Synthesis of Spiro1,4–Dihydropyridines: A Review

Author(s): Zahra Sadri, Farahnaz K. Behbahani*

Journal Name: Current Organic Synthesis

Volume 17 , Issue 5 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


The preparation of medicinally promising spiro1,4–dihydropyridines accompanied by their applications in biological and pharmaceutical activities is presented. Spiro1,4–dihydropyridines were synthesized using numerous reported methods including bronested acids such as p-TSA, AcOH, nano-ranged calix[4]arene tetracarboxylic acid, sulfamic acid, PEG-OSO3H, tetramethylguanidinium triflate; lewis acids including Zn(OTf)2, FeCl3, copper, alum, aluminosilicate nanoparticles, MnFe2O4 nanoparticles, manganese ferrite nanoparticles, BF3OEt2; under alkaline conditions such as Et3N and piperidine; ionic liquids such as [KAl(SO4)2·12H2O] and [Bmim]PF6, [MIM(CH2)4SO3H][HSO4]; and other miscellaneous procedures, for example, microwave-assisted catalyst and solvent-free conditions, using iodine, PEG-400, and NaCl.

Keywords: Spiro1, 4-dihydropyridines, heterocyclic, synthesis, multi-component, one-pot, bronested acids.

Guillaumet, G. [New serotonergic ligands with a benzopyran or dioxinopyridine structure: synthesis and activity]. J. Pharm. Belg., 1994, 49(3), 216-220.
[PMID: 7914534]
Appl., EP. European Patent 546.358, 1992 Chem. Abstr, 1994, 120, 164006d.
U. S. Patent 6686361 Ref. Zh. Khim, 2004, 19О101P.
U. S. Patent 6686361 Ref. Zh. Khim 2000, 19О101P.
(a) Westheimer, F.H.; Mauzeral, D. 1-Benzyldihydronicotinamide a model for reduced DPN. J. Am. Chem. Soc., 1955, 77, 2261-2664.
(b)Heravi, M.M.; Behbahani, F.K.; Oskooie, H.A.; Shoar, R.H. Catalytic aromatization of Hantzsch 1, 4-dihydropyridines by ferric perchlorate in acetic acid. Tetrahedron Lett., 2005, 46, 2775-2777.
(a) Shah, A. Kawase, M.; Gaveriya, H.; Motohashi, N.; Sakagami, H.; Varga, A.M. 3, 5-Dibenzoyl-1, 4-dihydropyridines: synthesis and MDR reversal in tumor cells. J. Bioorg. Chem., 2002, 10, 1051-1055.
(b) Behbahani, F.K.; Mohammadloo, M. L-Proline-catalyzed synthesis of fused dihydropyridines through Hantzsch. Eur. Chem. Bull., 2013, 2, 916-919.
(a) Shan, R.; Velazquez, C.; Knaus, E.E. Syntheses, calcium channel agonist antagonist modulation activities, and nitric oxide release studies of nitrooxyalkyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2,1,3-benzoxadiazol-4-yl)pyridine-5-carboxylate racemates, enantiomers, and diastereomers. J. Med. Chem., 2004, 47(1), 254-261.
[] [PMID: 14695839]
(b) Behbahani, F.K.; Mohammadloo, M. Synthesis of cyclic 1,4-dihydropridines catalyzed by Fe(ClO4)3/SiO2. (Book Chapter). New Research on Dihydropyridines, 2016, 39, 87-114.
(a) Sawada, Y.; Kayakiri, H.; Abe, Y.; Mizutani, T.; Inamura, N.; Asano, M.; Hatori, C.; Aramori, I.; Oku, T.; Tanaka, H. Discovery of the first nonpeptide full agonists for the human bradykinin B(2) receptor incorporating 4-(2-picolyloxy)quinoline and 1-(2-picolyl)benzimidazole frameworks. J. Med. Chem., 2004, 47(11), 2853-2863.
[] [PMID: 15139763]
(b) Behbahani, F.K.; Yazdanparast, B.B. Iron (III) phosphate catalyzed synthesis of 1, 4-dihydropyridines. Arab. J. Chem., 2019, 12, 1353-1357.
Janis, R.A.; Triggle, D.J. New developments in Ca2+ channel antagonists. J. Med. Chem., 1983, 26(6), 775-785.
[] [PMID: 6304312]
Böcker, R.H.; Guengerich, F.P. Oxidation of 4-aryl- and 4-alkyl-substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)-1,4-dihydropyridines by human liver microsomes and immunochemical evidence for the involvement of a form of cytochrome P-450. J. Med. Chem., 1986, 29(9), 1596-1603.
