Optimization of Three Component, One Pot Synthesis of aminobenzylnaphthol Exploiting Electrophilicity of azomethines Under Varying Conditions

Abstract

The synthesis of aminobenzylnaphthols by organocatalysis has generated interest due to the mild reaction conditions and environmental benefits. It has been shown that (1,4-diazacyclo[2.2.2]octane) has demonstrated high efficiency as an organocatalyst for the three component condensation reaction. These reactions lead to the synthesis of a novel class of aminobenzylnaphthols under various solvent conditions offering remarkable advantages like: mild reaction conditions, high yields, selectivity and simplicity. This protocol is particularly appealing for the synthesis of complex organic molecules with potential applications in pharmaceuticals and material science. Overall, the use of organocatalysts in aminobenzylnaphthol synthesis presents a versatile approach with potential for the further development maintaining the guidelines of greener chemistry.

Introduction

Compounds containing 1,3-aminooxygenated groups, especially aminonaphthols (Betti bases), are important in medicinal chemistry due to their biological activities such as analgesic, antibacterial, hypotensive, and bradycardiac effects. Since Betti’s discovery in 1900, various methods have been developed to synthesize aminonaphthols, typically involving the reaction of 2-naphthol with aldehydes and amines via imine intermediates or through hydrolysis of amidoalkylnaphthols.

Traditional synthesis methods face challenges like low yields, expensive catalysts, long reaction times, and complex workups. To address these, researchers are exploring greener, cost-effective techniques such as one-pot reactions using organocatalysts. Organocatalysts, especially derivatives of N,N-dialkylethanolamine like DABCO, offer advantages including mild reaction conditions, selectivity, and broad functional group compatibility.

This study evaluated various organocatalysts and solvents for the model reaction of 2-naphthol, benzaldehyde, and aniline. Non-polar benzene solvent and DABCO catalyst at 55°C gave the best yields (80–88%) in short reaction times (40–55 minutes). The method showed good tolerance for different substituted benzaldehydes, indicating versatility and efficiency for aminonaphthol synthesis.

Characterization of products was done using melting point determination, FTIR, ¹H and ¹³C NMR spectroscopy, confirming the success of the synthesis.

Conclusion

In conclusion , we have developed a high yielding protocol for the synthesis of aminocatalyst. This method operates efficiently under solvent benzene and demonstrates excellent substrate versatility, providing a valuable approach for the synthesis of aminonaphthol derivatives in organic chemistry .A novel series of arylaminonaphthols was synthesized through a one-pot three component reaction involving an aldehyde , an aromatic amine,and 2- naphthol, facilitated by DABCO under solvent benzene. This efficient methodology allows for the straight forward assembly of the desired compounds, show casing the effectiveness of DABCO as an organocatalyst and hightlighting the potential for practical applications in organic synthesis.

