Synthesis of amidoalkyl chromen-2-ones by one pot three component reaction under solvent free conditions

Abstract

A mild and efficient method for the functionalization of chromen-2-ones with amidoalkyl derivatives have been developed starting from 4-trifluoromethyl substituted chromen-2-ones, aromatic aldehydes and acetamide promoted by stannous chloride dihydrate in a one pot three component reaction under solvent free condition. Simple reaction conditions, high yields and environmentally benign procedure are the advantage of this protocol.

---

1. Introduction

Chromen-2-ones are ubiquitous structural motifs that represent a very important class of naturally occurring compounds.¹ They are reported to exhibit wide range of valuable biological activity properties including anti-oxidant, antibacterial, antifungal and anti-inflammatory activities.² Additionally, chromen-2-ones or coumarins also found to have substantial application in photo sensitizers, fluorescent, laser dyes³ and represent very useful synthetic building blocks in organic and medicinal chemistry (Fig. 1). Further, strategically positioned fluorine in organic molecule can lead to distinctive modifications in their biological properties owing to the strong electron withdrawing nature and large hydrophobic domain. These factors modify the bio-availability and stability of the molecule. Because of these reasons, they have become the popular building blocks in the design and synthesis of various agrochemicals,⁴ selective anti-bacterial agents, enzyme inhibitors, and enzyme receptor antagonists or agonists.⁵ On the other hand multicomponent reactions (MCRs) constitute a significant group of methods in organic synthesis⁶ and became very popular tools to form heterocyclic structures including complex structures when combined with subsequent transformations. They incorporate portions of three or more reactants into new products in a one pot reaction through powerful transformations.

Fig. 1 Some of the potent molecules with chromen-2-one skeleton.

Furthermore, solvent free multicomponent reactions gained popularity and it is often claimed that the best solvent in organic synthesis is no solvent.⁷ These protocols effectively answer the harmful effects of organic solvents to the environment and also provide a cleaner, safer, and economical,⁸ pollution free organic syntheses at source.

In the recent past a number of reports have appeared in the literature on synthesis of fused coumarins such as pyranocoumarins,⁹ pyranochalcones,¹⁰ and 7-hydroxy substituted fluorinated coumarins as fluorogenic analogues.¹¹

However, to the best of our knowledge, there are no reports available on the functionalization of chromen-2-ones with amidoalkyl derivatives. Whereas numerous reports¹² are available on the functionalization of naphthols with amidoalkyl derivatives which reported to exhibit depressor and bradycardia effects in humans¹³ and also important precursors of heterocycles.¹⁴ Based on the importance of chromen-2-one compounds in various ways and our continuous efforts to develop the new methodologies to synthesize the novel chromene compounds and study the biological activity aspects¹⁵ herein, we report the synthesis of so far unreported amidoalkyl trifluoromethyl substituted chromen-2-ones (6) by one pot three component reaction under solvent free condition.

2. Results and discussions

Initially, 7-hydroxy-4-trifluoromethyl chromen-2-one derivatives (3a–c) were prepared independently starting from the reaction of substituted phenols (1) and ethyltrifluoroacetoacetate (2) by Pechmann condensation promoted by dry ZnCl₂.¹⁶ (Scheme 1).

Scheme 1

Subsequently a model reaction was attempted to prepare 6a (Table 1) by reacting 3a with p-cyanobenzaldehyde (4a) and acetamide (5a) in presence of catalytic amount of stannous chloride dihydrate under solvent free conditions. Interestingly, exclusive formation of 6a was observed in moderate yields. To scrutinize the catalyst ratio, same reaction was carried out with 10 mol%, 20 mol%, and 30 mol% of stannous chloride dihydrate at 125 °C. Further, the reaction was also studied by employing various other acid catalysts as indicated in Table 1. However, it was observed that 20 mol% stannous chloride dihydrate at 125 °C gave the highest yield among all. Increasing the reaction temperature to 140 °C didn't improve the yields (entry2, Table 1). Poor yields were observed when the reaction was carried out in absence of catalyst.

Table 1 Optimization^b of reaction conditions for synthesis of 6a

Entry	Catalyst (mol%)	T (°C)	Time (h)	Yield^c (%) (6a)
a No catalyst.b 7-Hydroxy coumarin (3a) (0.5 mmol), p-cyanobenzaldehyde (4a) (0.55 mmol), acetamide (0.75 mmol) and catalyst were heated under solvent free condition at above mentioned temperature.c Yield refers to pure products after column chromatography.
1	SnCl2·2H2O (20)	125	1	72
2	SnCl2·2H2O (20)	140	1	68
3	SnCl2·2H2O (10)	125	1	60
4	SnCl2·2H2O (30)	125	1	69
5	InCl3 (20)	130	2	55
6	FeCl3 (20)	125	2	43
7	CeCl3 (20)	130	2	40
8	PTSA (20)	130	2	48
9	CuCl (20)	125	2	35
10	HClO4·SiO2 (20)	130	2	52
11	—^a	140	4	30
12	Acetic acid (200)	130	8	38

