Simple and efficient synthesis of novel N -dichloroacetyl-3,4-dihydro-2 H -1,4-benzoxazines

Article abstract of DOI:10.1515/hc-2012-0056

An easy synthetic route to N -dichloroacetyl- 3,4-dihydro-2 H -1,4-benzoxazine derivatives 3 involves cyclization of 2-aminophenols 1 with 1,2-dibromoethane and subsequent acylation of the resultant 3,4-dihydro- 2 H -1,4-benzoxazine derivatives 2 with dichloroacetyl chloride. All compounds were characterized by IR, 1 H NMR, 13 C NMR, ESI-MS and elemental analysis. The structure of 3a was determined by X-ray crystallographic analysis.

Full text of DOI:10.1515/hc-2012-0056

DOI 10.1515/hc-2012-0056ꢀ
ꢀHeterocycl. Commun. 2012; 18(3): 143–146
Ying Fu, Li-Hua Qu, Shan-Shan Zhang, Fei Ye*, Li-Xia Zhao, Shuang Gao and Zhi-Yong Xing
Simple and efficient synthesis of novel
N-dichloroacetyl-3,4-dihydro-2H-1,4-benzoxazines
Abstract: An easy synthetic route to N-dichloroacetyl- disadvantages. As part of our ongoing studies on the
3,4-dihydro-2H-1,4-benzoxazine derivatives
3 involves development of simple synthetic methods in heterocyclic
cyclization of 2-aminophenols 1 with 1,2-dibromoethane chemistry (Fu et al., 2011a,b), we report herein an efficient
and subsequent acylation of the resultant 3,4-dihydro- and convenient synthetic route to novel N-dichloroacetyl-
2H-1,4-benzoxazine derivatives 2 with dichloroacetyl chlo- 3,4-dihydrol-2H-1,4-benzoxazine derivatives, starting from
ride. All compounds were characterized by IR, 1H NMR, 13C readily available reactants (Scheme 1).
NMR, ESI-MS and elemental analysis. The structure of 3a
was determined by X-ray crystallographic analysis.
Results and discussion
The reaction of 2-aminophenols 1 with 1,2-dibromoethane
proceeded smoothly in DMSO in the presence of K2CO3 and
Keywords: acylation; cycloaddition; N-dichloroacetyl-
3,4-dihydro-2H-1,4-benzoxazine; synthesis.
*Corresponding author: Fei Ye, Department of Applied Chemistry,
Northeast Agricultural University, Harbin, 150030, China,
e-mail: yefei@neau.edu.cn
Ying Fu: Department of Applied Chemistry, Northeast Agricultural
University, Harbin, 150030, China
Li-Hua Qu: Department of Applied Chemistry, Northeast Agricultural
University, Harbin, 150030, China
Shan-Shan Zhang: Department of Applied Chemistry, Northeast
Agricultural University, Harbin, 150030, China
Li-Xia Zhao: Department of Applied Chemistry, Northeast
Agricultural University, Harbin, 150030, China
Shuang Gao: Department of Applied Chemistry, Northeast
Agricultural University, Harbin, 150030, China
Zhi-Yong Xing: Department of Applied Chemistry, Northeast
Agricultural University, Harbin, 150030, China
at 80°C to produce the corresponding 3,4-dihydro-2H-1,4-
benzoxazines 2 in moderate yields. The target compounds
3 were obtained by acylation of 2 with dichloroacetyl
chloride in benzene. The process was monitored by thin
layer chromatography. The reaction proceeded rapidly
and was exothermic. Accordingly, it was conducted at
low temperature. The structures of the intermediates 2
and products 3 are supported by their elemental analy-
sis results and the IR, H and C NMR spectral data. The
structure of 3a was further studied by single crystal X-ray
diffraction. The molecular structure and the packing view
are shown in Figures 1 and 2, respectively. The π-p-π con-
jugation of benzene ring, N1, and C9ꢀ ꢀO2 results in longer
bond length of C9 O2 [1.383(3) Å] than the typical Cꢀ ꢀO
bond length (1.21–1.23 Å). Owing to conjugation the bond
C8 N1 [1.333(3) Å] and C9 N1 [1.316(3) Å] are shorter than
the typical C N bond (1.472 Å).
