was striking to see that only 10 mol % of Et3N was needed
under the new conditions to provide the 42−44% conversions.
Obviously, at such a low stoichiometry Et3N could not account
for the amount of hydrogen that is incorporated into the
3.0
1.5
b
0
15.0
0
a
1
Determined by H NMR analysis using hexamethylbenzene as the
internal standard. A significant amount of propene was observed in
1
b
product and acetic acid byproduct. The H NMR spectra of
these reaction mixtures (without workup) did not show any
new signals besides those of the product, acetic acid, Et3N (as
the Et3NH+OAc− salt), and propene (in trace amounts),
indicating that solvent is not the hydrogen source. Thus, water
seemed to be the only possible hydrogen source in these new
conditions.
To prove support for that hypothesis, more water was added
into the reaction mixture while keeping Et3N at low
concentrations (Table 4). With a reduced amount of Et3N,
the reaction became more water tolerant (Table 2, entry 6 vs
Table 4, entry 1 and Table 2, entry 3 vs Table 4, entry 4). The
reaction reached 95% conversion at 70 °C in 24 h when 1.5
equiv of water was used along with 10 mol % of Et3N and
without addition of oxygen (entry 4). Increasing the amount of
water to 15 equiv gave a lower yield under similar conditions,
this reaction.
To fully elucidate the role of the amine in the reaction, a
more precise evaluation of Et3N loadings was undertaken
(Table 5). Again at low Et3N loading, little to no product was
generated (entries 1−6). However, at around 4.0 mol % of
Et3N, a dramatic change was observed in which the yield of 3a
jumped from 2% to 85% (entries 6 and 7). Further increases of
amine loading resulted in the nearly complete consumption of
1a and a slight decrease in the yield of 3a at the highest amine
loading (entries 8−12). These results indicate that Et3N has a
very specific role in the proper functioning of this reaction at a
value of about 1.5 times the ruthenium catalyst loading. This
survey was also conducted with another ruthenium source,
D
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Table 5. Survey of Amine Loadings with RuCl3
Table 6. Effect of Et3N Stoichiometry, Ruthenium Catalyst,
and Soluble Halide
a
a
entry
Et3N (mol %)
1a recovery (%)
3a yield (%)
a
Et3N
(mol %)
additive
(mol %)
3a yield
(%)
1
0
94
91
92
93
97
98
18
6
0
<1
<1
2
entry
Ru catalyst
2
1.0
2.0
2.5
3.0
3.5
4.0
4.5
5.0
10
1
2
3
4
5
6
RuCl3·xH2O
RuCl3·xH2O
0
10
0
0
95
12
93
43
70
44
81
82
15
78
80
75
65
49
68
43
28
3
4
allylRu(CO)3Br
allylRu(CO)3Br
allylRu(CO)3OAc
allylRu(CO)3OAc
allylRu(CO)3OAc
allylRu(CO)3OAc
allylRu(CO)3OAc
Ru3(CO)12
5
3
10
0
6
2
7
85
94
79
80
79
10
0
8
b
7
9
5
b
8
b
0
TBACl (3)
TBACl (3)
10
11
1
9
10
10
10
0
20
1
b
10
a
b
Determined by GC analysis using biphenyl as the internal standard.
11
Ru3(CO)12
TBACl (3)
TBACl (10)
TBACl (20)
TBACl (50)
TBAOAc (10)
TBAI (10)
LiCl (3)
b
12
Ru3(CO)12
b
[RuCl2(p-cymene)]2 (see Table S6), and again, a clear turnover
point was observed; this time between 2.0 and 2.5 mol % of
Et3N, illustrating that there is possibly a connection between
the oxidation state of the ruthenium and the required loading of
amine.
To gain additional information into the role of amine, a
stoichiometric reaction between RuCl3·xH2O and dicyclohexyl-
amine was run (Scheme 5). Dicyclohexylamine was chosen to
allow for identification of any oxidation products. Indeed, 52%
of cyclohexanone was observed in the reaction analysis by GC−
MS (single point calibration), a product that would arise from
hydrolysis of the oxidized amine.
13
Ru3(CO)12
0
b
14
Ru3(CO)12
0
b
15
Ru3(CO)12
0
b
16
Ru3(CO)12
0
b
17
Ru3(CO)12
0
b
18
Ru3(CO)12
0
LiOAc (3)
a
1
Determined by H NMR analysis using hexamethylbenzene as the
b
internal standard. These reactions were performed under 30 psi of
CO.
chloride (entries 12, 15, and 16). The effect of inorganic salts
was significantly less than their corresponding ammonium salts,
likely owing to the lower solubility of lithium salts (entries 11,
16, and 17).
Scheme 5
Further Reaction Optimization. As the standard reaction
conditions (1.1 equiv of 2, 1.5 equiv of H2O, 10 mol % of Et3N,
70 °C, 30 psi CO) were now established, it was prudent to
further explore the components of the reaction. The effect of
catalyst loading was briefly evaluated (Table 7). At loadings as
low as 1 mol %, the reaction still showed relatively good
conversion (entry 1), while at 2 or 3 mol % all of the starting
material was converted after 24 h (entries 2 and 3).
As different CO pressures have been used in the prior
experiments, a systematic study of CO pressures was warranted
to determine an optimum value. Furthermore, this is a
significant variable as lowering this parameter would allow for
reactions to be run using more common reaction assemblies.
To further explore the effect of the ruthenium source on the
reaction efficiency, a ruthenium catalyst and additive survey was
conducted (Table 6). As was the case with RuCl3·xH2O,
addition of Et3N to reactions employing allylRu(CO)3Br and
allylRu(CO)3OAc significantly improved the conversions
(entries 1−6). The observation that reactions with RuCl3 and
allylRu(CO)3Br showed higher conversions than reactions with
allylRu(CO)3OAc (entries 2, 4, and 6) indicated a possible
halide affect. Indeed, when tetrabutylammonium chloride
(TBACl) was added to a reaction catalyzed by allylRu-
(CO)3OAc, the conversion improved from 44 to 81% even
in the absence of Et3N (entries 7 and 8). The addition of Et3N
had no further impact on the yield for allylRu(CO)3OAc with
TBACl (entry 9). A significant improvement in conversion was
observed when TBACl was added to reaction containing
Ru3(CO)12, from 15 to 78% (entries 10 and 11). Further
increases to the TBACl loading actually had a negative effect on
overall conversion (entries 12−14). When other counteranions
were used with the tetraalkylammonium salt, lower conversions
were observed again demonstrating the unique effect of
Table 7. Effect of Catalyst Loading on Product Conversion
a
a
entry
RuCl3·xH2O (mol %)
2 recovery (%)
3a yield (%)
1
2
3
1
2
3
26
0
78
95
0
>99
a
1
Determined by H NMR analysis using hexamethylbenzene as the
internal standard.
E
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Pressures of CO ranging from 15 to 200 psi were therefore next
examined (Table 8). The reaction could still proceed at
pressures as low as 15 psi of CO, but would require longer
reaction time for full aldehyde conversion (entry 1). At CO
pressures of 30 psi and above, conversions did not change
significantly, indicating that saturation of the solvent by CO
might have occurred (entries 2−6). This was a significant
advance because it demonstrates that the reaction can now be
easily adapted to glass reactors.
acetate leaving group (entries 1−3). The use of diallyl
carbonate is of particular interest as the byproducts would be
CO2 and allyl alcohol. This change would create less acidic
reaction conditions than that occurs with the stoichiometric
formation of AcOH with the use of allyl acetate. Interestingly,
whereas allyl chloride gave good conversion to the desired
product, under the same reaction conditions, allyl bromide
yielded only trace amounts of product (entries 4 and 5). Allyl
alcohol reacted sluggishly when it was employed, likely due to
the poor leaving group ability of the hydroxyl group (entry 6).
Table 8. Effect of CO Pressure on Product Conversion
Table 10. Comparison of Leaving Groups on the Allyl
Component
a
a
entry
CO (psi)
2 recovery (%)
3a yield (%)
a
1
2
3
4
5
6
15
30
56
0
48
95
entry
X
3a yield (%)
1
2
3
4
5
6
OAc
OBz
80
95
98
78
1
60
3
95
90
0
>99
98
OC(O)OAllyl
120
0
Cl
200
0
95
Br
a
1
Determined by H NMR analysis using hexamethylbenzene as the
internal standard.
OH
7
a
1
Determined by H NMR analysis using hexamethylbenzene as the
internal standard.
Next, the effect of temperature on the conversion of 1a was
examined (Table 9). As a note, for convenience in monitoring
reactions, when conducting the temperature survey, reactions
were run in normal round-bottom flasks under a balloon of CO.
At temperatures as low as 40 °C, the reaction was still shown to
be active, but sluggish (entries 1 and 2). Increasing the
temperature to 50 °C resulted in only slightly higher
conversion than 40 °C (entries 3 and 4). Even at 60 °C for
18 h, the reaction had only progressed to about 25% conversion
and required another 6 h to approach 45%. At the 18 h time
point, the reaction at 70 °C was already at 48% conversion
(entries 5−7). As such, 70 °C was proven to be an optimal
temperature for the reaction of 1a and 2.
In addition to dioxane, several other solvents were evaluated
for their usefulness in the reaction (Table 11). The reaction
proceeded with allyl acetate as the solvent, but no impact on
the rate of the reaction was observed (entry 1). Ketones and
esters could be used as the solvent, showing that the reaction is
highly chemoselective for aldehydes as no byproduct resulting
from the allylation of the solvent was observed (entries 2−4).
Whereas a coordinating ethereal solvent such as THF gave full
conversion to product (entry 5), the use of solvents such as
DMF or DMSO afforded lower yields (entries 6 and 7). The
use of primary alcohols such as methanol and ethanol afforded
lower conversion, owing to the formation of acetals as detected
by 1H NMR spectroscopy (entries 8 and 9). However, if a more
hindered alcohol such as i-PrOH was employed, no acetal
formation was detected and there was full conversion to
product (entry 10). In light of several solvent options, the use
of dioxane was maintained due to its more favorable chemical
properties for the reaction, such as boiling point and solubility
of the reagents.
The leaving group on the allyl component was next
investigated (Table 10). The use of a benzoyl or carbonate
leaving group had slightly higher efficiency than the parent
Table 9. Effect of Reaction Temperature on Product
Conversion
The requirement for an allyl pro-nucleophile was demon-
strated as the use of propargyl derivatives were completely
unreactive under several different reaction conditions. In each
case, only starting material was recovered.
a
a
Studies into the Catalytic Cycle. To gain a deeper
understanding as to what species may be forming during the
course of the reaction, 1-methylallyl acetate and crotyl acetate
were each employed under the reaction conditions (Scheme 6).
In both cases, the same α-isomer was isolated as the sole
product with similarly low syn/anti ratios. This result suggests
that crotyl and 1-methylallyl acetates form the same
intermediate, which in turn leads to the same product mixture.
Scope of the Ruthenium-Catalyzed Nucleophilic
Allylation Reaction. Prior Published Work. Using the
optimized conditions, a wide range of aldehydes were shown
entry
temp (°C)
time (h)
2 recovery (%)
3a yield (%)
1
2
3
4
5
6
7
40
40
50
50
60
60
70
18
24
18
24
18
24
18
95
90
89
77
83
64
56
10
20
13
26
25
43
48
a
1
Determined by H NMR analysis using hexamethylbenzene as the
internal standard.
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under the reactions conditions when reacted with a range of
aldehydes (Figure 3).
Table 11. Survey of Reaction Solvents
Catalytic Nucleophilic Allylation with (E)-Cinnamyl Ac-
etate. Reaction Optimization. The use of E-cinnamyl acetate
(E)-6 is of interest as it would form an unsymmetrical π-allyl
complex, leading to a number of isomeric products. Initial
evaluation of conditions involved a 40 h reaction at 85 °C with
two solvents and several ruthenium catalyst systems (Table 12).
Overall, the use of dioxane gave poor yield of product as only
the use of RuCl3·xH2O gave close to 50% conversion of 1a
(entry 1). With either Ru3(CO)12/TBACl or Ru(bpy)-
(CO)2Cl2, only about 25% of 1a was converted, demonstrating
a significant difference in reactivity (entries 2 and 3). However,
the use of all three ruthenium sources in EtOH led to efficient
a
a
entry
solvent
2 recovery (%)
3a yield (%)
1
2
3
4
5
6
7
AllylOAc
EtOAc
N/A
18
25
0
91
94
acetone
cyclohexanone
THF
68
90
0
>99
49
DMF
44
39
50
7
1
DMSO
MeOH
EtOH
53
conversions of 1a (entries 4−7). Furthermore, qualitative H
b
8
b
10
NMR analysis showed nearly complete formation of the
branched product in EtOH as compared to dioxane, whereas
the linear product was formed in higher yield.
9
50
10
i-PrOH
5
100
a
Determined by 1H NMR analysis using as the internal standard.
Significant amounts of acetal formation were observed (74% w/
To reduce the reaction time and temperature, experiments
were run for 20 h at 75 °C with two different loadings of
ruthenium catalyst, and it was determined that 5 mol % of
RuCl3 led to higher conversions of the product (see Table
S14). However, the formation of acetals was noted in EtOH,
particularly with aliphatic aldehydes such as hydrocinnamalde-
hyde, detracting from productive reaction. To mitigate acetal
formation, a survey of solvents was conducted (see Table S15),
and it was found that the use of t-BuOH was appropriate to
avoid acetal formation and maintain high selectivity for the
desired product in the use of aliphatic aldehydes.
b
MeOH; 28% w/EtOH).
Scheme 6
The selective formation of anti-7a from (E)-cinnamyl acetate
was unexpected, as reactions employing crotyl acetate gave very
low syn/anti selectivity (vide infra). To probe if this result arose
from a 6-membered transition state, (Z)-cinnamyl acetate (Z)-6
was employed under the same conditions (Table 13). The use
of (Z)-6 led to the same composition of product 7a as from
(E)-6 and in similar yield and selectivity. Furthermore, only
(Z)-6 was recovered from the reactions, and no (E)-6 was
to be viable substrates for the allylation reaction employing allyl
acetate.6 This work emphasized the general nature of the
reaction and demonstrated that steric and electronic factors of
the aldehydes had a minimal effect on the course of the
allylation reaction. Furthermore, some chemoselectivity for the
reaction was demonstrated as aldehydes containing functional
groups prone to reduction (nitro, esters, and alkenes) were
stable under the reducing CO environment (Figure 2).
The general scope of the allyl pro-nucleophile was expanded,
and the chemoselective nature of the reaction further
demonstrated in a subsequent report that employed allyl pro-
nucleophiles with a substitution at the 2-position.34 The
substituents included ketone, ester, styrenyl, and protected
aldehyde functional groups that were all shown to be stable
1
observed in the crude reaction mixture by H NMR analysis.
Preparative Scale Allylation Reactions. Using the con-
ditions identified by the optimization, the allylation of a set of
aldehydes on a preparative scale (1.0 mmol) was performed
(Table 14). Good to excellent yields were observed with the
use of most aldehydes (most yields >70%). The use of electron-
rich aldehydes (1e) afforded lower yields than the electron-
neutral (1a) or electron-poor (1d, 1f, 1g, and 1h) aldehydes.
Decreased electron density in the aldehyde lowers the LUMO
Figure 2. Catalytic nucleophilic allylation of aldehydes.
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Figure 3. Extension to 2-substituted allylic acetates.
24 h were only obtainable after the concentration was doubled
(from 0.4 to 0.8 M) to increase the reaction rate. The successful
use of the aldehydes with easily reduced functional groups
(nitro, alkenyl, halide) under the reducing conditions further
highlights the chemoselectivity of the ruthenium-catalyzed
reaction.
Table 12. Effect of Solvent and Ruthenium Catalyst on
Conversion
In all cases, the anti/syn ratio of the products was >20:1,
revealing the preference for a single thermodynamically stable
intermediate leading to product. In general, the solvent choice
did not have an impact on the anti/syn ratio, except in the case
of 1m in EtOH, in which the anti/syn ratio was closer to 8:1.
