Gold catalyzed synthesis of tetrahydropyrimidines and octahydroquinazolines under ball milling conditions and evaluation of anticonvulsant potency

Abstract

A fast, mechanochemical and solvent-free synthesis of substituted tetrahydropyrimidines and octahydroquinazolines under Au(III)-catalysis has been developed. The practical feasibility, eco-friendliness and operational simplicity of this chemistry is exemplified by ball milling three components such as formaldehyde, amines and 2-butynedioates/dimedone in a shaker mill for as little as five minutes, thus avoiding the requirement of undesirable solvents and long reaction times. Moreover, this protocol furnishes the target compounds in high yields without any side products and in some cases offers products with excellent regioselectivity. Out of the 26 compounds screened for anticonvulsant potency, 11 compounds exhibited comparable activity against a standard drug.

Sunlight‐Assisted Photocatalytic Sustainable Synthesis of 1,4‐Disubstituted 1,2,3‐Triazoles and Benzimidazoles Using TiO2−Cu2(OH)PO4 Under Solvent‐Free Condition

“…Based on our previous research on sustainable synthesis, [46][47][48][49] we initiated our investigation to develop an efficient and ecobenign route for construction of 1,4-disubstituted-1,2,3-triazoles from phenyl acetylene and benzyl azide as model substrates. It is obvious that such transformation could happen in an effective manner, selection of catalyst is a crucial part.…”

Cycloisomerization of π‐Coupled Heteroatom Nucleophiles by Gold Catalysis: En Route to Regiochemically Defined Heterocycles

“…In this chemistry, the partial depletion of electron density at the β‐carbon of Au‐activated alkyne 348 paves way for the selective generation of enaminium intermediate 349 suitable for the regioselective synthesis of 6‐substituted tetrahydropyrimidines 350 over their 5‐substituted counterpart 351 (Scheme 68). [63] Importantly, these compounds exhibited comparable in vivo anticonvulsant potency with reference to the standard drug, phenytoin.…”

“…This Au(I)‐catalyzed process is thought to proceed through a sequential imine formation‐cationic π‐cyclization‐alkyne activation‐intramolecular hydroamination, in which the last step proceeds exclusively through a 6‐ endo ‐ dig selective cycloisomerization thereby avoids the formation of other potential regioisomeric products [405] . As a continuation of transition metal catalyzed multicomponent reactions by unconventional methods, [63,113,115,117–120,123,124] my team recently disclosed a ball‐milling assisted multicomponent reaction between aniline 345 , formaldehyde 346 and methyl/phenyl propiolates 347 by NaAuCl 4 .2H 2 O. In this chemistry, the partial depletion of electron density at the β‐carbon of Au‐activated alkyne 348 paves way for the selective generation of enaminium intermediate 349 suitable for the regioselective synthesis of 6‐substituted tetrahydropyrimidines 350 over their 5‐substituted counterpart 351 (Scheme 68).…”

“…In the aforementioned context coupled with the research interest on gold catalysis, [62–79] I have recently reviewed several gold catalyzed regioselective reactions such as intermolecular addition, [80] cycloaddition, [81] molecular rearrangement [82] and C‐H bond functionalization [83] as well as the contributing factors for selectivity of those reactions. Likewise, the focus of this review is to overview the gold‐catalyzed regioselective cycloisomerization of different π‐molecules owning a nucleophilic handle.…”

Synthesis and Photophysical Properties of 1,4-Dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-ones, and Derivatives Containing Tethered 1,2,3-Triazoles, from 4-Aminocoumarins

“…A quite similar mechanism could account for analogous transformations, such as the gold-catalyzed mechanochemical synthesis of tetrahydropyrimidines and octahydroquinazolines from enaminone derivatives of 1,3-dicarbonyl precursors. 23 The photophysical properties of the synthesized heterocycles were next examined, commencing with an analysis of their UV spectra ( Figure 2), measured between 250 and 400 nm, on 10 -4 M DMSO solutions. The coumarin ring oxygen atom has an sp 2 hybridization, being part of the -sys-…”