On the mechanism of the organocatalytic asymmetric epoxidation of α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/chem.201303942

Mechanistic studies on the organocatalytic epoxidation of α,β-unsaturated aldehydes explore the autoinductive behavior of the reaction and establish that the hydrate/peroxyhydrate of the product is acting as a phase-transfer catalyst. Based on these studies, an improved methodology that provides high selectivities and decreased catalyst loading, through the addition of chloral hydrate, is developed. Self-promotion: Mechanistic studies on the organocatalytic epoxidation of α,β-unsaturated aldehydes reveal the autoinductive behavior and establish that the hydrate/peroxyhydrate of the product is acting as a phase-transfer catalyst. Based on these results, an improved methodology that provides high selectivities and decreased catalyst loading, through the addition of chloral hydrate, has been developed (see scheme). Copyright

Full text of DOI:10.1002/chem.201303942

DOI: 10.1002/chem.201303942
Communication
&
Organocatalysis
On the Mechanism of the Organocatalytic Asymmetric
Epoxidation of a,b-Unsaturated Aldehydes
Rebecca L. Davis, Kim L. Jensen, Bjçrn Gschwend, and Karl Anker Jørgensen*[a]
Abstract: Mechanistic studies on the organocatalytic
epoxidation of a,b-unsaturated aldehydes explore the au-
toinductive behavior of the reaction and establish that the
hydrate/peroxyhydrate of the product is acting as
a phase-transfer catalyst. Based on these studies, an im-
proved methodology that provides high selectivities and
decreased catalyst loading, through the addition of chloral
hydrate, is developed.
Catalytic asymmetric epoxidations are powerful transforma-
tions in contemporary organic synthesis as they allow for the
formation of enantioenriched epoxides. Epoxides have been
shown to be highly useful intermediates in the synthesis of, for
example, natural products and pharmaceuticals.[1] The Sharp-
less and Jacobsen–Katsuki transition-metal-catalyzed, asym-
metric epoxidations are two fundamental reactions in this
area.[2] Furthermore, the role of the catalysts and the mecha-
nisms of these reactions are well-established.[3] More recently,
organocatalytic asymmetric epoxidation methods have been
developed, vastly increasing the range of synthetically accessi-
ble epoxides.[4] However, unlike their transition-metal-catalyzed
counterparts, the mechanisms of organocatalytic asymmetric
epoxidations are much less understood.[5]
Scheme 2. Generally accepted mechanism of the organocatalytic epoxida-
tion of a,b-unsaturated aldehydes.
excess for a wide range of a,b-unsaturated aldehydes. The pro-
posed, and generally accepted, mechanism for the organocata-
lytic epoxidation of a,b-unsaturated aldehydes is outlined in
Scheme 2. The first step in this catalytic cycle involves conden-
sation of the trimethylsilyl (TMS)-prolinol catalyst 2 with 1 to
form the iminium-ion intermediate 4. This is followed by the
nucleophilic addition of the peroxide to the b-carbon atom of
the iminium-ion species. In the next step, the epoxide is
formed via attack of the a-carbon atom on the electrophilic
oxygen atom of 5. Hydrolysis of the iminium-ion intermediate
6 produces the epoxyaldehyde and regenerates the catalyst.
Herein, we present a mechanistic study on the organocata-
lytic epoxidation reaction of a,b-unsaturated aldehydes
(Scheme 1).[4c] During the development and application of this
reaction, it was surprisingly found that the reaction rate in-
creased as the conversion increased. This unusual rate behav-
ior inspired us to explore the effects of solvent, products and
additives on the performance of the reaction. The complex
nature of this reaction was uncovered when the data showed
that the product formed is involved in the rate-limiting step of
the reaction. Based on our mechanistic findings, we have also
developed an improved protocol for this epoxidation reaction.
By the application of an achiral additive, our new procedure
allows for decreased catalyst loading and shorter reaction
times while maintaining high selectivity. The epoxidation reac-
One highly useful and widely employed organocatalytic
asymmetric epoxidation method involves the use of a secon-
dary amine catalyst in combination with an a,b-unsaturated al-
dehyde and hydrogen peroxide (Scheme 1).[4c,6,7] This method
has been shown to provide good yields and high enantiomeric
Scheme 1. Organocatalytic epoxidation of a,b-unsaturated aldehydes.
[a] Dr. R. L. Davis, Dr. K. L. Jensen, Dr. B. Gschwend, Prof. Dr. K. A. Jørgensen
Center for Catalysis, Department of Chemistry, Aarhus University
Langelandsgade 140, 8000 Aarhus C (Denmark)
Fax: (+45)8715-5956
E-mail: kaj@chem.au.dk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303942.
