An eco-friendly “on-water” protocol for efficient catalyst-free synthesis of the Hantzsch dihydropyridines from aryl, heteroaryl, alkyl, and vinylogous aldehydes has been developed with minimum auxiliary substances, toxic reagents, organic solvents, and disposal problems. 1. Introduction 4-Substituted 1,4-dihydropyridine framework has emerged as one of the most prolific chemotypes in the recent computational analysis of medicinal chemistry database due to its multifarious pharmaceutical applications. They serve as important analogues of NADH coenzymes [1] exhibiting neuroprotectant [2] and platelet anticoagulatory activity [3]. These compounds often act as cerebral anti-ischemic [3] agents in the treatments of Alzheimer’s disease and as chemosensitizers [4] in tumour therapy. Due to their high efficiency as Ca2+ channel blockers, the Hantzsch dihydropyridines also find immense applications in the treatment of cardiovascular disorders and hypertension [5]. 1,4-Dihydropyridine skeleton is also present in many vasodilator, bronchodilator, antiatherosclerotic, antitumor, antidiabetic, geroprotective, and hepatoprotective agents. Moreover, these compounds serve as important synthetic intermediates [6, 7] for the preparation of various pyridine derivatives through oxidative aromatization sequences. A number of synthetic protocols for the construction of the dihydropyridine skeleton are available in the literature using ammonia [8], refluxing ammonium hydroxide in a closed vessel microwave synthesizer [9], urea-silica gel [10], ammonium acetate in ethanol under microwave irradiation [11], ammonium hydroxide in ethanol [12], 2,4,6-trichloro-1,3,5-triazine [13], magnesium nitride [14] in water at an elevated temperature in a sealed vessel using stoichiometric excess of organic reactants, and many others. Many of the aforesaid protocols use expensive and toxic reagents (often in excess amounts than required for reaction stoichiometry), have complicated reaction setup, require long reaction times, and form byproducts due to various side reactions. Often these reactions are performed in various organic solvents posing a serious threat of fire hazard, especially when they are carried out under microwave irradiation. Several solvent-free protocols [10] have been developed using supported reagents, but still they require toxic organic solvents during product isolation. Also the disposal of the left-over inorganic supports remains problematic [10] which causes perturbation in the environment. In recent times, ammonium acetate has been judiciously utilized [15, 16] as a
References
[1]
D. Mauzerall and F. H. Westheimer, “1-Benzyldihydronicotinamide—a model for reduced DPN,” Journal of the American Chemical Society, vol. 77, no. 8, pp. 2261–2264, 1955.
[2]
V. Klusa, “Cerebrocrast. Neuroprotectant, cognition enhancer,” Drugs of the Future, vol. 20, no. 2, pp. 135–138, 1995.
[3]
R. S. Kumar, A. Idhayadhulla, A. J. A. Nasser, and J. Selvin, “Synthesis and anticoagulant activity of a new series of 1,4-dihydropyridine derivatives,” European Journal of Medicinal Chemistry, vol. 46, no. 2, pp. 804–810, 2011.
[4]
R. Boer and V. Gekeler, “Chemosensitizers in tumor therapy: new compounds promise better efficacy,” Drugs of the Future, vol. 20, no. 5, pp. 499–509, 1995.
[5]
F. Bossert, H. Meyer, and E. Wehinger, “4-Aryldihydropyridines, a new class of highly active calcium antagonists,” Angewandte Chemie International Edition, vol. 20, no. 9, pp. 762–769, 1981.
[6]
N. Nakamichi, Y. Kawashita, and M. Hayashi, “Activated carbon-promoted oxidative aromatization of Hantzsch 1,4-dihydropyridines and 1,3,5-trisubstituted pyrazolines using molecular oxygen,” Synthesis, no. 7, pp. 1015–1020, 2004.
[7]
B. Han, Q. Liu, Z. Liu et al., “A metal-free catalytic aerobic aromatization of Hantzsch 1,4-dihydropyridines by N-hydroxyphthalimide,” Synlett, no. 15, pp. 2333–2334, 2005.
[8]
A. McKillop and A. J. Boulton, “Synthesis of six-membered rings,” in Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees, Eds., vol. 2, pp. 87–88, Pergamon Press, London, UK, 1984.
[9]
L. ？hberg and J. Westman, “An efficient and fast procedure for the Hantzsch dihydropyridine synthesis under microwave conditions,” Synlett, no. 8, pp. 1296–1298, 2001.
