N-(2,2-Diphenylethyl)furan-2-carboxamide

Abstract

We report the synthesis of N-(2,2-diphenylethyl)furan-2-carboxamide. The compound was fully characterized by melting point determination, ¹H and ¹³C NMR spectroscopy, infrared spectroscopy, and mass spectrometry. The combined analytical data confirm both the successful synthesis and the structural integrity of the target molecule.

1. Introduction

The 2-phenethylamine scaffold is a common structural motif found throughout nature, appearing in a wide range of compounds—from simple open-chain molecules to more intricate polycyclic architectures. Its biological significance is most clearly demonstrated by the endogenous catecholamines—dopamine, norepinephrine, and epinephrine—which are classic examples of open-chain 2-phenethylamine derivatives. These neurotransmitters are central to the function of dopaminergic neurons, which play key roles in regulating voluntary movement, stress response, and mood modulation [1].

2,2-Diphenylethylamine 1 (Scheme 1) is an organic compound featuring a central ethylamine moiety substituted with two phenyl groups. The 2,2-diphenylethylamine scaffold contributes to lipophilicity and receptor-binding affinity, making it a valuable building block in medicinal chemistry, particularly in the development of psychoactive and neuroprotective agents [2]. There are many molecules sold as a medicinal drug containing a diphenyl fragment (Figure 1), such as Diphenhydramine (an antihistamine and sedative) [3], Modafinil (a central nervous system stimulant and eugeroic (wakefulness promoter) medication used primarily to treat narcolepsy) [4], and Tolpropamine (an antihistamine and anticholinergic used as an antipruritic) [5].

Furan is a versatile chemical structure often used in making new medicines, especially for heart-related diseases [6]. One group of furan-based compounds, called 5-aryl-furan-2-carboxamides, has shown strong potential in treating conditions like heart failure by blocking the urotensin-II receptor, which plays a major role in controlling blood vessels and heart function [6]. These compounds can be easily modified to improve how well they work in the body, how long they last, and how safely they act.

Another study explored the design and development of new hybrid compounds by combining the furan-2-carboxamide group with a 1,3,4-thiadiazole scaffold, aiming to create effective VEGFR-2 inhibitors. Guided by initial molecular docking results, the researchers synthesized a series of these hybrid molecules and evaluated their potential to inhibit VEGFR-2, a key target in cancer treatment. The compounds’ ability to stop the growth of human cancer cells was also tested, and an analysis was performed of how well they fitted and interacted with the VEGFR-2 active site. The reported compounds were compared to the known VEGFR-2 inhibitor pazopanib and showed promising results as selective and effective anti-cancer agents [7].

The synthesis of a hybrid molecule from 2,2-diphenylethylamine and furan-2-carbonyl chloride combines two bioactive scaffolds of neurological and cardiovascular relevance. This fusion may provide enhanced therapeutic potential, offering a promising route for developing multifunctional drugs with improved efficacy and selectivity. The title compound, although assigned the CAS number 1180329-05-8, has not been previously reported in the literature according to Reaxys.

2. Results and Discussion

In this work, we describe the successful synthesis of N-(2,2-diphenylethyl)furan-2-carboxamide 3, as illustrated in Scheme 1. The reaction begins by adding furan-2-carbonyl chloride 2 (1 mmol) to a solution of 2,2-diphenylethan-1-amine 1 (1 mmol) in dichloromethane. After stirring for 10 min, trimethylamine (1.5 mmol) is slowly added. Within 30 min, thin-layer chromatography (TLC) using a 1:2 mixture of petroleum ether and diethyl ether (R_f = 0.5) confirmed the formation of the target compound. This transformation follows the Schotten–Baumann reaction, a well-known and efficient method for forming amide bonds between amines and acyl chlorides.

The structure of the synthesized compound was confirmed through comprehensive spectral analysis, including ¹H-, ¹³C-NMR, IR, and mass spectrometry. The data unequivocally support the successful formation of the target molecule.

Looking at ¹H-NMR, the methylene group resonates at 3.87 ppm as a doublet of doublets, while the methine proton appears at 4.32 ppm as a triplet, consistent with the expected coupling pattern. The furan moiety is clearly identifiable through three characteristic multiplets: at 6.56 ppm (CH adjacent to oxygen), 7.02 ppm (CH not adjacent to oxygen), and 7.76 ppm (CH within the conjugated system). The amino group is observed as a triplet at 8.35 ppm, confirming its presence. Additionally, the aromatic region shows two multiplets in the ranges of 7.16–7.23 ppm and 7.27–7.33 ppm, integrating two and eight protons, respectively, supporting the presence of a substituted aromatic ring system. The ¹³C-NMR spectrum reflects all expected carbon environments. The methine and methylene carbons appear at 43.41 and 50.40 ppm, respectively. The carbonyl carbon gives a strong signal at 158.12 ppm, confirming the presence of a carbonyl group. Signals corresponding to the furan ring are observed at 112.23, 113.76, and 143.26 ppm, while the carbon between the carbonyl group and the furan oxygen atom is seen at 148.27 ppm. These assignments are consistent with the proposed heterocyclic structure. The IR spectrum displays characteristic absorptions indicative of amide bond formation, further validating the structural assignment.

