A green, catalyst-free, solvent-free, high yielding one step synthesis of functionalized benzo[f]furo[3,2-c]chromen-4-(5H)-ones and furo[3,2-c]quinolin-4-(5H)-ones

Abstract

A green, three-component reaction of 1-hydroxy-3H-benzo[f]chromen-3-ones and 4-hydroxyquinolin-2(1H)-ones, an aromatic aldehyde and isonitrile, was developed for the first time, which resulted in a variety of substituted functionalized benzo[f]furo[3,2-c]chromen-4-(5H)-ones and furo[3,2-c]quinolin-4-(5H)-ones in excellent yield. The merits of the presented protocol include the use of microwave irradiation, catalyst-free and solvent free conditions, high atom-efficiency and no need for work up or purification with column chromatography. The present method is milder yet more advanced than those previously reported for the synthesis of related structures, furo-chromen-4-ones, furopyrimidines, furopyranones etc. The synthesized compounds have been virtually screened against a series of therapeutic targets and have shown promising binding with some of them.

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Introduction

In the contemporary world of organic synthesis, the merits of a protocol is gauged by not the intricate complicacies involved in its bringing but is rather measured by inexpensive starting materials, speed, atom efficiency, energy requirements and compatibility with automation.¹ Reactions assisted by microwave irradiation, the use of environmentally-friendly reagents and catalysts, aqueous based or solvent-less protocols and atom economical processes have collectively contributed to propound the above school of modern synthesis.² In the same way, isocyanide based multi-component synthesis has revolutionized the art of molecular design in terms of its simple approach, yet complexity, diversity and uniqueness in the products formed.³ IMCRs such as the Ugi, Passerini, Groebke–Blackburn–Bienymé and related reactions are the masterpiece of simplicity, atom economy, synthetic efficiency and are highly compatible with the goals of green chemistry.⁴

The construction of benzo[f]furo[3,2-c]chromen-4-(5H)-ones and furo[3,2-c]quinolin-4-(5H)-ones is important from a thematic standpoint in organic synthesis. In general, there is limited literature on these atypical scaffolds in comparison to functionalized benzofuranones, which are known to possess a wide range of activities, such as antibacterial, antifungal, anti-trypanosomal, antioxidant and insecticidal.⁵ Some natural furo-benzochromenones (Fig. 1), such as the anticancerous tansinones, tanshinlactone and neo-tanshinlactone, were isolated from Salvia miltiorrhiza.⁶

Fig. 1 Structures of some naturally occurring bioactive furo-benzochromenones and furo-quinolones.

This class of compounds exhibited a wide array of biological activities, viz. antitumor, antibacterial, antiallergic, antioxidant and antiplatelet aggregation.⁷ Likewise, several furoquinolones, such as lunacrine, originate from plant sources and have been ascribed to various pharmacological activities, including phytotoxic activity against bacteria and other pathogens.⁸

In literature, there are several reports for the synthesis of furocoumarins and furopyrimidines and the most common method for their preparation remains a [4 + 1] cycloaddition reaction between coumarins/pyridines with aryl aldehydes and isonitriles under various conditions.⁹ Nair et al. (2006) synthesized furocoumarins and furoquinolones in a one-pot synthesis; however, the reaction took several hours (17 h) under reflux conditions in benzene.¹⁰ Later on, a similar reaction was attempted using dimethyl formamide as the solvent under microwave irradiation, but the products were purified on preparative TLC.¹¹ In general, most of these methods are marred by one or more drawbacks, such as long reaction times, toxic catalysts and reagents, the use of carcinogenic solvent, limited substrate scope, low to moderate yields, and tedious work-up and purification.^10–12 Lately, there have been a couple of environmentally benign protocols reported for the synthesis of furocoumarins and furopyridones albeit in the presence of an acid catalyst.¹² However, to the best of our knowledge, benzo[f]furo[3,2-c]chromen-4-(5H)-ones and furo[3,2-c]quinolin-4-(5H)-ones have never been involved in the reported methods and natural extension of the above reported methods on these scaffolds is not trivial.

In this context, we present the first synthesis of benzo[f]furo[3,2-c]chromen-4-(5H)-ones and furo[3,2-c]quinolin-4-(5H)-ones in minutes without any catalyst and solvent under microwave irradiation. Moreover, the products crystallized out in high yield in the reaction vial by mere addition of water : ethanol (4 : 1) or water : isopropanol (4 : 1) with further workup or column chromatography not required.

Results and discussion

In our continuous pursuit to explore isonitrile based multi-component reactions,¹³ we sought to explore en route towards the construction of annulated furanoid scaffolds from relatively less explored CH-acids e.g. 1-hydroxy-3H-benzo[f]chromen-3-ones and 4-hydroxyquinolin-2(1H)-ones as a natural extension of our work (Scheme 1).

Scheme 1 Microwave assisted one-pot protocol for the synthesis of annulated furans.

In a prototypical reaction, 1-hydroxy-3H-benzo[f]chromen-3-ones 1a, was reacted with 4-nitrobenzaldehyde 2a and tert-butyl isonitrile 3a without any solvent under microwave irradiation for 10 min, which to our delight, provided a 95% yield of the product 4a (Table 1, entry 1).

