Research And Application Of Allylation Reaction Of 2-alkylpyridines And Analogues Based On MBH Carbonates

Pyridines,isoquinolines and dihydroisoquinolines are common chemical structures in medicinal chemistry with a wide range of biological activities,such as antiviral,anti-tumor,and so on.In addition,pyridine and isoquinoline derivatives 2-arylethyl pyridines and quinolizidines are also important structures in medicinal chemistry,and are the core skeletons of many natural products and pharmaceuticals.Therefore,it is of great significance to develop efficient synthesis strategies and functionalization methods around the above important molecular structures.Allylation reaction is an important organic reaction for the construction of carbon-carbon and carbon-heteroatom bonds,and has been widely used in the synthesis of natural products and bioactive molecules.Since Tsuji et al.first reported palladium-catalyzed allylation of malonates with allyl compounds such as allyl acetates and allyl bromides in 1965,transition-metal-catalyzed allylation reactions have been widely developed.However,these reactions have some problems,such as heavy metal residues,harsh conditions,and environmental unfriendliness,which limit their application in drug synthesis.Morita–Baylis–Hillman（MBH）carbonates are commonly used allylation reagent,and have been widely used in the allylation reaction of active nucleophilic reagents.Compared to transition-metal-catalyzed allylation reactions,these reactions do not need the use of noble metal catalysts,and have advantages such as atomic economy,mild conditions,and environmental friendliness.However,theα-C（sp³）-H allylation reaction of inactive carbon nucleophilic reagents such as 2-alkylpyridines and 1-alkyl-3,4-dihydroisoquinolines with MBH carbonates has yet to be studied.In view of this,this dissertation hopes to develop a catalyst-free allylation reaction between 2-alkylpyridines or 1-alkyl-3,4-dihydroisoquinolines and MBH carbonates for the synthesis of structural diversified pyridine and 3,4-dihydroisoquinoline derivatives.Our work in this dissertation contains the three parts:the development of catalyst-free allylation reaction of 2-alkylpyridines,the development of catalyst-free allylation reaction of 1-alkyl-3,4-dihydroisoquinolines,and their application on the synthesis of 2-arylethyl pyridine derivatives and quinolizidine derivatives.In Chapter two,a catalyst-freeα-C（sp³）-H allylation reaction between 2-alkylpyridines and MBH carbonates was developed.Firstly,2-picoline 2-1a and MBH carbonate 2-2a were selected as the template substrates to explore the reaction conditions.After investigation on the reaction solvent and temperature,the optimal condition was obtained as follows:with anhydrous acetonitrile as the solvent and inventory ratio 2:1 of 2-picoline 2-1a and MBH carbonate 2-2a,the reaction was performed at 80℃under N₂ atmophere for 4 h,giving the target product 2-3a in 91%yield.Then,under the optimal reaction conditions,the substrate scopes and limitations of MBH carbonates were studied and it was found that phenyl substituted MBH carbonates containing electron-withdrawing groups on the phenyl ring,such as-NO₂,-CO₂Me and halogen,etc.,were found to be well tolerated,providing the desired products in moderate to good yields（69–78%）.Compared with electron-withdrawing groups on the phenyl ring,substrates containing electron-donating groups（-OMe）underwent a slightly sluggish reaction and the desired product could only be obtained in 47%yield.Besides aromatic substituents,aliphatic groups substituted MBH carbonates were tolerated.In addition,studies of the substrate scopes and limitations of 2-alkylpyridines found that alkyl substituents at the 3 or 5-positions of the 2-alkylpyridines were tolerated,giving the desired products in good yields（71–83%）.However,2,4-lutidine reacted with MBH carbonate led to complex results with several indistinct by-products formed,and only 39%yield of the target product was isolated.It is noteworthy that 2-methyl-4-bromopyridine and 1-methylisoquinoline were also compatible with the reaction conditions,but the reaction needs to be carried out at a higher reaction temperature（100℃）.In addition,substrates with large steric hindrance,such as 2,6-lutidine,are not tolerant of this reaction conditions.Under the above reaction conditions,this dissertation has synthesized 21α-C（sp³）-H allylation products of 2-alkylpyridines.In the above allylaction reaction of 2-alkylpyridines,no metal or any other catalysts are needed.The advantages such as easy operation,broad substrate scopes,and environmental friend makes this method more suitable for the