Paraldehyde as an acetaldehyde precursor in asymmetric michael reactions promoted by site-isolated incompatible catalysts

Article abstract of DOI:10.1002/chem.201302087

A song of ice and fire! The usually innocent paraldehyde can be used as an acetaldehyde precursor in an organocatalytic asymmetric Michael addition (see scheme) thanks to the proper combination of two immobilized catalysts. The site isolation induced by the polymeric supports has proven crucial to preclude deactivation of the otherwise incompatible catalysts.

Full text of DOI:10.1002/chem.201302087

COMMUNICATION
Site Isolation
X. Fan, C. Rodrꢀguez-Escrich,
S. Sayalero, M. A. Pericꢁs* . &&&& — &&&&
Paraldehyde as an Acetaldehyde
Precursor in Asymmetric Michael
Reactions Promoted by Site-Isolated
Incompatible Catalysts
A song of ice and fire! The usually
innocent paraldehyde can be used as
an acetaldehyde precursor in an orga-
nocatalytic asymmetric Michael addi-
tion (see scheme) thanks to the proper
combination of two immobilized cata-
lysts. The site isolation induced by the
polymeric supports has proven crucial
to preclude deactivation of the other-
wise incompatible catalysts.
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DOI: 10.1002/chem.201302087
Paraldehyde as an Acetaldehyde Precursor in Asymmetric Michael Reactions
Promoted by Site-Isolated Incompatible Catalysts
Xinyuan Fan,[a] Carles Rodrꢀguez-Escrich,[a] Sonia Sayalero,[a] and Miquel A. Pericꢁs*[a, b]
Synthetic organic chemists have traditionally regarded al-
dehydes as reactive electrophiles but the advent of organo-
catalysis helped to expand their role to become nucleophiles
upon enamine formation without the need for prefunctional-
ization. Indeed, several types of enolizable aldehydes can
undergo aminocatalytic activation.[1] However, limitations
are still encountered related to their molecular size. On one
hand, heavily substituted aldehydes react sluggishly, if at all;
on the other hand, acetaldehyde, the smallest enolizable al-
dehyde, has also proven a challenging substrate for several
Scheme 1. Use of paraldehyde as an acetaldehyde precursor.
reasons.[2] These are basically related to its high reactivity,
which is translated into undesired side reactions, as well as
to the inherent tendency of acetaldehyde to form oligomers.
form oligomers, which leads to its disappearance from the
reaction media due to side reactions, forced some of the au-
thors to add freshly distilled acetaldehyde to the reaction
mixture after a given time.[3] As a result of these drawbacks
we reasoned that use of an acetaldehyde precursor might be
a convenient alternative, so we turned our attention to the
cyclic trimer, paraldehyde. This is a stable liquid with a boil-
ing point of 1238C, even less expensive than acetaldehyde
itself. Other than its use as a solvent, paraldehyde has found
few uses in synthetic chemistry. Indeed, its ability to act as
an acetaldehyde precursor has been scarcely exploited in
the literature, being limited to the generation of bulk com-
pounds rather than in the preparation of complex mole-
cules.[12] Thus, we undertook some preliminary experiments
to assess the suitability of the acid-catalyzed depolymeriza-
tion of paraldehyde as a method for the steady production
of the aldehyde. The results, displayed in Table 1, show that
a strong acid is needed to use the cyclic trimer as a source
of acetaldehyde.
Since the pioneering works of List[3] and Hayashi[4] with di-
ACHTUNGTRENNUNG
arylprolinol silyl ethers,[5] tremendous efforts have been de-
voted to the use of acetaldehyde as a donor for aminocata-
lytic processes, including aldol[6] and Mannich reactions.[7]
More recently, a silylated pyrrolidine catalyst has been re-
ported to promote addition to nitroalkenes.[8] This was
shortly followed by a study with enzyme 4-OT,[9] which con-
tains a terminal proline as the catalytically active species. In
a remarkable attempt to expand the media suitable for this
reaction, Headley and co-workers showed that it could be
carried out in brine with a water compatible catalyst to
afford Michael products of acetaldehyde with high enantio-
selectivities.[10] Despite the numerous examples of amino-
ACHTUNGTRENNUNGcatalytic Michael addition of aldehydes to nitroalkenes and
the apparent simplicity of the reaction, the exact mechanism
and the nature of the species involved are still a matter of
debate.[11]
Excellent as the results reported may be, the problems in-
herent to acetaldehyde itself remain unsolved. First, the low
boiling point of this species (218C; Scheme 1) makes the ex-
perimental procedures cumbersome, especially for work on
a small scale. Secondly, its above-mentioned tendency to
The strongly acidic conditions required for the generation
of acetaldehyde, however, were expected to be incompatible
Table 1. Results of the acid decomposition of paraldehyde.[a]
[a] X. Fan, Dr. C. Rodrꢁguez-Escrich, Dr. S. Sayalero,
Prof. Dr. M. A. Pericꢂs
Institute of Chemical Research of Catalonia (ICIQ)
Av. Paꢃsos Catalans, 16, 43007 Tarragona (Spain)
Fax : (+34)977-920-243
[b]
Entry
Acid (10 mol%)
pKa
Ratio[c]
1
2
3
4
AcOH
PhCOOH
p-NO2C6H4COOH
p-MeC6H4SO3H
4.76
4.20
3.44
À2.80
100:0
100:0
100:0
30:70
E-mail: mapericas@iciq.es
[b] Prof. Dr. M. A. Pericꢂs
Departament de Quꢁmica Orgꢂnica
Universitat de Barcelona, 08080 Barcelona (Spain)
[a] Paraldehyde (0.1 mmol) and acid (0.01 mmol) were mixed in CDCl3
(0.5 mL) for 90 min. [b] pKa value in water. [c] Ratio of paraldehyde to
acetaldehyde in the crude mixture.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302087.
