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Relevant academic research and scientific papers

Reaction of Aldehydes/Ketones with Electron-Deficient 1,3,5-Triazines Leading to Functionalized Pyrimidines as Diels-Alder/Retro-Diels-Alder Reaction Products: Reaction Development and Mechanistic Studies

Catalytic inverse electron demand Diels-Alder (IEDDA) reactions of heterocyclic aza-dienes are rarely reported since highly reactive and electron-rich dienophiles are often found not compatible with strong acids such as Lewis acids. Herein, we disclose that TFA-catalyzed reactions of electron-deficient 1,3,5-triazines and electron-deficient aldehydes/ketones can take place. These reactions led to highly functionalized pyrimidines as products in fair to good yields. The reaction mechanism was carefully studied by the combination of experimental and computational studies. The reactions involve a cascade of stepwise inverse electron demand hetero-Diels-Alder (ihDA) reactions, followed by retro-Diels-Alder (rDA) reactions and elimination of water. An acid was required for both ihDA and rDA reactions. This mechanism was further verified by comparing the relative reactivity of aldehydes/ketones and their corresponding vinyl ethers in the current reaction system.

Organocatalytic Inverse-Electron-Demand Diels–Alder Reactions of Ketones with 1,3,5-Triazines

An organocatalytic version of the inverse-electron-demand Diels–Alder (IEDDA) reaction of 1,3,5-triazines was successfully developed. Hydrazine was used an effective organocatalyst for the direct IEDDA reaction of ketones with 1,3,5-triazines. This reaction has an expanded substrate scope relative to other 1,3,5-triazine IEDDA reactions and is also more operationally simple; thus, it is a succinct, economical, and green approach for the preparation of highly functionalized pyrimidines from readily available ketones.

Hydrazones as Productive Dienophiles in the Inverse Electron Demand Diels-Alder Reactions of 1,3,5-Triazines

Enamines, ynamines and amidines are common dienophiles for inverse electron demand Diels-Alder (IEDDA) reactions of 1,3,5-triazines, however, their wide utilization may be limited due to their poor stability to conventional purification methods such as silica gel chromatography. To address this limitation, oximes and hydrazones are envisioned as potential alternative dienophiles, even though they are primarily used as protecting groups due to their excellent stability or lack of reactivity. Through investigation of substituent effects and optimization of reaction conditions, oximes and hydrazones were developed as productive dienophiles for 1,3,5-triazine IEDDA reactions, leading to the desired IEDDA products in moderate (for oximes) to excellent (for hydrazones) yields. Hydrazones are air-stable and can be conveniently purified by conventional methods, therefore the introduction of hydrazones as productive dienophiles further expanded the scope of 1,3,5-triazine IEDDA reactions. Through investigation of substituent effects and optimization of reaction conditions, oximes and hydrazones are introduced as productive dienophiles to expand the scope of the inverse electron demand Diels-Alder (IEDDA) reactions of 1,3,5-triazines, leading to the desired IEDDA products in moderate (for oximes) to excellent (for hydrazones) yields.

INVERSE ELECTRON DEMAND DIELS-ALDER REACTIONS OF 2,4,6-TRIS(ETHOXYCARBONYL)-1,3,5-TRIAZINE AND 2,4,6-TRIS(METHYLTHIO)-1,3,5-TRIAZINE: PYRIMIDINE INTRODUCTION

A full investigation of the scope of the participation of 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine (la) and 2,4,6-tris(methylthio)-1,3,5-triazine (1b) in inverse electron demand Diels-Alder reactions suitable for the preparation of functionalized 5,6-disubstituted pyrimidines is detailed.The use of the resulting cycloadducts as immediate precursors to the parent 4,5-disubstituted pyrimidines is described.