Jesús Alcázar

Nickel electrocatalysis couples activated carboxylic acids with secondary alkylamine-derived pyridinium salts to form C(sp ³ )–C(sp ³ ) bonds. Controlled radical generation enables broad scope, stable operation and telescoped synthesis.

The diversification of lead compounds remains a crucial step in drug development, with bioactive molecules often requiring fine tuning of a range of important pharmaceutical properties. This is achieved through the synthesis of libraries of analogues with subtle modifications in functionality or structure. The complexity of many bioactive molecules, however, does not make this a trivial endeavour. Indeed, many transformations using established chemistry are not suitable due to functional group sensitivity or regiochemical challenges and can require large amounts of time and resources to be spent on multistep syntheses. The development of functional group tolerant transformations can allow the curation of a library of analogues directly from a common, complex precursors through late-stage modification. Harnessing the reactivity of C–H bonds on arenes, which are extremely prevalent in drug like compounds, allows for the addition of functionality to tune electronic and steric properties without the modification of existing functional groups that may be integral to binding properties. Particularly attractive is the installation of a halogen atom to a lead compound to provide opportunities for further diversification through emerging and established cross-coupling techniques as well as the modulation of pharmaceutical properties. Numerous conditions are available to perform C–H halogenation reactions on aromatic compounds. However, “one-size-fits-all” conditions are not reflective of the structural diversity across pharmaceutically relevant molecules and cannot accommodate the density and breadth of functionality. High-throughput screening has been used to optimise C–H functionalisation reactions. However, no such approach exists for the halogenation of pharmaceutical compounds. Here, we develop an automated, machine-learning aided, high-throughput workflow to investigate how varying acidity affects the C(sp ² )–H chlorination, bromination, and iodination of 32 complex pharmaceutical substrates. Different compounds are shown to require significantly different acidities and yields are improved by optimisation of TFA equivalents. 56 halogenated analogues of 22 pharmaceuticals were prepared using conditions determined by the high-throughput workflow with significant benefit to yield. xTB atomic descriptors were used to predict regiochemical outcomes in a computationally inexpensive way. We envision that the workflow could be used for future similar investigations.

Etherification and amination of aryl halide scaffolds are commonly used reactions in parallel medicinal chemistry to rapidly scan structure–activity relationships with abundant building blocks. Electrochemical methods for aryl etherification and amination demonstrate broad functional group tolerance and extended nucleophile scope compared to traditional methods. Nevertheless, there is a need for robust and scale‐transferable workflows for electrochemical compound library synthesis. Herein we describe a platform for automated electrochemical synthesis of C−X arylation (X=NH, OH) in flow to access compound libraries. A comprehensive Design of Experiment (DoE) study identifies an optimal protocol which generates high yields across>30 aryl halide scaffolds, diverse amines (including electron‐deficient sulfonamides, sulfoximines, amides, and anilines) and alcohols (including serine residues within peptides). Reaction sequences are automated on commercially available equipment to generate libraries of anilines and aryl ethers. The unprecedented application of potentiostatic alternating polarity in flow is essential to avoid accumulating electrode passivation. Moreover, it enables reactions to be performed in air, without supporting electrolyte and with high reproducibility over consecutive runs. Our method represents a powerful means to rapidly generate nucleophile independent C−X arylation compound libraries using flow electrochemistry.

Etherification and amination of aryl halide scaffolds are commonly used reactions in parallel medicinal chemistry to rapidly scan structure–activity relationships with abundant building blocks. Electrochemical methods for aryl etherification and amination demonstrate broad functional group tolerance and extended nucleophile scope compared to traditional methods. Nevertheless, there is a need for robust and scale‐transferable workflows for electrochemical compound library synthesis. Herein we describe a platform for automated electrochemical synthesis of C−X arylation (X=NH, OH) in flow to access compound libraries. A comprehensive Design of Experiment (DoE) study identifies an optimal protocol which generates high yields across>30 aryl halide scaffolds, diverse amines (including electron‐deficient sulfonamides, sulfoximines, amides, and anilines) and alcohols (including serine residues within peptides). Reaction sequences are automated on commercially available equipment to generate libraries of anilines and aryl ethers. The unprecedented application of potentiostatic alternating polarity in flow is essential to avoid accumulating electrode passivation. Moreover, it enables reactions to be performed in air, without supporting electrolyte and with high reproducibility over consecutive runs. Our method represents a powerful means to rapidly generate nucleophile independent C−X arylation compound libraries using flow electrochemistry.

