A tandem coupling/smiles rearrangement/cyclization approach to 1,4-benzooxazinones or 1,4-pyridooxazinones under mild conditions

Abstract

A facile and efficient approach to 1,4-benzooxazinone or 1,4-pyridooxazinone scaffolds is developed via Smiles rearrangement tandem reaction. 1,4-Benzooxazinones or 1,4-pyridooxazinones with diversity at two substituents on their scaffolds were synthesized conveniently in the presence of cesium carbonate at room temperature in good to excellent yields. The reaction mechanism is assumed by a tandem coupling/Smiles rearrangement/cyclization process.

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Introduction

1,4-Benzooxazinones or 1,4-pyridooxazinones are important heterocycle scaffolds and their derivatives have a substantial amount of biological activities, ranging from herbicides and fungicides to therapeutic usable drugs. For example in Fig. 1, compound A, a novel antibacterial or an important antifungal (anti-candida) agent,¹ is a potential agent for treating anxiety, depression and negative symptoms in schizophrenia.² Compound B, isolated from gramineous plants, has been used as plant resistance factors against microbial diseases and insects.³ Compound C, a new analgesic agent,⁴ is a potential drug for treating heart disease, arrhythmia and myocardial necrosis.⁵ Compound D, an antithrombotic agent,⁶ is an attractive target for drug discovery.^7,8

Fig. 1 Some biologically important compounds containing 1,4-benzooxazinone or 1,4-pyridooxazinone scaffold.

The 1,4-benzooxazinone scaffold has been the subject of extensive research in synthetic and medicinal organic chemistry. Three common approaches to 1,4-benzooxazinone scaffold employed 2-nitrophenols, 2-aminophenols or 2-halophenols as the precursors (Fig. 2). The first approach (path A) included three steps of O-alkylation, nitro reduction and intramolecular N-substitution.⁹ This method employed metal catalyst. In the second approach (path B), 2-aminophenols were treated with ethyl 2-bromoacetate to form 2-amidophenols, which then underwent intramolecular O-alkylation on heating in the presence of a base¹⁰ or using a recyclable ionic liquid medium-[omim][BF₄] at room temperature.¹¹ In the last approach (path C), Chen group^3a developed a CuI catalyzed one-pot synthetic method to construct 1,4-benzooxazinone scaffolds, which started from 2-halophenols, but a costly ligand was required; Zuo group¹² used 2-halophenols to synthesize diverse 1,4-benzooxazinones in the presence of a strong base on heating. The above three approaches might suffer from inconvenient operations and a limited number of suitable substrates for diverse synthesis. Therefore, concise and efficient methods to give these heterocyclic motifs are still in demand.

Fig. 2 Three common approaches to 1,4-benzooxazinone.

Recently, the tandem reaction for the synthesis of various heterocyclic compounds was reported in our lab.¹³ In particular, the reaction proceeded via a three-step sequence involving Smiles rearrangement^13a to provide the desired products in good yields. Herein, we report a novel and efficient procedure that presents a tandem reaction, involves a broad range of starting materials, and takes place at room temperature. The route of our process, illustrated in Scheme 1, is performed using simple starting materials, such as substituted 1,2-dihalobenzenes or 2-halonitroarenes, 2-hydroxyacetamide to form a 1,4-benzooxazinone or 1,4-pyridooxazinone ring system. The reactions can complete rapidly in the presence of cesium carbonate and DMF as solvent at room temperature.

Scheme 1 The synthesis of 1,4-benzooxazinones or 1,4-pyridooxazinones.

Results and discussion

In our preliminary experiments, 1,4-difluoro-2-nitrobenzene 1b and N-benzyl-2-hydroxyacetamide 2k were chosen as model substrates for the optimization of the reaction conditions including the bases and solvents. It was interesting to note that the product 3b was obtained in 71% yield after 5 h (Table 1, entry 6). We investigated the effect of solvents, the yield in DMF was acceptable (Table 1, entry 6). We also investigated the effect of the bases. The nature of the base had a pronounced impact on the process, and Cs₂CO₃ was proved to be more effective than K₂CO₃ or NaH (Table 1, entries 5–7). On the other hand, When 1b was reacted with 2k in the presence of a strong base such as NaH or t-BuOK, the low yields were obtained with the result of forming a non cyclized product. (Table 1, entries 7–8).

