CC BY-ND-NC 4.0 · SynOpen 2018; 02(03): 0222-0228
DOI: 10.1055/s-0037-1610205
letter
Copyright with the author

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.


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Azaspirocycles, which are nitrogen-containing spirocyclic scaffolds, play significant roles in synthetic and medicinal chemistry. Literature searches on azaspirocyclic scaffolds have shown that these derivatives possess a broad spectrum of biological and pharmacological properties such as antimitotic, cytotoxic, antibacterial, antimicrobial, ant-inflammatory, antioxidative and antidepressant activities.[1] A few examples of natural and synthetic drugs containing an azaspirocyclic skeleton are shown in Figure [1].[2] Consequently, great efforts have been made to synthesize diverse azaspirocycles libraries to facilitate the incorporation of these moieties into more biologically and pharmaceutically active molecules.[3] [4] [5] [6] [7]

Zoom Image
Figure 1 Structures of some natural and synthetic drugs containing an azaspirocyclic skeleton

Among the recently synthesized azaspirocycle-containing compounds, azaspiro[4.5]trienones have attracted a great deal of attention due to their chemistry and their biological activities.[8] Very recently, and in the light of the intense interest to develop constrained tamoxifen mimics, Srivastava et al. reported azaspiro[4,5]trienones as novel scaffolds for anticancer drug development (Figure [2], top structure).[9] Furthermore, these compounds serve as valuable intermediates for the construction of azaspiro-fused tricyclic cores with promising anticancer activity by inducing DNA damage (Figure [2]).[10] [11] [12] Therefore, more attention has been drawn to the synthesis of functionalized azaspiro[4.5]trienones suitable for further derivatization processes.[13–15]

Zoom Image
Figure 2 Recently reported cytotoxic azaspiro[4.5]trienones and cytotoxic alkaloids with azaspiro-fused tricyclic cores

Brominated substrates are excellent synthons for further functionalization because they can be further used in well-established cross-coupling reactions, whereas other approaches to such transformations are complex and often result in significant by-product formation.[16] In this respect, especially in light of the fact that brominated triene-diones are ideal scaffolds for further elaboration in the diversity-oriented synthesis, Qiu et al. have recently described the synthesis of 3-bromo-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione through a novel ZnBr2-promoted oxidative ipso-annulation of N-arylpropiolamide.[5]

In light of these findings and as a result of our interest in combination of the Ugi four-component reaction (Ugi-4CR) with efficient post-transformations for generating complex and diverse molecular libraries,[17] we wish to report herein, a simple procedure for the synthesis of fully functionalized 3-bromoazaspiro[4.5]trienones via Ugi-4CR followed by ipso-bromocyclization. (Scheme [1]).

Zoom Image
Scheme 1 Synthesis of 3-bromoazaspiro[4.5]trienones 6al via Ugi-4CR followed by ipso-bromocyclization

Ugi 4-CR of 4-methoxybenzaldehyde (1a), aniline (2a), phenylpropiolic acid (3), and tert-butyl isocyanide (4a) in methanol at room temperature furnished the corresponding Ugi adduct 5a in 83% yield. This compound was chosen as the model substrate to investigate the bromine-mediated ipso-cyclization conditions. Application of (NH4)2S2O8/TBHP (3 equiv/5 equiv) as the oxidant in the presence of N-methylmorpholine (NMM, 0.5 equiv) in acetonitrile at 80 °C under argon atmosphere produced the desired product 6a with a yield of 88%. After screening solvents under these conditions, acetonitrile was found to be the best solvent (Table [1], entries 1–7). When N-methyl-2-pyrrolidone (NMP) was used in place of NMM, a marginal decrease in yield was recorded (entry 8). The application of NMM gave 6a with a yield of 88%, while replacement with triethylamine (TEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and N,N-diisopropylethylamine (DIEA) resulted in lower yields (entries 9–11). Other radical initiators including di-tert-butyl peroxide (DTBP), benzoyl peroxide (BP), and m-chloroperoxybenzoic acid (m-CPBA) were then employed, but all failed to give satisfactory yields (entries 12–14).

Table 1 Optimization of the Reaction Conditions for the Synthesis of 3-Bromoazaspiro[4.5]trienone 6a

Entry

Oxidant (3 equiv/ 5 equiv)

Base (0.5 equiv)

