Syntheses of Novel (E)-N-Methyl-2-styryl-4-quinolones

Abstract

Two new synthetic routes for (E)-N-methyl-2-styryl-4-quinolones have been established, both starting from (E)-2′-cinnamoylaminoacetophenones. In the first, (E)-2′-cinnamoylamino­acetophenones are cyclized and then methylated, while in the second they are methylated followed by in situ cyclization.

Key words

ketones - quinolones - cyclization - N-methylation

References and Notes

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10

Physical Data of ( E )-2′-(4-Methoxycinnamoyl­-amino)acetophenone(3b): mp 106-109 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 2.68 (s, 3 H, 2-Me), 2.83 (s, 3 H, 4′′-OMe), 6.49 (d, 1 H, J = 15.6 Hz, H-α), 6.91 (d, 2 H, J = 8.9 Hz, H-3′′, H-5′′), 7.11 (ddd, 1 H, J = 8.0, 7.6, 1.2 Hz, H-5′), 7.51-7.60 (m, 3 H, H-4′, H-2′′, H-6′′), 7.70 (d, 1 H, J = 15.6 Hz, H-β), 7.91 (dd, 1 H, J = 8.0, 1.6 Hz, H-6′), 8.91 (dd, 1 H, J = 8.5, 1.2 Hz, H-3′), 11.98 (s, 1 H, NH). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 28.6 (2-Me), 55.3 (4′′-OMe), 114.2 (C-3′′, C-5′′), 119.5 (C-α), 120.8 (C-3′), 121.6 (C-1′), 122.2 (C-5′), 127.3 (C-1′′), 129.6 (C-2′′, C-6′′), 131.7 (C-6′), 135.1 (C-4′), 141.4 (C-2′), 141.8 (C-β), 161.1 (C-4′′), 165.2 (C=O), 202.9 (C-1). MS (ESI, +): m/z = 296 (100) [M + H]⁺, 318 (52) [M + Na]⁺, 591 (6) [2 × M + H]⁺, 613 (32) [2 × M + Na]⁺. Anal. Calcd for C₁₈H₁₇NO₃ (295.332): C, 73.20; H, 5.80; N, 4.74. Found: C, 72.90; H, 5.96; N, 4.92.

12

Optimized Experimental Procedure; Classical Heating Conditions: Potassium tert-butoxide (101.6 mg, 0.91 mmol) was added to a solution of the appropriate (E)-2′-cinna-moylaminoacetophenones 3a-c (0.75 mmol) in anhyd THF (60 mL). The mixture was heated at 80 ˚C with stirring, under a N₂ atmosphere for 4 h. After that period the mixture was poured into H₂O and ice and acidified at pH 5 with a 20% solution of HCl. The obtained solid was filtered and recrystallized from CH₂Cl₂-light petroleum to give (E)-2-styryl-4-quinolones 4a-c in good yields (4a, 91%; 4b, 82%; 4c, 74%).

14

Optimized Experimental Procedure; Microwave Irradiation: NaOH (263.2 mg, 6.55 mmol) was added to a solution of the appropriate (E)-2′-cinnamoylamino-aceto-phenones 3a-d (1.31 mmol) in t-BuOH (10 mL). The mixture was irradiated in a high-pressure vessel in an Ethos SYNTH microwave instrument (Milestone Inc.) during 18 min (8 min to reach 120 ˚C and 10 min at 120 ˚C). After that period the mixture was poured over H₂O and ice and was acidified at pH 5 with a 20% solution of HCl. The precipitate was filtered and recrystallized from CH₂Cl₂-light petroleum to give (E)-2-styryl-4-quinolones 4a-d in good yields (4a, 79%; 4b, 78%; 4c, 83%; 4d, 25%).

15

Physical Data of ( E ) - 2-(4-Methoxystyryl)-4-quinolone (4b): mp 222-223 ˚C. ^¹H NMR (300.13 MHz, DMSO-d ₆): δ = 3.81 (s, 3 H, 4′-OMe), 6.32 (s, 1 H, H-3), 6.95-7.05 (m, 3 H, H-α, H-3′, H-5′), 7.27-7.32 (m, 1 H, H-6), 7.59-7.66 (m, 5 H, H-7, H-8, H-β, H-2′, H-6′), 8.05 (d, 1 H, J = 8.1 Hz, H-5), 11.52 (s, 1 H, NH). ^¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 55.3 (4′-OMe), 106.9 (C-3), 114.5 (C-3′, C-5′), 118.2 (C-8), 119.6 (C-α), 122.9 (C-6), 124.7 (C-5), 125.1 (C-10), 128.2 (C-1′), 128.9 (C-2′, C-6′), 131.8 (C-7), 134.6 (C-β), 140.2 (C-9), 147.4 (C-2), 160.2 (C-4′), 176.9 (C-4). MS (ESI, +): m/z 278 (100) [M + H]⁺, 577 (4) [2 × M + Na]⁺. Anal. Calcd for C₁₈H₁₅NO₂ (277.317): C, 73.20; H, 5.80; N, 4.74. Found: C, 72.90; H, 5.96; N, 4.92.

