Study On Pd(Ⅱ) Catalyzed Asymmetric Aza-Wacker Type Oxidative Cyclization Reaction

Nitrogen containing heterocyclic compounds are an important branch of heterocyclic compounds,which count for extremely large number in organic compounds.These compounds,including the chiral monomers,are widely used in pharmaceutical chemistry,agricultural chemistry and material science etc.Therefore,synthesis of valuable natural nitrogen containing heterocyclic compounds or new nitrogen containing heterocyclic compounds starting from simple chemicals simply,efficiently and environmentally friendly,has been caught sustained attention by chemists.In recent decades,significant progress have been made in Pd（Ⅱ）catalyzed Aza-Wacker type oxidative cyclization reaction,which has become an important method for constructing of nitrogen-containing heterocyclic compounds.The addition of chiral ligands can induce the formation of chiral C-N bonds,leading to chiral nitrogen-containing heterocyclic compounds.The selection of chiral ligands and oxidants is crucial for asymmetric Aza-Wacker type oxidative cyclization reaction.Because of diversity and structural adjustability of chiral ligands,the methodology research of developing efficient and high enantioselective Pd（Ⅱ）/chiral ligand catalytic system for asymmetric Aza-Wacker type oxidative cyclization reaction has a bright prospect.In this paper,we develop a series of chiral oxazoline ligands based on cinchona alkaloids and apply them in Pd（Ⅱ）catalyzed Aza-Wacker type oxidative cyclization reaction.By employing oxygen as a green oxidant with the view of atom economy and environment friendliness,we completed the synthesis of a series of nitrogen containing heterocyclic compounds.The details of this paper are summarized as follows:（1）According to the structure characteristics of cinchona alkaloids,combined with the structural tunability of chiral oxazolines,we took quinine,quinidine,cinchonine and cinchonidine as the starting materials,the corresponding carboxylic acids were obtained through methylation,oxidation,cyanation then hydrolysis,respectively.The reaction between carboxylic acid and chiral amino alcohols led to 26 new chiral oxazoline ligands based on the structure of above four kinds of cinchona alkaloid.The structures of these compounds were confirmed by IR,1H NMR,13 C NMR and HRMS.（2）According to the feature of intramolecular Aza-Wacker type oxidative cyclization reaction,three kinds of aromatic anilines containing one double bond or two double bonds were synthesized.The first kind of substrates are 2-allyl-N-Ts substituted anilines,which were obtaind through Ts substitution of 2-amino benzyl alcohol,chlorination,followed by Grignard reaction.The second kind of substrates are 2-allyl-N-alkenyl（substituted）anilines,which were obtained through allyl substitution,allyl rearrangement reaction and olifen substitution reaction.The third kind of substrates are 2-（4-substituted）cinnamyl N-alkenyl anilines.The synthesis routes include bis-allylic substitution reaction of 2-iodine aniline,Grignard reaction of（substitued）cinnamyl chloride with N,N-diallyl-2-iodine aniline,deprotection of allyl and then olifen substitution reaction.By Pd（OAc）2/pyridine/O₂ or Pd（OAc）2/quinoline/O₂ catalytic system,the Aza-Wacker type oxidative cyclization reaction or tandem cyclization of three kinds of substrates proceed smoothly,leading to a variety of indolines and aryl fused pyrrolizidines in high yields with high chemoselectivity.（3）Employing oxygen as the oxidant,with Pd（Ⅱ）/cinchona alkaloid-oxazoline as the catalytic system,intramolecular asymmetric Aza-Wacker type oxidative cyclization of the first kind of aromatic nitrogen containing olefins was conducted.By controlling the reaction conditions,a series of 2,3-dihydro-1H-indole compounds were constructed conveniently,the substrates cover 10 aromatic nitrogen-containing olefins.In the reaction,by changing the solvent and reaction conditions,we obtained two catalytic systems: Pd（OAc）2/63g/Toluene/O₂ and Pd（TFA）2/64b/Me CN/O₂,with these two reaction conditions in hand,product with opposite configuration in high yield（up to 92%）and moderate enantioselectivity（up to 62%）were obtained.（4）The palladium catalyzed intramolecular asymmetric Aza-Wacker type oxidative tandem cyclization of the second and the third kind of aromatic nitrogen containing compounds bear two double bonds using oxygen as terminal oxidant was studied.A series of aryl fused pyrrolizidine derivatives were obtained,the substrates cover 36 aromatic nitrogen containing olefins bear two double bonds.For the second kind of substrates,the chiral ligand 64 b showed to be most effective,under the condition of Pd（OAc）2/64b/toluene/O₂ catalytic system,the asymmetric Aza-Wacker type oxidative tandem cyclization proceeded in high yield（up to 90%）with moderate enantioselectivity,the results were different when the substituent changed in the substrate.For the third kind of substrates,the chiral ligand 64 g showed to be most effective,under the condition of Pd（OAc）2/64g/p-xylene/O₂ catalytic system,the asymmetric Aza-Wacker type oxidative tandem cyclization proceeded with high enantioselectivity.The catalytic system showed good chiral induction and tolerance to functional groups.In conclusion,novel chiral oxazoline ligands based on the skeleton of cinchona alkaloids were synthesized,and their structures were adjustable,which showed good chiral induction in palladium catalyzed asymmetric Aza-Wacker type oxidative cyclization reaction and cascade cyclization reaction.