Facile construction of novel heterocyclic compounds: three-component, one-pot synthesis of 2-hydroxybenzoyl-1,2-dihydropyridine-3-carboxylates, ketones, pyridone-3-carboxylates and benzopyrido-1,3-oxazole-4-carboxylates

Abstract

A facile method has been developed for the preparation of novel heterocyclic compounds by the reaction of 3-formylchromones, benzylamines, and 2-aminophenols with 3-oxobutanoates. 3-Oxobutanoates bearing trifluoro or trichloro substituents and trifluoro containing 1,3-diketones facilitated the reaction. The reaction proceeds via a Schiff base mediated Michael addition followed by the selective addition of enamine to the carbonyl group adjacent to the trihalo group due to a strong electron withdrawing effect. The present three-component, one-pot protocol provided heterocyclic compounds without a catalyst.

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Introduction

The chromone¹ (4H-chromen-4-one, 4H-1-benzopyran-4-one) scaffold has been found in natural products and is structurally interesting due to the phenolic oxygen which is attached to an α,β-unsaturated ketone. Consequently, chromone chemistry continues to draw considerable attention from synthetic and medicinal chemists. 4-Oxo-4H-chromen-3-carbaldehyde (3-formylchromone) is a useful precursor for the preparation of biologically active compounds.² 3-Formylchromone has three functional groups, namely, an electrophilic centre at C-2, a conjugated carbonyl group at C-3 and an unsaturated keto function at C-4. Various useful heterocyclic compounds have been prepared by utilizing the electrophilic centre (C-2) and the conjugated second carbonyl group (C-3).³ Dihydropyridines, pyrano pyridopyrimidinones, benzopyranopyridinones and tricyclic benzopyrones have been prepared by the chemical transformation of 3-formylchromone with the retention of the chromone ring.⁴ Furthermore, the ring opening of pyran-4-one resulted in the formation of 2-hydroxybenzoyl derivatives.⁵ The previous approaches for the synthesis of 2-hydroxybenzoylpyridones and pyridines are depicted in Scheme 1. (I) Maiti et al.^5f reported 2-hydroxybenzoylpyridones by the reaction of 3-formylchromone with 3-oxo-N-phenylbutanamide in the presence of FeCl₃. (II) Li et al.^5g–i and Sharma et al.^5j reported from chromenyl acrylates with alkyl and aryl amines in the presence of base under reflux conditions, however, (III) Daich et al.^5k reported from the Knoevenagel derivative of 3-formylchromone with aniline in the presence of CsF. (IV) Kumar et al.^5d reported 2-hydroxybenzoylpyridines from the Knoevenagel derivative of 3-formylchromone in the presence of ammonium salt. (V) Romanelli et al.^3d reported a similar reaction from the Knoevenagel derivative of 3-formylchromone using a Wells–Dawson heteropolyacid as the catalyst.

Scheme 1 Previous approaches for the preparation of 2-pyridones and pyridines.

Our research focused on feasible reactions of salicylaldehydes and carbonyl compounds with 3-oxobutanoates bearing chloro, trichloro and trifluoro substituents. In this context, we studied the reactivity of salicylaldehydes with ethyl-4-chloro-3-oxobutanoate using piperidine to provide 2H-chromenes,^6a and in turn these derivatives were successfully converted to useful heterocycles.^6b–e We also studied the reactivity of salicyladehydes with ethyl-4,4,4-trichloro-3-oxobutanoate using piperidine to provide 2H-chromene-3-carboxylates.⁷ Next, we studied the reaction between carbonyl compounds and ethyl-4,4,4-trifluoro-3-oxobutanoate using piperidine to provide a series of (E)-α,β-unsaturated esters and ketones.⁸ Previously, we reported 3-formylchromone based heterocyclic compounds such as 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylates as potential anti-mycobacterial and anticancer agents.⁹ The present manuscript describes a facile approach for the preparation of novel heterocyclic compounds by a three-component, one-pot reaction between 3-formylchromones, benzylamines, 2-aminophenols and 3-oxobutanoates bearing trifluoro or trichloro substituents and trifluoro containing 1,3-diketones (Scheme 2).

Scheme 2 Present approaches for the preparation of heterocyclic compounds.

Results and discussion

In an initial experiment, we conducted the reaction between 3-formylchromone (1a, 1 equiv.), aniline (2a, 1 equiv.) and ethyl-4,4,4-trifluoro-3-oxobutanoate (3a, 1 equiv.) in dry DCM at room temperature for 24 h. This provided ethyl-2-hydroxy-5-(2-hydroxybenzoyl)-1-phenyl-2-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate 4a in 10% isolated yield (Scheme 3). Compound 4a was characterized by using IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS spectroscopic techniques. The result encouraged us to optimize the reaction conditions. The model reaction was investigated with various solvents such as acetonitrile, CH₃OH, C₂H₅OH, 1,4-dioxane, THF, ether, benzene, and toluene under reflux conditions. We found that acetonitrile produced compound 4a in 28% yield (Scheme 3, Table 1, entry 1). Experiments were carried out with changing of the mole ratio, time and temperature to improve the yield. However, the yield did not improve beyond 28% (4a). The reason could be the lone pair of electrons on the nitrogen atom of aniline which are in resonance and become less reactive.

Scheme 3 Synthesis of 2-hydroxybenzoyl-1,2-dihydropyridine-3-carboxylates and ketones.

Table 1 Synthesis of 2-hydroxybenzoyl-1,2-dihydropyridine-3-carboxylates and ketones

Entry	R^1	R^2	R^3	Compound	Yield^a (%)
a Isolated yields.
1	H (1a)		OC2H5 (3a)	4a	28
2	H (1a)		OC2H5 (3a)	4b	63
3	CH3 (1b)		OC2H5 (3a)	4c	65
4	Cl (1c)		OC2H5 (3a)	4d	60
5	H (1a)		OC2H5 (3a)	4e	68
6	H (1a)		OC2H5 (3a)	4f	62
7	H (1a)		OC2H5 (3a)	4g	66
8	H (1a)		OC2H5 (3a)	4h	52
9	H (1a)		CH3 (3e)	4i	44
10	H (1a)			4j	65
11	H (1a)			4k	40

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Furthermore, we carried out the reaction between 3-formylchromone (1a, 1 equiv.), benzylamine (2b, 1.2 equiv.) and ethyl-4,4,4-trifluoro-3-oxobutanoate (3a, 1.5 equiv.) in acetonitrile under reflux conditions for 2 h. The reaction proceeded smoothly and afforded ethyl-1-benzyl-2-hydroxy-5-(2-hydroxybenzoyl)-2-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate 4b in 63% yield (Scheme 3 and Table 1, entry 2). Compound 4b was characterized using IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS spectroscopic techniques. This work represents the first example of the construction of these novel heterocyclic compounds and the usefulness of this reaction is shown by the formation of a Schiff base, followed by Michael addition (C–C bond formation), ring opening (C–O bond cleaved), and intramolecular cyclization (C–N bond formation) in one-pot. We also investigated the present three-component, one-pot protocol with various β-ketoesters such as ethyl-3-oxobutanoate 3b, ethyl-3-oxo-3-phenylpropanoate 3c, and ethyl-4-chloro-3-oxobutanoate 3d. In all of these experiments, the 3-formylchromone 1a and benzylamine 2b provided the corresponding Schiff base, however the Schiff base did not react with the β-ketoesters (3b–d) to give the corresponding products. Among the tested β-ketoesters 3a–d, ethyl-4,4,4-trifluoro-3-oxobutanoate 3a only facilitated the reaction due to the strong electron withdrawing nature of the trifluoro group to produce the compounds.