1
13
Introduction
In conclusion, we have developed an easy and effi-
cient route for the synthesis of a series of novel N-dichlo-
roacetyl-3,4-dihydro-2H-1,4-benzoxazines via cyclization
and acylation with good yields. This synthetic reaction
has the advantages of readily available starting materials,
mild reaction conditions, and simple manipulations.
Substituted benzoxazine derivatives have attracted wide-
spread attention because of their broad applications as
fungicides and insecticides (Macias et al., 2006; Mizar
and Myrboh, 2006; Xue et al., 2010; Tang et al., 2011).
Moreover, benzoxazines are useful starting materials for
the synthesis of larger structures with valuable biological
activities (Largeron et al., 1999; Matsumoto et al., 1999;
Sakami et al., 2008). N-Dichloroacetylbenzoxazines have
been used as herbicide safeners that protect the crop from Conclusion
injury by herbicides (Hatzios and Burgos, 2004; Buono
et al., 2005, 2006). A number of synthetic routes to 1,4-ben- A facile and efficient route for the synthesis of a series of
zoxazines have been reported (Bunce et al., 2003; Domin- novel N-dichloroacetyl-3,4-dihydro-2H-1,4-benzoxazines
czaka et al., 2006; Majumdar et al., 2010; Manzo et al., via cyclization and acylation was developed. This syn-
2011); however, these methods have their own inherent thetic method has the advantages of readily available
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ꢀY. Fu et al.: Novel N-dichloroacetyl-3,4-dihydro-2H-1,4-benzoxazines
R1
R2
O
R1
R2
O
R1
R2
OH
Br
Br
Cl2CHCOCl
benzene
DMSO
K2CO3, 80oC
N
H
N
C
NH2
O
CHCl2
1a-g
2a-g
3a-g
1
: R1 = R2 = H;
: R = H, R2 = Cl;
: R1 = H, R2 = Me;
: R1 = H, R2 = Br;
d
a
b
c
1
e: R1 = H, R2 = Bu;
: R = Me, R2 = H;
: R1 = Cl, R2 = H
t
f
g
Scheme 1ꢀSynthesis of N-dichloroacetyl-1,4-benzoxazines 3.
was purified by column chromatography on silica gel eluting with
AcOEt and light petroleum (1:15).
starting materials, mild reaction conditions, and simple
manipulations.
3,4-Dihydro-2H-1,4-benzoxazine (2a) Red oil; yield 2.26 g (62%);
IR: ν 3381, 1609, 1283, 1205 cm-1; 1H NMR (CDCl3): δ 6.60–6.81 (m, 4H,
Ar-H), 4.25–4.33 (m, 2H, O-CH2), 3.59 (s, 1H, NH), 3.42–3.45 (m, 2H,
N-CH2); 13C NMR (CDCl3): δ 144.2, 133.7, 121.7, 118.9, 116.8, 115.7, 65.3,
41.0. Anal. Calcd for C8H9NO: C, 71.08; H, 6.72; N, 10.37. Found: C,
71.12; H, 6.68; N, 10.31.
Experimental
The infrared (IR) spectra were taken on a KJ-IN-27G infrared spec-
trophotometer in KBr pellets. The 1H NMR and 13C NMR spectra were
recorded on a Bruker AVANVE 300 nuclear spectrometer at 300
MHz and 75 MHz, respectively, with TMS as the internal standard.
The elemental analysis was performed on a FLASH EA1112 elemen-
tal analyzer. Mass spectra were recorded on a Waters Xevo TQ mass
spectrometer. The melting points were determined on a Beijng Taike
melting point apparatus (X-4) and are uncorrected. The reagents
were of analytical grade.
