Research Letters in Organic Chemistry
Volume 2008 (2008), Article ID 419054, 4 pages
doi:10.1155/2008/419054
Research Letter

C s 2 C O 3 /[bmim]Br as an Efficient, Green, and Reusable Catalytic System for the Synthesis of N-Alkyl Derivatives of Phthalimide under Mild Conditions

Alireza Hasaninejad,1 Abdolkarim Zare,2 Ahmad Reza Moosavi-Zare,2 Fatemeh Khedri,2 Rahimeh Rahimi,2 and Ali Khalafi-Nezhad3

1Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
2Department of Chemistry, Faculty of Sciences, Payame Noor University (PNU), Bushehr 1698, Iran
3Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran

Received 6 July 2008; Accepted 2 November 2008

Academic Editor: Nicos Petasis

Copyright © 2008 Alireza Hasaninejad et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Aza-conjugate addition of phthalimide to 𝛼 , 𝛽 -unsaturated esters efficiently achieves in the presence of catalytic amount of C s 2 C O 3 and ionic liquid 1-butyl-3-methylimidazolium bromide ([bmim]Br) under mild reaction conditions ( 7 0 ∘ C ) to afford N-alkyl phthalimides in high yields and relatively short reaction times.

1. Introduction

Over the past decade, room temperature ionic liquids have been emerged as a new class of stable and inert solvents. They exhibit high thermal stability, high polarity due to their ionic nature and a great ability to solubilize polar and nonpolar organic compounds. To date, various organic reactions have been carried out and investigated in ionic liquids, such as conjugate addition of sulfonamides [1, 2], azide ion [3], amines and N-heterocycles [4, 5], indoles [6], thiocyanide ion [7], active methylenes [8, 9], and thiols [10] to electrophilic alkenes, and other carbon-carbon, carbon-nitrogen, carbon-oxygen as well as carbon-sulfur bonds formation [11, 12].

N-alkyl derivatives of phthalimide have attracted much interest due to their potential use as antipsychotic [13], anti-inflammatory [14], hypolipidemic [15], agents and receptors [16], and so on. Moreover, these compounds are very useful intermediates in organic synthesis as they can be easily converted to primary amines (Gabriel synthesis) [17]. Therefore, there is a great deal of interest in the synthesis of this class of compounds. The aza-conjugate addition of phthalimide to electrophilic alkenes can be used as a useful synthetic route toward N-alkylated phthalimides [18–21]. Several catalysts have been applied to achieve this transformation such as Na/EtOH [18], AlM e 2 Cl [19], ZnO [20], and 1,4-diazabicyclo[2,2,2]octane [21]. However, these reported methods are associated with one or more of the following drawbacks: (i) moderate yield, (ii) relatively long reaction time, (iii) harsh conditions, (iv) the use of more reactive phthalimide salts instead of phthalimide, (v) difficult experimental procedure, and (vi) the necessity of stoichiometric amount of catalyst. Moreover, the aza-conjugate addition reaction of phthalimide has been scarcely studied. Therefore, it seems highly desirable to find an efficient new protocol for this reaction.

Cesium carbonate is a commercially available, heterogeneous, and environmentally benign basic catalyst that has been used in various organic transformations [22–28].

Considering the above subjects and also in continuation of our previous studies on green organic synthesis [20, 21, 29–32], we report here an efficient, green, and simple method for the preparation of N-alkyl phthalimides via aza-conjugate addition of phthalimide to α,β-unsaturated esters in the presence of catalytic amount of C s 2 C O 3 in [bmim]Br at 7 0 ∘ C (Scheme 1). This present method has none of the above disadvantages at all.

