Synthesis of 4-[(1H-Benzimidazol-2-yl)sulfanyl]benzaldehyde and 2-({4-[(1H-Benzimidazol-2-yl)sulfanyl]phenyl}methylidene)hydrazine-1-carbothioamide

Abstract

Here we describe the preparation of 2-(4-((1H-benzo[d]imidazol-2-yl)thio)-benzylidene)-hydrazine-1-carbothioamide in two steps. In the first step, 1,3-dihydro-2H-1,3-benzimidazole-2-thione was reacted with 4-fluorobenzaldehyde in DMSO to get 4-[(1H-benzimidazol-2-yl)sulfanyl]benzaldehyde in high yield. The reaction of the obtained aldehyde with thiosemicarbazide in ethanol at reflux temperature yielded 2-({4-[(1H-benzimidazol-2-yl)sulfanyl]phenyl}methylidene)hydrazine-1-carbothioamide. The structure of the synthesized compounds was established by NMR spectroscopy (¹H, ¹³C), mass spectrometry, and infrared spectroscopy.

1. Introduction

Benzimidazoles are one of the important heterocyclic templates for the intensive investigation in chemical sciences due to their well-known applications and interesting biological activity profile [1,2,3,4,5,6]. Thiosemicarbazone moiety is another privileged structure that is found in several molecules with a wide range of biological activities representing several important classes in drug discovery [7,8,9,10,11,12]. Thiosemicarbazones have been postulated as biologically active compounds and display different types of biological activity, such as anticancer [11,13], anti-HIV [14,15], anticonvulsant [16,17], antimalarial [18,19], anti-inflammatory [20], enzymatic inhibition [9,10,21], antiviral [22], antioxidant [23], antifungal [24], and antibacterial [24,25]. Additionally, the flexibility of thiosemicarbazones as nitrogen and sulfur donors consents them to bring on a great diversity of coordination modes [26].

In this communication, we describe an improved process for the preparation of 4-[(1H-benzimidazol-2-yl)sulfanyl]benzaldehyde [27]. We also report the preparation of 2-({4-[(1H-benzimidazol-2-yl)sulfanyl]phenyl}methylidene)hydrazine-1-carbothioamide via the condensation of the synthesized aldehyde with thiosemicarbazide. The authors trust that this is the first report that discloses the synthesis and spectral analysis of 2-({4-[(1H-benzimidazol-2-yl)sulfanyl]phenyl}methylidene)hydrazine-1-carbothioamide because the exact structure search in the SciFinder database for this compound did not provide any hit or reference. The reported compounds can be assessed.

2. Results and Discussion

Refluxing of 1,3-dihydro-2H-1,3-benzimidazole-2-thione with 4-fluorobenzaldehyde in DMSO/anhydrous K₂CO₃ mixture gave 4-((1H-benzo[d]imidazol-2-yl)thio)benzaldehyde 3. The product was isolated in 92% yield. The preparation of 3 is also provided in the literature [27], wherein a mixture of 1,3-dihydro-2H-1,3-benzimidazole-2-thione, 4-iodobenzaldehyde, CuI, 1,10-phenanthroline, K₂CO₃, and DMF was heated to 140 °C for 18 h. Further, the final product was purified by column chromatography to provide 3 in 87% yield. The current process does not make use of many reagents/parameters of the reported method, such as CuI, 1,10-phenanthroline, DMF, temperature, reaction duration, and column chromatography. These features make the current process an economical, safe, and less time-consuming process. Condensation of the latter with thiosemicarbazide in refluxing EtOH containing a catalytic amount of AcOH gave thiosemicarbazone derivative 4 (Scheme 1). The molecular structures of compounds 3 and 4 were established by spectral data. The IR spectrum of compound 3 displayed the presence of the imino group at 3153 cm⁻¹, carbonyl group at 1693 cm⁻¹, and C=N at 1590 cm⁻¹.(Figures S1 and S2) Additionally, compound 4 showed strong absorption bands at 3411, 3303, and 3158 cm⁻¹ for the NH₂/NH groups and 1594 cm⁻¹ for C=N. The ¹H NMR of 3 displayed the presence of singlet δ_H 12.52 for benzimidazole-NH and 9.95 for carboxaldehyde proton, and the aromatic protons (Ar-H) were found in the spectrum at δ_H 7.11–7.88. ¹³C NMR (DMSO-d₆) showed signals at δ_C 192.4 assigned to the C=O group, 143.7 ppm assigned to C=N, 140.9 ppm assigned to C-N, in addition to 109.5 ppm assigned aromatic carbons at δ_C 134.7. The ¹H NMR of 4 exhibited the presence of an amino group at δ_H 8.01, azomethine proton at δ_H 8.24, a singlet at δ_H 11.49 for NH-CS, and a singlet at 12.84 for imidazole-NH, in addition to the presence of Ar-Hs at 7.19–8.46 ppm. ¹³C NMR (DMSO-d₆) showed signals at δ_C 178.0 assigned to the C=S group, δ_C 145.9 assigned to CH=N, δ_C 143.7 assigned to C=N, δ_C 141.1 to C-N, and Ar-C at δ_C 135.3–111.1 (Figure S3–S6).

