A One-Pot Synthesis of Highly Functionalized Indolizines by 1,3-Dipolar Cycloaddition of Azomethine Ylides and Phosphorylated Hydroxyketenimines

Abstract

Alkyl 2-(alkylamino)-3-(quinolin-2-yl)indolizine-1-carboxylates were prepared by1,3-dipolar cycloaddition of azomethine ylides with phosphorylated hydroxyketenimines, generated in situ by a Nef isocyanide–Perkow cascade.

Key words

Nef reaction - Perkow reaction - cascade reaction - indolizines - dipolar cycloaddition - azomethine ylides

• References and Notes


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• 10 Quinolinylindolizines 5; General Procedure A mixture of 2-methylquinoline (0.286 g, 2 mmol) with pyridine or isoquinoline (4 mmol) and I₂ (0.506 g, 2 mmol) in MeCN (4 mL) was warmed to 60 °C for 2 h. (i-Pr)₂NEt (0.541 g, 4.2 mmol) and a solution of the appropriate ketenimine 1 (2 mmol) in MeCN (1 mL) were added, and the mixture was kept overnight at 60 °C then placed in a freezer for 24 h. The precipitate was collected by filtration and crystallized [hexane–EtOAc (1:5)]. Ethyl 2-(Cyclohexylamino)-3-quinolin-2-ylindolizine-1-carboxylate (5b) Yellow crystals; yield: 0.52 g (68%); mp 227–229 °C. IR (KBr): 3436, 3105, 2928, 2850, 1696, 1600, 1547, 1502, 1448, 1265, 1194 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.97–1.02 (m, 2 H), 1.11–1.26 (m, 3 H), 1.39–1.42 (m, 1 H), 1.48 (t, J = 7.1 Hz, 3 H), 1.58–1.61 (m, 2 H), 1.86–1.89 (m, 2 H), 2.97–2.03 (m, 1 H), 4.44 (q, J = 7.1 Hz, 2 H), 6.10 (br s, 1 H), 6.78 (t, J = 6.9 Hz, 1 H), 7.17 (t, J = 7.8 Hz, 1 H), 7.51 (t, J = 7.1 Hz, 1 H), 7.72 (t, J = 7.1 Hz, 1 H), 7.80 (d, J = 7.8 Hz, 1 H), 8.08–8.13 (m, 4 H), 9.93 (d, J = 7.0 Hz, 1 H). ¹³C NMR (125.7 MHz, CDCl₃): δ = 14.6 (Me), 24.7 (2 CH₂), 25.7 (CH₂), 33.7 (2 CH₂), 57.1 (CH₂O), 59.4 (CH), 94.9 (C), 111.1 (CH), 112.5 (C), 118.0 (C), 122.0 (CH), 124.2 (CH), 124.4 (CH), 125.3 (CH), 125.7 (C), 127.4 (CH), 128.6 (CH), 129.5 (CH), 135.3 (C), 136.1 (CH), 144.8 (CH), 147.3 (C), 152.3 (C), 166.3 (C=O). MS (EI): m/z (%) = 413 (100) [M⁺], 330 (46), 315 (53), 285 (34), 242 (30), 128 (50), 98 (40), 83 (35), 73 (55). Anal. Calcd for C₂₆H₂₇N₃O₂ (413.51): C, 75.52; H, 6.58; N, 10.16. Found: C, 75.98; H, 6.64; N, 10.22. X-ray Crystal-Structure Determination of 5b Yellow crystals of compound 5b suitable for single-crystal X-ray diffraction measurements (crystal dimensions: 0.18 × 0.12 × 0.09 mm) were grown by slow evaporation of a solution in EtOH–EtOAc. The unit cell dimensions were determined from 658 reflections. The structure was solved by direct methods and refined by full matrix least-squares calculations based on F² to a final R1 = 0.0404 and wR2 (all data) = 0.0805, by using SHELXL-2014 and WinGX-2013.3 programs.¹² Compound 5b crystallized in the monoclinic system with space group P2₁/n. A single molecule with molecular formula of C₂₆H₂₇N₃O₂ was found in the asymmetric unit, giving a total Z = 4 for the unit cell; a = 11.911(2), b = 10.311(2), c = 18.106(4), β = 90.68(3), cell volume V = 2223.5(8)ų; measurement temperature 293(2) K, measurement range: 2.036 < θ < 24.713; 3767 independent reflections and maximum/minimum residual electron density [e ų]: 0.136 /–0.13. All nonhydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were placed in ideal positions and refined as riding atoms with relative isotropic displacement parameters. An ORTEP view of the structure is shown in Figure 1. CCDC 1457966 contains the supplementary crystallographic data for compound 5b in this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 11 Methyl 2-(Cyclohexylamino)-3-quinolin-2-ylpyrrolo[2,1-a]isoquinoline-1-carboxylate (11a) Yellow crystals; yield: 0.61 g (80%); mp 231–233 °C. IR (KBr): 3347, 3110, 2928, 2850, 1689, 1599, 1546, 1502, 1448, 1265, 1194 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.94–1.01 (m, 2 H), 1.11–1.17 (m, 3 H), 1.39–1.42 (m, 1 H), 1.56–1.59 (m, 2 H), 1.86–1.88 (m, 2 H), 2.79–2.81 (m, 1 H), 4.04 (s, 3 H), 5.46 (br s, 1 H), 6.99 (d, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.9 Hz, 1 H), 7.50 (d, J = 6.8 Hz, 1 H), 7.51 (t, J = 8.5 Hz, 1 H), 7.62 (d, J = 7.9 Hz, 1 H), 7.72 (t, J = 7.9 Hz, 1 H), 7.79 (d, J = 7.9 Hz, 1 H), 8.13 (d, J = 6.8 Hz, 1 H), 8.14 (t, J = 8.5 Hz, 1 H), 8.27 (d, J = 8.6 Hz, 1 H), 8.94 (d, J = 8.6 Hz, 1 H), 9.54 (d, J = 7.5 Hz, 1 H). ¹³C NMR (125.7 MHz, CDCl₃): δ = 25.1 (2 CH₂), 25.7 (CH), 33.8 (2 CH2), 51.4 (MeO), 57.9 (CH), 101.8 (C), 112.8 (CH), 113.8 (C), 122.5 (C), 123.1 (CH), 123.2 (CH), 124.8 (C), 126.0 (CH), 126.3 (CH), 126.4 (CH), 126.6 (CH), 126.8 (CH), 127.1 (CH), 127.5 (C), 129.5 (CH), 129.9 (CH), 131.3 (C), 135.6 (CH), 141.7 (C), 147.5 (C), 152.1 (C), 166.9 (C=O). MS (EI): m/z (%) = 449 (100) [M]⁺, 416 (42), 374 (50), 346 (30), 308 (55), 279 (30), 240 (32), 208 (30), 167 (20), 128 (50), 83 (40), 55 (45). Anal. Calcd for C₂₉H₂₇N₃O₂ (449.54): C, 77.48; H, 6.05; N, 9.35. Found: C, 78.02; H, 6.11; N, 9.42.

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