Three-Component Reactions of 7-Hydroxy Coumarin Derivatives, Acetylenic Esters and Aromatic Aldehydes in the Presence of NEt₃

Abstract

Three-component reactions of 7-hydroxy-4-methyl coumarin or 7-hydroxy-4-(trifluoromethyl) coumarin, dialkyl acetylenedicarboxylates and aromatic aldehydes in the presence of NEt₃ lead to dialkyl (2E)-2-[aryl(hydroxy)methyl]-3-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]but-2-ene dioate or dialkyl (2E)-2-[aryl(hydroxy)methyl]-3-{(2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)oxy} but-2-ene dioate in good yields under mild reaction conditions.

7-hydroxy coumarins; dialkyl acetylenedicarboxylates; aromatic aldehydes; three-component reaction

Introduction

Coumarins form an exceptional class of oxygen-containing heterocyclic compounds, which exhibit significant biological activities, such as inhibitory of platelet aggregation,^1,2 inhibitory of steroid 5α-reductase,³ inhibitory of HIV-1 protease,⁴ antibacterial and anticancer activities.^5,6 Coumarin derivatives have been applied for treatment of various cancerous diseases including malignant melanoma, leukemia, renal cell carcinoma, prostate and breast cancer.^7-12 Moreover, coumarins were used as intermediates in the synthesis of chromenes, coumarones and 2-acylresorcinols.¹³ Owing to their important applications, various synthetic methodologies for the synthesis of coumarin derivatives have been developed. However, further scientific efforts are still on demand to seek for synthetic methodologies of novel coumarin-based scaffolds.

Recently, the reactions of phenols including phenol, 1-naphthol, 2-naphthol, 8-hydroxyquinoline, 1,6-dihydroxynaphthalene and hydroxybenzaldehydes as OH-acids with dimethyl acetylenedicarboxylate (DMAD) in the presence of a catalytic amount of triethylamine,¹⁵ pyridine¹⁶ and triphenylphosphine¹⁷ have been reported. In continuation of our general interest in the synthesis of heterocyclic compounds via three-component reactions,^17-20 we have investigated the reactions of 7-hydroxycoumarins 1 with acetylenic diesters 2 and arylaldehydes 3 in the presence of NEt₃ in tetrahydrofuran (THF) at ambient temperature to afford the corresponding three-component products (1:1:1 adduct) as novel coumarin derivatives 4 and compound 5 as 1:1 adduct in good yields (Scheme 1).

Scheme 1
Preparation of O-substituted coumarin derivatives.

Results and Discussion

Initially, the reaction of 7-hydroxy-4-methyl coumarin and DMAD with 4-nitro benzaldehyde as a model reaction was examined in the absence of base at room temperature, in which the starting materials were recovered intact without the formation of the expected multi-component reaction (MCR) product 4. When the reaction was carried out in the presence of NEt₃, the expected product 4 (1:1:1 adduct) was formed as light yellow powder. In order to find the appropriate base for the synthesis of 4a, the model reaction was investigated in THF using different bases and the results are presented in Table 1. Although all the bases (K₂CO₃, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) and NEt₃) promote the reaction, the highest yield of the product was obtained using NEt₃.

Table 1
Effect of different bases in the synthesis of 4a

Base	Yield of 4a / %
K2CO3	35
DBU	50
DABCO	40
NEt3	60

• DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DABCO: 1,4-diazabicyclo[2.2.2] octane.

The model reaction was further studied using different amounts of NEt₃under the same reaction conditions (Table 2). The results in Table 2 clearly show that 100 mol% of NEt₃ give the highest yield of the product 4a.

Table 2
Effect of NEt₃ mol% in the synthesis of 4a

NEt3 / mol%	Yield of 4a / %
50	30
60	40
70	45
100	60

In order to examine the scope and limitations of this method, we extended our study to a variety of aromatic aldehydes with electron-withdrawing and electrondonating substituents. The results in Table 3 clearly indicate the significant role of the substituent groups of the benzaldehyde ring in the reaction pathway for the synthesis of three-component products 4a-j(1:1:1 adduct). The reactions of 7-hydroxy-4-methyl coumarin and DMAD with benzaldehyde and electron-donating substituted benzaldehydes (X = H, CH₃, OCH₃, F, Cl, Br) in the presence of NEt₃ in THF at room temperature did not afford the corresponding product 4 and only compound 5 (1:1 adduct) was collected as sole product. Electron-withdrawing substituted benzaldehydes (X = NO₂, CN) reacted with 7-hydroxy-4-methyl or trifluoromethyl coumarins and dialkyl acetylenedicarboxylates under similar reaction conditions to give the corresponding three-component products 4a-j in good yields (38-60%). However, 4-trifluoromethylbenzaldehyde under similar condition unexpectedly gave only compound 5.

