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Communication

Synthesis of Methyl 2-((4R)-3-Acryloyl-4-phenyloxazolidin-2-yl)acetates

by
Hugo Pilotzi Xahuentitla
1,*,
Jesús Guadalupe Ortega Montes
1,
Dino Hernán Gnecco Medina
1,
Joel Luis Terán Vázquez
1,
Emanuel Hernández Núñez
2 and
Maria Laura Orea Flores
1,*
1
Centro de Química del Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla., Edif. IC9 Complejo de Ciencias C.U., Puebla 72570, Mexico
2
Departamento de Estudios de Posgrado e Investigación del Instituto Tecnológico Superior del Calkiní en el Estado de Campeche (ITESCAM), Av. AH Canun S/N San Felipe, Calkiní 24900, Mexico
*
Authors to whom correspondence should be addressed.
Molbank 2024, 2024(4), M1903; https://doi.org/10.3390/M1903
Submission received: 11 October 2024 / Accepted: 21 October 2024 / Published: 23 October 2024
(This article belongs to the Section Organic Synthesis and Biosynthesis)

Abstract

:
The chiral oxazolidine moiety is an important core in asymmetric synthesis due to its ability to participate in various stereoselective chemical reactions and because it forms part of more complex and important active compounds. Therefore, in this letter we report a convenient diastereoselective and practical strategy for the synthesis of chiral methyl 2-((4R)-3-acryloyl-4-phenyloxazolidin-2-yl)acetates, starting from (R)-(–)-2-phenylglycinol and methyl propiolate, which were obtained via two simple chemical and stereoselective reactions.

1. Introduction

Oxazolidines are five-membered heterocycles that contain an oxygen and nitrogen atom in the 1,3 positions [1]. Chiral oxazolidines are moieties in biologically active compounds [2,3] and act as intermediate materials in the asymmetric synthesis of various compounds [4,5]. Additionally, chiral oxazolidines have been used as catalysts [6,7] and as possible drugs [8,9].
Oxazolidines are mainly synthesized by the reaction of an amino alcohol with an aldehyde or a ketone; however, there are more synthetic methods to obtain them [10,11]. The optimization of routes for stereoselective synthesis of functionalized chiral oxazolidines in particular has received a great deal of effort [12,13].
In this sense, Agami and coworkers in 2002 reported the synthesis of methyl 2-((4R)-3-acryloyl-4-phenyloxazolidin-2-yl)acetate in a yield of 38% as a byproduct of an attempted aza-annulation reaction between a β-enaminoester derived from (R)-(−)-2-phenylglycinol and acryloyl chloride [14]. They argued that the poor performance of oxazolidine was due to the trimerization of the corresponding β-enaminoester.
Considering the above, in this communication we report a straightforward methodology for synthesizing specifically these methyl 2-((4R)-3-acryloyl-4-phenyloxazolidin-2-yl)acetates as the main product.

2. Results

2.1. Synthesis of Chiral Acrylamides

In this synthesis, to access methyl 2-(4R)-3-acryloyl-4-phenyloxazolidin-2-yl)acetates, we begin with the preparation of the respective chiral acrylamides 4 and 5, through the condensation reaction of (R)-(−)-2-phenylglycinol 1 and the corresponding acryloyl chlorides 2 or 3, in a biphasic system CH2Cl2:H2O (1:1), with K2CO3, r.t. for 2 h (completion of the reaction monitored by TLC) [15]. Chiral acrylamides 4 and 5 were obtained in yields greater than 90% after purification by column chromatography of SiO2 (Scheme 1).
Compounds 4 and 5 were successfully characterized by 1H and 13C NMR spectra. Those spectra show, respectively, the characteristic signals for the vinyl H for 4 at 5.7 ppm (d, J = 11.5 Hz), 6.12 ppm(dd, J = 10.5, 17.0 Hz), and 6.29 ppm (d, J = 15.5 Hz), and 5 at 6.39 ppm (d, J = 15.5 Hz), and 7.60 ppm (d, J = 15.5 Hz). On the other hand, in the 13C NMR spectra, the signal corresponding to the carbonyl group can be observed at 166.0 ppm for 4 and 166.3 ppm for 5 (please refer to the Supplementary Material).

