Home Ionic liquid catalyzed one-pot synthesis of spiropyran derivatives via three-component reaction in water
Article Open Access

Ionic liquid catalyzed one-pot synthesis of spiropyran derivatives via three-component reaction in water

  • Shuai-Shuai Jin , Mao-Hua Ding and Hong-Yun Guo EMAIL logo
Published/Copyright: March 18, 2013
Download Article (PDF)
Heterocyclic Communications
From the journal Heterocyclic Communications Volume 19 Issue 2

Abstract

The ionic liquid [H3N+CH2CH2OH][CH3COO-] (HEAA) catalyzes a three-component, one-pot condensation of malononitrile/ethyl cyanoacetate, 1,3-dicarbonyl compound/enol, and quinone or ninhydrin in water to afford a spiropyran derivative. This method has advantages of mild reaction conditions, short reaction time, and environmental friendliness.

Keywords: basic ionic liquid; environmental friendliness; [H3N+CH2CH2OH][CH3COO-]; one-pot

Introduction

Development of environmentally benign and clean synthetic procedures has become the goal of present day organic synthesis. Water plays an essential role in life processes and is also an environmentally friendly medium for organic reactions [1]. As multicomponent reactions (MCRs) are flexible, show good atom economy, and are eco-friendly, they have gained great importance in synthetic organic chemistry [2–4].

Ionic liquids are salts with melting points below 100°C, typically having broad liquid ranges, low vapor pressures, and high polarity. They are receiving considerable attention because they offer a unique environment for synthetic chemistry, biocatalysis, separation science, and electrochemistry [5]. The implementation of task-specific ionic liquids further enhances the versatility of classical ionic liquids where both reagent and medium are coupled [6–8].

Spiro compounds are important pharmacophores with analgesic, fungicidal, antidepressant, antitumor, and antibiotic activities [9, 10]. Likewise, polysubstituted spiropyran derivatives, important spiro heterocyclic molecules, have been reported for use in the pharmaceutical industry because they possess a broad spectrum of biological potency including antimicrobial, antiproliferative, antitumor, and antiviral activities [11, 12].

Currently, several methods have been reported for the preparation of spiropyran-fused heterocycles [13–16]. Although each of the known procedures for the synthesis of spiropyran systems has its merits, further studies are still necessary to develop facile, environmental, and economical multicomponent methodology. We now report a clean and efficient method for the preparation of spiropyran-fused heterocycles in water using the ionic liquid [H3N+CH2CH2OH][CH3COO-], abbreviated as HEAA, as a catalyst. The method is based on a three-component reaction of malononitrile or ethyl cyanoacetate, 1,3-dicarbonyl compound, and quinone or ninhydrin.

Results and discussion

In the initial research, we tested the reaction of ninhydrin (1a), malononitrile (2a), and 5,5-dimethylcyclohexane-1,3-dione (3b) as model substrates in the presence of HEAA in water (Scheme 1). Compounds 1a, 2a, and 3b (1 mmol each) were allowed to react in water (5 mL) in the presence of HEAA (0.01 mmol) at 90°C for 1 h. A single product 4b was obtained in 89% isolated yield. Encouraged by this result, we examined the effects of different solvents on the reaction. It was observed that pure water or in a mixture with ethanol was the most efficient medium to promote this reaction, and the spiropyran product was obtained with 88% to 94% yields. The use of other solvents, such as MeCN, DMSO, DMF, CH3COCH3, and CHCl3, led to lower yields. The reaction hardly proceeded in THF. In water, the best yield of the desired product was obtained at 90°C.

Scheme 1 Three-component synthesis of spiropyran derivatives 4a–d.
Scheme 1

Three-component synthesis of spiropyran derivatives 4a–d.

Additional products 4a, 4c,d derived from ninhidrin are shown in Scheme 1. The best yields were obtained for the reactions of malononitrile (2a) producing 4a–c, whereas the reaction of ethyl cyanoacetate (2b) leading to 4d was less efficient.

