CC BY-ND-NC 4.0 · SynOpen 2018; 02(03): 0222-0228
DOI: 10.1055/s-0037-1610205
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Synthesis of Fully Functionalized 3-Bromoazaspiro[4.5]trienones through Ugi Four-Component Reaction (Ugi-4CR) followed by ipso-Bromocyclization

a  Peptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran   Email: balalaie@kntu.ac.ir
b  Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
,
Hadiseh Bakhshaei Ghoroghaghaei
a  Peptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran   Email: balalaie@kntu.ac.ir
,
Nahid S. Alavijeh
a  Peptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran   Email: balalaie@kntu.ac.ir
,
Fatemeh Darvish
a  Peptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran   Email: balalaie@kntu.ac.ir
,
Frank Rominger
c  Organisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
,
Hamid Reza Bijanzadeh
d  Department of Environmental Sciences, Faculty of Natural Resources and Marine Sciences, Tarbiat Modares University, Tehran, Iran
› Author Affiliations
We would like to thank the Iran National Science Foundation (INSF, Grant No. 96003234) and the National Institute for Medical Research Development (NIMAD, Grant No. 963388) for their financial support.
Further Information

Publication History

Received: 03 May 2018

Accepted after revision: 19 July 2018

Publication Date:
19 July 2018 (online)


Abstract

Biologically attractive azaspiro[4.5]trienones have been prepared via Ugi four-component reaction (Ugi-4CR) followed by bromine-mediated ipso-cyclization. This allows a straightforward synthetic route to a diverse collection of fully functionalized 3-bromoaza­spiro[4,5]trienones in moderate to good yields that can be used as templates for further modifications.