2.2. Synthesis of Methyl 2-(4R)-3-Acryloyl-4-phenyloxazolidin-2-yl)acetates, 7 and 8

The next step was the condensation reaction between the chiral acrylamides and methyl propiolate 6. To a stirred solution of the corresponding acrylamide in acetonitrile at 0 °C, DABCO (10 mol%) was added. Subsequently, methyl propiolate was added drop-by-drop [16]. The reaction mixture was kept stirring for an additional 2 h. After purification by column chromatography of the reaction crude, we obtained the chiral oxazolidines 7 and 8, in yields greater than 80% and d.r. around 70:30 (Scheme 2).
Additionally, we conducted experiments with acrylamide 4, under the same conditions’ reactions, but using alternative bases to determine if the diastereomeric ratio could be improved. However, the consumption of acrylamide was not observed. The results of these experiments are presented in Table 1.
The diastereomeric ratio for each 4-phenyloxazolidine 7(a,b) and 8(a,b) was determined in the 1H NMR spectrum of the crude reaction, with the signal assigned to H-Bn. The spectrum of the diastereomeric mixture of 7(a,b) shows two signals appearing at 4.34 ppm (dd, J = 6.5, 8.5 Hz) for the major diastereoisomer and at 4.47 ppm (dd, J = 6.0, 8.5 Hz) for the minor diastereoisomer, yielding a d.r. = 74:26. On the other hand, the spectrum of the diastereomeric mixture of 8(a,b) shows signals at 4.37 ppm (dd, J = 6.5, 9.0 Hz) for the major diastereoisomer and at 4.51 ppm (dd, J = 6.0, 8.5 Hz) for the minor diastereoisomer, with a d.r. = 67:33. Furthermore, in the 13C NMR spectra, the signals corresponding to the hemiaminal carbon for each pair of diastereoisomers appear at around 87 ppm (please refer to the Supplementary Material).
We successfully separated the diastereoisomers from mixture 7(a,b) using column chromatography (SiO2, hexane:AcOEt, 70:30). The pure diastereoisomers 7a and 7b were analyzed by a NOESY-NMR experiment to determine the relative configuration of the new chiral center generated, which was established as (2R,4R) for 7a (major diastereoisomer) and (2S,4R) for 7b (minor diastereoisomer) (Figure 1). Please refer to the Supplementary Material.

3. Discussion

The condensation of (R)-()-2-phenylglycinol 1 with acryloyl chlorides 2 and 3 resulted in the formation of chiral acrylamides 4 and 5 in good chemical yields. The reaction was very chemoselective and clean, and no byproducts were observed.
In the second step, the condensation of chiral acrylamides 4 and 5 with methyl propiolate 6 was catalyzed with DABCO (10 mol%), maintaining the temperature at 0 °C. This facilitated the preparation of the chiral oxazolidines 7(a,b) and 8(a,b), in acceptable diastereomeric ratios. It is important to carry out the reaction at 0 °C because the various reactive sites of methyl propiolate 6 can lead to the formation of byproducts [17].
It should be noted that the 1H NMR analysis of the diastereomeric mixtures did not allow for the assignment of the relative configuration of the new chiral center. Consequently, we purified the diastereomeric mixture 7(a,b) by column chromatography (SiO2, hexane:AcOEt, 70:30) and were able to assign the configuration for each diastereoisomer. The relative configuration of the new chiral stereogenic center was deduced from correlations observed in the NOESY/NMR spectra of each diastereoisomer. The major diastereoisomer 7a was assigned the (2R,4R) configuration because of the correlation between benzylic hydrogen and the hydrogen located at the hemiaminal position, and the minor diastereoisomer 7b was determined to have the (2S,4R) configuration. The same behavior is expected for the mixture of compound 8(a,b).
As derived from these results, a plausible mechanism for the catalytic process is described. Initially, an aza-Michael addition of DABCO to methyl propiolate affords a zwitterionic allenolate intermediate [16,17], which abstracts a proton from the NH group of acrylamides. This process results in forming a DABCO-methyl acrylate adduct and the corresponding acrylimidate. The acrylimidate undergoes a second aza-Michael addition at the β-carbon of the adduct, generating another allenolate intermediate. Finally, an alkoxide is formed, which initiates a nucleophilic attack at β-carbon. Through this process, DABCO is regenerated, leading to the formation of the corresponding 4-phenyloxazolidine via final proton transfer (Scheme 3).
It is important to note that these highly functionalized oxazolidines have great potential as intermediates in the asymmetric synthesis of piperidine-derived alkaloids.

