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

Abstract

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

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.11 Sutoo, D.; Akiyama, K.; Yabe, K.; Hum. Brain Mapp. 2000, 11, 93.

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.22 Cai, K.; Nanga, R.; Lamprou, L.; Schinstine, C.; Elliott, M.; Hariharan, R.; Epperson, N.; Neuropsychopharmacology 2012, 37, 2764. 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.33 Foster, A. C.; Kemp, J. A.; Curr. Opin. Pharmacol. 2006, 6, 7.

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.44 Touré, B. B.; Hall D. G. In Multicomponent Reactions, 1st ed.; Zhu, J.; Bienaymé H., eds.; Wiley-VCH: Weinheim, Germany, 2005. 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.55 Habibi, A.; Rahmani, A.; Helv. Chim. Acta 2011, 94, 1806.

6 Dömling, A.; Wang, W.; Wang, K.; Chem. Rev. 2012, 112, 3083.
-77 Dömling, A.; Chem. Rev. 2006, 106, 17.

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.88 Dumas, A. M.; Fillion, E.; Acc. Chem. Res. 2010, 43, 440.

9 Lipson, V. V.; Gorobets, N. Y.; Mol. Divers. 2009, 13, 399.
-1010 Ivanov, A. S.; Chem. Soc. Rev. 2008, 37, 789. In addition, the design and development of environment-friendly catalysts have been the subject of intense research.1111 Climent, M. J.; Corma, A.; Iborra, S.; Chem. Rev. 2011, 111, 1072.

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.1212 Wang, D.; Zhang, X.; Wei, W.; Sun, Y.; Catal. Commun. 2012, 28, 159.

13 Wang, S. H.; Wang, Y. B.; Dai, Y. M.; Jehng, J. M.; Appl. Catal. , A 2012, 439, 135.

14 Neves, A. C. B.; Calvete, M. J. F.; Pinho e Melo, T. M. V. D.; Pereira, M. M.; Eur. J. Org. Chem. 2012, 32, 6309.
-1515 Winter, F.; van Dillen, A. J.; Jong, K. P.; Chem. Commun. 2005, 31, 3977. The HT-like compounds exhibit dual basic/acid properties1616 Ebitani, K.; Motokura, K.; Mori, K.; Mizugaki, T.; Kaneda, K.; J. Org. Chem. 2006, 71, 5440.,1717 Valente, J. S.; Cortez, J. H.; Cantu, M. S.; Ferrat, G.; Salinas, E. L.; Catal. Today 2010, 150, 340. and can be useful as bifunctional catalysts in different organic transformations.1818 Kshirsagar, S. W.; Patil, N. R.; Samant, S. D.; Tetrahedron Lett. 2010, 51, 2924.,1919 Xu, Z. P.; Zhang, J.; Adebajo, M. O.; Zhang, H.; Zhou, C.; Appl. Clay Sci. 2011, 53, 139.

As a part of our ongoing efforts in the field of MCR,2020 Godoi, M. N.; Costenaro, H. S.; Kramer, E.; Machado, P. S.; D'Oca, M. G. M.; Russowsky, D.; Quim. Nova 2005, 28, 1010.

21 Russowsky, D.; Benvenutti, E. V.; Roxo, G. S.; Grasel, F.; Lett. Org. Chem. 2007, 4, 39.

22 Marques, M. V.; Ruthner, M.; Fontoura, L. A. M.; Russowsky, D.; J. Braz. Chem. Soc. 2012, 23, 171.

23 Affeldt, R. F.; Benvenutti, V.; Russowsky, D.; New J. Chem. 2012, 36, 1502.
-2424 Costa, J. S.; Lopes, J. P. B.; Russowsky, D.; Petzhold, C. L.; Borges, A. C. A.; Ceschi, M. A.; Konrath, E.; Batassini, C.; Lunardi, P. S.; Gonçalves, C. A. S.; Eur. J. Med. Chem. 2013, 62, 556. 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.

