Synthesis of functionalized 1,2-dihydroisoquinolines via one-pot reactions of isoquinoline,alkyl propiolate,and thiazolidin-2,4-dione

Abstract

The reactive zwitterionic intermediates, generated from addition of isoquinoline to alkyl propiolates, react with thiazolidin-2,4-dione to afford 3-[1-(2,4-dioxothiazolidin-3-yl)isoquinolin-2(1H)-yl]acrylates in good yields. Using (Z)-5-arylidenethiazolidine-2,4-diones as the NH-acidic component leads to 3-{1-[(Z)-5-benzylidene-2,4-dioxothiazolidin-3-yl] isoquinolin-2(1H)-yl}acrylates in moderate to good yields in the absence of any catalysts under mild reaction conditions. The reaction between quinoline, ethyl propiolate, and thiazolidin-2,4-dione leads to ethyl 3-[2-(2,4-dioxothiazolidin-3-yl) quinolin-1(2H)-yl]acrylate.

Introduction

The prominence of 1,2-dihydroisoquinoline as a basic scaffold in many natural products and biologically active molecules^1–3 has promoted considerable efforts towards their synthesis.^4–8 Significant efforts continue to be given to the development of novel 1,2-dihydroisoquinoline-based structures and new methods for their construction. For instance, recently it was reported that 1,2-dihydroisoquinoline skeletons could be obtained through the direct addition of various carbon pronucleophiles to ortho-alkynylaryl aldimines catalyzed by a Lewis acid.^4,5 This scaffold could also be generated from isoquinolines via a multicomponent reaction.^6–12

The rich chemistry that stems from the addition of nucleophiles to activated acetylenic compounds has evoked considerable interest. Aromatic N-heterocycles are known to form zwitterions with activated acetylenes such as dimethyl acetylenedicarboxylate (DMAD). ¹³ It has been shown that these types of zwitterions can be trapped by a variety of organic acids.^14–17 In continuation of current interest in the development of new routes to heterocyclic and carbocyclic systems,^18–26 we became interested in developing novel and efficient methods to construct the new 1,2-dihydroisoquinoline-based structures, with a hope of finding active hits for our particular biological assays. Herein, we report a synthesis of 1,2-dihydroisoquinolines via the three-component reaction of isoquinoline, alkyl propiolates, and CH-acids, under mild reaction conditions.

Results and discussion

The reaction of isoquinoline (1) and ethyl propiolate (2a) or ethyl phenylpropiolate (2b) and in the presence of thiazolidin-2,4-dione (3) in CH₂Cl₂ at room temperature afforded (E)-ethyl 3-[1-(2,4-dioxothiazolidin-3-yl)isoquinolin-2(1H)-yl]acrylate (4a) and (E)-ethyl 3-[1-(2,4-dioxothiazolidin-3-yl)isoquinolin-2(1H)-yl]-3-phenylacrylate (4b), respectively (Scheme 1).

Scheme 1.

The products were characterized on the basis of their elemental analyses and their IR, ¹H NMR, and ¹³C NMR spectra. The mass spectra of these compounds exhibited molecular ion peaks at the appropriate m/z values. The ¹H NMR spectra of compounds 4 exhibited an AX system for the trans-olefinic protons with ³J = 13.6 Hz. The proton decoupled ¹³C NMR spectrum of 4 showed distinct resonances in agreement with the proposed structures.

Using (Z)-5-arylidenethiazolidine-2,4-diones (5) as the NH-acidic component in this reaction afforded (2E)-ethyl 3-{1-[(Z)-5-arylidene-2,4-dioxothiazolidin-3-yl]isoquinolin 2(1H)-yl}acrylates 6 (Scheme 2). Compounds 6 were again fully characterized from their IR, ¹H NMR, and ¹³C NMR spectral data.

Scheme 2.

Mechanistically, it is conceivable that the reaction involves initial formation of a 1:1 zwitterionic intermediate 7 between isoquinoline (1) and ethyl propiolate (2a).^27–29 This intermediate is protonated by the NH-acidic thiazolidine 3 and then attacked by the conjugate base of 3 to produce 4 (Scheme 3).

Scheme 3.

To extend our knowledge of these transformations, we performed the reaction of quinoline 10, ethyl propiolate (2a), and thiazolidin-2,4-dione (3) which led to (2E)-ethyl 3-[2-(2,4-dioxothiazolidin-3-yl)quinolin-1(2H)-yl]acrylate (11) (Scheme 4). Compound 11 was again fully characterized according to its IR, ¹H NMR, and ¹³C NMR spectra.