Changing the solvent to t-BuOH maintained the high level of
selectivity displayed with the other aldehydes. Similarly with 1l,
the use of t-BuOH gave a cleaner reaction profile. The primary
effect of solvent in the other reactions was to avoid formation
of acetals, especially in the case of the aliphatic aldehydes (1n,
1o, and 1p) in which the use of t-BuOH inhibited acetal
formation.
a
b
entry
Ru catalyst
solvent
1a recovery (%)
1
2
3
4
5
6
7
RuCl3·xH2O
dioxane
dioxane
dioxane
EtOH
49
76
73
28
23
22
12
Ru3(CO)12/TBACl
Ru(bpy)(CO)2Cl2
RuCl3·xH2O
Ru3(CO)12/TBACl
Ru(bpy)(CO)2Cl2
[RuCl2(p-cymene)]2
EtOH
EtOH
EtOH
Catalytic Nucleophilic Allylation with Vinyl Oxirane.
Reaction Optimization. To further the investigations into
unsymmetrical allyl pro-nucleophiles, vinyl oxirane 9 was next
evaluated under the standard reaction conditions (Table 15).
The use of Ru3(CO)12 and TBACl gave nearly full conversion
of 1a to 10a with complete selectivity (entry 1). In the case of
[RuCl2(p-cymene)]2 without TBACl, good conversion was
observed, but with much lower selectivity, as was the case with
RuCl3 (entries 2 and 4). However, upon the addition of 3 mol
% TBACl, 10a was formed selectively (entries 3 and 5).
To explore the reactivity of other aldehydes, the same
conditions with Ru3(CO)12/TBACl for 1a were applied to 1b,
a
When used, an equimolar amount of TBACl was added to Ru.
Determined by GC analysis using biphenyl as the internal standard.
b
and thereby decreased the energy of activation barrier for the
addition. Aldehydes with extended π-systems (1b and 1i) were
viable substrates under the reaction conditions and gave
comparable yields to 1a. Aryl aldehydes with increased steric
bulk, such as 1j and 1k, generated the allylation product in high
yield, which is in sharp contrast to the more sterically
encumbered alkyl aldehydes 1n and 1p which gave greatly
diminished yield. In the case of 1n, appreciable conversions in
Table 13. Effect of Double-Bond Geometry on Diastereomer Formation
a
a
a
a
a
entry
acetate
1a recovery (%)
anti-7a yield (%)
syn-7a yield (%)
8a yield (%)
acetal yield (%)
1
2
(E)-6
(Z)-6
3
6
73
70
3
5
8
8
1
1
a
1
Determined by H NMR analysis using hexamethylbenzene as the internal standard.
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a−c
Table 14. Aldehyde Scope for (E)-Cinnamyl Acetate
a
b
c
Reaction conditions: (A) EtOH, 0.4 M; (B) t-BuOH, 0.4 M; (C) t-BuOH, 0.8 M. Yield of isolated, purified products. Value in parentheses is the
anti/syn ratio.
Table 15. Effect of Ruthenium Catalyst and TBACl Loading on Conversion
a
a
a
entry
Ru catalyst
Ru3(CO)12
TBACl (mol %)
1a recovery (%)
10a yield (%)
11a yield (%)
1
2
3
3
0
3
0
3
7
15
8
92
62
90
49
91
0
19
0
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
RuCl3·xH2O
b
4
39
12
0
5
RuCl3·xH2O
5
a
b
1
Determined by H NMR analysis using hexamethylbenzene as the internal standard. Only 1.2 equiv of 9 was employed in this reaction.
1c, and 1e (Table 16). Under these conditions, there was a
significant amount of aldehyde remaining in each case using 3
mol % of Ru/TBACl, but the selectivity remained high for 10
(entries 1, 4, and 7). An increase to 5 mol % of Ru/TBACl
increased the yields of 10; however, in each case nearly all of
the allyl source was consumed (entries 2, 5, and 8). To further
improve the yields, the loadings of 9 and H2O were increased,
which led to higher yields of 10 (entries 3, 6, and 9). These
conditions were then used in the substrate survey.
As the vinyl oxirane used in these reactions was racemic, the
effect of using enantioenriched (S)-9 was tested which afforded
product 9a in racemic form suggesting that some stereo ablative
or racemization process was occurring (Scheme 7).
all aldehydes (most yields >80%). The use of electron-rich
aldehydes (1e) afforded the respective products in lower yields
than the electron-neutral (1a) or electron-poor (1d, 1f, 1g, and
1h) aldehydes. The use of 1e also required an increase in
reaction concentration (from 0.4 to 0.8 M) to achieve good
conversion in 24 h as the electron-rich aldehyde was slow to
react under these conditions. The aldehydes with extended π-
systems (1b and 1i) were also viable substrates and gave
comparable yields to 1a. With bulky aryl aldehydes, such as 1j
and 1k, the linear product was generated in high yields.
However, when the alkyl aldehydes with more steric
encumbrance (1n and 1p) were used, the product yield was
greatly diminished. As with the use of 1e, 1n required a reaction
concentration of 0.8 M to achieve appreciable conversion
values in 24 h. Heteroaromatic aldehydes (1j and 1m) reacted
well under the reaction conditions to give good to excellent
yields.
Preparative-Scale Allylation Reactions. Using the opti-
mized conditions, the allylation was performed on the same set
of aldehydes on a preparative scale (1.0 mmol) (Table 17).
Good to excellent yields were observed with the use of nearly
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Table 16. Effect of Ruthenium, 9, and H2O Loading on Conversion
a
1
Determined by H NMR analysis using hexamethylbenzene as the internal standard.
(entry 6). Employing Ru3(CO)12, on the other hand, yielded
13a in 78% with anti/syn selectivity of 1.8:1. Further attempts
to improve the anti/syn selectivity using a variety of additives
and conditions were ultimately unsuccessful (see Tables S20−
S23).
Scheme 7
To fully explore all reaction parameters, the effects of the
electronic properties of the reacting partners were investigated.
For this purpose, an allylic acetate containing an electron-
withdrawing group was used (Table 19). Initial attempts using
dioxane as the solvent gave the linear product 16a exclusively,
but in poor yield (entries 1−3). The use of EtOH did result in
the formation of branched product and in higher selectivities
than crotyl acetate (up to 14:1 favoring the syn isomer), but the
selectivity of branched/linear products dropped, and at best, a
2:1 ratio was obtained (entries 4−6). It was also observed that
higher yields were obtained if the reaction was conducted at
lower reaction temperature but over a longer period of time
(entry 6); however, this resulted in significantly lower anti/syn
ratio.
Potential for Large-Scale Reactions. Among the substrates
investigated, the allylation employing vinyl oxirane was a
particularly interesting case as the product of this reaction was a
linear 1,5-diol, which presented an synthetically useful target,
and a practical synthesis was sought. The reaction was
performed on a 10 mmol scale to afford a 97% yield after
column chromatography and a somewhat decreased E/Z ratio
of 10:1 (Scheme 8). Similarly, the reaction between 2-
methoxybenzaldehyde and allyl acetate was conducted on 10
mmol scale to yield 97% of the desired product.
In nearly all cases, the E-linear isomer was the major product;
however, the selectivities varied from excellent (>100:1) to
modest (4:1), and even in one case, with 1n, the Z-isomer was
the major product in an E/Z ratio of 1:1.5. These observations
demonstrate the effect that very sterically encumbered
aldehydes have on the transition state leading to the allylation.
An obvious trend is the relative low selectivity exhibited by the
alkyl aldehydes (1c, 1n, 1o, and 1p) and the electron-rich
aldehydes (1e and 1l). For 1n and 1p, this result could be
attributed to high steric encumbrance, but for 1c and 1o, it
might instead have to do with the greater flexibility of the R
group on the aldehyde that could destabilize the transition state
that leads to the E-linear product. The electron-deficient
aldehydes for the most part exhibited excellent E/Z selectivities,
with the possible exception of 1f, which was only 6:1.
Catalytic Nucleophilic Allylation with Other Allyl Pro-
nucleophiles. Two additional unsymmetrical allylic acetates
that were worthy of study to further explore electronic and
steric factors involved in reaction are crotyl acetate and ethyl
(E)-4-acetoxybut-2-enoate. For crotyl acetate, high yields and
the exclusive formation of the branched product were
promising; however, the product was formed with low
diastereomeric (anti/syn) selectivity (Table 18). Once again,
better yields were observed at higher reaction temperatures
(entries 1, 2, and 4), and little difference was found when
Ru3(CO)12 was used as the catalyst instead of RuCl3·xH2O
(entries 1 and 2). Crotyl carbonate showed similar reactivity
and selectivity (entry 4); but interestingly, crotyl benzoate was
completely unreactive when RuCl3 was used as the catalyst
Chiral Ligands in the Ruthenium-Catalyzed Nucleo-
philic Allylation Reaction. At the outset of studies to render
the reaction enantioselective, it was important to recognize that
allylruthenium agents typically react with carbonyl compounds
through a 6-membered transition state.35 This feature presents
the opportunity to apply methods that have been successfully
employed in other related reactions to induce stereo-
selection.1−5 Two viable strategies presented themselves: (1)
the inclusion of an chiral ion that will associate with the
ruthenium metal and direct the approach of the incoming
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a c
−
Table 17. Aldehyde Scope for Vinyl Oxirane
a
b
c
d
Reaction conditions: (A) 0.4 M; (B) 0.8 M. Yield of isolated, purified products. Value in parentheses is the E/Z ratio. E and Z isomers were fully
separable.
Table 18. Use of Crotyl Acetate as Allyl Pro-nucleophile
Scheme 8
a
entry
1
Ru catalyst
X
temp (°C) 13a yield (%) anti/syn
RuCl3·xH2O
Ru3(CO)12
OAc
75
75
95
75
75
75
42
69
94
79
0
1.6:1
1.1:1
1.5:1
1:1.1
N/A
1.8:1
b
2
OAc
3
4
5
RuCl3·xH2O
RuCl3·xH2O
RuCl3·xH2O
OAc
OCO2Et
OBz
b
6
Ru3(CO)12
OBz
78
a
1
Determined by H NMR analysis using hexamethylbenzene as the
aldehyde36 or (2) the formation of a discrete ligated ruthenium
complex that will prefer a particular 6-membered transition
state leading to enantioenriched products.37−41
b
internal standard. TBACl (3 mol %) was added to reaction.
Table 19. Use of Ethyl (E)-4-Acetoxybut-2-enoate as Allyl Pro-nucleophile
a
a
entry
solvent
temp (°C)
time (h)
15a yield (%)
anti/syn
16a yield (%)
1
2
3
4
5
6
dioxane
dioxane
dioxane
EtOH
75
60
60
75
60
60
20
20
40
20
20
40
0
0
47
23
40
26
19
27
0
40
25
54
1:14
1:13
1:8
EtOH
EtOH
a
1
Determined by H NMR analysis using hexamethylbenzene as the internal standard.
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Inspiration for the first approach came from the requirement
of a soluble chloride source to engender sufficient activity when
a zerovalent ruthenium complex was employed (Table 6). This
requirement implies that an anionic ruthenium carbonyl species
is needed to effect oxidative addition to allyl acetate. Therefore,
it was reasonable to assume that a chiral anion instead of
chloride or a chiral counteranion could influence the bond
forming event in the metal coordination sphere. Unfortunately,
neither of these approaches resulted in any enantioenrichment
of the product.
Table 21. Bidentate Oxazoline Ru-Complex Survey
To assess the second approach, a series of chiral ruthenium
complexes were employed in the reaction between 1a and 2
(Table 20). The first catalyst structure investigated was
a
b
entry
Ru catalyst
3a yield (%)
er
1
2
3
4
Cat 4
Cat 5a
Cat 6
Cat 7
58
90
46
94
51:49
60:40
51:49
51:49
Table 20. Survey of Chiral Ruthenium Complexes
a
Determined by GC analysis using biphenyl as the internal standard.
Determined by CSP-phase HPLC.
b
Table 22. Effect of Free Ligand Loading on
Enantioenrichment and Yield of 3a
a
b
entry
Ru catalyst
1a yield (%)
er
1
2
3
Cat 1
Cat 2
Cat 3
38
98
75
49:51
49:51
49:51
a
Determined by GC analysis using biphenyl as the internal standard.
Determined by CSP-phase HPLC.
b
designed with maximum binding to the ruthenium center in
mind by the tridentate Phe-box ligand42 (Cat 1, entry 1) which
has two Ru−N dative bonds to the ruthenium and a single C−
Ru bond as well. Also tested was a Pybox43 type ligand complex
(Cat 2, entry 2) which maintains the tridentate nature of Phe-
box but alters the electronic properties of the catalyst through
the exchanging of a C−Ru covalent bond for a N−Ru dative
bond. Lastly, a benzyl ruthenacycle41 (Cat 3, entry 3) was
employed as bidentate ligand with a C−Ru bond. Each of these
catalysts yielded 3a but in racemic form.
Next examined were bidentate ligand complexes containing
dative N−Ru bonds and included those with no carbon bridge
(Cat 4), a one-carbon bridge (Cat 5a), a two-carbon bridge
(Cat 6), or a mixed, pyridine−oxazoline backbone (Cat 7). The
adjustment of this bridge would allow for a different bite angle
for each complex on the ruthenium metal center, which would
in turn adjust the location of the stereogenic atoms in the
reaction sphere. Each of these complexes were tested under the
standard reaction conditions (Table 21). Although all
complexes were competent, only Cat 5a showed any
enantioenrichment (entry 2).
a
b
entry
L1 (mol %)
3a yield (%)
er
1
2
6
59
40
70:30
75:25
30
a
Determined by GC analysis using biphenyl as the internal standard.
Determined by CSP-phase HPLC.
b
exploring the identity of the substituents at the stereogenic
carbon of Cat 5a.
To expand the chemical space for Cat 5a, additional
bisoxazoline ligands were synthesized, complexed to ruthenium,
and tested under both the standard reaction conditions and
with an additional equivalent (with respect to Ru mol %) of the
corresponding ligand (Chart 1 and Table 23). In general, the
addition of ligand caused a higher er value, but with diminished
yield. The replacement of the p-cymene ring with a benzene
ring as the bound arene in Cat 5b resulted in an increase in
enantioenrichment as compared to Cat 5a both with and
without added ligand (Table 23, entries 1 and 2, vs Table 22,
entries 1 and 2). The use of a benzyl substituent in Cat 5c gave
a nearly racemic yield, but added ligand was able to approach
the selectivity of Cat 5a (entries 3 and 4), a trend that was
repeated with Cat 5d (entries 5 and 6). Interestingly, when a
catalyst related to Cat 5a but with a dimethyl bridge was used,
Cat 5e, the product was observed, but in racemic form (entry
7). The tert-butyl substituted Cat 5f inverted the sense of
enantioinduction, but added ligand in this case gave racemic
To determine if low selectivity resulted from ligand
dissociation from the ruthenium center, an experiment was
run with the addition of more ligand (Table 22) Interestingly,
an increase in the er value was observed, first to up to 70:30
with 6 mol % added ligand (entry 1) and then to a maximum of
75:25 with 30 mol % added ligand (entry 2). As this ligand
system seemed viable for the generation of an enantioselective
allylation reaction, further studies were directed toward
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Chart 1. Chiral Ruthenium Bisoxazoline Complexes and Ligands
alkyl-substituted bisoxazolines for this reaction. When the
phenyl ring of Cat 5a was bonded in such a way to exclude free
rotation as with the case of Cat 5i, all enantioenrichment was
lost (entry 15). However, when an additional ring was added, as
in the case of Cat 5j, the er was nearly unchanged (entries 17
and 18). The inclusion of additional phenyl rings at the 5 and/
or 5′ position of the bisoxazoline ring maintained enantioen-
richment and in the case of Cat 5l with added ligand, gave the
best er value yet observed of 22:78, albeit in a yield of 22%
(entry 22). Finally, the addition of methyl groups at the 2,3,5
position of the parent backbone, Cat 5m, resulted in little to no
enantioenrichment (entry 23).