Our interest synthesizing γ-nitroesters is due to the fact that these intermediates are considered advanced intermediates in the synthesis of GABA analogues.2525 Naciuk, F. F.; Vargas, D. Z.; D'Oca, C. R. M.; Moro, C. C.; Russowsky, D.; New J. Chem. 2015, 39, 1643.

26 Prescott, H. A.; Li, Z. -J.; Kemnitz, E.; Trunschke, A.; Deutsch, J.; Lieske, H.; Auroux, A. J.; J. Catal. 2005, 234, 119.
-2727 Bulbule, V. J.; Deshpande, V. H.; Velu, S.; Sudalai, A.; Sivasankar, S.; Sathe, V. T.; Tetrahedron 1999, 55, 9325. 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.2828 Santos, L. S. In Reactive Intermediates: MS Investigations in Solution; Santos, L. S., ed.; Wiley-VCH: Weinheim, Germany , 2010.

29 Santos, L. S.; J. Braz. Chem. Soc. 2011, 22, 1827.

30 Zhao, Z. -X.; Wang, H. -Y.; Guo, Y. -L.; Curr. Org. Chem. 2011, 15, 3734.

31 Santos, L. S.; Eur. J. Org. Chem. 2008, 235.

32 Eberlin, M. N.; Eur. J. Mass Spectrom. 2007, 13, 19.
-3333 Santos, L. S.; Knaack, L.; Metzger, J.; Int. J. Mass Spectrom. 2005, 246, 84.

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.3434 Peng, H.; Yuan, Z.; Wang, H. -Y.; Guo, Y. -L.; Liu, G.; Chem. Sci. 2013, 4, 3172.

35 Shankaraiah, N.; Markandeya, N.; Srinivasulu, V.; Sreekanth, K.; Reddy, C. R.; Santos, L. S.; Kamal, A.; J. Org. Chem. 2011, 76, 7017.

36 Silva, B. V.; Violante, F. A.; Pinto, A. C.; Santos, L. S.; Rapid Commun. Mass Spectrom. 2011, 25, 423.

37 Stoddard, R. L.; Luo, J.; van ver Wal, N.; O'Rourke, N. F.; Wulff, J. E.; McIndoe, J. S.; New J. Chem. 2014, 38, 5382.
-3838 Oliveira, C. C.; Marques, M. V.; Godoi, M. N.; Regiani, T.; Santos, V. G.; dos Santos, E. A. F.; Eberlin, M. N.; Sá, M. M.; Correia, C. R. D.; Org. Lett. 2014, 16, 5180. The present work also aims to apply on-line ESI-MS/MS to monitor the developed multicomponent reactions.

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.2525 Naciuk, F. F.; Vargas, D. Z.; D'Oca, C. R. M.; Moro, C. C.; Russowsky, D.; New J. Chem. 2015, 39, 1643.

The 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.].2626 Prescott, H. A.; Li, Z. -J.; Kemnitz, E.; Trunschke, A.; Deutsch, J.; Lieske, H.; Auroux, A. J.; J. Catal. 2005, 234, 119.

Encouraged by the fact that HT is able to promote the Henry reactions,2727 Bulbule, V. J.; Deshpande, V. H.; Velu, S.; Sudalai, A.; Sivasankar, S.; Sathe, V. T.; Tetrahedron 1999, 55, 9325. 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).

Scheme 1
Multicomponent synthesis of γ-nitroesters 5a-u.

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

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 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).

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.

Table 2
Synthesis of 5m-u in the presence of different alcohols

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.

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.2525 Naciuk, F. F.; Vargas, D. Z.; D'Oca, C. R. M.; Moro, C. C.; Russowsky, D.; New J. Chem. 2015, 39, 1643. 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).

Scheme 2
Synthesis of Michael adduct 6a.

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.

Table 3
Preparation of intermediate 6a

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 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).

Scheme 3
Transformation of intermediate 6 into γ-nitroester 5a.

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.

Scheme 4
Formation of 7a via a Knoevenagel-type reaction.

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.

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.

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).

Scheme 5
Preparation of 5a from benzylidene intermediate 9a.

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).