---

Encouraged by exclusive formation of 6a with 20 mol% of stannous chloride dihydrate in high yields, a similar reaction was conducted with 3b, 3c and 4-cyano benzaldehyde (4a), acetamide (5) independently under identical reaction conditions and obtained the desired products 6n, 6r in equally good yields. However, it is observed that formation of 6r required 140 °C temperature. With the optimized reaction conditions in hand, we set out to explore the scope and generality of this protocol. Thus compound 3a–c was reacted with variety of aromatic aldehydes containing different substituents on the aromatic ring and acetamide. The electronic properties of the groups on the phenyl ring of aldehyde had varied the yields of the desired product 6. Electron withdrawing groups at either ortho or para position to aldehyde afforded the corresponding products 6a, 6c, 6i, 6p, 6q, 6r, 6s in high yields compared to the electron releasing groups. Unfortunately, this method didn't work for aliphatic aldehydes. Furthermore, compound 3c reacted with p-cyanobenzaldehyde (4a), benzamide (5b) and found the formation of the desired product 6v in good yields. Results of products 6a–v depicted in Scheme 2.

Scheme 2 SnCl₂·2H₂O catalyzed synthesis of trifluoromethyl amidoalkyl chromen-2-ones under solvent free conditions. All the products were characterized by NMR, IR and mass spectroscopy. Yield refers to pure products after column chromatography.

Structure of the products 6 was established by their ¹H-NMR spectra, where the significant methine proton was coupled with adjacent –NH and appeared at δ 7.04 as a doublet and became singlet after D₂O exchange. Further, structure of a representative compound (6d) was unambiguously confirmed by single crystal X-ray diffraction analysis¹⁷ (Fig. 2).

Fig. 2 The molecular structure of 6d with the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radius.

A plausible mechanism for the formation of amidoalkyl 7-hydroxy-2-oxo-4-trifluoromethyl-2H-chromene (6) is illustrated in Scheme 3, where it is reasonable to assume that the reaction may proceed through the formation of ortho quinone methide by addition of 7-hydroxy 4-trifluoromethyl chromene 2-one (3a) to the aromatic aldehyde (4) and subsequently dehydration in the presence of acidic catalyst followed by Michael addition of the amide (5) leads to the formation of amidoalkyl 7-hydroxy-2-oxo-4-trifluoromethyl-2H-chromene (6).

Scheme 3 Plausible reaction mechanism to the synthesis of compound 6.

Exclusive formation of 6l–o presumably attributable in part to the o, p-directing electronic effect of 5,7-dihydroxyfunctional on the chromen-2-one. On the other hand, formation 6p–v is in agreement with the related reports.¹⁸ On the other hand this protocol was also verified with methyl derivative of 3a in lieu of CF₃ with varying aldehydes under identical reaction conditions as in Table 1 and obtained the products 6w and 6x in poor yields.

3. Experimental

3.1 General information

All reactions were carried out under air and monitored by TLC using Merck 60 F₂₅₄ pre coated silica gel plates (0.25 mm thickness) and the products were visualized by UV detection. Flash chromatography was carried out with silica gel (60–120 mesh). IR spectra were obtained on a Perkin-Elmer FTIR spectrophotometer neat or as KBr pellets. ¹H and ¹³C NMR spectra were recorded on a Bruker Avance (III) 300 & 500 MHz spectrometer. Data for ¹H NMR are reported as a chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, q = quartet, m = multiplet), coupling constant J (Hz), integration, and assignment, data for ¹³C are reported as a chemical shift. Mass spectra were recorded in ESI spectrometers. All high resolution mass spectra were recorded on QSTAR XL hybrid ms/ms system (Applied Bio systems/MDS sciex, Foster city, USA), equipped with an ESI source (IICT, Hyderabad).

3.1.1 General experimental procedure for the synthesis of N-((hydroxyl-2-oxo-4-(trifluoromethyl)-2H-chromenyl) (aryl) methyl) amide derivatives (6). A mixture of hydroxy coumarin (3a/3b/3c) (1 mmol), aldehyde (4) (1.1 mmol), amide (5) (1.5 mmol) and SnCl₂·2H₂O (20 mol%) was heated to 125 °C (in case of 3c 140 °C) for 1 h. As the reaction completed (by TLC), the reaction mixture was allowed to cool to room temperature and added H₂O (20 mL) and ethyl acetate (20 mL) followed by 5% HCl (10 mL). Then the mixture was extracted with ethyl acetate (3 × 20 mL), washed with water, brine respectively and dried over anhydrous Na₂SO₄. The organic phase was evaporated under reduced pressure to give the crude product. This was purified by column chromatography over silica gel using hexane and ethyl acetate as eluent to furnish the pure product 6.

3.1.2 N-((4-Cyanophenyl)(7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)methyl)acetamide (6a). Mp 204–205 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 7.86 (m, 1H), 7.66–7.44 (m, 5H), 7.16–6.99 (m, 2H), 6.56 (s, 1H), 2.09 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 169.3, 161.9, 159.6, 158.0, 153.0, 146.2, 141.1 (q, ²J_C–F = 32.4 Hz), 131.4, 127.6, 126.7, 125.2, 121.1 (q, ¹J_C–F = 275 Hz), 118.3, 114.3, 110.7 (q, ³J_C–F = 6.0 Hz), 109.7, 105.6, 46.3, 22.5 ppm; IR (KBr): 3396, 2925, 2229, 1739, 1677, 1283, 1138, 1079, 668 cm⁻¹; HRMS (ESI) anal. calcd for C₂₀H₁₃F₃N₂NaO₄ m/z 425.0719 [M + Na]⁺, found 425.0717.

