Study on guanidine-based task-specific ionic liquids as catalysts for direct aldol reactions without solvent

Article abstract of DOI:10.1039/b600277c

In this work, the effect of the anions of tetramethylguanidine-based ionic liquids on the catalytic activity in direct aldol reactions was studied. In solvent-free conditions at room temperature, [TMG][Ac] (1,1,3,3- tetramethylguanidinium acetate) was fou

Full text of DOI:10.1039/b600277c

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Study on guanidine-based task-specific ionic liquids as catalysts for direct
aldol reactions without solventw
Anlian Zhu, Tao Jiang,* Buxing Han,* Jun Huang, Jicheng Zhang and Xiumin Ma
Received (in Montpellier, France) 9th January 2006, Accepted 3rd March 2006
First published as an Advance Article on the web 16th March 2006
DOI: 10.1039/b600277c
In this work, the effect of the anions of tetramethylguanidine-based ionic liquids on the catalytic
activity in direct aldol reactions was studied. In solvent-free conditions at room temperature,
[
TMG][Ac] (1,1,3,3-tetramethylguanidinium acetate) was found to have the highest activity among
the ionic liquids including [TMG][Pr] (1,1,3,3-tetramethylguanidinium propionate), [TMG][n-Bu]
1,1,3,3-tetramethylguanidinium n-butyrate), [TMG][i-Bu] (1,1,3,3-tetramethylguanidinium
(
isobutyrate), [TMG][Lac] (1,1,3,3-tetramethylguanidinium lactate) and [TMG][TFA] (1,1,3,3-
tetramethylguanidinium trifluoroacetate). On the basis of this preliminary result, a series of direct
aldol reactions was performed using [TMG][Ac] as the catalyst, and satisfactory results with high
yields and good chemo- and regioselectivity were obtained. From combination of the reaction
results with UV–Vis spectroscopy studies, it was deduced that the reactions proceeded through an
enamine intermediate. The anion effect was believed to operate though its interaction with the
cation and the special structure of the enamine based on tetramethylguanidine may be the reason
for the unusual regioselectivity, which is different from that of aldol reactions catalyzed by proline
and its derivatives in organic solvents.
Ionic liquids (ILs) are organic salts and have been exten-
7
sively investigated in organic synthesis; they possess many
1
. Introduction
Aldol reactions are very powerful C–C bond forming reactions
and the products are important reaction intermediates in
organic synthesis. These reactions have been studied exten-
different properties compared with traditional organic sol-
vents. Ionic liquids have also been introduced into direct aldol
reactions mainly as green solvents to replace organic solvents
1
,2
sively. Classical aldol reactions are highly atom efficient but
suffer from poor selectivity. Stoichiometric or larger amounts
of reagents such as trimethylchlorosilane (TMSCl) have been
introduced into aldol reactions in the presence of a Lewis acid
8,9
such as DMF or DMSO. In recent years, a great number of
task-specific functional ionic liquids were synthesized for
10
different purposes.
1,1,3,3-Tetramethylguanidine-based
(TMG) ionic liquid synthesized in our previous work through
10b
simple neutralizing of equimolar TMG with acids has been
(
Mukaiyama aldol reaction) in order to overcome limitations
in the scope and improve the selectivity of these catalytic
3
reactions. However, these methods to some extent reduce
found to be useful in preparing an immobilized catalyst for
11
hydrogenation of olefins and absorbing SO from simulated
2
the atom efficiency of aldol reactions and at the same time
produce a great deal of waste. In recent years, green methods
for aldol reactions have been developed mainly by a return to
the direct catalytic procedures in searching for higher selectiv-
ity and atom efficiency, and in a number of instances they may
open up routes for highly efficient and environmentally
12
flue gases. Both of these uses are based on the electron lone
pair of the guanidine cation. Recently, we reported a green
method for direct aldol reactions catalyzed by [TMG][Lac]
(
1,1,3,3-tetramethylguanidinium lactate) at room temperature
13
without solvents. However, the reaction mechanism is still
not clear and ketones having higher steric hindrance still suffer
from low conversions even though good chemo- and regios-
electivities have been obtained. We know that ionic liquids
have been called ‘‘designer solvents’’ because their properties
can be easily tailored through changing the anions or cations,
but the relationship between the structure and the properties,
especially their effects on reactions, have not been well
4
friendly C–C bond forming processes. However, the reaction
rate is still very low for some ketones such as butanone and
cyclopentanone, which have high steric hindrance, and will
5
need one to two days to get moderate yields. Most of the
direct aldol reactions are proved to proceed through an
enamine or enolate intermediate based on multiple-step
acid–base catalysis with proline or diamine together with an
14
studied.