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Asymmetric Michael Reactions
COMMUNICATION
with the aminocatalyst used in the reactions involving this
species. Hence, we thought of exploiting the site isolation
principle.[13] To the best of our knowledge, the only example
of site isolation involving asymmetric organocatalytic pro-
To validate our hypothesis, a test reaction between para-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNGcesses has been described by Frꢄchet et al. and involved the
use of functionalized soluble star polymers to carry out cas-
cade reactions.[14] In our case, we postulated that the use of
solid-supported catalysts might be the solution to segregate
each individual process (i.e. acetaldehyde generation and
aminocatalytic reaction), thus preventing the two catalysts
from deactivating each other. Specifically, it was envisaged
that employing a polystyrene-supported diarylprolinol cata-
lyst 1[15] in combination with the commercially available sul-
fonic acid resin 2, could preclude the deleterious acid/base
reaction (Scheme 2 and Table 2).
Solvent screeening showed that lower conversion was ach-
ieved in either dioxane, THF or MeCN, albeit the Michael
adduct 4a was obtained in the same 90% ee as in CH2Cl2
(Table 2, entries 4–6). Gratifyingly, when catalyst 2 was con-
fined in a teabag, conversion was further increased, which
we attributed to a better isolation of the catalytically active
species (compare entries 2 and 10). No product was detected
when the reaction was carried out without the supported
sulfonic acid 2 (entry 1), proving the role of paraldehyde as
a precursor for the slow generation of acetaldehyde in the
reaction media. Screening of the acid co-catalyst loading
(entries 7–11) showed that a 10 mol% of 2 (entry 10) was
optimal for conversion and enantioselectivity, although even
a 0.5 mol% of the acid catalyst (entry 8) still gave good con-
version and enantioselectivity levels. A further increase in
the amount of the acid catalyst 2 from the optimal 10 to
20 mol% caused an apparent slight decrease of conversion,
probably due to partial decomposition of 4a. Increasing the
Scheme 2. a) Catalyst incompatibility (deactivation by acid/base reaction)
and b) resorting to site isolation to circumvent the problem (induced by
supporting the incompatible catalysts onto polystyrene). TIPS=triisopro-
pylsilyl.
Table 2. Optimization of conditions for the Michael addition.[a]
loading of the polymer-supported organocatalyst
1 to
20 mol%, however, raised the conversion to 69%
(entry 12). It is noteworthy that paraldehyde was used as re-
ceived in the course of this study.
It is generally accepted that organocatalytic procedures
are tolerant to moisture and can be performed in open air.
Nevertheless, conversion was significantly increased to 91%
when the reaction was carried out in degassed anhydrous
CH2Cl2 in a glovebox (Table 2, entry 13), which indicated
that oxygen and moisture are important issues in this partic-
ular reaction.[16] To fully understand this effect, two parallel
reactions were performed. Ten equivalents of water were
added to the first reaction (entry 14), whereas oxygen was
bubbled for 10 min in the other reaction at the start
(entry 15). Despite the fact that the enantioselectivities
matched the result previously obtained in the glovebox, con-
version sharply decreased in these two tests. Hence, we con-
cluded that both oxygen[17] and moisture[18] have a negative
effect on the conversion of the Michael addition of acetalde-
hyde to trans-b-nitrostyrene.[19]
Encouraged by the results obtained with this dual catalyt-
ic system, we decided to test the generality of this concept
with different substrates, and the results are shown in
Table 3.[20] It was established that the system was tolerant to
b-nitrostyrenes bearing o-fluoro, o-chloro, and o-bromo sub-
stituents (Table 3, entries 2–4), m- and p-chloro substituents
being also well tolerated (entries 5 and 6). Electron-rich ni-
Entry
Acidic cat.
Solv.
