Synthetic Strategy to Amido Alkyl Naphthols from Pyrazole Aldehydes using Silica Supported NaHSO4.SiO2 as an efficient Heterogeneous Catalyst

Abstract

A facile and eminent method has been reported for the preparation of amido alkyl naphthols. Amido alkyl naphthol derivatives were synthesized by the condensation of pyrazole aldehydes, β-naphthol and acetamide in the presence of a heterogeneous SiO2 supported sodium hydrogen sulphate catalyst using acetic acid as a solvent. This protocol is advantageous for its shorter reaction hours, simplest workup technique, excellent yields with easy recovery and reusability of the catalyst.1H, and 13C Nuclear Magnetic Resonance, Fourier transform infrared and Mass Spectroscopy were utilized for the characterization of synthesized products.

Introduction

Basically, multicomponent reactions have been reported since 1850 by Strecker¹ in α-amino acids.To avoid sequential syntheses involving many steps and to simplify synthetic routes, MCRs have been a better solution. With the help of MCRs, target molecules are synthesized in fewer steps, as reported by Ugi et.al².Ugi-MCRs have been proven to be an important synthetic tool in medicinal chemistry. Ugi-MCRs have greatly expanded the scope of enabling the design of diverse molecular scaffolds in modern drug discovery³. To improve the already known conventional MCRs and to design new bioactive structures, multiple-component routes have become the starting point. Several re-engineered MCRs have been identified by applying retrosynthetic analysis to cognate MCR⁴.

To discover novel chemical reactions, in combinatorial reaction findings, to understand the structure-reactivity relationships and to generate drug like chemical products, new multi-component reactions have become the heart of organic chemistry⁵.It was an extremely beneficial gadget for the convenient design of countless chemical compounds and reactions. In library synthesis and in Diversity-Oriented Synthesis, MCR chemistry plays a vital role⁶. The most important class of heterocycles with various biological activities were amidoalkyl naphthols. Pharmaceutical compounds with amido alkyl naphthol cores were used to treat brady cardiac, hypotensive, and cardiovascular diseases. Amido alkyl naphthols also have potential pharmaceutical activities like antipsychotic, antitumor, antirheumatic, anti-HIV, anticonvulsant, antimalarial, and antihypertensive properties. The evolution and advancement of eco-friendly technologies have become the most demanding in contemporary chemistry and chemical industry.

Literature survey considers various synthetic methods to prepare amido alkyl naphthols. Several new methods have been developed to improve the synthesize target compound involving various catalysts such as bipyridinium sulfonic acid chloride⁷, Phosphoric acid supported on alumina⁸,dodecylphosphonic acid⁹, ionic liquid-benzimidazolium¹⁰, Sulfonated polynaphthalene¹¹, bismuth(III) nitrate pentahydrate¹², trichloroacetic acid/cobalt (II) chloride¹³, SnCl₄·5H₂O¹⁴, tannic acid¹⁵, barium phosphate nano-powder¹⁶, boric acid¹⁷, Magnetic nanoparticle supported acidic ionic liquid¹⁸, nano-grapheneoxide¹⁹and zinc oxide nanoparticles²⁰ were reported. We now describe our current research related to amido alkylnaphthols synthesis using reusable eco-friendly heterogeneous silica supported NaHSO₄.SiO₂catalyst with a shorter reaction time(scheme 1).

Herein, we have investigated a potential, NaHSO₄.SiO₂catalysed preparation of amidoalkyl-2-naphthols via one-pot condensation reactions involving acetic acid solvent (Scheme 1).

Scheme 1

Experimental Methods and Materials

Chemicals Used

The chemicals utilized for the reaction were purchased from Sigma-Aldrich U.S.A. Thin Layer Chromatography with aluminium sheets previously coated with silica gel [(Merck, F-254 from Germany) of 0.2 mm thickness] was used to monitor the reaction progress. Silica gel [ (mesh size 230-400) Merck] was used to perform column chromatography.

