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Article

Aerial Oxygen-Driven Selenocyclization of O-Vinylanilides Mediated by Coupled Fe3+/Fe2+ and I2/I− Redox Cycles

by
Hao-Yuan Zhang
,
Tong-Tong Zeng
,
Zhen-Biao Xie
,
Ying-Ying Dong
,
Cha Ma
,
Shan-Shan Gong
and
Qi Sun
*
Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science and Technology Normal University, Nanchang 330013, China
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(21), 7386; https://doi.org/10.3390/molecules27217386
Submission received: 12 October 2022 / Revised: 23 October 2022 / Accepted: 24 October 2022 / Published: 31 October 2022
(This article belongs to the Special Issue Synthesis of Benzo-Fused Heterocycles)
Browse Figures
Versions Notes

Abstract

:
In the past decade, selenocyclization has been extensively exploited for the preparation of a wide range of selenylated heterocycles with versatile activities. Previously, selenium electrophile-based and FeCl3-promoted methods were employed for the synthesis of selenylated benzoxazines. However, these methods are limited by starting material availability and low atomic economy, respectively. Inspired by the recent catalytic selenocyclization approaches based on distinctive pathways, we rationally constructed an efficient and greener double-redox catalytic system for the access to diverse selenylated benzoxazines. The coupling of I2/I− and Fe3+/Fe2+ catalytic redox cycles enables aerial O2 to act as the driving force to promote the selenocyclization. Control and test redox experiments confirmed the roles of each component in the catalytic system, and a PhSeI-based pathway is proposed for the selenocyclization process.

Graphical Abstract

1. Introduction

Selenium-containing organic compounds, also known as organoselenium compounds, are an important and unique category of organic molecules. As shown in Figure 1, organoselenium compounds (1–8) exhibit versatile biological and pharmacological activities [1,2,3], such as antioxidant [4,5,6,7,8], antimicrobial [9,10,11], antiproliferative [12,13,14,15], and antiinflammatory activities [16]. Selenium-based probes (9–10) [17] have also been developed for highly sensitive fluorimetric detection of reactive oxygen species (ROS), such as ClO− [18] and O2•− [19], in living cells. In addition, the selenium-containing fused bicyclic heterocycle (11) and its analogs have been demonstrated as active organic field effect transistor materials [20]. In the realm of organic synthesis, organoselenium compounds also have a wide range of applications, such as ligands for organometallic catalysts (12) [21], synthetic intermediates [22,23,24], and even direct catalysts [25]. Therefore, a huge amount effort has been devoted to developing efficient synthetic methods for selenylated heterocycles over the past decade [26,27,28].
As an important heterocyclic scaffold, 3,1-benzoxazine is widely found in natural products and bioactive molecules [29,30,31]. Numerous types of substituted benzoxazines have been synthesized via either cation- or radical-initiated tandem cyclizations [32,33,34,35]. Among them, selenylated benzoxazines have been successfully synthesized from the selenocyclization of selenium electrophiles, such as PhSeCl, PhSe+CF3COO− [36], and N-(PhSe)succinimide with o-vinylanilides [37] (Figure 2a). However, this approach is limited by the availability of selenium electrophiles (RSeX) and difficult to apply to R-modified selenocyclizations. Fe3+-promoted selenocyclization with readily available diorganyl diselenides could be a good alternative approach [38,39,40,41]. In our experiments (Figure 2b), excess FeCl3 (2 equiv) was required to afford the desired products in 3−4 h due to the chelation of in situ-generated PhSe− with Fe3+. Since the generation of one PhSe+ is accompanied by the formation of one PhSe− and the consumption of one molecule of Fe3+, the efficiency of this method is low in terms of atomic economy. It is worth noting that Zhang and coworkers reported that the combination of a catalytic amount of FeCl3/benzoyl peroxide (BPO) and 2 equiv of I2 with diselenides afforded the desired products via both cation- and radical-initiated pathways [42] (Figure 2c). According to the mechanism proposed by Zhang et al., BPO facilitated the generation of RSeI and RSe•, while FeCl3 catalyzed the electrophilic cyclization of the neighboring aryl ring. More recently, Zhang et al. reported that I• generated from the redox reaction of FeCl3 and KI induced the RSe•-initiated reaction pathway and the oxidation of the radical intermediates by Fe3+, and aerial oxygen yielded the desired products in 24 h under refluxing conditions [43] (Figure 2d). Inspired by these previous research, we envisioned that only catalytic amount of I2 is actually needed to convert diselenide to RSeI, an ideal selenium electrophile [23,44], if the resulting I− could be recycled to I2 by a second oxidant. Many high-valent metals are capable of oxidizing I−, but their low-valent counterparts are prone to be oxidized by O2. Therefore, the insertion of a multivalent metal redox cycle into the I2/I− redox cycle and O2 may construct a double-redox catalytic system for selenylated benzoxazines, featuring greener reaction conditions and high atomic economy. Herein, we report an efficient aerial O2-driven selenocyclization approach mediated by coupled Fe3+/Fe2+ and I2/I− redox cycles (Figure 2e). Mechanistic investigation confirmed the roles of each component in this novel double-redox catalytic system and revealed the reasons why Fe3+ exhibited the best catalytic reactivity.

