Mechanistic studies on Lewis acid catalyzed Biginelli reactions in ionic liquids: Evidence for the reactive intermediates and the role of the reagents

Article abstract of DOI:10.1021/jo301806n

This paper describes the use of common Lewis acids supported in imidazolium-based ionic liquids as the catalysts to promote the Biginelli reaction. The ionic liquid effect and the reaction mechanism are discussed on the basis of nuclear magnetic resonance

Full text of DOI:10.1021/jo301806n

Article
pubs.acs.org/joc
Mechanistic Studies on Lewis Acid Catalyzed Biginelli Reactions in
Ionic Liquids: Evidence for the Reactive Intermediates and the Role
of the Reagents
Luciana M. Ramos,† Adrian Y. Ponce de Leon y Tobio,† Marcelo R. dos Santos,†
Heibbe C. B. de Oliveira,† Alexandre F. Gomes,‡ Fabio C. Gozzo,‡ Aline L. de Oliveira,†
and Brenno A. D. Neto*,†
†Laboratory of Medicinal and Technological Chemistry, University of Brasília, Chemistry Institute (IQ-UnB), Campus Universitar
́
io
Darcy Ribeiro, CEP 70904-970, P.O. Box 4478, Brasília DF, Brazil
‡Institute of Chemistry, University of Campinas (Unicamp), Campinas SP, Brazil
S
* Supporting Information
ABSTRACT: This paper describes the use of common Lewis
acids supported in imidazolium-based ionic liquids as the
catalysts to promote the Biginelli reaction. The ionic liquid
effect and the reaction mechanism are discussed on the basis of
nuclear magnetic resonance (NMR), electrospray ionization
mass spectrometry (ESI-MS), and theoretical calculations.
Indeed, the results showed that the ionic medium plays a
fundamental role in the synthesis of biologically active
dihydropyrimidinones due to the stabilization of the charged
intermediates proposed in the mechanism. When conducted in
an ionic liquid as solvent, the reaction mechanism is more
complex than in other Lewis acid catalyzed Biginelli reactions.
The Biginelli multicomponent reaction, first reported in
198314 by Pietro Biginelli,15 is a very elegant methodology to
directly obtain 3,4-dihydropyrimidin-2(1H)-one (DHPMs)
derivatives in a one-step procedure.16 DHPMs usually display
biological activity, and compounds such as enastron,17
monastrol,18 piperastrol19 (and analogues), and other deriva-
tives20 (Figure 1) are known as biologically active compounds
used as calcium channel modulators, adrenergic receptor
antagonists, mitotic Kinesin inhibitors, antivirals, antibacterials,
etc., as reviewed elsewhere.21
Since its discovery, the Biginelli MCR has experienced many
drawbacks such as long reaction times, need of excess of one of
the reactants, low yields, expansive catalysts, and others.22−25 In
this sense, ILs became a natural option for the observed efforts
to improve on the reaction conditions, times, yields, and
workup.26 Task-specific ILs have been also employed as
alternative acid27,28 and basic29,30 catalysts to perform this
reaction. Ultrasonic irradiation31 and metal-containing ILs (in
INTRODUCTION
■
Nowadays there is no doubt about the importance of ionic
liquids (ILs) and how efficient and promising the multi-
component reactions (MCRs) are. A multicomponent synthesis
performed in ILs has recently been described as “a perfect
synergy for eco-compatible heterocyclic synthesis”.1 Somehow, this
successful idea could be easily predicted, especially because ILs
are regarded as a possible pathway toward sustainability.2
Currently, it is possible to find many industrial processes
carried out in ILs.3 The tunable, unique, desired physicochem-
ical properties of ILs make this class of substances highly
studied and applied in many different areas.4−6 Indeed, the
impressive chemistry of ILs has been very recently reviewed.7
In the search for multiple-bond-forming efficiency, MCRs play
a central role, as recently reviewed.8 The possibility of
generating small molecule libraries, especially with biologically
active compounds, has brought MCRs to prominence.9 In this
context, many examples of different approaches are found in
the scientific literature to improve on both the chemical
selectivity and yields of MCRs.10−13
Received: August 27, 2012
Published: October 26, 2012
© 2012 American Chemical Society
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Table 1. Lewis Acids Tested As Promoters of the Biginelli
a,b
Reaction
d
entry
catalyst
ionic liquid (or organic solvent) yield (%)
1
2
traces
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·BF4
BMI·NTf2
BMI·PF6
MeCN
3
5
3
4
CdO
CdSO4·8H2O
CdCl2·H2O
CeCl3·7H2O
InCl3
42
30
72
61
3
5
Figure 1. Some examples of biologically active dihydropyrimidinones
(DHPMs).
6
7
8
Cr(CO)6
32
33
the anion) such as [InCl4]− and [FeCl4]− have also been
used as strategies to overcome all drawbacks associated with the
Biginelli reaction.
