Regioselective Synthesis of Cycloalkane-fused Pyrazolo[4,3-e]pyridines through Tandem Reaction of 5-aminopyrazoles, Cyclic Ketones and Electron-rich Olefins

Paola      Cuervo-Prado; Fabián      Orozco-López; Christian      Becerra-Rivas; Diego      Leon-Vargas; John      Lozano-Oviedo; Justo      Cobo
Abstract

Background: Pyrazolopyridines are interesting fused heterocyclic pharmacophores that combine pyrazole and pyridine; two privileged nuclei extensively studied and with a wide range of applications. They can be obtained by a broad variety of synthetic methods among which multicomponent reactions have gained importance, especially from 5-aminopyrazoles and dielectrophilic reagents. However, the search for new approaches more in tune with sustainable chemistry and the use of unconventional heating in three-component synthesis are open and highly relevant study fields.
Methods: A novel, practical and efficient three-component synthesis of cycloalkane-fused pyrazolo[ 4,3-e]pyridines was developed through a tandem reaction of 5-aminopyrazoles, cyclic ketones and electron-rich olefins, using microwave induction in perfluorinated solvent and iodine as catalyst.
Results: The microwave-induced three-component approach applied in this work promoted the construction of 10 new pyrazolopyridines with high speed and excellent control of regioselectivity, favoring the linear product with good yields; where the versatility of electron-rich olefins in iodine-catalyzed cascade heterocyclizations, granted the additional benefit of easy isolation and the possibility to reuse the fluorous phase.
Conclusion: Although pyrazolopyridines have been synthetically explored because of their structural and biological properties, most of the reported synthetic methods use common or even toxic organic solvents and conventional heating or multi-step processes. In contrast, this study applied a multicomponent methodology in a single step by microwave induction and with the versatility provided in this case by the use of perfluorinated solvent, which allowed easy isolation of the final product and recovery of the fluorous phase.
Graphical Abstract

[1]
Yun, D.; Yoon, S.Y.; Park, S.J.; Park, Y.J. The anticancer effect of natural plant alkaloid isoquinolines. Int. J. Mol. Sci.,  2021, 22(4), 1653.
 [http://dx.doi.org/10.3390/ijms22041653] [PMID:  33562110]

[2]
Afzal, O.; Kumar, S.; Haider, M.R.; Ali, M.R.; Kumar, R.; Jaggi, M.; Bawa, S. A review on anticancer potential of bioactive heterocycle quinoline. Eur. J. Med. Chem.,  2015, 97, 871-910.
 [http://dx.doi.org/10.1016/j.ejmech.2014.07.044] [PMID:  25073919]

[3]
Manaithiya, A.; Alam, O.; Sharma, V.; Naim, M.J.; Mittal, S.; Azam, F.; Husain, A.; Sheikh, A.A.; Imran, M.; Khan, I.A. Current status of novel pyridine fused derivatives as anticancer agents: An insight into future perspectives and structure activity relationship (SAR). Curr. Top. Med. Chem.,  2021, 21(25), 2292-2349.
 [http://dx.doi.org/10.2174/1568026621666210916171015] [PMID:  34530713]

[4]
Kaur, R.; Kumar, K. Synthetic and medicinal perspective of quinolines as antiviral agents. Eur. J. Med. Chem.,  2021, 215, 113220.
 [http://dx.doi.org/10.1016/j.ejmech.2021.113220] [PMID:  33609889]

[5]
Alizadeh, S.R.; Ebrahimzadeh, M.A. Antiviral activities of pyridine fused and pyridine containing heterocycles, a review (from 2000 to 2020). Mini Rev. Med. Chem.,  2021, 21(17), 2584-2611.
 [http://dx.doi.org/10.2174/18755607MTEzvNjcu0] [PMID:  33573543]

[6]
Kishbaugh, T.L. Pyridines and imidazopyridines with medicinal significance. Curr. Top. Med. Chem.,  2016, 16(28), 3274-3302.
 [http://dx.doi.org/10.2174/1568026616666160506145141] [PMID:  27150370]

