Stereospecific Synthesis of Highly Substituted Piperazines via an One-Pot Three Component Ring-Opening Cyclization from N-Activated Aziridines, Anilines, and Propargyl Carbonates

Abstract

A simple and efficient one-pot three-component synthetic route to highly substituted and functionalizable piperazines in high yields with excellent stereoselectivity (de, ee >99%) is reported. The SN2-type ring-opening of N-activated aziridines by anilines followed by Pd-catalyzed annulation with propargyl carbonates gives rise to the final piperazine products.

Stereoselective Synthesis of Hexahydroimidazo[1,2-a]quinolines via SN2-Type Ring-Opening Hydroarylation–Hydroamination Cascade Cyclization of Activated Aziridines with N-Propargylanilines

“…The activated aziridines and azetidines are attractive building blocks for the synthesis of high-value acyclic and cyclic nitrogenous compounds . Over the years, we have been involved in exploring and exploiting Lewis acid catalyzed S N 2-type ring-opening transformations of activated aziridines and azetidines to synthesize biologically relevant aza-heterocycles via ring-opening cyclization (ROC) or domino ring-opening cyclization (DROC) …”

A simple route to morpholine derivatives via copper‐acetylide addition to carbodiimide in the presence of oxiranes

“…Thin-layer chromatography (TLC) was performed using Silica gel 60 (Merck, item number 116835). 4 ]PF 6 (0.1 mmol), TBPAc (0.1 mmol), t BuOLi (1.0 mmol), carbodiimide (1.5 mmol), and ground 3-Å molecular sieves (250 mg) in NMP (3.0 mL) was stirred at 25°C under Ar. After 30 minutes, oxirane (1.0 mmol in 1.0-mL anhydrous NMP) was slowly added, and the resulting yellowish mixture was warmed up to 60°C.…”

“…Stirring was continued for 18 hours under Ar. After completion of the reaction (TLC monitoring), it was diluted by EtOAc (5 mL) and a saturated NH 4 Cl solution (5 mL). The mixture stirred for additional 30 minutes, and two layers were separated.…”

“…Among the methods developed for the synthesis of heterocyclic compounds, the domino ring opening/cyclization reactions of oxiranes or aziridines with appropriate reaction partners have found much interest in organic chemistry. [1][2][3][4] The easy handling, high stability, and low cost of oxiranes have made them among the most versatile starting materials both in laboratory and in industrial usage. [5][6][7][8] As far as we could ascertain, the regioselectivity of the ring opening reaction of oxiranes with different nucleophiles is very sensitive to electronic as well as steric effects of substrates and reaction media.…”

“…[24][25][26] Initially, we used phenyl acetylene (1a), N,N′-diisopropylcarbodiimide (2a), and methyl oxirane (3a) as the starting materials, CuI as precatalyst, and t BuOLi as base in NMP at 60°C. The desired product 4a was obtained only in 24% ( 4 ]PF 6 afforded a better yield (entry 4). The use of copper (II) salts completely suppressed the formation of the desired product 4a (entries 5-6).…”