Transition-Metal-Free Functionalization of Saturated and Unsaturated Amines to Bioactive Alkaloids Mediated by Sodium Chlorite

Abstract

New approaches to the synthesis of alkaloids through the straightforward functionalization of C(sp3)–H and C(sp2)=C(sp2) bonds of simple five and six-membered ring N-heterocycles are highlighted. The direct functionalization of preexisting N-heterocycles to advanced alkaloids intermediates is a chemical operation that commonly requires the intervention of transition or precious metals. Regardless the inherent unwanted waste production, the high economical cost of many transition metal catalysts limits their use globally. Here, we account our efforts directed toward the synthesis of bioactive alkaloids under an economic and ecological fashion by using NaClO2 as the key activating or oxidizing reagent that substitutes the use of transition metal catalysts. While undesired metal wastes are collected during the extraction process of a transition metal catalyzed reaction, innocuous NaCl is the commonly product waste when NaClO2 is employed in our chemical transformations. Beginning with the synthesis of 2,3-epoxyamides from allyl amines, we concluded with the functionalization of multiple and remote C(sp3)-H and C(sp3)–C(sp3) bonds in piperidine rings that enabled the preparation of important bioactive alkaloids. For the latter functionalization, a precise amount of co-oxidant reagent (NaOCl) and radical 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) were needed.

Organic Synthesis Using Nitroxides

“…The group of Sartillo-Piscil used piperidines 65 as the starting materials for different transformations (Scheme ). In their first paper in this context, the preparation of 3-alkoxyamine lactams 78 starting from piperidine 65 using TEMPO in combination with NaOCl/NaClO 2 was described (Scheme a). − In the first step, piperidine 65 gets oxidized by the TEMPO oxoammonium salt to its iminium ion and deprotonation leads to enamine 66 , which can add to TEMPO + , and the resulting iminium is finally oxidized to the desired product 78 by chlorite. Piperazines and morpholines react under such conditions to piperazine-2,3-diones and morpholine-3-ones, respectively .…”

On the Reaction Mechanism of the Selective C(sp3)–H Functionalization of N-Benzylpiperidines Mediated by TEMPO Oxoammonium Cation

“…3 In this regard, during the last six years our research group has developed, from simple saturated tertiary cyclic amines and under transition-metal-free conditions, a series of C–H oxidation reactions of cyclic amines to bioactive alkaloids or advanced alkaloid intermediates. 4 These strategies are grounded on a selective and dual C(sp 3 )–H functionalization of tertiary piperidines and pyrrolidines mediated by TEMPO and sodium oxychloride reagents (NaClO 2 and NaClO). 5…”

Asymmetric Synthesis of trans-3-Alkoxyamino-4-Oxygenated-2-Piperidones Mediated by Transition-Metal-Free Dual C-H Oxidation and Its CAL-B-Assisted Enzymatic Resolution

“…As a widely applied method in our research group [12,22,23], a tandem dual C−H oxidation was carried out using N-benzyl-4-hydroxy-piperidine 1 as starting material. The piperidine derivative was mixed with the TEMPO oxoammonium cation in the presence of sodium chlorite and sodium hypochlorite in acetonitrile to obtain the alkoxyamine lactam (rac-trans-3), which, after acylation, produces rac-trans-2 in good yield (Scheme 1).…”

“…Unfortunately, these catalysts are generally quite expensive and toxic, causing economic and ecological drawbacks [19,20]. Most recently, a dual C-H oxidation of piperidines to their corresponding piperidin-2-one derivatives under transition-metal-free conditions has shown to be an efficient, accessible, and eco-friendly approach for accessing biologically important alkaloids [21][22][23]. Although the 3,4-dioxygenated-2-pyperidone system could be considered a noncomplex molecular motif, there are only a few known approaches to accessing them in an asymmetric fashion [12].…”