Table of Contents Author Guidelines Submit a Manuscript
Journal of Chemistry
Volume 2013 (2013), Article ID 761982, 5 pages
http://dx.doi.org/10.1155/2013/761982
Research Article

A Novel Four-Component Reaction between Secondary Amines and Hydroxybenzaldehydes with Isocyanides in Water: An Efficient One-Pot and Green Synthesis of Benzo[b]furan Derivatives

1Payame Noor University, P.O. Box 19395-4697, Tehran, Iran
2Department of Chemistry, University of Zanjan, P.O. Box 45195-313, Zanjan, Iran

Received 25 May 2013; Accepted 11 August 2013

Academic Editor: Raquel G. Soengas

Copyright © 2013 Esmail Vessally 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

The novel benzo[b]furan derivatives, 7ai, were synthesized and characterized by Ugi four-component reaction between 2-hydroxybenzaldehyde derivative 1, a secondary amine 2, and an isocyanide 3 in water. Those reactions were carried out at room temperature with moderate to good yields in one pot.

1. Introduction

The isocyanide-based MCRs have widely been applied in the versatile Ugi and Passerini reactions [1]. The great potential of the isocyanides for development of the multicomponent reactions lies in the diversity of bond-forming processes available, their functional group tolerance, and the high levels of chemo-, regio-, and stereoselectivity often observed [210]. The four-component condensation between the aldehydes, isocyanides, and ammonium formate affords N-substituted 2-formylaminocarboxamides [11]. The reaction between salicylaldehyde, isocyanides, and ammonium formate under Ugi four-component condensation conditions affords benzo[b]furan derivatives in low yields [12].

The furan derivatives, obtained from both synthetic and natural sources, have attracted much interest due to their wide pharmaceutical applications [13, 14]. Many furans from natural resources indicate interesting biological activities, such as the cytotoxic and antitumor properties [15] as well as antispasmodic [16], antimicrobial [17], and several other potentially useful activities [18].

As a continuation of our recent studies on isocyanide chemistry [1922], we report the Ugi multicomponent reaction between 2-hydroxybenzaldehyde derivative 1, a secondary amine 2, and an isocyanide 3.

2. Experimental

Starting materials and solvents were purchased from Merck (Germany) and Fluka (Switzerland) and were used without further purification. The reactions were monitored by TLC and NMR techniques, which indicated that there were no side products. IR spectra were measured on a Perkin-Elmer RXI, FT-IR spectrometer. 1H and 13C NMR spectra (CDCl3) were recorded on a BrukerAvance spectrometer at 250.0 and 62.9 MHz, respectively. Elemental analyses were performed by using a Perkin-Elmer 2400(II) CHN/O analyzer. Mass spectra were recorded on a FINNIGAN-MATT 8430 mass spectrometer operating at an ionization potential of 20 eV. The TLC plates were prepared from Merck silica gel powder.

3. Synthesis of N,N-Dibenzyl-N-[5-nitro-2-(1,1,3,3-tetramethylbutylamino)-1-benzofuran-3-yl]amine (7a)

A mixture of dibenzylamine (0.19 mL, 1 mmol) and 2-hydroxy-5-nitrobenzaldehyde (0.167 g, 1 mmoL) (5 mL) was stirred in 5 mL water at room temperature for 60 minutes. To this mixture, 1,1,3,3-tetramethylbutyl isocyanide (0.17 mL, 1 mmoL) at 15°C was added rapidly, and the solution was allowed to stand for 24 h at room temperature. The solvent was removed under reduced pressure, and single-spot product (7a) was obtained. The mentioned product was purified through plate thin layer liquid chromatography PTLC method by using petroleum ether/diethyl ether (10 : 1) as eluent and red viscous oil was obtained. All other products (7b–i) were obtained by similar approach. The characterization data of the compounds are given below (7a–i).