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Communication
tion in Scheme 1 has been studied for trans-2-nonenal (1a)
(R=n-hexyl) using the TMS-prolinol catalyst 2 in both CH2Cl2
and EtOH—two solvents that have previously been shown to
promote high yields and selectivities.[4c,6a] Due to the heteroge-
neous nature of the reaction in CH2Cl2, all reactions were moni-
tored by using GC.[8] A plot of conversion versus time provides
a sigmoidal curve for the reaction in CH2Cl2, showing that the
rate increases over time (Figure 1). This is in contrast to the
Scheme 3. Effects of additives on the rate of epoxidation.[a] [a] Reaction
time: 6 h. Reactions were performed at room temperature with 0.5 mmol 1a
and 1.0 mmol H2O2 (35% aqueous) in 1.0 mL solvent. Values below additives
are % conversions as determined by CSP-GC. See Supporting Information for
details.
gave 60% conversion in 6 h, only 3% more than the reaction
with 10 mol% of 3a.
The results of these initial additive studies led us to consider
how epoxyaldehyde 3 was acting as a phase-transfer catalyst.
While using the epoxidation chemistry for other applications, it
was observed that it was problematic to determine the exact
conversion numbers by comparing the aldehyde CHO signals
in the NMR-spectrum. The product signal was usually smaller
than the other signals. The “hiding” of this proton led us to
the hypothesis that it is not 3, but its hydrate, that is accelerat-
ing the reaction. To test this hypothesis, a series of ketones
with different affinities for forming their corresponding hy-
drates were examined as additives in the epoxidation of trans-
2-nonenal (1a) (Scheme 3).[11] The two ketones with low affini-
ties for forming hydrates, acetone 8 and chloroacetone 9, had
little influence on the conversion, with 8 slightly slowing down
the reaction and 9 slightly increasing the rate. Ketones 10 and
11, which both have a high affinity for forming their hydrates,
were shown to dramatically increase the reaction rate, provid-
ing almost full conversion in 6 h. Finally, we examined the
effect of chloral hydrate 12 on the epoxidation. The addition
of 10 mol% of 12 resulted in 96% conversion in 6 h.[12,13] The
trend established by the ketone additives and the effectiveness
of the chloral hydrate in increasing the rate of reaction sug-
gests that it is not the epoxyaldehyde 3, but its hydrate 13
that is acting as a phase-transfer catalyst and promoting the
epoxidation in CH2Cl2 (Scheme 3). However, it should be noted
that these trends do not rule out the formation of the peroxy-
hydrate of 3 being involved in the reaction as H2O2 is more nu-
cleophilic than water.
Figure 1. Conversion versus time (min) for the organocatalytic epoxidation
of trans-2-nonenal (1a).[a] [a] Reactions were carried out on a 0.5 mmol scale
with 1.0 mmol H2O2 (35% aqueous) and 1 mol% of 2 in 1 mL of solvent (see
Supporting Information for details).
epoxidation in EtOH, which shows no rate increase. Monitoring
of the enantiomeric excess of the epoxy aldehyde 3a over the
course of the reactions in Figure 1 revealed that, in both cases,
the enantiomeric excess remains constant throughout the re-
action (97% ee for the reaction in CH2Cl2 and 86% ee in EtOH).
The rate acceleration observed in CH2Cl2 (Figure 1) suggests
that epoxyaldehyde 3 plays a role in the rate-limiting step of
the epoxidation reaction. To provide insight as to the role of
the product 3 in the heterogeneous reaction, its ability to pro-
mote the reaction was examined. We began by identifying
whether the epoxyaldehyde could independently catalyze the
reaction.[9] The addition of 10 mol% of epoxyaldehyde 3a to
a mixture of trans-2-heptenal (1b) and H2O2 in CH2Cl2 (without
the TMS-prolinol catalyst 2) generated no reaction. This shows
that 3 does not independently catalyze the reaction.
