Beyond the Antagonism: Self-Labeled Xanthone Inhibitors as Modeled "Two-in-One" Drugs in Cancer Therapy.

Self-labeled inhibitors (SLIs) are promising for creating links, ranging from cancer therapy and metastatic pathways to mechanistic elucidation. In this study, a new category of "two-in-one" fluorescent xanthone inhibitors was developed for the systematic evaluation of anticancer activity and the selective imaging of cytoplasm in vitro. These xanthone inhibitors presented high fluorescent brightness, working over a wide pH range enabled by a "switchable reaction" of the heterocyclic backbone. The strength and nature of fluorescence were probed via spectroscopic methods and density functional theory calculations on the molecular level, respectively. Along with the potent anticancer activity, which was demonstrated using MTT and clonogenic assays with high fluorescent brightness in the cytoplasm, SLI 3fd could be established as a modeled self-monitoring drug in cancer therapy.

Introduction

Enabled by the advancement of fluorescent spectroscopic and microscopic technologies, monitoring the real-time behavior of drug molecules inside of living cells has been well-established.[1] Traditionally, tracking drug molecules and their corresponding behavior (e.g., the alternation of the molecular structure and informational feedback) was dependent on the output of signals from the fluorescent label attached to the drug molecules.[2−5] However, extraneous fluorescent labels or drug delivery media could pose potential risks such as toxicity, residue, and metabolism, which would interfere with the normal cellular function.[6] Therefore, it is highly desired to design self-labeled inhibitors (SLIs) that not only play the role of antagonists but also report their own trace in cells and further potentially convey the information of intracellular delivery, metastatic pathways, and even mechanistic elucidation (Figure ).

Figure 1

Functionalized SLIs.

Xanthones represent a valuable category of natural products[7−12] because of their prominent pharmacological activities. They are known to serve as inhibitors for various targets such as tumors,[13,14] bacteria,[15,16] viruses,[17] fungi,[18] and others.[19−21] Recently, the fluorescence of xanthones has been investigated for selective labeling and recognition of multiscale chemical or biological species.[22,23] For example, Maity et al. developed a two-photon probe based on the xanthone framework for the selective detection of Cu+ in a physiologically reducing environment;[24] Umemoto et al. used a series of xanthone and thioxanthone derivatives to study the binding process of small molecules to RNA;[25] and Gosh et al. used acetylated xanthones to serve as fluorescent probes for embryonic stem cells.[26] However, to the best of our knowledge, no information is available about an SLI that couples at least two functions, viz., antagonism and fluorescence in one xanthone molecule, to inhibit cancer cells, track drug delivery, and report the response of intracellular homeostasis.

Given these considerations, we envisioned that an SLI model can be established based on a rational design, stepwise screening, and functional combination. Herein, we report a sequential approach to discover, characterize, and evaluate “two-in-one” fluorescent inhibitors, which includes three stages: (i) xanthone derivatives (3) were initially screened using fluorescent calorimetry, after which the strength and nature of fluorescence were meticulously probed using spectroscopic methods and density functional theory (DFT) calculations; (ii) the screened fluorescent molecules and quenched counterparts were subjected to MTT and clonogenic assays that shed light on the anticancer activity both in the short- and long-term; and (iii) in order to demonstrate the self-monitoring in cancer cells, the potent inhibitor 3fd was investigated using cell imaging to observe the subcellular localization.

Results and Discussion

In the first stage, synthetic efforts have been made to establish xanthone-based fluorescent compounds (3) (Figure a). The remarkable tolerance of the functional groups (R1 and R2) enabled the facile transfer of electrons across the π-conjugated fused rings, and different-sized diazaheterocycles (n) modulated the flexibility of the molecular skeleton. Accordingly, the rational preintroduction of electron withdrawing or donating groups in synthons 1 and 2 should tremendously affect the fluorescent performance of 3. Once the xanthone-based compounds (3) have been constructed, first-stage screening was carried out (Table S1). After rigorous calorimetry, six molecules (Figure b) with the highest fluorescent intensity were selected as candidates for the development of SLIs.

Figure 2

(a) Synthesis of xanthone-based compounds; (b) candidates with the highest light-emitting intensity; and (c) accidental discovery of the pH-tuned, switchable reaction-dependent fluorescent molecules.

For the sake of maximally dissolving the target compounds 3 in the deuterated solvent, a drop of perchloric acid was added when the nuclear magnetic resonance (NMR) characterization was carried out. Unexpectedly, we found that with the disappearance of fluorescence, all of the compounds (3) were transformed into the ring-opened counterparts (3′) (Figure c). Moreover, this accidental phenomenon encouraged us to tackle at least two important questions, viz.: (i) is the transformation reversible? and (ii) how can the essential relationship and the mechanism between the structural and fluorescent changes be demonstrated and confirmed?

As a result, an integrated investigation of fluorescent molecules 3ac–3ae and 3fc–3fe, which included spectroscopic properties, NMR, X-ray crystallographic analysis, DFT calculations, and electrochemistry was conducted. Ultraviolet–visible (UV–vis) absorption spectra (Figure a and Table , col. 2) and calculated electronic transitions (Table , col. 3) revealed that shifting the substitution groups (R2) from a more to a less electron-withdrawing state (F → Cl → Br) and increasing the size (n) of diazaheterocycles (1 → 2) lead to a small but a discernible red shift. At the same time, the fluorescence of these molecules was also examined. Several solvents were used to probe the effects of increased polarity on the emission wavelengths (λem) of 3ae (Figure S2). It was found that an apparent red shift will occur when the polarity of the solvents increases. The best excitation wavelengths (λex) and λem ranged from 449–470 to 519–526 nm (Figure b and Table , col. 4), respectively (Figures S3–S8). Importantly, the combination of electron donors and acceptors in the xanthone framework released most of its potential fluorescent properties, for example, large Stokes shifts (∼80 nm) (Figure c and Table , col. 5), high quantum yields (up to 0.671), and excellent fluorescent brightness (up to 74.72 mL mg–1 cm–1) (Table , col. 7). Consequently, these molecules could avoid self-quenching and enhance the number of labels that can be attached to a biological entity.

Figure 3

(a) UV–vis absorption spectra of the fluorescent molecules; (b) fluorescent spectra of compound 3fd under specific excitation wavelengths; and (c) Stokes shift of compound 3fd.

Table 1

Experimental and Calculated Electronic Transitions for Fluorescent Molecuesa

compd	λabs (nm)b	λabscal/λemcal (nm)c	λex/λem (nm)	λem – λabs (nm)d	Φe	ε/ε × Φ (mL mg–1 cm–1)f
3ac	440.5	421.9/514.3	464.0/519.5	79.0	0.476	42.64/19.91
3ad	440.0	421.0/514.4	449.0/520.0	80.0	0.464	50.07/23.23
3ae	441.5	421.4/515.9	466.0/520.5	79.0	0.428	23.56/10.08
3fc	442.0	424.3/514.6	461.0/525.5	83.5	0.671	111.53/74.72
3fd	443.0	424.1/514.5	470.0/526.0	83.0	0.663	81.07/53.75
3fe	443.5	423.6/516.6	470.0/526.0	82.5	0.329	113.48/37.33

Ethanol as the solvent.

λabs: maximal absorption wavelength.

Calculated transitions (λabscal/λemcal) were performed using the time-dependent DFT (TD-DFT) method on the B3LYP/6-311+G(2d,2p) level, and the polarizable continuum model (PCM) was used with ethanol as the solvent.

λem – λabs: Stokes shift.

Φ: quantum yield, rhodamine as the reference.

ε: absorption coefficient; ε × Φ: fluorescent brightness.

Having completed this preliminary study of spectroscopic properties, it is time to point out the proposed fluorescence mechanism. A combined method has been adopted to confirm the reversibility of the transformation illustrated in Figure c. When two drops of KOH solution were dropped into compounds 3′, the disappeared fluorescence of 3 reproduced in 10 s. The contrasting in situ 13C and 1H NMR spectra (for original data, see Supporting Information) between 3fd and 3fd′ revealed that once the transformation occurred, the chemical shifts of C1 (H1), C2, C4 (H4), C5, C7, and C8 moved to a lower field, whereas those of C3 and C6 moved to a higher field. The newly generated hydroxyl group (H9) introduced a chemical shift at 9.57 ppm (Figure a). These alterations in the characteristic peaks could partially verify that the transformation is reversible. In addition, clear evidence from the X-ray crystallographic interpretation of 3cb and 3cb′ solidified the previous deduction (Figure b).

Figure 4

(a) Contrasting 13C and 1H NMR spectra of compounds 3fd and 3fd′ and (b) X-ray crystal structures of compounds 3cb and 3cb′. Thermal ellipsoids are drawn at 30% probability.

To demonstrate the essential relationship between the structural and fluorescent changes, we next sought to use the DFT calculation of frontier molecular orbitals (FMOs) to elucidate the mechanism of fluorescence quenching (Figure ). For all molecules 3, an excellent agreement between the experimental and theoretical maximal absorptions or emissions was observed (Table , col. 3). The main absorption bands were due to three excitations with a high oscillator strength (f ≈ 0.40), viz., HOMO → LUMO, HOMO – 1 → LUMO, and HOMO → LUMO + 1, mainly of the π → π* or n → π* intramolecular charge transfer (ICT) characteristic. The emission band with a high oscillator strength (f ≈ 0.45), which was responsible for the fluorescence, lay on the π* → π ICT of LUMO → HOMO. It was obviously reflected in the population of the FMOs. For the ring-opening counterparts 3′, a higher energy (∼0.25 eV) needed to be supplied for the absorption, but the oscillator strength (f ≈ 0.20) was only half that of 3. In addition, once the rigid molecular framework was broken, the emission band of 3′ (LUMO → HOMO) shifted to the longer wavelength region (∼690 nm) with an extremely small oscillator strength (f ≈ 0.0002); meanwhile, the flexible structure restricted the ICT. On the other hand, the electrostatic potential also offered apparent evidence for the direction of electron mobility (Figure a). Therefore, the fluorescence quenching was caused by the ICT block, which was derived from a twisted ICT (TICT) via the rotation of C–C single bonds (C1–C2, C2–C3, and C4–C5) (Figure a). Afterward, the electrochemical property was also tested using cyclic voltammetry (Figure b). For instance, 3fd presented only one reversible reduction potential. The first onset of reduction was at −1.04 V, with a reversible reduction wave at −1.19 V. It was revealed that the molecules are electron-deficient and therefore can be considered as electron acceptors.

Figure 5

(a) FMOs and (b) their energetic values (ε) of compounds 3fd and 3fd′. GS: ground state and ES: excited state.

Figure 6

(a) Electrostatic potential map of compounds 3fd and 3fd′ and (b) cyclic voltammogram (CV) of the fluorescent molecules in anhydrous ethanol (1.0 × 10–4 M). Fc/Fc+ couple was used as an internal standard.

Having illustrated the fluorescent nature of the selected molecules, we next performed a second-stage screening. The anticancer activity in MTT and clonogenic assays was evaluated to identify the most promising fluorescent inhibitors in several human cell lines. For compounds that showed >50% inhibition, half-maximal inhibitory concentrations (IC50) were determined. For short-term treatment effects (Table ), we found that except for 3ac, all compounds presented definite cytotoxicity to many cancer cell lines (IC50 < 50 μM). In particular, compounds 3fe, 3fc′, and 3fd′ demonstrated potent anticancer activity, with IC50 < 10 μM in HepG2 liver carcinoma cells. It is also worth noting that the cytotoxicity of all molecules for embryonic lung fibroblasts MRC-5 is lower than that for the positive control cisplatin (DDP) (Table , entry 10), indicating that the screened inhibitors are effective against cancer cells (e.g., T47D and U251), yet have lower cytotoxicity to normal cells (e.g., MRC-5).

Table 2

MTT Assay for Short-Term Anticancer Activity

		anticancer activity (IC50) (μM)
entry	compd	MRC-5a	HepG2b	HT29c	SGC7901d	A549e
1	3ac		>100		>100	>100
2	3ad	34.9	30.9	26.9	18.7	34.3
3	3ae	31.3	15.4	18.8	17.8	27.5
4	3fc	48.0	18.9	29.8	26.7	39.6
5	3fd	33.1	11.2	26.8	14.8	33.5
6	3fe	34.8	9.5	13.3	13.5	27.5
7	3fc′	35.3	9.2	21.8	15.0	33.7
8	3fd′	34.0	7.7	14.1	10.5	26.4
9	3fe′	45.8	15.2	25.1	25.8	27.6
10f	DDP	8.2	3.0	14.3	2.3	8.4

Diploid fibroblasts.

Liver carcinoma cells.

Colorectal cancer cells.

Gastric carcinoma cells.

Cancerous alveolar epithelial cells.

Cisplatin: positive control.

To investigate the long-term treatment effects of inhibitors 3fd and 3fd′, a clonogenic assay was also performed in HepG2 liver carcinoma cells. This assay is used to determine the ability of a cell to proliferate indefinitely. IC50 values of 3fd and 3fd′ were estimated by dividing the mean number of colonies following compound treatment by the mean number of colonies in the absence of a compound. Compared with untreated controls, the number of colonies declined after treatment with a series of concentrations of 3fd and 3fd′ (Figure a), with IC50 values of 5.99 and 5.55 μM (Figure b), respectively. In any case, the perfect match for short-term (MTT assay) and long-term (clonogenic assay) treatments showed stable and continued activities in cancerous resistance.

Figure 7

(a) Clonogenic assay for long-term anticancer activity and (b) colony-forming ratio of inhibitors 3fd and 3fd′.

In view of the above scenario, the assembly of potent anticancer activity with inherent high fluorescent brightness in an inhibitor shows promise. Hence, we finally proposed a cell imaging program to validate the feasibility of inhibitor 3fd through the observation of the subcellular localization in HepG2 cells. The experiment was carried out with increasing concentrations of 3fd and staining of the nucleus with 4’,6-diamidino-2-phenylindole (DAPI). The results demonstrated that the accumulation of blue fluorescence in the nuclear compartment contrasts with the extensive green fluorescent inhibitor 3fd sequestered in the cytoplasm (Figure ). Increasing the incubation concentration of 3fd does not change its subcellular localization. Therefore, 3fd is preferentially localized to the cytoplasm. So far, as an antagonist, 3fd has presented extraordinary potency in several cancer cell lines; as a fluorescein, it has afforded extreme brightness; most importantly, as a model SLI, it lights up the way to the cell, reports where it is, and ultimately kills the cancerous enemy.

Figure 8

Confocal fluorescent images of HepG2 cells incubated with fluorescent inhibitor 3fd (green) or DAPI (blue).

