[2-{(5′-Amino-2′-fluoroacetophenone)-5-nitro}]acetophenone

Abstract

Herein we reported on a one-pot nitro reduction/nucleophilic aromatic substitution on 1-(2-fluoro-5-nitrophenyl)ethan-1-one using a mixture of acetic acid and iron powder in ethanol. The resultant target compound, a nitrated N bis-acetophenone, has many reactive handles; as such, it is a novel intermediate that can be deployed for the syntheses of a vast array of compounds not reported before. This compound is fully characterized using ¹H and ¹³C NMR spectroscopy, and HRMS.

1. Introduction

Nitroaromatics are organic molecules, characterized by a nitro (–NO₂) moiety directly attached to an aromatic ring [1]. They can be used as building blocks for the generation of compounds such as amines, amides, Schiff-Bases, or applied in agrochemicals and medicine [1]. In medicine, they have diverse applications, including antitubercular (macozinone), antiparasitic (fexinidazole), anti-inflammatory (nimesulide), and radiosensitizers (FLS-61) (Figure 1) [2]. Generally, the pharmacological utility of nitroaromatics is mainly attributed to the nitro group undergoing reduction when these molecules encounter a redox active biological system, leading to the generation of reactive intermediates that ultimately effect the desired pharmacological response [3].

Acetophenones have two chemical moieties: phenyl and acetyl moieties directly linked. They generally act as intermediates for the preparation of a wide range of compounds with versatile pharmacological applications, making them very important building blocks in medicinal chemistry [4]. Compound classes derived from acetophenones include hydrazone, oxime, chalcone, pyrazole, Schiff-base, Mannich-Bases, isoxazole, and thiazole [5]. Pharmacological applications of acetophenone derivatives include antidepressant (bupropion) [6], anticancer (alvocidib) [7], and analgesic (paracetamol) [8].

In this manuscript, we report the synthesis of a novel, nitrated N bis-acetophenone compound. This compound was realized in a one-pot, two-step syntheses, which included reduction and nucleophilic substitution.

2. Results and Discussion

Chemistry

The target compound was obtained in a one-pot, two-step synthetic route as presented in Scheme 1 below. Compound 1 underwent nitro reduction to generate 1a in situs, which caused a fluoride displacement in 1 through an aromatic nucleophilic substitution to afford compound 2 (Scheme 1) [9].

The structure of compound 2 was assigned using nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS), both of which confirmed the structure of the target compound (see Supplementary Materials Figure S1).

The NMR spectra signals were analysed based on their chemical shifts and/or multiplicities on ¹H and ¹³C. In the ¹H NMR spectrum, the singlet appearing at ca 2.7 ppm is indicative of the CH₃ of the methyl ketone moiety meta to the nitro group; the ¹³C peaks at ca 201 and 28 ppm are respectively assignable to the carbonyl and the methyl carbons of the methyl ketone moiety. The doublet at ca 2.6 ppm which integrates to three protons is indicative of the CH₃ of the methyl ketone moiety ortho to the fluoro group; these protons are split by the ortho fluorine atom to appear as a doublet with a coupling constant of 3.9 hertz (Hz). DMSO-d6 protons appear at ca 2.5 ppm. The carbonyl and the methyl carbons of this methyl ketone moiety appear at ca 195 (³J^CF = 3.2 Hz) and 31 (⁴J^CF = 5.9 Hz) ppm, respectively. Fluorine–carbon coupling with constant magnitude, together with DEPT135, was used to assign aromatic carbons. For example, the carbon directly attached to the fluorine atom has the largest coupling constant of 253.6 Hz, and it appears at 159 ppm; this carbon signal is absent in DEPT135 because it has no proton attached to it. The peak at approximately 118.90 ppm has the second largest coupling constant (²J^CF = 25.0 Hz), suggesting it is ortho to a fluorine atom. Moreover, this peak appears on DEPT135, suggesting that it has a hydrogen attached to it. The high-resolution mass spectrometry recorded the exact molecular ion (316 Da) of the compound of interest. DMSO-d6 carbons appear at ca 40 ppm.

