N-(3,4-Dimethoxyphenethyl)-2-propylpentanamide

Abstract

In this Short Note type article, we report the synthesis of a new hybrid molecule, N-(3,4-dimethoxyphenethyl)-2-propylpentanamide, using a solvent-minimized mechanochemical method that provides a simple and efficient synthetic approach. The process achieved high yield. The compound was confirmed by melting-point analysis, ¹H and ¹³C NMR, IR spectroscopy, and mass spectrometry.

1. Introduction

The 2-phenethyl moiety plays a crucial role in medicinal chemistry and is significant in biological applications. Important endogenous catecholamines, such as dopamine 1, norepinephrine 2, and epinephrine 3 (Figure 1), are open-chain 2-phenethylamines essential for dopaminergic neurons responsible for voluntary movement, stress response, and mood regulation [1]

Adrenergic neurotransmitters and their derivatives exert significant influence over complex brain activities, including cognition, emotional regulation, and memory [2]. Additionally, this unit serves as the structural core of numerous natural alkaloids, including morphine 4, and (S)-reticuline 5, (Figure 2), tied to complex cyclic structures formed through natural biosynthesis [3,4].

Homoveratrylamine is a dimethyl derivative of dopamine that has garnered significant interest for its effects on the central nervous system [5]. Compounds made from homoveratrylamine are being investigated for potential medical use in the management of serious conditions including Parkinson’s disease and heart failure [6].

Valproic acid is a commonly prescribed medication for seizure disorders, recognized for its role as an epigenetic agent. It induces histone acetylation and influences the methylation status of both DNA and histones, leading to changes in gene expression [7]. As a short-chain fatty acid, valproic acid, along with its sodium salt, functions as a GABA transaminase inhibitor and blocks voltage-gated sodium channels as well as T-type calcium channels [8]. Numerous phase I and II clinical trials are investigating valproic acid’s potential as an anti-cancer agent [9,10], particularly when paired with other chemotherapeutic medications. Moreover, it has demonstrated the capability to downregulate the surface expression of ACE2 and NRP1, which are important factors in mediating SARS-CoV-2 infection [11] understanding its relevance beyond neurological conditions [12,13].

The amide bond is vital in peptides, natural products, and pharmaceuticals, with its preparation from carboxylic acids and amines being crucial for drug production. It is important in synthetic organic chemistry as a building block and catalyst. Mechanochemical approaches to amidation have been developed, focusing on solvent-free amide synthesis through mechanochemical processes using activated carboxylic acid derivatives [14,15].

The design of novel hybrid molecules combining valproic acid and homoveratrylamine is a promising strategy for exploring multifunctional therapeutic agents. The rational conjugation of valproic acid, a clinically established antiepileptic and epigenetic modulator [16], with homoveratrylamine, a dopamine-derived moiety with central nervous system activity and therapeutic potential in Parkinson’s disease and cardiovascular disorders [17], may yield hybrid compounds with complementary or synergistic pharmacological profiles.

2. Results and Discussion

This study presents the implementation of mechanochemical synthesis for the preparation of N-(3,4-dimethoxyphenethyl)-2-propylpentanamide. The target amide was obtained by first activating valproic acid via its transformation into the corresponding acyl chloride, which was subsequently subjected to solvent-free amidation with homoveratrylamine (3,4-dimethoxyphenethylamine) under ball-milling conditions (Scheme 1).

Analysis of the spectral data (Figure S1: ¹H NMR; Figure S2: ¹³C NMR; Figure S3: IR; Figure S4: HRMS) confirms the successful synthesis and isolation of the target hybrid molecule. In addition, the narrow melting point range further indicates the high purity of compound 8.

3. Materials and Methods

All reagents and chemicals were purchased from commercial suppliers (Sigma-Aldrich S.A. and Riedel-de Haën, Sofia, Bulgaria) and were used without further purification. Mechanosynthesis was conducted using a Retsch Planetary Ball Mill PM 200 (University of Plovdiv, Faculty of Chemistry; RETSCH, Haan, Germany) equipped with a 25 mL stainless steel grinding jar. The grinding media consisted of 28 g of 12 mm hardened steel grinding balls. NMR spectra were recorded on a Bruker Avance II+600 spectrometer (BAS-IOCCP-Sofia, Bruker, Billerica, MA, USA), operating at 600 MHz for ¹H and 150.9 MHz for ¹³C. Spectra were acquired in DMSO-d₆, with chemical shifts (δ) referenced to tetramethylsilane (TMS, δ = 0.00 ppm) and coupling constants (J) reported in hertz (Hz). All NMR measurements were performed at ambient temperature (approximately 295 K). Melting points were determined using a Boetius hot-stage apparatus (University of Plovdiv, Faculty of Chemistry; Boetius, Germany) and are reported uncorrected. IR spectra were obtained on a Bruker Alpha II FT-IR spectrometer (University of Plovdiv, Faculty of Chemistry; Bruker, Billerica, MA, USA). High-resolution mass spectrometry (HRMS) analyses were conducted using a Q Exactive Plus mass spectrometer equipped with a heated electrospray ionization (HESI-II) source (Thermo Fisher Scientific, Bremen, Germany) and coupled to a Dionex Ultimate 3000RSLC UHPLC system (Thermo Fisher Scientific, Waltham, MA, USA). Thin-layer chromatography (TLC) was carried out on 0.2 mm silica gel 60 plates (Fluka, Merck KGaA, Darmstadt, Germany).