Scheme 4.

Conclusion

In conclusion, we have developed a convenient route to functionalized [isoquinolin-2(1H)-yl]acrylates from isoquinoline and activated acetylenes in the presence of thiazolidin-2,4-dione or (Z)-5-arylidenethiazolidine-2, 4-diones. Using quinoline produced quinolin-1(2H)-yl]acrylate 11. The advantage of the present procedure is that the reaction is performed under neutral conditions by simple mixing of the starting materials. The present can be considered as a practical route for the synthesis of functionalized dihydro isoquinoline ring systems.

Experimental

All of the chemicals used in this study were purchased from Merck and were used without further purification. Melting points were measured on an Electrothermal 9100 apparatus. Elemental analyses for C, H and were performed using a HeraeusCHN-O-Rapid analyzer. UV spectra were recorded on a Shimadzu UV-160A spectrometer. ¹H and ¹³C NMR spectra (CDCl₃) were measured with a Bruker DRX-300 Avance spectrometer. IR spectra were recorded on a Shimadzu IR-460 spectrometer. Mass spectra were recorded on a Finnigan-Mat 8430 spectrometer operating at an ionization potential of 70 eV. Chromatography columns were prepared from Aldrich silica gel? (70–230 mesh).

General procedure for the preparation of compounds 4, 6 and 11

To a stirred solution of thiazolidin-2,4-dione 3 or 5 (2 mmol) and alkyl propiolate 2, (2 mmol) in CH₂Cl₂ (10 mL) was added drop wise a mixture of isoquinoline or quinoline (2 mmol) in 4 mL of CH₂Cl₂ 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 column chromatography (SiO₂; hexane/AcOEt 4:1) to afford the pure adducts.

(2E)-Ethyl 3-[1-(2,4-dioxothiazolidin-3-yl)isoquinolin-2(1H)-yl]acrylate (4a)

Yield 0.3 g (87%), yellow crystals, mp 70–72 °C. IR (KBr, CHCl₃): 1687 (C=O), 1748 (C=O) cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ = 1.30 (3H, t, ³J 7.1 Hz, Me), 4.19 (2H, q, ³J 7.1 Hz, CH₂O), 4.84 (1H, d, ²J 3.7 Hz, CH₂S), 5.40 (1H, d, ³J 13.6 Hz, CH), 5.83 (1H, d, ³J 7.5 Hz, CH), 5.95 (1H, d, ²J 3.7 Hz, CH₂S), 6.38 (1H, d, ³J 7.5 Hz, CH), 7.05 (1H, d, ³J 7.6 Hz, CH), 7.06 (1H, s, CH), 7.14 (1H, d, ³J 7.6 Hz, CH), 7.19 (1H, t, ³J 7.5 Hz, CH), 7.32 (1H, t, ³J 7.5 Hz, CH), 7.48 (1H, d, ³J 13.6 Hz, CH). ¹³C NMR (75 MHz, CDCl₃) δ = 14.9 (Me), 35.9 (CH₂S), 55.0 (CH), 60.0 (CH₂O), 92.5 (CH), 107.3 (CH), 125.4 (CH), 126.0 (CH), 126.6 (CH), 127.8 (C), 128.0 (C), 129.4 (CH), 132.2 (CH), 146.3 (CH), 168.7, 172.2, 173.7, (3C=O). MS (EI, 70 eV): m/z (%) = 344 (M+, 5), 299 (25), 271 (40), 129 (85), 128 (27), 115 (100), 99 (80), 73 (43). Anal. calcd for C₁₇H₁₆N₂O₄S: C, 59.29; H, 4.68; N, 8.13. Found: C, 59.52; H, 4.61; N, 8.18%.