In order to evaluate the efficiency of the methodology, we investigated the substrate scope using 3-formylchromones 1a–c and benzylamines 2b–d. The electron withdrawing and donating groups were well tolerated to produce 2-hydroxybenzoylpyridine-3-carboxylates 4c–f in good yields (Table 1, entries 3–6). To expand the scope of the present method, next, 2-(1H-indol-3-yl)ethanamine 2e and ethanolamine 2f were examined. Accordingly, the reaction of 1a and 2e or 2f with ethyl-4,4,4-trifluoro-3-oxobutanoate 3a was carried out under optimized conditions. This provided the corresponding 2-hydroxybenzoyl-pyridine-3-carboxylates 4g and 4h (Table 1, entries 7 and 8).

Having achieved the preparation of 2-hydroxybenzoylpyridine-3-carboxylates 4a–h, we extended this protocol with trifluoro containing 1,3-diketones. Accordingly, 3-formylchromone 1a and benzylamine 2b, with 1,1,1-trifluoropentane-2,4-dione 3e, 4,4,4-trifluoro-1-phenylbutane-1,3-dione 3f, and 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione 3g were carried out under optimized conditions. The reactions proceeded smoothly to produce the corresponding 2-hydroxybenzoyl-1,2-dihydropyridinyl-3-ones 4i–k (Table 1, entries 9–11). Thus, the synthesized compounds 4a–k are new and well characterized using spectral data (see the ESI†).

In order to evaluate the mechanism, an experiment was carried out to monitor the reaction using ¹H NMR (Scheme 4). Accordingly, 3-formylchromone 1a and benzylamine 2b were stirred in CDCl₃ at room temperature for 10 min to provide the Schiff base (¹H NMR, see the ESI†). Then, ethyl-4,4,4-trifluoro-3-oxobutanoate 3a in CDCl₃ was added slowly to the Schiff base. The reaction mixture was refluxed and samples were obtained for reaction times of 2 h, 4 h, and 8 h to record the ¹H NMR spectrum (see the ESI†).

Scheme 4 ¹H NMR monitored reaction for 4b.

A plausible mechanism for this new reaction is depicted in Scheme 5. The 3-formylchromone 1a reacts with benzylamine 2b giving Schiff base A. Michael addition of ethyl-4,4,4-trifluoro-3-oxobutanoate 3a with Schiff base A gives benzyliminomethylchromenyl intermediate B (C–C bond formation). Then, intermediate B, by the cleavage of the C–O bond, gives intermediate C. Finally, intramolecular cyclization occurs by selective addition to the carbonyl group adjacent to the CF₃ group of the nucleophilic enamine in intermediate D, obtained from C, through a 1,5-H shift to give the target compound 4b.

Scheme 5 Plausible reaction mechanism for 4b.

Following the successful results with ethyl-4,4,4-trifluoro-3-oxobutanoate and trifluoro containing 1,3-diketones, we extended this protocol with ethyl-4,4,4-trichloro-3-oxobutanoate 3h. Accordingly, the reaction of 3-formylchromone 1a and benzylamine 2b with 3h was carried out in acetonitrile under reflux conditions for 6 h. Interestingly, this provided ethyl-1-benzyl-5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydropyridine-3-carboxylate 5a (Table 2, entry 1). The pyridone 5a was characterized using IR, ¹H NMR, ¹³C NMR, and HRMS spectroscopic techniques. This work also represents the first example of the construction of 2-hydroxybenzoylpyridone in a one-pot reaction. In order to evaluate the methodology, we carried out the reaction with substituted 3-formylchromones 1a–c and benzylamines 2b–d with ethyl-4,4,4-trichloro-3-oxobutanoate 3h. Electron withdrawing and donating groups were well tolerated and produced 2-hydroxybenzoylpyridone-3-carboxylates 5b–e (Table 2, entries 2–5). The compounds 5a–e are new and were well characterized using spectral data (see the ESI†).

Table 2 Synthesis of 2-hydroxybenzoylpyidone-3-carboxylates

Entry	R^1	R^2	Compound	Yield^a (%)
a Isolated yields.
1	H (1a)		5a	60
2	CH3 (1b)		5b	72
3	Cl (1c)		5c	78
4	H (1a)		5d	70
5	H (1a)		5e	74

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The above results indicated that the benzylamine and 3-formylchromone with ethyl-4,4,4-trifluoro-3-oxobutanoate, ethyl-4,4,4-trichloro-3-oxobutanoate and trifluoro containing 1,3-diketones provided the corresponding compounds in good yields. However, aniline provided the corresponding compound with low yield due to the presence of lone pair electrons on the nitrogen atom. Assuming that the aniline with a hydroxy group at the ortho position (2-aminophenol) may have an impact on the reactivity, a couple of experiments were carried out as shown below.

The reaction of 3-formylchromone 1a and 2-aminophenol 6a with ethyl-4,4,4-trifluoro-3-oxobutanoate 3a was carried out in acetonitrile under reflux conditions for 4 h. Interestingly, this provided ethyl-2-(2-hydroxybenzoyl)-4a-(trifluoromethyl)-4aH-benzo[d]pyrido[2,1-b][1,3]oxazole-4-carboxylate 7a (Table 3, entry 1). Compound 7a was characterized using IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS spectroscopic techniques. This work also represents the first example of the construction of 2-hydroxybenzoylbenzopyrido-1,3-oxazole-4-carboxylate in a one-pot reaction.

