2-Pyridone-Directed CuII-Catalyzed General Method of C(sp2)-H Activation for C-S, C-Se, and C-N Cross-Coupling: Easy Access to Aryl Thioethers, Selenide Ethers, and Sulfonamides and DFT Study.

We have demonstrated N-substituted 2-pyridones as an N,O-directing group for selective C(sp2)-H-activated thiolation, selenylation, and sulfonamidation of ortho C-H bonds of benzamides. This method utilizes a cost-effective Cu(II)-salt catalyst instead of precious metal catalysts, achieving high yields, including gram-scale synthesis and excellent functional group tolerance. We applied this protocol to access 30 different compounds with high yields, demonstrating thiolation of fluorine-substituted benzamides as well. Density functional theory (DFT) calculations support the mechanism, including acetate-supported concerted metalation deprotonation (CMD) steps and the unique role of dimethyl sulfoxide (DMSO) solvent. The facile synthesis of pharmaceutically important sulfonamides and other compounds highlights the method's potential in chemistry and medicinal chemistry.

C-H functionalization of pyridines.

Pyridine and its reduced form (piperidine) are the most common nitrogen heterocycles in FDA-approved drugs. Additionally, their presence in alkaloids, ligands for transition metals, catalysts, and organic materials with various properties makes them among the most important structural cores. Despite its importance, direct and selective functionalization of pyridine remains scarce due to its electron-poor nature and nitrogen coordination power. Instead, functionalized pyridine rings were primarily constructed from suitably substituted acyclic precursors. The focus on sustainable chemistry with minimum waste generation encourages chemists to develop direct C-H functionalization. This review summarizes different approaches to tackle the reactivity and regio- and stereoselectivity aspects for direct pyridine C-H functionalization.

Phosphite-Catalyzed C-H Allylation of Azaarenes via an Enantioselective [2,3]-Aza-Wittig Rearrangement.

A phosphite-mediated [2,3]-aza-Wittig rearrangement has been developed for the regio- and enantioselective allylic alkylation of six-membered heteroaromatic compounds (azaarenes). The nucleophilic phosphite adducts of N-allyl salts undergo a stereoselective base-mediated aza-Wittig rearrangement and dissociation of the chiral phosphite for overall C-H functionalization of azaarenes. This method provides efficient access to tertiary and quaternary chiral centers in isoquinoline, quinoline, and pyridine systems, tolerating a broad variety of substituents on both the allyl part and azaarenes. Catalysis with chiral phosphites is also demonstrated with synthetically useful yields and enantioselectivities.

An organocatalyst bound α-aminoalkyl radical intermediate for controlled aerobic oxidation of iminium ions.

A catalyst bound α-aminoalkyl radical intermediate from iminium is developed to control its formation and reactivity with aerobic oxygen. The influence of the catalyst was demonstrated via the ease of radical intermediate formation and its subsequent reactivity, including the first catalyst-controlled enantioselective aerobic oxidation with a chiral phosphite catalyst.

A removable functional group strategy for regiodivergent Wittig rearrangement products.

[1,2] and [2,3] Wittig rearrangements are competing reaction pathways, often leading to uncontrollable product distribution. We employ a single removable functional group to fulfill the dual role of attaining a reversible [2,3] and stabilizing radical intermediate for the [1,2] path to obtain both the Wittig products selectively for a broad range of substrates.

Development of the Vinylogous Pictet-Spengler Cyclization and Total Synthesis of (±)-Lundurine†A.

A novel vinylogous Pictet-Spengler cyclization has been developed for the generation of indole-annulated medium-sized rings. The method enables the synthesis of tetrahydroazocinoindoles with a fully substituted carbon center, a prevalent structural motif in many biologically active alkaloids. The strategy has been applied to the total synthesis of (±)-lundurine A.

Silica-Supported Oligomeric Benzyl Phosphate (Si-OBP) and Triazole Phosphate (Si-OTP) Alkylating Reagents.

The syntheses of silica-supported oligomeric benzyl phosphates (Si-OBP(n)) and triazole phosphates (Si-OTP(n)) using ring-opening metathesis polymerization (ROMP) for use as efficient alkylating reagents is reported. Ease of synthesis and grafting onto the surface of norbornenyl-tagged (Nb-tagged) silica particles has been demonstrated for benzyl phosphate and triazole phosphate monomers. It is shown that these silica polymer hybrid reagents, Si-OBP(n) and Si-OTP(n), can be used to carry out alkylation reactions with an array of different nucleophiles to afford the corresponding benzylated and (triazolyl)methylated products in good yield and high purity.

