Crystal structure of (E)-2-({4-hydroxy-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]phenyl} methylidene)-1-indanone, C₂₃H₂₆N₂O₃

Source of material

The mixture of 2-(4-hydroxy-3-methoxybenzylidene)-2,3-dihydroinden-1-one (21 mmol), paraformaldehyde (25 mmol) and N-methyl piperazine (21 mmol) was heated in 15 mL of acetonitrile (393 K) for 10 min. The product was purified by crystallization firstly from methanol-hexane and then from chloroform-hexane. [Yield: 40%, mp.: 471–473 K]. ¹H NMR (400 MHz, CDCl₃, p.p.m.) δ 7.87 (d, 1H, Ar—H, J = 7.7 Hz, indanone), 7.60–7.53 (m, 3H, Ar—H, indanone, vinylic-H), 7.40 (bt, 1H, Ar—H, J = 7.1 Hz, indanone), 6.97 (s, 1H, Ar—H), 7.11 (s, 1H, Ar—H), 3.98 (s, 2H, 3-CH2, indanone), 3.94 (s, 3H, –OCH₃), 3.79 (s, 2H, Ar—CH₂N–), 3.00–2.30 (m, 8H, CH₂-piperazine), 2.29 (s, 3H, –N—CH₃); ¹³C NMR (100 MHz, CDCl₃, p.p.m.) δ 194.4, 149.8, 149.5, 148.4, 138.5, 134.6, 134.5, 132.0, 127.8, 126.7, 126.3, 124.5, 124.4, 121.7, 113.7, 61.3, 56.2, 55.0, 52.7, 46.1, 32.6; Mass spectrum: 379.20 (M⁺ + 1); HRMS (ESI-MS) Calc.: 379.2022 for C₂₃H₂₇N₂O₃ [M + H]⁺, Found: 379.2025 [1].

Experimental details

H atom were placed in calculated positions with O—H = 0.82 Å, C—H = 0.93–0.96 Å, and refined using a riding model with U_iso(H) = 1.2U_eq(C) for the aromatic and methylene H atoms and U_iso(H) = 1.5U_eq(C,O) for the methyl and hydroxyl H atoms.

Discussion

Mannich bases have several biological activities such as antimicrobial [2], antifungal [3], anticonvulsant [4], anti-inflammatory [5], and cytotoxic/anticancer [6, 7] activities. The title Mannich base, 2-[4-hydroxy-5-methoxy-3-(4-methyl-piperazin-1-ylmethyl)-benzylidene]-indan-1-one (cf. the figure) can be concluded from the figure was synthesized starting from 2-(4-hydroxy-3-methoxybenzylidene)-indan-1-one, and was tested as inhibitors of the zinc metalloenzyme cytosolic human carbonic anhydrase (hCA I, and II) isoforms. The title compound is a strong hCA I (Ki: 484.02 ± 30.30 nM) and II inhibitor (Ki: 526.30 ± 112.9 nM).

In the title compound, the piperazine ring (N1/N2/C19—C22) adopts a chair conformation with the puckering parameters [8] of Q_T = 0.5697(19) Å, θ = 0.0(2)° and φ = 82(12)°, respectively. The 2,3-dihydro-1H-indene ring system (C1—C9) is essentially planar [the puckering parameters are Q(2) = 0.007(2) Å and φ(2) = 20(16)°] and its mean plane makes a dihedral angle of 9.27(7)° with the central benzene ring (C11—C16). The intramolecular O3—H3O⋯N1 hydrogen bonds stabilizes the molecular conformation of the title compound. In the crystal, molecules are linked by weak C—H⋯O, C—H⋯N and C—H⋯π interactions.