Deep Eutectic Solvents as Non-innocent and Environmentally Responsible Reaction Media for the Divergent Synthesis of Valuable N-Heterocycles from Azides

The increasing demand for environmentally friendly chemical processes has led to the development of more efficient and profitable strategies for the preparation of heterocyclic compounds with a low ecological footprint. Over the last few years, our group focused on the sustainable synthesis of functionalized heterocycles such as tetrahydrofuran, thiophene, pyridyl and indolyl derivatives in the so-called Deep Eutectic Solvents (DESs), which represent an emerging generation of bio-based solvents. In this communication, we report the divergent synthesis of a collection of valuable N-heterocycles like 2,5-diarylpyrazines, 2-aroylimidazoles, 2,4-diaroyl-6-arylpyrimidines, and 1,2,3-triazoles, which are important scaffolds in many biologically active and pharmaceutically relevant molecules,6 simply starting from substituted azides as substrates, and using DESs as both biodegradable solvents and effective catalysts, under mild conditions

2-Diphenylphosphinomethyl-3-methylpyrazine

The lateral metalation-electrophilic trapping reaction of alkyl-substituted pyrazines has always been challenging and poorly regioselective, with the corresponding derivatives often being isolated in moderate yield. In this contribution, we first report on the preparation of an unsymmetrically-substituted pyrazine, that is 2-diphenylphosphinomethyl-3-methylpyrazine, by subjecting to metalation with n-BuLi the commercially available 2,3-dimethylpyrazine, followed by interception of the putative lithiated benzyl-type intermediate with Ph2PCl. Such a functionalization has been successfully carried out in the absence of additional ligands, working either in THF at −78 °C or in a more environmentally friendly solvent like cyclopentyl methyl ether at 0 °C, with the desired phosphine derivative being isolated in 70–85% yield. The newly synthesized adduct has been fully characterized by means of multinuclear magnetic resonance spectroscopic techniques, and also by preparing a selenium derivative, which furnished single crystals that were suitable for X-ray analysis

Severe asthma features in children: A case–control online survey

Background: Very few studies have explored the distinguishing features of severe asthma in childhood in Europe, and only one study was conducted in Southern Europe. The aim of this study was to provide a detailed characterization of children with severe asthma treated in specialized pediatric asthma centers across Italy. Methods: We conducted a web-based data collection of family, environmental, clinical and laboratory characteristics of 41 patients aged 6–17 years with severe asthma, defined according to the recent guidelines of the European Respiratory Society and the American Thoracic Society, and 78 age-matched peers with non-severe persistent asthma. The patients have been enrolled from 16 hospital-based pediatric pulmonology and allergy centers in Northern, Central, and Southern Italy. Logistic regression analysis assessed the relationship between patients’ characteristics and severe asthma or non-severe persistent asthma. Results: Features independently and significantly associated with severe asthma included lifetime sensitization to food allergens [Odds ratio (OR), 4.73; 95% Confidence Interval (CI), 1.21–18.53; p = 0.03], lifetime hospitalization for asthma (OR, 3.71; 95% CI, 1.11–12.33; p = 0.03), emergency-department visits for asthma during the past year (OR = 11.98; 95% CI, 2.70–53.11; p = 0.001), and symptoms triggered by physical activity (OR = 12.78; 95% CI, 2.66–61.40; p = 0.001). Quality-of-life score was worse in patients with severe asthma than in subjects with non-severe persistent asthma (5.9 versus 6.6, p = 0.005). Self-perception of wellbeing was compromised in more than 40% of patients in both groups. Children with severe asthma had lower spirometric z scores than non-severe asthmatic peers (all p < 0.001), although 56% of them had a normal forced expiratory volume in 1 s. No differences were found between the two groups for parental education, home environment, patients’ comorbidities, adherence to therapy, exhaled nitric oxide values, and serum eosinophils and IgE. Conclusions: As expected, children with severe asthma had more severe clinical course and worse lung function than peers with non-severe persistent asthma. Unlike previous reports, we found greater sensitization to food allergens and similar environmental and personal characteristics in patients with severe asthma compared to those with non-severe persistent asthma. Psychological aspects are compromised in a large number of cases and deserve further investigation

Inter-society consensus for the use of inhaled corticosteroids in infants, children and adolescents with airway diseases

Background: In 2019, a multidisciplinary panel of experts from eight Italian scientific paediatric societies developed a consensus document for the use of inhaled corticosteroids in the management and prevention of the most common paediatric airways disorders. The aim is to provide healthcare providers with a multidisciplinary document including indications useful in the clinical practice. The consensus document was intended to be addressed to paediatricians who work in the Paediatric Divisions, the Primary Care Services and the Emergency Departments, as well as to Residents or PhD students, paediatric nurses and specialists or consultants in paediatric pulmonology, allergy, infectious diseases, and ear, nose, and throat medicine. Methods: Clinical questions identifying Population, Intervention(s), Comparison and Outcome(s) were addressed by methodologists and a general agreement on the topics and the strength of the recommendations (according to the GRADE system) was obtained following the Delphi method. The literature selection included secondary sources such as evidence-based guidelines and systematic reviews and was integrated with primary studies subsequently published. Results: The expert panel provided a number of recommendations on the use of inhaled corticosteroids in preschool wheezing, bronchial asthma, allergic and non-allergic rhinitis, acute and chronic rhinosinusitis, adenoid hypertrophy, laryngitis and laryngospasm. Conclusions: We provided a multidisciplinary update on the current recommendations for the management and prevention of the most common paediatric airways disorders requiring inhaled corticosteroids, in order to share useful indications, identify gaps in knowledge and drive future research

