Synthesis of 2,3-diaryl-3,4-dihydro-2H-1,3-benzoxazines and their fungicidal activities

Article abstract of DOI:10.1002/jhet.533

A series of novel 2,3-diaryl-3,4-dihydro-2H-1,3-benzoxazines have been prepared in high yields from o-arylaminomethylphenols and aromatic aldehydes in the presence of SnCl₄ for the first time, and their fungicidal activities were investigated t

Full text of DOI:10.1002/jhet.533

March 2011
Synthesis of 2,3-Diaryl-3,4-dihydro-2H-1,3-benzoxazines and
Their Fungicidal Activities
255
Zilong Tang,a,b* Weiwen Chen,a,b Zhonghua Zhu,a,b and Hanwen Liua,b
aSchool of Chemistry and Chemical Engineering, Hunan University of Science and Technology,
Xiangtan 411201, People’s Republic of China
bKey Laboratory of Theoretical Chemistry and Molecular Simulation of Ministry of Education,
Hunan University of Science and Technology, Xiangtan 411201,
People’s Republic of China
*E-mail: zltang67@yahoo.com.cn
Received February 4, 2010
DOI 10.1002/jhet.533
Published online 18 November 2010 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel 2,3-diaryl-3,4-dihydro-2H-1,3-benzoxazines have been prepared in high yields from
o-arylaminomethylphenols and aromatic aldehydes in the presence of SnCl4 for the first time, and their
fungicidal activities were investigated too. Some of the products showed good fungicidal activities
against Rhizoctonia solani justified by 100% activity of compound 1b.
J. Heterocyclic Chem., 48, 255 (2011).
INTRODUCTION
some drawbacks existed in previous methods. Hence,
both the preparation of novel 3,4-dihydro-1,3-benzoxa-
zines and the development of efficient method are still
of great importance. On the other hand, the reported bi-
ological studies of dihydro-1,3-benzoxazines were
mainly focused on the pharmacological activities. To the
best of our knowledge, few papers about the pesticidal
activities of dihydro-2H-1,3-benzoxazines and the prepa-
ration of 2,3-diaryl-3,4-dihydro-2H-1,3-benzoxazines
have been reported. Hence, herein, we present our
results of the synthesis of 2,3-diaryl-3,4-dihydro-2H-1,3-
benzoxazines mediated by SnCl4 (Scheme 1) and the
preliminary fungicidal activities of the products.
As 3,4-dihydro-2H-1,3-benzoxazines and 3,4-dihydro-
2H-1,3-oxazine containing compounds have been
reported to show different antimicrobial properties [1],
such as bactericidal, fungicidal, and many pharmacolog-
ical features [2] such as antitumour, antituberculosis,
and anthelmintic activity, these types of compounds
have been an important subject of researches. In addi-
tion, N-substituted 3,4-dihydro-2H-1,3-benzoxazines are
potential intermediates for the preparation of phenol-
formaldehyde resins [3]. Hence, the synthesis of these
compounds including the synthesis of benzoxazine
monomers containing special functional group has
attracted great interest. Several methods have been
reported for the preparation of these compounds in the
literature. For example, an important method was devel-
oped by Burke et al. [4], using Mannich-type condensa-
tion of phenols with primary amines and two equiva-
lents of formaldehyde. Condensations of o-aminomethyl-
phenol with aldehydes or ketones provided another route
[5]. Reactions of primary amines with oxygen-contain-
ing dihalocompounds established a way to prepare 3,4-
dissymmetric-substituted 3,4-dihydro-1,3-benzoxazines
[6]. Recently, rhodium-catalyzed reactions of 2-(alkeny-
loxy)benzylamines have been developed as a new way
to generate 3,4-dihydro-1,3-benzoxazines, which
involves an allylic cleavage followed by regioselective
carbonylation at the internal carbon atom [7]. However,
RESULTS AND DISCUSSION
The intermediate Schiff bases 3 were smoothly pre-
pared in 84 to 99% yields (Table 1) by condensation
reactions of substituted anilines 2 with salicylaldehyde,
and followed by reduction with NaBH4 affording o-ary-
laminomethylphenols 4 in 90 to 94% yields (Table 1)
[8,9]. It was found that only E isomer of Schiff base 3
was formed [9], possibly due to the stability and a
hydrogen bond between the hydroxyl group and the
nitrogen atom [9,10]. Then, reaction of o-aminomethyl
phenol 4c with 3-nitrobenzaldehyde 5c in the presence
of p-toluenesulfonic acid (TsOH) [2g,11] was performed
under reflux by removing the water of condensation
C
V
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256
Z. Tang, W. Chen, Z. Zhu, and H. Liu
Vol 48
NO2 group, and 1585 and 1610 cmꢁ1 for mC¼¼C bond.
Scheme 1. Synthesis of 2,3-diaryl-3,4-dihydro-2H-1,3-benzoxazines 1.
1
d ¼ 6.85 observed in H-NMR corresponds to OCHN
proton of benzoxazine ring. The downfield shift of
OCHN proton is due to the strong electron negative of
nitrogen and oxygen atoms. Particularly, the proton of
NCH2 group absorbs as two doublets at 4.00 and 4.19
instead of a singlet. These data strongly suggested the
formation of benzoxazine ring. In addition, the spectro-
scopic data-based structure was further confirmed by X-
ray crystallographic analysis of 1b (Fig. 1) [13]. It can
be seen clearly from the structure, in solid state, the
conformation of oxazine ring is a half-chair form with
two trans-axial orientation of both the N-aryl and 2-aryl
group. It apparently indicated that the nitrogen atom
adopted sp3 hybrid orbital.
