Palladium-Catalyzed Regioselective [3+2] Cycloadditions of α , β -Unsaturated Imines with Vinylethylene Carbonates: Access to Oxazolidines

: We reported palladium-catalyzed regioselective [3+2] cycloadditions of α , β -unsaturated imines with vinylethylene carbonates, providing the desired oxazolidines in moderate-to-high yields. This reaction provides a facile route for the highly regioselective synthesis of functional oxazolidines. The synthetic utility of the current method was also demonstrated by a gram-scale reaction.


Introduction
Oxazolidines have been demonstrated as an important part of many biologically active natural products, including drug-lead compounds [1].For example, Naphthyridinomycin shows antibacterial activity [2]; Vincazalidine A shows cytotoxic activity against A549 cells [3]; Goitrin exhibits antithyroid [4]; and Famoxadone has good antifungal activity against basidiomycetes, ascomycetes and oomycete (Scheme 1A) [5].In addition, oxazolidine motifs are also used as a part of a ligand to prompt chemical transformation [6][7][8][9].Accordingly, developing a new method for efficient synthesis of functional oxazolidines from readily available materials is highly appealing.

Studies on Various Palladium Catalysts
Initially, we chose α,β-unsaturated imine 1a and VEC 2a as the model substrates to investigate the catalytic conditions by employing six common palladium catalysts.1 entries 1 vs. 3-7).It is worth noting that the same yield of 3a (82%) was obtained by using Pd 2 dba 3 as a catalyst (Table 1 entry 2), while Pd(OAc) 2 was not a suitable catalyst and afforded a much lower yield (9% Table 1, entry 6).These results suggested that the anion of palladium salt is one of the determinants affecting the catalytic activity.

Screening of Different Bases
Overall, we chose Pd(PPh3)4 as the catalyst to screen different bases (Table 2).After extensive screening of various bases, Cs2CO3 proved to be best, providing the desired product 3a in an 82% yield (Table 2, entry 1).Other inorganic bases (Na2CO3, K2CO3, Na-HCO3, K2HPO4, and LiOH) were also suitable in the reaction, and the desired product 3a was obtained in a 57-76% yield (Table 2, entries 2-6).While organic bases were poor under the reaction condition, DMAP as a base was used, and only a 24% yield of 3a was produced (Table 2 entry 7).No product was received using DBU as a base (Table 2 entry 8).

Screening of Different Bases
Overall, we chose Pd(PPh 3 ) 4 as the catalyst to screen different bases (Table 2).After extensive screening of various bases, Cs 2 CO 3 proved to be best, providing the desired product 3a in an 82% yield (Table 2, entry 1).Other inorganic bases (Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , K 2 HPO 4 , and LiOH) were also suitable in the reaction, and the desired product 3a was obtained in a 57-76% yield (Table 2, entries 2-6).While organic bases were poor under the reaction condition, DMAP as a base was used, and only a 24% yield of 3a was produced (Table 2 entry 7).No product was received using DBU as a base (Table 2 entry 8).

Studies on Various Palladium Catalysts
Initially, we chose α,β-unsaturated imine 1a and VEC 2a as the model substrates to investigate the catalytic conditions by employing six common palladium catalysts.As outlined in Table 1, Pd(PPh3)4 displayed better catalytic activity (82% yield, Table 1, entry 1) than other palladium catalysts (Pd(dba)2, PdCl2, Pd2dba3•CHCl3, Pd(OAc)2, Pd(CH3CN)2Cl2) (Table 1 entries 1 vs. 3-7).It is worth noting that the same yield of 3a (82%) was obtained by using Pd2dba3 as a catalyst (Table 1 entry 2), while Pd(OAc)2 was not a suitable catalyst and afforded a much lower yield (9% Table 1, entry 6).These results suggested that the anion of palladium salt is one of the determinants affecting the catalytic activity.

