Allylic amines are valuable synthetic targets en route to diverse biologically active amine products. Current allylic C–H amination strategies remain limited with respect to the viable ...N-substituents. Herein, we disclose a new electrochemical process to prepare aliphatic allylic amines by coupling two abundant starting materials: secondary amines and unactivated alkenes. This oxidative transformation proceeds via electrochemical generation of an electrophilic adduct between thianthrene and the alkene substrates. Treatment of these adducts with aliphatic amine nucleophiles and base provides allylic amine products in high yield. This synthetic strategy is also amenable to functionalization of feedstock gaseous alkenes at 1 atm. In the case of 1-butene, high Z-selective crotylation is observed. This strategy, however, is not limited to the synthesis of simple building blocks; complex biologically active molecules are suitable as both alkene and amine coupling partners. Preliminary mechanistic studies implicate vinylthianthrenium salts as key reactive intermediates.
We describe a photocatalytic system that reveals latent photooxidant behavior from one of the most reducing conventional photoredox catalysts, N-phenylphenothiazine (PTH). This aerobic photochemical ...reaction engages difficult to oxidize feedstocks, such as benzene, in C(sp2)–N coupling reactions through direct oxidation. Mechanistic studies are consistent with activation of PTH via photooxidation and with Lewis acid cocatalysts scavenging inhibitors inextricably formed in this process.
We report carbene insertion into Si−H bonds of polyhedral oligomeric silsesquioxanes (POSS) for the synthesis of highly functionalized siloxane nanomaterials. Dirhodium(II) carboxylates catalyze ...insertion of aryl‐diazoacetates as carbene precursors to afford POSS structures containing both ester and aryl groups as orthogonal functional handles for further derivatization of POSS materials. Four diverse and structurally varied silsesquioxane core scaffolds with one, three, or eight Si−H bonds were evaluated with diazo reactants to produce a total of 20 new POSS compounds. Novel diazo compounds containing a fluorinated octyl group and boron‐dipyrromethene (BODIPY) chromophore demonstrate the use of highly functionalized substrates. Transformations of aryl(ester)‐functionalized POSS compounds derived from this method are demonstrated, including ester hydrolysis and Suzuki–Miyaura cross‐coupling.
Carbene insertion into Si−H bonds of silsesquioxane silanes was accomplished using RhII catalysis and diazo compounds as carbene precursors. Silsesquioxanes with up to eight Si−H bonds were functionalized up to gram‐scale. Diazo compounds with a fluorinated octyl group and BODIPY fluorophore were accessed to highlight the utility of diazo chemistry. Further transformations including a cross‐coupling and ester deprotection are demonstrated.
Oxidative alkene functionalization reactions are a fundamental class of complexity‐building organic transformations. However, the majority of established approaches rely on electrophilic reagents ...that limit the diversity of groups that can be installed. Recent advances have established a new approach that instead relies on the transformation of alkenes into thianthrene‐derived cationic electrophiles. These linchpin intermediates can be generated selectively and undergo a diverse array of mechanistically distinct reactions with abundant nucleophiles. Taken together, this unlocks a suite of net oxidative alkene transformations that have been elusive using conventional strategies. This Minireview describes these advances and is organized around the three distinct synthons formally accessible from alkenes via thianthrenation: 1) alkenyl cations; 2) vicinal dications; 3) allyl cations. Throughout the Minireview, we illustrate how thianthrenium salts address key limitations endemic to classic alkene‐derived electrophiles and highlight the mechanistic origins of these distinctions wherever possible.
The transformation of alkenes into thianthrene‐derived cationic electrophiles unlocks a suite of net oxidative alkene transformations that have been elusive using conventional strategies. These linchpin intermediates can be generated selectively and undergo a diverse array of mechanistically distinct reactions with abundant nucleophiles.
The H-bond donating ability for 127 compounds including drug fragments and isosteres have been quantified using a simple and rapid method with 31P NMR spectroscopy. Functional groups important to ...medicinal chemistry were evaluated including carboxylic acids, alcohols, phenols, thioic acids and nitrogen group H-bond donors. 31P NMR shifts for binding to a phosphine oxide probe have a higher correlation with equilibrium constants for H-bonding (log KHA) than acidity (pKa), indicating that these binding experiments are representative of H-bonding ability and not proton transfer. Additionally, 31P NMR binding data for carboxylic acid isosteres correlates with physicochemical properties such as lipophilicity, membrane permeability and plasma protein binding. This method has been used to evaluate the H-bond donating ability of small molecule drug compounds such as NSAIDs and antimicrobials.
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•H-bond donating ability of >100 compounds, drug fragments, and isosteres quantified.•Simple, rapid method using 31P NMR spectroscopy and commercially available probe.•High correlation between 31P NMR values and equilibrium constants for H-bonding.•31P NMR values correlate with physicochemical properties.