4. Materials and Methods

4.1. General

All commercial reagents and solvents were used without any further purification. The NMR spectra were recorded on a 500 MHz Bruker spectrophotometer, with CDCl3 as the solvent and TMS as the reference. The optical rotations were determined at room temperature using a PerkinElmer 341 polarimeter with a 1 dm cell holding a total volume of 1 mL and reference to the sodium D line. Infrared spectra were obtained using an ATR PerkinElmer spectrophotometer. Reactions were monitored by TLC on silica gel 60 F254 plates (Merck).

4.2. Synthesis of Chiral Acrylamides

To a solution of (R)-(−)-2-phenylglycinol 1 (1.45 mmol) in CH2Cl2 (2 mL), was added K2CO3 (2.18 mmol) in H2O (2 mL), then stirred. Afterwards, acryloyl chloride 2 or 3 (2.00 mmol) was added dropwise. The reaction was stirred for 2.0 h at room temperature and monitored by TLC (CH2Cl2:MeOH, 95:5). When the reaction ended, extractions were carried out with CH2Cl2 (3 × 15 mL). The organic phase was dried with anhydrous Na2SO4, filtered, and subsequently the solvent was concentrated under reduced pressure. The residue was purified by column chromatography on SiO2 (CH2Cl2:MeOH, 80:20).
(R)-N-(2-Hydroxy-1-phenylethyl)acrylamide 4 in 90% yield as white solid, melting point 120–123 °C, [α]D20 -119.0 (c 1, CH2Cl2). 1H NMR (500 MHz, CDCl3) δ ppm 3.88 (d, J = 5.0 Hz, 2H-CH2), 5.10 (dd, J = 5.5, 12.5 Hz, 1H-Bn), 5.66 (d, J = 11.5 Hz, 1H-CH2), 6.12 (dd, J = 10.5 Hz, 17.0 Hz, 1H-CH), 6.29 (d, J = 15.5 Hz, 1H-CH2), 6.51 (d, J = 7.0 Hz, 1H-NH), 7.26 (m, 5H-Ph) (Figure S1). 13C NMR (150 MHz, CDCl3) δ ppm 56.0, 66.4, 126.8, 127.4, 128.0, 128.9, 130.4, 138.8, 166.0 (Figure S2). IR: 1537, 1626, 3307 cm−1 (Figure S3).
(R,E)-3-(4-Fluorophenyl)-N-(2-hydroxy-1-phenylethyl)acrylamide 5 in 85% yield as white solid, melting point 157–160 °C, [α]D20 + 19.4 (c 1, CH2Cl2). 1H NMR (500 MHz, CDCl3) δ ppm 2.91 (s, 1H-OH), 3.93 (m, 2H-CH2), 5.19 (dd, J = 6.0, 11.0 Hz, 1H-Bn), 6.39 (d, J = 15.5 Hz, 1H-CH), 6.43 (d, J = 7.0 Hz, 1H-NH), 7.03 (t, J = 8.5 Hz, 2H-Ar), 7.30 (m, 5H-Ph), 7.45 (dd, 5.5, 9.0 Hz, 2H-Ar), 7.60 (d, J = 15.5 Hz, 1H-CH) (Figure S4). 13C NMR (150 MHz, CDCl3) δ ppm 56.3, 66.8, 115.9, 116.1 119.8, 126.8, 128.1, 129.0, 129.7, 129.8, 130.8, 138.7, 140.8, 166.3 (Figure S5). IR: 698, 1224, 1657, 3308 cm−1 (Figure S6).

