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

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

References and Notes

• 1a Amorese A. Arcadi A. Bernocchi E. Cacchi S. Cerrini S. Fedeli W. Ortar G. Tetrahedron  1989,  45:  813 
• 1b Arcadi A. Cacchi S. Fabrizi G. Marinelli F. Pace P. Tetrahedron  1996,  56:  6983 
• 1c Cacchi S. Ciattini PG. Morera E. Pace P. Synlett  1996,  545 
• 1d Arcadi A. Cacchi S. Fabrizi G. Marinelli F. Pace P. Synlett  1996,  568 
• 1e Cacchi S. Fabrizi G. Goggiamani A. ARKIVOC  2003,  (viii):  58 
• 2a Moreno-Mañas M. Pérez M. Pleeixats R. Tetrahedron Lett.  1999,  37:  7449 
• 2b Gürtler C. Buchwald SL. Chem. Eur. J.  1999,  5:  3107 
• 2c Blettner CG. König WA. Stenzel W. Shotten T. Tetrahedron Lett.  1999,  40:  2101 
• 2d Calò V. Nacci A. Monopoli A. Lopez L. di Cosmo A. Tetrahedron  2001,  57:  6071 
• 2e Littke AF. Fu GC. J. Am. Chem. Soc.  2001,  123:  6989 
• 2f Battistuzzi G. Cacchi S. Fabrizi G. Synlett  2002,  439 
• 2g Caló V. Nacci A. Monopoli A. Laera S. Cioffi N. J. Org. Chem.  2003,  68:  2929 
• 3 Cacchi S. Arcadi A. J. Org. Chem.  1983,  48:  4236 
• 4 Hiroshige M. Hauske JR. Zhou P. Tetrahedron Lett.  1995,  36:  4567 
• 5 Botella L. Nájera C. J. Org. Chem.  2005,  70:  4360 
• See, for example:
• 6a Kadin SB. inventors; US  4342781.  ; Chem. Abstr. 2001, 97, 215790
• 6b Morwick TM, and Paget CJ. inventors; EP  91795.  ; Chem. Abstr. 1983, 100, 103341
• 6c Curtze J, and Krummel G. inventors; DE  3817711.  ; Chem. Abstr. 1989, 112, 235327
• 7 β-Arylacrylamides were prepared in almost quantitative yields from 1 equiv of aryl iodides and 1.1 equiv of acryl-amide or N,N-dimethylacrylamide in MeCN at 100 °C in the presence of 0.01 equiv of the Herrmann catalyst and 3 equiv of Et₃N: Herrmann WA. Brossmer K. Reisinger C.-P. Priermeier T. Beller M. Fischer H. Angew. Chem., Int. Ed. Engl.  1995,  34:  1844 
• 8 Jeffery T. Tetrahedron Lett.  1985,  26:  2667 
• 10 Lane BS. Sames D. Org. Lett.  2004,  6:  2897 
• 12 Hay LA. Koenig TM. Ginah FO. Copp JD. Mitchell D. J. Org. Chem.  1998,  63:  5050 
• For some recent references, see:
• 13a Dhanak D, Kaura AC, and Shaw A. inventors; WO  2001085172.  ; Chem. Abstr. 2001, 135, 357951
• 13b Norman P. Curr. Opin. Invest. Drugs  2002,  3:  313 
• 13c Venet M. End D. Angibaud P. Curr. Top. Med. Chem.  2003,  3:  1095 
• 13d van Cutsem E. van de Velde H. Karasek P. Oettle H. Vervenne WL. Szawlowski A. Schoffski P. Post S. Verslype C. Neumann H. Safran H. Humblet Y. Perez RJ. Ma Y. von Hoff D. J. Clin. Oncol.  2004,  22:  1430 
• 13e Freeman GA. Andrews CW. Hopkins AL. Lowell GS. Schaller LT. Cowan JR. Gonzales SS. Koszalka GW. Hazen RJ. Boone LR. Ferris RG. Creech KL. Roberts GB. Short SA. Weaver K. Reynolds DJ. Milton J. Ren J. Stuart DI. Stammers DK. Chan JH. J. Med. Chem.  2004,  47:  5923 
• 13f Li Q. Woods KW. Wang W. Lin N.-H. Claiborne A. Gu W.-Z. Cohen J. Stoll VS. Hutchins C. Frost D. Rosenberg SH. Sham HL. Bioorg. Med. Chem. Lett.  2005,  15:  2033 
• 14 Ley SV. Thomas AW. Angew. Chem. Int. Ed.  2003,  42:  5400 
• 15 Klapars A. Buchwald SL. J. Am. Chem. Soc.  2002,  124:  14844 

9

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.

11

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.

16

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.