Conclusions

In summary, we have successfully developed the first model of an SLI in cancer therapy via an assembly line pathway that includes the systematic screening of fluorescent xanthone derivatives, the multidimensional evaluation of anticancer activity, and the functional embedment of the two inherent properties. The present results with SLI 3fd indicate that the fluorescent properties can avoid self-quenching and enhance the number of labels; simultaneously, the coherent short- and long-term resistance can ensure excellent anticancer activity. Importantly, the functional combination reveals a promising idea for tracking drug molecules on the micron scale. Moreover, with the tunable fluorescent intensity over a wide pH range, it also provides a new impetus for probing the effects of homeostasis to antagonism. It is worth pointing out that the SLI concept suggests in-depth insights into the informational feedback of intracellular delivery, metastatic pathways, mechanistic elucidation, and so forth. Further investigations into the quantitative pH-fluorescence response for cancer cells and the real-time imaging of an enzymatic target on the nanoscale are currently under way.

Experimental Section

General Methods

All commercially available reagents were purchased from Adamas Reagent Co. Ltd. and used without further purification unless otherwise stated. Melting points were determined using a melting point apparatus and are uncorrected. 1H (13C) NMR spectra were recorded at 500 (125) MHz using CDCl3, DMSO-d6, or their combination as the solvent. The chemical shifts (δ) are expressed in parts per million relative to the residual deuterated solvent signal, and coupling constants (J) are given in hertz. Infrared (IR) spectra were recorded on a Fourier transform infrared (FT-IR) spectrometer using KBr pellets. High-resolution mass spectrometry (HRMS) data were obtained in the electron impact (EI) mode at 70 eV. Anhydrous ethanol was used throughout the process of absorption and fluorescence determination. All samples were prepared at room temperature. Dilute hydrochloric acid or sodium hydroxide was used for tuning the pH values. UV–vis absorption spectra were obtained using 1.0 cm quartz cells. An ethanolic solution of compounds 3 (25 μg mL–1) was added to a 10 mL volumetric flask. The ethanolic solution was equilibrated for 2 min before measurement. The excitation slit was set to 5.0 nm. Fluorescent emission spectra were obtained using a xenon lamp and 1.0 cm quartz cells. An ethanolic solution of compounds 3 (25 μg mL–1) was added to a 10 mL volumetric flask. After dilution with different buffer solutions, the mixture was equilibrated for 2 min before measurement. The excitation and emission slits were set to 5.0 nm. The quantum yields of compounds 3 in anhydrous ethanol were determined by comparing the integrated fluorescence spectra of the samples with that of a standard (rhodamine 6G in anhydrous ethanol, 5.0 μg mL–1).

Computational Methods

All calculations were carried out using the Gaussian 03 program.[27] Geometry optimizations were performed with the B3LYP functional[28−30] and the 6-311+G(2d,2p) basis set[31] for the ground states. UV–vis absorptions (vertical excitation) were calculated using the TD-DFT method based on the optimized ground state geometry (GS, S0 state). For fluorescent emissions, the light emission was calculated based on the optimized excited states (ES, S1 state). The default self-consistent reaction field (SCRF) PCM was used with ethanol (dielectric constant ε = 24.852) as the solvent, while universal force field (UFF) radii were chosen as the atomic radii to define the molecular cavity. Vibrational frequencies were calculated for all stationary points to verify that each was a minimum (no imaginary frequencies) on the potential energy surface.

Cyclic Voltammetry

CVs were recorded on a Zahner IM6e electrochemical workstation using a Pt foil as the working electrode, a Pt wire as the counter electrode, and a Ag/AgCl electrode as the reference. Cyclic voltammetry curves run at a scan rate of 50 mV s–1 in anhydrous ethanol with 1.0 × 10–4 M substrate and 0.1 M [NBu4]+[PF6]− as the supporting electrolyte. Fc/Fc+ couple was used as an internal standard.

MTT Assay

Four carcinoma cell lines and one normal cell line, that is, diploid fibroblasts (MRC-5), liver carcinoma cells (HepG2), colorectal cancer cells (HT29), gastric carcinoma cells (SCG7910), and cancerous alveolar epithelial cells (A549) were obtained from the American Type Culture Collection (Manassas, VA). All cells were incubated at 37 °C under 5% CO2 and humidified air. The growth inhibition of human cancer cells by compounds 3 (3ac–3ae and 3fc–3fe) was assessed using the MTT assay, along with dimethyl sulfoxide (DMSO) as a control. Different human cancer cell lines were treated with compounds at various concentrations. After a 96 h incubation, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] was added to the wells (50 mL; 0.4 mg mL–1) and incubated for another 4 h. The medium was aspirated, and DMSO (150 mL) was added to each well. Absorbance was measured at 490 nm using a 2030 Multilabel Reader (Perkin-Elmer Victor X5, US). Compound concentrations causing 50% growth inhibition (IC50) were calculated.

Clonogenic Assay

Exponentially growing HepG2 cells were seeded at a density of 2 × 105 cells per well in 6-well plates and allowed to attach overnight; then, the cells were exposed to different concentrations of 3fd and 3fd′ (0.01, 0.1, 1, 10 μM) for 18 h, whereas control wells received the vehicle alone. Afterward, the vehicle and the compound-treated cells were replated into 6-well plates (700 cells/well) in triplicate. The plates were incubated for 10 days at 37 °C in an atmosphere of 5% CO2. The cells were washed [three times in ice–cold phosphate buffered saline (PBS)], fixed with prechilled methanol (20 min), stained with 0.5% methylene blue for 30 min, washed thoroughly in distilled H2O, and air-dried. Cell colonies containing more than 50 cells were counted. IC50 values of 3fd and 3fd′ were estimated by dividing the mean number of colonies following compound treatment by the mean number of colonies in the absence of the compound.

In Vitro Cell Imaging

The HepG2 cells (1.5 × 105 cells/well) were incubated at 37 °C with different concentrations of 3fd (2, 4, 6, 8, and 10 μM) and treated for 15 h. The medium was removed, and the cells were rinsed with ice-cold PBS before the fixation with fixative (5% paraformaldehyde/sucrose/PBS = 6:1:3) for 10 min at room temperature. After washing, the cells were incubated with DAPI (1 mg mL–1) for 20 min at room temperature in the dark. A drop of antifade solution was added, and the treated portion of the slide was covered with a glass coverslip. The fluorescence of the compound was detected and localized using a confocal microscope (Olympus FV1000) with a 100 oil objective. The optical sections were obtained in the Z axis and stored in the computer with a scanning mode.

Noncommercially Available Compounds

Heterocyclic ketene aminals (HKAs) 1 were prepared according to a procedure described in the literature.[32] The identity of the materials was confirmed using 1H and 13C NMR and by their spectra from mass spectrometry.

General Procedure for the Synthesis of Compounds 3

HKAs (1) (1.0 mmol) and 3-formylchromones (2) (1.0 mmol) were combined and dissolved in acetone (15 mL), followed by the addition of trimethylamine (10 mol%). Subsequently, the reaction mixture was stirred in a round-bottom flask (25 mL) at room temperature for 15 min. After the completion of the reaction as indicated by thin-layer chromatography (TLC), the mixture was filtered and washed with ethanol (3 × 5 mL). The crude solid was then dried and recrystallized from acetone to afford the pure products 3.

General Procedure for the Synthesis of Compounds 3′

One to eight drops of pure acid were dropped into compounds 3 (0.5 mmol). Subsequently, the reaction mixture was stirred in a round-bottom flask (5 mL) for 8–25 seconds (s) (Scheme ). After the completion of the reaction as indicated by TLC, the mixture was filtered and washed in succession with H2O (2 × 5 mL) and EtOH (2 × 5 mL). The residue was then dried to afford the pure products 3′.

Scheme 1

Transformative Synthesis of Compounds 3 and 3′

General Procedure for the Transformative Synthesis of Compounds 3 from 3′

Two to eight drops of basic solution (1.0 M) were dropped into compounds 3′ (0.5 mmol). Subsequently, the reaction mixture was stirred in a round-bottom flask (5 mL) for 10–20 s. After the completion of the reaction as indicated by TLC, the mixture was filtered and washed in succession with H2O (2 × 5 mL) and EtOH (2 × 5 mL). The residue was then dried to afford the pure products 3.

Characterization Data of Compounds 3

5-(4-Methoxybenzoyl)-9-methyl-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido[1,2-a]pyrimidin-7-one (3aa)

Isolated yield 95%; yellow solid, mp 234–235 °C; IR (KBr) (νmax, cm–1): 3429, 1583, 1498, 1415, 1250, 1167, 1082, 608; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.02–2.17 (m, 1H, CH2), 2.31 (s, 3H, ArCH3), 3.38–3.52 (m, 3H, NCH2 and CH2N), 3.84 (s, 3H, OCH3), 3.93–4.00 (m, 1H, NCH2), 6.10 (s, 1H, CH), 6.84 (d, J = 8.3 Hz, 1H, ArH), 6.90 (d, J = 8.5 Hz, 2H, ArH), 7.23–7.28 (m, 1H, ArH), 7.41 (d, J = 8.5 Hz, 2H, ArH), 7.70–7.74 (m, 2H, ArH), 12.02 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 19.9, 20.9, 38.8, 44.9, 55.8, 88.4, 93.3, 107.9, 113.9, 117.8, 124.3, 127.6, 130.4, 132.3, 133.4, 136.2, 137.6, 154.3, 156.4, 161.4, 180.6, 191.9; HRMS (ESI-TOF, [M]+): calcd for C24H22N2O4, 402.1574; found, 402.1576.

5-(4-Methoxybenzoyl)-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido[1,2-a]pyri-midin-7-one (3ab)

Isolated yield 94%; yellow solid, mp 210–213 °C; IR (KBr) (νmax, cm–1): 3436, 1644, 1600, 1498, 1422, 1384, 1341, 1295, 1251, 1169, 1126, 1021, 812, 755; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 1.95–2.05 (m, 2H, CH2), 3.45–3.47 (m, 3H, NCH2 and CH2N), 3.68–3.73 (m, 1H, NCH2), 3.83 (s, 3H, OCH3), 6.32 (s, 1H, CH), 7.00–7.05 (m, 3H, ArH), 7.09–7.12 (m, 1H, ArH), 7.36 (d, J = 7.7 Hz, 2H, ArH), 7.44–7.55 (m, 2H, ArH), 7.74 (d, J = 7.6 Hz, 1H, ArH), 11.63 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 19.3, 36.7, 44.8, 55.7, 88.1, 92.6, 107.0, 113.8, 118.3, 122.5, 124.3, 127.0, 129.9, 133.3, 135.5, 136.4, 155.5, 156.2, 160.7, 179.1, 190.4; HRMS (ESI-TOF, [M]+): calcd for C23H20N2O4, 388.1418; found, 388.1420.

9-Fluoro-5-(4-methoxybenzoyl)-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido-[1,2-a]pyrimidin-7-one (3ac)

Isolated yield 90%; yellow solid, mp 252–254 °C; IR (KBr) (νmax, cm–1): 3419, 1646, 1598, 1494, 1433, 1354, 1306, 1254, 1177, 1125, 1027, 842; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.04–2.10 (m, 2H, CH2), 3.44–3.46 (m, 2H, CH2N), 3.69–3.73 (m, 2H, NCH2), 3.84 (s, 3H, OCH3), 6.32 (s, 1H, CH), 7.00–7.03 (m, 2H, ArH), 7.09–7.11 (m, 1H, ArH), 7.35–7.42 (m, 4H, ArH), 7.46–7.48 (m, 1H, ArH), 11.60 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 19.3, 24.6, 36.9, 44.8, 55.7, 88.3, 93.0, 104.3, 106.2, 112.1, 113.9, 120.4, 122.5 (d, J = 23.8 Hz), 129.9, 133.2, 137.1, 152.4, 155.5, 160.8, 178.0, 190.6; HRMS (ESI-TOF, [M]+): calcd for C23H19FN2O4, 406.1323; found, 406.1329.

9-Chloro-5-(4-methoxybenzoyl)-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido-[1,2-a]pyrimidin-7-one (3ad)

Isolated yield 92%; yellow solid, mp 235–236 °C; IR (KBr) (νmax, cm–1): 3429, 1654, 1601, 1503, 1386, 1340, 1293, 1256, 1229, 1132, 1071, 1020, 758, 701; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.01–2.07 (m, 2H, CH2), 3.50–3.55 (m, 2H, CH2N), 3.67–3.73 (m, 2H, NCH2), 3.88 (s, 3H, OCH3), 6.34 (s, 1H, CH), 7.01 (d, J = 7.2 Hz, 2H, ArH), 7.08 (d, J = 8.1 Hz, 1H, ArH), 7.36 (d, J = 7.0 Hz, 2H, ArH), 7.47 (s, 1H, ArH), 7.55–7.57 (m, 1H, ArH), 7.65 (s, 1H, ArH), 11.59 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 19.2, 38.5, 44.9, 55.7, 88.4, 93.0, 105.9, 113.9, 120.6, 126.0, 126.7, 129.9, 133.2, 134.9, 137.3, 145.5, 154.8, 155.5, 160.8, 177.7, 190.6; HRMS (ESI-TOF, [M]+): calcd for C23H19ClN2O4, 422.1028; found, 422.1030.

9-Bromo-5-(4-methoxybenzoyl)-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido-[1,2-a]pyrimidin-7-one (3ae)

Isolated yield 93%; yellow solid, mp 232–234 °C; IR (KBr) (νmax, cm–1): 3428, 1641, 1595, 1498, 1419, 1354, 1251, 1175, 1132, 604; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.12–2.20 (m, 2H, CH2), 3.49–3.54 (m, 3H, NCH2 and CH2N), 3.84 (s, 3H, OCH3), 3.90–3.94 (m, 1H, NCH2), 6.12 (s, 1H, CH), 6.83 (d, J = 8.7 Hz, 1H, ArH), 6.91 (d, J = 8.6 Hz, 2H, ArH), 7.41 (d, J = 8.6 Hz, 2H, ArH), 7.49–7.51 (m, 1H, ArH), 7.75 (s, 1H, ArH), 7.98–8.03 (m, 1H, ArH), 12.00 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 19.9, 38.8, 45.0, 55.8, 88.8, 93.7, 106.5, 114.0, 115.5, 120.1, 126.2, 130.4, 130.4, 133.1, 137.8, 138.6, 155.1, 156.3, 161.5, 178.9, 192.2; HRMS (ESI-TOF, [M]+): calcd for C23H19BrN2O4, 466.0523; found, 466.0547.

