Inhibition of imidazolidinone intermediate formation in the aldol reactions catalyzed by zinc-prolinamide complexes

Article abstract of DOI:10.1016/j.tet.2011.09.025

The use of zinc salts as cocatalysts in aldol condensations catalyzed by single prolinamide (and in the extension by other more complex prolinamides) can prevent the formation of the parasitic intermediate imidazolidinone, with faster and also more stereoselective reactions than those catalyzed by the free amine. This new finding, together with this ion's already known properties, make zinc salts highly suitable additives for aldol reactions catalyzed for prolinamide derivatives.

Full text of DOI:10.1016/j.tet.2011.09.025

Tetrahedron 67 (2011) 8705e8709
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Tetrahedron
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Inhibition of imidazolidinone intermediate formation in the aldol reactions
catalyzed by zinceprolinamide complexes
*
Cecilia Andreu , Teresa Varea, Gregorio Asensio
Departament de Química Org aꢀ nica, Facultat de Farm aꢀ cia, Universitat de Val ꢀe ncia, 46100 Burjassot, Val ꢀe ncia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2011
Received in revised form 6 September 2011
Accepted 9 September 2011
Available online 12 September 2011
The use of zinc salts as cocatalysts in aldol condensations catalyzed by single prolinamide (and in the
extension by other more complex prolinamides) can prevent the formation of the parasitic intermediate
imidazolidinone, with faster and also more stereoselective reactions than those catalyzed by the free
amine. This new finding, together with this ion’s already known properties, make zinc salts highly
suitable additives for aldol reactions catalyzed for prolinamide derivatives.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aldol reaction
Imidazolidinone
Trifluoroacetic acid
Stereoselectivity
Zinceprolinamide
1
. Introduction
productive role in the catalysis, but removes catalytic loading from
2
c
the actual reaction. However, some groups now agree that this
cyclic intermediate plays a more active role, even as actual
L-Proline (Pro) and its derivatives have been employed in recent
5
years as simple chemical systems that mimic the action of enzymes
in a wide range of asymmetric organic transformations, especially
aldol addition. This kind of catalysts is known to operate via an
organocatalysts.
To date, very few mechanistic analyses of aldol reaction use
prolinamide derivatives. The studies of Gryko and Mor aꢁ n using
L-prolinethioamides and aromatic prolinamides, respectively, have
1
2
enamine mechanism (class I aldolase mimics).
Stability of prolinamides, their easy preparation, and the pres-
ence of an NH moiety in their structure, whose acidity is sufficient
to activate electrophiles by hydrogen bonding, imply that these
shown the formation of a stable cyclic imidazolidinone as the main
intermediate.
Zinc salts have been used as cocatalysts in aldol reactions. Dar-
2
bre et al. described the use of the Zn(Pro) complex to catalyze the
6
3
proline derivatives have been the most widely used to date. Pro-
linamide (Pde from now onward) is a simple compound that can
catalyze aldol condensation, although with slight stereoselectivity.
intermolecular reaction between aldehydes and ketones, which
was more effective than proline itself in an aqueous medium in
terms of both yield and stereoselectivity. After performing a broad
4
7
This compound can be used as a model to optimize basic reaction
conditions, which can then be extended to more sophisticated
derivatives. For this reason, it has been used in our experiments.
The mechanistic studies performed in the aldol reaction using
Pro as a catalyst2 have shown the presence of different kinds of
intermediates of varying stability (Scheme 1). The first is an imi-
nium carboxylate, derived from a hemiaminal between proline and
the ketone after dehydration. Iminium is in equilibrium with either
oxazolidinone or an enamine, the key intermediate in the addition
screening of different alternative water-compatible Lewis acids
cocatalysts with proline in a neutral medium, Penhoat et al. ob-
tained excellent results using zinc chloride in both, stereoselectivity
,5a
8
and conversion. Mlynarsky notably improved yield and stereo-
selectivity in condensation between different aldehydes and ke-
tones catalyzed by bis(prolinamides) by the addition of Zn(OTf) .
2
They proposed a model in which the enamine intermediate is
stabilized in water by coordination to zinc. The ion coordinates with
both the amide group of the catalyst and the carbonyl group of the
2
to the acceptor aldehyde. Oxazolidinone has traditionally been
9
considered a parasitic species that does not appear to play any
aldehyde, thus enabling condensation in a chiral enviroment.
In a previous work, we studied the role of zinc ion in enhancing
the rate and stereoselectivity of the aldol condensations catalyzed
by the simple Pde model. We concluded that this catalyzes the
reaction following the general mechanism of enamine nucleophilic
*
Corresponding author. Tel.: þ34 96 3543048; fax: þ34 96 3544328; e-mail
address: cecilia.andreu@uv.es (C. Andreu).
0
040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.025

