Synthesis of N-aryl 2-quinolinones via intramolecular C(sp²)–H amidation of Knoevenagel products

Abstract

A practical synthesis of N-aryl 2-quinolinones via K₂S₂O₈-mediated intramolecular C(sp²)–H amidation of Knoevenagel products was developed. The reaction proceeded smoothly in a biphasic solvent system composed of n-butyl acetate and H₂O.

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N-Aryl 2-quinolinones are ubiquitous structural motifs in a number of bioactive molecules, such as GPR119 agonists,¹ kinase inhibitors,² sodium channel inhibitors,³ neutrophil elastase inhibitors,⁴ anti-inflammatories,⁵ HIV inhibitors,⁶ and antimicrobials.⁷ Thus, the synthesis of N-aryl 2-quinolinones has attracted considerable attention in recent years.⁸ In particular, 4-unsubstituted N-aryl 2-quinolinones have been successfully prepared via a variety of transition metal-catalyzed coupling reactions from aryl halides, boronic acids, or triflates (Scheme 1).^5,6a,9 Despite these advances, it is desirable to develop an atom-economical and environmentally benign approach from easily available starting materials.

Scheme 1 Synthesis of 4-unsubstituted N-aryl 2-quinolinones via transition metal-catalyzed coupling reactions.

Over the past decade, radical C–H functionalization has emerged as a powerful and atom-efficient synthetic tool in heterocycle synthesis.^10,11 For example, 3,4-benzocoumarins were recently constructed via K₂S₂O₈ or (NH₄)₂S₂O₈ mediated intramolecular lactonization of 2-arylbenzoic acids (Scheme 2A).¹² And in 1972, Forrester et al. reported a rapid synthesis of N-phenylphenanthridone from N-phenyl biphenyl-2-carboxamide by oxidation with K₂S₂O₈ in water (Scheme 2B),¹³ albeit the poor substrate solubility and moderate conversion rate remained problematic. Inspired by these reports, and in continuation of our interest in the synthesis of biologically important heterocycles,¹⁴ herein we described an intramolecular C(sp²)–H amidation of Knoevenagel products 1 for the construction of N-aryl 2-quinolinones 2 (Scheme 2C).

Scheme 2 Synthesis of heterocycles via intramolecular radical C–H functionalization.

We began our investigation using (Z)-2-benzylidene-3-oxo-N-phenylbutanamide (1a)¹⁵ as the model substrate, which was readily prepared via L-proline catalyzed Knoevenagel condensation of benzaldehyde with acetoacetanilide (Scheme 3, see ESI† for details). To our delight, 1a underwent intramolecular amidation rapidly upon the treatment of 2 equiv. of K₂S₂O₈ in water under reflux conditions, affording N-phenyl 2-quinolinone 2a in 37% yield (entry 1, Table 1). However, the solubility of 1a was poor in water, and it could not be consumed completely. Thus, various organic-aqueous solvents (1 : 1, v/v) were screened to optimize the reaction conditions (entries 2–10, Table 1), and a biphasic solvent system composed of n-butyl acetate and H₂O was found to be superior to others (entry 9, Table 1). Notably, in the presence of a catalytic amount of AgNO₃, the yield was enhanced to 45% in CH₃CN/H₂O (entries 2 and 3, Table 1), but it was not improved in n-butyl acetate/H₂O (entries 9 and 10, Table 1). When the ratio of n-butyl acetate to H₂O was decreased, full conversion of 1a was observed in shorter reaction time (entries 9–12, Table 1), and the best result was obtained with n-butyl acetate/H₂O (1 : 19) in 73% yield (entry 12, Table 1). When Na₂S₂O₈ or (NH₄)₂S₂O₈ was used as oxidant instead of K₂S₂O₈, a comparable yield was obtained (entries 13 and 14, Table 1). Decreasing the amount of K₂S₂O₈ from 2 equiv. to 1 equiv. led to a lower yield (entry 15, Table 1).

Scheme 3 Synthesis of Knoevenagel products 1.