Table 3
Three-component reactions of 7-hydroxy-4-methyl coumarin or 7-hydroxy-4-(trifluoromethyl) coumarin with dialkyl acetylenedicarboxylates and aromatic aldehydes in the presence of NEt₃in THF

Compound	R	R'	X	Yield of 4a / %	Yield of 5a / %
4a	Me	Me	4-NO2	60	35
4b	Me	t-Bu	4-NO2	53	-
4c	Me	Me	2-NO2	50	47
4d	Me	t-Bu	2-NO2	41	-
4e	Me	Me	4-CN	55	42
4f	Me	t-Bu	4-CN	51	-
4g	CF3	Me	4-NO2	50	-
4h	CF3	t-Bu	4-NO2	30	-
4i	CF3	Me	2-NO2	42	-
4j	CF3	Me	4-CN	38	-
5	Me	Me	4-CF3	-	92
5	Me	Me	H	-	94
5	Me	Me	4-CH3	-	97
5	Me	Me	4-OCH3	-	98
5	Me	Me	4-F	-	97
5	Me	Me	4-Cl	-	92
5	Me	Me	4-Br	-	94

• ^a
  Isolated yields.

A plausible mechanism for the synthesis of compounds 4 and 5 is depicted in Scheme 2. It is assumed that deprotonation of coumarin 1 by NEt₃generates anion 6 that can subsequently perform Michael addition with dialkyl acetylenedicarboxylate 2 to give intermediate 7. Intermediate 7 could either protonate by ammonium salt to produce compound 5 or react with aldehyde 3 to form intermediate 8, which then protonates by ammonium salt to afford the coumarin derivatives 4.

Scheme 2
Proposed mechanism of preparation of O-substituted coumarin derivatives.

The structure of 4a was deduced from infrared (IR), ¹H, ¹³C, ¹⁹F nuclear magnetic resonance (NMR) and mass spectra, as well as elemental analysis. The IR spectrum of 4a showed a broad band between 3300-3400 cm^-1 corresponding to OH stretching absorption and a strong peak at 1740 cm^-1 attributed to C=O vibrations of the ester groups. The ¹H NMR spectrum of 4a exhibited a doublet at δ 2.44 ppm (⁴J_HH 1.2 Hz) for the methyl group, a singlet at δ 3.32 ppm for the OH group, two singlets at δ 3.72 and 3.79 ppm for the two methoxy groups, a singlet at δ 6.02 ppm for the aliphatic methine group (CH), a quartet at δ 6.26 ppm (⁴J_HH 1.2 Hz) for the CH group of heterocyclic moiety, a doublet of doublet at δ 6.94 ppm (³J_HH 8.8 Hz, ⁴J_HH 2.4 Hz), a doublet at δ 6.97 ppm (⁴J_HH 2.4 Hz) and a doublet at δ 7.57 ppm (³J_HH 8.8 Hz) for the three CH groups of the benzene ring of coumarin and two doublets at δ 7.63 and 8.20 ppm (³J_HH 8.4 Hz) for the four CH groups of the para-substituted benzene ring. The ¹³C NMR spectrum of 4a exhibited twenty one signals in agreement with the proposed structure. The mass spectrum of this compound displayed a molecular ion peak at m/ 469 (M⁺, 7) and other fragments at 437, 378, 287, 176 and 150 in accordance with the structure of 4a.

Similarly, the ¹H and ¹³C NMR spectra of 4b-4jdisplayed the expected characteristic resonances related to their structure.

The structure of the compound 5 is E and Z configuration isomers, as shown in Scheme 3.

Scheme 3
Geometric isomers of 5.