with chloroform azeotropically to prepare 2,3-diaryl-3,4-
dihydro-2H-1,3-benzoxazine 1a, the reaction gave the
desired product in only 11% yield along with an
unknown white solid (Table 2, entry 1). We next
attempted a mixed solvent of chloroform and cyclohex-
ane, (v:v ¼ 1:7) taking into account the higher azeo-
tropic ability of cyclohexane, the yield raised to 18%
(entry 2), but still far away from satisfaction. Here, it
should be noted that the addition of chloroform was to
increase the solubility of reactants. In literature, Lewis
acid SnCl4 was reported as an effective catalyst for many
reactions, such as acetalization and ketalization of alde-
hydes or ketones [12]. Therefore, we tried SnCl4 (20 mol
%) as catalyst, to our delight, it turned out that the reac-
tion of 4c with 5c in chloroform/cyclohexane (v:v ¼ 1:7)
gave product 1a in 95% yield at 85ꢀC (entry 3). To the
best of our knowledge, this is the first time to use SnCl4
as catalyst for the zaz-acetalization of aromatic aldehyde
with o-aminomethylphenol to prepare dihydro-1,3-benzox-
azine. But, the yield decreased when the amount of the
catalyst was increased to 25 mol % (entry 4). Thus, we
employed 20 mol % of SnCl4 for the synthesis of com-
pounds 1b–1o. Generally, under these conditions, 1b–1o
were prepared in 60 to 80% yields (entries 3–18). Com-
pounds possessing an electron-releasing group on the phe-
nyl group bond to the nitrogen atom gave higher yields
than those with an electro-withdrawing group. Electron-
releasing group increases the electron density of the nitro-
gen and hence increases its nucleophilicity. Moreover, it
was observed that, for compounds containing a methyl
group on the benzene ring connected with the nitrogen
atom, the yield mainly depended on the position of the
methyl group in the order of para > meto > ortho
regardless of the nature of the aryl group at position-2 of
the oxazine ring. The last two cases may be attributed to
the steric hindrace.
According to SOP procedure [14], fungicidal activities
of the prepared compound 1a–1o against Gibberella zeae,
Phytophythora capsici, Alternaria alternate, Botrytis cin-
erea, and Sclerotonia sclerotiorum were evaluated using
the mycelium growth rate test in concentration of 25 mg/
L, which was expressed as inhibition rate (%), and their
activities against Rhizoctonia solani using the leaf-disc
culture in concentration of 500 mg/L, which was
expressed as control efficacy (%). The results are summar-
ized in Table 3. In principle, it can be seen that most of
the compounds showed moderate to good activity. For the
tested compounds, the activity against Rhizoctonia solani
was the best as shown by compound 1b (100%) and 1e,
1g, and 1n (80% for three compounds). Moreover, com-
pounds possessing an electron-releasing group on the
phenyl group bond to the nitrogen atom showed higher
activities against Rhizoctonia solani than those with an
electro-withdrawing group. For other fungus, there was
not apparent structure-activity relationship. The insectici-
dal activities of the compounds 1 are in progress.
EXPERIMENTAL
All solvents were dried by standard procedure. Aromatic
aldehydes and substituted anilines were commercially
Table 1
The results of the preparation of Schiff base 3 and o-
aminomethylphenol 4.
Entry
R
Product 3 Yielda (%) Product 4 Yieldb (%)
1
2
3
4
5
6
2-CH3
3-CH3
4-CH3
4-Cl
4-OCH3
H
3a
3b
3c
3d
3e
3f
90
84
98
98
93
91
4a
4b
4c
4d
4e
4f
91
94
94
90
92
91
The structures of all the synthesized compounds were
established on the basis of their spectroscopic data and
elemental analysis. For compound 1b, strong absorptions
at 1530 and 1337 cmꢁ1 are attributed to the antisymmet-
rical and symmetrical stretch vibration absorption of the
a Isolated yield for reaction carried out in refluxing ethanol for 3 h.
b Isolated yield for reaction carried out in methanol at 0ꢀC for 40 min.
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Synthesis of 2,3-Diaryl-3,4-dihydro-2H-1,3-benzoxazines
257
Table 2
The results of the preparation of compound 1.
Entry
R
R1
Conditionsa
Product
Yieldb (%)
1
2
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
3-CH3
3-CH3
3-CH3
2-CH3
2-CH3
2-CH3
4-Cl
3-NO2
3-NO2
3-NO2
3-NO2
2-NO2
4-NO2
2-NO2
3-NO2
4-NO2
2-NO2
3-NO2
4-NO2
2-NO2
4-NO2
2-NO2
3-NO2
2-NO2
3-NO2
TsOH (20 mol %), CHCl3, reflux, 5 h
TsOH (20 mol %), reflux, 5 h, CHCl3/C6H12
SnCl4(20 mol %), 85ꢀC, 5 h, CHCl3/C6H12
SnCl4 (25 mol %), 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
SnCl4, 85ꢀC, 5 h, CHCl3/C6H12
1a
1a
1a
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
11c
18
95
85
80
67
69
68
65
63
65
64
69
60
66
61
73
70
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4-Cl
H
H
1m
1n
1o
4-CH3O
4-CH3O
a The mole ratio of n (aromatic aldehyde 5): n (aminomethyl phenol 4) ¼ 1.3:1 for all reactions. The amount of SnCl4: 20 mol % based on amino-
methyl phenol except for the cases marked in the table. C6H12: cyclohexane; CHCl3:C6H12 ¼ 1:7 (v:v).
b Isolated yield.
c An unknown white solid also formed.
available. Infrared spectra were recorded on a PE-2000 FT-IR.
1H and 13C-NMR spectra were recorded on Bruker Avance-
500 MHz spectrometer. Chemical shifts (d) are given in ppm
relative to Me4Si (0, 1H) or CDCl3 (77.0, 13C). Mass spectra
were obtained with Thermo Finnigan LCQ Advantage spec-
trometer. Elemental analysis was measured on PE 2400 II
CHNS instrument. Melting points were determined on a WRS-
1B digital melting point instrument and without correction.