[7]
Galán, A.; Moreno, L.; Párraga, J.; Serrano, Á.; Sanz, M.J.; Cortes, D.; Cabedo, N. Novel isoquinoline derivatives as antimicrobial agents. Bioorg. Med. Chem.,  2013, 21(11), 3221-3230.
 [http://dx.doi.org/10.1016/j.bmc.2013.03.042] [PMID:  23601815]

[8]
Musiol, R.; Jampilek, J.; Kralova, K.; Richardson, D.R.; Kalinowski, D.; Podeszwa, B.; Finster, J.; Niedbala, H.; Palka, A.; Polanski, J. Investigating biological activity spectrum for novel quinoline analogues. Bioorg. Med. Chem.,  2007, 15(3), 1280-1288.
 [http://dx.doi.org/10.1016/j.bmc.2006.11.020] [PMID:  17142046]

[9]
Mao, Y.; Soni, K.; Sangani, C.; Yao, Y. An overview of privileged scaffold: quinolines and isoquinolines in medicinal chemistry as anticancer agents. Curr. Top. Med. Chem.,  2020, 20(28), 2599-2633.
 [http://dx.doi.org/10.2174/1568026620999200917154225] [PMID:  32942976]

[10]
Bennani, F.E.; Doudach, L.; Cherrah, Y.; Ramli, Y.; Karrouchi, K.; Ansar, M.; Faouzi, M.E.A. Overview of recent developments of pyrazole derivatives as an anticancer agent in different cell line. Bioorg. Chem.,  2020, 97, 103470-103532.
 [http://dx.doi.org/10.1016/j.bioorg.2019.103470] [PMID:  32120072]

[11]
Lusardi, M.; Spallarossa, A.; Brullo, C. Amino-pyrazoles in medicinal chemistry: A review. Int. J. Mol. Sci.,  2023, 24(9), 7834.
 [http://dx.doi.org/10.3390/ijms24097834] [PMID:  37175540]

[12]
Szabó, G.; Fischer, J.; Kis-Varga, Á.; Gyires, K. New celecoxib derivatives as anti-inflammatory agents. J. Med. Chem.,  2008, 51(1), 142-147.
 [http://dx.doi.org/10.1021/jm070821f] [PMID:  18072726]

[13]
Signorello, M.G.; Rapetti, F.; Meta, E.; Sidibè, A.; Bruno, O.; Brullo, C. New series of pyrazoles and imidazo-pyrazoles targeting different cancer and inflammation pathways. Molecules,  2021, 26(19), 5735-5752.
 [http://dx.doi.org/10.3390/molecules26195735] [PMID:  34641279]

[14]
Kaushik, D.; Khan, S.A.; Chawla, G.; Kumar, S. N′-[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene] 2/4-substituted hydrazides: Synthesis and anticonvulsant activity. Eur. J. Med. Chem.,  2010, 45(9), 3943-3949.
 [http://dx.doi.org/10.1016/j.ejmech.2010.05.049] [PMID:  20573423]

[15]
Marengo, B.; Meta, E.; Brullo, C.; De Ciucis, C.; Colla, R.; Speciale, A.; Garbarino, O.; Bruno, O.; Domenicotti, C. Biological evaluation of pyrazolyl-urea and dihydro-imidazo-pyrazolyl-urea derivatives as potential anti-angiogenetic agents in the treatment of neuroblastoma. Oncotarget,  2020, 11(37), 3459-3472.
 [http://dx.doi.org/10.18632/oncotarget.27733] [PMID:  32973970]

[16]
Genin, M.J.; Biles, C.; Keiser, B.J.; Poppe, S.M.; Swaney, S.M.; Tarpley, W.G.; Yagi, Y.; Romero, D.L. Novel 1,5-diphenylpyrazole nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant: Lead identification and SAR of 3- and 4-substituted derivatives. J. Med. Chem.,  2000, 43(5), 1034-1040.
 [http://dx.doi.org/10.1021/jm990383f] [PMID:  10715167]

