4-(Benzoxazol-2-yl)phenyl 3-((3-Chloro-1,4-Naphthoquinon-2-yl)amino)phenyl Sulfate

Abstract

New 4-(benzoxazol-2-yl)phenyl 3-((3-chloro-1,4-naphthoquinon-2-yl)amino)phenyl sulfate was synthesized via the SuFEx click reaction between fluorosulfate-containing 1,4-naphthoquinone and 2-(4-hydroxyphenyl)benzoxazole. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was used as an organic base, while triethylamine was inactive in this reaction.

1. Introduction

A quinone molecular scaffold (Figure 1) is found in many synthetic and natural organic compounds with various biological activities [1,2]. One of such effects is antitumor activity, which stipulates obtaining new 1,4-naphthoquinone derivatives as prospective anticancer agents [3].

On the other hand, benzoxazole molecular scaffold (Figure 2) is one of the important heterocyclic moieties present in a range of biologically active compounds which possess antihistamine, anticonvulsant, antimicrobial, antiviral, antioxidant, anti-ulcer, antidepressant, antitumor, or analgesic effects [4,5]. Some examples of known therapeutics containing the benzoxazole pharmacophore are shown in Figure 2 [6]. Moreover, numerous benzoxazoles possess fluorescent properties and can be used as fluorescent labels [7].

In this work, we synthesized the novel compound 4-(benzoxazol-2-yl)phenyl 3-((3-chloro-1,4-naphthoquinon-2-yl)amino)phenyl sulfate, which includes both naphthoquinone and benzoxazole scaffolds. A product of this combination may exhibit beneficial properties from both moieties or demonstrate novel characteristics.

Joining molecular fragments via the sulfate linker can be achieved using the sulfur(VI) fluoride exchange (SuFEx) click reaction, which has been successfully used for the synthesis of small molecules [8,9] (Figure 3).

The SuFEx reaction can exploit the unique properties of the -SO₂F group and was used in this work for the synthesis of the title compound.

2. Results

Previously, we utilized the SuFEx reaction to obtain fluorosulfate-containing 1,4-naphthoquinones [10] and synthesized 3-((3-chloro-1,4-naphthoquinon-2-yl)amino)phenyl fluorosulfate (2) (Scheme 1) via the interaction between silyl ether 1 and SO₂F₂ in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). For this synthesis, we used a two-chamber reactor where gaseous SO₂F₂ was generated in the first chamber through the reaction between 1,1′-sulfonyldiimidazole (SDI), potassium fluoride, and formic acid. The click reaction proceeded simultaneously in the second chamber.

Further, we carried out the reaction between the naphthoquinone-based fluorosulfate 2 and 2-(4-hydroxyphenyl)benzoxazole in the presence of an organic base. For this study, we tried to use two bases—triethylamine and DBU. The reaction with triethylamine did not lead to a significant conversion of the starting materials. The synthesis in the presence of DBU was successful and led to 4-(benzoxazol-2-yl)phenyl 3-((3-chloro-1,4-naphthoquinon-2-yl)amino)phenyl sulfate (4) (Scheme 2).

The reaction was completed in 24 h and afforded the target product in 42% yield. Compound 4 is one of the first examples of molecules combining naphthoquinone and benzoxazole molecular scaffolds.

