Synthesis and fungicidal activity of novel 2,3-disubstituted-1,3- benzoxazines

Article abstract of DOI:10.3390/molecules17078174

A series of new 2,3-disubstituted-3,4-dihydro-2H-1,3-benzoxazines were prepared in moderate to excellent yields by aza-acetalizations of aromatic aldehydes with 2-(N-substituted aminomethyl)phenols in the presence of TMSCl. Their structures were confirmed

Full text of DOI:10.3390/molecules17078174

Molecules 2012, 17, 8174-8185; doi:10.3390/molecules17078174
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Fungicidal Activity of Novel
2,3-Disubstituted-1,3-benzoxazines
Zilong Tang 1,2,*, Zhonghua Zhu 1,2,3, Zanwen Xia 1,2, Hanwen Liu 1,2, Jinwen Chen 1,2
Wenjing Xiao 1 and Xiaoming Ou 2,4
,
1
School of Chemistry and Chemical Engineering, Hunan University of Science and Technology,
Xiangtan 411201, China; E-Mails: hua206@163.com (Z.Z.); xiazanwen163@163.com (Z.X.);
hwyliu@126.com (H.L.); lyr1976@163.com (J.C.); wenjing_xiao@yahoo.com (W.X.)
Key Laboratory of Theoretical Chemistry and Molecular Simulation of Ministry of Education,
Hunan University of Science and Technology, Xiangtan 411201, China; E-Mail: xmouhn@163.com
Jiangxi Dongbang Pharmaceutical Co. Ltd., Fengxin 330700, China
2
3
4
National Engineering Research Center for Agrochemicals, Hunan Research Institute of Chemical
Industry, Changsha 410014, China
* Author to whom correspondence should be addressed; E-Mail: zltang67@yahoo.com.cn;
Tel.: +86-731-5829-0187; Fax: +86-731-5829-0509.
Received: 10 June 2012; in revised form: 25 June 2012 / Accepted: 26 June 2012 /
Published: 6 July 2012
Abstract: A series of new 2,3-disubstituted-3,4-dihydro-2H-1,3-benzoxazines were
prepared in moderate to excellent yields by aza-acetalizations of aromatic aldehydes with
2-(N-substituted aminomethyl)phenols in the presence of TMSCl. Their structures were
1
confirmed by IR, H-NMR, 13C-NMR, MS and elemental analysis. The fungicidal
activities of the target compounds were preliminarily evaluated, and some compounds
exhibited good activity against Rhizoctonia solani.
Keywords:
2,3-disubstituted-1,3-benzoxazine;
synthesis;
chlorotrimethylsilane;
fungicidal activity

Molecules 2012, 17
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1. Introduction
3,4-dihydro-2H-1,3-benzoxazines exhibit a wide range of biological activity [1–11], such as
bactericidal, fungicidal, antitumour, antituberculosis, and anthelmintic effects, therefore, the synthesis
of these compounds has attracted great interest. Several elegant methods for the preparation of
these compounds have been documented in the literature [12–20]. Burke and co-workers disclosed
a Mannich-type condensation of phenols with primary amines and formaldehyde to provide
2-unsubstituted 3,4-dihydro-2H-1,3-benzoxazines [5,12–14]. Condensations of 2-aminomethylphenol
with aliphatic aldehydes or ketones provided another route to 3,4-dihydro-2H-1,3-benzoxazines
[15–17]. It was noted that condensation reactions could be operated without catalyst, but sometimes a
catalyst such as TsOH or triethylamine was necessary. Recently, rhodium-catalyzed reactions of
2-(alkenyloxy)benzylamines which involve an allylic cleavage followed by regioselective carbonylation
at the internal carbon atom have been developed as a new way to generate 3,4-dihydro-1,3-
benzoxazines [19,20]. Despite these advances, the synthesis of novel 3,4-dihydro-2H-1,3-benzoxazines
and the search for more efficient routes for drug discovery and medicinal chemistry are still highly
desirable. In our previous paper [21], a new method by SnCl4-mediated aza-acetalization reactions of
aromatic aldehydes with 2-arylaminomethyl phenols to synthesize substituted 3,4-dihydro-2H-1,3-
benzoxazines was developed and the compounds showed good fungicidal activity. Herein, we present
the synthesis of a series of novel 2-aryl-3-alkyl-3,4-dihydro-2H-1,3-benzoxazines, as a continuation of
our ongoing project aimed at searching for novel biological active nitrogen and oxygen linked heterocyclic
compounds, by reactions of aromatic aldehydes with 2-(N-substituted aminomethyl)-phenols in the
presence of chlorotrimethylsilane (TMSCl) [22–25], and also report their fungicidal activities.
2. Results and Discussion
2.1. Chemistry
The synthetic route to the title compounds 6a–n is shown in Scheme 1. Initially, the reaction of
fluorobenzaldehyde (5d) with 2-((4-methylphenyl)aminomethyl)phenol (4a) which was prepared in
high yield by reaction of salicylaldehyde and p-toluidine followed by reduction with NaBH4 in a
one-pot process [21,26,27] was chosen as model reaction for the synthesis of the title compounds 6a–n.
The reaction was carried out in a mixed solvent of chloroform and cyclohexane (v:v = 1:2) under
reflux in the presence of TMSCl (20 mol%) by removing the water of condensation azeotropically, and
the desired product 6a was obtained in 57% yield (Table 1, entry 1). It should be noted that the interest
in preparation of fluorine-containing 3,4-dihydro-2H-1,3-benzoxazines is due to the special structure
and biological character of fluorine atom, which was usually introduced in drugs and pesticides to
enhance or change the biological activity.