Table 3 Synthesis of 2-hydroxylbenzoylbenzopyrido-1,3-oxazole-4-carboxylates

Entry	R^1	R^2	R^3	Compound	Yield^a (%)
a Isolated yields.
1	H (1a)	H (6a)	OC2H5 (3a)	7a	33
2	CH3 (1b)	H (6a)	OC2H5 (3a)	7b	36
3	Cl (1c)	H (6a)	OC2H5 (3a)	7c	29
4	H (1a)	CH3 (6b)	OC2H5 (3a)	7d	40
5	H (1a)	Cl (6c)	OC2H5 (3a)	7e	28
6	H (1a)	H (6a)		7f	28

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In order to evaluate the methodology, reactions were carried out between substituted 3-formylchromones 1a–c and 2-aminophenols 6a–c with ethyl-4,4,4-trifluoro-3-oxobutanoate 3a under optimized conditions. The electron withdrawing and donating groups were well tolerated to produce 1,3-oxazole-4-carboxylates 7b–e (Table 3, entries 2–5). Furthermore, the reaction of 3-formylchromone 1a and 2-aminophenol 6a was carried out with 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione 3g to produce the corresponding benzopyrido-1,3-oxazole derivative 7f (Table 3, entry 6). Thus, the synthesized compounds 7a–f are new and were well characterized using spectral data (see the ESI†). Having achieved good results with 2-aminophenol, the three-component, one-pot protocol was tested with 2-aminobenzenethiol 6d. Accordingly, the reaction of 3-formylchromone 1a and 2-aminobenzenethiol 6d with ethyl-4,4,4-trifluoro-3-oxobutanoate 3a was carried out under optimized conditions, however, the corresponding product did not form. We also carried out the reaction with benzene-1,2-diamine 6e. Accordingly, the reaction of 3-formylchromone 1a and benzene-1,2-diamine 6e with ethyl-4,4,4-trifluoro-3-oxobutanoate 3a was carried out. The formation of an azepine derivative^5a was observed in the reaction between 3-formylchromone 1a and benzene-1,2-diamine 6e without the involvement of ethyl-4,4,4-trifluoro-3-oxobutanoate.

Conclusions

In summary, a facile and catalyst free method has been developed for the preparation of novel heterocyclic compounds such as 2-hydroxybenzoylpyridine-3-carboxylates, ketones, pyridone-3-carboxylates, and benzopyrido-1,3-oxazole-4-carboxylates by a three-component, one-pot protocol for the first time. β-Ketoesters having strong electron withdrawing substituents such as ethyl-4,4,4-trifluoro-3-oxobutanoate, ethyl-4,4,4-trichloro-3-oxobutanoate and trifluoro containing 1,3-diketones participated in the Michael addition with a Schiff base to produce the corresponding heterocyclic compounds. Due to the importance of these heterocyclic compounds, especially in pharmaceutical and medicinal chemistry, the present protocol can be extended for the synthesis of various biologically important heterocyclic compounds.

Experimental section

General

Ethyl-4,4,4-trifluoro-3-oxobutanoate, ethyl-4,4,4-trichloro-3-oxobutanoate, 1,1,1-trifluoropentane-2,4-dione, 4,4,4-trifluoro-1-phenylbutane-1,3-dione, 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione, and tryptamine were procured from Sigma-Aldrich. Benzyl amine, aniline, 2-aminophenol, benzene-1,2-diamine, 2-aminobenzenethiol and solvents were obtained from local suppliers. 3-Formylchromones were prepared as per the literature procedure. ¹H NMR and ¹³C NMR spectra were recorded on a Varian Gemini 200 MHz and Avance 300 MHz spectrometer in CDCl₃ using TMS as the internal standard. IR spectra were recorded on a Nicollet 740 FT-IR spectrometer. Mass spectra were obtained on an Agilent LCMS instrument. HRMS were measured on an Agilent Technologies 6510, Q-TOFLC/MS ESI-Technique. Melting points were determined in open glass capillary tubes on a Metler FP 51 melting point apparatus and are uncorrected. All reactions were monitored using thin layer chromatography (TLC) on pre-coated silica gel 60 F₂₅₄ (mesh); spots were observed under UV light. Merck silica gel (100–200 mesh) was used for chromatography.

General procedure for the preparation of ethyl-2-hydroxy-5-(2-hydroxybenzoyl)-1-phenyl-2-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (4a). Ethyl-4,4,4-trifluoro-3-oxobutanoate (3a, 1.5 mmol) was added to a stirred solution of 3-formylchromone (1a, 1 mmol) and aniline (2a, 1.2 mmol) in CH₃CN (2 mL). The contents were stirred under reflux conditions for 2 h. After completion of the reaction (TLC), the residue was purified by column chromatography using silica gel (100 : 200, ethyl-acetate/hexane 2 : 98) and afforded ethyl-2-hydroxy-5-(2-hydroxybenzoyl)-1-phenyl-2-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate 4a as a yellow solid in 28% yield; mp 128–130 °C; FT-IR (KBr): 3062, 1965, 1670, 1631, 1586, 1523, 1484, 1377, 1340, 1263, 1236, 1182, 1121, 1091, 957, 765, 700 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.46 (s, 1H, OH), 8.58 (s, 1H, OH), 8.22 (d, 1H, J = 1.5 Hz, hetero aromatic), 7.66 (d, 1H, J = 1.5 Hz, hetero aromatic), 7.50 (dd, 1H, J = 7.9, 1.6 Hz, aromatic), 7.47–7.44 (m, 1H, aromatic), 7.44–7.43 (m, 1H, aromatic), 7.42 (d, 2H, J = 2.1 Hz, aromatic), 7.42–7.41 (m, 1H, aromatic), 7.41–7.39 (m, 1H, aromatic), 7.02 (dd, 1H, J = 0.9, 8.3 Hz, aromatic), 6.91 (m, 1H, aromatic), 4.35 (q, 2H, J = 7.2 Hz, OCH₂), 1.39 (t, 3H, J = 7.2 Hz, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 193.1, 168.5, 161.8, 151.1, 140.0, 137.3, 135.2, 130.6, 128.9, 128.7, 123.1 (d, J = 295.1 Hz), 119.4, 118.7, 118.3, 109.7, 104.9, 86.0 (q, J = 33.6 Hz), 62.1, 14.1 ppm; MS (ESI): (m/z) 434 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₂H₁₉F₃NO₅ [M + H]⁺ 434.1209, found: 434.1209.

