Facile cyclization in the synthesis of highly fused diaza cyclooctanoid compounds using retrievable nano magnetite-supported sulfonic acid catalyst

Abstract

Magnetically separable Fe₃O₄–SO₃H nano particles have been prepared and established as an efficient catalyst for the synthesis of dihydrofuran fused cyclooctanoids via the dehydration reaction of dihydroxy cyclooctanoid heterocylces. Nanomagnetite, Fe₃O₄–SO₃H was prepared using an impregnation protocol and fully characterized by XRD, FT-IR, TEM, and FE-SEM-EDS. The catalyst was recycled for five consecutive cycles with almost unaltered catalytic activity. The dehydration step was performed keeping the acid sensitive amide linkage intact under ambient temperature and milder reaction conditions. The efficacy of the methodology lies in the excellent yield of product formation within a short span of reaction time avoiding undesirable side products due to the substrate decomposition by ring rupture and tedious purification and work-up procedure.

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Introduction

The functionalized cyclooctanes are frequently found in pharmacologically significant compounds and natural products. Because of their intriguing geometrical features and potential biological activities, the construction of cyclooctanoid frameworks has drawn significant attention from synthetic organic chemists for a long time.^1,2 In many natural products eight-membered carbo and heterocycles are fused with one or more five- or six-membered rings. For examples, the cyclooctanoid fusicoauritone (1),³ aleurodiscal (2),⁴ Kopsia alkaloid specially lapidilectam (3),⁵ ophiobolin A (4),⁶ serotobenine (5)⁷ and deoxyisoaustamide (6)⁸ are natural compounds containing fused penta- and hexacyclic rings (Fig. 1). Extensive investigation on the above mentioned eight membered hetero or carbocycle family shows that they have broad spectrum of bioactivity against fungi, nematodes, bacteria, the Plasmodium falciparum and cultured B-16 melanoma cells.^6,9,10 Marine-products cyclooctanoid (6) containing indole ring are presently considered as the affluent sources of active secondary metabolites (Fig. 1).⁸ Therefore, synthesis of cyclooctanoids fused with penta- and hexacyclic ring is very important. In recent years a variety of synthetic methodologies have been developed for the synthesis of fused cyclooctanoid rings which include olefin metathesis,¹¹ cycloadditions,¹² nucleophilic and electrophilic substitution reactions,¹³ a Mizoroki–Heck reaction,¹⁴ ring expansion reactions¹⁵ and other reactions.¹⁶ In our continuing endeavor to synthesize biologically potent heterocyclic compounds from ninhydrin,¹⁷ we wish to report herein a cyclization method for the synthesis of isoindole and benzofuran fused eight-membered spiro heterocycles following the Green Chemistry principles.

Fig. 1 Some important naturally occurring eight-membered heterocycles.

Catalysis is becoming a strategic field of science because it represents a new way to meet the challenges of energy and sustainability. In order to explore environmentally benign synthetic pathways, we need a catalyst system that not only shows high activity and selectivity (like a homogeneous system) but also can be separated and recovered easily after the reactions (like a heterogeneous system). In this respect nanocatalysts have recently been emerged as highly promising catalysts which mimic both homogeneous (high surface area, easily accessible) and heterogeneous (stable, easy to handle) catalyst systems. The main difficulty in the nanocatalyst mediated organic reaction is the separation and recovery of the catalyst through conventional filtration as it blocks the pores and valves of the filter papers. In this respect, the use of magnetically separable nanoparticles (MSNPs) such as iron oxide supported nano materials attributes excellent isolation and separation procedure from the reaction mixture by means of an external magnet because of their insolubility and paramagnetic nature. Moreover, they are inexpensive, easy to prepare, and most importantly easily recyclable for many times.¹⁸

Chlorosulfonic acid is a well-known strong organic acid, which is used as an active catalyst in organic syntheses. However, its direct application in the reaction mixture may cause the decomposition of the reactants and also derivation of several impurities. The best way to avoid the harmful effect of chlorosulfonic acid is by supporting it on a solid surface.¹⁹ In this regard, magnetically retrievable Fe₃O₄@SO₃H emerges as an efficient and sustainable acid catalyst for many organic reactions.^19,20 Here, we have exploited this acid catalyst for the construction of dihydrofuran ring in cyclooctanoid compounds (±)-2a–r/2a′–r′ starting from dihydroxy cyclooctanoid heterocylces (±)-1a–r/1a′–r′ (Scheme 1).

Scheme 1 Optimized reaction condition for the formation of fused cyclooctanoids.

