Synthesis and Safener Activity of Novel Substituted 4-Phenoxyacetyl-1,4-benzoxazines

Abstract

A novel class of 3-methyl-4-phenoxyacetyl-3,4-dihydro-2H-1,4benzoxazine 3 were synthesized via reduction, cyclization, and acylation reactions.The structures of the compounds were characterized by IR, 1 H-NMR, 13 C-NMR, MS, and elemental analyses. The configuration of 3f was determined by X-ray crystallography. The bioassay results demonstrated that most of these compounds could alleviate 2,4-D butylate injury to maize.1,4-Benzoxazine derivatives have received great attention in chemical and medicinal research because of their natural occurrence and important biological activities. 1 Several 3,4-dihydro-2H-1,4-benzoxazine derivatives have been reported as potassium channel openers (PCOs) in vascular smooth muscle. Some 1,4-benzoxazine derivatives are known to be central nervous system depressants, antibacterial agents, 2 antipsychotic agents, 3 calcium antagonists, 4 and antimicrobial agents agonists, 5 and so on. In particular, benzoxazine derivatives with particular biological activities were applied widely in the agrochemicals fields, including herbicide safener benoxacor. 6 Structure-activity correlations (SAR) are very important in the search for biological activity because they provide useful information about chemical substituents that are necessary for the required bioactivity. 7Base on the SAR, fenoxaprop-ethyl was used as the target herbicide, and replacing the pyrazoline core from mefenpyr-diethyl by a similar substituted isoxazoline resulted in the safener 5-phenyl-4,5-dihydroisoxazole-3-carboxylic acid ethyl ester, which were not sufficiently active for commercialization. However, combining the structural features of 5-phenyl-4,5-dihydroisoxazole-3carboxylic acid ethyl ester and the safener diphenyl acid led to the strong rice safener isoxadifen-ethyl (Scheme 1). 8 Using strategies of active substructure combination and bioisosteric replacement, Guan et al.