Table of Contents
ISRN Organic Chemistry
Volume 2013, Article ID 793159, 6 pages
http://dx.doi.org/10.1155/2013/793159
Research Article

Nanorod-Shaped Basic Catalyzed N,N-Diformylation of Bisuracil Derivatives: A Greener “NOSE” Approach

Department of Chemical Sciences, Tezpur University (A Central University), Napaam, Assam 784028, India

Received 14 May 2013; Accepted 10 June 2013

Academic Editors: R. Pohl and D. Sémeril

Copyright © 2013 Vijay K. Das and Ashim J. Thakur. 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

A feasible “NOSE” (nanoparticles-catalyzed organic synthesis enhancement) protocol has been developed for N,N-diformylation of bisuracil derivatives using nano-Al2O3 rods as an efficient, inexpensive, and recyclable catalyst under solvent-free reaction condition at 40°C. The catalyst was reused up to the 4th cycle without affecting the rate and yield of the N,N-diformylation products appreciably.

1. Introduction

The exercise of metal/metal oxide nanoparticles as a frontier between the homogeneous catalysis and heterogeneous catalysis [1] in organic synthesis has invoked tremendous interests [2] in the recent times. The interesting features inherited with these small particle sizes are their large surface area along with more edges and corners and distinct electronic, optical, magnetic, thermal, and chemical properties [35]. The crucial role of nanoparticles in organic transformations is their excellent catalytic activity, straightforward recoverability, better selectivity, criteria of evolution, and their versatile role in green chemistry [610]. Thus, the domain of metal nanoparticle catalysis [1113] should offer opportunities for mining new chemical reactions [1416] which include the synthesis of biologically important and synthetically challenging natural products. In the context of green chemistry [17], organic synthesis in solvent-free reaction condition [1821] has occupied a significant position in the recent years since solvent-free reaction condition involves the best reaction medium with “no medium” [22].

One of the key motifs present in the biopolymer RNA [2326] is uracil, a nucleobase of the pyrimidine family which participates in various functions in our life processes [27]. Uracil derivatives also have several potent medicinal properties such as bronchodilators and anticancer [28, 29], antiallergic [30, 31], antiviral [32, 33], antihypertensive, and adenosine receptor antagonists [34, 35]. Recently, our research group reported a greener protocol for the synthesis of bisuracil derivatives [36]. Bisuracil and their analogues have also been isolated from marine sea hare Dolabella auricularia [37]. Some of the N-substituted bisuracil analogues have been screened for bioactivities against several diseases [38].

To explore the possible applications of the metal/metal oxide nanoparticles in organic synthesis, we have been focusing on the advancement of a protocol termed “NOSE” (nanoparticles-catalyzed organic synthesis enhancement) [3941] chemistry in our laboratory. To the best of our knowledge, there has been no report on nano-rod-shaped Al2O3 catalyzed N,N-diformylation of bisuracil derivatives. Recently, we reported N-formylation of amines catalyzed by nano-Al2O3 under solvent-free reaction condition [39]. This work inspired us to focus on nano-Al2O3 catalysis for the N,N-diformylation of bisuracil analogous. Therefore, in this paper, we wish to account for the same (Scheme 1).

793159.sch.001
Scheme 1: N,N-diformylation of bisuracil derivatives 1(a–k).

Nano-Al2O3 draws our attention due to its crystalline size and shape, abrasive and insulating properties, less toxicity, large surface area, basic surface characteristics, high resistant towards bases and acids and excellent wear resistance [4044].

