A rapid and modified approach for C-7 amination and amidation of 4-methyl-7-nonafluorobutylsulfonyloxy coumarins under microwave irradiation

Abstract

A facile, efficient and reliable access for the synthesis of an array of 4-methyl-7-(alkyl/aryl/heteroaryl) amino and amido coumarins has been developed by treating 4-methyl-7-nonafluorobutylsulfonyloxy coumarin with various amines and pyridones in presence of a catalyst combination of Pd₂(dba)₃/xantphos under microwave irradiation. Nonaflates coupled efficiently to give the diaryl amines in acceptable to excellent yields whereas the corresponding triflate was unstable, yielding the detriflated product as well as the hydrolyzed product as competing side products along with the desired product. The wide bite angle (108°) of xantphos, employment of Cs₂CO₃ as a mild base and the utilization of TBAF·3H₂O as an additive proved to be key for success of the reaction.

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Introduction

The Buchwald–Hartwig cross-coupling reaction between amines and organic halides or triflates has emerged as one of the foremost methods for the creation of C(sp²)–N bonds under mild conditions.¹ The reaction provides an efficient pathway to a range of pharmaceuticals, natural products, dyes and polymers and hence has significantly extended its scope in recent years.² The development of more efficient ligands by Buchwald and co-workers³ has considerably increased the extent of these reactions and has found widespread use in pharmaceutical industries.⁴ The metal catalyzed cross-coupling reactions are considerably slow and usually take hours or days for complete conversion of reactants which is too long for medicinal chemistry research programs in which large libraries of compounds have to be made within a short period of time.⁵ The microwave assisted organic synthesis (MAOS) has indisputably became a powerful tool in drug discovery laboratories these days for the construction of versatile chemical entities due often to superior reaction rates, selectivity and product yields as compared to standard thermal conditions.⁶ It is well documented that microwave assistance can lead to enormous rate enhancement compared to conventional heating by significantly shortening the reaction times. Moreover, a better reproducibility, greater yields and less side reactions have often been observed when compared to standard heating methodologies.⁷

Coumarins are an important class of benzopyrones that are widely distributed throughout the plant kingdom either in free or combined state.⁸ They represent one of the most active classes of compounds and possess a wide spectrum of pharmacological activities.⁹ Coumarin derivatives have various therapeutic applications including photo chemotherapy, anti-tumor, anti-HIV therapy,¹⁰ and are also active as anti-bacterial,^11,12 anti-inflammatory¹³ and anti-viral agents.¹⁴ In addition, coumarins are found to be lipid lowering agents with moderate triglyceride lowering activity¹⁵ whereas hydroxycoumarins are powerful chain breaking anti-oxidants which prevent free radical injury.^16,17 The diverse biological activities of coumarins as anticoagulants and antithrombotics are extensively reported in literature.¹⁸ The coumarin motif is present within the chemical structure of pharmaceutical drugs such as warfarin, acenocoumarol, carbochromen etc. and in antibiotics such as novobiocin, clorobiocin and coumermycin A₁.¹⁹ Coumarin derivatives have also been used as luminescent probes, triplet sensitizers and photostable laser dyes.²⁰ For the past 20 years, these varied applications of coumarins have encouraged many researchers to synthesize and evaluate the pharmacological profile of new coumarin derivatives.²¹

The diverse applications of coumarins in various areas of chemistry have been well reported in literature. Furthermore, the structure activity relationship (SAR) studies of various heteroaryl/aryl coumarins have revealed that the presence of substituted heteroaryl/aryl groups in the coumarin moiety is an indispensable feature for their active pharmacological properties.²² However, the instability (lactone ring cleavage) of the coumarin nuclei in basic as well as prolonged heating conditions is broadly reported in literature.^22,23 As a continuation of our ongoing research program in medicinal chemistry,²⁴ we were interested in the synthesis of some substituted amino and amido coumarins which may possess significant biological activity. Continuing with our ongoing studies on microwave assisted synthesis²⁵ and considering the instability of coumarin nuclei to prolonged heating conditions, we decided to utilize the microwave irradiation for the synthesis of various amino and amido coumarins in view of the fact that the reaction could reach to completion within minutes as compared to classical heating. In this letter, we report a rapid and novel access for the synthesis of a variety of 4-methyl-7-(alkyl/aryl/heteroaryl) amino and amido coumarins 4a–t by utilizing the palladium catalyzed cross-coupling of 4-methyl-7-nonafluorobutylsulfonyloxycoumarins 3b with various aryl/heteroaryl amines under microwave irradiation.

Results and discussions

The parent coumarin scaffold 2 was synthesized using the modified Pechmann cyclization condition (Scheme 1) in which resorcinol 1 was treated with ethyl acetoacetate in 1-butyl-3-methylimidazolium chloroaluminate at 30 °C for 20 min.²⁶ The obtained hydroxy coumarin 2 was then converted to corresponding triflate 3a by treating it with trifluoromethane sulfonic anhydride in pyridine at −10 °C for 2 h. The intermediate thus obtained was then subjected to Buchwald–Hartwig amination with the intention of synthesizing a series of novel 4-methyl-7-(heteroaryl) amino/amidocoumarins of considerable pharmacological relevance.

Scheme 1 Synthesis of 4-methyl-7-trifluoromethylsulfonyloxy coumarin intermediate.

Initially, we carried out the reaction optimization by treating triflate 3a with aniline as the product formation could be easily identified by TLC and LC-MS. The identification of an effective catalyst combination is a major task in Buchwald coupling since a variety of catalysts in combination with various ligands have been developed hitherto.^3,27 An extensive literature survey revealed that the amination can be successfully carried out with Pd₂(dba)₃ or Pd(OAc)₂ in combination with various ligands like BINAP, dppf, xantphos, DPEphos etc.²⁸ We started our initial screening in Pd₂(dba)₃ since the obtained results could be easily reproducible with quantitative yields and are more efficient even though it is a little time consuming.^4a,d,29 Various in situ generated catalyst combinations and bases were tried in dioxane and the reaction was carried out at 120 °C for 30 min at 110 W in a microwave oven (Table 1). To our disappointment, in most of the cases we found the detriflated product 5 as the major product (>50%) with only traces of required product 4a (Scheme 2).