9
SnCl2
40
59
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
CoCl2·6H2O
MnO2
It is well-known that some common Lewis acids (SbCl3,34
Cu(OTf)2,35 ZrCl4,36 FeCl3,37 SnCl2,38 InBr3,39 ZnBr2, and
others40,41) are capable of promoting the Biginelli reaction,
despite the many problems associated with their use. The
reaction mechanism of this MCR is so far indisputable (as will
be discussed in due course). These metal catalysts are also
commonly supported and used under high temperatures
(typically above 100 °C), and in some cases, the presence of
an additional Bronsted acid is required.42
Nb2O5
11
43
59
13
59
66
4
BF3·OEt2
AlCl3·6H2O
FeSO4·7H2O
FeCl2·4H2O
FeCl3
Ni(OAc)2·4H2O
NiCl2·6H2O
NiSO4·6H2O
ZrOCl2·8H2O
MgCl2·6H2O
BaCl2·2H2O
ZnCl2
58
30
68
66
52
49
34
7
On the basis of our experience using ILs and our interest in
catalytic processes in this ionic media,43−46 we describe herein
that imidazolium-based ILs (Figure 2) are an excellent media to
ZnSO4·7H2O
Cs2CO3
c
CuO
9
CuSO4·5H2O
CuCl2·2H2O
CuCl2
54
73
77
76
87
46
52
48
44
31
7
Figure 2. Imidazolium-based ionic liquids commonly used in biphasic
catalysis.
CuCl2
CuCl2
support common metal Lewis acid with excellent results for the
Biginelli reaction. The ionic liquid effect and the proposed
reaction mechanism are also discussed.
CuCl2
CuCl2
MeOH
CuCl2
CHCl3
CuCl2
CH2Cl2
RESULTS AND DISCUSSION
■
CuCl2
THF
First, we investigated a series of Lewis acids as the Biginelli
reaction promoters (Scheme 1), and results are summarized in
Table 1.
CuCl2
H2O
a
b
R1 = Ph, R2 = Me, R3 = OEt, X = O. Benzaldehyde (3.00 mmol),
ethyl acetoacetate (3.00 mmol), urea (3.00 mmol), 1 mL of solvent,
c
and 10 mol % of the catalyst at 80 °C for 60 min to give 4a. Basic
character. Isolated yields.
d
Scheme 1. DHPMs Synthesis with Different Lewis Acids
product in 93% yield but after 4 h of reaction, indicating how
promising the catalytic system shown here is. The use of copper
catalysts, however, gave the best results (Table 1, entries 29 and
30), yielding the Biginelli adduct in 73% and 77% yield,
respectively. Copper chloride is a cheap and readily available
Lewis acid. Once the metal catalyst was selected (CuCl2), it was
tested in different ILs and other organic solvents to be sure
about the benefits of using ionic media rather than a classic
organic solvent (Table 1, entries 31−38). It is noted that the
use of BMI·PF6 gave by far the best result (87%) for only 60
min of reaction (Table 1, entry 32), and it was also better than
other commonly used solvents (Table 1, entries 33−38). It has
been reported42 that the use of a combined system with CuCl/
BF3·OEt2/AcOH in THF for 18 h gave the same product in a
similar yield. The results indicated how efficient and promising
It is worth highlighting that all tests were conducted with
equimolar quantities of the three components of the Biginelli
reaction and in only 60 min to evaluate the most active catalytic
system among all tested.
It can be deduced from Table 1 that some Lewis acids such
as CeCl3, InCl3, FeCl3, ZrOCl2, and MgCl2, (Table 1, entries 6,
7, 17, 21, and 22) are promising catalysts and give the desired
product above 60% of yield in the first reaction hour. Among
these metals, there is no doubt about the importance of iron.
For comparison purposes, it has been reported37 that the use of
FeCl3 with an additional amount of HCl resulted in the same
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this novel catalytic system (BMI·PF6, CuCl2) is, which was
further optimized.
The reaction temperature was varied, and the results are
better visualized in Figure 3. It is noted that the best reaction
Table 2. Dihydropyrimidinones Synthesized Using the
Developed Conditions (80 °C, BMI·PF6, CuCl2)
Figure 3. Temperature effect on the synthesis of DHPM 4a in
BMI·PF6 and CuCl2 as the catalyst.
temperatures were between 80 and 90 °C; thus, we decided to
carry out the reactions at lower temperature, i.e., at 80 °C.
Below this temperature, the isolated yields were not as good. It
was also noted, nevertheless, that at 50 °C the system is
relatively active and, in some cases, it may be a desired
condition. Above 90 °C, yields decrease, despite the fact that
the system remains active for all tested temperatures.
The reaction profile was also investigated and visualized in
Figure 4.
The catalytic system showed to be active for different
substrates and good to excellent yields were observed. The
biologically active monastrol (4d) was obtained in 80% in only
1 h of reaction. Oxo-enastron (4p) was also obtained in 77% at
the same time.