419054.scheme001
Scheme 1

2. Results and Discussion

We have found previously C s 2 C O 3 acts as an efficient basic reagent for N3-alkylation of N1-substituted pyrimidines [22], and N-arylation of nucleobases [23]. Moreover, this base has been frequently applied for alkylation and arylation reactions [24–28]. These subjects encouraged us to use C s 2 C O 3 as catalyst for N-alkylation of phthalimide via aza-conjugate addition reaction. Therefore, firstly we used different amounts of C s 2 C O 3 to accomplish aza-conjugate addition of phthalimide (2 mmol) to ethyl acrylate (2.4 mmol) in [bmim]Br (1 g) at range of 25–100ºC to provide compound 1a (Scheme 1). The results showed that the reaction proceeded efficiently in the presence of 20 mol% of C s 2 C O 3 at 70ºC and the product was obtained in 98% yield after 90 minutes. We also examined the reaction in the presence of sodium and potassium carbonate in which the product was produced in 59 and 82% within 240 and 180 minutes, respectively. Thus, we selected C s 2 C O 3 as catalyst for our reaction.

To compare the efficiency of ionic liquid versus the conventional solvents, we examined the reaction between phthalimide (2 mmol) and ethyl acrylate (2.4 mmol) using C s 2 C O 3 (20 mol%) in some conventional solvents (10 mL) at 70ºC (Table 1). As it can be seen from Table 1, higher yield and shorter reaction time were obtained in [bmim]Br. The reaction was also tested in solvent-free conditions; however, these conditions were not efficient (Table 1). Therefore, ionic liquid is an essential factor to promote our reaction.

tab1
Table 1: Comparing the reaction of phthalimide with ethyl acrylate in conventional solvents versus [bmim]Br.

After optimization of the reaction conditions, we reacted phthalimide with different α,β-unsaturated esters. The results are summarized in Table 2. As Table 2 indicates, all reactions proceeded efficiently and the N-alkyl phthalimides were produced in excellent yields and relatively short reaction times.

tab2
Table 2: Synthesis of N-alkyl phthalimides using C s 2 C O 3 /[bmim]Br catalytic system.

The interesting behavior of [bmim]Br/C s 2 C O 3 system lies in the fact that it can be reused after simple washing with E t 2 O, rendering this process more economical. The yields of compound 1a (model compound) in the 2nd and 3rd uses of the [bmim]Br/C s 2 C O 3 were almost as high as in the first use (see Table 3).

tab3
Table 3: Aza-conjugate addition of phthalimide to ethyl acrylate in the presence of recycled C s 2 C O 3 /[bmim]Br.

3. Experimental

All chemicals were purchased from Merck, (Germany) or Fluka, (Switzerland) Chemical Companies. The 1 H NMR (250 MHz) and 1 3 C NMR (62.5 MHz) were run on a Bruker Avance DPX-250, FT-NMR spectrometer. Mass spectra were recorded on a Shimadzu GC MS-QP 1000 EX apparatus. Melting points were recorded on a Büchi B-545 apparatus in open capillary tubes.

3.1. General Procedure for the Synthesis of N-Alkyl Phthalimides

To a well-ground mixture of phthalimide (0.294 g, 2 mmol) and C s 2 C O 3 (0.130 g, 0.4 mmol) in a 10 mL round-bottomed flask connected to a reflux condenser [bmim]Br (1 g) and α,β-unsaturated ester (2.4 mmol) were added. The resulting mixture was stirred in an oil bath (70ºC) for the times reported in Table 1. Afterward, the reaction mixture was cooled to room temperature and was extracted with E t 2 O (3 × 50 mL). The organic extracts were then combined. After removal of the solvent, the crude product was purified by short column chromatography on silica gel eluted with EtOAc/n-hexane (1/3). After isolation of the product and evaporation of the remaining E t 2 O in ionic liquid, the ionic liquid containing the catalyst (C s 2 C O 3 /[bmim]Br) was used for the next run under identical reaction conditions.