2. Results and Discussion

In the preliminary experiments, the catalytic reactivities of a series of multivalent transition metal salts, including Cu(acac)2, Co(acac)3, VO(acac)2, Ce(NH4)2(NO3)6, Ni(acac)2, MoO2(acac)2, PMA, Fe(acac)3, Fe(OTf)3, and FeCl3, were tested. The reaction of 1.0 equiv of o-vinylanilide 1a, 0.6 equiv of diselenide 2a, and 0.1 equiv of metal salt and I2 in CH3CN was refluxed under air atmosphere. The data summarized in Table 1 (Entry 1−10) indicate that all of these multivalent transition metals showed some catalytic effect. A major problem with these metal catalysts is that these reactions had difficulty in terms of completion. Among these metals, Fe3+ salts exhibited remarkably superior reactivity. In the presence of 10 mol% FeCl3, the selenocyclization took only 30 min to afford the desired benzoxazine product 3a with 93% yield. In addition, the experimental results (Table 1, Entry 11–14) showed that the FeCl3-catalyzed reaction exhibited notable solvent effects. Acetonitrile was proved as the most suitable solvent. In addition, we further reduced the amount of FeCl3 and I2 and found that the reaction could not go to completion when the amount of either FeCl3 or I2 was lowered to 5%.
With the optimized reaction conditions, we further explored the scope of this double-redox catalytic system in the synthesis of selenylated benzoxazines. The data in Table 2 showed that the new method tolerated a variety of substituents on both o-vinylanilide and diorganyl diselenide substrates at different positions. Generally, both strong electron-withdrawing -NO2 on the benzoyl moiety and more sterically hindered phenyl on the vinyl moiety resulted in lowered reaction rate. As shown in Table 2, selenylated benzoxazines 3a–3t were obtained in 80–93% yields in 0.5–2 h.
To elucidate the proposed roles of each key component in the catalytic system, a series of control experiments were performed. As shown in Scheme 1a,b, the absence of either catalytic amount of FeCl3 or I2 resulted in the formation of only a trace amount of 3a. When the reaction was conducted in argon atmosphere, it simply afforded 3a in 38% yield (Scheme 1c). The above experimental results clearly indicate that FeCl3, I2, and aerial O2 are essential to the catalytic system, but replacement of aerial O2 with pure O2 did not lead to improvement in the catalytic efficacy, suggesting that the proposed O2 oxidation of Fe2+ was not the rate-limiting step (Scheme 1d). Finally, the ineffectiveness of TEMPO on the proceeding of this reaction implies that radical species (RSe•) should not be involved in reaction pathway [45,46] (Scheme 1e).
To prove the existence and coupling of the proposed Fe3+/Fe2+ and I2/I− redox cycles, we further performed a series of control redox reactions without o-vinylanilide. As shown in Scheme 2a, a qualitative chromogenic assay (Figure S1a,b) showed that the treatment of Fe3+ with I− at ambient temperature caused an abrupt formation of a large amount of Fe2+ and I2. In another experiment, the exposure of FeCl2 in CH3CN to air at 80 °C for 10 min led to complete oxidation of Fe2+ to Fe3+ (Scheme 2b) as indicated by a chromogenic assay (Figure S1c). Surprisingly, we found that almost no Fe3+ could be detected after the aqueous solution of FeCl2 was exposed to air for 30 min at 80 °C. This result indicates that the efficacy of the aerial oxidation of Fe2+ is solvent dependent, which may possibly be one important reason why CH3CN is most suitable for this reaction. Finally, we tested the reaction of I2 with PhSeSePh (Scheme 2c). As shown in Figure S2a, the reaction proceeded very slowly at ambient temperature. As indicated by the decoloration of I2, refluxing at 80 °C significantly promoted the formation of PhSeI. However, it still took 3 h for the reaction to reach equilibrium (Figure S2b). When a catalytic amount of Fe3+ (10 mol%) was added, the decoloration time was significantly shortened to 30 min (Figure S2c). This result could be explained by the specific chelation of Fe3+ with diselenide and induced polarization of Se-Se bonds, which have been reported in numerous previous reports [38,39,40,41,47]. The revealed dual roles of Fe3+ well explained its superior catalytic activity compared with other multivalent metals in this selenocyclization reaction.
On the basis of the above control experiments and tested redox reactions, a plausible mechanism was proposed for the current catalytic selenocyclization system (Figure 3). At the beginning of the reaction, Fe3+ catalyzed the formation of PhSeI (2a), the reactive selenium electrophile, which quickly reacted with o-vinylanilide (1a) and formed the seleniranium intermediate (INT1). The intramolecular nucleophilic cyclization (INT2) followed by the deprotonation by the superoxide radical anion (O2•−) afforded the desired benzoxazine (3a). Meanwhile, the released I− was instantly oxidized back to I2 by Fe3+ to provide a continuous resource of PhSeI. The consumed Fe3+ was also quickly recycled by the aerial oxidation of Fe2+. Therefore, the selenocyclization was pushed forward by a green oxidant, aerial oxygen, and only catalytic amounts of FeCl3 and I2 were needed. Since k2 > k1 > k3 in the redox cycles, the majority of ion metal existed as Fe3+, and iodine existed as I2 during the reaction process, which was verified by a chromogenic assay (Figure S3).

