3-(4-Bromophenyl)-1-carbamothioyl-5-(2-carbamothioylhydrazinyl)-4,5-dihydro-1H-pyrazole-5-carboxylic Acid

Abstract

The reaction of 4-(4-bromophenyl)-2,4-dioxobutanoic acid with thiosemicarbazide, in a ratio of 1:2, when boiled in ethanol gives 3-(4-bromophenyl)-1-carbamothioyl-5-(2-carbamothioylhydrazinyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid with a good yield. This compound was fully characterized.

1. Introduction

Compounds whose structures are based on a pyrazoline fragment are of particular interest to the pharmaceutical industry as substances with anticancer [1,2,3], antimicrobial and antifungal [1,4] activity and to agriculture as herbicide detoxifiers [5] (Figure 1).

As a continuation of the development of methods for the synthesis of pyrazolines containing potentially functionalizable acyl groups at various positions of the pyrazoline cycle through the reaction of polycarbonyl compounds and substituted hydrazines (Scheme 1) [6,7], we synthesized a new representative of functionally substituted 1-carbamothioyl-3-carboxy-1H-pyrazoline 1 via a reaction of aroylpyruvic acid and thiosemicarbazide.

2. Results and Discussion

The title compound 1 was synthesized in several stages (Scheme 2). Initially, 4-(4-bromophenyl)-2,4-dioxobutanoic acid 3 was obtained via the Claisen condensation of 4-bromoacetophenone and diethyl oxalate. Then, as a result of the reaction of compound 3 and thiosemicarbazide 2, 3-(4-bromophenyl)-1-carbamothioyl-5-(2-carbamothioylhydrazinyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid 1, the target compound, was obtained for the first time.

The structure of compound 1 was unambiguously confirmed by X-ray diffraction analysis of a single crystal (CCDC 2310650) (Figure 2). Compound 1 crystallizes as a racemate in the centrosymmetric space group P21/c.

3. Materials and Methods

3.1. General Information

¹H and ¹³C NMR spectra (Supplementary Materials) were obtained on a Bruker Avance III 400 HD spectrometer (Fällanden, Switzerland) (at 400 and 100 MHz, respectively) in DMSO-d₆ using the solvent residual signal (in ¹H NMR, 2.50 for DMSO-d₆; in ¹³C NMR, 39.51 for DMSO-d₆) as an internal standard. IR spectrum was recorded on a Perkin Elmer Spectrum Two Spectrometer (Shelton, CT, USA) as mulls in mineral oil. The melting point was measured on the device of the Khimlabpribor PTP (USSR). Elemental analysis was carried out on a Vario MICRO Cube analyzer (Langenselbold, Germany). The single crystal X-ray analysis of compound 1 was performed on an Xcalibur Ruby diffractometer (Agilent Technologies, Wroclaw, Poland). An empirical absorption correction was introduced via the multi-scan method using the SCALE3 ABSPACK algorithm [8]. Using OLEX2 [9], the structure was solved with the SHELXT [10] program and refined by a full-matrix least-squares minimization in the anisotropic approximation of all non-hydrogen atoms with the SHELXL [11] program. Hydrogen atoms bound to carbon were positioned geometrically and refined using a riding model. Hydrogen atoms of OH, NH and NH₂ groups were refined independently with isotropic displacement parameters. Thin-layer chromatography (TLC) was performed on Macherey-Nagel Alugram Sil G/UV₂₅₄ (Düren, Germany) plates using EtOAc/MeOH, 3:1 v/v, as eluents and was manifested with iodine vapor. The starting compound 3 was obtained according to the reported procedures [12] from commercially available reagents. All procedures with compound 3 were performed in oven-dried glassware. All other solvents and reagents were purchased from commercial vendors and used as received.

3.2. 3-(4-Bromophenyl)-1-carbamothioyl-5-(2-carbamothioylhydrazinyl)-4,5-dihydro-1H-pyrazole-5-carboxylic Acid 1

A suspension of 2 g (7.4 mmol) 4-(4-bromophenyl)-2,4-dioxobutanoic acid 3 and 1.345 g (14.8 mmol) thiosemicarbazide 2 in 30 mL EtOH was refluxed for 2 h. Next, the reaction mixture was cooled to room temperature. The formed precipitate was filtered off and recrystallized from ethanol to yield the title compound 1. Yield: 1,84 г (76%); yellow solid; mp 253–255 °C (decomp.). ¹H NMR (DMSO-d₆, 400 MHz): δ = 3.50 d, 3.64 d (2H), 6.33 (s, 1H), 7.60–7.97 (m, 2H), 7.68 (d, 2H), 7.79 (d, 2H), 8.15 (d, 2H), 8.39 (s, 1H), 13.47 (br.s, 1H). ¹³C NMR (DMSO-d₆, 100 MHz): δ = 41.9, 83.5, 124.0, 128.8, 129.5, 131.6, 150.2, 169.1, 175.7, 183.3. IR (mineral oil): 3439, 3309, 3176, 1766, 1660 cm⁻¹. Anal.Calcd (%) for C₁₂H₁₃BrN₆O₂S₂: C 34.54; H 3.14; N 20.14. Found: C 34.79; H 3.08; N 20.06.

Crystal Data of 1. C₁₂H₁₃BrN₆O₂S₂∙H₂O, M = 435.33, monoclinic, space group P2₁/c, a = 9.2792(15) Å, b = 17.129(4) Å, c = 10.939(2) Å, β = 92.809(15)°, V = 1736.6(6) ų, T = 295(2) K, Z = 4, μ(Mo Kα) = 2.632 mm⁻¹. The final refinement parameters: R₁ = 0.0479 (for observed 3031 reflections with I > 2σ(I)); wR₂ = 0.1232 (for all independent 4020 reflections, R_int = 0.0446), S = 1.034. Largest diff. peak and hole were 0.451 and –0.907 ēÅ⁻³. Crystal structure of compound 1 was deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 2310650.