8-Phenyl-13a-(trifluoromethyl)-13aH-benzo[4,5]imidazo[1,2-a]chromeno[3,2-e]pyridine-6-carbonitrile

Abstract

A DABCO-catalyzed one-pot synthesis of a novel pentacyclic heterocycle featuring an unprecedented benzo[4,5]imidazo[1,2-a]chromeno[3,2-e]pyridine scaffold from 2-(cyanomethyl)benzimidazole and 3-trifluoroacetyl-4-phenyl-4H-chromene has been developed. This hybrid architecture merges three privileged pharmacophores—benzimidazole, chromene, and pyridine—into a rigid, nearly planar π-extended system decorated with trifluoromethyl and nitrile groups. The structure of 8-phenyl-13a-(trifluoromethyl)-13aH-benzo[4,5]imidazo[1,2-a]chromeno[3,2-e]pyridine-6-carbonitrile was unambiguously confirmed through NMR spectroscopy and X-ray diffraction analysis. A plausible mechanism involves Michael addition, hemiaminal formation, ring opening, recyclization, and oxidation.

1. Introduction

Fused polyheterocyclic systems, particularly those integrating multiple pharmacophoric units within a single molecular framework, have emerged as privileged scaffolds for drug discovery due to their structural complexity, conformational rigidity, and ability to engage multiple biological targets simultaneously. The strategic fusion of distinct heterocyclic cores through molecular hybridization has become a powerful approach in rational drug design, enabling the synergistic combination of complementary pharmacological properties while potentially overcoming limitations such as drug resistance, poor bioavailability, or off-target effects associated with parent compounds [1,2,3,4]. Hybrid heterocycles incorporating chromene motifs have emerged as particularly promising scaffolds [5,6,7,8,9,10,11].

In particular, the 5H-chromeno[2,3-b]pyridine system [12,13,14,15] is known as a privileged pharmacophore due to its ability to readily interact with a wide range of biological targets, and it is often used as a scaffold for the development of new drugs. Amlexanox is approved for the treatment of recurrent aphthous ulcers and exhibits anti-inflammatory, antiallergic, and immunomodulatory properties; remarkably, recent studies have revealed its efficacy in managing type 2 diabetes and obesity through inhibition of IKK-ε and TBK1 kinases [16]. Pranoprofen, a non-steroidal anti-inflammatory drug (NSAID) containing the chromeno[2,3-b]pyridine core, is widely used in ophthalmology for acute inflammatory conditions and postoperative ocular therapy [17]. The anti-inflammatory properties of the condensed chromone C are based on the inhibition of 15-Lipoxigenase (15-LOX) [18]. Chromenotacrine (D), a hybrid molecule combining chromene and tacrine moieties, functions as a selective acetylcholinesterase inhibitor with antioxidant and neuroprotective properties, showing promise for Alzheimer’s disease treatment [19]. Furthermore, chromeno[2,3-b]pyridine derivatives have demonstrated inhibition of mitogen-activated protein kinase (MK2) (compound E) [20] and β-site amyloid precursor protein-cleaving enzyme (BACE1) (F) [21], as well as anticancer activity (G) [22] (Figure 1).

On the other hand, benzo[4,5]imidazo[1,2-a]pyridines [23] represent another privileged scaffold that occurs in various derivatives exhibiting diversified biological activities such as antimalarial (compound H) [24], antiviral (I) [25], antifungal (J) [26], anticancer (K, L) [27,28], and compound M, which combines the structural fragments of benzo[4,5]imidazo[1,2-a]pyridine and chromeno[2,3-b]pyridine and is a potential SARS-CoV 2 inhibitor [29] (Figure 2).

In this context, we hypothesized that combining 2-(cyanomethyl)benzimidazole, a bifunctional synthon bearing both a nucleophilic methylene group and a benzimidazole nitrogen atom, with 3-trifluoroacetyl-4-phenyl-4H-chromene would trigger a cascade sequence yielding a structurally unprecedented hybrid scaffold.