6
acid additive as a superior bifunctional catalyst system.
As a continuation of our work in the direct aldol reaction
and applications of ILs, we synthesized a series of basic ILs
and studied the effects of anions of ILs on their catalytic
performance in these reactions. Herein we wish to report our
progress. The results showed that the anions significantly
affect the catalytic properties of ILs. A reaction mechanism
based on an enamine was suggested and, from the viewpoint of
Center for Molecular Science, Institute of Chemistry, Chinese
Academy of Sciences, Beijing, 100080, China. E-mail:
Jiangt@iccas.ac.cn; Hanbx@iccas.ac.cn; Fax: þ86-10-62562821
1
w Electronic supplementary information (ESI) available: H-NMR
data for compounds in Table 2. See DOI: 10.1039/b600277c
7
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intermolecular interactions, the difference in catalytic activity
of the ILs was interpreted. The special structure of the
enamine based on tetramethylguanidine was thought to be
the origin of the special regioselectivity.
2
. Experimental
The ionic liquids were prepared by neutralizing 1,1,3,3-tetra-
methylguanidine and the corresponding acids in ethanol ac-
1
0b
cording to the literature procedures.
The other starting
materials (A. R. grade) were purchased from Beijing Chemical
Reagents Company. The solid aldehydes were recrystallized
from a mixture of ethanol and water. Acetone was distilled
after being dried over anhydrous CaSO
4
overnight. Other
chemicals were used as received. H-NMR spectra of aldol
products were recorded as solutions in CDCl at room tem-
1
3
perature on a Bruker spectrometer at 300 MHz (the NMR
data are available as ESIw).
Typical procedures for direct aldol reactions catalyzed by ionic
liquids
Scheme 1 Synthesis of the 1,1,3,3-tetramethylguanidine-based ionic
liquids.
1
mmol aldehyde, 0.3 mmol ionic liquid, and 20 mmol ketone
were mixed in a flask and stirred for the desired time at room
temperature. The reactions were monitored by TLC. At the
end of the reaction, diethyl ether was added to the reaction
mixture to extract the products. The crude hydroxyl ketone
obtained from diethyl ether was purified by flash chromato-
graphy on silica gel (eluent: ethyl acetate–petroleum ether).
most sluggish, and the total conversion of the reaction is less
than 50% even after five days (Entry 6).
For the reaction of 4-nitrobenzaldehyde with 2-butanone
using [TMG][Ac] as the catalyst, the isolated yield can reach
92% in 24 h (Entry 8), which is much superior to 25% yields in
1
The product and the syn : anti ratio were analyzed by H-NMR
13
spectroscopy.
72 h using [TMG][Lac] as the catalyst (Entry 7). The isolated
yields of the reactions catalyzed by [TMG][Pr], [TMG][n-Bu], or
UV–Vis experiments
[TMG][i-Bu] (Entries 9–11) can also exceed 90% with a pro-
Mixtures of the ionic liquids and cyclopentanone were prepared
by mass on the same molar ratio as in the reaction mixtures
longed reaction time. But the reaction catalyzed by [TMG][TFA]
can only proceed to less than 10% after five days (Entry 12). We
have also found that all reactions of 4-nitrobenzaldehyde with
2-butanone catalyzed by all six ionic liquids give the same
regioselectivity at methylene, which is the same as in the anti-
(B1 : 66). The mixtures were stirred using a magnetic stirrer at
room temperature for 24 h to reach equilibrium. The UV–Vis
spectra were recorded using a TU-1021 UV–Vis spectrometer
produced by Beijing Instrument Company (the wavenumber
accuracy is ꢁ0.5 nm). Cyclopentanone was chosen as the blank.
15
body-mediated aldol addition but quite different from direct
aldol reactions catalyzed by proline and its derivatives in organic
16
17
solvents. Barbas and coworkers have also developed a direct
aldol reaction in buffered aqueous media catalyzed by cyclic
secondary amines, but can only achieve moderate regioselec-
tivity at methylene with equivalent yield.
