Conjugated Addition of Amines to Electron Deficient Alkenes: A Green Approach Anindita Mukherjee1, Rana Chatterjee2, Aramita De2, Satyajit Samanta2, Sachinta Mahato2, Nirnita Chakraborty Ghosal2, G. V. Zyryanov1,3, Adinath Majee2* 1Institute of Chemical Engineering, Ural Federal University, 19 Mira St., Ekaterinburg, 620002, Russia 2Department of Chemistry, Visva-Bharati University, Santiniketan, 731235, India 3Postovsky Institute of Organic Synthesis UB RAS, 22 Kovalevskaya St., Ekaterinburg, 620219, Russia Е-mail: adinath.majee@visva-bharati.ac.in Conjugated Addition of Amines Keywords: Introduction The formation of carbon-nitro- gen bond is very important task in or- ganic synthesis and conjugate addition of amines to electron deficient alkenes is an efficient route to develop the carbon- nitrogen bond [1]. As a consequence, β-amino ketone, nitriles, amide and car- boxylic ester functionalities occur in many natural products [2–4]. It provides an easy route to produce β-amino deriva- tives, which are attractive for their use as synthetic intermediates of anticancer agents, antibiotics and other drugs [5, 6]. It is noteworthy to mention that the classical method for the preparation of β-amino derivatives is via Mannich reac- tion [7]. The conjugate addition of amine to electron deficient alkenes is an alter- nate route to synthesize β-amino deriva- tives. In comparison with Michael reac- tion the conjugate addition of amine to electron deficient alkenes is, in contrast, atom economical and easy to operate. But usually both these additions are carried out in presence of a strong base or acid [8, 9]. Several methods are available in the literature by using different catalysts such as Yb(OTf )3 [10], CeCl3·7H2O-NaI [11], InCl3 [12], Cu(OTf )2 [13, 14], CAN [15], KF/alumina [16,17], LiClO4 [18], Bi(OTf )3 [19], Bi(NO)3 [20], SmI2 [21], Cu(acac)2/ionic liquid [22], ionic liquid/ quaternary ammonium salt [23, 24], boric acid [25], borax [26], ZrOCl2.8H2O [27], β-cyclodextrin [28], bromodimethylsulfo- nium bromide [29], [HP(HNCH2CH2)3N] NO3 [30], MnCl2 [31]etc. Although these methods have their own advantages and quite useful, but some of these methods used a large excess of reagents, hazardous solvents such as acetonitrile or 1,2-dichlo- roethane, require long time and harsh re- action. Ranu et al. reported these addition in the absence of catalysts or water as the reaction medium, but due to the solubi- lity problem of organic compounds the scope of the method is limited [32, 33]. So far, the reported methodologies are effective for either aromatic amines or aliphatic amines. So, in a consequence, development of a general, simple and en- vironmentally benign method is highly desirable. Considering the environmen- tally consciousness in chemical research, reactions in water have attracted much at- tention in recent times [34, 35]. In 2008, Varma et al. reported that tea and coffee extract can be used as good stabilizer for green synthesis of silver and palladium na- noparticles [36]. The authors first synthe- sized nanoparticles in presence of tea and coffee extract. This observation promoted us to consider the tea extract for some organic reactions. Interestingly, from the recent research we observed according to normal expectation that the extraction of normal tea is acidic in nature [37]. This observation motivated us to investigate the catalytic role of tea extract for simple organic reaction. So, in continuation of our research to develop green methodo- logy [38–41], we have observed that tea extract is very useful as solvent as well as catalyst for conjugate addition of a variety of amines to different Michael acceptors (Fig. 1). Results and discussion First of all, we prepared the required tea extract. In