N,N-Dibenzyl-N-[5-nitro-2-(1,1,3,3-tetramethylbutylamino)-1-benzofuran-3-yl]amine, 7a. Red viscous oil; yield: 98%. IR (KBr) ( , cm−1): 3400 (NH), 1646, 1530, 1476, 1346, 1223. 1H NMR (250 MHz, CDCl3) : 0.96 (9H, s, CMe3), 1.06 (6H, s, CMe2NH), 1.47 (2H, s, CH2CMe3), 4.20 (4H, s, 2CH2, benzyl), 4.10 (1H, s, NH, exchanged by D2O addition), 7.20–7.39 (11H, m, H–Ar), 7.89 (1H, dd, , , H-4, benzofuran), 8.15 (1H, d, , H-6, benzofuran). 13C NMR (62.9 MHz, CDCl3) dC: 30.03 (2CH3 of CMe2NH), 31.55 (3CH3, CMe3), 31.64 (C, CMe3), 54.21 (CH2, CH2CMe3), 56.01 (C, CMe2NH), 58.91 (2CH2, benzyl), 109.87, 111.50, 128.74 (3CH, benzofuran), 103.64, 114.93, 151.95, 158.32 (4C, benzofuran), 143.91 (C(NO2)), 127.34, 128.60, 129.18 (10CH), 138.96 ( ).

N,N-Dibenzyl-N-[2-(cyclohexylamino)-5-nitro-1-benzofuran-3-yl]amine, 7b. Red viscous oil; yield: 94%. IR (KBr) ( , cm−1): 3415 (NH), 2853, 1646, 1530, 1461, 1346, 1261. 1H NMR (250 MHz, CDCl3) : 1.10–1.81 (10H, 2m, 5CH2, cyclohexyl), 3.22 (1H, m, CH–N, cyclohexyl), 4.24 (4H, s, 2CH2, benzyl), 3.85 (1H, br s, NH, exchanged by D2O addition), 7.20–7.38 (11H, m, H–Ar), 7.86 (1H, dd, , , H-4, benzofuran), 8.09 (1H, d, , H-6, benzofuran). 13C NMR (62.9 MHz, CDCl3) : 24.70 (2CH2,β, cyclohexyl), 25.44 (1CH2,γ, cyclohexyl), 33.87 (2CH2,α, cyclohexyl), 48.07 (CH–N, cyclohexyl), 58.70 (2CH2, benzyl), 109.76, 111.68, 129.07 (3CH, benzofuran), 102.56, 115.05, 151.76, 157.68 (4C, benzofuran), 143.89 (C(NO2)), 127.27, 128.25, 129.15 (10CH), 138.96 ( ).

N-Benzyl-N-ethyl–N-[5-nitro-2-(1,1,3,3-tetramethylbutylamino)-1-benzofuran-3-yl]amine, 7c. Red viscous oil; yield: 70%. IR(KBr) ( , cm−1): 3479 (NH), 2775, 1638, 1551, 1504, 1374, 1289. 1H NMR (250 MHz, CDCl3) : 0.98 (9H, s, CMe3), 1.24 (6H, s, CMe2NH), 1.54 (2H, s, CH2CMe3), 1.59 (3H, CH3, NCH2CH3), 3.22 (CH2, NCH2), 4.17 (2H, s, CH2), 4.76 (1H, s, NH, exchanged by D2O addition), 7.22–7.27 (6H, m, H–Ar), 7.87 (1H, m, benzofuran), 8.12 (1H, s, H-4, benzofuran). 13C NMR (62.9 MHz, CDCl3) : 29.86 (CH3, NCH2CH3), 30.24 (2CH3, CMe2NH), 31.56 (3CH3, CMe3), 31.71 (C, CMe3), 49.02 (CH2, CH2CMe3), 54.35 (C, CMe2NH), 56.43 (CH2, benzyl), 59.73 (NCH2), 109.95, 115.12, 144.5, 158.05 (4C, benzofuran), 111.46, 114.23, 127.40 (3CH, benzofuran), 152.3 (C(NO2)), 126.95, 128.26, 128.71 (5CH), 128.24 (Cipso).