In the course of the executing these reactions, a color change
was observed when Et3N was added to the solution containing
the catalyst and solvent, except in the case of Cat 5e. A series of
experiments using variable amounts of Et3N were run to further
explore this effect (Table 24). Without Et3N, no immediate
color change was observed, the yield was very low, and the
product was racemic (entry 1). Increasing the amount of Et3N
increased the yield and selectivity to a maximum of 65:35
(entries 2−5).
Table 23. Complexed Bisoxazoline Ligand Survey
a
b
entry
Ru catalyst
L1
3a yield (%)
er
1
Cat 5b
−
L1a
−
93
69
60
5
68:32
75:25
55:45
58:42
57:43
60:40
51:49
2
3
Cat 5c
Cat 5d
Cat 5e
Cat 5f
Cat 5g
Cat 5h
Cat 5i
Cat 5j
Cat 5k
Cat 5l
Cat 5m
4
L1b
5
−
L1b
−
28
31
32
1
6
7
8
L1a
NA
9
−
L1c
−
61
54
24
45
53
18
56
1
35:65
48:52
51:49
54:46
52:48
54:46
49:51
10
11
12
13
14
15
16
17
18
19
20
21
22
23
L1d
−
L1e
−
DISCUSSION
L1f
NA
■
−
L1g
−
89
85
73
64
85
22
72
68:32
71:29
36:64
31:69
61:39
78:22
44:56
Roles of Reaction Components and Formulation of a
Catalytic Cycle. On the basis of the observations gathered
during the discovery and optimization of the present reaction,
several conclusions could be drawn that allowed the
formulation of a catalytic cycle and the identification of roles
of each reagent.
L1h
−
L1i
−
Rationale for Role of Soluble Chloride. In the first step of
the catalytic cycle, the formation of a π-allylruthenium complex
must form directly from allyl acetate and Ru3(CO)12. However,
this reaction is not feasible because it has been shown that
Ru3(CO)12 does not react with allyl acetate even in refluxing
toluene.32 Therefore, a different form of low-valent ruthenium
must participate in that step. The salutary effect of added halide
is likely the means by which this step is possible as it provides a
a
Determined by GC analysis using biphenyl as the internal standard.
Determined by CSP-phase HPLC.
b
product (entries 9 and 10). The alkyl-substituted complexes
Cat 5g and Cat 5h each gave racemic product, even with added
ligand (entries 11−14), similar to the benzyl-substituted
complexes, highlighting the general lack of selectivity for
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and k2 are Henry’s constants at temperatures T1 and T2, the
coefficient c was calculated to be 376.51 (R2 = 0.9882). Linear
regression provided k343 = 2158.1 (L·psi mol−1); thus, the
solubility of CO at 343 K (70 °C) is 4.63 × 10−4 mol·L−1.psi−1.
Table 24. Effect of Et3N Loading on Enantioselectivity
⎛
⎞
1
1
ln k − ln k = c
−
⎜
⎝
⎟
⎠
1
2
T
T
(2)
1
2
Assuming that other solutes do not significantly affect the
CO solubility, the amount of CO in the 2.5 mL dioxane
solution at 70 °C at 30 psi should be approximately 0.035
mmol, which is very close to the total amount of ruthenium
(0.030 mmol). Thus, 30 psi of CO translates to 1:1 molar ratio
of solvated CO/Ru. If the reaction is run under a balloon of
CO, the ratio of solvated CO/Ru is approximately 1:2. As such,
the reaction was slower at that pressure because not enough
CO is present in the solution and the rate of CO uptake by
ruthenium is faster than the rate of CO diffusion into the
solution at that pressure. The fact that the reaction does not
proceed faster at higher CO pressures indicated that the
concentration of CO is not present in the rate equation and the
necessary pre-equilibria prior to the turnover-limiting step are
saturated.
Role of Amine. On the basis of the evidence obtained in the
course of this study, it is highly likely that the role of amine in
the reaction is to aid in the reduction of higher valent
ruthenium species [Ru(III) or Ru(II)] to Ru(0) so the catalytic
cycle can begin. The evidence for this is as follows:
(1) If amine is acting only as a reductant for the catalyst, then
it should only be required for high oxidation states of
ruthenium precatalysts. Ru3(CO)12 is able to function without
added amine (as long as a soluble halide is present). However,
neither Ru(III) or Ru(II) sources reacted in the absence of
added amine.
a
b
entry
Et3N (mol %)
3a yield (%)
er
1
2
3
4
5
0
5
3
95
79
88
80
51:49
57:43
64:36
65:36
64:36
10
20
40
a
Determined by GC analysis using biphenyl as the internal standard..
Determined by CSP-phase HPLC.
b
more nucleophilic form of ruthenium needed for the oxidative
addition. As indicated in Table 6, entry 10, only 15%
conversion of aldehyde was observed in the absence of halide.
The effect of halides on the structure and reactivity of
ruthenium carbonyl complexes has been the subject of
countless investigations since the early 1980s but none
mentioned the effect in the allylation reaction.44 Geoffroy45 has
shown that halide anions (X−) can displace one or more CO
ligands in the Ru3(CO)12 complex to produce anionic species
such as [Ru3(CO)11X]−,46 [Ru3(CO)10X]−, [Ru4(CO)13X]−.
Amatore and Jutand have established the role of chloride ion
in palladium-catalyzed, cross-coupling reactions in which
anionic chloropalladium(0) ate species participate in the
oxidative addition step.47,48 By analogy, it can be postulated
that the rate enhancement caused by chloride observed in this
process arises from chloride-ligated anionic complexes formed
by displacement of carbon monoxide ligand(s) from the neutral
Ru(0) carbonyl species by chloride. These anionic complexes
should be more nucleophilic than the neutral Ru(0) complexes
and thus can readily react with allyl acetate to form the requisite
π-allylruthenium complex, which ultimately delivers the allyl
group to the aldehyde. It is possible that this process occurs by
the coordination of the aldehyde carbonyl to the ruthenium
center causing a shift of the π-allylruthenium from the η3- to the
η1- binding mode and the (η1-allyl)ruthenium undergoes the
nucleophilic attack at the carbonyl.49
(2) The amount of amine corresponds closely to the
stoichiometry needed to reduce each high-oxidation ruthenium
source to Ru(0) considering that Et3N acts as a two-electron
reductant. For reduction of RuCl3 to Ru(0), 1.5 mol equiv of
Et3N are required. The following equations illustrate this point.
For the full reduction of RuCl3 to Ru(0), a total of three
electrons would be needed:
Because Et3N is a two-electron reductant, 1.5 equiv would be
needed to provide the necessary electrons for full reduction of
RuCl3 (eq 3):
Rationale for Required CO Pressure. During the course of
optimization, it was observed that the minimum pressure of CO
required for efficient reactivity was 30 psi. A calculation of CO
solubility was conducted to explain this observation. Table 25
shows the available data for CO solubility in dioxane at
different temperatures.50,51 On the basis of eq 2, in which k1
Therefore, as shown, a requirement of around 4.5 mol % of
Et3N is needed to fully reduce 3 mol % of RuCl3, as observed in
Table 5, entries 6−8.
This same principle can be applied to the use of [RuCl2(p-
cymene)]2 for which 1 molar equiv of Et3N was required to
reduce Ru(II) to Ru(0) (see Table S6). The more gradual
turning point observed with the use of this catalyst may arise
because some Ru(0) is formed in the initial reduction from
Table 25. CO Solubility in Dioxane at 1 atm
temp (K)
solubility (10−4 mol·L−1·psi−1
)
290.1
296.4
306.7
315.8
3.79
3.93
4.07
4.21
N
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Ru(II) to Ru(0) even with low loadings of Et3N. RuCl3 needs
almost a full molar equivalent of Et3N before any appreciable
Ru(0) can be formed, thus explaining why some product was
formed when only 4.0 mol % of Et3N was used (Table 5).
(3) The oxidation of the amine should lead to the formation
of an iminium ion, which under the aqueous conditions of the
reaction should covert to a carbonyl compound. The use of
dicyclohexylamine and subsequent observation of cyclohex-
anone demonstrates this very fact. A 52% conversion of
dicyclohexylamine to cyclohexanone was observed, which
corresponds to the consumption of 0.21 mmol of amine
(from an initial loading of 0.40 mmol). The amount of amine
consumed is 1.72 times the RuCl3 loading of 0.12 mmol and
corresponds well with 1.5 reducing equivalents required for the
full reduction of Ru(III)Cl3 to a Ru(0) species.
Scheme 9
Taken together, these three points provide good evidence for
the role of amine as the means by which the higher oxidation
states of ruthenium are reduced to enter the catalytic cycle. The
action of the WGSR can also contribute to this reduction as the
use of RuCl3 without added amine in other WGSR-driven
reactions finds ample precedent.17
Formulation of the Catalytic Cycle. From these consid-
erations, a more complete mechanism for the full catalytic cycle
can be presented (Scheme 9). Following initial reduction of
higher valent ruthenium by the amine or the WGSR to the
Ru(0) species v or addition of chloride (in the case of
Ru3(CO)12), oxidative addition to allyl acetate occurs to give a
Ru(II) π-allyl species vi. The aldehyde next inserts into the
nucleophilic allylmetal species vi next inserts by coordination of
the carbonyl group to the Ru(II) center (via the η1 form of vi)
to generate vii. Hydrolysis of the alkoxide vii then releases the
homoallylic alcohol product and generates a Ru(II) hydroxide
species viii. By means of the water−gas shift reaction,52 CO
may undergo migratory insertion into the Ru(II)−OH bond
yielding ix which can be followed by a β-hydride elimination to
release CO2 and form x. Subsequent reductive elimination of
Ru(II) hydride x intermediate regenerates Ru(0) complex v,
and forms acetic acid as the second byproduct.
Configurational Stability of the π-Allylruthenium
Intermediate. Several studies have investigated the configura-
tional stability of the π-allyl moiety that forms after ruthenium
oxidatively adds into the allyl pro-nucleophile.32,53 The relative
rate of any isomerization event in comparison to the product
formation (by aldehyde insertion) is an important feature of the
reaction as this can influence the stereoselectivity of the
process. This situation does not obtain with the 2-substituted
allyl pro-nucleophiles, but in the case of unsymmetrical pro-
nucleophiles 6 and 9, the structure and configurational stability
of intermediates is crucial for determining the product
structure. The use of (E)-6 leads to the selective formation of
anti-7, as is expected if the allylation event proceeds through a
closed, six-membered transition state (Scheme 10),54 which has
been computationally documented for the ruthenium-catalyzed
allylation of aldehydes.35 The use of (E)-cinnamyl acetate in
other allylation reactions has also been demonstrated to be
selective for the anti-branched product.55
Scheme 10
allyl complex with the E-configuration (type 3). It is more likely
that the rearrangement pathway is operative as typical allylation
reactions that involve an open transition state form the syn-
product selectively.54 Therefore, a η3−η1−η3 rearrangement can
be invoked to explain the formation of the anti-7 product
(Scheme 11). Furthermore, the use of enantioenriched (S)-9
did not result in enriched 10 (Scheme 14), even though the
insertion of ruthenium in the allyl pro-nucleophile via a Sn2′
mechanism would result in a chiral π-allyl complex (Scheme
12). Again, a η3−η1−η3 rearrangement prior to aldehyde
insertion could result in the isomerization of the species,
yielding racemic 10. However, a nonselective aldehyde
insertion cannot be ruled out, in lieu of a nonconfigurationally
stable π-allyl, which would also result in the formation of
racemic 10.
Selective Formation of the Linear Product with Vinyl
Oxirane. Interestingly, the use of 9 under the optimized
conditions led to the selective formation of the linear
homoallylic alcohol with an E-double bond configuration, 10.
The branched product (11) was observed only as the minor
Scheme 11
The use of (Z)-6 also led to anti-7 selectively, not the
expected product syn-7 that would result from a closed
transition state. Two rationales could explain this observation:
(1) the reaction actually occurs through an open transition state
that is not sensitive of the double bond geometry (type 2)54 or
(2) the aldehyde insertion occurs after a rearrangement of the
π-allyl complex to form the more thermodynamically stable π-
O
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Rationale for Methylene-Bridged Bisoxazoline Selec-
tivity. Through the course of testing seven initial ligand
backbones (Cat 1−Cat 7), only a single structure was shown to
be capable of inducing enantioenrichment in the homoallylic
alcohol, namely Cat 5a. This observation is intriguing as the
difference between some of the catalysts is minimal. In the case
of Cat 1 and Cat 2, the distance between the ruthenium metal
center and stereogenic carbon is farther than the other catalysts
tested owning to the planar, three-carbon bridge present in the
ligand backbone, which might keep the stereodefining features
of the catalyst too far from the reaction center. In the case of
Cat 3, it is possible that the methyl group is not a large enough
group to influence the orientation of the aldehyde and allyl,
especially when one-half of the complex has no stereodefining
features, similar to Cat 7. However, in the cases of Cat 4−Cat
6, the difference of a single carbon in the backbone of the
ligand was enough to provide any stereoinduction only when a
single-carbon bridge was present as both a zero-carbon and
two-carbon bridge gave no stereoinduction (Cat 4 and Cat 6).
This trend seems peculiar considering how similar these
catalyst structures are.
The most likely rationales for these results include: (1) the
fact that Cat 5e also gave no enantioenrichment despite it being
very similar to Cat 5a/Cat 5b and (2) the dependence on the
inclusion of Et3N for reactivity and enantioenrichment. It is
highly likely that a hydrogen on the methylene bridge of Cat 5
is being removed, generating a new species (Cat 5b′) that
might be what leads to the enantioenrichment of 3a (Scheme
14). The complex Cat 5b′ would bind more tightly to the
ruthenium metal, as the one nitrogen is now anionic, likely
reducing the chance for ligand decomplexation and an increase
in a background, racemic reaction. The other initial ligand
backbones are unable to undergo a deprotonation event or, if
they can, as in the case of Cat 3, the resulting species is achiral.
Scheme 12
product when an alcohol solvent was used, and even then in
low yield. While the use of 9 as an allyl pro-nucleophile in
aldehyde allylations is known, it often selectively forms the
branched product56 or forms the linear product with E/Z ratios
that range from poor to selective for the Z-double bond
configuration.57 The use of 9 in this ruthenium-catalyzed
allylation of aldehydes is, therefore, a unique case for the highly
selective formation of the (E)-10 product. Alternative methods
to generate the linear product involve the use of allyl-boron
reagents but which are selective for the formation of Z
geometries.58−60 Araki and co-workers observe selective
formation of the linear product in the indium-mediated
allylation reaction using vinyl oxirane. To account for this
selectivity, two cyclic intermediates are rationalized to form
upon generation of the η1-allylindium, each containing an O−
In bond. The first consists of a 4-membered ring with an
exocyclic allyl that leads to the linear product (Scheme 13, a,
top). The intermediate that leads to the branched product
involves all of the atoms in a 6-membered ring (Scheme 13, a,
bottom). While this rationale can be applied in the formation of
linear product for the ruthenium catalyzed allylation, the
selective E-bond geometry cannot. Instead, it is possible that
the transition state resulting from the four-membered
intermediate as prescribed by Araki et al. has instead an
equatorial methyl-alkoxide bound to the ruthenium, which
would give the desired (E)-10 product (Scheme 13, b).
Other Allyl Pro-nucleophile Reactivities. The use of
crotyl acetate led to a nonselective formation of branched
diasteromers. The high branched selectivity corresponds to
reaction via the more stable η1-allyl ruthenium complex with
the increased steric contributions due to the methyl distal to
the ruthenium center prior to aldehyde insertion. The lack of
syn/anti selectivity points to a weak preference for an E or Z
vinyl methyl group during the course of η3−η1−η3 rearrange-
ments prior to aldehyde insertion. This rearrangement pathway
is known for both palladium61 and ruthenium53 catalysts, and a
mixture of syn and anti products can result from geometrically
pure starting crotyl.62
Scheme 14
Scheme 13
P
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Reaction solvents tetrahydrofuran (Fisher, HPLC grade) and DMSO
(Fisher, ACS grade) were dried by percolation through two columns
packed with neutral alumina under a positive pressure of argon.