9-Fluoro-5-(4-methylbenzoyl)-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido-[1,2-a]pyrimidin-7-one (3bc)

Isolated yield 86%; yellow solid, mp 247–249 °C; IR (KBr) (νmax, cm–1): 3419, 1650, 1593, 1499, 1429, 1352, 1303, 1256, 1188, 1119, 1061, 837, 759; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.06–2.10 (m, 2H, CH2), 2.26 (s, 3H, ArCH3), 3.52–3.56 (m, 2H, CH2N), 3.69–3.74 (m, 2H, NCH2), 6.32 (s, 1H, CH), 7.09–7.11 (m, 1H, ArH), 7.26–7.30 (m, 4H, ArH), 7.39–7.42 (m, 3H, ArH), 11.59 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 19.2, 21.3, 38.5, 44.8, 88.2, 93.0, 106.4, 112.0 (d, J = 23.8 Hz), 120.4, 122.6 (d, J = 22.5 Hz), 125.2, 128.0, 129.1, 137.0, 138.1, 139.7, 146.7, 152.4, 155.5, 178.1, 191.1; HRMS (ESI-TOF, [M]+): calcd for C23H19FN2O3, 390.1374; found, 390.1388.

9-Chloro-5-(4-methylbenzoyl)-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido-[1,2-a]pyrimidin-7-one (3bd)

Isolated yield 90%; yellow solid, mp 190–192 °C; IR (KBr) (νmax, cm–1): 3429, 1583, 1498, 1415, 1250, 1167, 1082, 608; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.05–2.13 (m, 2H, CH2), 2.38 (s, 3H, ArCH3), 3.55–3.72 (m, 4H, CH2N and NCH2), 6.31 (s, 1H, CH), 7.04 (d, J = 8.6 Hz, 1H, ArH), 7.23–7.28 (m, 4H, ArH), 7.42–7.51 (m, 2H, ArH), 7.64 (s, 1H, ArH), 12.07 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 19.3, 21.3, 38.5, 44.8, 88.4, 93.1, 106.2, 1120.3, 125.4, 126.1, 126.7, 128.0, 129.0, 134.8, 137.2, 138.0, 139.6, 154.7, 155.5, 177.8, 191.2; HRMS (ESI-TOF, [M]+): calcd for C23H19ClN2O3, 406.1079; found, 406.1078.

9-Bromo-5-(4-methylbenzoyl)-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido-[1,2-a]pyrimidin-7-one (3be)

Isolated yield 93%; yellow solid, mp 244–246 °C; IR (KBr) (νmax, cm–1): 3426, 1647, 1588, 1497, 1255, 1183, 1138, 1057, 756, 640; 1H NMR (500 MHz, DMSO-d6 + CDCl3) (δ, ppm): 2.04–2.10 (m, 2H, CH2), 2.38 (s, 3H, ArCH3), 3.52–3.56 (m, 2H, CH2N), 3.69–3.73 (m, 2H, NCH2), 6.35 (s, 1H, CH), 7.04 (d, J = 8.6 Hz, 1H, ArH), 7.26–7.29 (m, 4H, ArH), 7.40 (s, 1H, ArH), 7.69 (d, J = 8.5 Hz, 1H, ArH), 7.77 (s, 1H, ArH), 11.58 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + CDCl3) (δ, ppm): 19.2, 21.3, 38.2, 44.9, 88.4, 93.1, 106.1, 114.3, 121.0, 125.9, 128.0, 129.1, 137.2, 137.8, 138.1, 139.7, 155.2, 155.4, 177.7, 191.2; HRMS (ESI-TOF, [M]+): calcd for C23H19BrN2O3, 450.0574; found, 450.0576.

5-Benzoyl-9-methyl-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido[1,2-a]pyrimi-din-7-one (3ca)

Isolated yield 93%; yellow solid, mp 209–211 °C; IR (KBr) (νmax, cm–1): 3426, 1653, 1580, 1500, 1426, 1340, 1268, 1224, 1161, 1068, 626; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.03–2.14 (m, 1H, CH2), 2.29 (s, 3H, ArCH3), 3.38–3.50 (m, 3H, NCH2 and CH2N), 3.89–3.95 (m, 1H, NCH2), 6.06 (s, 1H, CH), 6.81–6.85 (m, 1H, ArH), 7.22–7.26 (m, 1H, ArH), 7.38–7.41 (m, 5H, ArH), 7.63 (s, 1H, ArH), 7.68 (s, 1H, ArH), 11.99 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 19.9, 21.0, 38.7, 44.8, 88.3, 93.4, 108.3, 117.8, 124.3, 127.6, 128.3, 128.6, 130.1, 132.3, 136.3, 137.3, 140.9, 154.4, 156.3, 180.6, 192.3; HRMS (ESI-TOF, [M]+): calcd for C23H20N2O3, 372.1468; found, 372.1479.

5-Benzoyl-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido[1,2-a]pyrimidin-7-one (3cb)

Isolated yield 89%; yellow solid, mp 212–215 °C; IR (KBr) (νmax, cm–1): 3429, 1654, 1601, 1503, 1340, 1293, 1256, 1132, 1071, 1020, 758; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.03–2.16 (m, 2H, CH2), 3.41–3.53 (m, 3H, NCH2 and CH2N), 3.94–3.97 (m, H, NCH2), 6.12 (s, 1H, CH), 6.93 (d, J = 8.2 Hz, 1H, ArH), 7.03–7.08 (m, 1H, ArH), 7.39–7.48 (m, 6H, ArH), 7.65 (s, 1H, ArH), 7.90 (d, J = 7.8 Hz, 1H, ArH), 11.99 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 19.9, 38.8, 44.9, 88.4, 93.4, 108.1, 118.1, 122.8, 124.6, 127.8, 128.3, 128.7, 130.1, 135.4, 137.4, 140.8, 156.3, 156.4, 180.4, 192.4; HRMS (ESI-TOF, [M]+): calcd for C22H18N2O3, 358.1312; found, 358.1320.

5-Benzoyl-9-fluoro-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido[1,2-a]pyrimi-din-7-one (3cc)

Isolated yield 85%; yellow solid, mp 220–224 °C; IR (KBr) (νmax, cm–1): 3440, 1652, 1588, 1501, 1433, 1352, 1311, 1255, 1192, 1119, 1061, 1021, 751, 620; 1H NMR (500 MHz, DMSO-d6) (δ, ppm): 2.00–2.08 (m, 2H, CH2), 3.50–3.85 (m, 4H, NCH2 and CH2N), 6.31 (s, 1H, CH), 7.08–7.11 (m, 1H, ArH), 7.36–7.44 (m, 5H, ArH), 7.46–7.51 (m, 3H, ArH), 11.57 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6) (δ, ppm): 19.2, 38.5, 44.8, 88.1, 93.0, 107.0, 106.6, 111.9 (d, J = 23.8 Hz), 120.4, 122.6 (d, J = 23.8 Hz), 125.1, 127.8, 128.6, 129.9, 136.9, 140.9, 152.5, 155.4, 156.6, 158.5, 178.1, 191.5; HRMS (ESI-TOF, [M]+): calcd for C22H17FN2O3, 376.1218; found, 376.1225.

5-Benzoyl-9-chloro-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido[1,2-a]pyrimi-din-7-one (3cd)

Isolated yield 87%; orange solid, mp 203–206 °C; IR (KBr) (νmax, cm–1): 3427, 1652, 1598, 1498, 1429, 1352, 1254, 1184, 1137, 1076, 625; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.12–2.26 (m, 2H, CH2), 3.51–3.62 (m, 2H, NCH2 and CH2N), 3.98–4.02 (m, 1H, NCH2), 6.18 (s, 1H, CH), 6.96 (d, J = 8.7 Hz, 1H, ArH), 7.35–7.51 (m, 5H, ArH), 7.74 (s, 1H, ArH), 7.91–7.94 (m, 1H, ArH), 12.07 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 19.4, 38.3, 44.4, 88.2, 93.2, 106.6, 119.3, 125.1, 126.7, 127.7, 127.8, 128.2, 129.8, 134.5, 137.7, 140.2, 154.2, 155.8, 178.5, 192.2; HRMS (ESI-TOF, [M]+): calcd for C22H17ClN2O3, 392.0922; found, 392.0909.

5-Benzoyl-9-bromo-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido[1,2-a]pyrimi-din-7-one (3ce)

Isolated yield 90%; orange solid, mp 207–209 °C; IR (KBr) (νmax, cm–1): 3431, 1652, 1594, 1501, 1425, 1345, 1253, 1184, 1133, 1070, 620; 1H NMR (500 MHz, DMSO-d6 + CDCl3) (δ, ppm): 2.13–2.19 (m, 2H, CH2), 3.51–3.57 (m, 3H, NCH2 and CH2N), 3.95–3.96 (m, 1H, NCH2), 6.14 (s, 1H, CH), 6.85 (d, J = 8.6 Hz, 1H, ArH), 7.39–7.43 (m, 5H, ArH), 7.50–7.53 (m, 1H, ArH), 7.63 (s, 1H, ArH), 7.95 (s, 1H, ArH), 11.95 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + CDCl3) (δ, ppm): 19.7, 38.7, 44.9, 88.5, 93.6, 106.8, 115.2, 120.2, 125.9, 128.2, 128.2, 128.6, 130.1, 137.7, 138.1, 140.6, 155.1, 156.1, 178.8, 192.4; HRMS (ESI-TOF, [M]+): calcd for C22H17BrN2O3, 436.0417; found, 436.0415.

9-Fluoro-5-(4-fluorobenzoyl)-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido[1,2-a]pyrimidin-7-one (3dc)

Isolated yield 85%; yellow solid, mp 236–239 °C; IR (KBr) (νmax, cm–1): 3423, 1652, 1600, 1498, 1436, 1352, 1311, 1256, 1155, 1119, 845, 600; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.00–2.08 (m, 2H, CH2), 3.52–3.60 (m, 3H, NCH2 and CH2N), 3.79–3.83 (m, 1H, NCH2), 6.31 (s, 1H, CH), 7.08–7.10 (m, 1H, ArH), 7.28–7.33 (m, 4H, ArH), 7.39–7.46 (m, 4H, ArH), 11.52 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 19.1, 38.5, 44.8, 88.1, 92.9, 106.8, 112.0 (d, J = 22.5 Hz), 115.5 (d, J = 21.3 Hz), 120.4, 122.7 (d, J = 23.8 Hz), 125.1, 130.4, 136.6, 137.3, 152.2, 155.3, 157.6 (d, J = 240.0 Hz), 163.0 (d, J = 247.5 Hz), 178.2, 189.7; HRMS (ESI-TOF, [M]+): calcd for C22H16F2N2O3, 394.1124; found, 394.1122.

9-Chloro-5-(4-fluorobenzoyl)-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido[1,2-a]pyrimidin-7-one (3dd)

Isolated yield 86%; yellow solid, mp 224–226.5 °C; IR (KBr) (νmax, cm–1): 3428, 1649, 1600, 1497, 1426, 1348, 1255, 1136, 597; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.04–2.21 (m, 1H, CH2), 3.46–3.58 (m, 3H, NCH2 and CH2N), 3.94–3.98 (m, 1H, NCH2), 6.12 (s, 1H, CH), 6.89–6.91 (m, 1H, ArH), 7.06–7.12 (m, 2H, ArH), 7.35–7.39 (s, 1H, ArH), 7.41–7.44 (m, 2H, ArH), 7.63 (s, 1H, ArH), 7.84–7.88 (m, 1H, ArH), 11.94 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 19.9, 38.2, 45.0, 88.6, 93.6, 107.2, 115.7 (d, J = 21.3 Hz), 119.7, 125.6, 127.3, 128.3, 130.6, 135.1, 136.8, 137.9, 154.7, 156.3, 164.0 (d, J = 248.8 Hz), 179.1, 191.3; HRMS (ESI-TOF, [M]+): calcd for C22H16ClFN2O3, 410.0828; found, 410.0827.

9-Bromo-5-(4-fluorobenzoyl)-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido[1,2-a]pyrimidin-7-one (3de)

Isolated yield 86%; yellow solid, mp 220–222 °C; IR (KBr) (νmax, cm–1): 3427, 1647, 1584, 1498, 1419, 1351, 1255, 1135, 646; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.05–2.23 (m, 2H, CH2), 3.51–3.59 (m, 3H, NCH2 and CH2N), 3.95–3.99 (m, 1H, NCH2), 6.13 (s, 1H, CH), 6.84 (d, J = 8.7 Hz, 1H, ArH), 7.08–7.13 (m, 2H, ArH), 7.42–7.46 (m, 2H, ArH), 7.51–7.54 (m, 1H, ArH), 7.64 (s, 1H, ArH), 8.01 (s, 1H, ArH), 11.96 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 19.9, 38.8, 45.0, 88.6, 93.6, 107.2, 115.8 (d, J = 21.3 Hz), 116.1, 120.1, 126.0, 130.4, 130.5, 130.6, 136.8, 137.9, 155.2, 156.3, 164.0 (d, J = 248.8 Hz), 179.0, 191.3; HRMS (ESI-TOF, [M]+): calcd for C22H16BrFN2O3, 454.0323; found, 454.0328.

5-(4-Chlorobenzoyl)-9-fluoro-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido[1,2-a]pyrimidin-7-one (3ec)

Isolated yield 84%; yellow solid, mp 251–254 °C; IR (KBr) (νmax, cm–1): 3423, 1650, 1589, 1500, 1435, 1356, 1307, 1256, 1188, 1123, 1090, 841, 767; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.07–2.11 (m, 2H, CH2), 3.38–3.56 (m, 4H, NCH2 and CH2N), 6.32 (s, 1H, CH), 7.10–7.13 (m, 1H, ArH), 7.30 (s, 1H, ArH), 7.39–7.44 (m, 4H, ArH), 7.52–7.55 (m, 2H, ArH), 11.49 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 19.2, 38.5, 44.8, 88.1, 92.9, 107.0, 112.1, 120.4, 122.8, 125.0, 128.7, 129.8, 134.6, 136.4, 139.6, 151.5, 152.5, 155.4, 178.0, 189.5; HRMS (ESI-TOF, [M]+): calcd for C22H16ClFN2O3, 410.0828; found, 410.0848.

