Synthesis and fungicidal activity of novel ureido-substituted 1,3-benzoxazines

Abstract

Ten novel ureido-substituted 1,3-benzoxazines were synthesized in moderate yields by La(OTf)₃-catalyzed reaction of some aldehydes with four ureido-substituted 2-aminomethylphenols which were prepared by a one-pot method. Evaluation of their fungicidal activity revealed that most compounds showed moderate to good activity and one of the ureido-substituted 2-aminomethylphenols showed activity against Rhizoctonia solani and Sclerotonia sclerotiorum comparable to the control compound, chlorothalonil.

Introduction

Urea derivatives play an important role as pesticides and as drugs. Many of them have good biological activity as herbicides, ¹ insecticides,^2–4 fungicides, ⁴ and plant growth regulators, ⁵ and as antiviral,^4,6 antitumor, ⁷ anticancer, ⁸ and antituberculosis agents. ⁹ They are also stearyl-CoA desaturase inhibitors, ¹⁰ and some are neuroprotection agents against Aβ-induced cytotoxicity. ¹¹ The ureido group has high cytokinin activity and selectivity, and a series of bioactive compounds can be formed by integration of a ureido group with 1,5-diarylpyrazoles ¹² and with other groups. ¹³ On the other hand, heterocyclic nitrogen compounds such as 1,3-benzoxazine derivatives have received more and more attention due to their wide range of biological activities including anti-inflammatory, ¹⁴ anti-mycobacterial, ¹⁵ anti-cancer, ¹⁶ anti-fungal^17,18 and anti-plasmodial activity, ¹⁹ and as CCR2 and CCR5 dual antagonists, ²⁰ and DNA-PK inhibitors. ²¹ Molecular hybridization, which involves the combination of two or more distinct bioactive units, is one of the successful strategies for the development of new drug classes.^22,23 Hence, in a continuation of our programs aimed at synthesizing new fungicidal compounds with high fungicidal potency,^17,18 we integrated the ureido group with the 1,3-benzoxazine ring to form novel ureido-substituted 1,3-benzoxazine hybrids. Here we wish to report the preparation and fungicidal activity of the target compounds.

Results and discussion

As shown in Scheme 1, the important intermediates (6a–d; R = H, Me; meta or para isomer) were synthesized using a literature method ¹³ by a one-pot reaction of p- or m-phenylenediamine (1) with N,N-diethylformyl chloride (2) in the presence of triethyl amine to form an N,N-diethyl-N’-aryl urea (3; meta or para isomer), followed by successive reaction with salicylaldehyde (4; R = H) or 5-methylsalicylaldehyde (4; R = Me) to give an imine (5; R = H, Me; meta or para isomer) and then with NaBH₄ to effect reduction of the imine to amine. The yields of the four ureido-substituted 2-aminomethylphenols (6a–d; R = H, Me; meta or para isomer) were all in the range of 58–64% clearly indicating that the methyl group on the benzene ring as well as the position of the ureido group did not have any apparent effect on the yield. We then investigated the use of several catalysts for the preparation of the simplest ureido-substituted 1,3-benzoxazine (7a; R, R¹ = H; para isomer) by reacting the ureido-substituted 2-aminomethylphenol (6a; R = H; para isomer) with formaldehyde (R¹ = H) in THF (40 mL) under nitrogen at 65°C for 5 h. It was found that the reaction did not work without a catalyst or with TsOH as catalyst. However, the desired product was obtained in 12% yield using SnCl₄. ¹⁷ The yield was improved to 50% by employing La(OTf)₃ (20 mol%) as catalyst (Table 1, entry 1) and so we concluded the optimum conditions to be: reactants plus La(OTf)₃ (20 mol%) in THF (40 mL) under nitrogen at 65°C for 5 h. Under these conditions, we prepared another nine ureido-substituted 1,3-benzoxazines (7b–j; R = H, Me; R¹ = H, aryl; meta or para isomer) by reacting each of the four ureido-substituted 2-aminomethylphenols (6a–d; R = H, Me; meta or para isomer) with formaldehyde (R¹ = H) or with o-, m- or p-nitrobenzaldehyde (R¹ = o-, m- or p-NO₂C₆H₄) and the yields are shown in Table 1. Generally speaking, compounds 7a–j with R = H gave higher yields than those with R = CH₃ group (Table 1, entry 1 versus 3, entry 6 versus 8). In addition, it was observed that compounds 7a–j with R¹ = H were more stable than those with R¹ = aryl, and compounds 7 are soluble in water.