a typical experimental pro- cedure, 2 g of tea leaves were dissolved in 20 mL of water and boiled it for 10–15 min. After filtration we got the extract which was used for the said reactions. It was observed that 2 mL of tea extract is sufficient to get the best result. Several structurally varied amines were coupled with the wide range of α, β-ethylenic com- pounds and the results are summarized in Table 1. A variety of aliphatic amines was examined to prove the general applicabi- lity of this present procedure and the cor- responding Michael adducts were isolated in excellent yields within a short reac- tion time. The aliphatic primary amines such as benzylamine, butylamine and cyclohexylamine were treated with dif- ferent Michael acceptors and correspond- ing monoadducts were isolated in good yields (Table 1, entries 1–5). The reaction of open chain bulky secondary amine like diisopropylamine proceeded very well (entries 6, 7). Cyclic secondary amines such as piperidine and morpholine un- derwent facile additions with acrylonitrile and acrylic esters respectively (Table  1, entries 6, 7). Aromatic amines are less reactive than aliphatic amines and took long reaction time. Both activated and weakly activated anilines were investiga- ted. The reactions proceeded smoothly at room temperature and the products were Fig. 1. Tea extract mediated conjugated addition of amines to electron deficient alkenes obtained in excellent yields. Several sub- stituted anilines such as methyl and me- thoxy anilines underwent efficient ad- ditions with acrylonitrile and methyl acrylate giving only monoadduct in high yields under present reaction condi- tions (Table  1, entries 10–14). Acid sen- sitive functional group in aniline such as 3,4-(methylenedioxy)aniline also reacted well to give the desired product in good Table 1 Tea extract-mediated Michael addition of amines to conjugated alkenesa aReaction conditions: 2 mmol of amine and 2 mmol of alkene were stirred in 2 mL of tea extract at room temperature; bIsolated yields. yields keeping methylenedioxy group unaffected (Table  1, entry 14). With re- gard to Michael acceptors, a wide range of structurally diverse electron deficient alkenes was used such as α, β-unsaturated nitrile and carboxylic ester. In general, the reactions are very clean. Both aliphatic and aromatic amines give the products in equally fair yields. In particular, in the case of primary amines the method pro- duces the corresponding β-amino deriva- tives without the problem of double-con- jugate addition. We have not observed any by-products for all reaction combinations which are supported by high yields of the protocol. All of the known synthesized compounds have been characterized by spectral data and the new compounds by spectral and analytical data. Conclusions In conclusion, we have developed a tea extract-mediated a highly efficient methodology for the synthesis of β-amino derivatives under milder reaction condi- tions at room temperature. General appli- cability, operational simplicity, aqueous media, mild reaction conditions, environ- ment friendly, high yields, and applica- tions of inexpensive and easily available catalyst are the advantages of the present procedure. We believe this aza-Michael reactions are of significant importance in both synthetic chemistry and industrial processes for the synthesis of β-amino de- rivatives. Experimental General: 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were run in CDCl3 solutions. IR spectra were taken as KBr plates. Elemental analyses were done by Perkin-Elmer autoanalyzer. Co- lumn chromatography was performed on silica gel (60–120 mesh, SRL, India). MnCl2.4H2O was purchased from NICE Chemicals, India. Tea leaves were pur- chased from