Results and discussion

In our initial study, we attempted to optimize the reaction conditions for the formation of (±)-2a/2a′ (R₁ = Me, R₂ = R₃ = R₄ = H) from (±)-1a/1a′ (R₁ = Me, R₂ = R₃ = R₄ = H) in presence of different solvents, catalysts, solid supports at different temperature and time (Scheme 1 and Table 1). From literature survey, it is known that, to carry out dehydration reaction in Dean–Stark apparatus, benzene is the most commonly used solvent. So at first, we tried to carry out the dehydration in (±)-1a/1a′ using benzene as the solvent. Unfortunately, no product was isolated after prolonged reflux (Table 1, entry 1). Then we tried to carry out the dehydration and subsequent intra-molecular etheration reaction under acid catalyzed condition in presence of several organo-acid catalysts such as lactic acid, formic acid, citric acid and acetic acid in benzene (Table 1, entries 2–5). In all the cases, trace amount of desired product was isolated through column chromatography and the structure of the product 2a and 2a′ was confirmed by IR, ¹H and ¹³C NMR spectroscopy, elemental analysis, and X-ray diffraction studies. To obtain the desired product with satisfactory yield, we employed higher acidic condition in the reaction, using acetic acid as solvent (Table 1, entry 6). But yield of the product (±)-2a/2a′ was still very low (30%) and unsatisfactory. When stronger Brønsted acid catalyst PTSA was used in benzene, moderate yield (48%) of the desired product was obtained (Table 1, entry 7), which increased further (65–68%) in dichloromethane (DCM) and dimethylformamide (DMF) solvent because of better solubility of the starting material (Table 1, entries 8 and 9). Since the yields are comparable in these two solvents, DCM was chosen as the best solvent for our reaction because of operational simplicity and easier work-up procedure. It was also clear from these studies that, –SO₃H functional group is acting as a better activating agent compared to –COOH group. So next, we employed several solid supports bearing –SO₃H group such as homogeneous polymeric acid–surfactant combined catalyst PEG–SO₃H and heterogeneous solid acid supports MSA and SSA as catalyst in DCM (Table 1, entries 11–13). Moderate yield of the product (±)-2a/2a′ under reduced reaction time and temperature in presence of SSA (Table 1, entry 13) incited us for further investigation on the optimization of the reaction condition using magnetic nano-catalysts bearing –SO₃H group on the surface. In this regard, two nano-catalysts Fe₃O₄–SO₃H and γ-Fe₃O₄@SiO₂–SO₃H (ref. 21 and 22) were considered since they have interesting structural features, high level of catalytic activity for large surface area and facile separation procedure using external magnets (Table 1, entries 14–20). Gratifyingly, significant increase in the product yield (92%) was obtained with drastic diminution of required temperature (30 °C) and reaction time (10 min) on employing nano-magnetite Fe₃O₄–SO₃H (50 mg) in DCM (Table 1, entry 18) after careful tuning of catalyst load (20–150 mg) under same reaction condition (Table 1, entries 14–19). Interestingly, comparable yield of (±)-2a/2a′ was observed using magnetically retrievable γ-Fe₃O₄@SiO₂–SO₃H as catalyst (Table 1, entry 20). Since nano-magnetite Fe₃O₄–SO₃H is easier to prepare compared to γ-Fe₃O₄@SiO₂–SO₃H, the former was chosen as the most suitable catalyst for the present reaction.

Table 1 Optimization studies for etheration reaction in (±)-1a/1a′ to form (±)-2a/2a′

Entry	Catalyst	Solvent	Catalyst load	Temperature (°C)	Time	Yield^a (%)
a Isolated yields.
1	__	Benzene	__	80	24 h	__
2	Lactic acid	Benzene	20 mol%	80	24 h	10
3	Formic acid	Benzene	20 mol%	80	24 h	8
4	Citric acid	Benzene	20 mol%	80	24 h	10
5	Acetic acid	Benzene	20 mol%	80	24 h	10
6	__	Acetic acid	__	80	24 h	30
7	PTSA	Benzene	20 mol%	80	24 h	48
8	PTSA	DCM	20 mol%	40	24 h	65
9	PTSA	DMF	20 mol%	80	24 h	68
10	PTSA	H2O	20 mol%	80	24 h	45
11	PEG–SO3H	DCM	500 mg	40	24 h	35
12	Melamine sulphonic acid (MSA)	DCM	500 mg	40	24 h	27
13	Silica sulfuric acid (SSA)	DCM	500 mg	40	3 h	47
14	Fe3O4–SO3H	DCM	100 mg	40	10 min	72
15	Fe3O4–SO3H	DCM	100 mg	30	10 min	72
16	Fe3O4–SO3H	DCM	150 mg	30	10 min	71
17	Fe3O4–SO3H	DCM	75 mg	30	10 min	80
18	Fe3O4–SO3H	DCM	50 mg	30	10 min	92
19	Fe3O4–SO3H	DCM	20 mg	30	10 min	85
20	γ-Fe3O4@SiO2–SO3H	DCM	50 mg	30	10 min	92

