Facile one-pot three-component synthesis of diverse 2,3-disubstituted isoindolin-1-ones using ZrO₂ nanoparticles as a reusable dual acid–base solid support under solvent-free conditions

Abstract

A facile one-pot three-component protocol for the synthesis of a series of multi-functionalized 2,3-disubstituted isoindolin-1-ones has been developed using ZrO₂ nanoparticles as a dual acid–base solid support under solvent-free conditions. The surface of the ZrO₂ nanoparticles, which is embedded with active hydroxyl groups, oxyanions and Zr⁴⁺ ions, efficiently catalyses the condensation of 2-carboxybenzaldehyde, aliphatic amines and a nucleophile (enamines/6-amino 1,3-dimethyluracil/1,3-cyclohexadiones/indole) to produce 2,3-disubstituted isoindolin-1-ones. Operational simplicity, reduced reaction time and temperature, elimination of solvent, high yields of products, wider substrate scope, utilization of ZrO₂ nanoparticles as a solid support, and its nearly undiminished catalytic activity after repeated applications, are the key features of the present methodology.

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Introduction

The wedding of two emergent areas of chemical research of the twenty-first century, nanocatalysis and green chemistry, holds the key to sustainability.^1a In recent years, metal-based nanoparticles (NPs) have been extensively used for the enhancement of the efficiency of organic synthesis.¹ These extremely small-sized NPs have a large surface area to volume ratio, which promotes enhanced catalysis. Moreover the nanocatalysts make the reactions operationally simpler and economical due to easy separation from the reaction mixtures.^1a,d As a part of our research interest in exploring the catalytic performance of NPs in multi-component synthesis of biologically significant heterocycles,² herein, we sought to explore the catalytic activity and efficiency of ZrO₂ NPs. The surface of ZrO₂ NPs is embedded with active hydroxyl groups, oxyanions and Zr⁴⁺ ions which attributes to the combined acid–base property.^2d,3 This interesting dual nature of ZrO₂ NPs has not been broadly explored, especially, in multi-component reactions under solvent-free conditions for the synthesis of bio-active building blocks.

The isoindoline scaffolds are very important because of their widespread occurrence in numerous drug molecules of natural and synthetic origin.⁴ The synthesis of isoindolin-1-ones has attracted a great deal of attention since this core structure is present in many natural products of profound biological potential such as zopiclone,⁵ pagoclone,⁶ nafodone⁷ and AKS 186 (ref. 8) (Fig. 1). Compounds with isoindolin-1-one structural motif are found in several antimicrobial,⁹ anti-viral,¹⁰ anti HIV,¹¹ antiarrhythmic,⁷ immunostimulant and anticancer¹² agents. Despite of their immense pharmacological, industrial and synthetic importance, comparatively less number of methodologies are reported in the literature for the synthesis of isoindoline-1-ones.¹³ On the other hand although these methods are helpful to construct the biologically important scaffold, several factors such as prolonged reaction time, high reaction temperature and presence of solvent in the synthesis restrict the ‘Green chemistry’ aspects.¹⁴ To the best of our knowledge, there is no efficient general protocol for the synthesis of isoindolin-1-one scaffolds using green catalyst. With the objective of developing a benign, clean, efficient and straightforward methodology for the synthesis of isoindoline-1-ones, herein, we wish to report our design by assembling the basic building blocks, 2-carboxybenzaldehyde (1), aliphatic amines (2) and a nucleophile (3) using ZrO₂ nanoparticles as a reusable dual acid–base solid support under solvent-free conditions (Scheme 1).

Fig. 1 Representative pharmacologically important compounds with isoindolin-1-one core.

Scheme 1 Synthesis of multi-functionalized isoindolin-1-one derivatives (4–7).

Results and discussion

During our initial studies towards the development of ZrO₂ NPs as a solid support for the one-pot three-component synthesis of isoindolin-1-ones (4) under solvent-free conditions, we attempted to optimize the reaction conditions taking 2-carboxybenzaldehyde (1), benzyl amine (2) and 5,5-dimethyl-3-p-tolylamino-cyclohex-2-enone (3) in 1 : 1 : 1 molar proportion (Scheme 2). In this process, various parameters such as the effect of catalysts, solid supports, temperature and solvents at different experimental conditions were investigated and the results are summarised in Table 1. When the mixture of reactants 1, 2 and 3 was heated at reflux in EtOH and DMF separately for 8 and 6 h respectively, the yield of the product 4a was achieved up to ∼60% (Table 1, entries 1 and 2). Under solvent-free conditions, the yield of the product 4a improved marginally (∼65%) within a reduced reaction time (∼4 h) (Table 1, entry 3). A significant improvement of the yield of product 4a (∼75%) was achieved with further reduction of reaction time (∼3 h) when the reaction was carried out in EtOH with the addition of ZrO₂ NPs as catalyst (20 mol%) (Table 1, entry 4). In presence of the same ZrO₂ NPs catalyst (20 mol%), the yield of the product did not improve much upon changing the reaction medium (e.g. H₂O, CHCl₃ and EtOH–H₂O in 4 : 1 v/v) (Table 1, entries 5–7). These results suggest that, the role of solvent is not so important to carry out the following synthesis. In this context, when we tried to optimize the reaction conditions by eliminating the solvent and using different solid supports (e.g. ZrO₂ NPs, silica gel of 60–120 mesh and Fe₃O₄–SiO₂ NPs), the yield of the product 4a was enhanced (Table 1, entries 8–10). Next we have done the optimization study taking basic alumina (500 mg) as solid support under the same reaction condition. The yield of the product decreased slightly (∼60%) with the generation of several side products (Table 1, entry 11). It suggests that, the reaction profile is not clear in presence of basic alumina as solid support. Gratifyingly, a cleaner reaction profile with high yield of 4a (∼85%) was observed when ZrO₂ NPs (500 mg) was used as solid support and the reaction mixture was stirred at 100 °C for 2 h (Table 1, entry 12). It is envisioned that, the amphoteric nature (dual acid and base) of the ZrO₂ NPs as solid support helps to generate the best yield of the final product 4a and also the adsorption of the reactant molecules on the solid surface of ZrO₂ NPs increases the local concentration of the reactants around the active sites considerably causing significant acceleration of the reaction rate. Then we carried out the optimization study to examine the influence of the stoichiometry of nano ZrO₂ (200 mg to 1.0 g) at different temperatures (50–100 °C) for the best yield of 4a (Table 1, entries 12–18). The study revealed that the best yield of the product 4a can be obtained when the substrates 1, 2 and 3 taking 1.0 mmol each are allowed to react on the solid surface of nano ZrO₂ (250 mg) at 70 °C under solvent-free conditions (Table 1, entry 18).

Scheme 2 Optimization of the reaction conditions.