To further explore the generality and scope of this reaction, we utilized acenaphthenequinone (1b) (Scheme 2) and 9,10-phenanthroquinone (1c) (Equation 1) as starting materials. The reactions of 1b in water were efficient producing the corresponding products 4e–j in yields greater than 85%. However, the reaction of 1c, 2a, and 3b in water furnished the desired product 4k in low yield. By contrast, the use of a mixture EtOH-H2O (1:1) as the reaction medium resulted in an increase of the yield of 4k to above 60%. Unfortunately, all attempted three-component reactions of 9,10-phenanthroquinone (1c) with ethyl cyanoacetate failed to yield the expected products.

Scheme 2 Three-component synthesis of spiroacenaphthylene derivatives 4e–j.
Scheme 2

Three-component synthesis of spiroacenaphthylene derivatives 4e–j.

A suggested mechanism by using the reactions of ninhidrin (1a) for illustration is given in Scheme 3. Compound 1 first undergoes Knoevenagel condensation with malononitrile or ethyl cyanoacetate 2 to generate the intermediate A. Then, compound A is involved in Michael addition with an anion derived from a 1,3-dicarbonyl compound 3 to give another intermediate product B. The catalyst HEAA may facilitate enolization of the substrate 3. It is suggested that the final product 4 is formed in the intramolecular cyclization of B (Scheme 3).

Scheme 3 Possible mechanism for the formation of product 4.
Scheme 3

Possible mechanism for the formation of product 4.

In the next phase of study the viability of catalysis by the recycled ionic liquid was evaluated. In this regard, preparation of 4b was chosen as the model. After completion of the reaction the filtrate was extracted with diethyl ether several times to remove unreacted starting materials and other organic contaminations. Water was then removed under reduced pressure and the residue of HEAA was dried before subsequent use. The results are presented in Table 1.

Table 1

Recyclability of the catalyst HEAAa.

EntryCycleYield (%)
1Fresh94
2First recycle93
3Second recycle91
4Third recycle90
5Fourth recycle90

aIsolated yields.

Known products were characterized by melting point, IR, and 1H NMR for comparison with the literature data. All new products were characterized by melting point, IR, 1H NMR, 13C NMR, and HR-MS.

Conclusion

We herein report the HEAA-catalyzed one-pot reaction for the synthesis of spiropyran derivatives in the presence of water. This reaction can be carried out under mild conditions and covers a range of substrates with excellent yields of spiropyran products. This protocol provides an efficient, environmentally friendly synthetic route to spiropyran derivatives.

Experimental

Melting points were determined with an X-4 microscopic melting point apparatus and are uncorrected. IR spectra were recorded on a NEXUS 670 spectrometer in KBr pellets. 1H NMR and 13C NMR spectra were measured in DMSO-d6 on a Bruker Avance II instrument at 500 MHz and 125 MHz, respectively. Synthesis of the ionic liquid has been previously reported [17]. The ionic liquid was formed quantitatively and in high purity as assessed by 1H NMR. All other chemicals (AR grade) were commercially available and used without further purification.

General procedure for the synthesis of compound 4

A mixture of compounds 1 (1 mmol), 2 (1 mmol), and 3 (1 mmol), the ionic liquid [H3N+CH2CH2OH][CH3COO-] (0.1 mmol) in water (5 mL) was stirred at 90°C for 30 min [monitored by thin-layer chromatography (TLC)]. After completion of the reaction, the mixture was cooled to room temperature and poured into water (10 mL). The solid product was collected by filtration and crystallized from ethanol to give pure compound 4.

2-Amino-1′,3′,5-trioxo-1′,3′,5,6,7,8-hexahydrospiro[chromene-4,2′-indene]-3-carbonitrile (4a)

This compound was obtained from 1a, 2a, and 3a as a yellow solid; yield 91% (0.29 g); mp >300°C (reported mp >300°C [18]); 1H NMR: δ 1.96 (m, 2H, CH2), 2.29 (m, 2H, CH2), 2.72 (m, 2H, CH2), 7.64 (s, 2H, NH2), 7.99–8.05 (m, 4H, ArH).