3. Materials and Methods

3.1. General Methods

The solvents and chemical reagents used in the current research work were purchased from commercial suppliers. All of the reactions were monitored by TLC plates coated with 0.25 mm silica gel 60 F254 and visualized by 254 nm UV. The silica gel used in column chromatography (particle size 32–63 μm) was purchased from Qingdao Haiyang Chemicals, China. 1H, 13C, and 19F NMR spectra were recorded on an AV-400 instrument (Bruker BioSpin, Faellanden, Switzerland) with chemical shifts referenced to DMSO-d6 or CDCl3 and reported in parts per million. Infrared spectra were obtained with a Vertex-70 instrument (Bruker Optics, Billerica, MA, US). HRMS spectra were acquired with a micrOTOF-Q II instrument (Bruker Daltonics, Billerica, MA, US)and reported as m/z. Melting points were measured on anX-4 melting point apparatus and were uncorrected (Tech Instrument, Beijing, China).The characterization data of new o-vinylanilides [37,48,49,50,51] including 1e, 1f, 1g, and 1h and known selenylated benzoxazines [36,52] including 3a, 3d, 3q, and 3r are listed in the Supplementary Materials. The NMR spectra of new o-vinylanilides and benzoxazines are provided in the Supplementary Materials.

3.2. General Synthetic Procedure and the Characterization of Selenylated Benzoxazines (3a–3t)

To a mixture of o-vinylanilide (0.1 mmol) and diorganyl diselenide (0.06 mmol) in CH3CN (2 mL), FeCl3 (0.01 mmol) and I2 (0.01 mmol) were added. The reaction was heated at 80 °C for 0.5–2 h and then concentrated in vacuo. Flash column chromatography on silica gel (PE/EA = 10:1) afforded the desired products 3a–3t in pure form.
4-Methyl-2-(4-nitrophenyl)-4-((phenylselanyl)methyl)-4H-benzo[d][1,3]oxazine (3b): a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.23 (s, 4H), 7.39–7.35 (m, 4H), 7.28–7.22 (m, 1H), 7.17–7.12 (m, 4H), 3.58 (d, J = 13.0 Hz, 1H), 3.38 (d, J = 13.0 Hz, 1H), 1.92 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 153.9, 149.2, 147.0, 138.4, 138.2, 132.8 (×2), 129.2, 129.0, 128.7 (×3), 127.6, 127.1 (×2), 125.8, 124.4, 123.9, 123.2 (×2), 119.1, 80.8, 59.5, 29.6; IR (KBr): vmax 3464, 3088, 3002, 2935, 1635, 1590, 1522, 1385, 1346, 1185, 1085, 939, 893, 810, 745 cm−1; HRMS (ESI+): m/z calcd for C22H19N2O3Se [M + H]+ 439.0555; found 439.0552.