Table 1 Effect of various ligands and bases in the coupling of triflate 3a with aniline^a

Entry	Catalyst	Ligand	Base	Solvent	Yield 5 (%)	Yield 2 (%)	Yield 4a (%)
a Reaction conditions: 4-methyl-7-trifluoromethylsulfonyloxy coumarin 3a (1 mmol), aniline (1.3 mmol), Pd2(dba)3 (5 mol%), ligand (0.1 mmol), base (2 mmol), dioxane, microwave irradiated at 110 W at 120 °C for 30 min.b 1 mmol of TBAF·3H2O used as an additive.c Reaction carried out for 15 min.d Reaction carried out at 100 °C.
1	Pd2(dba)3	BINAP	Cs2CO3	Dioxane	85	Traces	Nil
2	Pd2(dba)3	dppf	Cs2CO3	Dioxane	76	<10	Traces
3	Pd2(dba)3	Xantphos	Cs2CO3	Dioxane	28	45	15
4	Pd2(dba)3	DPEphos	Cs2CO3	Dioxane	50	32	Traces
5	Pd2(dba)3	Xantphos	Cs2CO3	Dioxane	35	23	30^b
6	Pd2(dba)3	Xantphos	Cs2CO3	Dioxane	Traces	20	40^b^,^c
7	Pd2(dba)3	Xantphos	Cs2CO3	Dioxane	Traces	18	45^b^,^d

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Scheme 2 Buchwald coupling of 4-methyl-7-trifluoromethylsulfonyloxy coumarin intermediate with aniline.

The triflate 3a was proved to be unstable and subsequent C–O bond cleavage occurred even within 30 min. of the commencement of the reaction. Even though we could see a little amount of product mass (15%) when xantphos was used as a ligand and Cs₂CO₃ as base in dioxane, the saponified product 2 of the triflate was obtained as a major product (Table 1, entry 3). Although the use of hydrated tetrabutyl ammonium fluoride (TBAF·3H₂O) as an additive with Cs₂CO₃ and xantphos suppressed the triflate saponification to some extent, the detriflated product 5 prevailed as a major competitor (Table 1, entry 5). Neither decreasing the reaction time nor the temperature gave acceptable conversion (Table 1, entries 6 and 7). Among the various bases screened (Cs₂CO₃, K₃PO₄, NaOtBu, NaOH), Cs₂CO₃, albeit in low yield, gave better conversions. The observed decomposition of aryl triflate could be plausibly due to the unstable nature of intermediate Pd(II) complex that is expected to arise from initial oxidative addition of the triflate to Pd(0).³⁰ It is presumed that the base promoted nucleophilic attack at the sulfur atom is too high in triflates which apparently caused the undesired phenol formation and resulted in lower yields of desired product.³¹

In order to circumvent the problems caused by instability and saponification of triflate, we tried the reaction optimization with corresponding nonaflates. The 4-methyl-7-nonafluorobutylsulfonyloxy coumarin intermediate 3b was synthesized by the reaction of hydroxy intermediate 2 with nonafluorobutane sulfonic anhydride in pyridine at −10 °C for 1 h (Scheme 3). Nonaflates are reported to be more stable than corresponding triflates and hence can be stored for longer periods.^31a,32 They are slightly more reactive than corresponding triflates and are considered as a practical alternative to triflates.³³ The strong electron-withdrawing property of the perfluorinated alkyl chain in combination with the SO₂ moiety dramatically enhances the reactivity of nonaflates and hence is an ideal tool for creating a good leaving group.³⁴ Moreover, it has been reported that the nonaflates are less prone to O–S bond cleavage than corresponding triflates which subsequently causes the hydrolysis.³⁵ Owing to these observations, we treated the nonaflate 3b with aniline in different Pd₂(dba)₃/ligand combinations and Cs₂CO₃ as base in various solvents and the reaction was carried out in a microwave oven at 120 °C at 110 W for 30 min (Table 2).

Scheme 3 Synthesis of 4-methyl-7-nonafluorobutylsulfonyloxycoumarin intermediate and its Buchwald coupling with various amines.

Table 2 Effect of various ligands and bases in the coupling of nonaflate 3b with aniline^a

Entry	Catalyst	Ligand	Base	Solvent	Yield 5 (%)	Yield 2 (%)	Yield 4a (%)
a Reaction conditions: 4-methyl-7-nonafluorobutylsulfonyloxy coumarin 3b (1 mmol), aniline (1.3 mmol), Pd2(dba)3 (5 mol%), ligand (0.1 mmol), Cs2CO3 (2 mmol), solvent, microwave irradiated at 110 W at 120 °C for 30 min.b 1 mmol of TBAF·3H2O used as an additive.c Reaction carried out at 100 °C.d 2 mmol of TBAF·3H2O used.
1	Pd2(dba)3	BINAP	Cs2CO3	Dioxane	28	18	48
2	Pd2(dba)3	dppf	Cs2CO3	Dioxane	15	76	Traces
3	Pd2(dba)3	DPEphos	Cs2CO3	Dioxane	24	20	35
4	Pd2(dba)3	Xantphos	Cs2CO3	Dioxane	Traces	35	60
5	Pd2(dba)3	Xantphos	Cs2CO3	NMP	15	35	42
6	Pd2(dba)3	Xantphos	Cs2CO3	DMF	Traces	44	30
7	Pd2(dba)3	Xantphos	Cs2CO3	Dioxane	15	Traces	75^b
8	Pd2(dba)3	Xantphos	Cs2CO3	Dioxane	Traces	Traces	96^c^,^d

