Iodine-Mediated Diastereoselective Cyclopropanation of Arylidene Malononotriles by 2,6-Dimethylquinoline

Abstract

A novel iodine-mediated reaction of 2,6-dimethylquinoline with Knoevenagel condensation products of malononitrile with benzaldehydes, leading to a facile, one-pot synthesis of 2-aryl-3-(6-methylquinolin-2-yl)cyclopropane-1,1-dicarbonitriles, in moderate to good yields, is described.

Keywords

diastereoselective reactions - cyclopropanation - small rings - iodine - N-heterocycles

• References and Notes

• 1a Rubin M, Rubina M, Gevorgyan V. Chem. Rev. 2007; 107: 3117
• 1b Cousins GS, Hoberg JO. Chem. Soc. Rev. 2000; 29: 165
• 2a Reissig H.-U, Zimmer R. Chem. Rev. 2003; 103: 1151
• 2b Reichelt A, Martin SF. Acc. Chem. Res. 2006; 39: 433
• 3a Katagiri T, Irie M, Uneyama K. Org. Lett. 2000; 2: 2423
• 3b Bryson TA, Koen JH. Jr, Roth GA. Synlett 1992; 723
• 4a Epstein JW, Brabander HJ, Fanshawe WJ, Hofmann CM, McKenzie TC, Safir SR, Osterberg AC, Cosulich DB, Lovell FM. J. Med. Chem. 1981; 24: 481
• 4b Vervisch K, D’hooghe M, Törnroos KW, De Kimpe N. Org. Biomol. Chem. 2009; 7: 3271
• 5a Kusumoto T, Nakayama A, Sato K, Hiyama T, Takehara S, Osawa M, Nakamura K. Chem. Lett. 1992; 2047
• 5b Kusumoto T, Nakayama A, Sato K, Hiyama T, Takehara S, Shoji T, Osawa M, Kuriyama T, Nakamura K, Fujisawa T. Tetrahedron Lett. 1991; 32: 939
• 6a Burgess K, Ho KK, Moye-Sherman D. Synlett 1994; 575
• 6b Stammer CH. Tetrahedron 1990; 46: 2231
• 6c Doyle MP, Forbes DC. Chem. Rev. 1998; 98: 911
• 6d Papageorgiou CD, Cubillo de Dios MA, Ley SV, Gaunt MJ. Angew. Chem. Int. Ed. 2004; 43: 4641
• 6e Ishikawa S, Sheppard TD, D’Oyley JM, Kamimura A, Motherwell WB. Angew. Chem. Int. Ed. 2013; 52: 10060
• 6f Zhu C, Yoshimura A, Ji L, Wei Y, Nemykin VN, Zhdankin VV. Org. Lett. 2012; 14: 3170
• 6g Hartikka A, Arvidsson PI. J. Org. Chem. 2007; 72: 5874
• 6h Goudreau SR, Marcoux D, Charette AB. J. Org. Chem. 2009; 74: 470
• 6i Xie H, Zu L, Li H, Wang J, Wang W. J. Am. Chem. Soc. 2007; 129: 10886
• 7 Lebel H, Marcoux JF, Molinaro C, Charette AB. Chem. Rev. 2003; 103: 977
• 8 Corey EJ, Chaykovsky M. J. Am. Chem. Soc. 1965; 87: 1353
• 9a Yavari I, Hosseinpour R, Pashazadeh R. Synlett 2012; 1662
• 9b Yavari I, Hosseinpour R, Pashazadeh R. Synlett 2012; 2103
• 9c Yavari I, Hosseinpour R, Pashazadeh R, Ghanbari E. Tetrahedron Lett. 2013; 54: 2785
• 9d Yavari I, Pashazadeh R, Hosseinpour R. Helv. Chim. Acta 2012; 95: 169
• 9e Yavari I, Hosseinpour R, Pashazadeh R, Ghanbari E, Skoulika S. Tetrahedron 2013; 69: 2462
• 10 Diastereoselective Synthesis of 4; General Procedure: A mixture of 2,6-dimethylquinoline (0.157 g, 1 mmol), pyridine (0.158 g, 2 mmol), and I₂ (0.253 g, 1 mmol) was warmed to 50 °C for 1 h. A solution of aryl aldehyde (1 mmol), malononitrile, and (i-Pr)₂NEt (0.284 g, 2.2 mmol) in MeCN (3 mL) was then added and the reaction mixture was stirred for 5 h. Upon completion of reaction, as evidenced by TLC, solvent was removed in vacuo, and the residue was diluted with CHCl₃ (20 mL), and washed with saturated K₂CO₃ solution (3 × 10 mL), and H₂O (3 × 10 mL). The organic layer was evaporated to give the crude product, which was purified by silica gel (Merck 230–240 mesh) column chromatography (gradient hexane–EtOAc) to afford 4.2-(4-Bromophenyl)-3-(6-methylquinolin-2-yl)cyclopropane-1,1-dicarbonitrile (4a): Yield: 0.23 g (60%); colorless powder; mp 200–202 °C. R_f  = 0.71 (hexane–EtOAc, 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.18 (d, J = 8.2 Hz, 1 H), 8.01 (d, J = 8.7 Hz, 1 H), 7.65–7.56 (m, 5 H), 7.36 (d, J = 8.2 Hz, 2 H), 4.50 (d, J = 8.2 Hz, 1 H), 3.76 (d, J = 8.2 Hz, 1 H), 2.58 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 148.3 (C), 146.2 (C), 137.6 (C), 136.8 (CH), 132.8 (CH), 132.4 (2 CH), 130.2 (2 CH), 129.9 (C), 129.1 (CH), 127.9 (C), 126.5 (CH), 123.7 (C), 121.7 (CH), 113.1 (CN), 112.3 (CN), 38.9 (CH), 37.3 (CH), 21.7 (Me), 16.0 [C(CN)₂]. IR (KBr): 2244, 1590, 1490 cm^–1. MS (EI): m/z (%) = 387 (5) [M]⁺, 360 (10), 353 (7), 307 (15), 282 (10), 266 (5), 242 (12), 232 (15), 207 (10), 182 (100), 157 (13), 142 (46), 127 (11), 115 (48), 101 (8), 89 (27), 75 (18), 63 (25), 51 (24). Anal. Calcd for C₂₁H₁₄BrN₃: C, 64.96; H, 3.63; N, 10.82. Found: C, 64.98; H, 3.67; N, 10.78. X-ray Crystal-Structure Determination of 4a: Formula: C₂₁H₁₄BrN₃; M_r 388.26; monoclinic; space group P21/n; a = 9.844(1), b = 14.911(1), c = 12.959(1) Å; Z = 4; V = 1828.1(3) Å³; D_calc. = 1.411 Mg/m³; Mo K_α radiation (0.71073 Å), T = 293(2) K; 3644 reflections collected on a Bruker P4 diffractometer, 3179 unique (R _int = 0.0670), 1555 unique reflections with I > 2σ(I). All non-hydrogen atoms have been located by difference Fourier maps and refined anisotropically. The hydrogen atoms have been placed on calculated positions and refined isotropically by using the Riding model. Final indices [I > 2σ(I)]: R1 = 0.0556, wR2 = 0.0999, GOF = 0.979. The crystallographic data of 4a have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC-976608. Copies of the data can be obtained, free of charge, via the internet (http://www.ccdc.cam.ac.uk/data_request/cif), e-mail: [e-mail], or fax: [phone].
• 11 Burnett AM. N, Johnson CK. Oak Ridge National Laboratory Report ORNL-6895 . Oak Ridge National Laboratory; Tennessee: 1996