2. Materials and Methods

2.1. General Experimental Methods

Rod-shaped nano-Al2O3 (the average particle diameter is 8.12 nm and average length 25.5 nm, = 185.63 m2 g−1, ρ = 3.98 g cm−3, and purity is 99.99%) were purchased from Sigma Aldrich and used as received. The chemicals and reagents were purchased from Sigma-Aldrich, Merck, M/S S.D. Fine Chemicals Pvt. Ltd., and Loba Chemie, and used without further purification. The XRD pattern was recorded with Rigaku X-ray diffractometer. Melting points were determined in a Büchi 504 apparatus. IR spectra were recorded as KBr pallets in a Nicolet (Impact 410) FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded in a 400 MHz NMR spectrophotometer (JEOL, JNM ECS) using tetramethylsilane (TMS) as the internal standard, and coupling constants are expressed in Hertz. Elemental analyses were carried out in a Perkin-Elmer CHN analyser (2400 series II). Mass spectra were recorded with a Waters Q-TOF Premier and an Acquity UPLC spectrometer. Visualization was accomplished with UV lamp or I2 stain. Reactions were monitored by thin-layer chromatography using aluminium sheets with silica gel 60 F254 (Merck).

2.2. General Procedure for N,N-Diformylation of Bisuracil Derivatives

In a two-neck round bottom flask (50 mL), nanorod-shaped basic Al2O3 (7.0 mol%, 7.12 mg) were taken, and then 1g (1.0 mmol, 414 mg) and formic acid (98%, 6.0 mmol, 0.23 mL) were added. After that, it was allowed to stir on a pre heated oil bath at 40°C for the required time (the progress of the reaction was judged by TLC). The reaction mixture was brought to room temperature after its completion, and ethyl acetate (3 × 10 mL) was added and then centrifuged (3,000 r.p.m) to recover the nanocatalyst. Having done this, the reaction mixture was washed with water and brine, dried over anhydrous Na2SO4, and concentrated in a rotary evaporator, and finally the crude product was purified by column chromatography (30% ethyl acetate: hexane as an eluent). The recovered catalyst was washed with hot ethanol (3 × 10 mL) to remove the organic impurities, decanted, dried in an oven at 80°C for 6 h, and reused for evaluating the performance in the next run in the reaction as shown in Scheme 2.

793159.sch.002
Scheme 2: Optimization of reaction condition.

3. Results and Discussion

With the previously reported catalyst characterizations in hand [39], to begin with, reaction of 6,6′-diamino-1,1′,3,3′-tetramethyl-5,5′-(benzylidene)bis[pyrimidine-2,4 (1H, 3H)-dione] [36] (1a, 1 mmol) with formic acid (6 mmol) was chosen as the model reaction (Scheme 2).

The optimization of the various parameters of this reaction is elaborated in Table 1. Initially, the reaction was carried out without using catalyst under solvent-free reaction condition at 40°C and 80°C which did not yield any product (Table 1, entries 1 and 2). Various solvents were also tested under the mentioned condition, but they all failed (Table 1, entries 3–11) to provide any product. These negative results suggested that we look for an effective catalyst in the present study. Next, various Lewis acid-base catalysts (Table 1, entries 12–14) along with the nanocatalysts (Table 1, entries 15–18) were surveyed to observe the influence on rate and yield of N,N-diformylation of 1a which were not fruitful. Interestingly, nanorod-shaped basic Al2O3 stood out as a choice of catalyst at 7 mol% loading (Table 1, entry 15) under solvent-free reaction condition at 40°C. During the course of our experiment, we observed that at higher temperature (Table 1, entry 19) and at lower/higher catalyst loading the yield of the products was poor (Table 1, entries 20–22). Thus, the yield of N,N-diformylation product of bisuracil derivatives is highly dependent upon the temperature and catalyst loading.

tab1
Table 1: Optimization of the reaction conditions for the N,N-diformylation of 1a (Scheme 1).