4-Methyl-4-((phenylselanyl)methyl)-2-(thiophen-2-yl)-4H-benzo[d][1,3]oxazine (3c): a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 2.2 Hz, 1H), 7.38 (d, J = 3.9 Hz, 1H), 7.31–7.30 (m, 2H), 7.21–7.18 (m, 2H), 7.06 (t, J = 4.8 Hz, 5H), 6.99 (t, J = 3.7 Hz, 1H), 3.49 (d, J = 10.2 Hz, 1H), 3.26 (d, J = 10.2 Hz, 1H), 1.79 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 151.9, 137.7, 135.8, 131.8 (×2), 129.4, 129.2, 129.0, 128.0, 127.9 (×3), 127.6, 126.6, 125.9, 125.3, 123.9, 122.1, 79.4, 38.6, 25.3; IR (KBr): vmax 3724, 2962, 1589, 1479, 1426, 1367, 1314, 1263, 1218, 1028, 804 cm−1; HRMS (ESI+): m/z calcd for C22H18NOSSe [M + H]+ 400.0269; found 400.0266.
8-Methyl-6-phenyl-8-((phenylselanyl)methyl)-8H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d][1,3]oxazine (3e): a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 7.5 Hz, 2H), 7.48–7.38 (m, 5H), 7.15–7.14 (m, 3H), 6.82 (s, 1H), 6.61 (s, 1H), 5.95 (d, J = 12.8 Hz, 1H), 5.92 (d, J = 12.8 Hz, 1H), 3.48 (d, J = 12.8 Hz, 1H), 3.35 (d, J = 12.8 Hz, 1H), 1.84 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 155.0, 147.7, 146.1, 134.0, 132.8 (×2), 132.5, 131.1, 130.4, 128.9 (×3), 128.1 (×2), 127.8 (×2), 126.9, 121.7, 106.2, 103.5, 101.3, 79.9, 39.5, 26.4; IR (KBr): vmax 3722, 2963, 1624, 1593, 1482, 1401, 1317, 1262, 1162, 1091, 1019, 805, 765 cm−1; HRMS (ESI+): m/z calcd for C23H20NO3Se [M + H]+ 438.0603; found 438.0604.
6-(4-Chlorophenyl)-8-methyl-8-((phenylselanyl)methyl)-8H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d][1,3]oxazine (3f): a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.5 Hz, 2H), 7.38–7.35 (m, 4H), 7.16–7.13 (m, 3H), 6.79 (s, 1H), 6.59 (s, 1H), 5.95 (d, J = 1.2 Hz, 1H), 5.93 (d, J = 1.2 Hz, 1H), 3.46 (d, J = 12.9 Hz, 1H), 3.31 (d, J = 12.9 Hz, 1H), 1.83 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 154.0, 147.7, 146.2, 137.2, 133.8, 132.7 (×2), 131.0, 130.3, 129.1 (×2), 129.0 (×3), 128.4 (×2), 127.0, 121.6, 106.2, 103.4, 101.3, 80.1, 39.6, 26.5; IR (KBr): vmax 3721, 2891, 1574, 1478, 1441, 1368, 1312, 1263, 1192, 1036, 939, 863, 830, 736 cm−1; HRMS (ESI+): m/z calcd for C23H21ClNO3Se [M + H]+ 474.8455; found 474.8457.
8-Methyl-8-((phenylselanyl)methyl)-6-(thiophen-2-yl)-8H-[1,3]dioxolo[4′,5′:4,5]benzo [1,2-d][1,3]oxazine (3g): a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.64 (d, J = 3.4 Hz, 1H), 7.45 (d, J = 4.8 Hz, 1H), 7.40–7.37 (m, 2H), 7.16–7.15 (m, 3H), 7.06 (t, J = 4.2 Hz, 1H), 6.76 (s, 1H), 6.59 (s, 1H), 5.94 (s, 1H), 5.92 (s, 1H), 3.47 (d, J = 12.8 Hz, 1H), 3.32 (d, J = 12.8 Hz, 1H), 1.82 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 151.7, 147.7, 145.9, 136.9, 133.9, 132.7 (×2), 130.4, 129.9, 129.7, 128.9 (×3), 127.6, 126.9, 121.6, 105.9, 103.6, 101.2, 80.4, 39.3, 26.3; IR (KBr): vmax 3725, 2944, 1626, 1591, 1478, 1421, 1365, 1308, 1263, 1183, 1035, 852, 804, 734 cm−1; HRMS (ESI+): m/z calcd for C21H18NO3SSe [M + H]+ 444.0167; found 444.0163.
