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Article

Copper Catalyzed Inverse Electron Demand [4+2] Cycloaddition for the Synthesis of Oxazines

by
Weiguang Yang
1,2,*,
Zitong Zhou
1,
Yu Zhao
1,
Danyang Luo
1,
Xiai Luo
3,
Hui Luo
2,
Liao Cui
1,* and
Li Li
1,*
1
Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China
2
Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524023, China
3
The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang 524023, China
*
Authors to whom correspondence should be addressed.
Catalysts 2022, 12(5), 526; https://doi.org/10.3390/catal12050526
Submission received: 14 April 2022 / Revised: 28 April 2022 / Accepted: 4 May 2022 / Published: 7 May 2022
(This article belongs to the Special Issue Catalysis in Green Chemistry and Organic Synthesis)
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Versions Notes

Abstract

:
A copper catalyzed tandem CuAAC/ring cleavage/[4+2] annulation reaction of terminal ynones, sulfonyl azides, and imines has been developed to synthesize the functionalized oxazines under mild conditions. Particularly, the intermediate N-sulfonyl acylketenimines undergo cycloaddition of an inverse electron demand Diels–Alder reaction with imines and a series of 1,3-oxazine derivatives were obtained successfully in good yields.

Graphical Abstract

1. Introduction

Oxazines, a six-membered ring containing one nitrogen and one oxygen atom, are important functionalized skeletons and play a crucial role in medicinal chemistry [1]. Its derivatives are widely used as therapeutic agents, such as analgesic (1) [2], anticancer (2) [3], antioxidant (3) [4], anti-inflammatory (4) [5], BACE1 inhibitors (5) [6], and anti-HIV (6) [7] (Figure 1). Owing to pharmacological activity, these types of oxazine derivatives have numerous applications in drug discovery and medicinal chemistry [1,8,9,10,11]. Consequently, there is an attendant interest in the development of novel, concise, and flexible routes to construct such oxazine rings.
Over the past decades, various reaction routes have been reported for the synthesis of 1,3-oxazine in the literature, involving the following six methods: (a) Mannich reaction by using an aromatic amines reaction with phenol and formaldehyde [12,13,14,15]. (b) Au catalyzed rearrangement of ortho-propargylic oximes via N-O Bond cleavage or Pd catalyzed cascade arene/alkyne annulation [16,17]. (c) [4+2] Cycloaddition of N-tosylhydrazones with ortho-quinone methides [18]. (d) Cycloaddition reaction of 2-azadienes derived and carbonyl compounds [19]. (e) [4+2] Cycloaddition reaction of α-fluorostyrenes with imines [20]. (f) Our previous study has disclosed that a semblable strategy about tandem CuAAC/ring cleavage/[4+2] annulation reaction from sulfonyl azides, terminal ynones, and oximes [21] (Scheme 1a–f). However, a majority of these reactions have been reported to need expensive metal catalysts and have poor regioselectivity, a long reaction time, and a high temperature while having low yields. Thus, an efficient and new route for the synthesis of multi-substituted 1,3-oxazine derivatives is still required.
On the other side, the [4+2] cycloaddition has become a venerable strategy in synthetic routes to create sophisticated frameworks, especially the inverse-electron-demand Diels–Alder reactions (IEDDA). These reactions between easily available chemicals enable the concise construction of six-membered rings under mild conditions [22,23,24,25,26]. During the past decade, a series of substrates or intermediates, such as alkenes, enol ethers, indoles, enamines, and enolates, have been successfully exploited to undergo such types of annulation reactions, enriched the toolbox of organic chemists for further studies, and delivered various chiral cyclohexenes or six-membered heterocycles [27,28,29,30,31,32,33,34,35,36]. The IEDDA has been a central initial reaction in domino sequences, especially with azadienes toward complex heterocycles.
Herein, we report a high-efficiency copper catalyzed inverse-electron-demand oxa-Diels–Alder reaction using terminal ynones, sulfonyl azides, and imines, and a series of novel 1,3-oxazine derivatives were obtained (Scheme 1g).

