Photoredox-catalyzed multicomponent Petasis reaction in batch and continuous flow with alkyl boronic acids

Abstract

Summary Multicomponent reactions (MCRs) are ideal platforms for the generation of a wide variety of organic scaffolds in a convergent and atom-economical manner. Many strategies for the generation of highly substituted and diverse structures have been developed and among these, the Petasis reaction represents a viable reaction manifold for the synthesis of substituted amines via coupling of an amine, an aldehyde and a boronic acid (BA). Despite its synthetic utility, the inherent drawbacks associated with the traditional two-electron Petasis reaction have stimulated continuous research towards more facile and tolerant methodologies. In this regard, we present the use of free alkyl BAs as effective radical precursors in this MCR through a single-electron transfer mechanism under mild reaction conditions. We have further demonstrated its applicability to photo-flow reactors, facilitating the reaction scale-up for the rapid assembly of complex molecular structures.

A continuous-flow protocol for photoredox-catalyzed multicomponent Petasis reaction

“… Note: Connect to the end of the reagent lines a needle ( Figure 3 ).

Scheme 1 General scheme of the reaction ( Oliva et al., 2021 )

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“…Recently, our group contributed to this field by applying alkyl boronic acids as efficient radical precursors as well as optimal substrates for application in flow, due to their inherent solubility in most organic solvents ( Oliva et al., 2021 ). It is worth mentioning that the use of free boronic acids as an alkyl radical source has been overlooked due to their high oxidation potential ( Li et al., 2016 ).…”

“…The protocol has been extended to the synthesis of three additional substrates. For the same experiment performed in batch, please refer to Oliva et al. (2021) .…”

“…The protocol is limited to alkyl boronic acids. For complete details on the generation and use of this protocol, please refer to Oliva et al. (2021) .…”

Multicomponent reactions and photo/electrochemistry join forces: atom economy meets energy efficiency

“…More interestingly, the method was implemented under photo-flow conditions, and product formation was obtained within 50 min of irradiation (using a 150 W blue light) (Scheme 116). 221 Scheme 114 Photocatalyzed A 3 -coupling reaction through a HAT process. In 2020, a modular approach that avoids the need of preformed unstable iminium ions or the use of highly nucleophilic organometallic reagents for the preparation of tertiary amines was accomplished by Kumar et al 222 In an attempt to develop a mild and robust approach, they optimized the reaction conditions employing secondary alkyl amines and alkyl aldehydes, together with alkyl iodides as radical precursors and tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) as an acidic additive.…”