9-Chloro-5-(4-chlorobenzoyl)-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido[1,2-a]pyrimidin-7-one (3ed)

Isolated yield 85%; yellow solid, mp 237–240 °C; IR (KBr) (νmax, cm–1): 3427, 1648, 1588, 1497, 1423, 1353, 1254, 1182, 1136, 1091, 632; 1H NMR (500 MHz, DMSO-d6) (δ, ppm): 2.02–2.06 (m, 2H, CH2), 3.50–3.54 (m, 2H, CH2N), 3.67–3.71 (m, 2H, NCH2), 6.32 (s, 1H, CH), 7.08 (d, J = 8.5 Hz, 1H, ArH), 7.26–7.30 (m, 1H, ArH), 7.39 (d, J = 7.5 Hz, 2H, ArH), 7.51–7.58 (m, 3H, ArH), 7.63 (s, 1H, ArH), 11.47 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6) (δ, ppm): 19.1, 38.6, 44.9, 88.2, 93.0, 106.8, 120.7, 125.3, 126.0, 126.7, 128.7, 129.8, 134.7, 135.1, 136.6, 139.6, 154.9, 155.3, 177.9, 189.6; HRMS (ESI-TOF, [M]+): calcd for C22H16Cl2N2O3, 426.0532; found, 426.0540.

9-Bromo-5-(4-chlorobenzoyl)-2,3,4,12a-tetrahydro-1H,7H-chromeno[3′,2′:5,6]pyrido[1,2-a]pyrimidin-7-one (3ee)

Isolated yield 88%; yellow solid, mp 236–239 °C; IR (KBr) (νmax, cm–1): 3427, 2499, 1416, 1249, 1085, 754, 634; 1H NMR (500 MHz, DMSO-d6 + CDCl3 + HClO4) (δ, ppm): 2.03–2.10 (m, 2H, CH2), 3.52–3.56 (m, 2H, CH2N), 3.69–3.73 (m, 2H, NCH2), 6.33 (s, 1H, CH), 7.03 (d, J = 8.5 Hz, 1H, ArH), 7.31 (s, 1H, ArH), 7.40 (d, J = 7.5 Hz, 2H, ArH), 7.53 (d, J = 7.5 Hz, 2H, ArH), 7.68 (d, J = 8.2 Hz, 1H, ArH), 7.78 (s, 1H, ArH), 11.49 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + CDCl3 + HClO4) (δ, ppm): 19.2, 38.6, 44.9, 88.2, 93.0, 106.7, 114.4, 121.0, 125.8, 128.7, 129.1, 129.8, 134.7, 136.5, 137.9, 139.6, 155.3, 177.8, 189.6; HRMS (ESI-TOF, [M]+): calcd for C22H16BrClN2O3, 470.0027; found, 470.0031.

6-(4-Methoxybenzoyl)-10-methyl-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido-[1,2-a][1,3]diazepin-8-one (3fa)

Isolated yield 96%; yellow solid, mp 202–204 °C; IR (KBr) (νmax, cm–1): 3429, 2927, 1657, 1570, 1498, 1425, 1347, 1242, 1167, 1029, 824, 604; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.00–2.06 (m, 3H, CH2), 2.15–2.25 (m, 1H, CH2), 2.31 (s, 3H, ArCH3), 3.59–3.62 (m, 2H, CH2N), 3.72–3.75 (m, 1H, NCH2), 3.83 (s, 3H, OCH3), 4.10–4.15 (m, 1H, NCH2), 6.13 (s, 1H, CH), 6.83–6.85 (m, 1H, ArH), 6.89–6.91 (m, 2H, ArH), 7.24–7.28 (m, 1H, ArH), 7.41 (d, J = 8.3 Hz, 2H, ArH), 7.69 (s, 1H, ArH), 7.69 (s, 1H, ArH), 12.03 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 21.0, 25.8, 26.7, 44.4, 54.0, 55.8, 91.3, 95.8, 109.2, 114.0, 118.0, 124.3, 127.6, 130.4, 132.1, 133.4, 136.3, 137.2, 154.5, 161.4, 162.8, 180.3, 192.0; HRMS (ESI-TOF, [M]+): calcd for C25H24N2O4, 416.1731; found, 416.1740.

6-(4-Methoxybenzoyl)-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido[1,2-a][1,3]-diazepin-8-one (3fb)

Isolated yield 93%; orange solid, mp 197–199 °C; IR (KBr) (νmax, cm–1): 3429, 2932, 1655, 1571, 1497, 1333, 1286, 1237, 1171, 1117, 1027, 834; 1H NMR (500 MHz, DMSO-d6 + CDCl3) (δ, ppm): 1.98–2.09 (m, 4H, CH2CH2), 3.67–3.75 (m, 3H, NCH2 and CH2N), 3.82 (s, 3H, OCH3), 4.18–4.22 (m, 1H, NCH2), 6.35 (s, 1H, CH), 6.98–7.01 (m, 3H, ArH), 7.05–7.08 (m, 1H, ArH), 7.35 (d, J = 8.2 Hz, 2H, ArH), 7.41 (s, 1H, CH), 7.50–7.53 (m, 1H, ArH), 7.73 (d, J = 8.2 Hz, 1H, ArH), 11.86 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + CDCl3): δ = 25.4, 26.0, 43.7, 53.2, 55.6, 90.6, 94.8, 108.4, 113.7, 118.4, 122.2, 124.2, 127.0, 129.9, 133.2, 135.4, 135.9, 156.3, 160.8, 161.7, 178.9, 190.4; HRMS (ESI-TOF, [M]+): calcd for C24H22N2O4, 402.1574; found, 402.1582.

10-Fluoro-6-(4-methoxybenzoyl)-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido-[1,2-a][1,3]diazepin-8-one (3fc)

Isolated yield 90%; yellow solid, mp 208–210 °C; IR (KBr) (νmax, cm–1): 3419, 1648, 1570, 1488, 1429, 1343, 1311, 1253, 1175, 1111, 1025, 833; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 1.98–2.08 (m, 4H, CH2CH2), 3.69–3.81 (m, 3H, NCH2 and CH2N), 3.82 (s, 3H, OCH3), 4.10–4.20 (m, 1H, NCH2), 6.38 (s, 1H, CH), 7.01 (d, J = 8.1 Hz, 2H, ArH), 7.09 (d, J = 5.7 Hz, 1H, ArH), 7.34–7.42 (m, 5H, ArH), 11.80 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 25.3, 25.9, 43.7, 53.1, 55.6, 90.7, 95.1, 107.6, 112.0, 112.8, 113.9, 120.6, 122.6, 125.1, 130.0, 133.1, 136.6, 152.6, 157.4 (d, J = 237.5 Hz), 160.8, 161.5, 177.9, 190.6; HRMS (ESI-TOF, [M]+): calcd for C24H21FN2O4, 420.1480; found, 420.1483.

10-Chloro-6-(4-methoxybenzoyl)-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido-[1,2-a][1,3]diazepin-8-one (3fd)

Isolated yield 91%; yellow solid, mp 189–191 °C; IR (KBr) (νmax, cm–1): 3429, 1649, 1571, 1495, 1423, 1341, 1253, 1174, 1128, 1029, 832; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.03–2.20 (m, 4H, CH2CH2), 3.61–3.72 (m, 3H, NCH2 and CH2N), 3.83 (s, 2H, OCH3), 4.12–4.16 (m, 1H, NCH2), 6.15 (s, 1H, CH), 6.87–6.91 (m, 3H, ArH), 7.36–7.41 (m, 3H, ArH), 7.71 (s, 1H, ArH), 7.85 (m, 1H, ArH), 12.02 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 25.7, 26.6, 44.5, 54.1, 55.8, 91.6, 96.1, 107.9, 114.0, 119.9, 125.6, 127.3, 128.0, 130.4, 133.1, 135.0, 138.2, 154.8, 161.6, 162.6, 178.8, 192.2; HRMS (ESI-TOF, [M]+): calcd for C24H21ClN2O4, 436.1184; found, 436.1190.

10-Bromo-6-(4-methoxybenzoyl)-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido-[1,2-a][1,3]diazepin-8-one (3fe)

Isolated yield 93%; yellow solid, mp 180–181 °C; IR (KBr) (νmax, cm–1): 3427, 1652, 1569, 1496, 1423, 1347, 1254, 1173, 1128, 1028, 824, 601; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.06–2.26 (m, 4H, CH2CH2), 3.59–3.79 (m, 3H, NCH2 and CH2N), 3.84 (s, 3H, OCH3), 4.10–4.14 (m, 1H, NCH2), 6.17 (s, 1H, CH), 6.83 (d, J = 8.6 Hz, 1H, ArH), 6.91 (d, J = 8.1 Hz, 2H, ArH), 7.41 (d, J = 8.1 Hz, 2H, ArH), 7.50–7.52 (m, 1H, ArH), 7.72 (s, 1H, ArH), 8.00 (s, 1H, ArH), 12.03 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 25.8, 26.6, 44.5, 54.2, 55.8, 91.7, 96.1, 107.9, 114.0, 115.3, 120.3, 126.1, 130.4, 130.4, 133.1, 137.8, 138.2, 155.3, 161.6, 162.6, 178.7, 192.3; HRMS (ESI-TOF, [M]+): calcd for C24H21BrN2O4, 480.0679; found, 480.0714.

10-Fluoro-6-(4-methylbenzoyl)-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido-[1,2-a][1,3]diazepin-8-one (3gc)

Isolated yield 89%; yellow solid, mp 218–222 °C; IR (KBr) (νmax, cm–1): 3423, 1654, 1568, 1489, 1434, 1380, 1325, 1256, 1215, 1119, 1033, 1000, 929, 730; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 1.03–2.10 (m, 4H, CH2CH2), 2.37 (s, 3H, ArCH3), 3.69–3.76 (m, 3H, NCH2 and CH2N), 4.10–4.27 (m, 1H, NCH2), 6.37 (s, 1H, CH), 7.08–7.11 (m, 1H, ArH), 7.27–7.42 (m, 7H, ArH), 11.80 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 21.3, 25.3, 25.9, 43.7, 53.1, 90.6, 95.1, 107.8, 111.9 (d, J = 22.5 Hz), 120.6, 122.6, 125.0, 128.0, 129.1, 136.5, 138.0, 139.8, 152.6, 157.4 (d, J = 240.0 Hz), 161.4, 178.0, 191.2; HRMS (ESI-TOF, [M]+): calcd for C24H21FN2O3, 404.1531; found, 404.1539.

10-Chloro-6-(4-methylbenzoyl)-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido-[1,2-a][1,3]diazepin-8-one (3gd)

Isolated yield 90%; yellow solid, mp 219–221 °C; IR (KBr) (νmax, cm–1): 3428, 1648, 1570, 1489, 1420, 1335, 1250, 1220, 1125, 771; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.00–2.25 (m, 4H, CH2CH2), 2.38 (s, 3H, ArCH3), 3.58–3.71 (m, 3H, NCH2CH2N), 4.12–4.16 (m, 1H, NCH2), 6.13 (s, 1H, CH), 6.87 (d, J = 8.6 Hz, 1H, ArH), 7.19 (d, J = 7.2 Hz, 2H, ArH), 7.31–7.32 (m, 2H, ArH), 7.35–7.36 (m, 1H, ArH), 7.66 (s, 1H, ArH), 7.84 (s, 1H, ArH), 12.04 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 21.3, 25.2, 26.1, 43.9, 53.6, 91.1, 95.6, 107.6, 119.4, 125.1, 126.8, 127.7, 128.0, 128.8, 134.5, 137.4, 137.6, 140.0, 154.4, 162.0, 178.3, 192.4; HRMS (ESI-TOF, [M]+): calcd for C24H21ClN2O3, 420.1235; found, 420.1253.

10-Bromo-6-(4-methylbenzoyl)-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido-[1,2-a][1,3]diazepin-8-one (3ge)

Isolated yield 92%; orange solid, mp 236–237 °C; IR (KBr) (νmax, cm–1): 3427, 1641, 1572, 1489, 1417, 1337, 1221, 1126, 647; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.00–2.34 (m, 4H, CH2CH2), 2.38 (s, 3H, ArCH3), 3.59–3.74 (m, 3H, NCH2 and CH2N), 4.13–4.17 (m, 1H7CH2), 6.14 (s, 1H, CH), 6.74–6.76 (m, 1H, ArH), 7.15–7.20 (m, 2H, ArH), 7.27–7.32 (m, 2H, ArH), 7.49–7.51 (m, 1H, ArH), 7.61 (s, 1H, ArH), 7.99 (s, 1H, ArH), 12.04 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 21.8, 25.7, 26.6, 44.5, 54.1, 91.6, 96.2, 108.0, 115.3, 120.3, 126.0, 128.5, 129.0, 129.1, 130.4, 137.9, 138.1, 140.6, 155.3, 162.6, 178.7, 192.9; HRMS (ESI-TOF, [M]+): calcd for C24H21BrN2O3, 464.0730; found, 464.0735.

6-Benzoyl-10-methyl-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido[1,2-a][1,3]-diazepin-8-one (3ha)

Isolated yield 92%; yellow solid, mp 227–230 °C; IR (KBr) (νmax, cm–1): 3428, 1653, 1567, 1497, 1423, 1341, 1273, 1215, 1161, 625; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.00–2.06 (m, 2H, CH2), 2.20–2.24 (m, 2H, CH2), 2.31 (s, 1H, ArCH3), 3.58–3.60 (m, 2H, CH2N), 3.74–3.76 (m, 1H, NCH2), 4.12–4.17 (m, 1H, NCH2), 6.09–6.13 (m, 1H, ArH), 6.82–6.85 (m, 1H, ArH), 7.24–7.26 (m, 1H, ArH), 7.38 (m, 5H, ArH), 7.58–7.62 (m, 1H, ArH), 7.68–7.69 (m, 1H, ArH), 12.05 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 20.5, 25.3, 26.1, 43.9, 53.5, 90.7, 95.3, 109.1, 117.5, 123.7, 127.1, 127.8, 128.2, 129.7, 131.6, 135.9, 136.4, 140.4, 154.0, 162.1, 179.9, 192.0; HRMS (ESI-TOF, [M]+): calcd for C24H22N2O3, 386.1625; found, 386.1628.

6-Benzoyl-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido[1,2-a][1,3]diazepin-8-one (3hb)

Isolated yield 91%; orange solid, mp 172–174 °C; IR (KBr) (νmax, cm–1): 3427, 1576, 1499, 1417, 1333, 1280, 1224, 1119, 752; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.01–2.04 (m, 2H, CH2), 2.18–2.31 (m, 2H, CH2), 3.56–3.59 (m, 2H, NCH2), 3.70–3.74 (m, 1H, NCH2), 4.11–4.15 (m, 1H, NCH2), 6.13 (s, 1H, CH), 6.93 (d, J = 8.2 Hz, 1H, ArH), 7.02–7.05 (m, 1H, ArH), 7.36–7.39 (m, 6H, ArH), 7.61 (s, 1H, CH), 7.89 (d, J = 7.7 Hz, 1H, ArH), 12.02 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 25.8, 26.6, 44.4, 53.9, 91.3, 95.8, 109.3, 118.2, 122.6, 124.5, 127.9, 128.3, 128.7, 130.2, 135.4, 137.0, 140.9, 156.6, 162.6, 180.2, 192.5; HRMS (ESI-TOF, [M]+): calcd for C23H20N2O3, 372.1468; found, 372.1477.