Thin-layer chromatography (TLC) was run on precoated silica
gel plates (Merck 60F254). Column chromatography was car-
ried out using flash silica gel. X-ray crystallographic analysis
2-(3-Nitrophenyl)-3-p-tolyl-3,4-dihydro-2H-benzo[e][1,3]oxa-
zine (1a). Yield 95%, m.p.: 123.6–125.5ꢀC; IR (KBr): 3093,
3070, 3022, 2978, 2857, 1611, 1583, 1528, 1513, 1490, 1457,
1380, 1346, 1272, 1265, 1227, 1197, 1149, 1127, 1108, 1083,
1033, 995, 956, 941, 923, 893, 821, 811, 805, 752, 734, 711,
694, 670, 594 cmꢁ1 1H-NMR (CDCl3, 500 MHz): d 2.27 (s,
;
3H, CH3), 4.25 (d, J ¼ 17.0 Hz, 1H, CH2), 4.35 (d, J ¼ 17.0
Hz, 1H, CH2), 6.56 (s, 1H, CH), 6.86 (d, J ¼ 8.0 Hz, 2H),
7.02–7.03 (m, 1H), 7.07–7.12 (m, 4H), 7.16 (d, J ¼ 2.5 Hz,
1H), 7.51 (t, J ¼ 8.0 Hz, 1H), 7.90 (d, J ¼ 8.5 Hz, 1H), 8.15–
8.17 (m, 1H), 8.45 (s, 1H); 13C-NMR (CDCl3, 125 MHz): d
20.68, 47.20, 87.61, 117.09, 120.14, 121.01 (2C), 121.16,
122.29, 123.23, 126.67, 128.37, 129.69, 129.91 (2C), 132.58,
133.09, 141.64, 146.95, 148.70, 152.39; MS (EI, 70 ev) m/z
(%): 346 (30) [Mþ], 240 (100), 223 (6), 193 (8), 165 (4), 118
(14), 107 (4), 91 (25), 77 (9), 65 (9), 51 (4); Anal. Calcd. for
C21H18N2O3: C 72.82; H 5.24; N 8.09. Found: C 72.53; H
5.22; N 8.06.
was performed on
a Bruker Smart CCD diffractometer
equipped with a graphite monochromator Mo Ka radiation (k
˚
¼ 0.71073 A).
Schiff bases 3a–f and corresponding o-arylaminomethyl
phenols 4a–f were prepared according to the method described
in references [8,9].
General procedure for the synthesis of 2,3-diaryl-3,4-
dihydro-2H-1,3-benzoxazines 1a-1o. Under nitrogen, into a
250-mL three-necked flask equipped with a Dean-stark, 2-((p-
toluidino)methyl)phenol 4c (1.07 g, 5 mmol), 3-nitrobenzalde-
hyde (0.98 g, 6.5 mmol), mixed solvent of chloroform and
cyclohexane (150 mL, v:v ¼ 1:7), and SnCl4 (0.26 g, 20 mol
%) were added and mixed with stirring. The solution was
heated at 85ꢀC for 5 h (checked by TLC), and the water of
condensation was removed by azeotropic distillation. Then,
triethyl amine was added to make solution at pH ¼ 8, fol-
lowed by addition of ethyl acetate (100 mL), and washed
sequentially with water (2 ꢂ 100 mL) and saturated brine (2
ꢂ 100 mL). The organic phase was dried over MgSO4 and
evaporated under reduced pressure. The obtained yellow oil
was purified by flash column chromatography (silica gel,
PE-EtOAc) affording the product 1a (1.64 g, 95% yield) as a
yellow solid.
2-(2-Nitrophenyl)-3-p-tolyl-3,4-dihydro-2H-benzo[e][1,3]oxa-
zine (1b). Yield 80%, m.p.:152.6–153.0ꢀC; IR (KBr): 3083,
3021, 2972, 2920, 1610, 1585, 1530, 1513, 1486, 1456,
1437, 1386, 1363, 1337, 1292, 1276, 1268, 1224, 1198,
1144, 1109, 1034, 1024, 1015, 978, 961, 935, 852, 839, 820,
782, 757, 736, 714, 687, 679, 632, 589 cmꢁ1 1H-NMR
;
(CDCl3, 500 MHz): d 2.25 (s, 3H, CH3), 4.00 (d, J ¼ 17.0
Hz, 1H, CH2), 4.19 (d, J ¼ 17.0 Hz, 1H, CH2), 6.85 (s, 1H,
CH), 6.86–6.88 (m, 1H), 7.00–7.06 (m, 6H), 7.17–7.20 (m,
1H), 7.44–7.47 (m, 2H), 7.61–7.63 (m, 1H), 7.72–7.74 (m,
1H); 13C-NMR (CDCl3, 125 MHz): d 20.74, 47.12, 85.52,
116.72, 120.45, 120.86 (2C), 121.13, 124.45, 126.72, 128.41,
128.76, 129.21, 129.80 (2C), 131.84, 132.76, 132.99, 146.74,
149.08, 152.60; MS (ESI): 347[MþH]þ; Anal. Calcd. for
C21H18N2O3: C 72.82; H 5.24; N 8.09. Found: C 73.11; H
5.26; N 8.05.
