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Article

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

by
Yuanbo Wang
1,
Yue Wang
2,*,
Tong Sun
1,
Qinglin Liu
1 and
Er-Qing Li
1,*
1
College of Chemistry, Zhengzhou University, Zhengzhou 450001, China
2
College of Advanced Interdisciplinary Science and Technology (CAIST), Henan University of Technology, Zhengzhou 450001, China
*
Authors to whom correspondence should be addressed.
Catalysts 2024, 14(8), 508; https://doi.org/10.3390/catal14080508
Submission received: 5 July 2024 / Revised: 1 August 2024 / Accepted: 1 August 2024 / Published: 6 August 2024
(This article belongs to the Special Issue Recent Applications of Metal Catalysts in Organic Synthesis, 2nd Edition)
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Abstract

:
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.

Graphical Abstract

1. 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.
Vinylethylene carbonates (VECs) have been proved to be one type of highly active C3 or C5 synthon for the synthesis of structurally diverse heterocyclic compounds [10,11,12,13,14,15]. In this context, a broad range of the electrophilic reagents involving aldehydes [16], enals [17], imines [18,19,20], azomethine imines [21], and electron-deficient alkenes [22], among others, have been applied in diverse Pd-catalyzed annulation reactions of VECs. Among these electrophilic coupling reagents, since Murai first reported Ru3(CO)12-catalyzed [4+1] cycloaddition of α, β-unsaturated imines with carbon monoxide [23], α,β-unsaturated imines have been thoroughly studied as a C4 synthon in a variety of [4+n] cycloadditions [24,25,26,27,28]. In 2017, Zhao and co-workers reported a palladium-catalyzed enantioselective [5+4] cycloaddition of azadienes with VECs [29,30]. In 2023, Deng and co-workers developed a palladium-catalyzed [5+4] cycloaddition by altering the steric hindrance of the α,β-unsaturated imines [31]. That is to say, α,β-unsaturated imines acting as C2 synthons are more challenging and rarely reported because of they are energetically and sterically unfavorable to perform [2+n] cycloadditions. In 2022, Wang and co-workers disclosed a sterically and temperature-controlled palladium-catalyzed divergent [4+5] and [2+3] cycloadditions of α,β-unsaturated imines and vinylethylene carbonates (Scheme 1B) [32]. In this reaction, the alkene part of α,β-unsaturated imines was used as a C2 synthon to perform [3+2] cycloadditions in high temperature. Simultaneously, Chen and co-workers realized a palladium-catalyzed [3+2] annulations of VECs with alkenes installed on cyclic N-sulfonyl imines (Scheme 1B) [33]. To the best of our knowledge, the imine part of α,β-unsaturated imines as a C2 synthon is challenging. Allowing for the significance of functional oxazolidine scaffolds and our interest in palladium-catalyzed cycloaddition reactions, we here decided to develop a highly efficient regioselective [3+2] cycloaddition of VECs with α,β-unsaturated imines, in which the α,β-unsaturated imines were used as a C2 synthon. It is worth noting that this method gives a complete regioselective bonding of the C=N bond and an expanded substrate scope under mild conditions compared to the conventional protocol (Scheme 1C).

2. Results

2.1. 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.

2.2. 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, NaHCO3, 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).

2.3. Screening of Solvents

Subsequently, a selection of solvents (e.g., CH2Cl2, CHCl3, MeCN, DMF, Et2O, EA, THF and 1,4-dioxane) were tested (Table 3, entries 2–9), and toluene was found to be the best, affording 3a in an 82% yield (Table 3, entry 1). Thus, the optimization condition was established as using Pd(PPh3)4 as a catalyst, and Cs2CO3 as a base in toluene at 40 °C (Table 3 entry 1).

2.4. Substrate Scope

After determining the optimized reaction conditions, the generality of palladium-catalyzed [2+3] cycloaddition was tested by using various α,β-unsaturated imines 1 with different substituents (Table 4). First, the R substituents of α,β-unsaturated imines were examined, and it was found that the electronic property and substituted position have a certain influence on the yields of 3, electron-donating and m-position substituents, resulting in lower yields (Table 4 entries 1–8). Next, we examined a range of Ar1 substituents of α,β-unsaturated imines including either electron-donating (4-MeC6H4 and 2,4,6-Me3C6H2) or withdrawing groups (4-FC6H4, 4-ClC6H4, and 2-FC6H4,) The corresponding oxazolidines 3i–3m were obtained in 22–68% isolated yields (Table 4, 9–13). In other words, when 4-MeC6H4- and 4-FC6H4-substituted α,β-unsaturated imines were used, the reaction could proceed smoothly, albeit with low yields (Table 4, entries 9 and 10). Finally, Ar2 substituents of α,β-unsaturated imines were also examined; the results showed that the electron-withdrawing substituents give the desired products in higher yields (Table 4, entries 14 and 15 vs. 16). When α,β-unsaturated imines 1q–1s were applied as a starting substrate, the reaction was also tolerant, affording the desired product 3q–3s in 37–53% yields (Table 4, entries 17–19). Finally, α,β-unsaturated imine 1t with a 3-MeC6H4 of Ar1 and 4-ClC6H4 of Ar2 was a suitable substrate to afford the desired product 3t in a 36% yield (Table 4, 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.