For long, the Biginelli reaction mechanism was the subject of
many discussions. Currently, there are three major proposals
accepted for this condensation: (i) The iminium mechanism,
(ii) the Knoevenagel mechanism, and (iii) the enamine
mechanism.47−49 Recently, it has been demonstrated that
electrospray ionization mass spectrometry (ESI-MS and -MS/
MS) is an excellent tool to study the Biginelli intermediates
formed during the transformation,50 especially because ESI-MS
is capable of “fishing” the formed ions from the solution,
leading them directly to the gas phase.51 The limitation,
however, was that the study was conducted using a Bronsted
acid,50 which is usually not preferable for an actual Biginelli
synthesis. Nevertheless, the potential of ESI-MS for studying
this reaction was unequivocally demonstrated. Thus, we
decided to use this important tool to evaluate which is the
preferred mechanism under the studied reaction conditions.
Fortunately, we were able to detect and characterize interesting
intermediates and transient species, as will be shown and
discussed. On the basis of these findings, a catalytic cycle was
proposed (Scheme 2) and is analyzed (discussed) below.
In the presence of ethyl acetoacetate and urea, intermediate I
is formed, which is found in equilibrium with intermediates V
and VI, as shown in Scheme 2. Benzaldehyde coordinates to
the metal center (copper) and forms II, which immediately
leads to III with water release. Intermediate III is then trapped
by ethyl acetoacetate forming IV through a direct addition to
CN. In the presence of urea, compound B is released
restoring I. Intermediate III can equally proceed through two
different pathways, i.e., (i) reacting with urea releasing
compound A and restoring I (substitution reaction instead of
an addition) or (ii) reacting with ethyl acetoacetate releasing
Figure 4. Reaction profile on the synthesis of DHPM 4a using CuCl2
as the catalyst and BMI·PF6 as the reaction media.
It is noted that in only 5 min of reaction the yield is near 30%
and that in 90 min yields are above 90%, reaching 95% of 4a by
the end of the reaction.
Once we optimized the reaction conditions, we decided to
extend the methodology to the synthesis of different DHPMs.
The results are summarized in Table 2.
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Scheme 2. Proposed Catalytic Cycle for the Synthesis of DHPMs
compound A giving VI (also a substitution reaction). In the
proposed cycle, 1,3-dicarbonyl compound and/or urea act to
stabilize the metal center and improve its reactivity. It is worth
noting that many metals catalyze the Biginelli reaction, but the
mechanism of the Lewis acid catalyzed reaction is much more
accepted as following traditional and expected reaction
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Figure 5. Key intermediates and products detected (and characterized) by ESI(+)-MS(/MS): (A) ESI(+)-MS of [I + H]+; (B) ESI(+)-MS/MS of
[III + H]+; (C) ESI(+)-MS of [V + H]+; (D) ESI(+)-MS of [VI + H]+; (E) ESI(+)-MS/MS of the key Biginelli reaction intermediate [A + H]+, i.e.,
the so-called iminium intermediate; (F) ESI(+)-MS/MS of the Biginelli adduct [DHPM + H]+.
pathways than properly asserted with scientific accuracy.
Indeed, this kind of catalytic transformation seems more an
assumption that has dominated the Biginelli MCR trans-
formation. Using ESI(+)-MS(/MS); however, we were able to
detect and characterize some key intermediates and products,
as shown in Figure 5.
The online monitoring of the Biginelli reaction allowed us to
detect and characterize exclusively the so-called iminium
intermediate (intermediate A, Scheme 2) indicating that,
under the development conditions, the preferred mechanistic
pathway is the iminium mechanism. The unsuccessful detection
of any intermediate of a direct addition of urea to the ethyl
acetoacetate corroborates this proposition. No key intermediate
of the enamine mechanism could be detected as well.
The proposed mechanism has a direct impact on many other
previously published propositions of the Lewis acid catalyzed
Biginelli reaction. The “text book” proposition mechanism for
the Biginelli reaction, which starts with a direct coordination
between the aldehyde and the metal center (used Lewis acid),
despite being essentially correct, is not completely appropriate,
since the Lewis acid is most likely acting as a precatalyst and
not as the actual catalytic species, which in turn may be formed
in situ with the components of the reaction itself. For many
cases, this proposition allows a better understanding on the
need of excess of some reagents and of high temperatures to
facilitate the formation of those species.
To better understand the ionic liquid effect, NMR experi-
ments (13C and APT NMR) were performed. 13C−{1H} NMR
gave interesting mechanistic insights, and the ionic liquid effect
could be partially evaluated as well. All experiments were
performed at 20 °C in a NMR tube containing a sealed capillary
tube charged with DMSO-d6 (external reference to set the scale
at 39.5 ppm) and using pure reagents (BMI·PF6, benzaldehyde,
ethyl acetoacetate, urea, and CuCl2) or mixtures of them. CuCl2
was soluble in pure benzaldehyde or pure ethyl acetoacetate or
in mixtures of any proportion. All mixture proportions used and
the related signals can be found in the Supporting Information.
First, we investigated the deshielding effect of the aldehyde
CO in the presence of CuCl2 and also considered the
resulting effect from the presence of the IL in the mixture
(aldehyde + CuCl2 + BMI·PF6). The results from these
experiments can be visualized in Figure 6.