3.1.3 N-((7-Hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8yl)phenyl)methyl)acetamide) (6b). Mp 251–253 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 7.80 (d, J = 9.4 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.36–7.16 (m, 5H), 7.08–6.98 (m, 2H), 6.54 (s, 1H), 2.06 (s, 3H) ppm; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆) (D₂O exchange): δ 7.50 (d, J = 8.9 Hz, 1H), 7.38–7.17 (m, 5H), 7.04 (d, J = 9.4 Hz, 1H), 7.0 (d, J = 9.1 Hz, 1H), 6.55 (s, 1H), 2.08 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 168.9, 159.8, 158.1, 153.0, 140.9 (q, ²J_C–F = 33 Hz), 140.4, 127.7, 126.3, 125.8, 124.7, 121.1 (q, ¹J_C–F = 276 Hz), 114.5, 113.7, 110.7 (q, ³J_C–F = 4.6 Hz), 105.5, 46.4, 22.6 ppm; IR (KBr): 3414, 1735, 1576, 1284, 1145, 826 cm⁻¹; HRMS (ESI) anal. calcd for C₁₉H₁₅F₃NO₄ m/z 378.0947 [M + H]⁺, found 378.0957.

3.1.4 N-((7-Hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)(4-(trifluoromethyl)phenyl)methyl) acetamide (6c). Mp 186–187 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 11.08 (br s, 1H), 7.93 (d, J = 10.1 Hz, 1H), 7.54–7.46 (m, 5H), 7.06 (d, J = 7.5 Hz, 1H), 7.01 (d, J = 10.1 Hz, 1H), 6.55 (s, 1H), 2.07 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 169.0, 159.4, 157.9, 152.9, 144.7, 141.0 (q, ²J_C–F = 32.4 Hz), 126.2, 125.0, 124.9, 124.4 (q, ³J_C–F = 3.8 Hz), 121.1 (q, ¹J_C–F = 275.6 Hz), 114.6, 113.6, 110.7 (q, ³J_C–F = 6.0 Hz), 105.6, 46.2, 22.6 ppm; IR (KBr): 3359, 2927, 1728, 1654, 1579, 1328, 1280, 1148, 869, 675 cm⁻¹; HRMS (ESI) anal. calcd for C₂₀H₁₃F₆NNaO₄ m/z 468.0641 [M + Na]⁺, found 468.0641.

3.1.5 N-((7-Hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)(4-methoxyphenyl)methyl)acetamide (6d). Mp 123–124 °C; ¹H NMR (300 MHz, CDCl₃): δ 7.65 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.9 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 6.80 (d, J = 8.7 Hz, 2H), 6.53 (s, 1H), 3.74 (s, 3H), 2.14 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 168.7, 159.5, 158.2, 157.9, 152.8, 141.1 (q, ²J_C–F = 32.4 Hz), 132.2, 127.0, 124.5, 124.5, 121.1 (q, ¹J_C–F = 276 Hz), 115.6, 113.7, 113.0, 110.6, 110.5 (q, ³J_C–F = 6.0 Hz), 105.6, 54.6, 46.2, 22.7 ppm; IR (KBr): 3378, 2928, 1741, 1578, 1511, 1280, 1142, 822 cm⁻¹; ESI (MS): m/z 430 [M + Na]⁺.

3.1.6 N-((3-Chlorophenyl)(7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)methyl)acetamide (6e). Mp 249–250 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 10.98 (br s, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.56–7.49 (m, 1H), 7.33 (s, 1H), 7.29–7.15 (m, 3H), 7.08–6.99 (m, 2H), 6.56 (s, 1H), 2.08 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 169.2, 159.7, 158.1, 143.2, 140.8 (q, ²J_C–F = 34 Hz), 133.0, 129.37, 126.3, 125.8, 125.0, 124.5, 121.2 (q, ¹J_C–F = 274 Hz), 115.0, 113.6, 111.1 (q, ³J_C–F = 4.3 Hz), 105.4, 45.9, 22.5 ppm; IR (KBr): 3413, 2923, 1745, 1644, 1511, 1400, 1286, 1078, 825, 547 cm⁻¹; HRMS (ESI) anal. calcd for C₁₉H₁₃ClF₃NNaO₄ m/z 434.0377 [M + Na]⁺, found 434.0378.