Table 1 Optimization of reaction conditions^a

Entry	Base	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: 1,4-difluoro-2-nitrobenzene 1b (1 equiv.), N-benzyl-2-hydroxyacetamide 2k (1.2 equiv.), base (3 equiv.), r.t. b Isolated yields.
1	K2CO3	THF	14	0
2	Cs2CO3	THF	14	43
3	K2CO3	CH3CN	12	12
4	Cs2CO3	CH3CN	12	63
5	K2CO3	DMF	24	56
6	Cs2CO3	DMF	5	71
7	NaH	DMF	6	0
8	t-ButOK	DMF	7	0
9	DBU	DMF	7	16

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In order to examine the diversity of the products, we chose a variety of aliphatic or aromatic 2-hydroxy-acetamides to perform this tandem reaction and the results are summarized in Table 2. According to our observation, the yields of the aliphatic substrates (Table 2, entries 7–11) were higher than for the aromatic substrates (Table 2, entries 1–6). In the reaction of aromatic 2-hydroxy-acetamides as substrates, the electron properties of substituents on the aromatic ring did not play an important role in this procedure.

Table 2 The synthesis of benzo[1,4]oxazin-3(4H)-one derivatives 4^a

Entry	R^1	2	Time (h)	Product	Yield (%)^b
a Reaction conditions: 3,4-difluorobenzonitrile 1c (1 equiv.), 2-hydroxyacetamide 2 (1.2 equiv.), Cs2CO3 (3 equiv.), r.t. b Isolated yields. c Reaction conducted at 60 °C.
1	4-ClC6H4	2a	7	4a	77^c
2	4-FC6H4	2b	4.5	4b	82
3	4-BrC6H4	2c	6.8	4c	78^c
4	4-MeC6H4	2d	6.5	4d	64
5	Ph	2e	6.8	4e	72
6	4-MeOC6H4	2f	4.5	4f	88
7	3,4-(MeO)2-C6H3(CH2)2	2g	2.2	4g	85
8	Pr	2h	3.3	4h	85
9	c-Hex	2i	2.8	4i	92
10	i-Pr	2j	3	4j	95

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To extend the substrate scope, we performed the reaction of 3,4-difluorobenzonitrile 1c with N-benzyl-2-hydroxyacetamide 2k in the presence of Cs₂CO₃ at room temperature for 3.5 h to obtain the desired 4-benzy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile 3c (Table 3, entry 3) in 92% yield. The result encouraged us to synthesize 1,4-benzooxazinone or 1,4-pyrido-oxazinone derivatives from different substrates under the same reaction condition (Table 3). As observed in Table 3, the substrates of 1,2-dihaloarenes or 2-halonitroarenes which have an electron-withdrawing group (Table 3, entries 1–9 and 13–15) or an electron-donating group (Table 3, entries 10–12) provided the desired products 3 in good yields. It was interesting that the symmetric compound 3i was obtained with an acceptable yield (Table 3, entry 9). Moreover, the substrates with a cyano group (Table 3, entries 3–4) could provide higher yields than the ones with nitro group (Table 3, entries 1–2) in a short time.

Table 3 The synthesis of benzo[1,4]oxazin-3(4H)-one derivatives 3^a

Entry	1	Time (h)	3	Yield^b (%)
a Reaction conditions : 1 (1 equiv.), N-benzyl-2-hydroxyacetamide 2k (1.2 equiv.), Cs2CO3 (3 equiv.), r.t. b Isolated yields. c Reaction conducted at 80 °C.
1	1a	5	3a	75
2	1b	5.5	3b	71
3	1c	3.5	3c	92
4	1d	5	3d	79
5	1e	9.5	3e	86
6	1f	4	3f	86
7	1g	4.8	3g	62
8	1h	5.5	3h	78
9	1i	4	3i	54^c
10	1j	9.5	3j	52^c
11	1k	7.5	3k	51^c
12	1l	7	3l	72
13	1m	3.5	3m	68
14	1n	3	3n	73^c
15	1o	6	3o	67^c

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The formation of 3 is the best explained by a mechanism^13a with a three-step sequence in Scheme 2. Firstly, reaction of 1k and 2k generates intermediate 5k for 3 h at room temperature, which can be observed by TLC monitoring. Secondly, the key step of Smiles rearrangement results in the formation of the spiro-type intermediate 7 (Meisenheimer complex). Then, intermediate 8, produced from spiro-type intermediate 7 leads to target compound 3 in the third step. The structure of 3k was confirmed by X-ray analysis (Fig. 3). The intermediate product 5k was also confirmed by NMR and mass spectrometry. The regiochemistry of all of the other compounds is assumed to be the same.