Scheme 6
A rational mechanism for the multicomponent synthesis of γ-nitroesters.

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).

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.

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).3939 George, L.; Veedu, R. N.; Sheibani, H.; Taherpour, A. A.; Flammang, R.; Wentrup, C.; J. Org. Chem. 2007, 72, 1399.

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.

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).

Scheme 7
A tentative mechanism based on ESI-MS studies.

The synthesis GABA derivatives (+/-)-Phenibut, (+/-)-Baclofen

Phenibut (4-amino-3-phenylbutanoic acid, 16) and 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.4040 Sytinsky, K. A.; Soldatenkov, A. T.; Prog. Neurobiol. 1978, 10, 89. Baclofen, meanwhile, is a muscle relaxant currently used in the treatment of neuropathic pain.4141 Mann, A.; Boulanger, T.; Brandau, B.; Durant, F.; Evrard, G.; Heaulme, M.; Desaulles, E.; Wermuth, C. G.; J. Med. Chem. 1991, 34, 1307. 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.4242 Hynes, P. S.; Stupple, P. A.; Dixon, D. J.; Org. Lett. 2008, 10, 1389.

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.4343 Chang, M. -Y.; Sun, P. -P.; Chen, S. -T.; Chang, N. -C.; Tetrahedron Lett. 2003, 44, 5271. 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).

Scheme 8
Synthesis of Phenibut (16) and Baclofen (17).

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. 1H 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 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 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, 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.

General procedure for the preparation of the HT and HT[Calc.] catalyst 4444 Rodrigues, J. C.; Costa, T. M. H.; Gallas, M. R.; Moro, C. C.; Phys. Chem. Miner. 2009, 36, 439.

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) and Al(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 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 0.15418 nm. Compared to typical patterns, the results show the transformation of HT into HT[Calc.].1212 Wang, D.; Zhang, X.; Wei, W.; Sun, Y.; Catal. Commun. 2012, 28, 159.

General procedure for the multicomponent synthesis of g-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 4-nitro-3-phenylbutanoate (5a)3636 Silva, B. V.; Violante, F. A.; Pinto, A. C.; Santos, L. S.; Rapid Commun. Mass Spectrom. 2011, 25, 423.

Yield 24.0 mg, 85% (hexane/ethyl acetate 70:30); brown oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 14.0, 37.7, 40.1, 60.8, 79.4, 127.3 (2C), 127.9, 128.9 (2C), 138.2, 170.5; IR νmax / cm-1 3031, 2985, 1723, 1547, 1453, 1430, 1376, 1224, 1168, 852, 767, 734, 698.

Ethyl 3-(4-clorophenyl)-4-nitrobutanoate (5b)3636 Silva, B. V.; Violante, F. A.; Pinto, A. C.; Santos, L. S.; Rapid Commun. Mass Spectrom. 2011, 25, 423.

Yield 22.5 mg, 83% (hexane/ethyl acetate 70:30); brown oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 13.9, 37.4, 39.5, 60.9, 79.0, 128.7 (2C), 129.0 (2C), 133.6, 136.7, 170.3; IR νmax / cm-1 2923, 2915, 1724, 1538, 1484, 1368, 1182, 1097, 1012, 826, 734, 717.

Ethyl 3-(4-bromophenyl)-4-nitrobutanoate (5c)3636 Silva, B. V.; Violante, F. A.; Pinto, A. C.; Santos, L. S.; Rapid Commun. Mass Spectrom. 2011, 25, 423.

Yield 27.8 mg, 88% (hexane/ethyl acetate 70:30); brown oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 14.0, 37.4, 39.6, 61.0, 79.0, 121.9, 129.0 (2C), 132.0 (2C), 137.2, 170.3; IR νmax / cm-1 2984, 1726, 1545, 1485, 1357, 1161, 1070, 1010, 829, 726, 715.

Ethyl 3-(4-fluorophenyl)-4-nitrobutanoate (5d)3636 Silva, B. V.; Violante, F. A.; Pinto, A. C.; Santos, L. S.; Rapid Commun. Mass Spectrom. 2011, 25, 423.

