A Simplified Approach to α-Ketothiocyanates, Thiocyanatoindoles and Chalcones Using Lithium Chloride

Authors

  • Dr. Nagesh Raghunath Sutar Associate Professor, Department of Chemistry, Affiliation Address: Smt. Chandibai Himathmal Mansukhani College, Ulhasnagar-421003 Maharashtra, India Author

DOI:

https://doi.org/10.32628/IJSRCH251051

Keywords:

α-ketothiocyanates, thiocyanatoindoles, Chalcone derivatives, Lithium chloride, high yields, simple procedure, regioselective

Abstract

A novel and highly efficient synthetic methodology have been established for the preparation of α-ketothiocyanates, thiocyanatoindoles and Chalcone derivatives. The method employs Lithium chloride in suitable solvent as a catalyst system, which demonstrated its high catalytic activity by affording α-ketothiocyanates, thiocyanatoindoles and Chalcone derivatives with high yields, reaction rates were found to be satisfactory. This methodology is distinguished by its ability to produce highly functionalized chalcones and to perform regioselective thiocyanation of structurally diverse ketones and Indoles.

References

Lawson, D.F., 1974. Chlorocyclophosphazene-epoxide reactions. Catalysis by lithium halides. The Journal of Organic Chemistry, 39(23), pp.3357-3360. DOI: https://doi.org/10.1021/jo00937a011

Nunomoto, S., Kawakami, Y. and Yamashita, Y., 1983. Cross-coupling reaction of 2-(1, 3-butadienyl) magnesium chloride with alkyl or aryl halides by lithium chloride-cupric chloride (Li2CuCl4), a superior catalyst. The Journal of Organic Chemistry, 48(11), pp.1912-1914. DOI: https://doi.org/10.1021/jo00159a028

Yang, J., Zhang, J., Li, T., Liu, Y., Jin, H., Ryu, D.H. and Zhang, L., 2025. Lithium Chloride‐Promoted Brønsted Acid‐Catalyzed Friedel‐Crafts Alkylation Reaction of Indoles with Aldehydes and Ketones “on Water”. Advanced Synthesis & Catalysis, 367(9), p.e202401542. DOI: https://doi.org/10.1002/adsc.202401542

Marques, M.V. and Sa, M.M., 2014. Lithium chloride-mediated stereoselective synthesis of cyclopropanecarboxamides from γ, δ-epoxy malonates through a domino cyclopropanation/lactonization/aminolysis process. The Journal of Organic Chemistry, 79(10), pp.4650-4658. DOI: https://doi.org/10.1021/jo500712t

Wu, X.A., Ying, P., Liu, J.Y., Shen, H.S., Chen, Y. and He, L., 2009. Lithium chloride–assisted selective hydrolysis of methyl esters under microwave irradiation. Synthetic Communications®, 39(19), pp.3459-3470. DOI: https://doi.org/10.1080/00397910902778001

Luisi, R., & Capriati, V. (Eds.). (2014). Lithium compounds in organic synthesis: from fundamentals to applications. John Wiley & Sons. DOI: https://doi.org/10.1002/9783527667512

Arigala, P., Sadu, V.S., Hwang, I.T., Hwang, J.S., Kim, C.U. and Lee, K.I., 2015. Copper‐Catalyzed Regio‐and Stereoselective Ring‐Opening of Cyclic Sulfamidates with Grignard Reagents assisted by Lithium Chloride. Advanced Synthesis & Catalysis, 357(9), pp.2027-2032. DOI: https://doi.org/10.1002/adsc.201400850

Kurono, N., Yamaguchi, M., Suzuki, K. and Ohkuma, T., 2005. Lithium chloride: An active and simple catalyst for cyanosilylation of aldehydes and ketones. The Journal of Organic Chemistry, 70(16), pp.6530-6532. DOI: https://doi.org/10.1021/jo050791t

(a) Mehta, R. G.; Liu, J.; Constantinou, A.; Thomas, C. F.; Hawthorne, M.; You, M.; Gerhauser, C.; Pezzuto, J. M.; Moon, R. C.; Moriarty, R. M. Cancer chemopreventive activity of brassinin, a phytoalexin from cabbage. Carcinogenesis 1995, 16, 399– 404, DOI: 10.1093/carcin/16.2.399. (b) Yasman, Y.; Edrada, R. A.; Wray, V.; Proksch, P. New 9-Thiocyanatopupukeanane Sesquiterpenes from the Nudibranch Phyllidia varicosa and Its Sponge-Prey Axinyssa aculeata. J. Nat. Prod. 2003, 66, 1512– 1514, DOI: 10.1021/np030237j7

