The Research on Selective Oxidation of C-H Bonds to Construct Polycarbonyl Compounds and Heterocyclic Structures Based on I2/DMSO System

Author:Wu Xia

Supervisor:wu an xin


Degree Year:2018





Diversity-oriented synthesis is one of the important synthetic strategies in organic synthesis.Especially in recent years,people’s eager pursuit of health has stimulated the chemists’ strong interest in drug research and development.Drug discovery is inevitably involved in the construction of small molecule libraries for drug activity screening,and the diversity-oriented synthesis strategy is very important in the construction of small molecule libraries! So how to build a more efficient diversity-oriented synthesis strategy to quickly build small molecule libraries?Inspired by the multi-component reaction,which was undergoing multi-step transformation to synthesize a stable structure,this thesis expects the self-classification behavior of molecules in a complex reaction system to be applied from non-covalent synthesis to covalent synthesis,with multi-component reactions being the organic unit reaction constructs a multi-component reaction system to generate in-situ metastable intermediates,which are then captured by other reaction reagents,thereby completing the construction of a more efficient diversity-oriented synthesis system and achieving a simple and fast construction of a small molecule library.It is expected that each reaction component will be implemented in this reaction without disturbing each other! In order to further prove that the self-sorting behavior of molecules in complex reaction systems is true.At the same time,it is also a new strategy to reveal the self-sorting behavior of microscopic particles in covalent synthesis,and thus has a macroscopic understanding of the self-sorting behavior of microscopic particles.In addition,through the construction of this reaction system,new reactions and new mechanisms are discovered,thereby creating a new skeleton,and further providing new research strategies and research ideas for the construction of complex structural molecules.In this thesis,methyl ketone,molecular iodine and dimethyl sulfoxide are used as multi-component reagents,which was combined with other organic elemental reactions to carry out logical design to form an efficient,diversity-oriented synthesis based on the I2/DMSO system.A selective C-H functionalization reaction is achieved to construct multiple polycarbonyl compounds and heterocyclic structures.Through systematic research,we provide more examples of molecular self-sorting behavior,further enrich the molecular self-sorting reaction network model,and solve the problem of the catalytic efficiency of molecular iodine and C-H bond oxidation of aliphatic methyl ketones,broadening the scope of application of the I2/DMSO reaction system.Specifically,it is divided into the following sections:In chapter 1,we first briefly summarize the high efficient diversity-oriented synthesis system based on multi-component reagents.Then,the coupling reaction,oxidation reaction,cyclization reaction,cascade cyclization reaction and other types of reactions were reviewed based on the I2/DMSO reaction system.The application and latest progress of the I2/DMSO reaction system in organic synthesis were reviewed in detail.Finally,the ideas of this thesis were put forward.In chapter 2,Based on the oxidative cross-coupling reaction,the aryl methyl ketone and benzamidine hydrochloride were used as substrates to realize the iodine-based oxidative coupling to construct the C-N bond,thereby completing the construction of the a-ketoimide skeleton.It provides a new strategy for the oxidative amidation of C(sp3)-H bonds.What’s more important is that we have solved the problem of the catalytic efficiency of molecular iodine in this reaction process and realized the catalytic cycle of molecular iodine.In chapter 3,based on the previous work and the I2/DMSO system,aryl methyl ketones and anilines were used as substrates to achieve selective oxidation of C-H/C-H bond cross-coupling to construct C-C bond,and a series of 4-amino benzils were synthesized.Which provides a new route for the site-selective oxidative coupling of aromatic amines.In chapter 4,based on the research of the previous two chapters,we achieved the in-situ formation of amines from ammonia,the use of aryl methyl ketones as nucleophiles,and the oxidation cross-coupling in I2/DMSO to construct a-ketoacyl sulfonyl Imine skeleton.In this process,ammonia is realized as a bisexual reagent to construct C-N bonds and N=S bonds.In chapter 5,the C-S bond cleavage is the key element of the reaction,in situ capture of carbon cations of dimethyl sulfide to form methylene intermediates,and then the cyclization reaction provides a new path for the construction of a series of multi-substituted pyridine compounds.In this reaction,dimethyl sulfoxide as a methylene agent provides a carbon atom for the pyridine ring.In chapter 6,The cleavage of isocyanic C=N as key elementary reaction,using aryl methyl ketones reacts with in-situ generated ethyl 2-aminoacetate or methyl 2-aminoacetate.This formal[3+2]cycloaddition reactionc can build 2,5-disubstituted oxazole compounds.For the first time,this reaction achieved a formal cycloaddition reaction of Lewis acid-promoted a-methylene isocyano compounds and the oxidation of aliphatic methyl ketones results in the formation of ketone aldehydes was realized.In chapter 7,based on the oxidative cyclization and the C-C bond cleavage strategy,2-pyridine acetic acid ethyl ester and aryl methyl ketone were used as substrates.Which undergoes multiple oxidation cleavage of C-H bonds to form C-C/C-N bonds,and further synthesis of indolizine to build biheterocycle skeleton through C-C bond cleavage.In this reaction,it was achieved that the same substrate showed different reactivity at same conditions.In chapter 8,Based on the cross-coupling reaction,3-methylpyrazol-5-one and methyl ketone were used as substrates to construct 2,3-dihydrooxepines skeletons by self-sequence oxidative cross-coupling reactions.For the first time in this reaction,activation of methyl in 3-methylpyrazol-5-one is involved in the cyclization reaction.In addition,this reaction achieves the catalytic cycling of molecular iodine and the oxidation of aliphatic methyl ketones to ketone aldehydes.In chapter 9,based on the open-loop/cyclization strategy,using Povarov reaction as the core organic unit reaction,the first application of 1,4-dithiane-2,5-diol as a C2 synthon to heterocycle synthesis was achieved.We first realized the synthesis of 2-acyl quinolines using aromatic amines,aryl methyl ketones and 1,4-dithiane-2,5-diol as substrates.In chapter 10,based on in situ cross-trapping strategy,using acetoacetate,aryl methyl ketone,and aromatic amines as substrates,in situ formation of ketaldehyde and enaminone intermediates,and further in-situ cross-trapping to construct of 2-formyl Pyrrole.This reaction realizes de novo synthesis of heteroaromatic aldehydes.In chapter 11,based on the oxidation amination and the C-H bond iodide reaction,2-methylamine pyridine and aryl methyl ketone are used as substrates to establish the two amination reaction of methyl C-H bond and the iodination of methylene C-H bond to build 1-Iodoimidazo[1,5-a]pyridines.In chapter 12,Summarized the whole work of the doctoral dissertation,and looked forward to how to further apply and expand the I2/DMSO system.