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One‐Pot Successive Turbo Grignard Reactions for the Facile Synthesis of α‐Aryl‐α‐Trifluoromethyl Alcohols

A novel straightforward one‐pot methodology for two successive turbo Grignard reagent ( i ‐PrMgCl·LiCl) reactions, was developed for a facile synthesis of α‐aryl‐α‐trifluoromethyl alcohols, motifs of value in pharmaceutical molecules. The method displayed broad functional group tolerance, including reducible groups. Dual roles of i ‐PrMgCl·LiCl were exploited in the tandem reaction with commercially available iodoarenes or iodoheteroarenes and 2,2,2‐trifluoroethyl trifluoroacetate. The process encompasses three successive reactions in a one‐pot process: the i ‐PrMgCl·LiCl‐mediated iodine/magnesium‐exchange reaction of iodoarenes or iodoheteroarenes; nucleophilic addition of various generated aryl or heteroaryl magnesium reagents to 2,2,2‐trifluoroethyl trifluoroacetate; and the reduction of in‐situ generated aryl trifluoromethyl ketones with i ‐PrMgCl·LiCl, to produce the corresponding α‐aryl or α‐heteroaryl‐α‐trifluoromethyl alcohols bearing various substituents, including reducible functional groups in good to excellent yields.Authors: Ryunosuke Kani, Toshiyasu Inuzuka, Yasuhiro Kubota, Kazumasa Funabikionlinelibrary.wiley.com/doi/abs/10.1002/ejoc.202000550?af=R

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Amide Bond Formation Strategies: Latest Advances on a Dateless Transformation

The amide function is unarguably of primary importance, being the constituent of natural and synthetic polymers and found in a wide variety of bioactive molecules. This review will discuss specifically the very recent advances in the area of amide synthesis, specially focusing on metal‐free strategies, based either on stoichiometric or on catalytic methods that were published in the last three years. The synthesis of amides remains one of the most important transformations and it is one of the more frequently performed reactions. In the pharmaceutical industry, the formation of the amide group is pivotal and among the more important transformations in the design of the synthetic plan. This review presents an overview of only very recent contributions, published in the last three years, to highlight the latest progress in this “dateless” reaction, with a special focus on metal‐free methodologies. New, more efficient and/or greener stoichiometric methods, as well as catalytic strategies, have been discussed, either for the “classic” coupling approach between an amine and a carboxylic acid (or its activated equivalent) or for more innovative approaches, mainly involving oxidation procedures to generate amides starting from amines.

Authors: Elisabetta Massolo, Margherita Pirola, Maurizio Benagliaonlinelibrary.wiley.com/doi/abs/10.1002/ejoc.202000080?af=R

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Synthesis of Sulfonyl Fluorides from Sulfonamides

A simple and practical method enables the late‐stage formation of sulfonyl fluorides from densely functionalized molecules under mild conditions in and high chemoselectivity. Sulfonamides react with Pyry‐BF4 and MgCl2 to form sulfonyl chlorides, which are converted in situ into sulfonyl fluorides in the presence of KF. A simple and practical synthesis of sulfonyl fluorides from sulfonamides is reported. The method capitalizes on the formation of the sulfonyl chloride by virtue of the reaction of Pyry‐BF4 and MgCl2, and subsequent in situ conversion to the more robust and stable sulfonyl fluoride by the presence of KF. The mild conditions and high chemoselectivity of the protocol enable the late‐stage formation of sulfonyl fluorides from densely functionalized molecules.

