Synthesis and safener activity of novel substituted 4-phenoxyacetyl-1,4-benzoxazines

Article abstract of DOI:10.3987/COM-15-13225

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.

Full text of DOI:10.3987/COM-15-13225

HETEROCYCLES, Vol. 91, No. 6, 2015, pp. 1253 - 1266. © 2015 The Japan Institute of Heterocyclic Chemistry
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 Science, Northeast Agricultural
University, Harbin, 150030, P.R. China; email: fuying@neau.edu.cn
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.
1
13
The structures of the compounds were characterized by IR, H-NMR, C-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).
O
O
O
O
N
O
OH
5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid ethyl ester diphenyl acid
O
O
N
O
isoxadifen-ethyl
Scheme 1. Design of isoxadifen-ethyl

O
O
O
R2
R1
N
C
O
CHCl2
benoxacor
phenoxy acid herbicides
O
R
O
N
O
Scheme 2. Design of the target compound
R3
R3
R3
O
R2
R1
O
R2
R1
O
N
R2
R1
O
Pd, H2
PhOCH2COCl, K2CO3
rt, 1 h
1.5 MPa, 60 °C, 10 h
N
H
NO2
O
OPh
2
1
3
Scheme 3. Route for synthesis of 4-phenoxyacetyl-3-methyl-3,4-dihydro-2H-1,4-benzoxazine
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.

Table 1. Structure and yields of compounds 2 and 3
Product R1
R2
H
R3
H
H
H
H
H
Cl
H
H
H
Yields of 2(%)
Yield of 3(%)
H
72
87
91
89
85
68
71
75
84
60
77
72
76
64
78
72
70
63
a
b
c
d
e
f
Me
MeO
tBu
Cl
H
H
H
H
Cl
H
Et
H
g
h
i
Br
H
H
Me
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
Figure 1. Molecular structure for compound 3f

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)°.
P1
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.
Figure 2. Packing view of the compound 3f, hydrogen bonds are described as dashed lines
Figure 3. C-H…π interactions of the compound 3f
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.
Table 2. Effect of detoxification of compounds 3a-i to growth index of maize a,b,c
Recovery of root
length
Recovery of
plant height
(%)
Recovery of
root weight
(%)
Recovery of
plant weight
(%)
Compound
(%)
28.42±1.21
18.69±0.83
-5.92±0.55
-10.00±1.08
42.00±0.96
12.27±0.67
9.37±0.51
2.13±0.32
25.31±1.04
-6.68±0.73
7.46±0.52
-16.92±0.82
43.10±1.84
36.99±1.09
94.48±2.13
74.62±1.42
29.40±0.63
66.51±1.15
45.56±1.05
28.68±1.32
88.00±1.54
80.39±2.01
-17.60±0.45
8.10±0.74
112.06±2.83
43.15±1.65
42.46±1.48
55.01±1.86
86.14±0.78
58.79±1.69
28.2±0.58
9.6±0.87
Benoxacor
3a
3b
3c
3d
3e
3f
16.27±1.17
37.41±1.56
51.56±1.83
17.47±1.12
35.37±1.24
21.23±1.69
32.08±1.57
17.06±0.98
3g
3h
3i
a data are means of three replicates
Treated with compounds -Treated with 2,4- D butylate
Contrast - Treated with 2,4- D butylate
b RecoveryRate (%) 
c water treated was used as contrast
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):
1
ν3371(N-H), 2970-2871(C-H), 1608-1427(C=C). H-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):
1
ν3369(N-H), 2970-2869(C-H), 1614-1454(C=C). H-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,
13
Ar-CH3), 1.05-1.07(d, 3H, J=6.4Hz, CH3); C-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.
1
IR(KBr, cm-1): ν3373(N-H), 2968-2833(C-H), 1620-1456(C=C). H-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),
13
1.18-1.21(m, 3H, CH3); C-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.
1
IR(KBr, cm-1): ν3398(N-H), 2966-2854(C-H), 1595-1456(C=C). H-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),
13
1.19-1.24 (m, 3H, CH3); C-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,
13
Ar-CH2-Me), 1.23-1.18(m, 6H, Ar-C-CH3, oxazine-CH3); C-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;
1
IR(KBr, cm-1): ν3364(N-H), 3034-2869(C-H), 1597-1498(C=C); H-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,
13
1H, N-H), 1.17-1.12 (d, J=9.0 Hz, 3H, oxazine-CH3); C-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,
13
3H, Ar-CH3)，1.16-1.14(d, J=8.0 Hz, 3H, oxazine-CH3); C-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,
13
oxazine-CH3); C-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-),
13
2.26(s, 3H, Ar-CH3)，1.25-1.23(d, J=9.0 Hz, 3H, oxazine-CH3); C-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,
1
mp 102-103 °С; IR(KBr, cm-1) ν3050-2851(C-H), 1654(C=O); H-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,
13
2H, O-CH2-)，3.70(s, 3H, Ar-O-CH3)，1.24-1.26(d, J=9.0 Hz, 3H, oxazine-CH3); C-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
1
solid；mp 95-96 °С; IR(KBr, cm-1): ν3063-2869(C-H), 1675(C=O); H-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
13
Hz, 3H, oxazine-CH3); C-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.
P1
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
13
Hz, J2=15.0 Hz, Ar-CH2-), 1.16-1.26(m, 6H, Ar-C-CH3, oxazine-CH3); C-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).

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