6-(4-Methoxyphenyl)-8-methyl-8-((phenylselanyl)methyl)-8H-[1,3]dioxolo[4′,5′:4,5]benzo [1,2-d][1,3]oxazine (3h): a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 8.7 Hz, 2H), 7.41–7.39 (m, 2H), 7.17–7.16 (m, 3H), 6.93 (d, J = 8.7 Hz, 2H), 6.80 (s, 1H), 6.62 (s, 1H), 5.96 (s, 1H), 5.94 (s, 1H), 3.88 (s, 3H), 3.48 (d, J = 12.7 Hz, 1H), 3.34 (d, J = 12.7 Hz, 1H), 1.84 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.1, 155.0, 147.7, 145.7, 134.3, 132.7 (×2), 129.6 (×2), 128.9 (×3), 126.9, 113.5 (×2), 105.9, 103.4, 101.2, 79.7, 55.3, 39.4, 26.2; IR (KBr): vmax 3715, 2963, 1601, 1505, 1478, 1367, 1310, 1258, 1172, 1088, 1032, 941, 763 cm−1; HRMS (ESI+): m/z calcd for C24H22NO4Se [M + H]+ 468.0709; found 468.0712.
2,4-Diphenyl-4-((phenylselanyl)methyl)-4H-benzo[d][1,3]oxazine (3i): a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 7.0 Hz, 1H), 7.45–7.37 (m, 8H), 7.32–7.26 (m, 3H), 7.22–7.14 (m, 5H), 3.95 (d, J = 13.1 Hz, 1H), 3.90 (d, J = 13.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 156.2, 142.3, 139.4, 133.4 (×3), 132.3, 131.4 (×2), 130.4, 129.2, 129.0 (×2), 128.4 (×2), 128.2 (×2), 128.0 (×2), 127.5, 127.1, 126.4, 126.0, 125.5, 124.6, 83.5, 39.3; IR (KBr): vmax 3515, 3438, 1956, 1628, 1482, 1455, 1316, 1260, 1082, 1022, 801, 763 cm−1; HRMS (ESI+): m/z calcd for C27H22NOSe [M + H]+ 456.0861; found 456.0862.
4-Phenyl-4-((phenylselanyl)methyl)-2-(p-tolyl)-4H-benzo[d][1,3]oxazine (3j): a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.2 Hz, 2H), 7.52–7.48 (m, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.34–7.26 (m, 4H), 7.19–7.18 (m, 2H), 7.09–7.05 (m, 1H), 7.02–6.97 (m, 1H), 3.60 (d, J = 12.6 Hz, 1H), 3.43 (d, J = 12.6 Hz, 1H), 1.94 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 156.1, 138.8, 135.8, 132.5, 132.3 (×2), 131.3, 130.7, 129.4, 129.1 (×2), 128.6 (×3), 128.1 (×2), 128.0 (×2), 127.7, 127.0, 126.6, 125.3, 123.0, 79.8, 38.2, 26.6; IR (KBr): vmax 3436, 1628, 1484, 1446, 1385, 1318, 1262, 1162, 1089, 1024, 758 cm−1; HRMS (ESI+): m/z calcd for C28H24NOSe [M + H]+ 470.1018; found 470.1015.