Although the carbon-carbon double bond in 5 is conjugated to the adjacent oxygen atom, the rotation about the C=C bond for the E and Z isomers is slow on the NMR time scale at room temperature, as confirmed by ¹H and ¹³C NMR spectra of 5. The assignment of the Z-configuration to the major geometric isomer of 5 is based on the ¹H NMR chemical shift of the olefinic proton, which migrated to lower field for the Z isomer due to the anisotropic effect of the adjacent ester group.

The ¹H NMR spectrum of the Z-isomer exhibited a doublet at δ 2.42 ppm (⁴J_HH 1.2 Hz) for the methyl group, two sharp singlets at δ 3.74 and 3.81 ppm for the two methoxy groups and a singlet at d 6.77 ppm for the olefinic proton, and the spectrum of the E-isomer displayed a doublet at δ 2.46 ppm (⁴J_HH 1.2 Hz) for the methyl group, two singlets at δ 3.73 and 3.92 ppm for the two methoxy groups and a singlet at δ 5.43 ppm for the olefinic proton. The ¹³C NMR spectrum of 5displayed 32 distinct resonances, in agreement with the presence of two E and Z geometric isomers. The structure of 5 was further confirmed by the mass spectrum, which displayed a molecular ion peak at m/ 318.

Experimental

Materials and methods

Dialkyl acetylenedicarboxylates, aromatic aldehydes and triethylamine were purchased from Fluka (Buchs, Switzerland) and used without further purification. 7-Hydroxy coumarin derivatives were prepared by known methods.²¹ Melting points were measured on an Electrothermal 9100 apparatus. IR spectra were recorded on a FT-IR Bruker vector 22 spectrometer; NMR spectra were recorded on a Bruker DRX-400 AVANCE instrument (400.1 MHz for ¹H, 100.6 MHz for ¹³C, 376.5 MHz for ¹⁹F NMR) with CDCl₃ as solvent. Chemical shifts are given in parts per million (δ) relative to tetramethylsilane (TMS), and coupling constants (J) are reported in hertz (Hz). Mass spectra were recorded on a Finnigan-Matt 8430 mass spectrometer operating at an ionization potential of 70 eV. Elemental analyses were performed using a Heracus CHN-O Rapid analyzer.

General procedure for the preparation of compounds 4a-j

To a magnetically-stirred solution of 7-hydroxy coumarin derivatives (2 mmol), aromatic aldehydes (2 mmol) and NEt₃ (2 mmol) in THF (8 mL) a mixture of dialkyl acetylenedicarboxylate (2 mmol) in THF (2 mL) was added in 15 min. The reaction mixture was then allowed to stand at room temperature for 0.5-10 h. After completion of the reaction as indicated by thin-layer chromatography (TLC) (n-hexane/EtOAc, 1:1), the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (Merck, 230-400 mesh) using a mixture of n-hexane/EtOAc (1:1) as eluent to afford the pure product as a light yellow powder.

Analytical data for dimethyl (2E)-2-[hydroxy(4-nitrophenyl)methyl]-3-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]but-2-enedioate (4a)

Light yellow powder; m.p. 144-146 ºC; IR (KBr) ν_max/cm^-13388, 3074, 2955, 2853, 1740, 1655, 1568, 1347, 1260, 1090; ¹H NMR (400.1 MHz, CDCl₃) δ 2.44 (d, 3H, J 1.2 Hz, CH₃), 3.32 (s, 1H, OH), 3.72 and 3.79 (2s, 6H, 2OCH₃), 6.02 (s, 1H, CH benzylic), 6.26 (q, 1H, J 1.2 Hz, CH heterocylic), 6.94 (dd, 1H, J 8.8, 2.4 Hz, Ar–H), 6.97 (d, 1H, J 2.4 Hz, Ar–H), 7.57 (d, 1H, J 8.8 Hz, Ar–H), 7.63 (d, 2H, J 8.4 Hz, 2Ar–H), 8.20 (d, 2H, J 8.4 Hz, 2Ar–H); ¹³C NMR (100.6 MHz, CDCl₃) δ 18.7, 53.0, 53.2, 68.8, 105.0, 113.2, 113.9, 116.6, 123.8, 126.2, 126.9, 130.8, 144.1, 147.5, 147.6, 152.0, 154.7, 157.7, 160.4, 161.4, 165.7; MS (EI, 70 eV) (%) 469 (M⁺, 7), 437 (7), 378 (15), 319 (11), 287 (38), 262 (15), 234 (16), 176 (43), 150 (100), 104 (23), 76 (15); anal. calcd. for C₂₃H₁₉NO₁₀ (469.41): C, 58.85; H, 4.08; N, 2.98%; found: C, 58.79; H, 4.13; N, 2.95%.