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We observed that the reaction conditions and nature of catalyst have a determining influence on this coupling reaction. Pd₂(dba)₃/xantphos catalytic system were found to be essential for better conversions and polar solvents like DMF, NMP were found to be ineffective (Table 2, entries 1–6). To our delight, we could see the product in considerably better yield when Cs₂CO₃ was used as a base along with the catalytic system in dioxane but still the hydrolyzed compound 2 remained as a competitive side-product (Table 2, entry 4). Fortunately, we obtained the product in an acceptable yield when TBAF·3H₂O (1 equiv.) was used as an additive along with Cs₂CO₃ in dioxane which significantly reduced the hydrolysis of the nonaflate (Table 2, entry 7). Finally, addition of one more equivalent of TBAF·3H₂O and reducing the reaction temperature to 100 °C procured the required diaryl amine 4a in 96% yield with 92% of isolated yield (Table 2, entry 8).

In the present study, the ligands having bite angle less than that of xantphos (108°) proved to be inefficient (Table 2, entries 1–3). The superiority of xantphos to other ligands might be attributed to the wide bite angle characteristic (Fig. 1) of the ligand which increased the steric bulk and enhanced the reductive elimination step by forming a cis complex in the catalytic cycle.³⁶ Increase in the solvation of TBAF·3H₂O in the reaction medium when its stoichiometric ratio was increased could be the prominent feature for the complete suppression of hydrolysis of the nonaflate.^31b,c In the current work, hydrated TBAF considerably reduced the saponification of the nonaflates when compared to triflates which is in agreement with earlier observations.^31b,c

Fig. 1 Structure of various ligands screened and their bite angles.

Our subsequent efforts were to study the effect of the base in the reaction system. Keeping this in mind, we explored the reaction by varying the bases and by keeping all the other parameters constant (Table 3). Among the various bases screened, Cs₂CO₃ gave excellent conversions which could be attributed to the unique properties of cesium cation like high ionic radius, low charge density and high polarizibility.^25c The usage of strong bases like NaOtBu and NaOH caused the substantial cleavage of the lactone ring (Table 3, entries 4, 5).

Table 3 Effect of various bases in the Buchwald coupling reaction^a

Entry	Base	Yield^b (%)
a Reaction conditions: 4-methyl-7-nonafluorobutylsulfonyloxy coumarin 3b (1 mmol), aniline (1.3 mmol), Pd2(dba)3 (5 mol%), xantphos (0.1 mmol), base (2 mmol), TBAF·3H2O (2 mmol), dioxane, microwave irradiated at 110 W at 100 °C for 30 min.b Isolated yield.
1	K2CO3	18
2	NaHCO3	25
3	Na2CO3	20
4	NaOH	Traces
5	NaOtBu	Traces
6	K3PO4	48
7	CsOAc	78
8	Cs2CO3	92

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With the optimized condition in hands, we shifted our attention to evaluate the generality of the developed protocol. A series of primary and secondary amines with various electronic and steric characteristics were effectively coupled with the nonaflate and our results are summarized in Table 4. Electron withdrawing amines gave slightly lesser yields even after 1 h whereas electron donating amines gave exceptional yields to produce the corresponding diaryl amines (Table 4, entries 4–8). The presence of electron-withdrawing groups might have reduced the nucleophilicity of the nitrogen in amines which considerably decreased the formation of coupled product. Sterically hindered amines gave slightly lesser yields even after continuing the reaction for 1 h. (Table 4, entries 12–14). Aliphatic primary amines didn't furnish any coupled product with the nonaflate in the optimized conditions and was proved to be inert.

Table 4 Buchwald coupling of the nonaflate intermediate with various amines^a

Entry	Nonaflate (3)	Amine (2)	Product	Yield^b (%)
a Reaction conditions: 4-methyl-7-nonafluorobutylsulfonyloxy coumarin 3b (1 mmol), amine (1.3 mmol), Pd2(dba)3 (5 mol%), xantphos (0.1 mmol), Cs2CO3 (2 mmol), TBAF·3H2O (2 mmol), dioxane, microwave irradiated at 110 W at 100 °C for 30 min.b Isolated yield.
1	3b			92
2	3b			94
3	3b			91
4	3b			82
5	3b			79
6	3b			76
7	3b			87
8	3b			90
9	3b			92
10	3b			88
11	3b			82
12	3b			79
13	3b			80
14	3b			82

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Our next attention was to elaborate the substrate scope by extending the reaction for the synthesis of cyclic amides. Keeping this in mind, we applied the optimized condition to a variety of heteroannulated pyridones (Scheme 4) and our results are depicted in Table 5.

Scheme 4 Buchwald coupling of 4-methyl-7-nonafluorobutylsulfonyloxycoumarin intermediate with various pyridones.

Table 5 Buchwald coupling of the nonaflate intermediate with various pyridones^a

Entry	Nonaflate (3)	Pyridones (2)	Product	Yield^b (%)
a Reaction conditions: 4-methyl-7-nonafluorobutylsulfonyloxy coumarin 3b (1 mmol), pyridone (1.3 mmol), Pd2(dba)3 (5 mol%), xantphos (0.1 mmol), TBAF·3H2O (2 mmol), Cs2CO3 (2 mmol), dioxane, microwave irradiated at 110 W at 100 °C for 30 min.b Isolated yield.
1	3b			91
2	3b			90
3	3b			87
4	3b			82
5	3b			93
6	3b			77

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Gratifyingly, under these conditions, all the pyridones coupled well enough to procure the cyclic amides at C-7 position of coumarins. Sterically hindered pyridones rendered the lactams in comparatively smaller yields than that of other pyridones as expected (Table 5, entries 4 & 6).

