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Cross‐electrophile coupling (XEC) between aryl halides and alkyl halides is a streamlined approach for C(sp2)−C(sp3) bond construction, which is highly valuable in medicinal chemistry. Based on a key NiII aryl amido intermediate, we developed a highly selective and scalable Ni‐catalyzed electrochemical XEC reaction between (hetero)aryl halides and primary and secondary alkyl halides. Experimental and computational mechanistic studies indicate that an amine secondary ligand slows down the oxidative addition process of the Ni‐polypyridine catalyst to the aryl bromide and a NiII aryl amido intermediate is formed in situ during the reaction process. The relatively slow oxidative addition is beneficial for enhancing the selectivity of the XEC reaction. The NiII aryl amido intermediate stabilizes the NiII–aryl species to prevent the aryl–aryl homo‐coupling side reactions and acts as a catalyst to activate the alkyl bromide substrates. This electrosynthesis system provides a facile, practical, and scalable platform for the formation of (hetero)aryl–alkyl bonds using standard Ni catalysts under mild conditions. The mechanistic insights from this work could serve as a great foundation for future studies on Ni‐catalyzed cross‐couplings. [ABSTRACT FROM AUTHOR]

Paired redox‐neutral electrolysis offers an attractive green platform for organic synthesis by avoiding sacrificial oxidants and reductants. Carboxylates are non‐toxic, stable, inexpensive, and widely available, making them ideal nucleophiles for C−C cross‐coupling reactions. Here, we report the electro/Ni dual‐catalyzed redox‐neutral decarboxylative C(sp3)−C(sp2) cross‐coupling reactions of pristine carboxylates with aryl bromides. At a cathode, a NiII(Ar)(Br) intermediate is formed through the activation of Ar−Br bond by a NiI‐bipyridine catalyst and subsequent reduction. At an anode, the carboxylates, including amino acid, benzyl carboxylic acid, and 2‐phenoxy propionic acid, undergo oxidative decarboxylation to form carbon‐based free radicals. The combination of NiII(Ar)(Br) intermediate and carbon radical results in the formation of C(sp3)−C(sp2) cross‐coupling products. The adaptation of this electrosynthesis method to flow synthesis and valuable molecule synthesis was demonstrated. The reaction mechanism was systematically studied through electrochemical voltammetry and density functional theory (DFT) computational studies. The relationships between the electrochemical properties of carboxylates and the reaction selectivity were revealed. The electro/Ni dual‐catalyzed cross‐coupling reactions described herein expand the chemical space of paired electrochemical C(sp3)−C(sp2) cross‐coupling and represent a promising method for the construction of the C(sp3)−C(sp2) bonds because of the ubiquitous carboxylate nucleophiles and the innate scalability and flexibility of electrochemical flow‐synthesis technology. [ABSTRACT FROM AUTHOR]

Aims: We sought to compare in‐office physical exam findings via standing cough test (SCT) versus 24‐hour pad weights among men seeking treatment for postprostatectomy stress urinary incontinence (SUI). Methods: A retrospective review of a single surgeon database of incontinence procedures was performed. Documentation of SUI severity (grades 0‐4) was completed by SCT preoperatively utilizing the Male Stress Incontinence Grading Scale (MSIGS). All patients had pads per day (PPD) and 24‐hour pad weights obtained. We determined the Spearman's correlation coefficient between these variables. Results: We identified 104 men who underwent anti‐incontinence surgery (AdVance Sling or artificial urinary sphincter [AUS]). In the sling group (65 patients), nearly all (97%) had minimal incontinence with SCT (MSIGS = 0‐2). In the AUS group (39 patients), most patients (69%) had an MSIGS 3 or 4 with SCT. Spearman's coefficient between quantification of SCT and pad weight for the overall group was ρ =.68 (P <.0001) demonstrating a strong positive correlation. PPD was also strongly correlated with pad weight (ρ =.55, P <.0001). As seen previously, SCT and PPD were correlated (ρ =.47, P <.0001). In a multivariable model predicting pad weight, the effect of SCT was greater than PPD (β = 83 [54‐111], P <.0001 vs 45 [2169], P =.0004). Conclusions: SCT findings strongly correlate to 24‐hour pad weights in the evaluation of male SUI. The SCT shows promise as a rapid, reliable, noninvasive measure of SUI severity before anti‐incontinence surgery. [ABSTRACT FROM AUTHOR]

Cross-electrophile coupling (XEC) between aryl halides and alkyl halides is a streamlined approach for C(sp 2 )-C(sp 3 ) bond construction, which is highly valuable in medicinal chemistry. Based on a key Ni II aryl amido intermediate, we developed a highly selective and scalable Ni-catalyzed electrochemical XEC reaction between (hetero)aryl halides and primary and secondary alkyl halides. Experimental and computational mechanistic studies indicate that an amine secondary ligand slows down the oxidative addition process of the Ni-polypyridine catalyst to the aryl bromide and a Ni II aryl amido intermediate is formed in situ during the reaction process. The relatively slow oxidative addition is beneficial for enhancing the selectivity of the XEC reaction. The Ni II aryl amido intermediate stabilizes the Ni II -aryl species to prevent the aryl-aryl homo-coupling side reactions and acts as a catalyst to activate the alkyl bromide substrates. This electrosynthesis system provides a facile, practical, and scalable platform for the formation of (hetero)aryl-alkyl bonds using standard Ni catalysts under mild conditions. The mechanistic insights from this work could serve as a great foundation for future studies on Ni-catalyzed cross-couplings., (© 2024 Wiley-VCH GmbH.)