6-Benzoyl-10-fluoro-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido[1,2-a][1,3]-diazepin-8-one (3hc)

Isolated yield 87%; yellow solid, mp 169–172 °C; IR (KBr) (νmax, cm–1): 3427, 1655, 1569, 1494, 1435, 1382, 1337, 1257, 1219, 1119, 1033, 783, 622; 1H NMR (500 MHz, DMSO-d6) (δ, ppm): 1.98–2.03 (m, 4H, CH2CH2), 3.69–3.81 (m, 3H, NCH2 and CH2N), 4.24–4.27 (m, 1H, NCH2), 6.38 (s, 1H, CH), 7.09–7.11 (m, 1H, ArH), 7.32 (s, 1H, ArH), 7.37–7.51 (m, 7H, ArH), 11.79 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6) (δ, ppm): 25.3, 25.9, 43.7, 53.1, 90.6, 95.1, 108.0, 112.0 (d, J = 22.5 Hz), 120.6, 122.7 (d, J = 23.8 Hz), 124.9, 127.8, 128.4, 128.6, 136.4, 140.9, 152.7, 157.4 (d, J = 238.8 Hz), 161.4, 178.0, 191.1; HRMS (ESI-TOF, [M]+): calcd for C23H19FN2O3, 390.1374; found, 390.1378.

6-Benzoyl-10-chloro-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido[1,2-a][1,3]-diazepin-8-one (3hd)

Isolated yield 87%; orange solid, mp 205–209 °C; IR (KBr) (νmax, cm–1): 3427, 1654, 1565, 1497, 1428, 1340, 1253, 1220, 1128, 623; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.00–2.05 (m, 2H, CH2), 2.21–2.28 (m, 2H, CH2), 3.56–3.60 (m, 2H, CH2N), 3.72–3.76 (m, 1H, NCH2), 4.13–4.16 (m, 1H, NCH2), 6.12 (s, 1H, CH), 6.87 (d, J = 8.7 Hz, 1H, ArH), 7.35–7.40 (m, 6H, ArH), 7.62 (s, 1H, ArH), 7.82–7.83 (m, 1H, ArH), 12.02 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 25.7, 26.6, 44.4, 54.1, 91.5, 96.1, 108.3, 119.9, 125.5, 127.2, 128.0, 128.3, 128.7, 130.3, 135.1, 137.9, 140.7, 154.9, 162.5, 178.9, 192.7; HRMS (ESI-TOF, [M]+): calcd for C23H19ClN2O3, 406.1079; found, 406.1090.

6-Benzoyl-10-bromo-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido[1,2-a][1,3]-diazepin-8-one (3he)

Isolated yield 90%; tangerine solid, mp 236–238 °C; IR (KBr) (νmax, cm–1): 3427, 1653, 1563, 1496, 1428, 1340, 1254, 1220, 1128, 619; 1H NMR (500 MHz, CDCl3) (δ, ppm): 1.89–2.21 (m, 4H, CH2CH2), 3.60–3.74 (m, 3H, NCH2 and CH2N), 4.13–4.18 (m, 1H, NCH2), 6.13 (s, 1H, CH), 6.81–6.83 (m, 1H, ArH), 7.38–7.42 (m, 5H, ArH), 7.49–7.50 (m, 1H, ArH), 7.62 (s, 1H, ArH), 7.97–7.99 (m, 1H, ArH), 12.04 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 25.7, 26.6, 44.5, 54.1, 91.6, 96.1, 108.3, 115.3, 120.3, 126.0, 128.3, 128.7, 129.0, 130.3, 137.9, 137.9, 140.7, 155.4, 162.5, 178.7, 192.8; HRMS (ESI-TOF, [M]+): calcd for C23H19BrN2O3, 450.0574; found, 450.0579.

6-(4-Fluorobenzoyl)-10-methyl-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido-[1,2-a][1,3]diazepin-8-one (3ia)

Isolated yield 89%; yellow solid, mp 243–246 °C; IR (KBr) (νmax, cm–1): 3426, 1654, 1564, 1497, 1428, 1341, 1272, 1215, 1157, 826, 639; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.06–2.09 (m, 2H, CH2), 2.16–2.27 (m, 2H, CH2), 2.31 (s, 3H, ArCH3), 3.58–3.65 (m, 2H, CH2N), 3.75–3.79 (m, 1H, NCH2), 4.16–4.21 (m, 1H, NCH2), 6.12 (s, 1H, CH), 6.84 (d, J = 8.3 Hz, 1H, ArH), 7.06–7.09 (m, 2H, ArH), 7.25–7.27 (m, 1H, ArH), 7.41–7.44 (m, 2H, ArH), 7.57 (s, 1H, ArH), 7.69 (s, 1H, ArH), 11.99 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 20.9, 25.8, 26.6, 44.4, 54.0, 91.1, 95.7, 109.8, 115.7 (d, J = 21.3 Hz), 118.0, 124.1, 127.6, 130.6 (d, J = 7.5 Hz), 132.2, 136.5, 137.0, 154.5, 162.6, 163.0, 165.0, 180.4, 191.1; HRMS (ESI-TOF, [M]+): calcd for C24H21FN2O3, 404.1531; found, 404.1543.

6-(4-Fluorobenzoyl)-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido[1,2-a][1,3]-diazepin-8-one (3ib)

Isolated yield 88%; yellow solid, mp 204–207 °C; IR (KBr) (νmax, cm–1): 3427, 1652, 1574, 1502, 1325, 1278, 1228, 1123, 887, 754; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.04–2.35 (m, 4H, CH2CH2), 3.58–3.65 (m, 2H, CH2N), 3.74–3.79 (m, 1H, NCH2), 4.16–4.20 (m, 1H, NCH2), 6.16 (s, 1H, CH), 6.94 (d, J = 8.2 Hz, 1H, ArH), 7.04–7.09 (m, 3H, ArH), 7.41–7.47 (m, 3H, ArH), 7.55 (s, 1H, CH), 7.90 (d, J = 7.8 Hz, 1H, ArH), 11.99 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 25.8, 26.6, 44.4, 54.0, 91.2, 95.7, 109.5, 115.7 (d, J = 21.3 Hz), 118.2, 122.7, 124.5, 127.9, 130.5 (d, J = 6.3 Hz), 135.5, 136.7, 137.0, 156.6, 162.6, 164.0 (d, J = 6.3 Hz), 180.2, 191.1; HRMS (ESI-TOF, [M]+): calcd for C23H19FN2O3, 390.1374; found, 390.1381.

10-Fluoro-6-(4-fluorobenzoyl)-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido-[1,2-a][1,3]diazepin-8-one (3ic)

Isolated yield 84%; yellow solid, mp 187–189 °C; IR (KBr) (νmax, cm–1): 3426, 1652, 1569, 1499, 1436, 1387, 1341, 1255, 1222, 1153, 1111, 831; 1H NMR (500 MHz, DMSO-d6) (δ, ppm): 2.02–2.07 (m, 4H, CH2CH2), 3.68–3.80 (m, 3H, NCH2 and CH2N), 4.22–4.27 (m, 1H, NCH2), 6.38 (s, 1H, CH), 7.08–7.12 (m, 1H, ArH), 7.28–7.46 (m, 7H, CH and ArH), 11.74 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6) (δ, ppm): 25.3, 25.9, 43.7, 53.1, 90.5, 95.1, 108.2, 111.9 (d, J = 22.5 Hz), 115.5 (d, J = 21.3 Hz), 120.6, 122.8 (d, J = 22.5 Hz), 125.0, 130.4, 136.1, 137.3, 152.7, 157.5 (d, J = 238.8 Hz), 161.4, 163.0 (d, J = 246.3 Hz), 178.1, 189.8; HRMS (ESI-TOF, [M]+): calcd for C23H18F2N2O3, 408.1280; found, 408.1280.

10-Chloro-6-(4-fluorobenzoyl)-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido-[1,2-a][1,3]diazepin-8-one (3id)

Isolated yield 84%; yellow solid, mp 232–234 °C; IR (KBr) (νmax, cm–1): 3427, 1652, 1563, 1498, 1428, 1341, 1254, 1220, 1095, 1045, 596; 1H NMR (500 MHz, CDCl3) (δ, ppm): 1.86–1.93 (m, 2H, CH2), 2.15–2.31 (m, 2H, CH2), 3.60–3.65 (m, 2H, CH2N), 3.75–3.79 (m, 1H, NCH2), 4.17–4.20 (m, 1H, NCH2), 6.15 (s, 1H, CH), 6.95–6.98 (m, 1H, ArH), 7.07–7.10 (m, 2H, ArH), 7.36–7.44 (m, 3H, ArH), 7.59 (s, 1H, ArH), 7.84 (s, 1H, ArH), 11.98 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 25.7, 26.6, 44.5, 54.1, 91.5, 95.9, 108.5, 115.7 (d, J = 21.3 Hz), 119.9, 125.5, 127.3, 128.1, 130.6 (d, J = 6.3 Hz), 135.2, 136.8, 137.5, 154.9, 162.5, 164.0 (d, J = 248.8 Hz), 178.8, 191.3; HRMS (ESI-TOF, [M]+): calcd for C23H18ClFN2O3, 424.0984; found, 424.0999.

10-Bromo-6-(4-fluorobenzoyl)-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido-[1,2-a][1,3]diazepin-8-one (3ie)

Isolated yield 87%; yellow solid, mp 239–242 °C; IR (KBr) (νmax, cm–1): 3427, 1567, 1498, 1419, 1341, 1254, 1220, 1125, 647; 1H NMR (500 MHz, DMSO-d6 + CDCl3) (δ, ppm): 2.06–2.12 (m, 4H, CH2CH2), 3.60–3.80 (m, 4H, NCH2 and CH2N), 6.20 (s, 1H, CH), 6.85–6.87 (m, 1H, ArH), 7.05–7.09 (m, 2H, ArH), 7.37–7.41 (m, 2H, ArH), 7.49–7.51 (m, 1H, ArH), 7.75 (s, 1H, ArH), 7.81 (s, 1H, ArH), 11.83 (br, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + CDCl3) (δ, ppm): 25.2, 25.9, 43.9, 53.5, 90.8, 95.4, 107.8, 114.4, 115.1 (d, J = 20.0 Hz), 115.4, 115.5, 120.3, 125.5, 129.4, 130.1 (d, J = 20.0 Hz), 136.8, 137.5, 155.1, 161.8, 177.9, 190.2; HRMS (ESI-TOF, [M]+): calcd for C23H18BrFN2O3, 468.0479; found, 468.0494.

10-Chloro-6-(4-chlorobenzoyl)-1,2,3,4,5,13a-hexahydro-8H-chromeno[3′,2′:5,6]pyrido-[1,2-a][1,3]diazepin-8-one (3jc)

Isolated yield 90%; orange solid, mp 234–236 °C; IR (KBr) (νmax, cm–1): 3427, 1649, 1569, 1489, 1423, 1379, 1335, 1250, 1220, 1126, 773; 1H NMR (500 MHz, CDCl3) (δ, ppm): 2.05–2.10 (m, 2H, CH2), 2.22–2.30 (m, 2H, CH2), 3.6–3.75 (m, 3H, NCH2 and CH2N), 4.16–4.18 (m, 1H, NCH2), 6.14 (s, 1H, CH), 6.88 (d, J = 8.7 Hz, 1H, ArH), 7.19 (d, J = 7.8 Hz, 2H, ArH), 7.26–7.28 (m, 1H, ArH), 7.31–7.32 (m, 1H, ArH), 7.36–7.38 (m, 1H, ArH), 7.67 (s, 1H, ArH), 7.84–7.86 (m, 1H, ArH), 12.05 (br, 1H, NH); 13C NMR (125 MHz, CDCl3) (δ, ppm): 25.2, 26.1, 44.0, 53.6, 91.1, 95.6, 107.6, 119.4, 125.1, 126.8, 127.5, 127.9, 128.9, 134.6, 137.3, 137.6, 140.1, 154.4, 162.1, 178.3, 192.5; HRMS (ESI-TOF, [M + H]+): calcd for C23H19Cl2N2O3, 441.0767; found, 441.0764.

Characterization Data of Compounds 3′

7-(2-Hydroxy-5-methylbenzoyl)-9-(4-methoxy-benzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-5-ium (3aa′)

Isolated yield 99%; light yellow solid, mp 212–214 °C; IR (KBr) (νmax, cm–1): 3254, 3072, 1727, 1657, 1592, 1483, 1358, 1309, 1252, 1168, 1094, 786, 619; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.14 (s, 3H, CH3), 2.15 (m, 2H, CH2), 3.54 (m, 2H, NCH2), 3.78 (s, 3H, OCH3), 4.42 (m, 2H, NCH2), 6.81–6.83 (m, 1H, ArH), 7.01–7.03 (m, 2H, ArH), 7.16–7.19 (m, 2H, ArH), 7.69–7.72 (m, 2H, ArH), 7.98 (s, 1H, N=CH), 8.47 (s, 1H, C=CH), 9.83 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.5, 20.0, 39.9, 52.4, 55.9, 114.4, 117.1, 119.2, 120.9, 122.7, 128.9, 129.0, 130.8, 132.7, 135.6, 145.0, 146.7, 151.7, 154.8, 164.0, 191.4, 192.2; HRMS (ESI-TOF, [M]+): calcd for C24H23N2O4, 403.1647; found, 403.1660.

7-(2-Hydroxybenzoyl)-9-(4-methoxybenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-5-ium (3ab′)

Isolated yield 99%; yellow solid, mp 214–216 °C; IR (KBr) (νmax, cm–1): 3271, 3078, 1661, 1596, 1492, 1311, 1248, 1169, 1093, 775, 620; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.19 (m, 2H, CH2), 3.56 (m, 2H, NCH2), 3.86 (s, 3H, OCH3), 4.49 (m, 2H, NCH2), 6.93–6.99 (m, 2H, ArH), 7.11–7.12 (m, 2H, ArH), 7.40–7.45 (m, 2H, ArH), 7.79–7.80 (m, 2H, ArH), 8.03 (s, 1H, N=CH), 8.64 (s, 1H, C=CH), 9.86 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.6, 40.1, 52.4, 56.1, 114.6, 117.1, 119.8, 120.0, 120.9, 123.8, 128.8, 131.0, 132.8, 134.5, 144.3, 146.8, 151.5, 156.6, 164.2, 191.1, 191.7; HRMS (ESI-TOF, [M]+): calcd for C23H21N2O4, 389.1490; found, 389.1496.

