Visible-light-driven metal-free C-H functionalization: access to new bioactive tetrahydroisoquinoline-butenolide hybrids via domino amine oxidation/vinylogous mannich reaction

An efficient metal-free visible-light-driven two-step domino reaction towards new bioactive tetrahydroisoquinoline-butenolide hybrid compounds was developed for the first time. The combination of fluorescein as photosensitizer and thiourea as an additive was found to be the most effective way to promote an aerobic amine oxidation/vinylogous Mannich domino reaction sequence with yields up to 97% for a broad substrate scope. Both experimental and computational evidence supported the crucial role of singlet oxygen in the developed C H functionalization reaction. Furthermore, the data suggest that thiourea is essential due to its ability to act as an electron-transfer mediator and/or scavenger of reactive oxygen species. In addition, in vitro studies of tetrahydroisoquinoline-butenolide hybrid compounds demonstrated their high antischistosomal and anti-cancer activities

Lewis Acids and Heteropoly Acids in the Synthesis of Organic Peroxides

Organic peroxides are an important class of compounds for organic synthesis, pharmacological chemistry, materials science, and the polymer industry. Here, for the first time, we summarize the main achievements in the synthesis of organic peroxides by the action of Lewis acids and heteropoly acids. This review consists of three parts: (1) metal-based Lewis acids in the synthesis of organic peroxides; (2) the synthesis of organic peroxides promoted by non-metal-based Lewis acids; and (3) the application of heteropoly acids in the synthesis of organic peroxides. The information covered in this review will be useful for specialists in the field of organic synthesis, reactions and processes of oxygen-containing compounds, catalysis, pharmaceuticals, and materials engineering

Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions

Most of the known approved drugs comprise functionalized heterocyclic compounds as subunits. Among them, non-fluorescent quinazolines with four different substitution patterns are found in a variety of clinically used pharmaceuticals, while 4,5,7,8-substituted quinazolines and those displaying their own specific fluorescence, favourable for cellular uptake visualization, have not been described so far. Here we report the development of a one-pot synthetic strategy to access these 4,5,7,8-substituted quinazolines, which are fluorescent and feature strong antiviral properties (EC$_{50}$ down to 0.6±0.1 μM) against human cytomegalovirus (HCMV). Merging multistep domino processes in one-pot under fully metal-free conditions leads to sustainable, maximum efficient and high-yielding organic synthesis. Furthermore, generation of artesunic acid–quinazoline hybrids and their application against HCMV (EC$_{50}$ down to 0.1±0.0 μM) is demonstrated. Fluorescence of new antiviral hybrids and quinazolines has potential applications in molecular imaging in drug development and mechanistic studies, avoiding requirement of linkage to external fluorescent markers

Speeding up Viedma Deracemization through Water catalyzed and Reactant Self‐catalyzed Racemization

Viedma deracemization is based on solution phase racemization, dissolution of racemic or scalemic conglomerates and crystal growth through autocatalytic cluster formation. With rate limiting racemization, its acceleration by appropriate catalysts may result in speeding up deracemization. A conglomerate‐forming chiral compound may principally racemize directly, or via reverse of its formation reaction. For a hydrazine derivative, we investigated available racemization pathways in presence of pyrrolidine or thiourea amine as base catalysts: via Mannich or aza‐Michael reaction steps and their reverse, or by enolization. Racemization by enolization was computationally found to dominate, both under water‐free conditions and in presence of water, involving a multitude of different pathways. Faster racemization in presence of water resulted indeed in more rapid deracemization, when the base was pyrrolidine. Under water‐free conditions, the role of water as enolization catalyst is assumed by chiral hydrazine itself – in autocatalytic racemization and in which both reactant and product are catalysts

Speeding up Viedma Deracemization through Water‐catalyzed and Reactant Self‐catalyzed Racemization

Viedma deracemization is based on solution phase racemization, dissolution of racemic or scalemic conglomerates and crystal growth through autocatalytic cluster formation. With rate limiting racemization, its acceleration by appropriate catalysts may result in speeding up deracemization. A conglomerate‐forming chiral compound may principally racemize directly, or via reverse of its formation reaction. For a hydrazine derivative, we investigated available racemization pathways in presence of pyrrolidine or thiourea amine as base catalysts: via Mannich or aza‐Michael reaction steps and their reverse, or by enolization. Racemization by enolization was computationally found to dominate, both under water‐free conditions and in presence of water, involving a multitude of different pathways. Faster racemization in presence of water resulted indeed in more rapid deracemization, when the base was pyrrolidine. Under water‐free conditions, the role of water as enolization catalyst is assumed by chiral hydrazine itself – in autocatalytic racemization and in which both reactant and product are catalysts

Speeding up Viedma Deracemization through Water-catalyzed and Reactant Self-catalyzed Racemization

Viedma deracemization is based on solution phase racemization, dissolution of racemic or scalemic conglomerates and crystal growth through autocatalytic cluster formation. With rate limiting racemization, its acceleration by appropriate catalysts may result in speeding up deracemization. A conglomerate-forming chiral compound may principally racemize directly, or via reverse of its formation reaction. For a hydrazine derivative, we investigated available racemization pathways in presence of pyrrolidine or thiourea amine as base catalysts: via Mannich or aza-Michael reaction steps and their reverse, or by enolization. Racemization by enolization was computationally found to dominate, both under water-free conditions and in presence of water, involving a multitude of different pathways. Faster racemization in presence of water resulted indeed in more rapid deracemization, when the base was pyrrolidine. Under water-free conditions, the role of water as enolization catalyst is assumed by chiral hydrazine itself – in autocatalytic racemization and in which both reactant and product are catalysts

Photoracemization-Based Viedma Ripening of a BINOL Derivative

Viedma ripening is a deracemization process that has been used to deracemize a range of chiral molecules. The method has two major requirements: the compound needs to crystallize as a conglomerate and it needs to be racemizable under the crystallization conditions. Although conglomerate formation can be induced in different ways, the number of racemization methods is still rather limited. To extend the scope of Viedma ripening, in the present research we applied UV-light-induced racemization in a Viedma ripening process, and report the successful deracemization of a BINOL derivative crystallizing as a conglomerate. Irradiation by UV light activates the target compound in combination with an organic base, required to promote the excited-state proton transfer (ESPT), leading thereafter to racemization. This offers a new tool towards the development of Viedma ripening processes, by using a cheap and “green” catalytic source like UV light to racemize suitable chiral compounds