Scheme 1.

Synthesis of compounds 7.

Table 1.

Yields of ureido-substituted 1,3-benzoxazines (7a–j; R = H, Me; R¹ = H, aryl; meta or para isomer) prepared by the La(OTf)₃-catalyzed condensation of a ureido-substituted 2-aminomethylphenol (6a–d; R = H, Me; meta or para isomer) with an aldehyde (R¹CHO; R¹ = H; o-, m- or p-NO₂C₆H₄) (Scheme 1) ^a .

Entry	Compd	Position of ureido group	R	R1	Yield/% b
1	7a	p	H	H	50
2	7b	p	H	o-NO2C6H4	42
3	7c	p	CH3	H	48
4	7d	p	CH3	p-NO2C6H4	55
5	7e	p	CH3	m-NO2C6H4	40
6	7f	m	H	H	52
7	7g	m	H	m-NO2C6H4	71
8	7h	m	CH3	H	50
9	7i	m	CH3	m-NO2C6H4	40
10	7j	m	CH3	p-NO2C6H4	45

a

Reaction conditions: a mixture of a ureido-substituted 2-aminomethylphenol (6a–d; R = H, Me; meta or para isomer) (2 mmol), an aldehyde (R¹CHO) (3 mmol), and La(OTf)₃ (0.4 mmol) as catalyst in THF (40 mL) was stirred under nitrogen at 65°C for 5 h.

b

Isolated yields.

The in vitro fungicidal activities of the prepared compounds 6a–d and 7a–j were evaluated adopting the mycelium growth rate test method. ¹⁸ The fungicidal activity was tested against Sclerotonia sclerotiorum, Botrytis cinerea, Rhizoctonia solani, Gibberella zeae, Phytophythora capsic and Magnaporthe oryzae at 50 µg mL^–1 using chlorothalonil as a reference compound. The activities were expressed as inhibition rate (%) and the results are summarized in Table 2. All compounds exhibited activities against the tested fungi, and some showed good activities. Compound 6a showed 94.2% activity against R. solani and 72.5% activity against M. oryzae, which are all higher than that of chlorothalonil (92.6, 53.8%). It also showed 94.6% activity against S. sclerotiorum, equal to that of chlorothalonil. This indicated that compound 6a displayed broad activity. Compounds 6d and 7e displayed 80.4 and 81.6% activity against G. zeae, respectively, which were all higher than that of chlorothalonil (73.3%). The activity of compound 7i (70.5%) against G. zeae was close to that of chlorothalonil. Moreover, 1,3-benzoxazines 7 with R¹ = Ar displayed relatively higher activity against G. zeae than those with R¹ = H (Table 2, entries 8, 9 versus 7; entry 11 versus 10; entries 13, 14 versus 12). In addition, ureido-substituted 2-aminomethylphenols 6 exhibited higher activity than the corresponding ureido-substituted 1,3-benzoxazines 7.

Table 2.

Fungicidal activity of four ureido-substituted 2-aminomethylphenols (6a–d; R = H, Me; meta or para isomer) and ten ureido-substituted 1,3-benzoxazines (7a–j; R = H, Me; R¹ = H, aryl; meta or para isomer) (Scheme 1) ^a .

Entry	Compd	S. sclerotiorum	B. cinerea	R. solani	P. capsici	G. zeae	M. oryzae
1	6a	94.6	51.6	94.2	35.7	40.9	72.5
2	6b	46.2	19.4	46.1	35.7	9.1	37.5
3	6c	75.6	34.5	50.0	6.3	49.4	47.5
4	6d	60.0	44.8	50.0	25.0	80.4	27.3
5	7a	57.7	22.6	44.7	28.6	36.4	12.5
6	7b	42.3	19.4	474	28.6	13.6	6.3
7	7c	34.4	17.2	16.7	12.5	40.7	27.3
8	7d	34.4	17.2	8.3	6.3	43.2	27.3
9	7e	69.4	37.9	50.0	6.3	81.6	45.5
10	7f	38.5	22.6	39.5	14.3	31.8	37.5
11	7g	31.3	24.1	16.7	6.3	49.4	18.2
12	7h	34.4	13.8	16.7	12.5	30.9	27.3
13	7i	56.3	24.1	33.3	18.8	70.5	36.4
14	7j	15.6	3.4	33.3	12.5	32.0	18.2
15	Chlorothalonil b	94.6	94.6	92.6	89.3	73.3	53.8

a

Inhibition rate (%).

b

Chlorothalonil used as reference compound.