Screening of Different Bases
Overall, we chose Pd(PPh3)4 as the catalyst to screen different bases (Table 2).After extensive screening of various bases, Cs2CO3 proved to be best, providing the desired product 3a in an 82% yield (Table 2, entry 1).Other inorganic bases (Na2CO3, K2CO3, Na-HCO3, K2HPO4, and LiOH) were also suitable in the reaction, and the desired product 3a was obtained in a 57-76% yield (Table 2, entries 2-6).While organic bases were poor under the reaction condition, DMAP as a base was used, and only a 24% yield of 3a was produced (Table 2 entry 7).No product was received using DBU as a base (Table 2 entry 8).

Gram-Scale Synthesis
Subsequently, the scale experiment was performed to demonstrate the robustness and practicality of this synthetic method.To our delight, the desired oxazolidine was obtained in a 58% yield.The experiment results suggested some mixtures were produced to result in a low yield of 3a (Scheme 2). a Unless otherwise noted, the reaction of 1a (0.1 mmol), 2a (0.20 mmol), Pd(PPh 3 ) 4 (10 mol%) was performed at 40 • C in 1.0 mL of toluene.b Isolated yield.

Gram-Scale Synthesis
Subsequently, the scale experiment was performed to demonstrate the robustness and practicality of this synthetic method.To our delight, the desired oxazolidine was obtained in a 58% yield.The experiment results suggested some mixtures were produced to result in a low yield of 3a (Scheme 2).diffraction analysis.a Unless otherwise noted, the reaction of 1a (0.1 mmol), 2a (0.20 mmol), Pd(PPh3)4 (10 mol%) was performed at 40 °C in 1.0 mL of toluene.b Isolated yield.

Gram-Scale Synthesis
Subsequently, the scale experiment was performed to demonstrate the robustness and practicality of this synthetic method.To our delight, the desired oxazolidine was obtained in a 58% yield.The experiment results suggested some mixtures were produced to result in a low yield of 3a (Scheme 2).

Materials and Methods
All commercially available reagents were used without further purification.The saolvents were treated prior to use according to the standard methods.All reactions were performed under nitrogen using solvents dried by standard methods.NMR spectra were obtained using a Bruker spectrometer (Billerica, MA, USA).Chemical shifts are expressed in parts per million (ppm) downfield from internal TMS. 1 H and 13 C chemical shifts are reported in ppm relative to either the residual solvent peak ( 13 C) or tetramethylsilane (δ = 0 ppm) as an internal standard.HRMS spectra were obtained on an Agilent 1290-6540 (Agilent, Santa Clara, CA, USA) UHPLC Q-Tof HR-MS spectrometer.X-ray crystallographic analyses were performed on an Oxford diffraction Gemini E diffractometer.Silica gel (200-300 mesh) was used for the chromatographic separations.

Materials and Methods
All commercially available reagents were used without further purification.The saolvents were treated prior to use according to the standard methods.All reactions were performed under nitrogen using solvents dried by standard methods.NMR spectra were obtained using a Bruker spectrometer (Billerica, MA, USA).Chemical shifts are expressed in parts per million (ppm) downfield from internal TMS. 1 H and 13 C chemical shifts are reported in ppm relative to either the residual solvent peak ( 13 C) or tetramethylsilane (δ = 0 ppm) as an internal standard.HRMS spectra were obtained on an Agilent 1290-6540 (Agilent, Santa Clara, CA, USA) UHPLC Q-Tof HR-MS spectrometer.X-ray crystallographic analyses were performed on an Oxford diffraction Gemini E diffractometer.Silica gel (200-300 mesh) was used for the chromatographic separations.

Conclusions
In conclusion, we have achieved a palladium-catalyzed [2+3] cycloadditions of acyclic α,β-unsaturated imines and vinylethylene carbonate for the synthesis of functional oxazolidines.A series of α,β-unsaturated imines bearing different substituents and VEC were therefore tested in the presence of Pd(PPh 3 ) 4 , and diverse oxazolidine derivatives were obtained in moderate-to-good yields with excellent regioselectivity.The reaction performed well on a gram scale, indicating that it was a practical tool for the synthesis of oxazolidine derivatives.A further study in an asymmetric field is ongoing and will be reported in the future.

