ISSN 2319-7625 (Online) (An International Research Journal), www.chemistry-journal.org
Synthesis of Pyridine Derivatives in Multicomponent
Cascade Coupling Strategy using Green Solvent
Kadari Swamy and Shankaraiah Pagilla
Department of Freshman Engineering, Vardhaman College of Engineering Shamshabad, Kacharam, Hyderabad, Telangan-500018, INDIA.
email: [email protected]
(Received on: December 1, 2017)
ABSTRACT
An expedient method developed for synthesis of 2-Amino-4, 6-diphenylnicotinonitrile derivatives following multicomponent reaction pathway by using an efficient and recyclable Polyethylene glycol as a solvent. It is an environmentally benign, inexpensive, non-hazardous and effective reaction medium for this reaction. Utilizing green chemistry protocol, pyridine derivatives were synthesized by using various aldehydes, acetophenone, malononitrile and ammonium acetate, finally the products were obtained in excellent yields in catalyst free conditions.
Keywords: 2-Amino-4, 6-diphenylnicotinonitrile, Polyethylene glycol, Catalyst free.
INTRODUCTION
Multi component reactions (MCRs) are an efficient and powerful technique in modern synthetic chemistry1-3. MCRs are an important in synthesis of heterocyclic scaffolds,
particularly useful in natural products and many other drugs4. In general synthetic procedures,
the organic solvents were used as reaction medium to provide homogeneous phase for molecular interactions and to take the reaction to be completion. Most of the organic solvents are harmful to environment and in many cases do not drive the reaction to be completion. Environmental concerns, newer, recyclable and biodegradable environmental congruous green solvents are preferable5. Prime focus of our solvent selection is unique properties such as
immiscible with organic solvents, inexpensive, thermally stable polyethylene glycol as solvent6-9. Pyridine and pyridine derivatives found in various pharmaceutical and natural
products, so the synthesis of pyridine derivatives plays an important in heterocyclic chemistry10-11. Here, we interested to synthesize pyridine containing 2-amino-3-cyano pyridine
adenosine receptor antagonists14, IKK-β inhibitors15, Potent inhibitor of HIV-1 integrase16,
androgen receptor modulator17 and anticancer drug18.
RESULTS AND DISCUSSION
Poly Ethylene Glycol (PEG) is non toxic, low expensive, easy to handle, thermally stable and reusable in various organic transformations, such as synthesis of β-amino sulphides, benzimidazoles, 3,4-dihydropyrimidinones, dibenzoxazapine and β-keto sulphides19-21. Poly
Ethylene Glycol (PEG) emerged as a powerful reaction medium to perform organic transformations under mild and multicomponent reaction conditions. These advantages of polyethylene glycol reactions inspired us to focus on the synthesis of bioactive 2-amino 3-cyano pyridine derivatives. Different aldehydes (1a-j), acetophenone (3), Malononitrile (2) and NH4OAc (4) were dissolved in equiportions of PEG-200 and water mixture taken in one
pot, refluxed to obtain 2-Amino-4, 6-diphenylnicotinonitrile derivatives (5a-j). The reaction was monitored by TLC and observed new spot in TLC and new spot structure was confirmed by previous reports and 1H NMR, 13C NMR, IR, Mass spectral values. (Scheme 1).
Scheme. 1
Optimization of the reaction
We practiced different methods for synthesis of 2-Amino-4, 6-diphenylnicotinonitrile derivatives and also proceeded the model reaction in a neat condition (absence of solvent and catalyst), product was afforded in trace yield. A variety of solvents were screened for this MCR’s such as water, ethanol, DMSO and DCM solvents, obtained the yields of products were found to be comparatively low (Table.1, Entry 2-5). However, it was found that PEG-200 to be an essential promoter for these reactions and given good yields (Table.1, Entry 6-8).