Yield 23 mg, 90% (hexane/ethyl acetate 70:30); brown oil; 1H NMR (300 MHz, CDCl3) δ 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 (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) δ 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 νmax / cm-1 2985, 2931, 1725, 1599, 1552, 1508, 1429, 1370, 1228, 1161, 1098, 1019, 830, 781, 768, 720, 702.

Ethyl 3-(4-cyanophenyl)-4-nitrobutanoate (5e)3636 Silva, B. V.; Violante, F. A.; Pinto, A. C.; Santos, L. S.; Rapid Commun. Mass Spectrom. 2011, 25, 423.

Yield 21.0 mg, 80% (hexane/ethyl acetate 70:30); yellow pale oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 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 νmax / cm-1 2982, 2934, 2230, 1729, 1610, 1548, 1378, 1226, 1158, 1090, 1018, 842, 784, 763, 718, 694.

Ethyl 3-(4-methoxyphenyl)-4-nitrobutanoate (5f)3636 Silva, B. V.; Violante, F. A.; Pinto, A. C.; Santos, L. S.; Rapid Commun. Mass Spectrom. 2011, 25, 423.

Yield 18.0 mg, 70% (hexane/ethyl acetate 70:30); brown oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 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 νmax / cm-1 2969, 2833, 1718, 1597, 1545, 1500, 1470, 1432, 1364, 1251, 1176, 1018, 829, 694.

Ethyl 3-(3,4-dimethoxyphenyl)-4-nitrobutanoate (5g)3636 Silva, B. V.; Violante, F. A.; Pinto, A. C.; Santos, L. S.; Rapid Commun. Mass Spectrom. 2011, 25, 423.

Yield 22.3 mg, 75% (hexane/ethyl acetate 70:30); brown oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 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 νmax / cm-1 2969, 2833, 1718, 1597, 1545, 1500, 1470, 1432, 1364, 1251, 1176, 1018, 829, 694.

Ethyl 4-nitro-3-(3,4,5-trimethoxyphenyl)butanoate (5h)3636 Silva, B. V.; Violante, F. A.; Pinto, A. C.; Santos, L. S.; Rapid Commun. Mass Spectrom. 2011, 25, 423.

Yield 31.0 mg, 95% (hexane/ethyl acetate 70:30); yellow solid; m.p. 91-93 °C; 1H NMR (300 MHz, CDCl3) δ 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) δ 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 νmax / cm-1 2946, 2830, 1724, 1591, 1545, 1462, 1421, 1396, 1353, 1319, 1270, 1251, 1217, 1176, 1129, 995, 905, 841, 773, 731.

Ethyl 4-nitro-3-(thiophen-2-yl)butanoate (5i)3636 Silva, B. V.; Violante, F. A.; Pinto, A. C.; Santos, L. S.; Rapid Commun. Mass Spectrom. 2011, 25, 423.

Yield 23.0 mg, 85% (hexane/ethyl acetate 80:20); brown oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 13.9, 35.5, 38.4, 60.9, 79.5, 124.7, 125.4, 126.9, 140.8, 170.2; IR νmax / cm-1 3108, 2985, 1708, 1545, 1432, 1382, 1203, 1176, 1024, 853, 701.

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) δ 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) δ 13.9, 35.6, 37.5, 60.8, 79.0, 122.1 (2C), 126.0 (2C), 126.6, 138.8, 170.5; IR νmax / 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.

Methyl 4-nitro-3-phenylbutanoate (5m)4545 Jensen, K. L.; Poulsen, P. H.; Donslund, B. S.; Morana, F.; Jorgensen, K. A.; Org. Lett. 2012, 14, 1516.

Yield 18.7 mg, 84% (hexane/ethyl acetate 75:25); brown oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 37.4, 40.2, 51.8, 79.3, 127.1 (2C), 127.9, 128.9 (2C), 138.2, 171.0; IR νmax / cm-1 2923, 2846, 1731, 1545, 1430, 1375, 1260, 1159, 1089, 1004, 870, 764, 702.

