HETEROCYCLES

Short Paper | Regular issue | Vol. 91, No. 6, 2015, pp. 1256-1268
Received, 13th April, 2015, Accepted, 13th May, 2015, Published online, 26th May, 2015.
DOI: 10.3987/COM-15-13225

■ Synthesis and Safener Activity of Novel Substituted 4-Phenoxyacetyl-1,4-benzoxazines

Fei Ye, Shi-Long Wu, Li-Xia Zhao, Hai-Tao Qu, Shuang Gao, and Ying Fu*

Department of Applied Chemistry, College of Sciences, Northeast Agricultural University, No.59 Mucai Street Harbin 150030, Heilongjiang, China

Abstract

A novel class of 3-methyl-4-phenoxyacetyl-3,4-dihydro-2H-1,4-benzoxazine 3 were synthesized via reduction, cyclization, and acylation reactions. The structures of the compounds were characterized by IR, 1H-NMR, 13C-NMR, MS, and elemental analyses. The configuration of 3f was determined by X-ray crystallography. The bioassay results demonstrated that most of these compounds could alleviate 2,4-D butylate injury to maize.

1,4-Benzoxazine derivatives have received great attention in chemical and medicinal research because of their natural occurrence and important biological activities.1 Several 3,4-dihydro-2H-1,4-benzoxazine derivatives have been reported as potassium channel openers (PCOs) in vascular smooth muscle. Some 1,4-benzoxazine derivatives are known to be central nervous system depressants, antibacterial agents,2 antipsychotic agents,3 calcium antagonists,4 and antimicrobial agents agonists,5 and so on. In particular, benzoxazine derivatives with particular biological activities were applied widely in the agrochemicals fields, including herbicide safener benoxacor.6
Structure-activity correlations (SAR) are very important in the search for biological activity because they provide useful information about chemical substituents that are necessary for the required bioactivity.7 Base on the SAR, fenoxaprop-ethyl was used as the target herbicide, and replacing the pyrazoline core from mefenpyr-diethyl by a similar substituted isoxazoline resulted in the safener 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid ethyl ester, which were not sufficiently active for commercialization. However, combining the structural features of 5-phenyl-4,5-dihydroisoxazole-3- carboxylic acid ethyl ester and the safener diphenyl acid led to the strong rice safener isoxadifen-ethyl (Scheme 1).8 Using strategies of active substructure combination and bioisosteric replacement, Guan et al. designed and synthesized novel dihalopropene derivatives with insecticidal activity.9 Recently many successful cases have been reported.10
As part of our ongoing work on the synthesis of nitrogen-containing heterocyclic herbicide safeners,11 herein 4-phenoxyacetylbenzoxazine derivatives were design and synthesized based on the SAR and active substructure combination keeping the benzoxazine as the parent skeleton structure (Scheme 2). Several approaches had been developed to benzoxazine derivatives with Mo/Fe/Al/Cr,12 AlCl3,13 CuI,14 pyridinium chlorochromate,15 [Ir(COD)Cl]2 with (S)-Segphos,16 HSiCl3,17 or 1,10-phenanthroline18 as catalysts. Most of these reported methods required harsh reaction conditions, expensive catalysts, or poor yields. However, simple benzoxazines ring closure could also been obtained by a tandem reduction-reductive amination reaction with Pd/C as catalyst in good yields.19-21 In view of the facts mentioned above and continuous of our previous work, the novel target molecules with potential herbicide safener activity, substituted 3-methyl-4-phenoxyacetyl-3,4-dihydro-2H-1,4-benzoxazine (3), were designed and synthesized with o-nitrophenoxyl ketone and phenoxyacetyl chloride as the starting material via reduction, cyclization, and acylation reactions (Scheme 3).