As the epoxyaldehyde 3 is shown to play no role in the rate-
limiting step of the homogeneous (EtOH as solvent) reaction, it
appears that 3 might be involved in the phase-transfer step of
the heterogeneous reaction.[10] The role of the epoxyaldehyde
3 in the rate-limiting step of the epoxidation of trans-2-none-
nal (1a) was further investigated by performing the reaction
with 2.5 mol% of the TMS-prolinol catalyst 2 and 10 mol% of
epoxyaldehyde 3a (Scheme 3). Examination of the reaction
mixture after 6 h showed an increase in conversion from 36%
(with no additives) to 57% (with 10 mol% of 3a). As the
epoxyaldehyde 3 is considered to be acting as a phase-transfer
catalyst, we were also interested in how a well-known phase-
transfer catalyst, tetrabutylammonium chloride (7), might
affect the reaction. The use of 10 mol% of 7 in the reaction
In addition to examining the role of epoxyaldehyde 3a as
a phase-transfer catalyst, we also explored the influence of this
chiral additive on the enantioselectivity of the reaction. To
assess the effects of a match-mismatch pairing of catalyst and
product on the enantioselectivity of the reaction, the epoxida-
tion of trans-2-heptenal (1b) was performed with ent-2 as the
catalyst and 10 mol% of 3a (97% ee) (Table 1). In the mis-
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Table 1. Effects of match-mismatch pairing.[a]
Table 2. Optimization of the organocatalytic epoxidation of a,b-unsatu-
rated aldehydes with chloral hydrate 12.[a]
Entry
3 [mol%]
12 [mol%]
t [h]
Conv. [%][b]
1
2
3
4
5
6
7
2.5
2.5
2.5
2.5
1
0
2.5
5
10
0
5
18
5
5
90
72
98
93
84
96
95
Entry
3a [mol%]
Cat.
t [h]
Conv. [%][b]
ee [%][b]
1
2
3
0
10
10
2
2
4
4
4
53
72
74
96
97
À97
5
60
24
24
ent-2
1
1
[a] Reactions were performed at room temperature with 0.5 mmol 1b
and 1.0 mmol H2O2 (35% aqueous) in 1.0 mL solvent. [b] Determined by
CSP-GC of the crude reaction mixture.
10
[a] Reactions were performed at room temperature with 0.5 mmol 1a
and 1.0 mmol H2O2 (35% aqueous) in 1.0 mL solvent. [b] Determined by
CSP-GC of the crude reaction mixture. In all entries the enantiomeric
excess remained between 96–98% ee.
matched case, the addition of 3a increases the rate of the re-
action, just as in the matched case. In both the matched and
mismatched cases the enantioselectivity remained at 96–97%
ee.[14]
with the chloral hydrate, which is observed by 19F NMR spec-
troscopy.
As shown in the additive studies, compounds that readily
form hydrates greatly influence the rate of the reaction; how-
ever, as mentioned previously this does not rule out the possi-
bility of other species, such as a peroxyhydrate, being the spe-
cies responsible for the rate increase.[15] In an attempt to deter-
mine if such peroxyhydrates are formed in significant amount,
a series of NMR studies were performed (see Supporting Infor-
mation for details). Monitoring the reaction of 12 with aqueous
H2O2 by 13C NMR spectroscopy showed a down field shift in
the hydrate carbon atom from 95.7 ppm to 103.6 ppm. It
should be noted that this shift was not observed when 12 was
combined with H2O alone. This suggests the forma-
tion of the peroxyhydrate of 12. Based on the results
of our experiments, we propose a new mechanism
for the catalytic cycle of this reaction (Scheme 4). In
this mechanism, the reaction still occurs through for-
mation of the iminium-ion intermediate 4 and a sub-
sequent addition of the peroxide followed by cycliza-
tion to form the epoxide 6. Unlike the previously pro-
posed catalytic cycle shown in Figure 1,[4c] in this
mechanism the epoxyaldehyde 3 plays an important
role in the phase-transfer step of the catalytic cycle.
Intrigued by how well chloral hydrate 12 was able
to accelerate the epoxidation of a,b-unsaturated al-
dehydes (Scheme 3), we next decided to investigate
how much of this additive was necessary to achieve
the fastest reaction times with both 2.5 and
1.0 mol% catalyst loading (Table 2). Varying the con-
centration of 12 from 0–10 mol% reveals that the re-
action is most efficient with 5 mol% of 12. The addi-
tion of only 2.5 mol% additive was found to be less
effective, whereas the addition of more than 5 mol%
of 12 resulted in a slight decrease in the rate of reac-
tion. This is likely due to condensation of the catalyst
The new methodology was also tested on two other alde-
hydes to demonstrate its generality (Table 3). The reactions
were performed without 12 and with 5 mol% of 12. In the ep-
oxidation of both 1c and 1d, the addition of chloral hydrate
showed a marked increase on the rate of the reaction and had
no effect of the enantioselectivity.
