New Synthesis of (Z)- and (E)-3-Styryl-4-quinolones

Abstract

A novel and efficient route for the synthesis of (Z)- and (E)-3-styryl-4-quinolones is described. Wittig reaction of 4-(chloroquinoline- and quinolone)-3-carbaldehydes with benzylic ylides is the key transformation for this synthetic route. The (Z)-1-methyl-3-styryl-4-quinolone is obtained with high diastereoselectivity from the reaction of 1-methyl-4-quinolone-3-carbaldehyde; while (E)-3-styryl-4-quinolone is prepared through the Wittig reaction of 4-chloroquinoline-3-carbaldehyde followed by acid hydrolysis. Both synthetic routes are efficient regardless of the substituents on the benzylic ylides.

Key words

4-chloroquinoline-3-carbaldehyde - 4-quinolone-3-carbaldehyde - 3-styryl-4-quinolone - 4-chloro-3-styrylquinoline - Wittig reaction

References and Notes

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16

Optimized Experimental Procedure
To a suspension of 4-quinolone-3-carbaldehyde (1, 1.16 mmol, 200.9 mg) in acetone (20 mL), anhyd K₂CO₃ (2.32 mmol, 320.6 mg) was added, and the mixture was stirred at r.t. for 30 min. p-Toluenesulfonyl chloride (1.74 mmol, 331.7 mg) was then added, and the mixture was stirred at r.t. for 3 h. After that time, the K₂CO₃ was filtered off, washed with acetone (2 × 20 mL), and the filtrate was concentrated. The residue was purified by silica gel column chromatography, first using CH₂Cl₂ as eluent (to remove the excess of p-toluenesulfonyl chloride) and then a mixture of CH₂Cl₂-acetone (5:1). The solvent was evaporated to dryness and the solid recrystallized from a mixture of CH₂Cl₂-light PE to give 1-tosyl-4-quinolone-3-carbaldehyde (2b) as a white solid (1.15 mmol, 376.4 mg, 99%).

17

Analytical Data for ( Z ) - 4′-nitro-3-styryl-1-tosyl-4-quinolone (5f) Mp 144-146 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 2.42 (s, 3 H, 4′′-CH₃), 6.86 (AB, 1 H, J = 12.3 Hz, H-β), 6.89 (AB, 1 H, J = 12.3 Hz, H-α), 7.29 (d, 2 H, J = 8.3 Hz, H-3′′,5′′), 7.43 (ddd, 1 H, J = 0.9, 7.2, 8.0 Hz, H-6), 7.48 (d, 2 H, J = 8.6 Hz, H-2′,6′), 7.48 (d, 2 H, J = 8.3 Hz, H-2′′,6′′), 7.61 (ddd, 1 H, J = 1.7, 7.2, 8.8 Hz, H-7), 8.14 (d, 1 H, J = 8.8 Hz, H-8), 8.17 (d, 2 H, J = 8.6 Hz, H-3′,5′), 8.35 (d, 1 H, J = 0.6 Hz, H-2), 8.40 (dd, 1 H, J = 1.7, 8.0 Hz, H-5) ppm. ^¹³C NMR (75.47 MHz, CDCl₃): δ = 21.7 (4′′-CH₃), 118.1 (C-8), 119.4 (C-3), 124.0 (C-3′,5′), 125.83 (C-10), 125.85 (C-6), 126.7 (C-α), 127.5 (C-5 and C-2′′,6′′), 129.7 (C-2′,6′), 130.1 (C-β), 130.4 (C-3′′,5′′), 132.8 (C-7), 133.4 (C-1′′), 136.3 (C-9), 136.9 (C-2), 144.1 (C-1′), 146.5 (C-4′), 146.8 (C-4′′), 177.4 (C-4) ppm. ESI⁺-MS: m/z (%) = 447.1 (100) [M + H]⁺, 469.1 (9) [M + Na]⁺. ESI⁺-HRMS: m/z calcd for [C₂₄H₁₈N₂O₅S + H]⁺: 447.10092; found: 447.10011.