Then, under the same conditions, compounds 6b–n were further prepared by reactions of aromatic
aldehydes 5a–e with 2-(N-substituted aminomethyl)phenols 4a–f, and all the experimental results are
listed in Table 1. The results clearly showed that all reactions gave the desired products in moderate to
excellent yields. It was observed that the reactions of nitrobenzaldehydes furnished the products in
higher yields than those with fluorobenzaldehyde or benzaldehyde.

Molecules 2012, 17
Scheme 1. Synthesis of 2,3-disubstituted 3,4-dihydro-2H-1,3-benzoxazines 6.
8176
R1
CHO
OH
H
C2H5OH
reflux
NaBH4
C
H2N R1
+
N
CH3OH
OH
R
2
R
1
3
R1
R1
H2
C
H
OH
Cat.
CHO
N
N
O
R2
4
R
R
R2
5
6
1
4a: R = H, R1 = 4-CH3C6H4; 4b: R= H, R1 = C6H5; 4c: R= H, R = 4-CH3OC6H4;
4d: R= H, R1 = 4-ClC6H4; 4e: R = H, R1 = CH2COOCH3; 4f: R = CH3, R1 = 4-CH3C6H4
5a: R2 = 2-NO ; 5b: R2 = 4-NO ; 5c: R2 = 3-NO ; 5d: R2 = 4-F; 5e: R2 = H
2
2
2
Moreover, the reactions of N-alkyl substituted aminomethylphenols gave higher yields than those of
N-aryl substituted ones. The lower yield of the latter can be attributed to its low nucleophilicity, which
was in turn caused by the conjugation effect between the electron pair on the nitrogen atom and the
aryl group. All these results indicated apparently that TMSCl was an efficient catalyst for the reactions,
and to the best of our knowledge, this is the first time to adopt TMSCl as catalyst for aza-acetalizations
of aromatic aldehydes with 2-aminomethylphenols to synthesize 3,4-dihydro-2H-1,3-benzoxazines.
Table 1. The results of the preparation of 1,3-benzoxazines 6 a.
Entry
R
H
H
H
H
H
H
H
CH3
CH3
CH3
H
H
H
R1
R2
4-F
4-F
4-F
4-F
4-F
3-NO2
H
2-NO2
3-NO2
4-NO2
4-NO2
2-NO2
3-NO2
Product Yield/% b
1
2
3
4
5
6
7
8
9
10
11
12
14
4-CH3C6H4
C6H5
4-CH3OC6H4
4-ClC6H4
CH2COOCH3
4-ClC6H4
6a
6b
6c
6d
6e
6f
57
55
53
59
62
67
57
75
78
78
73
88
90
4-ClC6H4
6g
6h
6i
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
C6H5
CH2COOCH3
CH2COOCH3
6j
6k
6l
6n
a
The mole ratio of n (aromatic aldehyde 5)/n (o-aminomethyl phenol 4) = 1.3:1 for all reactions.
TMSCl: 20 mol% based on aminomethyl phenol. CHCl3/C6H12 = 1:2 (v:v). Reaction time: 5 h.
Temperature: 85 C. b Isolated yield.
The structures of the products were established on the basis of their spectroscopic data (IR,
13
1H-NMR, C-NMR, MS) and elemental analysis [21]. All compounds exhibit characteristic signals
appropriately (see experimental section). This can be illustrated with compound 6l. In the IR spectrum,
a strong absorption at 1731 cm−1 corresponds to the stretching vibration of the C=O group, 1524 and
1365 cm−1 relate to the NO2 group, and 1607, 1585 cm−1 to the C=C bond. A singlet at 6.57 observed
1
in the H-NMR spectrum corresponds to the OCHN proton of the benzoxazine ring. The downfield

Molecules 2012, 17
8177
shift of this OCHN proton is due to the strong electronegativity of the nitrogen and oxygen atoms.
Particularly, the NCH2 proton absorbs as two doublets at 3.78 and 4.14 instead of a singlet.
Meanwhile, the mass spectrum (ESI-MS) displays a molecular ion peak at m/z 346 [M+NH4]+.
2.2. Fungicidal Activity Assay
According to standard operation procedure (SOP) developed by Hunan Branch of National
Pesticide R&D South Center of China [28], fungicidal activities of the prepared compounds 6a–n
against Gibberella zeae, Phytophythora capsici, Alternaria alternate, Botrytis cinerea and Sclerotonia
sclerotiorum were evaluated using the mycelium growth rate test in concentration of 25 µg/mL, which
was expressed as inhibition rate (%), and their activities against Rhizoctonia solani using the leaf-disc
culture in concentration of 500 µg/mL, which was expressed as control efficacy (%). The results are
summarized in Table 2. In general, the results demonstrated that most of the compounds displayed
moderate to good activity. Compounds 6k, 6l, 6n showed 100% activity against Rhizoctonia solani.
