Synlett 2010(3): 462-466  
DOI: 10.1055/s-0029-1219175
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Reactivity of 3-Iodo-4-quinolones in Heck Reactions: Synthesis of Novel (E)-3-Styryl-4-quinolones

Andreia I. S. Almeida, Artur M. S. Silva*, José A. S. Cavaleiro
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax: +351(234)370084; e-Mail: artur.silva@ua.pt;
Further Information

Publication History

Received 10 November 2009
Publication Date:
07 January 2010 (online)

Abstract

A new and efficient route for the synthesis of (E)-N-­methyl-3-styryl-4-quinolones is described. It involves the Heck ­reaction of N-methyl-3-iodo-4-quinolone, which is obtained by consecutive 3-iodination and NH-methylation of the unsubstituted 4-quinolone, with styrene derivatives. It is demonstrated that such a procedure is only efficient when the 3-iodo-4-quinolone has an N-protecting group. In some cases the branched regioisomers N-methyl-3-(1-phenylethenyl)-4-quinolones were also obtained as byproducts.

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16

Physical Data for Quinolin-4 (1 H )-one (1)
Mp 196-197 ˚. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 6.35 (d, 1 H, J = 7.2 Hz, H-3), 7.43 (ddd, 1 H, J = 7.8, 7.7, 0.8 Hz, H-6), 7.59 (d, 1 H, J = 8.1 Hz, H-8), 7.72 (ddd, 1 H, J = 8.1, 7.8, 1.3 Hz, H-7), 7.99 (d, 1 H, J = 7.2 Hz, H-2), 8.26 (d, 1 H, J = 7.7 Hz, H-5) ppm. ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 109.8 (C-3), 119.5 (C-8), 125.3 (C-6), 126.1 (C-5), 126.7 (C-10), 133.6 (C-7), 141.5 (C-2, C-9), 180.8 (C-4) ppm. ESI+-MS: m/z (%) = 146 (100) [M + H]+. ESI+-HRMS: m/z calcd for [C9H7NO + H]+: 146.0606; found: 146.0604.

17

Optimized Experimental Procedure
Sodium (0.4 g, 8.70 mmol) was added to a solution of
2′-aminoacetophenone (1 mL, 8.23 mmol) in an excess of methyl formate (23 mL), and the reaction mixture was stirred at 40 ˚C, under a nitrogen atmosphere. After 6 h, MeOH (10 mL) was added to the reaction mixture to destroy the remaining sodium and the mixture was poured into H2O (60 mL) and ice (30 g). The organic layer was extracted with EtOAc (4 × 100 mL), dried over anhyd Na2SO4, and the solvent evaporated to dryness. The residue was taken in acetone and purified by chromatography column using a (3:2) mixture of acetone-CH2Cl2 as eluent. The solvent was evaporated to dryness, and the residue was recrystallized from CH2Cl2-light PE to give quinolin-4 (1H)-one (1) as a yellowish solid (836.5 mg, 70%).

18

Physical Data for 3-Iodoquinolin-4 (1 H )-one (2)
Mp 217-218 ˚C. ¹H NMR (300.13 MHz, DMSO): δ = 7.38 (ddd, 1 H, J = 8.2, 7.6, 1.1 Hz, H-6), 7.58 (d, 1 H, J = 8.1 Hz, H-8), 7.69 (ddd, 1 H, J = 8.1, 7.6, 1.3 Hz, H-7), 8.10 (d, 1 H, J = 8.2 Hz, H-5), 8.52 (s, 1 H, H-2), 12.24 (s, 1 H, NH) ppm. ¹³C NMR (74.47 MHz, DMSO): δ = 80.7 (C-3), 118.5 (C-8), 122.5 (C-10), 124.1 (C-6), 125.5 (C-5), 131.9 (C-7), 139.6 (C-9), 144.8 (C-2), 173.0 (C-4) ppm. ESI+-MS: m/z (%) = 272 (100) [M + H]+, 294 (21) [M + Na]+. ESI+-HRMS: m/z calcd for [C9H6INO + H]+: 271.9572; found: 271.9579.

