Synthesis of Fully Functionalized 3-Bromoazaspiro[4.5]trienones through Ugi Four-Component Reaction (Ugi-4CR) followed by ipso-Bromocyclization

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.

Key words

alkynes - spiro compounds - cyclization - radical reaction - ring closure

• References

• 1 Zheng Y. Tice CM. Singh SB. Bioorg. Med. Chem. Lett. 2014; 24: 3673
• 2 Knox C. Law V. Jewison T. Liu P. Ly S. Frolkis A. Pon A. Banco K. Mak C. Neveu V. Nucleic Acids Res. 2010; 39: D1035
• 3a Li M. Song RJ. Li JH. Chin. J. Chem. 2017; 35: 299
• 3b Jia MQ. You SL. Chem. Commun. 2012; 6363
• 3c Ouyang XH. Song RJ. Liu B. Li JH. Chem. Commun. 2016; 2573
• 4a Tang BX. Zhang YH. Song RJ. Tang DJ. Deng GB. Wang ZQ. Xie YX. Xia YZ. Li HJ. J. Org. Chem. 2012; 77: 2837
• 4b Ouyang XH. Song RJ. Li Y. Liu B. Li JH. J. Org. Chem. 2014; 79: 4582
• 4c Wen J. Wei W. Xue S. Yang D. Lou Y. Gao C. Wang H. J. Org. Chem. 2015; 80: 4966
• 5a RajiReddy C. Ranjan R. Prajapati SK. Warudikar K. J. Org. Chem. 2017; 82: 6932
• 5b He Y. Qiu G. Org. Biomol. Chem. 2017; 15: 3485
• 5c Aparece MD. Vadola PA. Org. Lett. 2014; 16: 6008
• 6a Zhou Y. Zhang X. Zhang Y. Ruan L. Zhang J. Zhang-Negrerie D. Du Y. Org. Lett. 2016; 19: 150
• 6b Wei WT. Song RJ. Ouyang XH. Li Y. Li HB. Li JH. Org. Chem. Front. 2014; 1: 484
• 6c Song R. Xie Y. Chin. J. Chem. 2017; 35: 280
• 7a Qian PC. Liu Y. Song RJ. Xiang JN. Li JH. Synlett 2015; 26: 1213
• 7b Cui H. Wei W. Yang D. Zhang J. Xu Z. Wen J. Wang H. RSC Adv. 2015; 5: 84657
• 8a Godoi B. Schumacher RF. Zeni G. Chem. Rev. 2011; 111: 2837
• 8b Likhar PR. Subhas MS. Roy S. Kantam ML. Sridhar B. Seth RK. Biswas S. Org. Biomol. Chem. 2009; 7: 85
• 9 Yugandhar D. Nayak VL. Archana S. Shekar KC. Srivastava AK. Eur. J. Med. Chem. 2015; 101: 348
• 10 Weinreb SM. Chem. Rev. 2006; 106: 2531
• 11 Dutta S. Abe H. Aoyagi S. Kibayashi C. Gates KS. J. Am. Chem. Soc. 2005; 127: 15004
• 12 Abe H. Aoyagi S. Kibayashi C. J. Am. Chem. Soc. 2000; 122: 4583
• 13 Qiu G. Liu T. Ding Q. Org. Chem. Front. 2016; 3: 510
• 14 Yugandhar D. Kuriakose S. Nanubolu JB. Srivastava AK. Org. Lett. 2016; 18: 1040
• 15 Yugandhar D. Srivastava AK. ACS Comb. Sci. 2015; 17: 474
• 16 Saikia I. Borah AJ. Phukan P. Chem. Rev. 2016; 116: 6837; and references cited therein
• 17 Balalaie S. Shamakli M. Nikbakht A. Alavijeh NS. Rominger F. Rostamizadeh S. Bijanzadeh HR. Org. Biomol. Chem. 2017; 15: 5737
• 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) ų; rho = 1.389 g/cm³; T = 200(2) K; Theta_max = 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