3,4-Dihydro-6-chloro-2H-1,4-benzoxazine (2b)ꢁRed oil; yield 2.56
g (56%); IR: ν 3404, 1607, 1288, 1205 cm-1; 1H NMR (CDCl3): δ 6.56–6.70
(m, 3H, Ar-H), 4.21–4.24 (m, 2H, O-CH2), 3.60 (s, 1H, NH), 3.39–3.42 (m,
2H, CH); 13C NMR (CDCl3): δ 142.6, 134.6, 125.9, 118.3, 117.6, 114.9, 65.0,
40.6. Anal. Calcd for C8H8ClNO: C, 56.79; H, 4.77; N, 8.28. Found: C,
56.72; H, 4.81; N, 8.19.
3,4-Dihydro-6-methyl-2H-1,4-benzoxazineꢀ(2c) Red oil; yield
1
2.57 g (64%); IR: ν 3379, 1600, 1348, 1309 cm-1; H NMR (DMSO-d6):
δ 6.47–6.50 (d, J ꢀ=ꢀ 8.0 Hz, 1H, Ar-H), 6.34 (s, 1H, Ar-H), 6.23–6.26
(m, 1H, Ar-H), 4.03–4.06 (t, J ꢀ=ꢀ 4.5 Hz, 2H, O-CH2), 3.36 (s, 1H,
NH), 3.20–3.23 (t, J ꢀ=ꢀ 4.5 Hz, 2H, N-CH2), 2.09 (s, 1H, CH3); 13C NMR
(DMSO-d6): δ 141.5, 134.9, 130.0, 117.7, 116.1, 115.8, 65.0, 40.1, 20.9.
Anal. Calcd for C9H11NO: C, 72.44; H, 7.44; N, 9.39. Found: C, 72.41;
H, 7.39; N, 9.31.
General preparation of 3,4-dihydrol-
2H-1,4-benzoxazines 2a–g
A mixture of 2-aminophenol (1) (0.027 mol), anhydrous K2CO3 (7.5 g),
and DMSO (40 mL) was heated to 80°C and treated dropwise with
1,2-dibromoethane (5.2 g, 0.027 mol) with stirring for 6–8 h. The
mixture was filtered, treated with H2O (40 mL), and extracted with
AcOEt (3ꢃꢃ× 25 mL). The organic phase was dried over anhydrous
MgSO4 and concentrated under reduced pressure. The residue of 2
3,4-Dihydro-6-bromo-2H-1,4-benzoxazineꢀ(2d)ꢂRedꢂoil;ꢂyield
1
2.94 g (51%); IR: ν 3400, 1602, 1350, 1312 cm-1; H NMR (DMSO-d6):
δ 6.68–6.69 (m, 1H, Ar-H), 6.52–6.58 (m, 2H, Ar-H), 6.03 (s, 1H, NH),
4.06–4.09 (t, J ꢀ=ꢀ 4.5 Hz, 2H, O-CH2), 3.24–3.30 (m, 2H, CH); 13C NMR
(DMSO-d6): δ 142.70, 137.22, 118.90, 118.06, 116.72, 112.79, 64.88, 40.89.
Anal. Calcd for C8H8BrNO: C, 45.07; H, 3.79; N, 6.57%. Found: C, 45.02;
H, 3.75; N, 6.62%.
3,4-Dihydro-6-t-butyl-2H-1,4-benzoxazineꢀ(2e)ꢂRedꢂoil;ꢂyield
1
3.46 g (67%); IR: ν 3380, 1595, 1346, 1313 cm-1; H NMR (DMSO-d6):
δ 6.54–6.57 (m, 1H, Ar-H), 6.44–6.48 (m, 2H, Ar-H), 5.55 (s, 1H, NH),
4.04–4.07 (t, J ꢀ=ꢀ 4.5 Hz, 2H, O-CH2), 3.21–3.24 (m, 2H, CH), 1.19 (s, 9H,
C(CH3)3); 13C NMR (DMSO-d6): δ 143.7, 141.5, 134.5, 115.7, 114.0, 112.4,
65.1, 40.9, 34.2, 31.9, 31.9, 31.9. Anal. Calcd for C12H17NO: C, 75.34; H,
8.96; N, 7.33. Found: C, 75.38; H, 8.94; N, 7.41.