But, compared with compounds 6l (R1 = CH2COOCH3, R2 = 2-NO2) and 6n (R1 = CH2COOCH3,
R2 = 3-NO2), the activity of the isomer 6m (R1 = CH2COOCH3, R2 = 4-NO2) dramatically decreased to
0%. Similarly, the activity against Rhizoctonia solani and Sclerotonia sclerotiorum of compound 6h
with a methyl group on the position-6 of benzoxazine ring (R = Me) dramatically decreased to 0%
relative to the compound 6o (R = H, 100%, 60%) [21]. Also, the activity against Rhizoctonia solani
and Phytophythora capsici of compound 6i (R = Me) decreased to 0% and 3% compared with 6p
(R = H, 50%, 37%). But, the activity against Sclerotonia sclerotiorum of compound 6i increased to
52% compared with 6p (0%). In addition, some compounds displayed good activity against
Sclerotonia sclerotiorum as shown by 6k (91%), 6d (89%), 6f (89%), 6n (83%) and 6a (81%).
Table 2. Fungicidal activity of compounds 6a–n.
Sclerotonia
sclerotiorum
Phytophythor Gibberella
Alternaria
alternata /%
Botrytis
cinerea /%
Rhizoctonia
solani /%
Compd.
a capsici /%
zeae /%
/%
81
69
28
89
31
89
48
0
52
37
91
52
37
83
60
0
6a
6b
6c
6d
6e
39
21
18
55
21
24
27
9
3
0
0
0
40
37
40
49
35
40
40
26
23
16
0
0
33
0
31
10
13
0
0
21
0
25
17
8
28
29
14
52
7
46
51
0
0
0
0
0
0
0
0
0
0
50
100
100
0
100
100
50
6f
6g
6h
6i
6j
6k
6l
13
21
0
7
14
25
12
19
19
19
14
0
6m
6n
6o a
0
0
28
37
13
25
11
18
6p a
The preparation of 6o (R = H, R1 = 4-CH3C6H4, R2 = 2-NO2) and 6p (R = H, R1 = 4-CH3C6H4,
a
R2 = 3-NO2) see reference [21].

Molecules 2012, 17
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3. Experimental
3.1. Materials and Reagents
All solvents were dried by standard procedure. Aromatic aldehydes and substituted anilines were
1
commercially available. Infrared spectra were recorded on a PE-2000 FT-IR. H- and 13C-NMR
spectra were recorded on a Bruker Avance-500 MHz spectrometer. Chemical shifts () are given
relative to Me4Si (0, 1H) or CDCl3 (77.0, 13C). Mass spectra were obtained with Thermo Finnigan LCQ
Advantage spectrometer. Elemental analysis was measured on PE 2400 II CHNS instrument. Melting
points were determined on a WRS-1B digital melting point instrument. Thin-layer chromatography
(TLC) was run on precoated silica gel phates (Merck 60F254).
3.2. Chemical Synthesis
3.2.1. Synthesis of 2-(N-Substituted aminomethyl) Phenols 4a–f [21,26,27]
2-((4-Methylphenylamino)methyl)phenol (4a): Yield 91%. White solid, m.p.: 120.5–121.2 °C;
1H-NMR (CDCl3) δ: 2.30 (s, 3H, CH3), 4.42 (s, 2H, CH2), 6.79 (d, 2H, J = 8.5 Hz), 6.88–6.93 (m, 2H),
7.08 (d, 2H, J = 8.0 Hz), 7.16 (d, 1H, J = 7.5 Hz), 7.23 (t, 1H, J = 7.45 Hz); 13C-NMR (CDCl3)
δ: 20.60, 49.34, 116.25 (2C), 116.67, 119.98, 122.98, 128.67, 129.19, 129.91 (2C), 130.46, 144.64,
157.00; IR (KBr, cm−1) : 3435, 3260, 3032, 3011, 2977, 2861, 2734, 1614, 1592, 1512, 1467, 1456,
1402, 1291, 1249, 1232, 1187, 1110, 1057, 976, 911, 863, 834, 820, 801, 788, 753, 742, 719, 706.
1
2-((Phenylamino)methyl)phenol (4b): Yield 85%. White solid, m.p.: 129.4–130.8 °C; H-NMR
(CDCl3) δ: 4.45 (s, 2H, CH2), 6.87–6.97 (m, 5H), 7.18 (d, 1H, J = 7.5 Hz), 7.24~7.30 (m, 3H);
13C-NMR (CDCl3) δ: 48.71, 115.93 (2C), 116.66, 120.13, 120.85, 122.99, 128.78, 129.26, 129.43
(2C), 147.22, 156.76; IR (KBr, cm−1) : 3445, 3264, 30652, 2854, 1594, 1499, 1459, 1436, 1389,
1358, 1316, 1301, 1266, 1251, 1237, 1184, 1166, 1114, 1088, 1056, 1040, 1025, 971, 903, 841, 796,
754, 727, 689.
2-((4-Methoxyphenylamino)methyl)phenol (4c): Yield 85%. Purple solid, m.p.: 132.1–133.8 °C;
1H-NMR (CDCl3) δ: 3.78 (s, 3H, OCH3), 4.40 (s, 2H, CH2), 6.83–6.87 (m, 4H), 6.88~6.93 (m, 2H),
7.14 (d, 1H, J = 7 Hz), 7.23 (t, 1H, J = 7.5 Hz); 13C-NMR (CDCl3) δ: 50.24, 55.66, 114.77 (2C),
116.67, 117.85 (2C), 119.87, 122.78, 128.58, 129.18, 140.39, 154.61, 157.17; IR (KBr, cm−1) : 3444,
3253, 3000, 2956, 2862, 1714, 1637, 1593, 1510, 1468, 1457, 1409, 1358, 1289, 1249, 1225, 1177,
1112, 1058, 1033, 979, 909, 864, 830, 788, 759, 742, 717.