Secondary amide C=O stretching vibrations in the solid phase absorb strongly at 1680–1630 cm⁻¹, and in the IR spectra, we observe a strong signal at 1656.09 cm⁻¹. Regarding amide N-H deformation and C-N stretching vibrations, secondary amides (trans- form) (solid phase) absorb in the range of 1570–1515 cm⁻¹. A band at 1520.99 cm⁻¹ is observed in the infrared spectrum. Secondary amines have only one N-H stretching band, which is usually weak and occurs in the range of 3500–3300 cm⁻¹. In the solid and liquid phases, a band of medium intensity may be observed at 3450–3300 cm⁻¹. In the IR spectrum, it is observed at 3424.76 cm⁻¹. High-resolution mass spectrometry confirms the molecular ion peak at m/z = 314.1168, corresponding precisely to the calculated mass of the target compound, which has not been previously reported in the literature.

The combination of NMR, IR, and HRMS data provides clear evidence of the successful synthesis and structural integrity of the desired product.

3. Materials and Methods

All reagents and chemicals were purchased from commercial suppliers (Sigma-Aldrich S.A. and Riedel-de Haën, Sofia, Bulgaria) and used without any further purification. The NMR spectra were recorded using a Bruker Avance Neo 400 spectrometer (BAS-IOCCP—Sofia, Bruker, Billerica, MA, USA) operating at 400 MHz for ¹H and 101 MHz for ¹³C. Measurements were taken in DMSO-d₆, with chemical shifts referenced to tetramethylsilane (TMS, δ = 0.00 ppm) and coupling constants given in Hz. All NMR experiments were conducted at room temperature (around 295 K). Melting points were determined using a Boetius hot stage apparatus and are reported without correction. IR spectra were recorded on a Bruker Alpha II FT-IR spectrometer. High-resolution mass spectrometry (HRMS) was performed on a Q Exactive Plus spectrometer equipped with a heated electrospray ionization source (HESI-II) from Thermo Fisher Scientific (Bremen, Germany), connected to a Dionex Ultimate 3000RSLC UHPLC system (Thermo Fisher Scientific, Waltham, MA, USA). Thin-layer chromatography (TLC) was conducted on 0.2 mm Fluka silica gel 60 plates (Merck KGaA, Darmstadt, Germany).

3.1. Synthetic Procedure

A solution of 2,2-diphenylethan-1-amine 1 (1.0 mmol, 0.205 g (96%)) in dichloromethane (30 mL) was prepared, and an equimolar amount of furan-2-carbonyl chloride 2 (1.0 mmol, 0.1305 g) was added. After stirring for 10 min, triethylamine (1.2 mmol, 1.67 mL) was introduced. The reaction was allowed to proceed for 30 min, after which the mixture was washed sequentially with diluted hydrochloric acid, a saturated sodium carbonate solution, and brine. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting hybrid compound was purified by short-column chromatography using neutral aluminum oxide (Al₂O₃).

3.2. N-(2,2-Diphenylethyl)furan-2-carboxamide 3

Dark yellow solid (m.p. 118–120 °C), yield 93% (0.2818 g), R_f = 0.5 (petroleum/diethyl ether = 1/2), ¹H NMR (400 MHz, DMSO) δ 8.35 (t, J = 5.7 Hz, 1H), 7.76 (dd, J = 1.8, 0.8 Hz, 1H), 7.35–7.26 (m, 8H), 7.25–7.12 (m, 2H), 7.02 (dd, J = 3.4, 0.8 Hz, 1H), 6.56 (dd, J = 3.5, 1.8 Hz, 1H), 4.41 (t, J = 7.9 Hz, 1H), 3.87 (dd, J = 8.0, 5.7 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 158.14 (C=O), 148.27 (O=C-C-O), 145.29 (Ar), 143.26 (C=C-O), 128.90 (Ar), 128.38 (Ar), 126.82 (Ar), 113.76 (CH), 112.23 (CH), 50.40 (CH₂), 43.41 (CH). Electrospray ionization (ESI) m/z calculated for [M+Na]⁺ C₁₉H₁₇NNaO₂⁺ = 314.1157, found 314.1168 (mass error ∆m = 3.50 ppm). IR (KBr) ν_max., cm⁻¹: 3424 ν(N-H), 1656 ν(C=O), 1520 δ(N-H) + δ(C-N).