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

Sizwe J Zamisa; Adesola A Adeleke; Bernard Omondi

doi:10.1107/S2414314625007047

. 2025 Aug 12;10(Pt 8):x250704. doi: 10.1107/S2414314625007047

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

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

Editor: L Van Meervelt^b

PMCID: PMC12412685 PMID: 40917536

The title compound forms a crystal structure with near-coplanar heteroaryl units and perpendicular aromatic rings, assembling into a corrugated two-dimensional network along the crystallographic ac plane that is consolidated into a three-dimensional supramolecular architecture via hydrogen bonding.

Keywords: crystal structure, pyrimidines

Abstract

The asymmetric unit of the title compound, C₂₉H₂₂F₂N₄O, consists of one molecule in which the pyrimidinyl and anilinyl units exhibit near coplanarity, subtending a dihedral angle of 10.22 (7)°. In contrast, the dihydropyridine and phenyl rings are nearly perpendicular, making angles of 88.66 (7) and 89.14 (7)°. The crystal packing features alternating C—H⋯π and C—F⋯π interactions that generate a corrugated two-dimensional supramolecular network in the crystallographic ac plane. This structure is further consolidated into a three-dimensional architecture by C—H⋯F hydrogen bonding.

Structure description

The title compound is a nitrogen-rich heterocyclic molecule belonging to the pyrimido[4,5-b]quinoline class, characterized by a fused pyrimidine ring and quinoline moiety. This class of compound is often synthesized using multicomponent reactions, allowing efficient isolation of target products through single-pot procedures (Moosavi-Zare & Najafi, 2023 ▸). Tetrahydroquinolines and their fused derivatives, such as pyrimidine, have gathered significant interest from pharmaceutical researchers due to their broad pharmacological properties, including antimicrobial, anticancer, antimalarial, anti-inflammatory, and antihistaminic activities (Patel et al., 2024 ▸, Tawfeek et al., 2024 ▸). Moreover, pyrimidine-containing motifs, apart from their notable biological activities, have served as inhibitors for Abelson kinase (AbI kinase) and protein tyrosine phosphatase 1B (PTP1B) in cell signalling as well as a DNA intercalating agent (Esmaili et al., 2022 ▸). As such, there is continuous interest from medicinal scientists in designing new pyrimidine-quinoline pharmacophore drugs with enhanced medicinal efficacy. In a continuation of our research interest (Zamisa et al., 2023 ▸), we report herein the crystal structure of the title compound.

The asymmetric unit of the title compound contains one molecule with a tetrahydropyrimido[4,5-b]quinolin-6(7H)-one core, onto which the phenyl, 4-fluorophenyl and 4-fluoroanilinyl moieties are attached on atoms C7, N1 and C11, respectively (Fig. 1 ▸). The dihedral angle between the pyrimidinyl and anilinyl moieties tends towards co-planarity [10.22 (7)°] while the dihedral angles between the central dihydropyridine ring and the phenyl rings are 88.66 (7) and 89.14 (7)°. These values are comparable with those of reported chromenopyrimidine (Zamisa et al., 2022 ▸) and hexahydroquinolinyl formimidate (Zamisa & Omondi, 2022 ▸) derivatives. An intramolecular C—H⋯N hydrogen bond occurs between atom H17 of the anilinyl ring and the N3 atom of the pyrimidine ring (Table 1 ▸). The crystal packing features alternating intermolecular C10—H10⋯Cg1 and C15—F1⋯Cg2 interactions (Table 1 ▸), which form a corrugated two-dimensional supramolecular structure that propagates in the crystallographic ac plane as depicted in Fig. 2 ▸. These corrugated supramolecular sheets are further linked by C3—H3A⋯F2 and C4—H4A⋯F1 hydrogen bonds (Table 1 ▸), resulting in a three-dimensional supramolecular architecture.

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

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

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C3—H3A⋯F2ⁱ	0.99	2.70	3.3379 (18)	123
C4—H4A⋯F1ⁱⁱ	0.99	2.54	3.3829 (18)	143
C17—H17⋯N3	0.95	2.23	2.856 (2)	123
C10—H10⋯Cg1ⁱⁱⁱ	0.95	2.71	3.5471 (17)	147
C15—F1⋯Cg2^iv	1.3673 (18)	3.8721 (12)	4.7637 (18)	123.40 (9)

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

Representation of intermolecular C10—H10⋯Cg1 and C15—F1⋯Cg2 interactions in the crystal packing of the title compound viewed with a slight rotation along the crystallographic (a) b and (b) a axes.

Synthesis and crystallization

The precursors, 2-amino-1-(4-fluorophenyl)-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile and ethyl (E)-N-[3-cyano-1-(4-fluorophenyl)-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinolin-2-yl]formimidate were synthesized using modified literature procedures (Zamisa et al., 2022 ▸; Zamisa & Omondi, 2022 ▸). The title compound was synthesized by the following procedure. A solution of ethyl (E)-N-[3-cyano-1-(4-fluorophenyl)-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydronaphthalen-2-yl]formimidate (1 mmol) and the corresponding 4-fluoroaniline (1.2 mmol) in 10 ml of acetic acid was placed into a sealed 30 ml pressurized vial. The reaction mixture was exposed to microwave irradiation at 200 W using a single-mode microwave synthesis system, with the temperature maintained at 413 K for 20 minutes. The formation of the product was confirmed using thin-layer chromatography (TLC). Upon completion, distilled water was carefully layered onto the reaction mixture without agitation, resulting in the formation of a turbid suspension. This was allowed to stand overnight. The precipitated crude product was collected by vacuum filtration, washed with distilled water, and subsequently purified by recrystallization from a mixed solvent system of ethanol and water (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	C₂₉H₂₂F₂N₄O
M _r	480.50
Crystal system, space group	Monoclinic, P2₁/n
Temperature (K)	100
a, b, c (Å)	8.4575 (4), 11.5163 (5), 23.0761 (10)
β (°)	91.103 (2)
V (Å³)	2247.17 (17)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.10
Crystal size (mm)	0.22 × 0.14 × 0.13

Data collection
Diffractometer	Bruker SMART APEXII area detector
Absorption correction	Multi-scan (SADABS; Krause et al., 2015 ▸)
T_min, T_max	0.688, 0.746
No. of measured, independent and observed [I > 2σ(I)] reflections	15704, 5044, 3821
R _int	0.030
(sin θ/λ)_max (Å⁻¹)	0.650

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.042, 0.113, 1.04
No. of reflections	5044
No. of parameters	325
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.30, −0.24

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Computer programs: APEX2 and SAINT (Bruker, 2014 ▸), SHELXT (Sheldrick, 2015a ▸), SHELXL2018/3 (Sheldrick, 2015b ▸) and OLEX2 (Dolomanov et al., 2009 ▸).

Supplementary Material

Crystal structure: contains datablock(s) I. DOI: 10.1107/S2414314625007047/vm4070sup1.cif

x-10-x250704-sup1.cif^{(487.5KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S2414314625007047/vm4070Isup2.hkl

x-10-x250704-Isup2.hkl^{(401.5KB, hkl)}

x-10-x250704-Isup3.cml^{(9.1KB, cml)}

Supporting information file. DOI: 10.1107/S2414314625007047/vm4070Isup3.cml

CCDC reference: 2478466

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

Acknowledgments

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

full crystallographic data