Date: 6 October 2025 | Category: News
Authors: Parth Naik, Patrick O’Neill, Julia Bruno-Colmenarez, and Marcus Baumann
The Baumann Group at University College Dublin, in collaboration with Pfizer, have disclosed the development of a continuous flow process that facilitates lithiation of THF, with the lithiated species fragmenting into ethylene gas and a lithium enolate. The enolate can be trapped with TIPSOTf, giving a versatile silyl enol ether building block that was used in subsequent cycloaddition reactions, Figure 1.[1] This flow process can be completed at elevated temperatures, using n-hexyllithium, with the resulting intermediates stable over several hours.
Lithiation of THF: A powerful approach but with a concerning safety profile
Lithiation of THF offers a convenient method for formation of the Li-equivalent of acetaldehyde. However, this reaction generates two equivalents of the flammable gases ethylene and butane, and the process is highly exothermic; upon scale-up there are significant safety concerns. In this regard, flow chemistry offers a viable solution due to the improved control over heat and mass transfer under a miniaturised set-up.
Degradation of THF and formation of a silyl enol ether
While scoping of conditions for forming the silyl enol ether was undertaken in batch mode, translation into flow proved simple and gave several advantages including better mixing, better temperature control and the ability to control the formation of the gaseous by-products. Optimisation was achieved using a DoE approach with MiniTab, which rapidly identified temperatures of over 45 °C as being detrimental, and residence times of between 90 and 120 minutes as being optimal. At 39 °C, with residence time of 120 minutes, degradation of THF with nHexLi gave the desired TIPS-enol ether that was isolated in 76% yield, higher than when using batch (66%). This equates to a throughput of 13.1 mmol/h (at steady state) and a space time-yield of 87 g/(hL). Further refinements included using a more dilute solution of nHexLi (0.92 M relative to THF) to decrease viscosity and improve material flow, and quenching of the lithium enolate with freshly prepare aliquots of TIPSOTf.
Silyl enol ether use in situ
The silyl enol ether generated was used in situ within a range of cycloaddition reactions to afford strained ring systems, which are of increasing interest to the medicinal chemistry community. [2, 3, 4] Overall, [2 + 1], [2 + 2] and [2 + 3] cycloadditions were investigated to produce cyclopropanes, cyclobutanones (though photochemical and thermal pathways), isooxazolines and isoxazolidines, Figure 2. Methyl-substituted THF rings were also tolerated.
Figure 2: Representative examples of products prepared
Summary
A continuous flow approach has been used to generate a highly reactive Li-enolate intermediate that can be silylated and used in subsequent cycloaddition reactions to generate access to a range of species of interest to the medicinal chemistry community. In particular, the use of flow chemistry:
- Allowed the controlled release of by-products, improving the reaction safety profile
- Enabled exquisite control of thermal transfer
- Facilitated trapping of the reactive intermediate for subsequent reaction
- Ensured the intermediate was stable for several hours so gram-scale synthesis of the silyl enol ether intermediate could be achieved.
References:
[1] Generation of Lithium Ethenolate by Lithiation of Tetrahydrofuran in Flow Mode. (P. Naik, P. O’Neill, J. Bruno-Colmenarez, M. Baumann, Org. Proc. Res. Dev., 2025). https://doi.org/10.1021/acs.oprd.5c00240
[2] Put a Ring on It: Application of Small Aliphatic Rings in Medicinal Chemistry. (M. R. Bauer, P. Di Fruscia, S. C. C. Lucas, I. Michaelides, RSC Med. Chem. 2021, 12 (4), 448−471). https://doi.org/10.1039/D0MD00370K
[3] Rings in Clinical Trials and Drugs: Present and Future. (J. Shearer, J. L. Castro, A. D. G. Lawson, M. MacCoss, R. D. Taylor, J. Med. Chem. 2022, 65 (13), 8699−8712). https://doi.org/10.1021/acs.jmedchem.2c00473
[4] Advances in the Continuous Flow Synthesis of 3- and 4-Membered Ring Systems. (K. Donnelly, M. Baumann, Chem. Eur. J., 2024, 30, 32, e202400758). https://doi.org/10.1002/chem.202400758