Selective, Catalytic, and Dual C(sp³)–H Oxidation of Piperazines and Morpholines under Transition-Metal-Free Conditions

Abstract

By using cheap and innocuous reagents, such as NaClO 2 , NaOCl, and catalytic amounts of TEMPO, a new environmentally friendly protocol for the selective and catalytic TEMPO C(sp 3 )−H oxidation of piperazines and morpholines to 2,3-diketopiperazines (2,3-DKP) and 3morpholinones (3-MPs), respectively, has been developed. This novel direct access to 2,3-DKP from piperazines provides significant advantages over the traditional N-monoacylation/ intramolecular C−N cyclization procedure. Additionally, by modulating the amounts of TEMPO, 2-alkoxyamino-3morpholinone can be prepared from morpholine derivatives, which would enable further functionalization at the C2 position of the morpholine skeleton.

Transition‐Metal‐Free Deconstructive Lactamization of Piperidines

“…In recent years, our research group has developed efficient, accessible, economic, and environmentally friendly protocols for the functionalization of simple N‐heterocycle substrates to give relevant bioactive precursors . The success of this direct functionalization of pre‐existing N‐heterocycles lies in the highly selective C−H oxidation at the α position mediated by cheap and environmentally friendly reagents such as NaClO 2 , NaOCl, and 2,2,6,6‐tetramethylpiperidinyloxyl (TEMPO), in which, under modulated conditions, the C−H oxidation at the β position can be achieved, even under catalytic conditions …”

Facile Preparation of 4-(4-Nitrophenyl)morpholin-3-one via the Acid-Catalyzed Selective Oxidation of 4-(4-Nitrophenyl)morpholine by Sodium Chlorite as the Sole Oxidant

“…In the next step, we explored the oxidation of 4-(4-nitrophenyl) morpholine (Table ). When the oxidation reaction was performed according to the reference reaction condition, 98% of the substrate ( 3 ) was consumed. Aside from the generated target product 4-(4-nitrophenyl) morpholine-3-one, two side products ( 1a and 1b ) were detected, suggesting that a side chlorination reaction also occurred (Table , entry 1).…”

“…However, this process uses a large amount of iodine and sodium bicarbonate, which produces too much waste. In 2018, Sartillo-Piscil et al reported 2,2,6,6-tetramethylpiperidin-1-yloxy (TEMPO)-catalyzed oxidation of piperazines and morpholines under transition-metal-free conditions (Scheme , eq 6) . This protocol uses low-cost and environmentally friendly oxidants, including sodium chlorite and sodium hypochlorite.…”

The Utility of Oxoammonium Species in Organic Synthesis: Beyond Alcohol Oxidation

“…90,91 Later, in 2018, they expanded this methodology to piperazines and morpholines. 92 Zhang et al reported a TEMPO-mediated electrochemical oxidation of glycine to yield glyoxylate (not shown). 93 In 2018, Wang et al reported the C-H azidation of tetrahydroisoquinolines and tetrahydro-β-carbolines using TMSN3 and TEMPO + BF4 -.…”