4.3. Synthesis of Methyl 2-(4R)-3-Acryloyl-4-phenyloxazolidin-2-yl)acetates

To a solution of chiral acrylamide 4 or 5 (3.5 mmol) in CH3CN (10 mL) at 0 °C was added DABCO (10 mol%) in CH3CN (2 mL), and the mixture was stirred. Then, methyl propiolate 6 (5.26 mmol) was added dropwise. The reaction was stirred for 2.0 h at 0 °C and monitored by TLC (SiO2, CH2Cl2:MeOH, 95:5). When the reaction ended, the solvent was evaporated under reduced pressure. Then, the mixture was purified by column chromatography (SiO2, Hexane:AcOEt, 70:30).
Methyl 2-((4R)-3-acryloyl-4-phenyloxazolidin-2-yl)acetate 7(a,b) in 86% yield as a yellow pale oil, d.r. 74:26. 1H NMR (500 MHz, CDCl3) δ ppm 2.72 (m, H-CH2), 3.31 (d, J = 15.5 Hz, 1H-CH2), 3.44 (d, J = 15.0 Hz, 1H-CH2), 3.73 (s, H-OMe), 3.95 (d, J = 9.0 Hz, 1H-CH2), 4.06 (dd, J = 3.0, 8.5 Hz, 1H-CH2), 4.34 (dd, J = 6.5, 8.5 Hz, 1H-Bn), 4.48 (d, J = 6.0, 8.5 Hz, 1H-Bn), 5.02 (m, 1H-CH2), 5.48 (dd, J = 2.0, 10.5 Hz, 1H-CH2), 5.58 (d, J = 10.0 Hz, 1H-CH2), 5.88 (d, J = 7.5 Hz, 1H-CH2), 6.05 (dd, J = 10.5, 17.0 Hz, 1H-CH), 6.15 (dd, J = 2.5, 8.0 Hz, 1H-CH2), 6.25 (d, 16.5 Hz, 1H-CH2), 6.36 (d, J = 17.0 Hz, 1H-CH2), 7.21 (m, H-Ph) (Figure S7). 13C NMR (150 MHz, CDCl3) δ ppm 37.4, 38.9, 51.9, 52.0, 60.3, 60.3, 73.7, 74.0, 87.8, 88.0, 125.8, 125.9, 128.2, 128.4, 128.6, 129.2, 129.2, 129.4, 139.9, 141.3, 163.7, 165.1, 170.1, 170.3 (Figure S8). IR: 699, 1423, 1649, 1735 cm−1 (Figure S9).
Methyl 2-((2R,4R)-3-acryloyl-4-phenyloxazolidin-2-yl)acetate 7a, [α]D20 −26.1 (c 0.4, CH2Cl2). 1H NMR (500 MHz, CDCl3) δ ppm 2.72 (dd, J = 8.5, 15.0 Hz, 1H-CH2), 3.45 (d, J = 15.5 Hz, 1H-CH2), 3.75 (s, 3H-OMe), 4.07 (dd, J = 3.5, 8.5 Hz, 1H-CH2), 4.35 (dd, J = 6.5, 9.0 Hz, 1H-CH2), 5.04 (s, 1H-Bn), 5.59 (d, J = 10.0 Hz, 1H-CH2), 5.89 (dd, J = 3.5, 8.5 Hz, 1H-O-CH-N), 6.09 (d, J = 10.0, 16.5 Hz, 1H-CH), 6.38 (d, J = 17.0 Hz, 1H-CH2), 7.28 (5H-Ph) (Figure S10). 13C NMR (150 MHz, CDCl3) δ ppm 29.7, 38.9, 52.0, 60.3, 74.1, 87.8, 125.9, 128.2, 128.3, 129.2, 129.4, 139.8, 165.1, 170.2 (Figure S11). See COSY and NOESY spectra in Figures S12 and S13, respectively.
Methyl 2-((2S,4R)-3-acryloyl-4-phenyloxazolidin-2-yl)acetate 7b, [α]D20 −49.5 (c 0.5, CH2Cl2). 1H NMR (500 MHz, CDCl3) δ ppm 2.72 (dd, J = 8.5, 16.0 Hz, 1H-CH2), 3.32 (dd, J = 2.5, 15.5 Hz, 1H-CH2), 3.75 (s, 3H-OMe), 3.96 (dd, J = 2.5, 9.0 Hz, 1H-CH2), 4.47 (dd, J = 6.0, 9.0 Hz, 1H-Bn), 5.00 (d, J = 6.5 Hz, 1H-CH2), 5.47 (d, J = 10.5 Hz, 1H-CH2), 6.04 (dd, J = 10.5, 16.5 Hz, 1H-CH), 6.15 (dd, J = 3.0, 8.0 Hz, 1H-O-CH-N), 6.26 (d, J = 16.5 Hz, 1H-CH2), 7.21 (5H-Ph) (Figure S14). 13C NMR (150 MHz, CDCl3) δ ppm 29.7, 37.4, 51.9, 60.3, 73.7, 88.0, 125.8, 128.2, 128.5, 128.6, 129.1, 141.3, 163.7, 170.2 (Figure S15). See COSY and NOESY spectra in Figure S16 and Figure S17, respectively.
Methyl 2-((4R)-3-((E)-3-(4-fluorophenyl)acryloyl)-4-phenyloxazolidin-2-yl)acetate 8(a,b) in 81% yield as a yellow pail oil, d.r. 67:33. 1H NMR (500 MHz, CDCl3) δ ppm 2.77 (dd, J = 8.5, 16.0 Hz, H-CH2), 3.34 (dd, J = 3.0, 16.0 Hz, 1H-CH2), 3.46 (d, J = 15.5 Hz, 1H-CH2), 3.74 (s, 3H-OMe), 3.75 (s, 3H-OMe), 3.93 (d, J = 5.0 Hz, 1H-CH), 3.99 (dd, J = 2.0, 9.0 Hz, 1H-CH2), 4.08 (dd, J = 4.0, 9.0 Hz, 1H-CH2), 4.37 (dd, J = 6.5, 8.5 Hz, 1H-Bn), 4.51 (dd, J = 6.0, 8.5 Hz, 1H-Bn), 5.09 (m, H-CH2), 5.95 (d, J = 7.0 Hz, 1H-CH), 6.19 (dd, J = 3.0, 8.0 Hz, 1H-CH), 6.25 (d, J = 7.5 Hz, 1H-CH2), 6.05 (dd, J = 10.5, 17.0 Hz, 1H-CH), 6.15 (dd, J = 2.5, 8.0 Hz, 1H-CH2), 6.25 (d, 15.5 Hz, 1H-CH), 6.30 (d, J = 15.0 Hz, 1H-CH), 6.46 (d, J = 15.5 Hz, 1H-CH), 6.93 (m, H-Ph), 7.18 (m, H-Ar), 4.27 (m, H-Ph) (Figure S18). 13C NMR (150 MHz, CDCl3) δ ppm 37.5, 39.0, 51.9, 52.0, 56.1, 60.4, 60.6, 66.4, 73.7, 74.1, 87.9, 88.1, 115.8, 115.8, 115.8, 115.9, 116.0, 116.0, 118.0, 118.6, 120.3, 120.3, 139.2, 140.0, 140.2, 141.3, 141.4, 142.1, 162.5, 162.6, 162.7, 164.0, 164.5, 164.6, 164.7, 165.4, 166.2, 170.2, 170.3 (Figure S19). IR: 700, 1508, 1650, 1734 cm−1 (Figure S20).

