Facile Synthesis of Pyrido[2,1-a]isoindoles via Iron-Mediated 2-Arylpyridine C–H Bond Cleavage

Abstract

An iron-catalyzed reaction of 2-arylpyridine C–H bond with 2-bromoacetophenone is achieved, providing pyrido[2,1-a]-isoindoles in moderate to good yields. The regioselectivity stems from the domination of hindrance on the regioselective ortho-functionalization of 2-arylpyridines C–H bond.

Key words

iron - 2-arylpyridine - C–H bond cleavage - pyridoisoindole - regioselectivity

• References and Notes

• 1a Wang S, Cao L, Shi H, Dong Y, Sun J, Hu Y. Chem. Pharm. Bull. 2005; 53: 67
• 1b Peese KM, Gin DY. J. Am. Chem. Soc. 2006; 128: 8734
• 1c Orlemans EO. M, Verboom W, Scheltinga MW, Reinhoudt DN, Lelieveld P, Fiebig HH, Winterhalter BR, Double JA, Bibby MC. J. Med. Chem. 1989; 32: 1612
• 1d Diana P, Martorana A, Barraja P, Montalbano A, Dattolo G, Cirrincione G, Dall’Acqua F, Salvador A, Vedaldi D, Basso G, Viola G. J. Med. Chem. 2008; 51: 2387
• 1e Lübbers T, Angehrn P, Gmünder H, Herzig S. Bioorg. Med. Chem. Lett. 2007; 17: 4708
• 1f Martínez-Viturroa CM, Domínguez D. Tetrahedron Lett. 2007; 48: 4707
• 1g Simone FD, Gertsch J, Waser J. Angew. Chem. Int. Ed. 2010; 49: 5767
• 2 Romanov NN. Ukr. Khim. Zhur. 1981; 1280
• 3a Mitsumori T, Bendikov M, Dautel O, Wudl F, Shioya T, Sato H, Sato Y. J. Am. Chem. Soc. 2004; 126: 16793
• 3b Vlahovici A, Andrei M, Druta I. J. Lumin. 2002; 96: 279
• 3c Voitenko ZV, Pocholenko OA, Chkarov OO, Shishkin OV, Shishkina SV, Dall’Ava A, Vedrenne M, Sanchez M, Wolf J.-G. Eur. J. Org. Chem. 2001; 7: 1401
• 3d Vlahovici A, Druta I, Andrei M, Cotlet M, Dinica R. J. Lumin. 1999; 82: 155
• 4a Schiesser CH, Wille U, Matsubara H, Ryu I. Acc. Chem. Res. 2007; 40: 303
• 4b Dix I, Doll C, Hopf H, Jones PG. Eur. J. Org. Chem. 2002; 15: 2547
• 4c Burner S, Canesso R, Widmer U. Heterocycles 1994; 37: 239
• 4d RajanBabu TV. Acc. Chem. Res. 1991; 24: 139
• 5a Xie C, Zhang Y, Xu P. Synlett 2008; 3115
• 5b Huang X, Zhang T. Tetrahedron Lett. 2009; 50: 208
• 6a Liu Z, Shi F, Martinez PD. G, Raminelli C, Larock RC. J. Org. Chem. 2008; 73: 219
• 6b Huang X.-C, Liu Y.-L, Liang Y, Pi S.-F, Wang F, Li J.-H. Org. Lett. 2008; 10: 1525
• 6c Jin T, Yamamoto Y. Angew. Chem. Int. Ed. 2007; 46: 3323
• 6d Raminelli C, Liu Z, Larock RC. J. Org. Chem. 2006; 71: 4689