2-(4-Chlorophenyl)-4-phenyl-4-((phenylselanyl)methyl)-4H-benzo[d][1,3]oxazine (3k): a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 8.6 Hz, 2H), 7.44–7.36 (m, 8H), 7.33–7.29 (m, 3H), 7.24–7.12 (m, 5H), 3.93 (d, J = 13.2 Hz, 1H), 3.89 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 155.2, 142.1, 139.2, 137.6, 133.3 (×2), 130.8, 129.3 (×2), 129.0 (×2), 128.5 (×3), 128.4 (×2), 128.3 (×2), 127.4, 127.2, 126.6, 125.9, 125.6, 124.6, 83.7, 39.1; IR (KBr): vmax 3399, 1658, 1481, 1446, 1398, 1315, 1259, 1085, 1022, 939, 801, 736 cm−1; HRMS (ESI+): m/z calcd for C27H21ClNOSe [M + H]+ 490.0471; found 490.0472.
2-(4-Nitrophenyl)-4-phenyl-4-((phenylselanyl)methyl)-4H-benzo[d][1,3]oxazine (3l): a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.24 (s, 4H), 7.44–7.27 (m, 10H), 7.20–7.13 (m, 4H), 3.94 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 154.0, 149.4, 142.0, 138.8, 133.2 (×2), 130.6, 129.4, 129.0 (×2), 128.7 (×2), 128.5 (×3), 127.4, 127.2, 126.0, 125.9 (×2), 124.8, 123.9, 123.3 (×2), 84.3, 39.0; IR (KBr): vmax 3399, 2963, 1628, 1521, 1499, 1446, 1390, 1316, 1260, 1083, 1024, 801, 762 cm−1; HRMS (ESI+): m/z calcd for C27H21N2O3Se [M + H]+ 501.0712; found 501.0709.
4-Phenyl-4-((phenylselanyl)methyl)-2-(thiophen-2-yl)-4H-benzo[d][1,3]oxazine (3m): a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 3.6 Hz, 1H), 7.48–7.45 (m, 3H), 7.41–7.26 (m, 8H), 7.23–7.17 (m, 4H), 7.15–7.09 (m, 2H), 3.95 (d, J = 13.1 Hz, 1H), 3.86 (d, J = 13.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 152.9, 142.1, 139.5, 133.3 (×2), 130.9, 130.4, 130.2, 129.3, 129.0 (×2), 128.4 (×3), 128.3 (×2), 127.7, 127.3, 127.1, 126.2, 126.0, 125.3, 124.7, 83.9, 39.1; IR (KBr): vmax 3401, 2963, 1628, 1521, 1465, 1400, 1261, 1088, 1025, 802, 755 cm−1; HRMS (ESI+): m/z calcd for C25H20NOSSe [M + H]+ 462.0425; found 462.0415.
6-Bromo-2,4-diphenyl-4-((phenylselanyl)methyl)-4H-benzo[d][1,3]oxazine (3n): a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 6.2 Hz, 2H), 7.43 (t, J = 6.0 Hz, 1H), 7.38–7.32 (m, 5H), 7.29 (d, J = 5.8 Hz, 2H), 7.25–7.20 (m, 3H),7.15–7.07 (m, 5H), 3.81 (d, J = 10.6 Hz, 1H), 3.77 (d, J = 10.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 155.4, 140.5, 137.5, 132.6 (×2), 131.2, 130.8, 130.6 (×2), 129.4, 128.2, 128.0 (×3), 127.5 (×2), 127.4 (×2), 127.2 (×2), 127.0, 126.6, 126.3, 126.1, 124.9, 118.2, 82.3, 38.1; IR (KBr): vmax 3758, 2921, 1617, 1573, 1471, 1385, 1315, 1257, 1176, 1156, 1079, 1024, 966, 827, 735 cm−1; HRMS (ESI+): m/z calcd for C27H21BrNOSe [M + H]+ 533.9966; found 533.9949.