Fig. 3 X-ray structure of compound 3k.

Scheme 2 The proposed mechanism for the formation of 3k.

Conclusions

In line with increasing global environmental safety regulation, we designed a green, novel and efficient method to synthesize a variety of 1,4-benzooxazinones or 1,4-pyridooxazinones via Smiles rearrangement tandem reaction. Various 1,4-benzooxazinones or 1,4-pyridooxazinones with diversity at two substituents on their scaffolds were synthesized in good to excellent yields. To the best of our knowledge, this process is the easiest method for the synthesis of compound 3i successfully. This transition metal-free tandem process has potential applications in the synthesis of biologically and medicinally relevant compounds.

Experimental section

All reagents and solvents were pure analytical-grade materials purchased from commercial sources and were used without further purification, if not stated. All reactions were monitored by thin-layer chromatography (TLC). ¹H NMR spectra were recorded on a Bruker Avance 400 or 300 spectrometer at 400 or 300 MHz, using CDCl₃ as solvent and tetramethylsilane (TMS) as internal standard. ¹³C NMR spectra were run in the same instrument at 100 or 75 MHz. Melting points were determined on an XD-4 digital micro melting point apparatus. HRMS spectra were determined on a Q-TOF6510 spectrograph (Agilent).

General procedure for the synthesis of 4-benzyl-7-fluoro-2H-benzo[b][1,4]oxazine-3(4H)-one (3b)

To a 50 mL flask equipped with a magnetic stirrer were added N-benzyl-2-hydroxyacetamide 2k (0.12 g, 0.76 mmol), 1,4-difluoro-2-nitrobenzene 1b (0.1 g, 0.63 mmol) and Cs₂CO₃ (0.62 g, 1.89 mmol). The tube was evacuated and backfilled with N₂ (this procedure was repeated 3 times). DMF (10 mL) was added and the mixture was stirred for 5.5 h at room temperature. After completion of the reaction (monitored by TLC), the residue was poured into brine (100 mL). The aqueous solution was then extracted with dichloromethane (3×20 mL) and the combined organic layers were dried over anhydrous MgSO₄. The solvent was removed under vacuum to obtain the crude product. The crude product was purified by flash column chromatography on silica gel (EtOAC/n-hexane = 1 : 3) to afford pure product 3b in 71% yields.

4-(4-chlorophenyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (4a)

White solid (77%). mp 178–183 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.56–7.53 (d, 2H, J = 8.7 Hz), 7.33–7.32 (d, 1H, J = 1.8 Hz) 7.23–7.16 (m, 3H) 6.53–6.50 (d, 1H, J = 8.4 Hz) 4.83 (s, 2H) ¹³C NMR (75 MHz, CDCl₃) δ 163.5, 144.8, 135.6, 134.2, 133.2, 130.7, 129.9, 127.1, 120.7, 117.9, 117.1, 107.5, 67.9. HRMS calcd for C₁₅H₉N₂O₂Cl, 284.0472; found, 284.0476.

4-(4-fluorophenyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (4b)

White solid (82%). mp 157–164 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.32 (s, 1H) 7.26–7.25 (d, 2H, J = 5.52 Hz) 7.19–7.17 (d, 2H, J = 7.8 Hz) 7.19–7.17 (d, 1H, J = 7.8 Hz) 6.51–6.49 (d, 1H, J = 8.04 Hz) 4.83 (s, 2H) ¹³C NMR (100 MHz, CDCl₃) δ 164.0, 163.7, 161.5, 144.7, 134.4, 130.5, 130.4, 127.1, 120.7, 118.1, 117.6, 107.4, 67.9. HRMS calcd for C₁₅H₉FN₂O₂, 268.0703; found, 268.0700.

4-(4-bromophenyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (4c)

Pale yellow solid (78%). mp 176–183 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.72–7.69 (d, 2H, J = 8.7 Hz) 7.33–7.32 (d, 1H, J = 1.5 Hz) 7.20–7.14 (dd, 3H, J = 1.8 Hz) 6.53–6.50 (d, 1H, J = 8.7 Hz) 4.82 (s, 2H) ¹³C NMR (75 MHz, CDCl₃) δ 163.5, 144.8, 134.1, 133.8, 133.7, 130.3, 127.1, 123.6, 120.7, 117.9, 117.2, 107.6, 67.9. HRMS calcd for C₁₅H₉N₂O₂Br, 327.9935; found, 327.9939.