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

Entry	Solvent	Catalyst^b	Conditions	Temp. (°C)	Time (min)	Yield (%)^d
a General conditions: 1-hydroxy-3H-benzo[f]chromen-3-ones 1a (1 mmol), 4-nitrobenzaldehyde 2a (1 mmol), tert-butylisonitrile 3a (1.2 mmol).b Catalyst loading (10%).c Anton Paar Monowave 300 reactor. Irradiation power: 850 W; Ramp time: 1 min. 70 °C.d Isolated yield.e Starting material recovered.
1	Neat	—	MW^c	120	10	95
2	Neat	—	MW^c	120	2	50^e
3	Neat	—	MW^c	120	5	95
4	Neat	—	MW^c	120	20	91
5	Neat	—	MW^c	50	5	47
6	Neat	—	MW^c	50	20	62
7	Neat	—	Grinding	rt	30	21
8	ACN	—	MW^c	120	10	86
9	MeOH	—	MW^c	120	10	87
10	IPA	—	MW^c	120	10	87
11	IPA	pTSA	MW^c	120	10	92
12	IPA	HClO4	MW^c	120	10	90
13	IPA	CH3COOH	MW^c	120	10	89
14	IPA	FeCl3	MW^c	120	10	91

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Despite the excellent result, we explored various other conditions for the above reaction in order to target an optimum protocol for the transformation. To see the effect of microwave irradiation on the reaction, the reaction mixture was irradiated for various times (Table 1, entries 2–4) and different temperatures (Table 1, entries 5 and 6). It was found that reducing microwave irradiation to 5 minutes remained equally effective; however, reducing it further for 2 minutes brought down the yield of 4a and a lot of starting material remained unreacted (Table 1, entry 4). Likewise, lowering the temperature of the reaction did not yield fruitful results (Table 1, entries 5 and 6). In another reaction, substrates were ground for 30 min at room temperature; however, it resulted in meagre yield of the desired product (Table 1, entry 7).

The effect of different solvents like acetonitrile, methanol and isopropanol (Table 1, entries 8–10) as well as different acid catalysts like CH₃COOH, HClO₄ and FeCl₃ (Table 1, entries 12–14), resulted in lowering the yield of the product 4a. Thus, we led to infer that microwave irradiation at 120 °C for 5 minutes resulted in the best yields of the products. Hence, under the optimized reaction conditions, we reacted 1-hydroxy-3H-benzo[f]chromen-3-ones 1a (1 mmol), arylaldehydes 2a–f (1 mmol), isonitriles 3a–f (1.2 mmol) under microwave irradiation at 120 °C for 5 minutes to furnish excellent yields of the desired products.

After having the optimization conditions in hand, substrate scope and versatility with respect to the aldehyde and isocyanide were also examined (Table 2). The method seemed to tolerate various substituted aryl–aldehydes. Especially, the yields were better in the case of electron deficient arylaldehydes in comparison to electron rich arylaldehydes (Table 2). The lower yield in electron rich arylaldehyde was expected as the initial enone formed would be less electrophilic and hence less prone to isonitrile attack.

Table 2 Scope of the reaction for the synthesis of benzo[f]furo[3,2-c]chromen-4-(5H)-ones

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After having obtained success with 1-hydroxy-3H-benzo[f]chromen-3-ones, we extended the method on 4-hydroxyquinolin-2(1H)-ones and pleasingly, it worked equally well on this scaffold as evident from Table 3. The reaction tolerated various aryl–aldehydes as well as isonitriles and the general reactivity trend remained similar in both the series. The mechanism of this reaction presumably involves formation of an α,β-enone from 1-hydroxy-3H-benzo[f]chromen-3-one 1a or 4-hydroxyquinolin-2(1H)-one 1b and aldehyde 2a–f via a Knoevenagel condensation reaction (Scheme 2), which would subsequently react with the isocyanide 3a–f through a concerted [4 + 1] cycloaddition reaction followed by cyclisation resulting in the formation of a N-substituted iminolactone, which undergoes a [1,3]-proton shift to yield the desired product 4a–q or 5a–l (Scheme 2). The probability of the above mechanistic route has already been confirmed using DFT models.¹⁴

Table 3 Scope of the reaction for the synthesis of furo[3,2-c]quinolin-4-(5H)-ones

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Scheme 2 Proposed mechanism for the one-pot three component condensation reaction.

Finally, we decided to explore potential applications of these products in chemotherapeutic domains. We performed an “in silico target fishing experiment” using ChemMapper server¹⁵ to find prospective drug targets for these two scaffolds.¹⁶ The results of this experiment indicated that benzo[f]furo[3,2-c]chromen-4-(5H)-ones scaffold can be a hit for cyclin-dependent kinase 2 (CDK2) and estrogen receptor beta (ESR2) involved in cancer chemotherapeutics. Likewise, furo[3,2-c]quinolin-4-(5H)-ones may target biotin carboxylase (BC) and hematopoietic prostaglandin D synthase involved in antibacterials and inflammation.¹⁷ A detailed description is given in the ESI.†

Conclusions

In summary, a neat, atom and step economical, environmentally benign one pot multi-component synthetic route for the functionalized annulated furans in good yields has been devised under microwave irradiation. The yields of the reactions are excellent and purification of the products not needed. The present methodology can be used for the design of libraries and diversity oriented synthesis (DOS), and has potential for automation. Finally, the products of this synthesis are virtually propounded as potent therapeutic hits against some therapeutic targets and further work in this direction is under progress.

Experimental part

NMR spectra were recorded on a Bruker Avance® 400 and Jeol Resonance ECX-400II. Chemical shifts are reported in parts per million and are referenced to TMS. Spectra were processed using Bruker Topspin® 3.0.b.8 and MestReNova software. Mass spectrometry (HRMS) was performed using a Bruker daltronics microTOF-QII® spectrometer using ESI ionization with less than 5 ppm error for all HRMS analyses. Analytical Thin layer chromatography (TLC) was performed on a silica gel plate (Merck® 60F₂₅₄). IR spectra were recorded on a Perkin Elmer FT-IR spectrometer (Spectrun Two). Melting points were performed with a Ambassador® and Digital Melting point apparatus (Nutronics), Popular India. All solvents were distilled prior to use and all chemicals were purchased from Sigma-Aldrich® and used without further purification.

Microwave irradiation experiment

All microwave experiments were carried out in a dedicated Anton Paar Monowave 300 reactor® operating at a frequency of 2.455 GHz with continuous irradiation power of 0 to 300 W. The reactions were performed in a G10 Borosilicate glass vial sealed with Teflon septum and placed in a microwave cavity. Initially, microwave of required power was used and temperature ramped from room temperature to the desired temperature. Once this temperature was attained, the process vial was held at this temperature for required time. The reactions were continuously stirred. Temperature was measured by an IR sensor. After the experiments, a cooling jet cooled the reaction vessel to ambient temperature.