3. Materials and Methods

3.1. General

The uncorrected melting points were determined by a Stuart melting point apparatus. IR (KBr) was obtained from a Shimadzu 440 spectrometer (ν, cm⁻¹). NMR spectra were recorded by a JEOL ECA-500 spectrometer. The chemical shifts (δ in ppm) were recorded relative to tetramethylsilane (TMS). The elemental analyses were performed at the Microanalytical Center, Cairo University, Cairo (Egypt).

3.2. 4-[(1H-Benzimidazol-2-yl)sulfanyl]benzaldehyde (3)

A mixture of 1,3-dihydro-2H-1,3-benzimidazole-2-thione 1 (10 mmol, 1.5 g) and 4-fluorobenzaldehyde 2 (10 mmol, 1.24 g) in dimethyl sulfoxide (25 mL) was refluxed along with anhydrous potassium carbonate (2 g) for 1 h, cooled, and transferred into crushed ice. The obtained product was collected and recrystallized to afford 3 as colorless solid. Yield: 2.34 g (92%); m.p.: 164–166 °C (acetic acid/water, 7:3); IR (KBr, cm^–1): 3153 (NH), 3069 (arom.-CH), 1693 (C=O), 1590 cm⁻¹ (C=N); ¹H NMR (500 MHz, DMSO-d₆, δ/ppm): 7.10 (m, 1H, ArH), 7.20 (d, 2H, ArH, J = 5.0 Hz), 7.50 (dd, 3H, ArH, J = 5.0 Hz), 7.86 (d, 2H, ArH, J = 10.0 Hz), 9.95 (s, 1H, CHO), 12.52 (hump, 1H, benzimidazole-NH); ¹³C NMR (125 MHz, DMSO-d₆): δ 109.5, 110.5, 119.4, 122.6, 124.3, 128.1, 128.9, 129.8, 130.2, 130.3, 130.8, 132.2, 134.7 (Ar’C), 140.9 (C-N), 143.7, 147.1 (C=N), 192.2 (C=O). Anal. calcd for C₁₄H₁₀N₂OS: C, 66.12; H, 3.96; N, 11.02; found: C, 65.94; H, 3.81; N, 10.87.

3.3. 2-({4-[(1H-Benzimidazol-2-yl)sulfanyl]phenyl}methylidene)hydrazine-1-carbothioamide (4)

A solution of aldehyde 3 (10 mmol, 2.54 g) and thiosemicarbazide (10 mmol, 0.91 g) was refluxed in EtOH (30 mL) containing acetic acid (5 mL) for 3 h. The obtained solid was collected and recrystallized to give 4. Yellow crystals: yield: 2.45 g (75%); m.p., 268–270 °C (dioxane); IR (KBr, cm^–1): 3411, 3303, 3158 (NH₂/NH), 3014 (arom.-CH), 1594 (C=N); ¹H NMR (500 MHz, DMSO-d₆, δ/ppm): 7.15 (dd, 2H, ArH, J = 5.0 Hz), 7.41 (d, 1H, ArH, J = 5.0 Hz), 7.44 (d, 1H, ArH, J = 10.0 Hz), 7.57 (d, 1H, ArH, J = 5.0 Hz), 7.81 (d, 2H, ArH, J = 10.0 Hz), 8.01 (d, 2H, NH₂, J = 10.0 Hz), 8.24 (s, 1H, CH=N), 11.49 (s, 1H, NH-CS), 12.84 (s, 1H, benzimidazole-H); ¹³C NMR (125 MHz, DMSO-d₆): δ 111.1, 118.4, 121.7, 122.8, 128.2, 130.7, 133.1, 133.9, 135.3 (Ar’C), 141.1 (C-N), 143.7 (C=N), 145.9 (CH=N), 178.0 (C=S). Anal. calcd for C₁₅H₁₃N₅S₂: C, 55.02; H, 4.00; N, 21.39; found: C, 54.86; H, 3.84; N, 21.23.

Supplementary Materials

The following are available online in Figures S1–S6 (FTIR, ¹H NMR, and ¹³C NMR spectra of compounds 3 and 4).

Author Contributions

Conceptualization, M.T.U., H.K.T. and M.Y.A.S.; methodology, M.T.U., H.K.T. and M.Y.A.S.; formal analysis, M.T.U., H.K.T. and M.Y.A.S.; writing—original draft preparation, M.T.U., H.K.T. and M.Y.A.S. All authors have read and agreed to the published version of the manuscript.

Funding

The research was carried out with the financial support of Northern Border University, Kingdom of Saudi Arabia in the framework of the scientific project 2017-1-8-F-7413.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors would like to express their deep gratitude to Northern Border University, Kingdom of Saudi Arabia, for providing financial support for this research (project 2017-1-8-F-7535).

Conflicts of Interest

The authors declare no conflict of interest.

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Scheme

Scheme 1. Preparation of 4-[(1H-benzimidazol-2-yl)sulfanyl]benzaldehyde and 2-({4-[(1H-benzimidazol-2-yl)sulfanyl]phenyl}methylidene)hydrazine-1-carbothioamide.