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Z. Tang, W. Chen, Z. Zhu, and H. Liu
Vol 48
2-(2-Nitrophenyl)-3-m-tolyl-3,4-dihydro-2H-benzo[e][1,3]ox-
azine (1d). Yield 69%, m.p.: 138.1–139.0ꢀC; IR (KBr): 3072,
2947, 2906, 2862, 1606, 1586, 1535, 1489, 1456, 1445, 1378,
1340, 1301, 1273, 1236, 1216, 1199, 1169, 1140, 1109, 1036,
983, 958, 937, 852, 837, 782, 772, 756, 737, 690, 634, 597
1
cmꢁ1; H-NMR (CDCl3, 500 MHz): d 2.30 (s, 3H, CH3), 4.01
(d, J ¼ 17.0 Hz, 1H, CH2), 4.23 (dd, J ¼ 1.0 Hz, J ¼ 1.0 Hz,
1H, CH2), 6.80(d, J ¼ 7.5 Hz, 1H), 6.85–6.87 (m, 2H), 6.93–
6.95 (m, 1H), 6.98 (s, 1H, CH), 7.01 (d, J ¼ 8.0 Hz, 1H), 7.08
(s, 1H), 7.11 (t, J ¼ 8.0 Hz, 1H), 7.17–7.20 (m, 1H), 7.43–
7.48 (m, 2H), 7.61–7.62 (m, 1H), 7.73–7.74 (m, 1H); 13C-
NMR (CDCl3, 125 MHz): d 21.72, 46.79, 85.03, 116.76,
117.27, 120.41, 121.05 (2C), 121.13, 123.91, 124.47, 126.66,
128.41, 128.78, 129.02, 129.22, 131.83, 132.99, 139.02,
149.10, 152.44; MS (ESI): 347[MþH]þ; Anal. Calcd. for
C21H18N2O3: C 72.82; H 5.24; N 8.09. Found: C 73.12; H
5.28; N 8.06.
2-(3-Nitrophenyl)-3-m-tolyl-3,4-dihydro-2H-benzo[e][1,3]ox-
azine (1e). Yield 68%, m.p.: 101.3–102.0ꢀC; IR (KBr): 3092,
3025, 2979, 2918, 1602, 1585, 1529, 1488, 1475, 1380, 1348,
1314, 1271, 1238, 1219, 1181, 1123, 1113, 1087, 1046, 1032,
994, 958, 970, 942, 899, 891, 806, 776, 753, 735, 696, 688,
671, 599 cmꢁ1 1H-NMR (CDCl3, 500 MHz): d 2.32 (s, 3H,
;
CH3), 4.26 (d, J ¼ 17.0 Hz, 1H, CH2), 4.37 (d, J ¼ 17.0 Hz,
1H, CH2), 6.63 (s, 1H, CH), 6.82–6.89 (m, 3H), 7.00–7.04 (m,
3H), 7.15–7.19 (m, 2H), 7.51 (t, J ¼ 8.0 Hz, 1H), 7.89–7.91
(m, 1H), 8.15–8.17 (m, 1H), 8.44 (s, 1H); 13C-NMR (CDCl3,
125 MHz): d 21.65, 46.56, 86.98, 117.11, 117.24, 120.05,
121.07, 121.13, 122.20, 123.22, 123.54, 126.60, 128.35,
129.17, 129.72, 133.04, 139.24, 141.60, 148.64, 149.36,
152.15; MS (ESI): 347[MþH]þ; Anal. Calcd. for C21H18N2O3:
C 72.82; H 5.24; N 8.09. Found: C 72.53; H 5.20; N 8.05.
2-(4-Nitrophenyl)-3-m-tolyl-3,4-dihydro-2H-benzo[e][1,3]ox-
azine (1f). Yield 65%, m.p.: 126.2–126.9ꢀC; IR (KBr): 3042,
2976, 2876, 1607, 1584, 1554, 1541, 1512, 1489, 1456, 1378,
1350, 1306, 1239, 1221, 1189, 1169, 1128, 1110, 1038, 981,
Figure 1. ORTEP diagram of compound 1b.
2-(4-Nitrophenyl)-3-p-tolyl-3,4-dihydro-2H-benzo[e][1,3]oxa-
zine (1c). Yield 67%, m.p.: 93.7–96.9ꢀC; IR (KBr): 2920,
2859, 1614, 1583, 1516, 1490, 1455, 1442, 1386, 1343, 1318,
13002, 1224, 1205, 1144, 1109, 1033, 1014, 976, 960, 940,
905, 854, 829, 812, 760, 739, 712, 696, 589 cmꢁ1 1H-NMR
;
(CDCl3, 500 MHz): d 2.27 (s, 3H, CH3), 4.22 (d, J ¼ 17.0 Hz,
1H, CH2), 4.34 (d, J ¼ 16.5 Hz, 1H, CH2), 6.57 (s, 1H, CH),
6.86–6.88 (m, 2H), 6.99 (d, J ¼ 3.5 Hz, 1H), 7.06–7.10 (m,
4H), 7.16–7.19 (m, 1H), 7.74 (d, J ¼ 8.5 Hz, 2H), 8.18–8.21
(m, 2H); 13C-NMR (CDCl3, 125 MHz): d 20.64, 47.13, 87.72,
116.94, 120.10, 120.73 (3C), 121.14, 123.83, 123.99, 126.67,
127.92, 128.29, 129.87 (2C), 132.44, 146.41, 145.85, 147.69,
152.38; MS (ESI): 347[MþH]þ; Anal. Calcd. for C21H18N2O3:
C 72.82; H 5.24; N 8.09. Found: C 72.54; H 5.28; N 8.12.
956, 857, 826, 783, 767, 752, 739, 694, 609 cmꢁ1 1H-NMR
;
(CDCl3, 500 MHz): d 2.32 (s, 3H, CH3), 4.24 (d, J ¼ 16.0 Hz,
1H, CH2), 4.38 (d, J ¼ 7.0 Hz, 1H, CH2), 6.65 (s, 1H, CH),
6.83 (t, J ¼ 7.5 Hz, 1H), 6.85 (t, J ¼ 5.0 Hz, 2H), 7.00 (dd, J
Table 3
Fungicidal activities of compounds 1a–1o.