3-Methyl-3,4-dihydro-2H-1,4-benzoxazines 2 were prepared by reduction and cyclization at 55-60 ℃ with the pressures of 1.5 MPa for 10-25 h, and Pt/C was used as catalyst. Isopropanol and toluene were used as solvent. Herein was used as co-solvent and dehydrating agent. Isopropanol increased the solubility of the reactants in toluene. Series of 3-methyl-3,4-dihydro-2H-1,4-benzoxazine (2) were obtained in 68%-91% yields (Table 1). The target compounds 3 were obtained by acylation of 2 with phenoxyacetyl chloride in benzene by stirring the mixture for 1-1.5 h at room temperature. The process was monitored by TLC. The substitute group structure affected the yields significantly. According to the yields of 3, it was found that the electron-donating on the benzene ring increased the yields of 3. The compounds 3h gave the better yield than others with tert-butyl on position 6. However, the yield of 3d was the best for there was another chloride on position 8.

Finally, the single crystal of 3f was obtained by dissolving it in ethyl acetate and light petroleum, followed by slow evaporation. The X-ray data were collected on a Bruker AXSⅡ CCD area-detector diffractometer using graphite monochromated Mo Ka radiation (λ=0.71073 Å) at 293(2) K. The structure was solved by direct methods using SHELXS-97,22 and refined by full matrix least squares on F2, SHELXL-97.23
The compound, C20H21Cl2NO3, contained a six-membered and two benzene rings. The C5/C6/O1/C7/C8/N1 composed of the oxazine ring with the torsion angle of N1/C5/C6 and O1 being -1.58(72)°, which states N1/C5/C6 and O1 are almost coplanar. While the atom C7 and C8 deviated from the selected plane, just as what was shown in Figure 1. The oxazine ring adopted a half-chair

conformation. The dihedral angles between the oxazine ring and the adjacent benzene ring (C1/C2/C3/C4/C5/C6) were 4.93(14)°, which indicated two ring are close to coplanar. Besides, the dihedral angles of two benzene ring are 70.11(16)°.
The compound crystallized in the monoclinic space group , with two molecules in the unit cell. The packing view of the compound was shown in Figure 2. In the crystal structure, molecules were linked by weak intermolecular C-H…O hydrogen bonds and C-H…π interactions to form one-dimension chains, which stabilized the crystal structure (Figure 3). No significant π-π interactions were found in the crystal structure.

All the novel compounds 3a-i were evaluated for their protection of maize in vivo against the injury of 2,4-D butylate at the concentration of 0.244 g/m2 (Table 2). The recovery rates of the growth index could be attained almost 50%. Among the compounds tested, compound 3h showed the best activity against the injury of 2,4-D butylate, even better than the commercialized safener, benoxacor. That indicated the compound with bulk group link to benzene led to good activity. However, compounds 3b, 3c, and 3i did not show protection, they inhibited the root growth. They might be used as the candidate of herbicide because they are similar as phenoxy acid herbicide. The further bioassay was still investigated.

In conclusion, we have developed an efficient, fast and convenient method for the preparation of 4-phenoxyacetyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazine derivatives base on SAR and active substructure combination. The advantages of this method were readily available starting materials, mild reaction conditions, and good yields. The preliminary bioactivity results showed that compound 3d attained the best herbicide safener activity to 2,4-D butylate.

