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Synthesis, Electrochemistry and Antitumor Activity of 1’H, 3’H(Me)-spiro-[(aza)benzimidazoline-2’, 3-(1,2-diferrocenylcyclopropenes)], 2-(1,2-Diferrocenylvinyl)benz- and Azabenzimidazoles

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DOI: 10.4236/ojsta.2014.34007    4,015 Downloads   4,653 Views   Citations

ABSTRACT

A new method of synthesis of 2-(1,2-diferrocenylvinyl)benz- and azabenzimidazoles (3a-f), (4a-f) and 1’H,3’H(Me)-spiro-[(aza)benzimidazoline-2’,3-(1,2-diferrocenylcyclopropenes)] (5a-f) via reactions of diferrocenyl(methylsulfanyl)cyclopropenylium iodide (1) with aromatic o-diamines (2a-f) in the presence of Et3N (80°C - 82°C) is described. The structures of the resultant compounds are established using IR, 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis. The structure of one compound, cis-2-(1,2-diferrocenylvinyl)-1-methylbenzimidazole (3b), is confirmed by X-ray diffraction analysis. The electrochemical properties of compounds 3a, 3b, 3d and 5f are investigated using cyclic square wave voltammetry. Two electrochemical processes (I-II), attributed to oxidation of the ferrocene moieties, and the values of E0’(I), E0’(II), DE0’(II-I) and comporportionation constant Kcom are reported. The bioactivities of seven compounds 3a, 3c-f, 5d, 5f are evaluated. Compound 5f is the most active compound with a modest cytotoxic activity against six human cancer cell lines: U-251 (glioma), PC-3 (prostate cancer), K-562 (leukemia), HCT-15 (colon cancer), MCF-7 (breast cancer) and SKLU-1 (lung cancer).

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

García, J. , Ortiz-Frade, L. , Martínez-Klimova, E. , Ramos, J. , Flores-Alamo, M. , Apan, T. and Klimova, E. (2014) Synthesis, Electrochemistry and Antitumor Activity of 1’H, 3’H(Me)-spiro-[(aza)benzimidazoline-2’, 3-(1,2-diferrocenylcyclopropenes)], 2-(1,2-Diferrocenylvinyl)benz- and Azabenzimidazoles. Open Journal of Synthesis Theory and Applications, 3, 44-56. doi: 10.4236/ojsta.2014.34007.

