Aminium cation-radical catalysed selective hydration of (E)-aryl enynes

The hydration of carbon-carbon triple bonds is an important and atom economic synthetic transformation. Herein, we report a mild and selective method for the catalytic Markovnikov hydration of (E)-aryl enynes to the corresponding enones, mediated through the bench-stable aminium salt, tris(4-bromophenyl)ammoniumyl hexachloroantimonate (TBPA). The chemoselective and diastereoselective method proceeds under neutral metal-free conditions, delivering excellent product yields from terminal and internal alkyne units. The synthesis of biologically important (E)-3-styrylisocoumarins, including a formal synthesis of the natural product achlisocoumarin III, demonstrates the utility of this novel transformation.</p

The growing applications of SuFEx click chemistry

SuFEx (Sulfur Fluoride Exchange) is a modular, next generation family of click reactions, geared towards the rapid and reliable assembly of functional molecules. This review discusses the growing number of applications of SuFEx, which can be found in nearly all areas of modern chemistry; from drug discovery to materials science.</p

Metal‐Free Synthesis of Functional 1‐Substituted‐1,2,3‐Triazoles from Ethenesulfonyl Fluoride and Organic Azides

The boom in growth of 1,4-disubstituted triazole products, in particular, since the early 2000’s, can be largely attributed to the birth of click chemistry and the discovery of the CuI-catalyzed azide–alkyne cycloaddition (CuAAC). Yet the synthesis of relatively simple, albeit important, 1-substituted-1,2,3-triazoles has been surprisingly more challenging. Reported here is a straightforward and scalable click-inspired protocol for the synthesis of 1-substituted-1,2,3-triazoles from organic azides and the bench stable acetylene surrogate ethenesulfonyl fluoride (ESF). The new transformation tolerates a wide selection of substrates and proceeds smoothly under metal-free conditions to give the products in excellent yield. Under controlled acidic conditions, the 1-substituted-1,2,3-triazole products undergo a Michael addition reaction with a second equivalent of ESF to give the unprecedented 1-substituted triazolium sulfonyl fluoride salts.</p

Bifluoride Ion Mediated SuFEx Trifluoromethylation of Sulfonyl Fluorides and Iminosulfur Oxydifluorides.

SuFEx is a new-generation click chemistry transformation that exploits the unique properties of S−F bonds and their ability to undergo near-perfect reactions with nucleophiles. We report here the first SuFEx-based procedure for the efficient synthesis of pharmaceutically important triflones and bis(trifluoromethyl)sulfur oxyimines from sulfonyl fluorides and iminosulfur oxydifluorides, respectively. The new process involves rapid S−F exchange with trifluoromethyltrimethylsilane (TMSCF3) upon activation by potassium bifluoride in anhydrous DMSO. The reaction tolerates a wide selection of substrates and proceeds under mild conditions without need for chromatographic purification. A tentative mechanism is proposed involving nucleophilic displacement of S−F by the trifluoromethyl anion via a five-coordinate intermediate. The utility of late-stage SuFEx trifluoromethylation is demonstrated through the synthesis and selective anticancer properties of a bis(trifluoromethyl)sulfur oxyimine.</p

Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2-Substituted-Alkynyl-1-Sulfonyl Fluoride (SASF) Hubs

Diversity Oriented Clicking (DOC) is a unified click-approach for the modular synthesis of lead-like structures through application of the wide family of click transformations. DOC evolved from the concept of achieving “diversity with ease”, by combining classic C−C π-bond click chemistry with recent developments in connective SuFEx-technologies. We showcase 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs) as a new class of connective hub in concert with a diverse selection of click-cycloaddition processes. Through the selective DOC of SASFs with a range of dipoles and cyclic dienes, we report a diverse click-library of 173 unique functional molecules in minimal synthetic steps. The SuFExable library comprises 10 discrete heterocyclic core structures derived from 1,3- and 1,5-dipoles; while reaction with cyclic dienes yields several three-dimensional bicyclic Diels–Alder adducts. Growing the library to 278 discrete compounds through late-stage modification was made possible through SuFEx click derivatization of the pendant sulfonyl fluoride group in 96 well-plates—demonstrating the versatility of the DOC approach for the rapid synthesis of diverse functional structures. Screening for function against MRSA (USA300) revealed several lead hits with improved activity over methicillin.</p