N-Benzyl-N-ethyl–N-[2-(cyclohexylamino)-5-nitro-1-benzofuran-3-yl]amine, 7d. Red viscous oil; yield: 32%. IR(neat) ( , cm−1): 3418 (NH), 1633, 1505, 1455, 1393, 1299. 1H NMR (250 MHz, CDCl3) : 1.14–1.76 (10H, 2m, 5CH2, cyclohexyl), 2.64 (2H, s, NCH2), 2.16 (3H, s, NCH3), 3.24 (1H, m, CH–N, cyclohexyl), 4.71 (2H, s, CH2, benzyl), 4.26 (1H, br s, NH, exchanged by D2O addition), 7.24–7.34 (6H, m, H–Ar), 7.89 (1H, m, H-4, benzofuran), 8.04 (1H, H-6, benzofuran). 13C NMR (62.9 MHz, CDCl3) : 24.74–25.39 (5CH2, cyclohexyl), 25.39 (CH3, NCH2CH3), 33.00 (CH2, NCH2CH3), 33.79 (CH–N, cyclohexyl), 52.38 (CH2, benzyl), 110.01–129.09 (8CH, 6C).

N-Benzyl-N-methyl–N-[5-nitro-2-(1,1,3,3-tetramethylbutylamino)-1-benzofuran-3-yl]amine, 7e. Red viscous oil; yield: 95%. IR(KBr) ( , cm−1): 3479 (NH), 1626, 1551, 1478, 1358, 1292. 1H NMR (250 MHz, CDCl3) : 1.00 (9H, s, CMe3), 1.301 (6H, s, CMe2NH), 1.618 (2H, s, CH2CMe3), 2.86 (CH3, NCH3), 4.11 (2H, s, CH2), 4.31 (1H, s, NH, exchanged by D2O addition), 7.11–7.31 (6H, m, H–Ar), 7.89 (1H, dd, , = 2.3 Hz, H-4, benzofuran), 8.17 (1H, d, , H-4, benzofuran). 13C NMR (62.9 MHz, CDCl3) : 30.35 (2CH3, CMe2NH), 31.58 (3CH3, CMe3), 31.58 (C, CMe3), 54.30 (CH2, CH2CMe3), 55.45 (C, CMe2NH), 56.53 (CH2, benzyl), 60.97 (NCH3), 106.89, 115.14, 152.01, 157.25 (4C, benzofuran), 109.99, 111.90, 127.34 (3CH, benzofuran), 143.80 (C(NO2)), 127.34, 128.29, 129.03 (5CH), 138.78 (Cipso).

N-Benzyl-N-methyl–N-[2-(cyclohexylamino)-5-nitro-1-benzofuran-3-yl]amine, 7f. Red viscous oil; yield: 48%. IR(neat) ( , cm−1): 3444 (NH), 1632, 1556, 1483, 1341, 1298. 1H NMR (250 MHz, CDCl3) : 1.106–2.913 (10H, 2m, 5CH2, cyclohexyl), 3.113 (3H, s, NCH3), 3.372 (1H, m, CH–N, cyclohexyl), 4.048 (1H, d, CH2, benzyl), 4.584 (1H, d, CH2, benzyl), 4.474 (1H, s, NH, exchanged by D2O addition), 6.898–7.449 (5H, m, H–Ar), 7.897 (1H, dd, , , H-4, benzofuran), 8.176 (1H, dd, = 6.8 Hz, = 2.3 Hz, H-4, benzofuran), 8.645 (1H, dd, 3JHH = 6.8 Hz, 4JHH = 2.3Hz, H-4, benzofuran). 13C NMR (62.9 MHz, CDCl3) : 24.58 (2CH2,β, cyclohexyl), 25.44 (1CH2,γ, cyclohexyl), 33.87 (2CH2,α, cyclohexyl), 48.07 (CH–N, cyclohexyl), 53.77 (CH3, NCH3), 59.51 (CH2, benzyl), 128.23–129.08 (5C, benzofuran), 129.9–129.34 (3CH, benzofuran), 129.97 (C(NO2)), 127.14–128.11 (5CH).

N,N-Dibenzyl-N-[5-bromo-2-(1,1,3,3-tetramethylbutylamino)-1-benzofuran-3-yl]amine, 7g. Yellow viscous oil; yield: 95%. IR(neat) ( , cm−1): 3423 (NH), 2980, 1642, 1462, 1365, 1225. 1H NMR (250 MHz, CDCl3) : 0.96 (9H, s, CMe3), 1.05 (6H, s, CMe2NH), 1.44 (2H, s, CH2CMe3), 3.96 (1H, s, NH, exchanged by D2O addition), 4.14 (4H, s, CH2, benzyl), 7.05–7.49 (13H, m, H–Ar). 13C NMR (62.9 MHz, CDCl3) : 30.00 (2CH3, CMe2NH), 31.58 (3CH3, CMe3), 31.64 (C, CMe3), 54.32 (CH2, CH2CMe3), 55.83 (C, CMe2NH), 58.79 (2CH2, benzyl), 118.70, 121.11, 130.01 (3CH, benzofuran), 103.74, 115.48, 147.74, 156.78 (4 C, benzofuran), 111.44 (C(Br)), 127.18, 128.23, 129.21 (10 CH), 139.31 ( ).