References

[1] Komatsu, K. and Kitagawa, T. (2003) Cyclopropenylium Cations, Cyclopropenones, and Heteroanaloges—Recent Advances. Chemical Reviews, 103, 1371-1427.
http://dx.doi.org/10.1021/cr010011q
[2] Komatsu, K. and Yoshida, Z. (1996) Cyclopropenylium Salts. In: Meijere, A., Ed., Methods of Organic Chemistry (Houben-Weyl), E17d, Thieme, Stuttgart, 3079-3192.
[3] Klimova, E.I., Klimova, T., Hernández Ortega, S., Méndez Iturbide, D., García Marquez, A. and Martínez García, M. (2005) Diferrocenylcyclopropenyl Cations. Synthesis, Structures, and Some Chemical Properties. Journal of Organometallic Chemistry, 690, 3333-3339.
http://dx.doi.org/10.1016/j.jorganchem.2005.04.014
[4] Klimova, T., Klimova, E.I., Méndez Stivalet, J.M., Hernández-Ortega, S. and Martínez García, M. (2005) Diferrocenyl(methylthio)cyclopropenylium Iodide in the Synthesis of 2,3-Diferrocenyl-1-methylthio-1,3-dienes and -1,3, 5-trienes. European Journal Organic Chemistry, 4406-4413.
http://dx.doi.org/10.1002/ejoc.200500284
[5] Klimova, E.I., Mendez Stivalet, J.M., Klimova, T., Flores Alamo, M., Backinowsky, L.V., Ortiz Frade, L. and Martìnez Garcìa, M. (2010) Reactions of Diferrocenylmorpholinoand Methylsulfanyl-Cyclopropenylium Salts with β-Dicarbonyl Compounds and Diethyl Malonate. Synthetic Communications, 40, 839-854.
http://dx.doi.org/10.1080/00397910903014240
[6] Klimova, E.I., Klimova, T., Flores Alamo, M., Backinowsky, L.V. and Martìnez Garcìa, M. (2009) Intramolecular Transformations of 3-Cyanoaminoand 3-Cyanoimino-1,2-diferrocenylcyclopropenes. Molecules, 14, 3161-3175.
http://dx.doi.org/10.3390/molecules14093161
[7] Klimova, E.I., Vazquez Lopez, E.A., Flores-Alamo, M., Klimova, T. and Martìnez Garcìa, M. (2009) A Novel Synthesis of Ferrocenylpyridazines. European Journal Organic Chemistry, 25, 4352-4356.
http://dx.doi.org/10.1002/ejoc.200900505
[8] Klimova, E.I., Klimova, T., Backinowsky, L.V., Flores Alamo, M., Ortiz-Frade, L.A. and Martínez García, M. (2010) Novel Intramolecular Transformations of Amino(diferrocenyl)vinylcarbenes. Mendeleev Communications, 20, 312-313.
http://dx.doi.org/10.1016/j.mencom.2010.11.002
[9] Klimova, E.I., Ortiz-Frade, L.A., Klimova, T., González-Fuentes, M.A., Flores-Alamo, M., Backinowsky, L.V. and Martínez García, M. (2011) Intramolecular Conversions of (Aminoferrocenylpenta-1,4-dienyl)-ferrocenylcarbenes: Synthesis of Diferrocenylmono-, Bi-, Tricycles and Amino(diferrocenyl)hexa-1,3,5-trienes. Molecules, 16, 5574-5590.
http://dx.doi.org/10.3390/molecules16075574
[10] Vázquez López, E.A., Flores-Alamo, M., Martínez Mendoza, J.M. and Klimova, E.I. (2007) 4-(4-Nitrobenzyl)-pyridine in Reaction with Diferrocenyl(methylthio)-cyclopropenylium Iodide. Journal Mexican Chemistry Society, 51, 1115.
[11] Klimova Berestneva, T., Klimova, E.I., Flores-Alamo, M., Bakinovsky, L.V., Martìnez Garcìa, M., de Química, F., et al. (2006) Formation of 4,5-Diferrocenyl-6-methylthio-6H-1,2-oxazine N-Oxides and Migration of a Nitro Group in Reactions of 2,3-Diferrocenyl-1-methylthiocyclopropenylium Iodide with Nitroalkane. Synthesis, 21, 3706-3710.
http://dx.doi.org/10.1055/s-2006-950288
[12] Berestneva, T.K., Klimova, E.I., Flores Alamo, M., Méndez Iturbide, D. and Martìnez Garcìa, M. (2009) Synthesis, Structure, and Some Chemical Properties of Diferrocenyl-1,2,3-triazines. Journal of Heterocyclic Chemistry, 46, 477483.
http://dx.doi.org/10.1002/jhet.93
[13] Klimova, E.I., Flores Alamo, M., Cortez Maya, S., García-Ramos, J.C., Ortiz-Frade, L. and Méndez Stivalet, J.M. (2013) Novel Synthesis and Electrochemistry of 2-(1,2-Diferrocenylvinyl)imidazoline and -Imidazilidine Derivatives. Journal of Organometallic Chemistry, 743, 24-30.
http://dx.doi.org/10.1016/j.jorganchem.2013.06.003
[14] Klimova, E.I., Vázquez López, E.A., Flores Alamo, M., Ortiz-Frade, L.A., Hernández-Sánchez, G., Sotelo Domínguez, V.H. and Martínez García, M. (2012) 2-Arylimino(diferrocenyl)and (Di-p-anisyl)dihydropyrimidines: Novel Synthesis, Structures and Electrochemistry. Journal of Heterocyclic Chemistry, 49, 1156-1262.
[15] Eicher, T. and Hauptmann, S. (2006) The Chemistry of Heterocycles, Structures, Reactions, Synthesis and Applications. Wiley-VCH GmbH & Co. KGaA, Weinheim.
[16] Breslow, R. (1991) How Do Imidazole Groups Catalyze the Cleavage of RNA in Enzyme Models and in Enzymes? Evidence from “Negative Catalysis”. Accounts of Chemical Research, 24, 317-324.
http://dx.doi.org/10.1021/ar00011a001
