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

Key words

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

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]

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]

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]).

Scheme 1 Synthesis of 3-bromoazaspiro[4.5]trienones 6a–l 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.

Scheme 2 Substrate scope for the synthesis of fully functionalized 3-bromoazaspiro[4.5]trienones 6a–n

Initially, the effect of ring substituents on the aromatic aldehydes 6a–f 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.

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]).

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]).

Scheme 4 The proposed reaction mechanism for the synthesis of 3-bromoazaspiro[4.5]trienones 6a–l

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.

• 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