With this supportive optimized reaction condition in hand, a series of bisuracil derivatives (entries 1–11) bearing different aliphatic, aromatic, and heterocyclic moieties were examined to explore the scope and limitations of this reaction and the outcomes are presented in Table 2. It is clear from Table 2 that bisuracil derivatives carrying both electron donating and electron withdrawing groups in benzene ring underwent N,N-diformylation reaction smoothly producing good yields (Table 2, entries 1–8). However, longer reaction time was required for bisuracil derivatives substituted with furan and alkyl groups (Table 2, entries 9–11). It is worth mentioning that 6-amino-1,3-dimethyluracil when treated with formic acid under the current condition gave N,N-diformylation product in lower yield (26%, 9 h). The reactions were found to be clean, and no side products were formed.

tab2
Table 2: Nano-Al2O3 catalyzed N,N-diformylation of uracil and bisuracil derivatives.

To test the recyclability (vide Scheme 2) of nano-Al2O3, it was separated from the reaction mixture by adding ethyl acetate (10 mL), centrifuged at 3,000 rpm, to pellet out the catalyst. The separated particles were washed with hot ethanol (3 × 10 mL) to remove the organic impurities, decanted, dried in an oven at 80°C for 6 h, and reused for further reactions. The efficiency of the catalyst was found to be unaffected up to 4th run, and after that, its action started to decrease as shown in Table 3. The TONs were also retained from fresh up to the 5th cycle, and after that it decreased considerably.

tab3
Table 3: Recycling study of nano-Al2O3.

The recovered catalyst was also investigated through powder XRD and it was compared with the fresh nano-Al2O3 (Figure 1). In the powder XRD of the recovered catalyst after 6th run (Figure 1), the intensity of the peaks (4 0 0) and (1 0 0) weakened and became broad. It might be due to the blockage of the pores of the catalyst which caused a decrease in effective active sites and also due to the dislocation of the crystal planes after each run which in turn decreased the yield.

793159.fig.001
Figure 1: Comparison of XRD of fresh nano-Al2O3 with the recovered ones.

The SEM micrograph of the fresh nano-Al2O3 previously reported by us [39] was also compared with the recycled one (Figure 2) under the present study. As indicated in Figure 2, the recycled nano-Al2O3 revealed the aggregation of the particles responsible for reducing its surface area and hence deactivated the catalyst after 4th run which caused the lower yield of product.

793159.fig.002
Figure 2: SEM image of recovered nano-Al2O3 after 4th run.

4. Conclusions

In conclusion, we have demonstrated a novel method for synthesis the N,N-diformylation of bisuracil derivatives in good yield under solvent-free reaction condition at 40°C catalyzed by recyclable nano-Al2O3 rods. Nano-Al2O3 catalyzed organic transformations are less explored. We believe that this work would find wide applications for new chemical transformations, including those which enable the synthesis of complex natural products and derivatives.

Conflict of Interests

The authors declare no financial conflict of interests.

Acknowledgments

Vijay K. Das thanks UGC for a Rajiv Gandhi National Fellowship given to him. The authors would also like to acknowledge Mr. Prakash Kurmi, Department of Physics, Tezpur University, for carrying out XRD studies and fruitful discussions.

