Chinese Chemical Letters  2014, Vol.25 Issue (01):169-171   PDF    
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Faramarz Rostami-Charati.Efficient synthesis of functionalized hydroindoles via catalyst-free multicomponent reactions of ninhydrin in water[J]. Chin. Chem. Lett., 2014,25(01): 169-171   
Efficient synthesis of functionalized hydroindoles via catalyst-free multicomponent reactions of ninhydrin in water
Faramarz Rostami-Charati     
* Corresponding authors at:Department of Chemistry, Facualty of Science, Gonbad Kavous University, P.O. Box 163, Gonbad, Iran
Received:2013-7-20, Revised:2013-9-6, online:2013-11-5.
E-mail addresses:f_rostami_ch@yahoo.com
Abstract: An efficient synthesis of hydroindeno[1,2-b]indoles is described via three-component reaction of ninhydrin and cycloalkan-1,3-dione in the presence of primary amines in water as the green solvent in excellent yield.
Key words: Ninhydrin     Primary amine     Indole     Three-component reaction     1,3-Dicarbonyls    
1. Introduction

One of the powerful tools used to connect economic features with the green concerns is performing organic reactions in water; this strategy consists of two or more synthetic steps, which are carried out in water as a cheap, nontoxic, environmentally friendly solvent, in a one-step reaction, without isolation of any intermediate thus reducing time, saving money, energy and raw materials [1, 2, 3, 4, 5, 6, 7]. Indole moiety has been found in a wide variety of pharmacologically and biologically active compounds [8, 9]. For example, melatonin and indole-3-propionic acid (IPA) reduce reactive oxygen species that cause cellular damage and prevent death of neurons exposed to amyloid β-proteins, the agent responsible for Alzhimer’s disease [10]. Some indole derivatives function as dopamine agonists and/or selective serotonin reuptake inhibitors (SSRIs), the latter being a class of anti-depressants [11]. Acemetacin [12] and indometacin [13] are clinically used as antiinflammatory drugs and fluvastatin sodium [14] is a well-known HMG-CoA reductase inhibitor. Hence, we describe herein the reaction of cyclic-1,3-dione 1 and ninhydrin 3 in the presence of primary amines 2 in water as the green solvent.

2. Experimental

All chemicals used in this work were purchased from Fluka (Buchs, Switzerland) and were used without further purification. Melting points were measured on an Electrothermal 9100 apparatus. Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer. Mass spectra were recorded on a FINNIGAN-MAT 8430 spectrometer operating at an ionization potential of 70 eV. IR spectra were measured on a Shimadzu IR-460 spectrometer. 1H NMR and 13C NMRspectra were measured with a BRUKER DRX-500 AVANCE spectrometer at 500.1 and 125.8 MHz, respectively. 1H NMR and 13C NMR, spectra were obtained for solutions in CDCl3 using TMS as the internal standard or 85% H3PO4 as the external standard.

2.1. General procedure for preparation of compounds 4a-k

To a magnetically stirred solution of 1,3-activated dicarbonyl compound 1 (2mmol) and primary amine 2 (2mmol) in water (10mL) as the solventwas addedninhydrin 3 (2mmol).The reaction mixture was stirred for 4 h at 70 ℃. After completion of reaction (monitored by TLC), themixture of reactionwas purified in the room temperature by columnchromatography (silica gel (230-400 mesh, Merck) using n-hexane-EtOAc as eluent to give compound 4.

3. Results and discussion

The starting point for our experiments was to optimize the reaction conditions such as solvent and reactions time for the production of indol derivatives which are usable in a wide variety of pharmacologically and biologically active compounds (Table 1).

Table 1
Optimization of reaction conditions of compound 4a.
The reaction of 1,3-activated carbonyl compounds 1 and primary amines 2 in the presence of ninhydrin 3 produce hydroindol derivatives 4 in good yield (Scheme 1, Table 2).

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Scheme 1.Reaction of ninhydrin and 1,3-dione with primary amines.

Table 2
Functionalized hydroindoles.
The data obtained from elemental analysis, IR, 1H NMR and 13C NMR spectra confirmed all of the proposed products (Supporting information). The 1H NMR spectrum of 4a displayed one singlet at δ 2.46 for methyl proton, two singlets at δ 5.10 and δ 5.40 for OH groups. The carbonyl group resonances in the 13C NMR spectra of 4a appear at 192.5 (C=O), 198.2 (C=O). The mass spectra of 4a displayed the molecular ion peak at the appropriate m/z values. An uncertain mechanism for this conversion is offered in Scheme 2. The reaction starts with formation of imine 5. Then imine 5 was attack to activated carbonyl group in ninhydrin and produces another imine derivative 6. Intramolecular cyclization of 6 gives compound 4 (Scheme 2).

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Scheme 2.Proposed mechanism for the synthesis of compound 4.
4. Conclusion

In conclusion, we have described a convenient route to functionalized hydroindeno[1,2-b]indoles from a three-component reaction of ninhydrin, cyclic-1,3-dione and primary amines. The advantage of the present procedure is that the reaction is performed in water as the green solvent and by simple mixing of the starting materials. The procedure described here provides an acceptable one-pot method for the preparation of functionalized hydroindeno[1,2-b]indoles.

Acknowledgments

We gratefully acknowledge financial and spiritual support from Research Council of Gonbad Kavous University.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2013.09.016.

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