A plausible mechanism³⁷ of the coupling reaction of pyridone with nonaflate has been proposed (Scheme 5). The first step in the catalytic cycle is the formation of a true catalytic species (a coordinatively unsaturated electron rich palladium complex) which undergoes oxidative addition with coumarin nonflate to yield oxidative adduct complex 3. The subsequent step involves the complexation of pyridone with this palladium complex which increases the acidity of pyridone proton resulting in its deprotonation by Cs₂CO₃ to yield the complex 6. Finally, it undergoes reductive elimination to form the coupled diaryl amines and completes the catalytic cycle.

Scheme 5 Proposed mechanism of the coupling reaction.

Although the effect of TBAF in these reactions is quite unclear, it is speculated that TBAF possess some critical beneficial roles such as the stabilization of low-coordinated Pd(II) species 3 and 6 that are expected to form during the coupling process and acts as a phase-transfer catalyst in order to enhance the desired product formation.³⁸

Conclusion

We have achieved an efficient, modified and concise protocol for C-7 amination and amidation of 4-methyl-7-nonafluorobutylsulfonyloxy coumarins by the in situ generation of a Pd/xantphos catalyst system in presence of Cs₂CO₃ and TBAF·3H₂O under microwave irradiation. The nonaflates proved to be superior than corresponding triflates in terms of reactivity and stability to hydrolysis. The use of Cs₂CO₃ as a mild base which broadened the substrate scope and utilization of hydrated TBAF as an additive which significantly suppressed the nonaflate hydrolysis were proved to be the key for success of the reaction. This method provided a facile and reliable access to a variety of pharmacologically relevant coumarins and could be extended for the coupling of other densely functionalized heterocycles. The biological screening of the newly synthesized molecules will be done in due course and will be communicated shortly as a continuation of the current work.

Experimental

General information

All solvents and reagents were obtained from commercial suppliers and used without any further purification unless otherwise noted. All the reactions were carried out under the inert atmosphere of argon. Analytical TLC was performed on pre-coated aluminum sheets of silica (60 F254 nm) and visualized by short-wave UV light at λ 254. Melting points were determined on an EZ-melt automated melting point apparatus. ¹H NMR spectra were recorded at 400 MHz and 300 MHz using an internal deuterium lock. Chemical shifts were measured in δ (ppm). Data is presented as follows: chemical shift, multiplicity, coupling constant (J) in Hz, and integration. The following abbreviations are used for the splitting patterns: s for singlet, d for doublet, t for triplet, m for multiplet and br for broad. ¹³C NMR spectra were recorded at 100 MHz using an internal deuterium lock. ¹⁹F NMR spectra were recorded at 376.5 MHz in CFCl₃ using an internal deuterium lock. LC-MS analyses were performed using ESI/APCI, with an ATLANTIS C18 (50 × 4.6 mm to 5 μm) column and a flow rate of 1.2 mL min⁻¹.

Procedure for the synthesis of 4-methyl-7-nonafluorobutylsulfonyloxy coumarin 3b. To a solution of 4-methyl-7-hydroxy coumarin (2, 1 equiv.) in DCM, was added pyridine (2 equiv.) at −10 °C, followed by the addition of nonafluorobutane sulfonic anhydride (1.2 equiv.) drop wise. Reaction mixture was warmed to 0 °C and stirred for 1 h. Reaction mass was then diluted with DCM, bi-phased with water and extracted, organic layer was washed with NaHCO₃, brine solution and dried over Na₂SO₄ and distilled under reduced pressure. Crude compound was purified by column chromatography packed with 60–120 silica gel and eluted with 15 to 20% ethyl acetate in petroleum ether to obtain the titled compound 3b as colorless solid in 87% yield. MP: 86–88 °C; ¹H NMR (300 MHz, CDCl₃): δ 2.47, d, J = 1.08 Hz, 3H, CH₃; δ 6.37, 1H, ArH; δ 7.23–7.29, m, 2H, ArH; δ 7.69, d, J = 8.67 Hz, 1H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 23.2, CH₃; δ 115.3, δ 116.5, δ 116.9, m, CF₂; δ 118.9, m, CF₂; δ 126.7, m, CF₃; δ 132.2, δ 154.1–154.7 (2 peaks), δ 156.3, m, SO₂CF₂; δ 163.4, CO; ¹⁹F NMR (376.5 MHz, CDCl₃): δ −125.32 to −125.22, m; δ −120.77 to −120.68, m; δ −112.97 to −112.87, m; δ −80.59 to −80.52, m; LC-MS: calculated 394.2, observed 395.2.

General procedure for the synthesis of substituted diaryl amines 4a–t. To a solution of 4-methyl-7-nonafluorobutylsulfonyloxy coumarin (3b, 1 equiv.) in dioxane, were added a premixed solution of Pd₂(dba)₃ (5 mol%) and xantphos (0.1 equiv.) in dioxane. The solution was purged with argon and stirred at room temperature for 10 min, at which time the amine/pyridone (1.3 equiv.), Cs₂CO₃ (2 equiv.) and TBAF·3H₂O (2 equiv.) were added. The reaction solution was purged again with argon and then placed in the microwave and heated for 20–30 min. at 100 °C at 110 W. When TLC and LC-MS showed full consumption of starting materials, the reaction mixture was filtered, diluted with ethyl acetate, separated the ethyl acetate layer, given water wash, brine wash, dried over anhydrous sodium sulfate and distilled in vacuo to get the crude material. The crude product was purified by column chromatography and eluted in varying polarities to obtain the substituted diaryl amines 4a–t.