Gibberella
zeae (%)
Phytophythora
capsici (%)
Alternaria
alternate (%)
Botrytis
cinerea (%)
Rhizoctonia
solani (%)
Sclerotonia
sclerotiorum (%)
Compound
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
10.3
30.9
30.9
39.2
30.9
30.9
20.6
20.6
20.6
30.9
41.2
30.9
24.7
51.5
10.3
37.4
28.0
28.0
33.6
9.3
17.5
10.5
0
13.6
19.0
13.6
6.8
50.0
100
0
0
59.8
0
14.0
35.1
10.5
14.0
10.5
7.0
42.1
38.6
17.5
3.5
50.5
80.0
0
80.0
0
56.1
0
27.2
20.4
33.3
33.3
27.2
47.6
47.6
23.1
13.6
27.2
13.6
37.4
28.0
28.0
28.0
31.8
37.4
31.8
22.4
37.4
18.6
0
0
0
60.0
0
0
75
28.0
0
10.0
50.0
70.0
80.0
0
0
56.1
0
45.6
0
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Synthesis of 2,3-Diaryl-3,4-dihydro-2H-1,3-benzoxazines
259
¼ 7.0 Hz, J ¼ 3.5 Hz, 3H), 7.16–7.20 (m, 2H), 7.74 (d, J ¼
8.5 Hz, 2H), 8.19 (d, J ¼ 8.0 Hz, 2H); 13C-NMR (CDCl3, 125
MHz): d 21.69, 46.66, 87.22, 117.07, 117.12, 120.16, 120.92,
121.21, 123.53(2C), 123.91, 126.69, 127.95(2C), 128.36,
129.25, 139.31, 146.51, 147.81, 149.36, 152.32; MS (ESI):
347[MþH]þ. Anal. Calcd. for C21H18N2O3: C 72.82; H 5.24;
N 8.09. Found: C 73.60; H 5.21; N 8.13.
1H, CH2), 4.22 (d, J ¼ 17.0 Hz, 1H, CH2), 6.85 (s, 1H, CH ),
6.87–6.91 (m, 1H), 7.00 (d, J ¼ 9.5 Hz, 2H), 7.06–7.09 (m,
2H), 7.17–7.22 (m, 3H), 7.44–7.49 (m, 2H), 7.59–7.62 (m,
1H), 7.73–7.77 (m, 1H); 13C-NMR (CDCl3, 125 MHz): d
46.95, 85.09, 116.67, 119.81, 121.28, 121.98 (2C), 124.49,
126.60, 128.25, 128.57, 128.61, 129.14 (2C), 129.33, 131.94,
132.40, 147.54, 148.77, 152.28; MS (ESI): 367 [MþH]þ;
Anal. Calcd. for C20H15ClN2O3: C 65.49; H 4.12; N 7.64.
Found: C 65.75; H 4.10; N 7.68.
2-(2-Nitrophenyl)-3-o-tolyl-3,4-dihydro-2H-benzo[e][1,3]oxa-
zine (1g). Yield 63%, m.p.: 164.3–165.3ꢀC; IR (KBr): 3079,
3025, 2948, 2913, 1608, 1597, 1588, 1527, 1458, 1439, 1365,
1338, 1300, 1274, 1228, 1207, 1187, 1142, 1118, 1057, 1035,
1021, 977, 955, 937, 855, 841, 827, 780, 760, 737, 725, 714,
3-(4-Chlorophenyl)-2-(4-nitrophenyl)-3,4-dihydro-2H-ben-
zo[e][1,3]oxazine (1k). Yield 60%, m.p.: 135.9–137.6ꢀC; IR
(KBr): 3075, 3057, 2938, 2973, 2891, 2851, 1605, 1593, 1583,
1516, 1496, 1487, 1455, 1373, 1348, 1331, 1288, 1224, 1199,
1182, 1131, 1112, 1034, 1005, 963, 930, 902, 855, 830, 819,
1
684, 663, 634, 592 cmꢁ1; H-NMR (CDCl3, 500 MHz): d 2.20
(s, 3H, CH3), 3.93 (s, 2H, CH2), 6.76 (d, J ¼ 12.0 Hz, 1H),
6.83–6.86 (m, 1H), 6.98 (s, 1H, CH), 6.99–7.01 (dd, J ¼ 7.4
Hz, J ¼ 0.9 Hz, 1H), 7.03 (t, J ¼ 8.0 Hz, 1H), 7.09 (d, J ¼
8.0 Hz, 1H), 7.14 (d, J ¼ 7.0 Hz, 1H), 7.20–7.23 (m, 1H),
7.43–7.51 (m, 3H), 7.72 (d, J ¼ 7.5 Hz, 1H), 7.78 (dd, J ¼
1.5 Hz, J ¼ 1.0 Hz, 1H); 13C-NMR (CDCl3, 125 MHz): d
17.93, 47.84, 85.79, 116.61, 119.57, 121.08, 122.95, 124.92
(2C), 126.64, 127.06, 128.47, 128.77, 129.13, 131.19, 132.11,
133.17, 133.37, 148.11, 148.79, 152.44; MS (ESI):
347[MþH]þ; Anal. Calcd. for C21H18N2O3: C 72.82; H 5.24;
N 8.09. Found: C 72.51; H 5.21; N 8.05.