Reaction solvent toluene (Fisher, ACS grade) was dried by percolation
through a column packed with neutral alumina and a column packed
with Q5 reactant, a supported copper catalyst for scavenging oxygen,
under a positive pressure of argon. Reaction solvent dioxane (Fisher,
ACS grade) was distilled over sodium prior to use and had 26.5 μg/
mL of water. Reaction solvents methanol (Fisher, ACS grade), ethanol
(Fisher, ACS grade), and acetonitrile (Aldrich, ACS grade) were
distilled from CaH2. Solvents for filtration and chromatography were
certified ACS grade. Solvents for chromatography were: hexanes
(Optima grade), diethyl ether (ACS grade), and dichloromethane
(ACS grade).
CONCLUSION
■
The ruthenium-catalyzed allylation reaction employing CO as
the terminal reductant is a highly efficient and atom-economical
process for the formation of homoallylic alcohols from
aldehydes. The use of inexpensive and noncorrosive allyl
acetates and other allyl pro-nucleophiles, water, and a low
pressure of carbon monoxide can affect this transformation. For
the simple allyl acetates, reagents were used in near
stoichiometric amounts, even the CO gas, and only moderate
reagent excesses were required for the more reactive allyl pro-
nucleophiles. The use of nonsymmetrical allyl pro-nucleophiles
further illustrates the potential for a wide range of allyl pro-
nucleophiles to be employed in the reaction.
The role of each reaction component has been defined and
optimized, including the more definitive role of amine in the
reaction. The reaction is catalytic in ruthenium, and because the
stoichiometric byproducts are carbon dioxide and acetic acid, it
is environmentally benign and readily adaptable to large-scale
operation. The method shows good substrate generality,
functional group compatibility, and high tolerance to electronic
and steric factors. Most importantly, the reaction has been
shown to be highly chemoselective for reactions only at an
aldehyde carbonyl. The only substrates that do not react are the
ones that include unprotected N-heterocycles (such as pyridine,
pyrrole, or indole) or alkynes as these functional groups inhibit
the reaction owing to their strong binding to low valent
ruthenium.
The type of allyl pro-nucleophiles that can be employed in
the reaction has been expanded to include unsymmetrical allyl
sources as demonstrated through the use of (E)-cinnamyl
acetate and vinyl oxirane. Both of these allyl pro-nucleophiles
gave selective formation of a single constitutional isomer, often
in high selectivity. For (E)-cinnamyl acetate, only the anti-
branched product was formed across a wide range of aldehydes
examined. In the case of vinyl oxirane, the selective formation
of the linear product over the branched product is impressive as
well is the selective formation of the E-double bond isomer,
which is often the minor isomer formed when the linear
product is made. In both cases, the deliberate choice of solvent
and/or additives to the reaction was able to achieve this high
selectivity.
Reaction Setup. All carbonylation reactions were performed in
either: (1) a six-well autoclave (Figure S1), which allows for
independent control of gas pressure in each well via the individual
valves, equipped with a temperature probe connected to a magnetic
stirrer (IKA Labortechnik) bearing a heat control element OR (2) a
Fischer-Porter Tube submerged in an oil bath with the use of a
magnetic stirrer (IKA Labortechnik) for heating and a connected
temperature probe to maintain temperature.
1
NMR Spectroscopy. H and 13C spectra were recorded on a 500
1
MHz, H (126 MHz, 13C) spectrometer. Spectra were referenced to
1
residual chloroform (7.26 ppm, H; 77.16 ppm, 13C) or when the
1
chloroform peak is obscured in the H NMR spectrum, to isolated
singlets in the product spectrum corroborated with a more diluted
sample. Chemical shifts are reported in parts per million (ppm),
multiplicities are indicated by s (singlet), d (doublet), t (triplet), q
(quartet), quint (quintet), m (multiplet), and br (broad). Coupling
constants, J, are reported in Hertz with integration provided and
assignments indicated. Assignments are corroborated by 2D experi-
ments (COSY, HMQC, HMBC).
Infrared Spectroscopy. Infrared spectra (IR) were recorded on a
PerkinElmer Spectrum Two ATR spectrometer using neat sample.
Peaks are reported in cm−1 with indicated relative intensities: s
(strong, 67−100%); m (medium, 34−66%); w (weak, 0−33%).
Mass Spectrometry. Chemical Ionization (CI) spectra were
performed with methane reagent gas with either a doublefocusing
sector field or time-of-flight (TOF) mass analyzer. Electrospray
ionization (ESI) mass spectra were performed on a Micromass
Quattro spectrometer. Data are reported in the form of (m/z)
(intensity relative to the base peak = 100 where applicable).
Melting Points. Melting points (mp) were determined in vacuum-
sealed capillary tubes using a Thomas-Hoover melting point apparatus
and are corrected.
Finally the use of chiral ruthenium bisoxazoline complexes
has allowed for the enantioselective generation of homoallylic
alcohols, albeit in moderate enrichment. Of particular note was
the importance of the bisoxazoline backbone to the
effectiveness of the reaction as only a methylene-bridged
bisoxazoline was able to induce enantioenrichment. A survey of
bisoxazoline ring substituents did reveal that the proximity of
the stereocenter substituent to the ruthenium metal had a
significant impact on the ability of the complex to yield
enantioenriched product. Furthermore, the addition of free
ligand and a corresponding increase in er revealed that an
equilibrium between ligated and unligated ruthenium was likely
responsible for the rate of the background, racemic reaction
which is known to be highly efficient for the substrates
employed. Additional ligands that take into account the
observations and findings from this survey could allow for a
future, highly enantioselective reaction to be designed.
Elemental Analysis. Elemental analyses were performed by the
University of Illinois Microanalytical Service Laboratory or by
Robertson Microlit Laboratories and is the average of two runs.
Distillation. Bulb-to-bulb distillation was performed on a Buchi
̈
GKR-50 Kugelrohr with boiling points (bp) corresponding to
uncorrected air-bath temperatures (ABT). A vacuum of 10−5 to 10−8
mmHg was achieved using a diffusion pump.
Liquid Chromatography. Analytical thin-layer chromatography was
performed on silica gel 60 F254 plates. Visualization was accomplished
with UV light and/or potassium permanganate (KMnO4) solution.
Retention factor (Rf) values reported were measured using a 10 × 2
cm TLC plate in a developing chamber containing the solvent system
described. Flash column chromatography was performed using 40−63
μm particle size (230−400 mesh, 60 Å pore size) SiO2.
Gas Chromatography. Analytical gas chromatography (GC) was
performed using a Hewlett-Packard 5890 Series II gas chromatograph
fitted with a flame ionization detector (H2 carrier gas, 1 mL/min).
Injections were made on a Hewlett-Packard HP-1 (30 m) capillary
column. The injector temperature was 250 °C, the detector
temperature was 300 °C, with a split ratio of 100:1. Retention times
(tR) and integrated ratios were obtained using Agilent Chemstation
Software.
EXPERIMENTAL SECTION
■
General Experimental Procedures. General Reactions. All
reactions were performed in oven-dried (120 °C) and/or flame-dried
glassware under an atmosphere of dry nitrogen or argon, unless noted.
Chiral Stationary Phase HPLC. Analytical chiral stationary normal-
phase high-pressure liquid chromatography was performed on an
Q
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Agilent 1100 HPLC equipped with a Chiralpak IB-3 column or Astec
Cellulose DMP column.
Preparation of trans-(E)-1,4-Diphenylhexa-1,5-dien-3-ol (7b).
Following the general allylation procedure, 1b (126 μL, 1.0 mmol),
RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (252 μL, 1.5 mmol, 1.5
equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1
equiv), and EtOH (2.5 mL) were combined under 40 psi of CO at 85
°C for 24 h. Workup and purification by silica gel column
chromatography (80 g SiO2, 4.5 × 13.5 cm column, Et2O/hexane
(1:9 (750 mL) → 1:4 (600 mL) → 1:3 (300 mL))) provided 7b (228
mg, 85%) as a white solid. The spectroscopic data matched those from
Chemicals. Hydrocinnamaldehyde (Alfa), trans-cinnamaldehyde
(Aldrich), pyridine (Fisher), triethylamine (Fisher), allyl methyl
carbonate (Aldrich), benzaldehyde (Aldrich), furfural (Alfa), 4-
methoxybenzaldehyde (Aldrich), 4-(trifluoromethyl)benzaldehyde
(Oakwood), were distilled prior to use. 4-Nitrobenzaldehyde was
sublimed prior to use. Ruthenium(III) chloride hydrate and
triruthenium dodecacarbonyl were purchased from Strem Chemical
and stored and handled in a drybox and used as received. All other
reagents were purchased from Aldrich, Fisher, Oakwood, or Strem and
used as received.
the literature.64 Data for 7b: H NMR (500 MHz, CDCl3) 7.40−7.30
1
(m, 2H, C(aryl)H), 7.30−7.23 (m, 6H, C(aryl)H), 7.25−7.18 (m, 2H,
C(aryl)H), 6.54 (dd, J = 15.9, 1.3 Hz, 1H, C(2′)H), 6.22 (ddd, J =
17.1, 10.3, 8.8 Hz, 1H, C(3)H), 6.10 (dd, J = 15.9, 6.2 Hz, 1H,
C(1′)H), 5.32−5.21 (m, 2H, C(4)H), 4.52 (ddd, J = 7.5, 4.5, 1.7 Hz,
1H, C(1)H), 3.47 (dd, J = 8.9, 7.0 Hz, 1H, C(2)H), 2.00 (d, J = 3.4
Hz, 1H, br OH); 13C{1H} NMR (125 MHz, CDCl3) 140.7, 137.9,
136.9, 131.2, 129.8, 128.7, 128.7, 128.6, 128.5, 127.6, 127.0, 126.6,
118.4, 77.4, 77.4 77.2, 76.9, 75.2, 57.7; MS (ESI) 273.1 (MNa+, 100);
TLC Rf 0.365 (Et2O/hexane, 1:4) [UV, KMnO4].
General Procedures. General Allylation Procedure for Prepara-
tive-Scale Allylation Reactions of Allylic Acetates. In a glovebox, to a
glass Fischer−Porter tube (150 mL) containing a Teflon-coated,
magnetic stir bar were added RuCl3 (5 mol %) and (if indicated)
TBACl (5 mol %). The tube was covered with a rubber septa before
being removed from the glovebox. Outside the glovebox, the tube was
charged sequentially with solvent (EtOH, t-BuOH, or 1,4-dioxane,
1.25−2.5 mL), H2O (1.5 or 2.5 equiv), Et3N (0.1 equiv), allyl pro-
nucleophile (E)-6 or 9, and aldehyde 1 (1.00 mmol, 1.0 equiv) via
syringe. The Fischer−Porter tube then was charged with CO gas (100
psi) and pressure was released to a vented hood four times before the
CO gas was maintained at 40 psi and the valves were closed. The
Fischer−Porter tube was inserted into a preheated oil bath (either 75
or 85 °C) that was placed onto a magnetic stirrer with a temperature
probe inserted into the oil bath. The stirring and heating was
maintained for 24 h. Upon elapse of the reaction time, the
Fisher−Porter tube was removed from the oil bath and allowed cool
to ambient temperature (within 10 min) upon which time, the outlet
was connected to a vented hood and the pressure in the Fisher-Porter
tube was gently released. The inlet was then connected to a nitrogen
line, and the system was purged by N2 (which was passed through a
drying tube filled with Drierite) for 15 min before the autoclave was
opened. The reaction mixture was transferred to a 20 mL glass
scintillation vial with the aid of 3 mL of methylene chloride. The
solvent was removed under reduced pressure by rotary evaporation
(25 °C, 20 mmHg) before being purified by the indicated method.
Preparation of Products Resulting from the use of (E)-
Cinnamyl Acetate. Preparation of trans-1,2-Diphenylbut-3-en-1-
ol (7a).
Preparation of trans-1,4-Diphenylhex-5-en-3-ol (7c). Following
the general allylation procedure, 1c (132 μL, 1.0 mmol), RuCl3 (13.0
mg, 0.05 mmol, 0.05 equiv), (E)-6 (202 μL, 1.2 mmol, 1.2 equiv),
H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv),
and t-BuOH (2.5 mL) were combined under 40 psi of CO at 85 °C for
24 h. Workup and purification by silica gel column chromatography
(80 g SiO2, 4.5 × 13.5 cm column, Et2O/hexane (1:9 (750 mL) → 1:4
(500 mL))) provided 7c (197 mg, 78%) as a colorless oil. The
spectroscopic data matched those from the literature.65 Data for 7c:
1H NMR (500 MHz, CDCl3) 7.37−7.28 (m, 2H, C(aryl)H), 7.25−
7.19 (m, 3H, C(aryl)H), 7.19−7.13 (m, 3H, C(aryl)H), 7.13−7.08 (m,
2H, C(aryl)H), 6.11 (ddd, J = 16.9, 10.3, 9.2 Hz, 1H, C(3)H), 5.26−
5.18 (m, 2H, C(4)H), 3.81 (td, J = 7.7, 3.5 Hz, 1H, C(1)H), 3.28 (dd,
J = 9.2, 7.4 Hz, 1H, C(2)H), 2.84 (ddd, J = 13.9, 9.7, 5.4 Hz, 1H,
C(2a’)H), 2.63 (ddd, J = 13.7, 9.7, 6.9 Hz, 1H, C(2b’)H), 1.86 (s, 1H,
br OH), 1.77−1.59 (m, 2H, C(1′)H); 13C{1H} NMR (125 MHz,
CDCl3) 142.2, 141.4, 138.4, 128.8, 128.5, 128.5, 128.4, 128.4, 128.4,
128.0, 126.8, 125.8, 118.1, 77.4, 77.3, 77.1, 76.9, 73.3, 57.6, 36.1, 32.1.;
MS: (ESI) 275.1 (MNa+, 100); TLC Rf 0.262 (Et2O/hexane, 1:4)
[UV, KMnO4].
Following the general allylation procedure, 1a (102 μL, 1.0 mmol),
RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (202 μL, 1.2 mmol, 1.2
equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1
equiv), and EtOH (2.5 mL) were combined under 40 psi of CO at 85
°C for 24 h. Workup and purification by silica gel column
chromatography (70 g SiO2, 3.5 × 20.5 cm column, Et2O/hexane
(1:9 (500 mL) → 1:4 (500 mL))) provided 7a (191 mg, 85%) as a
colorless oil. The spectroscopic data matched those from the
Preparation of trans-1-(4-Nitrophenyl)-2-phenylbut-3-en-1-ol
(7d). Following the general allylation procedure, 1d (151 mg, 1.0
mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (202 μL, 1.2
mmol, 1.2 equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1
mmol, 0.1 equiv), and EtOH (2.5 mL) were combined under 40 psi of
CO at 85 °C for 24 h. Workup and purification by silica gel column
chromatography (70 g SiO2, 3.5 × 20.5 cm column, Et2O/hexane (1:4
(750 mL) → 1:7 (250 mL) → 1:3 (500 mL))) provided 7d (196 mg,
73%) as a yellow solid. The spectroscopic data matched those from the
literature.63 Data for 7b: 1H NMR (500 MHz, CDCl3) 8.08−8.01 (m,
2H, C(aryl′)H), 7.32−7.15 (m, 5H, C(aryl)H), 7.07−7.01 (m, 2H,
C(aryl′)H), 6.23 (ddd, J = 17.1, 10.2, 9.1 Hz, 1H, C(3)H), 5.32 (dd, J
= 10.1, 1.4 Hz, 1H, C(4)Hcis), 5.26 (dt, J = 17.1, 1.1 Hz, 1H,
C(4)Htrans), 4.93 (dd, J = 7.9, 2.2 Hz, 1H, C(1)H), 3.48 (t, J = 8.5
Hz, 1H, C(2)H), 2.51 (d, J = 2.3 Hz, 1H, br OH); 13C{1H} NMR
(125 MHz, CDCl3) 149.2, 147.2, 139.6, 136.9, 128.8, 128.2, 127.5,
127.2, 123.1, 119.6, 76.8, 76.5, 59.6; MS: (ESI) 292.1 (MNa+, 69);
TLC Rf 0.169 (Et2O/hexane, 1:4) [UV, KMnO4].
literature.63 Data for 7a: H NMR (500 MHz, CDCl3) 7.25−7.17
1
(m, 5H, C(aryl)H), 7.17−7.12 (m, 3H, C(aryl)H), 7.08−7.03 (m, 2H,
C(aryl)H), 6.26 (ddd, J = 17.1, 10.3, 8.9 Hz, 1H, C(3)H), 5.28 (ddd, J
= 10.2, 1.6, 0.7 Hz, 1H, C(4)Hcis), 5.23 (ddd, J = 17.0, 1.6, 0.9 Hz,
1H, C(4)Htrans), 4.86 (d, J = 7.7 Hz, 1H, C(1)H), 3.56 (t, J = 8.3 Hz,
1H, C(2)H), 2.51−2.23 (m, 1H, br OH); 13C{1H} NMR (125 MHz,
CDCl3) 142.0, 140.7, 138.0, 128.5, 128.5, 128.0, 127.6, 126.8, 126.7,
118.6, 77.4, 59.4; MS (ESI) 247.0 (MNa+, 62), 118.9 (100); TLC Rf
0.258 (Et2O/hexane, 1:4) [UV, KMnO4].