Solvent

Yield 6a (%)b

1

(NH4)2S2O8/TBHP

NMM

DMF

trace

2

(NH4)2S2O8/TBHP

NMM

EtOH

20

3

(NH4)2S2O8/TBHP

NMM

DCE

20

4

(NH4)2S2O8/TBHP

NMM

toluene

15

5

(NH4)2S2O8/TBHP

NMM

H2O

trace

6

(NH4)2S2O8/TBHP

NMM

H2O/MeCN

25

7

(NH4)2S2O8/TBHP

NMM

MeCN

88

8

(NH4)2S2O8/TBHP

NMP

MeCN

75

9

(NH4)2S2O8/TBHP

TEA

MeCN

40

10

(NH4)2S2O8/TBHP

DBU

MeCN

59

11

(NH4)2S2O8/TBHP

DIEA

MeCN

63

12

(NH4)2S2O8/DTBP

NMM

MeCN

23

13

(NH4)2S2O8/BPO

NMM

MeCN

20

14

(NH4)2S2O8/m-CPBA

NMM

MeCN

57

15

(NH4)2S2O8/TBHP

NMM

MeCN

41c

a Optimal reaction condition: 5a (1 equiv), NBS (1.5 equiv), (NH4)2S2O8 (3 equiv), TBHP (5 equiv), and NMM (0.5 equiv) in MeCN (2 mL) at 80 °C under argon atmosphere for 12 h.

b Isolated yield.

c This reaction was performed at room temperature.

After carrying out the Ugi 4-CR, the solvent was evaporated under reduced pressure, and the conditions were switched for the bromine-mediated ipso-cyclization, which gave compound 6a in 67% overall yield, comparable with the 73% total yield obtained in the two-step procedure. Subsequently, the scope of the reaction was investigated by using different aromatic aldehydes, anilines, and isocyanides (Scheme [2]).[18]

The structures of the products were confirmed based on NMR spectroscopy and HRMS (ESI) analysis. The characteristic resonances in the 1H NMR spectra of all synthesized compounds appeared as four double doublets with coupling constants 9.9 and 1.8 Hz for the sp2 C–H. The 13C NMR spectra of compounds exhibited characteristic signals at δ = 165.6, 166.9, 184.0 ppm associated with the carbonyls of the amidic moieties and unsaturated ketone.

Zoom Image
Scheme 2 Substrate scope for the synthesis of fully functionalized 3-bromoazaspiro[4.5]trienones 6an

Initially, the effect of ring substituents on the aromatic aldehydes 6af was examined. Both electron-donating and electron-withdrawing substituents on the phenyl ring were tolerated as outlined (Scheme [2]). With regard to the isocyanide component, tert-butyl isocyanide furnished the desired products in better yields than cyclohexyl isocyanide. A survey of aniline derivatives with differing substitution patterns revealed that aniline derivatives bearing substituents at the ortho-position were consistent with the optimal conditions, providing 6m and 6n in moderate to good yields.

Treatment of para-halogen-substituted anilines with 4-chlorobenzaldehyde (1b), phenylpropiolic acid (3), and tert-butyl isocyanide (4a) delivered product 6b, but he reaction did not proceed at all when the aniline ring contained a para-nitro group (Scheme [3]). It is noteworthy that, in all cases where yields were lower than average, the reaction was inefficient at the ipso-bromocyclization step, with a complex mixture of products being obtained.

Zoom Image
Scheme 3 The effect of halogen substituents on the aniline ring at the para-position

Crude products were purified on a silica gel column (EtOAc/n-hexane, 1:5) and the purified compounds were fully characterized by IR, 1H NMR, 13C NMR spectroscopy and HRMS analysis. In addition, in the case 6a, the structure was confirmed by single-crystal X-ray diffraction analysis (Figure [3]).

Zoom Image
Figure 3 ORTEP view of compound 6a

The proposed reaction mechanism involves the formation of vinyl radical I through the addition of a bromo radical generated from NBS and (NH4)2S2O8 to the alkyne group of the Ugi product. Subsequent intramolecular radical cyclization yields the intermediate II. Trapping of the radical intermediate II by the tert-butylperoxy radical generated from TBHP, and then elimination of tert-butyl alcohol provides the desired product (Scheme [4]).

Zoom Image
Scheme 4 The proposed reaction mechanism for the synthesis of 3-bromoazaspiro[4.5]trienones 6al

In conclusion, we have prepared a diverse array of fully functionalized 3-bromoazaspiro[4.5]trienones through Ugi-4CR followed by ipso-bromocyclization. Considering the biological importance of azaspiro[4.5]trienones and the potential utility of the bromo organic compounds to partake in further modifications, these compounds can be further exploited in the synthesis of lead compounds in medicinal chemistry.


#

Supporting Information

  • 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) 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

  • 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) 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

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Figure 1 Structures of some natural and synthetic drugs containing an azaspirocyclic skeleton
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Figure 2 Recently reported cytotoxic azaspiro[4.5]trienones and cytotoxic alkaloids with azaspiro-fused tricyclic cores
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Scheme 1 Synthesis of 3-bromoazaspiro[4.5]trienones 6al via Ugi-4CR followed by ipso-bromocyclization
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Scheme 2 Substrate scope for the synthesis of fully functionalized 3-bromoazaspiro[4.5]trienones 6an
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Scheme 3 The effect of halogen substituents on the aniline ring at the para-position
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Figure 3 ORTEP view of compound 6a
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Scheme 4 The proposed reaction mechanism for the synthesis of 3-bromoazaspiro[4.5]trienones 6al