New Synthesis of 2,3-Diarylacridin-9(10H)-ones and (E)-2-Phenyl-4-styrylfuro[3,2-c]quinolines

Abstract

A new synthesis of 2,3-diarylacridin-9(10H)-ones and (E)-2-phenyl-4-styrylfuro[3,2-c]quinolines is described. This was accomplished by the Heck reaction of (E)-3-iodo-2-styrylquinolin-4(1H)-ones with styrene, leading to (E,E)-2,3-distyrylquinolin-4(1H)-ones, which when heated at high temperatures, cyclise in two different ways. Electrocyclisation and further in situ oxidation leads to 2,3-diarylacridin-9(10H)-ones and tautomerisation, cyclisation by nucleophilic addition and further in situ oxidation produces (E)-2-phenyl-4-styrylfuro[3,2-c]quinolines.

(E)-2-styrylquinolin-4(1H)-ones - (E)-3-iodo-2-styryl­quinolin-4(1H)-ones - (E,E)-2,3-distyrylquinolin-4(1H)-ones - 2,3-diaryl­­acridin-9(10H)-ones - (E)-2-phenyl-4-styrylfuro[3,2-c]quinolines - Heck reaction - electrocyclisation

References

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41

Optimized Experimental Procedure for the Synthesis of ( E )-3-Iodo-2-styrylquinolin-4(1 H )-ones 2a-c
Na₂CO₃ (0.064 g, 0.61 mmol) and I₂ (0.15 g, 0.61 mmol) were added to a solution of the appropriate (E)-2-styryl-quinolin-4(1H)-one 1a-c (0.40 mmol) in anhyd THF (25 mL). The mixture was stirred, protected from the daylight (to avoid the E/Z isomerisation), at r.t. until complete consumption of the starting material (4-5 h) and then poured into an aq sat. solution of Na₂S₂O₃. The solid obtained was filtered, washed with H₂O and crystallised from EtOH. (E)-3-Iodo-2-styrylquinolin-4(1H)-ones 2a-c were obtained as yellow solids (2a, 211.7 mg, 93%; 2b, 201.7 mg, 82%; 2c, 236.2 mg, 95%).

42

Analytical Data for ( E )-3-Iodo-2-styrylquinolin-4(1 H )-one (2a) Mp 194-197 ˚C. ^¹H NMR (300.13 MHz, DMSO-d ₆): δ = 7.39 (ddd, 1 H, J = 8.0, 6.8, 1.2 Hz, H-6), 7.43 (d, 1 H, J = 16.4 Hz, H-α), 7.45-7.57 (m, 3 H, H-3′,4′,5′), 7.55 (d, 1 H, J = 16.4 Hz, H-β), 7.70-7.76 (m, 3 H, H-7, H-2′,6′), 7.80 (d, 1 H, J = 8.4 Hz, H-8), 8.11 (dd, 1 H, J = 8.0, 1.2 Hz, H-5), 11.97 (s, 1 H, NH) ppm. ^¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 87.5 (C-3), 118.3 (C-8), 120.8 (C-10), 124.0 (C-6), 125.5 (C-5), 126.4 (C-α), 127.4 (C-2′,6′), 129.2 (C-3′,5′), 129.7 (C-4′), 132.3 (C-7), 135.0 (C-1′), 137.1 (C-β), 139.4 (C-9), 147.6 (C-2), 173.4 (C-4) ppm. MS (ESI⁺): m/z (%) = 374 (100) [M + H]⁺, 396 (12) [M + Na]⁺, 769 (3) [2 M + Na]⁺. Anal. Calcd (%) for C₁₇H₁₂INO (373.19): C, 54.71; H, 3.24; N, 3.75. Found: C, 55.10; H, 3.17; N, 3.77.

