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Theoretical Research Aimed at Achieving Regioselective Control within the Hofmann-Löffler-Freytag Reaction

The Hofmann-Löffler-Freytag (HLF) reaction represents a distinctive radical-based procedure for the synthesis of nitrogen-containing heterocycles. Although the formation of piperidine and pyrrolidine rings is equally likely [1], due to the driving force being approximately the same, pyrrolidine rings are dominant product. (Figure 1. Interchanging bulky and activating group has the role of a mechanistic switch while guiding formation of the predominant product.) Finding a mechanistic switch that governs whether 1, 5-HAT or 1, 6- HAT reaction occurs is quite challenging. Possible candidates for a switch are presence/absence of steric bulk, presence/absence of chiral centers along the carbon chain, molecular flexibility and/or stereoelectronic effects. It has been shown that selective piperidine formation is plausible when C-H bonds at C5 and C6 carbon are equally reactive [2-4]. Placing a sulfoxide or sulfamide group at the C2 position endo and a bulky group exo leads to the formation of piperidine product in predominant fashion as has been demonstrated by Short et al [3, 4]. They have put forth an elucidation for predominant piperidine formation. Their reasoning is that elongated N-S 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 [3, 4]. Other works demonstrate predominant pyrrolidine products, although in almost all the cases C-H bonds at C5 are more reactive as compared to C-H bonds at the C6 position and the activating group is placed exo, with steric bulk having no significant influence on regioselectivity [5, 6]. Here presented are calculated thermodynamical and kinetic parameters in our search whether positioning of activating and/or bulky groups in exo and endo position are the switch between pyrrolidine and piperidine products. References: [1] D. Šakić, H. Zipse, Adv. Synth. Catal. 358 (2016) 3983–3991. [2] T. Duhamel, M. D. Martínez, I. K. Sideri, K. Muñiz, ACS Catal. 9 (2019) 7741–7745. [3] M. A. Short, J. M. Blackburn, J. L. Roizen, Angew. Chem. Int. Ed. 57 (2018) 296–299. [4] M. A. Short, M. F. Shehata, M. A. Sanders, J. L. Roizen, Chem. Sci. 11 (2020) 217–223. [5] T. Duhamel, C. J. Stein, C. Martínez, M. Reiher, K. Muñiz, ACS Catal. 8 (2018) 3918–3925. [6] P. Becker, T. Duhamel, C. J. Stein, M. Reiher, K. Muñiz, Angew. Chem. Int. Ed. 56 (2017) 8004–8008.

rearrangement ; radicals ; switch

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