Table 1 Optimization of reaction conditions for the synthesis of 4a

Entry	Solvent (5 ml)	Catalyst/solid support	Loading	Time (h)	Temp. (°C)	Yield^a (%)
a Isolated yields (%).
1	EtOH	—	—	8	Reflux	60
2	DMF	—	—	6	Reflux	58
3	—	—	—	4	Reflux	65
4	EtOH	ZrO2 NPs	20 mol%	3	Reflux	75
5	H2O	ZrO2 NPs	20 mol%	3	Reflux	72
6	CHCl3	ZrO2 NPs	20 mol%	3	Reflux	70
7	EtOH–H2O (4 : 1)	ZrO2 NPs	20 mol%	3	Reflux	75
8	—	ZrO2 NPs	500 mg	2	100	85
9	—	Silica gel (60–120 mesh)	500 mg	2	100	70
10	—	Fe3O4–SiO2 NPs	500 mg	2	100	68
11	—	Basic alumina	500 mg	2	100	60
12	—	ZrO2 NPs	500 mg	2	80	85
13	—	ZrO2 NPs	500 mg	2	70	86
14	—	ZrO2 NPs	500 mg	2	50	65
15	—	ZrO2 NPs	1000 mg	2	70	84
16	—	ZrO2 NPs	300 mg	2	70	87
17	—	ZrO2 NPs	200 mg	2	70	82
18	—	ZrO2 NPs	250 mg	2	70	87

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With the optimized reaction condition in hand (Table 1, entry 18), next the scope and generality of this protocol was assessed by employing various aliphatic amines and nucleophiles (enamines/6-amino 1,3-dimethyluracil/1,3-cyclohexadiones/indole) along with 2-carboxybenzaldehyde to obtain various isoindolin-1-ones derivatives (Table 2). In all cases, the formation of the final products (4–7) were confirmed by IR, ¹H NMR, ¹³C NMR spectroscopy, elemental analysis and also by matching the melting points of some of the compounds with the reported values.^13c,16 The X-ray crystal structures of 4t and 5c (Fig. 2) further confirm the formation of products without any ambiguity.

Table 2 Synthesis of multi-functionalized isoindolin-1-one derivatives (4–7)^a

a Isolated yield (%).

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Fig. 2 Crystal structures of compounds 4t and 5c. Color code: red, oxygen; blue, nitrogen; grey, carbon; white, hydrogen; greenish-yellow, fluorine (CCDC 1428628 and 1434728†).

The ZrO₂ NPs were prepared via sol–gel method by condensation of ZrO₂Cl₂·8H₂O under basic medium (see ESI† for details) and analyzed by different spectroscopic (FT-IR, UV-Vis) and analytical (XRD, FE-SEM, HR-TEM) techniques. Scanning electron microscopic (SEM) images taken at the operating voltage of 5.0 kV elucidate the morphology of the freshly prepared and 5 times reused ZrO₂ NPs. The SEM images show the formation of spherical and nearly uniform sized nanoparticles and also demonstrate that the grains of different size form soft aggregates under the processing conditions (Fig. 3a and b). The morphology and uniformity of particle size of freshly prepared and 5 times reused ZrO₂ NPs were further confirmed by high resolution transmission electron microscopy (HR-TEM) study (Fig. 3c and d). The crystallite size of ZrO₂ NPs in HR-TEM images is found to be within the range of 6–14 nm.

Fig. 3 SEM images of ZrO₂ NPs (a) before reaction and (b) after 5 times applications in reaction. HRTEM images of ZrO₂ NPs (c) before use in reaction and (d) after five times applications.

Elemental analyses of the as-synthesized ZrO₂ NPs were performed using EDX equipped onto TEM. Quantitative EDX analysis showed that Zr and O are the main elemental components (Fig. 4a). In the UV-Vis spectrum (Fig. 4b) of freshly prepared ZrO₂ nanoparticles, a maxima was observed at 259 nm, which is equivalent to a band gap of 4.76 eV. The powder X-ray diffraction pattern of the freshly prepared and reused ZrO₂ NPs (Fig. 4c) indicates the formation of tetragonal ZrO₂ (^tZrO₂) NPs and its unchanged surface nature after several reuses.¹⁴ The peaks at 2θ = 30.3°, 50.5° and 59.8° are assigned to the (101), (112) and (103) reflection planes respectively which supports the purely tetragonal nature of the synthesized NPs. The infrared spectrum of fresh ZrO₂ was depicted in Fig. 4d. The fresh ZrO₂ showed a characteristic broad band at 3453 cm⁻¹ and a broad band between 1600 and 1635 cm⁻¹, which are assigned to the O–H modes of chemisorbed water and/or terminated hydroxides at the surface of the nanoparticles.¹⁵

Fig. 4 (a) TEM-EDX spectra of ZrO₂ NPs, (b) UV-Vis spectrum of ZrO₂ NPs, (c) XRD spectra of (A) freshly prepared ZrO₂ NPs and (B) reused ZrO₂ NPs after 5th cycle, (d) FT-IR spectra of fresh ZrO₂ NPs.

A plausible mechanism for the formation of isoindolin-1-ones derivatives 4–7 in presence of ZrO₂ NPs under solvent free condition has been depicted in Scheme 3. The surface of ZrO₂ NPs is surrounded with active hydroxyl groups, oxyanions and Zr⁴⁺ ions which can act as dual acid–base catalyst for the condensation reactions. Initially, Zr⁴⁺ ion of ZrO₂ NPs acts as strong Lewis acid acceptor and activates the carbonyl group to facilitate the condensation between 2-carboxybenzaldehyde (1) and aliphatic amines (2) to generate intermediate 8. Then ZrO₂ NPs catalyse a Michael type addition between 8 and nucleophile 3 to produce intermediate 9. Subsequently, the acidic and basic sites of ZrO₂ NPs assist the intermediate 9 to undergo intramolecular electrophilic cyclization and tautomerization to furnish the final products isoindolin-1-ones 4–7.

Scheme 3 Plausible mechanism for the formation of isoindolin-1-one derivatives 4–7.

The reusability test of ZrO₂ NPs was carried out separately for the synthesis of 4a and 5a under the optimized reaction conditions (Table 1, entry 17). At the end of the reactions, the reaction mixtures were ultrasonicated with ethylacetate and ethanol to extract the products 4a and 7a from the surface of the solid support and the solid ZrO₂ nanoparticles were separated easily from the reaction mixture by simple decantation method. Then ZrO₂ NPs were washed three times with ethylacetate (3 × 5 ml), followed by washing with ethanol and chloroform, dried at room temperature under vacuum to eliminate residual solvents and used for the next cycle. The recyclability test for the synthesis of 4a and 5a were performed with the recovered catalyst upto five times. The result shows that ZrO₂ NPs retains its initial catalytic activity almost undiminished even after repeated applications (Fig. 5).

