Isoquinoline-catalyzed reaction between 4-hydroxycoumarin or 4-hydroxy-6-methylpyran-1-one and dialkyl acetylene dicarboxylates: synthesis of coumarin and pyranopyrane derivatives

ARTICLE

Isoquinoline-catalyzed reaction between 4-hydroxycoumarin or 4-hydroxy-6-methylpyran-1-one and dialkyl acetylene dicarboxylates: synthesis of coumarin and pyranopyrane derivatives

Mohammad Anary-AbbasinejadI, ^*; Hossein Anaraki-Ardakani^I; Mohammad Hossein Mosslemin^I; Hamid Reza Khavasi^II

^IDepartment of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran

^IIDepartment of Chemistry, Shahid Beheshti University, PO Box 1983963113, Tehran, Iran

ABSTRACT

In this work we report the reaction between dialkyl acetylenedicarboxylates and enolic systems such as 5,5-dimethyl-1,3-cyclohexanedione, 1,3-cyclohexanedione, 4-hydroxycoumarin or 4-hydroxy-6-methylpyran-1-one in the presence of isoquinoline, which leads to new coumarin and pyranopyran derivatives.

Keywords: acetylenedicarboxylic esters, isoquinoline, pyranopyran derivatives, coumarin derivatives

RESUMO

Neste trabalho, relatamos a reação entre dialquil acetilenodicarboxilatos e sistemas enólicos tais como 5,5-dimetil-1,3-ciclohexanodiona, 1,3-ciclohexanodiona, 4-hidroxicumarina ou 4-hidróxi-6-metilpiran-1-ona na presença de isoquinolina, a qual leva a novos derivados de cumarina e piranopirano.

Introduction

Coumarin is the structural motif of many natural and synthetic compounds that endows them with a wide range of biological activities. Given the development of coumarins as photosensitizers,¹ anti-HIV agents,² antibiotics,³ rodenticides, and oral anticoagulants,⁴ there is continuing interest in the synthesis of these materials.

The rich and fascinating chemistry stems from the addition of nucleophiles to activated acetylene compounds has evoked considerable interest. N-Heterocycles are known to form zwitterions with activated acetylene compounds such as dimethyl acetylenedicarboxylate.^5-11 These zwitterions intermediate can be trapped with a variety of electrophiles and proton donors, which is a novel protocol for the synthesis of heterocyclic compounds.^5-13 Trapping of the zwitterion formed by the addition of isoquinoline to dimethyl acetylenedicarboxylate (DMAD) with electrophiles such as isocyanates,¹⁴N-tosylimines,¹⁵ quinines¹⁶ and electrophilic styrenes,¹⁷ has been recently used for the synthesis of different isoquinoline-fuzed heterocyclic systems. Reaction of electron-deficient acetylene esters with isoquinoline or quinoline has been also studied in the presence of organic acidic compounds. Reaction of quinoline-DMAD zwitterion with C-H acidic compound indan-1, 3-dione was reported to afford pyrroloquinoline derivatives.¹⁸ Isoquinoline-DMAD zwitterion was also reported to react with N-H acidic compounds such as pyrrole, indole¹⁹ and amides²⁰ to afford substituted dihydroisoquinoline derivatives. In view of our interest in multicomponent reactions of nucleophiles with activated acetylenes and organic acidic compounds,^21-23 we wish to report herein the results of our studies on the reaction of isoquinoline with acetylenedicarboxylic esters in the presence of O-H acidic compounds such as 5,5-dimethyl-1,3-cyclohexanedione (Dimedone), 1,3-cyclohexanedione, 4-hydroxycoumarin or 4-hydroxy-6-methylpyran-1-one.