3-oxo-4-(p-tolyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (4d)

Pale yellow solid (64%). mp 149–151 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.37–7.35 (d, 2H, J = 8.08 Hz) 7.31–7.30 (d, 1H, J = 1.72 Hz) 7.16–7.12 (m, 3H) 6.53–6.51 (d, 1H, J = 8.4 Hz) 4.82 (s, 2H) 2.44 (s, 3H) ¹³C NMR (100 MHz, CDCl₃) δ 163.7, 144.7, 139.7, 134.7, 132.0, 131.0, 128.3, 126.9, 120.5, 118.2, 117.3, 107.1, 67.9, 21.3. HRMS calcd for C₁₆H₁₂N₂O₂, 264.0975; found, 264.0979.

3-oxo-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (4e)

White solid (72%). mp 171–177 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.59–7.51 (m, 3H) 7.32–7.31 (d, 1H, J = 1.72 Hz) 7.274–7.270 (m, 2H) 7.17–7.14 (dd, 1H, J = 1.76, 8.4 Hz) 6.50–6.48 (d, 1H, J = 8.4 Hz) 4.83 (s, 2H) ¹³C NMR (100 MHz, CDCl₃) δ 163.6, 144.7, 134.8, 134.5, 130.4, 129.5, 128.6, 127.0, 120.5, 118.2, 117.3, 107.2, 67.9. HRMS calcd for C₁₅H₁₀N₂O₂, 250.0815; found, 250.0818.

4-(4-methoxyphenyl)3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (4f)

Brown solid (88%). mp 149–151 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.31–7.30 (d, 1H, J = 1.72 Hz) 7.18–7.15 (m, 3H) 7.07–7.05 (dd, 2H, J = 2.16, 6.76 Hz) 6.54–6.52 (d, 1H, J = 8.4 Hz) 4.83 (s, 2H) 3.87 (s, 3H) ¹³C NMR (100 MHz, CDCl₃) δ 163.8, 160.2, 144.7, 134.9, 129.6, 127.0, 126.9, 120.5, 118.2, 117.3, 115.6, 107.1, 67.9, 55.6. HRMS calcd for C₁₆H₁₂N₂O₃, 280.0921; found, 280.0926.

4-(3,4-dimethoxyphenethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (4g)

White solid (85%). mp 162–167 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.32–7.36 (dd, 1H, J = 1.8, 8.4 Hz), 7.27–7.26 (d, 1H, J = 1.5 Hz) 7.03–7.00 (d, 1H, J = 8.4 Hz) 6.82–6.71 (m, 3H) 4.63 (s, 2H) 4.18–4.13 (dd, 2H, J = 7.8, 9.6 Hz) 3.87–3.86 (d, 6H, J = 1.5 Hz) 2.92–2.87 (dd, 2H, J = 6.3, 7.8 Hz) ¹³C NMR (75 MHz, CDCl₃) δ 163.6, 149.2, 148.1, 145.3, 132.7, 129.9, 127.2, 120.8, 118.1, 115.3, 112.0, 111.5, 106.9, 67.4, 55.9, 42.8, 32.8. HRMS calcd for C₁₉H₁₈N₂O₄,338.1339; found, 338.1329.

3-oxo-4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (4h)

White solid (85%). mp 131–137 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.36–7.33 (dd, 1H, J = 2.1, 8.7 Hz) 7.27–7.25 (d, 1H, J = 4.5 Hz) 7.05–7.02 (d, 1H, J = 8.4 Hz) 4.66 (s, 2H) 3.94–3.89 (t, 2H, J = 7.8, 15.3 Hz) 1.76–1.61 (m, 2H) 1.02–0.94 (t, 3H, J = 7.2, 14.7 Hz) ¹³C NMR (100 MHz, CDCl₃) δ 163.6, 145.2, 132.7, 127.2, 120.5, 118.2, 115.3, 106.8, 67.3, 42.8, 20.2, 11.1. HRMS calcd for C₁₂H₁₂N₂O_2, 216.0972; found, 216.0983.