Conclusion

In summary, we have developed an efficient method to prepare ureido-substituted 1,3-benzoxazines by La(OTf)₃-catalyzed reactions of ureido-substituted 2-aminomethylphenols with aldehydes under mild reaction conditions. The ureido-substituted 2-aminomethylphenols were synthesized by a one-pot reaction of phenylenediamine, N,N-diethylformyl chloride, substituted salicylaldehydes and NaBH₄. The fungicidal activities of the prepared compounds against plant fungi were evaluated, and some compounds showed good activities. Compound 6a exhibited 94.2, 94.6 and 72.5% activity against R. solani, S. sclerotiorum and M. oryzae respectively.

Experimental

NMR spectra were obtained on a Bruker AV-II 500 spectrometer (¹H NMR at 500 MHz, ¹³C NMR at 125 MHz) in CDCl₃ using TMS as internal standard. Chemical shifts (δ) are given in ppm and coupling constants (J) are given in hertz (Hz). Melting points were measured on a WRS-2A microcomputer melting point instrument and are uncorrected. HRMS were recorded on a Waters UPLC/XEVOQ-TOF LC/MS instrument. IR spectra were recorded on a Nicolet-6700 FTIR spectrometer. Solvents, reagents and catalysts were purchased from MERYER and Energy Chemical as analytical grades and used without further purification. Column chromatography was carried out using silica gel (200–300 mesh).

Synthesis of ureido-substituted 2-aminomethylphenols (6a–d; R = H, Me; meta or para isomer); general procedure

Under a nitrogen atmosphere, into a 100 mL three-necked round-bottom flask equipped with a condenser, p- or m-phenylenediamine (0.216 g, 2 mmol), N,N-diethylformyl chloride (0.49 g, 3.6 mmol), Et₃N (0.202 g, 2 mmol) and CH₂Cl₂ (30 mL) were added. The reaction was heated to 40°C in an oil bath for 12 h. After removing the solvent under reduced pressure, salicylaldehyde (0.733 g, 6 mmol) or 5-methylsalicylaldehyde (0.817 g, 6 mmol) and ethanol (40 mL) were added. The reaction mixture was refluxed for 5 h and cooled to room temperature. Then, NaBH₄ (0.11 g, 3 mmol) was added portion-wise at 0°C and the mixture was stirred for 1 h. After concentration, the mixture was diluted with ethyl acetate (40 mL) and the organic layer was washed successively with distilled water (20 mL × 3) and saturated NaCl solution (20 mL × 3). The organic solvent was dried over Na₂SO₄, evaporated under reduced pressure, and the residue purified by column chromatography (petroleum ether (boiling point is 60-90°C)/ethyl acetate = 2:1) affording product 6.

N,N-Diethyl-N′-(4-{[(2-hydroxyphenyl)methyl]amino}phenyl)urea ( 6a; R = H; para isomer): Yellow solid; m.p. 121.3–121.5°C; yield 64%; IR (KBr) ν: 3330, 2972, 1636, 1517, 1454, 1379, 1241, 1160, 753 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 7.17 (t, J = 8.5 Hz, 3H), 7.12 (d, J = 7.3 Hz, 1H), 6.86–6.84 (m, 2H), 6.72 (d, J = 7.7 Hz, 2H), 6.19 (s, 1H), 4.32 (s, 2H), 3.34 (q, J = 7.1 Hz, 4H), 1.20 (t, J = 7.1 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 156.8, 155.2, 143.2, 132.2, 128.9, 128.6, 123.2, 122.4, 119.7, 116.4, 116.3, 53.4, 48.9, 41.5, 13.9; HRMS (ESI) m/z calcd for C₁₈H₂₄N₃O₂: [M + H]⁺: 314.1869; found: 314.1861.