[17] Fife, T.H. (1993) Kinetic and Mechanistic Effects of Ease of Carbon-Nitrogen Bond Breaking in Amide Hydrolysis. The Mechanisms of Hydrolysis of N-Acylimidazoles and N-Acylbenzimidazoles. Accounts of Chemical Research, 26, 325-331.
http://dx.doi.org/10.1021/ar00030a005
[18] Schwoch, S., Kramer, W., Neidlein, R. and Suschitzky, H. (1994) 2,3-Dihydrospiro[1H-4and 5-azabenzimidazole-2,1′cyclohexane](=Spiro[cyclohexane-1,2′(3′H)-1′H-imidazo[4,5-b]pyridine] and Spiro[cyclohexane-1,2′(3′H)1′H-imidazo[4, 5-c]pyridine]): Reactions with Nucleophiles.. Helvetica Chimica Acta, 77, 2175-2190.
http://dx.doi.org/10.1002/hlca.19940770811
[19] Drewes, S.E., Malissar, D.G.S. and Roos, G.H.P. (1992) A Novel Imidazolidin-2-One Auxiliary for a Highly Stereoselective Aldol Route to β-Hydroxyesters. Tetrahedron: Asymmetry, 3, 515-516.
http://dx.doi.org/10.1016/S0957-4166(00)80254-2
[20] Corey, E.J. and Mehrotra, M.M. (1988) A Simple and Enantioselective Synthesis of (+)-Biotin. Tetrahedron Letters, 29, 57-60.
http://dx.doi.org/10.1016/0040-4039(88)80015-7
[21] Gridnev, A.A. and Mihalteva, I.M. (1994) Synthesis of 1-Alkylimidazoles. Synthetic Communications, 24, 1547-1555.
http://dx.doi.org/10.1080/00397919408010155
[22] Babin, V.N., Belousov, Yu.A., Gumenyuk, V.V., Materikova, V.V., Salimov, R.B. and Kochetkova, N.S. (1983) Reactions of Anionic Nitrogen Heterocycles with Iron Carbonyls. Journal of Organometallic Chemistry, 241, C41-C44.
http://dx.doi.org/10.1016/S0022-328X(00)98535-8
[23] Kaluz, S. and Toma, S. (1986) Addition of Cand S-nucleophiles to Acryloylferrocene and Cinnamoylferrocene Catalysed by KF/Al2O3. Collection of Czechoslovak Chemical Communications, 51, 2199-2206.
http://dx.doi.org/10.1135/cccc19862199
[24] Heydenhauss, D., Kramer, C.R. and Jaenecke, G. (1986) The Effect of Substituents on the Half-Wave Potential of 2-Ferrocenyl Substituted Imidazole and Benzimidazole. Zeitschrift fur Physikalische Chemie (Leipzig), 267, 33-44.
[25] Villemin, D. and Richard, M. (1987) Condensation on Alumina. III. Synthesis of 5-Alkylidene, 2-Thiohydantoin from 3-Acetyl, 2-Thiohydantoin. Synthetic Communications, 17, 283-289.
http://dx.doi.org/10.1080/00397918708077308
[26] Schvekhgeimer, M.G.A. (1991) Heteroarylferrocenes. Khimiya Geterotsiklicheskikh Soedinenii, 2, 147-163.
[27] Schvekhgeimer, M.G.A. (1996) Heterylferrocenes. Synthesis and Use. Russian Chemical Reviews, 65, 41-79.
http://dx.doi.org/10.1070/RC1996v065n01ABEH000199
[28] Sisko, J., Kassick, A.J., Mellinger, M., Filan, J.J., Allen, A. and Olsen, M.A. (2000) An Investigation of Imidazole and Oxazole Syntheses Using Aryl-Substituted TosMIC Reagents. Journal of Organic Chemistry, 65, 1516-1524.
http://dx.doi.org/10.1021/jo991782l
[29] Robinson, M.B. and Day, P. (1968) Mixed-Valence Chemistry: A Survey and Classification. Advances in Inorganic Chemistry and Radiochemistry, 10, 247-422.
http://dx.doi.org/10.1016/S0065-2792(08)60179-X
[30] Gritzner, G. and Küta, J. (1984) Physical and Biophysical Chemistry Division Commission on Electrochemistry. Pure and Applicated Chemistry, 56, 461-466.
[31] Sheldrick, G.M. (1994) SHELXS-97, Program for the Refinement of Crystal Structures. University of Gottingen, Gottingen.
[32] Monks, A., Scudiero, D., Skehan, P., Shoemaker, R., Paul, K., Vistica, D., Hose, C., Langley, J., Cronise, P., Vaigro-Wolff, A., Gray-Goodrich, M., Campbell, H., Mayo, J. and Boyd, M. (1991) Feasibility of a High-Flux Anticancer Drug Screen Using a Diverse Panel of Cultured Human Tumor Cell Lines. Journal of the National Cancer Institute, 83, 757-776.
http://dx.doi.org/10.1093/jnci/83.11.757
[33] Skehan, P., Storeng, R., Scudiero, D., Monks, A., McMahon, J., Vistica, D., Warren, J.T., Bokesch, H., Kenney, S. and Boyd, M.R. (1990) New Colorimetric Cytotoxicity Assay for Anticancer-Drug Screening. Journal of the National Cancer Institute, 82, 1107-1112.
http://dx.doi.org/10.1093/jnci/82.13.1107
[34] Bard, A.J. and Faulkner, L.R. (1980) Electrochemical Methods, Fundamentals and Applications. John Wiley and Sons, New York.
[35] Zanello, P. (2003) Inorganic Electrochemistry, Theory, Practice and Application. The Royal Society of Chemistry, Cambridge.
[36] Helfrick, J.C. and Bottomley, L.A. (2009) Cyclic Square Wave Voltammetry of Single and Consecutive Reversible Electron Transfer Reactions. Analytical Chemistry, 81, 9041-9047.
http://dx.doi.org/10.1021/ac9016874

  
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