18

Optimized Experimental Procedure: NaH (5.0 mg, 0.20 mmol) was added to a stirred suspension of the appropriate (E)-2-styryl-4-quinolone 4a-c (0.20 mmol) in anhyd THF (25 mL) and the reaction mixture was stirred at r.t. for 30 min. After that period an excess of MeI (0.25 mL, 4.04 mmol) was added and the reaction mixture was stirred for 5 h. Then, it was poured over H₂O, ice and Et₃N (56.3 mL, 4.04 mmol) and acidified with HCl to pH 6. The obtained yellow solid was filtered, dissolved in CHCl₃ and purified by preparative TLC using a 3:1-mixture of CH₂Cl₂-acetone as eluent. Two very close spots were collected, and the one with the lower R _f value was identified as (E)-1-methyl-2-styryl-4-quinolones 5a-c (5a, 55%; 5b, 53%; 5c, 47%) whereas that with the higher R _f value was identified as (E)-4-methoxy-2-styrylquinolines 6a-c (6a, 16%; 6b, 17%; 6c, 18%). During the reaction time and workup the reaction mixture had to be protected from the light, otherwise the (E)-1-methyl-2-styryl-4-quinolones 5a-c could isomerize into the Z-isomers.
Physical Data of ( E )-1-Methyl-2-styryl-4-quinolone (5a): mp 182-183 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 3.83 (s, 3 H, NMe), 6.54 (s, 1 H, H-3), 7.09 (d, 1 H, J = 15.8 Hz, H-α), 7.20 (d, 1 H, J = 15.8 Hz, H-β), 7.38-7.46 (m, 4 H,
H-3′, H-5′, H-4′, H-6), 7.51-7.56 (m, 3 H, H-2′, H-6′, H-8), 7.70 (dd, 1 H, J = 7.8, 1.6 Hz, H-7), 8.47 (dd, 1 H, J = 8.0, 1.6 Hz, H-5). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 35.7 (NMe), 109.7 (C-3), 115.4 (C-8), 121.7 (C-α), 123.5 (C-6), 126.7 (C-5), 126.9 (C-10), 127.3 (C-2′, C-6′), 129.0 (C-3′, C-5′), 129.5 (C-4′), 132.3 (C-7), 135.4 (C-1′), 138.0 (C-β), 141.7 (C-9), 151.8 (C-2), 178.0 (C-4). MS (ESI, +): m/z = 262 (100) [M + H]⁺. Anal. Calcd for C₁₈H₁₅NO (261.318): C, 82.73; H, 5.79; N, 5.36. Found: C, 82.61; H, 5.90; N, 5.15.

19

Physical Data of ( E )-4-Methoxy-2-(4-methoxy-styryl)quinoline ( 6b): mp 134-135 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 3.85 (s, 3 H, 4′-OMe), 4.12 (s, 3 H, 4-OMe), 6.94 (d, 2 H, J = 8.8 Hz, H-3′, H-5′), 6.98 (s, 1 H,
H-3), 7.24 (d, 1 H, J = 15.2 Hz, H-α), 7.45 (dt, 1 H, J = 7.7, 1.1 Hz, H-6), 7.58-7.66 (m, 3 H, H-β, H-2′, H-6′), 7.68 (ddd, 1 H, J = 8.0, 7.7, 1.4 Hz, H-7), 8.00 (d, 1 H, J = 8.0 Hz,
H-8), 8.14 (dd, 1 H, J = 7.7, 1.4 Hz, H-5). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 55.3 (4′-OMe), 55.6 (4-OMe), 97.6 (C-3), 114.2 (C-3′, C-5′), 120.6 (C-10), 121.6 (C-5), 125.1 (C-6), 127.3 (C-α), 128.5 (C-8), 128.6 (C-2′, C-6′), 128.2 (C-1′), 130.7 (C-7), 133.7 (C-β), 149.0 (C-9), 157.4 (C-2), 160.1 (C-4′), 162.4 (C-4). HRMS (ESI, +): m/z calcd for C₁₉H₁₈NO₂: 292.1332; found: 292.1322.

20

Physical Data of ( E )-1,3-Dimethyl-2-styryl-4-quinolone ( 7a): ^¹H NMR (300.13 MHz, CDCl₃): δ = 2.22 (s, 3 H, 3-Me), 3.81 (s, 3 H, NMe), 6.77 (d, 1 H, J = 16.6 Hz, H-α), 6.98 (d, 1 H, J = 16.6 Hz, H-β), 7.26-7.49 (m, 6 H, H-2′, H-3′,
H-4′, H-5′, H-6′, H-6), 7.56 (dd, 1 H, J = 7.4, 1.0 Hz, H-8), 7.65 (ddd, 1 H, J = 7.4, 7.9, 1.5 Hz, H-7), 8.51 (dd, 1 H, J = 7.9, 1.5 Hz, H-5). MS (ESI, +): m/z = 276 (100) [M + H]⁺.