R
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1H, C(4)Htrans), 4.81 (dd, J = 8.0, 1.7 Hz, 1H, C(1)H), 3.48 (t, J =
8.4 Hz, 1H, C(2)H), 2.35 (d, J = 2.3 Hz, 1H, br OH); 13C{1H} NMR
(125 MHz, CDCl3) 140.4, 140.3, 137.7, 133.2, 128.6, 128.4, 128.2,
128.2, 126.9, 119.0, 76.7, 59.6; MS: (ESI) 283.0 (MNa+ + 2, 17), 281.0
(MNa+, 58); TLC Rf 0.236 (Et2O/hexane, 1:4) [UV, KMnO4].
Preparation of trans-1-(4-Methoxyphenyl)-2-phenylbut-3-en-1-ol
(7e). Following the general allylation procedure, 7e (122 μL, 1.0
mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (252 μL, 1.5
mmol, 1.5 equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1
mmol, 0.1 equiv), and EtOH (2.5 mL) were combined under 40 psi of
CO at 85 °C for 24 h. Workup and purification by silica gel column
chromatography (70 g SiO2, 3.5 × 20.5 cm column, Et2O/hexane (1:9
(800 mL) → 1:4 (500 mL)) then 100% Et2O (100 mL)) provided 7e
(168 mg, 66%) as a yellow solid. The spectroscopic data matched
those from the literature.66 Data for 7e: 1H NMR (500 MHz, CDCl3)
7.23−7.18 (m, 2H, C(aryl)H), 7.17−7.12 (m, 1H, C(aryl)H), 7.10−
7.02 (m, 4H, C(aryl)H, C(aryl′)H), 6.78−6.71 (m, 2H, C(aryl′)H),
6.25 (ddd, J = 17.0, 10.3, 8.9 Hz, 1H, C(3)H), 5.27 (ddd, J = 10.2, 1.7,
0.7 Hz, 1H, C(4)Hcis), 5.24 (ddd, J = 17.1, 1.7, 0.9 Hz, 1H,
C(4)Htrans), 4.81 (dd, J = 7.9, 2.2 Hz, 1H, C(1)H), 3.75 (s, 3H,
C(5′)H3), 3.54 (t, J = 8.4 Hz, 1H, C(2)H), 2.28 (d, J = 2.4 Hz, 1H, bt
OH); 13C{1H} NMR (125 MHz, CDCl3) 158.9, 140.8, 138.3, 134.1,
128.4, 127.9, 126.6, 118.3, 113.4, 76.3, 76.9, 59.4, 55.2; MS (ESI)
277.1 (MNa+, 98); TLC Rf 0.142 (Et2O/hexane, 1:4) [UV, KMnO4].
Preparation of trans-1-(4-Bromophenyl)-2-phenylbut-3-en-1-ol
(7h). Following the general allylation procedure, 1h (185 mg, 1.0
mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (252 μL, 1.5
mmol, 1.5 equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1
mmol, 0.1 equiv), and EtOH (2.5 mL) were combined under 40 psi of
CO at 85 °C for 24 h. Workup and purification by silica gel column
chromatography (70 g SiO2, 3.5 × 20.5 cm column, Et2O/hexane (1:9
(750 mL) → 1:4 (500 mL) → 1:3 (300 mL))) provided 7h (278 mg,
90%) as a white solid. The spectroscopic data matched those from the
literature.63 Data for 7h: 1H NMR (500 MHz, CDCl3) 7.38−7.30 (m,
2H, C(aryl′)H), 7.25−7.19 (m, 2H, C(aryl)H), 7.19−7.11 (m, 1H,
C(aryl)H), 7.07−7.02 (m, 2H, C(aryl′)H), 7.02−6.95 (m, 2H,
C(aryl′)H), 6.22 (ddd, J = 17.1, 10.2, 9.0 Hz, 1H, C(3)H), 5.29
(ddd, J = 10.2, 1.6, 0.6 Hz, 1H, C(4)Hcis), 5.24 (ddd, J = 17.1, 1.6, 0.9
Hz, 1H, C(4)Htrans), 4.80 (d, J = 7.9 Hz, 1H, C(1)H), 3.47 (t, J = 8.4
Hz, 1H, C(2)H), 2.48−2.23 (m, 1H br OH); 13C{1H} NMR (125
MHz, CDCl3) 140.9, 140.3, 137.6, 131.1, 128.7, 128.5, 128.4, 127.0,
121.4, 119.0, 76.9, 76.7, 59.5; MS (ESI) 328.1 (MNa+ + 2, 8), 326.1
(MNa+, 10), 327.0 (47); TLC Rf 0.255 (Et2O/hexane, 1:4) [UV,
KMnO4].
Preparation of trans-2-Phenyl-1-(4-(trifluoromethyl)phenyl)but-
3-en-1-ol (7f). Following the general allylation procedure, 1f (137 μL,
1.0 mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (252 μL,
1.5 mmol, 1.5 equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL,
0.1 mmol, 0.1 equiv), and EtOH (2.5 mL) were combined under 40
psi of CO at 85 °C for 24 h. Workup and purification by silica gel
column chromatography (70 g SiO2, 3.5 × 20.5 cm column, Et2O/
hexane (1:9 (750 mL) → 1:4 (500 mL) → 1:3 (400 mL))) provided
7f (228 mg, 78%) as a colorless oil. The spectroscopic data matched
those from the literature.63 Data for 7f: 1H NMR (500 MHz, CDCl3)
7.46 (d, J = 8.2 Hz, 2H, C(aryl′)H), 7.28−7.21 (m, 4H, C(aryl)H),
7.21−7.15 (m, 1H, C(aryl)H), 7.10−7.01 (m, 2H, C(aryl′)H), 6.24
(ddd, J = 17.1, 10.2, 9.0 Hz, 1H, C(3)H), 5.30 (dd, J = 10.3, 1.5 Hz,
1H, C(4)Hcis), 5.25 (dt, J = 17.0, 1.2 Hz, 1H, C(4)Htrans), 4.89 (dd,
J = 7.6, 1.6 Hz, 1H, C(1)H), 3.51 (t, J = 8.4 Hz, 1H, C(2)H), 2.44 (d,
J = 2.4 Hz, 1H, br OH); 13C{1H} NMR (125 MHz, CDCl3) 145.9,
140.1, 137.3, 129.7 (q, J = 32.3 Hz), 128.7, 128.4, 127.1, 124.9 (q, J =
3.8 Hz), 124.3 (q, J = 272 Hz), 119.2, 76.8, 59.5; 19F{1H} NMR (470
MHz, CDCl3) δ −62.5; MS (ESI) 315.1 (MNa+, 23), 118.9 (100);
TLC Rf 0.254 (Et2O/hexane, 1:4) [UV, KMnO4].
Preparation of trans-1-(Naphthalen-2-yl)-2-phenylbut-3-en-1-ol
(7i). Following the general allylation procedure, 1i (156 μL, 1.0
mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (252 μL, 1.5
mmol, 1.5 equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1
mmol, 0.1 equiv), and EtOH (2.5 mL) were combined under 40 psi of
CO at 85 °C for 24 h. Workup and purification by silica gel column
chromatography (70 g SiO2, 3.5 × 20.5 cm column, Et2O/hexane
(1:20 (400 mL) → 1:9 (500 mL) → 1:4 (750 mL))) provided 7i (225
mg, 82%) as a white solid. The spectroscopic data matched those from
the literature.66 Data for 7i: H NMR (500 MHz, CDCl3) 7.80−7.75
1
(m, 1H, C(aryl′)H), 7.76−7.72 (m, 1H, C(aryl′)H), 7.71 (d, J = 8.6
Hz, 1H, C(aryl′)H), 7.65−7.59 (m, 1H, C(aryl′)H), 7.48−7.41 (m,
2H, C(aryl′)H), 7.29 (dd, J = 8.5, 1.7 Hz, 1H, C(aryl′)H), 7.22−7.17
(m, 2H, C(aryl)H), 7.16−7.12 (m, 1H, C(aryl)H), 7.11−7.08 (s, 1H,
C(aryl)H), 6.30 (ddd, J = 17.1, 10.2, 8.9 Hz, 1H, C(3)H), 5.29 (ddd, J
= 10.2, 1.6, 0.7 Hz, 1H, C(4)Hcis), 5.25 (ddd, J = 17.1, 1.6, 0.9 Hz,
1H, C(4)Htrans), 5.03 (dd, J = 7.6, 2.4 Hz, 1H, C(1)H), 3.68 (t, J =
8.2 Hz, 1H, C(2)H), 2.42 (d, J = 2.6 Hz, 1H, br OH); 13C{1H} NMR
(125 MHz, CDCl3) 140.7, 139.5, 137.9, 133.2, 133.0, 128.5, 128.5,
128.1, 127.7, 126.8, 126.0, 125.8, 124.8, 118.7, 77.4, 59.1; MS (ESI)
297.1 (MNa+, 80); TLC Rf 0.254 (Et2O/hexane, 1:4) [UV, KMnO4].
Preparation of trans-1-(4-Chlorophenyl)-2-phenylbut-3-en-1-ol
(7g). Following the general allylation procedure, 1g (141 mg, 1.0
mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (252 μL, 1.5
mmol, 1.5 equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1
mmol, 0.1 equiv), and EtOH (2.5 mL) were combined under 40 psi of
CO at 85 °C for 24 h. Workup and purification by silica gel column
chromatography (70 g SiO2, 3.5 × 20.5 cm column, Et2O/hexane (1:9
(750 mL) → 1:4 (500 mL) → 1:3 (300 mL))) provided 7g (234 mg,
90%) as a colorless oil. The spectroscopic data matched those from the
literature.63 Data for 7g: 1H NMR (500 MHz, CDCl3) 7.25−7.19 (m,
2H, C(aryl)H), 7.19−7.14 (m, 3H, C(aryl)H), 7.09−7.00 (m, 4H,
C(aryl)H), 6.23 (ddd, J = 17.1, 10.3, 9.0 Hz, 1H, C(3)H), 5.29 (ddd, J
= 10.2, 1.5, 0.6 Hz, 1H, C(4)Hcis), 5.25 (ddd, J = 17.1, 1.6, 1.0 Hz,
Preparation of trans-1-(Naphthalen-1-yl)-2-phenylbut-3-en-1-ol
(7j). Following the general allylation procedure, 1j (136 μL, 1.0
mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (252 μL, 1.5
mmol, 1.5 equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1
mmol, 0.1 equiv), and EtOH (2.5 mL) were combined under 40 psi of
S
DOI: 10.1021/acs.joc.7b02658
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CO at 85 °C for 24 h. Workup and purification by silica gel column
chromatography (70 g SiO2, 3.5 × 20.5 cm column, Et2O/hexane
(1:20 (900 mL) → 1:9 (500 mL) → 1:4 (500 mL))) provided 7j (220
mg, 81%) as a white solid. The spectroscopic data matched those from
the literature.66 Data for 7j: H NMR (500 MHz, CDCl3) 8.14−8.08
1
(m, 1H, C(aryl′)H), 7.89−7.81 (m, 1H, C(aryl′)H), 7.74 (dt, J = 8.2,
1.0 Hz, 1H, C(aryl′)H), 7.54 (dt, J = 7.2, 0.9 Hz, 1H, C(aryl′)H),
7.53−7.43 (m, 2H, C(aryl′)H), 7.41 (dd, J = 8.1, 7.2 Hz, 1H,
C(aryl′)H), 7.29−7.20 (m, 4H, C(aryl)H), 7.20−7.13 (m, 1H,
C(aryl)H), 6.32 (ddd, J = 17.1, 10.3, 8.4 Hz, 1H, C(3)H), 5.71 (dd,
J = 5.5, 3.1 Hz, 1H, C(4)Hcis), 5.21 (ddd, J = 10.3, 1.6, 0.8 Hz, 1H,
C(4)Htrans), 4.99 (ddd, J = 17.2, 1.6, 1.0 Hz, 1H, C(1)H), 3.94 (dd, J
= 8.5, 5.5 Hz, 1H, C(2)H), 2.30 (d, J = 3.2 Hz, 1H, br OH); 13C{1H}
NMR (125 MHz, CDCl3) 141.8, 137.8, 136.8, 133.8, 130.6, 129.0,
128.6, 128.3, 128.2, 126.8, 126.0, 125.4, 125.2, 124.7, 123.3, 118.7,
74.3, 56.7; MS (ESI) 297.1 (MNa+, 93); TLC Rf 0.303 (Et2O/hexane,
1:4) [UV, KMnO4].
Preparation of trans-2-Phenyl-1-(1-tosyl-1H-pyrrol-2-yl)but-3-en-
1-ol (7m). Following the general allylation procedure, 1m (249 mg, 1.0
mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (252 μL, 1.5
mmol, 1.5 equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1
mmol, 0.1 equiv), and t-BuOH (2.5 mL) were combined under 40 psi
of CO at 85 °C for 24 h. Workup and purification by silica gel column
chromatography (90 g SiO2, 4.5 × 13.5 cm column, Et2O/hexane
(1:10 w/1% Et3N (200 mL to treat column) and then (1:10 (850 mL)
→ 1:4 (500 mL) → 1:3 (600 mL) → 1:1 (300 mL))) provided 7m
(250 mg, 68%) as a colorless glassy oil. [Note: Compound is unstable
to SiO2]. Data for 7m: bp 125 °C (ABT, 10−5 mm Hg) 1H NMR (500
MHz, CDCl3) 7.62 (d, J = 8.4 Hz, 1H, C(6’)H), 7.28 (d, J = 8.4, 2H,
C(7’)H), 7.22 (dd, J = 3.3, 1.7 Hz, 1H, C(4′)H), 7.18−7.11 (m, 3H,
C(aryl)H), 7.01 (dd, J = 7.7, 1.8 Hz, 2H, C(aryl)H), 6.25−6.16 (ddd, J
= 8.5, 8.5, 1.7, 1H, C(3)), 6.20 (dd, J = 3.3, 1.8, 1H, C(2′)H), 6.15 (t, J
= 3.4 Hz, 1H, C(3′)), 5.25 (dd, J = 7.8, 4.2 Hz, 1H, C(1)H), 5.16
(ddd, J = 10.2, 1.6, 0.8 Hz, 1H, C(4)Hcis), 5.04 (dt, J = 17.1, 1.4 Hz,
1H, C(4)Htrans), 3.86 (t, J = 8.1 Hz, 1H, C(2)H), 2.58 (d, J = 4.2 Hz,
1H, br OH), 2.42 (s, 3H, C(9’)H3); 13C{1H} NMR (125 MHz,
CDCl3) 145.1 C(8’), 141.6 C(5), 138.2 C(3), 136.5 C(5′), 136.0
C(1′), 130.2 C(7’), 128.6 C(aryl), 128.1 C(aryl), 126.8 C(6’), 126.6
C(aryl), 123.5 C(4′), 117.7 C(4), 114.4 C(2′), 111.8 C(3′), 68.7
C(1), 55.0 C(2), 21.8 C(9’); IR (neat) 3554 (w), 3439 (w), 3149 (w),
3063 (w), 3029 (w), 2980 (w), 2923 (w), 1597 (w), 1494 (w), 1453
(w), 1403 (w), 1363 (w), 1307 (w), 1293 (w), 1190 (m), 1173 (s),
1152 (m), 1090 (m), 1058 (m), 1018 (w), 1000 (w), 920 (w), 813
(w), 781 (w), 756 (w), 723 (m), 701 (m), 674 (s), 590 (s), 544 (m);
MS (ESI) 390.1 (MNa+, 6), 352.1 (13), 351.1 (40), 350.1 (100); TLC
Rf 0.103 (Et2O/hexane, 1:4) [UV, KMnO4]. CHN Anal. Calcd for
C21H21NO3S (367.46): C, 68.64; H, 5.76; N, 3.81. Found: C, 68.99;
H, 5.59; N, 3.68.