Methyl 3-(4-methoxyphenyl)-4-nitrobutanoate (5n)4545 Jensen, K. L.; Poulsen, P. H.; Donslund, B. S.; Morana, F.; Jorgensen, K. A.; Org. Lett. 2012, 14, 1516.

Yield 18.2 mg, 72% (hexane/ethyl acetate 80:20); yellow solid; m.p. 84-86 °C; 1H NMR (300 MHz, CDCl3) δ 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) δ 37.6, 39.4, 51.8, 55.3, 79.6, 114.3 (2C), 128.3 (2C), 130.0, 159.1, 171.1; IR νmax / 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; 1H NMR (300 MHz, CDCl3) δ 1.12 (d, 3H, 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) δ 21.6 (2C), 38.0, 40.3, 68.3, 79.5, 127.3 (2C), 127.9, 128.9 (2C), 138.2, 170.0; IR νmax / 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.

Isopropyl 3-(4-methoxyphenyl)-4-nitrobutanoate (5p)

Yield 18.0 mg, 64% (hexane/ethyl acetate 70:30); yellow oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 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 νmax / cm-1 2982, 2934, 1729, 1615, 1553, 1515, 1378, 1256, 1347, 1178, 985, 785; HRMS calculated for [C14H19NO5 + Na]: 304.1161; found: 304.1163.

Butyl 3-(4-methoxyphenyl)-4-nitrobutanoate (5q)

Yield 14.6 mg, 55% (hexane/ethyl acetate 90:10); yellow oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 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 νmax / cm-1 2958, 2934, 1729, 1553, 1615, 1553, 1510, 1382, 1251, 1175, 984, 680; HRMS calculated for [C15H21NO5 + Na]: 318.1317; found: 318.1325.

tert -Butyl 4-nitro-3-phenylbutanoate (5r)

Yield 15.3 mg, 58% (hexane/ethyl acetate 85:25); yellow oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 27.8 (3C), 38.8, 40.5, 79.6, 81.3, 127.4 (2C), 127.9 (2C), 128.9, 138.3, 169.7; IR νmax / 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.

General procedure for the synthesis of g-nitroesters 5s-u

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 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.

Benzyl 4-nitro-3-phenylbutanoate (5s)

Yield 60% (hexane/ethyl acetate 70:30); brown oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 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 νmax / 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.

Allyl 4-nitro-3-phenylbutanoate (5t)

Yield 75% (hexane/ethyl acetate 70:30); brown oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 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 νmax / 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.

Prop-2-ynyl 4-nitro-3-phenylbutanoate (5u)

Yield 65% (hexane/ethyl acetate 80:20); pale yellow oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 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 νmax / 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.

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.

2,2-Dimethyl-5-(2-nitro-1-phenylethyl)-1,3-dioxane-4,6-dione (6a)4646 Li, J. -H.; Li, Z. -G.; Chen, Q. -G.; J. Chem. Res. 2004, 11, 758.

Yield 27.8 mg, 95%; viscous yellow oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 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 νmax / cm-1 2999, 2867, 1781, 1735, 1553, 1329, 1310, 1206, 1110, 758.

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.4747 Schuster, I.; Schuster, P.; Tetrahedron 1969, 25, 199. Yield 22.2 mg, 96%; yellow solid; m.p. 84-85 °C; 1H NMR (300 MHz, CDCl3) δ 1.82 (s, 6H), 7.45-7.56 (m, 3H), 8.06 (d, 2H, J 9.0 Hz), 8.42 (s, 1H); IR νmax / cm-1 2996, 1768, 1729, 1618, 1361, 1289, 1189, 764.

General procedure for the synthesis of β-lactams4848 Menicagli, R.; Samaritani, S.; Tetrahedron 1996, 52, 1425.

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.

4-Phenylpyrrolidin-2-one (14)4848 Menicagli, R.; Samaritani, S.; Tetrahedron 1996, 52, 1425.