3.1.7 N-((3-Bromophenyl)(7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)methyl)acetamide (6f). Mp 258–259 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 7.82 (d, J = 9.1 Hz, 1H), 7.55–7.48 (m, 2H, Ar-H, NH), 7.35–7.25 (m, 2H), 7.17 (d, J = 7.7 Hz, 1H), 7.05–6.98 (m, 2H), 6.56 (s, 1H), 2.08 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 168.9, 159.8, 157.8, 152.9, 143.2, 140.7 (q, ²J_C–F = 32.4 Hz), 129.7, 129.3, 129.1, 128.6, 125.9, 124.8, 124.7, 122.9, 121.4, 121.3 (q, ¹J_C–F = 275.6 Hz), 114.7, 113.6, 110.7 (q, ³J_C–F = 5.8 Hz), 105.3, 45.9, 22.5 ppm; IR (KBr): 3412, 1745, 1587, 1511, 1284, 1134, 826 cm⁻¹; HRMS (ESI) anal. calcd for C₁₉H₁₃BrF₃NNaO₄ m/z 477.9872 [M + Na]⁺, found 477.9875.

3.1.8 N-((2,4-Dichlorophenyl)(7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)methyl)acetamide (6g). Mp 250–251 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 10.77 (br s, 1H), 7.58–7.48 (m, 3H), 7.32 (d, J = 2.1 Hz, 1H), 7.20 (dd, J = 8.5, 2.1 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 6.98 (d, J = 9.1 Hz, 1H), 6.52 (s, 1H), 2.05 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 169.2, 160.23, 158.2, 153.7, 141 (q, ²J_C–F = 31.9 Hz), 136.7, 133.0, 132.4, 130.5, 128.5, 125.9, 125.2, 121.3 (q, ¹J_C–F = 275 Hz), 113.6, 113.4, 110.5 (q, ³J_C–F = 5.0 Hz), 105.4, 45.2, 22.3 ppm; IR (KBr): 3367, 2925, 1725, 1575, 1278, 1152, 1078, 866 cm⁻¹; HRMS (ESI) anal. calcd for C₁₉H₁₂Cl₂F₃NNaO₄ m/z 467.9987 [M + Na]⁺, found 467.9991.

3.1.9 N-((3,4-Dimethoxyphenyl)(7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)methyl)acetamide (6h). Mp 150–152 °C; ¹H NMR (300 MHz, CDCl₃): δ 10.45 (br s, 1H), 7.55 (d, J = 9.4 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.02–6.94 (m, 2H), 6.91–6.83 (m, 2H), 6.76 (d, J = 8.5 Hz, 1H), 6.55 (s, 1H), 3.83 (s, 6H), 2.17 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 168.8, 159.4, 158.2, 152.9, 148.2, 147.5, 141.1 (q, ²J_C–F = 35.5 Hz), 132.9, 124.5, 121.3 (q, ¹J_C–F = 275 Hz), 118.2, 115.5, 113.7, 110.5 (q, ³J_C–F = 5.8 Hz), 110.0, 105.7, 55.3, 55.3, 46.7, 22.8 ppm; IR (KBr): 3364, 2924, 1724, 1577, 1280, 1142, 1075 cm⁻¹; HRMS (ESI) anal. calcd for C₂₁H₁₈F₃NNaO₆ m/z 460.0978 [M + Na]⁺, found 460.0977.

3.1.10 N-((4-Fluorophenyl)(7-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)methyl)acetamide (6i). Mp 236–237 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 7.76 (d, J = 9.2 Hz, 1H), 7.54–7.47 (m, 1H), 7.39–7.29 (m, 2H), 7.07–6.91 (m, 4H), 6.55 (s, 1H), 2.06 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 169.0, 162.6, 159.6, 159.3, 158.2, 152.9, 141.3 (q, ²J_C–F = 31.3 Hz), 136.3, 136.2, 127.6, 127.5, 124.8, 121.1 (q, ¹J_C–F = 276.5 Hz), 115.2, 114.5, 114.2, 113.7, 110.6 (q, ³J_C–F = 5.5 Hz), 105.6, 46.0, 22.6 ppm; IR (KBr): 3414, 3079, 2924, 1737, 1577, 1286, 1149, 1084, 830 cm⁻¹; HRMS (ESI) anal. calcd for C₁₉H₁₃F₄NNaO₄ m/z 418.0672 [M + Na]⁺, found 418.0672.

3.1.11 N-((7-Hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)(4-isopropylphenyl)methyl)acetamide (6j). Mp 210–211 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 10.43 (br s, 1H), 7.54 (d, J = 9.1 Hz, 1H), 7.46 (dd, J = 9.1, 2.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 6.98 (d. J = 9.1 Hz, 1H), 6.87 (d, J = 9.1 Hz, 1H), 6.54 (s, 1H), 2.93–2.79 (m, 1H), 2.15 (s, 3H), 1.20 (d, J = 6.8 Hz, 6H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 168.8, 159.5, 158.3, 152.9, 146.9, 140.8 (q, ²J_C–F = 31 Hz), 137.4, 125.8, 125.7, 124.6, 121.1 (q, ¹J_C–F = 275 Hz), 115.5, 113.7, 110.5 (q, ³J_C–F = 6.0 Hz), 105.7, 46.6, 32.9, 23.4 (2C), 22.8 ppm; IR (KBr): 3412, 2964, 1740, 1581, 1282, 1139, 1078 cm⁻¹; HRMS (ESI) anal. calcd for C₂₂H₂₀F₃NNaO₄ m/z 442.1236 [M + Na]⁺, found 442.1237.