20

Optimized Experimental Procedure
A mixture of quinolin-4 (1H)-one (1, 300 mg, 2.07 mmol), Na2CO3 (329 mg, 3.11 mmol), and iodine (789 mg, 3.11 mmol) in dry THF (20 mL) was stirred at r.t. for 6 h, under a nitrogen atmosphere. After this period, the reaction mixture was poured into a sat. Na2S2O3 solution (40 mL). The organic layer was extracted with EtOAc (3 × 100 mL), dried over anhyd Na2SO4 and the solvent evaporated to dryness. The residue was recrystallized from CH2Cl2-light PE to give 3-iodoquinolin-4 (1H)-one (2, 454.6 mg, 81%), as a yellow solid.

22

Optimized Experimental Procedure
A mixture of 3-iodoquinolin-4 (1H)-one (2, 50 mg, 0.18 mmol), Ph3P (4.7 mg, 0.018 mmol), Et3N (25.1 µL, 0.18 mmol), tetrakis(triphenylphosphine)palladium(0) (10.4 mg, 0.009 mmol), and styrene 3a (103.4 µL, 0.9 mmol) in NMP (3 mL) was stirred at 100 ˚C for 5 h, under a nitrogen atmosphere. After this period, the reaction mixture was poured into H2O (40 mL) and ice (30 g). The organic layer was extracted with EtOAc (3 × 100 mL) and washed with H2O (100 mL). After initial purification by TLC using a (3:1) mixture of CH2Cl2-acetone, the solvent was evapor-ated to dryness and the residue recrystallized from CH2Cl2-light PE to give (E)-3-styrylquinolin-4 (1H)-one(4) as a yellow solid (20.5 mg, 46%). Traces of product 5 were found and 10% (5 mg) of the starting material was recovered.

23

Physical Data of ( E )-3-Styrylquinolin-4 (1 H )-one (4)
Mp 269-270 ˚C. ¹H NMR (300.13 MHz, CD3OD): δ = 7.23 (m, 1 H, H-4′), 7.27 (d, 1 H, J = 16.2 Hz, H-α), 7.38 (m, 3 H, H-6, H-3′,5′), 7.63 (m, 4 H, H-7, H-8, H-2′,6′), 7.91 (d, 1 H, J = 16.2 Hz, H-β), 8.24 (s, 1 H, H-2), 8.36 (dd, 1 H, J = 8.4, 0.9 Hz, H-5), 11.11 (s, 1 H, NH) ppm. ¹³C NMR (75.47 MHz, CD3OD): δ = 118.6 (C-3), 118.9 (C-8), 124.2 (C-6), 124.7 (C-α), 126.8 (C-5, C-2′,6′), 126.7 (C-10), 127.5 (C-4′), 128.2 (C-β), 129.4 (C-3′,5′), 132.2 (C-7), 138.8 (C-2), 139.8 (C-9), 139.8 (C-1′) 176.6 (C-4) ppm. ESI+-MS: m/z (%) = 248 (100) [M + H]+. Anal. Calcd (%) for C17H13NO (247.3): C, 82.57; H, 5.30; N, 5.66. Found: C, 82.47; H, 5.22; N, 5.62.

26

Physical Data for 1-Methyl-3-iodoquinolin-4 (1 H )-one (6)
Mp 177-178 ˚C. ¹H NMR (300.13 MHz, DMSO-d 6): δ = 3.00 (s, 3 H, NCH3), 7.47 (ddd, 1 H, J = 7.8, 6.8, 1.2 Hz, H-6), 7.70 (d, 1 H, J = 9.0 Hz, H-8) 7.79 (ddd, 1 H, J = 9.0, 6.8, 1.6 Hz, H-7), 8.32 (dd, 1 H, J = 7.8, 1.6 Hz, H-5) ppm. ¹³C NMR (75.47 MHz, DMSO-d 6): δ = 40.8 (NCH3), 80.3 (C-3), 117.3 (C-8), 124.3 (C-10), 125.0 (C-6), 127.5 (C-5), 132.9 (C-7), 141.4 (C-9), 150.2 (C-2), 173.8 (C-4) ppm. ESI+-MS: m/z (%) = 286 (100) [M + H]+, 308 (67) [M + Na]+. ESI+-HRMS: m/z calcd for [C10H8INO + H]+: 285.9729; found: 285.9728.

