Trifluorosulfonylation Cascade in Allenols: Stereocontrolled Synthesis of Bis(triflyl)enones

Trifluorosulfonylation Cascade in Allenols: Stereocontrolled Synthesis of Bis(triflyl)enones

Strike that, reverse it ! This study provided the first example of reversal of the native regioselectivity in the reaction of allenols with electrophiles as a novel functionalization reaction of the allene scaffold (see scheme).

Abstract

Herein, we report investigations embodying the first example of reversal of the native regioselectivity in the reaction of allenols with electrophiles. The effortlessness of C−C bond formation, mild reaction conditions, neither catalysts nor light irradiation, and exquisite selectivity, both in terms of functional‐group tolerance and chemo‐, site‐, and stereo‐selectivity, converts this trifluorosulfonylation‐rearrangement sequence into an appealing protocol for the preparation of novel functionalized enones. The synthetic utility of this method has been validated by the conversion of the initially prepared bis(triflyl)enones into a variety of bis(triflyl)‐functionalized molecules such as 1,3‐dienes, allylic alcohols, pyrroles, pyrazoles, and chromenes. Besides, DFT calculations have provided a reliable understanding of observed selectivity.

Wiley: Chemistry – A European Journal: Table of Contents
Authors: Carlos Lázaro‐MillaMilla, Jon Macicior, Hikaru Yanai, Pedro Almendros
doi.org/10.1002/chem.202001236

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Fused bicyclic 1,2,4‐triazoles with one extra sulfur atom: Synthesis, properties, and biological activity

Fused bicyclic 1,2,4‐triazoles with one extra sulfur atom: Synthesis, properties, and biological activity

Abstract

Fused heterocyclic systems with 1,2,4‐triazole scaffold arouse great interest from researchers in the branch of heterocyclic and medical chemistry because of their wide biological activities as they are considered as fungicidal, antimicrobial, analgesic, bronchodilators, antioxidant, anti‐inflammatory agents, and they are G‐quadruple stabilizers; the molecular docking data for coumarin‐containing 1,2,4‐triazoles indicate their ability to act as a urease inhibitor. Therefore, the present review aims to investigate new trends in the chemistry of heterocycles incorporating thiazolo[3,2‐b][1,2,4]triazoles, thiazolo[2,3‐c][1,2,4]triazoles, thiazino[5,1‐b][1,2,4]triazoles, thiazino[3,4‐b][1,2,4]triazoles, triazolothiazepines, and their biological characteristics. The main sections discuss: (a) the synthetic routes to the production of substituted fused heterocyclic systems, which include condensation reactions, multiple bond annulation, and the reactions of electrophilic heterocyclization. (b) Description of chemical and biological characteristics of these fused heterocycles.

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Silyl Anion Initiated Hydroboration of Aldehydes and Ketones

Silyl Anion Initiated Hydroboration of Aldehydes and Ketones

Hydroboration catalysts based on environmentally benign and earth abundant main group compounds offer high potential as an alternative to transition‐metal catalysts. Silicon is abundant and has no inherent toxicity, but has found limited use in hydroboration catalysis. In this work, it is shown that a silyl anion is an effective initiator for the hydroboration of carbonyl compounds requiring low catalyst loadings and mild conditions and with good functional group tolerance.

Abstract

Hydroboration is an emerging method for mild and selective reduction of carbonyl compounds. Typically, transition‐metal or reactive main‐group hydride catalysts are used in conjunction with a mild reductant such as pinacolborane. The reactivity of the main‐group catalysts is a consequence of the nucleophilicity of their hydride ligands. Silicon hydrides are significantly less reactive and are therefore not efficient hydroboration catalysts. Here, a readily prepared silyl anion is reported to be an effective initiator for the reduction of aldehydes and ketones requiring mild conditions, low catalyst loadings and with a good substrate scope. The silyl anion it is shown to activate HBpin to generate a reactive borohydride in situ which reacts with aldehydes and ketones to afford the hydroboration product.