N,N-Dibenzyl-N-[5-bromo-2-(cyclohexylamino)-1-benzofuran-3-yl]amine, 7h. Yellow viscous oil; yield: 90%. IR(neat) ( , cm−1): 3412 (NH), 2936, 1631, 1522, 1455, 1364, 1267. 1H NMR (250 MHz, CDCl3) : 0.8–1.81 (10H, 2m, 5CH2, cyclohexyl), 3.15 (1H, m, CH–N, cyclohexyl), 4.14 (4H, s, 2CH2, benzyl), 3.73 (1H, br s, NH, exchanged by D2O addition), 7.03–7.50 (13H, m, H–Ar). 13C NMR (62.9 MHz, CDCl3) : 24.79 (2CH2,β, cyclohexyl), 25.54 (1CH2,γ, cyclohexyl), 33.90 (2CH2,α of cyclohexyl), 50.37 (CHNH, cyclohexyl), 58.61 (2CH2, benzyl), 118.90, 121.27, 128.79 (3CH, benzofuran), 102.67, 115.51, 147.54, 156.22 (4C, benzofuran), 111.35 (C(Br)), 127.13, 128.20, 129.13 (10CH), 139.31 ( ).

N-Benzyl-N-ethyl–N-[5-bromo-2-(1,1,3,3-tetramethylbutylamino)-1-benzofuran-3-yl]amine, 7i. Yellow viscous oil; yield: 68%. IR(neat) ( , cm−1): 3501 (NH), 2999, 1668, 1565, 1465, 1374, 1238. 1H NMR (250 MHz, CDCl3) : 1.03 (9H, s, CMe3), 1.21 (6H, s, CMe2NH), 1.45 (2H, s, CH2CMe3), 2.17 (3H, s, ), 3.95 (1H, s, NH, exchanged by D2O addition), 4.16 (2H, CH2, NCH2), 5.29 (2H, s, CH2, benzyl), 7.04–7.6 (5H, m, H–Ar), 7.77, 7.8, 7.86 (3H, d, benzofuran). 13C NMR (62.9 MHz, CDCl3) : 30.96 (2CH3, CMe2NH), 31.43 (3CH3, CMe3), 31.52 (C, CMe3), 41.96 (CH3, NCH2CH3), 50.67 (CH2, CH2CMe3), 53.38 (CH2, NCH2), 55.26 (C, CMe2NH), 60.39 (CH2, benzyl), 111.22, 115.00, 116.91, 118.87, 121.12 (5CH), 123.12(C), 127.39, 127.64, 128.16 (3CH, benzofuran), 130.15 (C(Br)), 131.21, 135.42 (2C, benzofuran), 140.41, 141.18 ( ).

4. Results and Discussion

Here, we report a simple, one-pot, four-component reaction between electron-poor 2-hydroxybenzaldehyde derivative 1, secondary amines 2, and isocyanides 4, in water at room temperature, leading to benzo[b]furan derivatives 7 (Figure 1 and Table 1). The reaction proceeds smoothly and cleanly under mild conditions in water and is therefore considered to be a green chemistry method. The structures of the products were deduced from elemental analyses, IR, 1H NMR, and 13C NMR spectra.

tab1
Table 1: Condition and yield of reactions for synthesis of benzo[b]furan derivatives, 7a–i, in water.
761982.fig.001
Figure 1: Four-component synthesis of benzo[b]furan derivatives, 7a–i, in water.