3,4-Dihydro-7-chloro-2H-1,4-benzoxazine (2f) Red oil; yield 2.51 g
(55%); IR: ν 3377, 1622, 1301, 1278 cm-1; 1H NMR (DMSO-d6): δ 6.65–6.69
(m, 2H, Ar-H), 6.52–6.55 (m, 1H, Ar-H), 5.85 (s, 1H, NH), 4.08–4.11
(t, J ꢀ=ꢀ 4.5 Hz, 2H, O-CH2), 3.23–3.26 (t, J ꢀ=ꢀ 4.5 Hz, 2H, N-CH2); 13C NMR
(DMSO-d6): δ 144.1, 134.5, 121.1, 119.8, 116.1, 115.9, 65.2, 40.9. Anal.
Calcd for C8H8ClNO: C, 56.79; H, 4.77; N, 8.28. Found: C, 56.76; H, 4.75;
N, 8.21.
Figure 1ꢁStructure of 3a showing 30% probability ellipsoids.
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ꢀ145
Figure 2ꢀPacking view of 3a.
3,4-Dihydro-7-methyl-2H-1,4-benzoxazine (2g) Red oil; yield N-Dichloroacetyl-3,4-dihydro-6-methyl-2H-1,4-benzoxazine (3c)
1
2.62 g (65%); IR: ν 3381, 1597, 1298, 1269; H NMR (DMSO-d6): δ
White solid; yield 2.23 g (86%); mp 105–106°C; IR: ν 3020–2862, 1679
6.44 (s, 3H, Ar-H), 5.43 (s, 1H, NH), 4.05–4.08 (t, J ꢀ=ꢀ 4.5 Hz, 2H, cm-1; H NMR (CDCl3): δ 6.84–6.95 (m, 3H, Ar-H), 6.81 (s, 1H, Cl2CH),
1
O-CH2), 3.20–3.22 (t, J ꢀ=ꢀ 4.5 Hz, 2H, N-CH2), 2.10 (s, 3H, CH3); 13C
4.31–4.34 (t, J ꢀ=ꢀ 4.5 Hz, 2H, O-CH2), 3.97–4.01 (m, 2H, N-CH2), 2.30
NMR (DMSO-d6): δ 143.6, 132.7, 126.1, 121.8, 116.9, 115.4, 65.2, 40.9, (s, 3H, CH3); 13C NMR (CDCl3): δ 163.2, 145.3, 130.4, 128.9, 124.2, 122.8,
20.7. Anal. Calcd for C9H11NO: C, 72.44; H, 7.44; N, 9.39. Found: C,
72.47; H, 7.41; N, 9.33.
117.77, 66.6, 63.3, 41.32, 20.7; MS (EI): m/z 259 [M-1]. Anal. Calcd for
C11H11Cl2NO2: C, 50.96; H, 4.28; N, 5.41. Found: C, 50.88; H, 4.21; N, 5.53.
N-Dichloroacetyl-3,4-dihydro-6-bromo-2H-1,4-benzoxazine (3d)
White solid; yield 2.65 g (82%); mp 112–113°C; IR: ν 3010–2870, 1682
cm-1; 1H NMR (DMSO-d6): δ 7.22–7.24 (m, 2H, Ar-H), 6.80–6.82 (m, 1H,
Ar-H), 6.45 (s, 1H, Cl2CH), 4.34–4.37 (t, J ꢀ=ꢀ 4.5 Hz, 2H, O-CH2), 4.01–
4.05 (m, 2H, N-CH2); 13C NMR (DMSO-d6): δ 162.1, 146.6, 129.3, 126.7,
General preparation of N-dichloroacetyl-
3,4-dihydrol-2H-1,4-benzoxazines 3a–g
A mixture of compound 2 (0.01 mol), anhydrous Na2CO3 (1.05 g), 126.2, 119.62, 111.3, 67.2, 65.8, 43.7; MS (EI): m/z 323 [M-1]. Anal. Calcd
and benzene (25 mL) was stirred at 25°C and treated dropwise with for C10H8BrCl2NO2: C, 37.16; H, 2.50; N, 4.34. Found: C, 37.22; H, 2.45;
dichloroacetyl chloride (1.81 g, 0.012 mol). After the addition was N, 4.41.