2.5. 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).

2.6. The Suggested Catalytic Mechanism

In 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(PPh3)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).

3. 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. 1H and 13C chemical shifts are reported in ppm relative to either the residual solvent peak (13C) 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.
General Procedure: All the catalytic reactions were performed in a 10 mL Schlenk tube under N2. Typically, a mixture of α,β-unsaturated imines 1 (0.1 mmol), vinylethylene carbonates 2 (0.2 mmol), Pd(PPh3)4 (10 mol%) and Cs2CO3 (2.0 equiv.) (2 mol%) was charged into the Schlenk tube and stirred at 40 ºC until the substrate was consumed (monitored by TLC), and then it was purified by flash column chromatography (petroleum ether:AcOEt = 20:1), affording the corresponding products 3.
Analytical date for compounds 3 (available in the Supplementary Materials):
(E)-2-phenyl-3-(phenylsulfonyl)-2-styryl-4,4-divinyloxazolidine (3a): Prepared according to the general procedure as described above in an 82% yield (36 mg). It was purified by column chromatography (EtOAc/PE = 1:4) to afford the corresponding products 3. Mp: 111.9–112.9 °C. 1H NMR (600 MHz, Chloroform-d) δ 7.56–7.50 (m, 2H), 7.47–7.44 (m, 2H), 7.42–7.36 (m, 4H), 7.36–7.28 (m, 4H), 7.22 (t, J = 7.7 Hz, 2H), 6.94–6.72 (m, 2H), 6.36 (ddd, J = 25.6, 17.7, 10.9 Hz, 2H), 5.50–5.34 (m, 2H), 5.32–5.21 (m, 2H), 4.23–4.05 (m, 2H) ppm; 13C NMR (151 MHz, CDCl3) δ 145.5, 139.1, 137.8, 135.7, 133.3, 129.1, 129.0, 128.8, 128.7, 128.5, 127.9, 127.1, 125.0, 124.9, 117.2, 116.7, 100.0, 73.3, 70.5 ppm; HRMS (ESI) calcd for C27H26NO3S+ [M+H]+: 444.1628, found 444.1627.
(E)-2-phenyl-2-styryl-3-tosyl-4,4-divinyloxazolidine (3b): Prepared according to the general procedure as described above in a 56% yield (26 mg). It was purified by column chromatography (EtOAc/PE = 1:4) to afford a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.58 (d, J = 7.3 Hz, 2H), 7.46 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.33–7.30 (m, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 4.6 Hz, 2H), 6.34 (dd, J = 17.7, 10.9 Hz, 1H), 6.24 (dd, J = 17.6, 10.8 Hz, 1H), 5.34 (d, J = 10.9 Hz, 1H), 5.29–5.18 (m, 3H), 4.08 (q, J = 9.3 Hz, 2H), 2.30 (s, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ 142.5, 139.9, 139.5, 139.1, 137.9, 136.0, 132.5, 128.9, 128.8, 128.7, 128.6, 128.6, 128.4, 128.3, 127.8, 127.1, 116.6, 116.4, 99.9, 73.2, 70.0, 21.4 ppm; HRMS (ESI) calcd for C28H27NNaO3S+ [M+Na]+: 480.1604, found 480.1613.
(E)-3-((4-bromophenyl)sulfonyl)-2-phenyl-2-styryl-4,4-divinyloxazolidine (3c): Prepared according to the general procedure as described above in a 61% yield (32 mg). It was purified by column chromatography (EtOAc/PE = 1:4) to afford a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.55 (dd, J = 8.3, 1.4 Hz, 2H), 7.47–7.44 (m, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.35–7.30 (m, 2H), 7.29–7.25 (m, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 6.90–6.70 (m, 2H), 6.31 (ddd, J = 28.3, 17.7, 10.9 Hz, 2H), 5.55–5.30 (m, 2H), 5.30–5.14 (m, 2H), 4.30–3.93 (m, 2H) ppm; 13C NMR (151 MHz, CDCl3) δ 141.3, 139.3, 139.1, 137.8, 135.8, 133.0, 131.1, 129.9, 129.0, 128.8, 128.7, 128.5, 127.9, 127.1, 126.7, 117.0, 116.7, 100.0, 73.3, 70.2 ppm; HRMS (ESI) calcd for C27H24BrNNaO3S+ [M+Na]+: 544.0552, found 544.0560.