Equipments and an analytical instruments

Bruker (300MHz and 75Hz) spectrometer using CDCl₃ solvent was utilized to record ¹H NMR and ¹³C NMR.Spectrometer (4000-400cm^-1) of Perkin Elmer variety,using KBr pelletwas used for recording FT-IR spectrum. The HRMS spectrum was recorded using Q-T of-Mass Spectrometer.

Procedure for the synthesis of compounds 4a-4j:

To a mixture of pyrazole aldehyde (1 equiv.), 2-naphthol (1 equiv.) and acetamide (1 equiv.), the hetereogeneous catalyst NaHSO₄.SiO₂ (0.002g) was added. The whole content was dissolved in acetic acid solvent and stirred at 80⁰C in an oil bath. The complete consumption of the starting materials was confirmed by TLC. Then the catalyst was recovered by filtration. The crude mixture was purified using a column chromatographic method [ethylacetate (10): petroleum ether (90)] and afforded pure amidoalkylnaphthol.

Result and Discussion

To synthesize N-[(1,4-diphenyl-1H-pyrazol-3-yl)(2-hydroxynaphthalen-1-yl)methyl]acetamide, condensation of β -naphthol, pyrazole aldehyde, acetamide was employed. The whole content of the reaction mixture was stirred in acetic acid and NaHSO₄.SiO₂ catalyst, in a preheated oil bath at 80⁰C.The structures of the obtained products were characterized with various spectroscopic techniques like ¹HNuclear Magnetic Resonance, ¹³CNuclear Magnetic Resonance, Fourier transform infrared and High Resolution Mass spectroscopic techniques.

Table 1: Preparation of N-[(1,4-diphenyl -1H-pyrazol-3-yl)(2-hydroxynaphthalen-yl)methyl]acetamides.

Table 2:Screening of catalysts and solvents.

S.No	Catalysts used	Solvents used	TIME(hrs)	YIELD ( % )
1	None	EtOH	23.5	4.5
2	ZnO	Alcohol	18	30
3	Na2SO4	Ethanol	15	50
4	MgSO4	Ethanol	15	60
5	NaHSO4.SiO2	Water	20	40
6	NaHSO4.SiO2	Ethanol	15	55
7	NaHSO4.SiO2	Acetone	10	65
8	NaHSO4.SiO2	Acetic Acid	4-6	85-90

An optimization study for the synthesis of desired compounds was undertaken in order to improve the yield of the products. Initial screening trials were performed for the optimization of certain reaction parameters like temperature and time (Table1).The reaction was carried out using various solvents in order to monitor the solvent effect on the product formation(Table2). While EtOH, water and acetone were used as solvents, lower yields were observed. On using acetic acid as a solvent, the rate of reaction increased. Among the various catalysts used, NaHSO₄.SiO₂ was found to be the most efficient one. On conducting the reaction at 80°C usingNaHSO₄.SiO₂(0.002g)catalyst, the best result was obtained. On further increase in temperature and quantity of catalyst, the yield of the product did not increase. On seeing the astonishing results of the above reaction conditions, in order to improvise the scope of the present protocol, a library of amidoalkylnaphthols was synthesized under optimized conditions(Table2). The reaction modes of the different pyrazole aldehydes were quite similar and we got good yield of desired products while using pyrazole aldehydes with different substituents.

Figure 1: 1H NMR spectrum of the product 4a.

Figure 2: 13C NMR spectrum of the product 4a.

Figure 3: HR-MS data of the product 4a.

The ¹H NMR data of 4a showed, a three proton singlet-1.86 ppm which was attributed to methyl group protons. A singlet at 6.18ppm was due to methine proton and the one proton singlet at 9.23ppm was designated for aromatic alcohol. The singlet at 8.21ppm was attributed to an N-H proton. The singlet at 8.41ppm was attributed to the proton of the pyrazole group. Peaks from 6.84-8.82ppm were due to protons of the naphthalene group, and peaks from 7.40-7.58ppm were assigned to protons of the aromatic rings (figure 1). In the ¹³C NMR spectrum, peaks at 23.81ppm and 47.99ppm were due to aliphatic carbons. The peaks ranging between 115.6-153.4ppm were assigned to aromatic and naphthalene carbons (figure 2). The peak at 169.1ppm was attributed to carbonyl carbon. The HR-MS spectrum declared the peak of molecular ion (M+) at m/z433.5 (figure 3). Using elemental analysis, the formation of the product was firmly authenticated.