The increased demand for the synthesis of enriched hybridized Csp3 motifs and the urgency of discovering new drug molecules require the development of more efficient technologies and synthetic tools to accelerate drug discovery processes. Herein, we report a fully automated strategy for the addition of Csp3 enriched building blocks onto olefins via Giese addition to forge Csp3-Csp3 bonds. The developed fully automated protocol allowed the conversion of aldehydes (non-redox-active species) in-situ to electroactive imidazolidines and to employ them as precursors of C-centered radicals under photoredox catalyzed conditions for the synthesis of enriched fraction sp3 (Fsp3) character building blocks and bioactive compound libraries.

Etherification and amination of aryl halide scaffolds are commonly used reactions in parallel medicinal chemistry to rapidly scan structure-activity relationships with abundant building blocks. Electrochemical methods for aryl etherification and amination demonstrate broad functional group tolerance and extended nucleophile scope compared to traditional methods. Nevertheless, there is a need for robust and scale-transferable workflows for electrochemical library synthesis. Herein we describe a platform for automated electrochemical synthesis of C-X arylation (X = NH, OH) libraries in flow. A comprehensive DOE identifies an optimal protocol which generates high yields across > 30 aryl halide scaffolds, diverse amines (including electron-deficient sulfonamides, sulfoximines, amides, and anilines) and alcohols (including serine residues within peptides). Reaction sequences are automated on commercially available equipment to generate libraries of anilines and aryl ethers. The unprecedented application of potentiostatic alternating polarity in flow is essential to avoid accumulating electrode passivation. Moreover, it enables reactions to be performed in air, without supporting electrolytes and with high reproducibility over consecutive runs. Our method represents a powerful means to rapidly generate nucleophile independent C-X arylation libraries using flow electrochemistry.

In drug discovery, traditional automated library synthesis has typically involved single-step synthetic procedures targeting a single vector of interest. However, achieving greater structural diversity requires exploring multistep and multivectorial approaches. These methodologies enable the preparation of compounds with varying structures in a single experiment. Here, we present a novel method for multistep library synthesis in continuous flow. This approach offers unique opportunities, such as exploring linkers between two defined vectors or rapidly mapping synergistic structure-activity relationship (SAR) by concurrently exploring multiple vectors. Our method incorporates up to eight different synthetic methodologies, including established chemistries, metal-catalysed transformations, and modern metallaphotoredox couplings. This broad range of synthetic methodologies ensures a high level of diversity in the compounds generated, providing a powerful tool to accelerate exploration of the chemical space in drug discovery programs.

Alcohols represent a functional group class with unparalleled abundance and structural diversity. In an era of chemical synthesis that prioritizes reducing time to target and maximizing exploration of chemical space, harnessing these building blocks for carbon-carbon bond-forming reactions is a key goal in organic chemistry. In particular, leveraging a single activation mode to form a new C(sp ³ )–C(sp ³ ) bond from two alcohol subunits would enable access to an extraordinary level of structural diversity. In this work, we report a nickel radical sorting–mediated cross-alcohol coupling wherein two alcohol fragments are deoxygenated and coupled in one reaction vessel, open to air.

Light-mediated reactions have emerged as an indispensable tool in organic synthesis and drug discovery, enabling novel transformations and providing access to previously unexplored chemical space. Despite their widespread application in both academic and industrial research, the utilization of light as an energy source still encounters challenges regarding reproducibility and data robustness. Herein we present a comprehensive head-to-head comparison of commercially available batch photoreactors, alongside the introduction of the use of batch and flow photoreactors in parallel synthesis. Hence, we aim to establish a reliable and consistent platform for light-mediated reactions in high-throughput mode. Herein, we showcase the identification of several platforms aligning with the rigorous demands for efficient and robust high-throughput experimentation screenings and library synthesis.