[17]
Parmar, S.S.; Pandey, B.R.; Dwivedi, C.; Harbison, R.D. Anticonvulsant activity and monoamine oxidase inhibitory properties of 1,3,5-trisubstituted pyrazolines. J. Pharm. Sci.,  1974, 63(7), 1152-1155.
 [http://dx.doi.org/10.1002/jps.2600630730] [PMID:  4850598]

[18]
Taher, A.T.; Mostafa Sarg, M.T.; El-Sayed Ali, N.R.; Hilmy Elnagdi, N. Design, synthesis, modeling studies and biological screening of novel pyrazole derivatives as potential analgesic and anti-inflammatory agents. Bioorg. Chem.,  2019, 89, 103023-103035.
 [http://dx.doi.org/10.1016/j.bioorg.2019.103023] [PMID:  31185391]

[19]
Brullo, C.; Caviglia, D.; Spallarossa, A.; Alfei, S.; Franzblau, S.G.; Tasso, B.; Schito, A.M. Microbiological screening of 5-functionalized pyrazoles for the future development of optimized pyrazole-based delivery systems. Pharmaceutics,  2022, 14(9), 1770-1785.
 [http://dx.doi.org/10.3390/pharmaceutics14091770] [PMID:  36145518]

[20]
Verma, R.; Verma, S.K.; Rakesh, K.P.; Girish, Y.R.; Ashrafizadeh, M.; Sharath Kumar, K.S.; Rangappa, K.S. Pyrazole-based analogs as potential antibacterial agents against methicillin-resistance staphylococcus aureus (MRSA) and its SAR elucidation. Eur. J. Med. Chem.,  2021, 212, 113134-113158.
 [http://dx.doi.org/10.1016/j.ejmech.2020.113134] [PMID:  33395624]

[21]
Alfei, S.; Brullo, C.; Caviglia, D.; Piatti, G.; Zorzoli, A.; Marimpietri, D.; Zuccari, G.; Schito, A.M. Pyrazole-based water-soluble dendrimer nanoparticles as a potential new agent against staphylococci. Biomedicines,  2021, 10(1), 17-37.
 [http://dx.doi.org/10.3390/biomedicines10010017] [PMID:  35052697]

[22]
Yu, B.; Zhou, S.; Cao, L.; Hao, Z.; Yang, D.; Guo, X.; Zhang, N.; Bakulev, V.A.; Fan, Z. Design, synthesis, and evaluation of the antifungal activity of novel pyrazole–thiazole carboxamides as succinate dehydrogenase inhibitors. J. Agric. Food Chem.,  2020, 68(27), 7093-7102.
 [http://dx.doi.org/10.1021/acs.jafc.0c00062] [PMID:  32530619]

[23]
Desai, N.C.; Rajpara, K.M.; Joshi, V.V. Synthesis of pyrazole encompassing 2-pyridone derivatives as antibacterial agents. Bioorg. Med. Chem. Lett.,  2013, 23(9), 2714-2717.
 [http://dx.doi.org/10.1016/j.bmcl.2013.02.077] [PMID:  23511017]

[24]
Tandon, M.; Johnson, J.; Li, Z.; Xu, S.; Wipf, P.; Wang, Q.J. New pyrazolopyrimidine inhibitors of protein kinase d as potent anticancer agents for prostate cancer cells. PLoS One,  2013, 8(9), e75601.
 [http://dx.doi.org/10.1371/journal.pone.0075601] [PMID:  24086585]

[25]
van Linden, O.P.J.; Farenc, C.; Zoutman, W.H.; Hameetman, L.; Wijtmans, M.; Leurs, R.; Tensen, C.P.; Siegal, G.; de Esch, I.J.P. Fragment based lead discovery of small molecule inhibitors for the EPHA4 receptor tyrosine kinase. Eur. J. Med. Chem.,  2012, 47(1), 493-500.
 [http://dx.doi.org/10.1016/j.ejmech.2011.11.020] [PMID:  22137457]

[26]
Bernardino, A.M.R.; de Azevedo, A.R.; Pinheiro, L.C.S.; Borges, J.C.; Carvalho, V.L.; Miranda, M.D.; de Meneses, M.D.F.; Nascimento, M.; Ferreira, D.; Rebello, M.A.; Silva, V.A.G.G.; de Frugulhetti, I.C.P.P. Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives. Med. Chem. Res.,  2007, 16(7-9), 352-369.
 [http://dx.doi.org/10.1007/s00044-007-9035-6]

