New Reaction For The Halogenation Of Heteroaromatic Methyl Group

Aromatic heterocyclic methyl halide compounds are usually used as synthetic intermediates to synthesize important drug molecules and other functional molecules.Aromatic nitrogen heterocyclic methyl halide is an important reaction substrate in organic synthesis,with different nucleophiles to nucleophilic substitution reaction in the conversion of organic molecular functionalization.Traditional halogenation methods mainly include:?1?by N-bromosuccinimide?NBS?or N-chlorosuccinimide?NCS?directly with aromatic heterocyclic methyl to synthesis,but such reactions are complex,and prone to polyhalogenated side reactions.?2?conversion of the aromatic heterocyclic methyl group to hydroxymethyl group and then treated with phosphorus tribromide,thionyl chloride;but the reaction requires less readily available aromatic nitrogen heterocyclic methanol as the starting reaction substrate.It has recently been reported that 2-methylquinoline is used as a substrate and microwave-assisted ?-halogenation with 1,2-dichloroethane or 1,2-dibromoethane in the presence of tetrabutylammonium iodide.This reaction was a new method of 2-chloro or bromomethylquinoline,however,it has the disadvantage of narrow application range.It is more worth mentioning that these reactions cannot be used for iodination,the current method for the direct synthesis of aromatic azacyclo methyl iodide compounds from methyl aromatic nitrogen heterocycles has not been reported,therefore,it is important to develop methods of a methyl aromatic nitrogen heterocycle as raw materials,simple and efficient synthesis of 2-iodomethyl aromatic nitrogen heterocyclic compounds are groundbreaking.In this paper,two kinds of synthetic aromatic azacycloalkyl halide are developed.The first method is based on 2-methylquinoline as the reaction substrate and cuprous iodide as halogen source for the synthesis of 2-halomethyl quinoline derivatives with the assistance of TBHP.A new method for the preparation of 2-halomethyl quinoline compounds by direct halogenation.Compared to traditional method,this method expanded the source of halogen.We explored another method for the preparation of 2-iodomethylquinoline compounds by direct iodination of 2-methylquinoline,which was realized by use of elementary iodine as iodine source and Cu SO4·5H₂O as catalyst.Compared with the above methods,this reaction uses inexpensive elementary iodine as iodine source instead of substrate censorious organic iodine source,and inexpensive Cu SO4·5H₂O as catalyst.This newly developed synthetic method has the advantages of cheap and easily available raw materials,simple operation,high atomic economy,and excellent selectivity.We explored the reaction mechanism by a series of control experiments and explained the reaction mechanism.The main contents of this paper are as follows:1.The properties,application and synthetic methods of 2-halogenated methyl quinoline are summarized in this paper.2.?i?.2-Methyl quinoline and CuI were used as a model reaction to screen for the optimal reaction conditions.The amount of Cu I,the kinds and amount of oxidant,solvent,reaction temperature and reaction time of the reaction were investigated.2-methylquinoline?0.5 mmol?,Cu I?0.75 mmol?,TBHP?8 equiv.?in Me CN?2m L?at 70 °C for 8 h.?ii?.Under the optimized conditions,18 halogenated methyl quinolines were synthesized and their structures were elucidated by 1H,13 C NMR and HR MS.?iii?.The mechanism of the reaction was explored by a series of control experiments.The mechanism of the reaction was studied and proposed.3.?i?.2-Methyl quinoline and elementary iodine was used as a model reaction to screen for the optimal reaction conditions.The effect of the amount of elemental iodine,the kinds and amount of catalyst,solvent,reaction temperature and time on the model reaction was investigated.2-methylquinoline?0.5 mmol?,I2?0.25mmol?,Cu SO4·5H₂O?20 mol%?,Me CN 2 m L at 70 °C for 3 h.?ii?.Under the optimized conditions,23 iodinated methyl quinolines were synthesized and their structures were elucidated by 1H,13 C NMR and HR MS.?iii?.The mechanism of the reaction was explored by a series of control experiments.The mechanism of the reaction was studied and proposed.