General procedure for the preparation of 2-hydroxybenzoyl-2-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylates (4b–h) and ketones (4i–k). Ethyl-4,4,4-trifluoro-3-oxobutanoate (3a, 1.5 mmol) was added to a stirred solution of 3-formylchromone (1a, 1 mmol) and benzylamine (2b, 1.2 mmol) in CH₃CN (2 mL). The contents were stirred under reflux conditions for 2 h. After completion of the reaction (TLC), the residue was purified by column chromatography using silica gel (100 : 200, ethyl acetate/hexane 2 : 98) and afforded ethyl-1-benzyl-2-hydroxy-5-(2-hydroxybenzoyl)-2-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate 4b. Similarly, compounds 4c–h were prepared from the corresponding 3-formylchromones 1a–c, and benzylamines 2b–d. However, compounds 4i–k were prepared from 3-formylchromone 1a, benzylamine 2b and trifluoro containing 1,3-diketones such as 1,1,1-trifluoropentane-2,4-dione 3e, 4,4,4-trifluoro-1-phenylbutane-1,3-dione 3f, and 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione 3g under optimized conditions.
Ethyl-1-benzyl-2-hydroxy-5-(2-hydroxybenzoyl)-2-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (4b). Yellow solid; mp 111–113 °C; FT-IR (KBr): 3326, 3032, 2983, 1672, 1637, 1587, 1528, 1480, 1348, 1233, 1182, 971, 758, 701, 540, 454 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.4 (s, 1H, OH), 8.53 (s, 1H, OH), 8.14 (d, J = 1.5 Hz, 1H, hetero aromatic), 7.49 (d, J = 1.4 Hz, 1H, hetero aromatic), 7.41–7.30 (m, 4H, aromatic), 7.26 (m, 2H, aromatic), 7.21 (dd, J = 7.8, 1.5 Hz, 1H, aromatic), 6.97 (dd, J = 8.4, 0.9 Hz, 1H, aromatic), 6.76 (m, 1H, aromatic), 5.10 (d, J = 15.2 Hz, 1H, CH), 4.62 (d, J = 15.2 Hz, 1H, CH), 4.33 (q, J = 7.2 Hz, 2H, OCH₂), 1.37 (t, J = 7.2 Hz, 3H, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 192.5, 168.6, 161.6, 150.8, 137.7, 136.0, 134.9, 130.4, 129.1, 128.3, 128.1, 123.3 (d, J = 295.1 Hz), 119.3, 118.4, 118.2, 108.5, 103.8, 84.92 (q, J = 33.6 Hz), 62.0, 52.1, 14.1 ppm; MS (ESI): (m/z) 448 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₃H₂₁F₃NO₅ [M + H]⁺ 448.1366, found: 448.1355.
Ethyl-1-benzyl-2-hydroxy-5-(2-hydroxy-5-methylbenzoyl)-2-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (4c). Yellow solid; mp 115–117 °C; FT-IR (KBr): 3219, 2919, 1667, 1627, 1542, 1470, 1373, 1280, 1261, 1160, 1091, 968, 824, 720, 701, 536 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.13 (s, 1H, OH) 8.51 (s, 1H, OH), 8.14 (s, 1H, hetero aromatic), 7.49 (s, 1H, hetero aromatic), 7.41–7.31 (m, 3H, aromatic), 7.31–7.26 (m, 2H, aromatic), 7.19 (d, J = 7.0 Hz, 1H, aromatic), 6.95 (s, 1H, aromatic), 6.87 (d, J = 8.4 Hz, 1H, aromatic), 5.03 (d, J = 15.2 Hz, 1H, CH), 4.65 (d, J = 15.2 Hz, 1H, CH), 4.33 (q, J = 7.1 Hz, 2H, OCH₂), 2.17 (s, 3H, CH₃), 1.37 (t, J = 7.1 Hz, 3H, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 192.5, 168.6, 159.3, 150.6, 137.8, 135.9, 135.7, 130.2, 129.1, 128.4, 128.2, 127.6, 123.2 (d, J = 295.1 Hz), 119.1, 117.9, 108.6, 103.9, 84.8 (q, J = 34.5 Hz), 61.9, 52.1, 20.5, 14.1 ppm; MS (ESI): (m/z) 462 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₄H₂₃F₃NO₅ [M + H]⁺ 462.1528, found: 462.1495.
Ethyl-1-benzyl-5-(5-chloro-2-hydroxybenzoyl)-2-hydroxy-2-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (4d). Yellow solid; mp 128–130 °C; FT-IR (KBr): 3201, 2970, 1667, 1623, 1586, 1543, 1470, 1373, 1329, 1275, 1260, 1185, 1169, 1095, 969, 831, 695, 577 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.23 (s, 1H, OH) 8.53 (s, 1H, OH), 8.12 (d, J = 1.4 Hz, 1H, hetero aromatic), 7.48 (s, 1H, hetero aromatic), 7.43–7.26 (m, 6H, aromatic), 7.16 (d, J = 2.6 Hz, 1H, aromatic), 6.92 (d, J = 8.8 Hz, 1H, aromatic), 5.03 (d, J = 15.1 Hz, 1H, CH), 4.68 (d, J = 15.1 Hz, 1H, CH), 4.33 (q, J = 7.1 Hz, 2H, OCH₂), 1.38 (t, J = 7.1 Hz, 3H, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 191.1, 168.5, 159.9, 150.7, 137.3, 135.4, 134.5, 129.3, 128.6, 128.3, 123.2, 123.1 (d, J = 295.1 Hz), 119.7, 108.2, 104.3, 84.8 (q, J = 34.5 Hz), 62.1, 52.3, 14.0 ppm; MS (ESI): (m/z) 482 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₃H₂₀ClF₃NO₅ [M + H]⁺ 482.0982, found: 482.0971.