Yield 13.2 mg, 82%; brown oil; 1H NMR (300 MHz, CDCl3) δ 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) δ 37.9, 40.2, 49.5, 126.7, 127.0, 128.8, 142.6, 177.8; IR νmax / cm-1 3240, 2923, 2861, 1669, 1496, 1442, 1356, 1255, 1051, 742, 688, 627.

4-(4-Chlorophenyl)pyrrolidin-2-one (15)4848 Menicagli, R.; Samaritani, S.; Tetrahedron 1996, 52, 1425.

Yield 17.0 mg, 87%; brown oil; 1H NMR (300 MHz, CDCl3) δ 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), 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) δ 29.9, 39.9, 49.7, 128.4, 129.3, 133.2, 140.8, 177.8; IR νmax / cm-1 3194, 2923, 2840, 1673, 1485, 1259, 1089, 1006, 824, 718, 666.

General procedure for the synthesis of amino acids Phenibut and Baclofen4949 Corey, E. J.; Zhang, F. -Y.; Org. Lett. 2000, 2, 4257.

Into a round bottom flask, the β-lactam 14 or 15 (0.4 mmol) and 10 mL of HCl (6.0 mol L-1) were added. The mixture was submitted to magnetic stirring at reflux for 12 h. Afterwards, evaporation under vacuum leads to the synthesis of the γ-amino acids.

4-Amino-3-phenylbutanoic acid hydrochloride (Phenibut, 16) 4848 Menicagli, R.; Samaritani, S.; Tetrahedron 1996, 52, 1425.

Yield 18.9 mg, 88%; orange solid; m.p. 188-190 °C; 1H NMR (300 MHz, D2O) δ 2.65 (dd, 1H, J 15.8 and 8.8 Hz), 2.75 (dd, 1H, J 15.8 and 5.3 Hz), 3.10-3.30 (m, 3H), 7.26-7.36 (m, 5H); 13C NMR (75 MHz, D2O) δ 40.7, 42.4, 46.3, 130.3, 130.8, 131.8, 140.8, 177.9; IR νmax / cm-1 3317-2567, 1711, 1590, 1515, 1485, 1402, 1259, 1199, 1146, 972, 860, 761, 701.

4-Amino-3-(4-chlorophenyl)butanoic acid hydrochloride (Baclofen, 17) 4848 Menicagli, R.; Samaritani, S.; Tetrahedron 1996, 52, 1425.

Yield 22.2 mg, 89%; orange solid; m.p. 198-200 °C; 1H NMR (300 MHz, D2O) δ 2.73 (dd, 1H, J 16.4 and 8.8 Hz), 2.86 (dd, 1H, J 16.4 and 5.9 Hz), 3.20-3.48 (m, 3H), 7.33 (d, 2H, J 8.8 Hz), 7.43 (d, 2H, J 8.8 Hz); 13C NMR (75 MHz, D2O) δ 38.4, 39.6, 43.8, 129.4, 129.6, 133.5, 137.1, 175.5; IR νmax / cm-1 3279-2505, 1711, 1590, 1560, 1493, 1410, 1395, 1245, 1194, 1139, 970, 813, 760, 706.

Supplementary Information

Supplementary information (1H NMR and 13C NMR of selected compounds and powder X-ray diffraction of hydrotalcite and calcined hydrotalite) is available free of charge at http://jbcs.sbq.org.br as a PDF file.

https://minio.scielo.br/documentstore/1678-4790/LZRBy6cJ9VFFsHmGXY4hnTw/50ac0af75a5639478e5b472976f295189e4b66d5.pdf
  • FAPERGS/CAPES has sponsored the publication of this article.

