10-(4-Chloro­phen­yl)-4-[(4-fluoro­phen­yl)amino]-5-phenyl-5,8,9,10-tetra­hydro­pyrimido[4,5-b]quin­olin-6(7H)-one

Adesola A Adeleke; Sizwe J Zamisa; Bernard Omondi

doi:10.1107/S2414314625007758

. 2025 Sep 5;10(Pt 9):x250775. doi: 10.1107/S2414314625007758

10-(4-Chlorophenyl)-4-[(4-fluorophenyl)amino]-5-phenyl-5,8,9,10-tetrahydropyrimido[4,5-b]quinolin-6(7H)-one

Adesola A Adeleke ^a,^*, Sizwe J Zamisa ^a, Bernard Omondi ^a

Editor: L Van Meervelt^b

PMCID: PMC12498024 PMID: 41058876

The crystal structure of the title compound features a single asymmetric unit with distinct syn-clinal and orthogonal ring arrangements, forming corrugated two-dimensional sheets via C—H⋯π and C—F⋯π interactions that are further reinforced into a three-dimensional network by C—H⋯O, N—H⋯O hydrogen bonds and Cl⋯Cl contacts.

Keywords: crystal structure, pyrimidine, syn-clinal orientation

Abstract

The title compound, C₂₉H₂₂ClFN₄O, crystallizes with one molecule in the asymmetric unit. The pyrimidinyl and anilinyl moieties subtend a dihedral angle = 36.65 (5)°, while the dihydropyridine and phenyl rings are approximately orthogonal [dihedral angles = 81.65 (7) and 89.95 (7)°]. The crystal packing reveals alternating C—H⋯π and C—F⋯π interactions forming corrugated two-dimensional sheets along the ac plane, which are further linked into a three-dimensional network through N—H⋯O and C—H⋯O hydrogen bonds and Cl⋯Cl interactions.

Structure description

The title compound represents a heterocycle from the pyrimido[4,5-b]quinoline family, distinguished by its fused pyrimidine and quinoline framework. These scaffolds are typically constructed via efficient single-pot, multicomponent reactions (Moosavi-Zare & Najafi, 2023 ▸). Fused tetrahydroquinoline systems, especially those incorporating pyrimidine units, continue to attract pharmaceutical research due to their broad-spectrum bioactivity – including antimicrobial, anticancer, antimalarial, anti-inflammatory, and antihistaminic potential (Patel et al., 2024 ▸; Tawfeek et al., 2024 ▸). Beyond these applications, pyrimidine motifs have shown utility in modulating signaling enzymes such as Abl kinase and PTP1B, and can also function as DNA intercalators (Esmaili et al., 2022 ▸). Motivated by ongoing efforts to develop enhanced pyrimidine-quinoline-based therapeutics, we now report the crystallographic characterization of the title compound (Zamisa et al., 2023 ▸).

The crystal structure of the title compound consists of one molecule in the asymmetric unit (Fig. 1 ▸). The pyrimidinyl and anilinyl units exhibit near coplanarity, with a dihedral angle of 36.65 (7)°. In contrast, the dihydropyridine and the C–C18 and C24–C29 phenyl rings are nearly perpendicular, subtending dihedral angles of 81.65 (7) and 89.85 (7)°, respectively. These geometric parameters are comparable with those of reported for chromenopyrimidine (Zamisa et al. 2022 ▸) and hexahydroquinolinyl formimidate (Zamisa & Omondi, 2022 ▸) derivatives

Molecular structure of the title compound with displacement ellipsoids drawn at the 50% probablility level.

In the packing of the title compound, C—H⋯π hydrogen bonds are observed between the H10 atom of the pyrimidine ring and the centroid of the C24–C20 phenyl ring (Cg1), which form supramolecular chains along the crystallographic a-axis direction (Table 1 ▸). These chains are linked via C15—F1⋯Cg2 interactions (Cg2 is the centroid of the C18–C23 ring) to form supramolecular sheets that extend alongthe [111] direction (Fig. 2 ▸, Table 1 ▸). The O1 atom of the carbonyl group acts as a double acceptor for the N4—H4⋯O1 and C29—H29⋯O1 hydrogen bonding patterns, which together with Cl1⋯Cl1 contacts [3.2755 (5) Å < 3.50 Å ; (sum of van der Waals radii), symmetry code: −x + 2, −y + 2, −z + 2], link the sheets into a three-dimensional supramolecular architecture (Fig. 3 ▸, Table 1 ▸).