Characterizationof synthesized compounds (4a-4j)

Compound 4a: N-[(1,4-diphenyl-1H-pyrazol-3-yl)(2-hydroxynaphthalen-1-yl)methyl]acetamide;

White solid, R_f; 0.40.(20%EAPE);¹HNMR (300MHZ,CDCl₃) δ = 1.86(s,3H),5.35(s,1H),6.18(s,1H), 6.84-9.23(m,6H), 7.40-7.58 (m,10H), 8.4(s,1H),8.82(s,1H); ¹³C NMR: (75 MHz,CDCl₃) δ = 23.8,48.0,115.6,119.0,119.2, 119.9,123.3, 123.8,126.2, 126.3,126.5,127.3, 128.4,128.8,128.8,129.2,129.3, 132.2,133.1,139.7,149.1,153.4,169.1;HR-MS (ESI) [M]⁺ m/z: 433.50; Anal. Calcd.forC₂₈H₂₃N₃O₂: C, 77.55; H, 5.33; N, 9.66; O, 7.38; Found: C, 77.53; H,5.46; N,9.73; O,7.32.

Compound 4b: N-[(4,4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)(2-hydroxy naphthalen-1-yl)methyl]acetamide;

Whitish solid, Rf;0.43(20%EAPE); ¹HNMR (300MHZ,CDCl₃) δ = 1.84(s,3H),5.35(s,1H),6.16(s,1H),6.85-9.21(m,6H),7.45-7.73(m,9H), 8.03(s,1H), 8.65(s,1H);¹³CNMR:(75MHZ,CDCl₃) δ = 23.6,47.9,115.4, 118.9,119.2, 123.2,123.8, 126.2,126.4, 128.3,128.8, 129.3,130.2,133.5, 134.3,139.7,149.2, 153.4,169;HR-MS (ESI)[M]⁺(m/z): 467.14; Analysis Calculated for C₂₈H₂₂ClN₃O₂: C,71.87; H,4.74;Cl,7.58; N, 8.98; O,6.84; Found: C,71.77; H,4.64;Cl,7.68; N,8.88; O,6.85.

Compound 4c: N-[(4,4-bromophenyl)-1-phenyl-1H-pyrazol-3-yl)(2-hydroxy naphthalen-1-yl)methyl]acetamide;

brownish solid, Rf;0.43(20%EAPE); ¹HNMR(300MHZ,CDCl₃) δ ppm = 1.84(s,3H),5.35(s,1H) ,6.16(s,1H),6.85-9.21(m,6H),7.45-7.66(m,9H), 8.03(s,1H), 8.65(s,1H);¹³CNMR:(75MHZ,CDCl₃) δ ppm =23.6,47.9,115.4,118.9, 119.2,123.2, 123.8, 126.2,126.4, 128.3,128.8, 129.3, 130.2, 133.5,134.3,139.7,149.2,153.4,169; HR-MS(ESI) [M]⁺(m/z): 511.09; Anal. Calcd. for C₂₈H₂₂BrN₃O₂: C, 65.63; H, 4.33;Br,15.59; N, 8.20; O, 6.24; Found C, 66.01; H, 4.27;Br,15.68 N, 8.28; O, 6.25.

