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EDTA Catalyzed Green Protocol for Multicomponent Synthesis of Some Novel Highly Substituted Imidazoles in Water
Available online at www.sciencedirect.com
ScienceDirect Materials Today: Proceedings 4 (2017) 10498–10503
www.materialstoday.com/proceedings
ICEMS 2016
EDTA Catalyzed Green Protocol for Multicomponent Synthesis of Some Novel Highly Substituted Imidazoles in Water Shivam Bajpai, Sundaram Singh* Indian Institute of Technology (BHU), Varanasi – 221 005, U.P., India. Abstract
The multicomponent reaction of N-substituted isatin derivatives with ammonium acetate and substituted aromatic aldehydes in the presence of catalytic amount of EDTA readily gives rise to substituted imidazoles under controlled microwave irradiation in water. The presented method is mild, environmentally friendly, inexpensive and highly effective to give the products in good to excellent yields. The chemical structures of the respective synthesized compounds were confirmed by analytical and spectral data. © 2017 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of International Conference on Recent Trends in Engineering and Material Sciences (ICEMS-2016). Keywords:Imidazoles; N-substituted isatin derivatives; microwave irradiation; EDTA; multicomponent synthesis
1. Introduction Recently, a central objective in synthetic organic chemistry has been to develop greener and more economically competitive processes for the efficient synthesis of biologically active compounds with potential application in the pharmaceutical industries. _________________________________ *corresponding author. Tel/fax.: + 919451658650, E-mail: [email protected]
2214-7853© 2017 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of International Conference on Recent Trends in Engineering and Material Sciences (ICEMS2016).
Shivam Bajpai., Sundaram Singh / Materials Today: Proceedings 4 (2017) 10498–10503
10499
In this context, microwave assisted synthesis is simple with amazing versatility. It reduces the reaction time, increases yield and minimizes the formation of other waste. Moreover, it may allow access to compounds when the yields are too lowto be of practical convenience [1-2]. Presently, EDTA(ethylene diamine tetraacetic acid) has gained special attention as catalyst in organic synthesis due to many advantages such as excellent solubility in water, uncomplicated handling, inexpensiveness and ecofriendly nature [3]. The indole nucleus is known for pronounce biological activities and imidazole, being a core unit in many biological systems [4] viz. Histidine, Histamine and Biotin, has attracted attention in recent years. Different substituted imidazoles are reported to show wide spectrum of biological activities [5-9] In continuation to our research work on the synthesis of biologically interesting heterocyclic moieties, we report herein synthesis of some novel substituted imidazoles fused with indole nucleus and also we hope that this will be a very useful, simple, fast and scalable green protocol for the preparation of substituted imidazoles in water under microwave irradiation. 2. Experimental All chemicals were procured from Aldrich, USA, and E. Merck, Germany and used as such. Nsubstitutedisatins were prepared by earlier reported procedures. TLC was carried out on SiO2 gel (HF254, 200 mesh). IR spectra were recorded on a PerkinElmer FT/IR version10.03.05 spectrometer. NMR spectra were run on a JEOL AL300 FTNMR spectrometer. Elemental microanalysis was performed on Exeter Analytical Inc Model CE-440 CHN Analyzer. Melting points were measured in open capillaries and are uncorrected. The microwave assisted reactions were carried out in a “MAS-II, Microwave Synthesis System” having an output energy range of 0 to 1000 watts.
2.1General procedure for the synthesis of substituted imidazoles 4a-i To a mixture of isatin derivatives 1a-c (1 mmol), ammonium acetate 2 (5 mmol), substitutedaromatic aldehydes 3a-e (1 mmol) was taken in a 250 ml RB flask containing 25 ml of water. Now 30 mol% of EDTA was added was added to reaction mixture [Scheme 1]. The rection mixture was then irradiated at 500 W for 18-25 min. The progress of the reaction was monitored by TLC (n-hexane: ethyl acetate, 1:1). After completion of reaction, the reaction mixture was cooled, product was filtered, washed by water, dried and recrystallized with ethanol. .