Table 1 Optimization of the reaction conditions^a

Entry	Oxidant	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: 1a (5.0 mmol), oxidant (10.0 mmol), solvent (100 mL), reflux.b Isolated yield.c AgNO3 (10 mol%) was used as a catalyst.d Reaction occurred at 110 °C.e K2S2O8 (5.0 mmol) was used.
1	K2S2O8	H2O	0.5	37
2	K2S2O8	CH3CN/H2O (1 : 1)	3.0	Trace
3	K2S2O8	CH3CN/H2O (1 : 1)	3.0	45^c
4	K2S2O8	CH3COCH3/H2O (1 : 1)	3.0	Trace
5	K2S2O8	DMSO/H2O (1 : 1)	3.0	Trace^d
6	K2S2O8	PhCH3/H2O (1 : 1)	3.0	16
7	K2S2O8	Ethyl acetate/H2O (1 : 1)	3.0	30
8	K2S2O8	Ethyl butyrate/H2O (1 : 1)	3.0	47
9	K2S2O8	n-Butyl acetate/H2O (1 : 1)	3.0	59
10	K2S2O8	n-Butyl acetate/H2O (1 : 1)	3.0	54^c
11	K2S2O8	n-Butyl acetate/H2O (1 : 9)	1.0	72
12	K2S2O8	n-Butyl acetate/H2O (1 : 19)	0.5	73
13	Na2S2O8	n-Butyl acetate/H2O (1 : 19)	0.5	69
14	(NH4)2S2O8	n-Butyl acetate/H2O (1 : 19)	0.5	72
15	K2S2O8	n-Butyl acetate/H2O (1 : 19)	0.5	61^e

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Having optimized the reaction conditions, the scope of the intramolecular amidation was investigated (Table 2). Initially, Knoevenagel products 1b–h with different substitution patterns on the phenyl ring of the benzylidene moiety were examined. Functional groups including Me, OMe, F, Cl, and Br at the para-position were tolerated, and the desired products 2b–f were obtained in moderate to good yields. However, substrate bearing a strong electron withdrawing p-NO₂ group failed to furnish the desired product (not shown). When substrate 1g with a m-OMe substituent was used, two isomers 2g and 2g′ were isolated in a 1 : 1.3 ratio. The o-Me substituent was also tolerated, providing product 2h in 42% yield. Subsequently, Knoevenagel products 1i–p bearing both electron-donating and electron-withdrawing groups on the aniline ring were employed. The reaction proceeded smoothly, affording 2-quinolinones 2i–p in 43–72% yields. Notably, steric-hindered substrates 1o and 1p showed good reactivities. Furthermore, 2-quinolinones 2q bearing an ester group was successfully prepared in 64% yield.

Table 2 Synthesis of N-aryl 2-quinolinones 2 from Knoevenagel products 1^ab

a Reaction conditions: 1 (5.0 mmol), K₂S₂O₈ (10.0 mmol), n-butyl acetate/H₂O (1 : 19, 100 mL), reflux.b Isolated yield.c K₂S₂O₈ (20.0 mmol) was used.

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Chalcones and their heterocyclic analogues possess various interesting biological activities.¹⁶ To demonstrate the utility of this method, a novel chalcone analogue 4 containing a 2-quinolinone moiety was prepared. The condensation of 3-acetyl quinolinone 2a with benzaldehyde 3 in ethanolic NaOH solution afforded product 4 in 88% yield (Scheme 4).

Scheme 4 Synthesis of chalcone analogue 4.

Preliminary experiments were also carried out to probe the reaction mechanism. When 1 equiv. of the radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) was added in the reaction of 1a under the standard conditions, no desired product 2a was observed (Scheme 5A). The result indicated that this reaction might proceed through a radical mechanism. Besides, an intermolecular competition reaction between substrates 1a and 1a-d₅ was conducted. The kinetic isotope effect (KIE) value of k_H/k_D = 1.12 was determined, suggesting that the cleavage of C–H bond is not the rate-determine step (Scheme 5B).

Scheme 5 Preliminary mechanistic studies.

On the basis of the results and previous reports,^12,13 a plausible radical mechanism was proposed for the reaction (Scheme 6). Initially, the thermal decomposition of K₂S₂O₈ generated sulfate radical anions, which reacted with 1 to form the amidyl radical 5. Then, intramolecular addition of amidyl radical to the benzene ring afforded the aryl radical 6. Finally, hydrogen abstraction of 6 by sulfate radical anion gave the 2-quinolinone product 2.

Scheme 6 Plausible reaction mechanism.