4-Methyl-7-(phenylamino)-2H-chromen-2-one (4a). MP: 78–80 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.49, d, J = 1.28 Hz, 3H, CH₃; δ 3.94, br, 1H, NH; δ 6.49, s, 1H, ArH; δ 7.59–7.61, dd, J₁ = 1.72 Hz J₂ = 8.12 Hz, 2H, ArH; δ 7.64–7.67, dd, J₁ = 1.00 Hz J₂ = 8.48 Hz, 2H, ArH; δ 7.71–7.73, d, J = 7.8 Hz, 1H, ArH; δ 7.82–7.86, m, 1H, ArH; δ 7.92–8.05, m, 2H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 24.7, CH₃; δ 107.7, δ 110.5, δ 113.5, δ 117.9, δ 124.7, δ 125.6, δ 131.4, δ 132.7, δ 140.8, δ 141.7, δ 144.4, δ 148.3, δ 158.1, CO; LC-MS: calculated 251.1, observed 252.1; anal. calcd for C₁₆H₁₃NO₂: C, 76.48; H, 5.21; N, 5.57%, found: C, 76.39; H, 5.26; N, 5.53%.

4-Methyl-7-(pyridine-4-ylamino)-2H-chromen-2-one (4b). MP: 79–81 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.40, d, J = 2.08 Hz, 3H, CH₃; δ 3.94, br, 1H, NH; δ 7.15–7.18, dd, J₁ = 2.96 Hz J₂ = 7.92 Hz, 1H, ArH; δ 7.25–7.28, m, 2H, ArH; δ 7.35–7.37, d, J = 8.24 Hz, 1H, ArH; δ 7.83–7.90, m, 2H, ArH; δ 8.26–8.28, dd, J₁ = 1.4 Hz J₂ = 8.16 Hz, 1H, ArH; δ 8.40–8.42, d, J = 8.92 Hz, 1H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 24.7, CH₃; δ 110.2, δ 117.9, δ 118.8, δ 118.7, δ 125.8, δ 129.9, δ 132.9, δ 136.2, δ 141.8, δ 146.6, δ 155.4, δ 157.6, CO; LC-MS: calculated 252.2, observed 253.2; anal. calcd for C₁₅H₁₂N₂O₂: C, 71.42; H, 4.79; N, 11.10%, found: C, 71.36; H, 4.87; N, 11.08%.

4-Methyl-7-(pyrimidin-2-ylamino)-2H-chromen-2-one (4c). MP: 81–84 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.36, d, J = 1.16 Hz, 3H, CH₃; δ 3.83, br, 1H, NH; δ 6.38, s, 1H, ArH; δ 6.64–6.66, dd, J₁ = 1.76 Hz J₂ = 7.84 Hz, 1H, ArH; δ 6.83–6.84, d, J = 3.36 Hz, 1H, Ar H; δ 7.27–7.29, m, 2H, ArH; δ 7.87–7.89, dd, J₁ = 1.44 Hz J₂ = 8.48 Hz, 2H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 24.7, CH₃; δ 110.7, δ 113.8, δ 118.0, δ 121.5, δ 125.8, δ 132.7, δ 140.1, δ 141.9, δ 146.5, δ 154.9, δ 159.1, CO; δ 160.6; LC-MS: calculated 253.1, observed 254.1; anal. calcd for C₁₄H₁₁N₃O₂: C, 66.40; H, 4.38; N, 16.59%, found: C, 66.48; H, 4.38; N, 16.54%.

7-(4-Fluorophenylamino)-4-methyl-2H-chromen-2-one (4d). MP: 83–85 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.47, d, J = 1.56 Hz, 3H, CH₃; δ 3.96, br, 1H, NH; δ 6.33, s, 1H, ArH; δ 7.27–7.29, m, 2H, ArH; δ 7.44–7.47, m, 2H, ArH; δ 7.76–7.80, m, 2H, ArH; δ 8.04, d, J = 8.20 Hz, 1H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 24.7, CH₃; δ 110.6, δ 113.8, δ 118.0, δ 121.5, δ 125.8, δ 132.7, δ 140.2, δ 141.9, δ 146.5, δ 148.5, δ 154.9, m, CF; δ 160.1, CO; LC-MS: calculated 269.2, observed 270.2; anal. calcd for C₁₆H₁₂FNO₂: C, 71.37; H, 4.49; N, 5.20%, found: C, 71.49; H, 4.41; N, 5.17%.

Methyl 4-(4-methyl-2-oxo-2H-chromen-7-ylamino)benzoate (4e). MP: 96–98 °C; ¹H NMR (300 MHz, CDCl₃): δ 2.49, d, J = 1.17 Hz, 3H, CH₃; δ 3.88, br, 1H, NH; δ 3.96, s, 3H, OCH₃; δ 6.34, s, 1H, ArH; δ 7.47–7.51, m, 3H, ArH; δ 7.64–7.72, m, 3H, ArH; δ 8.14–8.17, dd, J₁ = 1.68 Hz J₂ = 6.51 Hz, 1H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 23.2, CH₃; δ 54.3, CH₃(ester); δ 111.4, δ 112.6, δ 114.5, δ 117.8, δ 121.1, δ 121.8, δ 129.8, δ 133.1, δ 142.2, δ 146.4, δ 154.2, δ 156.1, δ 159.8, CO; 165.4, CO(ester); LC-MS: calculated 309.1, observed 310.1; anal. calcd for C₁₈H₁₅NO₄: C, 69.89; H, 4.89; N, 4.53%, found: C, 69.94; H, 4.86; N, 4.51%.