2. Results and Discussion

2.1. Synthesis and Spectroscopy

In continuation of our research on the chemical transformations of highly polarized 4H-chromenes [30,31], we investigated the interaction of chromene 1 with 2-(cyanomethyl)benzimidazole [32]. This resulted in a complex mixture of products, from which benzo[4,5]imidazo[1,2-a]chromeno[3,2-e]pyridine 3 was isolated in pure form and identified (Scheme 1). The reaction was carried out by refluxing compounds 1 and 2 in a 1:1 ratio in acetonitrile for 12 h in the presence of DABCO (0.5 equiv). The product was isolated by means of column chromatography on silica gel. The moderate yield (34%) reflects the complexity of the multistep cascade involving at least five discrete transformations with potential competing pathways.

The starting chromene 1 [33] (Figures S1–S3), the synthesis of which has not been previously described in the literature, was obtained from 2-[hydroxy(phenyl)methyl]phenol as a precursor of o-quinone methide [34] and 1,1,1-trifluoro-4-morpholinobut-3-en-2-one (Scheme 2). The high degree of polarization of the double bond in the pyran ring of the chromene 1 makes it susceptible to attack by nucleophiles, ambiphilic reagents, and 1,3-dipoles. Consequently, this heterocycle could potentially serve as an excellent substrate for Michael additions and 1,3-dipolar cycloaddition reactions.

The structure of compound 3 was confirmed using a complex of spectral analysis methods. IR spectroscopy showed an absorption band at 2226 cm⁻¹ characteristic of the nitrile group. The ¹H NMR spectrum displayed a characteristic singlet at δ 7.42 ppm assigned to H-7, along with a number of doublet and multiplet signals (δ 6.90–8.15 ppm) integrating for 13 aromatic protons consistent with the fused framework plus phenyl substituent. Notably, the absence of aliphatic proton signals confirmed the presence of a 2H-chromene fragment (Figure S4). The presence of a trifluoromethyl group was detected by the characteristic quartet signal at 123.8 ppm with ¹J_CF = 298.1 Hz in the ¹³C NMR spectrum, as well as by the signal of the carbon atom bonded with it in the region of 84.6 ppm with ²J_CF = 31.6 Hz (Figure S5). In the DEPT spectra, the number of carbon atoms directly bonded to protons is consistent with the considered structure (Figure S6).

In addition, the structure of compound 3 was confirmed using X-ray diffraction data (Figure 3). The molecular structure reveals a nearly planar fused pentacyclic core comprising chromene, benzimidazole, and dihydropyridine rings, indicating extensive π-conjugation. Subtle puckering occurs at the sp³-hybridized bridgehead carbon C-13a (C-2 in CIF numbering) connected with the trifluoromethyl group. The phenyl ring at C-8 (C-18 in CIF numbering) is nearly perpendicular to the fused ring system (dihedral angles C32–C31–C18–C17 = −86.36° and C36–C31–C18–C19 = −86.68°), which minimizes steric repulsion with the H-16 and H-20 hydrogen atoms while completely disrupting π-conjugation. The trifluoromethyl group adopts a pseudo-axial orientation relative to the heterocyclic framework and F–C–F angles averaging 107.3°, consistent with tetrahedral geometry. The nitrile group is essentially coplanar with the dihydropyridine ring, enabling effective π-conjugation extension. In the crystal lattice, molecules are arranged in a herringbone-like pattern typical of planar aromatic systems. No classical hydrogen bonds are present due to the absence of strong donors; however, the structure is stabilized by π-π stacking interactions between the pyrido[1,2-a]benzimidazole moieties and benzene rings of the chromene fragment of adjacent molecules, with interplanar distances ranging from 3.4 to 3.6 Å (Figure 4).