21

Optimized Experimental Procedure: NaH (68.0 mg, 2.84 mmol) was added to a solution of the appropriate (E)-2′-cinnamoylaminoacetophenone 3a-c (1.89 mmol) in anhyd THF (20 mL). The mixture was stirred at r.t. for 30 min and then an excess of MeI (0.18 mL, 2.84 mmol) was added. The reaction mixture was stirred at r.t. for a period of time (see Table  [³] ) and then an excess of NaH (45.3 mg, 1.89 mmol) was added. After 24 h, the reaction was poured into H₂O, ice and Et₃N (39 mL, 2.84 mmol) and acidified with HCl to pH 6. The yellow solid obtained was filtered and taken in CHCl₃. The organic layer was extracted with EtOAc (3 × 100 mL), dried with anhyd Na₂SO₄ and concentrated. The crude product was purified by preparative TLC using a 3:2-mixture of EtOAc-light petroleum as eluent. The desired (E)-1-methyl-2-styryl-4-quinolones 5a-c were obtained as the main component and corresponded to the spot with lower R _f value (5a, 68%; 5b, 66%; 5c, 86%) and compound 7a-c were obtained as the spot with high R _f value (7a, traces; 7b, 2%; 7c, 4%). In some cases some starting material and traces of the (E)-2′-(N-cinnamoyl-N-methylamino)acetophenones 8a-c were recovered.

23

Physical Data of ( E ) - 2′-[ N -Methyl- N -(4-nitrocinna-moyl)amino]acetophenone (8d): mp 165-166 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 2.48 (s, 3 H, 2-Me), 3.38 (s, 3 H, NMe), 6.28 (d, 1 H, J = 15.5 Hz, H-α), 7.32 (dd, 1 H, J = 7.9, 1.1 Hz, H-6′), 7.41 (d, 2 H, J = 8.8 Hz, H-2′′, H-6′′), 7.54 (ddd, 1 H, J = 7.4, 7.5, 1.1 Hz, H-4′), 7.64 (ddd, 1 H, J = 7.4, 7.9, 1.5 Hz, H-5′), 7.70 (d, 1 H, J = 15.5 Hz, H-β), 7.79 (dd, 1 H, J = 7.5, 1.5 Hz, H-3′), 8.14 (d, 2 H, J = 8.8 Hz, H-3′′,
H-5′′). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 29.4 (2-Me), 37.8 (NMe), 122.1 (C-α), 124.0 (C-3′′, C-5′′), 128.4 (C-2′′, C-6′′), 128.5 (C-1′), 128.8 (C-4′), 129.5 (C-6′), 130.0 (C-3′), 133.2 (C-5′), 139.7 (C-β), 141.1 (C-1′′), 141.2 (C-2′), 144.5 (C-4′′), 165.0 (C=O), 199.1 (C-1). HRMS (ESI, +): m/z calcd for C₁₈H₁₇N₂O₄: 325.1183; found: 325.1174.

24

Physical Data ( E ) - 1-Methyl-2-(4-nitrostyryl)-4-quinolone (5d): ^¹H NMR (300.13 MHz, CH₃OD): δ = 3.86 (s, 3 H, NMe), 6.54 (s, 1 H, H-3), 7.24 (AB, 1 H, J = 16.0 Hz, H-α), 7.24 (AB, 1 H, J = 16.0 Hz, H-β), 7.43 (ddd, 1 H, J = 7.8, 7.3, 0.7 Hz, H-6), 7.55 (d, 1 H, J = 8.5 Hz, H-8), 7.70 (d, 2 H, J = 8.8 Hz, H-2′, H-6′), 7.70-7.76 (m, 1 H, H-7), 8.30 (d, 2 H, J = 8.8 Hz, H-3′, H-5′), 8.48 (dd, 1 H, J = 7.8, 1.5 Hz, H-5). ^¹³C NMR (75.47 MHz, CH₃OD): δ = 35.9 (NMe), 110.2 (C-3), 115.4 (C-8), 123.8 (C-6), 124.3 (C-3′, C-5′), 126.2 (C-α), 126.8 (C-5), 126.9 (C-10), 127.9 (C-2′, C-6′), 132.6 (C-7), 135.3 (C-β), 141.5 (C-1′), 141.7 (C-9), 147.8 (C-4′), 150.5 (C-2), 178.1 (C-4). HRMS (ESI, +): m/z calcd for C₁₈H₁₅N₂O₃: 307.1083; found: 307.1073.