2-(3′,5′-Bis((dodecyloxy)carbonyl)-2′,6′-dimethyl-1′,4′-dihydro-[3,4′-bipyridin]-1-ium-1-yl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide

Abstract

Indane-1,3-dione and 1,4-dihydropyridine (1,4-DHP) scaffolds are of significant interest in medicinal chemistry. Herein, we report the synthesis characterization of a new lipid-like indane-1,3-dione–1,4-DHP betaine, 2-(3′,5′-bis((dodecyloxy)carbonyl)-2′,6′-dimethyl-1′,4′-dihydro-[3,4′-bipyridin]-1-ium-1-yl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide (3). Compound 3 was synthesized from 2,2-dicyanomethylideneindan-1,3-dione (1) oxide and a didodecyl-substituted 1,4-DHP derivative 2 and characterized by UV–Vis spectroscopy, ¹H-NMR, ¹³C-NMR, and HRMS. The obtained results demonstrate a promising strategy for the design of delivery agents, exploiting the lipid-like properties of the synthesized betaine.

1. Introduction

Indane-1,3-dione is a well-established and multifunctional chemical scaffold that has found broad utility across diverse research areas, including medicinal chemistry organic electronics, optical sensing, and non-linear optical (NLO) applications [1]. Over the past several years, indane-1,3-dione has been widely employed as a valuable synthon in organic transformations owing to its availability and versatile reactivity [2,3]. Indane-1,3-dione derivatives is also widely used electron acceptor in the design of dyes for solar cell applications [4,5], photoinitiators for polymerization [6], and chromophores for NLO [7,8] applications. The structural similarity between indane-1,3-dione and indanone has led to sustained interest in this scaffold as a versatile intermediate for the design of biologically active molecules [9].

N-heterocyclic compounds form a major class of organic molecules with broad biological relevance and extensive used applications in medicine. Among these, pyridine and related dihydropyridine and pyridinium derivatives are prominent structural motifs present in numerous pharmaceutical agents [10,11]. Pyridinium-containing lipophilic 1,4-dihydropyridine (1,4-DHP) derivatives have attracted considerable attention due to their ability to self-assemble into liposomal structures and their potential applications in DNA delivery [12]. Moreover, 4-(N-dodecylpyridinium)-1,4-DHP has been shown to cross the blood–brain barrier and to inhibit calcium channels [13].

In view of the significant relevance of both indane-1,3-dione and 1,4-dihydropyridine moieties in medicinal chemistry, we report herein the synthesis and characterization of a new lipid-like compound—indane-1,3-dione–1,4-DHP betaine, 2-(3′,5′-bis((dodecyloxy)carbonyl)-2′,6′-dimethyl-1′,4′-dihydro-[3,4′-bipyridin]-1-ium-1-yl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide (3).

2. Results and Discussion

Synthesis of the target betaine 3 is described in Scheme 1. Reaction completion was monitored by TLC, after which the crude product was purified by flash chromatography.

The substrates 1 and 2 for this reaction were synthesized according to previously reported procedures. 2-(dicyanomethylidene)indan-1,3-dione oxide (1) was obtained by oxidation of 2-(dicyanomethylene)indane-1,3-dione (also known as (1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)malononitrile) with hydrogen peroxide in dioxane [14]. Didodecyl 2′,6′-dimethyl-1′,4′-dihydro-[3,4′-bipyridine]-3′,5′-dicarboxylate (2) was prepared in a Hantzsch-type reaction from dodecyl 3-oxobutanoate, 3-pyridinecarboxaldehyde and ammonium acetate under reflux in ethanol [15].

In the ¹H-NMR spectrum of betaine 3, the characteristic protons of the 1,4-DHP moiety appear as a singlet at 5.11 ppm corresponding to the proton at the fourth position, and as a broad singlet at 6.97 ppm assigned to the proton of N–H group. Nitrogen quaternization leads to strong deshielding of the pyridinium ring protons, which resonate at 10.20–10.00 ppm compared with 8.52–8.31 ppm for the corresponding protons in the precursor pyridyl-1,4-DHP 2 [15], as well as deshielding of another pyridinium ring proton, observed at 7.83 ppm versus 7.58 ppm in compound 2 [15]. The aromatic protons of the indane-1,3-dione moiety appear as a multiplet in the range of 7.53–7.37 ppm overlapping with the signal of one pyridinium proton. In the UV–Vis spectrum two absorption bands at 235 nm and 386 nm were observed.

The structure of target compound 3 was successfully confirmed by spectroscopic methods, including ¹H-NMR (Figure S1, Supplementary Materials), ¹³C-NMR (Figure S2, Supplementary Materials), 2D NMR (HSQC) (Figure S3, Supplementary Materials), UV–Vis spectrometry (Figure S6, Supplementary Materials), and HRMS data (Figure S4, Supplementary Materials). Based on HPLC data, the purity of the obtained compound 3 is >95%.