construction of structural diversified pyridine derivatives.In Chapter three,a catalyst-freeα-C（sp³）-H allylation reaction between 1-alkyl-3,4-dihydroisoquinolines and MBH carbonates was developed.Firstly,1-ethyl-3,4-dihydroisoquinoline 3-1a and MBH carbonate 3-2a were selected as the template substrates to explore the reaction conditions.After investigation on the reaction solvent and temperature,the optimal condition was obtained as follows:with anhydrous acetonitrile as the solvent and inventory ratio 1:1.5 of 1-ethyl-3,4-dihydroisoquinoline 3-1a and MBH carbonate 3-2a,the reaction was performed at 80℃under N₂ atmophere for 2 h,giving the target product 3-3aa in 87%yield.Then,under the optimal reaction conditions,the substrate scopes and limitations were studied.It was found that when the R group of 1-alkyl-3,4-dihydroisoquinolines 3-1 was substituted by other aliphatic groups（such as ⁿBu,Bn,and phenylpropyl）,the reactions could be tolerated and the desired products could be obtained with good yields（77–78%）.Substrates with large steric hindrance（such as R=ⁱPr or cyclohexyl）could also successfully carry out this reaction.When 1-benzyl-3,4-dihydroisoquinoline was used as the substrate,the yield of the reaction（56%）was slightly lower,which is probably due to the oxidation at the benzyl position.In addition,substrates containing various electron-withdrawing groups on the aromatic ring of 1-alkyl-3,4-dihydroisoquinolines could obtain the target products in excellent yields（86–93%）,while substrates containing electron-donating group（-OMe）have slightly lower yields（64–69%）of the target products,probably due to their higher hydrolytic tendency of the imine moiety in the 3,4-dihydroisoquinolines with methoxy group.When the phenyl ring of 3,4-dihydroisoquinolines is substituted by heterocycles,the corresponding products could also be obtained in moderate to good yields（63–79%）.Under the above reaction conditions,this dissertation synthesized25α-C（sp³）-H allylation products of 1-alkyl-3,4-dihydroisoquinoline.It can be used in rapid construction of structural diversified allylation products of 3,4-dihydroisoquinolines.In Chapter four,the application of above developed allylation reactions on the synthesis of biological important 2-arylethyl pyridine and quinolizidine derivatives.Firstly,using the allylation product 2-3a of 2-picoline as the substrate,carboxylic acid4-1 was obtained through hydrolysis reaction.Then,carboxylic acid 4-1 was reacted with aliphatic amines and aromatic amines under different coupling conditions to obtain 17 amide derivatives.At the same time,12 dihydroisoxazole derivatives were obtained by using the allylation product 2-3j as the substrate for the[3+2]cycloaddition withα-chloroformaldoximes.Then,this dissertation explored the derivatization of the allylation product 3-3 of 1-alkyl-3,4-dihydroisoquinolines.The allylation product 3-3 has two cyclization paths:6-exo-trig（lactamization）and 6-endo-trig（aza-Michael addition）,which are mainly affected by the ester groups on the substrate 3-3 and reducing agents.When the allylation products of 1-alkyl-3,4-dihydroisoquinolines and MBH carbonate（EWG=CO₂Me）were used as the substrates,Na BH（Ac O）₃ was used as the reducing agent,and toluene was used as the solvent,the lactamization reaction could be carried out to obtain 4 quinolizidinone derivatives;When the allylation products of 1-alkyl-3,4-dihydroisoquinolines and MBH carbonate（EWG=CO₂^tBu）were used as the substrate,Na BH₄ was used as the reducing agent,and methanol was used as the solvent,the intramolecular aza-Michael addition reaction could occur to obtain 4 quinolizidine derivatives.After determining the reaction conditions for intramolecular cyclization,further research found that 1-alkyl-3,4-dihydroisoquinolines and MBH carbonate（EWG=CO₂Me）could undergo a one-pot reaction of allylation and intramolecular cyclization,simplifying the experimental operation.To sum up,this dissertation has developed MBH carbonates participated catalyst-freeα-C（sp³）-H allylation reactions of 2-alkylpyridines or 1-alkyl-3,4-dihydroisoquinolines,and their applications on the synthesis of 2-arylethyl pyridine and quinolizidine derivatives have also been explored.In the above allylation reactions,no additional catalysts are needed,and hence is more environmental friend.The reaction can be carried out under suitable solvent and temperature,with simple operation and wide range of substrate applications.The allylation products can be further transformed into structural diversified pyridine or quinolizidine derivatives.The above allylation reactions have potential application value in medicinal chemistry.