Photochemical Synthesis of Lactones, Cyclopropanes and ATRA Products: Revealing the Role of Sodium Ascorbate.

Light-mediated processes have received significant attention, since they have re-surfaced unconventional reactivity platforms, complementary to conventional polar chemistry. γ-Lactones and cyclopropanes are prevalent moieties, found in numerous natural products and pharmaceuticals. Among various methods for their synthesis, light-mediated protocols are coming to the spotlight, although these are contingent upon the use of photoorgano- or metal-based catalysts. Herein, we introduce a novel photochemical activation of iodo-reagents via the use of cheap sodium ascorbate or ascorbic acid to enable their homolytic scission and addition onto double bonds. The developed protocol was applied successfully to the formal [3+2] cycloaddition for the synthesis of γ-lactones, traditional atom transfer radical addition (ATRA) reactions and the one-pot two-step conversion of alkenes to cyclopropanes. In all cases, the desired products were obtained in good to high yields, while the reaction mechanism was thoroughly investigated. Depending on the nature of the iodo-reagent, a halogen or a hydrogen-bonded complex is formed, which initiates the process.

Photochemical Aminochlorination of Alkenes without the Use of an External Catalyst.

The niche field of photochemistry offers opportunities that are not found in "traditional" ground state chemical pathways. Aminochlorinated derivatives are an interesting family of 1,2-difunctionalised compounds that provide access to a variety of natural products and pharmaceutical active substances. A practical, catalyst-free chloroamination protocol is described herein, providing access to intermediates of great importance, utilising mild and photochemical reaction conditions (370 nm), where N-chlorosulfonamides are used as both nitrogen and chlorine sources. A wide variety of olefins, decorated with a plethora of functional groups, was tested providing excellent results (28 examples, 18-88 % yield). Mechanistic studies (UV-Vis, control experiments and quantum yield measurement) were also performed.

A Unified Mechanism for the PhCOCOOH-mediated Photochemical Reactions: Revisiting its Action and Comparison to Known Photoinitiators.

Since 2014, we have introduced in literature the use of phenylglyoxylic acid (PhCOCOOH), a small and commercially available organic molecule, as a potent promoter in a variety of photochemical processes. Although PhCOCOOH has a broad scope of photochemical reactions that can promote, the understanding of its mode of action in our early contributions was moderate. Herein, we are restudying and revisiting the mechanism of action of PhCOCOOH in most of these early contributions, providing a unified mechanism of action. Furthermore, the understanding of its action as a photoinitiator opened a new comparison study with known and commercially available photoinitiators.

Photochemical Functionalization of Heterocycles with EBX Reagents: C-H Alkynylation versus Deconstructive Ring Cleavage*.

The development of novel methodologies for the functionalization of saturated heterocycles is highly desirable. Herein, we report a cheap and efficient photochemical method for the C-H functionalization of saturated O-heterocycles, as well as the deconstructive ring-cleavage of S-heterocycles, employing hypervalent iodine alkynylation reagents (ethynylbenziodoxolones, EBX). This photochemical alkynylation is performed utilizing phenylglyoxylic acid as the photoinitiator, leading to the corresponding products in good to high yields, under household fluorescent light bulb irradiation. When O-heterocycles were employed, the expected α-C-H alkynylation took place. In contrast, oxidative ring-opening to form a thioalkyne and an aldehyde was observed with S-heterocycles. Preliminary mechanistic experiments are presented to give first insights into this puzzling divergent reactivity.

Photocatalytic Atom Transfer Radical Addition to Olefins Utilizing Novel Photocatalysts.

Photocatalysis is a rapidly evolving area of research in modern organic synthesis. Among the traditional photocatalysts, metal-complexes based on ruthenium or iridium are the most common. Herein, we present the synthesis of two photoactive, ruthenium-based complexes bearing pyridine-quinoline or terpyridine ligands with extended aromatic conjugation. Our complexes were utilized in the atom transfer radical addition (ATRA) of haloalkanes to olefins, using bromoacetonitrile or bromotrichloromethane as the source of the alkyl group. The tailor-made ruthenium-based catalyst bearing the pyridine-quinoline bidentate ligand proved to be the best-performing photocatalyst, among a range of metal complexes and organocatalysts, efficiently catalyzing both reactions. These photocatalytic atom transfer protocols can be expanded into a broad scope of olefins. In both protocols, the photocatalytic reactions led to products in good to excellent isolated yields.

Organocatalytic activation of hydrogen peroxide: towards green and sustainable oxidations.

The advent of organocatalysis provided an additional option in every researcher's arsenal, towards the development of elegant and sustainable protocols for various organic transformations. Oxidation reactions are considered to be key in organic synthesis since oxygenated functionalities appear in many natural products. Hydrogen peroxide is categorized as a green oxidant, since its only by-product is water, offering novel opportunities for the development of green and sustainable protocols. In this review article, we intend to present recent developments in the field of the organocatalytic activation of hydrogen peroxide, providing useful insight into the applied oxidative protocols. At the same time, we will present some interesting mechanistic studies, providing information on the oxygen transfer processes.

