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Article

Synthesis and Fungicidal Activity of Novel 2,3-Disubstituted-1,3-benzoxazines

by
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
2
Key Laboratory of Theoretical Chemistry and Molecular Simulation of Ministry of Education, Hunan University of Science and Technology, Xiangtan 411201, China
3
Jiangxi Dongbang Pharmaceutical Co. Ltd., Fengxin 330700, China
4
National Engineering Research Center for Agrochemicals, Hunan Research Institute of Chemical Industry, Changsha 410014, China
*
Author to whom correspondence should be addressed.
Molecules 2012, 17(7), 8174-8185; https://doi.org/10.3390/molecules17078174
Submission received: 10 June 2012 / Revised: 25 June 2012 / Accepted: 26 June 2012 / Published: 6 July 2012
(This article belongs to the Section Organic Chemistry)
Browse Figure
Versions Notes

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 confirmed by IR, 1H-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.

1. Introduction

3,4-dihydro-2H-1,3-benzoxazines exhibit a wide range of biological activity [1,2,3,4,5,6,7,8,9,10,11], 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 [12,13,14,15,16,17,18,19,20]. 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 [5,12,13,14]. Condensations of 2-aminomethylphenol with aliphatic aldehydes or ketones provided another route to 3,4-dihydro-2H-1,3-benzoxazines [15,16,17]. 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) [22,23,24,25], 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 17 08174 g001 550
Scheme 1. Synthesis of 2,3-disubstituted 3,4-dihydro-2H-1,3-benzoxazines 6.
Scheme 1. Synthesis of 2,3-disubstituted 3,4-dihydro-2H-1,3-benzoxazines 6.
Molecules 17 08174 g001
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
Table 1. The results of the preparation of 1,3-benzoxazines 6 a.
Table 1. The results of the preparation of 1,3-benzoxazines 6 a.
EntryRR1R2ProductYield/% b
1H4-CH3C6H44-F6a57
2HC6H54-F6b55
3H4-CH3OC6H44-F6c53
4H4-ClC6H44-F6d59
5HCH2COOCH34-F6e62
6H4-ClC6H43-NO26f67
7H4-ClC6H4H6g57
8CH34-CH3C6H42-NO26h75
9CH34-CH3C6H43-NO26i78
10CH34-CH3C6H44-NO26j78
11HC6H54-NO26k73
12HCH2COOCH32-NO26l88
14HCH2COOCH33-NO26n90
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, 1H-NMR, 13C-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 in the 1H-NMR spectrum corresponds to the OCHN proton of the benzoxazine ring. The downfield 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 compounds6l (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
Table 2. Fungicidal activity of compounds 6a–n.
Table 2. Fungicidal activity of compounds 6a–n.
Compd.Phytophythor a capsici /%Gibberella zeae /%Sclerotonia sclerotiorum /%Alternaria alternata /%Botrytis cinerea /%Rhizoctonia solani /%
6a39408113280
6b2137690290
6c1840280140
6d55498921520
6e213531070
6f24408925460
6g27404817510
6h9260800
6i323521370
6j01637211450
6k0091025100
6l0052012100
6m0333713190
6n00832519100
6o a2831601119100
6p a37100181450
a The preparation of 6o (R = H, R1 = 4-CH3C6H4, R2 = 2-NO2) and 6p (R = H, R1 = 4-CH3C6H4, R2 = 3-NO2) see reference [21].

3. Experimental

3.1. Materials and Reagents

All solvents were dried by standard procedure. Aromatic aldehydes and substituted anilines were commercially available. Infrared spectra were recorded on a PE-2000 FT-IR. 1H- and 13C-NMR spectra were recorded on a Bruker Avance-500 MHz spectrometer. Chemical shifts (δ) 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) ν: 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.
2-((Phenylamino)methyl)phenol (4b): Yield 85%. White solid, m.p.: 129.4–130.8 °C; 1H-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) ν: 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) ν: 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, 4H); 13C-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) ν: 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.
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, 1H), 6.9 8(d, J = 7.0 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H); 13C-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) ν: 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) ν : 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.: 66.5–66.9 °C; 1H-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, 2H); 13C-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) ν: 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.: 85.0–86.2 °C; 1H-NMR (CDCl3) δ: 4.33 (d, J = 4.5 Hz, 2H), 6.61 (s, 1H), 6.83–6.89 (m, 2H), 6.97–7.04 (m, 4H), 7.14–7.19 (m, 3H), 7.26–7.29 (m, 2H), 7.50–7.53 (m, 2H); 13C-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) ν: 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.
2-(4-Fluorophenyl)-3-(4-methoxyphenyl)-3,4-dihydro-2H-1,3-benzoxazine (6c): Yield: 53%. White solid, m.p.: 76.9–77.4 °C; 1H-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 (m, 2H); 13C-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) ν: 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) ν: 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), 7.59–7.62 (m, 2H); 13C-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) ν: 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, 1H), 8.43 (s, 1H); 13C-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) ν: 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.: 108.6–108.8 °C; 1H-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), 7.20 (d, J = 9.0 Hz, 2H), 7.28–7.36 (m, 3H), 7.51 (d, J = 8.0 Hz, 2H); 13C-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) ν: 3432, 3044, 2980, 1887, 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, 6H), 7.43–7.46 (m, 2H), 7.49–7.51 (m, 1H), 7.72–7.73 (m, 1H); 13C-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) ν: 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) ν: 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, 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); 13C-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) ν: 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.: 117.2–118.8 °C; 1H-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) ν: 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 (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) ν: 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) ν: 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), 7.98 (d, J = 7.5 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.52 (s, 1H); 13C-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) ν: 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 containingTween 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 mediumwithout sample was used as the blank control. The inocula, 6.5 mm in diameter, were removed fromthe 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:
Molecules 17 08174 i001
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.
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 plantswere 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 and6n (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.

References

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  • Sample Availability: Samples of the compounds 6a–n are available from the authors.

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MDPI and ACS Style

Tang, Z.; Zhu, Z.; Xia, Z.; Liu, H.; Chen, J.; Xiao, W.; Ou, X. Synthesis and Fungicidal Activity of Novel 2,3-Disubstituted-1,3-benzoxazines. Molecules 2012, 17, 8174-8185. https://doi.org/10.3390/molecules17078174

AMA Style

Tang Z, Zhu Z, Xia Z, Liu H, Chen J, Xiao W, Ou X. Synthesis and Fungicidal Activity of Novel 2,3-Disubstituted-1,3-benzoxazines. Molecules. 2012; 17(7):8174-8185. https://doi.org/10.3390/molecules17078174

Chicago/Turabian Style

Tang, Zilong, Zhonghua Zhu, Zanwen Xia, Hanwen Liu, Jinwen Chen, Wenjing Xiao, and Xiaoming Ou. 2012. "Synthesis and Fungicidal Activity of Novel 2,3-Disubstituted-1,3-benzoxazines" Molecules 17, no. 7: 8174-8185. https://doi.org/10.3390/molecules17078174

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