Optimized Conditions for the Palladium‐Catalyzed Hydrogenolysis of Benzyl and Naphthylmethyl Ethers: Preventing Saturation of Aromatic Protecting Groups

https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.202000401?af=R

Optimized Conditions for the Palladium‐Catalyzed Hydrogenolysis of Benzyl and Naphthylmethyl Ethers: Preventing Saturation of Aromatic Protecting Groups

Tuning of a palladium catalyst reactivity allows the chemoselective removal of benzyl and naphthyl protecting groups under batch or continuous flow conditions. Hydrogenation of the aromatic groups does not occur under these conditions thus allowing access to pure synthetic glycans.

While carrying out palladium‐catalyzed hydrogenolysis to deprotect synthetic oligosaccharides, saturation of the benzyl and naphthylmethyl ether groups to their corresponding ether was observed. In order to suppress this unwanted hydrogenation, we report a scalable practical approach using a catalyst pre‐treatment strategy, which is effective under batch or continuous flow conditions. This suppressed the unwanted hydrogenation side‐products and created a selective catalyst for hydrogenolysis of benzyl and naphthylmethyl ethers. We demonstrate the efficient deprotection of a set of structurally diverse oligosaccharides (5 examples, > 73 %).

Authors: Conor Crawford, Stefan Oscarson

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Identification of N‐ or O‐Alkylation of Aromatic Nitrogen Heterocycles and N‐Oxides Using 1H–15N HMBC NMR Spectroscopy

https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.202000329?af=R

Identification of N‐ or O‐Alkylation of Aromatic Nitrogen Heterocycles and N‐Oxides Using 1H–15N HMBC NMR Spectroscopy

An analytical method based on 1H–15N, 1H–13C HMBC and 13C{1H} NMR spectroscopy has been developed that allows unambiguous diagnosis of the occurrence of N‐ or O‐alkylation of aromatic N‐heterocycles and N ‐oxides. A systematic large upfield shift inthe 15N NMR chemical shift is shown to be characteristic of N‐alkylation of aromatic N‐heterocycles (Δ(δN) ≈ –100 ppm). A much smaller systematic change in δN is indicative of N ‐oxide O‐alkylation (ca. –40 ppm).

A series of representative diazines and pyridine N ‐oxides were subjected to alkylation using several different alkylating agents. The 15N NMR chemical shifts (δN values) of the diazines, pyridine N ‐oxides and derived alkylation products were determined using 1H‐15N HMBC NMR spectroscopy at natural 15N abundance. The changes in the 15N NMR chemical shifts (Δ(δN) values) that occurred on going from starting materials to products in these reactions were analyzed. N‐alkylation of diazines resulted in large upfield shifts of the δN values of the alkylated nitrogen (of the order of 100 ppm or greater). While O‐alkylation of pyridine N ‐oxides resulted in upfield shifts of the δN values of the N ‐(alkoxy)pyridinium nitrogen, the Δ(δN) values were of a much smaller magnitude (ca . –42 ppm) than those observed for N‐alkylations of diazines. Nitrogen NMR spectroscopic data from the literature of relevance to alkylation of azines, diazines, azine N ‐oxides and diazine N ‐oxides was gathered together, and using this in tandem with our 15N NMR spectroscopic data, we have been able to corroborate our observations on the trends observed in the Δ(δN) values associated with N‐ and O‐alkylation reactions of aromatic N‐heterocycles and N ‐oxides. An analysis protocol that relies on synergistic evaluation of 1H‐15N HMBC and 1H‐13C HMBC NMR spectra has been developed that enables unambiguous diagnosis of the occurrence of N‐alkylation of aromatic N‐heterocycles and O‐alkylation of aromatic N ‐oxides.