3.1.12 N-((7-Hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)(phenyl)methyl)benzamide (6k). Mp 104–106 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 8.45 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 7.0 Hz, 2H), 7.57–7.37 (m, 6H), 7.32–7.21 (m, 4H), 7.05 (d, J = 9.1 Hz, 1H), 6.59 (s, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 165.6, 159.6, 158.1, 152.9, 141.0 (q, ²J_C–F = 32.4 Hz), 140.3, 133.8, 132.1, 131.0, 129.0, 128.0, 127.8, 127.7, 126.5, 126.6, 125.9, 124.8, 121.1 (q, ¹J_C–F = 275 Hz), 115.1, 113.8, 110.8 (q, ³J_C–F = 4.9 Hz), 105.7, 47.2 ppm; IR (KBr): 3418, 2926, 1743, 1577, 1279, 1143, 695 cm⁻¹; ESI (MS): m/z 440 [M + H]⁺;

3.1.13 N-((5,7-Dihydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)(4-methoxyphenyl)methyl) acetamide (6l). Mp 165–166 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 10.53 (br s, 1H), 7.71 (d, J = 9.4 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 9.4 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 6.58 (s, 1H), 6.53 (br s, 1H), 3.80 (s, 3H), 2.09 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 168.9, 159.9, 158.9, 157.8, 154.9, 153.7, 140.9 (q, ²J_C–F = 33.5 Hz), 133.1, 127.0, 126.5, 121.1 (q, ¹J_C–F = 275 Hz), 113.0, 109.6 (q, ³J_C–F = 8.2 Hz), 107.3, 99.9, 96.9, 54.7, 46.2, 22.9 ppm; IR (KBr): 3106, 2922, 1723, 1614, 1512, 1389, 1273, 1143 cm⁻¹; HRMS (ESI) anal. calcd for C₂₀H₁₇F₃NO₆ m/z 424.1002 [M + H]⁺, found 424.1005.

3.1.14 N-((5, 7-Dihydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)(4-fluorophenyl)methyl)acetamide (6m). Mp 166–168 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 10.76 (br s, 1H), 10.63 (br s, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.34–7.38 (m, 2H), 6.99–6.92 (m, 2H), 6.89 (d, J = 9.4 Hz, 1H), 6.55 (s, 1H), 6.48 (br s, 1H), 2.05 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 168.8, 161.7, 160.0, 159.8, 158.4, 153.9, 154.8, 140.4 (q, ²J_C–F = 34 Hz), 137.4, 127.6, 127.5, 121.4 (q, ¹J_C–F = 276 Hz), 114.3, 114.1, 109.7 (q, ³J_C–F = 7.5 Hz) 107.0, 99.5, 96.6, 45.7, 22.6 ppm; IR (KBr): 3198, 2925, 1723, 1615, 1389, 1273, 1143, 864 cm⁻¹; ESI (MS): m/z 412 [M + H]⁺.

3.1.15 N-((4-Cyanophenyl)(5,7-dihydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)methyl)acetamide (6n). Mp 160–161 °C; ¹H NMR (500 MHz, CDCl₃ + DMSO-d₆): δ 7.86 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.7 Hz, 1H), 6.53 (s, 1H), 6.46 (br s, 1H), 2.07 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 169.3, 159.9, 158.5, 155.2, 154.0, 147.2, 140.6 (q, ²J_C–F = 35 Hz), 131.3, 126.7, 126.5, 126.4, 121.0 (q, ¹J_C–F = 274 Hz), 118.5, 109.8 (q, ³J_C–F = 6.5 Hz), 109.4, 106.1, 99.6, 96.8, 46.3, 22.6 ppm; IR (KBr): 3334, 2925, 2231, 1725, 1613, 1385, 1273, 1145 cm⁻¹; HRMS (ESI) anal. calcd for C₂₀H₁₃F₃N₂NaO₅ m/z 441.0665 [M + Na]⁺, found 441.0666.

3.1.16 N-((5, 7-Dihydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-8-yl)(4-(trifluoromethyl)phenyl)methyl)acetamide (6o). Mp 140–142 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 10.89 (br s, 1H), 10.78 (br s, 1H), 8.10–7.99 (m, 1H), 7.58–7.36 (m, 4H), 6.92–6.81 (m, 1H), 6.53 (s, 1H), 6.47 (br s, 1H), 2.06 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 168.8, 159.8, 158.2, 154.9, 153.9, 146.1, 140.2 (q, ²J_C–F = 33 Hz), 127.3 (q, ²J_C–F = 32 Hz), 126.2, 124.2 (q, ³J_C–F = 3.3 Hz), 124.0 (q, ¹J_C–F = 272 Hz), 121.1 (q, ¹J_C–F = 275 Hz), 109.7 (q, ³J_C–F = 7.7 Hz), 106.4, 99.4, 96.5, 45.9, 22.5 ppm; IR (KBr): 3331, 2924, 1730, 1619, 1327, 1159, 863 cm⁻¹; HRMS (ESI) anal. calcd for C₂₀H₁₄F₆NO₅ m/z 462.0770 [M + H]⁺, found 462.0769.

