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

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.

Key words

3-iodo-4-quinolones - 3-styryl-4-quinolones - Heck ­reaction - N-methylation - iodination

References and Notes

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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.