A novel access to indole-3-substituted dihydrocoumarins in artificial sweetener saccharin based functional ionic liquids

Abstract

An efficient new multicomponent protocol for the C-3 functionalization of indoles with dihydrocoumarin has been developed using an artificial sweetener (saccharin)-based functional ionic liquid (imidazolium saccharinate). The reaction consists of the Knoevenagel coupling of salicylaldehyde and Meldrum's acid followed by a Michael type reaction with indole, resulting in concomitant lactonization via decarboxylative elimination to yield indole-3-dihydro-coumarins in good to excellent yields at room temperature.

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The indole ring system is the architectural core of the most widely distributed heterocycles found in nature.¹ The substituted indole moiety has become a fascinating molecular scaffold in drug discovery, because of its presence in numerous drugs, medicinal leads and biologically active natural products.² The essential amino acid tryptophan, the neurotransmitter serotonin and several important alkaloids and biological agents, like CK-636 and CK-666,³ are indole derivatives in which the third position is substituted. Furthermore, indoles substituted with heterocyclic rings at the 3-position, such as Meridianin A,⁴ Primprinine,⁵ Labradorin,⁶ Martefragin A⁷ and Almazole C⁸ (Fig. 1), have exhibited important biological activity.

Fig. 1 Representative biologically active molecules that possess a 3-substituted indole moiety.

In recent years, environmentally benign synthesis has gained great importance for sustainability and this has resulted in an increased use of green protocols in organic synthesis. Ionic liquids (ILs) have been recently revealed to have dual properties as solvents and catalysts.⁹ The introduction of functional ionic liquids has added further interest in this area.¹⁰

In continuation of our work on the green synthesis of bioactive natural and drug like molecules,¹¹ we have developed a novel synthetic strategy for the synthesis of indole-3-substituted dihydrocoumarins using the functional ionic liquid imidazolium saccharinate. To the best of our knowledge there is no direct method reported for the synthesis of indole-3-subsituted dihydrocoumarins.

Indoles and dihydrocoumarins are two intensely studied classes of compounds in drug discovery, therefore the synthesis of bifunctional compounds incorporating both of these moieties is desirable. The construction of a C-3-substituted indole ring has been previously carried out via hydroindolation of indoles with alkynes¹² and Friedel–Crafts alkylation.¹³

Jean-Yves Laronze et al. have utilized these three components (indole, subsituted aldehyde and Meldrum's acid) for the synthesis of indole-2-pyrrolidones¹⁴ and β-substituted tryptophan esters¹⁵ using a multistep process. However, they have reported zero percent yield with salicylaldehyde, indole and Meldrum's acid (Scheme 1). Here, we wish to report the synthesis of indole-3-substituted dihydrocoumarins using indole, salicylaldehyde and Meldrum's acid in the presence of functional ionic liquid imidazolium saccharinate via a multicomponent protocol (Scheme 1).

Scheme 1 Previous and present work with indole, Meldrum's acid and carbonyl compounds.

It is worth mentioning that, during the course of the reaction, at first two C–C bonds are formed followed by concomitant lactonization. For the optimization of the reaction conditions, we first took the condensation of indole, salicylaldehyde and Meldrum's acid as a model reaction and applied the reaction in organic solvents such as dichloromethane, chloroform and acetonitrile using triethylamine and potassium carbonate as a catalyst, which resulted in the formation of bis-indole as the sole product. Raising the reaction temperature to 60 °C, formation of the side product bis-indole took place in a short time. When imidazole was used as a catalyst (in acetonitrile) we obtained the desired product, indole-3-substituted dihydrocoumarin, in 60% yield in 30 h (Table 1). We observed that imidazole as a catalyst drives the reaction towards the desired product in low to moderate yields. To further optimize the reaction, we synthesized some imidazole based functional ionic liquids (FIL).

Table 1 Optimization of the reaction conditions with indole, salicylaldehyde and Meldrum's acid with different solvents and catalysts^a

Entry	Solvent	Catalyst	T/°C	Time (h)	Yield^d (%)
a Reaction conditions: indole (1.0 mmol), Meldrum's acid (1.0 mmol), salicylaldehyde (1.0 mmol), solvent/ionic liquid (2.0 mL) and catalyst (10 mol %), rt. b Catalytic amount. c 5 equiv. d Isolated yield.
1	CH2Cl2	TEA^b	rt	25	0
2	CHCl3	TEA	rt	25	0
3	CH3CN	TEA	rt	25	0
4	CH3CN	imidazole^a	rt	30	60
5	CH3CN	K2CO3^c	rt	25	0
6	[C4MIM]Sac	None	rt	8	93
7	[C2MIM]Sac	None	rt	8	86
8	[C5MIM]Sac	None	rt	8	87
9	[bmim][OH]	None	rt	8	60
10	[bmim][Br]	None	rt	8	50

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One of the attractive features of functional ionic liquids in synthesis and catalysis is that both the cationic and anionic components can be modified, so that a liquid can be customized for specific applications. In our previously reported work,¹⁶ we functionalized the cationic part of ILs and in continuation here we have functionalized the anionic part of the IL with saccharin, an artificial sweetening agent.