Wiley: Chemistry – A European Journal: Table of Contents
Authors: Martin W. Stanford, Alessandro Bismuto, Michael J. Cowley
doi.org/10.1002/chem.202000897

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Solar‐Assisted eBiorefinery: Photoelectrochemical Pairing of Oxyfunctionalization and Hydrogenation Reactions

Solar‐Assisted eBiorefinery: Photoelectrochemical Pairing of Oxyfunctionalization and Hydrogenation Reactions

A biocatalytic photoelectrochemical platform for solar‐assisted dual biotransformations is constructed by wiring a Mo‐doped BiVO4 photocathode and a hierarchical porous ITO electrode. The deliberate integration of enzymatic redox processes into the photoelectrochemical cell simultaneously facilitates peroxygenase‐ and ene‐reductase‐mediated enantioselective synthesis of high‐value chemicals using solar‐powered electrons and water.

Abstract

Inspired by natural photosynthesis, biocatalytic photoelectrochemical (PEC) platforms are gaining prominence for the conversion of solar energy into useful chemicals by combining redox biocatalysis and photoelectrocatalysis. Herein, we report a dual biocatalytic PEC platform consisting of a molybdenum (Mo)‐doped BiVO4 (Mo:BiVO4) photoanode and an inverse opal ITO (IO‐ITO) cathode that gives rise to the coupling of peroxygenase and ene‐reductase‐mediated catalysis, respectively. In the PEC cell, the photoexcited electrons generated from the Mo:BiVO4 are transferred to the IO‐ITO and regenerate reduced flavin mononucleotides to drive ene‐reductase‐catalyzed trans‐hydrogenation of ketoisophrone to (R )‐levodione. Meanwhile, the photoactivated Mo:BiVO4 evolves H2O2 in situ via a two‐electron water‐oxidation process with the aid of an applied bias, which simultaneously supplies peroxygenases to drive selective hydroxylation of ethylbenzene into enantiopure (R )‐1‐phenyl‐1‐hydroxyethane. Thus, the deliberate integration of PEC systems with redox biocatalytic reactions can simultaneously produce valuable chemicals on both electrodes using solar‐powered electrons and water.

Wiley: Angewandte Chemie International Edition: Table of Contents
Authors: Da Som Choi, Jinhyun Kim, Frank Hollmann, Chan Beum Park
doi.org/10.1002/anie.202006893

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Exploration of the Fluoride Reactivity of Aryltrifluoroborate on Selective Cleavage of Diphenylmethylsilyl Groups

Exploration of the Fluoride Reactivity of Aryltrifluoroborate on Selective Cleavage of Diphenylmethylsilyl Groups

The unique fluoride reactivity of phenyltrifluoroborate in the desilylation of diphenylmethylsilyl groups is controlled by substituents on the benzene ring. The fluorine on trifluoroborate interacts with silicon and activates the Si–O bond to enable selective desilylation of the diphenylmethylsilyl group. Selective desilylation of a primary silyl ether in the presence of a secondary silyl ether by the trifluoroborate was also successful.

The first known report on the fluoride catalytic reactivity of potassium aryltrifluoroborate is described. The fluoride reactivity of phenyltrifluoroborate was controlled by substituents on the trifluoroborate‐attached benzene, such as the methoxy group at the para‐position and the methyl group at the ortho‐position. In addition, the selective aryltrifluoroborate‐catalyzed cleavage of the diphenylmethylsilyl group was achieved.

Wiley: European Journal of Organic Chemistry: Table of Contents
Authors: Katsumasa Fujiki, Katsunori Tanaka
onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.202000707

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Palladium-Catalyzed meta-C–H Allylation of Arenes: A Unique Combination of a Pyrimidine-Based Template and Hexafluoroisopropanol

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Journal of the American Chemical Society

Journal of the American Chemical Society: Latest Articles (ACS Publications)
Authors: Sukdev Bag†, Surya K†, Arup Mondal†, Ramasamy Jayarajan†, Uttam Dutta†, Sandip Porey†, Raghavan B. Sunoj*†, and Debabrata Maiti*†‡
feedproxy.google.com/~r/acs/jacsat/~3/kVD3tpd3hlM/jacs.0c05223