(E)-3-((4-nitrophenyl)sulfonyl)-2-phenyl-2-styryl-4,4-divinyloxazolidine (3d): Prepared according to the general procedure as described above in an 84% yield (41 mg). It was purified by column chromatography (EtOAc/PE = 1:3) to afford a yellow oil. 1H NMR (600 MHz, Chloroform-d) δ 7.89 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 7.5 Hz, 2H), 7.42–7.36 (m, 4H), 7.33 (t, J = 7.3 Hz, 2H), 7.24 (t, J = 7.6 Hz, 2H), 6.88 (s, 1H), 6.77 (d, J = 16.1 Hz, 1H), 6.35 (dd, J = 17.6, 10.9 Hz, 2H), 5.47–5.34 (m, 2H), 5.33–5.24 (m, 2H), 4.33–3.99 (m, 2H) ppm; 13C NMR (151 MHz, CDCl3) δ 149.1, 147.6, 138.9, 138.8, 137.7, 135.6, 133.5, 129.5, 129.3, 129.1, 128.9, 128.7, 128.3, 128.0, 127.1, 123.0, 117.6, 117.0, 100.0, 73.4, 70.6 ppm; HRMS (ESI) calcd for C27H25N2O5+ [M+H]+: 489.1479, found 489.2101.
(E)-2-phenyl-2-styryl-3-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4-divinyloxazolidine (3e): Prepared according to the general procedure as described above in a 60% yield (31 mg). It was purified by column chromatography (EtOAc/PE = 1:4) to afford a white oil. 1H NMR (600 MHz, CDCl3) δ 7.55–7.49 (m, 2H), 7.47–7.43 (m, 2H), 7.43–7.35 (m, 4H), 7.35–7.28 (m, 4H), 7.22 (t, J = 7.7 Hz, 2H), 6.99–6.74 (m, 2H), 6.36 (ddd, J = 25.6, 17.7, 10.9 Hz, 2H), 5.50–5.34 (m, 2H), 5.32–5.21 (m, 2H), 4.21–3.99 (m, 2H) ppm; 13C NMR (151 MHz, CDCl3) δ 145.5, 139.1, 138.9, 137.8, 135.7, 133.3, 133.2 (q, J = 33.1 Hz), 129.1, 129.0, 128.8, 128.7, 128.6, 128.5, 127.9, 127.1, 125.0 (q, J = 3.8 Hz), 123.3 (q, J = 273.1 Hz), 117.2, 116.7, 100.0, 73.3, 70.5 ppm; HRMS (ESI) calcd for C28H23F3NNaO3S+ [M+Na]+: 534.1321, found 534.1328.
(E)-3-((4-fluorophenyl)sulfonyl)-2-phenyl-2-styryl-4,4-divinyloxazolidine (3f): Prepared according to the general procedure as described above in a 72% yield (27mg). It was purified by column chromatography (EtOAc/PE = 1:3) to afford a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.58–7.53 (m, 2H), 7.47 (d, J = 7.8 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.34–7.22 (m, 6H), 6.89 (d, J = 16.1 Hz, 1H), 6.82 (dd, J = 16.1, 0.9 Hz, 1H), 6.76 (td, J = 8.8, 1.3 Hz, 2H), 6.38–6.31 (m, 1H), 6.31–6.25 (m, 1H), 5.36 (dd, J = 10.9, 1.1 Hz, 1H), 5.31 (dd, J = 17.7, 1.0 Hz, 1H), 5.25 (dd, J = 4.5, 1.2 Hz, 1H), 5.23 (dd, J = 11.4, 1.1 Hz, 1H), 4.10 (ddd, J = 22.5, 9.3, 1.2 Hz, 2H) ppm; 13C NMR (151 MHz, CDCl3) δ 165.2, 163.6, 139.4, 139.2, 138.3, 137.9, 135.8, 132.9, 131.1, 131.0, 129.1, 129.0, 128.8, 128.7, 128.5, 127.1, 117.0, 116.6, 115.0, 114.9, 99.9, 73.3, 70.2 ppm; 19F NMR (565 MHz, CDCl3) δ −106.5 ppm. HRMS (ESI) calcd for C27H24FNNaO3S+ [M+Na]+: 484.1353, found 484.1361.
(E)-3-((4-methoxyphenyl)sulfonyl)-2-phenyl-2-styryl-4,4-divinyloxazolidine (3g): Prepared according to the general procedure as described above in a 30% yield (14 mg). It was purified by column chromatography (EtOAc/PE = 1:3) to afford a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.67–7.55 (m, 2H), 7.47 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.35–7.20 (m, 6H), 6.93–6.78 (m, 2H), 6.58 (d, J = 9.0 Hz, 2H), 6.35 (dd, J = 17.8, 11.0 Hz, 1H), 6.25 (dd, J = 17.7, 10.7 Hz, 1H), 5.34 (d, J = 11.0 Hz, 1H), 5.27 (d, J = 17.7 Hz, 1H), 5.24 (dd, J = 14.2, 3.4 Hz, 2H), 4.08 (q, J = 9.2 Hz, 2H), 3.76 (s, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ 162.2, 139.9, 139.3, 138.0, 136.0, 134.2, 132.6, 130.5, 129.0, 128.9, 128.8, 128.7, 128.3, 127.8, 127.1, 116.6, 116.4, 113.0, 99.8, 73.2, 70.0, 55.5 ppm; HRMS (ESI) calcd for C28H27NNaO4S+ [M+Na]+: 496.1553, found 496.1561.
