A green procedure for one-pot synthesis of N,Ν΄-alkylidene bisamides under solvent- and catalyst-free conditions

Document Type : Article


1 Division of Organic Chemistry, Department of Chemistry, Iran University of Science and Technology, Tehran, Iran.

2 Department of Green Chemistry, Chemistry & Chemical Engineering Research Center of Iran, Tehran, P.O. Box 14335-186, Iran.


An effective solvent- and catalyst-free method was introduced for synthesis of symmetrical N, N’-alkylidene bisamides as high usage compounds in organic chemistry. In order to show the generality, the synthesis was done with various benzamides and aldehydes to obtain various derivatives in high yields.


Main Subjects

1. Yamazaki, T., Nunami, K.I., and Goodman, M. "Cyclic retro-inverso dipeptides with two aromatic side chains. II. Conformational analysis", Biopolymers, 31, p. 1513 (1991).
2. Goodman, M. and Shao, H. "Peptidomimetic building blocks for drug discovery", Pure & Appl. Chem., 68, p. 1303 (1996).
3. Noyes, W.A. and Forman, D.B. "Aldehyde-amide condensation. I. reactions between aldehydes and acetamide", J. Am. Chem. Soc., 55, p. 3493 (1933).
4. Brace, N.O. and Mantell, G.J. "Hydrophobic compounds and polymers from long chain alkanamideformaldehyde condensation reactions", J. Org. Chem., 26, p. 5176 (1961).
5. Magat, E.E., Faris, B.F., Reith, J.E., and Salisbury, L.F. "Acid-catalyzed reactions of nitriles. I. The reaction of nitriles with formaldehyde1", J. Am. Chem. Soc., 73, p. 1028 (1951).
6. Fernandez, A.H., Alvarez, R.M., and Abajo, T.M. "Improved synthesis of symmetrical N, N'-alkylidene bisamides", Synthesis, 1996, pp. 1299-1301 (1996).
7. Zhu, S., Xu, G., Chu, Q., Xu, Y., and Qui, C. "Synthesis of  fluorine-containing symmetrical N, Nalkylidene bisamides", J. Fluorine Chem., 93, p. 69 (1999).
8. Selvam, N.P., Saranya, S., and Perumal, P.T. "A convenient and efficient protocol for the synthesis of symmetrical N, N0-alkylidine bisamides by sulfamic acid under solvent-free conditions ", Can. J. Chem., 85, p. 32 (2008).
9. Milenkovic, A., Fache, F., Faure, R., and Lemaire, M. "Activated imines and aminal derivatives: Potential precursors of amino acids", Synth. Commun., 29, p. 1535 (1999).
10. Volochnyuk, M.D., Ryabukhin, V.S., Plaskon, S.A., and Grygorenkoa, O.O. "Organosilicon compounds as water scavengers in reactions of carbonyl compounds", Synthesis, 22, pp. 3719-3743 (2009).
11. (a) Bhatnagar, G.S., Pandya, K.C. "Condensation of aldehydes with amides", Proceedings, Indian Academy of Sciences, Section A, 24, pp. 487-495 (1946), (b) Bhatnagar, G.S., Pandya, K.C. "The condensation of aldehydes with amides", Proceedings, Indian Academy of Sciences, Section A, 10A, pp. 285-288 (1939).
12. Ghafuri, H. and Roshani, M. "Aqueous formic acid: an efficient, inexpensive and environmentally friendly organocatalyst for three-component Strecker synthesis of aminonitriles and imines with excellent yields", RSC Adv., 4, pp. 58280-58286 (2014). 
13. Ghafuri, H., Khodashenas, S., and Naimi-Jamal, M.R. "Aqueous formic acid: an efficient, inexpensive and environmentally friendly catalyst for diastereoselective synthesis of amino carbonyl derivatives", J. Iran. Chem., Soc, 12, pp. 599-604 (2015).
14. Chaudhuri, M.K., Hussain, S., Kantam, M.L., and Neelima, B. "Boric acid: a novel and safe catalyst for aza-Michael reactions in water", Tetrahedron Lett., 46, p. 8329 (2005).
15. Tu, S.J., Tu, S., Fang, F., et. al. "One-pot synthesis of 3, 4-dihydropyrimidin-2 (1H)-ones using boric acid as catalyst", Tetrahedron Lett., 44, p. 6153 (2003).
16. Chaudhuri, M.K. and Hussain, S. "Boric acid catalyzed thia-Michael reactions in water or alcohols", J. Mol. Cat. A., 269, pp. 214-217 (2007).
17. Kondaiah, G.C.M., and et. al. "Boric acid: an efficient and environmentally benign catalyst for transesterifi- cation of ethyl acetoacetate", Tetrahedron Lett., 49, p. 106 (2008).
18. Rawalay, S.S. and Beam, C.F. "Preparation of new N-[. alpha.-(benzylidenamino) benzyl] benzamides and N, N'-benzylidenebis (benzamides)", J. Chem. Eng. Data., 27, p. 475 (1982).