(a) Kokorekin, V. A.; Terent’ev, A. O.; Ramenskaya, G. V.; Grammatikova, N. E.; Rodionova, G. M.; Ilovaiskii, A. I. Synthesis and Antifungal Activity of Arylthiocyanates. Pharm. Chem. J. 2013, 47, 26– 29, DOI: 10.1007/s11094-013-0973-7 (b) Dutta, S.; Abe, H.; Aoyagi, S.; Kibayashi, C.; Gates, K. S. DNA Damage by Fasicularin. J. Am. Chem. Soc. 2005, 127, 15004– 15005, DOI: 10.1021/ja053735i (c) Piña, I. C.; Gautschi, J. T.; Wang, G.-Y.-S.; Sanders, M. L.; Schmitz, F. J.; France, D.; CornellKennon, S.; Sambucetti, L. C.; Remiszewski, S. W.; Perez, L. B.; Bair, K. W.; Crews, P. Psammaplins from the Sponge Pseudoceratina purpurea: Inhibition of Both Histone Deacetylase and DNA Methyltransferase. J. Org. Chem. 2003, 68, 3866, DOI: 10.1021/jo034248t

Kelly, T. R., Kim, M. H., & Curtis, A. D. (1993). Structure correction and synthesis of the naturally occurring benzothiazinone BMY 40662. The Journal of Organic Chemistry, 58(21), 5855-5857. DOI: https://doi.org/10.1021/jo00073a057

(a) Bacon, R. G. R. Chapter 27─Thiocyanates, Thiocyanogen, and Related Compounds. Org. Sulfur Compd. 1961, 306– 325, DOI: 10.1016/B978-1-4831-9982-5.50030-0 (b) Bayarmagnai, B.; Matheis, C.; Jouvin, K.; Goossen, L. J. Synthesis of Difluoromethyl Thioethers from Difluoromethyl Trimethylsilane and Organothiocyanates Generated In Situ. Angew. Chem. 2015, 127, 5845– 5848, DOI: 10.1002/ange.201500899 (c) Maurya, C. K.; Mazumder, A.; Gupta, P. K. Phosphorus pentasulfide mediated conversion of organic thiocyanates to thiols. Beilstein J. Org. Chem. 2017, 13, 1184– 1188, DOI: 10.3762/bjoc.13.117 (d) Danoun, G.; Bayarmagnai, B.; Gruenberg, M. F.; Goossen, L. J. Sandmeyer trifluoromethylthiolation of arenediazonium salts with sodium thiocyanate and Ruppert–Prakash reagent. Chem. Sci. 2014, 5, 1312– 1316, DOI: 10.1039/c3sc53076k (d) Renard, P. Y.; Schwebel, H.; Vayron, P.; Josien, L.; Valleix, A.; Mioskowski, C. Easy Access to Phosphonothioates. Chem. - Eur. J. 2002, 8, 2910– 2916 (e) Wang, C.; Geng, X.; Zhao, P.; Zhou, Y.; Wu, Y. D.; Cui, Y. F.; Wu, A. X. I2/CuCl2-promoted one-pot three-component synthesis of aliphatic or aromatic substituted 1,2,3-thiadiazoles. Chem. Commun. 2019, 55, 8134–8137,DOI:10.1039/C9CC04254G (f) Alizadeh, A.; Moafi, L. 2016. Convenient One-Pot Synthesis of Spirooxindole Derivatives Containing a 1,3,4-Thiadiazine Scaffold. Synlett, 27, 1828– 1831, DOI: 10.1055/s-0035-1561618 (g) Bisogno, F. R.; Cuetos, A.; Lavandera, I.; Gotor, V. Simple and quick preparation of α-thiocyanate ketones in hydroalcoholic media. Access to 5-aryl-2-imino-1,3-oxathiolanes. Green Chem. 2009, 11, 452– 454, DOI: 10.1039/b900137a.

