Visible-Light Mediated Arbuzov-Like Reaction with Thiophenols

We hereby disclose, a visible light mediated addition of sulfenyl radicals to trialkyl phosphites to access functionalized phosphorothioates. The use of cheap and readily available Eosin Y as a photocatalyst under mild energy efficient conditions bypassing the use of external oxidants forms the chief highlight of the work. The protocol is scalable and mechanistic studies indicate that the reaction proceeds through an ionic-Arbuzov like pathway from phosphoranyl radicals.     

Aqueous Electrochemical Reduction of Carbon Dioxide and Carbon Monoxide into Methanol with Cobalt Phthalocyanine

Conversion of CO₂ into valuable molecules is a field of intensive investigation with the aim of developing scalable technologies for making fuels using renewable energy sources. While electrochemical reduction into CO and formate are approaching industrial maturity, a current challenge is obtaining more reduced products like methanol. However, literature on the matter is scarce, and even more for the use of molecular catalysts. Here, we demonstrate that cobalt phthalocyanine, a well‐known catalyst for the electrochemical conversion of CO₂ to CO, can also catalyze the reaction from CO₂ or CO to methanol in aqueous electrolytes at ambient conditions of temperature and pressure. The studies identify formaldehyde as a key intermediate and an unexpected pH effect on selectivity. This paves the way for establishing a sequential process where CO₂ is first converted to CO which is subsequently used as a reactant to produce methanol. Under ideal conditions, the reaction shows a global Faradaic efficiency of 19.5 % and chemical selectivity of 7.5 %.     

Oxyfunctionalization of the Remote C−H Bonds of Aliphatic Amines by Decatungstate Photocatalysis

Aliphatic amines, oxygenated at remote positions within the molecule, represent an important class of synthetic building blocks to which there are currently no direct means of access. Reported herein is an efficient and scalable solution that relies upon decatungstate photocatalysis under acidic conditions using either H₂O₂ or O₂ as the terminal oxidant. By using these reaction conditions a series of simple and unbiased aliphatic amine starting materials can be oxidized to value‐added ketone products. Lastly, NMR spectroscopy using in situ LED‐irradiated samples was utilized to monitor the kinetics of the reaction, thus enabling direct translation of the reaction into flow.     

Low‐Temperature,Rapid Copolymerization of Acrylic Acid and Sodium Acrylate in Water

Regulating the aqueous polymerization of acrylic acid (AA) is a major opportunity for future materials design, requiring the development of scalable, industry‐oriented procedures that afford modest molar mass and dispersity control without long reaction times and environmentally demanding conditions. To address these challenges, this report presents the rapid copolymerization of aqueous mixtures of AA and sodium acrylate using an inexpensive and scalable protocol based on alkyl iodides/sodium iodide as mediators in water. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1414–1419     

Mechanochemical Approach for Air-Tolerant and Extremely Fast Lithium-Based Birch Reductions in Minutes

Birch reduction has been widely used in organic synthesis for over half a century as a powerful method to dearomatize arenes into 1,4-cyclohexadiene derivatives. However, the conventional Birch reduction reaction using liquid ammonia requires laborious procedures to ensure inert conditions and low temperatures. Although several ammonia-free modifications have been reported, the development of an operationally simple, efficient, and scalable protocol remains a challenge. Herein, we report an ammonia-free lithium-based Birch reduction in air without special operating conditions using a ball-milling technique. This method is characterized by its operational simplicity and an extremely short reaction time (within 1 min), probably owing to the in situ mechanical activation of lithium metal, broad substrate scope, and no requirement for dry bulk solvents. The potential of our flash Birch reaction is also demonstrated by the efficient reduction of bioactive target molecules and gram-scale synthesis.     

A fast low-pressure transport route to large black phosphorus single crystals

Black phosphorus, a promising candidate for lithium battery electrodes, can be prepared by a low-pressure transport reaction route representing the first effective and scalable access to this element modification. Crystal sizes larger than 1 cm were obtained at low-pressure conditions in silica ampoules. X-ray phase analyses, EDX, ICP-MS and optical microscopy were applied to characterize the resulting black phosphorus. The present method drastically improves the traditional preparation ways like mercury catalysis, bismuth-flux or high-pressure techniques and represents an easy, non-toxic, fast and highly efficient method to achieve black phosphorus. In contrast to a previously reported low-pressure route the present transport reaction allows an up-scaling to higher masses of starting materials, a larger black phosphorus yield and faster reaction time under retention of the high product crystallinity.     

A General Protocol for Robust Sonogashira Reactions in Micellar Medium

A robust and general protocol for a sustainable copper‐free Sonogashira cross coupling under micellar aqueous reaction conditions with high turnover was developed. By using the commercially available catalyst CataCXium A Pd G3 and THF as co‐solvent, various alkyne substrates were efficiently cross‐coupled with a broad range of aryl halides, providing improved yields and low catalyst loadings. The reaction parameters were optimized to render the process operationally simple, robust and scalable. The method gives access to alkynylated arenes, heterocyclic compounds, and monofunctionalized products from dihalogenated substrates with an improved selectivity achieved by the micellar aqueous reaction conditions.     

