Thietanyl Protection in the Synthesis of 8-Substituted 1-Benzyl-3-methyl-3,7-dihydro- 1H-purine-2,6-diones

Author(s): Ferkat Khaliullin*, Yuliya Shabalina

Journal Name: Current Organic Synthesis

Volume 17 , Issue 7 , 2020


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Graphical Abstract:


Abstract:

Aim and Objective: 1-Аlkyl-3,7-dihydro-1H-purine-2,6-diones containing no substituents in the N7 position can be synthesized only using protecting groups, for example, benzyl protection. However, in the case of synthesis of 1-benzyl-3,7-dihydro-1H-purine-2,6-diones, the use of benzyl protection may lead to simultaneous debenzylation of both N1 and N7 positions. Therefore, it is necessary to use other protective groups for the synthesis of 1-benzyl-3,7-dihydro-1H-purine-2,6-diones.

Materials and Methods: 8-Bromo- and 8-amino-substituted 1-benzyl-3-methyl-3,7-dihydro-1H-purine-2,6-diones unsubstituted in the N7 position were synthesized with the use of thietanyl protecting group. The thietane ring was introduced via the reaction of 8-bromo-3-methyl-3,7-dihydro-1H-purine-2,6-dione with 2-chloromethylthiirane, giving rise to 8-bromo-3-methyl-7-(thietan-3-yl)-3,7-dihydro-1H-purine-2,6-dione. The subsequent alkylation with benzyl chloride yielded 1-benzyl-8-bromo-3-methyl-7-(thietan-3-yl)-3,7-dihydro-1H-purine-2,6-dione, which was oxidized with hydrogen peroxide to be converted to 1-benzyl-8-bromo-3-methyl-7-(1,1-dioxothietan- 3-yl)-3,7-dihydro-1H-purine-2,6-dione. This product reacted with amines to give 8-amino-substituted 1-benzyl-3- methyl-7-(1,1-dioxothietan-3-yl)-3,7-dihydro-1H-purine-2,6-diones. The reaction of 8-substituted 1-benzyl-3- methyl-7-(1,1-dioxothietan-3-yl)-3,7-dihydro-1H-purine-2,6-diones with sodium isopropoxide resulted in the removal of the thietanyl protection and afforded target 8-substituted 1-benzyl-3-methyl-3,7-dihydro-1H-purine-2,6- diones. The structures of the targets compounds have been deduced upon their elemental analysis and spectral data (IR, 1H NMR, 13C NMR and 15N NMR).

Results and Discussion: A new 8-substituted 1-benzyl-3-methyl-3,7-dihydro-1H-purine-2,6-diones unsubstituted in the N7 position were synthesized using thietanyl protecting group.

Conclusion: The present study described a new route to synthesize some new 1,8-disubstituted 3-methyl-3,7- dihydro-1H-purine-2,6-diones unsubstituted in the N7 position starting from available 8-bromo-3-methyl-3,7- dihydro-1H-purine-2,6-dione with use of thietanyl protecting group. The advantages of this protocol are the possibility of the synthesis of 1-benzyl-substituted 3,7-dihydro-1H-purine-2,6-diones, the stability of the thietanyl protecting group upon nucleophilic substitution by amines of the bromine atom in the position 8, as well as mild conditions, and simple execution of experiments.

Keywords: Alkylation, amines, nucleophilic substitution, oxidation, protecting groups, purine-2, 6-diones, thietanes.