We also used N-benzyl-tert-butylamine in above reaction, but the yields of the corresponding products 7 were very low, and several by-products were observed. As indicated in Table 1, the reactions proceeded efficiently with electron-withdrawing 2-hydroxybenzaldehyde derivatives 1, while electron-releasing 2-hydroxybenzaldehyde derivatives are not suitable starting materials in these reactions. The high yields of 7a–i can be explained by the greater electrophilicity of carbonyl groups of electron-withdrawing 2-hydroxybenzaldehyde derivatives relative to the carbonyl groups of electron-releasing 2-hydroxybenzaldehyde derivatives. 1,1,3,3-Tetramethylbutyl isocyanide leads to decreasing the yield of 7 due to steric effects.

Although we have not established the mechanism of the reaction in an experimental manner, a plausible reaction sequence that accounts for the formation of 7 was shown in Figure 2. Thus, the condensation of 2-hydroxybenzaldehyde derivative 1 and secondary amine 2 gives an iminium ion intermediate 3, which is then attacked by the alkyl isocyanide 4 to afford intermediate 5. The cyclization of the ionic intermediate 5 leads to the benzofuran 6. Tautomerization of 6 could then lead to formation of the benzo[b]furan derivatives 7.

761982.fig.002
Figure 2: Proposed mechanism for the formation of benzo[b]furan derivatives, 7a-i, in water.

5. Conclusion

In this work, we have developed a mild and efficient protocol for the preparation of benzo[b]furan derivatives. Our method offers several advantages over existing methods, including good yields, cleaner reactions, and simple workup which make it a useful and environmentally attractive strategy for the synthesis of benzo[b]furan derivatives, with promising bioactivity.

Conflict of Interests

The authors have no conflict of interests with any trademark mentioned in  the paper.

Acknowledgment

The authors are thankful to the Payame Noor University for the financial support of this research work.

