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).
Scheme 1.
Synthesis of chiral acrylamides 4 and 5.
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).
Scheme 2.
Synthesis of chiral 4-pheniloxazolidines 7(a,b) and 8(a,b).
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.
Table 1.
Conducted experiments to synthesize 4-pheniloxazolidine 7(a,b) with 4 using different bases.
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.
Figure 1.
Major and minor diastereoisomers 7a and 7b, respectively.
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).
Scheme 3.
Mechanistic proposal for the synthesis of N-acryloyl-4-phenyloxazolidines.
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.
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