2.2Characterization data for compounds 4a-i 4-Benzyl-2-(4-chlorophenyl)-3,4-dihydroimidazo[4,5-b]indole (4a). Brown solid. IR spectrum, υ, cm-1: 3400, 3305, 3130, 2998, 2913, 1657, 1609, 1566, 1444, 1321, 1235, 1121, 1051, 872, 752, 647. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 5.54 (2H, s, CH2); 7.11- 8.61 (13H, m, Ar-H); 9.04 (1H, s, NH). Found, %: C, 73.86; H, 4.45; Cl, 9.89; N, 11.80. C22H16ClN3. Calculated, %: C, 73.84; H, 4.51; Cl, 9.91; N, 11.74.
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4-Benzyl-2-(3-chlorophenyl)-3,4-dihydroimidazo[4,5-b]indole (4b). Brown solid. IR spectrum, υ, cm-1: 3394, 3258, 3010, 2898, 1645, 1614, 1582, 1461, 1320, 1230, 1131, 1050, 870, 748, 649. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 5.51 (2H, s, CH2); 7.16- 8.59 (13H, m, Ar-H); 9.12 (s, 1H, NH). Found, %: C, 73.81; H, 4.44; Cl, 9.90; N, 11.85. C22H16ClN3. Calculated, %: C, 73.84; H, 4.51; Cl, 9.91; N, 11.74. 4-Benzyl-2-(2-nitrophenyl)-3,4-dihydroimidazo[4,5-b]indole (4c). Brown solid. IR spectrum, υ, cm-1: 3417, 3200, 2962, 2920, 1671, 1619, 1579, 1456, 1335, 1241, 1152, 1044, 885, 756, 661. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 5.70 (2H, s, CH2); 7.23- 8.72 (13H, m, ArH); 9.45 (1H, s, NH). Found, %: C, 71.70; H, 4.35; N, 15.25; O, 8.71. C22H16N4O2. Calculated, %: C, 71.73; H, 4.38; N, 15.21; O, 8.69. 4-Benzyl-2-(3-nitrophenyl)-3,4-dihydroimidazo[4,5-b]indole (4d). Brown solid. IR spectrum, υ, cm-1: 3364, 3161, 2960, 2874, 1662, 1611, 1576, 1445, 1330, 1224, 1157, 1020, 882, 759, 654. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 5.62 (2H, s, CH2); 7.32- 8.66 (13H, m, ArH); 9.80 (1H, s, NH). Found, %: C, 71.70; H, 4.39; N, 15.18; O, 8.74. C22H16N4O2. Calculated, %: C, 71.73; H, 4.38; N, 15.21; O, 8.69. Ethyl 2-(2-(4-chlorophenyl) imidazo[4,5-b]indol-4(3H)-yl)acetate (4e). Brown solid. IR spectrum, υ, cm-1: 3427, 3260, 3119, 3022, 2928, 2892, 1739, 1675, 1616, 1581, 1442, 1351, 1248, 1164, 1050, 861, 761, 643. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 1.15- 1.21 (3H, t, J= 7.2, CH3); 4.20- 4.24 (2H, q, J=6.9, CH2); 5.29 (2H, s, CH2); 7.30- 8.37 (8H, m, Ar-H); 9.51 (1H, s, NH). Found, %: C, 64.56; H, 4.46; Cl, 10.00; N, 11.89; O, 9.09. C19H16ClN3O2.Calculated, %: C, 64.50; H, 4.56; Cl, 10.02; N, 11.88; O, 9.04. Ethyl 2-(2-(3-chlorophenyl) imidazo[4,5-b]indol-4(3H)-yl)acetate (4f). Brown solid. IR spectrum, υ, cm-1: 3391, 3269, 3099, 3002, 2938, 2823, 1727, 1653, 1611, 1562, 1441, 1364, 1239, 1142, 1019, 877, 757, 650. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 1.24- 1.30 (3H, t, J= 7.4, CH3); 4.26- 4.31 (2H, q, J=7.2, CH2); 5.18 (2H, s, CH2); 7.23- 8.47 (8H, m, Ar-H); 9.62 (s, 1H, NH). Found, %: C, 64.48; H, 4.60; Cl, 10.04; N, 11.85; O, 9.07. C19H16ClN3O2Calculated, %: C, 64.50; H, 4.56; Cl, 10.02; N, 11.88; O, 9.04. Ethyl 2-(2-phenylimidazo[4,5-b]indol-4(3H)-yl)acetate (4g). Brown solid. IR spectrum, υ, cm1: 3440, 3312, 3124, 2982, 2913, 1734, 1670, 1613, 1575, 1450, 1349, 1229, 1123, 1042, 890, 761, 657 cm-1. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 1.28- 1.33 (3H, t, J= 6.9, CH3); 4.16- 4.20 (2H, q, J=6.9, CH2); 5.30 (2H, s, CH2); 7.29- 8.41 (9H, m, Ar-H); 9.70 (1H, s, NH). Found, %: C, 71.41; H, 5.42; N, 13.20; O, 9.98. C19H17N3O2. Calculated, %: C, 71.46; H, 5.37; N, 13.16; O, 10.02. Ethyl 2-(2-(3-nitrophenyl)imidazo[4,5-b]indol-4(3H)-yl)acetate (4h). Brown solid. IR spectrum, υ, cm-1: 3400, 3280, 3076, 2984, 2907, 2845, 1730, 1655, 1617, 1557, 1440, 1361, 1222, 1159, 1033, 899, 764, 653. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 1.37- 1.43 (3H, t, J= 7.2, CH3); 4.27- 4.32 (2H, q, J=6.9, CH2);
Shivam Bajpai., Sundaram Singh / Materials Today: Proceedings 4 (2017) 10498–10503
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5.48 (2H, s, CH2); 7.35- 8.56 (8H, m, Ar-H); 9.81 (s, 1H, NH). Found, %: C, 62.59; H, 4.40; N, 15.41; O, 17.60. C19H16N4O4. Calculated, %: C, 62.63; H, 4.43; N, 15.38; O, 17.56. 2-(3-Chlorophenyl)-4-ethyl-3,4-dihydroimidazo[4,5-b]indole (4i). Brown solid. IR spectrum, υ, cm-1: 3381, 3203, 2989, 2844, 1677, 1618, 1559, 1465, 1457, 1338, 1266, 1191, 1013, 885, 745, 656. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 1.35-1.40 (3H, t, J= 6.9, CH3); 4.284.34 (2H, q, J=7.2, CH2); 7.42- 8.51 (8H, m, ArH); 9.67 (1H, s, NH). Found, %: C, 68.99; H, 4.81; Cl, 12.02; N, 14.18. C17H14ClN3. Calculated, %: C, 69.03; H, 4.77; Cl, 11.99; N, 14.21. 3. Results and discussion Multicomponent reaction of isatin derivatives 1a-c with ammonium acetate 2 and substituted aromatic aldehydes 3a-e in the presence of catalytic amount of EDTA under microwave irradiation at 500 W, afforded imidazole derivatives 4a-i in good to excellent yield (Scheme 1 & Table 1).
Scheme 1: Synthesis of substituted imidazoles4a-i
Table 1: Synthesis of substituted imidazoles(4a-i).a
Entry
R1
R2
R3
R4
% Yield
M. P.
4a 4b 4c 4d 4e 4f 4g 4h 4i
CH2Ph CH2Ph CH2Ph CH2Ph CH2COOEt CH2COOEt CH2COOEt CH2COOEt C2H5
H H NO2 H H H H H H
H Cl H NO2 H Cl H NO2 Cl
Cl H H H Cl H H H H
84 82 84 85 86 84 80 86 84
188 136 110 176 205 212 172 162 215
a
Reaction condition: Isatin derivatives 1a-c, ammonium acetate 2, substituted aromatic aldehydes 3a-e (1.0:5.0:1.0) and 30 mol % EDTA in water were microwave irradiated at 500W to produce solid products 4a-i.