General procedure for the microwave-assisted three component reaction

Benzo[f]naphthochromen-3-ones 1a or 4-hydroxyquinolin-2(1H)-ones 1b (1.0 mmol), aryl–aldehyde 2a–f (1.0 mmol) and isonitrile 3a–f (1.2 mmol) was mixed well in a G10 process vial capped with Teflon septum. After a pre-stirring of 1 or 2 minutes, the vial was subjected to microwave irradiation with the initial ramp time of 1 minute at 70 °C. The temperature was then raised to 120 °C with the holding time of 5 minutes. After completion of the reaction, the ethanol : water (1 : 4) or isopropanol : water (1 : 4) was added into it and the precipitated solids were filtered. All the products were characterized through their ¹H, ¹³C NMR, IR and HRMS. ¹³C NMR for compound 4p, 5d, 5f, 5g, 5k and 5l could not be recorded even at higher scans due to their lower solubility in the deuterated solvents.

2-(tert-Butylamino)-3-(4′-nitrophenyl)-4H-benzo[f]furo[3,2-c]chromen-4-one (4a). Reddish orange solid (95%), Mp decomp. 275–276 °C, IR (KBr, cm⁻¹): ν_max = 3381, 2977, 2345, 1704, 1603, 1508, 1202. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.38 (s, 9H), 6.36 (s, 1H), 7.56–7.65 (m, 2H), 7.69–7.79 (m, 1H), 7.83 (dt, 2H, J = 8.8 & 2.5 Hz), 8.05 (d, 2H, J = 9.2 Hz), 8.23 (dt, 2H, J = 8.9 & 2.4 Hz), 8.89 (d, 1H, J = 8.4 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 30.0, 53.4, 99.6, 106.1, 109.9, 117.1, 123.0, 124.1, 125.8, 126.2, 128.4, 129.1, 130.1, 130.6, 130.7, 138.1, 145.4, 150.5, 151.5, 155.9, 156.7. HRMS (ESI) m/z calcd. for C₂₅H₂₀N₂O₅ [M]⁺: 428.1366, found: 428.1361.

2-(Cyclohexylamino)-3-(4′-chlorophenyl)-4H-benzo[f]furo[3,2-c]chromen-4-one (4b). Pale yellow solid (75%), Mp 190–192 °C, IR (KBr, cm⁻¹): ν_max = 3299, 2930, 2865, 1707, 1606, 1561, 1505. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.12–1.22 (m, 1H), 1.26–1.46 (m, 4H), 1.58–1.67 (m, 1H), 1.72–1.81 (m, 2H), 1.92–2.04 (m, 2H), 3.41–3.53 (m, 1H), 6.78 (d, 1H, J = 7.6 Hz), 7.40–7.49 (m, 2H), 7.50–7.61 (m, 4H), 7.64–7.70 (m, 1H), 7.92 (d, 1H, J = 9.0 Hz), 7.98 (d, 1H, J = 7.9 Hz), 8.70 (d, 1H, J = 8.4 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 24.8, 25.2, 33.1, 53.0, 92.3, 106.2, 111.0, 116.7, 124.3, 125.6, 125.8, 127.7, 127.9, 128.7, 129.2, 129.4, 130.0, 130.5, 131.4, 149.3, 149.4, 155.2, 156.7. HRMS (ESI) m/z calcd. for C₂₇H₂₂ClNO₃ [M − H]⁺: 442.1204, found: 442.1201.

3-(4′-Chlorophenyl)-2-((2′′,4′′,4′′-trimethylpentan-2-yl)amino)-4H-benzo[f]furo[3,2-c]chromen-4-one (4c). Yellow solid (87%), Mp 170–172 °C, IR (KBr, cm⁻¹): ν_max = 1709, 1613, 1562, 1494, 1439, 1209. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.03 (s, 9H), 1.39 (s, 6H), 1.85 (s, 2H), 5.87 (s, 1H), 7.48 (d, 2H, J = 8.5 Hz), 7.57–7.68 (m, 4H), 7.74 (t, 1H, J = 7.6 Hz), 8.08 (t, 2H, J = 9.3 Hz), 8.99 (d, 1H, J = 8.4 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 30.0, 31.3, 31.4, 53.7, 56.7, 100.9, 106.3, 110.2, 117.1, 124.1, 125.8, 126.1, 127.8, 128.0, 129.1, 129.4, 130.1, 130.2, 131.2, 131.7, 150.3, 151.0, 154.9, 156.7. HRMS (ESI) m/z calcd. for C₂₉H₂₈ClNO₃ [M − H]⁺: 472.1673, found: 472.1670.

3-(4′-Chlorophenyl)-2-((2-morpholinoethyl)amino)-4H-benzo[f]furo[3,2-c]chromen-4-one (4d). Yellow solid (80%), Mp 198–200 °C, IR (KBr, cm⁻¹): ν_max = 3392, 2961, 2839, 1725, 1612, 1563, 1508. ¹H NMR (400 MHz, CDCl₃): δ_H = 2.49 (t, 4H, J = 4.2 Hz), 2.67 (t, 2H, J = 6.0 Hz), 3.57 (q, 2H, J = 5.6 Hz), 3.66 (t, 4H, J = 4.3 Hz), 5.38 (t, 1H, J = 5.2 Hz), 7.41 (d, 2H, J = 8.5 Hz), 7.47–7.57 (m, 4H), 7.67 (t, 1H, J = 7.5 Hz), 7.80 (d, 1H, J = 9.0 Hz), 7.88 (d, 1H, J = 8.8 Hz), 8.85 (d, 1H, J = 8.5 Hz). ¹³C NMR (100 MHz, CDCl₃): δ_C = 40.9, 53.3, 57.0, 67.1, 95.6, 107.2, 111.3, 117.3, 125.1, 126.0, 126.6, 128.0, 128.8, 128.9, 129.1, 129.9, 130.5, 130.6, 150.6, 151.5, 155.6, 157.9. HRMS (ESI) m/z calcd. for C₂₇H₂₃ClN₂O₄ [M − H]⁺: 473.1262, found: 473.1259.

