Metal-free photocycloaddition of unactivated alkenes

Date: 25 April 2025 | Category: News

Authors: Diarmuid O’Hanlon, Sharon Davin, Brian Glennon and Marcus Baumann* 

The Baumann group at University College Dublin have reported the use of the Vapourtec E-Series flow chemistry system equipped with a medium-pressure Hg-lamp and a low-pass filter to undertake metal-free [2+2] cycloaddition reactions of unactivated alkenes [1].

It was noted that use of acetone as a co-solvent was crucial and the use of a continuous flow photoreactor led to process intensification, reducing the residence time to a mere 30 – 45 minutes. Integration of membrane separation technologies meant that in-line separation was possible, and scalability was facile, with multigram quantities of 3-azabicyclo[3.2.0] heptane products prepared within a short time period, equating to a space-time yield (STY) of 71 g/h/L.  

[2 + 2] cyclisation: readily facilitated through continuous flow technology 

In recent years the field of photochemistry has experienced a significant resurgence of interest, which is likely due to the technological advances in the undertaking of this class of reaction. In particular, the [2 + 2] cyclisation of unactivated alkene species provides a valuable means for preparation of cyclobutane-containing species, which are prevalent in a number of natural products and pharmaceutical agents [2]. Typically, this class of reactions exploits the differentiation in electronics between the two alkene species, classically with an electron-rich and an electron-deficient partner. An exception to this rule is the Kochi–Salomon reaction, first reported in 1982 where a copper catalyst enables the [2 + 2] coupling to two unactivated alkenes [3, 4]. However, there are several limitations to this including the requirement for moisture-sensitive copper species and substrate limitations.

Working from Burns’ previous efforts [5], Baumann and co-workers readily screened reaction conditions within the Vapourtec E-Series equipped with a medium-pressure Hg-lamp and a low-pass filter. It was quickly seen that the presence of acetone was crucial for shortening residence times, which was attributed to the acetone acting as a triplet photosensitiser. Importantly, when compared with the original copper-containing procedure, the absence of copper did not diminish yields provided that acetone was used as a co-catalyst.

In-line purification adds further efficiency

Incorporation of an in-line work-up, using a Zaiput membrane separator and injected streams of diethyl ether and 1M aqueous sodium hydroxide solution, allowed collection of the organic phase with only solvent removal necessary for isolation of pure product.

Overall, a broad range of functionality was tolerated, with both cyclic and aliphatic N-alkyl groups affording the desired product in high yields. While in some instances, an increase of the residence time from 30 to 45 minutes was necessary for full conversion, multi-gram quantities of pure materials were easily accessible on scale-up. Unfortunately, the presence of aryl groups was troublesome, leading to diminished yields.

Summary 

Continuous flow processing enabled the [2 + 2] photoaddition of unactivated alkenes in a reliable manner that was also scalable. Inclusion of in-line separation techniques reduced the number of manual operations required, meaning that work-up was simple.

References: 

[1] Metal-free [2+2]-photocycloaddition of unactivated alkenes enabled by continuous flow processing. (D. O’Hanlon, S. Davin, G. Blennon, M. Baumann, Chem. Commun., 2025, 61, 1403 – 1406). https://doi.org/10.1039/D4CC06000H 

[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. N. Michaelides, J. E. Nelson, R. I. Storer, B. C. Whitehurst, RSC Med. Chem., 2021, 12, 448 – 471). https://doi.org/10.1039/D0MD00370K 

[3] Copper(I) catalysis in photocycloadditions. II. Cyclopentene, cyclohexene, and cycloheptene. (R. G. Salomon, K. Folting, W. E. Streib, J. K. Kochi, J. Am. Chem. Soc., 1974, 96, 4, 1145 – 1152). https://doi.org/10.1021/ja00811a031 

[4] Copper(I) catalysis in photocycloadditions. I. Norbornene. (R. G. Salomon, J. K. Kochi, J. Am. Chem. Soc., 1974, 96, 4, 1137 – 1144). https://doi.org/10.1021/ja00811a030 

[5] Aqueous Amine-Tolerant [2+2] Photocycloadditions of Unactivated Olefins. (C. M. F. Mansson, N. Z. Burns, J. Am. Chem. Soc., 2022, 144, 19689 – 19694). https://doi.org/10.1021/jacs.2c08778 

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