Ionic liquid effect over the biginelli reaction under homogeneous and heterogeneous catalysis

Article abstract of DOI:10.1021/cs400291t

Bronsted and Lewis acid catalysts with ionic tags under homogeneous and heterogeneous conditions have been tested to perform the Biginelli synthesis of 3,4-dihydropyrimidin-2(1H)-one (DHPMs). Metal-containing ionic liquids were evaluated as the catalysts

Full text of DOI:10.1021/cs400291t

Research Article
pubs.acs.org/acscatalysis
Ionic Liquid Effect over the Biginelli Reaction under Homogeneous
and Heterogeneous Catalysis
Haline G. O. Alvim,† Tatiani B. de Lima, Heibbe C. B. de Oliveira, Fabio C. Gozzo,
,‡
§
†
§
⊥
∥
,‡
,†
Julio L. de Macedo, Patricia V. Abdelnur, Wender A. Silva,* and Brenno A. D. Neto*
†
‡
Laboratory of Medicinal and Technological Chemistry, Laboratory for Bioactive Compounds Synthesis,
University of Brasília (IQ-UnB), Campus Universitario Darcy Ribeiro, CEP 70904970, P. O. Box 4478, Brasília-DF, Brazil
§
Institute of Chemistry, University of Campinas, Campinas, SP, Brazil
⊥
∥
Laboratory of Catalysis, Institute of Chemistry, University of Brasília, P. O. Box 4478, CEP 70904970, Brasília, DF, Brasil
o
Embrapa Agroenergia, PqEB s/n Avenida W3 Norte (final), Edifício Embrapa Agroenergia, CEP: 70770-901, P. O. Box 40315
*
S Supporting Information
ABSTRACT: Bronsted and Lewis acid catalysts with ionic tags under homogeneous
and heterogeneous conditions have been tested to perform the Biginelli synthesis of
3
,4-dihydropyrimidin-2(1H)-one (DHPMs). Metal-containing ionic liquids were evaluated
as the catalysts with reasonable results (homogeneous systems). Heterogeneous catalysts
zeolite β and H PW O supported on zeolite β) have been tested, as well, with good to
(
3
12 40
excellent results. The use of a functionalized acid ionic liquid with a heteropolyacid in the
anion moiety (homogeneous system) gave the best results using no excess of the three
reagents. The preferred mechanistic pathway was investigated by electrospray ionization
(
tandem) mass spectrometry in both positive and negative ion modes with very elucidative
results. The ionic liquid effect and its origin were also investigated using mass spectrometry
and DFT calculations.
KEYWORDS: Biginelli, ionic liquids, homogeneous and heterogeneous catalysis, mechanism and mass spectrometry
INTRODUCTION
paramount importance in never-ending biologically active
1
■
6−18
compound syntheses and discovery.
Modern catalysis and related methodologies are centered on
the development of more efficient catalysts, which must be used
under both more sustainable and eco-friendly conditions; hence,
envisaging all possible principles of the so-called green
chemistry, with special attention to strategies to approach a
19
Among MCRs, the Biginelli reaction (Scheme 1) is used to
the direct synthesis of 3,4-dihydropyrimidin-2(1H)-one (DHPM)
a
Scheme 1. The Biginelli Reaction
1
renewable chemical industry. In this sense, major concerns
regarding waste minimization and sustainability, which are
2
significant current issues in catalysis, are noted.
On the basis of those considerations, many attempts are pre-
sently found to connect the advantages and beneficial features
3
−7
of catalytic chemistry carried out in ionic liquids (ILs)
with multicomponent reactions (MCRs).
8
−10
a
Definitely, the
Note it is possible to use homogeneous or heterogeneous conditions
to perform the reaction.
description of such combination as “a perfect synergy for
eco-compatible heterocyclic synthesis” is far from overrated.
11
20
21
22
ILs have been described as one possible pathway to environ-
derivatives. DHPMs such as enastron, monastrol, piperas-
23 24
12
mental acceptability, and nowadays, the use of ILs in the
trol, and other derivatives have already displayed interesting
biological activities. Moreover, many DHPMs are being studied
because of their activities as calcium channel modulators, mitotic
Kinesin inhibitors, adrenergic receptor antagonists, antibacterials,
13
chemical industry is a reality under expansion. The use of
heterogeneous and homogeneous catalysts to perform MCRs
14
(
also in ILs) is a subject that has been very recently reviewed.
25
antivirals, and others, as reviewed elsewhere. Considering all
It is currently known that these two types of catalysis play
important roles for many chemical transformations, and both
have some advantages and disadvantages. Whether the catalytic
system performing the MCR is heterogeneous or homogeneous,
Received: April 17, 2013
Revised: May 10, 2013
15
the chemistry and biology of MCRs play a prominent role of
©
XXXX American Chemical Society
1420
dx.doi.org/10.1021/cs400291t | ACS Catal. 2013, 3, 1420−1430

ACS Catalysis
Research Article
attractive features of DHPMs, methodologies to improve the
Biginelli synthesis under more amenable and sustainable condi-
it may have a beneficial effect for the Biginelli reaction with
encouraging results. The use of preformed or in situ-prepared
catalysts gave similar results. Table 1 summarizes the screening
45
26
tions naturally appeared, and ILs became once more an
27
attractive medium to perform the reaction. Functionalized ILs,
also known as task-specific ionic liquids (TSILs) have already been
employed with success as catalysts for the Biginelli reaction.