2.2. Proposed Mechanism

A plausible mechanism (Scheme 3) involves initial reversible deprotonation of the acidic methylene group in 2-(cyanomethyl)benzimidazole by DABCO, generating a stabilized carbanion I. This nucleophile undergoes regioselective Michael addition to the β-carbon (C-2) of the enone system in chromene 1, forming adduct II. Intramolecular nucleophilic attack of the benzimidazole nitrogen atom on the electrophilic carbonyl carbon atom of the trifluoroacetyl group then yields hemiaminal intermediate III. Subsequent ring opening of the dihydropyran moiety via C–O bond cleavage generates open-chain species IV, which undergoes recyclization through attack of the phenoxide oxygen on the hemiaminal carbon atom to form cyclic N,O-acetal V. Finally, air-mediated oxidation of the dihydropyran ring affords the conjugated pentacyclic product 3. The closest to this transformation is the synthesis of 1,2,3,11a-tetrahydro-6H-chromeno[3,2-e]imidazo[1,2-a]pyridin-6-ones reported by Savych et al. [18]. However, in this case, more highly polarized chromones and heterocyclic ketene aminals as Michael donors instead of 2-(cyanomethyl)benzimidazole were used.

The resulting benzo[4,5]imidazo[1,2-a]chromeno[3,2-e]pyridine scaffold represents a structurally novel architecture merging benzimidazole, pyridine, and chromene units and decorated with a bridgehead trifluoromethyl substituent, and a nitrile functionality. The nitrile group offers versatile handles for further derivatization (e.g., hydrolysis to carboxylic acid, reduction to amine, or participation in click chemistry). The presence of both strong electron-withdrawing groups (CF₃ and CN), combined with extended π-conjugation, creates a polarized electronic structure potentially favorable for interactions with biological targets containing complementary electrostatic features.

3. Materials and Methods

All synthetic manipulations were performed in air. All reagents and solvents (purity) were purchased from commercial vendors and used as received. ¹H and ¹³C (proton-decoupled) NMR spectra (at 400 and 100 MHz, respectively), as well as DEPT-135 spectra, were registered on a JEOL JNM-ECX400 spectrometer (Tokyo, Japan) in DMSO-d₆ or CDCl₃. Chemical shifts were referenced internally to the residual solvent signal (DMSO-d₆: 2.50 ppm for ¹H nuclei, 39.5 ppm for ¹³C nuclei; CDCl₃: 7.26 ppm for ¹H nuclei, 77.2 ppm for ¹³C nuclei). IR spectra were registered on a Shimadzu IRAffinity-1 spectrometer (Kyoto, Japan) equipped with a Specac Diamond ATR GS10800-B accessory. Elemental analysis was performed on an automated Euro Vector EA-3000 CHNS analyzer (Pavia, Italy) using L-cystine as a standard. Melting points were determined using the capillary method on an SRS OptiMelt MPA100 instrument (Sunnyvale, CA, USA). Reaction progress and purity of the obtained compounds were monitored via TLC on Merck Silica gel 60 F₂₅₄ plates (eluent—CH₂Cl₂).

3.1. Synthesis and Characterization of 2,2,2-Trifluoro-1-(4-phenyl-4H-chromen-3-yl)ethanone (1)

A mixture of 2-[hydroxy(phenyl)methyl]phenol (0.60 g, 3 mmol) and 1,1,1-trifluoro-4-morpholinobut-3-en-2-one (0.63 g, 3 mmol) in acetic acid (15 mL) was heated under reflux for 3.5 h, diluted with 15 mL of methanol and kept at −30 °C for 24 h. The precipitated solid was filtered off and purified via recrystallization from ethanol to afford 1 (0.60 g, 66%).

Colorless crystals, mp 98–100 °C. ¹H NMR (400 MHz, CDCl₃) δ, ppm: 8.02 (s, 1H), 7.27–7.06 (m, 9H), 5.06 (s, 1H). ¹³C NMR (100 MHz, CDCl₃) δ, ppm: 178.6 (q, ²J_CF = 35.3 Hz, C), 155.9 (q, ⁴J_CF = 5.7 Hz, CH), 148.4 (C), 144.6 (C), 130.2 (CH), 128.8 (2CH), 128.3 (CH), 128.0 (2CH), 127.2 (CH), 126.3 (CH), 123.8 (C), 116.9 (CH), 116.5 (q, ¹J_CF = 289.9 Hz, C), 114.7 (C), 38.5 (CH). FTIR, v_max: 1688, 1630, 1576, 1485, 1454, 1321, 1225, 1175, 1136, 1103, 1032, 964, 907, 756, 735, 696 cm⁻¹. Calc. for C₁₇H₁₁F₃O₂: C 67.11, H 3.64. Found: C 67.19, H 3.59.