[27]
Gudmundsson, K.S.; Johns, B.A.; Wang, Z.; Turner, E.M.; Allen, S.H.; Freeman, G.A.; Boyd, F.L., Jr; Sexton, C.J.; Selleseth, D.W.; Moniri, K.R.; Creech, K.L. Synthesis of novel substituted 2-phenylpyrazolopyridines with potent activity against herpesviruses. Bioorg. Med. Chem.,  2005, 13(18), 5346-5361.
 [http://dx.doi.org/10.1016/j.bmc.2005.05.043] [PMID:  16039862]

[28]
Vanegas, S.; Rodríguez, D.; Ochoa-Puentes, C. An efficient and eco‐friendly one‐pot synthesis of pyrazolopyridines mediated by choline chloride/urea eutectic mixture. ChemistrySelect,  2019, 4(11), 3131-3134.
 [http://dx.doi.org/10.1002/slct.201900314]

[29]
Johns, B.A.; Gudmundsson, K.S.; Turner, E.M.; Allen, S.H.; Samano, V.A.; Ray, J.A.; Freeman, G.A.; Boyd, F.L., Jr; Sexton, C.J.; Selleseth, D.W.; Creech, K.L.; Moniri, K.R. Pyrazolopyridine antiherpetics: SAR of C2′ and C7 amine substituents. Bioorg. Med. Chem.,  2005, 13(7), 2397-2411.
 [http://dx.doi.org/10.1016/j.bmc.2005.01.044] [PMID:  15755642]

[30]
Menezes, C.M.S.; Sant’Anna, C.M.R.; Rodrigues, C.R.; Barreiro, E.J. Molecular modeling of novel 1H-pyrazolo[3,4-b]pyridine derivatives designed as isosters of the antimalarial mefloquine. J. Mol. Struct. THEOCHEM,  2002, 579(1-3), 31-39.
 [http://dx.doi.org/10.1016/S0166-1280(01)00677-7]

[31]
Frolova, L.V.; Malik, I.; Uglinskii, P.Y.; Rogelj, S.; Kornienko, A.; Magedov, I.V. Multicomponent synthesis of 2,3-dihydrochromeno[4,3-d]pyrazolo[3,4-b]pyridine-1,6-diones: a novel heterocyclic scaffold with antibacterial activity. Tetrahedron Lett.,  2011, 52(49), 6643-6645.
 [http://dx.doi.org/10.1016/j.tetlet.2011.10.012] [PMID:  22162894]

[32]
Abdel-Monem, Y.K.; Abou El-Enein, S.A.; El-Sheikh-Amer, M.M. Design of new metal complexes of 2-(3-amino-4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-1-yl)aceto-hydrazide: Synthesis, characterization, modelling and antioxidant activity. J. Mol. Struct.,  2017, 1127, 386-396.
 [http://dx.doi.org/10.1016/j.molstruc.2016.07.110]

[33]
Bogza, S.L.; Kobrakov, K.I.; Malienko, A.A.; Perepichka, I.F.; Sujkov, S.Y.; Bryce, M.R.; Lyubchik, S.B.; Batsanov, A.S.; Bogdan, N.M. A versatile synthesis of pyrazolo[3,4-c]isoquinoline derivatives by reaction of 4-aryl-5-aminopyrazoles with aryl/heteroaryl aldehydes: The effect of the heterocycle on the reaction pathways. Org. Biomol. Chem.,  2005, 3(5), 932-940.
 [http://dx.doi.org/10.1039/b417002d] [PMID:  15731881]

[34]
Moree, W.J.; Goldman, P.; Demaggio, A.J.; Christenson, E.; Herendeen, D.; Eksterowicz, J.; Kesicki, E.A.; McElligott, D.L.; Beaton, G. Identification of ring-fused pyrazolo pyridin-2-ones as novel poly(ADP-ribose)polymerase-1 inhibitors. Bioorg. Med. Chem. Lett.,  2008, 18(18), 5126-5129.
 [http://dx.doi.org/10.1016/j.bmcl.2008.07.091] [PMID:  18713665]