One can observe a signal related to the CO group of
benzaldehyde at 191.6 ppm. Upon CuCl2 addition, almost no
shift is noted (0.1 ppm only). The addition of BMI·PF6,
however, does affect the chemical shift of the CO group. In
the presence of the IL, the CO group is deshielded to 192.8
ppm. It is worth noting that the temperature of the experiment
is only 20 °C and that the reaction requires higher temperatures
to achieve excellent yields. In the presence of all components
(benzaldehyde, ethyl acetoacetate, urea, CuCl2, and BMI·PF6),
the aldehyde signal is also observed at ∼192.8 ppm. This
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Figure 8 clearly depicts the IL effect over the formation of
species VI. After 4 h of reaction, the presence of VI was noted
(∼166.6 ppm) and also the coordination of the aldehyde
(∼167.9 ppm). It is also important to highlight that the ionic
liquid effect over the ethyl acetoacetate is not as pronounced as
was noticed for the benzaldehyde, and almost no changes in
chemical shifts could be noted (see Figure 8A,C), once more
indicating the preference of urea addition to the aldehyde
(forming the intermediate A, Scheme 2) instead of any addition
to the 1,3-dicarbonyl compound.
Theoretical calculations were also performed and discussed
to contribute to the understanding of the ionic liquid effect and
the activation of the catalytic species shown in the proposed
catalytic cycle (Scheme 2). All structures had their geometries
fully optimized by density functional theory (DFT) calcu-
lations.
In a first moment, we envisage the possibility of stabilizing
the complexation of the aldehyde to the metal center
considering the so-called ‘text-book’ mechanism, as shown in
Figure 9.
The calculated length for the CO bond of benzaldehyde is
1.2091 Å. In the presence of CuCl2 this length slightly increases
to 1.2384 Å. The O---Cu length is 1.9538 Å and H---Cl length
2.6523 Å. In the presence of the anion (hexafluorophosphate),
both the O---Cu and H---Cl lengths are shorter (1.9275 and
2.6326 Å, respectively). In the meantime, the anion also favors
lengthening of the CO bond to 1.2426 Å. The Cl−Cu−Cl
bond angle is 148.81° in the absence and 116.19° in the
presence of [PF6]−; thus, a square planar complex geometry is
much more likely. These results demonstrate the pronounced
effect of the presence of IL on the system. The calculated
benzaldehyde heat of formation (ΔH) is −9.21 kcal/mol (ΔG
= +5.02 kcal/mol). The calculated binding energy for the
aldehyde and the Lewis acid is −17.33 kcal/mol with ΔH =
−16.91 kcal/mol (ΔG = −10.61 kcal/mol). In the presence of
the anion, this binding energy becomes −29.87 kcal/mol with
ΔH = −28.66 kcal/mol (ΔG = −14.45 kcal/mol), thus showing
how spontaneous and stabilizing is the effect of the IL.
Furthermore, these results help to understand the deshielded
effect in the aldehyde observed by the NMR experiments, and
in this case, experimental and theoretical approaches are in full
accordance.
Figure 6. 13C−{1H} NMR expansion: (A) pure benzaldehyde; (B)
mixture of benzaldehyde and CuCl2; (C) mixture of benzaldehyde,
CuCl2 and BMI·PF6. A sealed capillary tube charged with DMSO-d6
was used as the external reference to set the scale (39.5 ppm).
Despite the interesting results, we decided to investigate the
same effect but considering the proposed catalytic cycle (see
Scheme 2 and Figure 10) once these previous calculations
could be used to corroborate the expected effect considering
the actual mechanism for the transformation and explain the
aldehyde activation by the presence of the IL.
subject was also further evaluated and discussed in the
theoretical calculations.
The in situ formation of the copper complex I (Scheme 2)
was also investigated by 13C NMR experiments upon mixing of
all components in the NMR tube. The results are shown in
Figure 7.
We monitored the changes in chemical shift of the
benzaldehyde hydrogens and clearly noted the appearance of
novel species formed in situ, indicating the formation of the
iminium intermediate and also suggesting the formation of II
and III. The APT was recorded at 20 °C and after 4 h following
the mixture. APT was used to follow the aromatic C−H from
the aldehyde (or from its formed derivatives).
The effect of the IL over ethyl acetoacetate and the
formation of species VI (Scheme 2) were equally followed by
13C NMR (Figure 8).
The theoretical investigation was based on the key
intermediates I and II and the association of II with [PF6]−.
Intermediate I had its geometry optimized toward a better
visualization of the benzaldehyde coordination effect to form II,
which in turn is a key complex to form A (see Scheme 2).
Considering the optimized geometry of II, the calculated ΔH is
−2.72 kcal/mol (ΔG = +7.26 kcal/mol) and the binding energy
is −3.47 kcal/mol. In the presence of [PF6]−, however, the
effect of the IL was clearly observed. Upon [PF6]− association,
these values greatly changed, and ΔH was −16.96 kcal/mol
(ΔG = +2.06 kcal/mol) and the binding energy was −18.54
kcal/mol. The results show the positive effect of the IL in the
formation of the cycle’s key intermediates, allowing a better
understanding on the origin of the ionic liquid effect over the
Biginelli reaction.