Fig. 5 Reusability test of ZrO₂ NPs for the formation of 4a (blue bar) and 5a (green bar).

Conclusions

In summary, an efficient, green and sustainable methodology for the synthesis of a series of biologically important multi-functionalized isoindolin-1-one derivatives has been developed. The method involves one-pot three-component condensation of 2-carboxybenzaldehyde, aliphatic amines and a nucleophile (enamines/6-amino 1,3-dimethyluracil/1,3-cyclohexadiones/indole) in presence of ZrO₂ nanoparticles as a reusable dual acid–base solid support under solvent-free conditions. The surface of the ZrO₂ nanoparticles which is embedded with active hydroxyl groups, oxyanions and Zr⁴⁺ ions, efficiently catalyses the condensation to produce 2,3-disubstituted isoindolin-1-ones. This is a promising approach from sustainable and practical chemistry viewpoints since the general synthetic protocol offers several advantages including short reaction times, readily available starting materials, recyclability of the catalyst and high isolated yields of the products. This simple, environmentally benign and convenient methodology may be useful in design and synthesis of other biologically important molecules.

Experimental section

General methods

Solvents and chemicals were purchased from commercial suppliers and used without further purification. Catalyst and starting materials were prepared according to reported procedure. Melting points were measured in open capillary tubes and were uncorrected. JASCO FT/IR-6300 spectrophotometer was used for IR spectra. ¹H (300 MHz) and ¹³C NMR (75 MHz) spectra were performed on Bruker instrument (300 MHz) in DMSO-d₆. Elemental analyses (C, H and N) were recorded using Perkin-Elmer 240C elemental analyzer. The X-ray diffraction data for crystallized compounds were collected with MoKα radiation at 296 K using the Bruker APEX-II CCD System. The morphological analysis of the resultant nanoparticles was confirmed by HRTEM, using a HRTEM, JEOL JEM 2010 at an accelerating voltage of 200 kV and fitted with a CCD camera. The crystallinity of synthesized ZrO₂ nanoparticles was determined and confirmed by XRD analysis. The diffractogram was documented from PANalytical, XPERT-PRO diffractometer using Cu_α (λ = 1.54060) as X-ray source. ZEISS Evo-MA 10 Scanning Electron Microscope was used for SEM study.

General synthetic procedure for the preparation of compounds 4–7

An equimolar mixture of 2-carboxybenzaldehyde (1) (1.0 mmol), aliphatic amine (2) (1.0 mmol) and a nucleophile (3a–d) (1.0 mmol) was dissolved in minimum quantity of ethanol (0.5 ml) in a 50 ml round bottomed flask. Then the mixture was soaked on ZrO₂ nanoparticles (250 mg) by stirring for 10 min and the solvent was removed under reduced pressure at 50 °C. The resulting solid mixture was stirred at 65–70 °C in an oil bath for 1.0–2 h. Progress of the reactions was monitored by thin layer chromatography (TLC). At the end of the reaction, the products (4–7) were extracted from the surface of ZrO₂ nanoparticles using ethylacetate, followed by ethanol under ultrasonication. The ZrO₂ nano-particles were separated by decantation method and the separated organic phase was collected in another round bottom flask. The organic layer was concentrated by evaporating the solvent and then it was purified by column chromatography on silica gel (60–120 mesh) using ethylacetate/hexane (∼2 : 3) as the eluent.

Characterization data of 4a–u

4a. White crystalline solid, mp 160–162 °C; IR (KBr) 3321, 1689, 1616, 1560 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.83 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 7.8 Hz, 3H), 7.20–7.16 (m, 3H), 6.87 (d, J = 7.5 Hz, 2H), 6.38 (s, 1H), 6.09 (d, J = 8.1 Hz, 2H), 5.62 (s, 1H), 4.85 (d, J = 14.7 Hz, 1H), 4.36 (d, J = 14.7 Hz, 1H), 2.32–2.24 (m, 1H), 2.16 (s, 3H), 2.12–2.06 (d, J = 16.5 Hz, 1H), 1.80 (d, J = 16.5 Hz, 1H), 1.65 (d, J = 16.5 Hz, 1H), 0.86 (s, 3H), 0.83 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.7, 168.2, 161.3, 145.7, 138.2, 136.8, 134.4, 132.7, 132.2, 130.0, 128.9, 128.8, 128.5, 127.5, 125.3, 124.6, 122.9, 103.1, 56.1, 50.1, 45.9, 40.8, 32.1, 30.1, 26.7, 21.1; C₃₀H₃₀N₂O₂ (450.57): calcd C 79.97, H 6.71, N 6.22; found C 79.79, H 6.40, N 6.08.

4b. White crystalline solid, mp 148–150 °C; IR (KBr) 3326, 1687, 1612, 1559 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.84 (d, J = 7.5 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.28 (bs, 3H), 7.23–7.19 (m, 3H), 6.61 (d, J = 8.7 Hz, 2H), 6.41 (s, 1H), 6.18 (d, J = 8.7 Hz, 2H), 5.52 (s, 1H), 4.85 (d, J = 14.4 Hz, 1H), 4.40 (d, J = 14.7 Hz, 1H), 3.65 (s, 3H), 2.28 (d, J = 16.8 Hz, 1H), 2.10 (d, J = 16.2 Hz, 1H), 1.80–1.61 (m, 2H), 0.88 (s, 3H), 0.85 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.6, 168.3, 161.8, 158.6, 145.8, 138.2, 132.6, 132.2, 129.7, 128.8, 128.8, 128.5, 127.5, 127.2, 124.5, 122.8, 114.6, 102.8, 56.2, 55.7, 50.0, 45.9, 40.7, 32.0, 30.1, 26.7; C₃₀H₃₀N₂O₃ (466.57): calcd C 77.23, H 6.48, N 6.00; found C 76.93, H 6.25, N 5.78.

4c. White crystalline solid, mp 182–184 °C; IR (KBr) 3332, 1689, 1615, 1562 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.84 (d, J = 7.5 Hz, 1H), 7.55–7.42 (m, 2H), 7.29–7.19 (m, 6H), 6.78 (t, J = 8.4 Hz, 2H), 6.40 (s, 1H), 6.21–6.16 (m, 2H), 5.51 (s, 1H), 4.87 (d, J = 14.4 Hz, 1H), 4.38 (d, J = 14.7 Hz, 1H), 2.28 (d, J = 16.5 Hz, 1H), 2.10 (d, J = 6.9 Hz, 1H), 1.78–1.62 (m, 2H), 0.89 (s, 3H), 0.86 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.1, 167.6, 160.2, 145.0, 137.5, 132.3, 132.1, 131.5, 128.2, 128.0, 127.9, 127.8, 127.7, 126.9, 126.7, 126.6, 123.9, 122.2, 122.1, 115.8, 115.5, 103.1, 55.4, 49.4, 45.3, 40.1, 31.5, 29.4, 26.0; C₂₉H₂₇FN₂O₂ (454.53): calcd C 76.63, H 5.99, N 6.16; found C 76.93, H 6.10, N 5.98.