Dittmer, D.; Katritzky, A.; Rees, C.1984. Comprehensive Heterocyclic Chemistry; Pergamon: Oxford, UK, 1984; vol. 7, p. 178.

Prakash, O. and Saini, N. 1993. Hypervalent Iodine in Organic Synthesis: One Pot Facile Syntheses of α-Thiocyanatoacetophenones, 2-Hydroxy-, and 2-Mercapto-4-arylthiazoles Using [Hydroxy (tosyloxy) iodo] benzene. Synthetic communications, 23(10), pp.1455-1462. DOI: https://doi.org/10.1080/00397919308011236

Yadav, J.S., Reddy, B.S. and Srinivas, M., 2004. A novel and efficient method for the synthesis of α-azidoketones and α-ketothiocyanates. Chemistry letters, 33(7), pp.882-883. DOI: https://doi.org/10.1246/cl.2004.882

Prakash, O.; Kaur, H.; Batra, H.; Rani, N.; Singh, S. P.; Moriarty, R. M. 2001. α-Thiocyanation of Carbonyl and β-Dicarbonyl Compounds Using (Dichloroiodo) benzene−Lead (II) Thiocyanate. The Journal of Organic Chemistry, 66 (6), 2019-2023, DOI: 10.1021/jo001504i DOI: https://doi.org/10.1021/jo001504i

Prakash, O.; Rani, N.; Sharma, V.; Moriarty, R. M. α-Thiocyanation of Ketones and Esters Using (Dichloroiodo)benzene-Lead (II) Thiocyanate. Synlett. 1997; 1997(11): 1255-1256, DOI: 10.1055/s-1997-1027 DOI: https://doi.org/10.1055/s-1997-1027

Iranpoor, N., Firouzabadi, H. and Shaterian, H., 2000. Efficient conversion of silyl ethers to thiocyanates with Ph3P (SCN) 2. Synlett, 2000(01), pp.65-66. DOI: https://doi.org/10.1055/s-2000-6452

Yadav, J.S., Reddy, B.S., Reddy, U.S. and Krishna, A.D., 2007. Iodine/MeOH as a novel and versatile reagent system for the synthesis of α-ketothiocyanates. Tetrahedron letters, 48(30), pp.5243-5246. DOI: https://doi.org/10.1016/j.tetlet.2007.05.143

Kumar, A., Ahamd, P. and Maurya, R.A., 2007. Direct α-thiocyanation of carbonyl and β-dicarbonyl compounds using potassium peroxydisulfate–copper (II). Tetrahedron letters, 48(8), pp.1399-1401. DOI: https://doi.org/10.1016/j.tetlet.2006.12.103

Reddy, B.S., Reddy, S.M.S. and Madan, C., 2011. NBS or DEAD as effective reagents in α-thiocyanation of enolizable ketones with ammonium thiocyanate. Tetrahedron letters, 52(13), pp.1432-1435. DOI: https://doi.org/10.1016/j.tetlet.2011.01.035

Kumar, A. and Pathak, S.R., 2005. Direct-thiocyanation of ketones using Cerium (IV) ammonium nitrate. Letters in Organic Chemistry, 2(8), pp.745-748. DOI: https://doi.org/10.2174/157017805774717373

Lenin, R. and M. Raju, R., 2010. A simple and efficient thiocyanation of indoles, anilines and keto compounds catalyzed by a polystyrene resin amberlyst-15. Letters in Organic Chemistry, 7(5), pp.392-395. DOI: https://doi.org/10.2174/157017810791514878

D. S. Bhalerao, K. G. Agamanchi, Efficient and Novel Method for Thiocyanation of Aromatic and Hetero-aromatic Compounds Using Bromodimethylsulfonium Bromide and Ammonium Thiocyanate, Synlett, 2007, 2952-2956. DOI: https://doi.org/10.1055/s-2007-992367

Wu, L., & Yang, X. (2012). Efficient α-Thiocyanation of Ketones Using Pyridinium Hydrobromide Perbromide. Phosphorus, Sulfur, and Silicon and the Related Elements, 187(6), 748–753. https://doi.org/10.1080/10426507.2011.616561 DOI: https://doi.org/10.1080/10426507.2011.616561

Wu, L., Yang, X. and Yan, F., 2011. I2O5 as a mild, inexpensive, and environmentally benign oxidant for the α-thiocyanation of ketones. Journal of Sulfur Chemistry, 32(2), pp.105-110. DOI: https://doi.org/10.1080/17415993.2010.548099