4-(4-Methyl-2-oxo-2H-chromen-7-ylamino)benzonotrile (4f). MP: 85–87 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.49, d, J = 1.52 Hz, 3H, CH₃; δ 3.95, br, 1H, NH; δ 6.49, s, 1H, ArH; δ 7.59–7.64, m, 2H, ArH; δ 7.71, d, J = 7.8 Hz, 1H, ArH; δ 7.82–7.86, dd, J₁ = 1.24 Hz J₂ = 7.72 Hz, 2H, ArH; δ 8.02, d, J = 7.76 Hz, 2H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 24.7, CH₃; δ 108.5, δ 109.8, δ 117.9, δ 118.8, δ 125.9, δ 129.8, CN; δ 132.9, δ 136.2, δ 141.6, δ 141.8, δ 146.3, δ 146.6, δ 155.4, δ 156.6, δ 159.5, CO; LC-MS: calculated 276.2, observed 277.2; anal. calcd for C₁₇H₁₂N₂O₂: C, 73.90; H, 4.38; N, 10.14%, found: C, 73.99; H, 4.34; N, 10.11%.

7-(p-Tolylamino)-4-methyl-2H-chromen-2-one (4g). MP: 84–86 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.49, d, J = 1.64 Hz, 3H, CH₃; δ 3.14, s, 3H, CH₃; δ 3.76, br, 1H, NH; δ 6.49, s, 1H, ArH; δ 6.84–6.89, m, 2H, ArH; δ 6.96–6.99, dd, J₁ = 1.24 Hz J₂ = 7.76 Hz, 2H, ArH; δ 7.46–7.49, dd, J₁ = 1.36 Hz J₂ = 7.92 Hz, 2H, ArH; δ 7.78, d, J = 7.76 Hz, 1H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 23.4, CH₃; δ 26.2, CH₃; δ 111.1, δ 112.2, δ 114.3, δ 117.8, δ 121.8, δ 129.7, δ 131.1, δ 133.2, δ 139.6, δ 142.4, δ 154.3, δ 155.8, δ 159.5, CO; LC-MS: calculated 265.1, observed 266.1; anal. calcd for C₁₇H₁₅NO₂: C, 76.96; H, 5.70; N, 5.28%, found: C, 77.02; H, 5.68; N, 5.22%.

7-(4-Methoxyphenylamino)-4-methyl-2H-chromen-2-one (4h). MP: 88–90 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.49, d, J = 1.56 Hz, 3H, CH₃; δ 3.88, br, 1H, NH; δ 3.93, s, 3H, OCH₃; δ 6.34, s, 1H, ArH; δ 7.54–7.59, m, 3H, ArH; δ 7.64–7.72, m, 3H, ArH; δ 8.14–8.17, dd, J₁ = 2.24 Hz J₂ = 8.68 Hz, 1H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 21.1, CH₃; δ 55.8, OCH₃; δ 110.2, δ 117.9, δ 118.8, δ 125.9, δ 129.8, δ 132.9, δ 136.8, δ 141.6, δ 141.8, δ 146.0, δ 146.6, δ 155.5, δ 156.3, δ 159.5, CO; LC-MS: calculated 281.2, observed 282.2; anal. calcd for C₁₇H₁₅NO₃: C, 72.58; H, 5.37; N, 4.98%, found: C, 72.71; H, 5.28; N, 4.94%.

4-Methyl-7-(thiophen-3-ylamino)-2H-chromen-2-one (4i). MP: 74–76 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.47, d, J = 1.12 Hz, 3H, CH₃; δ 3.82, br, 1H, NH; δ 6.27, s, 1H, ArH; δ 6.52–6.55, dd, J₁ = 1.72 Hz J₂ = 3.32 Hz, 1H, ArH; δ 6.81, d, J = 3.32 Hz, 2H, ArH; δ 7.23–7.26, m, 1H, ArH; δ 7.54–7.59, m, 2H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 23.2, CH₃; δ 105.6, δ 108.7, δ 113.6, δ 114.9, δ 115.4, δ 123.6, δ 127.8, δ 129.5, δ 129.9, δ 144.7, δ 153.6, δ 155.5, δ 159.4, CO; LC-MS: calculated 257.1, observed 258.1; anal. calcd for C₁₄H₁₁NO₂S: C, 65.35; H, 4.31; N, 5.44%, found: C, 65.38; H, 4.31; N, 5.41%.

7-(Furan-3-ylamino)-4-methyl-2H-chromen-2-one (4j). MP: 77–79 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.47, d, J = 1.16 Hz, 3H, CH₃; δ 3.84, br, 1H, NH; δ 6.29, s, 1H, ArH; δ 6.54-6.56, dd, J₁ = 1.76 Hz J₂ = 3.36 Hz, 1H, ArH; δ 6.83, d, J = 3.36 Hz, 2H, ArH; δ 7.27–7.29, m, 1H, ArH; δ 7.57–7.61, m, 2H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 24.8, CH₃; δ 110.7, δ 116.5, δ 118.4, δ 126.9, δ 127.8, δ 127.6, δ 129.1, δ 131.9, δ 135.4, δ 143.4, δ 148.3, δ 148.9, δ 158.1, CO; LC-MS: calculated 241.2, observed 242.2; anal. calcd for C₁₄H₁₁NO₃: C, 69.70; H, 4.60; N, 5.81%, found: C, 69.84; H, 4.52; N, 5.77%.