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Shivam Bajpai., Sundaram Singh / Materials Today: Proceedings 4 (2017) 10498–10503
In order to find optimum reaction conditions, several parameters were investigated. Expectedly, efficiency of the EDTA was affected by their amount (mol %). Therefore, a set of experiments using different amounts of EDTA were taken into account for the multicomponent reaction of Nbenzylisatin with ammonium acetate and pchlorobenzaldehyde. The synthetic route was drastically dependent on the presence of catalyst and only poor yield (34 %) was observed in the absence of catalyst after 35 min. It was found that the yield of product is increased with enhancing catalyst concentration (10- 30 Mol %) and the best yield of 84% was obtained with 30 mol % of EDTA. However, further addition of catalyst concentration (> 30 mol%) did not improve the reaction rate and product yield. The multicomponent reaction of N-benzylisatinwith ammonium acetate and
p-chlorobenzaldehyde
was
investigated in detail using different molar proportions of reactants and it was found that the best result is obtained using N-benzylisatin, ammonium acetate, p-chlorobenzaldehyde in the molar proportion 1.0: 5.0: 1.0 at 500W under microwave irradiation. The chemical structures of the respective synthesized substituted imidazoles4a-i were established by their spectral data. 4. Conclusion A novel synthetic route has been developed for the synthesis of highly substituted imidazoles in water using catalytic amount of EDTA under microwave irradiation. The yield of the products was obtained up to 86% at 500W. The advantage of presented method is its facile reaction conditions, high yield and the product can be isolated very easily without the use of column chromatography. The simplicity of the presented protocol makes it an interesting alternative to other approaches and the catalyst is expected to contribute to the development of environmentally benign methods. Acknowledgements The authors are thankful to IIT(BHU),Varanasi, India for financial support. References [1] Nefzi, A., Ostresh, J. M., Houghten, R. A., The current status of heterocyclic combinatorial libraries, Chem. Rev. 97(1997)449–472. . [2] V. Polshettiwar, R. S. Varma, Aqueous microwave chemistry: a clean and green synthetic tool for rapid drug discovery, Chem. Soc. Rev. 37(2008) 1546–1557. [3] M. Prabhakar, EDTA-catalyzed fast and efficient eco-friendly synthesis of dicoumarol derivatives in water, Journal of Chemical and Pharmaceutical Research. 5(2013)89-93. [4] Grimmett, M. R., 1980. Advances in Heterocyclic Chemistry, vol. 12, Academic Press, New York. [5] A. K. Jain, V. Ravichandran, M. Sisodiya, R. K. Agrawal, Synthesis and antibacterial evaluation of 2-substituted-4,5diphenyl-N-alkyl imidazole derivatives, Asian Pac. J. Trop. Med., 3( 2010) 471-474. [6] J. Pandey, V. K. Tiwari, S. S.Verma, V. Chaturvedi, S. Bhatnagar, S. Sinha, Synthesis and antitubercular screening of imidazole derivatives, Eur. J. Med. Chem. 44( 2009) 3350-3355.
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[7] D. Sharma, B. Narasimhan, P. Kumar, V. Judge, R. Narang, , E. De Clercq, J. Balzarini, Synthesis, antimicrobial and antiviral evaluation of substituted imidazole derivatives, Eur. J. Med. Chem. 44(2009) 2347-2353. [8] A. Puratchikody, M. Doble, Antinociceptive and antiinflammatory activities and QSAR studies on 2-substituted-4,5-diphenyl1H-imidazoles, Bioorg. Medicinal Chem.15 (2007) 1083- 1090. [9] S. Baroniya, Z. Anwer, P. K. Sharma, R. Dudhe, N. Kumar, Recent advancement in imidazole as anticancer agents: A review, Der Pharmacia Sinica. 1(2010)172-182.