2. Results and Discussion

We began the study on a multicomponent reaction by choosing N-Benzylideneaniline 1a, with sulfonyl azides 2a and but-3-yn-2-one 3a as the model substrates to synthesize 2,3-dihydro-4H-1,3-oxazin-4-ylidene 4a. The reaction was carried out in the presence of CuCl in acetone at room temperature for 4 h, and 4a was isolated in a 21% yield (Table 1, entry 1). Based on this finding, the reaction conditions were screened. First, the solvents were screened, and a lower or comparable yield was obtained when THF, DMF, DCM, and DMSO were used as solvents, while MeCN gave 4a the highest yield of 84% (Table 1, entry 2–6). Then, the effects of catalysts were screened, and most CuI-catalysts exhibited a higher catalytic reactivity than CuII-catalysts in this reaction (Table 1, entries 7–13). Other catalysts such as AgTFA failed to produce the desired product (Table 1, entries 14). The effects of different additives were also evaluated, and the screening results revealed that additive-free achieved a superior result compared to an added base or acid (Table 1, entries 15–19). The reason maybe is that the terminal ynones will take a self-condensation under the base conditions according to previous reports [37,38,39]. Ultimately, we investigated the effect of reaction time and temperature and get the optimized conditions (Table 1, entries 20–24).
With this optimized condition in hand (Table 1, entries 6), the substrate diversity of the reaction was explored, as depicted in Scheme 2. Firstly, the scope of N-Benzylideneanilines were examined. It was found that the R1 with the electron-donating group (including OMe, Me) was superior to the electron-withdrawing group (including CN, NO2, Cl, etc). The 4-N(Me)2C6H4 group (4h) presented the highest yield (91%) as well as 4-MeC6H4 (4b) in 79% yields. The R1 with electron-withdrawing groups such as 4-nitrophenyl (4g) and 4-cyanobenzene (4f) were well-tolerated and showed a moderate reaction effect. In addition, 1-naphthyl was also tested in the reaction and afforded the desired products 4i in 63%. Presumably, because of the steric hindrance effect and strong electronic effect, 2-Me, 3-Me, and 2-furan failed to generate the desired products.
The scope of sulfonyl azides were further examined under optimized conditions. Surprisingly, Alkyl 4j–4m then was screened to participate in the transformation and smoothly get the desired compound in a moderate yield (68–74%). With R2 changed by aromatic substituents or aliphatic aryl groups, 4n–4t were well-tolerated and gave satisfactory yields (51–82%). The 4-OMeC6H4 group (4t) as an electron-donating group provided excellent yields in 88% yields. Likewise, when R3 was an n-pentyl or –Ph group, the terminal ynones afforded acceptable yields (4u, 52% and 4v, 56%).
The structures of (4a–4v) 1,3-oxazine products are unreported, and their structures were confirmed by 1HNMR, 13CNMR, IR, and HRMS. The structure of 4a unambiguously was confirmed by X-ray crystallography (Figure 2, CCDC deposition number 2164715).
A possible reaction pathway for the formation of 2,3-dihydro-4H-1,3-oxazin-4-ylidene (4a) from precursors 1a, 2a, and 3a is shown in Scheme 3. Thus, in keeping with earlier proposals, the substrates 2a and 3a are expected to react, in the presence of the copper (I) catalyst, so as to form the metallated triazole A that fragments with accompanying loss of nitrogen to form a highly active intermediate α-acyl-N-sulfonyl ketenimine B. This last species is captured by 1a via inverse electron demand [4+2] cycloaddition to deliver the observed product 4a.

3. Materials and Methods

3.1. General Methods

All melting points were determined on a Yanaco melting point apparatus and were uncorrected. IR spectra were recorded as KBr pellets on a Nicolet FT-IR 5DX spectrometer. All spectra of 1H NMR (400 MHz) and 13C NMR (100 MHz) were recorded on a Bruker AVANCE NEO 400 MHz spectrometer in DMSO-d6 or CDCl3 (otherwise as indicated), with TMS used as an internal reference and the J values given in Hz. HRMS were obtained on a Thermo Scientific Q Exactive Focus Orbitrap LC-MS/MS spectrometer. All imines (1a–2i, see Supplementary Materials Section 1), sulfonyl azides (2a–2l, see Supplementary Materials Section 1), and terminal alkynes (2a–2b, see Supplementary Materials Section 1) were prepared by literature methods [40,41,42].

