The Heck Reaction of β-Arylacrylamides: An Approach to 4-Aryl-2-quinolones

Roberta Bernini; Sandro Cacchi; Ilse De Salve; Giancarlo Fabrizi

doi:10.1055/s-2006-951505

LETTER

The Heck Reaction of β-Arylacrylamides: An Approach to 4-Aryl-2-quinolones

Roberta Bernini^a, Sandro Cacchi*^b, Ilse De Salve^b, Giancarlo Fabrizi*^b
^a Dipartimento A.B.A.C, Università degli Studi della Tuscia, Via S. Camillo De Lellis, 01100 Viterbo, Italy
^b Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi ‘La Sapienza’, P. le A. Moro 5, 00185 Rome, Italy
Fax: +39(06)49912780.; e-Mail: sandro.cacchi@uniroma1.it;

Abstract

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Abstract

The Heck reaction of β-arylacrylamides with aryl iodides afforded the corresponding vinylic substitution products usually in high yields. The nature of β-substituents, aryl iodides and substituents at the nitrogen atom influences the stereochemical outcome. N,N-Dimethyl-β-arylacrylamides gave vinylic substitution products with higher stereoselectivity than the corresponding N-unsubstituted β-arylacrylamides. β-Arylacrylamides containing ortho-substituents led to the formation of only one stereoisomer. The procedure was used to prepare 4-aryl-2-quinolones from β-(o-bromophenyl)acrylamide through a sequential Heck reaction and copper-catalyzed cyclization process.

Key words

cinnamamides - 2-quinolones - cyclization - palladium catalysis - copper catalysis

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References

References and Notes

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Typical Procedure for the Reaction of β-Arylacrylamides with p -Iodoanisole.
To a stirred solution of 1h (0.113 g, 0.50 mmol), p-iodo-anisole (0.093 mg, 0.75 mmol) and Et₃N (348 µL, 2.5 mmol), Pd(OAc)₂ (0.006 g, 0.025 mmol) was added. The reaction mixture was stirred for 12 h at 100 °C. Then, the mixture was diluted with EtOAc and washed with H₂O. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by chromatog-raphy (silica gel, 35 g; n-hexane-EtOAc, 30:70) to give 0.144 g (87% yield) of 2h: mp 163-165 °C. IR (KBr): 3294, 3177, 1654 cm^-1. ¹H NMR (CDCl₃): δ = 7.69 (dd, J = 8.4, 1.33 Hz, 1 H), 7.43 (m, 1 H), 7.32-7.27 (m, 3 H), 7.23-7.21 (m, 2 H), 6.87-6.85 (m, 2 H), 6.49 (s, 1 H) 5.28-5.16 (d, 2 H),1.61 (s, 3 H). ¹³C NMR (CDCl₃): δ = 167.2, 160.1, 148.6, 139.0, 132.8, 130.3, 130.2, 129.4, 128.1, 127.4, 122.3, 119.7, 113.6, 54.8. MS: m/z (rel. int.) = 332 (100) [M⁺], 334 (73), 252 (54). Anal. Calcd for C₁₆H₁₄BrNO₂: C, 57.85; H, 4.25; Br, 24.05; N; 4.22. Found: C, 57.77; H, 4.28; Br, 24.02; N, 4.26.

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Typical Procedure for the Reaction of β-Arylacrylamides with Ethyl p -Iodobenzoate. To a stirred solution of 1h (0.113 g, 0.50 mmol), ethyl p-iodobenzoate (209 µL, 1.25 mmol) and Et₃N (348 µL, 2.5 mmol), Pd(OAc)₂ (0.001 g, 0.005 mmol) was added. The reaction mixture was stirred for 24 h at 100 °C. Then, the mixture was diluted with EtOAc and washed with H₂O. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by chromatog-raphy (silica gel, 35 g; n-hexane-EtOAc, 25:75) to give 0.152 g (82% yield) of 2ac: mp 235-237 °C. IR (KBr): 3338, 3181, 1668 cm^-1. ¹H NMR (CDCl₃): δ = 8.03 (d, J = 8.3 Hz, 2 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.45 (t, J = 7.6 Hz, 1 H), 7.35-7.30 (m, 4 H), 6.61 (s, 1 H) 5.32-5.25 (d, 2 H), 4.37 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H). ¹³C NMR (CDCl₃): δ = 166.5, 165.5, 147.9, 142.1, 138.2, 132.9, 130.4, 130.3, 129.8, 129.3, 127.5, 126.6, 123.5, 122.2, 60.6, 13.8. MS: m/z (rel. int.) = 374 (50) [M⁺], 376 (100), 294 (34). Anal. Calcd for C₁₈H₁₆BrNO₃: C, 57.77; H, 4.31; Br, 21.35; N; 3.74. Found: C, 57.69; H, 4.35; Br, 21.38; N, 3.70.

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Typical Procedure for the Preparation of 2-Quinolones 4.
To a stirred solution of 1h (0.113 g, 0.50 mmol), p-iodo-anisole (0.093 g, 0.75 mmol) and Et₃N (348 µL, 2.5 mmol), Pd(OAc)₂ (0.006 g, 0.025 mmol) was added. The reaction mixture was stirred for 12 h at 100 °C. Then, the mixture was diluted with EtOAc and washed with H₂O. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. Then, 2 mL of dioxane, CuI (0.019 g, 0.1 mmol), NaI (0.149 g, 1 mmol), K₃PO₄ (0.212 g, 1 mmol), N,N-dimethylethylendiammine (21.3 µL, 0.2 mmol) and were added to the crude mixture. The mixture was stirred for 24 h at 120 °C. Then, the mixture was diluted with EtOAc and washed with a sat. NH₄Cl solution. The organic layer was dried over Na₂SO₄ concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 35 g; n-hexane-EtOAc, 30:70) to give 0.97 g (77% yield) of 4b: mp 196-198 °C. IR (KBr): 3131, 1672 cm^-1. ¹H NMR (DMSO-d ₆): δ = 11.82 (s, 1 H), 7.51 (t, J = 8 Hz, 1 H), 7.44-7.36 (m, 4 H), 7.13-7.07 (m, 3 H), 6.34 (s, 1 H), 3.82 (s, 3 H). ¹³C NMR (DMSO-d ₆): δ = 161.3, 159.6, 151.1, 139.3, 130.4, 130.1, 128.8, 126.2, 121.7, 120.9, 118.5, 115.8, 114.1, 55.2. MS: m/z (rel. int.) = 251 (100) [M⁺], 252 (25), 236 (25) 220 (12). Anal. Calcd for C₁₆H₁₃NO₂: C, 76.48; H, 5.21; N; 5.57. Found: C, 76.55; H, 5.18; N, 5.53.