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Figure 7. (A) 13C−{1H} NMR expansion of the C−H aromatic region of pure benzaldehyde. (B) 13C−{1H} NMR (APT) expansion of the C−H
aromatic region of a mixture of benzaldehyde, ethyl acetoacetate, urea, BMI·PF6, and CuCl2. A sealed capillary tube charged with DMSO-d6 was used
as the external reference to set the scale (39.5 ppm).
Finally, the temperature effect (increase from 25 to 80 °C)
was considered in the theoretical calculations, once all these
previously discussed results were performed at room temper-
ature (25 °C i.e. 298.15 K). Since the importance of the
temperature to perform the Biginelli reaction under the
developed conditions has been experimentally demonstrated
(see Figure 3), we decided to calculate the same data for
intermediate II and for II + [PF6]− at the best reaction
temperature (80 °C, i.e., 353.15 K). At this temperature (80
°C), ΔH values of −2.51 kcal/mol (ΔG = +8.97 kcal/mol) and
−16.53 kcal/mol (ΔG = +5.35 kcal/mol) were obtained in the
absence and presence of the anion, respectively. These results
clearly demonstrate that the entropic effect plays an important
role in the reaction, as demonstrated experimentally (see Figure
3), and they also showed interesting features on the positive
ionic liquid effect over the reaction. Even at a higher
temperature (80 °C), the ΔG value in the presence of the
anion is lower than that observed at room temperature (25 °C)
in its absence. This is in accordance with the expected effect of
the IL by stabilizing polar and charged intermediates through
ion-pairing and formation of supramolecular aggregates in a
well ordered network.52
with copper and to stabilize the metal center. Thus, for
many cases, excess of the reagents is required.
iii. The IL is capable of facilitating the formation of the key
catalytic intermediates (Scheme 2) and of stabilizing
them through ion-pairing (and aggregate) formation, as
indicated by theoretical calculations and NMR.
iv. The aldehyde activation is more efficient in the presence
of the IL, as demonstrated by NMR, which is in full
accordance with a previous report53 and as we have
recently observed for aminolysis reactions.44
Results presented herein, indeed, open up a new avenue
toward the understanding of the Biginelli reaction mechanism
and also allow a more rational design of new catalysts capable
of promoting DHPMs syntheses under more sustainable
conditions.
EXPERIMENTAL SECTION
■
General Methods. ESI-MS and ESI-MS/MS measurements were
performed in the positive-ion mode (m/z 50−2000 range) on an
HDMS instrument. This instrument has a hybrid quadrupole/ion
mobility/orthogonal acceleration time-of-flight (oa-TOF) geometry
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 80 °C. ESI source
conditions were as follows: capillary voltage 3.0 kV, sample cone 20 V,
extraction cone 3 V. The theoretical treatment of the systems included
in this work was performed using the density functional theory (DFT)
approach of the Gaussian 09 series of programs. The geometry
optimizations were carried out using the B3LYP/6-311G(d,p) level of
calculation. At the same level of theory, the fundamental vibrational
frequency calculations (using a scale factor of 0.967) were carried out
to ensure the true minima and were also used to compute zero-point
vibrational energy (ZPVE) and to derive the thermochemical
corrections for the heat of formation, Gibbs free energy, and the
In summary, we have developed an efficient and simple
protocol for DHPM synthesis in ILs. The novel proposed
catalytic cycle for the Biginelli reaction and the ionic liquid
effect were investigated by ESI-MS and -MS/MS, NMR, and
theoretical calculations indicating the following:
i. The actual catalytic cycle is, indeed, more complex than
the usually presented “text book” mechanism.
ii. The reagents used for the Biginelli reaction themselves
are also responsible to form the active catalytic species
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Figure 9. Optimized geometries of benzaldehyde and reactive
intermediates considering the “text book” mechanism from the
Biginelli reaction at the B3LYP/6-311G(d,p) level of theory.
Figure 10. Optimized geometries of intermediates I (A), II (B), and II
considering the association with the anion [PF6]− (C) at the B3LYP/
6-311G(d,p) level of theory.
Figure 8. (A) 13C−{1H} NMR expansion of pure ethyl acetoacetate.
(B) 13C−{1H} NMR expansion after CuCl2 addition. (C) 13C−{1H}
NMR expansion of a mixture of ethyl acetoacetate and CuCl2 after
addition of BMI·PF6. (D) 13C−{1H} NMR expansion of a mixture of
ethyl acetoacetate, CuCl2, benzaldehyde, and BMI·PF6 after 4 h. A
sealed capillary tube charged with DMSO-d6 was used as the external
reference to set the scale (39.5 ppm).
weighing factor corresponding to line broadening to 1.0 Hz was
applied.
