Synthesis Of Sterically Hindered Amines Through 1,6-Aza-Conjugate Addition Of Anilines To δ-Cyano Substituted Para-quinone Methide

Objective:Hindered amines with fully substituted α carbon centers are a very important type of structural blocks,It is widely present in various natural medicines and pharmacologically active molecules and has extremely important physiological and biological activities.Therefore,it is very important to obtain such compounds quickly and efficiently.The current research on 1,6-conjugated addition reactions involving para-quinone methides is mainly to construct tertiary carbon chiral centers by functionalizing δ-monosubstituted substrates.There are few studies on large hindered amine compounds,and due to the limitation of the structural stability of para-quinone methides,the current research focuses on the 1,6-conjugated addition reaction of pre-synthesized para-quinone methides with two large sterically hindered substituents(such as t-butyl)in the alpha position.The substrate structure is very limited,therefore,there is an urgent need to further expand the scope of p-QMs and apply them to solve existing synthesis problems.This paper envisions a method for 1,6-aza conjugated addition of pre-prepared δ-cyano-δ-aryl disubstituted para-quinone methides using primary amine as a nucleophile,in this way,a series of non-cyclic,sterically hindered amines with completely substituted α carbon centers can be obtained quickly and efficiently.Method:In this paper,stable p-QMs are synthesized to improve the structural limitations of the substrate,the reaction conditions are optimized,and the appropriate acidic catalyst is selected to mediate,so that the addition reaction has a high single selectivity.This enriches the database of acyclic,sterically hindered amines with fully substituted α carbon centers.Results:By optimizing the reaction conditions,we first determined the template reaction conditions.At room temperature,methanol solution can effectively inhibit the formation of side reaction products,making the reaction highly selective.Moreover,the δ-cyano-δ-aryl disubstituted and aniline can generate the target product to the greatest extent and increase the output under the acid catalysis of PTSA.After determining the reaction conditions,we expanded the substrates of different substituted δ-Ar substituted para-quinone methides and found that whether the electron donating group,electron withdrawing group or polyarylnaphthalene substitution on the aryl group,It responds well at room temperature with a yield of over 85 percent.It also has good tolerance to the substitution of different groups in the α position of para-quinone methides.Then we studied the substrate range of different amines Differently substituted anilines are the effective components of this method.They are all well tolerated and obtain a higher reaction yield.In addition,cyclic secondary amines such as morpholine and imidazole are also suitable nucleophiles.Conclusion:This is the first report of 1,6-aza conjugated addition reaction of amine with δ-cyano-δ-aryl disubstituted para-quinone methides.It can effectively synthesize sterically hindered amines with completely substituted α carbon centers.The reaction enriches the substrate range,the conditions are mild,the reaction is rapid,at the same time,it is highly selective,the step is economical,and it can efficiently obtain the desired product in large quantities.It will provide a more efficient and faster method for preparing amines with diverse structures and space hindered.It can be dedicated to the research of pharmaceutical chemistry and has certain versatility in the modular preparation of sterically hindered amines containing medicinal value.