(2E)-Ethyl 3-[1-(2,4-dioxothiazolidin-3-yl)isoquinolin-2(1H)-yl]-3-phenylacrylate (4b)

Yield 0.4 g (85%), yellow crystals, mp 71–73 °C. IR (KBr, CHCl₃): 1691 (C=O), 1739 (C=O) cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ = 1.05 (3H, t, ³J 7.1 Hz, Me), 3.96 (2H, q, ³J 7.1 Hz, CH₂O), 4.87 (1H, d, ²J 3.1 Hz, CH₂S), 4.65 (1H, d, ²J 3.1 Hz, CH₂S), 5.77 (1H, d, ³J 7.7 Hz, CH), 6.07 (1H, d, ³J 7.9 Hz, CH), 7.08 (1H, s, CH), 7.09 (1H, d, ³J 7.5 Hz, CH), 7.12 (1H, d, ³J 7.5 Hz, CH), 7.23 (1H, t, ³J 7.6 Hz, CH), 7.24 (1H, s, CH), 7.34 (1H, t, ³J 7.6 Hz, CH), 7.45–7.48 (5H, m, CH). ¹³C NMR (75 MHz, CDCl₃) δ = 14.5 (Me), 35.9 (CH₂S), 54.9 (CH), 60.0 (CH₂O), 94.5 (CH), 109.3 (CH), 125.4 (CH), 126.0 (CH), 126.6 (CH), 127.8 (C), 128.0 (C), 129.0 (2CH), 129.2 (2CH), 129.5 (CH), 129.8 (CH), 132.0 (CH), 134.6 (C), 157.0 (C), 167.5, 171.2, 172.7, (3C=O). MS (EI, 70 eV): m/z (%) = 420 (M⁺, 8), 375 (31), 347 (42), 175 (85), 129 (87), 128 (29), 115 (100), 73 (42). Anal. calcd for C₂₃H₂₀N₂O₄S: C, 65.70; H, 4.79; N, 6.66. Found: C, 65.94; H, 4.73; N, 6.71%.

(2E)-Ethyl 3-{1-[(Z)-5-benzylidene-2,4-dioxothiazolidin-3-yl]isoquinolin-2(1H)-yl}acrylate (6a)

Yield 0.32 g (75%), yellow crystals, mp 73–75 °C. IR (KBr, CHCl₃): 1676 (C=O), 1735 (C=O) cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ = 1.35 (3H, t, ³J 7.1 Hz, Me), 4.30 (2H, q, ³J 7.1 Hz, CH₂O), 6.12 (1H, d, ³J 9.1 Hz, CH), 6.65 (1H, d, ³J 9.1 Hz, CH), 7.06 (1H, d, ³J 14.7 Hz, CH), 7.20 (1H, s, CH), 7.45–7.55 (9H, m, CH), 7.93 (1H, d, ³J 14.7 Hz, CH), 7.96 (1H, s, CH). ¹³C NMR (75 MHz, CDCl₃) δ = 14.3 (Me), 56.3 (CH), 62.1 (CH₂O), 94.5 (CH), 108.7 (CH), 121.4 (C), 125.3 (CH), 125.9 (CH), 126.4 (CH), 127.4 (C), 128.8 (C), 129.0 (2CH), 129.1 (2CH), 129.4 (CH), 129.8 (CH), 132.0 (CH), 134.5 (C), 135.5 (CH), 146.7 (CH), 167.9, 171.3, 172.9, (3C=O). MS (EI, 70 eV): m/z (%) = 432 (M⁺, 7), 387 (30), 359 (44), 342 (35), 204 (100), 129 (86), 99 (81), 90 (24), 73 (46). Anal. calcd for C₂₄H₂₀N₂O₄S: C, 66.65; H, 4.66; N, 6.48. Found: 66.68; H, 4.63; N, 6.50%.

(E)-Ethyl 3-{1-[(Z)-5-(3-methylbenzylidene)-2,4-dioxothiazolidin-3-yl]isoquinolin-2(1H)-yl}acrylate (6b)

Yield 0.31 g (71%), yellow crystals, mp 84–86 °C. IR (KBr, CHCl₃): 1682 (C=O), 1748 (C=O) cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ = 1.33 (³H, t, ³J 7.1 Hz, Me), 2.43 (3H, s, Me), 4.31 (2H, q, ³J 7.1 Hz, CH₂O), 6.11 (1H, d, ³J 9.1 Hz, CH), 6.63 (1H, d, ³J 9.1 Hz, CH), 7.06 (1H, d, ³J 14.7 Hz, CH), 7.22 (1H, s, CH), 7.27–7.45 (8H, m, CH), 7.93 (1H, d, ³J 14.7 Hz, CH), 7.95 (1H, s, CH). (75 MHz, CDCl₃) δ = 14.4 (Me), 21.8 (Me), 57.1 (CH), 62.3 (CH₂O), 96.4 (CH), 108.9 (CH), 121.4 (C), 125.5 (CH), 125.8 (CH), 126.6 (CH), 127.5 (C), 128.7 (C), 129.0 (2CH), 129.2 (2CH), 129.8 (CH), 132.0 (CH), 134.5 (C), 135.5 (CH), 136.3 (C), 147.0 (CH), 167.5, 170.9, 171.8, (3C=O). MS (EI, 70 eV): m/z (%) = 446 (M⁺, 5), 341 (12), 268 (16), 197 (16), 170 (100), 148 (36), 129 (27), 97 (36), 57 (54), 43 (45). Anal. calcd for C₂₅H₂₂N₂O₄S: C, 67.25; H, 4.97; N, 6.27. Found: C, 67.00; H, 4.93; N, 6.31%.