References

[1] Knapp S(1995) Synthesis of complex nucleoside antibiotics.Chem Rev 95:1859- 1876.doi:10.1021/cr00038a006. [2] Mannhold R,Kubinyi H(2006) Nucleic acid drugs.In: Dingermann T, Steinhilber D, Folkers G(eds) Molecular biology in medicinal chemistry. Wiley, Weinhein. doi: 10.1002/3527602666. [3] Wang YK, Izawa T, Kobayashi S,Ohno M (1982) Stereocontrolled synthesis of (+)- negamycin from an acylic homoallylamine by 1,3-asymmetric induction. J Am Chem Soc 104:6465-6466. doi:10.1021/ja00387a060. [4] Cardellicchio C, Capozzi MAM , Naso F (2010) The Betti bases: the awakening of a sleeping beauty.Tetrahedron 21:507-517.doi : 10. 1016/j.tetasy.2010.03.020. [5] Elmendorf HG , Walls CD , Wolf C(2012) Compositions and methods for the treatment of giardiasis . US Patent 20, 120, 283,267. [6] Gerlach M, Maul C(2007) Substituted 1 and 2- naphthol Mannich bases. US Patent 7, 202,242B2. [7] Gyemant N, Engi H ,Schelz Z, Szatmari I, Toth D, Fulop F , Molnar J, de Witte P (2010) In vitro and in vivo multidrug resistance reversal activity by a Betti- base derivative of tylosin.Br J Cancer 103:178-185.doi:10.1038/sj.bje.6605716. [8] Shen AY, Tsai CT, Chen CL(1999) Synthesis and cardiovascular evaluation of N-substituted 1-aminomethyl-2-naphthols.Eur J Med Chem 34:877-882.doi:10.1016/S0223-5234(99)00204-4. [9] Szatmari I,Fulop F(2013) Synthesis, transformationsand applications of aminonaphthol derivatives prepared via modified Mannich reactions. Tetrahedron 69:1255-1278.doi:10.1016/j.tet.2012.11.055. [10] Salama TA (2013) Silicon - induced general, mild, and efficient one pot, three- component synthesis of amidoalkyl naphthol libraries. Synlett24:713-718.doi:10.1055/s-0032-1318392 [11] Safari J, Zarnegar Z (2013) A magnetic nanoparticle-supported sulfuric acid as a highly efficient and reusable catalyst for rapid Synthesis of amidoalkylnaphthols.J Mil Catal A 379:269-276.doi:10.1016/j.molcata.2013.08.028. [12] Rostamizadeh S,Abdollahi F, Shadjou N, Amani AM(2013) MCM- 41-SO3H: a novel reusable nanocatalyst for synthesis of amidoalkylnaphthols under solvent - free conditions. Monatsh Chem 144:1191-1196.doi 10.1007/s00706-013-0936-4. [13] Lei ZK, Xiao L, Lu XQ, Huang H,Liu CJ(2013) Graphite supported perchloric acid ( HClO4- C):an efficient and recyclable heterogeneous catalyst for the one - pot synthesis of amidoalkylnaphthols. Molecules 18:1653-1659.doi:10.3390/ molecules18021653. [14] Das VK, Borah M, Thakur AJ(2013) Piper-betle-shaped nano- S-catalyzed synthesis of 1-amidoalkyl-2-naphthols under solvent -free reaction condition: A greener \" Nanoparticle-Catalyzed Organic Synthesis Enhancement\" approach. J Org Chem 78:3361-3366.doi:10.1021/jo302682k. [15] Csutortoki R, Szatmari I,Fulop F(2013) Syntheses of amidocarbamido- and carbamatoalkylnaphthols. Curr Org Synth 10:564-583. [16] Mulla SA, Salama TA, Pathan MY, Inamdar SM, Chavan SS(2012) Solvent-free,highly efficient one-pot multi-component synthesis of 1-amido and 1-carbamato-alkyl naphthols/phenols catalyzed by ethylammonium nitrate as reusable ionic liquid under neat reaction condition at ambient temperature. Tetrahedron Lett 54:672-675.doi:10.1016/j.tetlet.2012.12.004. [17] Kotadia DA, Soni SS(2012) Silica gel supported - SO3H functionalised benzimidazolium based ionic liquid as a mild and effective catalyst for rapid Synthesis of 1-amidoalkyl-2-naphthols. J Mol Catal A 353:44-49.doi:10.1016/j.molcata.2011.11.003. [18] ZolfigolMA , Khazaei A, Moosavi - Zare AR, Zare A, Khakyzadeh V (2011) Rapid synthesis of 1-amidoalkyl-2-naphthols over sulfonic acid functionalized imidazolium salts. Appl Catal A 400: 70-81.doi:10.1016/j.apcata.2011.04.013. [19] Tamaddon F, Bistgani JM (2011) [MeC(OH)2]+ClO4-: a new efficient organocatalyst for the preparation of 1- amido- and 1-carbamato- alkyl naphthols. Synlett2011:2947-2950.doi:10.1055/s-0031-1289906. [20] Mistry SR , Joshi RS, Maheria KC(2011) Zeolite H- BEA catalysed multicomponent reaction: one-pot synthesis of amidoalkylnaphthols -biologically active drug - like molecules. J Chem Sci 123:427-432.doi:10.1007/s12039-011-0095-2. [21] Shaterian HR, Yarahmadi H, Ghashang M (2008) Silica supported perchloric acid (HClO4-SiO2): an efficient and recyclable heterogeneous catalyst for the one - pot synthesis of . amidoalkyl-2-naphthols Tetrahedron 64:1263-1269.doi:10.1016/j.tet.2007.11.070. [22] Shaterian HR, Yarahmadi H, Ghashang M (2008) An efficient, simple and expedition synthesis of 1-amidoalkyl-2-naphthols as \"drug like\" molecules for biological screening. Bioorg Med Chem Lett 