[35]
Becerra-Ruiz, M.; Vargas, V.; Jara, P.; Tirapegui, C.; Carrasco, C.; Nuñez, M.; Lezana, N.; Galdámez, A.; Vilches-Herrera, M. Blue‐fluorescent probes for lipid droplets based on dihydrochromeno‐fused pyrazolo‐ and pyrrolopyridines. Eur. J. Org. Chem.,  2018, 2018(34), 4795-4801.
 [http://dx.doi.org/10.1002/ejoc.201701633]

[36]
García, M.; Romero, I.; Portilla, J. Synthesis of fluorescent 1,7-Dipyridyl-bis-pyrazolo[3,4- b:4′,3′- e]pyridines: Design of reversible chemosensors for nanomolar detection of Cu 2+. ACS Omega,  2019, 4(4), 6757-6768.
 [http://dx.doi.org/10.1021/acsomega.9b00226] [PMID:  31459798]

[37]
Chen, J.; Liu, W.; Ma, J.; Xu, H.; Wu, J.; Tang, X.; Fan, Z.; Wang, P. Synthesis and properties of fluorescence dyes: Tetracyclic pyrazolo[3,4-b]pyridine-based coumarin chromophores with intramolecular charge transfer character. J. Org. Chem.,  2012, 77(7), 3475-3482.
 [http://dx.doi.org/10.1021/jo3002722] [PMID:  22428730]

[38]
Sudheer, S.; Quraishi, M.A. The corrosion inhibition effect of aryl pyrazolo pyridines on copper in hydrochloric acid system: Computational and electrochemical studies. RSC Advances,  2015, 5(52), 41923-41933.
 [http://dx.doi.org/10.1039/C5RA03966E]

[39]
Gálvez, J.; Quiroga, J.; Insuasty, B.; Abonía, R. Microwave-assisted and iodine mediated synthesis of 5-n-alkyl-cycloalkane[d]-pyrazolo[3,4-b]pyridines from 5-aminopyrazoles and cyclic ketones. Tetrahedron Lett.,  2014, 55(12), 1998-2002.
 [http://dx.doi.org/10.1016/j.tetlet.2014.02.015]

[40]
Lee, S.; Park, S.B. An efficient one-step synthesis of heterobiaryl pyrazolo[3,4-b]pyridines via indole ring opening. Org. Lett.,  2009, 11(22), 5214-5217.
 [http://dx.doi.org/10.1021/ol902147u] [PMID:  19835392]

[41]
Jiang, B.; Liu, Y.P.; Tu, S.J. Facile three‐component synthesis of macrocyclane‐fused pyrazolo[3,4‐ b]pyridine derivatives. Eur. J. Org. Chem.,  2011, 2011(16), 3026-3035.
 [http://dx.doi.org/10.1002/ejoc.201100127]

[42]
Wang, S.L.; Liu, Y.P.; Xu, B.H.; Wang, X.H.; Jiang, B.; Tu, S.J. Microwave-assisted chemoselective reaction: A divergent synthesis of pyrazolopyridine derivatives with different substituted patterns. Tetrahedron,  2011, 67(48), 9417-9425.
 [http://dx.doi.org/10.1016/j.tet.2011.09.081]

[43]
Chen, Z.; Shi, Y.; Shen, Q.; Xu, H.; Zhang, F. Facile and efficient synthesis of pyrazoloisoquinoline and pyrazolopyridine derivatives using recoverable carbonaceous material as solid acid catalyst. Tetrahedron Lett.,  2015, 56(33), 4749-4752.
 [http://dx.doi.org/10.1016/j.tetlet.2015.06.044]

[44]
Hao, W.J.; Xu, X.P.; Bai, H.W.; Wang, S.Y.; Ji, S.J. Efficient multicomponent strategy to pentacyclic pyrazole-fused naphtho[1,8-fg]isoquinolines through cleavage of two carbon-carbon bonds. Org. Lett.,  2012, 14(18), 4894-4897.
 [http://dx.doi.org/10.1021/ol302452j] [PMID:  22967112]