Acknowledgments

The authors would like to acknowledge FAPERGS, CNPq (Universal No. 455791/2014-7) and CAPES for their financial support and fellowships (C. R. M. D'O.; J. C. S.; E. P. G.). Fondecyt (11130086 and 1140642), Anillo Cientifico ACT1107, PIEI-UTalca, and Chile CORFO (FCR-CSB 09CEII-6991) are greatly acknowledged

References

  • 1
    Sutoo, D.; Akiyama, K.; Yabe, K.; Hum. Brain Mapp 2000, 11, 93.
  • 2
    Cai, K.; Nanga, R.; Lamprou, L.; Schinstine, C.; Elliott, M.; Hariharan, R.; Epperson, N.; Neuropsychopharmacology 2012, 37, 2764.
  • 3
    Foster, A. C.; Kemp, J. A.; Curr. Opin. Pharmacol 2006, 6, 7.
  • 4
    Touré, B. B.; Hall D. G. In Multicomponent Reactions, 1st ed.; Zhu, J.; Bienaymé H., eds.; Wiley-VCH: Weinheim, Germany, 2005.
  • 5
    Habibi, A.; Rahmani, A.; Helv. Chim. Acta 2011, 94, 1806.
  • 6
    Dömling, A.; Wang, W.; Wang, K.; Chem. Rev 2012, 112, 3083.
  • 7
    Dömling, A.; Chem. Rev. 2006, 106, 17.
  • 8
    Dumas, A. M.; Fillion, E.; Acc. Chem. Res 2010, 43, 440.
  • 9
    Lipson, V. V.; Gorobets, N. Y.; Mol. Divers. 2009, 13, 399.
  • 10
    Ivanov, A. S.; Chem. Soc. Rev 2008, 37, 789.
  • 11
    Climent, M. J.; Corma, A.; Iborra, S.; Chem. Rev. 2011, 111, 1072.
  • 12
    Wang, D.; Zhang, X.; Wei, W.; Sun, Y.; Catal. Commun 2012, 28, 159.
  • 13
    Wang, S. H.; Wang, Y. B.; Dai, Y. M.; Jehng, J. M.; Appl. Catal. , A 2012, 439, 135.
  • 14
    Neves, A. C. B.; Calvete, M. J. F.; Pinho e Melo, T. M. V. D.; Pereira, M. M.; Eur. J. Org. Chem. 2012, 32, 6309.
  • 15
    Winter, F.; van Dillen, A. J.; Jong, K. P.; Chem. Commun. 2005, 31, 3977.
  • 16
    Ebitani, K.; Motokura, K.; Mori, K.; Mizugaki, T.; Kaneda, K.; J. Org. Chem. 2006, 71, 5440.
  • 17
    Valente, J. S.; Cortez, J. H.; Cantu, M. S.; Ferrat, G.; Salinas, E. L.; Catal. Today 2010, 150, 340.
  • 18
    Kshirsagar, S. W.; Patil, N. R.; Samant, S. D.; Tetrahedron Lett. 2010, 51, 2924.
  • 19
    Xu, Z. P.; Zhang, J.; Adebajo, M. O.; Zhang, H.; Zhou, C.; Appl. Clay Sci 2011, 53, 139.
  • 20
    Godoi, M. N.; Costenaro, H. S.; Kramer, E.; Machado, P. S.; D'Oca, M. G. M.; Russowsky, D.; Quim. Nova 2005, 28, 1010.
  • 21
    Russowsky, D.; Benvenutti, E. V.; Roxo, G. S.; Grasel, F.; Lett. Org. Chem. 2007, 4, 39.
  • 22
    Marques, M. V.; Ruthner, M.; Fontoura, L. A. M.; Russowsky, D.; J. Braz. Chem. Soc 2012, 23, 171.
  • 23
    Affeldt, R. F.; Benvenutti, V.; Russowsky, D.; New J. Chem. 2012, 36, 1502.
  • 24
    Costa, J. S.; Lopes, J. P. B.; Russowsky, D.; Petzhold, C. L.; Borges, A. C. A.; Ceschi, M. A.; Konrath, E.; Batassini, C.; Lunardi, P. S.; Gonçalves, C. A. S.; Eur. J. Med. Chem 2013, 62, 556.
  • 25