3. Materials and Methods

3.1. General Information

Chemicals and solvents used in this study were purchased from Sigma-Aldrich (Pty) Ltd. (Johannesburg, South Africa), Merck (Pty) Ltd. (Johannesburg, South Africa), and Ambeed. Merck (60F₂₅₄) silica gel plates (Merck, Johannesburg, South Africa) supported on aluminium sheets, which were used to perform thin layer chromatography (TLC) for monitoring reaction progress. Developed TLC plates were visualized under ultraviolet (UV254 and 366 nm) light or stained with iodine vapour. NMR spectra (¹H and ¹³C) were recorded on a Bruker Biospin 600 MHz spectrometer (Rheinstetten/Ettlingen, Germany). Chemical shifts are given in parts per million (ppm) values and are referenced to deuterated dimethylsulfoxide (DMSO-d₆). Chemical shifts for deuterated DMSO-d₆ appear at 2.5 and 39.5 ppm for ¹H and ¹³C NMR spectra, respectively. Proton coupling patterns are abbreviated as follows: s (singlet), d (doublet), m (multiplet). Coupling constants (J) are reported in Hz. NMR data were analysed using MestReNova Software, version 5.3.2e4936. Melting points (mp) were established with a Büchi melting point B-545 instrument. The high-resolution mass spectra (HRMS) were recorded by means of a Bruker micrOTOF-Q II mass spectrometer (Rheinstetten/Ettlingen, Germany) using atmospheric pressure chemical ionization (APCI) in positive ion mode.

3.2. Generation of [2-{(5′-Amino-2′-fluoroacetophenone)-5-nitro}]acetophenone, 2

Into a round bottom flask containing 1-(2-fluoro-5-nitrophenyl)ethan-1-one (5 g, 27 mmoles), reduced iron powder (5 eq, 7.5 g, 136 mmoles), 10 mL of acetic acid and 15 mL of ethanol were added, and the resultant mixture was stirred under reflux for 24 h, after which it was cooled to room temperature, and 50 mL of dichloromethane (DCM) was added. The mixture was filtered to remove the iron mass (residue), while the filtrate was washed with water, then flushed through a silica gel column using DCM:methanol (10:1) as the mobile phase. Fractions containing the desired compound were combined and concentrated using a rotatory evaporator. The resultant crude was recrystallized from ethanol and dried to afford the target compound in 58% yield (5 g) [9].

[2-{(5′-Amino-2′-fluoroacetophenone)-5-nitro}]acetophenone, 2.

Mustard, plate, mp 136.4–138 °C, yields: 58. ¹H NMR (600 MHz, DMSO-d₆) δ 10.95 (s, 1H), 8.76 (d, J = 2.7 Hz, 1H), 8.18 (dd, J = 9.5, 2.6 Hz, 1H), 7.72 (dd, J = 6.4, 2.8 Hz, 1H), 7.63 (dt, J = 8.8, 3.5 Hz, 1H), 7.45 (dd, J = 10.7, 8.7 Hz, 1H), 7.02 (d, J = 9.4 Hz, 1H), 2.74 (s, 3H), 2.60 (d, J = 3.9 Hz, 3H). ¹³C NMR (151 MHz, DMSO) δ 201.40, 195.41 (³J^CF = 3.2 Hz), 159.27 (¹J^CF = 253.6 Hz), 152.32, 137.09, 135.00 (⁴J^CF = 2.8 Hz), 131.90 (³J^CF = 9.4 Hz), 130.07, 130.06, 126.79 (²J^CF = 13.7 Hz), 126.65 (³J^CF = 2.8 Hz), 118.90 (²J^CF = 25.0 Hz), 117.71, 114.15, 31.29 (⁴J^CF = 5.9 Hz), 28.58. HRMS-APCI m/z calcd for C₁₆H₁₄FN₂O₄, 317.0922, found: 317.0932.

4. Conclusions

Nitro-containing compounds have broad applications. In medicine, this compound class has produced several drugs against different clinical indications including tuberculosis, cancer, and sleeping sickness. Acetophenones are versatile chemical intermediates, used for the generation of diverse compounds including hydrazone, chalcones, oxime, and pyrazole, all of which have great pharmacological applications.

In this study, we have executed a one-pot, two-step synthetic procedure to generate a nitrated bisacetophenone. The structural integrity of this compound was confirmed using nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. The small size of this compound and its poly functionalized nature make it a versatile intermediate that can act as a starting point for the syntheses of novel compounds with diverse applications.