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44

Optimized Experimental Procedure for the Heck Reaction of ( E )-3-Iodo-2-styrylquinolin-4(1 H )-one 2a-c with Styrene: Synthesis of ( E , E )-2,3-distyrylquinolin-4(1 H )-ones 4a-c Styrene (138.8 µL, 1.6 mmol) was added to a mixture of the appropriate (E)-3-iodo-2-styrylquinolin-4(1H)-one 2a-c (0.24 mmol), tetrakis(triphenylphosphine)palladium(0) (13.94 mg, 1.2 ¥ 10^-² mmol), and Et₃N (33.4 µl, 0.24 mmol) in MeCN (6 mL). The mixture was heated at reflux until consumption of the starting material, which was confirmed by TLC (Table  [¹] ). The mixture was then poured into H₂O, extracted with CHCl₃, and dried over anhyd Na₂SO₄. The solvent was evaporated and the residue dissolved in CH₂Cl₂ and purified by TLC using a mixture of EtOAc-light PE (3:2) as eluent. The (E,E)-2,3-distyrylquinolin-4(1H)-ones 4a-c were obtained as yellow solids in good yields (4a, 52.2 mg, 62%; 4b, 55.0 mg, 65%; 4c, 49.3 mg, 58%).

45

Analytical Data of ( E,E )-2,3-Distyrylquinolin-4(1 H )-one (4a) Mp 207-208 ˚C. ^¹H NMR (500.13 MHz, DMSO-d ₆): δ = 7.24 (t, 1 H, J = 7.6 Hz, H-4′′), 7.32-7.39 (m, 5 H, H-6, H-8, H-2′,6′, H-α′), 7.41 (t, 1 H, J = 7.5 Hz, H-4′), 7.48 (t, 2 H, J = 7.5 Hz, H-3′,5′), 7.52 (d, 1 H, J = 16.4 Hz, H-β), 7.56 (d, 2 H, J = 7.6 Hz, H-2′′,6′′), 7.67 (dt, 1 H, J = 8.0, 1.2 Hz, H-7), 7.70 (d, 1 H, J = 16.4 Hz, H-α), 7.78 (t, 2 H, J = 7.6 Hz, H-3′′,5′′), 7.85 (d, 1 H, J = 16.0 Hz, H-β′), 8.17 (dd, 1 H, J = 8.1, 1.2 Hz, H-5), 11.69 (br s, NH) ppm. ^¹³C NMR (125.77 MHz, DMSO-d ₆): δ = 115.4 (C-3), 118.6 (C-8), 121.3 (C-α), 122.4 (C-10), 123.1 (C-α′), 124.4 (C-6), 125.2 (C-5), 126.1 (C-2′′,6′′), 127.0 (C-4′′), 127.5 (C-3′′,5′′), 128.7 (C-3′,5′), 129.0 (C-2′,6′), 129.2 (C-4′), 131.0 (C-β′), 131.6 (C-7), 135.7 (C-β,1′), 136.4 (C-1′′), 138.6 (C-9), 145.5 (C-2), 175.9 (C-4). MS (ESI⁺): m/z (%) = 350 (100) [M + H]⁺. HRMS (ESI⁺): m/z calcd for [C₂₅H₂₀NO + H]⁺: 350.15394; found: 350.15345.

46

Optimized Experimental Procedure for the Synthesis of 2,3-Diarylacridin-9(10 H )-ones 5a-c and ( E )-2-phenyl-4-styrylfuro[3,2- c ]quinolines 7a-c
Iodine (1.82 mg, 7.15 ¥ 10^-³ mmol) and PTSA (1.36 mg, 7.15 ¥ 10^-² mmol) were added to a solution of the appropriate (E,E)-2,3-distyrylquinolin-4(1H)-one 4a-c (7.15 ¥ 10^-² mmol) in 1,2,4-trichlorobenzene (3 mL), and the mixture was refluxed (see Table  [²] for reaction time). After cooling the reaction mixture was purified by column chromatography using light PE as eluent to remove the 1,2,4-trichlorobenzene. Then, the mixture was removed from the column using CH₂Cl₂ as eluent and was purified by TLC using a mixture of EtOAc-light PE (3:2) as eluent. Two main compounds were isolated in each case: That with the lower R _f value corresponded to the 2,3-diarylacridin-9(10H)-ones 5a-c which were isolated as yellow compounds in moderate yields (5a, 9.4 mg, 38%; 5b, 8.7 mg, 35%; 5c, 9.9 mg, 40%); and that with higher R _f value corresponded to (E)-2-phenyl-4-styrylfuro[3,2-c]quinolines 7a-c obtained as yellow compounds also in moderate yields (7a, 10.2 mg, 41%; 7b, 10.9 mg, 44%; 7c, 13.9 mg, 56%).