Conclusions

In summary, we have developed an efficient synthesis of N-aryl 2-quinolinones via K₂S₂O₈-mediated intramolecular C(sp²)–H amidation of Knoevenagel products. A biphasic solvent system n-butyl acetate/H₂O (1 : 19) has been established to improve the substrate solubility and the conversion rate. The readily available starting materials, short reaction time, acceptable yields, easy operation, and environmental friendliness make the present method an attractive approach to prepare N-aryl 2-quinolinone derivatives.

Acknowledgements

This work was supported by the Natural Science Foundation of Hubei Province (2016CFB320), Qingmiao Plan Project of Hubei University of Chinese Medicine, and Doctoral Starting up Foundation of Hubei University of Chinese Medicine. We are grateful to Key Laboratory of Chinese Medicine Resource and Compound Prescription of Ministry of Education for support.

Notes and references

1. M. Lv, H. Zhang and G. Wang, CN 104447693A, 2015.
2. (a) T. Inukai, J. Takeuchi, T. Yasuhiro, M. A. Wolf, V. D. Pawal, A. Chakrabarti and S. K. Chittimalla, WO 2015068767A1, 2015; (b) Q. Tang, X. Zhai, Y. Tu, P. Wang, L. Wang, C. Wu, W. Wang, H. Xie, P. Gong and P. Zheng, Bioorg. Med. Chem. Lett., 2016, 26, 1794; (c) M.-H. Chen, P. Fitzgerald, S. B. Singh, E. A. O'Neill, C. D. Schwartz, C. M. Thompson, S. J. O'Keefe, D. M. Zaller and J. B. Doherty, Bioorg. Med. Chem. Lett., 2008, 18, 2222.
3. M. Weiss, A. Boezio, C. Boezio, J. R. Butler, M. Y. Chu-Moyer, E. F. Dimauro, T. Dineen, R. Graceffa, A. Guzman-Perez, H. Huang, C. Kreiman, D. La, I. E. Marx, B. C. Milgrim, H. N. Nguyen, E. Peterson, K. Romero and B. Sparling, WO 2014201206A1, 2014.
4. H. Bladh and J. Larsson, WO 2005021509A1, 2005.
5. M. Berger, H. Rehwinkel, E. May and H. Schaecke, WO 2010009814A1, 2010.
6. (a) K. Babaoglu, K. L. Bjornson, P. Hrvatin, E. Lansdon, J. O. Link, H. Liu, R. McFadden, M. L. Mitchell, Y. Qi, P. A. Roethle and L. Xu, WO 2013103724A1, 2013; (b) B. R. R. Kesteleyn, D. L. N. G. Surleraux and G. Y. P. Hache, WO 2008037784A1, 2008.
7. T. Sumana, P. Iyengar and C. Sanjeevarayappa, J. Appl. Chem., 2015, 4, 818.
8. For selected recent examples, see: (a) T. Hirata, I. Takahashi, Y. Suzuki, H. Yoshida, H. Hasegawa and O. Kitagawa, J. Org. Chem., 2016, 81, 318; (b) H. Liu, W. Han, C. Li, Z. Ma, R. Li, X. Zheng, H. Fu and H. Chen, Eur. J. Org. Chem., 2016, 389; (c) O. Khoumeri, F.-X. Vanelle, M. D. Crozet, T. Terme and P. Vanelle, Synlett, 2016, 27, 1547; (d) A.-F. E. Mourad, A. A. Amer, K. M. El-Shaieb, A. M. Ali and A. A. Aly, J. Heterocycl. Chem., 2016, 53, 383; (e) X. Li, X. Li and N. Jiao, J. Am. Chem. Soc., 2015, 137, 9246; (f) R. Kancherla, T. Naveen and D. Maiti, Chem.–Eur. J., 2015, 21, 8360; (g) Y. Deng, W. Gong, J. He and J.-Q. Yu, Angew. Chem., Int. Ed., 2014, 53, 6692; (h) Y. Dong, B. Liu, P. Chen, Q. Liu and M. Wang, Angew. Chem., Int. Ed., 2014, 53, 3442; (i) Z. Wang, L. Xue, Y. He, L. Weng and L. Fang, J. Org. Chem., 2014, 79, 9628.
