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

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.


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 NaBH 4 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. 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. The structures of the products were established on the basis of their spectroscopic data (IR, 1 H-NMR, 13 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 NO 2 group, and 1607, 1585 cm −1 to the C=C bond. A singlet at 6.57 observed in the 1 H-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 NCH 2 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+NH 4 ] + .

Biological Assay
where I is the inhibition rate, D 1 is the average diameter of myceliain the blank test, and D 0 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 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.