2-(tert-Butylamino)-3-(4′-bromophenyl)-4H-benzo[f]furo[3,2-c]chromen-4-one (4e). Yellow solid (82%), Mp decomp. 280–281 °C, IR (KBr, cm⁻¹): ν_max = 3378, 2978, 1724, 1617, 1562, 1499, 1212. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.36 (s, 9H), 5.87 (s, 1H), 7.57 (dt, 2H, J = 8.6 & 1.9 Hz), 7.60–7.68 (m, 4H), 7.76–7.82 (m, 1H), 8.05–8.12 (m, 2H), 8.95 (d, 1H, J = 8.4 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 30.0, 53.4, 102.8, 106.2, 109.9, 117.1, 119.9, 124.1, 125.9, 126.1, 128.3, 129.0, 129.7, 130.1, 130.5, 130.7, 132.0, 150.6, 151.6, 154.8, 156.7. HRMS (ESI) m/z calcd. for C₂₅H₂₀BrNO₃ [M]⁺: 461.0621, found: 461.0619.

2-(Cyclohexylamino)-3-(4′-bromophenyl)-4H-benzo[f]furo[3,2-c]chromen-4-one (4f). Brown solid (70%), Mp 175–177 °C; IR (KBr, cm⁻¹): ν_max = 3378, 2980, 1723, 1563, 1496, 1212. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.09–1.24 (m, 1H), 1.27–1.48 (m, 4H), 1.57–1.68 (m, 1H), 1.71–1.84 (m, 1H), 1.90–2.07 (m, 1H), 3.44–3.56 (m, 1H), 6.81 (d, 1H, J = 7.6 Hz), 7.48 (dt, 2H, J = 8.5 & 2.4 Hz), 7.53–7.62 (m, 4H), 7.70 (t, 1H, J = 7.7 Hz), 7.95 (d, 1H, J = 9.0 Hz), 8.00 (d, 1H, J = 8.0 Hz), 8.75 (d, 1H, J = 8.4 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 24.8, 25.2, 33.1, 53.0, 92.3, 106.2, 110.9, 116.8, 119.1, 124.3, 125.6, 125.9, 128.0, 128.8, 129.3, 129.8, 130.0, 130.7, 131.8, 149.4, 149.5, 155.2, 156.7. HRMS (ESI) m/z calcd. for C₂₇H₂₂BrNO₃ [M − H]⁺: 486.0699, found: 486.0691.

3-(4′-Bromophenyl)-2-((2′′,4′′,4′′-trimethylpentan-2-yl)amino)-4H-benzo[f]furo[3,2-c]chromen-4-one (4g). Light yellow solid (85%); Mp 168–170 °C; IR (KBr, cm⁻¹): ν_max = 3379, 2963, 2900, 1728, 1612, 1558, 1496, 1216. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.04 (s, 9H), 1.40 (s, 6H), 1.86 (s, 2H), 5.90 (s, 1H), 7.54 (dt, 2H, J = 8.4 & 2.4 Hz), 7.62 (dt, 2H, J = 9.0 & 2.3 Hz), 7.73–7.79 (m, 2H), 7.73–7.79 (m, 1H), 8.10 (t, 2H, J = 9.2 Hz), 9.01 (d, 1H, J = 8.4 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 30.1, 31.3, 31.5, 53.7, 56.7, 100.7, 106.3, 110.2, 117.1, 119.7, 124.1, 125.8, 126.1, 128.0, 129.1, 129.8, 130.1, 130.2, 130.7, 132.0, 150.3, 151.0, 154.9, 156.7. HRMS (ESI) m/z calcd. for C₂₉H₂₈BrNO₃ [M − H]⁺: 516.1168, found: 516.1167.

3-(4′-Bromophenyl)-2-((2-morpholinoethyl)amino)-4H-benzo[f]furo[3,2-c]chromen-4-one (4h). Yellow orange solid (81%), Mp 210–211 °C, IR (KBr, cm⁻¹): ν_max = 3379, 2965, 2841, 1731, 1611, 1567, 1502, 1429. ¹H NMR (400 MHz, CDCl₃): δ_H = 2.35–2.55 (br m, 4H), 2.67 (t, 2H, J = 5.8 Hz), 3.45 (q, 2H, J = 5.5 Hz), 3.62–3.78 (br m, 4H), 5.38 (t, 1H, J = 2.2 Hz), 7.41–7.66 (m, 6H), 7.68 (t, 1H, J = 7.1 Hz), 7.82 (d, 1H, J = 8.9 Hz), 7.89 (d, 1H, J = 8.0 Hz), 8.87 (d, 1H, J = 8.4 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 31.2, 53.9, 58.6, 66.7, 92.5, 106.9, 111.6, 117.5, 119.6, 125.2, 126.2, 126.7, 128.7, 129.4, 130.0, 130.2, 130.7, 131.4, 132.2, 150.0, 150.1, 156.7, 157.4. HRMS (ESI) m/z calcd. for C₂₇H₂₃BrN₂O₂ [M]⁺: 518.0835, found: 518.0834.

2-(tert-Butylamino)-3-(2′-chloro-5′-nitrophenyl)-4H-benzo[f] furo[3,2-c]chromen-4-one (4i). Orange solid (85%), Mp decomp. 280–281 °C, IR (KBr, cm⁻¹): ν_max = 3361, 3097, 2973, 1734, 1621, 1521, 1344. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.43 (s, 9H), 6.30 (s, 1H), 7.63–7.70 (m, 2H), 7.78–7.84 (m, 1H), 7.87 (d, 1H, J = 8.8 Hz), 8.10 (t, 2H, J = 9.1 Hz), 8.26 (dd, 1H, J = 8.8 & 2.8 Hz), 8.31 (d, 1H, J = 2.8 Hz), 8.94 (d, 1H, J = 8.4 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 30.1, 53.3, 95.6, 106.4, 111.5, 117.1, 123.8, 124.1, 125.8, 126.2, 127.9, 128.3, 129.1, 130.1, 130.2, 130.5, 131.3, 141.9, 145.9, 150.2, 150.5, 155.8, 156.5. HRMS (ESI) m/z calcd. for C₂₅H₁₉ClN₂O₅ [M]⁺: 462.0977, found: 462.0972.

