Regioselective Synthesis of Fluorosulfonyl 1,2,3-Triazoles from Bromovinylsulfonyl Fluoride

A regioselective metal-free preparation of 4-fluorosulfonyl 1,2,3-triazoles from organic azides and a hitherto underexplored bromovinylsulfonyl fluoride building block is described. This reaction is very general and was extended to the synthesis of various sulfonates, sulfonamides, and sulfonic acid derivatives of triazoles and other azole heterocycles which would otherwise be difficult to access by existing methods

Rhodium(II)-Catalyzed Asymmetric Sulfur(VI) Reduction of Diazo Sulfonylamidines

Diazo sulfonylamidines readily undergo enantioselective oxygen transfer from sulfur to carbon atom in the presence of chiral rhodium­(II) carboxylates resulting in chiral sulfinylamidines. This unusual asymmetric atom transfer “reduction” occurs rapidly under mild conditions, and sulfinylamidines are obtained in excellent yield

Generation and Aerobic Oxidation of Azavinyl Captodative Radicals

We describe a cascade reaction that selectively incorporates oxygen into the carbon−carbon backbone of alkynes using air as the source. The process starts by lithiating readily available, electron-deficient 1,2,3-triazoles, resulting in an amphoteric lithium ketenimine intermediate. This intermediate can react with both electrophiles and nucleophiles. Under the conditions outlined in this study, we generate azavinyl radicals, which are a rare subset of captodative radicals. When exposed to atmospheric oxygen, these radicals efficiently transform into α-oxygenated amidinesa class of compounds that has not been extensively studied. This process uniquely utilizes molecular oxygen without requiring metal or photocatalysts, and it occurs under mild conditions. Our mechanistic studies provide insights into the intricate sequence involved in the formation and selective capture of azavinyl captodative radicals

Transannulation of 1‑Sulfonyl-1,2,3-triazoles with Heterocumulenes

Readily available 1-mesyl-1,2,3-triazoles are efficiently converted into a variety of imidazolones and thiazoles by Rh­(II)-catalyzed denitrogenative reactions with isocyanates and isothiocyanates, respectively. The proposed triazole–diazoimine equilibrium results in the formation of highly reactive azavinyl metal-carbenes, which react with heterocumulenes causing an apparent swap of 1,2,3-triazole core for another heterocycle

Transannulation of 1‑Sulfonyl-1,2,3-triazoles with Heterocumulenes

Readily available 1-mesyl-1,2,3-triazoles are efficiently converted into a variety of imidazolones and thiazoles by Rh­(II)-catalyzed denitrogenative reactions with isocyanates and isothiocyanates, respectively. The proposed triazole–diazoimine equilibrium results in the formation of highly reactive azavinyl metal-carbenes, which react with heterocumulenes causing an apparent swap of 1,2,3-triazole core for another heterocycle

Transannulation of 1‑Sulfonyl-1,2,3-triazoles with Heterocumulenes

Readily available 1-mesyl-1,2,3-triazoles are efficiently converted into a variety of imidazolones and thiazoles by Rh­(II)-catalyzed denitrogenative reactions with isocyanates and isothiocyanates, respectively. The proposed triazole–diazoimine equilibrium results in the formation of highly reactive azavinyl metal-carbenes, which react with heterocumulenes causing an apparent swap of 1,2,3-triazole core for another heterocycle

Selective and Orthogonal Post-Polymerization Modification using Sulfur(VI) Fluoride Exchange (SuFEx) and Copper-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) Reactions

Functional polystyrenes and polyacrylamides, containing combinations of fluorosulfate, aromatic silyl ether, and azide side chains, were used as scaffolds to demonstrate the postpolymerization modification capabilities of sulfur­(VI) fluoride exchange (SuFEx) and CuAAC chemistries. Fluorescent dyes bearing appropriate functional groups were sequentially attached to the backbone of the copolymers, quantitatively and selectively addressing their reactive partners. This combined SuFEx and CuAAC approach proved to be robust and versatile, allowing for a rare accomplishment: triple orthogonal functionalization of a copolymer under essentially ambient conditions without protecting groups

Selectivity Optimization of Substituted 1,2,3-Triazoles as α7 Nicotinic Acetylcholine Receptor Agonists