[1]
Monteiro, J.P.; Alves, M.G.; Oliveira, P.F.; Silva, B.M. structure-bioactivity relationships of methylxanthines: trying to make sense of all the promises and the drawbacks. Molecules, 2016, 21, 974-1-32.
[2]
Fisone, G.; Borgkvist, A.; Usiello, A. Caffeine as a psychomotor stimulant: Mechanism of action. Cell. Mol. Life Sci., 2004, 61(7-8), 857-872.
[http://dx.doi.org/10.1007/s00018-003-3269-3] [PMID: 15095008]
[3]
Szopa, A.; Poleszak, E.; Wyska, E.; Serefko, A.; Wośko, S.; Wlaź, A.; Pieróg, M.; Wróbel, A.; Wlaź, P. Caffeine enhances the antidepressant-like activity of common antidepressant drugs in the forced swim test in mice. Naunyn Schmiedebergs Arch. Pharmacol., 2016, 389(2), 211-221.
[http://dx.doi.org/10.1007/s00210-015-1189-z] [PMID: 26614569]
[4]
Chapman, R.F.; Mickleborough, T.D. The effects of caffeine on ventilation and pulmonary function during exercise: An often-overlooked response. Phys. Sportsmed., 2009, 37(4), 97-103.
[http://dx.doi.org/10.3810/psm.2009.12.1747] [PMID: 20048546]
[5]
Boison, D. Methylxanthines, seizures, and excitotoxicity. Handb. Exp. Pharmacol., 2011, 200(200), 251-266.
[http://dx.doi.org/10.1007/978-3-642-13443-2_9] [PMID: 20859799]
[6]
Foukas, L.C.; Daniele, N.; Ktori, C.; Anderson, K.E.; Jensen, J.; Shepherd, P.R. Direct effects of caffeine and theophylline on p110 δ and other phosphoinositide 3-kinases. Differential effects on lipid kinase and protein kinase activities. J. Biol. Chem., 2002, 277(40), 37124-37130.
[http://dx.doi.org/10.1074/jbc.M202101200] [PMID: 12145276]
[7]
Glogowski, J.; Danforth, D.R.; Ciereszko, A. Inhibition of alkaline phosphatase activity of boar semen by pentoxifylline, caffeine, and theophylline. J. Androl., 2002, 23(6), 783-792.
[PMID: 12399523]
[8]
Van der Walt, M.M. Terre’Blanche, G. 1,3,7-Triethyl-substituted xanthines - possess nanomolar affinity for the adenosine A1 receptor. Bioorg. Med. Chem., 2015, 23, 6641-6649.
[http://dx.doi.org/10.1016/j.bmc.2015.09.012] [PMID: 26392370]
[9]
Hayallah, A.M.; Sandoval-Ramírez, J.; Reith, U.; Schobert, U.; Preiss, B.; Schumacher, B.; Daly, J.W.; Müller, C.E. 1,8-disubstituted xanthine derivatives: synthesis of potent A2B-selective adenosine receptor antagonists. J. Med. Chem., 2002, 45(7), 1500-1510.
[http://dx.doi.org/10.1021/jm011049y] [PMID: 11906291]
[10]
Bansal, R.; Kumar, G.; Gandhi, D.; Yadav, R.; Young, L.C.; Harvey, A.L. Synthesis of 8-(cyclopentyloxy)phenyl substituted xanthine derivatives as adenosine A2A ligands. Arzneimittelforschung, 2010, 60(3), 131-136.
[PMID: 20422944]
[11]
Basu, S.; Barawkar, D.A.; Ramdas, V.; Patel, M.; Waman, Y.; Panmand, A.; Kumar, S.; Thorat, S.; Naykodi, M.; Goswami, A.; Reddy, B.S.; Prasad, V.; Chaturvedi, S.; Quraishi, A.; Menon, S.; Paliwal, S.; Kulkarni, A.; Karande, V.; Ghosh, I.; Mustafa, S.; De, S.; Jain, V.; Banerjee, E.R.; Rouduri, S.R.; Palle, V.P.; Chugh, A.; Mookhtiar, K.A. Design and synthesis of novel xanthine derivatives as potent and selective A2B adenosine receptor antagonists for the treatment of chronic inflammatory airway diseases. Eur. J. Med. Chem., 2017, 134, 218-229.
[http://dx.doi.org/10.1016/j.ejmech.2017.04.014] [PMID: 28415011]
[12]
Allwood, M.B.; Cannan, B.; van Aalten, D.M.F.; Eggleston, I.M. Efficient synthesis of 1,3,7-substituted xanthines by a safety-catch protection strategy. Tetrahedron, 2007, 63, 12294-12302.
[http://dx.doi.org/10.1016/j.tet.2007.09.067]
[13]