[] [PMID: 3746811]
Gordeev, M.F.; Patel, D.V.; Gordon, E.M. Approaches to combinatorial synthesis of heterocycles: A solid-phase synthesis of 1, 4-dihydropyridines. J. Org. Chem., 1996, 61, 924-928.
Ahirrao, P. Recent developments in antitubercular drugs. Mini Rev. Med. Chem., 2008, 8(14), 1441-1451.
[] [PMID: 19075802]
Sirisha, K.; Bikshapathi, D.; Achaiah, G.; Reddy, V.M. Synthesis, antibacterial and antimycobacterial activities of some new 4-aryl/heteroaryl-2,6-dimethyl-3,5-bis-N-(aryl)-carbamoyl-1,4-dihydropyridines. Eur. J. Med. Chem., 2011, 46(5), 1564-1571.
[] [PMID: 21382653]
El-Ashmawy, M.B.; El-Sherbeny, M.A.; El-Gohary, N.S. Synthesis and antitumor screening of new series of pyrimido-[4,5- b]quinolines and [1,2,4]triazolo[20, 30:3,4]pyrimido[6,5-b]quinolines. Med. Chem. Res., 2013, 22, 2724-2736.
Samai, S.; Chandra Nandi, G.; Chowdhury, S.; Singh, M.S. L-Proline catalyzed synthesis of densely functionalized pyrido [2, 3-d] pyrimidines via three-component one-pot domino Knoevenagel aza-Diels–Alder reaction. Tetrahedron, 2011, 67, 5935-5941.
Abbas, H.A.S.; Hafez, H.N.; El-Gazzar, A.R.B.A. Synthesis, in vitro antimicrobial and in vivo antitumor evaluation of novel pyrimidoquinolines and its nucleoside derivatives. Eur. J. Med. Chem., 2011, 46(1), 21-30.
[] [PMID: 21074295]
Marco-Contelles, J.; León, R.; de los Ríos, C.; Samadi, A.; Bartolini, M.; Andrisano, V.; Huertas, O.; Barril, X.; Luque, F.J.; Rodríguez-Franco, M.I.; López, B.; López, M.G.; García, A.G.; Carreiras, Mdo.C.; Villarroya, M. Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget directed ligands for the treatment of Alzheimer’s disease. J. Med. Chem., 2009, 52(9), 2724-2732.
[] [PMID: 19374444]
Edraki, N.; Mehdipour, A.R.; Khoshneviszadeh, M.; Miri, R. Dihydropyridines: evaluation of their current and future pharmacological applications. Drug Discov. Today, 2009, 14(21-22), 1058-1066.
[] [PMID: 19729074]
Alizadeh, A.; Mikaeili, A.; Firuzyar, T. One-pot, pseudo five-component synthesis of spirooxindole derivatives containing fused 1, 4-dihydropyridines in water. Synthesis, 2012, 44, 1380-1384.
Poomathi, N.; Mayakrishnan, S.; Muralidharan, D.; Srinivasan, R.; Perumal, P.T. Reaction of isatins with 6-amino uracils and isoxazoles: isatin ring opening vs. annulations and regioselective synthesis of isoxazole fused quinoline scaffolds in water. Green Chem., 2015, 17, 3362-3372.
Dabiri, M.; Noroozi Tisseh, Z.; Bazgir, A. An efficient synthesis of fluorescent spiro [benzopyrazoloquinoline-indoline] triones and spiro [acenaphthylenebenzopyrazoloquinoline] triones. Monatsh. Chem., 2012, 143, 139-143.
Rahmati, A.; Khalesi, Z. A one-pot, three-component synthesis of spiro [indoline-isoxazolo [4′, 3′: 5, 6] pyrido [2, 3-d] pyrimidine] triones in water. Tetrahedron, 2012, 68, 8472-8479.
Vilches-Herrera, M.; Spannenberg, A.; Langer, P.; Iaroshenko, V.O. Novel and efficient synthesis of 4, 7-dihydro-1H-pyrrolo [2, 3-b] pyridine derivatives via one-pot, three-component approach from N-substituted 5-amino-3-cyanopyrroles, various carbonyl and active methylene compounds. Tetrahedron, 2013, 69, 5955-5967.
Sun, Y.; Sun, J.; Yan, C-G. Synthesis of spiro[dihydropyridine-oxindoles] via three-component reaction of arylamine, isatin and cyclopentane-1,3-dione. Beilstein J. Org. Chem., 2013, 9, 8-14.
[] [PMID: 23399791]
Sarkar, P.; Mukhopadhyay, C. Nano-ranged calix [4] arene tetracarboxylic acid catalyzed expeditious protocol for spiro [dihydropyridine-oxindoles] synthesis. Tetrahedron Lett., 2016, 57, 4306-4310.