3. Materials and Methods

General Information and Compounds Synthesis

The LC/MS analysis utilized an Agilent Infinity chromatograph (Santa Clara, CA, USA) coupled with an Accurate Mass QTOF 6530 mass detector (Santa Clara, CA, USA). Liquid chromatography was performed using a Zorbax Eclipse Plus C18 column (1.8 μm particle size, 2.1 × 50 mm dimensions) with a mobile phase of water and acetonitrile (15:85% v/v) at a flow rate of 0.2 mL/min. The mass spectrometric detection employed electrospray ionization (ESI) operating in positive mode. The NMR spectra were obtained using a Bruker AVANCE III HD spectrometer (Billerica, MA, USA) operating at 400 MHz for ¹H and 100 MHz for ¹³C nuclei. Fourier-transform infrared (FTIR) spectroscopic analysis was conducted on an Agilent Cary 630 FTIR spectrometer (Santa Clara, CA, USA). The UV–Vis spectrum was recorded on a SF-2000 UV–Vis spectrophotometer (OKB SPECTR LLC, Saint-Petersburg, Russia). The melting point determination was performed using a Cole-Parmer SMP30 Melting Point Apparatus (Staffordshire, UK) with a heating rate of 3 °C/min. Reaction progress was monitored using thin-layer chromatography (TLC) performed on silica gel 60 F254 plates which were manufactured by Merck (Rahway, NJ, USA). Elemental analysis was performed with a Carlo Erba instrument (Waltham, MA, USA).

Compounds 2 [10] and 3 [11,12] were prepared according to the literature methods.

4-(Benzoxazol-2-yl)phenyl 3-((3-chloro-1,4-naphthoquinon-2-yl)amino)phenyl sulfate (4). Compounds 2 (0.25 mmol) and 3 (0.25 mmol) were placed in a round-bottom flask and dissolved in dichloromethane (DCM, 3 mL). DBU (0.3 mmol) was added, and the resulting mixture was stirred for 24 h at room temperature (TLC monitoring, eluent: hexane–ethyl acetate, 8:2). Product 4 was purified using column chromatography on silica gel. Red-orange crystals; yield 42%; M.p. 177.5–179.5 °C; ¹H NMR (CDCl₃), δ, ppm: 8.35 (2H, d, J = 9 Hz, H-10, H-11), 8.15 (1H, d, J = 8 Hz, H-1), 8.11 (1H, d, J = 8 Hz, H-4), 7.79–7.81 (1H, m, H-16), 7.75 (1H, t, J = 8 Hz, H-3), 7.69 (1H, t, J = 7 Hz, H-2), 7.64 (1H, s, NH), 7.59–7.62 (1H, m, H-13), 7.50 (2H, d, J = 9 Hz, H-9, H-12), 7.38–7.45 (3H, m, H-7, H-14, H-15), 7.18 (1H, d, J = 8 Hz, H-6), 7.07 (1H, d, J = 8 Hz, H-8), 7.01 (1H, s, H-5). The atom numbering used for the ¹H NMR signal assignment is shown in Figure 4. ¹³C NMR (CDCl₃), δ, ppm: 180.3, 177.5, 161.6, 152.6, 150.9, 150.2, 141.1, 139.4, 136.1, 135.29, 135.26, 133.4, 132.4, 129.9, 129.8, 129.7, 127.4, 127.3, 125.9, 125.2, 123.2, 121.9, 120.3, 117.8, 117.0, 116.7, 111.0. Found, %: C 60.56, H 2.83, N 4.92. C₂₉H₁₇ClN₂O₇S. Calculated, %: C 60.79, H 2.99, N 4.89. IR spectrum, cm⁻¹: 681 (C-Cl), 1338 (S=O), 1647 (arom.); 3277 (N-H). UV–Vis spectrum (acetonitrile), λ_max, nm (log ε): 276 (4.58), 458 (3.50). LC/MS (ESI⁺); m/z: 573.0519 [M + H]⁺ experimental ([C₂₉H₁₇ClN₂O₇S + H]⁺ = 573.0518 theor.), 595.0337 [M + Na]⁺ experimental ([C₂₉H₁₇ClN₂O₇S + Na]⁺ = 595.0337 theor.).

The NMR, HRMS, IR, and UV–Vis spectra of compound 4 are shown in Figures S1–S5.

4. Conclusions

In this work, we presented the synthesis and characterization of new compound 4 containing the benzoxazole and 1,4-naphthoquinone moieties. The title compound is of great interest for further studies as a possible anticancer agent.