Authors: Marina Pérez‐Palau, Josep Cornellaonlinelibrary.wiley.com/doi/abs/10.1002/ejoc.202000022?af=R

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Sustainable Amidation Reactions – Recent Advances

Herein, we present a selection of sustainable amidation processes, that have contributed to solving the problems associated with traditional methods. Novel reagents and methods are described, including boron‐based reagents, the use of metallic and organometallic catalysts as well as metal‐free methods using milder and versatile oxidants. Due to the widespread occurrence of amides in modern pharmaceuticals and biologically active compounds, amidation reaction is one of the most important reactions in organic chemistry. Traditional methods to form amide bonds involve the coupling of a carboxylic acid with an amine and require the pre‐activation of the carboxylic acid moiety. Sustainable routes are replacing these existing methods since large amounts of waste are produced. Recently, novel reagents and methods for amide bond formation have emerged with the development of boron reagents, as well as the use of more sustainable metallic and organometallic catalysts. This review compiles the most recent efforts towards sustainable approaches that contribute to solving the problems associated with traditional methods. The new routes are based on promising reagents to performed more versatile and efficient amidation reactions.

Authors: A. Sofia Santos, Artur M. S. Silva, M. Manuel B. Marquesonlinelibrary.wiley.com/doi/abs/10.1002/ejoc.202000106?af=R

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Continuous Flow Organophosphorus Chemistry

Organophosphorus derivatives are widespread compounds that chemists find from the bench to the plant, with numerous daily life applications. Besides their common utility for a wide range of notorious reactions such as the Wittig and HWE olefinations, the Arbuzov reaction, the Staudinger reaction, the Mitsunobu reaction as well as ligands for a large variety of organometallic complexes, organophosphorus compounds have also found numerous applications as active pharmaceutical ingredients and agrochemicals. Some organophosphorus derivatives are also infamously known as Chemical Warfare Agents. Within the context of generalized adoption of new process technologies in the Chemistry Toolbox, this review intends to give an update on the most recent and significant advances in continuous flow organophosphorus chemistry. Selected examples in methodology, total synthesis and for the preparation of industrially relevant targets are discussed for illustrating the assets of flow chemistry.Authors: Romain Morodo, Pauline Bianchi, Jean-Christophe M. Monbaliuonlinelibrary.wiley.com/doi/abs/10.1002/ejoc.202000430?af=R

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Stereochemistry and Recent Applications of Axially Chiral Organic Molecules

This minireview summarizes the recent applications of axially chiral organic molecules. Steric scales ranking, novel atropisomeric scaffolds, and recent atroposelective organocatalytic approaches are reviewed considering the literature of the last decade This minireview covers the literature of the last decade related to the stereochemistry of axially chiral molecules. The first section reviews the use of dynamic NMR and dynamic HPLC for the ranking of the steric size of common organic moieties. The second and third sections describe the recent advances in the preparation of new atropisomeric scaffolds, and in the asymmetric synthesis of stereogenic axes by means of atroposelective organocatalysis.

Authors: Michele Mancinelli, Giorgio Bencivenni, Daniel Pecorari, Andrea Mazzantionlinelibrary.wiley.com/doi/abs/10.1002/ejoc.201901918?af=R

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Distal γ‐C(sp3)−H Olefination of Ketone Derivatives and Free Carboxylic Acids

We herein report the distal γ‐C(sp 3 )–H olefination of ketone derivatives and free carboxylic acids. Fine tuning of our previously reported imino‐acid directing group and use of the ligand combination of mono‐ N ‐protected amino acid (MPAA) ligands and electron‐deficient 2‐pyridone ligands were critical for the γ‐C(sp 3 )–H olefination of ketone substrates. In addition, MPAA ligands were found to enable the γ‐C(sp 3 )–H olefination of free carboxylic acids to form diverse 6‐membered lactones. Besides alkyl carboxylic acids, benzylic C(sp 3 )–H also could be functionalized to form 3,4‐dihydroisocoumarin structures in a single step from 2‐methyl benzoic acid derivatives. The utility of these protocols was demonstrated in large scale reactions and diversifications of the γ‐C(sp 3 )–H olefinated products.
Authors: Han Seul Park, Zhoulong Fan, Ru-Yi Zhu, Jin-Quan Yu

onlinelibrary.wiley.com/doi/abs/10.1002/anie.202003271?af=R

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Reductive Deamination with Hydrosilanes Catalyzed by B(C6F5)3

