Novel 3-component Staudinger reaction synthesises β-lactams in excellent yield

Journal of Flow Chemistry

Date: 17 October 2024 | Category: Headline NewsNews

The Baumann group from University College Dublin are continuing to showcase the versatility and advantages of flow chemistry. In their latest disclosure they outline development of a novel 3-component Staudinger reaction, allowing rapid access to a diverse library of β-lactams [1]. In the reaction sequence two transformations were telescoped: imine generation and Wolff rearrangement/cyclisation, with flow chemistry allowing facile scale-up of both steps, Figure 1. Finally, the overall sequence was much more rapid than the analogous batch process (33 minutes in flow versus 72 h in batch).

 

 

Multicomponent reactions to generate molecular complexity

Multicomponent reactions (MCRs) are an excellent means for generating molecular complexity rapidly by exploiting the reactivity of the different building blocks. Commonly used MCRs within medicinal chemistry include the Biginelli reaction [2] and the Ugi reaction [3], which can both generate amide-containing products. The Staudinger reaction is also well-known and often used to generate β-lactams through a [2+2] cycloaddition between a ketene and an imine. However, development of a 3-component Staudinger reaction (showcased here) is difficult due to the requirement for mixing of ketene precursors, usually acid chlorides, with the imine precursors, usually aldehydes and amines, and can lead to undesired side-reactions. In cases like this, exploitation of the latent chemical reactivity of particular reagents can be extremely powerful and provide elegant solutions to an otherwise difficult problem.

It was known from previous work [4] that when using diazoketones as ketene precursors, exclusion of light inhibited formation of the ketene intermediate. This was key and offered the opportunity to develop conditions for imine generation and subsequent ketene formation in one-pot, enabling telescoping of steps with minimal manual intervention.

Imine formation was achieved through flowing the aldehyde, amine and diazoketone mixture through a packed bed reactor (PBR), in this case a glass Vapourtec column containing sand and alumina (Al2O3) that fits modularly within an E-Series flow chemistry system, effecting rapid dehydration of the hemiaminal intermediate to give the imine in quantitative yield within 3 minutes but, importantly, avoiding reaction with the diazoketone. The second step exploited the instability of diazoketones under UV light: upon irradiation with 420 nm light at 60 W using the Vapourtec UV-150 photochemical reactor, the diazoketone underwent rapid rearrangement to the ketene which then reacted directly with the imine to give the β-lactam product. Yields were typically in the order of 85%, and scale-up to 4 mmol resulted in no significant decrease in yield (83%).

For this particular reaction, the use of flow chemistry enabled:

  • Tuning the reactivity of individual reagents through use of a PBR for dehydration and monochromatic LEDs for ketene generation;
  • Rapid generation of a small library of β-lactams;
  • Efficient control of heat and mass transfer;
  • Scalability due to the narrow tubing diameter allowing full light penetration and uniform irradiation;
  • Telescoping of reaction steps without isolation of potentially unstable intermediates.

Professor Marcus Baumann commented, “The use of Vapourtec’s modular photoreactors has been crucial for our work in the past years. This allowed us to quickly modify our set-ups and screen various wavelengths and light intensities to optimise a variety of new photochemical reactions. Moreover, innovative new tools developed are allowing us to investigate new processes including those using solids in flow. The development of Vapourtec’s photo-CSTR module is a great example of this as it allowed us to overcome process challenges and selectivity difficulties at the same time.”

References:

[1] Expedited access to β-lactams via a telescoped three-component Staudinger reaction in flow (F. Minuto, A. Basso, M. Baumann, J. Flow. Chem., 2024. https://doi.org/10.1007/s41981-024-00333-0)

[2] Advances in Biginelli reaction: a comprehensive review (A. Chandravarkar, T. Aneeja, G. Anilkumar, J. Heterocycl. Chem., 2024, 61, 5 – 28) https://doi.org/10.1002/jhet.4742

[3] Two decades of recent advances of Ugi reactions: synthetic and pharmaceutical applications (M. A. Fouad, H. Abdel-Hamid, M. S. Ayoup, RSC Advances, 2020, 10, 42644 – 42681) https://doi.org/10.1039/D0RA07501A

[4] Ketene 3-Component Staudinger Reaction (K-3CSR) to β-Lactams: A New Entry in the Class of Photoinduced Multicomponent Reactions (F. Minuto, C. Lambruschini, A. Basso, Eur. J. Org. Chem., 2021, 22, 3270 – 3273) https://doi.org/10.1002/ejoc.202100577