Table 1. Biginelli Reaction with Different Protic (MSI
cation) Metal-Containing ILs as Catalysts
28−30
a
Despite all improvements experienced toward better reaction
conditions, this transformation still has many drawbacks associated
with it. Problems such as low yields, long reaction times, cost,
nonsustainable catalysts, and purification issues, among others,
catalyst
(10 mol %)
ionic liquid (or organic
solvent) (1.0 mL)
yield (%) yield (%)
entry
(1 h)
(4h)
1
2
MSI·Fe Cl7
H O
traces
16
26
3
2
2
31−35
MSI·Fe Cl7
MeOH
EtOH
MeCN
PhMe
2
are still challenging the scientific community.
In addition, the
3
MSI·Fe Cl7
2
main drawback is the fact that the Biginelli reaction usually
requires a (large) excess of at least one of the three commonly
used reagents (i.e., aldehyde, 1,3-dycarbonyl compound, or
4
MSI·Fe Cl7
2
5
MSI·Fe Cl7
4
2
6
MSI·Fe Cl7
CH Cl2
traces
4
2
2
(thio)urea); hence, a major limitation toward a greener and
7
MSI·Fe Cl7
THF
2
sustainable process.
8
MSI·Fe Cl7
BMI·NTf2
BMI·PF6
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
29
27
40
37
26
29
40
27
32
18
32
22
21
2
Recently, we have demonstrated the importance of BMI·PF6
9
MSI·Fe Cl7
2
to direct the formation and stabilization of some reactive
36
10
MSI·Fe Cl7
73
70
60
44
47
43
52
32
50
54
47
2
intermediates of the Biginelli reaction carried out in ILs. Due
to our interest in the development of more sustainable catalytic
1
1
MSI·FeCl4
3
7,38
12
13
(MSI) ·FeCl4
2
reaction conditions
ILs,
and our interest in the chemistry of
3
9,40
(MSI) ·SnCl5
2
we report herein new results under heterogeneous
1
1
1
1
1
1
2
4
5
6
7
8
9
0
(MSI) ·CuCl4
2
and homogeneous catalysis to promote the Biginelli reaction.
The developed conditions were then applied in the synthesis of
biologically active DHPMs (e.g., enastron, monastrol, piperas-
trol). Finally, we also investigated both the mechanism and the
origin of the ionic liquid effect over this reaction on the basis of
mass spectrometry analyses and DFT calculations.
MSI·CuCl2
(MSI) ·CoCl4
2
(MSI) ·ZnCl4
2
(MSI) ·ZrCl5
2
(MSI) ·MnCl4
2
MSI·InCl4
a
Reactions were carried out with benzaldehyde (3.00 mmol), ethyl
RESULTS AND DISCUSSION
■
acetoacetate (3.00 mmol), and urea (3.00 mmol) at 90 °C. All reactions
were conducted under homogenous catalytic conditions, and all yields
refer to te isolated product (4a).
Initially, we investigated the combination of a Bronsted acid TSIL
with metal-containing (Lewis acid) anions as the catalysts to
promote the Biginelli reaction (Scheme 2) using benzaldehyde,
ethyl acetoacetate, and urea as the model reaction (Scheme 2).
We also envisaged the reaction using the proportion
for the Lewis acid metal for the anion and the best solvent/
medium for the reaction.
1
.00:1.00:1.00 between the reagents toward a more efficient
and greener process. The reaction performed with no catalyst
resulted in only traces of the product independent of the reaction
media, including the commonly used ILs (Scheme 2).
The reactions were initially analyzed using MSI·Fe Cl over
2
7
60 min to evaluate the most active reaction media (Table 1,
entries 1−10). It is worth highlighting that reactions performed
in ILs, but in the absence of any catalyst, gave poor results
(down to 35% at 90 °C). These results, indeed, are not
surprising, since it is necessary to have a synergic effect using
protic (acidic) ILs as the catalyst for the Biginelli reaction and
under ultrasound irradiation to obtain good results, as already
The efficiency of anionic Lewis acids with imidazolium cations
41
42
has already been demonstrated by us and by others for
different reactions. The cooperative effect of this combination
(
protic and metal-containing ILs as catalysts) may be very
43,44
promising for catalysis, as some have recently explored.
The
46
sulfonic acid group was chosen because some have demonstrated
demonstrated. After BMI·BF proved to be the best media for
4
Scheme 2. Synthesis of the Bronsted Task-Specific Ionic Liquid (MSI cation) with Lewis Acid Anions Tested as the Catalysts for
a
the Model Biginelli Reaction
1
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the Biginelli reaction, both other metal-containing catalysts and
longer reaction times (4 h) were evaluated, as well (Table 1,
entries 10−20). For all reactions, the product precipitates in
the reaction media, allowing easy separation through filtration.
