Regio- and Diastereoselective Synthesis of Novel Polycyclic Pyrrolo[2,1-a]isoquinolines Bearing Indeno[1,2-b]quinoxaline Moieties by a Three-Component [3+2]-Cycloaddition Reaction

Abstract

A regio- and diastereoselective synthesis of 2,3-dihydro-10b′H-spiro[indeno[1,2-b]quinoxaline-11,1′-pyrrolo[2,1-a]isoquinoline]-2′,3′-diylbis(phenylmethanone) derivatives containing four contiguous chiral stereocenters was achieved through 1,3-dipolar cycloaddition of isoquinolinium N-ylides in a one-pot three-component reaction. The desired products were obtained in short reaction times and in moderate to high yields (up to 92%) under relatively mild reaction conditions. The structure and relative stereochemistry of the desired product was confirmed by X-ray diffraction analysis.

Key words

pyrroloisoquinolines - indenoquinoxalines - spiro compounds - diastereoselectivity - 1,3-dipolar cycloaddition - multicomponent reaction

• References and Notes

• 1a Marco E, Laine W, Tardy C, Lansiaux A, Iwao M, Ishibashi F, Bailly C, Gago F. J. Med. Chem. 2005; 48: 3796
• 1b Xiang L, Xing D, Wang W, Wang R, Ding Y, Du L. Phytochemistry 2005; 66: 2595
• 1c Wang RF, Yang XW, Ma CM, Cai SQ, Li JN, Yukihiro S. Heterocycles 2004; 63: 1443
• 1d Zhang Q, Tu G, Zhao Y, Cheng T. Tetrahedron 2002; 58: 6795
• 1e Reddy MV. R, Rao MR, Rhodes D, Hansen MS. T, Rubins K, Bushman FD, Venkateswarlu Y, Faulkner DJ. J. Med. Chem. 1999; 42: 1901
• 1f Andersen RJ, Faulkner DJ, Heng HC, Van Duyne GD, Clardy J. J. Am. Chem. Soc. 1985; 107: 5492
• 2a Tangdenpaisal K, Worayuthakarn R, Karnkla S, Ploypradith P, Intachote P, Sengsai S, Saimanee B, Ruchirawat S, Chittchang M. Chem. Asian J. 2015; 10: 925
• 2b Theppawong A, Ploypradith P, Chuawong P, Ruchirawat S, Chittchang M. Chem. Asian J. 2015; 10: 2631
• 2c Plisson F, Huang XC, Zhang H, Khalil Z, Capon RJ. Chem. Asian J. 2012; 7: 1616
• 3 Su B, Cai C, Deng M, Liang D, Wang L, Wang Q. Bioorg. Med. Chem. Lett. 2014; 24: 2881
• 4 Cavallito CJ, Gray AP. FR 2135297, 1972 ; Chem. Abstr. 1973, 79, 96989
• 5 Maryanoff BE, Vaught JL, Shank RP, McComsey DF, Costanzo MJ, Nortey SO. J. Med. Chem. 1990; 33: 2793
• 6 Maryanoff BE, McComsey DF, Gardocki JF, Shank RP, Constanzo MJ, Nortey SO, Schneider CR, Setler PE. J. Med. Chem. 1987; 30: 1433
• 7 Kurasawa Y, Kim HO. J. Heterocycl. Chem. 2002; 39: 551
• 8 Monge A, Palop JA, Urbasos I, Fernández-Alvarez E. J. Heterocycl. Chem. 1989; 26: 1623
• 9 Vicente E, Pérez-Silanes S, Lima LM, Ancizu S, Burguete A, Solano B, Villar R, Aldana I, Monge A. Bioorg. Med. Chem. 2009; 17: 385
• 10 Becker I. J. Heterocycl. Chem. 2008; 45: 1005