(E)-3-((3-bromophenyl)sulfonyl)-2-phenyl-2-styryl-4,4-divinyloxazolidine (3h): Prepared according to the general procedure as described above in a 32% yield (16 mg). It was purified by column chromatography (EtOAc/PE = 1:4) to afford a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.54–7.52 (m, 2H), 7.49 (d, J = 7.1 Hz, 2H), 7.46–7.42 (m, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.35–7.28 (m, 4H), 7.28–7.23 (m, 2H), 6.99 (t, J = 7.9 Hz, 1H), 6.93–6.73 (m, 2H), 6.34 (ddd, J = 21.8, 17.6, 10.8 Hz, 2H), 5.48–5.35 (m, 2H), 5.35–5.19 (m, 2H), 4.14 (q, J = 9.3 Hz, 2H) ppm; 13C NMR (151 MHz, CDCl3) δ 143.9, 139.1, 138.8, 137.9, 135.8, 134.8, 133.0, 131.3, 129.4, 129.3, 128.9, 128.8, 128.5, 128.5, 127.8, 127.2, 126.7, 121.9, 117.1, 116.6, 99.9, 73.4, 70.3 ppm; HRMS (ESI) calcd for C27H24BrNNaO3S+ [M+Na]+: 544.0552, found 544.0560.
(E)-2-(4-methylstyryl)-2-phenyl-3-(phenylsulfonyl)-4,4-divinyloxazolidine (3i): Prepared according to the general procedure as described above in a 27% yield (12 mg). It was purified by column chromatography (EtOAc/PE = 1:3) to afford a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.59–7.56 (m, 2H), 7.37–7.28 (m, 6H), 7.25 (dd, J = 9.1, 5.8 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 7.13 (t, J = 7.9 Hz, 2H), 6.83 (d, J = 16.1 Hz, 1H), 6.78 (d, J = 16.1 Hz, 1H), 6.36 (dd, J = 17.7, 10.9 Hz, 1H), 6.24 (dd, J = 17.6, 10.8 Hz, 1H), 5.35 (d, J = 11.0 Hz, 1H), 5.28 (d, J = 17.7 Hz, 1H), 5.23 (d, J = 11.0 Hz, 1H), 5.21 (d, J = 4.2 Hz, 1H), 4.09 (dd, J = 20.8, 9.2 Hz, 2H), 2.37 (s, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ 142.3, 139.8, 139.2, 138.3, 138.0, 133.1, 132.6, 131.8, 129.4, 128.9, 128.8, 128.4, 127.9, 127.8, 127.1, 116.7, 116.4, 100.1, 73.3, 70.1, 21.3 ppm; HRMS (ESI) calcd for C28H27NNaO3S+ [M+Na]+: 480.1604, found 480.1613.
(E)-2-(4-fluorostyryl)-2-phenyl-3-(phenylsulfonyl)-4,4-divinyloxazolidine (3j): Prepared according to the general procedure as described above in a 22% yield (10 mg). It was purified by column chromatography (EtOAc/PE = 1:4) to afford a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.59–7.52 (m, 2H), 7.43 (dd, J = 8.6, 5.4 Hz, 2H), 7.37–7.29 (m, 4H), 7.26 (dd, J = 9.7, 5.2 Hz, 2H), 7.13 (dd, J = 10.4, 5.3 Hz, 2H), 7.05 (t, J = 8.6 Hz, 2H), 6.83 (d, J = 16.1 Hz, 1H), 6.75 (d, J = 16.1 Hz, 1H), 6.34 (dd, J = 17.7, 10.9 Hz, 1H), 6.27 (dd, J = 17.7, 10.7 Hz, 1H), 5.38–5.33 (m, 1H), 5.31–5.26 (m, 1H), 5.25 (d, J = 2.3 Hz, 1H), 5.23 (d, J = 4.4 Hz, 1H), 4.09 (q, J = 9.3 Hz, 2H) ppm; 13C NMR (151 MHz, CDCl3) δ 162.8 (d, J = 247.9 Hz), 142.2, 139.6, 139.1, 137.9, 132.1 (d, J = 3.3 Hz), 131.9, 131.6, 128.9, 128.9, 128.8, 128.7, 128.3, 128.0, 127.9, 116.8, 116.5, 115.7, 115.6, 99.9, 73.2, 70.2, ppm; 19F NMR (565 MHz, CDCl3) δ −113.3 ppm. HRMS (ESI) calcd for C27H24FNNaO3S+ [M+Na]+: 484.1353, found 484.1363.
(E)-2-phenyl-3-(phenylsulfonyl)-2-(2,4,6-trimethylstyryl)-4,4-divinyloxazolidine (3k): Prepared according to the general procedure as described above in a 53% yield (26 mg). It was purified by column chromatography (EtOAc/PE = 1:3) to afford a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.57 (dd, J = 8.3, 1.4 Hz, 2H), 7.34–7.29 (m, 2H), 7.26–7.21 (m, 2H), 7.18–7.14 (m, 2H), 7.11 (dd, J = 8.5, 7.1 Hz, 2H), 7.03 (d, J = 16.3 Hz, 1H), 6.91 (s, 2H), 6.44 (dd, J = 17.7, 10.8 Hz, 1H), 6.39 (d, J = 16.4 Hz, 1H), 6.20 (dd, J = 17.6, 10.8 Hz, 1H), 5.44–5.32 (m, 2H), 5.28 (d, J = 10.9 Hz, 1H), 5.20 (d, J = 17.7 Hz, 1H), 4.42–4.06 (m, 2H), 2.34 (s, 6H), 2.30 (s, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ 142.1, 139.3, 139.2, 137.8, 136.6, 136.1, 133.2, 132.9, 131.7, 131.1, 129.2, 129.0, 128.8, 128.8, 128.1, 127.9, 127.8, 116.8, 116.3, 100.0, 73.1, 70.2, 21.3, 21.0 ppm; HRMS (ESI) calcd for C30H31NNaO3S+ [M+Na]+: 508.1917, found 508.1927.