4-cyclohexyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (4i)

White solid (92%). mp 135–137 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.35–7.32 (dd, 1H, J = 1.8, 8.4 Hz) 7.27–7.26 (d, 1H, J = 1.8 Hz) 7.24–7.21 (d, 1H, J = 8.4 Hz) 4.53 (s, 2H) 4.28–4.12 (m, 1H) 2.40–2.27 (m, 2H) 1.94–1.72 (m, 5H) 1.47–1.21 (m, 3H) ¹³C NMR (100 MHz, CDCl₃) δ 165.5, 146.5, 134.1, 127.1, 120.8, 118.1, 116.7, 106.8, 69.8, 57.3, 29.3, 26.3, 25.2. HRMS calcd for C₁₅H₁₆N₂O_2, 256.1285; found, 256.1281.

4-isopropyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (4j)

White solid (95%). mp 136–142 °C. ¹H NMR (300 MHz, CDCl₃) δ 7.36–7.32 (dd, 1H, J = 2.1, 8.7 Hz) 7.28–7.27 (d, 1H, J = 1.8 Hz) 7.22–7.19 (d, 1H, J = 8.7 Hz) 4.81–4.67 (m, 1H) 4.54 (s, 2H) 1.57–1.55 (d, 6H, J = 6.9 Hz) ¹³C NMR (100 MHz, CDCl₃) δ 165.3, 146.4, 133.5, 127.1, 120.8, 118.1, 116.5, 106.8, 68.3, 47.9, 19.7. HRMS calcd for C₁₂H₁₂N₂O_2, 216.0952; found, 216.0950.

4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbonitrile (4k)

White solid (92%). mp 132–136 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.36–7.21 (m, 5H) 7.26 (s, 1H) 7.19–7.20 (d, 1H, J = 1.8 Hz) 6.94–6.92 (d, 1H, J = 8.4 Hz) 5.18 (s, 2H) 4.79 (s, 2H) ¹³C NMR (100 MHz, CDCl₃) δ 164.1, 145.2, 134.9, 132.8, 129.1, 127.9, 127.2, 126.5, 120.4, 118.1, 116.2, 107.1, 67.4, 45.0. HRMS calcd for C₁₆H₁₂N₂O_2, 264.0972; found, 264.0973.

4-benzyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (3a)

Yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.84–7.83 (d, 1H, J = 2.48 Hz) 7.81–7.78 (dd, 1H, J = 2.48, 8.88 Hz) 7.36–7.22 (m, 5H) 6.98–6.95 (d, 1H, J = 8.92 Hz) 5.21 (s, 2H) 4.82 (s, 2H) ¹³C NMR (100 MHz, CDCl₃) δ 164.1, 144.9, 143.5, 134.8, 134.3, 129.1, 127.9, 126.6, 118.7, 115.5, 112.64, 67.4, 45.2. HRMS calcd for C₁₅H₁₂N₂O₄, 284.0689; found, 284.0694.

4-benzyl-7-fluoro-2H-benzo[b][1,4]oxazine-3(4H)-one (3b)

Yellow solid (71%). mp 71–75 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.33–7.22 (m, 5H) 6.80–6.76(dd, 1H, J = 5.28, 9 Hz) 6.73–6.70 (dd, 1H, J = 2.76, 8.92 Hz) 6.60–6.55 (m, 1H) 5.12 (s, 2H) 4.71 (s, 2H) ¹³C NMR (100 MHz, CDCl₃) δ 164.0, 160.1, 157.7, 146.3, 135.7, 128.9, 127.6, 125.1, 116.3, 109.3, 105.1, 67.7, 45.1. HRMS calcd for C₁₅H₁₂NFO₂, 257.0925; found, 257.0926.

4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carbonitrile (3d)

Pale yellow solid (79%). mp 92–96 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.28–7.27 (d, 1H, J = 1.76 Hz) 7.26–7.22 (m, 5H) 7.21–7.20 (d, 1H, J = 1.8 Hz) 7.04–7.00 (q, 1H, J = 7.92 Hz) 5.71 (s, 2H) 4.67 (s, 2H) ¹³C NMR (100 MHz, CDCl₃) δ 165.6, 148.6, 134.9, 131.4, 129.5, 128.7, 127.7, 127.2, 124.8, 122.0, 117.6, 101.9, 68.4, 45.1. HRMS calcd for C₁₆H₁₂N₂O₂, 264.0972; found, 264.0978.

