Catalyst-Free Synthesis of Fused Triazolo-Diazepino[5,6-b]Quinoline Derivatives via a Sequential Ugi-4CR–Nucleophilic Substitution–Intramolecular Click Reaction

Dedicated to Prof. Lutz Tietze on the occasion of his 75^th birthday

Abstract

A convenient, post-transformational reaction has been ­developed for the construction of highly diversified quinoline-fused triazolo-diazepinones featuring four diversification points by employing a catalyst-free Ugi four-component–nucleophilic substitution–intra­molecular click cycloaddition sequence. This approach provides a wide scope of products with good yields and high bond-forming efficiency.

Keywords

fused triazolo-diazepino[5,6-b]quinolone - sequential Ugi-4CR - nucleophilic substitution - intramolecular click reaction

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• 22 Procedure for the Synthesis of 5a To a solution of 2-chloro-3-formylquinoline (1a, 191 mg, 1 mmol) in MeOH (5 mL), benzylamine (2a, 0.132 mL, 1 mmol), phenylpropynoic acid (3a, 146 mg, 1 mmol), and cyclohexyl isocyanide (4a, 0.124 mL, 1 mmol) were added, respectively. The solution was stirred for 24 h at r.t. with reaction progress being monitored by TLC. After completion of reaction, the colorless solid was filtered and washed with EtOH to yield the Ugi product 5a (0.477 g, yield 89%). N-Benzyl-N-[1-(2-chloroquinolin-3-yl)-2-(cyclohexylamino)-2-oxoethyl]-3-phenylpropiolamide (5a) Rotamer ratio = 77:23; colorless solid (0.509 g, 95%); mp 202–204 °C. IR (KBr): ν_max = 3290 (NH), 2210 (C≡C), 1624 (C=O) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.05–1.90 (m, 10 H, 5 CH₂ of cyclohexyl), 3.73–3.87 (m, 1 H, CHNH of cyclohexyl), 4.64 (d, J = 15.2 Hz, 1 H, CH₂Ph of minor rotamer), 4.80–4.91 (m, 1 H, CH₂Ph of minor and major rotamer), 5.28 (d, J = 16.5 Hz, 1 H, CH₂Ph of major rotamer), 6.36 (s, 1 H, CH of major rotamer), 6.41 (d, J = 8.0 Hz, 1 H, NH of minor rotamer), 6.54 (s, 1 H, CH of minor rotamer), 6.71 (d, J = 7.9 Hz, 1 H, NH of major rotamer), 6.91–7.04 (m, 5.2 H, Ar), 7.25–7.40 (m, 5 H, Ar), 7.51–7.57 (m, 1.5 H, Ar), 7.65–7.70 (m, 1 H, Ar), 7.79–7.84 (m, 2 H, Ar), 8.10 (s, 1 H, Ar of minor rotamer), 8.46 (s, 1 H, Ar of major rotamer) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 24.7, 25.4, 32.6, 48.9, 51.7, 58.3, 81.8 (C≡C of alkyne), 91.7 (C≡C of alkyne), 119.7, 119.9, 126.7, 126.8, 127.2, 127.3, 127.5, 127.8, 128.0, 128.1, 128.3, 128.5, 128.6, 130.3, 131.1, 132.5, 136.3, 137.0, 140.1, 147.0, 150.9, 155.9 (C=O), 156.4(C=O), 166.6 (C=O), 167.0 (C=O) ppm. General Procedure for the Synthesis of 6a–o To a solution of aldehyde 1a,b (1 mmol) in MeOH (5 mL), amine 2a–c (1 mmol), acid 3a,b (1 mmol), and isocyanide 4a,b (1 mmol) were added, respectively. The solution was stirred for 24 h at r.t. After completion of the reaction, solvent was removed under reduced pressure and subsequently dissolved in DMF (3 mL). Sodium azide (1.5 mmol) was added to the mixture, the reaction vessel was evacuated and backfilled with argon, sealed and heated at 120 °C for 6 h. Reaction progress was monitored by TLC. After completion of reaction, the mixture was cooled to r.t., and then water (5 mL) was added, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over Na₂SO₄, filtered, and evaporated in vacuo. The residue was purified by column chromatography using n-hexane/EtOAc (1:1) as eluent. 