Ethyl-2-hydroxy-5-(2-hydroxybenzoyl)-1-(4-methoxybenzyl)-2-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (4e). Wine red viscous liquid; FT-IR (KBr): 3446, 2986, 1667, 1620, 1585, 1373, 1335, 1284, 1175, 1094, 971, 761 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.41 (s, 1H, OH) 8.54 (s, 1H, OH), 8.12 (d, J = 1.5 Hz, 1H, hetero aromatic), 7.48 (d, J = 1.5 Hz, 1H, hetero aromatic), 7.42–7.38 (m, 1H, aromatic), 7.23–7.18 (m, 3H, aromatic), 6.97 (dd, J = 8.2, 0.9 Hz, 1H, aromatic), 6.91–6.85 (m, 2H), 6.80–6.73 (m, 1H), 5.00 (d, J = 14.9 Hz, 1H, CH), 4.56 (d, J = 14.9 Hz, 1H, CH), 4.33 (q, J = 7.1 Hz, 2H, OCH₂), 3.80 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 192.4, 168.6, 161.5, 159.6, 150.7, 137.8, 134.8, 130.4, 129.9, 127.6, 123.2 (d, J = 295.1 Hz), 119.4, 118.4, 118.1, 114.5, 108.3, 103.6, 84.9 (q, J = 33.6 Hz), 61.9, 55.2, 51.6, 14.0 ppm; MS (ESI): (m/z) 478 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₄H₂₃F₃NO₆ [M + H]⁺ 478.1477, found: 478.1472.
Ethyl-1-(4-fluorobenzyl)-2-hydroxy-5-(2-hydroxybenzoyl)-2-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (4f). Yellow solid; mp 96–98 °C; FT-IR (KBr): 3071, 2989, 1667, 1629, 1582, 1566, 1532, 1375, 1343, 1267, 1232, 1216, 1152, 1101, 974, 824, 758, 659 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.38 (s, 1H, OH) 8.56 (s, 1H, OH), 8.13–8.10 (m, 1H, hetero aromatic), 7.47 (s, 1H, aromatic), 7.44–7.40 (m, 1H, aromatic), 7.28–7.21 (m, 4H, aromatic), 7.05 (t, J = 8.6 Hz, 2H, aromatic), 6.99 (d, J = 8.3 Hz, 1H, aromatic), 6.82–6.77 (m, 1H, aromatic), 5.08 (d, J = 15.2 Hz, 1H, CH), 4.57 (d, J = 15.2 Hz, 1H, CH), 4.33 (q, J = 7.1 Hz, 2H, OCH₂), 1.37 (t, J = 7.1 Hz, 3H, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 192.6, 168.6, 161.6, 150.5, 137.7, 135.0, 131.9, 130.4, 130.1, 130.0, 119.3, 118.5, 118.3, 116.1, 116.0, 108.7, 103.9, 84.9 (d, J = 33.6 Hz), 62.0, 51.5, 14.1 ppm; MS (ESI): (m/z) 466 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₃H₂₀F₄NO₅ [M + H]⁺ 466.1272, found: 466.1261.
Ethyl-1-(2-(1H-indol-3-yl)ethyl)-2-hydroxy-5-(2-hydroxybenzoyl)-2-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (4g). Yellow solid; mp 167–169 °C; FT-IR (KBr): 3383, 3012, 2928, 1662, 1626, 1565, 1531, 1485, 1377, 1340, 1239, 1188, 1159, 1096, 1028, 972, 761, 735, 656 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.22 (s, 1H, OH) 8.51 (s, 1H, OH), 8.07 (d, J = 1.5 Hz, 1H, hetero aromatic), 8.02 (s, 1H, NH), 7.50 (d, J = 7.8 Hz, 1H, aromatic), 7.37–7.30 (m, 1H, aromatic), 7.28 (d, J = 8.1 Hz, 1H, aromatic), 7.12 (t, J = 7.0 Hz, 1H, aromatic), 7.05 (dd, J = 10.9, 4.0 Hz, 1H, aromatic), 7.00–6.94 (m, 3H, aromatic), 6.88 (d, J = 2.2 Hz, 1H, aromatic), 6.69–6.61 (m, 1H, aromatic), 4.34 (q, J = 7.1 Hz, 3H, OCH₂), 3.62–3.50 (m, 1H, CH), 3.29–3.17 (m, 1H, CH), 3.15–3.02 (m, 1H, CH), 1.38 (t, J = 7.1 Hz, 3H, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 192.2, 168.7, 161.0, 151.8, 137.9, 136.2, 134.5, 130.1, 126.6, 123.1 (d, J = 295.1 Hz), 122.9, 122.4, 119.7, 119.3, 118.4, 118.1, 117.9, 111.4, 111.0, 107.6, 103.1, 85.11 (q, J = 33.6 Hz), 61.8, 50.9, 28.2, 14.1 ppm; MS (ESI): (m/z) 523 [M + Na]⁺; HRMS (ESI) (m/z) calcd for C₂₆H₂₄F₃N₂O₅ [M + H]⁺ 501.1631, found: 501.1621.