Table.2 Optimization conditions for the reaction Entry Solvent Temperature oC Time (hr) Yield(%)b
1. Neat 80 4 Trace
2. Water 80 4 10
3. Ethanol 80 4 30
4. DMSO 80 4 20
5. DCM 80 4 20
6. PEG-200 80 4 60
7. PEG-Water (2:8) 80 4 70
All the compounds were purified and calculated the yields were recorded in the
Table.1, The generality of this reaction was investigated for the synthesis of various 2-amino-3-cyanopyridines derivatives by using various aldehydes (1a-j), acetophenone (3), malononitrile (2), and ammonium acetate (4) in PEG-200 water mixture as reaction medium. In general, all the reactions were very clean, and the 2-Amino-4, 6-diphenylnicotinonitrile derivatives were obtained in high yields.
Table.3. Synthesis of various 2-Amino-4, 6-diphenylnicotinonitrile derivatives by MCR
Entry R-CHO ArCOCH3 Time (h) Yield (%)
5a. Ph- Ph- 4 75
5b. 4-Cl-Ph- Ph- 4 73
5c. 4-Br- Ph- Ph- 4 72
5d. 4-OH- Ph- Ph- 4 70
5e. 4-CH3- Ph- Ph- 4 75 5f. 4-OCH3- Ph- Ph- 4 73 5g. 1-Naphtha- Ph- 4 70 5h. 4-NO2-Ph- Ph- 4 78 5i. Pyridine-2- Ph- 4 70
5j. Furan-2- Ph- 4 70
EXPERIMENTAL
Materials and methods
Pre coated silica-gel plates (E. Merck-60 F254, 0.2mm layer) for TLC and Column
chromatography packed with Silica gel (60-120 mesh) were used. Fischer-John apparatus was used for melting point detection. Thermo Nicolet Nexus 670 FT-IR spectrometer was used to record IR spectrum. 1H NMR and 13C NMR spectra were recorded on Bruker Avance 400
MHz and 75 MHz instrument using CDCl3 and TMS were used as internal standard.
ESI-HRMS spectra recorded on Finnigan MAT 1020 mass spectrometer.
General Procedure for the Synthesis of 2-Amino-4, 6-diphenylnicotinonitrile derivatives
A mixture of aldehyde (1.0 mmol), malononitrile (1.0 mmol), ketone (1.0 mmol), and ammonium acetate (1.0 mmol), 2 ml of polyethylene glycol-200 and 2 ml of water taken in 50 ml roung bottom flask and stirred at 80o C for the appropriate time. reaction was monitored
by TLC, in inteval times after completion of the reaction, the reaction mixture was poured into water and extracted by ethyl acetate. The organic solvent was removed under reduced pressure, and the crude product was purified by column chromatography.
SPECTRAL DATA
1) 2-Amino-4, 6-diphenylnicotinonitrile (5a): Yield: 75%, White solid, m.p: 181-183 oC. 1H
NMR (400 MHz, CDCl3, ppm): = 8.10(s, 1H ), 7.20-7.48 (m, 6H ), 6.90 (s, 7H ), 6.83
(s, 1H), 5.45 (s, 2H) ; 13C NMR (75 MHz, CDCl
132.23, 129, 128, 126.55, 124, 118, 111, 98.56, 77.01, 77, 76.89 ppm; IR KBr (cm-1): ν =
3129, 2991, 2914, 2264, 1751, 1627, 1573, 1476, 1403, 1342, 1243, 1233, 1178, 1102, 1037, 978, 747, 522; MS m/z (ESI): 272 (M+H) +. HRMS: m/z cacl for C
18H13N3.
2) 2-Amino-4-(4-chlorophenyl)-6-phenylnicotinonitrile (5b): Yield: 73%, white solid, m.p:227-229 oC. 1H NMR (400 MHz,CDCl
3, ppm): = 7.99 (s, 1H ), 7.87-7.93 (d, 2H, NH2 ),
7.35-7.59 (m, 7H ), 7.26-7.34 (t, 1H), 7.14-7.23(t, 1H).; 13C NMR (75 MHz, CDCl
3): 165, 158,
142, 141, 139, 135, 134, 133, 132, 131, 116, 115,91, 81.; IR KBr (cm-1): 3463, 3129, 2991, 2203, 1751,1642, 1587, 1465, 1243, 1178, 1037, 747, 522 cm-1 ; MS (ESI) m/z : 305 (M+H)2 +.