3
. Results and discussion
Six ionic liquids based on tetramethylguanidine (Scheme 1)
were used to catalyze aldol reactions of 4-nitrobenzaldehyde
with cyclopentanone and 2-butanone. The results are listed in
Table 1. The reaction of 4-nitrobenzaldehyde with cyclopen-
tanone catalyzed by [TMG][Ac] can be completed in two
hours. The isolated yield of the target aldol adducts is 85%
The above results indicate that [TMG][Ac] has the highest
catalytic activity for the direct aldol reactions among the six
ionic liquids, and the six ionic liquid catalyzed reactions have
the same excellent regioselectivity at methylene. Therefore, we
conducted a series of aldol reactions using [TMG][Ac] and the
successful results are collected in Table 2. All of the reactions
involving electron deficient aromatic aldehydes can be carried
out and completed in shorter times and comparable or even
better yields compared with the corresponding reactions cat-
alyzed by [TMG][Lac] in our previous work. However the
reactions cannot occur when benzaldehyde or an aliphatic
aldehyde were used as the acceptor.
(
Entry 2) because a by-product was produced. Mass spectro-
scopy (ESI) measurement showed that the molecular weight of
the by-product was 386.14, indicating that the by-product was
an adduct of two 4-nitrobenzaldehyde molecules with one
cyclopentanone molecule. In our previous work, the same
reaction catalyzed by [TMG][Lac] could achieve 96% yield
for the target aldol adducts in a prolonged reaction time of
about 24 h (Entry 1). The reactions catalyzed by [TMG][Pr],
For the reactions of 4-nitrobenzaldehyde with acetone,
cyclohexanone and acetophenone (Entries 1, 3, 4), good yields
can be obtained in less than 7 h while 24 h were required when
[TMG][Lac] was used as the catalyst. For those ketones with
[
TMG][n-Bu], or [TMG][i-Bu] were little slower than that
catalyzed by [TMG][Ac] and more by-products were produced
Entries 3–5). The reaction catalyzed by [TMG][TFA] was the
(
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Table 1 Direct aldol reaction of 4-nitrobenzaldehyde with cyclopentanone or 2-butanone catalyzed by the six different ionic liquids
Yield (%)
(syn/anti)
Entry
1
Ketones
Ionic liquids
[TMG][Lac]
Products
Reaction time/h
24
a
96 (68/32)
b
Cyclopentanone
b
2
Cyclopentanone
[TMG][Ac]
2
85 (75/25)
b
3
4
5
6
7
8
9
Cyclopentanone
Cyclopentanone
Cyclopentanone
Cyclopentanone
2-Butanone
[TMG][Pr]
3
3.5
4
74 (71/29)
b
[TMG][n-Bu]
[TMG][i-Bu]
[TMG][TFA]
[TMG][Lac]
[TMG][Ac]
68 (72/28)
b
65 (70/30)
b
120
72
o50 (65/35)
a
25 (68/32)
b
b
2-Butanone
24
92 (63/37)
b
2-Butanone
[TMG][PrA]
[TMG][n-BuA]
[TMG][i-BuA]
[TMG][TFA]
36
92 (65/35)
b
1
1
0
1
2
2-Butanone
36
92 (53/47)
b
2-Butanone
48
90 (63/37)
1
2-Butanone
120
o10 (not detected)
a
b
Ref. 13. Determined by H-NMR.
1
non-equivalent a-hydrogens, the regioselectivity was further
studied using the reaction of 4-nitrobenzaldehyde with 2-
pentanone (Entry 2), 3-nitrobenzaldehyde with 2-butanone
The other important selectivity for the reactions of ketones
possessing an alkyl-substituted group at the a-position is
syn/anti diastereoselectivity. As shown in Tables 1 and 2, the
corresponding aldol adducts are more syn-diastereoselective
when the present six ILs are used as catalysts, which suggests
that perhaps the same transition state exists in the reactions
for different ILs with the same cations.
(
Entry 5), and terephthalic aldehyde with 2-butanone (Entry
). The same regioselectivity and high yields can be obtained
6
for all of the three reactions. Moreover, when terephthalic
aldehyde was used, the reaction had good chemoselectivity
and only one product illustrated in Entry 6 was produced in
good yield, leaving the other aldehyde group unreacted. For
the reaction of heliotropin with cyclopentanone (Entry 7), the
sole product was obtained with good selectivity but the same
reaction does not occur using [TMG][Lac] or [TMG][TFA] as
the catalyst.