4d. White crystalline solid, mp 190–192 °C; IR (KBr) 3299, 1688, 1683, 1615, 1566 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.93 (d, J = 7.2 Hz, 1H), 7.62–7.50 (m, 2H), 7.35–7.25 (m, 6H), 7.12 (d, J = 8.7 Hz, 2H), 6.47 (s, 1H), 6.18 (d, J = 8.4 Hz, 2H), 5.57 (s, 1H), 4.94 (d, J = 14.7 Hz, 1H), 4.43 (d, J = 14.4 Hz, 1H), 2.33 (d, J = 16.5 Hz, 1H), 2.16 (d, J = 16.5 Hz, 1H), 1.88–1.72 (m, 2H), 0.96 (s, 3H), 0.94 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.6, 167.9, 159.6, 145.3, 137.8, 135.4, 132.5, 131.9, 129.2, 128.6, 128.5, 128.2, 127.3, 126.0, 124.3, 122.5, 104.0, 55.7, 49.9, 45.7, 40.4, 32.0, 29.8, 26.3; C₂₉H₂₇ClN₂O₂ (470.98): calcd C 73.95, H 5.78, N 5.95; found C 73.59, H 5.40, N 5.68.

4e. White crystalline solid, mp 220–222 °C; IR (KBr) 3339, 1689, 1610, 1568 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.87 (d, J = 7.2 Hz, 1H), 7.54–7.47 (m, 2H), 7.28–7.19 (m, 6H), 7.01 (d, J = 4.8 Hz, 2H), 6.40 (s, 1H), 6.16 (s, 1H), 6.07 (s, 1H), 5.58 (s, 1H), 4.89 (d, J = 14.7 Hz, 1H), 4.35 (d, J = 14.4 Hz, 1H), 2.31 (d, J = 16.8 Hz, 1H), 2.12 (d, J = 16.5 Hz, 1H), 1.85–1.68 (m, 2H), 0.90 (s, 3H), 0.89 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.6, 167.9, 159.6, 145.1, 138.0, 137.8, 134.6, 132.5, 131.9, 130.1, 128.7, 128.5, 128.3, 127.4, 126.3, 124.7, 124.4, 122.7, 122.5, 104.4, 55.7, 49.7, 45.7, 40.5, 32.1, 29.9, 26.2; C₂₉H₂₇ClN₂O₂ (470.98): calcd C 73.95, H 5.78, N 5.95; found C 73.61, H 5.47, N 5.75.

4f. White crystalline solid, mp 210–212 °C; IR (KBr) 3358, 1679, 1618, 1560 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.92 (d, J = 7.2 Hz, 1H), 7.60–7.47 (m, 2H), 7.39–7.35 (m, 3H), 7.32–7.28 (m, 3H), 7.25–7.22 (q, J₁ = 7.2 Hz, J₂ = 1.8 Hz, 1H), 7.14–7.09 (m, 2H), 6.55–6.52 (q, J₁ = 7.5 Hz, J₂ = 1.8 Hz, 1H), 6.48 (s, 1H), 5.86 (s, 1H), 4.87 (d, J = 14.7 Hz, 1H), 4.56 (d, J = 14.4 Hz, 1H), 2.44 (d, J = 17.4 Hz, 1H), 2.27 (d, J = 16.8 Hz, 1H), 1.90–1.80 (m, 2H), 1.00 (s, 3H), 0.99 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.7, 168.2, 160.3, 144.8, 142.6, 134.3, 132.5, 131.8, 129.9, 129.5, 128.7, 128.6, 128.4, 127.4, 127.3, 127.0, 126.9, 124.5, 122.9, 104.5, 55.5, 49.8, 45.7, 40.8, 32.2, 29.7, 26.4; C₂₉H₂₇ClN₂O₂ (470.98): calcd C 73.95, H 5.78, N 5.95; found C 73.68, H 5.50, N 5.60.

4g. White crystalline solid, mp 228–230 °C; IR (KBr) 3284, 1689, 1622, 1565 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.85 (d, J = 7.5 Hz, 1H), 7.56–7.46 (m, 2H), 7.28–7.20 (m, 6H), 6.89–6.83 (m, 1H), 6.39 (s, 1H), 6.23–6.20 (m, 1H), 6.10–6.06 (m, 1H), 5.45 (s, 1H), 4.89 (d, J = 14.4 Hz, 1H), 4.34 (d, J = 14.4 Hz, 1H), 2.30 (d, J = 16.5 Hz, 1H), 2.12 (d, J = 16.8 Hz, 1H), 1.78–1.55 (m, 2H), 0.90 (s, 3H), 0.89 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.6, 167.9, 159.7, 145.1, 137.9, 133.4, 132.5, 131.8, 128.7, 128.6, 128.3, 127.5, 127.4, 125.0, 124.9, 124.3, 122.5, 121.5, 121.3, 117.0, 116.7, 104.3, 55.8, 49.8, 45.8, 40.4, 32.0, 29.8, 26.3; C₂₉H₂₆ClFN₂O₂ (488.98): calcd C 71.23, H 5.36, N 5.73; found C 70.93, H 5.40, N 5.55.

4h. White crystalline solid, mp 210–212 °C; IR (KBr) 3393, 1685, 1610, 1567 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.89–7.85 (m, 1H), 7.85–7.43 (m, 2H), 7.27–7.17 (m, 8H), 6.42–6.38 (m, 1H), 6.10–6.03 (m, 2H), 5.55 (d, J = 12.0 Hz, 1H), 4.92–4.88 (m, 1H), 4.41–4.36 (m, 1H), 2.34–2.25 (m, 1H), 2.16–2.06 (m, 2H), 1.81–1.69 (m, 1H), 0.91–0.85 (m, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.3, 167.5, 159.5, 144.9, 137.5, 135.5, 132.2, 131.9, 128.2, 127.9, 127.0, 125.9, 124.0, 122.2, 119.4, 103.8, 55.4, 49.4, 45.4, 40.2, 31.7, 29.5, 26.0; C₂₉H₂₇BrN₂O₂ (515.44): calcd C 67.58, H 5.28, N 5.43; found C 67.25, H 5.05, N 5.22.

