Lewis Acid Promoted Cyanation Of Phenols

Phenols as environmentally sound,inexpensive,and widely available feedstock,not only are key structural scaffolds in many natural products,pharmaceuticals,agrochemicals,materials,and catalysts,but also are used as synthetic intermediates for important organic compounds.Moreover,phenols are important components and industrial precursors to daily supplies,including resin,bisphenol A,herbicides,detergents,etc.Therefore,many efforts from chemists and pharmaceutical scientists were devoted to the modification of phenols at their ortho-,meta-,and para-positions with the direct C-H functionalization being the most popular by chemists because of its high efficiency in synthesis of complex organic molecules from readily available starting materials,and significant achievement have been made.While the C-H functionalization of phenols are mainly focused on alkylation,arylation and halogenation,the kinds of other reaction such as cyanation are very rare.On one hand,aromatic nitriles are crucial structure skeletons and intermediates in organic and fine chemical synthesis,especially in the pharmaceutical synthesis.On the other hand,cyano(-CN)can be also effectively converted into various useful functional groups,such as–NH₂(amine),-CHO(aldehyde),-CONH₂(amide),-COOH(carboxyl acid),azocyclic compounds and so on.Therefore,the studies of cyanation of phenols are highly desirable.Up to now,numerous methods for the preparation of aromatic nitriles have been established,and they can be divided into three categories according to cyanating reagent:nucleophilic-,electrophilic-and radical-cyanation.The cyanides used in nucleophilic cyanation include KCN,CuCN,Na CN,TMSCN,K₄[Fe(CN)₆],etc,which have the risk of generating hazardous HCN and leading to environmental pollution.Besides,the cyanating reagents employed in electrophilic cyanation,such as 1-cyanobenzotriazole(SnCl)and Ph OCN,are usually prepared from Cl CN or Br CN that possess safety issue.The examples of radical cyanation are rare.Therefore,to develop a new,green,safe and low toxicity cyanation or cyanation reagent for the synthesis of aromatic nitriles is not only of great theoretical significance,but also of great practical value.Meanwhile,the use of green,safe,and low toxic cyanation reagent is consistent with the concept of green chemistry.In this thesis,the direct cyanation of phenols including phenol,naphthol and biphenol deriveratives were systematically investigated using N-cyano-N-phenyl-p-toluenesulfonamide NCTS or methyl thiocyanate CH₃SCN as electrophilic cyanation reagent as cyano source in order to avoid releasing highly toxic HCN.Phenols were successfully converted into the corresponding 2-cyanophenols.The contents of dissertation are summarized as following four parts:In chapter 1,two aspects are included:(1)brief introduction of the applications of cyano-contained compounds in natural products,drugs,pesticides,spice,materials,organic synthesis and so on;(2)the advance of the cyanation of aromatic compounds.In chapter 2,a Lewis acid-mediated direct cyanation of naphthols employing low toxic,stable,inexpensiveandreadilyavailable N-cyanon-N-phenyl-p-toluenesulfonamide as cyanation reagent was developed.For example,the reaction of 7-tert-butyldimethylsiloxy-2-naphthol can be effectively converted into the corresponding sulfonyl-protected cyanated product 2a with the yield up to 88%,when in the presence of Sn Cl₄.The protocol was successful for the cyanation of naphthol and its derivatives under mild conditions,which may provide a direct and practical access to valuable products.In chapter 3,an efficient and mild Lewis acid-promoted site-selective cyanation of meta-phenols was established using commercially available methyl thiocyanate as a cyanation reagent.For instance,when in the presence of BF₃·OEt₂,the reaction of5,6,7,8-tetrahydro-2-naphthol proceeds well to afford the cyanated product 2A in 87%yield with high regioselectivity.This protocol not only features broad substrate scope,excellent regioselectivity and gram-scale synthesis,but also may be applied for the synthesis of biologically active molecules.In chapter 4,the electrophilic cyanation of 2,2'-biphenols was firstly developed.The cyanation of 2,2'-biphenols with a trifloromethanesulfonyl as the protecting group using commercially available methyl thiocyanate as cyano source is successfully achieved in the presence of Lewis acid.For example,the mono-cyano product 3a'a was obtained with 80%yield mediated by BCl₃using OTf-protected2,2'-biphenol as a model substrate.The protocol may be applied for the synthesis and modification of biologically active compounds,chiral catalysts and ligands.