• 11 Guillon J, Moreau S, Mouray E, Sinou V, Forfar I, Fabre SB, Desplat V, Millet P, Parzy D, Jarry C, Grellier P. Bioorg. Med. Chem. 2008; 16: 9133
• 12 Abouzid KA. M, Khalil NA, Ahmed EM, Abd El-Latif HA, El-Araby ME. Med. Chem. Res. 2010; 19: 629
• 13 Wagle S, Adhikari AV, Kumari NS. Eur. J. Med. Chem. 2009; 44: 1135
• 14 Kleim JP, Bender R, Billhardt UM, Meichsner C, Riess G, Rösner M, Winkler I, Paessens A. Antimicrob. Agents Chemother. 1993; 37: 1659
• 15 Kulkarni NV, Revankar VK, Kirasur BN, Hugar MH. Med. Chem. Res. 2012; 21: 663
• 16 Amin KM, Ismail MM. F, Noaman E, Soliman DH, Ammar YA. Bioorg. Med. Chem. 2006; 14: 6917
• 17 Dailey S, Feast JW, Peace RJ, Sage IC, Till S, Wood EL. J. Mater. Chem. 2001; 11: 2238
• 18 Mizuno T, Wei W.-H, Eller LR, Sessler JL. J. Am. Chem. Soc. 2002; 124: 1134
• 19 Crossley JC, Johnston LA. Chem. Commun. 2002; 1122
• 20a Gazit A, App H, McMahon G, Chen J, Levitzki A, Bohmer FD. J. Med. Chem. 1996; 39: 2170
• 20b Sehlstedt U, Aich P, Bergman J, Vallberg H, Nordén B, Gräslund A. J. Mol. Biol. 1998; 278: 31
• 20c Ling R, Yoshida M, Mariano PS. J. Org. Chem. 1996; 61: 4439
• 21a Eryazici I, Moorefield CN, Durmus S, Newkome GR. J. Org. Chem. 2006; 71: 1009
• 21b Tu SJ, Jia RH, Jiang B, Zhang JY, Zhang Y, Yao CS, Ji SJ. Tetrahedron 2007; 63: 381
• 22 Sandeep C, Padmashali B, Kulkarni RS. Tetrahedron Lett. 2013; 54: 6411
• 23 Prasanna P, Kumar SV, Gunasekaran P, Perumal S. Tetrahedron Lett. 2013; 54: 3740
• 24 Wu L, Sun J, Yan C.-G. Org. Biomol. Chem. 2012; 10: 9452
• 25 García Ruano JL, Fraile A, Martín MR, González G, Fajardo C, Martín-Castro AM. J. Org. Chem. 2011; 76: 3296
• 26 Moghaddam FM, Khodabakhshi MR, Ghahremannejad Z, Foroushani BK, Ng SW. Tetrahedron Lett. 2013; 54: 2520
• 27 Matloubi Moghaddam F, Kiamehr M, Khodabakhshi MR, Jebeli Javan M, Fathi S, Villinger A, Iaroshenko VO, Langer P. Helv. Chim. Acta 2013; 96: 2103
• 28 Matloubi Mogaddam F, Eslami M, Siahpoosh A, Golfam H. New J. Chem. 2019; 43: 10318
• 29 Alizadeh A, Moafi L. Heterocycl. Commun. 2017; 23: 375
• 30 Alizadeh A, Mohammadi R, Bayat F, Zhu LG. Tetrahedron 2017; 73: 4433
• 31 1-Aryl-2-(11H-indeno[1,2-b]quinoxalin-11-ylidene)ethanones 3; General Procedure NaOAc (1.5 mmol) was added to a solution of ninhydrin (1 mmol) and the appropriate phenylenediamine 1 (1 mmol) in EtOH (4 mL), and the solution was stirred for 1 h at r.t. Then, the appropriate 1-aryl-2-(triphenylphosphoranylidene)ethanone 4 (1.5 mmol) was added and the mixture was stirred at the reflux until the reaction was complete (TLC; 2 h). The mixture was then filtered and the product was recrystallized from EtOH.
