Efficient Synthesis of Indole Derivatives Containing the Tetrazole Moeity Utilizing an Ugi-Azide Post-Transformation Strategy

Dedicated to Prof. Bernhard Breit on the occasion of his birthday

Abstract

An efficient strategy has been developed for the synthesis of indole derivatives containing the tetrazole moiety using a AuCl₃-catalyzed cyclization reaction. The precursors of the cycloadduct were easily prepared by an Ugi-azide 4-CR in methanol at room temperature. The merit of this protocol lies in its operational simplicity, readily available starting materials, high yields of product, and good functional group tolerance.

Key words

Ugi-azide post-transformation strategy - metal catalyzed alkyne cyclization - heterocyclization - indole - tetrazole

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• 26 HRMS data were collected using an Apex-QC-FT- ICR instrument with ESI. General Procedure for the Synthesis of Compounds 5a–i 2-(Phenylethynyl)aniline in MeOH (5 ml) and cyclohexanone (1 mmol) were stirred at room temperature for 2 h, then the requisite isocyanide (1 mmol) and trimethylsilyl azide were added. The mixture was stirred for 24 h until the reaction was completed. Then, the desired product was either filtered off as a white solid filtered for 5a–e (ketone derivatives) or purified using column chromatography on silica gel (n-hexane/EtOAc, 9:1) for 5f–i (aldehyde derivatives). The yields were in the range of 75–92%. General Procedure for the Synthesis of Compounds 6a–i The products 5a–i (1mmol) and AuCl₃ (5 mol%, 15 mg) were added to a reaction flask containing toluene (10 mL). After 12 h the toluene was evaporated under reduced pressure. The crude products were purified by silica gel chromatography (n-hexane/EtOAc, 7:1) to obtain the indole derivatives. N-[4-(tert-Butyl)-1-(1-cyclohexyl-1H-tetrazol-5-yl) cyclohexyl]-2-(phenylethynyl) aniline (5d) Colorless solid; yield 440 mg, (80%); R_f = 0.45 (PE/EtOAc 3:1); mp 142–146 °C. IR (KBr): ν = 1586, 2197, 3377 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 0.84 (s, 9 H, t-Bu), 1.16–1.34 (m, 4 H, H_Cyclohexyl), 1.42–1.68 (m, 5 H, H_Cyclohexyl), 1.73–1.93 (m, 8 H, H_Cyclohexyl), 2.87–2.91 (m, 2 H, H_Cyclohexyl), 4.72 (m, 1 H, CHN), 5.07 (s, 1 H, NH), 6.08 (d, 1 H, J = 8.1 Hz, H-Ar), 6.63 (t, 1 H, J = 7.5 Hz, H-Ar), 6.86–6.92 (dt, 1 H, J = 7.2, 1.5 Hz, H-Ar), 7.3(dd, 1 H, J = 8.1, 1.2 Hz, H-Ar), 7.34–7.43(m, 3 H, H-Ar), 7.53–7.56 (m, 2 H, H-Ar) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 23.7, 24.8, 25.6, 27.5, 32.4, 33.5, 39.0, 47.6, 54.4, 59.2, 85.6, 95.7, 108.8, 111.8, 118.0, 123.0, 128.6, 128.7, 129.9, 131.3, 132.1, 145.4, 153.3 ppm. 1-[4-(tert-Butyl)-1-(1-cyclohexyl-1H-tetrazol-5-yl) cyclohexyl]-2-phenyl-1H-indole (6d) Colorless solid; yield 417.6 mg (87%); R_f = 0.38 (PE/EtOAc, 3:1); mp 178–181 °C. IR (KBr): ν = 1453, 1611, 2940 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 0.78 (s, 9 H, t-Bu), 0.88–1.56 (m, 17 H, H_Cyclohexyl), 2.10–2.30 (m, 2 H, H_Cyclohexyl), 3.10–3.15 (m, 1 H, H_Cyclohexyl), 6.47 (s, 1 H, H-3 indole), 6.82 (t, 1 H, J = 8.4 Hz, H-Ar), 6.89(dt, 1 H, J = 7.2, 1.2 Hz, H-Ar), 7.01 (t, 1 H, J = 7.2, H-Ar), 7.46–7.59(m, 6 H, H-Ar) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 14.1, 23.9, 24.7, 25.3, 25.4, 26.9, 27.4, 31.2, 32.3, 32.8, 38.1, 38.6, 46.9, 47.0, 58.1, 62.5, 108.1, 112.4, 120.5, 121.3, 122.6, 124.0, 126.0, 128.3, 128.4, 137.1, 137.5, 140.9, 156.4 ppm. HRMS (ESI): m/z calcd for C₃₁H₄₀N₅ [M + H]⁺: 482.3272; found: 482.3288; C₃₁H₃₉N₅Na [M + Na]⁺: 504.3097; found: 504.3106. Colorless crystal (polyhedron), dimensions 0.130 × 0.120 × 0.050 mm³, crystal system triclinic, space group P, Z = 2, a = 10.4530(5) Å, b = 12.9781(6) Å, c = 13.3411(6) Å, α = 108.2879(14)°, β = 112.3234(14)°, γ = 100.5989(14)°, V = 1491.99(12) ų, ρ = 1.189 g cm^–3, T = 200(2) K, θ _max= 22.980°, raduiation Mo Kα, λ = 0.71073 Å, 0.5° ω scans with CCD area detector, covering the asymmetric unit in reciprocal space with a mean redundancy of 3.1 and a completeness of 98.3% to a resoltion of 0.91 Å, 12857 reflections measured, 4082 unique (R _(int) = 0.0380), 2672 observed (I > 2σ(I)), intensities were corrected for Lorentz and polarization effects, an empirical scaling and absorption correction was applied using SADABS based on the Laue symmetry of the reciprocal space, μ = 0.09 mm^–1, T _min = 0.93, T _max = 0.96, structure refined against F ² with a full-matrix least-squares algorithm using the SHELXL-2014/7 (Sheldrick, 2014) software, 393 parameters refined, hydrogen atoms were treated using appropriate riding models, goodness of fit 1.05 for observed reflections, final residual values R1(F) = 0.052, wR(F²) = 0.125 for observed reflections, residual electron density –0.21 to 0.14 eÅ^–3. 27CCDC 1551544 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 27 Sheldrick GM. Acta Crystallogr., Sect. C: Struct. Chem. 2015; 71: 3