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

Ali Nikbakht; Saeed Balalaie; Fatemeh Baghestani; Frank Rominger

doi:10.1055/s-0037-1610502

Synlett, Table of Contents

Synlett 2018; 29(14): 1892-1896
DOI: 10.1055/s-0037-1610502

letter

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

Ali Nikbakht

^aPeptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran Email: balalaie@kntu.ac.ir

,

Saeed Balalaie *

^aPeptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran Email: balalaie@kntu.ac.ir

^bMedical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

,

Fatemeh Baghestani

^aPeptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran Email: balalaie@kntu.ac.ir

,

Frank Rominger

^cOrganisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany

› Author Affiliations

Abstract

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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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References

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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) Å³, 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

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