(E)-2-(4-chlorostyryl)-2-phenyl-3-(phenylsulfonyl)-4,4-divinyloxazolidine (3l): Prepared according to the general procedure as described above in a 63% yield (30 mg). It was purified by column chromatography (EtOAc/PE = 1:4) to afford a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.49 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.41–7.34 (m, 5H), 7.33–7.28 (m, 1H), 7.20 (d, J = 8.6 Hz, 2H), 7.16 (t, J = 7.8 Hz, 2H), 6.89–6.74 (m, 2H), 6.36 (dd, J = 17.7, 10.9 Hz, 1H), 6.23 (dd, J = 17.6, 10.7 Hz, 1H), 5.37 (d, J = 10.8 Hz, 1H), 5.29 (d, J = 17.8 Hz, 1H), 5.23 (dd, J = 14.2, 3.4 Hz, 2H), 4.18–3.91 (m, 2H) ppm; 13C NMR (151 MHz, CDCl3) δ 142.1, 139.0, 138.4, 137.9, 135.7, 134.9, 133.1, 132.0, 130.4, 128.8, 128.6, 128.3, 128.1, 127.9, 127.2, 116.9, 116.7, 99.4, 73.2, 70.2 ppm; HRMS (ESI) calcd for C27H24ClNNaO3S+ [M+Na]+: 500.1058, found 500.1066.
(E)-2-(2-fluorostyryl)-2-phenyl-3-(phenylsulfonyl)-4,4-divinyloxazolidine (3m): Prepared according to the general procedure as described above in a 68% yield (31 mg). It was purified by column chromatography (EtOAc/PE = 1:4) to afford a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.59–7.55 (m, 3H), 7.38–7.23 (m, 7H), 7.18–7.11 (m, 3H), 7.10–7.05 (m, 2H), 7.00 (d, J = 16.3 Hz, 1H), 6.34 (dd, J = 17.7, 10.9 Hz, 1H), 6.25 (dd, J = 17.6, 10.8 Hz, 1H), 5.36 (d, J = 10.9 Hz, 1H), 5.31 (d, J = 17.7 Hz, 1H), 5.23 (dd, J = 14.2, 3.4 Hz, 2H), 4.27–4.03 (m, 2H) ppm; 13C NMR (151 MHz, CDCl3) δ 160.6 (d, J = 250.5 Hz), 142.2, 139.6, 139.0, 137.8, 131.8, 131.4 (d, J = 4.7 Hz), 129.6 (d, J = 8.4 Hz), 128.9, 128.8, 128.2, 128.0 (d, J = 2.7 Hz), 128.0, 127.9, 124.9, 124.9, 124.3, 1234.2, 123.9 (d, J = 12.1 Hz), 116.8, 116.0, 115.8, 99.8, 73.3, 70.2 ppm; HRMS (ESI) calcd for C27H24FNNaO3S+ [M+Na]+: 484.1353, found 484.1361.
(E)-2-(4-chlorophenyl)-3-(phenylsulfonyl)-2-styryl-4,4-divinyloxazolidine (3n): Prepared according to the general procedure as described above in a 77% yield (37 mg). It was purified by column chromatography (EtOAc/PE = 1:3) to afford a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 6.93 (dd, J = 16.3, 8.5 Hz, 4H), 6.17 (t, J = 2.5 Hz, 1H), 4.43 (s, 1H), 4.02 (dt, J = 9.3, 6.5 Hz, 4H), 3.75 (dd, J = 20.7, 2.5 Hz, 1H), 2.70 (dd, J = 20.9, 2.5 Hz, 1H), 1.96–1.69 (m, 4H), 1.49 (ddt, J = 10.1, 7.3, 2.9 Hz, 4H), 0.98 (t, J = 7.4 Hz, 6H) ppm; 13C NMR (151 MHz, CDCl3) δ 142.1, 139.0, 138.3, 137.9, 135.7, 134.9, 133.1, 132.0, 130.3, 128.7, 128.5, 128.3, 128.0, 127.9, 127.2, 116.8, 116.7, 99.4, 73.2, 70.2 ppm; HRMS (ESI) calcd for C27H24ClNNaO3S+ [M+Na]+: 500.1058, found 500.1065.
(E)-2-(4-fluorophenyl)-3-(phenylsulfonyl)-2-styryl-4,4-divinyloxazolidine (3o): Prepared according to the general procedure as described above in an 84% yield (38 mg). It was purified by column chromatography (EtOAc/PE = 1:2) to afford a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.58–7.50 (m, 2H), 7.46 (d, J = 7.3 Hz, 2H), 7.41–7.33 (m, 5H), 7.30 (t, J = 7.3 Hz, 1H), 7.15 (t, J = 7.9 Hz, 1H), 6.91 (t, J = 8.7 Hz, 1H), 6.87 (d, J = 16.1 Hz, 1H), 6.82 (d, J = 16.1 Hz, 1H), 6.35 (dd, J = 17.7, 10.9 Hz, 2H), 6.25 (dd, J = 17.7, 10.7 Hz, 2H), 5.37 (d, J = 10.9 Hz, 1H), 5.30 (d, J = 17.7 Hz, 1H), 5.25 (d, J = 12.8 Hz, 1H), 5.21 (d, J = 5.8 Hz, 1H), 4.09 (d, J = 1.2 Hz, 2H) ppm; 13C NMR (151 MHz, CDCl3) δ 163.0 (d, J = 248.3 Hz), 142.2, 139.1, 137.9, 135.8, 135.6, 132.9, 131.9, 130.9, 130.9, 128.7, 128.6, 128.5, 128.2, 128.0, 127.1, 116.8, 116.6, 114.7, 114.5, 99.4, 73.2, 70.2 ppm; 19F NMR (565 MHz, CDCl3) δ −113.0 ppm. HRMS (ESI) calcd for C27H24FNNaO3S+ [M+Na]+: 484.1353, found 484.1362.