N,N-Diethyl-N’-(4-{[(2-hydroxy-5-methylphenyl)methyl]amino}phenyl)urea ( 6b, R = Me; para isomer): White solid; m.p. 120.4–122.1°C; yield 61%; IR (KBr) ν: 3325, 3297, 2972, 1638, 1537, 1422, 1320, 1247, 1171, 779 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 7.11 (t, J = 7.7 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 7.02–7.00 (m, 2H), 6.83 (d, J = 8.0 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 6.44 (s, 1H), 6.40–6.38 (m, 1H), 4.22 (s, 2H), 3.31 (q, J = 7.1 Hz, 4H), 1.16 (t, J = 7.1 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 156.4, 154.7, 148.1, 139.9, 129.4, 128.9, 128.8, 123.3, 119.8, 116.4, 111.7, 110.0, 107.5, 47.9, 41.6, 13.8; HRMS (ESI) m/z calcd for C₁₉H₂₆N₃O₂: [M + H]⁺: 328.2025; found: 328.2018.

N,N-Diethyl-N’-(3-{[(2-hydroxyphenyl)methyl]amino}phenyl)urea ( 6c, R = H; meta isomer): Yellow solid; m.p. 134.8–137.2°C; yield 58%; IR (KBr) ν: 3386, 3125, 2971, 1636, 1602, 1512, 1418, 1360, 1256, 1161, 774 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 7.19 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 6.74 (dd, J = 14.4, 7.8 Hz, 3H), 6.18 (s, 1H), 4.28 (s, 2H), 3.34 (q, J = 7.1 Hz, 4H), 2.26 (s, 3H), 1.20 (t, J = 7.1 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 155.1, 154.4, 143.2, 132.2, 129.3, 129.1, 128.8, 122.8, 122.3, 116.2, 116.2, 48.9, 41.5, 20.4, 13.9; HRMS (ESI) m/z calcd for C₁₈H₂₄N₃O₂: [M + H]⁺: 314.1869; found: 314.1858.

N,N-Diethyl-N’-(3-{[(2-hydroxy-5-methylphenyl)methyl]amino}phenyl)urea ( 6d, R = Me; meta isomer): White solid; m.p. 119.5–120.4°C; yield 62%; IR (KBr) ν: 3411, 3322, 3248, 2971, 1638, 1613, 1539, 1423, 1346, 1250, 1172, 776 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 7.17 (d, J = 1.7 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.93 (s, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.47 (dd, J = 8.0, 1.6 Hz, 1H), 6.28 (s, 1H), 4.31 (s, 2H), 3.36 (q, J = 7.2 Hz, 4H), 2.26 (s, 3H), 1.22 (t, J = 7.1 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 154.5, 154.2, 148.1, 140.2, 129.5, 129.4, 129.3, 129.0, 122.9, 116.3, 111.6, 109.9, 107.3, 77.2, 77.0, 76.8, 48.1, 41.6, 20.5, 13.9; HRMS (ESI) m/z calcd for C₁₉H₂₆N₃O₂: [M + H]⁺: 328.2025; found: 328.2020.

Synthesis of ureido-substituted 1,3-benzoxazines ( 7a–j; R = H, Me; R¹ = H, aryl; meta or para isomer); representative procedure for 7a (R, R¹ = H; para isomer)

Under a nitrogen atmosphere, into a 100 mL three-necked round-bottom flask equipped with a condenser, compound 6a (0.627 g, 2 mmol), paraformaldehyde (0.091 g, 3 mmol), La(OTf)₃ (0.234 g, 0.4 mmol) and THF (40 mL) were added. The reaction was stirred at 65°C for 5 h. The solvent was evaporated under reduced pressure, and the residue purified by column chromatography (petroleum ether (boiling point is 60-90°C)/ethyl acetate = 3:1) affording product 7a.

N,N-Diethyl-N’-[4-(3,4-dihydro-2H-1,3-benzoxazin-3-yl)phenyl]urea ( 7a; R, R¹ = H; para isomer): White solid; m.p. 143.8–144.6°C; yield 50%; IR (KBr) ν: 3352, 2968, 1632, 1585, 1518, 1421, 1337, 1223, 1156, 758 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 7.25–7.23 (m, 2H), 7.10 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 7.4 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.16 (s, 1H), 5.30 (s, 2H), 4.57 (s, 2H), 3.34 (d, J = 14.3 Hz, 4H), 1.19 (t, J = 7.1 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 154.8, 154.2, 144.1, 133.3, 127.8, 126.7, 121.5, 120.8, 120.7, 119.2 (2C), 116.8, 80.0, 53.4, 50.8, 41.5 (2C), 13.7 (2C); HRMS (ESI) m/z calcd for C₁₉H₂₄N₃O₂: [M + H]⁺: 326.1869; found: 326.1860.