8706
C. Andreu et al. / Tetrahedron 67 (2011) 8705e8709
Scheme 1. Intermediates proposed for proline and prolinamide derivatives in catalyzed asymmetric aldol condensation.
addition to the acceptor aldehyde. Zn2þ acts by preventing the
base-catalyzed reaction, by diminishing the basicity of the amine
nitrogen of Pde, and by also favoring enamine formation in an
aqueous medium. The prolinamide geometry with the pyrrolidine
nitrogen and the amide function fits the coordination sphere of
2
þ
Zn to form a five-member ring. This coordination sphere can be
completed with either another prolinamide molecule or another
donor species present in the solution to afford very stable
complexes.10
Based on our previous results and those described in the liter-
2
,6
2þ
ature, we decided to study the possible role of Zn in inhibiting
the formation of the above-described parasitic intermediate imi-
dazolidinone to hence, contribute to an increase in both the yield
and the stereoselectivity of the reaction.
2
2
. Results and discussion
.1. Imidazolidinone formation kinetics
Fig. 1. Imidazolidinone 1 formation kinetics at rt in the absence of additives and in the
presence of zinc acetate or/and trifluoroacetic acid.
First of all, we studied the formation of the imidazolidinone
intermediate between Pde and acetone (1) by NMR under different
conditions. For this purpose, we recorded the H NMR spectra of
1
formed in methanol in less than 1 h, even when an almost stoi-
chiometric amount of acetone was used. In contrast, the reaction in
chloroform was very slow, and imidazolidinone and Pde were
present in the solution after 9 days (80:20 ratio). This observation is
consistent if one considers that the cyclic intermediate is formed
from charged iminium, which is stabilized and forms more quickly
in polar solvents.
The formation of the cyclic intermediate from the zinc complex
or from the trifluoroacetate salt was studied in methanol. Behavior
was very similar to that observed in the acetone/water mixture
explained above. As the complex was not soluble in chloroform,
this solvent could not be used.
Pde, ZnPde
2
(prepared in situ by mixing 0.5 equiv of zinc acetate
/TFA (0.5:1:1) at
and 1 equiv of Pde), Pde/TFA (1:1) and ZnPde
2
different times using an acetone/water mixture (85/15) as the
deuterated solvent. We employed this solvent because zinc com-
plexes are not soluble in the amounts required to perform the
spectrum, when using less water. Fig. 1 shows the kinetics of cyclic
imidazolidinone formation in all cases. Free Pde was completely
converted into imidazolidinone after 12 h. On the other hand, when
2
þ
Pde was complexed with the Lewis acid Zn , the cyclic in-
termediate formed much more slowly. Protonation of Pde or its zinc
complex (ZnPde
2
) by Br o€ nsted acid TFA practically inhibited the
formation of this intermediate (Spectra in Supplementary data).
Previously, Gryko et al. described that the use of protonated
L-
2.2. Comparison of catalytic activity
prolinethioamide catalysts, instead of the free base, for the direct
aldol condensation between 4-nitrobenzaldehyde and acetone
could improve both the yield and the stereoselectivity of the re-
action. These authors studied different acids to protonate the cat-
alyst to find a relationship among the pKa of the acid, the amount of
imidazolidinone intermediate formed, and the yield and stereo-
selectivity of the aldol product. The best results were achieved in
cases in which fewer cyclic intermediate levels were detected.
We also carried out the study of imidazolidinone formation (1)
by NMR using methanol and chloroform as solvents. In these cases,
As mentioned in the Introduction, Zn2 has been used by dif-
þ
7e10
ferent groups to improve aldol condensation reactions.
In order
to determine the relationship between improved performance
when using zinc and inhibition in the intermediate formation, we
synthesized this compound and checked its activity as a catalyst.
We used the aldol reaction between acetone and p-nitro-
benzaldehyde as a benchmark (Scheme 2). In all cases, excess en-
antiomer had an R configuration.
Table 1 and Fig. 2 show the results obtained for the various
catalysts used. The fastest reaction was catalyzed by the ZnPde
complex (100% after 3 h). In agreement with the results described
6
b
3
b,c,11
1.5 equiv of acetone in relation to Pde were added and the spectra
2
were recorded at different times. Imidazolidinone completely