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Development of a Scalable Synthesis of the Small Molecule TGFßR1 Inhibitor BMS-986260

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Organic Process Research & Development

Organic Process Research & Development: Latest Articles (ACS Publications)

Authors: Muthalagu Vetrichelvan‡, Souvik Rakshit†, Sathishkumar Chandrasekaran†, Karthikeyan Chinnakalai†, Chetan Padmakar Darne?, Dyamanna Doddalingappa‡, Indasi Gopikumar‡, Anuradha Gupta‡, Arun Kumar Gupta‡, Ananta Karmakar‡, Thirumalai Lakshminarasimhan†, David K. Leahy§, Senthil Palani†, Vignesh Radhakrishnan‡, Richard Rampulla?, Antony Savarimuthu†, Varadharajan Subramanian†, Upender Velaparthi?, Jayakumar Warrier?, Martin D. Eastgate§, Robert M. Borzilleri?, Arvind Mathur?, and Rajappa Vaidyanathan*†
feedproxy.google.com/~r/acs/oprdfk/~3/F-TTpxLtIkM/acs.oprd.0c00232

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Partially Fluorinated Copolymers as Oxygen Sensitive 19F MRI Agents

Partially Fluorinated Copolymers as Oxygen Sensitive 19F MRI Agents

Fluorine power ! The synthesis of densely fluorinated monomers and their copolymerization into water‐soluble 19F MRI agents is reported. These copolymers demonstrate improved 19F MRI sensitivity compared to state‐of‐the‐art materials and enable non‐invasive quantification of solution oxygenation.

Abstract

Effective diagnosis of disease and its progression can be aided by 19F magnetic resonance imaging (MRI) techniques. Specifically, the inherent sensitivity of the spin–lattice relaxation time (T 1) of 19F nuclei to oxygen partial pressure makes 19F MRI an attractive non‐invasive approach to quantify tissue oxygenation in a spatiotemporal manner. However, there are only few materials with the adequate sensitivity to be used as oxygen‐sensitive 19F MRI agents at clinically relevant field strengths. Motivated by the limitations in current technologies, we report highly fluorinated monomers that provide a platform approach to realize water‐soluble, partially fluorinated copolymers as 19F MRI agents with the required sensitivity to quantify solution oxygenation at clinically relevant magnetic field strengths. The synthesis of a systematic library of partially fluorinated copolymers enabled a comprehensive evaluation of copolymer structure–property relationships relevant to 19F MRI. The highest‐performing material composition demonstrated a signal‐to‐noise ratio that corresponded to an apparent 19F density of 220 mm , which surpasses the threshold of 126 mm 19F required for visualization on a three Tesla clinical MRI. Furthermore, the T 1 of these high performing materials demonstrated a linear relationship with solution oxygenation, with oxygen sensitivity reaching 240×10−5 mmHg−1s−1. The relationships between material composition and 19F MRI performance identified herein suggest general structure–property criteria for the further improvement of modular, water‐soluble 19F MRI agents for quantifying oxygenation in environments relevant to medical imaging.

Wiley: Chemistry – A European Journal: Table of Contents
Authors: Nicholas G. Taylor, Sang Hun Chung, Albert L. Kwansa, Rob R. Johnson, Aaron J. Teator, Nina J. B. Milliken, Karl M. Koshlap, Yaroslava G. Yingling, Yueh Z. Lee, Frank A. Leibfarth
doi.org/10.1002/chem.202001505

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Reconciling Electrostatic and n→π* Orbital Contributions in Carbonyl Interactions

Reconciling Electrostatic and n→π* Orbital Contributions in Carbonyl Interactions

Carbonyls reconciled : Electrostatics and orbital interactions have both been implicated in governing carbonyl interactions. A combined experimental and computational approach reconciles these conflicting explanations of the physiochemical origin of the interaction, demonstrating that orbital delocalisation augments electrostatic control, but for very close carbonyl contacts.