27

Optimized Experimental Procedure
A mixture of 3-iodoquinolin-4 (1H)-one (2, 200 mg, 0.74 mmol), PS-TBD (1.39 mmol/1 g, 1.33 g, 1.85 mmol) and MeI (0.47 mL, 7.4 mmol) in fresh dry THF (40 mL) was stirred at r.t. for 3 h. After this period, the reaction mixture was poured into a mixture of H2O (100 mL) and Et3N (8 mL) and neutralized with HCl (10%). The PS-TBD was filtered off, and the organic layer was extracted with EtOAc (3 × 150 mL), dried over anhyd Na2SO4, and the solvent evaporated to dryness. The product 1-methyl-3-iodoquinolin-4 (1H)-one (6) was recrystallized from CH2Cl2-light PE and obtained as a yellow solid (200.4 mg, 95%).

28

Physical Data for 1-Methyl-3-(1-phenylvinyl)quinolin-4 (1 H )-one (8a) ¹H NMR (300.13 MHz, CDCl3): δ = 3.81 (s, 3 H, NCH3), 5.65 (d, 1 H, J = 1.7 Hz, H-2′), 5.78 (d, 1 H, J = 1.7 Hz, H-2′), 7.31 (m, 3 H, H-3′′,4′′,5′′), 7.44 (m, 4 H, H-6, H-8, H-2′′,6′′), 7.55 (s, 1 H, H-2), 7.70 (ddd, 1 H, J = 7.8, 7.4, 1.6 Hz, H-7), 8.52 (dd, 1 H, J = 8.3, 1.6 Hz, H-5) ppm. ¹³C NMR (75.47 MHz, CDCl3): δ = 40.7 (NCH3), 115.1 (C-8), 116.6 (C-2′), 122.4 (C-3), 123.8 (C-6), 127.1 (C-10), 127.2 (C-2′′,6′′), 127.5 (C-4′′), 127.7 (C-5), 128.3 (C-3′′,5′′), 132.0 (C-7), 140.0 (C-9), 141.3 (C-1′′), 143.5 (C-2), 143.8 (C-1′), 176.2 (C-4) ppm. ESI+-HRMS: m/z calcd for [C18H15NO + H]+: 262.1232; found: 262.1226.

30

Physical Data for ( E )-3-(4-Methoxystyryl)-1-methylquinolin-4 (1 H )-one (7b)
Mp 134.7-135.0 ˚C. ¹H NMR (300.13 MHz, CDCl3): δ = 3.82 (s, 3 H, OCH3), 3.83 (s, 3 H, NCH3), 6.87 (d, 2 H, J = 8.7 Hz, H-2′,6′), 7,01 (d, 1 H, J = 16.3 Hz, H-α), 7.38 (m, 2 H, H-6, H-8), 7,44 (d, 2 H, J = 8.7 Hz, H-3′,5′), 7.56 (d, 1 H, J = 16.3 Hz, H-β), 7.65 (ddd, 1 H, J = 7.8, 7.4, 1.4 Hz, H-7), 7.69 (s, 1 H, H-2), 8.52 (d, 1 H, J = 7.5 Hz, H-5) ppm. ¹³C NMR (75.47 MHz, CDCl3): δ = 40.9 (OCH3), 55.3 (NCH3), 114.0 (C-3′,5′), 115.2 (C-8), 118.8 (C-3), 120.4 (C-α), 123.8 (C-6), 126.5 (C-10), 127.2 (C-5), 127.5 (C-2′,6′), 127.8 (C-β), 131.0 (C-1′), 131.7 (C-7), 139.2 (C-9), 141.6 (C-2), 158.9 (C-4′), 176.1 (C-4) ppm. ESI+-MS: m/z (%) = 292 (100) [M + H]+, 314 (10) [M + Na]+. ESI+-HRMS: m/z calcd for [C19H17NO2 + H]+: 292.1338; found: 292.1335.