2-Amino-7,7-dimethyl-1′,3′,5-trioxo-1′,3′,5,6,7,8-hexahydrospiro[chromene-4,2′-indene]-3-carbonitrile (4b)

This compound was obtained from 1a, 2a, and 3b as a yellow solid; yield 94% (0.33 g), mp >300°C (reported mp >300°C, [18]); 1H NMR: δ 1.04 (s, 6H, 2CH3), 2.19 (s, 2H, CH2), 2.62 (s, 2H, CH2), 7.64 (s, 2H, NH2), 7.99–8.05 (m, 4H, ArH).

7′-Amino-1,2′,3,4′-tetraoxo-1,1′,2′,3,3′,4′-hexahydrospiro[indene-2,5′-pyrano[2,3-d]pyrimidine]-6′-carbonitrile (4c)

This compound was obtained from 1a, 2a, and 3c as a yellow solid; yield 90% (0.29 g); mp >300°C (reported mp >300°C, [18]); 1H NMR: δ 7.77 (s, 2H, NH2), 8.04 (m, 4H, ArH), 11.30 (s, 1H, NH), 12.75 (s, 1H, NH).

Ethyl 7′-amino-1,2′,3,4′-tetraoxo-1,1′,2′,3,3′,4′-hexahydrospiro[indene-2,5′-pyrano[2,3-d]pyrimidine]-6′-carboxylate (4d)

This compound was obtained from 1a, 2b, and 3c as a yellow solid; yield 81% (0.30 g); mp >300°C; IR: ν 3380, 3281, 1703, 1671, 1507, 1403, 1330 cm-1; 1H NMR: δ 0.30 (m, 3H, CH3), 3.57 (m, 2H, CH2), 8.18 (s, 2H, NH2), 7.90 (m, 4H, ArH), 11.17 (s, 1H, NH); 12.49 (s, 2H, NH2); 13C NMR: δ 202.4, 166.6, 162.3, 159.7, 153.6, 149.0, 141.8, 135.0, 121.7, 87.7, 73.6, 59.4, 51.2, 30.7, 12.3; MS (ESI): m/z 384.1 (M+H)+. HR-MS (ESI, m/z): Calcd for [C18H14N3O7+H]+ 384.0832, found 384.0814.

2′-Amino-2,5′-dioxo-5′,6′,7′,8′-tetrahydro-2H-spiro[acenaphthylene-1,4′-chromene]-3′-carbonitrile (4e)

This compound was obtained from 1b, 2a, and 3a as a white solid; yield 94% (0.32 g); mp 247–248°C; (reported mp 245–247°C, [19]); 1H NMR: δ 1.94 (m, 2H, CH2), 2.16 (m, 2H, CH2), 2.71–2.72 (d, 2H, J = 5 Hz, CH2), 7.30 (s, 2H, NH2), 7.40–8.27 (m, 6H, ArH).

2′-Amino-7′,7′-dimethyl-2,5′-dioxo-5′,6′,7′,8′-tetrahydro-2H-spiro[acenaphthylene-1,4′-chromene]-3′-carbonitrile (4f)

This compound was obtained from 1b, 2a, and 3b as a light yellow solid; yield 92% (0.34 g); mp 268–269°C (reported mp 268–270°C, [20]); 1H NMR: δ 1.02 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.11 (1H, d, J = 16 Hz, CHaCHb), 2.06 (1H, d, J = 16 Hz, CHaCHb), 2.63 (s, 2H, CH2), 7.32 (s, 2H, NH2), 7.38–8.28 (m, 6H, ArH).

7′-Amino-2,2′,4′-trioxo-1′,2′,3′,4′-tetrahydro-2H-spiro[acenaphthylene-1,5′-pyrano[2,3-d]pyrimidine]-6′-carbonitrile (4g)

This compound was obtained from 1b, 2a, and 3c as a yellow solid; yield 86% (0.31 g); mp >300°C (reported mp >300°C, [20]); 1H NMR: δ 7.47 (s, 2H, NH2), 7.55–8.31 (m, 6H, ArH); 11.07 (s, 1H, NH), 12.41 (s, 1H, NH).