C. Andreu et al. / Tetrahedron 67 (2011) 8705e8709
8707
seem to contribute are faster imidazolidinone formation from Pde
(
Fig. 1) and the poor catalytic activity shown by the cyclic species.
When Pde was protonated by the Br o€ nsted acid TFA, no imida-
Scheme 2. Aldol reactions studied in this work.
zolidinone was formed. However, the reaction catalyzed by the TFA
salt was only slightly faster than that catalyzed by imidazolidinone.
Indeed protonation of pyrrolidine nitrogen helps diminish its nu-
cleophilic capacity, which prevents not only imidazolidinone for-
mation, but also the formation of the active enamine species. When
Table 1
Results for the aldol reaction between acetone and p-nitrobenzaldehyde catalyzed
by the studied catalysts
TFA was added to the ZnPde
obtained somewhere between that observed in the reaction cata-
lyzed by ZnPde and that found when the trifluoroacetate salt of
2
complex, an intermediate rate was
Catalysta
Time (h)
Yieldb
% eec
2
Pde
(
12
72
48
3
100
15
18
100
90
14
14
44
33
44
Pde was the catalyst, and was closer to the former. Under these
conditions, pyrrolidine nitrogen can be protonated or complexed by
the zinc ion, and is the second most important species, as we have
Pdeeacetone)imidazolidinone
PdeþTFA
ZnPde2
1
0
ZnPde2þTFA
a
24
previously reported (Scheme 3).
2
þ
Reactions in acetone with 5% distilled water. Complexes were prepared in situ
using zinc acetate as salt.
These results indicate that Zn , as a Lewis acid, plays a similar
role to that of Br o€ nsted acid, and that it also acts by inhibiting the
formation of the parasitic cyclic intermediate. The high stability of
b
Determined by NMR.
HPLC (IC, Hex/i-proh 94/6, 1 ml/min).
c
the ZnPde
2
complex results from the coordination of Zn2þ to both
Fig. 2. The reactions at rt in acetone with 5% distilled water. Yield was determined by NMR, and the ee by chiral HPLC.
6
by Gryko and Mor aꢁ n, cyclic imidazolidinone catalyzed condensa-
tion, but the reaction was slower and achieved lower stereo-
selectivity (only 15% after 72 h).
groups: pyrrolidine nitrogen and amide (Scheme 4). The individual
affinity of pyrrolidine nitrogen by zinc must be lower than its af-
þ
finity by the Br o€ nsted acid (H ), which makes this nitrogen more
Initially Pde catalyzes condensation more slowly than its zinc
complex, and this tendency becomes greater as the reaction prog-
resses (extension Fig. 2). This fact can be easily explained if we
consider the Lewis character of the zinc ion, which coordinates to
the O of the acceptor aldehyde; this makes it more electrophilic and
favors the addition of the activated donor (Fig. 3). Moreover, and
taking into account that the rate of the reaction catalyzed by the
free amine progressively decreases over time, the other factors that
nucleophile in the complex than in the protonated species, and
which also favors its attack on the ketone. On the other hand, co-
ordination of zinc to the amide group in the complex lowers the
nucleophilicity of its nitrogen making imidazolidinone formation
more difficult when imine is formed, and favoring in this case the
formation of the enamine active species.
10
2.3. Characteristics of the imidazolidinone intermediate
Imidazolidinone (1) remained stable in solution for several
days, especially in methanol (Supplementary data). In this solvent,
a slow and progressive deuteration of the CH groups was
3
observed (75% after 10 days), indicating the existence of an equi-
librium between the cyclic species and the imine/enamine
intermediates (Scheme 1). The presence of all these species was
4
confirmed by reduction of isolated imidazolidinone with NaBH in
methanol, which yields, along with the starting material and Pde,
N-isopropyl prolinamide.
The high stability of the cyclic intermediate accounts for its poor
catalytic activity in aldol condensation, and also the progressive
Fig. 3. Coordination of Zn2 to Pdeeenamine and to the acceptor aldehyde. Re attack
þ
7e
was favored to minimize the steric interaction between the aromatic ring (aldehyde)
and the CH
clarity purposes.
3
group (enamine). Only one molecule of Pde is shown in the complex for