Preparation of trans-1-(2-Methoxyphenyl)-2-phenylbut-3-en-1-ol
(7k). Following the general allylation procedure, 1k (136 mg, 1.0
mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (252 μL, 1.5
mmol, 1.5 equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1
mmol, 0.1 equiv), and EtOH (2.5 mL) were combined under 40 psi of
CO at 85 °C for 24 h. Workup and purification by silica gel column
chromatography (70 g SiO2, 3.5 × 20.5 cm column, Et2O/hexane (1:9
(750 mL) → 1:4 (500 mL) → 1:3 (250 mL))) provided 7k (235 mg,
92%) as a colorless oil. The spectroscopic data matched those from the
literature.66 Data for 7k: 1H NMR (500 MHz, CDCl3) 7.25−7.10 (m,
8H, C(aryl)H), 6.85 (td, J = 7.5, 1.1 Hz, 1H, C(aryl′)H), 6.78 (dt, J =
7.6, 1.1 Hz, 1H, C(aryl′)H), 6.30 (ddd, J = 17.1, 10.3, 8.5 Hz, 1H,
C(3)H), 5.20 (ddd, J = 10.3, 1.8, 0.8 Hz, 1H, C(4)Hcis), 5.14 (dd, J =
6.9, 5.8 Hz, 1H, C(1)H), 5.09 (ddd, J = 17.2, 1.8, 1.1 Hz, 1H,
C(4)Htrans), 3.74 (s, 3H, C(5′)H3), 2.65 (d, J = 5.9 Hz, 1H, br OH);
13C{1H} NMR (125 MHz, CDCl3) 156.5, 141.8, 138.1, 130.3, 128.4,
128.4, 128.2, 128.1, 126.4, 120.5, 117.7, 110.4, 74.0, 56.81, 55.3; MS
(ESI) 277.1 (MNa+, 68), 237.0 (100); TLC Rf 0.242 (Et2O/hexane,
1:4) [UV, KMnO4].
Preparation of trans-2,2-Dimethyl-4-phenylhex-5-en-3-ol (7n).
Following the general allylation procedure, 1n (109 μL, 1.0 mmol),
RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (252 μL, 1.5 mmol, 1.5
equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1
equiv), and t-BuOH (1.25 mL) were combined under 40 psi of CO at
85 °C for 24 h. Workup and purification by silica gel column
chromatography (70 g SiO2, 3.5 × 20.5 cm column, Et2O/hexane
(1:50 (800 mL) → 1:20 (500 mL) → 1:13 (500 mL) → 1:9 (500
mL))) provided 7n (27 mg, 13%) as a colorless oil. The spectroscopic
Preparation of trans-1-(Furan-2-yl)-2-phenylbut-3-en-1-ol (7l).
Following the general allylation procedure, 1l (83 μL, 1.0 mmol),
RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (252 μL, 1.5 mmol, 1.5
equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1
equiv), and t-BuOH (2.5 mL) were combined under 40 psi of CO at
85 °C for 24 h. Workup and purification by silica gel column
chromatography (70 g SiO2, 3.5 × 20.5 cm column, Et2O/hexane
(1:20 (900 mL) → 1:13 (500 mL) → 1:9 (1000 mL) → 1:7 (500
mL))) provided 7l (195 mg, 91%) as a colorless oil. The spectroscopic
data matched those from the literature.66 Data for 7l: H NMR (500
1
data matched those from the literature.67 Data for 7n: H NMR (500
1
MHz, CDCl3) 7.32 (dd, J = 1.9, 0.9 Hz, 1H, C(4′)H), 7.27−7.21 (m,
2H, C(aryl)H), 7.21−7.12 (m, 3H, C(aryl)H), 6.28−6.17 (ddd, J =
8.5, 8.5, 1.8 1H, C(3)H), 6.21 (dt, J = 3.2, 0.7 Hz, 1H, C(3′)H), 6.06
(dt, J = 3.2, 0.7 Hz, 1H, C(2′)H), 5.28 (ddd, J = 10.2, 1.6, 0.9 Hz, 1H,
C(4)Hcis), 5.24 (d, J = 2.6 Hz, 1H, C(4)Htrans), 4.90 (dd, J = 7.9, 4.0
Hz, 1H, C(1)H), 3.84 (t, J = 8.3 Hz, 1H, C(2)H), 2.27 (d, J = 4.2 Hz,
1H, br OH); 13C{1H} NMR (125 MHz, CDCl3) 154.3, 141.9, 140.5,
137.7, 128.6, 128.2, 126.9, 118.6, 110.2, 110.1, 107.7, 71.1, 56.0; MS
(ESI) 237.0 (MNa+, 68), 197.0 (100); TLC Rf 0.200 (Et2O/hexane,
1:4) [UV, KMnO4].
MHz, CDCl3) 7.39−7.35 (m, 2H, C(aryl)H), 7.31 (t, J = 7.3 Hz, 2H,
C(aryl)H), 7.24−7.19 (m, 1H, C(aryl)H), 6.50 (d, J = 15.9 Hz, 1H,
C(4)Hcis), 6.28 (ddd, J = 15.8, 8.2, 6.3 Hz, 1H, C(4)Htrans), 3.35 (dd, J
= 10.6, 2.3 Hz, 1H, C(H)1), 2.51 (ddt, J = 14.1, 6.0, 1.7 Hz, 1H,
C(2)H), 2.17 (dddd, J = 14.3, 10.5, 8.3, 1.1 Hz, 1H, C(3)H), 1.70−
1.62 (m, 1H, C(1)OH), 0.96 (d, J = 1.2 Hz, 9H, C(2’′)H3 × 3);
13C{1H} NMR (125 MHz, CDCl3) 137.4, 132.9, 128.7, 128.2, 127.3,
126.2, 78.8, 77.4, 66.0, 35.9, 34.9, 25.9, 25.9, 15.4; MS (ESI) 204.1
(MH+, 6), 118.1 (100); TLC Rf 0.358 (Et2O/hexane, 1:4) [KMnO4].
T
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the literature.69 Data for 10a: 1H NMR (500 MHz, CDCl3) 7.31−7.26
(m, 3H, C(aryl′)H), 7.24−7.14 (m, 2H, C(aryl′)H), 5.78−5.48 (m,
2H, C(4)H, C(3)H), 4.64 (dd, J = 7.4, 5.5 Hz, 1H, C(1)H), 3.99 (d, J
= 4.7 Hz, 1H, C(5)H), 2.61−2.48 (m, 1H, br C(1)OH)), 2.48−2.37
(m, 1H, C(2)H), 2.14 (s, 1H, br C(5)OH); 13C{1H} NMR (125
MHz, CDCl3) 144.0, 132.8, 128.5, 128.5, 127.7, 125.9, 73.6, 63.4, 42.2;
MS (ESI) 201.0 (MNa+, 100); TLC Rf 0.241 (Et2O/CH2Cl2, 4:1)
[UV, KMnO4].
Preparation of trans-3-Phenylnon-1-en-4-ol (7o). Following the
general allylation procedure, 1o (120 μL, 1.0 mmol), RuCl3 (13.0 mg,
0.05 mmol, 0.05 equiv), (E)-6 (252 μL, 1.5 mmol, 1.5 equiv), H2O (27
μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv), and t-
BuOH (2.5 mL) were combined under 40 psi of CO at 85 °C for 24 h.
Workup and purification by silica gel column chromatography (80 g
SiO2, 4.5 × 13.5 cm column, benzene/CH2Cl2 (1:1, 1500 mL)) and
then (24 g SiO2, 2.5 × 13.5 cm column, Et2O/hexane (1:99 (500 mL)
→ 1:50 (500 mL) → 1:20 (200 mL)) provided 7o (125 mg, 57%) as a
colorless oil. The spectroscopic data matched those from the
Preparation of (2E,6E)-7-Phenylhepta-2,6-diene-1,5-diol (10b).
Following the general allylation procedure, 1b (126 μL, 1.0 mmol),
RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), TBACl (13.9 mg, 0.05 mmol,
0.05 equiv), 9 (201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL, 2.5 mmol,
2.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL)
were combined under 40 psi of CO at 75 °C for 24 h. Workup and
purification by silica gel column chromatography (80 g SiO2, 4.5 ×
13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600 mL)) then
Et2O/MeOH (20:1, 400 mL) provided 10b (175 mg, 87%) as a
colorless oil with an E/Z ratio of 20:1. An analytically pure sample was
prepared via distillation. Data for 10b: bp 110 °C (ABT, 10−5 mm
Hg); IR (neat) 3326 (m), 3082 (w), 3058 (w), 3026 (w), 2923 (w),
2867 (w), 1670 (w), 1578 (w), 1599 (w), 1494 (w), 1449 (w); MS
(ESI) 227.1 (MNa+, 100); TLC Rf 0.228 (Et2O/CH2Cl2, 4:1) [UV,
KMnO4]. CHN Anal. Calcd for C13H16O2 (204.27): C, 76.44; H, 7.90.
Found: C, 76.20; H, 7.81. A portion of the material was sacrificially
literature.68 Data for 7o: H NMR (500 MHz, CDCl3) 7.35−7.29
1
(m, 2H, C(aryl)H), 7.25−7.17 (m, 3H, C(aryl;)H), 6.13 (ddd, J =
17.0, 10.3, 9.1 Hz, 1H, C(3)H), 5.26−5.17 (m, 2H, C(4)Hcis,
C(4)Htrans), 3.79 (q, J = 4.0, 3.3 Hz, 1H, C(1)H), 3.25 (dd, J = 9.3, 7.0
Hz, 1H, C(2)H), 1.83−1.71 (m, 1H, C(1)OH), 1.42−1.14 (m, 8H,
C(4′)CH2, C(3′)CH2, C(2′)CH2, C(1′)CH2), 0.85 (t, J = 7.0 Hzf,
3H, C(5′)H3); 13C{1H} NMR (125 MHz, CDCl3) 138.5, 128.8,
128.1, 126.8, 118.0, 77.4, 74.1, 57.6, 34.5, 31.9, 25.5, 22.7, 14.2; MS
(ESI) 241.1 (MNa+, 100); TLC Rf 0.351 (Et2O/hexane, 1:4)
[KMnO4].
1
purified to yield pure E-product and the spectra data is as follows: H
NMR (500 MHz, CDCl3) 7.39−7.36 (m, 2H, C(aryl′)H), 7.34−7.29
(m, 2H, C(aryl′)H), 7.25−7.22 (m, 1H, C(aryl′)H), 6.60 (dd, J =
15.7, 1.1 Hz, 1H, C(2′)H), 6.24 (dd, J = 15.9, 6.4 Hz, 1H, C(1′)H),
5.91−5.67 (m, 2H, C(4)H, C(3)H), 4.36 (d, J = 6.3 Hz, 1H, C(1)H),
4.19−4.10 (m, 2H, C(5)H2), 2.53−2.25 (m, 2H, C(2)H2), 2.03 (s,
1H, br C(1)OH), 1.68 (d, J = 7.2 Hz, 1H, C(5)OH); 13C{1H} NMR
(125 MHz, CDCl3) 136.6 C(3′), 133.0 C(4), 131.6 C(1′), 130.6
C(2′), 128.7 C(aryl′), 128.0 C(3), 127.9 C(aryl′), 126.6 C(aryl′), 72.1
C(1), 63.6 C(5), 40.5 C(2).
Preparation of trans-1-Cyclohexyl-2-phenylbut-3-en-1-ol (7p).
Following the general allylation procedure, 1p (112 mg, 1.0 mmol),
RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), (E)-6 (252 μL, 1.5 mmol, 1.5
equiv), H2O (27 μL, 1.5 mmol, 1.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1
equiv), and t-BuOH (2.5 mL) were combined under 40 psi of CO at
85 °C for 24 h. Workup and purification by silica gel column
chromatography (80 g SiO2, 4.5 × 13.5 cm column, benzene/CH2Cl2
(1:1, 1500 mL)) and then (24 g SiO2, 2.5 × 13.5 cm column, Et2O/
hexane (1:99 (500 mL) → 1:50 (500 mL) → 1:25 (200 mL))
provided 7p (36 mg, 16%) as a colorless oil. The spectroscopic data
matched those from the literature.63 Data for 7p: 1H NMR (500 MHz,
CDCl3) 7.35−7.28 (m, 2H, C(aryl)H), 7.25−7.19 (m, 3H, C(aryl)H),
6.14 (ddd, J = 17.1, 10.2, 9.1 Hz, 1H, C(3)H), 5.26−5.14 (m, 2H,
C(4)Hcis, C(4)Htrans, 3.57 (ddd, J = 7.1, 4.0, 2.7 Hz, 1H, C(1)H),
3.46−3.43 (m, 1H, C(2)H), 1.92−1.77 (m, 1H, C(1′)H), 1.75−1.68
(m, 2H, C(cyclohex)H), 1.65 (d, J = 3.4 Hz, 1H, C(1)OH), 1.63−1.56
(m, 2H, C(cyclohex)H), 1.28−1.23 (m, 2H, C(cyclohex)H), 1.17−
1.03 (m, 4H, C(cyclohex)H); 13C{1H} NMR (125 MHz, CDCl3)
142.2, 138.6, 128.9, 128.1, 126.7, 117.8, 78.2, 77.4, 53.8, 39.7, 30.4,
26.7, 26.6, 26.5, 26.1; MS (ESI) 253.1 (MNa+, 100); TLC Rf 0.352
(Et2O/hexane, 1:4) [KMnO4].
Preparation of (E)-7-Phenylhept-2-ene-1,5-diol (10c). Following
the general allylation procedure, 1c (132 μL, 1.0 mmol), RuCl3 (13.0
mg, 0.05 mmol, 0.05 equiv), TBACl (13.9 mg, 0.05 mmol, 0.05 equiv),
9 (201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL, 2.5 mmol, 2.5 equiv),
Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL) were
combined under 40 psi of CO at 75 °C for 24 h. Workup and
purification by silica gel column chromatography (80 g SiO2, 4.5 ×
13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600 mL)) then
Et2O/MeOH (20:1, 400 mL) provided 10c (183 mg, 90%) as a
colorless oil with an E/Z ratio of 6:1. The spectroscopic data matched
those from the literature.70 Data for 10c: 1H NMR (500 MHz, CDCl3)
7.31−7.26 (m, 2H, C(aryl)H), 7.22−7.17 (m, 3H, C(aryl)H), 5.82−
5.65 (m, 2H, C(3)H, C(4)H), 4.15−4.09 (m, 2H, C(5)H2), 3.71−
3.64 (m, 1H, C(1)H), 2.80 (dt, J = 13.6, 8.0 Hz, 1H, C(1′)Ha), 2.68
(dt, J = 13.7, 8.1 Hz, 1H, C(1′)Hb), 2.37−2.24 (m, 1H, C(2′)Ha),
2.25−2.13 (m, 1H C(2′)Ha), 2.08−1.90 (m, 2H, br C(1)OH, br
C(5)OH), 1.84−1.73 (m, 2H, C(2)H2); 13C{1H} NMR (125 MHz,
CDCl3) 142.1, 132.7, 128.6, 128.6, 128.5, 126.0, 70.4, 63.5, 40.5, 38.7,
32.1; MS (ESI) 229.0 (MNa+, 100); TLC Rf 0.253 (Et2O/CH2Cl2,
4:1) [UV, KMnO4].