[10]
J. S. Yadav, B. V. Subba Reddy, P. Thirupati, et al., “Unprecedented synthesis of Hantzsch 1,4-dihydropyridines under biginelli reaction conditions,” Synthetic Communications, vol. 31, no. 3, pp. 425–430, 2001.
[11]
M. Anniyappam, D. Muralidharan, and P. T. Perumal, “Synthesis of Hantzsch 1, 4-dihydropyridines under microwave irradiation,” Synthetic Communications, vol. 32, no. 4, pp. 659–663, 2002.
[12]
R. S. Varma, Advances in Green Chemistry: Chemical Syntheses Using Microwave Irradiation, AstraZeneca Research Foundation India, Bangalore, India, 2003.
[13]
G. V. M. Sharma, K. L. Reddy, P. S. Lakshmi, and P. R. Krishna, “‘In situ’ generated “HCl”—an efficient catalyst for solvent-free Hantzsch reaction at room temperature: Synthesis of new dihydropyridine glycoconjugates,” Synthesis, no. 1, Article ID P05205SS, pp. 55–58, 2006.
[14]
K. L. Bridgwood, G. E. Veitch, and S. V. Ley, “Magnesium nitride as a convenient source of ammonia: preparation of dihydropyridines,” Organic Letters, vol. 10, no. 16, pp. 3627–3629, 2008.
[15]
B. Khalili, P. Jajarmi, B. Eftekhari-Sis, and M. M. Hashemi, “Novel one-pot, three-component synthesis of new 2-alkyl-5-aryl-(1H)-pyrrole-4-ol in water,” Journal of Organic Chemistry, vol. 73, no. 6, pp. 2090–2095, 2008.
[16]
M. M. Heravi, S. Sadjadi, H. A. Oskooie, R. H. Shoar, and F. F. Bamoharram, “A direct oxidative route for the synthesis of pyrimidines using heteropolyacids,” Tetrahedron Letters, vol. 50, no. 6, pp. 662–666, 2009.
[17]
G. Sabitha, G. S. K. K. Reddy, C. S. Reddy, and J. S. Yadav, “A novel TMSI-mediated synthesis of Hantzsch 1,4-dihydropyridines at ambient temperature,” Tetrahedron Letters, vol. 44, no. 21, pp. 4129–4131, 2003.
[18]
N. Tewari, N. Dwivedi, and R. P. Tripathi, “Tetrabutylammonium hydrogen sulfate catalyzed eco-friendly and efficient synthesis of glycosyl 1,4-dihydropyridines,” Tetrahedron Letters, vol. 45, no. 49, pp. 9011–9014, 2004.
[19]
J. H. Lee, “Synthesis of Hantsch 1,4-dihydropyridines by fermenting bakers' yeast,” Tetrahedron Letters, vol. 46, no. 43, pp. 7329–7330, 2005.
[20]
A. Kumar and R. A. Maurya, “Efficient synthesis of Hantzsch esters and polyhydroquinoline derivatives in aqueous micelles,” Synlett, no. 6, pp. 883–885, 2008.
[21]
A. Debache, R. Boulcina, A. Belfaitah, S. Rhouati, and B. Carboni, “One-pot synthesis of 1,4-dihydropyridines via a phenylboronic acid catalyzed Hantzsch three-component reaction,” Synlett, no. 4, pp. 509–512, 2008.
[22]
A. Debache, W. Ghalem, R. Boulcina, A. Belfaitah, S. Rhouati, and B. Carboni, “An efficient one-step synthesis of 1,4-dihydropyridines via a triphenylphosphine-catalyzed three-component Hantzsch reaction under mild conditions,” Tetrahedron Letters, vol. 50, no. 37, pp. 5248–5250, 2009.
[23]
S. Tang, R. Bourne, R. Smith, and M. Poliakoff, “The 24 principles of green engineering and green chemistry: ‘Improvements Productively’,” Green Chemistry, vol. 10, no. 3, pp. 268–269, 2008.
[24]
R. Breslow, “Hydrophobic effects on simple organic reactions in water,” Accounts of Chemical Research, vol. 24, no. 6, pp. 159–164, 1991.
[25]
J. B. F. N. Engberts and M. J. Blandamer, “Understanding organic reactions in water: from hydrophobic encounters to surfactant aggregates,” Chemical Communications, no. 18, pp. 1701–1708, 2001.
[26]
S. Mecking, A. Held, and F. M. Bauers, “Aqueous catalytic polymerization of olefins,” Angewandte Chemie International Edition, vol. 41, no. 4, pp. 544–561, 2002.
