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1. A machine-learning tool to predict substrate-adaptive conditions for Pd-catalyzed C–N couplings

   https://doi.org/10.1126/science.adg2114  

   Rinehart, N. I.; Saunthwal, Rakesh K.; Wellauer, Joël; Zahrt, Andrew F.; Schlemper, Lukas; Shved, Alexander S.; Bigler, Raphael; Fantasia, Serena; Denmark, Scott E. (September 2023, Science)

   Machine-learning methods have great potential to accelerate the identification of reaction conditions for chemical transformations. A tool that gives substrate-adaptive conditions for palladium (Pd)–catalyzed carbon-nitrogen (C–N) couplings is presented. The design and construction of this tool required the generation of an experimental dataset that explores a diverse network of reactant pairings across a set of reaction conditions. A large scope of C–N couplings was actively learned by neural network models by using a systematic process to design experiments. The models showed good performance in experimental validation: Ten products were isolated in more than 85% yield from a range of couplings with out-of-sample reactants designed to challenge the models. Importantly, the developed workflow continually improves the prediction capability of the tool as the corpus of data grows. 

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2. Mechanochemical Solvent‐Free Suzuki–Miyaura Cross‐Coupling of Amides via Highly Chemoselective N−C Cleavage

   https://doi.org/10.1002/anie.202114146  

   Zhang, Jin; Zhang, Pei; Shao, Lei; Wang, Ruihong; Ma, Yangmin; Szostak, Michal (December 2021, Angewandte Chemie International Edition)

   Abstract Although cross‐coupling reactions of amides by selective N−C cleavage are one of the most powerful and burgeoning areas in organic synthesis due to the ubiquity of amide bonds, the development of mechanochemical, solid‐state methods remains a major challenge. Herein, we report the first mechanochemical strategy for highly chemoselective, solvent‐free palladium‐catalyzed cross‐coupling of amides by N−C bond activation. The method is conducted in the absence of external heating, for short reaction time and shows excellent chemoselectivity for σ N−C bond activation. The reaction shows excellent functional group tolerance and can be applied to late‐stage functionalization of complex APIs and sequential orthogonal cross‐couplings exploiting double solventless solid‐state methods. The results extend mechanochemical reaction environments to advance the chemical repertoire of N−C bond interconversions to solid‐state environmentally friendly mechanochemical methods. 

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3. Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling

   https://doi.org/10.1021/jacs.3c09554  

   Akana, Michelle E.; Tcyrulnikov, Sergei; Akana-Schneider, Brett D.; Reyes, Giselle P.; Monfette, Sebastien; Sigman, Matthew S.; Hansen, Eric C.; Weix, Daniel J. (January 2024, Journal of the American Chemical Society)

   Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)–C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous ligands, especially 2,2’-bipyridines. Precise prediction, selection, and design of optimal ligands remains challenging, despite significant increases in reaction scope and mechanistic understanding. Molecular parame-terization and statistical modeling provide a path to the development of improved bipyridine ligands that will enhance the selectivity of existing reactions and broaden the scope of electrophiles that can be coupled. Herein, we describe the generation of a computational lig-and library, correlation of observed reaction outcomes with features of the ligands, and in silico design of improved bipyridine ligands for Ni-catalyzed cross-electrophile coupling. The new nitrogen-substituted ligands display a fivefold increase in selectivity for product formation versus homodimerization when compared to the current state of the art. This increase in selectivity and yield was general for several cross-electrophile couplings, including the challenging coupling of an aryl chloride with an N-alkylpyridinium salt. 

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4. Suzuki–Miyaura Cross-Coupling of Amides Using Well-Defined, Air- and Moisture-Stable Nickel/NHC (NHC = N-Heterocyclic Carbene) Complexes

   https://doi.org/10.3390/catal10040372  

   Buchspies, Jonathan; Rahman, Md. Mahbubur; Szostak, Michal (April 2020, Catalysts)

   In this Special Issue on N-Heterocyclic Carbenes and Their Complexes in Catalysis, we report the first example of Suzuki–Miyaura cross-coupling of amides catalyzed by well-defined, air- and moisture-stable nickel/NHC (NHC = N-heterocyclic carbene) complexes. The selective amide bond N–C(O) activation is achieved by half-sandwich, cyclopentadienyl [CpNi(NHC)Cl] complexes. The following order of reactivity of NHC ligands has been found: IPr > IMes > IPaul ≈ IPr*. Both the neutral and the cationic complexes are efficient catalysts for the Suzuki–Miyaura cross-coupling of amides. Kinetic studies demonstrate that the reactions are complete in < 1 h at 80 °C. Complete selectivity for the cleavage of exocyclic N-acyl bond has been observed under the experimental conditions. Given the utility of nickel catalysis in activating unreactive bonds, we believe that well-defined and bench-stable [CpNi(NHC)Cl] complexes will find broad application in amide bond and related cross-couplings of bench-stable acyl-electrophiles. 

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5. NMR “Crystallography” for Uniformly ( ¹³ C, ¹⁵ N)‐Labeled Oriented Membrane Proteins

   https://doi.org/10.1002/anie.201915110  

   Awosanya, Emmanuel O.; Lapin, Joel; Nevzorov, Alexander A. (January 2020, Angewandte Chemie International Edition)

   Abstract In oriented‐sample (OS) solid‐state NMR of membrane proteins, the angular‐dependent dipolar couplings and chemical shifts provide a direct input for structure calculations. However, so far only¹H–¹⁵N dipolar couplings and¹⁵N chemical shifts have been routinely assessed in oriented¹⁵N‐labeled samples. The main obstacle for extending this technique to membrane proteins of arbitrary topology has remained in the lack of additional experimental restraints. We have developed a new experimental triple‐resonance NMR technique, which was applied to uniformly doubly (¹⁵N,¹³C)‐labeled Pf1 coat protein in magnetically aligned DMPC/DHPC bicelles. The previously inaccessible¹H_α–¹³C_αdipolar couplings have been measured, which make it possible to determine the torsion angles between the peptide planes without assuming α‐helical structure a priori. The fitting of three angular restraints per peptide plane and filtering by Rosetta scoring functions has yielded a consensus α‐helical transmembrane structure for Pf1 protein. 

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