Anil Kumar, M., Reddy, K.K.K., Reddy, M.V., Reddy, C.D. and Reddy, C.S., 2008. Oxone as a mild, inexpensive, and environmentally benign oxidant for the α-thiocyanation of ketones. Synthetic Communications®, 38(13), pp.2089-2095. DOI: https://doi.org/10.1080/00397910802029349

Dezhen W., Xiaojuan Y. and Liqiang W., SelectfluorTM: A novel and efficient reagent for the rapid α-thiocyanation of ketones, J. Chem. Sci. Vol. 124, No. 4, July 2012, pp. 901–905. DOI: https://doi.org/10.1007/s12039-012-0270-0

Khazaei, A., Zolfigol, M.A., Mokhlesi, M. and Pirveysian, M., 2012. Citric acid as a trifunctional organocatalyst for thiocyanation of aromatic and heteroaromatic compounds in aqueous media. Canadian Journal of Chemistry, 90(5), pp.427-432. DOI: https://doi.org/10.1139/v2012-013

(a)Verma S, Srivastava AK, Pandey OP; A Review on Chalcones Synthesis and their Biological Activity; PharmaTutor; 2018; 6(2); 22-39; http://dx.doi.org/10.29161/PT.v6.i2.2018.22 (b) G.D. Carlo, N. Mascolo, A.A. Izzo, F. Capasso. 1999. Flavonoids: old and new aspects of a class of natural therapeutic drugs, Life Sci., 65, 337-53, doi: 10.1016/s0024-3205(99)00120-4.

Elkanzi, N.A., Hrichi, H., Alolayan, R.A., Derafa, W., Zahou, F.M. and Bakr, R.B., 2022. Synthesis of chalcones derivatives and their biological activities: a review. ACS omega, 7(32), pp.27769-27786., DOI: 10.1021/acsomega.2c01779 DOI: https://doi.org/10.1021/acsomega.2c01779

Zhang, S.; Li, T.; Zhang, L.; Wang, X.; Dong, H.; Li, L.; Fu, D.; Li, Y.; Zi, X.; Liu, H.-M.; Zhang, Y.A novel chalcone derivative S17 induces apoptosis through ROS dependent DR5 up-regulation in gastric cancer cells. Sci. Rep. 2017, 7 (1), 9873, DOI: 10.1038/s41598-017-10400-3 DOI: https://doi.org/10.1038/s41598-017-10400-3

(a) Hailemariam, A.; Feyera, M.; Deyou, T.; Abdissa, N. Antimicrobial Chalcones from the Seeds of Persicaria lapathifolia. Biochem. Pharmacol. 2018, 7 (1), 1000237, DOI: 10.4172/2167-0501.1000237 (b) Mothana, R. A.; Arbab, A. H.; ElGamal, A. A.; Parvez, M. K.; Al-Dosari, M. S. Isolation and Characterization of Two Chalcone Derivatives with Anti-Hepatitis B Virus Activity from the Endemic Socotraen Dracaena cinnabari (Dragon’s Blood Tree). Molecules. 2022, 27 (3), 952, DOI: 10.3390/molecules27030952 (c) Ma, Q. G.; Li, T.; Wei, R. R.; Liu, W. M.; Sang, Z. P.; Song, Z. W. Characterization of chalcones from Medicago sativa L. and their hypolipidemic and antiangiogenic activities. Journal of agricultural and food chemistry 2016, 64 (43), 8138– 8145, DOI: 10.1021/acs.jafc.6b03883 (d) Kil, Y. S.; Choi, S. K.; Lee, Y. S.; Jafari, M.; Seo, E. K. Chalcones from Angelica keiskei: evaluation of their heat shock protein inducing activities. J. Nat. Prod. 2015, 78 (10), 2481– 2487, DOI: 10.1021/acs.jnatprod.5b00633

Gomes, M. N.; Muratov, E. N.; Pereira, M.; Peixoto, J. C.; Rosseto, L. P.; Cravo, P. V.; Andrade, C. H.; Neves, B. J. Chalcone derivatives: promising starting points for drug design. Molecules. 2017, 22 (8), 1210, DOI: 10.3390/molecules22081210 DOI: https://doi.org/10.3390/molecules22081210