6-Bromo-2-methyl-4-phenyl-4-((phenylselanyl)methyl)-4H-benzo[d][1,3]oxazine (3o): a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.36–7.35 (m, 2H), 7.30–7.23 (m, 6H), 7.15–7.14 (m, 3H), 6.94 (d, J = 6.2 Hz, 2H), 3.68 (d, J = 10.6 Hz, 1H), 3.63 (d, J = 10.6 Hz, 1H), 1.97 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.0, 141.0, 136.8, 132.4 (×2), 131.2, 129.4 (×2), 128.0 (×2), 127.6, 127.5 (×2), 127.3, 126.8, 126.4, 125.2, 124.9, 117.9, 82.0, 38.0, 20.6; IR (KBr): vmax 3722, 2890, 1598, 1574, 1478, 1411, 1368, 1312, 1263, 1193, 1036, 936, 863, 831, 783 cm−1; HRMS (ESI+): m/z calcd for C22H19BrNOSe [M + H]+ 471.9810; found 471.9803.
4-(((2-Chlorophenyl)selanyl)methyl)-4-methyl-2-phenyl-4H-benzo[d][1,3]oxazine (3p): a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 7.7 Hz, 3H), 7.50–7.42 (m, 3H), 7.34–7.27 (m, 4H), 7.19 (s, 2H), 7.07 (t, J = 7.4 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 3.60 (d, J = 12.6 Hz, 1H), 3.42 (d, J = 12.6 Hz, 1H), 1.94 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 156.1, 147.0, 138.8, 132.4, 131.2, 129.4, 128.1 (×2), 128.0 (×2), 127.7, 126.6, 125.3, 124.4, 123.9, 123.0, 119.1, 79.8, 38.2, 26.6; IR (KBr): vmax 3742, 2942, 2883, 1624, 1593, 1572, 1487, 1451, 1319, 1284, 1245, 1173, 1092, 1067, 1029, 935, 819, 760 cm−1; HRMS (ESI+): m/z calcd for C22H19ClNOSe [M + H]+ 428.0315; found 428.0307.
6-(4-Methoxyphenyl)-8-methyl-8-((methylselanyl)methyl)-8H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d][1,3]oxazine (3s): a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.82 (s, 1H), 6.69 (s, 1H), 5.98 (s, 2H), 3.97 (s, 3H), 3.05 (d, J = 13.0 Hz, 1H), 2.95 (d, J = 13.0 Hz, 1H), 1.84 (d, J = 8.7 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 162.2, 155.1, 147.6, 145.8, 134.4, 129.6 (×2), 121.9, 113.6 (×2), 105.9, 103.4, 101.2, 80.0, 55.3, 36.9, 31.4, 30.2, 26.0, 6.4; IR (KBr): vmax 3741, 3410, 2960, 2899, 2836, 1614, 1505, 1479, 1311, 1256, 1172, 1086, 1034, 941, 838, 806 cm−1; HRMS (ESI+): m/z calcd for C19H20NO4Se [M + H]+ 406.0552; found 406.0550.
4-(((4-Methoxyphenyl)selanyl)methyl)-4-methyl-2-phenyl-4H-benzo[d][1,3]oxazine (3t): a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 7.2 Hz, 2H), 7.55–7.48 (m, 3H), 7.44 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 4.1 Hz, 2H), 7.28–7.23 (m, 1H), 7.19 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 3.69 (d, J = 11.0 Hz, 1H), 3.50 (d, J = 11.0 Hz, 1H), 1.96 (s, 3H); 13C NMR (100 MHz, CDCl3): δ159.2, 156.0, 138.8, 134.6, 132.3 (×2), 131.6, 129.5, 128.4 (×2), 128.2 (×2), 127.0, 126.8, 125.6, 123.0, 122.1 115.0 (×2), 55.3, 26.6, 15.7; IR (KBr): vmax 3727, 3046, 2996, 2941, 2907, 2837, 1932, 1849, 1794, 1618, 1592, 1272, 1489, 1448, 1369, 1318, 1029, 967, 838, 890, 835, 814, 751 cm−1; HRMS (ESI+): m/z calcd for C23H22NO2Se [M + H]+ 424.0810; found 424.0805.