Compound 4d: N-[(2-hydroxynaphthalen-1-yl)(4-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)methyl]acetamide;

brown solid, Rf ;0.38(20%EAPE); ¹HNMR (300MHZ,CDCl₃) δ ppm = 1.84(s,3H),3.83(s,3H),5.35(s,1H),6.16(s,1H),6.85-9.21(m,6H),7.05-7.68(m,9H),8.03(s,1H), 8.65(s,1H);¹³CNMR:(75MHZ,CDCl₃) δ ppm =23.6,47.9,55.8,114.8,115.4,118.9,119.2,119.9,123.2,123.8,124.4, 126.2, 126.3,126.4,128.3,128.8,129.3,133.5,139.7,153.4,160.6,169.0;HR-MS(ESI) [M]⁺(m/z): 463.19; Elemental Analysis Calculated forC₂₉H₂₅N₃O₃: C,75.14; H, 5.44; N,9.07; O,10.35; Found: C,75.13; H,5.34; N,9.08; O,10.38.

Compound4e: N-[(4,4-ethoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)(2-hydroxynaphthalen-1-yl)methyl]acetamide;

Yellowish white solid, Rf ;0.36 (20%EAPE); ¹HNMR (300MHZ,CDCl₃) δ ppm =1.31 (s,3H), 1.84(s,3H), 4.09 (s,2H), 5.35(s,1H),6.16(s,1H),6.85-9.21(m,6H), 7.05-7.68(m,9H),8.03(s,1H), 8.65 (s,1H) ;¹³CNMR:(75MHZ,CDCl₃) δ =14.8,23.6,115.4,47.9,64.6, 114.9,115.4,118.9, 119.2,119.9,123.2, 123.7, 123.8,126.2,126.3,126.4,128.3,128.8,129.3,133.5,139.7,149.2,153.4,159.4,169.0;HRMS (ESI) [M]⁺ m/z: 477.21; Elemental Analysis Calculated for C₃₀H₂₇N₃O₃: C, 75.45; H, 5.70; N, 8.80; O, 10.05; Found: C,75.77; H, 5.67; N,8.82; O,10.05.

Compound 4f: N-[(1-(2,4-dinitrophenyl)-4-phenyl-1H-pyrazol-3-yl)(2-hydroxynaphthalen-1-yl)methyl]acetamide;

Yellow solid, Rf ;0.48(20%EAPE); ¹HNMR (300MHZ,CDCl₃) δ ppm = 1.85(s,3H),5.35(s,1H),6.16(s,1H),6.85-9.21(m,6H),7.41-8.92(m,8H),8.03(s,1H), 8.65(s,1H) ;¹³CNMR: (75MHZ,CDCl₃) δ =23.6,47.9,115.4,118.9,119.2, 120.6,123.2, 123.8,124.7, 126.3,126.4, 127.5,127.6,128.3,128.7, 128.8,129.2, 132.1,133.5,136.1,142.1,146.3,149.2,153.4,169; HR-MS (ESI) [M]⁺(m/z): 523.16; Elemental Analysis Calculated for C₂₈H₂₁N₅O₆: C,64.24; H, 4.04; N, 13.38; O, 18.34; Found C, 63.89; H, 4.02; N, 13.41; O, 18.29.

Compound 4g: N-[(4-(4-chlorophenyl)-1-(2,4-dinitrophenyl)-1H-pyrazol-3-yl)(2-hydroxynaphthalen-1-yl)methyl]acetamide;

Yellow solid, Rf ;0.52 (20%EAPE): ¹HNMR (300MHZ,CDCl₃) δ ppm= 1.84(s,3H), 5.35(s,1H), 6.16 (s,1H),6.85-9.21(m,5H),7.41-8.92(m,8H),8.03(s,1H), 8.65(s,1H) ;¹³CNMR: (75MHZ,CDCl₃) δ ppm =23.6,47.9,115.4, 118.9, 119.2, 123.2,123.8,124.7, 126.3, 126.4,127.6,128.3, 128.8,128.9,129.3,130.2, 133.5,134.3,136.1,142.1,146.3,149.2,153.4,169;HR-MS (ESI) [M]⁺(m/z): 557.11; Elemental Analysis Calculated for C₂₈H₂₀ClN₅O₈: C,60.28; H, 3.61;Cl,6.35; N, 12.55; O, 17.21; Found: C,60.31; H, 3.59;Cl,6.36 N, 12.58; O, 17.19.