Ethyl 2′-amino-2,5′-dioxo-5′,6′,7′,8′-tetrahydro-2H-spiro[acenaphthylene-1,4′-chromene]-3′-carboxylate (4h)

This compound was obtained from 1b, 2b, and 3a as a yellow solid; yield 90%, (0.35 g); mp 226–227°C (reported mp 225–227°C, [19]); 1H NMR: δ -0.04 (m, 3H, CH3), 1.88 (m, 2H, CH2), 2.09 (m, 2H, CH2), 2.70 (m, 2H, CH2), 3.30 (m, 2H, CH2), 7.93 (s, 2H, NH2), 7.25–8.11 (m, 6H, ArH).

Ethyl 2′-amino-7′,7′-dimethyl-2,5′-dioxo-5′,6′,7′,8′-tetrahydro-2H-spiro[acenaphthylene-1,4′-chromene]-3′-carboxylate (4i)

This compound was obtained from 1b, 2b, and 3b as a white solid; yield 89% (0.42 g); mp 258–260°C (reported mp 259–262°C, [20]); 1H NMR: δ 0.04 (m, 3H, CH3), 0.94 (s, 3H, CH3), 1.01 (s, 3H, CH3), 1.92 (d, 1H, J = 16 Hz, CHaCHb), 2.07 (d, 1H, J = 16 Hz, CHaCHb), 2.55 (d, 1H, J = 17.5 Hz, CHa2CHb2), 2.65 (d, 1H, J = 17.5 Hz, CHa2Hb2), 3.31 (m, 2H, CH2), 7.23–8.10 (m, 6H, ArH), 7.93 (s, 2H, NH2).

Ethyl 7′-amino-2,2′,4′-trioxo-1′,2′,3′,4′-tetrahydro-2H-spiro[acenaphthylene-1,5′-pyrano[2,3-d]pyrimidine]-6′-carboxylate (4j)

This compound was obtained from 1b, 2b, and 3c as a white solid; yield 85% (0.42 g); mp >300°C (reported mp >300°C, [20]); 1H NMR: δ -0.08 (m, 3H, CH3), 3.21 (m, 2H, CH2), 7.35–8.14 (m, 6H, ArH), 8.12 (s, 2H, NH2), 10.89 (s, 1H, NH), 12.29 (s, 1H, NH).

2-Amino-7,7-dimethyl-5,10′-dioxo-5,6,7,8-tetrahydro-10′H-spiro[chromene-4,9′-phenanthrene]-3-carbonitrile (4k)

This compound was obtained from 1c, 2a, and 3b as a white solid; yield 67% (0.27 g); mp >300°C; IR: ν 3380, 3327, 3211, 2960, 2196, 1681, 1651, 1601, 1480, 1449, 1415, 1348, 1322 cm-1; 1H NMR: δ 7.19–8.39 (m, 8H, ArH), 7.21 (s, 2H, NH2); 2.08 (1H, d, J = 16 Hz, CHaCHb), 2.19 (1H, d, J = 16 Hz, CHaCHb), 2.56 (1H, d, J = 17 Hz, CHaCHb), 2.80 (1H, d, J = 17 Hz, CHaCHb), 1.08 (s, 3H, CH3), 1.10 (s, 3H, CH3); 13C NMR: δ 197.1, 194.9, 163.6, 157.9, 143.2, 137.0, 134.9, 129.1, 128.9, 128.5, 128.3, 128.2, 127.3, 127.2, 123.6, 123.3, 117.5, 115.2, 60.8, 59.7, 49.9, 47.5, 32.5, 28.1, 26.9; MS (ESI): m/z 397.2 (M+H)+. HR-MS (ESI, m/z): Calcd for [C25H21N2O3+H]+ 397.1552, found 397.1541.