7-(5-Fluoro-2-hydroxybenzoyl)-9-(4-methoxybenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]-pyrimidin-5-ium (3ac′)

Isolated yield 99%; light yellow solid, mp 224–226 °C; IR (KBr) (νmax, cm–1): 3261, 3075, 1660, 1604, 1479, 1425, 1319, 1263, 1163, 1093, 788, 621; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.18 (m, 2H, CH2), 3.55 (m, 2H, NCH2), 3.85 (s, 3H, OCH3), 4.48 (m, 2H, NCH2), 6.96–6.99 (m, 1H, ArH), 7.09–7.11 (m, 2H, ArH), 7.17–7.19 (m, 1H, ArH), 7.25–7.28 (m, 1H, ArH), 7.78–7.80 (m, 2H, ArH), 8.03 (s, 1H, N=CH), 8.63 (s, 1H, C=CH), 9.86 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 18.1, 40.6, 52.9, 56.6, 115.1, 116.8, 117.0, 119.0, 120.6, 121.0, 121.3, 121.5, 125.0, 129.3, 133.3, 144.4, 147.6, 152.1, 153.2, 155.0, 156.9, 164.8, 190.2, 192.1; HRMS (ESI-TOF, [M]+): calcd for C23H20FN2O4, 407.1396; found, 407.1408.

7-(5-Chloro-2-hydroxybenzoyl)-9-(4-methoxybenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]-pyrimidin-5-ium (3ad′)

Isolated yield 99%; yellow solid, mp 144–146 °C; IR (KBr) (νmax, cm–1): 3250, 3077, 1658, 1590, 1464, 1420, 1318, 1227, 1173, 1093, 787, 622; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.17 (m, 2H, CH2), 3.55 (m, 2H, NCH2), 3.84 (s, 3H, OCH3), 4.46 (m, 2H, NCH2), 6.98 (m, 1H, ArH), 7.10 (m, 2H, ArH), 7.35 (m, 1H, ArH), 7.43 (m, 1H, ArH), 7.78 (m, 2H, ArH), 8.01 (s, 1H, N=CH), 8.60 (s, 1H, C=CH), 9.88 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.6, 40.1, 52.4, 56.1, 114.6, 119.0, 119.8, 120.6, 123.5, 125.6, 128.8, 129.7, 132.8, 133.6, 144.2, 147.1, 151.7, 155.0, 164.2, 189.6, 191.8; HRMS (ESI-TOF, [M]+): calcd for C23H20ClN2O4, 423.1101; found, 423.1102.

7-(5-Bromo-2-hydroxybenzoyl)-9-(4-methoxybenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]-pyrimidin-5-ium (3ae′)

Isolated yield 99%; light yellow solid, mp 254–255 °C; IR (KBr) (νmax, cm–1): 3255, 3078, 1659, 1592, 1463, 1418, 1316, 1227, 1172, 1093, 789, 622; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.16 (m, 2H, CH2), 3.54 (m, 2H, NCH2), 3.82 (s, 3H, OCH3), 4.44 (m, 2H, NCH2), 6.90–6.92 (m, 1H, ArH), 7.06–7.08 (m, 2H, ArH), 7.44 (s, 1H, ArH), 7.50–7.52 (m, 1H, ArH), 7.73–7.75 (m, 2H, ArH), 7.99 (s, 1H, N=CH), 8.58 (s, 1H, C=CH), 9.87 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.5, 40.0, 52.4, 56.0, 110.9, 114.5, 119.4, 119.6, 120.5, 126.1, 128.8, 132.5, 132.8, 136.4, 144.3, 147.0, 151.7, 155.4, 164.1, 189.5, 191.8; HRMS (ESI-TOF, [M]+): calcd for C23H20BrN2O4, 467.0595; found, 467.0614.

7-(5-Fluoro-2-hydroxybenzoyl)-9-(4-methylbenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]-pyrimidin-5-ium (3bc′)

Isolated yield 99%; light yellow solid, mp 232–234 °C; IR (KBr) (νmax, cm–1): 3279, 3074, 1660, 1610, 1480, 1429, 1319, 1272, 1220, 1092, 782, 621; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.17 (m, 2H, CH2), 2.36 (s, 3H, CH3), 3.57 (m, 2H, NCH2), 4.46 (m, 2H, NCH2), 6.94–6.96 (m, 1H, ArH), 7.15–7.17 (m, 1H, ArH), 7.17–7.19 (m, 1H, ArH), 7.23 (m, 1H, ArH), 7.35–7.36 (m, 2H, ArH), 7.63–7.65 (m, 2H, ArH), 8.07 (s, 1H, N=CH), 8.59 (s, 1H, C=CH), 10.01 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.5, 21.5, 40.1, 52.4, 116.2, 116.4, 118.6, 119.2, 120.5, 121.1, 124.3, 129.7, 130.2, 133.8, 144.9, 145.0, 147.6, 151.8, 152.7, 154.5, 189.6, 193.4; HRMS (ESI-TOF, [M]+): calcd for C23H20FN2O3, 391.1447; found, 391.1463.

7-(5-Chloro-2-hydroxybenzoyl)-9-(4-methylbenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]-pyrimidin-5-ium (3bd′)

Isolated yield 99%; yellow solid, mp 137–139 °C; IR (KBr) (νmax, cm–1): 3274, 1660, 1593, 1468, 1410, 1241, 1096, 779, 623; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.16 (m, 2H, CH2), 2.34 (s, 3H, CH3), 3.56 (m, 2H, NCH2), 4.44 (m, 2H, NCH2), 6.94–6.96 (m, 1H, ArH), 7.31–7.39 (m, 4H, ArH), 7.61–7.62 (m, 2H, ArH), 8.57 (s, 1H, N=CH), 8.57 (s, 1H, C=CH), 10.01 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.4, 21.5, 40.1, 52.4, 119.0, 120.4, 123.5, 125.3, 129.7, 130.0, 133.6, 133.8, 144.8, 145.1, 147.6, 151.8, 155.1, 189.5, 193.4; HRMS (ESI-TOF, [M]+): calcd for C23H20ClN2O3, 407.1151; found, 407.1163.

7-(5-Bromo-2-hydroxybenzoyl)-9-(4-methylbenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]-pyrimidin-5-ium (3be′)

Isolated yield 99%; white solid, mp 230–232 °C; IR (KBr) (νmax, cm–1): 3242, 3083, 1662, 1619, 1461, 1316, 1221, 1091, 780, 621; 1H NMR (500 MHz, DMSO-d6 + CDCl3 + HClO4) (δ, ppm): 2.21 (m, 2H, CH2), 2.39 (s, 3H, CH3), 3.62 (m, 2H, NCH2), 4.50 (m, 2H, NCH2), 6.90–6.92 (m, 1H, ArH), 7.33–7.34 (m, 2H, ArH), 7.43–7.46 (m, 2H, ArH), 7.63–7.65 (m, 2H, ArH), 8.09 (s, 1H, N=CH), 8.65 (s, 1H, C=CH), 10.09 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + CDCl3 + HClO4) (δ, ppm): 17.7, 21.7, 40.1, 52.4, 112.0, 119.1, 119.4, 120.7, 125.7, 129.7, 130.2, 132.6, 133.7, 136.4, 144.8, 145.1, 147.5, 151.8, 155.7, 189.1, 193.1; HRMS (ESI-TOF, [M]+): calcd for C23H20BrN2O3, 451.0646; found, 451.0653.

9-Benzoyl-7-(2-hydroxy-5-methylbenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-5-ium (3ca′)

Isolated yield 99%; white solid, mp 208–210 °C; IR (KBr) (νmax, cm–1): 3266, 3069, 1660, 1592, 1484, 1315, 1224, 1162, 1092, 768, 625; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.16 (s, 3H, CH3), 2.18 (m, 2H, CH2), 3.59 (m, 2H, NCH2), 4.47 (m, 2H, NCH2), 6.83–6.84 (m, 1H, ArH), 7.16 (s, 1H, ArH), 7.19–7.21 (m, 1H, ArH), 7.53–7.56 (m, 2H, ArH), 7.64–7.67 (m, 1H, ArH), 7.71–7.72 (m, 2H, ArH), 8.06 (s, 1H, N=CH), 8.60 (s, 1H, C=CH), 10.10 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.5, 20.0, 40.1, 52.5, 117.1, 118.4, 120.9, 123.0, 128.9, 129.1, 129.9, 130.8, 133.8, 135.4, 136.6, 146.3, 147.4, 151.8, 154.6, 191.1, 194.1; HRMS (ESI-TOF, [M]+): calcd for C23H21N2O3, 373.1541; found, 373.1554.

9-Benzoyl-7-(2-hydroxybenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-5-ium (3cb′)

Isolated yield 99%; white solid, mp 226–228 °C; IR (KBr) (νmax, cm–1): 3425, 3286, 2355, 1662, 1604, 1487, 1444, 1317, 1278, 1235, 1092, 764; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.18 (m, 2H, CH2), 3.59 (m, 2H, NCH2), 4.46 (m, 2H, NCH2), 6.88–6.94 (m, 2H, ArH), 7.36–7.40 (m, 2H, ArH), 7.52–7.55 (m, 2H, ArH), 7.63–7.66 (m, 1H, ArH), 7.69–7.70 (m, 2H, ArH), 8.07 (s, 1H, N=CH), 8.58 (s, 1H, C=CH), 10.11 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.4, 40.0, 52.5, 117.1, 118.4, 120.0, 123.3, 129.1, 129.8, 130.9, 133.8, 134.7, 136.6, 146.4, 147.5, 151.9, 156.7, 191.1, 194.3; HRMS (ESI-TOF, [M]+): calcd for C22H19N2O3, 359.1385; found, 359.1390.

9-Benzoyl-7-(5-fluoro-2-hydroxybenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-5-ium (3cc′)

Isolated yield 99%; light yellow solid, mp 214–218 °C; IR (KBr) (νmax, cm–1): 3294, 3077, 1661, 1589, 1482, 1430, 1329, 1274, 1222, 1164, 1092, 761, 623; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.17 (m, 2H, CH2), 3.58 (m, 2H, NCH2), 4.43 (m, 2H, NCH2), 6.89–6.92 (m, 1H, ArH), 7.11–7.13 (m, 2H, ArH), 7.17–7.19 (m, 1H, ArH), 7.50–7.53 (m, 2H, ArH), 7.61–7.68 (m, 3H, ArH), 8.06 (s, 1H, N=CH), 8.55 (s, 1H, C=CH), 10.11 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.4, 40.9, 52.5, 116.2, 116.4, 118.6, 120.4, 121.0, 121.2, 123.9, 129.1, 129.8, 133.8, 136.5, 146.2, 147.8, 152.0, 152.7, 154.4, 156.3, 189.8, 194.3; HRMS (ESI-TOF, [M]+): calcd for C22H18FN2O3, 377.1290; found, 377.1303.

9-Benzoyl-7-(5-chloro-2-hydroxybenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-5-ium (3cd′)

Isolated yield 99%; white solid, mp 131–133 °C; IR (KBr) (νmax, cm–1): 3288, 1659, 1591, 1466, 1409, 1231, 1093, 763, 627; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.19 (m, 2H, CH2), 3.59 (m, 2H, NCH2), 4.48 (m, 2H, NCH2), 6.96–6.98 (m, 1H, ArH), 7.33 (m, 1H, ArH), 7.39–7.41 (m, 1H, ArH), 7.55–7.58 (m, 2H, ArH), 7.67–7.69 (m, 1H, ArH), 7.72–7.74 (m, 2H, ArH), 8.07 (s, 1H, N=CH), 8.66 (s, 1H, C=CH), 10.12 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.5, 40.2, 52.5, 118.8, 118.9, 120.4, 123.5, 125.5, 129.2, 129.7, 129.9, 133.6, 133.9, 136.5, 145.7, 147.8, 151.8, 155.0, 189.4, 193.9; HRMS (ESI-TOF, [M]+): calcd for C22H18ClN2O3, 393.0995; found, 393.1008.

9-Benzoyl-7-(5-bromo-2-hydroxybenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-5-ium (3ce′)

Isolated yield 99%; light yellow solid, mp 227–229 °C; IR (KBr) (νmax, cm–1): 3268, 3077, 1660, 1591, 1463, 1319, 1221, 1090, 764, 624; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.17 (m, 2H, CH2), 3.58 (m, 2H, NCH2), 4.43 (m, 2H, NCH2), 6.87–6.88 (m, 1H, ArH), 7.40 (s, 1H, ArH), 7.45–7.47 (m, 1H, ArH), 7.51–7.54 (m, 2H, ArH), 7.63–7.67 (m, 3H, ArH), 8.04 (s, 1H, N=CH), 8.56 (s, 1H, C=CH), 10.12 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.4, 40.0, 52.5, 110.9, 118.3, 119.4, 120.4, 125.7, 129.1, 129.8, 132.5, 133.8, 136.5, 146.2, 147.7, 152.0, 155.4, 189.4, 194.3; HRMS (ESI-TOF, [M]+): calcd for C22H18BrN2O3, 437.0490; found, 437.0504.

7-(5-Fluoro-2-hydroxybenzoyl)-9-(4-fluorobenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyri-midin-5-ium (3dc′)

Isolated yield 99%; light yellow solid, mp 213–215 °C; IR (KBr) (νmax, cm–1): 3294, 3075, 1661, 1596, 1487, 1352, 1226, 1160, 1091, 786, 614; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.19 (m, 2H, CH2), 3.59 (m, 2H, NCH2), 4.49 (m, 2H, NCH2), 6.96–6.98 (m, 1H, ArH), 7.16–7.17 (m, 1H, ArH), 7.24–7.28 (m, 1H, ArH), 7.37–7.40 (m, 2H, ArH), 7.84–7.87 (m, 2H, ArH), 8.08 (s, 1H, N=CH), 8.66 (s, 1H, C=CH), 9.99 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.5, 40.2, 52.5, 116.2, 116.4, 118.5, 119.3, 120.5, 121.0, 124.4, 133.2, 145.1, 147.7, 151.7, 152.7, 154.6, 156.4, 164.5, 166.5, 189.5, 192.2; HRMS (ESI-TOF, [M]+): calcd for C22H17F2N2O3, 395.1196; found, 395.1216.