Compound 4h: N-[(4-(4-bromophenyl)-1-(2,4-dinitrophenyl)-1H-pyrazol-3-yl)(2-hydroxynaphthalen-1-yl)methyl]acetamide;

Brown solid, Rf ;0.58 (20%EAPE): ¹HNMR (300MHZ,CDCl₃) δ ppm = 1.85(s,3H), 5.33(s,1H),6.16(s,1H),6.85-9.21(m,6H),7.53-8.92(m,7H),8.03(s,1H), 8.65(s,1H) ; ¹³CNMR:(75MHZ,CDCl₃) δ =23.6,47.9,115.4,118.9, 119.2, 120.6, 121.7,123.1, 123.2,123.8,124.7, 126.3,126.4, 127.6,128.3, 128.8, 129.7,131.1, 133.5, 136.1, 142.1,146.3,149.2,153.4,169;HR-MS(ESI) [M]⁺(m/z): 601.06; Elemental Analysis Calculated for C₂₈H₂₀BrN₅O₆: C, 55.83; H, 3.35;Br,13.26; N, 11.63; O, 15.94; Found C, 55.84; H, 3.38;Br,13.31; N, 11.71; O, 15.89.

Compound 4i: N-[(1-(2,4-dinitrophenyl)-4-(4-methoxyphenyl-1H pyrazol-3-yl)(2-hydroxynaphthalen-1-yl)methyl]acetamide;

White solid, Rf ;0.50(20%EAPE): ¹HNMR (300MHZ,CDCl₃) δ ppm = 1.84(s,3H),3.83(s,3H), 5.35(s,1H),6.16(s,1H),6.85-9.21(m,6H),7.05-8.92(m,7H),8.03(s,1H), 8.65(s,1H) ; ¹³CNMR:(75MHZ,CDCl₃) δ ppm =23.6,47.9,55.8,114.8,115.4,118.9,119.2,120.6, 123.2,123.8,124.4,124.7,126.2,126.3,126.4,127.6, 128.3,128.8,133.5,136.1,142.1, 146.3,149.2,153.4,160.6,169;HR-MS (ESI) [M]⁺(m/z): 553.16; Elemental Analysis Calculated for C₂₉H₂₃N₅O₇: C,62.93; H, 4.19; N, 12.65; O,20.23; Found C, 62.89; H, 4.21;N, 12.71; O, 20.31.

Compound 4j: N-[(1-(2,4-dinitrophenyl)-4-(4-ethoxyphenyl-1H-pyrazol-3-yl)(2-hydroxynaphthalen-1-yl)methyl]acetamide;

White solid, Rf ;0.46(20%EAPE); ¹HNMR (300MHZ,CDCl₃) δ ppm = 1.84(s,3H),5.35 (s,1H), 6.16(s,1H),6.85-9.21(m,6H),7.05-8.92(m,7H),8.03(s,1H), 8.65(s,1H); ¹³CNMR:(75MHZ,CDCl₃) δ ppm =14.8,23.6,47.9,64.6, 114.9,115.4,118.9, 119.2,120.6,123.2, 123.7,123.8,124.7,125.8,126.3,126.4,127.6, 128.3,128.8, 133.5,136.1,142.1,146.3, 149.2,153.4,159.4,169;HR-MS(ESI) [M]⁺(m/z): 567.18; Elemental Analysis Calculated forC₃₀H₂₅N₅O₇: C, 63.49; H, 4.44;N, 12.34; O, 19.73; Found: C, 63.51; H,4.43; N,12.44; O,19.68.