19. (a) Selvakumar, K., Shanmugaprabha, T., Kumaresan, M., and Sami, P. "One-pot multi-component synthesis of N,N0-alkylidene bisamides and imidazoles using heteropoly-11-tungsto-1-vanadophosphoric acid supported on natural clay as catalyst: A green approach", Synth. Commun., 47, pp. 2115-2126 (2017). (b) Lambat. T.L., Deo, S.S., Inam, F.S., et. al.  Montmorillonite K10: An efficient organo heterogeneous catalyst for one-pot synthesis of new N,N'-alkylidene bisamide derivatives under solvent free condition", Karbala Int. J. Modern Sci., pp. 1-6 (2016). (c) Ramachandran, S.A., P.S., Miglani, S.K., Singh, M.P., et. al. "Design, synthesis and optimization of bisamide derivatives as CSF1R inhibitors", Bioorg. Med. Chem. Lett., 27, pp. 2153-2160 (2017). (d) Soliman, H.A., Mubarak, A.Y., and Elmorsy, S.S. "An efficient synthesis of bis(indolyl) methanes and N, N'-alkylidene bisamides by Silzic under solvent free conditions", Chin. Chem. Lett., 27, pp. 353-356 (2016). (e) Harichandran, G., Amalraj, S.D., and Shanmugan, P. "An efficient synthesis of symmetrical N, N-alkylidene bisamides catalyzed by phosphotungstic acid", Ind. J. Chem., 50B, pp. 77-82 (2011). (f) Azizi, N. and Alipour, M. "Eco-efficiency and scalable synthesis of bisamides in deep eutectic solvent", J. Mol. Liq., 206, pp. 268-271 (2015).
20. Karimi-Jaberi, Z. and Pooladian, B. "A mild, efficient, and environmentally friendly synthesis of N, N'-arylidene bisamides using B(HSO4)3 under solvent-free conditions", Monatsh. Chem., 144, pp. 659-663 (2013).
21. Maleki, B. and Baghayeri, M. "Synthesis of symmetrical N,N0-alkylidene bis-amides catalyzed by silica coated magnetic NiFe2O4 nanoparticles supported polyphosphoric acid (NiFe2O4@SiO2-PPA) and its application toward silver nanoparticle synthesis for electrochemical detection of glucose", RSC Adv., 5, pp. 79746-79758 (2015).
22. Tajbakhsh, M., Hosseinzadeh, R., Alinezhad, H., and Rezaee, P. "Efficient synthesis of symmetrical bisamides from aldehydes and amides catalyzed by silica-bonded s-sulfonic acid nanoparticles", Synth. Commun., 43, pp. 2370-2379 (2013).
23. Sha ee, M.R.M. "One-pot preparation of N, N0- alkylidene bisamide derivatives catalyzed by silica supported magnesium chloride (SiO2-MgCl2)", Lett. Org. Chem., 8, pp. 562-567 (2011).
24. Pollock, B.M. and Roos, E.E "Seed and seedling vigor", Seed Biology, I. Importance, Development and Germination, 48, pp. 314-387 (1972).
25. Harichandran, G., Amalraj, D.S., and Shanmugam, P. "Boric acid catalyzed efficient synthesis of symmetrical N, N0-alkylidene bisamides", J. Iran. Chem., Soc., 8, pp. 298-305 (2011).
26. Gawad, A., Nagwa, M., Georgey, H.H., et al. "Synthesis and antitumor activity of some 2, 3-disubstituted quinazolin-4 (3H)-ones and 4, 6-disubstituted-1, 2, 3, 4-tetrahydroquinazolin-2H-ones", Eur. J. Med. Chem., 45, pp. 6058-6067 (2010).
27. Tron, G.C., Minassi, A., and Appendino, G. "Pietro biginelli: The man behind the reaction", Eur. J. Org. Chem., 28, pp. 5541-5550 (2011).
28. Pandey, M., Kumar, A., and Trivedi, N. "An investigation leading to preparation of tetrahydroquinazoline derivatives involving ureidoalkylation and amidoalkylation reactions", Indian J. Chem., Sect B., 47, pp. 1910-1914 (2008).
29. Abbasinejad, M.A., Mosslemin, M.H., and Hassanabadi, M., et al. "p-toluene sulfonic acid-catalyzed, solvent-free synthesis of symmetrical bisamides by reaction between aldehydes and amides", Synth. Commun., 40, pp. 2209-2214 (2010).
30. Tamaddon, F., Kargar-Shooroki, H., and Jafari, A.A. "Molybdate and silica sulfuric acids as heterogeneous alternatives for synthesis of gem-bisamides and bisurides from aldehydes and amides, carbamates, nitriles or urea", J. Mol. Catal. A: Chem., 368, pp. 66-71 (2013).
31. Zhang, Y., Zhong, Z., Han, Y., et. al. "A convenient synthesis of bisamides with BF3 etherate as catalyst", Tetrahedron., 69, pp. 11080-11083 (2013).
32. Mirjalili, B.F. and Mirhoseini, M.A. "Tandem synthesis of N,N0-alkylidenebisamides promoted by nano- SnCl4.SiO2", J. Chem. Sci., 125, pp. 1481-1486 (2013).