(E)-2-(3-bromophenyl)-3-(phenylsulfonyl)-2-styryl-4,4-divinyloxazolidine (3p): Prepared according to the general procedure as described above in a 32% yield (15 mg). It was purified by column chromatography (EtOAc/PE = 1:4) to afford a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.61–7.54 (m, 2H), 7.49–7.44 (m, 2H), 7.43–7.30 (m, 7H), 7.20–7.12 (m, 3H), 6.87 (d, J = 16.1 Hz, 1H), 6.81 (d, J = 16.2 Hz, 1H), 6.37–6.29 (m, 1H), 6.28–6.21 (m, 1H), 5.39 (d, J = 10.9 Hz, 1H), 5.31 (d, J = 17.7 Hz, 1H), 5.23 (t, 2H), 4.14–4.06 (m, 2H) ppm; 13C NMR (151 MHz, CDCl3) δ 142.1, 141.9, 138.9, 137.7, 135.7, 133.1, 132.2, 132.0, 131.8, 129.3, 128.7, 128.5, 128.2, 128.1, 128.0, 127.7, 127.2, 122.1, 117.0, 116.7, 99.2, 73.3, 70.2 ppm; HRMS (ESI) calcd for C27H24BrNNaO3S+ [M+Na]+: 544.0552, found 544.0560.
(E)-2-(4-chlorophenyl)-2-styryl-3-tosyl-4,4-divinyloxazolidine (3q): Prepared according to the general procedure as described above in a 37% yield (18 mg). It was purified by column chromatography (EtOAc/PE = 1:3) to afford a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.40–7.30 (m, 4H), 7.27 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.1 Hz, 2H), 6.82 (q, J = 16.1 Hz, 2H), 6.36 (dd, J = 17.7, 10.9 Hz, 1H), 6.22 (dd, J = 17.6, 10.7 Hz, 1H), 5.37 (d, J = 10.9 Hz, 1H), 5.29 (d, J = 17.8 Hz, 1H), 5.23 (dd, J = 14.1, 3.4 Hz, 2H), 4.08 (d, J = 1.3 Hz, 2H), 2.32 (s, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ 142.8, 139.3, 139.1, 138.4, 137.9, 135.8, 134.9, 132.9, 130.3, 128.7, 128.7, 128.6, 128.5, 128.3, 127.9, 127.1, 116.7, 116.6, 99.3, 73.1, 70.1, 21.4 ppm; HRMS (ESI) calcd for C28H26ClNNaO3S+ [M+Na]+: 514.1214, found 514.1223.
(E)-2-(3,5-dimethylphenyl)-3-(phenylsulfonyl)-2-styryl-4,4-divinyloxazolidine (3r): Prepared according to the general procedure as described above in a 53% yield (25 mg). It was purified by column chromatography (EtOAc/PE = 1:3) to afford a yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 7.7 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.34–7.26 (m, 4H), 7.17–7.05 (m, 4H), 6.98–6.81 (m, 3H), 6.34 (dddd, J = 19.3, 17.6, 10.9, 1.4 Hz, 2H), 5.43–5.29 (m, 2H), 5.31–5.12 (m, 2H), 4.12 (t, J = 1.6 Hz, 2H), 2.20 (s, 6H) ppm; 13C NMR (151 MHz, CDCl3) δ 142.2, 139.5, 138.1, 137.3, 132.3, 131.7, 130.6, 129.1, 128.7, 128.3, 128.2, 127.7, 127.2, 126.8, 116.7, 116.2, 99.9, 73.2, 70.2, 21.4 ppm; HRMS (ESI) calcd for C29H29NNaO3S+ [M+Na]+: 494.1760, found 494.1768.
(E)-2-(4-chlorostyryl)-2-(3,5-dimethylphenyl)-3-(phenylsulfonyl)-4,4-divinyloxazolidine (3s): Prepared according to the general procedure as described above in a 50% yield (25 mg). It was purified by column chromatography (EtOAc/PE = 1:4) to afford a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.48–7.41 (m, 2H), 7.39–7.27 (m, 5H), 7.19–7.07 (m, 4H), 6.93 (s, 1H), 6.87 (s, 2H), 6.43–6.29 (m, 2H), 5.44–5.34 (m, 2H), 5.31–5.20 (m, 2H), 4.14 (s, 2H), 2.23 (s, 6H) ppm; 13C NMR (151 MHz, CDCl3) δ 142.1, 139.4, 138.8, 138.0, 137.3, 134.6, 134.0, 131.7, 131.0, 130.6, 129.8, 129.8, 128.9, 128.4, 128.2, 127.7, 126.8, 116.8, 116.3, 99.7, 73.2, 70.2, 21.4 ppm; HRMS (ESI) calcd for C29H28ClNNaO3S+ [M+Na]+: 528.1371, found 528.1378.
(E)-2-(4-chlorostyryl)-3-(phenylsulfonyl)-2-(m-tolyl)-4,4-divinyloxazolidine (3t): Prepared according to the general procedure as described above in a 36% yield (20 mg). It was purified by column chromatography (EtOAc/PE = 1:3) to afford a white oil. 1H NMR (600 MHz, CDCl3) δ 7.40 (d, J = 8.4 Hz, 3H), 7.38–7.32 (m, 3H), 7.31–7.29 (m, 2H), 7.25 (s, 1H), 7.21–7.06 (m, 4H), 6.83 (s, 2H), 6.32 (ddd, J = 25.1, 17.6, 10.8 Hz, 2H), 5.43–5.29 (m, 2H), 5.26–5.16 (m, 2H), 4.10 (d, J = 2.1 Hz, 2H), 2.23 (s, 3H) ppm; 13C NMR (151 MHz, CDCl3) δ 142.2, 139.2, 139.1, 137.9, 137.5, 134.5, 134.0, 131.8, 131.2, 129.7, 129.4, 128.8, 128.3, 128.2, 127.8, 127.7, 126.1, 116.8, 116.4, 99.7, 73.2, 70.2, 21.4 ppm; HRMS (ESI) calcd for C28H27ClNO3S+ [M+H]+: 492.1395, found 492.1405.