3.2. Selected Physical and Spectral Data

Ethyl 3-Phthalimido Propanoate (1a)
Colorless solid; mp 59-60 ∘ C (Lit. [20] mp 60-61 ∘ C ); IR (KBr): 3051, 2968, 1774, 1716 c m − 1 ; 1 H NMR (CDC l 3 ): δ 1.11 (t, 3H, J = 7.1 Hz, C H 3 ), 2.57 (t, 2H, J = 7.2 Hz, O=CC H 2 ), 3.86 (t, 2H, J = 7.2 Hz, NC H 2 ), 4.06 (q, 2H, J = 7.1 Hz, OC H 2 ), 7.57–7.70 (m, 4H); 1 3 C NMR (CDC l 3 ): δ 13.8, 32.7, 33.5, 64.3, 122.9, 131.7, 133.8, 167.5, 170.6; MS (m/z): 247 ( M + ).

2-Hydroxy-3-(2-Methoxyphenoxy)Propyl 3-Phthalimido Propanoate (1g)
Pale yellow oil (Lit. [21] oil); IR (neat): 3480, 3049, 2948, 1770, 1715  c m − 1 ; 1 H NMR (CDC l 3 ): δ 2.63 (t, 2H, J = 7.0 Hz, O=CC H 2 ), 3.67 (s, 3H, C H 3 ), 3.80–390 (m, 5H), 4.11–4.19 (m, 3H), 6.73–6.80 (m, 4H), 7.54 (m, 2H), 7.68 (m, 2H); 1 3 C NMR (CDC l 3 ): δ 32.8, 33.6, 55.7, 65.7, 67.9, 70.5, 111.9, 114.2, 120.9, 121.8, 123.2, 131.7, 134.0, 147.8, 149.3, 168.0, 170.8; MS (m/z): 399 ( M + ).

4. Conclusions

In summary, we have developed a new method for the synthesis of N-alkyl phthalimides as biologically interesting compounds via aza-conjugate addition reaction. This new strategy has the advantage of high yield, short reaction time, mild conditions, ease of product isolation, potential for recycling of the catalytic system, and compliance with the green chemistry protocols.

Acknowledgments

The authors appreciate Persian Gulf University and Payame Noor University Research Councils for the financial support of this work.