N,N-Diethyl-N’-{4-[2-(2-nitrophenyl)-3,4-dihydro-2H-1,3-benzoxazin-3-yl]phenyl}urea ( 7b; R = H; R¹ = o-NO₂C₆H₄; para isomer): Yellow solid; m.p. 168.2–168.6°C; yield 42%; IR (KBr) ν: 3430, 3074, 2968, 1656, 1585, 1522, 1417, 1338, 1225, 1156, 767 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 7.72, (dd J = 7.3, 1.9 Hz, 1H), 7.64–7.62 (m, 1H), 7.47–7.41 (m, 2H), 7.21–7.16 (m, 3H), 7.06–7.04 (m, 2H), 7.02–6.97 (m, 2H), 6.85 (d, J = 6.6 Hz, 2H), 6.14 (s, 1H), 4.20 (d, J = 16.9 Hz, 1H), 4.00 (d, J = 17.0 Hz, 1H), 3.33 (q, J = 7.1 Hz, 4H), 1.18 (t, J = 7.1 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 154.7, 152.6, 149.0, 144.4, 134.9, 132.9, 131.8, 129.1, 128.7, 128.3, 126.6, 124.3, 121.9 (2C), 121.1, 121.0 (2C), 120.3, 116.6, 85.5, 47.7, 41.6 (2C), 13.9 (2C); HRMS (ESI) m/z calcd for C₂₅H₂₇N₄O₄: [M + H]⁺: 447.2032; found: 447.2013.

N,N-Diethyl-N’-[4-(6-methyl-3,4-dihydro-2H-1,3-benzoxazin-3-yl)phenyl]urea ( 7c; R = Me; R¹ = H; para isomer): Yellow solid; m.p. 135.2–137.1°C; yield 48%; IR (KBr) ν: 3337, 2977, 1629, 1584, 1508, 1446, 1366, 1223, 1166, 816 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 7.27–7.21 (m, 2H), 7.03 (t, J = 5.9 Hz, 2H), 6.90 (d, J = 8.2 Hz, 1H), 6.80 (s, 1H), 6.69 (d, J = 8.3 Hz, 1H), 6.20 (s, 1H), 5.27 (s, 2H), 4.52 (s, 2H), 3.33 (q, J = 7.1 Hz, 4H), 2.24 (s, 3H), 1.18 (t, J = 7.1 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 154.8, 151.9, 144.2, 133.3, 129.9, 128.3, 126.9, 121.5 (2C), 120.4, 119.2 (2C), 116.5, 79.9, 50.7, 41.5 (2C), 20.5, 13.9 (2C); HRMS (ESI) m/z calcd for C₂₀H₂₆N₃O₂: [M + H]⁺: 340.2025; found: 340.2016.

N,N-Diethyl-N’-{4-[6-methyl-2-(4-nitrophenyl)-3,4-dihydro-2H-1,3-benzoxazin-3-yl]phenyl}urea ( 7d; R = Me; R¹ = p-NO₂C₆H₄; para isomer): Yellow oil; yield 55%; IR (KBr) ν: 3337, 2974, 1642, 1517, 1419, 1345, 1230, 1160, 787 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 8.17 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.25 (t, J = 6.0 Hz, 1H), 7.11 (t, J = 6.0 Hz, 2H), 6.97 (dd, J = 8.3, 1.4 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.67 (s, 1H), 6.49 (s, 1H), 6.22 (s, 1H), 4.30 (d, J = 16.9 Hz, 1H), 4.18 (d, J = 17.0 Hz, 1H), 3.34 (q, J = 7.1 Hz, 4H), 2.21 (s, 3H), 1.19 (t, J = 7.1 Hz, 6H); ¹³C NMR (125MHz, CDCl₃): δ 154.7, 150.1, 147.6, 146.4, 144.6, 134.5, 130.3, 128.8, 127.9 (2C), 126.9, 123.7 (2C), 121.6 (2C), 121.2 (2C), 119.6, 116.6, 87.7, 47.6, 41.5 (2C), 20.5, 13.9 (2C); HRMS (ESI) m/z calcd for C₂₆H₂₉N₄O₄: [M + H]⁺: 461.2189; found: 461.2180.