Table 1. Hydrogen-bond geometry (Å, °).

Cg1 and Cg2 are the centroids of the C24–C29 and C18–C23 rings, respectively.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N4—H4⋯O1ⁱ	0.88	2.17	3.0036 (16)	159
C29—H29⋯O1ⁱ	0.95	2.46	3.3169 (18)	150
C10—H10⋯Cg1ⁱⁱ	0.95	2.74	3.5719 (18)	147
C15—F1⋯Cg2ⁱⁱⁱ	1.3604 (18)	3.1604 (13)	4.4286 (18)	154.70 (10)

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

Representation of the C10—H10⋯Cg1 and C15—F1⋯Cg2 interactions in the crystal packing of the title compound.

Representation of (a) the C29—H29⋯O1 and N4—H4⋯O1 hydrogen bonds in the crystal packing of the title compound and (b) the formation of a three dimensional supramolecular structure formed *via* alternating double-acceptor hydrogen bonds involving the O1 atom (cyan-coloured dashed lines) and Cl⋯Cl contacts (magenta-coloured dashed lines). Gold and grey colors indicate symmetry relationships with the asymmetric unit. Light grey represents the asymmetric unit contents, while golden-yellow indicates inversion symmetry. Symmetry code: (i) −x, −y, −z + 1.

Synthesis and crystallization

The stepwise intermediates: 2-amino-1-(4-chlorophenyl)-5-oxo-4-phenylhexahydroquinoline-3-carbonitrile and ethyl (E)-N-(3-cyano-1-(4-chlorophenyl)-5-oxo-4-phenylhexahydroquinolin-2-yl)formimidate were synthesized via adapted literature protocols (Zamisa et al., 2022 ▸; Zamisa & Omondi, 2022 ▸). Following established methods, the synthesis involved combining 1 mmol of the formimidate derivative with 1.2 mmol of 4-fluoroaniline in 10 ml of acetic acid. This mixture was sealed in a 30 ml high-pressure vial and subjected to microwave irradiation (200 W) at 413 K for 20 minutes using a single-mode microwave reactor. The formation of the product was confirmed using thin-layer chromatography (TLC). After the reaction, distilled water was carefully layered onto the mixture, creating a cloudy suspension that was left undisturbed overnight. The resulting solid was harvested by vacuum filtration, rinsed with distilled water, and purified via recrystallization using an ethanol–water solvent system (Zamisa et al., 2023 ▸).

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸.

Table 2. Experimental details.

Crystal data
Chemical formula	C₂₉H₂₂ClFN₄O
M _r	496.95
Crystal system, space group	Triclinic, P
Temperature (K)	100
a, b, c (Å)	8.4512 (2), 11.6756 (3), 12.7892 (3)
α, β, γ (°)	106.100 (1), 101.492 (2), 97.612 (2)
V (Å³)	1164.29 (5)
Z	2
Radiation type	Mo Kα
μ (mm⁻¹)	0.20
Crystal size (mm)	0.23 × 0.14 × 0.08

Data collection
Diffractometer	Bruker SMART APEX2 area detector
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 ▸)
T_min, T_max	0.696, 0.746
No. of measured, independent and observed [I > 2σ(I)] reflections	17352, 5250, 4225
R _int	0.027
(sin θ/λ)_max (Å⁻¹)	0.651

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.038, 0.095, 1.04
No. of reflections	5250
No. of parameters	325
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.30, −0.26

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Computer programs: COSMO and SAINT (Bruker, 2009 ▸), SHELXT2018/2 (Sheldrick, 2015a ▸), SHELXL2018/3 (Sheldrick, 2015b ▸) and OLEX2 (Dolomanov et al., 2009 ▸).

Supplementary Material

Crystal structure: contains datablock(s) I. DOI: 10.1107/S2414314625007758/vm4071sup1.cif

x-10-x250775-sup1.cif^{(524KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S2414314625007758/vm4071Isup2.hkl

x-10-x250775-Isup2.hkl^{(417.7KB, hkl)}

x-10-x250775-Isup3.cml^{(9.1KB, cml)}

Supporting information file. DOI: 10.1107/S2414314625007758/vm4071Isup3.cml

CCDC reference: 2484308

Additional supporting information: crystallographic information; 3D view; checkCIF report

Acknowledgments

We thank the University of KwaZulu-Natal for their support of this research.

full crystallographic data