References

  1. A. Zare, A. Hasaninejad, A. Khalafi-Nezhad, A. R. Moosavi Zare, and A. Parhami, “Organic reactions in ionic liquids: MgO as efficient and reusable catalyst for the Michael addition of sulfonamides to α,β-unsaturated esters under microwave irradiation,” Arkivoc, vol. 2007, no. 13, pp. 105–115, 2007.
  2. A. Zare, A. Hasaninejad, A. R. Moosavi Zare, A. Parhami, H. Sharghi, and A. Khalafi-Nezhad, “Zinc oxide as a new, highly efficient, green, and reusable catalyst for microwave-assisted Michael addition of sulfonamides to α,β-unsaturated esters in ionic liquids,” Canadian Journal of Chemistry, vol. 85, no. 6, pp. 438–444, 2007.
  3. L.-W. Xu, L. Li, C.-G. Xia, S.-L. Zhou, and J.-W. Li, “The first ionic liquids promoted conjugate addition of azide ion to α,β-unsaturated carbonyl compounds,” Tetrahedron Letters, vol. 45, no. 6, pp. 1219–1221, 2004.
  4. L. Yang, L.-W. Xu, W. Zhou, L. Li, and C.-G. Xia, “Highly efficient aza-Michael reactions of aromatic amines and N-heterocycles catalyzed by a basic ionic liquid under solvent-free conditions,” Tetrahedron Letters, vol. 47, no. 44, pp. 7723–7726, 2006.
  5. J.-M. Xu, C. Qian, B.-K. Liu, Q. Wu, and X.-F. Lin, “A fast and highly efficient protocol for Michael addition of N-heterocycles to α,β-unsaturated compound using basic ionic liquid [bmIm]OH as catalyst and green solvent,” Tetrahedron, vol. 63, no. 4, pp. 986–990, 2007.
  6. J. S. Yadav, B. V. S. Reddy, G. Baishya, K. V. Reddy, and A. V. Narsaiah, “Conjugate addition of indoles to α,β-unsaturated ketones using Cu(OTf)2 immobilized in ionic liquids,” Tetrahedron, vol. 61, no. 40, pp. 9541–9544, 2005.
  7. L. D. S. Yadav, R. Patel, V. K. Rai, and V. P. Srivastava, “An efficient conjugate hydrothiocyanation of chalcones with a task-specific ionic liquid,” Tetrahedron Letters, vol. 48, no. 44, pp. 7793–7795, 2007.
  8. H. Hagiwara, T. Okabe, T. Hoshi, and T. Suzuki, “Catalytic asymmetric 1,4-conjugate addition of unmodified aldehyde in ionic liquid,” Journal of Molecular Catalysis A, vol. 214, no. 1, pp. 167–174, 2004.
  9. B. Ni, Q. Zhang, and A. D. Headley, “Pyrrolidine-based chiral pyridinium ionic liquids (ILs) as recyclable and highly efficient organocatalysts for the asymmetric Michael addition reactions,” Tetrahedron Letters, vol. 49, no. 7, pp. 1249–1252, 2008.
  10. B. C. Ranu and S. S. Dey, “Catalysis by ionic liquid: a simple, green and efficient procedure for the Michael addition of thiols and thiophosphate to conjugated alkenes in ionic liquid, [pmIm]Br,” Tetrahedron, vol. 60, no. 19, pp. 4183–4188, 2004.
  11. R. D. Rogers and K. R. Seddon, Eds., Ionic Liquids As Green Solvents: Progress and Prospects, R. D. Rogers and K. R. Seddon, Eds., An American Chemical Society Publication, Washington, DC, USA, 2005.
  12. P. Wasserscheid and T. Welton, Ionic Liquids in Synthesis, Wiley-VCH, Weinheim, Germany, 2003.
  13. M. H. Norman, D. J. Minick, and G. C. Rigdon, “Effect of linking bridge modifications on the antipsychotic profile of some phthalimide and isoindolinone derivatives,” Journal of Medicinal Chemistry, vol. 39, no. 1, pp. 149–157, 1996.
  14. L. M. Lima, P. Castro, A. L. Machado, et al., “Synthesis and anti-inflammatory activity of phthalimide derivatives, designed as new thalidomide analogues,” Bioorganic & Medicinal Chemistry, vol. 10, no. 9, pp. 3067–3073, 2002.
  15. J. M. Chapman, Jr., G. H. Cocolas, and I. H. Hall, “Hypolipidemic activity of phthalimide derivatives. 3. A comparison of phthalimide and 1,2-benzisothiazolin-3-one 1,1-dioxide derivatives to phthalimidine and 1,2-benzisothiazoline 1,1-dioxide congeners,” Journal of Medicinal Chemistry, vol. 26, no. 2, pp. 243–246, 1983.
  16. A. Raasch, O. Scharfenstein, C. Tränkle, U. Holzgrabe, and K. Mohr, “Elevation of ligand binding to muscarinic M2 acetylcholine receptors by bis(ammonio)alkane-type allosteric modulators,” Journal of Medicinal Chemistry, vol. 45, no. 17, pp. 3809–3812, 2002.
