Aryldiazonium Tetrafluoroborate Salts as Green and Efficient Coupling Partners for the Suzuki–Miyaura Reaction: From Optimisation to Mole Scale

The use of aryldiazonium tetrafluoroborate salts as coupling partners in the Suzuki–Miyaura reaction was investigated from a process chemistry perspective including safety evaluation, solvent and catalyst screening and multivariate factor optimisation. Optimised conditions were applied to a range of substrates to evaluate the scope and limitations of the reaction, and one example was carried out on mole scale to demonstrate the practicality and scalability of the process

Alkene Dihydroxylation with Malonoyl Peroxides: Catalysis Using Fluorinated Alcohols

The effect of fluorinated alcohols on the dihydroxylation of alkenes using cyclopropyl malonoyl peroxide is described. Addition of perfluoro-<i>tert</i>-butyl alcohol to a toluene solution of alkene and peroxide increases the rate of product formation and the stereoselectivity observed, providing a simple and effective method for acceleration of this important class of reaction. Basic hydrolysis of the crude reaction mixture provides access to <i>syn</i>-diols in high yield and stereoselectivity

C–H Arylation of Heterocyclic <i>N</i>‑Oxides Through <i>in Situ</i> Diazotisation Of Anilines without Added Promoters: A Green And Selective Coupling Process

A green and selective method for the generation of biaryl compounds through C–H arylation of heterocyclic <i>N</i>-oxides, in which the addition of ascorbic acid as a promoter is not required for either the generation of an aryldiazonium species or the subsequent arylation, is presented. Reaction conditions were optimized through multivariate data analysis, including orthogonal projections to latent structures (OPLS) and design of experiments (DoE) methodologies, resulting in further sustainability improvements, and were then applied to a range of substrates to establish the scope and limitations of the process. The reaction was studied using <i>in situ</i> infrared spectroscopy and a mechanism is presented that accounts for the available data from this and previous studies. The reaction was also performed on a multigram scale, with calorimetry studies to support further scale-up of this promoter-free transformation

Retraction of “Ascorbic Acid-Promoted C–H Arylation of Heterocyclic <i>N</i>‑Oxides through in Situ Diazotisation of Anilines: A Green and Selective Coupling Process”

Retraction of “Ascorbic Acid-Promoted C–H Arylation of Heterocyclic <i>N</i>‑Oxides through in Situ Diazotisation of Anilines: A Green and Selective Coupling Process

Alkene Dioxygenation with Malonoyl Peroxides: Synthesis of γ‑Lactones, Isobenzofuranones, and Tetrahydrofurans

Treatment of homoallylic alcohols or carboxylic acids with malonoyl peroxide <b>1</b> provides a stereoselective method for the preparation of tetrahydrofurans, γ-lactones, and isobenzofuranones in 44–82% yield and up to 27:1 <i>trans</i> selectivity. Application of this simple and effective heterocyclization in the synthesis of the antidepressant citalopram is also described

Regioselective Three-Component Reaction of Pyridine <i>N</i>‑Oxides, Acyl Chlorides, and Cyclic Ethers

A novel three-component reaction of pyridine <i>N</i>-oxides, acyl chlorides, and cyclic ethers is described. Treatment of an electron-deficient pyridine <i>N</i>-oxide with an acyl chloride in the presence of a cyclic ether at 25–50 °C leads to a substituted pyridine as a single regioisomer in up to 58% isolated yield. Isotopic-labeling experiments and substrate scope support the reaction proceeding through a carbene intermediate

Regioselective Three-Component Reaction of Pyridine <i>N</i>‑Oxides, Acyl Chlorides, and Cyclic Ethers

A novel three-component reaction of pyridine <i>N</i>-oxides, acyl chlorides, and cyclic ethers is described. Treatment of an electron-deficient pyridine <i>N</i>-oxide with an acyl chloride in the presence of a cyclic ether at 25–50 °C leads to a substituted pyridine as a single regioisomer in up to 58% isolated yield. Isotopic-labeling experiments and substrate scope support the reaction proceeding through a carbene intermediate

Alkene <i>anti</i>-Dihydroxylation with Malonoyl Peroxides

Malonoyl peroxide <b>1</b>, prepared in a single step from the commercially available diacid, is an effective reagent for the <i>anti</i>-dihydroxylation of alkenes. Reaction of <b>1</b> with an alkene in the presence of acetic acid at 40 °C followed by alkaline hydrolysis leads to the corresponding diol (35–92%) with up to 13:1 <i>anti</i>-selectivity. A mechanism consistent with experimental findings is proposed that accounts for the selectivity observed

Optimized Chemical Probes for REV-ERBα

REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (<b>1</b>) for potency, selectivity, and bioavailability. Potent REV-ERBα agonists <b>4</b>, <b>10</b>, <b>16</b>, and <b>23</b> are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine <b>4</b> demonstrated in vivo bioavailability after either iv or oral dosing