(a) Tamuly, C.; Saikia, I.; Hazarika, M.; Bordoloi, M.; Hussain, N.; Das, M. R.; Deka, K. 2015. Bio-derived ZnO nanoflower: a highly efficient catalyst for the synthesis of chalcone derivatives RSC Adv., 5, 8604–8608. DOI: 10.1039/C4RA14225J. (b) Mulugeta, D.; Abdisa, B.; Belay, A.; Endale, A., .2018. Microwave Assisted Efficient Synthesis of Flavone using ZnO Nanoparticles as Catalyst under Solvent-free Conditions, Chem. Mater. Res.,10, 1–10. DOI: https://doi.org/10.1039/C4RA14225J

Narender T, Reddy KP. A simple and highly efficient method for the synthesis of chalcones by using borontrifluoride-etherate. Tetrahedron letters. 2007 Apr 30;48(18):3177-80. DOI: https://doi.org/10.1016/j.tetlet.2007.03.054

Climent, M.J., Corma, A., Iborra, S. and Velty, A., 2004. Activated hydrotalcites as catalysts for the synthesis of chalcones of pharmaceutical interest. Journal of Catalysis, 221(2), pp.474-482. DOI: https://doi.org/10.1016/j.jcat.2003.09.012

Li, J.T., Yang, W.Z., Wang, S.X., Li, S.H. and Li, T.S., 2002. Improved synthesis of chalcones under ultrasound irradiation. Ultrasonics Sonochemistry, 9(5), pp.237-239. DOI: https://doi.org/10.1016/S1350-4177(02)00079-2

Ritter, M., Martins, R.M., Rosa, S.A., Malavolta, J.L., Lund, R.G., Flores, A.F. and Pereira, C.M., 2015. Green synthesis of chalcones and microbiological evaluation. Journal of the Brazilian Chemical Society, 26(6), pp.1201-1210. DOI: https://doi.org/10.5935/0103-5053.20150084

Petrov, O., Ivanova, Y. and Gerova, M., 2008. SOCl2/EtOH: Catalytic system for synthesis of chalcones. Catalysis Communications, 9(2), pp.315-316. DOI: https://doi.org/10.1016/j.catcom.2007.06.013

Saı̈d Sebti, Abderrahim Solhy, Rachid Tahir, Saı̈d Boulaajaj, José A Mayoral, José M Fraile, Abdelali Kossir, Hammou Oumimoun, Calcined sodium nitrate/natural phosphate: an extremely active catalyst for the easy synthesis of chalcones in heterogeneous media, Tetrahedron Letters, Volume 42, Issue 45, 2001,Pages 7953-7955, https://doi.org/10.1016/S0040-4039(01)01698-7. DOI: https://doi.org/10.1016/S0040-4039(01)01698-7

Perozo-Rondón, E.; Martín-Aranda, R.M.; Casal, B.; Durán-Valle, C.J.; Lau, W.N.; Zhang, X.F.; Yeung, K.L. Sonocatalysis in solvent free conditions: An efficient eco-friendly methodology to prepare chalcones using a new type of amino graftedzeolites. Catal. Today, 2006, 114(2-3), 183-187. DOI: https://doi.org/10.1016/j.cattod.2006.01.003

Thirunarayanan, G.; Vanangamudi, G. Synthesis of some 4-bromo1-naphthyl chalcones using silica-sulfuric acid reagent under solvent free conditions. Arkivoc, 2006, xii, 58-64. DOI: https://doi.org/10.3998/ark.5550190.0007.c07

Dong, F.; Jian, C.; Zhenghao, F.; Kai, G.; Zuliang, L. Synthesis of chalcones via Claisen–Schmidt condensation reaction catalyzed by acyclic acidic ionic liquids. Catal. Commun., 2008, 9(9), 1924- 1927. DOI: https://doi.org/10.1016/j.catcom.2008.03.023

Sebti, S.; Solhy, A.; Tahir, R.; Abdelatif, S.; Boulaajaj, S.; Mayoral, J.A.; Garcıa, J.; Fraile, J.M.; Kossir, A.; Oumimoun, H. Application of natural phosphate modified with sodium nitrate in the synthesis of chalcones: a soft and clean method. J. Catal., 2003, 213(1), 1-6. DOI: https://doi.org/10.1016/S0021-9517(02)00017-9