4-benzyl-6-(trifluoromethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (3e)

White solid (54%). mp 132–136 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.35–7.22 (m, 5H) 7.24 (s, 1H) 7.16–7.14 (d, 1H, J = 8.28 Hz) 6.96–6.94 (d, 1H, J = 8.44 Hz) 5.18 (s, 2H) 4.77 (s, 2H) ¹³C NMR (100 MHz, CDCl₃) δ 164.3, 145.2, 135.3, 131.6, 129.0, 127.8, 126.9, 124.9, 122.3, 119.9, 117.3, 115.8, 67.5, 44.9. HRMS calcd for C₁₆H₁₂NF₃O₂, 307.0893; found, 307.0886.

4-benzyl-2H-benzo[b][1,4]oxazine-3(4H)-one (3f)

Yellow solid (86%). mp 73–75 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.30–7.24 (m, 5H) 6.99–6.87 (m, 4H) 5.15 (s, 2H) 4.71 (s, 2H) ¹³C NMR (100 MHz, CDCl₃) δ 164.7, 145.4, 135.9, 128.9, 127.5, 126.6, 123.9, 122.8, 116.9, 115.7, 67.7, 44.9. HRMS calcd for C₁₅H₁₃NO₂, 239.1019; found, 239.1021.

4-benzyl-5-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (3g)

Yellow solid (62%). mp 88–97 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.51–7.50 (d, 2H, J = 1.28 Hz) 7.35–7.22 (m, 3H) 7.00–6.99 (d, 1H, J = 2.24 Hz) 6.88–6.85 (dd, 1H, J = 2.28, 8.6 Hz) 6.79–6.77 (d, 1H, J = 8.68 Hz) 5.14 (s, 2H) 4.73(s, 2H) ¹³C NMR (100 MHz, CDCl₃) δ 164.1, 145.9, 135.5, 128.9, 128.9, 127.7, 127.5, 126.6, 122.7, 117. 4, 116.4, 67.6, 44.9. HRMS calcd for C₁₅H₁₂NClO₂, 273.0614; found, 273.0610.

4-benzyl-8-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one (3h)

Yellow oil (78%). ¹H NMR (400 MHz, CDCl₃) δ 7.21–7.13 (m, 5H) 6.97–6.90 (m, 3H) 5.51 (s, 2H) 4.54(s, 2H) ¹³C NMR (100 MHz, CDCl₃) δ 167.3, 150.9, 136.4, 128.4, 127.7, 127.3, 127.1, 125.9, 125.5, 123.9, 115.8, 69.2, 47.0. HRMS calcd for C₁₅H₁₂NClO₂, 273.0629; found, 273.0640.

4,6-dibenzyl-6,8-dihydrobenzo[1,2-b;5,4-b]bis([1,4]oxazine)-3,7(2H,4H)-dione (3i)

Red Brown solid (54%). mp 188–203 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.29–7.26 (m, 6H) 6.99–6.97 (dd, 4H, J = 3.56, 7.36 Hz) 6.66 (s, 1H) 6.37 (s, 1H) 4.87 (s, 4H) 4.65 (s, 4H) ¹³C NMR (100 MHz, CDCl₃) δ 164.1, 141.5, 135.5, 128.9, 127.7, 126.5, 123.9, 106.1, 103.8, 67.8, 45.2. HRMS calcd for C₂₄H₂₀N₂O₄, 400.1496; found, 400.1493.

4-benzyl-5-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (3j)

Yellow solid (51%). mp 86–95 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.24–7.09 (m, 5H) 7.18–7.16 (d, 1H, J = 2.68 Hz) 7.11–7.09 (d, 1H, J = 7.12 Hz) 6.77–6.75 (q, 1H, J = 5.4 Hz) 5.22 (s, 2H) 4.52 (s, 2H) 2.32 (s, 3H) ¹³C NMR (100 MHz, CDCl₃) δ 168.1, 149.6, 136.7, 129.4, 128.5, 128.4, 127.2, 126.8, 126.4, 124.9, 114.8, 69.2, 48.1, 21.0. HRMS calcd for C₁₆H₁₅NO₂, 253.1156; found, 253.1151.