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Having prepared (±)-2a/2a′ successfully, we decided to explore the scope and generality of this reaction in the synthesis of other analogues. At first, racemic mixtures of diaza-cyclooctanoid derivatives (±)-1a–r/1a′–r′ have been prepared from ninhydrin following the reported procedure.^17b The diaza-cyclooctanoid compounds (±)-1a–r/1a′–r′ derived from different aliphatic 1,2-diamines (1,2-ethylenediamine, (±)-1,2-propylenediamine and (±)-trans-1,2-cyclohexanediamine) were treated with Fe₃O₄–SO₃H under optimized reaction condition (Table 1, entry 18) to get fused eight membered heterocycles. As evident from Table 2, etheration reaction proceeded well with various electron-withdrawing and donating phenols and 1,2-diamine derivatives (Scheme 1 and Table 2). In all the cases reaction time is short (10 min) and yield of the product formation is high (Table 2). The isolated yellow colored solid products (±)-2a–r/2a′–r′ are fully characterized by ¹H and ¹³C NMR spectroscopy. When diaza-cyclooctanoids (±)-(R,S)-1a–f/(S,R)-1a′–f′ cyclized in presence of Fe₃O₄–SO₃H (±)-(R,S)-2a–f/(S,R)-2a′–f′ were formed which is established by X-ray crystal data analysis (Fig. 2). The other possible diastereomer (R,R or S,S) is not formed in the reactions. Therefore, retention of configuration takes place at the chiral centre adjacent to amide nitrogen (Scheme 2). The same reaction was also carried out for (±)-(R,S,S)-1g–l/(S,R,R)-1g′–l′, as predicted from the above results reaction passed through retention of configuration to furnish (±)-(R,S,S)-2g–l/(S,R,R)-2g′–l′ (Scheme 2 and Fig. 3). Then etheration reaction was carried out with compounds having four stereo-centre (±)-(R,S,S,S)-1m–r/(S,R,R,R)-1m′–r′. As expected, products (±)-(R,S,S,S)-2m–r/(S,R,R,R)-2m′–r′ were isolated from the reaction mixture which is established by X-ray crystal structure analysis (Fig. 4). So it is clear from the above information that the cyclization reaction is enantioselective.

Table 2 Scope of highly fused cyclooctanoid rings syntheses

(±)-2a/2a′ (92%)	(±)-2b/2b′ (90%)	(±)-2c/2c′ (89%)
(±)-2d/2d′ (91%)	(±)-2e/2e′ (92%)	(±)-2f/2f′ (94%)
(±)-2g/2g′ (89%)	(±)-2h/2h′ (86%)	(±)-2i/2i′ (84%)
(±)-2j/2j′ (85%)	(±)-2k/2k′ (88%)	(±)-2l/2l′ (92%)
(±)-2m/2m′ (85%)	(±)-2n/2n′ (81%)	(±)-2o/2o′ (78%)
(±)-2p/2p′ (80%)	(±)-2q/2q′ (83%)	(±)-2r/2r′ (89%)

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Fig. 2 Crystal structure of compound 2a and 2a′. Color code: red, oxygen; blue, nitrogen; grey, carbon; white, hydrogen.†

Scheme 2 Synthesis of isoindole fused cyclooctanoid rings as a racemic mixture.

Fig. 3 Crystal structure of compound 2g and 2g′. Color code: red, oxygen; blue, nitrogen; green, chlorine; large white, carbon; small white, hydrogen.†

Fig. 4 Crystal structure of compound 2n and 2n′. Color code: red, oxygen; blue, nitrogen; green, chlorine; large white, carbon; small white, hydrogen.†

A possible mechanism for the formation of spirofuran fused eight-membered heterocycles 2 from dihydroxy eight-membered heterocycles 1 is depicted in Scheme 3. The initially formed hydrogen bond between aliphatic hydroxyl and –SO₃H group provokes the breaking of C–O bond to generate dehydrated cationic intermediate 3. Finally, intramolecular nucleophilic attack of hydroxyl group of phenol to the imine carbon produces the oxonium intermediate 4 which subsequently loses proton to form furan ring fused eight-membered heterocycles 2. During the intramolecular nucleophilic attack via S¹_N process, the phenolic hydroxyl group attacks from the same face of the double bond where the aromatic phenols are aligned, as a result retention of configuration takes place at the stereogenic centre.

Scheme 3 Plausible mechanism for the formation of furan ring using NP Fe₃O₄–SO₃H as catalyst.

The crystal structure analysis of (±)-2a/2a′, (±)-2g/2g′ and (±)-2n/2n′ reveals that in the crystalline state two enantiomeric molecules are locked in antiparallel fashion stabilized by two intermolecular hydrogen bonds between –NH– and C=O groups (Fig. 2–4). The hydrogen bonding distance increases with the increase of the bulkiness of the substituents on 1,2-diamine moieties. In all the cases the central diazacyclooctane rings adopt a tub or boat like conformation rather than crown or boat–chair conformation (Fig. 2–4). The substituents around the diazacyclooctane rings are alternatively in up and down orientation due to steric reasons. In (R,S,S,S)-2n and (S,R,R,R)-2n′ the central boat diazacyclooctane ring is further fused with chair cyclohexane ring (Fig. 4).

The reusability test of Fe₃O₄–SO₃H nanoparticles was carried out under optimized conditions by stirring (±)-1a/1a′ in DCM medium (Table 1, entry 18). When the magnetic stirring of the reaction mixture was discontinued, the magnetic Fe₃O₄–SO₃H MNPs were adsorbed on the surface of the magnetic stirring bar and separated easily from the reaction mixture without filtration. Then Fe₃O₄–SO₃H MNPs catalyst was washed three times with ethanol (3 × 5 mL), dried at room temperature under vacuum to eliminate residual solvents and used for the next cycle. The dehydration reaction of (±)-1a/1a′ was performed with recovered catalyst upto five times without any significant loss of the catalytic activity (Fig. 5).

Fig. 5 Reusability of Fe₃O₄–SO₃H MNPs for the formation of densely fused cyclooctanoid.