Kunde, L.B.; Gade, S.M.; Kalyani, V.S.; Gupte, S.P. Catalytic synthesis of chalcone and flavanone using Zn–Al hydrotalcite adhere ionic liquid. Catal. Commun., 2009, 10(14), 1881-1888. DOI: https://doi.org/10.1016/j.catcom.2009.06.018

Solhy, A.; Tahir, R.; Sebti, S.; Skouta, R.; Bousmina, M.; Zahouily, M.; Larzek, M. Efficient synthesis of chalcone derivatives catalyzed by re-usable hydroxyapatite. Appl. Catal. A., 2010, 374, 189-193. DOI: https://doi.org/10.1016/j.apcata.2009.12.008

Rajput, J.K.; Kaur, G. Silicotungstic acid catalysed Claisen Schmidt condensation reaction: an efficient protocol for synthesis of 1,3-diaryl-2 propenones. Tetrahedron Lett., 2012, 53(6), 646- 649. DOI: https://doi.org/10.1016/j.tetlet.2011.11.109

Krishnakumar, B.; Velmurugan, R.; Swaminathan, M. TiO2–SO4-2as a novel solid acid catalyst for highly efficient, solvent free and easy synthesis of chalcones under microwave irradiation. Catal. Commun., 2011, 12(5), 375-379. DOI: https://doi.org/10.1016/j.catcom.2010.10.015

Kumar, D.; Suresh Sandhu, J.S. An efficient green protocol for the synthesis of chalcones by a Claisen–Schmidt reaction using bismuth(III)chloride as a catalyst under solvent-free condition. Green Chem. Lett. Rev., 2010, 3(4), 283-286. DOI: https://doi.org/10.1080/17518251003776893

Bhagat, S.; Sharma, R.; Sawant, D.; Sharma, L.; Chakraborti, A. LiOH•H2O as a novel dual activation catalyst for highly efficient and easy synthesis of 1,3-diaryl-2-propenones by Claisen–Schmidt condensation under mild conditions. J. Mol. Catal. A. Chem., 2006, 244(1-2), 20-24. DOI: https://doi.org/10.1016/j.molcata.2005.08.039

Kumar, A.; Akanksha, Zirconium chloride catalyzed efficient synthesis of 1,3-diaryl-2-propenones in solvent free conditions via aldol condensation. J. Mol. Catal. A. Chem., 2007, 274(1-2), 212- 216. DOI: https://doi.org/10.1016/j.molcata.2007.05.016

Sashidhara, K.V.; Rosaiah, J.N.; Kumar, A. Iodine-catalyzed mild and efficient method for the synthesis of chalcones. Synth. Commun., 2009, 39(13), 2288-2296. DOI: https://doi.org/10.1080/00397910802654724

Jayapal, M.; Sreedhar, N. Anhydrous K2CO3 as Catalyst for the synthesis of Chalcones under Microwave Irradiation. J. Pharm. Sci. Res., 2010, 2, 644-647.

Sathyanarayana, S., Krishnamurty, H. G. 1988. Corroborative studies on the highly efficient preparation of 2′-hydroxychalcones using partially dehydrated barium hydroxide catalyst. Current Science, 57(20), 1114-1116.

Bhuiyan MMH, Hossain MI, Mahmud MM and Al-Amin M. 2011. Microwave-assisted Efficient Synthesis of Chalcones as Probes for Antimicrobial Activities Chemistry Journal, 1(1), 21-28.

Montes-Avila J, Diaz-Camacho SP, Sicairos-Felix J, Delgado-Vargas F, Rivero, I.A. 2009. Natural and synthetic 2'-hydroxy-chalcones and aurones: antioxidant and lipoxygenase inhibitory activity. Bioorg. Med. Chem., 17, 6780–6785. DOI: https://doi.org/10.1016/j.bmc.2009.02.052

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10-09-2025

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[1]
Dr. Nagesh Raghunath Sutar, “A Simplified Approach to α-Ketothiocyanates, Thiocyanatoindoles and Chalcones Using Lithium Chloride”, Int J Sci Res Chemi, vol. 10, no. 5, pp. 01–14, Sep. 2025, doi: 10.32628/IJSRCH251051.