market. Amines and alkenes are all commercial materials. All liquid reagents were distilled before use. Preparation of tea extract: 2 g of tea leaves (any marketed) were dissolved in 20 mL of water and boiled it for 10–15 min. After filtration we got the extract which was used for the reactions. General procedure for the synthe- sis of β-amino derivatives: A mixture of amine (2 mmol) and alkene (2 mmol) was stirred in 2 mL of tea extract at room temperature as required for completion (TLC). After completion of the reaction the reaction mixture was extracted with ethyl acetate (40 mL). The extract was washed with water (2 × 10 mL) and brine solution (1 × 10 mL) and dried over an- hydrous sodium sulphate. Evaporation of solvent followed by short column chro- matography of the crude product over silica gel (hexane/ ethyl acetate) furnished the analytically pure product. The known compounds have been identified by com- parison of spectra data (IR  and NMR). The spectral and analytical data of the compounds which are not readily found provided below. 3-(Cyclohexylamino)propanenitrile (Table 1, entry 4): Colorless oil; IR2928, 2246, 1722, 1666, 1558, 1455 cm-1; 1H NMR δ 2.85 (t, J = 5.1 Hz, 2H), 2.45 (t, J = 5.1 Hz, 2H), 2.43(m, 1H) 1.80–1.63 (m, 5H), 1.25–1.16 (m, 6H). Calculated for C9H16N2: C, 71.01; H, 10.59; N, 18.40 %. Found: C, 60.82; H, 10.35; N, 18.13 %. 3-(4-Methoxy-phenylamino)-pro- panenitrile (Table 1, entry 12): Color- less liquid; IR3377, 2244, 1842, 1617, 1514, 1289 cm-1; 1H NMR δ 6.80 (d, J = 5.1 Hz, 2H). 6.61 (d, J = 5.1 Hz, 2H), 3.75 (s, 3H), 3.47 (t, J = 4.8 Hz, 2H), 2.61 (t, J = 4.8 Hz, 2H), (N-H) not identified; 13C NMR δ 152.9, 140.3, 118.5, 115.1 (2C), 114.8 (2C), 55.8, 40.8, 18.2. Calculated for C10H12N2O: C, 68.16; H, 6.86; N, 15.90 %. Found: C, 67.98; H, 6.53; N, 15.62 %. 3 - ( 4 - Me t hy l - p h eny l am i n o ) - pro - panenitrile (Table 1, entry 13): Colorless liquid; IR3559, 2253, 1615, 1522, 1404 cm-1; 1H NMR δ 7.00 (d, J = 6.0 Hz, 2H), 6.53 (d, J = 6.0 Hz, 2H), 3.47 (d, J = 5.1 Hz, 2H), 2.60 (d, J = 5.1 Hz, 2H), 2.24 (s, 3H) (N-H) not identified; 13C NMR δ 143.9, 130.2 (2C), 127.7, 118.5, 113.2 (2C), 40.0, 20.4, 18.0. Calculated for C10H12N2: C, 74.97; H, 7.55; N, 17.48 %. Found: C, 74.63; H, 7.38; N, 17.16 %. Acknowledgements A. Majee acknowledges financial sup- port from the DST-RSF Major Research Project (Ref. No. INT/RUS/RSF/P-08). G. V. Zyryanov acknowledges the Rus- sian Science Foundation – Russia (Ref. №  16–43–02020) for funding. We are thankful to the DST-FIST and UGC-SAP programmes. References 1. Permutter P. Conjugated Addition Reactions in Organic Synthesis. Oxford: Pergam- on Press; 1992. 373 p. 2. Bartoli G, Cimarelli C, Marcantoni E, Palmieri G, Petrini M. Chemo- and diastere- oselective reduction of β-enamino esters: A convenient synthesis of both cis- and trans-γ-amino alcohols and β-amino esters. J Org Chem. 1994;59(18):5328–35. DOI:10.1021/jo00097a039. 3. Elango S, Yan TH. A short synthesis of (+)-narciclasine via a strategy derived from stereocontrolled epoxide formation and SnCl4-catalyzed arene-epoxide coupling. J Org Chem. 2002;67(20):6954–9. DOI:10.1021/jo020155k. 4. Elango S, Yan TH. A short synthesis of (+)-lycoricidine. Tetrahedron. 2002;58(36):7335–8. DOI:10.1016/S0040–4020(02)00736–6. 5. Banik BK, Becker FF, Banik I. Synthesis of anticancer β-lactams: Mechanism of ac- tion. Bioorg Med Chem. 2004;12(10):2523–8. DOI:10.1016/j.bmc.2004.03.033. 6. Graul A, Castaner J. Atorvastatin calcium. Hypolipidemic HMG-CoA reductase in- hibitor. Drugs Future. 1997;22(9):956. PMID:9399600. 