N-(2-Aminophenyl)-benzamide Inhibitors of Class I HDAC Enzymes with Antiproliferative and Antifibrotic Activity.

Inhibitors of histone deacetylases (HDACs) have received special attention as novel anticancer agents. Among various types of synthetic inhibitors, benzamides constitute an important class, and one is an approved drug (chidamide). Here, we present a novel class of HDAC inhibitors containing the N-(2-aminophenyl)-benzamide functionality as the zinc-binding group linked to various cap groups, including the amino acids pyroglutamic acid and proline. We have identified benzamides that inhibit HADC1 and HDAC2 at nanomolar concentrations, with antiproliferative activity at micromolar concentrations against A549 and SF268 cancer cell lines. Docking studies shed light on the mode of binding of benzamide inhibitors to HDAC1, whereas cellular analysis revealed downregulated expression of EGFR mRNA and protein. Two benzamides were investigated in a mouse model of bleomycin-induced pulmonary fibrosis, and both showed efficacy on a preventative dosing schedule. N-(2-Aminophenyl)-benzamide inhibitors of class I HDACs might lead to new approaches for treating fibrotic disorders.

Hexafluoroisopropanol-Promoted or Brønsted Acid-Mediated Photochemical [2+2] Cycloadditions of Alkynes with Maleimides.

Although the use of light stimulating organic transformations has been known for more than a century, there is an increasing research interest on expanding the established knowledge. While [2+2] cycloadditions are promoted photochemically, literature precedent on the reaction between alkynes and maleimides is limited and only a handful of examples exist, focusing mainly on N-aliphatic maleimides. Herein, the differences in reactivity between N-alkyl and N-aryl maleimides were identified, and the use of hexafluoroisopropanol (HFIP) or trifluoroacetic acid (TFA) as viable solutions was proposed in order to achieve high yields. In the case of N-alkyl maleimides, both HFIP-mediated or TFA-promoted reactions were established using LED 370 nm irradiation, without the use of an external photocatalyst. In the case of N-aryl maleimides, thioxanthone (THX) was employed as the energy transfer photocatalyst along with LED 427 nm irradiation and HFIP. Mechanistic studies were performed, supporting the pivotal role of HFIP or TFA, in acquiring good to high yields in both classes of maleimides.

Aldehyde-catalyzed epoxidation of unactivated alkenes with aqueous hydrogen peroxide.

The organocatalytic epoxidation of unactivated alkenes using aqueous hydrogen peroxide provides various indispensable products and intermediates in a sustainable manner. While formyl functionalities typically undergo irreversible oxidations when activating an oxidant, an atropisomeric two-axis aldehyde capable of catalytic turnover was identified for high-yielding epoxidations of cyclic and acyclic alkenes. The relative configuration of the stereogenic axes of the catalyst and the resulting proximity of the aldehyde and backbone residues resulted in high catalytic efficiencies. Mechanistic studies support a non-radical alkene oxidation by an aldehyde-derived dioxirane intermediate generated from hydrogen peroxide through the Payne and Criegee intermediates.

Synthesis of γ-Lactones Utilizing Ketoacids and Trimethylsulfoxonium Iodide.

The Johnson-Corey-Chaykovsky epoxidation is one of the oldest methods for the synthesis of terminal epoxides from carbonyl compounds. Herein we present a simplified extension of the Johnson-Corey-Chaykovsky epoxidation, where ketoacids are employed as the substrates and commercially available trimethylsulfoxonium iodide is employed as the carbon-atom homologating reagent. A variety of lactones are produced in a single step in synthetically useful yields.

Photocatalytic Synthesis of γ-Lactones from Alkenes: High-Resolution Mass Spectrometry as a Tool To Study Photoredox Reactions.

A mild photocatalytic manifold for the synthesis of γ-lactones has been developed. Utilizing Ru(bpy)3Cl2 as the photocatalyst, a cheap and reproducible synthetic protocol for γ-lactones has been introduced. Mechanistic studies revealed the successful monitoring of photocatalytic reactions and radical intermediates via high-resolution mass spectrometry.

Green Organocatalytic Synthesis of Isoxazolines via a One-Pot Oxidation of Allyloximes.

A green, sustainable, organocatalytic, and efficient synthesis of isoxazolines from allyloximes was developed. A 2,2,2-trifluoroacetophenone-catalyzed oxidation of allyloximes, utilizing H2O2 as the green oxidant, was taken advantage of in order to introduce a cheap and environmentally friendly protocol for the synthesis of substituted isoxazolines. A variety of substitution patterns, both aromatic and aliphatic moieties, are well tolerated, leading to isoxazolines in moderate to excellent yields.