Arya, A.K.; Gupta, S.K.; Kumar, M. A domino protocol for the efficient synthesis of structurally diverse benzothiazolylquinoline-2, 5-diones and their spiro analogues. Tetrahedron Lett., 2012, 53, 6035-6038.
Paul, S.; Das, A.R. Dual role of the polymer supported catalyst PEG-OSO3H in aqueous reaction medium: synthesis of highly substituted structurally diversified coumarin and uracil fused spirooxindoles. Tetrahedron Lett., 2013, 54, 1149-1154.
Rad-Moghadam, K.; Youseftabar-Miri, L. Tetramethylguanidinium triflate: An efficient catalyst solvent for the convergent synthesis of fused spiro [1, 4-dihydropyridine-oxindole] compounds. J. Fluor. Chem., 2012, 135, 213-219.
Safaei, S.; Mohammadpoor-Baltork, I.; Khosropour, A.R.; Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Khavasi, H.R. One-pot three-component synthesis of pyrano [3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-ones. ACS Comb. Sci., 2013, 15(3), 141-146.
[] [PMID: 23406379]
Mondal, A.; Mukhopadhyay, C. FeCl3-catalyzed combinatorial synthesis of functionalized spiro [Indolo-3, 10′-indeno [1, 2-b] quinolin]-trione derivatives. ACS Comb. Sci., 2015, 17(7), 404-408.
[] [PMID: 26086799]
Periyaraja, S.; Shanmugam, P.; Mandal, A.B.; Senthil Kumar, T.; Ramamurthy, P. Unusual reactivity of 1-aminoanthraquinone in copper catalyzed multicomponent reaction with isatins and aryl alkynes: synthesis and photophysical properties of regioisomeric fluorescent 3-spiroheterocyclic 2-oxindoles. Tetrahedron, 2013, 69, 2891-2899.
Mohammadi, A.A.; Taheri, S.; Amouzegar, A. Synthesis of Novel 1H‐Imidazol [1, 2‐a] Indeno [2, 1‐e] Pyridine‐6 (5H)‐Ones Derivatives via a One‐Pot Four‐Component Condensation Reaction. J. Heterocycl. Chem., 2016, 53, 805-808.
De, K.; Bhaumik, A.; Banerjee, B.; Mukhopadhyay, C. An expeditious and efficient synthesis of spiro-pyrazolo [3, 4-b] pyridines catalysed by recyclable mesoporous aluminosilicate nanoparticles in aqueous-ethanol. Tetrahedron Lett., 2015, 56, 1614-1618.
Ghahremanzadeh, R.; Rashid, Z.; Zarnani, A.H.; Naeimi, H. Synthesis of novel spirooxindoles in water by using MnFe2O4 nanoparticles as an efficient magnetically recoverable and reusable catalyst. Appl. Catal. A, 2013, 467, 270-278.
Naeimi, H.; Rashid, Z.; Zarnani, A.H.; Ghahremanzadeh, R. Efficient synthesis of novel spiro-furo-pyrido-pyrimidine-indolines by manganese ferrite nanoparticles as a highly active magnetically reusable nanocatalyst in water. New J. Chem., 2014, 38, 348-357.
Gao, H.; Sun, J.; Yan, C.G. Selective synthesis of functionalized spiro[indoline-3,2′-pyridines] and spiro[indoline-3,4′-pyridines] by Lewis acid catalyzed reactions of acetylenedicarboxylate, arylamines, and isatins. J. Org. Chem., 2014, 79(9), 4131-4136.
[] [PMID: 24693861]
Gao, H.; Sun, J.; Yan, C.G. Molecular diversity of acid-catalyzed one-pot reaction of arylamines, methyl propiolate, and isatins. Mol. Divers., 2014, 18(3), 511-519.
[] [PMID: 24664284]
Kiruthika, S.E.; Lakshmi, N.V.; Banu, B.; Paramasivan, T.; Perumal, P.T. A facile strategy for the one pot multicomponent synthesis of spiro dihydropyridines from amines and activated alkynes. Tetrahedron Lett., 2011, 52, 6508-6511.
Ghahremanzadeh, R.; Rashid, Z.; Zarnani, A.H.; Naeimi, H. A facile one-pot ultrasound assisted for an efficient synthesis of 1H-spiro[furo[3,4-b]pyridine-4,3′-indoline]-3-carbonitriles. Ultrason. Sonochem., 2014, 21(4), 1451-1460.
[] [PMID: 24613467]
Alizadeh, A.; Firuzyar, T.; Mikaeili, A. Efficient one-pot synthesis of spirooxindole derivatives containing 1, 4-dihydropyridine-fused-1, 3-diazaheterocycle fragments via four-component reaction. Synthesis, 2010, 3913-3917
