A Convenient Synthesis of Functionalized 2,3-Diazaspiro[4.4]nona-1,6,8-trienes

Abstract

A convenient Michael addition/cyclization sequence of alkyl isocyanide–acetylenic ester zwitterionic adducts with various pyrazolone derivatives, leading to the formation of dialkyl 6-(alkylamino)-1-methyl-4-oxo-3-phenyl-9-aryl-2,3-diazaspiro[4.4]nona-1,6,8-triene-7,8-dicarboxylates in moderate to good yields, is described. The structure of the target compounds was confirmed by an X-ray diffraction study.

Key words

spiro compounds - 4-arylidenepyrazolones - alkyl isocyanides - acetylenic esters - domino reaction

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• 10 Typical Procedure for the Preparation of Compounds 4To a stirred mixture of 2 (1 mmol) and 3 (1.2 mmol) in dry toluene (3 mL) was added 1 (1.0 mmol). The mixture was heated at 80 °C for 4 h. After completion (TLC monitoring), the solvent was removed under reduced pressure and the residue was purified by column chromatography (SiO₂; n-hexane/EtOAc 4:1) to afford the products 4a–m.Dimethyl 6-(cyclohexylamino)-1-methyl-4-oxo-3,9-diphenyl-2,3-diazaspiro[4.4]nona-1,6,8-triene-7,8-dicarboxylate (4a)Yellow powder; yield: 0.38 g (70%); mp 142–144 °C. IR (KBr): 3443, 2930, 1725, 1658, 1588, 1450, 1351, 1253, 1209 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ = 0.88–0.91 (m, 2 H, CH₂), 1.10–1.13 (m, 2 H, CH₂), 1.22–1.31 (m, 2 H, CH₂), 1.46–1.58 (m, 2 H, CH₂), 1.61–1.79 (m, 2 H, CH₂), 2.06 (s, 3 H, Me), 2.85 (br s, 1 H, N-CH), 3.71 (s, 3 H, MeO), 3.75 (s, 3 H, MeO), 7.16 (d, ³ J = 8.6 Hz, 2 H, Ar-H), 7.20 (t, ³ J = 8.7 Hz, 2 H, Ar-H), 7.20 (t, ³ J = 8.7 Hz, 1 H, Ar-H), 7.23 (t, ³ J = 7.4 Hz, 1 H, Ar-H), 7.41 (t, ³ J = 7.7 Hz, 2 H, Ar-H), 7.72 (d, ³ J = 8.5 Hz, 2 H, Ar-H), 8.29 (br s, 1 H, NH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.1 (Me), 24.5 (CH₂), 24.6 (CH₂), 24.8 (CH₂), 34.5 (CH₂), 34.6 (CH₂), 51.0 (MeO), 52.1 (MeO), 54.1 (N-CH), 73.1 (C), 100.7 (C), 119.3 (2 CH), 123.3 (C), 125.9 (CH), 127.5 (2 CH), 128.1 (CH), 128.6 (2 CH), 129.0 (2 CH), 131.9 (C), 137.3 (C), 138.8 (C), 157.2 (C), 161.6 (C), 165.4 (C=O), 166.5 (C=O), 168.0 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 513 (100) [M⁺], 482 (4), 399 (13), 367 (22), 340 (18), 312 (12), 232 (15), 129 (13), 105 (10), 77(20), 55 (25). Anal. Calcd for C₃₀H₃₁N₃O₅ (513.59): C, 70.16; H, 6.08; N, 8.18. Found: C, 70.44; H, 6.10; N 8.21.
• 11 X-Ray Crystal Structure Determination of 4aThe X-ray diffraction measurement was carried out with a STOE IPDS 2T diffractometer with graphite-monochromated Mo-K_α radiation. A crystal suitable for X-ray analysis was obtained from EtOH solution, mounted on a glass fiber and used for data collection. Compound 4a crystallized in the monoclinic crystal system and P 21/c space group. For the unit cell a = 7.9800(16) Å, b = 12.750(3) Å, c = 26.360(5) Å, α = 90°, β = 94.07(3)°, γ = 90°, Z = 4, cell volume = 2675.2(10) ų and orientation matrixes for data collection were obtained by least-square refinement of the diffraction data from 4237 reflections for compound 4a. Diffraction data were collected in a series of ω scans in 1° oscillations and integrated by using the STOE X-AREA software package (see ref.¹³). The structure was solved by direct methods and subsequent difference Fourier maps and then refined on F ² to final R ₁ = 0.0508 and wR ₂ (all data) = 0.1176 by a full-matrix least-squares procedure by using anisotropic displacement parameters. Atomic factors are from the International Tables for X-ray Crystallography. All non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were placed in ideal positions and refined as riding atoms with relative isotropic displacement parameters. All refinements were performed with use of the X-STEP32, SHELXL-2014, and WinGX-2013.3 programs (see ref.¹⁴).
• 12 CCDC-1822520 contains the supplementary crystallographic data for compound 4a in this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
• 13 X-AREA: Program for the Acquisition and Analysis of Data, Version 1.30; STOE & Cie GmbH: Darmstadt, 2005;

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