Substituent-Dependent Chemoselective Synthesis of Highly Functionalized­ Benzo[h]quinolines and 4-Benzylpyrans from 2-Methyl-5-nitro-benzonitrile

Dedicated to Prof. Uli Kazmaier on his 59^th birthday

Abstract

A facile, efficient and atom-economic synthesis of highly substituted benzo[h]qninolines was established by reaction of 2-methyl-5-nitrobenzonitrile with suitably functionalized 2H-pyran-2-ones under basic conditions. We observed that the presence of a thiomethyl group at the C-4 position of pyran provides 6-aryl-4-(2-cyano-4-nitrobenzyl)-2-oxo-2H-pyran-3-carbonitrile exclusively without any trace of benzo[h]quinolines. Depending on the nature of the functional group at C-4 of the pyran ring, different products were achieved. To probe the mechanism, we performed control experiments and isolated 3-(1-amino-7-nitro-3-thiophen-2-yl-naphthalen-2-yl)-3-piperidin-1-yl-acrylonitrile, which, on further treatment with base, provided the benzo[h]quinolines. The structure of one the products was characterized by single-crystal X-ray diffraction.

Key words

2H-pyran-2-one - 2-methyl-5-nitro-benzonitrile - benzo[h]quinoline - 4-benzylpyran - chemoselective