18

Analytical Data for ( E ) - 4′-Nitro-3-styryl-1-tosyl-4-quinolone (6f) Mp 219-220 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 2.41 (s, 3 H, 4′′-CH₃), 7.29 (d, 1 H, J = 16.6 Hz, H-α), 7.34 (d, 2 H, J = 8.8 Hz, H-3′′,5′′), 7.44 (ddd, 1 H, J = 0.8, 7.2, 8.0 Hz, H-6), 7.61 (ddd, 1 H, J = 1.7, 7.2, 8.7 Hz, H-7), 7.69 (d, 2 H, J = 8.8 Hz, H-2′,6′), 7.79 (d, 2 H, J = 8.8 Hz, H-2′′,6′′), 7.89 (d, 1 H, J = 16.6 Hz, H-β), 8.21 (d, 1 H, J = 8.7 Hz, H-8), 8.24 (d, 2 H, J = 8.8 Hz, H-3′,5′), 8.43 (dd, 1 H, J = 1.7, 8.0 Hz, H-5), 8.84 (s, 1 H, H-2) ppm. ^¹³C NMR (75.47 MHz, CDCl₃): δ = 21.8 (4′′-CH₃), 118.1 (C-8), 119.6 (C-3), 124.1 (C-3′,5′), 126.0 (C-6), 126.2 (C-α), 126.3 (C-10), 126.9 (C-2′,6′), 127.6 (C-2′′,6′′), 127.7 (C-5), 129.0 (C-β), 130.5 (C-3′′,5′′), 132.8 (C-7), 133.5 (C-1′′), 135.8 (C-9), 136.7 (C-2), 144.2 (C-1′), 146.8 (C-4′ and C-4′′), 177.0 (C-4) ppm. ESI⁺-MS: m/z (%) = 447.1 (100) [M + H]⁺. ESI⁺-HRMS: m/z calcd for [C₂₄H₁₈N₂O₅S + H]⁺: 447.10092; found: 447.10023.

19

Analytical Data for ( E ) - 1-Methyl-4′-nitro-3-styryl-4-quinolone (6d) Mp >300 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 3.92 (s, 3 H, N-CH₃), 7.24 (d, 1 H, J = 16.1 Hz, H-α), 7.45 (d, 1 H, J = 8.5 Hz, H-8), 7.47 (ddd, 1 H, J = 1.2, 7.4, 7.8, H-6), 7.62 (d, 2 H, J = 8.8 Hz, H-2′,6′), 7.72 (ddd, 1 H, J = 1.5, 7.4, 8.5 Hz, H-7), 7.81 (s, 1 H, H-2), 7.92 (d, 1 H, J = 16.1 Hz, H-β), 8.19 (d, 2 H, J = 8.8 Hz, H-3′,5′), 8.57 (dd, 1 H, J = 1.5, 7.8 Hz, H-5) ppm. ^¹³C NMR (75.47 MHz, CDCl₃): δ = 41.1 (N-CH₃), 115.4 (C-8), 117.4 (C-3), 124.1 (C-3′,5′), 124.5 (C-6), 126.3 (C-β), 126.5 (C-2′,6′), 127.0 (C-10), 127.5 (C-5), 127.6 (C-α), 132.3 (C-7), 139.3 (C-9), 143.7 (C-2), 145.2 (C-1′), 146.3 (C-4′), 176.3 (C-4) ppm. ESI⁺-MS: m/z (%) = 307.1 (100) [M + H]⁺, 329.1 (5) [M + Na]⁺. ESI⁺-HRMS: m/z calcd for [C₁₈H₁₄N₂O₃ + H]⁺: 307.10772; found: 307.10785.