3.1.17 N-((8-Hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl) (4-(trifluoromethyl) phenyl) methyl) acetamide (6p). Mp 230–232 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 10.13 (br s, 1H), 8.40–8.26 (m, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H), 7.35–7.28 (m, 1H), 7.21–7.15 (m, 1H), 6.74 (s, 1H), 6.66–6.59 (m, 1H), 2.07 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 169.4, 157.6, 144.6, 142.7, 142.2, 140.9 (q, ²J_C–F = 33 Hz), 132.6, 128.3 (q, ²J_C–F = 32.4 Hz), 127.2, 125.3, 124.6, 124.5 (q, ³J_C–F = 3.8 Hz), 123.5 (q, ¹J_C–F = 271 Hz) 123.5, 120.8 (q, ¹J_C–F = 275 Hz), 114.8 (q, ³J_C–F = 5.5 Hz), 114.5, 112.5, 51.0, 22.3 ppm; IR (KBr): 3420, 3307, 2926, 1750, 1655, 1328, 1283, 1166, 1067 cm⁻¹; ESI (MS): m/z 468 [M + Na]⁺.

3.1.18 N-((4-Bromophenyl)(8-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)methyl)acetamide (6q). Mp 216–218 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 10.14 (br s, 1H), 8.41 (d, J = 8.1 Hz, 1H), 7.44–7.30 (m, 3H), 7.22–7.13 (m, 3H), 6.75 (s, 1H), 6.58–6.51 (m, 1H), 2.05 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 169.5, 157.7, 142.6, 142.1, 141.1 (q, ²J_C–F = 33 Hz), 139.3, 132.8, 130.7, 128.6, 123.5, 120.9 (q, ¹J_C–F = 276 Hz), 120.3, 114.7 (q, ³J_C–F = 5.5 Hz), 114.5, 112.5, 51.2, 22.4 ppm; IR (KBr): 3293, 2926, 1747, 1650, 1283, 1146 cm⁻¹; HRMS (ESI) anal. calcd for C₁₉H₁₃BrF₃NNaO₄ m/z 477.9872 [M + Na]⁺, found 477.9875.

3.1.19 N-((4-Cyanophenyl)(8-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)methyl)acetamide (6r). Mp 249–250 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 8.18–8.04 (m, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 1H), 7.22–7.17 (m, 1H), 6.75 (s, 1H), 6.61 (d, J = 8.5 Hz, 1H), 2.09 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 169.5, 157.7, 146.1, 142.8, 142.2, 140.9 (q, ²J_C–F = 31.9 Hz), 132.5, 131.6, 127.7, 122.8, 123.7, 120.9 (q, ¹J_C–F = 275.6 Hz), 118.2, 115.1 (q, ³J_C–F = 5.5 Hz), 114.7, 114.6, 112.7, 110.1, 51.0, 22.4 ppm; IR (KBr): 3297, 2239, 1750, 1651, 1285, 1171, 1143, 888 cm⁻¹; HRMS (ESI) anal. calcd for C₂₀H₁₄F₃N₂O₄ m/z 403.0900 [M + H]⁺, found 403.0903.

3.1.20 N-((8-Hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)(2-nitrophenyl)methyl)acetamide (6s). Mp 267–268 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 8.26–8.13 (m, 1H), 7.93–9.88 (m, 1H), 7.64–7.43 (m, 3H), 7.17–7.04 (m, 3H), 6.76 (s, 1H), 2.03 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 169.5, 157.9, 142.6, 142.6, 140.7 (q, ²J_C–F = 32.9 Hz), 136.5, 134.0, 133.1, 131.7, 129.4, 128.8, 126.4, 123.6, 122.8, 121.0 (q, ¹J_C–F = 275 Hz), 115.0 (q, ³J_C–F = 6.5 Hz), 114.2, 112.7, 48.8, 22.2 ppm; IR (KBr): 3277, 2924, 1749, 1529, 1283, 1140, 886 cm⁻¹; HRMS (ESI) anal. calcd for C₁₉H₁₃F₃N₂NaO₆ m/z 445.0617 [M + Na]⁺, found 445.0618.

3.1.21 N-((2,4-Dichlorophenyl)(8-hydroxy-2-oxo-4-(trifluoro methyl)-2H-chromen-7-yl)methyl)acetamide (6t). Mp 278–279 °C; ¹H NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 8.10–8.18 (m, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.26–7.13 (m, 4H), 6.77 (s, 1H), 6.73 (d, J = 7.9 Hz, 1H), 2.03 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 168.7, 157.6, 148.6, 142.6, 142.4, 140.2 (q, ²J_C–F = 34.2 Hz) 134.7, 132.6, 129.4, 128.2, 124.1, 123.0, 120.8 (q, ¹J_C–F = 275 Hz), 115.7 (q, ³J_C–F = 4.9 Hz), 114.1, 112.7, 47.1, 22.1 ppm; IR (KBr): 3402, 3084, 2923, 1744, 1652, 1286, 1143, 897 cm⁻¹; HRMS (ESI) anal. calcd for C₁₉H₁₃Cl₂F₃NO₄ m/z 446.0168 [M + H]⁺, found 446.0166.