• References

• 1 Tewey KM, Chen GL, Nelson EM, Liu LF. J. Biol. Chem. 1984; 259: 9182
• 2 Pommier Y, Covey JM, Kerrigan D, Markovits J, Pharm R. Nucleic Acids Res. 1987; 15: 6713
• 3 Larsen AK, Grondard L, Couprie J, Desoize B, Comoe L, Jardillier JC, Riou JF. Biochem. Pharmacol. 1993; 46: 1403
• 4 Makhey D, Gatto B, Yu C, Liu A, Liu LF, LaVoie EJ. Med. Chem. Res. 1996; 56: 2795
• 5 Nabiev I, Chourpa I, Riou JF, Nguyen CH, Lavelle F, Manfait M. Biochemistry 1994; 33: 9013
• 6a Zishiri VK, Joshi MC, Hunter R, Chibale K, Smith PJ, Summers RL, Martin RE, Egan TJ. J. Med. Chem. 2011; 54: 6959
• 6b Bellot F, Coslédéric F, Vendier L, Brocard J, Meunier B, Robert A. J. Med. Chem. 2010; 53: 4103
• 6c Klingenstein R, Melnyk P, Leliveld SR, Ryckebusch A, Korth C. J. Med. Chem. 2006; 49: 5300
• 7 Michael JP. Nat. Prod. Rep. 2008; 25: 166
• 8 Chen YW, Chen YL, Tseng CH, Liang CC, Yang CN, Yao YC, Lu PJ, Tzeng CC. J. Med. Chem. 2011; 54: 4446
• 9 Lilienkampf A, Mao J, Wan B, Wang Y, Franzblau SG, Kozikowski AP. J. Med. Chem. 2009; 52: 2109
• 10a Nandhakumar R, Suresh T, Jude AL. C, Kannan VR, Mohan PS. Eur. J. Med. Chem. 2007; 42: 1128
• 10b Kategaonkar AH, Shinde PV, Kategaonhar AH, Pasale SK, Shingate BB, Shingare MS. Eur. J. Med. Chem. 2010; 45: 3142
• 10c Sabatini S, Gosetto F, Manfroni G, Tabarrini O, Kaatz GW, Patel D, Cecchetti V. J. Med. Chem. 2011; 54: 5722
• 11 Mahata PK, Venkatesh C, Kumar UK. S, Ila H, Junjappa H. J. Org. Chem. 2003; 68: 3966
• 12 Piechowska J, Gryko DT. J. Org. Chem. 2011; 76: 10220
• 13 Younes L, Vincent H, Chandrasekaran Y, Desce MB, Acher FC, Nicolas P. J. Org. Chem. 2012; 77: 8294
• 14 Yadav DK, Rai R, Kumar N, Singh S, Misra S, Sharma P, Shaw P, Pérez-Sanchez H, Mancera RL, Choi HE, Kim MH, Pratap R. Scientific Reports 2017; 6: 38128
• 15a Jenekhe SA, Lu L, Alam MM. Macromolecules 2001; 34: 7315
• 15b Aggarwal AK, Jenekhe SA. Macromolecules 1991; 24: 6806
• 15c Zhang X, Shetty AS, Jenekhe SA. Macromolecules 1999; 32: 7422
• 16 Skraup ZH. Monatsh. Chem. 1881; 2: 139
• 17 Doebner O, Miller WV. Ber. Dtsch. Chem. Ges. 1884; 17: 1698
• 18 Cohn BE, Gustavson RG. J. Am. Chem. Soc. 1928; 50: 2709
• 19 Warren FL. J. Chem. Soc. 1936; 1366
• 20 Peters O, Friedrichsen W. Tetrahedron Lett. 1995; 36: 8581
• 21 Riesgo EC, Jin X, Thummel RP. J. Org. Chem. 1996; 61: 3017
• 22 Luo Y, Pan X, Wu J. Org. Lett. 2011; 13: 1150
• 23a Sakai N, Tamura K, Shimamura K, Ikeda R, Konakahara T. Org. Lett. 2012; 14: 836
• 23b Huang H, Jiang H, Chen K, Liu H. J. Org. Chem. 2009; 74: 5476
• 24 Korivi RP, Cheng CH. J. Org. Chem. 2006; 71: 7079
• 25 Jiang B, Si YG. J. Org. Chem. 2002; 67: 9449
• 26 Zhao P, Yan X, Yin H, Xi C. Org. Lett. 2014; 16: 1120
• 27 Al-Mutairi TM, Al-Hazimi HM, El-Baih FM. J. Saudi. Chem. Soc. 2009; 13: 199
• 28 Janin YL, Bisagni E, Carrez D. J. Heterocycl. Chem. 1993; 30: 1129
• 29 Pratap R, Ram VJ. Tetrahedron Lett. 2007; 48: 2755
• 30 Singh S, Yadav p, Sahu SN, Sharone A, Kumar B, Ram VJ. Synlett 2014; 25: 2599
• 31 Singh S, Panwar R, Althagafi, Sharma V, Chaudhary S. Tetrahedron Lett. 2015; 56: 5203
• 32 Singh S, Panwar R, Yadav P, Althagafi I, Sahu SN, Pratap R. RSC Adv. 2015; 5: 18335
• 33a Tominaga Y, Ushirogochi A, Matsuda Y. J. Heterocycl. Chem. 1987; 24: 1557
• 33b Gompper R, Kutter E, Töpfl W. Justus Liebigs Ann. Chem. 1962; 659: 90
• 33c Ram VJ, Verma M. Indian J. Chem. 1990; 29B: 624
• 34a Pratap R, Kumar B, Ram VJ. Tetrahedron 2006; 34: 8158
• 34b Pratap R, Kumar B, Ram VJ. Tetrahedron 2006; 62: 8158
• 34c Farhanullah F, Agarwal N, Goel A, Ram VJ. J. Org. Chem. 2003; 68: 2983
• 34d Tominaga Y, Ushirogouchi A, Matsuda Y, Kobayashi G. Chem. Pharm. Bull. 1984; 32: 3384
• 34e Ram VJ, Verma M, Hussaini FA, Shoeb A. J. Chem. Res., Synop. 1991; 98
• 35 Crystal data for C₂₄H₂₃FN₄O₂: A red crystal (0.220 × 0.200 × 0.180 mm³) was mounted on a capillary tube for indexing and intensity data collection at 298 K with an Oxford Xcalibur Sapphire3 CCD single-crystal diffractometer (Mo Kα radiation, λ = 0.71073 Å). Routine Lorentz and polarization corrections were applied, and an absorption correction was performed using the ABSCALE 3 program [CrysAlis Pro software system, Version 171.34; Oxford Diffraction Ltd., Oxford U. K., 2011]. Patterson methods were used to locate the heavy atoms (SHELXS-86), and the remaining atoms were located from successive Fourier maps (SHELXL-97). All the non-hydrogen atoms were refined anisotropically. All hydrogen atoms were calculated after each cycle of refinement using a Riding model, with C–H = 0.93 Å + U_iso(H) = 1.2U_eq(C) for aromatic H atoms, and with C–H = 0.97 Å + U_iso(H) = 1.2U_eq(C) for methylene H atoms. Crystal data: CCDC No 1862527 for C₂₄H₂₃FN₄O₂; M_r = 416.45, crystal system: monoclinic; space group C 2/c; a = 16.9960(14) Å, b = 8.9323(6) Å, c = 26.3854(19 Å, α = 90, β = 101.583, γ = 90; V = 3924.1(5); Z = 8, ρ_calcd = 1.410 Mg/m³ g cm^–3; μ = 0.099 mm^–1; F(000) = 1744.0, R1 = 0.0558 (3860) and wR2 = 01420 (5075) for I>2σ(I) and 226 parameters, R1= 0.0558 (3860) and wR2 = 01420 (5075), gof = 0.904 for all data.