  17. M. B. Smith and J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, John Wiley & sons, New York, NY, USA, 4th edition, 2001.
  18. O. A. Moe and D. T. Warner, “1,4 Addition reactions. III. The addition of cyclic imides to α,β-unsaturated aldehydes. A synthesis of β-alanine hydrochloride,” Journal of the American Chemical Society, vol. 71, no. 4, pp. 1251–1253, 1949.
  19. G. Cardillo, A. De Simone, L. Gentilucci, P. Sabatino, and C. Tomasini, “Michael-type addition of phthalimide salts to chiral α,β-unsaturated imides,” Tetrahedron Letters, vol. 35, no. 28, pp. 5051–5054, 1994.
  20. A. Zare, A. Hasaninejad, A. Khalafi-Nezhad, A. R. Moosavi Zare, A. Parhami, and G. R. Nejabat, “A green solventless protocol for Michael addition of phthalimide and saccharin to acrylic acid esters in the presence of zinc oxide as a heterogeneous and reusable catalyst,” Arkivoc, vol. 2007, no. 1, pp. 58–69, 2007.
  21. G. H. Imanzadeh, A. Khalafi-Nezhad, A. Zare, A. Hasaninejad, A. R. Moosavi Zare, and A. Parhami, “Michael addition of phthalimide and saccharin to α,β-unsaturated esters under solvent-free conditions,” Journal of the Iranian Chemical Society, vol. 4, no. 2, pp. 229–237, 2007.
  22. A. Khalafi-Nezhad, A. Zare, A. Parhami, and M. N. Soltani Rad, “Practical synthesis of some novel unsymmetrical 1,3-dialkyl pyrimidine derivatives at room temperature,” Arkivoc, vol. 2006, no. 12, pp. 161–172, 2006.
  23. A. Khalafi-Nezhad, A. Zare, A. Parhami, M. N. Soltani Rad, and G. R. Nejabat, “Microwave-assisted N-nitroarylation of some pyrimidine and purine nucleobases,” Canadian Journal of Chemistry, vol. 84, no. 7, pp. 979–985, 2006.
  24. S. Kotha and K. Singh, “N-Alkylation of diethyl acetamidomalonate: synthesis of constrained amino acid derivatives by ring-closing metathesis,” Tetrahedron Letters, vol. 45, no. 52, pp. 9607–9610, 2004.
  25. F. Chu, E. E. Dueno, and K. W. Jung, “Cs2CO3 promoted O-alkylation of alcohols for the preparation of mixed alkyl carbonates,” Tetrahedron Letters, vol. 40, no. 10, pp. 1847–1850, 1999.
  26. F. Churruca, R. SanMartin, I. Tellitu, and E. Domínguez, “Regioselective diarylation of ketone enolates by homogeneous and heterogeneous catalysis: synthesis of triarylethanones,” Tetrahedron Letters, vol. 44, no. 31, pp. 5925–5929, 2003.
  27. R. N. Salvatore, R. A. Smith, A. K. Nischwitz, and T. Gavin, “A mild and highly convenient chemoselective alkylation of thiols using Cs2CO3-TBAI,” Tetrahedron Letters, vol. 46, no. 51, pp. 8931–8935, 2005.
  28. C. Geraci, M. Piattelli, and P. Neri, “Regioselective synthesis of calix[8]crowns by direct alkylation of p-tert-butylcalix[8]arene,” Tetrahedron Letters, vol. 37, no. 22, pp. 3899–3902, 1996.
  29. A. Khalafi-Nezhad, A. Parhami, A. Zare, A. R. Moosavi Zare, A. Hasaninejad, and F. Panahi, “Trityl chloride as a novel and efficient organic catalyst for room temperature preparation of bis(indolyl)methanes under solvent-free conditions in neutral media,” Synthesis, vol. 617, pp. 617–621, 2008.
  30. A. Zare, A. Hasaninejad, M. H. Beyzavi, et al., “Zinc oxide-tetrabutylammonium bromide tandem as a highly efficient, green, and reusable catalyst for the Michael addition of pyrimidine and purine nucleobases to α,β-unsaturated esters under solvent-free conditions,” Canadian Journal of Chemistry, vol. 86, no. 4, pp. 317–324, 2008.
  31. A. Zare, A. Hasaninejad, A. Khalafi-Nezhad, A. Parhami, and A. R. Moosavi Zare, “A solventless protocol for the Michael addition of aromatic amides to α,β-unsaturated esters promoted by microwave irradiation,” Journal of the Iranian Chemical Society, vol. 5, no. 1, pp. 100–105, 2008.
  32. A. Hasaninejad, A. Zare, H. Sharghi, and M. Shekouhy, “P2O5/SiO2 an efficient, green and heterogeneous catalytic system for the solvent-free synthesis of N-sulfonyl imines,” Arkivoc, vol. 2008, no. 11, pp. 64–74, 2008.