3.2. General Procedure for the Synthesis of 2,3-Dihydro-4H-1,3-Oxazin-4-Ylidenes (4a–4v)

The solution of (E)-N,1-diphenylmethanimine (1, 91 mg, 0.5 mmol), CuI (95 mg, 0.05 mmol) in MeCN (1.0 mL) was added. Then, the mixture of TsN3 (2, 147.8 mg, 0.75 mmol) and But-3-yn-2-one (3, 51.0 mg, 0.75 mmol) was added in MeCN (2 mL). After the reaction mixture was stirred at room temperature for 4 h (monitored by TLC), the solvent was removed. The residue was purified by flash chromatography (silica gel, 33% EtOAc in petroleum ether (60–90 ℃)) to give the corresponding products 4a–4v. Details of the compound characterizations:
4-Methyl-N-(6-methyl-2,3-diphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene) benzenesulfonamide (4a) (176 mg, 84%), a white solid, m.p. = 164.9–166.4 °C (Rf = 0.30 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 2H), 7.44–7.36 (m, 5H), 7.26–7.12 (m, 7H), 6.60 (s, 1H), 6.51 (s, 1H), 2.38 (s, 3H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 156.9, 142.0, 140.5, 139.9, 135.4, 129.8, 129.0 (2C), 128.9 (2C), 128.7 (2C), 127.3 (3C), 126.5 (2C), 126.3 (2C), 97.4, 89.7, 21.5, 20.4; IR νmax (KBr) 3063, 3036, 2920, 1639, 1545, 1366, 1084 cm–1; HRMS (ESI-TOF) m/z: Calculated for C24H22N2O3S, [M+H]+ 419.1427, Found 419.1427.
4-Methyl-N-(6-methyl-3-phenyl-2-(p-tolyl)-2,3-dihydro-4H-1,3-oxazin-4-ylidene) benzenesulfonamide (4b) (171 mg, 79%), a white solid, m.p. = 158.1–160.0 °C (Rf = 0.30 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.6 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.24 (t, J = 7.8 Hz, 2H), 7.17 (t, J = 8.6 Hz, 5H), 7.12 (t, J = 8.0 Hz, 2H), 6.59 (s, 1H), 6.47 (s, 1H), 2.37 (s, 3H), 2.34 (s, 3H), 1.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 157.1, 142.1, 140.6, 140.0, 139.9, 132.5, 129.5 (2C), 129.1 (2C), 128.9 (2C), 127.3 (2C), 127.2, 126.6 (2C), 126.3 (2C), 97.3, 89.8, 21.5, 21.4, 20.5; IR νmax (KBr) 3117, 3059, 2920, 1640, 1546, 1303, 1084 cm–1; HRMS (ESI-TOF) m/z: Calculated for C25H24N2O3S, [M+H]+ 433.1581, Found 433.1582.
N-(2-(4-Fluorophenyl)-6-methyl-3-phenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene)-4-methylbenzenesulfonamide (4c) (161 mg, 74%), a white solid, m.p. = 162.4–163.2 °C (Rf = 0.20 in 1:4 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.0 Hz, 2H), 7.43–7.39 (m, 2H), 7.27–7.17 (m, 5H), 7.10–7.02 (m, 4H), 6.62 (s, 1H), 6.48 (s, 1H), 2.37 (s, 3H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 163.4 (d, J = 248.4 Hz, 1C), 156.9, 142.1, 140.4, 139.7, 131.2 (d, J = 3.2 Hz, 1C), 129.2 (d, J = 8.6 Hz, 2C), 129.0 (2C) 128.9 (2C), 127.4, 126.6 (2C), 126.2 (2C), 115.8 (d, J = 21.8 Hz, 2C), 97.3, 89.1, 21.4, 20.3; IR νmax (KBr) 3109, 3067, 2970, 1639, 1546, 1431, 1084 cm–1; HRMS (ESI-TOF) m/z: Calculated for C24H21FN2O3S, [M+H]+ 437.1330, Found 437.1333.
N-(2-(4-Chlorophenyl)-6-methyl-3-phenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene)-4-methylbenzenesulfonamide (4d) (176 mg, 78%), a white solid, m.p. = 191.2–191.3 °C (Rf = 0.20 in 1:4 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.0 Hz, 2H), 7.39–7.32 (m, 4H), 7.26 (t, J = 7.6 Hz, 2H), 7.20 (t, J = 7.4 Hz, 3H), 7.10 (t, J = 7.2 Hz, 2H), 6.61 (s, 1H), 6.48 (s, 1H), 2.37 (s, 3H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 156.9, 142.4, 140.4, 139.8, 136.0, 134.1, 129.2 (2C), 129.1 (2C), 129.0 (2C), 128.8 (2C), 127.5, 126.6 (2C), 126.4 (2C), 97.5, 89.2, 21.6, 20.5; IR νmax (KBr) 2971, 2919, 2839, 1720, 1496, 1366, 1088 cm–1; HRMS (ESI-TOF) m/z: Calculated for C24H21ClN2O3S, [M+H]+ 453.1034, Found 453.1038.