Table 2. Effect of Reagent Concentrations Variation for the
Model Reaction
a
reagent (mol %)
entry benzaldehyde
urea ethyl acetoacetate isolated yield (%) (4a)
The TSIL chloroferrate derivative (MSI·FeCl , Table 1, entry 11)
4
showed good results but lower than the nonfunctionalized IL
1
2
3
4
5
6
7
3.00
3.00
3.00
4.50
3.00
3.00
9.00
3.00
3.00
4.50
3.00
3.00
9.00
3.00
3.00
4.50
3.00
3.00
9.00
3.00
3.00
65
65
57
82
74
60
85
47
BMI·FeCl (88−91%), as previously reported. The same is true
4
for the TSIL with the indate anion (MSI·InCl , Table 1, entry 20)
4
when compared with the nonfunctionalized IL BMI·InCl
4
48
(95−98%). These experiments show that the presence of a
functionalization on the system indeed results in a destabilization
of the catalytic system, thus lowering the obtained yields. It is
worth highlighting, however, that those better yields (already
reported) are described with reagent excess and optimized
conditions. The use of MSI·Fe Cl (Table 1, entry 10) proved to
a
BMI·BF (1.0 mL), 90 °C, 7 mol % (MSI·Fe Cl ) for 4 h of reaction.
4
2
7
52
2
7
ILs. Drago and co-workers reported the evaluation of several
strong acids using pyridine as the basic probe. They observed
that HPW was the strongest acid when compared with
CF SO H, p-CH C H SO H, H SO , and others. Some
doped Keggin heteropolyacids and HPW have already
been tested as the catalyst for the Biginelli reaction in solvent-
free versions (with good results). When tested under micro-
wave irradiation or supported in silica, demonstrated yields
ranged from reasonable to very good. The use of HPW
in acetic acid as the solvent has also been described, but it
required long reaction times, and the use of pure acetic acid
with reagent excess is not a sustainable condition. To the best
of our knowledge, despite all promising results, experiments
conducted in ILs to probe the effect on the reaction have not yet
been described. Moreover, some drawbacks of such methodo-
logies were the reagent excess and, in one of the cases, the
requirement of a large catalyst load to obtain satisfactory results.
Considering the expected superacid behavior in ILs, we sup-
ported the HPW in those three ILs and monitored the Biginelli
reaction (Table 3).
be a promising system, and reactions performed with different
solvents (Table 1, entries 1−7) gave poor results when compared
with BMI·BF4 (Table 1, entry 10) as the ionic medium.
BMI·NTf (Table 1, entry 8) and BMI·PF (Table 1, entry 9) also
3
3
3
6
4
3
2
4
53
54
2
6
gave worse results compared with BMI·BF (Table 1, entry 10),
4
but much better yields than those in organic solvents. The system
then had the temperature and catalyst concentration optimized
55
56
(Figure 1) for the reaction.
The reaction profile (Figure S1 in the Supporting Information)
showed that, under homogeneous catalytic conditions and using
equimolar proportions of each reagent, the reaction requires 4 h
to complete under optimized conditions. The effect of reagent
excess was then tested under the same experimental conditions
57
(Table 2).
It can be seen from Table 2 that an aldehyde excess has a
direct beneficial effect over the reaction yields. Urea and ethyl
acetoacetate excess have the opposite effect, indicating the
preferred mechanism among the three accepted mechanisms
(
i.e., iminium, enamine and Knoevenagel mechanism, Support-
ing Information Scheme S1) is the iminium mechanism. These
results are in full accordance with kinetic experiments recently
reported, which indicate that an aldehyde excess favors the
iminium mechanism. The preferred mechanism pathway for
the transformation under the developed conditions will be
discussed in due course. It is clear from Table 2, however, that
the iron-containing catalyst may be of great utility for the
Biginelli synthesis, as will be shown herein.
Table 3 shows that BMI·NTf was the best IL for all cases,
2
whereas for BMI·PF , the known anion degradation was
6
58
noted, making BMI·PF not a good medium for the Biginelli
reaction under the tested conditions. After 4 h and with 4 mol %
6
49
of HPW in BMI·NTf , the desired Biginelli adduct 4a was
2
obtained almost quantitatively. It is worth highlighting that 4a
was synthesized with equimolar quantities of the reagents, thus
representing a significant improvement on the reaction conditions.
Heterogeneous catalytic conditions by using zeolite beta as
the acid catalyst have also been investigated in ILs. Zeolite β
framework has a tridimensional channel system with micro-
pores of 0.68 × 0.73 nm ([100] and [010] directions) and
0.56 × 0.56 nm ([001] direction) and that its disordered
It has been already reviewed that Bronsted acid (and
Bronsted acid TSILs) may behave as superacids when sup-
5
0,51
ported (embedded) in ILs.