3) 2-Amino-4-(4-bromophenyl)-6-phenylnicotinonitrile (5c): Yield: 72%, Yellow solid. M.p: 191-193 oC. 1H NMR (400 MHz, CDCl
3 ppm): = 8.2 (d, 2H), 8.01 (s, 1H), 7.30-7.71
(m, 10H). ; 13C NMR (75 MHz, CDCl
3): =165, 159, 143, 141, 137, 135, 134, 133, 132, 129,
121, 115, 92, 81 ppm; IR KBr (cm-1): ν = 3448, 2924, 2853, 2243, 1613, 1578, 1508, 1495,
1458, 1381, 1265, 755, 575; MS m/z (ESI): 352(M+H) +. HRMS m/z cacl for C
18H12N3Br. 4) 2-Amino-4-(4-hydroxyphenyl)-6-phenylnicotinonitrile (5d):Yield 70%, white solid, m.p: 226-230 oC. 1H NMR (400 MHz,CDCl
3, ppm): = 7.90-8.10 (m, 3H ), 7.75 (d, 1H ),
7.39- 7.61(m, 7H) 5.40 (s,1H, OH).; 13C NMR (75 MHz, CDCl
3): =164.52, 164, 158.23, 158,
141, 139.11, 134.21, 133, 132, 130, 120, 114, 106, 80 ppm; IR (KBr): ν = 3389,3168,3056, 2264, 1723, 1620, 1598, 1540, 1481, 1340, 1245, 1098, 842, 741, 610, 551 cm-1; MS m/z
(ESI): 288(M+H) +. HRMS m/z cacl for C
18H13N3O.
5) 2-Amino-6-phenyl-4-p-tolylnicotinonitrile (5e):Yield: 75%. White solid, m.p: 170-173
oC. 1H NMR (400 MHz,CDCl
3): = 7.27-7.70 (m, 10H ), 4.15 (m, 1H ), 3.85 (m, 1H), 1.25(m,
3H) ppm; 13C NMR (75 MHz, CDCl
3): = 159, 154, 153, 150, 139, 137, 135, 132, 131, 129,
125, 119, 113, 105, 89, 79, 36 ppm; IR KBr (cm-1): ν = 3462, 3305, 2967, 2924, 2832, 2203,
1751, 1638, 1577, 1509, 1452, 1368, 1296, 1250, 1176, 1109, 1025, 821, 767, 701, 520; MS m/z (ESI): 352(M+H) +. HRMS m/z cacl for C
19H15N3.
6) 2-Amino-4-(4-methoxyphenyl)-6-phenylnicotinonitrile (5f): Yield: 73%, White solid, m.p: 178-180 oC.1H NMR (400 MHz,CDCl
3): = 8.10 (d, 1H ), 7.31-7.64 (m, 8H ), 5.42 (s,
1H), 2.15(s, 3H) ppm; 13C NMR (75 MHz, CDCl
3): =163, 162.5, 162, 161.5, 160, 154, 139,
131.5, 131, 130.5, 130, 129, 128, 114, 111, 77, 76.5 ppm; IR KBr (cm-1): 3463, 3306, 3182,
2967, 2924, 2632, 2204, 1639, 1577, 1509, 1452, 1250, 1179, 1109, 1025, 929, 767, 620 cm-1;
MS m/z (ESI): 288(M+H) +.
7) 2-Amino-4-(naphthalen-1-yl)-6-phenylnicotinonitrile (5g): Yield 70%, White solid, m.p:175-177 oC. 1H NMR (400 MHz, CDCl3 ppm): = 8.75(s, 1H), 8.17-8.21(S, 3H), 7.70
(s, 2H ), 7.22-7.56 (m, 6H ), 6.9 (s, 1H), 6.78 (s, 1H), 76.31(s, 1H). 13C NMR (75 MHz,
CDCl3): =159, 158.96, 154, 147, 144.62, 144, 143, 142, 141, 136, 135, 131, 129, 128.5, 128,
127, 126, 123, 109, 96, 90 ppm; IR KBr (cm-1): 3463, 3129, 2991, 2814, 2204, 1751, 1627,
8) 2-Amino-4-(4-nitrophenyl-6-phenylnicotinonitrile (5h): Yield: 78%, Yellow liquid, b.p: 371-373 oC. 1H NMR (400 MHz, CDCl
3, ppm): = 7.60-7.23 (m, 8H), 6.99-6.75 (m. 3H),
6.10 (s, 1H); 13C NMR (75 MHz, CDCl
3, ppm): 165, 164.9, 159, 144, 141, 137, 133, 132, 129,
121, 116.5, 116, 92, 82, 81.5, 81; IR (KBr): ν 3462, 3308, 3182, 2967, 2924, 2832, 2204, 1639, 1577, 1509, 1452, 1250, 1171, 1025, 821, 707,620 cm-1; MS m/z (ESI): 273(M+H) +.