4. 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(PPh3)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.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal14080508/s1, Figure S1. 1H-NMR spectrum of the reaction product of 3a; Figure S2. 13C-NMR spectrum of the reaction product of 3a; Figure S3. 1H-NMR spectrum of the reaction product of 3b; Figure S4. 13C-NMR spectrum of the reaction product of 3b; Figure S5. 1H-NMR spectrum of the reaction product of 3c; Figure S6. 13C-NMR spectrum of the reaction product of 3c; Figure S7. 1H-NMR spectrum of the reaction product of 3d; Figure S8. 13C-NMR spectrum of the reaction product of 3d; Figure S9. 1H-NMR spectrum of the reaction product of 3e; Figure S10. 13C-NMR spectrum of the reaction product of 3e; Figure S11. 1H-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. 1H-NMR spectrum of the reaction product of 3g; Figure S15. 13C-NMR spectrum of the reaction product of 3g; Figure S16. 1H-NMR spectrum of the reaction product of 3h; Figure S17. 13C-NMR spectrum of the reaction product of 3h; Figure S18. 1H-NMR spectrum of the reaction product of 3i; Figure S19. 13C-NMR spectrum of the reaction product of 3i; Figure S20. 1H-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. 1H-NMR spectrum of the reaction product of 3k; Figure S24. 13C-NMR spectrum of the reaction product of 3k; Figure S25. 1H-NMR spectrum of the reaction product of 3l; Figure S26. 13C-NMR spectrum of the reaction product of 3l; Figure S27. 1H-NMR spectrum of the reaction product of 3m; Figure S28. 13C-NMR spectrum of the reaction product of 3m; Figure S29. 1H-NMR spectrum of the reaction product of 3n; Figure S30. 13C-NMR spectrum of the reaction product of 3n; Figure S31. 1H-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. 1H-NMR spectrum of the reaction product of 3p; Figure S35. 13C-NMR spectrum of the reaction product of 3p; Figure S36. 1H-NMR spectrum of the reaction product of 3q; Figure S37. 13C-NMR spectrum of the reaction product of 3q; Figure S38. 1H-NMR spectrum of the reaction product of 3r; Figure S39. 13C-NMR spectrum of the reaction product of 3r; Figure S40. 1H-NMR spectrum of the reaction product of 3s; Figure S41. 13C-NMR spectrum of the reaction product of 3s; Figure S42. 1H-NMR spectrum of the reaction product of 3t; Figure S43. 13C-NMR spectrum of the reaction product of 3t; Figure S44. Crystal data and structure refinement for 3a.