In this sense, we decided to
support a strong known Bronsted acid (H PW O ; HPW) to
3
12 40
help in the promotion of the Biginelli reaction carried out in
Figure 1. (A) Temperature and (B) catalyst concentration optimization using the model reaction (3.00 mmol of each reagent). The catalyst
concentration was optimized at 90 °C (B), and the temperature was optimized with 10 mol % (A) of MSI·Fe Cl in BMI·BF (1.0 mL). Importantly,
2
7
4
when the reaction was carried out with 7 mol % of the catalyst and at 90 °C, the desired product was obtained at 65% of yield (data not shown).
1
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Table 3. Biginelli Reaction Promoted by HPW as the
Catalyst in Ionic Liquids (1.0 mL)
Table 4. Biginelli Reaction Promoted by Zeolite Beta as the
Catalyst in Ionic Liquids (1.0 mL)
a
a
entry catalyst (mol %) ionic liquid (1.0 mL) time (h) yield (%) of 4a
entry catalyst (mol %) ionic liquid (1.0 mL) time (h) yield (%) of 4a
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
1
1
1
1
1
1
1
1
1
1
1
1
2
3
4
5
BMI·NTf2
BMI·PF6
BMI·BF4
BMI·NTf2
BMI·PF6
BMI·BF4
BMI·NTf2
BMI·PF6
BMI·BF4
BMI·NTf2
BMI·PF6
BMI·BF4
BMI·NTf2
BMI·NTf2
BMI·NTf2
BMI·NTf2
1
1
1
2
2
2
3
3
3
4
4
4
4
4
4
4
37
30
30
41
41
33
55
42
37
69
46
40
71
87
99
99
1
2
3
4
5
6
7
8
9
0
1
1
1
1
1
1
1
1
1
1
1
1
2
3
4
5
BMI·NTf
BMI·PF
BMI·BF
2
1
1
1
2
2
2
3
3
3
4
4
4
3
3
3
3
23
46
26
22
19
12
65
b
11
50
b
20
90
99
99
99
b
b
b
b
b
6
4
BMI·NTf
2
b
BMI·PF6
BMI·BF4
BMI·NTf2
BMI·PF6
BMI·BF4
b
b
1
BMI·NTf2
1
1
1
1
1
1
1
11
BMI·PF6
BM·BF4
BMI·NTf2
BMI·NTf2
BMI·NTf2
BMI·NTf2
b
12
13
14
15
16
a
a
Reactions were performed with 3.00 mmol of each reagent (model
b
Reactions were performed with 3.00 mmol of each reagent (model
reaction) at 90 °C as homogeneous systems. The system is dark, and
product/reagent degradation was noted.
b
reaction) at 90 °C as heterogeneous systems. The system is dark, and
product/reagent degradation was noted.
Table 5. Biginelli Reaction Promoted by Zeolite Beta Doped
with HPW (1%) as the Catalyst in Ionic Liquids (1.0 mL)
structure also shows as mesoporous, originating from the
intergrowth of both polymorphs A and B. Some of us have
a
59
shown that the acidity of zeolite β is strongly dependent on its
entry catalyst (mol %) ionic liquid (1.0 mL) time (h) yield (%) of 4a
60
activation procedure. The presence of strong Bronsted sites
was observed only at lower calcination temperature (450 °C).
These kinds of acid zeolites have been used for several
1
2
1
1
1
1
1
1
1
1
1
1
1
1
2
3
4
5
BMI·NTf2
BMI·PF6
BMI·BF4
BMI·NTf2
BMI·PF6
BMI·BF4
BMI·NTf2
BMI·PF6
BMI·BF4
BMI·NTf2
BMI·PF6
BMI·BF4
BMI·NTf2
BMI·NTf2
BMI·NTf2
BMI·NTf2
1
1
1
2
2
2
3
3
3
4
4
4
3
3
3
3
2
6
4
b
3
61−63
catalyzed reactions, as reviewed elsewhere;
surprising that no study is found for the Biginelli reaction
or any multicomponent reaction) promoted by any zeolite
however, it is
4
20
14
10
41
b
b
b
5
(
6
when supported in ILs, despite the promising features of this
combination. Some groups have described a catalytic system
combining a TSIL (Bronsted acid ILs) supported in zeolitic
structures as an ecoapproach for the synthesis of spiro
7
8
9
11
59
b
10
11
12
13
14
15
16
64
compounds. In this sense, some experiments have been carried
out envisaging the achievement of an efficient catalytic system
through the combination of the acid zeolite beta embedded in
ILs. Moreover, the results could be used for comparing the
efficiency of this heterogeneous system with homogeneous
catalytic systems when applied to the Biginelli reaction carried
out in ILs. Table 4 summarizes the obtained results of the
heterogeneous catalytic system.
b
62
85
75
77
b
b
a
Reactions were performed with 3.00 mmol of each reagent (model
b
reaction) at 90 °C as heterogeneous systems. The system is dark and
Reactions carried out in BMI·PF and BMI·BF could not be
product/reagent degradation was noted.
6
4
tagged as “green” because of anion and product degradation.