[27]
N. E. Leadbeater and M. Marco, “Rapid and amenable Suzuki coupling reaction in water using microwave and conventional heating,” Journal of Organic Chemistry, vol. 68, no. 3, pp. 888–892, 2003.
[28]
K. Yamaguchi, M. Matsushita, and N. Mizuno, “Efficient hydration of nitriles to amides in water, catalyzed by ruthenium hydroxide supported on alumina,” Angewandte Chemie International Edition, vol. 43, no. 12, pp. 1576–1580, 2004.
[29]
S. Minakata, D. Kano, Y. Oderaotoshi, and M. Komatsu, “Silica-water reaction media: its application to the formation and ring opening of aziridines,” Angewandte Chemie International Edition, vol. 43, no. 1, pp. 79–81, 2004.
[30]
N. E. Leadbeater, “Fast, easy, clean chemistry by using water as a solvent and microwave heating: the Suzuki coupling as an illustration,” Chemical Communications, vol. 23, pp. 2881–2902, 2005.
[31]
S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb, and K. B. Sharpless, “‘On water’: unique reactivity of organic compounds in aqueous suspension,” Angewandte Chemie International Edition, vol. 44, no. 21, pp. 3275–3279, 2005.
[32]
H. Buchammagari, Y. Toda, M. Hirano, H. Hosono, D. Takeuchi, and K. Osakada, “Room temperature-stable electride as a synthetic organic reagent: application to pinacol coupling reaction in aqueous media,” Organic Letters, vol. 9, no. 21, pp. 4287–4289, 2007.
[33]
N. Shapiro and A. Vigalok, “Highly efficient organic reactions “on water”, “in water”, and both,” Angewandte Chemie International Edition, vol. 47, no. 15, pp. 2849–2852, 2008.
[34]
Q.-Y. Zhang, B.-K. Liu, W.-Q. Chen, Q. Wu, and X. F. Lin, “A green protocol for synthesis of benzo-fused N,S-, N,O- and N,N-heterocycles in water,” Green Chemistry, vol. 10, no. 9, pp. 972–977, 2008.
[35]
L. D. S. Yadav, S. Singh, and V. K. Rai, “Catalyst-free, step and pot economic, efficient mercaptoacetylative cyclisation in H2O: synthesis of 3-mercaptocoumarins,” Green Chemistry, vol. 11, no. 6, pp. 878–882, 2009.
[36]
J. W. Yang, M. T. Hechavarria Fouseca, and B. List, “A metal-free transfer hydrogenation: organocatalytic conjugate reduction of α, β-unsaturated aldehydes,” Angewandte Chemie International Edition, vol. 43, no. 48, pp. 6660–6662, 2004.
[37]
A. E. Abdalla, D. Tirzite, G. Tirzitis, and J. P. Roozen, “Antioxidant activity of 1,4-dihydropyridine derivatives in β-carotene-methyl linoleate, sunflower oil and emulsions,” Food Chemistry, vol. 66, no. 2, pp. 189–195, 1999.
[38]
R. A. Olek, W. Ziolkowski, J. J. Kaczor, L. Greci, J. Popinigis, and J. Antosiewicz, “Antioxidant activity of NADH and its analogue—an in vitro study,” Journal of Biochemistry and Molecular Biology, vol. 37, no. 4, pp. 416–421, 2004.
[39]
B. E. Norcross, G. Clement, and M. Weinstein, “The Hantzsch pyridine synthesis: a factorial design experiment for the introductory organic laboratory,” Journal of Chemical Education, vol. 46, no. 10, pp. 694–695, 1969.
[40]
A. P. Dicks, “A review of aqueous organic reactions for the undergraduate teaching laboratory,” Green Chemistry Letters and Reviews, vol. 2, no. 1, pp. 9–21, 2009.
[41]
Material safety data sheet, http://msds.chem.ox.ac.uk/AM/ammonium_acetate.
[42]
Material safety data sheet, http://msds.chem.ox.ac.uk/AM/ammonia_anhydrous.
[43]
Material safety data sheet, http://msds.chem.ox.ac.uk/AM/ammonia_hydroxide.
[44]
Material safety data sheet, http://msds.chem.ox.ac.uk/PA/paraformaldehyde.
[45]
Material safety data sheet, http://msds.chem.ox.ac.uk/FO/formaldehyde.
[46]
F. Tamaddon, Z. Razmi, and A. A. Jafari, “Synthesis of 3, 4-dihydropyrimidin-2(1H)-ones and 1, 4-dihydropyridines using ammonium carbonate in water,” Tetrahedron Letters, vol. 51, no. 8, pp. 1187–1189, 2010.