5. Conclusions

In this communication, we report a simple two-step synthesis of two N-acryloyl-4-phenyloxazolidines 7(a,b) and 8(a,b) from chiral acrylamides 4 and 5 derived from (R)-(−)-2-phenylglycinol 1 and their condensation with methyl propiolate 6, catalyzed by DABCO. These compounds obtained in good chemical and stereochemical yields as mixtures of diastereoisomers show significant potential for functionalization, providing access to compounds that may exhibit biological activity. Finally, it is worth highlighting that we successfully purified the diastereomeric mixture of 7, which is the first time that each diastereomer 7a and 7b has been individually described.

Supplementary Materials

IR and NMR spectra of compounds are available online.

Author Contributions

Conceptualization, H.P.X.; performing synthesis, J.G.O.M.; investigation, D.H.G.M.; resources, M.L.O.F. and D.H.G.M.; writing—original draft preparation, H.P.X.; review and editing, J.L.T.V. and E.H.N.; supervision, M.L.O.F. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the VIEP-BUAP, grant number 100130955-VIEP 2023.

Data Availability Statement

Data are contained within the article and Supplementary Material.

Acknowledgments

H.P.X thanks CONAHCYT for the Postdoctoral Scholarship 592119. J.G.O.M thanks CONAHCYT for the Scholarship 1298566.

