Remote and multiple functionalization of piperidines without the use of transition‐metal catalysts and elaborate directing groups is one of the major challenges in organic synthesis. Herein is reported an unprecedented two‐step protocol that enables the multiple functionalization of piperidines to either 4‐substituted or trans‐3,4‐disubstituted 2‐piperidones. First, by exploiting the duality of TEMPO reactivity, which under oxidative and thermal conditions fluctuates between cationic and persistent‐radical form, a novel multiple C(sp3)‐H oxidation of piperidines to α,β‐unsaturated 2‐piperidones was developed. Second, the intrinsic low reactivity of the unsaturated piperidones toward conjugated Grignard additions was overcome by using trimethylsilyl chloride (TMSCl) as Lewis acid. Subsequently, conjugated Grignard addition/electrophilic trapping protocol provided substituted 2‐piperidone intermediates, some of which were then transformed into pharmaceutical alkaloids.
The C−H functionalization of unreactive sp3 carbon atoms under transition‐metal‐free conditions contribute, not only to the invention of novel methodologies and synthetic strategies, but also to the development of greener and more sustainable organic chemical processes. With this aim in mind, the direct functionalization of simple piperidines into substituted 2‐piperidones and relevant pharmaceutical alkaloids was achieved thought the development of two transition‐metal‐free cascade reactions. For more information see the Communication by F. Sartillo‐Piscil et al. on page 4671 ff.
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