A Simplified Protocol for Routine Chemoselective Syntheses of Piperazines Substituted In the 1-Position by an Electron Withdrawing Group



Druh Článek v odborném periodiku
Časopis / Zdroj Current organic synthesis
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Doi http://dx.doi.org/10.2174/1570179411666141001232644
Obor Organická chemie
Klíčová slova 1-monosubstituted piperazine; ionically-bound substrate; metal catalysis; piperazine; piperazine-1-ium cation; resin supported metal ion; solid phase synthesis
Popis We report a simplified protocol for the routine direct chemoselective preparation of various piperazines substituted in the 1-position by an electron withdrawing group. These syntheses are based on the reaction of piperazine-1-ium cation with different electrophilic reagents such as acyl chlorides, anhydrides, sulfonyl chlorides, carbamoyl chlorides, and nitrourea as well. Piperazine-1-ium cation was chosen because the reactions of piperazine with electrophilic reagents in different solvents at usual temperatures are not chemoselective and provide mixtures comprising 1-substituted, 1,4-disubstituted and unsubstituted piperazine as well. Simultaneously, the mono-protonation of piperazine is the simplest synthetic method for its protection/deprotection in comparison with the currently used mono-benzylation, mono-Boc-protection, etc. Computer modeling of acid-base equilibria for piperazine and model 1-acetylpiperazine was used as the basis for the prediction of reaction conditions suitable for the synthesis. It was found that for in situ generating of starting piperazine-1-ium cation from piperazine the application of acetic acid as reaction medium or the chemisorption of piperazine on weakly acidic cation-exchanger resin were highly acceptable in terms of both reaction times and yields. The using of resin supported piperazine-1-ium cation in reaction with carboxylic anhydrides or nitrourea is an example of the solid phase synthesis with ionically bonded substrate. Furthermore, syntheses in acetic acid medium were effectively catalyzed by Cu+, Cu2+ or Al3+ ions supported on weakly acidic cation-exchanger resin as well. Finally, it was observed that application of the solid support metal catalysis afforded target products in shortened reaction times and in 82-95% yields.
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