5-Benzyl-N-cyclohexyl-4-oxo-3-phenyl-5,6-dihydro-4H-[1,2,3]triazolo[5′,1′:3,4][1,4]diazepino[5,6-b]quinoline-6-carboxamide (6a) Pale yellow solid (0.439 g, 81%); mp 187–189 °C. IR (KBr): ν_max = 3382 (NH), 1657 (C=O) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 0.43–1.36 (m, 10 H, 5 CH₂ of cyclohexyl), 3.23–3.33 (m, 1 H, CHNH of cyclohexyl), 4.96 (AB-q, J = 14.4 Hz, 2 H, CH₂Ph), 5.18 (s, 1 H, CH), 5.34 (d, J = 7.7 Hz, 1 H, NH), 7.26–7.34 (m, 5 H, Ar), 7.39–7.53 (m, 4 H, Ar), 7.62 (d, J = 7.8 Hz, 1 H, Ar), 7.69 (s, 1 H, Ar), 7.73 (t, J = 7.1 Hz, 1 H, Ar), 8.03–8.09 (m, 3 H, Ar) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 24.5, 24.6, 25.0, 32.0, 32.3 (5 CH₂ of cyclohexyl), 49.4 (CH₂Ph), 51.8 (CHNH of cyclohexyl), 62.6 (CH), 123.3, 127.5, 127.6, 127.7, 128.4, 128.6, 128.7, 129.2 (2 C), 129.3, 129.4, 129.5, 131.7, 135.5, 139.9, 140.0, 144.8, 146.8, 150.1, 158.9 (C=O), 164.7 (C=O) ppm. HRMS (ESI): m/z calcd for C₃₃H₃₁N₆O₂ [M + H]⁺: 543.2503; found: 543.2510; m/z calcd for C₃₃H₃₀N₆NaO₂ [M + Na]⁺: 565.2322; found: 565.2326; m/z calcd for C₃₃H₃₀KN₆O₂ [M + K]⁺: 581.2062; found: 581.2070; m/z calcd for C₆₆H₆₁N₁₂O₄ [2M + H]⁺: 1085.4933; found: 1085.4959; m/z calcd for C₆₆H₆₀N₁₂NaO₄ [2M + Na]⁺: 1107.4753; found: 1107.4759; m/z calcd for C₆₆H₆₀KN₁₂O₄ [2M + K]⁺: 1123.4492; found: 1123.4509. N-(tert-Butyl)-9-methyl-5-(4-methylbenzyl)-4-oxo-3-phenyl-5,6-dihydro-4H-[1,2,3]triazolo[5′,1′:3,4][1,4]diazepino[5,6-b]quinoline-6-carboxamide (6o) Pale yellow solid (0.435 g, 80%); mp 272–274 °C. IR (KBr): ν_max = 3340 (NH), 1667 (C=O) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 0.85 (s, 9 H, CMe₃), 2.34 (s, 3 H, Me), 2.56 (s, 3 H, Me), 4.93 (s, 2 H, CH₂Ph), 5.08 (s, 2 H, CH and NH), 7.13 (d, J = 7.8 Hz, 2 H, Ar), 7.26 (d, J = 7.8 Hz, 2 H, Ar), 7.41–7.53 (m, 4 H, Ar), 7.64–7.67 (m, 2 H, Ar), 8.05–8.08 (m, 2 H, Ar), 8.13 (d, J = 8.7 Hz, 1 H, Ar) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 21.1 (Me), 21.7 (Me), 27.8 (CMe ₃), 51.6 (CMe₃), 52.2 (CH₂Ph), 63.1 (CH), 123.6, 126.1, 126.2, 127.5, 127.7, 128.4, 128.6, 129.1, 129.3, 129.4, 129.9, 132.7, 134.0, 138.6, 138.8, 138.9, 144.2, 145.5, 149.9, 158.9 (C=O), 164.8 (C=O) ppm. HRMS (ESI): m/z calcd for C₃₃H₃₃N₆O₂ [M + H]⁺: 545.2664; found: 545.2660; m/z calcd for C₃₃H₃₂N₆NaO₂ [M + Na]⁺: 567.2482; found: 567.2479; m/z calcd for C₃₃H₃₂KN₆O₂ [M + K]⁺: 583.2223; found: 583.2218; m/z calcd for C₆₆H₆₅KO₄ [2M + H]⁺: 1089.5259; found: 1089.5246; m/z calcd for C₆₆H₆₄N₁₂NaO₄ [2M + Na]⁺: 1111.5072; found: 1111.5066; m/z calcd for C₆₆H₆₄KN₁₂O₄ [2M + K]⁺: 1127.4817; found: 1127.480. Colorless crystal (needle), dimensions 0.150 × 0.040 × 0.021 mm³, crystal system monoclinic, space group P2₁/c, Z = 4, a = 13.6737(4) Å, b = 16.7252(5) Å, c = 13.3234(4) Å, α = 90°, β = 114.541(2)°, γ = 90°, V = 2771.75(15) ų, ρ = 1.305 g/cm³, T = 100(2) K, θ _max = 68.565°, radiation Mo Kα, λ = 1.54186 Å, 0.5° omega scans with CCD area detector, covering the asymmetric unit in reciprocal space with a mean redundancy of 5.06 and a completeness of 99.0% to a resolution of 0.83 Å, 25512 reflections measured, 5035 unique (R(int) = 0.0374), 3856 observed (I > 2σ(I)), intensities were corrected for Lorentz and polarization effects, an empirical scaling and absorption correction was applied using X-Area LANA 1.70.0.0 (STOE, 2017) based on the Laue symmetry of the reciprocal space, μ = 0.67 mm^–1, T _min = 0.61, T _max = 1.84, structure refined against F ² with a full-matrix least-squares algorithm using the SHELXL-2016/6 (Sheldrick, 2016) software,²³ 376 parameters refined, hydrogen atoms were treated using appropriate riding models, goodness of fit 1.03 for observed reflections, final residual values R1(F) = 0.057, wR(F ²) = 0.157 for observed reflections, residual electron density –0.30 to 0.32 eÅ^–3. CCDC 1578505 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
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