Scheme 1 . 1 .
Scheme 1. Selected natural products and synthetic bioactive compounds and study background.Scheme 1. Selected natural products and synthetic bioactive compounds and study background.

2. 6 .
The Suggested Catalytic MechanismIn light of our experimental observations and previous reports[34,35], we proposed a possible mechanism as outlined in Scheme 3. In the presence of Pd(PPh 3 ) 4 , vinylethylene carbonate 2a was decarboxylated to generate a π-allylpalladium zwitterionic intermediate complex A. Next, the intermediate A engaged in a nucleophilic attack on the ketimine part of α,β-unsaturated imine 1a, giving the zwitterionic intermediate B. Finally, the nitrogen anion attacked the internal position of the electrophilic π-allylpalladium moiety to afford the five-membered oxazole ring product 3a and regenerated the palladium catalyst (Scheme 3).
H-NMR spectrum of the reaction product of 3b; FigureS4.13C-NMR spectrum of the reaction product of 3b; FigureS5.1 H-NMR spectrum of the reaction product of 3c; FigureS6.13C-NMR spectrum of the reaction product of 3c; Figure S7. 1 H-NMR spectrum of the reaction product of 3d; Figure S8. 13C-NMR spectrum of the reaction product of 3d; Figure S9. 1 H-NMR spectrum of the reaction product of 3e; Figure S10. 13C-NMR spectrum of the reaction product of 3e; Figure S11. 1 H-NMR spectrum of the reaction product of 3f; Figure S12. 13C-NMR spectrum of the reaction product of 3f; Figure S13. 19F-NMR spectrum of the reaction product of 3f; Figure S14. 1 H-NMR spectrum of the reaction product of 3g; Figure S15. 13C-NMR spectrum of the reaction product of 3g; Figure S16. 1 H-NMR spectrum of the reaction product of 3h; Figure S17. 13C-NMR spectrum of the reaction product of 3h; Figure S18. 1 H-NMR spectrum of the reaction product of 3i; Figure S19. 13C-NMR spectrum of the reaction product of 3i; Figure S20. 1 H-NMR spectrum of the reaction product of 3j; Figure S21. 13C-NMR spectrum of the reaction product of 3j; Figure S22. 19F-NMR spectrum of the reaction product of 3j; Figure S23. 1 H-NMR spectrum of the reaction product of 3k; Figure S24. 13C-NMR spectrum of the reaction product of 3k; Figure S25. 1 H-NMR spectrum of the reaction product of 3l; Figure S26. 13C-NMR spectrum of the reaction product of 3l; Figure S27. 1 H-NMR spectrum of the reaction product of 3m; Figure S28. 13C-NMR spectrum of the reaction product of 3m; Figure S29. 1 H-NMR spectrum of the reaction product of 3n; Figure S30. 13C-NMR spectrum of the reaction product of 3n; Figure S31. 1 H-NMR spectrum of the reaction product of 3o; Figure S32. 13C-NMR spectrum of the reaction product of 3o; Figure S33. 19F-NMR spectrum of the reaction product of 3o; Figure S34. 1 H-NMR spectrum of the reaction product of 3p; Figure S35. 13C-NMR spectrum of the reaction product of 3p; Figure S36. 1 H-NMR spectrum of the reaction product of

Table 1 .
Optimization of palladium catalysts a .

Table 1 .
Optimization of palladium catalysts a .

Table 2 .
Optimization of the bases a .

Table 2 .
Optimization of the bases a .

Table 1 .
Optimization of palladium catalysts a .

Table 2 .
Optimization of the bases a .

Table 3 .
Optimization of solvents a .

Table 3 .
Optimization of solvents a .
Catalysts 2024, 14, x FOR PEER REVIEW 5 of 12 entry 20).It should be noted that all of these examples showed exclusive regioselectivity.The structure and relative configuration of 3a were determined by single-crystal X-ray diffraction analysis.