Ethyl-2-hydroxy-5-(2-hydroxybenzoyl)-1-(2-hydroxyethyl)-2-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (4h). Pale yellow solid; mp 123–120 °C; FT-IR (KBr): 3464, 3160, 2987, 1664, 1620, 1587, 1543, 1427, 1369, 1338, 1265, 1243, 1163, 1089, 1044, 979, 952, 769 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.45 (s, 1H, OH) 8.61 (s, 1H, OH), 8.14 (d, J = 1.3 Hz, 1H, hetero aromatic), 7.74 (s, 1H, hetero aromatic), 7.45 (t, J = 7.1 Hz, 2H, aromatic), 7.02 (d, J = 8.1 Hz, 1H, aromatic), 6.90 (t, J = 7.40 Hz, 1H, aromatic), 4.32 (q, J = 7.1 Hz, 2H, OCH₂), 4.13 (dt, J = 14.5, 3.7 Hz, 1H, CH), 3.84 (s, 2H, CH₂), 3.62–3.48 (m, 1H, CH), 2.03 (d, J = 3.4 Hz, 1H, OH), 1.36 (t, J = 7.1 Hz, 3H, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 192.8, 168.6, 161.5, 152.2, 135.0, 130.7, 128.0, 123.1 (d, J = 295.1 Hz), 119.5, 118.6, 118.1, 108.0, 103.1, 84.77 (q, J = 33.6 Hz), 62.7, 61.9, 52.1, 14.0 ppm; MS (ESI): (m/z) 402 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₁₈H₁₉F₃NO₆ [M + H]⁺ 402.1159, found: 402.1176.
1-(1-Benzyl-2-hydroxy-5-(2-hydroxybenzoyl)-2-(trifluoromethyl)-1,2-dihydropyridin-3-yl)ethanone (4i). Yellow solid; mp 103–105 °C; FT-IR (KBr): 3052, 2928, 1626, 1583, 1537, 1396, 1263, 1215, 1188, 1156, 1078, 970, 754, 704, 594 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ = 11.32 (s, 1H, OH), 9.40 (s, 1H, OH), 8.08 (d, J = 1.5 Hz, 1H, hetero aromatic), 7.52 (d, J = 1.2 Hz, 1H, hetero aromatic), 7.42–7.30 (m, 4H, aromatic), 7.27–7.24 (m, 2H, aromatic), 7.19 (dd, J = 7.8, 1.5 Hz, 1H, aromatic), 6.98 (dd, J = 8.4, 1.1 Hz, 1H, aromatic), 6.76 (m, 1H, aromatic), 5.09 (d, J = 15.1 Hz, 1H, CH), 4.63 (d, J = 15.2 Hz, 1H, CH), 2.53 (s, 3H, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 202.3, 192.3, 161.6, 151.5, 139.6, 135.7, 135.0, 130.2, 129.1, 128.4, 128.3, 123.2 (d, J = 296.1 Hz), 119.3, 118.5, 118.3, 111.6, 108.7, 85.9 (q, J = 33.6 Hz), 52.0, 26.3 ppm; MS (ESI): (m/z) 418 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₂H₁₉F₃NO₄ [M + H]⁺ 418.1266, found: 418.1264.
(5-Benzoyl-1-benzyl-6-hydroxy-6-(trifluoromethyl)-1,6-dihydropyridin-3-yl)(2-hydroxyphenyl)methanone (4j). Yellow solid; mp 118–120 °C; FT-IR (KBr): 3421, 3061, 2924, 1644, 1618, 1581, 1483, 1444, 1339, 1280, 1244, 1196, 1175, 1149, 1096, 985, 760, 695, 536 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.28 (s, 1H, OH) 9.43 (s, 1H, OH), 7.77 (d, J = 0.9 Hz, 1H, aromatic), 7.75 (d, J = 1.5 Hz, 1H, hetero aromatic), 7.70 (d, J = 1.5 Hz, 1H, hetero aromatic), 7.63–7.59 (m, 1H, aromatic), 7.58 (d, J = 1.6 Hz, 1H, aromatic), 7.50 (t, J = 7.7 Hz, 2H, aromatic), 7.41–7.33 (m, 4H, aromatic), 7.31 (m, 2H, aromatic), 7.21 (dd, J = 1.7, 8.0 Hz, 1H, aromatic), 6.94 (dd, J = 0.9, 8.4 Hz, 1H, aromatic), 6.73 (m, 1H, aromatic), 5.15 (d, J = 15.1 Hz, 1H, CH), 4.70 (d, J = 15.1 Hz, 1H, CH) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 200.4, 192.4, 161.5, 150.7, 141.2, 137.1, 135.7, 135.0, 133.2, 130.3, 129.5, 129.2, 128.6, 128.5, 128.4, 123.1 (d, J = 294.2 Hz), 119.1, 118.3, 118.2, 111.3, 108.1, 86.3 (q, J = 33.6 Hz), 52.1 ppm; MS (ESI): (m/z) 480 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₇H₂₁F₃NO₄ [M + H]⁺ 480.1393, found: 480.1402.
(1-Benzyl-2-hydroxy-5-(2-hydroxybenzoyl)-2-(trifluoromethyl)-1,2-dihydropyridin-3-yl)(furan-2-yl) methanone (4k). Wine red viscous liquid; FT-IR (KBr): 3031, 2927, 1628, 1584, 1536, 1460, 1389, 1338, 1283, 1246, 1176, 1131, 976, 760, 700, 664, 539 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.36 (brs, 1H, OH), 9.36 (s, 1H, OH), 8.26 (d, J = 1.5 Hz, 1H, hetero aromatic), 7.68 (brs, 1H, aromatic), 7.59 (s, 1H, aromatic), 7.32–7.41 (m, 5H, aromatic), 7.23–7.31 (m, 3H, aromatic), 6.93 (d, J = 8.2 Hz, 1H, aromatic), 6.76 (t, J = 7.9 Hz, 1H, aromatic), 6.60 (m, 1H, aromatic), 5.12 (d, J = 15.1 Hz, 1H, CH), 4.68 (d, J = 15.1 Hz, 1H, CH) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 192.5, 184.2, 161.6, 151.4, 150.6, 147.6, 139.8, 135.7, 135.0, 130.4, 129.1, 128.4, 128.3, 123.0 (d, J = 294.2 Hz), 120.8, 119.2, 118.3, 118.2, 112.5, 110.3, 108.4, 86.0 (q, J = 33.6 Hz), 52.1 ppm; MS (ESI): (m/z) 470 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₅H₁₉F₃NO₅ [M + H]⁺ 470.1209, found: 470.1197.