Preparation of Products Resulting from the Use of
Vinyloxirane.
Preparation of (E)-5-Phenylpent-2-ene-1,5-diol (10a). Following the
general allylation procedure, 1a (102 μL, 1.0 mmol), RuCl3 (13.0 mg,
0.05 mmol, 0.05 equiv), TBACl (13.9 mg, 0.05 mmol, 0.05 equiv), 9
(201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL, 2.5 mmol, 2.5 equiv),
Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL) were
combined under 40 psi of CO at 75 °C for 24 h. Workup and
purification by silica gel column chromatography (80 g SiO2, 4.5 ×
13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600 mL)) then
Et2O/MeOH (20:1, 400 mL) provided 10a (150 mg, 88%) as a white
solid as just the E-isomer. The spectroscopic data matched those from
Preparation of (E)-5-(4-Nitrophenyl)pent-2-ene-1,5-diol (10d).
Following the general allylation procedure, 1d (151 mg, 1.0 mmol),
U
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RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), TBACl (13.9 mg, 0.05 mmol,
0.05 equiv), 9 (201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL, 2.5 mmol,
2.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL)
were combined under 40 psi of CO at 75 °C for 24 h. Workup and
purification by silica gel column chromatography (80 g SiO2, 4.5 ×
13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600 mL)) then
Et2O/MeOH (20:1, 400 mL) provided 10d (190 mg, 85%) as a yellow
solid with an E/Z ratio of greater than 100:1. An analytically pure
sample was prepared via recrystallization from hexanes. Data for 10d:
and the spectra data is as follows: 1H NMR (500 MHz, CDCl3) 7.63−
7.59 (m, 2H, C(3′)H), 7.47 (dq, J = 7.8, 0.9 Hz, 2H, C(2′)H), 5.79
(dtt, J = 15.4, 5.3, 1.1 Hz, 1H, C(4)H), 5.69 (dddt, J = 15.3, 7.8, 6.5,
1.3 Hz, 1H, C(3)H), 4.81 (ddd, J = 7.7, 4.7, 2.3 Hz, 1H, C(1)H), 4.12
(dd, J = 5.3, 2.5 Hz, 2H, C(5)H2), 2.57−2.49 (m, 1H, C(2)Ha), 2.49−
2.43 (m, 1H, C(2)Hb), 2.28 (d, J = 3.3 Hz, 1H, br C(1)OH), 1.53 (s,
1H, br C(5)OH); 13C{1H} NMR (125 MHz, CDCl3) 147.9 C(1′),
133.6 C(4), 129.9 (q, J = 32.3 Hz, C(4′)), 127.5 C(3), 126.2 C(2′),
125.5 (q, J = 3.8 Hz, C(3′) × 2), 124.3 (q, J = 272.3 Hz, C(5′)), 73.0
C(1), 63.4 C(5), 42.4 C(2); 19F{1H} NMR (470 MHz, CDCl3) δ
−62.5.
1
mp 100−102 °C; H NMR (500 MHz, CDCl3) 8.21 (dd, J = 8.6, 5.1
Hz, 2H, C(3′)H), 7.53 (dd, J = 8.9, 0.7 Hz, 1H, C(2′)H), 5.79 (dtt, J =
15.4, 5.2, 1.1 Hz, 1H, C(4)H), 5.70 (dddt, J = 15.2, 7.6, 6.3, 1.3 Hz,
1H, C(3)H), 4.87 (dt, J = 7.9, 3.8 Hz, 1H, C(1)H), 4.14 (td, J = 5.2,
1.6 Hz, 2H, C(5)CH2), 2.59−2.52 (m, 1H, C(2)Ha), 2.46 (dddd, J =
14.2, 8.4, 7.5, 0.9 Hz, 1H, C(2)Hb), 2.30 (d, J = 3.4 Hz, 1H, br
C(1)OH), 1.46 (t, J = 5.5 Hz, 1H, br C(5)OH); 13C{1H} NMR (125
MHz, CDCl3) 151.2 C(4′), 147.5 C(1′), 134.1 C(4), 126.8 C(3),
126.7 C(3′), 123.8 C(2′), 72.6 C(1), 63.3 C(5), 42.5 C(2); IR (neat)
3331 (w), 2920 (w) 2854 (w), 1672 (w), 1599 (w), 1515 (s), 1428
(w); MS (ESI) 246.0; (MNa+, 100); TLC Rf 0.178 (Et2O/CH2Cl2,
4:1) [UV, KMnO4]. CHN Anal. Calcd for C11H13NO4 (223.23): C,
59.19; H, 5.87; N, 6.27. Found: C, 58.96; H, 5.67; N, 6.21.
Preparation of (E)-5-(4-Chlorophenyl)pent-2-ene-1,5-diol (10g).
Following the general allylation procedure, 1g (141 mg, 1.0 mmol),
RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), TBACl (13.9 mg, 0.05 mmol,
0.05 equiv), 9 (201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL, 2.5 mmol,
2.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL)
were combined under 40 psi of CO at 75 °C for 24 h. Workup and
purification by silica gel column chromatography (80 g SiO2, 4.5 ×
13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600 mL)) then
Et2O/MeOH (20:1, 400 mL) and then subsequent distillation
provided 10g (176 mg, 83%) as a colorless oil with an E/Z ratio of
1
Preparation of (E)-5-(4-Methoxyphenyl)pent-2-ene-1,5-diol
(10e). Following the general allylation procedure, 1e (122 μL, 1.0
mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), TBACl (13.9 mg,
0.05 mmol, 0.05 equiv), 9 (201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL,
2.5 mmol, 2.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane
(1.25 mL) were combined under 40 psi of CO at 75 °C for 24 h.
Workup and purification by silica gel column chromatography (80 g
SiO2, 4.5 × 13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600
mL)) then Et2O/MeOH (20:1, 400 mL) provided 10e (110 mg, 53%)
as a yellow oil with an E/Z ratio of 4:1. An analytically pure sample
was prepared via distillation. Data for 10e: bp 110 °C (ABT, 10−8 mm
Hg); 1H NMR (500 MHz, CDCl3) 7.27 (d, J = 8.4 Hz, 2H, C(2′)H),
6.88 (dd, J = 8.1, 4.2 Hz, 2H, C(3′)H), 5.82−5.73 (m, 1H, C(4)H),
5.69 (dddt, J = 15.4, 7.3, 6.6, 1.0 Hz, 1H, C(3)H), 4.69 (dd, J = 7.2, 6.2
Hz, 1H, C(1)H), 4.10 (d, J = 5.3 Hz, 2H, C(5)H2), 3.81 (s, 3H,
C(5′)H3), 2.54−2.42 (m, 2H, C(2)H2), 2.02 (s, 1H, C(1)OH), 1.47
(s, 1H, C(5)OH); 13C{1H} NMR (125 MHz, CDCl3) 159.2 C(4′),
136.2 C(1′), 132.7 C(1), 128.6 C(3), 127.1 C(2′), 114.0 C(3′), 73.4
C(1), 63.6 C(5), 55.4 C(5′), 42.2 C(2); IR (neat): 3350 (w), 3003
(w), 2926 (w), 2838 (w), 1670 (w), 1612 (w), 1586 (w), 1512 (s),
1463.10 (w), 1442 (w), 1424 (w)); MS (ESI) 231.0 (MNa+, 100);
HRMS (ES+,TOF) calcd for C12H16O3Na 231.0997, found 231.1003;
TLC Rf 0.211 (Et2O/CH2Cl2, 4:1) [UV, KMnO4].
14:1. Data for 10g: bp 120 °C (ABT, 0.05 mmHg); H NMR (500
MHz, CDCl3) 7.31 (dd, J = 6.5, 2.2 Hz, 2H, C(3′)H), 7.28 (dd, J =
6.2, 2.2 Hz, 2H, C(2′)H), 5.80−5.71 (m, 1H, C(4)H), 5.71−5.59 (m,
1H, C(3)H), 4.70 (dd, J = 7.7, 5.1 Hz, 1H, C(1)H), 4.09 (dd, J = 5.6,
1.3 Hz, 2H, C(5)H2), 2.55−2.31 (m, 2H, C(2)H2), 1.99−1.66 (m, 2H,
br C(1)OH, br C(5)OH); 13C{1H} NMR (125 MHz, CDCl3) 142.5
C(4′), 133.3 C(1′), 133.2 C(4), 128.7 C(3′), 127.9 C(3), 127.3 C(2′),
72.9 C(1), 63.4 C(5), 42.3 C(2); IR (neat) 3325 (m), 3029 (w), 2923
(w), 2868 (w), 1671 (w), 1597 (w), 1490 (m), 1408 (m); MS (ESI)
237.0 (MNa+ + 2, 25), 235.0 (MNa+, 65), 177.1 (100); TLC Rf 0.306
(Et2O/CH2Cl2, 4:1) [UV, KMnO4]. CHN Anal. Calcd for
C11H13O2Cl (212.67): C, 62.12; H, 6.16. Found: C, 61.91; H, 6.17.
Preparation of (E)-5-(4-Bromophenyl)pent-2-ene-1,5-diol (10h).
Following the general allylation procedure, 1h (185 mg, 1.0 mmol),
RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), TBACl (13.9 mg, 0.05 mmol,
0.05 equiv), 9 (201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL, 2.5 mmol,
2.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL)
were combined under 40 psi of CO at 75 °C for 24 h. Workup and
purification by silica gel column chromatography (80 g SiO2, 4.5 ×
13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600 mL)) then
Et2O/MeOH (20:1, 400 mL) and then subsequent distillation
provided 10h (220 mg, 85%) as a colorless oil with an E/Z ratio of
18:1. Data for 10h: bp 130 °C (ABT, 0.05 mmHg); IR (neat) 3340
(m), 2925 (w), 2869 (w), 1671 (w), 1592 (w), 1487 (m), 1404 (m);
MS (ESI) 282.9 (MNa+ + 2, 41), 280.9 (MNa+, 41); TLC Rf 0.301
(Et2O/CH2Cl2, 4:1) [UV, KMnO4]. CHN Anal. Calcd for
C11H13O2Br (257.13): C, 51.38; H, 5.10. Found C, 51.07; H, 4.81.
A portion of the material was sacrificially purified to yield pure E-
product and the spectra data is as follows: 1H NMR (500 MHz,
CDCl3) 7.46 (dd, J = 6.7, 1.8 Hz, 2H, C(3′)H), 7.21 (dd, J = 6.7, 1.7
Hz, 2H, C(2′)H), 5.79−5.71 (m, 1H, C(4)H), 5.66 (dddt, J = 15.3,
7.7, 6.6, 1.3 Hz, 1H, C(3)H), 4.69 (dd, J = 7.8, 5.1 Hz, 1H, C(1)H),
4.09 (dd, J = 5.7, 1.5 Hz, 2H, C(5)H2), 2.51−2.34 (m, 2H, C(2)H2),
1.95−1.79 (m, 1H, br C(1)OH), 1.80−1.75 (m, 1H, br C(5)OH).
13C{1H} NMR (125 MHz, CDCl3) 143.0 C(4′), 133.2 C(4), 131.6
C(3′), 127.9 C(3), 127.7 C(2′), 121.4 C(1′), 73.0 C(1), 63.4 C(5),
42.3 C(2).
Preparation of (E)-5-(4-(Trifluoromethyl)phenyl)pent-2-ene-1,5-
diol (10f). Following the general allylation procedure, 1f (137 μL, 1.0
mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), TBACl (13.9 mg,
0.05 mmol, 0.05 equiv), 9 (201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL,
2.5 mmol, 2.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane
(2.5 mL) were combined under 40 psi of CO at 75 °C for 24 h.
Workup and purification by silica gel column chromatography (80 g
SiO2, 4.5 × 13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600
mL)) then Et2O/MeOH (20:1, 400 mL) and then subsequent
recrystallization from hexanes provided 10f (217 mg, 88%) as a white
solid with an E/Z ratio of 6:1. Data for 10f: mp 42−44 °C; IR (neat)
3547 (w), 3368 (w), 2924 (w), 2868 (w), 1596 (w), 1477 (w), 1402
(w); MS (ESI) 26.91 (MNa+, 12), 229.0 (40), 211.1 (100); TLC Rf
0.258 (Et2O/CH2Cl2, 4:1) [UV, KMnO4]. CHN Anal. Calcd for
C12H13F3O2 (246.23): C, 58.54; H, 5.32. Found: C, 58.21; H, 5.13. A
portion of the material was sacrificially purified to yield pure E-product
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(2.5 mL) were combined under 40 psi of CO at 75 °C for 24 h.
Workup and purification by silica gel column chromatography (80 g
SiO2, 4.5 × 13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600
mL)) then Et2O/MeOH (20:1, 400 mL) provided 10k (183 mg, 88%)
as a slightly yellow solid after a subsequent distillation with an E/Z
ratio of 17:1. Data for 10k: bp 125 °C (ABT, 0.05 mmHg); mp 70−72
°C; IR (neat) 3292 (m), 3200 (w), 2958 (w), 2928 (w), 2904 (w),
2837 (w), 1669 (w), 1600 (m), 1587 (w), 1488 (m), 1462 (m), 1438
(m), 1420 (m); MS (ESI) 231.1 (MNa+, 30), 173.1 (100); TLC Rf
0.301 (Et2O/CH2Cl2, 4:1) [UV, KMnO4]. CHN Anal. Calcd for
C12H16O3 (208.26): C, 69.21; H, 7.74. Found C, 68.85; H, 7.70. A
portion of the material was sacrificially purified to yield pure E-product
Preparation of (E)-5-(Naphthalen-2-yl)pent-2-ene-1,5-diol (10i).
Following the general allylation procedure, 1i (156 mg, 1.0 mmol),
RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), TBACl (13.9 mg, 0.05 mmol,
0.05 equiv), 9 (201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL, 2.5 mmol,
2.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL)
were combined under 40 psi of CO at 75 °C for 24 h. Workup and
purification by silica gel column chromatography (80 g SiO2, 4.5 ×
13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600 mL)) then
Et2O/MeOH (20:1, 400 mL) and then subsequent recrystallization
from hexanes provided 10i (220 mg, 95%) as a white solid with an E/
1
and the spectra data is as follows: H NMR (500 MHz, CDCl3) 7.32
(dd, J = 7.5, 1.7 Hz, 1H, C(aryl′)H), 7.28−7.21 (m, 1H, C(aryl′)H),
6.96 (td, J = 7.5, 1.1 Hz, 1H, C(aryl′)H), 6.87 (dd, J = 8.2, 1.0 Hz, 1H,
C(aryl′)H), 5.74 (ddd, J = 4.7, 3.1, 1.8 Hz, 2H, C(4)H, C(3)H),
5.00−4.91 (m, 1H, C(1)H), 4.16−4.04 (m, 2H, C(5)H2), 3.84 (s, 3H,
C(7’)), 2.76 (s, 1H, br C(1)OH), 2.67−2.42 (m, 2H, C(2)H2), 1.92−
1.80 (m, 1H, br C(5)OH); 13C{1H} NMR (125 MHz, CDCl3) 156.4
C(aryl′), 132.2 C(4), 131.9 C(1′), 129.4 C(3), 128.5 C(aryl′), 126.9
C(aryl′), 120.8 C(aryl′), 110.6 C(3′), 70.0 C(1), 63.7 C(5), 55.4
C(7’), 40.3 C(2).