Powder XRD study was carried out to confirm the crystalline nature of as-synthesized iron oxide nanoparticles. The XRD pattern of Fe₃O₄ and Fe₃O₄–SO₃H NPs are displayed in Fig. 6a and b respectively. The diffraction peaks from the (220), (311), (400), (422) and (440) lattice planes are observed at 2θ = 32.9°, 35.36°, 44.9°, 53.7° and 62.35° respectively (Fig. 6a). The peaks in the respective XRD patterns are equivalent to the Bragg reflections of face centered cubic (FCC) iron oxide and confirm both the identity and purity of the sample. Similar pattern of peaks is also obtained in Fe₃O₄–SO₃H NPs XRD spectra (Fig. 6b), with slight alterations in the nature of peaks. The presence of sulfonic acid group coated on the surface of Fe₃O₄ NPs might cause slight changes in the XRD spectra of Fe₃O₄–SO₃H NPs.¹⁹

Fig. 6 XRD spectra of (a) Fe₃O₄ and (b) Nanocat-Fe₃O₄–SO₃H MNPs.

Field emission scanning electron microscopy (FE-SEM) at operating voltage of 5.0 kV is employed to know the morphology and size of Nanocat-Fe₃O₄–SO₃H nanoparticles (Fig. 7a). It is clear from the image in Fig. 7a that the spherical shaped Nanocat-Fe₃O₄–SO₃H nanoparticles have diameter in the range of ∼23 to ∼43 nm. Energy dispersive spectroscopy (EDS) analysis of the prepared Nanocat-Fe₃O₄–SO₃H nano-particle (sulfur peak) confirms the incorporation of –SO₃H group on the surface which comes from the reaction of Fe₃O₄ NPs with chlorosulfonic acid (Fig. 7b).

Fig. 7 (a) SEM image of Fe₃O₄–SO₃H NPs; (b) SEM-EDS of Nanocat-Fe₃O₄–SO₃H; and TEM images of Fe₃O₄–SO₃H NPs (c) before use in reaction and (d) after five times applications.

In order to confirm the formation of Nanocat-Fe₃O₄–SO₃H nanoparticles and to inspect its morphology, high-resolution transmission electron microscopic (HRTEM) analysis is performed (Fig. 7c and d). TEM analysis reveals that the prepared nanoparticles are uniform in size and mostly spherical in shape and the size of the nanoparticles is in the range of ∼14 to ∼23 nm. The characterization of the nano-Fe₃O₄–SO₃H by TEM images, before (Fig. 7c) and after five times applications (Fig. 7d) shows the unaltered particle size.

Conclusions

In summary, we have successfully demonstrated a robust and magnetically recoverable Fe₃O₄–SO₃H MNPs catalyzed dehydration reaction for the formation of spirofuran fused eight-membered heterocycles. These potentially bioactivity cyclooctanoid heterocylces have intriguing structural and geometrical features. Most importantly these alkaloids analogous are readily prepared from inexpensive starting materials in moderate to high yield under mild conditions in air.^17b In the final step of the synthesis the dehydration reaction for the formation of dihydrofuran ring using Fe₃O₄–SO₃H MNPs was very straightforward, efficient and highly economical. In addition, the employment of iron oxides as acid catalysts is also more environmentally acceptable and safer in terms of toxicity compared to other transition metal catalysts.

Experimental

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. Perkin-Elmer 782 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 crystals were positioned at 50 mm from the CCD. Frames were measured with a counting time of 5 s. Data analyses were carried out with the Bruker APEX2 and Bruker SAINT program. The structures were solved using direct methods with the Shelxs97 program (Sheldrick, 2008). The morphological analysis of the resultant nanoparticles was confirmed by TEM. The sample suspension is drop casted on a carbon coated copper grid and the excess solution was removed by tissue paper and allowed to air dry at room temperature overnight. TEM study was monitored on a HRTEM, JEOL JEM 2010 at an accelerating voltage of 200 kV and fitted with a CCD camera. The crystallinity of synthesized Fe₃O₄ and Fe₃O₄–OSO₃H nanoparticles was determined and confirmed by XRD analysis. The diffractogram was documented from PANalytical, XPERT-PRO diffractrometer using Cu_α (λ= 1.54060) as X-ray source. Hitachi S-4800 Field Emission Scanning Electron Microscope (Hitachi S-4800 FE-SEM) operating voltage 5.0 kV is used for SEM.

Preparation of Fe₃O₄ nano particle¹⁹

FeCl₃·6H₂O (8.1 g) and urea (5.4 g) were stirred in 300 mL double distilled water at 85 to 90 °C for 2 h. The resultant brown colored reaction mixture was cooled to room temperature and FeSO₄·7H₂O (4.2 g) was added into it. The pH of the resultant solution was maintained at 10 by addition of 0.1 M NaOH solution. The molar ratio of Fe(III) to Fe(II) in the above system was nearly 2.0. The obtained hydroxides were kept under ultrasonication in the sealed flask at room temperature for 30 min. After ageing for 5 h, the obtained black powder of Fe₃O₄ nano particles was washed several times with distilled water, and dried under vacuum.

Preparation of Fe₃O₄–SO₃H catalyst¹⁹

In a two neck round bottom flask, one neck was equipped with a dropping funnel and other neck is fixed with water vacuum to suck HCl gas generated during the reaction. Magnetite, Fe₃O₄ nano particles (3.0 g) was then poured into round bottom flask and neat chlorosulfonic acid was added (1.0 mL) drop by drop over a period of 10 min at room temperature. HCl gas generated immediately from the reaction was removed by suction. After complete addition of chlorosulfonic acid, the mixture was stirred vigorously for 30 min and solid brown magnetic sulfonic acid, Nanocat-Fe–SO₃H (3.45 g) was collected.