800, 753, 743, 724, 711, 642, 624, 602, 559 cmꢁ1 1H-NMR
;
(CDCl3, 500 MHz): d 4.24 (d, J ¼ 17.0 Hz, 1H, CH2), 4.34
(d, J ¼ 1 7.0 Hz, 1H, CH2), 6.56 (s, 1H, CH), 6.89–6.94 (m,
2H), 7.00 (d, J ¼ 8.0 Hz, 1H), 7.11–7.12 (m, 2H), 7.17–7.19
(m, 1H), 7.20–7.24 (m, 2H), 7.72–7.74 (m, 2H), 8.19–8.21 (m,
2H); 13C-NMR (CDCl3, 125 MHz): d 47.24, 87.23, 117.02,
119.61, 121.39, 121.90 (3C), 123.90 (2C), 126.66, 127.84,
127.90 (2C), 128.53, 129.29 (2C), 145.83, 147.78, 152.12; MS
(EI, 70 ev) m/z (%): 366 (35) [Mþ], 260 (100), 213 (17), 178
(4%), 138 (10), 111 (12), 78 (7), 51 (5); Anal. Calcd. for
C20H15ClN2O3: C 65.49; H 4.12; N 7.64. Found: C 65.15; H
4.08; N 7.60.
2-(3-Nitrophenyl)-3-o-tolyl-3,4-dihydro-2H-benzo[e][1,3]oxa-
zine (1h). Yield 65%, m.p.: 85.0–86.1ꢀC; IR (KBr): 3023,
2933, 2885, 1598, 1585, 1533, 1490, 1456, 1434, 1386, 1380,
1349, 1336, 1227, 1215, 1188, 1149, 1082, 1033, 986, 959,
2-(2-Nitrophenyl)-3-phenyl-3,4-dihydro-2H-benzo[e][1,3]ox-
azine (1l). Yield 66%, m.p.: 130.9–131.7ꢀC; IR (KBr): 3023,
2948, 2860, 1598, 1585, 1535, 1496, 1486, 1455, 1396, 1365,
1273, 1223, 1136, 1110, 1036, 981, 957, 853, 783, 756, 735,
893, 807, 764, 755, 742 724, 695, 673, 588 cmꢁ1 1H-NMR
;
(CDCl3, 500 MHz): d 2.51 (s, 3H, CH3), 4.14 (d, J ¼ 17.0 Hz,
1H, CH2), 4.25 (d, J ¼ 17.0 Hz, 1H, CH2), 6.34 (s, 1H, CH),
6.86–6.92 (m, 2H), 7.05–7.13 (m, 3H), 7.20–7.25 (m, 2H),
7.36 (d, J ¼ 7.5 Hz, 1H), 7.53 (t, J ¼ 8.0 Hz, 1H), 7.99 (d, J
¼ 2.5 Hz, 1H), 8.16–8.18 (m, 1H), 8.54–8.55 (m, 1H); 13C-
NMR (CDCl3, 125 MHz): d 18.59, 47.37, 87.92, 117.08,
119.86, 121.15, 122.35, 123.10, 123.31, 125.03, 126.69,
126.86, 128.23, 129.57, 131.07, 133.13, 133.17, 141.43,
148.11, 148.52, 152.28; MS (ESI): 347[MþH]þ; Anal. Calcd.
for C21H18N2O3: C 72.82; H 5.24; N 8.09%. Found: C 73.12;
H 5.28; N 8.06.
1
717, 694, 591 cmꢁ1; H-NMR (CDCl3, 500 MHz): d 4.04 (d,
J ¼ 17.0 Hz, 1H, CH2), 4.26 (d, J ¼ 17.0 Hz, 1H, CH2), 6.89
(s, 1H, CH), 6.92–6.94 (m, 1H), 6.96–7.03 (m, 2H), 7.11 (s,
1H), 7.16–7.23 (m, 3H), 7.25–7.28 (m, 2H), 7.46–7.49 (m,
2H), 7.63–7.65 (m, 1H), 7.75–-7.77 (m, 1H); 13C-NMR
(CDCl3, 125 MHz): d 46.78, 85.24, 116.75, 120.36, 120.55
(3C), 121.20, 123.12, 124.50, 126.69, 128.47, 128.79, 129.26
(3C), 131.88, 132.87, 149.08, 152.50; MS(EI, 70 ev) m/z (%)
¼ 332 (29) [Mþ], 315 (22), 284 (4), 226 (10), 209 (72), 196
(12), 181 (12), 179 (28), 151 (19), 152 (36), 134 (7), 120 (6),
104 (20), 92 (23), 77 (100), 65 (9), 51 (41); Anal. Calcd. for
C20H16N2O3: C 72.28; H 4.85; N 8.43. Found: C 71.95; H
4.82; N 8.39.
2-(4-Nitrophenyl)-3-o-tolyl-3,4-dihydro-2H-benzo[e][1,3]oxa-
zine (1i). Yield 64%, m.p.: 128.5–129.8ꢀC; IR (KBr): 3074,
2955, 2886, 1607, 1584, 1520, 1486, 1456, 1380, 1345, 1333,
1228, 1214, 1183, 1140, 1106, 1033, 1019, 1011, 975, 953,
2-(3-Nitrophenyl)-3-phenyl-3,4-dihydro-2H-benzo[e][1,3]ox-
azine (1m). Yield 61%, m.p.: 90.3–91.8ꢀC; IR (KBr): 3030,
2962, 2875, 1605, 1502, 1488, 1456, 1398, 1364, 1252, 1227,
1138, 1127, 1085, 994, 957, 893, 783, 757, 735, 713, 694, 592
932, 858, 837, 763, 752, 742, 723, 709, 601 cmꢁ1 1H-NMR
;
(CDCl3, 500 MHz): d 2.50 (s, 3H, CH3), 4.12 (d, J ¼ 16.5 Hz,
1H, CH2), 4.23 (d, J ¼ 17.0 Hz, 1H, CH2), 6.35 (s, 1H, CH),
6.86–6.92 (m, 2H), 7.05–7.11 (m, 3H), 7.22–7.26 (m, 2H),
7.36–7.38 (m, 1H), 7.84 (d, J ¼ 8.5 Hz, 2H), 8.22–8.23 (m,
2H); 13C-NMR (CDCl3, 125 MHz): d 18.59, 47.40, 88.16,
116.97, 119.89, 121.17, 123.19, 123.75, 124.25, 125.02,
126.73, 126.88, 128.03, 128.21, 130.44, 131.08, 133.04,
146.32, 147.61, 148.18, 152.35; MS (ESI): 347[MþH]þ; Anal.