Introducing Deep Eutectic Solvents in Enolate Chemistry: Synthesis of 1-Arylpropan-2-ones under Aerobic Conditions

Alkoxide-mediated enolization of 1-arylpropan-2-ones and their fluorinated derivatives, followed by α-functionalization with nucleophilic addition and substitution reactions, has been accomplished in the enviromentally friendly eutectic mixture choline chloride/urea, under aerobic conditions. The usefulness of this new protocol has also been exemplified through the synthesis of a small selection of building-block like molecules through Pd-catalyzed α-arylation reaction

Solvent-catalyzed umpolung carbon-sulfur bond-forming reactions by nucleophilic addition of thiolate and sulfinate ions to in situ-derived nitrosoalkenes in deep eutectic solvents

The low transition temperature mixture formed by lactic acid and choline chloride proved to be effective for an umpolung carbon. sulfur bond formation at the α-position of α-chloro oximes. Aliphatic, aromatic, and heteroaromatic thiolate and sulfinate ions can be smoothly added to in situ-derived nitrosoalkenes affording the corresponding sulfenylated or sulfonylated adducts, respectively, in a very good yield (up to &gt;98%). This methodology offers the advantage of working at room temperature and under air in biodegradable and cost-effective reaction mixtures, which can be used both as solvents and catalysts (20 mol %), thereby avoiding the use of anhydrous, hazardous volatile organic solvents and an inert atmosphere

Nucleophilic Addition of Thiolate and Sulfinate Ions to in Situ-derived Nitrosoalkenes in Low Transition Temperature Mixtures

The environmental impact associated with chemical synthesis has recently posed severe and compelling demands for sustainable chemistry, and the development of cost-effective and environmentally benign reactions systems in place of volatile and harsh organic compounds represents an active field of research. A new generation of solvents emerged in the last decade as promising green media are: the Low-Transition-Temperature Mixtures (LTTMs). They can be prepared by mixing natural high-melting-point starting materials, which form a liquid by hydrogen-bond interactions.[1] In this communication we will discuss the potential benefits of using environmentally friendly, bio-based LTTMs (e.g. L-lactic acid/Choline Chloride) in direct nucleophilic addition of thiolates and sulfinates ions to in situ-derived nitrosoalkenes affording the corresponding sulfenylated or sulfonylated adducts respectively, in very good yield (up to >98%, Scheme 1).[2] This methology offers the advantage of working at room temperature and under air in biodegradable and cost-effective reaction mixtures

Advances in Deep Eutectic Solvents and Water: Applications in Metal- and Biocatalyzed Processes, in the Synthesis of APIs, and other Biologically Active Compounds

Owing to a growing awareness towards environmental impact, the search for “greener”, safer, and cost-effective solvents able to replace petroleum-derived solvents has never been greater today. In this context, the use of environmentally responsible solvents like water and the so-called Deep Eutectic Solvents (DESs), constructed from bio-based compounds, has recently experienced important growth in several fields of sciences. This short review highlights the key features of the chemistry of water and (hydrated) DESs when applied to metal- and biocatalyzed transformations as well as to the synthesis of Active Pharmaceutical Ingredients (APIs) and other biologically relevant compounds by providing, through discussion of all relevant literature over the past five years, a comparison of the outcomes of the reactions when carried out in one or the other solvent

Synthesis of thiophenes in a deep eutectic solvent: heterocyclodehydration and iodocyclization of 1-mercapto-3-yn-2-ols in a choline chloride/glycerol medium

The heterocyclodehydration and iodocyclization of readily available 1-mercapto-3-yn-2-ols has been performed in a deep eutectic solvent (DES), that is, ChCl/Gly (1:2 molar ratio; ChCl=choline chloride, Gly=glycerol), as a non-conventional green solvent. The processes, carried out at 50&nbsp;°C for 8&nbsp;h in the presence of the PdI2/KI catalytic system or at room temperature for 5&nbsp;h with 1.2&nbsp;equiv of I2, led to the formation of the corresponding thiophenes and 3-iodothiophenes in good to high yields. The DES/catalytic system could be easily recycled several times without appreciable loss of activity, after extraction of the thiophene product with hexane or Et2O. The alkynylation reaction of α-mercapto ketones, necessary for the preparation of the alkynylthiol substrates, was also successfully accomplished in the above protic eutectic mixture competitively with protonolysis

Synthesis of Tetrahydrofurans via chemoselective addition of organolithium and grignard reagents to γ-chloroketones in deep eutectic solvents and water

Synthesis of Tetrahydrofurans via chemoselective addition of organolithium and grignard reagents to γ-chloroketones in deep eutectic solvents and wate