9) 2'-Amino-6'-phenyl-2, 4'-bipyridine-3'-carbonitrile (5i): Yield: 70%, White solid, m.p: 211-214 oC. 1H NMR (400 MHz,CDCl
3, ppm): = 8.10 (m, 3H), 7.70 (s, 1H ), 7.22-7.59(m,
6H), 6.88 (s, 1H), 6.78 (s, 1H); 13C NMR (75 MHz, CDCl3): 162, 155, 154, 151, 139, 137,
135, 132, 131, 129, 126, 118,112, 89, 78.5, 78, 77.5; IR KBr (cm-1): 3462, 3389, 3145, 2964,
2261, 1723, 1620, 1540, 1451, 1340, 1248, 1098, 842, 741, MS m/z (ESI): 273 (M+H) +. 10) 2-Amino-4-(furan-2yl)-6-phenylniconitrile (5j): Yield: 70%, Yellow solid, m.p:155-157oC. 1H NMR (400 MHz, CDCl
3, ppm): = 7.96 (s, 1H), 7.57-7.70 (m, 4H), 7.27-7.5. (d,
2H), 6.85- 7.25 (m, 4H,); 13C NMR (75 MHz, CDCl
3): = 162, 152, 147, 144, 141, 133, 132,
131, 120, 116, 115, 109, 96.5, 96, 91.5, 91ppm; IR (KBr): ν 3390, 3169, 3056, 2264, 1710, 1504, 1489, 1381, 1265, 1245, 1101, 1065, 841, 748 cm-1; MS m/z (ESI): 262 (M+H) +.
CONCLUSION
In summary, we have developed an efficient and facile method for the synthesis of 2-Amino-4, 6-diphenylnicotinonitrile derivatives by treatment of aldehydes, ketones, malononitrile, and ammonium acetate using PEG-200 as a recyclable medium without the addition of any additive or organic co-solvent. The mild reaction conditions, less expensive of reaction medium, operational simplicity, and high yields are the advantages of the green chemistry protocols. Therefore environmental benign and sustainability by avoiding of quenching steps, this type of MCRs brings us closer to the notion of ideal synthesis.
ACKNOWLEDGMENTS
We thankful to Department of freshman engineering, Vardhaman Engineering College, Hyderabad, India for constant encouragement generously supported and facilitations provided in this research work as well as financial support.
REFERENCES
1. R.V.A. Orru, M. de Greef, Synthesis. 10, 1471 (2003).
2. D.J. Ramon, Y. Miguel, Angew. Chem. Int. Ed. 44, 1602 (2005).
3. (a) Ugi, S. Heck, Comb. Chem. High Throughput Screen. 4, 1 (2001). (b) L. Weber, K. Illgen, M. Almstetter, Synlett. 366 (1999).
4. (a) B.E. Evans, J. Med. Chem. 31, 2235 (1988). (b) A.A. Patchett, R.P. Nargund, Ann.
Rep.Med. Chem. 35, 289 (2000).
5. (a) C. Jiminez-Gonzales, A. D. Curzons, D. J. C. Constable V. L. Cunningham, Int. J. Life
Cycle Assess. 9, 115 (2004). (b) G. P. Taber, D. M. Pfistere J. C. Colberg, Org. Process
6. S. Chandrasekhar, C. Narsihmulu, S. Shameem Sultana, N. Ramakrishna Reddy, Org.
Lett. 4, 4399 (2002).