We have synthesized 1-methyl-3-(n-alkyl) imidazolium saccharinate ([C_nMIM]Sac) from the sodium salt of saccharin with 1-methyl-3-(n-alkyl) imidazolium bromide in acetone (Scheme 2).

Scheme 2 Representative procedure for synthesis of [C_nMIM]Sac.

We synthesized 1-methyl-3-(n-butyl) imidazolium saccharinate ([C₄MIM]Sac), 1-methyl-3-(n-ethyl) imidazolium saccharinate([C₂MIM]Sac), 1-methyl-3-(n-pentyl) imidazolium saccharinate([C₅MIM]Sac) by using the above protocol.

It is interesting to report that the ionic liquid [C₄MIM]Sac gave the best results at room temperature (Table 1). Raising the reaction temperature to 60 °C resulted in lower yields. We observed similar results with [C₅MIM]Sac and [C₂MIM]Sac. We also synthesized 1-methyl-3-(n-butyl) imidazolium bromide and 1-methyl-3-(n-butyl) imidazolium hydroxide, which gave moderate yields. In the present study functional ionic liquids work as catalysts as well as reaction media without using any additional catalyst or solvent. It has been recognized that hydrogen bonding plays an important role in the behaviour and catalytic activity of ionic liquids. The catalytic efficiency of most ionic liquids is strongly influenced by the synergetic effects between the C-2 hydrogen of the bmim and the counter anion of the functional ionic liquid.¹⁷

This optimized methodology was then applied to several indole derivatives on a 1 mmol scale (Table 2). The corresponding indole-3-substituted dihydrocoumarin products were efficiently synthesised with the reaction of 5-methoxy, 7-ethyl, 2-phenyl, 2-methyl, N-methyl, N-ethyl, N-allyl and N-butyl indoles with salicylaldehyde or 4-methoxy salicylaldehyde and Meldrum's acid at room temperature using [C₄MIM]Sac. The reaction with electron-deficient 5-bromo-1H-indole was also successful, giving the corresponding product in high yield (85%). The structures of the indole-3-substituted dihydrocoumarins were confirmed by elemental analysis, ¹H NMR, ¹³C NMR and mass spectroscopy.

Table 2 Synthesis of indole-3-substituted dihydrocoumarins with substituted indoles, salicylaldehyde derivatives, and Meldrum's acid^a

a Reaction conditions: indole derivative (1.0 mmol), Meldrum's acid (1.0 mmol), salicylaldehyde derivative (1.0 mmol), ionic liquid (2.0 mL), rt, 8–10 h. b Isolated yield.

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The proposed mechanism is given in Scheme 3. The reaction involves the Knoevenagel coupling of salicylaldehyde and Meldrum's acid, which undergoes a Michael type reaction with the indole followed by concomitant lactonization via decarboxylative elimination. It was also observed that the ionic liquid showed good reusability in at least four subsequent reactions under the same reaction conditions without any considerable loss in the reaction yield (Table 3).

Scheme 3 Reaction mechanism for the formation of indole-3-substituted dihydrocoumarins.

Table 3 Reusability of 1-methyl-3-(n-butyl) imidazolium Saccharinate [(C₄MIM)Sac] in indole-3-dihydrocoumarin synthesis^a

Run	1	2	3	4
a Reaction conditions: Indole (1.0 mmol), Meldrum's acid (1.0 mmol), salicylaldehyde (1.0 mmol), ionic liquid (2.0 mL), rt, 8 h. b Isolated yield.
Yield^b (%)	93	91	87	85

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Conclusions

In conclusion, we have developed an efficient new multicomponent reaction for the synthesis of indole-3-substituted dihydrocoumarin derivatives using an artificial sweetener (saccharin)-based functional ionic liquid ([C₄MIM]Sac)-mediated synthesis (FILMs) at room temperature. The advantages of this protocol are good yields, reusable medium, operational simplicity. The applicability of this strategy for the synthesis of other coumarin heterocycles is currently under investigation.

Acknowledgements

Authors P. K., V. D. and S. S. thank CSIR-UGC New Delhi for the award of a senior research fellowship. The authors also acknowledge SAIF-CDRI for providing the spectral and analytical data. The CDRI communication no. is 8305.

