Synthesis of (R)-(+)-3-(1-hydroxyethylidene)-1-(1-phenylethyl)piperidine-2,4-dione, novel Tetramic Acid Analogue

Alan Aguilar-Aguilar; Ángel Palillero-Cisneros; Félix May-Moreno; Jorge R. Juarez-Posadas; Joel L. Terán; David M. Aparicio

doi:10.20944/preprints202604.0354.v1

Submitted:

03 April 2026

Posted:

06 April 2026

You are already at the latest version

Abstract

Herein, starting from (R)-(+)-α-methylbenzylamine, we report an efficient synthesis and full characterization of a new (R)-3-(1-hydroxyethylidene)-1-(1-phenylethyl)piperidine-2,4-dione, a new tetramic acid analogue. The key steps involved a non-classical Corey-Chaykovsky intramolecular cy-clization reaction to access the corresponding zwitterion, followed by a sequential desul-furization/reduction and condensation procedure. The key intermediate was obtained in 5 steps, and the desired product 7 with an overall 58% yield.

Keywords:

(R)-phenylethylamine

;

non-classical Corey-Chaykovsky

;

zwitterion

;

3-acyltetramic acid

Subject:

Chemistry and Materials Science - Organic Chemistry

1. Introduction

Nitrogen-containing heterocycles are formidable chemical structures most widely found in biological and pharmaceutical products. Specifically, 3-acyltetramic acids are produced by a wide range of organisms [1,2,3,4] and have shown interesting pharmaceutical properties, including antibacterial, [5,6] herbicidal, [7] and antitumoral activity [8] (Figure 1, top). This is due to naturally occurring properties that confer a large lipophilic residue on their pyrrolidine-2,4-dione core; they show an amphiphilic or detergent-like character, enabling them to interact with cellular membranes, and can form stable chelate complexes with metal ions [9]. Although pyrrolidinone 3-acyl tetramic acids have been extensively studied, there are scarcely any reports regarding their saturated 6-membered analogues as precursors of pyridone-based natural products mediated by enzyme-catalyzed TrdC Dieckmann cyclization [10,11,12] (Figure 1, bottom). Therefore, the discovery of a new methodology to access these six heterocyclic member substrates in high yields, at low cost, and with a few synthesis steps, represents a main goal in this field.

As a part of our program research efforts directed toward obtaining novel nitrogen heterocyclic intermediates, and taking into account that our research group previously had investigated the preparation of a nitrogen heterocycle compound via zwitterionic intermediates obtained thought a non-classical Corey-Chaykovsky reaction and demonstrated its utility in accessing an important bioactive substance [13], we now applied this experience in the synthesis of the six-member nitrogen heterocycle tetramic acid analogue.

2. Results and Discussion

To synthesize the key intermediate zwitterionic compound 4, we commence by first condensing (R)-(+)-α-methylbenzylamine in methanol with methyl acrylate, followed by an amidation reaction with bromoacetyl bromide in a biphasic medium, which allowed us to get the corresponding haloamide 2 in 98% yield after two steps. Then, 2 was condensed with dimethyl sulfide to access the corresponding sulfonium salt 3, which was subjected under basic conditions to the non-classical Corey-Chaykovsky 6-exo-trig cyclization reaction to generate the desired zwitterionic heterocycle 4. Then, we ventured into the reduction/desulfurization reaction by implementing the conditions reported by Russell et al.,[14] where the use of zinc dust and acetic acid as solvent generated the core piperidine-2,4-dione 5 in 98% yield (Scheme 1).

With compound 5 in hand, we turned our attention to the obtention of the desired 3-Acyl tetramic acid. It is important to mention the immediate employment of compound 5 for the next reaction to avoid the dimerization process [15]. In this sense, we approach this study considering the previously reported work of Moloney et al., [16] in which the acylation sequence is mediated by N,N´-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). As we can see in Table 1, the only use of DMAP or the mixture of DMAP (0.5 equiv.) and DCC, delivered the O-acylated derivative 6, while, when DMAP (1.2 equiv.), and DCC (1.1 equiv) were employed, we obtained the desired 3-acyl tetramic acid 7 in 65% yield in accordance with Moloney's report (Scheme 2).

Table 6. vs C-Acyl 7 from piperidin-2,4-dione 5.

Entry	DMAP (equiv.)	DCC (equiv)	Acylating agent (equiv)	Compound 6 Yield (%)	Compound 7 Yield (%)
1	1	---	Acetyl chloride, (1)	80	---
2	0.1	(1.1)	Acetic acid, (1.1)	85	5
3	0.5	(1.1)	Acetic acid, (1.1)	75	15
4	1.2	(1.1)	Acetic acid, (1.1)	---	65

All experiments were carried out at room temperature.