N,N-Diethyl-N’-{4-[6-methyl-2-(3-nitrophenyl)-3,4-dihydro-2H-1,3-benzoxazin-3-yl]phenyl}urea ( 7e; R = Me; R¹ = m-NO₂C₆H₄; para isomer): Yellow oil; yield 40%; IR (KBr) ν: 3340, 2973, 1643, 1518, 1419, 1348, 1227, 1159, 789 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 8.44 (s, 1H), 8.18–8.10 (m, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.12 (d, J = 8.9 Hz, 2H), 6.97 (dd, J = 8.3, 1.3 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.67 (s, 1H), 6.48 (s, 1H), 6.22 (s, 1H), 4.31 (d, J = 17.0 Hz, 1H), 4.21 (d, J = 17.0 Hz, 1H), 3.34 (q, J = 7.1 Hz, 4H), 2.20 (s, 3H), 1.19 (t, J = 7.1 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 154.7, 150.0, 148.5, 144.7, 141.6, 134.6, 133.1, 130.3, 129.5, 128.9, 128.5, 126.9, 124.4, 123.1, 122.2, 121.9, 121.2, 119.6, 116.7, 87.5, 47.6, 41.5 (2C), 20.5, 13.9 (2C); HRMS (ESI) m/z calcd for C₂₆H₂₉N₄O₄: [M + H]⁺: 461.2189; found: 461.2179.

N,N-Diethyl-N’-[3-(3,4-dihydro-2H-1,3-benzoxazin-3-yl)phenyl]urea ( 7f; R, R¹ = H; meta isomer):

Light yellow solid; m.p. 143.7–145.2°C; yield 52%; IR (KBr) ν: 3319, 2965, 1639, 1607, 1542, 1439, 1367, 1224, 1168, 754 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 7.34 (t, J = 2.0 Hz, 1H), 7.12 (dt, J = 15.5, 8.0 Hz, 2H), 7.01 (d, J = 7.4 Hz, 1H), 6.89–6.79 (m, 3H), 6.76 (dd, J = 8.2, 2.2 Hz, 1H), 6.25 (s, 1H), 5.35 (s, 2H), 4.63 (s, 2H), 3.36 (q, J = 7.2 Hz, 4H), 1.22 (t, J = 7.2 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 154.4, 154.3, 148.9, 140.2, 129.4, 127.7, 126.8, 121.0, 120.7, 116.9, 112.5, 112.1, 109.3, 79.1, 50.3, 41.6 (2C), 13.9 (2C); HRMS (ESI) m/z calcd for C₁₉H₂₄N₃O₂: [M + H]⁺: 326.1869; found: 326.1858.

N,N-Diethyl-N’-{3-[2-(3-nitrophenyl)-3,4-dihydro-2H-1,3-benzoxazin-3-yl]phenyl}urea ( 7g; R = H; R¹ = m-NO₂C₆H₄; meta isomer): White solid; m.p. 150.2–151.7°C; yield 71%; IR (KBr) ν: 3335, 3269, 2975, 1641, 1586, 1452, 1378, 1221, 1180, 756 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 8.40 (s, 1H), 8.20–8.07 (m, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.57 (s, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.14 (dd, J = 14.3, 6.5 Hz, 2H), 7.02 (d, J = 8.2 Hz, 1H), 6.93–6.79 (m, 4H), 6.66 (s, 1H), 6.42 (s, 1H), 4.41 (d, J = 16.9 Hz, 1H), 4.26 (d, J = 17.0 Hz, 1H), 3.36 (q, J = 7.1 Hz, 4H), 1.21 (t, J = 7.1 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 154.4, 151.9, 149.9, 148.5, 141.5, 140.4, 133.0, 129.6, 129.4, 128.2, 126.6, 123.1, 122.1, 121.0, 119.9, 117.0, 113.7, 113.7, 111.6, 86.5, 46.4, 41.5 (2C), 13.9 (2C); HRMS (ESI) m/z calcd for C₂₅H₂₇N₄O₄: [M + H]⁺: 447.2032; found: 447.2011.