Preparation of γ-Fe₃O₄@SiO₂–SO₃H catalyst^21,22

Nano-Fe₃O₄@SiO₂ was synthesized according to the previously published literature method.²² Magnetic Fe₃O₄ nano particles (1.0 g) were initially diluted via the sequential addition of water (20 mL), ethanol (60 mL), and concentrated aqueous ammonia (1.5 mL, 28 wt%). The resulting dispersion was then homogenized by ultrasonic vibration in a water bath. A solution of TEOS (tetraethyl orthosilicate) (0.45 mL) in ethanol (10 mL) was then added to the dispersion in a drop-wise manner under continuous mechanical stirring. Following a 12 h period of stirring, the resulting γ-Fe₃O₄@SiO₂ nano particles were collected by magnetic separation and washed three times with ethanol.

Chlorosulfonic acid (0.5 g, 4.5 mmol) was added in a drop-wise manner to a cooled (ice-bath) solution of γ-Fe₃O₄@SiO₂ (1.0 g) in n-hexane (5 mL) over a period of 2 h. Upon completion of the addition, the mixture was stirred for another 3 h until complete dissipation of HCl occurred from the reaction vessel. The resulting MNPs were separated using an external magnet and washed with methanol before being dried in an oven at 60 °C to give γ-Fe₃O₄@SiO₂–SO₃H as a brown powder.

General synthesis of compounds (±)-2a–r/2a′–r′

A mixture of dihydroxy cyclooctanoid heterocylces (±)-1a–r/1a′–r′ (2.0 mmol) and Fe₃O₄–SO₃H (50 mg) in dichloromethane (10.0 mL) was stirred for 10 min (as mentioned in Table 1). When the magnetic stirring of the reaction mixture was discontinued, the magnetic Fe₃O₄–SO₃H MNPs were adsorbed on the surface of the magnetic stirring bar and easily separated from the reaction mixture without filtration. Then dichloromethane was evaporated under vacuum and reaction mass was sonicated with ethylacetate (3 × 10 mL). The combined ethylacetate was evaporated to get yellow solids of (±)-2a–r/2a′–r′. Yellow solid (±)-2a–r/2a′–r′ was further purified through crystallization from DMSO solvent.

Spectral data for synthesized compounds

(±)-2a/2a′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3295, 1698 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.67 (t, J = 5.7 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.59 (t, J = 6.6 Hz, 1H), 7.44–7.40 (m, 3H), 7.28 (t, J = 7.2 Hz, 1H), 7.20 (t, J = 6.9 Hz, 1H), 7.07 (d, J = 6.9 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.83–6.77 (m, 2H), 5.41 (s, 1H), 4.15–4.14 (m, 1H), 3.19–3.16 (m, 1H), 2.85–2.81 (m, 2H), 2.12 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 191.0, 167.1, 164.4, 155.0, 145.0, 138.7, 134.3, 133.8, 133.7, 131.9, 131.5, 130.8, 130.6, 130.5, 129.3, 124.1, 123.4, 122.8, 120.1, 118.9, 110.0, 102.5, 95.2, 45.0, 40.5, 39.6, 20.8; C₂₇H₂₀N₂O₃ (420.47): calcd C 77.13, H 4.79, N 6.66; found C 77.11, H 4.74, N 6.61.

(±)-2b/2b′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3293, 1701 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.82 (t, J = 5.4 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.73–7.68 (m, 1H), 7.57–7.51 (m, 3H), 7.39 (t, J = 7.5 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 4.8 Hz, 2H), 5.54 (s, 1H), 4.27–4.25 (m, 1H), 3.33–3.25 (m, 1H), 2.97–2.86 (m, 2H), 2.32 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.5, 166.7, 164.1, 155.5, 144.2, 138.2, 135.9, 133.9, 133.4, 133.1, 131.2, 130.6, 130.4, 130.2, 126.2, 123.4, 123.2, 122.5, 119.8, 118.6, 112.6, 102.6, 94.1, 44.3, 40.6, 39.6, 20.1; C₂₇H₁₉ClN₂O₃ (452.92): calcd C 71.29, H 4.21, N 6.16; found C 71.41, H 4.14, N 6.10.

(±)-2c/2c′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3286, 1706 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.76 (t, J = 5.7 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 6.9 Hz, 1H), 7.52–7.44 (m, 3H), 7.32 (t, J = 7.5 Hz, 1H), 7.23 (t, J = 6.9 Hz, 1H), 7.11 (d, J = 6.9 Hz, 1H), 7.02–6.99 (m, 2H), 6.89 (d, J = 7.8 Hz, 1H), 5.53 (s, 1H), 4.21–4.19 (m, 1H), 3.29–3.24 (m, 1H), 2.91–2.87 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.5, 166.6, 164.1, 159.6, 156.5, 152.7, 144.2, 138.2, 135.3, 135.2, 133.9, 133.3, 131.1, 130.6, 130.4, 130.2, 123.2, 122.5, 119.8, 118.6, 115.0, 114.7, 110.8, 110.6, 102.7, 94.0, 44.7, 40.6, 39.6; C₂₆H₁₇FN₂O₃ (424.44): calcd C 73.58, H 4.04, N 6.60; found C 73.72, H 3.95, N 6.53.