The use of BMI·NTf , however, was shown to be promising. In
2
The strategy of doping the zeolite with HPW showed poor
results. Indeed, a fast degradation of the product and the
aldehyde was observed. Lower yields were observed when
compared with those described in Table 4, even though 4a
could be obtained in 85% in 3 h with 3 mol % of the catalyst
the third reaction hour (Table 4, entry 7), compound 4a was
obtained in 65%. With 3 mol % of the catalyst, the reaction
reaches almost quantitative yields in 3 h (Table 4, entry 14),
thus showing great potential for use of the heterogeneous
system in ILs. One drawback is that the product precipitates
in the reaction media, thus making the product and catalyst
(
Table 5, entry 14).
Overall, when comparing the catalytic systems (homogeneous
(
heterogeneous) separation a difficult task.
Because of the promising results obtained by the hetero-
and heterogeneous) described herein, the homogeneous systems
showed some advantages, such as:
geneous catalytic system, we decided to support the HPW (1%)
in the zeolite beta and test the formed heterogeneous system.
Some of us have recently described the citronellal cyclization
(i) No product/reagent degradation was noted;
(ii) The system is easy to handle, and the product separation
is easier, since only one filtration is necessary (the product
precipitates in the reaction media);
(iii) The metal-containing catalysts could be prepared in situ;
(iv) It is easier to visualize the reaction.
65
using supported HPW on MCM-41 and some HPW deriva-
tives as efficient catalysts in the esterification reaction of oleic
66
acid with ethanol. The obtained results for the Biginelli reaction
are summarized in Table 5.
1
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Research Article
Despite the fact that the heterogeneous catalysis proceeds
faster (3 h) than the homogeneous (4 h), the promising
features of the homogeneous systems and the drawbacks for the
heterogeneous systems (product and catalyst separation)
prompted us to perform the synthesis of other MSI-derivative
catalysts, as shown in Scheme 3, and to test them under
homogeneous catalytic conditions.
Scheme 3. Synthesis of the Bronsted IL (MSI cation) with
Lewis Anions Tested as the Catalysts for the Model Biginelli
Reaction
Figure 2. Catalyst’s recycling (5 mol % of the catalyst ((MSI) PW),
3
4
h in BMI·NTf (1 mL) at 90 °C; recharges using 3.00 mmol of each
2
reagent).
It is noted from Table 7 that all compounds could be obtained
at least with very good yields (above 76%). The biologically
active compounds Monastrol (4e, 98%) and its oxo-analogue
4d, 99%), Enastron (4j, 76%), Dimethylenastron (4k, 87%),
and Piperastrol (4n, 85%) were obtained in excellent yields
see Table 7), thus showing that different methodologies could
be used for a straightforward synthesis of a desired DHPM
derivative.
6
7
The catalyst (MSI) PW has already been described and
3
68
69
applied for esterification and desulfurization of fuels. Some
3
−
heteropolyanions (PW O ) with other cations (rather than
imidazolium) have also been used for Prins reactions, esterifi-
cation, and desulfurization of fuels. For the above-mentioned
reasons, we envisaged this combination could be very useful for
Biginelli synthesis (Table 6).
1
2
40
(
70
7
1
72
(
To investigate the mechanism with (MSI) PW as the catalyst,
3
Table 6. Biginelli Reaction Promoted by (MSI) PW as the
Catalyst in Ionic Liquids (1.0 mL)
3
high-resolution electrospray ionization quadrupole-time-of-flight
mass spectrometry (ESI-QTOF-MS) analyses were performed.
Very recently, we have determined the role of the reagents for
the in situ formation of some reactive intermediates for a Lewis
a
entry catalyst (mol %) ionic liquid (1.0 mL) time (h) yield (%) of 4a
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
1
1
1
1
1
1
1
1
1
1
1
1
2
3
4
5
BMI·NTf2
1
1
1
2
2
2
3
3
3
4
4
4
4
4
4
4
6
36
b
acid-catalyzed version of the Biginelli reaction. The potential
BMI·PF6
BMI·BF4
15
b
of MS to evaluate the Biginelli reaction has already been
6
reported, and it proved to be efficient for studying all three
BMI·NTf2
16
17
73
b
accepted mechanisms (see Supporting Information Scheme S1
BMI·PF6
BMI·BF4
b
for the mechanisms). The soft ionization from the ESI source
allows continuous snapshots of the reaction with a gentle transfer
5
BMI·NTf2
60
31
10
65
33
15
71
77
87
99
74
b
b
from the solution to the gas phase, thus allowing excellent
BMI·PF6
BMI·BF4
online monitoring of several reactions with the possibility of
75
detection and characterization of supramolecular species
1
1
1
1
1
1
1
BMI·NTf2
BMI·PF6
BMI·BF4
BMI·NTf2
BMI·NTf2
BMI·NTf2
BMI·NTf2
7
6,77
b
b
(including transient intermediates of catalyzed reactions ).
First, the best catalyst ((MSI) PW) was characterized in both
3
positive (Supporting Information Figure S2) and negative
Figure 3) ion modes.
(
It is noted that the most intense set of signals (m/z 953−
−
9
63) is attributed to PW3 (PW = PW O ), indicating an
12 40
a
excellent dissociation of the acidic hydrogens and the relative
stability of the triply charged anionic species. The doubly
charged anionic species [PW + H]2 was also detected (m/z
Reactions were performed with 3.00 mmol of each reagent (model
b
reaction) at 90 °C as homogeneous systems. The system is dark, and
−
product/reagent degradation was noted.