ScienceDirect Materials Today: Proceedings 4 (2017) 10498–10503
www.materialstoday.com/proceedings
ICEMS 2016
EDTA Catalyzed Green Protocol for Multicomponent Synthesis of Some Novel Highly Substituted Imidazoles in Water Shivam Bajpai, Sundaram Singh* Indian Institute of Technology (BHU), Varanasi – 221 005, U.P., India. Abstract
The multicomponent reaction of N-substituted isatin derivatives with ammonium acetate and substituted aromatic aldehydes in the presence of catalytic amount of EDTA readily gives rise to substituted imidazoles under controlled microwave irradiation in water. The presented method is mild, environmentally friendly, inexpensive and highly effective to give the products in good to excellent yields. The chemical structures of the respective synthesized compounds were confirmed by analytical and spectral data. © 2017 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of International Conference on Recent Trends in Engineering and Material Sciences (ICEMS-2016). Keywords:Imidazoles; N-substituted isatin derivatives; microwave irradiation; EDTA; multicomponent synthesis
1. Introduction Recently, a central objective in synthetic organic chemistry has been to develop greener and more economically competitive processes for the efficient synthesis of biologically active compounds with potential application in the pharmaceutical industries. _________________________________ *corresponding author. Tel/fax.: + 919451658650, E-mail: [email protected]
2214-7853© 2017 Elsevier Ltd. All rights reserved. Selection and Peer-review under responsibility of International Conference on Recent Trends in Engineering and Material Sciences (ICEMS2016).
Shivam Bajpai., Sundaram Singh / Materials Today: Proceedings 4 (2017) 10498–10503
10499
In this context, microwave assisted synthesis is simple with amazing versatility. It reduces the reaction time, increases yield and minimizes the formation of other waste. Moreover, it may allow access to compounds when the yields are too lowto be of practical convenience [1-2]. Presently, EDTA(ethylene diamine tetraacetic acid) has gained special attention as catalyst in organic synthesis due to many advantages such as excellent solubility in water, uncomplicated handling, inexpensiveness and ecofriendly nature [3]. The indole nucleus is known for pronounce biological activities and imidazole, being a core unit in many biological systems [4] viz. Histidine, Histamine and Biotin, has attracted attention in recent years. Different substituted imidazoles are reported to show wide spectrum of biological activities [5-9] In continuation to our research work on the synthesis of biologically interesting heterocyclic moieties, we report herein synthesis of some novel substituted imidazoles fused with indole nucleus and also we hope that this will be a very useful, simple, fast and scalable green protocol for the preparation of substituted imidazoles in water under microwave irradiation. 2. Experimental All chemicals were procured from Aldrich, USA, and E. Merck, Germany and used as such. Nsubstitutedisatins were prepared by earlier reported procedures. TLC was carried out on SiO2 gel (HF254, 200 mesh). IR spectra were recorded on a PerkinElmer FT/IR version10.03.05 spectrometer. NMR spectra were run on a JEOL AL300 FTNMR spectrometer. Elemental microanalysis was performed on Exeter Analytical Inc Model CE-440 CHN Analyzer. Melting points were measured in open capillaries and are uncorrected. The microwave assisted reactions were carried out in a “MAS-II, Microwave Synthesis System” having an output energy range of 0 to 1000 watts.
2.1General procedure for the synthesis of substituted imidazoles 4a-i To a mixture of isatin derivatives 1a-c (1 mmol), ammonium acetate 2 (5 mmol), substitutedaromatic aldehydes 3a-e (1 mmol) was taken in a 250 ml RB flask containing 25 ml of water. Now 30 mol% of EDTA was added was added to reaction mixture [Scheme 1]. The rection mixture was then irradiated at 500 W for 18-25 min. The progress of the reaction was monitored by TLC (n-hexane: ethyl acetate, 1:1). After completion of reaction, the reaction mixture was cooled, product was filtered, washed by water, dried and recrystallized with ethanol. .
