Studies On The Tandem Acylation And In Situ [3,3]-Sigamatropic Rearrangement Reaction Of 2-benzylpyridine N-oxides

In organic synthesis,intramolecular rearrangement reaction is one of the most important reactions.Among of them,the [3,3]-sigamatropic rearrangement reaction has been widely applied in the synthesis of various drugs and natural products.The Claisen rearrangement reaction is the first [3,3]-sigamatropic rearrangement reaction.In 1912,Rainer Ludwig Claisen first reported the formation of ortho-allylphenol by the rearrangement of allyl phenyl ether.As an effective method for constructing new C–C bonds,it was later applied to various ether compounds with a structure in which an allyl group and a carbon-carbon double bond are connected,thereby playing an irreplaceable role in organic synthesis.Besides,the Cope rearrangement reaction was discovered by Arthur Clay Cope in 1940,referring to the rearrangement of1,5-diene compounds at high temperatures.As a high stereoselectivity reaction,it plays an important role in the pericyclic reactions.After that,a variety of heteroatom-containing [3,3]-sigamatropic rearrangements were discovered.Generally,the [3,3]-sigamatropic rearrangements are usually involved in tandem reaction,such as tandem vinylation,[3,3]-sigamatropic rearrangement for the synthesis of pyrrole or indole derivatives,tandem addition,[3,3]-sigamatropic rearrangement for the synthesis of benzofuran derivatives,and tandem acylation,[3,3]-sigamatropic rearrangement for the synthesis of oxazole derivatives,etc.The tandem reaction meets the requirements of atomic economics and green chemistry,also follows the sustainable development concept.As a consequence,based on[3,3]-siamatropic rearrangement and tandem process,how to synthesize various pharmacologically active intermediates and natural products has gradually become a research hotspot for contemporary organic chemists.In the past few decades,pyridine derivatives are considered important moieties in many pharmacologically active compounds as well as in organic materials.Due to the containing of N–O bond,pyridine N-oxide provides a new process for the synthesis of pyridine derivatives.In 1947,Katada first reported the rearrangement reaction of pyridine N-oxide with acetic anhydride,after hydrolysis,to 2-pyridone.Later,in 1954,Boekelheide expanded this rearrangement reaction to 2-alkyl substituted pyridine N-oxides and obtained the corresponding pyridyl carbinol derivatives.Later,the rearrangement of various alkyl-substituted pyridine N-oxides were extensively studied.In recent years,2-benzylpyridine derivatives have attracted strong attention due to their unique pharmacological activity.However,the related research of 2-benzylpyridine N-oxides has been rarely reported.Based on the above challenges,this dissertation will give in-depth research on the tandem acylation and[3,3]-sigamatropic rearrangement of 2-benzylpyridine N-oxides.This dissertation has been divided into five parts.The first chapter is a background part,where the three main types of [3,3]-sigamatropic rearrangement,including Claisen rearrangement,Cope rearrangement,and heteroatom-containing[3,3]-sigamatropic rearrangement were summarized.At the same time,the mechanism of the Boekelheide reaction and its application were also elaborated.In chapter 2,we have developed an effective and practical method for the synthesis of 2-benzylacyloxy pyridine compounds.This reaction proceeds via sequential acylation and in situ [3,3]-sigmatropic rearrangement of 2-benzylpyridine N-oxide and its derivatives under mild conditions(23 examples,55-96% yield).Moreover,we also sought to scale up the reaction to the gram scale and got the desired product in good yield(85%).Simultaneously,application to the synthesis of phenyl-2-pyridyl methanol was briefly explored.In chapter 3,we further developed a “one-pot three steps” method for the synthesis of phenyl-2-pyridyl methanol,which undergoes the process of tandem acylation,in situ [3,3]-sigamatropic rearrangement and hydrolysis reaction.grati obtained as follows: trifluoroacetic anhydride was as an acylating agent in 1.2equivalent,N,N-diisopropylethylamine was as a base and the mixture was stirred in toluene for 6 h at room temperature.This method achieved the direct transformation from 2-benzylpyridine N-oxide to phenyl-2-pyridyl methanol in an atomic economic manner.The fourth part is the experimental procedure part,and the fifth part is a summary of the whole dissertation.In conclusion,this dissertation demonstrated the tandem acylation and [3,3]-sigamatropic rearrangement of 2-benzylpyridine N-oxides.More importantly,we also developed a new derivative reaction of2-benzylpyridine N-oxide with benzenecarboximidoyl chloride,which provides a new route for the synthesis of various complex amide compounds.These studies are of great significance to the reactivity of 2-benzylpyridine N-oxide and the application of [3,3]-sigamatropic rearrangement reaction.