9-Oxo-2-(p-tolyl)-4,9-dihydropyrazolo[5,1-b]quinazoline-3a(3H)-carboxylic Acid

Abstract

Compounds based on the pyrazoloquinazoline scaffold are of significant interest in synthetic organic chemistry owing to their potential biological activity. In this work, we describe the synthesis of a new derivative with this scaffold, 9-oxo-2-(p-tolyl)-4,9-dihydropyrazolo[5,1-b]quinazoline-3a(3H)-carboxylic acid, obtained by reacting 2,4-dioxo-4-(p-tolyl)butanoic acid with 2-aminobenzohydrazide in a 1:1 ratio when mixed in ethanol. The compound was characterized by ¹H/¹³C NMR, IR, and X-ray diffraction analysis.

1. Introduction

The pyrazoloquinazoline scaffold is a promising nitrogen-containing heterocycle of significant pharmacological interest. Compounds bearing this scaffold have been explored as potential therapeutic agents with diverse activities, including antimicrobial [1,2], antioxidant [3,4], and antitumor effects [5] (Figure 1).

As a continuation of the development of methods for the synthesis of pyrazolines by the reaction of aroylpyruvic acids and substituted hydrazines in various proportions [6,7,8,9] (Scheme 1), we report a novel 9-oxo-2-(p-tolyl)-4,9-dihydropyrazolo[5,1-b]quinazoline-3a(3H)-carboxylic acid 1 obtained from the reaction 2,4-dioxo-4-(p-tolyl)butanoic acid and 2-aminobenzohydrazide. Although a similar synthetic strategy for the preparation of pyrazoloquinazolines has been reported [10], our approach utilizes a β-diketone as the starting material, unlike the β-ketoester employed previously.

2. Results and Discussion

The title compound 1 was synthesized in several steps (Scheme 2). Initially, 2,4-dioxo-4-(p-tolyl)butanoic acid 3 was obtained by the Claisen condensation of 1-(p-tolyl)ethan-1-one and diethyl oxalate. Then, as a result of the reaction of compound 3 and 2-aminobenzohydrazide 2, 9-oxo-2-(p-tolyl)-4,9-dihydropyrazolo[5,1-b]quinazoline-3a(3H)-carboxylic acid 1, the target compound, was obtained for the first time.

Our analysis suggests two plausible mechanisms. The first is derived from literature data [11], whereas the second is modeled on analogous transformations that we previously observed [8,9].

The structure of compound 1 was unambiguously confirmed by X-ray diffraction analysis of a single crystal (CCDC 2503244) (Figure 2). Compound 1 crystallizes as a racemate in the centrosymmetric space group P − 1. The asymmetric unit contains three independent molecules of 1 (only one of them is shown in Figure 2).

In this work, the target compound 1 was successfully synthesized and characterized. Investigation of its biological properties constitutes the subsequent phase of our research program.

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. The 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 by the multi-scan method using the SCALE3 ABSPACK algorithm [12]. Using OLEX2 [13], the structure was solved with the SHELXT [14] program and refined by the full-matrix least-squares minimization in the anisotropic approximation for all non-hydrogen atoms with the SHELXL [15] program. Hydrogen atoms bound to carbon were positioned geometrically and refined using a riding model. Hydrogen atoms of OH and NH groups were refined independently with isotropic displacement parameters. Thin-layer chromatography (TLC) was performed on silica gel 60 F254 (Filter-bio, Nantong, China) plates using Toluene/EtOAc, 1:1 υ/υ, as eluents and was manifested with iodine vapor. The starting compound 3 was obtained according to the reported procedures [16] 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. 9-Oxo-2-(p-tolyl)-4,9-dihydropyrazolo[5,1-b]quinazoline-3a(3H)-carboxylic Acid 1

A suspension of 1.364 g (6.6 mmol) 2,4-dioxo-4-(p-tolyl)butanoic acid 3 and 1 g (6.6 mmol) 2-aminobenzohydrazide 2 in 15 mL EtOH was stirred for 2 h. The formed precipitate was filtered off and recrystallized from acetic acid to yield the title compound 1. Yield: 1.39 g (65%); light yellow solid; m.p. 245–247 °C (decomp.). ¹H NMR (DMSO-d₆, 400 MHz): δ = 2.37 (s, 3H), 3.65 (d, 1H, J = 17.5 Hz), 3.90 (d, 1H, J = 17.5 Hz), 6.87 (t, 1H, J = 7.8 Hz), 6.97 (d, 1H, J = 8.0 Hz), 7.31 (d, 2H, J = 8.2 Hz), 7.37 (t, 1H, J = 7.8 Hz), 7.73 (d, 2H, J = 8.2 Hz), 7.77 (d, 1H, J = 8.0 Hz), 8.16 (s, 1H), 13.29 (s, 1H) ppm. ¹³C NMR (DMSO-d₆, 100 MHz): δ = 20.9, 44.1, 78.0, 115.2, 115.7, 118.9, 126.8 (2C), 127.7, 127.8, 129.3 (2C), 133.4, 140.6, 146.1, 155.0, 156.2, 171.8 ppm. IR (mineral oil): 3355, 3332, 3274, 1747, 1726 cm⁻¹. Anal.Calcd (%) for C₁₈H₁₅N₃O₃: C 67.28; H 4.71; N 13.08. Found: C 67.45; H 4.62; N 12.96.

Crystal Data of 1. C₁₈H₁₅N₃O₃, M = 321.33, triclinic, space group P−1, a = 11.2015(12) Å, b = 14.5766(13) Å, c = 15.9294(15) Å, α = 100.824(8)°, β = 100.914(8)°, γ = 108.031(9)°, V = 2342.4(4) ų, T = 295(2) K, Z = 6, μ(Mo Kα) = 0.095 mm⁻¹. The final refinement parameters: R₁ = 0.0597 [for observed 5844 reflections with I > 2σ(I)]; wR₂ = 0.1534 (for all independent 10888 reflections, R_int = 0.0323), S = 1.025. Largest diff. Peak and hole 0.232 and −0.232 ēÅ⁻³. Crystal structure of compound 1 was deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 2503244.