Abstract

Interactions between carbonyl groups are prevalent in protein structures. Earlier investigations identified dominant electrostatic dipolar interactions, while others implicated lone pair n→π* orbital delocalisation. Here these observations are reconciled. A combined experimental and computational approach confirmed the dominance of electrostatic interactions in a new series of synthetic molecular balances, while also highlighting the distance‐dependent observation of inductive polarisation manifested by n→π* orbital delocalisation. Computational fiSAPT energy decomposition and natural bonding orbital analyses correlated with experimental data to reveal the contexts in which short‐range inductive polarisation augment electrostatic dipolar interactions. Thus, we provide a framework for reconciling the context dependency of the dominance of electrostatic interactions and the occurrence of n→π* orbital delocalisation in C=O⋅⋅⋅C=O interactions.

Wiley: Angewandte Chemie International Edition: Table of Contents
Authors: Kamila B. Muchowska, Dominic J. Pascoe, Stefan Borsley, Ivan V. Smolyar, Ioulia K. Mati, Catherine Adam, Gary S. Nichol, Kenneth B. Ling, Scott L. Cockroft
www.onlinelibrary.wiley.com/doi/abs/10.1002/anie.202005739

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Transformations of Aryl Ketones via Ligand‐Promoted C−C Bond Activation

Transformations of Aryl Ketones via Ligand‐Promoted C−C Bond Activation

The unstrained carbon–carbon bond of an aryl ketone can be activated by a Pd‐catalyzed ligand‐promoted β‐carbon elimination reaction. In this way, aryl ketones can be transformed into useful aryl borates, and also to biaryls, aryl nitriles, and aryl alkenes. The utility of this strategy was demonstrated by the late‐stage diversification of several drug molecules.

Abstract

The coupling of aromatic electrophiles (aryl halides, aryl ethers, aryl acids, aryl nitriles etc.) with nucleophiles is a core methodology for the synthesis of aryl compounds. Transformations of aryl ketones in an analogous manner via carbon–carbon bond activation could greatly expand the toolbox for the synthesis of aryl compounds due to the abundance of aryl ketones. An exploratory study of this approach is typically based on carbon–carbon cleavage triggered by ring‐strain release and chelation assistance, and the products are also limited to a specific structural motif. Here we report a ligand‐promoted β‐carbon elimination strategy to activate the carbon–carbon bonds, which results in a range of transformations of aryl ketones, leading to useful aryl borates, and also to biaryls, aryl nitriles, and aryl alkenes. The use of a pyridine‐oxazoline ligand is crucial for this catalytic transformation. A gram‐scale borylation reaction of an aryl ketone via a simple one‐pot operation is reported. The potential utility of this strategy is also demonstrated by the late‐stage diversification of drug molecules probenecid, adapalene, and desoxyestrone, the fragrance tonalid as well as the natural product apocynin.

Wiley: Angewandte Chemie International Edition: Table of Contents
Authors: Hanyuan Li, Biao Ma, Qi‐Sheng Liu, Mei‐Ling Wang, Zhen‐Yu Wang, Hui Xu, Ling‐Jun Li, Xing Wang, Hui‐Xiong Dai
www.onlinelibrary.wiley.com/doi/abs/10.1002/anie.202006740

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Cooperative Ni/Cu‐Catalyzed Asymmetric Propargylic Alkylation of Aldimine Esters

Cooperative Ni/Cu‐Catalyzed Asymmetric Propargylic Alkylation of Aldimine Esters

It takes two : A highly efficient propargylic alkylation reaction was developed that delivers high yields with excellent enantiomeric ratios through dual Ni/Cu catalysis (up to 99 % ee ). This Ni/Cu bimetallic system provides a reliable and a versatile approach for the development of a wide range of useful stereocontrolled reactions.