General procedure for the preparation of 2-hydroxybenzoyl-1,2-dihydropyridone-3-carboxylates (5a–e). Ethyl-4,4,4-trichloro-3-oxobutanoate (3h, 1.5 mmol) was added to a stirred solution of 3-formylchromone (1a, 1 mmol) and benzylamine (2b, 1.2 mmol) in CH₃CN (2 mL). The contents were stirred under reflux conditions for 6 h. After completion of the reaction (TLC), the residue was purified by column chromatography using silica gel (100 : 200, ethyl acetate/hexane 24 : 76) and afforded ethyl-1-benzyl-5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydropyridine-3-carboxylate 5a. Similarly, compounds 5b–e were prepared from the corresponding 3-formylchromones 1a–c and benzylamines 2b–d with 3h.
Ethyl-1-benzyl-5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (5a). Colourless solid; mp 104–106 °C; FT-IR (KBr): 3050, 2977, 1729, 1650, 1622, 1537, 1481, 1425, 1340, 1271, 1237, 1175, 1146, 1115, 1018, 949, 885, 754, 699 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.36 (s, 1H, OH), 8.51 (d, J = 2.6 Hz, 1H, hetero aromatic), 8.13 (d, J = 2.6 Hz, 1H, hetero aromatic), 7.51 (t, J = 7.4 Hz, 1H, aromatic), 7.44–7.28 (m, 6H, aromatic), 7.06 (d, J = 8.3 Hz, 1H, aromatic), 6.85 (t, J = 7.5 Hz, 1H, aromatic), 5.24 (s, 2H, CH₂), 4.39 (q, J = 7.1 Hz, 2H, OCH₂), 1.38 (t, J = 7.1 Hz, 3H, CH₃); ¹³C NMR (75 MHz, CDCl₃): δ 194.2, 164.0, 162.4, 158.6, 146.1, 143.5, 136.4, 134.7, 131.3, 129.2, 128.7, 128.7, 120.3, 118.9, 118.7, 118.3, 115.7, 61.6, 53.1, 14.2 ppm; MS (ESI): (m/z) 400 [M + Na]⁺; HRMS (ESI) calcd for C₂₂H₁₉NO₅Na [M + Na]⁺ 400.1155, found: 400.1148.
Ethyl-5-(2-hydroxybenzoyl)-1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (5b). Yellow solid; mp 142–144 °C; FT-IR (KBr): 3050, 2923, 1732, 1654, 1580, 1451, 1378, 1344, 1302, 1226, 1207, 1140, 1020, 960, 835, 737, 701, 674 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 11.15 (s, 1H), 8.51 (d, J = 2.7 Hz, 1H, hetero aromatic), 8.12 (d, J = 2.7 Hz, 1H, hetero aromatic), 7.42–7.36 (m, 5H, aromatic), 7.31 (dd, J = 8.4, 2.0 Hz, 1H, aromatic), 7.12 (d, J = 1.3 Hz, 1H, aromatic), 6.96 (d, J = 8.5 Hz, 1H, aromatic), 5.23 (s, 2H, CH₂), 4.39 (q, J = 7.1 Hz, 2H, OCH₂), 2.21 (s, 3H, CH₃), 1.39 (t, J = 7.1 Hz, 3H, CH₃); ¹³C NMR (75 MHz, CDCl₃): δ 194.1, 163.9, 160.3, 158.6, 146.0, 143.5, 137.3, 134.8, 131.0, 129.2, 128.7, 128.7, 120.1, 120.4, 118.4, 118.1, 115.7, 61.4, 52.9, 20.3, 14.1 ppm; MS (ESI): (m/z) 414 [M + Na]⁺; HRMS (ESI) (m/z) calcd for C₂₃H₂₂O₅N [M + H]⁺ 392.1492, found: 392.1481.
Ethyl-5-(2-hydroxybenzoyl)-1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (5c). Colourless solid; mp 130–132 °C; FT-IR (KBr): 3444, 3013, 1728, 1623, 1603, 1537, 1426, 1404, 1340, 1270, 1204, 1175, 1122, 1019, 949, 825, 741, 703, 641 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 11.20 (s, 1H), 8.50 (d, J = 2.7 Hz, 1H, hetero aromatic), 8.13 (d, J = 2.7 Hz, 1H, hetero aromatic), 7.45 (dd, J = 8.9, 2.6 Hz, 1H, aromatic), 7.43–7.36 (m, 5H, aromatic), 7.35 (d, J = 2.5 Hz, 1H, aromatic), 7.03 (d, J = 8.9 Hz, 1H, aromatic), 5.23 (s, 2H, CH₂), 4.40 (q, J = 7.1 Hz, 2H, OCH₂), 1.39 (t, J = 7.1 Hz, 3H, CH₃); ¹³C NMR (75 MHz, CDCl₃): δ 193.1, 163.7, 160.7, 158.2, 146.1, 143.1, 136.1, 134.4, 130.2, 129.3, 128.9, 128.8, 123.7, 120.7, 120.3, 119.1, 115.1, 61.6, 53.3, 14.1 ppm; MS (ESI): (m/z) 412 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₂H₁₉O₅NCl [M + H]⁺ 412.0946, found: 412.0932.
Ethyl-5-(2-hydroxybenzoyl)-1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (5d). Colourless solid; mp 100–102 °C; FT-IR (KBr): 3050, 2853, 1726, 1650, 1624, 1536, 1515, 1426, 1341, 1270, 1218, 1179, 1144, 1035, 803, 752, 656 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.37 (s, 1H, OH), 8.49 (d, J = 2.4 Hz, 1H, hetero aromatic), 8.12 (d, J = 2.4 Hz, 1H, hetero aromatic), 7.51 (t, J = 7.4 Hz, 1H, aromatic), 7.37 (d, J = 7.4 Hz, 1H, aromatic), 7.33 (d, J = 8.3 Hz, 2H, aromatic), 7.06 (d, J = 8.3 Hz, 1H, aromatic), 6.91 (d, J = 8.5 Hz, 2H, aromatic), 6.86 (t, J = 7.4 Hz, 1H, aromatic), 5.17 (s, 2H, CH₂), 4.39 (q, J = 7.1 Hz, 2H, OCH₂), 3.81 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H, CH₃); ¹³C NMR (75 MHz, CDCl₃): δ 194.2, 164.0, 162.4, 159.9, 158.7, 145.9, 143.4, 136.3, 131.3, 130.4, 126.6, 120.1, 118.9, 118.7, 118.4, 115.6, 114.5, 61.5, 55.2, 52.7, 14.2 ppm; MS (ESI): (m/z) 430 [M + Na]⁺; HRMS (ESI) (m/z) calcd for C₂₃H₂₂NO₆ [M + H]⁺ 408.1247, found: 408.1261.
Ethyl-1-(4-fluorobenzyl)-5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (5e). Colourless solid; mp 120–122 °C; FT-IR (KBr): 3052, 2982, 1722, 1625, 1603, 1538, 1511, 1401, 1342, 1272, 1222, 1142, 1092, 802, 758, 657, 593, 439 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.35 (s, 1H, OH), 8.51 (d, J = 2.7 Hz, 1H, hetero aromatic), 8.15 (d, J = 2.7 Hz, 1H, hetero aromatic), 7.56–7.50 (m, 1H, aromatic), 7.42–7.39 (m, 3H, aromatic), 7.11–7.05 (m, 3H, aromatic), 6.91–6.86 (m, 1H, aromatic), 5.21 (s, 2H, CH₂), 4.39 (q, J = 7.1 Hz, 2H, OCH₂), 1.41–1.35 (t, J = 7.1 Hz, 3H, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 194.2, 163.8, 163.8, 163.7, 162.4, 161.8, 158.5, 145.9, 143.5, 136.4, 131.3, 130.6, 130.6, 120.3, 118.9, 118.8, 118.3, 116.2, 116.0, 115.9, 61.5, 52.7, 14.1 ppm; MS (ESI): (m/z) 418 [M + Na]⁺; HRMS (ESI) (m/z) calcd for C₂₂H₁₉FNO₅ [M + H]⁺ 396.1247, found: 396.1263.