EXPERIMENTAL
The IR spectra were taken on a ALPHA-T infrared spectrophotometer in KBr pellets or film. The NMR spectra were recorded on Bruker AVANVE 300 MHz with CDCl3 as the solvent and TMS as the internal standard. The elemental analysis was performed on FLASH EA1112 elemental analyzer. The mass spectrum was recorded on a Waters Xevo TQ spectrometer. X-Ray diffraction data were collected on a Brukcr AXSII CCD area-detector diffractometer, Mo Kα. The melting points were determined on a Beijing Taike melting point apparatus(X-4) and are uncorrected. All the reagents were of analytical reagents grade.
General procedure for the preparation of 3-methyl-3,4-dihydro-2H-1,4-benzoxazine (2a-i)21
Pt/C (2 g) was added to solution of compounds 1 (50 mmol) in mixture of toluene (200 mL) and isopropanol (100 mL). The reaction mixture was stirred in H2 at 60 °С, 1.5 Mpa for 10 h. Then the mixture was filtered, and the filtrate was dried over magnesium sulfate anhydrous, and the toluene was removed under vacuum. The crude product was separated on silica gel by column chromatography [V (EtOAc): V (light petroleum) = 1:4] until the compounds 2 were collected. The physical and spectra data of the compounds 2 were as follows:
3-Methyl-3,4-dihydro-2H-1,4-benzoxazine (2a). Yield 72%. Light yellow oil. IR(film, cm-1): ν3371(N-H), 2970-2871(C-H), 1608-1427(C=C). 1H-NMR(DMSO-d6, 300 MHz): δ 6.24-6.67(m, 4H, Ar-H), 5.63(m, 1H, N-H), 4.05-4.12, 3.58-3.63(m, 2H, O-CH2), 2.11(s, 1H, N-CH), 1.08(m, 3H, CH3); 13C-NMR(CDCl3, 75 MHz): δ 143.71, 133.49, 121.36, 118.84, 116.52, 115.45, 70.75, 45.17, 17.83. Anal. Calcd for C9H11NO: C 72.44, H 7.44, N 9.39. Found: C 72.42, H 7.48, N 9.35.
3,6-Dimethyl-3,4-dihydro-2H-1,4-benzoxazine (2b). Yield 87%. Light yellow oil. IR(film, cm-1): ν3369(N-H), 2970-2869(C-H), 1614-1454(C=C). 1H-NMR(DMSO-d6, 300 MHz): δ 6.24-6.52(m, 3H, Ar-H), 5.59(m, 1H, N-H), 4.05-4.08, 3.55-3.57(m, 2H, O-CH2), 3.34-3.35(m, 1H, N-CH), 2.11(s, 3H, Ar-CH3), 1.05-1.07(d, 3H, J=6.4Hz, CH3); 13C-NMR(DMSO-d6, 75 MHz): δ 141.20, 134.72, 129.99, 117.69, 115.86, 115.63, 70.46, 44.89, 20.96, 17.80. Anal. Calcd for C10H13NO: C 73.57, H 8.03, N 8.59. Found: C 73.61, H 8.05, N 8.64.
3-Methyl-6-methoxyl-3,4-dihydro-2H-1,4-benzoxazine (2c). Yield 91%. White solid, mp 60-61 °С. IR(KBr, cm-1): ν3373(N-H), 2968-2833(C-H), 1620-1456(C=C). 1H-NMR(CDCl3, 300 MHz): δ 6.18-6.73(m, 3H, Ar-H), 4.14-4.18(m, 1H, N-H), 3.71-3.77(m, 5H, O-CH2- and Ar-O-CH3), 3.53-3.58(m, 1H, N-CH), 1.18-1.20(m, 3H, CH3); 13C-NMR(CDCl3, 75 MHz): δ 154.47, 137.84, 133.97, 116.66, 103.49, 101.17, 70.61, 55.62, 45.32, 17.82. Anal. Calcd for C10H13NO2: C 67.00, H 7.32, N 7.82. Found: C 67.08, H 7.41, N 7.75.