4i. White crystalline solid, mp 178–180 °C; IR (KBr) 3380, 3274, 1693, 1539 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.84 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.28–7.13 (m, 7H), 6.89–6.84 (m, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.42 (s, 1H), 5.90 (s, 1H), 5.73 (d, J = 7.8 Hz, 1H), 5.58 (s, 1H), 4.81 (d, J = 15.0 Hz, 1H), 4.43 (d, J = 14.4 Hz, 1H), 2.23 (d, J = 16.5 Hz, 1H), 2.05 (d, J = 16.5 Hz, 1H), 1.94 (d, J = 17.7 Hz, 1H), 1.74 (d, J = 17.1 Hz, 1H), 0.87 (s, 3H), 0.80 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 195.1, 168.4, 161.3, 157.7, 145.3, 137.7, 137.3, 132.7, 131.5, 129.8, 128.8, 128.4, 128.1, 127.4, 124.4, 122.6, 116.0, 113.9, 112.2, 102.6, 56.0, 49.8, 45.6, 40.5, 31.9, 29.7, 26.4; C₂₉H₂₈N₂O₃ (452.54): calcd C 76.97, H 6.24, N 6.19; found C 76.80, H 5.95, N 6.10.

4j. White crystalline solid, mp 148–150 °C; IR (KBr) 3348, 1680, 1600, 1559 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.72 (d, J = 7.5 Hz, 1H), 7.49–7.44 (m, 1H), 7.38–7.33 (m, 1H), 7.23–7.15 (m, 6H), 7.12–7.08 (m, 3H), 6.47–6.45 (m, 2H), 6.37 (s, 1H), 4.67 (d, J = 14.4 Hz, 1H), 4.45 (s, 1H), 4.41–4.37 (m, 1H), 3.91–3.84 (m, 1H), 3.77–3.70 (m, 1H), 2.26 (d, J = 16.6 Hz, 1H), 2.10 (d, J = 16.5 Hz, 1H), 1.90 (d, J = 16.8 Hz, 1H), 1.71 (d, J = 16.5 Hz, 1H), 0.91 (s, 3H), 0.89 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 193.4, 167.8, 162.6, 145.7, 137.7, 136.4, 132.1, 131.7, 128.8, 128.5, 128.2, 128.1, 127.7, 127.3, 126.1, 124.1, 122.6, 101.4, 55.7, 49.4, 46.6, 45.3, 39.2, 31.4, 29.7, 27.0; C₃₀H₃₀N₂O₂ (450.57): calcd C 79.97, H 6.71, N 6.22; found C 79.72, H 6.50, N 6.01.

4k. White crystalline solid, mp 218–220 °C; IR (KBr) 3336, 1686, 1617, 1557 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.91 (d, J = 7.2 Hz, 1H), 7.61–7.48 (m, 2H), 7.35 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 7.5 Hz, 2H), 7.08 (d, J = 7.2 Hz, 2H), 6.97 (d, J = 7.2 Hz, 2H), 6.48 (s, 1H), 6.21 (d, J = 7.2 Hz, 2H), 5.64 (s, 1H), 4.81 (d, J = 14.4 Hz, 1H), 4.52 (d, J = 14.4 Hz, 1H), 2.36–2.33 (m, 4H), 2.26 (s, 3H), 2.18–2.05 (m, 1H), 1.95 (d, J = 16.8 Hz, 1H), 1.84 (d, J = 16.8 Hz, 1H), 0.98 (s, 3H), 0.97 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.4, 168.0, 160.4, 145.6, 136.8, 136.4, 134.8, 134.2, 132.3, 131.9, 129.6, 128.9, 128.6, 128.4, 125.1, 124.1, 122.6, 102.9, 55.7, 50.0, 45.2, 40.5, 31.9, 29.7, 26.6, 21.1, 20.8; C₃₁H₃₂N₂O₂ (464.59): calcd C 80.14, H 6.94, N 6.03; found C 79.93, H 6.81, N 5.85.

4l. White crystalline solid, mp 186–188 °C; IR (KBr) 3293, 1686, 1625, 1571 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.84–7.81 (d, J = 7.2 Hz, 1H), 7.51–7.43 (m, 2H), 7.25–7.20 (m, 3H), 7.03–6.98 (m, 2H), 6.89–6.82 (m, 2H), 6.34 (s, 1H), 6.17 (s, 1H), 6.16–6.08 (m, 1H), 5.52 (s, 1H), 4.64 (d, J = 14.4 Hz, 1H), 4.43 (d, J = 14.7 Hz, 1H), 2.27 (d, J = 16.5 Hz, 1H), 2.12 (d, J = 16.5 Hz, 1H), 1.87 (s, 2H), 0.90 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.7, 167.9, 163.7, 160.5, 159.3, 145.1, 138.0, 134.7, 133.6, 132.6, 131.7, 130.3, 130.2, 130.1, 128.8, 126.3, 124.6, 124.3, 122.7, 115.2, 114.9, 104.4, 55.4, 50.0, 44.7, 40.7, 32.2, 29.7, 26.5; C₂₉H₂₆ClFN₂O₂ (464.59): calcd C 71.23, H 5.36, N 5.73; found C 71.04, H 5.11, N 5.48.

4m. White crystalline solid, mp 192–194 °C; IR (KBr) 3346, 1681, 1614, 1563 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.79 (d, J = 7.5 Hz, 1H), 7.57–7.41 (m, 2H), 7.35–7.28 (m, 3H), 7.20–7.18 (m, 3H), 6.99–6.93 (m, 2H), 6.56–6.53 (m, 2H), 6.43 (s, 1H), 4.64–4.45 (m, 3H), 4.04–3.84 (m, 2H), 2.35 (d, J = 16.2 Hz, 1H), 2.22 (d, J = 16.5 Hz, 1H), 2.08 (d, J = 16.8 Hz, 1H), 1.95 (d, J = 16.8 Hz, 1H), 1.02 (s, 3H), 1.00 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 193.6, 167.9, 163.7, 162.3, 160.5, 145.7, 136.5, 133.4, 132.2, 131.7, 130.4, 130.3, 128.8, 128.3, 127.8, 126.1, 124.1, 122.6, 115.1, 114.8, 101.3, 55.4, 49.6, 46.6, 44.4, 39.3, 31.5, 29.5, 27.3; C₃₀H₂₉FN₂O₂ (468.56): calcd C 76.90, H 6.24, N 5.98; found C 76.67, H 6.03, N 5.78.