2-(Cyclohexylamino)-3-(2′-chloro-5′-nitrophenyl)-4H-benzo[f]furo[3,2-c]chromen-4-one (4j). Brown solid (84%), Mp 215–220 °C, IR (KBr, cm⁻¹): ν_max = 3403, 2932, 2852, 1723, 1628, 1527, 1345. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.08–1.43 (m, 5H), 1.59 (br s, 1H), 1.75 (br s, 2H), 1.97 (br s, 2H), 3.40–3.53 (m, 1H), 7.14 (s, 1H), 7.64 (br s, 2H), 7.73–7.93 (m, 2H), 7.95–8.15 (m, 2H), 8.16–8.43 (m, 2H), 8.86 (br s, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 24.6, 25.1, 33.1, 33.2, 52.8, 87.4, 99.4, 106.4, 116.9, 123.5, 124.4, 125.6, 126.1, 128.0, 128.1, 128.9, 129.4, 130.1, 130.4, 131.4, 141.9, 145.7, 149.5, 155.6, 156.6. HRMS (ESI) m/z calcd. for C₂₇H₂₁ClN₂O₅ [M − H]⁺: 488.1133, found: 488.1129.

3-(2′-Chloro-5′-nitrophenyl)-2-((2′′,4′′,4′′-trimethylpentan-2-yl)amino)-4H-benzo[f]furo[3,2-c]chromen-4-one (4k). Light yellow solid (91%), Mp 194–196 °C, IR (KBr, cm⁻¹): ν_max = 3357, 2964, 2901, 1728, 1615, 1532, 1344, 1214. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 0.98 (s, 9H), 1.44 (d, 6H, J = 11.0 Hz), 1.86 (q, 2H, J = 7.5 Hz), 6.25 (s, 1H), 7.59–7.68 (m, 2H), 7.72–7.79 (m, 1H), 7.87 (d, 1H, J = 8.8 Hz), 8.04 (d, 1H, J = 9.0 Hz), 8.08 (d, 1H, J = 7.9 Hz), 8.26 (td, 2H, J = 9.0 & 2.8 Hz), 8.94 (d, 1H, J = 8.5 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 30.1, 30.3, 31.2, 31.4, 53.2, 56.6, 94.4, 106.4, 111.7, 117.1, 123.7, 124.0, 125.6, 126.1, 127.9, 128.0, 129.0, 129.9, 130.1, 130.5, 131.5, 142.0, 145.9, 150.1, 155.7, 156.5. HRMS (ESI) m/z calcd. for C₂₉H₂₇ClN₂O₃ [M − H]⁺: 518.1603, found: 518.1609.

2-(tert-Butylamino)-3-(4′-chlorophenyl)-4H-benzo[f]furo[3,2-c]chromen-4-one (4l). Yellow solid (89%), Mp 210–211 °C, IR (KBr, cm⁻¹): ν_max = 3397, 2942, 2862, 1660, 1597, 1508, 1338. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.36 (s, 9H), 5.85 (s, 1H), 7.50 (dt, 2H, J = 8.4 & 2.9 Hz), 7.60–7.69 (m, 4H), 7.75–7.83 (m, 1H), 8.09 (d, 2H, J = 9.2 Hz), 8.95 (d, 1H, J = 8.4 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 30.0, 53.4, 103.0, 106.2, 110.0, 117.1, 124.1, 126.0, 126.1, 127.8, 128.3, 129.0, 129.3, 130.1, 130.5, 131.3, 131.7, 150.6, 151.6, 154.89, 156.7. HRMS (ESI) m/z calcd. for C₂₅H₂₀ClNO₃ [M]⁺: 417.1126, found: 417.1123.

2-(Cyclohexylamino)-3-(4′-nitrophenyl)-4H-benzo[f]furo[3,2-c]chromen-4-one (4m). Brown solid (85%), Mp decomp. 265–266 °C, IR (KBr, cm⁻¹): ν_max = 2980, 1709, 1606, 1562, 1501, 1211. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.12–1.26 (m, 1H), 1.29–1.51 (m, 4H), 1.61–1.70 (m, 1H), 1.73–1.88 (m, 2H), 1.95–2.12 (m, 2H), 3.51–3.65 (m, 1H), 7.27 (d, 1H, J = 7.4 Hz), 7.55 (d, 1H, J = 9.0 Hz), 7.59 (t, 1H, J = 7.2 Hz), 7.69 (t, 1H, J = 7.3 Hz), 7.79 (dt, 2H, J = 8.8 & 2.0 Hz), 7.96 (d, 1H, J = 8.0 Hz), 8.00 (d, 1H, J = 4.0 Hz), 8.24 (d, 2H, J = 8.9 Hz), 8.66 (d, 1H, J = 8.4 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 24.8, 25.2, 32.9, 53.1, 91.1, 105.9, 110.4, 116.7, 122.9, 124.1, 125.5, 125.9, 128.0, 128.8, 129.6, 130.0, 138.2, 144.5, 149.6, 149.8, 156.1, 156.6. HRMS (ESI) m/z calcd. for C₂₇H₂₂N₂O₅ [M]⁺: 453.1444, found: 453.1440.

3-(4′-Nitrophenyl)-2-((2′′,4′′,4′′-trimethylpentan-2-yl)amino)-4H-benzo[f]furo[3,2-c]chromen-4-one (4n). Red solid (92%), Mp 192–193 °C, IR (KBr, cm⁻¹): ν_max = 3397, 2974, 1714, 1616, 1553, 1494. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.04 (s, 9H), 1.49 (s, 6H), 1.95 (s, 2H), 6.48 (s, 1H), 7.64–7.70 (m, 2H), 7.74–7.80 (m, 1H), 7.88 (dt, 1H, J = 8.2 & 1.8 Hz), 8.11 (t, 2H, J = 8.8 Hz), 8.27 (dt, 2H, J = 8.8 & 2.4 Hz), 9.0 (d, 1H, J = 8.4 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 30.1, 31.3, 31.5, 53.3, 56.7, 97.8, 106.2, 110.1, 117.1, 123.0, 124.1, 125.7, 126.2, 128.1, 129.2, 130.1, 130.3, 130.6, 138.2, 145.2, 150.3, 151.0, 155.9, 156.7. HRMS (ESI) m/z calcd. for C₂₉H₂₈N₂O₅ [M − H]⁺: 483.1914, found: 483.1905.