Annulation reactions of allenyl esters: an approach to bicyclic diones and medium-sized rings.

A flexible approach to construct sterically congested bicyclo-alkenedione frameworks is reported. Under the action of potassium carbonate, α-sulphonyl cycloalkanones are added to functionalized allenyl esters, leading to a lactone intermediate that is subsequently reduced to initiate an intramolecular aldol cyclization to [3.2.1], [3.3.1], and [4.3.1] bicycles. Oxidation then affords bicyclic diones in good three-step yields. Under exceptionally mild conditions, these bicycles are converted to highly functionalized medium-sized rings through a Grob-type fragmentation.

Brønsted acid catalyzed enantioselective indole aza-Claisen rearrangement mediated by an arene CH-O interaction.

Although the aromatic aza-Claisen rearrangement is a general strategy for accessing substituted aromatic amines, there are no highly enantioselective examples of this process. We report the first Brønsted acid catalyzed enantioselective indole aza-Claisen rearrangement for the synthesis of chiral 3-amino-2-substituted indoles. We present evidence for an arene CH-O interaction as a source of activation and stereoinduction, which is an unprecedented phenomenon in enantioselective Brønsted acid catalysis. The products of this reaction can be transformed into 3-aminooxindoles, which are prevalent in many biologically active small molecules.

Synthesis of a Library of 1,5,2-Dithiazepine 1,1-Dioxides. Part 1: A One-Pot Sulfonylation/Thia-Michael Protocol.

A novel one-pot sulfonylation/intramolecular thia-Michael protocol is reported for the synthesis of 1,5,2-dithiazepine 1,1-dioxides. Sulfonylation between cysteine ethyl ester/cysteamine and 2-chloroethanesulfonyl chloride, followed by in situ intramolecular thia-Michael addition, was achieved and afforded the titled 1,5,2-dithiazepine-1,1-dioxide scaffolds. Diversification was demonstrated for future library synthesis.

Blue Fluorescence of Cyano-tryptophan Predicts Local Electrostatics and Hydrogen Bonding in Biomolecules.

Cyano-tryptophan is an unnatural fluorescent amino acid that emits in the visible region. Along with the structural similarity with tryptophan, the unique photophysical properties of this fluorophore make it an ideal probe for biophysical research. Herein, combining fluorescence spectroscopy, infrared spectroscopy, and molecular dynamics simulations, we show that the cyano-tryptophan's emission energy quantifies the underlying bond-specific noncovalent interactions in terms of the electric field. We further report the use of fluorophore's emission energy to predict its hydrogen bond characteristics. We demonstrate that combining experiments with molecular dynamics simulations can provide the hydrogen bonding status of the nitrile moiety. In addition, we report a method to differentiate between aqueous and nonaqueous hydrogen-bonding partners. Using a phenomenological approach, we demonstrate that the presence of the cyano-indole moiety is responsible for the distinct correlations between the fluorophore's emission and the electrostatic forces on the nitrile bond. As indole is a privileged scaffold for both native amino acids and nucleobases, cyano-indoles will have many multifaceted applications.

Phosphite mediated asymmetric N to C migration for the synthesis of chiral heterocycles from primary amines.

A phosphite mediated stereoretentive C-H alkylation of N-alkylpyridinium salts derived from chiral primary amines was achieved. The reaction proceeds through the activation of the N-alkylpyridinium salt substrate with a nucleophilic phosphite catalyst, followed by a base mediated [1,2] aza-Wittig rearrangement and subsequent catalyst dissociation for an overall N to C-2 alkyl migration. The scope and degree of stereoretention were studied, and both experimental and theoretical investigations were performed to support an unprecedented aza-Wittig rearrangement-rearomatization sequence. A catalytic enantioselective version starting with racemic starting material and chiral phosphite catalyst was also established following our understanding of the stereoretentive process. This method provides efficient access to tertiary and quaternary stereogenic centers in pyridine systems, which are prevalent in drugs, bioactive natural products, chiral ligands, and catalysts.

[1,3]-Claisen Rearrangement via Removable Functional Group Mediated Radical Stabilization.

A thermal O-to-C [1,3]-rearrangement of α-hydroxy acid derived enol ethers was achieved under mild conditions. The 2-aminothiophenol protection of carboxylic acids facilitates formation of the [1,3] precursor and its thermal rearrangement via stabilization of a radical intermediate. Experimental and theoretical evidence for dissociative radical pair formation, its captodative stability via aminothiophenol, and a unique solvent effect are presented. The aminothiophenol was deprotected from rearrangement products as well as after derivatization to useful synthons.