General Procedure for the Biginelli Reactions. A sealed
Schlenk tube containing 1 mL of BMI.PF6, 3.00 mmol of the aldehyde,
3.00 mmol of the 1,3-dicarbonyl compound, 3.00 of urea (or thiourea),
and CuCl2 (10 mol %) was allowed to react at 80 °C. After the time
indicated in Table 2, the substrates were purified by chromatographic
column eluted with mixtures of hexane/ethyl acetate.
binding energy. Zero-point energies and thermodynamic functions
were calculated at 298.15 and 353.15 K and 1 atm. The optimized
geometries were used for the single-point calculation at B98/6-
311+G(3df,2p) level of calculation. To avoid a basis-set superposition
error (BSSE) the heat of formation, Gibbs free energy and the binding
energy were counter-poise corrected using a standard approach by
Boys and Bernardi.54 NMR spectra were recorded on a 7.05 T
instrument using a 5-mm internal diameter probe operating at 300
MHz for 1H and at 75 MHz for 13C. Chemical shifts were expressed in
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. Investigative experiments were performed at 20 °C in a
NMR tube containing a sealed capillary tube charged with DMSO-d6
(external reference to set the scale at 39.5 ppm) and using pure
reagents (BMI.PF6, benzaldehyde, ethyl acetoacetate, urea, and CuCl2)
or homogeneous mixtures of them. Typically, 13C−{1H} NMR data
were collected with 256 free induction decays (FIDs) and 64 K data
points using a 15 μs pulse width (90° pulse angle). Prior to Fourier
transformation (FT), the FIDs were zero-filled and an exponential
Ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-
1
carboxylate (4a): H NMR (DMSO-d6, 300 MHz) δ ppm 9.22 (s,
1H), 7.76 (s, 1H), 7.29−7.18 (m, 5H), 5.14 (s,1H), 3.97 (q, 2H, J =
6.8 Hz), 2.24 (s, 3H), 1.07 (t, 3H, J = 6.8 Hz); 13C NMR (DMSO-d6,
75 MHz) δ ppm 165.8, 152.6, 148.8, 145.3, 128.8, 127.7, 126.7, 99.7,
59.6, 54.4, 18.2, 14.5; FT- IR (KBr, cm−1) 3252, 3109, 2972, 1728,
1689, 1645, 1468, 1230, 1097, 778; mp 212−213 °C (lit.55 213−214
°C); 95% (2.85 mmol, 742 mg).
Ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyr-
1
imidine-5-carboxylate (4b): H NMR (DMSO-d6, 300 MHz) δ ppm
10.14 (s, 1H), 9.93 (s, 1H), 8.46(s, 1H), 7.65 (t, 1H, J = 7.9 Hz),
7.44−7.36 (m, 3H), 5.82 (d,1H, J = 2.7 Hz), 4.76 (q, 2H, J = 7.2 Hz),
2.99 (s, 3H), 1.87 (t, 3H, J = 7.1 Hz); 13C NMR (DMSO-d6, 75 MHz)
δ ppm 165.9, 157.8, 152.7, 148.6, 146.7, 129.8, 128.8, 117.3, 114.6,
99.8, 59.6, 54.3, 18.2, 14.6; FT-IR (KBr, cm−1) 3514, 3364, 3250,
3104, 2978, 1722, 1638, 1600, 1475, 1305, 1221, 1056, 771; mp 168−
170 °C (lit.56 mp 165−168 °C); 84% (2.52 mmol, 696 mg).
10191
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Article
5-Acetyl-3,4-dihydro-4-(3-hydroxyphenyl)-6-methylpyrimidin-
7.32−7.22 (m, 5H), 5.25 (s, 1H), 3.43 (q, J = 6.2 Hz), 1.06 (s, 3H);
13C NMR (DMSO-d6, 75 MHz) δ ppm 194.7, 152.6, 148.6, 144.6,
128.9, 128.8, 110.0, 56.5, 30.7, 19.3; FT-IR (KBr, cm−1) 3287, 3241,
2914, 1706, 603, 1466, 1248, 764; mp 238−240 °C (lit.61 mp 238−
240 °C); 98% (2.94 mmol, 677 mg).
1
2(1H)-one (4c): H NMR (DMSO-d6, 300 MHz) δ ppm 10.18 (s,
1H), 9.94 (s, 1H), 8.56 (s, 1H), 7.88 (t, 1H, J = 7.1 Hz), 7.42 (t, 1H, J
= 10.5 Hz), 5.94 (s,1H), 3.04 (s, 3H), 2.85 (s, 3H); 13C NMR
(DMSO-d6, 75 MHz) δ ppm 194.9, 157.9, 152.6, 148.4, 146.1, 130.0,
117.5, 114.8, 113.7, 110.0, 54.3, 30.7, 19.4.); FT-IR (KBr, cm−1) 3248,
3107, 2942, 1707, 1657, 1606, 1462, 1235, 742; mp 214−215 °C; 84%
(2.52 mmol, 621 mg).
5-Acetyl-4-(4-chlorophenyl)-3,4-dihydro-6-methyl-2(1H)-pyrimi-
1
dinone (4m): H NMR (DMSO-d6, 300 MHz) δ ppm 10.02 (s, 1H),
8.65 (s, 1H), 8.14 (d, 2H, J = 7.8 Hz), 8.03 (d, 2H, J = 8.1 Hz), 6.02
(s,1H), 4.02 (s, 2H), 1.81 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ
ppm 194.64, 152.58, 148.98, 129.1, 129.3, 128.9, 110.0, 53.5, 30.9,
19.5; FT-IR (KBr, cm−1) 3290, 3118,2998, 1696, 1613, 1493, 1430,
1225, 837, 563; mp 214−215 °C (lit.62 mp 216 °C); 97% (2.91 mmol,
770 mg).