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Cordero, F.M.; Giomi, D.; Lascialfari, L. Five-Membered Ring Systems. With O and N Atoms. In Progress in Heterocyclic Chemistry; Elsevier Ltd.: Amsterdam, The Netherlands, 2013; Volume 25, pp. 291–317. [Google Scholar] [CrossRef]
  2. Qian, X.; Xu, X.; Li, Z.; Li, Z.; Song, G. Syntheses, Structures and Bioactivities of Fluorine-Containing Phenylimino-Thia(Oxa)Zolidine Derivatives as Agricultural Bioregulators. J. Fluor. Chem. 2004, 125, 1609–1620. [Google Scholar] [CrossRef]
  3. Morales-Monarca, G.-H.; Gnecco, D.; Terán, J.L. Diastereoselective Functionalization of Chiral N-Acyl-1,3-oxazolidines and Their Applications in the Synthesis of Bioactive Molecules. Eur. J. Org. Chem. 2022, 33. [Google Scholar] [CrossRef]
  4. Carbonnelle, A.-C.; Gotta, V.; Roussi, G. β-Amino alcohol-N-oxides as precursors of chiral oxazolidines: Synthesis of (R)-(-)-cryptostyline I. Heterocycles 1993, 36, 1763–1769. [Google Scholar] [CrossRef]
  5. Pytkowicz, J.; Stéphany, O.; Marinkovic, S.; Inagaki, S.; Brigaud, T. Straightforward Synthesis of Enantiopure (R)- and (S)-Trifluoroalaninol. Org. Biomol. Chem. 2010, 8, 4540–4542. [Google Scholar] [CrossRef] [PubMed]
  6. Kang, Y.F.; Wang, R.; Liu, L.; Da, C.S.; Yan, W.J.; Xu, Z.Q. Enantioselective Alkynylation of Aromatic Aldehydes Catalyzed by New Chiral Oxazolidine Ligands. Tetrahedron Lett. 2005, 46, 863–865. [Google Scholar] [CrossRef]
  7. Pichon-Barré, D.; Zhang, Z.; Cador, A.; Vives, T.; Roisnel, T.; Baslé, O.; Jarrige, L.; Cavallo, L.; Falivene, L.; Mauduit, M. Chiral Oxazolidines Acting as Transient Hydroxyalkyl-Functionalized N-Heterocyclic Carbenes: An Efficient Route to Air Stable Copper and Gold Complexes for Asymmetric Catalysis. Chem. Sci. 2022, 13, 8773–8780. [Google Scholar] [CrossRef] [PubMed]
  8. Khrapova, A.V.; Saroyants, L.V.; Yushin, M.Y.; Zukhairaeva, A.S.; Velikorodov, A.V. Prospects of Using Pharmacologically Active Compounds for the Creation of Antimycobacterial Drugs. Pharm. Chem. J. 2022, 55, 1108–1114. [Google Scholar] [CrossRef]
  9. Santos, R.V.C.; Cunha, E.G.C.; de Mello, G.S.V.; Rizzo, J.Â.; de Oliveira, J.F.; de Lima, M.D.C.A.; Pitta, I.D.R.; Pitta, M.G.D.R.; Rêgo, M.J.B.M. New Oxazolidines Inhibit the Secretion of Ifn-γ and Il-17 by Pbmcs from Moderate to Severe Asthmatic Patients. Med. Chem. 2021, 17, 289–297. [Google Scholar] [CrossRef] [PubMed]
  10. Bergmann, E.D. The Oxazolidines. Chem. Rev. 1953, 53, 309–352. Available online: https://pubs.acs.org/doi/pdf/10.1021/cr60165a005?casa_token=c5gTUV5TSy0AAAAA:bJvrnoQca-SUnvzNdfG9X9fOpZLUAFQehdKNJiUWRpCWP2uqbDa3cPfzhH6toVcZawywHXc9T4n5_ctv_Q (accessed on 17 July 2024). [CrossRef]
  11. Reyes-Bravo, E.; Gnecco, D.; Juárez, J.R.; Orea, M.L.; Bernès, S.; Aparicio, D.M.; Terán, J.L. Diastereoselective Synthesis of New Zwitterionic Bicyclic Lactams, Scaffolds for Construction of 2-Substituted-4-Hydroxy Piperidine and Its Pipecolic Acid Derivatives. RSC Adv. 2022, 12, 4187–4190. [Google Scholar] [CrossRef] [PubMed]
  12. Das, A.; Buzzetti, L.; Puriņš, M.; Waser, J. Palladium-Catalyzed Trans-Hydroalkoxylation: Counterintuitive Use of an Aryl Iodide Additive to Promote C-H Bond Formation. ACS Catal. 2022, 12, 7565–7570. [Google Scholar] [CrossRef] [PubMed]