8708
C. Andreu et al. / Tetrahedron 67 (2011) 8705e8709
Scheme 3. The equilibrium between the different species derived from Pde in the presence of TFA and zinc acetate.
Scheme 4. Inhibition by Zn2þ of imidazolidinone intermediate formation (in the ZnPde
complex, only the coordination between the ion and Pde is shown, but other donor species
2
can be present).
slowing noted when Pde is in used. The stereochemical results are
very similar with both catalysts (Fig. 2) indicating a great similarity
in the active species derived from them.
With any of the catalysts used, Re attack was always favored by
steric considerations (Fig. 3), and the enantiomer formed had
a preferentially R configuration. However when zinc was used as
the cocatalyst, coordination of the ion to the O of the acceptor al-
dehyde fixed it more rigidly, thereby improving the stereo-
selectivity in the addition process.10
(TLC) on Merck silica plates 60 F254. NMR spectra were recorded
with Bruker DRX 300 spectrometers in the indicated deuterated
solvents, and infrared spectra on a Nicolet is10 spectrophotometer
provided with an ATR accessory. High performance liquid chro-
matography (HPLC) was performed with a Merck Hitachi Lachrom
system. For the analytical work, a Chiralpak IC column (5
mm,
250ꢀ4.6 mm ID, Hex/i-proh 94/6, 1 ml/min, wavelength for de-
tection fixed at 254 nm) was used.
2
4.2. Characterization of ZnPde complex
3
. Conclusions
Isolated10 or in situ prepared complex Zn eProlinamide 1:2,
2þ
By way of conclusion, zinceprolinamide complexes catalyze
prepared by mixing the stoichiometric amounts of Pde and zinc
the aldol reaction following the general mechanism of stereo-
selective enamine nucleophilic addition to the acceptor aldehyde.
acetate dehydrate, was characterized by NMR, IR and ESI-MS(þ).
1
ZnPde
2
. H NMR (MeOD): 1.75e1.95 (m, 3H), 2.33e2.45 (m, 1H),
2
þ
Zn plays a role in preventing the nonspecific base-catalyzed
reaction by diminishing the basicity of the amine nitrogen of
prolinamide, and by also maintaining the conformation of the
acceptor fixed during the addition, and by finally preventing the
formation of the parasitic intermediate imidazolidinone. This re-
sults in faster reactions that are also more stereoselective than
those catalyzed by the free amine. Similar results have been ob-
tained when using Br o€ nsted acids but, in this case, and due to the
13
3
3
3
.00e3.20 (m, 2H), 3.95e4.05 (m, 1H). C NMR (MeOD): 27.44 (t),
max (solid/cm ): 3345,
273, 3166, 1668, 1557, 1385. ESI-MS (MeOD): 351, 291, 236.
ꢁ
1
2.36 (t), 48.62 (t), 60.16 (d), 180.27 (s). IR
n
þ
4
.3. General procedure for the aldol reaction
Aldehyde (0.165 mmol, 25 mg) and catalyst (5% of the zinc
significant decrease in the nucleophilicity of nitrogen, reactions
are much slower.
The stereoselectivity achieved with the simple model under
study (Pde) was always modest. However, these conclusions can be
applied to more complex models.
complex, 10% of Pde or 10% of Pdeeacetone imidazolidinone) were
added to an acetone/water mixture (2.375e0.125 ml) in a capped
vial. The resulting mixture was stirred at rt and monitored by TLC.
The reaction was quenched by addition of saturated ammonium
chloride solution and evaporation of acetone in vacuum. Then,
water was extracted with methylene chloride and the organic
phase was dried over sodium sulfate. Crude material was employed
to determine the yield by NMR and the ee by chiral HPLC.
4
4
. Experimental
.1. General
Reaction products were purified previously by column chro-
matography (hexane/ethyl acetate, 4:1) and characterized by NMR
and chiral HPLC. Data were consistent with those described in the
All the commercially available reagents were purchased from
Aldrich. Reactions were monitored by thin-layer chromatography
3
b,c
literature.

C. Andreu et al. / Tetrahedron 67 (2011) 8705e8709
8709
4
2
2
.3.1. 4-Hydroxy-4-(p-nitrophenyl)-butan-2-one. 1H NMR (CDCl
3
):
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.4. Synthesis of the imidazolidinone derived from Pde and
(
acetone
Pde (100mg) was dissolved in a mixture of acetone/methanol
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(
1
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10
dryness, yielding a solid that was identified as compound (1).
3
(
.4.1. Pdeeacetone imidazolidinone. 1H NMR (CDCl
.45 (s, 3H), 1.60e2.02 (m, 3H), 2.06e2.29 (m, 1H), 2.56e2.66 (m,
H), 2.88e3.02 (m, 1H), 3.92 (1H, dd, J¼9.76, 4.75 Hz), 6.67 (1H, br
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4
1
1
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4
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5
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(
3
): 23.63 (q), 25.65 (t), 25.82 (t), 30.72 (q), 48.69
t), 63.98 (d), 74.84 (s).
þ
HRMS (EI ) calcd for C
8
H
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N
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O 154.1106, found 154.1104. Anal.
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N 18.10. Mp 140e142 C.
H
8 14
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ꢂ
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(
Supplementary data
1
1
Supplementary data associated with this article can be found, in
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