Ethyl 6-methyl-4-(3-hydroxyphenyl)-2-thioxo-1,2,3,4-tetrahydro-
1
pyrimidine-5-carboxylate (4d): H NMR (DMSO-d6, 300 MHz) δ
ppm 10.28 (s, 1H), 9.59 (s, 1H), 9.44 (s, 1H), 7.09 (t, 1H, J = 7.9 Hz),
6.65 (m, 3H), 5.09 (d, 1H, J = 2.7 Hz), 3.98 (q, 2H, J = 6.7 Hz), 2.27
(s, 3H), 1.08 (t, 3H, J = 6.9 Hz); 13C NMR (DMSO-d6, 75 MHz) δ
ppm 174.6, 165.6, 157.9, 145.3, 145.2, 129.9, 117.5, 115.0, 113.7,
101.2, 60.5, 54.4, 17.6, 14.4; FT-IR (KBr, cm−1) 3304, 3179, 3109,
2982, 1662, 1573, 1479, 1375, 1293, 1196, 1117, 747; mp 180−181 °C
(lite.57 mp 180−183 °C); 80% (2.40 mmol, 702 mg).
1-[4-(4-Chlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyri-
1
midin-5-yl]ethanone (4n): H NMR (DMSO-d6, 300 MHz) δ ppm
11.11 (s, 1H), 10.75 (s, 1H), 8.55 (d, 2H, J = 8.4 Hz), 8.08 (d, 2H),
6.05 (d,1H, J = 3.6 Hz), 3.09 (s, 3H), 2.93 (s, 3H); 13C NMR
(DMSO-d6, 75 MHz) δ ppm 195.1, 174.7, 145.5, 142.3, 132.8, 131.7,
129.8, 110.8, 53.1, 31.0, 18.8; FT-IR (KBr, cm−1) 3292, 3170, 2978,
1707, 1609, 1572, 1450, 1357, 1199, 1014, 826; mp 212−213 °C (lit.56
mp 214−216 °C); 68% (2.04 mmol, 573 mg).
1-[1,2,3,4-Tetrahydro-4-(3-hydroxyphenyl)-6-methyl-2-thioxo-5-
1
pyrimidinyl]ethanone (4e): H NMR (DMSO-d6, 300 MHz) δ ppm
10.24 (s, 1H), 9.70 (s, 1H), 9.47 (s, 1H), 7.10 (t, 1H, J = 6.9 Hz), 6.64
(d, 2H, J = 8.1 Hz), 5.19 (s, 1H), 3.44 (s, 1 H), 2.29 (s, 3H), 2.12 (s,
3H); 13C NMR (DMSO-d6, 75 MHz) δ ppm 195.3, 174.3, 157.9,
144.8, 130.1, 117.6, 115.1, 113.8, 110.8, 54.2, 30.8, 18.7; FT-IR (KBr,
cm−1) 3514, 3272, 3184, 2993, 1621, 1582, 1486, 1372, 1193, 742,
571; mp 223−225 °C; 82% (2.46 mmol, 645 mg).
Ethyl-6-methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (4f): 1H NMR (DMSO-d6, 300 MHz) δ ppm 9.39
(s, 1H), 8.16 −7.68 (m, 4H), 3.89 (q, 2H, J = 2.7 Hz), 2.28 (s, 3H),
1.10 (t, 3H, J = 6.9 Hz); 13C NMR (DMSO-d6, 75 MHz) δ ppm 165.1,
151.8, 149.5, 147.7, 147.0, 133.0, 130.3, 122.4, 121.0, 98.3, 59.4, 53.6,
17.9, 14.0; FT-IR (KBr, cm−1) 3330, 3213, 3105, 2965, 1709, 1631,
1520, 1456, 1343, 1221, 1084, 810, 686, 530; mp 240−242 °C (lit.58
mp 239−241 °C); 84% (2.52 mmol, 769 mg).
Ethyl 4-(4-chlorophenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-
1
pyrimidine-5-carboxylate (4o): H NMR (DMSO-d6, 300 MHz) δ
ppm 9.24 (s, 1H), 7.77 (s, 1H), 7.34 (d, 2H, J = 7.2 Hz), 7.23 (d, 2H, J
= 7.5 Hz), 5.14 (s,1H), 3.94 (q, 2H, J = 6.7 Hz), 2.24 (s, 3H), 1.07 (t,
3H, J = 7.1 Hz); 13C NMR (DMSO-d6, 75 MHz) δ ppm 165.9, 152.73,
149.3, 144.4, 132.4, 129.1, 128.8, 99.6, 59.9, 54.1, 19.5, 14.6; FT-IR
(KBr, cm−1) 3331, 3167, 3105, 2978, 1668, 1570, 1197, 747; mp 168−
169 °C; 66% (1.98 mmol, 584 mg).