Author Contributions

E.-Q.L. conceived and designed the experiments; Y.W. (Yuanbo Wang), T.S. and Q.L. performed the experiments; Y.W. (Yue Wang) analyzed the data; E.-Q.L. wrote the paper. All authors have read and agreed to the published version of the manuscript.

Funding

We are grateful to the National Natural Science Foundation of China (21702189), Science and technology research and development plan joint fund (cultivation of superior disciplines) project (222301420042), and Zhengzhou University (JC21253007) of China for financial support of this research, as well as the Natural Science Foundation of Henan Province (242300420545) and the Start-up Grant of Henan University of Technology (2022BS051).

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

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Catalysts 14 00508 sch001
Scheme 1. Selected natural products and synthetic bioactive compounds and study background.
Scheme 1. Selected natural products and synthetic bioactive compounds and study background.
Catalysts 14 00508 sch001
Catalysts 14 00508 sch002
Scheme 2. Gram-scale synthesis.
Scheme 2. Gram-scale synthesis.
Catalysts 14 00508 sch002
Catalysts 14 00508 sch003
Scheme 3. Proposed mechanism for the palladium-catalyzed [2+3] cycloadditions.
Scheme 3. Proposed mechanism for the palladium-catalyzed [2+3] cycloadditions.
Catalysts 14 00508 sch003
Table 1. Optimization of palladium catalysts a.
Table 1. Optimization of palladium catalysts a.
Catalysts 14 00508 i001
Entry[Pd]Yield (%) b
1Pd(PPh3)482
2Pd2dba382
3Pd(dba)267
4PdCl220
5Pd2dba3·CHCl378
6Pd(OAc)29
7Pd(CH3CN)2Cl275
a Unless otherwise noted, the reaction of 1a (0.1 mmol), 2a (0.20 mmol), [Pd] (10 mol%), xantphos (20 mol%), Cs2CO3 (2.0 equiv.) was performed at 40 °C in 1.0 mL of toluene. b Isolated yield.
Table 2. Optimization of the bases a.
Table 2. Optimization of the bases a.
Catalysts 14 00508 i002
EntryBaseYield (%) b
1Cs2CO382
2Na2CO357
3K2CO376
4LiOH64
5NaHCO357
6K2HPO459
7DMAP24
8DBU-
a Unless otherwise noted, the reaction of 1a (0.1 mmol), 2a (0.20 mmol), Pd(PPh3)4 (10 mol%), bases (2.0 equiv) was performed at 40 °C in 1.0 mL of toluene. b Isolated yield.
Table 3. Optimization of solvents a.
Table 3. Optimization of solvents a.
Catalysts 14 00508 i003
EntrySolventYield (%) b
1Toluene82
2CH2Cl272
3CHCl345
4MeCN49
5DMF24
6Et2O73
7EtOAc66
8THF67
91,4-dioxane57
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 solvent. b Isolated yield.
Table 4. Substrate scope for [2+3] cycloadditions of α,β-unsaturated imines 1 and VECs 2a a.
Table 4. Substrate scope for [2+3] cycloadditions of α,β-unsaturated imines 1 and VECs 2a a.
Catalysts 14 00508 i004
EntryRAr1Ar2Yield (%) b
1PhPhPh82 (3a)
24-MeC6H4PhPh56 (3b)
34-BrC6H4PhPh61 (3c)
44-NO2C6H4PhPh84 (3d)
54-CF3C6H4PhPh60 (3e)
64-FC6H4PhPh72 (3f)
74-MeOC6H4PhPh30 (3g)
83-BrC6H4PhPh32 (3h)
9Ph4-MeC6H4Ph27 (3i)
10Ph4-FC6H4Ph22 (3j)
11Ph2,4,6-Me3C6H2Ph53 (3k)
12Ph4-ClC6H4Ph63 (3l)
13Ph2-FC6H4Ph68 (3m)
14PhPh4-ClC6H477 (3n)
15PhPh4-FC6H484 (3o)
16PhPh3-BrC6H432 (3p)
174-MeC6H4Ph4-ClC6H437 (3q)
18PhPh3,5-MeC6H353 (3r)
19Ph4-ClC6H43,5-MeC6H350 (3s)
20Ph3-MeC6H44-ClC6H436 (3t)
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.
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MDPI and ACS Style

Wang, Y.; Wang, Y.; Sun, T.; Liu, Q.; Li, E.-Q. Palladium-Catalyzed Regioselective [3+2] Cycloadditions of α,β-Unsaturated Imines with Vinylethylene Carbonates: Access to Oxazolidines. Catalysts 2024, 14, 508. https://doi.org/10.3390/catal14080508

AMA Style

Wang Y, Wang Y, Sun T, Liu Q, Li E-Q. Palladium-Catalyzed Regioselective [3+2] Cycloadditions of α,β-Unsaturated Imines with Vinylethylene Carbonates: Access to Oxazolidines. Catalysts. 2024; 14(8):508. https://doi.org/10.3390/catal14080508

Chicago/Turabian Style

Wang, Yuanbo, Yue Wang, Tong Sun, Qinglin Liu, and Er-Qing Li. 2024. "Palladium-Catalyzed Regioselective [3+2] Cycloadditions of α,β-Unsaturated Imines with Vinylethylene Carbonates: Access to Oxazolidines" Catalysts 14, no. 8: 508. https://doi.org/10.3390/catal14080508

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