Cyclopropanes are desirable structural motifs with valuable applications in drug discovery and beyond. Established alkene cyclopropanation methods give rise to cyclopropanes with a limited array of ...substituents, are difficult to scale, or both. Herein, we disclose a new cyclopropane synthesis through the formal coupling of abundant carbon pronucleophiles and unactivated alkenes. This strategy exploits dicationic adducts derived from electrolysis of thianthrene in the presence of alkene substrates. We find that these dielectrophiles undergo cyclopropanation with methylene pronucleophiles via alkenyl thianthrenium intermediates. This protocol is scalable, proceeds with high diastereoselectivity, and tolerates diverse functional groups on both the alkene and pronucleophile coupling partners. To validate the utility of this new procedure, we prepared an array of substituted analogs of an established cyclopropane that is en route to multiple pharmaceuticals.
A new protocol for diastereoselective cyclopropanation from unactivated alkenes and acidic carbon pronucleophiles is reported. The method is scalable and amenable to synthesis of medicinally relevant molecules.
A detailed mechanistic study of the Z-selective allylic functionalization via thianthrenium salts is presented. Kinetic analyses, deuterium labeling experiments, and computational methods are used to ...rationalize the observed reactivity and selectivity. We find that the reaction proceeds via a rate-determining and stereodetermining allylic deprotonation of an alkenylthianthrenium species. The Z-configuration of the resultant allylic ylide is translated into the Z-allylic amine product through a sequence of subsequent fast and irreversible steps: protonation to form a Z-allylic thianthrenium electrophile and then regioselective substitution by the nucleophile. In the stereodetermining deprotonation step, computational studies identified a series of stabilizing nonbonding interactions in the Z-alkene-forming transition state that contribute to the stereoselectivity.
The catalytic activity, kinetics, and quantification of H‐bonding ability of incompletely condensed polyhedral oligomeric silsesquioxane (POSS) silanols are reported. POSS‐triols, a homogeneous model ...for vicinal silica surface sites, exhibit enhanced H‐bonding compared with other silanols and alcohols as quantified using a 31P NMR probe. Evaluation of a Friedel–Crafts addition reaction shows that phenyl‐POSS‐triol is active as an H‐bond donor catalyst whereas other POSS silanols studied are not. An in‐depth kinetic study (using RPKA and VTNA) highlights the concentration‐dependent H‐bonding behavior of POSS‐triols, which is attributed to intermolecular association forming an off‐cycle dimeric species. Binding constants provide additional support for reduced H‐bond ability at higher concentrations, which is attributed to competitive association. POSS‐triol self‐association disrupts H‐bond donor abilities relevant for catalysis by reducing the concentration of active monomeric catalyst.
Elucidating the POSSible activity: The catalytic activity, kinetics, and quantification of H‐bonding ability of incompletely condensed polyhedral oligomeric silsesquioxane (POSS) silanols are reported. Evaluation of a Friedel–Crafts addition reaction shows that phenyl‐POSS‐triol is active as an H‐bond donor catalyst whereas other POSS silanols studied are not. Kinetic studies were carried out to highlight the concentration‐dependent H‐bonding behavior of POSS‐triols.
We report carbene insertion into Si−H bonds of polyhedral oligomeric silsesquioxanes (POSS) for the synthesis of highly functionalized siloxane nanomaterials. Dirhodium(II) carboxylates catalyze ...insertion of aryl‐diazoacetates as carbene precursors to afford POSS structures containing both ester and aryl groups as orthogonal functional handles for further derivatization of POSS materials. Four diverse and structurally varied silsesquioxane core scaffolds with one, three, or eight Si−H bonds were evaluated with diazo reactants to produce a total of 20 new POSS compounds. Novel diazo compounds containing a fluorinated octyl group and boron‐dipyrromethene (BODIPY) chromophore demonstrate the use of highly functionalized substrates. Transformations of aryl(ester)‐functionalized POSS compounds derived from this method are demonstrated, including ester hydrolysis and Suzuki–Miyaura cross‐coupling.
Carbene insertion into Si−H bonds of silsesquioxane silanes was accomplished using RhII catalysis and diazo compounds as carbene precursors. Silsesquioxanes with up to eight Si−H bonds were functionalized up to gram‐scale. Diazo compounds with a fluorinated octyl group and BODIPY fluorophore were accessed to highlight the utility of diazo chemistry. Further transformations including a cross‐coupling and ester deprotection are demonstrated.
Oxidative alkene functionalization reactions are a fundamental class of complexity‐building organic transformations. However, the majority of established approaches rely on electrophilic reagents ...that limit the diversity of groups that can be installed. Recent advances have established a new approach that instead relies on the transformation of alkenes into thianthrene‐derived cationic electrophiles. These linchpin intermediates can be generated selectively and undergo a diverse array of mechanistically distinct reactions with abundant nucleophiles. Taken together, this unlocks a suite of net oxidative alkene transformations that have been elusive using conventional strategies. This Minireview describes these advances and is organized around the three distinct synthons formally accessible from alkenes via thianthrenation: 1) alkenyl cations; 2) vicinal dications; 3) allyl cations. Throughout the Minireview, we illustrate how thianthrenium salts address key limitations endemic to classic alkene‐derived electrophiles and highlight the mechanistic origins of these distinctions wherever possible.
The transformation of alkenes into thianthrene‐derived cationic electrophiles unlocks a suite of net oxidative alkene transformations that have been elusive using conventional strategies. These linchpin intermediates can be generated selectively and undergo a diverse array of mechanistically distinct reactions with abundant nucleophiles.
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