20

Optimized Experimental Procedure
A mixture of NaH (37 mg, 1.56 mmol for reaction with 3a-c and 19 mg, 0.78 mmol for reaction with 3d) and the appropriate phosphonium halide 3a-d (1.56 mmol for 3a-c and 0.78 mmol for 3d) in refluxing dry THF (20 mL) was stirred for the requisite time (Tables  [¹] and  [²] ). The appear-ance of an orange colour and the disappearance of the suspension of phosphonium salt indicated the ylide formation. Subsequently, the appropriate 3-carbaldehyde 2a,b and 7 (0.52 mmol) was added, and reflux was continued for the time noted in Tables  [¹] and  [²] . After cooling to r.t., the reaction mixture was poured onto ice (20 g) and H₂O (20 mL), and the pH value was adjusted to 5 with dilute HCl. In the case of precipitation, the solid was filtered off, washed with H₂O (3 × 50 mL), dissolved in CHCl₃ (50 mL), washed with H₂O (2 × 50 mL), and the organic solvent evaporated to dryness. If no solid precipitated, the organic layer was extracted with CHCl₃ (3 × 50 mL), and the solvent was evaporated to dryness. In all the cases, the residues were dissolved in CH₂Cl₂.
For the reaction of 1-methyl-4-quinolone-3-carbaldehyde (2a) the residue was purified by silica gel column chromatography with a mixture of CH₂Cl₂-EtOAc (4:1), leading to the isolation of two products, in each case. The components with the higher R _f value were identified as (E)-1-methyl-3-styryl-4-quinolones 6a-d with the slower eluting components being (Z)-1-methyl-3-styryl-4-quinolones 5a-d. These compounds were recrystallized from a mixture of CH₂Cl₂-light PE. For the reaction of 1-tosyl-4-quinolone-3-carbaldehyde (2b) the residue was purified by preparative TLC with a mixture of light PE-EtOAc (4:1), in the case of 5e and 6e, and with a mixture of light PE-EtOAc (2:1), in the case of 5f and 6f. In both cases, the component of higher R _f value was identified as (E)-3-styryl-1-tosyl-4-quinolones 6e,f with the second being the (Z)-3-styryl-1-tosyl-4-quinolones 5e,f. For the reaction of 4-chloroquinoline-3-carbaldehyde (7), the residue was purified by silica gel column chromatography, eluting with a mixture of light PE-EtOAc (7:1 to 4:1), leading to the isolation of two products, in each case. In this case, the component of higher R _f value was identified as (Z)-4-chloro-3-styrylquinolines 8a-d and the second as (E)-4-chloro-3-styrylquinolines 9a-d. These compounds were recrystallized from a mixture of CH₂Cl₂-light PE.

21

Analytical Data for ( Z ) - 4-Chloro-4′-ethoxy-3-styryl-quinoline (8c) Mp 89-91 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 1.38 (t, 3 H, J = 7.0 Hz, 4′-OCH₂CH ₃), 3.97 (q, 2 H, J = 7.0 Hz, 4′-OCH ₂CH₃), 6.67 (d, 1 H, J = 12.0 Hz, H-α), 6.72 (d, 2 H, J = 8.7 Hz, H-3′,5′), 6.88 (d, 1 H, J = 12.0 Hz, H-β), 7.09 (d, 2 H, J = 8.7 Hz, H-2′,6′), 7.64 (ddd, 1 H, J = 1.3, 6.9, 8.3 Hz, H-6), 7.73 (ddd, 1 H, J = 1.4, 6.9, 8.3 Hz, H-7), 8.04 (d, 1 H, J = 8.3 Hz, H-8), 8.28 (dd, 1 H, J = 1.4, 8.3 Hz, H-5), 8.63 (s, 1 H, H-2) ppm. ^¹³C NMR (75.47 MHz, CDCl₃): δ = 14.8 (4′-OCH₂ CH₃), 63.4 (4′-OCH₂CH₃), 114.5 (C-3′,5′), 122.2 (C-α), 124.0 (C-5), 126.5 (C-10), 127.6 (C-6), 128.2 (C-1′), 129.5 (C-8), 129.8 (C-7), 129.9 (C-3), 130.3 (C-2′,6′), 133.6 (C-β), 140.5 (C-4), 147.2 (C-9), 151.3 (C-2), 158.8 (C-4′) ppm. ESI⁺-MS: m/z (%) = 310.1 (100) [M + H]⁺. Anal. Calcd (%) for C₁₉H₁₆ClNO (309.8): C, 73.66; H, 5.21; N, 4.52. Found: C, 73.55; H, 5.23; N, 4.55.