7. N. V. Shitole, K. F. Shelke, S. A. Sadaphal, B. B. Shingate, M. S. Shingare, Green
Chemistry Letters and Reviews. 3, 83 (2010).
8. B. S. Dawane et al., Green Chemistry Letters and Reviews. 3, 205 (2010).
9. Z. Zhou, Y. Zhao, H. Zhen, Z. Lin, Q. Ling, Appl. Organomet. Chem.30, 924 (2016). 10. D. N. Survase, H. V. Chavan, S. B. Dongare, V. B. Helavi, Synth. Commun.. 46, 1665–
1670 (2016).
11. L. C. W. Chang et al., J. Med. Chem. 50, 828 (2007).
12. M.T. Cocco, C. Congiu, V. Lilliu,V. Onnis, Bioorg. Med. Chem. 15, 1859 (2007)
13. K. Guo, R. Mutter, W. Heal, T.K.R. Reddy, H. Cope, S. Pratt, M.J. Thompson, B. Chen,
Eur. J. Med. Chem. 43, 93 (2008).
14. B.C.H. May, J.A. Zorn, J. Witkop, J. Sherrill, A.C. Wallace, G. Legname, S.B. Prusiner, F.E. Cohen, J. Med. Chem. 50, 65(2007).
15. M. Mantri, O. De Graaf, J. Van Veldhoven, A. Göblyös, J.K. Von Frijtag Drabbe Künzel, T. Mulder-Krieger, R. Link, H. De Vries, M.W. Beukers, J. Brussee, A.P. Ijzerman, J.
Med. Chem. 51, 4449(2008).
16. T. Murata, M. Shimada, S. Sakakibara, T. Yoshino, H. Kadono, T. Masuda, M. Shimazaki, T. Shintani, K. Fuchikami, K. Sakai, H. Inbe, K. Takeshita, T. Niki, M. Umeda, K.B. Bacon, K.B. Ziegelbauer, T.B. Lowinger, Bioorg. Med. Chem. Lett. 13, 913 (2003). 17. J. Deng, T. Sanchez, L.Q. Al-Mawsawi, R. Dayam, R.A. Yunes, A. Garofalo, M.B.
Bolger, N. Neamati, Bioorg. Med. Chem. 15, 4985 (2007).
18. A.S. Girgis, A. Kalmouch, H.M. Hosni, Amino Acids.26, 139 (2004).
19. (a) A. Djemilia, S. Lakrouta, Z. Cheraieta, Malika Berredjema Nour-Eddine Aoufa. Green
chemistry Letters and Reviews. 8, 48-53 (2015). (b) A. E. Dı´az-A´ lvarez, J. Francos,
Beatriz Lastra-Barreira, Pascale Crochet Victorio Cadierno. Chem. Comm. 47, 6208 (2011). (c) H.A. Ashraf, M. I. Tamer, M.A. khaled, L. Jochen, N.T. Heather, D.G. Bernard, A.P. Gary, Bioorg. Med. Chemistry. 17, 5974 (2009).
20. (a) Yogesh R. Jorapur, Guruswamy Rjagopal, Prakash J. Saikia, Ravinder R. pal, Tet. Lett. 49, 1495(2008). (b) B. Das, V. saidi Reddy, M. Krishnaiah, Tet. Lett. 47, 8471(2016). (c) R. Mallepalli, L. Yeramnchi, R. Bntu, L. Nagarapu, Synlett. 2730 (2011). (d) Ahmed Kamal, D. Rajasekhar Reddy, Rajendar, Tet. Lett. 47, 2261 (2006).
21. (a) Yogesh R. Jorapura, Gurusamy Rajagopal, Prakash J. Saikia, Ravindra R. Pal. Tet. Lett. 49, 1495 (2008) (b) N. Suryakiran, T. Srikanth Reddy, K. Ashalatha, M. Lakshman, Y. Venkateswarlu, Tet. Lett. 47, 3853 (2006) (c) L. Suman Jain, Sweety Singhal, Bir Sain,
Green Chem. 9, 740 (2007) (d) Mukhopadhyay, Pradeep Kumar Tapaswi. Tet. Lett. 49,