Structure 7 was fully characterized by NMR spectroscopy. Despite its five-member analogue being described by Moloney as four types of tautomeric enol forms in solution,[16] compound 7 exhibits non-similar behavior, as the ¹H-NMR analysis showed, the presence of only two enol forms is due to the stabilizing intramolecular C−H•••O hydrogen bond usually present in lactams containing the chiral auxiliary a-methylbenzylamine as the chemical shift of the benzylic proton is centered around 6 ppm in each tautomer [17] . The equilibrium is shown by a dynamic internal tautomerization between two, the exo-enol vs endo-enol tautomer, where the methyl group of the minor endo-enol is centered around 2.49 ppm while for the major exo-enol tautomer appears around 2.59 ppm (Figure 2). All shifts’ assignations were confirmed by two-dimensional NMR spectroscopy studies. Finally, the major tautomer is favored due to the more electrophilic character of the exo-ketone in accordance with the previously studied report by Gromak [18].

3. Materials and Methods

3.1. General

All reagents and solvents were purchased from commercial sources. ¹H NMR and ¹³C NMR spectra were recorded at 500 MHz and 125 MHz respectively, in CDCl₃ using a Bruker Avance III Spectrometer. Chemical shifts are given in ppm and reported to the residual solvent peak (CHCl₃ 7.26 ppm and 77.16 ppm). Data are reported as follows: chemical shift (d), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant(s) (J, Hz), and integration. Analytical TLC was performed on silica gel 60F254 plates. Column chromatography was carried out on silica gel 60 (63-200 mm). Mass spectra were recorded on JEOL The JM-Station JMS-700 at a voltage of 70 eV. Optical rotations were measured on Perkin-Elmer 341 polarimeter at room temperature. Infrared spectra were obtained using a Thermo Scientific Nicolet (Waltham, MA, USA).

3.2. Synthesis of Methyl (R)-3-((1-phenylethyl)amino)propanoate (1)

To a solution of (R)-(+)-a-methylbenzylamine (2 g, 16.5 mmol) in methanol (16.5 mL, 1M) was slowly added methyl acrylate (1.80 mL, 19.80mmol), the mixture was stirred at room temperature, until the consumption of total starting material was observed through TLC (24 hours, hexane/ethyl acetate 1:1), the crude reaction was concentrated under reduce pressure, and purified over column chromatography (hexane/ethyl acetate 6:4) to give a colorless oil in quantitative yield.

¹H NMR (500 MHz, CDCl₃) δ 7.38 – 7.21 (m, 6H), 3.80 (q, J = 6.6 Hz, 1H), 3.69 (s, 3H), 2.78 (m, 1H), 2.71 (m, 1H), 2.50 (m, 2H), 1.37 (d, J = 6.5 Hz, 3H). ¹³C NMR (126 MHz, CDCl3) δ 173.5, 145.6, 128.6, 127.1, 126.7, 58.3, 51.7, 43.0, 34.8, 24.6. [α]_D =+ 41.0 (c = 1.0, CHCl₃).

3.3. Synthesis of Methyl (R)-3-(2-bromo-N-(1-phenylethyl)acetamido)propanoate (2)

Methyl (R)-3-((1-phenylethyl)amino)propanoate (16.50 mmol, 3.42 g), was dissolved in 1:1 CH₂Cl₂/H₂O (50/50 mL), and K₂CO₃ (33.00 mmol) was added. The resulting mixture was cooled to 0°C, and bromoacetyl bromide (1.72 mL, 19.80 mmol) was slowly added (dropwise), then warmed to room temperature, and stirred for 12 hours. The crude reaction was extracted with CH₂Cl₂ (3 x 30 mL). The organic phases were combined and dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and then purified by column chromatography on silica gel (hexane/ethyl acetate 6:4), to obtain the pure desired compound as a colorless oil in 98% yield.

¹H NMR (500 MHz, CDCl₃) δ 7.43 – 7.28 (m, 5H), 5.18 (q, J = 6.9 Hz, 1H), 3.98 (m, 2H), 3.62 (s, 3H), 3.52 (m, 2H), 2.43 (m, 2H), 1.70 (m, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 172.1, 166.9, 139.4, 129.0, 128.2, 127.0, 77.4, 77.2, 76.9, 56.7, 51.7, 39.3, 32.7, 26.5, 18.1. [α]_D = +78.6 (c = 1.0, CH₂Cl₂).

3.4. Synthesis of (R)-(2-((3-methoxy-3-oxopropyl)(1-phenylethyl)amino)-2-oxoethyl)dimethylsulfonium bromide (3)

To a solution of methyl (R)-3-(2-bromo-N-(1-phenylethyl)acetamido)propanoate (1 g, 3.04 mmol) in methanol (3 mL, 1M), was added dimethyl sulfide (1.8 mL, 24.36 mmol) at room temperature, and the reaction was stirred for 24 hours. The crude was concentrated under vacuum, and the resulting solid was recrystallized (CH₂Cl₂/ethyl acetate 1:3) to give a white solid in a 93% yield.