Analytical data for di-tert-butyl (2E)-2-[hydroxy(4-nitrophenyl) methyl]-3-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]but-2-enedioate (4b)

Light yellow powder; m.p. 147-149 ºC; IR (KBr) ν_max/cm^-13425, 2927, 2856, 1728, 1611, 1568, 1346, 1262, 1093; ¹H NMR (400.1 MHz, CDCl₃) δ 1.26 and 1.36 (2s, 18H, 2CMe₃), 2.45 (d, 3H, J 1.2 Hz, CH₃), 3.88 (s, 1H, OH), 5.98 (s, 1H, CH benzylic), 6.26 (q, 1H, J 1.2 Hz, CH heterocylic), 6.96 (dd, 1H, J 8.6, 2.4 Hz, Ar–H), 7.02 (d, 1H, J 2.4 Hz, Ar–H), 7.57 (d, 1H, J 8.4 Hz, Ar–H), 7.64 (d, 2H, J 8.8 Hz, 2Ar–H), 8.22 (d, 2H, J 8.8 Hz, 2Ar–H); ¹³C NMR (100.6 MHz, CDCl₃) δ 18.8, 27.6, 27.7, 68.7, 84.1, 84.2, 105.5, 113.4, 113.9, 116.4, 123.5, 125.9, 126.8, 129.5, 145.5, 147.4, 148.2, 152.0, 154.7, 158.2, 159.9, 160.5, 164.8; MS (EI, 70 eV) (%) 553 (M⁺, 1), 407 (3), 176 (94), 148 (100), 91 (22), 57 (28); anal. calcd. for C₂₉H₃₁NO₁₀ (553.57): C, 62.92; H, 5.64; N, 2.53%; found: C, 62.85; H, 5.61; N, 2.58%.

Analytical data for dimethyl (2E)-2-[hydroxy(2-nitrophenyl) methyl]-3-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]but-2-enedioate (4c)

Light yellow powder; m.p. 104-106 ºC; IR (KBr) ν_max/cm^-13429, 3084, 2956, 2855, 1734, 1610, 1527, 1349, 1262, 1085; ¹H NMR (400.1 MHz, CDCl₃) δ 2.41 (d, 3H, J 0.8 Hz, CH₃), 3.37 (s, 1H, OH), 3.68 and 3.77 (2s, 6H, 2OCH₃), 6.20 (q, 1H, J 1.2 Hz, CH heterocylic), 6.48 (1H, s, CH benzylic), 6.76 (d, 1H, J 2.4 Hz, Ar–H), 6.87 (dd, 1H, J 8.8, 2.4 Hz, Ar–H), 7.43 (td, 1H, J 7.4, 1.2 Hz, Ar–H), 7.51 (d, 1H, J 8.8 Hz, Ar–H), 7.67 (td, 1H, J 8.0, 1.2 Hz, Ar–H), 7.91 (dd, 1H, J 8.0, 1.2 Hz, Ar–H), 8.00 (dd, 1H, J 8.0, 0.8 Hz, Ar–H); ¹³C NMR (100.6 MHz, CDCl₃) δ 18.7, 52.9, 53.1, 66.1, 104.3, 113.0, 113.4, 115.0, 124.6, 126.0, 129.1, 129.3, 133.6, 133.8, 135.3, 142.0, 147.7, 152.2, 154.5, 158.1, 160.7, 161.4, 165.7; MS (EI, 70 eV) (%) 469 (M⁺, 7), 392 (19), 364 (16), 348 (32), 333 (18), 316 (13), 277 (23), 259 (30), 230 (12), 202 (16), 176 (81), 148 (100), 120 (33), 59 (49); anal. calcd. for C₂₃H₁₉NO₁₀ (469.41): C, 58.85; H, 4.08; N, 2.98%; found: C, 58.91; H, 4.11; N, 2.94%.

