Date: 27 June 2025 | Category: News
Authors: Stefano Bonciolini, Antonio Pulcinella, Matteo Leone, Debora Schiroli, Adrián Luguera Ruiz, Andrea Sorato, Maryne A. J. Dubois, Ranganath Gopalakrishnan, Geraldine Masson, Nicola Della Ca’, Stefano Protti, Maurizio Fagnoni, Eli Zysman-Colman, Magnus Johansson & Timothy Noël*
The Noël group, from the Van’t Hoff Institute for Molecular Sciences at the University of Amsterdam, have developed a method for the C1 homologation and alkylation of carboxylic acids with aldehydes, a technique that exploits deoxygenative cross-electrophile coupling, in the presence of Eosin Y, an organophotocatalyst, under visible light irradiation [1]. In this case, the use of flow chemistry was vital for successful scale-up, as in batch at scales over 1 mmol a significant drop in yield of desired product was seen, which was attributed to non-uniform irradiation which limited light penetration. The Vapourtec UV-150 photochemical reactor mounted within the R-Series system was therefore used, although the photocatalyst had to be switched to Ru(bpy)3(PF6)2, providing the desired homologated proline species in 60% yield on 4 mmol scale, giving 620 mg of product in only 8 minutes of irradiation compared to 12 hours under batch conditions.
Figure 1: Flow-based C1 homologation and alkylation of carboxylic acids
Providing an alternative to the Arndt-Eistert reaction
Traditionally, C1 homologation of carboxylic acids has been achieved through the Arndt-Eistert reaction [2]. While this approach is chemically reliable, there are significant limitations, particularly in relation to safety; toxic and explosive diazomethane is required, limiting widespread adoption and scalability. Flow chemistry can provide some alleviation of these safety issues, but the quest for less hazardous approaches is still desirable. Other approaches, such as the Kowalsky ester homologation [3] and Barton’s photoinduced C1 homologation of N-hydroxy-2-thiopyridone esters [4] both suffer from drawbacks including the requirement for organolithium reagents, poor functional group tolerance and long synthetic sequences. The coupling between N-(acyloxy)phthalimides (NHPI-based esters) and aldehyde sulfonyl hydrazones provides a straightforward approach to solving this issue.
Initial experiments in batch focused on treatment of ethyl glyoxalate-derived 4-trifluoromethyl-phenyl sulfonyl hydrazone with the redox active ester N-Boc (L)-Proline N-(acyloxy)phthalimide, in the presence of Hantzsch ester as the reductive quencher, and disodium Eosin Y (EYNa2) at 456 nm. Once optimised, a range of N-(acyloxy)phthalimides were coupled with a range of sulfonyl hydrazones to give the C1 homologated products in good yield, with a broad range of functionality tolerated and the possibility to undertake late-stage functionalisation of peptides on the solid phase. Importantly, challenging redox active esters could be used, allowing the generation of quaternary centres, albeit in reduced yields.
Scale-up necessitated the use of flow chemistry because, in batch, scales above 1 mmol suffered from poor light penetration that resulted in non-uniform irradiation. After some optimisation, the alkylation was successful on 4 mmol scale, providing the target material after only 8 minutes of irradiation, significantly less time than required for batch.
Summary
The use of flow chemistry, in particular the UV-150 photoreactor mounted in the Vapourtec R-Series system has allowed the scale-up of C1 homologation of a peptide-based substrate to give the product rapidly in good yield.
Contact us today to talk about how the use of continuous flow processing can aid your research endeavours.
References:
[1] Metal-free photocatalytic cross-electrophile coupling enables C1 homologation and alkylation of carboxylic acids with aldehydes (S. Bonciolini, A. Pulcinella, M. Leone, D. Schiroli, A. Luguera Ruiz, A. Sorato, M. A. J. Dubois, R. Gopalakrishnan, G. Masson, N. Della Ca’, S. Protti, M. Fagnoni, E. Zysman-Colman, M. Johansson, T. Noël, Nature Commun., 2024, 15, 1509 – 1518). https://doi.org/10.1038/s41467-024-45804-z
[2] The Arndt–Eistert Reaction in Peptide Chemistry: A Fae Access to Homopeptides. (J. Podlech, D. Seebach, 1995, Angew. Chem. Int. Ed., 34, 471 – 472). https://doi.org/10.1002/anie.199504711
[3] (a) Ester homologation via α-bromo α-keto dianion rearrangement. (C. J. Kowalski, M. S. Haque, K. W. Fields, J. Am. Chem. Soc., 107, 1429 – 1430). https://doi.org/10.1021/ja00291a063 (b) Ester homologation revisited: a reliable, higher yielding and better understood procedure. (C. J. Kowalski, R. E. Reddy, J. Org. Chem., 1992, 57, 7194 – 7208). https://doi.org/10.1021/jo00052a038
[4] (a) Homologation of acids via carbon radicals generated from the acyl derivatives of N-hydroxy-2-thiopyridone. (The two-carbon problem). (D. H. R. Barton, C.-Y. Chern, J. C. Jaszberenyi, Tetrahedron Lett., 1991, 32, 3309 – 3312). https://doi.org/10.1016/S0040-4039(00)92693-5 (b) Homologation of carboxylic acids by improved methods based on radical chain chemistry of acyl derivatives of N-hydroxy-2-thiopyridone. (D. H. R. Barton, C.-Y. Chern, J. C. Jaszberenyi, 1992, Tetrahedron Lett., 33, 5013 – 5016). https://doi.org/10.1016/S0040-4039(00)61176-0