4. Conclusions

In summary, a novel double-redox catalytic system was rationally constructed to provide efficient access to a variety of selenylated benzoxazines. The combination of only catalytic amounts of FeCl3 and I2 and the use of aerial oxygen as the end oxidant make this approach greener and more atomically efficient than conventional methods based on selenium electrophiles and FeCl3. This new method is widely applicable to a great diversity of o-vinylanilide and diorganyl diselenide substrates. Mechanistic investigation confirmed that the coupling of I2/I− and Fe3+/Fe2+ catalytic redox cycles enabled aerial O2 to act as the driving force to promote the selenocyclization reaction, which proceeds via a PhSeI-based pathway.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/molecules27217386/s1: characterization data of new o-vinylanilides and known selenylated benzoxazines, Figures S1–S3: The chromogenic assays of the control redox reactions without o-vinylanilide and Figures S4–S51: The NMR spectra of new o-vinylanilides and all products.

Author Contributions

Conceptualization, H.-Y.Z. and Q.S.; methodology, H.-Y.Z.; validation, Z.-B.X.; formal analysis, T.-T.Z.; investigation, H.-Y.Z.; resources, Y.-Y.D.; writing—original draft preparation, S.-S.G.; writing—review and editing, Q.S.; visualization, C.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (21961013 for Q.S.) and the Science and Technology Project of the Dept. of Education of Jiangxi Province (GJJ211136 for S.-S.G.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of all compounds are available from the authors.

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Molecules 27 07386 g001 550
Figure 1. Representative organoselenium compounds.
Figure 1. Representative organoselenium compounds.
Molecules 27 07386 g001
Molecules 27 07386 g002 550
Figure 2. Previous and current selenocyclization methods.
Figure 2. Previous and current selenocyclization methods.
Molecules 27 07386 g002
Molecules 27 07386 sch001 550
Scheme 1. Control experiments.
Scheme 1. Control experiments.
Molecules 27 07386 sch001
Molecules 27 07386 sch002 550
Scheme 2. Separated control redox reactions without o-vinylanilide.
Scheme 2. Separated control redox reactions without o-vinylanilide.
Molecules 27 07386 sch002
Molecules 27 07386 g003 550
Figure 3. Proposed reaction mechanism.
Figure 3. Proposed reaction mechanism.
Molecules 27 07386 g003
Table
Table 1. Optimization of reaction conditions 1.
Table 1. Optimization of reaction conditions 1.
Molecules 27 07386 i001
EntryMn+SolventReaction Time (h)Isolated Yield (%)
1Cu(acac)2CH3CN855
2Co(acac)3CH3CN851
3VO(acac)2CH3CN1245
4Ce(NH4)2(NO3)6CH3CN252
5Ni(acac)2CH3CN822
6MoO2(acac)2CH3CN827
7PMACH3CN528
8Fe(OTf)3CH3CN992
9Fe(acac)3CH3CN194
10FeCl3CH3CN0.593
11FeCl3DCE355
12FeCl3THF473
13FeCl3DMSO380
14FeCl3EtOH681
1 Reaction conditions: 1a (0.10 mmol), 2a (0.06 mmol), FeCl3 (0.01 mmol), I2 (0.01 mmol), solvent (2.0 mL), 80 °C, air.
Table
Table 2. Aerial O2-driven double-redox synthesis of selenylated benzoxazines (3a–3t).
Table 2. Aerial O2-driven double-redox synthesis of selenylated benzoxazines (3a–3t).
Molecules 27 07386 i002
Molecules 27 07386 i003
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Zhang, H.-Y.; Zeng, T.-T.; Xie, Z.-B.; Dong, Y.-Y.; Ma, C.; Gong, S.-S.; Sun, Q. Aerial Oxygen-Driven Selenocyclization of O-Vinylanilides Mediated by Coupled Fe3+/Fe2+ and I2/I− Redox Cycles. Molecules 2022, 27, 7386. https://doi.org/10.3390/molecules27217386

AMA Style

Zhang H-Y, Zeng T-T, Xie Z-B, Dong Y-Y, Ma C, Gong S-S, Sun Q. Aerial Oxygen-Driven Selenocyclization of O-Vinylanilides Mediated by Coupled Fe3+/Fe2+ and I2/I− Redox Cycles. Molecules. 2022; 27(21):7386. https://doi.org/10.3390/molecules27217386

Chicago/Turabian Style

Zhang, Hao-Yuan, Tong-Tong Zeng, Zhen-Biao Xie, Ying-Ying Dong, Cha Ma, Shan-Shan Gong, and Qi Sun. 2022. "Aerial Oxygen-Driven Selenocyclization of O-Vinylanilides Mediated by Coupled Fe3+/Fe2+ and I2/I− Redox Cycles" Molecules 27, no. 21: 7386. https://doi.org/10.3390/molecules27217386

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