1
432−1448), thus in accordance with the good stability of the
conjugate base. A low-intensity set of signals in the range of
2−
Once more, BMI·NTf was shown to be the best reaction
m/z 1635−1651 ([PW + MSI + (MSI − H)] , where MSI −
H is the zwitterionic MSI derivative, i.e., the dissociation of the
acid hydrogen from the side group) could be attributed to the
neutral zwitterionic species (MSI − H) associated with [PW +
MSI]2 (m/z 1532−1548), which in turn was also detected
2
media. The catalyst (MSI) PW has the advantage of being
3
completely ionic, thus rendering it possibly a more efficient
support in the tested ILs and allowing the possibility of
recycling. Indeed, five runs were conducted (Figure 2), and
from the third run on, a slight loss of the catalytic activity was
noted, indicating a slight catalyst leaching from the ionic media.
Once we had optimized all the catalytic reaction conditions
with the different developed catalysts, we decided to extend the
methodology to the synthesis of different DHPMs to compare
five developed catalytic systems. The results are summarized
in Table 7.
−
−
(see Figure 3). No set of signals related to [PW + 2H] was
noted. To probe the ionic liquid effect and its influence on the
catalyst behavior, a mixture of (MSI) PW and BMI·NTf was
3
2
analyzed (Figure 4) and compared with the spectrum in the
absence of any IL (Figure 3).
In the presence of BMI·NTf , the set of signals of m/z 1432−
2
2−
1448 ([PW + H] ) almost disappeared, thus showing that
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Table 7. Dihydropyrimidinones (DHPMs) Synthesized Using the Developed Conditions with Different Catalysts at 90 °C Using
3.00 mmol of Each Reagent and 1.0 mL of the Ionic Liquid
a
b
7
mol % of the catalyst, 4 h in BMI·BF , and 9.00 mmol of the aldehyde (homogeneous system). 4 mol % of the catalyst, 4 h in BMI·NTf
4 2
c d
(
(
homogeneous system). 3 mol % of the catalyst, 3 h in BMI·NTf (heterogeneous system). 3 mol % of the catalyst, 3 h in BMI·NTf2
2
e
heterogeneous system). 5 mol % of the catalyst, 4 h in BMI·NTf (homogeneous system).
2
in the presence of the IL, the dissociation of the acid is even
more effective, hence, making the acidic character of the catalyst
stronger. A set of signals of m/z 1501−1517 appeared and was
attributed to [PW + BMI] , where BMI is the imidazolium
cation (1-n-butyl-3-methylimidazolium of 139 Da). The MS
data clearly showed a more effective dissociation of the acidic
moiety, thus, in accordance with the expected superacid
behavior of Bronsted acids supported in ILs.
first step could be intercepted, indicating the addition takes
place in a reversible manner and the preferred pathway is the
iminium mechanism.
To gain insights into the mechanism and mainly into the ionic
liquid effect in the stabilization of the charged intermediates,
theoretical calculations were also performed and discussed. The
theoretical investigations were centered on the key intermedi-
ates from the iminium mechanism (Scheme 4), that is, the
iminium cation (ion of m/z 149, Figure 5A, Int I) and the ion
from the addition to the iminium (ion of m/z 279, Figure 5B,
2−
After the catalyst and catalyst + BMI·NTf interactions and
2
behavior characterizations, the model reaction was monitored
online, and interesting signals could be detected and
characterized by collision-induced dissociation (CID) showing
some Biginelli reaction intermediates in high resolution ESI-
QTOF product ion spectra (Figure 5).
Int II). We have also considered the association with the anion
−
[
NTf ] (bis(trifluoromethylsulfonyl)imide)) to those ions in
2
both cis and trans conformations (Figure 6).
It is shown in Figure 6 that upon association with the anion
It is noted that the iminium mechanism (Scheme 4, also see
Supporting Information Scheme S1) is clearly favored under
the tested conditions. The key intermediate of m/z 149 was
isolated and characterized. The intermediate of m/z 279 could
also be isolated and characterized by ESI(+)-MS/MS. An
intermediate of m/z 237 from the Knoevenagel mechanism
should also be noted; however, only the intermediate from the
(
cis or trans conformations), intermediates Int I and Int II
change their conformations in a similar manner. When Int I is close
to the anion, the anion changes its conformation from cis to trans
(Figure 6E), and this was not observed for intermediate Int II. This
conformational change allows a better ion-pairing formation with
steric interactions minimized. The thermodynamics involved in
1
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Figure 3. ESI(−)-QTOF mass spectrum of the catalyst (MSI) PW.
3
3
−
MSI = functionalized cation (205 Da) and PW = [PW O ] .
12
40
the stabilization of intermediates through ion-pairing has been
investigated, as well (Table 8).
Figure 4. (A) ESI(−)-QTOF mass spectrum of the catalyst (MSI) PW.