• 32 Products 6a–o : General Procedure A mixture of isoquinoline (1 mmol) and the appropriate phenacyl bromide 5 (1 mmol) in CH₃CN (3 mL) was stirred at r.t. for 15 min. Et₃N (1 mmol) and the appropriate ketone 3 (1 mmol) were added, and the mixture was stirred under reflux until the reaction was complete (TLC; hexane–EtOAc, 1:2). The pure products was then simply collected by filtration and dried in air. (2′-Benzoyl-2′,3′-dihydro-10b′H-spiro[indeno[1,2-b]quinoxaline-11,1′-pyrrolo[2,1-a]isoquinolin]-3′-yl)(4-tolyl)methanone (6b) Orange solid; yield: 411 mg (69%); mp 207–209 °C. IR (KBr) = 1679, 1615, 14.99, 1460, 1328, 1238, 1130 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ_H = 2.41 (s, 3 H, CH₃), 5.23 (d, ³ J _HH = 7.5 Hz, 1 H, CH pyrrolidine), 5.31 (d, ³ J _HH = 5.4 Hz, 1 H, olefinic CH), 5.36 (d, ³ J _HH = 7.7 Hz, 1 H, N–CH pyrrolidine), 6.25–6.28 (t, ³ J _HH = 7.5 Hz, 1 H, H–Ar), 6.38 (s, 1 H, benzylic CH), 6.43 (d, ³ J _HH = 5.4 Hz, 1 H, olefinic CH–N), 6.53 (d, ³ J _HH = 7.5 Hz, 1 H, H–Ar), 6.56–6.60 (t, ³ J _HH = 7.5 Hz, 2 H, H–Ar), 6.65 (d, ³ J _HH = 7.5 Hz, 1 H, H–Ar), 6.70–6.75 (m, 3 H, H–Ar), 6.99–7.02 (t, ³ J _HH = 7.5 Hz, 1 H, H–Ar), 7.20–7.23 (t, ³ J _HH = 7.5 Hz, 1 H, H–Ar), 7.32 (d, ³ J _HH = 7.5 Hz, 3 H, H–Ar), 7.62 (d, ³ J _HH = 7.5 Hz, 1 H, H–Ar), 7.78–7.81 (m, 3 H, H–Ar), 8.07 (d, ³ J _HH = 9.5 Hz, 1 H, H–Ar), 8.10 (d, ³ J _HH = 8.0 Hz, 2 H, H–Ar), 8.32 (d, ³ J _HH = 9.4 Hz, 1 H, H–Ar). ¹³C NMR (125 MHz, CDCl₃): δ_C = 21.7, 57.3, 65.3, 65.9, 69.8, 98.3, 121.2, 124.0, 124.1, 124.6, 126.1, 127.1, 127.2, 127.4, 127.6, 128.5, 128.9, 129.0, 129.1, 129.6, 129.7, 129.8, 130.9, 132.5, 132.8, 132.9, 134.0, 136.6, 137.3, 141.5, 142.2, 144.3, 144.7, 154.5, 160.4, 197.0, 197.4. Anal. calcd for C₄₁H₂₉N₃O₂ (595.70): C, 82.67; H, 4.91; N, 7.05. Found: C, 82.64; H, 4.96; N, 6.97. Crystal Data for 6b: C₄₁H₂₉N₃O₂: M_W = 595.67, monoclinic, P21/c, a = 10.0450(8) Å, b = 17.0959(14) Å, c = 18.8967(15) Å, β = 104.646(2)°, V = 3139.7(4) ų, Z = 4, D _c = 1.293 mg/m³, F(000) = 1281; crystal dimensions: 0.26 × 0.15 × 0.12 mm, radiation, Mo Kα (λ = 0.71073 Å), 3.424 ≤ 2θ ≤ 26.999, intensity data were collected at 123(2) K with a Bruker APEX area-detector diffractometer, employing the ω/2θ scanning technique, in the range –12 ≤ h ≤ 12, –21 ≤ k ≤ 21, –24 ≤ l ≤ 24. The structure was solved by a direct method; all nonhydrogen atoms were positioned and anisotropic thermal parameters were refined from 6837 observed reflections with R _(into) = 0.0404 by a full-matrix least-squares technique converging to R1 = 0.0520, and wR2 = 0.1166 [I > 2σ(I)].
• 33 CCDC 1949927 contains the supplementary crystallographic data for compound 6b. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.