completed the mixture was stirred for an additional 45 min. The
organic phase was rinsed with water, dried over anhydrous MgSO4,
N-Dichloroacetyl-3,4-dihydro-6-t-butyl-2H-1,4-benzoxazine (3e)
and concentrated under reduced pressure. Crude product 3 was crys- White crystalline solid; yield 2.41 g (80%); mp 55–56°C; IR: ν 3050–
tallized from a mixture of EtOAc and light petroleum.
2870, 1678 cm-1; 1H NMR (DMSO-d6): δ 7.12–8.00 (m, 3H, Ar-H), 6.85 (s,
1H, Cl2CH), 4.27–4.30 (t, J ꢀ=ꢀ 4.5 Hz, 2H, O-CH2), 3.91–3.94 (t, J ꢀ=ꢀ 4.5 Hz,
2H, N-CH2), 1.23 (s, 9H, C(CH3)3); 13C NMR (DMSO-d6): δ 161.8, 144.98,
142.7, 124.7, 123.8, 120.7, 117.0, 67.4, 65.8, 44.2, 34.5, 31.7, 31.7, 31.7; MS
N -Dichloroacetyl-3,4-dihydro-2H-1,4-benzoxazineꢀ(3a)ꢂWhite
solid; yield 2.25 g (92%); mp 102–103°C; IR: ν 3050–2870, 1676 cm-1;
1H NMR (DMSO-d6): δ 7.87–7.89 (m, 1H, Ar-H), 7.33–7.39 (m, 1H, Ar-H), (EI): m/z 301 [M-1]. Anal. Calcd for C14H17Cl2NO2: C, 55.80; H, 5.69; N,
7.08–7.13 (m, 1H, Ar-H), 6.93 (s, 1H, Cl2CH), 6.89–6.91 (d, J ꢀ=ꢀ 6.6 Hz,
1H, Ar-H), 4.32–4.35 (t, J ꢀ=ꢀ 4.5 Hz, 2H, O-CH2), 3.93–3.96 (t, J ꢀ=ꢀ 4.5
4.65. Found: C, 55.84; H, 5.61; N, 4.74.
Hz, 2H, NCH2); 13C NMR (DMSO-d6): δ 161.8, 147.3, 126.8, 125.5, 124.1, N-Dichloroacetyl-3,4-dihydro-7-chloro-2H-1,4-benzoxazineꢀ(3f)
120.5, 117.6, 67.2, 65.9, 43.9; MS (EI): m/z 245 [M-1]. Anal. Calcd for
White solid; yield 2.48 g (89%); mp 100–101°C; IR: ν 3051–2891, 1680
C10H9Cl2NO2: C, 48.98; H, 3.70; N, 5.72. Found: C, 48.89; H, 3.74; N, cm-1; 1H NMR (DMSO-d6): δ 7.87–7.89 (m, 1H, Ar-H), 7.36 (s, 1H, Ar-H),
5.26.
7.02 (s, 1H, Cl2CH), 6.98–7.00 (m, 1H, Ar-H), 4.34–4.37 (t, J ꢀ=ꢀ 4.5 Hz,
2H, O-CH2), 3.93–3.96 (t, J ꢀ=ꢀ 4.5 Hz, 2H, N-CH2); 13C NMR (DMSO-d6):
N-Dichloroacetyl-3,4-dihydro-6-chloro-2H-1,4-benzoxazine δ 162.0, 148.1, 130.3, 125.5, 124.6, 120.5, 117.3, 67.1, 66.2, 43.7; MS (EI):
(3b) White solid; yield 2.26 g (81%); mp 106–107°C; IR: ν 3050– m/z 279 [M-1]. Anal. Calcd for C10H8Cl3NO2: C, 43.02; H, 2.89; N, 5.02.