Abstract

A novel Ni/Cu dual catalysis gives rise to fundamentally new cooperative reactivity and enables the regio‐ and enantioselective propargylic alkylation reaction. A diverse set of α‐quaternary propargylated amino ester derivatives were synthesized in good yields with excellent enantioselectivity (up to 99 % ee ). This work highlights the power of cooperative catalysis, which can be expected to have broad implications in homogeneous catalysis beyond the highly valuable synthetic intermediates.

Wiley: Angewandte Chemie International Edition: Table of Contents
Authors: Lingzi Peng, Zhuozhuo He, Xianghong Xu, Chang Guo
www.onlinelibrary.wiley.com/doi/abs/10.1002/anie.202005019

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Sulfone Group as a Versatile and Removable Directing Group for Asymmetric Transfer Hydrogenation of Ketones

Sulfone Group as a Versatile and Removable Directing Group for Asymmetric Transfer Hydrogenation of Ketones

En route : The sulfone group facilitates the formation of a range of reduction substrates through asymmetric transfer hydrogenation (ATH) of ketones, and its ready removal provides a route to challenging enantiomerically enriched alcohols.

Abstract

The sulfone functional group has a strong capacity to direct the asymmetric transfer hydrogenation (ATH) of ketones in the presence of [(arene)Ru(TsDPEN)H] complexes by adopting a position distal to the η6‐arene ring. This preference provides a means for the prediction of the sense of asymmetric reduction. The sulfone group also facilitates the formation of a range of reduction substrates, and its ready removal provides a route to enantiomerically enriched alcohols that would otherwise be extremely difficult to prepare by direct ATH of the corresponding ketones.

Wiley: Angewandte Chemie International Edition: Table of Contents
Authors: Vijyesh K. Vyas, Guy J. Clarkson, Martin Wills
doi.org/10.1002/anie.202004658

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A Highly Selective and Sensitive Chemiluminescent Probe for Real‐Time Monitoring of Hydrogen Peroxide in Cells and Animals

A Highly Selective and Sensitive Chemiluminescent Probe for Real‐Time Monitoring of Hydrogen Peroxide in Cells and Animals

Peroxide triggered, peroxide excited : Real‐time monitoring of hydrogen peroxide (H2O2) in rat brains has been achieved by combining a unique H2O2 sensing strategy and a peroxide bond excited chemiluminescent scaffold. This direct activation of phenoxy‐dioxetane by a tandem Payne/Dakin reaction provides a highly selective, sensitive, and rapid detection of H2O2 in chemical systems, the cellular environment, and living animals.

Abstract

Selective and sensitive molecular probes for hydrogen peroxide (H2O2), which plays diverse roles in oxidative stress and redox signaling, are urgently needed to investigate the physiological and pathological effects of H2O2. A lack of reliable tools for in vivo imaging has hampered the development of H2O2 mediated therapeutics. By combining a specific tandem Payne/Dakin reaction with a chemiluminescent scaffold, H2O2‐CL‐510 was developed as a highly selective and sensitive probe for detection of H2O2 both in vitro and in vivo. A rapid 430‐fold enhancement of chemiluminescence was triggered directly by H2O2 without any laser excitation. Arsenic trioxide induced oxidative damage in leukemia was successfully detected. In particular, cerebral ischemia‐reperfusion injury‐induced H2O2 fluxes were visualized in rat brains using H2O2‐CL‐510 , providing a new chemical tool for real‐time monitoring of H2O2 dynamics in living animals.

Wiley: Angewandte Chemie International Edition: Table of Contents
Authors: Sen Ye, Nir Hananya, Ori Green, Hansen Chen, Angela Qian Zhao, Jiangang Shen, Doron Shabat, Dan Yang
doi.org/10.1002/anie.202005429

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Solid Phase Synthesis of Sulfonimidamide Pseudopeptides and Library Generation

Solid Phase Synthesis of Sulfonimidamide Pseudopeptides and Library Generation

In this work the sulfonimidamide functionality has been combined with peptides forming sulfonimidamide pseudopeptides as potential new modalities in drug discovery. Three alternative synthetic methods to generate the pseudopeptides have been developed, all harmonized with classical solid‐phase peptide synthesis (SPPS), including both on‐ and off‐resin sulfonimidamide synthesis. The methods allow late stage modifications and parallel syntheses.