Conclusion

We have successfully determined that silica supported sodium hydrogen sulphate is a dynamic and ecofriendly green catalyst for the synthesis of N-[(1,4-diphenyl-1H-pyrazol-3-yl)(2-hydroxynaphthalen-1-yl)methyl]acetamide. The derivatives of synthesized compounds (4a-4j) were obtained via domino reaction of pyrazole aldehydes, 2-naphthol, acetamide using acetic acid as solvent with heterogeneous NaHSO₄.SiO₂ as a catalyst at 80⁰C in excellent yields. The results were upgraded by catalyst screening and solvent screening (Table2).The primary aim of the present study is to develop a highly efficient, cost-effective, and environmentally benign catalyst. This methodology involves conveniently obtainable solvents, a clean process, and precise reaction time. We have done the structural confirmation with various spectral characterizations of the synthesized compounds. The assessments of the biological activities of the synthesized products are under study.

Acknowledgement

The Authors Thanks (CDST-FIST) Department of chemistry, A.V.V.M. SPC for recording FTIR,C.L.R.I, Adayar, Chennai, thanks to Sastra University, Thanjavur for recording NMR spectroscopy, IIT Madras for recording HRMS.

Conflict of Interest

There are no conflict of interest.

Funding Sources

There is no funding source.

References

1. Strecker, A. Justus Liebigs Ann. Chem.1850, 75, 27.DOI: 10.1007/3-540-30031-7_261.

2. Ugi, I.; Domling, A.; Horl, W. Endeavour.1994, 18, 115. https://doi.org/10.1016/S0160-9327(05)80086-9

3. Ganem, B.AccChem Res. 2009,42, 3, 463–472.doi: 10.1021/ar800214s

4. Weber,L.;Illgen,K.;Almstetter,M. Synlett.1999, 3, 366–374. DOI:10.1055/s-1999-2612

5. Moosavi-Zarea,A. R.;Zolfigolb,M. A.;Panah, F. D.; Balalaie, S.Mol. Catal. 449 (2018) 142–151 https://doi.org/10.1016/j.mcat.2017.09.037

6. Shaterian, H. R.;Azizi, K.; Fahimi. Arab. J. Chem.2017, 10, 1, S42-S55http://dx.doi.org/10.1016/j.arabjc.2012.07.006

7. Kotadia, D. A.; Saurabh S. Soni. J. Mol.Catal. A. Chem. 2012, 44– 49, 353– 354.doi:10.1016/j.molcata.2011.11.003

8. Pourmousavi, S. A.; Moghimi, P.;Ghorbani, F.; Zamani. M. J. Mol. Struct. 2017, 1144, 87-102.doi: 10.1016/j.molstruc.2017.05.010.

9. Jaberi, Z. K.; Jokar, M.; Abbasi, S. Z.J. Chem. 2013, Article ID 341649, 5.http://dx.doi.org/10.1155/2013/341649

10. Wang, M.; Liang, Y.; Zhang, T. T.;Gao, J. J. Chem. Nat. Compd. 2012, 48, 2,DOI:10.1007/s10600-012-0200-x

11. Singh, R. K.;Duvedi, R. Arab. J. Chem.2018, 11, 1, 91-98 http://dx.doi.org/10.1016/j.arabjc.2014.08.022

12. Taghrir,H.; Ghashang,M.;Biregan, M.N.;Chin. Chem. Lett. 2016, 27, 119–126.http://dx.doi.org/10.1016/j.cclet.2015.08.011

13. Jaberi, Z. K.; Fakhraei, H. Bull. Chem. Soc. Ethiop.2012, 26, 3, 473-478. http://dx.doi.org/10.4314/bcse.v26i3.18

14. Zhang, Q.;Gao, Y. H.; Qin, S. L.;Wei, H. X.;Catalysts2017, 7, 351; doi:10.3390/catal7110351

15. Fatemeh Hakimia,b,*, Fatemeh Mirjalilia, Mehdi Fallah-Mehrjardi Asian J. Green Chem.2019, 4,183-191. DOI:10.22034/AJGC/2020.2.6

16. Singh,R. K.;Bala, R.; Kumar,S. Indian J. Chem. 2016, 55B, 381-386. DOI: 10.22034/AJGC/2020.2.6.