9. (a) P. J. Manley and M. T. Bilodeau, Org. Lett., 2004, 6, 2433; (b) A. C. Tadd, A. Matsuno, M. R. Fielding and M. C. Willis, Org. Lett., 2009, 11, 583; (c) T. Ullrich and F. Giraud, Tetrahedron Lett., 2003, 44, 4207; (d) D. F. C. Moffat and S. Pintat, WO 2008053158A1, 2008.
10. For recent reviews, see: (a) J.-T. Yu and C. Pan, Chem. Commun., 2016, 52, 2220; (b) Q.-Z. Zheng and N. Jiao, Chem. Soc. Rev., 2016, 45, 4590.
11. For selected recent examples, see: (a) J. Davies, T. D. Svejstrup, D. Fernandez Reina, N. S. Sheikh and D. Leonori, J. Am. Chem. Soc., 2016, 138, 8092; (b) E. A. Wappes, S. C. Fosu, T. C. Chopko and D. A. Nagib, Angew. Chem., 2016, 128, 10128; (c) C. J. Evoniuk, S. P. Hill, K. Hanson and I. V. Alabugin, Chem. Commun., 2016, 52, 7138; (d) A. K. Yadav and L. D. S. Yadav, Chem. Commun., 2016, 52, 10621; (e) D. Ma, W. Chen, G. Hu, Y. Zhang, Y. Gao, Y. Yin and Y. Zhao, Green Chem., 2016, 18, 3522; (f) X.-Z. Zhang, D.-L. Ge, S.-Y. Chen and X.-Q. Yu, RSC Adv., 2016, 6, 66320; (g) C. Pan, B. Huang, W. Hu, X. Feng and J.-T. Yu, J. Org. Chem., 2016, 81, 2087.
12. (a) J. Gallardo-Donaire and R. Martin, J. Am. Chem. Soc., 2013, 135, 9350; (b) Y. Wang, A. V. Gulevich and V. Gevorgyan, Chem.–Eur. J., 2013, 19, 15836; (c) J.-J. Dai, W.-T. Xu, Y.-D. Wu, W.-M. Zhang, Y. Gong, X.-P. He, X.-Q. Zhang and H.-J. Xu, J. Org. Chem., 2015, 80, 911; (d) N. P. Ramirez, I. Bosque and J. C. Gonzalez-Gomez, Org. Lett., 2015, 17, 4550.
13. A. R. Forrester, A. S. Ingram and R. H. Thomson, J. Chem. Soc., Perkin Trans. 1, 1972, 2847.
14. (a) Y. Zheng, W. Zou, L. Luo, J. Chen, S. Lin and Q. Sun, RSC Adv., 2015, 5, 66104; (b) L. Luo, L. Meng, Y. Peng, Y. Xing, Q. Sun, Z. Ge and R. Li, Eur. J. Org. Chem., 2015, 631; (c) Y.-Q. Peng, L.-C. Luo, J. Gong, J. Huang and Q. Sun, Chin. Chem. Lett., 2015, 26, 1016; (d) L. Luo, L. Meng, Q. Sun, Z. Ge and R. Li, RSC Adv., 2014, 4, 6845; (e) L. Luo, L. Meng, Q. Sun, Z. Ge and R. Li, Tetrahedron Lett., 2014, 55, 259.
15. (a) S. Perrone, A. Salomone, A. Caroli, A. Falcicchio, C. Citti, G. Cannazza and L. Troisi, Eur. J. Org. Chem., 2014, 5932; (b) X. Liu, Q. Zhang, D. Zhang, X. Xin, R. Zhang, F. Zhou and D. Dong, Org. Lett., 2013, 15, 776.
16. (a) H. Wei, J. L. Ruan and X. J. Zhang, RSC Adv., 2016, 6, 10846; (b) D. K. Mahapatra, S. K. Bharti and V. Asati, Eur. J. Med. Chem., 2015, 101, 496; (c) D. Kumar, M. Kumar, A. Kumar and S. K. Singh, Mini-Rev. Med. Chem., 2013, 13, 2116; (d) S. N. A. Bukhari, M. Jasamai and I. Jantan, Mini-Rev. Med. Chem., 2012, 12, 1394; (e) N. K. Sahu, S. S. Balbhadra, J. Choudhary and D. V. Kohli, Curr. Med. Chem., 2012, 19, 209.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, characterization data, ¹H and ¹³C NMR spectra of all products. See DOI: 10.1039/c6ra21286g

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