2.2Characterization data for compounds 4a-i 4-Benzyl-2-(4-chlorophenyl)-3,4-dihydroimidazo[4,5-b]indole (4a). Brown solid. IR spectrum, υ, cm-1: 3400, 3305, 3130, 2998, 2913, 1657, 1609, 1566, 1444, 1321, 1235, 1121, 1051, 872, 752, 647. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 5.54 (2H, s, CH2); 7.11- 8.61 (13H, m, Ar-H); 9.04 (1H, s, NH). Found, %: C, 73.86; H, 4.45; Cl, 9.89; N, 11.80. C22H16ClN3. Calculated, %: C, 73.84; H, 4.51; Cl, 9.91; N, 11.74.
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4-Benzyl-2-(3-chlorophenyl)-3,4-dihydroimidazo[4,5-b]indole (4b). Brown solid. IR spectrum, υ, cm-1: 3394, 3258, 3010, 2898, 1645, 1614, 1582, 1461, 1320, 1230, 1131, 1050, 870, 748, 649. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 5.51 (2H, s, CH2); 7.16- 8.59 (13H, m, Ar-H); 9.12 (s, 1H, NH). Found, %: C, 73.81; H, 4.44; Cl, 9.90; N, 11.85. C22H16ClN3. Calculated, %: C, 73.84; H, 4.51; Cl, 9.91; N, 11.74. 4-Benzyl-2-(2-nitrophenyl)-3,4-dihydroimidazo[4,5-b]indole (4c). Brown solid. IR spectrum, υ, cm-1: 3417, 3200, 2962, 2920, 1671, 1619, 1579, 1456, 1335, 1241, 1152, 1044, 885, 756, 661. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 5.70 (2H, s, CH2); 7.23- 8.72 (13H, m, ArH); 9.45 (1H, s, NH). Found, %: C, 71.70; H, 4.35; N, 15.25; O, 8.71. C22H16N4O2. Calculated, %: C, 71.73; H, 4.38; N, 15.21; O, 8.69. 4-Benzyl-2-(3-nitrophenyl)-3,4-dihydroimidazo[4,5-b]indole (4d). Brown solid. IR spectrum, υ, cm-1: 3364, 3161, 2960, 2874, 1662, 1611, 1576, 1445, 1330, 1224, 1157, 1020, 882, 759, 654. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 5.62 (2H, s, CH2); 7.32- 8.66 (13H, m, ArH); 9.80 (1H, s, NH). Found, %: C, 71.70; H, 4.39; N, 15.18; O, 8.74. C22H16N4O2. Calculated, %: C, 71.73; H, 4.38; N, 15.21; O, 8.69. Ethyl 2-(2-(4-chlorophenyl) imidazo[4,5-b]indol-4(3H)-yl)acetate (4e). Brown solid. IR spectrum, υ, cm-1: 3427, 3260, 3119, 3022, 2928, 2892, 1739, 1675, 1616, 1581, 1442, 1351, 1248, 1164, 1050, 861, 761, 643. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 1.15- 1.21 (3H, t, J= 7.2, CH3); 4.20- 4.24 (2H, q, J=6.9, CH2); 5.29 (2H, s, CH2); 7.30- 8.37 (8H, m, Ar-H); 9.51 (1H, s, NH). Found, %: C, 64.56; H, 4.46; Cl, 10.00; N, 11.89; O, 9.09. C19H16ClN3O2.Calculated, %: C, 64.50; H, 4.56; Cl, 10.02; N, 11.88; O, 9.04. Ethyl 2-(2-(3-chlorophenyl) imidazo[4,5-b]indol-4(3H)-yl)acetate (4f). Brown solid. IR spectrum, υ, cm-1: 3391, 3269, 3099, 3002, 2938, 2823, 1727, 1653, 1611, 1562, 1441, 1364, 1239, 1142, 1019, 877, 757, 650. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 1.24- 1.30 (3H, t, J= 7.4, CH3); 4.26- 4.31 (2H, q, J=7.2, CH2); 5.18 (2H, s, CH2); 7.23- 8.47 (8H, m, Ar-H); 9.62 (s, 1H, NH). Found, %: C, 64.48; H, 4.60; Cl, 10.04; N, 11.85; O, 9.07. C19H16ClN3O2Calculated, %: C, 64.50; H, 4.56; Cl, 10.02; N, 11.88; O, 9.04. Ethyl 2-(2-phenylimidazo[4,5-b]indol-4(3H)-yl)acetate (4g). Brown solid. IR spectrum, υ, cm1: 3440, 3312, 3124, 2982, 2913, 1734, 1670, 1613, 1575, 1450, 1349, 1229, 1123, 1042, 890, 761, 657 cm-1. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 1.28- 1.33 (3H, t, J= 6.9, CH3); 4.16- 4.20 (2H, q, J=6.9, CH2); 5.30 (2H, s, CH2); 7.29- 8.41 (9H, m, Ar-H); 9.70 (1H, s, NH). Found, %: C, 71.41; H, 5.42; N, 13.20; O, 9.98. C19H17N3O2. Calculated, %: C, 71.46; H, 5.37; N, 13.16; O, 10.02. Ethyl 2-(2-(3-nitrophenyl)imidazo[4,5-b]indol-4(3H)-yl)acetate (4h). Brown solid. IR spectrum, υ, cm-1: 3400, 3280, 3076, 2984, 2907, 2845, 1730, 1655, 1617, 1557, 1440, 1361, 1222, 1159, 1033, 899, 764, 653. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 1.37- 1.43 (3H, t, J= 7.2, CH3); 4.27- 4.32 (2H, q, J=6.9, CH2);
Shivam Bajpai., Sundaram Singh / Materials Today: Proceedings 4 (2017) 10498–10503
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5.48 (2H, s, CH2); 7.35- 8.56 (8H, m, Ar-H); 9.81 (s, 1H, NH). Found, %: C, 62.59; H, 4.40; N, 15.41; O, 17.60. C19H16N4O4. Calculated, %: C, 62.63; H, 4.43; N, 15.38; O, 17.56. 2-(3-Chlorophenyl)-4-ethyl-3,4-dihydroimidazo[4,5-b]indole (4i). Brown solid. IR spectrum, υ, cm-1: 3381, 3203, 2989, 2844, 1677, 1618, 1559, 1465, 1457, 1338, 1266, 1191, 1013, 885, 745, 656. 1H NMR specrtum (300 MHz), δ, ppm (J, Hz): 1.35-1.40 (3H, t, J= 6.9, CH3); 4.284.34 (2H, q, J=7.2, CH2); 7.42- 8.51 (8H, m, ArH); 9.67 (1H, s, NH). Found, %: C, 68.99; H, 4.81; Cl, 12.02; N, 14.18. C17H14ClN3. Calculated, %: C, 69.03; H, 4.77; Cl, 11.99; N, 14.21. 3. Results and discussion Multicomponent reaction of isatin derivatives 1a-c with ammonium acetate 2 and substituted aromatic aldehydes 3a-e in the presence of catalytic amount of EDTA under microwave irradiation at 500 W, afforded imidazole derivatives 4a-i in good to excellent yield (Scheme 1 & Table 1).
Scheme 1: Synthesis of substituted imidazoles4a-i
Table 1: Synthesis of substituted imidazoles(4a-i).a
Entry
R1
R2
R3
R4
% Yield
M. P.
4a 4b 4c 4d 4e 4f 4g 4h 4i
CH2Ph CH2Ph CH2Ph CH2Ph CH2COOEt CH2COOEt CH2COOEt CH2COOEt C2H5
H H NO2 H H H H H H
H Cl H NO2 H Cl H NO2 Cl
Cl H H H Cl H H H H
84 82 84 85 86 84 80 86 84
188 136 110 176 205 212 172 162 215
a
Reaction condition: Isatin derivatives 1a-c, ammonium acetate 2, substituted aromatic aldehydes 3a-e (1.0:5.0:1.0) and 30 mol % EDTA in water were microwave irradiated at 500W to produce solid products 4a-i.