2-((4-Chlorophenylamino)methyl)phenol (4d): Yield 89%. White solid, m.p.: 121.7–122.4 °C;
1H-NMR (CDCl3) δ: 4.40 (s, 2H, CH2), 6.77 (d, J = 9Hz, 2H), 6.90 (t, J = 6.5 Hz, 2H), 7.17–7.28 (m,
13
4H); C-NMR (CDCl3) δ: 48.42, 116.62, 116.89 (2C), 120.31, 122.66, 125.52, 128.86, 129.28 (2C),
129.38, 145.77, 156.39; IR (KBr, cm−1) : 3435, 3257, 3013, 2969, 2938, 2729, 2626, 1594, 1492,
1462, 1454, 1403, 1392, 1357, 1314, 1285, 1250, 1232, 1181, 1120, 1109, 1097, 1060, 1008, 974, 907,
866, 844, 829, 815, 796, 770, 758, 667.

Molecules 2012, 17
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2-((3-Methoxycarbonylmethylamino)methyl)phenol (4e): Yield 74%. White solid, m.p.: 84.9–85.9 °C;
1H-NMR (CDCl3) δ: 3.46 (s, 2H), 3.76 (s, 3H), 4.00 (s, 2H), 6.77~6.80 (m, 1H), 6.85 (d, J = 8.0 Hz,
13
1H), 6.9 8(d, J = 7.0 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H); C-NMR (CDCl3) δ: 48.57, 51.99, 52.07,
116.44, 119.19, 121.72, 128.66, 129.00, 157.81, 171.83; IR (KBr, cm−1) : 3451, 3352, 2894, 2857,
2118, 1898, 1735, 1616, 1587, 1484, 1429, 1369, 1302, 1260, 1224, 1206, 1185, 1136, 1104, 1037,
988, 929, 899, 866, 847, 756, 720.
2-((4-Methylphenylamino)methyl)-6-methylphenol (4f): Yield: 85%. White solid, m.p.: 81.0–81.7 °C;
1H-NMR (CDCl3) δ: 2.24 (s, 3H), 2.28 (s, 3H), 4.37 (s, 2H), 6.77 (t, J = 7.5Hz, 3H), 6.98 (d,
J = 7.5 Hz, 1H), 7.05 (dd, J = 8.0 Hz, J = 7.5 Hz, 3H), 8.93 (s, 1H, OH); 13C-NMR (CDCl3) δ: 15.73,
20.51, 49.34, 116.14 (2C), 119.32, 122.08, 125.47, 126.13, 129.77 (2C), 130.29, 130.33, 144.54,
155.07; IR (KBr, cm−1)  : 3421, 3335, 2919, 2853, 2731, 1714, 1615, 1592, 1517, 1471, 1446, 1432,
1314, 1259, 1237, 1217, 1123, 1085, 1051, 1012, 930, 883, 822, 812, 762.
3.2.2. Synthesis of 3,4-Dihydro-2H-1,3-benzoxazines 6a–n
General Procedure: Under nitrogen, into a 250 mL three-necked flask equipped with a Dean-Stark
trap, 2-(benzaminomethyl)phenol (4b, 0.99 g, 5 mmol), 4-nitrobenzaldehyde (5b, 0.98 g, 6.5 mmol), a
mixed solvent of chloroform and cyclohexane (150 mL, v:v = 1:2), and TMSCl (0.11 g, 20 mol%)
were added with stirring. The solution was heated at 85 C for 5 h (checked by TLC), and the water of
condensation was removed by azeotropic distillation of most of solvent. Then, triethylamine was added
to make solution pH = 8, followed by addition of ethyl acetate (100 mL), and the mixture was washed
sequentially with water (2 × 100 mL) and saturated brine (2 × 100 mL). The organic phase was
dried over Na2SO4, and evaporated under reduced pressure. The obtained yellow oil was purified by
recrystallization from ethyl acetate-petroleum ether giving the product 6k (73% yield) as a yellow solid.
2-(4-Fluorophenyl)-3-p-tolyl-3,4-dihydro-2H-1,3-benzoxazine (6a): Yield: 57%. White solid, m.p.:
1
66.5–66.9 °C; H-NMR (CDCl3) δ: 2.27 (s, 3H, CH3), 4.29 (s, 2H), 6.54 (s, 1H), 6.82–6.88 (m, 2H),
6.95 (d, J = 8.5 Hz, 1H), 7.00 (t, J = 8.5 Hz, 2H), 7.07 (s, 4H), 7.13 (t, J = 7.0 Hz, 1H), 7.50 (t, J = 6.0 Hz,
13
2H); C-NMR (CDCl3) δ: 20.67, 46.59, 88.17, 115.39, 115.56, 116.90, 120.47, 120.60 (2C), 120.70,
126.61, 128.08, 128.55, 128.61, 129.82, 131.95, 135.02 (d, JCF = 3.0 Hz), 147.30, 152.83, 161.55,
163.51; IR (KBr, cm−1) : 3427, 2922, 2869, 2339, 1612, 1585, 1514, 1505, 1456, 1382, 1339, 1232,
1217, 1194, 1154, 1128, 1034, 975, 949, 898, 819, 753, 714; MS (ESI): 320 [M+H]+. Anal. Calcd for
C21H18FNO: C, 78.98; H, 5.68; N, 4.39; Found: C, 78.46; H, 5.64; N, 4.42.