Three series of substituted <i>anti</i>-1,2,3-triazoles (IND, PPRD, and QND), synthesized by cycloaddition from azide and alkyne building blocks, were designed to enhance selectivity and potency profiles of a lead α7 nicotinic acetylcholine receptor (α7-nAChR) agonist, TTIn-1. Designed compounds were synthesized and screened for affinity by a radioligand binding assay. Their functional characterization as agonists and antagonists was performed by fluorescence resonance energy transfer assay using cell lines expressing transfected cDNAs, α7-nAChRs, α4β2-nAChRs, and 5HT_3A receptors, and a fluorescence cell reporter. In the IND series, a tropane ring of TTIn-1, substituted at N1, was replaced by mono- and bicyclic amines to vary length and conformational flexibility of a carbon linker between nitrogen atom and N1 of the triazole. Compounds with a two-carbon atom linker optimized binding with K_d’s at the submicromolar level. Further modification at the hydrophobic indole of TTIn-1 was made in PPRD and QND series by fixing the amine center with the highest affinity building blocks in the IND series. Compounds from IND and PPRD series are selective as agonists for the α7-nAChRs over α4β2-nAChRs and 5HT_3A receptors. Lead compounds in the three series have EC₅₀’s between 28 and 260 nM. Based on the EC₅₀, affinity, and selectivity determined from the binding and cellular responses, two of the leads have been advanced to behavioral studies described in the companion article (DOI: 10.1021/acschemneuro.5b00059)

DataSheet1_Electrochemical Studies of the Cycloaddition Activity of Bismuth(III) Acetylides Towards Organic Azides Under Copper(I)-Catalyzed Conditions.pdf

Time-dependent monitoring of the reactive intermediates provides valuable information about the mechanism of a synthetic transformation. However, the process frequently involves intermediates with short lifetimes that significantly challenge the accessibility of the desired kinetic data. We report in situ cyclic voltammetry (CV) and nuclear magnetic resonance (NMR) spectroscopy studies of the cycloaddition reaction of organobismuth(III) compounds with organic azides under the copper(I)-catalyzed conditions. A series of bismuth(III) acetylides carrying diphenyl sulfone scaffolds have been synthesized to study the underlying electronic and steric effects of the tethered moieties capable of transannular oxygen O···Bi interactions and para-functionality of the parent phenylacetylene backbones. While belonging to the family of copper-catalyzed azide-alkyne cycloaddition reactions, the reaction yielding 5-bismuth(III)-triazolide is the sole example of a complex catalytic transformation that features activity of bismuth(III) acetylides towards organic azides under copper(I)-catalyzed conditions. Stepwise continuous monitoring of the copper(I)/copper(0) redox activity of the copper(I) catalyst by cyclic voltammetry provided novel insights into the complex catalytic cycle of the bismuth(III)-triazolide formation. From CV-derived kinetic data, reaction rate parameters of the bismuth(III) acetylides coordination to the copper(I) catalyst (KA) and equilibrium concentration of the copper species [cat]eq. are compared with the overall 5-bismuth(III)-triazolide formation rate constant kobs obtained by 1H-NMR kinetic analysis.</p

Cognitive Improvements in a Mouse Model with Substituted 1,2,3-Triazole Agonists for Nicotinic Acetylcholine Receptors

The α7 nicotinic acetylcholine receptor (nAChR) is a recognized drug target for dementias of aging and certain developmental disorders. Two selective and potent α7-nAChR agonists, winnowed from a list of 43 compounds characterized in a companion article (DOI: 10.1021/acschemneuro.5b00058), 5-((quinuclid-3-yl)-1<i>H</i>-1,2,3-triazol-4-yl)-1<i>H</i>-indole (IND8) and 3-(4-hydroxyphenyl-1,2,3-triazol-1-yl) quinuclidine (QND8), were evaluated for cognitive improvement in both short- and long-term memory. Tacrine, a centrally active acetylcholinesterase inhibitor, and PNU-282987, a congeneric α7 nAChR agonist, were employed as reference standards. Three behavioral tests, modified Y-maze, object recognition test (ORT), and water maze, were performed in scopolamine-induced amnesic mice. Intraperitoneal injection of these two compounds significantly improved the cognitive impairment in a modified Y-maze test (5 μmol/kg for IND8 and 10 μmol/kg for QND8), ORT (10 μmol/kg), and water maze test (25 μmol/kg). For delay induced memory deficit or natural memory loss in mice, IND8 and QND8 at 10 μmol/kg were able to enhance memory comparable to PNU-282987 when evaluated using ORT time delay model. Cognitive enhancement of IND8 and QND8 was mediated through α7-nAChRs as evidenced by its complete abolition after pretreatment with a selective α7-nAChR antagonist, methyllycaconitine. These data demonstrate that IND8 and QND8 and their congeners are potential candidates for treatment of cognitive disorders, and the substituted triazole series formed by cycloaddition of alkynes and azides warrant further preclinical optimization