| Pyrimidine heterocycles frequently appear as the core of bioactive compounds and pharmaceuticals. Dozens of marketed drugs containing the skeleton of pyrimidine have been used to treat cancer, cardiovascular disease and virus infection etc. Consequently, the development of efficient methodologies for the synthesis of pyrimidine heterocycles has been of great interest in organic synthesis.The inverse electron demand Diels-Alder(IEDDA) reactions of 1,3,5-triazines with various electron-rich dienophiles are among the most widely utilized synthetic methodologies to prepare pyrimidine heterocycles. They have been applied in the preparation of highly functionalized pyrimidines and the total syntheses of related natural products. Thus far, multiple dienophiles have been developed for the 1,3,5-triazine IEDDA reactions, and could be categorized into two groups: the classical non-aromatic electron-rich alkenes and alkynes, and the later discovered electron-rich aromatic heterocycles. However, due to its low reactivity only non-aromatic dienophiles with high reactivity, such as enamines, ynamines and amidines, can be used in the IEDDA reactions of 1,3,5-triazine, which limit the scope of these reactions. And the availability of these non-aromatic dienophiles has been limited due to their poor stability. In addition, the mechanism of the IEDDA reactions of 1,3,5-triazines with non-aromatic dienophiles has not been carefully studied. To address above problems, we aimed at the development of productive and stable alternative dienophiles for 1,3,5-triazine IEDDA reactions and the study of the mechanism of these reactions.In chapter two, the IEDDA reactions of 1,3,5-triazines with oximes and hydrazones as enamine dienophiles were studied. And hydrazones were introduced as productive dienophiles for the 1,3,5-triazine IEDDA reactions. Eventually, hydrazine-catalyzed IEDDA reactions of 1,3,5-triazines with ketones containing α-H as enamine dienophiles have been developed.1. The IEDDA reactions of 1,3,5-triazines with oximes and hydrazones were investigated. By screening of reaction conditions and investigation of O-substituent effects of oximes, the desired IEDDA products were obtained in 88% yield by using O-benzyl oximes in TFA/Ac OH(1:9) at 100 oC. The exploration of reaction conditions and N,N-substituent effects of hydrazones showed that N-piperidin-1-yl hydrazone under the conditions of DMF/Ac OH(1:1) as solvents at 60 °C was optimal for the IEDDA reactions of hydrazones to produce the IEDDA product in 92% yield. These studies revealed that hydrazones were more reactive than oximes. Therefore, the scope for the hydrazone IEDDA reactions was further investigated. With the exception of cyclobutyl hydrazone, various acyclic and cyclic hydrazones were good substrates to produce the desired IEDDA products in 60-92% yields. Cyclic hydrazones were more reactive than acyclic hydrazones.2. Hydrazine-catalyzed IEDDA reactions of 1,3,5-triazines with ketones containing α-protons were studied. After exploring several reaction conditions, an acceptable condition was discovered as heating a mixture of 0.1 equiv. of piperidin-1-amine hydrazine and TFA, 2.0 equiv. of ketones, and 1.0 equiv. of 1,3,5-triazines in Et OH at reflux. With the optimal reaction conditions in hand, the scope of this catalytic IEDDA reaction was explored. All the tested cyclic and acyclic ketones, even low-boiling acetone, were good substrates to produce pyrimidine products in 42-91% yields. More remarkably, heteroaryl ketones and aryl ketones with various functional groups, such as halo, alkoxy and nitro groups, produced aryl substituted pyrimidines in good yields. A mechanism for the hydrazine-catalyzed IEDDA reaction was proposed. This catalytic IEDDA reaction afforded a succinct, economical and green approach to the synthesis of pyridimine heterocycles from readily available ketones containing α-protons.In chapter three, the IEDDA reactions of 1,3,5-triazines with aldehydes/ketones containing α-protons as direct enol dienophiles and the reaction mechanism have been carefully investigated.1. Reaction conditions and scope of these IEDDA reactions were investigated. We found that all the tested aldehydes/ketones containing α- protons with the exception of cyclobutanone were good substrates for the current IEDDA reactions. However, the reactions of aldehydes with 1,3,5-triazines suffered lower yields. In addition, aldehydes/ketones were found more reactive than their corresponding vinyl ethers in 1,3,5-triazine IEDDA reactions.2. The reaction mechanism was carefully studied by the combination of experimental investigation and computational studies. The results of both experimental and computational analysis indicated that:(1) the cascade reactions started with a step-wise inverse electron demand hetero-Diels-Alder(ih DA) reaction and followed by a retro-Diels-Alder(r DA) reaction and elimination of water(referred as to the IRE path);(2) an acid was required for both ih DA and r DA reactions. Based on the reaction mechanism, we speculated aldehydes/ketones may enolize to their enols and provide a proton to activate 1,3,5-triazine, so they were more reactive than their corresponding vinyl ethers in 1,3,5-triazine IEDDA reactions.3. Inspired by the above results, we investigated the amine-catalyzed IEDDA reactions of 1,3,5-triazines with ketones containing α-protons, and discovered that 3-aminobenzoic acid could speed up the reaction and increase the yield.In chapter four, the competition reactions between the [4+2] reactions and formal [3+3] reactions of 1,3,5-triazines with ketones containing α-protons on both sides of the carbonyl group were studied. These studies expanded the application of 1,3,5-triazines in synthesis of heterocyclic compounds.1. We systematically investigated the effects of the substituents on the two α-carbons of ketones to produce pyrimidine products by the [4+2] reaction pathway and pyridine products by the [3+3] pathway. The results showed that:(1) The [4+2] reaction was the sole pathway in the reactions of 1,3,5-triazines with cyclic ketones to produce only pyrimidine products;(2) in the reactions of 1,3,5-triazines with symmetrical acyclic ketones: when the substituents were H, only pyrimidine product was prepared via the [4+2] reaction pathway; when the substituents were alkyls, both pyrimidine and pyridine products can be prepared by the two reaction pathways and the ratio of pyridine product to pyrimidine product decreased with the increase of steric hindrance of the substituents;(3) in the reactions of 1,3,5-triazines with asymmetrical acyclic ketones: both pyrimidine and pyridine products can be produced via the two reaction pathways, but only pyrimidine products were yielded if the steric hindrance of the substituents were large enough.2. Ethyl acetoacetate and 2,4,6-tris(trifluoromethyl)-1,3,5-triazine were employed to study the mechanisms of the formal [3+3] reaction. By isolating reaction intermediates and comparing with the results in chapter three, we proposed the combined mechanisms of the IEDDA reactions and the formal [3+3] reactions of ketones with 1,3,5-triazines. |
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