Anion-catalyzed addition of gamma-silylallenyl esters to aldehydes: a new entry into [3.2.1] bicyclic natural products.

A significant improvement in the generality and reactivity of MBH-type reactions is made possible by anion catalysis and a 1,3-Brook rearrangement. In this new reaction, both aliphatic and aromatic aldehydes are rapidly added to silylallenes, leading to gamma-carbinol allenoates at low temperatures. The utility of these reaction products is demonstrated by a fast-tracked synthesis of a [3.2.1] bisoxa bicycle that makes up the framework of many biologically active natural products, including vitisinol D, an antithrombotic agent.

Selective one-pot synthesis of allenyl and alkynyl esters from beta-ketoesters.

A convenient method is described for the dehydration of beta-ketoesters to generate conjugated and deconjugated alkynyl esters and conjugated allenyl esters. This sequential one-pot method involves the formation of a vinyl triflate monoanion intermediate that leads to the selective formation of alkynes or allenes depending on additives and conditions used. Product outcomes appear to be a function of unique mono- and dianion mechanisms which are described.

Click chemistry based rapid one-pot synthesis and evaluation for protease inhibition of new tetracyclic triazole fused benzodiazepine derivatives.

We describe herein a one-pot synthesis of novel tetracyclic scaffolds that incorporate a fusion of a proline, 1,2,3-triazole ring with [1,4]-benzodiazepin-8(4H)-one ring systems following click chemistry. The expected peptide bond formation followed by in situ 1,3-dipolar cycloaddition in absence of any catalyst led to the formation of new triazole fused benzodiazepine derivatives.

Allenoate Prenucleophiles: A Triply Diastereoselective Approach to ß-Hydroxy Esters Containing All-Carbon α-Quaternary Centers.

Allenyl esters activated by titanium(IV) underwent additions to a wide range of aldehydes in high regio- and diastereoselectivities leading to products containing an all-carbon quaternary center bearing an α-vinyl group that was installed with high selectivity for the Z-geometry. An aldol product was also converted to an indanone offering a new route to this important compound class. Product triple diastereoselectivity has been rationalized using a concerted transition-state model.

High-Throughput Screening for Bacterial Glycosyltransferase Inhibitors.

The enteropathogenic and enterohemorrhagic Escherichia coli NleB proteins as well as the Salmonella enterica SseK proteins are type III secretion system effectors that function as glycosyltransferase enzymes to post-translationally modify host substrates on arginine residues. This modification is unusual because it occurs on the guanidinium groups of arginines, which are poor nucleophiles, and is distinct from the activity of the mammalian O-linked N-acetylglucosaminyltransferase. We conducted high-throughput screening assays to identify small molecules that inhibit NleB/SseK activity. Two compounds, 100066N and 102644N, both significantly inhibited NleB1, SseK1, and SseK2 activities. Addition of these compounds to cultured mammalian cells was sufficient to inhibit NleB1 glycosylation of the tumor necrosis factor receptor type 1-associated DEATH domain protein. These compounds were also capable of inhibiting Salmonella enterica strain ATCC 14028 replication in mouse macrophage-like cells. Neither inhibitor was significantly toxic to mammalian cells, nor showed in vitro cross-reactivity with the mammalian O-linked N-acetylglucosaminyltransferase. These compounds or derivatives generated from medicinal chemistry refinements may have utility as a potential alternative therapeutic strategy to antibiotics or as reagents to further the study of bacterial glycosyltransferases.

Transition Metal, Azide, and Oxidant-Free Homo- and Heterocoupling of Ambiphilic Tosylhydrazones to the Regioselective Triazoles and Pyrazoles.

With N-tosylhydrazone as an ambiphilic reagent, an unprecedented cyclization reaction of two identical or different tosylhydrazones has been developed to access various 4,5-disubstituted-2H-triazoles under transition metal, azide, and oxidant-free conditions. A mechanistic rationalization study led to the identification of several electronically diverse unsaturated systems for regioselective synthesis of 1- and 2-substituted 1,2,3-triazoles and pyrazoles.

Development and Application of a Recyclable High-Load Magnetic Co/C Hybrid ROMP-Derived Benzenesulfonyl Chloride Reagent and Utility of Corresponding Analogues.

The development and application of high-load, recyclable magnetic Co/C hybrid ROMP-derived benzenesulfonyl chloride and analogues is reported. The regeneration and utility of these reagents in the methylation/alkylation of various carboxylic acids is demonstrated via efficient retrieval of the magnetic reagent with a neodymium magnet. Additional reactions employing the analogue sulfonic acid and in situ generated magnetic benzenesulfonyl azide are also reported.