Calcd. for C21H18N2O3: C 72.82; H 5.24; N 8.09. Found: C
72.51; H 5.20; N 8.04.
cmꢁ1
;
1H-NMR (CDCl3, 500 MHz): d 4.04(d, J ¼ 17.0 Hz,
1H, CH2), 4.26 (d, J ¼ 17.0 Hz, 1H, CH2), 6.62 (s, 1H, CH),
6.82–6.92 (m, 3H), 7.02–7.06 (m, 3H), 7.16–7.20 (m, 2H),
7.25–7.28 (m, 1H), 7.51–7.55 (m, 2H), 7.66–7.76 (m, 2H);
13C-NMR (CDCl3, 125 MHz): d 47.02, 87.23, 116.90, 120.45,
120.62 (3C), 121.41, 123.22, 125.00, 126.73, 128.51, 129.02,
129.28 (3C), 132.11, 132.90, 149.09, 152.78; MS (ESI): 333
[MþH]þ; Anal. Calcd. for C20H16N2O3: C 72.28; H 4.85; N
8.43. Found: C 72.65; H 4.81; N 8.38.
3-(4-Chlorophenyl)-2-(2-nitrophenyl)-3,4-dihydro-2H-ben-
zo[e][1,3]oxazine (1j). Yield 69%, m.p.: 140.7–141.3ꢀC; IR
(KBr): 3035, 2936, 2875, 1609, 1592, 1522, 1494, 1457, 1384,
1361, 1342, 1304, 1276, 1224, 1203, 1113, 1098, 1034, 1020,
1008, 980, 949, 936, 855, 826, 782 750, 740, 727, 645, 596
3-(4-Methoxyphenyl)-2-(2-nitrophenyl)-3,4-dihydro-2H-ben-
zo[e][1,3]oxazine (1n). Yield 73%, m.p.: 165.-166.9ꢀC; IR
(KBr): 3076, 2968, 1607, 1579, 1531, 1509, 1488, 1456, 1388,
1364, 1299, 1270, 1242, 1225, 1199, 1145, 1108, 1034, 1022,
975, 960, 854, 830, 783, 758, 737, 685, 631, 589 cmꢁ1 1H-
;
cmꢁ1
;
1H-NMR (CDCl3, 500 MHz): d 3.99 (d, J ¼ 17.0 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

260
Z. Tang, W. Chen, Z. Zhu, and H. Liu
Vol 48
Berlion, M.; Villard, J.; Filliond, H. Eur J Med Chem 1991, 26, 469;
(e) Benameur, L.; Bouaziz, Z.; Nebois, P.; Bartoli, M.-H.; Boitard, M.;
Fillion, H. Chem Pharm Bull 1996, 44, 605; (f) Wang, S.; Li, Y.;
You, Q.; Liu, Y.; Lu, A. Bioorg Med Chem Lett 2008, 18, 4095. (g)
Pasternak, A.; Goble, S. D.; Struthers, M.; Vicario, P. P.; Ayala, J. M.;
Salvo, J. D.; Kilburn, R.; Wisniewski, T.; DeMartino, J. A.; Mills,
S. G.; Yang, L. Med Chem Lett 2010, 20, 4.
NMR (CDCl3, 500 MHz): d 3.75 (s, 3H, OCH3), 4.01 (d, J ¼
17.0 Hz, 1H, CH2), 4.17(d, J ¼ 17.0 Hz, 1H, CH2), 6.77–6.79
(m, 2H), 6.87–6.92 (m, 2H), 6.94 (s, 1H, CH), 7.04 (d, J ¼
8.0 Hz, 1H), 7.09–7.11 (m, 2H), 7.21–7.25 (m, 1H), 7.46–7.48
(m, 2H), 7.64–7.66 (m, 1H), 7.75–7.76 (m, 1H); 13C-NMR
(CDCl3, 125 MHz): d 47.48, 55.29, 85.96, 114.17 (2C),
116.59, 120.41, 121.06, 123.18 (2C), 124.28, 126.64, 128.27,
128.59, 129.06, 131.75, 132.77, 142.48, 148.95, 152.63,
155.92; MS (ESI): 363 [MþH]þ; Anal. Calcd. for
C21H18N2O3: C 69.60; H 5.01; N 7.73. Found: C 69.31; H
4.98; N 7.69.
[3] (a) Kopf, P. W.; Wagner, E. R. J Polym Sci Polym Chem
Ed 1973, 11, 939; (b) Riess, G.; Schwob, J. M.; Guth, G.; Roche, M.;
Laude, B. Polym Prepr 1984, 25, 41; (c) Wang, Y.-X.; Ishida, H. Mac-
romolecules 2000, 33, 2839; (d) Ejfler, J.; Krauzy-Dziedzic, K.; Sza-
fert, S.; Lis, T.; Sobota, P. Macromolecules 2009, 42, 4008.
[4] (a) Burke, W. J. J Am Chem Soc 1949, 71, 609; (b) Burke,
W. J.; Wayne, S. C. J Am Chem Soc 1952, 74, 1518; (c) Burke, W.
J.; Kolbezen, M. J.; Stephens, C. W. J Am Chem Soc 1952, 74, 3601;
(d) Burke, W. J.; Ec, K. C.; Murdock, G. J Am Chem Soc 1954, 76,
1677; (e) Rivera, A.; Ospina, E.; Sanchez, A.; Joseph-Nathan, P. Het-
erocycles 1986, 24, 2507.