    Naciuk, F. F.; Vargas, D. Z.; D'Oca, C. R. M.; Moro, C. C.; Russowsky, D.; New J. Chem. 2015, 39, 1643.
  • 26
    Prescott, H. A.; Li, Z. -J.; Kemnitz, E.; Trunschke, A.; Deutsch, J.; Lieske, H.; Auroux, A. J.; J. Catal. 2005, 234, 119.
  • 27
    Bulbule, V. J.; Deshpande, V. H.; Velu, S.; Sudalai, A.; Sivasankar, S.; Sathe, V. T.; Tetrahedron 1999, 55, 9325.
  • 28
    Santos, L. S. In Reactive Intermediates: MS Investigations in Solution; Santos, L. S., ed.; Wiley-VCH: Weinheim, Germany , 2010.
  • 29
    Santos, L. S.; J. Braz. Chem. Soc. 2011, 22, 1827.
  • 30
    Zhao, Z. -X.; Wang, H. -Y.; Guo, Y. -L.; Curr. Org. Chem. 2011, 15, 3734.
  • 31
    Santos, L. S.; Eur. J. Org. Chem. 2008, 235.
  • 32
    Eberlin, M. N.; Eur. J. Mass Spectrom. 2007, 13, 19.
  • 33
    Santos, L. S.; Knaack, L.; Metzger, J.; Int. J. Mass Spectrom 2005, 246, 84.
  • 34
    Peng, H.; Yuan, Z.; Wang, H. -Y.; Guo, Y. -L.; Liu, G.; Chem. Sci. 2013, 4, 3172.
  • 35
    Shankaraiah, N.; Markandeya, N.; Srinivasulu, V.; Sreekanth, K.; Reddy, C. R.; Santos, L. S.; Kamal, A.; J. Org. Chem. 2011, 76, 7017.
  • 36
    Silva, B. V.; Violante, F. A.; Pinto, A. C.; Santos, L. S.; Rapid Commun. Mass Spectrom 2011, 25, 423.
  • 37
    Stoddard, R. L.; Luo, J.; van ver Wal, N.; O'Rourke, N. F.; Wulff, J. E.; McIndoe, J. S.; New J. Chem. 2014, 38, 5382.
  • 38
    Oliveira, C. C.; Marques, M. V.; Godoi, M. N.; Regiani, T.; Santos, V. G.; dos Santos, E. A. F.; Eberlin, M. N.; Sá, M. M.; Correia, C. R. D.; Org. Lett 2014, 16, 5180.
  • 39
    George, L.; Veedu, R. N.; Sheibani, H.; Taherpour, A. A.; Flammang, R.; Wentrup, C.; J. Org. Chem. 2007, 72, 1399.
  • 40
    Sytinsky, K. A.; Soldatenkov, A. T.; Prog. Neurobiol. 1978, 10, 89.
  • 41
    Mann, A.; Boulanger, T.; Brandau, B.; Durant, F.; Evrard, G.; Heaulme, M.; Desaulles, E.; Wermuth, C. G.; J. Med. Chem. 1991, 34, 1307.
  • 42
    Hynes, P. S.; Stupple, P. A.; Dixon, D. J.; Org. Lett. 2008, 10, 1389.
  • 43
    Chang, M. -Y.; Sun, P. -P.; Chen, S. -T.; Chang, N. -C.; Tetrahedron Lett 2003, 44, 5271.
  • 44
    Rodrigues, J. C.; Costa, T. M. H.; Gallas, M. R.; Moro, C. C.; Phys. Chem. Miner. 2009, 36, 439.
  • 45
    Jensen, K. L.; Poulsen, P. H.; Donslund, B. S.; Morana, F.; Jorgensen, K. A.; Org. Lett. 2012, 14, 1516.
  • 46
    Li, J. -H.; Li, Z. -G.; Chen, Q. -G.; J. Chem. Res. 2004, 11, 758.
  • 47
    Schuster, I.; Schuster, P.; Tetrahedron 1969, 25, 199.
  • 48
    Menicagli, R.; Samaritani, S.; Tetrahedron 1996, 52, 1425.
  • 49
    Corey, E. J.; Zhang, F. -Y.; Org. Lett. 2000, 2, 4257.

Publication Dates

  • Publication in this collection
    Feb 2017

History

  • Received
    20 Feb 2016
  • Accepted
    09 June 2016
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