Results and Discussion

In an initial experiment, the reaction of diethyl acetylenedicarboxylate (DEAD, 1) with dimedone (2) in the presence of isoquinoline (3) in dichloromethane afforded ethyl 5,6,7,8-tetrahydro-7,7-dimethyl-2,5-dioxo-2H-chromene-4-carboxylate (4a) in 95% yield (Scheme 1). The product was characterized on the basis of spectroscopic data. In the ¹H NMR spectrum the two methylene groups was observed at δ 2.41 and 2.72 ppm as two single signals. The resonance signals due to the two ethoxycarbonyl groups appeared as a triplet at δ 1.34 (J 7.2 Hz) and a quartet at δ 4.38 (J 7.2 Hz), supporting the IR absorption at 1726 cm^-1. A singlet was observed at δ 1.33 for the two methyl groups. The olefinic proton appeared at δ 6.14 ppm as a singlet. In the ¹³C NMR spectrum twelve distinct signals were observed, which is consistent with the proposed structure. The structure and regiochemistry of compound 4a was unambiguously established by single crystal X-ray analysis (Figure 1). The distinction between γ- and δ-lactonization products 3 and 4 was based on the X-ray crystallographic data. As shown in Scheme 1, the reaction was found to be applicable to DMAD. The spectral data for compound 4b were very similar to compound 4a, with exceptions of the signals due to the alkoxycarbonyl groups.

A reasonable mechanism for the formation of compound 4a is illustrated in Scheme 2. The zwitterion, formed from isoquinoline and DEAD (2) was protonated with dimedone to afford the cation 6 and the enolate ion 7. The anion 7 then underwent Michael addition to cation 6 to furnish the zwitterion 8, which was transformed into another zwitterion by an intramolecular proton transfer. Zwitterion intermediate 9 underwent lactonization to produce cation 10 and ethoxide anion. Finally, ethoxide anion absorbed a proton from the cation 10 and promoted the elimination of isoquinoline to furnish the product 4a.

Under similar conditions, the reaction of isoquinoline with DMAD and 4-hydroxycoumarin (11) led to methyl 2,5-dihydro-2,5-dioxopyrano[3,2-c]chromene-4-carboxylate 12a in 90% yield (Scheme 3). In the ¹H NMR spectrum of compound 12a methoxy group was observed at δ 4.02 ppm as a single signal. A singlet was observed at δ 6.41 for the olefinic proton. The aromatic protons appeared at δ 6.27-8.12 ppm. In the ¹³C NMR spectrum fourteen distinct signals were observed, which is consistent with the proposed structure.

As shown in Scheme 3, similar product 12b was obtained when DEAD was used as the activated acetylene. However, treatment of ditertiobutyl acetylenedicarboxylate (DTAD, 2c) with isoquinoline and 4-hydroxycoumarin (11), and separation of the reaction mixture by column chromatography afforded di-tert-butyl 2-(4-hydroxy-2-oxo-2H-chromen-3-yl)fumarate 13 in 95% yield (Scheme 4). The ¹H NMR spectrum of compound 13 exhibited two sharp single signals at δ 1.43 and 1.52 ppm for two t-butyl groups. The olefinic proton appeared at δ 6.91 ppm as a singlet. A broad singlet was observed for O-H proton (removed by addition of D₂O) at δ 10.35 ppm. Aromatic protons were observed at δ 7.28-8.00 ppm. ¹³C NMR spectrum showed sixteen resonances in agreement with the proposed structure.

The reaction of isoquinoline-DMAD zwitterion was also carried out towards 4-hydroxy-6-methylpyran-1-one (14) and methyl 2, 5-dihydro-7-methyl-2, 5-dioxopyrano [4, 3-b] pyran-4-carboxylate 15 was obtained in 90% yield (Scheme 5). The ¹H NMR spectrum of compound 15 exhibited four sharp single signals at δ 2.38 (3 H), 3.97 (3 H), 6.24 (1 H) and 6.33 (1 H) for two methyl and two methine protons. ¹³C NMR spectrum showed ten distinct resonances in agreement with the proposed structure.

Conclusions

From the above results, we conclude that treatment of enolic systems such as dimedone, 4-hydroxycoumarin or 4-hydroxy-6-methylpyran-1-one with acetylene-dicarboxylates and isoquinoline can lead to the formation of some fused heterocycles. The whole reaction can be considered as an addition reaction between acetylene derivative and enolic system, followed by a δ-lactonization one, catalized by isoquinoline. The presented method has the advantage of being performed under neutral conditions and requires no activation or modification of the reagents.