7. Ishitani H, Ueno M, Kobayashi S. Enantioselective mannich-type reactions using a novel chiral zirconium catalyst for the synthesis of optically active β-amino acid derivatives. J Am Chem Soc. 2000;122(34):8180–6. DOI:10.1021/ja001642p. 8. Jenner G. Catalytic high pressure synthesis of hindered β-aminoesters. Tetrahedron Lett. 1995;36(2):233–6. DOI:10.1016/0040–4039(94)02215-W. 9. D’Angelo J, Maddaluno J. Enantioselective Synthesis of B-Amino Esters through High-Pressure-Induced Addition of Amines to A, B-Ethylenic Esters. J Am Chem Soc. 1986;108(25):8112–4. DOI:10.1021/ja00285a051. 10. Matsubara S, Yoshiyoka M, Utimoto K. Lanthanoid Triflate Catalyzed Conjugate Addition of Amines to α, β-Unsaturated Esters. A Facile Route to Optically Active β-Lactam. Chem Lett. 1994;23(5):827–30. DOI:10.1246/cl.1994.827. 11. Bartoli G, Bartolacci M, Giuliani A, Marcantoni E, Massimo M, Torregiani E. Im- proved heteroatom nucleophilic addition to electron-poor alkenes promoted by CeCl3·7H2O/NaI system supported on alumina in solvent-free conditions. J Org Chem. 2005;70(1):169–74. DOI:10.1021/jo048329g. 12. Loh TP, Wei LL. Indium trichloride-catalyzed conjugate addition of amines to α, β-ethylenic compounds in water. Synlett. 1998;9:975–6. DOI:10.1016/j.tet- let.2005.03.112. 13. Wabnitz TC, Spencer JB. Convenient synthesis of Cbz-protected β-amino ketones by a copper-catalysed conjugate addition reaction. Tetrahedron Lett. 2002;43(21):3891– 4. DOI:10.1016/S0040–4039(02)00654–8. 14. Xu LW, Li JW, Xia CG, Zhou SL, Hu XX. Efficient Copper-Catalyzed Chemo Selec- tive Conjugate Addition of Aliphatic Amines to α, β-Unsaturated Compounds in Water. Synlett. 2003;25:2425–7. DOI:10.1055/s-2003–42125. 15. Duan Z, Xuan X, Li T, Yang C, Wu Y. Cerium(IV) ammonium nitrate (CAN) cata- lyzed aza-Michael addition of amines to α, β-unsaturated electrophiles. Tetrahedron Lett. 2006;47(31):5433–6. DOI:10.1016/j.tetlet.2006.05.182. 16. Yang L, Xu LW, Xia CG. Highly efficient KF/Al2O3-catalyzed versatile hetero-Mi- chael addition of nitrogen, oxygen, and sulfur nucleophiles to α, β-ethylenic com- pounds. Tetrahedron Lett. 2005;46(19):3279–82. DOI:10.1016/j.tetlet.2005.03.112. 17. Shaikh NS, Deshpande VH, Bedekar AV. Clay catalyzed chemoselective Michael type addition of aliphatic amines to α, β-ethylenic compounds. Tetrahedron. 2001;57(43):9045–8. DOI:10.1016/S0040–4020(01)00911–5. 18. Azizi N, Saidi MR. LiClO4 accelerated Michael addition of amines to α, β-unsaturated olefins under solvent-free conditions. Tetrahedron. 2004;60(2):383–7. DOI:10.1016/j.tet.2003.11.012. 19. Varala R, Alam MM, Adapa SR. Chemoselective Michael type addition of ali- phatic amines to α, β-ethylenic compounds using bismuth triflate catalyst. Synlett. 2003;5:720–2. DOI:10.1055/s-2003–38345. 20. Srivastava N, Banik BK. Bismuth nitrate-catalyzed versatile Michael reactions. J Org Chem. 2003;68(6):2109–14. DOI:10.1021/jo026550s. 21. Reboule I, Gil R, Collin J. Aza-Michael reactions catalyzed by samarium diiodide. Tetrahedron Lett. 2005;46(45):7761–4. DOI:10.1016/j.tetlet.2005.09.039. 22. Kantam ML, Neeraja V, Kavita B, Neelima B, Chaudhuri MK, Hussain S. Cu(acac)2 immobilized in ionic liquids: A recoverable and reusable catalytic system for aza-Mi- chael reactions. Adv Synth Catal. 2005;347(6):763–6. DOI:10.1002/adsc.200404361. 23. Xu LW, Li JW, Zhou SL, Xia CG. A green, ionic liquid and quaternary ammonium salt-catalyzed aza-Michael reaction of α, β-ethylenic compounds with amines in wa- ter. New J Chem. 2004;28(2):183–4. DOI:10.1039/b312047c. 24. Karodia N, Liu X, Ludley P, Pletsas D, Stevenson G. The ionic liquid ethyltri-n-bu- tylphosphonium tosylate as solvent for the acid-catalysed hetero-Michael reaction. Tetrahedron. 2006;62(48):11039–43. DOI:10.1016/j.tet.2006.09.052. 25. Chaudhuri MK, Hussain S, Kantam ML, Neelima B. Boric acid: A novel and safe catalyst for aza-Michael reactions in water. Tetrahedron Lett. 2005;46(48):8329–31. DOI:10.1016/j.tetlet.2005.09.167. 