Research in the Schindler lab is focused on the development of novel and innovative synthetic methods. In particular, we are highly interested in the discovery of new reactions between carbonyl compounds and alkenes. We recently became aware of the challenges associated with the reaction of imines and alkenes in [2+2] cycloaddition reactions, which have the potential to provide four-membered azetidine heterocycles as products. Azetidines have found increased use in drug discovery as rigid amine backbones or as bioisosteres for larger ring analogs, which prompted us to develop a new synthetic entry to azetidine heterocycles through a [2+2] cycloaddition approach.
This approach would hold several advantages over previous synthetic methods to access azetidines, since it would be 100% atom-economical, require minimal prefunctionalization, and rely on the use of easily accessible starting materials. We were surprised to see that this approach has been met with limited success in the literature. While carbonyl compounds and alkenes quite readily undergo [2+2] cycloaddition under photochemical conditions, commonly referred to as the Paternò-Büchi reaction, the corresponding aza Paternò-Büchi reaction suffers from additional relaxation pathways accessible upon photoexcitation of the imine (Fig. 1). As a result, there exists only a small number of examples, in which photoexcited imines successfully undergo photocycloaddition to alkenes.
We were inspired by work from Sivaguru and coworkers1, who showed that the aforementioned limitations can be overcome when an excited state alkene is used in the reaction instead. However, we realized that in order to make this approach more accessible to a broader community, we needed to overcome several obstacles. Previous reports required conditions, in particular the use of UV light and high catalyst loadings, which is difficult to realize on an industrial scale, and results in limited functional group tolerance and diminished yields.
Motivated by this idea, we started evaluating conditions to develop a protocol that could proceed under milder conditions by utilizing visible light activation. Acknowledging pioneering work by the Yoon group2,3, we wondered if a triplet state alkene accessed through a triplet energy transfer event from a visible light photocatalyst would react with an adjacent C=N double bond. To test this hypothesis, we irradiated our substrate with catalytic amounts of an iridium photocatalyst with blue LED lights and indeed formed the desired product! In fact, these conditions proved successful for a number of substrates in high yields, short reaction times and very low catalyst loadings (Fig. 2).
The N-O bond in the azetidine products can function as a protecting group that can be readily removed under reductive conditions (e.g. zinc metal) in high yields.
We hope that this work will provide a new reaction platform to access highly functionalized azetidines and inspire the development of novel synthetic methodologies for their synthesis!
Interested about more details of this visible-light mediated aza Paternò-Büchi reaction?
The full article can be found here.
1. Kumarasamy, E., Kandappa, S. K., Raghunathan, R., Jockusch, S. & Sivaguru, J. Realizing an aza Paternò–Büchi reaction. Angew. Chem. Int. Ed. 56, 7056-7061 (2017).
2. Lu, Z. & Yoon, T. P. Visible light photocatalysis of [2+2] styrene cycloadditions by energy transfer. Angew. Chem. Int. Ed. 51, 10329-10332 (2012).
3. Hurtley, A. E., Lu, Z. & Yoon, T. P. [2+2] Cycloaddition of 1,3‐dienes by visible light photocatalysis. Angew. Chem. Int. Ed. 53, 8991-8994 (2014).