References

1. (a) K. Huguchi and T. Kawasaki, Nat. Prod. Rep., 2007, 24, 843; (b) S. E. O'Connor and J. J. Maresh, Nat. Prod. Rep., 2006, 23, 532; (c) T. Kawasaki and K. Huguchi, Nat. Prod. Rep., 2005, 22, 761; (d) M. Somei and F. Yamada, Nat. Prod. Rep., 2004, 21, 278.
2. (a) B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo, R. M. Freidinger, W. L. Whitter, G. F. Lundell, D. F. Veber and P. S. Anderson, J. Med. Chem., 1988, 31, 2235; (b) D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103, 893.
3. (a) M. Gompel, M. Leost, E. B. D. Joffe, L. Puricelli, L. H. Franco, J. Palermo and L. Meijer, Bioorg. Med. Chem. Lett., 2004, 14, 1703; (b) M. A. A. Radwan and M. El-Sherbiny, Bioorg. Med. Chem., 2007, 14, 1206.
4. S. Takahashi, T. Mathsunase, C. Hasegawa, H. Saito, D. Fujita, F. Kiwchi and Y. Tsuda, Chem. Pharm. Bull., 1998, 46, 1527.
5. S. R. Naik, J. Harindran and A. B. Varde, J. Biotechnol., 2001, 88, 1.
6. G. R. Pettit, J. C. Knight, D. L. Herald, R. Davenport, R. K. Pettit, B. E. Tucker and J. M. Schmidt, J. Nat. Prod., 2002, 65, 1793.
7. A. Nishida, M. Fuwa, Y. Fujikawa, E. Nakahata, A. Furuno and M. Nakagawa, Tetrahedron Lett., 1998, 39, 5983.
8. (a) G. Guella, I. Mancini, I. N'Diaye and F. Pietra, Helv. Chim. Acta, 1994, 77, 1999; (b) I. N'Diaye, G. Guella, I. Mancini and F. Pietra, Tetrahedron Lett., 1996, 37, 3049.
9. (a) P. Wasserscheid and W. Keim, Angew. Chem., Int. Ed., 2000, 39, 3772; (b) M. J. Earle and K. R. Seddon, Pure Appl. Chem., 2000, 72, 1391; (c) C. M. Gordon, Appl. Catal., A, 2001, 222, 101.
10. (a) T. Jiang, X. Ma, Y. Zhou, S. Liang, J. Zhang and B. Han, Green Chem., 2008, 10, 465; (b) D. Li, F. Shi, J. Peng, S. Guo and Y. Deng, J. Org. Chem., 2004, 69, 3582; (c) G. Tao, L. He, W. Liu, L. Xu, W. Xiong, T. Wang and Y. Kou, Green Chem., 2006, 8, 639.
11. (a) A. Kumar, V. D. Tripathi and P. Kumar, Green Chem., 2011, 13, 51; (b) A. Kumar and S. Sharma, Green Chem., 2011, 13, 2017.
12. (a) D. Xia, Y. Wang, Z. Du, Q.-Y. Zheng and C. Wang, Org. Lett., 2012, 14, 588; (b) C. Nevado and A. M. Echavarren, Synthesis, 2005, 167; (c) S. F. Kirsch, Synthesis, 2008, 3183; (d) T. Kitamura, Eur. J. Org. Chem., 2009, 1111; (e) M. Beller, J. Seayad, A. Tillack and H. Jiao, Angew. Chem., Int. Ed., 2004, 43, 3368.
13. (a) X. Liu, L. Lin and X. Feng, Acc. Chem. Res., 2011, 44, 574; (b) M. Bandini, A. Melloni, S. Tommasi and A. Umani-Ronchi, Synlett, 2005, 1199.
14. L. Jeannin, T. Nagy, E. Vassileva, J. Sapi and J.-Y. Laronze, Tetrahedron Lett., 1995, 36, 2057.
15. M. Boisbrun, L. Jeannin, L. Toupet and J.-Y. Laronze, Eur. J. Org. Chem., 2000, 3051.
16. A. Kumar, G. Gupta and S. Srivastava, Green Chem., 2011, 13, 2459.
17. (a) A. R. Gholap, K. Venkatesan, T. Daniel, R. J. Lahoti and K. V. Srinivasan, Green Chem., 2003, 5, 693; (b) X. Fu, Z. Zhang, C. Li, L. Wang, H. Ji, Y. Yang, T. Zou and G. Gao, Catal. Commun., 2009, 10, 665.

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Footnote

† Electronic Supplementary Information (ESI) available. See DOI: 10.1039/c2ra21284f

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