3-Methyl-6-tert-butyl-3,4-dihydro-2H-1,4-benzoxazine (2d). Yield 89%. Light yellow oil. IR(film, cm-1): ν3369 (N-H), 2962-2867(C-H), 1610-1446(C=C). 1H-NMR (CDCl3, 300 MHz): δ 6.65-6.77(m, 3H, Ar-H), 4.17-4.21(m, 1H, N-H), 3.74-3.81(m, 2H, O-CH2), 3.55-3.58(m, 1H, N-CH), 1.27-1.35(m, 9H, Ar-C(CH3)3), 1.19-1.21(d, 3H, J = 6.4 Hz, CH3); 13C-NMR (CDCl3, 75 MHz): δ 144.38, 141.55, 132.58, 115.93, 115.93, 112.77, 70.82, 45.33, 34.10, 31.54, 31.54, 31.54, 17.86. Anal. Calcd for C9H7NO: C 76.04, H 9.33, N 6.83. Found: C 76.09, H 9.38, N 6.80.
3-Methyl-6-chloro-3,4-dihydro-2H-1,4-benzoxazine (2e). Yield 85%. White solid, mp 80-81 °С.IR (KBr, cm-1): ν3365(N-H), 2975-2871(C-H), 1596-1442(C=C). 1H-NMR(CDCl3, 300 MHz): δ 6.56-6.72(m, 3H, Ar-H), 4.16-4.21(m, 1H, N-H), 3.72-3.78(m, 2H, O-CH2), 3.51-3.57(m, 1H, N-CH), 1.18-1.21(m, 3H, CH3); 13C-NMR (CDCl3, 75 MHz): δ 142.17, 134.46, 125.95, 118.18, 117.35, 114.69, 70.56, 44.98, 17.72. Anal. Calcd for C9H10ClNO: C 59.00, H 5.51, N 7.65. Found: C 59.06, H 5.46, N 7.62.
3-Methyl-6,8-dichloro-3,4-dihydro-2H-1,4-benzoxazine (2f). Yield 68%. White solid; mp 75-76 °С. IR(KBr, cm-1): ν3398(N-H), 2966-2854(C-H), 1595-1456(C=C). 1H-NMR(CDCl3, 300 MHz,): δ 6.47-6.73(m, 2H, Ar-H), 4.28-4.32(m, 1H, N-H), 3.78-3.84(m, 2H, O-CH2), 3.53-3.59(m, 1H, N-CH), 1.19-1.24 (m, 3H, CH3); 13C-NMR(CDCl3, 75 MHz): δ 138.16, 135.26, 125.74, 121.82, 118.52, 113.07, 70.93, 44.88, 17.57. Anal. Calcd for C9H9Cl2NO: C 49.77, H 4.18, N 6.45. Found: C 49.82, H 4.25, N 6.39.
3-Methyl-6-ethyl-3,4-dihydro-2H-1,4-benzoxazine (2g). Yield 71%. Yellow liquid. IR(film, cm-1): ν3370(N-H), 2965-2871(C-H), 1612-1456(C=C); 1H-NMR(CDCl3, 300 MHz)：δ 6.46-6.75(m, 3H, Ar-H), 4.16-4.20(m, 1H, O-CH2)，3.74-3.80(m, 1H, O-CH2-,), 3.33-3.58(m, 2H, N-CH-, N-H)，2.54-2.51(m, 2H, Ar-CH2-Me), 1.23-1.18(m, 6H, Ar-C-CH3, oxazine-CH3); 13C-NMR(CDCl3, 75 MHz): δ 141.76, 137.42, 133.24, 118.17, 116.30, 114.89, 70.82, 45.34, 28.32, 17.89, 15.92.
3-Methyl-6-bromo-3,4-dihydro-2H-1,4-benzoxazine (2h). Yield 75%. White solid, mp 85-86 °С; IR(KBr, cm-1): ν3364(N-H), 3034-2869(C-H), 1597-1498(C=C); 1H-NMR(CDCl3, 300 MHz): δ 6.63-6.75(m, 3H, Ar-H), 4.15-4.20 (m, 1H, O-CH2-), 3.71-3.77 (m, 2H, O-CH2-, N-CH-), 3.48-3.58 (m, 1H, N-H), 1.17-1.12 (d, J=9.0 Hz, 3H, oxazine-CH3); 13C-NMR(CDCl3, 75 MHz): δ 142.73, 134.78, 121.22, 117.86, 117.61, 113.26, 70.52, 45.00, 17.70.