47

Analytical Data of 2,3-Diphenylacridin-9(10 H )-one (5a)
Mp 283-284 ˚C. ^¹H NMR (300.13 MHz, DMSO-d ₆): δ = 7.15-7.17 (m, 2 H, H-2′,6′), 7.21-7.32 (m, 9 H, H-3′,4′,5′, H-2′′,3′′,4′′,5′′,6′′, H-7), 7.55 (s, 1 H, H-4), 7.58 (d, 1 H, J = 8.0 Hz, H-5), 7.77 (ddd, 1 H, J = 8.0, 7.0, 1.1 Hz, H-6), 8.20 (s, 1 H, H-1), 8.26 (dd, 1 H, J = 8.0, 1.1 Hz, H-8), 11.92 (s, 1 H, NH) ppm. ^¹³C NMR (125.77 MHz, DMSO-d ₆): δ = 117.5 (C-5), 118.9 (C-4), 119.6 (C-9a), 120.7 (C-7), 121.3 (C-8a), 126.1 (C-4′), 126.6 (C-8), 127.5 (C-4′′), 127.6 (C-1), 128.1 (C-3′′,5′′), 128.2 (C-3′,5′), 129.3 (C-2′,6′), 129.6 (C-2′′,6′′), 133.5 (C-2), 133.6 (C-6), 140.1 and 140.2 (C-1′ and C-1′′), 140.4 (C-4a), 141.0 (C-4b), 145.4 (C-3), 176.5 (C-9). HRMS (ESI⁺): m/z calcd for [C₂₅H₁₈NO + H]⁺: 348.1383; found: 348.1384.

48

Analytical Data of ( E )-2-Phenyl-4-styrylfuro[3,2- c ]quinoline (7a) Mp 154-156 ˚C. ^¹H NMR (300.13 MHz, DMSO-d ₆): δ = 7.41 (t, 1 H, J = 7.0 Hz, H-4′′), 7.48-7.55 (m, 1 H, H-4′), 7.53 (t, 1 H, J = 7.0 Hz, H-3′′,5′′), 7.61 (t, 2 H, J = 7.6 Hz, H-3′,5′), 7.70 (dd, 1 H, J = 7.7, 7.4 Hz, H-8), 7.78 (ddd, 1 H, J = 8.0, 7.7, 1.3 Hz, H-7), 7.89 (d, 1 H, J = 17.4 Hz, H-α), 7.91 (d, 2 H, J = 7.0 Hz, H-2′′,6′′), 8.08 (d, 1 H, J = 17.4 Hz, H-β), 8.11 (d, 2 H, J = 7.6 Hz, H-2′,6′), 8.15 (d, 1 H, J = 8.0 Hz, H-6), 8.25 (s, 1 H, H-3), 8.39 (dd, 1 H, J = 7.4, 1.3 Hz, H-9) ppm. ^¹³C NMR (125.77 MHz, DMSO-d ₆): δ = 101.6 (C-3), 115.7 (C-9a), 119.8 (C-9), 120.9 (C-3a), 124.7 (C-2′,6′), 125.4 (C-α), 126.8 (C-8), 127.6 (C-2′′,6′′), 128.9, 129.06 and 129.12 (C-3′′,4′′,5′′, C-1′, C-4′, C-7), 129.26 (C-3′,5′), 129.32 (C-6), 135.2 (C-β), 136.2 (C-1′′), 145.0 (C-5a), 150.0 (C-4), 154.9 (C-2), 155.7 (C-9b) ppm. HRMS (ESI⁺): m/z calcd for [C₂₅H₁₈NO + H]⁺: 348.1383; found: 348.1378.

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