N-(2-(4-Bromophenyl)-6-methyl-3-phenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene)-4-methylbenzenesulfonamide (4e) (179 mg, 72%), a white solid, m.p. = 207.4–209.2 °C (Rf = 0.22 in 1:4 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.32–7.24 (m, 4H), 7.21 (d, J = 7.8 Hz, 3H), 7.10 (d, J = 7.6 Hz, 2H), 6.61 (s, 1H), 6.46 (s, 1H), 2.38 (s, 3H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.5, 156.7, 142.1, 140.3, 139.7, 134.6, 132.0 (2C), 129.1 (2C), 129.0 (2C) 128.9 (2C), 127.4, 126.4 (2C), 126.3 (2C), 124.2, 97.4, 89.1, 21.5, 20.4; IR νmax (KBr) 3117, 3059, 2920, 1500, 1496, 1304, 1084 cm–1; HRMS (ESI-TOF) m/z: Calculated for C24H21BrN2O3S, [M+H]+ 497.0529, Found 497.0521.
N-(2-(4-Cyanophenyl)-6-methyl-3-phenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene)-4-methylbenzenesulfonamide (4f) (162 mg, 73%), a white solid, m.p. = 163.5–165.2 °C (Rf = 0.10 in 1:4 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.69–7.65 (m, 4H), 7.57 (d, J = 8.0 Hz, 2H), 7.30–7.19 (m, 5H), 7.10 (d, J = 8.4 Hz, 2H), 6.63 (s, 1H), 6.54 (s, 1H), 2.38 (s, 3H), 2.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 156.4, 142.3, 140.6, 140.1, 139.6, 132.6 (2C), 129.1 (2C), 129.0 (2C), 128.0 (2C), 127.6, 126.4 (2C), 126.3 (2C), 117.9, 113.9, 97.7, 88.7, 21.5, 20.3; IR νmax (KBr) 3117, 3059, 2920, 1497, 1412, 1304, 1084 cm–1; HRMS (ESI-TOF) m/z: Calculated for C25H21N3O3S, [M+H]+ 444.1107, Found 444.1146.
4-Methyl-N-(6-methyl-2-(4-nitrophenyl)-3-phenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene)benzenesulfonamide (4g) (130 mg, 56%), a white solid, m.p. = 221.3–223.2 °C (Rf = 0.20 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.4 Hz, 2H), 7.68–7.63 (m, 4H), 7.30–7.19 (m, 5H), 7.12 (d, J = 7.6 Hz, 2H), 6.65 (s, 1H), 6.59 (s, 1H), 2.38 (s, 3H), 2.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 165.6, 148.8, 142.5, 142.4, 140.2, 139.6, 129.3 (2C), 129.2 (2C), 128.4 (2C), 127.8, 126.5 (2C), 126.4 (2C), 124.1 (2C), 97.8, 88.7, 21.6, 20.4; IR νmax (KBr) 3113, 2994, 2924, 1620, 1497, 1304, 1087 cm–1; HRMS (ESI-TOF) m/z: Calculated for C24H21N3O5S, [M+H]+ 464.1275, Found 464.1279.
N-(2-(4-(Dimethylamino)phenyl)-6-methyl-3-phenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene)-4-methylbenzenesulfonamide (4h) (210 mg, 91%), a white solid, m.p. = 188.3–189.6 °C (Rf = 0.25 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 2H), 7.27–7.17 (m, 7H), 7.11 (d, J = 7.6 Hz, 2H), 6.63 (d, J = 8.4 Hz, 2H), 6.58 (s, 1H), 6.41 (s, 1H), 2.95 (s, 6H), 2.36 (s, 3H), 1.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 157.4, 151.2, 141.9, 140.7, 140.0, 129.0 (2C), 128.7 (2C), 128.5 (2C), 127.1, 126.7 (2C), 126.3 (2C), 122.0, 111.7 (2C), 96.9, 90.1, 40.2 (2C), 21.5, 20.4; IR νmax (KBr) 3043, 2955, 2808, 1539, 1450, 1277, 1084 cm–1; HRMS (ESI-TOF) m/z: Calculated for C26H27N3O3S, [M+H]+ 462.1846, Found 462.1848.
