Date: 14 July 2025 | Category: News
Authors: Jennifer Morvan, Koen P. L. Kuijpers, Dayne Fanfair, Bingqing Tang, Karolina Bartkowiak, Lars van Eynde, Evelien Renders, Jesus Alcazar, Peter J. J. A. Buijnsters, Mary-Ambre Carvalho,* and Alexander X. Jones
Scientists at Janssen in Belgium and Spain have used the Vapourtec Ion electrochemical reactor to successfully develop a reproducible and broadly applicable method for electrochemical arylation in flow [1]. Use of a flow cell provided significant advantage over batch, with improved yields and selectivity. Uniform reaction conditions were used to synthesize over one hundred C–N and C–O arylation products in an automated manner. Furthermore, preparation of a drug derivative could be achieved on 10 mmol scale, affording 2.06 g of material in only 24 hours without any further optimization or amendments to the electrochemical system.
Figure 1: Novel flow platform enabled electrochemical synthesis of compound libraries in the presence of a diverse range of amines and alcohols.
Aryl ethers, anilines and electrochemistry within drug discovery
Aryl ether and anilines are common motifs in drug discovery and, while they can be prepared through use of palladium- or nickel-mediated coupling reactions, there are some limitations to these approaches. Electrochemistry is a useful alternative tool for their synthesis that can have general applicability, avoiding the requirement for extensive optimisation between substrates. In addition, electrochemistry offers the option for control of cell voltage and current, as well as achieve high levels of chemo-[2] and regio-selectivity[3], and functional group tolerance [4]. However, adoption in both academia and industry has been slow due to a lack of standardized equipment and workflows, as well as poor reproducibility when transferring between reactors and inconsistent results upon scale-up.
AC current using flow technology is key
Initial C–O coupling optimisation focused on use of a batch reactor, but yields were poor and inconsistent. Switching to the Vapourtec Ion electrochemical reactor using DC current gave good yields, but sequential reactions led to deterioration of the electrode that could only be reversed through use of abrasive washing with a celite suspension. This therefore reduced the applicability of this process to library synthesis. However, switching to AC both halted electrode deterioration and, because the oxidative and reductive redox steps occurred successively at the same electrode, diffusion limitations were effectively eliminated. Results were consistent, allowing rapid optimisation of the reaction parameters through both high-throughput screening in flow and Design of Experiments (DoE).
Using these tools, optimal conditions for C–O and C–N aryl couplings were identified, the reaction scope determined, and library generation initiated. For C–O coupling, a range of functional groups were tolerated, including esters, boronic acids and sulfones, as well as heterocycles. Under C–N coupling conditions, arylation proceeded smoothly with secondary alkyl amines, anilines, sulfonamides and dimethylsulfoximine. There were some limitations, for example primary linear amines underwent dimerization and coupling with tertiary alcohols was impeded, but overall the yields were good and the reaction reliable.
Of particular note is that this methodology was used to prepare a new cereblon binder that is of interest for PROTAC applications, four unnatural amino acids through derivatization of protected bromo-phenylalanine, and allowed the electrochemical serine arylation of an oligopeptide, Figure 2. Finally, synthesis of a drug derivative could be scaled-up to 10 mmol scale, affording 2.06 g of a product (55% yield) in only 24 hours, without any requirement for changes to the electrochemical system.
Figure 2: Examples of compounds prepared. (a) Cereblon binder; (b) unnatural amino acid; (c) peptide; (d) drug derivative.
References:
[1] Electrochemical C–O and C–N Arylation using Alternating Polarity in flow for Compound Libraries (J. Morvan, K. P. L. Kuijpers, D. Fanfair, B. Tang, K. Bartkowiak, L. van Eynde, E. Renders, J. Alcazar, P. J. J. A. Buijnsters, M.-A. Carvalho, A. X. Jones, Angew. Chem. Int. Ed., 2025, 64, 20241338). https://doi.org/10.1002/anie.202413383
[2] a) Electrochemistry for the Chemoselective Modification of Peptides and Proteins (A. S. Mackay, R. J. Payne, L. R. Malins, J. Am. Chem. Soc., 144 (1), 23–41). https://doi.org/10.1021/jacs.1c11185; (b) Chemoselective Electrosynthesis Using Rapid Alternating Polarity (Y. Kawamata, K. Hayashi, E. Carlson, S. Shaji, D Waldmann, B. J. Simmons, J. T. Edwards, C. W. Zapf, M. Saito, P. S. Baran, J. Am. Chem. Soc., 2021, 143 (40), 16580–16588). https://doi.org/10.1021/jacs.1c06572
[3] Electrochemical reactor dictates site selectivity in N-heteroarene carboxylations. (G.-Q. Sun, P. Yu, W. Zhang, W. Zhang, Y. Wang, L.-L. Liao, Z. Zhang, L. Li, Z. Lu, D.-G. Yu, S. Lin, Nature, 2023, 615, 67–72). https://doi.org/10.1038/s41586-022-05667-0
[4] (a) A Survival Guide for the “Electro-curious”. (C. Kingston, M. D. Palkowitz, Y. Takahira, J. C. Vantourout, B. K. Peters, Y. Kawamata, P. S. Baran, Acc. Chem. Res., 53 (1), 72–83). https://doi.org/10.1021/acs.accounts.9b00539; (b) Translating batch electrochemistry to single-pass continuous flow conditions: an organic chemist’s guide. (S. Maljuric, W. Jud, C. O. Kappe, D. Cantillo, J. Flow Chem., 2020, 10, 181 –190). https://doi.org/10.1007/s41981-019-00050-z; (c) Unleashing the Potential to Electrify Process Chemistry: From Bench to Plant (K. Lam, K. M. P. Wheelhouse, Org. Proc. Res. Dev., 2021, 25 (12), 2579–2580). https://doi.org/10.1021/acs.oprd.1c00434