3-(4-Methoxyphenyl)-2-(3-nitrophenyl)-3,4-dihydro-2H-ben-
zo[e][1,3]oxazine (1o). Yield 70%, m.p.: 103.2–106.1ꢀC; IR
(KBr): 3070, 3093, 2950, 2832, 1610, 1582, 1528, 1512, 1488,
1456, 1345, 1252, 1227, 1197, 1179, 1127, 1085, 1038, 994,
957, 893, 826, 783, 757, 735, 712, 694, 670 cmꢁ1 1H-NMR
;
(CDCl3, 500 MHz): d 3.77 (s, 3H, OCH3), 4.26 (d, J ¼ 17.0
Hz, 1H, CH2), 4.34 (d, J ¼ 17.0 Hz, 1H, CH2), 6.48 (s, 1H,
CH), 6.81–6.83 (m, 2H), 6.90–6.91 (m, 2H), 7.05 (d, J ¼ 8.0
Hz, 1H), 7.16–7.18 (m, 2H), 7.20–7.23 (m, 1H), 7.53 (t, J ¼
8.0 Hz, 1H), 7.94 (d, J ¼ 8.0 Hz, 1H), 8.17–8.1 9(m, 1H),
8.49 (s, 1H); 13C-NMR (CDCl3, 125 MHz): d 47.99, 55.36,
88.17, 114.31(2C), 116.96, 120.10, 121.10, 122.22, 123.12,
123.34(2C), 126.60, 128.25, 129.54, 133.07, 141.41, 142.61,
148.50, 152.44, 155.77; MS(EI, 70 ev) m/z (%) ¼ 362 (72)
[Mþ], 345(17), 256(100), 239(38), 227(7), 209(11), 196(19),
183(8), 168(48), 152(10), 1D40(19), 135(30), 122(51),
106(25), 92(20), 77(41), 64(19); Anal. Calcd. for C21H18N2O3:
C 69.60; H 5.01; N 7.73. Found: C 69.85; H 5.05; N 7.69.
[5] (a) McDonagh, A. F.; Smith, H. E. J Org Chem 1968, 33,
1; (b) Neuvonen, K.; Pihlaja, K. J Chem Soc Perkin Trans 2 1988,
461; (c) Szatmari, I.; Martinek, T. A.; Lazar, L.; Fulop, F. Eur J Org
Chem 2004, 2231.
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cek, A. E. J Chem Soc Chem Commun 1994, 2763; (b) Campi, E. M.;
Jackson, W. R.; McCubbin, Q. J.; Trnacek, A. E. Aust J Chem 1996,
49, 219.
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C.; Palmieri, G.; Volpini, E. Tetrahedron 2001, 57, 6089.
¨
[9] Karakas, A.; Elmali, A.; Unver, H.; Svoboda, I. J Mol
Struct 2004, 702, 103.
[10] Arod, F.; Gardon, M.; Pattison, P.; Chapuis, G. Acta Crys-
tallogr Sect C 2005, 61, o317.
Acknowledgment. The authors thank the Natural Science Foun-
dation of Hunan Province (No. 06JJ50016) and the Scientific
Research Foundation for the Returned Overseas Chinese Scholars
of State Education Ministry for the financial support of this work.
We are also grateful to Dr. Ou Xiaoming for his help with the
investigation of fungicidal activities.
[11] (a) Caserio, F. F.; Roberts, J. D. J Am Chem Soc 1958, 80,
5837; (b) Daignault, R. A. Org Synth 1973, V, 303.
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3, 125; (b) Erickson, J. L. E.; Collins, J. F. E. J Org Chem 1965, 30,
1050.
[13] Tang, Z.-l.; Zhu, Z.-H.; Zhang, C.-Y.; Chen, W.-W.; Liu,
H.-W.; Huang, K.-L. Z. Kristallogr. NCS 225 2010, DOI: 10.1524/
ncrs. 2010.00xx. CCDC no. 1267/2884. The single-crystal growth was
carried out in ethyl acetate and petroleum ether at room temperature.
X-ray crystallographic analysis was performed on a Bruker Smart
CCD diffractometer equipped with a graphite monochromator Mo Ka
radiation (k ¼ 0.71073E). Crystal data for 1b: empirical formula ¼
C21H18N2O3, formula weight ¼ 346.37, crystal dimensions ¼ 0.44 ꢂ
REFERENCES AND NOTES
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Colomb Cienc Quim Farm 1980, 3, 63; (b) Gomez, P. G.; Pabon, H.
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3
˚
0.39 ꢂ 0.26 mm , triclinic, space group P-1, a ¼ 9.0481(7) A, b ¼
˚
˚
10.2521(9) A, c ¼ 10.7292(9) A, a ¼ 66.675(2), b ¼ 81.279(2), c ¼
73.525(2), l ¼ 0.089 mmꢁ1, V ¼ 875.53(13) A , Z ¼ 2, Dc ¼ 1.314
3
˚
[2] (a) Kuehne, M. E.; Konopka, E. A. J Med Pharm Chem
1962, 5, 257; (b) Chylinska, J. B.; Urbanski, T.; Mordarski, M. J Med
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Br J Pharmacol 1971, 43, 649; (d) Bouaziz, Z.; Riondel, J.; Mey, A.;
g/cm3, F(000) ¼ 364, S ¼ 1.051, R1 ¼ 0.0488, wR2 ¼ 0.1390.
[14] Liu, A.; Ou, X.; Huang, M.; Wang, X.; Liu, X.; Wang, Y.;
Chen, C.; Yao, J. Pest Manag Sci 2005, 61, 166.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet