Construction Of Amide Bonds Based On Radicals Generated By Photo-/Electro-redox

Amide bond is not only the backbone of proteins,peptides and some synthetic polymers,but also commonly found in drugs,pesticides and materials.In addition,amides are vital intermediates for the synthesis of other types of compounds such as amines,isonitriles,and heterocycles.At present,many methods for the synthesis of amide bonds have been developed,but most of them require excess amounts of coupling reagents,and excess amounts of base to neutralize the acids generated in the reaction.These methods are not only costly,but also produce wastes that are harmful to the environment.Due to the importance of amides,the development of new synthetic methods for amides is still one of the most important tasks in organic synthesis.With the increasingly serious environmental damage and the shortage of resources,the main challenge for the construction of amide bond is to develop green and efficient synthesis methods.In order to develop green and efficient synthesis methods of amide bonds,in addition to optimizing traditional synthesis methods,more and more attention has been paid to find the new synthetic methods through the high activity intermediate.So far,chemists have developed free radicals as active intermediates to build various chemical bonds.However,synthesis of amides using free radicals as intermediates has been seldom reported.There are many challenges for developing the green methods for amide synthesis,such as the limitation of substrates scope,elevating temperature to overcome the high kinetic barrier,anhydrous conditions,poor selectivity of active intermediates.The advantage of building amide bonds through free radical intermediates is that the activity of free radical intermediates is high so that the synthesis of amides can be carried out at room temperature.Amide bonds are constructed by radical intermediates generated in situ by green methods such aselectrosynthesis or photoredox catalysis to avoid the high temperature.Because solvents have little effect on free radicals,using the radical intermediates can avoid the side effect from the water which was formed during the synthetic process.The concentration of radicals produced by electrosynthesis or photoredox catalysis is relatively low,so the radicals in this kind of reaction have good chemical selectivity,resulting in a high yield of the amides.At the same time,owing to the inherent green chemical property of electrochemical synthesis and photoredox catalysis,the methodologies by electrochemical or photochemical means is sustainable.This thesis mainly describes the methodology of amide bond synthesis via free radical intermediates.In chapter 2,a catalyst-free method for amide synthesis from thiocarboxylic acids and amines has been developed.Thiocarboxylic acids as the acyl source for amide synthesis can avoid epimerization of chiral carbon center,and the reaction conditions are mild.Therefore,thiocarboxylic acids attract more and more attention in the amide synthesis.In this protocol,aryl thiocarboxylic acids can be oxidized by the air to form the aryl acyl disulfides.Then the disulfides react with amines to form amides.However,the alkyl thiocarboxylic acids ger low yield of amides when react with amine in the air.The amides productivity is improved after the constant current conducted into the alkyl thiocarboxylic acid reaction.The mechanism studies showed that the thiocarboxylic acids are oxidized by single electron transfer to acryl sulfur radicals,which undergo the self-coupling reaction to form the acyl disulfides.No product is detected after the reductant of disulfide is added into the reaction system,which proves that the disulfide is a key intermediate for the amide synthesis.The aryl sulfur radical can be stabilized by the aromatic ring,so it's easier to be formed from thiocarboxylic compare to alkyl sulfur radical.The alkyl carboxylic acids need to be electrochemically oxidized first,and then react with amine to get high yield of amides.In this way,amides can be obtained in very high yield without the use of any catalysts and activators.This method has broad scope of substrates including aromatic amine with electron donating group and electron withdrawing group.The practical value of this amide synthetic method was proved by the synthesis of drug molecular under standard condition.In chapter 3,the electrochemical Beckmann rearrangement,i.e.the direct electrolysis of ketoximes to amides,is presented for the first time.Beckmann rearrangement is not only one of the important amide synthetic methods,but also an important mean of introducing nitrogen atoms into the carbon skeleton structure.Traditional Beckmann rearrangement needs excess amount of strong acids and elevated temperature.These hash conditions require expensive reaction equipment to avoid the corrosion of acids.The use of excess acid neither meet the standards of green chemistry and nor be compatible with those acid-sensitive functional groups.Using a constant current as the driving force,this Beckmann rearrangement can be easily carried out under neutral conditions at room temperature.We find that solvents with strong hydrogen bond ability are essential to this electrochemical rearrangement after the optimization of reaction conditions.Under standard reaction conditions,various kinds of amides were obtained by our electrochemical Beckmann rearrangement.The aromatic ketoximes with electron donating group can obtain high-yield products.The ketoximes with E/Z isomers can selectively transfer to amides in this electrochemical Beckmann rearrangement.We synthesized acetaminophen,an antipyretic,on a gramscale by this method,demonstrating the potential practical value of Beckmann reaction.Based on a series of mechanism study experiments,a novel radical Beckmann rearrangement mechanism was also proposed.This electrochemical Beckmann rearrangement does not follow the trans-migration rule of the classical Beckmann rearrangement(migration of "trans" substituent to nitrogen).The disadvantage of the electrochemical Beckmann rearrangement reactions reported in the previous chapter is the need to precisely control the total charge to ensure that the substrate reaction is complete without oxidation of the product.To solve this problem,the organic photoredox catalyzed Beckmann rearrangement has benn tried.we reported the first visible light induced photoredox catalyzed Beckmann rearrangement reaction in Chapter 4.Using the cheap organic dye 10-methyl-9-phenylacridinium perchlorate as a photocatalyst,the 9 W of blue LEDs as the light source,Ketoxime is efficiently converted to amides by free radical Beckmann rearrangement.During the optimization of reaction condition,we find that fluorine alcohol with strong hydrogen bond ability is critical to this reaction.This photoredox catalyzed Beckmann rearrangement could not only get excellent yield of amides,but also didn't need additional additives.The scaled-up reaction on the gram scale proves the possibility of industrial application of the method.The visible light-induced Beckmann rearrangement overcomes the problem of over-oxidation in electrochemistry,and the mechanism of Beckmann rearrangement reaction undergoing free radicals is further proved.In chapter 5,The transamidation reaction of secondary amides induced by visible light using Bengal Rose Red as a photosensitizer has been reported.There are a lot of secondary amides in nature,and they are the raw materials for the synthesis of amides through transamidation.The transamidation of secondary amide has been facing two challenges: high barrier is required to activate amide bonds in substrates;the reaction is thermally neutral,that is,the conversion rate of the reaction depends on the energy difference between the substrate amide and the product amide.Here we report that arylglycine esters and enamides are driven by visible light to synthesize biologically active acyl Mannich base derivatives by transamidation.The strategy of this method is that activation of secondary amides by transferring to N-acyl imines,to initiate the transamidation process.This strategy overcome the high barrier of amide bond activation.Another strategy is that the hydrolysis of imine,to drive the balance of transamidation move to the direction of product formation,which can solve the problem of thermoneutral process.This visible light-induced transamidation has broad scope of substrates,amides with electron with-drawing group or electron donating group can obtain high-yield products.The scaled-up reaction on the gram scale proves the possibility of industrial application of the method.The detailed mechanism was clearly proved by a series of mechanism study experiments.