2-(4-Fluorophenyl)-3-phenyl-3,4-dihydro-2H-1,3-benzoxazine (6b): Yield: 55%. White solid, m.p.:
1
85.0–86.2 °C; H-NMR (CDCl3) δ: 4.33 (d, J = 4.5 Hz, 2H), 6.61 (s, 1H), 6.83–6.89 (m, 2H),
13
6.97–7.04 (m, 4H), 7.14–7.19 (m, 3H), 7.26–7.29 (m, 2H), 7.50–7.53 (m, 2H); C-NMR (CDCl3) δ:
46.14, 87.59, 115.37, 115.54, 116.86, 120.09, 120.29, 120.68, 122.18, 126.51, 128.06, 128.43, 128.49,
129.24, 134.78 (d, JCF = 3.0 Hz), 149.58, 152.61, 156.67, 161.47, 163.43; IR (KBr, cm−1) : 3040,
2959, 2853, 2369, 1942, 1899, 1601, 1581, 1509, 1495, 1451, 1394, 1346, 1293, 1226, 1158, 1125,
1110, 1033, 1014, 976, 952, 937, 822, 764, 697; Anal. Calcd for C20H16FNO: C, 78.67; H, 5.28; N,
4.59; Found: C, 78.24; H, 5.31; N, 4.56.

Molecules 2012, 17
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2-(4-Fluorophenyl)-3-(4-methoxyphenyl)-3,4-dihydro-2H-1,3-benzoxazine (6c): Yield: 53%. White
1
solid, m.p.: 76.9–77.4 °C; H-NMR (CDCl3) δ: 3.74 (s, 3H, OCH3), 4.27 (d, J = 4.0 Hz, 2H), 6.42 (s,
1H), 6.78 (d, J = 9.0 Hz, 2H), 6.85–6.88 (m, 2H), 6.96–7.03 (m, 3H), 7.10–7.16 (m, 3H), 7.51–7.54
13
(m, 2H); C-NMR (CDCl3) δ: 47.37, 55.40, 88.83, 114.25, 114.63, 115.25, 115.42, 116.78, 117.93,
120.66, 122.92, 126.54, 127.98, 128.52, 128.58, 129.16, 134.86 (d, JCF = 3.1 Hz), 143.08, 152.89,
161.43, 163.39; IR (KBr, cm−1) : 3256, 2954, 2911, 1839, 2052, 1908, 1870, 1605, 1581, 1509, 1490,
1456, 1437, 1379, 1346, 1240, 1230, 1153, 1105, 1038, 1019, 980, 956, 894, 836, 759, 605; Anal.
Calcd for C21H18FNO2: C, 75.21; H, 5.41; N, 4.18; Found: C, 75.53; H, 5.39; N, 4.20.
2-(4-Fluorophenyl)-3-(4-chlorophenyl)-3,4-dihydro-2H-1,3-benzoxazine (6d): Yield: 59%. White
solid, m.p.: 80.7–81.3 °C; 1H-NMR (CDCl3) δ: 4.29 (s, 2H), 6.51 (s, 1H), 6.83-6.87 (m, 2H), 6.95 (d,
J = 8.0 Hz, 1H), 6.99 (t, J = 8.5 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 7.14 (t, J = 7.0 Hz, 1H), 7.19 (d,
J = 8.5 Hz, 2H), 7.46–7.49 (m, 2H); 13C-NMR (CDCl3) δ: 46.65, 87.58, 115.44, 115.61, 116.89,
119.89, 120.88, 121.68, 126.53, 127.33, 128.24, 128.38, 128.44, 129.15 (2C), 134.35 (d, JCF = 3.1 Hz),
148.09, 152.47, 161.52, 163.48; IR (KBr, cm−1) : 3436, 3059, 2955, 1894, 1710, 1605, 1584, 1507,
1488, 1457, 1381, 1342, 1224, 1158, 1022, 1006, 982, 959, 952, 838, 830, 763, 724; Anal. Calcd for
C20H15ClFNO: C, 70.69; H, 4.45; N, 4.12; Found: C, 70.37; H, 4.47; N, 4.09.
Methyl 2-(2-(4-Fluorophenyl)-2H-1,3-benzoxazin-3(4H)-yl)acetate (6e): Yield: 62%. White solid,
m.p.: 119.8–120.3 °C; 1H-NMR (CDCl3) δ: 3.42 (s, 2H), 3.68 (s, 3H, CH3), 3.94 (d, J = 17.0 Hz, 1H),
4.25 (d, J = 17.0 Hz, 1H), 5.95 (s, 1H), 6.89–6.98 (m, 3H), 7.05–7.08 (m, 2H), 7.16–7.20 (m, 1H),
13
7.59–7.62 (m, 2H); C-NMR (CDCl3) δ: 49.47, 49.91, 51.84, 89.87, 115.23, 115.42, 116.63, 119.07,
121.06, 127.66, 128.02, 128.59, 128.66, 133.46 (d, JCF = 3.0 Hz), 133.48, 153.30, 171.36; IR (KBr, cm−1)
: 3472, 3084, 3061, 2956, 2909, 1909, 1747, 1607, 1582, 1510, 1487, 1450, 1389, 1341, 1310, 1248,
1219, 1157, 1138, 1107, 1032, 1000, 992, 948, 903, 861, 827, 761; MS (ESI): 319 [M+NH4]+. Anal.