Conv. [%][b]
ee [%][c]
1
–
CH2Cl2
CH2Cl2
CH2Cl2
dioxane
THF
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
5
–
–
2[d]
3[d]
4[d]
5[d]
6[d]
7
pTsOH (10%)
2 (10%)
2 (10%)
2 (10%)
2 (10%)
2 (0.5%)
2 (1%)
42
15
10
32
45
41
46
47
40
69
91
35
55
90
90
90
90
90
90
90
91
90
90
91
90
91
8
9
10
11
2 (5%)
2 (10%)
2 (20%)
2 (10%)
2 (10%)
2 (10%)
2 (10%)
12[e]
13[e,f]
14[e,g]
15[e,h]
[a] Reactions were carried out with trans-b-nitrostyrene (0.1 mmol),
paraldehyde (0.33 mmol) in presence of 10 mol% catalyst 1, and
a
teabag with the acidic catalyst 2 in 0.5 mL CH2Cl2 unless otherwise
noted; [b] conversion was measured by 1H NMR spectroscopy; [c] ee was
measured by chiral HPLC analysis; [d] catalyst 2 was used without
teabag; [e] 20 mol% of catalyst 1 was used; [f] reaction was carried out
in a glove box in degassed anhydrous CH2Cl2; [g] 10 equivalents of water
were added; [h] oxygen was bubbled into the reaction mixture for 10 min
at the beginning.
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M. A. Pericꢂs et al.
Table 3. Michael addition of acetaldehyde catalyzed by the combination
of PS-supported catalysts.[a]
ate yield but with excellent enantioselectivity (entry 10).
The proposed order of the events takes place as depicted
in Scheme 3. First, the sulfonic acid resin 2 depolymerizes
paraldehyde to acetaldehyde. Then, acetaldehyde diffuses
out of the teabag and condenses with the supported amino-
catalyst 1 to form the corresponding enamine A. This, in
turn, reacts with the nitroolefin 3 and generates the Michael
product 4.
Entry
1[d]
Product
4
Yield [%][b]
77
ee [%][c]
4a
91
In summary, by taking advantage of the properties inher-
ent to immobilized species, we have been able to combine
two otherwise incompatible catalysts, such as diarylprolinol
silyl ether and an arylsulfonic acid. This application of the
site-isolation principle has allowed us to use paraldehyde as
a precursor of acetaldehyde, which results in much more
convenient and easy to reproduce experimental procedures.
These conditions have proven successful in promoting a
one-pot, two-step procedure that gives rise to acetaldehyde
Michael adducts in good yields with excellent enantioselec-
tivities. Furthermore, a significant, negative effect of both
moisture and oxygen on the outcome of the reaction has
been observed. This is in contrast with common assumptions
done in organocatalysis and thus should help in expanding
knowledge and improving practices in this field. The appli-
cation of the dual catalysis under site isolation developed
here to other reactions involving acetaldehyde, as well as
studies concerning the recyclability of this dual catalytic
system are currently underway.
2
4b
74
94
3
4
5
4c
4d
4e
61
65
71
89
87
92
6
4 f
61
89
7
8
4g
4h
44
51
92
91
9
4i
4j
54
35
91
94
Experimental Section
General method: Catalyst 1 (20 mol%, 0.04 mmol), catalyst 2 (10 mol%,
0.02 mmol) in a homemade teabag and trans-b-nitrostyrene (0.2 mmol)
were mixed in a vial with degassed anhydrous CH2Cl2 (1 mL) in a glove-
box. Then, paraldehyde (0.66 mmol) was added and the vial was sealed
and shaken at room temperature. After 24 h, the mixture was filtered
and washed with CH2Cl2 (3ꢅ1 mL). The filtrates were combined and the
solvent was removed under reduced pressure. The product was purified
by flash chromatography on silicagel, with hexanes/ethyl acetate mixtures
as the eluent.
10
[a] Reactions were carried out in the glovebox with the nitroolefin sub-
strate (0.2 mmol), paraldehyde (0.66 mmol), 20 mol% organocatalyst 1,
and a teabag containing the sulfonic acid resin 2 (10 mol%) in 1.0 mL de-
gassed anhydrous CH2Cl2. [b] Isolated yield. [c] ee was measured by
chiral HPLC analysis. [d] The aldehyde product was characterized with-
out reduction.
troalkenes were also tested with
our dual catalytic system and
the slow generation of acetalde-
hyde, which is pumped steadily
into the reaction media, al-
lowed us to generate their cor-
responding Michael adducts in
good yields with excellent enan-
tioselectivities (entries 7–9). In
addition, an aliphatic substrate
also worked using this catalytic
system. Thus, (E)-1-nitro-4-
phenyl-1-butene gave rise to
Scheme 3. Proposed order of the events (left) and picture illustrating the practical setup for site-isolation
the Michael product in moder- (right).
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Asymmetric Michael Reactions
COMMUNICATION
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Financial support from the Institute of Chemical Research of Catalonia
(ICIQ) Foundation, MINECO (grants CTQ2008–00947/BQU and
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Keywords: acetaldehyde
·
Michael
reaction
·
organocatalysts · paraldehyde · site isolation
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[16] After the reaction, the color of catalyst 1 was dark red when using
moist solvent, while light yellow with dry and degassed solvent in a
glovebox (see the Supporting Information for the reaction picture).
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7.
[19] The effect of moisture on the depolymerization of paraldehyde goes
in the same direction. In two parallel experiments, paraldehyde in
CDCl3 was shaken with 10 mol% 2 in open air and in the glovebox.
After 1 hour, the reaction in open air shows a conversion of 8%,
whereas that in the glovebox has progressed to about 20%.
[20] For stability reasons, the products were isolated as alcohols after re-
duction with NaBH4.
Received: May 31, 2013
Published online: && &&, 0000
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