[45]
Aggarwal, R.; Kumar, S. 5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines. Beilstein J. Org. Chem.,  2018, 14, 203-242.
 [http://dx.doi.org/10.3762/bjoc.14.15]

[46]
Nikpassand, M.; Zare Fekri, L.; Naddaf Rahro, P. Solvent-free synthesis and DFT studies on mechanistic pathway of 4-Aryl-4,10-Dihydroindeno[1,2- b]Pyrazolo[4,3- e]Pyridin-5(1H)-ones. Polycycl. Aromat. Compd.,  2022, 42(6), 3166-3176.
 [http://dx.doi.org/10.1080/10406638.2020.1855217]

[47]
Wan, J.P.; Zhou, Y.; Jiang, K.; Ye, H. Thioacetamide as an ammonium source for multicomponent synthesis of pyridines from aldehydes and electron-deficient enamines or alkynes. Synthesis,  2014, 46(23), 3256-3262.
 [http://dx.doi.org/10.1055/s-0034-1378635]

[48]
Miao, X.Y.; Hu, Y.J.; Liu, F.R.; Sun, Y.Y.; Sun, D.; Wu, A.X.; Zhu, Y.P. Synthesis of diversified Pyrazolo[3,4-b]pyridine Frameworks from 5-Aminopyrazoles and alkynyl aldehydes via switchable C≡C bond activation approaches. Molecules,  2022, 27(19), 6381.
 [http://dx.doi.org/10.3390/molecules27196381] [PMID:  36234926]

[49]
Wan, J.P.; Jing, Y.; Hu, C.; Sheng, S. Metal-free synthesis of fully substituted pyridines via ring construction based on the domino reactions of enaminones and aldehydes. J. Org. Chem.,  2016, 81(15), 6826-6831.
 [http://dx.doi.org/10.1021/acs.joc.6b01149] [PMID:  27367181]

[50]
Zhang, F.; Li, C.; Qi, C. A one-pot three-component strategy for highly diastereoselective synthesis of spirocycloalkane fused pyrazolo[3,4- b]pyridine derivatives using recyclable solid acid as a catalyst. Org. Chem. Front.,  2020, 7(17), 2456-2466.
 [http://dx.doi.org/10.1039/D0QO00591F]

[51]
Li, C.; Zhang, F.; Shen, Z. An efficient domino strategy for synthesis of novel spirocycloalkane fused pyrazolo[3,4-b]pyridine derivatives. Tetrahedron,  2020, 76(52), 131727.
 [http://dx.doi.org/10.1016/j.tet.2020.131727]

[52]
Chebanov, V.A.; Sakhno, Y.I.; Desenko, S.M.; Chernenko, V.N.; Musatov, V.I.; Shishkina, S.V.; Shishkin, O.V.; Kappe, C.O. Cyclocondensation reactions of 5-aminopyrazoles, pyruvic acids and aldehydes. Multicomponent approaches to pyrazolopyridines and related products. Tetrahedron,  2007, 63(5), 1229-1242.
 [http://dx.doi.org/10.1016/j.tet.2006.11.048]

[53]
Robert Khumalo, M.; Maddila, S.N.; Maddila, S.; Jonnalagadda, S.B. A multicomponent, facile and catalyst-free microwave-assisted protocol for the synthesis of pyrazolo-[3,4- b]-quinolines under green conditions. RSC Advances,  2019, 9(53), 30768-30772.
 [http://dx.doi.org/10.1039/C9RA04604F] [PMID:  35529349]

[54]
Wang, Z.; Gao, L.; Xu, Z.; Ling, Z.; Qin, Y.; Rong, L.; Tu, S.J. Green synthesis of novel spiro[indoline-3,4′-pyrazolo[3,4-b]pyridine]-2,3′(7′H)- dione, spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline]-2′,3-dione, and spiro[benzo [h]pyrazolo[3,4-b]quinoline-7,3′-indoline]-2′,8(5H)-dione derivatives in aqueous medium. Tetrahedron,  2017, 73(4), 385-394.
 [http://dx.doi.org/10.1016/j.tet.2016.12.015]