(±)-2d/2d′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3306, 1699 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.86 (br s, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.71 (t, J = 6.3 Hz, 1H), 7.59–7.54 (m, 3H), 7.41–7.30 (m, 3H), 7.19–7.06 (m, 3H), 5.59 (s, 1H), 4.32–4.25 (m, 1H), 3.36–3.32 (m, 1H), 2.97–2.93 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.9, 167.0, 164.5, 155.8, 144.4, 138.6, 136.2, 134.3, 133.8, 131.5, 131.0, 130.7, 130.6, 128.9, 126.5, 123.7, 123.6, 122.9, 120.2, 119.0, 111.9, 103.0, 94.3, 44.8, 40.6, 39.6; C₂₆H₁₇ClN₂O₃ (440.89): calcd C 70.83, H 3.89, N 6.35; found C 70.70, H 3.81, N 6.29.

(±)-2e/2e′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3298, 1704 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.79 (t, J = 5.7 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.66 (t, J = 6.6 Hz, 1H), 7.53–7.46 (m, 3H), 7.40–7.23 (m, 3H), 7.17–7.12 (m, 2H), 6.99 (d, J = 8.7 Hz, 1H), 5.55 (s, 1H), 4.22–4.20 (m, 1H), 3.27–3.26 (m, 1H), 2.92–2.89 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.9, 167.1, 164.5, 156.3, 144.5, 138.6, 136.7, 134.3, 133.8, 131.8, 131.5, 131.0, 130.8, 130.6, 126.5, 123.6, 122.9, 120.2, 119.0, 114.1, 112.6, 102.9, 94.4, 44.8, 40.6, 39.6; C₂₆H₁₇BrN₂O₃ (485.34): calcd C 64.34, H 3.53, N 5.77; found C 64.49, H 3.47, N 5.70.

(±)-2f/2f′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3301, 1700 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.77 (t, J = 5.4 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.67 (t, J = 6.9 Hz, 1H), 7.55–7.47 (m, 3H), 7.36 (t, J = 7.5 Hz, 1H), 7.27 (t, J = 6.9 Hz, 1H), 7.15 (d, J = 6.9 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.61 (s, 1H), 5.53 (s, 1H), 4.25–4.24 (m, 1H), 3.64 (s, 3H), 3.29–3.27 (m, 1H), 2.95–2.91 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.6, 166.7, 164.1, 155.3, 150.5, 144.5, 138.3, 134.4, 134.0, 133.2, 131.1, 130.5, 130.4, 130.2, 123.1, 122.4, 119.7, 118.6, 114.1, 110.4, 108.8, 102.4, 94.5, 55.8, 45.1, 40.6, 39.6; C₂₇H₂₀N₂O₄ (436.47): calcd C 74.30, H 4.62, N 6.42; found C 74.42, H 4.56, N 6.47.

(±)-2g/2g′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3299, 1698 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.23 (d, J = 6.9 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.76–7.69 (m, 2H), 7.60–7.52 (m, 2H), 7.43–7.29 (m, 2H), 7.19 (d, J = 6.9 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.95–6.89 (m, 2H), 5.55 (s, 1H), 3.96 (t, J = 13.2 Hz, 1H), 3.37–3.35 (m, 1H), 3.01–2.95 (dd, J₁ = 3.9 Hz, J₂ = 14.1 Hz, 1H), 2.25 (s, 3H), 1.12 (d, J = 11.7 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.9, 166.4, 163.3, 154.6, 144.5, 138.4, 133.8, 133.3, 133.0, 131.5, 131.1, 130.5, 130.4, 131.1, 128.9, 123.7, 123.0, 122.5, 119.7, 119.2, 109.5, 102.2, 95.2, 47.5, 45.6, 44.9, 20.4, 17.1; C₂₈H₂₂N₂O₃ (434.50): calcd C 77.40, H 5.10, N 6.45; found C 77.27, H 5.02, N 6.40.

(±)-2h/2h′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3280, 1694 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.28 (d, J = 6.3 Hz, 1H), 7.95–7.09 (m, 10H), 5.57 (s, 1H), 3.95 (t, J = 13.5 Hz, 1H), 3.40–3.37 (m, 1H), 3.02–2.98 (dd, J₁ = 2.7 Hz, J₂ = 13.2 Hz, 1H), 2.10 (s, 3H), 1.17 (d, J = 15.6 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.8, 166.4, 163.4, 155.5, 144.1, 138.4, 135.8, 133.8, 133.4, 132.6, 131.1, 130.6, 130.3, 130.2, 126.2, 123.3, 123.2, 122.6, 119.8, 119.3, 112.4, 102.6, 94.5, 47.7, 45.5, 44.6, 20.1, 17.1; C₂₈H₂₁ClN₂O₃ (468.94): calcd C 71.72, H 4.51, N 5.97; found C 71.87, H 4.44, N 5.91.