3,7-Dimethyl-3,4-dihydro-2H-1,4-benzoxazine (2i). Yield 84%. White solid, mp 37-38 °С; IR (KBr, cm-1): ν3364(N-H)，3024-2869(C-H), 1623-1515(C=C); 1H-NMR(CDCl3, 300 MHz): δ 6.48-6.61(m, 3H, Ar-H), 4.14-4.17 (m, H, O-CH2-)，3.72-3.76 (m, 1H, O-CH2-), 3.41-3.51(m，2H，N-CH-, N-H )，2.21(s, 3H, Ar-CH3)，1.16-1.14(d, J=8.0 Hz, 3H, oxazine-CH3); 13C-NMR(CDCl3, 75 MHz): δ 143.67, 130.84, 128.61, 121.77, 117.02, 115.57, 70.87, 45.29, 20.60,17.76.
General procedure for the preparation of 3-methyl-4-acetyl-3,4-dihydro-2H-1,4–benzoxazine (3a-i)
Phenoxyacetyl chloride (21 mmol) was dropwise added to the mixture of K2CO3 (15.2 mmol, 1.6 g), 3-methyl-3,4-dihydro-2H-1,4-benzoxazine (14 mmol) and benzene (34 mL) at room temperature for 1 h. Then the mixture was filtered, and the filtrate was washed and dried over magnesium sulfate anhydrous. The benzene was removed under vacuum. The crude products were recrystallized with EtOAc and light petroleum. The physical and spectra data of the compounds 3a-i were as follows:
3-Methyl-4-phenoxyacetyl-3,4-dihydro-2H-1,4-benzoxazine (3a). Yield 60%. White solid, mp 56-57 °С; IR(KBr, cm-1): ν3061-2893(C-H)，1655(C=O); 1H-NMR(CDCl3, 300 MHz): δ 6.90-7.32(m, 9H, Ar-H)，4.83-4.96(m, 3H, N-CH-, O-CH2-C=O), 4.13-4.20 (m, 2H, O-CH2-), 1.23-1.27(d, J= 9.0 Hz, 3H, oxazine-CH3); 13C-NMR(CDCl3, 75 MHz): δ 166.40, 157.77, 146.10, 129.67, 129.67, 126.60, 124.30, 122.79 121.83, 120.66, 117.12, 114.67, 114.67, 70.04, 67.50, 44.57, 15.43. ESI-MS: 284 [M+H+]. Anal. Calcd for C17H17NO3: C 72.07, H 6.05, N 4.94. Found: C 72.11, H 6.12, N 4.89.
3,6-Dimethyl-4-phenoxyacetyl-3,4-dihydro-2H-1,4-benzoxazine (3b). Yield 77%. White solid；mp 95-96 °С IR(KBr, cm-1): ν3059-2900 (C-H)，1659(C=O); 1H-NMR(CDCl3, 300 MHz): δ 7.27-7.33(m, 3H, Ar-H), 6.81-7.00(m, 5H, Ar-H), 4.83-4.94(m, 3H, N-CH-, O-CH2-C=O), 4.08-4.18(m, 2H, O-CH2-), 2.26(s, 3H, Ar-CH3)，1.25-1.23(d, J=9.0 Hz, 3H, oxazine-CH3); 13C-NMR(CDCl3, 75 MHz): δ 166.34, 157.82, 143.88, 130.06, 129.66, 129.66, 127.24, 124.48, 122.42, 121.80, 116.75, 114.68, 114.68, 69.93, 67.65, 45.18, 20.81, 15.45. ESI-MS: 298 [M+H+]. Anal. Calcd for C18H19NO3: C 72.71, H 6.44, N 4.71. Found: C 72.68, H 6.45, N 4.78.