Corresponding author: Hong-Yun Guo, College of Chemical Engineering and Materials, Zhejiang University of Technology, Hangzhou, 310014, China

References

[1] Saeed, B.; Masoumeh, S.-A.; Morteza, B. Tetramethylammonium hydroxide: an efficient and versatile catalyst for the one-pot synthesis of tetrahydrobenzo[b]pyran derivatives in aqueous media. Catal. Commun. 2007, 8, 1724–1728.Search in Google Scholar

[2] Weber, L.; Illgen, K.; Almstetter, M. Discovery of new multi component reactions with combinatorial methods. Synlett 1999, 3, 366–374.Search in Google Scholar

[3] Wan, J. P.; Gan, S. F.; Sun, G. L.; Pan, Y. J. Novel regioselectivity: three-component cascade synthesis of unsymmetrical 1,4- and 1,2-dihydropyridines. J. Org. Chem. 2009, 74, 2862–2865.Search in Google Scholar

[4] Tu, S.; Jiang, B.; Zhang, Y.; Jia, R.; Zhang, J.; Yao, C.; Feng, S. An efficient and chemoselective synthesis of N-substituted 2-aminopyridines via a microwave-assisted multicomponent reaction. Org. Biomol. Chem. 2007, 5, 355–359.Search in Google Scholar

[5] Welton, T. Room-temperature ionic liquids, solvents for synthesis and catalysis. Chem. Rev. 1999, 99, 2071.Search in Google Scholar

[6] Cole, A. C.; Jensen, J. L.; Ntai, I.; Tran, K. L. T.; Weave, K. J.; Forbes, D. C.; Davis, J. H. Novel Brønsted acidic ionic liquids and their use as dual solvent-catalysts. Chem. Soc. 2002, 124, 5962–5963.Search in Google Scholar

[7] Darvatkar, N. B.; Deorukhkar, A. R.; Bhilare, S. V.; Salunkhe, M. M. Ionic liquid-mediated Knoevenagel condensation of Meldrum’s acid and aldehydes. Synth. Commun. 2006, 36, 3043–3051.Search in Google Scholar

[8] Xu, D. Q.; Yang, W. L.; Luo, S. P.; Wang, B. T.; Wu, J.; Xu, Z. Y. Fischer indole synthesis in Brønsted acidic ionic liquids: a green, mild, and regiospecific reaction system. Eur. J. Org. Chem. 2007, 11, 1007–1012.Search in Google Scholar

[9] Jones, G.; Rae, W. J. Knoevenagel condensation products from some cyclic ketones: structure and stereochemistry. Tetrahedron 1966, 55, 3021–3027.10.1016/S0040-4020(01)82281-XSearch in Google Scholar

[10] Joshi, K. C.; Chand. P. Biologically active indole derivatives. Pharmazie 1982, 37, 1–12.Search in Google Scholar

[11] Ali, R. K.; Fahime, S. Novel mono- and bis(spiro-2-amino-4H-pyrans): alum-catalyzed reaction of 4-hydroxycoumarin and malononitrile with isatins, quinones, or ninhydrin. Synthesis 2010, 10, 1731–1735.Search in Google Scholar

[12] Kang, T. H.; Matsumoto, K.; Murakami, Y.; Takayama, H.; Kitajima, M.; Aimi, N.; Watanabe, H. Pteropodine and isopteropodine positively modulate the function of rat muscarinic M1 and 5-HT2 receptors expressed in Xenopus oocyte. Eur. J. Pharmacol. 2002, 444, 39–45.Search in Google Scholar

[13] Shanthi, G.; Subbulakshmi, G.; Perumal, P. T. A new InCl3-catalyzed, facile and efficient method for the synthesis of spirooxindoles under conventional and solvent-free microwave conditions. Tetrahedron 2007, 63, 2057–2063.Search in Google Scholar

[14] Zhu, S.-L.; Ji, S.-J.; Zhang, Y. A simple and clean procedure for three-component synthesis of spirooxindoles in aqueous medium. Tetrahedron 2007, 63, 9365–9372.Search in Google Scholar

[15] Kumar, R. S.; Perumal, S. Novel three-component tandem reactions of cyclic mono ketones, isatin and sarcosine: formation of dispiropyrrolidines. Terahedron Lett. 2007, 48, 7164–7168.Search in Google Scholar