3
(B) ESI(−)-QTOF mass spectrum of the catalyst (MSI) PW in the
3
−
presence of BMI·NTf . Note the anion [NTf ] of m/z 280 (see the
inset). BMI = 1-n-butyl-3-methylimidazolium cation (139 Da).
2
2
Table 8. Thermodynamics Parameters Calculated at the
M062X/6-311++g(2d,2p)//B3LYP/6-31+G(d,p) Level of
Theory for the Ion-Pairing of Intermediates Int I and Int II
(Monastrol (4e) and its oxo-analogue (4d), Enastron (4j),
Dimethylenastron (4k), and Piperastrol (4n)) were obtained in
excellent yields under different conditions. ESI-MS analyses
showed that under the best homogeneous conditions (using
−
upon Association with [NTf2]
binding
step/
parameter
ΔG
ΔH
ΔS
energy
(kcal mol−1) (kcal mol−1) (cal mol K−1
−1
)
(kcal mol−1)
(MSI) PW as the catalyst) the iminium mechanism is favored,
3
Int I + NTf2
−84.05
−83.04
−76.80
−73.95
−96.01
−94.34
−89.94
−86.1s1
−40.13
−37.88
−44.09
−40.80
−97.00
−95.37
−90.86
−87.07
and two key intermediates were detected and characterized via
ESI-MS/MS. MS analyses also revealed the origin for the high
stability of the conjugate base using the Bronsted acid catalyst
(cis)
Int I + NTf2
(
trans)
Int II + NTf2
cis)
Int II + NTf2
trans)
(
MSI) PW, allowing a better understanding of the superacid
3
50,51
behavior of Bronsted acids when supported in ILs.
Finally,
(
theoretical calculations helped us to understand the efficiency of
the stabilization of the charged intermediates of the Biginelli
reaction in ILs. The calculated values showed how spontaneous,
(
−
No significant difference was noted for [NTf ] in either of
efficient, and strong the associations of those positively charged
2
−
its conformations, only a slight difference favoring the trans
isomer. For all cases, the Gibbs free energy shows a highly
favored process, in accordance with the stabilization of charged
intermediates promoted by ILs through ion-paring and forma-
tion of aggregates (ionic liquid effect). A large binding energy is
intermediates with the anion ([NTf
2
] ) are. It also allowed us to
understand the ionic liquid effect over the reaction through ion-
pairing and aggregate formation. The application of the described
catalysts under optimized conditions for other multicomponent
reactions is underway and will be published in due course.
also noted for all cases, indicating a strong interaction between
−
EXPERIMENTAL SECTION
the charged intermediates and [NTf ] . Theoretical calculated
■
2
values are in accordance with the observed ionic liquid effect
over the Biginelli reaction expressed by testing homogeneous
and heterogeneous conditions. For all cases, ILs were better
than organic solvents. It is necessary to bear in mind that in the
General. Chemicals and solvents were purchased from
commercial sources. Liquid reagents and solvents were distilled
prior to use.
ESI-MS and ESI-MS/MS measurements were performed in the
positive ion mode (m/z 50−2000 range) on a HDMS
instrument. This instrument has a hybrid quadrupole/ion
mobility/orthogonal acceleration time-of-flight (oa-TOF) geom-
etry and was used in the TOF V+ mode. All samples were
dissolved in methanol to form 50 μM solutions and were directly
infused into the ESI source at a flow rate of 10 μL/min after
5 min at 90 °C. ESI source conditions were as follows: capillary
voltage 3.0 kV, sample cone 20 V, extraction cone 3 V.
All electronic structure calculations performed in this work
were performed within Kohn−Sham density functional theory
ionic medium, additional associations (with both imidazolium
−
cations and [NTf ] anions) will take place, therefore, with
2
additional stabilizing effects over the system. In this sense,
theoretical calculations were important and point firmly to the
spontaneous formation of supramolecular aggregates with the
charged intermediates.
In summary, we have demonstrated the efficiency of several
catalytic conditions to perform the Biginelli reaction with a
considerable ionic liquid effect. Heterogeneous and homoge-
neous conditions were tested, and homogeneous conditions
were shown to be more appropriate for many cases, avoiding
product/reagent degradation. Five biologically active compounds
78,79
(DFT) formalism.
The geometry optimizations were carried
out using the B3LYP/6-31+G(d,p) level of calculation. At the
1
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Figure 5. Model reaction catalyzed by (MSI) PW in the presence of BMI·NTf . (A) ESI(+)-QTOF product ion spectrum of m/z 149. (B) ESI(+)-
3
2
QTOF product ion spectrum of m/z 279. (C) ESI(+)-QTOF product ion spectrum of m/z 237. (D) ESI(+)-QTOF mass spectrum of the model
reaction.
