Arenes and Heteroarenes C-H Functionalization Under Enabling Conditions: Electrochemistry, Photoelectrochemistry & Flow Technology.

C-H bond functionalization generates molecular complexity in single-step transformation. However, the activation of C-H bonds requires expensive metals or stoichiometric amounts of oxidizing/reducing species. In many cases, they often require pre-functionalization of starting molecules. Such pre-activating measures cause waste generation and their separation from the final product is also troublesome. In such a scenario, reactions activating elements generating from renewable energy resources such as electricity and light would be more efficient, green, and cost-effective. Further, incorporation of growing flow technology in chemical transformation processes will accelerate the safer accesses of valuable products. Arenes & heteroarenes are ubiquitous in pharmaceuticals, natural products, medicinal compounds, and other biologically important molecules. Herein, we discussed enabling tools and technologies used for the recent C-H bonds functionalization of arenes and heteroarenes.

Selenoneine-inspired selenohydantoins with glutathione peroxidase-like activity.

Chronic diseases such as cystic fibrosis, inflammatory bowel diseases, rheumatoid arthritis, and cardiovascular illness have been linked to a decrease in selenium levels and an increase in oxidative stress. Selenium is an essential trace element that exhibits antioxidant properties, with selenocysteine enzymes like glutathione peroxidase being particularly effective at reducing peroxides. In this study, a series of synthetic organoselenium compounds were synthesized and evaluated for their potential antioxidant activities. The new selenohydantoin molecules were inspired by selenoneine and synthesized using straightforward methods. Their antioxidant potential was evaluated and proven using classical radical scavenging and metal-reducing methods. The selenohydantoin derivatives exhibited glutathione peroxidase-like activity, reducing hydroperoxides. Theoretical calculations using Density Functional Theory (DFT) revealed the selenone isomer to be the only one occurring in solution, with selenolate as a possible tautomeric form in the presence of a basic species. Cytocompatibility assays indicated that the selenohydantoin derivatives were non-toxic to primary human aortic smooth muscle cells, paving the way for further biological evaluations of their antioxidant activity. The results suggest that selenohydantoin derivatives with trifluoro-methyl (-CF3) and chlorine (-Cl) substituents have significant activities and could be potential candidates for further biological trials. These compounds may contribute to the development of effective therapies for chronic diseases such cardiovascular diseases.

Electrohalogenation of organic compounds.

Herein, we present an overview of recent advances in the electrochemical halogenation of organic compounds. Halogen-containing compounds are essential building blocks for post-functionalization in academic research and in different industrial sectors, notably pharmaceutical companies. One of the main advantages of using electrosynthesis is its environmentally-friendly characteristics. Electrosynthesis is recognized as a methodology that can fulfill different criteria of the green chemistry concept and constitutes a promising tool in the development of new procedures in organic synthesis. In this review we target sp, sp2 and sp3 carbon fluorination, chlorination, bromination and iodination reactions using electrolysis as a redox medium. Mechanistic insights and substrate reactivity are also discussed.

Electrochemical Phosphorylation of Organic Molecules.

Organophosphorus chemistry is a broad field with multi-dimensional applications in research area of organic, biology, drug design and agrochemicals. Conventional methods have been adopted extensively to access phosphorylated compounds that rely on the use of toxic, moisture sensitive phosphorylating agents and occur in the presence of oxidants, catalysts, as well as high temperatures and harsh conditions are required for complete transformations. However, recent progress has been made for phosphorylation reactions using electricity to introduce green and sustainable synthetic procedures. These reactions can be performed at mild conditions and proceed with excellent atom economy. Herein, we targeted electrochemical phosphorylation reactions with generation of new bonds such as C(sp3 ) -P, C(sp2 ) -P, O-P, N-P, S-P and Se-P. This review is aimed to offer an overview of recent developments in the synthetic methodology to easy access of organophosphorus compounds using electrochemistry.

Electrochemical synthesis of selenyl-dihydrofurans via anodic selenofunctionalization of allyl-naphthol/phenol derivatives and their anti-Alzheimer activity.

Herein, we report an eco-friendly, electrosynthetic approach for the intramolecular oxyselenylation of allyl-naphthol/phenol derivatives. This reaction proceeds with 0.2 equiv. of nBu4NClO4 as an electrolyte and Pt working electrodes in an undivided cell, resulting in the selenyl-dihydrofurans in good to excellent yields. Furthermore, several of the synthesized products presented a high percentage of acetylcholinesterase (AChE) inhibition, highlighting their potential anti-Alzheimer activity.

SeCl2-Mediated Approach Toward Indole-Containing Polysubstituted Selenophenes.

A novel and efficient SeCl2-mediated chalcogenative cyclization strategy toward 3-selenophen-3-yl-1 H-indoles from readily available and conveniently substituted propargyl indoles is described. It entails an unprecedented selenirenium-induced 1,2-indolyl shift prompted by the electrophilic addition of SeCl2 to the triple bond of the propargyl indole, followed by cyclization through the intermediacy of a 1-seleno-1,3-diene. The reaction takes place at room temperature and shows excellent selectivity, broad substrate scope, and wide functional group tolerance.

A solvent- and metal-free synthesis of 3-chacogenyl-indoles employing DMSO/I2 as an eco-friendly catalytic oxidation system.