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Shivam Bajpai., Sundaram Singh / Materials Today: Proceedings 4 (2017) 10498–10503
In order to find optimum reaction conditions, several parameters were investigated. Expectedly, efficiency of the EDTA was affected by their amount (mol %). Therefore, a set of experiments using different amounts of EDTA were taken into account for the multicomponent reaction of Nbenzylisatin with ammonium acetate and pchlorobenzaldehyde. The synthetic route was drastically dependent on the presence of catalyst and only poor yield (34 %) was observed in the absence of catalyst after 35 min. It was found that the yield of product is increased with enhancing catalyst concentration (10- 30 Mol %) and the best yield of 84% was obtained with 30 mol % of EDTA. However, further addition of catalyst concentration (> 30 mol%) did not improve the reaction rate and product yield. The multicomponent reaction of N-benzylisatinwith ammonium acetate and
p-chlorobenzaldehyde
was
investigated in detail using different molar proportions of reactants and it was found that the best result is obtained using N-benzylisatin, ammonium acetate, p-chlorobenzaldehyde in the molar proportion 1.0: 5.0: 1.0 at 500W under microwave irradiation. The chemical structures of the respective synthesized substituted imidazoles4a-i were established by their spectral data. 4. Conclusion A novel synthetic route has been developed for the synthesis of highly substituted imidazoles in water using catalytic amount of EDTA under microwave irradiation. The yield of the products was obtained up to 86% at 500W. The advantage of presented method is its facile reaction conditions, high yield and the product can be isolated very easily without the use of column chromatography. The simplicity of the presented protocol makes it an interesting alternative to other approaches and the catalyst is expected to contribute to the development of environmentally benign methods. Acknowledgements The authors are thankful to IIT(BHU),Varanasi, India for financial support. References [1] Nefzi, A., Ostresh, J. M., Houghten, R. A., The current status of heterocyclic combinatorial libraries, Chem. Rev. 97(1997)449–472. . [2] V. Polshettiwar, R. S. Varma, Aqueous microwave chemistry: a clean and green synthetic tool for rapid drug discovery, Chem. Soc. Rev. 37(2008) 1546–1557. [3] M. Prabhakar, EDTA-catalyzed fast and efficient eco-friendly synthesis of dicoumarol derivatives in water, Journal of Chemical and Pharmaceutical Research. 5(2013)89-93. [4] Grimmett, M. R., 1980. Advances in Heterocyclic Chemistry, vol. 12, Academic Press, New York. [5] A. K. Jain, V. Ravichandran, M. Sisodiya, R. K. Agrawal, Synthesis and antibacterial evaluation of 2-substituted-4,5diphenyl-N-alkyl imidazole derivatives, Asian Pac. J. Trop. Med., 3( 2010) 471-474. [6] J. Pandey, V. K. Tiwari, S. S.Verma, V. Chaturvedi, S. Bhatnagar, S. Sinha, Synthesis and antitubercular screening of imidazole derivatives, Eur. J. Med. Chem. 44( 2009) 3350-3355.
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[7] D. Sharma, B. Narasimhan, P. Kumar, V. Judge, R. Narang, , E. De Clercq, J. Balzarini, Synthesis, antimicrobial and antiviral evaluation of substituted imidazole derivatives, Eur. J. Med. Chem. 44(2009) 2347-2353. [8] A. Puratchikody, M. Doble, Antinociceptive and antiinflammatory activities and QSAR studies on 2-substituted-4,5-diphenyl1H-imidazoles, Bioorg. Medicinal Chem.15 (2007) 1083- 1090. [9] S. Baroniya, Z. Anwer, P. K. Sharma, R. Dudhe, N. Kumar, Recent advancement in imidazole as anticancer agents: A review, Der Pharmacia Sinica. 1(2010)172-182.