Calcd for C17H16FNO3: C, 67.76; H, 5.35; N, 4.65; Found: C, 67.42; H, 5.32; N, 4.63.
2-(3-Nitrophenyl)-3-(4-chlorophenyl)-3,4-dihydro-2H-1,3-benzoxazine (6f): Yield: 67%. Yellow solid,
m.p.: 145.1–145.8 °C; 1H-NMR (CDCl3) δ: 4.26 (d, J = 17.0 Hz, 1H), 4.36 (d, J = 17.0 Hz, 1H), 6.55
(s, 1H), 6.87 (d, J = 4.5 Hz, 2H), 7.02 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 7.17 (q, J = 4.5 Hz,
1H), 7.21 (d, J = 8.5 Hz, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 8.5 Hz,
13
1H), 8.43 (s, 1H); C-NMR (CDCl3) δ: 47.25, 87.02, 117.08, 119.54, 121.34, 122.11 (3C), 123.34,
126.59, 127.98, 128.53, 129.26 (2C), 129.76, 132.91, 140.99, 147.78, 148.59, 152.00; IR (KBr, cm−1)
: 3444, 3074, 3040, 2973, 2873, 1884, 1732, 1594, 1583, 1521, 1495, 1455, 1386, 1348, 1231, 1198,
1131, 1095, 1034, 990, 954, 893, 824, 808, 757, 725, 706; Anal. Calcd for C20H15ClN2O3: C, 66.49; H,
4.12; N, 7.64; Found: C, 66.68; H, 4.14; N, 7.61.
3-(4-Chlorophenyl)-2-phenyl-3,4-dihydro-2H-1,3-benzoxazine (6g): Yield: 57%. White solid, m.p.:
1
108.6–108.8 °C; H-NMR (CDCl3) δ: 4.27 (d, J = 16.5 Hz, 1H), 4.32 (d, J = 16.5 Hz, 1H), 6.57 (s,
1H), 6.83–6.88 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.0 Hz, 2H), 7.14 (t, J = 8.5 Hz, 1H),
13
7.20 (d, J = 9.0 Hz, 2H), 7.28–7.36 (m, 3H), 7.51 (d, J = 8.0 Hz, 2H); C-NMR (CDCl3) δ: 46.55,
88.02, 116.58, 116.87, 120.06, 120.19, 120.71, 121.48, 126.52, 127.10, 128.16, 128.59, 128.96,
129.12, 129.33, 129.72, 134.44, 138.69, 148.29, 152.75; IR (KBr, cm−1) : 3432, 3044, 2980, 1887,

Molecules 2012, 17
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1711, 1609, 1575, 1500, 1479, 1368, 1346, 1220, 1141, 1036, 1001, 968, 854, 836, 831, 768, 720;
Anal. Calcd for C20H16ClNO: C, 74.65; H, 5.01; N, 4.35; Found: C, 75.98; H, 4.98; N, 4.33.
8-Methyl-2-(2-nitrophenyl)-3-p-tolyl-3,4-dihydro-2H-1,3-benzoxazine (6h): Yield: 75%. Yellow solid,
m.p.: 138.3–139.3 °C; 1H-NMR (CDCl3) δ: 2.24 (s, 3H, CH3), 2.32 (s, 3H,CH3), 3.98 (d, J = 17.0 Hz,
1H), 4.19 (d, J = 17.0 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 6.75 (t, J = 7.0 Hz, 1H), 7.03 (t, J = 9.0 Hz,
13
6H), 7.43–7.46 (m, 2H), 7.49–7.51 (m, 1H), 7.72–7.73 (m, 1H); C-NMR (CDCl3) δ: 15.81, 20.65,
47.04, 85.43, 119.65, 120.29, 120.70 (2C), 124.05, 124.35, 125.60, 128.28, 129.08, 129.34, 129.64
(2C), 131.79, 132.49, 132.99, 146.69, 148.92, 150.36; IR (KBr, cm−1) : 3433, 3082, 2981, 2918,
1611, 1594, 1531, 1514, 1468, 1439, 1389, 1365, 1224, 1200, 1144, 968, 820, 766, 735; Anal. Calcd
for C22H20N2O3: C, 73.32; H, 5.59; N, 7.77; Found: C, 73.59; H, 5.56; N, 7.73.
8-Methyl-2-(3-nitrophenyl)-3-p-tolyl-3,4-dihydro-2H-1,3-benzoxazine (6i): Yield: 78%. Yellow solid,
m.p.: 118.4–118.7 °C; 1H-NMR (CDCl3) δ: 2.28 (s, 3H, CH3), 2.37 (s, 3H, CH3), 4.25 (d, J = 17.0 Hz,
1H), 4.35 (d, J = 17.0 Hz, 1H), 6.61 (s, 1H), 6.71 (d, J = 7.0 Hz, 1H), 6.75 (t, J = 7.0 Hz, 1H), 7.03 (d,
J = 7.0 Hz, 1H), 7.07–7.12 (m, 4H), 7.51 (t, J = 8.0 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 8.15–8.17 (m,
1H), 8.43 (s, 1H); 13C-NMR (CDCl3) δ: 15.86, 20.62, 46.98, 87.55, 119.39, 120.41, 120.77 (2C),
122.01, 123.16, 124.02, 125.99, 129.31, 129.65, 129.80 (2C), 132.29, 132.75, 141.66, 146.99, 148.59,
150.19; IR (KBr, cm−1) : 3434, 3090, 3026, 2917, 2856, 1714, 1612, 1595, 1579, 1528, 1514, 1472,
1451, 1378, 1345, 1222, 1194, 1127, 1079, 998, 967, 940, 811, 767, 730, 691; Anal. Calcd for
C22H20N2O3: C, 73.32; H, 5.59; N, 7.77; Found: C, 73.64; H, 5.56; N, 7.74.