4-Methyl-N-(6-methyl-2-(naphthalen-2-yl)-3-phenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene)benzenesulfonamide (4i) (147 mg, 63%), a white solid, m.p. = 142.9–144.3 °C (Rf = 0.20 in 1:4 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.87–7.81 (m, 4H), 7.72 (t, J = 8.0 Hz, 2H), 7.54–7.51 (m, 3H), 7.26–7.17 (m, 7H), 6.66 (s, 1H), 6.63 (s, 1H), 2.38 (s, 3H), 1.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.5, 157.1, 142.1, 140.5, 140.0, 133.7, 132.6, 132.5, 129.1 (2C), 128.9 (3C), 128.5, 127.7, 127.3 (3C), 126.8 (2C), 126.4 (2C), 126.3 (2C), 97.3, 89.9, 21.5, 20.4; IR νmax (KBr) 3113, 3059, 1632, 1501, 1308, 1150, 1084 cm–1; HRMS (ESI-TOF) m/z: Calculated for C28H24N2O3S, [M+H]+ 469.1581, Found 469.1584.
N-(6-Methyl-2,3-diphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene) methane sulfonamide (4j) (116 mg, 68%), a white solid, m.p. = 175.4–176.0 °C (Rf = 0.30 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.45–7.41 (m, 2H), 7.39–7.36 (m, 3H), 7.32–7.26 (m, 2H), 7.22 (t, J = 8.4 Hz, 3H), 6.50 (s, 1H), 6.45 (s, 1H), 2.90 (s, 3H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 157.0, 139.8, 135.4, 129.8, 128.9 (2C), 128.7 (2C), 127.3 (3C), 126.7 (2C), 97.5, 89.7, 43.0, 20.3; IR νmax (KBr) 3109, 3059, 2936, 1632, 1551, 1493, 1119 cm–1; HRMS (ESI-TOF) m/z: Calculated for C18H18N2O3S, [M+H]+ 343.1111, Found 343.1111.
N-(6-Methyl-2,3-diphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene) ethane sulfonamide (4k) (123 mg, 69%), a white solid, m.p. = 140.7–142.2 °C (Rf = 0.25 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.46–7.41 (m, 2H), 7.38–7.36 (m, 3H), 7.28 (t, J = 7.2 Hz, 2H), 7.20 (t, J = 8.0 Hz, 3H), 6.50 (s, 1H), 6.46 (s, 1H), 2.99–2.89 (m, 2H), 2.01 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 157.3, 139.8, 135.4, 129.8, 128.8 (2C), 128.7 (2C), 127.3 (2C), 127.2, 126.9 (2C), 97.6, 89.7, 49.3, 20.3, 8.3; IR νmax (KBr) 3063, 2986, 2940, 1647, 1497, 1431, 1115 cm–1; HRMS (ESI-TOF) m/z: Calculated for C19H20N2O3S, [M+H]+ 357.1268, Found 357.1273.
N-(6-Methyl-2,3-diphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene)propane-1-sulfonamide (4l) (133 mg, 72%), a white solid, m.p. = 140.7–142.4 °C (Rf = 0.28 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.45–7.41 (m, 2H), 7.38–7.36 (m, 3H), 7.28 (t, J = 7.6 Hz, 2H), 7.20 (t, J = 7.6 Hz, 3H), 6.49 (s, 1H), 6.46 (s, 1H), 2.96–2.84 (m, 2H), 2.00 (s, 3H), 1.78–1.68 (m, 2H), 0.91 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.3, 157.2, 139.8, 135.4, 129.8, 128.8 (2C), 128.7 (2C), 127.3 (2C), 127.2, 126.9 (2C), 97.6, 89.7, 56.7, 20.3, 17.3, 12.9; IR νmax (KBr) 3109, 2971, 2874, 1639, 1555, 1369, 1115 cm–1; HRMS (ESI-TOF) m/z: Calculated for C20H22N2O3S, [M+H]+ 371.1424, Found 371.1424.
N-(6-Methyl-2,3-diphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene)butane-1-sulfonamide (4m) (142 mg, 74%), a white solid, m.p. = 127.6–129.9 °C (Rf = 0.35 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.46–7.42 (m, 2H), 7.38–7.36 (m, 3H), 7.28 (t, J = 7.2 Hz, 2H), 7.18 (t, J = 8.0 Hz, 3H), 6.49 (s, 1H), 6.46 (s, 1H), 2.98–2.86 (m, 2H), 2.00 (s, 3H), 1.72–1.64 (m, 2H), 1.35–1.25 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 157.2, 139.8, 135.4, 129.8, 128.8 (2C), 128.7 (2C), 127.3 (2C), 127.2, 127.0 (2C), 97.6, 89.7, 54.7, 25.7, 21.4, 20.3, 13.6; IR νmax (KBr) 3109, 2971, 2932, 1636, 1547, 1288, 1111 cm–1; HRMS (ESI-TOF) m/z: Calculated for C21H24N2O3S, [M+H]+ 385.1581, Found 385.1579.