(±)-2i/2i′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3291, 1697 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.27 (d, J = 5.7 Hz, 1H), 7.95 (d, J = 5.7 Hz, 1H), 7.73–6.93 (m, 10H), 5.60 (s, 1H), 3.96 (t, J = 13.2 Hz, 1H), 3.35–3.33 (m, 1H), 2.97 (d, J = 12.9 Hz, 1H), 1.15 (d, J = 15.0, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.7, 166.3, 163.5, 159.6, 156.4, 152.7, 144.0, 138.3, 134.9, 134.8, 133.8, 133.3, 131.1, 130.6, 130.3, 130.2, 123.2, 122.5, 119.8, 119.3, 115.0, 114.7, 110.8, 110.5, 102.8, 94.3, 47.6, 45.5, 45.1, 17.0; C₂₇H₁₉FN₂O₃ (438.46): calcd C 73.96, H 4.37, N 6.39; found C 73.86, H 4.32, N 6.33.

(±)-2j/2j′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3296, 1694 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.26 (d, J = 5.7 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.73–7.01 (m, 10H), 5.57 (s, 1H), 3.93 (t, J = 12.9 Hz, 1H), 3.37–3.33 (m, 1H), 2.95 (d, J = 11.1 Hz, 1H), 1.12 (d, J = 15.0 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.8, 166.4, 163.5, 155.5, 144.0, 138.4, 135.4, 133.8, 133.4, 131.1, 130.7, 130.3, 130.2, 128.5, 126.1, 123.3, 123.2, 122.6, 119.8, 119.3, 111.5, 102.7, 94.3, 47.6, 45.5, 44.7, 17.1; C₂₇H₁₉ClN₂O₃ (454.92): calcd C 71.29, H 4.21, N 6.16; found C 71.18, H 4.16, N 6.10.

(±)-2k/2k′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3299, 1699 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.23 (d, J = 6.9 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.71–7.65 (m, 2H), 7.52–7.48 (m, 2H), 7.39–7.32 (m, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.16–7.12 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 5.56 (s, 1H), 3.96 (t, J = 13.2 Hz, 1H), 3.30–3.28 (m, 1H), 2.99–2.94 (dd, J₁ = 2.7 Hz, J₂ = 12.9 Hz, 1H), 1.11 (d, J = 15.6 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 191.1, 166.8, 163.8, 156.3, 144.4, 138.7, 136.3, 134.1, 133.8, 131.8, 131.5, 131.1, 130.7, 130.6, 126.4, 123.6, 123.0, 120.2, 119.7, 114.0, 112.5, 103.0, 94.7, 48.0, 45.9, 45.1, 17.4; C₂₇H₁₉BrN₂O₃ (499.37): calcd C 64.94, H 3.84, N 5.61; found C 64.80, H 3.78, N 5.54.

(±)-2l/2l′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3316, 1697 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.24 (d, J = 6.6 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.75–7.71 (m, 2H), 7.68–7.51 (m, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.29 (t, J = 6.9 Hz, 1H), 7.17 (d, J = 6.2 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 6.82–6.78 (m, 1H), 6.63 (s, 1H), 5.56 (s, 1H), 3.95 (t, J = 13.5 Hz, 1H), 3.66 (s, 3H), 3.37–3.35 (m, 1H), 3.00–2.95 (dd, J₁ = 3.9 Hz, J₂ = 14.1 Hz, 1H), 1.12 (d, J = 15.6 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.9, 166.4, 163.5, 155.2, 150.5, 144.3, 138.4, 133.9, 133.8, 133.3, 133.2, 131.1, 130.4, 130.1, 123.1, 122.5, 119.7, 119.2, 114.1, 110.3, 108.7, 102.4, 94.8, 55.8, 47.6, 45.6, 45.3, 17.1; C₂₈H₂₂N₂O₄ (450.50): calcd C 74.65, H 4.92, N 6.22; found C 74.79, H 4.84, N 6.15.

(±)-2m/2m′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3294, 1692 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 7.84 (d, J = 6.6 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.51–7.44 (m, 2H), 7.35–7.27 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 6.6 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.68–6.63 (m, 2H), 5.31 (s, 1H), 4.03–4.00 (m, 1H), 2.91–2.88 (m, 1H), 2.01 (s, 3H), 1.53–1.33 (m, 6H), 0.95–0.91 (m, 1H), 0.22–0.18 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.7, 166.8, 162.4, 154.4, 145.4, 138.3, 134.0, 133.3, 133.2, 131.6, 131.0, 130.3, 130.2, 130.0, 128.7, 123.7, 122.8, 122.4, 119.7, 119.2, 110.0, 104.4, 94.8, 57.2, 53.4, 45.0, 31.0, 30.9, 25.2, 24.3, 20.4; C₃₁H₂₆N₂O₃ (474.56): calcd C 78.46, H 5.52, N 5.90; found C 78.30, H 5.45, N 5.81.

(±)-2n/2n′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3295, 1690 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.13 (d, J = 6.9 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.73–7.65 (m, 2H), 7.58–7.48 (m, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 6.9 Hz, 1H), 7.05–7.02 (m, 2H), 5.54 (s, 1H), 4.24–4.01 (m, 1H), 3.12–3.09 (m, 1H), 2.27 (s, 3H), 1.84–1.80 (m, 1H), 1.64–1.55 (m, 5H), 1.17–1.14 (m, 1H), 0.48–0.46 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.6, 166.9, 162.5, 155.4, 145.1, 138.3, 135.9, 134.1, 133.5, 133.0, 131.1, 130.6, 130.3, 130.0, 126.3, 123.5, 123.0, 122.6, 119.9, 119.4, 112.9, 104.9, 94.3, 57.4, 53.6, 44.8, 31.1, 31.0, 25.3, 24.5, 20.1; C₃₁H₂₅ClN₂O₃ (509.01): calcd C 73.15, H 4.95, N 5.50; found C 73.05, H 4.91, N 5.45.