References

  1. D. Astruc, F. Lu, and J. R. Aranzaes, “Nanoparticles as recyclable catalysts: the frontier between homogeneous and heterogeneous catalysis,” Angewandte Chemie—International Edition, vol. 44, no. 48, pp. 7852–7872, 2005. View at Publisher · View at Google Scholar · View at Scopus
  2. J. Grunes, J. Zhu, and G. A. Somorjai, “Catalysis and nanoscience,” Chemical Communications, vol. 9, no. 18, pp. 2257–2260, 2003. View at Google Scholar · View at Scopus
  3. J. Rautio, P. Perämäki, J. Honkamo, and H. Jantunen, “Effect of synthesis method variables on particle size in the preparation of homogeneous doped nano ZnO material,” Microchemical Journal, vol. 91, no. 2, pp. 272–276, 2009. View at Publisher · View at Google Scholar · View at Scopus
  4. M. T. Reetz and E. Westermann, “Phosphane-free palladium-catalyzed coupling reactions: the decisive role of Pd nanoparticles,” Angewandte Chemie—International Edition, vol. 39, no. 1, pp. 165–168, 2000. View at Publisher · View at Google Scholar
  5. C. Ramarao, S. V. Ley, S. C. Smith, I. M. Shirley, and N. DeAlmeida, “Encapsulation of palladium in polyurea microcapsules,” Chemical Communications, no. 10, pp. 1132–1133, 2002. View at Google Scholar · View at Scopus
  6. J. A. Gladysz, “Recoverable catalysts. Ultimate goals, criteria of evaluation, and the green chemistry interface,” Pure and Applied Chemistry, vol. 73, no. 8, pp. 1319–1324, 2001. View at Google Scholar · View at Scopus
  7. J. A. Gladysz, “Introduction: recoverable catalysts and reagents—perspective and prospective,” Chemical Reviews, vol. 102, no. 10, pp. 3215–3216, 2002. View at Publisher · View at Google Scholar · View at Scopus
  8. G. Pacchioni, “Quantum chemistry of oxide surfaces: from CO chemisorption to the identification of the structure and nature of point defects on MgO,” Surface Review and Letters, vol. 7, no. 3, pp. 277–306, 2000. View at Publisher · View at Google Scholar · View at Scopus
  9. D. M. Cox, D. J. Trevor, R. L. Whetten, and A. Kaldor, “Aluminum clusters: ionization thresholds and reactivity toward deuterium, water, oxygen, methanol, methane, and carbon monoxide,” Journal of Physical Chemistry, vol. 92, no. 2, pp. 421–429, 1988. View at Google Scholar · View at Scopus
  10. V. Polshettiwar and R. S. Varma, “Green chemistry by nano-catalysis,” Green Chemistry, vol. 12, no. 5, pp. 743–754, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. V. Polshettiwar, B. Baruwati, and R. S. Varma, “Self-assembly of metal oxides into three-dimensional nanostructures: synthesis and application in catalysis,” ACS Nano, vol. 3, no. 3, pp. 728–736, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. V. Polshettiwar, M. N. Nadagouda, and R. S. Varma, “The synthesis and applications of a micro-pine-structured nanocatalyst,” Chemical Communications, no. 47, pp. 6318–6320, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. A. Fihri, R. Sougrat, R. B. Rakhi et al., “Nanoroses of nickel oxides: synthesis, electron tomography study, and application in CO oxidation and energy storage,” ChemSusChem, vol. 5, no. 7, pp. 1241–1248, 2012. View at Publisher · View at Google Scholar
  14. K. Shimizu, R. Sato, and A. Satsuma, “Direct C–C cross-coupling of secondary and primary alcohols catalyzed by a γ-alumina-supported silver subnanocluster,” Angewandte Chemie—International Edition, vol. 48, no. 22, pp. 3982–3986, 2009. View at Publisher · View at Google Scholar · View at Scopus
