Efficient Synthesis of a Series of Novel Octahydroquinazoline-5-ones via a Simple on-Water Urea-Catalyzed Chemoselective Five-Component Reaction

Abstract

Multicomponent reactions (MCRs) have become a powerful tool for drug discovery and development owing to their advantages of fast and efficient construction of a large library of products with complexity and diversity. However, conventional MCRs usually proceed in environmentally unfriendly organic solvents rather than in water, a green solvent used by nature for biological chemistry. Herein, a simple and efficient on-water urea-catalyzed chemoselective five-component reaction (5CR) has been developed for the synthesis of a series of novel octahydroquinazoline-5-ones (6), the derivatives of quinazolinones possessing diverse biological activities. The molecular structure of 6{1,1,12} has been confirmed by single-crystal X-ray diffraction. The 5CR can proceed at room temperature under normal atmospheric pressure in good yields and afford a large library of octahydroquinazoline-5-ones with various aromatic and aliphatic substituents at N-1, C-2, and N-3. In addition, a green method has been developed for the synthesis of enaminones, important intermediates in the 5CR and in synthetic chemistry.

Metal-Free Multicomponent Tandem Polymerizations of Alkynes, Amines, and Formaldehyde toward Structure- and Sequence-Controlled Luminescent Polyheterocycles

“…50 The proposed mechanism is shown in Figure 1B: in the presence of acetic acid, 1a first reacts with aniline 2 through a hydroamination reaction to afford intermediate A, and another half of 2 reacts with formaldehyde 3 to form Schiff base B at the same time. Intermediates A and B then react together through an aza-ene type reaction to furnish intermediate C. 51,52 In the presence of excess amount of 3, C undergoes a nucleophilic addition with 3 to afford intermediate D, followed by a cyclization reaction to produce 4a; without an excess amount of 3 in the system, C will directly undergo an amidation cyclization at elevated temperature to generate five-member ring-containing intermediate E, which is then converted to 5a through an imine− enamine tautomerization.…”

Catalyst‐Free Multicomponent Tandem Polymerizations of Aliphatic Amines, Activated Alkyne, and Formaldehyde toward Poly(tetrahydropyrimidine)s

“…[40,41] However, only aromatic amines were applicable for the acetic acid-assisted MCTP, and the activated internal alkyne monomer with hydrophilic 2-(2-methoxyethoxy)ethyl groups was required to improve the solubility of polymer product in methanol. [42,43] Aliphatic amines with high nucleophilicity and strong alkalinity might form salts with acetic acid and precipitate out from the reaction solution to stop polymerization, or undergo other reactions to produce undesired sideproduct, and hence were difficult to produce polymeric product with well-defined regular strucure and high molecular weight. [18,33] Acid-free condition was hence crucial for the corresponding polymerization of aliphatic amines.…”

Discovery of Dihydropyrrol-2-ones as Novel G0/G1-Phase Arresting Agents Inducing Apoptosis

“…Multicomponent reaction (MCR) has advantages of atom economy, high efficiency, and fast building structural diversity and complexity of compound libraries − and becomes a powerful tool in drug synthesis and discovery. ,, Considering that heterocycles have diverse bioactivities, we are interested in their MCR synthesis − and bioactivities . Pyrrolidone rings are important heterocycles with a wide range of pharmacological activities, such as G0/G1-phase arresting agents VI .…”