Authors: Kevin J. Sheehy, Lorraine M. Bateman, Niko T. Flosbach, Martin Breugst, Peter A. Byrne

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Transition‐Metal‐Free Carbon Isotope Exchange of Phenyl Acetic Acids

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202002341?af=R

Transition‐Metal‐Free Carbon Isotope Exchange of Phenyl Acetic Acids

Just Labeled : Transition‐metal‐free carbon isotope exchange on phenyl acetic acids is described. Utilizing the universal precursor CO2, the carbon isotope can be inserted into the carboxylic acid position, with no need of precursor synthesis. This procedure enabled the labeling of 15 pharmaceuticals and was compatible with [14C] and [13C]. A proof of concept with [11C] was also obtained with low molar activity valuable for distribution studies.

Abstract

A transition‐metal‐free carbon isotope exchange procedure on phenyl acetic acids is described. Utilizing the universal precursor CO2, this protocol allows the carbon isotope to be inserted into the carboxylic acid position, with no need of precursor synthesis. This procedure enabled the labeling of 15 pharmaceuticals and was compatible with carbon isotopes [14C] and [13C]. A proof of concept with [11C] was also obtained with low molar activity valuable for distribution studies.

Authors: Gianluca Destro, Kaisa Horkka, Olivier Loreau, David‐Alexandre Buisson, Lee Kingston, Antonio Del Vecchio, Magnus Schou, Charles S. Elmore, Frédéric Taran, Thibault Cantat, Davide Audisio

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Simulation vs. Understanding: A Tension, in Quantum Chemistry and Beyond. Part A. Stage Setting

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201902527?af=R

Simulation vs. Understanding: A Tension, in Quantum Chemistry and Beyond. Part A. Stage Setting

There is a wave breaking over us —a wave of simulation and artificial intelligence. In three reflective Essays we make a case for true understanding, for scientific story‐telling, as well as a role for pleasure and the emotions within science in general and quantum chemistry in particular.

Abstract

We begin our tripartite Essay with a triangle of understanding, theory and simulation. Sketching the intimate tie between explanation and teaching, we also point to the emotional impact of understanding. As we trace the development of theory in chemistry, Dirac’s characterization of what is known and what is needed for theoretical chemistry comes up, as does the role of prediction, and Thom’s phrase “To predict is not to explain.” We give a typology of models, and then describe, no doubt inadequately, machine learning and neural networks. In the second part, we leave philosophy, beginning by describing Roald’s being beaten by simulation. This leads us to artificial intelligence (AI), Searle’s Chinese room, and Strevens’ account of what a go ‐playing program knows. Back to our terrain—we ask “Quantum Chemistry, † ca. 2020?” Then move to examples of AI affecting social matters, ranging from trivial to scary. We argue that moral decisions are hardly to be left to a computer. At this point, we try to pull the reader up, giving the opposing view of an optimistic, limitless future a voice. But we don’t do justice to that view—how could we? We return to questioning the ascetic dimension of scientists, their romance with black boxes. Onward: In the 3rd part of this Essay, we work our way up from pessimism. We trace (another triangle!) the special interests of experimentalists, who want the theory we love, and reliable numbers as well. We detail in our own science instances where theory gave us real joy. Two more examples‐on magnetic coupling in inorganic diradicals, and the way to think about alkali metal halides, show us the way to integrate simulation with theory. Back and forth is how it should be—between painfully‐obtained, intriguing numbers, begging for interpretation, in turn requiring new concepts, new models, new theoretically grounded tools of computation. Through such iterations understanding is formed. As our tripartite Essay ends, we outline a future of consilience, with a role both for fact‐seekers, and searchers for understanding. Chemistry’s streak of creation provides in that conjoined future a passage to art and to perceiving, as we argue we must, the sacred in science.

Authors: Roald Hoffmann, Jean‐Paul Malrieu

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6-Amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol Derivatives as Efficacious Mitochondrial Uncouplers in STAM Mouse Model of Nonalcoholic Steatohepatitis

http://feedproxy.google.com/~r/acs/jmcmar/~3/FWMvK6adOsM/acs.jmedchem.0c00542

TOC Graphic

Journal of Medicinal Chemistry
DOI: 10.1021/acs.jmedchem.0c00542

Authors: Joseph M. Salamoun†#, Christopher J. Garcia†#, Stefan R. Hargett‡, Jacob H. Murray†, Sing-Young Chen§, Martina Beretta§, Stephanie J. Alexopoulos§, Divya P. Shah§, Ellen M. Olzomer§, Simon P. Tucker??, Kyle L. Hoehn*‡§, and Webster L. Santos*†