Herein, we describe a solvent- and metal-free method for the synthesis of 3-chalcogenyl-indoles from indoles and diorganyl dichalcogenides using an equivalent amount of DMSO as an oxidant, under catalysis by molecular iodine. This mild and eco-friendly approach allowed the preparation of a wide range of 3-selenyl- and 3-sulfenyl-indoles in good to excellent yields.

Continuous flow reactions in the preparation of active pharmaceutical ingredients and fine chemicals.

Herein, we present an overview of continuous flow chemistry, including photoflow and electroflow technologies in the preparation of active pharmaceutical ingredients (APIs) and fine chemical intermediates. Examples highlighting the benefits and challenges associated with continuous flow processes, mainly involving continuous thermal, photo- and electrochemical transformations, are drawn from the relevant literature, especially our experience and collaborations in this area, with emphasis on the synthesis and prospective scale-up.

Electrochemical reduction of 5-benzylidene thiazolidine-2,4-diones: a greener approach to the preparation of glitazone APIs.

A transition-metal free methodology for the chemoselective reduction of benzylidene thiazolidine-2,4-diones and similar heterocycles is described, allowing the preparation of a broad scope of the corresponding reduced derivatives in up to 90% yield. The protocol has a simple and safe experimental setup, in which water was employed as the hydrogen source. To further demonstrate the synthetic utility of this transformation, the antidiabetic API Pioglitazone was prepared in 81% yield. To the best of our knowledge, this is the first hydride and transition-metal free protocol for the synthesis of Pioglitazone, highlighting its potential utility as a greener alternative in both academic and industrial synthesis.

Scaled up and telescoped synthesis of propofol under continuous-flow conditions.

Herein we report a machine-assisted and scaled-up synthesis of propofol, a short-acting drug used in procedural sedation, which is extensively in demand during this COVID-19 pandemic. The continuous-flow protocol proved to be efficient, with great potential for industrial translation, reaching a production up to 71.6 g per day with process intensification (24 h-continuous experiments). We have successfully telescoped a continuous flow approach obtaining 5.74 g of propofol with productivity of 23.0 g/day (6 h-continuous experiment), proving the robustness of the method in both separated and telescoped modes. Substantial progress was also achieved for the in-line workup, which provides greater safety and less waste, also relevant for industrial application. Overall, the synthetic strategy is based on the Friedel-Crafts di-isopropylation of low-cost p-hydroxybenzoic acid, followed by a decarboxylation reaction, giving propofol in up to 84% overall yield and very low by-product formation. The continuous flow synthesis of propofol 3 is presented as a two-step protocol. The isopropylated intermediate 2 was obtained from 4-hydroxybenzoic acid (1) in up 43.8 g, 85% yield and 30 min residence time. Propofol 3 was then obtained in 71.6 g, 87% yield, and 16 min residence time. A safe and cost-competitive machine-assisted protocol is described with a process intensification demonstration (24 h experiments) and a telescoped process intensification (6 h).

Versatile Electrochemical Synthesis of Selenylbenzo[b]Furan Derivatives Through the Cyclization of 2-Alkynylphenols.

We report an electrochemical oxidative intramolecular cyclization reaction between 2-alkynylphenol derivatives and different diselenides species to generate a wide variety of substituted-benzo[b]furans. Driven by the galvanostatic electrolysis assembled in an undivided cell, it provided efficient transformation into oxidant-, base-, and metal-free conditions in an open system at room temperature. With satisfactory functional group compatibility, the products were obtained in good to excellent yields.

Concise two-step chemical synthesis of molnupiravir.

A concise synthesis of molnupiravir in a one-pot two-step approach starting from uridine is described. Formally, herein, two sets of one-pot two-reaction steps introducing simplicity for purifications and using chemically available reagents are presented. In this context, molnupiravir was obtained in up to 68% overall yield and multigram-scale. In addition, HPLC analysis showed the molnupiravir purity above 99%.

Visão das cores em escolares: avaliação de um novo teste / Color vision in school children: evaluation of a new test

Objetivos: comparar os resultados de um teste de visão de cores padrão (teste de Ishihara) com um teste criado pelos autores (teste do giz de cera) na detecção da discromatopsia congêntia. Pacientes e Métodos: foi realizado um estudo transversal com 712 crianças da rede pública (3 escolas) e privada (1 escola) de Porto Alegre, Rio Grande do Sul. Desta amostra aleatória haviam sido excluídas crianças com dificuldades na alfabetização e doenças sistêmicas e oculares reconhecidas. Foram aplicados sequêncialmente os testes de Ishihara (versão resumida de 14 pranchas) e o teste do giz de cera (desenvolvido pelos autores). Cada teste foi aplicada por examinadores diferentes e avaliados por um terceiro examinador. Resultados: o teste do giz de cera apresentou especifidade de 100 por cento (99,3-100 por cento) e sensibilidade de 38,5 por cento (15,1-67,7 por cento), quando comparado ao teste de Ishihara. A prevalência da discromatopsia congênita nesta amostra foi de 2,6 por cento nos meninos e 0,9 por cento nas meninas. Conclusões: o teste do giz de cera apresentou especifidade superior ao teste de ishihara no grupo estudado, mas sua sensibilidade não se mostrou adequada para um teste de rastreamento. Há necessidade de aperfeiçoa-lo para aumentar sua sensibilidade, isto é sua capacidade de detectar a discromatopsia congênita