¹H NMR (500 MHz, CDCl₃) δ 7.27–7.40 (m,5H), 5.94 (d, J = 10.8,1H), 5.66 (d, J = 10.8, 1H), 5.19 (q, J = 6.9, 1H), 3.55 (s, 3H,), 3.41 (m, 2H), 3.34 (s, 3H,), 3.30 (s, 3H,), 2.37 (m, 2H), 1.70 (d, J = 6.9, 3H,). ¹³C NMR (126 MHz, CDCl₃) δ 171.2, 163.6, 126.4, 138.7, 55.9, 51.3, 49.2, 32.1, 26.8, 24.7, 17.2. [α]_D = +142.0 (c = 2.0, EtOH).

3.5. Synthesis of (R)-5-(dimethylsulfonio)-6-oxo-1-(1-phenylethyl)-1,2,3,6-tetrahydropyridin-4-olate (4)

(R)-(2-((3-methoxy-3-oxopropyl)(1-phenylethyl)amino)-2-oxoethyl)dimethylsulfonium bromide (1.10 g, 2.83 mmol) was dissolved in methanol (2.83mL, 1M), then KOH (0.31 g, 5.67 mmol) was added in one portion at room temperature, and the mixture was stirred for 1 hour. Finally, the crude was filtered over celite and concentrated by reduced pressure; the resulting solid was recrystallized (CH₂Cl₂/hexane 1:3) to give a white solid in quantitative yield.

¹H NMR (500 MHz, CDCl₃) δ 7.36 – 7.22 (m, 5H), 5.95 (q, J = 7.1 Hz, 1H), 3.19 (ddd, J = 12.4, 8.0, 6.4 Hz, 1H), 3.00 (s, 3H), 2.90 (m, 1H), 2.32 (m, 2H), 1.51 (d, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 188.2, 166.8, 141.7, 128.4, 127.3, 127.1, 74.5, 49.6, 38.3, 37.1, 27.0, 26.7, 16.0. M.P. 139°C - 140°C, [α]_D = +70.5 (c = 1.0, MeOH).

3.6. Synthesis of (R)-1-(1-phenylethyl)piperidine-2,4-dione (5)

To a solution of (R)-5-(dimethylsulfonio)-6-oxo-1-(1-phenylethyl)-1,2,3,6-tetrahydropyridin-4-olate (0.1 g, 0.36 mmol) in glacial acetic acid (0.36 mL, 1M) at room temperature was added in one portion zinc dust (0.35 g, 5.340 mmol), the reaction mixture was stirred for 24 hours. Ethyl acetate was added (10 mL), and the crude was filtered over a thin bed of silica gel. The organic phase was washed with brine, dried over Na₂SO_4, and concentrated under reduced pressure to give a pale-yellow oil in a 98% yield.

¹H NMR (500 MHz, CDCl₃) δ 7.25 (m, 5H), 5.98 (q, J = 7.2 Hz, 1H), 3.35 (s, 2H), 3.31 (m, 1H), 3.08 (m, 1H), 2.38 (m, 1H), 2.23 (m, 1H), 1.48 (d, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ ¹³C NMR (126 MHz, CDCl₃) δ 204.0, 166.2, 139.6, 128.8, 127.9, 127.3, 50.5, 49.6, 38.9, 37.6, 15.7. [α]_D = +7.1 (c = 1.0, CH₂Cl₂).

3.7. Synthesis of (R)-6-oxo-1-(1-phenylethyl)-1,2,3,6-tetrahydropyridin-4-yl acetate (6)

To a solution of acetic acid (0.057 mL, 1.0 mmol) in CH₂Cl₂ were added DCC (0.208 g, 1.0 mmol), (R)-1-(1-phenylethyl)piperidine-2,4-dione (0.2 g, 0.92 mmol), and DMAP (0.010 g, 0.09 mmol). The mixture was stirred for 24 hours at room temperature. The crude reaction mixture was extracted with CH₂Cl₂. Concentration in vacuo followed by flash chromatography (hexane/ethyl acetate 7:3) over silica gel gives the mixture of products 6, 85% yield as a colorless oil and 7, 5% yield as a pale-yellow oil.

Compound 6: ¹H NMR (500 MHz, CDCl₃) δ 7.39 – 7.24 (m, 5H), 6.00 (q, J = 7.1 Hz, 1H), 5.85 (s, 1H), 3.32 (ddd, J = 12.4, 9.2, 6.2 Hz, 1H), 3.01 (ddd, J = 12.7, 6.9, 6.1 Hz, 1H), 2.50 – 2.38 (m, 2H), 2.20 (s, 3H), 1.53 (d, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ ¹³C NMR (126 MHz, CDCl₃) δ 167.8, 164.8, 159.5, 140.6, 128.6, 127.5, 127.3, 111.7, 49.5, 38.9, 27.4, 21.2, 15.7. [α]_D =+43.1 (c 0.96, CH₂Cl₂).