Supporting Information

 
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  • 18 Sequential U4-CR/ipso-Bromocyclization to Synthesize Compounds 6a–o; General ProcedureTo a solution of aldehyde 1a (1 mmol) in methanol (5 mL) was added aniline 2a (1 mmol), and the reaction mixture was stirred at room temperature for 2 h. Then, phenylpropiolic acid 3a (1 mmol) was added and stirring was continued for 15 min, followed by addition of isocyanide 4a (1 mmol); the solution was then stirred for 24 h at room temperature. The solvent was removed under reduced pressure and MeCN (10 mL) was added to the residue. N-Bromosuccinimide (1.5 mmol), (NH4)2S2O8 (3 mmol), TBHP (5 mmol) and NMM (0.5 mmol) were added and the reaction mixture was stirred at 80 °C for 12 h under an argon atmosphere. The progress of the reaction was monitored using TLC (n-hexane–EtOAc, 5:1). The resulting reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, appropriate mixture of n-hexane/ethyl acetate) to afford 6a.2-(3-Bromo-2,8-dioxo-4-phenyl-1-azaspiro[4.5]deca-3,6,9-trien-1-yl)-N-(tert-butyl)-2-(4-methoxyphenyl)acetamide (6a)Yield: 357 mg (67%); colorless solid; m.p. 240–242 °C; 1H NMR (CDCl3, 300 MHz): δ = = 1.30 (s, 9 H, 3 Me), 3.79 (s, 3 H, -OCH3), 4.77 (s, 1 H, C(sp3)-H), 5.50 (s, 1 H, N-H), 6.21 (dd, J = 9.9, 1.8 Hz, 1 H, =CH), 6.24 (dd, J = 9.9, 1.8 Hz, 1 H, =CH), 6.53 (dd, J = 9.9, 3.1 Hz, 1 H, =CH), 6.70 (dd, J = 9.9, 3.1 Hz, 1 H, =CH), 6.83 (d, J = 8.7 Hz, 2 H, H-Ar), 7.20–7.28 (m, 2 H, H-Ar), 7.30–7.34 (m, 3 H, H-Ar), 7.36 (d, J = 8.7 Hz, 2 H, H-Ar). 13C NMR (75 MHz CDCl3,): δ = 28.5, 51.9, 55.3, 62.1, 69.5, 114.3, 120.1, 127.1, 127.8, 128.5, 130.0, 130.1, 131.0, 132.1, 132.2, 144.4, 152.3, 160.2, 165.6, 166.9, 184.0. HRMS (ESI): m/z [M+H]+ calcd. for C28H28 79BrN2O4: 535.1227; found: 535.1232; m/z [M+Na]+ calcd. for C28H27 79BrN2NaO4: 557.1046; found: 557.1050; m/z [M+K]+ calcd. for C28H27 79BrKN2O4: 573.0786; found: 573.0791; m/z [2 M+H]+ calcd. for C56H55 79Br2N4O8: 1069.2381; found: 1069.2394; m/z [2 M+Na]+ calcd. for C56H54 79Br2N4NaO8: 1091.2201; found: 1091.2213; m/z [2 M+K]+ calcd. for C56H54 79Br2KN4O8: 1107.1940; found: 1107.1952. IR: 1663, 1708, 3316 cm–1.Crystal used for X-ray crystallographic analysis: colorless needle, dimensions 0.64 × 0.05 × 0.04 mm. Crystal system: trigonal; space group: R3c; Z = 18; a = 36.587(8) Å, b = 36.587(8) Å, c = 9.942(2) Å, α = 90 deg, β = 90 deg, γ = 120 deg; V = 11525(6) Å3; rho = 1.389 g/cm3; T = 200(2) K; Thetamax = 17.402 deg; Radiation Mo Kα; λ = 0.71073 Å; 0.5 deg omega-scans with CCD area detector, covering the asymmetric unit in reciprocal space with a mean redundancy of 23.1 and a completeness of 99.8% to a resolution of 1.19 Å. 19242 Reflections measured, 1586 unique (R(int) = 0.1093), 1419 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, mu = 1.64 mm–1, T min = 0.67, T max = 0.95, structure refined against F2 with a full-matrix least-squares algorithm using the SHELXL-2016/6 (Sheldrick, 2016) software.19 316 Parameters were refined, hydrogen atoms were treated using appropriate riding models. Flack absolute