Constantin, S.; Lupascu, F.G.; Apotrosoaei, M.; Vasincu, I.M.; Lupascu, D.; Buron, F.; Routier, S.; Profire, L. Synthesis and biological evaluation of the new 1,3-dimethylxanthine derivatives with thiazolidine-4-one scaffold. Chem. Cent. J., 2017, 11, 12-1-13.
[14]
Hayallah, A.M.; Elgaher, W.A.; Salem, O.I.; Alim, A.A.; Alim, M.A. Design and synthesis of some new theophylline derivatives with bronchodilator and antibacterial activities. Arch. Pharm. Res., 2011, 34(1), 3-21.
[http://dx.doi.org/10.1007/s12272-011-0101-8] [PMID: 21468910]
[15]
Chen, Y.; Wang, B.; Guo, Y.; Zhou, Y.; Pan, L.; Xiong, L.; Shujing, Y.U.; Zhengming, L.I. Synthesis and biological activities of novel methyl xanthine derivatives. Chem. Res. Chin. Univ., 2014, 30, 98-102.
[http://dx.doi.org/10.1007/s40242-014-3173-4]
[16]
Lee, D.; Lee, S.; Liu, K.H.; Bae, J.S.; Baek, D.J.; Lee, T. Solid-Phase Synthesis of 1,3,7,8-Tetrasubstituted Xanthine Derivatives on Traceless Solid Support. ACS Comb. Sci., 2016, 18(1), 70-74.
[http://dx.doi.org/10.1021/acscombsci.5b00148] [PMID: 26616892]
[17]
Romanenko, N.I.; Pakhomova, O.A.; Ivanchenko, D.G.; Kamyshnyi, A.M.; Polishchuk, N.N. Synthesis and Biological Activity of 8-Benzylidenehydrazino-3-Methyl-7-β-Methoxyethylxanthines. Pharm. Chem. J., 2014, 48(7), 444-447.
[http://dx.doi.org/10.1007/s11094-014-1128-1]
[18]
Hisham, M.; Youssif, B.G.M.; Osman, E.E.A.; Hayallah, A.M.; Abdel-Aziz, M. Synthesis and biological evaluation of novel xanthine derivatives as potential apoptotic antitumor agents. Eur. J. Med. Chem., 2019, 176, 117-128.
[http://dx.doi.org/10.1016/j.ejmech.2019.05.015] [PMID: 31108261]
[19]
Gulevskaya, A.V.; Pozharskii, A.F. Synthesis of N-Substituted Xanthines. Chem. Heterocycl. Compd., 1991, 27(1), 1-23.
[http://dx.doi.org/10.1007/BF00633208]
[20]
Bridson, P.K.; Lin, X.; Melman, N.; Ji, X.D.; Jacobson, K.A. Synthesis and adenosine receptor affinity of 7-β-D-ribofuranosylxanthine. Nucleosides Nucleotides, 1998, 17(4), 759-768.
[http://dx.doi.org/10.1080/07328319808004673] [PMID: 9708335]
[21]
Billen, G.; Okyayuz-Baklouti, I.; Anagnostopulos, H.; Mullner, S. Alkylxanthine phosphonates and alkylxanthine phosphine oxides and their use as pharmaceuticals. U.S. Patent. 5,728,686, 1998 17 March..
[22]
Khaliullin, F.A.; Shabalina, Yu.V.; Sharafutdinov, R.M. Thietanyl protection in the synthesis of 1-alkyl-8-bromo-3-methyl-3,7-dihydro-1H-purine-2,6-diones. Russ. J. Org. Chem., 2010, 46(5), 689-692.
[http://dx.doi.org/10.1134/S1070428010050167]
[23]
Khaliullin, F.A.; Shabalina, Yu.V.; Sharafutdinov, R.M. Thietanyl protection in the synthesis of 1-alkyl-8-amino-3-methyl-3,7-dihydro-1H-purine-2,6-diones. Russ. J. Org. Chem., 2015, 51(10), 1434-1437.
[http://dx.doi.org/10.1134/S1070428015100139]
[24]
Khaliullin, F.A.; Kataev, B.A.; Strokin, Yu.V. Alkylation of xanthine and benzimidazole derivatives with epithiochlorohydrin. Chem. Heterocycl. Compd., 1991, 27, 410.
[http://dx.doi.org/10.1007/BF00480840]
[25]
Leśniak, S.; Kinart, W.J.; Lewkowski, J. Comprehensive Heterocyclic Chemistry III; Elsevier: Amsterdam, 2008, Vol. 2, pp. 389-428.
[http://dx.doi.org/10.1016/B978-008044992-0.00207-8]
[26]
Khaliullin, F.A.; Klen, E.E. Thietane ring as a novel protecting group. Russ. J. Org. Chem., 2009, 45(1), 135-138.
[http://dx.doi.org/10.1134/S1070428009010187]


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Article Details

VOLUME: 17
ISSUE: 7
Year: 2020
Page: [535 - 539]
Pages: 5
DOI: 10.2174/1570179417666200628015511
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