Phase Transfer Catalyzed Preparation of 4-Methylbenzenesulfonyl Imidazole for Regioselective Synthesis of Mono-6-(4-methylbenzenesulfonyl)-β-cyclodextrin

I Wayan Muderawan(1*), I Wayan Mudianta(2), Made Kurnia Wiastuti Giri(3)

(1) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Ganesha University of Education, Singaraja 81117, Bali, Indonesia
(2) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Ganesha University of Education, Singaraja 81117, Bali, Indonesia
(3) Study Program of Medicine, Faculty of Medicine, Ganesha University of Education, Singaraja 81117, Bali, Indonesia
(*) Corresponding Author


The preparation of 4-methylbenzenesulfonyl imidazole by using triethylamine as an effective phase‐transfer catalyst (PTC) under mild biphasic conditions has been studied intensively. The method can be used for large-scale preparation with high purity and high yield of 4-methylbenzene-sulfonyl imidazole. The result in 4-methylbenzenesulfonyl imidazole has been successfully applied for the regioselective synthesis of mono-6-(4-methylbenzenesulfonyl)-β-cyclodextrin in an aqueous medium. This synthetic methodology concept, together with the synthetic versatility of PTC, provides a general and reliable general strategy for the practical and industrial regioselective synthesis of highly valuable mono-6-(4-methylbenzenesulfonyl)-β-cyclodextrin as a key intermediate for the single functional isomer mono-substituted cyclodextrin derivatives. As characterized by FTIR, NMR and mass spectrometry, mono-6-(4-methylbenzenesulfonyl)-β-cyclodextrin was obtained in high purity.


phase transfer catalysis; 4-methylbenzene-sulfonyl imidazole; regioselective synthesis; mono-6-(4-methylbenzenesulfonyl)-β-cyclodextrin

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[1] Crini, G., 2014, Review: A history of cyclodextrins, Chem. Rev., 114 (21), 10940–10975.

[2] Kurkov, S.V., and Loftsson, T., 2013, Cyclodextrins, Int. J. Pharm., 453 (1), 167–180.

[3] Jansook, P., Ogawa, N., and Loftsson, T., 2018, Cyclodextrins: Structure, physicochemical properties and pharmaceutical applications, Int. J. Pharm., 535 (1-2), 272–284.

[4] Liu, J.Y., Zhang, X., and Tian, B.R., 2020, Selective modification at the different positions of cyclodextrins: A review of strategy, Turk. J. Chem., 44 (2), 261–278.

[5] Kasal, P., and Jindřich, J., 2021, Mono-6-substituted cyclodextrins–Synthesis and applications, Molecules, 26 (16), 5065.

[6] Tang, W., Ng, S.C., and Sun, D., 2013, Modified Cyclodextrins for Chiral Separation, Springer-Verlag, Heidelberg, Berlin.

[7] Byun, H.S., Zhong, N., and Bittman, R., 2000, 6A-O-p-Toluenesulfonyl β-cyclodextrin, Org. Synth., 77, 225.

[8] Makosza, M., and Fedoryński, M., 2020, Interfacial processes–The key steps of phase transfer catalyzed reaction, Catalysts, 10 (12), 1436.

[9] Joshi, D.R., and Adhikari, N., 2019, Phase transfer catalysis in organic synthesis, World J. Pharm. Res., 8 (8), 508–515.

[10] Senthamizh Selvi, R., Nanthini, R., and Sukanyaa, G., 2012, The basic principle of phase-transfer catalysis, some mechanistic aspects and important applications, Int. J. Sci. Technol. Res., 1 (3), 61–63.

[11] Novokshonov, V.V., Xuan, N.T.T., and Shaglaeva, N.S., 2019, Synthesis of 6I-O-(4-methylbenzenesulfonyl)-β-cyclodextrin, Russ. J. Org. Chem., 55 (10), 1616–1617.

[12] Srivastava, K.K., Srivastava, S., Alam, M.T., and Rituraj, R., 2014, Spectrometric determination of reliable association constant of weakly bounded charge transfer complex in solution, Int. J. Curr. Res., 6 (3), 5481–5486.

[13] Popr, M., Hybelbauerová, S., and Jindřich, J., 2014, A complete series of 6-deoxy-monosubstituted tetraalkylammonium derivatives of α-, β-, and γ-cyclodextrin with 1, 2, and 3 permanent positive charges, Beilstein J. Org. Chem., 10, 1390–1396.

[14] Poulson, B.G., Alsulami, Q.A., Sharfalddin, A., El Agammy, E.F., Mouffouk, F., Emwas, A.H., Jaremko, L., and Jaremko, M., 2022, Cyclodextrins: Structural, chemical, and physical properties, and applications, Polysaccharides, 3 (1), 1–31.

[15] Jouffroy, M., Armspach, D., Matt, D., and Toupet, L., 2013, Regioselective di- and tetra-functionalisation of γ-cyclodextrin using capping methodology, Org. Biomol. Chem., 11 (22), 3699–3705.

[16] Xiao, S., Wang, Q., Yu, F., Peng, Y., Yang, M., Sollogoub, M., Sinaÿ, P., Zhang, Y., Zhang, L., and Zhou, D., 2012, Conjugation of cyclodextrin with fullerene as a new class of HCV entry inhibitors, Bioorg. Med. Chem., 20 (18), 5616–5622.

[17] Lai, W.F., 2019, “Design of Cyclodextrin-Based Systems for Intervention Execution” in Delivery of Therapeutics for Biogerontological Inventions, Academic Press, Cambridge, US, 49–59.

[18] Raoov, M., Mohamad, S., and Abas, M.R., 2014, Synthesis and characterization of β-cyclodextrin functionalized ionic liquid polymer as a macroporous material for the removal of phenols and As(V), Int. J. Mol. Sci., 15 (1), 100–119.

[19] Lai, X.H., and Ng, S.C., 2004, Convenient synthesis of mono-(6A-N-allylamino-6A-deoxy)permethylated β-cyclodextrin: A promising chiral selector for an HPLC chiral stationary phase, Tetrahedron Lett., 45 (23), 4469–4472.

[20] Xiao, S., Wang, Q., Si, L., Zhou, X., Zhang, Y., Zhang, L., and Zhou, D., 2016, Synthesis and biological evaluation of novel pentacyclic triterpene α-cyclodextrin conjugates as HCV entry inhibitors, Eur. J. Med. Chem., 124, 1–9.

[21] Yin, J.J., Sharma, S., Shumyak, S.P., Wang, Z.X., Zhou, Z.W., Zhang, Y., Guo, P., Li, C.Z., Kanwar, J.R., Yang, T., Mohapatra, S.S., Liu, W., Duan, W., Wang, J.C., Li, Q., Zhang, X., Tan, J., Jia, L., Liang, J., Wei, M.Q., Li, X., and Zhou, S.F., 2013, Synthesis and biological evaluation of novel folic acid receptor-targeted, β-cyclodextrin-based drug complexes for cancer treatment, PLoS One, 8 (5), e62289.

[22] Onozula, S., Kojima, M., Hattori, K., and Toda, F., 1980, The regiospecific mono tosylation of cyclodextrins, Bull. Chem. Soc. Jpn., 53 (11), 3221–3224.

[23] Tripodo, G., Wischke, C., Neffe, A.T., and Lendlein, A., 2013, Efficient synthesis of pure monotosylated beta-cyclodextrin and its dimers, Carbohydr. Res., 381, 59–63.

[24] Ueno, A., and Breslow, R., 1982, Selective sulfonation of a secondary hydroxyl group of β-cyclodextrin, Tetrahedron Lett., 23 (34), 3451–3454.


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