8-Methyl-2-(4-nitrophenyl)-3-p-tolyl-3,4-dihydro-2H-1,3-benzoxazine (6j): Yield: 78%. Yellow solid,
m.p.: 130.1–130.9 °C; 1H-NMR (CDCl3) δ: 2.27 (s, 3H, CH3), 2.35 (s, 3H, CH3), 4.22 (d, J = 17.0 Hz,
1H), 4.35 (d, J = 17.0 Hz, 1H), 6.62 (s, 1H), 6.71 (d, J = 7.0 Hz, 1H), 6.75 (t, J = 7.5 Hz, 1H), 7.03 (d,
13
J = 7.0 Hz, 1H), 7.06–7.10 (m, 4H), 7.69 (d, J = 8.5 Hz, 2H), 8.19 (d, J = 8.5 Hz, 2H); C-NMR
(CDCl3) δ: 15.84, 20.60, 47.13, 87.71, 119.40, 120.43, 120.62 (2C), 123.82, 124.06, 124.27, 125.83,
127.63, 129.29, 129.79 (2C), 130.46, 132.24, 146.51, 146.89, 147.66, 150.29; IR (KBr, cm−1) : 3436,
3024, 2963, 2919, 2855, 1608, 1596, 1517, 1469, 1384, 1347, 1227, 1198, 1128, 1083, 1013, 957, 903,
855, 845, 834, 761, 738, 721; Anal. Calcd for C22H20N2O3: C, 73.32; H, 5.59; N, 7.77; Found: C,
73.01; H, 6.02; N, 7.74.
2-(4-Nitrophenyl)-3-phenyl-3,4-dihydro-2H-1,3-benzoxazine (6k): Yield: 73%. Yellow solid, m.p.:
1
117.2–118.8 °C; H-NMR (CDCl3) δ: 4.25 (d, J = 17.0 Hz, 1H), 4.40 (d, J = 17.0 Hz, 1H), 6.64 (s,
1H), 6.87 (d, J = 7.5 Hz, 2H), 7.00–7.03 (m, 2H), 7.17–7.21 (m, 3H), 7.26–7.31 (m, 2H), 7.74 (d,
J = 8.5 Hz, 2H), 8.19 (d, J = 7.0 Hz, 2H); 13C-NMR (CDCl3) δ: 46.72, 87.22, 116.51, 116.95, 119.96,
120.28, 121.15, 122.68, 123.84, 124.26, 126.60, 127.86, 128.31, 129.34 (2C), 130.46, 146.28, 147.68,
149.21, 152.21; IR (KBr, cm−1) : 3444, 3087, 3056, 3038, 3007, 2970, 2912, 1707, 1596, 1581, 1522,
1492, 1453, 1388, 1346, 1230, 1208, 1144, 1109, 1034, 978, 958, 888, 853, 828, 759, 741; Anal. Calcd
for C20H16N2O3: C, 72.28; H, 4.85; N, 8.43; Found: C, 72.59; H, 4.83; N, 8.39.
Methyl 2-(2-(2-nitrophenyl)-2H-1,3-benzoxazin-3(4H)-yl)acetate (6l): Yield: 88%. White solid, m.p.:
108.6–109.0 °C; 1H-NMR (CDCl3) δ: 3.38 (s, 2H), 3.66 (s, 3H, CH3), 3.78 (d, J = 17.5 Hz, 1H), 4.14

Molecules 2012, 17
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(d, J = 17.0 Hz, 1H), 6.57 (s, 1H), 6.94–7.00 (m, 3H), 7.21–7.24 (m, 1H), 7.49–7.53 (m, 1H), 7.57–7.60
(m, 1H), 7.81–7.84 (m, 2H); 13C-NMR (CDCl3) δ: 48.99, 51.33, 51.92, 87.19, 116.58, 119.18, 121.39,
124.71, 127.86, 128.20, 128.26, 129.41, 131.95, 132.16, 148.86, 152.95, 170.57; IR (KBr, cm−1) :
3446, 3010, 2958, 2881, 1953, 1912, 1731, 1607, 1585, 1524, 1488, 1461, 1444, 1424, 1365, 1275,
1263, 1222, 1122, 1109, 1034, 1002, 963, 780, 761, 742; MS (ESI): 346 [M+NH4]+. Anal. Calcd for
C17H16N2O5: C, 62.19; H, 4.91; N, 8.53; Found: C, 62.47; H, 4.88; N, 8.49.