18:788-793.doi: 10.1016/j.tet.2007.11.070. [23] Karmakar B, Banerji J (2011) A competent pot and atom- efficient synthesis of Betti bases over nanocrystalline MgO involving a modified Mannich type reaction.Tetrahedron Lett 52:4957-4960.doi:10.1016/j.tetlet.2011.07.075. [24] Periasamy M, Anwar S, Reddy MN(2009) Simple and convenient methods for synthesis, resolution and application of aminonaphthols. Indian J Chem B 48: 1261- 1273. [25] Ghandi M, Olyaei A, Raoufmoghaddam S (2008) One - pot , three-component uncatalysedquantitive Synthesis of new aminonaphthols. Indian J Chem B 48: 1261-1273. [26] Oyaei A, Raoufmoghaddam S, Sadeghpour M, EbadzadehB(2010) Convenient and efficient method for the synthesis of N-heteroaryl aminonaphthols under solvent-free conditions. Chin J Chem 28:825-832.doi:10.1002/ cjoc.201090153. [27] Hosseinian A, Shaterian HR (2012) NaHSO4. H2O catalyzed multicomponent synthesis of 1-(benzothiazolylamino)methyl-2-naphthols under solvent - free conditions. Phosphorus Sulfur Silicon 187:1056-1063.doi:10.1080/10426507.2012.664221. [28] Buckley BR, Neary SP(2010) Organocatalysis. Annu Rep Prog Chem Sect B Org Chem 106:120-135.doi:10.1039/B927086H. [29] Grondal C, Jeanty M, Enders D(2010) Organocatalytic cascade reactions as a new tool in total synthesis. Nar Chem 2:167-178.doi:10.1038/nchem.539. [30] Marcelli T, van Maarseveen JH, Hiemstra H(2006) Cupreines and cupreidines:an emerging class of bifunctional cinchona organocatalysts. Angew Chem Int Ed 45:7496-7504. doi: 10.1002/anie. 200602318. [31] Liu G, Zhang S, Li H, Zhang T, Wang W(2011) Organocatalytic enantioselective Friedel-Crafts reactions of 1-naphthols with aldimines.Org Lett 13:838-831. doi:10.1021/oll02987n. [32] Ramachary DB, Babul Reddy G (2007) A new organocatalyst for Friedel-Crafts alkylation of 2- naphthols with isatins: application of an organi- click strategy for the cascade synthesis of highly functionalized molecules. Tetrahedron Lett 48: 7618-7623. doi:10.1016/j.tetlet.2007.08.129. [33] Shahrisa A, Safa KD, Esmati S(2014) Synthesis, spectroscopic and DFT studies of novel fluorescent dyes: 3-aminoimidazo[1,2-a] pyridines processing 4-pyrone moieties.Spectrochim Acta A 117:614-621.doi:10.1016/j saa.2013.09.056. [34] Shahrisa A, Esmati S, Miri R, Firuzi I, Edraki N, Nejati M (2013) Cytotoxic activity assessment, QSAR and docking study of novel bis- carboxamide derivatives of 4- pyrones synthesized by Ugi four- component reaction. Eur J Med Chem 66:388-399.doi:10.1016/j.ejmech.2013.05.045. [35] Shahrisa A, Esmati S (2013) Three novel sequential reactions for the facile synthesis of library of bisheterocycles possessing the 3-aminoimidazo[1,2-a] pyridine core catalysed by bismuth (III) chloride. Synlett24:595-602.doi:10.1055/s-0032-1318221. [36] ShahrisaA,MiriR,Esmati S, Saraei M, MehdipourAR,Sharifi M(2012) Synthesis and calcium channel antagonist activity of novel 1,4-dihydropyridine derivatives possesing 4-pyrone moieties. Med Chem Res 21:284-292.doi:10.1007/s00044-010-9534-8. [37] ShahrisaA, Esmati S, Nazari MG(2012) Boric acid as a mild and efficient catalyst for one - pot synthesis of 1-amidoalkyl-2-naphthols under solvent -free conditions. J Chem Sci 124:927-931.doi:10.1007/s12039-012-0285-6. [38] Dindulkar SD, Puranik VG,Jeong YT(2012) Supported copper triflate as an efficient catalytic system for the synthesis of highly functionalized 2-naphthol Mannich bases under solvent free condition. Tetrahedron Lett 53:4376-4380.doi:10.1016/j.tetlet.2012.06/022. [39] Ganesan SS, Rajendran N, Sundarakumar SI, Ganesan A, PemiahB(2013) 2-naphthol in glycerol: a versatile pair for efficient and convenient synthesis of aminonaphthols, naphtho-1,3-oxazines,and benzoxanthene. Synthesis 45:1564-1568.doi:10.1055/s-0033-1338430. [40] Saidi MR, Azizi N, Naimi- Jamal MR(2001) Lithium perchlorate assisted one- pot three-component aminoalkylation of electron- rich aromatic compounds. Tetrahedron Lett 43:8111-8113.doi:10.1016/S0040-4039(01)01732-4. [41] Katritzky AR, Abdel - Fattah AA, Tymoshenko DO, Belyakov SA, Ghiviriga I, Steel PJ(1999) Amino ( hetero) arylmethylation of phenols with N- [ alpha- amino( hetero) arylmethyl ] benzotriazoles. J Org Chem 64:6071-6075.doi: 10.1021/jo9903609. [42] Kumar A, Gupta MK, Kumar M( 2010) Non - ionic surfactant catalyzed synthesis of Betti bases in water . Tetrahedron Lett 51:1582-1584. doi:10.1016/ j.tetlet.2010.01.056.

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Copyright © 2025 Sushma Rani, M. K. Singh . This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.