New multicomponent reaction for the direct synthesis of β-aryl-γ-nitroesters promoted by hydrotalcite-derived mixed oxides as heterogeneous catalyst

Article abstract of DOI:10.5935/0103-5053.20160175

A new approach based on multicomponent/domino combined reactions for the synthesis of γ-nitroesters promoted by a mixed aluminium-magnesium oxides derived from hydrotalcite-like material was developed. Different γ-nitroesters were synthesized in 15-95percent yield using Meldrum's acid, aromatic aldehydes, nitromethane and different alcohols as reagents and solvents. The γ-aminobutyric acid derivatives, Phenibut and Baclofen, were prepared in 63 and 61percent overall yield, respectively, through a two steps synthetic strategy. A mechanistic pathway was proposed based on the gas chromatography mass spectrometry (GC-MS) and electrospray ionization mass spectrometry (ESI-MS) experiments.

Full text of DOI:10.5935/0103-5053.20160175

http://dx.doi.org/10.5935/0103-5053.20160175
J. Braz. Chem. Soc., Vol. 28, No. 2, 285-298, 2017.
Printed in Brazil - ©2017 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Article
New Multicomponent Reaction for the Direct Synthesis of β-Aryl-γ-nitroesters
Promoted by Hydrotalcite-Derived Mixed Oxides as Heterogeneous Catalyst
Caroline R. M. D’Oca,a Fabricio F. Naciuk,a Jéssica C. Silva,a Esthéfani P. Guedes,a
Celso C. Moro,b Marcelo G. M. D’Oca,c Leonardo S. Santos,d Fabiane M. Natchigalle
and Dennis Russowsky*,a
aLaboratório de Sínteses Orgânicas and bLaboratório de Sólidos e Superfícies, Instituto de Química,
Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9500, 91501-970 Porto Alegre-RS, Brazil
cLaboratório Kolbe de Síntese Orgânica, Escola de Química e Alimentos, Universidade Federal do
Rio Grande, Av. Italia, km 08, Rio Grande-RS, Brazil
dLaboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources Universidad de
Talca, 2 Norte 685, Talca, Chile
eNanobiotechnology Division at University of Talca, Fraunhofer Chile Research Foundation,
Center for Systems Biotechnology, PO Box 747, Talca, Chile
A new approach based on multicomponent/domino combined reactions for the synthesis of
γ-nitroesters promoted by a mixed aluminium-magnesium oxides derived from hydrotalcite-like
material was developed. Different γ-nitroesters were synthesized in 15-95% yield using Meldrum’s
acid, aromatic aldehydes, nitromethane and different alcohols as reagents and solvents. The
γ-aminobutyric acid derivatives, Phenibut and Baclofen, were prepared in 63 and 61% overall
yield, respectively, through a two steps synthetic strategy. A mechanistic pathway was proposed
based on the gas chromatography mass spectrometry (GC-MS) and electrospray ionization mass
spectrometry (ESI-MS) experiments.
Keywords: GABA, baclofen, mixed Al-Mg oxides, hydrotalcite, multicomponent, domino
Introduction
molecules from available starting materials via a single
pathway.4 MCRs have unique advantages, such as a high
bond-forming efficiency, simple and short procedures,
a high level of atomic economy and low impact on the
environment.5-7
The structural simplicity of Meldrum’s acid (1),
combined with its unique properties, has made this a
versatile reagent in organic syntheses, especially those
based on the multicomponent process.8-10 In addition, the
design and development of environment-friendly catalysts
have been the subject of intense research.11
The hydrotalcite like compounds (HT), also known as
layered double hydroxides (LDH), are anionic clay materials
that have been extensively investigated as heterogeneous
base catalysts.12-15 The HT-like compounds exhibit dual
basic/acid properties16,17 and can be useful as bifunctional
catalysts in different organic transformations.18,19
As a part of our ongoing efforts in the field of MCR,20-24
herein we disclose our studies on the development of a
Gamma aminobutyric acid (GABA) and L-glutamic
acid are the two major neurotransmitters that regulate
neuronal activity in the brain. While L-glutamic acid is a
neurotransmitter that induces an excitatory effect, GABA
acts as the major inhibitory neurotransmitter.1
The widespread presence of GABA and L-glutamic acid
in the brain is related to various functions of the central
nervous system (CNS), including novice chemical abuse
disorders, making them two of the most promising targets
for the development of neuropsychiatric drugs.2 Due to
their fundamental role in neurotransmission, these systems
are involved in a range of commercially available drugs,
such as Phenibut, Baclofen, Gabapentin, and Pregabalin.3
Multicomponent reactions (MCRs) have been used as a
versatile synthetic method for the preparation of complex
*e-mail: dennis@iq.ufrgs.br

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New Multicomponent Reaction for the Direct Synthesis of b-Aryl-g-nitroesters
J. Braz. Chem. Soc.
Scheme 1. Multicomponent synthesis of γ-nitroesters 5a-u.
new multicomponent/domino combined approach for the
direct synthesis of γ-nitroesters (5) from the reaction of
Meldrum’s acid (1), aromatic aldehydes 2, nitromethane
(3) and an alcohol 4 as the solvent, promoted by calcined
hydrotalcite-like compounds.
Our interest synthesizing γ-nitroesters is due to the
fact that these intermediates are considered advanced
intermediates in the synthesis of GABA analogues.25-27
Thus, the development of multicomponent methodologies
permitting the rapid access to this class of compounds is of
great interest. To our best knowledge, this tetracomponent
synthesis of γ-nitroesters was not reported in the literature.
To gain insights about the mechanistic details of
this new multicomponent process, we have used the
mass spectrometric techniques which are recognized as
a powerful method to reveal details of several reaction
processes.28-33
Encouraged by the fact that HT is able to promote the
Henry reactions,27 we hypothesized that HT[Calc.] could
promote the in situ preparation of nitrostyrenes through a
Knoevenagel-type reaction from aldehydes and nitromethane.
Once the nitrostyrene is present in the reaction media, the
1,4-addition of Meldrum’s acid takes place, performing a
one-pot multicomponent synthesis of γ-nitroesters.
According to this assumption, our approach was based
on a new MCR/domino combined reaction of Meldrum’s
acid (1), aromatic aldehydes 2, nitromethane (3) and an
alcohol 4 as the solvent. In this process, the calcined
hydrotalcite (HT[Calc.]), used as catalyst, proved to be
essential to afford the γ-nitroesters 5 (Scheme 1).
To our satisfaction, the reactions carried out in EtOH
afforded the γ-nitroesters 5a-j in reasonable to good yields.
The results are shown in Table 1.
Table 1. Multicomponent synthesis of β-aryl-γ-nitroesters 5a-l
Electrospray ionization mass spectrometry (ESI-MS)
has become the central technique, as it often allows real-time
detection and ESI-tandem mass spectrometric (MS/MS)
characterization of reactants, intermediates and final
products. Major reaction processes have been investigated
via ESI-MS techniques, and even transient reaction
intermediates and catalyst complexes have been intercepted
and characterized.34-38 The present work also aims to
apply on-line ESI-MS/MS to monitor the developed
multicomponent reactions.
entry
1
R1
R2
Nitroester
5a
Yield / %
88
C6H5
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
2
4-Cl–C6H4
4-Br–C6H4
4-F–C6H4
5b
5c
83
3
88
4
5d
5e
90
5
4-CN–C6H4
4-MeO–C6H4
3,4-(MeO)2–C6H3
80
6
5f
70
7
5g
75
8
3,4,5-(MeO)3–C6H2 EtOH
5h
5i
95
Results and Discussion
9
2-thienyl
3-thienyl
nBu
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
85
10
11
12
13
14
15
5j
83
The multicomponent/domino combined approach
5k
5l
15
iPr
17
Previous studies from our laboratory demonstrated the
ability of HT to promote the direct Michael addition of
1,3-dicarbonyl compounds to nitrostyrenes, resulting in the
formation of β-aryl-γ-nitrocarbonyl compounds. We also
observed that HT combined with Meldrum’s acid resulted
in the formation of γ-nitroesters directly.25
C6H5
5a
88a
85b
70c
C6H5
5a
C6H5
5a
a1st recycle; b2nd recycle; c3rd recycle.
The activity of HT was attributed to the increase in
the basicity of this material by the formation of mixed
The results show the multicomponent process occurred
in a single step promoted by HT[Calc.] and was effective for
both electron-withdrawing or electron-donating groups
attached to the aromatic ring (Table 1, entries 2-5 and
magnesium and aluminium oxides after thermal treatment
26
that we called HT[Calc.]
.

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Table 2. Synthesis of 5m-u in the presence of different alcohols
entries 6-8, respectively). Nitroesters with heteroaromatic
substituents were also synthesized in good yields (entries
9 and 10, respectively). However, the employment of
aliphatic aldehydes afforded the γ-nitroesters in very poor
yields. This fact was interpreted as being a consequence
of the auto-condensation of aldehydes under basic media
(entries 11 and 12, respectively). Experiments investigating
the recycling of the HT[Calc.] catalyst were performed by
the isolation and re-calcination of HT[Calc.]. The 1st reuse
resulted in a slightly diminished yield. The 2nd and 3rd reuses
confirmed the gradual decrease in the activity (entries 13,
14 and 15, respectively).
entry
R1
C6H5
R2
Nitroesters
Yield / %
1
2
3
4
5
6
7
8
9
MeOH
MeOH
iPrOH
iPrOH
nBuOH
tBuOH
BnOH
allyl
5m
5n
5o
5p
5q
5r
5s
84
72
4-MeO–C6H4
C6H5
75
4-MeO–C6H4
4-MeO–C6H4
C6H5
64
55
58
C6H5
60b
75b
65b
C6H5
5t
C6H5
propargyl
5u
The behavior of the multicomponent reaction in the
presence of ethyl malonate instead of Meldrun’s acid was
also investigated. In this case, the main product was identified
as a γ-nitro-dicarbonylic compound formed in only a 30%
yield. This result indicates the combination of Meldrum’s
acid and HT is essential to the preparation of γ-nitroesters in
one step. As only ethyl esters were produced, we speculate
that this was due to the use of ethanol as the solvent in
the multicomponent process. To prove this assumption,
a set of reactions were carried out in the presence of
different alcohols, with the goal of producing different
alkyl esters. The MCRs were performed in methanol (4b),
isopropanol (4c), n-butanol (4d), tert-butanol (4e), benzyl
alcohol (4f), allyl alcohol (4g) and propargyl alcohol (4h)
aSee Table 1, entry 1; bsynthesized by the opening reaction of 6a.
as shown in the Scheme 1. The results are shown in
Table 2.
In all cases, the γ-nitroesters 5m-u were formed in
reasonable to good yields. These reactions proved the direct
participation of the alcoholic solvent, which also acted
as a reagent. The influence of each type of alcohol is not
totally clear. For example, low yields of γ-nitroesters were
observed in n-BuOH or tert-BuOH (Table 2, entries 5 and 6,
respectively). The chemical structures of γ-nitroesters 5a-u
prepared from different aromatic aldehydes are depicted
in the Figure 1.
Figure 1. Structurally diverse γ-nitroesters prepared via the new tetracomponent reaction.

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New Multicomponent Reaction for the Direct Synthesis of b-Aryl-g-nitroesters
J. Braz. Chem. Soc.
Scheme 2. Synthesis of Michael adduct 6a.
Table 3. Preparation of intermediate 6a
Speculating about the reaction mechanism, we presumed
that the alcoholic solvent is able to promote the opening
and transesterification of the Meldrum’s acid moiety in
the Michael adduct initially formed.25 The adduct 6a was
not isolated during the multicomponent process. Thus, we
focused our efforts on its isolation and characterization.
Assuming the nitrostyrene 7a is being formed during the
course of the multicomponent process, we performed
two sets of specific reactions using Meldrum’s acid and
nitrostyrene (Scheme 2).
entry
1
Catalyst
HT[Calc.]
HT[Calc.]
HT[Calc.]
DIPEA
DIPEA
DIPEA
DIPEA
DABCO
DABCO
DBU
Solvent time / h Temperature / °C Yielda / %
CH2Cl2
CH3CN
THF
24
24
24
8
25
25
80
61
95
45
67
95
95
95
95
50
95
2
3
60
4
CH3CN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
25
5
8
25
6
24
8
25
7
reflux
60
8
5
The first set was performed in presence of HT[Calc.] in non-
alcoholic solvents because γ-nitroesters 5a were produced
in the presence of EtOH. In the second set, an amine base-
catalyzed conjugated addition was used in ethanol as the
solvent. Under both of these new conditions, we were able
to isolate the intermediate 6a in good yields. Unfortunately,
attempts to purify 6a by column chromatography were
unsuccessful due to the degradation of the product on silica.
Thus, the yields of these reactions were inferred by 1H
nuclear magnetic resonance (NMR) spectra from the crude
mixture after carefully removing the HT[Calc.] from the crude
mixture of organics. The results are shown in the Table 3.
As seen in Table 3, the HT[Calc.] was able to promote the
Michael addition of Meldrum’s acid to the nitrostyrene
in different non-protic solvents such as CH2Cl2, CH3CN,
and tetrahydrofuran (THF) to afford compound 6a in
good yields (entries 1, 2, and 3, respectively). The use of
tertiary amines as basic catalysts also furnished 6 in both
non-protic (entry 4) and protic solvents (entries 5-10).
It is important to note that even with EtOH under reflux
conditions (entries 7 and 9, respectively) no degradation
of 6a was observed, revealing that the transformation
from 6a to 5a does not occur through the use of basic
media containing simple amines. To ensure that the
transformation could be made independently, 6a was
9
3
reflux
25
10
11
24
24
Et3N
25
aYields estimated by 1H NMR analysis; THF: tetrahydrofuran;
DIPEA: N,N-diisopropylethylamine; DABCO: 1,4-diazabicyclo[2.2.2]
octane; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.
reacted with EtOH in the presence of HT[Calc.] for 24 h under
reflux conditions. After this time, the HT[Calc.] was filtered
off, and the volatiles were removed under vacuum. The
crude product was purified by column chromatography
to afford the 5a in a 90% yield, confirming the pivotal
action of HT[Calc.] in this step (Scheme 3).
We believe that the presence of metal centers of HT[Calc.]
could be act as weak Lewis acid sites coordinating with the
oxygen base Lewis site of Meldrum’s acid moiety, aiding
the starting the process to transformation of 6a into 5a.
Thus, this could evidence a dual acid/base properties of the
HT[Calc.]. This idea was supported by the ESI-MS studies
and will be discussed later.
A tentative mechanistic pathway by GC-MS studies
Once the formation of nitrostyrene 7a was suggested
during the course of the reaction, we decided to investigate
Scheme 3. Transformation of intermediate 6 into γ-nitroester 5a.

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the ability of HT in the formation of 7a by Henry reaction,
followed by a direct dehydration step. The reaction was
performed from aldehyde 2a and nitromethane (3), in the
presence of HT[Calc.] and EtOH under reflux as shown in
Scheme 4.
The reaction was carefully monitored through the
gas chromatography-mass spectrometry (GC-MS)
analysis. After 30 min, the chromatogram showed
signals corresponding to benzaldehyde (Rt = 4.29 min,
m/z 106), nitrostyrene (7a) (Rt = 10.49 min, m/z 149),
and nitroaldol 8a (Rt = 11.02 min, m/z 167) (Figure 2a).
Analysis of aliquots after 1.0 and 1.5 h of reaction
time showed a gradual increase in the formation of 7a,
confirming its formation under the conditions of the MCR
protocol.
The nitroester 5a was the main product. Because the
GC-MS analysis was useful in monitoring this step, we
decided to extend the method to follow the course of the
MCR process to identify other possible intermediates.
A new experiment was started, and the first analysis
was made 10 min after all of the components had been
mixed. At this time, the chromatogram did not reveal
the presence of 7a. Instead, a signal at Rt = 16.08 min
(m/z 232) was observed. This signal was characterized
as being the benzylidene adduct 9a, most likely formed
from the Knoevenagel-type condensation of Meldrum’s
acid (1) and benzaldehyde (Figure 2B). After 1.0 h, the
nitrostyrene (7a) at Rt = 10.50 min (m/z 149) and nitroaldol
8a at Rt = 11.20 min (m/z 167) were detected. The desired
nitroester 5a was also identified at Rt = 14.65 min (m/z 237)
as well as the benzylidene adduct 9a at Rt = 16.14 min
(m/z 232) (Figure 2C). Other aliquots were analyzed
after 3.0, 5.0, 8.0, and 11.0 h, respectively. From these
chromatograms, we observed gradual decreases in the
signals of 7a and 9a and an increase in the signal of
γ-nitroester 5a.
After 24 h, the GC-MS analysis revealed that the
γ-nitroester 5a was the principal component as well as
the almost complete consumption of all of the reagents
(Figure 2D).
As we postulated, the formation of adduct 6a occurred
via the Michael addiction of Meldrum’s acid to nitrostyrene,
and we decided to confirm that the benzylidene derivative
was also involved in the formation of γ-nitroesters. Thus,
9a was prepared independently by the condensation of
Meldrum’s acid and benzaldehyde in presence of HT[Calc.]
under refluxing EtOH. The benzylidene adduct was isolated
in a 98% yield.
Scheme 4. Formation of 7a via a Knoevenagel-type reaction.
Figure 2. (A) GC-MS after 30 min of Henry reaction in the presence of HT[Calc.]. Detection of intermediates 7a and 8a; (B) GC-MS after 10 min
of the MCR process. Detection of the benzylidene adduct 9a; (C) GC-MS after 1.0 hour of the MCR process. Detection of intermediates 7a,
8a and 9a as well as the final product the nitroester 5a; (D) GC-MS after 24 hours of the MCR process.

290
New Multicomponent Reaction for the Direct Synthesis of b-Aryl-g-nitroesters
J. Braz. Chem. Soc.
Next, nitromethane was added to benzylidene in the
(2a, 1 mmol) and nitromethane (3, 5 mmol) in conditions
showed in Table 1, for the synthesis of nitroesters. The
monitoring of the reaction was realized by the removal of
aliquots (100 µL) every 5 minutes.
The aliquots were diluted in 1.5 mL of the solvent used
in the reaction medium (MeOH) and filtered for direct
injection into the ion source of the mass spectrometer using
a syringe pump at a flow rate of 15 µL min-1.
The monitoring by ESI-MS/MS showed one major
pathway in the multicomponent process. In the first event, the
Knoevenagel condensation of benzaldehyde and Meldrum’s
acid leads to formation of benzylidene intermediate 9a
of m/z 255 ([M + Na]+) (Figure 3A). After 30 minutes of
reaction, the benzylidene acts as a Michael acceptor for the
addition of nitromethane (3), affording the Michael adduct 6a
of m/z 316 ([M + Na]+) (Figure 3B). The spectrum obtained
after 60 minutes in the presence of HT[Calc.] (50 mg) and
MeOH (3 mL) under reflux already shows the presence of the
nitroester 5a of m/z 246 ([M + Na]+) formed from a domino
transformation process of 6a into nitroester 5a (Figure 3C).
To prove the statement above, the Michael adduct 6a
was submitted to an opening reaction. At t1 = 5 min, it was
possible to identify the presence of two species of m/z 214
([M + Na]+) and m/z 258 ([M + Na]+), corresponding to
ketene derivatives 10 and 11, respectively, both as sodiated
species (Figure 4A).39
presence of HT[Calc.] in EtOH as the solvent. After 6 hours
of reflux, we obtained the respective γ-nitroester 5a in a
95% yield after purification by column chromatography
(Scheme 5).
Based on these results, we postulated a combined
multicomponent/domino reaction sequence to explain the
formation of γ-nitroesters 5a-u. However, it seems that
two different competitive MCRs can explain the formation
of the common intermediate 6a. One of them occurs via
Knoevenagel-type condensation of Meldrum’s acid and
benzaldehyde to afford the benzylidene intermediate
9a. The second one also starts with a Knoevenagel-type
condensation of nitromethane and benzaldehyde to form the
nitrostyrene 7a. The conversion of common intermediate 6a
in the γ-nitroester occurs through a one pot domino process,
with the loss of acetone and CO2 along with including an
esterification step (Scheme 6).
Investigation of the mechanistic pathway by ESI-MS/MS
studies
In this study, we describe the results of the mechanistic
investigation of the MCR synthesis of γ-nitroesters by ESI-
MS/MS. To accomplish this task, model experiments were
performed using Meldrum’s acid (1, 1 mmol), benzaldehyde
Scheme 5. Preparation of 5a from benzylidene intermediate 9a.
Scheme 6. A rational mechanism for the multicomponent synthesis of γ-nitroesters.

Vol. 28, No. 2, 2017
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After 20 minutes, the presence of a new species of
m/z 290 ([M + Na]+) was observed, which was identified
as the malonic acid methyl half-ester intermediate 12
(Figure 4B).After 1 hour, the main product observed was 5a
of m/z 246 ([M + Na]+), formed through a decarboxylation
reaction (Figure 4C).
According to the experiments carried out, we rationalized
that the reaction occurs initially by Knoevenagel
condensation to form 9a, followed by Michael addiction
of Meldrum’s acid to produce the adduct 6a. These steps
were related to the multicomponent process. The opening
of Meldrum’s acid moiety of 6a can occur by a possible two
pathways to form directly the half-ester 12 or via ketene
intermediates wards the opening of Meldrum’s moiety
occur via ketene intermediate 11. Both intermediates 11
and 12 can be transformed into the γ-nitroesters 5a through
further simple loss of CO2 and/or MeOH addition. The
opening process of Meldrum’s acid moiety of 6a and their
subsequent transformation into de γ-nitroester 5a were
related to a domino process (Scheme 7).
Baclofen (4-amino-3-(4-chlorophenyl)butanoic acid, 17)
are both lipophilic analogues of γ-aminobutyric acid
(GABA), and they exhibit different pharmacological
properties. Phenibut is mainly used as a tranquilizer or
increasingly as a mood modulator.40 Baclofen, meanwhile,
is a muscle relaxant currently used in the treatment of
neuropathic pain.41 The (−)-(R)-enantiomer is identified
as being responsible for the biological activity; however,
Baclofen is commercialized in its racemic form.
To demonstrate the potential application of the
γ-nitroesters in the synthesis of the GABA-derivatives, the
Phenibut (16) and Baclofen (17) were prepared in two steps
from the γ-nitroesters 5a and 5b, respectively. The reduction
of the nitro group in the presence of NaBH4/NiCl2·6H2O in
ethanol led directly to the isolation of the lactams 14 and
15 in yields of 82 and 87%, respectively.42
The transformation of the respective lactams into
the GABA-derivatives was achieved in presence
of HCl 6 mol L-1, under reflux for 12 hours.43
Afterwards, Phenibut was isolated in an 88% yield,
and Baclofen was produced in an 89% yield, both in
the chloridrate form. Thus, Phenibut and Bacofen were
expeditiously synthesized from Meldrum’s acid in only
3 steps in overall yields of 63 and 61%, respectively
(Scheme 8).
The synthesis GABA derivatives (+/−)-Phenibut,
(+/−)-Baclofen
Phenibut (4-amino-3-phenylbutanoic acid, 16) and
Figure 3. ESI-MS spectra from a solution of benzaldehyde/Meldrum’s acid/nitromethane/HT at different reaction times of (A) t1 = 5 min; (B) t2 = 30 min;
(C) t3 = 60 min.

292
New Multicomponent Reaction for the Direct Synthesis of b-Aryl-g-nitroesters
J. Braz. Chem. Soc.
Figure 4. ESI-MS spectra from the solution of a one pot domino transformation of 6a into γ-nitroester 5a at different times of (A) t1 = 5 min;
(B) t2 = 20 min; (C) t3 = 60 min.
Conclusions
and chromatography were of reagent grade. Flash
chromatography was performed using silica gel
(230-400 mesh). All reactions were monitored by
thin-layer chromatography on 0.25 mm silica plates (60F-
In the present work, a new multicomponent reaction
between Meldrum’s acid, aromatic aldehydes, nitromethane
and alcoholic solvents was developed to afford the direct
synthesis of β-aryl-γ-nitroesters 5a-u with yields ranging
between 15 and 95%. It was demonstrated that the
hydrotalcite-derived metal oxides as heterogeneous catalyst,
plays a role promoting the one pot single-step process. The
use of GC and ESI-MS analysis for monitoring the course of
the reactions revealed the convergent mechanistic pathways
towards the formation of a common intermediate 6 in a
multicomponent process, while its transformation into the
γ-nitroesters occurs through a domino process. Thus, the
γ-nitroesters 5a and 5b produce by this way were easily
converted into the lipophilic GABA derivatives Phenibut
(16) and Baclofen (17) in 3 steps in 63 and 61% overall
yields, respectively.
1
254) and visualized with UV light or iodine. H NMR
and 13C NMR spectra were recorded either on a 300, 75
or 400, 100 MHz spectrometers, respectively. Chemical
shifts (d) are reported in ppm relative to tetramethylsilane
(TMS). The multiplicity of signals is expressed as: s
(singlet); d (doublet); dd (double doublet); t (triplet); q
(quartet) and m (multiplet), and the coupling constant
3J is expressed in hertz (Hz). Infrared (IR) spectra were
recorded on aVarian 640-IR spectrometer and are expressed
in cm-1 in the range of 4000-400 cm-1. Melting points were
measured on Olympus BX41 microscope equipped with a
Mettler-Toledo FP82HT hotplate. ESI-MS and ESI-MS/MS
experiments in the positive ion-mode were performed on a
high-resolution hybrid quadrupole (Q) and orthogonal time-
of-flight (TOF) mass spectrometer (Q-TOF Micro, Waters-
Micromass, UK) with a constant nebulizer temperature
of 100 °C and a capillary voltage of 3.0 V. The cone and
extractor potentials were set to 15 and 4.5 V, respectively,
Experimental
All solvents for the routine isolation of products

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293
Scheme 7. A tentative mechanism based on ESI-MS studies.
Scheme 8. Synthesis of Phenibut (16) and Baclofen (17).
with a m/z scan range of 70-1000. Samples were directly
infused into the ESI source at flow rates of 15 µL min-1 by
means of a microsyringe pump.
formed was filtered and washed with deionized water
until the pH of the filtrate was 7. Then, the precipitate
was dried in the oven at 105 °C for 12 h, and finally, it
was macerated to produce a white-powder. The obtained
HT powder was calcined in a conventional oven at
450 °C for 4 h to afford a new white powder that was
called hydrotalcite calcined. The specific surface area
(BET multipoint technique) of HT[Calc.] was obtained from
samples previously degassed at 120 °C under vacuum
for 10 h by N2 adsorption desorption isotherms using a
Tristar 3020 Kr Micromeritics equipment. The specific
surface area was estimated as 130 5 m2 g-1. The X-ray
diffraction (XRD) measurements were carried out using
a Siemens D-500 powder diffractometer. Data were
collected with Cu Kα radiation with a wavelength of
General procedure for the preparation of the HT and HT[Calc.]
catalyst44
Hydrotalcite (HT, Mg/Al ratio 3:1) was synthesized
by a co-precipitation method at ambient conditions
under variable pH values. An aqueous solution (50 mL)
containing Mg(NO3)2·6H2O (0.09 mol) andAl(NO3)3·9H2O
(0.03 mol) was slowly added (2 h) to a second solution
(100 mL) containing NaHCO3 (0.25 mol) under vigorous
stirring at 80 °C, and it was continuously stirred for
additional 2 h at the same temperature. The precipitate

294
New Multicomponent Reaction for the Direct Synthesis of b-Aryl-g-nitroesters
J. Braz. Chem. Soc.
0.15418 nm. Compared to typical patterns, the results
(dd, 1H, J 12.0 and 9.0 Hz), 4.72 (dd, 1H, J 12.0 and
6.0 Hz), 7.17 (d, 2H, J 9.0 Hz), 7.29 (d, 2H, J 9.0 Hz);
13C NMR (75 MHz, CDCl3) d 14.0, 37.7, 39.5, 60.9, 79.3,
115.9 (2C, d, J 22 Hz), 129.0 (2C, d, J 7.7 Hz), 133.9 (d,
J 4.4 Hz), 162.2 (d, J 246.6 Hz), 170.4; IR nmax / cm-1 2985,
2931, 1725, 1599, 1552, 1508, 1429, 1370, 1228, 1161,
1098, 1019, 830, 781, 768, 720, 702.
12
show the transformation of HT into HT[Calc.]
.
General procedure for the multicomponent synthesis of
γ-nitroesters 5a-r
A mixture of aromatic aldehydes 2a-j (1 mmol),
Meldrum’s acid (1, 1.0 mmol), nitromethane (3,
5.0 mmol) and hydrotalcite (0.05 g) was stirred at reflux
for 24 h in an alcoholic solvent (1.0 mL). Afterwards,
the resulting mixture was filtered through Celite using
CH2Cl2 as the eluent. The filtrate was concentrated and
purified by column chromatography on silica gel using a
gradient of hexanes and ethyl acetate as the eluent to give
the γ-nitroesters 5a-r.
Ethyl 3-(4-cyanophenyl)-4-nitrobutanoate (5e)36
Yield 21.0 mg, 80% (hexane/ethyl acetate 70:30);
yellow pale oil; 1H NMR (300 MHz, CDCl3) d 1.19 (t, 3H,
J 6.0 Hz), 2.77 (m, 2H), 4.01-4.13 (m, 3H), 4.65 (dd, 1H,
J 15.0 and 9.0 Hz), 4.77 (dd, 1H, J 12.0 and 6.0 Hz), 7.38
(d, 2H, J 6.0 Hz), 7.66 (d, 2H, J 9.0 Hz); 13C NMR (75 MHz,
CDCl3) d 14.0, 37.1, 40.0, 61.2, 78.5, 112.1, 118.2, 128.3
(2C), 132.8 (2C), 143.6, 169.9; IR nmax / cm-1 2982, 2934,
2230, 1729, 1610, 1548, 1378, 1226, 1158, 1090, 1018,
842, 784, 763, 718, 694.
Ethyl 4-nitro-3-phenylbutanoate (5a)36
Yield 24.0 mg, 85% (hexane/ethyl acetate 70:30); brown
oil; 1H NMR (300 MHz, CDCl3) d 1.17 (t, 3H, J 7.5 Hz),
2.76 (d, 2H, J 6.0 Hz), 3.99 (q, 1H, J 7.5 Hz), 4.08 (q, 2H,
J 7.5 Hz), 4.63 (dd, 1H, J 12.0 and 9.0 Hz), 4.73 (dd, 1H,
J 12.0 and 7.5 Hz), 7.22-7.36 (m, 5H); 13C NMR (75 MHz,
CDCl3) d 14.0, 37.7, 40.1, 60.8, 79.4, 127.3 (2C), 127.9,
128.9 (2C), 138.2, 170.5; IR nmax / cm-1 3031, 2985, 1723,
1547, 1453, 1430, 1376, 1224, 1168, 852, 767, 734, 698.
Ethyl 3-(4-methoxyphenyl)-4-nitrobutanoate (5f)36
Yield 18.0 mg, 70% (hexane/ethyl acetate 70:30); brown
oil; 1H NMR (300 MHz, CDCl3) d 1.18 (t, 3H, J 6.0 Hz),
2.74 (m, 2H), 3.78 (s, 3H), 3.94 (m, 1H), 4.08 (q, 2H,
J 7.5 Hz), 4.59 (dd, 1H, J 12.0 and 6.0 Hz), 4.70 (dd, 1H,
J 12.0 and 6.0 Hz), 6.85 (d, 2H, J 9.0 Hz), 7.14 (d, 2H,
J 9.0 Hz); 13C NMR (75 MHz, CDCl3) d 14.0, 37.9, 39.5,
55.2, 60.9, 79.7, 114.3 (2C), 128.4 (2C), 130.1, 159.1,
170.6; IR nmax / cm-1 2969, 2833, 1718, 1597, 1545, 1500,
1470, 1432, 1364, 1251, 1176, 1018, 829, 694.
Ethyl 3-(4-clorophenyl)-4-nitrobutanoate (5b)36
Yield 22.5 mg, 83% (hexane/ethyl acetate 70:30); brown
oil; 1H NMR (300 MHz, CDCl3) d 1.18 (t, 3H, J 7.5 Hz),
2.69 (dd, 1H, J 15.0 and 9.0 Hz), 2.76 (dd, 1H, J 15.0 and
6.0 Hz), 3.97 (q, 1H, J 6.0 Hz), 4.08 (q, 1H, J 7.5 Hz), 4.60
(dd, 1H, J 15.0 and 9.0 Hz), 4.72 (dd, 1H, J 12.0 and 6.0 Hz),
7.17 (d, 2H, J 9.0 Hz), 7.31 (d, 2H, J 9.0 Hz); 13C NMR
(75 MHz, CDCl3) d 13.9, 37.4, 39.5, 60.9, 79.0, 128.7 (2C),
129.0 (2C), 133.6, 136.7, 170.3; IR nmax / cm-1 2923, 2915,
1724, 1538, 1484, 1368, 1182, 1097, 1012, 826, 734, 717.
Ethyl 3-(3,4-dimethoxyphenyl)-4-nitrobutanoate (5g)36
Yield 22.3 mg, 75% (hexane/ethyl acetate 70:30); brown
oil; 1H NMR (300 MHz, CDCl3) d 1.19 (t, 3H, J 7.5 Hz),
2.74 (d, 2H, J 9.0 Hz), 3.86 (s, 3H), 3.88 (s, 3H), 3.93
(m, 1H), 4.09 (q, 2H, J 6.0 Hz), 4.61 (dd, 1H, J 12.0 and
9.0 Hz), 4.71 (dd, 1H, J 12.0 and 6.0 Hz), 6.72-6.84 (m,
3H); 13C NMR (75 MHz, CDCl3) d 14.0, 37.8, 39.9, 55.8,
55.9, 60.9, 79.6, 110.6, 111.4, 119.2, 130.6, 148.6, 149.1,
170.6; IR nmax / cm-1 2969, 2833, 1718, 1597, 1545, 1500,
1470, 1432, 1364, 1251, 1176, 1018, 829, 694.
Ethyl 3-(4-bromophenyl)-4-nitrobutanoate (5c)36
Yield 27.8 mg, 88% (hexane/ethyl acetate 70:30); brown
oil; 1H NMR (300 MHz, CDCl3) d 1.17 (t, 3H, J 7.5 Hz),
2.70 (m, 1H), 3.95 (m, 1H), 4.07 (m, 2Hz), 4.60 (dd, 1H,
J 12.0 and 9.0 Hz), 4.71 (dd, 1H, J 15.0 and 6.0 Hz), 7.12
(d, 2H, J 6.0 Hz), 7.45 (d, 2H, J 6.0 Hz); 13C NMR (75 MHz,
CDCl3) d 14.0, 37.4, 39.6, 61.0, 79.0, 121.9, 129.0 (2C),
132.0 (2C), 137.2, 170.3; IR nmax / cm-1 2984, 1726, 1545,
1485, 1357, 1161, 1070, 1010, 829, 726, 715.
Ethyl 4-nitro-3-(3,4,5-trimethoxyphenyl)butanoate (5h)36
Yield 31.0 mg, 95% (hexane/ethyl acetate 70:30);
yellow solid; m.p. 91-93 °C; 1H NMR (300 MHz, CDCl3) d
1.20 (t, 3H, J 7.5 Hz), 2.75 (d, 2H, J 7.5 Hz), 3.82 (s, 3H),
3.85 (s, 6H), 3.90 (m, 1H), 4.11 (q, 2H, J 7.0 Hz), 4.60-
4.78 (m, 2H), 6.42 (s, 2H); 13C NMR (75 MHz, CDCl3) d
14.1, 37.8, 40.4, 56.1, 60.8, 61.0, 79.4, 104.2, 104.3, 133.9,
137.5, 153.5 (2C), 170.6; IR nmax / cm-1 2946, 2830, 1724,
1591, 1545, 1462, 1421, 1396, 1353, 1319, 1270, 1251,
1217, 1176, 1129, 995, 905, 841, 773, 731.
Ethyl 3-(4-fluorophenyl)-4-nitrobutanoate (5d)36
Yield 23 mg, 90% (hexane/ethyl acetate 70:30); brown
oil; 1H NMR (300 MHz, CDCl3) d 1.17 (t, 3H, J 7.5 Hz),
2.72 (m, 2Hz), 3.96 (m, 1H), 4.06 (q, 2H, J 6.0 Hz), 4.60

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295
Ethyl 4-nitro-3-(thiophen-2-yl)butanoate (5i)36
40.3, 68.3, 79.5, 127.3 (2C), 127.9, 128.9 (2C), 138.2,
170.0; IR nmax / cm-1 3031, 2985, 2923, 1731, 1545, 1461,
1432, 1378, 1270, 1197, 1104, 963, 898, 825, 760, 699;
HRMS calculated for [C13H17NO4-HNO2]: 204.1151; found:
204.1197.
Yield 23.0 mg, 85% (hexane/ethyl acetate 80:20); brown
oil; 1H NMR (300 MHz, CDCl3) d 1.22 (t, 3H, J 7.5 Hz),
2.81 (d, 2H, J 6.0 Hz), 4.12 (q, 2H, J 7.5 Hz), 4.30 (m, 1H),
4.65 (dd, 1H, J 12.0 and 9.0 Hz), 4.76 (dd, 1H, J 12.0 and
6.0 Hz), 6.93 (m, 2H), 7.22 (m, 1H); 13C NMR (75 MHz,
CDCl3) d 13.9, 35.5, 38.4, 60.9, 79.5, 124.7, 125.4, 126.9,
140.8, 170.2; IR nmax / cm-1 3108, 2985, 1708, 1545, 1432,
1382, 1203, 1176, 1024, 853, 701.
Isopropyl 3-(4-methoxyphenyl)-4-nitrobutanoate (5p)
Yield 18.0 mg, 64% (hexane/ethyl acetate 70:30);
yellow oil; 1H NMR (300 MHz, CDCl3) d 1.14 (m, 6H),
2.69 (m, 2H), 3.78 (s, 3H), 3.92 (m, 1H), 4.58 (dd, 1H,
J 12.3 and 8.1 Hz), 4.68 (dd, 1H, J 12.4 and 6.9 Hz),
4.93 (h, 1H, J 6.3 Hz), 6.85 (d, 2H, J 9 Hz), 7.14 (d, 2H,
J 8.7 Hz); 13C NMR (75 MHz, CDCl3) d 21.6 (2C), 38.1,
39.6, 55.2, 68.3, 79.7, 114.3 (2C), 128.4 (2C), 130.0, 159.1,
170.1; IR nmax / cm-1 2982, 2934, 1729, 1615, 1553, 1515,
1378, 1256, 1347, 1178, 985, 785; HRMS calculated for
[C14H19NO5 + Na]: 304.1161; found: 304.1163.
Ethyl 4-nitro-3-(thiophen-3-yl)butanoate (5j)
Yield 20.0 mg, 83% (hexane/ethyl acetate 80:20); rose
oil; 1H NMR (300 MHz, CDCl3) d 1.20 (t, 3H, J 6.0 Hz),
2.75 (d, 2H, J 6.0 Hz), 4.11 (q, 2H, J 6.0 Hz), 4.11-4.14
(m, 1H), 4.62 (dd, 1H, J 10.5 and 6.0 Hz), 4.72 (dd, 1H,
J 9.0 and 6.0 Hz), 6.98 (d, 1H, J 6.0 Hz), 7.13 (s, 1H), 7.32
(m, 1H); 13C NMR (75 MHz, CDCl3) d 13.9, 35.6, 37.5,
60.8, 79.0, 122.1 (2C), 126.0 (2C), 126.6, 138.8, 170.5;
IR nmax / cm-1 3100, 2982, 2925, 1724, 1553, 1368, 1171,
1024, 791; elemental analysis calculated for C10H13NO4S:
C 49.37, H 5.39, N 5.76; found: C 49.77, H 5.08,
N 5.78.
Butyl 3-(4-methoxyphenyl)-4-nitrobutanoate (5q)
Yield 14.6 mg, 55% (hexane/ethyl acetate 90:10);
1
yellow oil; H NMR (300 MHz, CDCl3) d 0.88 (t, 3H,
J 7.5 Hz), 1.27 (m, 2H), 1.51 (m, 2H), 2.73 (d, 2H,
J 7.6 Hz), 3.78 (s, 3H), 3.93 (m, 1H), 4.02 (t, 2H, J 6.6 Hz),
4.59 (dd, 1H, J 12.4 and 8.1 Hz), 4.69 (dd, 1H, J 12.3 and
7.2 Hz), 6.86 (d, 2H, J 6.6 Hz), 7.14 (d, 2H, J 6.6 Hz);
13C NMR (75 MHz, CDCl3) d 13.6, 19.0, 30.5, 37.9, 39.5,
55.2, 64.7, 79.7, 114.3 (2C), 128.3 (2C), 130.0, 159.2,
170.7; IR nmax / cm-1 2958, 2934, 1729, 1553, 1615, 1553,
1510, 1382, 1251, 1175, 984, 680; HRMS calculated for
[C15H21NO5 + Na]: 318.1317; found: 318.1325.
Methyl 4-nitro-3-phenylbutanoate (5m)45
Yield 18.7 mg, 84% (hexane/ethyl acetate 75:25);
1
brown oil; H NMR (300 MHz, CDCl3) d 2.70 (d, 2H,
J 9.0 Hz), 3.56 (s, 3H), 3.92 (m, 1H), 4.56 (dd, 1H, J 12.0
and 9.0 Hz), 4.67 (dd, 1H, J 12.0 and 6.0 Hz), 7.21 (m,
5H); 13C NMR (75 MHz, CDCl3) d 37.4, 40.2, 51.8, 79.3,
127.1 (2C), 127.9, 128.9 (2C), 138.2, 171.0; IR nmax / cm-1
2923, 2846, 1731, 1545, 1430, 1375, 1260, 1159, 1089,
1004, 870, 764, 702.
tert-Butyl 4-nitro-3-phenylbutanoate (5r)
Yield 15.3 mg, 58% (hexane/ethyl acetate 85:25);
yellow oil; 1H NMR (300 MHz, CDCl3) d 1.33 (s, 9H), 2.67
(dd, 2H, J 7.6 and 2.9 Hz), 1.14 (d, 3H, J 6.4 Hz), 2.73 (d,
2H, J 7.6 Hz), 3.92-4.02 (m, 1H), 4.63 (dd, 1H, J 12.3 and
7.6 Hz), 4.72 (dd, 1H, J 12.3 and 7.0 Hz), 4.87-4.97 (m,
1H), 7.21-7.36 (m, 5H); 13C NMR (75 MHz, CDCl3) d 27.8
(3C), 38.8, 40.5, 79.6, 81.3, 127.4 (2C), 127.9 (2C), 128.9,
138.3, 169.7; IR nmax / cm-1 3066, 2923, 1714, 1537, 1455,
1435, 1364, 1271, 1242, 1149, 842, 767, 724, 692; HRMS
calculated for [C18H28NO5]: 192.0655; found: 192.0645;
elemental analysis calculated for C18H28NO5: C 63.38, H
7.22, N 5.28; found: C 64.02, H 6.94, N 5.13.
Methyl 3-(4-methoxyphenyl)-4-nitrobutanoate (5n)45
Yield 18.2 mg, 72% (hexane/ethyl acetate 80:20);
yellow solid; m.p. 84-86 °C; 1H NMR (300 MHz, CDCl3)
d 2.74 (d, 2H, J 7.5 Hz), 3.62 (s, 3H), 3.79 (s, 3H), 3.93 (q,
1H, J 12 Hz), 4.59 (dd, 1H, J 12.0 and 9.0 Hz), 4.70 (dd,
1H, J 12.0 and 6.0 Hz), 6.85 (d, 2H, J 9.0 Hz), 7.14 (d, 2H,
J 9.0 Hz); 13C NMR (75 MHz, CDCl3) d 37.6, 39.4, 51.8,
55.3, 79.6, 114.3 (2C), 128.3 (2C), 130.0, 159.1, 171.1;
IR nmax / cm-1 2957, 2834, 1733, 1614, 1548, 1514, 1439,
1270, 1268, 1179, 1092, 890, 750.
Isopropyl 4-nitro-3-phenylbutanoate (5o)
Yield 18.8 mg, 75% (hexane/ethyl acetate 75:25);
yellow oil; H NMR (300 MHz, CDCl3) d 1.12 (d, 3H,
General procedure for the synthesis of γ-nitroesters 5s-u
1
J 6.4 Hz), 1.14 (d, 3H, J 6.4 Hz), 2.73 (d, 2H, J 7.6 Hz),
3.92-4.02 (m, 1H), 4.63 (dd, 1H, J 12.3 and 7.6 Hz), 4.72
(dd, 1H, J 12.3 and 7.0 Hz), 4.87-4.97 (m, 1H), 7.21-7.36
(m, 5H); 13C NMR (75 MHz, CDCl3) d 21.6 (2C), 38.0,
A mixture of adduct 6a (1.0 mmol), HT (0.05 g) and
benzylic, allylic or propargyl alcohol (1.0 mmol) was
submitted to reaction in the presence of 3.0-5.0 mL of
MeCN under reflux for 24 h. Afterwards, the resulting

296
New Multicomponent Reaction for the Direct Synthesis of b-Aryl-g-nitroesters
J. Braz. Chem. Soc.
mixture was filtered through Celite using CH2Cl2 as the
eluent. The filtrate was concentrated and purified by
column chromatography on silica gel using a gradient
of hexanes and ethyl acetate as the eluent to give the
γ-nitroesters 5s-u.
2,2-Dimethyl-5-(2-nitro-1-phenylethyl)-1,3-dioxane-4,6-
dione (6a)46
1
Yield 27.8 mg, 95%; viscous yellow oil; H NMR
(300 MHz, CDCl3) d 1.39 (s, 3H), 1.72 (s, 3H), 4.05 (d, 1H,
J 3.3 Hz), 4.65 (m, 1H), 5.03 (dd, 1H, J 14.1 and 6.6 Hz),
5.40 (dd, 1H, J 13.9 and 8.7 Hz), 7.33 (m, 5H); 13C NMR
(75 MHz, CDCl3) d 27.6, 28.1, 41.9, 48.5, 75.9, 105.9,
128.7, 128.8, 128.9, 129.0, 129.2, 135.1, 163.9, 164.4;
IR nmax / cm-1 2999, 2867, 1781, 1735, 1553, 1329, 1310,
1206, 1110, 758.
Benzyl 4-nitro-3-phenylbutanoate (5s)
Yield 60% (hexane/ethyl acetate 70:30); brown oil;
1H NMR (300 MHz, CDCl3) d 2.85 (d, 2H, J 6.0 Hz), 4.03
(quint, 1H, J 6.0 Hz), 4.65 (dd, 1H, J 12.0 and 6.0 Hz),
4.73 (dd, 1H, J 12.0 and 6.0 Hz), 5.09 (s, 2H), 7.22-7.37
(m, 10H); 13C NMR (75 MHz, CDCl3) d 37.6, 40.1, 66.7,
79.3, 127.3 (2C), 128.0, 128.2 (2C), 128.3, 128.5 (2C),
129.0 (2C), 135.3, 138.0, 170.4; IR nmax / cm-1 3025, 2920,
1738, 1544, 1381, 1211, 1179, 1009, 726, 702, 548, 459;
elemental analysis calculated for C17H17NO4: C 68.21, H
5.72, N 4.68; found: C 67.55, H 5.72, N 4.41.
General procedure for the synthesis of 5-benzylidene-2,2-
dimethyl-1,3-dioxane-4,6-dione (9a)
Benzaldehyde (1.0 mmol), Meldrum’s acid (1.1 mmol)
and HT (0.05 g) in ethanol were added into a round bottom
flask. The mixture was submitted to magnetic stirring at
reflux for 2 h. Afterwards, the ethanol was removed under
vacuum, and the crude product was dissolved in 10.0 mL of
CH2Cl2 followed by filtering through Celite. The filtrate was
concentrated under vacuum to afford the benzylidene 9a.47
Yield 22.2 mg, 96%; yellow solid; m.p. 84-85 °C; 1H NMR
(300 MHz, CDCl3) d 1.82 (s, 6H), 7.45-7.56 (m, 3H), 8.06
(d, 2H, J 9.0 Hz), 8.42 (s, 1H); IR nmax / cm-1 2996, 1768,
1729, 1618, 1361, 1289, 1189, 764.
Allyl 4-nitro-3-phenylbutanoate (5t)
Yield 75% (hexane/ethyl acetate 70:30); brown oil;
1H NMR (300 MHz, CDCl3) d 2.73 (d, 2H, J 9.0 Hz), 3.92
(quint, 1H, J 6.0 Hz), 4.45 (m, 2H), 4.56 (dd, 1H, J 15.0
and 9.0 Hz), 4.65 (dd, 1H, J 12.0 and 9.0 Hz), 5.11-5.19 (m,
2H), 5.73 (m, 1H), 7.14-7.29 (m, 5H); 13C NMR (75 MHz,
CDCl3) d 37.5, 40.0, 65.5, 79.3, 118.5, 127.3, 127.9 (2C),
129.0 (2C), 131.5, 138.1, 170.2; IR nmax / cm-1 3025, 2928,
1730, 1551, 1374, 1163, 985, 936, 768, 693; elemental
analysis calculated for C13H15NO4: C 62.64, H 6.07, N 5.62;
found: C 62.34, H 6.10, N 5.23.
General procedure for the synthesis of β-lactams48
Nitroesters 5a-b (1.0 mmol) and NiCl2·6H2O
(10.0 mmol) dissolved in 5 mL of ethanol were added
into a round bottom flask. The mixture was submitted to
magnetic stirring in an ice bath, followed by the addition of
NaBH4 (10.0 mmol), and then it was stirred for 2 h at 0 °C.
Afterwards, 20 mL of NH4Cl was added into the flask and
extracted with CHCl3 (3 × 20.0 mL). The organic phases
were combined, dried with MgSO4 anhydrous, filtered
through Celite and evaporated under vacuum.
Prop-2-ynyl 4-nitro-3-phenylbutanoate (5u)
Yield 65% (hexane/ethyl acetate 80:20); pale yellow oil;
1H NMR (300 MHz, CDCl3) d 2.39 (t, 1H, J 3.0 Hz), 2.76
(d, 2H J 6.0 Hz), 3.93 (quint, 1H, J 7.5 Hz), 4.62 (m, 4H),
7.14-7.30 (m, 5H); 13C NMR (75 MHz, CDCl3) d 37.3, 40.0,
52.3, 75.2, 77.0, 79.2, 127.3 (2C), 128.1, 129.0 (2C), 137.9,
169.8, IR nmax / cm-1 3292, 3033, 2928, 2126, 1738, 1551,
1374, 1155, 985, 766, 693, 637, 532; elemental analysis
calculated for C13H13NO4: C 63.15, H 5.30, N 5.67; found:
C 63.11, H 5.25, N 5.43.
4-Phenylpyrrolidin-2-one (14)48
Yield 13.2 mg, 82%; brown oil; 1H NMR (300 MHz,
CDCl3) d 2.51 (dd, 1H, J 16.9 and 8.8 Hz), 2.74 (dd, 1H,
J 16.9 and 8.8 Hz), 3.43 (dd, 1H, J 9.4 and 7.0 Hz), 3.64-
3.82 (m, 2H), 6.90 (s, 1H), 7.25-7.35 (m, 5H); 13C NMR
(75 MHz, CDCl3) d 37.9, 40.2, 49.5, 126.7, 127.0, 128.8,
142.6, 177.8; IR nmax / cm-1 3240, 2923, 2861, 1669, 1496,
1442, 1356, 1255, 1051, 742, 688, 627.
General procedure for the synthesis of Michael adduct 6a
Nitrostyrene (1 mmol), Meldrum’s acid (1.1 mmol)
and Et3N (1.0 mmol) in CH2Cl2 were added into a round
bottom flask. The mixture was submitted to magnetic
stirred at room temperature overnight. The crude product
was diluted in 5.0 mL of CH2Cl2 and washed with HCl
(5%, 3 × 5.0 mL). The organic phases were dried with
MgSO4, filtered and evaporated under vacuum afford
adduct 6a.
4-(4-Chlorophenyl)pyrrolidin-2-one (15)48
Yield 17.0 mg, 87%; brown oil; 1H NMR (300 MHz,
CDCl3) d 2.45 (dd, 1H, J 16.9 and 8.8 Hz), 2.74 (dd, 1H,
J 16.9 and 8.8 Hz), 3.39 (t, 1H, J 7.6 Hz), 3.62-3.82 (m, 2H),

Vol. 28, No. 2, 2017
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297
6.52 (s, 1H), 7.19 (d, 2H, J 7.0 Hz), 7.32 (d, 2H, J 7.0 Hz);
13C NMR (75 MHz, CDCl3) d 29.9, 39.9, 49.7, 128.4, 129.3,
133.2, 140.8, 177.8; IR nmax / cm-1 3194, 2923, 2840, 1673,
1485, 1259, 1089, 1006, 824, 718, 666.
References
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Submitted: February 20, 2016
Published online: June 9, 2016
FAPERGS/CAPES has sponsored the publication of this article.