Experimental

Melting points were determined with an electrothermal 9100 apparatus. Elemental analyses were performed using a Heraeus CHN-O-Rapid analyzer. Mass spectra were recorded on a Finnigan- MAT (San Jose, CA, USA) 8430 mass spectrometer operating at 70 eV. IR spectra were recorded on a Shimadzu (Tokyo, Japan) IR-470 spectrometer. ¹H and ¹³C NMR spectra were recorded on BRUKER DRX-300 AVANCE spectrometer at 300.1 and 75.46 MHz, respectively. ¹H and ¹³C NMR spectra were obtained on solution in CDCl₃ using TMS as internal standard. The chemicals used in this work were purchased from Fluka (Buchs, Switzerland) and were used without further purification.

General procedure

To a magnetically stirred solution of the enolizable compound (1 mmol) and isoquinoline (1 mmol) in 10 mL acetone was added dropwise a mixture of acetylenedicarboxylates (1 mmol) in 5 mL acetone at room temperature. The reaction mixture was then stirred for 24 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using hexane-ethyl acetate as eluent to afford the pure title compounds.

Ethyl 5,6,7,8-tetrahydro-7,7-dimethyl-2,5-dioxo-2H-chromene-4-carboxylate (4a)

Colorless crystals; yield 0.25 g (95%), mp 96-98 °C; IR(KBr) ν_max/cm^-1: 1760, 1733 (C=O). MS (m/z, %): 264 (M⁺, 8). ¹H NMR (300.1 MHz, CDCl₃): δ 1.13 (6 H, s, 2 CH₃), 1.34 (3 H, t, ³J_HH 7.2 Hz_, OCH₂CH₃), 2.41, 2.72 (4H, 2s, 2CH₂), 4.38 (2H, q, ³J_HH 7.2 Hz, OCH₂CH_3,), 6.14 (1H, s, CH) ppm. ¹³C NMR (75.46 MHz, CDCl₃): δ 14.29 (OCH₂CH₃), 28.65 (2Me), 32.95 (C (Me) ₂), 42.54, 51.09, (2CH₂) 62.99 (OCH₂CH₃), 111.86 (CH), 112.19(O-C=C), 146.47(C-CO₂Et), 159.56(O-C=C), 165.77, 174.38, 192.74 (3C=O) ppm. Anal.Calc. for C₁₄H₁₆O₅: C, 63.63; H, 6.10%. Found: C, 63.81; H, 5.9%.

Crystal data for 4a

Formula (C₁₄ H₁₆ O₅): Fw = 264.27, trigonal, space group R-3, crystal dimensions 0.50 × 0.49 × 0.45 mm, a = 22.5641(18) Å , b = 22.5641(18) Å , c = 13.2610(13) Å, α = 90 deg, β = 90 deg, γ = 120 deg. V = 5847.1(9) Å ³, Z = 18, D_calc. = 1.351 mg m^-3, 1.86^°< θ < 29.12^°, F(000) = 2520; section of the reciprocal lattice: -19 < h < 30, -30 < k < 26, -14 < l < 18; of the 6231 reflections that were collected, 3384 were unique with I > 2Σ(I); absorption coefficient 0.103 mm^-1. R1 = 0.0398 for I > 2Σ(I) and wR2 = 0.0993; largest peak (0.380 e Å^-3) and hole (-0.185 e Å^-3).

Crystal data analyses: Stoe IPDSII two-circle diffractometer, Mo_Ka radiation (λ = 0.71073 Å), T = 120(2) K, graphite monochromator; numerical absorption correction. Structure solution by direct methods using SHELXS and refinement by full-matrix least-squares on F² using SHELXL of the X-STEP32 suite of programs,²⁴ all non-hydrogen atoms were refined anisotropically.

The crystallographic data of 4a have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC-706464. Copies of the data can be obtained free of charge (http://www.ccdc.cam.ac.uk/data_reques/cif, e-mail: [e-mail], or fax: [phone]).