[55]
Wu, L.; Ma, S.; Yan, F.; Yang, C. Sulfamic-acid-catalyzed simple and efficient synthesis of 4-aryl-3-methyl-1-phenyl-1H-benzo[g]pyrazolo[3,4-b]quinoline-5,10-diones under solvent-free conditions. Monatsh. Chem.,  2010, 141(5), 565-568.
 [http://dx.doi.org/10.1007/s00706-010-0282-8]

[56]
Zhu, G.; Gao, L.; Yu, Q.; Qin, Y.; Xi, J.; Rong, L. An Efficient Synthesis of 1′,7′,8′,9′‐Tetrahydrospiro[indoline‐3,4′‐pyrazolo[3,4‐ b]quinoline]‐2,5′(6′ H)‐dione derivatives in aqueous medium. J. Heterocycl. Chem.,  2018, 55(4), 871-878.
 [http://dx.doi.org/10.1002/jhet.3111]

[57]
Abonia, R. Solvent-free and self-catalyzed three-component synthesis of diversely Substituted Pyrazolo[1,4]thiazepinones of potential antitumor activity. Curr. Org. Synth.,  2014, 11(5), 773-786.
 [http://dx.doi.org/10.2174/1570179411666140327002045]

[58]
Becerra-Rivas, C.; Cuervo-Prado, P.; Orozco-López, F. Efficient catalyst-free tricomponent synthesis of new spiro[cyclohexane-1,4′-pyrazolo[3,4- e][1, 4]thiazepin]-7′(6′ H)-ones. Synth. Commun.,  2019, 49(3), 367-376.
 [http://dx.doi.org/10.1080/00397911.2018.1554143]

[59]
Low, J.N.; Cobo, J.; Insuasty, B.; Orozco, F.; Glidewell, C. rac -3-(5-Amino-3-methyl-1-phenyl-1 H -pyrazol-4-yl)-2-phenylthiazolidin-4-one: Sheets built from N—H...N and C—H...π(arene) hydrogen bonds. Acta Crystallogr. C,  2004, 60(7), o486-o488.
 [http://dx.doi.org/10.1107/S0108270104011540] [PMID:  15237171]

[60]
Fochi, M.; Bernardi, L.; Caruana, L. Catalytic asymmetric aza-diels–alder reactions: The povarov cycloaddition reaction. Synthesis,  2013, 46(2), 135-157.
 [http://dx.doi.org/10.1055/s-0033-1338581]

[61]
Dagousset, G.; Drouet, F.; Masson, G.; Zhu, J. Chiral Brønsted acid-catalyzed enantioselective multicomponent Mannich reaction: Synthesis of anti-1,3-diamines using enecarbamates as nucleophiles. Org. Lett.,  2009, 11(23), 5546-5549.
 [http://dx.doi.org/10.1021/ol9023985] [PMID:  19886612]

[62]
(a) Kouznetsov, V.V. Recent synthetic developments in a powerful imino Diels–Alder reaction (Povarov reaction): Application to the synthesis of N-polyheterocycles and related alkaloids. Tetrahedron,  2009, 65(14), 2721-2750.
 [http://dx.doi.org/10.1016/j.tet.2008.12.059]; 
(b) Kouznetsov, V.V.; Meléndez Gómez, C.M.; Rojas Ruíz, F.A.; del Olmo, E. Simple entry to new 2-alkyl-1,2,3,4-tetrahydroquinoline and 2,3-dialkylquinoline derivatives using BiCl3-catalyzed three component reactions of anilines and aliphatic aldehydes in the presence (or lack) of N-vinyl amides. Tetrahedron Lett.,  2012, 53(25), 3115-3118.
 [http://dx.doi.org/10.1016/j.tetlet.2012.04.008]

[63]
Ghashghaei, O.; Masdeu, C.; Alonso, C.; Palacios, F.; Lavilla, R. Recent advances of the Povarov reaction in medicinal chemistry. Drug Discov. Today. Technol.,  2018, 29, 71-79.
 [http://dx.doi.org/10.1016/j.ddtec.2018.08.004] [PMID:  30471676]