26. Hussain S, Bharadwaj SK, Chaudhuri MK, Kalita H. Borax as an efficient metal- free catalyst for hetero-Michael reactions in an aqueous medium. Eur J Org Chem. 2007;2:374–8. DOI:10.1002/ejoc.200600691. 27. Hashemi MM, Eftekhari-Sis B, Abdollahifar A, Khalili B. ZrOCl2·8H2O on mont- morillonite K10 accelerated conjugate addition of amines to α, β-unsaturated al- kenes under solvent-free conditions. Tetrahedron. 2006;62(4):672–7. DOI:10.1016/j. tet.2005.10.006. 28. Surendra K, Krishnaveni NS, Sridhar R, Rao KR. β-Cyclodextrin promoted aza- Michael addition of amines to conjugated alkenes in water. Tetrahedron Lett. 2006;47(13):2125–7. DOI:10.1016/j.tetlet.2006.01.124. 29. Khan AT, Parvin T, Gazi S, Choudhury LH. Bromodimethylsulfonium bromide me- diated Michael addition of amines to electron deficient alkenes. Tetrahedron Lett. 2007;48(22):3805–8. DOI:10.1016/j.tetlet.2007.03.163. 30. Fetterly BM, Jana NK, Verkade JG. [HP(HNCH2CH2)3N]NO3: An efficient ho- mogeneous and solid-supported promoter for aza and thia-Michael reactions and for Strecker reactions. Tetrahedron. 2006;62(2–3):440–56. DOI:10.1016/j. tet.2005.09.117. 31. Roy A, Kundu D, Kundu SK, Majee A, Hajra A. Manganese (II) chloride-cata- lyzed conjugated addition of amines to electron deficient alkenes in methanol- water medium. The Open Catalysis Journal.2010;3(1):34–9. DOI:10.2174/187621 4X01003010034. 32. Ranu BC, Dey SS, Hajra A. Solvent-free, catalyst-free Michael-type addition of amines toelectron-deficient alkenes. ARKIVOC. 2002;7:76–81. DOI:10.3998/ ark.5550190.0003.709. 33. Ranu BC, Banerjee S. Significant rate acceleration of the aza-Michael reaction in water. Tetrahedron Lett. 2007;48(1):141–3. DOI:10.1016/j.tetlet.2006.10.142. 34. Kobayashi S, Manabe K. Development of novel Lewis acid catalysts for selective or- ganic reactions in aqueous media. Acc Chem Res. 2002;35(2):209–17. DOI:10.1021/ ar000145a. 35. Kobayashi S, Sugiura M, Kitagawa H, Lam WWL. Rare-earth metal triflates in or- ganic synthesis. Chem Rev. 2002;102(6):2227–302. DOI:10.1021/cr010289i. 36. Mallikarjuna NN, Varma RS. Green synthesis of silver and palladium nanoparticles at room temperature using coffee and tea extract. Green Chem. 2008;10(8):859–62. DOI:10.1039/b804703k. 37. Vuong QV, Golding JB, Stathopoulos CE, Roach PD. Effects of aqueous brewing solution pH on the extraction of the major green tea constituents. Food Res Int. 2013;53(2):713–9. Doi:10.1016/j.foodres.2012.09.017. 38. Ghosal NC, Santra S, Das S, Hajra A, Zyryanov GV, Majee A. Organocatalysis by an aprotic imidazolium zwitterion: Regioselective ring-opening of aziridines and applicable to gram scale synthesis. Green Chem. 2016;18(2):565–74. DOI:10.1039/ c5gc01323b. 39. Santra S, Kopchuk DS, Kovalev IS, Zyryanov GV, Majee A, Charushin VN, Chupak- hin ON. Solvent-free synthesis of pillar[6]arenes. Green Chem. 2016;18(2):423–6. DOI:10.1039/c5gc01505g. 40. Mahato S, Santra S, Chatterjee R, Zyryanov GV, Hajra A, Majee A. Brønsted acidic ionic liquid-catalyzed tandem reaction: an efficient approach towards regioselective synthesis of pyrano[3,2-c]coumarins under solvent-free conditions bearing lower E-factors. Green Chem. Forthcoming 2017. DOI:10.1039/c7gc01158j. 41. Santra S, Rahman M, Roy A, Majee A, Hajra A. Nano-indium oxide: An efficient catalyst for one-pot synthesis of 2,3-dihydroquinazolin-4(1H)-ones with a greener prospect. Catal Commun. 2014;49:52–7. DOI:10.1016/j.catcom.2014.01.032. Cite this article as (как цитировать эту статью) Mukherjeel A, Chatterjeel R, De A, Samantal S, Mahatol S, Ghosal NC, Zyry- anov GV, Majee A. Conjugated Addition of Amines to Electron Deficient Alkenes: A Green Approach. Chimica Techno Acta. 2017:4(2);140–147. DOI: 10.15826/ chimtech.2017.4.2.029.