(E)-Ethyl 3-{1-[(Z)-5-(4-methylbenzylidene)-2,4-dioxothiazolidin-3-yl]isoquinolin-2(1H)-yl}acrylate (6c)

Yield 0.36 g (85%), yellow crystals, mp 85–87 °C. IR (KBr, CHCl₃): 1673 (C=O), 1738 (C=O) cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ = 1.38 (3H, t, ³J 7.1 Hz, Me), 2.43 (3H, s, Me), 4.27 (2H, q, ³J 7.1 Hz, CH₂O), 6.03 (1H, d, ³J 14.7 Hz, CH), 6.60 (1H, d, ³J 7.5 Hz, CH), 7.30 (1H, s, CH), 7.31 (2H, d, ³J 7.5 Hz, CH), 7.41 (2H, d, ³J 7.5 Hz, CH), 7.55 (1H, t, ³J 7.9 Hz, CH), 7.70 (1H, t, ³J 7.5 Hz, CH), 7.85 (1H, s, CH), 8.18–8.21 (2H, m, CH), 8.45 (1H, d, ³J 7.5 Hz, CH), 8.74 (1H, d, ³J 14.7 Hz, CH). ¹³C NMR (75 MHz, CDCl₃) δ = 14.3 (Me), 22.0 (Me), 58.3 (CH), 62.2 (CH2O), 96.5 (CH), 108.8 (CH), 121.4 (C), 125.5 (CH), 125.8 (CH), 126.7 (CH), 127.6 (C), 128.9 (C), 129.0 (2CH), 129.2 (2CH), 129.8 (CH), 132.7 (CH), 134.7 (C), 135.6 (CH), 136.5 (C), 146.5 (CH), 168.9, 172.5, 173.3, (3C=O). MS (EI, 70 eV): m/z (%) = 446 (M⁺, 5), 341 (12), 268 (16), 197 (16), 170 (100), 148 (36), 129 (27), 97 (36), 57 (54), 43 (45). Anal. calcd for C₂₅H₂₂N₂O₄S: C, 67.25; H, 4.97; N, 6.27. Found: C, 67.03; H, 4.93; N, 6.31%.

(2E)-Ethyl 3-{1-[(Z)-5-(4-nitrobenzylidene)-2,4-dioxothiazolidin-3-yl]isoquinolin-2(1H)-yl}acrylate (6d)

Yield 0.32 g (72%), yellow crystals, mp 96–98 °C. IR (KBr, CHCl₃): 1671 (C=O), 1737 (C=O) cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ = 1.38 (3H, t, ³J 7.1 Hz, Me), 4.43 (2H, q, ³J 7.1 Hz, CH₂O), 6.96 (1H, d, ³J 7.2 Hz, CH), 7.05 (1H, d, ³J 14.7 Hz, CH), 7.31 (1H, s, CH), 7.51 (1H, t, ³J 7.5 Hz, CH), 7.57–7.70 (3H, m, CH), 7.94 (1H, d, ³J 14.7 Hz, CH), 7.74 (1H, s, CH), 8.05 (2H, d, ³J 8.3 Hz, 2CH), 8.37 (2H, d, ³J 8.8 Hz, 2CH), 8.68 (1H, d, ³J 7.2 Hz, CH). ¹³C NMR (75 MHz, CDCl₃) δ = 14.3 (Me), 58.3 (CH), 62.2 (CH₂O), 96.5 (CH), 108.8 (CH), 121.4 (C), 125.5 (CH), 125.8 (CH), 126.8 (CH), 127.7 (C), 128.9 (C), 129.0 (2CH), 129.5 (2CH), 129.9 (CH), 132.7 (CH), 134.7 (C), 139.7 (CH), 144.5 (C), 146.5 (CH), 168.9, 172.5, 173.3, (3C=O). MS (EI, 70 eV): m/z (%) = 477 (M⁺, 6), 432 (28), 404 (28), 342 (35), 249 (100), 135 (29), 129 (83), 99 (89), 73 (39). Anal. calcd for C₂₄H₁₉N₃O₆S: C, 60.37; H, 4.01; N, 8.80. Found: C, 60.31; H, 4.09; N 8.75%.