General procedure for the preparation of 2-hydroxy-benzoyl-trifluoromethyl-benzopyrido-1,3-oxazole-4-carboxylates (7a–f). Ethyl-4,4,4-trifluoro-3-oxobutanoate (3a, 1.5 mmol) was added to a stirred solution of 3-formylchromone (1a, 1 mmol) and 2-aminophenol (6a, 1.2 mmol) in CH₃CN (2 mL). The contents were stirred under reflux conditions for 4 h. After completion of the reaction (TLC), the residue was purified by column chromatography using silica gel (100 : 200, ethyl acetate/hexane 8 : 92) and afforded ethyl-2-(2-hydroxybenzoyl)-4a-(trifluoromethyl)-4aH-benzo[d]pyrido[2,1-b][1,3]oxazole-4-carboxylate 7a. Similarly, compounds 7b–f were prepared from the corresponding 3-formylchromones 1a–c and 2-aminophenols 6a–c with 3a and 3g.
Ethyl-2-(2-hydroxybenzoyl)-4a-(trifluoromethyl)-4aH-benzo[d]pyrido[2,1-b][1,3]oxazole-4-carboxylate (7a). Yellow solid; mp 160–162 °C; FT-IR (KBr): 3066, 2963, 1699, 1622, 1590, 1528, 1488, 1314, 1287, 1213, 1179, 1161, 1069, 966, 764, 737, 707 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.49 (s, 1H, OH), 8.25 (s, 1H, hetero aromatic), 7.98 (s, 1H, hetero aromatic), 7.49–7.59 (m, 2H, aromatic), 7.14–7.24 (m, 3H, aromatic), 7.08 (d, 2H, J = 8.3 Hz, aromatic), 7.02–6.94 (m, 1H, aromatic), 4.30 (m, 2H, OCH₂), 1.38 (t, 3H, J = 7.0 Hz, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 193.2, 162.5, 162.1, 148.2, 138.2, 135.7, 135.6, 131.0, 129.7, 127.1, 122.9, 121.2 (d, J = 296.9 Hz), 119.5, 118.9, 118.5, 112.2, 111.4, 110.5, 106.2, 84.3 (q, J = 35.4 Hz), 61.2, 14.2 ppm; MS (ESI): (m/z) 454 [M + Na]⁺; HRMS (ESI) (m/z) calcd for C₂₂H₁₇F₃NO₅ [M + H]⁺ 432.1053, found: 432.1044.
Ethyl-2-(2-hydroxy-5-methylbenzoyl)-4a-(trifluoromethyl)-4aH-benzo[d]pyrido[2,1-b][1,3]oxazole-4-carboxylate (7b). Yellow solid; mp 125–127 °C; FT-IR (KBr): 3090, 2925, 1722, 1626, 1584, 1527, 1488, 1398, 1315, 1261, 1196, 1180, 1065, 971, 758 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 11.25 (s, 1H, OH), 8.24 (d, J = 1.0 Hz, 1H, hetero aromatic), 7.98 (d, J = 1.2 Hz, 1H, hetero aromatic), 7.34 (dd, J = 8.4, 2.1 Hz, 1H, aromatic), 7.31 (d, J = 1.5 Hz, 1H, aromatic), 7.23–7.15 (m, 3H, aromatic), 7.09–7.05 (m, 1H, aromatic), 6.99 (d, J = 8.4 Hz, 1H, aromatic), 4.44–4.30 (m, 2H, OCH₂), 2.35 (s, 3H, CH₃), 1.38 (t, J = 7.0 Hz, 3H, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 193.1, 162.5, 159.9, 148.2, 138.0, 136.7, 135.7, 130.6, 129.7, 128.0, 127.0, 122.9, 121.2 (d, J = 296.1 Hz), 119.2, 118.2, 112.3, 111.3, 110.5, 106.1, 94.3 (q, J = 35.4 Hz), 61.2, 20.6, 14.2 ppm; MS (ESI): (m/z) 466 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₃H₁₉F₃NO₅ [M + H]⁺ 446.1215, found: 446.1188.
Ethyl-2-(5-chloro-2-hydroxybenzoyl)-4a-(trifluoromethyl)-4aH-benzo[d]pyrido[2,1-b][1,3]oxazole-4-carboxylate (7c). Yellow solid; mp 150–152 °C; FT-IR (KBr): 3088, 2983, 1720, 1692, 1625, 1584, 1528, 1494, 1466, 1319, 1280, 1258, 1235, 1208, 1069, 966, 753 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 11.34 (s, 1H, OH), 8.23 (d, J = 1.1 Hz, 1H, hetero aromatic), 7.99 (d, J = 1.1 Hz, 1H, hetero aromatic), 7.51–7.45 (m, 2H, aromatic), 7.25–7.21 (m, 2H, aromatic), 7.20–7.17 (m, 1H, aromatic), 7.11–7.07 (m, 1H, aromatic), 7.04 (d, J = 8.8 Hz, 1H, aromatic), 4.44–4.31 (m, 2H, OCH₂), 1.39 (t, J = 7.1 Hz, 3H, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 191.9, 162.3, 130.5, 148.3, 138.4, 135.5, 135.2, 129.8, 129.5, 127.4, 123.6, 123.0, 121.1 (d, J = 296.1 Hz), 120.2, 120.1, 111.9, 11.4, 110.7, 106.6, 94.3 (q, J = 35.4 Hz), 61.3, 14.2 ppm; MS (ESI): (m/z) 466 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₂H₁₆ClF₃NO₅ [M + H]⁺ 466.0669, found: 466.0632.
Ethyl-2-(2-hydroxybenzoyl)-8-methyl-4a-(trifluoromethyl)-4aH-benzo[d]pyrido[2,1-b][1,3]oxazole-4-carboxylate (7d). Yellow solid; mp 182–184 °C; FT-IR (KBr): 3082, 2922, 1702, 1621, 1587, 1526, 1401, 1349, 1267, 1213, 1189, 1060, 965, 816, 759, 663 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.51 (s, 1H, OH) 8.25 (s, 1H, hetero aromatic), 7.96 (s, 1H, hetero aromatic), 7.49–7.59 (m, 2H, aromatic), 6.95–7.10 (m, 5H, aromatic), 4.27–4.45 (m, 2H, OCH₂), 2.34 (s, 3H, CH₃), 1.38 (t, 3H, J = 7.2 Hz, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 193.2, 162.5, 162.1, 146.3, 138.2, 135.7, 135.5, 133.1, 131.0, 129.6, 127.5, 120.5 (d, J = 297.1 Hz), 119.5, 118.9, 118.5, 112.1, 111.1, 110.9, 106.2, 95.1 (d, J = 35.7 Hz), 61.2, 21.1, 14.2 ppm; MS (ESI): (m/z) 446 [M + H]⁺; HRMS-ESI (m/z) calcd for C₂₃H₁₉F₃NO₅ [M + H]⁺ 446.1209, found: 446.1223.
Ethyl-8-chloro-2-(2-hydroxybenzoyl)-4a-(trifluoromethyl)-4aH-benzo[d]pyrido[2,1-b][1,3]oxazole-4-carboxylate (7e). Yellow solid; mp 170–172 °C; FT-IR (KBr): 3086, 2923, 1701, 1624, 1592, 1530, 1485, 1396, 1295, 1237, 1208, 1162, 1069, 983, 821, 758, 693 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.45 (s, 1H, OH), 8.24 (d, J = 1.0 Hz, 1H, hetero aromatic), 7.87 (d, J = 0.8 Hz, 1H, hetero aromatic), 7.59–7.49 (m, 2H, aromatic), 7.15 (dd, J = 6.1, 1.9 Hz, 2H, aromatic), 7.11–7.05 (m, 2H, aromatic), 7.02–6.95 (m, 1H, aromatic), 4.46–4.28 (m, 2H, OCH₂), 1.38 (t, J = 7.1 Hz, 3H, CH₃) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 193.1, 162.2, 162.2, 146.9, 137.9, 136.0, 135.5, 131.0, 130.9, 128.2, 126.7, 121.0 (d, J = 296.1 Hz), 119.3, 119.0, 118.6, 112.9, 112.0, 111.1, 106.9, 95.9 (d, J = 35.4 Hz), 61.4, 14.2 ppm; MS (ESI): (m/z) 466 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₂H₁₆ClF₃NO₅ [M + H]⁺ 466.0663, found: 466.0388.
[4-(2-Furylcarbonyl)-4a-(trifluoromethyl)-4aH-benzo[d]pyrido[2,1-b][1,3]oxazol-2-yl](2-hydroxyphenyl)methanone (7f). Yellow solid; mp 154–156 °C; FT-IR (KBr): 3063, 1628, 1588, 1510, 1463, 1278, 1246, 1189, 1155, 1086, 977, 754, 711 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ 11.51 (s, 1H), 8.33 (brs, 1H hetero aromatic), 8.05 (brs, 1H, hetero aromatic), 7.69 (d, J = 0.8 Hz, 1H), 7.67–7.60 (m, 1H), 7.60–7.52 (m, 1H), 7.28 (s, 1H), 7.25–7.18 (m, 3H), 7.09 (dd, J = 10.7, 5.6 Hz, 2H), 7.02 (t, J = 7.2 Hz, 1H), 6.60 (dd, J = 3.5, 1.7 Hz, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃): δ 193.2, 176.8, 162.1, 152.5, 148.7, 146.7, 137.9, 135.8, 135.3, 131.0, 129.5, 127.2, 122.9, 120.4 (d, J = 296.5 Hz), 119.6, 119.5, 118.9, 118.5, 112.5, 112.2, 111.5, 110.6, 94.6 (d, J = 35.7 Hz) ppm; MS (ESI): (m/z) 454 [M + H]⁺; HRMS (ESI) (m/z) calcd for C₂₄H₁₅F₃NO₅ [M + H]⁺ 454.0902, found: 454.0866.

Acknowledgements

The authors thank Dr S. Chandrasekhar, Director, CSIR-IICT for constant encouragement. B. China Raju acknowledges SERB-DST, New Delhi for financial support (SB/EMEQ-301/2013).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra10185a

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