3. Materials and Methods

3.1. General Information

All reagents were purchased from BLDpharm (Karlsruhe, Germany), Sigma-Aldrich (St. Louis, MO, USA) or Merck KGaA (Darmstadt, Germany) in >97% purity and used without further purification. TLC was performed on 20 × 20 cm, silica gel 60 F₂₅₄ aluminum sheets (Merck KGaA, Darmstadt, Germany). Silica gel of particle size 35–70 µm (Merck KGaA, Darmstadt, Germany) was used for column chromatography for purifications of the compounds. Flash column chromatography was accomplished using flow chromatography (Armen Instrument—Spot Flash System Interchim, Montluçon, France). ¹H-NMR spectra were recorded with a Bruker Avance Neo (400 MHz) spectrometer, but ¹³C-NMR spectra were recorded with a Bruker Avance Neo (151 MHz) spectrometer (Bruker Biospin Gmbh, Rheinstetten, Germany). The coupling constants J are expressed in Hertz (Hz). The chemical shifts in the hydrogen and carbon atoms are presented in parts per million (ppm) and referred to the residual signals of the non-deuterated CDCl₃ (δ: 7.26) solvent for ¹H-NMR spectra and CDCl₃ (δ: 77.2) solvent for ¹³C-NMR, respectively. Multiplicities are abbreviated as s = singlet; bs = broad singlet; d = doublet; t = triplet; and m = multiplet. Low-resolution mass spectra (MS) were determined on an Acquity UPLC system (Waters, Milford, MA, USA) connected to a Waters SQ detector2 operating in the electrospray ionization (ESI) positive on mode on a Waters Acquity UPLC^® BEH C18 column (1.7 μm, 2.1 mm × 50 mm), using gradient elution with acetonitrile (0.01% formic acid) in water (0.01% formic acid). High-resolution mass spectra (HRMS) were determined on an Acquity UPLC system (Waters, Milford, MA, USA) connected to a Waters Synapt GII Q-ToF operating in the ESI positive ion mode on a Waters Acquity UPLC^® BEH C18 column (1.7 µm, 2.1 mm × 50 mm), using gradient elution with acetonitrile (0.01% formic acid) in water (0.01% formic acid).

3.2. Synthesis

2,2-dicyanomethylideneindan-1,3-dione oxide (1) (0.6 mmol, 135 mg) was added portion wise to a stirred solution of compound 2 (0.6 mmol, 367 mg) in MeCN (50 mL) at 60 °C under an inert atmosphere (Ar). The reaction mixture was stirred under reflux for 8 h, and the progress of the reaction was monitored by TLC. After completion, the solvent was evaporated under vacuum, and the resulting residue was purified by flash chromatography using a DCM/MeOH as the eluent, with a linear gradient from 5% to 6% MeOH over 15 min. The solvent was evaporated and the residue dried under high vacuum, giving 2-(3′,5′-bis((dodecyloxy)carbonyl)-2′,6′-dimethyl-1′,4′-dihydro-[3,4′-bipyridin]-1-ium-1-yl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ide (3) as a pale yellow amorphous solid (324 mg, 43%). R_f = 0.25 (EtOAc:PE = 1:1).

¹H-NMR (400 MHz, CDCl₃) δ 10.20 (s, 1H), 10.00 (dt, J = 6.4, 1.4 Hz, 1H), 7.83 (dt, J = 7.9, 1.4 Hz, 1H), 7.53–7.37 (m, 5H), 6.97 (bs, 1H), 5.11 (s, 1H), 4.10–4.01 (m, 4H), 2.43 (s, 6H), 1.64–1.53 (m, 4H), 1.31–1.19 (m, 36H), 0.89–0.85 (m, 6H) ppm.

¹³C-NMR (101 MHz, CDCl₃) δ 183.3, 167.0, 147.5, 146.4, 136.8, 136.5, 135.8, 133.8, 131.8, 124.8, 119.9, 102.2, 64.7, 39.0, 32.1, 29.8, 29.8, 29.7, 29.5, 29.4, 28.9, 26.3, 22.8, 19.7, 14.3 ppm.

UV–Vis (EtOH) λ_max, nm (log ε): 235 (4.50); 386 (3.96).

HRMS (TOF MS ES+): calculated [C₄₇H₆₆N₂O₆ + H] 755.4999; found 755.4985.

4. Conclusions

The lipid-like indane-1,3-dione–1,4-DHP betaine 3 was synthesized from 2,2-dicyanomethylideneindan-1,3-dione oxide (1) and didodecyl 2′,6′-dimethyl-1′,4′-dihydro-[3,4′-bipyridine]-3′,5′-dicarboxylate (2). The structure of compound 3 was confirmed by UV–Vis spectroscopy, ¹H-NMR, ¹³C-NMR and HRMS. The synthesized betaine exhibited lipid-like behavior and may be useful for the development of liposomal delivery systems.