N-(6-Methyl-2,3-diphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene)-1-phenyl methanesulfonamide (4n) (148 mg, 71%), a white solid, m.p. = 154.1–155.6 °C (Rf = 0.30 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.33–7.25 (m, 9H), 7.20 (t, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 4H), 6.40 (s, 1H), 6.33 (s, 1H), 4.12 (q, 2H), 1.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 157.6, 139.5, 135.0, 131.1 (2C), 130.3, 129.7, 128.9 (2C), 128.6 (2C), 128.1 (2C), 127.8, 127.5 (2C), 127.4 (3C), 97.4, 89.8, 60.7, 20.1; IR νmax (KBr) 3040, 2970, 2870, 1647, 1493, 1354, 1107 cm–1; HRMS (ESI-TOF) m/z: Calculated for C24H22N2O3S, [M+H]+ 419.1424, Found 418.1351.
N-(6-Methyl-2,3-diphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene) benzene sulfonamide (4o) (145 mg, 72%), a white solid, m.p. = 153.1–154.7 °C (Rf = 0.30 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.6 Hz, 2H), 7.48–7.35 (m, 7H), 7.28–7.17 (m, 4H), 7.13 (d, J = 8.4 Hz, 2H), 6.61 (s, 1H), 6.52 (s, 1H), 2.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8, 157.0, 143.3, 139.8, 135.4, 131.5, 129.8, 128.9 (2C), 128.7 (2C), 128.4 (2C), 127.3, 127.2 (2C), 126.6 (2C), 126.2 (2C), 97.4, 89.7, 20.4; IR νmax (KBr) 3059, 1636, 1501, 1454, 1362, 1308, 1157, 1088 cm–1; HRMS (ESI-TOF) m/z: Calculated for C23H20N2O3S, [M+H]+ 405.1268, Found 405.1271.
4-Chloro-N-(6-methyl-2,3-diphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene) benzene sulfonamide (4p) (164 mg, 75%), a white solid, m.p. = 141.9–143.1 °C (Rf = 0.40 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.4 Hz, 2H), 7.44–7.41 (m, 2H), 7.39–7.33 (m, 5H), 7.28–7.18 (m, 3H), 7.12 (d, J = 8.0 Hz, 2H), 6.57 (s, 1H), 6.52 (s, 1H), 2.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 157.1, 141.9, 139.6, 137.7, 135.1, 129.9, 128.9 (2C), 128.8 (2C), 128.6 (2C), 127.7 (2C), 127.5, 127.3 (2C), 126.6 (2C), 97.3, 89.7, 20.4; IR νmax (KBr) 3098, 3067, 2974, 1543, 1393, 1431, 1084 cm–1; HRMS (ESI-TOF) m/z: Calculated for C23H19ClN2O3S, [M+H]+ 439.0878, Found 439.0879.
4-Bromo-N-(6-methyl-2,3-diphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene) benzene sulfonamide (4q) (178 mg, 74%), a white solid, m.p. = 160.6–161.9 °C (Rf = 0.35 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.44–7.36 (m, 5H), 7.28–7.18 (m, 3H), 7.11 (d, J = 7.6 Hz, 2H), 6.57 (s, 1H). 6.52 (s, 1H), 2.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 157.2, 142.4, 139.6, 135.1, 131.6 (2C), 129.9, 128.9 (2C), 128.8 (2C), 127.9 (2C), 127.5, 127.3 (2C), 126.7 (2C), 126.2, 97.3, 89.7, 20.4; IR νmax (KBr) 3117, 3086, 1639, 1510, 1458, 1393, 1138, 1084 cm–1; HRMS (ESI-TOF) m/z: Calculated for C23H19BrN2O3S, [M+H]+ 483.0373, Found 483.0376.
N-(6-Methyl-2,3-diphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene)-4-nitro benzenesulfonamide (4r) (148 mg, 66%), a white solid, m.p. = 176.3–177.7 °C (Rf = 0.30 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.45–7.36 (m, 5H), 7.30–7.21 (m, 3H), 7.12 (d, J = 7.2 Hz, 2H), 6.54 (d, J = 7.2 Hz, 2H), 2.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.0, 157.5, 149.3, 149.0, 139.3, 134.8, 130.1, 129.1 (2C), 128.8 (2C), 127.8, 127.5 (2C), 127.3 (2C), 126.8 (2C), 123.7 (2C), 97.3, 89.8, 20.4; IR νmax (KBr) 3105, 1624, 1435, 1300, 1169, 1142, 1084 cm–1; HRMS (ESI-TOF) m/z: Calculated for C23H19N3O5S, [M+H]+ 450.1118, Found 450.1122.