  13. Feng, H.; Zhang, Y.; Zhang, Z.; Chen, F.; Huang, L. Copper-Catalyzed Annulation/A 3 -Coupling Cascade: Diastereodivergent Synthesis of Sterically Hindered Monocyclic Oxazolidines Bearing Multiple Stereocenters. Eur. J. Org. Chem. 2019, 2019, 1931–1939. [Google Scholar] [CrossRef]
  14. Agami, C.; Dechoux, L.; Hebbe, S. Asymmetric Synthesis of Nitrogen Heterocycles by Reaction of Chiral β-Enaminocarbonyl Substrates with Acrylate Derivatives. Tetrahedron Lett. 2002, 43, 2521–2523. [Google Scholar] [CrossRef]
  15. Aparicio, D.M.; Gnecco, D.; Juárez, J.R.; Orea, M.L.; Mendoza, A.; Waksman, N.; Salazar, R.; Fores-Alamo, M.; Terán, J.L. Diastereoselective Synthesis of Aryl and Alkyl Trans-Glycidic Amides from Pseudoephedrine-Derived Sulfonium Salt. Chemospecific Exo-Tet Ring Closure for Morpholin-3-Ones. Tetrahedron 2012, 68, 10252–10256. [Google Scholar] [CrossRef]
  16. Mola, L.; Font, J.; Bosch, L.; Caner, J.; Costa, A.M.; Etxebarría-Jardí, G.; Pineda, O.; De Vicente, D.; Vilarrasa, J. Nucleophile-Catalyzed Additions to Activated Triple Bonds. Protection of Lactams, Imides, and Nucleosides with MocVinyl and Related Groups. J. Org. Chem. 2013, 78, 5832–5842. [Google Scholar] [CrossRef] [PubMed]
  17. Tejedor, D.; López-Tosco, S.; Cruz-Acosta, F.; Méndez-Abt, G.; García-Tellado, F. Acetylides from Alkyl Propiolates as Building Blocks for C3 Homologation. Angew. Chem. In. Ed. 2009, 48, 2090–2098. [Google Scholar] [CrossRef] [PubMed]
Scheme 1. Synthesis of chiral acrylamides 4 and 5.
Scheme 1. Synthesis of chiral acrylamides 4 and 5.
Molbank 2024 m1903 sch001
Scheme 2. Synthesis of chiral 4-pheniloxazolidines 7(a,b) and 8(a,b).
Scheme 2. Synthesis of chiral 4-pheniloxazolidines 7(a,b) and 8(a,b).
Molbank 2024 m1903 sch002
Figure 1. Major and minor diastereoisomers 7a and 7b, respectively.
Figure 1. Major and minor diastereoisomers 7a and 7b, respectively.
Molbank 2024 m1903 g001
Scheme 3. Mechanistic proposal for the synthesis of N-acryloyl-4-phenyloxazolidines.
Scheme 3. Mechanistic proposal for the synthesis of N-acryloyl-4-phenyloxazolidines.
Molbank 2024 m1903 sch003
Table 1. Conducted experiments to synthesize 4-pheniloxazolidine 7(a,b) with 4 using different bases.
Table 1. Conducted experiments to synthesize 4-pheniloxazolidine 7(a,b) with 4 using different bases.
entryBaseYield 7(a,b)d.r. 7(a,b)
1DABCO (10 mol%)86%74:26 1
2DMAP (1 eq.)not observed-----
3DBU (10 mol%)not observed-----
1 Ratio determined by 1H NMR analysis of the crude mixture.
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Pilotzi Xahuentitla, H.; Ortega Montes, J.G.; Gnecco Medina, D.H.; Terán Vázquez, J.L.; Hernández Núñez, E.; Orea Flores, M.L. Synthesis of Methyl 2-((4R)-3-Acryloyl-4-phenyloxazolidin-2-yl)acetates. Molbank 2024, 2024, M1903. https://doi.org/10.3390/M1903

AMA Style

Pilotzi Xahuentitla H, Ortega Montes JG, Gnecco Medina DH, Terán Vázquez JL, Hernández Núñez E, Orea Flores ML. Synthesis of Methyl 2-((4R)-3-Acryloyl-4-phenyloxazolidin-2-yl)acetates. Molbank. 2024; 2024(4):M1903. https://doi.org/10.3390/M1903

Chicago/Turabian Style

Pilotzi Xahuentitla, Hugo, Jesús Guadalupe Ortega Montes, Dino Hernán Gnecco Medina, Joel Luis Terán Vázquez, Emanuel Hernández Núñez, and Maria Laura Orea Flores. 2024. "Synthesis of Methyl 2-((4R)-3-Acryloyl-4-phenyloxazolidin-2-yl)acetates" Molbank 2024, no. 4: M1903. https://doi.org/10.3390/M1903

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