Methyl 2-(2-(4-nitrophenyl)-2H-1,3-benzoxazin-3(4H)-yl)acetate (6m): Yield: 91%. White solid, m.p.:
137.2–138.9 °C; 1H-NMR (CDCl3) δ: 3.37 (s, 2H), 3.71 (s, 3H, CH3), 3.94 (d, J = 17.0 Hz, 1H), 4.21
(d, J = 17.0 Hz, 1H), 6.03 (s, 1H), 6.92–7.00 (m, 3H), 7.20 (t, J = 7.0 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H),
8.24 (d, J =8.5 Hz, 2H); 13C-NMR (CDCl3) δ: 49.11, 50.41, 51.97, 89.34, 116.68, 118.80, 121.45,
123.68 (2C), 127.72, 127.92 (2C), 128.26, 144.90, 147.82, 152.70, 171.04; IR (KBr, cm−1) : 3468,
3079, 3038, 2854, 1745, 1609, 1580, 1523, 1488, 1447, 1420, 1384, 1346, 1313, 1221, 1134, 1109,
992, 952, 904, 826, 764; Anal. Calcd for C17H16N2O5: C, 62.19; H, 4.91; N, 8.53; Found: C, 62.50; H,
4.89; N, 8.57.
Methyl 2-(2-(3-nitrophenyl)-2H-1,3-benzoxazin-3(4H)-yl)acetate (6n): Yield: 90%. White solid, m.p.:
161.6–162.3 °C; 1H-NMR (CDCl3) δ: 3.38 (s, 2H), 3.70 (s, 3H, CH3), 3.96 (d, J = 17.0 Hz, 1H), 4.23
(d, J = 17.0 Hz, 1H), 6.03 (s, 1H), 6.93–7.01 (m, 3H), 7.20 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H),
13
7.98 (d, J = 7.5 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.52 (s, 1H); C-NMR (CDCl3) δ: 49.28, 50.32,
51.96, 89.17, 116.80, 118.85, 121.47, 122.18, 123.44, 127.69, 128.30, 129.58, 133.06, 140.10, 148.48,
152.77, 171.02; IR (KBr, cm−1) : 3431, 2957, 2905, 1756, 1607, 1582, 1525, 1486, 1456, 1440, 1418,
1379, 1343, 1250, 1216, 1197, 1184, 1129, 1110, 1002, 956, 914, 757, 685; Anal. Calcd for
C17H16N2O5: C, 62.19; H, 4.91; N, 8.53; Found: C, 62.49; H, 4.93; N, 8.56.
3.3. Biological Assay [28]
The in vitro inhibition of the title compounds against five strains of phytopathogenic fungi
Phytophythora capsici, Gibberella zeae, Sclerotonia sclerotiorum, Alternaria alternata and Botrytis
cinerea was performed according to standard method NY/T1156.5–2006, and antifungal activity
assays adopted drug-containing medium method. Stock solution of every test compound was prepared
in DMF (20 g/L) and then diluted to the required test concentrations (500 mg/L) with water containing
Tween 80 (0.4 mg/L). Solutions of the test compounds (2 mL) were added to potato dextrose agar
(PDA) medium (38 mL, 45 °C) to provide the final concentration of 25 mg/L. The mixed medium
without sample was used as the blank control. The inocula, 6.5 mm in diameter, were removed from
the margins of actively growing colonies of mycelium, placed in the centers of the above plates. Four
replicates per treatment. Percentages of growth inhibition were calculated by comparing the mean
value of the diameters of the mycelia in the test plates after placing in 28 °C biochemical incubator
thermostat for 4 days. The inhibition percent was calculated according to the following equation:
I = (D1 – D0)/D1 × 100%
where I is the inhibition rate, D1 is the average diameter of myceliain the blank test, and D0 is the
average diameter of mycelia in the presence of compounds. The results are given in Table 2.

Molecules 2012, 17
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Activity against Rhizoctonia solani. Compounds tested for control of rice sheath blight pathogen,
Rhizoctonia solani, on rice seedlings at the fifth-leaf stage were formulated in water and DMF (5 + 1
by volume) (containing 2.5 g/L Tween 80) to 500 mg/L solutions, and applied to the rice seedlings as
foliar sprays using a hand-held spray gun. The next day the seedlings were inoculated with the chaff
medium within Rhizoctonia solani (the causal fungus of the rice sheath blight). Then the plants were
immediately placed in a temperature- and humidity-controlled chamber at 28 °C for 4 days. After
treatment, percentage of disease control in the treated seedlings was compared to that of seedlings with
a treatment in the absence of the experimental compounds, and fungicidal activity was estimated. Four
replicates were included in the evaluation, and the biological effect was reported as the average of the
four replicates. The results are given in Table 2.
4. Conclusions
In summary, we have demonstrated TMSCl is an efficient catalyst for aza-acetalizations of aromatic
aldehydes with 2-(N-substituted aminomethyl)phenols, and a series of novel 2,3-disubstituted-3,4-
dihydro-2H-1,3-benzoxazines 6a–n were prepared in moderate to excellent yields. The fungicidal
activities of the prepared compounds were preliminarily evaluated, and some compounds exhibited
good activity against Rhizoctonia solani as shown by 6k, 6l, 6n (100% at concentration of 500 μg/mL),
and some compounds displayed good activity against Sclerotonia sclerotiorum as shown by 6a, 6d, 6f,
6k and 6n (81–91% at concentration of 25 μg/mL).
Acknowledgments
The authors thank the National Natural Science Foundation of China (21042011), Scientific
Research Fund of Hunan Provincial Education Department (10A034), Hunan Provincial Natural
Science Foundation (11JJ3016) and the Open Project of Key Laboratory of Theoretical Chemistry and
Molecular Simulation of Ministry of Education (LKF0906) for the financial support of this work. The
authors also thank the National Engineering Research Center for Agrochemicals for biological assay.
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© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).