New Multicomponent Reaction for the Direct Synthesis of β-Aryl-γ-nitroesters Promoted by Hydrotalcite-Derived Mixed Oxides as Heterogeneous Catalyst

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.


Introduction
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 molecules from available starting materials via a single pathway. 4][10] In addition, the design and development of environment-friendly catalysts have been the subject of intense research. 113][14][15] The HT-like compounds exhibit dual basic/acid properties 16,17 and can be useful as bifunctional catalysts in different organic transformations. 18,19s a part of our ongoing efforts in the field of MCR, [20][21][22][23][24] herein we disclose our studies on the development of a 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.
][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.

Results and Discussion
The multicomponent/domino combined approach 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. 25he activity of HT was attributed to the increase in the basicity of this material by the formation of mixed magnesium and aluminium oxides after thermal treatment that we called HT [Calc.] . 26couraged 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.
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 (  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) 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.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. 25The 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).
The first set was performed in presence of HT [Calc.] in nonalcoholic solvents because γ-nitroesters 5a were produced in the presence of EtOH.In the second set, an amine basecatalyzed 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 1 H 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 CH 2 Cl 2 , CH 3 CN, 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 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  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 = 10.49min, m/z 149), and nitroaldol 8a (Rt = 11.02min, 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.Next, nitromethane was added to benzylidene in the 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 CO 2 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 (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 t 1 = 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). 39heme 5. Preparation of 5a from benzylidene intermediate 9a.Scheme 6.A rational mechanism for the multicomponent synthesis of γ-nitroesters.
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 CO 2 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).
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 NaBH 4 /NiCl 2 •6H 2 O in ethanol led directly to the isolation of the lactams 14 and 15 in yields of 82 and 87%, respectively. 42he transformation of the respective lactams into the GABA-derivatives was achieved in presence of HCl 6 mol L -1 , under reflux for 12 hours. 43fterwards, 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).

Conclusions
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.

Experimental
All solvents for the routine isolation of products 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-254) and visualized with UV light or iodine. 1 H NMR and 13 C 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 3 J is expressed in hertz (Hz).Infrared (IR) spectra were recorded on a Varian 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 timeof-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, General procedure for the preparation of the HT and HT [Calc.]catalyst 44 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(NO 3 ) 2 •6H 2 O (0.09 mol) and Al(NO 3 ) 3 •9H 2 O (0.03 mol) was slowly added (2 h) to a second solution (100 mL) containing NaHCO 3 (0.25 mol) under vigorous stirring at 80 °C, and it was continuously stirred for additional 2 h at the same temperature.The precipitate 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 N 2 adsorption desorption isotherms using a Tristar 3020 Kr Micromeritics equipment.The specific surface area was estimated as 130 ± 5 m 2 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 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 CH 2 Cl 2 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 4-nitro-3-phenylbutanoate (5a) 36 mixture was filtered through Celite using CH 2 Cl 2 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.

General procedure for the synthesis of Michael adduct 6a
Nitrostyrene (1 mmol), Meldrum's acid (1.1 mmol) and Et 3 N (1.0 mmol) in CH 2 Cl 2 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 CH 2 Cl 2 and washed with HCl (5%, 3 × 5.0 mL).The organic phases were dried with MgSO 4 , filtered and evaporated under vacuum afford adduct 6a.

Figure 2 .
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.

Table 2 .
Synthesis of 5m-u in the presence of different alcohols a See Table1, entry 1; b synthesized by the opening reaction of 6a.Figure1.Structurally diverse γ-nitroesters prepared via the new tetracomponent reaction.