structure parameter 0.077(16), goodness of fit 1.15 for observed reflections, final residual values R1(F) = 0.071, wR(F2) = 0.145 for observed reflections, residual electron density –0.30 to 0.38 eÅ–3. CCDC 1587337 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/data-request/cif.2-(3-Bromo-2,8-dioxo-4-phenyl-1-azaspiro[4.5]deca-3,6,9-trien-1-yl)-2-(4-bromophenyl)-N-(tert-butyl)acetamide (6c)Yield: 355 mg (61%); colorless solid; m.p. 250–252 °C; 1H NMR (CDCl3, 300 MHz): δ = 1.29 (s, 9 H, 3 Me), 4.60 (s, 1 H, C(sp3)-H), 5.51 (s, 1 H, N-H), 6.25 (dd, J = 9.9, 1.8 Hz, 1 H, =CH), 6.37 (dd, J = 9.9, 1.8 Hz, 1 H, =CH), 6.44 (dd, J = 10.0, 3.0 Hz, 1 H, =CH), 6.81 (dd, J = 10.0, 3.0 Hz, 1 H, =CH), 7.24–7.28 (m, 2 H, H-Ar), 7.31–7.36 (m, 5 H, H-Ar), 7.49 (d, J = 8.4 Hz, 2 H, H-Ar). 13C NMR (75 MHz, CDCl3): δ = 28.5, 52.2, 62.3, 69.6, 119.9, 123.5, 127.8, 128.7, 130.0, 130.2, 130.9, 132.4, 132.6, 133.0, 134.4, 143.8, 144.1, 152.5, 165.8, 166.0, 183.7. HRMS (ESI): m/z [M+H]+ calcd. for C27H25 79Br2N2O3: 583.0226; found 583.0233; m/z [M+Na]+ calcd. for C27H24 79Br2N2NaO3: 605.0046; found: 605.0051; m/z [M+K]+ calcd. for C27H24 79Br2KN2O3: 620.9785; found: 620.9794. IR: 1621, 1692, 1709, 3417 cm–1.2-(3-Bromo-2,8-dioxo-4-phenyl-1-azaspiro[4.5]deca-3,6,9-trien-1-yl)-N-cyclohexyl-2-(4-fluorophenyl)acetamide (6h)Yield: 263 mg (48%); colorless solid; m.p. 268–269 °C; 1H NMR (CDCl3, 300 MHz): δ = 1.015–1.14 (m, 3 H, H-cyc), 1.22–1.32 (m, 2 H, H-cyc), 1.57 (s, 3 H, H-cyc), 1.76–1.93 (m, 2 H, H-cyc), 3.76–3.78 (m, 1 H, H-cyc), 4.83 (s, 1 H, C(sp3)-H), 5.65 (d, J = 7.8 Hz, 1 H, N-H), 6.27 (d, J = 9.9 Hz, 1 H, =CH), 6.32 (d, J = 9.9 Hz, 1 H, =CH), 6.50 (dd, J = 9.9, 2.4 Hz, 1 H, =CH), 6.78 (dd, J = 9.9, 2.4 Hz, 1 H, =CH), 7.04 (t, J = 8.7 Hz, 2 H, H-Ar), 7.27 (d, J = 7.2 Hz, 2 H, H-Ar), 7.35 (d, J = 7.2 Hz, 2 H, H-Ar), 7.40–7.65 (m, 3 H, H-Ar). 13C NMR (75 MHz, CDCl3): δ = 24.5, 24.6, 25.3, 32.5, 32.7, 49.1, 61.1, 69.6, 116.2 (d, 2 J C–F = 21.0 Hz), 119.8, 127.8, 128.4, 128.6, 130.2 (d, 3 J C–F = 7.8 Hz), 131.0, 131.4, 131.5, 132.6, 132.7, 143.9, 144.2, 152.6, 161.4, 165.9, 166.4, 183.8. HRMS (ESI): m/z [M+H]+ calcd. for C29H27 79BrFN2O3: 549.1184; found: 549.1187; m/z [M+K]+ calcd. for C29H26 79BrFKN2O3: 587.0742; found: 587.0746. IR: 1659, 1713, 3254 cm–1. N-(tert-butyl)-2-(3,6-dibromo-2,8-dioxo-4-phenyl-1-azaspiro[4.5]deca-3,6,9-trien-1-yl)-2-phenylacetamide (6m)Yield: 222 mg (38%); yellow solid; m.p. 238–239 °C; 1H NMR (CDCl3, 300 MHz): δ = 1.36 (s, 9 H, 3 Me), 5.38 (s, 1 H, C(sp3)-H), 5.97 (br. s, 1 H, N-H), 6.26 (dd, J = 9.9, 1.6 Hz, 1 H, =CH), 6.28 (d, J = 1.6 Hz, 1 H, =CH), 7.20–7.42 (m, 11 H, H-Ar, =CH). 13C NMR (75 MHz, CDCl3 ): δ = 28.6, 52.0, 63.3, 72.7, 121.0, 128.0, 128.2, 128.6, 129.1, 129.7, 130.2, 130.6, 130.9, 131.7, 135.9, 142.8, 144.0, 152.5, 166.6, 167.2, 181.9. MS (ESI): m/z [M+H]+ found for C27H24 79Br2N2O3: 582.6; m/z [M+H]+ found for C27H24 81Br2N2O3: 584.6; IR: 1713, 3322 cm–1.
    • 19a Sheldrick GM. Bruker Analytical X-ray-Division: Madison, Wisconsin 2014
    • 19b Sheldrick GM. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2015; 71: 3