Analytical data for di-tert-butyl (2E)-2-[hydroxy(2-nitrophenyl) methyl]-3-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]but-2-enedioate (4d)

Light yellow powder; m.p. 149-151 ºC; IR (KBr) ν_max/cm^-13428, 2925, 2855, 1730, 1611, 1528, 1346, 1265, 1089; ¹H NMR (400.1 MHz, CDCl₃) δ 1.24 and 1.33 (2s, 18H, 2CMe₃), 2.43 (d, 3H, J 1.2 Hz, CH₃), 3.43 (s, 1H, OH), 6.23 (q, 1H, J 1.2 Hz, CH heterocylic), 6.49 (s, 1H, CH benzylic), 6.91 (d, 1H, J 2.4 Hz, Ar–H), 6.95 (dd, 1H, J 8.2, 2.4 Hz, Ar–H), 7.46 (td, 1H, J 7.4, 1.2 Hz, Ar–H), 7.53 (d, 1H, J 8.8 Hz, Ar–H), 7.68 (td, 1H, J 8.2, 1.2 Hz, Ar–H), 7.98 (dd, 1H, J 8.4, 1.2 Hz, Ar–H), 8.03 (d, 1H, J 8.1 Hz, Ar–H); ¹³C NMR (100.6 MHz, CDCl₃) δ 18.8, 27.5, 27.6, 66.5, 83.5, 83.7, 105.1, 113.4, 113.5, 115.9, 124.6, 125.6, 128.8, 129.2, 131.7, 133.5, 135.8, 143.5, 147.8, 152.1, 154.6, 158.8, 160.0, 160.8, 164.8; MS (EI, 70 eV) (%) 553 (M⁺, 1), 423 (2), 316 (15), 201 (26), 176 (100), 148 (100), 119 (15), 91 (25), 57 (21); anal. calcd. for C₂₉H₃₁NO₁₀ (553.57): C, 62.92; H, 5.64; N, 2.53%; found: C, 62.88; H, 5.69; N, 2.47%.

Analytical data for dimethyl (2E)-2-[(4-cyanophenyl) (hydroxy)methyl]-3-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy] but-2-enedioate (4e)

Light yellow powder; m.p. 138-140 ºC; IR (KBr) ν_max/cm^-13426, 3050, 2925, 2855, 2229, 1735, 1263, 1091; ¹H NMR (400.1 MHz, CDCl₃) δ 2.42 (d, 1H, J 0.8 Hz, OH), 2.44 (d, 3H, J 1.2 Hz, CH₃), 3.72 and 3.79 (2s, 6H, 2OCH₃), 5.96 (s, 1H, CH benzylic), 6.26 (q, 1H, J 1.2 Hz, CH heterocylic), 6.91 (dd, 1H, J8.8, 2.4 Hz, Ar–H), 6.95 (d, 1H, J 2.4 Hz, Ar–H), 7.56 (d, 1H, J 7.2 Hz, Ar–H), 7.57 (d, 2H, J 8.4 Hz, 2Ar–H), 7.64 (d, 2H, J 8.4 Hz, 2Ar–H); ¹³C NMR (100.6 MHz, CDCl₃) δ 18.7, 52.0, 53.2, 68.9, 105.0, 111.9, 113.1, 113.9, 116.6, 118.6, 126.2, 126.7, 130.9, 132.4, 144.1, 145.6, 152.0, 154.7, 157.7, 160.4, 161.5, 165.0. MS (EI, 70 eV) (%) 449 (M⁺, 19), 417 (12), 358 (42), 319 (23), 287 (100), 259 (15), 242 (11), 214 (13), 187 (52), 148 (45), 130 (88), 102 (29), 59 (8); anal. calcd. for C₂₄H₁₉NO₈ (449.42): C, 64.14; H, 4.26; N, 3.12%; found: C, 64.07; H, 4.31; N, 3.08%.

