| This four-chapter dissertation focus on the strategy of diversity-oriented synthesis (DOS) and its application in the construction of three different kinds of pyrimidine-fused heterocyclic scaffolds from the same starting material ( 4,6-dichloropyrimidine-5-carbaldehyde).In Chapter One, the development of diversity-oriented synthesis is reviewed. As an important and widely applied strategy in the design and syntheses of complex and diversed libraries, DOS can merge with chemical genetics and provide efficient solutions to biological and medical challenges. Developing methodologies for the syntheses of novel diversed pyrimidine-fused heterocycles with potential pharmacological properties is a good practice of DOS, and the resulted compound libraries are the bases for screening against biological targets.In Chapter Two, a novel iminium ion isomerization reaction is discussed. To apply the DOS strategy, an initial design of intramolecular azomethine ylide [3+2] cycloaddition reaction with pyrimidine carbaldehyde as starting material was performed and an unexpected new product was acquired. The structure was determined to possess tetrahydro pyrimido[4,5-d]pyrimidine scaffold by X-ray crystallography. Following this, a systematic study of this reaction is discussed. The precursor 4-amino-6-phenylthiopyrimidin-5-carbaldehyde was prepared by amine and subsequent thiophenol substitution of the 4,6-dichloropyrimidine-5-carbaldehyde. The precursor was then reacted with ten selected secondary amines in refluxing xylene and led to tetrahydropyrimido[4,5-d]pyrimidine derivatives with 10-78% yields. The reaction results can be summarized as follow: (1) Reaction of pyrimidine aldehyde containing various N-substitutents proceed well; (2) The reactions are slow when secondary amine contains a large group; (3) The various substitutents of secondary amines led to two regioisomers without significant selectivity. The isolation and characterization of regioisomers supported an iminium ion isomerization mechanism. In addition, the oxidation of 6-phenylthio group to the corresponding sulfone compound results in 70% yields, and the sulfones can be further derivatized via nucleophilic substitution with 67-90% yields. Thus an efficient methodology to access structurally diverse library of tetrahydropyrimido [4,5-d]pyrimidines was developed.In Chapter Three, the discussed DOS method focused on imino Diels-Alder reaction to develop novel hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridine scaffold. The key step of this method can be considered as a tandem reaction, imines formed in situ from allylaminopyrimidinealdehydes and anilines, followed by the intramolecular inverse electron demand hetero Diels-Alder reaction. Seven key precursors 4-allylaminopyrimidine-5-carbaldehydes were prepared via the nucleophilic substitution of various allylamines to 4,6-dichloropyrimidine-5- carbaldehyde. The desired hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridine derivatives were obtained by this one-pot reaction under the catalysis of trifluoroacetic acid with 49-98% yields. The reaction results can be summarized as follow: (1) The reactions with aromatic amines containing electron-withdrawing groups were faster than those with electron-donating groups; (2) When the anilines had an ortho substituent, the reactions were either slow or resulted no desired product; (3) When the anilines had a strong electro-effect substituent, the reactions were extremely regioselective; (4) The reaction of secondary aryl amines could yield the desired products in refluxing toluene with p-toluenesufonic acid using a Dean-Stark apparatus; (5) All the products were determined to be cis-con gured by comparison of 1H NMR spectra with the X-ray confirmed compound. In addition, the oxidation of 6-phenylthio group to the corresponding sulfoxide compound results in 75% yields, and the sulfoxides can be further derivatized to the corresponding 6-substituted hexahydrobenzo[b] pyrimido[4,5-h][1,6] naphthyridines via nucleophilic substitutions with 55-98% yields. Thus an efficient methodology to access structurally diverse library of hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridine was developed.In Chapter Four, another strategy using ene reaction to access epiminopyrimido[4,5-b]azepine scaffold was developed. The key intermediate for this synthetic route was same as the hetero Diels-Alder reaction discussed in Chapter Three. Under the catalysis of p-toluenesufonic acid, the reactions were heated in refluxing toluene with a Dean-Stark apparatus. The titled compounds were acquired via an intramolecular imine Ene reaction following the in situ imine formation of allylaminopyrimidinealdehydes and primary amines. Sixteen epiminopyrimido[4,5-b] azepine derivatives were synthesized with 44-97% yields. The reaction results can be summarized as follow: (1) The electron density of pyrimidine aldehyde has great influence on the reaction outcome. When the electron density is lower, the reaction yield is higher; (2) The reactions with primary amines containing electron-donating groups are faster than those with electron-withdrawing groups; (3) When the primary anilines had an ortho substituent, the reactions were slow and low yielding. Besides, the key precursors were treated in refluxing xylene, and epoxypyrimido[4,5-b]azepine derivatives were isolated with 72-95% yields via carbonyl Ene reaction. Carbonyl Ene reaction demands higher reaction temperature. Another DOS method was developed utilizing Imine-Ene reaction and Carbonyl-Ene reaction.
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