Broad‑Scope Azetidines from Simple Substrates
Continuing to take a closer look at the innovative chemical research that Fluorochem reagents find themselves involved in, we present the development of a new photocatalytic technique to expand the scope of azetidines, from the lab of Professor Michael Willis at the University of Oxford.
Despite the prevalence of nitrogen-containing saturated heterocycles within biologically active molecules, azetidines remain an uncommon feature in drug molecules. As small, rigid, structures with good solubility and metabolic stability, they are promising three-dimensional scaffolds for drug development. Their underrepresentation lies in their difficult syntheses and the limited patterns of substitution accessible by current methods. Recent advances have widened the scope of azetidines, but these still rely on multi-step production of somewhat contrived, pre-functionalised substrates – reducing the variety in the available azetidine products
Reporting in Nature Catalysis, Benedict Williams et al set out to produce a more general approach, using the [2+2] photocycloaddition of imine and alkene: the aza Paternò–Büchi reaction. The standard Paternò–Büchi reaction between an excited carbonyl and an alkene is well-established, the aza variant, less so. The imine in its triplet state must undergo the cycloaddition before decaying to the ground state, fragmenting or undergoing photoreduction. Previously, this has been achieved using cyclic imines (the enforced planarity reducing intersystem crossing), or by transposing the reaction and activating the alkene instead. This in turn restricts the nature of olefins available, as a good match of frontier molecular orbital energies is required. A more general procedure, allowing a wide variety of alkenes to react with an accessible, acyclic imine could produce a greater variety of azetidines, in a more straightforward manner.
Sulfonyl imines provide a convenient, acyclic substrate, with the necessary photochemical properties. Historically their accessible excited states have been used addition reactions, via a fragmentation. The sulfonyl can be tuned for the correct reactivity, avoiding the fragmentation usually observed. Initially, density functional theory (DFT) calculations assessed the suitability of imines with a range of -SO2X groups. From this, -SO2CF3, -SO2Me and -SO2F imines were calculated to exceed the necessary barrier to fragmentation of 4 kcal mol-1 (i.e. greater than the diffusion limit). However, the -SO2Me substituted imine was calculated to have a substantial barrier to addition into isobutene, so initial experiments were performed on the fluorinated sulfonyl imines
Using the metal-free, visible light activated, photocatalyst 2-isopropylthioxanthone (ITX), 3-methylenepentane and anisaldehyde-derived sulfonyl imines validated the DFT studies, with the -SO2CF3 and -SO2F imines producing azetidines as single regioisomers in yields of 54% and 94% respectively. Further computational work suggested that the choice of sulfonyl group is important to this selectivity, ensuring that initial addition of the alkene to the nitrogen of the imine is favoured over addition to the carbon. The -SO2F substituent not only raises the S-N σ*, preventing fragmentation, but ensures the LSOMO is highly localised on the nitrogen.
With the greater yield, single step synthesis using fluorosulfonyl isocyanate, and the tantalising promise of sulfamoyl fluoride azetidine products capable of the sulfur fluoride exchange (SuFEx) click reaction, the -SO2F based imines were used to fully explore the scope of the reaction. The photocatalyst was switched to the less reducing 3-fluorothioxanthone (3-F-TX), to better handle a wider range of imines. While the alkenes were used in excess (usually up to 10 equivalents), mild reaction conditions meant that they were recoverable.
Using this approach, a large amount of aryl imines were capable of the [2+2] photocycloaddition: the reaction was successful with steric bulk close to the centre of reaction, a range electronically modifying groups, as well as with heteroaromatics (so far, poorly represented in aza Paternò–Büchi reactions). It was also robust enough that imines could be generated in situ, directly from the corresponding aldehydes. Turning to the olefin partner, even more variety is demonstrated: styrenes, di- and tri-substituted alkenes, as well as those substituted with B, N & O heteroatoms all successfully generated a range of azetidines. The ease in which spirocyclic azetidines can be formed using this reactivity is particularly noteworthy, as their synthesis is often prohibitively lengthy by other routes. The procedure was also tolerant of various reactive functional groups on both partners with many electrophilic species, as well as the normally photoredox unstable sulfonyl tetrazole and phthalimide, all performing well. However, simple, terminal alkenes are very slow to react, but this does produce the opportunity for excellent regioselectivity (>20:1) for di- versus monosubstituted alkenes within the same substrate.
This approach is flexible, with evidence that it can generalised to other methods of excitation, with an iridium-based photocatalyst used to produce one example. As the reaction is driven by the imine-derived triplet state intermediate, it enables a wide scope of alkenes, with very little limiting their selection, beyond the monosubstituted and extremely electron poor.
The sulfamoyl fluoride azetidines produced have excellent scope for further functionalisation: Red-Al easily cleanly releases the amine, so the sulfonyl fluoride can function as a traceless activating group. Arene oxidation with RuIO4 can produce a range of proline homologues. Perhaps most excitingly, the products are also viable candidates for SuFEx chemistry, with direct chemical biology applications, or the trivial generation of azetidine sulfamides – ideal for rapid library synthesis. Clean reaction conditions and tolerance for functional groups also allows more elaborate transformations to be telescoped, as the authors demonstrate with a one-pot cycloaddition and Suzuki coupling.
The strength of this work lies in how permissive the reaction design proved to be: the imines employed are simple, easily accessed, acyclic substrates rather than highly engineered scaffolds; the olefins need no intrinsic excitability or pre‑activation and the demonstrated tolerance across a wide spectrum of these alkene partners underscores the lack of constraint on reactants. This not only highlights the robustness and generality of the catalytic strategy, but also opens the door to broad synthetic applications, where readily available feedstocks can rapidly create structural diversity.
Dr M. Tomsett – Technical Liason Officer
B. A. Williams, M. J. Tilby, N.A. Parker, M. R. Uehling, J. C. Hethcox, D. Kalyani, M. C. Willis. A modular synthesis of azetidines from reactive triplet imine intermediates using an intermolecular aza Paternò–Büchi reaction. Nat Catal 8, 939–947 (2025)
W. Wang, M. K. Brown. Photosensitized [4+2]- and [2+2]-Cycloaddition Reactions of N-Sulfonylimines. Angew. Chem. Int. Ed. 2023, 62, e202305622
E. R. Weaving, Y. Yeh, G. G. Terrones, S. G. Parikh, I. Kevlishvili, H. J. Kulik, C. S. Schindler. Visible light–mediated aza Paternò–Büchi reaction of acyclic oximes and alkenes to azetidines. Science 384, 1468-1476 (2024)
Willis Research Group
