Study On The Synthesis Of N-heterocycle-substituted Polyfluoroarenes

It is confirmed that the installation of a fluorine atom or fluorine group can make N-heterocycle-arenes show a huge advantage with respect to these nonfluorinated counterparts on physical,chemical and biological activities.Due to the high reactivity of fluorination reagent and tremendous C-F bond energy,there is a limited types of fluorinated N-heterocycle-arenes.The present strategy suffers from the problems of step economy and chemoselectivity.From the point of practicability,developing novel synthesis method would be an effective solution.C-F bond activation and functionalization can be an alternative because of the easy access of polyfluoro compounds.Besides,the mechanism study of selective C-F activation would be significant,contributing to deepen the understanding of C-F bond activation.The main contents of this paper are as follows:2-bromoquinoline/quinoxaline derivatives were synthesized by quinoxalin-2-ol/ quinolone-2-ol derivatives through the method of bromination reaction,obtaining in moderate to good yields.The directing cross-coupling reaction of 2-bromoquinoline/quinoxaline derivatives with electron-deficient polyfluoroarenes was developed through the optimization of catalyst,ligand,base and solvent.To probe the practicability of the methodology,several of polyfluoroarenes and quinolone/quinoxaline bromides were also tested.The optimum reaction conditions were obtained as follows: n(2-bromoquinoline/quinoxaline derivatives): n(polyfluoroarenes): n(Cu I): n(1,10-phenanthrine): n(K3PO4)=1.0: 1.5: 0.1: 0.1: 2.0.A mixture of xylene and DMF(volume ratio 1:1)was used as solvent.The reactions were conducted at 110 oC for 12 h.On the basis of this methodology,large-scale preparation was studied.The selective C-F activation/C-N formation reaction of fluorinated N-heterocycle-arenes with aniline derivatives was developed.Polyfluoroaryl oxazolines were obtained by the reaction of condensation and cyclization,using fluorobenzoic acid and ethanolamine as materials.A series of oxazoline-substituted fluorinated diphenylamine were synthesized by the C-F activation/C-N coupling reaction of polyfluoroaryl oxazolines with aniline derivatives without transition metal catalyst.The structures were characterized by 1H NMR,13 C NMR,19 F NMR and HR-MS(ESI-TOF).Reactions of aniline derivatives with functional groups such as-F,-Cl,-CH3,-OCH3 occurred in excellent yields.This method can be used to activate the ortho C-F bond of oxazoline ring,reaction time and feed ratio on the selective activation of C-F bond were also studied,prolonging the reaction time and increasing the proportion of the coupling reagent had no effect on the structure of the products.Besides,the mechanism of selective C-F activation of polyfluoroaryl oxazolines was also studied.Different heterocyclic polyfluoroarenes were synthesized to studied the effect of directing group;theoretical calculation and control-experiment were combined to discuss the impact of coordination on the activation of C-F bond,the optimal structure of the intermediates is obtained;the effect of intramolecular hydrogen bonding on the selective activation of C-F bond was also investigated.Based on the experimental results of directing group,coordination and intramolecular hydrogen bonding,a plausible mechanism of selective ortho C-F bond of polyfluoroaryl oxazolines with aniline derivatives was proposed.