Methyl 5,6,7,8-tetrahydro-7,7-dimethyl-2,5-dioxo-2H-chromene-4-carboxylate (4b)

Colorless crystals; yield 0.25 g (95%), mp 96-98 °C; IR(KBr) ν_max/cm^-1: 1741, 1679(C=O). MS (m/z, %): 250 (M⁺, 10). ¹H NMR (300.1 MHz, CDCl₃): δ 1.19 (6 H, s, 2CH₃), 2.46, 2.86 (4H,2s,2CH₂), 3.85 (3H,s,OCH₃), 6.25 (1H,s,CH) ppm. ¹³C NMR (75.46 MHz, CDCl₃): δ 28.07 (2Me), 32.40 (C(Me)₂), 41.87, 50.39, (2CH₂) 53.05 (OCH₃), 111.24 (CH), 111.67 (O-C=C), 145.56 (C-CO₂Me), 158.99 (O-C=C), 165.76, 174.16, 192.46(3C=O) ppm. Anal.Calc. for C₁₃H₁₄O₅: C, 62.39; H, 5.64%. Found: C, 62.42; H, 5.73%.

Methyl 5,6,7,8-tetrahydro-2,5-dioxo-2H-chromene-4-carboxylate (4c)

Colorless oil; yield 0.19 g (90%). IR(KBr) ν_max/cm^-1: 1739, 1672 (C=O). MS (m/z, %): 222 (M⁺, 8). ¹H NMR (300.1 MHz, CDCl₃): δ 2.21 (2H, m, CH₂), 2.61 (2H,t, CH₂, ³J_HH 6.3 Hz), 2.92 (2H, t, CH₂, ³J_HH 6.3 Hz), 3.97 (3H, s, OCH₃), 6.23 (1H, s, CH) ppm. ¹³C NMR (75.46 MHz, CDCl₃): δ 19.87, 28.55 and 36.53 (3CH₂), 53.24 (OCH₃), 112.16 (CH), 112.45 (O-C=C), 145.92(C-CO₂Me), 158.78 (O-C=C), 165.9, 175.55, 192.42 (3C=O) ppm. Anal.Calc. for C₁₁H₁₀O₅: C, 59.46; H, 4.54%. Found: C, 59.52; H, 4.41%.

Ethyl 5,6,7,8-tetrahydro-2,5-dioxo-2H-chromene-4-carboxylate (4d)

Colorless oil; yield 0.20 g (85%). IR(KBr) ν_max/cm^-1: 1760, 1686 (C=O), MS (m/z, %): 236 (M⁺, 15). ¹H NMR (300.1 MHz, CDCl₃): δ 1.37 (3H, t, ³J_HH 7.3 Hz, OCH₂CH₃), 2.18 (2H, m, CH₂), 2.59 (2H, t, CH₂, ³J_HH 6.3 Hz), 2.89 (2H, t, CH₂, ³J_HH 6.3 Hz), 4.40 (2H,q, ³J_HH 7.3 Hz, OCH₂CH₃), 6.17 (1H, s, CH) ppm.

¹³C NMR (75.46 MHz, CDCl₃): δ 13.86 (OCH₂CH₃), 19.87, 28.54 and 36.52 (3CH₂), 62.55 (OCH₂CH₃), 111.91 (CH), 112.43(O-C=C), 146.32 (C-CO₂Et), 158.87 (O-C=C), 165.41, 175.46, 192.43 (3C=O) ppm. Anal.Calc. for C₁₂H₁₂O₅: C, 61.01; H, 5.12%. Found: C, 61.18; H, 5.28%.