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Rhodium(III)‐Catalyzed Atroposelective Synthesis of Biaryls by C−H Activation and Intermolecular Coupling with Sterically Hindered Alkynes

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202002208?af=R

Rhodium(III)‐Catalyzed Atroposelective Synthesis of Biaryls by C−H Activation and Intermolecular Coupling with Sterically Hindered Alkynes

Dynamic : Rhodium(III)‐catalyzed atroposelective synthesis of biaryls has been realized by intermolecular annulation of benzamides with symmetric and nonsymmetric sterically hindered alkynes. The reaction proceeds by C−H activation and dynamic kinetic transformation of the alkyne with regiospecificity and excellent enantioselectivity.

Abstract

Reported herein is the atroposelective synthesis of biaryl NH isoquinolones by RhIII‐catalyzed C−H activation of benzamides and intermolecular [4+2] annulation for a broad scope of 2‐substituted 1‐alkynylnaphthalenes, as well as sterically hindered, symmetric diarylacetylenes. The axial chirality is constructed based on dynamic kinetic transformation of the alkyne in redox‐neutral annulation with benzamides, with alkyne insertion being stereodetermining. The reaction accommodates both benzamides and heteroaryl carboxamides and proceeds in excellent regioselectivity (if applicable) and enantioselectivities (average 91.8 % ee ). An enantiomerically and diastereomerically pure rhodacyclic complex was prepared and offers insight into enantiomeric control of the coupling system, wherein the steric interactions between the amide directing group and the alkyne substrate dictate both the regio‐ and enantioselectivity.

Authors: Fen Wang, Zisong Qi, Yuxia Zhao, Shuailei Zhai, Guangfan Zheng, Ruijie Mi, Zhiyan Huang, Xiaolin Zhu, Xiaoming He, Xingwei Li

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Light‐Promoted Nickel Catalysis: Etherification of Aryl Electrophiles with Alcohols Catalyzed by a NiII‐Aryl Complex

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202003359?af=R

Light‐Promoted Nickel Catalysis: Etherification of Aryl Electrophiles with Alcohols Catalyzed by a NiII‐Aryl Complex

The light fantastic : A highly effective C−O coupling reaction of (hetero)aryl electrophiles with primary and secondary alcohols is reported. Catalyzed by a NiII‐aryl complex under long‐wave UV irradiation in the presence of a soluble amine base without any additional photosensitizer, the reaction enables the etherification of aryl bromides and aryl chlorides as well as sulfonates with a wide range of primary and secondary aliphatic alcohols.

Abstract

A highly effective C−O coupling reaction of (hetero)aryl electrophiles with primary and secondary alcohols is reported. Catalyzed by a NiII‐aryl complex under long‐wave UV (390–395 nm) irradiation in the presence of a soluble amine base without any additional photosensitizer, the reaction enables the etherification of aryl bromides and aryl chlorides as well as sulfonates with a wide range of primary and secondary aliphatic alcohols, affording synthetically important ethers. Intramolecular C−O coupling is also possible. The reaction appears to proceed via a NiI–NiIII catalytic cycle.

Authors: Liu Yang, Huan‐Huan Lu, Chu‐Hui Lai, Gang Li, Wei Zhang, Rui Cao, Fengyi Liu, Chao Wang, Jianliang Xiao, Dong Xue

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Predicting Regioselectivity in Radical C−H Functionalization of Heterocycles through Machine Learning

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202000959?af=R

Predicting Regioselectivity in Radical C−H Functionalization of Heterocycles through Machine Learning

Mechanism‐based computational statistics allowed the machine learning prediction of regioselectivity in radical C−H functionalization of heterocycles. The developed random forest model with physical organic features achieved satisfying performance without any experimental input.