For selected examples, see:
• 7a Peng X, Zhu Y, Ramirez TA, Zhao B, Shi Y. Org. Lett. 2011; 13: 5244
• 7b Li B, Wu Z.-H, Gu Y.-F, Sun C.-L, Wang B.-Q, Shi Z.-J. Angew. Chem. Int. Ed. 2011; 50: 1109
• 7c Chen Q, Ilies L, Yoshikai N, Nakamura E. Org. Lett. 2011; 13: 3232
• 7d Xiao F, Shuai Q, Zhao F, Baslé O, Deng G, Li C.-J. Org. Lett. 2011; 13: 1614
• 7e Jia X, Zhang S, Wang W, Luo F, Cheng J. Org. Lett. 2009; 11: 3120
• 7f Wang W, Pan C, Chen F, Cheng J. Chem. Commun. 2011; 47: 3978
• 7g Gao K, Yoshikai N. J. Am. Chem. Soc. 2011; 133: 400
• 7h Tsai AS, Tauchert ME, Bergman RG, Ellman JA. J. Am. Chem. Soc. 2011; 133: 1248
• 7i Kitahara M, Umeda N, Hirano K, Satoh T, Miura M. J. Am. Chem. Soc. 2011; 133: 2160
• 7j Ackermann L, Vicente R, Potukuchi HK, Pirovano V. Org. Lett. 2010; 12: 5032
• 7k Gao K, Lee P.-S, Fujita T, Yoshikai N. J. Am. Chem. Soc. 2010; 132: 12249
• 7l Li M, Ge H. Org. Lett. 2010; 12: 3464
• 7m Kim J, Chang S. J. Am. Chem. Soc. 2010; 132: 10272
• 7n Luo N, Yu Z. Chem. Eur. J. 2010; 16: 787
• 7o Wang X, Truesdale L, Yu J.-Q. J. Am. Chem. Soc. 2010; 132: 3648
• 7p Jia X, Yang D, Wang W, Luo F, Cheng J. J. Org. Chem. 2009; 74: 9470
• 7q Ackermann L, Vicente R. Org. Lett. 2009; 11: 4922
• 7r Jia X, Yang D, Zhang S, Cheng J. Org. Lett. 2009; 11: 4716
• 7s Ye Z, Wang W, Luo F, Zhang S, Cheng J. Org. Lett. 2009; 11: 3974
• 7t Yu W.-Y, Sit WN, Zhou Z, Chan AS.-C. Org. Lett. 2009; 11: 3174
• 7u Kakiuchi F, Kochi T, Mutsutani H, Kobayashi N, Urano S, Sato M, Nishiyama S, Tanabe T. J. Am. Chem. Soc. 2009; 131: 11310
• 7v Zhao X, Dimitrijevic E, Dong VM. J. Am. Chem. Soc. 2009; 131: 3466
• 7w Kochi T, Urano S, Seki H, Mizushima E, Sato M, Kakiuchi F. J. Am. Chem. Soc. 2009; 131: 2792
• 7x Kalyani D, Deprez NR, Desai LV, Sanford MS. J. Am. Chem. Soc. 2005; 127: 7330
• 8 The ICP test confirmed that FeI₂ contained copper (830 ppm) and palladium (3 ppm). However, as shown in Table 1, copper and palladium exhibited low activity for this transformation.
• 9a Bradsher CK, Beavers LE. J. Am. Chem. Soc. 1955; 77: 453
• 9b Mousseau JJ, Fortier A, Charette AB. Org. Lett. 2010; 12: 516
• 10a Sun C.-L, Li B.-J, Shi Z.-J. Chem. Rev. 2011; 111: 1293
• 10b Norinder J, Matsumoto A, Yoshikai N, Nakamura E. J. Am. Chem. Soc. 2008; 130: 5858
• 10c Yoshikai N, Asako S, Yamakawa T, Ilies L, Nakamura E. Chem. Asian J. 2011; 6: 3059
• 11 General Experimental Details: Under an air atmosphere, a reaction tube was charged with 2-arylpyridine (0.2 mmol), 2-bromo-1-phenylethanone (0.24 mmol), FeI₂ (25 mol%), CsI (0.25 mmol) and toluene–NMP (15:1, 1.5 mL). The mixture was stirred at 130 °C for 48 h in a sealed tube. After the completion of the reaction, as monitored by TLC, the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel to give the product. (10-Methylpyrido[2,1-a]isoindol-6-yl)(phenyl)-methanone (3d): ¹H NMR (500 MHz, CDCl₃): δ = 10.70 (d, J = 7.0 Hz, 1 H), 8.37 (d, J = 8.5 Hz, 1 H), 7.67–7.68 (m, 2 H), 7.51–7.55 (m, 4 H), 7.37 (d, J = 7.0 Hz, 1 H), 7.12–7.15 (m, 1 H), 7.00 (d, J = 7.0 Hz, 1 H), 6.71 (d, J = 8.5 Hz, 1 H), 2.88 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 183.8, 142.2, 137.9, 135.1, 132.6, 131.9, 130.5, 128.6, 128.2, 127.7, 125.3, 122.9, 120.2, 118.6, 118.0, 117.0, 114.1, 26.8. IR (prism): 1716, 1578, 1558, 1485, 1473, 1439, 1416, 1297, 1264, 1228, 1165, 1148, 1108, 1043, 1017, 972, 865, 848, 803, 775, 753, 736, 710, 701, 682, 656 cm^–1. HRMS (EI): m/z [M + H]⁺ C₂₀H₁₆NO: 286.1232; found: 286.1225