(2E)-Ethyl 3-{1-[(Z)-2,4-dioxo-5-((thiophen-2-yl)methylene)thiazolidin-3-yl]isoquinolin-2(1H) yl}acrylate (6e)

Yield 0.28 g (70%), yellow crystals, mp 73–75 °C. IR (KBr, CHCl₃): 1689 (C=O), 1735 (C=O) cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ = 1.36 (3H, t, ³J 7.1 Hz, Me), 4.29 (2H, q, ³J 7.1 Hz, CH₂O), 6.12 (1H, d, ³J 9.1 Hz, CH), 6.63 (1H, d, ³J 9.1 Hz, CH), 7.05 (1H, d, ³J 14.7 Hz, CH), 7.29 (1H, s, CH), 7.45–7.55 (7H, m, CH), 7.92 (1H, d, ³J 14.7 Hz, CH), 7.96 (1H, s, CH). ¹³C NMR (75 MHz, CDCl₃) δ = 14.3 (Me), 56.3 (CH), 62.1 (CH₂O), 94.5 (CH), 108.7 (CH), 121.4 (C), 125.3 (CH), 125.9 (CH), 126.4 (CH), 127.4 (C), 128.8 (C), 129.0 (CH), 129.1 (CH), 129.4 (CH), 130.5 (CH), 132.9 (CH), 134.3 (CH), 137.5 (C), 148.5 (CH), 167.9, 171.3, 172.9, (3C=O). MS (EI, 70 eV): m/z (%) = 438 (M⁺, 8), 393 (29), 365 (42), 342 (34), 209 (100), 129 (89), 99 (88), 96 (31), 73 (38). Anal. calcd for C₂₂H₁₈N₂O₄S₂: 60.26; H, 4.14; N, 6.39. Found: C, 60.33; H, 4.07; N, 6.41%.

(2E)-Ethyl 3-[2-(2,4-dioxothiazolidin-3-yl)quinolin-1(2H)-yl]acrylate (11)

Yield 0.22 g (65%), yellow crystals, mp 86–88 °C. IR (KBr, CHCl₃): 1685 (C=O), 1736 (C=O) cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ = 1.33 (3H, t, ³J 7.1 Hz, Me), 4.22 (2H, q, ³J 7.1 Hz, CH₂O), 4.61 (1H, d, ²J 3.7 Hz, CH₂S), 5.30 (1H, d, ³J 13.6 Hz, CH), 5.50 (1H, d, ²J 3.7 Hz, CH₂S), 5.99 (1H, dd, ³J 9.9 Hz, ³J 4.3 Hz, CH), 6.80 (1H, d, ³J 4.3 Hz, CH), 6.89 (1H, d, ³J 9.8 Hz, CH), 7.05 (1H, d, ³J 7.6 Hz, CH), 7.14 (1H, d, ³J 7.6 Hz, CH), 7.19 (1H, t, ³J 7.5 Hz, CH), 7.32 (1H, t, ³J 7.5 Hz, CH), 7.48 (1H, d, ³J 13.6 Hz, CH). ¹³C NMR (75 MHz, CDCl₃) δ = 14.9 (Me), 35.9 (CH₂S), 55.0 (CH), 60.0 (CH₂O), 92.5 (CH), 107.3 (CH), 122.4 (CH), 123.0 (CH), 124.6 (CH), 129.3 (C), 129.1 (C), 130.1 (CH), 135.7 (CH), 149.3 (CH), 168.7, 172.2, 173.7, (3C=O). MS (EI, 70 eV): m/z (%) = 344 (M⁺, 5), 299 (25), 271 (40), 129 (85), 128 (27), 115 (100), 99 (80), 73 (43). Anal. calcd for C₁₇H₁₆N₂O₄S: C, 59.29; H, 4.68; N, 8.13. Found: C, 59.32; H, 4.61; N 8.05%.