Compound 7: ¹H NMR (500 MHz, CDCl₃) δ 7.33 – 7.16 (m, 7H), 5.92 (q, J = 7.1 Hz, 1H), 3.18 (tdd, J = 17.4, 8.6, 5.9 Hz, 1H), 2.91 (tt, J = 11.8, 6.0 Hz, 1H), 2.43 – 2.27 (m, 3H), 1.50 (d, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 198.2, 195.6, 192.4, 191.5, 171.7, 164.2, 140.7, 139.3, 128.8, 128.6, 128.0, 127.5, 127.3, 127.3, 107.2, 102.7, 50.5, 49.7, 37.8, 37.5, 36.8, 33.8, 26.2, 25.1, 15.8, 15.6. [α]_D =+354.6 (c 1.0, CH₃OH).

3.8. Synthesis of (R)-(+)-3-(1-hydroxyethylidene)-1-(1-phenylethyl)piperidine-2,4-dione (7)

To a solution of acetic acid (0.028 mL, 0.50mmol) in CH₂Cl₂ were added DCC (0.104 g, 0.50 mmol), (R)-1-(1-phenylethyl)piperidine-2,4-dione (0.1 g, 0.46 mmol), and DMAP (0.067 g, 0.55 mmol). The mixture was stirred overnight at room temperature. The crude reaction mixture was washed with CH₂Cl₂. Concentration in vacuo followed by flash chromatography (hexane/ethyl acetate 8:2) over silica gel gives the desired product as a pale-yellow oil in a 65% yield.

¹H NMR (500 MHz, CDCl₃) δ 7.33 – 7.16 (m, 7H), 5.92 (q, J = 7.1 Hz, 1H), 3.18 (tdd, J = 17.4, 8.6, 5.9 Hz, 1H), 2.91 (tt, J = 11.8, 6.0 Hz, 1H), 2.43 – 2.27 (m, 3H), 1.50 (d, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 198.2, 195.6, 192.4, 191.5, 171.7, 164.2, 140.7, 139.3, 128.8, 128.6, 128.0, 127.5, 127.3, 127.3, 107.2, 102.7, 50.5, 49.7, 37.8, 37.5, 36.8, 33.8, 26.2, 25.1, 15.8, 15.6. [α]_D =+354.6 (c 1.0, CH₃OH), HRMS (FAB): Calcd for C₁₅H₁₈NO₃: 260.1287 Found: 260.1282.

In conclusion, we have developed an efficient six-step synthesis of (R)-(+)-3-(1-hydroxyethylidene)-1-(1-phenylethyl)piperidine-2,4-dione starting from (R)-(+)-a-methylbenzylamine with an overall of 58% yield as a new tetramic acid analogue. The methodology highlights the utility of the non-classical Corey-Chaykovsky reaction to access zwitterionic intermediates and their subsequent transformation into new six-membered nitrogen heterocycles, which opens the possibility to access novel biologically important tetramic acid analogues. NMR studies confirmed that this kind of tetramic acid exists as a dynamic mixture of two enol tautomers, with the exo-enol form being predominant.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/doi/s1.

Author Contributions

Conceptualization, D.M.A. and J.L.T.; methodology, A.A.A. and F.M.M.; validation, A. P.C., D.M.A. and J.L.T.; formal analysis, A.A.A.; investigation, J.L.T.; resources, J.R.J.P.; data curation, J.R.J.P.; writing—original draft preparation, J.L.T.; writing—review and editing, D.M.A.; visualization, J.L.T. and D.M.A.; funding acquisition, J.L.T. and D.M.A. All authors have read and agreed to the published version of the manuscript.

Funding

The authors thank the Secretariat of Science, Humanities, Technology, and Innovation (SECIHTI) for its financial support for project CBF-2025-I-1805 and project CBF-2025-I-2262.

Data Availability Statement

Data presented in this study are included in the Supplementary Materials.

Acknowledgments

F.M.M. thanks SECIHTI for the Scholarship 2086645. The author thanks FAP and HAR for technical support in the laboratory.

Conflicts of Interest

The authors declare no conflicts of interest

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Figure 1. - Examples of pyrrolidin- and piperidin-, 3-acyltetramic acids show interesting biological properties.

Scheme 1. Synthesis of piperidine-2,4-dione 5 starting from (R)-(+)-α-methylbenzylamine.

Scheme 2. Synthesis of o-acyl or c-acyl compounds.

Figure 2. ¹H-NMR spectra of tautomeric enol forms in the solution of compound 7.

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