2-((Ethoxymethyl)amino)-3-(4′-nitrophenyl)-4H-benzo[f]furo[3,2-c]chromen-4-one (4o). Brown solid (89%), Mp 219–220 °C, IR (KBr, cm⁻¹): ν_max = 3373, 2960, 2855, 2821, 1657, 1603, 1414. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.17 (t, 3H, J = 7.1 Hz), 4.13 (q, 2H, J = 7.1 Hz), 4.25 (d, 2H, J = 6.2 Hz), 7.56–7.61 (m, 2H), 7.64–7.69 (m, 1H), 7.79 (dt, 2H, J = 9.0 & 2.5 Hz), 7.92–8.03 (m, 3H), 8.24 (dt, 2H, J = 9.0 & 2.5 Hz), 8.61 (d, 1H, J = 8.6 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 14.7, 45.1, 61.5, 92.1, 106.5, 111.1, 117.4, 123.7, 124.9, 126.1, 126.7, 128.7, 129.5, 130.5, 130.6, 138.3, 145.4, 150.4, 150.6, 156.6, 157.2, 171.1. HRMS (ESI) m/z calcd. for C₂₄H₁₈N₂O₆ [M]⁺: 430.1165, found: 430.1161.

2-(tert-Butylamino)-3-(3′,4′-dimethoxyphenyl)-4H-benzo[f]furo[3,2-c]chromen-4-one (4p). Yellow solid (70%), IR (KBr, cm⁻¹): ν_max = 3372, 2959, 2854, 1654, 1602, 1412. ¹H NMR (400 MHz, CDCl₃): δ_H = 1.45 (s, 9H), 3.92 (s, 3H), 3.93 (s, 3H), 4.21 (br s, 1H), 6.96 (d, 1H, J = 8.3 Hz), 7.08 (dd, 1H, J = 8.2 & 2.0 Hz), 7.14 (d, 1H, J = 2.0 Hz), 7.53–7.60 (m, 2H), 7.67–7.73 (m, 1H), 7.86 (d, 1H, J = 9.0 Hz), 7.92 (d, 1H, J = 7.6 Hz), 9.03 (d, 1H, J = 8.8 Hz). HRMS (ESI) m/z calcd. for C₂₇H₂₅NO₅ [M]⁺: 443.1733, found: 443.1721.

3-(4′-Chlorophenyl)-2,6-(dimethylphenylamino)-4H-benzo[f]furo[3,2-c]chromen-4-one (4q). Yellow-greenish solid (89%), Mp 195–196 °C, IR (KBr, cm⁻¹): ν_max = 3290, 2360, 1713, 1649, 1619, 1585, 1218, 1091, 813. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 2.19 (s, 6H), 4.01 (s, 1H), 7.01–7.06 (m, 3H), 7.27–7.33 (m, 4H), 7.44 (dt, 2H, J = 8.8 & 2.0 Hz), 7.51–7.54 (m, 1H), 7.58–7.61 (m, 2H), 7.64 (d, 1H, J = 11.6 Hz). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 18.7, 126.3, 126.7, 127.8, 128.6, 128.7, 128.8, 129.0, 130.4, 130.6, 131.1, 131.3, 131.7, 134.4, 136.8, 139.1, 150.6, 150.7, 153.2, 153.5, 157.3, 162.8. HRMS (ESI) m/z calcd. for C₂₉H₂₀ClNO₃ [M]⁺: 465.1126, found: 465.1107.

2-(Cyclohexylamino)-3-(4′-nitrophenyl)-furo[3,2-c]quinolin-4(5H)-one (5a). Dark red solid (85%), Mp decomp. 200–210 °C, IR (KBr, cm⁻¹): ν_max = 3397, 2942, 2862, 1660, 1597, 1508, 1338. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.06–1.21 (m, 1H), 1.23–1.48 (m, 4H), 1.49–1.66 (m, 1H), 1.66–1.84 (m, 2H), 1.84–2.06 (m, 2H), 3.54–3.75 (m, 1H), 6.84 (d, 1H, J = 7.8 Hz), 7.21–7.27 (m, 1H), 7.31–7.51 (m, 2H), 7.79 (d, 1H, J = 7.8 Hz), 7.85 (dt, 2H, J = 7.4 & 2.5 Hz), 8.19 (dt, 2H, J = 8.9 & 2.5 Hz), 11.67 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 24.8, 25.2, 33.1, 52.6, 93.1, 110.7, 114.8, 115.4, 118.7, 122.1, 122.7, 127.6, 130.1, 135.1, 139.5, 144.1, 147.8, 155.8, 158.5. HRMS (ESI) m/z calcd. for C₂₃H₂₁N₃O₄ [M − H]⁺: 402.1448, found: 402.1442.

3-(4′-Chlorophenyl)-2-((2′′,4′′,4′′-trimethylpentan-2-yl)amino)furo[3,2-c]quinolin-4(5H)-one (5b). Dark red solid (89%), Mp decomp. 200-210 °C, IR (KBr, cm⁻¹): ν_max = 3373, 2865, 2862, 1657, 1609, 1503, 1414. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 0.99 (s, 9H), 1.44 (s, 6H), 1.82 (s, 2H), 6.21 (s, 1H), 7.24–7.35 (m, 1H), 7.38–7.48 (m, 2H), 7.78 (d, 1H, J = 7.8 Hz), 7.89 (dt, 2H, J = 8.9 & 2.4 Hz), 8.21 (dt, 2H, J = 8.9 & 1.8 Hz), 11.69 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 30.3, 31.3, 31.4, 53.0, 56.6, 97.6, 110.7, 114.2, 115.6, 118.7, 122.3, 122.8, 127.9, 130.4, 135.4, 139.5, 144.5, 148.6, 155.7, 158.5. HRMS (ESI) m/z calcd. for C₂₅H₂₇N₃O₄ [M − H]⁺: 432.1917, found: 432.1911.