4n. White crystalline solid, mp 212–214 °C; IR (KBr) 3391, 1677, 1617, 1569 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.64 (d, J = 6.9 Hz, 1H), 7.28–7.20 (m, 2H), 7.09–7.00 (m, 3H), 6.70–6.64 (m, 2H), 6.16 (s, 1H), 4.32–4.29 (m, 2H), 3.70 (s, 1H), 2.58–2.39 (m, 2H), 2.12–2.05 (m, 2H), 1.88–1.80 (m, 1H), 1.65–1.60 (m, 1H), 0.83–0.79 (m, 6H), 0.72–0.67 (m, 2H), 0.54–0.50 (m, 2H), 0.45–0.43 (m, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 193.2, 167.7, 163.6, 162.4, 160.3, 145.8, 133.6, 133.5, 132.2, 131.6, 130.3, 130.2, 128.1, 123.8, 122.6, 114.9, 114.6, 100.2, 55.5, 49.6, 44.2, 42.3, 39.4, 31.4, 29.4, 27.4, 19.0, 13.3; C₂₇H₃₁FN₂O₂ (434.54): calcd C 74.63, H 7.19, N 6.45; found C 74.35, H 6.95, N 6.18.

4o. White crystalline solid, mp 192–194 °C; IR (KBr) 3278, 1683, 1624, 1574 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.86 (d, J = 7.2 Hz, 1H), 7.59–7.54 (m, 1H), 7.50–7.45 (m, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.13–7.07 (m, 2H), 6.54 (s, 1H), 6.44–6.42 (m, 2H), 5.82 (s, 1H), 3.89–3.85 (m, 1H), 3.07–3.02 (m, 1H), 2.42 (s, 2H), 2.34 (d, J = 17.1 Hz, 1H), 2.22 (d, J = 16.8 Hz, 1H), 1.66–1.59 (m, 2H), 1.36–1.29 (m, 2H), 1.07 (s, 3H), 1.06 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.9, 167.9, 159.4, 145.2, 138.3, 134.8, 132.2, 131.9, 130.2, 128.5, 126.4, 124.9, 123.9, 123.1, 122.6, 104.6, 54.7, 50.0, 40.9, 40.5, 32.6, 30.3, 28.4, 27.8, 20.1, 13.7; C₂₆H₂₉ClN₂O₂ (436.97): calcd C 71.46, H 6.69, N 6.41; found C 71.20, H 6.43, N 6.26.

4p. White crystalline solid, mp 202–204 °C; IR (KBr) 1705, 1693, 1650 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.84 (d, J = 6.6 Hz, 1H), 7.56–7.54 (m, 1H), 7.49–7.47 (m, 1H), 7.35 (d, J = 7.2 Hz, 1H), 6.99–6.94 (m, 1H), 6.63–6.61 (m, 1H), 6.47–6.43 (m, 2H), 5.71 (s, 1H), 3.89–3.85 (m, 1H), 3.06–3.01 (m, 1H), 2.40 (s, 2H), 2.28–2.11 (m, 2H), 1.63–1.61 (m, 2H), 1.33–1.31 (m, 2H), 1.06 (s, 6H), 0.94–0.88 (m, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.8, 167.8, 159.5, 158.1, 154.8, 145.2, 133.6, 132.2, 131.8, 128.4, 127.7, 125.4, 125.3, 123.8, 122.5, 121.6, 121.4, 117.1, 116.8, 104.4, 54.6, 49.9, 40.8, 40.4, 32.4, 30.3, 28.4, 27.7, 20.1, 13.6; C₂₆H₂₈ClFN₂O₂ (454.96): calcd C 68.64, H 6.20, N 6.16; found C 68.46, H 6.01, N 5.92.

4q. White crystalline solid, mp 188–190 °C; IR (KBr) 3340, 1688, 1615, 1563 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H; ¹H NMR (300 MHz, DMSO-d₆) 7.87 (d, J = 7.5 Hz, 1H), 7.60–7.55 (m, 1H), 7.50–7.46 (m, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.08 (t, J = 8.1 Hz, 1H), 6.67–6.63 (m, 1H), 6.48 (s, 1H), 6.14 (d, J = 7.2 Hz, 1H), 6.01 (s, 1H), 5.80 (s, 1H), 3.85–3.80 (m, 1H), 3.68 (s, 3H), 3.13–3.09 (m, 1H), 2.54–2.42 (m, 3H), 1.98–1.94 (m, 2H), 1.67–1.60 (m, 2H), 1.41–1.24 (m, 3H), 0.92 (t, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 195.3, 167.8, 162.2, 160.0, 145.4, 138.0, 132.0, 129.8, 128.3, 123.8, 122.7, 117.2, 111.6, 111.0, 104.5, 55.2, 54.8, 40.4, 36.5, 30.4, 27.7, 21.6, 20.1, 13.7; C₂₅H₂₈N₂O₃ (404.50): calcd C 74.23, H 6.98, N 6.93; found C 73.93, H 6.60, N 6.78.

4r. White crystalline solid, mp 160–162 °C; IR (KBr) 3350, 1684, 1612, 1566 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.77 (d, J = 7.5 Hz, 1H), 7.54–7.49 (m, 1H), 7.44–7.39 (m, 1H), 7.31–7.27 (m, 2H), 7.23–7.13 (m, 4H), 7.07 (d, J = 7.5 Hz, 2H), 6.53–6.50 (m, 2H), 6.47 (s, 1H), 4.73 (d, J = 15.0 Hz, 1H), 4.44 (d, J = 14.4 Hz, 1H), 4.35 (s, 1H), 3.90–3.75 (m, 2H), 2.43–2.40 (m, 1H), 2.31 (s, 3H), 2.24–2.16 (m, 2H), 1.96–1.78 (m, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.1, 167.8, 163.7, 145.7, 136.8, 136.4, 134.8, 132.0, 131.8, 128.8, 128.6, 128.5, 127.9, 127.7, 127.2, 124.0, 122.6, 102.6, 55.8, 46.6, 45.0, 36.0, 25.9, 21.1, 20.7; C₂₉H₂₈N₂O₂ (436.54): calcd C 79.79, H 6.46, N 6.42; found C 79.57, H 6.27, N 6.31.

4s. White crystalline solid, mp 194–196 °C; IR (KBr) 3318, 1684, 1617, 1559 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.93 (d, J = 7.2 Hz, 1H), 7.63–7.51 (m, 2H), 7.39–7.28 (m, 3H), 7.13 (d, J = 8.4 Hz, 2H), 6.95 (t, J = 8.4 Hz, 2H), 6.48 (s, 1H), 6.21 (d, J = 8.4 Hz, 2H), 5.52 (s, 1H), 4.90 (d, J = 14.4 Hz, 1H), 4.44 (d, J = 14.7 Hz, 1H), 2.55–2.49 (m, 1H), 2.33–2.22 (m, 1H), 2.17–2.12 (m, 1H), 1.98–1.88 (m, 1H), 1.82–1.81 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 195.2, 167.9, 161.4, 145.2, 135.3, 133.9, 133.8, 132.5, 132.0, 131.8, 130.3, 130.2, 129.3, 128.7, 125.8, 124.3, 122.7, 115.1, 114.8, 105.1, 55.7, 44.9, 36.4, 27.4, 21.3; C₂₇H₂₂ClFN₂O₂ (460.92): calcd C 70.36, H 4.81, N 6.08; found C 70.18, H 4.58, N 5.91.