Scheme 4. The Proposed Iminium Mechanism for the Biginelli Reaction under Acidic Conditions
same level of theory, the fundamental vibrational frequency
calculations were carried out to ensure the true minima, to
compute zero-point vibrational energy (ZPVE), and to derive
the thermochemical corrections for the heat of formation, Gibbs
free energy, and the binding energy. The calculated frequencies
were scaled by a factor of 0.9642, and the ZPVE and thermo-
dynamic functions were calculated at 298.15 K and 1 atm. The
optimized geometries were used for the single point calculation
at the M06-2X/6-311++g(2d,2p) level of calculation. The
M06-2X meta exchange-correlation functional is recommend for
applications involving main-group thermochemistry, kinetics,
noncovalent interactions, and electronic excitation energies to
80
valence and Rydberg states. To avoid a basis-set superposition
error, the thermodynamics properties and binding energies
were counter-poise-corrected using the standard approach by
81
Boys and Bernardi. All theoretical calculations were carried out
82
using the Gaussian 09 program suite.
NMR spectra were recorded on a 7.05 T instrument using
a 5-mm internal diameter probe operating at 300 MHz for
1
13
H and at 75 MHz for C. Chemical shifts were expressed in
1
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Figure 6. Optimized geometries at the B3LYP/6-31+G(d,p) level of theory. (A) Anion (NTf ) cis. (B) Anion (NTf ) trans. (C) Int I (iminium).
2
2
−
(
D) Int II (addition to the iminium). (E) Int I associated with the anion [NTf ] . Note the anion changed to its trans conformation. (F) Int II
associated with the anion [NTf ] (cis). (G) Int I associated with the anion [NTf ] (trans). (H) Int II associated with the anion [NTf ] (trans).
2
−
−
−
2
2
2
parts per million (ppm) and referenced by the signals of the
residual hydrogen atoms of the deuterated solvent (DMSO-d6),
as indicated in the legends.
metal chloride salt with MSI·Cl and heating (80 °C) under inert
atmosphere for 1 h, affording the metal catalysts in quantitative
72
yields. The known (MSI) PW was prepared by treating the
3
Zeolite β in the ammonium form was calcined at 450 °C for
zwitterionic solid (15 mmol) with HPW (5 mmol) in 30 mL of
water:methanol (1:1) at 50 °C for 24 h. Afterward, the solvent
was concentrated under vacuum, and the white solid precipitated
was washed with ethyl ether and dried in vacuum, affording the
desired product in quantitative yield.
General Procedure for the Biginelli Reaction with the
Five Different Methods.
1
h in a muffle furnace. The zeolite full characterization has
60
been described elsewhere. The 12-tungstophosphoric acid
H PW O ·nH O or HPW) was obtained from commercial
(
3
12 40
2
sources and dried at 200 °C for 1 h before its utilization. Zeolite β
doped with HPW (1%) was prepared by the aqueous impregnation
procedure. The zeolitic structure was stirred in a HPW solution at
8
0 °C until dryness, affording the doped zeolite quantitatively.
(
a) A sealed Schlenk tube containing 1 mL of BMI·BF , 9.00
83
4
The known MSI cation was synthesized as follow: To a
solution of 1,3-propanesultone (20 mmol) dissolved in ethanol
100 mL) was added 1-methylimidazole (20 mmol), and the
mmol of the aldehyde, 3.00 mmol of the 1,3-dicarbonyl
compound, 3.00 mmol of urea (or thiourea), and MSI·Fe Cl
2
7
(
(
7 mol %) was allowed to react at 90 °C for 4 h. Products
mixture was allowed to react at 100 °C for 24 h. The white
zwitterionic solid formed was washed with ethyl acetate, filtered,
and dried in vacuum. Afterward, a stoichiometric amount of acid
were purified by chromatographic column eluted with
mixtures of hexane/ethyl acetate, or if the product pre-
cipitated in the reaction medium, it was filtered and
washed with cold ethanol.
(
HCl) was added to an aqueous solution of the zwitterionic
solid, and the mixture was heated at 50 °C for 18 h. The solution
was concentrated under vacuum, and a white solid precipitated
after the addition of toluene. The solid with MSI cation was
washed with ethyl acetoacetate and dried in vacuum at 50 °C for
(
b) A sealed Schlenk tube containing 1 mL of BMI·NTf2,
3.00 mmol of the aldehyde, 3.00 mmol of the 1,3-dicarbonyl
compound, 3.00 mmol of urea (or thiourea), and HPW
(4 mol %) was allowed to react at 90 °C for 4 h. Substrates
were purified by a chromatographic column eluted with mix-
tures of hexane/ethyl acetate, or if the product precipitated
6
h. Alternatively, dry HCl can be bubbled in a suspension of
the zwitterionic solid in CH Cl for 24 h. All metal (anion)-
2
2
containing catalysts (see Table 1) were obtained by mixing the
1
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in the reaction medium, it was filtered and washed with cold
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AUTHOR INFORMATION
Corresponding Author
E-mail: wender@unb.br and brenno.ipi@gmail.com.
■
*
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Notes
The authors declare no competing financial interest.
1
(
ACKNOWLEDGMENTS
■
(
B.A.D.N. thanks INCT-Catalysis and all founding sources. This
work has been supported in part by CAPES, CNPq, FINEP-
MCT, FINATEC, FAPESP, FAPDF, DPP-UnB, and ANP-
PETROBRAS.
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dx.doi.org/10.1021/cs400291t | ACS Catal. 2013, 3, 1420−1430