3-Methyl-4-phenoxyacetyl-6-methoxy-3,4-dihydro-2H-1,4-benzoxazine (3c). Yield 72%. White solid, mp 102-103 °С; IR(KBr, cm-1) ν3050-2851(C-H), 1654(C=O); 1H-NMR(CDCl3, 300 MHz): δ 7.27-7.32(m, 3H, Ar-H), 6.67-7.02(m, 5H, Ar-H), 4.81-4.94(m, 3H, N-CH-, O-CH2-C=O), 4.05-4.16(m, 2H, O-CH2-)，3.70(s, 3H, Ar-O-CH3)，1.24-1.26(d, J=9.0 Hz, 3H, oxazine-CH3); 13C-NMR(CDCl3, 75 MHz)：δ 166.28, 157.80, 153.34, 140.09, 129.688, 129.69, 123.06, 121.87, 117.43, 114.64, 114.64, 112.90, 109.05, 69.70, 67.69, 55.77, 45.23, 15.50. ESI-MS: 314 [M+H+]. Anal. Calcd for C18H19NO4: C 68.99, H 6.11, N 4.47. Found: C 68.87, H 6.08, N 4.52.
3-Methyl-4-phenoxyacetyl-6-tert-butyl-3,4-dihydro-2H-1,4-benzoxazine (3d). Yield 76%. White solid；mp 95-96 °С; IR(KBr, cm-1): ν3063-2869(C-H), 1675(C=O); 1H-NMR(CDCl3, 300 MHz): δ 6.85-7.31(m, 8H, Ar-H)，4.80-4.96(m, 3H, N-CH-, O-CH2-C=O), 4.19-4.13(m, 2H, O-CH2-), 1.27(s, 12H, oxazine-CH3, Ar-C(CH3)3); 13C-NMR(CDCl3, 75 MHz): δ 166.27, 157.87, 143.64, 129.61, 129.61, 123.68, 122.17, 121.74, 121.74, 121.03, 116.35, 114.59, 114.59, 70.10, 67.35, 45.08, 34.28, 31.42, 31.42, 31.42, 15.35. ESI-MS: 340 [M+H+]. Anal. Calcd for C21H25NO3: C 74.31, H 7.42, N 4.13. Found: C 74.28, H 7.45, N 4.18.
3-Methyl-4-phenoxyacetyl-6-chloro-3,4-dihydro-2H-1,4-benzoxazine (3e). Yield 64%. White solid, mp 85-86 °С, IR(KBr, cm-1): ν3065-2893(C-H), 1652(C=O); 1H-NMR(CDCl3, 300 MHz): δ 6.83-7.33(m, 8H, Ar-H), 4.87(s, 2H, O-CH2-C=O), 4.78(m, 1H, N-CH-), 4.09-4.19(m, 2H, O-CH2-) 1.26-1.24(d, J=9.0Hz, 3H, oxazine-CH3); 13C-NMR(CDCl3, 75 MHz): δ 166.36, 157.58, 144.54, 129.76, 129.76, 126.23, 125.30, 124.05, 123.59, 122.04, 118.04, 114.62, 114.62, 69.73, 68.00, 46.75, 15.68. ESI-MS: 318 [M+H+]. Anal. Calcd for C17H16ClNO3: C 64.26, H 5.08, N 4.41. Found: C 64.30, H 5.02, N 4.38.
3-Methyl-4-phenoxyacetyl-6,8-dichlor-3,4-dihydro-2H-1,4-benzoxazine (3f). Yield 78%. White solid, mp 49-50 °С; IR(KBr, cm-1): ν2972-2892(C-H), 1677(C=O); 1H-NMR(CDCl3, 300 MHz): δ 6.87-7.69(m, 7H, Ar-H), 4.84(s, 2H, O-CH2-C=O), 4.71(m, 1H, N-CH-), 4.11-4.31(m, 2H, O-CH2-)，1.24-1.23(d, J=4.5 Hz, 3H, oxazine-CH3); 13C-NMR(CDCl3, 75 M Hz): δ 166.53, 157.40, 140.87, 129.81, 129.81, 126.41, 124.94, 124.53, 122.78, 122.34, 122.17, 114.52, 114.52, 70.27, 68.05, 45.99, 15.70. ESI-MS: 352 [M+H+]. Anal. Calcd for C17H15Cl2NO3: C 57.97, H 4.29, N 3.98. Found: C 57.92, H 4.21, N 4.05.
Crystal data for compound 3f: C17H15Cl2NO3, triclinic, space group , a=9.0786(18) Å, b=10.568(2) Å, c=10.798(2) Å, V=3025.6(10) Å3, α=106.88(3), β=97.94(3), γ=93.77(3), Z=2, Dc=1.342 cm-3, μ=0.352 mm-1, F(000)= 412. Independent reflections were obtained in the range of 3.22° < θ < 25.00, 1464. The final least-square cycle gave R1= 0.0648, ωR2 = 0.1209 for 3413 reflections with I > 2σ(I). The maximum and minimum differences of peak and hole are 0.306 and -0.297 e/Å3, respectively.