Decatungstate-Photocatalyzed Dearomative Hydroacylation of Indoles: Direct Synthesis of 2-Acylindolines

We report herein a convenient and scalable dearomative hydroacylation reaction of indoles. Employing readily available aldehydes as the acyl source and TBADT as an inexpensive direct HAT photocatalyst, a variety of indoles derivatives were converted into synthetically interesting 2-acylindolines in good to excellent yields as well as great diastereoselectivity under mild conditions. An asymmetric version of the reaction was successfully developed and an experimental mechanistic investigation was carried out in order to gain further insights on the assumed reaction pathway.     

Selective ortho methylation of nitroheteroaryls by vicarious nucleophilic substitution

An efficient and scalable three-step one-pot approach to 6-methyl-5-nitroisoquinoline (1) from inexpensive 5-nitroisoquinoline, utilizing the vicarious nucleophilic substitution (VNS) as a key step, is described. The optimized reaction conditions can be applied to a limited number of other aromatic and heteroaromatic nitro compounds. Attempts to understand the observed selectivity in the VNS step led to the discovery of two new reaction pathways under VNS conditions, one leading to an isoxazole and the other resulting in the formal cyclopropanation of an aromatic nitro compound.     

Synthesis of liquid crystals using Suzuki–Miyaura coupling reactions using mesoporous,ligand-free Pd/Si3N4 catalysts in aqueous media

We report a ligand-free Pd/Si₃N₄ catalysed Suzuki–Miyaura aryl–aryl cross-coupling reaction using mixtures of water-miscible solvents, such as dimethoxyethane, ethanol and isopropanol with water and several bases, such as sodium carbonate and potassium phosphate. The reaction time and catalyst concentration were optimised and the heterogeneous nature of the reaction was investigated. The optimised reaction conditions were used to synthesise a standard liquid crystal using environmentally friendly solvents and a Pd/Si₃N₄ catalyst. This reaction is scalable to produce larger quantities.     

Chemoselective Schmidt reaction mediated by triflic acid: selective synthesis of nitriles from aldehydes

An excellent utility of Schmidt reaction of aldehydes to access corresponding nitriles in an instantaneous reaction is demonstrated. The reaction of aldehydes with NaN(3) and TfOH furnishes the corresponding nitriles in near quantitative yields and tolerates a variety of electron-withdrawing and electron-donating substituents on the substrates. Formanilides, a common side product in Schmidt reaction, is not observed in this reaction. Besides these advantages, the salient feature of this reaction is that it exhibits a remarkable chemoselectivity, as acid and ketone functionalities are well tolerated under the reaction conditions. The reaction is easily scalable, high yielding, and nearly instantaneous.     

Direct Dehydroxytrifluoromethoxylation of Alcohols

The first example of a direct dehydroxytrifluoromethoxylation of alcohols has been developed. This method generated an alkyl fluoroformate in situ from alcohols, followed by nucleophilic trifluoromethoxylation with trifluoromethyl arylsulfonate (TFMS) as the trifluoromethoxylation reagent. The reaction is operationally simple and scalable, and it proceeds under mild reaction conditions to provide access to a wide range of trifluoromethyl ethers from alcohols. In addition, this method is suitable for the late‐stage trifluoromethoxylation of complex small molecules.     

Selective Synthesis of Z‐Cinnamyl Ethers and Cinnamyl Alcohols through Visible Light‐Promoted Photocatalytic E to Z Isomerization

A photocatalytic E to Z isomerization of alkenes using an iridium photosensitizer under mild reaction conditions is disclosed. This method provides scalable and efficient access to Z‐cinnamyl ether and allylic alcohol derivatives in high yields with excellent stereoselectivity. Importantly, this method also provides a powerful strategy for the selective synthesis of Z‐magnolol and honokiol derivatives possessing potential biological activity.     

Mild Deoxygenation of Aromatic Ketones and Aldehydes over Pd/C Using Polymethylhydrosiloxane as the Reducing Agent

Herein, a practical and mild method for the deoxygenation of a wide range of benzylic aldehydes and ketones is described, which utilizes heterogeneous Pd/C as the catalyst together with the green hydride source, polymethylhydrosiloxane. The developed catalytic protocol is scalable and robust, as exemplified by the deoxygenation of ethyl vanillin, which was performed on a 30 mmol scale in an open‐to‐air setup using only 0.085 mol % Pd/C catalyst to furnish the corresponding deoxygenated product in 93 % yield within 3 hours at room temperature. Furthermore, the Pd/C catalyst was shown to be recyclable up to 6 times without any observable decrease in efficiency and it exhibited low metal leaching under the reaction conditions.     

Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow

Selective N-monomethylation of anilines has been achieved under continuous flow conditions using dimethyl carbonate as a green methylating agent in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene. Our methodology takes advantage of the expanded process windows available in the continuous flow regime to safely induce monomethylation in superheated solvents at high pressure. We propose selective N-monomethylation is achieved via an in situ protection-deprotection pathway, which is supported by the observed reactivities of several putative reaction intermediates. The robust and scalable method was applicable to a broad range of primary aniline substrates including ortho-, meta-, and para-substituted anilines, as well as electron-rich and electron-deficient anilines. The synthetic precursor of diazepam, 5-chloro-2-(methylamino)benzophenone, was selectively synthesized under our optimized conditions.     

Hypervalent Iodine(III)‐Mediated Oxidative Fluorination of Alkylsilanes by Fluoride Ions

The first example of a hypervalent iodine(III)‐mediated oxidative fluorination of alkylsilanes by fluoride ions without the use of transition metals is demonstrated. This reaction is operationally simple, scalable, and proceeds under mild reaction conditions. Mechanistic studies suggest the involvement of a single‐electron transfer resulting from the interaction of an organopentafluorosilicate and aryliodonium difluoride, which were generated in situ from the corresponding alkylsilane and iodosobenzene, respectively, in the presence of fluoride ions.     

Concise Large-Scale Synthesis of Tomatidine,A Potent Antibiotic Natural Product

Tomatidine has recently generated a lot of interest amongst the pharmacology, medicine, and biology fields of study, especially for its newfound activity as an antibiotic agent capable of targeting multiple strains of bacteria. In the light of its low natural abundance and high cost, an efficient and scalable multi-gram synthesis of tomatidine has been developed. This synthesis uses a Suzuki–Miyaura-type coupling reaction as a key step to graft an enantiopure F-ring side chain to the steroidal scaffold of the natural product, which was accessible from low-cost and commercially available diosgenin. A Lewis acid-mediated spiroketal opening followed by an azide substitution and reduction sequence is employed to generate the spiroaminoketal motif of the natural product. Overall, this synthesis produced 5.2 g in a single pass in 15 total steps and 15.2% yield using a methodology that is atom economical, scalable, and requires no flash chromatography purifications.     

Continuous Flow Magnesiation of Functionalized Heterocycles and Acrylates with TMPMgCl⋅LiCl

A flow procedure for the metalation of functionalized heterocycles (pyridines, pyrimidines, thiophenes, and thiazoles) and various acrylates using the strong, non‐nucleophilic base TMPMgCl?LiCl is reported. The flow conditions allow the magnesiations to be performed under more convenient conditions than the comparable batch reactions, which often require cryogenic temperatures and long reaction times. Moreover, the flow reactions are directly scalable without further optimization. Metalation under flow conditions also allows magnesiations that did not produce the desired products under batch conditions, such as the magnesiation of sensitive acrylic derivatives. The magnesiated species are subsequently quenched with various electrophiles, thereby introducing a broad range of functionalities.     

Liquid‐Phase Synthesis of 2′‐Methyl‐RNA on a Homostar Support through Organic‐Solvent Nanofiltration

Due to the discovery of RNAi, oligonucleotides (oligos) have re‐emerged as a major pharmaceutical target that may soon be required in ton quantities. However, it is questionable whether solid‐phase oligo synthesis (SPOS) methods can provide a scalable synthesis. Liquid‐phase oligo synthesis (LPOS) is intrinsically scalable and amenable to standard industrial batch synthesis techniques. However, most reported LPOS strategies rely upon at least one precipitation per chain extension cycle to separate the growing oligonucleotide from reaction debris. Precipitation can be difficult to develop and control on an industrial scale and, because many precipitations would be required to prepare a therapeutic oligonucleotide, we contend that this approach is not viable for large‐scale industrial preparation. We are developing an LPOS synthetic strategy for 2′‐methyl RNA phosphorothioate that is more amenable to standard batch production techniques, using organic solvent nanofiltration (OSN) as the critical scalable separation technology. We report the first LPOS‐OSN preparation of a 2′‐Me RNA phosphorothioate 9‐mer, using commercial phosphoramidite monomers, and monitoring all reactions by HPLC, ³¹P NMR spectroscopy and MS.     

Electrospun copper oxide nanoparticles as an efficient heterogeneous catalyst for N-arylation of indole

The N-arylation of indoles with a variety of aryl bromides is reported using copper oxide nanoparticles as a heterogeneous catalyst. These copper oxide nanoparticles, which were produced in a novel, facile, and scalable fashion via an electrospinning technique, resulted in an excellent product yield under mild conditions. Moreover, the catalyst was easily recovered and reused several times without significant loss of activity.