4-(3-Hydroxyphenyl)-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-
dione (4p): 1H NMR (DMSO-d6, 300 MHz) δ ppm 9.88 (s, 1H), 9.54
(s, 1H), 9.23 (s, 1H), 7.09−6.86 (m, 1H), 6.66−6.39 (m, 3H), 4.87 (d,
J = 3.6 Hz), 2.65−2.54 (m, 2H), 2.29- 2.16 (m, 2H), 1.66−1.57 (m,
2H); 13C NMR (DMSO-d6, 75 MHz) δ ppm 210.6, 205.1, 157.8,
155.9, 138.2, 129.9, 118.4, 115.9, 114.7, 86.9, 82.2, 56.5, 18.9, 14.4;
FT-IR (KBr, cm−1) 3464, 3349, 3170, 2949, 1678, 1663, 1621, 1592,
1514, 1460, 1170, 765, 632; mp 198−199 °C; 77% (2.31 mmol, 634
mg).
5-Acetyl-3,4-dihydro-6-methyl-4-(3-nitrophenyl)pyrimidin-2(1H)-
one (4g): 1H NMR (DMSO-d6, 300 MHz) δ ppm 9.37 (s, 1H), 8.14−
7.6 (m, 4H), 5.4 (d, 1H, J = 3 Hz), 2.33 (s, 3H), 2.19 (s, 3H); 13C
NMR (DMSO-d6, 75 MHz) δ ppm 194.1, 152.0, 149.2, 147.9, 146.5,
133.0, 130.2, 122.4, 121.1, 109.5, 53.0, 30.7, 19.1; FT-IR (KBr, cm−1)
3357, 3271, 3057, 1721, 1683, 1591, 1532, 1347, 1239, 764, 693, 578;
mp 261−262 °C; 94% (2.82 mmol, 776 mg).
ASSOCIATED CONTENT
* Supporting Information
■
[1,2,3,4-Tetrahydro-6-methyl-4-(3-nitrophenyl)-2-thioxo-5-
S
1
pyrimidinyl]ethanone (4h): H NMR (DMSO-d6, 300 MHz) δ ppm
NMR spectra related with this manuscript and Cartesian
coordinates and energy and thermal corrections for all of the
calculated structures. These materials are available free of
charge via the Internet at http://pubs.acs.org.
10.48 (s, 1H), 9.09 (s, 1H), 8.17−7.65 (m. 4H), 5.44 (d, 1H, J = 3.9
Hz), 2.38 (s, 3H), 2.25 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ
ppm 199.9, 179.7, 153.1, 150.3, 150.1, 138.2, 135.6, 127.9, 115.4, 58.1,
35.9, 23.6; FT-IR (KBr, cm−1) 3300, 3182, 3063, 1676, 1610, 1528,
1343, 1183, 1076, 764; mp 168−170 °C; 87% (2.61 mmol, 760 mg).
1,2,3,4-Tetrahydro-6-methyl-2-oxo-5-pyrimidinecarboxylic acid
AUTHOR INFORMATION
Corresponding Author
*Tel: (+) 55 61 31073867. Fax: (+) 55 61 32734149. E-mail:
brenno.ipi@gmail.com.
1
■
ethyl ester (4i): H NMR (DMSO-d6, 300 MHz) δ ppm 4.58 (q,
2H, J = 3.7 Hz), 3.43 (d, 2H), 1.07 (t, 3H, J = 7.0 Hz); FT-IR (KBr,
cm−1): 3356, 2928, 1621, 1571, 1242, 664; mp 258−259 °C (lit.59 mp
256−258 °C); 70% (2.10 mmol, 387 mg). This compound showed to
be unstable and degradation is noted. The mp was measured just after
purification in a sealed capillary tube.
1,2,3,6-Tetrahydro-4-methyl-2-thioxo-5-pyrimidinecarboxylic
acid, ethyl ester (4j): 1H NMR (DMSO-d6, 300 MHz) δ ppm 4.56 (m,
2H), 4.68 (m, 2H), 2.19 (s, 3H), 1.20 (t, 3H, J = 3.6 Hz); FT-IR (KBr,
cm−1) 3257, 2985, 2913, 1700, 1534, 1229, 1098, 920, 620; mp 212−
213 °C; 64% (1.92 mmol, 385 mg). This compound showed to be
unstable and degradation is noted. The mp was measured just after
purification in a sealed capillary tube.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been supported by CAPES, CNPq, FINEP-
MCT, FINATEC, FAPESP, FAPDF, and DPP-UnB. B.A.D.N.
also thanks INCT-Catalysis and LNLS for the use of their
facilities.
Ethyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-
1
5-carboxylate (4k): H NMR (DMSO-d6, 300 MHz) δ ppm 11.15
REFERENCES
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129.0, 128.8, 100.7, 60.1, 53.9, 17.7, 14.6; FT-IR (KBr, cm−1) 3322,
34663176, 3111, 1670, 1575, 1470, 1277, 1197, 1105, 696; mp 201−
202 °C (lit.60 mp 201 °C); 60% (1.80 mmol, 497 mg).
■
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