3-Methyl-4-phenoxyacetyl-6-ethyl-3,4-dihydro-2H-1,4-benzoxazine (3g). Yield 72%. White solid, mp 95-96 °С; IR(KBr, cm-1): ν3052-2870(C-H), 1673.23(C=O); 1H-NMR(CDCl3, 300 MHz): δ 6.83-7.32(m, 8H, Ar-H), 4.82-4.95(m, 3H, N-CH-, O-CH2-C=O), 4.09-4.18(m, 2H, O-CH2-), 2.52-2.60(q, 2H, J1=7.5 Hz, J2=15.0 Hz, Ar-CH2-), 1.16-1.26(m, 6H, Ar-C-CH3, oxazine-CH3); 13C-NMR(CDCl3, 75 MHz): δ 166.33, 157.82, 144.02, 136.58, 129.64, 129.64, 126.08, 123.29, 122.48, 121.79, 116.78, 114.64, 114.64, 69.97, 67.69, 44.83, 28.20, 15.67, 15.67. ESI-MS: 312 [M+H+]. Anal. Calcd for C19H21NO3: C 73.29, H 6.80, N 4.50. Found: C 73.32, H 6.75, N 4.42.
3-Methyl-4-phenoxyacetyl-6-bromo-3,4-dihydro-2H-1,4-benzoxazine (3h). Yield 70%. White solid, mp 95-96 °С; IR(KBr, cm-1): ν3060-2932(C-H), 1654(C=O); 1H-NMR(CDCl3, 300 MHz): δ 6.78-7.34(m, 8H, Ar-H), 4.83-4.95(m, 3H, N-CH-, O-CH2-C=O), 4.09-4.20(m, 2H, O-CH2-), 1.24-1.26(d, J=6.6 Hz, 3H, oxazine-CH3); 13C-NMR(CDCl3, 75 MHz): δ 166.35, 157.55, 145.03, 129.77, 129.14, 126.87, 124.00, 122.04, 120.65, 118.49, 117.11, 114.60, 112.33, 69.74, 67.91, 46.85, 15.67. ESI-MS: 364 [M+2]. Anal. Calcd for C17H16BrNO3: C 56.37, H 4.45, N 3.87. Found: C 56.42, H 4.52, N 3.81.
3,7-Dimethyl-4-phenoxyacetyl-3,4-dihydro-2H-1,4-benzoxazine (3i). Yield 63%. White solid, mp 43-44 °С; IR(KBr, cm-1): ν2966-2931(C-H)，1684(C=O); 1H-NMR(CDCl3, 300 MHz): δ 6.71-7.29(m, 8H, Ar-H), 4.81-4.92(m, 3H, N-CH-Me, O-CH2-C=O), 4.09-4.15(m, 2H, O-CH2-C), 2.29(s, 3H, Ar-CH3), 1.20(s, 3H, oxazine-CH3); 13C-NMR(CDCl3, 75 MHz): δ 166.24, 157.81, 145.86, 129.61, 129.61, 123.94, 121.75, 121.47, 121.47, 120.17, 117.36, 114.67, 114.67, 70.04, 67.02, 26.95, 20.97, 15.29. ESI-MS: 298 [M+1]. Anal. Calcd for C18H19NO3: C 72.71, H 6.44, N 4.71. Found: C 72.65, H 6.41, N 4.78.
Biological activity: Maize (Dongnong 253) seeds were moistened with warm water about 30 min. The untreated or safener-treated maize were soaked by title compounds (10mg/kg) for 12 h, and then germinated for 24 h at 26.5 °С. The seeds were planted 1.5 cm deep in plastic trays, in which soil was treated with 0.244 g/m2 2,4-D butylate. Trays were incubated at 28 °С for 7 days. The effects of the title compound on the detoxification of 2,4-D butylate in soil were determined by testing the growth level.