Abstract

Radical C−H bond functionalization provides a versatile approach for elaborating heterocyclic compounds. The synthetic design of this transformation relies heavily on the knowledge of regioselectivity, while a quantified and efficient regioselectivity prediction approach is still elusive. Herein, we report the feasibility of using a machine learning model to predict the transition state barrier from the computed properties of isolated reactants. This enables rapid and reliable regioselectivity prediction for radical C−H bond functionalization of heterocycles. The Random Forest model with physical organic features achieved 94.2 % site accuracy and 89.9 % selectivity accuracy in the out‐of‐sample test set. The prediction performance was further validated by comparing the machine learning results with additional substituents, heteroarene scaffolds and experimental observations. This work revealed that the combination of mechanism‐based computational statistics and machine learning model can serve as a useful strategy for selectivity prediction of organic transformations.

Authors: Xin Li, Shuo‐Qing Zhang, Li‐Cheng Xu, Xin Hong

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Kinetic and Dynamic Kinetic Resolution of Racemic Tertiary Bromides by Pentanidium‐Catalyzed Phase‐Transfer Azidation

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202000138?af=R

Kinetic and Dynamic Kinetic Resolution of Racemic Tertiary Bromides by Pentanidium‐Catalyzed Phase‐Transfer Azidation

Now resolved : Under base‐free conditions, enantiomerically enriched azides and bromides were obtained through the pentanidium‐catalyzed kinetic resolution (KR) of racemic tertiary bromides (see scheme). Furthermore, new experimental observations and DFT modeling of the reaction pathways enabled better understanding of the contrasting enantioconvergent azidation of tertiary bromides, thus establishing it as a dynamic kinetic resolution (DKR).

Abstract

We have developed a method to afford enantiomerically enriched tertiary azides and bromides through pentanidium‐catalyzed kinetic resolution (KR) of racemic tertiary bromides under base‐free conditions. We found that the absence of water is crucial to attain a high selectivity factor (s ). On the other hand, new experimental observations and DFT modeling led us to propose that enantioconvergent azidation of tertiary bromides proceeded through dynamic kinetic resolution (DKR). The investigations particularly identified the crucial roles of base and water in the enantioconvergent process, thus supporting the proposal that the tertiary bromide isomerizes in the presence of base and water through a SN2X pathway.

Authors: Jingyun Ren, Xu Ban, Xin Zhang, Siu Min Tan, Richmond Lee, Choon‐Hong Tan

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Tailored Palladium Catalysts for Selective Synthesis of Conjugated Enynes by Monocarbonylation of 1,3‐Diynes

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201915386?af=R

Tailored Palladium Catalysts for Selective Synthesis of Conjugated Enynes by Monocarbonylation of 1,3‐Diynes

Precise synthesis : The new “built‐in‐base” ligand Neolephos was designed and applied in the Pd‐catalyzed monocarbonylation of 1,3‐diynes. The precise synthesis of conjugated enynes was achieved in good‐to‐high yield with excellent chemo‐ and stereoselectivity. The presented methodology can be used for simple diversification of natural products and pharmaceuticals.

Abstract

For the first time, the monoalkoxycarbonylation of easily available 1,3‐diynes to give synthetically useful conjugated enynes has been realized. Key to success was the design and utilization of the new ligand 2,2′‐bis(tert ‐butyl(pyridin‐2‐yl)phosphanyl)‐1,1′‐binaphthalene (Neolephos), which permits the palladium‐catalyzed selective carbonylation under mild conditions, providing a general preparation of functionalized 1,3‐enynes in good‐to‐high yields with excellent chemoselectivities. Synthetic applications that showcase the possibilities of this novel methodology include an efficient one‐pot synthesis of 4‐aryl‐4H ‐pyrans as well as the rapid construction of various heterocyclic, bicyclic, and polycyclic compounds.