7-(5-Chloro-2-hydroxybenzoyl)-9-(4-fluorobenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyri-midin-5-ium (3dd′)

Isolated yield 99%; light yellow solid, mp 126–129 °C; IR (KBr) (νmax, cm–1): 3276, 3080, 1659, 1592, 1468, 1410, 1232, 1161, 1093, 786, 619; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.18 (m, 2H, CH2), 3.59 (m, 2H, NCH2), 4.48 (m, 2H, NCH2), 6.96–6.98 (m, 1H, ArH), 7.33–7.42 (m, 4H, ArH), 7.81–7.84 (m, 2H, ArH), 8.05 (s, 1H, N=CH), 8.65 (s, 1H, C=CH), 10.01 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.5, 40.2, 52.5, 116.2, 116.4, 118.9, 120.5, 123.5, 125.5, 129.7, 133.1, 133.6, 145.3, 147.7, 151.7, 155.0, 164.5, 166.5, 189.4, 192.3; HRMS (ESI-TOF, [M]+): calcd for C22H17ClFN2O3, 411.0901; found, 411.0910.

7-(5-Bromo-2-hydroxybenzoyl)-9-(4-fluorobenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyri-midin-5-ium (3de′)

Isolated yield 99%; yellow solid, mp 139–141 °C; IR (KBr) (νmax, cm–1): 3354, 1660, 1593, 1466, 1407, 1233, 1094, 787, 620; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.18 (m, 2H, CH2), 3.58 (m, 2H, NCH2), 4.47 (m, 2H, NCH2), 6.90–6.92 (m, 1H, ArH), 7.35–7.38 (m, 2H, ArH), 7.43 (s, 1H, ArH), 7.51–7.53 (m, 1H, ArH), 7.80–7.83 (m, 2H, ArH), 8.04 (s, 1H, N=CH), 8.63 (s, 1H, C=CH), 10.00 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.5, 41.5, 52.5, 110.9, 116.2, 116.4, 118.9, 119.3, 120.4, 126.0, 132.5, 133.1, 136.5, 145.3, 147.6, 151.7, 155.4, 164.5, 166.5, 189.3, 192.4; HRMS (ESI-TOF, [M]+): calcd for C22H17BrFN2O3, 455.0396; found, 455.0406.

9-(4-Chlorobenzoyl)-7-(5-fluoro-2-hydroxybenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyri-midin-5-ium (3ec′)

Isolated yield 99%; yellow solid, mp 145–147 °C; IR (KBr) (νmax, cm–1): 3272, 3082, 1661, 1589, 1484, 1430, 1267, 1215, 1161, 1093, 785, 623; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.16 (m, 2H, CH2), 3.56 (m, 2H, CH2), 4.44 (m, 2H, CH2), 6.91–6.94 (m, 1H, ArH), 7.11–7.13 (m, 2H, ArH), 7.19–7.22 (m, 1H, ArH), 7.55–7.57 (m, 2H, ArH), 7.70–7.72 (m, 2H, ArH), 8.05 (s, 1H, N=CH), 8.58 (s, 1H, C=CH), 10.01 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.4, 40.1, 52.5, 116.3, 116.4, 118.6, 120.5, 121.0, 121.1, 124.1, 129.2, 131.8, 135.2, 138.9, 145.6, 147.8, 151.8, 152.7, 154.5, 156.5, 189.5, 192.8; HRMS (ESI-TOF, [M]+): calcd for C22H17ClFN2O3, 411.0901; found, 411.0914.

7-(5-Chloro-2-hydroxybenzoyl)-9-(4-chlorobenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyri-midin-5-ium (3ed′)

Isolated yield 99%; yellow solid, mp 226–229 °C; IR (KBr) (νmax, cm–1): 3259, 3084, 1663, 1465, 1318, 1219, 1090, 783, 624; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.18 (m, 2H, CH2), 3.58 (m, 2H, NCH2), 4.47 (m, 2H, NCH2), 6.96–6.97 (m, 1H, ArH), 7.33 (s, 1H, ArH), 7.41–7.42 (m, 1H, ArH), 7.60–7.62 (m, 2H, ArH), 7.74–7.75 (m, 2H, ArH), 8.06 (s, 1H, N=CH), 8.65 (s, 1H, C=CH), 10.04 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.5, 40.2, 52.5, 119.8, 120.5, 123.5, 125.4, 129.2, 129.8, 131.8, 133.7, 135.3, 139.0, 145.5, 147.9, 151.7, 155.1, 189.5, 192.7; HRMS (ESI-TOF, [M]+): calcd for C22H17Cl2N2O3, 427.0605; found, 427.0613.

7-(5-Bromo-2-hydroxybenzoyl)-9-(4-chlorobenzoyl)-1,2,3,4-tetrahydropyrido[1,2-a]pyri-midin-5-ium (3ee′)

Isolated yield 99%; yellow solid, mp 230–232 °C; IR (KBr) (νmax, cm–1): 3257, 3084, 1663, 1588, 1463, 1316, 1220, 1091, 784, 623; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.25 (m, 2H, CH2), 3.65 (m, 2H, NCH2), 4.44 (m, 2H, NCH2), 6.78–6.80 (m, 1H, ArH), 7.33–7.39 (m, 3H, ArH), 7.53 (s, 1H, ArH), 7.58–7.68 (m, 2H, ArH), 8.08 (s, 1H, N=CH), 8.33 (s, 1H, C=CH), 10.10 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 17.4, 39.8, 52.6, 111.3, 117.9, 119.7, 120.9, 122.5, 129.1, 131.1, 133.2, 134.6, 138.0, 139.6, 146.3, 147.3, 152.2, 157.8, 190.4, 193.7; HRMS (ESI-TOF, [M]+): calcd for C22H17BrClN2O3, 471.0100; found, 471.0113.

8-(2-Hydroxy-5-methylbenzoyl)-10-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1H-pyrido-[1,2-a][1,3]diazepin-6-ium (3fa′)

Isolated yield 99%; light yellow solid, mp 189–191 °C; IR (KBr) (νmax, cm–1): 3282, 3078, 1648, 1590, 1482, 1311, 1260, 1168, 1092, 789, 620; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.04–2.05 (m, 2H, NCH2), 2.17 (m, 2H, NCH2), 2.17 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 3.81 (m, 2H, CH2), 4.68 (m, 2H, CH2), 6.83–6.85 (m, 1H, ArH), 7.04–7.06 (m, 2H, ArH), 7.18–7.22 (m, 2H, ArH), 7.75–7.77 (m, 2H, ArH), 7.98 (s, 1H, N=CH), 8.63 (s, 1H, C=CH), 9.53 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 20.1, 23.6, 24.0, 44.8, 56.0, 57.8, 114.4, 117.1, 121.6, 122.6, 123.0, 128.9, 130.9, 132.9, 135.5, 144.7, 148.1, 154.7, 156.2, 164.1, 191.1, 192.2; HRMS (ESI-TOF, [M]+): calcd for C25H25N2O4, 417.1803; found, 417.1821.

8-(2-Hydroxybenzoyl)-10-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]-diazepin-6-ium (3fb′)

Isolated yield 99%; yellow solid, mp 265–267 °C; IR (KBr) (νmax, cm–1): 3305, 3078, 1646, 1590, 1492, 1447, 1316, 1166, 1093, 776, 621; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.06 (m, 2H, NCH2), 2.16 (m, 2H, NCH2), 3.80 (m, 2H, CH2), 3.82 (s, 3H, OCH3), 4.69 (m, 2H, CH2), 6.92–6.96 (m, 2H, ArH), 7.06–7.07 (m, 2H, ArH), 7.39–7.41 (m, 2H, ArH), 7.75–7.77 (m, 2H, ArH), 8.01 (s, 1H, N=CH), 8.66 (s, 1H, C=CH), 9.54 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 23.6, 23.9, 44.8, 56.0, 57.8, 114.5, 117.1, 120.0, 121.7, 122.5, 123.5, 128.8, 131.1, 132.9, 134.7, 144.6, 148.2, 156.2, 156.8, 164.2, 191.0, 192.2; HRMS (ESI-TOF, [M]+): calcd for C24H23N2O4, 403.1647; found, 403.1658.

8-(5-Fluoro-2-hydroxybenzoyl)-10-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]diazepin-6-ium (3fc′)

Isolated yield 99%; yellow solid, mp 141–143 °C; IR (KBr) (νmax, cm–1): 3411, 3078, 1650, 1591, 1480, 1260, 1171, 1094, 790, 618; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.06–2.07 (m, 2H, NCH2), 2.16 (m, 2H, NCH2), 3.81 (m, 2H, CH2), 3.85 (s, 3H, OCH3), 4.71 (m, 2H, CH2), 6.96–6.98 (m, 1H, ArH), 7.09–7.10 (m, 2H, ArH), 7.19–7.20 (m, 1H, ArH), 7.25–7.29 (m, 1H, ArH), 7.79–7.81 (m, 2H, ArH), 8.03 (s, 1H, N=CH), 8.71 (s, 1H, C=CH), 9.50 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 23.7, 24.0, 44.8, 56.1, 57.7, 114.5, 116.3, 116.5, 118.6, 120.9, 121.1, 122.1, 122.3, 124.4, 128.8, 133.0, 143.9, 148.5, 152.8, 154.5, 156.2, 156.2, 164.3, 189.5, 191.9; HRMS (ESI-TOF, [M]+): calcd for C24H22FN2O4, 421.1553; found, 421.1569.

8-(5-Chloro-2-hydroxybenzoyl)-10-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1H-pyrido-[1,2-a][1,3]diazepin-6-ium (3fd′)

Isolated yield 99%; light yellow solid, mp 150–152 °C; IR (KBr) (νmax, cm–1): 3396, 1645, 1595, 1466, 1318, 1262, 1172, 1092, 787, 622; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.05 (m, 2H, NCH2), 2.14 (m, 2H, NCH2), 3.81 (s, 3H, OCH3), 4.67 (m, 2H, CH2), 6.94–6.95 (m, 1H, ArH), 7.04–7.06 (m, 2H, ArH), 7.33 (m, 1H, ArH), 7.37–7.39 (m, 1H, ArH), 7.73–7.75 (m, 2H, ArH), 7.99 (s, 1H, N=CH), 8.64 (s, 1H, C=CH), 9.57 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 23.6, 23.9, 44.8, 56.0, 57.8, 114.4, 119.0, 121.6, 122.0, 123.5, 125.3, 128.8, 129.7, 132.9, 133.7, 144.5, 148.5, 155.1, 156.3, 164.2, 189.4, 192.2; HRMS (ESI-TOF, [M]+): calcd for C24H22ClN2O4, 437.1257; found, 437.1267.

8-(5-Bromo-2-hydroxybenzoyl)-10-(4-methoxybenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]diazepin-6-ium (3fe′)

Isolated yield 99%; yellow solid, mp 131–133 °C; IR (KBr) (νmax, cm–1): 3405, 3080, 1649, 1590, 1463, 1408, 1320, 1228, 1171, 1093, 790, 621; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.04–2.05 (m, 2H, NCH2), 2.15 (m, 2H, NCH2), 3.81 (m, 2H, CH2), 3.82 (s, 3H, OCH3), 4.68 (m, 2H, CH2), 6.90–6.92 (m, 1H, ArH), 7.06–7.07 (m, 1H, ArH), 7.45 (s, 1H, ArH), 7.50–7.52 (m, 2H, ArH), 7.74–7.76 (m, 2H, ArH), 7.99 (s, 1H, N=CH), 8.67 (s, 1H, C=CH), 9.56 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 23.6, 24.0, 44.8, 56.0, 57.8, 110.8, 114.5, 119.4, 121.7, 122.0, 126.0, 128.7, 132.5, 132.9, 136.5, 144.3, 148.5, 155.5, 156.3, 164.2, 189.3, 192.1; HRMS (ESI-TOF, [M]+): calcd for C24H22BrN2O4, 481.0752; found, 481.0764.

8-(5-Fluoro-2-hydroxybenzoyl)-10-(4-methylbenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]diazepin-6-ium (3gc′)

Isolated yield 99%; yellow solid, mp 130–132 °C; IR (KBr) (νmax, cm–1): 3376, 3079, 1652, 1581, 1482, 1433, 1267, 1224, 1094, 785, 620; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.07 (m, 2H, NCH2), 2.14–2.15 (m, 2H, NCH2), 2.37 (s, 3H, CH3), 3.83 (m, 2H, CH2), 4.70 (m, 2H, CH2), 6.94–6.96 (m, 1H, ArH), 7.16–7.18 (m, 1H, ArH), 7.23–7.27 (m, 1H, ArH), 7.35–7.36 (m, 2H, ArH), 7.66–7.67 (m, 2H, ArH), 8.06 (s, 1H, N=CH), 8.69 (s, 1H, C=CH), 9.71 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 21.5, 23.6, 24.0, 44.9, 57.8, 116.3, 116.5, 118.6, 120.9, 121.1, 121.4, 122.0, 124.2, 129.7, 130.4, 133.8, 144.9, 145.0, 149.0, 152.8, 154.5, 156.4, 189.4, 193.6; HRMS (ESI-TOF, [M]+): calcd for C24H22FN2O3, 405.1603; found, 405.1624.

8-(5-Chloro-2-hydroxybenzoyl)-10-(4-methylbenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]diazepin-6-ium (3gd′)

Isolated yield 99%; light yellow solid, mp 194–196 °C; IR (KBr) (νmax, cm–1): 3395, 1079, 1649, 1468, 1407, 1319, 1228, 1177, 1096, 783, 624; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.07 (m, 2H, NCH2), 2.07 (m, 2H, NCH2), 2.38 (s, 3H, CH3), 3.84 (m, 2H, CH2), 6.97–6.98 (m, 1H, ArH), 7.36–7.38 (m, 3H, ArH), 7.41–7.43 (m, 1H, ArH), 7.67–7.68 (m, 2H, ArH), 8.05 (s, 1H, N=CH), 8.72 (s, 1H, C=CH), 9.72 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 21.6, 23.7, 24.0, 44.9, 57.8, 119.1, 121.4, 122.0, 123.5, 125.4, 129.7, 130.4, 133.7, 144.8, 145.0, 148.9, 155.2, 156.3, 189.3, 193.5; HRMS (ESI-TOF, [M]+): calcd for C24H22ClN2O3, 421.1308; found, 421.1319.