2-(Cyclohexylamino)-3-(4′-chlorophenyl)-furo[3,2-c]quinolin-4(5H)-one (5c). Light yellow solid (81%), Mp decomp. 212–214 °C, IR (KBr, cm⁻¹): ν_max = 3096, 2896, 1711, 1211, 1003. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.02–1.18 (m, 1H), 1.19–1.42 (m, 4H), 1.53–1.61 (m, 1H), 1.63–1.76 (m, 2H), 1.83–1.99 (m, 2H), 3.41–3.58 (m, 1H), 3.41–3.53 (m, 1H), 6.26 (d, 1H, J = 8.0 Hz) 7.22 (td, 1H, J = 6.7 & 1.6 Hz), 7.34–7.44 (m, 4H), 7.58 (dt, 2H, J = 8.5 & 2.6 Hz), 7.77 (d, 1H, J = 7.8 Hz), 11.57 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 24.8, 25.2, 33.2, 52.8, 94.7, 110.9, 115.3, 115.4, 118.6, 121.9, 127.3, 127.5, 130.0, 130.5, 131.6, 135.0, 147.4, 154.7, 158.6. HRMS (ESI) m/z calcd. for C₂₃H₂₁ClN₂O₂ [M − H]⁺: 391.1207, found: 391.1201.

3-(4′-Chlorophenyl)-2-((2-morpholinoethyl)amino)furo[3,2-c]quinolin-4(5H)-one (5d). Light yellow solid (84%), Mp decomp. 263 °C, IR (KBr, cm⁻¹): ν_max = 3367, 2962, 2864, 2825, 1664, 1592, 1506, 1419. ¹H NMR (400 MHz, CDCl₃): δ_H = 2.47 (s, 4H), 2.62 (s, 2H), 3.42–3.52 (m, 2H), 3.66 (s, 4H), 5.26 (s, 1H), 7.21–7.30 (m, 3H), 7.35–7.42 (m, 3H), 7.61 (dt, 2H, J = 7.8 & 2.6 Hz), 7.82 (d, 1H, J = 7.2 Hz), 10.53 (s, 1H). HRMS (ESI) m/z calcd. for C₂₃H₂₂ClN₃O₃ [M]⁺: 423.1344, found: 423.1341.

2-(2-Morpholinoethylamino)-3-(4′-nitrophenyl)furo[3,2-c]quinolin-4(5H)-one (5e). Orange solid (89%); Mp decomp. 262–263 °C, IR (KBr, cm⁻¹): ν_max = 3363, 3164, 2959, 2860, 1661, 1603, 1569, 1508. ¹H NMR (400 MHz, CDCl₃): δ_H = 2.51 (s, 4H), 2.61–2.71 (m, 2H), 3.52–3.60 (m, 2H), 3.64–3.70 (m, 4H), 5.61 (br s, 1H), 7.21–7.31 (m, 2H), 7.37–7.43 (m, 1H), 7.84 (dt, 3H, J = 9.3 & 2.4 Hz), 8.27 (d, 2H, J = 8.8 Hz), 9.51 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 49.1, 53.7, 58.6, 66.8, 93.0, 111.2, 115.3, 116.0, 119.3, 122.7, 123.5, 128.2, 130.4, 135.6, 140.1, 144.5, 148.2, 157.3, 159.1. HRMS (ESI) m/z calcd. for C₂₃H₂₄N₄O₅ [M − H]⁺: 433.1506, found: 433.1501.

3-(4′-Bromophenyl)-2-((2-morpholinoethyl)amino)furo[3,2-c]quinolin-4(5H)-one (5f). Yellow solid (81%), Mp decomp. 258–259 °C, IR (KBr, cm⁻¹): ν_max = 3369, 2963, 2864, 2821, 1655, 1602, 1498. ¹H NMR (400 MHz, CDCl₃): δ_H = 2.47 (s, 4H), 2.61 (s, 2H), 3.42–3.51 (m, 2H), 3.66 (s, 4H), 5.25 (br s, 1H), 7.21–7.30 (m, 3H), 7.35–7.41 (m, 1H), 7.54 (s, 4H), 7.82 (d, 1H, J = 7.8 Hz), 10.49 (s, 1H). HRMS (ESI) m/z calcd. for C₂₃H₂₂BrN₃O₃ [M − H]⁺: 466.0760, found: 466.0765.

3-(4′-Chlorophenyl)-2-(pentylamino)furo[3,2-c]quinolin-4(5H)-one (5g). Yellow solid (78%), Mp 218–220 °C, IR (KBr, cm⁻¹): ν_max = 3369, 2956, 2863, 2827, 1661, 1606, 1500, 1416. ¹H NMR (400 MHz, CDCl₃): δ_H = 0.85–0.95 (m, 3H), 1.30–1.43 (m, 4H), 1.55–1.70 (m, 2H), 3.40 (t, 2H, J = 7.8 Hz), 4.40 (br s, 1H), 7.15–7.25 (m, 2H), 7.27–7.35 (m, 2H), 7.41 (dt, 2H, J = 8.5 & 1.8 Hz), 7.58 (dt, 2H, J = 8.5 & 1.8 Hz), 7.82 (d, 1H, J = 7.8 Hz), 11.17 (s, 1H). HRMS (ESI) m/z calcd. for C₂₂H₂₁ClN₂O₂ [M − H]⁺: 379.1207, found: 379.1207.