Analytical data for di-tert-butyl (2E)-2-[(4-cyanophenyl) (hydroxy)methyl]-3-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy] but-2-enedioate (4f)

Light yellow powder; m.p. 129-131 ºC; IR (KBr) ν_max/cm^-13431, 2925, 2855, 2230, 1728, 1610, 1261, 1095; ¹H NMR (400.1 MHz, CDCl₃) δ 1.28 and 1.34 (2s, 18H, 2CMe₃), 2.45 (d, 3H, J 0.8 Hz, CH₃), 3.78 (d, 1H, J8.8 Hz, OH), 5.93 (d, 1H, J 7.6 Hz, CH benzylic), (q, 1H, J 1.2 Hz, CH heterocylic), 6.94 (dd, 1H, J8.8, 2.8 Hz, Ar–H), 7.02 (d, 1H, J 2.4 Hz, Ar–H), 7.56 (d, 1H, J 8.4 Hz, Ar–H), 7.58 (d, 2H, J 8.4 Hz, 2Ar–H), 7.66 (d, 2H, J 8.4 Hz, 2Ar–H); ¹³C NMR (100.6 MHz, CDCl₃) δ 18.8, 27.7, 29.7, 68.8, 84.0, 84.1, 105.5, 111.5, 113.3, 113.9, 116.4, 118.7, 125.9, 126.7, 129.7, 132.1, 145.4, 146.2, 151.9, 154.7, 158.2, 159.9, 160.5, 164.9; MS (EI, 70 eV) (%) 533 (M⁺, 2), 459 (3), 433 (13), 403 (4), 358 (4), 316 (7), 288 (4), 227 (17), 176 (100), 148 (80), 130 (30), 102 (18), 57 (16); anal. calcd. for C₃₀H₃₁NO₈ (533.58): C, 67.53; H, 5.86; N, 2.63%; found: C, 67.58; H, 5.90; N, 2.59%.

Analytical data for dimethyl (2E)-2-[hydroxy(4-nitrophenyl) methyl]-3-{(2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)oxy} but-2-enedioate (4g)

Light yellow powder; m.p. 168-170 ºC; IR (KBr)ν_max/cm^-13513, 3089, 2955, 2852, 1739, 1567, 1346, 1263, 1088; ¹H NMR (400.1 MHz, CDCl₃) δ 3.58 (m, 1H, OH), 3.75 and 3.80 (2s 6H, 2OCH₃), 5.98 (s, 1H, CH benzylic), 6.76 (s, 1H, CH heterocylic), 7.00-7.03 (m, 2H, 2Ar–H), 7.62 (d, 2H, J 8.4 Hz, 2Ar–H), 7.72 (dd, 1H, J 8.0, 2.0 Hz, Ar–H), 8.21 (d, 2H, J8.8 Hz, 2Ar–H); ¹³C NMR (100.6 MHz, CDCl₃) δ 53.1, 53.4, 68.9, 105.2, 110.0, 113.9, 114.5 (q, J 5.5 Hz, CH), 121.3 (q, J 275.6 Hz, CF₃), 123.8, 126.9, 127.2, 132.3, 141.1 (q, J 33.4 Hz, C), 142.9, 147.0, 147.7, 155.7, 158.5, 158.7, 161.1, 165.5; ¹⁹F NMR (376.5 MHz, CDCl₃) δ –64.77; MS (EI, 70 eV) (%) 523 (M⁺, 3), 432 (22), 341 (89), 241 (39), 202 (74), 173 (12), 150 (100), 104 (21), 59 (16); anal. calcd. for C₂₃H₁₆F₃NO₁₀ (523.38): C, 52.78; H, 3.08; N, 2.68%; found: C, 52.84; H, 3.04; N, 2.61%.

Analytical data for di-tert-butyl (2E)-2-[hydroxy(4-nitrophenyl) methyl]-3-{(2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)oxy} but-2-enedioate (4h)