2870, 1674 cm-1; H NMR (DMSO-d6): δ 7.97–8.02 (m, 1H, Ar-H), 7.40 Found: C, 42.94; H, 2.84; N, 4.91.
1
(s, 1H, Cl2CH), 7.14–7.18 (m, 1H, Ar-H), 6.95–6.98 (d, J ꢀ=ꢀ 8.8 Hz, 1H,
Ar-H), 4.33–4.36 (t, J ꢀ=ꢀ 4.5 Hz, 2H, O-CH2), 3.93–3.96 (t, J ꢀ=ꢀ 4.5 Hz,
N-Dichloroacetyl-3,4-dihydro-7-methyl-2H-1,4-benzoxazine (3g)
2H, N-CH2); 13C NMR (DMSO-d6): δ 162.2, 146.2, 126.4, 123.4, 123.4, White solid; yield 2.33 g (90%); mp 83–84°C; IR: ν 3041–2950, 1678
1
119.2, 119.2, 67.2, 65.8, 43.6; MS (EI): m/z 279 [M-1]. Anal. Calcd for
cm-1; H NMR (DMSO-d6): δ 7.73–7.80 (m, 1H, Ar-H), 7.29–7.35 (m, 1H,
C10H8Cl3NO2: C, 43.02; H, 2.89; N, 5.02. Found: C, 42.88; H, 2.89; N, Ar-H), 6.74 (s, 1H, Cl2CH), 6.71 (s, 1H, Ar-H), 4.28–4.31 (t, J ꢀ=ꢀ 4.5 Hz,
4.81.
2H, O-CH2), 3.89–3.92 (t, J ꢀ=ꢀ 4.5 Hz, 2H, N-CH2), 2.23 (s, 3H, Me); 13C
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146ꢀ
ꢀY. Fu et al.: Novel N-dichloroacetyl-3,4-dihydro-2H-1,4-benzoxazines
NMR (DMSO-d6): δ 161.6, 147.0, 136.4, 123.7, 122.9, 121.3, 117.7, 77.2, 65.9, supplementary publication number CCDC 821009. Copies of the
44.1, 20.9; MS (EI): m/z 259 [M-1]. Anal. Calcd for C11H11Cl2NO2: C, data can be obtained, free of charge, on application to CCDC,
50.96; H, 4.28; N, 5.41. Found: C, 51.03; H, 4.24; N, 5.36.
12 Union Road, Cambridge CB21EZ, UK [fax: +44(1223)336033 or
e-mail: deposit@ccdc.cam. ac.uk].
Acknowledgments: This work was supported by the Na-
tional Nature Science Foundation of China (No. 31101473),
the China Postdoctoral Science Foundation funded
project (No. 2011M501006), the Science and Technology
Research Project of Heilongjiang Education Department
(No. 12521015, 12521002), the Research Science Founda-
tion in Technology Innovation of Harbin (2010RFQYN108,
2012RFQXN015, 2012RFXXN002), and Northeast Agricul-
tural University Doctor Foundation funded project.
X-Ray data collection and structure
refinement
The X-ray data were collected on a Bruker AXS II CCD area detec-
tor diffractometer using graphite monochromated Mo Kα radia-
tion (λ = 0.071073 nm) at 298(2) K. The structure was solved by
direct methods using SHELXS-97, and refined by full matrix
least squares on F2 using full matrix least squares procedures.
Minimum and maximum, final electron density were -0.559 and
0.391 e Å-3. Symmetry equivalent reflections were used to opti-
mize crystal shape and size. Crystallographic data have been
deposited at the Cambridge Crystallographic Data Centre as Received April 16, 2012; accepted May 25, 2012
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