7-(N-(4-Fluorophenyl)-N-methylamino)-4-methyl-2H-chromen-2-one (4k). MP: 87–89 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.49, d, J = 1.68 Hz, 3H, CH₃; δ 3.55, s, 3H, NCH₃; δ 6.33, s, 1H, ArH; δ 7.24–7.29, m, 2H, ArH; δ 6.71–6.73, dd, J₁ = 1.48 Hz J₂ = 8.56 Hz, 2H, ArH; δ 7.05–7.08, dd, J₁ = 1.76 Hz J₂ = 7.96 Hz, 2H, ArH; δ 7.26, d, J = 8.72 Hz, 1H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 23.4, CH₃; δ 43.9, NCH₃; δ 111.7, δ 112.8, δ 114.8, δ 118.1, δ 118.7, δ 123.1, δ 130.1, δ 147.2, δ 150.9, δ 153.6, δ 154.9, m, CF; δ 155.8, δ 159.8, CO; LC-MS: calculated 283.1, observed 284.1; anal. calcd for C₁₇H₁₄FNO₂: C, 72.07; H, 4.98; N, 4.94%, found: C, 72.12; H, 4.96; N, 4.92%.

tert-Butyl 4-(4-methyl-2-oxo-2H-chromen-7-yl)piperazine-1-carboxylate (4l). MP: 112–114 °C; ¹H NMR (400 MHz, CDCl₃): δ 1.53, s, 9H, t-Bu; δ 2.49, d, J = 1.08 Hz, 3H, CH₃; δ 3.61–3.69, m, 4H, CH₂; δ 3.69–3.73, m, 4H, CH₂; δ 6.79, s, 1H, ArH; δ 7.22–7.28, m, 2H, ArH; δ 7.46, d, J = 8.84 Hz, 1H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 23.2, CH₃; δ 30.7, Boc CH₃; δ 50.8, CH₂; δ 51.7, CH₂; δ 81.9, Boc C; δ 106.9, δ 112.8, δ 113.3, δ 114.7, δ 129.9, δ 151.5, δ 153.4, δ 154.9, δ 156.4, Boc CO; δ 159.5, CO; LC-MS: calculated 334.2, observed 245.2; anal. calcd for C₁₉H₂₄N₂O₄: C, 66.26; H, 7.02; N, 8.13%, found: C, 66.38; H, 7.12; N, 8.17%.

7-(4-Hydroxy-4-phenylpiperidin-1-yl)-4-methyl-2H-chromen-2-one (4m). MP: 106–108 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.49, d, J = 1.64 Hz, 3H, CH₃; δ 2.51–2.54, m, 4H, CH₂; δ 2.62, s, 1H, OH; δ 3.363.41, m, 4H, CH₂; 6.39, s, 1H, ArH; δ 6.85–6.89, m, 2H, ArH; δ 7.57, d, J = 8.84 Hz, 1H, ArH; δ 7.72–7.74, m, 5H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 24.7, CH₃; δ 40.3, δ 45.8, δ 76.6, δ 106.9, δ 112.8, δ 113.3, δ 114.7, δ 128.4, δ 129.9, δ 130.5, δ 131.2, δ 142.3, δ 151.4, δ 153.3, δ 155.1, δ 159.6, CO; LC-MS: calculated 335.2, observed 336.2; anal. calcd for C₂₁H₂₁NO₃: C, 75.20; H, 6.31; N, 4.18%, found: C, 75.34; H, 6.27; N, 4.12%.

4-Methyl-7-(4-(2-methylpyridin-4-yl)piperazin-1-yl)-2H-chromen-2-one (4n). MP: 112–114 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.18, d, J = 2.4 Hz, 3H, CH₃; δ 2.48, s, 3H, CH₃; δ 3.40–3.52, m, 8H, CH₂; δ 6.91, s, 1H, ArH; δ 7.00–7.02, d, J = 7.6 Hz, 1H, ArH; δ 7.10–7.14, dd, J₁ = 2.8 Hz J₂ = 7.6 Hz, 1H, ArH; δ 8.20–8.21, d, J = 6.8 Hz, 1H, ArH; δ 7.27–7.34, m, 2H, ArH; δ 8.46, d, J = 7.2 Hz, 1H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 23.4, CH₃; δ 27.3, CH₃; δ 31.7, δ 44.6, δ 51.7, δ 106.9, δ 113.5, δ 113.7, δ 115.4, δ 122.6, δ 124.7, δ 129.8, δ 151.2, δ 151.4, δ 153.2, δ 154.9, δ 159.5, δ 160.4, δ 163.3, CO; LC-MS: calculated 335.1, observed 336.1; anal. calcd for C₂₀H₂₁N₃O₂: C, 71.62; H, 6.31; N, 12.53%, found: C, 71.68; H, 6.27; N, 12.51%.

4-(Trifluoromethyl)-1-(4-methyl-2-oxo-2H-chromen-7-yl)pyridin-2(1H)-one (4o). MP: 92–94 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.49, d, J = 1.76 Hz, 3H, CH₃; δ 6.21, d, J = 7.80 Hz, 1H, ArH; δ 6.33, s, 1H, ArH; δ 7.34, s, 1H, ArH; δ 7.46–7.49, m, 4H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 24.7, CH₃; δ 108.5, δ 110.8, δ 113.8, δ 117.6, δ 121.5, δ 125.8, δ 132.7, δ 140.2, δ 141.9, m, CF₃; δ 146.5, δ 148.5, δ 154.9, δ 160.7, CO (pyridone); δ 163.1, CO; LC-MS: calculated 321.2, observed 322.2; anal. calcd for C₁₆H₁₀F₃NO₃: C, 59.82; H, 3.14; N, 4.36%, found: C, 59.96; H, 3.04; N, 4.34%.

1-(4-Methyl-2-oxo-2H-chromen-7-yl)pyridin-2(1H)-one (4p). MP: 79–82 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.41, d, J = 2.08 Hz, 3H, CH₃; δ 7.15–7.18, dd, J₁ = 1.76 Hz J₂ = 7.92 Hz, 1H, ArH; δ 7.27, s, 1H, ArH; δ 7.35, d, J = 8.24 Hz, 2H, ArH; δ 7.83–7.90, m, 2H, ArH; δ 8.26–8.28, m, 2H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 24.7, CH₃; δ 110.0, δ 116.6, δ 117.9, δ 125.6, δ 131.4, δ 132.7, δ 140.5, δ 140.8, δ 141.7, δ 144.4, δ 146.6, δ 149.9, δ 158.0, CO (pyridone); δ 160.6, CO; LC-MS: calculated 253.2, observed 254.2; anal. calcd for C₁₅H₁₁NO₃: C, 71.14; H, 4.38; N, 5.53%, found: C, 71.24; H, 4.36; N, 5.47%.