Authors: Jiawang Liu, Ji Yang, Carolin Schneider, Robert Franke, Ralf Jackstell, Matthias Beller

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Intracellular Reactions Promoted by Bis(histidine) Miniproteins Stapled Using Palladium(II) Complexes

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202002032?af=R

Intracellular Reactions Promoted by Bis(histidine) Miniproteins Stapled Using Palladium(II) Complexes

Cell entry : A palladium(II)‐stapled bis(histidine) unit at the basic site of miniproteins leads to cell‐permeable derivatives that enable depropargylation reactions within the interior of living mammalian cells. Both the metal bridge and the peptide scaffolding are essential for the internalization, and for observing the intracellular transformations.

Abstract

The generation of catalytically active metalloproteins inside living mammalian cells is a major research challenge at the interface between catalysis and cell biology. Herein we demonstrate that basic domains of bZIP transcription factors, mutated to include two histidine residues at i and i+4 positions, react with palladium(II) sources to generate catalytically active, stapled pallado‐miniproteins. The resulting constrained peptides are efficiently internalized into living mammalian cells, where they perform palladium‐promoted depropargylation reactions without cellular fixation. Control experiments confirm the requirement of the peptide scaffolding and the palladium staple for attaining the intracellular reactivity.

Authors: Soraya Learte‐Aymamí, Cristian Vidal, Alejandro Gutiérrez‐González, José L. Mascareñas

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Highly Active Superbulky Alkaline Earth Metal Amide Catalysts for Hydrogenation of Challenging Alkenes and Aromatic Rings

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202001160?af=R

Highly Active Superbulky Alkaline Earth Metal Amide Catalysts for Hydrogenation of Challenging Alkenes and Aromatic Rings

Bulk=Hulk : Superbulky alkaline earth metal amide complexes were found to be extremely active catalysts for alkene hydrogenation, clearly extending the substrate scope. Even various arenes, including benzene, can be reduced under relatively mild conditions.

Abstract

Two series of bulky alkaline earth (Ae) metal amide complexes have been prepared: Ae[N(TRIP)2]2 (1 ‐Ae) and Ae[N(TRIP)(DIPP)]2 (2 ‐Ae) (Ae=Mg, Ca, Sr, Ba; TRIP=Sii Pr3, DIPP=2,6‐diisopropylphenyl). While monomeric 1 ‐Ca was already known, the new complexes have been structurally characterized. Monomers 1 ‐Ae are highly linear while the monomers 2 ‐Ae are slightly bent. The bulkier amide complexes 1 ‐Ae are by far the most active catalysts in alkene hydrogenation with activities increasing from Mg to Ba. Catalyst 1 ‐Ba can reduce internal alkenes like cyclohexene or 3‐hexene and highly challenging substrates like 1‐Me‐cyclohexene or tetraphenylethylene. It is also active in arene hydrogenation reducing anthracene and naphthalene (even when substituted with an alkyl) as well as biphenyl. Benzene could be reduced to cyclohexane but full conversion was not reached. The first step in catalytic hydrogenation is formation of an (amide)AeH species, which can form larger aggregates. Increasing the bulk of the amide ligand decreases aggregate size but it is unclear what the true catalyst(s) is (are). DFT calculations suggest that amide bulk also has a noticeable influence on the thermodynamics for formation of the (amide)AeH species. Complex 1 ‐Ba is currently the most powerful Ae metal hydrogenation catalyst. Due to tremendously increased activities in comparison to those of previously reported catalysts, the substrate scope in hydrogenation catalysis could be extended to challenging multi‐substituted unactivated alkenes and even to arenes among which benzene.

Authors: Johannes Martin, Christian Knüpfer, Jonathan Eyselein, Christian Färber, Samuel Grams, Jens Langer, Katharina Thum, Michael Wiesinger, Sjoerd Harder

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Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202001824?af=R

Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids

The conversion of carboxylic acids into ketones using combined photoredox/ N‐heterocyclic carbene (NHC) catalysis has been developed. In situ activation of a carboxylic acid followed by generation of an acyl azolium allows productive radical–radical coupling to afford ketones in good to excellent yields. This single‐electron, reductive alkylation was applied in the late‐stage functionalization of various pharmaceutical compounds.