In summary, mechanistic studies on the organocatalytic ep-
oxidation of a,b-unsaturated aldehydes in CH2Cl2 reveal that
the reaction exhibits an increase in rate as it proceeds. This
autoinductive behavior is dependent on the solvent employed
and is thought to result from the products ability to act as
Scheme 4. Proposed catalytic cycle for reaction in CH2Cl2.
Chem. Eur. J. 2014, 20, 64 – 67
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Table 3. Scope of the organocatalytic epoxidation of a,b-unsaturated al-
dehydes with chloral hydrate 12.[a]
[5] For selected examples, see: a) G. Carrea, S. Colonna, A. D. Meek, G. Otto-
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[8] To ensure that the contact area between the two phases in the hetero-
geneous reaction did not affect the studies; all reactions were carried
out in 32ꢅ11.6 mm screw cap vials and were stirred at 900 rpm. For full
details on this and the methods for monitoring the reaction rates, see
Supporting Information.
Entry
1
12 [mol%] t [h] Conv. [%][b] ee [%][b]
1
2
3
4
1c: R1 =iPr, R2 =H
1c: R1 =iPr, R2 =H
1d: R1 =CO2Et, R2 =H
1d: R1 =CO2Et, R2 =H
0
5
0
5
6
6
3
3
42
74
77
89
ND[c]
97
86
86
[a] Reactions were performed at room temperature with 0.5 mmol 1a
and 1.0 mmol H2O2 (35% aqueous) in 1.0 mL solvent. [b] Determined by
CSP-GC of the crude reaction mixture. [c] ND=not determined.
a phase-transfer catalyst. Further studies revealed that it is
likely the peroxyhydrate of the epoxyaldehyde that is responsi-
ble for the observed rate acceleration. Based on these studies,
it has been determined that the addition of chloral hydrate to
the reaction significantly increases the rate of reaction. This im-
proved methodology for the organocatalytic epoxidation of
a,b-unsaturated aldehydes provides high selectivities and low
catalyst loading, making it as efficient a method as those em-
ploying transition-metal catalysts and increasing its applicabili-
ty in an industrial setting.
[9] For examples of an autocatalytic reaction, see for example: a) K. Soai, T.
Shibata, I. Sato, Acc. Chem. Res. 2000, 33, 382; b) M. Szlosek, B. Figadꢆre,
Angew. Chem. 2000, 112, 1869; Angew. Chem. Int. Ed. 2000, 39, 1799;
c) H. Fujisawa, T. Nakagawa, T. Mukaiyama, Adv. Synth. Catal. 2004, 346,
1241; d) M. Mauksch, S. B. Tsogoeva, I. M. Martynova, S. Wei, Angew.
Chem. 2007, 119, 397; Angew. Chem. Int. Ed. 2007, 46, 393; e) S. Kamio-
ka, D. Ajami, J. Rebek Jr., Chem. Commun. 2009, 7324.
[10] For an example of an asymmetric phase-transfer catalyzed epoxidation
of a,b-unsaturated ketones, see: T. Ooi, D. Ohara, M. Tamura, K. Maruo-
ka, J. Am. Chem. Soc. 2004, 126, 6844.
Acknowledgements
This work was made possible by grants from Aarhus University,
OChemSchool, Carlsberg Foundation, FNU and the Swiss Na-
tional Science Foundation.
[11] J. P. Guthrie, J. Am. Chem. Soc. 2000, 122, 5529, and references therein.
[12] Additional studies on the chloral hydrate 9 revealed that the additive
was unable to catalyze the epoxidation reaction in the absence of the
TMS-prolinol catalyst 2. These studies also reveal that this additive has
no effect on the rate of the reaction in EtOH.
[13] The role of acid in affecting the rate of the reaction was also tested by
adding 10 mol% benzoic acid. After 6 h, the reaction gave 66% conver-
sion, providing a similar rate increase as 10 mol% of epoxyaldehyde
3a. It seems likely that the acid could be involved in the formation of
the hydrate of epoxyaldehyde 3a.
[14] The lack of a mismatch effect was confirmed by experiments using an-
other chiral aldehyde (l-glyceraldehyde acetonide). The addition of
10 mol% of this aldehyde with both enantiomers of the catalyst result-
ed in 95–96% ee. See Supporting Information for details.
[15] In addition to the possibility of forming a peroxyhydrate, the formation
of a peroxy hemiaminal was also considered. 19F NMR studies on the
catalyst 2 with 12 and H2O2 showed the formation of a new peak up-
field (À62.6 ppm) suggesting the formation of a small amount of such
a species. See Supporting Information for details.
Keywords: asymmetric epoxidation
reaction mechanisms
·
organocatalysis
·
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Received: October 11, 2013
Published online on December 2, 2013
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