3-Methyl-1-(4-methyl-2-oxo-2H-chromen-7-yl)pyridin-2(1H)-one (4q). MP: 82–84 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.43, d, J = 2.16 Hz, 3H, CH₃; δ 2.47, s, 3H, CH₃; δ 6.43, s, 1H, ArH; δ 7.15, d, J = 8.04 Hz, 1H, ArH; δ 7.25–7.29, m, 1H, ArH; δ 7.68–7.71, dd, J₁ = 1.96 Hz J₂ = 8.04 Hz, 1H, ArH; δ 7.83–7.86, dd, J₁ = 2.12 Hz J₂ = 8.28 Hz, 1H, ArH; δ 8.19–8.25, m, 2H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 18.2, CH₃; δ 24.7, CH₃; δ 107.7, δ 109.2, δ 123.6, δ 127.3, δ 135.7, δ 137.1, δ 143.8, δ 148.3, δ 148.9, δ 149.7, δ 155.1, δ 160.8, CO (pyridone); δ 162.9, CO; LC-MS: calculated 267.3, observed 268.3; anal. calcd for C₁₆H₁₃NO₃: C, 71.90; H, 4.90; N, 5.24%, found: C, 71.98; H, 4.86; N, 5.22%.

3-Methoxy-7-(4-methyl-2-oxo-2H-chromen-7-yl)-1,7-naphthyridin-8(7H)-one (4r). MP: 120–122 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.49, d, J = 2.24 Hz, 3H, CH₃; δ 4.11, s, 3H, OCH₃; δ 7.14–7.17, dd, J₁ = 2.96 Hz J₂ = 7.92 Hz, 2H, ArH; δ 7.27, s, 1H, ArH; δ 7.36, d, J = 7.24 Hz, 1H, ArH; δ 7.52, d, J = 7.64 Hz, 1H, ArH; δ 7.80–7.82, dd, J₁ = 1.12 Hz J₂ = 7.88 Hz, 2H, ArH; δ 8.20–8.28, d, J = 6.84 Hz, 1H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 24.7, CH₃; δ 30.5, OCH₃; δ 110.2, δ 117.9, δ 118.8, δ 125.9, δ 129.8, δ 132.9, δ 136.2, δ 141.6, δ 141.8, δ 146.4, δ 146.6, δ 154.7, δ 155.4, δ 156.6, CO (pyridone); δ 159.5, CO; LC-MS: calculated 334.2, observed 335.2; anal. calcd for C₁₉H₁₄N₂O₄: C, 68.26; H, 4.22; N, 8.38%, found: C, 68.38; H, 4.18; N, 8.32%.

5-Methyl-1-(4-methyl-2-oxo-2H-chromen-7-yl)pyridin-2(1H)-one (4s). MP: 82–84 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.40, d, J = 2.24 Hz, 3H, CH₃; δ 2.41, s, 3H, CH₃; δ 6.41, s, 1H, ArH; δ 7.13–7.16, dd, J₁ = 1.36 Hz J₂ = 7.92 Hz, 1H, ArH; δ 7.22–7.27, m, 1H, ArH; δ 7.66–7.69, dd, J₁ = 2.04 Hz J₂ = 8.12 Hz, 1H, ArH; δ 7.81–7.83, dd, J₁ = 1.4 Hz J₂ = 7.88 Hz, 1H, ArH; δ 8.20–8.25, m, 2H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 18.5, CH₃; δ 24.7, CH₃; δ 110.2, δ 117.9, δ 118.8, δ 125.9, δ 129.8, δ 132.9, δ 136.2, δ 141.6, δ 141.8, δ 146.3, δ 146.6, δ 155.4, δ 156.6, CO (pyridone); δ 159.5, CO; LC-MS: calculated 267.3, observed 268.3; anal. calcd for C₁₆H₁₃NO₃: C, 71.90; H, 4.90; N, 5.24%, found: C, 71.95; H, 4.90; N, 5.20%.

3-Chloro-7-(4-methyl-2-oxo-2H-chromen-7-yl)-1,7-naphthyridin-8(7H)-one (4t). MP: 116–118 °C; ¹H NMR (400 MHz, CDCl₃): δ 2.49, d, J = 2.36 Hz, 3H, CH₃; δ 6.34, s, 1H, ArH; δ 6.47–6.53, m, 2H, ArH; δ 7.37–7.41, m, 2H, ArH; δ 7.54–7.56, dd, J₁ = 2.24 Hz J₂ = 8.04 Hz, 1H, ArH; δ 8.72, s, 1H, ArH; δ 9.21, s, 1H, ArH; ¹³C NMR (100 MHz, CDCl₃): δ 23.4, CH₃; δ 109.9, δ 114.3, δ 114.5, δ 119.0, δ 120.5, δ 129.3, δ 133.2, δ 134.7, δ 136.2, δ 139.1, δ 141.3, δ 149.7, δ 152.2, δ 152.7, δ 155.1, δ 162.8, CO (pyridone); δ 163.6, CO; LC-MS: calculated 338.2, observed 339.2 & 341.2; anal. calcd for C₁₈H₁₁ClN₂O₃: C, 63.82; H, 3.27; N, 8.27%, found: C, 63.94; H, 3.23; N, 8.21%.

Acknowledgements

The authors are thankful to the Chairman, Department of Industrial Chemistry, Kuvempu University for providing all the facilities to carry out the research work. The authors are also thankful to SAIF, Indian Institute of Technology, Madras for rendering the analytical data and SIF, Indian Institute of Science, Bangalore for providing the spectra.

References

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra01720j

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