3.1.22 N-((4-Fluorophenyl)(8-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)methyl)acetamide (6u). Mp 225–227 °C; ¹H NMR (300 MHz, CDCl₃): δ 8.14 (d, J = 8.49 Hz, 1H), 7.32–7.22 (m, 3H), 7.15 (d, J = 8.3 Hz, 1H), 6.99–6.91 (m, 2H), 6.71 (s, 1H), 6.55 (d, J = 8.3 Hz, 1H), 2.08 (s, 3H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 169.7, 162.9, 159.7, 158.0, 142.8, 142.2, 141.0 (q, ²J_C–F = 33.0 Hz), 136.9, 136.4, 132.5, 131.9, 131.7, 131.5, 131.4, 128.9, 128.8, 128.3, 128.2, 123.4, 121.0 (q, ¹J_C–F = 275 Hz), 115.0 (q, ³J_C–F = 6.0 Hz), 114.8, 114.5, 112.5, 50.5, 22.4 ppm; IR (KBr): 3366, 2924, 1752, 1509, 1284, 1152, 881 cm⁻¹; HRMS (ESI) anal. calcd for C₁₉H₁₄F₄NO₄ m/z 396.08535 [M + H]⁺, found 396.08531.

3.1.23 N-((4-Cyanophenyl)(8-hydroxy-2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)methyl)benzamide (6v). Mp 266–267 °C; ¹H NMR (500 MHz, CDCl₃ + DMSO-d₆): δ 10.35 (br s, 1H), 8.61 (d, J = 7.4 Hz, 1H), 7.90 (d, J = 6.6 Hz, 2H), 7.67–7.36 (m, 8H), 7.25 (d, J = 5.8 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.79 (s, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃ + DMSO-d₆): δ 166.0, 157.6, 146.2, 142.7, 142.2, 140.2 (q, ²J_C–F = 33.6 Hz), 133.7, 132.6, 131.6, 130.9, 128.1, 127.7, 127.3, 123.7, 121.1 (q, ¹J_C–F = 274 Hz) 118.1, 115.5 (q, ³J_C–F = 5.5 Hz), 114.3, 112.6, 109.9, 50.7 ppm; IR (KBr): 3423, 3284, 2922, 2228, 1750, 1638, 1283, 1139, 697 cm⁻¹; HRMS (ESI) anal. calcd for C₂₅H₁₆F₃N₂O₄ m/z 465.1056 [M + H]⁺, found 465.1057.

3.1.24 N-((7-Hydroxy-4-methyl-2-oxo-2H-chromen-8-yl)(phenyl)methyl)acetamide (6w). Mp 265–270 °C; ¹H NMR (500 MHz, CDCl₃ + DMSO-d₆): δ 10.57 (br s, 1H), 7.86 (d, J = 9.1 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.34–7.29 (m, 2H), 7.25 (t, J = 7.5 Hz, 2H), 7.13 (t, J = 7.0 Hz, 1H), 7.03 (d, J = 9.3 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H) 6.06 (s, 1H), 2.39 (s, 3H), 2.06 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃ + DMSO-d₆): δ 168.7, 159.5, 158.2, 152.3, 151.3, 140.6, 120.5, 126.1, 125.6, 124.2, 114.4, 112.5, 112.2, 110.2, 46.4, 22.1, 18.2 ppm; IR (KBr): 3372, 2960, 1704, 1649, 1511, 1246, 1067 cm⁻¹; HRMS (ESI) anal. calcd for C₁₉H₁₈NO₄ m/z 324.1230 [M + H]⁺, found 324.1230.

3.1.25 N-((4-cyanophenyl)(7-hydroxy-4-methyl-2-oxo-2H-chromen-8-yl)methyl)acetamide (6x). Mp 260–266 °C; ¹H NMR (500 MHz, CDCl₃ + DMSO-d₆): δ 10.76 (br s, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.07 (s, 1H), 2.38 (s, 3H), 2.05 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃ + DMSO-d₆): δ 168.5, 159.3, 158.2, 152.6, 151.2, 146.6, 131.2, 126.7, 124.9, 124.8, 118.2, 113.3, 112.3, 112.0, 110.2, 109.2, 46.1, 22.4, 18.1 ppm; IR (KBr): 3372, 2960, 1704, 1649, 1511, 1246, 1067 cm⁻¹; HRMS (ESI) anal. calcd for C₂₀H₁₆N₂NaO₄ m/z 371.1002 [M + Na]⁺, found 371.1008.

4. Conclusions

In conclusion, we have developed an efficient methodology to synthesize a series of amidoalkyl based trifluoromethyl substituted chromen-2-ones, in a one pot three component reaction under solvent free condition. Higher yields, simple reaction condition, and environmentally benign procedure are the advantages of this protocol.