Abstract

As a key element in the construction of complex organic scaffolds, the formation of C−C bonds remains a challenge in the field of synthetic organic chemistry. Recent advancements in single‐electron chemistry have enabled new methods for the formation of various C−C bonds. Disclosed herein is the development of a novel single‐electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium in situ followed by a radical–radical coupling was made possible merging N‐heterocyclic carbene (NHC) and photoredox catalysis. The utility of this protocol in synthesis was showcased in the late‐stage functionalization of a variety of pharmaceutical compounds. Preliminary investigations using chiral NHCs demonstrate that enantioselectivity can be achieved, showcasing the advantages of this protocol over alternative methodologies.

Authors: Anna V. Davies, Keegan P. Fitzpatrick, Rick C. Betori, Karl A. Scheidt

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A Transient‐Directing‐Group Strategy Enables Enantioselective Reductive Heck Hydroarylation of Alkenes

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202001069?af=R

A Transient‐Directing‐Group Strategy Enables Enantioselective Reductive Heck Hydroarylation of Alkenes

You come and go : A commercially available chiral transient directing group (l tert ‐leucine) facilitates the enantioselective reductive Heck hydroarylation of internal styrene substrates. This operationally simple reaction shows high functional‐group tolerance and generates enantioenriched 1,2‐diaryl ethane motifs in synthetically useful yields under mild conditions.

Abstract

Metal‐coordinating directing groups have seen extensive use in the field of transition‐metal‐catalyzed alkene functionalization; however, their waste‐generating installation and removal steps limit the efficiency and practicality of reactions that rely on their use. Inspired by developments in asymmetric organocatalysis, where reactions rely on reversible covalent interactions between an organic substrate and a chiral mediator, we have developed a transient‐directing‐group approach to reductive Heck hydroarylation of alkenyl benzaldehyde substrates that proceeds under mild conditions. Highly stereoselective migratory insertion is facilitated by in situ formation of an imine from catalytic amounts of a commercially available amino acid additive. Computational studies reveal an unusual mode of enantioinduction by the remote chiral center in the transient directing group.

Authors: Lucas J. Oxtoby, Zi‐Qi Li, Van T. Tran, Tuğçe G. Erbay, Ruohan Deng, Peng Liu, Keary M. Engle

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Enantioselective Synthesis of N–C Axially Chiral Compounds by Cu‐Catalyzed Atroposelective Aryl Amination

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201914876?af=R

Enantioselective Synthesis of N–C Axially Chiral Compounds by Cu‐Catalyzed Atroposelective Aryl Amination

Don’t turn N‐C ! Atropo‐enantioselective N−C coupling was achieved with excellent enantioselectivity at room temperature with a simple catalytic system. The key to solving this long‐standing challenge was the use of a chiral Cu catalyst in combination with hypervalent iodine reagents as coupling partners.

Abstract

N−C axially chiral compounds have emerged recently as appealing motifs for drug design. However, the enantioselective synthesis of such molecules is still poorly developed and surprisingly no metal‐catalyzed atroposelective N‐arylations have been described. Herein, we disclose an unprecedented Cu‐catalyzed atroposelective N−C coupling that proceeds at room temperature. Such mild reaction conditions, which are a crucial parameter for atropostability of the newly generated products, are operative thanks to the use of hypervalent iodine reagents as a highly reactive coupling partners. A large panel of the N−C axially chiral compounds was afforded with very high enantioselectivity (up to >99 % ee ) and good yields (up to 76 %). Post‐modifications of thus accessed atropisomeric compounds allows further expansion of the diversity of these appealing compounds.

Authors: Johanna Frey, Alaleh Malekafzali, Isabel Delso, Sabine Choppin, Françoise Colobert, Joanna Wencel‐Delord

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Nickel‐Catalyzed Cross‐Coupling of Sulfonamides With (Hetero)aryl Chlorides

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202002392?af=R

Nickel‐Catalyzed Cross‐Coupling of Sulfonamides With (Hetero)aryl Chlorides

Ancillary Ligation : The development of the first nickel‐catalyzed protocols for the cross‐coupling of sulfonamides with inexpensive and abundant (hetero)aryl chlorides and phenol derivatives is enabled by use of appropriate bisphosphine ligation.