Ghahremanzadeh, R.; Moghaddam, M.M.; Bazgir, A.; Akhondi, M.M. An Efficient Four‐component Synthesis of Spiro [indoline‐pyrazolo [4′, 3′: 5, 6] pyrido [2, 3‐d] pyrimidine] triones. Chin. J. Chem., 2012, 30, 321-326.
Shirvan, S.A.; Ghahremanzadeh, R.; Moghaddam, M.M.; Bazgir, A.; Zarnani, A.H.; Akhondi, M.M. A Novel Method for the Synthesis of Spiro [indoline‐Pyrazolo [4′, 3′: 5, 6] pyrido [2, 3‐d] pyrimidine] triones by Alum as a Reusable Catalyst. J. Heterocycl. Chem., 2012, 49, 951-954.
Kumar, M.; Sharma, K.; Arya, A.K. Use of SO3H-functionalized halogenfree ionic liquid ([MIM (CH2)4SO3H][HSO4]) as efficient promoter for the synthesis of structurally diverse spiroheterocycles. Tetrahedron Lett., 2012, 53, 4604-4607.
Hatamjafari, F. New Protocol to Synthesize Spiro‐1, 4‐dihydropyridines by Using a Multicomponent Reaction of Cyclohexanone, Ethyl Cyanoacetate, Isatin, and Primary Amines under Microwave Irradiation. Synth. Commun., 2006, 36, 3563-3570.
Sharma, G.; Sharma, R.; Sharma, M.; Dandia, A.; Bansal, P. Synthesis and synergistic, additive inhibitory effects of novel spiro derivatives against ringworm infections Russ. J. Bioorg. Chem, 2013, 39, 318-328.
Yuvaraj, P.; Manivannan, K.; Reddy, B.S.R. Microwave-assisted efficient and highly chemoselective synthesis of oxazolo [5, 4-B] quinoline-fused spirooxindoles via catalyst-and solvent-free three-component tandem Knoevenagel/Michael addition reaction. Tetrahedron Lett., 2015, 56, 78-81.
Zhang, M.; Liua, Y-H.; Shanga, Z-R.; Hu, H-C.; Zhang, Z-H. Supported molybdenum on graphene oxide/Fe3O4: An efficient, magnetically separable catalyst for one-pot construction of spiro-oxindole dihydropyridines in deep eutectic solvent under microwave irradiation. Catal. Commun., 2017, 88, 39-44.
Zhang, W-H.; Chen, M-N.; Hao, Y.; Jiang, X.; Zhou, X-L.; Zhang, Z-H. Choline chloride and lactic acid: A natural deep eutectic solvent for one-pot rapid construction of spiro [indoline-3, 4′-pyrazolo [3, 4-b] pyridines]. J. Mol. Liq., 2019, 278, 124-129.
Iarosnko, V.O.; Dudkin, S.; Sosnovskikh, V.Y.; Villinger, A.; Langer, P. Recyclization in the Series of Spiro[indole-3,5′-pyrimido[4,5-b]quinoline]-2,2′,4′-triones Prepared by a Three-Component Reaction of Isatins with (Thio)barbituric Acids and Electron-Rich Anilines. Synthesis, 2013, 45, 971-977.
Maryamabadi, A.; Hasaninejad, A.; Nowrouzi, N.; Mohebbi, G.; Asghari, B. Application of PEG-400 as a green biodegradable polymeric medium for the catalyst-free synthesis of spiro-dihydropyridines and their use as acetyl and butyrylcholinesterase inhibitors. Bioorg. Med. Chem., 2016, 24(6), 1408-1417.
[] [PMID: 26879857]
Dandia, A.; Laxkar, A.K.; Singh, R. New multicomponent domino reaction on water: highly diastereoselective synthesis of spiro [indoline-3, 4′-pyrazolo [3, 4-b] pyridines] catalyzed by NaCl. Tetrahedron Lett., 2012, 53, 3012-3017.
Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, E.J.; Terrel, R. The enamine alkylation and acylation of carbonyl compounds. J. Am. Chem. Soc., 1963, 85, 207-222.
Dyachenko, V.D.; Nesterov, V.N.; Dyachenko, I.V. Multicomponent synthesis of 2-alkylthio-6-amino-3,5-dicyano-1,4-dihydropyridine-4-spirocycloalkanes. Molecular and crystal structure of 6-amino-2-(2-methylbenzylthio)-3,5-dicyano-1,4-dihydropyridine-4-spirocyclopentane. Russ. J. Gen. Chem., 2011, 81, 751-755.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 27 July, 2020
Page: [324 - 343]
Pages: 20
DOI: 10.2174/1570179417666200415150027
Price: $65

Article Metrics

PDF: 22
PRC: 1