N-(6-Methyl-2,3-diphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene)-4-(trifluoromethyl)benzenesulfonamide (4s) (120 mg, 51%), a white solid, m.p. = 166.0–166.7 °C (Rf = 0.40 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.45–7.36 (m, 5H), 7.29–7.21 (m, 3H), 7.13 (d, J = 7.6 Hz, 2H), 6.58 (s, 1H), 6.53 (s, 1H), 2.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 157.4, 146.7, 139.5, 135.0, 133.2 (q, J = 32.6 Hz, 1C), 130.0, 129.0 (2C), 128.8 (2C), 127.7, 127.3 (2C), 126.7 (4C), 125.6 (q, J = 3.7 Hz, 2C), 123.5 (q, J = 271.1 Hz, 1C), 97.3, 89.8, 20.4; IR νmax (KBr) 3507, 3475, 2924, 1539, 1427, 1141, 1084 cm–1; HRMS (ESI-TOF) m/z: Calculated for C24H19F3N2O3S, [M+H]+ 473.1141, Found 473.1145.
4-Methoxy-N-(6-methyl-2,3-diphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene)benzenesulfonamide (4t) (178 mg, 82%), a white solid, m.p. = 135.5–136.5 °C (Rf = 0.20 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 2H), 7.45–7.42 (m, 2H), 7.38–7.34 (m, 3H), 7.24 (d, J = 7.6 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.12 (d, J = 7.6 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.60 (s, 1H), 6.51 (s, 1H), 3.82 (s, 3H), 1.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 162.0, 156.8, 139.9, 135.4, 129.8, 128.8 (2C), 128.8 (3C), 128.2 (2C), 127.3 (2C), 127.2, 126.5 (2C), 113.6 (2C), 97.3, 89.7, 55.5, 20.4; IR νmax (KBr) 3102, 3067, 2947, 1647, 1593, 1498, 1258, 1084 cm–1; HRMS (ESI-TOF) m/z: Calculated for C24H22N2O4S, [M+H]+ 435.1373, Found 435.1376.
4-Methyl-N-(2,3,6-triphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene) benzene sulfonamide (4u) (125 mg, 52%), a white solid, m.p. = 135.1–136.6 °C (Rf = 0.20 in 1:4 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz, 4H), 7.54–7.46 (m, 3H), 7.43–7.35 (m, 5H), 7.28 (t, J = 7.2 Hz, 3H), 7.22–7.16 (m, 5H), 6.72 (s, 1H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 157.5, 142.1, 140.5, 139.9, 135.1, 132.3, 131.0, 129.8, 129.1 (2C), 128.9 (2C), 128.8 (4C), 127.3, 127.2 (2C), 127.1 (2C), 126.4 (2C), 126.3 (2C), 94.8, 89.9, 21.5; IR νmax (KBr) 3063, 2970, 1610, 1578, 1497, 1296, 1138, 1080 cm–1; HRMS (ESI-TOF) m/z: Calculated for C29H24N2O3S, [M+H]+ 481.1581, Found 481.1584.
4-Methyl-N-(6-pentyl-2,3-diphenyl-2,3-dihydro-4H-1,3-oxazin-4-ylidene) benzenesulfonamide (4v) (133 mg, 56%), a white solid, m.p. = 159.3–160.9 °C (Rf = 0.42 in 1:3 v/v ethyl acetate/60–90 petroleum ether); 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.0 Hz, 2H), 7.34–7.21 (m, 12H), 7.08 (t, J = 7.4 Hz, 1H), 5.70 (d, J = 6.0 Hz, 1H), 5.15 (d, J = 6.0 Hz, 1H), 2.42 (s, 3H), 2.05–1.97 (m, 1H), 1.27–1.20 (m, 2H), 1.13–1.05 (m, 2H), 0.88–0.80 (m, 2H), 0.75 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.2, 160.7, 143.1, 138.9, 136.7, 132.0, 129.3 (3C), 129.0 (2C), 128.9 (2C), 127.4 (2C), 127.1 (2C), 125.2, 118.6 (2C), 63.8, 61.0, 44.0, 30.7, 22.3, 22.0, 21.6, 13.8; IR νmax (KBr) 2954, 2928, 2866, 1639, 1501, 1458, 1088 cm–1; HRMS (ESI-TOF) m/z: Calculated for C28H30N2O3S, [M+H]+ 475.2050, Found 475.2076.