[64]
Shindoh, N.; Tokuyama, H.; Takemoto, Y.; Takasu, K. Auto-tandem catalysis in the synthesis of substituted quinolines from aldimines and electron-rich olefins: cascade Povarov-hydrogen-transfer reaction. J. Org. Chem.,  2008, 73(19), 7451-7456.
 [http://dx.doi.org/10.1021/jo8009243] [PMID:  18759484]

[65]
Li, Y.; Cao, X.; Liu, Y.; Wan, J.P. Regioselective three-component synthesis of 2,3-disubstituted quinolines via the enaminone modified Povarov reaction. Org. Biomol. Chem.,  2017, 15(45), 9585-9589.
 [http://dx.doi.org/10.1039/C7OB02411H] [PMID:  29114679]

[66]
Breugst, M.; von der Heiden, D. Mechanisms in iodine catalysis. Chemistry,  2018, 24(37), 9187-9199.
 [http://dx.doi.org/10.1002/chem.201706136] [PMID:  29469220]

[67]
Dang, T.T.; Boeck, F.; Hintermann, L. Hidden Brønsted acid catalysis: Pathways of accidental or deliberate generation of triflic acid from metal triflates. J. Org. Chem.,  2011, 76(22), 9353-9361.
 [http://dx.doi.org/10.1021/jo201631x] [PMID:  22010906]

[68]
Truesdale, V.W.; Luther, G.W.; Greenwood, J.E. The kinetics of iodine disproportionation: A system of parallel second-order reactions sustained by a multi-species pre-equilibrium. Phys. Chem. Chem. Phys.,  2003, 5(16), 3428-3435.
 [http://dx.doi.org/10.1039/b303351a]

[69]
Xu, X-P.; Ji, S-J.; Zhang, Y.; Jiang, J.; Chu, X-Q.; Jiang, R.; Li, D-H. Friedel-crafts alkylation of indoles by tert-enamides in acetic acid. Synlett,  2012, 23(5), 751-754.
 [http://dx.doi.org/10.1055/s-0031-1290605]

[70]
Protti, S.; Palmieri, A. Sustainable Organic Synthesis: Tools and Strategies; Royal Society of Chemistry, 2021, pp. 315-338.
 [http://dx.doi.org/10.1039/9781839164842]

[71]
Andrade, C.K.Z.; Alves, L.M. Environmentally benign solvents in organic synthesis: Current topics. Curr. Org. Chem.,  2005, 9, 195-218.
 [http://dx.doi.org/10.2174/1385272053369178]

[72]
 Available from: 
          https://www.pmel.noaa.gov/foci/operations/2003/Instructions/MF03-03/Fluorinert.pdf

[73]
Ryu, I.; Matsubara, H.; Yasuda, S.; Nakamura, H.; Curran, D.P. Phase-vanishing reactions that use fluorous media as a phase screen. Facile, controlled bromination of alkenes by dibromine and dealkylation of aromatic ethers by boron tribromide. J. Am. Chem. Soc.,  2002, 124(44), 12946-12947.
 [http://dx.doi.org/10.1021/ja027965y] [PMID:  12405811]

[74]
Ryu, I.; Matsubara, H.; Nakamura, H.; Curran, D.P. Phase‐vanishing methods based on fluorous phase screen: A simple way for efficient execution of organic synthesis. Chem. Rec.,  2008, 8(6), 351-363.
 [http://dx.doi.org/10.1002/tcr.20161] [PMID:  19107865]

[75]
Curran, D.P. Fluorous methods for synthesis and separation of organic molecules. Pure Appl. Chem.,  2000, 72(9), 1649-1653.
 [http://dx.doi.org/10.1351/pac200072091649]
Cite As
Current Organic Synthesis

Regioselective Synthesis of Cycloalkane-fused Pyrazolo[4,3-e]pyridines through Tandem Reaction of 5-aminopyrazoles, Cyclic Ketones and Electron-rich Olefins

Abstract

Graphical Abstract