4t. White crystalline solid, mp 120–122 °C; IR (KBr) 3296, 1682, 1623, 1578 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.88 (t, J = 7.2 Hz, 1H), 7.86–7.40 (m, 3H), 7.03–6.99 (m, 2H), 6.52–6.45 (m, 3H), 5.43 (d, J = 6.0 Hz, 1H), 3.89–3.82 (m, 1H), 3.18–3.12 (m, 1H), 2.56–2.55 (m, 2H), 2.46–2.41 (m, 2H), 2.27 (d, J = 7.8 Hz, 3H), 1.98–1.96 (m, 2H), 1.70–1.65 (m, 2H), 1.42–1.35 (m, 2H), 0.98–0.91 (m, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 195.2, 167.9, 162.6, 145.5, 136.6, 134.3, 132.0, 129.7, 128.3, 125.2, 123.8, 122.7, 103.9, 54.9, 40.4, 36.6, 30.4, 27.7, 21.6, 20.8, 20.1, 13.7; C₂₅H₂₈N₂O₂ (388.50): calcd C 77.29, H 7.26, N 7.21; found C 77.45, H 7.40, N 7.10.

4u. White crystalline solid, mp 162–164 °C; IR (KBr) 3360, 1685, 1611, 1561 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.77 (d, J = 6.6 Hz, 1H), 7.55–7.40 (m, 3H), 7.29–7.24 (m, 5H), 6.88–6.82 (m, 1H), 6.49–6.45 (m, 3H), 5.25 (s, 1H), 4.88 (d, J = 14.7 Hz, 1H), 4.38 (d, J = 14.1 Hz, 1H), 4.26 (m, 1H), 3.89–3.69 (m, 2H), 2.43 (d, J = 16.2 Hz, 1H), 2.27–2.12 (m, 2H), 1.88–1.77 (m, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 194.3, 167.8, 163.6, 145.7, 137.9, 132.1, 131.7, 130.4, 129.3, 128.8, 128.5, 128.2, 128.0, 127.9, 127.8, 127.3, 126.2, 124.1, 122.6, 115.9, 115.6, 102.7, 56.0, 45.9, 45.5, 35.9, 25.8, 20.6; C₂₈H₂₅FN₂O₂ (440.50): calcd C 76.34, H 5.72, N 6.36; found C 76.03, H 5.50, N 6.28.

Characterization data of 5a–d

5a. White crystalline solid, mp 200–202 °C; IR (KBr) 3450, 1684, 1619, 1496 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.69 (d, J = 6.9 Hz, 1H), 7.49–7.41 (m, 2H), 7.26–7.20 (m, 6H), 7.05 (s, 2H), 5.69 (s, 1H), 4.56 (d, J = 15.3 Hz, 1H), 4.38 (d, J = 15.0 Hz, 1H), 3.34 (s, 3H), 2.79 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 168.0, 159.5, 154.5, 151.1, 147.1, 138.5, 133.1, 131.3, 128.4, 128.2, 127.4, 127.1, 122.7, 122.2, 80.5, 57.2, 44.1, 30.4, 27.1; C₂₁H₂₀N₄O₃ (376.40): calcd C 67.01, H 5.36, N 14.88; found C 66.85, H 5.10, N 14.48.

5b. White crystalline solid, mp 142–144 °C; IR (KBr) 3459, 1682, 1619, 1496 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.74 (d, J = 7.2 Hz, 1H), 7.55–7.52 (m, 1H), 7.47–7.42 (m, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.14 (d, J = 7.8 Hz, 2H), 7.00 (d, J = 7.8 Hz, 2H), 6.30 (s, 1H), 4.72 (d, J = 14.4 Hz, 1H), 4.43 (d, J = 14.7 Hz, 1H), 4.27 (s, 2H), 3.37 (s, 3H), 3.11 (s, 3H), 2.26 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 167.8, 162.9, 151.5, 150.7, 144.4, 137.1, 134.0, 132.5, 131.5, 128.8, 128.6, 128.3, 123.8, 123.1, 81.8, 56.9, 44.9, 28.5, 28.4, 21.0; C₂₂H₂₂N₄O₃ (390.43): calcd C 67.68, H 5.68, N 14.35; found C 67.44, H 5.49, N 14.18.

5c. White crystalline solid, mp 180–182 °C; IR (KBr) 3446, 1682, 1629 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.73 (d, J = 7.5 Hz, 1H), 7.60–7.54 (m, 1H), 7.48–7.42 (m, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.29–7.25 (m, 2H), 6.90 (t, J = 8.4 Hz, 2H), 6.29 (s, 1H), 4.55 (s, 2H), 4.38 (s, 2H), 3.37 (s, 3H), 3.18 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 167.7, 163.6, 162.8, 160.4, 151.5, 150.6, 144.2, 132.8, 132.6, 131.2, 130.1, 130.0, 128.8, 123.7, 123.1, 115.0, 114.7, 81.4, 56.5, 44.1, 28.6, 28.4; C₂₁H₁₉FN₄O₃ (394.39): calcd C 63.95, H 4.86, N 14.21; found C 63.70, H 4.62, N 14.02.

5d. White crystalline solid, mp 160–162 °C; IR (KBr) 3342, 1691, 1631, 1591 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.68 (d, J = 7.5 Hz, 1H), 7.59–7.55 (m, 1H), 7.48–7.41 (m, 2H), 6.33 (s, 1H), 4.56 (s, 2H), 3.80–3.75 (m, 1H), 3.41 (s, 3H), 3.39 (s, 3H), 2.97–2.93 (m, 1H), 1.61–1.53 (m, 2H), 1.32–1.25 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 168.0, 163.0, 151.8, 151.0, 144.5, 132.4, 131.6, 128.8, 123.5, 123.2, 81.3, 56.0, 40.1, 30.2, 29.0, 28.5, 20.0, 13.6; C₁₈H₂₂N₄O₃ (342.39): calcd C 63.14, H 6.48, N 16.36; found C 62.97, H 6.29, N 16.15.

Characterization data of 6a–d

6a. White milky powder, mp 220 (reported)^13c/216–218 (observed)°C; IR (KBr) 3422, 1700, 1653 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 10.99 (bs, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.43–7.29 (m, 2H), 7.23–7.09 (m, 6H), 5.60 (s, 1H), 4.75 (d, J = 15.0 Hz, 1H), 3.95 (d, J = 15.0 Hz, 1H), 2.21 (s, 2H), 1.97–1.89 (m, 2H), 0.89 (s, 3H), 0.88 (s, 3H); C₂₃H₂₃NO₃ (361.43): calcd C 76.43, H 6.41, N 3.88; found C 76.10, H 6.29, N 3.69.