3.2. Synthesis and Characterization of 8-Phenyl-13a-(trifluoromethyl)-13aH-benzo[4,5]imidazo[1,2-a]chromeno[3,2-e]pyridine-6-carbonitrile (3)

A mixture of 2,2,2-trifluoro-1-(4-phenyl-4H-chromen-3-yl)ethanone 1 (0.30 g, 1 mmol), 2-(cyanomethyl)benzimidazole 2 (0.16 g, 1 mmol), and DABCO (55 mg, 0.5 mmol) in acetonitrile (5 mL) was refluxed for 12 h, cooled to −30 °C, and kept overnight. The precipitated solid was collected by filtration, purified by means of silica gel column chromatography (eluent—CH₂Cl₂), and recrystallized from methanol to afford 3 (0.15 g, 34%).

Orange crystals, mp 240–241 °C. ¹H NMR (400 MHz, DMSO-d₆) δ, ppm: 8.15 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.67–7.45 (m, 7H), 7.42 (s, 1H), 7.41–7.37 (m, 1H), 7.31–7.26 (m, 1H), 7.17–7.12 (m, 1H), 6.90 (d, J = 8.0 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ, ppm: 149.8 (C), 148.4 (C), 143.93 (C), 143.87 (C), 139.5 (CH), 135.0 (CH), 133.8 (C), 132.5 (C), 130.4 (CH), 130.2 (br. signal, CH), 129.7 (br. signal, 3CH), 129.4 (CH), 126.4 (CH), 125.1 (CH), 124.9 (CH), 123.8 (q, ¹J_CF = 298.1 Hz, C), 121.4 (C), 121.2 (CH), 116.9 (CH), 114.9 (CH, C), 114.6 (C), 102.1 (C), 84.6 (q, ²J_CF = 31.6 Hz, C). FTIR, v_max: 3061, 2226, 1589, 1564, 1443, 1418, 1339, 1254, 1204, 1180, 1134, 1094, 1007, 939, 889, 764, 750, 737, 702 cm⁻¹. Calc. for C₂₆H₁₄F₃N₃O: C 70.75; H 3.20; N 9.52. Found: C 70.69; H 3.17; N 9.46.

3.3. X-Ray Crystallography

X-ray structural analysis of compound 3 was carried out on a Stoe STADI VARI diffractometer equipped with a Pilatus100K detector using Cu Kα radiation (λ = 1.5418 Å) at 295(2) K. Crystals suitable for X-ray diffraction were grown from ethanol through the slow evaporation of the solvent at room temperature. Data collection, as well as determination and refinement of unit-cell parameters, was performed using the CrysAlisPro software package (version 1.171.33.66) [35]. The structure was solved and refined using the SHELX97 program package [36]. Molecular graphics and preparation of the manuscript were performed with the OLEX2 software package [37].

Selected crystallographic data: C₂₆H₁₄F₃N₃O, M = 441.40, monoclinic, a = 9.2933(2), b = 14.3417(4), c = 15.1408(5) Å, α = 90°, β = 91.442(2)°, γ = 90°, V = 2017.35(10) ų, T = 295 K, space group P2₁/n, Z = 4, d_calc = 1.453 g/cm³. An orange prismatic single crystal with dimensions of 0.200 × 0.200 × 0.200 mm was selected for data collection. A total of 21,351 reflections were measured in the range 4.25° ≤ θ ≤ 72.89°, yielding 3991 independent reflections (R_int = 0.0513). Final refinement based on I > 2σ(I) gave R₁ = 0.0382 and wR₂ = 0.0770 for 298 refined parameters, S = 1.021. Hydrogen atoms were placed geometrically and refined using the riding model. CCDC 1939479 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures (accessed on 17 February 2026).

4. Conclusions

In this work, we described the preparation of a π-extended pentacyclic heterocyclic system, 8-phenyl-13a-(trifluoromethyl)-13aH-benzo[4,5]imidazo[1,2-a]chromeno[3,2-e]pyridine-6-carbonitrile. Structural elucidation by means of NMR spectroscopy and X-ray diffraction revealed a unique fused framework with a N,O-acetal fragment.