4-benzyl-7-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (3k)

Orange solid (51%). mp 86–95 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.34–7.25 (m, 5H) 6.88–6.86 (d, 1H, J = 8.12 Hz) 6.76–6.74 (d, 1H, J = 8.2 Hz) 6.69 (s, 1H) 5.14 (s, 2H) 4.68 (s, 2H) 2.19 (s, 3H) ¹³C NMR (100 MHz, CDCl₃) δ 164.9, 143.2, 136.1, 132.4, 128.9, 128.6, 127.4, 126.6, 124.4, 116.6, 116.2, 67.8, 44.9, 21.1. HRMS calcd for C₁₆H₁₅NO₂, 253.1176; found, 253.1187.

7-amino-4-benzyl-2H-benzo[b][1,4]oxazine-3(4H)-one (3l)

Orange solid (72%). mp 137–140 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.32–7.31 (d, 2H, J = 1.28 Hz) 7.29–7.23 (m, 3H) 6.67–6.65 (d, 1H, J = 8.6 Hz) 6.39–6.38 (d, 1H, J = 2.52 Hz) 6.26–6.23 (dd, 1H, J = 2.52, 8.6 Hz) 5.11 (s, 2H) 4.68 (s, 2H) 4.04 (s, 2H) ¹³C NMR (100 MHz, CDCl₃) δ 163.9, 146.4, 142.9, 136.2, 128.8, 127.3, 126.6, 120.7, 116.5, 109.2, 104.1, 67.8, 44.9. HRMS calcd for C₁₅H₁₄N₂O₂, 254.1128; found, 254.1127.

1-benzyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (3m)

Pale yellow solid (52%). mp 101–109 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.02–7.99 (dd, 1H, J = 1.4, 8.4 Hz) 7.46–7.44 (d, 2H, J = 7.12 Hz) 7.29–7.19 (m, 3H) 7.27–7.26 (d, 1H, J = 1.48 Hz) 6.92–6.89 (q, 1H, J = 1.28 Hz) 5.35 (s, 2H) 4.68 (s, 2H) ¹³C NMR (100 MHz, CDCl3) δ 164.6, 141.6, 141.1, 140.7, 137.1, 128.6, 128.4, 127.4, 123.5, 119.3, 67.5, 42.7. HRMS calcd for C₁₄H₁₂N₂O₂, 240.0972; found, 240.0976.

1-benzyl-7-(trifluoromethyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (3n)

Yellow oil (73%). ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1H) 7.44 (s, 1H) 7.41–7.40 (d, 2H, J = 1.48 Hz) 7.31–7.23 (m, 3H) 5.37 (s, 2H) 4.77 (s, 2H) ¹³C NMR (400 MHz, CDCl₃) δ 164.2, 144.1, 140.2, 138.2, 136.5, 128.7, 128.5, 127.7, 124.5, 122.6, 121.8, 67.3, 43.1. HRMS calcd for C₁₅H₁₁N₂F₃O₂, 308.0845; found, 308.0842.

4-benzyl-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (3o)

Yellow solid (67%). mp 137–140 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H) 8.11–8.10 (d, 1H, J = 5.4 Hz) 7.36–7.23 (m, 5H) 6.80–6.78 (d, 1H, J = 5.4 Hz) 5.14 (s, 2H) 4.79 (s, 2H) ¹³C NMR (100 MHz, CDCl₃) δ 164.3, 144.6, 141.5, 138.7, 135.1, 134.9, 129.1, 127.9, 126.7, 109.7, 67.5, 44.6. HRMS calcd for C₁₄H₁₂N₂O₂, 240.0972; found, 240.0979.

N-benzyl-2-(5-methyl-2-nitrophenoxy)acetamide (5k)

Yellow solid (71%). mp 95–99 °C. ¹H NMR (300 MHz, CDCl3) δ 7.95–7.91 (d, 1H, J = 4.5 Hz) 7.65 (s, 1H) 7.36–7.27 (m, 5H) 6.94–6.91 (dd, 1H, J = 0.9, 8.4 Hz) 6.84 (s, 1H) 4.66 (s, 2H) 4.59–4.57 (d, 2H, J = 6.3 Hz) 2.44 (s, 3H) ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 151.1, 147.3, 137.6, 136.7, 128.7, 127.7, 127.6, 126.7, 122.5, 115.1, 67.8, 43.1, 21.9. HRMS calcd for C₁₆H₁₆N₂O₄, 300.1283; found, 300.1276.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (No. 21172131) and State Key Laboratory of Natural and Biomimetic Drugs of Peking University (No. K20090205) for financial support of this research.

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Footnote

† Electronic supplementary information (ESI) available. CCDC reference number 864981. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ra20334k

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