As for the reaction mechanism, we believe that all of the
aldol reactions catalyzed by the six tetramethylguanidine-
based ILs followed the same reaction mechanism because they
possess the same chemo-, regio- and diastereoselectivity, per-
haps proceeding through a thermodynamically-controlled
process with enamine as an intermediate. To get evidence for
7
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Table 2 The direct aldol reactions catalyzed by [TMG] [Ac]
Yields (%)
(syn/anti)
Entry
1
Aldehyde
Ketone
Product
Time/h
7
Acetone
92
75 (60/40)
85 (65/35)
92
2
3
4
5
6
7
2-Pentanone
Cyclohexanone
Acetophenone
2-Butanone
36
6
6
24
24
48
90 (58/42)
90 (64/36)
60 (65/35)
2-Butanone
Cyclopentanone
our hypothesis, a UV–Vis method was used to detect the new
conjugate system based on guanidine and enamine (the wave-
length of the maximum absorbance of the ionic liquids in
n-hexane is about 220 nm). We found that there were new
maximum absorbances at a wavelength of about 346 nm after
cyclopentanone was mixed with the six ionic liquids (Fig. 1)
separately at room temperature, which was believed to be the
conjugated absorbance of the tetramethylguanidine and the
enamine double bonds, suggesting that all six ionic liquids can
form the same intermediates.
When the regioselectivity of asymmetric ketones such as
2-butanone was considered, the enamine double bond and the
guanidine double bond must be inclined to adopt an (E)-config-
uration in order to minimize 1,3-diolefin strain. The possible
structures for the enamine of 2-butanone are illustrated in
Scheme 2. There is no doubt that the structure ‘‘b’’ has higher
steric energy due to higher hindrance, so structure ‘‘a’’ is the
more stable intermediate for the enamine, which perhaps indi-
cates why the regioselectivity is at the much more substituted
a-hydrogen. In Scheme 3, we illustrate a possible process for how
a direct aldol reaction is performed using 2-butanone as a model.
It has been suggested by Saito and Yamamoto that reac-
tions catalyzed by proline and diamine with acid additives
showed a higher catalytic activity through the electronic
1
6b
tuning of the acid function.
In this work, we believe that
the difference in catalytic activity for the six ILs with different
anions might also come from the effect of the anions on the
Fig. 1 The UV–Vis spectroscopy of the six ionic liquids mixed with
cyclopentanone using cyclopentanone as the blank.
Scheme 2 The possible structure for the enamine intermediate.
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direct aldol reactions, and found that the guanidine-based IL
ꢂ
with [Ac] as the anion ([TMG][Ac]) has the highest catalytic
activity among these ionic liquids including [TMG][Lac],
[TMG][Pr], [TMG][n-Bu], [TMG][i-Bu] and [TMG][TFA]. A
series of direct aldol reactions catalyzed by [TMG][Ac] can be
carried out, and even the ketones with high hindrance such as
2
-butanone and 2-pentanone can give good yields in a reason-
able reaction time. The regioselectivity of the reactions is
different from the direct aldol reactions catalyzed by proline
and its derivatives. Combining these results with the spectro-
scopy studies, we suggest that: (1) the effect of anion on the
reaction operates through its interaction with the cation and
this study might provide a successful example for designing
ionic liquids for a specific reaction; (2) the reaction perhaps
proceeds through an enamine intermediate, and the special
structure of the guanidine-based enamine is the origin of the
special regioselectivity.
Scheme 3 The possible reaction mechanism for the aldol reaction
catalyzed by 1,1,3,3-tetramethylguanidine-based ionic liquids.
electronic distribution of the cations; and the difference in
electronic distribution of the cations might then lead to the
different intensity of interactions between the cation and the
substrates. From the UV–Vis spectra for the six ILs mixed
with cyclopentanone, we can see that following the sequence of
Acknowledgements
We wish to thank the National Natural Science Foundation of
China (20332030, 20473105) for financial support.
[
TMG][Ac], [TMG][Lac] to [TMG][TFA] (Fig. 1), the intensity
References
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the conjugated acid of the anions increased because of the
increase in the atom electron negativity, which in other words
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anion in the ILs and a decrease in the electron density of the
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1
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1
1
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4
. Conclusions
In this work, we have studied the effect of anions of 1,1,3,3-
tetramethylguanidine-based ILs on their catalytic activity in
7
40 | New J. Chem., 2006, 30, 736–740 This journal is ꢀc the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2006