References and notes

1. (a) D. H. Murray, J. Mendez and S. A. Brown, The Natural Coumarins: Occurrence, Chemistry and Biochemistry, J. Wiley & Sons, New York, 1982; (b) T. K. Mandal, V. V. Kuznetsov and A. T. Soldatenkov, Chem. Heterocycl. Compd., 1994, 30, 867; (c) M. V. Kulkarni, G. M. Kulkarni, C. H. Lin and C. M. Sun, Curr. Med. Chem., 2006, 13, 2795.
2. (a) R. O'Kennedy and R. D. Thornes, Coumarins: Biology, Applications and Mode of Action, J. Wiley & Sons, Chichester, 1997; (b) K. C. Fylaktakidou, D. J. Hadjipavlou-Litina, K. E. Litinas and D. N. Nicolaides, Curr. Pharm. Des., 2004, 10, 3813; (c) W. Zhang and G. Pugh, Tetrahedron Lett., 2001, 42, 5613.
3. (a) T. Berthelot, J. C. Talbot, G. Laïn, G. Deleris and L. Latxague, J. Pept. Sci., 2005, 11, 153; (b) K. S. Lee, H. J. Kim, G. H. Kim, I. Shin and J. I. Hong, Org. Lett., 2008, 10, 49; (c) Y. R. Zhao, Q. Zheng, K. Dakin, K. Xu, M. L. Martinez and W. H. Li, J. Am. Chem. Soc., 2004, 126, 4653; (d) J. M. Serin, D. W. Brousmiche and J. M. J. Frechet, J. Am. Chem. Soc., 2002, 124, 11848.
4. (a) J. T. Welch, Tetrahedron, 1987, 43, 3123; (b) A. V. Fokin and A. F. Kolomiyets, J. Fluorine Chem., 1988, 40, 247.
5. (a) R. Smits, C. D. Cadicamoo, K. Burger and B. Koksch, Chem. Soc. Rev., 2008, 37, 1727; (b) K. L. Kirk, J. Fluorine Chem., 2006, 127, 1013; (c) X. L. Qiu, W. D. Meng and F. L. Qing, Tetrahedron, 2004, 60, 6711.
6. (a) A. J. Wangelin, H. Neumann, D. Gordes, S. Klaus, D. Strubing and M. Beller, Chem. – Eur. J., 2003, 9, 4286; (b) M. K. Sinha, K. Khoury, E. Herdtweckb and A. Dömling, Org. Biomol. Chem., 2013, 11, 4792; (c) C. D. Graaff, E. Ruijter and R. V. A. Orru, Chem. Soc. Rev., 2012, 41, 3969; (d) N. Isambert and R. Lavilla, Chem. – Eur. J., 2008, 14, 8444; (e) Multicomponent reactions, ed. J. Zhu and H. Bienayme, Wiley-VCH, Weinheim, 2005.
7. S. S. Maya and C. Sushobhan, RSC Adv., 2012, 2, 4547.
8. (a) Z. L. Shen, S. J. Ji and T. P. Loh, Tetrahedron Lett., 2005, 46, 507; (b) L. S. Zhi, J. J. Shun and J. Z. Wei, Synth. Commun., 2005, 35, 1903; (c) S. J. Tong, S. Z. Jian, Q. W. Ai and S. L. Tong, Synth. Commun., 2005, 35, 2339.
9. K. Bahador, K. Saeed and E. Khalil, Tetrahedron Lett., 2012, 53, 1445.
10. W. Gajanan, A. Rahul, K. Neha, R. Ravi, K. Naveen Kumar and S. Dinkar, Bioorg. Med. Chem. Lett., 2010, 20, 4675.
11. M. T. Christopher, E. C. Krystal, N. Stuart, J. S. David, E. W. Nancy, H. W. Nichola and R. W. Gareth, J. Fluorine Chem., 2006, 127, 1554.
12. (a) M. A. Amrollahi, B. B. F. Mirjalili and H. Emtiazi, J. Chem. Sci., 2013, 125, 561; (b) D. Robita and S. Rajesh k, Asian J. Chem., 2012, 24, 5665; (c) N. Hazeri, M. T. Maghsoodlou, S. M. Habibikhorassani, J. Aboonajmi and M. Safarzaei, Chem. Sci. Trans., 2013, 2, 330; (d) Q. Zhang, J. Luo and Y. Wei, Green Chem., 2010, 12, 2246.
13. S. Puri, B. Kaur, A. Parmar and H. Kumar, Org. Prep. Proced. Int., 2012, 44, 91.
14. T. A. Salama, Synlett, 2013, 24, 713.
15. E. N. Reddy, A. Krishnaiah, K. C. Ganesh, P. Sujitha and B. N. Jagadeesh, Bioorg. Med. Chem. Lett., 2012, 22, 7261.
16. H. V. Pechmann and C. Duisberg, Ber. Dtsch. Chem. Ges., 1883, 16, 2119.
17. ESI.†.
18. (a) L. Guixia, W. Wei, Z. Shilei, Z. Tangzhi, L. Hao and W. Wei, Org. Lett., 2011, 13, 828; (b) B. Hai-Peng, C. Wen-Wen, L. Chao-Jun, B. Hai-Peng and L. Yong-Min, Org. Lett., 2009, 11, 3246; (c) A. Subbarayappa, M. Darapaneni Chandra and P. D. Rajendra, Eur. J. Org. Chem., 2012, 18, 3520.

---

Footnote

† CCDC 929729. For crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra00166d

---