Date: 20 March 2025 | Category: News
Authors: Kristína Plevová, Véronique Michelet and Sylvain Antoniotti
Sylvain Antoniotti, Kristína Plevová and Véronique Michelet, from the Université Côte d’Azur, have successfully used the Vapourtec R-Series system to achieve scale-up of a tandem cyclisation/hydroalkoxylation process using heterogeneous gold nanoparticles supported on TiO2. In particular, the use of flow allowed scale-up by a factor of 10 without reducing efficiency [1].
Figure 1: General reaction conditions for the tandem cyclisation/hydroalkoxylation sequence.
Gold catalysis in synthesis
Homogenous gold catalysis has become a stalwart for synthesis of drug-like molecules and interesting targets, whereas its cousin, heterogeneous gold catalysis, has remained underutilised. However, in recent years, this has started to change, and heterogeneous gold catalysis, either through immobilisation of gold salts on a suitable surface, heterogenization of gold complexes, or use of nanoparticles (Au NPs), has started to receive attention.
The use of heterogeneous catalysts can provide significant advantages, such as catalyst recycling, easier implementation within a continuous flow set-up using a fixed-bed reactor [2], high surface area to volume ratios and access to differing reaction mechanisms, which is particularly true for Au NPs.
We are grateful for the following valuable insight from Sylvain Antoniotti, Vice-president of Université Côte d’Azur:
“We always perform testing of our solid catalyst in continuous flow reactors. In most instances, we observe improved yields and purities by shifting from reaction times in batch to residence times in flow. This allows for optimal reaction conditions. It also facilitates multistep reactions in cases where one-pot / multicatalytic conditions are not suitable”.
Reaction scope and applicability
The tandem cyclisation/hydroalkoxylation reaction was amenable to a range of substrates bearing a variety of functional groups, including ethers, halogens and alkyl species. In addition, the total synthesis of a bioactive isochromene derivative was achieved, a motif that is found in several natural products and shows biological properties such as antibacterial, antifungal, antitumoral and antimicrobial activity.
While reaction optimisation was achieved using batch mode, translation into flow and scale-up was facile; the Au-TiO2 NPs were simply placed in a glass heated reactor. Increasing scale from 1 mmol, to 2 mmol to 9.7 mmol in flow was readily achievable, and yields were maintained or even improved with larger batches. In addition, no further purification of the final product was necessary.
References
[1] Small gold nanoparticles for tandem cyclization/reduction and cyclization/hydroalkoxylation reactions. (K. Plevová, V. Michelet, S. Antoniotti, Commun. Chem., 2024, 7, 248). https://doi.org/10.1038/s42004-024-01336-7
[2] Flow chemistry: recent developments in the synthesis of pharmaceutical products. (R. Porta, M. Benaglia, A. Puglisi, Org. Proc. Res. Dev., 2016, 20, 2 – 25). https://doi.org/10.1021/acs.oprd.5b00325
Learn more about the fixed bed reactor