Three-Component Reactions of Arynes, Amines, and Nucleophiles via a One-Pot Process

Abstract

An unprecedented three-component reaction of arynes, tertiary amines, and nucleophiles has been demonstrated through ammonium salt intermediates. This protocol allows access to tertiary aniline derivatives containing the piperazine motif in good-to-excellent yields. Expansively, this reaction can produce biologically important 2-(4-phenylpiperazin-1-yl)ethyl-containing molecules using arynes, 1,4-diazabicyclo(2.2.2)octane (DABCO), and nucleophiles via a one-pot process.

Asymmetric Synthesis of γ-Secondary Amino Alcohols via a Borrowing-Hydrogen Cascade

“…Acyclic secondary amines coupled to both (±)-1-phenylallyl alcohol and (±)-2-(2-naphthyl)­allyl alcohol, affording the desired alcohols 38 and 39 with 90% ee, respectively. A series of piperazine derivatives that are significant pharmaceutical structures were than investigated, and the alcohol products 40 – 48 were obtained with 85–94% ee. The absolute configuration of 46 was also assigned as (R)-configuration by X-ray analysis.…”

N-Arylation of DABCO with Diaryliodonium Salts: General Synthesis of N-Aryl-DABCO Salts as Precursors for 1,4-Disubstituted Piperazines

“…In our study aimed to fill the above gap in modern arylation methods, we chose highly nucleophilic 1,4-diazobicyclo[2.2.2]­octane (DABCO) as a model substrate to start with. Here, we present a general method for the N-arylation of DABCO, providing the first preparative access to the hitherto elusive DABCO-derived quaternary ammonium salts. , Previous attempts to obtain them using S N Ar or aryne chemistry were unsuccessful; the initially formed salts rapidly underwent a ring opening under the reaction conditions employed. , At the same time, a few examples of their generation and in situ ring-opening reactions with nucleophiles have been recently reported, including by our group . Such reactions could serve a basis for a rapid and modular synthesis of 1,4-disubstituted N -arylpiperazines (vide infra), which represent a common structural motif in many pharmaceuticals (Figure ).…”

Sulfonylation of 1,4‐Diazabicyclo[2.2.2]octane: Charge‐Transfer Complex Triggered C−N Bond Cleavage

“…Synthetically, DABCO is a useful building block for the preparation of 1,4‐disubstituted piperazines . Pioneered by the work of Ross and Finkelstein, the ring‐opening of DABCO,, prompted by nucleophilic attack on the highly reactive N ‐alkyl quaternary ammonium salts (derived from in situ coupling of DABCO with alkyl, aryl and heteroaryl halides, arynes, pyridine N ‐oxides etc. ), has been extensively developed for the preparation of 1,4‐disubstituted piperazines (Scheme ).…”