Alexander Pashenko

Buchwald–Hartwig C-N coupling is a central method for constructing (hetero)aryl–nitrogen bonds. Yet condition translatability is often problematic from one substrate to another, even among closely related substrates, especially for heteroaryl halides. In this work, we demonstrate an approach to solving this task using the six available bromoimidazo[1,5-a]pyridine regioisomers and a representative nucleophile panel comprising benzamide, aniline, morpholine, and benzylamine as a model study. A limited-scale HTE campaign was conducted with an in-house ligand set, a fixed palladium source, and two bases. Reaction performance was assessed by LCMS with internal standard calibration, and targeted hits were verified by preparative re-runs and NMR-confirmed product assignment. The resulting conversion and product yield maps reveal strong dependence on bromide position, nucleophile class, and ligand/base selection. The 6- and 8-bromo isomers show the broadest productive reactivity profiles, whereas the 5- and 7-isomers are active in narrow condition windows. The imidazole–ring 1- and 3-bromo isomers react readily but do not provide isolable, structurally confirmed target products. Methodologically, this work demonstrates that a compact HTE workflow can rapidly define useful ligand/base combinations for heteroaryl bromides while preventing misleading conclusions from conversion-only analysis. The same approach can be applied as an early-stage reactivity screen for other heteroaryl halide series.

A novel approach for a safe generation of the diazomethane-contained organic solution has been proposed using a serial flow reactor. The productivity of the diazomethane generation has reached 0.45 mol/h. Several chiral diazoketones have been prepared in quantities up to 150 g through the reaction of diazomethane with mixed anhydrides, generated in situ by treatment of Boc-protected α-amino-acids with ethyl chloroformate. The synthesized diazoketones are crystalline sub-stances stable up to 110-142 °C and can easily be purified on silica gel and stored for a long term. The overall stability and availability on a large scale allow considering such diazoketones as promising bench-stable regents for the broad scope of applications. The quantum chemical studies show that the stability of diazoketones is probably connected with conjugation of the carbonyl group with diazo moiety. As an example of applicability: the reaction of diazoketones with concentrated HBr gives corresponding pure chiral α-bromoketones without additional purification was demonstrated.

Aim. DNA-encoded libraries technologies (DELT) are gradually becoming an important part of standard drug discovery toolbox. DELT is looking to find its place between classic low-molecular-weight drug candidates on the one hand, and high-molecular-weight antibodies and peptides on the other hand. On its natural path to overcoming the “childhood diseases” typical for every novel technology, DELT has reached a point where the chemical diversity of DNA-encoded libraries (DELs) becomes an important factor to look out for. In this paper, we aim to take a closer look at the chemical diversity of DELs in their present state and find the ways to improve it.Results and discussion. We have identified the DEL-viable building blocks from the Enamine Ltd. stock collection, as well as from Chemspace Ltd. virtual collection, using the SMARTS set, which takes into account all the necessary structural restrictions. Using modern cheminformatics tools, such as Synt-On, we have analyzed the scaffold diversity of both stock and virtual core bi- and tri-functional building blocks (BBs) suitable for DNA-tolerant reactions. The identification of scaffolds from the most recently published on-DNA heterocyclization reactions and analysis of their inclusion into the existing BBs space have shown that novel DNA-tolerant heterocyclizations are extremely useful for expanding chemical diversity in DEL technologies.Conclusions. The analysis performed allowed us to recognize which functional groups should be prioritized as the most impactful when the new BBs are designed. It is also made clear that the development of new DNA-tolerant reactions, including heterocyclizations, have a significant potential to further expand DEL molecular diversity.

Catalytic borylations of sp³ C–H bonds occur with high selectivities for primary C–H bonds or secondary C–H bonds that are activated by nearby electron-withdrawing substituents. Catalytic borylation at tertiary C–H bonds has not been observed. Here we describe a broadly applicable method for the synthesis of boron-substituted bicyclo[1.1.1]pentanes and (hetero)bicyclo[2.1.1]hexanes by an iridium-catalysed borylation of the bridgehead tertiary C–H bond. This reaction is highly selective for the formation of bridgehead boronic esters and is compatible with a broad range of functional groups (>35 examples). The method is applicable to the late-stage modification of pharmaceuticals containing this substructure and the synthesis of novel bicyclic building blocks. Kinetic and computational studies suggest that C–H bond cleavage occurs with a modest barrier and that the turnover-limiting step of this reaction is an isomerization that occurs prior to reductive elimination that forms the C–B bond.