| This dissertation deals with the [3+2] cycloaddition and1,5-electrocyclization ofazomethine ylides and their applications in the synthesis of novelpyrrolidine-containing scaffolds. The research includes the [3+2] cycloaddition ofazomethine ylides stabilized by aromatic rings (i.e. pyrimidine), the1,5-electrocyclization of azomethine ylides from the reaction of Baylis-Hillmanadducts with aldehydes and the1,5-electrocyclization of azomethine ylides from1,6-H shift in a pyrimidine system. It is divided into four chapters.In Chapter One, the [3+2] cycloadditions and1,5-electrocyclizations of azomethineylides were reviewed.Azomethine ylide is one of the most important intermediates in synthetic organicchemistry and has been widely used in the synthesis of natural products and bioactivemolecules. A variety of methods preparing azomethine ylides have been reported, forexample, the ring-opening reaction of aziridine, the reaction of aldehydes withsecondary amines and1,2-H shift of imine.The [3+2] cycloaddition of azomethine ylides is one of the most efficientapproaches to prepare pyrrolidine derivatives. Up to four chiral centers may begenerated simultaneously by this reaction in high regio-and stereo-selectivity. Theintramolecular azomethine ylide reaction can provide direct access to polycyclicscaffolds of considerable complexity with high stereoselectivity. Moreover, the inertolefins could be used as the dipolarophile in this reaction. According to reports, the[3+2] cycloaddition of an azomethine ylide, generated from an amine and an aldehyde,needs a withdrawing group which serves dual purposes: increasing the acidity of theα-proton to promote the formation of the azomethine ylide and stabilizing the resulted negatively charged carbon. Among the withdrawing groups, carbonyl is most used andaromatic rings are less studied.The1,5-electrocyclization of azomethine ylides can be used to synthesize thefive-membered nitrogen-containing heterocyclic compounds. Up to now, there aremany reports about the1,5-eletctocyclization reactions of azomethine ylides althoughthese studies are not as in-depth as those of the [3+2] cycloadditions.This dissertation is focused on the [3+2] cycloadditions of azomethine ylidesstabilized by aromatic rings including a pyrimidine ring and the1,5-electrocyclizationof azomethine ylides. It is aimed at developing methods for building library synthesisof novel drug-like pyrrolidine-containing compounds.In Chapter Two, the intramolecular and intermolecular [3+2] cycloaddition ofazomethine ylides stabilized by aromatic rings, such as pyrimidine, benzene andpyridine, were studied.At first, we systematically studied the intramolecular [3+2] cycloadditions ofazomethine ylides stabilized by a pyrimidine ring. We found thatN-allyl-5-((butyl-amino)methyl)-6-chloro-N-methylpyrimidin-4-amine could reactwith benzaldehyde in refluxing toluene with removal of water using a Dean-Stark trapto yield (2R*,3aR*,9bR*)-1-butyl-9-chloro-5-methyl-2-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[2',3':4,5]pyrido[2,3-d]pyrimidine as the onlydesired product. Further investigations showed that a variety of substitutedbenzaldehydes and heteroaromatic aldehydes were suitable to this reaction; both alkyland aryl groups could be used as the substitutents of secondary amine; the pyrimidinemight be substituted at the second or sixth position; and several inert alkenyl andalkynyl groups except (E)-N-methyl-N-(but-2-en-1-yl)-could be used as thedipolarophile to participate in the reaction. Subsequently, several linkers between thedipolarophile and pyrimidine moity were investigated and found that the NMe waseffective, and the O and S atoms were not suitable. The X-Ray structure analysis ofthe representative products indicated that the intramolecular [3+2] cycloadditionoccurred with a S-shaped azomethine ylide intermediate and in an endo approachingmanner. Secondly, the reaction was expanded to other aromatic ring systems. The resultsshowed that both benzene and pyridine rings could be used as the stabilizing groupsof azomethine ylides in the intramolecular cycloadditions. The electronegativity inbenzene ring had significant impact on this reaction. Strong electron-withdrawinggroups were more favorable to this cycloaddition in the benzene ring system. Thepresence of substituents at the third position of benzene ring was favorable to thiscycloaddition.Lastly, the intermolecular [3+2] cycloadditions of azomethine ylides stabilized byaromatic rings were investigated. The results showed that benzene ring, pyridine ringand pyrimidine ring were all suitable to be used as stabilizing groups of azomethineylides. However, both endo and exo isomers were obtained, and the Michael additionreaction byproduct between the secondary amine and N-methy maleamic was yielded.When KOAc was added in the reaction, the Michael addition could be inhibited tosome extent.In summary, the intramolecular [3+2] cycloadditions of azomethine ylidesstabilized by aromatic rings were carried out in high regioselectivity andstereoselectivity with an S-shaped azomethine ylide transition state and in an endoapproaching manner. However, the mixture of both endo and exo isomers wereobtained with a Michael addition byproduct in the intermolecular reactions.In Chapter Three, the1,5-electrocyclization of azomethine ylides generated fromaldehydes and a Baylis–Hillman adduct was investigated, and a synthetic strategy ofmulti-substituted4,5-dihydro-pyrrole, pyrrole and pyrrolidine was developed.Firstly, the cyclization conditions were investigated. We found that under refluxingtoluene removal of water using a Dean-Stark trap, the cyclization could proceedquickly to yield the trans4,5-dihydro-pyrrole as the only cyclization product. Thereasults are consistent with the1,5-electrocyclization mechanism. Furtherinvestigation revealed substituted benzaldehydes, heteroaromatic aldehydes andcertain aliphatic aldehydes were suitable to this reaction. Apart from the aromaticamine-substituted Baylis–Hillman adducts, a variety of Baylis–Hillman adducts couldbe used in this cyclization. The yields of above reactions are between50%–79%. Subsequently, the reaction mechanism was discussed. We speculate that the reactionunderwent a1,5-electrocyclization mechanism. The carbonyl on the Baylis–Hillmanadduct plays a key role for the1,5-electrocyclization. On the one hand, it increases theacidity of α-H of N to facilitate the formation of azomethine ylide; On the other hand,it could induce the reaction transition state to the optimal conformation to give4,5-dihydro-pyrrole in high stereoselectivity. Finally, oxidation-reduction reactions of4,5-dihydro-pyrrole were investigated. The results showed that4,5-dihydro-pyrrolecould be aromatized by DDQ to give a pyrrole and be reduced by NaBH(OAc)3togive a pyrrolidine in high stereoselectivity.In Chapter Four, the1,5-electrocyclization of the azomethine ylides generated from1,6-H shift in a pyrimidine system leading to the6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine derivates was investigated.Firstly, the cyclization conditions were investigated. We found that under refluxingxylene, the reaction of methyl2-(N-(5-formyl-6-(phenylthio)pyrimidin-4-yl)-N-methylamino)acetate with aniline could proceed in high stereoselectivity to givecis-methyl6,7-dihydro-7-methyl-5-(phenylamino)-4-(phenylthio)-5H-pyrrolo[2,3-d]pyrimidine-6-carboxylate. Subsequently, the scope of amines was investigated.The results showed that both primary aromatic and aliphatic amines were suitable tothis reaction and the yields were between54%–85%. Then, the cyclization wasexpanded to other pyrimidine substrates substituted by several animo acid esters. Wefound that the reaction of chiral substrate with aniline could yield the chiralcyclization product. Finally, the reaction mechanism was discussed. We speculatedthat the reaction occurred via a1,6-H shift to form an azomethine ylide, and followedby the1,5-electrocyclization of the azomethine ylide. This reaction could be used toconstruct a library of6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine derivatives.
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