I mean defunct. Combinations of the boron Lewis acid B(C6F5)3 and hydrosilanes enable the reductive cleavage of C−N bonds in various, mainly benzylic amines and heterocumulenes. By this, these functionalized substrates can be converted into the corresponding hydrocarbons in moderate to good yields.AbstractThe strong boron Lewis acid tris(pentafluorophenyl)borane B(C6F5)3 is known to catalyze the dehydrogenative coupling of certain amines and hydrosilanes at elevated temperatures. At higher temperature, the dehydrogenation pathway competes with cleavage of the C−N bond and defunctionalization is obtained. This can be turned into a useful methodology for the transition‐metal‐free reductive deamination of a broad range of amines as well as heterocumulenes such as an isocyanate and an isothiocyanate.
Authors: Huaquan Fang, Martin Oestreich


onlinelibrary.wiley.com/doi/abs/10.1002/anie.202004651?af=R

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Total Synthesis of (±)‐Phyllantidine: Development and Mechanistic Evaluation of a Ring Expansion for Installation of Embedded Nitrogen‐Oxygen Bonds

N−O Problem: The development of a concise total synthesis of (±)‐phyllantidine (1), a member of the securinega family of alkaloids, from 1,4‐cyclohexadiene is described. The synthesis features a key ring expansion which allows for the facile installation of an embedded nitrogen‐oxygen (N−O) bond, allowing for the rapid construction of the oxazabicyclo[3.3.1]nonane core of (1).AbstractThe development of a concise total synthesis of (±)‐phyllantidine (1), a member of the securinega family of alkaloids containing an unusual oxazabicyclo[3.3.1]nonane core, is described. The synthesis employs a unique synthetic strategy featuring the ring expansion of a substituted cyclopentanone to a cyclic hydroxamic acid as a key step that allows facile installation of the embedded nitrogen‐oxygen (N−O) bond. The optimization of this sequence to effect the desired regiochemical outcome and its mechanistic underpinnings were assessed both computationally and experimentally. This synthetic approach also features an early‐stage diastereoselective aldol reaction to assemble the substituted cyclopentanone, a mild reduction of an amide intermediate without N−O bond cleavage, and the rapid assembly of the butenolide found in (1) via use of the Bestmann ylide.
Authors: Kyle M. Lambert, Joshua B. Cox, Lin Liu, Amy C. Jackson, Sam Yruegas, Kenneth B. Wiberg, John L. Wood


onlinelibrary.wiley.com/doi/abs/10.1002/anie.202003829?af=R

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Oxidation of Alkynyl Boronates to Carboxylic Acids, Esters, and Amides

A general efficient protocol for the synthesis of carboxylic acids, esters, and amides through oxidation of alkynyl boronateswas developed. This approach displays a broad substrate scope, including aryl and alkyl alkynes, and exhibits excellent functional group tolerance. Water, primary and secondary alcohols, and amines are suitable nucleophiles for this transformation.AbstractA general efficient protocol was developed for the synthesis of carboxylic acids, esters, and amides through oxidation of alkynyl boronates, generated directly from terminal alkynes. This protocol represents the first example of C(sp)−B bond oxidation. This approach displays a broad substrate scope, including aryl and alkyl alkynes, and exhibits excellent functional group tolerance. Water, primary and secondary alcohols, and amines are suitable nucleophiles for this transformation. Notably, amino acids and peptides can be used as nucleophiles, providing an efficient method for the synthesis and modification of peptides. The practicability of this methodology was further highlighted by the preparation of pharmaceutical molecules.
Authors: Chenchen Li, Pei Zhao, Ruoling Li, Bing Zhang, Wanxiang Zhao


onlinelibrary.wiley.com/doi/abs/10.1002/anie.202000988?af=R

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A controlled attraction

Nature Reviews Chemistry, Published online: 07 May 2020; doi:10.1038/s41570-020-0192-1Uncharged polymers on the surface of charged colloidal particles can help to control their self-assembly into ordered structures.Authors: Gabriella

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