Paired redox-neutral electrolysis offers an attractive green platform for organic synthesis by avoiding sacrificial oxidants and reductants. Carboxylates are non-toxic, stable, inexpensive, and widely available, making them ideal nucleophiles for C-C cross-coupling reactions. Here, we report the electro/Ni dual-catalyzed redox-neutral decarboxylative C(sp 3 )-C(sp 2 ) cross-coupling reactions of pristine carboxylates with aryl bromides. At a cathode, a Ni II (Ar)(Br) intermediate is formed through the activation of Ar-Br bond by a Ni I -bipyridine catalyst and subsequent reduction. At an anode, the carboxylates, including amino acid, benzyl carboxylic acid, and 2-phenoxy propionic acid, undergo oxidative decarboxylation to form carbon-based free radicals. The combination of Ni II (Ar)(Br) intermediate and carbon radical results in the formation of C(sp 3 )-C(sp 2 ) cross-coupling products. The adaptation of this electrosynthesis method to flow synthesis and valuable molecule synthesis was demonstrated. The reaction mechanism was systematically studied through electrochemical voltammetry and density functional theory (DFT) computational studies. The relationships between the electrochemical properties of carboxylates and the reaction selectivity were revealed. The electro/Ni dual-catalyzed cross-coupling reactions described herein expand the chemical space of paired electrochemical C(sp 3 )-C(sp 2 ) cross-coupling and represent a promising method for the construction of the C(sp 3 )-C(sp 2 ) bonds because of the ubiquitous carboxylate nucleophiles and the innate scalability and flexibility of electrochemical flow-synthesis technology., (© 2024 GDCh.)

A hydroxylamine-derived electrophilic aminating reagent produces a transient and bulky aminium radical intermediate upon in situ activation by either TMSOTf or TFA and a subsequent electron transfer from an iron(II) catalyst. Density functional theory calculations were used to examine the regioselectivity of arene C-H amination reactions on diversely substituted arenes. The calculations suggest a simple charge-controlled regioselectivity model that enables prediction of the major C(sp 2 )-H amination product.

Ni-catalyzed electrochemical aryl amination (e-amination) is an attractive, emerging approach to building C-N bonds. Here, we report in-depth experimental and computational studies that examined the mechanism of Ni-catalyzed e-amination reactions. Key Ni II -amine dibromide and Ni II aryl amido intermediates were chemically synthesized and characterized. The combination of experiments and DFT calculations suggest (1) there is coordination of an amine to the Ni II catalyst before the cathodic reduction and oxidative addition steps, (2) a stable Ni II aryl amido intermediate is produced from the cathodic half-reaction, a critical step in controlling the selectivity between cross-coupling and undesired homo-coupling reaction pathways, (3) the diazabicycloundecene additive shifts the aryl halide oxidative addition mechanism from a Ni I -based pathway to a Ni 0 -based pathway, and (4) redox-active bromide in the supporting electrolyte functions as a redox mediator to promote the oxidation of the stable Ni II aryl amido intermediate to a Ni III aryl amido intermediate. Subsequently, the Ni III aryl amido intermediate undergoes facile reductive elimination to provide a C-N cross-coupling product at room temperature. Overall, our results provide new fundamental understandings about this e-amination reaction and guidance for further development of other Ni-catalyzed electrosynthetic reactions such as C-C and C-O cross-couplings.

alpha-Glucans such as starch and glycogen are abundant in the human oropharynx, the main site of group A Streptococcus (GAS) infection. However, the role in pathogenesis of GAS extracellular alpha-glucan binding and degrading enzymes is unknown. The serotype M1 GAS genome encodes two extracellular proteins putatively involved in alpha-glucan binding and degradation; pulA encodes a cell wall anchored pullulanase and amyA encodes a freely secreted putative cyclomaltodextrin alpha-glucanotransferase. Genetic inactivation of amyA, but not pulA, abolished GAS alpha-glucan degradation. The DeltaamyA strain had a slower rate of translocation across human pharyngeal epithelial cells. Consistent with this finding, the DeltaamyA strain was less virulent following mouse mucosal challenge. Recombinant AmyA degraded alpha-glucans into beta-cyclomaltodextrins that reduced pharyngeal cell transepithelial resistance, providing a physiologic explanation for the observed transepithelial migration phenotype. Higher amyA transcript levels were present in serotype M1 GAS strains causing invasive infection compared with strains causing pharyngitis. GAS proliferation in a defined alpha-glucan-containing medium was dependent on the presence of human salivary alpha-amylase. These data delineate the molecular mechanisms by which alpha-glucan degradation contributes to GAS host-pathogen interaction, including how GAS uses human salivary alpha-amylase for its own metabolic benefit.