References

  1. I. Ugi, S. Lohberger, and R. Karl, “The Passerini and Ugi reactions,” in Comprehensive Organic Synthesis, B. M. Trost and I. Fleming, Eds., Pergamon Press, Oxford, UK, 1991. View at Google Scholar
  2. J. Sapi and J.-Y. Laronze, “Indole based multicomponent reactions towards functionalized heterocycles,” Arkivoc, vol. 2004, no. 7, pp. 208–222, 2004. View at Google Scholar · View at Scopus
  3. J. Zhu and H. Bienayme, Multicomponent Reactions, Wiley-VCH, Weinheim, Germany, 2005.
  4. I. Ugi, “The α-addition of immonium ions and anions to isonitriles accompanied by secondary reactions,” Angewandte Chemie International Edition, vol. 1, no. 1, pp. 8–16, 1962. View at Google Scholar
  5. N. Hazeri, M. T. Maghsoodlou, S. M. Habibi-Khorassani et al., “Synthesis of novel 2-pyridyl- substituted 2,5-dihydro-2-imino- and 2-amino- furan derivatives via a three component condensation of alkyl isocyanides and acetylenic esters with di-(2-pyridyl) ketone or 2-pyridinecarboxaldehyde,” Arkivoc, vol. 2007, no. 1, pp. 173–179, 2007. View at Google Scholar · View at Scopus
  6. A. Dömling, B. Beck, E. Herdtweck et al., “Parallel synthesis of arrays of 1,4,5-trisubstituted 1-(4-piperidyl)- imidazoles by IMCR: a novel class of aspartyl protease inhibitors,” Arkivoc, vol. 2007, no. 12, pp. 99–109, 2007. View at Google Scholar · View at Scopus
  7. A. Dömling and I. Ugi, “Multicomponent Reactions with Isocyanides,” Angewandte Chemie International Edition, vol. 39, no. 18, pp. 3168–3210, 2000. View at Google Scholar
  8. I. Ugi, B. Werner, and A. Dömling, “The chemistry of isocyanides, their multicomponent reactions and their libraries,” Molecules, vol. 8, no. 1, pp. 53–66, 2003. View at Google Scholar · View at Scopus
  9. I. Ugi, “Recent progress in the chemistry of multicomponent reactions,” Pure and Applied Chemistry, vol. 73, no. 1, pp. 187–191, 2001. View at Google Scholar · View at Scopus
  10. A. Dömling, “Recent developments in isocyanide based multicomponent reactions in applied chemistry,” Chemical Reviews, vol. 106, no. 1, pp. 17–89, 2006. View at Google Scholar
  11. I. Ugi and C. Steinbrückner, “Isonitrile, IX. α-addition von immonium-ionen und carbonsäure-anionen an isonitrile,” Chemische Berichte, vol. 94, no. 10, pp. 2802–2814, 1961. View at Google Scholar
  12. R. Bossio, S. Marcaccini, P. Paoli, R. Pepino, and C. Polo, “Studies on isocyanides and related compounds. Synthesis of benzofuran derivatives,” Synthesis, no. 11, pp. 999–1000, 1991. View at Google Scholar · View at Scopus
  13. N. E. Shevchenko, “Synthesis of 3-substituted furylethylamines,” Chemistry of Heterocyclic Compounds, vol. 35, no. 2, pp. 164–166, 1999. View at Google Scholar · View at Scopus
  14. S. Morris Kupchan, M. A. Eakin, and A. M. Thomas, “Tumor inhibitors. 69. Structure-cytotoxicity relationships among the sesquiterpene lactones,” Journal of Medicinal Chemistry, vol. 14, no. 12, pp. 1147–1152, 1971. View at Google Scholar · View at Scopus
  15. M. M. Bandurraga, W. Fenical, S. F. Donovan, and J. Clardy, “Pseudopterolide, an irregular diterpenoid with unusual cytotoxic properties from the Caribbean sea whip Pseudopterogorgia acerosa (Pallas) (Gorgonacea),” Journal of the American Chemical Society, vol. 104, no. 23, pp. 6463–6465, 1982. View at Google Scholar · View at Scopus
  16. J. Kobayashi, Y. Ohizumi, H. Nakamura, and Y. Hirata, “Hippospongin, a novel furanosesterterpene possessing antispasmodic activity from the Okinawan marine sponge Hippospongia sp,” Tetrahedron Letters, vol. 27, no. 19, pp. 2113–2116, 1986. View at Google Scholar · View at Scopus
  17. M. W. Khan, M. J. Alam, M. A. Rashid, and R. Chowdhury, “A new structural alternative in benzo[b]furans for antimicrobial activity,” Bioorganic and Medicinal Chemistry, vol. 13, no. 16, pp. 4796–4805, 2005. View at Publisher · View at Google Scholar · View at Scopus
  18. B. A. Keay and P. W. Dibble, “Furans and their benzo derivatives: applications,” in Comprehensive Heterocyclic Chemistry II, A. R. Katritzky, C. W. Rees, and E. V. Scriven, Eds., Pergamon, New York, NY, USA, 1996. View at Google Scholar
  19. A. Souldozi and A. Ramazani, “The reaction of (N-isocyanimino)triphenylphosphorane with benzoic acid derivatives: a novel synthesis of 2-aryl-1,3,4-oxadiazole derivatives,” Tetrahedron Letters, vol. 48, no. 9, pp. 1549–1551, 2007. View at Publisher · View at Google Scholar · View at Scopus
  20. A. Souldozi, A. Ramazani, N. Bouslimani, and R. Welter, “The reaction of (N-isocyanimino)triphenylphosphorane with dialkyl acetylenedicarboxylates in the presence of 1,3-diphenyl-1,3-propanedione: a novel three-component reaction for the stereoselective synthesis of dialkyl (Z)-2-(5,7-diphenyl-1,3,4-oxadiazepin-2-yl)-2-butenedioates,” Tetrahedron Letters, vol. 48, no. 14, pp. 2617–2620, 2007. View at Publisher · View at Google Scholar · View at Scopus
  21. E. Ahmadi, A. Ramazani, and M. N. Haghighi, “A novel four-component reaction of diethylamine, an aromatic aldehyde and an alkyl isocyanide with dialkyl acetylenedicarboxylates in the presence of silica gel: an efficient route for the regio- and stereoselective synthesis of sterically congested alkenes,” Tetrahedron Letters, vol. 48, no. 39, pp. 6954–6957, 2007. View at Publisher · View at Google Scholar · View at Scopus
  22. E. Vessally, A. Ramazani, and E. Yaaghubi, “Green synthesis and characterization of novel α-acyloxycarboxamides through three-component reaction between pyridine carbaldehydes, cyclohexyl isocyanide, and benzoic acid derivatives,” Monatshefte fur Chemie, vol. 142, no. 11, pp. 1143–1147, 2011. View at Publisher · View at Google Scholar · View at Scopus