  15. A. Murugadoss, P. Goswami, A. Paul, and A. Chattopadhyay, “‘Green’ chitosan bound silver nanoparticles for selective C–C bond formation via in situ iodination of phenols,” Journal of Molecular Catalysis A, vol. 304, no. 1-2, pp. 153–158, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. C. A. Witham, W. Huang, C. Tsung, J. N. Kuhn, G. A. Somorjai, and F. D. Toste, “Converting homogeneous to heterogeneous in electrophilic catalysis using monodisperse metal nanoparticles,” Nature Chemistry, vol. 2, no. 1, pp. 36–41, 2010. View at Publisher · View at Google Scholar · View at Scopus
  17. P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice, Oxford Publication, New York, NY, USA, 1998.
  18. M. A. P. Martins, C. P. Frizzo, D. N. Moreira, L. Buriol, and P. Machado, “Solvent-free heterocyclic synthesis,” Chemical Reviews, vol. 109, no. 9, pp. 4140–4182, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. P. J. Walsh, H. Li, and C. A. de Parrodi, “A green chemistry approach to asymmetric catalysis: solvent-free and highly concentrated reactions,” Chemical Reviews, vol. 107, no. 6, pp. 2503–2545, 2007. View at Publisher · View at Google Scholar · View at Scopus
  20. K. Tanaka and F. Toda, “Solvent-free organic synthesis,” Chemical Reviews, vol. 100, no. 3, pp. 1025–1074, 2000. View at Google Scholar · View at Scopus
  21. G. Nagendrappa, “Organic synthesis under solvent-free condition: an environmentally benign procedure—II,” Resonance, vol. 7, no. 10, pp. 59–68, 2002. View at Google Scholar
  22. K. Tanaka, Solvent-Free Organic Synthesis, Wiley-VCH, Weinheim, Germany, 2009.
  23. M. Fathalla, C. M. Lawrence, N. Zhang, J. L. Sessler, and J. Jayawickramarajah, “Base-pairing mediated non-covalent polymers,” Chemical Society Reviews, vol. 38, no. 6, pp. 1608–1620, 2009. View at Publisher · View at Google Scholar · View at Scopus
  24. S. Sivakova and S. J. Rowan, “Nucleobases as supramolecular motifs,” Chemical Society Reviews, vol. 34, no. 1, pp. 9–21, 2005. View at Publisher · View at Google Scholar · View at Scopus
  25. M. W. Powner, B. Gerland, and J. D. Sutherland, “Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions,” Nature, vol. 459, no. 7244, pp. 239–242, 2009. View at Publisher · View at Google Scholar · View at Scopus
  26. O. S. Pedersen and E. B. Pedersen, “Non-nucleoside reverse transcriptase inhibitors: the NNRTI boom,” Antiviral Chemistry and Chemotherapy, vol. 10, no. 6, pp. 285–314, 1999. View at Google Scholar · View at Scopus
  27. A. R. Dinner, G. M. Blackburn, and M. Karplus, “Uracil-DNA glycosylase acts by substrate autocatalysis,” Nature, vol. 413, no. 6857, pp. 752–755, 2001. View at Publisher · View at Google Scholar · View at Scopus
  28. F. C. Tucci, Y. F. Zhu, Z. Guo et al., “3-(2-aminoalkyl)-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methyluracils as orally bioavailable antagonists of the human gonadotropin releasing hormone receptor,” Journal of Medicinal Chemistry, vol. 47, no. 14, pp. 3483–3486, 2004. View at Publisher · View at Google Scholar · View at Scopus
  29. D. P. Sutherlin, D. Sampath, M. Berry et al., “Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available Pan-PI3-kinase and dual Pan-PI3-kinase/mTOR inhibitors for the treatment of cancer,” Journal of Medicinal Chemistry, vol. 53, no. 3, pp. 1086–1097, 2010. View at Publisher · View at Google Scholar · View at Scopus
  30. S. Manta, E. Tsoukala, N. Tzioumaki, C. Kiritsis, J. Balzarini, and D. Komiotis, “Synthesis of 4,6-dideoxy-3-fluoro-2-keto-β-d-glucopyranosyl analogues of 5-fluorouracil, N6-benzoyl adenine, uracil, thymine, N4-benzoyl cytosine and evaluation of their antitumor activities,” Bioorganic Chemistry, vol. 38, no. 2, pp. 48–55, 2010. View at Publisher · View at Google Scholar · View at Scopus
  31. T. Lundqvist, S. L. Fisher, G. Kern et al., “Exploitation of structural and regulatory diversity in glutamate racemases,” Nature, vol. 447, no. 7146, pp. 817–822, 2007. View at Publisher · View at Google Scholar · View at Scopus