8-(5-Bromo-2-hydroxybenzoyl)-10-(4-methylbenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]diazepin-6-ium (3ge′)

Isolated yield 99%; light yellow solid, mp 140–142 °C; IR (KBr) (νmax, cm–1): 3292, 3077, 1649, 1584, 1464, 1404, 1317, 1227, 1176, 1093; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.04 (m, 2H, NCH2), 2.16 (m, 2H, NCH2), 2.36 (s, 3H, CH3), 3.84 (m, 2H, CH2), 4.69 (m, 2H, CH2), 6.90–6.92 (m, 1H, ArH), 7.35–7.37 (m, 2H, ArH), 7.45 (s, 1H, ArH), 7.50–7.52 (m, 1H, ArH), 7.64–7.66 (m, 2H, ArH), 8.04 (s, 1H, N=CH), 8.69 (s, 1H, C=CH), 9.75 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 21.5, 23.7, 24.0, 44.9, 57.8, 110.9, 119.5, 121.2, 122.0, 125.9, 129.7, 130.3, 132.6, 133.7, 136.5, 145.0, 149.0, 155.6, 156.4, 189.2, 193.6; HRMS (ESI-TOF, [M]+): calcd for C24H22BrN2O3, 465.0803; found, 465.0814.

10-Benzoyl-8-(2-hydroxy-5-methylbenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]-diazepin-6-ium (3ha′)

Isolated yield 99%; light yellow solid, mp 206–208 °C; IR (KBr) (νmax, cm–1): 3290, 1650, 1585, 1482, 1348, 1227, 1092, 782, 621; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.07 (m, 2H, NCH2), 2.14 (m, 2H, NCH2), 2.14 (s, 3H, CH3), 3.84 (m, 2H, CH2), 4.66 (m, 2H, CH2), 6.80–6.82 (m, 1H, ArH), 7.17–7.19 (m, 2H, ArH), 7.49–7.52 (m, 2H, ArH), 7.62 (m, 1H, ArH), 7.68–7.70 (m, 2H, ArH), 8.04 (s, 1H, N=CH), 8.61 (s, 1H, C=CH), 9.91 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 20.0, 21.5, 23.6, 23.9, 44.8, 57.8, 117.2, 120.8, 122.4, 122.8, 128.9, 129.7, 130.3, 130.9, 133.8, 135.6, 144.9, 145.7, 148.5, 154.9, 156.4, 191.1, 193.9; HRMS (ESI-TOF, [M]+): calcd for C24H23N2O3, 387.1698; found, 387.1709.

10-Benzoyl-8-(2-hydroxybenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]diazepin-6-ium (3hb′)

Isolated yield 99%; white solid, mp 233–234 °C; IR (KBr) (νmax, cm–1): 3418, 3018, 1651, 1591, 1449, 1318, 1234, 1094, 994, 766; 1H NMR (500 MHz, DMSO-d6 + CDCl3 + HClO4) (δ, ppm): 1.84 (m, 2H, NCH2), 1.93 (m, 2H, NCH2), 3.58 (m, 2H, CH2), 4.36 (m, 2H, CH2), 6.53–6.59 (m, 2H, ArH), 7.03–7.06 (m, 1H, ArH), 7.12–7.17 (m, 3H, ArH), 7.23–7.29 (m, 1H, ArH), 7.34–7.35 (m, 2H, ArH), 8.86 (s, 1H, N=CH), 8.19 (s, 1H, C=CH), 9.79 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + CDCl3 + HClO4) (δ, ppm): 23.4, 23.6, 44.6, 58.0, 117.3, 119.5, 128.5, 119.5, 120.5, 122.5, 128.5, 129.4, 131.2, 133.2, 135.3, 135.9, 146.5, 148.3, 156.3, 158.4, 191.1, 194.6; HRMS (ESI-TOF, [M]+): calcd for C23H21N2O3, 373.1541; found, 373.1546.

10-Benzoyl-8-(5-fluoro-2-hydroxybenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]-diazepin-6-ium (3hc′)

Isolated yield 99%; yellow solid, mp 131–133 °C; IR (KBr) (νmax, cm–1): 3279, 3079, 1652, 1580, 1483, 1435, 1323, 1266, 1221, 1158, 1093, 778, 625; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.08 (m, 2H, NCH2), 2.16–2.17 (m, 2H, NCH2), 3.85 (m, 2H, CH2), 4.71 (m, 2H, CH2), 6.93–6.96 (m, 1H, ArH), 7.16–7.18 (m, 1H, ArH), 7.23–7.26 (m, 1H, ArH), 7.54–7.57 (m, 2H, ArH), 7.67–7.70 (m, 2H, ArH), 7.74–7.76 (m, 2H, ArH), 8.08 (s, 1H, N=CH), 8.73 (s, 1H, C=CH), 9.84 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 23.6, 24.0, 44.9, 57.8, 116.2, 116.4, 118.6, 120.9, 121.1, 121.9, 124.3, 129.1, 130.1, 134.0, 136.5, 145.7, 149.2, 152.7, 154.5, 156.4, 189.4, 194.2; HRMS (ESI-TOF, [M]+): calcd for C23H20FN2O3, 391.1447; found, 391.1466.

10-Benzoyl-8-(5-chloro-2-hydroxybenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]-diazepin-6-ium (3hd′)

Isolated yield 99%; white solid, mp 189–191 °C; IR (KBr) (νmax, cm–1): 3282, 3081, 1651, 1587, 1466, 1327, 1224, 1173, 1093, 771, 626; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.08 (m, 2H, NCH2), 2.16 (m, 2H, NCH2), 3.85 (m, 2H, CH2), 4.69 (m, 2H, CH2), 6.94–6.96 (m, 1H, ArH), 7.33 (s, 3H, ArH), 7.38–7.40 (m, 1H, ArH), 7.53–7.56 (m, 2H, ArH), 7.65–7.68 (m, 1H, ArH), 7.72–7.73 (m, 2H, ArH), 8.06 (s, 1H, N=CH), 8.71 (s, 1H, C=CH), 9.89 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 23.6, 24.0, 44.9, 57.9, 119.0, 120.6, 121.9, 123.5, 125.3, 129.1, 129.7, 130.0, 133.7, 133.9, 136.5, 145.8, 149.2, 155.1, 156.5, 189.3, 194.3; HRMS (ESI-TOF, [M]+): calcd for C23H20ClN2O3, 407.1151; found, 407.1162.

10-Benzoyl-8-(5-bromo-2-hydroxybenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]-diazepin-6-ium (3he′)

Isolated yield 99%; yellow solid, mp 142–143 °C; IR (KBr) (νmax, cm–1): 3276, 3082, 1650, 1581, 1464, 1402, 1318, 1225, 1093, 773, 623; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.08 (m, 2H, NCH2), 2.17 (m, 2H, NCH2), 3.86 (m, 2H, CH2), 4.71 (m, 2H, CH2), 6.91–6.93 (m, 1H, ArH), 7.45 (s, 1H, ArH), 7.51–7.53 (m, 1H, ArH), 7.56–7.58 (m, 2H, ArH), 7.67–7.70 (m, 1H, ArH), 7.74–7.75 (m, 2H, ArH), 8.06 (s, 1H, N=CH), 8.74 (s, 1H, C=CH), 9.85 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 23.7, 24.0, 44.9, 57.8, 110.8, 119.4, 120.8, 121.9, 126.0, 129.1, 130.1, 132.6, 134.0, 136.5, 145.7, 149.2, 155.5, 156.4, 189.2, 194.2; HRMS (ESI-TOF, [M]+): calcd for C23H20BrN2O3, 451.0646; found, 451.0656.

10-(4-Fluorobenzoyl)-8-(2-hydroxy-5-methylbenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]diazepin-6-ium (3ia′)

Isolated yield 99%; light yellow solid, mp 130–133 °C; IR (KBr) (νmax, cm–1): 3281, 3080, 1652, 1588, 1486, 1343, 1227, 1159, 1093, 788, 618; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.06 (m, 2H, NCH2), 2.13 (m, 2H, NCH2), 2.14 (s, 3H, CH3), 3.82 (m, 2H, CH2), 4.64 (m, 2H, CH2), 6.79–6.81 (m, 1H, ArH), 7.17–7.19 (m, 2H, ArH), 7.25–7.29 (m, 2H, ArH), 7.75–7.78 (m, 2H, ArH), 8.01 (s, 1H, N=CH), 8.58 (s, 1H, C=CH), 9.78 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 19.9, 23.5, 23.9, 44.8, 58.0, 116.0, 116.2, 117.1, 120.3, 122.4, 129.0, 130.9, 133.0, 133.1, 135.7, 146.2, 148.6, 155.0, 156.4, 164.3, 166.3, 191.1, 193.2; HRMS (ESI-TOF, [M]+): calcd for C24H22FN2O3, 405.1603; found, 405.1618.

10-(4-Fluorobenzoyl)-8-(2-hydroxybenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]-diazepin-6-ium (3ib′)

Isolated yield 99%; light yellow solid, mp 248–249 °C; IR (KBr) (νmax, cm–1): 3295, 3079, 1651, 1591, 1489, 1450, 1317, 1233, 1154, 1092, 780, 619; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.07–2.09 (m, 2H, NCH2), 2.17–2.18 (m, 2H, NCH2), 3.86 (m, 2H, CH2), 4.74 (m, 2H, CH2), 6.93–6.99 (m, 2H, ArH), 7.39–7.45 (m, 4H, ArH), 7.87–7.89 (m, 2H, ArH), 8.06 (s, 1H, N=CH), 8.76 (s, 1H, C=CH), 9.65 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 23.7, 24.0, 44.9, 57.8, 116.2, 116.4, 117.1, 120.0, 121.3, 122.4, 123.6, 131.1, 133.3, 134.6, 145.3, 148.8, 164.6, 166.6, 190.8, 192.5; HRMS (ESI-TOF, [M]+): calcd for C23H20FN2O3, 391.1447; found, 391.1462.

8-(5-Fluoro-2-hydroxybenzoyl)-10-(4-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]diazepin-6-ium (3ic′)

Isolated yield 99%; light yellow solid, mp 217–219 °C; IR (KBr) (νmax, cm–1): 3298, 3076, 1654, 1597, 1482, 1345, 1227, 1154, 1092, 786, 617; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.07 (m, 2H, NCH2), 2.16 (m, 2H, NCH2), 3.83 (m, 2H, CH2), 4.68 (m, 2H, CH2), 6.93–6.95 (m, 1H, ArH), 7.13–7.16 (m, 1H, ArH), 7.22–7.23 (m, 1H, ArH), 7.32–7.35 (m, 2H, ArH), 7.81–7.83 (m, 2H, ArH), 8.05 (s, 1H, N=CH), 8.68 (s, 1H, C=CH), 9.72 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 23.6, 23.9, 44.9, 57.9, 107.2, 116.1, 116.3, 116.4, 118.6, 121.0, 121.1, 122.0, 124.1, 133.1, 145.4, 149.1, 152.7, 154.5, 156.3, 164.5, 166.5, 189.4, 192.7; HRMS (ESI-TOF, [M]+): calcd for C23H19F2N2O3, 409.1353; found, 409.1369.

8-(5-Chloro-2-hydroxybenzoyl)-10-(4-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]diazepin-6-ium (3id′)

Isolated yield 99%; yellow solid, mp 218–220 °C; IR (KBr) (νmax, cm–1): 3292, 3078, 1652, 1590, 1467, 1404, 1326, 1226, 1163, 1094, 787, 619; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.07 (m, 2H, NCH2), 2.15–2.16 (m, 2H, NCH2), 3.84 (m, 2H, CH2), 4.69 (m, 2H, CH2), 6.94–6.96 (m, 1H, ArH), 7.32–7.35 (m, 3H, ArH), 7.38–7.39 (m, 1H, ArH), 7.80–7.83 (m, 2H, ArH), 8.03 (s, 1H, N=CH), 8.69 (s, 1H, C=CH), 9.74 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 23.6, 23.9, 44.9, 57.9, 116.1, 116.3, 119.0, 120.9, 121.9, 123.5, 125.2, 129.7, 133.1, 133.7, 145.4, 149.1, 155.1, 156.4, 164.5, 166.5, 189.2, 192.8; HRMS (ESI-TOF, [M]+): calcd for C23H19ClFN2O3, 425.1057; found, 425.1072.

8-(5-Bromo-2-hydroxybenzoyl)-10-(4-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]diazepin-6-ium (3ie′)

Isolated yield 99%; light yellow solid, mp 134–136 °C; IR (KBr) (νmax, cm–1): 3406, 3082, 1650, 1588, 1466, 1405, 1229, 1162, 1094, 789, 618; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.03 (m, 2H, NCH2), 2.07 (m, 2H, NCH2), 3.83 (m, 2H, CH2), 4.68 (m, 2H, CH2), 6.89–6.91 (m, 1H, ArH), 7.32–7.36 (m, 2H, ArH), 7.43 (s, 1H, ArH), 7.49–7.51 (m, 1H, ArH), 7.80–7.83 (m, 2H, ArH), 8.02 (s, 1H, N=CH), 8.69 (s, 1H, C=CH), 9.73 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 23.6, 24.0, 44.9, 57.9, 110.9, 116.1, 116.3, 119.4, 120.9, 121.9, 125.9, 132.6, 133.1, 136.5, 145.4, 149.1, 155.5, 156.4, 164.4, 166.5, 189.1, 192.7; HRMS (ESI-TOF, [M]+): calcd for C23H19BrFN2O3, 469.0552; found, 469.0564.

8-(5-Chloro-2-hydroxybenzoyl)-10-(4-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-pyrido[1,2-a][1,3]diazepin-6-ium (3jc′)

Isolated yield 99%; yellow solid, mp 120–123 °C; IR (KBr) (νmax, cm–1): 3081, 1649, 1583, 1467, 1408, 1228, 1178, 1093, 783, 621; 1H NMR (500 MHz, DMSO-d6 + HClO4) (δ, ppm): 2.06 (m, 2H, NCH2), 2.17 (m, 2H, NCH2), 3.99 (m, 2H, CH2), 4.72 (m, 2H, CH2), 6.98–6.99 (m, 1H, ArH), 7.38–7.45 (m, 4H, ArH), 7.68–7.69 (m, 2H, ArH), 8.06 (s, 1H, N=CH), 8.74 (s, 1H, C=CH), 9.68 (s, 1H, OH); 13C NMR (125 MHz, DMSO-d6 + HClO4) (δ, ppm): 23.7, 24.0, 44.9, 57.7, 119.1, 121.6, 122.0, 123.5, 125.5, 129.7, 130.4, 133.7, 144.6, 145.0, 148.9, 155.2, 156.3, 189.3, 193.4; HRMS (ESI-TOF, [M]+): calcd for C23H19Cl2N2O3, 441.0762; found, 441.0773.