1
Z ratio of greater than 100:1. Data for 10i: mp 72−74 °C; H NMR
(500 MHz, CDCl3) 7.86−7.80 (m, 3H, C(aryl′)H), 7.79 (d, J = 1.5
Hz, 1H, C(2′)H), 7.51−7.44 (m, 3H, C(aryl′)H), 5.85−5.68 (m, 2H,
C(4)H, C(3)H), 4.90 (td, J = 6.5, 5.6, 2.1 Hz, 1H, C(1)H), 4.10 (t, J =
4.5 Hz, 2H, C(5)H2), 2.63−2.50 (m, 2H, C(2)H2), 2.35−2.28 (m, 1H,
br C(1)OH), 1.61 (d, J = 4.8 Hz, 1H, br C(5)OH); 13C{1H} NMR
(125 MHz, CDCl3) 141.4 C(1′), 133.4 C(quat, aryl′), 133.1 C(quat,
aryl′), 133.0 C(4), 128.4 C(aryl′), 128.3 C(3), 128.1 C(aryl′), 127.8
C(aryl′), 126.3 C(aryl′), 126.0 C(aryl′), 124.6 C(2′), 124.1 C(), 73.8
C(1), 63.5 C(5), 42.2 C(2); IR (neat) 3325 (m), 3054 (w), 2904 (w),
2867 (w), 1671 (w), 1634 (w), 1601 (w), 1508 (w), 1424 (w); MS
(ESI) 251.1 (MNa+, 8), 193.1 (100); TLC Rf 0.283 (Et2O/CH2Cl2,
4:1) [UV, KMnO4]. CHN Anal. Calcd for C15H16O2 (228.29): C,
78.92; H, 7.06. Found: C, 78.76; H, 7.05.
Preparation of (E)-5-(Furan-2-yl)pent-2-ene-1,5-diol (10l). Fol-
lowing the general allylation procedure, 1l (83 μL, 1.0 mmol), RuCl3
(13.0 mg, 0.05 mmol, 0.05 equiv), TBACl (13.9 mg, 0.05 mmol, 0.05
equiv), 9 (201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL, 2.5 mmol, 2.5
equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL) were
combined under 40 psi of CO at 75 °C for 24 h. Workup and
purification by silica gel column chromatography (80 g SiO2, 4.5 ×
13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600 mL)) then
Et2O/MeOH (20:1, 400 mL) provided 10l (150 mg, 89%) as a
colorless oil with an E/Z ratio of 5.5:1. Data for 10l: bp 100 °C (ABT,
0.05 mmHg); IR (neat): 3325 (m), 2913 (w), 2869 (w), 1672 (w),
1505 (w), 1424 (m); MS (ESI) 191.1 (MNa+, 60), 133.2 (100);
HRMS (ES+,TOF) calcd for C9H12O3Na 191.0684, found 191.0680;
TLC Rf 0.301 (Et2O/CH2Cl2, 4:1) [KMnO4]. A portion of the
material was sacrificially purified to yield pure E-product and the
Preparation of (E)-5-(Naphthalen-1-yl)pent-2-ene-1,5-diol (10j).
Following the general allylation procedure, 1j (136 μL, 1.0 mmol),
RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), TBACl (13.9 mg, 0.05 mmol,
0.05 equiv), 9 (201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL, 2.5 mmol,
2.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL)
were combined under 40 psi of CO at 75 °C for 24 h. Workup and
purification by silica gel column chromatography (80 g SiO2, 4.5 ×
13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600 mL)) then
Et2O/MeOH (20:1, 400 mL) and then subsequent recrystallization
from hexanes provided 10j (210 mg, 92%) as a white solid with an E/
1
spectra data is as follows: H NMR (500 MHz, CDCl3) 7.38 (dd, J =
1.9, 0.8 Hz, 1H, C(4′)H), 6.36−6.32 (m, 1H, C(3′)H), 6.25 (tt, J =
3.3, 0.8 Hz, 1H, C(2′)H), 5.80 (dtt, J = 15.4, 5.4, 1.1 Hz, 1H, C(4)H),
5.70 (dtt, J = 15.3, 7.0, 1.3 Hz, 1H, C(3)H), 4.75 (dd, J = 7.4, 5.7 Hz,
1H, C(1)H), 4.11 (dd, J = 5.6, 1.1 Hz, 2H, C(5)H2), 2.63 (dddd, J =
7.2, 5.0, 3.0, 1.1 Hz, 2H, C(2)H2), 2.15 (d, J = 17.0 Hz, 1H, br
C(1)OH), 1.57 (s, 1H, br C(5)OH); 13C{1H} NMR (125 MHz,
CDCl3) 156.1 C(1′), 142.2 C(4′), 133.1 C(4), 127.6 C(3), 110.3
C(3′), 106.3 C(2′), 67.3 C(1), 63.5 C(5), 38.6 C(2).
1
Z ratio of greater than 100:1. Data for 10j: mp 70−72 °C; H NMR
(500 MHz, CDCl3) 8.06 (dd, J = 7.4, 1.1 Hz, 1H, C(10′)H), 7.88 (dd,
J = 7.5, 2.1 Hz, 1H, C(aryl′)H), 7.78 (dt, J = 8.2, 1.0 Hz, 1H,
C(aryl′)H), 7.65 (dt, J = 7.3, 0.9 Hz, 1H, C(aryl′)H), 7.56−7.44 (m,
3H, C(aryl′)H), 5.84−5.80 (m, 2H, C(4)H, C(3)H), 5.53 (dt, J = 7.8,
3.6 Hz, 1H, C(1)H), 4.12 (t, J = 4.7 Hz, 2H, C(5)H2), 2.81−2.68 (m,
1H, C(2)Ha), 2.65−2.56 (m, 1H, C(2)Hb), 2.33 (d, J = 3.3 Hz, 1H, br
C(1)OH), 1.63 (d, J = 5.8 Hz, 1H, br C(5)OH); 13C{1H} NMR (125
MHz, CDCl3) 139.6 C(1′), 133.9 C(aryl′), 132.8 C(4), 130.4
C(aryl′), 129.1 C(aryl′), 128.8 C(3), 128.2 C(aryl′), 126.2 C(aryl′),
125.7 C(aryl′), 125.6 C(aryl′), 123.0 C(10’), 122.9 C(3), 70.4 C(1),
63.6 C(5), 41.3 C(2); IR (neat) 3341 (m), 3049 (w), 2915 (w), 2868
(w), 1670 (w), 1597 (w), 1511 (w), 1427 (w); MS (ESI) 251.1
(MNa+, 8), 194.1 (25), 193.1 (100); TLC Rf 0.305 (Et2O/CH2Cl2,
4:1) [UV, KMnO4]. CHN Anal. Calcd for C15H16O2 (228.29): C,
78.92; H, 7.06. Found: C, 78.58; H, 7.05.
Preparation of (E)-5-(1-tosyl-1H-pyrrol-2-yl)pent-2-ene-1,5-diol
(10m). Following the general allylation procedure, 1m (250 mg, 1.0
mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), TBACl (13.9 mg,
0.05 mmol, 0.05 equiv), 9 (201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL,
2.5 mmol, 2.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane
(2.5 mL) were combined under 40 psi of CO at 75 °C for 24 h.
Workup and purification by silica gel column chromatography (80 g
SiO2, 4.5 × 13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600
mL)) then Et2O/MeOH (20:1, 400 mL) provided 10m (290 mg,
90%) as a white solid after recrystallization from hexanes with an E/Z
Preparation of (E)-5-(2-Methoxyphenyl)pent-2-ene-1,5-diol
(10k). Following the general allylation procedure, 1k (136 mg, 1.0
mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05 equiv), TBACl (13.9 mg,
0.05 mmol, 0.05 equiv), 9 (201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL,
2.5 mmol, 2.5 equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane
1
ratio of 16:1. Data for 10m: mp 80−82 °C; H NMR (500 MHz,
CDCl3) 7.72−7.62 (m, 2H, C(6’)H), 7.30−7.27 (m, 2H,, C(7’)H),
W
DOI: 10.1021/acs.joc.7b02658
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
7.27 (d, J = 0.9 Hz, 1H, C(4′)H), 6.29 (ddd, J = 3.5, 1.7, 0.7 Hz, 1H,
C(3′)H), 6.25 (t, J = 3.4 Hz, 1H, C(2′)H), 5.73−5.62 (m, 2H, C(4)H,
C(3)H), 4.93 (td, J = 6.7, 4.1 Hz, 1H, C(1)H), 4.05 (t, J = 4.7 Hz, 2H,
C(5)H2), 2.82 (d, J = 4.2 Hz, 1H, br C(1)OH), 2.57 (ddd, J = 6.6, 4.1,
1.2 Hz, 2H, C(2)H2), 2.40 (s, 3H, C(9’)H3), 1.52−1.45 (m, 1H, br
C(5)OH); 13C{1H} NMR (125 MHz, CDCl3) 145.3 C(8’), 137.5
C(1′), 136.4 C(5′), 132.3 C(4), 130.2 C(6’), 128.4 C(3), 126.8 C(7’),
123.7 C(4′), 112.8 C(3′), 111.8 C(2′), 65.3 C(1), 63.6 C(5), 38.4
C(2), 21.7 C(9’); IR (neat) 3547 (w), 3368 (w), 2924 (w), 2868 (w),
1596 (w), 1477 (w), 1402 (w); MS (EI) 344.1 (MNa+, 13), 304.1
(100); TLC Rf 0.269 (Et2O/CH2Cl2, 4:1) [UV, KMnO4]. CHN Anal.
Calcd for C16H19NO4S (321.39): C, 59.80; H, 5.96; N, 4.36. Found:
C, 60.06; H, 5.93, N, 4.39.
Preparation of (E)-5-Cyclohexylpent-2-ene-1,5-diol (10p). Follow-
ing the general allylation procedure, 1p (112 mg, 1.0 mmol), RuCl3
(13.0 mg, 0.05 mmol, 0.05 equiv), TBACl (13.9 mg, 0.05 mmol, 0.05
equiv), 9 (201 μL, 2.5 mmol, 2.5 equiv), H2O (45 μL, 2.5 mmol, 2.5
equiv), Et3N (14 μL, 0.1 mmol, 0.1 equiv), and dioxane (1.25 mL)
were combined under 40 psi of CO at 75 °C for 24 h. Workup and
purification by silica gel column chromatography (80 g SiO2, 4.5 ×
13.5 cm column, Et2O/CH2Cl2 (1:1 (500 mL) → 4:1 (600 mL)) then
Et2O/MeOH (20:1, 400 mL) provided 10p (45 mg, 24%) as a
colorless oil. The spectroscopic data matched those from the
literature.73 Data for 10p: H NMR (500 MHz, CDCl3) 5.79−5.70
1
(m, 2H, C(4)H, C(3)H), 4.16−4.10 (m, 2H, C(5)H2), 3.42−3.37 (m,
1H, C(1)H), 2.34−2.29 (m, 1H, C(1)OH), 2.17−2.11 (m, 1H,
C(cyclohexyl)H), 1.87−1.82 (m, 1H, C(cyclohexyl)H), 1.79−1.74 (m,
2H, C(2)H2), 1.70−1.64 (m, 2H, C(cyclohexyl)H), 1.53 (s, 1H, br
OH), 1.45−1.40 (m, 1H, C(cyclohexyl)H), 1.39−1.32 (m, 1H,
C(cyclohexyl)H), 1.29−0.97 (m, 5H, C(cyclohexyl)H); 13C{1H}
NMR (125 MHz, CDCl3) 132.3, 129.6, 75.4, 63.4, 43.4, 37.2, 29.2,
28.4, 26.7, 26.4, 26.3; MS (ESI) 207.1 (MNa+, 100); TLC Rf 0.280
(Et2O/CH2Cl2, 4:1) [KMnO4].
Preparation of (E)-6,6-Dimethylhept-2-ene-1,5-diol and (Z)-6,6-
Dimethylhept-2-ene-1,5-diol (10n). Following the general allylation
procedure, 1n (109 μL, 1.0 mmol), RuCl3 (13.0 mg, 0.05 mmol, 0.05
equiv), TBACl (13.9 mg, 0.05 mmol, 0.05 equiv), 9 (201 μL, 2.5
mmol, 2.5 equiv), H2O (45 μL, 2.5 mmol, 2.5 equiv), Et3N (14 μL, 0.1
mmol, 0.1 equiv), and dioxane (1.25 mL) were combined under 40 psi
of CO at 75 °C for 24 h. Workup and purification by silica gel column
chromatography (80 g SiO2, 4.5 × 13.5 cm column, Et2O/CH2Cl2
(1:1 (500 mL) → 4:1 (600 mL)) then Et2O/MeOH (20:1, 400 mL)
provided (E)-10n (19 mg, 22%) as a colorless oil and (Z)-10n (58 mg,
37%) as a colorless oil. The spectroscopic data for (Z)-10n matched
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b02658.
those from the literature.71 Data for (E)-10n: H NMR (500 MHz,
1
CDCl3) 5.75 (ddd, J = 4.3, 2.8, 1.1 Hz, 2H, C(3)H, C(4)H), 4.18−
4.03 (m, 2H, C(5)H2), 3.25 (dd, J = 10.6, 2.2 Hz, 1H, C(1)OH),
2.36−2.30 (m, 1H, C(2)Ha), 1.99 (dddd, J = 14.1, 10.7, 4.7, 2.4 Hz,
1H, C(2)Hb), 1.93−1.79 (m, 2H, br C(1)OH, br C(5)OH), 0.91 (s,
9H. C(2′)H3 x3); 13C{1H} NMR (125 MHz, CDCl3) 132.1 C(4),
130.7 C(3), 78.8 C(1), 63.6 C(5), 34.9 C(2), 34.9 C(1′), 25.9 C(2′)
IR (neat): 3342 (s), 2955 (s), 2916 (m), 2870 (m), 1671 (w), 1479
(w), 1467 (m), 1430 (m); MS (ESI) 181.1 (MNa+, 100); HRMS (ES
+, TOF) calcd for C9H18O2Na, 181.1204, found 181.1198; TLC Rf
Optimization studies, GC response factors/retention
1
times, and H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: sdenmark@illinois.edu.
■
ORCID
1
0.309 (Et2O/CH2Cl2, 4:1) [KMnO4]. Data for (Z)-10n: H NMR
Scott E. Denmark: 0000-0002-1099-9765
(500 MHz, CDCl3) 5.98−5.83 (m, 1H, C(4)H), 5.75−5.63 (m, 1H,
C(5)H), 4.25 (dddd, J = 12.4, 7.5, 1.5, 0.7 Hz, 1H, C(5)Ha), 4.05 (dd,
J = 12.3, 6.7 Hz, 1H), C(5)Hb, 3.23 (dd, J = 10.2, 2.5 Hz, 1H, C(1)H),
2.32−2.16 (m, 2H, C(2)H2), 2.09 (s, 2H, br C(1)OH, br C(5)OH),
0.94 (s, 9H, C(2′)H3 × 3); 13C{1H} NMR (125 MHz, CDCl3) 131.6,
131.2, 78.5, 77.4, 66.0, 57.8, 35.1, 29.8, 25.8, 15.4; MS (ESI) 181.1
(MNa+, 100), 123.2 (6); TLC Rf 0.429 (EtOAc/hexane, 1:4)
[KMnO4].
Author Contributions
†S.T.N. and S.M.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Science Foundation for
generous financial support (NSF CHE 1649579). We are also
grateful to the Milliken Company for financial support. We
thank Eastman Chemicals for a gift of vinyl oxirane.
Preparation of (E)-Dec-2-ene-1,5-diol (10o). Following the general
allylation procedure, 1o (120 μL, 1.0 mmol), RuCl3 (13.0 mg, 0.05
mmol, 0.05 equiv), TBACl (13.9 mg, 0.05 mmol, 0.05 equiv), 9 (201
μL, 2.5 mmol, 2.5 equiv), H2O (45 μL, 2.5 mmol, 2.5 equiv), Et3N (14
μL, 0.1 mmol, 0.1 equiv), and dioxane (2.5 mL) were combined under
40 psi of CO at 75 °C for 24 h. Workup and purification by silica gel
column chromatography (80 g SiO2, 4.5 × 13.5 cm column, Et2O/
CH2Cl2 (1:1 (500 mL) → 4:1 (600 mL)) then Et2O/MeOH (20:1,
400 mL) provided 10o (119 mg, 70%) as a colorless oil with an E/Z
ratio of 4:1. The spectroscopic data matched those from the
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