N,N-Diethyl-N’-[3-(6-methyl-3,4-dihydro-2H-1,3-benzoxazin-3-yl)phenyl]urea ( 7h; R = Me; R¹ = H; meta isomer): White solid; m.p. 119.5–120.4°C; yield 50%; IR (KBr) ν: 3334, 2968, 1635, 1609, 1538, 1411, 1379, 1224, 1176, 774 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 7.33 (t, J = 2.1 Hz, 1H), 7.13 (t, J = 8.1 Hz, 1H), 6.90 (dd, J = 8.3, 1.6 Hz, 1H), 6.85 (dd, J = 8.0, 1.8 Hz, 1H), 6.80 (d, J = 1.0 Hz, 1H), 6.78–6.73 (m, 1H), 6.70 (d, J = 8.3 Hz, 1H), 6.31 (s, 1H), 5.31 (s, 2H), 4.58 (s, 2H), 3.35 (q, J = 7.2 Hz, 4H), 2.23 (s, 3H), 1.22–1.19 (m, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 154.4, 152.0, 148.9, 140.2, 129.9, 129.3, 128.3, 127.0, 120.6, 116.5, 112.4, 112.0, 109.3, 78.9, 50.3, 41.5 (2C), 20.5, 13.9 (2C); HRMS (ESI) m/z calcd for C₂₀H₂₆N₃O₂: [M + H]⁺: 340.2025; found: 340.2014.

N,N-Diethyl-N’-{3-[6-methyl-2-(3-nitrophenyl)-3,4-dihydro-2H-1,3-benzoxazin-3-yl]phenyl}urea ( 7i; R = Me; R¹ = m-NO₂C₆H₄; meta isomer): Yellow solid; m.p. 151.6–152.9°C; yield 40%; IR (KBr) ν: 3294, 2969, 1633, 1607, 1531, 1403, 1346, 1221, 1157, 765cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 8.40 (s, 1H), 8.17–8.08 (m, 1H), 7.87 (dd, J = 7.8, 0.9 Hz, 1H), 7.53 (t, J = 1.9 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.14 (t, J = 8.1 Hz, 1H), 6.94 (dt, J = 17.9, 5.0 Hz, 2H), 6.87–6.84 (m, 2H), 6.65 (s, 1H), 6.63 (s, 1H), 6.31 (s, 1H), 4.37 (d, J = 16.8 Hz, 1H), 4.22 (d, J = 17.0 Hz, 1H), 3.39–3.34 (m, 4H), 2.18 (s, 3H), 1.23–1.20 (m, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 154.4, 150.0, 149.7, 148.6, 141.6, 140.3, 133.1, 130.3, 129.6, 129.5, 128.9, 126.9, 123.1, 122.2, 119.6, 116.8, 113.8, 113.6, 111.7, 86.4, 46.6, 41.6 (2C), 20.5, 13.9 (2C); HRMS (ESI) m/z calcd for C₂₆H₂₉N₄O₄: [M + H]⁺: 461.2189; found: 461.2179.

N,N-Diethyl-N’-{3-[6-methyl-2-(4-nitrophenyl)-3,4-dihydro-2H-1,3-benzoxazin-3-yl]phenyl}urea ( 7j; R = Me; R¹ = p-NO₂C₆H₄; meta isomer): Yellow oil; yield 45%; IR (KBr) ν: 2927, 1644, 1607, 1523, 1439, 1344, 1223, 794 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ 8.15 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 1.8 Hz, 1H), 7.14 (t, J = 8.1 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.83 (dd, J = 8.1, 2.0 Hz, 2H), 6.64 (d, J = 4.9 Hz, 2H), 6.36 (s, 1H), 4.36 (d, J = 16.9 Hz, 1H), 4.19 (d, J = 16.9 Hz, 1H), 3.37 (q, J = 7.1 Hz, 4H), 2.18 (s, 3H), 1.22 (t, J = 7.1 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃): δ 154.4, 149.9, 149.8, 147.6, 146.5, 140.4, 130.4, 130.3, 129.4, 128.8, 127.9 (2C), 126.9, 123.7 (2C), 119.6, 116.6, 113.5, 111.4, 86.5, 46.4, 41.5 (2C), 20.5, 13.9 (2C); HRMS (ESI) m/z calcd for C₂₆H₂₉N₄O₄: [M + H]⁺: 461.2189; found: 461.2181.