Light yellow powder; m.p. 143-145 ºC; IR (KBr) ν_max/cm^-13488, 2980, 2856, 1748, 1728, 1567, 1346, 1266, 1085; ¹H NMR (400.1 MHz, CDCl₃) δ 1.31 and 1.36 (2s, 18H, 2CMe₃), 3.78 (d, 1H, J 9.2 Hz, OH), 5.98 (d, 1H, J 8.4 Hz, CH benzylic), 6.76 (s, 1H, CH heterocylic), 7.04 (d, 1H, J 2.4 Hz, Ar–H), 7.07 (dd, 1H, J 6.6, 2.4 Hz, Ar–H), 7.63 (d, 2H, J 8.4 Hz, 2Ar–H), 7.72 (dd, 1H, J 7.2, 1.6 Hz, Ar–H), 8.24 (d, 2H, J 8.2 Hz, 2Ar–H); ¹³C NMR (100.6 MHz, CDCl₃) δ 27.6, 27.7, 68.8, 84.3, 84.4, 105.7, 109.7, 114.3, 114.5 (q, J 5.6 Hz, CH), 120.3 (q, J217.5 Hz, CF₃), 123.6, 126.8, 126.9 (q, J 2.9 Hz, C), 130.6, 141.2 (q, J 31.2 Hz, C), 144.6, 147.5, 147.8, 155.7, 158.5, 159.2, 159.6, 164.6; MS (EI, 70 eV) (%) 607 (M⁺, 2), 495 (29), 432 (8), 403 (4), 345 (13), 316 (9), 230 (96), 202 (28), 175 (8), 151 (39), 105 (5), 57 (100); anal. calcd. for C₂₉H₂₈F₃NO₁₀ (607.54): C, 57.33; H, 4.65; N, 2.31%; found: C, 57.29; H, 4.72; N, 2.26%.

Analytical data for dimethyl (2E)-2-[hydroxy(2-nitrophenyl) methyl]-3-{(2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)oxy} but-2-enedioate (4i)

Light yellow powder; m.p. 142-144 ºC; IR (KBr) ν_max/cm^-13448, 3098, 2975, 2855, 1737, 1612, 1529, 1349, 1265, 1083; ¹H NMR (400.1 MHz, CDCl₃) δ 3.1 (s, 1H, OH), 3.71 and 3.78 (2s, 6H, 2OCH₃), 6.46 (s, 1H, CH benzylic), 6.72 (s, 1H, CH heterocylic), 6.85 (d, 1H, J 2.8 Hz, Ar–H), 6.92 (dd, 1H, J8.8, 2.4 Hz, Ar–H), 7.46 (td, 1H, J 7.8, 1.2 Hz, Ar–H), 7.64-7.70 (m, 2H, 2Ar–H), 7.94 (dd, 1H, J 8.4, 1.2 Hz, Ar–H), 8.00 (d, 1H, J 6.8 Hz, Ar–H); ¹³C NMR (100.6 MHz, CDCl₃) δ 52.9, 53.2, 66.2, 104.7, 109.5, 113.8, 114.1 (q, J 5.3 Hz, CH), 119.1, 121.4 (q, J 280.7 Hz, CF₃), 124.6, 126.8, 129.2, 129.3, 133.7, 134.9, 135.1, 141.2 (q, J 34.4 Hz, C), 147.7, 155.6, 158.7, 159.0, 161.1, 165.5; MS (EI, 70 eV) (%) 523 (M⁺, 1), 492 (3), 446 (24), 418 (23), 402 (60), 371 (11), 331 (21), 241 (100), 202 (41), 173 (23), 157 (52), 59 (28); anal. calcd. for C₂₃H₁₆F₃NO₁₀ (523.38): C, 52.78; H, 3.08; N, 2.68%; found: C, 52.82; H, 3.05; N, 2.70%.

Analytical data for dimethyl (2E)-2-[(4-cyanophenyl) (hydroxy)methyl]-3-{(2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)oxy}but-2-enedioate (4j)

