Functionalization of Heteroarenes Under Continuous Flow

This in turn provides a platform for future innovations towards the designing of novel transformations under continuous flow. Thus, this volume will appeal to both the novices in this field as well as to experts in academia and industry.status: publishe

Ex situ gas generation for lab scale organic synthesis

Synthetic organic reactions involving gaseous reagents are frequently avoided in the research lab for practical and safety reasons. Nevertheless, reactive gases often represent convenient building blocks with high potential for atom economy. This review article aims at highlighting ex situ gas generation methods as safe and easily executable procedures for organic synthesis. Especially the advent of two-chamber type reactors has been responsible for the renewed interest in gas-liquid biphasic transformations. With the exemption of carbon monoxide, a discussion is provided on the scientific work from the last decade which employs ex situ generated gaseous reagents, generated on-demand and in a place other than the reaction mixture itself. Features of these protocols which are especially appealing to a laboratory bench-scale context will be underscored, with an emphasis on safety and synthetic diversity allowed by the gas-mediated reactions.status: Published onlin

Enantioselective Hydroamination of Alkenes with Sulfonamides Enabled by Proton-Coupled Electron Transfer

status: Published onlin

Enantioselective Hydroamination of Alkenes with Sulfonamides Enabled by Proton-Coupled Electron Transfer

An enantioselective, radical-based method for the intramolecular hydroamination of alkenes with sulfonamides is reported. These reactions are proposed to proceed via N-centered radicals formed by proton-coupled electron transfer (PCET) activation of sulfonamide N-H bonds. Noncovalent interactions between the neutral sulfonamidyl radical and a chiral phosphoric acid generated in the PCET event are hypothesized to serve as the basis for asymmetric induction in a subsequent C-N bond forming step, achieving selectivities of up to 98:2 er. These results offer further support for the ability of noncovalent interactions to enforce stereoselectivity in reactions of transient and highly reactive open-shell intermediates.status: publishe

Non-innocent probes in direct sonication: Metal assistance in oxidative radical CH functionalization

Direct sonication by means of ultrasound horns constitutes a widely used technique in chemical process technology. However, the direct contact between the metal probe and the reaction mixture does not always leave the chemical system unaffected. In this report, we study the tert-butyl hydroperoxide-mediated trifluoromethylation of heterocyclic structures, and the influence of sonication thereon. Metal leaching is observed during the process and further examined, showing that several metals can interfere significantly with the chemical reaction under study. Notably, vanadium metal was found to increase the reaction rate exceptionally well, rendering it a useful additive for this type of reactions. Ultimately, some mechanistic considerations are offered, to provide more insight into the nature of the catalytic effect of leached metals.status: publishe

Perfluorooxosulfate Salts as SOF₄-Gas-Free Precursors to Multidimensional SuFEx Electrophiles

Sulfur(VI) Fluoride Exchange (SuFEx) chemistry stands as a well-established method for swiftly constructing complex molecules in a modular fashion. An especially promising segment of this toolbox is reserved for multidimensional SuFEx hubs: three or more substituents pluggable into a singular S(VI) centre to make ‘beyond-linear’ clicked constructions. Sulfurimidoyl difluorides (RNSOF2) stand out as the prime example of this, however their preparation from the scarcely available thionyl tetrafluoride (SOF4) renders this chemistry only available to a select few laboratories with access to this gas. In this work, we identify silver pentafluorooxosulfate (AgOSF5) as a viable SuFEx hub with reactivity equal to SOF4. The AgF2-mediated oxidation of SOCl2 gives rise to the hexacoordinate AgOSF5 adduct, which in contact with primary amines produces the sulfurimidoyl fluorides in high yields. In addition, we have found this workflow to be fully extendable to the trifluoromethyl homologue, AgOSF4CF3, and we propose the use of AgOSF4X salts as a general route to azasulfur SuFEx electrophiles from commercial starting materials

Copper-Catalyzed, Aerobic Synthesis of <i>N</i>H‑Sulfonimidamides from Primary Sulfinamides and Secondary Amines

NH-Sulfonimidamides are prepared by copper-catalyzed coupling of primary sulfinamides with secondary amines. Neither a ligand nor an additive is needed, and air is the terminal oxidant. The reactions occur at room temperature, show good functional group tolerance, and lead to products in good yields. A sulfanenitrile is proposed as an intermediate in this oxidative amination

De-risking S–F bond formation: A gas cylinder-free strategy to access S(IV) and S(VI) fluorinated compounds.

The sulfur-fluorine partnership occupies a privileged position in fluorine chemistry given the functional versatility that it imparts to organic structures. Despite this, available methodologies to forge S–F bonds are limited compared to C–F bond formation. Here, we describe a synthetic protocol that selectively enables the oxidative halogenation of aliphatic, aromatic, and heteroaromatic thiols to their corresponding SF4Cl, SO2F and SF3 derivatives. Selective oxidation of thiols to either S(IV)–F or S(VI)–F compounds is achieved by employing bench-stable calcium hypochlorite as chlorine surrogate (CLOgen), in the presence of KF as fluoride source. DFT calculations provided insight into the mechanistic aspects of the transformation and rationalized the observed isomeric preference towards the SF4Cl derivatives. Ultimately, this glovebox-free method selectively dispatches three classes of compounds upon reaction condition finetuning. Furthermore, first-in-class transformations are reported, including the preparation of aliphatic SF4Cl intermediates, their transformation into aliphatic sulfur pentafluoride analogs, and posttransformations that allow accessing highly complex SF4-bridged scaffolds

An Extrusion Strategy for On-demand SF5Cl Gas Generation from a Commercial Disulfide

Herein, we report a novel methodology for the ex-situ generation of SF5Cl by employing 4,4′-dipyridyl disulfide as a safe commercial reagent obviating the need for lecture bottles. The method is applicable to certain SF5Cl-involving transformations using a two-chamber reactor. Moreover, easily applying SF5Cl in both polar and non-polar media is rendered feasible while avoiding the use of glovebox techniques. This report also suggests 1H-19F HOESY as a simple and fast stereochemistry indication for chloropentafluorosulfanylated olefins

Discovery of a potent protein kinase D inhibitor: insights in the binding mode of pyrazolo[3,4-d] pyrimidine analogues

In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP. Therefore we suggest an alternate binding mode where the compounds are flipped 180 degrees. This possible alternate binding mode for pyrazolo[3,4-d]pyrimidine based compounds could pave the way for a new class of specific protein kinase inhibitors for kinases sensitive towards pyrazolo[3,4-d]pyrmidines.crosscheck: This document is CrossCheck deposited related_data: Supplementary Information identifier: Klaas Verschueren (ORCID) identifier: Joachim Demaerel (ORCID) identifier: Arnout R. D. Voet (ResearcherID) identifier: Wim M. De Borggraeve (ORCID) identifier: Wim M. De Borggraeve (ResearcherID) copyright_licence: The Royal Society of Chemistry has an exclusive publication licence for this journal copyright_licence: This article is freely available. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (CC BY 3.0) history: Received 2 December 2016; Accepted 31 January 2017; Accepted Manuscript published 9 February 2017; Advance Article published 15 February 2017; Version of Record published 23 March 2017status: publishe