Use of pyridinium ionic liquids as catalysts for the synthesis of 3,5-bis(dodecyloxycarbonyl)-1,4-dihydropyridine derivative

Abstract

The synthesis of cationic amphiphilic 1,4-dihydropyridine derivative, potential gene delivery agent is achieved via an efficient multi-step sequence. The key step of this approach is a two-component Hantzsch type cyclisation of 3-oxo-2-[1-phenylmethylidene]-butyric acid dodecyl ester and 3-amino-but-2-enoic acid dodecyl ester utilising bis(2-hydroxyethyl)ether as a solvent and 1-butyl-4-methylpyridinium chloride as a catalyst. The 1,4-dihydropyridine derivative with long alkyl ester chains at positions 3 and 5 of the 1,4-DHP ring — 3,5-bis(dodecyloxycarbonyl)-2,6-dimethyl-4-phenyl-1,4-dihydropyridine was obtained in substantially higher yield with respect to classical Hantzsch synthesis. Bromination of this compound followed by nucleophilic substitution of bromine with pyridine gave the desired cationic amphiphilic 1,4-dihydropyridine.

Studies of the physicochemical and structural properties of self-assembling cationic pyridine derivatives as gene delivery agents

“…Interestingly, that other newly synthesised compounds with electrondonating substituent containing pyridinium moieties at the cationic part of amphiphiles (compounds 6b-d) showed average or poor activity in contrast to the previously described 1,4-DHP amphiphiles, where b-or g-picolinium or p-dimethylaminopyridinium moieties containing 1,4-DHP amphiphiles possessed delivery activity comparable with 1,4-DHP derivative 1a, while 1,4-DHP derivatives containing saturated cationic heterocyclic moieties at the head-group did not show any delivery activity (Pajuste et al, 2011).…”

“…The bromination of 2,6-methyl groups of compound 2 was performed with NBS according to the reported method giving 2,6-bis(bromomethyl)-3,5-bis(dodecyloxycarbonyl)-4-phenyl-1,4-dihydropyridine (5) (Pajuste et al, 2011). 1 H and 13 C NMR spectra data of compounds 2 and 5 were identical to those reported in the literature (Pajuste et al, 2011).…”

“…The synthesis of the starting 1,4-dihydropyridine derivative 2 has already been reported in the literature (Pajuste et al, 2011). For further transformations, firstly we performed oxidation of compound 2 with in situ generated nitric oxide using the methodology described by Dubur and Uldrikis (1972) (Scheme 1, path A) to obtain pyridine derivative 3.…”

Experimental and Theoretical Studies of Bromination of Diethyl 2,4,6‐Trimethyl‐1,4‐dihydropyridine‐3,5‐dicarboxylate

“…N ‐Bromosuccinimide (NBS) is a widely used as a brominating as well as a mild and selective oxidizing agent for many classes of organic compounds. It has been reported by our laboratories that bromination of methyl groups at the positions 2 and 6 of Hantzsch‐type N‐unsubstituted and N‐substituted 2,6‐dimethyl‐4‐aryl‐1,4‐dihydropyridine‐3,5‐dicarboxylates in methanol at room temperature leads to the formation of various brominated products in good yields, depending on the amount and type of halogenation reagent .…”

A clean procedure for the synthesis of 1,4-dihydropyridines via Hantzsch reaction in water

“…[10] Additionally, this method has difficulty in the synthesis of different substituted biologically active Hantzsch esters derivatives. Then, some improved synthetic methods for preparing these 1,4-DHPs compounds have been reported by condensation of aldehydes, ammonium salts, and b-keto esters in the presence of Lewis acid, [11,12] Bronsted acid,[13Á15] solid acid, [16] base, [17,18] biocatalysts, [19,20] organocatalysts [21], and ionic liquids [22,23] as catalysts. Recently, the progress of modified Hantzsch reactions in aqueous medium, solvent-, and/or catalyst-free synthesis has attracted the attention of chemists because they are environmentally benign processes.…”