4. Conclusions

In summary, we have developed an operationally simple and effective means for preparing 2,3-dihydro-4H-1,3-oxazin-4-ylidenes from a mixture of the corresponding imines, sulfonyl azides, and terminal ynones, through CuAAC/ring cleavage/[4+2] annulation process, base-free, and stirred at room temperatures. This methodology appears quite flexible and offers a capacity to generate forms of the title products that will be particularly useful in, for example, building more 1,3-oxazines block facility.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal12050526/s1, Scheme S1: Structures of the starting materials 1a–1b, Scheme S2: Structures of the starting materials 2a–2l, Scheme S3: Structures of the starting materials 3a–3b, Scheme S4: X-ray Crystallographic Data for Compound 4a, Figures S1–S44: 1H NMR and 13C NMR spectra of 2,3-dihydro-4H-1,3-oxazin-4-ylidenes (4a–4v).

Author Contributions

Conceptualization, methodology, and supervision W.Y., H.L., L.C. and L.L.; experiment, Z.Z., Y.Z., D.L. and X.L.; spectroscopic characterization Z.Z. and Y.Z.; writing—review and editing, W.Y., H.L., L.C. and L.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Applied Basic Research Fund Project of Guangdong Province of China (NO. 2019A1515110918); Science and Technology Planning Program of Zhanjiang (NO. 2021A05247); and Medical Scientific Research Foundation of Guangdong Province (NO. A2021037 and A2020202) to W. Yang; Science and Technology Program of Guangdong Province (NO. 2019B090905011) to H. Luo.

Data Availability Statement

Data are contained within the article or Supplementary Material.

Acknowledgments

We are grateful to Zunnan Huang’s project of Key Discipline Construction Project of Guangdong Medical University (4SG21004G) and Yun Liu’s project of Innovation and Entrepreneurship Team Leads the Pilot Program of Zhanjiang (2020LHJH005) for support.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 12 00526 g001 550
Figure 1. Examples of oxazine drug candidates.
Figure 1. Examples of oxazine drug candidates.
Catalysts 12 00526 g001
Catalysts 12 00526 sch001 550
Scheme 1. Synthesis of 1,3-oxazines: (a) mannich reaction; (b) rearrangement; (c–f) [4+2] cycloaddition reaction; (g) this work, CuAAC/ring cleavage/[4+2] annulation reaction.
Scheme 1. Synthesis of 1,3-oxazines: (a) mannich reaction; (b) rearrangement; (c–f) [4+2] cycloaddition reaction; (g) this work, CuAAC/ring cleavage/[4+2] annulation reaction.
Catalysts 12 00526 sch001
Catalysts 12 00526 sch002 550
Scheme 2. The synthesis of products 4a–4v.
Scheme 2. The synthesis of products 4a–4v.
Catalysts 12 00526 sch002
Catalysts 12 00526 g002 550
Figure 2. X-ray crystal structure of compound 4a.
Figure 2. X-ray crystal structure of compound 4a.
Catalysts 12 00526 g002
Catalysts 12 00526 sch003 550
Scheme 3. Plausible reaction mechanism.
Scheme 3. Plausible reaction mechanism.
Catalysts 12 00526 sch003
Table
Table 1. Optimization of conditions a.
Table 1. Optimization of conditions a.
Catalysts 12 00526 i001
EntryCat.
(10 mol%)		Base
(0.75 mmol)		Solvent
(2 mL)		Temp.
(°C)		Time
(h)		Yield
(%) b
1CuCI-Acetonert4.021
2CuCI-THFrt4.065
3CuCI-DMFrt4.012
4CuCI-DCMrt4.021
5CuCI-DMSOrt4.015
6CuCI-MeCNrt4.084
7CuI-MeCNrt4.078
8Cu(OAc)2-MeCNrt4.071
9Cu(acac)2-MeCNrt4.022
10CuO-MeCNrt4.0Trace
11CuBr-MeCNrt4.065
12Cu(SO4)2-MeCNrt4.0Trace
13Cu(TFA)2-MeCNrt4.032
14AgTFA-MeCNrt4.00
15CuCIDMAPMeCNrt4.0Trace
16CuCITsOHMeCNrt4.0Trace
17CuCIK2CO3MeCNrt4.012
18CuCIHOAcMeCNrt4.024
19CuCIEt3NMeCNrt4.042
20CuCI-MeCN404.076
21CuCI-MeCN604.062
22CuCI-MeCN804.041
23CuCI-MeCNrt3.077
24CuCI-MeCNrt5.084
a Reaction conditions: To 1a (0.5 mmol), Cat. 10 mol%, base 1.5 equivalent in the solvent (2 mL) was added 2a (0.75 mmol) and 3a (0.75 mmol), stirred at specified temperatures and times (monitored by TLC). b Isolated yields.
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Yang, W.; Zhou, Z.; Zhao, Y.; Luo, D.; Luo, X.; Luo, H.; Cui, L.; Li, L. Copper Catalyzed Inverse Electron Demand [4+2] Cycloaddition for the Synthesis of Oxazines. Catalysts 2022, 12, 526. https://doi.org/10.3390/catal12050526

AMA Style

Yang W, Zhou Z, Zhao Y, Luo D, Luo X, Luo H, Cui L, Li L. Copper Catalyzed Inverse Electron Demand [4+2] Cycloaddition for the Synthesis of Oxazines. Catalysts. 2022; 12(5):526. https://doi.org/10.3390/catal12050526

Chicago/Turabian Style

Yang, Weiguang, Zitong Zhou, Yu Zhao, Danyang Luo, Xiai Luo, Hui Luo, Liao Cui, and Li Li. 2022. "Copper Catalyzed Inverse Electron Demand [4+2] Cycloaddition for the Synthesis of Oxazines" Catalysts 12, no. 5: 526. https://doi.org/10.3390/catal12050526

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