3.1. Synthetic Procedure

3.1.1. Obtaining 2-Propylpentanoyl Chloride 7

Valproic acid (1.0 mmol, 0.1442 g) was dissolved in toluene (20 mL), and an excess of thionyl chloride (1.2 mmol, 0.087 mL) was added. The reaction mixture was refluxed at 110–115 °C for 2 h to convert the carboxylic acid into the corresponding acid chloride. After completion, the volatile components and excess toluene were removed under reduced pressure using a rotary evaporator. The resulting residue was dissolved in a small volume of dichloromethane and used directly in the subsequent reaction without further purification.

3.1.2. Synthesis of N-(3,4-Dimethoxyphenethyl)-2-propylpentanamide 8

2-(3,4-dimethoxyphenyl)ethan-1-amine (1 mmol, 0.1812 g), 2-propylpentanoyl chloride (1 mmol, 0.1626 g), and Et₃N (0.168 mL, 1.2 mmol) were placed in a 25 mL stainless steel grinding jar, along with four 12 mm hardened steel grinding balls. Mechanochemical reaction was performed in a Retsch PM 200 planetary ball mill with constant rotation of planetary (500 rpm) for 1 min. Progress of the reaction was monitored by thin-layer chromatography (petroleum ether/diethyl ether 1:3 (v/v)), confirming complete consumption of the amine starting material. Subsequent to that, the milling jar contents underwent a double wash with dichloromethane (10 mL) and water (5 mL) each, leading to the separation of the two layers. The aqueous layer was then subjected to extraction with dichloromethane (2 × 10 mL), and the combined organic fractions were washed with dilute aqueous hydrochloric acid (HCl:H₂O = 1:4), saturated aqueous sodium carbonate (Na₂CO₃), and brine. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by short-column chromatography on neutral aluminum oxide (Al₂O₃) using CH₂Cl₂ as eluent to afford the new hybrid molecule 8.

• N-(3,4-dimethoxyphenethyl)-2-propylpentanamide 8

White solid (m.p. 108–109 °C), yield 93% (0.2859 g), R_f = 0.47 (petroleum/diethyl ether = 1/3 v/v), ¹H NMR (600 MHz, DMSO) δ 7.74 (t, J = 5.7 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.63 (dd, J = 8.2, 2.1 Hz, 1H), 3.67 (s, 3H), 3.64 (s, 3H), 3.20 (q, J = 7.1, 5.8 Hz, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.05–1.98 (m, 1H), 1.37–1.30 (m, 2H), 1.16–1.10 (m, 2H), 1.09–1.02 (m, 4H), 0.74 (t, J = 7.2 Hz, 6H). ¹³C NMR (151 MHz, DMSO) δ 175.15 (C=O), 149.05 (C_sp²-OCH₃), 147.66 (C_sp²-OCH₃), 132.49 (C_sp²H), 120.91 (C_sp²H), 113.03 (C_sp²H), 112.32 (C_sp²H), 55.99 (OCH₃), 55.79 (OCH₃), 45.73 (CH), 40.50 (CH₂NH), 35.36 (CH₂CH₂NH), 35.34 (2 × CHCH₂CH₂CH₃), 20.65 (2 × CH₂CH₂CH₃), 14.46 (2 × CH₃). Electrospray ionization (ESI) m/z calculated for [M + Na]⁺ C₁₈H₂₉NNaO₃⁺ = 330.2040, found 330.2031 (mass error ∆m = −2.73 ppm). IR (KBr) v_max, cm⁻¹: 3289 ν (N-H), 2955 ν_as (CH₃), 2930 ν_as (CH₂), 2871 ν_s (CH₃), 1640 ν (C=O), 1452 δ_as (CH₃), 1389 δ_s (CH₃).