22

Analytical Data for ( E ) - 4-Chloro-4′-ethoxy-3-styryl-quinoline (9c)
Mp 154-155 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 1.45 (t, 3 H, J = 7.0 Hz, 4′-OCH₂CH ₃), 4.08 (q, 2 H, J = 7.0 Hz, 4′-OCH ₂CH₃), 6.94 (d, 2 H, J = 8.8 Hz, H-3′,5′), 7.29 (d, 1 H, J = 16.5 Hz, H-β), 7.49 (d, 1 H, J = 16.5 Hz, H-α), 7.56 (d, 2 H, J = 8.8 Hz, H-2′,6′), 7.64 (ddd, 1 H, J = 1.1, 7.0, 8.3 Hz, H-6), 7.71 (ddd, 1 H, J = 1.4, 7.0, 8.3 Hz, H-7), 8.09 (dd, 1 H, J = 1.1, 8.3 Hz, H-8), 8.26 (dd, 1 H, J = 1.4, 8.3 Hz, H-5), 9.18 (s, 1 H, H-2) ppm. ^¹³C NMR (75.47 MHz, CDCl₃): δ = 14.8 (4′-OCH₂ CH₃), 63.6 (4′-OCH₂CH₃), 114.8 (C-3′,5′), 120.0 (C-α), 124.4 (C-5), 126.4 (C-10), 127.9 (C-6), 128.37 (C-2′,6′), 128.40 (C-3), 129.2 (C-1′), 129.5 and 129.6 (C-7 and C-8), 132.7 (C-β), 138.9 (C-4), 147.4 (C-9), 148.1 (C-2), 159.5 (C-4′) ppm. ESI⁺-MS: m/z (%) = 310.1 (100) [M + H]⁺. Anal Calcd for C₁₉H₁₆ClNO (309.8): C, 73.66; H, 5.21; N, 4.52. Found: C, 73.82; H, 5.22; N, 4.50.

23

Analytical Data for ( E )-4′-Chloro-3-styryl-4 -quinolone (11b) Mp >300 ˚C. ^¹H NMR (300.13 MHz, DMSO-d ₆): δ = 7.23 (d, 1 H, J = 16.3 Hz, H-α), 7.37 (dd, 1 H, J = 7.5, 7.8 Hz, H-6), 7.41 (d, 2 H, J = 8.4 Hz, H-3′,5′), 7.53 (d, 2 H, J = 8.4 Hz, H-2′,6′), 7.58 (d, 1 H, J = 7.9 Hz, H-8), 7.67 (dd, 1 H, J = 7.5, 7.9 Hz, H-7), 7.82 (d, 1 H, J = 16.3 Hz, H-β), 8.21 (d, 1 H, J = 7.8 Hz, H-5), 8.29 (s, 1 H, H-2), 12.19 (br s, 1 H, NH) ppm. ^¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 116.5 (C-3), 118.4 (C-8), 123.6 (C-6), 125.1 (C-α), 125.2 (C-β), 125.4 (C-5 and C-10), 127.4 (C-2′,6′), 128.6 (C-3′,5′), 130.9 (C-4′), 131.5 (C-7), 137.5 (C-1′), 138.6 (C-9), 139.2 (C-2), 175.2 (C-4) ppm. ESI⁺-MS: m/z (%) = 282.0(100) [M + H]⁺. ESI⁺-HRMS: m/z calcd for [C₁₇H₁₂ClNO + H]⁺: 282.06802; found 282.06801.

24

Optimized Experimental Procedure A suspension of a mixture of (Z)- and (E)-4-chloro-3-styrylquinoline 8a-d and 9a-d (0.19 mmol) in 40% aq formic acid (6 mL) was refluxed for the appropriate time (Table  [4] ). The resulting suspension was cooled in ice for 30 min, the pH value adjusted to 5 with Na₂CO₃, and the precipitate formed was filtered off and washed with H₂O. The pure (E)-3-styryl-4-quinolone derivatives 11a-d were collected as a white solids (11a-c) or an orange solid (11d) without the need for further purification.