Methyl 2,5-dihydro-2,5-dioxopyrano[3,2-c]chromene-4-carboxylate (12a)

Colorless crystals; yield 0.24 g (90%), mp 191 °C dec.; IR(KBr) ν_max/cm^-1: 1758, 1715(C=O). MS (m/z, %): 272 (M⁺, 6). ¹H NMR (300.1 MHz, CDCl₃): δ 4.02 (3H, s, OCH₃), 6.41(1H, s, CH), 7.42-8.12 (4H, m, arom) ppm. ¹³C NMR (75.46 MHz, CDCl₃): δ 54.04(OCH₃), 101.22(CH), 113.16, 113.58, 117.83, 124.31, 125.83, 135.67, 147.02, 154.01, 157.35 (c, arom), 157.51, 163.13, 164.99 (3C=O) ppm. Anal.Calc. for C₁₄H₈O₆: C, 61.77; H, 2.96%. Found: C, 61.89; H, 2.81%.

Ethyl 2,5-dihydro-2,5-dioxopyrano[3,2-c]chromene-4-carboxylate (12b)

Colorless crystals; yield 0.25 g (90%), mp 180 °C dec.; IR(KBr) ν_max/cm^-1: 1739, 1726(C=O). MS (m/z, %): 286 (M⁺, 5). ¹H NMR (300.1 MHz, CDCl₃): δ 1.42 (3H, t, ³J_HH 7.2 Hz_, OCH₂CH₃), 4.49 (2H, q, ³J_HH 7.2 Hz, OCH₂CH_3,), 6.40(1H, s, CH), 7.42-8.12 (4H, m, arom) ppm. ¹³C NMR (75.46 MHz, CDCl₃): δ 13.69 (OCH₂CH₃), 62.53 (OCH₂CH₃), 102.11(CH), 113.41, 113.63, 117.51, 124.04, 125.70, 135.43, 147.27, 154.04, 157.22 (c, arom), 157.60, 162.74, 164.39 (3C=O) ppm. Anal. Calc. for C₁₅H₁₀O₆: C, 62.94; H, 3.52%. Found: C, 62.83; H, 3.61%.

Ditertbutyl 2-(4-hydroxy-2-oxo-2H-chromen-3-yl)fumarate (13)

Colorless crystals; yield 0.36 g (95%), mp 72-73 °C; IR(KBr) ν_max/cm^-1: 1712, 1660(C=O). MS (m/z, %): 388 (M⁺, 7). ¹H NMR (300.1 MHz, CDCl₃): δ 1.43, 1.52 (18H, 2s, 2t-Bu), 6.91(1H, s, CH), 7.28-8.00 (4H arom), 10.35(1H, broad singlet,OH) ppm. ¹³C NMR (75.46 MHz, CDCl₃): δ 29.72 (2C (CH₃)₃), 83.61, 84.33 (2C (CH₃)₃), 101.96, 116.40, 116.43, 124.08, 124.48, 132.08, 132.77, 136.37, 152.93, 162.05 (aromatic and olefinic carbons), 162.15, 166.37, 167.41 (3C=O) ppm. Anal.Calc. for C₂₁H₂₄O₇: C, 64.94; H, 6.23%. Found: C, 65.09; H, 6.17%.

Methyl 2, 5-dihydro-7-methyl-2, 5-dioxopyrano [4, 3-b] pyran-4-carboxylate (15)

Colorless crystals; yield 0.21 g (90%), mp 96-98 °C; IR(KBr) ν_max/cm^-1: 1756, 1721(C=O). MS (m/z, %): 236 (M⁺, 7). ¹H NMR (300.1 MHz, CDCl₃): δ 2.38 (3H, s, CH₃), 3.97(3H, s, OCH₃), 6.24, 6.33 (2H, 2s, 2CH) ppm. ¹³C NMR (75.46 MHz, CDCl₃): δ 19.88(CH₃), 52.87(OCH₃), 99.48, 111.56, 146.64, 157.92, 157.99 (olefinic carbons) 164.94, 167.83, 167.88 (3C=O) ppm. Anal.Calc. for C₁₁H₈O₆: C, 55.94; H, 3.41%. Found: C, 55.81; H, 3.53%.

Supplementary Information

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

Received: March 17, 2009

Web Release Date: November 26, 2009

Supplementary Information

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Publication Dates

• Publication in this collection
  16 Mar 2010
• Date of issue
  2010

History

• Accepted
  26 Nov 2009
• Received
  17 Mar 2009