6b. White milky powder, mp 247 (reported)^13c/242–244 (observed)°C; IR (KBr) 2957, 1708, 1609 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.44 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.29–7.21 (m, 2H), 7.09–7.03 (m, 4H), 5.93 (s, 1H), 4.74 (d, J = 14.7 Hz, 1H), 4.07 (d, J = 15.0 Hz, 1H), 2.35–2.28 (m, 5H), 1.28–1.25 (m, 2H), 1.06 (s, 3H), 1.03 (s, 3H); C₂₄H₂₅NO₃ (375.46): calcd C 76.77, H 6.71, N 3.73; found C 76.40, H 6.42, N 3.61.

6c. White milky powder, mp 229 (reported)^13c/230–232 (observed)°C; IR (KBr) 3200, 1710, 1620 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 10.97 (bs, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.39–7.27 (m, 2H), 7.16–7.08 (m, 3H), 7.03–6.97 (m, 2H), 5.58 (s, 1H), 4.60 (d, J = 15.0 Hz, 1H), 4.06 (d, J = 15.0 Hz, 1H), 2.30–2.15 (m, 2H), 2.01–1.97 (m, 2H), 1.70–1.64 (m, 2H); C₂₁H₁₈FNO₃ (351.37): calcd C 71.78, H 5.16, N 3.99; found C 71.45, H 5.01, N 3.68.

6d. White milky powder, mp 226–228 °C; IR (KBr) 3229, 1705, 1650 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.46 (t, J = 6.9 Hz, 1H), 7.27–7.24 (m, 3H), 6.01 (s, 1H), 3.78–3.71 (m, 1H), 2.83–2.74 (m, 1H), 2.47–2.28 (m, 3H), 1.55–1.50 (m, 2H), 1.42–1.38 (m, 3H), 1.09 (s, 3H), 1.06 (s, 3H), 0.87 (t, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 185.8, 170.0, 146.6, 132.0, 131.2, 127.2, 122.5, 121.8, 107.6, 54.8, 49.1, 44.6, 39.9, 32.0, 29.9, 28.2, 28.1, 19.9, 13.6; C₂₀H₂₅NO₃ (327.41): calcd C 73.37, H 7.70, N 4.28; found C 73.05, H 7.50, N 4.13.

Characterization data of 7a–d

7a. White powder, mp 209.4–211.2 (reported)¹⁶/206–208 (observed)°C, IR (KBr) 3252, 1664 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.88 (s, 1H), 8.02–8.00 (m, 1H), 7.49–7.37 (m, 3H), 7.25–7.11 (m, 8H), 6.89–6.66 (m, 2H), 5.61 (m, 1H), 5.38–5.33 (m, 1H), 3.83–3.78 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 167.5, 146.8, 138.0, 137.4, 132.2, 131.8, 128.9, 128.6, 127.9, 127.5, 126.9, 125.2, 123.9, 123.2, 122.1, 119.4, 118.3, 112.4, 109.1, 57.8, 43.3; C₂₃H₁₈N₂O (338.40): calcd C 81.63, H 5.36, N 8.28; found C 81.93, H 5.40, N 8.48.

7b. White powder, mp 200–202 °C, IR (KBr) 3270, 1669 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 11.26 (s, 1H), 7.87–7.84 (m, 1H), 7.56–7.50 (m, 3H), 7.39 (d, J = 8.1 Hz, 1H), 7.26–7.23 (m, 1H), 7.12–7.00 (m, 5H), 6.77 (t, J = 7.2 Hz, 1H), 6.58–6.56 (m, 1H), 5.72 (s, 1H), 5.02 (d, J = 15.3 Hz, 1H), 3.73 (d, J = 15.3 Hz, 1H), 2.25 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 166.5, 145.9, 136.5, 135.7, 134.0, 131.3, 130.9, 128.6, 127.7, 127.0, 125.9, 124.3, 123.0, 122.2, 120.9, 118.5, 117.4, 111.5, 108.2, 56.8, 42.1, 20.1; C₂₄H₂₀N₂O (352.42): calcd C 81.79, H 5.72, N 7.95; found C 81.45, H 5.60, N 7.83.

7c. Isolated as gummy liquid; ¹H NMR (300 MHz, DMSO-d₆) δ_H 11.30 (s, 1H), 7.90–7.88 (m, 1H), 7.59 (s, 1H), 7.51–7.49 (m, 2H), 7.41 (d, J = 8.1 Hz, 1H), 7.25–7.17 (m, 3H), 7.10–7.02 (m, 3H), 6.76 (t, J = 7.2 Hz, 1H), 6.70 (s, 1H), 5.77 (s, 1H), 5.00 (d, J = 15.3 Hz, 1H), 3.88 (d, J = 15.3 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 167.6, 163.3, 160.1, 146.9, 137.5, 134.3, 134.2, 132.3, 131.8, 130.1, 130.0, 128.7, 126.9, 125.2, 123.9, 123.2, 121.9, 119.4, 118.4, 115.7, 115.4, 112.4, 109.1, 57.9, 42.8; C₂₃H₁₇FN₂O (356.39): calcd C 77.51, H 4.81, N 7.86; found C 77.29, H 4.60, N 7.80.

7d. White powder, mp 208.2–208.8 (reported)¹⁶/206–208 (observed)°C, IR (KBr) 3218, 1672 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 11.24 (s, 1H), 7.80–7.75 (m, 1H), 7.66 (s, 1H), 7.50–7.48 (m, 2H), 7.38 (d, J = 8.1 Hz, 1H), 7.28–7.24 (m, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.77–6.72 (m, 1H), 6.57 (s, 1H), 5.95 (s, 1H), 3.75–3.66 (m, 1H), 2.80–2.75 (m, 1H), 1.46–1.44 (m, 2H), 1.21–1.17 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 167.3, 146.8, 137.3, 132.3, 131.9, 128.5, 126.7, 125.3, 123.7, 122.9, 121.8, 119.3, 118.4, 112.3, 109.6, 57.9, 39.3, 30.2, 19.9, 13.9; C₂₀H₂₀N₂O (304.39): calcd C 78.92, H 6.62, N 9.20; found C 78.69, H 6.48, N 9.07.

Acknowledgements

K. D. and S. M. thank UGC, New Delhi, India for offering them Senior Research Fellowship (SRF) and Junior Research Fellowship (JRF) respectively. The financial assistance of CSIR, New Delhi is gratefully acknowledged [Major Research Project, No. 02(0007)/11/EMR-II]. Crystallography was performed at the DST-FIST, India-funded Single Crystal Diffractometer Facility at the Department of Chemistry, University of Calcutta. We also acknowledge Center for Research in Nanoscience and Nanotechnology (CRNN), University of Calcutta for instrumental facilities.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1428628 and 1434728. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra00870d

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