(±)-2o/2o′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3296, 1687 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.12 (d, J = 6.9 Hz, 1H), 7.93 (d, J = 6.9 Hz, 1H), 7.75–7.52 (m, 4H), 7.36 (d, J = 6.6 Hz, 1H), 7.32 (t, J = 6.9 Hz, 1H), 7.19–6.93 (m, 4H), 5.61 (s, 1H), 4.33–4.27 (m, 1H), 3.13–3.07 (m, 1H), 1.87–1.85 (m, 1H), 1.66–1.60 (m, 5H), 1.19–1.15 (m, 1H), 0.48–0.45 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.5, 166.8, 162.5, 159.7, 156.5, 152.5, 144.9, 138.2, 135.1, 133.9, 133.4, 131.0, 130.2, 129.9, 122.9, 122.4, 119.8, 119.3, 114.8, 114.5, 111.2, 111.1, 110.9, 110.5, 105.0, 94.0, 57.2, 53.5, 45.1, 31.0, 30.9, 25.2, 24.3; C₃₀H₂₃FN₂O₃ (478.53): calcd C 75.30, H 4.84, N 5.85; found C 75.14, H 4.75, N 5.78.

(±)-2p/2p′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3285, 1689 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.07 (d, J = 6.9 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.70–7.61 (m, 2H), 7.53–7.46 (m, 2H), 7.32–7.21 (m, 3H), 7.12 (d, J = 6.9 Hz, 1H), 7.02–6.97 (m, 2H), 5.55 (s, 1H), 4.31–4.23 (m, 1H), 3.11–3.07 (m, 1H), 1.87–1.84 (m, 1H), 1.61–1.48 (m, 5H), 1.20–1.16 (m, 1H), 0.49–0.45 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.5, 166.8, 162.5, 155.3, 144.8, 138.2, 135.6, 133.9, 133.4, 131.0, 130.5, 130.2, 129.9, 128.3, 126.2, 123.3, 123.0, 122.5, 119.8, 119.3, 111.9, 104.8, 93.9, 57.2, 53.5, 44.8, 31.0, 30.9, 25.2, 24.4; C₃₀H₂₃ClN₂O₃ (494.98): calcd C 72.80, H 4.68, N 5.66; found C 72.93, H 4.62, N 5.57.

(±)-2q/2q′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3299, 1685 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.14 (d, J = 6.9 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.76–7.68 (m, 2H), 7.59–7.46 (m, 3H), 7.39 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.21–7.17 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 5.62 (s, 1H), 4.31–4.23 (m, 1H), 3.11–3.07 (m, 1H), 1.87–1.84 (m, 1H), 1.67–1.54 (m, 5H), 1.20–1.16 (m, 1H), 0.49–0.45 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 190.9, 167.2, 162.8, 156.1, 145.2, 138.6, 136.4, 134.3, 133.8, 131.6, 131.4, 130.9, 130.6, 130.2, 126.4, 123.4, 122.9, 120.2, 119.7, 114.1, 112.9, 105.1, 94.3, 57.6, 53.9, 45.1, 31.4, 31.3, 25.5, 24.7; C₃₀H₂₃BrN₂O₃ (539.43): calcd C 66.80, H 4.30, N 5.19; found C 66.95, H 4.26, N 5.12.

(±)-2r/2r′. Yellow amorphous solid, mp > 300 °C, IR (KBr) 3290, 1692 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.09 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.75–7.67 (m, 2H), 7.58–7.50 (m, 2H), 7.41 (t, J = 6.6 Hz, 1H), 7.33 (t, J = 10.8 Hz, 1H), 7.18 (d, J = 6.9 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.85 (dd, J₁ = 1.8 Hz, J₂ = 8.7 Hz, 1H), 6.62 (s, 1H), 5.57 (s, 1H), 4.28–4.26 (m, 1H), 3.68 (m, 3H), 3.16–3.12 (m, 1H), 1.83–1.80 (m, 1H), 1.69–1.58 (m, 5H), 1.21–1.20 (m, 1H), 0.48–0.47 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ_H 191.0, 167.2, 162.8, 155.8, 150.7, 145.6, 138.7, 134.5, 134.4, 133.6, 131.3, 130.7, 130.5, 130.4, 123.2, 122.8, 120.1, 119.6, 114.2, 111.1, 109.3, 105.0, 94.9, 57.6, 56.3, 53.8, 45.8, 31.4, 31.2, 25.6, 24.7; C₃₁H₂₆N₂O₄ (490.56): calcd C 75.90, H 5.34, N 5.71; found C 75.78, H 5.30, N 5.66.

Acknowledgements

S.P. and K.D. thank CSIR and UGC, New Delhi, India, for offering them Senior Research Fellowship (SRF) respectively. The author Md. M. R. Mollick gratefully acknowledge the Department of Science & Technology (DST), Govt. of India for providing fellowship under the INSPIRE program. 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 994163–994165. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra03384a

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