  32. J. B. Parker, M. A. Bianchet, D. J. Krosky, J. I. Friedman, L. M. Amzel, and J. T. Stivers, “Enzymatic capture of an extrahelical thymine in the search for uracil in DNA,” Nature, vol. 449, no. 7161, pp. 433–437, 2007. View at Publisher · View at Google Scholar · View at Scopus
  33. A. Okamoto, “Chemical approach toward efficient DNA methylation analysis,” Organic and Biomolecular Chemistry, vol. 7, no. 1, pp. 21–26, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. A. Samanta, D. D. Leonidas, S. Dasgupta, T. Pathak, S. E. Zographos, and N. G. Oikonomakos, “Morpholino, piperidino, and pyrrolidino derivatives of pyrimidine nucleosides as inhibitors of ribonuclease A: synthesis, biochemical, and crystallographic evaluation,” Journal of Medicinal Chemistry, vol. 52, no. 4, pp. 932–942, 2009. View at Publisher · View at Google Scholar · View at Scopus
  35. R. Rico-Gómez, J. M. López-Romero, J. Hierrezuelo, J. Brea, M. I. Loza, and M. Pérez-González, “Synthesis of new mannosyl, galactosyl and glucosyl theophylline nucleosides with potential activity as antagonists of adenosine receptors. DEMA-induced cyclization of glycosylideneiminouracils,” Carbohydrate Research, vol. 343, no. 5, pp. 855–864, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. S. Das and A. J. Thakur, “A clean, highly efficient and one-pot green synthesis of aryl/alkyl/heteroaryl-substituted bis(6-amino-1,3-dimethyluracil-5-yl)methanes in water,” European Journal of Organic Chemistry, no. 12, pp. 2301–2308, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. J. W. Blunt, B. R. Copp, W. P. Hu, M. H. G. Munro, P. T. Northcotec, and M. R. Prinsepd, “Marine natural products,” Natural Product Reports, vol. 26, no. 1, pp. 170–224, 2008. View at Google Scholar
  38. V. E. Semenov, V. D. Akamsin, V. S. Reznik et al., “New type of pyrimidinophanes with α,ω-bis(uracil-1-yl)alkane and bis(uracil-5-yl)methane units,” Mendeleev Communications, vol. 11, no. 3, pp. 96–97, 2001. View at Google Scholar · View at Scopus
  39. V. K. Das, R. R. Devi, P. K. Raul, and A. J. Thakur, “Nano rod-shaped and reusable basic Al2O3 catalyst for N-formylation of amines under solvent-free conditions: a novel, practical and convenient 'NOSE' approach,” Green Chemistry, vol. 14, no. 3, pp. 847–854, 2012. View at Publisher · View at Google Scholar · View at Scopus
  40. V. K. Das, R. R. Devi, and A. J. Thakur, “Recyclable, highly efficient and low cost nano-MgO for amide synthesis under SFRC: a convenient and greener “NOSE” approach,” Applied Catalysis A, vol. 456, pp. 118–125, 2013. View at Publisher · View at Google Scholar
  41. V. K. Das, M. Borah, and A. J. Thakur, “Piper-betle-shaped nano-S-catalyzed synthesis of 1-amidoalkyl-2-naphthols under solvent-free reaction condition: a greener nanoparticle-catalyzed organic synthesis enhancement approach,” Journal of Organic Chemistry, vol. 78, no. 7, pp. 3361–3366, 2013. View at Publisher · View at Google Scholar
  42. M. Shojaie-Bahaabad and E. Taheri-Nassaj, “Economical synthesis of nano alumina powder using an aqueous sol-gel method,” Materials Letters, vol. 62, no. 19, pp. 3364–3366, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. C. Huang, J. Wang, and C. Huang, “Sintering behavior and microwave dielectric properties of nano alpha-alumina,” Materials Letters, vol. 59, no. 28, pp. 3746–3749, 2005. View at Publisher · View at Google Scholar · View at Scopus
  44. Y. Zhang, J. Liu, R. He, Q. Zhang, X. Zhang, and J. Zhu, “Synthesis of alumina nanotubes using carbon nanotubes as templates,” Chemical Physics Letters, vol. 360, no. 5-6, pp. 579–584, 2002. View at Publisher · View at Google Scholar · View at Scopus