[16] Redkin, R. G.; Shemchuk, L. A.; Chernykh, V. P.; Shishkin, O. V.; Shishkina, S. V. Synthesis and molecular structure of spirocyclic 2-oxindole derivatives of 2-amino-4H-pyran condensed with the pyrazolic nucleus. Tetrahedron 2007, 63, 11444–11450.Search in Google Scholar

[17] Yuan, X. L.; Zhang, S. J.; Lu, X. M. Hydroxyl ammonium ionic liquids: synthesis, properties, and solubility of SO2. J. Chem. Eng. Data 2007, 52, 596–599.Search in Google Scholar

[18] He, Y.; Guo, H. Y.; Tian, J. J. A simple three-component synthesis of spiropyran derivatives. J. Chem. Res. 2011, 35, 528–530.Search in Google Scholar

[19] Minoo, D.; Mahboobeh, B.; Mostafa, B. Ammonium salt catalyzed multicomponent transformation: simple route to functionalized spirochromenes and spiroacridines. Tetrahedron 2009, 65, 9443–9447.Search in Google Scholar

[20] Mina, S.; Majid, M. H.; Yahya S. B.; Hossein, A. O. One-pot three-component synthesis of the spiroacenaphthylene derivatives. Tetrahedron 2010, 66, 5345–5348.Search in Google Scholar

Received: 2012-7-27
Accepted: 2012-11-13
Published Online: 2013-03-18
Published in Print: 2013-04-01

©2013 by Walter de Gruyter Berlin Boston

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Articles in the same Issue

  1. Masthead
  2. Masthead
  3. Reviews
  4. A fascinating decade for the synthesis of 1,2-azoles
  5. Substituted benzothiazoles: synthesis and medicinal characteristics
  6. Preliminary Communication
  7. Synthesis of thiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives
  8. Research Articles
  9. Ultrasonic-assisted Cu-catalyzed multicomponent synthesis of furo[3,4-b]pyrazolo[4,3-f]quinolinones
  10. Synthesis of dihydropyrrolo[2,1-a]isoquinolines via isocyanide-based four-component reaction
  11. Efficient oxidative cyclization of N-acylhydrazones for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles using t-BuOI under neutral conditions
  12. Synthesis and transformations of 1-[2-(toluene-4-sulfonamido)ethyl]thiourea
  13. Synthesis of new heterocyclic compounds containing benzimidazole moiety as inhibitors of breast cancer cell growth
  14. An approach to C-glycosidic conjugates of isoflavones
  15. Ionic liquid catalyzed one-pot synthesis of spiropyran derivatives via three-component reaction in water
https://doi.org/10.1515/hc-2012-0159
Keywords for this article
basic ionic liquid; environmental friendliness; [H3N+CH2CH2OH][CH3COO-]; one-pot
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Masthead
  2. Masthead
  3. Reviews
  4. A fascinating decade for the synthesis of 1,2-azoles
  5. Substituted benzothiazoles: synthesis and medicinal characteristics
  6. Preliminary Communication
  7. Synthesis of thiazolo[4,5-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives
  8. Research Articles
  9. Ultrasonic-assisted Cu-catalyzed multicomponent synthesis of furo[3,4-b]pyrazolo[4,3-f]quinolinones
  10. Synthesis of dihydropyrrolo[2,1-a]isoquinolines via isocyanide-based four-component reaction
  11. Efficient oxidative cyclization of N-acylhydrazones for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles using t-BuOI under neutral conditions
  12. Synthesis and transformations of 1-[2-(toluene-4-sulfonamido)ethyl]thiourea
  13. Synthesis of new heterocyclic compounds containing benzimidazole moiety as inhibitors of breast cancer cell growth
  14. An approach to C-glycosidic conjugates of isoflavones
  15. Ionic liquid catalyzed one-pot synthesis of spiropyran derivatives via three-component reaction in water
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 19.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hc-2012-0159/html
Scroll to top button