Many synthetic routes have been explored to make small molecule sulfonimidamides (SIAs), however, its introduction into larger molecules such as oligopeptides has not been studied before. We herein demonstrate three alternative and complementary methods for synthesis of SIA based pseudopeptides, on solid phase, using both on and off‐resin SIA‐synthesis, via sulfonimidoyl chlorides from sulfonamides, in high conversion. Beside evaluation of various resins such as 2‐CTC, Wang, and Rink amide‐ChemMatrix, the possibilities to further N‐functionalize and cyclize the SIA functionality on solid support are shown. The diastereomers of SIA containing pseudopeptides could in most cases be separated using normal reverse phase preparative HPLC. The solid phase SIA methodology has many advantages when it comes to handling and purification as compared to in solution, and will therefore enable exploration of the SIA group as isosteric substitutions and peptidomimetic building blocks in the development of drug‐like pseudopeptides in many ways. Of particular note these approaches facilitate combinatorial library synthesis as demonstrated herein.

Wiley: European Journal of Organic Chemistry: Table of Contents
Authors: Praveen K. Chinthakindi, Andrea Benediktsdottir, Per I. Arvidsson, Yantao Chen, Anja Sandström
onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.202000108

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C‐H Functionalization of Biaryl Compounds

C‐H Functionalization of Biaryl Compounds

We comprehensively summarize the C–H functionalization of biaryl compounds. The contents include annulation, alkylation, alkenylation, arylation, acylation, acetoxylation, amination, aminocarbonylation, cyanation, halogenation, silylation of biaryls.

In recent years, C–C, C–N, and C–O bonds constructed by C–H functionalization have reached considerable attention due to excellent functional group tolerance, cost‐effectiveness, and atom‐economy. Biaryl compounds are one of the important skeletons in the field of organic chemistry, and have been extensively applied to pharmaceuticals, functional materials, and agrochemicals. However, there have been far fewer reports on C–H functionalization by employing biaryls as substrates. Herein we comprehensively review the C–H functionalization of biaryls including annulation/substitution reactions. The discussion is subdivided according to specific reaction types. In summary, we analyzed the corresponding reaction from the points of view of conditions, directing groups, mechanism, and applications. We hope that this minireview will be beneficial for more synthetic chemists to grasp the design of C–H functionalization of biaryl compounds and enlighten them with more ideas on this issue.

Wiley: European Journal of Organic Chemistry: Table of Contents
Authors: Ju Wang, Chen‐Fu Liu, Quan Zheng, Guo‐Wu Rao
onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.202000071

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Diastereoselectivity in Passerini Reactions of Chiral Aldehydes and in Ugi Reactions of Chiral Cyclic Imines

Diastereoselectivity in Passerini Reactions of Chiral Aldehydes and in Ugi Reactions of Chiral Cyclic Imines

This minireview reports some examples of diastereoselective isocyanide‐based multicomponent reactions, focusing on the intermolecular Passerini reaction of chiral enantiopure aldehydes and on the Ugi‐Joullié reaction of chiral enantiopure cyclic imines.

Diastereoselectivity in Passerini and Ugi reactions of chiral aldehydes/imines remains challenging. Moreover, the Ugi reaction of chiral acyclic imines is complicated by their easy racemization/epimerization, whereas this problem is nearly completely suppressed using chiral cyclic imines in a modification called Ugi‐Joullié reaction. Thus 3‐component modification also allows a better diastereoselectivity thanks to the higher steric rigidity of rings. This review presents an overview of the current knowledge on diastereoselective Passerini reaction of chiral aldehydes, and on diastereoselective Ugi‐Joullié reaction of chiral cyclic imines, focusing on the results gathered by the authors’ research group.

Wiley: European Journal of Organic Chemistry: Table of Contents
Authors: Chiara Lambruschini, Lisa Moni, Luca Banfi
onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.202000016

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