Abstract

The development of Ni‐catalyzed C−N cross‐couplings of sulfonamides with (hetero)aryl chlorides is reported. These transformations, which were previously achievable only with Pd catalysis, are enabled by use of air‐stable (L )NiCl(o ‐tol) pre‐catalysts (L=PhPAd‐DalPhos and PAd2‐DalPhos ), without photocatalysis. The collective scope of (pseudo)halide electrophiles (X=Cl, Br, I, OTs, and OC(O)NEt2) demonstrated herein is unprecedented for any reported catalyst system for sulfonamide C−N cross‐coupling (Pd, Cu, Ni, or other). Preliminary competition experiments and relevant coordination chemistry studies are also presented.

Authors: Ryan T. McGuire, Connor M. Simon, Arun A. Yadav, Michael J. Ferguson, Mark Stradiotto

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Sodium Dithionite‐Mediated Decarboxylative Sulfonylation: Facile Access to Tertiary Sulfones

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202001589?af=R

Sodium Dithionite‐Mediated Decarboxylative Sulfonylation: Facile Access to Tertiary Sulfones

Piece of cake : A straightforward multicomponent decarboxylative cross coupling of redox‐active esters, sodium dithionite and electrophiles was established to construct sterically bulky sulfones. The inorganic salt sodium dithionite not only served as the sulfur dioxide source, but also acted as an efficient radical initiator for the decarboxylation.

Abstract

A straightforward multicomponent decarboxylative cross coupling of redox‐active esters (N‐hydroxyphthalimide ester), sodium dithionite, and electrophiles was established to construct sterically bulky sulfones. The inorganic salt sodium dithionite not only served as the sulfur dioxide source, but also acted as an efficient radical initiator for the decarboxylation. Notably, diverse naturally abundant carboxylic acids and artificially prepared carboxyl‐containing drugs with multiple heteroatoms and sensitive functional groups successfully underwent this decarboxylative sulfonylation to provide sterically bulky tertiary sulfones. Mechanistic studies further demonstrated that decarboxylation was the rate‐determining step and occurred via a single‐electron transfer (SET) process with the assistance of sodium dithionite.

Authors: Yaping Li, Shihao Chen, Ming Wang, Xuefeng Jiang

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Recent Developments in C–C Bond Formation Using Catalytic Reductive Coupling Strategies

http://dx.doi.org/10.1055/s-0040-1707128

Synthesis
DOI: 10.1055/s-0040-1707128

Metal-catalyzed reductive coupling processes have emerged as a powerful methodology for the introduction of molecular complexity from simple starting materials. These methods allow for an orthogonal approach to that of redox-neutral strategies for the formation of C–C bonds by enabling cross-coupling of starting materials not applicable to redox-neutral chemistry. This short review summarizes the most recent developments in the area of metal-catalyzed reductive coupling utilizing catalyst turnover by a stoichiometric reductant that becomes incorporated in the final product.1 Introduction2 Ni Catalysis3 Cu Catalysis4 Ru, Rh, and Ir Catalysis4.1 Alkenes4.2 1,3-Dienes4.3 Allenes4.4 Alkynes4.5 Enynes5 Fe, Co, and Mn Catalysis6 Conclusion and Outlook
[…]

© Georg Thieme Verlag Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

Authors: Agrawal, Toolika

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Validating the 1,2-Difluoro Motif As a Hybrid Bioisostere of CF3 and Et Using Matrix Metalloproteinases As Structural Probes

http://feedproxy.google.com/~r/acs/jmcmar/~3/o-RmWaxu_XI/acs.jmedchem.0c00648

TOC Graphic

Journal of Medicinal Chemistry
DOI: 10.1021/acs.jmedchem.0c00648

Authors: Nathalie Erdeljac†, Christian Thiehoff†, Ravindra P. Jumde‡, Constantin G. Daniliuc†, Sandra Ho¨ppner§, Andreas Faust§, Anna K. H. Hirsch*‡?, and Ryan Gilmour*†

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