Light yellow powder; m.p. 142-144 ºC; IR (KBr) ν_max/cm^-13398, 3081, 2960, 2853, 2238, 1728, 1613, 1262, 1062; ¹H NMR (400.1 MHz, CDCl₃) δ 3.1 (s, 1H, OH), 3.74 and 3.80 (2s, 6H, 2OCH₃), 5.92 (s, 1H, CH benzylic), 6.75 (s, 1H, CH heterocylic), 6.99-7.01 (m, 2H, 2Ar–H), 7.56 (d, 2H, J 8.4 Hz, 2Ar–H), 7.65 (d, 2H, J 8.0 Hz, 2Ar–H), 7.71 (d, H, J 8.0 Hz, Ar–H); ¹³C NMR (100.6 MHz, CDCl₃) δ 53.1, 53.3, 69.0, 105.1, 112.1, 113.9, 114.5 (q, J 5.7 Hz, CH), 118.5, 121.3 (q, J 275.5 Hz, CF₃), 126.7, 127.1 (q, J 2.1 Hz, C), 129.1 (q, J 5.1 Hz, C), 132.4, 133.0, 141.1 (q, J 32.9 Hz, C), 142.5, 145.2, 155.7, 158.5, 158.8, 161.4, 165.5; ¹⁹F NMR (376.5 MHz, CDCl₃) δ –64.76; MS (EI, 70 eV) (%) 503 (M⁺, 3), 471 (4), 439 (5), 412 (29), 373 (37), 341 (100), 313 (11), 241 (41), 202 (20), 182 (18), 157 (15), 130 (69), 102 (15), 59 (6); anal. calcd. for C₂₄H₁₆F₃NO₈ (503.39): C, 57.27; H, 3.20; N, 2.78%; found: C, 57.31; H, 3.23; N, 2.69%.

Analytical data for dimethyl 2-[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]but-2-enedioate (5)

White powder; m.p. 110-112 ºC; IR (KBr) ν_max/cm^-1 3082, 2956, 2852, 1725, 1610, 1265, 1093; (Z-isomer, 60%) ¹H NMR (400.1 MHz, CDCl₃) δ 2.42 (d, 3H, J 1.2 Hz, CH₃), 3.74 and 3.81 (2s, 6H, 2OCH₃), 6.21 (q, 1H, J 1.2 Hz, CH heterocylic), 6.77 (s, 1H, CH vinylic), 6.98 (dd, 1H, J 8.8, 2.4 Hz, Ar–H), 7.11 (d, 1H, J 2.1 Hz, Ar–H), 7.58 (d, 1H, J8.8 Hz, Ar–H); ¹³C NMR (100.6 MHz, CDCl₃) δ 18.8, 52.2, 53.4, 103.8, 112.8, 113.2, 115.8, 117.1, 126.0, 148.6, 152.2, 154.8, 159.2, 160.7, 161.9, 163.4; (E-isomer, 40%) ¹H NMR (400.1 MHz, CDCl₃) δ 2.46 (d, 3H, J 1.2 Hz, CH₃), 3.73 and 3.92 (2s, 6H, 2OCH₃), 5.43 (s, 1H, CH vinylic), 6.30 (q, 1H, J 1.2 Hz, CH heterocylic), 6.86 (d, 1H, J 2.8 Hz, Ar–H), 7.08-7.11 (m, 1H, Ar–H), 7.66 (d, 1H, J 8.8 Hz, Ar–H); ¹³C NMR (100.6 MHz, CDCl₃) δ 18.7, 52.1, 53.3, 103.0, 108.8, 114.7, 116.4, 118.0, 126.4, 151.8, 154.6, 157.9, 155.5, 160.2, 162.6, 165.2; MS (EI, 70 eV) (%) 318 (M⁺, 63), 287 (25), 259 (100), 231 (17), 202 (8), 174 (7), 147 (16); anal. calcd. for C₁₆H₁₄O₇ (318.28): C, 60.38; H, 4.43; O, 35.19%; found: C, 60.31; H, 4.41; O, 35.24%.

Conclusions

In summary, we have reported a simple and efficient procedure for the synthesis of novel coumarin derivatives via a three-component reaction of 7-hydroxy-4-alkyl coumarins, dialkyl acetylenedicarboxylates and aromatic aldehydes. Scope and limitations of the reaction were studied. The simplicity of the present procedure and the mild reaction conditions make it an interesting alternative to other existing approaches.

Acknowledgments

We are thankful to the Research Council of Mazandaran University for the support of this work.

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• Supplementary data are available free of charge at http://jbcs.sbq.org.br as PDF file.

Data availability

https://minio.scielo.br/documentstore/1678-4790/Md8vn3mGj9FGwhKVs9gMyXs/01098b81dcdd97ae0a28e88e6aba4fe5768e12c6.pdf

Publication Dates

• Publication in this collection
  Feb 2015

History

• Received
  02 Sept 2014
• Accepted
  31 Oct 2014