SUPPLEMENTARY MATERIAL
Crystallographic data for the structural analysis of 3f has been deposited with the Cambridge Crystallographic Data Centre (CCDC 1040927). These data can be obtained free of charge from The Cambridge Crystallographic Datavia www.ccdc.cam.ac.uk/data_request/cif.

ACKNOWLEDGMENT
This work was supported by the National Nature Science Foundation of China (No. 31401787), China Postdoctoral Science Foundation（2014M551208), Natural Science Foundation of Heilongjiang Province (B201212), and the Science and Technology Research Project of Heilongjiang Education Department (No. 12531027).

References

1. A. K. Prasad, C. Mukherjee, D. Sharma, S. Rastogi, A. Mangalam, A. Jha, C. E. Olsen, S. A. Patkar, and V. S. Parmar, J Mol. Catal. B-Enzym., 2006, 40, 101. CrossRef
2. V. M. Ismailov, I. A. Mamedov, and N. N. Yusubov, Russ. J. Org. Chem., 2004, 40, 284. CrossRef
3. S. Mayer, A. Arrault, G. Guillaumet, and J. Y. Merour, J. Heterocycl. Chem., 2001, 38, 221. CrossRef
4. S. Mayer, G. Guillaumet, and J. Y. Merour, Heterocycles, 2001, 55, 1873. CrossRef
5. K. C. Majumdar, K. Ray, and S. Ponra, Tetrahedron Lett., 2010, 51, 5437. CrossRef
6. M. Robert, O. Michael, and S. Heinz., EP1283829B1.
7. D. D. Buono, L. Scarponi, and L. Espen, Phytochemistry, 2007, 68, 2614. CrossRef
8. H. Ahrens, G. Lange, T. Muller, C. Rosinger, L. Willms, and A. van Almsick, Angew. Chem. Int. Ed., 2013, 52, 9388. CrossRef
9. A. Y. Guan, Y. K. Qin, J. F. Wang, and B. Li, J. Fluorine Chem., 2013, 156, 120. CrossRef
10. A. Y. Guan, C. L. Liu, X. P. Yang, and M. Dekeyser, Chem. Rev., 2014, 114, 7079. CrossRef
11. (a) S. Gao, Y. Fu, L. X. Zhao, Z. Y. Xing, and F. Ye, Heterocycles, 2012, 85, 903; CrossRef (b) F. Ye, L. Yang, H. T. Li, Y. Fu, and W. J. Xu, J. Heterocycl. Chem., 2010, 47, 229.
12. B. Matthias and K. Burghard, DE102008062906.
13. M. Kawase and Y. Kikugawa, Chem. Pharm. Bull., 1981, 29, 1615. CrossRef
14. M. K. Parai and G. Panda, Tetrahedron Lett., 2009, 50, 4703. CrossRef
15. J. W. Bloweres, J. P.Brennan, and J. E. Saxton, J. Chem. Soc., Perkin Trans. 1, 1987, 9, 2079. CrossRef
16. K. Gao, C. B. Yu, D. S. Wang, and Y. G. Zhou, Adv. Synth. Catal., 2012, 354, 483. CrossRef
17. Q. A. Chen, D. S. Wang, Y. G. Zhou, Y. Duan, H. J. Fan, Y. Yang, and Z. Zhang, J. Am. Chem. Soc., 2011, 133, 6126. CrossRef
18. Y. Jiang, L. X. Liu, W. C. Yuan, and X. M. Zhang, Synlett, 2012, 1797.
19. R. A. Bunce, D. M. Herron, and L. Y. Hale, J. Heterocycl. Chem., 2003, 40, 1031. CrossRef
20. P. G. Baraldi, G. Saponaro, A. R.Moorman, R. Romagnoli, D. Preti, S. Baraldi, E. Ruggiero, K. Varani, M. Targa, F. Vincenzi, P. A. Borea, and M. A. Tabrizi, J. Med. Chem., 2012, 55, 6608. CrossRef
21. Y. Fu, J. Wang, Q. S. Zhao, X. M. Wang, Z. Y. Xing, and F. Ye, Indian J. Heterocycl. Chem., 2014, 24, 41.
22. G. M. Sheldrick, SHELXS-97, Program for X-Ray Crystal Structure Solution, University of Göttingen, Göttingen, Germany (1997).
23. G. M. Sheldrick, SHELXL-97, Program for X-Ray Crystal Structure Refinement, University of Göttingen, Göttingen, Germany (1997).