3-(2′,6′-Dichlorophenyl)-2-((2-morpholinoethyl)amino)furo[3,2-c]quinolin-4(5H)-one (5h). Yellow solid (87%), Mp decomp. 271–272 °C, IR (KBr, cm⁻¹): ν_max = 3433, 2938, 2856, 1661, 1602, 1491, 1350. ¹H NMR (400 MHz, CDCl₃): δ_H = 2.41 (s, 4H), 2.54 (t, 2H, J = 5.7 Hz), 3.36 (q, 2H, J = 5.7 Hz), 3.60 (t, 4H, J = 4.4 Hz), 4.77 (t, 1H, J = 5.4 Hz), 7.19–7.34 (m, 4H), 7.42–7.47 (m, 2H), 7.81 (dd, 1H, J = 7.8 Hz), 11.31 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ_C = 40.3, 53.2, 57.0, 67.1, 92.0, 112.2, 116.4, 117.2, 119.2, 122.4, 127.5, 127.8, 129.5, 130.0, 135.3, 137.4, 149.2, 155.0, 160.3. HRMS (ESI) m/z calcd. for C₂₃H₂₁Cl₂N₃O₃ [M − H]⁺: 456.0876, found 456.0871.

3-(4′-Bromophenyl)-2-(cyclohexylamino)furo[3,2-c]quinolin-4(5H)-one (5i). Yellow solid (82%), Mp decomp. 271–272 °C, IR (KBr, cm⁻¹): ν_max = 3433, 2938, 2856, 1661, 1602, 1491, 1350. ¹H NMR (400 MHz, DMSO-d₆): δ_H = 1.11–1.30 (m, 3H), 1.31–1.45 (m, 2H), 1.60–1.70 (m, 1H), 1.70–1.82 (m, 2H), 2.02–2.10 (m, 2H), 3.50–3.66 (m, 1H), 4.20 (br s, 1H), 7.15–7.26 (m, 1H), 7.30–7.35 (m, 2H), 7.50–7.60 (m, 3H), 7.83 (d, 1H, J = 7.8 Hz), 11.36 (s, 1H). ¹³C NMR (100 MHz, DMSO-d₆): δ_C = 25.4, 25.8, 33.7, 53.3, 95.0, 111.5, 115.8, 115.9, 119.0, 119.1, 122.5, 127.8, 130.9, 131.4, 132.5, 135.6, 148.0, 155.2, 159.2. HRMS (ESI) m/z calcd. for C₂₃H₂₁BrN₂O₂ [M − H]⁺: 435.0702, found 435.0701.

2-(Cyclohexylamino)-3-(2′,6′-dichlorophenyl)furo[3,2-c]quinolin-4(5H)-one (5j). White solid (84%), Mp 265–266 °C, IR (KBr, cm⁻¹): ν_max = 3433, 2938, 2856, 1661, 1602, 1491, 1350. ¹H NMR (400 MHz, CDCl₃): δ_H = 1.10–1.35 (m, 8H), 1.52–1.65 (m, 2H), 1.67–1.77 (m, 1H), 1.97–2.11 (m, 2H), 3.38–3.57 (m, 1H), 3.74 (d, 1H, J = 8.0 Hz), 7.18–7.34 (m, 4H), 7.45 (d, 2H, J = 8.0 Hz), 7.83 (d, 1H, J = 7.8 Hz), 10.78 (s, 1H). ¹³C NMR (100 MHz, CDCl₃): δ_C = 25.0, 25.4, 25.6, 34.3, 53.7, 92.4, 112.2, 116.2, 117.1, 119.3, 122.4, 127.4, 127.9, 129.5, 130.0, 135.2, 137.4, 149.0, 154.3, 160.0. HRMS (ESI) m/z calcd. for C₂₃H₂₀Cl₂N₂O₂ [M − H]⁺: 425.0818, found 425.0814.

2-(tert-Butylamino)-3-(3′,4′-dimethoxyphenyl)furo[3,2-c]quinolin-4(5H)-one (5k). Yellow solid (71%), IR (KBr, cm⁻¹): ν_max = 3432, 2935, 2852, 1657, 1487, 1343. ¹H NMR (400 MHz, CDCl₃): δ_H = 1.39 (s, 9H), 3.92 (s, 3H), 3.93 (s, 3H), 6.95 (d, 1H, J = 8.2 Hz), 7.10 (dd, 1H, J = 8.2 & 2.0 Hz), 7.20–7.28 (m, 2H), 7.29–7.40 (m, 2H), 7.85 (d, 1H, J = 7.8 Hz), 11.2 (s, 1H). HRMS (ESI) m/z calcd. for C₂₃H₂₄N₂O₄ [M]⁺: 392.1736, found 392.1729.

3-(4′-Methoxyphenyl)-2-((2-morpholinoethyl)amino)furo[3,2-c]quinolin-4(5H)-one (5l). Yellow solid (69%), IR (KBr, cm⁻¹): ν_max = 3430, 2930, 2852, 1648, 1485, 1341.¹H NMR (400 MHz, CDCl₃): δ_H = 2.45 (s, 4H), 2.59 (t, 2H, J = 5.6 Hz), 3.44 (q, 2H, J = 5.8 Hz), 3.63 (t, 4H, J = 4.5 Hz), 5.17 (s, 1H), 6.98 (dt, 2H, J = 8.8 & 3.0 Hz), 7.20–7.29 (m, 3H), 7.32–7.38 (m, 1H), 7.56 (dt, 2H, J = 8.0 & 3.8 Hz), 7.82 (dd, 1H, J = 8.0 & 1.0 Hz), 10.33 (s, 1H). HRMS (ESI) m/z calcd. for C₂₄H₂₅N₃O₄ [M]⁺: 419.1845, found 419.1839.

Acknowledgements

This work was financially supported by Department of Science and Technology (DST), Govt. of India (Grant no. SR/FT/CS-55/2011). The authors M. K. and T. K. would like to thank CSIR, Delhi and MHRD for the award of SRF and postdoctoral fellowship, respectively. The authors are also grateful to Punjab University for procuring NMR data.

References

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Footnote

† Electronic supplementary information (ESI) available: Representative ¹H, ¹³C NMR and HRMS spectra. See DOI: 10.1039/c5ra00733j

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