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Hofmann-Löffler-Freytag (HLF) is a well-established reaction used for late-stage functionalization for producing pyrrolidine rings, and more rarely piperidine rings, via C-H activation. However, according to Šakić and Zipse, [1] the driving force for the formation of piperidine and pyrrolidine rings is roughly the same. Having this in mind, there are several published works where selective piperidine formation has been realized.[2–4] It was hypothesized by Muñiz et al.[2] that an intermolecular process leads to the formation of the piperidine ring. Nonetheless, intramolecular hydrogen atom transfer (HAT) processes are much faster in comparison with intermolecular HAT processes. Short et al.[4]proposed an explanation for predominant piperidine formation when sulfoxide is in -position.[3, 4] Namely, the elongated N- S and and S-O bond and the compressed O-S-N angle geometrically favor seven-membered transition state, as in 1, 6-HAT for the C-H abstraction. Herein we propose alternative explanation. After formation of a C6 radical via 1, 6-HAT, it subsequently rearranges via 1, 5-HAT to a more stable C2 radical. This depletes the pool of intermediates needed for piperidine synthesis. If C6 radical is more stable than C2, due to phenyl ring stabilization of C6 radical, [2] then the piperidine ring is formed. In this light, substitution of C2 position is outlined as vital for a feasible synthesis of products containing piperidine. Therefore, relative stabilities of the C2, C5 and C6 radicals have a crucial effect on the regioselectivity of the HLF reaction. |
