Recent advances in the chemistry of ketyl radicals

Abstract

Ketyl radicals are valuable reactive intermediates for synthesis and are used extensively to construct complex, functionalized products from carbonyl substrates. Single electron transfer (SET) reduction of the C[double bond, length as m-dash]O bond of aldehydes and ketones is the classical approach for the formation of ketyl radicals and metal reductants are the archetypal reagents employed. The past decade has, however, witnessed significant advances in the generation and harnessing of ketyl radicals. This tutorial review highlights recent, exciting developments in the chemistry of ketyl radicals by comparing the varied contemporary - for example, using photoredox catalysts - and more classical approaches for the generation and use of ketyl radicals. The review will focus on different strategies for ketyl radical generation, their creative use in new synthetic protocols, strategies for the control of enantioselectivity, and detailed mechanisms where appropriate.

Fig. 1. Some properties of ketyl radicals and their anions.

Scheme 1. Zinc–NH₃-mediated ketyl olefin couplings (Cheng, 2013).

Scheme 2. Cross-coupling of sodium ketyl radicals and aryl iodides to give tertiary benzylic alcohols (Studer, 2016).

Scheme 3. Ketyl radical intermediates in a Ti(iii)-catalyzed enantioselective cyclization of ketonitriles (Streuff, 2012).

Scheme 4. Carbonyl–alkene coupling featuring pyridine–boryl radicals (Li, 2018).

Scheme 5. Ketyl radicals in lactone–alkene couplings using SmI₂–H₂O (Procter, 2012).

Scheme 6. Ketyl radicals in lactone cascade cyclizations to give fused bicycles using SmI₂–H₂O (Procter, 2012).

Scheme 7. Enantioselective cyclization cascades of Sm(iii) ketyl radicals (Procter, 2017).

Scheme 8. Ketyl radicals in NHC-catalysed decarboxylative coupling of activated carboxylic acids and aldehydes (Ohmiya, 2019).

Scheme 9. Proton-coupled electron transfer in photocatalytic ketyl–olefin cyclisations (Knowles, 2013).

Scheme 10. Photocatalytic enantioselective aza-pinacol cyclization employing a chiral phosphoric acid and exploiting PCET (Knowles, 2013).

Scheme 11. Enantioselective reduction of aromatic ketones through the integration of enzymatic and photoredox catalysis (Hyster, 2019).

Scheme 12. Photocatalytic synthesis of substituted indoles and isoquinolines by ketyl–ynamide coupling and radical Smiles rearrangement (Ye, 2020).

Scheme 13. Dual photocatalytic and organocatalytic, direct β-functionalization of cyclic ketones (MacMillan, 2013).

Scheme 14. Enantioselective [2+2] photocycloaddition involving α,β-unsaturated ketones and using a transition–metal photocatalyst and Lewis acid co-catalyst. (Yoon, 2014).

Scheme 15. Photocatalytic homo-coupling of aldehydes and ketones (Rueping, 2015).

Scheme 16. Photocatalytic allylation of aldehydes and ketones involving ketyl radicals (Chen, 2016).

Scheme 17. Synergistic Lewis acid/photoredox catalysis in intermolecular ketyl–olefin couplings involving aldehydes and alkenylpyridines (Ngai, 2017).

Scheme 18. Enantioselective photocatalytic cross-coupling of nitrones and aldehydes (Huang, 2018).

Scheme 19. Photocatalytic cross-coupling of N-aryl amines with aldehydes and ketones, enabled by PCET (Wang, 2018).

Scheme 20. A redox neutral pathway for the generation of ketyl radical derivatives and their coupling with alkynes (Nagib, 2018).

Scheme 21. Enantioselective, Rh-catalysed, visible light-mediated [3+2] cycloaddition of cyclopropyl ketones and alkenes or alkynes (Meggers, 2018).

Scheme 22. Enantioselective, photocatalytic radical-coupling of activated ketones and N-aryl glycines (Jiang, 2018).

Scheme 23. Violet light-mediated allylation and benzylation of aldehydes and ketones (König, 2018).

Scheme 24. Visible light-initiated 1,2-functionalisation of alkenes by radical perfluoroalkylation/alkenyl migration (Studer, 2018).

Scheme 25. Visible light-initiated radical allylation using homoallylic alcohols and base (Studer, 2020).

Scheme 26. Photocatalytic Minisci-type reactions using ketyl-radical derivatives generated from aldehydes (Huang, 2020).

Scheme 27. Electrochemical ketyl–olefin coupling using unactivated ketones and unactivated alkenes (Baran, 2020).

Scheme 28. A ketyl radical in the pivotal ketone–ester pinacol coupling en route to (−)-actinophyllic acid (Kwon, 2016).

Scheme 29. Contrasting the reactivity of tin and samarium ketyl radicals in the total synthesis of (+)-steenkrotin A (Ding, 2016).

Scheme 30. SmI₂-mediated ketyl radical formation in a cyclization cascade en route to (+)-pleuromutilin (Procter, 2013).

Scheme 31. A SmI₂-mediated ketyl–olefin cyclization in the total synthesis of (+)-pleuromutilin (Reisman, 2018).

Scheme 32. SmI₂-mediated ketyl radical formation in a cyclization cascade approach to (±)-phomoidride D (Wood, 2018).

Scheme 33. Control of conformation in a SmI₂-mediated ketyl–olefin cyclization en route to (±)-atropurpuran (Qin, 2016).

Scheme 34. The effect of HMPA on a SmI₂-mediated ‘ketyl–olefin’ cyclization in the total synthesis of (−)-stemoamide (Honda, 2011).

Áron Péter

Soumitra Agasti

Oliver Knowles

Emma Pye

David J. Procter